Benzoheterocyclic compounds and vasopressin antagonist and oxytocin antagonist compositions containing a benzoheterocyclic compound

TECHNICAL FIELD
The present invention relates to a vasopressin antagonist and oxytocin antagonist containing a benzoheterocyclic compound as an active ingredient.
BACKGROUND ART
Some of benzoheterocyclic compounds being used as the active ingredients in the vasopressin antagonists and oxytocin antagonists which are represented by the general formula (1) containing novel compounds.
Some benzohetrocyclic compounds having chemical structural formulae similar to those of benzoheterocyclic compounds according to the present invention are disclosed in EP-A-0382185 A2 (Publication Date: Aug. 15, 1990); WO 91/05549 (Publication Date: May 2, 1991) and EP-A-0470514A1 (Publication Date: Feb. 12, 1992). Furthermore, EP-A-0514667A1 (Publication Date: Nov. 25, 1992) discloses benzoheterocyclic compounds, and is known as the junior patent application of the present invention.
The substituents bonded at 1-position in the benzoheterocyclic compounds disclosed in these prior art references are substantially different from the substituents bonded at 1-position in the benzoheterocyclic compounds according to the present invention.
DISCLOSURE OF THE INVENTION
The benzoheterocyclic compounds or a salts thereof of the present invention are prepresented by the general formula (1) as follows: ##STR2## wherein, R.sup.1 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkanoyloxy group, an amino-lower alkoxy group which may have the substituents selected from the group consisting of lower alkyl group and lower alkanoyl group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, or an aminocarbonyl-lower alkoxy group which may have lower alkyl groups as the substituents;
R.sup.4 is a hydrogen atom, a group of the formula: ##STR3## (wherein R.sup.6 and R.sup.7 are the same or different, and are each a hydrogen atom, a lower alkyl group, a lower alkenyl group or a benzoyl group having halogen atoms as the substituents on the phenyl ring),
a lower alkenyloxy group, a hydroxyl group-substituted lower alkyl group, a group of the formula: ##STR4## (wherein A is a lower alkylene group;
R.sup.8 and R.sup.9 are the same or diffrent, and are each a hydrogen atom or a lower alkyl group; further R.sup.8 and R.sup.9 may form a 5- to 6-membered saturated or unsaturated heterocyclic group by combining with the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom, said heterocyclic group may be substituted with lower alkyl groups),
a group of the formula --O--R.sup.10 (wherein R.sup.10 is an amino acid residue),
a lower alkoxycarbonyl-substituted lower alkylidene group, a lower alkoxycarbonyl-substituted lower alkyl group, a carboxy-substituted lower alkyl group, a group of the formula: ##STR5## (wherein A is the same as defined above;
R.sup.11 and R.sup.12 are the same or different, and are each a hydrogen atom, a lower alkyl group which may have hydroxyl groups as the substituents, a piperidinyl group which may have phenyl-lower alkyl group on the piperidine ring, a carbamoyl-substituted lower alkyl group, a pyridyl-substituted lower alkyl group, a pyridyl group,
a group of the formula: ##STR6## (wherein A is a lower alkylene group;
R.sup.39 and R.sup.40 are the same or different, and are each a hydrogen atom or a lower alkyl group which may have hydroxyl group as the substituents;
further R.sup.39 and R.sup.40 may form a 5- or 6-membered saturated heterocyclic group, by combining with the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom, said heterocyclic group may have lower alkyl groups on the heterocyclic ring), a pyrazinyl-substituted lower alkyl group which may have, as the substituents, lower alkyl groups on the pyrazine ring, pyrrolyl-substituted lower alkyl group which may have, as the substituents, lower alkyl groups on the pyrrole ring, a pyrrolidinyl-substituted lower alkyl group which may have, as the substituents, lower alkyl groups on the pyrrolidine ring, or a phenyl group which may have halogen atoms on the phenyl ring;
further, R.sup.11 and R.sup.12 may form 5 to 7-membered saturated heterocyclic group, by combining with the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom; said heterocyclic group may be substituted with a lower alkyl group, a lower alkoxycarbonyl group, an amino group which may have the substituents selected from the group consisting of a lower alkyl group and a lower alkanoyl group, a lower alkoxycarbonyl-substituted lower alkyl group, a phenyl group which may have halogen atoms on the phenyl ring, a cyano-substituted lower alkyl group, a lower alkenyl group, an oxyranyl-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group, a lower alkyl group having 1 to 2 substituents selected from the group consisting of a hydroxyl group and an amino group which may have lower alkyl group, or a pyrrolidinylcarbonyl-lower alkyl group),
group of the formula: ##STR7## (wherein A is the same as defined above;
R.sup.23 and R.sup.24 are the same or different, and are each a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl-substituted lower alkyl group, a carboxy-substituted lower alkyl group, a piperidinyl group which may have lower alkyl groups on the piperidine ring, a group of the formula: ##STR8## (wherein B is an alkylene group;
R.sup.23A and R.sup.24A are the same or different, and are each a hydrogen atom or a lower alkyl group;
further R.sup.23A and R.sup.24A may form a 5- to 6-membered saturated hetero-cyclic group, by combining with the adjacnet nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom), further R.sup.23 and R.sup.24 may form a 5- to 7-membered hetero-cyclic group group, by combining with the adjacent nitrogen atom being bonded, thereto together with or without other nitrogen atom or oxygen atom), a pyrrolidinylcarbonyl-lower alkoxy group having lower alkoxycarbonyl group on the pyrrolidine ring, a lower alkoxy-substituted lower alkanoyloxy group, a group of the formula: ##STR9## (wherein A is the same as defined above;
B is a lower alkylene group; R.sup.25 and R.sup.26 are the same or different, and are each a hydrogen atom or a lower alkyl group), an amino-substituted lower alkylidene group, a group of the formula: ##STR10## (wherein A is the same as defined above;
R.sup.27 and R.sup.28 are the same or different, and are each a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylsulfonyl group, an aminothiocarbonyl group which may have lower alkyl groups as the substituents, a group of the formula: ##STR11## (wherein R.sup.41 is a hydrogen atom or a cyano group;
R.sup.42 is a lower alkyl group or an amino group which may have a lower alkyl groups as the substituents),
a carbamoyl group, a lower alkoxycarbonyl group, a cycloalkyl group, a phenyl-lower alkyl group which may have halogen atoms as the substituents on the phenyl ring, a cyano-substituted lower alkyl group, a halogen atom-substituted lower alkylsulfonyl group, an amino-substituted lower alkyl group which may have lower alkylgroups as the substituents;
further, R.sup.27 and R.sup.28 may form a 5- to 10-membered single ring or binary ring saturated or unsaturated heterocyclic group, said heterocyclic group may be substituted with an oxo group, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group or a lower alkanoylamino group on the heterocyclic ring), a cyano group, a cyano-substituted lower alkyl group, a phenylsulfonyloxy group which may have lower alkyl groups as the substituents on the phenyl ring, a lower alkoxy group having hydroxy groups, a group of the formula: ##STR12## (wherein A is the same as defined above;
R.sup.29 is a hydrogen atom or a lower alkyl group;
R.sup.30 is a lower alkenyl group, a cycloalkyl group or a lower alkynyl group;
further R.sup.29 and R.sup.30 may form a 5- to 6-memberedsaturated heterocyclic group, by combining with the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom; said heterocyclic group may be substituted with a lower alkyl group, a lower alkanoyl group, an amino group which may have the substituent selected from the group consisting of a lower alkyl group, and a lower alkanoyl group, a lower alkylsulfonyl group, a lower alkoxycarbonyl group or an aminocarbonyl group which may have lower alkyl groups as the substituents),
