Benzoheterocyclic compounds

TECHNICAL FIELD
This invention relates to novel benzoheterocyclic compounds which have excellent vasopressin antagonistic activities and are useful as vasodilator, hypotensive agent, water diuretics, platelet aggregation inhibitor.
DISCLOSURE OF THE INVENTION
The benzoheterocyclic compounds of this invention have the following formula: ##STR2## wherein R.sup.1 is hydrogen atom, a halogen atom, a lower alkyl, an amino having optionally a lower alkyl substituent, or a lower alkoxy,
R.sup.2 is hydrogen atom, a halogen atom, a lower alkoxy, a phenyl(lower)alkoxy, hydroxy, a lower alkyl, an amino having optionally a lower alkyl substituent, a carbamoyl-substituted lower alkoxy, an amino-substituted lower alkoxy having optionally a lower alkyl substituent, or a benzoyloxy which has optionally a halogen substituent on the phenyl ring,
R.sup.3 is a group of the formula: ##STR3## or a group of the formula: ##STR4## R.sup.4 is hydrogen atom, a benzoyl which has optionally a halogen substituent on the phenyl ring, or a lower alkyl,
R.sup.5 is a group of the formula: ##STR5## �wherein R.sup.16 is a halogen atom; a lower alkyl which has optionally a substituent selected from a halogen atom and hydroxy; hydroxy; a lower alkoxy; a lower alkanoyloxy; a lower alkylthio; a lower alkanoyl; carboxy; a lower alkoxycarbonyl; cyano; nitro; an amino which has optionally a substituent selected from a lower alkyl and a lower alkanoyl; phenyl; a cycloalkyl; a lower alkanoyloxy-substituted lower alkoxy; a carboxy-substituted lower alkoxy; a halogen-substituted lower alkoxy; a carbamoyl-substituted lower alkoxy; a hydroxy-substituted lower alkoxy; a lower alkoxycarbonyl-substituted lower alkoxy; a phthalimido-substituted lower alkoxy; an aminocarbonyl-lower alkoxy having a lower alkyl substituent; or a group of the formula: ##STR6## (A is a lower alkylene, and R.sup.6 and R.sup.7 are the same or different and are each hydrogen atom, a lower alkyl having optionally a hydroxy substituent, a lower alkanoyl, or benzoyl, or R.sup.6 and R.sup.7 may bind together with nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen or oxygen atom wherein the heterocyclic group has optionally a substituent selected from piperidinyl and a lower alkyl); and m is an integer of 0 to 3!, a phenyl-lower alkoxycarbonyl, a lower alkanoyl, a phenyl-lower alkanoyl, a cycloalkyl-lower alkanoyl, a cycloalkylcarbonyl, tricyclo�3.3.1.1!-decanylcarbonyl, naphthylcarbonyl, pyridylcarbonyl, furoyl, thenoyl, a phenoxy-lower alkanoyl which phenyl ring has optionally 1 to 3 substituents selected from a lower alkyl, a lower alkoxy and an amino having optionally a lower alkanoyl substituent, a phthalimido-substituted lower alkanoyl, a lower alkoxycarbonyl-lower alkanoyl, a carboxy-lower alkanoyl, a naphthyloxy-lower alkanoyl, a halogen-substituted lower alkanoyl, a group of the formula: ##STR7## (wherein R.sup.8 is hydrogen atom, a lower alkyl, a phenyl-lower alkoxycarbonyl, a carbamoyl-lower alkyl, an amino-lower alkanoyl having optionally a lower alkyl substituent, or a lower alkanoyl), an anilinocarbonyl which has optionally a lower alkyl substituent on the phenyl ring, phenoxycarbonyl, a phenylsulfonyl which has optionally a substituent selected from a halogen atom and a lower alkyl on the phenyl ring, quinolylsulfonyl, or a group of the formula: ##STR8## (wherein B is a lower alkylene, n is an integer of 0 or 1, and R.sup.9 and R.sup.10 are the same or different and are each hydrogen atom, a lower alkyl having optionally a hydroxy substituent, a cycloalkyl, a phenyl-lower alkyl, a lower alkanoyl, a lower alkenyl, a phenoxy-lower alkyl, a phenyl which has optionally 1 to 3 substituents selected from an amino-lower alkyl having optionally a lower alkanoyl substituent, a lower alkyl, a lower alkoxy and a halogen atom, a phthalimido-substituted lower alkyl, an amino-lower alkyl having optionally a lower alkanoyl substituent, a lower alkynyl, or an amino-lower alkyl having optionally a lower alkyl substituent, or R.sup.9 and R.sup.10 may bind together with nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen or oxygen atom wherein the heterocylic group has optionally a substituent selected from a lower alkyl, a lower alkoxycarboyl and piperidinyl),
R.sup.11 is hydrogen atom or a lower alkyl,
R.sup.12 is a cycloalkyl, or a phenyl which has optionally 1 to 3 substituents selected from a lower alkoxy, a lower alkyl and a halogen atom,
W is a group of the formula: --(CH.sub.2).sub.p -- (p is an integer of 3 to 5), or a group of the formula: --CH.dbd.CH--(CH.sub.2).sub.q -- (q is an integer of 1 to 3), the carbon atom of these groups: --(CH.sub.2).sub.p -- and --CH.dbd.CH--(CH.sub.2).sub.q -- being optionally replaced by oxygen atom, sulfur atom, sulfinyl, sulfonyl, or a group of the formula: ##STR9## (R.sup.13 is hydrogen atom, a cycloalkyl, or a lower alkyl), and further said --(CH.sub.2).sub.p -- and --CH.dbd.CH--(CH.sub.2).sub.q -- groups having optionally 1 to 3 substituents selected from a lower alkyl having optionally a hydroxy substituent, a lower alkoxycarbonyl, carboxy, hydroxy, oxo, a lower alkanoyloxy having optionally a halogen substituent, an amino-lower alkyl having optionally a substituent selected from a lower alkyl and a lower alkanoyl, a lower alkanoyloxy-substituted lower alkyl, a lower alkyl sulfonyloxy-lower alkyl, an azido-lower alkyl, a group of the formula: ##STR10## an aminocarbonyloxy having optionally a lower alkyl substituent, a lower alkoxy, a lower alkoxycarbonyl-substituted lower alkoxy, a carboxy-substituted lower alkoxy, an aminocarbonyl-lower alkoxy having optionally a lower alkyl substituent, an amino-lower alkoxy having optionally a substituent selected from a lower alkyl and a lower alkanoyl, a phthalimido-substituted lower alkoxy, hydroxyimino, a lower alkanoyloxy-imino, a lower alkylidene, a halogen atom, azido, sulfoxyimino, a group of the formula: ##STR11## (R.sup.81 is hydrogen atom or a lower alkyl), hydrazino, pyrrolyl, an amino-lower alkanoyloxy having optionally a lower alkyl substituent, a group of the formula: ##STR12## (A is as defined above, and R.sup.82 and R.sup.83 are the same or different and are each hydrogen atom, a lower alkyl, a carbamoyl-substituted lower alkyl, a hydroxy-substituted lower alkyl, or a pyridyl-lower alkyl, or R.sup.82 and R.sup.83 may bind together with nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen, oxygen or sulfur atom wherein the heterocyclic group has optionally a substituent selected from oxo, a lower alkyl, a lower alkanoyl, and carbamoyl), and a group of the formula: ##STR13## (wherein n is as defined above, and R.sup.14 and R.sup.15 are the same or different and are each hydrogen atom, a lower alkyl, a lower alkenyl, a lower alkanoyl, a cycloalkyl, an oxiranyl-substituted lower alkyl, a lower alkyl having optionally 1 to 2 substituents selected from a lower alkoxy, hydroxy and an amino having optionally a lower alkyl substituent, a phenyl-lower alkyl, a pyridyl-lower alkyl, a lower alkylsulfonyl, benzoyl, a lower alkoxycarbonyl, anilinocarbonyl, an aminocarbonyl having optionally a lower alkyl substituent, a cyano-substituted lower alkyl, a lower alkoxycarbonyl-substituted lower alkyl, a carbamoyl-substituted lower alkyl, a carboxy-substituted lower alkyl, a tetrahydropyranyloxy-substituted lower alkyl, a lower alkanoyloxy-substituted lower alkyl, a piperidinyl having optionally a phenyl-lower alkyl substituent on the piperidinyl ring, a halogen-substituted lower alkanoyl, an imidazolyl-substituted lower alkanoyl, an amino-lower alkanoyl having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl, an aminocarbonyl-lower alkyl having optionally a lower alkyl substituent, or a phenyl-lower alkoxycarbonyl, or R.sup.14 and R.sup.15 may bind together with nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen or oxygen, wherein the heterocyclic group may optionally have a substituent selected from a lower alkyl, a phenyl-lower alkyl or a lower alkanoyl).
The benzoheterocyclic compounds of the formula (1) and their salts have excellent vasopressin antagonistic activities and vasodilating activity, hypotensive activity, activity for inhibiting saccharide release in liver, activity for inhibiting growth of mesangium cells, water diuretic activity, platelet agglutination inhibitory activity and are useful as vasodilator, hypotensive agent, water diuretics, platelet agglutination inhibitor and are used for the prophylaxis and treatment of hypertension, edema, ascites, heart failure, renal function disorder, vasopressin parasecretion syndrome (SIADH), hepatocirrhosis, hyponatremia, hypokaliemia, diabetic, circulation disorder, and the like.
Each group in the above formula (1) includes specifically the following groups.
The "lower alkoxy" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.
The "lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, and the like.
The "halogen atom" includes fluorine atom, chlorine atom, bromine atom and iodine atome.
The "amino having optionally a lower alkyl substituent" includes an amino having optionally one or two substituents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino, and the like.
The "lower alkenyl" includes a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms, for example, vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl, and the like.
The "lower alkyl which has optionally a substituent selected from a halogen atom and hydroxy" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which may optionally have 1 to 3 substituents selected from a halogen atom and hydroxy, for example, in addition to the above-mentioned lower alkyl groups, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dichlorohexyl, and the like.
The "lower alkylene" includes a straight chain or branched chain alkylene group having 1 to 6 carbon atoms, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene, and the like.
The "lower alkanoyloxy" includes a straight chain or branched chain alkanoyloxy group having 1 to 6 carbon atoms, for example, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, hexanoyloxy, and the like.
The "lower alkylthio" includes a straight chain or branched chain alkylthio group having 1 to 6 carbon atoms, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, hexylthio, and the like.
The "lower alkanoyl" includes a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanolyl, and the like.
The "lower alkoxycarbonyl" includes a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like.
The "amino having optionally a substituent selected from a lower alkyl and a lower alkanoyl" includes an amino having optionally one or two substituents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, N-methyl-N-hexylamino, N-methyl-N-acetylamino, N-acetylamino, N-formylamino, N-propionylamino, N-butyrylamino, N-isobutyrylamino, N-pentanoylamino, N-tert-butylcarbonylamino, N-hexanoylamino, N-ethyl-N-acetylamino, and the like.
The "cycloalkyl" includes a cycloalkyl having 3 to 8 carbon atoms, for example, cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The "lower alkanoyloxy-substituted lower alkoxy" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkanoyloxy group having 2 to 6 carbon atoms, for example, acetyloxymethoxy, 2-propionyloxyethoxy, 1-butyryloxyethoxy, 3-acetyloxypropoxy, 4-acetyloxybutoxy, 4-isobutyryloxybutoxy, 5-pentanoyloxypentyloxy, 6-acetyloxyhexyloxy, 6-tert-butylcarbonyloxyhexyloxy, 1,1-dimethyl-2-hexanoyloxyethoxy, 2-methyl-3-acetyloxypropoxy, and the like.
The "carbamoyl-substituted lower alkoxy" includes a carbamoyl-substituted alkoxy group wherein the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, carbamoylmethoxy, 2-carbamoylethoxy, 1-carbamoylethoxy, 3-carbamoylpropoxy, 4-carbamoylbutoxy, 5-carbamoylpentyloxy, 6-carbamoylhexyloxy, 1,1-dimethyl-2-carbamoylethoxy, 2-methyl-3-carbamoylpropoxy, and the like.
The "hydroxy-substituted lower alkoxy" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms and having 1 to 3 hydroxy substitutents, for example, hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 4-hydroxybutoxy, 3,4-dihydroxybutoxy, 1,1-dimethyl-2-hydroxyethoxy, 5-hydroxypentyloxy, 6-hydroxyhexyloxy, 2-methyl-3-hydroxypropoxy, 2,3,4-trihydroxybutoxy, and the like.
The "lower alkoxycarbonyl-substituted lower alkoxy" includes an alkoxycarbonyl-substituted straight chain or branched chain alkoxy group having 1 to 6 carbon atoms wherein the alkoxycarbonyl moiety is a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, for example, methoxycarbonylmethoxy, 3-methoxycarbonylpropoxy, ethoxycarboxymethoxy, 3-ethoxycarbonylpropoxy, 4-ethoxycarbonylbutoxy, 5-isopropoxycarbonylpentyloxy, 6-propoxycarbonylhexyloxy, 1,1-dimethyl-2-butoxycarbonylethoxy, 2-methyl-3-tert-butoxycarbonylpropoxy, 2-pentyloxycarbonylethoxy, hexyloxycarbonylmethoxy, and the like.
The "carboxy-substituted lower alkoxy" includes a carboxy-substituted alkoxy group wherein the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, carboxymethoxy, 2-carboxyethoxy, 1-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy, 1,1-dimethyl-2-carboxyethoxy, 2-methyl-3-carboxypropoxy, and the like.
The "phthalimido-substituted lower alkoxy" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by phthalimido group, for example, phthalimidomethoxy, 2-phthalimidoethoxy, 1-phthalimidoethoxy, 3-phthalimidopropoxy, 4-phthalimidobutoxy, 5-phthalimidopentyloxy, 6-phthalimidohexyloxy, 1,1-dimethyl-2-phthalimidoethoxy, 2-methyl-3-phthalimidopropoxy, and the like.
The "5- or 6-membered saturated heterocyclic group which is formed by binding the groups R.sup.6 and R.sup.7 together with the nitrogen atom to which they bond with or without being intervened with nitrogen or oxygen atom" includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, and the like.
The "heterocyclic group having a substituent selected from piperidinyl and a lower alkyl" includes a heterocyclic group having 1 to 3 substituents selected from piperidinyl and a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, 4-methylpiperiazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-hexylpiperazinyl, 4-(1-piperidinyl)piperidinyl, 3-(1-piperidinyl)pyrrolidinyl, 3-(1-piperidinyl)-4-methylpiperazinyl, 3-(1-piperidinyl)morpholino, and the like.
The "phenyl(lower)alkanoyl" includes a phenylalkanoyl wherein the alkanoyl moiety is a straight chain or branched chain alkanoyl group having 2 to 6 carbon atoms, for example, phenylacetyl, 3-phenylpropionyl, 2-phenylpropionyl, 4-phenylbutyryl, 2,2-dimethyl-3-phenylpropionyl, 5-phenylpentanoyl, 6-phenylhexanoyl, and the like.
The "cycloalkyl-lower alkanoyl" includes C.sub.3 -C.sub.8 cycloalkyl-alkanoyl group wherein the alkanoyl moiety is a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms, for example, cyclohexylacetyl, 3-cyclopropylpropionyl, 2-cyclopentylpropionyl, 4-cyclohexylbutyryl, 2,2-dimethyl-3-cycloheptylpropionyl, 5-cyclooctylpentanoyl, 6-cyclohexylhexanoyl, and the like.
The "cycloalkylcarbonyl" includes a cycloalkylcarbonyl having 3 to 8 carbon atoms, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, and the like.
The "amino having optionally a lower alkanoyl substituent" includes an amino having optionally a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, amino, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, tert-butylcarbonylamino, hexanoylamino, and the like.
The "phenoxy-lower alkanoyl which phenyl ring has optionally 1 to 3 substituents selected from a lower alkyl, a lower alkoxy and an amino having optionally a lower alkanoyl substituent" includes a phenoxyalkanoyl group wherein the alkanoyl moiety is a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms and the phenyl ring has optionally 1 to 3 substituents selected from a straight chain or branched chain alkyl having 1 to 6 carbon atoms, a straight chain or branched chain alkoxy having 1 to 6 carbon atoms and an amino having optionally a straight chain or branched chain alkanoyl having 1 to 6 carbon atoms, for example, phenoxyacetyl, 3-phenoxypropionyl, 2-phenoxypropionyl, 4-phenoxybutyryl, 2,2-dimethyl-3-phenoxypropionyl, 5-phenoxypentanoyl, 6-phenoxyhexanoyl, (2-aminophenoxy)acetyl, 3-(4-aminophenoxy)propionyl, (2-methylphenoxy)acetyl, (4-methylphenoxy)acetyl, (3-methylphenoxy)acetyl, (3-methoxyphenoxy)acetyl, (3-acetylaminophenoxy)acetyl, 4-(2-propionylaminophenoxy)butyryl, 2,2-dimethyl-3-(4-butyrylaminophenoxy)propionyl, 5-(2-pentanoylaminophenoxy)pentanoyl, 6-(4-hexanoylaminophenoxy)hexanoyl, 3-(2-ethylphenoxy)propionyl, 2-(4-propylphenoxy)propionyl, 4-(4-butylphenoxy)butyryl, 5-(3-pentylphenoxy)pentanoyl, 6-(4-hexylphenoxy)hexanoyl, (2,3-dimethylphenoxy)acetyl, (2,5-dimethylphenoxy)acetyl, (3,4-dimethylphenoxy)acetyl, (3,4,5-trimethylphenoxy)acetyl, 3-(4-ethoxyphenoxy)propionyl, 2-(2-propoxyphenoxy)propionyl, 4-(3-butoxyphenoxy)butyryl, 5-(4-pentyloxyphenoxy)pentanoyl, 6-(4-hexyloxyphenoxy)hexanoyl, (3,4-dimethoxyphenoxy)acetyl, (3,5-dimethoxyphenoxy)acetyl, (2,4-dimethoxyphenoxy)acetyl, (3,4,5-trimethoxyphenoxy)acetyl, (2-acetylamino-4-methylphenoxy)acetyl, (4-acetylamino-3-methoxyphenoxy)acetyl, and the like.
The "phthalimido-substituted lower alkanoyl" includes a straight chain or branched chain alkanoyl group having 2 to 6 carbon atoms which is substituted by phthalimido group, for example, 2-phthalimidoacetyl, 3-phthalimidopropionyl, 2-phthalimidopropionyl, 4-phthalimidobutyryl, 2,2-dimethyl-3-phthalimidopropionyl, 5-phthalimidopentanoyl, 6-phthalimidohexanoyl, 3-methyl-4-phthalimidobutyryl, and the like.
The "lower alkoxycarbonyl-lower alkanoyl" includes an alkoxycarbonyl-alkanoyl group wherein the alkoxy moiety is a straight chain or branched chain alkoxy having 1 to 6 carbon atoms and the alkanoyl moiety is a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms, for example, methoxycarbonylacetyl, 3-methoxycarbonylpropionyl, ethoxycarbonylacetyl, 3-ethoxycarbonylpropionyl, 4-ethoxycarbonylbutyryl, 3-propoxycarbonylpropionyl, 2-methoxycarbonylpropionyl, 6-propoxycarbonylhexanoyl, 5-isopropoxycarbonylpentanoyl, 2,2-dimethyl-3-butoxycarbonylpropionyl, 2-methyl-3-tert-butoxycarbonylpropionyl, pentyloxycarbonylacetyl, hexyloxycarbonylacetyl, and the like.
The "carboxy-lower alkanoyl" includes a carboxyalkanoyl group wherein the alkanoyl moiety is a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms, for example, carboxyacetyl, 3-carboxypropionyl, 2-carboxypropionyl, 4-carboxybutyryl, 2,2-dimethyl-3-carboxypropionyl, 5-carboxypentanoyl, 6-carboxyhexanoyl, and the like.
The "naphthyloxy-lower alkanoyl" includes a naphthyloxy-alkanoyl group wherein the alkanoyl moiety is a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms, for example, naphtyloxyacetyl, 3-naphtyloxypropionyl, 2-naphtyloxypropionyl, 4-naphthyloxybutyryl, 2,2-dimethyl-3-naphthyloxypropionyl, 5-naphthyloxypentanoyl, 6-naphthyloxyhexanoyl, and the like.
The "phenyl-lower alkoxycarbonyl" includes a phenylalkoxycarbonyl wherein the alkoxycarbonyl moiety is a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, for example, benzyloxycarbonyl, 2-phenylethoxycarbonyl, 1-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, 5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl, 1,1-dimethyl-2-phenylethoxycarbonyl, 2-methyl-3-phenylpropoxycarbonyl, and the like.
The "lower alkyl having optionally a hydroxy substituent" includes a straight chain or branched chain alkyl having 1 to 6 carbon atoms and having optionally 1 to 3 hydroxy substituents, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyethyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 6-hydroxyhexyl, 2-methyl-3-hydroxypropyl, 2,3,4-trihydroxybutyl, and the like.
The "phenyl-lower alkyl" includes a phenylalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl, and the like.
The "phenoxy-lower alkyl" includes a phenoxyalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, phenoxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl, 5-phenoxypentyl, 6-phenoxyhexyl, 1,1-dimethyl-2-phenoxyethyl, 2-methyl-3-phenoxypropyl, and the like.
The "phenyl which has optionally 1 to 3 substituents selected from a lower alkyl, a lower alkoxy and a halogen atom" includes a phenyl group which has optionally 1 to 3 substituents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms and a halogen atom, for example, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-pentyloxyphenyl, 2,4-dimethoxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3-ethoxy-4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dipentyloxyphenyl, 3,4,5-trimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromophenyl, 3,4,5-trichlorophenyl, 2-methoxy-3-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl, 3-chloro-4-methylphenyl, 3-methoxy-4-methyl-5-iodophenyl, 3,4-dimethoxy-5-bromophenyl, 3,5-diiodo-4-methoxyphenyl, and the like.
The "amino-lower alkyl having optionally a lower alkyl substituent" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an amino group having optionally 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, (N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl, and the like.
The "5- or 6-membered saturated heterocyclic group which is formed by binding the groups R.sup.9 and R.sup.10 together with the nitrogen atom to which they bond with or without being intervened with nitrogen or oxygen atom" includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, and the like.
The "heterocyclic group having a substituent selected from a lower alkyl, a lower alkoxycarbonyl and piperidinyl" includes a heterocyclic group having 1 to 3 substituents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a straight chain or branched chain alkoxycarbonyl having 1 to 6 carbon atoms and piperidinyl, for example, in addition to the above-mentioned heterocyclic groups having a substituent of a lower alkyl and piperidinyl, 4-methoxycarbonylpiperazinyl, 4-ethoxycarbonylpiperidinyl, 3-propoxycarbonylpyrrolidinyl, 2-pentyloxycarbonylmorpholino, 4-hexyloxycarbonylpiperidinyl, 4-ethoxycarbonyl-3-methylpiperidinyl, 3-methyl-4-ethoxycarbonylpiperazinyl, and the like.
The "5- or 6-membered saturated heterocyclic group which is formed by binding the groups R.sup.14 and R.sup.15 together with the nitrogen atom to which they bond with or without being intervened with nitrogen or oxygen atom" includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, and the like.
The "heterocyclic group having a lower alkyl substituent" includes a heterocyclic group having 1 to 3 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-hexylpiperazinyl, and the like.
The heterocyclic ring in the formula (1) includes tetrahydroquinolyl, 2,3,4,5-tetrahydro-1H-benzazepinyl, 1,2,3,4,5,6-hexahydrobenzazocinyl, 1,2-dihydroquinolyl, 2,3-dihydro-1H-benzazepinyl, 1,2,3,4-tetrahydrobenzazocinyl, and the like.
The heterocyclic ring in the formula (1) wherein the carbon atom in the group of the formula: --(CH.sub.2).sub.p -- or --CH.dbd.CH--(CH.sub.2).sub.q -- for W is replaced by oxygen atom, sulfur atom, sulfinyl, sulfonyl, or a group of the formula: ##STR14## (R.sup.13 is hydrogen atom or a lower alkyl) includes a heterocylic group wherein the carbon atom in the group of the formula: --(CH.sub.2).sub.p -- or --CH.dbd.CH--(CH.sub.2).sub.q -- for W is replaced by oxygen atom, sulfur atom, sulfinyl, sulfonyl, or a group of the formula: ##STR15## (R.sup.13 is hydrogen atom or a straight chain or branched chain alkyl having 1 to 6 carbon atoms), for example, 3,4-dihydro-2H-1,4-benzoxazinyl, 1,2,3,5-tetrahydro-4,1-benzoxazepinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,2,3,4,5,6-hexahydro-1,5-benzodiazocinyl, 5-methyl-1,2,3,4,5,6-hexahydro-1,5-benzodiazocinyl, 4-methyl-1,2,3,4-tetrahydroquinoxalinyl, 1,2,3,4-tetrahydro-5,1-benzoxazepinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, 2,3,4,5-tetrahydro-1,5-benzothiazepinyl, 1,2,3,5-tetrahydro-4,1-benzothiazepinyl, 4-ethyl-1,2,3,4-tetrahydroquinoxalinyl, 4-propyl-1,2,3,4-tetrahydroquinoxalinyl, 4-butyl-1,2,3,4-tetrahydroquinoxalinyl, 4-pentyl-1,2,3,4-tetrahydroquinoxalinyl, 4-hexyl-1,2,3,4-tetrahydroquinoxalinyl, 2,3,4,5-tetrahydro-1H-1,4-benzodiazepinyl, 4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinyl, 4-ethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinyl, 4-propyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinyl, 4-butyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinyl, 4-pentyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinyl, 4-hexyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinyl, 2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl, 5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl, 5-ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl, 5-propyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl, 5-butyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl, 5-pentyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl, 5-hexyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinyl, 3,4-dihydro-1-oxo-2H-1,4-benzothiazepinyl, 3,4-dihydro-1,1-dioxo-2H-1,4-benzothiazepinyl, 1-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepinyl, 1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazepinyl, 4-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepinyl, 4,4-dioxo-1,2,3,5-tetrahydro-4,1-benzothiazepinyl, and the like.
The "halogen-substituted lower alkoxy" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which has 1 to 3 substituents of a halogen atom, for example, trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 4,4,4-trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, 3-chloro-2-methylpropoxy, 6-bromohexyloxy, 5,6-dichlorohexyloxy, and the like.
The "halogen-substituted lower alkanoyl" includes a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms which has 1 to 3 substituents of a halogen atom, for example, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, 2-chloroacetyl, 2-bromoacetyl, 2-fluoroacetyl, 2-iodoacetyl, 2,2-difluoroacetyl, 2,2-dibromoacetyl, 3,3,3-trifluoropropionyl, 3,3,3-trichloropropionyl, 3-chloropropionyl, 2,3-dichloropropionyl, 4,4,4-trichlorobutyryl, 4-fluorobutyryl, 5-chloropentanoyl, 3-chloro-2-methylpropionyl, 6-bromohexanoyl, 5,6-dibromohexanoyl, and the like.
The "aminocarbonyl-lower alkoxy having a lower alkyl substituent" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by an aminocarbonyl group having 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methylaminocarbonylmethoxy, 1-ethylaminocarbonylethoxy, 2-propylaminocarbonylethoxy, 3-isopropylaminocarbonylpropoxy, 4-butylaminocarbonylbutoxy, 5-pentylaminocarbonylpentyloxy, 6-hexylaminocarbonylhexyloxy, dimethylaminocarbonylmethoxy, 3-diethylaminocarbonylpropoxy, diethylaminocarbonylmethoxy, (N-ethyl-N-propylamino)carbonylmethoxy, 2-(N-methyl-N-hexylamino)carbonylethoxy, and the like.
The "carbamoyl-lower alkyl" includes a carbamoyl-substituted alkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, carbamoylmethyl, 2-carbamoylethyl, 1-carbamoylethyl, 3-carbamoylpropyl, 4-carbamoylbutyl, 5-carbamoylpentyl, 6-carbamoylhexyl, 1,1-dimethyl-2-carbamoylethyl, 2-methyl-3-carbamoylpropyl, and the like.
The "amino-lower alkanoyl having optionally a lower alkyl substituent" includes a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms which is substituted by an amino group having optionally 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, 2-aminoacetyl, 3-aminopropionyl, 2-aminopropionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 2,2-dimethyl-3-aminopropionyl, 2-methyl-3-aminopropionyl, 2-methylaminoacetyl, 2-ethylaminopropionyl, 3-propylaminopropionyl, 3-isopropylaminopropionyl, 4-butylaminobutyryl, 5-pentylaminopentanoyl, 6-hexylaminohexanoyl, 2-dimethylaminoacetyl, 2-diethylaminoacetyl, 2-(N-ethyl-N-propylamino)acetyl, 3-(N-methyl-N-hexylamino)propionyl, and the like.
The "amino-lower alkyl having optionally a lower alkanoyl substituent" includes a straight chain or branched chain alkyl having 1 to 6 carbon atoms which is substituted by an amino group having optionally a substituent of a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, acetylaminomethyl, 1-acetylaminoethyl, 2-propionylaminoethyl, 3-isopropionylaminopropyl, 4-butyrylaminobutyl, 5-pentanoylaminopentyl, 6-hexanoylaminohexyl, formylaminomethyl, and the like.
The "anilinocarbonyl having optionally a lower alkyl substituent on the phenyl ring" includes an anilinocarbonyl group having optionally 1 to 3 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms on the phenyl ring, for example, anilinocarbonyl, 2-methylanilinocarbonyl, 3-methylanilinocarbonyl, 4-methylanilinocarbonyl, 2-ethylanilinocarbonyl, 3-ethylanilinocarbonyl, 4-ethylanilinocarbonyl, 4-isopropylanilinocarbonyl, 3-butylanilinocarbonyl, 4-pentylanilinocarbonyl, 4-hexylanilinocarbonyl, 3,4-dimethylanilinocarbonyl, 3,4-diethylanilinocarbonyl, 2,4-dimethylanilinocarbonyl, 2,5-dimethylanilinocarbonyl, 2,6-dimethylanilinocarbonyl, 3,4,5-trimethylanilinocarbonyl, and the like.
The "phenylsulfonyl which has optionally a substituent selected from a halogen and a lower alkyl on the phenyl ring" includes a phenylsulfonyl group which has optionally 1 to 3 substitutents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and a halogen atom, for example, phenylsulfonyl, 2-chlorophenylsulfonyl, 3-chlorophenylsulfonyl, 4-chlorophenylsulfonyl, 2-fluorophenylsulfonyl, 3-fluorophenylsulfonyl, 4-fluorophenylsulfonyl, 2-bromophenylsulfonyl, 3-bromophenylsulfonyl, 4-bromophenylsulfonyl, 2-iodophenylsulfonyl, 3-iodophenylsulfonyl, 4-iodophenylsulfonyl, 3,4-dichlorophenylsulfonyl, 3,5-dichlorophenylsulfonyl, 2,6-dichlorophenylsulfonyl, 2,3-dichlorophenylsulfonyl, 2,4-dichlorophenylsulfonyl, 3,4-difluorophenylsulfonyl, 3,5-dibromophenylsulfonyl, 3,4,5-trichlorophenylsulfonyl, 2-ethyl-3-chlorophenylsulfonyl, 2-methylphenylsulfonyl, 3-methylphenylsulfonyl, 4-methylphenylsulfonyl, 2-ethylphenylsulfonyl, 3-ethylphenylsulfonyl, 4-ethylphenylsulfonyl, 4-isopropylphenylsulfonyl, 3-butylphenylsulfonyl, 4-pentylphenylsulfonyl, 4-hexylphenylsulfonyl, 3,4-dimethylphenylsulfonyl, 3,4-diethylphenylsulfonyl, 2,4-dimethylphenylsulfonyl, 2,5-dimethylphenylsulfonyl, 2,6-dimethylphenylsulfonyl, 3,4,6-trimethylphenylsulfonyl, 3,4,5-trimethylphenylsulfonyl, 3-chloro-4-methylphenylsulfonyl, 4-methyl-5-iodophenylsulfonyl, 3,4-dimethyl-5-bromophenylsulfonyl, 3,5-diiodo-4-methylphenylsulfonyl, and the like.
The "phthalimido-substituted lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by phthalimido group, for example, phthalimidomethyl, 2-phthalimidoethyl, 1-phthalimidoethyl, 3-phthalimidopropyl, 4-phthalimidobutyl, 5-phthalimidopentyl, 6-phthalimidohexyl, 1,1-dimethyl-2-phthalimidoethyl, 2-methyl-3-phthalimidopropyl, and the like.
The "lower alkynyl" includes a straight chain or branched chain alkynyl having 2 to 6 carbon atoms, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 2-hexynyl, and the like.
The "benzoyl which has optionally a halogen substituent on the phenyl ring" includes a benzoyl group which has optionally 1 to 3 substituents of a halogen atom on the phenyl ring, for example, benzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2-fluorobenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2-bromobenzoyl, 3-bromobenzoyl, 4-bromobenzoyl, 2-iodobenzoyl, 3-iodobenzoyl, 4-iodobenzoyl, 3,4-dichlorobenzoyl, 3,5-dichlorobenzoyl, 2,6-dichlorobenzoyl, 2,3-dichlorobenzoyl, 2,4-dichlorobenzoyl, 3,4-difluorobenzoyl, 3,5-dibromobenzoyl, 3,4,5-trichlorobenzoyl, and the like.
The "phenyl-lower alkoxy" includes a phenylalkoxy group wherein the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 1,1-dimethyl-2-phenylethoxy, 2-methyl-3-phenylpropoxy, and the like.
The "amino-lower alkoxy having optionally a substituent selected from a lower alkyl and a lower alkanoyl" include a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by an amino group having optionally 1 to 2 substituents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, aminomethoxy, 2-aminoethoxy, 1-aminoethoxy, 3-aminopropoxy, 4-aminobutoxy, 5-aminopentyloxy, 6-aminohexyloxy, 1,1-dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, acetylaminomethoxy, 1-acetylaminoethoxy, 2-propionylaminoethoxy, 3-isopropionylaminopropoxy, 4-butyrylaminobutoxy, 5-pentanoylaminopentyloxy, 6-hexanoylaminohexyloxy, formylaminomethoxy, methylaminomethoxy, 1-ethylaminoethoxy, 2-propylaminoethoxy, 3-isopropylaminopropoxy, 4-butylaminobutoxy, 5-pentylaminopentyloxy, 6-hexylaminohexyloxy, dimethylaminomethoxy, (N-ethyl-N-propylamino)methoxy, 2-(N-methyl-N-hexylamino)ethoxy, and the like.
The "benzoyloxy which has optionally a halogen substituent on the phenyl ring" includes a benzoyloxy group which has optionally 1 to 3 substituents of a halogen atom on the phenyl ring, for example, benzoyloxy, 2-chlorobenzoyloxy, 3-chlorobenzoyloxy, 4-chlorobenzoyloxy, 2-fluorobenzoyloxy, 3-fluorobenzoyloxy, 4-fluorobenzoyloxy, 2-bromobenzoyloxy, 3-bromobenzoyloxy, 4-bromobenzoyloxy, 2-iodobenzoyloxy, 3-iodobenzoyloxy, 4-iodobenzoyloxy, 3,4-dichlorobenzoyloxy, 3,5-dichlorobenzoyloxy, 2,6-dichlorobenzoyloxy, 2,3-dichlorobenzoyloxy, 2,4-dichlorobenzoyloxy, 3,4-difluorobenzoyloxy, 3,5-dibromobenzoyloxy, 3,4,5-trichlorobenzoyloxy, and the like.
The "lower alkanoyloxy-substituted lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkanoyloxy group having 2 to 6 carbon atoms, for example, acetyloxymethyl, 2-propionyloxyethyl, 1-butyryloxyethyl, 3-acetyloxypropyl, 4-acetyloxybutyl, 4-isobutyryloxybutyl, 5-pentanoyloxypentyl, 6-acetyloxyhexyl, 6-tert-butylcarbonyloxyhexyl, 1,1-dimethyl-2-hexanoyloxyethyl, 2-methyl-3-acetyloxypropyl, and the like.
The "lower alkylsulfonyloxy-lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkylsulfonyloxy group having 1 to 6 carbon atoms, for example, methylsulfonyloxymethyl, 1-ethylsulfonyloxyethyl, 2-propylsulfonyloxyethyl, 3-isopropylsulfonyloxypropyl, 4-butylsulfonyloxybutyl, 5-pentylsulfoyloxypentyl, 6-hexylsulfonyloxyhexyl, 1,1-dimethyl-2-methylsulfoyloxyethyl, 2-methyl-3-ethylsulfonyloxypropyl, and the like.
The "azido-lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an azido group, for example, azidomethyl, 1-azidoethyl, 2-azidoethyl, 3-azidopropyl, 4-azidobutyl, 5-azidopentyl, 6-azidohexyl, 1,1-dimethyl-2-azidoethyl, 2-methyl-3-azidopropyl, and the like.
The "lower alkanoyloxyimino" includes a straight chain or branched chain alkanoyloxyimino group having 1 to 6 carbon atoms, for example, formyloxyimino, acetyloxyimino, propionyloxyimino, butyryloxyimino, isobutyryloxyimino, pentanoyloxyimino, tert-butylcarbonyloxyimino, hexanoyloxyimino, and the like.
The "lower alkylidene" includes a straight chain or branched chain alkylidene group having 1 to 6 carbon atoms, for example, methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, hexylidene, and the like.
The "oxiranyl-substituted lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by oxiranyl group, for example, oxiranylmethyl, 1-oxiranylethyl, 2-oxiranylethyl, 3-oxiranylpropyl, 4-oxiranylbutyl, 5-oxiranylpentyl, 6-oxiranylhexyl, 1,1-dimethyl-2-oxiranylethyl, 2-methyl-3-oxiranylpropyl, and the like.
The "lower alkyl having 1 to 2 substituents selected from a lower alkoxy, hydroxy and an amino having optionally a lower alkyl substituent" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and having 1 to 2 substituents selected from a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, hydroxy and an amino having optionally a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methoxymethyl, 1-ethoxyethyl, 2-propoxyethyl, 3-isopropoxypropyl, 4-butoxybutyl, 5-pentyloxypentyl, 6-hexyloxyhexyl, 1,1-dimethyl-2-methoxyethyl, 2-methyl-3-ethoxypropyl, 3-methoxy-2-hydroxypropyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyethyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,6-dihydroxyhexyl, 5-hydroxypentyl, 6-hydroxyhexyl, 6-(N-ethyl-N-methylamino)-5-methoxyhexyl, 2-methyl-3-hydroxypropyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, ethylaminomethy, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, tert-butylaminomethyl, pentylaminomethyl, hexylaminomethyl, dimethylaminomethyl, diethylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, dipentylaminomethyl, dihexylaminomethyl, N-methyl-N-ethylaminomethyl, N-methyl-N-propylaminomethyl, N-methyl-N-butylaminomethyl, N-methyl-N-hexylaminomethyl, 1-methylaminoethyl, 2-ethylaminoethyl, 3-propylaminopropyl, 4-butylaminobutyl, 1,1-dimethyl-2-pentylaminoethyl, 5-hexylaminopentyl, 6-dimethylaminohexyl, 4-dimethylaminobutyl, 2-diethylaminoethyl, 1-(N-methyl-N-hexylamino)ethyl, 3-dihexylaminopropyl, 6-diethylaminohexyl, 4-dibutylaminobutyl, 2-(N-methyl-N-pentylamino)ethyl, 2-hydroxy-3-diethylaminopropyl, 3-hydroxy-4-methylaminobutyl, 5-hydroxy-6-diethylaminohexyl, 4-hydroxy-5-dimethylaminopentyl, 4-hydroxy-5-methylaminopentyl, 4-hydroxy-5-diethylaminopentyl, 5-hydroxy-6-ethylaminohexyl, 5-hydroxy-6-isopropylaminohexyl, 5-hydroxy-6-aminohexyl, and the like.
The "aminocarbonyloxy having optionally a lower alkyl substituent" includes an aminocarbonyloxy group having optionally 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, aminocarbonyloxy, methylaminocarbonyloxy, ethylaminocarbonyloxy, propylaminocarbonyloxy, isopropylaminocarbonyloxy, butylaminocarbonyloxy, tert-butylaminocarbonyloxy, pentylaminocarbonyloxy, hexylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, dipropylaminocarbonyloxy, dibutylaminocarbonyloxy, dipentylaminocarbonyloxy, dihexylaminocarbonyloxy, N-methyl-N-ethylaminocarbonyloxy, N-ethyl-N-propylaminocarbonyloxy, N-methyl-N-butylaminocarbonyloxy, N-methyl-N-hexylaminocarbonyloxy, and the like.
The "lower alkanoyloxy having optionally a halogen substituent" includes a straight chain or branched chain alkanoyloxy group having 1 to 6 carbon atoms which has optionally 1 to 3 substituents of a halogen atom, for example, in addition to the above lower alkanoyl group, 2,2,2-trifluoroacetyloxy, 2,2,2-trichloroacetyloxy, 2-chloroacetyloxy, 2-bromoacetyloxy, 2-fluoroacetyloxy, 2-iodoacetyloxy, 2,2-difluoroacetyloxy, 2,2-dibromoacetyloxy, 3,3,3-trifluoropropionyloxy, 3,3,3-trichloropropionyloxy, 3-chloropropionyloxy, 2,3-dichloropropionyloxy, 4,4,4-trichlorobutyryloxy, 4-fluorobutyryloxy, 5-chloropentanoyloxy, 3-chloro-2-methylpropionyloxy, 6-bromohexanoyloxy, 5,6-dibromohexanoyloxy, and the like.
The "amino-lower alkyl having optionally a substituent selected from a lower alkyl and a lower alkanoyl" include a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an amino group having optionally 1 to 2 substituents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, acetylaminomethyl, 1-acetylaminoethyl, 2-propionylaminoethyl, 3-isopropionylaminopropyl, 4-butyrylaminobutyl, 5-pentanoylaminopentyl, 6-hexanoylaminohexyl, formylaminomethyl, methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, (N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl, and the like.
The "amino-lower alkanoyloxy having optionally a lower alkyl substituent" includes a straight chain or branched chain alkanoyloxy having 2 to 6 carbon atoms which is substituted by an amino group having optionally 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, 2-aminoacetyloxy, 3-aminopropionyloxy, 2-aminopropionyloxy, 4-aminobutyryloxy, 5-aminopentanoyloxy, 6-aminohexanoyloxy, 2,2-dimethyl-3-aminopropionyloxy, 2-methyl-3-aminopropionyloxy, 2-methylaminoacetyloxy, 2-ethylaminopropionyloxy, 3-propylaminopropionyloxy, 3-isopropylaminopropionyloxy, 4-butylaminobutyryloxy, 5-pentylaminopentanoyloxy, 6-hexylaminohexanoyloxy, 2-dimethylaminoacetyloxy, 2-diethylaminoacetyloxy, 2-(N-ethyl-N-propylamino)acetyloxy, 3-(N-methyl-N-hexylamino)propionyloxy, and the like.
The "pyridyl-lower alkyl" include a pyridylalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, (4-pyridyl)methyl, 1-(3-pyridyl)ethyl, 2-(2-pyridyl)ethyl, 3-(2-pyridyl)propyl, 4-(3-pyridyl)butyl, 5-(4-pyridyl)pentyl, 6-(2-pyridyl)hexyl, 1,1-dimethyl-2-(3-pyridyl)ethyl, 2-methyl-3-(4-pyridyl)propyl, and the like.
The "5- or 6-membered saturated heterocyclic group which is formed by binding the groups R.sup.82 and R.sup.83 together with the nitrogen atom to which they bond with or without being intervened with nitrogen, oxygen or sulfur atom" includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, and the like.
The above heterocyclic group which has a substituent selected from oxo, a lower alkyl, a lower alkanoyl and carbamoyl includes the above heterocyclic groups which have 1 to 3 substituents selected from oxo, a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, and carbamoyl group, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-hexylpiperazinyl, 2-methylthiomorpholino, 4-acetylpiperazinyl, 2-propionylmorpholino, 3-butyrylthiomorpholino, 3-pentanoylpyrrolidinyl, 4-hexanoylpiperidinyl, 3-methyl-4-acetylpiperazinyl, 2-carbamoylpyrrolidinyl, 4-carbamoylpiperazinyl, 3-carbamoylthiomorpholino, 2-carbamoylmorpholino, 3-carbamoylpiperidinyl, 1-oxo-thiomorpholino, 1,1-dioxothiomorpholino, and the like.
The "lower alkylsulfonyl" includes a straight chain or branched chain alkylsulfonyl group having 1 to 6 carbon atoms, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, and the like.
The "aminocarbonyl having optionally a lower alkyl substituent" includes an aminocarbonyl group having optionally 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, tert-butylaminocarbonyl, pentylaminocarbonyl, hexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, dibutylaminocarbonyl, dipentylaminocarbonyl, dihexylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, N-ethyl-N-propylaminocarbonyl, N-methyl-N-butylaminocarbonyl, N-methyl-N-hexylaminocarbonyl, and the like.
The "cyano-substituted lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by cyano group, for example, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyanopentyl, 6-cyanohexyl, 1,1-dimethyl-2-caynoethyl, 2-methyl-3-cyanopropyl, and the like.
The "lower alkoxycarbonyl-substituted lower alkyl" includes an alkoxycarbonyl-substituted straight chain or branched chain alkyl group having 1 to 6 carbon atoms wherein the alkoxycarbonyl moiety is a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, for example, methoxycarbonylmethyl, 3-methoxycarbonylpropyl, ethoxycarboxymethyl, 3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-isopropoxycarbonylpentyl, 6-propoxycarbonylhexyl, 1,1-dimethyl-2-butoxycarbonylethyl, 2-methyl-3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl, and the like.
The "carboxy-substituted lower alkyl" includes a carboxy-substituted alkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, carboxymethyl, 2-carboxyethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl, and the like.
The "tetrahydropyranyloxy-substituted lower alkyl" includes a tetrahydropyranyloxy-substituted straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, (2-tetrahydropyranyloxy)methyl, 2-(3-tetrahydropyranyloxy)ethyl, 1-(4-tetrahydropyranyloxy)ethyl, 3-(2-tetrahydropyranyloxy)propyl, 4-(3-tetrahydropyranyloxy)butyl, 5-(4-tetrahydropyranyloxy)pentyl, 6-(2-tetrahydropyranyloxy)hexyl, 1,1-dimethyl-2-(3-tetrahydropyranyloxy)ethyl, 2-methyl-3-(4-tetrahydropyranyloxy)propyl, and the like.
The "piperidinyl having optionally a phenyl-lower alkyl substituent" includes a piperidinyl which has optionally a substituent of a phenylalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, piperidinyl, 1-benzyl-4-piperidinyl, 1-(2-phenylethyl)-3-piperidinyl, 1-(1-phenylethyl)-2-piperidinyl, 1-(3-phenylpropyl)-4-piperidinyl, 1-(4-phenylbutyl)-4-piperidinyl, 1-(5-phenylpentyl)-4-piperidinyl, 1-(6-phenylhexyl)-4-piperidinyl, 1-(1,1-dimethyl-2-phenylethyl)-3-piperidinyl, 1-(2-methyl-3-phenylpropyl)-2-piperidinyl, and the like.
The "imidazolyl-substituted lower alkanoyl" includes an imidazolyl-substituted alkanoyl group wherein the alkanoyl moiety is a straight chain or branched chain alkanoyl group having 2 to 6 carbon atoms, for example, (1-imidazolyl)acetyl, 3-(2-imidazolyl)propionyl, 2-(4-imidazolyl)propionyl, 4-(1-imidazolyl)butyryl, 2,2-dimethyl-3-(2-imidazolyl)propionyl, 5-(4-imidazolyl)pentanoyl, 6-(1-imidazolyl)hexanoyl, and the like.
The "amino-lower alkanoyl having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl" includes a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms which is substituted by an amino group having optionally 1 to 2 substituents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, for example, 2-aminoacetyl, 3-aminopropionyl, 2-aminopropionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 2,2-dimethyl-3-aminopropionyl, 2-methyl-3-aminopropionyl, 2-methylaminoacetyl, 2-ethylaminopropionyl, 3-propylaminopropionyl, 3-isopropylaminopropionyl, 4-butylaminobutyryl, 5-pentylaminopentanoyl, 6-hexylaminohexanoyl, 2-dimethylaminoacetyl, 2-diethylaminoacetyl, 2-(N-ethyl-N-propylamino)acetyl, 3-(N-methyl-N-hexylamino)propionyl, 2-methoxycarbonylaminoacetyl, 2-ethoxycarbonylaminoacetyl, 3-propoxycarbonylaminopropionyl, 4-butoxycarbonylaminobutyryl, 2-tert-butoxycarbonylaminoacetyl, 5-pentyloxycarbonylaminopentanoyl, 6-hexyloxycarbonylaminohexanoyl, 2-(N-methyl-N-tert-butoxycarbonylamino)acetyl, and the like.
The "aminocarbonyl-lower alkyl having a lower alkyl substituent" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an aminocarbonyl group having 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methylaminocarbonylmethyl, 1-ethylaminocarbonylethyl, 2-propylaminocarbonylethyl, 3-isopropylaminocarbonylpropyl, 4-butylaminocarbonylbutyl, 5-pentylaminocarbonylpentyl, 6-hexylaminocarbonylhexyl, dimethylaminocarbonylmethyl, 3-diethylaminocarbonylpropyl, diethylaminocarbonylmethyl, (N-ethyl-N-propylamino)carbonylmethyl, 2-(N-methyl-N-hexylamino)carbonylethyl, and the like.
The "amino-substituted lower alkoxy having optionally a lower alkyl substituent" includes an amino-substituted straight chain or branched chain alkoxy having 1 to 6 carbon atoms which has optionally 1 to 2 substituents of a straight chain or branched chain alkyl having 1 to 6 carbon atoms, such as aminomethoxy, 2-aminoethoxy, 1-aminoethoxy, 3-aminopropoxy, 4-aminobutoxy, 5-aminopentyloxy, 6-aminohexyloxy, 1,1-dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, methylaminomethoxy, 1-ethylaminoethoxy, 2-propylaminoethoxy, 3-isopropylaminopropoxy, 4-butylaminobutoxy, 5-pentylaminopentyloxy, 6-hexylaminohexyloxy, dimethylaminomethoxy, (N-ethyl-N-propylamino)methoxy, 2-(N-methyl-N-hexylamino)ethoxy, and the like.
The compounds of the present invention can be prepared by various processes, for example, by the processes shown in the following reaction schemes. ##STR16## wherein R.sup.1, R.sup.2, R.sup.3, and W are the same as defined above.
The process of Reaction Scheme-1 is carried out by reacting a benzoheterocyclic compound of the formula (2) and a carboxylic acid compound of the formula (3) by a conventional amido bond forming reaction. The amido bond forming reaction can be carried out under the conditions for the conventional amido bond forming reaction, for example,
(a) a mixed acid anhydride process, i.e. a process of reacting the carboxylic acid compound (3) with an alkylhalocarboxylic acid to form a mixed acid anhydride and reacting the resultant with the amine compound (2),
(b) an activated ester process, i.e. a process of converting the carboxylic acid compound (3) into an activated ester, such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and reacting the resultant with the amine compound (2),
(c) a carbodiimide process, i.e. a process of condensing the carboxylic acid compound (3) and the amine compound (2) in the presence of an activating agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc.,
(d) other processes, i.e. a process of converting the carboxylic acid compound (3) into a carboxylic anhydride by treatment with a dehydrating agent such as acetic anhydride, and reacting the resultant with the amine compound (2); a process of reacting an ester of the carboxylic acid compound (3) with a lower alcohol and the amine compound (2) at a high temperature under high pressure; a process of reacting an acid halide compound of the carboxylic acid compound (3), i.e. a carboxylic acid halide, with the amine compound (2), and the like.
The mixed acid anhydride used in the above mixed acid anhydride process (a) is obtained by the known Schotten-Baumann reaction, and the reaction product is used without isolation from the reaction mixture for the reaction with the amine compound (2) to give the desired compound of the formula (1). The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. The basic compound is any conventional compounds used for the Schotten-Baumann reaction and includes, for example, organic basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo�4.3.0!nonene-5 (DBN), 1,8-diazabicyclo�5.4.0!undecene-7 (DBU), 1,4-diazabicyclo�2.2.2!octane (DABCO), etc., and inorganic basic compounds such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc. The reaction is usually carried out at a temperature of from about -20.degree. C. to about 100.degree. C., preferably from about 0.degree. C. to about 50.degree. C., for about 5 minutes to about 10 hours, preferably about 5 minutes to about 2 hours.
The reaction of the thus obtained mixed acid anhydride with the amine compound (2) is usually carried out at a temperature of from about -20.degree. C. to about 150.degree. C., preferably about 10.degree. C. to about 50.degree. C., for about 5 minutes to about 10 hours, preferably about 5 minutes to about 5 hours. The mixed acid anhydride process is usually carried out in an appropriate solvent. The solvent is any conventional solvents which are usually used in the mixed acid anhydride process and includes, for example, halogenated hydrocarbons (e.g. chloroform, dichloromethane dichloroethane, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), or a mixture of these solvents. The alkylhalocarboxylic acid used in the mixed acid anhydride process includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. In said process, the carboxylic acid compound (3), the alkylhalocarboxylic acid and the amine (2) are usually used in each equimolar amount, but preferably, the alkylhalocarboxylic acid and the carboxylic acid compound (3) are used each in an amount of about 1 to 1.5 mole to 1 mole of the amine (2).
Among the above other processes (d), in case of the process of reacting the carboxylic acid halide with the amine compound (2), the reaction is usually carried out in the presence of a basic compound in an appropriate solvent. The basic compound is any conventional compounds and includes, in addition to the basic compounds used for the above-mentioned Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride. etc. The solvent includes, in addition to the solvents used for the above-mentioned mixed acid anhydride process, alcohols (e.g. methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve, methylcellosolve, etc.), acetonitrile, pyridine, acetone, water, and the like. The amount of the amine compound (2) and the carboxylic acid halide is not critical, but the carboxylic acid halide is usually used at least in equimolar amount, preferably about 1 to 5 moles to 1 mole of the amine compound (2). The reaction is usually carried out at a temperature of from about -20.degree. C. to about 180.degree. C., preferably from about 0.degree. C. to about 150.degree. C., for about 5 minutes to about 30 hours.
The amido bond forming reaction in the above Reaction Scheme-1 may also be carried out by reacting the carboxylic acid compound (3) and the amine (2) in the presence of a condensation agent, i.e. phosphoric compounds such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl phosphorocyanidate, diphenylphosphoric azide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, etc. The reaction is usually carried out in the presence of the solvent and basic compound as used in the above reaction of the carboxylic acid halide and the amine (2) at a temperature of from about -20.degree. C. to about 150.degree. C., preferably about 0.degree. C. to about 100.degree. C., for about 5 minutes to about 30 hours. The condensation agent and the carboxylic acid compound (3) are used at least in equimolar amount, preferably about 1 to 2 moles, to 1 mole of the amine (2). ##STR17## wherein R.sup.1, R.sup.2, R.sup.4 and W are as defined above, R.sup.5a is the same as R.sup.5 as defined above except excluding an anilinocarbonyl having optionally a lower alkyl substituent on the phenyl ring, a phenylsulfonyl having optionally a substituent selected from a halogen atom and a lower alkyl on the phenyl ring and quinolylsulfonyl.
The reaction of the compound (2b) and the compound (4) is carried out in the same manner as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1. ##STR18## wherein R.sup.1, R.sup.2, R.sup.11, R.sup.12 and W are as defined above.
The reaction of the compound (5) and the compound (6) is carried out under the same conditions as used in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1. ##STR19## wherein R.sup.1, R.sup.2, R.sup.5 and W are as defined above, and R.sup.4a is a lower alkyl, R.sup.17 and R.sup.18 are each hydrogen atom or a lower alkyl, and X is a halogen atom.
The reaction of the compound (7) and the compound (8) is usually carried out in an inert solvent in the presence or absence of a basic compound. The inert solvent includes, for example, aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride, etc.), lower alcohols (e.g. methanol, ethanol, isopropanol, butanol, tert-butanol, etc.), acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, etc., or a mixture of these solvents. The basic compound includes, for example, carbonates (e.g. sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, etc.), sodium hydride, potassium, sodium, sodium amide, metal alcoholates (e.g. sodium methoxide, sodium ethoxide, etc.), and organic basic compounds (e.g. pyridine, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo�4.3.0!nonene-(5) (DBN), 1,8-diazabicyclo�5.4.0!undecene-7 (DBU), 1,4-diazabicyclo�2.2.2!octane (DABCO), etc.). The amount of the compound (7) and the compound (8) is not critical, but the compound (8) is usually used at least in equivalent amount, preferably 1 to 10 moles, to 1 mole of the compound (7). The reaction is usually carried out at a temperature of from about 0.degree. C. to about 200.degree. C., preferably from about 0.degree. C. to about 170.degree. C., for about 30 minutes to about 30 hours. In the reaction, an alkali metal halide (e.g. sodium iodide, potassium iodide, etc.) may be added to the reaction system.
The reaction of the compound (7) and the compound (9) is carried out in an appropriate solvent or without solvent in the presence of a reducing agent. The solvent includes, for example, water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), acetonitrile, formic acid, acetic acid, ethers (e.g. dioxane, diethyl ether, diglyme, tetrahydrofuran, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), or a mixture of these solvents. The reducing agent includes, for example, formic acid, fatty acid alkali metal salts (e.g. sodium formate, etc.), hydrogenating reducing agents (e.g. sodium boro hydride, sodium cyanoboro hydride, lithium aluminum hydride, etc.), catalystic reducing agents (e.g. palladium black, palladium-carbon, platinum oxide, platinum black, Raney nickel, etc.).
When formic acid is used as the reducing agent, the reaction is usually carried out at a temperature of from room temperature to about 200.degree. C., preferably about 50.degree. C. to about 150.degree. C., for about 1 to 10 hours. The formic acid is usually used in a large excess amount to the compound (7).
When a hydrogenating reducing agent is used, the reaction is usually carried out at a temperature of about -30.degree. C. to about 100.degree. C., preferably about 0.degree. C. to about 70.degree. C., for about 30 minutes to about 12 hours. The reducing agent is usually used in an amount of 1 to 20 moles, preferably 1 to 6 moles, to 1 mole of the compound (7). When lithium aluminum hydride is used as the reducing agent, it is preferable to use a solvent selected from ethers (e.g. diethyl ether, dioxane, tetrahydrofuran, diglyme, etc.) and aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.).
When a catalytic reducing agent is used, the reaction is usually carried out under atmospheric pressure to about 20 atm., preferably atmospheric pressure to about 10 atm. under hydrogen atmosphere or in the presence of a hydrogen donor (e.g. formic acid, ammonium formate, cyclohexene, hydrazine hydrate, etc.) at a temperature of about -30.degree. C. to about 100.degree. C., preferably about 0.degree. C. to about 60.degree. C., for about 1 to 12 hours. The catalytic reducing agent is usually used in an amount of about 0.1 to 40% by weight, preferably about 1 to 20% by weight, of the amount of the compound (7). The compound (9) is usually used at least in equivalent amount, preferably equivalent to a large excess amount, to the compound (7). ##STR20## wherein R.sup.1, R.sup.2, R.sup.12, R.sup.17, R.sup.18, X and W are as defined above, and R.sup.11a is a lower alkyl. ##STR21## wherein R.sup.1, R.sup.2, R.sup.11, X and W are as defined above, and R.sup.12a is a cycloalkyl.
The reaction of the compound (10) and the compound (11) in the Reaction Scheme-5A and the reaction of the compound (12) and the compound (13) in the Reaction Scheme-5B are carried out in the same manner as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.
Besides, the reaction of the compound (10) and the compound (9) in the Reaction Scheme-5A is carried out in the same manner as in the reaction of the compound (7) and the compound (9) in the above Reaction Scheme-4. ##STR22## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.16, R.sup.6, R.sup.7, X, W, and A are as defined above, l is 0 or an integer of 1 to 3, l' and l" are each an integer of 1 to 3, provided that l+l' and l+l" are each an integer not more than 3. ##STR23## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.16, X, W, A, l, l', and l" are as defined above, and R.sup.19 is a lower alkanoyloxy, R.sup.20 is a lower alkanoyloxy, hydroxy or phthalimido, R.sup.21 is the same as R.sup.19 and R.sup.20, and M is an alkali metal (e.g. potassium, sodium, etc.).
The reaction of the compound (1g) and the compound (14) in the Reaction Scheme-6A and the reaction of the compound (1g) and the compound (15) or (16) in the Reaction Scheme-6B can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. In the reaction, an alkali metal halide (e.g. sodium iodide, potassium iodide, etc.) may be added to the reaction system. ##STR24## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.16, W, l, l', l" and A are as defined above.
The reaction of converting the compound (1j) into the compound (1k) can be carried out by reacting the compound (1j) with hydrazine in an appropriate solvent or by hydrolyzing the compound (1j). The solvent used in the reaction with hydrazine includes water and further the same solvent as used in the reaction of the compound (2b) and the compound (4) in the above Reaction Scheme-2. The reaction is usually carried out at a temperature of from room temperature to about 120.degree. C., preferably about 0.degree. C. to about 100.degree. C., for about 0.5 to 5 hours. Hydrazine is usually used in an amount of at least 1 mole, preferably about 1 to 5 moles, to 1 mole of the compound (1j).
The hydrolysis can be carried out in an appropriate solvent or without solvent in the presence of an acid or a basic compound. The solvent includes, for example, water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g. acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, mineral acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.) and organic acids (e.g. formic acid, acetic acid, aromatic sulfonic acids, etc.). The basic compound includes, for example, metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), and the like. The reaction is usually carried out at a temperature of from room temperature to about 200.degree. C., preferably from room temperature to about 150.degree. C., for about 10 minutes to 25 hours. ##STR25## wherein R.sup.1, R.sup.2, R.sup.4, W, R.sup.16, l, l', l", X, and A are as defined above, and R.sup.22 is a lower alkanoyl.
The reaction of the compound (1l) and the compound (17) is carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the Reaction Scheme-4. In the reaction, an alkali metal halide (e.g. sodium iodide, potassium iodide, etc.) may be added to the reaction system.
The reaction of converting the compound (1m) into the compound (1l) can be carried out under the same condition as in the hydrolysis of the compound (1j) in the Reaction Scheme-7. ##STR26## wherein R.sup.1, R.sup.2, R.sup.4, W, R.sup.16, l, l', l", and X are as defined above, and R.sup.23 is a lower alkyl, a lower alkanoyloxy-substituted lower alkyl, a halogen-substituted lower alkyl, a carboxy-substituted lower alkyl, a carbamoyl-substituted lower alkyl, a hydroxy-substituted lower alkyl, a lower alkoxycarbonyl-substituted lower alkyl, a phthalimido-substituted lower alkyl, an aminocarbonyl-lower alkyl having optionally a lower alkyl substituent, or a group of the formula: ##STR27## (A, R.sup.6 and R.sup.7 are as defined above).
The reaction of the compound (1n) and the compound (18) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. In the reaction, an alkali metal halide (e.g. sodium iodide, potassium iodide, etc.) may be added to the reaction system. ##STR28## wherein R.sup.1, R.sup.2, R.sup.4, W, R.sup.16, R.sup.17, R.sup.18, l, X, and A are as defined above, and R.sup.6' is hydrogen atom, a lower alkyl having optionally a hydroxy substituent, a lower alkanoyl, or benzoyl, R.sup.7a is a lower alkyl having optionally a hydroxy substituent, and R.sup.7b is a lower alkanoyl or benzoyl.
The reaction of the compound (1p) and the compound (19) or the compound (9) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) or the compound (9) in the above Reaction Scheme-4.
The reaction of the compound (1p) and the compound (20) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the Reaction Scheme-1.
Besides, the compound (1r) can also be obtained by reacting the compound (1p) with a compound of the formula: (R.sup.7b).sub.2 O(R.sup.7b is as defined above). The reaction can be carried out in an appropriate solvent or without solvent in the presence or absence, preferably presence, of a basic compound. The solvent includes, for example, the above-mentioned aromatic hydrocarbons, lower alcohols (e.g. methanol, ethanol, propanol, etc.), dimethylformamide, dimethylsulfoxide, and further halogenated hydrocarbons (e.g. chloroform, methylene chloride, etc.), acetone, pyridine, etc. The basic compound includes, for example, tertiary amines (e.g. triethylamine, pyridine, etc.), sodium hydroxide, potassium hydroxide, sodium hydride, and the like. The above reaction can also be carried out in a solvent such as acetic acid or benzoic acid in the presence of a mineral acid (e.g. sulfuric acid, etc.). The acid anhydride is usually used in an equimolar amount or more, preferably 1 to 10 moles, to 1 mole of the starting compound, and the reaction is usually carried out at a temperature of about 0.degree. C. to about 200.degree. C., preferably from about 0.degree. C. to about 150.degree. C., for about 0.5 to 15 hours. ##STR29## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.9, R.sup.10, W, and B are as defined above.
The reaction of the compound (1s) and the compound (21) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1. ##STR30## wherein R.sup.1, R.sup.2, R.sup.4, W, R.sup.9, R.sup.10, X, and B are as defined above.
The reaction of the compound (1u) and the compound (21) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. In the reaction, an alkali metal halide (e.g. sodium iodide, potassium iodide, etc.) may be added to the reaction system. ##STR31## wherein R.sup.1, R.sup.2, R.sup.4, W, and B are as defined above, and R.sup.24 is a lower alkyl.
The reaction of the compound (2b) and the compound (22) can be carried out in an appropriate inert solvent. The inert solvent includes, for example, aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, etc.), lower alcohols (e.g. methanol, ethanol, isopropanol, butanol, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride, etc.), acetic acid, ethyl acetate, acetonitrile, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, and the like. The amount of the compound (2b) and the compound (22) is not critical, but the compound (22) is usually used in an amount of at least one mole, preferably 1 to 2 moles, to 1 mole of the compound (2b). The reaction is usually carried out at a temperature of from about 0.degree. C. to about 150.degree. C., preferably from about 0.degree. C. to about 100.degree. C., for about 30 minutes to about 10 hours.
The esterification of the compound (1w) is usually carried out by reacting the starting compound with an alcohol (e.g. methanol, ethanol, isopropanol, etc.) in the presence of a mineral acid (e.g. hydrochloric acid, sulfuric acid, etc.) and a halogenating agent (e.g. thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, etc.) at a temperature of 0.degree. C. to 150.degree. C., preferably 50.degree. C. to 100.degree. C., for about 1 to 10 hours.
The hydrolysis of the compound (1x) can be carried out under the same conditions as in the hydrolysis of the compound (1j) in the Reaction Scheme-7. ##STR32## wherein R.sup.1, R.sup.2, R.sup.4, W, B, M, and X are as defined above, and R.sup.25 is a phenyl which has optionally 1 to 3 substituents selected from a lower alkyl, a lower alkoxy and an amino having optionally a lower alkanoyl substituent, or naphthyl, and R.sup.25' is a phenoxy which has optionally 1 to 3 substituents selected from a lower alkyl, a lower alkoxy and an amino having optionally a lower alkanoyl substituent, naphthyloxy or phthalimido.
The reaction of the compound (1u) and the compound (23) or (23a) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.
The compound (1y) wherein R.sup.25' is phthalimido can be converted into the compound (1y) wherein R.sup.25' is amino under the same conditions as in the reaction of converting the compound (1j) into the compound (1k) in the above Reaction Scheme-7. ##STR33## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, and R.sup.26 is oxo, R.sup.27 is hydroxy, and W' is the same as W, provided that the substituents on the group --(CH.sub.2).sub.p -- or --CH.dbd.CH--(CH.sub.2).sub.q -- are 0 to 2, and R.sup.28 and R.sup.29 are the same or different and are each hydrogen atom, a lower alkenyl, a cycloalkyl, an oxiranyl-substituted lower alkyl, a lower alkyl having 1 to 2 substituents selected from a lower alkoxy, hydroxy and an amino having optionally a lower alkyl substituent, a phenyl-lower alkyl, a pyridyl-lower alkyl, a cyano-substituted lower alkyl, a lower alkoxycarbonyl-substituted lower alkyl, a carbamoyl-substituted lower alkyl, a carboxy-substituted lower alkyl, a tetrahydropyranyloxy-substituted lower alkyl, a lower alkanoyloxy-substituted lower alkyl, a piperidinyl which has optionally a phenyl-lower alkyl substituent, an aminocarbonyl-lower alkyl having optionally a lower alkyl substituent, or a lower alkyl, or R.sup.28 and R.sup.29 may bind together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen or oxygen atom, which heterocyclic ring may optionally have a substituent selected from a lower alkyl, a phenyl-lower alkyl, or a lower alkanoyl.
The conversion of the compound (1A) into the compound (1B) is carried out by reduction thereof. The reducing reaction is preferably carried out by using a hydrogenating reducing agent (e.g. lithium aluminum hydride, sodium boro hydride, diborane, etc.). The reducing agent is usually used in an amount of at least one mole, preferably 1 to 15 moles, to 1 mole of the starting compound. The reducing reaction is usually carried out in an appropriate solvent, for example, water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, etc.), or a mixture of these solvents, at a temperature of from about -60.degree. C. to about 150.degree. C., preferably about -30.degree. C. to about 100.degree. C., for about 10 minutes to 15 hours. When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, etc.
