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: ##STR3## 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: ##STR4## or a group of the formula: ##STR5## 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: ##STR6## [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: ##STR7## (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 alkoxy-carbonyl, 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: ##STR8## (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: ##STR9## (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: ##STR10## (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: ##STR11## 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: ##STR12## (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: ##STR13## (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: ##STR14## (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 alkoxy-carbonyl, 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-dihyroxypropyl, 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, cyclopropyl, 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-tertbutoxycarbonylpropoxy, 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 optonally 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: ##STR15## (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: ##STR16## (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-propylamninopropionyloxy, 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. ##STR17## 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). ##STR18## 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. ##STR19## 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. ##STR20## 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., peferably 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). ##STR21## 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. ##STR22## 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. ##STR23## 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. ##STR24## 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 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. ##STR25## 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. ##STR26## 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 (1i) can be carried out under the same condition as in the hydrolysis of the compound (1j) in the Reaction Scheme-7. ##STR27## 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: ##STR28## (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. ##STR29## 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, peferably 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. ##STR30## wherein R.sup.1, R.sup.2, R.sup.4, 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. ##STR31## 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. ##STR32## 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. ##STR33## 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 ##STR34## 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., peferably 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 solents (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., peferably 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. ##STR35## 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 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, tetra-hydrofuran, 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., peferably 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. ##STR36## 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.14 a 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 the 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-l. 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: HCOOR.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). ##STR37## 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. ##STR38## 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., peferably 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. ##STR39## 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. ##STR40## 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. ##STR41## 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. ##STR42## 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. ##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.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. ##STR44## 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. ##STR45## 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. ##STR46## 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. ##STR47## 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. ##STR48## 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. ##STR49## 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. ##STR50## 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. ##STR51## 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: ##STR52## (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: ##STR53## (A, R.sup.82 and R83 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. ##STR54## 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. ##STR55## 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 (1g) 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. ##STR56## 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. ##STR57## 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 soslvents, 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. ##STR58## 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 to 150.degree. C., preferably at 50 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.degree. C., for about 0.5 to 30 hours. ##STR59## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.62 b, and W' are as defined above, R.sup.51a is hydroxyamino, 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. ##STR60## 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: ##STR61## and R.sup.69 is a group of the formula: ##STR62## (R.sup.14 and R.sup.15 are as defined above), or ##STR63## (R.sup.7 D 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., preferaly 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, ##STR64## 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. ##STR65## 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. ##STR66## 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: ##STR67## (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: ##STR68## 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: ##STR69## (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: ##STR70## (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: ##STR71## (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 (1OO) 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 (1OO) 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. ##STR72## 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. ##STR73## 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., peferably 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. ##STR74## 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. ##STR75## 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). ##STR76## 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. ##STR77## 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. ##STR78## 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. ##STR79## 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). ##STR80## 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. ##STR81## 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. ##STR82## 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: ##STR83## (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. ##STR84## 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. ##STR85## 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). ##STR86## 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 suspendions 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 1
Film coated tablets are prepared from the following components.
______________________________________Components Amount______________________________________4-Methylamino-1-[4-(3,5-dichlorobenzoyl- 150 g amino)benzoyl]-1,2,3,4-tetrahydroquinoline Avicel (tradename of microcrystalline cellulose, 40 g manufactured by Asahi Chemical Industry Co., Ltd., Japan) Corn starch 30 g Magnesium stearate 2 g Hydroxypropyl methylcellulose 10 g Polyethylene glycol-6000 3 g Castor oil 40 g Ethanol 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 2
Tablets are prepared from the following components.
______________________________________Components Amount______________________________________1-[4-(N-Butylanilinoacetylamino)benzoyl]- 150 g 2,3,4,5-tetrahydroy-1H-benzazepine Citric acid 1.0 g Lactose 33.5 g Dicalcium phosphate 70.0 g Pullonic F-68 30.0 g Sodium laurylsulfate 15.0 g Polyvinylpyrrolidone 15.0 g Polyethylene glycol (Carbowax 1500) 4.5 g Polyethylene glycol (Carbowax 6000) 45.0 g Corn starch 30.0 g Dry sodium stearate 3.0 g Dry magnesium stearate 3.0 g Ethanol 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 3
An injection preparation is prepared from the following components.
______________________________________Components Amount______________________________________4-Methyl-1-[4-(2,3-dimethylbenzoyl- 5 g amino)benzoyl]-2,3,4,5-tetrahydro 1H-1,4-benzodiazepine Polyethylene qlycol (molecular weight: 4000) 0.3 g Sodium chloride 0.9 g Polyoxyethylene sorbitan monooleate 0.4 g Sodium metabisulfite 0.1 g Methyl-paraben 0.18 g Propyl-paraben 0.02 g Distilled 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. 86-88.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. 185-188.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. 134-136.degree. C.
1-(2-Nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 152-154.degree. C.
3-Methyl-1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 109-110.degree. C.
4-Methyl-1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 134-136.degree. C.
2-Methyl-1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 143-145.degree. C.
1-(4-Nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder, m.p. 143-145.degree. C.
1-(3-Methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 100-102.degree. C.
1-(3-Methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder, m.p. 146-148.degree. C.
1-(4-Nitrobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, white powder, m.p. 83-85.degree. C.
1-(4-Nitrobenzoyl)-3,4-dihydro-2H-1,4-benzoxazine, yellow powder, m.p. 167-169.degree. C.
1-(4-Nitrobenzoyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine, yellow powder, m.p. 196-198.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. 146-148.degree. C.
1-(4-Nitrobenzoyl)-4-n-propyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, yellow powder, m.p. 131-133.degree. C.
1-(4-Nitrobenzoyl)-5-chloro-1,2,3,4-tetrahydroquinoline, white powder, m.p. 134-136.degree. C.
1-(4-Nitrobenzoyl)-6-methoxy-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 149-151.degree. C.
1-(4-Nitrobenzoyl)-6-methyl-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 109-110.degree. C.
1-(4-Nitrobenzoyl)-7-methoxy-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 139-141.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. 189-190.degree. C.
1-(4-Nitrobenzoyl)-3-hydroxymethyl-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 97-100.degree. C.
1-(4-Nitrobenzoyl)-3-ethoxycarbonyl-1,2,3,4-tetrahydroquinoline, pale yellow powder, m.p. 162-163.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. 128-130.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. 197-200.degree. C.
4-Methyl-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 197-199.degree. C.
2-Methyl-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder, m.p. 204-206.degree. C.
1-(4-Aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder, m.p. 172-174.degree. C.
1-(3-Methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 156-158.degree. C.
1-(3-Methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 165-167.degree. C.
1-(4-Aminobenzoyl)-1,2,3,4,5,6-hexahydrobenzazocine, white powder, m.p. 177-179.degree. C.
1-(4-Aminobenzoyl)-3,4-dihydro-2H-1,4-benzoxazine, white powder, m.p. 192-194.degree. C.
1-(4-Aminobenzoyl)-1,2,3,5-tetrahydro-4,1-benzoxazepine, yellow powder, m.p. 196-198.degree. C.
1-(4-Aminobenzoyl)-4-methyl-1,2,3,4-tetrahydroquinoxaline, yellow powder, m.p. 210-212.degree. C.
1-(4-Aminobenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, white powder, m.p. 159-161.degree. C.
1-(4-Aminobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, brown powder, m.p. 169-171.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. 151-153.degree. C.
1-(4-Aminobenzoyl)-5-chloro-1,2,3,4-tetrahydroquinoline, white powder, m.p. 174-175.degree. C.
1-(4-Aminobenzoyl)-6-methoxy-1,2,3,4-tetrahydroquinoline, pale yellow powder, m.p. 159-160.degree. C.
1-(4-Aminobenzoyl)-6-methyl-1,2,3,4-tetrahydroquinoline, white powder, m.p. 145-146.degree. C.
1-(4-Aminobenzoyl)-7-methoxy-1,2,3,4-tetrahydroquinoline, pale yellow powder, m.p. 150-152.degree. C.
1-(4-Aminobenzoyl)-3-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydroquinoline, light beige powder, m.p. 157-159.degree. C.
1-(4-Aminobenzoyl)-3-(1-pyrrolidinyl)-1,2,3,4-tetrahydroquinoline, pale yellow powder, m.p. 173-174.5.degree. C.
1-(4-Aminobenzoyl)-2,3-dihydro-4(1H)-quinolinone, pale yellow powder, m.p. 178-180.degree. C.
1-(4-Aminobenzoyl)-3-hydroxymethyl-1,2,3,4-tetrahydroquinoline, white powder, m.p. 179-181.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 9) as white powder, m.p. 72-74.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. 181-183.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. 139-142.degree. C.
5-Dimethylamino-1-(3-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 139-141.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. 222-223.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. 144.5-145.5.degree. C.
1-(2-Nitrobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, yellow powder, m.p. 177-180.degree. C.
1-(3-Nitrobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, yellow powder, m.p. 145-146.degree. C.
6-Fluoro-1-(4-nitrobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow needles, m.p. 145-146.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. 120-122.degree. C.
5-Dimethylamino-1-(3-methoxy-4-amino)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 121-123.degree. C.
4-(N-Methy-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. 186-188.degree. C.
1-(4-Aminobenzoyl)-4-isopropyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, white powder, m.p. 191-192.degree. C.
1-(4-Aminobenzoyl)-4-cyclohexyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, white powder, m.p. 149.5-150.5.degree. C.
1-(4-Aminobenzoyl)-5-methyl-1,2,3,4,5,6-hexahydro-1,5-benzodiazocine, yellow powder, m.p. 143-145.degree. C.
1-(4-Aminobenzoyl)-1,2,3,4-tetrahydro-5,1-benzoxazepine, yellow powder, m.p. 163.5-164.5.degree. C.
1-(2-Aminobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, yellow powder, m.p. 144-146.degree. C.
1-(3-Aminobenzoyl)-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, white powder, mp. 153-155.degree. C.
6-Fluoro-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline, white powder, m.p. 160.5-161.5.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. 147-148.degree. C.
5-Hydroxy-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder (ethyl acetate/n-hexane), m.p. 148-150.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. 107-108.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-nitorobenzoyl)-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. 117-119.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. 180-182.degree. C.
5-(4-Nitrobenzoyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine, yellow powder, m.p. 162-163.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. 194.5-195.5.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. 162-164.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. 154-155.degree. C.
5-Ethoxycarbonylmethoxy-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder (recrystallized from ethyl acetate/n-hexane), m.p. 231-232.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
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. 123-125.degree. C.
3-Dimethylamino-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 175-177.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. 207-210.degree. C.
5-(4-Aminobenzoyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine, yellow powder, m.p. 193-195.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. 243-244.degree. C. (recrystallized from ethyl acetate/diisopropyl ether)
5-Methylaminocarbonyloxy-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 207-208.degree. C. (recrystallized from ethyl acetate/n-hexane)
5-Dimethylaminocarbonyloxy-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 155-156.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. 133.5-134.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. 90-92.degree. C. (recrystallized from ethanol)
1-(4-Nitrobenzoyl)-1,2,3,5-tetrahydro-4,1-benzothiazepine, yellow powder, m.p. 185-187.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. 123-125.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. 201.5-202.5.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. 136-138.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. 152-152.5.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. 215-216.degree. C. (recrystallized from ethyl acetate/n-hexane)
5-Methylaminocarbonyloxy-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 192-195.degree. C. (recrystallized from ethyl acetate/n-hexane)
5-Dimethylaminocarbonyloxy-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 228-230.degree. C. (recrystallized from ethyl acetate/diisopropyl ether)
5-Methyl-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, white powder, m.p. 155-156.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. 193-195.degree. C. (recrystallized from ethanol)
1-(4-Aminobenzoyl)-1,2,3,5-tetrahydro-4,1-benzothiazepine, white powder, m.p. 179-180.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. 163-165.degree. C. (recrystallized from diethyl ether/dichloromethane)
5-Oxo-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine, yellow powder, m.p. 195-197.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. 190-192.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. 111-114.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. 154-156.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. 161-163.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. 156-157.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. 160-160.5.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. 202.5-203.5.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______________________________________1 #STR87##______________________________________Example 2 Structure -2 STR88## -3 STR89## - Crystalline form: Light yellow powder Recrystallization solvent: Methanol Melting Point: 198.5-199.5.degree. C. Form: Free Example 3 Structure -2 - - 0##4 STR91## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 200.5-201.5.degree. C. Form: Free Example 4 Structure -2 STR92## -5 STR93## Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 206-207.degree. C. Form: Free Example 5 Structure -2 STR94## -6 STR95## - Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 216-217.degree. C. Form: Free Example 6 Structure -2 STR96## -7 STR97## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 202-203.degree. C. Form: Free Example 7 Structure -2 STR98## -8 STR99## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 212-213.degree. C. Form: Free Example 8 Structure -2 STR100## -9 STR101## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 167.5-168.5.degree. C. Form: Free Example 9 Structure -2 STR102## -0 STR103## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 205-206.degree. C. Form: Free Example 10 Structure -2 STR104## -1 STR105## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: >300.degree. C. NMR analysis: 1) Form: Free Example 11 Structure -2 STR106## -2 STR107## - Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 176-177.degree. C. Form: Free Example 12 Structure -2 STR108## -3 STR109## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 219-220.degree. C. Form: Free Example 13 Structure -2 STR110## -4 STR111## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 193-194.degree. C. Form: Free Example 14 Structure -2 STR112## -5 STR113## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 232-233.degree. C. Form: Free Example 15 Structure -2 STR114## -6 STR115## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 209-210.degree. C. Form: Free Example 16 Structure -2 STR116## -7 STR117## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 184.5-185.5.degree. C. Form: Free Example 17 Structure -2 STR118## -8 STR119## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 224.5-225.5.degree. C. Form: Free Example 18 Structure -2 STR120## -9 STR121## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 220.5-221.5.degree. C. Form: Free Example 19 Structure -2 STR122## -0 STR123## - Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 231-232.degree. C. Form: Free Example 20 Structure -2 STR124## -1 STR125## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: >300.degree. C. NMR analysis: 2) Form: Free Example 21 Structure -2 STR126## -2 STR127## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 208-209.degree. C. Form: Free Example 22 Structure -2 STR128## -3 STR129## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 234.5-235.5.degree. C. Form: Free Example 23 Structure -2 STR130## -4 STR131## - Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 263.5-264.5.degree. C. Form: Free Example 24 Structure -2 STR132## -5 STR133## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 237-238.degree. C. Form: Free Example 25 Structure -2 STR134## -6 STR135## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 234-235.degree. C. Form: Free Example 26 Structure -2 STR136## -7 STR137## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 236.5-237.5.degree. C. Form: Free Example 27 Structure -2 STR138## -8 STR139## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 206.5-207.5.degree. C. Form: Free Example 28 Structure -2 STR140## -9 STR141## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 210-211.degree. C. Form: Free Example 29 Structure -2 STR142## -0 STR143## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 210.5-211.5.degree. C. Form: Free Example 30 Structure -2 STR144## -1 STR145## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 178-179.degree. C. Form: Free Example 31 Structure -2 STR146## -2 STR147## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 192-193.degree. C. Form: Free Example 32 Structure -2 STR148## -3 STR149## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 217-218.degree. C. Form: Free Example 33 Structure -2 STR150## -4 STR151## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 143-144.degree. C. Form: Free Example 34 Structure -2 STR152## -5 STR153## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 170.5-171.5.degree. C. Form: Free Example 35 Structure -2 STR154## -6 STR155## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 169.5-170.5.degree. C. Form: Free Example 36 Structure -2 STR156## -7 STR157## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 174.5-175.5.degree. C. Form: Free Example 37 Structure -2 STR158## -8 STR159## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 148.5-149.5.degree. C. Form: Free Example 38 Structure -2 STR160## -9 STR161## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 165-166.degree. C. Form: Free Example 39 Structure -2 STR162## -0 STR163## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 243-244.degree. C. Form: Free Example 40 Structure -2 STR164## -1 STR165## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 199-200.degree. C. Form: Free Example 41 Structure -2 STR166## -2 STR167## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 232.5-233.5.degree. C. Form: Free Example 42 Structure -2 STR168## -3 STR169## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 178.5-179.5.degree. C. Form: Free Example 43 Structure -2 STR170## -4 STR171## - Crystalline form: White powder Recrystallization solvent: Methanol Melting point: 205.5-206.5.degree. C. Form: Free Example 44 Structure -2 STR172## -5 STR173## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 234-235.degree. C. Form: Free Example 45 Structure -2 STR174## -6 STR175## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 225-226.degree. C. Form: Free Example 46 Structure -2 STR176## -7 STR177## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 224-225.degree. C. Form: Free Example 47 Structure -2 STR178## -8 STR179## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 236-237.degree. C. Form: Free Example 48 Structure -2 STR180## -9 STR181## - Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 175.5-176.5.degree. C. Form: Free Example 49 Structure -2 STR182## -0 STR183## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 231-232.degree. C. Form: Free Example 50 Structure -2 STR184## -1 STR185## - Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 204-205.degree. C. Form: Free Example 51 Structure -2 STR186## -2 STR187## - Crystalline form: White powder Recrystallization solvent: Methanol Melting point: 190-191.degree. C. Form: Free Example 52 Structure -2 STR188## -3 STR189## - Crystalline form: White powder Recrystallization solvent: Methanol Melting point: 156-157.degree. C. Form: Free Example 53 Structure -2 STR190## -4 STR191## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 200-201.degree. C. Form: Free Example 54 Structure -2 STR192## -5 STR193## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 206-207.degree. C. Form: Free Example 55 Structure -2 STR194## -6 STR195## - Crystalline form: Colorless amorphous NMR analysis: 3) Form: Free Example 56 Structure -2 STR196## -7 STR197## - Crystalline form: White powder Recrystallization solvent: Methanol Melting point: 215.5-216.5.degree. C. Form: Free Example 57 Structure -2 STR198## -8 STR199## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 189-190.degree. C. Form: Free Example 58 Structure -2 STR200## -9 STR201## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 203.5-204.5.degree. C. Form: Free Example 59 Structure -2 STR202## -0 STR203## - Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 254.5-255.5.degree. C. Form: Free Example 60 Structure -2 STR204## -1 STR205## - Crystalline form: Brown powder Recrystallization solvent: Methanol Melting Point: 182.5-183.5.degree. C. Form: Free Example 61 Structure -2 STR206## -2 STR207## - Crystalline form: Colorless amorphous NMR analysis: 4) Form: Free Example 62 Structure -2 STR208## -3 STR209## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 263-264.degree. C. Form: Free Example 63 Structure -2 STR210## -4 STR211## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ethanol Melting Point: 217-218.degree. C. Form: Free Example 64 Structure -2 STR212## -5 STR213## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ethanol Melting Point: 183-184.degree. C. Form: Free Example 65 Structure -2 STR214## -6 STR215## - Crystalline form: Yellow powder Recrystallization solvent: Dichloromethane/ethanol Melting Point: 207.5-208.5.degree. C. Form: Free Example 66 Structure -2 STR216## -7 STR217## - Crystalline form: Yellow powder Recrystallization solvent: Dichloromethane/ethanol Melting Point: 251-252.degree. C. Form: Free Example 67 Structure -2 STR218## -8 STR219## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ethanol Melting Point: 208.5-209.5.degree. C. Form: Free Example 68 Structure -2 STR220## -9 STR221## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ethanol Melting Point: 231-232.degree. C. Form: Free Example 69 Structure -2 STR222## -0 STR223## - Crystalline form: Colorless amorphous NMR analysis: 5) Form: Free Example 70 Structure -2 STR224## -1 STR225## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 134-135.degree. C. Form: Free Example 71 Structure -2 STR226## -2 STR227## - Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting point: 115-116.degree. C. Form: Free Example 72 Structure -2 STR228## -3 STR229## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 178.5-179.5.degree. C. Form: Free Example 73 Structure -2 STR230## -4 STR231## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 182.5-183.5.degree. C. Form: Free Example 74 Structure -2 STR232## -5 STR233## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 164-165.degree. C. Form: Free Example 75 Structure -2 STR234## -6 STR235## - Crystalline form: Colorless amorphous NMR analysis: 6) Form: Free Example 76 Structure -2 STR236## -7 STR237## - Crystalline form: Yellow amorphous NMR analysis: 7) Form: Free Example 77 Structure -2 STR238## -8 STR239## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 155-156.degree. C. Form: Free Example 78 Structure -2 STR240## -9 STR241## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 182.5-183. 