a phenylsulfonyloxy-substituted lower alkyl group which may have lower alkyl groups as the substituents on the phenyl ring, a phthalimide-substituted lower alkyl group a cyano-substituted lower alkylidene group, a halogen atoms-substituted lower alkyl group, an imidazolyl-substituted lower alkyl group, a 1,2,4-triazolyl-substituted lower alkoxy group, a 1,2,3,4-tetrazolyl-substituted lower alkoxy group, a 1,2,3,5-tetrazolyl-substituted lower alkoxy group, a 1,2,3,4-tetrazolyl-substituted lower alkyl group, a 1,2,3,5-tetrazolyl-substituted lower alkyl group, 1,2,4-triazolyl-substituted lower alkyl group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a pyridylthio-substituted lower alkoxy group, a pyrimidinylthio-substituted lower alkoxy group which may have lower alkyl groups on the pyrimidine ring, a imidazolthio-substituted lower alkoxy group, a pyridylsulfinyl-substituted lower alkoxy group, a pyridylsulfonyl-substituted lower alkoxy group, an imidazolylsulfinyl-substituted lower alkoxy group and an imidazolylsulfonyl-substituted lower alkoxy group;
R.sup.5 is a hydrogen atom or a hydroxyl group;
R.sup.4 and R.sup.5 may form an oxo group by combining together;
R.sup.2 is a hydrogen atom, a lower alkyl group, a hydroxyl group, a halogen atom or a lower alkoxy group;
R.sup.3 is a group of the formula ##STR13## (wherein R.sup.13 is a halogen atom, a hydrogen group, a carbamoyl group, a piperazinyl-lower alkoxy group having a lower alkanoyl group at 4-position in the piperazine ring, an imidazolyl-substituted lower alkoxy group, a piperidinyl-lower alkoxy group having lower alkanoylamino groups on the piperidine ring, a 1,2,4-triazolyl-substituted alkoxy group, an ureido-substituted lower alkoxy group which may have lower alkyl groups, or an amino-substituted lower alkoxy group which may have lower alkyl groups as the substituents;
m is 0 or an integer of 1 to 3),
a phenyl-lower alkanoylamino group having 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkoxy group, a lower alkyl group and a nitro group, a group of the formula: ##STR14## (wherein n is 1 or 2), or a group of the formula: ##STR15## the carbon-carbon bond between 4- and 5-positions in the benzoazepin skeleton is a single bond or double bond;
provided that when R.sup.1 is a hydrogen atom or a halogen atom;
R.sup.4 is a hydrogen atom, a group of the formula: ##STR16## (wherein R.sup.6 and R.sup.7 are the same as defined above, excluding a benzoyl group having halogen atoms as the substituents on the phenyl group),
a group of the formula: ##STR17## (wherein A is the same as defined above;
R.sup.8 and R.sup.9 are the same or different and are each a hydrogen atom or a lower alkyl group), a hydroxy-substituted lower alkyl group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, or a group of the formula: ##STR18## (wherein A is the same as defined above;
R.sup.27 and R.sup.28 are the same or different, and are each a hydrogen atom or a lower alkyl group); and
R.sup.5 is a hydrogen atom or a hydroxyl group or R.sup.4 and R.sup.5 may form an oxo group by combinig together; further when R.sup.3 is a group of the formula ##STR19## then R.sup.13 should be of a carbamoyl group, a piperazinyl-lower alkoxy group having a lower alkanoyl group at 4-position in the piperazine ring, an imidazolyl-substituted lower alkoxy group a piperidinyl-substituted lower alkoxy group having lower alkanoylamino group on the piperidine ring, an 1,2,4-triazolyl-substituted lower alkoxy group or an ureido-substituted lower alkoxy group which may have lower alkyl groups).
According to an extensive research work made by the present inventors, there have been found the facts that each one of benzoheterocyclic compounds represented by the above-mentioned general formula (1) possess excellent vasopressin antagonistic activity and oxytocinantagonistic activity.
The vasopressin antagonists according to the present invention possess various pharmacological activities, for example, vasodilating activity, anti-hypertension, activity for inhibiting release of hepatic sugar, activity for inhibiting proliferation of mesangial cells, water diuretic activity, activity for inhibiting agglutination of platelets and antiemetic activity, thus they are useful as vasodilators, hypotensives, water diuretics and platelets agglutination inhibitors. So that they are effective for prophilaxis and treatments of hypertension, edema, hydroperitonia, heart falilure, renal function disorder, syndrome of inappropriate secretion of vasopressin or syndrome of inappropriate secretion of antidiuretic hormone (SIADH), hepatic cirrhosis, hyponatremia, hypokalemia, diabetes mellitus, circulation insufficiency, motion sickness and the like.
The oxytocin antagonists according to the present invention possess activity for inhibiting contraction of the uterus smooth muscle, activity for inhibiting secretion of milk, activity for inhibiting synthesis and release of prostaglandins, vasodilation, thus, they are effective for prophylaxis and treatments of oxytocin related diseases, particularly early birth, prevention of birth before cesarean section, dysmenorrhea and the like.
Furthermore, the benzoheterocyclic compounds according to the present invention have the features in that they have less side-effects, while they sustain the pharmacological activities for long period of time.
More specifically, examples of the respective groups shown by general formula (1) described above include the following:
As to the lower alkoxy group, there may be exemplified straight or branched alkoxy groups having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups, etc.
As to the lower alkyl group, there may be exemplified straight or branched alkyl groups having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isoporpyl, butyl, tert-butyl, pentyl and hexyl groups, etc.
Specific examples of the halogen atom are fluorine, chlorine, bromine and iodine atoms.
As to the lower alkenyl group, there may be exemplified straight or branched alkenyl groups having 2 to 6 carbon atoms, for example, vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl and 2-hexenyl groups, etc.
As to the lower alkenyloxy group, there may be exemplified straight or branched alkenyloxy groups having 2 to 6 carbon atoms, for example, vinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 1-methylallyloxy, 2-pentenyloxy and 2-hexenyloxy groups, etc.
As to the lower alkylene group, there may be exemplified straight chain or branched chain alkylene groups having 1 to 6 carbon atoms, for example, methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene and hexamethylene groups, etc.
As to the lower alkanoyloxy group, there may be exemplified straight chain or branched chain alkanoyloxy groups having 1 to 6 carbon atoms, for example, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy and hexanoyloxy groups, etc.
As to the hydroxy-substituted lower alkyl group, there may be exemplified straight chain or branched chain alkyl groups having 1 to 6 carbon atoms which contains 1 to 3 hydroxy groups as substituent(s), 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 and 2,3,4-trihydroxybutyl groups, etc.
As to the aminocarbonyl-lower alkoxy group having a lowr alkyl group as a substituent(s) means straight chain or branched chain alkoxy groups having 1 to 6 carbon atoms which contains as substituent(s) one or two straight chain or branched chain alkyl groups 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 and 2-(N-methyl-N-hexylamino)carbonylethoxy groups, etc.
As to the lower alkoxycarbonyl-substituted lower alkyl group, there may be exemplified straight chain or branched chain alkoxycarbonylalkyl groups having 1 to 6 carbon atoms in which the alkoxycarbonyl moiety is a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms; specific examples are methoxycarbonylmethyl, 3-methoxycarbonylpropyl, ethoxycarbonylmethyl, 3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-isopropoxycarbonylpentyl, 6-propoxycarbonylhexyl, 1,1-dimethyl-2-butoxycarbonylethyl, 2-methyl-3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl and hexyloxycarbonylmethyl groups, etc.
As to the carboxy-substituted lower alkyl group, there may be exemplified carboxyalkyl groups in which 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 and 2-methyl-3-carboxypropyl groups, etc.