The reaction of converting the compound (1A) into the compound (1C) is usually carried out in an appropriate solvent or without solvent in the presence or absence of a dehydrating agent. The solvent includes, for example, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), aprotic polar solvents (e.g. dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc.), or a mixture of these solvents. The dehydrating agent includes, for example, conventional drying agent used for dehydrating solvents (e.g. molecular sieves, etc.), mineral acids (e.g. hydrochloric acid, sulfuric acid, borone trifluoride, etc.), organic acids (e.g. p-toluenesulfonic acid, etc.), and the like. The reaction is usually carried out at a temperature of from room temperature to about 250.degree. C., preferably from about 50.degree. C. to about 200.degree. C., for about 1 to 48 hours. The amount of the compound (24) is not critical, but it is usually used at least in an equivalent amount, preferably equimolar to largely excess to the amount of the compound (1A). The dehydrating agent is preferably used in a largely excess amount in case of the drying agent and in a catalytic amount in case of the acid.
The subsequent reducing reaction can be carried out by various methods, for example by catalytically hydrogenating the compound in an appropriate solvent in the presence of a catalyst. The solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, diethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g. dimethylformamide, etc.), or a mixture of these solvents. The catalyst includes, for example, palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel, and the like. The catalyst is usually used in an amount of 0.02 to 1 part by weight to 1 part by weight of the starting compound. The reaction is usually carried out at a temperature of from about -20.degree. C. to about 100.degree. C., preferably about 0.degree. C. to about 70.degree. C., under a hydrogen atmospheric pressure of 1 to 10 atm. for about 0.5 to 20 hours.
Although the reducting reaction can be carried out under the above conditions, it is preferably carried out by using a hydrogenating reducing agent. The hydrogenating reducing agent includes, for example, lithium aluminum hydride, sodium borohydride, diborane, etc., and it is usually used in an amount of at least one mole, preferably 1 to 10 moles, to 1 mole of the compound (1A). The reaction is usually carried out in an appropriate solvent, such as water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, diglyme, etc.), dimethylformamide, or a mixture of these solvents, at a temperature of about -60.degree. C. to about 50.degree. C., preferably about -30.degree. C. to room temperature, for about 10 minutes to about 5 hours. When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran, diglyme, etc.
The compound (1C) wherein at least one of R.sup.28 and R.sup.29 is hydrogen atom can be converted into the compound (1C) wherein at least one of R.sup.28 and R.sup.29 is a lower alkyl by reacting the compound (1C) with the compound (8) or the compound (9) under the same conditions as in the reaction of the compound (7) and the compound (8) or (9) in the above Reaction Scheme-4. ##STR34## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.14, R.sup.15, W', and M are as defined above, and R.sup.31 is a phenyl-lower alkyl, and R.sup.30 is a lower alkoxycarbonyl.
The reaction of converting the compound (1D) into the compound (1E) can be carried out under the same conditions as in the reaction of converting the compound (1A) into the compound (1B) in the above Reaction Scheme-15.
The reaction of converting the compound (1D) into the compound (1F) can be carried out under the same conditions as in the hydrolysis reaction of the compound (1j) in the above Reaction Scheme-7.
The reaction of the compound (1F) and the compound (25) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.
The halogenation of the compound (1F) can be carried out under a conventional condition for halogenation of a carboxylic acid. The reaction of the thus-obtained carboxylic acid halide of the compound (1F) with the compound (26) is carried out in an appropriate solvent in the presence or absence of a basic compound. The solvent includes, for example, halogenated hydrocarbons (e.g. methylene chloride, chloroform, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), alcohols (e.g. methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, etc.), pyridine, acetone, acetonitrile, water, or a mixture of these solvents. The basic compound includes, for example, organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, DBN, DBU, DABCO, etc., inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride, silver carbonate, alcoholates (e.g. sodium methylate, sodium ethylate, etc.), and the like. The compound (26) is usually used in an amount of at least 1 mole, preferably 1 to 1.5 mole, to 1 mole of the carboxylic acid halide of the compound (1F). The reaction is usually carried out at a temperature of from -30.degree. C. to about 180.degree. C., preferably from about 0.degree. C. to about 150.degree. C., for about 5 minutes to 30 hours.
The reaction of the compound (1H) and the compound (27) is carried out in an appropriate solvent or without solvent at a temperature of from about 0.degree. C. to about 200.degree. C., preferably from room temperature to about 150.degree. C. The solvent includes the same solvents as used in the above reaction of the carboxylic acid halide of the compound (1F) and the compound (26). The compound (27) is preferably used in an amount largely excess to the compound (1H). The reaction is usually completed in a reaction time of about 1 to 5 hours.
The reaction of converting the compound (1I) into the compound (1J) can be carried out by reducing the compound. The reducing reaction is usually carried out by catalytically hydrogenating the compound in an appropriate solvent in the presence of a catalyst. The solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, etc.), acetic acid, or a mixture of these solvents. The catalyst includes, for example, palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel, and the like. The catalyst is usually used in an amount of 0.02 to 1 part by weight to 1 part by weight of the starting compound. The reaction is usually carried out at a temperature of from about -20.degree. C. to about 100.degree. C., preferably about 0.degree. C. to about 80.degree. C., under a hydrogen atmospheric pressure of 1 to 10 atm. for about 0.5 to 20 hours. ##STR35## wherein R.sup.1, R.sup.2, R.sup.3, W', l, R.sup.17, R.sup.18, and X are as defined above, and R.sup.14a is hydrogen atom, a lower alkyl, a lower alkanoyl, a lower alkenyl, a cycloalkyl, an oxiranyl-substituted lower alkyl, a lower alkyl having 1 to 2 substituents selected from a lower alkoxy, hydroxy and an amino having optionally a lower alkyl substituent, a phenyl-lower alkyl, a pyridyl-lower alkyl, a lower alkylsulfonyl, benzoyl, a lower alkoxycarbonyl, anilinocarbonyl, an aminocarbonyl having optionally a lower alkyl substituent, a cyano-substituted lower alkyl, a lower alkoxycarbonyl-substituted lower alkyl, a carbamoyl-substituted lower alkyl, a carboxy-substituted lower alkyl, a tetrahydropyranyloxy-substituted lower alkyl, a lower alkanoyloxy-substituted lower alkyl, a piperidinyl having optionally a phenyl-lower alkyl substituent, a halogen-substituted lower alkanoyl, an imiazolyl-substituted lower alkanoyl, an amino-lower alkanoyl having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl, an aminocarbonyl-lower alkyl having optionally a lower alkyl substituent, or a phenyl-lower alkoxycarbonyl, R.sup.15a is a lower alkyl, a cycloalkyl, an oxiranyl-substituted lower alkyl, a lower alkyl having 1 to 2 substituents selected from a lower alkoxy, hydroxy and an amino having optionally a lower alkyl substituent, a phenyl-lower alkyl, a pyridyl-lower alkyl, a lower alkylsulfonyl, a cyano-substituted lower alkyl, a lower alkoxycarbonyl-substituted lower alkyl, a carbamoyl-substituted lower alkyl, a carboxy-substituted lower alkyl, a tetrahydropyranyloxy-substituted lower alkyl, a lower alkanoyloxy-substituted lower alkyl, a piperidinyl having optionally a phenyl-lower alkyl substituent, an aminocarbonyl-lower alkyl having optionally a lower alkyl substituent, or a lower alkenyl, and R.sup.15b is a lower alkanoyl, a phenyl-lower alkoxycarbonyl, benzoyl, a lower alkoxycarbonyl, a halogen-substituted lower alkanoyl, an imidazolyl-substituted lower alkanoyl, or an amino-lower alkanoyl having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl.
The reaction of the compound (1K) and the compound (28) or the compound (9) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) or the compound (9) in the above Reaction Scheme-4.
The reaction of the compound (1K) and th e compound (29) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1. The compound (1M) can also be obtained by reacting the compound (1K) with a compound of the formula (R.sup.15b).sub.2 O (wherein R.sup.15b is as defined above). The reaction can be carried out under the same conditions as in the reaction of the compound (1p) and the compound of the formula: (R.sup.7b).sub.2 O as described hereinbefore.
The compound (1M) wherein R.sup.15b is formyl can also be prepared by reacting the compound (1K) with a formate of the formula: HCOCR.sup.82 (R.sup.82 is a lower alkyl). The reaction is usually carried out in the solvent as used in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4 or without solvent, at a temperature of about 0.degree. C. to about 200.degree. C., preferably about 0.degree. C. to about 170.degree. C., for about 30 minutes to about 30 hours. The formate is preferably used in a largely excess amount to the compound (1K). ##STR36## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.16, W, l, l' and l" are as defined above, and R.sup.32 is a lower alkoxycarbonyl-substituted lower alkoxy, R.sup.33 is a carbamoyl-substituted lower alkoxy, R.sup.34 is a carboxy-substituted lower alkoxy, R.sup.44 is an amino having optionally a lower alkyl substituent, and R.sup.45 is an aminocarbonyl-lower alkoxy having optionally a lower alkyl substituent.
The conversion of the compound (1N) into the compound (10) can be carried out by reacting the compound with aqueous ammonia in an appropriate solvent in an autoclave. The solvent includes the same solvents as used in the reaction of the carboxylic acid halide and the amine (2) in the above Reaction Scheme-1. The aqueous ammonia is used in a largely excess amount to the compound (1N). The reaction proceeds advantageously by adding an ammonium halide (e.g. ammonium chloride, etc.) to the reaction system. The reaction is usually carried out at a temperature of from room temperature to about 200.degree. C., preferably from room temperature to about 150.degree. C., for about 1 to 10 hours.
The reaction of converting the compound (1N) into the compound (1P) can be carried out under the same conditions as in the hydrolysis of the compound (1j) in the above Reaction Scheme-7.
The reaction of the compound (1P) and the compound (30) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1. ##STR37## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.16, W, l, l' and l" are as defined above.
The reducing reaction in the above reaction scheme is usually carried out, for example, (i) with a reducing catalyst in an appropriate solvent or (ii) with a reducing agent such as a mixture of a metal or metal salt with an acid, or a mixture of a metal or metal salt with an alkali metal hydroxide, a sulfide or an ammonium salt in an appropriate inert solvent.
In case of using a reducing catalyst, the solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, etc.), or a mixture of these solvents. The catalyst includes, for example, palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel, and the like. The catalyst is usually used in an amount of 0.02 to 1 part by weight to 1 part by weight of the starting compound. The reaction is usually carried out at a temperature of from about -20.degree. C. to about 150.degree. C., preferably about 0.degree. C. to about 100.degree. C., under a hydrogen pressure of 1 to 10 atm. for about 0.5 to 10 hours. In the reaction, an acid such as hydrochloric acid may optionally added to the reaction system.
In case of the above method (ii), the reducting agent includes a mixture of iron, zinc, tin or stannous chloride and a mineral acid (e.g. hydrochloric acid, sulfuric acid, etc.), or a mixture of iron, ferrous sulfate, zinc or tin and an alkali metal hydroxide (e.g. sodium hydroxide, etc.), a sulfide (e.g. ammonium sulfide, etc.), aqueous ammonia, or an ammonium salt (e.g. ammonium chloride, etc.). The inert solvent includes, for example water, acetic acid, methanol, ethanol, dioxane, and the like. The reducing reaction conditions are determined depending on the kinds of the reducting agent, but in case of using a reducing agent comprising stannous chloride and hydrochloric acid, for example, it is preferably carried out at a temperature of about 0.degree. C. to room temperature for about 0.5 to 10 hours. The reducing agent is usually used in an amount of at least one mole, preferably 1 to 5 moles, to 1 mole of the starting compound. ##STR38## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.16, R.sup.17, R.sup.18, l, l', l" and W are as defined above, and R.sup.36 is a lower alkyl, R.sup.37 is a lower alkanoyl, and R.sup.35 is hydrogen atom, a lower alkyl or a lower alkanoyl.
The reaction of the compound (1S) and the compound (31) or the compound (9) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) or the compound (9) in the above Reaction Scheme-4.
The reaction of the compound (1S) and the compound (32) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1. Besides, the compound (1U) can also be obtained by reacting the compound (1S) with a compound of the formula: (R.sup.37).sub.2 O (R.sup.37 is as defined above). The reaction is carried out under the same conditions as in the above reaction of the compound (1p) and a compound of the formula: (R.sup.7b).sub.2 O.
The compound (1) wherein R.sup.8 is a phenyl-lower alkoxycarbonyl can be converted into the compound (1) wherein R.sup.8 is hydrogen atom in the same manner as in the reaction of converting the compound (1I) into the compound (1J) in the above Reaction Scheme-16.
Other derivatives of the starting compound (2) can be prepared, for example, by the process as shown in the following reaction scheme. ##STR39## wherein R.sup.1, R.sup.2, and W are as defined above.
The reaction of the compound (2) and the compound (33) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.
The reaction of converting the compound (34) into the compound (2a) can be carried out under the same conditions as in the reducing reaction in the above Reaction Scheme-19.
The starting compound (5) can be prepared, for example, by the process of the following reaction scheme. ##STR40## wherein R.sup.1, R.sup.2, and W are as defined above, and R.sup.38 is a lower alkyl.
The reaction of the compound (2) and the compound (35) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.
The reaction of converting the compound (36) into the compound (5) can be carried out under the same conditions as in the hydrolysis reaction in the above Reaction Scheme-7. ##STR41## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.16, l, l', l", X, and W are as defined above, and R.sup.39 is a lower alkanoyl.
The reaction of the compound (1W) and the compound (37) can be carried out under the same conditions as in the reaction of the compound (1n) and the compound (18) in the above Reaction Scheme-9.
The hydrolysis reaction of the compound (1X) can be carried out under the same conditions as in the hydrolysis of the compound (1j) in the above Reaction Scheme-7. ##STR42## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.16, l, l', l", and W are as defined above, R.sup.40 is a lower alkanoyl, and R.sup.41 is a hydroxy-substituted lower alkyl.
The reaction of converting the compound (1Y) into the compound (1Z) can be carried out under the same conditions as in the reaction of converting the compound (1A) into the compound (1B) in the above Reaction Scheme-15. ##STR43## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.16, l, l', l", and W are as defined above, R.sup.42 is a lower alkoxycarbonyl and R.sup.43 is carboxyl.
The reaction of converting the compound (1aa) into the compound (1bb) can be carried out under the same conditions as in the hydrolysis of the compound (1j) in the above Reaction Scheme-7.
The esterification reaction of the compound (1bb) can be carried out under the same conditions as in the esterification of the compound (1w) in the above Reaction Scheme-13. ##STR44## wherein R.sup.1, R.sup.2, R.sup.4, and W are as defined above, and R.sup.46 is a phenyl having optionally a lower alkyl substituent.
The reaction of the compound (2b) and the compound (38) is usually carried out in an appropriate solvent or without solvent in the presence or absence, preferably in the absence, of a basic compound. The solvent and basic compound are the same as those used in the reaction of the carboxylic acid halide and the amine (2) in the above Reaction Scheme-1.
The compound (38) is usually used in an amount of about 1 to 5 moles, preferably about 1 to 3 moles, to 1 mole of the compound (2b). The reaction is usually carried out at a temperature of from about 0.degree. C. to about 200.degree. C., preferably from room temperature to about 150.degree. C., for about 5 minutes to about 30 hours. In the reaction, a boron compound (e.g. boron trifluoride etherate, etc.) may be added to the reaction system. ##STR45## wherein R.sup.1, R.sup.2, R.sup.4, W, and X are as defined above, and R.sup.47 is a phenylsulfonyl which has optionally a substituent selected from a halogen atom and a lower alkyl on the phenyl ring, or quinolylsulfonyl.
The reaction of the compound (2b) and the compound (39) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. ##STR46## wherein R.sup.1, R.sup.2, R.sup.4, W, R.sup.17, R.sup.18, and X are as defined above, R.sup.48 is a phenyl-lower alkoxycarbonyl, a lower alkanoyl, an amino-lower alkanoyl having optionally a lower alkyl substituent, and R.sup.49 is a lower alkyl or a carbamoyl-lower alkyl.
The reaction of the compound (1ee) and the compound (40) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.
The reaction of the compound (1ee) and the compound (41) or the compound (9) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) or the compound (9) in the above Reaction Scheme-4, provided that in the reaction product (1ff) produced by the reaction of the compound (1ee) and the compound (9), the group R.sup.49 is a lower alkyl. ##STR47## wherein R.sup.1, R.sup.2, R.sup.5, and W are as defined above, and R.sup.50 is a benzoyl having optionally a halogen substituent on the phenyl ring.
The reaction of the compound (7) and the compound (42) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1. ##STR48## wherein R.sup.1, W', R.sup.26, R.sup.2, and R.sup.3 are as defined above, R.sup.103 is hydroxy or sulfoxy, and R.sup.51 is hydroxyimino or sulfoxyimino.
The reaction of the compound (1A) and the compound (43) is usually carried out in an appropriate inert solvent in the presence or absence of a basic compound. The basic compound includes, for example, inorganic basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., and organic basic compounds such as piperidine, pyridine, triethylamine, 1,5-diazabicyclo�4.3.0!nonene-5 (DBN), 1,8-diazabicyclo�5.4.0!undecene-7 (DBU), 1,4-diazabicyclo�2.2.2!octane (DABCO), etc. The inert solvent includes, for example, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, ethylene glycol monomethyl ether, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc., or a mixture of these solvents. The compound (43) is usually used at least in equivalent amount, preferably 1 to 5 moles, to 1 mole of the compound (1A). The reaction is usually carried out at a temperature of from room temperature to about 200.degree. C., preferably from about 50.degree. C. to 150.degree. C., for about 1 to 10 hours. ##STR49## wherein R.sup.1, W', R.sup.27, R.sup.2, M, and R.sup.3 are as defined above, and R.sup.52 is a halogen atom.
The halogenation of the compound (1B) is usually carried out in an appropriate solvent or without solvent by reacting the compound (1B) with a halogenating agent.
The halogenating agent includes mineral acids (e.g. hydrochloric acid, hydrobromic acid, etc.), N,N-diethyl-1,2,2-trichlorovinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, methanesulfonyl chloride, or a combination of a phenyl-lower alkyl halide (e.g. p-toluenesulfonyl chloride, etc.) and a basic compound. The basic compound includes the same compounds as used in the reaction of the compound (1A) and the compound (43) in the above Reaction Scheme-30. The solvent includes, for example, ethers (e.g. dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g. chloroform, methylene chloride, carbon tetrachloride, etc.), and the like. The amount of the halogenating agent may vary depending on the kinds of the halogenating agents, and in case of a combination of a phenyl-lower alkyl halide (e.g. p-toluenesulfonyl chloride, etc.) and a basic compound, it is used in an amount of at least 1 mole, preferably 1 to 2 moles, to 1 mole of the compound (1B), and in case of other halogenating agents, it is used at least in an equimolar amount, usually in a largely excess amount, to the compound (1B). The reaction is usually carried out at a temperature of from room temperature to about 150.degree. C., preferably from room temperature to about 80.degree. C., for about 1 to 80 hours.
The reaction of the compound (1jj) and the compound (44) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.
The reducing reaction of the compound (1kk) can be carried out under the same conditions as in the reducing reaction using a reducing catalyst for converting the compound (1A) into the compound (1C) in the above Reaction Scheme-15. ##STR50## wherein R.sup.1, W', R.sup.2, R.sup.3, R.sup.27, X, and A are as defined above, R.sup.53 is a lower alkanoyloxy having optionally a halogen substituent, R.sup.54 is a lower alkoxy, an amino-lower alkanoyloxy having optionally a lower alkyl substituent, or a group of the formula: ##STR51## (A, R.sup.82 and R.sup.83 are as defined above), R.sup.55 is a lower alkoxycarbonyl-substituted lower alkoxy, R.sup.56 is a carboxy-substituted lower alkoxy, R.sup.57 is an aminocarbonyl-lower alkoxy having optionally a lower alkyl substituent, R.sup.54a is a lower alkyl, an amino-lower alkanoyl having optionally a lower alkyl substituent, or a group of the formula: ##STR52## (A, R.sup.82 and R.sup.83 are as defined above), R.sup.55a is a lower alkoxycarbonyl-substituted lower alkyl, R.sup.58 and R.sup.59 are the same or different and are each hydrogen atom or a lower alkyl, and R.sup.22a is a lower alkanoyl having optionally a halogen substituent. ##STR53## wherein R.sup.1, W', R.sup.2, R.sup.3, X, R.sup.27, and A are as defined above, and R.sup.61 and R.sup.62 are the same or different and are each hydrogen atom, a lower alkyl or a lower alkanoyl.
The reaction of the compound (1B) and the compound (45) or the compound (46) in the Reaction Scheme-32A can be carried out under the same conditions as in the reaction of the compound (1n) and the compound (18) in the above Reaction Scheme-9.
The reaction of the compound (1B) and the compound (47) and the reaction of the compound (1B) and the compound (48) can be carried out under the same conditions as in the reaction of the compound (1n) and the compound (18) in the above Reaction Scheme-9.
The reaction of converting the compound (1oo) into the compound (1pp) can be carried out under the same conditions as in the hydrolysis reaction of the compound (1j) in the above Reaction Scheme-7.
The reaction of the compound (1oo) and the compound (49) and the reaction of the compound (1pp) and the compound (49) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.
The reaction of the compound (1B) and the compound (49a) in the Reaction Scheme-32B can be carried out under the same conditions as in the reaction of the compound (1n) and the compound (18) in the above Reaction Scheme-9. ##STR54## wherein R.sup.1, W', R.sup.2, R.sup.3, R.sup.27, R.sup.61, R.sup.62, M, and X are as defined above, R.sup.60 is a halogen-substituted lower alkyl, R.sup.64 is a phthalimido-substituted lower alkyl, R.sup.63 is an amino-lower alkoxy having optionally a substituent selected from a lower alkyl and a lower alkanoyl, or a phthalimido-substituted lower alkoxy, and R.sup.65 is an amino-substituted lower alkyl.
The reaction of the compound (1B) and the compound (50) and the reaction of the compound (1B) and the compound (52) can be carried out under the same conditions as in the reaction of the compound (1n) and the compound (18) in the above Reaction Scheme-9.
The reaction of the compound (1rr) and the compound (51) or the compound (23a) can be carried out under the same conditions as in the reaction of the compound (19) and the compound (14) in the above Reaction Scheme-6.
The reaction of converting the compound (1tt) into the compound (1uu) can be carried out under the same conditions as in the reaction of converting the compound (1j) into the compound (1k) in the above Reaction Scheme-7. ##STR55## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.61, W', A, R.sup.17, R.sup.18, and X are as defined above, R.sup.62a is a lower alkyl, and R.sup.62b is a lower alkanoyl.
The reaction of the compound (1vv) and the compound (53) or the compound (9) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) or the compound (9) in the above Reaction Scheme-4.
The reaction of the compound (1vv) and the compound (54) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.
The reaction of the compound (1vv) and the compound (55) can be carried out under the same conditions as in the reaction of the compound (1p) and the compound of the formula: (R.sup.7b).sub.2 O in the above Reaction Scheme-10. ##STR56## wherein R.sup.1, R.sup.2, R.sup.3, and W' are as defined above, R.sup.58' and R.sup.59' are the same or different and are each hydrogen atom, a lower alkyl, or a lower alkanoyl.
The reaction of converting the compound (1yy) into the compound (1zz) is usually carried out by reducing the compound (1yy).
The reducting reaction is preferably carried out by using a hydrogenating reducing agent. The hydrogenating reducing agent includes, for example, lithium aluminum hydride, sodium boro hydride, diborane, etc. The reducing agent is usually used in an amount of at least one mole, preferably 1 to 15 moles, to 1 mole of the starting compound. The reducing reaction is usually carried out in an appropriate solvent, such as water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, etc.), or a mixture of these solvents, at a temperature of about -60.degree. C. to about 150.degree. C., preferably about -30.degree. C. to 100.degree. C., for about 10 minutes to about 5 hours. When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran, diglyme, etc. ##STR57## wherein R.sup.1, W', R.sup.2, R.sup.3, R.sup.62a, R.sup.62b, X, R.sup.17, R.sup.18, and A are as defined above, R.sup.58a is hydrogen atom, a lower alkyl or a lower alkanoyl.
The reaction of the compound (1AA) and the compound (53) or the compound (9) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) or the compound (9) in the above Reaction Scheme-4.
The reaction of the compound (1AA) and the compound (54) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.
The reaction of the compound (1AA) and the compound (55) can be carried out under the same conditions as in the reaction of the compound (1p) and the compound of the formula: (R.sup.7b).sub.2 O in the above Reaction Scheme-10.
The compound (1BB) wherein R.sup.62b is formyl can also be prepared by reacting the compound (1AA) with a formate of the formula: HCOOR.sup.82 under the same conditions as in the reaction of the compound (1K) and the compound of the formula: HCOOR.sup.82 as described hereinbefore.
The compounds of the formula (1) wherein W is sulfur atom or sulfinyl, or R.sup.82 and R.sup.83 bind together with the nitrogen atom to which they bond to form thiomorpholino or 1-oxo-thiomorpholino can be converted into the corresponding compounds of the formula (1) wherein W is sulfinyl or sulfonyl, or R.sup.82 and R.sup.83 bind together with the nitrogen atom to which they bond to form 1-oxo-thiomorpholino or 1,1-dioxo-thiomorpholino, respectively, by oxidation thereof.
The oxidation reaction is carried out in an appropriate solvent in the presence of an oxidizing agent. The solvent includes, for example, water, organic acids (e.g. formic acid, acetic acid, trifluoroacetic acid, etc.), alcohols (e.g. methanol, ethanol, etc.), halogenated hydrocarbons (e.g. chloroform, dichloromethane, etc.), or a mixture of these solvents. The oxidizing agent includes, for example, peracids (e.g. performic acid, peracetic acid, trifluoro-peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, o-carboxy-perbenzoic acid, etc.), hydrogen peroxide, sodium metaperiodate, dichromic acid, dichromates (e.g. sodium dichromate, potassium dichromate, etc.), permanganic acid, permanganates (e.g. potassium permanganate, sodium permanganate, etc.), lead salts (e.g. lead tetraacetate, etc.), and the like. The oxidizing agent is usually used in an amount of at least 1 mole, preferably 1 to 2 moles, to 1 mole of the starting compound. Besides, in cases of the oxidation of converting the sulfur atom into sulfonyl group, the oxidizing agent is usually used at least 2 moles, preferably 2 to 4 moles, to 1 mole of the starting compound. The above reaction is usually carried out at a temperature of about -10.degree. C. to about 40.degree. C., preferably from about -10.degree. C. to room temperature, for about 1 to 100 hours.
The compound (1) wherein R.sup.16 or R.sup.2 is a lower alkoxy can be converted into the correspond compound (1) wherein R.sup.16 or R.sup.2 is hydroxy by heating the compound in a mixture of an acid (e.g. hydrobromic acid, hydrochloric acid, etc.) and a solvent (e.g. water, methanol, ethanol, isopropyl alcohol, etc.) at 30.degree. to 150.degree. C., preferably at 50.degree. to 120.degree. C.
Besides, the compound (1) wherein R.sup.16 or R.sup.2 is hydroxy can also be prepared by hydrolysis of the above compound (1) wherein R.sup.16 or R.sup.2 is a lower alkoxy. The hydrolysis can be carried out in an appropriate solvent in the presence of an acid. The solvent includes, for example, water, lower alcohols (e.g. methanol, ethanol, isopropyl alcohol, etc.), ethers (e.g. dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride, etc.), polar solvents (e.g. acetonitrile, etc.), or a mixture of these solvents. The acid includes, for example, mineral acids (e.g. hydrochloric acid, hydrobromic acid, etc.), Lewis acids (e.g. boron trifluoride, aluminum chloride, boron tribromide, etc.), iodides (e.g. sodium iodide, potassium iodide, etc.), or a mixture of the above Lewis acid and iodide. The reaction is usually carried out at a temperature of from room temperature to about 150.degree. C., preferably from room temperature to about 100 C., for about 0.5 to 30 hours. ##STR58## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.62b, and W' are as defined above, R.sup.51a is hydroxyimino, and R.sup.66 is a lower alkanoyloxyimino.
The reaction of the compound (1ii') and the compound (54) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.
The reaction of the compound (1ii') and the compound (55) can be carried out under the same conditions as in the reaction of the compound (1p) and the compound of the formula: (R.sup.7b).sub.2 O in the above Reaction Scheme-10. ##STR59## wherein R.sup.1, R.sup.2, R.sup.3, W', R.sup.26, R.sup.14, R.sup.15, R.sup.62b, X and M are as defined above, R.sup.67 is methylidene, R.sup.68 is a group of the formula: ##STR60## and R.sup.69 is a group of the formula: ##STR61## (R.sup.14 and R.sup.15 are as defined above), or ##STR62## (R.sup.7D is an amino having optionally a substituent selected from a lower alkyl and a lower alkanoyl, R.sup.70 is a lower alkylsulfonyl, and W" is the same as the above W, provided that the number of the substituent in the groups --(CH.sub.2).sub.p -- and --CH.dbd.CH--(CH.sub.2).sub.q -- is 0 or 1.
The reaction of converting the compound (1A) into the compound (1EE) is carried out in an appropriate solvent in the presence of a Wittig reagent and a basic compound. The Wittig reagent includes, for example, a phosphoric compound of the formula:
�(R.sup.71).sub.3 P.sup.+ --CH.sub.2 --R.sup.72 !X.sup.- (A)
wherein R.sup.71 is phenyl, R.sup.72 is hydrogen atom or a lower alkyl, and X is a halogen atom. The basic compound includes inorganic bases (e.g. metallic sodium, metallic potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.), metal alcoholates (e.g. sodium methylate, sodium ethylate, potassium t-butoxide, etc.), alkyl or aryl lithiums or lithium amides (e.g. methyl lithium, n-butyl lithium, phenyl lithium, lithium diisopropylamide, etc.), organic bases (e.g. pyridine, piperidine, quinoline, triethylamine, N,N-dimethylaniline, etc.). The solvent includes any solvent which does not affect on the reaction, for example, ethers (e.g. diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g. n-hexane, heptane, cyclohexane, etc.), amines (e.g. pyridine, N,N-dimethylaniline, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), alcohols (e.g. methanol, ethanol, isopropanol, etc.), and the like. The reaction is usually carried out at a temperature of about -80.degree. C. to about 150.degree. C., preferably about -80.degree. C. to about 120.degree. C., for about 0.5 to 15 hours.
The reaction of converting the compound (1EE) into the compound (1LL) can be carried out under the same conditions as in the catalytically hydrogenation reaction for converting the compound (1A) into the compound (1C) in the above Reaction Scheme-15.
The reaction of converting the compound (1EE) into the compound (1FF) is carried out under the same conditions as in the reaction of converting the compound (1) wherein W is sulfur atom or sulfinyl into the corresponding compound (1) wherein W is sulfinyl or sulfonyl respectively as described herebefore.
The reaction of the compound (1FF) and the compound (25) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.
The reaction of converting the compound (1EE) into the compound (1E) can be carried out by firstly subjecting it to hydroboration reaction and then to oxidation.
The hydroboration reaction is carried out in a solvent such as ethers (e.g. diethyl ether, tetrahydrofuran, dioxane, etc.) in the presence of a hydroborating agent at a temperature of from about 0.degree. C. to about 50.degree. C., preferably about 0.degree. C. to room temperature, for about 1 to 10 hours. The hydroborating agent includes boron hydride compounds, for example, BH.sub.3.tetrahydrofuran, BH.sub.3.S(CH.sub.3).sub.2, BH.sub.2 Cl, (CH.sub.3).sub.2 CHC(CH.sub.3).sub.2 BH.sub.2, (CH.sub.3).sub.2 CHCH(CH.sub.3)BH, ##STR63## and the like.
The subsequent oxidation is carried out in water in the presence of an oxidizing agent. The oxidizing agent includes, for example, alkaline hydrogen peroxides (e.g. hydrogen peroxide--sodium hydroxide, etc.), and air oxidation is also used. The reaction is usually carried out at a temperature of from room temperature to about 150.degree. C., preferably from room temperature to about 100.degree. C., for 0.5 to 7 hours.
The hydroborating agent and the oxidizing agent are each used in an amount of at least 1 mole, preferably 1 to 2 mole, to 1 mole of the compound (1EE).
The reaction of the compound (1E) and the compound (54) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.
The reaction of the compound (1E) and the compound (55) can be carried out under the same conditions as in the reaction of the compound (1p) and the compound of the formula: (R.sup.7b).sub.2 O in the above Reaction Scheme-10.
The reaction of the compound (1E) and the compound (56) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.
The reaction of the compound (1HH) and the compound (44) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.
The reducing reaction of the compound (1JJ) can be carried out under the same conditions as in the catalytic hydrogenation reaction for converting the compound (1A) into the compound (1C) in the above Reaction Scheme-15.
The reaction of converting the compound (1EE) into the compound (1MM) can be carried out by reacting with an oxidizing agent in an appropriate solvent in the presence of a co-oxidizing agent.
The solvent used for the reaction with an oxidizing agent includes, for example, pyridine, ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), esters (e.g. ethyl acetate, etc.), water, alcohols (e.g. methanol, ethanol, isopropanol, t-butanole, etc.), or a mixture of these solvents. The co-oxidizing agent includes, for example, organic amine N-oxides (e.g. pyridine N-oxide, N-ethyldiisopropylamine N-oxide, N-methylmorpholine N-oxide, trimethylamine N-oxide, triethylamine N-oxide, etc.). The oxidizing agent includes, for example, osmium tetraoxide, and the like. The oxidizing agent is usually used in an amount of at least 1 mole, preferably 1 to 5 moles, to 1 mole of the starting compound. The reaction is usually carried out at a temperature of from -20.degree. C. to 150.degree. C., preferably from room temperature to 100.degree. C., for about 1 to 10 hours. ##STR64## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.27, W', M, and X are as defined above, R.sup.73 is an aminocarbonyl having optionally a lower alkyl substituent, R.sup.74 is an aminocarbonyloxy having optionally a lower alkyl substituent, R.sup.74' is a lower alkyl.
The reaction of the compound (1A) and the compound (57) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.
The reaction of the compound (1A) and the compound (59) is carried out in an appropriate solvent in the presence of an acid. The solvent includes the same solvent as used in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. The acid includes, for example, mineral acids (e.g. hydrochloride acid, sulfuric acid, etc.), sulfonic acids (e.g. methanesulfonic acid, p-toluenesulfonic acid, etc.), alkanoic acids (e.g. trifluoroacetic acid, etc.), and the like. The compound (59) is used in an amount of at least 1 mole, preferably 1 to 5 moles, to 1 mole of the compound (1A). The reaction is usually carried out at a temperature of from room temperature to about 150.degree. C., preferably from room temperature to about 100.degree. C., for about 1 to 7 hours.
The reaction of the compound (1A) and the compound (58) can be carried out under the same conditions as in the reaction of the compound (2b) and the compound (38) in the above Reaction Scheme-26. ##STR65## wherein R.sup.1, R.sup.2, R.sup.3, X, and q are as defined above, and R.sup.75, R.sup.76 and R.sup.77 are each a lower alkyl, and the carbon atom in the formula: --(CH.sub.2).sub.q -- may be substituted by oxygen atom, sulfur atom, sulfinyl, sulfonyl, or a group of the formula: ##STR66## (R.sup.13 is as defined above), and further the group: --(CH.sub.2).sub.q -- may optionally have 1 to 3 substituents selected from a lower alkyl having optionally a hydroxy substituent, a lower alkoxycarbonyl, carboxyl, hydroxy, oxo, a lower alkanoyloxy having optionally a halogen substituent, an amino-lower alkyl having optionally a substituent selected from a lower alkyl and a lower alkanoyl, a lower alkanoyloxy-substituted lower alkyl, a lower alkylsulfonyloxy-lower alkyl, an azido-lower alkyl, a group of the formula: ##STR67## an aminocarbonyloxy having optionally a lower alkyl substituent, a lower alkoxy, a lower alkoxycarbonyl-substituted lower alkoxy, a carboxy-substituted lower alkoxy, an aminocarbonyl-lower alkoxy having optionally a lower alkyl substituent, an amino-lower-alkoxy having optionally a substituent selected from a lower alkyl and a lower alkanoyl, a phthalimido-substituted lower alkoxy, hydroxyimino, a lower alkanoyloxyimino, a lower alkylidene, a halogen atom, azido, sulfoxyimino, a group of the formula: ##STR68## (R.sup.81 is hydrogen atom or a lower alkyl), hydrazino, pyrrolyl, an amino-lower alkanoyloxy having optionally a lower alkyl substituent, a group of the formula: ##STR69## (A is as defined above, and R.sup.82 and R.sup.83 are the same or different and are each hydrogen atom, a lower alkyl, a carbamoyl-substituted lower alkyl, a hydroxy-substituted lower alkyl, or a pyridyl-lower alkyl, or R.sup.82 and R.sup.83 may bind together with nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen, oxygen or sulfur atom wherein the heterocyclic group has optionally a substituent selected from oxo, a lower alkyl, a lower alkanoyl, and carbamoyl), and a group of the formula: ##STR70## (n is as defined above, and R.sup.14 and R.sup.15 are the same or different and are each hydrogen atom, a lower alkyl, a lower alkenyl, a lower alkanoyl, a cycloalkyl, an oxiranyl-substituted lower alkyl, a lower alkyl having 1 to 2 substituents selected from a lower alkoxy, hydroxy and an amino having optionally a lower alkyl substituent, a phenyl-lower alkyl, a pyridyl-lower alkyl, a lower alkylsulfonyl, benzoyl, a lower alkoxycarbonyl, anilinocarbonyl, an aminocarbonyl having optionally a lower alkyl substituent, a cyano-substituted lower alkyl, a lower alkoxycarbonyl-substituted lower alkyl, a carbamoyl-substituted lower alkyl, a carboxy-substituted lower alkyl, a tetrahydropyranyloxy-substituted lower alkyl, a lower alkanoyloxy-substituted lower alkyl, a piperidinyl having optionally a phenyl-lower alkyl substituent on the piperidinyl ring, a halogen-substituted lower alkanoyl, an imidazolyl-substituted lower alkanoyl, an amino-lower alkanoyl having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl, an aminocarbonyl-lower alkyl having optionally a lower alkyl substituent, or a phenyl-lower alkoxycarbonyl, or R.sup.14 and R.sup.15 may bind together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen or oxygen atom, which heterocyclic group may optionally have a substituent selected from a lower alkyl, a phenyl-lower alkyl and a lower alkanoyl.
The reaction of the compound (100) and the compound (60) is carried out in an appropriate solvent in an autoclave. The solvent includes any solvent as used in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. The reaction is usually carried out at a temperature of from room temperature to about 200.degree. C., preferably from room temperature to about 150.degree. C., for about 1 to 7 hours.
The subsequent deamination reaction is carried out in an appropriate solvent in the presence of a basic compound. The solvent includes the same solvent as used in the above reaction of the compound (100) and the compound (60). The basic compound includes any basic compound as used in the reaction of converting the compound (1A) into the compound (1EE) in the above Reaction Scheme-38. The reaction is usually carried out at a temperature of from room temperature to about 150.degree. C., preferably from room temperature to about 100.degree. C., for about 1 to 10 hours. ##STR71## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.14, M, and W' are as defined above, R.sup.78 is an oxiranyl-substituted lower alkyl, R.sup.79 is a lower alkoxy, or an amino having optionally a lower alkyl substituent, and R.sup.80 is a lower alkyl having 2 substituents selected from hydroxy, a lower alkoxy, and an amino having optionally a lower alkyl substituent.
The reaction of the compound (1QQ) and the compound (61) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.
The reaction of the compound (1QQ) and the compound (62) can be carried out by firstly reacting them in trifluoroacetic acid at a temperature of about 0.degree. C. to about 100.degree. C., preferably about 0.degree. C. to about 50.degree. C., for about 1 to 7 hours, followed by hydrolysis of the resultant.
The hydrolysis is carried out in an appropriate solvent or without solvent in the presence of an acid or a basic compound. The solvent includes, for example, water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g. acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, mineral acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acids (e.g. formic acid, acetic acid, aromatic sulfonic acid, etc.), and the like. The basic compound includes, for example, metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.). The reaction is usually carried out at a temperature of from room temperature to about 200.degree. C., preferably from room temperature to about 150.degree. C., for about 0.5 to 25 hours. ##STR72## wherein R.sup.1, R.sup.2, R.sup.3, and W' are as defined above, and R.sup.81 is hydroxyimino or a lower alkanoyloxyimino.
The reaction of converting the compound (1SS) into the compound (1ll) is carried out by catalytically hydrogenating the compound (1SS) in an appropriate solvent in the presence of a catalyst. The solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.,), ethers (e.g. diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, diethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g. dimethylformamide, etc.), or a mixture of these solvents. The catalyst includes, for example, palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromate, Raney nickel, and the like. The catalyst is usually used in an amount of 0.02 to 1 part by weight to 1 part by weight of the compound (1SS). The reaction is usually carried out at a temperature of from about -20.degree. C. to about 100.degree. C., preferably about 0.degree. C. to about 70.degree. C., under a hydrogen atmospheric pressure of 1 to 10 atm. for about 0.5 to 20 hours.
Alternatively, the reducing reaction can also be carried out by using a hydrogenating reducing agent. The hydrogenating reducing agent includes, for example, lithium aluminum hydride, sodium boro hydride, diborane, etc. The reducing agent is usually used in an amount of at least one mole, preferably 1 to 10 moles, to 1 mole of the compound (1SS). The reaction is usually carried out in an appropriate solvent, such as water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, diglyme, etc.), acetic acid, and the like, at a temperature of about 0.degree. C. to about 200.degree. C., preferably about 0.degree. C. to 170.degree. C., for about 10 minutes to about 10 hours. When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran, diglyme, etc. ##STR73## wherein R.sup.1, R.sup.2, R.sup.3, W', l, R.sup.14a are as defined above, and R.sup.83 is phenyl or a lower alkyl.
The reaction of the compound (1K) and the compound (63) can be carried out under the same conditions as in the reaction of the compound (2b) and the compound (38) in the above Reaction Scheme-26. ##STR74## wherein R.sup.1, R.sup.2, R.sup.3, W', l, R.sup.14a are as defined above.
The reaction of the compound (1K) and the glyconitrile (64) can be carried out in an appropriate solvent. The solvent includes the same solvent as used in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. The reaction is usually carried out at a temperature of from about 0.degree. C. to about 150.degree. C., preferably about 0.degree. C. to about 100.degree. C., for about 1 to 10 hours. The glyconitrile (64) is used in an amount of at least 1 mole, preferably 1 to 2 moles, to 1 mole of the compound (1K). ##STR75## wherein R.sup.1, R.sup.2, R.sup.3, W', l, R.sup.14a are as defined above, R.sup.84 is a lower alkoxycarbonyl-substituted lower alkyl, R.sup.85 is an amino having optionally a lower alkyl substituent, R.sup.86 is an aminocarbonyl-lower alkyl having optionally a lower alkyl substituent, and R.sup.87 is a carboxy-substituted lower alkyl.
The reaction of the compound (1VV) and the compound (65) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.
The hydrolysis reaction of the compound (1VV) can be carried out under the same conditions as in the hydrolysis reaction of the compound (1QQ) and the compound (62) in the above Reaction Scheme-41. ##STR76## wherein R.sup.1, R.sup.2, R.sup.3, W', l, X, and R.sup.14a are as defined above, R.sup.88 is a tetrahydropyranyloxy-substituted lower alkyl, R.sup.89 is a lower alkanoyloxy-substituted lower alkyl, R.sup.90 is a hydroxy-substituted lower alkyl, and R.sup.91 is a lower alkanoyl.
The reaction of the compound (1YY) and the compound (66) can be carried out in a solvent such as acetic acid at a temperature of about 0.degree. C. to about 200.degree. C., preferably about 0.degree. C. to about 150.degree. C., for about 0.5 to 15 hours.
The hydrolysis reaction of the compound (1YY) can be carried out under the same conditions as in the hydrolysis reaction of the compound (1QQ) and the compound (62) in the above Reaction Scheme-41, wherein a pyridinium salt (e.g. pyridinium p-toluenesulfonate, etc.) may be used as the acid. ##STR77## wherein R.sup.1, R.sup.2, R.sup.3, W', and R.sup.26 are as defined above.
The reaction of converting the compound (1A) into the compound (1bbb) can be carried out under the same conditions as in the reaction of converting the compound (1A) into the compound (1C) in the above Reaction Scheme-15. ##STR78## wherein R.sup.1, R.sup.2, R.sup.3 and W' are as defined above, R.sup.92 and R.sup.93 are each a lower alkoxy.
The reaction of the compound (1ll) and the compound (68) is carried out in an appropriate solvent in the presence of an acid. The solvent includes, for example, water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g. acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, mineral acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acids (e.g. formic acid, acetic acid, aromatic sulfonic acids, etc.). The reaction is usually carried out at a temperature of from room temperature to about 200.degree. C., preferably from room temperature to about 150.degree. C., for about 0.5 to 5 hours. The compound (68) is usually used in an amount of at least 1 mole, preferably 1 to 2 moles, to 1 mole of the compound (1ll). ##STR79## wherein R.sup.1, R.sup.2, R.sup.3, W', and R.sup.14a are as defined above, R.sup.94 is a halogen-substituted lower alkanoyl, R.sup.95 is an imidazolyl-substituted lower alkanoyl or an amino-lower alkanoyl having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl, and R.sup.96 is imidazolyl, or an amino having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl.
The reaction of the compound (1ddd) and the compound (69) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. ##STR80## wherein R.sup.1, R.sup.2, R.sup.3, and W' are as defined above, R.sup.97 is a lower alkanoyloxy having a halogen substituent, R.sup.98 is an amino having optionally a lower alkyl substituent, and R.sup.99 is an amino-lower alkanoyloxy having optionally a lower alkyl substituent.
The reaction of the compound (1fff) and the compound (70) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. ##STR81## wherein R.sup.1, R.sup.2, R.sup.3, W', R.sup.82, and R.sup.83 are as defined above, R.sup.100 is a carboxy-substituted lower alkoxy, and R.sup.101 is a group of the formula: ##STR82## (A, R.sup.82 and R.sup.83 are as defined above).
The reaction of the compound (1hhh) and the compound (71) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1. ##STR83## wherein R.sup.1, R.sup.2, R.sup.3, W", X, and R.sup.82 are as defined above, and R.sup.102 is hydrogen atom or a lower alkyl, provided that in the compound (1jjj), the groups of the formulae: --NH--R.sup.102 and --OH are substituted at the positions adjacent each other.
The reaction of the compound (1jjj) and the compound (72) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. ##STR84## wherein R.sup.1, R.sup.2, R.sup.3, W', R.sup.26 and X are as defined above, and R.sup.104 is a lower alkyl.
The reaction of the compound (1A) and the compound (73) can be carried out in an appropriate solvent. The solvent includes, for example, ethers (diethyl ether, dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), saturated hydrocarbons (e.g. pentane, hexane, heptane, cyclohexane, etc.), or a mixture of these solvents. The reaction is usually carried out at a temperature of from about -70.degree. C. to about 50.degree. C., preferably from about -30.degree. C. to room temperature, for about 1 to 6 hours. The compound (73) is used in an amount of at least 1 mole, preferably 1 to 5 moles, to 1 mole of the compound (1A). ##STR85## wherein R.sup.1, R.sup.2, R.sup.3, W', R.sup.58', R.sup.59', and A are as defined above, and R.sup.105 is a lower alkylsulfonyloxy.
The reaction of the compound (1mmm) and the compound (74) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.
Among the active compounds (1) of this invention, the compounds having an acidic group can easily be converted into salts by treating with a pharmaceutically acceptable basic compound. The basic compound includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, etc., alkali metal carbonates or hydrogen carbonates such as sodium carbonate, sodium hydrogen carbonate, etc., alkali metal alcoholates such as sodium methylate, potassium ethylate, etc. Besides, among the active compounds (1) of this invention, the compounds having a basic group can easily be converted into acid addition salts thereof by treating with a pharmaceutically acceptable acid. The acid includes, for example, inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, etc., and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, benzoic acid, etc. These salts are useful as an active ingredient as like as the compounds (1) in the free form.
In addition, the compounds (1) of this invention include stereoisomers and optical isomers, and these isomers are also useful as the active ingredient in this invention.
The compounds of this invention thus obtained can easily be isolated and purified by conventional isolation methods. The isolation methods are, for example, distillation method, recrystallization method, column chromatography, ion exchange chromatography, gel chromatography, affinity chromtography, preparative thin layer chromatography, extraction with a solvent, and the like.
The compounds and their salts of this invention are useful as a vasopressin antagonist and are used in the form of a conventional pharmaceutical preparation. The preparation is prepared by using conventional dilutents or carriers such as fillers, thickening agents, binders, wetting agents, disintegrators, surfactants, lubricants, and the like. The pharmaceutical preparations may be selected from various forms in accordance with the desired utilities, and the representative forms are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), and the like. In order to form in tablets, there are used carriers such as vehicles (e.g. lactose, white sugar, sodium chloride, glucose, urea, starches, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.), binders (e.g. water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrators (e.g. dry starch, sodium arginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, etc.), disintegration inhibitors (e.g. white sugar, stearin, cacao butter, hydrogenated oils, etc.), absorption promoters (e.g. quaternary ammonium base, sodium laurylsulfate, etc.), wetting agents (e.g. glycerin, starches, etc.), adsorbents (e.g. starches, lactose, kaolin, bentonite, colloidal silicates, etc.), lubricants (e.g. purified talc, stearates, boric acid powder, polyethylene glycol, etc.), and the like. Moreover, the tablets may also be in the form of a conventional coated tablet, such as sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film coating tablets, or double or multiple layer tablets. In the preparation of pills, the carriers include vehicles (e.g. glucose, lactose, starches, cacao butter, hydrogenated vegetable oils, kaolin, talc, etc.), binders (e.g. gum arabic powder, tragacanth powder, gelatin, ethanol, etc.), disintegrators (e.g. laminaran, agar, etc.), and the like. In the preparation of suppositories, the carriers include, for example, polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides, and the like. Capsules can be prepared by charging a mixture of the compound of this invention with the above carriers into hard gelatin capsules or soft capsules in a usual manner. In the preparation of injections, the solutions, emulsions or suspensions are sterilized and are preferably made isotonic with the blood. In the preparation of these solutions, emulsions and suspensions, there are used conventional diluents, such as water, ethyl alcohol, macrogol (propylene glycol), ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the pharmaceutical preparations may also be incorporated with sodium chloride, glucose, or glycerin in an amount sufficient to make them isotonic, and may also be incorporated with conventional solubilizers, buffers, anesthetizing agents. Besides, the pharmaceutical preparations may optionally be incorporated with coloring agents, preservatives, perfumes, flavors, sweeting agents, and other medicaments, if required.
The amount of the active compound of this invention (active ingredient) to be incorporated into the anti-vasopressin preparations is not specified but may be selected from a broad range, but usually, it is preferably in the range of 1 to 70% by weight, more preferably 5 to 50% by weight.
The anti-vasopressin preparation of this invention may be administered in any method, and suitable method for administration may be determined in accordance with various forms of preparation, ages, sexes and other conditions of the patients, the degree of severity of diseases, and the like. For instance, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. The injections are intraveneously administered alone or together with a conventional auxiliary liquid (e.g. glucose, amino acid solutions), and further are optionally administered alone in intramuscular, intracutaneous, subcutaneous, or intraperitoneal route, if required. Suppositories are administered in intrarectal route.
The dosage of the anti-vasopressin agent of this invention may be selected in accordance with the usage, ages, sexes and other conditions of the patients, the degree of severity of the diseases, and the like, but is usually in the range of about 0.6 to 50 mg of the active compound of this invention per 1 kg of body weight of the patient per day. The active compound is preferably contained in an amount of 10 to 1000 mg per the dosage unit.

BRIEF DESCRIPTION OF DRAWING
FIG. 1 to FIG. 4 show a chart of NMR (CDCl.sub.3) of the compounds in Examples 978 and 979.

BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is illustrated by the following Preparations of anti-vasopressin agent, Reference Examples of processes for preparing the starting compounds to be used for preparing the active compounds, Examples of processes for preparing the active compounds, and Experiments of the activities of the active compounds of this invention.
______________________________________Preparation 1Film coated tablets are prepared from the followingcomponents.Components Amount______________________________________4-Methylamino-1-�4-(3,5-dichlorobenzoyl- 150 gamino)benzoyl!-1,2,3,4-tetrahydroquinolineAvicel (tradename of microcrystalline cellulose, 40 gmanufactured by Asahi Chemical IndustryCo., Ltd., Japan)Corn starch 30 gMagnesium stearate 2 gHydroxypropyl methylcellulose 10 gPolyethylene glycol-6000 3 gCastor oil 40 gEthanol 40 g______________________________________
The active component of this invention, Avicel, corn starch and magnesium stearate are mixed and kneaded and the mixture is tabletted using a conventional pounder (R 10 mm) for sugar coating. The tablets thus obtained are coated with a film coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil and ethanol to give film coated tablets.
______________________________________Preparation 2Tablets are prepared from the following components.Components Amount______________________________________1-�4-(N-Butylanilinoacetylamino)benzoyl!- 150 g2,3,4,5-tetrahydroy-1H-benzazepineCitric acid 1.0 gLactose 33.5 gDicalcium phosphate 70.0 gPullonic F-68 30.0 gSodium laurylsulfate 15.0 gPolyvinylpyrrolidone 15.0 gPolyethylene glycol (Carbowax 1500) 4.5 gPolyethylene glycol (Carbowax 6000) 45.0 gCorn starch 30.0 gDry sodium stearate 3.0 gDry magnesium stearate 3.0 gEthanol q.s.______________________________________
The active compound of this invention, citric acid, lactose, dicalcium phosphate, Pullonic F-68 and sodium laurylstearate are mixed. The mixture is screened with No. 60 screen and is granulated with an alcohol solution containing polyvinylpyrrolidone, carbowax 1500 and 6000. If required, an alcohol is added thereto so that the powder mixture is made a paste-like mass. Corn starch is added to the mixture and the mixture is continuously mixed to form uniform particles. The resulting particles are passed through No. 10 screen and entered into a tray and then dried in an oven at 100.degree. C. for 12 to 14 hours. The dried particles are screened with No. 16 screen and thereto are added dry sodium laurylsulfate and dry magnesium stearate, and the mixture is tabletted to form the desired shape.
The core tablets thus prepared are vanished and dusted with talc in order to guard from wetting. Undercoating is applied to the core tablets. In order to administer the tablets orally, the core tablets are vanished several times. In order to give round shape and smooth surface to the tablets, further undercoating and coating with lubricant are applied thereto. The tablets are further coated with a coloring coating material until the desired colored tablets are obtained. After drying, the coated tablets are polished to obtain the desired tablets having uniform gloss.
______________________________________Preparation 3An injection preparation is prepared from thefollowing components.Components Amount______________________________________4-Methyl-1-�4-(2,3-dimethylbenzoyl- 5 gamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinePolyethylene glycol (molecular weight: 4000) 0.3 gSodium chloride 0.9 gPolyoxyethylene sorbitan monooleate 0.4 gSodium metabisulfite 0.1 gMethyl-paraben 0.18 gPropyl-paraben 0.02 gDistilled water for injection 10.0 ml______________________________________
The above parabens, sodium metabisulfite and sodium chloride are dissolved in distilled water of half volume of the above with stirring at 80.degree. C. The solution thus obtained is cooled to 40.degree. C., and the active compound of this invention and further polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. To the solution is added distilled water for injection to adjust to the desired volume, and the solution is sterilized by filtering with an appropriate filter paper to give an injection preparation.
REFERENCE EXAMPLE 1
To a solution of 1,2,3,4-tetrahydroquinoline (28.7 g) in acetone (400 ml) and water (200 ml) is added potassium carbonate (38.8 g), and thereto is added p-nitrobenzoyl chloride (40 g) under ice-cooling and the mixture is stirred at room temperature overnight. To the reaction mixture is added a suitable amount of water. The precipitated crystal is collected by filtration and dried to give 1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline (40.8 g) as white powder, m.p. 86.degree.-88.degree. C.
REFERENCE EXAMPLE 2
To a solution of 10% Pd--C (5 g) in ethanol (500 ml) is added 1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline (53.4 g) and the mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. After the reduction, 10% Pd--C is removed by filtration, and the filtrate is concentrated under reduced pressure to give 1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (46.7 g) as yellow powder, m.p. 185.degree.-188.degree. C.
REFERENCE EXAMPLE 3
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 1.
1-(3-Nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, white powder, m.p. 134.degree.-136.degree. C.
1-(2-Nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 152.degree.-154.degree. C.
3-Methyl-1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 109.degree.-110.degree. C.
4-Methyl-1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 134.degree.-136.degree. C.
2-Methyl-1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 143.degree.-145.degree. C.
1-(4-Nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder, m.p. 143.degree.-145.degree. C.
1-(3-Methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 100.degree.-102.degree. C.
1-(3-Methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder, m.p. 146.degree.-148.degree. C.
1-(4-Nitrobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, white powder, m.p. 83.degree.-85.degree. C.
1-(4-Nitrobenzoyl)-3,4-dihydro-2H-1,4-benzoxazine, yellow powder, m.p. 167.degree.-169.degree. C.
1-(4-Nitrobenzoyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine, yellow powder, m.p. 196.degree.-198.degree. C.
1-(4-Nitrobenzoyl)-4-methyl-1,2,3,4-tetrahydroquinoxaline, brown powder
.sup.1 H-NMR (CDCl.sub.3) .delta.: 3.03 (3H, s), 3.54 (2H, t, J=5.7 Hz), 4.06 (2H, t, J=5.7 Hz), 6.2-6.5 (2H, m), 6.70 (1H, d, J=8.2 Hz), 6.9-7.1 (1H, m), 7.54 (2H, d, J=8.8 Hz), 8.13 (2H, d, J=8.8 Hz)
1-(4-Nitrobenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.7-2.0 (1H, m), 2.0-2.3 (1H, m), 2.8-3.0 (1H, m), 2.98 (3H, s), 3.0-3.2 (1H, m), 3.4-3.6 (1H, m), 4.6-4.8 (1H, m), 6.5-6.7 (2H, m), 6.94 (1H, d, J=8.1 Hz), 7.1-7.2 (1H, m), 7.33 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.9 Hz)
1-(4-Nitrobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, brown oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.44 (3H, s), 3.0-3.3 (3H, m), 3.77 (1H, d, J=13.7 Hz), 4.06 (1H, d, J=13.6 Hz), 4.9-5.1 (1H, m), 6.59 (1H, d, J=7.7 Hz), 6.97 (1H, t, J=7.6 Hz), 7.15 (1H, t, J=7.4 Hz), 7.2-7.5 (3H, m), 8.03 (2H, d, J=8.8 Hz)
1-(3-Methoxy-4-nitrobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, yellow powder, m.p. 146.degree.-148.degree. C.
1-(4-Nitrobenzoyl)-4-n-propyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, yellow powder, m.p. 131.degree.-133.degree. C.
1-(4-Nitrobenzoyl)-5-chloro-1,2,3,4-tetrahydroquinoline, white powder, m.p. 134.degree.-136.degree. C.
1-(4-Nitrobenzoyl)-6-methoxy-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 149.degree.-151.degree. C.
1-(4-Nitrobenzoyl)-6-methyl-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 109.degree.-110.degree. C.
1-(4-Nitrobenzoyl)-7-methoxy-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 139.degree.-141.degree. C.
1-(4-Nitrobenzoyl)-3-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydroquinoline, yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.29 (3H, s), 2.35-3.20 (11H, m), 3.86-4.15 (2H, m), 6.48-6.63 (1H, m), 6.89 (1H, t, J=7.4 Hz), 7.05 (1H, t, J=7.4 Hz), 7.22 (1H, d, J=7.4 Hz), 7.52 (2H, d, J=8.8 Hz), 8.11 (2H, d, J=8.8 Hz)
1-(4-Nitrobenzoyl)-3-(1-pyrrolidinyl)-1,2,3,4-tetrahydroquinoline, yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.70-1.95 (4H, m), 2.52-3.30 (7H, m), 3.80-4.22 (2H, m), 6.52 (1H, brs), 6.88 (1H, t, J=7.6 Hz), 6.96-7.11 (1H, m), 7.20 (2H, d, J=7.6 Hz), 7.54 (2H, d, J=8.8 Hz), 8.12 (2H, d, J=8.8 Hz)
1-(4-Nitrobenzoyl)-4-oxo-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 189.degree.-190.degree. C.
1-(4-Nitrobenzoyl)-3-hydroxymethyl-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 97.degree.-100.degree. C.
1-(4-Nitrobenzoyl)-3-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline, pale yellow powder, m.p. 162.degree.-163.degree. C.
1-(4-Nitrobenzoyl)-4-dimethylamino-1,2,3,4-tetrahydroquinoline, light brown oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.80-2.02 (1H, m), 2.20-2.50 (7H, m), 3.47 (1H, t, J=4.9 Hz), 3.70-3.88 (1H, m), 4.06-4.25 (1H, m), 6.46 (1H, d, J=7.5 Hz), 6.89 (1H, t, J=7.5 Hz), 7.05 (1H, t, J=7.5 Hz), 7.34 (1H, d, J=7.5 Hz), 7.50 (2H, d, J=7.0 Hz), 8.10 (2H, d, J=7.0 Hz)
REFERENCE EXAMPLE 4
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.
1-(3-Aminobenzoyl)-1,2,3,4-tetrahydroquinoline, white powder, m.p. 128.degree.-130.degree. C.
1-(2-Aminobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.01 (2H, quint, J=6.6 Hz), 2.81 (2H, t, J=6.6 Hz), 3.86 (2H, t, J=6.4 Hz), 4.6-4.8 (2H, m), 6.43 (1H, t, J=7 Hz), 6.66 (1H, d, J=8 Hz), 6.79 (1H, dd, J=1.4 Hz, J=7.6 Hz), 6.8-7.2 (5H, m)
3-Methyl-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 197.degree.-200.degree. C.
4-Methyl-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 197.degree.-199.degree. C.
2-Methyl-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 204.degree.-206.degree. C.
1-(4-Aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder, m.p. 172.degree.-174.degree. C.
1-(3-Methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 156.degree.-158.degree. C.
1-(3-Methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 165.degree.-167.degree. C.
1-(4-Aminobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, white powder, m.p. 177.degree.-179.degree. C.
1-(4-Aminobenzoyl)-3,4-dihydro-2H-1,4-benzoxazine, white powder, m.p. 192.degree.-194.degree. C.
1-(4-Aminobenzoyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine, yellow powder, m.p. 196.degree.-198.degree. C.
1-(4-Aminobenzoyl)-4-methyl-1,2,3,4-tetrahydroquinoxaline, yellow powder, m.p. 210.degree.-212.degree. C.
1-(4-Aminobenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, white powder, m.p. 159.degree.-161.degree. C.
1-(4-Aminobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, brown powder, m.p. 169.degree.-171.degree. C.
1-(3-Methoxy-4-aminobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.41 (3H, s), 2.9-3.2 (3H, m), 3.61 (3H, s), 3.6-4.2 (4H, m), 4.8-5.2 (1H, m), 6.38 (1H, d, J=8.1 Hz), 6.6-6.8 (3H, m), 6.9-7.2 (2H, m), 7.2-7.4 (1H, m)
1-(4-Aminobenzoyl)-4-n-propyl-2,3,4,5-tetrahydro-1H-1,4-benzazepine, brown powder, m.p. 151.degree.-153.degree. C.
1-(4-Aminobenzoyl)-5-chloro-1,2,3,4-tetrahydroquinoline, white powder, m.p. 174.degree.-175.degree. C.
1-(4-Aminobenzoyl)-6-methoxy-1,2,3,4-tetrahydroquinoline, pale yellow powder, m.p. 159.degree.-160.degree. C.
1-(4-Aminobenzoyl)-6-methyl-1,2,3,4-tetrahydroquinoline, white powder, m.p. 145.degree.-146.degree. C.
1-(4-Aminobenzoyl)-7-methoxy-1,2,3,4-tetrahydroquinoline, pale yellow powder, m.p. 150.degree.-152.degree. C.
1-(4-Aminobenzoyl)-3-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydroquinoline, light beige powder, m.p. 157.degree.-159.degree. C.
1-(4-Aminobenzoyl)-3-(1-pyrrolidinyl)-1,2,3,4-tetrahydroquinoline, pale yellow powder, m.p. 173.degree.-174.5.degree. C.
1-(4-Aminobenzoyl)-2,3-dihydro-4(1H)-quinolinone, pale yellow powder, m.p. 178.degree.-180.degree. C.
1-(4-Aminobenzoyl)-3-hydroxymethyl-1,2,3,4-tetrahydroquinoline, white powder, m.p. 179.degree.-181.degree. C.
1-(4-Aminobenzoyl)-3-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline, pale yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.21 (3H, t, J=7.1 Hz), 3.00-3.24 (3H, m), 3.70-4.30 (6H, m), 6.48 (2H, d, J=8.5 Hz), 6.69 (1H, d, J=7.9 Hz), 6.77-7.30 (5H, m)
1-(4-Aminobenzoyl)-4-dimethylamino-1,2,3,4-tetrahydroquinoline, brown oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.83-2.05 (1H, m), 2.13-2.30 (1H, m), 2.34 (6H, m), 3.55-3.83 (2H, m), 3.89 (1H, brs), 3.97-4.18 (1H, m), 6.47 (2H, d, J=7.0 Hz), 6.68 (1H, d, J=7.9 Hz), 6.85-7.05 (2H, m), 7.20 (2H, d, J=7.0 Hz), 7.37 (1H, d, J=7.4 Hz)
REFERENCE EXAMPLE 5
To terephthalic acid monomethyl ester (15 g) is added thionyl chloride (100 ml) and the mixture is refluxed for 2 hours. The thionyl chloride is distilled off under reduced pressure to give terephthalic acid chloride monomethyl ester. Separately, to a solution of 1,2,3,4-tetrahydroquinoline (14.4 g) in dichloromethane (200 ml) is added triethylamine (16.9 g) and further thereto is added slowly terephthalic acid chloride monomethyl ester obtained above under ice-cooling. Then, the mixture is stirred at room temperature for 1 hour. After completion of the reaction, water is added to the reaction mixture. The mixture is extracted with dichloromethane and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane) to give 1-(4-methoxycarbonylbenzoyl)-1,2,3,4-tetrahydroquinoline (22.7 g) as white powder, m.p. 72.degree.-74.degree. C.
REFERENCE EXAMPLE 6
To a solution of 1-(4-methoxycarbonylbenzoyl)-1,2,3,4-tetrahydroquinoline (22.7 g) in methanol (300 ml) is added 5% aqueous sodium hydroxide solution (150 ml) and the mixture is refluxed for 2 hours. Methanol is distilled off under reduced pressure and the resulting residue is acidified with diluted hydrochloric acid, extracted with diethyl ether, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting crystal is collected by filtration to give 1-(4-carboxybenzoyl)-1,2,3,4-tetrahydroquinoline (13.2 g) as white powder, m.p. 181.degree.-183.degree. C.
REFERENCE EXAMPLE 7
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 1.
5-Dimethylamino-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, pale yellow powder, m.p. 139.degree.-142.degree. C.
5-Dimethylamino-1-(3-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 139.degree.-141.degree. C.
4-(N-Methyl-N-ethylamino)-1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, pale yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.11 (3H, t, J=7.1 Hz), 1.90-2.25 (2H, m), 2.30 (3H, s), 2.57 (2H, q, J=7.1 Hz), 3.55-3.85 (2H, m), 4.00-4.21 (1H, m), 6.35-6.60 (1H, m), 6.80-6.98 (1H, t, J=7.9 Hz), 7.00-7.15 (1H, m), 7.33-7.60 (3H, m), 8.10 (2H, d, J=8.8 Hz)
4-Dimethylamino-1-(3-methoxy-4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, brown oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.80-2.05 (1H, m), 2.33 (6H, s), 2.30-2.50 (1H, m), 3.40-3.52 (1H, m), 3.78 (3H, s), 3.70-3.88 (1H, m), 4.04-4.24 (1H, m), 6.52 (1H, d, J=8.2 Hz), 6.85-7.13 (4H, m), 7.28-7.38 (1H, m), 7.71 (1H, d, J=8.2 Hz)
1-(4-Nitrobenzoyl)-4-ethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.16 (3H, t, J=7.1 Hz), 2.5-2.7 (2H, m), 3.0-3.3 (3H, m), 3.98 (2H, q, J=14 Hz), 4.8-5.0 (1H, m), 6.59 (1H, d, J=7.7 Hz), 6.96 (1H, t, J=7.7 Hz), 7.14 (1H, t, J=7.4 Hz), 7.2-7.4 (3H, m), 8.02 (2H, d, J=8.8 Hz)
1-(4-Nitrobenzoyl)-4-isopropyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, yellow powder, m.p. 222.degree.-223.degree. C.