5.degree. C. Form: Free Example 79 Structure -2 STR242## -0 STR243## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 164.5-165.5.degree. C. Form: Free Example 80 Structure -2 STR244## -1 STR245## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 165-167.degree. C. Form: Free Example 81 Structure -2 STR246## -2 STR247## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 124-125.degree. C. Form: Free Example 82 Structure -2 STR248## -3 STR249## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 140.5-141.5.degree. C. Form: Free Example 83 Structure -2 STR250## -4 STR251## - Crystalline form: Colorless amorphous NMR analysis: 8) Form: Free Example 84 Structure -2 STR252## -5 STR253## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 211-212.degree. C. Form: Free Example 85 Structure -2 STR254## -6 STR255## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 178-179.degree. C. Form: Free Example 86 Structure -2 STR256## -7 STR257## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 212.5-213.5.degree. C. Form: Free Example 87 Structure -2 STR258## -8 STR259## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 193-194.degree. C. Form: Free Example 88 Structure -2 STR260## -9 STR261## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 203-204.degree. C. Form: Free Example 89 Structure -2 STR262## -0 STR263## - Crystalline form: Colorless amorphous NMR analysis: 9) Form: Free Example 90 Structure -2 STR264## -1 STR265## - Crystalline form: Colorless amorphous NMR analysis: 10) Form: Free Example 91 Structure -2 STR266## -2 STR267## - Crystalline form: Colorless amorphous NMR analysis: 11) Form: Free Example 92 Structure -2 STR268## -3 STR269## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 156.5-157.5.degree. C. Form: Free Example 93 Structure -2 STR270## -4 STR271## - Crystalline form: Colorless amorphous NMR analysis: 12) Form: Free Example 94 Structure -2 STR272## -5 STR273## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 203.5-204.5.degree. C. Form: Free Example 95 Structure -2 STR274## -6 STR275## - Crystalline form: Colorless amorphous NMR analysis: 13) Form: Free Example 96 Structure -2 STR276## -7 STR277## - Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 126-127.degree. C. Form: Free Example 97 Structure -2 STR278## -8 STR279## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 158.5-159.5.degree. C. Form: Free Example 98 Structure -2 STR280## -9 STR281## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 129-130.degree. C. Form: Free Example 99 Structure -2 STR282## -0 STR283## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 131.5-132.5.degree. C. Form: Free Example 100 Structure -2 STR284## -1 STR285## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 140-141.degree. C. Form: Free Example 101 Structure -2 STR286## -2 STR287## - Crystalline form: White powder Recrystallization solvent: Methanol Meltinq Point: 138.5-139.5.degree. C. Form: Free Example 102 Structure -2 STR288## -3 STR289## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 128-129.degree. C. Form: Free Example 103 Structure -2 STR290## -4 STR291## - Crystalline form: White powder Recrystaliization solvent: Methanol Melting Point: 160-161.degree. C. Form: Free Example 104 Structure -5 STR292## -1 STR293## - Crystalline form: White powder Recrystaliization solvent: Methanol Melting Point: 175-176.degree. C. Form: Free Example 105 Structure5 STR294## -7 STR295## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 197-198.degree. C. Form: Free Example 106 Structure5 STR296## -8 STR297## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 204-2O0.degree. C. Form: Free Example 107 Structure -5 STR298## -9 STR299## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 174-175.degree. C. Form: Free Example 108 Structure -5 STR300## -0 STR301## - Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 202-203.degree. C. Form: Free Example 109 Structure -5 STR302## -1 STR303## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 203-204.degree. C. Form: Free Example 110 Structure -5 STR304## -2 STR305## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 170.5-171.5.degree. C. Form: Free Example 111 Structure -5 STR306## -3 STR307## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 149-150.degree. C. Form: Free Example 112 Structure -5 STR308## -4 STR309## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 185-186.degree. C. Form: Free Example 113 Structure -5 STR310## -5 STR311## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ethanoi Melting Point: 225-226.degree. C. Form: Free Example 114 Structure -6 STR312## -7 STR313## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 234-235.degree. C. Form: Free Example 115 Structure -6 STR314## -8 STR315## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 149.5-150.5.degree. C. Form: Free Example 116 Structure -6 STR316## -9 STR317## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ethanol Melting Point: 197-198.degree. C. Form: Free Example 117 Structure -0 STR318## -1 STR319## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 204-205.degree. C. Form: Free Example 118 Structure -0 STR320## -2 STR321## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 224.5-225.5.degree. C. Form: Free Example 119 Structure -0 STR322## -3 STR323## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ethanol Melting Point: 189.5-190.5.degree. C. Form: Free Example 120 Structure -2 STR324## -4 STR325## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 221.5-222.5.degree. C. Form: Free Example 121 Structure -2 STR326## -5 STR327## - Crystalline form: Colorless needles Recrystallization solvent: Methanol Melting Point: 154-155.degree. C. Form: Free Example 122 Structure -2 STR328## -6 STR329## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 165-166.degree. C. Form: Free Example 123 Structure -2 STR330## -7 STR331## - Crystalline form: Colorless needles Recrystallization solvent: Methanol Melting Point: 141-142.degree. C. Form: Free Example 124 Structure -2 STR332## -8 STR333## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 165.5-166.5.degree. C. Form: Free Example 125 Structure -2 STR334## -9 STR335## - Crystalline form: Colorless needles Recrystallization solvent: Methanol Melting point: 164-165.degree. C. Form: Free Example 126 Structure -2 STR336## -0 STR337## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 203.5-204.5.degree. C. Form: Free Example 127 Structure -2 STR338## -1 STR339## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ethanol Melting Point: 236.5-237.5.degree. C. Form: Free Example 128 Structure -2 STR340## -2 STR341## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 206.5-207.5.degree. C. Form: Free Example 129 Structure -2 STR342## -3 STR343## - Crystalline form : White powder Recrystallization solvent: Methanol Melting Point: 271-272.degree. C. Form: Free Example 130 Structure -2 STR344## -4 STR345## - Crystalline form: White powder Recrystallization solvent: Methanol Meiting Point: 246-247.degree. C. Form: Free Example 131 Structure -5 STR346## -6 STR347## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 210-211.degree. C. Form: Free Example 132 Structure -5 STR348## -7 STR349## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 230.5-231.5.degree. C. Form: Free Example 133 Structure -5 STR350## -8 STR351## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 203-204.degree. C. Form: Free Example 134 Structure -5 STR352## -9 STR353## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 170-171.degree. C. Form: Free Example 135 Structure -5 STR354## -0 STR355## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 225.5-226.5.degree. C. Form: Free Example 136 Structure -5 STR356## -1 STR357## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 210.5-211.5.degree. C. Form: Free Example 137 Structure -5 STR358## -2 STR359## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 183-184.degree. C. Form: Free Example 138 Structure -5 STR360## -3 STR361## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 191.5-192.5.degree. C. Form: Free Example 139 Structure -5 STR362## -4 STR363## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 203.5-204.5.degree. C. Form: Free Example 140 Structure -5 STR364## -5 STR365## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 215.5-216.5.degree. C. Form: Free Example 141 Structure -5 STR366## -6 STR367## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 211.5-212.5.degree. C. Form: Free Example 142 Structure -5 STR368## -7 STR369## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 280.5-281.5.degree. C. Form: Free Example 143 Structure -5 STR370## -8 STR371## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 235.5-236.5.degree. C. Form: Free Example 144 Structure -5 STR372## -9 STR373## - Crystalline form: White powder Recrystallization solvent: Ethanol/dichloromethane Melting Point: 249.5-250.5.degree. C. Form: Free Example 145 Structure -5 STR374## -0 STR375## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 217-218.degree. C. Form: Free Example 146 Structure -5 STR376## -1 STR377## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 201.5-203.degree. C. Form: Free Example 147 Structure -7 STR378## -2 STR379## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 221-222.degree. C. Form: Free Example 148 Structure -7 STR380## -3 STR381## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 193-194.degree. C. Form: Free Example 149 Structure -7 STR382## -4 STR383## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 176-177.degree. C. Form: Free Example 150 Structure -7 STR384## -5 STR385## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 188-189.5.degree. C. Form: Free Example 151 Structure -7 STR386## -6 STR387## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 227-228.degree. C. Form: Free Example 152 Structure -7 STR388## -7 STR389## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 186-187.degree. C. Form: Free Example 153 Structure -0 STR390## -8 STR391## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 135-136.degree. C. Form: Free Example 154 Structure -0 STR392## -9 STR393## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 173-174.degree. C. Form: Free Example 155 Structure -0 STR394## -0 STR395## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 174.5-175.5.degree. C. Form: Free Example 156 Structure -0 STR396## -1 STR397## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 156-157.degree. C. Form: Free Example 157 Structure -0 STR398## -2 STR399## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 153-154.degree. C. Form: Free Example 158 Structure -0 STR400## -3 STR401## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 169-170.degree. C. Form: Free Example 159 Structure -0 STR402## -3 STR403## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 185-186.degree. C. Form: Free Example 160 Structure -4 STR404## -5 STR405## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 213-214.degree. C. Form: Free Example 161 Structure -4 STR406## -6 STR407## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 240-241.degree. C. Form: Free Example 162 Structure -4 STR408## -7 STR409## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 225-226.degree. C. Form: Free Example 163 Structure -4 STR410## -8 STR411## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 209.5-210.5.degree. C. Form: Free Example 164 Structure -4 STR412## -9 STR413## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 198-199.degree. C. Form: Free Example 165 Structure -4 STR414## -0 STR415## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 214.5-215.5.degree. C. Form: Free Example 166 Structure -4 STR416## -1 STR417## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 196.5-197.5.degree. C. Form: Free Example 167 Structure -4 STR418## -2 STR419## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 194-195.degree. C. Form: Free Example 168 Structure -4 STR420## -3 STR421## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 191-192.degree. C. Form: Free Example 169 Structure -4 STR422## -5 STR423## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ethanol Melting Point: 227-228.degree. C. Form: Free Example 170 Structure -4 STR424## -1 STR425## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 182-183.degree. C. Form: Free Example 171 Structure -4 STR426## -7 STR427## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 222-223.degree. C. Form: Free Example 172 Structure -4 STR428## -8 STR429## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 204-205.degree. C. Form: Free Example 173 Structure -4 STR430## -9 STR431## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 194-195.degree. C. Form: Free Example 174 Structure -4 STR432## -0 STR433## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 213-214.degree. C. Form: Free Example 175 Structure -4 STR434## -1 STR435## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 201-202.degree. C. Form: Free Example 176 Structure -4 STR436## -2 STR437## - Crystalline form: Colorless needles Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 173-174.degree. C. Form: Free Example 177 Structure -4 STR438## -3 STR439## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 150.5-151.5.degree. C. Form: Free Example 178 Structure -4 STR440## -0 STR441## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 207.5-208.5.degree. C. Form: Free Example 179 Structure -4 STR442## -6 STR443## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 256.5-257.5.degree. C. Form: Free Example 180 Structure -5 STR444## -1 STR445## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 199.5-200.5.degree. C. Form: Free Example 181 Structure -5 STR446## -9 STR447## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 211-212.degree. C. Form: Free Example 182 Structure -5 STR448## -0 STR449## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 189.5-190.5.degree. C. Form: Free Example 183 Structure -5 STR450## -9 STR451## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 176.5-177.5.degree. C. Form: Free Example 184 Structure -5 STR452## -0 STR453## - Crystalline form: Yellow powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 202-203.degree. C. Form: Free Example 185 Structure -5 STR454## -0 STR455## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 219-220.degree. C. Form: Free Example 186 Structure -5 STR456## -6 STR457## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 272-273.degree. C. Form: Free Example 187 Structure -6 STR458## -1 STR459## - Crystalline form: Yellow powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 146-147.degree. C. Form: Free Example 188 Structure -6 STR460## -9 STR461## - Crystalline form: Yellow powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 229.5-230.5.degree. C. Form: Free Example 189 Structure -6 STR462## -7 STR463## - Crystalline form: Yellow powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 119.5-120.5.degree. C. Form: Free Example 190 Structure -6 STR464## -8 STR465## - Crystalline form: Yelllow powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 189-190.degree. C. Form: Free Example 191 Structure -6 STR466## -9 STR467## - Crystalline form: Yellow powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 207-208.degree. C. Form: Free Example 192 Structure -6 STR468## -0 STR469## - Crystalline form: Yellow powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 196.5-197.5.degree. C. Form: Free Example 193 Structure -6 STR470## -1 STR471## - Crystalline form: Yellow powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 182-183.degree. C. Form: Free Example 194 Structure -6 STR472## -2 STR473## - Crystalline form: Yellow powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 172-173.degree. C. Form: Free Example 195 Structure -6 STR474## -0 STR475## - Crystalline form: Yellow powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 197.5-198.5.degree. C. Form: Free Example 196 Structure -6 STR476## -6 STR477## - Crystalline form: Yellow powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 227-228.degree. C. Form: Free Example 197 Structure -7 STR478## -9 STR479## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 216.5-217.5.degree. C. Form: Free Example 198 Structure -7 STR480## -1 STR481## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 207-208.degree. C. Form: Free Example 199 Structure -7 STR482## -6 STR483## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 236-237.degree. C. Form: Free Example 200 Structure -7 STR484## -7 STR485## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 199.5-200.5.degree. C. Form: Free Example 201 Structure -7 STR486## -8 STR487## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 171.5-172.5.degree. C. Form: Free Example 202 Structure -7 STR488## -9 STR489## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 222.5-223.5.degree. C. Form: Free Example 203 Structure -7 STR490## -0 STR491## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 209.5-210.5.degree. C. Form: Free Example 204 Structure -9 STR492## -1 STR493## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 14) Form: Hydrochloride Example 205 Structure -9 STR494## -6 STR495## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 15) Form: Hydrochloride Example 206 Structure -9 STR496## -0 STR497## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 16) Form: Hydrochloride Example 207 Structure -9 STR498## -9 STR499## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 17) Form: Hydrochloride Example 208 Structure -9 STR500## -8 STR501## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 18) Form: Hydrochloride Example 209 Structure -9 STR502## -7 STR503## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 19) Form: Hydrochloride Example 210 Structure -9 STR504## -0 STR505## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 20) Form: Hydrochloride Example 211 Structure -9 STR506## -0 STR507## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 159.5-1600.5.degree. C. Form: Free Example 212 Structure -9 STR508## -2 STR509## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 189.5-190.5.degree. C. Form: Free Example 213 Structure -9 STR510## -9 STR511## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 170.5-171.5.degree. C. Form: Free Example 214 Structure -9 STR512## -1 STR513## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 165-166.degree. C. Form: Free Example 215 Structure -9 STR514## -1 STR515## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 173.5-174.5.degree. C. Form: Free Example 216 Structure -9 STR516## -2 STR517## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 182-183.degree. C. Form: Free Example 217 Structure -9 STR518## -3 STR519## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 225.5-226.5.degree. C. Form: Free Example 219 Structure -8 STR520## -6 STR521## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 21) Form: Hydrochloride Example 220 Structure -8 STR522## -9 STR523## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 147.5-148.5.degree. C. Form: Free Example 221 Structure -8 STR524## -1 STR525## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 136-137.degree. C. Form: Free Example 222 Structure -8 STR526## -2 STR527## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 191.5-192.5.degree. C. Form: Free Example 223 Structure -8 STR528## -4 STR529## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 145-146.degree. C. Form: Free Example 224 Structure -5 STR530## -6 STR531## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 22) Form: Hydrochloride Example 225 Structure -5 STR532## -7 STR533## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 23) Form: Hydrochloride Example 226 Structure -5 STR534## -8 STR535## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 24) Form: Hydrochloride Example 227 Structure -5 STR536## -9 STR537## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 25) Form: Hydrochloride Example 228 Structure -5 STR538## -1 STR539## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 26) Form: Hydrochloride Example 229 Structure -5 STR540## -4 STR541## - Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 27) Form: Hydrochloride Example 230 Structure -7 STR542## -0 STR543## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 206-207.degree. C. Form: Free Example 231 Structure -6 STR544## -3 STR545## - Crystalline form: White powder Recrystallization solvent: Chloroform/metahnol Melting Point: 211-213.degree. C. Form: Free Example 232 Structure -7 STR546## -8 STR547## - Crystalline form: White powder Recrystallization solvent: Chloroform/metahnol Melting Point: 228.5-229.5.degree. C. Form: Free Example 233 Structure -9 STR548## -0 STR549## - Crystalline form: White powder Recrystallization solvent: Chloroform/metahnol Melting Point: 237-238.degree. C. Form: Free Example 234 Structure -1 STR550## -0 STR551## - Crystalline form: White powder Recrystallization solvent: Chloroform/metahnol Melting Point: 226-228.degree. C. Form: Free Example 235 Structure -2 STR552## -0 STR553## - Crystalline form: White powder Recrystallization solvent: Chloroform/metahnol Melting Point: 220-222.degree. C. Form: Free Example 236 Structure -3 STR554## -0 STR555## - Crystalline form: Colorless amporphous NMR analysis: 28) Form: Free Example 237 Structure -4 STR556## -0 STR557## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 162-165.degree. C. Form: Free Example 238 Structure -5 STR558## -6 STR559## - Crystalline form: Light brown amorphous NMR analysis: 29) Form: Free Example 239 Structure -7 STR560## -6 STR561## - Crystalline form: Light brown amorphous NMR analysis: 30) Form: Free Example 240 Structure -8 STR562## -9 STR563## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 215-217.degree. C. Form: Free Example 241 Structure -0 STR564## -9 STR565## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 221-223.degree. C. Form: Free Example 242 Structure -1 STR566## -9 STR567## - Crystalline form: Colorless amorphous NMR analysis: 31) Form: Free Example 243 Structure -2 STR568## -9 STR569## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 207-210.degree. C. Form: Free Example 244 Structure -3 STR570## -9 STR571## - Crystalline form: Colorless amorphous NMR analysis: 32) Form: Free Example 245 Structure -9 STR572## -9 STR573## - Crystalline form: Colorless amorphous NMR analyss: 33) Form: Free Example 246 Structure -4 STR574## -9 STR575## - Crystalline form: Colorless amorphous NMR analysis: 34) Form: Free Example 247 Structure -5 