As to the phenyl-lower alkanoylamino group which contains as 1 to 3 substituent, on the phenyl ring, selected from the group consisting of a halogen atom, a lower alkoxy group, a lower alkyl group and nitro group, there may be exemplified phenylalkanoylamino groups which contain as 1 to 3 substituent(s), on the phenyl ring, selected from the group consisting of 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, a halogen atom and nitro group; for exmaple, 2-methoxyphenylacetylamino, 3-methoxyphenylacetylamino, 4-methoxyphenylacetylamino, 3-(2-ethoxyphenyl)propionylamino, 2-(3-ethoxyphenyl)propionylamino, 4-(4-ethoxyphenyl)butyrylamino, 2,2-dimethyl-3-(4-isopropoxyphenyl)propionylamino, 5-(4-pentyloxyphenyl)pentanoylamino, 2,4-dimethoxyphenylacetylamino, 4-hexyloxyphenylacetylamino, 3,4-dimethoxyphenylacetylamino, 2-(3-ethoxy-4-methoxyphenyl)propionylamino, 3-(2,3-dimethoxyphenyl)propionylamino, 4-(3,4-diethoxyphenyl)butyrylamino, 2,5-dimethoxyphenylacetylamino, 6-(2,6-dimethoxyphenyl)hexanoylamino, 3,5-dimethoxyphenylacetylamino, 3,4-dipentyloxyphenylacetylamino, 3,4,5-trimethoxyphenylacetylamino, 2-chlorophenylacetylamino, 3-chlorophenylacetylamino, 4-chlorophenylacetylamino, 2-fluorophenylacetylamino, 3-fluorophenylacetylamino, 3-(4-fluorophenyl)propionylamino, 2-(2-bromophenyl)propionylamino, 4-(3-bromophenyl)butyrylamino, 5-(4-bromophenyl)pentanoylamino, 6-(2-iodophenyl)hexanoylamino, 3-iodophenylacetylamino, 3-(4-iodophenyl)propionylamino, 4-(3,4-dichlorophenyl)butrylamino, 3,4-dichlorophenylacetylamino, 2,6-dichlorophenylacetylamino, 2,3-dichlorophenylacetylamino, 2,4-dichlorophenylacetylamino, 3,4-difluorophenylacetylamino, 3-(3,5-dibromophenyl)propionylamino, 3,4,5-trichlorophenylacetylamino, 2-methoxy-3-chlorophenylacetylamino, 2-methylphenylacetylamino, 3-methylphenylacetylamino, 4-methylphenylacetylamino, 3-(2-ethylphenyl)propionylamino, 2-(3-ethylphenyl)propionylamino, 4-(4-ethylphenyl)butyrylamino, 5-(4-isopropylphenyl)pentanoylamino, 6-(3-butylphenyl)hexanoylamino, 3-(4-pentylphenyl)propionylamino, 4-hexylphenylacetylamino, 3,4-dimethylphenylacetylamino, 3,4-diethylphenylacetylamino, 2,4-dimethylphenylacetylamino, 2,5-dimethylphenylacetylamino, 2,6-dimethylphenylacetylamino, 3,4,5-trimethylphenylacetylamino, 3-chloro-4-methylphenylacetylamino, 3-methoxy-4-methyl-5-iodophenylacetylamino, 3,4-dimethoxy-5-bromophenylacetylamino, 3,5-diiodo-4-methoxyphenylacetylamino, 2-nitrophenylacetylamino, 3-nitrophenylacetylamino, 3,4-dinitrophenylacetylamino and 3,4,5-trinitrophenylacetylamino groups, etc.
As to the lower alkoxycarbonyl-substituted lower alkylidene group, there may be exemplified straight chain or branched chain alkylidene groups having 1 to 6 carbon atoms which are substituted with a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms; for example, ethoxycarbonylmethylidene, 2-methoxycarbonylethylidene, 3-isopropoxycarbonylpropylidene, 2-propoxycarbonylisopropylidene, 4-butoxycarbonylbutylidene, 5-pentyloxycarbonylpentylidene and 6-hexyloxycarbonylhexylidene groups, etc.
As to the 5 or 6-membered saturated or unsaturated heterocyclic group formed by combing R.sup.8 and R.sup.9 together with the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom, there may be exemplified pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolyl, imidazolyl, 1,2,4-triazolyl, 1,2,4-triazolyl, pyrazolyl, 2-pyrrolinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyazolidinyl, 1,2-dihydropyridyl and 1,2,3,4-tetrahydropyridyl groups, etc.
As to the heterocyclic groups described above which are further substituted with a lower alkyl group, there may be exemplified heterocyclic groups as described above which are substituted with 1 to 3 straight chain or branched chain alkyl groups 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, 2-methylimidazolyl, 3-methyl-1,2,4-triazolyl, 3-methylpyrrolyl, 3-methylpyrazolyl and 4-methyl-1,2-dihydropyridyl groups, etc.
As to the amino acid residue, there may be exemplified alanyl-, .beta.-alanyl, arginyl, cystationyl, cystyl, glycyl, histidyl, homoseryl, isoleucyl, lanthionyl, leucyl lysyl, methionyl, norleucyl, norvalyl, ornithyl, prolyl, sarcosyl, seryl, threonyl, tyronyl, tyrosyl, valyl, .alpha.-aspartyl, .beta.-aspartyl, aspartoyl, asparaginyl, .alpha.-glutamyl, .gamma.-glutamyl, glutaminyl, cysteinyl, homocysteinyl, tryptophyl and dimethylglycyl groups, etc.
As to the amino-lower alkoxy group which may optionally contain as the substituents selected from the group consisting of a lower alkyl group and a lower alkanoyl group, there may be exemplified straight chain or branched chain alkoxy groups having 1 to 6 carbon atoms which may contain 1 to 2 substituents selected from the group consisting of 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; there may be exemplified, aminomethoxy, 2-aminoethoxy, 1-aminoethoxy, 3-aminopropoxy, 4-amionobutoxy, 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 and 2-(N-methyl-N-hexylamino)ethoxy groups, etc.
As to the lower alkoxycarbonyl-substituted lower alkoxy group, there may be exemplified straight chain or branched chain alkoxycarbonylalkoxy groups having 1 to 6 carbon atoms in which the alkoxycarbonyl moiety is a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms; for example, methoxycarbonylmethoxy, 3-methoxycarbonylpropoxy, ethoxycarbonylmethoxy, 3-ethoxycarbonylpropoxy, 4-ethoxycarbonylbutoxy, 5-isopropoxycarbonylpentyloxy, 6-propoxycarbonylhexyloxy, 1,1-dimethyl-2-butoxycarbonylethoxy, 2-methyl-3-tert-butoxycarbonylpropoxy, 2-pentyloxycarbonylethoxy and hexyloxycarbonylmethoxy groups, etc.
As the carboxy-substituted lower alkoxy group, there may be exemplified carboxyalkoxy groups in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for exmaple, carboxymethoxy, 2-carboxyethoxy, 1-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy, 1,1-dimethyl-2-carboxyethoxy and 2-methyl-3-carboxypropoxy groups, etc.
As to the piperidinyl group which may optionally contain a phenyl-lower alkyl group on the piperidine ring, there may be exemplified piperidinyl groups which may optionally contain phenylalkyl groups on the piperidine ring and in which 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 and 1-(2-methyl-3-phenylpropyl)-2-piperidinyl groups, etc.
As to the carbamoyl-substituted lower alkyl group, there may be exemplified carbamoyl-substituted alkyl groups in which 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 and 2-methyl-3-carbamoylpropyl groups, etc.
As to the lower alkanoyl group, there may be exemplified straight chain or branched chain alkanoyl groups having 1 to 6 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl and hexanoyl groups, etc.