1-(4-Nitrobenzoyl)-4-cyclohexyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, brown oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.0-1.5 (5H, m), 1.5-2.1 (5H, m), 2.4-2.7 (1H, m), 2.9-3.3 (3H, m), 3.94 (2H, s), 4.9-5.1 (1H, m), 6.57 (1H, d, J=7.7 Hz), 6.8-7.0 (1H, m), 7.0-7.2 (1H, m), 7.2-7.4 (3H, m), 8.01 (2H, d, J=8.8 Hz)
1-(4-Nitrobenzoyl)-5-methyl-1,2,3,4,5,6-hexahydro-1,5-benzodiazocine, yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.5-2.1 (2H, m), 2.40 (3H, s), 2.3-2.6 (1H, m), 2.8-3.2 (2H, m), 3.50 (1H, d, J=13.4 Hz), 3.84 (1H, d, J=13.4 Hz), 4.8-5.0 (1H, m), 7.0-7.3 (4H, m), 7.41 (2H, d, J=8.9 Hz), 8.00 (2H, d, J=8.9 Hz)
1-(4-Nitrobenzoyl)-1,2,3,4-tetrahydro-5,1-benzoxazepine, white powder, m.p. 144.5.degree.-145.5.degree. C.
1-(2-Nitrobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, yellow powder, m.p. 177.degree.-180.degree. C.
1-(3-Nitrobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, yellow powder, m.p. 145.degree.-146.degree. C.
6-Fluoro-1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow needles, m.p. 145.degree.-146.degree. C.
REFERENCE EXAMPLE 8
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.
5-Dimethylamino-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 120.degree.-122.degree. C.
5-Dimethylamino-1-(3-methoxy-4-amino)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 121.degree.-123.degree. C.
4-(N-Methyl-N-ethylamino)-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline, orange amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.11 (3H, t, J=7.1 Hz), 1.90-2.20 (2H, m), 2.28 (3H, s), 2.26 (2H, q, J=7.1 Hz), 3.60-4.25 (5H, m), 6.48 (2H, d, J=8.5 Hz), 6.69 (1H, d, J=7.9 Hz), 6.80-7.05 (2H, m), 7.24 (2H, d, J=8.5 Hz), 7.46 (1H, d, J=6.2 Hz)
4-Dimethylamino-1-(3-methoxy-4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline, pale yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.83-2.04 (1H, m), 2.15-2.32 (1H, m), 2.33 (6H, s), 3.50-3.82 (2H, m), 3.64 (3H, s), 3.95-4.18 (3H, m), 6.50 (1H, d, J=7.9 Hz), 6.65 (1H, dd, J=7.9 Hz, 1.1 Hz), 6.78-7.03 (4H, m), 7.34 (1H, dd, J=7.5 Hz, 1.5 Hz)
1-(4-Aminobenzoyl)-4-ethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, white powder, m.p. 186.degree.-188.degree. C.
1-(4-Aminobenzoyl)-4-isopropyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, white powder, m.p. 191.degree.-192.degree. C.
1-(4-Aminobenzoyl)-4-cyclohexyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, white powder, m.p. 149.5.degree.-150.5.degree. C.
1-(4-Aminobenzoyl)-5-methyl-1,2,3,4,5,6-hexahydro-1,5-benzodiazocine, yellow powder, m.p. 143.degree.-145.degree. C.
1-(4-Aminobenzoyl)-1,2,3,4-tetrahydro-5,1-benzoxazepine, yellow powder, m.p. 163.5.degree.-164.5.degree. C.
1-(2-Aminobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, yellow powder, m.p. 144.degree.-146.degree. C.
1-(3-Aminobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, white powder, mp. 153.degree.-155.degree. C.
6-Fluoro-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline, white powder, m.p. 160.5.degree.-161.5.degree. C.
REFERENCE EXAMPLE 9
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 1.
1-(2-Chloro-4-nitrobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.40 (3H, s), 2.96-3.33 (3H, m), 3.60-3.79 (1H, m), 3.96-4.23 (1H, m), 4.70-4.91 (1H, m), 6.80-7.43 (5H, m), 7.80-7.99 (1H, m), 8.08-8.21 (1H, m)
1-(3-Methyl-4-nitrobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.43 (3H, s), 2.48 (3H, s), 2.92-3.28 (3H, m), 3.91 (2H, AB-q, J=13.9 Hz, 45.5 Hz), 4.77-5.01 (1H, m), 6.54-6.70 (1H, m), 6.88-7.37 (5H, m), 7.62-7.78 (1H, m)
5-Dimethylamino-1-(2-chloro-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.23-2.57 (10H, m), 2.68-5.15 (3H, m), 6.79-7.45 (4H, m), 7.49-8.39 (3H, m)
5-Oxo-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder (ethyl acetate/n-hexane), m.p. 147.degree.-148.degree. C.
5-Hydroxy-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder (ethyl acetate/n-hexane), m.p. 148.degree.-150.degree. C.
5-Methoxy-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.47-2.48 (4H, m), 2.70-3.10 (1H, m), 3.26-3.64 (3H, m), 4.29-5.12 (2H, m), 6.60 (1H, d, J=7.7 Hz), 6.88-7.67 (5H, m), 7.92-8.12 (2H, m)
5-Ethoxycarbonylmethoxy-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 107.degree.-108.degree. C. (recrystallized from ethyl acetate/n-hexane)
5-(4-Bromobutoxy)-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49-2.55 (8H, m), 2.72-3.07 (1H, m), 3.24-3.77 (4H, m), 4.40-5.15 (2H, m), 6.53-6.66 (1H, m), 6.91-7.06 (1H, m), 7.07-7.80 (4H, m), 7.94-8.13 (2H, m)
5-(4-Dimethylaminobutoxy)-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless oil
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.51-1.88 (6H, m), 2.23-2.61 (4H, m), 2.27 (3H, s), 2.35 (3H, s), 2.74-3.14 (1H, m), 3.55-3.77 (2H, m), 4.48-5.11 (2H, m), 6.54-6.66 (1H, m), 6.91-7.04 (1H, m), 7.06-7.80 (4H, m), 7.93-8.11 (2H, m)
5-�4-(Phthalimid-1-yl)propoxy-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.48-2.56 (6H, m), 2.71-3.05 (1H, m), 3.40-4.05 (4H, m), 4.47-5.11 (2H, m), 6.50-6.64 (1H, m), 6.84-7.03 (1H, m), 7.03-7.20 (1H, m), 7.20-7.57 (2H, m), 7.57-7.93 (5H, m), 7.97-8.20 (2H, m)
5-Chloro-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, light brown powder
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.75-3.3 (4H, m), 4.6-6.25 (3H, m), 6.45-6.7 (1H, m), 6.8-7.5 (4H, m), 7.55-7.7 (1H, m), 7.9-8.1 (2H, m)
5-Oxo-1-(2-chloro-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, pale yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.95-2.45 (2H, m), 2.94 (1H, t, J=6 Hz), 3.05-5.3 (2H, m), 6.96-7.1 (1H, m), 7.12-7.5 (3H, m), 7.75-7.85 (1H, m), 7.95-8.1 (1H, m), 8.14 (1H, s)
4-Dimethylaminomethyl-1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, white powder, m.p. 117.degree.-119.degree. C.
3-Dimethylamino-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.5-1.7 (1H, m), 2.1-2.4 (1H, m), 2.42 (6H, s), 2.6-2.7 (1H, m), 2.8-3.0 (3H, m), 5.1-5.3 (1H, m), 6.62 (1H, d, J=7.8 Hz), 6.95 (1H, t, J=7.7 Hz), 7.14 (1H, t, J=7.5 Hz), 7.2-7.4 (3H, m), 8.00 (2H, d, J=8.9 Hz)
3-Dimethylamino-1-(3-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.5-1.7 (1H, m), 2.0-2.3 (1H, m), 2.41 (6H, s), 2.5-2.8 (1H, m), 2.8-3.0 (3H, m), 3.75 (3H, s), 5.1-5.3 (1H, m), 6.6-6.8 (2H, m), 6.9-7.3 (4H, m), 7.59 (1H, d, J=8.3 Hz)
4-(4-Nitrobenzoyl)-3,4-dihydro-2H-1,4-benzothiazine, yellow powder, m.p. 180.degree.-182.degree. C.
5-(4-Nitrobenzoyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine, yellow powder, m.p. 162.degree.-163.degree. C.
REFERENCE EXAMPLE 10
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.
1-(2-Chloro-4-aminobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, white powder
(recrystallized from methanol/diethyl ether), m.p. 194.5.degree.-195.5.degree. C.
1-(3-Methyl-4-aminobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.01 (3H, s), 2.41 (3H, s), 2.82-3.21 (3H, m), 3.50-4.21 (4H, m), 4.78-5.14 (1H, m), 6.24-6.40 (1H, m), 6.59-6.82 (2H, m), 6.90-7.18 (3H, m), 7.19-7.34 (1H, m)
5-Dimethylamino-1-(2-chloro-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder (recrystallized from dichloromethane/diethyl ether), m.p. 162.degree.-164.degree. C.
5-Dimethylamino-1-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (recrystallized from methanol/diethyl ether)
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.23-2.80 (11H, m), 2.90-3.38 (1H, m), 3.50-5.19 (6H, m), 5.87-6.41 (2H, m), 6.65-7.56 (5H, m)
5-Methoxy-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder (recrystallized from ethyl acetate/n-hexane), m.p. 154.degree.-155.degree. C.
5-Ethoxycarbonylmethoxy-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white-powder (recrystallized from ethyl acetate/n-hexane), m.p. 231.degree.-232.degree. C.
5-(4-Dimethylaminobutoxy)-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.47-1.83 (6H, m), 1.83-2.54 (4H, m), 2.29 (6H, s), 2.61-3.00 (1H, m), 3.36-3.76 (2H, m), 4.35-5.20 (2H, m), 6.27-6.48 (2H, m), 6.57-6.76 (1H, m), 6.90-7.61 (5H, m)
5-�4-(Phthalimid-1-yl)propoxy!-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.30-2.47 (6H, m), 2.57-3.01 (1H, m), 3.30-4.06 (4H, m), 4.34-5.20 (2H, m), 6.30-6.53 (2H, m), 6.57-6.78 (1H, m), 6.87-7.57 (5H, m), 7.62-7.76 (2H, m), 7.76-7.97 (2H, m)
5-Chloro-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, pale yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.35-4.3 (7H, m), 4.55-6.7 (2H, m), 6.3-6.55 (2H, m), 6.6-6.8 (1H, m), 6.85-7.45 (5H, m)
5-Oxo-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, pale yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.95-2.35 (2H, m), 2.89 (2H, t, J=6.3 Hz), 3.0-5.3 (4H, m), 6.35-6.47 (2H, m), 6.72-6.83 (1H, m), 7.0-7.15 (2H, m), 7.18-7.32 (2H, m), 7.81-7.93 (1H, m)
5-Oxo-1-(2-chloro-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.85-2.3 (2H, m), 2.87 (2H, t, J=6.2 Hz), 3.1-4.75 (4H, m), 6.15-7.5 (6H, m), 7.65-7.9 (1H, m)
4-Dimethylaminomethyl-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline, white powder, m.p. 123.degree.-125.degree. C.
3-Dimethylamino-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 175.degree.-177.degree. C.
3-Dimethylamino-1-(3-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.5-1.7 (1H, m), 2.1-2.3 (1H, m), 2.3-2.6 (1H, m), 2.40 (6H, s), 2.7-3.0 (3H, m), 3.60 (3H, s), 3.8-4.0 (2H, br), 5.2-5.4 (1H, m), 6.37 (1H, d, J=8.2 Hz), 6.5-6.8 (3H, m), 6.9-7.4 (3H, m)
4-(4-Aminobenzoyl)-3,4-dihydro-2H-1,4-benzothiazine, yellow powder, m.p. 207.degree.-210.degree. C.
5-(4-Aminobenzoyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine, yellow powder, m.p. 193.degree.-195.degree. C.
REFERENCE EXAMPLE 11
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 1.
5-Carbamoyloxy-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 243.degree.-244.degree. C. (recrystallized from ethyl acetate/diisopropyl ether)
5-Methylaminocarbonyloxy-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 207.degree.-208.degree. C. (recrystallized from ethyl acetate/n-hexane)
5-Dimethylaminocarbonyloxy-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 155.degree.-156.degree. C. (recrystallized from ethyl acetate/diisopropyl ether/n-hexane)
5-Methylidenyl-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless prisms, m.p. 133.5.degree.-134.degree. C. (recrystallized from ethyl acetate/diisopropyl ether)
5-Oxo-6-methyl-1-(2-chloro-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless prisms, m.p. 90.degree.-92.degree. C. (recrystallized from ethanol)
1-(4-Nitrobenzoyl)-1,2,3,5-tetrahydro-4,1-benzothiazepine, yellow powder, m.p. 185.degree.-187.degree. C. (recrystallized from dichloromethane/diethyl ether)
5-Dimethylamino-1-(2-dimethylamino-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder, m.p. 123.degree.-125.degree. C. (recrystallized from diethyl ether/dichloromethane)
5-Oxo-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, white powder, m.p. 201.5.degree.-202.5.degree. C. (recrystallized from diethyl ether/dichloromethane)
5-Oxo-4-methyl-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, white powder, m.p. 136.degree.-138.degree. C. (recrystallized from diethyl ether/dichloromethane)
5-Dimethylamino-1-(3-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.16-3.18 (11H, m), 2.18 (3H, s), 3.40-5.15 (2H, m), 6.50-7.68 (6H, m), 7.70-7.84 (1H, m)
5-Dimethylamino-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.19-2.86 (11H, m), 2.20 (3H, s), 2.94-3.24 (1H, m), 3.36-5.18 (1H, m), 6.49-8.20 (7H, m)
5-Dimethylamino-1-(2-fluoro-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.21-2.66 (10H, m), 2.66-5.11 (3H, m), 6.63-8.25 (7H, m)
5-Dimethylamino-1-(3-fluoro-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 152.degree.-152.5.degree. C. (recrystallized from chloroform/diethyl ether)
REFERENCE EXAMPLE 12
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.
5-Carbamoyloxy-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 215.degree.-216.degree. C. (recrystallized from ethyl acetate/n-hexane)
5-Methylaminocarbonyloxy-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 192.degree.-195.degree. C. (recrystallized from ethyl acetate/n-hexane)
5-Dimethylaminocarbonyloxy-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 228.degree.-230.degree. C. (recrystallized from ethyl acetate/diisopropyl ether)
5-Methyl-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 155.degree.-156.degree. C. (recrystallized from ethyl acetate/n-hexane)
5-Oxo-6-methyl-1-(2-chloro-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 193.degree.-195.degree. C. (recrystallized from ethanol)
1-(4-Aminobenzoyl)-1,2,3,5-tetrahydro-4,1-benzothiazepine, white powder, m.p. 179.degree.-180.degree. C. (recrystallized from dichloromethane/diethyl ether)
5-Dimethylamino-1-(2-dimethylamino-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 163.degree.-165.degree. C. (recrystallized from diethyl ether/dichloromethane)
5-Oxo-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder, m.p. 195.degree.-197.degree. C. (recrystallized from diethyl ether/dichloromethane)
5-Oxo-4-methyl-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1,4-benzazepine, yellow powder, m.p. 190.degree.-192.degree. C. (recrystallized from diethyl ether/dichloromethane)
5-Dimethylamino-1-(2-ethoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 111.degree.-114.degree. C. (recrystallized from diethyl ether)
5-Dimethylamino-1-(3-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 0.66-2.56 (14H, m), 2.93-5.22 (4H, m), 6.23-7.80 (7H, m)
5-Dimethylamino-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 154.degree.-156.degree. C. (recrystallized from methanol/diethyl ether)
5-Dimethylamino-1-(2-fluoro-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 161.degree.-163.degree. C. (recrystallized from dichloromethane/diethyl ether)
5-Dimethylamino-1-(3-fluoro-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 156.degree.-157.degree. C. (recrystallized from methanol/diethyl ether)
5-Oxo-1-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless prisms, m.p. 160.degree.-160.5.degree. C. (recrystallized from methanol/diethyl ether)
Example 1
To a solution of 1,2,3,4-tetrahydroquinoline (28.7 g) in acetone (400 ml) and water (200 ml) is added potassium carbonate (38.8 g) and further thereto is added 4-benzoylaminobenzoyl chloride (56 g) under ice-cooling. The mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography and recrystallized from methanol to give 1-�4-(benzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (57 g) as white powder, m.p. 202.5.degree.-203.5.degree. C.
Using the suitable starting materials, the compounds as shown in the following Table 1 are obtained in the same manner as in Example 1.
TABLE 1__________________________________________________________________________ ##STR86##__________________________________________________________________________Example 2Structure ##STR87## ##STR88##R.sup.2 : HR.sup.3 : ##STR89##Crystalline form: Light yellow powderRecrystallization solvent: MethanolMelting Point: 198.5-199.5.degree. C.Form: FreeExample 3Structure ##STR90## ##STR91##R.sup.2 : HR.sup.3 : ##STR92##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 200.5-201.5.degree. C.Form: FreeExample 4Structure ##STR93## ##STR94##R.sup.2 : HR.sup.3 : ##STR95##Crystalline form: Yellow powderRecrystallization solvent: MethanolMelting Point: 206-207.degree. C.Form: FreeExample 5Structure ##STR96## ##STR97##R.sup.2 : HR.sup.3 : ##STR98##Crystalline form: Yellow powderRecrystallization solvent: MethanolMelting Point: 216-217.degree. C.Form: FreeExample 6Structure ##STR99## ##STR100##R.sup.2 : HR.sup.3 : ##STR101##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 202-203.degree. C.Form: FreeExample 7Structure ##STR102## ##STR103##R.sup.2 : HR.sup.3 : ##STR104##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 212-213.degree. C.Form: FreeExample 8Structure ##STR105## ##STR106##R.sup.2 : HR.sup.3 : ##STR107##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 167.5-168.5.degree. C.Form: FreeExample 9Structure ##STR108## ##STR109##R.sup.2 : HR.sup.3 : ##STR110##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 205-206.degree. C.Form: FreeExample 10Structure ##STR111## ##STR112##R.sup.2 : HR.sup.3 : ##STR113##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: >300.degree. C.NMR analysis: 1)Form: FreeExample 11Structure ##STR114## ##STR115##R.sup.2 : HR.sup.3 : ##STR116##Crystalline form: Yellow powderRecrystallization solvent: MethanolMelting Point: 176-177.degree. C.Form: FreeExample 12Structure ##STR117## ##STR118##R.sup.2 : HR.sup.3 : ##STR119##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 219-220.degree. C.Form: FreeExample 13Structure ##STR120## ##STR121##R.sup.2 : HR.sup.3 : ##STR122##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 193-194.degree. C.Form: FreeExample 14Structure ##STR123## ##STR124##R.sup.2 : HR.sup.3 : ##STR125##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 232-233.degree. C.Form: FreeExample 15Structure ##STR126## ##STR127##R.sup.2 : HR.sup.3 : ##STR128##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 209-210.degree. C.Form: FreeExample 16Structure ##STR129## ##STR130##R.sup.2 : HR.sup.3 : ##STR131##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 184.5-185.5.degree. C.Form: FreeExample 17Structure ##STR132## ##STR133##R.sup.2 : HR.sup.3 : ##STR134##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 224.5-225.5.degree. C.Form: FreeExample 18Structure ##STR135## ##STR136##R.sup.2 : HR.sup.3 : ##STR137##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 220.5-221.5.degree. C.Form: FreeExample 19Structure ##STR138## ##STR139##R.sup.2 : HR.sup.3 : ##STR140##Crystalline form: Yellow powderRecrystallization solvent: MethanolMelting Point: 231-232.degree. C.Form: FreeExample 20Structure ##STR141## ##STR142##R.sup.2 : HR.sup.3 : ##STR143##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: >300.degree. C.NMR analysis: 2)Form: FreeExample 21Structure ##STR144## ##STR145##R.sup.2 : HR.sup.3 : ##STR146##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 208-209.degree. C.Form: FreeExample 22Structure ##STR147## ##STR148##R.sup.2 : HR.sup.3 : ##STR149##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 234.5-235.5.degree. C.Form: FreeExample 23Structure ##STR150## ##STR151##R.sup.2 : HR.sup.3 : ##STR152##Crystalline form: Yellow powderRecrystallization solvent: MethanolMelting Point: 263.5-264.5.degree. C.Form: FreeExample 24Structure ##STR153## ##STR154##R.sup.2 : HR.sup.3 : ##STR155##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 237-238.degree. C.Form: FreeExample 25Structure ##STR156## ##STR157##R.sup.2 : HR.sup.3 : ##STR158##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 234-235.degree. C.Form: FreeExample 26Structure ##STR159## ##STR160##R.sup.2 : HR.sup.3 : ##STR161##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 236.5-237.5.degree. C.Form: FreeExample 27Structure ##STR162## ##STR163##R.sup.2 : HR.sup.3 : ##STR164##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 206.5-207.5.degree. C.Form: FreeExample 28Structure ##STR165## ##STR166##R.sup.2 : HR.sup.3 : ##STR167##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 210-211.degree. C.Form: FreeExample 29Structure ##STR168## ##STR169##R.sup.2 : HR.sup.3 : ##STR170##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 210.5-211.5.degree. C.Form: FreeExample 30Structure ##STR171## ##STR172##R.sup.2 : HR.sup.3 : ##STR173##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 178-179.degree. C.Form: FreeExample 31Structure ##STR174## ##STR175##R.sup.2 : HR.sup.3 : ##STR176##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 192-193.degree. C.Form: FreeExample 32Structure ##STR177## ##STR178##R.sup.2 : HR.sup.3 : ##STR179##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 217-218.degree. C.Form: FreeExample 33Structure ##STR180## ##STR181##R.sup.2 : HR.sup.3 : ##STR182##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 143-144.degree. C.Form: FreeExample 34Structure ##STR183## ##STR184##R.sup.2 : HR.sup.3 : ##STR185##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 170.5-171.5.degree. C.Form: FreeExample 35Structure ##STR186## ##STR187##R.sup.2 : HR.sup.3 : ##STR188##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 169.5-170.5.degree. C.Form: FreeExample 36Structure ##STR189## ##STR190##R.sup.2 : HR.sup.3 : ##STR191##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 174.5-175.5.degree. C.Form: FreeExample 37Structure ##STR192## ##STR193##R.sup.2 : HR.sup.3 : ##STR194##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 148.5-149.5.degree. C.Form: FreeExample 38Structure ##STR195## ##STR196##R.sup.2 : HR.sup.3 : ##STR197##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 165-166.degree. C.Form: FreeExample 39Structure ##STR198## ##STR199##R.sup.2 : HR.sup.3 : ##STR200##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 243-244.degree. C.Form: FreeExample 40Structure ##STR201## ##STR202##R.sup.2 : HR.sup.3 : ##STR203##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 199-200.degree. C.Form: FreeExample 41Structure ##STR204## ##STR205##R.sup.2 : HR.sup.3 : ##STR206##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 232.5-233.5.degree. C.Form: FreeExample 42Structure ##STR207## ##STR208##R.sup.2 : HR.sup.3 : ##STR209##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 178.5-179.5.degree. C.Form: FreeExample 43Structure ##STR210## ##STR211##R.sup.2 : HR.sup.3 : ##STR212##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 205.5-206.5.degree. C.Form: FreeExample 44Structure ##STR213## ##STR214##R.sup.2 : HR.sup.3 : ##STR215##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 234-235.degree. C.Form: FreeExample 45Structure ##STR216## ##STR217##R.sup.2 : HR.sup.3 : ##STR218##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 225-226.degree. C.Form: FreeExample 46Structure ##STR219## ##STR220##R.sup.2 : HR.sup.3 : ##STR221##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 224-225.degree. C.Form: FreeExample 47Structure ##STR222## ##STR223##R.sup.2 : HR.sup.3 : ##STR224##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 236-237.degree. C.Form: FreeExample 48Structure ##STR225## ##STR226##R.sup.2 : HR.sup.3 : ##STR227##Crystalline form: Yellow powderRecrystallization solvent: MethanolMelting Point: 175.5-176.5.degree. C.Form: FreeExample 49Structure ##STR228## ##STR229##R.sup.2 : HR.sup.3 : ##STR230##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 231-232.degree. C.Form: FreeExample 50Structure ##STR231## ##STR232##R.sup.2 : HR.sup.3 : ##STR233##Crystalline form: Yellow powderRecrystallization solvent: MethanolMelting Point: 204-205.degree. C.Form: FreeExample 51Structure ##STR234## ##STR235##R.sup.2 : HR.sup.3 : ##STR236##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 190-191.degree. C.Form: FreeExample 52Structure ##STR237## ##STR238##R.sup.2 : HR.sup.3 : ##STR239##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 156-157.degree. C.Form: FreeExample 53Structure ##STR240## ##STR241##R.sup.2 : HR.sup.3 : ##STR242##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 200-201.degree. C.Form: FreeExample 54Structure ##STR243## ##STR244##R.sup.2 : HR.sup.3 : ##STR245##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 206-207.degree. C.Form: FreeExample 55Structure ##STR246## ##STR247##R.sup.2 : HR.sup.3 : ##STR248##Crystalline form: Colorless amorphousNMR analysis: 3)Form: FreeExample 56Structure ##STR249## ##STR250##R.sup.2 : HR.sup.3 : ##STR251##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 215.5-216.5.degree. C.Form: FreeExample 57Structure ##STR252## ##STR253##R.sup.2 : HR.sup.3 : ##STR254##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 189-190.degree. C.Form: FreeExample 58Structure ##STR255## ##STR256##R.sup.2 : HR.sup.3 : ##STR257##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 203.5-204.5.degree. C.Form: FreeExample 59Structure ##STR258## ##STR259##R.sup.2 : HR.sup.3 : ##STR260##Crystalline form: Yellow powderRecrystallization solvent: MethanolMelting Point: 254.5-255.5.degree. C.Form: FreeExample 60Structure ##STR261## ##STR262##R.sup.2 : HR.sup.3 : ##STR263##Crystalline form: Brown powderRecrystallization solvent: MethanolMelting Point: 182.5-183.5.degree. C.Form: FreeExample 61Structure ##STR264## ##STR265##R.sup.2 : HR.sup.3 : ##STR266##Crystalline form: Colorless amorphousNMR analysis: 4)Form: FreeExample 62Structure ##STR267## ##STR268##R.sup.2 : HR.sup.3 : ##STR269##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 263-264.degree. C.Form: FreeExample 63Structure ##STR270## ##STR271##R.sup.2 : HR.sup.3 : ##STR272##Crystalline form: White powderRecrystallization solvent: Dichloromethane/ethanolMelting Point: 217-218.degree. C.Form: FreeExample 64Structure ##STR273## ##STR274##R.sup.2 : HR.sup.3 : ##STR275##Crystalline form: White powderRecrystallization solvent: Dichloromethane/ethanolMelting Point: 183-184.degree. C.Form: FreeExample 65Structure ##STR276## ##STR277##R.sup.2 : HR.sup.3 : ##STR278##Crystalline form: Yellow powderRecrystallization solvent: Dichloromethane/ethanolMelting Point: 207.5-208.5.degree. C.Form: FreeExample 66Structure ##STR279## ##STR280##R.sup.2 : HR.sup.3 : ##STR281##Crystalline form: Yellow powderRecrystallization solvent: Dichloromethane/ethanolMelting Point: 251-252.degree. C.Form: FreeExample 67Structure ##STR282## ##STR283##R.sup.2 : HR.sup.3 : ##STR284##Crystalline form: White powderRecrystallization solvent: Dichloromethane/ethanolMelting Point: 208.5-209.5.degree. C.Form: FreeExample 68Structure ##STR285## ##STR286##R.sup.2 : HR.sup.3 : ##STR287##Crystalline form: White powderRecrystallization solvent: Dichloromethane/ethanolMelting Point: 231-232.degree. C.Form: FreeExample 69Structure ##STR288## ##STR289##R.sup.2 : HR.sup.3 : ##STR290##Crystalline form: Colorless amorphousNMR analysis: 5)Form: FreeExample 70Structure ##STR291## ##STR292##R.sup.2 : HR.sup.3 : ##STR293##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 134-135.degree. C.Form: FreeExample 71Structure ##STR294## ##STR295##R.sup.2 : HR.sup.3 : ##STR296##Crystalline form: Yellow powderRecrystallization solvent: MethanolMelting Point: 115-116.degree. C.Form: FreeExample 72Structure ##STR297## ##STR298##R.sup.2 : HR.sup.3 : ##STR299##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 178.5-179.5.degree. C.Form: FreeExample 73Structure ##STR300## ##STR301##R.sup.2 : HR.sup.3 : ##STR302##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 182.5-183.5.degree. C.Form: FreeExample 74Structure ##STR303## ##STR304##R.sup.2 : HR.sup.3 : ##STR305##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 164-165.degree. C.Form: FreeExample 75Structure ##STR306## ##STR307##R.sup.2 : HR.sup.3 : ##STR308##Crystalline form: Colorless amorphousNMR analysis: 6)Form: FreeExample 76Structure ##STR309## ##STR310##R.sup.2 : HR.sup.3 : ##STR311##Crystalline form: Yellow amorphousNMR analysis: 7)Form: FreeExample 77Structure ##STR312## ##STR313##R.sup.2 : HR.sup.3 : ##STR314##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 155-156.degree. C.Form: FreeExample 78Structure ##STR315## ##STR316##R.sup.2 : HR.sup.3 : ##STR317##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 182.5-183.5.degree. C.Form: FreeExample 79Structure ##STR318## ##STR319##R.sup.2 : HR.sup.3 : ##STR320##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 164.5-165.5.degree. C.Form: FreeExample 80Structure ##STR321## ##STR322##R.sup.2 : HR.sup.3 : ##STR323##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 165-167.degree. C.Form: FreeExample 81Structure ##STR324## ##STR325##R.sup.2 : HR.sup.3 : ##STR326##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 124-125.degree. C.Form: FreeExample 82Structure ##STR327## ##STR328##R.sup.2 : HR.sup.3 : ##STR329##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 140.5-141.5.degree. C.Form: FreeExample 83Structure ##STR330## ##STR331##R.sup.2 : HR.sup.3 : ##STR332##Crystalline form: Colorless amorphousNMR analysis: 8)Form: FreeExample 84Structure ##STR333## ##STR334##R.sup.2 : HR.sup.3 : ##STR335##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 211-212.degree. C.Form: FreeExample 85Structure ##STR336## ##STR337##R.sup.2 : HR.sup.3 : ##STR338##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 178-179.degree. C.Form: FreeExample 86Structure ##STR339## ##STR340##R.sup.2 : HR.sup.3 : ##STR341##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 212.5-213.5.degree. C.Form: FreeExample 87Structure ##STR342## ##STR343##R.sup.2 : HR.sup.3 : ##STR344##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 193-194.degree. C.Form: FreeExample 88Structure ##STR345## ##STR346##R.sup.2 : HR.sup.3 : ##STR347##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 203-204.degree. C.Form: FreeExample 89Structure ##STR348## ##STR349##R.sup.2 : HR.sup.3 : ##STR350##Crystalline form: Colorless amorphousNMR analysis: 9)Form: FreeExample 90Structure ##STR351## ##STR352##R.sup.2 : HR.sup.3 : ##STR353##Crystalline form: Colorless amorphousNMR analysis: 10)Form: FreeExample 91Structure ##STR354## ##STR355##R.sup.2 : HR.sup.3 : ##STR356##Crystalline form: Colorless amorphousNMR analysis: 11)Form: FreeExample 92Structure ##STR357## ##STR358##R.sup.2 : HR.sup.3 : ##STR359##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 156.5-157.5.degree. C.Form: FreeExample 93Structure ##STR360## ##STR361##R.sup.2 : HR.sup.3 : ##STR362##Crystalline form: Colorless amorphousNMR analysis: 12)Form: FreeExample 94Structure ##STR363## ##STR364##R.sup.2 : HR.sup.3 : ##STR365##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 203.5-204.5.degree. C.Form: FreeExample 95Structure ##STR366## ##STR367##R.sup.2 : HR.sup.3 : ##STR368##Crystalline form: Colorless amorphousNMR analysis: 13)Form: FreeExample 96Structure ##STR369## ##STR370##R.sup.2 : HR.sup.3 : ##STR371##Crystalline form: Yellow powderRecrystallization solvent: MethanolMelting Point: 126-127.degree. C.Form: FreeExample 97Structure ##STR372## ##STR373##R.sup.2 : HR.sup.3 : ##STR374##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 158.5-159.5.degree. C.Form: FreeExample 98Structure ##STR375## ##STR376##R.sup.2 : HR.sup.3 : ##STR377##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 129-130.degree. C.Form: FreeExample 99Structure ##STR378## ##STR379##R.sup.2 : HR.sup.3 : ##STR380##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 131.5-132.5.degree. C.Form: FreeExample 100Structure ##STR381## ##STR382##R.sup.2 : HR.sup.3 : ##STR383##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 140-141.degree. C.Form: FreeExample 101Structure ##STR384## ##STR385##R.sup.2 : HR.sup.3 : ##STR386##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 138.5-139.5.degree. C.Form: FreeExample 102Structure ##STR387## ##STR388##R.sup.2 : HR.sup.3 : ##STR389##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 128-129.degree. C.Form: FreeExample 103Structure ##STR390## ##STR391##R.sup.2 : HR.sup.3 : ##STR392##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 160-161.degree. C.Form: FreeExample 104Structure ##STR393## ##STR394##R.sup.2 : HR.sup.3 : ##STR395##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 175-176.degree. C.Form: FreeExample 105Structure ##STR396## ##STR397##R.sup.2 : HR.sup.3 : ##STR398##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 197-198.degree. C.Form: FreeExample 106Structure ##STR399## ##STR400##R.sup.2 : HR.sup.3 : ##STR401##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 204-205.degree. C.Form: FreeExample 107Structure ##STR402## ##STR403##R.sup.2 : HR.sup.3 : ##STR404##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 174-175.degree. C.Form: FreeExample 108Structure ##STR405## ##STR406##R.sup.2 : HR.sup.3 : ##STR407##Crystalline form: Yellow powderRecrystallization solvent: MethanolMelting Point: 202-203.degree. C.Form: FreeExample 109Structure ##STR408## ##STR409##R.sup.2 : HR.sup.3 : ##STR410##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 203-204.degree. C.Form: FreeExample 110Structure ##STR411## ##STR412##R.sup.2 : HR.sup.3 : ##STR413##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 170.5-171.5.degree. C.Form: FreeExample 111Structure ##STR414## ##STR415##R.sup.2 : HR.sup.3 : ##STR416##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 149-150.degree. C.Form: FreeExample 112Structure ##STR417## ##STR418##R.sup.2 : HR.sup.3 : ##STR419##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 185-186.degree. C.Form: FreeExample 113Structure ##STR420## ##STR421##R.sup.2 : HR.sup.3 : ##STR422##Crystalline form: White powderRecrystallization solvent: Dichloromethane/ethanolMelting Point: 225-226.degree. C.Form: FreeExample 114Structure ##STR423## ##STR424##R.sup.2 : HR.sup.3 : ##STR425##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 234-235.degree. C.Form: FreeExample 115Structure ##STR426## ##STR427##R.sup.2 : HR.sup.3 : ##STR428##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 149.5-150.5.degree. C.Form: FreeExample 116Structure ##STR429## ##STR430##R.sup.2 : HR.sup.3 : ##STR431##Crystalline form: White powderRecrystallization solvent: Dichloromethane/ethanolMelting Point: 197-198.degree. C.Form: FreeExample 117Structure ##STR432## ##STR433##R.sup.2 : HR.sup.3 : ##STR434##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 204-205.degree. C.Form: FreeExample 118Structure ##STR435## ##STR436##R.sup.2 : HR.sup.3 : ##STR437##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 224.5-225.5.degree. C.Form: FreeExample 119Structure ##STR438## ##STR439##R.sup.2 : HR.sup.3 : ##STR440##Crystalline form: White powderRecrystallization solvent: Dichloromethane/ethanolMelting Point: 189.5-190.5.degree. C.Form: FreeExample 120Structure ##STR441## ##STR442##R.sup.2 : HR.sup.3 : ##STR443##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 221.5-222.5.degree. C.Form: FreeExample 121Structure ##STR444## ##STR445##R.sup.2 : HR.sup.3 : ##STR446##Crystalline form: Colorless needlesRecrystallization solvent: MethanolMelting Point: 154-155.degree. C.Form: FreeExample 122Structure ##STR447## ##STR448##R.sup.2 : HR.sup.3 : ##STR449##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 165-166.degree. C.Form: FreeExample 123Structure ##STR450## ##STR451##R.sup.2 : HR.sup.3 : ##STR452##Crystalline form: Colorless needlesRecrystallization solvent: MethanolMelting Point: 141-142.degree. C.Form: FreeExample 124Structure ##STR453## ##STR454##R.sup.2 : HR.sup.3 : ##STR455##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 165.5-166.5.degree. C.Form: FreeExample 125Structure ##STR456## ##STR457##R.sup.2 : HR.sup.3 : ##STR458##Crystalline form: Colorless needlesRecrystallization solvent: MethanolMelting Point: 164-165.degree. C.Form: FreeExample 126Structure ##STR459## ##STR460##R.sup.2 : HR.sup.3 : ##STR461##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 203.5-204.5.degree. C.Form: FreeExample 127Structure ##STR462## ##STR463##R.sup.2 : HR.sup.3 : ##STR464##Crystalline form: White powderRecrystallization solvent: Dichloromethane/ethanolMelting Point: 236.5-237.5.degree. C.Form: FreeExample 128Structure ##STR465## ##STR466##R.sup.2 : HR.sup.3 : ##STR467##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 206.5-207.5.degree. C.Form: FreeExample 129Structure ##STR468## ##STR469##R.sup.2 : HR.sup.3 : ##STR470##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 271-272.degree. C.Form: FreeExample 130Structure ##STR471## ##STR472##R.sup.2 : HR.sup.3 : ##STR473##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 246-247.degree. C.Form: FreeExample 131Structure ##STR474## ##STR475##R.sup.2 : HR.sup.3 : ##STR476##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 210-211.degree. C.Form: FreeExample 132Structure ##STR477## ##STR478##R.sup.2 : HR.sup.3 : ##STR479##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 230.5-231.5.degree. C.Form: FreeExample 133Structure ##STR480## ##STR481##R.sup.2 : HR.sup.3 : ##STR482##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 203-204.degree. C.Form: FreeExample 134Structure ##STR483## ##STR484##R.sup.2 : HR.sup.3 : ##STR485##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 170-171.degree. C.Form: FreeExample 135Structure ##STR486## ##STR487##R.sup.2 : HR.sup.3 : ##STR488##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 225.5-226.5.degree. C.Form: FreeExample 136Structure ##STR489## ##STR490##R.sup.2 : HR.sup.3 : ##STR491##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 210.5-211.5.degree. C.Form: FreeExample 137Structure ##STR492## ##STR493##R.sup.2 : HR.sup.3 : ##STR494##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 183-184.degree. C.Form: FreeExample 138Structure ##STR495## ##STR496##R.sup.2 : HR.sup.3 : ##STR497##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 191.5-192.5.degree. C.Form: FreeExample 139Structure ##STR498## ##STR499##R.sup.2 : HR.sup.3 : ##STR500##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 203.5-204.5.degree. C.Form: FreeExample 140Structure ##STR501## ##STR502##R.sup.2 : HR.sup.3 : ##STR503##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 215.5-216.5.degree. C.Form: FreeExample 141Structure ##STR504## ##STR505##R.sup.2 : HR.sup.3 : ##STR506##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 211.5-212.5.degree. C.Form: FreeExample 142Structure ##STR507## ##STR508##R.sup.2 : HR.sup.3 : ##STR509##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 280.5-281.5.degree. C.Form: FreeExample 143Structure ##STR510## ##STR511##R.sup.2 : HR.sup.3 : ##STR512##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 235.5-236.5.degree. C.Form: FreeExample 144Structure ##STR513## ##STR514##R.sup.2 : HR.sup.3 : ##STR515##Crystalline form: White powderRecrystallization solvent: Ethanol/dichloromethaneMelting Point: 249.5-250.5.degree. C.Form: FreeExample 145Structure ##STR516## ##STR517##R.sup.2 : HR.sup.3 : ##STR518##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 217-218.degree. C.Form: FreeExample 146Structure ##STR519## ##STR520##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR521##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 201.5-203.degree. C.Form: FreeExample 147Structure ##STR522## ##STR523##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR524##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 221-222.degree. C.Form: FreeExample 148Structure ##STR525## ##STR526##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR527##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 193-194.degree. C.Form: FreeExample 149Structure ##STR528## ##STR529##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR530##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 176-177.degree. C.Form: FreeExample 150Structure ##STR531## ##STR532##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR533##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 188-189.5.degree. C.Form: FreeExample 151Structure ##STR534## ##STR535##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR536##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 227-228.degree. C.Form: FreeExample 152Structure ##STR537## ##STR538##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR539##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 186-187.degree. C.Form: FreeExample 153Structure ##STR540## ##STR541##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR542##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 135-136.degree. C.Form: FreeExample 154Structure ##STR543## ##STR544##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR545##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 173-174.degree. C.Form: FreeExample 155Structure ##STR546## ##STR547##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR548##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 174.5-175.5.degree. C.Form: FreeExample 156Structure ##STR549## ##STR550##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR551##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 156-157.degree. C.Form: FreeExample 157Structure ##STR552## ##STR553##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR554##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 153-154.degree. C.Form: FreeExample 158Structure ##STR555## ##STR556##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR557##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 169-170.degree. C.Form: FreeExample 159Structure ##STR558## ##STR559##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR560##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 185-186.degree. C.Form: FreeExample 160Structure ##STR561## ##STR562##R.sup.2 : HR.sup.3 : ##STR563##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 213-214.degree. C.Form: FreeExample 161Structure ##STR564## ##STR565##R.sup.2 : HR.sup.3 : ##STR566##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 240-241.degree. C.Form: FreeExample 162Structure ##STR567## ##STR568##R.sup.2 : HR.sup.3 : ##STR569##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 225-226.degree. C.Form: FreeExample 163Structure ##STR570## ##STR571##R.sup.2 : HR.sup.3 : ##STR572##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 209.5-210.5.degree. C.Form: FreeExample 164Structure ##STR573## ##STR574##R.sup.2 : HR.sup.3 : ##STR575##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 198-199.degree. C.Form: FreeExample 165Structure ##STR576## ##STR577##R.sup.2 : HR.sup.3 : ##STR578##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 214.5-215.5.degree. C.Form: FreeExample 166Structure ##STR579## ##STR580##R.sup.2 : HR.sup.3 : ##STR581##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 196.5-197.5.degree. C.Form: FreeExample 167Structure ##STR582## ##STR583##R.sup.2 : HR.sup.3 : ##STR584##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 194-195.degree. C.Form: FreeExample 168Structure ##STR585## ##STR586##R.sup.2 : HR.sup.3 : ##STR587##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 191-192.degree. C.Form: FreeExample 169Structure ##STR588## ##STR589##R.sup.2 : HR.sup.3 : ##STR590##Crystalline form: White powderRecrystallization solvent: Dichloromethane/ethanolMelting Point: 227-228.degree. C.Form: FreeExample 170Structure ##STR591## ##STR592##R.sup.2 : HR.sup.3 : ##STR593##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 182-183.degree. C.Form: FreeExample 171Structure ##STR594## ##STR595##R.sup.2 : HR.sup.3 : ##STR596##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 222-223.degree. C.Form: FreeExample 172Structure ##STR597## ##STR598##R.sup.2 : HR.sup.3 : ##STR599##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 204-205.degree. C.Form: FreeExample 173Structure ##STR600## ##STR601##R.sup.2 : HR.sup.3 : ##STR602##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 194-195.degree. C.Form: FreeExample 174Structure ##STR603## ##STR604##R.sup.2 : HR.sup.3 : ##STR605##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 213-214.degree. C.Form: FreeExample 175Structure ##STR606## ##STR607##R.sup.2 : HR.sup.3 : ##STR608##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 201-202.degree. C.Form: FreeExample 176Structure ##STR609## ##STR610##R.sup.2 : HR.sup.3 : ##STR611##Crystalline form: Colorless needlesRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 173-174.degree. C.Form: FreeExample 177Structure ##STR612## ##STR613##R.sup.2 : HR.sup.3 : ##STR614##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 150.5-151.5.degree. C.Form: FreeExample 178Structure ##STR615## ##STR616##R.sup.2 : HR.sup.3 : ##STR617##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 207.5-208.5.degree. C.Form: FreeExample 179Structure ##STR618## ##STR619##R.sup.2 : HR.sup.3 : ##STR620##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 256.5-257.5.degree. C.Form: FreeExample 180Structure ##STR621## ##STR622##R.sup.2 : HR.sup.3 : ##STR623##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 199.5-200.5.degree. C.Form: FreeExample 181Structure ##STR624## ##STR625##R.sup.2 : HR.sup.3 : ##STR626##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 211-212.degree. C.Form: FreeExample 182Structure ##STR627## ##STR628##R.sup.2 : HR.sup.3 : ##STR629##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 189.5-190.5.degree. C.Form: FreeExample 183Structure ##STR630## ##STR631##R.sup.2 : HR.sup.3 : ##STR632##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 176.5-177.5.degree. C.Form: FreeExample 184Structure ##STR633## ##STR634##R.sup.2 : HR.sup.3 : ##STR635##Crystalline form: Yellow powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 202-203.degree. C.Form: FreeExample 185Structure ##STR636## ##STR637##R.sup.2 : HR.sup.3 : ##STR638##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 219-220.degree. C.Form: FreeExample 186Structure ##STR639## ##STR640##R.sup.2 : HR.sup.3 : ##STR641##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 272-273.degree. C.Form: FreeExample 187Structure ##STR642## ##STR643##R.sup.2 : HR.sup.3 : ##STR644##Crystalline form: Yellow powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 146-147.degree. C.Form: FreeExample 188Structure ##STR645## ##STR646##R.sup.2 : HR.sup.3 : ##STR647##Crystalline form: Yellow powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 229.5-230.5.degree. C.Form: FreeExample 189Structure ##STR648## ##STR649##R.sup.2 : HR.sup.3 : ##STR650##Crystalline form: Yellow powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 119.5-120.5.degree. C.Form: FreeExample 190Structure ##STR651## ##STR652##R.sup.2 : HR.sup.3 : ##STR653##Crystalline form: Yellow powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 189-190.degree. C.Form: FreeExample 191Structure ##STR654## ##STR655##R.sup.2 : HR.sup.3 : ##STR656##Crystalline form: Yellow powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 207-208.degree. C.Form: FreeExample 192Structure ##STR657## ##STR658##R.sup.2 : HR.sup.3 : ##STR659##Crystalline form: Yellow powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 196.5-197.5.degree. C.Form: FreeExample 193Structure ##STR660## ##STR661##R.sup.2 : HR.sup.3 : ##STR662##Crystalline form: Yellow powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 182-183.degree. C.Form: FreeExample 194Structure ##STR663## ##STR664##R.sup.2 : HR.sup.3 : ##STR665##Crystalline form: Yellow powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 172-173.degree. C.Form: FreeExample 195Structure ##STR666## ##STR667##R.sup.2 : HR.sup.3 : ##STR668##Crystalline form: Yellow powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 197.5-198.5.degree. C.Form: FreeExample 196Structure ##STR669## ##STR670##R.sup.2 : HR.sup.3 : ##STR671##Crystalline form: Yellow powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 227-228.degree. C.Form: FreeExample 197Structure ##STR672## ##STR673##R.sup.2 : HR.sup.3 : ##STR674##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 216.5-217.5.degree. C.Form: FreeExample 198Structure ##STR675## ##STR676##R.sup.2 : HR.sup.3 : ##STR677##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 207-208.degree. C.Form: FreeExample 199Structure ##STR678## ##STR679##R.sup.2 : HR.sup.3 : ##STR680##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 236-237.degree. C.Form: FreeExample 200Structure ##STR681## ##STR682##R.sup.2 : HR.sup.3 : ##STR683##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 199.5-200.5.degree. C.Form: FreeExample 201Structure ##STR684## ##STR685##R.sup.2 : HR.sup.3 : ##STR686##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 171.5-172.5.degree. C.Form: FreeExample 202Structure ##STR687## ##STR688##R.sup.2 : HR.sup.3 : ##STR689##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 222.5-223.5.degree. C.Form: FreeExample 203Structure ##STR690## ##STR691##R.sup.2 : HR.sup.3 : ##STR692##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 209.5-210.5.degree. C.Form: FreeExample 204Structure ##STR693## ##STR694##R.sup.2 : HR.sup.3 : ##STR695##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 14)Form: HydrochlorideExample 205Structure ##STR696## ##STR697##R.sup.2 : HR.sup.3 : ##STR698##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 15)Form: HydrochlorideExample 206Structure ##STR699## ##STR700##R.sup.2 : HR.sup.3 : ##STR701##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 16)Form: HydrochlorideExample 207Structure ##STR702## ##STR703##R.sup.2 : HR.sup.3 : ##STR704##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 17)Form: HydrochlorideExample 208Structure ##STR705## ##STR706##R.sup.2 : HR.sup.3 : ##STR707##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 18)Form: HydrochlorideExample 209Structure ##STR708## ##STR709##R.sup.2 : HR.sup.3 : ##STR710##Crystalline form: Yellow powderRecrystallization solvent: Ethanol/waterNMR analysis: 19)Form: HydrochlorideExample 210Structure ##STR711## ##STR712##R.sup.2 : HR.sup.3 : ##STR713##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 20)Form: HydrochlorideExample 211Structure ##STR714## ##STR715##R.sup.2 : HR.sup.3 : ##STR716##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 159.5-160.5.degree. C.Form: FreeExample 212Structure ##STR717## ##STR718##R.sup.2 : HR.sup.3 : ##STR719##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 189.5-190.5.degree. C.Form: FreeExample 213Structure ##STR720## ##STR721##R.sup.2 : HR.sup.3 : ##STR722##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 170.5-171.5.degree. C.Form: FreeExample 214Structure ##STR723## ##STR724##R.sup.2 : HR.sup.3 : ##STR725##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 165-166.degree. C.Form: FreeExample 215Structure ##STR726## ##STR727##R.sup.2 : HR.sup.3 : ##STR728##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 173.5-174.5.degree. C.Form: FreeExample 216Structure ##STR729## ##STR730##R.sup.2 : HR.sup.3 : ##STR731##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 182-183.degree. C.Form: FreeExample 217Structure ##STR732## ##STR733##R.sup.2 : HR.sup.3 : ##STR734##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 225.5-226.5.degree. C.Form: FreeExample 219Structure ##STR735## ##STR736##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR737##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 21)Form: HydrochlorideExample 220Structure ##STR738## ##STR739##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR740##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 147.5-148.5.degree. C.Form: FreeExample 221Structure ##STR741## ##STR742##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR743##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 136-137.degree. C.Form: FreeExample 222Structure ##STR744## ##STR745##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR746##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 191.5-192.5.degree. C.Form: FreeExample 223Structure ##STR747## ##STR748##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR749##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 145-146.degree. C.Form: FreeExample 224Structure ##STR750## ##STR751##R.sup.2 : HR.sup.3 : ##STR752##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 22)Form: HydrochlorideExample 225Structure ##STR753## ##STR754##R.sup.2 : HR.sup.3 : ##STR755##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 23)Form: HydrochlorideExample 226Structure ##STR756## ##STR757##R.sup.2 : HR.sup.3 : ##STR758##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 24)Form: HydrochlorideExample 227Structure ##STR759## ##STR760##R.sup.2 : HR.sup.3 : ##STR761##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 25)Form: HydrochlorideExample 228Structure ##STR762## ##STR763##R.sup.2 : HR.sup.3 : ##STR764##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 26)Form: HydrochlorideExample 229Structure ##STR765## ##STR766##R.sup.2 : HR.sup.3 : ##STR767##Crystalline form: White powderRecrystallization solvent: Ethanol/waterNMR analysis: 27)Form: HydrochlorideExample 230Structure ##STR768## ##STR769##R.sup.2 : HR.sup.3 : ##STR770##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 206-207.degree. C.Form: FreeExample 231Structure ##STR771## ##STR772##R.sup.2 : HR.sup.3 : ##STR773##Crystalline form: White powderRecrystallization solvent: Chloroform/methanolMelting Point: 211-213.degree. C.Form: FreeExample 232Structure ##STR774## ##STR775##R.sup.2 : HR.sup.3 : ##STR776##Crystalline form: White powderRecrystallization solvent: Chloroform/methanolMelting Point: 228.5-229.5.degree. C.Form: FreeExample 233Structure ##STR777## ##STR778##R.sup.2 : HR.sup.3 : ##STR779##Crystalline form: White powderRecrystallization solvent: Chloroform/methanolMelting Point: 237-238.degree. C.Form: FreeExample 234Structure ##STR780## ##STR781##R.sup.2 : HR.sup.3 : ##STR782##Crystalline form: White powderRecrystallization solvent: Chloroform/methanolMelting Point: 226-228.degree. C.Form: FreeExample 235Structure ##STR783## ##STR784##R.sup.2 : HR.sup.3 : ##STR785##Crystalline form: White powderRecrystallization solvent: Chloroform/methanolMelting Point: 220-222.degree. C.Form: FreeExample 236Structure ##STR786## ##STR787##R.sup.2 : HR.sup.3 : ##STR788##Crystalline form: Colorless amorphousNMR analysis: 28)Form: FreeExample 237Structure ##STR789## ##STR790##R.sup.2 : HR.sup.3 : ##STR791##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 162-165.degree. C.Form: FreeExample 238Structure ##STR792## ##STR793##R.sup.2 : HR.sup.3 : ##STR794##Crystalline form: Light brown amorphousNMR analysis: 29)Form: FreeExample 239Structure ##STR795## ##STR796##R.sup.2 : HR.sup.3 : ##STR797##Crystalline form: Light brown amorphousNMR analysis: 30)Form: FreeExample 240Structure ##STR798## ##STR799##R.sup.2 : HR.sup.3 : ##STR800##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 215-217.degree. C.Form: FreeExample 241Structure ##STR801## ##STR802##R.sup.2 : HR.sup.3 : ##STR803##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 221-223.degree. C.Form: FreeExample 242Structure ##STR804## ##STR805##R.sup.2 : HR.sup.3 : ##STR806##Crystalline form: Colorless amorphousNMR analysis: 31)Form: FreeExample 243Structure ##STR807## ##STR808##R.sup.2 : HR.sup.3 : ##STR809##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 207-210.degree. C.Form: FreeExample 244Structure ##STR810## ##STR811##R.sup.2 : HR.sup.3 : ##STR812##Crystalline form: Colorless amorphousNMR analysis: 32)Form: FreeExample 245Structure ##STR813## ##STR814##R.sup.2 : HR.sup.3 : ##STR815##Crystalline form: Colorless amorphousNMR analysis: 33)Form: FreeExample 246Structure ##STR816## ##STR817##R.sup.2 : HR.sup.3 : ##STR818##Crystalline form: Colorless amorphousNMR analysis: 34)Form: FreeExample 247Structure ##STR819## ##STR820##R.sup.2 : HR.sup.3 : ##STR821##Crystalline form: Colorless amorphousNMR analysis: 35)Form: FreeExample 248Structure ##STR822## ##STR823##R.sup.2 : HR.sup.3 : ##STR824##Crystalline form: Light yellow powderRecrystallization solvent: EthanolMelting Point: 186-187.degree. C.Form: FreeExample 249Structure ##STR825## ##STR826##R.sup.2 : HR.sup.3 : ##STR827##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 190-191.degree. C.Form: FreeExample 250Structure ##STR828## ##STR829##R.sup.2 : HR.sup.3 : ##STR830##Crystalline form: Light yellow scalesRecrystallization solvent: Ethanol/waterMelting Point: 230-231.degree. C.Form: FreeExample 251Structure ##STR831## ##STR832##R.sup.2 : HR.sup.3 : ##STR833##Crystalline form: Light yellow needlesRecrystallization solvent: EthanolMelting Point: 227-228.degree. C.Form: FreeExample 252Structure ##STR834## ##STR835##R.sup.2 : HR.sup.3 : ##STR836##Crystalline form: Colorless needlesRecrystallization solvent: Ethyl acetateMelting Point: 192.degree. C.Form: FreeExample 253Structure ##STR837## ##STR838##R.sup.2 : HR.sup.3 : ##STR839##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 186.5-189.degree. C.Form: FreeExample 254Structure ##STR840## ##STR841##R.sup.2 : HR.sup.3 : ##STR842##Crystalline form: Light yellow scalesRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 165-167.degree. C.Form: FreeExample 255Structure ##STR843## ##STR844##R.sup.2 : HR.sup.3 : ##STR845##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 169-170.degree. C.Form: FreeExample 256Structure ##STR846## ##STR847##R.sup.2 : HR.sup.3 : ##STR848##Crystalline form: Colorless scalesRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 174-177.degree. C.Form: FreeExample 257Structure ##STR849## ##STR850##R.sup.2 : HR.sup.3 : ##STR851##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 114-118.degree. C.Form: FreeExample 258Structure ##STR852## ##STR853##R.sup.2 : HR.sup.3 : ##STR854##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 170-172.degree. C.Form: FreeExample 259Structure ##STR855## ##STR856##R.sup.2 : HR.sup.3 : ##STR857##Crystalline form: White powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 179-181.degree. C.Form: FreeExample 260Structure ##STR858## ##STR859##R.sup.2 : HR.sup.3 : ##STR860##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 118-121.degree. C.Form: FreeExample 261Structure ##STR861## ##STR862##R.sup.2 : HR.sup.3 : ##STR863##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 144-148.degree. C.Form: FreeExample 262Structure ##STR864## ##STR865##R.sup.2 : HR.sup.3 : ##STR866##Crystalline form: Colorless scalesRecrystallization solvent: Ethyl acetateMelting Point: 156-157.degree. C.Form: FreeExample 263Structure ##STR867## ##STR868##R.sup.2 : HR.sup.3 : ##STR869##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 204-206.degree. C.Form: FreeExample 264Structure ##STR870## ##STR871##R.sup.2 : HR.sup.3 : ##STR872##Crystalline form: Light yellow powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 165-167.degree. C.Form: FreeExample 265Structure ##STR873## ##STR874##R.sup.2 : HR.sup.3 : ##STR875##Crystalline form: Light yellow amorphousNMR analysis: 36)Form: FreeExample 266Structure ##STR876## ##STR877##R.sup.2 : HR.sup.3 : ##STR878##Crystalline form: White powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 122-124.degree. C.Form: FreeExample 267Structure ##STR879## ##STR880##R.sup.2 : HR.sup.3 : ##STR881##Crystalline form: Light yellow powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 116-117.degree. C.Form: FreeExample 268Structure ##STR882## ##STR883##R.sup.2 : HR.sup.3 : ##STR884##Crystalline form: White powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 121-123.degree. C.Form: FreeExample 269Structure ##STR885## ##STR886##R.sup.2 : HR.sup.3 : ##STR887##Crystalline form: Colorless needlesRecrystallization solvent: Ethyl acetateMelting Point: 186-187.degree. C.Form: FreeExample 270Structure ##STR888## ##STR889##R.sup.2 : HR.sup.3 : ##STR890##Crystalline form: White powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 139-142.degree. C.Form: FreeExample 271Structure ##STR891## ##STR892##R.sup.2 : HR.sup.3 : ##STR893##Crystalline form: Light yellow amorphousNMR analysis: 37)Form: FreeExample 272Structure ##STR894## ##STR895##R.sup.2 : HR.sup.3 : ##STR896##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 149.5-152.5.degree. C.Form: FreeExample 273Structure ##STR897## ##STR898##R.sup.2 : HR.sup.3 : ##STR899##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 150-152.5.degree. C.Form: FreeExample 274Structure ##STR900## ##STR901##R.sup.2 : HR.sup.3 : ##STR902##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 150.degree. C.Form: FreeExample 275Structure ##STR903## ##STR904##R.sup.2 : HR.sup.3 : ##STR905##Crystalline form: Colorless needlesRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 101-104.degree. C.Form: FreeExample 276Structure ##STR906## ##STR907##R.sup.2 : HR.sup.3 : ##STR908##Crystalline form: White powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 120-122.degree. C.Form: FreeExample 277Structure ##STR909## ##STR910##R.sup.2 : HR.sup.3 : ##STR911##Crystalline form: Light yellow amorphousNMR analysis: 38)Form: FreeExample 278Structure ##STR912## ##STR913##R.sup.2 : HR.sup.3 : ##STR914##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 183-186.degree. C.Form: FreeExample 279Structure ##STR915## ##STR916##R.sup.2 : HR.sup.3 : ##STR917##Crystalline form: Light brown powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 139-142.degree. C.Form: FreeExample 280Structure ##STR918## ##STR919##R.sup.2 : HR.sup.3 : ##STR920##Crystalline form: Light yellow powderRecrystallization solvent: EthanolMelting Point: 162-165.degree. C.Form: FreeExample 281Structure ##STR921## ##STR922##R.sup.2 : HR.sup.3 : ##STR923##Crystalline form: Light yellow scalesRecrystallization solvent: Ethyl acetateMelting Point: 224-227.degree. C.Form: FreeExample 282Structure ##STR924## ##STR925##R.sup.2 : HR.sup.3 : ##STR926##Crystalline form: Light yellow amorphousNMR analysis: 39)Form: FreeExample 283Structure ##STR927## ##STR928##R.sup.2 : HR.sup.3 : ##STR929##Crystalline form: Light yellow powderRecrystallization solvent: Ethanol/waterMelting Point: 162-164.degree. C.Form: FreeExample 284Structure ##STR930## ##STR931##R.sup.2 : HR.sup.3 : ##STR932##Crystalline form: Light yellow powderRecrystallization solvent: EthanolMelting Point: 238-241.degree. C. (decomposed)Form: HydrochlorideExample 285Structure ##STR933## ##STR934##R.sup.2 : HR.sup.3 : ##STR935##Crystalline form: Light yellow amorphousNMR analysis: 40)Form: FreeExample 286Structure ##STR936## ##STR937##R.sup.2 : HR.sup.3 : ##STR938##Crystalline form: Colorless amorphousNMR analysis: 41)Form: FreeExample 287Structure ##STR939## ##STR940##R.sup.2 : HR.sup.3 : ##STR941##Crystalline form: Colorless needlesRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 168-169.degree. C.Form: FreeExample 288Structure ##STR942## ##STR943##R.sup.2 : HR.sup.3 : ##STR944##Crystalline form: Light brown powderRecrystallization solvent: EthanolMelting Point: 189-191.degree. C.Form: FreeExample 289Structure ##STR945## ##STR946##R.sup.2 : HR.sup.3 : ##STR947##Crystalline form: White powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 200-202.degree. C.Form: FreeExample 290Structure ##STR948## ##STR949##R.sup.2 : HR.sup.3 : ##STR950##Crystalline form: Colorless scalesRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 143-146.degree. C.Form: FreeExample 291Structure ##STR951## ##STR952##R.sup.2 : HR.sup.3 : ##STR953##Crystalline form: White powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 117-117.5.degree. C.Form: FreeExample 292Structure ##STR954## ##STR955##R.sup.2 : HR.sup.3 : ##STR956##Crystalline form: Light brown powderRecrystallization solvent: Diethyl ether/ethyl acetateMelting Point: 225-226.degree. C.Form: FreeExample 293Structure ##STR957## ##STR958##R.sup.2 : HR.sup.3 : ##STR959##Crystalline form: White powderRecrystallization solvent: n-Hexane/ethanolMelting Point: 175-176.5.degree. C.Form: FreeExample 294Structure ##STR960## ##STR961##R.sup.2 : HR.sup.3 : ##STR962##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 234-236.degree. C.Form: FreeExample 295Structure ##STR963## ##STR964##R.sup.2 : HR.sup.3 : ##STR965##Crystalline form: Colorless scalesRecrystallization solvent: Ethyl acetateMelting Point: 172-174.degree. C.Form: FreeExample 296Structure ##STR966## ##STR967##R.sup.2 : HR.sup.3 : ##STR968##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 154-155.degree. C.Form: FreeExample 297Structure ##STR969## ##STR970##R.sup.2 : HR.sup.3 : ##STR971##Crystalline form: Light yellow needlesRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 181.5-183.5.degree. C.Form: FreeExample 298Structure ##STR972## ##STR973##R.sup.2 : HR.sup.3 : ##STR974##Crystalline form: White powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 173-175.degree. C.Form: FreeExample 299Structure ##STR975## ##STR976##R.sup.2 : HR.sup.3 : ##STR977##Crystalline form: White powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 137-138.degree. C.Form: FreeExample 300Structure ##STR978## ##STR979##R.sup.2 : HR.sup.3 : ##STR980##Crystalline form: Light yellow amorphousNMR analysis: 42)Form: FreeExample 301Structure ##STR981## ##STR982##R.sup.2 : HR.sup.3 : ##STR983##Crystalline form: Colorless needlesRecrystallization solvent: Diethyl ether/ethyl acetateMelting Point: 129-130.degree. C.Form: FreeExample 302Structure ##STR984## ##STR985##R.sup.2 : HR.sup.3 : ##STR986##Crystalline form: Colorless needlesRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 181-183.degree. C.Form: FreeExample 303Structure ##STR987## ##STR988##R.sup.2 : HR.sup.3 : ##STR989##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 248-249.degree. C.Form: FreeExample 304Structure ##STR990## ##STR991##R.sup.2 : HR.sup.3 : ##STR992##Crystalline form: Light yellow amorphousNMR analysis: 43)Form: FreeExample 305Structure ##STR993## ##STR994##R.sup.2 : HR.sup.3 : ##STR995##Crystalline form: Light yellow needlesRecrystallization solvent: EthanolMelting Point: 94-96.degree. C.Form: FreeExample 306Structure ##STR996## ##STR997##R.sup.2 : HR.sup.3 : ##STR998##Crystalline form: Light brown powderRecrystallization solvent: Ethyl acetateMelting Point: 159-161.degree. C.Form: FreeExample 307Structure ##STR999## ##STR1000##R.sup.2 : HR.sup.3 : ##STR1001##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 180-183.degree. C.Form: FreeExample 308Structure ##STR1002## ##STR1003##R.sup.2 : HR.sup.3 : ##STR1004##Crystalline form: Light brown powderRecrystallization solvent: EthanolMelting Point: 177-180.degree. C.Form: FreeExample 309Structure ##STR1005## ##STR1006##R.sup.2 : HR.sup.3 : ##STR1007##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 91-93.degree. C.Form: FreeExample 310Structure ##STR1008## ##STR1009##R.sup.2 : HR.sup.3 : ##STR1010##Crystalline form: Light brown scalesRecrystallization solvent: EthanolMelting Point: 155-156.5.degree. C.Form: FreeExample 311Structure ##STR1011## ##STR1012##R.sup.2 : HR.sup.3 : ##STR1013##Crystalline form: Colorless scalesRecrystallization solvent: Ethyl acetateMelting Point: 172.5-175.degree. C.Form: FreeExample 312Structure ##STR1014## ##STR1015##R.sup.2 : HR.sup.3 : ##STR1016##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 148-150.5.degree. C.Form: FreeExample 313Structure ##STR1017## ##STR1018##R.sup.2 : HR.sup.3 : ##STR1019##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 172-173.degree. C.Form: FreeExample 314Structure ##STR1020## ##STR1021##R.sup.2 : HR.sup.3 : ##STR1022##Crystalline form: Colorless scalesRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 133-135.degree. C.Form: FreeExample 315Structure ##STR1023## ##STR1024##R.sup.2 : HR.sup.3 : ##STR1025##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 217-219.degree. C.Form: FreeExample 316Structure ##STR1026## ##STR1027##R.sup.2 : HR.sup.3 : ##STR1028##Crystalline form: Colorless needlesRecrystallization solvent: Ethyl acetateMelting Point: 226-227.5.degree. C.Form: FreeExample 317Structure ##STR1029## ##STR1030##R.sup.2 : HR.sup.3 : ##STR1031##Crystalline form: Colorless amorphousNMR analysis: 44)Form: FreeExample 318Structure ##STR1032## ##STR1033##R.sup.2 : HR.sup.3 : ##STR1034##Crystalline form: White powderRecrystallization solvent: DichloromethaneMelting Point: 234-235.degree. C.Form: FreeExample 319Structure ##STR1035## ##STR1036##R.sup.2 : HR.sup.3 : ##STR1037##Crystalline form: Colorless prismsRecrystallization solvent: MethanolMelting Point: 218-218.5.degree. C.Form: FreeExample 320Structure ##STR1038## ##STR1039##R.sup.2 : HR.sup.3 : ##STR1040##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 202.5-206.degree. C.Form: FreeExample 321Structure ##STR1041## ##STR1042##R.sup.2 : HR.sup.3 : ##STR1043##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 174-176.degree. C.Form: FreeExample 322Structure ##STR1044## ##STR1045##R.sup.2 : HR.sup.3 : ##STR1046##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 216-218.degree. C.Form: FreeExample 323Structure ##STR1047## ##STR1048##R.sup.2 : HR.sup.3 : ##STR1049##Crystalline form: White powderMelting Point: >300.degree. C.NMR analysis: 45)Form: FreeExample 324Structure ##STR1050## ##STR1051##R.sup.2 : HR.sup.3 : ##STR1052##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 250.5-251.degree. C.Form: FreeExample 325Structure ##STR1053## ##STR1054##R.sup.2 : HR.sup.3 : ##STR1055##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 223-225.degree. C.Form: FreeExample 326Structure ##STR1056## ##STR1057##R.sup.2 : HR.sup.3 : ##STR1058##Crystalline form: Colorless prismsrRecrystallization solvent: MethanolMelting Point: 213-214.degree. C.Form: FreeExample 327Structure ##STR1059## ##STR1060##R.sup.2 : HR.sup.3 : ##STR1061##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 246-247.degree. C.Form: FreeExample 328Structure ##STR1062## ##STR1063##R.sup.2 : HR.sup.3 : ##STR1064##Crystalline form: Colorless prismsRecrystallization solvent: MethanolMelting Point: 248-251.degree. C.Form: FreeExample 329Structure ##STR1065## ##STR1066##R.sup.2 : HR.sup.3 : ##STR1067##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 268.5-270.5.degree. C.Form: FreeExample 330Structure ##STR1068## ##STR1069##R.sup.2 : HR.sup.3 : ##STR1070##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 174-176.degree. C.Form: HydrochlorideExample 331Structure ##STR1071## ##STR1072##R.sup.2 : HR.sup.3 : ##STR1073##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 130-134.degree. C.Form: FreeExample 332Structure ##STR1074## ##STR1075##R.sup.2 : HR.sup.3 : ##STR1076##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 214-217.degree. C.Form: HydrochlorideExample 333Structure ##STR1077## ##STR1078##R.sup.2 : HR.sup.3 : ##STR1079##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 218-220.degree. C.Form: HydrochlorideExample 334Structure ##STR1080## ##STR1081##R.sup.2 : HR.sup.3 : ##STR1082##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 222-225.degree. C.Form: FreeExample 335Structure ##STR1083## ##STR1084##R.sup.2 : HR.sup.3 : ##STR1085##Crystalline form: Colorless needlesRecrystallization solvent: Methanol/diethyl etherMelting Point: 171-172.degree. C.Form: FreeExample 336Structure ##STR1086## ##STR1087##R.sup.2 : HR.sup.3 : ##STR1088##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 235.5-236.degree. C.Form: DihydrochlorideExample 337Structure ##STR1089## ##STR1090##R.sup.2 : HR.sup.3 : ##STR1091##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 241-243.degree. C.Form: FreeExample 338Structure ##STR1092## ##STR1093##R.sup.2 : HR.sup.3 : ##STR1094##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 187-191.degree. C.Form: FreeExample 339Structure ##STR1095## ##STR1096##R.sup.2 : HR.sup.3 : ##STR1097##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 240-244.degree. C.Form: HydrochlorideExample 340Structure ##STR1098## ##STR1099##R.sup.2 : HR.sup.3 : ##STR1100##Crystalline form: Colorless prismsRecrystallization solvent: Methanol/diethyl etherMelting Point: 181-182.degree. C.Form: FreeExample 341Structure ##STR1101## ##STR1102##R.sup.2 : HR.sup.3 : ##STR1103##Crystalline form: Colorless prismsRecrystallization solvent: Methanol/diethyl etherMelting Point: 188-190.degree. C.Form: DihydrochlorideExample 342Structure ##STR1104## ##STR1105##R.sup.2 : HR.sup.3 : ##STR1106##Crystalline form: White powderRecrystallization solvent: Isopropyl alcoholMelting Point: 218-218.5.degree. C.Form: HydrochlorideExample 343Structure ##STR1107## ##STR1108##R.sup.2 : HR.sup.3 : ##STR1109##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 243-245.5.degree. C.Form: FreeExample 344Structure ##STR1110## ##STR1111##R.sup.2 : HR.sup.3 : ##STR1112##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 130-133.degree. C.Form: FreeExample 345Structure ##STR1113## ##STR1114##R.sup.2 : HR.sup.3 : ##STR1115##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 155-158.degree. C.Form: FreeExample 346Structure ##STR1116## ##STR1117##R.sup.2 : HR.sup.3 : ##STR1118##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl powderMelting Point: 208-210.degree. C.Form: HydrochlorideExample 347Structure ##STR1119## ##STR1120##R.sup.2 : HR.sup.3 : ##STR1121##Crystalline form: Colorless prismsRecrystallization solvent: Methanol/diethyl etherMelting Point: 154-155.degree. C.Form: HydrochlorideExample 348Structure ##STR1122## ##STR1123##R.sup.2 : HR.sup.3 : ##STR1124##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 142-143.degree. C.Form: FreeExample 349Structure ##STR1125## ##STR1126##R.sup.2 : HR.sup.3 : ##STR1127##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 120-125.degree. C.Form: HydrochlorideExample 350Structure ##STR1128## ##STR1129##R.sup.2 : HR.sup.3 : ##STR1130##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 91-95.degree. C.Form: HydrochlorideExample 351Structure ##STR1131## ##STR1132##R.sup.2 : HR.sup.3 : ##STR1133##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 145-146.5.degree. C.Form: FreeExample 352Structure ##STR1134## ##STR1135##R.sup.2 : HR.sup.3 : ##STR1136##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 105-105.5.degree. C.Form: FreeExample 353Structure ##STR1137## ##STR1138##R.sup.2 : HR.sup.3 : ##STR1139##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 151-155.degree. C.Form: DihydrochlorideExample 354Structure ##STR1140## ##STR1141##R.sup.2 : HR.sup.3 : ##STR1142##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 135.5-137.5.degree. C.Form: FreeExample 355Structure ##STR1143## ##STR1144##R.sup.2 : HR.sup.3 : ##STR1145##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 178-178.5.degree. C.Form: FreeExample 356Structure ##STR1146## ##STR1147##R.sup.2 : HR.sup.3 : ##STR1148##Crystalline form: White powderRecrystallization solvent: DichloromethaneMelting Point: 266.5-268.degree. C.Form: FreeExample 357Structure ##STR1149## ##STR1150##R.sup.2 : HR.sup.3 : ##STR1151##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 123-124.degree. C.Form: FreeExample 358Structure ##STR1152## ##STR1153##R.sup.2 : HR.sup.3 : ##STR1154##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 212-213.5.degree. C.Form: FreeExample 359Structure ##STR1155## ##STR1156##R.sup.2 : HR.sup.3 : ##STR1157##Crystalline form: Colorless scalesRecrystallization solvent: Ethyl acetateMelting Point: 160.5-162.degree. C.Form: FreeExample 360Structure ##STR1158## ##STR1159##R.sup.2 : HR.sup.3 : ##STR1160##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 103-105.degree. C.Form: FreeExample 361Structure ##STR1161## ##STR1162##R.sup.2 : HR.sup.3 : ##STR1163##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 145-146.degree. C.Form: FreeExample 362Structure ##STR1164## ##STR1165##R.sup.2 : HR.sup.3 : ##STR1166##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 247-250.degree. C.Form: FreeExample 363Structure ##STR1167## ##STR1168##R.sup.2 : HR.sup.3 : ##STR1169##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 198-199.degree. C.Form: FreeExample 364Structure ##STR1170## ##STR1171##R.sup.2 : HR.sup.3 : ##STR1172##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 181.5-182.5.degree. C.Form: FreeExample 365Structure ##STR1173## ##STR1174##R.sup.2 : HR.sup.3 : ##STR1175##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 170-170.5.degree. C.Form: FreeExample 366Structure ##STR1176## ##STR1177##R.sup.2 : HR.sup.3 : ##STR1178##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 156-158.degree. C.Form: FreeExample 367Structure ##STR1179## ##STR1180##R.sup.2 : HR.sup.3 : ##STR1181##Crystalline form: White powderRecrystallization solvent: Diethyl etherMelting Point: 168.5-170.5.degree. C.Form: FreeExample 368Structure ##STR1182## ##STR1183##R.sup.2 : HR.sup.3 : ##STR1184##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 177-181.5.degree. C.Form: HydrochlorideExample 369Structure ##STR1185## ##STR1186##R.sup.2 : HR.sup.3 : ##STR1187##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 211-213.degree. C.Form: FreeExample 370Structure ##STR1188## ##STR1189##R.sup.2 : HR.sup.3 : ##STR1190##Crystalline form: White powderNMR analysis: 46)Form: FreeExample 371Structure ##STR1191## ##STR1192##R.sup.2 : HR.sup.3 : ##STR1193##Crystalline form: White powderRecrystallization solvent: Methanol/ethyl acetateMelting Point: 166-167.degree. C.Form: FreeExample 372Structure ##STR1194## ##STR1195##R.sup.2 : HR.sup.3 : ##STR1196##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 127-131.degree. C.Form: FreeExample 373Structure ##STR1197## ##STR1198##R.sup.2 : HR.sup.3 : ##STR1199##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 170-171.degree. C.Form: FreeExample 374Structure ##STR1200## ##STR1201##R.sup.2 : HR.sup.3 : ##STR1202##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 125-126.degree. C.Form: FreeExample 375Structure ##STR1203## ##STR1204##R.sup.2 : HR.sup.3 : ##STR1205##Crystalline form: Light yellow amorphousNMR analysis: 47)Form: HydrochlorideExample 376Structure ##STR1206## ##STR1207##R.sup.2 : HR.sup.3 : ##STR1208##Crystalline form: Colorless amorphousNMR analysis: 48)Form: Hydrochloride__________________________________________________________________________
1) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.92 (1H, t, J=6.2 Hz), 1.98 (1H, t, J=6.4 Hz), 2.8 (2H, t, J=6.4 Hz), 3.76 (2H, t, J=6.2 Hz), 6.75 (1H, d, J=7.6 Hz), 6.86 (2H, d, J=8.6 Hz), 6.8-7.1 (2H, m), 7.20 (1H, d, J=7 Hz), 7.30 (2H, d, J=8.6 Hz), 7.72 (2H, d, J=8.6 Hz), 7.84 (2H, d, J=8.6 Hz), 10.13 (1H, s)
2) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 2.05 (2H, quint, J=6.4 Hz), 2.91 (2H, t, J=6.4 Hz), 3.86 (2H, t, J=6.4 Hz), 6.85 (1H, d, J=7.6 Hz), 6.9-7.2 (2H, m), 7.30 (1H, d, J=7.2 Hz), 7.44 (2H, d, J=8.5 Hz), 7.85 (2H, d, J=8.5 Hz), 8.1-8.2 (4H, m), 10.65 (1H, s), 13.2-13.4 (1H, br)
3) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.9-2.1 (2H, m), 2.84 (2H, t, J=6.5 Hz), 3.82 (6H, s), 3.90 (2H, t, J=6.6 Hz), 6.5-7.2 (7H, m), 7.35 (2H, d, J=8.7 Hz), 7.55 (2H, d, J=8.7 Hz), 8.05 (1H, s)
4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.9-2.1 (2H, m), 2.37 (6H, s), 2.84 (2H, t, J=6.6 Hz), 3.90 (2H, t, J=6.6 Hz), 6.71 (1H, d, J=7.9 Hz), 6.8-7.2 (4H, m), 7.35 (2H, d, J=8.6 Hz), 7.44 (2H, s), 7.56 (2H, d, J=8.6 Hz), 8.00 (1H, s)
5) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.9-2.2 (2H, m), 2.12 (3H, s), 2.84 (2H, t, J=6.6 Hz), 3.89 (2H, t, J=6.5 Hz), 6.71 (1H, d, J=7.8 Hz), 6.87 (1H, t, J=7 Hz), 6.99 (1H, t, J=7.3 Hz), 7.15 (1H, d, J=6.5 Hz), 7.28 (2H, d, J=8.6 Hz), 7.41 (2H, d, J=8.6 Hz), 8.03 (1H, s)
6) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.8-1.3 (6H, m), 1.6-2.3 (9H, m), 2.83 (2H, t, J=6.6 Hz), 3.89 (2H, t, J=6.5 Hz), 6.72 (1H, d, J=7.9 Hz), 6.8-7.1 (2H, m), 7.15 (1H, d, J=7.4 Hz), 7.28 (2H, d, J=8.3 Hz), 7.44 (2H, d, J=8.4 Hz), 7.9-8.1 (1H, m)
7) .sup.1 H-NMR (CDCl.sub.3) .delta.: 2.02 (2H, quint, J=6.5 Hz), 2.81 (2H, t, J=6.6 Hz), 3.69 (2H, s), 3.87 (2H, t, J=6.6 Hz), 6.66 (1H, d, J=8.2 Hz), 6.8-7.0 (2H, m), 7.13 (1H, d, J=7.3 Hz), 7.2-7.4 (9H, m), 7.59 (1H, s)
8) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.7-2.1 (17H, m), 2.83 (2H, t, J=6.7 Hz), 3.90 (2H, t, J=6.6 Hz), 6.68 (1H, d, J=8.1 Hz), 6.8-7.1 (2H, m), 7.14 (1H, d, J=7 Hz), 7.32 (2H, d, J=8.7 Hz), 7.39 (1H, s), 7.46 (2H, d, J=8.7 Hz)
9) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.99 (2H, quint, J=6.5 Hz), 2.82 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=6.5 Hz), 6.8-7.1 (4H, m), 7.1-7.3 (2H, m), 7.4-7.6 (3H, m), 7.67 (1H, S), 7.8-8.0 (3H, m), 8.42 (1H, s)
10) .sup.1 H-NMR (CDCl.sub.3) .delta.: 2.00 (2H, quint, J=6.5 Hz), 2.83 (2H, t, J=6.6 Hz), 3.85 (2H, t, J=6.6 Hz), 3.86 (3H, s), 6.8-7.1 (6H, m), 7.1-7.3 (2H, m), 7.64 (1H, s), 7.8-8.0 (3H, m), 8.22 (1H, s)
11) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.98 (2H, quint, J=6.5 Hz), 2.82 (2H, t, J=6.5 Hz), 3.81 (2H, t, J=6.5 Hz), 3.84 (3H, s), 6.8-7.5 (10H, m), 7.68 (1H, s), 7.95 (1H, d, J=8.2 Hz), 8.52 (1H, s)
12) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.7-1.9 (2H, m), 2.70 (2H, t, J=6.6 Hz), 3.70 (2H, t, J=6.4 Hz), 6.8-7.3 (6H, m), 7.4-7.7 (2H, m), 7.8-7.9 (5H, m), 8.04 (1H, d, J=8 Hz), 8.33 (1H, s), 8.90 (1H, s)
13) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.7-2.1 (17H, m), 2.84 (2H, t, J=6.5 Hz), 3.89 (2H, t, J=6.4 Hz), 6.8-7.2 (6H, m), 7.42 (1H, s), 7.56 (1H, s), 7.81 (1H, d, J=8.1 Hz)
14) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.0-1.5 (5H, m), 1.5-2.0 (5H, m), 2.2-3.8 (8H, m), 4.2-5.2 (3H, m), 6.77 (1H, d, J=7.2 Hz), 7.1-7.4 (4H, m), 7.47 (2H, d, J=8.6 Hz), 7.58 (1H, d, J=6.2 Hz), 10.06 (1H, s), 10.9-12.1 (1H, br)
15) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 2.5-3.8 (6H, m), 4.2-5.2 (3H, m), 6.81 (1H, d, J=6.8 Hz), 7.1-7.3 (4H, m), 7.5-7.7 (3H, m), 7.8-8.0 (1H, m), 7.97 (2H, d, J=1.8 Hz), 10.66 (1H, s), 11.1-12.3 (1H, br)
16) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 2.20 (3H, s), 2.27 (3H, s), 2.5-3.8 (6H, m), 4.3-5.3 (3H, m), 6.82 (1H, d, J=7.2 Hz), 7.1-7.4 (7H, m), 7.5-7.8 (3H, m), 10.43 (1H, s), 11.0-12.2 (1H, br)
17) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 2.34 (3H, s), 2.5-3.7 (6H, m), 4.3-5.2 (3H, m), 6.82 (1H, d, J=6.8 Hz), 7.2-7.7 (11H, m), 10.41 (1H, s), 10.8-12.3 (1H, br)
18) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 2.38 (3H, s), 2.5-3.8 (6H, m), 4.3-5.3 (3H, m), 6.81 (1H, d, J=7.0 Hz), 7.1-7.5 (6H, m), 7.5-7.8 (5H, m), 10.35 (1H, s), 10.9-12.2 (1H, br)
19) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 2.37 (3H, s), 2.5-3.7 (6H, m), 4.3-5.2 (3H, m), 6.81 (1H, d, J=7.2 Hz), 7.2-7.4 (6H, m), 7.5-7.7 (3H, m), 7.84 (2H, d, J=8.0 Hz), 10.31 (1H, S), 10.9-12.2 (1H, br)
20) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 2.5-3.8 (6H, m), 4.3-5.2 (3H, m), 6.82 (1H, d, J=7.4 Hz), 7.2-7.3 (4H, m), 7.5-7.8 (5H, m), 7.75 (1H, d, J=1.8 Hz), 10.70 (1H, s), 10.8-12.2 (1H, br)
21) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 2.5-3.8 (9H, m), 4.3-4.7 (1H, m), 4.7-5.1 (2H, m), 6.8-7.1 (3H, m), 7.1-7.4 (2H, m), 7.5-7.7 (2H, m), 7.8-8.0 (3H, m), 9.79 (1H, s), 10.8-12.2 (1H, br)
22) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 0.8-1.2 (3H, m), 1.7-2.2 (2H, m), 2.5-3.8 (5H, m), 4.3-5.2 (3H, m), 6.80 (1H, d, J=7.2 Hz), 7.1-7.3 (4H, m), 7.6-7.7 (3H, m), 7.85 (1H, s), 7.96 (2H, d, J=1.8 Hz), 10.62 (1H, s), 10.8-12.0 (1H, br)
23) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 0.8-1.1 (3H, m), 1.7-2.1 (2H, m), 2.37 (3H, s), 2.7-3.8 (5H, m), 4.4-5.2 (3H, m), 6.81 (1H, d, J=7.6 Hz), 7.2-7.4 (6H, m), 7.6-7.7 (3H, m), 7.84 (2H, d, J=8.2 Hz), 10.29 (1H, s), 10.5-11.8 (1H, br)
24) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 0.8-1.2 (3H, m), 1.7-2.1 (2H, m), 2.38 (3H, s), 2.6-3.8 (5H, m), 4.3-5.2 (3H, m), 6.81 (1H, d, J=7.0 Hz), 7.2-7.5 (6H, m), 7.6-7.8 (5H, m), 10.33 (1H, s), 10.5-11.7 (1H, br)
25) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 0.8-1.2 (3H, m), 1.7-2.1 (2H, m), 2.6-3.8 (5H, m), 3.8-5.2 (3H, m), 6.82 (1H, d, J=7.2 Hz), 7.1-7.5 (8H, m), 7.5-7.7 (3H, m), 10.42 (1H, s), 10.7-12.0 (1H, br)
26) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 0.8-2.0 (15H, m), 2.2-2.5 (1H, m), 2.6-3.7 (5H, m), 4.3-5.2 (3H, m), 6.76 (1H, d, J=7.0 Hz), 7.1-7.4 (4H, m), 7.46 (2H, d, J=8.6 Hz), 7.61 (1H, d, J=6.4 Hz), 10.03 (1H, s), 10.5-11.8 (1H, br)
27) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 0.8-1.1 (3H, m), 1.7-2.0 (2H, m), 2.20 (3H, s), 2.29 (3H, s), 2.6-3.7 (5H, m), 4.3-5.2 (3H, m), 6.82 (1H, d, J=7.0 Hz), 7.2-7.4 (7H, m), 7.5-7.7 (3H, m), 10.41 (1H, s), 10.6-12.0 (1H, br)
28) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.21 (3H, t, J=7.1 Hz), 3.00-3.25 (3H, m), 4.00-4.30 (4H, m), 6.63 (1H, d, J=7.8 Hz), 6.86 (1H, t, J=7.3 Hz), 7.00 (1H, t, J=6.3 Hz), 7.10-7.31 (3H, m), 7.40-7.57 (3H, m), 7.77 (2H, d, J=1.9 Hz), 8.76 (1H, brs)
29) .sup.1 H-NMR (CDCl.sub.3) .delta.: 2.29 (3H, s), 2.32 (3H, s), 2.34 (3H, s), 2.50-3.15 (11H, m), 3.79 (1H, dd, J=13.2 Hz, 7.3 Hz), 4.05 (1H, dd, J=13.2 Hz, 5.7 Hz), 6.62 (1H, d, J=7.7 Hz), 6.82-7.48 (8H, m), 7.53 (2H, d, J=8.4 Hz), 8.05 (1H, brs)
30) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.65-2.01 (4H, m), 2.31 (3H, s), 2.35 (3H, s), 2.55-3.02 (6H, m), 3.09 (1H, dd, J=15 Hz, 5 Hz), 3.70 (1H, dd, J=12.5 Hz, 8.0 Hz), 4.22 (1H, dd, J=12.5 Hz, 5 Hz), 6.67 (1H, d, J=7.8 Hz), 6.80-7.32 (7H, m), 7.37 (2H, d, J=8.6 Hz), 7.53 (1H, d, J=8.3 Hz), 7.66 (1H, brs)
31) .sup.1 H-NMR (CDCl.sub.3) .delta.: 2.80 (1H, dd, J=16.1 Hz, 5.3 Hz), 3.16 (1H, dd, J=15.8 Hz, 5.3 Hz), 3.75-4.50 (3H, m), 4.87-5.10 (3H, m), 6.80-7.60 (14H, m), 7.74 (2H, d, J=1.9 Hz), 8.47 (1H, brs)
32) .sup.1 H-NMR (CDCl.sub.3) .delta.: 2.35 (6H, s), 2.72-3.10 (3H, m), 3.65-3.78 (1H, m), 4.06-4.18 (1H, m), 6.60-7.62 (9H, m), 7.74 (2H, d, J=1.8 Hz), 8.52 (1H, brs)
33) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.87 t, 3H, s), 2.68 (1H, dd, J=5.6 Hz, 16 Hz), 3.14 (1H, dd, J=5.6 Hz, 16 Hz), 3.70-3.95 (2H, m), 4.32-4.50 (1H, m), 6.29 (1H, d, J=7.6 Hz), 6.90-7.80 (11H, m), 9.16 (1H, brs)
34) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.62 (1H, brs), 1.90-2.25 (2H, m), 2.55 (3H, s), 3.78 (1H, t, J=5.1 Hz), 3.95 (2H, t, J=6.7 Hz), 6.69 (1H, t, J=7.9 Hz), 6.90-7.13 (2H, m), 7.23-7.40 (3H, m), 7.42-7.56 (3H, m), 7.77 (2H, d, J=1.9 Hz), 8.53 (1H, brs)
35) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.80-2.02 (1H, m), 2.20-2.35 (1H, m), 2.31 (6H, s), 3.52 (1H, t, J=5.4 Hz), 3.68-3.83 (1H, m), 3.95-4.15 (1H, m), 6.59 (1H, d, J=7.8 Hz), 6.81-7.10 (2H, m), 7.16-7.50 (6H, m), 7.80 (2H, d, J=1.8 Hz), 9.13 (1H, brs)
36) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.35-1.60 (1H, m), 1.65-2.20 (3H, m), 2.65-3.20 (5H, m), 3.81 (2H, d, J=6.5 Hz), 4.90-5.10 (1H, m), 6.60 (1H, d, J=8.0 Hz), 6.90 (1H, t, J=8.0 Hz), 7.00-7.50 (6H, m)
37) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.30-2.25 (4H, m), 2.55-3.20 (3H, m), 3.35 (2H, s), 3.80 (2H, s), 4.90-5.10 (1H, m), 6.62 (1H, d, J=8.0 Hz), 6.85-7.45 (12H, m), 9.27 (1H, brs)
38) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.35-2.25 (4H, m), 2.33 (3H, s), 2.60-3.20 (3H, m), 3.12 (2H, s), 3.61 (2H, s), 5.00 (1H, brs), 6.50-7.60 (13H, m), 9.14 (1H, brs)
39) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.27 (3H, t, J=7.1 Hz), 1.25-2.50 (12H, m), 2.70-3.10 (4H, m), 3.05 (2H, s), 4.15 (2H, q, J=7.0 Hz), 4.90-5.10 (1H, m), 6.63 (1H, d, J=7.5 Hz), 6.91 (1H, t, J=7.5 Hz), 7.00-7.50 (6H, m), 9.14 (1H, brs)
40) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.30-1.65 (1H, m), 1.80-2.25 (5H, m), 2.70-3.20 (3H, m), 4.01 (2H, d, J=5.0 Hz), 4.90-5.10 (1H, m), 6.61 (1H, d, J=7.7 Hz), 6.89 (1H, t, J=7.0 Hz), 7.00-7.45 (6H, m), 9.05 (1H, brs)
41) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.18 (6H, s), 1.30-2.20 (4H, m), 2.60-3.20 (3H, m), 3.30 (2H, s), 3.73 (2H, s), 4.90-5.10 (1H, m), 6.61 (1H, d, J=7.3 Hz), 6.70-7.45 (12H, m), 9.50 (1H, brs)
42) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.19 (3H, t, J=7.0 Hz), 1.30-1.70 (1H, m), 1.75-2.20 (3H, m), 2.65-3.15 (3H, m), 3.46 (2H, q, J=7.0 Hz), 3.88 (2H, s), 4.90-5.10 (1H, m), 6.55-7.45 (13H, m), 8.36 (1H, brs)
43) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.08 (3H, t, J=7.2 Hz), 1.05-2.25 (14H, m), 2.25-3.25 (10H, m), 4.90-5.10 (1H, m), 6.64 (1H, d, J=7.6 Hz), 6.90 (1H, t, J=7.2 Hz), 6.94-7.50 (6H, m), 11.50 (1H, brs)
44) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.06 (3H, t, J=7.5 Hz), 1.30-2.20 (6H, m), 2.60-3.20 (3H, m), 3.65 (1H, m), 3.95 (1H, brs), 4.90-5.10 (1H, m), 6.50-6.75 (3H, m), 6.75-7.05 (2H, m), 7.05-7.55 (8H, m), 8.67 (1H, brs)
45) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.28-1.57 (1H, m), 1.69-2.20 (3H, m), 2.59-3.15 (3H, m), 4.74-4.98 (1H, m), 6.62-6.80 (1H, m), 6.86-7.37 (5H, m), 7.50-7.70 (2H, m), 8.95-9.02 (1H, m), 9.03-9.15 (2H, m), 10.85 (1H, s)
46) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.40-1.66 (5H, m), 1.72-2.20 (7H, m), 2.63-3.18 (3H, m), 3.42 (2H, t, J=6.7 Hz), 4.00 (2H, t, J=6.3 Hz), 4.91-5.13 (1H, m), 6.58-6.72 (1H, m), 6.82-7.00 (3H, m), 7.02-7.30 (4H, m), 7.36-7.51 (2H, m), 7.70-7.88 (2H, m), 7.91 (1H, s)
47) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 2.05-2.95 (8H, m), 3.43-3.70 (1H, m), 4.08-4.30 (1H, m), 4.72-5.00 (1H, m), 6.70-8.08 (11H, m), 10.8 (1H, s), 11.1 (1H, brs)
48) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 2.10-3.00 (8H, m), 3.47-3.70 (1H, m), 4.07-4.33 (1H, m), 4.75-4.98 (1H, m), 6.78-6.91 (1H, m), 7.05-7.22 (2H, m), 7.30-7.97 (9H, m), 10.75 (1H, s), 10.94 (1H, brs)
Example 377
To a solution of 1-�4-(4-formylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.3 g) in methanol (10 ml) is added gradually sodium borohydride (59 mg) under ice-cooling and the mixture is stirred at room temperature for 2 hours. Water is added to the mixture and the solvent is distilled off under reduced pressure. The resulting residue is extracted with dichloromethane, washed with water, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from methanol to give 1-�4-(4-hydroxymethylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (165 mg) as white powder, m.p. 224.5.degree.-225.5.degree. C.
Using the suitable starting materials, the compound of the above Example 37 is obtained in the same manner as in Example 377.
Example 378
To a solution of 1-�4-(4-methoxycarbonylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.5 g) in methanol (20 ml) is added 5% aqueous sodium hydroxide solution (10 ml) and the mixture is stirred at room temperature overnight. Methanol is distilled off under reduced pressure and the resulting residue is acidified with diluted aqueous hydrochloric acid solution. The precipitated crystal is collected by filtration to give 1-�4-(4-carboxybenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.4 g) as white powder, m.p. >300.degree. C.
.sup.1 H-NMR (DMSO-d.sub.6) .delta.: 2.05 (2H, quint, J=6.4 Hz), 2.91 (2H, t, J=6.4 Hz), 3.86 (2H, t, J=6.4 Hz), 6.85 (1H, d, J=7.6 Hz), 6.9-7.2 (2H, m), 7.30 (1H, d, J=7.2 Hz), 7.44 (2H, d, J=8.5 Hz), 7.85 (2H, d, J=8.5 Hz), 8.1-8.2 (4H, m), 10.65 (1H, s), 13.2-13.4 (1H, br)
Using the suitable starting materials, the compounds of the above Examples 39, 241, 252, 253 and 362 are obtained in the same manner as in Example 378.
Example 379
To a solution of 1-�4-(3-acetyloxybenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (1.5 g) in methanol (20 ml) is added 5% aqueous sodium hydroxide solution (10 ml) and the mixture is stirred at room temperature overnight. Methanol is distilled off under reduced pressure and the resulting residue is acidified with diluted aqueous hydrochloric acid solution. The precipitated crystal is collected by filtration and recrystallized from methanol to give 1-�4-(3-hydroxybenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (1.22 g) as white powder, m.p. 217.degree.-218.degree. C.
Using the suitable starting materials, the compounds of the above Examples 10, 343, 356, 364 and 365 are obtained in the same manner as in Example 379.
Example 380
To a solution of 1-�4-(3-hydroxybenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.4 g) in acetone (5 ml) are added potassium carbonate (0.22 g) and ethyl iodide (0.34 g), and the mixture is refluxed for 5 hours. Then, acetone is distilled off under reduced pressure and water is added to the residue. The precipitated crystal is collected by filtration, and recrystallized from methanol to give 1-�4-(3-ethoxybenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.36 g) as white powder, m.p. 170.5.degree.-171.5.degree. C.
Using the suitable starting materials, the compounds of the above Examples 11, 12, 13, 14, 33, 35, 48, 50-55, 90-92, 97-100, 109-111, 120-122, 136-138, 165-167, 175-177, 192-194, 211, 212, 214, 321, 322, 330-333, 335, 336, 339-342, 344-355, 357-366 and 370-374 are obtained in the same manner as in Example 380.
Example 381
Ethanol (50 ml) is added to 10% Pd--C (0.1 g) and thereto is added-1-�4-(3-nitrobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.73 g). The mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. After completion of the reduction, 10% Pd--C is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is extracted with dichloromethane and the extract is dried over magnesium sulfate. The solvent is distilled off under reduced pressure and recrystallized from methanol to give 1-�4-(3-aminobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.54 g) as white powder, m.p. 205.5.degree.-206.5.degree. C.
Using the suitable starting materials, the compounds of the above Examples 24, 334 and 338 are obtained in the same manner as in Example 381.
Example 382
To a solution of 1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (0.5 g) in dichloromethane (20 ml) is added triethylamine (0.3 g), and thereto is added benzoyl chloride (0.28 g) under ice-cooling. The mixture is stirred at room temperature for 1 hour. To the reaction mixture is added water and extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1) and recrystallized from methanol to give 1-�4-(benzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (245 mg) as white powder, m.p. 202.5.degree.-203.5.degree. C.
Using the suitable starting materials, the compounds of the above Examples 2-119, 131-373, 375 and 376 are obtained in the same manner as in Example 382.
Example 383
Thionyl chloride (10 ml) is added to 1-(4-carboxybenzoyl)-1,2,3,4-tetrahydroquinoline (0.5 g) and the mixture is refluxed for 1 hour. Thionyl chloride is distilled off under reduced pressure to give 4-�1-(1,2,3,4-tetrahydroquinolyl)carbonyl!benzoyl chloride. Separately, to a solution of m-anisidine (0.27 g) in dichloromethane (20 ml) is added triethylamine (0.34 g), and thereto is added gradually the above obtained 4-�1-(1,2,3,4-tetrahydroquinolyl)carbonyl!benzoyl chloride under ice-cooling and the mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from methanol to give 1-�4-(3-methoxyanilinocarbonyl)benzoyl!-1,2,3,4-tetrahydroquinoline (203 mg) as colorless needles, m.p. 154.degree.-155.degree. C.
Using the suitable starting materials, the compounds of the above Examples 120, 122-130 and 374 are obtained in the same manner as in Example 383.
Example 384
To 4-oxo-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline(0.7 g) are added tetrahyrdofuran (10 ml) and methanol (10 ml). To the mixture is added sodium borohydride (0.1 g) in portions and the mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the mixture is extracted with dichloromethane. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane.fwdarw.dichloromethane:methanol=20:1), and recrystallized from ethanol to give 4-hydroxy-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.4 g) as white powder, m.p. 215.degree.-217.degree. C.
Example 385
To 3-ethoxycarbonyl-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.6 g) are added an aqueous solution of sodium hydroxide (0.1 g) in water (1 ml) and ethanol (5 ml). The mixture is stirred at room temperature for 15 minutes, and acidified with diluted hydrochloric acid, extracted with dichloromethane. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane.fwdarw.dichloromethane:methanol=50:1), and recrystallized from ethanol to give 3-carboxy-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.4 g) as white powder, m.p. 221.degree.-223.degree. C.
Example 386
To 3-carboxy-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (3.7 g) are added tetrahydrofuran (50 ml) and thionyl chloride (5 ml). The mixture is reacted at 60.degree. C. for 1 hour. The reaction mixture is concentrated and to the residue is added acetone (20 ml). To the mixture is added dropwise a solution of sodium azide (1.0 g) in water (5 ml) under ice-cooling. The reaction mixture is stirred at the same temperature for 30 minutes and extracted with dichloromethane, dried over magnesium sulfate. The solvent is concentrated and to the resulting residue are added anhydrous toluene (30 ml) and benzyl alcohol (1.7 g). The mixture is refluxed for 1 hour. The reaction mixture is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane.fwdarw.dichloromethane:methanol=50:1) to give 3-benzyloxycarbonylamino-1-�4-(3,5-dichlorobenzoylamino)benzoyl)-1,2,3,4-tetrahydroquinoline (3.7 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.80 (1H, dd, J=16.1 Hz, 5.3 Hz), 3.16 (1H, dd, J=15.8 Hz, 5.3 Hz), 3.75-4.50 (3H, m), 4.87-5.10 (3H, m), 6.80-7.60 (14H, m), 7.74 (2H, d, J=1.9 Hz), 8.47 (1H, brs)
Example 387
To 3-benzyloxycarbonylamino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (3.3 g) are added acetic acid (40 ml) and 10% Pd--C (0.4 g) and the reaction mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. One hour thereafter, the catalyst is removed by filtration and the filtrate is concentrated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1), and recrystallized from ethanol to give 3-amino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (1.6 g) as white powder, m.p. 207.degree.-210.degree. C.
Example 388
To 3-amino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.5 g) are added methanol (10 ml), 37% formaline (0.8 ml) and sodium cyanoborohydride (0.16 g). To the mixture is added acetic acid (0.5 ml) under ice-cooling and the mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the mixture is basified with potassium carbonate and extracted with dichloromethane. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane.fwdarw.dichloromethane:methanol=20:1) to give 3-dimethylamino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.3 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3) .delta.: 2.35 (6H, s), 2.72-3.10 (3H, m), 3.65-3.78 (1H, m), 4.06-4.18 (1H, m), 6.60-7.62 (9H, m), 7.74 (2H, d, J=1.8 Hz), 8.52 (1H, brs)
Using the suitable starting materials, the compounds of the above Examples 246, 247, 375 and 376 are obtained in the same manner as in Example 388.
Example 389
To 3-amino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.44 g) are added dichloromethane (5 ml) and acetic anhydride (0.12 g) and the mixture is stirred for 1 hour. The reaction mixture is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane.fwdarw.dichloromethane:methanol=50:1) to give 3-acetylamino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.3 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.87 (3H, s), 2.68 (1H, dd, J=5.6 Hz, 16 Hz), 3.14 (1H, dd, J=5.6 Hz, 16 Hz), 3.70-3.95 (2H, m), 4.32-4.50 (1H, m), 6.29 (1H, d, J=7.6 Hz), 6.90-7.80 (11H, m), 9.16 (1H, brs)
Using the suitable starting materials, the compound of the above Example 242 is obtained in the same manner as in Example 389.
Example 390
To 4-oxo-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline(0.5 g) are added 40% solution of methylamine in methanol (5 ml), molecular sieves 4A (1 g) and dimethylformamide (6 ml), and the mixture is refluxed for 4 hours. After cooling, the reaction mixture is filtered and to the filtrate is added sodium borohydride (80 mg), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated and water is added to the resulting residue, and extracted with ethyl acetate. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to give 4-methylamino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.2 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.62 (1H, brs), 1.90-2.25 (2H, m), 2.55 (3H, s), 3.78 (1H, t, J=5.1 Hz), 3.95 (2H, t, J=6.7 Hz), 6.99 (1H, d, J=7.9 Hz), 6.90-7.13 (2H, m)
Using the suitable starting materials, the compounds of the above Examples 238, 239, 244, 247, 375 and 376 are obtained in the same manner as in Example 390.
Example 391
To 3-carboxy-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.7 g) are added dimethylformamide (7 ml), diethyl cyanophosphate (0.3 ml) and dimethylamine hydrochloride (0.15 g). Further thereto is added triethylamine (0.8 ml) and the mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and extracted with ethyl acetate. The solvent is concentrated and to the resulting residue is added diethyl ether. The precipitated crystal is collected by filtration to give 3-dimethylamido-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.5 g) as light yellow powder, m.p. 186.degree.-187.degree. C.
Example 392
To a solution of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (3.0 g) in dichloromethane (50 ml) is added succinic anhydride (1.4 g) and the mixture is stirred at room temperature for 4.5 hours. The reaction mixture is evaporated under reduced pressure in order to remove the solvent therefrom, and the resulting crystal is recrystallized from ethyl acetate to give 1-�4-(3-carboxypropionylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (3.61 g) as colorless needles, m.p. 192.degree. C.
Using the suitable starting materials, the compound of the above Example 253 is obtained in the same manner as in Example 392.
Example 393
1-�4-(3-Carboxypropionylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) is dissolved in dimethylformamide (1 ml) and thereto is added dropwise diethyl cyanophosphate (0.25 g) under ice-cooling. The mixture is stirred at room temperature for 30 minutes and then cooled again with ice. Thereto are added dropwise a solution of diethylamine (0.11 g) in dimethylformamide (1 ml) and triethylamine (0.34 g). The mixture is stirred at room temperature for 16 hours. The solvent is distilled off under reduced pressure and water is added to the resulting residue. The mixture is extracted with dichloromethane. The organic layer is washed successively with diluted hydrochloric acid, water, saturated sodium hydrogen carbonate solution, water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate), and recrystallized from n-hexane/ethyl acetate to give 1-�4-(3-diethylaminocarbonylpropionylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.42 g) as colorless scales, m.p. 165.degree.-167.degree. C.
Using the suitable starting materials, the compounds of the above Examples 255-263 are obtained in the same manner as in Example 393.
Example 394
To a solution of 1-�4-(2-chloroacetylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (2.06 g) in dimethylformamide (5 ml) are added sodium iodide (0.90 g), potassium carbonate (1.1 g) and cyclohexylamine (0.89 g), and the mixture is stirred at room temperature for 2 hours. Dimethylformamide is distilled off under reduced pressure and water is added to the resulting residue. The mixture is extracted with dichloromethane. The organic layer is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate), and recrystallized from n-hexane/ethyl acetate to give 1-�4-(2-cyclohexylaminoacetylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (2.03 g) as white powder, m.p. 139.degree.-142.degree. C.
Using the suitable starting materials, the compounds of the above Examples 271-309 and 317 are obtained in the same manner as in Example 394.
Example 395
o-Cresol (0.36 g) is dissolved in dimethylsulfoxide (4 ml) containing sodium hydroxide powder (0.18 g) and thereto is added 1-�4-(2-chloroacetylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.03 g). The mixture is stirred at 90.degree. C. for 7.5 hours. The reaction mixture is poured into ice-water (300 ml) and the precipitated crystal is collected by filtration, washed with water, and purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1), and recrystallized from ethyl acetate to give 1-{4-�2-(2-methylphenoxy)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (546 mg) as colorless scales, m.p. 172.5.degree.-175.degree. C.
Using the suitable starting materials, the compounds of the above Examples 310 and 312-316 are obtained in the same manner as in Example 395.
Example 396
A mixture of 1-{4-�2-(6-bromohexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.00 g), sodium acetate (0.36 g), sodium iodide (0.55 g) and acetic acid (20 ml) is refluxed for 1 day. The solvent is distilled off and the resulting residue is extracted with ethyl acetate. The organic layer is washed successively with 2N aqueous sodium hydroxide solution and saturated saline solution, and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=500:1), and recrystallized from ethanol to give 1-{4-�2-(6-acetyloxyhexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (1.07 g) as white powder, m.p. 145.degree.-146.degree. C.
Using the suitable starting materials, the compound of the above Example 360 is obtained in the same manner as in Example 396.
Example 397
A mixture of 1-{4-�2-(6-bromohexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g), diethylamine (0.16 ml), triethylamine (0.21 ml) and acetonitrile (20 ml) is refluxed overnight. The solvent is distilled off and the resulting residue is dissolved in chloroform, washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=200:1.fwdarw.50:1) and converted into the hydrochloride thereof in methanol. The product is recrystallized from methanol/diethyl ether to give 1-{4-�2-(6-diethylaminohexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (0.42 g) as white powder, m.p. 91.degree.-95.degree. C.
Using the suitable starting materials, the compounds of the above Examples 330, 332, 333, 335, 336, 339, 341, 342, 344-349, 352-355, 357 and 366 are obtained in the same manner as in Example 397.
Example 398
A mixture of 1-{4-�2-(6-bromohexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (4.00 g), potassium phthalimide (2.02 g) and dimethylformamide (100 ml) is stirred at 100.degree. C. for 5 hours. The reaction mixture is filtered and the filtrate is distilled off. The resulting residue is extracted with ethyl acetate and the organic layer is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane), and recrystallized from methanol/diethyl ether to give 1-{4-�2-(6-phthalimidohexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (4.06 g) as white powder, m.p. 145.degree.-146.5.degree. C.
Using the suitable starting materials, the compounds of the above Examples 331, 340, 364 and 365 are obtained in the same manner as in Example 398.
Example 399
A mixture of 1-{4-�2-�6-phthalimidohexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (3.75 g), hydrazine hydrate (0.44 ml) and ethanol (30 ml) is refluxed for 3.5 hours. The precipitated crystal is collected by filtration, dried and purified by silica gel column chromatography (eluent; chloroform:methanol:aqueous ammonia=100:10:1), and recrystallized from methanol/diethyl ether to give 1-{4-�2-(6-aminohexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.52 g) as white powder, m.p. 135.5.degree.-137.5.degree. C.
Using the suitable starting materials, the compounds of the above Examples 284, 344 and 345 are obtained in the same manner as in Example 399.
Example 400
A mixture of 1-{4-�2-(6-aminohexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g), acetic anhydride (20 ml) and two drops of conc. sulfuric acid is stirred at room temperature for 3 hours. To the reaction mixture is added aqueous 2N aqueous sodium hydroxide solution under ice-cooling and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=200:1), and recrystallized from methanol/diethyl ether to give 1-{4-�2-(6-acetylaminohexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.60 g) as colorless needles, m.p. 171.degree.-172.degree. C.
Example 401
A mixture of 1-{4-�2-(6-aminohexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g), benzoyl chloride (0.20 ml), triethylamine and dichloromethane (20 ml) is stirred at room temperature for 1 hour. The reaction mixture is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is recrystallized from ethanol to give 1-{4-�2-(6-benzoylaminohexyloxy)benzoylamino!benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.71 g) as white powder, m.p. 178.degree.-178.5.degree. C.
Using the suitable starting materials, the compounds of the above Examples 348 and 357 are obtained in the same manner as in Examples 400 and 401.
Example 402
A mixture of 1-�4-(2-ethoxycarbonylmethoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.00 g), aqueous ammonia (100 ml), ammonium chloride (0.3 g) and methanol (150 ml) is heated at 100.degree. C. for 4 hours in a sealed tube. The solvent is distilled off and the resulting residue is extracted with chloroform, washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=50:1), and recrystallized from methanol/diethyl ether to give 1-�4-(2-carbamoylmethoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.43 g) as white powder, m.p. 198.degree.-199.degree. C.
Example 403
A mixture of 1-�4-(2-chloro-4-aminobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g), acetic anhydride (15 ml), acetic acid (5 ml) and a drop of sulfuric acid is stirred at room temperature for 1 hour. To the reaction mixture is added aqueous 2N aqueous sodium hydroxide solution and the mixture is extracted with chloroform. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is recrystallized from methanol/diethyl ether to give 1-�4-(2-chloro-4-acetylaminobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.28 g) as white powder, m.p. 214.degree.-243.degree. C.
Using the suitable starting materials, the compound of the above Example 44 is obtained in the same manner as in Example 403.
Example 404
A mixture of 1-�4-(1-benzyloxycarbonyl-4-piperidinylcarbonylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (8.00 g), 10% Pd--C (0.8 g) and ethanol (250 ml) is subjected to catalytic hydrogenation at 50.degree. C. under 4 atm. of hydrogen pressure for 6 hours. The catalyst is removed by filtration and the filtrate is evaporated under reduced pressure. The resulting residue is extracted with ethyl acetate and washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol:ammonium hydroxide=50:10:1) to give 1-{4-�4-(4-piperidinyl)benzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (4.80 g), and a part (0.5 g) thereof is converted into the hydrochloride thereof in methanol. The hydrochloride is recrystallized from methanol/diethyl ether to give 1-{4-�4-(4-piperidinyl)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (0.42 g) as white powder, m.p. 177.degree.-181.5.degree. C.
Example 405
Using the suitable starting materials, the following compound is obtained in the same manner as in the above Examples 1, 382 and 388.
1-�4-(4-Dimethylaminobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline, colorless amorphous
.sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.90-2.00 (2H, m), 2.82 (2H, t, J=6.5 Hz), 2.98 (6H, s), 3.77 (2H, t, J=6.5 Hz), 6.70-7.30 (6H, m), 7.32 (2H, d, J=8.6 Hz), 7.73 (2H, d, J=8.6 Hz), 8.00-8.20 (1H, m), 8.39 (1H, d, J=2.2 Hz), 10.37 (1H, s)
Using the suitable starting materials, the following compounds are obtained in the same manner as in Example 1.
TABLE 2__________________________________________________________________________ ##STR1209##__________________________________________________________________________Example 406Structure ##STR1210## ##STR1211##R.sup.2 : HR.sup.3 : ##STR1212##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 216-218.degree. C.Form: FreeExample 407Structure ##STR1213## ##STR1214##R.sup.2 : HR.sup.3 : ##STR1215##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 181-183.degree. C.Form: FreeExample 408Structure ##STR1216## ##STR1217##R.sup.2 : HR.sup.3 : ##STR1218##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 207-208.degree. C.Form: FreeExample 409Structure ##STR1219## ##STR1220##R.sup.2 : HR.sup.3 : ##STR1221##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 213-214.degree. C.Form: FreeExample 410Structure ##STR1222## ##STR1223##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1224##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 136-138.degree. C.Form: FreeExample 411Structure ##STR1225## ##STR1226##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1227##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 130-132.degree. C.Form: FreeExample 412Structure ##STR1228## ##STR1229##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1230##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 143-145.degree. C.Form: FreeExample 413Structure ##STR1231## ##STR1232##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1233##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 171-173.degree. C.Form: FreeExample 414Structure ##STR1234## ##STR1235##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1236##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 162-164.degree. C.Form: FreeExample 415Structure ##STR1237## ##STR1238##R.sup.2 : HR.sup.3 : ##STR1239##Crystalline form: Colorless amorphousNMR analysis: 49)Form: FreeExample 416Structure ##STR1240## ##STR1241##R.sup.2 : HR.sup.3 : ##STR1242##Crystalline form: Colorless amorphousNMR analysis: 50)Form: FreeExample 417Structure ##STR1243## ##STR1244##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1245##Crystalline form: Colorless amorphousNMR analysis: 51)Form: FreeExample 418Structure ##STR1246## ##STR1247##R.sup.2 : HR.sup.3 : ##STR1248##Crystalline form: Colorless needlesRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 228.5-230.degree. C.Form: FreeExample 419Structure ##STR1249## ##STR1250##R.sup.2 : HR.sup.3 : ##STR1251##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 205.5-206.5.degree. C.Form: FreeExample 420Structure ##STR1252## ##STR1253##R.sup.2 : HR.sup.3 : ##STR1254##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 210-212.degree. C.Form: FreeExample 421Structure ##STR1255## ##STR1256##R.sup.2 : HR.sup.3 : ##STR1257##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 166-167.degree. C.Form: FreeExample 422Structure ##STR1258## ##STR1259##R.sup.2 : HR.sup.3 : ##STR1260##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 191.5-192.5.degree. C.Form: FreeExample 423Structure ##STR1261## ##STR1262##R.sup.2 : HR.sup.3 : ##STR1263##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 209-210.degree. C.Form: FreeExample 424Structure ##STR1264## ##STR1265##R.sup.2 : HR.sup.3 : ##STR1266##Crystalline form: Colorless amorphousNMR analysis: 52)Form: FreeExample 425Structure ##STR1267## ##STR1268##R.sup.2 : HR.sup.3 : ##STR1269##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 148-149.degree. C.Form: FreeExample 426Structure ##STR1270## ##STR1271##R.sup.2 : HR.sup.3 : ##STR1272##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 157-158.degree. C.Form: FreeExample 427Structure ##STR1273## ##STR1274##R.sup.2 : HR.sup.3 : ##STR1275##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 194.5-195.5.degree. C.Form: FreeExample 428Structure ##STR1276## ##STR1277##R.sup.2 : HR.sup.3 : ##STR1278##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 179.5-180.5.degree. C.Form: FreeExample 429Structure ##STR1279## ##STR1280##R.sup.2 : HR.sup.3 : ##STR1281##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 190-191.degree. C.Form: FreeExample 430Structure ##STR1282## ##STR1283##R.sup.2 : HR.sup.3 : ##STR1284##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 159-160.degree. C.Form: FreeExample 431Structure ##STR1285## ##STR1286##R.sup.2 : HR.sup.3 : ##STR1287##Crystalline form: Colorless amorphousNMR analysis: 53)Form: HydrochlorideExample 432Structure ##STR1288## ##STR1289##R.sup.2 : HR.sup.3 : ##STR1290##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 155-156.degree. C.Form: FreeExample 433Structure ##STR1291## ##STR1292##R.sup.2 : HR.sup.3 : ##STR1293##Crystalline form: Colorless amorphousNMR analysis: 54)Form: FreeExample 434Structure ##STR1294## ##STR1295##R.sup.2 : HR.sup.3 : ##STR1296##Crystalline form: Colorless amorphousNMR analysis: 55)Form: FreeExample 435Structure ##STR1297## ##STR1298##R.sup.2 : HR.sup.3 : ##STR1299##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 175-177.degree. C.Form: FreeExample 436Structure ##STR1300## ##STR1301##R.sup.2 : HR.sup.3 : ##STR1302##Crystalline form: Colorless amorphousNMR analysis: 56)Form: FreeExample 437Structure ##STR1303## ##STR1304##R.sup.2 : HR.sup.3 : ##STR1305##Crystalline form: Colorless amorphousNMR analysis: 57)Form: FreeExample 438Structure ##STR1306## ##STR1307##R.sup.2 : HR.sup.3 : ##STR1308##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 219-220.degree. C.Form: FreeExample 439Structure ##STR1309## ##STR1310##R.sup.2 : HR.sup.3 : ##STR1311##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 215-218.degree. C.Form: FreeExample 440Structure ##STR1312## ##STR1313##R.sup.2 : HR.sup.3 : ##STR1314##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 128.5-129.5.degree. C.Form: FreeExample 441Structure ##STR1315## ##STR1316##R.sup.2 : HR.sup.3 : ##STR1317##Crystalline form: Colorless amorphousNMR analysis: 58)Form: FreeExample 442Structure ##STR1318## ##STR1319##R.sup.2 : HR.sup.3 : ##STR1320##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 153-154.degree. C.Form: FreeExample 443Structure ##STR1321## ##STR1322##R.sup.2 : HR.sup.3 : ##STR1323##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 150-153.degree. C.Form: FreeExample 444Structure ##STR1324## ##STR1325##R.sup.2 : HR.sup.3 : ##STR1326##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 139-141.degree. C.Form: FreeExample 445Structure ##STR1327## ##STR1328##R.sup.2 : HR.sup.3 : ##STR1329##Crystalline form: Colorless amorphousNMR analysis: 59)Form: FreeExample 446Structure ##STR1330## ##STR1331##R.sup.2 : HR.sup.3 : ##STR1332##Crystalline form: Colorless amorphousNMR analysis: 60)Form: FreeExample 447Structure ##STR1333## ##STR1334##R.sup.2 : HR.sup.3 : ##STR1335##Crystalline form: Colorless amorphousNMR analysis: 61)Form: FreeExample 448Structure ##STR1336## ##STR1337##R.sup.2 : HR.sup.3 : ##STR1338##Crystalline form: Colorless amorphousNMR analysis: 62)Form: FreeExample 449Structure ##STR1339## ##STR1340##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1341##Crystalline form: Colorless amorphousNMR analysis: 63)Form: FreeExample 450Structure ##STR1342## ##STR1343##R.sup.2 : HR.sup.3 : ##STR1344##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 172.5-173.5.degree. C.Form: FreeExample 451Structure ##STR1345## ##STR1346##R.sup.2 : HR.sup.3 : ##STR1347##Crystalline form: Colorless prismsRecrystallization solvent: Methanol/diethyl etherMelting Point: 122.5-123.degree. C.Form: FreeExample 452Structure ##STR1348## ##STR1349##R.sup.2 : HR.sup.3 : ##STR1350##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 198-199.5.degree. C.Form: FreeExample 453Structure ##STR1351## ##STR1352##R.sup.2 : HR.sup.3 : ##STR1353##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 118-119.5.degree. C.Form: HydrochlorideExample 454Structure ##STR1354## ##STR1355##R.sup.2 : HR.sup.3 : ##STR1356##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 163-165.degree. C.Form: HydrochlorideExample 455Structure ##STR1357## ##STR1358##R.sup.2 : HR.sup.3 : ##STR1359##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 246-248.degree. C.Form: HydrochlorideExample 456Structure ##STR1360## ##STR1361##R.sup.2 : HR.sup.3 : ##STR1362##Crystalline form: White powderRecrystallization solvent: Chloroform/ethanolMelting Point: 204-205.degree. C.Form: FreeExample 457Structure ##STR1363## ##STR1364##R.sup.2 : HR.sup.3 : ##STR1365##Crystalline form: Colorless prismsRecrystallization solvent: Methanol/diethyl etherMelting Point: 127-128.degree. C.Form: HydrochlorideExample 458Structure ##STR1366## ##STR1367##R.sup.2 : HR.sup.3 : ##STR1368##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 220-221.degree. C.Form: FreeExample 459Structure ##STR1369## ##STR1370##R.sup.2 : HR.sup.3 : ##STR1371##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 190-192.degree. C.Form: FreeExample 460Structure ##STR1372## ##STR1373##R.sup.2 : HR.sup.3 : ##STR1374##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 189-191.degree. C.Form: HydrochlorideExample 461Structure ##STR1375## ##STR1376##R.sup.2 : HR.sup.3 : ##STR1377##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 173-174.degree. C.Form: FreeExample 462Structure ##STR1378## ##STR1379##R.sup.2 : HR.sup.3 : ##STR1380##Crystalline form: White powderRecrystallization solvent: Dichloromethane/ethanolMelting Point: 129-130.degree. C.Form: FreeExample 463Structure ##STR1381## ##STR1382##R.sup.2 : HR.sup.3 : ##STR1383##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 130-133.degree. C.Form: HydrochlorideExample 464Structure ##STR1384## ##STR1385##R.sup.2 : HR.sup.3 : ##STR1386##Crystalline form: Light yellow powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 170.5-172.degree. C.Form: HydrochlorideExample 465Structure ##STR1387## ##STR1388##R.sup.2 : HR.sup.3 : ##STR1389##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 126-131.degree. C.Form: HydrochlorideExample 466Structure ##STR1390## ##STR1391##R.sup.2 : HR.sup.3 : ##STR1392##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 182-185.degree. C.Form: DihydrochlorideExample 467Structure ##STR1393## ##STR1394##R.sup.2 : HR.sup.3 : ##STR1395##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 116-121.degree. C.Form: HydrochlorideExample 468Structure ##STR1396## ##STR1397##R.sup.2 : HR.sup.3 : ##STR1398##Crystalline form: Colorless prismsRecrystallization solvent: Methanol/diethyl etherMelting Point: 178-182.5.degree. C.Form: FreeExample 469Structure ##STR1399## ##STR1400##R.sup.2 : HR.sup.3 : ##STR1401##Crystalline form: Colorless particlesRecrystallization solvent: Methanol/diethyl etherMelting Point: 185-187.degree. C.Form: FreeExample 470Structure ##STR1402## ##STR1403##R.sup.2 : HR.sup.3 : ##STR1404##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 215-217.degree. C.Form: FreeExample 471Structure ##STR1405## ##STR1406##R.sup.2 : HR.sup.3 : ##STR1407##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 176-178.degree. C.Form: FreeExample 472Structure ##STR1408## ##STR1409##R.sup.2 : HR.sup.3 : ##STR1410##Crystalline form: Light yellow powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 194.5-197.degree. C.Form: FreeExample 473Structure ##STR1411## ##STR1412##R.sup.2 : HR.sup.3 : ##STR1413##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 161.5-165.5.degree. C.Form: HydrochlorideExample 474Structure ##STR1414## ##STR1415##R.sup.2 : HR.sup.3 : ##STR1416##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 152-153.degree. C.Form: FreeExample 475Structure ##STR1417## ##STR1418##R.sup.2 : HR.sup.3 : ##STR1419##Crystalline form: Colorless needlesRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 147-148.degree. C.Form: FreeExample 476Structure ##STR1420## ##STR1421##R.sup.2 : HR.sup.3 : ##STR1422##Crystalline form: Light yellow powderRecrystallization solvent: Ethyl acetateMelting Point: 215-217.degree. C.Form: FreeExample 477Structure ##STR1423## ##STR1424##R.sup.2 : HR.sup.3 : ##STR1425##Crystalline form: Colorless amorphousNMR analysis: 64)Form: FreeExample 478Structure ##STR1426## ##STR1427##R.sup.2 : HR.sup.3 : ##STR1428##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 180-181.degree. C.Form: FreeExample 479Structure ##STR1429## ##STR1430##R.sup.2 : HR.sup.3 : ##STR1431##Crystalline form: Colorless amorphousNMR analysis: 65)Form: FreeExample 480Structure ##STR1432## ##STR1433##R.sup.2 : HR.sup.3 : ##STR1434##Crystalline form: Colorless amorphousNMR analysis: 66)Form: FreeExample 481Structure ##STR1435## ##STR1436##R.sup.2 : HR.sup.3 : ##STR1437##Crystalline form: Colorless amorphousNMR analysis: 67)Form: FreeExample 482Structure ##STR1438## ##STR1439##R.sup.2 : HR.sup.3 : ##STR1440##Crystalline form: Colorless scalesRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 165-167.degree. C.Form: FreeExample 483Structure ##STR1441## ##STR1442##R.sup.2 : HR.sup.3 : ##STR1443##Crystalline form: Colorless amorphousNMR analysis: 68)Form: FreeExample 484Structure ##STR1444## ##STR1445##R.sup.2 : HR.sup.3 : ##STR1446##Crystalline form: Colorless amorphousNMR analsysi: 69)Form: FreeExample 485Structure ##STR1447## ##STR1448##R.sup.2 : HR.sup.3 : ##STR1449##Crystalline form: Colorless amorphousNMR analysis: 70)Form: FreeExample 486Structure ##STR1450## ##STR1451##R.sup.2 : HR.sup.3 : ##STR1452##Crystalline form: Colorless amorphousNMR analysis: 71)Form: FreeExample 487Structure ##STR1453## ##STR1454##R.sup.2 : HR.sup.3 : ##STR1455##Crystalline form: Colorless amorphousNMR analysis: 72)Form: FreeExample 488Structure ##STR1456## ##STR1457##R.sup.2 : HR.sup.3 : ##STR1458##Crystalline form: Colorless amorphousNMR analysis: 73)Form: FreeExample 489Structure ##STR1459## ##STR1460##R.sup.2 : HR.sup.3 : ##STR1461##Crystalline form: Light yellow amorphousNMR analysis: 74)Form: FreeExample 490Structure ##STR1462## ##STR1463##R.sup.2 : HR.sup.3 : ##STR1464##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 182-182.5.degree. C.Form: FreeExample 491Structure ##STR1465## ##STR1466##R.sup.2 : HR.sup.3 : ##STR1467##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 244-245.degree. C.Form: FreeExample 492Structure ##STR1468## ##STR1469##R.sup.2 : HR.sup.3 : ##STR1470##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 220-221.5.degree. C.Form: FreeExample 493Structure ##STR1471## ##STR1472##R.sup.2 : HR.sup.3 : ##STR1473##Crystalline form: Light yellow amorphousNMR analysis: 75)Form: FreeExample 494Structure ##STR1474## ##STR1475##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1476##Crystalline form: Light yellow amorphousNMR analysis: 76)Form: FreeExample 495Structure ##STR1477## ##STR1478##R.sup.2 : HR.sup.3 : ##STR1479##Crystalline form: Colorless needlesRecrystallization solvent: Methanol/diethyl etherMelting Point: 171-172.degree. C.Form: FreeExample 496Structure ##STR1480## ##STR1481##R.sup.2 : HR.sup.3 : ##STR1482##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 178-178.5.degree. C.Form: FreeExample 497Structure ##STR1483## ##STR1484##R.sup.2 : HR.sup.3 : ##STR1485##Example 498Structure ##STR1486## ##STR1487##R.sup.2 : HR.sup.3 : ##STR1488##Example 499Structure ##STR1489## ##STR1490##R.sup.2 : HR.sup.3 : ##STR1491##Example 500Structure ##STR1492## ##STR1493##R.sup.2 : HR.sup.3 : ##STR1494##Example 501Structure ##STR1495## ##STR1496##R.sup.2 : HR.sup.3 : ##STR1497##Example 502Structure ##STR1498## ##STR1499##R.sup.2 : HR.sup.3 : ##STR1500##Example 502Structure ##STR1501## ##STR1502##R.sup.2 : HR.sup.3 : ##STR1503##Example 503Structure ##STR1504## ##STR1505##R.sup.2 : HR.sup.3 : ##STR1506##Example 504Structure ##STR1507## ##STR1508##R.sup.2 : HR.sup.3 : ##STR1509##Crystalline form: Light yellow scalesRecrystallization solvent: Ethanol/waterMelting Point: 129-131.degree. C.Form: FreeExample 505Structure ##STR1510## ##STR1511##R.sup.2 : HR.sup.3 : ##STR1512##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 199-201.degree. C.Form: FreeExample 506Structure ##STR1513## ##STR1514##R.sup.2 : HR.sup.3 : ##STR1515##Crystalline form: Colorless amorphousNMR analysis: 77)Form: FreeExample 507Structure ##STR1516## ##STR1517##R.sup.2 : HR.sup.3 : ##STR1518##Crystalline form: White powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 187.5-189.degree. C.Form: FreeExample 508Structure ##STR1519## ##STR1520##R.sup.2 : 2-ClR.sup.3 : ##STR1521##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 161-164.degree. C.Form: FreeExample 509Structure ##STR1522## ##STR1523##R.sup.2 : HR.sup.3 : ##STR1524##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 242-243.degree. C.Form: FreeExample 510Structure ##STR1525## ##STR1526##R.sup.2 : 3-OCH.sub.3R.sup.3 : 4-NHCOCH.sub.2 ClCrystalline form: White powderRecrystallization solvent: Dichloroethane/diethyl etherMelting Point: 186-188.degree. C.Form: FreeExample 511Structure ##STR1527## ##STR1528##R.sup.2 : HR.sup.3 : ##STR1529##Crystalline form: Colorless amorphousNMR analysis: 78)Form: FreeExample 512Structure ##STR1530## ##STR1531##R.sup.2 : HR.sup.3 : ##STR1532##Crystalline form: Colorless amorphousNMR analysis: 79)Form: Free__________________________________________________________________________
49) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.11 (3H, t, J=7.1 Hz), 1.90-2.25 (2H, m), 2.29 (3H, s), 2.55 (2H, q, J=7.1 Hz), 3.62-3.90 (2H, m), 4.00-4.20 (1H, m), 6.63 (1H, d, J=7.9 Hz), 6.85-7.10 (2H, m), 7.25-7.80 (9H, m), 8.25 (1H, brs)
50) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.10 (3H, t, J=7.1 Hz), 1.90-2.20 (2H, m), 2.28 (3H, s), 3.60-3.90 (2H, m), 3.95-4.20 (1H, m), 6.62 (1H, d, J=7.9 Hz), 6.80-7.10 (2H, m), 7.20 (2H, d, J=8.6 Hz), 7.31-7.55 (4H, m), 7.80 (2H, d, J=1.9 Hz), 9.05 (1H, brs)
51) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.80-2.05 (1H, m), 2.15-2.50 (1H, m), 2.34 (6H, s), 2.51 (3H, s), 3.48-3.62 (1H, m), 3.72 (3H, s), 3.70-3.85 (1H, m), 4.00-4.22 (1H, m), 6.64 (1H, d, J=7.8 Hz), 6.84-7.58 (9H, m), 8.16 (1H, brs), 8.40 (1H, d, J=8.7 Hz)
52) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.16 (3H, t, J=7.1 Hz), 2.40-2.70 (2H, m), 2.90-3.30 (3H, m), 3.80-4.20 (2H, m), 4.80-5.00 (1H, m), 6.60-6.80 (1H, m), 7.00-7.70 (10H, m), 8.24 (1H, s)
53) .sup.1 H-NMR(DMSO-d.sub.6) .delta.; 1.0-2.5 (10H, m), 2.34 (3H, s), 3.30-3.80 (4H, m), 4.50-5.30 (3H, m), 6.70-7.00 (1H, m), 7.10-7.80 (11H, m), 10.43 (1H, s), 10.5-12.0 (1H, br)
54) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.10-2.10 (10H, m), 2.40-2.70 (1H, m), 2.80-3.20 (3H, m), 3.92 (2H, s), 4.90-5.20 (1H, m), 6.50-6.70 (1H, m), 6.80-7.60 (8H, m), 7.75 (2H, s), 8.73 (1H, s)
55) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.10-2.20 (10H, m), 2.40-2.70 (1H, m), 2.90-3.30 (3H, m), 3.93 (2H, s), 4.90-5.20 (1H, m), 6.62 (1H, d, J=7.6 Hz), 6.90-7.70 (10H, m), 8.29 (1H, s)
56) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.50-2.10 (2H, m), 2.38 (6H, s), 2.30-2.70 (1H, m), 2.70-3.00 (2H, m), 3.45 (1H, d, J=13 Hz), 3.81 (1H, d, J=14 Hz), 4.70-5.00 (1H, m), 7.0-7.50 (12H, m), 8.23 (1H, s)
57) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.50-2.10 (2H, m), 2.42 (3H, s), 2.40-2.70 (1H, m), 2.80-3.00 (2H, m), 3.52 (1H, d, J=13 Hz), 3.85 (1H, d, J=13 Hz), 4.70-5.00 (1H, m), 7.00-7.70 (12H, m), 8.54 (1H, s)
58) .sup.1 H-NMR(CDCl.sub.3) .delta.; 2.43 (3H, s), 2.47 (3H, s), 3.00-3.30 (3H, m), 3.76 (1H, d, J=14 Hz), 4.06 (1H, d, J=14 Hz), 4.90-5.20 (1H, m), 6.50-6.80 (3H, m), 6.90-7.50 (6H, m), 7.70-8.00 (2H, m), 8.48 (1H, d, J=8 Hz), 10.58 (1H, s)
59) .sup.1 H-NMR(CDCl.sub.3) .delta.; 2.41 (3H, s), 2.44 (3H, s), 2.90-3.20 (3H, m), 3.74 (1H, d, J=13 Hz), 4.07 (1H, d, J=14 Hz), 4.80-5.00 (1H, m), 6.67 (1H, d, J=7 Hz), 6.76 (1H, d, J=7 Hz), 7.00-7.50 (8H, m), 7.55 (1H, s), 7.70-7.90 (2H, m)
60) .sup.1 H-NMR(CDCl.sub.3) .delta.; 2.41 (3H, s), 2.80-3.20 (3H, m), 3.73 (1H, d, J=13 Hz), 4.03 (1H, d, J=14 Hz), 6.66 (2H, d, J=7.6 Hz), 6.90-8.00 (10H, m), 8.57 (1H, s)
61) .sup.1 H-NMR(CDCl.sub.3) .delta.; 2.40 (3H, s), 2.90-3.20 (3H, m), 3.73 (1H, d, J=13 Hz), 4.07 (1H, d, J=13 Hz), 4.70-5.00 (1H, m), 6.60-6.80 (2H, m), 6.90-8.00 (10H, m), 8.54 (1H, s)
62) .sup.1 H-NMR(CDCl.sub.3) .delta.; 2.41 (3H, s), 2.90-3.20 (3H, m), 3.75 (1H, d, J=14 Hz), 4.08 (1H, d, J=14 Hz), 4.80-5.00 (1H, m), 6.67 (1H, d, J=7.6 Hz), 6.82 (1H, d, J=7.6 Hz), 6.90-7.90 (10H, m), 8.08 (1H, s)
63) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.23 (3H, t, J=7 Hz), 1.40-1.70 (1H, m), 1.90-2.20 (3H, m), 2.70-3.30 (3H, m), 3.40-3.60 (5H, m), 3.91 (2H, s), 5.00-5.20 (1H, m), 6.60-7.40 (11H, m), 8.12 (1H, d, J=8 Hz), 8.99 (1H, s)
64) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.35-1.70 (1H, m), 1.80-2.20 (3H, m), 2.25-2.35 (1H, m), 2.65-3.20 (3H, m), 4.01 (2H, s), 4.05-4.17 (2H, m), 4.90-5.10 (1H, m), 6.61 (1H, d, J=7.5 Hz), 6.75-7.50 (12H, m), 8.44 (1H, brs)
65) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.13 (3H, t, J=7.0 Hz), 1.30-1.65 (4H, m), 1.80-2.20 (3H, m), 2.28 (3H, s), 2.65-3.40 (5H, m), 4.90-5.10 (1H, m), 6.63 (1H, d, J=7.8 Hz), 6.75-7.00 (3H, m), 7.00-7.45 (8H, m), 8.85 (1H, brs)
66) .sup.1 H-NMR(CDCl.sub.3) .delta.; 0.88 (3H, t, J=7.4 Hz), 1.16 (3H, t, J=7.0 Hz), 1.35-2.20 (6H, m), 2.27 (3H, s), 2.60-3.20 (3H, m), 3.20-3.45 (2H, m), 3.85-4.10 (1H, m), 4.90-5.10 (1H, m), 6.63 (1H, d, J=7.4 Hz), 6.77 (2H, d, J=8.5 Hz), 6.92 (1H, t, J=8.0 Hz), 7.00-7.45 (8H, m), 8.85 (1H, brs)
67) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.17 (3H, t, J=7.0 Hz), 1.35-1.65 (4H, m), 2.60-3.45 (5H, m), 4.20 (2H, q, J=7.0 Hz), 4.90-5.10 (1H, m), 6.63 (1H, d, J=7.6 Hz), 6.80-7.45 (12H, m), 8.66 (1H, brs)
68) .sup.1 H-NMR(CDCl.sub.3) .delta.; 0.96 (6H, d, J=6.6 Hz), 1.35-1.65 (1H, m), 1.80-2.25 (4H, m), 2.65-3.15 (3H, m), 3.19 (2H, d, J=7.3 Hz), 3.99 (2H, s), 4.90-5.10 (1H, m), 6.60 (1H, d, J=7.8 Hz), 6.75-7.05 (4H, m), 7.05-7.40 (8H, m), 8.15 (1H, brs)
69) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.19 (3H, t, J=7.0 Hz), 1.35-1.65 (1H, m), 1.80-2.25 (3H, m), 2.70-3.20 (3H, m), 3.44 (2H, q, J=7.0 Hz), 3.77 (3H, s), 3.87 (2H, s), 4.90-5.10 (1H, m), 6.25-6.50 (3H, m), 6.67 (1H, d, J=7.5 Hz), 6.85-7.45 (8H, m), 8.29 (1H, brs)
70) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.05 (3H, t, J=7.1 Hz), 1.35-1.65 (1H, m), 1.85-2.25 (3H, m), 2.65-3.30 (5H, m), 3.74 (2H, s), 4.95-5.15 (1H, m), 6.63 (1H, d, J=7.5 Hz), 6.80-7.55 (11H, m), 9.51 (1H, brs)
71) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.30-1.65 (1H, m), 1.80-2.30 (3H, m), 2.65-3.15 (3H, m), 3.75 (2H, s), 3.74 (2H, s), 4.95-5.10 (1H, m), 6.45-6.70 (3H, m), 6.88 (1H, t, J=6.8 Hz), 7.00-7.45 (8H, m), 8.74 (1H, brs)
72) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.30-1.70 (1H, m), 1.75-2.25 (6H, m), 2.65-3.15 (3H, m), 3.78 (2H, d, J=5.4 Hz), 4.28 (2H, d, J=5.5 Hz), 4.53 (1H, brs), 4.90-5.10 (1H, m), 5.89 (1H, brs), 6.50-6.70 (3H, m), 6.89 (1H, t, J=7.5 Hz), 7.00-7.40 (8H, m), 8.61 (1H, brs)
73) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.35-1.65 (1H, m), 1.70-2.20 (8H, m), 2.65-3.20 (3H, m), 3.25-3.55 (4H, m), 3.88 (2H, s), 4.90-5.10 (1H, m), 5.79 (1H, brs), 6.55-7.40 (13H, m), 8.37 (1H, brs)
74) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.35-2.00 (8H, m), 2.65-3.20 (3H, m), 3.30-3.35 (2H, m), 3.60-3.85 (2H, m), 3.90 (2H, s), 4.95-5.15 (1H, m), 6.55-7.00 (5H, m), 7.00-7.40 (8H, m), 7.65-7.90 (4H, m), 8.22 (1H, brs)
75) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.16 (3H, t, J=7.0 Hz), 2.39 (3H, s), 2.80-3.20 (3H, m), 3.44 (2H, q, J=7.0 Hz), 3.65-4.20 (4H, m), 4.80-5.05 (1H, m), 6.50-7.45 (13H, m), 8.50 (1H, brs)
76) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.23 (3H, t, J=7.0 Hz), 2.41 (3H, s), 2.75-3.20 (3H, m), 3.40-3.60 (5H, m), 3.65-3.90 (1H, m), 3.92 (2H, s), 3.90-4.20 (1H, m), 4.85-5.10 (1H, m), 6.65-7.45 (11H, m), 8.13 (1H, d, J=8.4 Hz), 9.01 (1H, brs)
77) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.80-1.95 (1H, m), 2.20-2.70 (10H, m), 3.50-3.60 (1H, m), 3.63-3.80 (1H, m), 4.00-4.15 (1H, m), 6.60 (1H, d, J=7.6 Hz), 6.92 (1H, t, J=7.6 Hz), 7.02 (1H, t, J=6.3 Hz), 7.20-7.65 (9H, m), 7.87 (1H, brs)
78) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.40-1.62 (1H, m), 1.84-2.22 (3H, m), 2.65-3.19 (3H, m), 3.97 (2H, t, J=4.9 Hz), 4.43 (2H, t, J=4.9 Hz), 4.95-5.18 (1H, m), 6.60-6.77 (1H, m), 6.85-7.02 (2H, m), 7.02-7.30 (5H, m), 7.40-7.68 (3H, m), 8.20-8.32 (1H, m), 9.62-9.81 (1H, m)
79) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.38-1.65 (1H, m), 1.84-2.21 (3H, m), 2.64-3.15 (3H, m), 3.81 (2H, t, J=5.7 Hz), 4.25 (2H, t, J=5.7 Hz), 4.90-5.13 (1H, m), 6.58-6.71 (1H, m), 6.82-7.00 (1H, m), 7.00-7.52 (10H, m), 8.11 (1H, brs)
Example 513
To a solution of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.06 g) in dichloromethane (80 ml) is added o-methylphenyl isocyanate (0.66 g) under ice-cooling. The mixture is stirred-at room temperature for 4 hours. After completion of the reaction, the solvent is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:1), and recrystallized from ethyl acetate to give 1-�4-(2-methylanilinocarbonylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.97 g) as white powder, m.p. 182.degree.-182.5.degree. C.