STR576## -9 STR577## - Crystalline form: Colorless amorphous NMR analysis: 35) Form: Free Example 248 Structure -6 STR578## -9 STR579## - Crystalline form: Light yellow powder Recrystallization solvent: Ethanol Melting Point: 186-187.degree. C. Form: Free Example 249 Structure -7 STR580## -8 STR581## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 190-191.degree. C. Form: Free Example 250 Structure -7 STR582## -9 STR583## - Crystalline form: Light yellow scales Recrystallization solvent: Ethanol/water Melting Point: 230-231.degree. C. Form: Free Example 251 Structure -7 STR584## -0 STR585## - Crystalline form: Light yellow needles Recrystallization solvent: Ethanol Melting Point: 227-228.degree. C. Form: Free Example 252 Structure -7 STR586## -1 STR587## - Crystalline form: Colorless needles Recrystallization solvent: Ethyl acetate Melting Point: 192.degree. C. Form: Free Example 253 Structure -7 STR588## -2 STR589## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 186.5-189.degree. C. Form: Free Example 254 Structure -7 STR590## -3 STR591## - Crystalline form: Light yellow scales Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 165-167.degree. C. Form: Free Example 255 Structure -7 STR592## -4 STR593## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 169-170.degree. C. Form: Free Example 256 Structure -7 STR594## -5 STR595## - Crystalline form: Colorless scales Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 174-177.degree. C. Form: Free Example 257 Structure -7 STR596## -6 STR597## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 114-118.degree. C. Form: Free Example 258 Structure -7 STR598## -7 STR599## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 170-172.degree. C. Form: Free Example 259 Structure -7 STR600## -8 STR601## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 179-181.degree. C. Form: Free Example 260 Structure -7 STR602## -9 STR603## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 118-121.degree. C. Form: Free Example 261 Structure -7 STR604## -0 STR605## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 144-148.degree. C. Form: Free Example 262 Structure -7 STR606## -1 STR607## - Crystalline form: Colorless scales Recrystallization solvent: Ethyl acetate Melting Point: 156-157.degree. C. Form: Free Example 263 Structure -7 STR608## -2 STR609## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 204-206.degree. C. Form: Free Example 264 Structure -7 STR610## -3 STR611## - Crystalline form: Light yellow powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 165-167.degree. C. Form: Free Example 265 Structure -7 STR612## -4 STR613## - Crystalline form: Light yellow amorphous NMR analysis: 36) Form: Free Example 266 Structure -7 STR614## -5 STR615## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 122-124.degree. C. Form: Free Example 267 Structure -7 STR616## -6 STR617## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 116-117.degree. C. Form: Free Example 268 Structure -7 STR618## -7 STR619## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 121-123.degree. C. Form: Free Example 269 Structure -7 STR620## -8 STR621## - Crystalline form: Colorless needles Recrystallization solvent: Ethyl acetate Melting Point: 186-187.degree. C. Form: Free Example 270 Structure -7 STR622## -9 STR623## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 139-142.degree. C. Form: Free Example 271 Structure -7 STR624## -0 STR625## - Crystalline form: Light yellow amorphous NMR analysis: 37) Form: Free Example 272 Structure -7 STR626## -1 STR627## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 149.5-152.5.degree. C. Form: Free Example 273 Structure -7 STR628## -2 STR629## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 150-152.5.degree. C. Form: Free Example 274 Structure -7 STR630## -3 STR631## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 150.degree. C. Form: Free Example 275 Structure -7 STR632## -4 STR633## - Crystalline form: Colorless needles Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 101-104.degree. C. Form: Free Example 276 Structure -7 STR634## -5 STR635## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 120-122.degree. C. Form: Free Example 277 Structure -7 STR636## -6 STR637## - Crystalline form: Light yellow amorphous NMR analysis: 38) Form: Free Example 278 Structure -7 STR638## -7 STR639## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 183-186.degree. C. Form: Free Example 279 Structure -7 STR640## -8 STR641## - Crystalline form: Light brown powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 139-142.degree. C. Form: Free Example 280 Structure -7 STR642## -9 STR643## - Crystalline form: Light yellow powder Recrystallization solvent: Ethanol Melting Point: 162-165.degree. C. Form: Free Example 281 Structure -7 STR644## -0 STR645## - Crystalline form: Light yellow scales Recrystallization solvent: Ethyl acetate Melting Point: 224-227.degree. C. Form: Free Example 282 Structure -7 STR646## -1 STR647## - Crystalline form: Light yellow amorphous NMR analysis: 39) Form: Free Example 283 Structure -7 STR648## -2 STR649## - Crystalline form: Light yellow powder Recrystallization solvent: Ethanol/water Melting Point: 162-164.degree. C. Form: Free Example 284 Structure -7 STR650## -3 STR651## - Crystalline form: Light yellow powder Recrystallization solvent: Ethanol Melting Point: 238-241.degree. C. (decomposed) Form: Free Example 285 Structure -7 STR652## -4 STR653## - Crystalline form: Light yellow amorphous NMR analysis: 40) Form: Free Example 286 Structure -7 STR654## -5 STR655## - Crystalline form: Colorless amorphous NMR analysis: 41) Form: Free Example 287 Structure -7 STR656## -6 STR657## - Crystalline form: Colorless needles Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 168-169.degree. C. Form: Free Example 288 Structure -7 STR658## -7 STR659## - Crystalline form: Light brown powder Recrystallization solvent: Ethanol Melting Point: 189-191.degree. C. Form: Free Example 289 Structure -7 STR660## -8 STR661## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 200-202.degree. C. Form: Free Example 290 Structure -7 STR662## -9 STR663## - Crystalline form: Colorless scales Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 143-146.degree. C. Form: Free Example 291 Structure -7 STR664## -0 STR665## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 117-117.5.degree. C. Form: Free Example 292 Structure -7 STR666## -1 STR667## - Crystalline form: Light brown powder Recrystallization solvent: Diethyl ether/ethyl acetate Melting Point: 225-226.degree. C. Form: Free Example 293 Structure -7 STR668## -2 STR669## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethanol Melting Point: 175-176.5.degree. C. Form: Free Example 294 Structure -7 STR670## -3 STR671## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 234-236.degree. C. Form: Free Example 295 Structure -7 STR672## -4 STR673## - Crystalline form: Colorless scales Recrystallization solvent: Ethyl acetate Melting Point: 172-174.degree. C. Form: Free Example 296 Structure -7 STR674## -5 STR675## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 154-155.degree. C. Form: Free Example 297 Structure -7 STR676## -6 STR677## - Crystalline form: Light yellow needles Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 181.5-183.5.degree. C. Form: Free Example 298 Structure -7 STR678## -7 STR679## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 173-175.degree. C. Form: Free Example 299 Structure -7 STR680## -8 STR681## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 137-138.degree. C. Form: Free Example 300 Structure -7 STR682## -9 STR683## - Crystalline form: Light yellow amorphous NMR analysis: 42) Form: Free Example 301 Structure -7 STR684## -0 STR685## - Crystalline form: Colorless needles Recrystallization solvent: Diethyl ether/ethyl acetate Melting Point: 129-130.degree. C. Form: Free Example 302 Structure -7 STR686## -1 STR687## - Crystalline form: Colorless needles Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 181-183.degree. C. Form: Free Example 303 Structure -7 STR688## -2 STR689## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 248-249.degree. C. Form: Free Example 304 Structure -7 STR690## -3 STR691## - Crystalline form: Light yellow amorphous NMR analysis: 43) Form: Free Example 305 Structure -7 STR692## -4 STR693## - Crystalline form: Light yellow needles Recrystallization solvent: Ethanol Melting Point: 94-96.degree. C. Form: Free Example 306 Structure -7 STR694## -5 STR695## - Crystalline form: Light brown powder Recrystallization solvent: Ethyl acetate Melting Point: 159-161.degree. C. Form: Free Example 307 Structure -7 STR696## -6 STR697## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 180-183.degree. C. Form: Free Example 308 Structure -7 STR698## -7 STR699## - Crystalline form: Light brown powder Recrystallization solvent: Ethanol Melting Point: 177-180.degree. C. Form: Free Example 309 Structure -7 STR700## -8 STR701## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 91-93.degree. C. Form: Free Example 310 Structure -7 STR702## -9 STR703## - Crystalline form: Light brown scales Recrystallization solvent: Ethanol Melting Point: 155-156.5.degree. C. Form: Free Example 311 Structure -7 STR704## -0 STR705## - Crystalline form: Colorless scales Recrystallization solvent: Ethyl acetate Melting Point: 172.5-175.degree. C. Form: Free Example 312 Structure -7 STR706## -1 STR707## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 148-150.5.degree. C. Form: Free Example 313 Structure -7 STR708## -2 STR709## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 172-173.degree. C. Form: Free Example 314 Structure -7 STR710## -3 STR711## - Crystalline form: Colorless scales Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 133-135.degree. C. Form: Free Example 315 Structure -7 STR712## -4 STR713## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 217-219.degree. C. Form: Free Example 316 Structure -7 STR714## -5 STR715## - Crystalline form: Colorless needles Recrystallization solvent: Ethyl acetate Melting Point: 226-227.5.degree. C. Form: Free Example 317 Structure -7 STR716## -6 STR717## - Crystalline form: Colorless amorphous NMR analysis: 44) Form: Free Example 318 Structure -7 STR718## -7 STR719## - Crystalline form: White powder Recrystallization solvent: Dichloromethane Melting Point: 234-235.degree. C. Form: Free Example 319 Structure -7 STR720## -8 STR721## - Crystalline form: Colorless prisms Recrystallization solvent: Methanol Melting Point: 218-218.5.degree. C. Form: Free Example 320 Structure -7 STR722## -9 STR723## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 202.5-206.degree. C. Form: Free Example 321 Structure -7 STR724## -0 STR725## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 174-176.degree. C. Form: Free Example 322 Structure -7 STR726## -1 STR727## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 216-218.degree. C. Form: Free Example 323 Structure -7 STR728## -2 STR729## - Crystalline form: White powder Melting Point: >300.degree. C. NMR analysis: 45) Form: Free Example 324 Structure -7 STR730## -3 STR731## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 250.5-251.degree. C. Form: Free Example 325 Structure -7 STR732## -4 STR733## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 223-225.degree. C. Form: Free Example 326 Structure -7 STR734## -5 STR735## - Crystalline form: Colorless prismsr Recrystallization solvent: Methanol Melting Point: 213-214.degree. C. Form: Free Example 327 Structure -7 STR736## -6 STR737## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 246-247.degree. C. Form: Free Example 328 Structure -7 STR738## -7 STR739## - Crystalline form: Colorless prisms Recrystallization solvent: Methanol Melting Point: 248-251.degree. C. Form: Free Example 329 Structure -7 STR740## -8 STR741## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 268.5-270.5.degree. C. Form: Free Example 330 Structure -7 STR742## -9 STR743## - Crystalline form: White powder Recrystallization solvent: Methano/diethyl ether Melting Point: 174-176.degree. C. Form: Free Example 331 Structure -7 STR744## -0 STR745## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 130-134.degree. C. Form: Free Example 332 Structure -7 STR746## -1 STR747## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 214-217.degree. C. Form: Hydrochloride Example 333 Structure -7 STR748## -2 STR749## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 218-220.degree. C. Form: Hydrochloride Example 334 Structure -7 STR750## -3 STR751## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 222-225.degree. C. Form: Free Example 335 Structure -7 STR752## -4 STR753## - Crystalline form: Colorless needles Recrystallization solvent: Methanol/ditehyl ether Melting Point: 171-172.degree. C. Form: Free Example 336 Structure -7 STR754## -5 STR755## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 235.5-236.degree. C. Form: Dihydrochloride Example 337 Structure -7 STR756## -6 STR757## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 241-243.degree. C. Form: Free Example 338 Structure -7 STR758## -7 STR759## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 187-191.degree. C. Form: Free Example 339 Structure -7 STR760## -8 STR761## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 240-244.degree. C. Form: Hydrochloride Example 340 Structure -7 STR762## -9 STR763## - Crystalline form: Colorless prisms Recrystallization solvent: Methanol/diethyl ether Melting Point: 181-182.degree. C. Form: Free Example 341 Structure -7 STR764## -0 STR765## - Crystalline form: Colorless prisms Recrystallization solvent: Methanol/diethyl ether Melting Point: 188-190.degree. C. Form: Dihydrochloride Example 343 Structure -7 STR766## -1 STR767## - Crystalline form: White powder Recrystallization solvent: Isopropyl alcohol Melting Point: 218-218.5.degree. C. Form: Hydrrochloride Example 343 Structure -7 STR768## -2 STR769## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 243-245.5.degree. C. Form: Free Example 344 Structure -7 STR770## -3 STR771## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 130-133.degree. C. Form: Free Example 345 Structure -7 STR772## -4 STR773## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 155-158.degree. C. Form: Free Example 346 Structure -7 STR774## -5 STR775## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 208-210.degree. C. Form: Hydrochloride Example 347 Structure -7 STR776## -6 STR777## - Crystalline form: Colorless prisms Recrystallization solvent: Methanol/diethyl ether Melting Point: 154-155.degree. C. Form: Hydrochloride Example 348 Structure -7 STR778## -7 STR779## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 142-143.degree. C. Form: Free Example 349 Structure -7 STR780## -8 STR781## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 120-125.degree. C. Form: Hydrochloride Example 350 Structure -7 STR782## -9 STR783## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 91-95.degree. C. Form: Hydrochloride Example 351 Structure -7 STR784## -0 STR785## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 145-146.5.degree. C. Form: Free Example 352 Structure -7 STR786## -1 STR787## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 105-105.5.degree. C. Form: Free Example 353 Structure -7 STR788## -2 STR789## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 151-155.degree. C. Form: Dihydrochloride Example 354 Structure -7 STR790## -3 STR791## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 135.5-137.5.degree. C. Form: Free Example 355 Structure -7 STR792## -4 STR793## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 178-178.5.degree. C. Form: Free Example 356 Structure -7 STR794## -5 STR795## - Crystalline form: White powder Recrystallization solvent: Dichloromethane Melting Point: 266.5-268.degree. C. Form: Free Example 357 Structure -7 STR796## -6 STR797## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 123-124.degree. C. Form: Free Example 358 Structure -7 STR798## -7 STR799## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 212-213.5.degree. C. Form: Free Example 359 Structure -7 STR800## -8 STR801## - Crystalline form: Colorless scales Recrystallization solvent: Ethyl acetate Melting Point: 160.5-162.degree. C. Form: Free Example 360 Structure -7 STR802## -9 STR803## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 103-105.degree. C. Form: Free Example 361 Structure -7 STR804## -0 STR805## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 145-146.degree. C. Form: Free Example 362 Structure -7 STR806## -1 STR807## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 247-250.degree. C. Form: Free Example 363 Structure -7 STR808## -2 STR809## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 198-199.degree. C. Form: Free Example 364 Structure -7 STR810## -3 STR811## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 181.5-182.5.degree. C. Form: Free Example 365 Structure -7 STR812## -4 STR813## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 170-170.5.degree. C. Form: Free Example 366 Structure -7 STR814## -5 STR815## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 156-158.degree. C. Form: Hydrochloride Example 367 Structure -7 STR816## -6 STR817## - Crystalline form: White powder Recrystallization solvent: Diethyl ether Melting Point: 168.5-170.5.degree. C. Form: Free Example 368 Structure -7 STR818## -7 STR819## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 177-181.5.degree. C. Form: Hydrochloride Example 369 Structure -7 STR820## -8 STR821## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 211-213.degree. C. Form: Free Example 370 Structure -7 STR822## -9 STR823## - Crystalline form: White powder NMR analysis: 46) Form: Free Example 371 Structure -7 STR824## -0 STR825## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 166-167.degree. C. Form: Free Example 372 Structure -7 STR826## -1 STR827## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 127-131.degree. C. Form: Free Example 373 Structure -7 STR828## -2 STR829## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 170-171.degree. C. Form: Free Example 374 Structure -7 STR830## -3 STR831## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 125-126.degree. C. Form: Free Example 375 Structure -4 STR832## -5 STR833## - Crystalline form: Light yellow amorphous NMR analysis: 47) Form: Hydrochloride Example 376 Structure -4 STR834## -6 STR835## - Crystalline form: Colorless amorphous NMR analysis: 48) Form: Free______________________________________ 1) .sup.1 H--NMR(CDCl.sub.3).delta.: 1.92(1H, t, J=6.2Hz), 1.98 (1H, t, J=6.4Hz), 2.8(2H, t, J=6.4Hz), 3.76 (2H, t, J=6.2Hz), 6.75(1H, d, J=7.6Hz), 6.86 (2H, d, J=8.6Hz), 6.8-7.1(2H, m), 7.20(1H, d, J=7Hz), 7.30(2H, d), J=8.6Hz), 7.71(2H, d, J=8.6Hz), 7.84(2H, d, J=8.6Hz), 10.13(1H, s) 2) .sup.1 H--NMR(DMSO-d.sub.6).delta.: 2.05(2H, quint, J=6.4Hz), 2.91(2H, t, J=6.4Hz), 3.86(2H, t, J=6.4Hz), 6.85(1H, d, J=7.6Hz), 6.9-7.2(2H, m), 7.30(1H, d, J=7.2Hz), 7.44(2H, d, J=8.5Hz), 7.85(2H, d, J=8.5Hz), 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=6.5Hz), 3.82(6H, s), 3.90(2H, t, J=6.6Hz), 6.5-7.2(7H, m), 7.35(2H, d, J=8.7Hz), 7.55(2H, d, J=8.7Hz), 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=6.6Hz), 3.90(2H, t, J=6.6Hz), 6.71(1H, d, J=7.9Hz), 6.8-7.2(4H, m), 7.35(2H, d, J=8.6Hz), 7.44(2H, s), 7.56(2H, d), J=8.6Hz), 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=6.6Hz), 3.89(2H, t, J=6.5Hz), 6.71(1H, d, J=7.8Hz), 6.87(1H, t, J=7Hz), 6.99 (1H, t, J=7.3Hz), 7.15(1H, d, J=6.5Hz), 7.28 (2H, d, J=8.6Hz), 7.41(2H, d, J=8,6Hz), 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=6.6Hz), 3.89(2H, t, J=6.5Hz), 6.72(1H, d, J=7.9Hz), 6.8-7.1(2H, m), 7.15(1H, d, J=7.4Hz), 7.28(2H, d, J=8.3Hz), 7.44(2H, d, J=8.4Hz), 7.9-8.1(1H, m) 7) .sup.1 H--NMR(CDCl.sub.3).delta.: 2.02(2H, quint, J=6.5Hz), 2.81(2H, t, J=6.6Hz), 3.69(2H, s), 3.87(2H, t, J=6.6Hz), 6.66(1H, d, J=8.2Hz), 6.8-7.0(2H, m), 7.13(1H, d, J=7.3Hz), 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=6.7Hz), 3.90(2H, t, J=6.6Hz), 6.68(1H, d, J=8.1Hz), 6.8-7.1(2H, m), 7.14(1H, d, J=7Hz), 7.32(2H, d, J=8.7Hz), 7.39(1H, s), 7.46(2H, d, J=8.7Hz) 9) .sup.1 H--NMR(CDCl.sub.3).delta.: 1.99(2H, quint, J=6.5Hz), 2.82(2H, t, J=6.6Hz), 3.82(2H, t, J=6.5Hz), 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), 8.43(1H, s) 10) .sup.1 H--NMR(CDCl.sub.3).delta.: 2.00(2H, quint, J=6.5Hz), 2.83(2H, t, J=6.6Hz), 3.85(2H, t, J=6.6Hz), 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=6.5Hz), 2.82(2H, t, J=6.5Hz), 3.81(2H, t, J=6.5Hz), 3.84(3H, s), 6.8-7.5(10H, m), 7.68(1H, s), 7.95 (1H, d, J=8.2Hz), 8.52(1H, s) 12) .sup.1 H--NMR(CDCl.sub.3).delta.: 1.7-1.9(2H, m), 2.70(2H, t, J=6.6Hz), 3.70(2H, t, J=6.4Hz), 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=6.5Hz), 3.89(2H, t, J=6.4Hz), 6.8-7.2(6H, m), 7.42(1H, s), 7.56(1H, s), 7.81(1H, d, J=8.1Hz) 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=7.2Hz), 7.1-7.4(4H, m), 7.47(2H, d, J=8.6Hz), 7.58(1H, d, J=6.2Hz), 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=6.8Hz), 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=7.2Hz), 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=6.8Hz), 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=7.0Hz), 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=7.2Hz), 7.2-7.4 (6H, m), 7.5-7.7(3H, m), 7.84(2H, d, J=8.0Hz), 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=7.4Hz), 7.2-7.3(4H, m), 7.5- 7.8(5H, m), 7.75(1H, d, J=1.8Hz), 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(32H, m), 6.80(1H, d, J=7.2Hz), 7.1-7.3(4H, m), 7.6-7.7(3H, m), 7.85 (1H, s), 7.96(2H, d, J=1.8Hz), 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=7.6Hz), 7.2-7.4(6H, m), 7.6-7.7 (3H, m), 7.84(2H, d, J=8.2Hz), 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), 1.71-2.1(2H, m), 2.38(3H, s), 2.6-3.8(5H, m), 4.3-5.2(3H, m), 6.81(1H, d, J=7.0Hz), 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=7.2Hz), 7.1-7.5(8H, m), 7.5-7.76(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=7.0Hz), 7.1-7.4(4H, m), 7.46(2H, d, J=8.6Hz), 7.61(1H, d, J=6.4Hz), 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=7.0Hz), 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=7.1Hz), 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=7.3Hz), 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=1.9Hz), 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), 7.3Hz), 4.05(1H, dd, J=13.2Hz, 5.7Hz), 6.62 (1H, d, J=7.7Hz), 6.82-7.48(8H, m), 7.53(2H, d, J=8.4Hz), 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=15Hz, 5Hz), 3.70(1H, dd), J=12.5Hz, 8.0Hz), 4.22(1H, dd, J=12.5Hz, 5Hz), 6.67(1H, d, J=7.8 Hz), 6.80-7.32(7H, m), 7.37(2H, d, J=8.6Hz), 7.53(1H, d, J=8.3Hz), 7.66(1H, brs) 31) .sup.1 H--NMR(CDCl.sub.3).delta.: 2.80(1H, dd, J=16.1Hz, 5.3 Hz), 3.16(1H, dd, J=15.8Hz, 5.3Hz), 3.75-4.50 (3H, m), 4.87-5.10(3H, m), 6.80-7.60(14H, m), 7.74(2H, d, J=1.9Hz), 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=1.8Hz), 8.52(1H, brs) 33) .sup.1 H--NMR(CDCl.sub.3).delta.: 1.87(3H, s), 2.68(1H, dd, J=5.6Hz, 16Hz), 3.14(1H, dd, J=5.6Hz, 16Hz), 3.70-3.95(2H, m), 4.32-4.50(1H, m), 6.29(1H, d, J=7.6Hz), 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=5.1Hz), 3.95(2H, t, J=6.7Hz), 6.69(1H, t, J=7.9Hz), 6.90-7.13 (2H, m), 7.23-7.40(3H, m), 7.42-7.56(3H, m), 7.77 (2H, d, J=1.9Hz), 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=5.4Hz), 3.68-3.83(1H, m), 3.95-4.15(1H, m), 6.59(1H, d, J=7.8Hz), 6.81-7.10(2H, m), 7.16-7.50(6H, m), 7.80(2H, d, J=1.8Hz), 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=6.5Hz), 4.90-5.10(1H, m), 6.60(1H, d, J=8.0Hz), 6.90 (1H, t, J=8.0Hz), 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=8.0Hz), 6.85-7.45(12H, m), 9.27(1H, br) 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=7.1Hz), 1.25- 2.50(12H, m), 2.70-3.10(4H, m), 3.05(2H, s), 4.15(2H, q, J=7.0Hz), 4.90-5.10(1H, m), 6.63 (1H, d, J=7.5Hz), 6.91(1H, t, J=7.5Hz), 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=5.0Hz), 4.90-5.10(1H, m), 6.61(1H, d, J=7.7Hz), 6.89 (1H, t, J=7.0Hz), 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), 3.373(2H, s), 4.90-5.10(1H, m), 6.61(1H, d, J=7.3Hz), 6.70- 7.45(12H, m), 9.50(1H, brs) 42) .sup.1 H--NMR(CDCl.sub.3).delta.: 1.19(3H, t, J=7.0Hz), 1.30- 1.70(1H, m), 1.75-2.20(3H, m), 2.65-3.15(3H, m), 3.46(2H, q, J=7.0Hz), 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=7.2Hz), 1.05- 2.25(14H, m), 2.25-3.25(10H, m), 4.90-5.10(1H, m), 6.64(1H, d, J=7.6Hz), 6.90(1H, t, J=7.2Hz), 6.94-7.50(6H, m), 11.50(1H, brs) 44) .sup.1 H--NMR(CDCl.sub.3).delta.: 1.06(3H, t, J=7.5Hz), 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=6.7Hz), 4.00(2H, t, J=6.3Hz), 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. 224.5-225.5.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. 217-218.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. 170.5-171.5.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. 205.5-206.5.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. 202.5-203.5.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. 154-155.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. 215-217.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. 221-223.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. 207-210.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. 186-187.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. 165-167.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. 139-142.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. 172.5-175.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. 145-146.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. 91-95.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. 145-146.5.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. 