As to the amino group which may optionally contain as a substituent selected from the group consisting of a lower alkyl group and a lower alkanoyl group, there may be exemplified amino groups which may optionally contain 1 to 2 substituents selected from the group consisting of 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 exmaple, 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 and N-ethyl-N-acetylamino groups, etc.
As to the lower alkoxycarbonyl-substituted lower alkyl group, there may be exemplified straight chain or branched chain alkoxycarbonylalkyl groups having 1 to 6 carbon atoms in which the alkoxycarbonyl moiety is a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms; for exmaple, methoxycarbonylmethyl, 3-methoxycarbonylpropyl, ethoxycarbonylmethyl, 3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-isopropxycarbonylpentyl, 6-propoxycarbonylhexyl, 1,1-dimethyl-2-butoxycarbonylethyl, 2-methyl-3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl and hexyloxycarbonylmethyl groups etc.
As to the carboxy-substituted lower alkyl group, there may be exemplified carboxyalkyl groups in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for exmaple, carboxymethyl, 2-carboxy-ethyl, 1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl and 2-methyl-3-carboxypropyl groups, etc.
As to the piperidinyl group which may optionally contain a lower alkyl group on the piperidine ring, there may be exemplified piperidinyl groups which may optionally contain a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for example, piperidinyl, 1-methyl-4-piperidinyl, 1-ethyl-3-piperidinyl, 1-propyl-2-piperidinyl, 1-butyl-4-piperidinyl, 1-pentyl-4-piperidinyl and 1-hexyl-4-piperidinyl groups, etc.
As to the pyrrolidinylcarbonyl-lower alkoxy group which contains a lower alkoxycarbonyl group on the pyrrolidine ring, there may be exemplified pyrrolidinylcarbonylalkoxy groups which have a straight chain or branched chain alkoxycarbonyl group of 1 to 6 carbon atoms on the pyrrolidine ring and in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for exmaple, 2-methoxycarbonyl-1-pyrrolidinylmethoxy, 1-(2-ethoxycarbonyl-1-pyrrolidinylcarbonyl)ethoxy, 2-(3-propoxycarbonyl-1-pyrrolidinylcarbonyl)ethoxy, 3-(2-butoxycarbonyl-1-pyrrolidinylcarbonyl)propoxy, 4-(3-pentyloxycarbonyl-1-pyrrolidinylcarbonyl)butoxy, 5-(2-hexyloxycarbonyl-1-pyrrolidinylcarbonyl)pentyloxy and 6-(2-methoxycarbonyl-1-pyrrolidinylcarbonyl)hexyloxy groups, etc.
As to the lower alkoxycarbonyl group, there may be exemplified straight chain or branched chain alkoxycarbonyl groups having 1 to 6 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups, etc.
As to the lower alkoxy-substituted lower alkanoyloxy group, there may be exemplified alkanoyloxy groups which are substituted with a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms and in which the alkanoyloxy moiety is a straight chain or branched chain alkanoyloxy group having 2 to 6 carbon atoms; for example, methoxyacetyloxy, 3-ethoxypropionyloxy, 2-propoxypropionyloxy, 4-butoxybutyryloxy, 2,2-dimethyl-3-pentyloxypropionyloxy, 5-hexyloxypentanoyloxy and 6-methoxyhexanoyloxy groups, etc.
As to the amino group which may contain a lower alkyl group, there may be exemplified amino groups which may optionally contain 1 to 2 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms as substituents; 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 and N-methyl-N-hexylamino groups, etc.
As to the amino-substituted lower alkylidene group which may optionally contain lower alkyl groups as substituents, there may be exemplified straight chain or branched chain amino-substituted alkylidene groups having 1 to 6 carbon atoms which may optionally contain 1 to 2 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms as substituents; for example, aminomethylidene, 2-ethylaminoethylidene, 3-propylaminopropylidene, 2-isopropylaminopropylidene, 4-butylaminobutylidene, 5-pentylaminopentylidene, 6-hexylaminohexylidene, 3-dimethylaminopropylidene, 3-(N-methyl-N-butylamino)-propylidene, 2-dipentylaminoethylidene and 4-(N-methyl-N-hexylamino)butylidene groups, etc.
As to the cyano-substituted lower alkyl group, there may be exemplified cyanoalkyl groups in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for example, cyanomethyl, 2-cyanoethy, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyanopentyl, 6-cyanohexyl, 1,1-dimethyl-2-cyanoethyl and 2-methyl-3-cyanopropyl groups, etc.
As to the phthalimido-substituted lower alkyl group, there may be exemplified phthalimido-substituted alkyl groups in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, phthalimidomethyl, 2-phthalimidoethyl, 1-phthalimidoethyl, 3-phthalimidopropyl, 4-phthalimidobutyl, 5-phthalimidopentyl, 6-phthalimidohexyl, 1,1-dimethyl-2-phthalimidoethyl and 2-methyl-3-phthalimidopropyl groups, etc.
As to the lower alkoxy group having a phenylsulfonyloxy group which may optionally contain a lower alkyl group as substituent(s) on the phenyl ring or having hydroxy group, there may be exemplified straight chain or branched chain alkoxy groups having 1 to 6 carbon atoms and having a phenylsulfonyloxy group which may optionally contain 1 to 3 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms as substituent(s) on the phenyl ring or having 1 to 3 hydroxy groups; for example, (2-methylphenylsulfonyloxy)methoxy, 2-(4-methylphenylsulfonyloxy)ethoxy, 3-(phenylsulfonyloxy)propoxy, 4-(3-methylphenylsulfonyloxy)butoxy, 5-(2-ethylphenylsulfonyloxy)pentyloxy, 6-(3-propylphenylsulfonyloxy)hexyloxy, (4-butylphenylsulfonyloxy)methoxy, 2-(2-pentylphenylsulfonyloxy)ethoxy, 1-(3-hexylphenylsulfonyloxy)ethoxy, 3-(3,4-dimethylphenylsulfonyloxy)propoxy, 2-(3,4,5-trimethylphenylsulfonyloxy)ethoxy, 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 and 2,3,4-trihydroxybutoxy groups, etc.
As to the phenylsulfonyloxy-substituted lower alkyl group which may optionally contain a lower alkyl group as substituent(s) on the phenyl ring, there may be exemplified phenylsulfonyloxy-substituted straight chain or branched chain alkyl groups having 1 to 6 carbon atoms which may optionally contain 1 to 3 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms as substituent(s) on the phenyl ring; for example, (2-methylphenylsulfonyloxy)methyl, 2-(4-methylphenylsulfonyloxy)ethoxy, 3-(phenylsulfonyloxy)propyl, 4-(3-methylphenylsulfonyloxy)butyl, 5-(2-ethylphenylsulfonyloxy)pentyl, 6-(3-propylphenylsulfonyloxy)hexyl, (4-butylphenylsulfonyloxy)methyl, 2-(2-pentylphenylsulfonyloxy)ethyl, 1-(3-hexylphenylsulfonyloxy)ethyl, 3-(3,4-dimethylphenylsulfonyloxy)propyl and 2-(3,4,5-trimethylphenylsulfonyloxy)ethyl groups, etc.
As to the 5- or 6-membered saturated heterocyclic group formed by combining R.sup.29 and R.sup.30 or R.sup.23A and R.sup.24A together with the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom, there may be exemplified, pyrrolidinyl, piperidinyl, piperazinyl and morpholino groups, etc.