Using the suitable starting materials, the compounds of the above Examples 491-492 are obtained in the same manner as in Example 513.
Example 514
A mixture of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g), phenylsulfonyl chloride (0.29 ml), triethylamine (0.32 ml) and dichloromethane (30 ml) is stirred at room temperature overnight. The reaction mixture is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from methanol/diethyl ether to give 1-(4-phenylsulfonylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.27 g) as colorless prisms, m.p. 178.degree.-182.5.degree. C.
Using the suitable starting materials, the compounds of the above Examples 469-471, 498, 502 and 503 are obtained in the same manner as in Example 514.
Example 515
To a solution of 1-�4-(4-piperidinylcarbonylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g) in dimethylformamide (20 ml) is added 60% sodium hydride dispersion in mineral oil (82 mg) and the mixture is stirred at room temperature for 30 minutes. Thereto is added methyl iodide (0.14 ml) and the mixture is stirred at room temperature overnight. The solvent is distilled off and the resulting residue is extracted with chloroform, and washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=10:1), and recrystallized from methanol/n-hexane to give 1-{4-�N-(1-methyl-4-piperidinylcarbonyl)-N-methylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.03 g) as light yellow powder, m.p. 194.5.degree.-197.degree. C.
Using the suitable starting materials, the compounds of the above Examples 497 and 501 are obtained in the same manner as in Example 515.
Example 516
6-Fluoro-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (0.15 g) is dissolved in dichloromethane (10 ml) and thereto is added triethylamine (0.31 ml). To the mixture is added dropwise a solution of 3,5-dichlorobenzoyl chloride (0.14 g) in dichloromethane (2.0 ml) under ice-cooling, and the mixture is stirred for 30 minutes under ice-cooling, and further, at room temperature for 1 hour. To the mixture are added triethylamine (0.31 ml) and 3,5-dichlorobenzoyl chloride (0.14 ml). The mixture is stirred at room temperature for 4 hours. The reaction mixture is washed with water, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:5.fwdarw.1:4), and recrystallized from ethyl acetate/n-hexane to give 6-fluoro-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline (0.12 g) and 6-fluoro-1-{4-�bis-(3,5-dichlorobenzoyl)amino!benzoyl}-1,2,3,4-tetrahydroquinoline.
The former: White powder, m.p. 205.5.degree.-206.5.degree. C.
The latter: White powder, m.p. 210.5.degree.-212.degree. C.
Example 517
Using the suitable starting materials, the compounds of the above Examples 450 and 504 are obtained in the same manner as in Example 378.
Example 518
Using the suitable starting materials, the compounds of the above Examples 450-467, 495, 496, 499, 500, 511 and 512 are obtained in the same manner as in Example 380.
Example 519
Using the suitable starting materials, the compounds of the above Examples 449, 474-489, 493 and 494 are obtained in the same manner as in Example 394.
Example 520
Using the suitable starting materials, the compounds of the above Examples 453, 455, 457, 459, 460, 463-467, 495, 496 and 499 are obtained in the same manner as in Example 397.
Example 521
Using the suitable starting materials, the compound of the above Example 461 is obtained in the same manner as in Example 396.
Example 522
Using the suitable starting materials, the compound of the above Example 456 is obtained in the same manner as in Example 398.
Example 523
Using the suitable starting materials, the compound of the above Example 459 is obtained in the same manner as in Example 399.
Example 524
Using the suitable starting materials, the compounds of the above Examples 495 and 496 are obtained in the same manner as in Examples 400 and 401.
Example 525
Using the suitable starting materials, the compound of the above Example 458 is obtained in the same manner as in Example 402.
Using the suitable starting materials, the compounds of the following Table 3 are obtained in the same manner as in Examples 1 and 382.
TABLE 3______________________________________ ##STR1533##______________________________________Example 527Structure ##STR1534## ##STR1535##R.sup.2 : 2-ClR.sup.3 : ##STR1536##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 225-226.degree. C.Form: FreeExample 528Structure ##STR1537## ##STR1538##R.sup.2 : 2-ClR.sup.3 : ##STR1539##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 142.5-145.degree. C.Form: FreeExample 529Structure ##STR1540## ##STR1541##R.sup.2 : 2-ClR.sup.3 : ##STR1542##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 213-215.degree. C.Form: FreeExample 530Structure ##STR1543## ##STR1544##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR1545##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 167-167.5.degree. C.Form: FreeExample 531Structure ##STR1546## ##STR1547##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR1548##Crystalline form: Colorless scalesRecrystallization solvent: Methanol/diethyl etherMelting Point: 217-221.degree. C.Form: FreeExample 532Structure ##STR1549## ##STR1550##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR1551##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 182-184.degree. C.Form: FreeExample 533Structure ##STR1552## ##STR1553##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR1554##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 209-210.degree. C.Form: FreeExample 534Structure ##STR1555## ##STR1556##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1557##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 148-149.degree. C.Form: FreeExample 535Structure ##STR1558## ##STR1559##R.sup.2 : HR.sup.3 : ##STR1560##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 202-203.degree. C.Form: FreeExample 536Structure ##STR1561## ##STR1562##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR1563##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 218-219.degree. C.Form: FreeExample 537Structure ##STR1564## ##STR1565##R.sup.2 : 2-ClR.sup.3 : ##STR1566##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 159-160.degree. C.Form: FreeExample 538Structure ##STR1567## ##STR1568##R.sup.2 : 2-ClR.sup.3 : ##STR1569##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 201-202.degree. C.Form: FreeExample 539Structure ##STR1570## ##STR1571##R.sup.2 : 2-ClR.sup.3 : ##STR1572##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 205-207.degree. C.Form: FreeExample 540Structure ##STR1573## ##STR1574##R.sup.2 : 3-OHR.sup.3 : ##STR1575##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 201.5-202.5.degree. C.Form: FreeExample 541Structure ##STR1576## ##STR1577##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR1578##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 226-228.degree. C.Form: FreeExample 542Structure ##STR1579## ##STR1580##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR1581##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 218-221.degree. C.Form: FreeExample 543Structure ##STR1582## ##STR1583##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR1584##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 156-157.degree. C.Form: FreeExample 544Structure ##STR1585## ##STR1586##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR1587##Crystalline form: White powderNMR analysis: 80)Form: FreeExample 545Structure ##STR1588## ##STR1589##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1590##Crystalline form: Colorless amorphousNMR analysis: 81)Form: FreeExample 546Structure ##STR1591## ##STR1592##R.sup.2 : HR.sup.3 : ##STR1593##Crystalline form: Colorless amorphousNMR analysis: 82)Form: FreeExample 547Structure ##STR1594## ##STR1595##R.sup.2 : HR.sup.3 : ##STR1596##Crystalline form: Light yellow amorphousNMR analysis: 83)Form: FreeExample 548Structure ##STR1597## ##STR1598##R.sup.2 : HR.sup.3 : ##STR1599##Crystalline form: Colorless amorphousNMR analysis: 84)Form: FreeExample 549Structure ##STR1600## ##STR1601##R.sup.2 : HR.sup.3 : ##STR1602##Crystalline form: Colorless amorphousNMR analysis: 85)Form: FreeExample 550Structure ##STR1603## ##STR1604##R.sup.2 : 3-OCH.sub.2 CH.sub.3R.sup.3 : ##STR1605##Crystalline form: White powderRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 135-136.degree. C.Form: FreeExample 551Structure ##STR1606## ##STR1607##R.sup.2 : 3-OCH.sub.2 CH.sub.3R.sup.3 : ##STR1608##Crystalline form: Colorless prismsRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 122-123.degree. C.Form: FreeExample 552Structure ##STR1609## ##STR1610##R.sup.2 : 3-OCH.sub.2 CH.sub.3R.sup.3 : ##STR1611##Crystalline form: Colorless prismsRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 118-119.degree. C.Form: FreeExample 553Structure ##STR1612## ##STR1613##R.sup.2 : ##STR1614##R.sup.3 : ##STR1615##Crystalline form: Colorless prismsRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 145-147.degree. C.Form: FreeExample 554Structure ##STR1616## ##STR1617##R.sup.2 : ##STR1618##R.sup.3 : ##STR1619##Crystalline form: Light yellow needlesRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 169.5-170.5.degree. C.Form: FreeExample 555Structure ##STR1620## ##STR1621##R.sup.2 : 3-OHR.sup.3 : ##STR1622##Crystalline form: Colorless prismsRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 194-195.degree. C.Form: FreeExample 556Structure ##STR1623## ##STR1624##R.sup.2 : 3-OHR.sup.3 : ##STR1625##Crystalline form: Colorless needlesRecrystallization solvent: n-Hexane/ethyl acetateMelting Point: 202-204.degree. C.Form: FreeExample 557Structure ##STR1626## ##STR1627##R.sup.2 : HR.sup.3 : ##STR1628##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 242-243.degree. C.Form: FreeExample 558Structure ##STR1629## ##STR1630##R.sup.2 : HR.sup.3 : ##STR1631##Crystalline form: Light yellow powderNMR analysis: 86)Form: FreeExample 559Structure ##STR1632## ##STR1633##R.sup.2 : HR.sup.3 : ##STR1634##Crystalline form: Light yellow powderNMR analysis: 87)Form: FreeExample 560Structure ##STR1635## ##STR1636##R.sup.2 : HR.sup.3 : ##STR1637##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 237-238.degree. C.Form: FreeExample 561Structure ##STR1638## ##STR1639##R.sup.2 : HR.sup.3 : ##STR1640##Crystalline form: Colorless prismsRecrystallization solvent: DioxaneMelting Point: 258-259.degree. C.Form: FreeExample 562Structure ##STR1641## ##STR1642##R.sup.2 : HR.sup.3 : ##STR1643##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 182.5-183.5.degree. C.Form: FreeExample 563Structure ##STR1644## ##STR1645##R.sup.2 : HR.sup.3 : ##STR1646##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 209-211.degree. C.Form: FreeExample 564Structure ##STR1647## ##STR1648##R.sup.2 : HR.sup.3 : ##STR1649##Crystalline form: Colorless prismsRecrystallization solvent: DioxaneMelting Point: 210-211.degree. C.Form: FreeExample 565Structure ##STR1650## ##STR1651##R.sup.2 : HR.sup.3 : ##STR1652##Crystalline form: Colorless needlesRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 176-178.degree. C.Form: FreeExample 566Structure ##STR1653## ##STR1654##R.sup.2 : HR.sup.3 : ##STR1655##Crystalline form: Light yellow amorphousNMR analysis: 88)Form: FreeExample 567Structure ##STR1656## ##STR1657##R.sup.2 : HR.sup.3 : ##STR1658##Crystalline form: White powderRecrystallization solvent: Dioxane/waterMelting Point: 272-273.degree. C.Form: FreeExample 568Structure ##STR1659## ##STR1660##R.sup.2 : HR.sup.3 : ##STR1661##Crystalline form: Colorless prismsRecrystallization solvent: DioxaneMelting Point: 253-254.degree. C.Form: FreeExample 569Structure ##STR1662## ##STR1663##R.sup.2 : HR.sup.3 : ##STR1664##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 248.5-249.5.degree. C.Form: FreeExample 570Structure ##STR1665## ##STR1666##R.sup.2 : HR.sup.3 : ##STR1667##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 266.5-267.5.degree. C.Form: FreeExample 571Structure ##STR1668## ##STR1669##R.sup.2 : HR.sup.3 : ##STR1670##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 252-253.degree. C.Form: FreeExample 572Structure ##STR1671## ##STR1672##R.sup.2 : HR.sup.3 : ##STR1673##Crystalline form: Light yellow powderNMR analysis: 89)Form: FreeExample 573Structure ##STR1674## ##STR1675##R.sup.2 : HR.sup.3 : ##STR1676##Crystalline form: Light brown powderNMR analysis: 90)Form: FreeExample 574Structure ##STR1677## ##STR1678##R.sup.2 : HR.sup.3 : ##STR1679##Crystalline form: White powderRecrystallization solvent: Diethyl etherMelting Point: 198.5-199.5.degree. C.Form: FreeExample 575Structure ##STR1680## ##STR1681##R.sup.2 : HR.sup.3 : ##STR1682##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 297-299.degree. C.Form: FreeExample 576Structure ##STR1683## ##STR1684##R.sup.2 : 2-ClR.sup.3 : ##STR1685##Crystalline form: Colorless amorphousNMR analysis: 91)Form: FreeExample 577Structure ##STR1686## ##STR1687##R.sup.2 : 2-ClR.sup.3 : ##STR1688##Crystalline form: White powderRecrystallization solvent: Ethanol/petroleum etherMelting Point: 202-203.degree. C.Form: FreeExample 578Structure ##STR1689## ##STR1690##R.sup.2 : HR.sup.3 : ##STR1691##Crystalline form: Colorless amorphousNMR analysis 92)Form: FreeExample 579Structure ##STR1692## ##STR1693##R.sup.2 : HR.sup.3 : ##STR1694##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 232-233.degree. C.Form: FreeExample 580Structure ##STR1695## ##STR1696##R.sup.2 : HR.sup.3 : ##STR1697##Crystalline form: Colorless amorphousNMR analysis: 93)Form: FreeExample 581Structure ##STR1698## ##STR1699##R.sup.2 : HR.sup.3 : ##STR1700##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 256.5-257.degree. C.Form: FreeExample 582Structure ##STR1701## ##STR1702##R.sup.2 : HR.sup.3 : ##STR1703##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 193-194.degree. C.Form: FreeExample 583Structure ##STR1704## ##STR1705##R.sup.2 : HR.sup.3 : ##STR1706##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 227-230.degree. C.Form: FreeExample 584Structure ##STR1707## ##STR1708##R.sup.2 : HR.sup.3 : ##STR1709##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 199.5-202.degree. C.Form: FreeExample 585Structure ##STR1710## ##STR1711##R.sup.2 : HR.sup.3 : ##STR1712##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 219-220.degree. C.Form: FreeExample 586Structure ##STR1713## ##STR1714##R.sup.2 : HR.sup.3 : ##STR1715##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 190-191.5.degree. C.Form: FreeExample 587Structure ##STR1716## ##STR1717##R.sup.2 : HR.sup.3 : ##STR1718##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 184-185.degree. C.Form: FreeExample 588Structure ##STR1719## ##STR1720##R.sup.2 : HR.sup.3 : ##STR1721##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 223-224.degree. C.Form: FreeExample 589Structure ##STR1722## ##STR1723##R.sup.2 : HR.sup.3 : ##STR1724##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 178-181.degree. C.Form: FreeExample 590Structure ##STR1725## ##STR1726##R.sup.2 : HR.sup.3 : ##STR1727##Crystalline form: Colorless needlesRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 168-168.5.degree. C.Form: FreeExample 591Structure ##STR1728## ##STR1729##R.sup.2 : HR.sup.3 : ##STR1730##Crystalline form: Colorless amorphousNMR analysis: 94)Form: FreeExample 592Structure ##STR1731## ##STR1732##R.sup.2 : HR.sup.3 : ##STR1733##Crystalline form: Colorless amorphousNMR analysis: 95)Form: FreeExample 593Structure ##STR1734## ##STR1735##R.sup.2 : HR.sup.3 : ##STR1736##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 196-197.degree. C.Form: FreeExample 594Structure ##STR1737## ##STR1738##R.sup.2 : HR.sup.3 : ##STR1739##Crystalline form: Colorless amorphousNMR analysis: 96)Form: FreeExample 595Structure ##STR1740## ##STR1741##R.sup.2 : HR.sup.3 : ##STR1742##Crystalline form: White powderRecrystallization solvent: Ethanol/waterMelting Point: 188-199.degree. C.Form: FreeExample 596Structure ##STR1743## ##STR1744##R.sup.2 : HR.sup.3 : ##STR1745##Crystalline form: Colorless amorphousNMR analysis: 97)Form: FreeExample 597Structure ##STR1746## ##STR1747##R.sup.2 : HR.sup.3 : ##STR1748##Crystalline form: Colorless amorphousNMR analysis: 98)Form: FreeExample 598Structure ##STR1749## ##STR1750##R.sup.2 : HR.sup.3 : ##STR1751##Crystalline form: Colorless prismsRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 203-204.degree. C.Form: FreeExample 599Structure ##STR1752## ##STR1753##R.sup.2 : HR.sup.3 : ##STR1754##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 196-197.degree. C.Form: FreeExample 600Structure ##STR1755## ##STR1756##R.sup.2 : HR.sup.3 : ##STR1757##Crystalline form: Colorless amorphousNMR analysis: 99)Form: FreeExample 601Structure ##STR1758## ##STR1759##R.sup.2 : HR.sup.3 : ##STR1760##Crystalline form: Colorless amorphousNMR analysis: 100)Form: FreeExample 602Structure ##STR1761## ##STR1762##R.sup.2 : HR.sup.3 : ##STR1763##Crystalline form: Colorless amorphousNMR analysis: 101)Form: FreeExample 603Structure ##STR1764## ##STR1765##R.sup.2 : HR.sup.3 : ##STR1766##Crystalline form: Colorless amorphousNMR analysis: 102)Form: FreeExample 604Structure ##STR1767## ##STR1768##R.sup.2 : HR.sup.3 : ##STR1769##Crystalline form: Colorless amorphousNMR analysis: 103)Form: FreeExample 605Structure ##STR1770## ##STR1771##R.sup.2 : HR.sup.3 : ##STR1772##Crystalline form: Colorless amorphousNMR analysis: 104)Form: FreeExample 606Structure ##STR1773## ##STR1774##R.sup.2 : HR.sup.3 : ##STR1775##Crystalline form: Colorless amorphousNMR analysis: 105)Form: FreeExample 607Structure ##STR1776## ##STR1777##R.sup.2 : HR.sup.3 : ##STR1778##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 169-171.degree. C.Form: FreeExample 608Structure ##STR1779## ##STR1780##R.sup.2 : HR.sup.3 : ##STR1781##Crystalline form: Colorless needlesRecrystallization solvent: Ethanol/diethyl etherMelting Point: 178-181.degree. C.Form: FreeExample 609Structure ##STR1782## ##STR1783##R.sup.2 : HR.sup.3 : ##STR1784##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 187-188.degree. C.Form: FreeExample 610Structure ##STR1785## ##STR1786##R.sup.2 : HR.sup.3 : ##STR1787##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 181-183.degree. C.Form: FreeExample 611Structure ##STR1788## ##STR1789##R.sup.2 : HR.sup.3 : ##STR1790##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 124-127.degree. C.Form: FreeExample 612Structure ##STR1791## ##STR1792##R.sup.2 : HR.sup.3 : ##STR1793##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 179-181.degree. C.Form: FreeExample 613Structure ##STR1794## ##STR1795##R.sup.2 : HR.sup.3 : ##STR1796##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 148-150.degree. C.Form: FreeExample 614Structure ##STR1797## ##STR1798##R.sup.2 : HR.sup.3 : ##STR1799##Crystalline form: Colorless amorphousNMR analysis: 106)Form: FreeExample 615Structure ##STR1800## ##STR1801##R.sup.2 : 2-ClR.sup.3 : ##STR1802##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 219-220.degree. C.Form: FreeExample 616Structure ##STR1803## ##STR1804##R.sup.2 : HR.sup.3 : ##STR1805##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 226-228.degree. C.Form: FreeExample 617Structure ##STR1806## ##STR1807##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1808##Crystalline form: Colorless amorphousNMR analysis: 107)Form: FreeExample 618Structure ##STR1809## ##STR1810##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1811##Crystalline form: Colorless amorphousNMR analysis: 108)Form: FreeExample 619Structure ##STR1812## ##STR1813##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1814##Crystalline form: Colorless amorphousNMR analysis: 109)Form: FreeExample 620Structure ##STR1815## ##STR1816##R.sup.2 : HR.sup.3 : ##STR1817##Crystalline form: Colorless amorphousNMR analysis: 110)Form: FreeExample 621Structure ##STR1818## ##STR1819##R.sup.2 : HR.sup.3 : ##STR1820##Crystalline form: Colorless amorphousNMR analysis: 111)Form: FreeExample 622Structure ##STR1821## ##STR1822##R.sup.2 : HR.sup.3 : ##STR1823##Crystalline form: Colorless amorphousNMR analysis: 112)Form: FreeExample 623Structure ##STR1824## ##STR1825##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1826##Crystalline form: Colorless amorphousNMR analysis: 113)Form: FreeExample 624Structure ##STR1827## ##STR1828##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1829##Crystalline form: Colorless amorphousNMR analysis: 114)Form: FreeExample 625Structure ##STR1830## ##STR1831##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR1832##Crystalline form: Colorless amorphousNMR analysis: 115)Form: FreeExample 626Structure ##STR1833## ##STR1834##R.sup.2 : HR.sup.3 : ##STR1835##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 183-184.degree. C.Form: FreeExample 627Structure ##STR1836## ##STR1837##R.sup.2 : HR.sup.3 : ##STR1838##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 219-220.degree. C.Form: FreeExample 628Structure ##STR1839## ##STR1840##R.sup.2 : HR.sup.3 : ##STR1841##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 240-241.degree. C.Form: FreeExample 629Structure ##STR1842## ##STR1843##R.sup.2 : HR.sup.3 : ##STR1844##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 205-206.degree. C.Form: FreeExample 630Structure ##STR1845## ##STR1846##R.sup.2 : HR.sup.3 : ##STR1847##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 238-239.degree. C.Form: FreeExample 631Structure ##STR1848## ##STR1849##R.sup.2 : HR.sup.3 : ##STR1850##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 233-234.degree. C.Form: FreeExample 632Structure ##STR1851## ##STR1852##R.sup.2 : 2-ClR.sup.3 : ##STR1853##Crystalline form: Colorless amorphousNMR analysis: 116)Form: FreeExample 633Structure ##STR1854## ##STR1855##R.sup.2 : 2-ClR.sup.3 : ##STR1856##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 259.5-260.5.degree. C.Form: Free______________________________________
80) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.24-5.26 (18H, m), 6.39-7.59 (13H, m)
81) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.70-2.10 (m, 2H), 2.15-2.60 (m, 12H), 3.56 (t, J=5.8 Hz, 1H), 3.65-3.95 (m, 4H) 4.05-4.25 (m, 1H), 6.64 (d, J=7.7 Hz, 1H), 6.85-7.50 (m, 9H), 8.11 (brs, 1H), 8.42 (d, J=8.8 Hz, 1H)
82) .sup.1 H-NMR(CDCl.sub.3) .delta.; 2.00-2.90 (m, 3H), 2.49 (s, 3H), 3.70-3.90 (m, 1H), 4.00-4.20 (m, 1H), 4.80-5.00 (m, 1H), 6.89 (d, J=6.3 Hz, 1H), 6.95-7.65 (m, 11H), 7.70 (brs, 1H)
83) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.95-2.90 (m, 2H), 2.48 (s, 3H), 2.55 (s, 3H), 3.77 (t, J=5.1 Hz, 1H), 3.92 (t, J=6.7 Hz, 2H), 6.72 (d, J=8.0 Hz, 1H), 6.90-7.15 (m, 2H), 7.15-7.70 (m, 9H), 7.81 (brs, 1H)
84) .sup.1 H-NMR(CDCl.sub.3) .delta.; 2.11 (s, 3H), 2.20-2.40 (m, 2H), 2.50 (s, 3H), 3.80-4.10 (m, 1H), 4.12-4.25 (m, 1H), 6.03 (t, J=4.3 Hz, 1H), 6.80-7.65 (m, 12H), 7.80 (brs, 1H)
85) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.80-2.40 (m, 5H), 2.45 (s, 3H), 2.81 (s, 3H), 3.55-3.82 (m, 1H), 4.15-4.40 (m, 1H), 5.90-6.10 (m, 1H), 6.80-7.80 (m, 12H), 8.67 (brs, 1H)
86) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.95-2.35 (2H, m), 2.75-3.0 (2H, m), 3.0-5.4 (2H, m), 6.55-7.95 (11H, m), 8.09 (1H, s)
87) .sup.1 H-NMR(DMSO-d.sub.6) .delta.; 1.85-2.2 (2H, m), 2.7-2.95 (2H, m), 3.5-5.0 (2H, m), 6.8-7.8 (12H, m), 10.60 (1H, s)
88) .sup.1 H-NMR(CDCl.sub.3) .delta.; 0.8-1.1 (3H, m), 1.2-2.35 (6H, m), 2.35-5.25 (6H, m), 6.63 (1H, d, J=7.7 Hz), 6.8-7.6 (9H, m), 7.67 (1H, d, J=8.2 Hz), 7.9-8.15 (1H, m)
89) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.7-2.9 (7H, m), 4.5-6.5 (3H, m), 6.55-6.75 (1H, m), 6.85-7.6 (12H, m)
90) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.65-3.1 (7H, m), 4.7-6.6 (3H, m), 6.6-6.8 (1H, m), 6.85-7.65 (12H, m)
91) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.8-2.4 (2H, m), 2.86 (2H, t, J=6 Hz), 3.1-5.15 (2H, m), 6.85-7.5 (8H, m), 7.5-7.85 (3H, m), 8.19 (1H, s)
92) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.46-2.28 (4H, m), 2.37 (3H, s), 2.58-2.90 (1H, m), 4.57-5.10 (2H, m), 6.59 (1H, d, J=7.6 Hz), 6.91-7.52 (11H, m), 7.62 (1H, d, J=7.6 Hz), 8.10-8.40 (1H, m)
93) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.45-1.91 (2H, m), 1.91-2.65 (2H, m), 2.65-2.90 (1H, m), 4.63-5.22 (2H, m), 6.63 (1H, d, J=7.4 Hz), 7.34-8.03 (11H, m), 10.16-10.44 (1H, m)
94) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.08-1.47 (3H, m), 1.50-1.97 (2H, m), 1.97-2.48 (2H, m), 2.65-3.02 (1H, m), 4.00-4.43 (4H, m), 4.52-5.15 (2H, m), 6.50-6.79 (1H, m), 6.90-7.70 (10H, m), 8.26-8.60 (1H, m)
95) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.56-2.67 (4H, m), 2.46 (3H, s), 2.67-3.03 (1H, m), 3.82-4.32 (2H, m), 4.45-5.15 (2H, m), 5.43-5.83 (1H, m), 6.20-6.45 (1H, m), 6.50-6.86 (2H, m), 6.86-7.70 (10H, m), 7.76-8.10 (1H, m)
96) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.52-1.90 (2H, m), 1.90-2.54 (2H, m), 2.67-3.05 (1H, m), 3.74-4.32 (2H, m), 4.38-5.17 (2H, m), 5.52-5.98 (1H, brs), 6.20-6.48 (1H, brs), 6.55-6.84 (1H, m), 6.89-7.55 (9H, m), 7.55-7.77 (1H, m), 8.15-8.86 (1H, brs)
97) .sup.1 H-NMR(DMSO-d.sub.6) .delta.; 1.26-2.49 (4H, m), 2.57-2.93 (1H, m), 4.07-4.43 (2H, m), 4.44-4.98 (2H, m), 6.62-6.87 (1H, m), 6.92-7.80 (11H, m), 10.57 (1H, s), 12.74 (1H, s)
98) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.52-1.89 (2H, m), 1.89-2.56 (2H, m), 2.65-3.02 (1H, m), 3.90-4.40 (2H, m), 4.40-5.07 (2H, m), 6.58-6.78 (1H, m), 6.90-7.70 (10H, m), 8.57-8.81 (1H, brs)
99) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.49-1.89 (2H, m), 1.89-2.60 (2H, m), 2.63-3.23 (7H, m), 4.04-4.49 (2H, m), 4.52-5.21 (2H, m), 6.52-6.80 (1H, m), 6.89-7.84 (10H, m), 8.08-8.52 (1H, m)
100) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.41-1.86 (6H, m), 1.86-2.53 (4H, m), 2.25 (3H, s), 2.29 (3H, s), 2.43 (3H, s), 2.60-2.97 (1H, m), 3.36-3.77 (2H, m), 4.40-5.10 (2H, m), 6.54-6.72 (1H, m), 6.88-7.67 (11H, m), 8.27-8.58 (1H, m)
101) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.44-1.85 (6H, m), 1.85-2.61 (4H, m), 2.32 (3H, s), 2.35 (3H, s), 2.61-3.00 (1H, m), 3.33-3.76 (2H, m), 4.40-5.20 (2H, m), 6.57-6.75 (1H, m), 6.90-7.70 (11H, m), 8.50-8.93 (1H, m)
102) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.49-2.04 (6H, m), 2.10-3.02 (5H, m), 2.47 (6H, s), 3.40-3.88 (2H, m), 4.30-5.17 (2H, m), 6.59-6.78 (1H, m), 6.93-7.76 (10H, m), 8.75-9.40 (1H, m)
103) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.47-2.47 (6H, m), 2.44 (3H, s), 2.62-3.03 (1H, m), 3.47-4.03 (4H, m), 4.48-5.17 (2H, m), 6.51-6.74 (1H, m), 6.87-7.62 (11H, m), 7.62-7.77 (2H, m), 7.77-8.03 (3H, m)
104) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.42-2.32 (6H, m), 2.44 (3H, s), 2.57-2.97 (1H, m), 3.12-3.83 (4H, m), 4.39-5.13 (2H, m), 6.50-6.71 (1H, m), 6.90-7.73 (12H, m)
105) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.50-2.63 (9H, m), 2.47 (3H, s), 2.66-3.07 (1H, m), 3.10-3.88 (4H, m), 4.40.5.17 (2H, m), 5.87-6.23 (1H, brs), 6.60-6.79 (1H, m), 6.94-7.60 (11H, m), 7.67 (1H, s)
106) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.20-2.53 (13H, m), 2.63-2.82, 3.00-3.13, 3.50-3.67, 4.05-4.23 (total 3H, m), 6.55-8.00 (13H, m)
107) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.41 (9H, s), 1.20-2.55 (10H, m), 3.42-4.20 (5.8H, m), 5.00-5.20 (0.2H, m), 6.60-7.67 (10H, m), 7.99 (1H, brs), 8.26 (1H, d, J=8.4 Hz)
108) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.2-3.0 (10H, m), 3.0-5.2 (6H, m), 6.5-7.7 (8H, m), 8.22 (1H, d, J=8.4 Hz), 8.36 (1H, s)
109) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.2-3.0 (10H, m), 3.0-5.2(6H, m), 6.3-7.7 (10H, m)
110) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.5-1.7 (1H, m), 2.2-2.7 (2H, m), 2.40 (6H, s), 2.7-3.0 (3H, m), 5.1-5.3 (1H, m), 6.67 (1H, d, J=7.7 Hz), 6.9-7.5 (10H, m), 7.69 (1H, d, J=6 Hz), 8.06 (1H, s)
111) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.4-1.7 (1H, m), 2.1-2.7 (2H, m), 2.40 (6H, s), 2.44 (3H, s), 2.7-3.0 (3H, m), 5.1-5.3 (1H, m), 6.68 (1H, d, J=7.8 Hz), 6.9-7.5 (11H, m), 7.66 (1H, s)
112) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.5-1.8 (1H, m), 2.1-2.7 (2H, m), 2.38 (6H, s), 2.7-3.0 (3H, m), 5.1-5.3 (1H, m), 6.66 (1H, d, J=7.7 Hz), 6.9-7.0 (9H, m), 7.57 (1H, d, J=8.3 Hz), 8.42 (1H, s)
113) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.5-1.8 (1H, m), 2.1-2.7 (2H, m), 2.41 (6H, s), 2.48 (3H, s), 2.7-3.0 (3H, m), 3.68 (3H, s), 5.2-5.4 (1H, m), 6.6-6.8 (2H, m), 6.9-7.5 (8H, m), 8.09 (1H, s), 8.26 (1H, d, J=8.1 Hz)
114) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.5-1.7 (1H, m), 2.1-2.3 (1H, m), 2.41 (6H, s), 2.4-2.6 (1H, m), 2.8-3.0 (3H, m), 3.71 (3H, s), 5.2-5.4 (1H, m), 6.6-6.8 (2H, m), 6.9-7.5 (7H, m), 7.7-7.8 (1H, m), 8.27 (1H, d, J=8.4 Hz), 8.57 (1H, s)
115) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.5-1.7 (1H, m), 2.1-2.7 (2H, m), 2.41 (6H, s), 2.7-3.0 (3H, m), 3.71 (3H, s), 5.2-5.4 (1H, m), 6.6-7.6 (8H, m), 7.70 (1H, d, J=8.3 Hz), 8.24 (1H, d, J=8.5 Hz), 8.59 (1H, s)
116) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.8-2.3 (3H, m), 2.7-2.9 (2H, m), 3.5-3.7 (1H, m), 6.8-8.0 (10H, m), 8.7-9.1 (1H, br)
Example 634
To a mixture of 5-oxo-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (4 g) and pyridine (50 ml) is added hydroxylamine hydrochloride (1.84 g) and the mixture is refluxed for 2.5 hours. The reaction solution is concentrated and water is added to the resulting residue. The precipitated crystal is collected by filtration, and recrystallized from dioxane/water to give 5-hydroxyimino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (2 g) as white powder, m.p. 272.degree.-273.degree. C.
Example 635
5-Chloro-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.8 g) is dissolved in dimethylformamide and thereto is added sodium azide (0.18 g) at room temperature. The mixture is stirred at room temperature overnight, and further reacted with heating at 50.degree. C. for 5 hours. Water is added to the reaction mixture and the precipitated crystal is collected by filtration to give 5-azido-1-�4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.68 g) as light brown powder.
.sup.1 H-NMR(CDCl.sub.3) .delta.; 1.65-3.1 (8H, m), 4.7-6.6 (3H, m), 6.6-6.8 (1H, m), 6.85-7.65 (12H, m)
Example 636
5-Azido-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.63 g) is dissolved in ethanol and thereto is added 10% Pd--C (0.1 g). The mixture is subjected to catalytic hydrogenation at room temperature under 1 atm. of hydrogen. Pd--C is removed by filtration and the filtrate is evaporated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from diethyl ether to give 5-amino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.34 g) as white powder, m.p. 198.5.degree.-199.5.degree. C.
Example 637
To 5-hydroxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.58 g) are added acetic anhydride (8.0 ml) and pyridine (2.0 ml). The mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the precipitated crystal is collected by filtration, and recrystallized from ethyl acetate/n-hexane to give 5-acetyloxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.56 g) as white powder, m.p. 193.degree.-194.degree. C.
Example 638
5-Ethoxycarbonylmethoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.00 g) is dissolved in methanol (35 ml) and thereto are added aqueous ammonia (20 ml) and ammonium chloride (0.50 g). The mixture is heated at 100.degree. C. for 3.5 hours in a sealed tube. After cooling, the reaction solution is concentrated under reduced pressure and acidified with hydrochloric acid, and extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=15:1) to give 5-carbamoylmethoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.68 g) as colorless amorphous.
.sup.1 H-NMR(CDCl.sub.3) .delta.; 1.56-2.67 (4H, m), 2.46 (3H, s), 2.67-3.03 (1H, m), 3.82-4.32 (2H, m), 4.45-5.15 (2H, m), 5.43-5.83 (1H, m), 6.20-6.45 (1H, m), 6.50-6.86 (2H, m), 6.86-7.70 (10H, m), 7.76-8.10 (1H, m)
Using the suitable starting materials, the compounds of the above Examples 593 and 594 are obtained in the same manner as in Example 638.
Example 639
5-Ethoxycarbonylmethoxy-1-�4-(2,4-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.94 g) is dissolved in ethanol (100 ml) and thereto is added 5N aqueous sodium hydroxide solution (0.50 ml). The mixture is stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure and to the resulting residue is added diluted hydrochloric acid and then extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is distilled off. The resulting residue is washed with n-hexane and collected by filtration to give 5-carboxymethoxy-1-�4-(2,4-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.79 g) as colorless amorphous.
.sup.1 H-NMR(CDCl.sub.3) .delta.; 1.52-1.89 (2H, m), 1.89-2.56 (2H, m), 2.65-3.02 (1H, m), 3.90-4.40 (2H, m), 4.40-5.07 (2H, m), 6.58-6.78 (1H, m), 6.90-7.70 (10H, m), 8.57-8.81 (1H, brs)
Using the suitable starting materials, the compounds of the above Examples 595 and 596 are obtained in the same manner as in Example 639.
Example 640
5-Carboxymethoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) is dissolved in dimethylformamide (20 ml) and thereto are added dimethylamine hydrochloride (0.20 g) and diethyl chlorophosphate (0.33 g). To the mixture is added triethylamine (1.0 ml) under ice-cooling, and the mixture is stirred under ice-cooling for 30 minutes, and at room temperature for more 2 hours. Water is added to the reaction solution and the precipitated crystal is collected by filtration and recrystallized from ethyl acetate/n-hexane to give 5-dimethylaminocarbonylmethoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) as colorless prisms, m.p. 203.degree.-204.degree. C.
Using the suitable starting materials, the compounds of the above Examples 599 and 600 are obtained in the same manner as in Example 640.
Example 641
5-�3-(Phthalimid-1-yl)propoxy!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.26 g) is dissolved in ethanol (100 ml) and thereto is added hydrazine hydrate (1.0 ml). The mixture is refluxed with stirring for 1 hour. The reaction solution is evaporated under reduced pressure and to the resulting residue is added dichloromethane. The insoluble materials are removed by filtration. The filtrate is purified by silica gel column chromatography (eluent; dichloromethane:methanol:aqueous ammonia=70:10:1) to give 5-(3-aminopropoxy)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g) as colorless amorphous.
.sup.1 H-NMR(CDCl.sub.3) .delta.; 1.42-2.32 (6H, m), 2.44 (3H, s), 2.57-2.97 (1H, m), 3.12-3.83 (4H, m), 4.39-5.13 (2H, m), 6.50-6.71 (1H, m), 6.90-7.73 (12H, m)
Example 642
A solution of 5-dimethylamino-1-�3-methoxy-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) in dichloromethane (30 ml) is added dropwise to a solution of 1M boron tribromide in dichloromethane (5.46 ml) at -45.degree. C. After completion of the dropping, the mixture is stirred for 1 day while the temperature of the reaction mixture is gradually raised to room temperature. To the reaction solution is added water and the mixture is neutralized with sodium hydrogen carbonate, and extracted with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=500:1), and recrystallized from methanol/diethyl ether to give 5-dimethylamino-1-�3-hydroxy-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.33 g) as white powder, m.p. 201.5.degree.-202.5.degree. C.
Using the suitable starting materials, the compounds of the above Examples 10, 32, 343, 356, 535, 555 and 556 are obtained in the same manner as in Example 642.
Example 643
To a solution of 4-�4-(2-methylbenzoylamino)benzoyl!-3,4-dihydro-2H-1,4-benzazepine (0.5 g) in dichloromethane (10 ml) is added m-chloroperbenzoic acid (0.58 g) under ice-cooling, and the mixture is stirred at room temperature for 6 hours. The above reaction solution is poured into an aqueous solution of sodium carbonate (0.6 g) in water (10 ml) and the mixture is extracted with dichloromethane. The extract is washed with water, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=100:1), and recrystallized from diethyl ether/dichloromethane to give 4-�4-(2-methylbenzoylamino)benzoyl!-3,4-dihydro-2H-1,4-benzothiazine-1,1-dioxide (0.49 g) as white powder, m.p. 219.degree.-220.degree. C.
Using the suitable starting materials, the compound of the above Example 630 is obtained in the same manner as in Example 643.
Example 644
To a suspension of 4-�4-(2-methylbenzoylamino)benzoyl!-3,4-dihydro-2H-1,4-benzothiazine (0.5 g) in methanol (15 ml) is added an aqueous solution of sodium metaperiodate (0.28 g) in water (2.5 ml) and the mixture is stirred at room temperature for 72 hours. Water is added to the reaction solution and extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=100:1), and recrystallized from dichloromethane/diethyl ether to give 4-�4-(2-methylbenzoylamino)benzoyl!-3,4-dihydro-2H-1,4-benzothiazin-1-oxide (0.34 g) as white powder, m.p. 240.degree.-241.degree. C.
Using the suitable starting materials, the compound of the above Example 631 is obtained in the same manner as in Example 644.
Example 645
5-Hydroxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (3.57 g) is dissolved in dichloromethane (30 ml) and pyridine (1.1 ml), and thereto is added dropwise methanesulfonyl chloride (0.9 ml) in small portions at 0.degree. C. Then, the mixture is stirred at room temperature for 3 days. The solvent is distilled off and the resulting residue is poured into ice-water. The precipitated crystal is collected by filtration, washed with water, and dried to give 5-chloro-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (3.10 g) as light yellow powder.
.sup.1 H-NMR(CDCl.sub.3) .delta.; 1.7-2.9 (8H, m), 4.5-6.5 (3H, m), 6.55-6.75 (1H, m), 6.85-7.6 (12H, m)
Example 646
5-Hydroxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (2.69 g) is dissolved in dimethylformamide (30 ml) and thereto are added 60% sodium hydride dispersion in mineral oil (0.44 g) and ethyl bromoacetate (1.00 ml) under ice-cooling, and the mixture is stirred at room temperature for 4 hours. The reaction solution is poured into an aqueous ammonium chloride solution under ice-cooling, and extracted with ethyl acetate. The extract is dried over magnesium sulfate and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:2), and recrystallized from ethyl acetate/n-hexane to give 5-ethoxycarbonylmethoxy-1-�4-(2-methylbenzoylamino)benzoyl-2,3,4,5-tetrahydro-1H-benzazepine (2.10 g) as white powder, m.p. 178.degree.-181.degree. C.
Using the suitable starting materials, the compounds of the above Examples 585-588 and 590-606 are obtained in the same manner as in Example 646.
Example 647
Using the suitable starting materials, the compounds of the above Examples 546 and 578-581 are obtained in the same manner as in Example 384.
Example 648
Using the suitable starting materials, the compounds of the above Examples 537-545, 547, 549-556, 561-564, 566, 568-571, 577, 601-603 and 607-625 are obtained in the same manner as in Example 388.
Example 649
Using the suitable starting materials, the compounds of the above Examples 549, 568-571, 575 and 606 are obtained in the same manner as in Example 389.
Example 650
Using the suitable starting materials, the compounds of the above Examples 537-545, 547, 549-556, 561-566, 568-571, 575, 577, 607, 608 and 613-625 are obtained in the same manner as in Example 390.
Example 651
Using the suitable starting materials, the compounds of the above Examples 601-603, 605 and 606 are obtained in the same manner as in Example 397.
Example 652
Using the suitable starting materials, the compound of the above Example 604 is obtained in the same manner as in Example 398.
Example 653
Using the suitable starting materials, the following compound is obtained in the same manner as in Examples 1, 382, 388 and 390.
5-Methylamino-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 184.5.degree.-185.5.degree. C. (recrystallized from ethanol)
Using the suitable starting materials, the compounds of the following Table 4 are obtained in the same manner as in Examples 1 and 382.
TABLE 4__________________________________________________________________________ ##STR1857##__________________________________________________________________________Example 654Structure ##STR1858## ##STR1859##R.sup.2 : 2-OHR.sup.3 : ##STR1860##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 193.5-196.degree. C.Form: FreeExample 655Structure ##STR1861## ##STR1862##R.sup.2 : 2-OHR.sup.3 : ##STR1863##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 195-198.degree. C.Form: FreeExample 656Structure ##STR1864## ##STR1865##R.sup.2 : 2-OC.sub.2 H.sub.5R.sup.3 : ##STR1866##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 230.5-231.5.degree. C.Form: FreeExample 657Structure ##STR1867## ##STR1868##R.sup.2 : 2-OC.sub.2 H.sub.5R.sup.3 : ##STR1869##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 223-224.5.degree. C.Form: FreeExample 658Structure ##STR1870## ##STR1871##R.sup.2 : 2-OC.sub.2 H.sub.5R.sup.3 : ##STR1872##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 173-174.degree. C.Form: FreeExample 659Structure ##STR1873## ##STR1874##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR1875##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 174-175.degree. C.Form: FreeExample 660Structure ##STR1876## ##STR1877##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR1878##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 198-200.degree. C.Form: FreeExample 661Structure ##STR1879## ##STR1880##R.sup.2 : 3-CH.sub.3R.sup.3 : ##STR1881##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 149-150.5.degree. C.Form: FreeExample 662Structure ##STR1882## ##STR1883##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR1884##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 183-185.degree. C.Form: FreeExample 663Structure ##STR1885## ##STR1886##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR1887##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 203-207.degree. C.Form: FreeExample 664Structure ##STR1888## ##STR1889##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR1890##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 221-222.degree. C.Form: FreeExample 665Structure ##STR1891## ##STR1892##R.sup.2 : 2-FR.sup.3 : ##STR1893##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 189-191.degree. C.Form: FreeExample 666Structure ##STR1894## ##STR1895##R.sup.2 : 2-FR.sup.3 : ##STR1896##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 215.5-217.degree. C.Form: FreeExample 667Structure ##STR1897## ##STR1898##R.sup.2 : 2-FR.sup.3 : ##STR1899##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 192-194.degree. C.Form: FreeExample 668Structure ##STR1900## ##STR1901##R.sup.2 : 3-FR.sup.3 : ##STR1902##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 195-196.degree. C.Form: FreeExample 669Structure ##STR1903## ##STR1904##R.sup.2 : 3-FR.sup.3 : ##STR1905##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 202-204.5.degree. C.Form: FreeExample 670Structure ##STR1906## ##STR1907##R.sup.2 : HR.sup.3 : ##STR1908##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 183-187.degree. C.Form: FreeExample 671Structure ##STR1909## ##STR1910##R.sup.2 : HR.sup.3 : ##STR1911##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 120-122.degree. C.Form: FreeExample 672Structure ##STR1912## ##STR1913##R.sup.2 : HR.sup.3 : ##STR1914##Crystalline form: White powderRecrystallization solvent: Chloroform/diethyl etherMelting Point: 208-210.degree. C.Form: FreeExample 673Structure ##STR1915## ##STR1916##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR1917##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 182-183.degree. C.Form: FreeExample 674Structure ##STR1918## ##STR1919##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR1920##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 257-259.degree. C.Form: FreeExample 675Structure ##STR1921## ##STR1922##R.sup.2 : 2-OC.sub.2 H.sub.5R.sup.3 : ##STR1923##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 134-135.degree. C.Form: FreeExample 676Structure ##STR1924## ##STR1925##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR1926##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 167-169.degree. C.Form: FreeExample 677Structure ##STR1927## ##STR1928##R.sup.2 : 2-ClR.sup.3 : ##STR1929##Crystalline form: Light brown prismsRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 170-172.degree. C.Form: FreeExample 678Structure ##STR1930## ##STR1931##R.sup.2 : ##STR1932##R.sup.3 : ##STR1933##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 181.5-182.5.degree. C.Form: FreeExample 679Structure ##STR1934## ##STR1935##R.sup.2 : ##STR1936##R.sup.3 : ##STR1937##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 176.5-177.degree. C.Form: FreeExample 680Structure ##STR1938## ##STR1939##R.sup.2 : 2-ClR.sup.3 : ##STR1940##Crystalline form: Yellow amorphousNMR analysis: 117)Form: FreeExample 681Structure ##STR1941## ##STR1942##R.sup.2 : 2-ClR.sup.3 : ##STR1943##Crystalline form: Yellow amorphousNMR analysis: 118)Form: FreeExample 682Structure ##STR1944## ##STR1945##R.sup.2 : HR.sup.3 : ##STR1946##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 236-239.degree. C.Form: FreeExample 683Structure ##STR1947## ##STR1948##R.sup.2 : HR.sup.3 : ##STR1949##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 153-154.degree. C.Form: FreeExample 684Structure ##STR1950## ##STR1951##R.sup.2 : HR.sup.3 : ##STR1952##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 128-130.degree. C.Form: FreeExample 685Structure ##STR1953## ##STR1954##R.sup.2 : HR.sup.3 : ##STR1955##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 231-234.degree. C.Form: FreeExample 686Structure ##STR1956## ##STR1957##R.sup.2 : HR.sup.3 : ##STR1958##Crystalline form: White powderRecrystallization solvent: Ethyl acetateMelting Point: 246-248.degree. C.Form: FreeExample 687Structure ##STR1959## ##STR1960##R.sup.2 : HR.sup.3 : ##STR1961##Crystalline form: White powderRecrystallization solvent: Ethanol/waterMelting Point: 248-248.5.degree. C.Form: FreeExample 688Structure ##STR1962## ##STR1963##R.sup.2 : HR.sup.3 : ##STR1964##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 204-205.degree. C.Form: FreeExample 689Structure ##STR1965## ##STR1966##R.sup.2 : HR.sup.3 : ##STR1967##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: >300.degree. C.NMR analysis: 119)Form: FreeExample 690Structure ##STR1968## ##STR1969##R.sup.2 : HR.sup.3 : ##STR1970##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 292-294.degree. C.Form: FreeExample 691Structure ##STR1971## ##STR1972##R.sup.2 : 2-N(CH.sub.3).sub.2R.sup.3 : ##STR1973##Crystalline form: Colorless amorphousNMR analysis: 120)Form: FreeExample 692Structure ##STR1974## ##STR1975##R.sup.2 : 2-N(CH.sub.3).sub.2R.sup.3 : ##STR1976##Crystalline form: Colorless amorphousNMR analysis: 121)Form: FreeExample 693Structure ##STR1977## ##STR1978##R.sup.2 : 2-ClR.sup.3 : ##STR1979##Crystalline form: Colorless amorphousNMR analysis: 122)Form: FreeExample 694Structure ##STR1980## ##STR1981##R.sup.2 : 2-ClR.sup.3 : ##STR1982##Crystalline form: Colorless amorphousNMR analysis: 123)Form: FreeExample 695Structure ##STR1983## ##STR1984##R.sup.2 : 2-ClR.sup.3 : ##STR1985##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 198.5-199.degree. C.Form: FreeExample 696Structure ##STR1986## ##STR1987##R.sup.2 : 2-ClR.sup.3 : ##STR1988##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 168-170.degree. C.Form: FreeExample 697Structure ##STR1989## ##STR1990##R.sup.2 : 2-ClR.sup.3 : ##STR1991##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 175-176.degree. C.Form: FreeExample 698Structure ##STR1992## ##STR1993##R.sup.2 : 2-ClR.sup.3 : ##STR1994##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 177-178.degree. C.Form: FreeExample 699Structure ##STR1995## ##STR1996##R.sup.2 : 2-ClR.sup.3 : ##STR1997##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 222-223.5.degree. C.Form: FreeExample 700Structure ##STR1998## ##STR1999##R.sup.2 : 2-ClR.sup.3 : ##STR2000##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 243-244.degree. C.Form: FreeExample 701Structure ##STR2001## ##STR2002##R.sup.2 : HR.sup.3 : ##STR2003##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 180-181.degree. C.Form: FreeExample 702Structure ##STR2004## ##STR2005##R.sup.2 : HR.sup.3 : ##STR2006##Crystalline form: Colorless amorphousNMR analysis: 124)Form: FreeExample 703Structure ##STR2007## ##STR2008##R.sup.2 : HR.sup.3 : ##STR2009##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 231-233.degree. C.Form: FreeExample 704Structure ##STR2010## ##STR2011##R.sup.2 : HR.sup.3 : ##STR2012##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 196-198.degree. C.Form: FreeExample 705Structure ##STR2013## ##STR2014##R.sup.2 : 2-ClR.sup.3 : ##STR2015##Crystalline form: Colorless amorphousNMR analysis: 125)Form: FreeExample 706Structure ##STR2016## ##STR2017##R.sup.2 : 2-ClR.sup.3 : ##STR2018##Crystalline form: Yellow amorphousNMR analysis: 126)Form: FreeExample 707Structure ##STR2019## ##STR2020##R.sup.2 : HR.sup.3 : ##STR2021##Crystalline form: Yellow powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 146-147.degree. C.Form: FreeExample 708Structure ##STR2022## ##STR2023##R.sup.2 : HR.sup.3 : ##STR2024##Crystalline form: Colorless amorphousNMR analysis: 127)Form: FreeExample 709Structure ##STR2025## ##STR2026##R.sup.2 : HR.sup.3 : ##STR2027##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 220-221.degree. C.Form: FreeExample 710Structure ##STR2028## ##STR2029##R.sup.2 : HR.sup.3 : ##STR2030##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 170-172.degree. C.Form: FreeExample 711Structure ##STR2031## ##STR2032##R.sup.2 : HR.sup.3 : ##STR2033##Crystalline form: Colorless amorphousNMR analysis: 128)Form: FreeExample 712Structure ##STR2034## ##STR2035##R.sup.2 : HR.sup.3 : ##STR2036##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 224-225.degree. C.Form: FreeExample 713Structure ##STR2037## ##STR2038##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2039##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 193-196.degree. C.Form: FreeExample 714Structure ##STR2040## ##STR2041##R.sup.2 : 2-ClR.sup.3 : ##STR2042##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 212-214.degree. C.Form: FreeExample 715Structure ##STR2043## ##STR2044##R.sup.2 : 2-ClR.sup.3 : ##STR2045##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 211-213.degree. C.Form: FreeExample 716Structure ##STR2046## ##STR2047##R.sup.2 : 2-ClR.sup.3 : ##STR2048##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 213-215.degree. C.Form: FreeExample 717Structure ##STR2049## ##STR2050##R.sup.2 : 2-ClR.sup.3 : ##STR2051##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 199-201.degree. C.Form: FreeExample 718Structure ##STR2052## ##STR2053##R.sup.2 : 2-ClR.sup.3 : ##STR2054##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 238-240.degree. C.Form: FreeExample 719Structure ##STR2055## ##STR2056##R.sup.2 : 2-ClR.sup.3 : ##STR2057##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 188-189.degree. C.Form: FreeExample 720Structure ##STR2058## ##STR2059##R.sup.2 : HR.sup.3 : ##STR2060##Crystalline form: Colorless prismsRecrystallization solvent: Dioxane/waterMelting Point: 135.5-137.degree. C.Form: FreeExample 721Structure ##STR2061## ##STR2062##R.sup.2 : HR.sup.3 : ##STR2063##Crystalline form: White powderRecrystallization solvent: Isopropyl alcohol/petroleum etherMelting Point: 192-193.degree. C.Form: FreeExample 722Structure ##STR2064## ##STR2065##R.sup.2 : HR.sup.3 : ##STR2066##Crystalline form: Colorless needlesRecrystallization solvent: Ethyl acetateMelting Point: 239-240.degree. C.Form: FreeExample 723Structure ##STR2067## ##STR2068##R.sup.2 : HR.sup.3 : ##STR2069##Crystalline form: Colorless amorphousNMR analysis: 129)Form: FreeExample 724Structure ##STR2070## ##STR2071##R.sup.2 : HR.sup.3 : ##STR2072##Crystalline form: Colorless amorphousNMR analysis: 130)Form: FreeExample 725Structure ##STR2073## ##STR2074##R.sup.2 : HR.sup.3 : ##STR2075##Crystalline form: Colorless needlesRecrystallization solvent: Ethanol/petroleum etherMelting Point: 193-194.degree. C.Form: FreeExample 726Structure ##STR2076## ##STR2077##R.sup.2 : HR.sup.3 : ##STR2078##Crystalline form: Light yellow prismsRecrystallization solvent: EthanolMelting Point: 245.5-247.degree. C.Form: FreeExample 727Structure ##STR2079## ##STR2080##R.sup.2 : HR.sup.3 : ##STR2081##Crystalline form: Colorless prismsRecrystallization solvent: Ethanol/petroleum etherMelting Point: 142-144.degree. C.Form: FreeExample 728Structure ##STR2082## ##STR2083##R.sup.2 : HR.sup.3 : ##STR2084##Crystalline form: Light yellow prismsRecrystallization solvent: EthanolMelting Point: 214-217.degree. C.Form: FreeExample 729Structure ##STR2085## ##STR2086##R.sup.2 : HR.sup.3 : ##STR2087##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 205-207.degree. C.Form: FreeExample 730Structure ##STR2088## ##STR2089##R.sup.2 : HR.sup.3 : ##STR2090##Crystalline form: Colorless needlesRecrystallization solvent: Ethanol/diethyl etherMelting Point: 201-203.degree. C.Form: FreeExample 731Structure ##STR2091## ##STR2092##R.sup.2 : HR.sup.3 : ##STR2093##Crystalline form: Colorless needlesRecrystallization solvent: Ethanol/diethyl etherMelting Point: 180-182.degree. C.Form: FreeExample 732Structure ##STR2094## ##STR2095##R.sup.2 : HR.sup.3 : ##STR2096##Crystalline form: Light yellow scalesRecrystallization solvent: Ethanol/diethyl etherMelting Point: 178-180.degree. C.Form: FreeExample 733Structure ##STR2097## ##STR2098##R.sup.2 : HR.sup.3 : ##STR2099##Crystalline form: Colorless needlesRecrystallization solvent: Methanol/diethyl etherMelting Point: 208-213.degree. C.Form: FreeExample 734Structure ##STR2100## ##STR2101##R.sup.2 : HR.sup.3 : ##STR2102##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl etherMelting Point: 175-177.degree. C.Form: FreeExample 735Structure ##STR2103## ##STR2104##R.sup.2 : HR.sup.3 : ##STR2105##Crystalline form: White powderNMR analysis: 131)Form: FreeExample 736Structure ##STR2106## ##STR2107##R.sup.2 : HR.sup.3 : ##STR2108##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 277-279.degree. C.Form: FreeExample 737Structure ##STR2109## ##STR2110##R.sup.2 : HR.sup.3 : ##STR2111##Crystalline form: Colorless amorphousNMR analysis: 132)Form: FreeExample 738Structure ##STR2112## ##STR2113##R.sup.2 : HR.sup.3 : ##STR2114##Crystalline form: Colorless amorphousNMR analysis: 133)Form: FreeExample 739Structure ##STR2115## ##STR2116##R.sup.2 : HR.sup.3 : ##STR2117##Crystalline form: Colorless amorphousNMR analysis: 134)Form: FreeExample 740Structure ##STR2118## ##STR2119##R.sup.2 : HR.sup.3 : ##STR2120##Crystalline form: Colorless amorphousNMR analysis: 135)Form: FreeExample 741Structure ##STR2121## ##STR2122##R.sup.2 : HR.sup.3 : ##STR2123##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 213-214.degree. C.Form: FreeExample 742Structure ##STR2124## ##STR2125##R.sup.2 : HR.sup.3 : ##STR2126##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 216-217.degree. C.Form: FreeExample 743Structure ##STR2127## ##STR2128##R.sup.2 : 2-ClR.sup.3 : ##STR2129##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 165-167.degree. C.Form: FreeExample 744Structure ##STR2130## ##STR2131##R.sup.2 : HR.sup.3 : ##STR2132##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 202-206.degree. C.Form: FreeExample 745Structure ##STR2133## ##STR2134##R.sup.2 : 2-ClR.sup.3 : ##STR2135##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 220-221.5.degree. C.Form: FreeExample 746Structure ##STR2136## ##STR2137##R.sup.2 : HR.sup.3 : ##STR2138##Crystalline form: Colorless needlesRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 186-186.5.degree. C.Form: FreeExample 747Structure ##STR2139## ##STR2140##R.sup.2 : 2-ClR.sup.3 : ##STR2141##Crystalline form: Colorless amorphousNMR analysis: 136)Form: FreeExample 748Structure ##STR2142## ##STR2143##R.sup.2 : HR.sup.3 : ##STR2144##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 136-140.degree. C.Form: FreeExample 749Structure ##STR2145## ##STR2146##R.sup.2 : 2-ClR.sup.3 : ##STR2147##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 151-153.degree. C.Form: FreeExample 750Structure ##STR2148## ##STR2149##R.sup.2 : HR.sup.3 : ##STR2150##Crystalline form: Colorless needlesRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 155-156.degree. C.Form: FreeExample 751Structure ##STR2151## ##STR2152##R.sup.2 : HR.sup.3 : ##STR2153##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 189-190.degree. C.Form: FreeExample 752Structure ##STR2154## ##STR2155##R.sup.2 : HR.sup.3 : ##STR2156##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 188-190.degree. C.Form: FreeExample 753Structure ##STR2157## ##STR2158##R.sup.2 : HR.sup.3 : ##STR2159##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 233-235.degree. C.Form: FreeExample 754Structure ##STR2160## ##STR2161##R.sup.2 : HR.sup.3 : ##STR2162##Crystalline form: Colorless amorphousNMR analysis: 137)Form: FreeExample 755Structure ##STR2163## ##STR2164##R.sup.2 : HR.sup.3 : ##STR2165##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 176-179.degree. C.Form: FreeExample 756Structure ##STR2166## ##STR2167##R.sup.2 : HR.sup.3 : ##STR2168##Crystalline form: Colorless needlesRecrystallization solvent: Methanol/diethyl etherMelting Point: 183-185.degree. C.Form: Free__________________________________________________________________________
117) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.3-2.3 (4H, m), 3.1-3.4 (3H, m), 3.8-4.6 (2H, m), 5.0-5.3 (2H, m), 5.8-6.1 (1H, m), 6.8-8.5 (11H, m)
118) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.6-2.2 (4H, m), 2.46, 2.53 (3H, each s), 3.1-3.5 (3H, m), 3.8-4.6 (2H, m), 5.0-5.3 (2H, m), 5.8-6.1 (1H, m), 6.8-8.0 (11H, m)
119) .sup.1 H-NMR(DMSO-d.sub.6) .delta.; 2.33 (3H, s), 3.36 (2H, m), 3.89 (1H, m), 4.41 (1H, m), 5.07 (1H, m), 5.40 (1H, d, J=14.8 Hz), 6.85 (1H, d, J=7.2 Hz), 7.15-7.65 (11H, m), 10.35 (1H, s)
120) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.25-5.05 (22H, m), 6.65-7.65 (11H, m), 7.75-8.25 (1H, m)
121) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.15-5.05 (19H, m), 6.75-7.85 (11H, m), 7.85-8.25 (1H, m)
122) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.25-2.85 (8H, m), 2.95-4.95 (2H, m), 6.75-7.85 (10H, m), 9.25-9.75 (1H, m)
123) .sup.1 H-NMR(CDCl.sub.3) .delta.; 0.20-0.70 (4H, m), 0.95-2.35 (6H, m), 2.65-5.00 (2H, m), 6.75-7.90 (10H, m), 8.65-9.25 (1H, m)
124) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.20-3.15 (11H, m), 3.45-3.70 (1H, m), 4.05-5.20 (1H, m), 6.60-7.65 (10H, m), 8.15-8.45 (2H, m)
125) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.19 (3H, t, J=7 Hz), 1.25-3.25 (8H, m), 3.46 (2H, q, J=7 Hz), 3.40-4.10 (3H, m), 4.45-5.10 (1H, m), 6.65-7.75 (12H, m), 8.30-8.60 (1H, m)
126) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.10-1.30 (3H, m), 1.50-2.35 (4H, m), 2.65-3.05 (2H, m), 3.35-3.60 (2H, m), 3.80-4.05 (2H, m), 4.65-5.15 (2H, m), 6.55-7.85 (12H, m), 8.35-8.65 (1H, m)
127) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.20 (3H, t, J=7 Hz), 1.10-3.15 (11H, m), 3.45-3.65 (3H, m), 3.88 (2H, s), 3.95-5.15 (1H, m), 6.55-7.65 (13H, m), 8.37 (1H, s)
128) .sup.1 H-NMR(CDCl.sub.3) .delta.; 2.45 (3H, s), 3.40 (3H, s), 4.01 (2H, m), 4.38 (2H, m), 7.20-7.77 (13H, m)
129) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.35-4.55 (22H, m), 6.3-7.8 (13H, m)
130) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.10 (6H, t, J=7 Hz), 1.35-5.1 (23H, m), 6.55-7.8 (13H, m)
131) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.94-3.21 (3H, m), 3.30-4.82 (3H, m), 6.57 (1H, d, J=7.5 Hz), 6.86-8.10 (11H, m), 8.72 (1H, brs)
132) .sup.1 H-NMR(DMSO-d.sub.6) .delta.; 1.57-1.85 (2H, m), 1.85-2.28 (2H, m), 2.33 (3H, s), 2.64-2.86 (1H, m), 4.53-5.07 (1H, m), 5.79-5.94 (1H, m), 6.47-7.68 (2H, br), 6.64-6.77 (1H, m), 6.96-7.62 (12H, m)
133) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.61-1.97 (2H, m), 2.00-2.54 (2H, m), 2.47 (3H, s), 2.60-3.23 (7H, m), 4.76-5.22 (1H, m), 5.94-6.19 (1H, m), 6.61-6.74 (1H, m), 6.91-7.62 (12H, m)
134) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.68-1.97 (2H, m), 2.03-2.53 (2H, n), 2.61-3.24 (7H, m), 4.76-5.22 (1H, m), 5.97-6.17 (1H, m), 6.59-6.74 (1H, m), 6.92-7.13 (1H, m), 7.13-7.58 (9H, m), 7.66-7.85 (1H, m), 7.85-8.00 (1H, m)
135) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.57-1.93 (2H, m), 1.93-2.54 (2H, m), 2.54-2.72 (1H, m), 2.79-3.09 (3H, m), 3.90-4.32 (2H, m), 4.49-5.18 (2H, m), 6.31-6.93 (2H, m), 6.96-7.63 (10H, m), 7.63-7.89 (1H, m), 7.89-8.16 (1H, m)
136) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.44-1.95 (2H, m), 1.95-2.28 (2H, m), 2.40-2.67 (3H, m), 2.73-3.38 (3H, m), 3.40-3.97 (1H, m), 4.50-5.20 (1H, m), 6.67-8.11 (11H, m)
137) .sup.1 H-NMR(CDCl.sub.3) .delta.; 1.50-2.10 (3H, m), 2.10-2.28 (1H, m), 2.36 (3H, s), 2.48 (3H, s), 2.68-2.97 (1H, m), 3.26-3.47 (1H, m), 4.16 (1H, d, J=13.8 Hz), 4.25 (1H, d, J=13.8 Hz), 5.95 (1H, brs), 6.60-6.76 (1H, m), 6.97-7.52 (8H, m), 7.52-7.73 (2H, m), 7.73-7.97 (2H, m)
Example 757
A mixture of 5-dimethylamino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (10 g), methyl iodide (1.7 ml) and chloroform (10 ml) is heated with stirring at 100.degree. C. for 3 hours in an autoclave. After completion of the reaction, the solvent is distilled off under reduced pressure and the resulting residue is dissolved in methanol. The mixture is treated with IRA-400 (trade mark; Organo Co., Ltd., OH.sup.- type). Methanol is distilled off and the resulting residue is suspended in t-butyl alcohol (90 ml), and thereto is added potassium t-butoxide (2.3 g). The mixture is refluxed for 5 hours. The solvent is distilled off under reduced pressure, and the resulting residue is dissolved in dichloromethane. The mixture is washed successively with water and saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and to the resulting residue is added dichloromethane/diethyl ether. The precipitated crude crystal is recrystallized from ethanol to give 1-�4-(2-chlorobenzoylamino)benzoyl!-2,3-dihydro-1H-benzazepine (5.15 g) as colorless needles, m.p. 205.degree.-207.degree. C.