135.5-137.5.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. 171-172.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. 178-178.5.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. 198-199.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. 214-243.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. 177-181.5.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______________________________________1 #STR836##______________________________________Example 406 Structure - 2 STR837## 3 STR838## -4 STR839## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 216-218.degree. C. Form: Free Example 407 Structure - 2 STR840## 3 STR841## -5 STR842## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 181-183.degree. C. Form: Free Example 408 Structure - 2 STR843## 3 STR844## -6 STR845## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 207-208.degree. C. Form: Free Example 409 Structure - 2 STR846## 3 STR847## -7 STR848## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 213-214.degree. C. Form: Free Example 410 Structure - 2 STR849## 0 STR850## -7 STR851## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 136-138.degree. C. Form: Free Example 411 Structure - 2 STR852## 0 STR853## -6 STR854## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 130-132.degree. C. Form: Free Example 412 Structure - 2 STR855## 0 STR856## -5 STR857## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 143-145.degree. C. Form: Free Example 413 Structure - 2 STR858## 0 STR859## -4 STR860## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 171-173.degree. C. Form: Free Example 414 Structure - 2 STR861## 0 STR862## -8 STR863## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 162-164.degree. C. Form: Free Example 415 Structure - 2 STR864## 9 STR865## -7 STR866## - Crystalline form: Colorless amorphous NMR analysis: 49) Form: Free Example 416 Structure - 2 STR867## 9 STR868## -4 STR869## - Crystalline form: Colorless amorphous NMR analysis: 50) Form: Free Example 417 Structure - 2 STR870## 4 STR871## -6 STR872## - Crystalline form: Colorless amorphous NMR analysis: 51) Form: Free Example 418 Structure - 2 STR873## 0 STR874## -4 STR875## - Crystalline form: Colorless needles Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 228.5-230.degree. C. Form: Free Example 419 Structure - 2 STR876## 1 STR877## -4 STR878## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting point: 205.5-206.5.degree. C. Form: Free Example 420 Structure - 2 STR879## 1 STR880## -2 STR881## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting point: 210-212.degree. C. Form: Free Example 421 Structure - 2 STR882## 3 STR883## -6 STR884## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 166-167.degree. C. Form: Free Example 422 Structure - 2 STR885## 3 STR886## -7 STR887## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 191.5-192.5.degree. C. Form: Free Example 423 Structure - 2 STR888## 3 STR889## -4 STR890## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 209-210.degree. C. Form: Free Example 424 Structure - 2 STR891## 3 STR892## -5 STR893## - Crystalline form: Colorless amorphous NMR analysis: 52) Form: Free Example 425 Structure - 2 STR894## 3 STR895## -8 STR896## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 148-149.degree. C. Form: Free Example 426 Structure - 2 STR897## 4 STR898## -6 STR899## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 157-158.degree. C. Form: Free Example 427 Structure - 2 STR900## 4 STR901## -7 STR902## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 194.5-195.5.degree. C. Form: Free Example 428 Structure - 2 STR903## 4 STR904## -4 STR905## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 179.5-180.5.degree. C. Form: Free Example 429 Structure - 2 STR906## 4 STR907## -5 STR908## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 190-191.degree. C. Form: Free Example 430 Structure - 2 STR909## 4 STR910## -8 STR911## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 159-160.degree. C. Form: Free Example 431 Structure - 2 STR912## 5 STR913## -6 STR914## - Crystalline form: Colorless amorphous NMR analysis: 53) Form: Hydrochloride Example 432 Structure - 2 STR915## 5 STR916## -7 STR917## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 155-156.degree. C. Form: Free Example 433 Structure - 2 STR918## 5 STR919## -4 STR920## - Crystalline form: Colorless amorphous NMR analysis: 54) Form: Free Example 434 Structure - 2 STR921## 5 STR922## -5 STR923## - Crystalline form: Colorless amorphous NMR analysis: 55) Form: Free Example 435 Structure - 2 STR924## 5 STR925## -8 STR926## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 175-177.degree. C. Form: Free Example 436 Structure - 2 STR927## 6 STR928## -6 STR929## - Crystalline form: Colorless amorphous NMR analysis: 56) Form: Free Example 437 Structure - 2 STR930## 6 STR931## -7 STR932## - Crystalline form: Colorless amorphous NMR analysis: 57) Form: Free Example 438 Structure - 2 STR933## 7 STR934## -6 STR935## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 219-220.degree. C. Form: Free Example 439 Structure - 2 STR936## 7 STR937## -7 STR938## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 215-218.degree. C. Form: Free Example 440 Structure - 2 STR939## 8 STR940## -9 STR941## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 128.5-129.5.degree. C. Form: Free Example 441 Structure - 2 STR942## 8 STR943## -0 STR944## - Crystalline form: Colorless amorphous NMR analysis: 58) Form: Free Example 442 Structure - 2 STR945## 8 STR946## - -1 STR947## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 153-154.degree. C. Form: Free Example 443 Structure - 2 STR948## 8 STR949## -2 STR950## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 150-153.degree. C. Form: Free Example 444 Structure - 2 STR951## 8 STR952## -3 STR953## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 139-141.degree. C. Form: Free Example 445 Structure - 2 STR954## 8 STR955## -4 STR956## - Crystalline form: Colorless amorphous NMR analysis: 59) Form: Free Example 446 Structure - 2 STR957## 8 STR958## -9 STR959## - Crystalline form: Colorless amorphous NMR analysis: 60) Form: Free Example 447 Structure - 2 STR960## 8 STR961## -5 STR962## - Crystalline form: Colorless amorphous NMR analysis: 61) Form: Free Example 448 Structure - 2 STR963## 8 STR964## -6 STR965## - Crystalline form: Colorless amorphous NMR analysis: 62) Form: Free Example 449 Structure - 2 STR966## 1 STR967## -8 STR968## - Crystalline form: Colorless amorphous NMR analysis: 63) Form: Free Example 450 Structure - 2 STR969## 7 STR970## -9 STR971## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 172.5-173.5.degree. C. Form: Free Example 451 Structure - 2 STR972## 7 STR973## -0 STR974## - Crystalline form: Colorless prisms Recrystallization solvent: Methanol/diethyl ether Melting Point: 122.5-123.degree. C. Form: Free Example 452 Structure - 2 STR975## 7 STR976## -1 STR977## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 198-199.5.degree. C. Form: Free Example 453 Structure - 2 STR978## 7 STR979## -2 STR980## - Crystalline from: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 118-119.5.degree. C. Form: Hydrochloride Example 454 Structure - 2 STR981## 7 STR982## -3 STR983## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 163-165.degree. C. Form: Dihydrochloride Example 455 Structure - 2 STR984## 7 STR985## -4 STR986## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 246-248.degree. C. Form: Hydrochloride Example 456 Structure - 2 STR987## 7 STR988## -5 STR989## - Crystalline form: White powder Recrystallization solvent: Chloroform/ethanol Melting Point: 204-205.degree. C. Form: Free Example 457 Structure - 2 STR990## 7 STR991## -6 STR992## - Crystalline form: Colorless prisms Recrystallization solvent: Methanol/diethyl ether Melting Point: 127-128.degree. C. Form: Hydrochloride Example 458 Structure - 2 STR993## 7 STR994## -7 STR995## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 220-221.degree. C. Form: Free Example 459 Structure - 2 STR996## 7 STR997## -8 STR998## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 190-192.degree. C. Form: Free Example 460 Structure - 2 STR999## 7 STR1000## -9 STR1001## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 189-191.degree. C. Form: Hydrochloride Example 461 Structure - 2 STR1002## 7 STR1003## -0 STR1004## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 173-174.degree. C. Form: Free Example 462 Structure - 2 STR1005## 7 STR1006## -1 STR1007## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ethanol Melting Point: 129-130.degree. C. Form: Free Example 463 Structure - 2 STR1008## 7 STR1009## -2 STR1010## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 130-133.degree. C. Form: Hydrochloride Example 464 Structure - 2 STR1011## 7 STR1012## -3 STR1013## - Crystalline form: Light yellow powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 170.5-172.degree. C. Form: Hydrochloride Example 465 Structure - 2 STR1014## 7 STR1015## -4 STR1016## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 126-131.degree. C. Form: Hydrochloride Example 466 Structure - 2 STR1017## 7 STR1018## -5 STR1019## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 182-185.degree. C. Form: Dihydrochloride Example 467 Structure - 2 STR1020## 7 STR1021## -6 STR1022## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 116-121.degree. C. Form: Hydrochloride Example 468 Structure - 2 STR1023## 7 STR1024## -7 STR1025## - Crystalline form: Colorless prisms Recrystallization solvent: Methanol/diethyl ether Melting Point: 178-182.5.degree. C. Form: Free Example 469 Structure - 2 STR1026## 7 STR1027## -8 STR1028## - Crystalline form: Colorless particles Recrystallization solvent: Methanol/diethyl ether Melting Point: 185-187.degree. C. Form: Free Example 470 Structure - 2 STR1029## 7 STR1030## -9 STR1031## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 215-217.degree. C. Form: Free Example 471 Structure - 2 STR1032## 7 STR1033## -0 STR1034## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 176-178.degree. C. Form: Free Example 472 Structure - 2 STR1035## 7 STR1036## -1 STR1037## - Crystalline form: Light yellow powder Recrystallization solvent: Methanol/n-hexane Melting Point: 194.5-197.degree. C. Form: Free Example 473 Structure - 2 STR1038## 7 STR1039## -2 STR1040## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 161.5-165.5.degree. C. Form: Hydrochloride Example 474 Structure - 2 STR1041## 7 STR1042## -3 STR1043## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point 152-153.degree. C. Form: Free Example 475 Structure - 2 STR1044## 7 STR1045## -4 STR1046## - Crystalline form: Colorless needles Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 147-148.degree. C. Form: Free Example 476 Structure - 2 STR1047## 7 STR1048## -5 STR1049## - Crystalline form: Light yellow powder Recrystallization solvent: Ethyl acetate Melting Point: 25-217.degree. C. Form: Free Example 477 Structure - 2 STR1050## 7 STR1051## -6 STR1052## - Crystalline form: Colorless amorphous NMR analysis: 64) Form: Free Example 478 Structure - 2 STR1053## 7 STR1054## -7 STR1055## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 180-181.degree. C. Form: Free Example 479 Structure - 2 STR1056## 7 STR1057## -8 STR1058## - Crystalline form: Colorless amorphous NMR analysis: 65) Form: Free Example 480 Structure - 2 STR1059## 7 STR1060## -9 STR1061## - Crystalline form: Colorless amorphous NMR analysis: 66) Form: Free Example 481 Structure - 2 STR1062## 7 STR1063## -0 STR1064## - Crystalline form: Colorless amorphous NMR analysis: 67) Form: Free Example 482 Structure - 2 STR1065## 7 STR1066## -1 STR1067## - Crystalline form: Colorless scales Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 165-167.degree. C. Form: Free Example 483 Structure - 2 STR1068## 7 STR1069## -2 STR1070## - Crystalline form: Colorless amorphous NMR analysis: 68) Form: Free Example 484 Structure - 2 STR1071## 7 STR1072## -3 STR1073## - Crystalline form: Colorless amorphous NMR analysis: 69) Form: Free Example 485 Structure - 2 STR1074## 7 STR1075## -4 STR1076## - Crystalline form: Colorless amorphous NMR analysis: 70) Form: Free Example 486 Structure - 2 STR1077## 7 STR1078## -5 STR1079## - Crystalline form: Colorless amorphous NMR analysis: 71) Form: Free Example 487 Structure - 2 STR1080## 7 STR1081## -6 STR1082## - Crystalline form: Colorless amorphous NMR analysis: 72) Form: Free Example 488 Structure - 2 STR1083## 7 STR1084## -7 STR1085## - Crystalline form: Colorless amorphous NMR analysis: 73) Form: Free Example 489 Structure - 2 STR1086## 7 STR1087## -8 STR1088## - Crystalline form: Light yellow amorphous NMR analysis: 74) Form: Free Example 490 Structure - 2 STR1089## 7 STR1090## -9 STR1091## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 182-182.5.degree. C. Form: Free Example 491 Structure - 2 STR1092## 7 STR1093## -0 STR1094## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 244-245.degree. C. Form: Free Example 492 Structure - 2 STR1095## 7 STR1096## -1 STR1097## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 220-221.5.degree. C. Form: Free Example 493 Structure 2 STR1098## 2 STR1099## -3 STR1100## - Crystalline form: Light yellow amorphous NMR analysis: 75) Form: Free Example 494 Structure 2 STR1101## 2 STR1102## -3 STR1103## - Crystalline form: Light yellow amorphous NMR analysis: 76) Form: Free Example 495 Structure - 2 STR1104## 7 STR1105## -4 STR1106## - Crystalline form: Colorless needles Recrystallization solvent: Methanol/diethyl ether Melting Point: 171-172.degree. C. Form: Free Example 496 Structure - 2 STR1107## 7 STR1108## -5 STR1109## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 178-178.5.degree. C. Form: Free Example 497 Structure - 2 STR1110## 7 STR1111## -6 STR1112## - Example 498 Structure - 2 STR1113## 7 STR1114## -7 STR1115## - Example 499 Structure - 2 STR1116## 7 STR1117## -8 STR1118## - Example 500 Structure - 2 STR1119## 7 STR1120## -9 STR1121## - Example 501 Structure - 2 STR1122## 7 STR1123## -0 STR1124## - Example 502 Structure - 2 STR1125## 7 STR1126## -1 STR1127## - Example 503 Structure - 2 STR1128## 7 STR1129## -2 STR1130## - Example 504 Structure - 2 STR1131## 7 STR1132## -3 STR1133## - Crystalline form: Light yellow scales Recrystallization solvent: Ethanol/water Melting Point: 129-131.degree. C. Form: Free Example 505 Structure - 2 STR1134## 7 STR1135## -4 STR1136## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 199-201.degree. C. Form: Free Example 506 Structure - 2 STR1137## 5 STR1138## -6 STR1139## - Crystalline form: Colorless amorphous NMR analysis: 77) Form: Free Example 507 Structure - 2 STR1140## 5 STR1141## -8 STR1142## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 187.5-189.degree. C. Form: Free Example 508 Structure - 2 STR1143## 6 STR1144## -7 STR1145## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 161-164.degree. C. Form: Free Example 509 Structure - 2 STR1146## 6 STR1147## -4 STR1148## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 242-243.degree. C. Form: Free Example 510 Structure - 2 STR1149## 1 STR1150## -R.sup.3 : 4-NHCOCH.sub.2 Cl Crystalline form: White powder Recrystallization solvent: Dichloroethane/diethyl ether Melting Point: 186-188.degree. C. Form: Free Example 511 Structure - 2 STR1151## 7 STR1152## -7 STR1153## - Crystalline form: Colorless amorphous NMR analysis: 78) Form: Free Example 512 Structure - 2 STR1154## 7 STR1155## -8 STR1156## - Crystalline form: Colorless amorphous NMR analysis: 79) Form: Free______________________________________ 49) .sup.1 H-NMR(CDCl.sub.3).delta.; 1.11(3H, t, J=7.1Hz), 1.90-2.25 (2H, m), 2.29(3H, s), 2.55(2H, q, J=7.1Hz), 3.62-3.90(2H, m), 4.00-4.20(1H, m), 6.63(1H, d, J=7.9Hz), 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=7.1Hz), 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=7.9Hz), 6.80-7.10(2H, m), 7.20(2H, d, J=8.6Hz), 7.31-7.55(4H, m), 7.80 (2H, d, J=1.9Hz), 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=7.8Hz), 6.84-7.58(9H, m), 8.16 (1H, brs), 8.40(1H, d, J=8.7Hz) 52) .sup.1 H-NMR(CDCl.sub.3).delta.; 1.16(3H, t, J=7.1Hz), 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=7.6Hz), 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=13Hz), 3.81(1H, d, J=14Hz), 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=13Hz), 3.85(1H, d, J=13Hz), 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=14Hz), 4.06(1H, d, J=14Hz), 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=8Hz), 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=13Hz), 4.07(1H, d, J=14Hz), 4.80-5.00(1H, m), 6.67(1H, d, J=7Hz), 6.76(1H, d, J=7Hz), 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=13Hz), 4.03(1H, d, J=14Hz), 6.66 (2H, d, J=7.6Hz), 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=13Hz), 4.07(1H, d, J=13Hz), 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=14Hz), 4.08(1H, d, J=14Hz), 4.80- 5.00(1H, m), 6.67(1H, d, J=7.6Hz), 6.82(1H, d, J=7.6Hz), 6.90-7.90(10H, m), 8.08(1H, s) 63) .sup.1 H-NMR(CDCl.sub.3).delta.; 1.23(3H, t, J=7Hz), 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=8Hz), 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=7.5Hz), 6.75-7.50(12H, m), 8.44(1H, brs) 65) .sup.1 H-NMR(CDCl.sub.3).delta.; 1.13(3H, t, J=7.0Hz), 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=7.8Hz), 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=7.4Hz), 1.16(3H, t, J=7.0Hz), 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=7.4Hz), 6.67(2H, d, J=8.5Hz), 6.92(1H, t, J=8.0Hz), 7.00-7.45(8H, m), 8.85(1H, brs) 67) .sup.1 H-NMR(CDCl.sub.3).delta.; 1.17(3H, t, J=7.0Hz), 1.35-1.65 (4H, m), 2.60-3.45(5H, m), 4.20(2H, q, J=7.0Hz), 4.90-5.10(1H, m), 6.63(1H, d, J=7.6Hz), 6.80- 7.45(12H, m), 8.66(1H, brs) 68) .sup.1 H-NMR(CDCl.sub.3).delta.; 0.96(6H, d, J=6.6Hz), 1.35-1.65 (1H, m), 1.80-2.25(4H, m), 2.65-3.15(3H, m), 3.19 (2H, d, J=7.3Hz), 3.99(2H, s), 4.90-5.10(1H, m), 6.60(1H, d, J=7.8Hz), 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=7.0Hz), 1.35-1.65 (1H, m), 1.80-2.25(3H, m), 2.70-3.20(3H, m), 3.44 (2H, q, J=7.0Hz), 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=7.5Hz), 6.85-7.45(8H, m), 8.29(1H, brs) 70) .sup.1 H-NMR(CDCl.sub.3).delta.; 1.05(3H, t, J=7.1Hz), 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=7.5Hz), 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=6.8Hz), 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=5.4Hz), 4.28 (2H, d, J=5.5Hz), 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=7.5Hz), 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=7.0Hz), 2.39(3H, s), 2.80-3.20(3H, m), 3.44(2H, q, J=7.0Hz), 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=7.0Hz), 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=7.6Hz), 6.92 (1H, t, J=7.6Hz), 7.02(1H, t, J=6.3Hz), 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=4.9Hz), 4.43 (2H, t, J=4.9Hz), 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=5.7Hz), 4.25 (2H, t, J=5.7Hz), 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. 182-182.5.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. 178-182.5.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 9) 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 ar 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. 194.5-197.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. 205.5-206.5.degree. C.
The latter: White powder, m.p. 210.5-212.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______________________________________1 #STR1157##______________________________________ Example 527 Structure2 STR1158## - R.sup.2 : 2-Cl -3 STR1159## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 225-226.degree. C. Form: Free Example 528 Structure -4 STR1160## - R.sup.2 : 2-Cl -5 STR1161## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 142.5-145.degree. C. Form: Free Example 529 Structure -6 STR1162## - R.sup.2 : 2-Cl -7 STR1163## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 213-215.degree. C. Form: Free Example 530 Structure -8 STR1164## - R.sup.2 : 3-CH.sub.3 -9 STR1165## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 167-167.5.degree. C. Form: Free Example 531 Structure -0 STR1166## - R.sup.2 : 3-CH.sub.3 -1 STR1167## - Crystalline form: Colorless scales Recrystallization solvent: Methanol/diethyl ether Melting Point: 217-221.degree. C. Form: Free Example 532 Structure -2 STR1168## - R.sup.2 : 3-CH.sub.3 -3 STR1169## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 182-184.degree. C. Form: Free Example 533 Structure -4 STR1170## - R.sup.2 : 3-CH.sub.3 -5 STR1171## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 209-210.degree. C. Form: Free Example 534 Structure -6 STR1172## - R.sup.2 : 3-OCH.sub.3 -7 STR1173## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting point: 148-149.degree. C. Form: Free Example 535 Structure -8 STR1174## - R.sup.2 : H -9 STR1175## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting point: 202-203.degree. C. Form: Free Example 536 Structure -0 STR1176## - R.sup.2 : 3-CH.sub.3 -1 STR1177## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 218-219.degree. C. Form: Free Example 537 Structure -2 STR1178## - R.sup.2 : 2-Cl -3 STR1179## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 159-160.degree. C. Form: Free Example 538 Structure -4 STR1180## - R.sup.2 : 2-Cl -5 STR1181## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 201-202.degree. C. Form: Free Example 539 Structure -6 STR1182## - R.sup.2 : 2-Cl -7 STR1183## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 205-207.degree. C. Form: Free Example 540 Structure -8 STR1184## - R.sup.2 : 3-OH -9 STR1185## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting point: 201.5-202.5.degree. C. Form: Free Example 541 Structure -0 STR1186## - R.sup.2 : 2-OCH.sub.3 -1 STR1187## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 226-228.degree. C. Form: Free Example 542 Structure -2 STR1188## - R.sup.2 : 2-OCH.sub.3 -3 STR1189## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 218-221.degree. C. Form: Free Example 543 Structure -4 STR1190## - R.sup.2 : 2-OCH.sub.3 -5 STR1191## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 156-157.degree. C. Form: Free Example 544 Structure -6 STR1192## - R.sup.2 : 2-OCH.sub.3 -7 STR1193## - Crystalline form: White powder NMR analysis: 80) Form: Free Example 545 Structure -8 STR1194## - R.sup.2 : 3-OCH.sub.3 -9 STR1195## - Crystalline form: Colorless amorphous NMR analysis: 81) Form: Free Example 546 Structure -0 STR1196## - R.sup.2 : H -1 STR1197## - Crystalline form: Colorless amorphous NMR analysis: 82) Form: Free Example 547 Structure -2 STR1198## - R.sup.2 : H -3 STR1199## - Crystalline form: Light yellow amorphous NMR analysis: 83) Form: Free Example 548 Structure -4 STR1200## - R.sup.2 : H -5 STR1201## - Crystalline form: Colorless amorphous NMR analysis: 84) Form: Free Example 549 Structure -6 STR1202## - R.sup.2 : H -7 STR1203## - Crystalline form: Colorless amorphous NMR analysis: 85) Form: Free Example 550 Structure -8 STR1204## - R.sup.2 : 3-OCH.sub.2 CH.sub.3 -9 STR1205## - Crystalline form: White powder Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 135-136.degree. C. Form: Free Example 551 Structure -0 STR1206## - R.sup.2 : 3-OCH.sub.2 CH.sub.3 -1 STR1207## - Crystalline form: Colorless prisms Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 122-123.degree. C. Form: Free Example 552 Structure -2 STR1208## - R.sup.2 : 3-OCH.sub.2 CH.sub.3 -3 STR1209## - Crystalline form: Colorless prisms Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 118-119.degree. C. Form: Free Example 553 Structure -4 STR1210## -5 STR1211## -6 STR1212## - Crystalline form: Colorless prisms Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 145-147.degree. C. Form: Free Example 554 Structure -7 STR1213## -8 STR1214## -9 STR1215## - Crystalline form: Light yellow needles Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 169.5-170.5.degree. C. Form: Free Example 555 Structure -0 STR1216## - R.sup.2 : 3-OH -1 STR1217## - Crystalline form: Colorless prisms Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 194-195.degree. C. Form: Free Example 556 Structure -2 STR1218## - R.sup.2 : 3-OH -3 STR1219## - Crystalline form: Colorless needles Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 202-204.degree. C. Form: Free Example 557 Structure -4 STR1220## - R.sup.2 : H -5 STR1221## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 242-243.degree. C. Form: Free Example 558 Structure -6 STR1222## - R.sup.2 : H -7 STR1223## - Crystalline form: Light yellow powder NMR analysis: 86) Form: Free Example 559 Structure -8 STR1224## - R.sup.2 : H -9 STR1225## - Crystalline form: Light yellow powder NMR analysis: 87) Form: Free Example 560 Structure -0 STR1226## - R.sup.2 : H -1 STR1227## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 237-238.degree. C. Form: Free Example 561 Structure -2 STR1228## - R.sup.2 : H -3 STR1229## - Crystalline form: Colorless prisms Recrystallization solvent: Dioxane Melting Point: 258-259.degree. C. Form: Free Example 562 Structure -4 STR1230## - R.sup.2 : H -5 STR1231## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 182.5-183.5.degree. C. Form: Free Example 563 Structure -6 STR1232## - R.sup.2 : H -7 STR1233## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 209-211.degree. C. Form: Free Example 564 Structure -8 STR1234## - R.sup.2 : H -9 STR1235## - Crystalline form: Colorless prisms Recrystallization solvent: Dioxane Melting Point: 210-211.degree. C. Form: Free Example 565 Structure -0 STR1236## - R.sup.2 : H -1 STR1237## - Crystalline form: Colorless needles Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 176-178.degree. C. Form: Free Example 566 Structure -2 STR1238## - R.sup.2 : H -3 STR1239## - Crystalline form: Light yellow amorphous NMR analysis: 88) Form: Free Example 567 Structure -4 STR1240## - R.sup.2 : H -5 STR1241## - Crystalline form: White powder Recrystallization solvent: Dioxane/water Melting Point: 272-273.degree. C. Form: Free Example 568 Structure -6 STR1242## - R.sup.2 : H -7 STR1243## - Crystalline form: Colorless prisms Recrystallization solvent: Dioxane Melting Point: 253-254.degree. C. Form: Free Example 569 Structure -8 STR1244## - R.sup.2 : H -9 STR1245## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 248.5-249.5.degree. C. Form: Free Example 570 Structure -0 STR1246## - R.sup.2 : H -1 STR1247## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 266.5-267.5.degree. C. Form: Free Example 571 Structure -2 STR1248## - R.sup.2 : H -3 STR1249## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 252-253.degree. C. Form: Free Example 572 Structure -4 STR1250## - R.sup.2 : H -5 STR1251## - Crystalline form: Light yellow powder NMR analysis: 89) Form: Free Example 573 Structure -6 STR1252## - R.sup.2 : H -7 STR1253## - Crystalline form: Light brown powder NMR analysis: 90) Form: Free Example 574 Structure -8 STR1254## - R.sup.2 : H -9 STR1255## - Crystalline form: White powder Recrystallization solvent: Diethyl ether Melting Point: 198.5-199.5.degree. C. Form: Free Example 575 Structure -0 STR1256## - R.sup.2 : H -1 STR1257## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 297-299.degree. C. Form: Free Example 576 Structure -2 STR1258## - R.sup.2 : 2-Cl -3 STR1259## - Crystalline form: Colorless amorphous NMR analysis: 91) Form: Free Example 577 Structure -4 STR1260## - R.sup.2 : 2-Cl -5 STR1261## - Crystalline form: White powder Recrystallization solvent: Ethanol/petroleum ether Melting Point: 202-203.degree. C. Form: Free Example 578 Structure -6 STR1262## - R.sup.2 : H -7 STR1263## - Crystalline form: Colorless amorphous NMR analysis: 92) Form: Free Example 579 Structure -8 STR1264## - R.sup.2 : H -9 STR1265## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 232-233.degree. C. Form: Free Example 580 Structure -0 STR1266## - R.sup.2 : H -1 STR1267## - Crystalline form: Colorless amorphous NMR analysis: 93) Form: Free Example 581 Structure -2 STR1268## - R.sup.2 : H -3 STR1269## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting point: 256.5-257.degree. C. Form: Free Example 582 Structure -4 STR1270## - R.sup.2 : H -5 STR1271## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 193-194.degree. C. Form: Free Example 583 Structure -6 STR1272## - R.sup.2 : H -7 STR1273## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 227-230.degree. C. Form: Free Example 584 Structure -8 STR1274## - R.sup.2 : H -9 STR1275## - Crystalline form: White powder Recrystallization soivent: Ethyl acetate/n-hexane Melting Point: 199.5-202.degree. C. Form: Free Example 585 Structure -0 STR1276## - R.sup.2 : H -1 STR1277## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 219-220.degree. C. Form: Free Example 586 Structure -2 STR1278## - R.sup.2 : H -3 STR1279## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 190-191.5.degree. C. Form: Free Example 587 Structure -4 STR1280## - R.sup.2 : H -5 STR1281## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 184-185.degree. C. Form: Free Example 588 Structure -6 STR1282## - R.sup.2 : H -7 STR1283## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 223-224.degree. C. Form: Free Example 589 Structure -8 STR1284## - R.sup.2 : H -9 STR1285## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 178-181.degree. C. Form: Free Example 590 Structure -0 STR1286## - R.sup.2 : H -1 STR1287## - Crystalline form: Colorless needles Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 168-168.5.degree. C. Form: Free Example 591 Structure -2 STR1288## - R.sup.2 : H -3 STR1289## - Crystalline form: Colorless amorphous NMR analysis: 94) Form: Free Example 592 Structure -4 STR1290## - R.sup.2 : H -5 STR1291## - Crystalline form: Colorless amorphous NMR analysis: 95) Form: Free Example 593 Structure -6 STR1292## - R.sup.2 : H -7 STR1293## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 195-197.degree. C. Form: Free Example 594 Structure -8 STR1294## - R.sup.2 : H -9 STR1295## - Crystalline form: Colorless amorphous NMR analysis: 96) Form: Free Example 595 Structure -0 STR1296## - R.sup.2 : H -1 STR1297## - Crystalline form: White powder Recrystallization solvent: Ethanol/water Melting Point: 188-189.degree. C. Form: Free Example 596 Structure -2 STR1298## - R.sup.2 : H -3 STR1299## - Crystalline form: Colorless amorphous NMR analysis: 97) Form: Free Example 597 Structure -4 STR1300## - R.sup.2 : H -5 STR1301## - Crystalline form: Colorless amorphous NMR analysis: 98) Form: Free Example 598 Structure -6 STR1302## - R.sup.2 : H -7 STR1303## - Crystalline form: Colorless prisms Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 203-204.degree. C. Form: Free Example 599 Structure -8 STR1304## - R.sup.2 : H -9 STR1305## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 196-197.degree. C. Form: Free Example 600 Structure -0 STR1306## - R.sup.2 : H -1 STR1307## - Crystalline form: Colorless amorphous NMR analysis: 99) Form: Free Example 601 Structure -2 STR1308## - R.sup.2 : H -3 STR1309## - Crystalline form: Colorless amorphous NMR analysis: 100) Form: Free Example 602 Structure -4 STR1310## - R.sup.2 : H -5 STR1311## - Crystalline form: Colorless amorphous NMR analysis: 101) Form: Free Example 603 Structure -6 STR1312## - R.sup.2 : H -7 STR1313## - Crystalline form: Colorless amorphous NMR analysis: 102) Form: Free Example 604 Structure -8 STR1314## - R.sup.2 : H -9 STR1315## - Crystalline form: Colorless amorphous NMR analysis: 103) Form: Free Example 605 Structure -0 STR1316## - R.sup.2 : H -1 STR1317## - Crystalline form: Colorless amorphous NMR analysis: 104) Form: Free Example 606 Structure -2 STR1318## - R.sup.2 : H -3 STR1319## - Crystalline form: Colorless amorphous NMR analysis: 105) Form: Free Example 607 Structure -4 STR1320## - R.sup.2 : H -5 STR1321## - Crystalline form: Cololess needles Recrystallization solvent: Ethanol Melting Point: 169-171.degree. C. Form: Free Example 608 Structure -6 STR1322## - R.sup.2 : H -7 STR1323## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol/diethyl ether Melting Point: 178-181.degree. C. Form: Free Example 609 Structure -8 STR1324## - R.sup.2 : H -9 STR1325## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 187-188.degree. C. Form: Free Example 610 Structure -0 STR1326## - R.sup.2 : H -1 STR1327## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 181-183.degree. C. Form: Free Example 611 Structure -2 STR1328## - R.sup.2 : H -3 STR1329## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 124-127.degree. C. Form: Free Example 612 Structure -4 STR1330## - R.sup.2 : H -5 STR1331## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 179-181.degree. C. Form: Free Example 613 Structure -6 STR1332## - R.sup.2 : H -7 STR1333## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 148-150.degree. C. Form: Free Example 614 Structure -8 STR1334## - R.sup.2 : H -9 STR1335## - Crystalline form: Colorless amorphous NMR analysis: 106) Form: Free Example 615 Structure -0 STR1336## - R.sup.2 : 2-Cl -1 STR1337## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 219-220.degree. C. Form: Free Example 616 Structure -2 STR1338## - R.sup.2 : H -3 STR1339## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 226-228.degree. C. Form: Free Example 617 Structure -4 STR1340## - R.sup.2 : 3-OCH.sub.3 -5 STR1341## - Crystalline form: Colorless amorphous NMR analysis: 107) Form: Free Example 618 Structure -6 STR1342## - R.sup.2 : 3-OCH.sub.3 -7 STR1343## - Crystalline form: Colorless amorphous NMR analysis: 108) Form: Free Example 619 Structure -8 STR1344## - R.sup.2 : 3-OCH.sub.3 -9 STR1345## - Crystalline form: Colorless amorphous NMR analysis: 109) Form: Free Example 620 Structure -0 STR1346## - R.sup.2 : H -1 STR1347## - Crystalline form: Colorless amorphous NMR analysis: 110) Form: Free Example 621 Structure -2 STR1348## - R.sup.2 : H -3 STR1349## - Crystalline form: Colorless amorphous NMR analysis: 111) Form: Free Example 622 Structure -4 STR1350## - R.sup.2 : H -5 STR1351## - Crystalline form: Colorless amorphous NMR analysis: 112) Form: Free Example 623 Structure -6 STR1352## - R.sup.2 : 3-OCH.sub.3 -7 STR1353## - Crystalline form: Colorless amorphous NMR analysis: 113) Form: Free Example 624 Structure -8 STR1354## - R.sup.2 : 3-OCH.sub.3 -9 STR1355## - Crystalline form: Colorless amorphous NMR analysis: 114) Form: Free Example 625 Structure -0 STR1356## - R.sup.2 : 3-OCH.sub.3 -1 STR1357## - Crystalline form: Colorless amorphous NMR analysis: 115) Form: Free Example 626 Structure -2 STR1358## - R.sup.2 : H -3 STR1359## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 183-184.degree. C. Form: Free Example 627 Structure -4 STR1360## - R.sup.2 : H -5 STR1361## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 219-220.degree. C. Form: Free Example 628 Structure -6 STR1362## - R.sup.2 : H -7 STR1363## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 240-241.degree. C. Form: Free Example 629 Structure -8 STR1364## - R.sup.2 : H -9 STR1365## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 205-206.degree. C. Form: Free Example 630 Structure -0 STR1366## - R.sup.2 : H -1 STR1367## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 238-239.degree. C. Form: Free Example 631 Structure -2 STR1368## - R.sup.2 : H -3 STR1369## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 233-234.degree. C. Form: Free Example 632 Structure -4 STR1370## - R.sup.2 : 2-Cl -5 STR1371## - Crystalline form: Colorless amorphous NMR analysis: 116) Form: Free Example 633 Structure -6 STR1372## - R.sup.2 : 2-Cl -7 STR1373## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting 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), 2.4 (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- 5.2 (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. 272-273.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 9) 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. 198.5-199.5.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. 193-194.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. 203-204.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. 201.5-202.5.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 9) 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. 219-220.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. 240-241.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 9) 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. 178-181.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. 184.5-185.5.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______________________________________1 #STR1374##______________________________________Example 654 Structure2 STR1375## - R.sup.2 : 2-OH -3 STR1376## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 193.5-196.degree. C. Form: Free Example 655 Structure -4 STR1377## - R.sup.2 : 2-OH -5 STR1378## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 195-198.degree. C. Form: Free Example 656 Structure -6 STR1379## - R.sup.2 : 2-OC.sub.2 H.sub.5 -7 STR1380## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 230.5-231.5.degree. C. Form: Free Example 657 Structure -8 STR1381## - R.sup.2 : 2-OC.sub.2 H.sub.5 -9 STR1382## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 223-224.5.degree. C. Form: Free Example 658 Structure -0 STR1383## - R.sup.2 : 2-OC.sub.2 H.sub.5 -1 STR1384## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 173-174.degree. C. Form: Free Example 659 Structure -2 STR1385## - R.sup.2 : 3-CH.sub.3 -3 STR1386## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 174-175.degree. C. Form: Free Example 660 Structure -4 STR1387## - R.sup.2 : 3-CH.sub.3 -5 STR1388## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 198-200.degree. C. Form: Free Example 661 Structure6 STR1389## - R.sup.2 : 3-CH.sub.3 -7 STR1390## - Crystalline form: White powder Recrystaliization solvent: Methanol/n-hexane Melting Point: 149-150.5.degree. C. Form: Free Example 662 Structure -8 STR1391## - R.sup.2 : 2-CH.sub.3 -9 STR1392## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 183-185.degree. C. Form: Free Example 663 Structure -0 STR1393## - R.sup.2 : 2-CH.sub.3 -1 STR1394## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 203-207.degree. C. Form: Free Example 664 Structure -2 STR1395## - R.sup.2 : 2-CH.sub.3 -3 STR1396## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 221-222.degree. C. Form: Free Example 665 Structure -4 STR1397## - R.sup.2 : 2-F -5 STR1398## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 189-191.degree. C. Form: Free Example 666 Structure6 STR1399## - R.sup.2 : 2-F -7 STR1400## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 215.5-217.degree. C. Form: Free Example 667 Structure -8 STR1401## - R.sup.2 : 2-F -9 STR1402## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 192-194.degree. C. Form: Free Example 668 Structure -0 STR1403## - R.sup.2 : 3-F -1 STR1404## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 195-196.degree. C. Form: Free Example 669 Structure -2 STR1405## - R.sup.2 : 3-F -3 STR1406## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 202-204.5.degree. C. Form: Free Example 670 Structure -4 STR1407## - R.sup.2 : H -5 STR1408## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 183-187.degree. C. Form: Free Example 671 Structure -6 STR1409## - R.sup.2 : H -7 STR1410## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 120-122.degree. C. Form: Free Example 672 Structure -8 STR1411## - R.sup.2 : H -9 STR1412## - Crystalline form: White powder Recrystallization solvent: Chloroform/ diethyl ether Melting Point: 208-210.degree. C. Form: Free Example 673 Structure -0 STR1413## - R.sup.2 : 2-OCH.sub.3 -1 STR1414## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 182-183.degree. C. Form: Free Example 674 Structure -2 STR1415## - R.sup.2 : 2-OCH.sub.3 -3 STR1416## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 257-259.degree. C. Form: Free Example 675 Structure -4 STR1417## - R.sup.2 : 2-OC.sub.2 H.sub.5 -5 STR1418## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ diethyl ether Melting Point: 134-135.degree. C. Form: Free Example 676 Structure -6 STR1419## - R.sup.2 : 2-OCH.sub.3 -7 STR1420## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 167-169.degree. C Form: Free Example 677 Structure -8 STR1421## - R.sup.2 : 2-Cl -9 STR1422## - Crystalline form: Light brown prisms Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 170-172.degree. C. Form: Free Example 678 Structure -0 STR1423## -1 STR1424## -2 STR1425## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 181.5-182.5.degree. C. Form: Free Example 679 Structure -3 STR1426## -4 STR1427## -5 STR1428## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 176.5-177.degree. C. Form: Free Example 680 Structure -6 STR1429## - R.sup.2 : 2-Cl -7 STR1430## - Crystalline form: Yellow amorphous NMR analysis: 117) Form: Free Example 681 Structure -8 STR1431## - R.sup.2 : 2-Cl -9 STR1432## - Crystalline form: Yellow amorphous NMR analysis: 118) Form: Free Example 682 Structure -0 STR1433## - R.sup.2 : H -1 STR1434## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 236-239.degree. C. Form: Free Example 683 Structure -2 STR1435## - R.sup.2 : H -3 STR1436## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 153-154.degree. C. Form: Free Example 684 Structure -4 STR1437## - R.sup.2 : H -5 STR1438## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 128-130.degree. C. Form: Free Example 685 Structure -6 STR1439## - R.sup.2 : H -7 STR1440## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 231-234.degree. C. Form: Free Example 686 Structure -8 STR1441## - R.sup.2 : H -9 STR1442## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 246-248.degree. C. Form: Free Example 687 Structure -0 STR1443## - R.sup.2 : H -1 STR1444## - Crystalline form: White powder Recrystallization solvent: Ethanol/water Melting Point: 248-248.5.degree. C. Form: Free Example 688 Structure -2 STR1445## - R.sup.2 : H -3 STR1446## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ diethyl ether Melting Point: 204-205.degree. C. Form: Free Example 689 Structure -4 STR1447## - R.sup.2 : H -5 STR1448## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ diethyl ethyl Melting Point: >300.degree. C. NMR analysis: 119) Form: Free Example 690 Structure -6 STR1449## - R.sup.2 : H -7 STR1450## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ diethyl ether Melting Point: 292-294.degree. C. Form: Free Example 691 Structure -8 STR1451## - R.sup.2 : 2-N(CH.sub.3).sub.2 -9 STR1452## - Crystalline form: Colorless amorphous NMR analysis: 120) Form: Free Example 692 Structure -0 STR1453## - R.sup.2 : 2-N(CH.sub.3).sub.2 -1 STR1454## - Crystalline form: Colorless amorphous NMR analysis: 121) Form: Free Example 693 Structure -2 STR1455## - R.sup.2 : 2-Cl -3 STR1456## - Crystalline form: Colorless amorphous NMR analysis: 122) Form: Free Example 694 Structure -4 STR1457## - R.sup.2 : 2-Cl -5 STR1458## - Crystalline form: Colorless amorphous NMR analysis: 123) Form: Free Example 695 Structure -6 STR1459## - R.sup.2 : 2-Cl -7 STR1460## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 198.5-199.degree. C. Form: Free Example 696 Structure -8 STR1461## - R.sup.2 : 2-Cl -9 STR1462## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/ dichloromethane Melting Point: 168-170.degree. C. Form: Free Example 697 Structure -0 STR1463## - R.sup.2 : 2-Cl -1 STR1464## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/ dichloromethane Melting Point: 175-176.degree. C. Form: Free Example 698 Structure -2 STR1465## - R.sup.2 : 2-Cl -3 STR1466## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/ dichloromethane Melting Point: 177-178.degree. C. Form: Free Example 699 Structure -4 STR1467## - R.sup.2 : 2-Cl -5 STR1468## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/ dichloromethane Melting Point: 222-223.5.degree. C. Form: Free Example 700 Structure -6 STR1469## - R.sup.2 : 2-Cl -7 STR1470## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/ dichloromethane Melting Point: 243-244.degree. C. Form: Free Example 701 Structure -8 STR1471## - R.sup.2 : H -9 STR1472## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/ dichloromethane Melting Point: 180-181.degree. C. Form: Free Example 702 Structure -0 STR1473## - R.sup.2 : H -1 STR1474## - Crystalline form: Colorless amorphous NMR analysis: 124) Form: Free Example 703 Structure -2 STR1475## - R.sup.2 : H -3 STR1476## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/ dichloromethane Melting Point: 231-233.degree. C. Form: Free Example 704 Structure -4 STR1477## - R.sup.2 : H -5 STR1478## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/ dichloromethane Melting Point: 196-198.degree. C. Form: Free Example 705 Structure -6 STR1479## - R.sup.2 : 2-Cl -7 STR1480## - Crystalline form: Colorless amorphous NMR analysis: 125) Form: Free Example 706 Structure -8 STR1481## - R.sup.2 : 2-Cl -9 STR1482## - Crystalline form: Yellow amorphous NMR analysis: 126) Form: Free Example 707 Structure -0 STR1483## - R.sup.2 : H -1 STR1484## - Crystalline form: Yellow powder Recrystallization solvent: Diethyl ether/ dichloromethane Melting Point: 146-147.degree. C. Form: Free Example 708 Structure -2 STR1485## - R.sup.2 : H -3 STR1486## - Crystalline form: Colorless amorphous NMR analysis: 127) Form: Free Example 709 Structure -4 STR1487## - R.sup.2 : H -5 STR1488## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/ dichloromethane Melting Point: 220-221.degree. C. Form: Free Example 710 Structure -6 STR1489## - R.sup.2 : H -7 STR1490## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/ dichloromethane Melting Point: 170-172.degree. C. Form: Free Example 711 Structure -8 STR1491## - R.sup.2 : H -9 STR1492## - Crystalline form: Colorless amorphous NMR analysis: 128) Form: Free Example 712 Structure -0 STR1493## - R.sup.2 : H -1 STR1494## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 224-225.degree. C. Form: Free Example 713 Structure -2 STR1495## - R.sup.2 : 3-OCH.sub.3 -3 STR1496## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 193-196.degree. C. Form: Free Example 714 Structure -4 STR1497## - R.sup.2 : 2-Cl -5 STR1498## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 212-214.degree. C. Form: Free Example 715 Structure -6 STR1499## - R.sup.2 : 2-Cl -7 STR1500## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 211-213.degree. C. Form: Free Example 716 Structure -8 STR1501## - R.sup.2 : 2-Cl -9 STR1502## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 213-215.degree. C. Form: Free Example 717 Structure -0 STR1503## - R.sup.2 : 2-Cl -1 STR1504## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 199-201.degree. C. Form: Free Example 718 Structure -2 STR1505## - R.sup.2 : 2-Cl -3 STR1506## - Crystalline form: White powder Recrystallization solvent: Ethnaol Melting Point: 238-240.degree. C. Form: Free Example 719 Structure -4 STR1507## - R.sup.2 : 2-Cl -5 STR1508## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 188-189.degree. C. Form: Free Example 720 Structure -6 STR1509## - R.sup.2 : H -7 STR1510## - Crystalline form: Colorless prisms Recrystallization solvent: Dioxane/water Melting Point: 135.5-137.degree. C. Form: Free Example 721 Structure -8 STR1511## - R.sup.2 : H -9 STR1512## - Crystalline form: White powder Recrystallization solvent: Isopropyl alcohol/ petroleum ether Melting Point: 192-193.degree. C. Form: Free Example 722 Structure -0 STR1513## - R.sup.2 : H -1 STR1514## - Crystalline form: Colorless needles Recrystallization solvent: Ethyl acetate Melting Point: 239-240.degree. C. Form: Free Example 723 Structure -2 STR1515## - R.sup.2 : H -3 STR1516## - Crystalline form: Colorless amorphous NMR analysis: 129) Form: Free Example 724 Structure -4 STR1517## - R.sup.2 : H -5 STR1518## - Crystalline form: Colorless amorphous NMR analysis: 130) Form: Free Example 725 Structure -6 STR1519## - R.sup.2 : H -7 STR1520## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol/petroleum ether Melting Point: 193-194.degree. C. Form: Free Example 726 Structure -8 STR1521## - R.sup.2 : H -9 STR1522## - Crystalline form: Light yellow prisms Recrystallization solvent: Ethanol Melting Point: 245.5-247.degree. C. Form: Free Example 727 Structure -0 STR1523## - R.sup.2 : H -1 STR1524## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol/petroleum ether Melting Point: 142-144.degree. C. Form: Free Example 728 Structure -2 STR1525## - R.sup.2 : H -3 STR1526## - Crystalline form: Light yellow prisms Recrystallization solvent: Ethanol Melting Point: 214-217.degree. C. Form: Free Example 729 Structure -4 STR1527## - R.sup.2 : H -5 STR1528## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 205-207.degree. C. Form: Free Example 730 Structure -6 STR1529## - R.sup.2 : H -7 STR1530## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol/diethyl ether Melting Point: 201-203.degree. C. Form: Free Example 731 Structure -8 STR1531## - R.sup.2 : H -9 STR1532## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol/diethyl ether Melting Point: 180-182.degree. C. Form: Free Example 732 Structure -0 STR1533## - R.sup.2 : H -1 STR1534## - Crystalline form: Light yellow scales Recrystallization solvent: Ethanol/diethyl ether Melting Point: 178-180.degree. C. Form: Free Example 733 Structure -2 STR1535## - R.sup.2 : H -3 STR1536## - Crystalline form: Colorless needles Recrystallization solvent: Methanol/diethyl ether Melting Point: 208-213.degree. C. Form: Free Example 734 Structure -4 STR1537## - R.sup.2 : H -5 STR1538## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 175-177.degree. C. Form: Free Example 735 Structure -6 STR1539## - R.sup.2 : H -7 STR1540## - Crystalline form: White powder NMR analysis: 131) Form: Free Example 736 Structure -8 STR1541## - R.sup.2 : H -9 STR1542## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/ /n-hexane Melting Point: 277-279.degree. C. Form: Free Example 737 Structure -0 STR1543## - R.sup.2 : H -1 STR1544## - Crystalline form: Colorless amorphous NMR analysis: 132) Form: Free Example 738 Structure -2 STR1545## - R.sup.2 : H -3 STR1546## - Crystalline form: Colorless amorphous NMR analysis: 133) Form: Free Example 739 Structure -4 STR1547## - R.sup.2 : H -5 STR1548## - Crystalline form: Colorless amorphous NMR analysis: 134) Form: Free Example 740 Structure -6 STR1549## - R.sup.2 : H -7 STR1550## - Crystalline form: Colorless amorphous NMR analysis: 135) Form: Free Example 741 Structure -8 STR1551## - R.sup.2 : H -9 STR1552## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 213-214.degree. C. Form: Free Example 742 Structure -0 STR1553## - R.sup.2 : H -1 STR1554## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 216-217.degree. C. Form: Free Example 743 Structure -2 STR1555## - R.sup.2 : 2-Cl -3 STR1556## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 165-167.degree. C. Form: Free Example 744 Structure -4 STR1557## - R.sup.2 : H -5 STR1558## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 202-206.degree. C. Form: Free Example 745 Structure -6 STR1559## - R.sup.2 : 2-Cl -7 STR1560## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 220-221.5.degree. C. Form: Free Example 746 Structure -8 STR1561## - R.sup.2 : H -9 STR1562## - Crystalline form: Colorless needles Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 186-186.5.degree. C. Form: Free Example 747 Structure -0 STR1563## - R.sup.2 : 2-Cl -1 STR1564## - Crystalline form: Colorless amorphous NMR anaylsis: 136) Form: Free Example 748 Structure -2 STR1565## - R.sup.2 : H -3 STR1566## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 136-140.degree. C. Form: Free Example 749 Structure -4 STR1567## - R.sup.2 : 2-Cl -5 STR1568## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 151-153.degree. C. Form: Free Example 750 Structure -6 STR1569## - R.sup.2 : H -7 STR1570## - Crystalline form: Colorless needles Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 155-156.degree. C. Form: Free Example 751 Structure -8 STR1571## - R.sup.2 : H -9 STR1572## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 189-190.degree. C. Form: Free Example 752 Structure -0 STR1573## - R.sup.2 : H -1 STR1574## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 188-190.degree. C. Form: Free Example 753 Structure -2 STR1575## - R.sup.2 : H -3 STR1576## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 233-235.degree. C. Form: Free Example 754 Structure -4 STR1577## - R.sup.2 : H -5 STR1578## - Crystalline form: Colorless amorphous NMR analysis: 137) Form: Free Example 755 Structure -6 STR1579## - R.sup.2 : H -7 STR1580## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 176-179.degree. C. Form: Free Example 756 Structure -8 STR1581## - R.sup.2 : H -9 STR1582## - Crystalline form: Colorless needles Recrystallization solvent: Methanol/diethyl ether Melting 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), 6.8-8.8(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=14.8Hz), 6.85(1H, d, J=7.2Hz), 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), 7.75-8.25(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=7Hz), 1.25-3.25 (8H, m), 3.46(2H, q, J=7Hz), 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=7Hz), 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=7Hz), 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=7.5Hz), 6.86-8.10(11H, m), 8.72(1H, br) 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, m), 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=13.8Hz), 4.25 (1H, d, J=13.8Hz), 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. 