As to the heterocyclic groups described above which are substituted with a lower alkyl group, a lower alkanoyl group, an amino group which may optionally contain substituent(s) selected from the group consisting of a lower alkyl group and a lower alkanoyl group, a ower alkylsulfonyl group, a lower alkoxycarbonyl group or an aminocarbonyl group which may optionally contain a lower alkyl group as a substituent, there may be exemplified those heterocyclic groups described above which are substituted with 1 to 3 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms, straight chain or branched chain alkanoyl groups having 1 to 6 carbon atoms, amino groups which may optionally contain as 1 to 2 substituents selected from the group consisting of 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, a straight chain or branched chain alkylsulfonyl group having 1 to 6 carbon atoms, a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, or an aminocarbonyl group which may optionally contain 1 to 2 straight chain or branched chain alkyl groups as substituent(s); examples of such heterocyclic groups include 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-hexylpiperazinyl, 4-acetylpiperazinyl, 4-hexanoylpiperidinyl, 4-formylpiperidinyl, 2-propionylpyrrolidinyl, 3-butyrylmorpholino, 4-pentanoylpiperazinyl, 4-ethylaminopiperidinyl, 4-dimethylaminopiperidinyl, 3-methyl-4-acetylpiperazinyl, 3-methylaminomorpholino, 2-aminopyrrolidinyl, 3-(N-methyl-N-hexylamino)piperazinyl, 4-(N-methyl-N-butylamino)piperidinyl, 4-acetylaminopiperidinyl, 3-propionylaminopyrrolidinyl, 3-butyrylaminopiperazinyl, 3-pentanoylaminomorpholino, 4-(N-methyl-N-acetylamino)piperidinyl, 4-methylsulfonylpiperazinyl, 4-ethoxycarbonylpiperazinyl, 4-methylaminocarbonyl, piperazinyl, 4-ethylsulfonylpiperidinyl, 3-propylsulfonylmorpholino, 2-butylsulfonylpyrrodinyl, 3-methoxycarbonylmorpholino, 3-methyl-4-ethoxycarbonylpiperidinyl, 3-ethoxycarbonylpyrrolidinyl, 4-dimethylaminocarbonylpiperidinyl, 3-ethylaminocarbonylmorpholino and 2-(N-methyl-N-propylamino)carbonylpyrrolidinyl groups, etc.
As to the 5- to 7-membered saturated heterocyclic group formed by combining R.sup.11 and R.sup.12 together with the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom, there may be exemplified, pyrrolidinyl, piperidinyl, piperazinyl, morpholino and homopiperazinyl groups, etc.
As to the heterocyclic groups described above which are substituted with a lower alkyl group, a lower alkoxycarbonyl group, an amino group which may optionally contain as substituent(s) selected from the group consisting of a lower alkyl group and a lower alkanoyl group, a lower alkoxycarbonyl-substituted lower alkyl group, a phenyl group which may optionally contain a halogen atom on the phenyl ring, a cyano-substituted lower alkyl group, a lower alkenyl group, an oxiranyl-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group, a lower alkyl group having 1 to 2 substituents selected from the group consisting of hydroxy group and an amino group which may optionally contain a lower alkyl group, or a pyrrolidinylcarbonyl lower alkyl group, there may be exemplified heterocyclic groups described above which are substituted with 1 to 3 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms, straight chain or branched chain alkoxycarbonyl groups having 1 to 6 carbon atoms, an amino group which may optionally contain 1 to 2 substituent(s) selected from the group consisting of a straight or branched alkyl group having 1 to 6 carbon atoms and straight chain or branched chain alkanoyl groups having 1 to 6 carbon atoms, a straight chain or branched chain alkoxycarbonylalkyl group in which the alkoxycarbonyl moiety is a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, a phenyl group which may optionally contain 1 to 3 halogen atoms on the phenyl ring, a cyanoalkyl group in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms, an oxiranyl substituted alkyl group in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a carbamoyl-substituted alkyl group in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and having 1 to 2 substituents selected from the group consisting of hydroxy group and an amino group which may optionally contain a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, or a pyrrolidinylcarbonyl alkyl group in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; examples of such heterocyclic groups include 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-hexylpiperazinyl, 4-tert-butoxycarbonylpiperazinyl, 4-ethoxycarbonylpiperidinyl, 2-methoxycarbonylpyrrolidinyl, 3-pentyloxycarbonylmorpholino, 4-hexyloxycarbonylpiperazinyyl, 4-acetylaminopiperidinyl, 4-dimethylaminopiperidinyl, 3-methylaminomorpholino, 2-aminopyrrolidinyl, 3-(N-methyl-N-hexylamino)piperazinyl, 4-(N-methyl-N-acetylamino)piperidinyl, 4-methylhomopiperazinyl, 4-ethoxycarbonylhomopiperazinyl, 4-acetylaminohomopiperazinyl, 4-dimethylaminohomopiperazinyl, 4-ethoxycarbonylmethylpiperazinyl, (4-chlorophenyl)piperazinyl, 4-cyanomethylpiperazinyl, 4-allylpiperazinyl, 4-(oxiranylmethyl)piperazinyl, 4-carbamoylmethylpiperazinyl, 4-(2-hydroxyethyl)piperazinyl, 4-(2-hydroxy-3-isopropylaminopropyl)piperazinyl, 3-(3-chlorophenyl)pyrrolidinyl, 4-(2-cyanoethyl)piperidinyl, 3-(2-butenyl)morpholino, 4-(1-oxiranylethyl)homopiperazinyl, 3-(2-carbamoylethyl)piperidinyl, 2-hydroxymethylpyrrolidinyl, 2-(2-hydroxy-3-diethylaminopropyl)morpholino, 3-(2-hydroxyethyl)homopiperazinyl, 4-[(1-pyrrolidinyl)carbonylmethyl]piperazinyl, 2-[2-(1-pyrrolidinyl)carbonylethyl]pyrrolidinyl, 3-[1-(1-pyrrolidinyl)carbonylethyl]morpholino, 4-[3-(1-pyrrolidinyl)carbonylpropyl]piperidinyl and 4-[(1-pyrrolidinyl)carbonylmethyl]homopiperazinyl groups, etc.
As to the 5- to 10-membered monocyclic or bicyclic saturated or unsaturated heterocyclic group formed by combining R.sup.27 and R.sup.28 together with the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom, there may be exemplified pyrrolidinyl, piperidinyl, piperazinyl, morpholino, imidazolyl, isoindolyl and 1,2,3,4,5,6,7-octahydroisoindolyl groups, etc.
As to the heterocyclic groups described above which are substituted with oxo group, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group or a lower alkanoylamino group, there may be exemplified those heterocyclic groups described above which are substituted with 1 to 3 oxo groups, straight chain or branched chain alkyl groups having 1 to 6 carbon atoms, straight chain or branched chain alkoxycarbonyl groups having 1 to 6 carbon atoms, straight chain or branched chain alkanoyl groups having 1 to 6 carbon atoms or amino groups having a straight chain or branched chain alkanoyl group of 1 to 6 carbon atoms; examples of such heterocyclic groups include 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-hexylpiperazinyl, 2-methylmorpholino, 4-formylpiperidinyl, 4-acetylpiperazinyl, 2-propanoylmorpholino, 3-butyrylmorpholino, 3-pentanoylpyrrolidinyl, 4-hexanoylpiperidinyl, 3-methyl-4-acetylpiperazinyl, 4-methylimidazolyl, 2-acetylimidazolyl, 4-tert-butoxycarbonylpiperazinyl, 4-ethoxycarbonylpiperidinyl, 2-methoxycarbonylpyrrolidinyl, 3-pentyloxycarbonlmorpholino, 4-hexyloxycarbonylpiperazinyl, 2-tert-butoxycarbonylimidazolyl, 1,3-dioxo-1,2,3,4,5,6,7-octahydroisoindolyl, 3-pentanoylaminomorpholino, 4-acetylaminopiperidinyl, 3-propionylaminopyrrolidinyl, 3-butyrylaminopiperazinyl and 2-hexanoylaminoimidazolyl groups, etc.