Example 758
1-�4-(2-Chlorobenzoylamino)benzoyl!-2,3-dihydro-1H-benzazepine (4.7 g) is dissolved in dichloromethane (50 ml) and thereto is added 80% m-chloroperbenzoic acid (3 g). The mixture is stirred at room temperature overnight. The dichloromethane layer is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1) to give 4,5-epoxy-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (4.26 g) as white powder.
.sup.1 H-NMR(CDCl.sub.3) .delta.; 1.94-3.21 (3H, m), 3.30-4.82 (3H, m), 6.57 (1H, d, J=7.5 Hz), 6.86-8.10 (11H, m), 8.72 (1H, brs)
Example 759
A mixture of 4,5-epoxy-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g), dimethylamine hydrochloride (2.6 g), triethylamine (4.5 g) and methanol (15 ml) is refluxed for 19 hours. After completion of the reaction, the solvent is distilled off and the resulting residue is dissolved in dichloromethane. The mixture is washed successively with water and saturated saline solution. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from ethanol/diethyl ether to give trans-5-dimethylamino-4-hydroxy-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as colorless needles, m.p. 180.degree.-182.degree. C.
Using the suitable starting materials, the compounds of the above Examples 733 and 734 are obtained in the same manner as in Example 759.
Example 760
Methyltriphenylphosphonium bromide (4.30 g) is suspended in tetrahydrofuran (100 ml) and thereto is added potassium t-butoxide (1.58 g) under ice-cooling. The mixture is stirred at -5.degree. C. for 1 hour and thereto is added 5-oxo-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.60 g) and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into ice-water (200 ml) and extracted with ethyl acetate. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:2), and recrystallized from ethyl acetate/n-hexane to give 5-methylidene-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.34 g) as white powder, m.p. 216.degree.-217.degree. C.
Using the suitable starting materials, the compound of the above Example 743 is obtained in the same manner as in Example 760.
Example 761
5-Methylidene-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (2.84 g) is suspended in tetrahydrofuran (50 ml) and thereto is added 1M solution of boran-tetrahydrofuran complex in tetrahydrofuran (43 ml). The mixture is stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution is cooled with ice, and thereto is added water (70 ml). After termination of the evolution of hydrogen gas, to the reaction solution are added 25% aqueous sodium hydroxide solution (7.0 ml), and subsequently 31% aqueous hydrogen peroxide solution (4.7 ml), and the mixture is heated with stirring at 50.degree. C. for 1 hour. After cooling, to the reaction solution is added saturated saline solution and the tetrahydrofuran layer is collected, washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-hydroxymethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.96 g) as white powder, m.p. 202.degree.-206.degree. C.
Using the suitable starting materials, the compound of the above Example 745 is obtained in the same manner as in Example 761.
Example 762
5-Methylidene-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.81 g) is dissolved in dichloromethane (30 ml) and thereto is added m-chloroperbenzoic acid (0.57 g). The mixture is stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution is washed successively with aqueous sodium hydrogensulfite solution, aqueous sodium hydrogen carbonate solution and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified with silica gel column chromatography (eluent; ethyl acetate:n-hexane=2:3) to give 5,5-epoxy-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g) as colorless amorphous.
.sup.1 H-NMR(CDCl.sub.3) .delta.; 1.44-1.95 (2H, m), 1.95-2.28 (2H, m), 2.40-2.67 (3H, m), 2.73-3.38 (3H, m), 3.40-3.97 (1H, m), 4.50-5.20 (1H, m), 6.67-8.11 (11H, m)
Using the suitable starting materials, the compound of the above Example 746 is obtained in the same manner as in Example 762.
Example 763
To 5-methylidene-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.60 g) are added successively t-butyl alcohol (6.0 ml), water (1.2 ml), pyridine (0.3 ml), osmium tetroxide (1.2 mg) and trimethylamine N-oxide dihydrate (0.22 g), and the mixture is refluxed with stirring for 2.5 hours. After cooling, to the reaction solution is added 20% aqueous sodium hydrogen-sulfite solution (10 ml), and the mixture is stirred at room temperature for 1.5 hour. The reaction solution is extracted with a mixture of ethyl acetate/tetrahydrofuran (1:1). The extract is washed successively with diluted hydrochloric acid and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-hydroxymethyl-5-hydroxy-1-(4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) as white powder, m.p. 136.degree.-140.degree. C.
Using the suitable starting materials, the compound of the above Example 749 is obtained in the same manner as in Example 763.
Example 764
To 5-hydroxymethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.40 g) are added acetic anhydride (4.0 ml) and pyridine (0.5 ml), and the mixture is stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution is poured into ice-water and extracted with ethyl acetate. The extract is washed successively with diluted hydrochloric acid and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-acetyloxymethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.43 g) as colorless needles, m.p. 155.degree.-156.degree. C.
Example 765
5-Hydroxymethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.70 g) is dissolved in a mixture (30 ml) of dichloromethane/acetonitrile (1:1) and thereto are added methanesulfonyl chloride (0.8 ml) and pyridine (1.0 ml), and the mixture is refluxed with stirring for 2 hours. After cooling, the reaction solution is evaporated under reduced pressure and to the resulting residue is added water and then extracted with ethyl acetate. The extract is washed successively with diluted hydrochloric acid and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-methanesulfonyloxymethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.72 g) as white powder, m.p. 189.degree.-190.degree. C.
Example 766
5-Methanesulfonyloxymethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.49 g) is dissolved in a mixture (25 ml) of acetonitrile/dimethylformamide (4:1) and thereto is added sodium azide (0.11 g). The mixture is refluxed with stirring for 3.5 hours. After cooling, the reaction solution is poured into ice-water (40 ml), extracted with ethyl acetate, washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:2), and recrystallized from ethyl acetate/n-hexane to give 5-azidomethyl-1-�4-(2-methylbenzoylamino)benzoly!-2,3,4,5-tetrahydro-1H-benzazepine (0.29 g) as white powder, m.p. 188.degree.-189.degree. C.
Example 767
5-Azidomethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.27 g) is suspended in ethanol (50 ml) and the mixture is subjected to catalytic hydrogenation at room temperature under 3 kg/cm.sup.2 for 6 hours by using 10% Pd--C (27 mg). The catalyst is removed by filtration with celite and the filtrate is distilled off and the resulting residue is recrystallized from ethanol to give 5-aminomethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.12 g) as colorless needles, m.p. 233.degree.-235.degree. C.
Example 768
To 5,5-epoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.30 g) is added 30% solution of methylamine in methanol (30 ml), and the mixture is refluxed for 14 hours. After completion of the reaction, the reaction solution is evaporated under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane 1:1.fwdarw.dichloromethane:methanol:aqueous ammonia=60:10:1) to give 5-hydroxymethyl-5-methylamino-1-�4-(2-methylbenzoylamino!benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (A; 35.3 mg) and 5-methylaminomethyl-5-hydroxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (B; 109 mg).
(A); Colorless amorphous
.sup.1 H-NMR(CDCl.sub.3) .delta.; 1.50-2.10 (3H, m), 2.10-2.28 (1H, m), 2.36 (3H, s), 2.48 (3H, s), 2.68-2.97 (1H, m), 3.26-3.47 (1H, m), 4.16 (1H, d, J=13.8 Hz), 4.25 (1H, d, J=13.8 Hz), 5.95 (1H, brs), 6.60-6.76 (1H, m), 6.97-7.52 (8H, m), 7.52-7.73 (2H, m), 7.73-7.97 (2H, m)
(B); White powder (recrystallized from ethyl acetate/n-hexane)
m.p. 176.degree.-179.degree. C.
Example 769
5-Methylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1 g) is dissolved in dimethylformamide (10 ml) and thereto are added potassium carbonate (0.5 g) and ethyl iodide (0.45 g). The mixture is stirred at room temperature overnight. After completion of the reaction, the reaction solution is poured into ice-water and the precipitated crystal is collected by filtration, and purified by silica gel column chromatography (eluent; dichloromethane:methanol=90:1), and recrystallized from diisopropyl alcohol/petroleum ether to give 5-(N-methyl-N-ethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (50 mg) as white powder, m. p. 192.degree.-193.degree. C.
Using the suitable starting materials, the compounds of the above Examples 244, 246-248, 330, 339, 342, 346, 350, 366, 375, 376, 406-418, 453, 455, 457, 460, 464, 467, 506, 507, 537-545, 547, 549-556, 561-566, 568-571, 577, 601-603, 607-625, 654-672, 675, 677-681, 691-695, 697, 698, 701-705, 707, 708, 712, 713, 715, 716, 719, 720 and 722-725 are obtained in the same manner as in Example 769.
Example 770
To a suspension of 5-methylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (3 g) in methanol (30 ml) are added potassium carbonate (1.5 g) and epichlorohydrine (5.7 ml), and the mixture is refluxed for 3 hours. The solvent is distilled off and to the resulting residue is added water and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=80:1) to give 5-(N-methyl-N-oxiranylmethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (C; 1.92 g) and 5-�N-methyl-N-(2-hydroxy-3-methoxypropyl)amino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (D; 0.38 g).
(C); Colorless needles (recrystallization from ethyl acetate)
m.p. 239.degree.-240.degree. C.
(D); Colorless amorphous
.sup.1 H-NMR(CDCl.sub.3) .delta.; 1.35-4.55 (22H, m), 6.3-7.8 (13H, m)
Example 771
5-�N-Methyl-N-oxiranylmethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) is dissolved in methanol (10 ml) and thereto is added diethylamine (0.13 ml). The mixture is refluxed for 3 hours. After completion of the reaction, the solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1.fwdarw.dichloromethane:methanol:aqueous ammonia=9:1:0.1) to give 5-�N-methyl-N-(2-hydroxy-3-diethylaminopropyl)amino!-1-(4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as colorless amorphous.
.sup.1 H-NMR(CDCl.sub.3) .delta.; 1.10 (6H, t, J=7 Hz), 1.35-5.1 (23H, m), 6.55-7.8 (13H, m)
Example 772
A solution of 5-hydroxyimino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.06 g) in acetic anhydride (10 ml) and pyridine (10 ml) is stirred at room temperature overnight. After completion of the reaction, the reaction solution is concentrated. To the resulting residue is added water and the mixture is extracted with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=80:1), and recrystallized from ethanol/petroleum ether to give 5-acetyloxyimino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.75 g) as colorless prisms, m.p. 142.degree.-144.degree. C.
Example 773
Using the suitable starting materials, the compounds of the above Examples 671 and 672 are obtained in the same manner as in Example 380.
Example 774
Using the suitable starting materials, the compounds of the above Examples 674, 699, 700, 706, 718 and 730 are obtained in the same manner as in Example 384.
Example 775
Using the suitable starting materials, the compounds of the above Examples 654-672, 675, 677-687, 691-695, 697, 698, 701-705, 707, 708, 712, 713, 715, 716 and 719-725 are obtained in the same manner as in Example 390.
Example 776
Using the suitable starting materials, the compounds of the above Examples 654-672, 675, 677-679, 691-693, 698, 701-705, 707, 708, 712, 713, 715, 716 and 719-725 are obtained in the same manner as in Example 388.
Example 777
Using the suitable starting materials, the compounds of the above Examples 705, 706 and 708 are obtained in the same manner as in Example 394.
Example 778
Using the suitable starting materials, the compound of the above Example 671 is obtained in the same manner as in Example 397.
Example 779
Using the suitable starting materials, the compound of the above Example 672 is obtained in the same manner as in Example 402.
Example 780
Using the suitable starting materials, the compound of the above Example 726 is obtained in the same manner as in Example 634.
Example 781
Using the suitable starting materials, the compound of the above Example 740 is obtained in the same manner as in Examples 638 and 640.
Example 782
Using the suitable starting materials, the compound of the above Example 689 is obtained in the same manner as in Example 643.
Example 783
Using the suitable starting materials, the compound of the above Example 690 is obtained in the same manner as in Example 644.
Example 784
Using the suitable starting materials, the following compound is obtained in the same manner as in Examples 1, 382, 388 and 390.
5-Dimethylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride, colorless needles (recrystallized from ethanol/water), m.p. 233.degree.-237.degree. C.
REFERENCE EXAMPLE 13
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 1.
5-(2-Chloroacetyloxy)-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 156.degree.-159.degree. C. (recrystallized from ethyl acetate/n-hexane)
5-(2-Dimethylaminoacetyloxy)-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 108.degree.-109.degree. C. (recrystallized from ethyl acetate/n-hexane)
5-Oxo-7-chloro-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 157.5.degree.-159.5.degree. C. (recrystallized from diethyl ether/dichloromethane)
5-Oxo-8-chloro-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 151.5.degree.-153.5.degree. C. (recrystallized from diethyl ether/dichloromethane)
REFERENCE EXAMPLE 14
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.
5-(2-Dimethylaminoacetyloxy)-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.63-1.98 (2H, m), 1.98-2.25 (1H, m), 2.27 (3H, s), 2.43 (3H, s), 2.65-3.23 (2H, m), 3.38 (2H, s), 3.67 (2H, brs), 4.77-5.28 (1H, m), 6.04-6.31 (1H, m), 6.31-6.56 (2H, m), 6.58-6.86 (1H, m), 6.86-7.46 (5H, m)
5-Oxo-7-chloro-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 193.degree.-193.5.degree. C. (recrystallized from diethyl ether/dichloromethane)
5-Oxo-8-chloro-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 171.degree.-174.degree. C. (recrystallized from diethyl ether/dichloromethane)
REFERENCE EXAMPLE 15
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 1.
5-Dimethylaminocarbonylmethoxy-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 129.degree.-131.degree. C. (recrystallized from ethyl acetate/n-hexane)
6-Oxo-1-(4-nitrobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, yellow needles
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.65-2.3 (4H, m), 2.5-5.2 (4H, m), 6.7-6.9 (1H, m), 7.27-7.5 (4H, m), 7.90-8.15 (3H, m)
6-Chloro-5-oxo-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 198.degree.-202.degree. C. (recrystallized from dichloromethane/diethyl ether)
REFERENCE EXAMPLE 16
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.
5-Dimethylaminocarbonylmethoxy-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.52-2.10 (3H, m), 2.10-3.20 (2H, m), 2.97 (3H, s), 3.05 (3H, s), 4.03-4.48 (2H, m), 4.50-5.35 (2H, m), 6.26-6.57 (2H, m), 6.57-6.88 (1H, m), 6.88-7.76 (5H, m)
6-Oxo-1-(4-aminobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, light yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.7-2.2 (4H, m), 2.5-5.2 (6H, m), 6.42 (2H, d, J=8.7 Hz), 6.75-6.9 (1H, m), 7.05-7.4 (4H, m), 7.95-8.1 (1H, m)
6-Chloro-5-oxo-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 166.degree.-169.degree. C. (recrystallized from dichloromethane/diethyl ether)
9-Chloro-5-oxo-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder, m.p. 192.5.degree.-195.degree. C. (recrystallized from dichloromethane/diethyl ether)
REFERENCE EXAMPLE 17
5-Dimethylamino-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (86.0 g) is dissolved in ethanol (800 ml), and thereto is added platinum oxide (10 g). The mixture is subjected to hydrogenation at ordinary temperature under atmospheric pressure of hydrogen for 4 hours. The catalyst is removed by filtration, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=200:1.fwdarw.100:1), and further purified by silica gel thin layer chromatography (developer; chloroform:methanol=10:1), and recrystallized from methanol/diethyl ether to give 5-dimethylamino-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (G) (Rf: 0.52, 27.4 g) and 5-dimethylamino-1-(2-methyl-4-amino-benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (H) (Rf: 0.48, 12.3 g).
(G): White powder
M.p. 154.degree.-156.degree. C. �.alpha.!.sub.D.sup.22 =0.degree. C. (c=1.0, chloroform)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-1.50 (1H, m), 1.50-2.00 (1H, m), 2.00-2.35 (11H, m), 2.90-5.18 (5H, m), 6.00-6.76 (3H, m), 6.81-7.64 (4H, m)
(H): White powder
M.p. 169.5.degree.-170.degree. C.
�.alpha.!.sub.D.sup.22 =0.degree. (c=1.5, chloroform)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.11-2.90 (13H, m), 2.91-5.23 (5H, m), 6.15-6.53 (1H, m), 6.57-7.62 (6H, m)
Using the suitable starting materials, the compounds of the following Table 5 are obtained in the same manner as in above Examples 1 and 382.
TABLE 5______________________________________ ##STR2169##______________________________________Example 785Structure ##STR2170## ##STR2171##R.sup.2 : HR.sup.3 : ##STR2172##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 174-175.degree. C.Form: FreeExample 786Structure ##STR2173## ##STR2174##R.sup.2 : HR.sup.3 : ##STR2175##Crystalline form: Colorless prismsRecrystallization solvent: Ethanol/diethyl etherMelting Point: 176-178.degree. C.Form: FreeExample 787Structure ##STR2176## ##STR2177##R.sup.2 : HR.sup.3 : ##STR2178##Crystalline form: Colorless prismsRecrystallization solvent: Ethyl acetate/petroleum etherMelting Point: 154.5-155.degree. C.Form: FreeExample 788Structure ##STR2179## ##STR2180##R.sup.2 : HR.sup.3 : ##STR2181##Crystalline form: Colorless amorphousNMR analysis: 138)Form: FreeExample 789Structure ##STR2182## ##STR2183##R.sup.2 : HR.sup.3 : ##STR2184##Crystalline form: Colorless scalesRecrystallization solvent: EthanolMelting Point: 197-198.degree. C.Form: FreeExample 790Structure ##STR2185## ##STR2186##R.sup.2 : HR.sup.3 : ##STR2187##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 248-249.degree. C.Form: FreeExample 791Structure ##STR2188## ##STR2189##R.sup.2 : HR.sup.3 : ##STR2190##Crystalline form: Colorless needlesRecrystallization solvent: Ethanol/n-hexaneMelting Point: 162-163.degree. C.Form: FreeExample 792Structure ##STR2191## ##STR2192##R.sup.2 : HR.sup.3 : ##STR2193##Crystalline form: Colorless prismsRecrystallization solvent: Ethanol/petroleum etherMelting Point: 235-236.5.degree. C.Form: FreeExample 793Structure ##STR2194## ##STR2195##R.sup.2 : HR.sup.3 : ##STR2196##Crystalline form: Colorless amorphousNMR analysis: 139)Form: FreeExample 794Structure ##STR2197## ##STR2198##R.sup.2 : HR.sup.3 : ##STR2199##Crystalline form: Colorless prismsRecrystallization solvent: DioxaneMelting Point: 269-271.degree. C.Form: FreeExample 795Structure ##STR2200## ##STR2201##R.sup.2 : HR.sup.3 : ##STR2202##Crystalline form: Colorless prismsRecrystallization solvent: DimethylformamideMelting Point: 286-287.degree. C.Form: FreeExample 796Structure ##STR2203## ##STR2204##R.sup.2 : HR.sup.3 : ##STR2205##Crystalline form: Colorless needlesRecrystallization solvent: AcetonitrileMelting Point: 227-228.degree. C.Form: FreeExample 797Structure ##STR2206## ##STR2207##R.sup.2 : HR.sup.3 : ##STR2208##Crystalline form: Colorless amorphousNMR analysis: 140)Form: FreeExample 798Structure ##STR2209## ##STR2210##R.sup.2 : HR.sup.3 : ##STR2211##Crystalline form: Colorless prismsRecrystallization solvent: Ethyl acetate/petroleum etherMelting Point: 167-168.degree. C.Form: FreeExample 799Structure ##STR2212## ##STR2213##R.sup.2 : HR.sup.3 : ##STR2214##Crystalline form: Colorless amorphousNMR analysis: 141)Example 800Structure ##STR2215## ##STR2216##R.sup.2 : HR.sup.3 : ##STR2217##Crystalline form: Colorless needlesRecrystallization solvent: Diethyl etherMelting Point: 164-171.degree. C.Form: K.sup..sym.Example 801Structure ##STR2218## ##STR2219##R.sup.2 : HR.sup.3 : ##STR2220##Crystalline form: Colorless amorphousNMR analysis: 142)Form: FreeExample 802Structure ##STR2221## ##STR2222##R.sup.2 : HR.sup.3 : ##STR2223##Crystalline form: Colorless amorphousNMR analysis: 143)Form: FreeExample 803Structure ##STR2224## ##STR2225##R.sup.2 : HR.sup.3 : ##STR2226##Crystalline form: Colorless amorphousNMR analysis: 144)Form: FreeExample 804Structure ##STR2227## ##STR2228##R.sup.2 : HR.sup.3 : ##STR2229##Crystalline form: Colorless amorphousNMR analysis: 145)Form: FreeExample 805Structure ##STR2230## ##STR2231##R.sup.2 : HR.sup.3 : ##STR2232##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 207-208.degree. C.Form: FreeExample 806Structure ##STR2233## ##STR2234##R.sup.2 : HR.sup.3 : ##STR2235##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 187-189.degree. C.Form: FreeExample 807Structure ##STR2236## ##STR2237##R.sup.2 : HR.sup.3 : ##STR2238##Crystalline form: Colorless prismsRecrystallization solvent: Ethanol/petroleum etherMelting Point: 217-218.degree. C.Form: FreeExample 808Structure ##STR2239## ##STR2240##R.sup.2 : HR.sup.3 : ##STR2241##Crystalline form: Colorless needlesRecrystallization solvent: Ethyl acetateMelting Point: 170-171.degree. C.Form: FreeExample 809Structure ##STR2242## ##STR2243##R.sup.2 : HR.sup.3 : ##STR2244##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 239.5-241.degree. C.Form: FreeExample 810Structure ##STR2245## ##STR2246##R.sup.2 : HR.sup.3 : ##STR2247##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 190-191.degree. C.Form: FreeExample 811Structure ##STR2248## ##STR2249##R.sup.2 : HR.sup.3 : ##STR2250##Crystalline form: Colorless prismsRecrystallization solvent: Diethyl etherMelting Point: 163-163.5.degree. C.Form: FreeExample 812Structure ##STR2251## ##STR2252##R.sup.2 : HR.sup.3 : ##STR2253##Crystalline form: Colorless prismsRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 208-210.degree. C.Form: FreeExample 813Structure ##STR2254## ##STR2255##R.sup.2 : HR.sup.3 : ##STR2256##Crystalline form: White powderNMR analysis: 146)Form: FreeExample 814Structure ##STR2257## ##STR2258##R.sup.2 : HR.sup.3 : ##STR2259##Crystalline form: Colorless amorphousNMR analysis: 147)Form: FreeExample 815Structure ##STR2260## ##STR2261##R.sup.2 : HR.sup.3 : ##STR2262##Crystalline form: Colorless needlesRecrystallization solvent: Ethanol/n-hexaneMelting Point: 250-252.degree. C.Form: FreeExample 816Structure ##STR2263## ##STR2264##R.sup.2 : HR.sup.3 : ##STR2265##Crystalline form: Colorless prismsRecrystallization solvent: Ethyl acetateMelting Point: 214-216.degree. C.Form: FreeExample 817Structure ##STR2266## ##STR2267##R.sup.2 : HR.sup.3 : ##STR2268##Crystalline form: Colorless prismsRecrystallization solvent: Ethanol/n-hexaneMelting Point: 243-245.degree. C.Form: FreeExample 818Structure ##STR2269## ##STR2270##R.sup.2 : HR.sup.3 : ##STR2271##Crystalline form: Colorless prismsRecrystallization solvent: Diethyl etherMelting Point: 159-162.degree. C.Form: FreeExample 819Structure ##STR2272## ##STR2273##R.sup.2 : HR.sup.3 : ##STR2274##Crystalline form: Colorless amorphousNMR analysis: 148)Form: FreeExample 820Structure ##STR2275## ##STR2276##R.sup.2 : HR.sup.3 : ##STR2277##Crystalline form: Colorless prismsRecrystallization solvent: Ethyl acetateMelting Point: 287-289.degree. C.Form: FreeExample 821Structure ##STR2278## ##STR2279##R.sup.2 : HR.sup.3 : ##STR2280##Crystalline form: Colorless prismsRecrystallization solvent: Diethyl etherMelting Point: 170-171.degree. C.Form: FreeExample 822Structure ##STR2281## ##STR2282##R.sup.2 : HR.sup.3 : ##STR2283##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 204-205.degree. C.Form: FreeExample 823Structure ##STR2284## ##STR2285##R.sup.2 : HR.sup.3 : ##STR2286##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 273-273.5.degree. C.Form: FreeExample 824Structure ##STR2287## ##STR2288##R.sup.2 : HR.sup.3 : ##STR2289##Crystalline form: Colorless amorphousNMR analysis: 149)Form: FreeExample 825Structure ##STR2290## ##STR2291##R.sup.2 : HR.sup.3 : ##STR2292##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 240-241.degree. C.Form: FreeExample 826Structure ##STR2293## ##STR2294##R.sup.2 : HR.sup.3 : ##STR2295##Crystalline form: White powderRecrystallization solvent: Acetonitrile/ethanolMelting Point: 231-232.degree. C.Form: FreeExample 827Structure ##STR2296## ##STR2297##R.sup.2 : HR.sup.3 : ##STR2298##Crystalline form: White powderRecrystallization solvent: Acetonitrile/ethanolMelting Point: 222-224.degree. C.Form: FreeExample 828Structure ##STR2299## ##STR2300##R.sup.2 : HR.sup.3 : ##STR2301##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 235-237.degree. C.Form: FreeExample 829Structure ##STR2302## ##STR2303##R.sup.2 : HR.sup.3 : ##STR2304##Crystalline form: Colorless amorphousNMR analysis: 150)Form: FreeExample 830Structure ##STR2305## ##STR2306##R.sup.2 : HR.sup.3 : ##STR2307##Crystalline form: Colorless amorphousNMR analysis: 151)Form: FreeExample 831Structure ##STR2308## ##STR2309##R.sup.2 : HR.sup.3 : ##STR2310##Crystalline form: Colorless amorphousNMR analysis: 152)Form: FreeExample 832Structure ##STR2311## ##STR2312##R.sup.2 : HR.sup.3 : ##STR2313##Crystalline form: Colorless amorphousNMR analysis: 153)Form: FreeExample 834Structure ##STR2314## ##STR2315##R.sup.2 : HR.sup.3 : ##STR2316##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 247-248.degree. C.Form: FreeExample 835Structure ##STR2317## ##STR2318##R.sup.2 : HR.sup.3 : ##STR2319##Crystalline form: Colorless amorphousNMR analysis: 154)Form: FreeExample 836Structure ##STR2320## ##STR2321##R.sup.2 : HR.sup.3 : ##STR2322##Crystalline form: Colorless amorphousNMR analysis: 155)Form: FreeExample 837Structure ##STR2323## ##STR2324##R.sup.2 : HR.sup.3 : ##STR2325##Crystalline form: Colorless amorphousNMR analysis: 156)Form: FreeExample 838Structure ##STR2326## ##STR2327##R.sup.2 : HR.sup.3 : ##STR2328##Crystalline form: Colorless amorphousNMR analysis: 157)Form: FreeExample 839Structure ##STR2329## ##STR2330##R.sup.2 : HR.sup.3 : ##STR2331##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 234-235.degree. C.Form: FreeExample 840Structure ##STR2332## ##STR2333##R.sup.2 : HR.sup.3 : ##STR2334##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 234-235.degree. C.Form: FreeExample 841Structure ##STR2335## ##STR2336##R.sup.2 : HR.sup.3 : ##STR2337##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 226-228.degree. C.Form: FreeExample 842Structure ##STR2338## ##STR2339##R.sup.2 : HR.sup.3 : ##STR2340##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 230-231.degree. C.Form: FreeExample 843Structure ##STR2341## ##STR2342##R.sup.2 : HR.sup.3 : ##STR2343##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 186-188.degree. C.Form: FreeExample 844Structure ##STR2344## ##STR2345##R.sup.2 : HR.sup.3 : ##STR2346##Crystalline form: Colorless prismsRecrystallization solvent: Chloroform/methanolMelting Point: 286-290.degree. C.Form: FreeExample 845Structure ##STR2347## ##STR2348##R.sup.2 : HR.sup.3 : ##STR2349##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 186-188.5.degree. C.Form: FreeExample 846Structure ##STR2350## ##STR2351##R.sup.2 : HR.sup.3 : ##STR2352##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 220-222.degree. C.Form: FreeExample 847Structure ##STR2353## ##STR2354##R.sup.2 : HR.sup.3 : ##STR2355##Crystalline form: White powderNMR analysis: 158)Form: FreeExample 848Structure ##STR2356## ##STR2357##R.sup.2 : HR.sup.3 : 4-NHCOCH.sub.2 CONH.sub.2Crystalline form: Colorless prismsRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 189-192.degree. C.Form: FreeExample 849Structure ##STR2358## ##STR2359##R.sup.2 : 2-ClR.sup.3 : ##STR2360##Crystalline form: Colorless amorphousNMR analysis: 159)Form: FreeExample 850Structure ##STR2361## ##STR2362##R.sup.2 : 2-ClR.sup.3 : ##STR2363##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 207-209.degree. C. (decomposed)Form: FreeExample 851Structure ##STR2364## ##STR2365##R.sup.2 : 2-ClR.sup.3 : ##STR2366##Crystalline form: White powderNMR analysis: 160)Form: K.sup..sym.Example 852Structure ##STR2367## ##STR2368##R.sup.2 : 2-ClR.sup.3 : ##STR2369##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 193-194.degree. C.Form: FreeExample 853Structure ##STR2370## ##STR2371##R.sup.2 : HR.sup.3 : ##STR2372##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 185.5-186.degree. C.Form: FreeExample 854Structure ##STR2373## ##STR2374##R.sup.2 : HR.sup.3 : ##STR2375##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 223.5-226.degree. C. (decomposed)Form: FreeExample 855Structure ##STR2376## ##STR2377##R.sup.2 : HR.sup.3 : ##STR2378##Crystalline form: Colorless amorphousNMR analysis: 161)Form: FreeExample 856Structure ##STR2379## ##STR2380##R.sup.2 : HR.sup.3 : ##STR2381##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 225.5-227.degree. C.Form: FreeExample 857Structure ##STR2382## ##STR2383##R.sup.2 : HR.sup.3 : ##STR2384##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 212-214.degree. C.Form: FreeExample 858Structure ##STR2385## ##STR2386##R.sup.2 : HR.sup.3 : ##STR2387##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 230.5-233.degree. C.Form: FreeExample 859Structure ##STR2388## ##STR2389##R.sup.2 : HR.sup.3 : ##STR2390##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 212.5-215.degree. C. (decomposed)Form: FreeExample 860Structure ##STR2391## ##STR2392##R.sup.2 : HR.sup.3 : ##STR2393##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 192-194.5.degree. C.Form: FreeExample 861Structure ##STR2394## ##STR2395##R.sup.2 : HR.sup.3 : ##STR2396##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 175-177.degree. C.Form: FreeExample 862Structure ##STR2397## ##STR2398##R.sup.2 : HR.sup.3 : ##STR2399##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 205.5-209.5.degree. C.Form: FreeExample 863Structure ##STR2400## ##STR2401##R.sup.2 : HR.sup.3 : ##STR2402##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 191-193.5.degree. C.Form: FreeExample 864Structure ##STR2403## ##STR2404##R.sup.2 : HR.sup.3 : ##STR2405##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 204-205.5.degree. C.Form: FreeExample 865Structure ##STR2406## ##STR2407##R.sup.2 : HR.sup.3 : ##STR2408##Crystalline form: Light yellow prismsRecrystallization solvent: EthanolMelting Point: 221-223.degree. C.Form: FreeExample 866Structure ##STR2409## ##STR2410##R.sup.2 : HR.sup.3 : ##STR2411##Crystalline form: Colorless prismsRecrystallization solvent: Ethyl acetateMelting Point: 171-173.degree. C.Form: FreeExample 867Structure ##STR2412## ##STR2413##R.sup.2 : HR.sup.3 : ##STR2414##Crystalline form: Colorless prismsRecrystallization solvent: Ethyl acetateMelting Point: 185-187.degree. C.Form: FreeExample 868Structure ##STR2415## ##STR2416##R.sup.2 : HR.sup.3 : ##STR2417##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 190-192.degree. C.Form: FreeExample 869Structure ##STR2418## ##STR2419##R.sup.2 : HR.sup.3 : ##STR2420##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 175-177.degree. C.Form: FreeExample 870Structure ##STR2421## ##STR2422##R.sup.2 : HR.sup.3 : ##STR2423##Crystalline form: Colorless powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 148-151.degree. C.Form: FreeExample 871Structure ##STR2424## ##STR2425##R.sup.2 : HR.sup.3 : ##STR2426##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 200-202.degree. C.Form: FreeExample 872Structure ##STR2427## ##STR2428##R.sup.2 : HR.sup.3 : ##STR2429##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 200-202.degree. C.Form: FreeExample 873Structure ##STR2430## ##STR2431##R.sup.2 : HR.sup.3 : ##STR2432##Crystalline form: Light yellow powderRecrystallization solvent: AcetoneMelting Point: 235-238.degree. C.Form: FreeExample 874Structure ##STR2433## ##STR2434##R.sup.2 : HR.sup.3 : ##STR2435##Crystalline form: Light yellow powderRecrystallization solvent: AcetoneMelting Point: 198-201.degree. C.Form: FreeExample 875Structure ##STR2436## ##STR2437##R.sup.2 : HR.sup.3 : ##STR2438##Crystalline form: Light yellow needlesRecrystallization solvent: Chloroform/ethyl acetateMelting Point: 232-237.degree. C.Form: FreeExample 876Structure ##STR2439## ##STR2440##R.sup.2 : HR.sup.3 : ##STR2441##Crystalline form: Colorless prismsRecrystallization solvent: Chloroform/ethyl acetateMelting Point: 224-227.degree. C.Form: FreeExample 877Structure ##STR2442## ##STR2443##R.sup.2 : HR.sup.3 : ##STR2444##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 211-214.degree. C.Form: FreeExample 878Structure ##STR2445## ##STR2446##R.sup.2 : HR.sup.3 : ##STR2447##Crystalline form: Colorless powderRecrystallization solvent: Dichloromethane/n-hexaneMelting Point: 238-243.degree. C.Form: FreeExample 879Structure ##STR2448## ##STR2449##R.sup.2 : HR.sup.3 : ##STR2450##Crystalline form: Colorless amorphousNMR analysis: 162)Form: FreeExample 880Structure ##STR2451## ##STR2452##R.sup.2 : HR.sup.3 : ##STR2453##Crystalline form: Colorless amorphousNMR analysis: 163)Form: FreeExample 881Structure ##STR2454## ##STR2455##R.sup.2 : HR.sup.3 : ##STR2456##Crystalline form: Colorless prismsRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 198-202.degree. C.Form: FreeExample 882Structure ##STR2457## ##STR2458##R.sup.2 : HR.sup.3 : ##STR2459##Crystalline form: Colorless prismsRecrystallization solvent: Chloroform/ethyl acetateMelting Point: 226-229.degree. C.Form: FreeExample 883Structure ##STR2460## ##STR2461##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2462##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 139-140.degree. C.Form: FreeExample 884Structure ##STR2463## ##STR2464##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2465##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 149-152.degree. C.Form: FreeExample 885Structure ##STR2466## ##STR2467##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2468##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 180.5-182.degree. C.Form: FreeExample 886Structure ##STR2469## ##STR2470##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2471##Crystalline form: White powderRecrystallization solvent: Chloroform/diethyl etherMelting Point: 211-214.degree. C.Form: FreeExample 887Structure ##STR2472## ##STR2473##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2474##Crystalline form: White powderRecrystallization solvent: Chloroform/diethyl etherMelting Point: 171-174.5.degree. C.Form: FreeExample 888Structure ##STR2475## ##STR2476##R.sup.2 : HR.sup.3 : ##STR2477##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 203-205.degree. C.Form: FreeExample 889Structure ##STR2478## ##STR2479##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2480##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 202-202.5.degree. C.Form: FreeExample 890Structure ##STR2481## ##STR2482##R.sup.2 : 3-OCH.sub.2 CONH.sub.2R.sup.3 : ##STR2483##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 130-133.degree. C.Form: FreeExample 891Structure ##STR2484## ##STR2485##R.sup.2 : ##STR2486##R.sup.3 : ##STR2487##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 104.5-106.degree. C.Form: FreeExample 892Structure ##STR2488## ##STR2489##R.sup.2 : HR.sup.3 : ##STR2490##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 197-198.degree. C.Form: FreeExample 893Structure ##STR2491## ##STR2492##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2493##Crystalline form: White powderRecrystallization solvent: Dichloromethane/ethyl acetateMelting Point: 191-192.degree. C.Form: FreeExample 894Structure ##STR2494## ##STR2495##R.sup.2 : HR.sup.3 : ##STR2496##Crystalline form: Colorless columnarRecrystallization solvent: Ethanol/petroleum etherMelting Point: 211-213.degree. C.Form: FreeExample 895Structure ##STR2497## ##STR2498##R.sup.2 : HR.sup.3 : ##STR2499##Crystalline form: Colorless amorphousNMR analysis: 164)Form: FreeExample 896Structure ##STR2500## ##STR2501##R.sup.2 : HR.sup.3 : ##STR2502##Crystalline form: Colorless amorphousNMR analysis: 165)Form: FreeExample 897Structure ##STR2503## ##STR2504##R.sup.2 : HR.sup.3 : ##STR2505##Crystalline form: Colorless amorphousNMR analysis: 166)Form: FreeExample 898Structure ##STR2506## ##STR2507##R.sup.2 : HR.sup.3 : ##STR2508##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 224-228.degree. C.Form: Free______________________________________
138) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.3-2.95 (19H, m), 3.05-3.3 (1H, m), 3.85-4.1 (2H, m), 4.3-4.6 (1H, m), 6.64 (1H, d, J=7.8 Hz), 6.9-7.8 (12H, m)
139) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.1-2.3 (13H, m), 2.65-3.2 (1H, m), 4.55-5.6 (3H, m), 6.55-6.7 (1H, m), 6.9-7.6 (12H, m)
140) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.3-4.15 (19H, m), 4.3-5.0 (1H, m), 6.65 (1H, d, J=7.7 Hz), 6.9-8.05 (12H, m)
141) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.4-3.0 (9H, m), 3.05-3.6 (3H, m), 3.9-4.1 (1H, m), 4.35-4.55 (1H, m), 4.9-5.65 (1H, m), 6.67 (1H, d, J=7.4 Hz), 6.85-7.6 (12H, m), 7.6-7.85 (2H, m)
142) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.3-2.85 (21H, m), 3.2-4.0 (4H, m), 4.3-4.4 (1H, m), 4.45-5.2 (2H, m), 6.61 (1H, d, J=7.6 Hz), 6.9-7.65 (12H, m)
143) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.3-3.45 (17H, m), 3.8-5.7 (5H, m), 6.5-7.65 (13H, m)
144) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.25-3.1 (14H, m), 3.3-4.0 (4H, m), 4.15-4.4 (1H, m), 4.45-5.2 (1H, m), 6.64 (1H, d, J=7.4 Hz), 6.9-7.7 (12H, m)
145) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.9-3.25 (16H, m), 3.9-5.9 (2H, m), 6.65 (1H, d, J=7.4 Hz), 6.85-7.5 (11H, m), 7.9-8.3 (1H, m)
146) .sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.3-2.15 (4H, m), 2.32 (3H, s), 2.8-3.05 (1H, m), 4.24 (2H, AB-q, J=12.8, 15.4 Hz), 4.35-4.55 (1H, m), 4.9-5.25 (1H, m), 6.68 (1H, d, J=7.6 Hz), 6.9-7.45 (9H, m), 7.52 (2H, d, J=8.6 Hz), 8.9-9.05 (1H, m), 10.31 (1H, s)
147) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.5-2.35 (4H, m), 2.45 (3H, s), 2.6-2.85 (1H, m), 3.32 (3H, s), 4.19 (2H, AB-q, J=12.2 Hz, 15.6 Hz), 5.0-5.2 (1H, m), 5.82 (1H, d, J=10.3 Hz), 6.69 (1H, d, J=7.8 Hz), 6.75-7.95 (12H, m)
148) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.2-3.3 (17H, m), 3.45 (2H, AB-q, J=14.7, 22.9 Hz), 3.9-4.35 (2H, m), 6.60 (2H, d, J=7.7 Hz), 6.8-8.0 (11H, m), 8.39 (1H, s)
149) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.45-3.40 (8H, m), 2.23 (3H, s), 2.33 (3H, s), 2.46 (3H, s), 4.44-5.23 (1H, m), 6.54-6.78 (1H, m), 6.84-7.94 (12H, m)
150) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.50-1.92 (3H, m), 1.92-2.05 (1H, m), 2.47 (3H, s), 2.55-3.06 (5H, m), 3.43-5.76 (8H, m), 6.63-6.82 (1H, m), 6.97-8.08 (12H, m)
151) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.43-2.65 (4H, m), 2.48 (3H, s), 2.69-3.25 (5H, m), 3.90-5.40 (8H, m), 6.64-6.94 (1H, m), 6.94-7.77 (12H, m)
152) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.50-1.90 (3H, m), 1.90-2.20 (1H, m), 2.20-2.64 (4H, m), 2.32 (3H, s), 2.47 (3H, s), 2.64-3.27 (1H, m), 3.36-3.83 (4H, m), 3.93-4.52 (2H, m), 4.52-5.27 (2H, m), 6.57-6.82 (1H, m), 6.93-7.87 (12H, m)
153) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.52-1.93 (2H, m), 1.93-2.23 (4H, m), 2.23-2.57 (1H, m), 2.45 (3H, s), 2.72-3.02 (1H, m), 3.02-3.77 (8H, m), 3.93-4.50 (2H, m), 4.50-5.20 (2H, m), 6.60-6.80 (1H, m), 6.94-7.64 (11H, m), 8.16 (1H, brs)
154) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.48-2.60 (8H, m), 2.46 (3H, s), 2.65-3.01 (1H, m), 3.20-3.74 (2H, m), 3.80-5.14 (4H, m), 5.30-5.84 (1H, m), 6.51-8.14 (13H, m)
155) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.54-1.91 (2H, m), 1.91-2.20 (1H, m), 2.22-2.64 (1H, m), 2.44 (3H, s), 2.70-3.13 (1H, m), 3.60-4.40 (4H, m), 4.50-5.20 (2H, m), 6.07-8.00 (13H, m), 9.93 (1H, s)
156) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.56-1.92 (2H, m), 1.92-2.19 (1H, m), 2.19-2.60 (1H, m), 2.46 (3H, s), 2.66-3.26 (4H, m), 3.33-3.95 (4H, m). 4.00-5.20 (4H, m), 6.58-6.82 (1H, m), 6.93-8.21 (12H, m)
157) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.57-2.17 (3H, m), 2.21-2.68 (1H, m), 2.47 (3H, s), 2.73-3.04 (1H, m), 3.91-4.42 (4H, m), 4.50-5.17 (2H, m), 6.61-6.99 (2H, m), 6.99-8.10 (14H, m), 8.21-8.71 (2H, m)
158) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.31 (3H, d, J=6.7 Hz), 1.53-1.90 (1H, m), 2.29-2.58 (1H, m), 2.47 (3H, s), 2.94-3.63 (2H, m), 4.57-5.05 (1H, m), 6.68-6.82 (1H, m), 7.10-7.59 (10H, m), 7.72 (1H, s), 7.78-7.96 (1H, m)
159) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-2.60 (17H, m), 2.65-5.10 (3H, m), 6.85-3.85 (12H, m)
160) .sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.40-1.75 (1H, m), 1.90-2.15 (1H, m), 2.33 (3H, s), 2.50-2.80 (2H, m), 3.10-3.50 (1H, m), 4.40-4.65 (1H, m), 6.85-7.60 (10H, m), 7.85 (1H, s), 10.44 (1H, s)
161) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.30-2.70 (11H, m), 3.00-5.20 (3H, m), 6.58 (1H, d, J=8 Hz), 6.90-7.05 (1H, m), 7.10-7.70 (10H, m)
162) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.25-2.90 (4H, m), 2.44 (6H, s), 2.79-3.57 (2H, m), 2.79 (6H, s), 4.10-5.25 (1H, m), 6.60-6.80 (1H, m), 6.94-7.60 (10H, m), 8.23 (1H, d, J=6.2 Hz), 12.41 (1H, m)
163) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.25-3.00 (4H, m), 2.42 (6H, s), 2.99 (6H, s), 3.40-3.65 (2H, m), 4.01-5.15 (1H, m), 6.58-7.59 (12H, m), 7.94 (1H, brs)
164) .sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.40-2.18 (4H, m), 2.34 (3H, s), 2.47 (3H, s), 2.54-3.50 (4H, m), 4.30-5.08 (1H, m), 6.56-6.82 (1H, m), 6.87-7.48 (10H, m), 7.48-7.75 (2H, m), 10.35 (1H, s)
165) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.08-5.20 �20H, m, 1.30 (3H, t, J=7.2 Hz), 3.41 (2H, s), 4.22 (2H, q, J=7.2 Hz)!, 6.49-7.73 (8H, m), 9.25-9.58 (1H, m)
166) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.17-2.80 (4H, m), 2.05 (3H, s), 2.42 (6H, s), 3.02-3.53 (2H, m), 4.06-5.15 (1H, m), 6.55-7.80 (12H, m), 8.53-8.74 (2H, m)
Example 899
To a solution of 5-acetyloxyimino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.48 g) in acetic acid (20 ml) is added platinum oxide (0.05 g) and the mixture is subjected to catalytic reduction under hydrogen atmosphere. After completion of the reaction, the catalyst is removed by filtration, and the filtrate is concentrated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1.fwdarw.10:1), and recrystallized from ethanol/diethyl ether to give 5-amino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.19 g) as colorless prisms, m.p. 176.degree.-178.degree. C.
Example 900
To a solution of 5-methylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dichloromethane (10 ml) is added triethylamine (0.24 ml). Subsequently, thereto is added methanesulfonyl chloride (0.14 ml) under ice-cooling, and then, the mixture is warmed to room temperature and stirred overnight. Water is added to the reaction solution, extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1), and recrystallized from ethanol to give 5-(N-methyl-N-methanesulfonylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.48 g) as colorless scales, m.p. 197.degree.-198.degree. C.
Example 901
To a solution of 5-methylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dichloromethane is added triethylamine (0.24 ml). Subsequently, thereto is added benzoyl chloride (0.2 ml) under ice-cooling, and the temperature thereof is raised to room temperature, and the mixture is stirred overnight. Water is added to the reaction solution and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1), and recrystallized from ethanol to give 5-(N-methyl-N-benzoylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.64 g) as colorless needles, m.p. 248.degree.-249.degree. C.
Example 902
A mixture of 5-amino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) and ethyl formate (10 ml) is refluxed for 4 hours. The reaction solution is concentrated and the resulting residue is recrystallized from ethanol/petroleum ether to give 5-formylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as colorless columnar crystal, m.p. 211.degree.-213.degree. C.
Using the suitable starting materials, the compounds of above Examples 825 and 894 are obtained in the same manner as in above Example 902.
Example 903
To a solution of 5-amino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dichloromethane (10 ml) is added triethylamine (0.22 ml). Subsequently, thereto is added di-tert-butyl dicarbonate (0.34 g) at room temperature and the mixture is stirred for 2 hours. Then, thereto is added additional di-tert-butyl dicarbonate (0.1 g) and the mixture is stirred for 1 hour. The reaction mixture is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:1) to give 5-t-butoxycarbonylamino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.66 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.1-2.3 (13H, m), 2.65-3.2 (1H, m), 4.55-5.6 (3H, m), 6.55-6.7 (1H, m), 6.9-7.6 (12H, m)
Using the suitable starting materials, the compound of above Example 791 is obtained in the same manner as in above Example 903.
Example 904
To a solution of 5-amino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dichloromethane (10 ml) is added phenyl isocyanate (0.2 g) under ice-cooling. The mixture is stirred at the same temperature for 30 minutes, and the temperature thereof is raised to room temperature and then the mixture is stirred overnight. The reaction solution is distilled off and the resulting residue is recrystallized from dioxane to give 5-anilinocarbonylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.65 g) as colorless prisms, m.p. 269.degree.-271.degree. C.
Using the suitable starting materials, the compound of above Example 795 is obtained in the same manner as in above Example 904.
Example 905
To a solution of 5-methylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in methanol (10 ml) is added glycolonitrile (50%, 0.19 ml) and the mixture is stirred at room temperature for 20 minutes, and then refluxed for 30 minutes. Thereto is added additional glycolonitrile (0.5 ml) and the mixture is refluxed for 5.5 hours. The reaction solution is concentrated and to the resulting residue is added ethyl acetate. The precipitated crystal is collected by filtration, and recrystallized from acetonitrile to give 5-(N-methyl-N-cyanomethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.32 g) as colorless needles, m.p. 227.degree.-228.degree. C.
Example 906
To 5-(N-methyl-N-oxiranylmethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.62 g) is added trifluoroacetic acid (1.22 ml) under ice-cooling and the mixture is stirred for 4 hours. The reaction solution is neutralized with aqueous sodium carbonate solution, and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is dissolved in methanol (10 ml). Thereto is added 40% aqueous sodium hydroxide solution (10 ml) and water (10 ml), and the mixture is stirred at room temperature overnight. Methanol is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-�N-methyl-N-(2,3-dihydroxypropyl)amino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.3-4.15 (19H, m), 4.3-5.0 (1H, m), 6.65 (1H, d, J=7.7 Hz), 6.9-8.05 (12H, m)
Example 907
A mixture of 5-methylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.64 g), acetonitrile (20 ml), potassium carbonate (0.6 g) and ethyl bromoacetate (0.44 ml) is refluxed for 3 hours. The reaction solution is concentrated and water is added to the resulting residue, and the mixture is extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1), and recrystallized from ethyl acetate/petroleum ether to give 5-(N-methyl-N-ethoxycarbonylmethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.82 g) as colorless prisms, m.p. 167.degree.-168.degree. C.
Using the suitable starting materials, the compounds of above Examples 785, 787, 799, 800, 802-806, 808, 811, 819, 824, 826, 827, 845, 848, 849, 850, 852, 855-858, 860, 861, 863-882, 885-893 and 895-898 are obtained in the same manner as in above Example 907.
Example 908
5-(N-Methyl-N-ethoxycarbonylmethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) is dissolved in saturated solution of ammonia in methanol (20 ml), and the mixture is heated at 100.degree. C. for 8 hours in a sealed tube. The reaction solution is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-(N-methyl-N-carbamoylmethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.4-3.0 (9H, m), 3.05-3.6 (3H, m), 3.9-4.1 (1H, m), 4.35-4.55 (1H, m), 4.9-5.65 (1H, m), 6.67 (1H, d, J=7.4 Hz), 6.85-7.6 (12H, m), 7.6-7.85 (2H, m)
Example 909
To a solution of 5-(N-methyl-N-ethoxycarbonylmethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dioxane (10 ml) is added aqueous solution (1 ml) of sodium hydroxide (0.07 g) and the mixture is stirred at room temperature for 2 days. The reaction solution is concentrated and to the resulting residue is added water. The insoluble materials are removed by filtration. The filtrate is neutralized with 10% hydrochloric acid and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and to the resulting residue is added a solution of potassium ethylhexanoate (0.2 g) in dichloromethane (20 ml). The solvent is distilled off, and diethyl ether is added to the resulting residue. The precipitated crystal is collected by filtration, and recrystallized from diethyl ether to give potassium 2-�N-methyl-N-{1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepin-5-yl}amino!acetate (0.6 g) as colorless needles, m.p. 164.degree.-171.degree. C.
Example 910
To a solution of 5-methylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.5 g) in dimethylformamide (20 ml) are added potassium carbonate (0.6 g), potassium iodide (0.72 g) and 2-(3-bromopropyloxy)-3,4,5,6-tetrahydro-2H-pyrane (0.97 g) and the mixture is stirred at room temperature overnight. The reaction solution is concentrated and to the resulting residue is added water. The mixture is extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane.fwdarw.dichloromethane:methanol=50:1) to give 5-{N-methyl-N-�3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl!amino}-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.3 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3); 1.3-2.85 (21H, m), 3.2-4.0 (4H, m), 4.3-4.4 (1H, m), 4.45-5.2 (2H, m), 6.61 (1H, d, J=7.6 Hz), 6.9-7.65 (12H, m)
Example 911
To 5-{N-methyl-N-�3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl!amino}-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) is added a mixture of acetyl chloride (0.5 ml) and acetic acid (5 ml) at room temperature, and the mixture is stirred overnight. The reaction solution is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1), and further purified again by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:2) to give 5-�N-methyl-N-(3-acetyloxypropyl)amino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.06 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.3-3.45 (17H, m), 3.8-5.7 (5H, m), 6.5-7.65 (13H, m)
Example 912
To a solution of 5-{N-methyl-N-�3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl!amino}-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) in ethanol (10 ml) is added pyridinium p-toluenesulfonate (0.03 g) and the mixture is heated at 60.degree. C. overnight. After the mixture is refluxed for more 2 hours, water and pyridinium p-toluenesulfonate (0.03 g) are added thereto. The mixture is refluxed for 4 hours. The reaction solution is concentrated and to the resulting residue is added dichloromethane. The mixture is basified with aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-�N-methyl-N-(3-hydroxypropyl)amino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.26 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.25-3.1 (14H, m), 3.3-4.0 (4H, m), 4.15-4.4 (1H, m), 4.45-5.2 (1H, m), 6.64 (1H, d, J=7.4 Hz), 6.9-7.7 (12H, m)
Example 913
To a solution of 5-amino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in acetic acid (10 ml) is added dropwise 2,5-dimethoxytetrahydrofuran (0.19 ml), and the mixture is refluxed for 1 hour. The reaction solution is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from ethyl acetate/n-hexane to give 5-(1-pyrrolyl)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.31 g) as colorless prisms, m.p. 208.degree.-210.degree. C.
Example 914
To a solution of 5-amino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (2.5 g) in dichloromethane (30 ml) is added triethylamine (0.96 ml) and further thereto is added dropwise chloroacetyl chloride (0.55 ml) under ice-cooling. The mixture is stirred for 5 minutes. The reaction solution is concentrated and to the resulting residue is added water. The precipitated crystal is collected by filtration, washed with water, and dried to give 5-(2-chloroacetylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.4 g) as white powder.
.sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.3-2.15 (4H, m), 2.32 (3H, s), 2.8-3.05 (1H, m), 4.24 (2H, AB-q, J=12.8, 15.4 Hz), 4.35-4.55 (1H, m), 4.9-5.25 (1H, m), 6.68 (1H, d, J=7.6 Hz), 6.9-7.45 (9H, m), 7.52 (2H, d, J=8.6 Hz), 8.9-9.05 (1H, m), 10.31 (1H, s)
Using the suitable starting materials, the compound of above Example 814 is obtained in the same manner as in above Example 914.
Example 915
A mixed solution of 5-(2-chloroacetylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g), imidazole (0.1 g) and potassium carbonate (0.19 g) in acetonitrile (30 ml) is refluxed for 8 hours. The reaction solution is concentrated and the resulting residue is washed with water and separated by decantation. The remainder is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1.fwdarw.15:1), and recrystallized from ethanol/n-hexane to give 5-�2-(1-imidazolyl)acetylamino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.15 g) as colorless needles, m.p. 250.degree.-252.degree. C.
Using the suitable starting materials, the compound of above Example 818 is obtained in the same manner as in above Example 915.
Example 916
To a solution of 5-(2-chloroacetylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dimethylformamide (20 ml) are added dimethylamine hydrochloride (0.21 g) and potassium carbonate (0.54 g), and the mixture is stirred at room temperature for 2 days. The reaction solution is concentrated and water is added to the resulting residue. The precipitated crystal is collected by filtration, and recrystallized from ethyl acetate to give 5-(2-dimethylaminoacetylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.24 g) as colorless prisms, m.p. 214.degree.-216.degree. C.
Using the suitable starting materials, the compounds of above Examples 816, 817, 820, 821, 826 and 827 are obtained in the same manner as above Example 916.
Example 917
A mixture of 5-methylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g), N,N-dimethyl-2-chloroacetamide (0.19 g) and potassium carbonate (0.22 g) is refluxed for 24 hours. The reaction solution is concentrated and water is added to the resulting residue. The mixture is extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-�N-methyl-N-(dimethylaminocarbonylmethyl)amino!-1-�4-(2-methylbenzoyl amino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.05 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.2-3.3 (17H, m), 3.45 (2H, AB-q, J=14.7, 22.9 Hz), 3.9-4.35 (2H, m), 6.60 (1H, d, J=7.7 Hz), 6.8-8.0 (11H, m), 8.39 (1H, s)
Example 918
To a solution of t-butoxycarbonylglycine (0.84 g) in dimethylformamide (20 ml) are added diethyl cyanophosphate (0.73 ml) and 5-amino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.74 g), and further thereto is added triethylamine (1.8 ml) under ice-cooling. The mixture is stirred for 30 minutes, and then stirred at room temperature overnight. The reaction solution is concentrated and water is added to the resulting residue. The precipitated crystal is collected by filtration, washed with water, and recrystallized from ethyl acetate to give 5-(2-aminoacetylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (E) (0.16 g). Separately, the filtrate is concentrated and purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from diethyl ether to give 5-�2-(t-butoxycarbonylamino)acetylamino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (F) (0.19 g).
(E): Colorless prisms, m.p. 287.degree.-289.degree. C.
(F): Colorless prisms, m.p. 170.degree.-171.degree. C.
Example 919
5-Oxo-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) is suspended in tetrahydrofuran (20 ml), and thereto is added dropwise a 3.0M solution of methyl magnesium bromide in diethyl ether (1.5 ml) at room temperature. The mixture is stirred at room temperature for 1 hour. The reaction solution is poured into ice-water (20 ml), and extracted with ethyl acetate. The extract is dried over magnesium sulfate, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=2:3.fwdarw.1:1), and recrystallized from ethyl acetate/n-hexane to give 5-methyl-5-hydroxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g) as white powder, m.p. 204.degree.-205.degree. C.
Example 920
To a solution of 5-carboxymethoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1.50 g) in dimethylformamide (60 ml) are added successively thiomorpholine (0.66 ml), diethyl cyanophosphate (0.89 g) and triethylamine (1.37 ml) with stirring under ice-cooling. The mixture is stirred for 30 minutes under ice-cooling, and at room temperature for 20 minutes. Water (60 ml) is added to the reaction solution, and extracted with dichloromethane. The extract is dried over magnesium sulfate, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=5:2.fwdarw.3:1), and recrystallized from ethyl acetate/n-hexane to give 5-(thiomorpholinocarbonylmethoxy)-1-�4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.60 g) as white powder, m.p. 235.degree.-237.degree. C.
Using the suitable starting materials, the compounds of above Examples 829-838 are obtained in the same manner as in above Example 920.
Example 921
To a solution of 5-(thiomorpholinocarbonylmethoxy)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.40 g) in dichloromethane (40 ml) is added 80% m-chloroperbenzoic acid (175 mg) with stirring at -8.degree. C., and the mixture is stirred at -8.degree. C. for 1 hour. To the reaction solution is added 20% aqueous sodium hydrogensulfite solution (40 ml) and the mixture is stirred at room temperature for 30 minutes. The dichloromethane layer is collected, washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to give 5-�(1-oxothiomorpholino)carbonylmethoxy!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.32 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.50-1.92 (3H, m), 1.92-2.05 (1H, m), 2.47 (3H, s), 2.55-3.06 (5H, m), 3.43-5.76 (8H, m), 6.63-6.82 (1H, m), 6.97-8.08 (12H, m)
Example 922
To a solution of 5-(thiomorpholinocarbonylmethoxy)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.40 g) in dichloromethane (40 ml) is added 80% m-chloroperbenzoic acid (0.35 g), and the mixture is stirred at room temperature for 1 hour. The reaction solution is washed successively with an aqueous sodium hydrogensulfite solution and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off to give 5-�(1,1-dioxothiomorpholino)carbonylmethoxy!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.41 g) as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.43-2.65 (4H, m), 2,48 (3H, s), 2.69-3.25 (5H, m), 3.90-5.40 (8H, m), 6.64-6.94 (1H, m), 6.94-7.77 (12H, m)
Example 923
To a solution of 5-oxo-1-�4-(2-hydroxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (400 mg) in acetone (20 ml) are added potassium carbonate (210 mg), potassium iodide (250 mg) and 2-chloroacetamide (120 mg), and the mixture is refluxed for 2 hours. The insoluble materials are removed by filtration, and the filtrate is distilled off. Dichloromethane is added to the resulting residue, and the mixture is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-oxo-1-�4-(2-carbamoylmethoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (436 mg) as white powder, m.p. 226.degree.-228.degree. C.
Using the suitable starting materials, the compound of above Example 842 is obtained in the same manner as above Example 923.
Example 924
A mixture of 5-methylamino-4-hydroxy-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.13 g), ethyl .alpha.-bromoacetate (58 mg), diisopropylethylamine (49 mg) and acetonitrile (5 ml) is refluxed for 10 hours. Acetonitrile is distilled off under reduced pressure, and the resulting residue is dissolved in dichloromethane, washed with water, dried over magnesium sulfate, and distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from chloroform/methanol to give 7-�4-(2-chlorobenzoylamino)benzoyl!-1-methyl-1,2,3,4a,5,6,7,11b-octahydro-3-oxo�1!benzazepino�4,5-b!�1,4!oxazine (80 mg) as colorless prisms, m.p. 286.degree.-290.degree. C.
Example 925
To a solution of 5-oxo-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (1 g) in methanol (20 ml) and dichloromethane (20 ml) is added hydroxylamine-O-sulfonic acid (0.28 g) with stirring at room temperature, and the mixture is stirred at the same temperature for 1 hour. Subsequently, to the reaction solution is added with stirring an aqueous solution of potassium carbonate (0.34 g) in water (1 ml) at room temperature, and the mixture is stirred at the same temperature for 2 hours. The precipitated crystal is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give potassium {1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepin-5-yl}imino-O-sulfonate (0.4 g) as white powder.
.sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.40-1.75 (1H, m), 1.90-2.15 (1H, m), 2.33 (3H, s), 2.50-2.80 (2H, m), 3.10-3.50 (1H, m), 4.40-4.65 (1H, m), 6.85-7.60 (10H, m), 7.85 (1H, s), 10.44 (1H, s)
Example 926
Using the suitable starting materials, the compounds of above Examples 841-843, 868-870, 888 and 889 are obtained in the same manner as in above Example 380.
Example 927
Using the suitable starting materials, the compounds of above Examples 876-878 are obtained in the same manner as in above Example 381.
Example 928
Using the suitable starting materials, the compounds of above Examples 840, 842 and 846 are obtained in the same manner as in above Example 384.
Example 929
Using the suitable starting materials, the compounds of above Examples 788-790, 796-804, 805, 808, 811, 814, 818, 819, 824, 826, 827, 837, 845, 848, 850, 852, 855, 856-858, 860, 861, 863-882, 885, 886, 888-893 and 895-898 are obtained in the same manner as in above Example 388.