205-207.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. 180-182.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. 216-217.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 1 M 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. 202-206.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 9), 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. 136-140.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. 155-156.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. 189-190.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 9) as white powder, m.p. 188-189.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. 233-235.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 compeltion 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. 176-179.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. 192-193.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. 239-240.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. 142-144.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. 233-237.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. 156-159.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. 108-109.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. 157.5-159.5.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. 151.5-153.5.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. 193-193.5.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. 171-174.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. 129-131.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. 198-202.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. 166-169.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. 192.5-195.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. 154-156.degree. C.; [.alpha.].sub.D.sup.22 =0.degree. (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. 169.5-170.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______________________________________1 #STR1583##______________________________________Example 785 Structure -2 STR1584## -3 STR1585## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 174-175.degree. C. Form: Free Example 786 Structure -4 STR1586## -5 STR1587## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol/diethyl ether Melting Point: 176-178.degree. C. Form: Free Example 787 Structure -6 STR1588## -7 STR1589## - Crystalline form: Colorless prisms Recrystallization solvent: Ethyl acetate/petroleum ether Melting Point: 154.5-155.degree. C. Form: Free Example 788 Structure -8 STR1590## -9 STR1591## - Crystalline form: Colorless amorphous NMR analysis: 138) Form: Free Example 789 Structure -0 STR1592## -1 STR1593## - Crystalline form: Colorless scales Recrystallization solvent: Ethanol Melting Point: 197-198.degree. C. Form: Free Example 790 Structure -2 STR1594## -3 STR1595## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 248-249.degree. C. Form: Free Example 791 Structure -4 STR1596## -5 STR1597## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol/n-hexane Melting Point: 162-163.degree. C. Form: Free Example 792 Structure -6 STR1598## -7 STR1599## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol/petroleum ether Melting Point: 235-236.5.degree. C. Form: Free Example 793 Structure -8 STR1600## -9 STR1601## - Crystalline form: Colorless amorphous NMR analysis: 139) Form: Free Example 794 Structure -0 STR1602## -1 STR1603## - Crystalline form: Colorless prisms Recrystallization solvent: Dioxane Melting Point: 269-271.degree. C. Form: Free Example 795 Structure -2 STR1604## -3 STR1605## - Crystalline form: Colorless prisms Recrystallization solvent: Dimethylformamide Melting Point: 286-287.degree. C. Form: Free Example 796 Structure -4 STR1606## -5 STR1607## - Crystalline form: Colorless needles Recrystallization solvent: Acetonitrile Melting Point: 227-228.degree. C. Form: Free Example 797 Structure -6 STR1608## -7 STR1609## - Crystalline form: Colorless amorphous NMR analysis: 140) Form: Free Example 798 Structure -8 STR1610## -9 STR1611## - Crystalline form: Colorless prisms Recrystallization solvent: Ethyl acetate/petroleum ether Melting Point: 167-168.degree. C. Form: Free Example 799 Structure -0 STR1612## -1 STR1613## - Crystalline form: Colorless amorphous NMR analysis: 141) Example 800 Structure -2 STR1614## -3 STR1615## - Crystalline form: Colorless needles Recrystallization solvent: Diethyl ether Melting Point: 164-171.degree. C. Form: K.sup..sym. Example 801 Structure -4 STR1616## -5 STR1617## - Crystalline form: Colorless amorphous NMR analysis: 142) Form: Free Example 802 Structure -6 STR1618## -7 STR1619## - Crystalline form: Colorless amorphous NMR analysis: 143) Form: Free Example 803 Structure -8 STR1620## -9 STR1621## - Crystalline form: Colorless amorphous NMR analysis: 144) Form: Free Example 804 Structure -0 STR1622## -1 STR1623## - Crystalline form: Colorless amorphous NMR analysis: 145) Form: Free Example 805 Structure -2 STR1624## -3 STR1625## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 207-208.degree. C. Form: Free Example 806 Structure -4 STR1626## -5 STR1627## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 187-189.degree. C. Form: Free Example 807 Structure -6 STR1628## -7 STR1629## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol/petroleum ether Melting Point: 217-218.degree. C. Form: Free Example 808 Structure -8 STR1630## -9 STR1631## - Crystalline form: Colorless needles Recrystallization solvent: Ethyl acetate Melting Point; 170-171.degree. C. Form: Free Example 809 Structure -0 STR1632## -1 STR1633## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 239.5-241.degree. C. Form: Free Example 810 Structure -2 STR1634## -3 STR1635## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 190-191.degree. C. Form: Free Example 811 Structure -4 STR1636## -5 STR1637## - Crystalline form: Colorless prisms Recrystallization solvent: Diethyl ether Melting Point: 163-163.5.degree. C. Form: Free Example 812 Structure -6 STR1638## -7 STR1639## - Crystalline form: Colorless prisms Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 208-210.degree. C. Form: Free Example 813 Structure -8 STR1640## -9 STR1641## - Crystalline form: White powder NMR analysis: 146) Form: Free Example 814 Structure -0 STR1642## -1 STR1643## - Crystalline form: Colorless amorphous NMR analysis: 147) Form: Free Example 815 Structure -2 STR1644## -3 STR1645## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol/n-hexane Melting Point: 250-252.degree. C. Form: Free Example 816 Structure -4 STR1646## -5 STR1647## - Crystalline form: Colorless prisms Recrystallization solvent: Ethyl acetate Melting Point: 214-216.degree. C. Form: Free Example 817 Structure -6 STR1648## -7 STR1649## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol/n-hexane Melting Point: 243-245.degree. C. Form: Free Example 818 Structure -8 STR1650## -9 STR1651## - Crystalline form: Colorless prisms Recrystallization solvent: Diethyl ether Melting Point: 159-162.degree. C. Form: Free Example 819 Structure -0 STR1652## -1 STR1653## - Crystalline form: Colorless amorphous NMR analysis: 148) Form: Free Example 820 Structure -2 STR1654## -3 STR1655## - Crystalline form: Colorless prisms Recrystallization solvent: Ethyl acetate Melting Point: 287-289.degree. C. Form: Free Example 821 Structure -4 STR1656## -5 STR1657## - Crystalline form: Colorless prisms Recrystallization solvent: Diethyl ether Melting Point: 170-171.degree. C. Form: Free Example 822 Structure -6 STR1658## -7 STR1659## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 204-205.degree. C. Form: Free Example 823 Structure -8 STR1660## -9 STR1661## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 273-273.5.degree. C. Form: Free Example 824 Structure -0 STR1662## -1 STR1663## - Crystalline form: Colorless amorphous NMR analysis: 149) Form: Free Example 825 Structure -2 STR1664## -3 STR1665## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 240-241.degree. C. Form: Free Example 826 Structure -4 STR1666## -5 STR1667## - Crystalline form: White powder Recrystallization solvent: Acetonitrile/ethanol Melting Point: 231-232.degree. C. Form: Free Example 827 Structure -6 STR1668## -7 STR1669## - Crystalline form: White powder Recrystallization solvent: Acetonitrile/ethanol Melting Point: 222-224.degree. C. Form: Free Example 828 Structure -8 STR1670## -9 STR1671## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 235-237.degree. C. Form: Free Example 829 Structure -0 STR1672## -1 STR1673## - Crystalline form: Colorless amorphous NMR analysis: 150) Form: Free Example 830 Structure -2 STR1674## -3 STR1675## - Crystalline form: Colorless amorphous NMR analysis: 151) Form: Free Example 831 Structure -4 STR1676## -5 STR1677## - Crystalline form: Colorless amorphous NMR analysis: 152) Form: Free Example 832 Structure -6 STR1678## -7 STR1679## - Crystalline form: Colorless amorphous NMR analysis: 153) Form: Free Example 834 Structure -8 STR1680## -9 STR1681## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 247-248.degree. C. Form: Free Example 835 Structure -0 STR1682## -1 STR1683## - Crystalline form: Colorless amorphous NMR analysis: 154) Form: Free Example 836 Structure -2 STR1684## -3 STR1685## - Crystalline form: Colorless amorphous NMR analysis: 155) Form: Free Example 837 Structure -4 STR1686## -5 STR1687## - Crystalline form: Colorless amorphous NMR analysis: 156) Form: Free Example 838 Structure -6 STR1688## -7 STR1689## - Crystalline form: Colorless amorphous NMR analysis: 157) Form: Free Example 839 Structure -8 STR1690## -9 STR1691## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 234-235.degree. C. Form: Free Example 840 Structure -0 STR1692## -1 STR1693## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 234-235.degree. C. Form: Free Example 841 Structure -2 STR1694## -3 STR1695## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 226-228.degree. C. Form: Free Example 842 Structure -4 STR1696## -5 STR1697## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 230-231.degree. C. Form: Free Example 843 Structure -6 STR1698## -7 STR1699## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 186-188.degree. C. Form: Free Example 844 Structure -8 STR1700## -9 STR1701## - Crystalline form: Colorless prisms Recrystallization solvent: Chloroform/methanol Melting Point: 286-290.degree. C. Form: Free Example 845 Structure -0 STR1702## -1 STR1703## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 186-188.5.degree. C. Form: Free Example 846 Structure -2 STR1704## -3 STR1705## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 220-222.degree. C. Form: Free Example 847 Structure -4 STR1706## -5 STR1707## - Crystalline form: White powder NMR analysis: 158) Form: Free Example 848 Structure -6 STR1708## - R.sup.3 : 4-NHCOCH.sub.2 CONH.sub.2 Crystalline form: Colorless prisms Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 189-192.degree. C. Form: Free Example 849 Structure -7 STR1709## -8 STR1710## - Crystalline form: Colorless amorphous NMR analysis: 159) Form: Free Example 850 Structure -9 STR1711## -0 STR1712## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 207-209.degree. C. (decomposed) Form: Free Example 851 Structure -1 STR1713## -2 STR1714## - Crystalline form: White powder NMR analysis: 160) Form: K.sup..sym. Example 852 Structure -3 STR1715## -4 STR1716## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 193-194.degree. C. Form: Free Example 853 Structure -5 STR1717## -6 STR1718## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 185.5-186.degree. C. Form: Free Example 854 Structure -7 STR1719## -8 STR1720## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 223.5-226.degree. C. (decomposed) Form: Free Example 855 Structure -9 STR1721## -0 STR1722## - Crystalline form: Colorless amorphous NMR analysis: 161) Form: Free Example 856 Structure -1 STR1723## -2 STR1724## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 225.5-227.degree. C. Form: Free Example 857 Structure -3 STR1725## -4 STR1726## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 212-214.degree. C. Form: Free Example 858 Structure -5 STR1727## -6 STR1728## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 230.5-233.degree. C. Form: Free Example 859 Structure -7 STR1729## -8 STR1730## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 212.5-215.degree. C. (decomposed) Form: Free Example 860 Structure -9 STR1731## -0 STR1732## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 192-194.5.degree. C. Form: Free Example 861 Structure -1 STR1733## -2 STR1734## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 175-177.degree. C. Form: Free Example 862 Structure -3 STR1735## -4 STR1736## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 208.5-209.5.degree. C. Form: Free Example 863 Structure -5 STR1737## -6 STR1738## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 191-193.5.degree. C. Form: Free Example 864 Structure -7 STR1739## -8 STR1740## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 204-205.5.degree. C. Form: Free Example 865 Structure -9 STR1741## -0 STR1742## - Crystalline form: Light yellow prisms Recrystallization solvent: Ethanol Melting Point: 221-223.degree. C. Form: Free Example 866 Structure -1 STR1743## -2 STR1744## - Crystalline form: Colorless prisms Recrystallization solvent: Ethyl acetate Melting Point: 171-173.degree. C. Form: Free Example 867 Structure -3 STR1745## -4 STR1746## - Crystalline form: Colorless prisms Recrystallization solvent: Ethyl acetate Melting Point: 185-187.degree. C. Form: Free Example 868 Structure -5 STR1747## -6 STR1748## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 190-192.degree. C. Form: Free Example 869 Structure -7 STR1749## -8 STR1750## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 175-177.degree. C. Form: Free Example 870 Structure -9 STR1751## -0 STR1752## - Crystalline form: Colorless powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 148-151.degree. C. Form: Free Example 871 Structure -1 STR1753## -2 STR1754## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 200-202.degree. C. Form: Free Example 872 Structure -3 STR1755## -4 STR1756## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 200-202.degree. C. Form: Free Example 873 Structure -5 STR1757## -6 STR1758## - Crystalline form: Light yellow powder Recrystallization solvent: Acetone Melting Point: 235-238.degree. C. Form: Free Example 874 Structure -7 STR1759## -8 STR1760## - Crystalline form: Light yellow powder Recrystallization solvent: Acetone Melting Point: 198-201.degree. C. Form: Free Example 875 Structure -9 STR1761## -0 STR1762## - Crystalline form: Light yellow needles Recrystallization solvent: Chloroform/ethyl acetate Melting Point: 232-237.degree. C. Form: Free Example 876 Structure -1 STR1763## -2 STR1764## - Crystalline form: Colorless prisms Recrystallization solvent: Chloroform/ethyl acetate Melting Point: 224-227.degree. C. Form: Free Example 877 Structure -3 STR1765## -4 STR1766## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 211-214.degree. C. Form: Free Example 878 Structure -5 STR1767## -6 STR1768## - Crystalline form: Colorless powder Recrystallization solvent: Dichloromethane/n-hexane Melting Point: 238-243.degree. C. Form: Free Example 879 Structure -7 STR1769## -8 STR1770## - Crystalline form: Colorless amorphous NMR analysis: 162) Form: Free Example 880 Structure -9 STR1771## -0 STR1772## - Crystalline form: Colorless amorphous NMR analysis: 163) Form: Free Example 881 Structure -1 STR1773## -2 STR1774## - Crystalline form: Colorless prisms Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 198-202.degree. C. Form: Free Example 882 Structure -3 STR1775## -4 STR1776## - Crystalline form: Colorless prisms Recrystallization solvent: Chloroform/ethyl acetate Melting Point: 226-229.degree. C. Form: Free Example 883 Structure -5 STR1777## -6 STR1778## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 139-140.degree. C. Form: Free Example 884 Structure -7 STR1779## -8 STR1780## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 149-152.degree. C. Form: Free Example 885 Structure -9 STR1781## -0 STR1782## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 180.5-182.degree. C. Form: Free Example 886 Structure -1 STR1783## -2 STR1784## - Crystalline form: White powder Recrystallization solvent: Chloroform/diethyl ether Melting Point: 211-214.degree. C. Form: Free Example 887 Structure -3 STR1785## -4 STR1786## - Crystalline form: White powder Recrystallization solvent: Chloroform/diethyl ether Melting Point: 171-174.5.degree. C. Form: Free Example 888 Structure -5 STR1787## -6 STR1788## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 203-205.degree. C. Form: Free Example 889 Structure -7 STR1789## -8 STR1790## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 202-202.5 Form: Free Example 890 Structure -9 STR1791## -0 STR1792## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 130-133.degree. C. Form: Free Example 891 Structure -1 STR1793## -2 STR1794## -3 STR1795## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 104.5-106.degree. C. Form: Free Example 892 Structure -4 STR1796## -5 STR1797## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 197-198.degree. C. Form: Free Example 893 Structure -6 STR1798## -7 STR1799## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/ethyl acetate Melting Point: 191-192.degree. C. Form: Free Example 894 Structure -8 STR1800## -9 STR1801## - Crystalline form: Colorless columnar Recrystallization solvent: Ethanol/petroleum ether Melting Point: 211-213.degree. C. Form: Free Example 895 Structure -0 STR1802## -1 STR1803## - Crystalline form: Colorless amorphous NMR analysis: 164) Form: Free Example 896 Structure -2 STR1804## -3 STR1805## - Crystalline form: Colorless amorphous NMR analysis: 165) Form: Free Example 897 Structure -4 STR1806## -5 STR1807## - Crystalline form: Colorless amorphous NMR analysis: 166) Form: Free Example 898 Structure -6 STR1808## -7 STR1809## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting 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=7.8Hz), 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=7.7Hz), 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=7.4Hz), 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=7.6Hz), 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=7.4Hz), 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=7.4Hz), 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=7.6Hz), 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=12.2Hz, 15.6Hz), 5.0-5.2(1H, m), 5.82(1H, d, J=10.3Hz), 6.69(1H, d, J=7.8Hz), 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, 22.9Hz), 3.9-4.35(2H, m), 6.60(2H, d, J=7.7Hz), 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), 3.92-4.42 (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=6.7Hz), 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=8Hz), 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=6.2Hz), 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=7.2Hz), 3.41(2H, s), 4.22(2H, q, J=7.2Hz)], 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 9) 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. 176-178.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 9) as colorless scales, m.p. 197-198.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. 248-249.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. 211-213.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 aceate=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. 269-271.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. 227-228.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. 167-168.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. 164-171.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 dimethyformamide (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. 208-210.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. 250-252.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. 214-216.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-methylbenzoylamino)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. 287-289.degree. C.