As to the cyano-substituted lower alkylidene group, there may be exemplified straight chain or branched chain alkylidene groups having 1 to 6 carbon atoms, for example, cyanomethylidene, 2-cyanoethylidene, 3-cyanopropylidene, 2-cyanopropylidene, 4-cyanobutylidene, 5-cyanopentylidene and 6-cyanohexylidene groups, etc.
As to the piperazinyl-lower alkoxy group having a lower alkanoyl group at the 4-position of the piperazine ring, there may be exemplified piperazinylalkoxy groups which contains a straight or branched alkanoyl group having 1 to 6 carbon atoms on the piperazine ring at the 4-position thereof and in which the alkoxy moiety is a straight or branched alkoxy group having 1 to 6 carbon atoms; examples of such groups include 3-(4-acetyl-1-piperazinyl)propoxy, 2-(4-acetyl-1-piperazinyl)ethoxy, (4-acetyl-1-piperazinyl)methoxy, 1-(4-propionyl-1-piperazinyl)ethoxy, 4-(4-butyryl-1-piperazinyl)butoxy, 5-(4-pentanoyl-1-piperazinyl)pentyloxy, 6-(4-hexanoyl-1-piperazinyl)hexyloxy and 3-(4-formyl-1-piperazinyl)propoxy groups, etc.
As to the lower alkyl group which may optionally contain hydroxy group, there may be exemplified straight chain or branched chain alkyl groups having 1 to 6 carbon atoms which may optionally contain 1 to 3 hydroxy groups; for examles those lower alkyl groups and hydroxy-substituted lower alkyl groups described hereinabove.
As to the pyridyl-substituted lower alkyl group, there may be exemplified pyridyl-substituted alkyl groups in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for example, (2-pyridyl)methyl, (3-pyridyl)methyl, (4-pyridyl)methyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 3-(2-pyridyl)propyl, 3-(3-pyridyl)propyl, 3-(4-pyridyl)propyl, 4-(2-pyridyl)butyl, 4-(3-pyridyl)butyl, 4-(4-pyridyl)butyl, 5-(2-pyridyl)pentyl, 5-(3-pyridyl)pentyl, 5-(4-pyridyl)pentyl, 6-(2-pyridyl)hexyl, 6-(3-pyridyl)hexyl, 6-(4-pyridyl)hexyl, 1,1-dimethyl-2-(2-pyridyl)ethyl, 1,1-dimethyl-2-(3-pyridyl)ethyl, 1,1-dimethyl-(4-pyridyl)ethyl, 2-methyl-3-(2-pyridyl)propyl, 2-methyl-3-(3-pyridyl)propyl and 2-methyl-3-(4-pyridyl)propyl groups, etc.
As to the amino-substituted lower alkyl group which may optionally contain a lower alkyl group, there may be exemplified straight chain or branched chain alkyl groups having 1 to 6 carbon atoms which are substituted with an amino group that may optionally contain 1 to 2 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms as the substituents; 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, 2-diethylaminoethyl, 2-dimethylaminoethyl, (N-ethyl-N-propylamino)methyl and 2-(N-methyl-N-hexylamino)ethyl groups, etc.
As to the lower alkynyl group, there may be exemplified straight chain or branched chain alkynyl groups having 2 to 6 carbon atoms, for example, ethynyl, propargyl, 2-butynyl, 1-methyl-2-propargyl, 2-pentynyl and 2-hexynyl groups, etc.
As to the lower alkylsulfonyl group, there may be exemplified sulfonyl groups having a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.
As to the lower alkanoylamino group, there may be exemplified amino groups containing a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, acetylamino, propionylamino, isopropionylamino, butyrylamino, pentanoylamino, hexanoylamino and formylamino groups, etc.
As to the cycloalkyl group, there may be exemplified cycloalkylcarbonyl groups having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
As to the halogen atom-substituted lower alkyl group, there may be exemplified straight chain or branched chain alkyl groups having 1 to 6 carbon atoms which contain 1 to 3 halogen atoms as substituent(s); for example, 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 and 5,6-dichlorohexyl groups, etc.
As to the imidazolyl-substituted lower alkyl group, there may be exemplified imidazolyl-substituted alkyl groups in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for example, (1-imidazolyl)methyl, 2-(1-imidazolyl)ethyl, 1-(2-imidazolyl)ethyl, 3-(4-imidazolyl)propyl, 4-(5-imidazolyl)butyl, 5-(1-imidazolyl)pentyl, 6-(2-imidazolyl)hexyl, 1,1-dimethyl-2-(1-imidazolyl)ethyl and 2-methyl-3-(1-imidazlyl)propyl groups, etc.
As to the 1,2,4-triazolyl-substituted lower alkoxy group, there may be exemplified 1,2,4-triazolyl-substituted alkoxy groups in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for example, (1-1,2,4-triazolyl)methoxy, 2-(1-1,2,4-triazolyl)ethoxy, 1-(1-2,4-triazolyl)ethoxy, 3-(3-1,2,4-triazolyl)propoxy, 4-(5-1,2,4-triazolyl)butoxy, 5-(1-1,2,4-triazolyl)pentyloxy, 6-(3-1,2,4-triazolyl)hexyloxy, 1,1-dimethyl-2-(5-1,2,4-triazolyl)ethoxy and 2-methyl-3-(1-1,2,4-triazolyl)propoxy groups, etc.
As to the 1,2,3,4-tetrazolyl-substituted lower alkoxy group, there may be exemplified 1,2,3,4-tetrazolyl-substituted alkoxy groups in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for example, (1-1,2,3,4-tetrazolyl)methoxy, 2-(1-2,3,4-tetrazolyl)ethoxy, 1-(5-1,2,3,4-tetrazolyl)ethoxy, 3-(1-1,2,3,4-tetrazolyl)propoxy, 4-(5-1,2,3,4-tetrazolyl)butoxy, 5-(1-1,2,3,4-tetrazolyl)pentyloxy, 6-(5-1,2,3,4-tetrazolyl)hexyloxy, 1,1-dimethyl-2-(1-1,2,3,4-tetrazolyl)ethoxy and 2-methyl-3-(5-1,2,3,4-tetrazolyl)propoxy groups, etc.
As to the 1,2,3,4,5-tetrazolyl-substituted lower alkoxy group, there may be exemplified 1,2,3,5-tetrazolyl-substituted alkoxy groups in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for example, (1-1,2,3,5-tetrazolyl)methoxy, 2-(1-1,2,3,5-tetrazolyl)ethoxy, 1-(4-1,2,3,5-tetrazolyl)ethoxy, 3-(1-1,2,3,5-tetrazolyl)propoxy, 4-(4-1,2,3,5-tetrazolyl)butoxy, 5-(1-1,2,3,5-tetrazolyl)pentyloxy, 6-(4-1,2,3,5-tetrazolyl)hexyloxy, 1,1-dimethyl-2-(1-1,2,3,5-tetrazolyl)ethoxy and 2-methyl-3-(4-1,2,3,5-tetrazolyl)propoxy groups, etc.
As to the 1,2,3,4-tetrazolyl-substituted lower alkyl group, there may be exemplified 1,2,3,4-tetrazolyl-substituted alkyl groups in which the alkyl moiethy is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for exmaple, (1-1,2,3,4-tetrazolyl)methyl, 2-(1-1,2,3,4-tetrazolyl)ethyl, 1-(5-1,2,3,4-tetrazolyl)ethyl, 3-(1-1,2,3,4-tetrazolyl)propyl, 4-(5-1,2,3,4-tetrazolyl)butyl, 5-(1-1,2,3,4-tetrazolyl)pentyl, 6-(5-1,2,3,4-tetrazolyl)hexyl, 1,1-dimethyl-2-(1-1,2,3,4-tetrazolyl)ethyl and 2-methyl-3-(5-1,2,3,4-tetrazolyl)propyl groups, etc.