Example 930
Using the suitable starting materials, the compound of above Example 848 is obtained in the same manner as in above Example 393.
Example 931
Using the suitable starting materials, the compounds of above Examples 841 and 842 are obtained in the same manner as in above Example 402.
Example 932
Using the suitable starting materials, the compounds of above Examples 882 and 897 are obtained in the same manner as in above Example 403.
Example 933
Using the suitable starting materials, the compound of above Example 809 is obtained in the same manner as in above Example 634.
Example 934
Using the suitable starting materials, the compounds of above Examples 828-838 are obtained in the same manner as in above Example 640.
Example 935
Using the suitable starting materials, the compound of above Example 810 is obtained in the same manner as in above Example 772.
Example 936
Using the suitable starting materials, the compound of above Example 788 is obtained in the same manner as in above Example 771.
Example 937
Using the suitable starting materials, the compounds of above Examples 785, 787, 788-790, 796-805, 806, 807, 808, 811, 814, 818, 819, 845, 848, 849, 850, 852, 855, 856-858, 860, 861, 863-882, 885, 886, 888-893 and 896-898 are obtained in the same manner as in above Example 390.
Example 938
To 5-methanesulfonyloxymethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) is added a 30% solution of methylamine in methanol (50 ml), and the mixture is heated at 100.degree. C. for 3 hours in a sealed tube. After cooling, the reaction solution is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol:aqueous ammonia=100:10:1) to give 5-methylaminomethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.07 g).
.sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.40-2.18 (4H, m), 2.34 (3H, s), 2.47 (3H, s), 2.54-3.50 (4H, m), 4.30-5.08 (1H, m), 6.56-6.82 (1H, m), 6.87-7.48 (10H, m), 7.48-7.75 (2H, m), 10.35 (1H, s)
Using the suitable starting materials, the compounds of above Examples 823-825 are obtained in the same manner as in above Example 938.
Using the above suitable starting materials, the compounds of the following Table 6 are obtained in the same manner as in Examples 1 and 382.
TABLE 6______________________________________ ##STR2509##______________________________________Example 939Structure ##STR2510## ##STR2511##R.sup.2 : HR.sup.3 : ##STR2512##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 208-211.degree. C.Form: FreeExample 940Structure ##STR2513## ##STR2514##R.sup.2 : HR.sup.3 : ##STR2515##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 171.5-172.5.degree. C.Form: FreeExample 941Structure ##STR2516## ##STR2517##R.sup.2 : HR.sup.3 : ##STR2518##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 151-154.degree. C.Form: FreeExample 942Structure ##STR2519## ##STR2520##R.sup.2 : HR.sup.3 : ##STR2521##Crystalline form: Colorless amorphousNMR analysis: 167)Form: FreeExample 943Structure ##STR2522## ##STR2523##R.sup.2 : HR.sup.3 : ##STR2524##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 180-183.degree. C.Form: FreeExample 944Structure ##STR2525## ##STR2526##R.sup.2 : HR.sup.3 : ##STR2527##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 109-110.degree. C.Form: FreeExample 945Structure ##STR2528## ##STR2529##R.sup.2 : HR.sup.3 : ##STR2530##Crystalline form: Colorless oilNMR analysis: 168)Form: FreeExample 946Structure ##STR2531## ##STR2532##R.sup.2 : HR.sup.3 : ##STR2533##Crystalline form: Colorless oilNMR analysis: 169)Form: FreeExample 947Structure ##STR2534## ##STR2535##R.sup.2 : HR.sup.3 : ##STR2536##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 177-178.5.degree. C.Form: FreeExample 948Structure ##STR2537## ##STR2538##R.sup.2 : HR.sup.3 : ##STR2539##Crystalline form: Colorless amorphousNMR analysis: 170)Form: FreeExample 949Structure ##STR2540## ##STR2541##R.sup.2 : HR.sup.3 : ##STR2542##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 162-165.degree. C.Form: FreeExample 950Structure ##STR2543## ##STR2544##R.sup.2 : HR.sup.3 : ##STR2545##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 212-215.degree. C.Form: FreeExample 951Structure ##STR2546## ##STR2547##R.sup.2 : HR.sup.3 : ##STR2548##Crystalline form: Colorless oilNMR analysis: 171)Form: FreeExample 952Structure ##STR2549## ##STR2550##R.sup.2 : HR.sup.3 : ##STR2551##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 112-114.degree. C.Form: FreeExample 953Structure ##STR2552## ##STR2553##R.sup.2 : HR.sup.3 : ##STR2554##Crystalline form: Colorless oilNMR analysis: 172)Form: FreeExample 954Structure ##STR2555## ##STR2556##R.sup.2 : HR.sup.3 : ##STR2557##Crystalline form: Colorless amorphousNMR analysis: 173)Form: FreeExample 955Structure ##STR2558## ##STR2559##R.sup.2 : HR.sup.3 : ##STR2560##Crystalline form: Light yellow amorphousNMR analysis: 174)Form: FreeExample 956Structure ##STR2561## ##STR2562##R.sup.2 : HR.sup.3 : ##STR2563##Crystalline form: White powderRecrystallization solvent: Diethyl etherMelting Point: 189-193.degree. C.Form: FreeExample 957Structure ##STR2564## ##STR2565##R.sup.2 : HR.sup.3 : ##STR2566##Crystalline form: Colorless amorphousNMR analysis: 175)Form: FreeExample 958Structure ##STR2567## ##STR2568##R.sup.2 : HR.sup.3 : ##STR2569##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 234-238.degree. C.Form: FreeExample 959Structure ##STR2570## ##STR2571##R.sup.2 : HR.sup.3 : ##STR2572##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 183-184.5.degree. C.Form: FreeExample 960Structure ##STR2573## ##STR2574##R.sup.2 : HR.sup.3 : ##STR2575##Crystalline form: Brown oilNMR analysis: 176)Form: FreeExample 961Structure ##STR2576## ##STR2577##R.sup.2 : HR.sup.3 : ##STR2578##Crystalline form: Colorless amorphousNMR analysis: 177)Form: FreeExample 962Structure ##STR2579## ##STR2580##R.sup.2 : HR.sup.3 : ##STR2581##Crystalline form: Colorless amorphousNMR analysis: 178)Form: FreeExample 963Structure ##STR2582## ##STR2583##R.sup.2 : HR.sup.3 : ##STR2584##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 202.5-204.5.degree. C.Form: FreeExample 964Structure ##STR2585## ##STR2586##R.sup.2 : HR.sup.3 : ##STR2587##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 199.5-201.degree. C.Form: FreeExample 965Structure ##STR2588## ##STR2589##R.sup.2 : HR.sup.3 : ##STR2590##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 196.5-197.degree. C.Form: FreeExample 966Structure ##STR2591## ##STR2592##R.sup.2 : HR.sup.3 : ##STR2593##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 204-205.degree. C.Form: FreeExample 967Structure ##STR2594## ##STR2595##R.sup.2 : HR.sup.3 : ##STR2596##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 175-177.degree. C.Form: FreeExample 968Structure ##STR2597## ##STR2598##R.sup.2 : HR.sup.3 : ##STR2599##Crystalline form: Pink amorphousNMR analysis: 179)Form: FreeExample 969Structure ##STR2600## ##STR2601##R.sup.2 : HR.sup.3 : ##STR2602##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 186-189.degree. C.Form: FreeExample 970Structure ##STR2603## ##STR2604##R.sup.2 : 2-ClR.sup.3 : ##STR2605##Crystalline form: Colorless prismsRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 211-212.degree. C.Form: FreeExample 971Structure ##STR2606## ##STR2607##R.sup.2 : HR.sup.3 : ##STR2608##Crystalline form: Colorless amorphousNMR analysis: 180)Form: FreeExample 972Structure ##STR2609## ##STR2610##R.sup.2 : HR.sup.3 : ##STR2611##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 206-207.degree. C.Form: FreeExample 973Structure ##STR2612## ##STR2613##R.sup.2 : HR.sup.3 : ##STR2614##Crystalline form: Colorless amorphousNMR analysis: 181)Form: FreeExample 974Structure ##STR2615## ##STR2616##R.sup.2 : HR.sup.3 : ##STR2617##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 152-154.degree. C.Form: FreeExample 975Structure ##STR2618## ##STR2619##R.sup.2 : HR.sup.3 : ##STR2620##Crystalline form: Colorless amorphousNMR analysis: 182)Form: FreeExample 976Structure ##STR2621## ##STR2622##R.sup.2 : HR.sup.3 : ##STR2623##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 204-206.degree. C.Form: FreeExample 977Structure ##STR2624## ##STR2625##R.sup.2 : HR.sup.3 : ##STR2626##Crystalline form: Colorless needlesRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 162-163.degree. C.Form: Free______________________________________
167) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.14-2.83 (13H, m), 2.43 (3H, s), 2.95-5.19 (4H, m), 4.12 (2H, t, J=6.2 Hz), 6.27-6.83 (2H, m), 6.83-7.36 (6H, m), 7.36-7.67 (4H, m), 7.93-8.11 (1H, m), 9.77 (1H, brs)
168) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.11-2.98 (11H, m), 2.80 (3H, s), 3.69 (2H, s), 2.98-5.24 (2H, m), 6.50-7.71 (12H, m), 9.37 (1H, brs)
169) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-2.80 (14H, m), 2.99 (3H, s), 3.39-5.20 (2H, m), 4.00 (2H, s), 6.49-7.67 (12H, m), 8.51 (1H, brs)
170) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-1.98 (3H, m), 1.98-2.82 (10H, m), 2.82-3.20 (2H, m), 3.34-5.15 (2H, m), 6.48-7.68 (15H, m), 7.86 (1H, brs)
171) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-2.84 (10H, m), 2.40 (3H, s), 2.90-5.20 (2H, m), 3.79 (2H, d, J=2.7 Hz), 4.33 (1H, br), 6.30-7.68 (12H, m), 8.67 (1H, brs)
172) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-2.85 (14H, m), 2.72 (3H, s), 2.98-5.20 (2H, m), 3.62 (2H, s), 6.50-7.75 (12H, m), 9.18 (1H, brs)
173) .sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.28-2.62 (4H, m), 2.07 (3H, s), 2.34 (6H, s), 3.04-3.57 (2H, m), 3.99-4.86 (1H, m), 6.62-7.88 (12H, m), 10.12-10.20 (2H, m)
174) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.39 (3H, t, J=7.1 Hz), 1.64-2.68 (4H, m), 2.42 (6H, s), 3.04-3.58 (2H, m), 3.98-5.01 (1H, m), 4.38 (2H, q, J=7.1 Hz), 6.57-8.57 (13H, m)
175) .sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.67-5.02 (7H, m), 3.35 (6H, s), 6.75-8.17 (12H, m), 8.46 (1H, s), 10.54 (1H, s)
176) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.21 (3H, t, J=7.1 Hz), 1.95-2.30 (2H, m), 2.88 (2H, t, J=6.2 Hz), 3.40-3.65 (2H, m), 3.70-4.50 (2H, m), 3.91 (2H, s), 6.66 (1H, d, J=8.5 Hz), 6.70-7.00 (3H, m), 7.10-7.50 (7H, m), 7.81 (1H, d, J=2.5 Hz), 8.44 (1H, s)
177) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.21 (3H, t, J=7 Hz), 1.30-5.20 (11H, m), 3.48 (2H, q, J=7 Hz), 3.90 (2H, s), 6.53 (1H, d, J=8.3 Hz), 6.65-7.00 (4H, m), 7.00-7.40 (6H, m), 7.51 (1H, d, J=2.5 Hz), 8.40 (1H, s)
178) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.21 (3H, t, J=7 Hz), 1.20-5.20 (15H, m), 3.90 (2H, s), 6.48 (1H, d, J=8.3 Hz), 6.50-7.70 (11H, m), 8.39 (1H, s)
179) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.60-2.20 (1H, m), 2.10-2.35 (1H, m), 2.45 (3H, s), 2.70-2.95 (2H, m), 3.25-3.45 (1H, m), 4.60-4.85 (1H, m), 7.10-7.80 (12H, m)
180) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.65-2.15 (4H, m), 2.46 (3H, s), 2.6-5.15 (4H, m), 6.75-6.95 (1H, m), 7.15-7.55 (10H, m), 7.61 (1H, s), 7.95-8.1 (1H, m)
181) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.60-2.15 (3H, m), 2.15-2.90 (2H, m), 2.90-3.22 (6H, m), 4.00-4.50 (2H, m), 4.13 (2H, s), 4.58-5.22 (2H, m), 6.53-6.80 (1H, m), 6.90-7.90 (7H, m), 8.48 (1H, s)
182) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.48-2.20 (3H, m), 2.20-2.85 (2H, m), 2.85-3.27 (6H, m), 4.05-4.47 (2H, m), 4.47-5.22 (2H, m), 6.50-6.76 (1H, m), 6.76-6.91 (1H, m), 6.91-7.69 (9H, m), 7.69-8.13 (1H, m), 9.28 (1H, s), 11.87 (1H, brs)
Example 978
5-Dimethylamino-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (H) (1.00 g) is dissolved in dichloromethane (30 ml), and thereto is added triethylamine (0.48 ml) under ice-cooling, and further added dropwise 2-methylbenzoyl chloride (0.44 ml). The mixture is stirred at room temperature for 1 hour. The reaction solution is washed with water, and dried over magnesium sulfate. The solvent is distilled off, and the resulting residue is crystallized by adding thereto ethyl acetate. The precipitated crystal is recrystallized from dichloromethane/ethyl acetate to give 5-dimethylamino-1-�2-methyl-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.92 g) as white powder, m.p. 191.degree.-192.degree. C. HPLC retention time: 7.5 minutes
Column; Wakosil II 5C.sub.18 (trade mark; Wako Pure Chemical Co., Ltd.)
Solvent; acetonitrile: 50 mN aqueous Na.sub.2 SO.sub.4 solution:acetic acid=27:73:1
Rate; 1.0 ml/min.
�.alpha.!.sub.D.sup.22 =0.degree. (c=1.0, chloroform)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.15-3.25 (17H, m), 3.35-5.14 (2H, m), 6.62-8.05 (12H, m)
Charts of .sup.1 H-NMR (CDCl.sub.3) of the starting compound (H) and the compound obtained in Example 978 are shown in FIG. 1 and FIG. 2, respectively.
Example 979
Using 5-dimethylamino-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (G) (1.00 g), 5-dimethylamino-1-�2-methyl-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (0.48 g) is obtained in the same manner as in Example 978 except that methanol/diethyl ether is used instead of ethyl acetate as recrystallization solvent, as white powder, m.p. 183.degree.-185.degree. C.
HPLC retention time: 8.1 minutes (the conditions of HPLC are same as those in Example 978)
�.alpha.!.sub.D.sup.22 =0.degree. (c=1.3, chloroform)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-3.20 (17H, m), 3.35-5.15 (2H, m), 6.50-6.80 (1H, m), 6.86-7.62 (10H, m), 7.65-8.09 (1H, m)
Charts of .sup.1 H-NMR (CDCl.sub.3) of the starting compound (G) and the compound obtained in Example 979 are shown in FIG. 3 and FIG. 4, respectively.
REFERENCE EXAMPLE 18
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 1.
7-Methoxy-5-oxo-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless needles, m.p. 178.degree.-178.5.degree. C. (recrystallized from ethyl acetate/n-hexane)
7-Methoxy-5-oxo-1-(2-chloro-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 150.degree.-151.degree. C. (recrystallized from ethyl acetate/n-hexane)
7-Methoxy-5-oxo-1-(3-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 116.degree.-118.degree. C. (recrystallized from ethyl acetate/n-hexane)
7-Chloro-5-oxo-1-(3-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder, m.p. 156.degree.-158.degree. C. (recrystallized from diethyl ether/dichloromethane)
REFERENCE EXAMPLE 19
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.
7-Methoxy-5-oxo-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 172.5.degree.-173.5.degree. C. (recrystallized from ethyl acetate/n-hexane)
7-Methoxy-5-oxo-1-(2-chloro-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 153.degree.-155.degree. C. (recrystallized from ethyl acetate/n-hexane)
7-Methoxy-5-oxo-1-(3-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless needles, m.p. 170.degree.-171.degree. C. (recrystallized from ethyl acetate/n-hexane)
7-Chloro-5-oxo-1-(3-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.; 2.05-2.30 (2H, m), 2.85-3.00 (2H, m), 3.70 (3H, s), 3.85-4.30 (4H, m), 6.42 (1H, d, J=8.1 Hz), 6.64 (1H, dd, J=1.7 Hz, 8.1 Hz), 6.72 (1H, d, J=8.5 Hz), 6.80 (1H, d, J=1.8 Hz), 7.19 (1H, dd, J=2.6 Hz, 8.5 Hz), 7.81 (1H, d, J=2.5 Hz)
Using the suitable starting materials, the compounds of the following Table 7 are obtained in the same manner as in above Examples 1 and 382.
TABLE 7______________________________________ ##STR2627##______________________________________Example 980Structure ##STR2628## ##STR2629##R.sup.2 : HR.sup.3 : ##STR2630##Crystalline form: Colorless amorphousNMR analysis: 183)Form: FreeExample 981Structure ##STR2631## ##STR2632##R.sup.2 : HR.sup.3 : ##STR2633##Crystalline form: Colorless amorphousNMR analysis: 184)Form: FreeExample 982Structure ##STR2634## ##STR2635##R.sup.2 : HR.sup.3 : ##STR2636##Crystalline form: Colorless amorphousNMR analysis: 185)Form: FreeExample 983Structure ##STR2637## ##STR2638##R.sup.2 : HR.sup.3 : ##STR2639##Crystalline form: Colorless amorphousNMR analysis: 186)Form: FreeExample 984Structure ##STR2640## ##STR2641##R.sup.2 : HR.sup.3 : ##STR2642##Crystalline form: Colorless amorphousNMR analysis: 187)Form: FreeExample 985Structure ##STR2643## ##STR2644##R.sup.2 : 2-ClR.sup.3 : ##STR2645##Crystalline form: Colorless amorphousNMR analysis: 188)Form: FreeExample 986Structure ##STR2646## ##STR2647##R.sup.2 : 2-ClR.sup.3 : ##STR2648##Crystalline form: Colorless amorphousNMR analysis: 189)Form: FreeExample 987Structure ##STR2649## ##STR2650##R.sup.2 : HR.sup.3 : ##STR2651##Crystalline form: White powderRecrystallization solvent: Ethanol/waterMelting Point: 267-268.degree. C.Form: FreeExample 988Structure ##STR2652## ##STR2653##R.sup.2 : HR.sup.3 : ##STR2654##Crystalline form: White powderRecrystallization solvent: Ethanol/waterMelting Point: 264-266.degree. C.Form: FreeExample 989Structure ##STR2655## ##STR2656##R.sup.2 : HR.sup.3 : ##STR2657##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 218-220.degree. C.Form: FreeExample 990Structure ##STR2658## ##STR2659##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2660##Crystalline form: Yellow oilNMR analysis: 190)Form: FreeExample 991Structure ##STR2661## ##STR2662##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2663##Crystalline form: Yellow oilNMR analysis: 191)Form: FreeExample 992Structure ##STR2664## ##STR2665##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2666##Crystalline form: Yellow powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 174-177.degree. C.Form: FreeExample 993Structure ##STR2667## ##STR2668##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2669##Crystalline form: Yellow amorphousNMR analysis: 192)Form: FreeExample 994Structure ##STR2670## ##STR2671##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2672##Crystalline form: Colorless amorphousNMR analysis: 193)Form: FreeExample 995Structure ##STR2673## ##STR2674##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2675##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 163-165.degree. C.Form: FreeExample 996Structure ##STR2676## ##STR2677##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2678##Crystalline form: Colorless amorphousNMR analysis: 194)Form: FreeExample 997Structure ##STR2679## ##STR2680##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2681##Crystalline form: Colorless amorphousNMR analysis: 195)Form: Free______________________________________
183) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-2.83 (11H, m), 2.96-5.21 (2H, m), 4.55 (2H, s), 6.48-7.72 (13H, m), 8.30 (1H, brs)
184) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-2.85 (11H, m), 1.58 (3H, d, J=6.8 Hz), 2.23 (3H, s), 2.95-5.19 (4H, m), 6.38-7.70 (12H, m), 8.69 (1H, brs)
185) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-2.85 (14H, m), 2.26 (3H, s), 2.96-5.19 (4H, m), 6.36-7.68 (12H, m), 8.72 (1H, brs)
186) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.09-2.72 (11H, m), 1.53 (3H, d, J=6.9 Hz), 2.24 (3H, s), 2.93-5.21 (4H, m), 6.30-7.78 (12H, m), 8.76 (1H, brs)
187) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-2.82 (14H, m), 2.96-5.20 (4H, m), 6.38-7.70 (12H, m), 8.54 (1H, brs)
188) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.64-2.28 (2H, m), 2.41 (3H, s), 2.60-2.90 (2H, m), 2.90-3.70 (1H, m), 3.76 (3H, s), 4.10-5.10 (1H, m), 6.60-7.70 (10H, m), 8.51 (1H, s)
189) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.64-2.43 (2H, m), 2.67-2.97 (2H, m), 3.00-3.70 (1H, m), 3.77 (3H, s), 4.20-5.10 (1H, m), 6.60-7.75 (10H, m), 8.51 (1H, s)
190) .sup.1 H-NMR (CDCl.sub.3) .delta.; 2.00-2.35 (2H, m), 2.49 (3H, s), 2.89 (2H, t, J=6.2 Hz), 3.72 (3H, s), 3.40-4.80 (2H, m), 6.74 (2H, d, J=8.5 Hz), 6.80-7.00 (2H, m), 7.25-7.60 (5H, m), 7.80 (1H, d, J=2.6 Hz), 8.16 (1H, s), 8.37 (1H, d, J=8.6 Hz)
191) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.90-2.40 (2H, m), 2.90 (2H, t, J=6.2 Hz), 3.75 (3H, s), 3.40-4.80 (2H, m), 6.74 (1H, d, J=8.5 Hz), 6.80-7.00 (2H, m), 7.10-7.50 (4H, m), 7.73 (1H, dd, J=2.3 Hz, 6 Hz), 7.80 (1H, d, J=2.5 Hz), 8.38 (1H, d, J=8.8 Hz), 8.65 (1H, s)
192) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-2.10 (13H, m), 2.90-5.20 (6H, m), 6.56 (1H, d, J=8.4 Hz), 6.69 (1H, d, J=7 Hz), 6.85-7.70 (7H, m), 8.15 (1H, s), 8.31 (1H, d, J=8.4 Hz)
193) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.30-0.65 (4H, m), 1.20-2.50 (7H, m), 2.50 (3H, s), 3.10-5.20 (2H, m), 3.75 (3H, s), 6.60 (1H, d, J=8.3 Hz), 6.70-7.60 (8H, m), 8.14 (1H, s), 8.20-8.40 (1H, m)
194) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.80-2.50 (10H, m), 2.90-4.10 (6H, m), 6.50-7.80 (9H, m), 8.32 (1H, d, J=8 Hz), 8.62 (1H, s)
195) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.30-0.65 (4H, m), 0.70-2.40 (6H, m), 2.60-5.20 (6H, m), 6.50-7.80 (9H, m), 8.30 (1H, d, J=8 Hz), 8.62 (1H, s)
REFERENCE EXAMPLE 20
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 1.
7-Methyl-5-oxo-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white needles
.sup.1 H-NMR (CDCl.sub.3) .delta.; 2.20 (2H, brs), 2.32 (3H, s), 2.88 (2H, t, J=6.3 Hz), 3.40-4.79 (2H, m), 6.57 (1H, d, J=8.0 Hz), 7.04 (1H, d, J=7.7 Hz), 7.36 (2H, d, J=8.6 Hz), 7.62 (1H, d, J=1.7 Hz), 8.04 (2H, d, J=8.7 Hz)
7-Dimethylamino-5-oxo-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, red brown prisms (recrystallized from dichloromethane/diethyl ether)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.75-2.47 (2H, m), 2.60-3.62, 4.51-4.92 (total 4H, m), 2.93 (6H, s), 6.46 (1H, dd, J=2.2 Hz, 7.0 Hz), 6.52 (1H, d, J=7.0 Hz), 7.33 (2H, d, J=7.0 Hz), 8.00 (2H, d, J=7.0 Hz)
7-Bromo-5-oxo-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder (recrystallized from dichloromethane/diethyl ether), m.p. 177.degree.-182.degree. C.
7-Chloro-5-oxo-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder (recrystallized from dichloromethane/diethyl ether)
.sup.1 H-NMR (CDCl.sub.3) .delta.;1.78-2.37 (2H, m), 2.48 (3H, s), 2.88 (2H, t, J=6.1 Hz), 3.30-5.12 (2H, m), 6.47-6.82 (1H, m), 6.82-7.09 (1H, m), 7.09-7.27 (1H, m), 7.48-8.35 (3H, m)
6-Oxo-1-(2-chloro-4-nitrobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.7-2.1 (4H, m), 2.85-4.7 (4H, m), 7.12 (1H, d, J=8.4 Hz), 7.17-7.51 (4H, m), 7.89 (1H, dd, J=7.8 Hz, 2.1 Hz), 8.11 (1H, d, J=2.2 Hz)
8-Chloro-6-oxo-1-(2-chloro-4-nitrobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.7-2.15 (4H, m), 2.85-4.8 (4H, m), 7.14 (1H, d, J=8.5 Hz), 7.16 (1H, d, J=8.4 Hz), 7.34 (1H, dd, J=8.3 Hz, 2.5 Hz), 7.85 (1H, d, J=2.5 Hz), 7.94 (1H, dd, J=8.4 Hz, 2.2 Hz), 8.13 (1H, d, J=2.1 Hz)
8-Methyl-6-oxo-1-(2-chloro-4-nitrobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.65-2.2 (4H, m), 2.33 (3H, s), 2.7-5.0 (4H, m), 7.0-7.25 (3H, m), 7.67 (1H, d, J=2.0 Hz), 7.89 (1H, dd, J=8.4 Hz, 2.2 Hz), 8.10 (1H, d, J=2.1 Hz)
8-Methoxy-6-oxo-1-(2-chloro-4-nitrobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, light yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.6-2.05 (4H, m), 2.8-5.2 (4H, m), 3.78 (3H, s), 6.88 (1H, dd, J=8.6 Hz, 3.1 Hz), 7.11 (1H, d, J=8.4 Hz), 7.12 (1H, d, J=8.6 Hz), 7.38 (1H, d, J=3.0 Hz), 7.90 (1H, dd, J=8.4 Hz, 2.2 Hz), 8.11 (1H, d, J=2.2 Hz)
7-Chloro-5-oxo-1-(2-chloro-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder (recrystallized from diethyl ether/dichloromethane), m.p. 125.degree.-126.5.degree. C.
REFERENCE EXAMPLE 21
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.
7-Methyl-5-oxo-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder
.sup.1 H-NMR (CDCl.sub.3) .delta.; 2.13 (2H, brs), 2.32 (3H, s), 2.86 (2H, t, J=6.2 Hz), 2.89-5.29 (2H, m), 3.86 (2H, brs), 6.41 (2H, m), 6.65 (1H, d, J=8.1 Hz), 7.06 (3H, m), 7.65 (1H, d, J=1.7 Hz)
7-Dimethylamino-5-oxo-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow needles (recrystallized from dichloromethane/diethyl ether)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.78-2.49 (2H, m), 2.64-3.78, 4.07-5.02 (total 4H, m), 2.93 (6H, m), 3.96 (2H, m), 6.38 (2H, d, J=8.7 Hz), 6.55 (1H, dd, J=2.7, 8.7 Hz), 6.62 (1H, d, J=8.7 Hz), 6.96-7.18 (3H, m)
7-Bromo-5-oxo-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder (recrystallized from methanol/diethyl ether)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.98-2.37 (2H, m), 2.88 (2H, t, J=6.3 Hz), 3.52-4.55 (4H, m), 6.28-6.57 (2H, m), 6.57-6.76 (1H, m), 6.92-7.20 (2H, m), 7.28-7.42 (1H, m), 7.90-8.09 (1H, m)
7-Chloro-5-oxo-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder (recrystallized from dichloromethane/diethyl ether), m.p. 190.degree.-191.degree. C.
6-Oxo-1-(2-chloro-4-aminobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, light yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.3-2.25 (4H, m), 2.8-4.4 (6H, m), 6.1-6.9 (3H, m), 6.95-7.75 (3H, m), 7.8-8.3 (1H, m)
8-Chloro-6-oxo-1-(2-chloro-4-aminobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, light yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.59-2.2 (4H, m), 2.6-4.4 (6H, m), 6.1-6.9 (3H, m), 6.95-7.5 (2H, m), 7.8-8.05 (1H, m)
7-Chloro-5-oxo-1-(2-chloro-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder (recrystallized from diethyl ether/dichloromethane), m.p. 188.degree.-191.5.degree. C.
Using the suitable starting materials, the compounds of the following Table 8 are obtained in the same manner as in above Examples 1 and 382.
TABLE 8______________________________________ ##STR2682##______________________________________Example 998Structure ##STR2683## ##STR2684##R.sup.2 : HR.sup.3 : ##STR2685##Crystalline form: White powderNMR analysis: 196)Form: FreeExample 999Structure ##STR2686## ##STR2687##R.sup.2 : HR.sup.3 : ##STR2688##Crystalline form: White powderNMR analysis: 197)Form: FreeExample 1000Structure ##STR2689## ##STR2690##R.sup.2 : HR.sup.3 : ##STR2691##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 200-205.degree. C.Form: FreeExample 1001Structure ##STR2692## ##STR2693##R.sup.2 : HR.sup.3 : ##STR2694##Crystalline form: Colorless amorphousNMR analysis: 198)Form: FreeExample 1002Structure ##STR2695## ##STR2696##R.sup.2 : HR.sup.3 : ##STR2697##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 234-238.degree. C.Form: FreeExample 1003Structure ##STR2698## ##STR2699##R.sup.2 : HR.sup.3 : ##STR2700##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 174-178.degree. C.Form: FreeExample 1004Structure ##STR2701## ##STR2702##R.sup.2 : 2-ClR.sup.3 : ##STR2703##Crystalline form: Light yellow amorphousNMR analysis: 199)Form: FreeExample 1005Structure ##STR2704## ##STR2705##R.sup.2 : 2-ClR.sup.3 : ##STR2706##Crystalline form: Light yellow amorphousNMR analysis: 200)Form: FreeExample 1006Structure ##STR2707## ##STR2708##R.sup.2 : 2-ClR.sup.3 : ##STR2709##Crystalline form: Light yellow amorphousNMR analysis: 201)Form: FreeExample 1007Structure ##STR2710## ##STR2711##R.sup.2 : 2-ClR.sup.3 : ##STR2712##Crystalline form: Light yellow amorphousNMR analysis: 202)Form: FreeExample 1008Structure ##STR2713## ##STR2714##R.sup.2 : 2-ClR.sup.3 : ##STR2715##Crystalline form: Light yellow amorphousNMR analysis: 203)Form: FreeExample 1009Structure ##STR2716## ##STR2717##R.sup.2 : 2-ClR.sup.3 : ##STR2718##Crystalline form: Light yellow amorphousNMR analysis: 204)Form: FreeExample 1010Structure ##STR2719## ##STR2720##R.sup.2 : HR.sup.3 : ##STR2721##Crystalline form: Colorless amorphousNMR analysis: 205)Form: FreeExample 1011Structure ##STR2722## ##STR2723##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2724##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 153-155.degree. C.Form: FreeExample 1012Structure ##STR2725## ##STR2726##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2727##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 142-143.degree. C.Form: FreeExample 1013Structure ##STR2728## ##STR2729##R.sup.2 : HR.sup.3 : ##STR2730##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 176-178.degree. C.Form: FreeExample 1014Structure ##STR2731## ##STR2732##R.sup.2 : HR.sup.3 : ##STR2733##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 186-188.degree. C.Form: FreeExample 1015Structure ##STR2734## ##STR2735##R.sup.2 : 2-ClR.sup.3 : ##STR2736##Crystalline form: Colorless amorphousNMR analysis: 206)Form: FreeExample 1016Structure ##STR2737## ##STR2738##R.sup.2 : 2-ClR.sup.3 : ##STR2739##Crystalline form: Colorless amorphousNMR analysis: 207)Form: FreeExample 1017Structure ##STR2740## ##STR2741##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2742##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 191-191.5.degree. C.Form: FreeExample 1018Structure ##STR2743## ##STR2744##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2745##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 210-212.degree. C.Form: FreeExample 1019Structure ##STR2746## ##STR2747##R.sup.2 : HR.sup.3 : ##STR2748##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 196-198.degree. C.Form: FreeExample 1020Structure ##STR2749## ##STR2750##R.sup.2 : HR.sup.3 : ##STR2751##Crystalline form: Colorless amorphousNMR analysis: 208)Form: FreeExample 1021Structure ##STR2752## ##STR2753##R.sup.2 : 2-ClR.sup.3 : ##STR2754##Crystalline form: Colorless amorphousNMR analysis: 209)Form: FreeExample 1022Structure ##STR2755## ##STR2756##R.sup.2 : 2-ClR.sup.3 : ##STR2757##Crystalline form: Colorless amorphousNMR analysis: 210)Form: FreeExample 1023Structure ##STR2758## ##STR2759##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2760##Crystalline form: Colorless amorphousNMR analysis: 211)Form: FreeExample 1024Structure ##STR2761## ##STR2762##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2763##Crystalline form: Colorless amorphousNMR analysis: 212)Form: FreeExample 1025Structure ##STR2764## ##STR2765##R.sup.2 : 2-ClR.sup.3 : ##STR2766##Crystalline form: Colorless amorphousNMR analysis: 213)Form: FreeExample 1026Structure ##STR2767## ##STR2768##R.sup.2 : 2-ClR.sup.3 : ##STR2769##Crystalline form: Colorless amorphousNMR analysis: 214)Form: FreeExample 1027Structure ##STR2770## ##STR2771##R.sup.2 : 2-ClR.sup.3 : ##STR2772##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 207-208.degree. C.Form: FreeExample 1028Structure ##STR2773## ##STR2774##R.sup.2 : 2-ClR.sup.3 : ##STR2775##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 201-202.degree. C.Form: FreeExample 1029Structure ##STR2776## ##STR2777##R.sup.2 : 2-ClR.sup.3 : ##STR2778##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 193-194.degree. C.Form: FreeExample 1030Structure ##STR2779## ##STR2780##R.sup.2 : HR.sup.3 : ##STR2781##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 205-208.degree. C.Form: FreeExample 1031Structure ##STR2782## ##STR2783##R.sup.2 : HR.sup.3 : ##STR2784##Crystalline form: White powderRecrystallization solvent: EthanolMelting Point: 214-216.degree. C.Form: FreeExample 1032Structure ##STR2785## ##STR2786##R.sup.2 : HR.sup.3 : ##STR2787##Crystalline form: Yellow needlesRecrystallization solvent: EthanolMelting Point: 223-226.degree. C.Form: FreeExample 1033Structure ##STR2788## ##STR2789##R.sup.2 : HR.sup.3 : ##STR2790##Crystalline form: Colorless needlesRecrystallization solvent: Ethanol/diethyl etherMelting Point: 203-206.degree. C.Form: FreeExample 1034Structure ##STR2791## ##STR2792##R.sup.2 : HR.sup.3 : ##STR2793##Crystalline form: Colorless needlesRecrystallization solvent: Ethanol/diethyl ether/n-hexaneMelting Point: 168-171.degree. C.Form: FreeExample 1035Structure ##STR2794## ##STR2795##R.sup.2 : HR.sup.3 : ##STR2796##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 206-208.degree. C.Form: FreeExample 1036Structure ##STR2797## ##STR2798##R.sup.2 : HR.sup.3 : ##STR2799##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 229-232.degree. C.Form: FreeExample 1037Structure ##STR2800## ##STR2801##R.sup.2 : HR.sup.3 : ##STR2802##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 220-222.degree. C.Form: FreeExample 1038Structure ##STR2803## ##STR2804##R.sup.2 : HR.sup.3 : ##STR2805##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 232-233.5.degree. C.Form: FreeExample 1039Structure ##STR2806## ##STR2807##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2808##Crystalline form: Colorless amorphousNMR analysis: 215)Form: FreeExample 1040Structure ##STR2809## ##STR2810##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2811##Crystalline form: Colorless amorphousNMR analysis: 216)Form: FreeExample 1041Structure ##STR2812## ##STR2813##R.sup.2 : HR.sup.3 : ##STR2814##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 147-151.degree. C.Form: FreeExample 1042Structure ##STR2815## ##STR2816##R.sup.2 : HR.sup.3 : ##STR2817##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 127-129.degree. C.Form: FreeExample 1043Structure ##STR2818## ##STR2819##R.sup.2 : HR.sup.3 : ##STR2820##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 109-112.degree. C.Form: FreeExample 1044Structure ##STR2821## ##STR2822##R.sup.2 : HR.sup.3 : ##STR2823##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 198-200.degree. C.Form: FreeExample 1045Structure ##STR2824## ##STR2825##R.sup.2 : HR.sup.3 : ##STR2826##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 210-211.degree. C.Form: FreeExample 1046Structure ##STR2827## ##STR2828##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2829##Crystalline form: Colorless amorphousNMR analysis: 217)Form: FreeExample 1047Structure ##STR2830## ##STR2831##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2832##Crystalline form: Colorless amorphousNMR analysis: 218)Form: FreeExample 1048Structure ##STR2833## ##STR2834##R.sup.2 : HR.sup.3 : ##STR2835##Crystalline form: Colorless amorphousNMR analysis: 219)Form: FreeExample 1049Structure ##STR2836## ##STR2837##R.sup.2 : HR.sup.3 : ##STR2838##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 243-243.5.degree. C.Form: FreeExample 1050Structure ##STR2839## ##STR2840##R.sup.2 : HR.sup.3 : ##STR2841##Crystalline form: Colorless prismsRecrystallization solvent: Ethanol/petroleum etherMelting Point: 207-209.degree. C.Form: FreeExample 1051Structure ##STR2842## ##STR2843##R.sup.2 : HR.sup.3 : ##STR2844##Crystalline form: Colorless needlesRecrystallization solvent: Ethanol/petroleum etherMelting Point: 239-241.degree. C.Form: FreeExample 1052Structure ##STR2845## ##STR2846##R.sup.2 : 2-ClR.sup.3 : ##STR2847##Crystalline form: Colorless amorphousNMR analysis: 220)Form: FreeExample 1053Structure ##STR2848## ##STR2849##R.sup.2 : 2-ClR.sup.3 : ##STR2850##Crystalline form: Colorless amorphousNMR analysis: 221)Form: FreeExample 1054Structure ##STR2851## ##STR2852##R.sup.2 : 2-ClR.sup.3 : ##STR2853##Crystalline form: Light yellow amorphousNMR analysis: 222)Form: FreeExample 1055Structure ##STR2854## ##STR2855##R.sup.2 : 2-ClR.sup.3 : ##STR2856##Crystalline form: Light yellow amorphousNMR analysis: 223)Form: FreeExample 1056Structure ##STR2857## ##STR2858##R.sup.2 : 2-ClR.sup.3 : ##STR2859##Crystalline form: White powderRecrystallization solvent: Diethyl ether/dichloromethaneMelting Point: 169.5-173.degree. C.Form: FreeExample 1057Structure ##STR2860## ##STR2861##R.sup.2 : 2-ClR.sup.3 : ##STR2862##Crystalline form: Colorless amorphousNMR analysis: 224)Form: FreeExample 1058Structure ##STR2863## ##STR2864##R.sup.2 : 2-ClR.sup.3 : ##STR2865##Crystalline form: Colorless amorphousNMR analysis 225)Example 1059Structure ##STR2866## ##STR2867##R.sup.2 : 2-ClR.sup.3 : ##STR2868##Crystalline form: Colorless amorphousNMR analysis: 226)Form: FreeExample 1060Structure ##STR2869## ##STR2870##R.sup.2 : 2-ClR.sup.3 : ##STR2871##Crystalline form: Colorless amorphousNMR analysis: 227)Form: FreeExample 1061Structure ##STR2872## ##STR2873##R.sup.2 : 2-ClR.sup.3 : ##STR2874##Crystalline form: Colorless amorphousNMR analysis: 228)Form: FreeExample 1062Structure ##STR2875## ##STR2876##R.sup.2 : 2-ClR.sup.3 : ##STR2877##Crystalline form: Colorless amorphousNMR analysis: 229)Form: FreeExample 1063Structure ##STR2878## ##STR2879##R.sup.2 : 2-ClR.sup.3 : ##STR2880##Crystalline form: Colorless amorphousNMR analysis: 230)Form: FreeExample 1064Structure ##STR2881## ##STR2882##R.sup.2 : 2-ClR.sup.3 : ##STR2883##Crystalline form: Colorless amorphousNMR analysis: 231)Form: FreeExample 1065Structure ##STR2884## ##STR2885##R.sup.2 : 2-ClR.sup.3 : ##STR2886##Crystalline form: Colorless amorphousNMR analysis: 232)Form: FreeExample 1066Structure ##STR2887## ##STR2888##R.sup.2 : 2-ClR.sup.3 : ##STR2889##Crystalline form: Colorless amorphousNMR analysis: 233)Form: FreeExample 1067Structure ##STR2890## ##STR2891##R.sup.2 : 2-ClR.sup.3 : ##STR2892##Crystalline form: Colorless amorphousNMR analysis: 234)Form: FreeExample 1068Structure ##STR2893## ##STR2894##R.sup.2 : 2-ClR.sup.3 : ##STR2895##Crystalline form: Colorless amorphousNMR analysis: 235)Form: FreeExample 1069Structure ##STR2896## ##STR2897##R.sup.2 : 2-ClR.sup.3 : ##STR2898##Crystalline form: Colorless amorphousNMR analysis: 236)Form: FreeExample 1070Structure ##STR2899## ##STR2900##R.sup.2 : 2-ClR.sup.3 : ##STR2901##Crystalline form: Colorless amorphousNMR analysis: 237)Form: Free______________________________________
196) .sup.1 H-NMR (CDCl.sub.3) .delta.; 2.14 (2H, brs), 2.33 (3H, s), 2.46 (3H, s), 2.85 (2H, t, J=6.1 Hz), 4.83 (2H, brs), 6.64 (1H, d, J=8.1 Hz), 7.07 (1H, d, J=8.0 Hz), 7.21-7.48 (8H, m), 7.65 (1H, m), 7.74 (1H, brs)
197) .sup.1 H-NMR (CDCl.sub.3) .delta.; 2.12 (2H, brs), 2.33 (3H, s), 2.85 (2H, t, J=6.2 Hz), 2.88-5.28 (2H, m), 6.63 (1H, d, J=8.1 Hz), 7.06 (1H, dd, J=1.7 Hz, 8.1 Hz), 7.19-7.69 (9H, m), 8.26 (1H, brs)
198) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.49 (4H, m), 1.25-5.13 (9H, m), 2.33 (3H, s), 2.45 (3H, s), 6.53 (1H, m), 6.79 (1H, m), 7.07-7.42 (9H, m), 7.73 (1H, m)
199) .sup.1 H-NMR (CDCl.sub.3) .delta.; 2.04 (2H, brs), 2.29 (3H, s), 2.82 (2H, t, J=5.9 Hz), 2.85-5.29 (2H, m), 6.82-7.69 (10H, m), 8.31 (1H, brs)
200) .sup.1 H-NMR (CDCl.sub.3) .delta.; 2.05 (2H, brs), 2.29 (3H, s), 2.44 (3H, s), 2.79 (2H, t, J=5.5 Hz), 2.82-5.28 (2H, m), 6.82-8.12 (11H, m)
201) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.40-4.85 (11H, m), 2.51 (3H, s), 6.78-7.63 (10H, m), 8.64 (1H, brs)
202) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.40-4.85 (11H, m), 2.45 (3H, s), 2.50 (3H, s), 6.78-7.55 (10H, m), 8.10 (1H, brs)
203) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.49 (4H, m), 1.25-4.85 (9H, m), 2.28 (3H, s), 6.77-7.62 (10H, m), 8.64 (1H, brs)
204) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.48 (4H, m), 1.26-4.85 (9H, m), 2.29 (3H, s), 2.44 (3H, s), 6.78-7.58 (10H, m), 8.18 (1H, brs)
205) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.14 (6H, d, J=6.3 Hz), 1.52-2.20 (7H, m), 2.20-2.60 (1H, m), 2.64-3.66 (10H, m), 4.00-4.50 (4H, m), 4.50-5.23 (2H, m), 6.57-7.90 (11H, m), 8.10-8.30 (1H, m), 9.97 (1H, s)
206) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.24-2.08 (4H, m), 2.08-2.26 (3H, m), 2.26-3.16 (4H, m), 3.47-4.03 (4H, m), 4.18-4.92 (1H, m), 6.40-7.94 (10H, m), 8.45-9.03 (1H, m)
207) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.26-2.10 (4H, m), 2.10-2.28 (3H, m), 2.28-3.20 (1H, m), 3.43-4.06 (4H, m), 4.20-4.93 (1H, m), 6.40-8.00 (10H, m), 8.78-9.30 (1H, m)
208) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-1.98 (4H, m), 1.98-3.10 (7H, m), 3.30-3.90 (4H, m), 3.90-5.10 (1H, m), 6.45-8.25 (12H, m)
209) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.06-1.94 (4H, m), 1.94-3.19 (10H, m), 3.19-3.90 (4H, m), 3.90-5.10 (1H, m), 6.44-8.60 (11H, m)
210) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.06-1.97 (4H, m), 1.97-3.20 (7H, m), 3.20-3.92 (4H, m), 3.92-5.10 (1H, m), 6.44-8.55 (11H, m)
211) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.07-1.98 (4H, m), 1.98-3.10 (10H, m), 3.37-5.20 (8H, m), 6.44-6.86 (3H, m), 6.97-7.60 (6H, m), 8.13 (1H, s), 8.19-8.38 (1H, m)
212) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.08-1.99 (4H, m), 1.99-3.13 (7H, m), 3.33-5.14 (8H, m), 6.40-6.90 (3H, m), 6.95-7.56 (5H, m), 7.63-7.87 (1H, m), 8.17-8.37 (1H, m), 8.60 (1H, s)
213) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.30-0.64 (4H, m), 0.70-3.42 (9H, m), 3.42-5.10 (5H, m), 6.40-8.70 (11H, m)
214) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.30-0.76 (4H, m), 0.80-3.43 (6H, m), 3.50-5.00 (5H, m), 6.40-9.04 (11H, m)
215) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.25-3.25 (14H, m), 3.55-5.06 (2H, m), 6.43-7.00 (2H, m), 7.00-7.71 (8H, m), 7.91-8.45 (1H, m)
216) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.11-3.20 (17H, m), 3.28-5.12 (2H, m), 6.41-7.01 (2H, m), 7.02-7.63 (8H, m), 7.76-8.21 (1H, m)
217) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.92-2.29 (2H, m), 2.36 (3H, s), 2.45 (3H, s), 2.84 (2H, t, J=6.3 Hz), 3.32-4.64 (2H, m), 6.40-8.10 (11H, m)
218) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.92-2.25 (2H, m), 2.34 (3H, s), 2.83 (2H, t, J=6.3 Hz), 3.21-4.52 (2H, m), 6.39-7.97 (10H, m), 8.43 (1H, brs)
219) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.7-2.15 (4H, m), 2.5-5.2 (4H, m), 6.75-6.9 (1H, m), 7.27-7.6 (9H, m), 7.65-7.85 (1H, m), 7.9-8.15 (2H, m)
220) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.65-2.1 (4H, m), 2.44 (3H, s), 2.8-4.5 (4H, m), 6.75-8.0 (12H, m)
221) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.65-2.3 (4H, m), 2.7-4.8 (4H, m), 6.75-8.4 (12H, m)
222) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.45-2.15 (4H, m), 2.45-2.55 (3H, m), 2.85-4.6 (4H, m), 6.8-8.25 (11H, m)
223) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.5-2.2 (4H, m), 2.8-4.7 (4H, m), 6.8-8.4 (11H, m)
224) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.75-2.25 (2H, m), 2.30-2.70 (3H, m), 2.70-2.95 (2H, m), 3.20-5.10 (2H, m), 6.70-8.40 (11H, m)
225) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-2.60 (8H, m), 2.60-5.10 (3H, m), 6.80-7.90 (10H, m), 8.20-8.60 (1H, m)
226) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-2.60 (10H, m), 2.60-5.10 (3H, m), 6.80-8.15 (11H, m)
227) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.30-0.70 (4H, m), 1.20-2.45 (6H, m), 2.60-5.10 (3H, m), 6.80-7.95 (10H, m), 8.15-8.50 (1H, m)
228) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-2.40 (5H, m), 2.60-5.35 (7H, m), 5.80-6.15 (1H, m), 6.75-7.95 (10H, m), 8.20-8.70 (1H, m)
229) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-2.55 (7H, m), 2.60-5.35 (7H, m), 5.85-6.05 (1H, m), 6.70-7.10 (2H, m), 7.10-7.90 (8H, m), 8.15-8.60 (1H, m)
230) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.00-1.20 (6H, m), 1.00-2.40 (5H, m), 2.60-5.10 (4H, m), 6.80-8.00 (10H, m), 8.15-8.65 (1H, m)
231) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.80-2.50 (13H, m), 2.60-5.10 (4H, m), 6.70-8.85 (10H, m), 8.25-8.60 (1H, m)
232) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.30-2.60 (11H, m), 2.60-5.10 (3H, m), 6.80-8.15 (11H, m)
233) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-2.50 (13H, m), 2.50-5.10 (3H, m), 6.75-8.40 (11H, m)
234) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.30-0.65 (4H, m), 1.20-2.30 (6H, m), 2.35-2.55 (3H, m), 2.60-5.10 (3H, m), 6.75-8.35 (11H, m)
235) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-2.60 (8H, m), 2.60-5.40 (7H, m), 5.80-6.15 (1H, m), 6.80-8.20 (11H, m)
236) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.25-2.60 (10H, m), 2.60-5.40 (7H, m), 5.75-6.10 (1H, m), 6.75-7.10 (2H, m), 7.10-8.40 (9H, m)
237) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.95-1.20 (6H, m), 0.95-2.25 (5H, m), 2.40-2.60 (3H, m), 2.60-5.10 (4H, m), 6.75-7.05 (2H, m), 7.10-8.30 (9H, m)
REFERENCE EXAMPLE 22
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 1.
8-Chloro-6-oxo-1-(4-nitrobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, yellow prisms
.sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.3-2.2 (4H, m), 2.6-5.0 (4H, m), 7.05-8.5 (7H, m)
5-Oxo-7-methyl-1-(2-chloro-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, light yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.71-2.32 (2H, m), 2.29 (3H, s), 2.86 (2H, t, J=6.3 Hz), 3.10-5.30 (2H, m), 6.84-8.38 (6H, m)
5-Oxo-7-methyl-1-(3-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, light yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 2.17 (2H, brs), 2.34 (3H, s), 2.84 (2H, t, J=6.0 Hz), 3.10-5.29 (2H, m), 3.77 (3H, s), 6.67 (1H, d, J=7.9 Hz), 6.85 (2H, m), 7.10 (1H, d, J=8.0 Hz), 7.57-7.65 (2H, m)
5-Oxo-7-dimethylamino-1-(2-chloro-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.66-2.38 (2H, m), 2.65-2.88 (2H, m), 2.92 (6H, s), 3.08-3.64, 4.58-5.01 (total 2H, m), 6.49 (1H, dd, J=3.1, 8.7 Hz), 6.82 (1H, d, J=8.7 Hz), 6.90 (1H, d, J=3.1 Hz), 7.02-7.37 (1H, m), 7.94 (1H, dd, J=1.9, 8.4 Hz), 8.08 (1H, d, J=1.9 Hz)
REFERENCE EXAMPLE 23
Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.
8-Chloro-6-oxo-1-(4-aminobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, light yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.7-2.2 (4H, m), 2.3-4.8 (6H, m), 6.4-6.6 (2H, m), 6.74 (1H, d, J=8.5 Hz), 7.1-7.4 (3H, m), 7.99 (1H, d, J=2.6 Hz)
8-Methyl-6-oxo-(2-chloro-4-aminobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, colorless amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.4-2.1 (4H, m), 2.15-2.6 (3H, m), 2.7-4.4 (6H, m), 6.15-6.35 (1H, m), 6.51 (1H, s), 6.6-6.85 (1H, m), 6.9-7.25 (2H, m), 7.72 (1H, s)
8-Methoxy-6-oxo-(2-chloro-4-aminobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, light yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.4-2.2 (4H, m), 2.7-5.0 (9H, m), 6.25 (1H, dd, J=8.3 Hz, 2.2 Hz), 6.51 (1H, d, J=2.2 Hz), 6.66 (1H, d, J=8.3 Hz), 6.88 (1H, dd, J=8.6 Hz, 3.0 Hz), 7.23 (1H, d, J=8.6 Hz), 7.43 (1H, d, J=3.0 Hz)
5-Oxo-7-chloro-1-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, colorless particles (recrystallized from methanol/diethyl ether), m.p. 206.degree.-208.degree. C.
5-Oxo-7-methyl-1-(2-chloro-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, light yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 2.09 (2H, brs), 2.29 (3H, s), 3.10-5.00 (2H, m), 3.78 (2H, brs), 6.34-7.54 (6H, m)
5-Oxo-7-methyl-1-(3-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, light yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 2.12 (2H, brs), 2.32 (3H, s), 2.85 (2H, t, J=5.9 Hz), 3.30-5.00 (2H, m), 3.65 (3H, s), 3.98 (2H, brs), 6.40 (1H, d, J=8.1 Hz), 6.64-6.76 (3H, m), 7.06 (1H, dd, J=1.6, 8.1 Hz), 7.63 (1H, d, J=2.0 Hz)
5-Oxo-7-dimethylamino-1-(2-chloro-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.60-2.32 (2H, m), 2.67-5.13 (4H, m), 2.92 (6H, s), 3.75 (2H, s), 6.31 (1H, dd, J=2.1, 8.3 Hz), 6.46 (1H, d, J=2.1 Hz), 6.48 (1H, dd, J=3.1, 8.7 Hz), 6.66-6.89 (2H, m), 6.95 (1H, d, J=3.1 Hz)
Using the suitable starting materials, the compounds of the following Table 9 are obtained in the same manner as in above Examples 1 and 382.