(F): Colorless prisms, m.p. 170-171.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 3.0 M 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. 204-205.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. 235-237.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. 226-228.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. 286-290.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 patassium 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)benozyl]-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______________________________________1 #STR1810##______________________________________Example 939 Structure - 2 STR1811## 3 STR1812## -4 STR1813## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 208-211.degree. C. Form: Free Example 940 Structure - 2 STR1814## 3 STR1815## -5 STR1816## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 171.5-172.5.degree. C. Form: Free Example 941 Structure - 2 STR1817## 3 STR1818## -6 STR1819## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 151-154.degree. C. Form: Free Example 942 Structure - 2 STR1820## 3 STR1821## -7 STR1822## - Crystalline form: Colorless amorphous NMR analysis: 167) Form: Free Example 943 Structure - 2 STR1823## 3 STR1824## -8 STR1825## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 180-183.degree. C. Form: Free Example 944 Structure - 2 STR1826## 3 STR1827## -9 STR1828## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 109-110.degree. C. Form: Free Example 945 Structure - 2 STR1829## 3 STR1830## -0 STR1831## - Crystalline form: Colorless oil NMR analysis: 168) Form: Free Example 946 Structure - 2 STR1832## 3 STR1833## -1 STR1834## - Crystalline form: Colorless oil NMR analysis: 169) Form: Free Example 947 Structure - 2 STR1835## 3 STR1836## -2 STR1837## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 177-178.5.degree. C. Form: Free Example 948 Structure - 2 STR1838## 3 STR1839## -3 STR1840## - Crystalline form: Colorless amorphous NMR analysis: 170) Form: Free Example 949 Structure - 2 STR1841## 3 STR1842## -4 STR1843## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 162-165.degree. C. Form: Free Example 950 Structure - 2 STR1844## 3 STR1845## -5 STR1846## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 212-215.degree. C. Form: Free Example 951 Structure - 2 STR1847## 3 STR1848## -6 STR1849## - Crystalline form: Colorless oil NMR analysis 171) Form: Free Example 952 Structure - 2 STR1850## 3 STR1851## -7 STR1852## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 112-114.degree. C. Form: Free Example 953 Structure - 2 STR1853## 3 STR1854## -8 STR1855## - Crystalline form: Colorless oil NMR analysis: 172) Form: Free Example 954 Structure - 2 STR1856## 3 STR1857## -9 STR1858## - Crystalline form: Colorless amorphous NMR analysis: 173) Form: Free Example 955 Structure - 2 STR1859## 3 STR1860## -0 STR1861## - Crystalline form: Light yellow amorphous NMR anlaysis: 174) Form: Free Example 956 Structure - 2 STR1862## 3 STR1863## -1 STR1864## - Crystalline form: White powder Recrystallization solvent: Diethyl ether Melting Point: 189-193.degree. C. Form: Free Example 957 Structure - 2 STR1865## 3 STR1866## -2 STR1867## - Crystalline form: Colorless amorphous NMR analysis: 175) Form: Free Example 958 Structure - 2 STR1868## 3 STR1869## -4 STR1870## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 234-238.degree. C. Form: Free Example 959 Structure - 2 STR1871## 5 STR1872## -6 STR1873## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 183-184.5.degree. C. Form: Free Example 960 Structure - 2 STR1874## 5 STR1875## -7 STR1876## - Crystalline form: Brown oil NMR analysis: 176) Form: Free Example 961 Structure - 2 STR1877## 8 STR1878## -7 STR1879## - Crystalline form: Colorless amorphous NMR analysis: 177) Form: Free Example 962 Structure - 2 STR1880## 9 STR1881## -0 STR1882## - Crystalline form: Colorless amorphous NMR analysis: 178) Form: Free Example 963 Structure - 2 STR1883## 1 STR1884## -2 STR1885## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 202.5-204.5.degree. C. Form: Free Example 964 Structure - 2 STR1886## 1 STR1887## -3 STR1888## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 199.5-201.degree. C. Form: Free Example 965 Structure - 2 STR1889## 4 STR1890## -2 STR1891## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 196.5-197.degree. C. Form: Free Example 966 Structure - 2 STR1892## 5 STR1893## -2 STR1894## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 204-205.degree. C. Form: Free Example 967 Structure - 2 STR1895## 6 STR1896## -2 STR1897## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 175-177.degree. C. Form: Free Example 968 Structure - 2 STR1898## 7 STR1899## -2 STR1900## - Crystalline form: Pink amorphous NMR analysis: 179) Form: Free Example 969 Structure - 2 STR1901## 8 STR1902## -2 STR1903## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 186-189.degree. C. Form: Free Example 970 Structure - 2 STR1904## 9 STR1905## -0 STR1906## - Crystalline form: Colorless prisms Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 211-212.degree. C. Form: Free Example 971 Structure - 2 STR1907## 1 STR1908## -2 STR1909## - Crystalline form: Colorless amorphous NMR analysis: 180) Form: Free Example 972 Structure - 2 STR1910## 3 STR1911## -2 STR1912## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 206-207.degree. C. Form: Free Example 973 Structure - 2 STR1913## 4 STR1914## -5 STR1915## - Crystalline form: Colorless amorphous NMR analysis: 181) Form: Free Example 974 Structure - 2 STR1916## 6 STR1917## -7 STR1918## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 152-154.degree. C. Form: Free Example 975 Structure - 2 STR1919## 8 STR1920## -9 STR1921## - Crystalline form: Colorless amorphous NMR analysis: 182) Form: Free Example 976 Structure - 2 STR1922## 6 STR1923## -0 STR1924## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 204-206.degree. C. Form: Free Example 977 Structure - 2 STR1925## 1 STR1926## -2 STR1927## - Crystalline form: Colorless needles Recrystallization solvent: Ethyl acetate/n-hexane Melting 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=6.2Hz), 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=2.7Hz), 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=7.1Hz), 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=7.1Hz), 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=7.1Hz), 1.95- 2.30(2H, m), 2.88(2H, t, J=6.2Hz), 3.40-3.65 (2H, m), 3.70-4.50(2H, m), 3.91(2H, s), 6.66(1H, d, J=8.5Hz), 6.70-7.00(3H, m), 7.10-7.50(7H, m), 7.81(1H, d, J=2.5Hz), 8.44(1H, s) 177) .sup.1 H-NMR(CDCl.sub.3).delta.: 1.21(3H, t, J=7Hz), 1.30-5.20 (11H, m), 3.48(2H, q, J=7Hz), 3.90(2H, s), 6.53 (1H, d, J=8.3Hz), 6.65-7.00(4H, m), 7.00-7.40 (6H, m), 7.51(1H, d, J=2.5Hz), 8.40(1H, s) 178) .sup.1 H-NMR(CDCl.sub.3).delta.; 1.21(3H, t, J=7Hz), 1.20-5.20 (15H, m), 3.90(2H, s), 6.48(1H, d, J=8.3Hz), 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. 191-192.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 Exmaple 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. 183-185.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 Exmaple 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. 178-178.5.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. 150-151.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. 116-118.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. 156-158.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. 172.5-173.5.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. 153-155.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. 170-171.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______________________________________1 #STR1928##______________________________________Example 980 Structure2 STR1929## - R.sup.2 : H -4 STR1930## - Crystalline form: Colorless amorphous NMR analysis: 183) Form: Free Example 981 Structure -2 STR1931## - R.sup.2 : H -5 STR1932## - Crystalline form: Colorless amorphous NMR analysis: 184) Form: Free Example 982 Structure -2 STR1933## - R.sup.2 : H -6 STR1934## - Crystalline form: Colorless amorphous NMR analysis: 185) Form: Free Example 983 Structure -2 STR1935## - R.sup.2 : H -7 STR1936## - Crystalline form: Colorless amorphous NMR analysis: 186) Form: Free Example 984 Structure -2 STR1937## - R.sup.2 : H -8 STR1938## - Crystalline form: Colorless amorphous NMR analysis: 187) Form: Free Example 985 Structure -9 STR1939## - R.sup.2 : 2-Cl -0 STR1940## - Crystalline form: Colorless amorphous NMR analysis: 188) Form: Free Example 986 Structure -9 STR1941## - R.sup.2 : 2-Cl -1 STR1942## - Crystalline form: Colorless amorphous NMR analysis: 189) Form: Free Example 987 Structure -9 STR1943## - R.sup.2 : H -0 STR1944## - Crystalline form: White powder Recrystallization solvent: Ethanol/water Melting Point: 267-268.degree. C. Form: Free Example 988 Structure -9 STR1945## - R.sup.2 : H -1 STR1946## - Crystalline form: White powder Recrystallization solvent: Ethanol/water Melting Point: 264-266.degree. C. Form: Free Example 989 Structure -2 STR1947## - R.sup.2 : H -0 STR1948## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 218-220.degree. C. Form: Free Example 990 Structure -3 STR1949## - R.sup.2 : 3-OCH.sub.3 -0 STR1950## - Crystalline form: Yellow oil NMR analysis: 190) Form: Free Example 991 Structure -3 STR1951## - R.sup.2 : 3-OCH.sub.3 -1 STR1952## - Crystalline form: Yellow oil NMR analysis: 191) Form: Free Example 992 Structure -4 STR1953## - R.sup.2 : 3-OCH.sub.3 -0 STR1954## - Crystalline form: Yellow powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 174-177.degree. C. Form: Free Example 993 Structure -5 STR1955## - R.sup.2 : 3-OCH.sub.3 -0 STR1956## - Crystalline form: Yellow amorphous NMR analysis: 192) Form: Free Example 994 Structure -6 STR1957## - R.sup.2 : 3-OCH.sub.3 -0 STR1958## - Crystalline form: Colorless amorphous NMR analysis: 193) Form: Free Example 995 Structure -4 STR1959## - R.sup.2 : 3-OCH.sub.3 -1 STR1960## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 163-165.degree. C. Form: Free Example 996 Structure -5 STR1961## - R.sup.2 : 3-OCH.sub.3 -1 STR1962## - Crystalline form: Colorless amorphous NMR analysis: 194) Form: Free Example 997 Structure -6 STR1963## - R.sup.2 : 3-OCH.sub.3 -1 STR1964## - Crystalline form: Colorless amorphous NMR analysis: 195) Form: Free______________________________________ 183) .sup.1 HNMR(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 HNMR(CDCl.sub.3).delta.; 1.10-2.85(11H, m), 1.58(3H, d, J=6.8Hz), 2.23(3H, s), 2.95-5.19(4H, m), 6.38-7.70(12H, m), 8.69(1H, brs) 185) .sup.1 HNMR(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 HNMR(CDCl.sub.3).delta.; 1.09-2.72(11H, m), 1.53(3H, d, J=6.9Hz), 2.24(3H, s), 2.93-5.21(4H, m), 6.30-7.78(12H, m), 8.76(1H, brs) 187) .sup.1 HNMR(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 HNMR(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 HNMR(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 HNMR(CDCl.sub.3).delta.; 2.00-2.35(2H, m), 2.49(3H, s), 2.89(2H, t, J=6.2Hz), 3.72(3H, s), 3.40-4.80(2H, m), 6.74(2H, d, J=8.5Hz) 6.80-7.00(2H, m), 7.25-7.60(5H, m), 7.80(1H, d, J=2.6Hz), 8.16(1H, s), 8.37(1H, d, J=8.6 Hz) 191) .sup.1 HNMR(CDCl.sub.3).delta.; 1.90-2.40(2H, m), 2.90(2H, t, J=6.2Hz), 3.75(3H, s), 3.40-4.80(2H, m), 6.74(1H, d, J=8.5Hz), 6.80-7.00(2H, m), 7.10-7.50(4H, m), 7.73(1H, dd, J=2.3Hz, 6Hz), 7.80(1H, d, J=2.5Hz), 8.38(1H, d, J=8.8Hz), 8.65(1H, s) 192) .sup.1 HNMR(CDCl.sub.3).delta.; 1.10-2.10(13H, m), 2.80-5.20(6H, m), 6.56(1H, d, J=8.4Hz), 6.69(1H, d, J=7Hz), 6.85-7.70(7H, m), 8.15(1H, s), 8.31(1H, d, J=8.4Hz) 193) .sup.1 HNMR(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=8.3Hz), 6.70-7.60(8H, m), 8.14(1H, s), 8.20-8.40(1H, m) 194) .sup.1 HNMR(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=8Hz), 8.62(1H, s) 195) .sup.1 HNMR(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=8Hz), 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. 177-182.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. 125-126.5.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. 190-191.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. 188-191.5.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______________________________________1 STR1965##______________________________________Example 998 Structure2 STR1966## - R.sup.2 : H -4 STR1967## - Crystalline form: White powder NMR analysis: 196) Form: Free Example 999 Structure -2 STR1968## - R.sup.2 : H -5 STR1969## - Crystalline form: White powder NMR analysis: 197) Form: Free Example 1000 Structure -6 STR1970## - R.sup.2 : H -4 STR1971## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 200-205.degree. C. Form: Free Example 1001 Structure -7 STR1972## - R.sup.2 : H -4 STR1973## - Crystalline form: Colorless amorphous NMR analysis: 198) Form: Free Example 1002 Structure -8 STR1974## - R.sup.2 : H -4 STR1975## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 234-238.degree. C. Form: Free Example 1003 Structure -9 STR1976## - R.sup.2 : H -4 STR1977## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 174-178.degree. C. Form: Free Example 1004 Structure -2 STR1978## - R.sup.2 : 2-Cl -5 STR1979## - Crystalline form: Light yellow amorphous NMR analysis: 199) Form: Free Example 1005 Structure -2 STR1980## - R.sup.2 : 2-Cl -4 STR1981## - Crystalline form: Light yellow amorphous NMR analysis: 200) Form: Free Example 1006 Structure -6 STR1982## - R.sup.2 : 2-Cl -5 STR1983## - Crystalline form: Light yellow amorphous NMR analysis: 201) Form: Free Example 1007 Structure -6 STR1984## - R.sup.2 : 2-Cl -4 STR1985## - Crystalline form: Light yellow amorphous NMR analysis: 202) Form: Free Example 1008 Structure -7 STR1986## - R.sup.2 : 2-Cl -5 STR1987## - Crystalline form: Light yellow amorphous MNR analysis: 203) Form: Free Example 1009 Structure -7 STR1988## - R.sup.2 : 2-Cl -4 STR1989## - Crystalline form: Light yellow amorphous NMR analysis: 204) Form: Free Example 1010 Structure -0 STR1990## - R.sup.2 : H -1 STR1991## - Crystalline form: Colorless amorphous NMR analysis: 205) Form: Free Example 1011 Structure -3 STR1992## - R.sup.2 : 3-OCH.sub.3 -2 STR1993## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 153-155.degree. C. Form: Free Example 1012 Structure -3 STR1994## - R.sup.2 : 3-OCH.sub.3 -4 STR1995## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 142-143.degree. C. Form: Free Example 1013 Structure -5 STR1996## - R.sup.2 : H -2 STR1997## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 176-178.degree. C. Form: Free Example 1014 Structure -5 STR1998## - R.sup.2 : H -4 STR1999## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 186-188.degree. C. Form: Free Example 1015 Structure -5 STR2000## - R.sup.2 : 2-Cl -2 STR2001## - Crystalline form: Colorless amorphous NMR analysis: 206) Form: Free Example 1016 Structure -5 STR2002## - R.sup.2 : 2-Cl -4 STR2003## - Crystalline form: Colorless amorphous NMR analysis: 207) Form: Free Example 1017 Structure -5 STR2004## - R.sup.2 : 3-OCH.sub.3 -2 STR2005## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 191-191.5.degree. C. Form: Free Example 1018 Structure -5 STR2006## - R.sup.2 : 3-OCH.sub.3 -4 STR2007## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 210-212.degree. C. Form: Free Example 1019 Structure -6 STR2008## - R.sup.2 : H -2 STR2009## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 196-198.degree. C. Form: Free Example 1020 Structure -6 STR2010## - R.sup.2 : H -4 STR2011## - Crystalline form: Colorless amorphous NMR analysis: 208) Form: Free Example 1021 Structure -6 STR2012## - R.sup.2 : 2-Cl -2 STR2013## - Crystalline form: Colorless amorphous NMR analysis: 209) Form: Free Example 1022 Structure -6 STR2014## - R.sup.2 : 2-Cl -4 STR2015## - Crystalline form: Colorless amorphous NMR analysis: 210) Form: Free Example 1023 Structure -6 STR2016## - R.sup.2 : 3-OCH.sub.3 -2 STR2017## - Crystalline form: Colorless amorphous NMR analysis: 211) Form: Free Example 1024 Structure -6 STR2018## - R.sup.2 : 3-OCH.sub.3 -4 STR2019## - Crystalline form: Colorless amorphous NMR analysis: 212) Form: Free Example 1025 Structure -7 STR2020## - R.sup.2 : 2-Cl -2 STR2021## - Crystalline form: Colorless amorphous NMR analysis: 213) Form: Free Example 1026 Structure -7 STR2022## - R.sup.2 : 2-Cl -4 STR2023## - Crystalline form: Colorless amorphous NMR analysis: 214) Form: Free Example 1027 Structure -8 STR2024## - R.sup.2 : 2-Cl -4 STR2025## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 207-208.degree. C. Form: Free Example 1028 Structure -8 STR2026## - R.sup.2 : 2-Cl -2 STR2027## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 201-202.degree. C. Form: Free Example 1029 Structure -9 STR2028## - R.sup.2 : 2-Cl -4 STR2029## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 193-194.degree. C. Form: Free Example 1030 Structure -8 STR2030## - R.sup.2 : H -4 STR2031## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 205-208.degree. C. Form: Free Example 1031 Structure -9 STR2032## - R.sup.2 : H -4 STR2033## - Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 214-216.degree. C. Form: Free Example 1032 Structure -0 STR2034## - R.sup.2 : H -4 STR2035## - Crystalline form: Yellow needles Recrystallization solvent: Ethanol Melting Point: 223-226.degree. C. Form: Free Example 1033 Structure -1 STR2036## - R.sup.2 : H -4 STR2037## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol/diethyl ether Melting Point: 203-206.degree. C. Form: Free Example 1034 Structure -2 STR2038## - R.sup.2 : H -4 STR2039## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol/diethyl ether/n-hexane Melting Point: 168-171.degree. C. Form: Free Example 1035 Structure -3 STR2040## - R.sup.2 : H -4 STR2041## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 206-208.degree. C. Form: Free Example 1036 Structure -3 STR2042## - R.sup.2 : H -4 STR2043## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 229-232.degree. C. Form: Free Example 1037 Structure -4 STR2044## - R.sup.2 : H -2 STR2045## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 220-222.degree. C. Form: Free Example 1038 Structure -4 STR2046## - R.sup.2 : H -4 STR2047## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 232-233.5.degree. C. Form: Free Example 1039 Structure -5 STR2048## - R.sup.2 : 2-CH.sub.3 -2 STR2049## - Crystalline form: Colorless amorphous NMR analysis: 215) Form: Free Example 1040 Structure -6 STR2050## - R.sup.2 : 2-CH.sub.3 -4 STR2051## - Crystalline form: Colorless amorphous NMR analysis: 216) Form: Free Example 1041 Structure -7 STR2052## - R.sup.2 : H -8 STR2053## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 147-151.degree. C. Form: Free Example 1042 Structure -7 STR2054## - R.sup.2 : H -9 STR2055## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 127-129.degree. C. Form: Free Example 1043 Structure -7 STR2056## - R.sup.2 : H -0 STR2057## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 109-112.degree. C. Form: Free Example 1044 Structure -1 STR2058## - R.sup.2 : H -2 STR2059## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 198-200.degree. C. Form: Free Example 1045 Structure -2 STR2060## - R.sup.2 : H -4 STR2061## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 210-211.degree. C. Form: Free Example 1046 Structure -3 STR2062## - R.sup.2 : 2-CH.sub.3 -4 STR2063## - Crystalline form: Colorless amorphous NMR analysis: 217) Form: Free Example 1047 Structure -3 STR2064## - R.sup.2 : 2-CH.sub.3 -4 STR2065## - Crystalline form: Colorless amorphous NMR analysis: 218) Form: Free Example 1048 Structure -4 STR2066## - R.sup.2 : H -4 STR2067## - Crystalline form: Colorless amorphous NMR analysis: 219) Form: Free Example 1049 Structure -5 STR2068## - R.sup.2 : H -4 STR2069## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 243-243.5.degree. C. Form: Free Example 1050 Structure -6 STR2070## - R.sup.2 : H -2 STR2071## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol/petroleum ether Melting Point: 207-209.degree. C. Form: Free Example 1051 Structure -6 STR2072## - R.sup.2 : H -4 STR2073## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol/petroleum ether Melting Point: 239-241.degree. C. Form: Free Example 1052 Structure -7 STR2074## - R.sup.2 : 2-Cl -2 STR2075## - Crystalline form: Colorless amorphous NMR analysis: 220) Form: Free Example 1053 Structure -8 STR2076## - R.sup.2 : 2-Cl -4 STR2077## - Crystalline form: Colorless amorphous NMR analysis: 221) Form: Free Example 1054 Structure -9 STR2078## - R.sup.2 : 2-Cl -2 STR2079## - Crystalline form: Light yellow amorphous NMR analysis: 222) Form: Free Example 1055 Structure -9 STR2080## - R.sup.2 : 2-Cl -4 STR2081## - Crystalline form: Light yellow amorphous NMR analysis: 223) Form: Free Example 1056 Structure -0 STR2082## - R.sup.2 : 2-Cl -4 STR2083## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 169.5-173.degree. C. Form: Free Example 1057 Structure -0 STR2084## - R.sup.2 : 2-Cl -2 STR2085## - Crystalline form: Colorless amorphous NMR analysis: 224) Form: Free Example 1058 Structure -1 STR2086## - R.sup.2 : 2-Cl -4 STR2087## - Crystalline form: Colorless amorphous NMR analysis: 225) Example 1059 Structure -2 STR2088## - R.sup.2 : 2-Cl -4 STR2089## - Crystalline form: Colorless amorphous NMR analysis: 226) Form: Free Example 1060 Structure -3 STR2090## - R.sup.2 : 2-Cl -4 STR2091## - Crystalline form: Colorless amorphous NMR analysis: 227) Form: Free Example 1061 Structure -4 STR2092## - R.sup.2 : 2-Cl -4 STR2093## - Crystalline form: Colorless amorphous NMR analysis: 228) Form: Free Example 1062 Structure -5 STR2094## - R.sup.2 : 2-Cl -4 STR2095## - Crystalline form: Colorless amorphous NMR analysis: 229) Form: Free Example 1063 Structure -6 STR2096## - R.sup.2 : 2-Cl -4 STR2097## - Crystalline form: Colorless amorphous NMR analysis: 230) Form: Free Example 1064 Structure -7 STR2098## - R.sup.2 : 2-Cl -4 STR2099## - Crystalline form: Colorless amorphous NMR analysis: 231) Form: Free Example 1065 Structure -8 STR2100## - R.sup.2 : 2-Cl -4 STR2101## - Crystalline form: Colorless amorphous NMR analysis: 232) Form: Free Example 1066 Structure -9 STR2102## - R.sup.2 : 2-Cl -4 STR2103## - Crystalline form: Colorless amorphous NMR analysis: 233) Form: Free Example 1067 Structure -0 STR2104## - R.sup.2 : 2-Cl -4 STR2105## - Crystalline form: Colorless amorphous NMR analysis: 234) Form: Free Example 1068 Structure -1 STR2106## - R.sup.2 : 2-Cl -2 STR2107## - Crystalline form: Colorless amorphous NMR analysis: 235) Form: Free Example 1069 Structure -2 STR2108## - R.sup.2 : 2-Cl -2 STR2109## - Crystalline form: Colorless amorphous NMR analysis: 236) Form: Free Example 1070 Structure -3 STR2110## - R.sup.2 : 2-Cl -2 STR2111## - Crystalline form: Colorless amorphous NMR analysis: 237) Form: Free______________________________________ 196) .sup.1 HNMR(CDCl.sub.3).delta.; 2.14(2H, brs), 2.33(3H, s), 2.46(3H, s), 2.85(2H, t, J=6.1Hz), 4.83(2H, brs), 6.64(1H, d, J=8.1Hz), 7.07(1H, d J=8.0Hz), 7.21-7.48(8H, m), 7.65(1H, m), 7.74(1H, brs) 197) .sup.1 HNMR(CDCl.sub.3).delta.; 2.12(2H, brs), 2.33(3H, s), 2.85(2H, t, J=6.2Hz), 2.88-5.28(2H, m), 6.63(1H, d, J=8.1Hz), 7.06(1H, dd, J=1.7Hz 8.1Hz), 7.19-7.69(9H, m), 8.26(1H, brs) 198) .sup.1 HNMR(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 HNMR(CDCl.sub.3).delta.; 2.04(2H, brs), 2.29(3H, s), 2.82(2H, t, J=5.9Hz), 2.85-5.29(2H, m), 6.82-7.69(10H, m), 8.31(1H, brs) 200) .sup.1 HNMR(CDCl.sub.3).delta.; 2.05(2H, brs), 2.29(3H, s), 2.44(3H, s), 2.79(2H, t, J=5.5Hz), 2.82-5.28(2H, m), 6.82-8.12(11H, m) 201) .sup.1 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(CDCl.sub.3).delta.; 1.14(6H, d, J=6.3Hz), 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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(CDCl.sub.3).delta.; 1.92-2.29(2H, m), 2.36(3H, s), 2.45(3H, s), 2.84(2H, t, J=6.3Hz), 3.32-4.64(2H, m), 6.40-8.10(11H, m) 218) .sup.1 HNMR(CDCl.sub.3).delta.; 1.92-2.25(2H, m), 2.34(3H, s), 2.83(2H, t, J=6.3Hz), 3.21-4.52(2H, m), 6.39-7.97(10H, m), 8.43(1H, brs) 219) .sup.1 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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 HNMR(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. 206-208.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 stuitable starting materials, the compounds of the following Table 9 are obtained in the same manner as in above Examples 1 and 382.
TABLE 9______________________________________1 #STR2112##______________________________________Example 1071 Structure2 STR2113## -3 STR2114## -4 STR2115## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 227-230.degree. C. Form: Free Example 1072 Structure -2 STR2116## -5 STR2117## -4 STR2118## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol/petroleum ether Melting Point: 216-218.degree. C. Form: Free Example 1073 Structure -2 STR2119## -5 STR2120## -6 STR2121## - Crystalline form: Colorless prisms Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 227-228.degree. C. Form: Free Example 1074 Structure -2 STR2122## -7 STR2123## -6 STR2124## - Crystalline form: White powder NMR analysis: 238) Form: Free Example 1075 Structure -2 STR2125## -7 STR2126## -4 STR2127## - Crystalline form: White powder NMR analysis: 239) Form: Free Example 1076 Structure -2 STR2128## -8 STR2129## -6 STR2130## - Crystalline form: Light yellow amorphous NMR analysis: 240) Form: Free Example 1077 Structure -2 STR2131## -8 STR2132## -4 STR2133## - Crystalline form: Light yellow amorphous NMR analysis: 241) Form: Free Example 1078 Structure -2 STR2134## -2 STR2135## -6 STR2136## - Crystalline form: Colorless amorphous NMR analysis: 242) Form: Free Example 1079 Structure -2 STR2137## -2 STR2138## -4 STR2139## - Crystalline form: Colorless amorphous NMR analysis: 243) Form: Free Example 1080 Structure -2 STR2140## -9 STR2141## -6 STR2142## - Crystalline form: Light yellow powder Recrystallization solvent: Ethyl acetate/diethyl ether Melting Point: 179-181.degree. C. Form: Free Example 1081 Structure -2 STR2143## -9 STR2144## -4 STR2145## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/diethyl ether Melting Point: 213-216.degree. C. Form: Free Example 1082 Structure -2 STR2146## -3 STR2147## -6 STR2148## - Crystalline form: Light yellow powder Recrystallization solvent: Ethyl acetate/diethyl ether Melting Point: 185-187.degree. C. Form: Free Example 1083 Structure -2 STR2149## -5 STR2150## -6 STR2151## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 249-251.degree. C. Form: Free Example 1084 Structure -2 STR2152## -5 STR2153## -4 STR2154## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 239-241.degree. C. Form: Free Example 1085 Structure -2 STR2155## -3 STR2156## -4 STR2157## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/diethyl ether Melting Point: 208-210.degree. C. Form: Free Example 1086 Structure -2 STR2158## -0 STR2159## -6 STR2160## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 178-108.5.degree. C. Form: Free Example 1087 Structure -2 STR2161## -1 STR2162## -4 STR2163## - Crystalline form: Colorless amorphous NMR analysis: 244) Form: Free Example 1088 Structure -2 STR2164## -2 STR2165## -4 STR2166## - Crystalline form: Colorless amorphous NMR analysis: 245) Form: Free Example 1089 Structure -2 STR2167## -3 STR2168## -4 STR2169## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether NMR analysis: 246) Form: Free Example 1090 Structure -2 STR2170## -3 STR2171## -6 STR2172## - Crystalline form: Colorless amorphous NMR analysis: 247) Form: Free Example 1091 Structure -2 STR2173## -3 STR2174## -4 STR2175## - Crystalline form: Colorless amorphous NMR analysis: 248) Form: Free Example 1092 Structure -2 STR2176## -5 STR2177## -6 STR2178## - Crystalline form: Colorless amorphous NMR analysis: 249) Form: Free Example 1093 Structure -2 STR2179## -2 STR2180## -6 STR2181## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 205-206.degree. C. Form: Free Example 1094 Structure -2 STR2182## -0 STR2183## -6 STR2184## - Crystalline form: Colorless amorphous NMR analysis: 250) Form: Free Example 1095 Structure -2 STR2185## -1 STR2186## -4 STR2187## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 172.5-174.degree. C. Form: Free Example 1096 Structure -2 STR2188## -2 STR2189## -4 STR2190## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 215-216.5.degree. C. Form: Free Example 1097 Structure -2 STR2191## -6 STR2192## -4 STR2193## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 133-136.degree. C. Form: Free Example 1098 Structure -2 STR2194## -4 STR2195## -6 STR2196## - Crystalline form: Colorless amorphous NMR analysis: 251) Form: Free Example 1099 Structure -2 STR2197## -4 STR2198## -4 STR2199## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 179-180.degree. C. Form: Free Example 1100 Structure -2 STR2200## -5 STR2201## -6 STR2202## - Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 167.5-169.5.degree. C. Form: Free Example 1101 Structure -2 STR2203## -5 STR2204## -4 STR2205## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 176-178.degree. C. Form: Free Example 1102 Structure -2 STR2206## -7 STR2207## -6 STR2208## - Crystalline form: Colorless amorphous NMR analysis: 252) Form: Free Example 1103 Structure -2 STR2209## -0 STR2210## -4 STR2211## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 185-188.degree. C. Form: Free Example 1104 Structure -2 STR2212## -8 STR2213## -6 