As to the 1,2,3,5-tetrazolyl-substituted lower alkyl group, there may be exemplified 1,2,3,5-tetrazolyl-substituted alkyl groups in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for exmaple, (1-1,2,3,5-tetrazolyl)methyl, 2-(1-1,2,3,5-tetrazolyl)ethyl, 1-(4-1,2,3,5-tetrazolyl)ethyl, 3-(1-1,2,3,5-tetrazolyl)propyl, 4-(4-1,2,3,5-tetrazolyl)butyl, 5-(1-1,2,3,5-tetrazolyl)pentyl, 6-(4-1,2,3,5-tetrazolyl)hexyl, 1,1-dimethyl-2-(1-1,2,3,5-tetrazolyl)ethyl and 2-methyl-3-(4-1,2,3,5-tetrazolyl)propyl groups, etc.
As to the 1,2,4-triazolyl-substituted lower alkyl group, there may be exemplified 1,2,4-triazolyl-substituted alkyl groups in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for exmaple, (1-1,2,4-triazolyl)methyl, 2-(1-1,2,4-triazolyl)ethyl, 1-(1-1,2,4-triazolyl)ethyl, 3-(3-1,2,4-triazolyl)propyl, 4-(5-1,2,4-triazolyl)butyl, 5-(1-1,2,4-triazolyl)pentyl, 6-(3-1,2,4,-triazolyl)hexyl, 1,1-dimethyl-2-(5-1,2,4-triazolyl)ethyl and 2-methyl-3-(1-1,2,4-triazolyl)propyl groups, etc.
As to the phenyl group which may optionally contain a halogen atom on the phenyl group, there may be exemplified phenyl groups which may optionally contain 1 to 3 halogen atoms as the substituents on the phenyl ring; for exmaple, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorphenyl, 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 and 3,4,5-trichlorophenyl groups, etc.
As to the oxiranyl-substituted lower alkyl group, there may be exemplified oxiranyl-substituted alkyl groups in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for example, oxiranylmethyl, 2-oxiranylethyl, 1-oxiranylethyl, 3-oxiranylpropyl, 4-oxiranylbutyl, 5-oxiranylpentyl, 6-oxiranylhexyl, 1,1-dimethyl-2-oxiranylethyl and 2-methyl-3-oxiranylpropyl groups, etc.
As to the lower alkyl group having 1 to 2 substituents selected from the group consisting of hydroxy group and an amino group which may optionaly contain a lower alkyl group, there may be exemplified straight chain or branched chain alkyl groups having 1 to 6 carbon atoms and having 1 to 2 substituents selected from the group consisting of hydroxy group and an amino group which may optionally contain as substituent(s) 1 to 2 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms; for examples, alkyl groups include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyethyl, 4-hydroxybutyl, 3,4-dihydrooxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,6-dihydroxyhexyl, 5-hydroxypentyl, 6-hydroxyhexyl, 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, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, tert-butylaminomethyl, pentylamiinomethyl, 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, 2-hydroxy-3-isopropylaminopropyl, 5-hydroxy-6-diethylaminohexyl, 4-hydroxy-5-dimethylaminopentyl, 4-hydroxy-5-methylaminopentyl, 4-hydroxy-5-diethylaminopentyl, 5-hydroxy-6-ethylaminohexy, 5-hydroxy-6-isopropylaminohexyl and 5-hydroxy-6-aminohexyl groups, etc.
As to the imidazolyl-substituted lower alkoxy group, there may be exemplified imidazolyl-substituted alkoxy groups in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for example, (1-imidazolyl)methoxy, 2-(1-imidazolyl)ethoxy, 1-(2-imidazolyl)ethoxy, 3-(4-imidazolyl)propoxy, 4-(5-imidazolyl)butoxy, 5-(1-imidazolyl)pentyloxy, 6-(2-imidazolyl)hexyloxy, 1,1-dimethyl-2-(1-imidazolyl)ethoxy and 2-methyl-3-(1-imidazolyl)propoxy groups, etc.
As to the piperidinyl-lower alkoxy group having a lower alkanoylamino group on the piperidine ring, there may be exemplified piperidinylalkoxy groups which contain an amino group having a straight chain or branched chain alkanoyl group of 1 to 6 carbon atoms on the piperidine ring in which the alkoxy moiety is a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms; examples include 3-(4-acetylamino-1-piperidinyl)propoxy, 2-(3-acetylamino-1-piperidinyl)ethoxy, (4-acetylamino-1-piperidinyl)methoxy, 1-(2-propionylamino-1-piperidinyl)ethoxy, 4-(4-butyrylamino-1-piperidinyl)butoxy, 5-(3-pentanoylamino-1-piperidinyl)pentyloxy, 6-(4-hexanoylamino-1-piperidinyl)hexyloxy and 3-(4-formylamino-1-piperidinyl)propoxy groups, etc.
As to the ureido-substituted lower alkoxy group which may optionally contain a lower alkyl group, there may be exemplified straight chain or branched chain alkoxy groups having 1 to 6 carbon atoms which may optionally contain as substituent(s) 1 to 2 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms; for example, ureidomethoxy, 2-ureidoethoxy, 1-ureidoethoxy, 3-ureidopropoxy, 4-ureidobutoxy, 5-ureidopentyloxy, 6-ureidohexyloxy, 1,1-dimethyl-2-ureidoethoxy, 2-methyl-3-ureidopropoxy, N'-methylureidomethoxy, 1-(N'-ethylureido)ethoxy, 2-(N'-propylureido)ethoxy, 3-(N'-isopropylureido)propoxy, 4-(N'-butylureido)butoxy, 5-(N'-pentylureido)pentyloxy, 6-(N'-hexylureido)hexyloxy, N',N'-dimethylureidomethoxy, (N'-ethyl-N'-propylureido)methoxy and 2-(N'-methyl-N'-hexylureido)ethoxy groups, etc.
As to the lower alkoxycarbonyl-substituted lower alkoxy group, there may be exemplified straight chain or branched chain alkoxycarbonylalkoxy groups in which the alkoxycarbonyl moiety is a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms; for example, methoxycarbonylmethoxy, 3-methoxycarbonylpropoxy, ethoxycarbonylmethoxy, 3-ethoxycarbonylpropoxy, 4-ethoxycarbonylbutoxy, 5-isopropoxycarbonylpentyloxy, 6-propoxycarbonylhexyloxy, 1,1-dimethyl-2-butoxycarbonylethoxy, 2-methyl-3-tert-butoxycarbonylpropoxy, 2-pentyloxycarbonylethoxy and hexyloxycarbonylmethoxy groups, etc.
As to the carboxy-substituted lower alkoxy, there may be exemplified carboxyalkoxy groups in which 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 and 2-methyl-3-carboxypropoxy groups, etc.
As to the 5- to 7-membered saturated heterocyclic group formed by combining R.sup.23 and R.sup.24 together with the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom, there may be exemplified pyrrolidinyl, piperidinyl, piperazinyl, morpholino and homopiperazinyl groups, etc.
As to the heterocyclic groups described above which are substituted with a lower alkyl group, there may be exemplified those heterocyclic groups described above which are substituted with 1 to 3 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms; examples include 4-methylpiperazinyl, 4-ethylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-hexylpiperazinyl and 4-methylhomopiperazinyl groups, etc.