TABLE 9______________________________________ ##STR2902##______________________________________Example 1071Structure ##STR2903## ##STR2904##R.sup.2 : 2-ClR.sup.3 : ##STR2905##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 227-230.degree. C.Form: FreeExample 1072Structure ##STR2906## ##STR2907##R.sup.2 : 2-ClR.sup.3 : ##STR2908##Crystalline form: Colorless needlesRecrystallization solvent: Ethanol/petroleum etherMelting Point: 216-218.degree. C.Form: FreeExample 1073Structure ##STR2909## ##STR2910##R.sup.2 : 2-ClR.sup.3 : ##STR2911##Crystalline form: Colorless prismsRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 227-228.degree. C.Form: FreeExample 1074Structure ##STR2912## ##STR2913##R.sup.2 : HR.sup.3 : ##STR2914##Crystalline form: White powderNMR analysis: 238)Form: FreeExample 1075Structure ##STR2915## ##STR2916##R.sup.2 : HR.sup.3 : ##STR2917##Crystalline form: White powderNMR analysis: 239)Form: FreeExample 1076Structure ##STR2918## ##STR2919##R.sup.2 : 2-ClR.sup.3 : ##STR2920##Crystalline form: Light yellow amorphousNMR analysis: 240)Form: FreeExample 1077Structure ##STR2921## ##STR2922##R.sup.2 : 2-ClR.sup.3 : ##STR2923##Crystalline form: Light yellow amorphousNMR analysis: 241)Form: FreeExample 1078Structure ##STR2924## ##STR2925##R.sup.2 : 2-ClR.sup.3 : ##STR2926##Crystalline form: Colorless amorphousNMR analysis: 242)Form: FreeExample 1079Structure ##STR2927## ##STR2928##R.sup.2 : 2-ClR.sup.3 : ##STR2929##Crystalline form: Colorless amorphousNMR analysis: 243)Form: FreeExample 1080Structure ##STR2930## ##STR2931##R.sup.2 : 2-ClR.sup.3 : ##STR2932##Crystalline form: Light yellow powderRecrystallization solvent: Ethyl acetate/diethyl etherMelting Point: 179-181.degree. C.Form: FreeExample 1081Structure ##STR2933## ##STR2934##R.sup.2 : 2-ClR.sup.3 : ##STR2935##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/diethyl etherMelting Point: 213-216.degree. C.Form: FreeExample 1082Structure ##STR2936## ##STR2937##R.sup.2 : 2-ClR.sup.3 : ##STR2938##Crystalline form: Light yellow powderRecrystallization solvent: Ethyl acetate/diethyl etherMelting Point: 185-187.degree. C.Form: FreeExample 1083Structure ##STR2939## ##STR2940##R.sup.2 : HR.sup.3 : ##STR2941##Crystalline form: Colorless prismsRecrystallization solvent: EthanolMelting Point: 249-251.degree. C.Form: FreeExample 1084Structure ##STR2942## ##STR2943##R.sup.2 : HR.sup.3 : ##STR2944##Crystalline form: Colorless needlesRecrystallization solvent: EthanolMelting Point: 239-241.degree. C.Form: FreeExample 1085Structure ##STR2945## ##STR2946##R.sup.2 : 2-ClR.sup.3 : ##STR2947##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/diethyl etherMelting Point: 208-210.degree. C.Form: FreeExample 1086Structure ##STR2948## ##STR2949##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2950##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 178-180.5.degree. C.Form: FreeExample 1087Structure ##STR2951## ##STR2952##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2953##Crystalline form: Colorless amorphousNMR analysis: 244)Form: FreeExample 1088Structure ##STR2954## ##STR2955##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR2956##Crystalline form: Colorless amorphousNMR analysis: 245)Form: FreeExample 1089Structure ##STR2957## ##STR2958##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR2959##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherNMR analysis: 246)Form: FreeExample 1090Structure ##STR2960## ##STR2961##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR2962##Crystalline form: Colorless amorphousNMR analysis: 247)Form: FreeExample 1091Structure ##STR2963## ##STR2964##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR2965##Crystalline form: Colorless amorphousNMR analysis: 248)Form: FreeExample 1092Structure ##STR2966## ##STR2967##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR2968##Crystalline form: Colorless amorphousNMR analysis: 249)Form: FreeExample 1093Structure ##STR2969## ##STR2970##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR2971##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 205-206.degree. C.Form: FreeExample 1094Structure ##STR2972## ##STR2973##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR2974##Crystalline form: Colorless amorphousNMR analysis: 250)Form: FreeExample 1095Structure ##STR2975## ##STR2976##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR2977##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 172.5-174.degree. C.Form: FreeExample 1096Structure ##STR2978## ##STR2979##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR2980##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 215-216.5.degree. C.Form: FreeExample 1097Structure ##STR2981## ##STR2982##R.sup.2 : HR.sup.3 : ##STR2983##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 133-136.degree. C.Form: FreeExample 1098Structure ##STR2984## ##STR2985##R.sup.2 : 2-ClR.sup.3 : ##STR2986##Crystalline form: Colorless amorphousNMR analysis: 251)Form: FreeExample 1099Structure ##STR2987## ##STR2988##R.sup.2 : 2-ClR.sup.3 : ##STR2989##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 179-180.degree. C.Form: FreeExample 1100Structure ##STR2990## ##STR2991##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2992##Crystalline form: White powderRecrystallization solvent: Methanol/n-hexaneMelting Point: 167.5-169.5.degree. C.Form: FreeExample 1101Structure ##STR2993## ##STR2994##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR2995##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 176-178.degree. C.Form: FreeExample 1102Structure ##STR2996## ##STR2997##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR2998##Crystalline form: Colorless amorphousNMR analysis: 252)Form: FreeExample 1103Structure ##STR2999## ##STR3000##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3001##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 185-188.degree. C.Form: FreeExample 1104Structure ##STR3002## ##STR3003##R.sup.2 : HR.sup.3 : ##STR3004##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 180-181.5.degree. C.Form: FreeExample 1105Structure ##STR3005## ##STR3006##R.sup.2 : HR.sup.3 : ##STR3007##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 181-184.degree. C.Form: FreeExample 1106Structure ##STR3008## ##STR3009##R.sup.2 : HR.sup.3 : ##STR3010##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 186.5-187.degree. C.Form: FreeExample 1107Structure ##STR3011## ##STR3012##R.sup.2 : HR.sup.3 : ##STR3013##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 183-184.degree. C.Form: FreeExample 1108Structure ##STR3014## ##STR3015##R.sup.2 : HR.sup.3 : ##STR3016##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 151-153.degree. C.Form: FreeExample 1109Structure ##STR3017## ##STR3018##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3019##Crystalline form: Colorless amorphousNMR analysis: 253)Form: FreeExample 1110Structure ##STR3020## ##STR3021##R.sup.2 : HR.sup.3 : ##STR3022##Crystalline form: Colorless amorphousNMR analysis: 254)Form: FreeExample 1111Structure ##STR3023## ##STR3024##R.sup.2 : HR.sup.3 : ##STR3025##Crystalline form: White needlesRecrystallization solvent: Ethanol/n-hexaneMelting Point: 191-195.degree. C.Form: FreeExample 1112Structure ##STR3026## ##STR3027##R.sup.2 : HR.sup.3 : ##STR3028##Crystalline form: White powderRecrystallization solvent: Diethyl ether/n-hexaneMelting Point: 227-230.degree. C.Form: FreeExample 1113Structure ##STR3029## ##STR3030##R.sup.2 : 2-ClR.sup.3 : ##STR3031##Crystalline form: Colorless amorphousNMR analysis: 289)Form: FreeExample 1114Structure ##STR3032## ##STR3033##R.sup.2 : 2-ClR.sup.3 : ##STR3034##Crystalline form: Light yellow amorphousNMR analysis: 255)Example 1115Structure ##STR3035## ##STR3036##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3037##Crystalline form: White powderRecrystallization solvent: Diethyl ether/n-hexaneMelting Point: 172-174.degree. C.Form: FreeExample 1116Structure ##STR3038## ##STR3039##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3040##Crystalline form: Colorless amorphousNMR analysis: 305)Form: FreeExample 1117Structure ##STR3041## ##STR3042##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3043##Crystalline form: Colorless amorphousNMR analysis: 290)Form: FreeExample 1118Structure ##STR3044## ##STR3045##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3046##Crystalline form: Colorless amorphousNMR analysis: 291)Form: FreeExample 1119Structure ##STR3047## ##STR3048##R.sup.2 : HR.sup.3 : ##STR3049##Crystalline form: Colorless amorphousNMR analysis: 264)Form: FreeExample 1120Structure ##STR3050## ##STR3051##R.sup.2 : HR.sup.3 : ##STR3052##Crystalline form: Colorless amorphousNMR analysis: 265)Form: FreeExample 1121Structure ##STR3053## ##STR3054##R.sup.2 : 2-ClR.sup.3 : ##STR3055##Crystalline form: Colorless amorphousNMR analysis: 266)Form: FreeExample 1122Structure ##STR3056## ##STR3057##R.sup.2 : 2-ClR.sup.3 : ##STR3058##Crystalline form: Colorless amorphousNMR analysis: 267)Form: FreeExample 1123Structure ##STR3059## ##STR3060##R.sup.2 : HR.sup.3 : ##STR3061##Crystalline form: Colorless amorphousNMR analysis: 268)Form: FreeExample 1124Structure ##STR3062## ##STR3063##R.sup.2 : HR.sup.3 : ##STR3064##Crystalline form: Colorless amorphousNMR analysis: 269)Form: FreeExample 1125Structure ##STR3065## ##STR3066##R.sup.2 : 2-ClR.sup.3 : ##STR3067##Crystalline form: Colorless amorphousNMR analysis: 270)Form: FreeExample 1126Structure ##STR3068## ##STR3069##R.sup.2 : 2-ClR.sup.3 : ##STR3070##Crystalline form: Colorless amorphousNMR analysis: 271)Form: FreeExample 1127Structure ##STR3071## ##STR3072##R.sup.2 : HR.sup.3 : ##STR3073##Crystalline form: Colorless amorphousNMR analysis: 272)Form: FreeExample 1128Structure ##STR3074## ##STR3075##R.sup.2 : HR.sup.3 : ##STR3076##Crystalline form: Colorless amorphousNMR analysis: 273)Form: FreeExample 1129Structure ##STR3077## ##STR3078##R.sup.2 : 2-ClR.sup.3 : ##STR3079##Crystalline form: Colorless amorphousNMR analysis: 274)Form: FreeExample 1130Structure ##STR3080## ##STR3081##R.sup.2 : 2-ClR.sup.3 : ##STR3082##Crystalline form: Colorless amorphousNMR analysis: 275)Form: FreeExample 1131Structure ##STR3083## ##STR3084##R.sup.2 : HR.sup.3 : ##STR3085##Crystalline form: Colorless amorphousNMR analysis: 276)Form: FreeExample 1132Structure ##STR3086## ##STR3087##R.sup.2 : HR.sup.3 : ##STR3088##Crystalline form: Colorless amorphousNMR analysis: 277)Form: FreeExample 1133Structure ##STR3089## ##STR3090##R.sup.2 : 2-ClR.sup.3 : ##STR3091##Crystalline form: Colorless amorphousNMR analysis: 278)Form: FreeExample 1134Structure ##STR3092## ##STR3093##R.sup.2 : 2-ClR.sup.3 : ##STR3094##Crystalline form: Colorless amorphousNMR analysis: 279)Form: FreeExample 1135Structure ##STR3095## ##STR3096##R.sup.2 : HR.sup.3 : ##STR3097##NMR analysis: 280)Form: FreeExample 1136Structure ##STR3098## ##STR3099##R.sup.2 : HR.sup.3 : ##STR3100##NMR analysis: 281)Form: FreeExample 1137Structure ##STR3101## ##STR3102##R.sup.2 : 2-ClR.sup.3 : ##STR3103##NMR analysis: 282)Form: FreeExample 1138Structure ##STR3104## ##STR3105##R.sup.2 : 2-ClR.sup.3 : ##STR3106##NMR analysis: 283)Form: FreeExample 1139Structure ##STR3107## ##STR3108##R.sup.2 : 2-ClR.sup.3 : ##STR3109##NMR analysis: 306)Form: FreeExample 1140Structure ##STR3110## ##STR3111##R.sup.2 : 2-ClR.sup.3 : ##STR3112##Crystalline form: Colorless amorphousNMR analysis: 284)Form: FreeExample 1141Structure ##STR3113## ##STR3114##R.sup.2 : 2-ClR.sup.3 : ##STR3115##Crystalline form: Colorless amorphousNMR analysis: 285)Form: FreeExample 1142Structure ##STR3116## ##STR3117##R.sup.2 : 2-ClR.sup.3 : ##STR3118##Crystalline form: Colorless amorphousNMR analysis: 286)Form: FreeExample 1143Structure ##STR3119## ##STR3120##R.sup.2 : 2-ClR.sup.3 : ##STR3121##Crystalline form: Colorless amorphousNMR analysis: 287)Form: FreeExample 1144Structure ##STR3122## ##STR3123##R.sup.2 : HR.sup.3 : ##STR3124##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 203-207.degree. C.Form: FreeExample 1145Structure ##STR3125## ##STR3126##R.sup.2 : HR.sup.3 : ##STR3127##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 199-203.degree. C.Form: FreeExample 1146Structure ##STR3128## ##STR3129##R.sup.2 : HR.sup.3 : ##STR3130##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 210-212.degree. C.Form: FreeExample 1147Structure ##STR3131## ##STR3132##R.sup.2 : HR.sup.3 : ##STR3133##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 211-214.degree. C.Form: FreeExample 1148Structure ##STR3134## ##STR3135##R.sup.2 : 2-ClR.sup.3 : ##STR3136##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 186-189.degree. C.Form: FreeExample 1149Structure ##STR3137## ##STR3138##R.sup.2 : 2-ClR.sup.3 : ##STR3139##Crystalline form: Colorless amorphousNMR analysis: 288)Form: FreeExample 1150Structure ##STR3140## ##STR3141##R.sup.2 : 2-ClR.sup.3 : ##STR3142##Crystalline form: Colorless amorphousNMR analysis: 292)Form: FreeExample 1151Structure ##STR3143## ##STR3144##R.sup.2 : 2-ClR.sup.3 : ##STR3145##Crystalline form: Colorless amorphousNMR analysis: 293)Form: FreeExample 1152Structure ##STR3146## ##STR3147##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3148##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 144-145.degree. C.Form: FreeExample 1153Structure ##STR3149## ##STR3150##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3151##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 149-150.degree. C.Form: FreeExample 1154Structure ##STR3152## ##STR3153##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3154##Crystalline form: Colorless amorphousNMR analysis: 294)Form: FreeExample 1155Structure ##STR3155## ##STR3156##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3157##Crystalline form: Colorless amorphousNMR analysis: 295)Form: FreeExample 1156Structure ##STR3158## ##STR3159##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3160##Crystalline form: Colorless amorphousNMR analysis: 301)Form: FreeExample 1157Structure ##STR3161## ##STR3162##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3163##Crystalline form: Colorless amorphousNMR analysis: 302)Form: FreeExample 1158Structure ##STR3164## ##STR3165##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3166##Crystalline form: Colorless amorphousNMR analysis: 303)Form: FreeExample 1159Structure ##STR3167## ##STR3168##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3169##Crystalline form: Colorless amorphousNMR analysis: 304)Form: FreeExample 1160Structure ##STR3170## ##STR3171##R.sup.2 : HR.sup.3 : ##STR3172##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/diisopropyl etherMelting Point: 191-193.degree. C.Form: FreeExample 1161Structure ##STR3173## ##STR3174##R.sup.2 : HR.sup.3 : ##STR3175##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/diisopropyl etherMelting Point: 221-223.degree. C.Form: FreeExample 1162Structure ##STR3176## ##STR3177##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3178##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 159-161.degree. C.Form: FreeExample 1163Structure ##STR3179## ##STR3180##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3181##Crystalline form: White powderRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 174-175.degree. C.Form: FreeExample 1164Structure ##STR3182## ##STR3183##R.sup.2 : 2-ClR.sup.3 : ##STR3184##Crystalline form: Colorless amorphousNMR analysis: 256)Form: FreeExample 1165Structure ##STR3185## ##STR3186##R.sup.2 : 2-ClR.sup.3 : ##STR3187##Crystalline form: Colorless amorphousNMR analysis: 257)Form: FreeExample 1166Structure ##STR3188## ##STR3189##R.sup.2 : HR.sup.3 : ##STR3190##Crystalline form: Colorless amorphousNMR analysis: 258)Form: FreeExample 1167Structure ##STR3191## ##STR3192##R.sup.2 : 2-ClR.sup.3 : ##STR3193##Crystalline form: Colorless amorphousNMR analysis: 259)Form: FreeExample 1168Structure ##STR3194## ##STR3195##R.sup.2 : HR.sup.3 : ##STR3196##Crystalline form: Colorless amorphousNMR analysis: 260)Form: FreeExample 1169Structure ##STR3197## ##STR3198##R.sup.2 : 2-ClR.sup.3 : ##STR3199##Crystalline form: Colorless amorphousNMR analysis: 261)Form: FreeExample 1170Structure ##STR3200## ##STR3201##R.sup.2 : HR.sup.3 : ##STR3202##Crystalline form: Colorless amorphousNMR analysis: 296)Form: FreeExample 1171Structure ##STR3203## ##STR3204##R.sup.2 : 2-ClR.sup.3 : ##STR3205##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl ether/n-hexaneMelting Point: 159-162.degree. C.Form: FreeExample 1172Structure ##STR3206## ##STR3207##R.sup.2 : 2-ClR.sup.3 : ##STR3208##Crystalline form: Colorless needlesRecrystallization solvent: Ethanol/diethyl ether/n-hexaneMelting Point: 221-224.degree. C.Form: FreeExample 1173Structure ##STR3209## ##STR3210##R.sup.2 : 2-ClR.sup.3 : ##STR3211##Crystalline form: Colorless prismsRecrystallization solvent: Ethanol/diethyl etherMelting Point: 199-202.degree. C.Form: FreeExample 1174Structure ##STR3212## ##STR3213##R.sup.2 : 2-ClR.sup.3 : ##STR3214##Crystalline form: Colorless prismsRecrystallization solvent: Ethanol/diethyl etherMelting Point: 215-218.degree. C.Form: FreeExample 1175Structure ##STR3215## ##STR3216##R.sup.2 : 2-ClR.sup.3 : ##STR3217##Crystalline form: Colorless needlesRecrystallization solvent: Ethanol/diethyl ether/n-hexaneMelting Point: 167-170.degree. C.Form: FreeExample 1176Structure ##STR3218## ##STR3219##R.sup.2 : 2-ClR.sup.3 : ##STR3220##Crystalline form: White powderRecrystallization solvent: Ethanol/diethyl ether/n-hexaneMelting Point: 191-193.degree. C.Form: FreeExample 1177Structure ##STR3221## ##STR3222##R.sup.2 : 2-ClR.sup.3 : ##STR3223##Crystalline form: Light yellow amorphousNMR analysis: 262)Form: FreeExample 1178Structure ##STR3224## ##STR3225##R.sup.2 : 2-ClR.sup.3 : ##STR3226##Crystalline form: Light yellow amorphousNMR analysis: 263)Form: FreeExample 1179Structure ##STR3227## ##STR3228##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3229##Crystalline form: Colorless amorphousNMR analysis: 297)Form: FreeExample 1180Structure ##STR3230## ##STR3231##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3232##Crystalline form: Colorless amorphousNMR analysis: 298)Form: FreeExample 1181Structure ##STR3233## ##STR3234##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3235##Crystalline form: Colorless amorphousNMR analysis: 299)Form: FreeExample 1182Structure ##STR3236## ##STR3237##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3238##Crystalline form: Colorless amorphousNMR analysis: 300)Form: FreeExample 1183Structure ##STR3239## ##STR3240##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3241##Crystalline form: Colorless amorphousNMR analysis: 307)Form: FreeExample 1184Structure ##STR3242## ##STR3243##R.sup.2 : 3-OCH.sub.3R.sup.3 : ##STR3244##Crystalline form: Colorless amorphousNMR analysis: 308)Form: FreeExample 1185Structure ##STR3245## ##STR3246##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3247##Crystalline form: Colorless amorphousNMR analysis: 309)Form: FreeExample 1186Structure ##STR3248## ##STR3249##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3250##Crystalline form: Colorless amorphousNMR analysis: 310)Form: FreeExample 1187Structure ##STR3251## ##STR3252##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3253##Crystalline form: Colorless amorphousNMR analysis: 311)Form: FreeExample 1188Structure ##STR3254## ##STR3255##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3256##Crystalline form: Colorless amorphousNMR analysis: 312)Form: Free______________________________________
238) .sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.4-2.1 (4H, m), 2.34 (3H, s), 2.8-5.4 (4H, m), 7.09 (1H, d, J=8.4 Hz), 7.15-7.7 (9H, m), 7.76 (1H, d, J=2.6 Hz), 10.41 (1H, s)
239) .sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.5-2.2 (4H, m), 2.8-5.2 (4H, m), 7.09 (1H, d, J=8.4 Hz), 7.2-7.7 (9H, m), 7.76 (1H, d, J=2.6 Hz), 10.63 (1H, s)
240) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.65-2.2 (4H, m), 2.25-2.65 (6H, m), 2.75-4.6 (4H, m), 6.8-8.15 (11H, m)
241) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.4-2.25 (4H, m), 2.25-2.55 (3H, m), 2.7-4.8 (4H, m), 6.8-8.3 (11H, m)
242) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.4-2.1 (4H, m), 2.35-2.6 (3H, m), 2.8-5.2 (7H, m), 6.8-8.05 (11H, m)
243) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.4-2.15 (4H, m), 2.4-5.2 (7H, m), 6.8-7.85 (10H, m), 7.9-8.3 (1H, m)
244) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-2.38 (11H, m), 2.98-5.10 (3H, m), 6.45-7.04 (2H, m), 7.05-7.86 (8H, m), 8.00-8.50 (1H, m)
245) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.05-2.78 (14H, m), 2.78-5.18 (2H, m), 6.36-7.03 (2H, m), 7.06-7.90 (8H, m), 7.98-8.39 (1H, m)
246) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.75-2.54 (2H, m), 2.60-4.03 (4H, m), 3.37 (3H, brs), 5.17 (2H, s), 6.60-6.83 (3H, m), 6.90-7.07 (1H, m), 7.07-7.20 (1H, m), 7.22-7.50 (6H, m), 7.73-7.84 (1H, m)
247) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.60-2.40 (2H, m), 2.45 (3H, s), 2.65-3.06 (2H, m), 3.06-5.28 (2H, m), 3.35 (3H, brs), 6.59-7.60 (9H, m), 7.67-7.88 (1H, m), 8.12 (1H, brs)
248) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.60-2.52 (2H, m), 2.64-5.32 (4H, m), 3.37 (3H, brs), 6.60-7.98 (10H, m), 8.50 (1H, brs)
249) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.18-3.15 (12H, m), 3.40-4.38 (5H, m), 6.58-7.75 (10H, m), 8.30-8.71 (1H, m)
250) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.26-0.71 (4H, m), 1.15-3.29 (10H, m), 3.40-4.95 (5H, m), 6.60-7.85 (10H, m), 8.18-8.68 (1H, m)
251) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.25-0.72 (4H, m), 1.16-2.35 (6H, m), 2.35-3.30 (4H, m), 3.43-4.98 (2H, m), 6.57-7.94 (10H, m), 8.22-8.89 (1H, m)
252) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.69-2.90 (9H, m), 2.90-5.10 (5H, m), 6.40-7.85 (10H, m), 8.25-8.54 (1H, m)
253) .sup.1 H-NMR (CDCl.sub.3) .delta.; 2.17 (2H, brs), 2.34 (3H, s), 2.49 (3H, s), 2.87 (2H, t, J=6.0 Hz), 3.10-5.00 (2H, m), 3.70 (3H, s), 6.67 (1H, d, J=8.0 Hz), 6.85-6.88 (2H, m), 7.09 (1H, dd, J=1.5, 8.0 Hz), 7.21-7.50 (4H, m), 7.64 (1H, d, J=1.9 Hz), 8.11 (1H, m), 8.33 (1H, d, J=8.8 Hz)
254) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.42-5.06 (13H, m), 6.51 (1H, d, J=7.8 Hz), 6.76 (1H, m), 7.01-7.63 (10H, m), 8.53 (1H, m)
255) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.26-4.93 (16H, m), 6.69-7.73 (10H, m), 8.62-8.84 (1H, m)
256) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.45-1.90 (2H, m), 1.90-2.33 (2H, m), 2.33-3.25 (4H, m), 3.60-3.93 (3H, m), 4.45-5.15 (2H, m), 6.40-8.25 (11H, m)
257) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.49-1.97 (2H, m), 1.97-3.10 (3H, m), 3.58-3.98 (3H, m), 4.60-5.26 (2H, m), 6.44-8.36 (11H, m)
258) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.82-2.13 (1H, m), 2.13-2.43 (1H, m), 2.50 (3H, s), 2.57 (3H, s), 3.69-4.06 (3H, m), 3.78 (3H, s), 6.45-6.80 (2H, m), 6.85-7.00 (1H, m), 7.18-7.80 (9H, m)
259) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.72-2.05 (1H, m), 2.11-2.40 (1H, m), 2.51 (3H, s), 2.57 (3H, s), 3.40-4.20 (3H, m), 3.77 (3H, s), 6.35-6.64 (1H, m), 6.79-6.96 (1H, m), 7.15-8.13 (9H, m)
260) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.71-2.05 (1H, m), 2.07-2.32 (1H, m), 2.33 (6H, s), 2.47 (3H, s), 3.50-3.80 (2H, m), 3.76 (3H, s), 3.95-4.17 (1H, m), 6.40-6.70 (2H, m), 6.90-7.03 (1H, m), 7.14-7.77 (8H, m), 7.90-8.14 (1H, m)
261) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.76-2.70 (2H, m), 2.30 (6H, s), 2.47 (3H, s), 3.23-4.40 (3H, m), 3.73 (3H, s), 6.30-6.65 (2H, m), 6.65-8.76 (9H, m)
262) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.68-2.35 (2H, m), 2.36-5.11 �13H, m, 2.45 (3H, s), 2.92 (6H, s)!, 6.56 (1H, dd, J=3.1, 8.7 Hz), 6.78-7.06 (2H, m), 6.82 (1H, d, J=8.7 Hz), 7.11-7.68 (6H, m), 7.97 (1H, brs)
263) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.69-2.30 (2H, m), 2.59-5.10 �10H, m, 2.92 (6H, s)!, 6.56 (1H, dd, J=3.1, 8.8 Hz), 6.72-7.90 (9H, m), 8.42 (1H, brs)
264) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.49 (1H, brs), 1.82-2.01 (1H, m), 2.03-2.26 (1H, m), 2.46 (3H, s), 2.54 (3H, s), 3.67-3.76 (1H, m), 3.86 (2H, t, J=6.8 Hz), 6.67 (1H, d, J=8.6 Hz), 6.93 (1H, dd, J=8.6, 2.5 Hz), 7.13-7.43 (9H, m), 8.15 (1H, brs)
265) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.58 (1H, brs), 1.86-2.03 (1H, m), 2.08-2.30 (1H, m), 2.56 (3H, s), 3.69-3.78 (1H, m), 3.91 (2H, t, J=6.5 Hz), 6.69 (1H, d, J=8.7 Hz), 6.94 (1H, dd, J=8.6, 2.5 Hz), 7.33-7.47 (6H, m), 7.54-7.63 (2H, m), 7.67-7.77 (1H, m), 8.16 (1H, brs)
266) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.50 (1H, brs), 1.76-2.23 (2H, m), 2.42 (3H, s), 2.47 (3H, s), 3.55-3.94 (3H, m), 6.28-7.78 (10H, m), 8.91 (1H, brs)
267) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.46 (1H, brs), 1.82-2.28 (2H, m), 2.50 (3H, s), 3.52-4.08 (3H, m), 6.34-7.75 (10H, m), 8.61 (1H, brs)
268) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.80-2.31 (2H, m), 2.32 (3H, s), 2.48 (3H, s), 3.51-3.82 (2H, m), 3.95-4.15 (1H, m), 6.59 (1H, d, J=8.6 Hz), 6.90 (1H, dd, J=8.6, 2.5 Hz), 7.16-7.61 (9H, m), 7.88 (1H, brs)
269) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.86-2.04 (1H, m), 2.13-2.31 (1H, m), 2.33 (3H, s), 3.53-3.62 (1H, m), 3.76 (1H, dt, J=12.8, 6.4 Hz), 6.60 (1H, d, J=8.7 Hz), 6.91 (1H, dd, J=8.7, 2.5 Hz), 7.33-7.52 (6H, m), 7.54-7.66 (2H, m), 7.73-7.82 (1H, m), 8.07 (1H, brs)
270) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.65-2.27 (2H, m), 2.28 (6H, s), 2.48 (3H, s), 3.37-4.07 (3H, m), 6.33-7.91 (10H, m), 8.20 (1H, brs)
271) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.71-2.26 (2H, m), 2.28 (6H, s), 3.36-4.10 (3H, m), 6.35-2.95 (10H, m), 8.59 (1H, brs)
272) .sup.1 H-NMR (CDCl.sub.3) .delta.; 2.02-2.23 (2H, m), 2.28 (3H, s), 2.47 (3H, s), 2.56 (3H, s), 3.73-4.07 (3H, m), 4.68 (1H, brs), 6.61 (1H, d, J=8.1 Hz), 6.72-6.83 (1H, m), 7.17-7.63 (11H, m), 8.03 (1H, brs)
273) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.61 (1H, brs), 1.87-2.25 (2H, m), 2.29 (3H, s), 2.56 (3H, s), 3.67-3.78 (1H, m), 3.91 (2H, t, J=6.9 Hz), 6.52-6.79 (2H, m), 7.09-7.15 (1H, m), 7.30-7.90 (8H, m), 8.23 (1H, brs)
274) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.58 (1H, brs), 1.82-2.23 (2H, m), 2.27 (3H, s), 2.48 (3H, s), 2.50 (3H, s), 3.47-4.05 (3H, m), 6.23-6.83 (2H, m), 7.00-7.50 (7H, m), 7.53-7.74 (1H, m), 8.28 (1H, brs)
275) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.60 (1H, brs), 1.82-2.35 (5H, m), 2.49 (3H, s), 3.41-4.08 (3H, m), 6.30-6.80 (1H, m), 6.98-7.68 (8H, m), 7.31-7.82 (1H, m), 8.77 (1H, brs)
276) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.76-2.03 (2H, m), 2.27 (3H, s), 2.32 (6H, s), 2.47 (3H, s), 3.48-3.58 (1H, m), 3.66 (1H, dt, J=12.7, 6.1 Hz), 3.97-4.14 (1H, m), 6.48 (1H, d, J=8.2 Hz), 6.65-6.77 (1H, m), 7.14-7.59 (9H, m), 7.96 (1H, brs)
277) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.75-2.04 (2H, m), 2.27 (3H, s), 2.33 (6H, s), 3.48-3.58 (1H, m), 3.67 (1H, dt, J=12.7, 6.1 Hz), 3.98-4.16 (1H, m), 6.48 (1H, d, J=8.2 Hz), 6.72 (1H, dd, J=8.2, 1.9 Hz), 7.16 (1H, d, J=1.9 Hz), 7.27-7.91 (8H, m), 8.31 (1H, brs)
278) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.72-2.05 (2H, m), 2.28 (9H, s), 2.47 (3H, s), 3.16-4.34 (3H, m), 6.38-7.79 (10H, m), 8.37 (1H, brs)
279) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.65-2.07 (2H, m), 2.28 (9H, s), 3.26-4.38 (3H, m), 6.34-8.06 (10H, m), 8.53 (1H, brs)
280) Two stereoisomers: Both colorless amorphous
Isomer A
�.alpha.!.sub.D.sup.22 =0.degree. (chloroform, c=1.0)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.04 (3H, d, J=6.9 Hz), 1.59 (1H, brs), 2.25-2.45 (1H, m), 2.49 (3H, s), 2.52 (3H, s), 3.53-3.69 (2H, m), 3.91 (1H, abq, J=7.2, 12.9 Hz), 6.60 (1H, d, J=8.6 Hz), 6.93 (1H, dd, J=8.6, 2.5 Hz), 7.18-7.60 (9H, m), 7.76 (1H, brs)
Isomer B
�.alpha.!.sub.D.sup.22 =0.degree. (chloroform, c=1.0)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.06 (3H, d, J=6.9 Hz), 1.60 (1H, brs), 2.21-2.43 (1H, m), 2.47 (3H, s), 2.52 (3H, s), 3.51-3.66 (2H, m), 3.93 (1H, abq, J=7.5, 12.9 Hz), 6.60-6.68 (1H, m), 6.95 (1H, dt, J=7.5, 1.8 Hz), 7.03 (1H, dt, J=7.4, 1.4 Hz), 7.17-7.55 (8H, m), 7.81 (1H, brs)
281) Two stereoisomers: Both colorless amorphous
Isomer A
�.alpha.!.sub.D.sup.22 =0.degree. (chloroform, c=1.0)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.04 (3H, d, J=6.9 Hz), 1.55 (1H, brs), 2.23-2.46 (1H, m), 2.53 (3H, s), 3.53-3.67 (2H, m), 3.91 (1H, abq, J=7.1, 12.9 Hz), 6.61 (1H, d, J=8.6 Hz), 6.93 (1H, dd, J=8.6, 2.5 Hz), 7.28-7.52 (6H, m), 7.54-7.65 (2H, m), 7.70-7.79 (1H, m), 8.16 (1H, brs)
Isomer B
�.alpha.!.sub.D.sup.22 =0.degree. (chloroform, c=1.0)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.06 (3H, d, J=6.9 Hz), 1.61 (1H, brs), 2.21-2.42 (1H, m), 2.51 (3H, s), 3.48-3.67 (2H, m), 3.90 (1H, abq, J=7.4, 12.9 Hz), 6.59-6.67 (1H, m), 6.94 (1H, dt, J=7.5, 1.9 Hz), 7.03 (1H, dt, J=7.4, 1.4 Hz), 7.23-7.75 (8H, m), 8.41 (1H, brs)
282) Two stereoisomers: Both colorless amorphous
Isomer A
�.alpha.!.sub.D.sup.22 =0.degree. (chloroform, c=1.0)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 0.99 (3H, d, J=6.5 Hz), 1.37 (1H, brs), 2.16-2.40 (1H, m), 2.46 (3H, s), 2.48 (3H, s), 3.38-3.96 (3H, m), 6.30-7.28 (10H, m), 8.26 (1H, brs)
Isomer B
�.alpha.!.sub.D.sup.22 =0.degree. (chloroform, c=1.0)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.03 (3H, d,J=6.7 Hz), 1.44 (1H, brs), 2.17-2.40 (1H, m), 2.45 (3H, s), 2.47 (3H, s), 3.40-3.98 (3H, m), 6.47-7.73 (10H, m), 8.23 (1H, brs)
283) Two stereoisomers: Both colorless amorphous
Isomer A
�.alpha.!.sub.D.sup.22 =0.degree. (chloroform, c=1.0)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.00 (3H, d, J=6.6 Hz), 1.40 (1H, brs), 2.18-2.42 (1H, m), 2.47 (3H, s), 3.36-4.02 (3H, m), 6.32-7.78 (10H, m), 8.55 (1H, brs)
Isomer B
�.alpha.!.sub.D.sup.22 =0.degree. (chloroform, c=1.0)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.03 (3H, d, J=6.5 Hz), 1.39 (1H, brs), 2.14-2.39 (1H, m), 2.45 (3H, s). 3.34-3.98 (3H, m), 6.53-7.98 (10H, m), 8.78 (1H, brs)
284) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.05-1.25 (3H, m), 1.25-2.80 (10H, m), 3.00-5.10 (3H, m), 6.75-8.40 (11H, m)
285) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.00-2.80 (12H, m), 3.00-5.10 (3H, m), 6.70-7.80 (10H, m), 8.30-8.80 (1H, m)
286) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.95-2.80 (15H, m), 2.80-5.15 (3H, m), 6.70-7.05 (2H, m), 7.10-7.80 (10H, m), 7.95-8.45 (1H, m)
287) .sup.1 H-NMR (CDCl.sub.3) .delta.; 0.80-2.60 (16H, m), 2.60-5.05 (4H, m), 6.70-7.70 (10H, m), 7.85-8.40 (1H, m)
288) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.30-2.60 (8H, m), 2.60-5.10 (3H, m), 6.60-7.95 (10H, m), 8.25-8.70 (1H, m)
289) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.27-4.91 (19H, m), 6.68-7.73 (10H, m), 8.40-8.71 (1H, m)
290) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.81-2.54 (6H, m), 2.15 (3H, s), 2.41 (3H, s), 2.46 (3H, s), 3.61-3.71 (3H, m), 6.91-7.43 (10H, m), 8.60 (1H, s)
291) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.86-2.50 (3H, m), 2.28 (9H, s), 2.49 (3H, s), 6.60-7.47 (10H, m), 7.75 (1H, m)
292) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.15-2.55 (13H, m), 2.55-5.10 (3H, m), 6.60-8.40 (11H, m)
293) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.15-2.45 (10H, m), 2.55-5.10 (3H, m), 6.60-7.80 (10H, m), 8.30-8.70 (1H, m)
294) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-2.60 (4H, m), 2.41 (6H, s), 2.49 (3H, s), 3.76 (3H, s), 2.60-5.20 (3H, m), 6.50-6.80 (3H, m), 6.90-7.60 (6H, m), 8.13 (1H, s), 8.30 (1H, d, J=8.5 Hz)
295) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.15-2.50 (4H, m), 2.41 (6H, s), 2.60-5.20 (3H, m), 3.77 (3H, s), 6.50-7.50 (8H, m), 7.65-7.80 (1H, m), 8.31 (1H, d, J=8.4 Hz), 8.61 (1H, s)
296) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.55-3.13 (12H, m), 2.44 (3H, s), 4.60-5.14 (2H, m), 6.28 (1H, dd, J=2.5, 8.5 Hz), 6.48 (1H, d, J=8.5 Hz), 6.99 (1H, d, J=2.5 Hz), 7.07-7.58 (8H, m), 7.80 (1H, brs)
297) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.01-2.88, 3.22-4.41, 4.90-5.28 �total 18H, 1.17 (3H, t, J=7.2 Hz), 2.40 (3H, s), 3.77 (3H, s)!, 6.55 (1H, d, J=8.1 Hz), 6.60-7.98 (8H, m), 8.23-8.75 (2H, m)
298) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.00-3.04, 3.24-4.45. 4.91-5.27 �total 21H, m, 1.17 (3H, t, J=7.0 Hz), 2.39 (3H, s), 2.50 (3H, s), 3.75 (3H, s)!, 8.56 (1H, d, J=8.3 Hz), 6.69 (1H, d, J=8.3 Hz), 6.82-7.75 (7H, m), 8.05-8.49 (2H, m)
299) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.21-4.62, 4.90-5.43 (total 15H, m), 5.70-6.11 (1H, m), 6.35-7.90 (9H, m), 8.07-8.92 (2H, m)
300) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-4.68, 5.01-5.3 �total 18H, m, 2.50 (3H, s)!, 5.72-6.14 (1H, m), 6.49-7.69 (9H, m), 8.01-8.58 (2H, m)
301) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.25-2.80 (14H, m), 3.00-5.10 (6H, m), 6.40-8.00 (11H, m)
302) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.30-2.90 (11H, m), 3.00-5.10 (6H, m), 6.40-7.80 (10H, m), 8.00-8.35 (1H, m)
303) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-2.80 (16H, m), 2.85-5.15 (6H, m), 6.40-7.80 (11H, m)
304) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.10-2.80 (13H, m), 2.90-5.10 (6H, m), 6.40-7.85 (10H, m), 7.90-8.20 (1H, m)
305) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.27-5.28 (19H, m), 3.75 (3H, s), 6.51 (1H, d, J=7.9 Hz), 6.69-6.81 (2H, m), 7.05-7.49 (6H, m), 8.14 (1H, m), 8.27 (1H, d, J=8.4 Hz)
306) Two stereoisomers: Both colorless amorphous
Isomer A
�.alpha.!.sub.D.sup.22 =0.degree. (chloroform, c=1.0)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 0.78-1.02 (3H, m), 2.23-2.52 (1H, m), 2.39 (6H, s), 2.48 (3H, s), 3.17-4.30 (3H, m), 6.85-7.84 (10H, m), 8.17 (1H, brs)
Isomer B
�.alpha.!.sub.D.sup.22 =0.degree. (chloroform, c=1.0)
.sup.1 H-NMR (CDCl.sub.3) .delta.; 0.73-1.00 (3H, m), 2.17-2.52 (1H, m), 2.39 (6H, s), 2.49 (3H, s), 3.15-4.33 (3H, m), 6.36-7.55 (8H, m), 7.58-7.83 (2H, m), 8.19 (1H, brs)
307) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.25-4.44, 4.98-5.41 �total 17H, m, 2.40 (3H, s), 3.76 (3H, s)!, 5.72-6.13 (1H, m), 6.56 (1H, d, J=8.4 Hz), 6.69 (1H, d, J=7.9 Hz), 6.77-7.93 (7H, m), 8.32 (1H, d, J=8.3 Hz), 8.49-8.95 (1H, m)
308) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.23-5.42 (20H, m), 5.78-6.09 (1H, m), 6.56 (1H, d, J=8.3 Hz), 6.61-7.82 (8H, m), 8.14 (1H, s), 8.30 (1H, d, J=8 Hz)
309) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-2.70 (11H, m), 2.80-4.90 (9H, m), 6.40-7.70 (10H, m), 8.30-8.70 (1H, m)
310) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-2.80 (8H, m), 2.85-5.05 (9H, m), 6.40-7.80 (10H, m), 8.10-8.50 (1H, m)
311) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-2.75 (13H, m), 2.80-5.10 (9H, m), 6.40-8.00 (11H, m)
312) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-2.80 (10H, m), 2.90-5.10 (9H, m), 6.40-7.80 (10H, m), 8.00-8.40 (1H, m)
Example 1189
By using di-p-toluoyl-L-tartaric acid monohydride or di-p-toluoyl-D-tartaric acid monohydride, the compound obtained in above Example 408 is optically resolved to give the following compounds.
(+)-5-Dimethylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride White amorphous
�.alpha.!.sub.D.sup.25 =+234.degree. (methanol, c=0.2)
Purity; more than 99% ee, determined by HPLC using an optical active column
HPLC conditions;
Mobile phase; n-hexane:ethanol:diethylamine=950:50:1
Flow rate; 1.0 ml/min.
Column; CHIRALCEL OD, 25 cm.times.0.46 cm (manufactured by Daicel Chemical Ind. Ltd.)
Concentration of sample; 0.1% in methanol
Retention time; 34 minutes
.sup.1 H-NMR (DMSO-d.sub.6) .delta.; 0.85-1.20, 1.56-4.06, 4.94-5.21 (total 13H, m), 2.36 (3H, s), 6.79 (1H, d, J=7.6 Hz), 7.12-7.60 (8H, m), 7.62 (2H, d, J=8.4 Hz), 8.00 (1H, d, J=7.6 Hz), 10.43 (1H, s), 11.80 (1H, brs)
(-)-5-Dimethylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride White amorphous
�.alpha.!.sub.D.sup.25 =-23.1.degree. (methanol, c=0.2)
Purity; more than 99% ee, determined by HPLC using an optical active column, and the conditions are the same as above except that the retention time is 40 minutes.
.sup.1 H-NMR (DMSO-d.sub.6) .delta.; 0.83-1.19, 1.55-4.06, 4.94-5.20 (total 13H, m), 2.36 (3H, s), 6.80 (1H, d, J=7.8 Hz), 7.12-7.60 (8H, m), 7.63 (2H, d, J=8.5 Hz), 8.00 (1H, d, J=7.8 Hz), 10.44 (1H, s), 11.74 (1H, brs)
Pharmacological Test
Experiment 1: V.sub.1 receptor binding assay
Using rat liver plasma membrane preparations prepared according to Ichihara's method �cf: Akira Ichihara, J. Bio. Chem., 258, 9283 (1983)!, the plasma membrane ((50000 dpm, 2.times.10.sup.-10 M) of �.sup.3 H!-Arg-vasopressin and a test compound (60 .mu.g, 10.sup.-8 -10.sup.-4 M) are incubated at 37.degree. C. for 10 minutes in 100 mM Tris-HCl buffer (pH: 8.0, 250 .mu.l) containing 5 mM MgCl.sub.2, 1 mM EDTA and 0.1% BSA. After incubation, the mixture is filtered three times using the glass filter (GF/F) so as to separate the membrane preparation combined with vasopressin and then washed with the buffer (5 ml). This glass filter is taken out and mixed with liquid scintillation cocktail. The amount of �.sup.3 H!-vasopressin combined with the membrane is measured by liquid scintillation counter and the rate of the inhibitory effect of the test compound is estimated according to the following equation. ##EQU1## C.sup.1 : The amount of �.sup.3 H!-vasopressin combined with the membrane in the presence of the test compound (in prescribed amount).
C.sup.0 : The amount of �.sup.3 H!-vasopressin combined with the membrane in the absence of the test compound.
B.sup.1 : The amount of (.sup.3 H!-vasopressin combined with the membrane in the presence of the excess amount of vasopressin (10.sup.-6 M).
The results are expressed as IC.sub.50 values, which is the concentration of the test compound required to achieve the inhibitory effect in the rate of 50%.
The results are shown in the following Table 10.
Test compound
1. 1-(4-Benzoylaminobenzoyl)-1,2,3,4-tetrahydroquinoline
2. 1-�4-(3-Chlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
3. 1-�4-(3-Methoxybenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
4. 1-�4-(3-Cyanobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
5. 1-�4-(3-Aminobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
6. 1-�4-(2,3-Dimethylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
7. 1-�4-(2-Methylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
8. 1-�4-(2-Trifluoromethylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
9. 1-�4-(2-Nitrobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
10. 1-�4-(3,5-Dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
11. 1-�4-(3,3-Dimethylbutyrylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
12. 1-�4-(2-Cyclohexylacetylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
13. 1-�4-(2-Phenylacetylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
14. 1-(4-Cyclohexylcarbonylaminobenzoyl)-1,2,3,4-tetrahydroquinoline
15. 1-(4-Cycloheptylcarbonylaminobenzoyl)-1,2,3,4-tetrahydroquinoline
16. 1-(4-Cyclooctylcarbonylaminobenzoyl)-1,2,3,4-tetrahydroquinoline
17. 1-(4-Tricyclo�3.3.1.1!decanylcarbonylaminobenzoyl)-1,2,3,4-tetrahydroquinoline
18. 1-(4-(.alpha.-Naphthylcarbonylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
19. 1-�4-(3-Thenoyl)benzoyl!-1,2,3,4-tetrahydroquinoline
20. 1-�2-(.beta.-Naphthylcarbonylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
21. 1-�4-(4-Methoxyanilinocarbonyl)benzoyl!-1,2,3,4-tetrahydroquinoline
22. 1-�4-(2-Methylanilinocarbonyl)benzoyl!-1,2,3,4-tetrahydroquinoline
23. 1-�4-(3-Chloroanilinocarbonyl)benzoyl!-1,2,3,4-tetrahydroquinoline
24. 1-�4-(3,5-Dichloroanilinocarbonyl)benzoyl!-1,2,3,4-tetrahydroquinoline
25. 1-(4-Cyclohexylaminocarbonylbenzoyl)-1,2,3,4-tetrahydroquinoline
26. 1-(4-Cyclohexylcarbonylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine
27. 1-(4-Benzoylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine
28. 1-�4-(2-Methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
29. 1-�4-(3-Methoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
30. 1-�4-(3-Chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
31. 1-�4-(3-Cyanobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
32. 1-�4-(3,5-Dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
33. 1-�4-(2,3-Dimethylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
34. 1-(4-Cyclohexylcarbonylaminobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine
35. 1-(4-Benzoylaminobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine
36. 1-�4-(2-Methylbenzoylamino)benzoyl!-1,2,3,4,5,6-hexahydrobenzazocine
37. 1-�4-(3-Methoxybenzoylamino)benzoyl!-1,2,3,4,5,6-hexahydrobenzazocine
38. 1-�4-(2,3-Dimethylbenzoylamino)benzoyl!-1,2,3,4,5,6-hexahydrobenzazocine
39. 1-�4-(3,5-Dichlorobenzoylamino)benzoyl!-1,2,3,4,5,6-hexahydrobenzazocine
40. 1-(4-Cyclohexylcarbonylaminobenzoyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine
41. 1-(4-(3-Methylbenzoylamino)benzoyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine
42. 1-�4-(2,3-Dimethylbenzoylamino)benzoyl!-1,2,3,5-tetrahydro-4,1-benzoxazepine
43. 1-�4-(3,5-Dichlorobenzoylamino)benzoyl!-1,2,3,5-tetrahydro-4,1-benzoxazepine
44. 3-Methyl-1-(4-cyclohexylcarbonylaminobenzoyl)-1,2,3,4-tetrahydroquinoline
45. 3-Methyl-1-(4-benzoylaminobenzoyl)-1,2,3,4-tetrahydroquinoline
46. 3-Methyl-1-�4-(2-methylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
47. 3-Methyl-1-�4-(3-methoxybenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
48. 3-Methyl-1-�4-(2,3-dimethylbenzoylamino)-benzoyl!-1,2,3,4-tetrahydroquinoline
49. 3-Methyl-1-�4-(3,5-dichlorobenzoylamino)-benzoyl!-1,2,3,4-tetrahydroquinoline
50. 4-Methyl-1-(4-cyclohexylcarbonylaminobenzoyl)-1,2,3,4-tetrahydroquinoxalin
51. 4-Methyl-1-�4-(2-methylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoxaline
52. 4-Methyl-1-�4-(2,3-dimethylbenzoylamino)-benzoyl!-1,2,3,4-tetrahydroquinoxaline
53. 4-Methyl-1-�4-(3,5-dichlorobenzoylamino)-benzoyl!-1,2,3,4-tetrahydroquinoxaline
54. 2-Methyl-1-�4-(3,5-dichlorobenzoylamino)-benzoyl!-1,2,3,4-tetrahydroquinoline
55. 4-Methyl-1-�4-(3,5-dichlorobenzoylamino)-benzoyl!-1,2,3,4-tetrahydroquinoline
56. 1-�4-(2-Bromobenzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine
57. 1-�4-(3-Nitrobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
58. 1-�4-(3-Trifluoromethylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
59. 1-�4-(3-Ethoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
60. 1-�4-(3,5-Dimethoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
61. 1-�4-(2-Chloro-4-nitrobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
62. 1-�4-(2,4-Dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
63. 1-�4-(2-Chloro-6-fluorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
64. 1-�4-(2,6-Dimethylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
65. 1-�4-(2-Chloro-4-aminobenzoylamino)benzoyl!-2,3,4,5 -tetrahydro-1H-benzazepine
66. 1-�4-(2-Chloro-4-acetylaminobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
67. 1-�4-(3-Aminobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
68. 1-{4-�2-(4-Isopropylaminobutoxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride
69. 1-�4-(3-Hydroxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
70. 1-{4-�2-(4-Aminobutoxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
71. 1-{4-�2-(2-Diethylaminoethoxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride
72. 1-{4-�2-(4-Acetylaminobutoxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
73. 1-{4-�2-(6-Phthalimidohexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
74. 1-{4-�2-(6-Morpholinohexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
75. 1-{4-�2-(6-�4-Methyl-1-piperazinyl!hexyloxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepinedihydrochloride
76. 1-(3-Methoxy-4-cyclohexylcarbonylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine
77. 1-(3-methoxy-4-benzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
78. 1-�3-Methyl-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
79. 4-Methyl-1-(4-cyclohexylcarbonylaminobenzoyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine hydrochloride
80. 4-Methyl-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine hydrochloride
81. 4-Methyl-1-�4-(2,3-dimethylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine hydrochloride
82. 4-Methyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine hydrochloride
83. 4-Methyl-1-�4-(3-methoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
84. 4-Methyl-1-�4-(3-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
85. 4-Methyl-1-�4-(2,3,5-trichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
86. 4-Propyl-1-�4-(2,3-dimethylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine hydrochloride
87. 5-Methyl-1-(4-benzoylaminobenzoyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
88. 5-Methyl-1-(4-cyclohexylcarbonylaminobenzoyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
89. 5-Methyl-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
90. 5-Methyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
91. 5-Methyl-1-�4-(2,3-dimethylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine
92. 4-Methyl-1-�3-methoxy-4-(3,5-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
93. 3-(1-Pyrrolidinyl)-1-�4-(2,3-dimethylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
94. 6-Methyl-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
95. 6-Methoxy-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
96. 3-Hydroxymethyl-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
97. 4-Methylamino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
98. 3-Amino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
99. 3-Acetylamino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
100. 4-Dimethylamino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
101. 1-�4-(2-t-Butylaminoacetylamino)benzoyl!-2,3,4,5-tetrahydroquinoline-1H-benzazepine
102. 1-{4-�2-(N-Cyclohexyl-N-ethyl)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
103. 1-{4-�2-(1-Piperidinyl)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
104. 1-�4-(2-Phenoxyacetylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
105. 1-�4-(2-Phthalimidoacetylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
106. 1-{4-�2-(1,1-Dimethyl-2-phenoxyethyl)aminoacetylamino!benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine
107. 1-{4-�2-(3-Methylphenoxy)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
108. 1-{4-�2-(3-Methoxyanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
109. 1-{4-�2-(.beta.-Naphthyloxy)acetyamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
110. 1-{4-�2-(4-Methylanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
111. 1-{4-�2-(3-Methoxyphenoxy)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
112. 1-�4-(4-Pyridylcarbonylaminobenzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
113. 1-{4-�2-(2,4-Dimethylanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
114. 1-{4-�2-(N-Ethylanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
115. 1-{4-�2-(N-Allylanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
116. 1-{4-�2-(2-Chloroanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
117. 1-{4-�2-(4-Acetyloxybutoxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
118. 1-�4-(2-Carboxymethoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
119. 1-�4-(2-Carbamoylmethoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
120. 1-{4-�2-(4-Hydroxybutoxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
121. 1-�4-(2-Ethoxycarbonylmethoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
122. 6-Fluoro-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
123. 6-Fluoro-1-{4-�di-(3,5-dichlorobenzoyl)amino!benzoyl}-1,2,3,4-tetrahydroquinoline
124. 1-�4-(2-Diethylaminocarbonylmethoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
125. 1-{4-�2-(2-�(N-(2-hydroxyethyl)-N-methylamino!ethoxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine hydrochloride
126. 1-�4-(2-Methylanilinocarbonylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
127. 1-�4-(2-Chlorophenylsulfonylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
128. 1-{4-�2-(4-Aminomethylanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
129. 1-{4-�2-(N-Phenyl-N-(3-acetylaminopropyl)amino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
130. 1-{4-�2-(N-Phenyl-N-propargylamino)acetyl-amino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
131. 4-(N-Methyl-N-ethylamino)-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
132. 5-Dimethylamino-1-�4-(2,4-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
133. 4-Dimethylamino-1-�3-methoxy-4-(2-methylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
134. 5-Dimethylamino-1-�3-methoxy-4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
135. 1-�4-(2,3-Dimethylbenzoylamino)benzoyl!-4-ethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
136. 1-�4-(3,5-Dichlorobenzoylamino)benzoyl!-4-isopropyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
137. 1-�4-(2-Methylbenzoylamino)benzoyl!-5-methyl-1,2,3,4,5,6-hexahydro-1,5-benzodiazocine
138. 1-�4-(2-Methylbenzoylamino)benzoyl!-1,2,3,4-tetrahydro-5,1-benzoxazepine
139. 5-Oxo-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
140. 4-Methyl-1-�2-chloro-4-(3,5-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
141. 5-Methylamino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
142. 5-(N-Acetyl-N-methylamino)-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
143.5-Hydroxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
144. 4-Dimethylamino-1-�3-methoxy-4-(2,3-dimethylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
145. 4-Dimethylaminomethyl-1-�4-(2-methylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
146. 4-Dimethylaminomethyl-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
147. 5-Methoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
148. 4-Methyl-1-�3-methyl-4-(2,4-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine
149. 5-Methoxy-1-�4-(2,4-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
150. 4-Dimethylamino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
151. 4-Acetyloxy-1-�4-(2-methylbenzoylamino)benzoyl!-1,2,3,4-tetrahydroquinoline
152. 5-Hydroxyimino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
153. 5-Acetyloxy-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
154. 5-Ethoxycarbonylmethoxy-1-�4-(2,4-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
155. 4-Allylamino-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
156. 5-Dimethylamino-1-�3-methoxy-4-(2,3,5-trichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
157. 4-�4-(2-Methylbenzoylamino)benzoyl!-3,4-dihydro-2H-1,4-benzothiazine
158. 5-Dimethylamino-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
159. 5-Dimethylamino-1-�4-(2-methylanilinocarbonyl)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
160. 5-Ethoxycarbonylmethoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
161. 5-(4-dimethylaminobutoxy)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
162. 5-Carboxymethoxy-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
163. 5-Dimethylaminocarbonylmethoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
164. 5-Carbamoylmethoxy-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
165. 5-Dimethylamino-1-�3-ethoxy-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
166. 5-�4-(2-Methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1,5-benzothiazepine
167. 5-Amino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
168. 5-Dimethylamino-1-�3-hydroxy-4-�2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
169. 5-n-Propylamino-1-�4-(2,4-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
170. 5-Dimethylamino-1-�3-benzyloxy-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
171. 5-�4-(2-Methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1,5-benzothiazepin-1-oxide
172. 5-�3-(Phthalimid-1-yl)-propoxy!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
173. 5-(3-Aminopropoxy)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
174. 5-(3-Acetylaminopropoxy)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
175. 5-Dimethylamino-1-�2-chloro-4-(2-t-butylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
176. 5-Methylamino-1-�2-chloro-4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
177. 5-Dimethylamino-1-�2-methoxy-4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
178. 5-Hydroxy-1-�4-(3,5-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
179. 5-Dimethylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
180. 5-Dimethylamino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
181. 5-Methylamino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
182. 5-Methylamino-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
183. 5-Dimethylamino-1-�2-methoxy-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
184. 5-Dimethylamino-1-�2-chloro-4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
185. 5-Methylamino-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl-2,3,4,5-tetrahydro-1H-benzazepine
186. 5-Cyclopropylamino-1-�2-chloro-4-(2,4-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
187. 5-Dimethylaminocarbonyloxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
188. 5-Dimethylamino-1-�4-(2-trifluoromethylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
189. 5-Dimethylamino-1-�3-(2-chlorobenzoyloxy)-4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
190. 5-(N-Methyl-N-Allylamino)-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
191. 5-Carbamoyloxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
192. 1-�4-(2-Methylbenzoylamino)benzoyl!-1,2,3,5-tetrahydro-4,1-benzothiazepine
193. 4-Oxo-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
194. 1-�4-(2-Methylbenzoylamino)benzoyl!-1,2,3,5-tetrahydro-4,1-benzothiazepine-1,1-dioxide
195. 5-Methylaminocarbonylmethoxy-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
196. 5-Methylaminocarbonyloxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahyro-1H-benzazepine
197. 5-Dimethylamino-1-�2-dimethylamino-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
198. 5-Methylamino-1-�2-chloro-4-(2-trifluoromethylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
199. 5-Cyclopropylamino-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
200. 5-Cyclopropylamino-1-�2-chloro-4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
201. 5-Allylamino-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
202. 5-(1-Piperidinyl)-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
203. 5-(4-Benzyl-1-piperazinyl)-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
204. 5-(1-Pyrrolidinyl)-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
205. 5-(4-Acetyl-1-piperazinyl)-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
206. 5-(4-Methyl-1-piperazinyl)-1-(4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
207. 1-�4-(2-Chlorobenzoylamino)benzoyl!-2,3-dihydro-1H-benzazepine
208. 5-Methyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
209. 5-Methylidene-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
210. 5-Hydroxy-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
211. 5-(1-Morpholino)-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
212. 5-Dimethylamino-1-�4-(2-fluorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
213. 5-Dimethylamino-1-�4-(2,4-difluorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
214. 4-Hydroxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
215. 5-Hydroxymethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
216. 5-Dimethylamino-4-hydroxy-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
217. 1-�4-(2-Methylbenzoylamino)benzoyl!-1,2-dihydroquinoline
218. 5-Dimethylamino-1-�2-methyl-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine (the compound of Example 979)
219. 5-Dimethylamino-1-�2-methyl-4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
220. 5-Dimethylamino-1-�2-methyl-4-(2,4-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
221. 5-Methylamino-1-{2-chloro-4-�2-(N-ethylanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
222. 5-Hydroxy-1-{2-chloro-4-�2-(N-ethylanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
223. 5-Dimethylamino-1-�2-fluoro-4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
224. 5-Methylamino-4-hydroxy-1-�2-chloro-4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine.hydrochloride
225. 5-Hydroxymethyl-5-hydroxy-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
226. 5-Dimethylamino-1-�2-fluoro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
227. 5-Dimethylamino-1-�3-methyl-4-(2,4-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
228. 5-(N-Methyl-N-ethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
229. 5-Ethylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
230. 5-Dimethylamino-1-�4-(3,5-difluorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
231. 5-Acetyloxymethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
232. 5-Dimethylamino-1-�3-fluoro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
233. 4,4-Dimethoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
234. 5-Acetyloxyimino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
235. 5-Methylsulfonyloxymethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
236. 5,5-Epoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
237. 5-Hydroxymethyl-5-hydroxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
238. 5-Hydroxy-1-�2-methoxy-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
239. 5-Dimethylamino-1-�4-(2-carbamoylmethoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
240. 5-Hydroxy-6-methyl-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
241. 5-(2-Dimethylaminoethyl)amino-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
242. 5-Hydroxymethyl-5-methylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
243. 5-Methylaminomethyl-5-hydroxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
244. 5-Aminomethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
245. 5-�N-Methyl-N-(3-methoxy-2-hydroxypropyl)amino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
246. 5-�N-Methyl-N-(3-diethylamino-2-hydroxypropyl)amino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
247. 5-Dimethylamino-1-�3-methoxy-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
248. 5-Dimethylamino-1-�3-methoxy-4-(2,4-dichlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
249. 5-Dimethylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine.hydrochloride
250. 5-Azidomethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
251. 7-�4-(2-Chlorobenzoylamino)benzoyl!-1-methyl-1,2,3,4a,5,6,7,11b-octahydro-3-oxo�1!benzazepino�4,5-b!-�1,4!oxazine
252. 5-Benzylamino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
253. 5-Amino-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
254. 5-Dimethylamino-4-methyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
255. 5-Acetylaminomethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
256. 5-Hydroxy-4-methyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
257. 5-�2-(2-Pyridyl)ethylamino!-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
258. 5-(N-Methyl-N-methanesulfonylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
259. 5-(N-Methyl-N-benozylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
260. 5-Ethoxycarbonylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
261. 5-Methyl-5-hydroxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
262. 5-(N-Methyl-N-ethoxycarbonylmethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
263. 5-Cyclopentylamino-1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
264. 5-�N-Methyl-N-(2,3-dihydroxypropyl)amino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
265. 5-(N-Methyl-N-cyanomethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
266. 5-(N-Methyl-N-carbamoylmethylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
267. 5-{N-Methyl-N-�3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl!amino}-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
268. 5-Dimethylaminomethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
269. 5-Formylaminomethyl-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
270. 5-�N-Methyl-N-(3-acetyloxypropyl)amino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
271. 5-�N-Methyl-N-(3-hydroxypropyl)amino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
272. Potassium {1-�2-chloro-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepin-5-yl}imino-o-sulfonate
273. 5-Dimethylamino-1-(4-benzoylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine
274. 5-(1-Benzyl-4-piperidinyl)amino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
275. 5-(2-Dimethylaminoacetyloxy)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
276. 5-Dimethylamino-1-�4-(3-methoxybenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
277. 5-�(4-Methyl-1-piperazinyl)carbonylmethoxy!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
278. 5-Morpholinocarbonylmethoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
279. 5-Thiomorpholinocarbonylmethoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
280. 5-Anilinocarbonylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
281. 5-(1-Oxothiomorpholino)carbonylmethoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
282. 5-Hydrazino-1-(4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
283. 5-Methylaminocarbonylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
284. 5-�(2-.alpha.-Carbamoyl-1-pyrrolidinyl)carbonylmethoxy!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
285. 5-(Carbamoylmethylaminocarbonylmethoxy)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
286. 5-(1,1-Dioxothiomorpholino)carbonylmethoxy-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
287. 7-Chloro-5-methylamino-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
288. 5-�(4-Acetyl-1-piperazinyl)carbonylmethoxy!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
289. 5-Dimethylamino-1-�4-(3-nitrobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
290. 5-�(4-Pyridyl)methylaminocarbonylmethoxy!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
291. 5-�2-(Methylamino)acetylamino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
292. 5-Dimethylamino-1-�4-(3-aminobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
293. 5-{�N-Methyl-N-(2-hydroxyethyl)amino!carbonylmethoxy}-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
294. 5-Dimethylamino-1-�3-(2-diethylaminoethoxy)-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
295. 5-�N-Methyl-N-(dimethylaminocarbonylmethyl)amino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
296. Potassium 2-�N-methyl-N-{1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepin-5-yl}amine!acetate
297. 5-{N-Methyl-N-�2-(1-imidazolyl)acetyl!amino}-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
298. 5-Dimethylamino-1-�4-(2-dimethylaminobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
299. 5-�(2-Aminoacetyl)amino!-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
300. 5-Dimethylamino-1-�4-(3-acetylaminobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
301. 5-(2-t-Butoxycarbonylaminoacetylamino)-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
302. 5-Methylamino-7-chloro-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
303. 5-Dimethylamino-7-chloro-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
304. 5-Dimethylamino-7-chloro-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
305. 5-Dimethylamino-1-�4-(phenylacetylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
306. 5-Dimethylamino-1-�4-(3-phenylpropionylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
307. 5-Methylamino-7-chloro-1-{4-�(N-ethylanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
308. 5-Dimethylamino-7-chloro-1-{4-�(N-ethylanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
309. 5-Dimethylamino-1-�4-(2-bromobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
310. 5-Cyclopropylamino-7-chloro-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
311. 5-Cyclopropylamino-7-chloro-1-�4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
312. 5-hydroxy-1-{4-�2-(4-isopropylaminobutoxy)benzoylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
313. 5-Dimethylaminocarbonylmethoxy-1-{4-�(N-ethylanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
314. 5-(N-Methyl-N-ethylamino)-1-�2-chloro-4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
315. 5-Dimethylamino-1-{4-�(2-chloroanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
316. 5-Dimethylamino-1-{4-�(2-methylanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
317. 5-Dimethylamino-1-{4-�(N-methyl-2-methylanilino)acetylamino!benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine
318. 5-Methylamino-9-chloro-1-�4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
319. 5-Dimethylamino-1-�4-(phenoxyacetylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
320. 6-Methylamino-1-�4-(2-methylbenzoylamino)benzoyl!-1,2,3,4,5,6-hexahydrobenzazocine
321. 5-Methylamino-7-chloro-1-�3-methoxy-4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
322. 5-Cyclopropylamino-7-chloro-1-�3-methoxy-4-(2-chlorobenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
323. 5-Methylamino-7-chloro-1-�3-methoxy-4-(2-methylbenzoylamino)benzoyl!-2,3,4,5-tetrahydro-1H-benzazepine
TABLE 10______________________________________Test TestComp. IC.sub.50 Comp. IC.sub.50No. (.mu.M) No. (.mu.M)______________________________________26 0.071 78 0.1027 0.095 88 0.3428 0.056 90 0.3829 0.15 114 0.01130 0.15 115 0.01232 0.30 116 0.0433 0.092 117 0.2236 0.41 119 0.04946 0.40 120 0.2956 0.025 121 0.4557 0.46 124 0.1558 0.40 125 0.09159 0.31 130 0.02360 0.18 143 0.1562 0.098 147 0.2863 0.14 161 0.1464 0.069 163 0.2267 0.34 164 0.1568 0.013 172 0.2669 0.066 173 0.1570 0.041 174 0.1471 0.18 187 0.4572 0.12 188 0.4774 0.10 192 0.05475 0.069 193 0.1776 0.042 195 0.1777 0.085 196 0.40207 0.16 284 0.29208 0.11 285 0.18209 0.074 286 0.40214 0.27 287 0.064215 0.13 288 0.26222 0.096 290 0.21231 0.16 293 0.19235 0.088 298 0.29236 0.16 302 0.071238 0.39 303 0.19244 0.23 304 0.21250 0.19 307 0.024252 0.36 308 0.11255 0.046 309 0.43256 0.049 310 0.065266 0.29 311 0.078269 0.48 312 0.056274 0.11 313 0.032275 0.18 315 0.38277 0.23 316 0.47278 0.30 321 0.059279 0.15 322 0.044280 0.47 323 0.064281 0.18______________________________________
Pharmacological Test
Experiment 2: V.sub.2 receptor binding assay
Using rat kidney plasma membrane preparations prepared according to O. Hechter's method �cf: J. Bio. Chem., 253, 3211 (1978)!, the plasma membrane (100000 dpm, 4.times.10.sup.-10 M) of �.sup.3 H!-Arg-vasopressin and a test compound (0.6 mg, 10.sup.-10 -10.sup.-5 M) are incubated at 4.degree. C. for 3 hours in 100 mM Tris-HCl buffer (pH: 8.0, 250 .mu.l) containing 5 mM MgCl.sub.2, 1 mM EDTA and 0.1% BSA. After incubation, the mixture is filtered using the glass filter (GF/F) so as to separate the membrane preparation combined with vasopressin and then washed twice with the buffer (5 ml). This glass filter is taken out and mixed with liquid scintillation cocktail. The amount of �.sup.3 H!-vasopressin combined with the membrane is measured by liquid scintillation counter and the rate of the inhibitory effect of the test compound is estimated according to the following equation. ##EQU2## C.sup.1 : The amount of �.sup.3 H!-vasopressin combined with the membrane in the presence of the test compound (in prescribed amount).
C.sup.0 : The amount of �.sup.3 H!-vasopressin combined with the membrane in the absence of the test compound.
B.sup.1 : The amount of �.sup.3 H!-vasopressin combined with the membrane in the presence of the excess amount of vasopressin (10.sup.-6 M).
The results are expressed as IC.sub.50 values, which is the concentration of the test compound required to achieve the inhibitory effect in the rate of 50%.
The results are shown the following Table 11.
TABLE 11______________________________________Test TestComp. IC.sub.50 Comp. IC.sub.50No. (.mu.M) No. (.mu.M)______________________________________1 0.98 28 0.0182 0.20 29 0.0693 0.40 30 0.0294 0.58 31 0.0985 1.2 32 0.0166 0.076 33 0.0077 0.20 34 0.0498 0.32 35 0.209 0.53 36 0.02810 0.082 37 0.1611 1.05 38 0.02912 1.97 39 0.07113 1.02 40 0.3314 0.23 41 0.2015 0.13 42 0.06316 0.17 43 0.1717 0.23 44 0.05018 1.0 45 0.1919 1.7 46 0.01820 1.4 47 0.2021 1 48 0.02122 0.33 49 0.06323 1.07 50 1.324 1.09 51 0.4025 1.67 52 0.3226 0.025 53 1.627 0.070 54 0.1155 0.091 86 0.5856 0.037 87 0.04657 0.16 88 0.02158 0.14 89 0.03559 0.24 90 0.01460 0.15 91 0.00561 0.090 92 0.4162 0.023 93 0.5263 0.046 94 0.09564 0.007 95 0.08965 0.081 96 0.03966 0.45 97 0.02467 0.050 98 0.4568 0.19 99 1.669 0.12 100 0.01170 0.012 101 0.6071 0.085 102 0.2972 0.16 103 0.5474 0.51 104 0.3775 0.30 105 0.7276 0.017 106 0.4477 0.090 107 0.03278 0.084 108 0.1279 0.53 109 0.4980 0.070 110 0.04481 0.15 111 0.08782 0.17 112 0.2983 0.73 113 0.2884 0.11 114 0.00685 0.068 115 0.006116 0.039 146 0.056117 0.24 147 0.009118 0.55 148 0.34119 0.059 149 0.004120 0.28 150 0.14121 0.18 151 0.18122 0.10 152 0.039123 0.10 153 0.063124 0.13 154 0.063125 0.28 155 0.028126 0.062 156 0.15127 0.99 157 0.38128 0.23 158 0.018129 0.29 159 0.020130 0.007 160 0.020131 0.027 161 0.009132 0.013 162 0.059133 0.022 163 0.009134 0.048 164 0.010135 0.081 165 0.098136 0.18 166 0.070137 0.41 167 0.032138 0.11 168 0.083139 0.10 169 0.071140 0.024 170 0.25141 0.010 171 0.87142 0.008 172 0.023143 0.008 173 0.008144 0.02 174 0.007145 0.06 175 0.038176 0.004 206 0.088177 0.15 207 0.045178 0.012 208 0.007179 0.040 209 0.004180 0.034 210 0.004181 0.038 211 0.12182 0.005 212 0.035183 0.26 213 0.033184 0.023 214 0.058185 0.005 215 0.006186 0.030 216 0.91187 0.029 217 0.37188 0.039 218 0.022189 0.087 219 0.023190 0.082 220 0.026191 0.009 221 0.024192 0.111 222 0.010193 0.036 223 0.022194 0.21 224 0.38195 0.010 225 0.030196 0.013 226 0.019197 0.99 227 0.029198 0.040 228 0.029199 0.019 229 0.029200 0.024 230 0.020201 0.023 231 0.007202 0.14 232 0.020203 0.070 233 0.15204 0.11 234 0.14205 0.074 235 0.006236 0.006 267 0.12237 0.041 268 0.018238 0.020 269 0.003239 0.17 270 0.046240 0.022 271 0.030241 0.006 272 0.40242 0.17 273 0.027243 0.40 274 0.024244 0.018 275 0.018245 0.059 276 0.032246 0.027 277 0.016247 0.048 278 0.013248 0.060 279 0.008250 0.12 280 0.045251 0.094 281 0.011252 0.063 262 0.38253 0.052 283 0.096254 0.016 284 0.019255 0.005 285 0.008256 0.004 286 0.019257 0.045 287 0.007258 0.20 288 0.015259 0.25 289 0.071260 0.13 290 0.021261 0.011 291 0.13262 0.029 292 0.18263 0.053 293 0.065264 0.030 294 0.33265 0.025 295 0.026266 0.013 296 0.25297 0.051 311 0.013298 0.10 312 0.29299 0.22 313 0.012300 0.48 314 0.096301 0.14 315 0.025302 0.011 316 0.060303 0.025 317 0.072304 0.024 318 0.060305 0.038 319 0.058306 0.077 320 0.039307 0.010 321 0.012308 0.023 322 0.025309 0.015 323 0.014310 0.008______________________________________
Experiment 3: Anti-antidiuretic activity (effect on endogenous ADH)
A test compound or solvent (dimethylformamide) is administered into a caudal vein of untreated, unrestrained SD rats (male, weight: 300-350 g) and the amount of urine, which is spontaneously excreted for a period of 2 hours thereafter, is collected and measured by using a metabolic gauge. During this measurement, the rats are allowed to take water and feed freely.
The amount of urine of control rats (solvent-treated group) is regarded as 100%, and the results are expressed as ED.sub.3 value, which is the dose of the test compound to be required to excrete the urine by three times than that of the control rats. The results are shown in the following Table 12.
TABLE 12______________________________________Test compound No. ED.sub.3 (mg/kg)______________________________________6 1033 1.9178 4.2249 0.4*.sup.)______________________________________ *.sup.) : Physicological saline solution was used as a solvent instead of dimethylformamide.
Using the suitable starting materials, the compounds of the following Table 13 are obtained in the same manner as in Examples 1 and 382.
TABLE 13______________________________________ ##STR3257##______________________________________Example 1190Structure ##STR3258## ##STR3259##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3260##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 210-213.degree. C.Form: FreeExample 1191Structure ##STR3261## ##STR3262##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3263##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 184.5-186.degree. C.Form: FreeExample 1192Structure ##STR3264## ##STR3265##R.sup.2 : HR.sup.3 : ##STR3266##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 201.5-202.5.degree. C.Form: FreeExample 1193Structure ##STR3267## ##STR3268##R.sup.2 : 2-ClR.sup.3 : ##STR3269##Crystalline form: White powderRecrystallization solvent: Dichloromethane/diethyl etherMelting Point: 159-162.degree. C. (decomposed)Form: FreeExample 1194Structure ##STR3270## ##STR3271##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3272##Crystalline form: White powderRecrystallization solvent: diethyl ether/DichloromethaneMelting Point: 237-240.degree. C.Form: FreeExample 1195Structure ##STR3273## ##STR3274##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3275##Crystalline form: White powderRecrystallization solvent: diethyl ether/DichloromethaneMelting Point: 269-272.5.degree. C.Form: FreeExample 1196Structure ##STR3276## ##STR3277##R.sup.2 : HR.sup.3 : ##STR3278##Crystalline form: Colorless prismsRecrystallization solvent: Ethanol/dichloromethaneMelting Point: 201-202.degree. C.Form: FreeExample 1197Structure ##STR3279## ##STR3280##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3281##Crystalline form: White powderRecrystallization solvent: MethanolMelting Point: 204-206.degree. C.Form: FreeExample 1198Structure ##STR3282## ##STR3283##R.sup.2 : 2-ClR.sup.3 : ##STR3284##Crystalline form: Colorless amorphousNMR analysis: 313)Form: FreeExample 1199Structure ##STR3285## ##STR3286##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3287##Crystalline form: Colorless amorphousNMR analysis: 314)Form: FreeExample 1200Structure ##STR3288## ##STR3289##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3290##Crystalline form: Colorless amorphousNMR analysis: 315)Form: FreeExample 1201Structure ##STR3291## ##STR3292##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3293##Crystalline form: Colorless amorphousNMR analysis: 316)Form: FreeExample 1202Structure ##STR3294## ##STR3295##R.sup.2 : 2-ClR.sup.3 : ##STR3296##Crystalline form: Colorless amorphousNMR analysis: 317)Form: FreeExample 1203Structure ##STR3297## ##STR3298##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3299##Crystalline form: Light brown amorphousNMR analysis: 318)Form: HydrochlorideExample 1204Structure ##STR3300## ##STR3301##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3302##Crystalline form: Colorless amorphousNMR analysis: 319)Form: FreeExample 1205Structure ##STR3303## ##STR3304##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3305##Crystalline form: Colorless amorphousNMR analysis: 320)Form: HydrochlorideExample 1206Structure ##STR3306## ##STR3307##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3308##Crystalline form: Colorless amorphousNMR analysis: 321)Form: HydrochlorideExample 1207Structure ##STR3309## ##STR3310##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3311##Crystalline form: Colorless amorphousNMR analysis: 322)Form: FreeExample 1208Structure ##STR3312## ##STR3313##R.sup.2 : 2-OCH.sub.3R.sup.3 : ##STR3314##Crystalline form: Light yellow prismsRecrystallization solvent: Ethyl acetate/n-hexaneMelting Point: 187-189.degree. C.Form: FreeExample 1209Structure ##STR3315## ##STR3316##R.sup.2 : HR.sup.3 : ##STR3317##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 227-231.degree. C.Form: FreeExample 1210Structure ##STR3318## ##STR3319##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3320##Crystalline form: White powderRecrystallization solvent: Methanol/diethyl etherMelting Point: 191-192.degree. C.Form: FreeExample 1211Structure ##STR3321## ##STR3322##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3323##Crystalline form: Colorless amorphousNMR analysis: 323)Form: FreeExample 1212Structure ##STR3324## ##STR3325##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3326##Crystalline form: Colorless amorphousNMR analysis: 324)Form: FreeExample 1213Structure ##STR3327## ##STR3328##R.sup.2 : 2-CH.sub.3R.sup.3 : ##STR3329##Crystalline form: White amorphousNMR analysis: 325)Form: Hydrochloride______________________________________
313) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.40-2.30 (4H, m), 2.36 (3H, s), 2.60-2.92 (2H, m), 4.35-5.18 (2H, m), 6.69-6.87 (1H, m), 6.87-7.04 (1H, m), 7.05-8.06 (8H, m), 8.25-8.60 (1H, m)
314) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.43-2.26 (4H, m), 2.38 (3H, s), 2.42 (3H, s), 2.61-2.91 (1H, m), 2.91-3.40 (1H, m), 4.49-5.08 (2H, m), 6.40-7.68 (10H, m), 7.68-7.93 (1H, m)
315) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.32-2.25 (4H, m), 2.25-2.54 (3H, m), 2.59-3.42 (2H, m), 4.45-5.08 (2H, m), 6.40-7.80 (10H, m), 8.00-8.38 (1H, m)
316) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.42-1.89 (2H, m), 1.90-2.30 (2H, m), 2.57-2.95 (2H, m), 3.36-3.64 (3H, m), 4.51-5.17 (2H, m), 6.52-7.80 (10H, m), 8.11-8.41 (1H, m)
317) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.18-2.25 (4H, m), 2.25-2.59 (3H, m), 2.59-2.88 (1H, m), 2.88-4.32 (1H, m), 4.32-5.05 (2H, m), 6.44-8.08 (10H, m), 8.52-9.00 (1H, m)
318) .sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.35-2.45 (7H, m), 2.6-3.0 (8H, m), 3.2-4.2 (6H, m), 4.45-4.85 (2H, m), 6.75-7.7 (11H, m)
319) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.20-2.89, 3.22-4.33, 4.48-5.05, 5.75-6.32 �total 17H, m {2.45 (s)}!, 6.52-7.78 (10H, m), 8.10-8.71 (1H, m)
320) .sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.49-3.05 �11H, m {2.35 (s), 2.40 (s)}!, 3.71-5.04 (3H, m), 5.28-5.88 (1H, m), 6.64-7.98 (10H, m), 8.58 (3H, brs), 10.32, 10.48 (total 1H, each s)
321) .sup.1 H-NMR (DMSO-d.sub.6) .delta.; 1.50-3.70 �17H, m }2.36, 2.40 (each s), 2.87, 2.89, 2.94 (each s)}!, 4.05-5.08 (3H, m), 5.90-6.28 (1H, m), 6.62-7.98 (10H, m), 10.36, 10.52 (total 1H, each brs), 10.94 (1H, brs)
322) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.53-2.91 �14H, m {2.42, 2.47 (each s)}!, 3.09-4.27 (5H, m), 4.70-5.12 (1H, m), 5.89-6.36 (1H, m), 6.57-7.94 (11H, m)
323) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.32-2.23 (2H, m), 2.23-2.68 (7H, n), 2.68-3.84 (8H, m), 3.84-5.23 (4H, m), 6.47-7.88 (11H, m)
324) .sup.1 H-NMR (CDCl.sub.3) .delta.; 1.45-2.32 (5H, m), 2.44 (3H, s), 2.63-3.21 (1H, m), 3.40-5.01 (4H, m), 6.28-7.93 (10H, m), 8.10-8.43 (1H, m)
325) .sup.1 H-NMR (DMSO-d.sub.6) .delta.; 0.71-3.46, 4.15-4.44 �total 23H, 2.35 (s), 2.42 (s), 2.86 (s)!, 6.71-7.88 (10H, m), 10.16-10.58 (2H, m)

Number	Name	Date
3035047	Perron et al.	May 1962
4582909	Butler et al.	Apr 1986
4677112	Butler et al.	Jun 1987
4760064	Tominaga et al.	Jul 1988

	Number	Date	Country
Parent	76804	Jun 1993
Parent	851541	Mar 1992

Benzoheterocyclic compounds

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