STR2214## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 180-181.5.degree. C. Form: Free Example 1105 Structure -2 STR2215## -9 STR2216## -6 STR2217## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 181-184.degree. C. Form: Free Example 1106 Structure -2 STR2218## -8 STR2219## -4 STR2220## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 186.5-187.degree. C. Form: Free Example 1107 Structure -2 STR2221## -9 STR2222## -4 STR2223## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 183-184.degree. C. Form: Free Example 1108 Structure -2 STR2224## -6 STR2225## -6 STR2226## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 151-153.degree. C. Form: Free Example 1109 Structure -2 STR2227## -0 STR2228## -1 STR2229## - Crystalline form: Colorless amorphous NMR analysis: 253) Form: Free Example 1110 Structure -2 STR2230## -2 STR2231## -3 STR2232## - Crystalline form: Colorless amorphous NMR analysis: 254) Form: Free Example 1111 Structure -2 STR2233## -4 STR2234## -3 STR2235## - Crystalline form: White needles Recrystallization solvent: Ethanol/n-hexane Melting Point: 191-195.degree. C. Form: Free Example 1112 Structure -2 STR2236## -5 STR2237## -3 STR2238## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/n-hexane Melting Point: 227-230.degree. C. Form: Free Example 1113 Structure -2 STR2239## -6 STR2240## -1 STR2241## - Crystalline form: Colorless amorphous NMR analysis: 289) Form: Free Example 1114 Structure -2 STR2242## -6 STR2243## -3 STR2244## - Crystalline form: Light yellow amorphous NMR analysis: 255) Example 1115 Structure -2 STR2245## -7 STR2246## -1 STR2247## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/n-hexane Melting Point: 172-174.degree. C. Form: Free Example 1116 Structure -2 STR2248## -8 STR2249## -1 STR2250## - Crystalline form: Colorless amorphous NMR analysis: 305) Form: Free Example 1117 Structure -2 STR2251## -6 STR2252## -1 STR2253## - Crystalline form: Colorless amorphous NMR analysis: 290) Form: Free Example 1118 Structure -2 STR2254## -7 STR2255## -1 STR2256## - Crystalline form: Colorless amorphous NMR analysis: 291) Form: Free Example 1119 Structure -2 STR2257## -9 STR2258## -6 STR2259## - Crystalline form: Colorless amorphous NMR analysis: 264) Form: Free Example 1120 Structure -2 STR2260## -9 STR2261## -4 STR2262## - Crystalline form: Colorless amorphous NMR analysis: 265) Form: Free Example 1121 Structure -2 STR2263## -0 STR2264## -6 STR2265## - Crystalline form: Colorless amorphous NMR analysis: 266) Form: Free Example 1122 Structure -2 STR2266## -0 STR2267## -4 STR2268## - Crystalline form: Colorless amorphous NMR analysis: 267) Form: Free Example 1123 Structure -2 STR2269## -1 STR2270## -6 STR2271## - Crystalline form: Colorless amorphous NMR analysis: 268) Form: Free Example 1124 Structure -2 STR2272## -1 STR2273## -4 STR2274## - Crystalline form: Colorless amorphous NMR analysis: 269) Form: Free Example 1125 Structure -2 STR2275## -2 STR2276## -6 STR2277## - Crystalline form: Colorless amorphous NMR analysis: 270) Form: Free Example 1126 Structure -2 STR2278## -2 STR2279## -4 STR2280## - Crystalline form: Colorless amorphous NMR analysis: 271) Form: Free Example 1127 Structure -2 STR2281## -8 STR2282## -6 STR2283## - Crystalline form: Colorless amorphous NMR analysis: 272) Form: Free Example 1128 Structure -2 STR2284## -8 STR2285## -4 STR2286## - Crystalline form: Colorless amorphous NMR analysis: 273) Form: Free Example 1129 Structure -2 STR2287## -3 STR2288## -6 STR2289## - Crystalline form: Colorless amorphous NMR analysis: 274) Form: Free Example 1130 Structure -2 STR2290## -3 STR2291## -4 STR2292## - Crystalline form: Colorless amorphous NMR analysis: 275) Form: Free Example 1131 Structure -2 STR2293## -9 STR2294## -6 STR2295## - Crystalline form: Colorless amorphous NMR analysis: 276) Form: Free Example 1132 Structure -2 STR2296## -9 STR2297## -4 STR2298## - Crystalline form: Colorless amorphous NMR analysis: 277) Form: Free Example 1133 Structure -2 STR2299## -4 STR2300## -6 STR2301## - Crystalline form: Colorless amorphous NMR analysis: 278) Form: Free Example 1134 Structure -2 STR2302## -4 STR2303## -4 STR2304## - Crystalline form: Colorless amorphous NMR analysis: 279) Form: Free Example 1135 Structure -2 STR2305## -0 STR2306## -6 STR2307## - NMR analysis: 280) Form: Free Example 1136 Structure -2 STR2308## -0 STR2309## -4 STR2310## - NMR analysis: 281) Form: Free Example 1137 Structure -2 STR2311## -1 STR2312## -6 STR2313## - NMR analysis: 282) Form: Free Example 1138 Structure -2 STR2314## -1 STR2315## -4 STR2316## - NMR analysis: 283) Form: Free Example 1139 Structure -2 STR2317## -2 STR2318## -6 STR2319## - NMR analysis: 306) Form: Free Example 1140 Structure -2 STR2320## -3 STR2321## -6 STR2322## - Crystalline form: Colorless amorphous NMR analysis: 284) Form: Free Example 1141 Structure -2 STR2323## -4 STR2324## -3 STR2325## - Crystalline form: Colorless amorphous NMR analysis: 285) Form: Free Example 1142 Structure -2 STR2326## -4 STR2327## -1 STR2328## - Crystalline form: Colorless amorphous NMR analysis: 286) Form: Free Example 1143 Structure -2 STR2329## -6 STR2330## -1 STR2331## - Crystalline form: Colorless amorphous NMR analysis: 287) Form: Free Example 1144 Structure -2 STR2332## -7 STR2333## -1 STR2334## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 203-207.degree. C. Form: Free Example 1145 Structure -2 STR2335## -7 STR2336## -3 STR2337## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 199-203.degree. C. Form: Free Example 1146 Structure -2 STR2338## -8 STR2339## -1 STR2340## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 210-212.degree. C. Form: Free Example 1147 Structure -2 STR2341## -8 STR2342## -3 STR2343## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 211-214.degree. C. Form: Free Example 1148 Structure -2 STR2344## -9 STR2345## -1 STR2346## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 186-189.degree. C. Form: Free Example 1149 Structure -2 STR2347## -9 STR2348## -3 STR2349## - Crystalline form: Colorless amorphous NMR analysis: 288) Form: Free Example 1150 Structure -2 STR2350## -0 STR2351## -1 STR2352## - Crystalline form: Colorless amorphous NMR analysis: 292) Form: Free Example 1151 Structure -2 STR2353## -0 STR2354## -3 STR2355## - Crystalline form: Colorless amorphous NMR analysis: 293) Form: Free Example 1152 Structure -2 STR2356## -1 STR2357## -1 STR2358## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 144-145.degree. C. Form: Free Example 1153 Structure -2 STR2359## -1 STR2360## -3 STR2361## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 149-150.degree. C. Form: Free Example 1154 Structure -2 STR2362## -2 STR2363## -1 STR2364## - Crystalline form: Colorless amorphous NMR analysis: 294) Form: Free Example 1155 Structure -2 STR2365## -2 STR2366## -3 STR2367## - Crystalline form: Colorless amorphous NMR analysis: 295) Form: Free Example 1156 Structure -2 STR2368## -3 STR2369## -1 STR2370## - Crystalline form: Colorless amorphous NMR analysis: 301) Form: Free Example 1157 Structure -2 STR2371## -3 STR2372## -3 STR2373## - Crystalline form: Colorless amorphous NMR analysis: 302) Form: Free Example 1158 Structure -2 STR2374## -4 STR2375## -1 STR2376## - Crystalline form: Colorless amorphous NMR analysis: 303) Form: Free Example 1159 Structure -2 STR2377## -4 STR2378## -3 STR2379## - Crystalline form: Colorless amorphous NMR analysis: 304) Form: Free Example 1160 Structure -2 STR2380## -5 STR2381## -6 STR2382## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/diisopropyl ether Melting Point: 191-193.degree. C. Form: Free Example 1161 Structure -2 STR2383## -5 STR2384## -4 STR2385## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/diisopropyl ether Melting Point: 221-223.degree. C. Form: Free Example 1162 Structure -2 STR2386## -5 STR2387## -6 STR2388## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 159-161.degree. C. Form: Free Example 1163 Structure -2 STR2389## -5 STR2390## -4 STR2391## - Crystalline form: White powder Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 174-175.degree. C. Form: Free Example 1164 Structure -2 STR2392## -6 STR2393## -6 STR2394## - Crystalline form: Colorless amorphous NMR analysis: 256) Form: Free Example 1165 Structure -2 STR2395## -6 STR2396## -4 STR2397## - Crystalline form: Colorless amorphous NMR analysis: 257) Form: Free Example 1166 Structure -2 STR2398## -7 STR2399## -6 STR2400## - Crystalline form: Colorless amorphous NMR analysis: 258) Form: Free Example 1167 Structure -2 STR2401## -8 STR2402## -6 STR2403## - Crystalline form: Colorless amorphous NMR analysis: 259) Form: Free Example 1168 Structure -2 STR2404## -9 STR2405## -6 STR2406## - Crystalline form: Colorless amorphous NMR analysis: 260) Form: Free Example 1169 Structure -2 STR2407## -0 STR2408## -6 STR2409## - Crystalline form: Colorless amorphous NMR analysis: 261) Form: Free Example 1170 Structure -2 STR2410## -1 STR2411## -6 STR2412## - Crystalline form: Colorless amorphous NMR analysis: 296) Form: Free Example 1171 Structure -2 STR2413## -2 STR2414## -6 STR2415## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether/n-hexane Melting Point: 159-162.degree. C. Form: Free Example 1172 Structure -2 STR2416## -2 STR2417## -3 STR2418## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol/diethyl ether/n-hexane Melting Point: 221-224.degree. C. Form: Free Example 1173 Structure -2 STR2419## -3 STR2420## -1 STR2421## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol/diethyl ether Melting Point: 199-202.degree. C. Form: Free Example 1174 Structure -2 STR2422## -3 STR2423## -3 STR2424## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol/diethyl ether Melting Point: 215-218.degree. C. Form: Free Example 1175 Structure -2 STR2425## -4 STR2426## -1 STR2427## - Crystalline form: Colorless needles Recrystallization solvent: Ethanol/diethyl ether/n-hexane Melting Point: 167-170.degree. C. Form: Free Example 1176 Structure -2 STR2428## -4 STR2429## -3 STR2430## - Crystalline form: White powder Recrystallization solvent: Ethanol/diethyl ether/n-hexane Melting Point: 191-193.degree. C. Form: Free Example 1177 Structure -2 STR2431## -5 STR2432## -1 STR2433## - Crystalline form: Light yellow amorphous NMR analysis: 262) Form: Free Example 1178 Structure -2 STR2434## -5 STR2435## -3 STR2436## - Crystalline form: Light yellow amorphous NMR analysis: 263) Form: Free Example 1179 Structure -2 STR2437## -6 STR2438## -3 STR2439## - Crystalline form: Colorless amorphous NMR analysis: 297) Form: Free Example 1180 Structure -2 STR2440## -6 STR2441## -1 STR2442## - Crystalline form: Colorless amorphous NMR analysis: 298) Form: Free Example 1181 Structure -2 STR2443## -7 STR2444## -3 STR2445## - Crystalline form: Colorless amorphous NMR analysis: 299) Form: Free Example 1182 Structure -2 STR2446## -7 STR2447## -1 STR2448## - Crystalline form: Colorless amorphous NMR analysis: 300) Form: Free Example 1183 Structure -2 STR2449## -8 STR2450## -3 STR2451## - Crystalline form: Colorless amorphous NMR analysis: 307) Form: Free Example 1184 Structure -2 STR2452## -9 STR2453## -1 STR2454## - Crystalline form: Colorless amorphous NMR analysis: 308) Form: Free Example 1185 Structure -2 STR2455## -0 STR2456## -1 STR2457## - Crystalline form: Colorless amorphous NMR analysis: 309) Form: Free Example 1186 Structure -2 STR2458## -0 STR2459## -3 STR2460## - Crystalline form: Colorless amorphous NMR analysis: 310) Form: Free Example 1187 Structure -2 STR2461## -1 STR2462## -1 STR2463## - Crystalline form: Colorless amorphous NMR analysis: 311) Form: Free Example 1188 Structure -2 STR2464## -1 STR2465## -1 STR2466## - Crystalline form: Colorless amorphous NMR 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=8.4Hz), 7.15-7.7 (9H, m), 7.76(1H, d, J=2.6Hz), 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=8.4Hz), 7.2-7.7(9H, m), 7.76 (1H, d, J=2.6Hz), 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=6.0Hz), 3.10-5.00 (2H, m), 3.70(3H, s), 6.67(1H, d, J=8.0Hz), 6.85-6.88(2H, m), 7.09(1H, dd, J=1.5, 8.0Hz), 7.21-7.50(4H, m), 7.64(1H, d, J=1.9Hz), 8.11 (1H, m), 8.33(1H, d, J=8.8Hz) 254) .sup.1 H-NMR(CDCl.sub.3).delta.; 1.42-5.06(13H, m), 6.51(1H, d, J=7.8Hz), 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(2H, 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, 8.7Hz), 6.87-7.06(2H, m), 6.82(1H, d, J=8.7Hz), 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), 182-2.01(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=6.8Hz), 6.67 (1H, d, J=8.6Hz), 6.93(1H, dd, J=8.6, 2.5Hz), 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=6.5Hz), 6.69(1H, d, J=8.7Hz), 6.94(1H, dd, J=8.6, 2.5Hz), 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=8.6Hz), 6.90(1H, dd, J=8.6, 2.5 Hz), 7.16-7.61(9H, m), 7.88(1H, brs) 3.52-4.08(3H, m), 6.34-7.75 (10H, m), 8.61(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, 6.4Hz), 6.60(1H, d, J=8.7Hz), 6.91 (1H, dd, J=8.7, 2.5Hz), 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), 6.35-7.95(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=8.1Hz), 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=6.9Hz), 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, 6.1Hz), 3.97-4.14(1H, m), 6.48 (1H, d, J=8.2Hz), 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, 6.1Hz), 3.98-4.16(1H, m), 6.48(1H, d, J=8.2Hz), 6.72(1H, dd, J=8.2, 1.9Hz), 7.16(1H, d, J=1.9Hz), 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=6.9Hz), 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, 12.9Hz), 6.60(1H, d, J=8.6Hz), 6.93(1H, dd, J=8.6, 2.5Hz), 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=6.9Hz), 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, 12.9Hz), 6.60-6.68(1H, m), 6.95(1H, dt, J=7.5, 1.8Hz), 7.03(1H, dt, J=7.4, 1.4Hz), 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=6.9Hz), 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, 12.9Hz), 6.61 (1H, d, J=8.6Hz), 6.93(1H, dd, J=8.6, 2.5Hz), 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=6.9Hz), 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, 12.9Hz), 6.59- 6.67(1H, m), 6.94(1H, dt, J=7.5, 1.9Hz), 7.03 (1H, dt, J=7.4, 1.4Hz), 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=6.5Hz), 1.37 (1H, brs), 2.61-2.40(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=6.7Hz), 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=6.6Hz), 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=6.5Hz), 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), 8.03-8.80(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), 8.06(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=8.5Hz) 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=8.4Hz), 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=8.5Hz), 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=7.2Hz), 2.40(3H, s), 3.77(3H, s)], 6.55(1H, d, J=8.1Hz), 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=7.0Hz), 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=8.3Hz), 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=7.9Hz), 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=8.4Hz), 6.69(1H, d, J=7.9Hz), 6.77-7.93(7H, m), 8.32(1H, d, J=8.3Hz), 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=8.3Hz), 6.61-7.82(8H, m), 8.14(1H, s), 8.30(1H, d, J=8Hz) 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 acitive 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]decanylcarbonylamino-benzoyl)-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)benzoy]-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-l,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)acetylamino]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-methyl-benzoylamino)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-Cycloropropylamino-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-pipetazinyl)-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-1-12-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-methyl-benzoylamino)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-a-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 Test Comp. IC.sub.50 Comp. IC.sub.50 No. (.mu.M) No. (.mu.M)______________________________________26 0.071 78 0.10 27 0.095 88 0.34 28 0.056 90 0.38 29 0.15 114 0.011 30 0.15 115 0.012 32 0.30 116 0.04 33 0.092 117 0.22 36 0.41 119 0.049 46 0.40 120 0.29 56 0.025 121 0.45 57 0.46 124 0.15 58 0.40 125 0.091 59 0.31 130 0.023 60 0.18 143 0.15 62 0.098 147 0.28 63 0.14 161 0.14 64 0.069 163 0.22 67 0.34 164 0.15 68 0.013 172 0.26 69 0.066 173 0.15 70 0.041 174 0.14 71 0.18 187 0.45 72 0.12 188 0.47 74 0.10 192 0.054 75 0.069 193 0.17 76 0.042 195 0.17 77 0.085 196 0.40 207 0.16 284 0.29 208 0.11 285 0.18 209 0.074 286 0.40 214 0.27 287 0.064 215 0.13 288 0.26 222 0.096 290 0.21 231 0.16 293 0.19 235 0.088 298 0.29 236 0.16 302 0.071 238 0.39 303 0.19 244 0.23 304 0.21 250 0.19 307 0.024 252 0.36 308 0.11 255 0.046 309 0.43 256 0.049 310 0.065 266 0.29 311 0.078 269 0.48 312 0.056 274 0.11 313 0.032 275 0.18 315 0.38 277 0.23 316 0.47 278 0.30 321 0.059 279 0.15 322 0.044 280 0.47 323 0.064 281 0.18______________________________________
Pharmacological Test
Experiment 2: V.sub.2 receptor binding assay
Using rat kidney plasma membrane preparations prepared according to 0. 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 in the following Table 11.
TABLE 11______________________________________Test Test Comp. IC.sub.50 Comp. IC.sub.50 No. (.mu.M) No. (.mu.M)______________________________________1 0.98 28 0.018 2 0.20 29 0.069 3 0.40 30 0.029 4 0.58 31 0.098 5 1.2 32 0.016 6 0.076 33 0.007 7 0.20 34 0.049 8 0.32 35 0.20 9 0.53 36 0.028 10 0.082 37 0.16 11 1.05 38 0.029 12 1.97 39 0.071 13 1.02 40 0.33 14 0.23 41 0.20 15 0.13 42 0.063 16 0.17 43 0.17 17 0.23 44 0.050 18 1.0 45 0.19 19 1.7 46 0.018 20 1.4 47 0.20 21 1 48 0.021 22 0.33 49 0.063 23 1.07 50 1.3 24 1.09 51 0.40 25 1.67 52 0.32 26 0.025 53 1.6 27 0.070 54 0.11 55 0.091 86 0.58 56 0.037 87 0.046 57 0.16 88 0.021 58 0.14 89 0.035 59 0.24 90 0.014 60 0.15 91 0.005 61 0.090 92 0.41 62 0.023 93 0.52 63 0.046 94 0.095 64 0.007 95 0.089 65 0.081 96 0.039 66 0.45 97 0.024 67 0.050 98 0.45 68 0.19 99 1.6 69 0.12 100 0.011 70 0.012 101 0.60 71 0.085 102 0.29 72 0.16 103 0.54 74 0.51 104 0.37 75 0.30 105 0.72 76 0.017 106 0.44 77 0.090 107 0.032 78 0.084 108 0.12 79 0.53 109 0.49 80 0.070 110 0.044 81 0.15 111 0.087 82 0.17 112 0.29 83 0.73 113 0.28 84 0.11 114 0.006 85 0.068 115 0.006 116 0.039 146 0.056 117 0.24 147 0.009 118 0.55 148 0.34 119 0.059 149 0.004 120 0.28 150 0.14 121 0.18 151 0.18 122 0.10 152 0.039 123 0.10 153 0.063 124 0.13 154 0.063 125 0.28 155 0.028 126 0.062 156 0.15 127 0.99 157 0.38 128 0.23 158 0.018 129 0.29 159 0.020 130 0.007 160 0.020 131 0.027 161 0.009 132 0.013 162 0.059 133 0.022 163 0.009 134 0.048 164 0.010 135 0.081 165 0.098 136 0.18 166 0.070 137 0.41 167 0.032 138 0.11 168 0.083 139 0.10 169 0.071 140 0.024 170 0.25 141 0.010 171 0.87 142 0.008 172 0.023 143 0.008 173 0.008 144 0.02 174 0.007 145 0.06 175 0.038 176 0.004 206 0.088 177 0.15 207 0.045 178 0.012 208 0.007 179 0.040 209 0.004 180 0.034 210 0.004 181 0.038 211 0.12 182 0.005 212 0.035 183 0.26 213 0.033 184 0.023 214 0.058 185 0.005 215 0.006 186 0.030 216 0.91 187 0.029 217 0.37 188 0.039 218 0.022 189 0.087 219 0.023 190 0.082 220 0.026 191 0.009 221 0.024 192 0.011 222 0.010 193 0.036 223 0.022 194 0.21 224 0.38 195 0.010 225 0.030 196 0.013 226 0.019 197 0.99 227 0.029 198 0.040 228 0.029 199 0.019 229 0.029 200 0.024 230 0.020 201 0.023 231 0.007 202 0.14 232 0.020 203 0.070 233 0.15 204 0.11 234 0.14 205 0.074 235 0.006 236 0.006 267 0.12 237 0.041 268 0.018 238 0.020 269 0.003 239 0.17 270 0.046 240 0.022 271 0.030 241 0.006 272 0.40 242 0.17 273 0.027 243 0.40 274 0.024 244 0.018 275 0.018 245 0.059 276 0.032 246 0.027 277 0.016 247 0.048 278 0.013 248 0.060 279 0.008 250 0.12 280 0.045 251 0.094 281 0.011 252 0.063 282 0.38 253 0.052 283 0.096 254 0.016 284 0.019 255 0.005 285 0.008 256 0.004 286 0.019 257 0.045 287 0.007 258 0.20 288 0.015 259 0.25 289 0.071 260 0.13 290 0.021 261 0.011 291 0.13 262 0.029 292 0.18 263 0.053 293 0.065 264 0.030 294 0.33 265 0.025 295 0.026 266 0.013 296 0.25 297 0.051 311 0.013 298 0.10 312 0.29 299 0.22 313 0.012 300 0.48 314 0.096 301 0.14 315 0.025 302 0.011 316 0.060 303 0.025 317 0.072 304 0.024 318 0.060 305 0.038 319 0.058 306 0.077 320 0.039 307 0.010 321 0.012 308 0.023 322 0.025 309 0.015 323 0.014 310 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 10 33 1.9 178 4.2 249 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______________________________________1 #STR2467##______________________________________Example 1190 Structure - 2 R.sup.2 : 2-OCH.sub.3 - 3 STR2469## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 210-213.degree. C. Form: Free Example 1191 Structure - 4 R.sup.2 : 2-CH.sub.3 - 5 STR2471## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 184.5-186.degree. C. Form: Free Example 1192 Structure - 6 R.sup.2 : H - 7 STR2473## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 201.5-202.5.degree. C. Form: Free Example 1193 Structure - 8 R.sup.2 : 2-Cl - 9 STR2475## - Crystalline form: White powder Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 159-162.degree. C. (decomposed) Form: Free Example 1194 Structure - 0 R.sup.2 : 2-OCH.sub.3 - 1 STR2477## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 237-240.degree. C. Form: Free Example 1195 Structure - 2 R.sup.2 : 2-OCH.sub.3 - 3 STR2479## - Crystalline form: White powder Recrystallization solvent: Diethyl ether/dichloromethane Melting Point: 269-272.5.degree. C. Form: Free Example 1196 Structure - 8 R.sup.2 : H - 1 STR2481## - Crystalline form: Colorless prisms Recrystallization solvent: Ethanol/dichloromethane Melting Point: 201-202.degree. C. Form: Free Example 1197 Structure - 4 R.sup.2 : 2-CH.sub.3 - 5 STR2483## - Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 204-206.degree. C. Form: Free Example 1198 Structure - 6 R.sup.2 : 2-Cl - 7 STR2485## - Crystalline form: Colorless amorphous NMR analysis: 313) Form: Free Example 1199 Structure - 8 R.sup.2 : 2-CH.sub.3 - 9 STR2487## - Crystalline form: Colorless amorphous NMR analysis: 314) Form: Free Example 1200 Structure - 0 R.sup.2 : 2-CH.sub.3 - 1 STR2489## - Crystalline form: Colorless amorphous NMR analysis: 315) Form: Free Example 1201 Structure - 2 R.sup.2 : 2-OCH.sub.3 - 3 STR2491## - Crystalline form: Colorless amorphous NMR analysis: 316) Form: Free Example 1202 Structure - 4 R.sup.2 : 2-Cl - 5 STR2493## - Crystalline form: Colorless amorphous NMR analysis: 317) Form: Free Example 1203 Structure - 6 R.sup.2 : 2-OCH.sub.3 - 7 STR2495## - Crystalline form: Light brown amorphous NMR analysis: 318) Form: Hydrochloride Example 1204 Structure - 8 R.sup.2 : 2-OCH.sub.3 - 9 STR2497## - Crystalline form: Colorless amorphous NMR analysis: 319) Form: Free Example 1205 Structure - 0 R.sup.2 : 2-CH.sub.3 - 1 STR2499## - Crystalline form: Colorless amorphous NMR analysis: 320) Form: Hydrochloride Example 1206 Structure - 2 R.sup.2 : 2-CH.sub.3 - 3 STR2501## - Crystalline form: Colorless amorphous NMR analysis: 321) Form: Hydrochloride Example 1207 Structure - 4 R.sup.2 : 2-OCH.sub.3 - 5 STR2503## - Crystalline form: Colorless amorphous NMR analysis: 322) Form: Free Example 1208 Structure - 6 R.sup.2 : 2-OCH.sub.3 - 7 STR2505## - Crystalline form: Light yellow prisms Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 187-189.degree. C. Form: Free Example 1209 Structure - 8 R.sup.2 : H - 9 STR2507## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 227-231.degree. C. Form: Free Example 1210 Structure - 0 R.sup.2 : 2-CH.sub.3 - 1 STR2509## - Crystalline form: White powder Recrystallization solvent: Methanol/diethyl ether Melting Point: 191-192.degree. C. Form: Free Example 1211 Structure - 2 R.sup.2 : 2-CH.sub.3 - 3 STR2511## - Crystalline form: Colorless amorphous NMR analysis: 323) Form: Free Example 1212 Structure - 4 R.sup.2 : 2-CH.sub.3 - 5 STR2513## - Crystalline form: Colorless amorphous NMR analysis: 324) Form: Free Example 1213 Structure - 6 R.sup.2 : 2-CH.sub.3 - 7 STR2515## - Crystalline form: White amorphous NMR analysis: 325) Form: Hydrochloride______________________________________ 313) .sup.1 HNMR (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 HNMR (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 HNMR (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 HNMR (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 HNMR (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 HNMR (DMSOd.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 HNMR (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 HNMR (DMSOd.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 HNMR (DMSOd.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 HNMR (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 HNMR (CDCl.sub.3) .delta.; 1.32-2.23(2H, m), 2.23-2.68(7H, m) 2.68-3.84(8H, m), 3.84-5.23(4H, m), 6.47-7.88(11H, m) 324) .sup.1 HNMR (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 HNMR (DMSOd.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	Date	Country
1-274338	Oct 1989	JPX
2-66063	Mar 1990	JPX
2-105580	Apr 1990	JPX
2-181858	Jul 1990	JPX
3-182066	Apr 1991	JPX

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
Parent	474544	Jun 1995
Parent	076804	Jun 1993
Parent	851541	Mar 1992

Benzoheterocyclic compounds

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Entry
Yoshitake Yamamura, Hidenori Ogawa, Tomihiko Chihara, Kazumi Kondo, Toshiyuki Onogawa, Shigeki Nakamura, Toyo Mori, Michiaki Tominaga and Youichi Yabucchi, OPC-21268, An Orally Effective, Nonpeptide Vasopressin V1 Receptor Antagonist, Science, vol. 252, pp. 572-574 (Apr. 1991).
Ogawa et al., CAS printout of WO 91/05549, May 1991.