As to the benzoyl group having halogen atom(s) on the phenyl ring as substituent(s), there may be exemplified benzoyl groups having 1 to 3 halogen atoms as substituent(s) on the phenyl ring; for example, 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, 2,6-dichlorobenzoyl, 2,3-dichlorobenzoyl, 2,4-dichlorobenzoyl, 3,4-diffluorobenzoyl, 3,5-dibromobenzoyl and 3,4,5-trichlorobenzoyl groups, etc.
As to the 5- to 6-membered saturated heterocyclic group formed by combining R.sup.39 and R.sup.40 together with the adjacent nitrogen atom being bonded thereto, together with or without other nitrogen atom or oxygen atom, there may be exemplified pyrrolidinyl, piperidinyl, piperazinyl and morpholino groups, etc.
As to the heterocyclic groups described above which are substituted with a lower alkyl group, there may be exemplified those heterocyclic groups described above which are substituted with 1 to 3 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms; examples include 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 1-methylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino and 4-hexylpiperazinyl groups, etc.
As to the pyrazinyl-substituted lower alkyl group which may optionally contain a lower alkyl group as substituent(s) on the pyrazine ring, there may be exemplified pyrazinylalkyl groups which may optionally contain as a substituent(s) 1 to 3 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms and in which the alkyl moety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for example, (2-pyrazinyl)methyl, 2-(3-pyrazinyl)ethyl, 1-(2-pyrazinyl)ethyl, 3-(2-pyrazinyl)propyl, 4-(3-pyrazinyl)butyl, 5-(2-pyrazinyl)pentyl, 6-(3-pyrazinyl)hexyl, 1,1-dimethyl-2-(2-pyrazinyl)ethyl, 2-methyl-3-(3-pyrazinyl)propyl, (5-methyl-2-pyrazinyl)methyl, 2-(2-ethyl-3-pyrazinyl)ethyl, 1-(6-propyl-2-pyrazinyl)ethyl, 3-(2-butyl-5-pyrazinyl)-propyl, 4-(3-pentyl-6-pyrazinyl)butyl, 5-(6-hexyl-3-pyrazinyl)pentyl, 6-(5-methyl-3-pyrazinyl)hexyl, 1,1-dimethyl-2-(6-methyl-2-pyrazinyl)ethyl, 2-methyl-3-(5-methyl-2-pyrazinyl)propyl, (5,6-dimethyl-2-pyrazinyl)-methyl and (3,5,6-trimethyl-2-pyrazinyl)methyl groups, etc.
As to the pyrrolyl-substituted lower alkyl group which may optionally contain a lower alkyl group as a substituent(s) on the pyrrole ring, there may be exemplified pyrrolylalkyl groups which may optionally contain as a substituent(s) 1 to 3 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms and in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for example, (2-pyrrolyl)methyl, 2-(2-pyrrolyl)ethyl, 1-(3-pyrrolyl)ethyl, 3-(2-pyrrolyl)propyl, 4-(3-pyrrolyl)butyl, 5-(2-pyrrolyl)pentyl, 6-(3-pyrrolyl)hexyl, 1,1-dimethyl-2-(2-pyrrolyl)ethyl, 2-methyl-3-(3-pyrrolyl)propyl, (5-ethyl-2-pyrrolyl)methyl, 2-(1-methyl-2-pyrrolyl)ethyl, 1-(3-propyl-2-pyrrolyl)ethyl, 3-(1-butyl-2-pyrrolyl)propyl, 4-(3-pentyl-5-pyrrolyl)butyl, 5-(4-hexyl-3-pyrrolyl)pentyl, 6-(2-methyl-4-pyrrolyl)hexyl, 1,1-dimethyl-2-(2-methyl-1-pyrrolyl)ethyl, 2-methyl-3-(1-methyl-3-pyrrolyl)propyl, (1,3-dimethyl-2-pyrrolyl)methyl and (1,2,3-trimethyl-4-pyrrolyl)methyl groups, etc.
As to the phenyl group having halogen atom(s) on the phenyl ring as substituent(s), there may be exemplified phenyl groups having 1 to 3 halogen atoms as substituent(s) on the phenyl ring; for example, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-idophenyl, 3-iodophenyl, 4-iodophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromophenyl and 3,4,5-trichlorophenyl groups, etc.
As to the pyrrolidinylcarbonyl-lower alkyl group, there may be exemplified pyrrolidinylcarbonylalkyl groups in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for example (1-pyrrolidinyl)carbonylmethyl, 2-(1-pyrrolidinyl)carbonylethyl, 1-(1-pyrrolidinyl)carbonylethyl, 3-(2-pyrrolidinyl)carbonylpropyl, 4-(3-pyrrolidinyl)carbonylbutyl, 5-(1-pyrrolidinyl)carbonylpentyl, 6-(1-pyrrolidinyl)carbonylhexyl, 1,1-dimethyl-2-(2-pyrrolidinyl)carbonylethyl and 2-methyl-3-(3-pyrrolidinyl)carbonylpropyl groups, etc.
As to the aminothiocarbonyl group which may optionally contain a lower alkyl group as substituent(s), there may be exemplified aminothiocarbonyl groups which may optionally contain as substituent(s) 1 to 2 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms; for example, aminothiocarbonyl, methylaminothiocarbonyl, ethylaminothiocarbonyl, propylaminothiocarbonyl, isopropylaminothiocarbonyl, butylaminothiocarbonyl, tert-butylaminothiocarbonyl, pentylaminothiocarbonyl, hexylaminothiocarbonyl, dimethylaminothiocarbonyl, diethylaminothiocarbonyl, dipropylaminothiocarbonyl, dibutylaminothiocarbonyl, dipentylaminothiocarbonyl, dihexylaminothiocarbonyl, N-methyl-N-ethylaminothiocarbonyl, N-ethyl-N-propylaminothiocarbonyl, N-methyl-N-butylaminothiocarbonyl and N-methyl-N-hexylaminothiocarbonyl groups, etc.
As to the phenyl-lower alkyl group which may optionally contain a halogen atom as substituent(s) on the phenyl ring, there may be exemplified phenylalkyl groups in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and which may optionally contain 1 to 3 halogen atoms on the phenyl ring; for example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 2-chlorobenzyl, 2-(3-chlorophenyl)ethyl, 2-fluorobenzyl, 1-(4-chlorophenyl)ethyl, 3-(2-fluorophenyl)propyl, 4-(3-fluorophenyl)butyl, 5-(4-fluorophenyl)pentyl, 1,1-dimethyl-2-(2-bromophenyl)ethyl, 6-(3-bromophenyl)hexyl, 4-bromobenzyl, 2-(2-iodophenyl)ethyl, 1-(3-iodophenyl)ethyl, 3-(4-iodophenyl)propyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl, 2,6-dichlorobenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 3,4-difluorobenzyl, 3,5-dibromobenzyl, 3,4,5-trichlorobenzyl, 3,5-dichloro-4-hydroxybenzyl, 3,5-dimethyl-4-hydroxybenzyl and 2-methoxy-3-chlorobenzyl groups, etc.
As to the halogen-substituted lower alkylsulfonyl group, there may be exemplified straight chain or branched chain alkyl groups having 1 to 6 carbon atoms which contains as substituent(s) 1 to 3 halogen atoms; for example, trifluoromethylsufonyl, trichloromethylsulfonyl, trichloromethylsufonyl, chloromethylsulfonyl, bromomethylsulfonyl, fluoromethylsulfonyl, iodomethylsulfonyl, difluoromethylsulfonyl, dibromomethylsulfonyl, 2-chloroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, 2,2,2-trichloroethylsulfonyl, 3-chloropropylsulfonyl, 2,3-dichloropropylsulfonyl, 4,4,4-trichlorobutylsulfonyl, 4-fluorobutylsulfonyl, 5-chloropentylsulfonyl, 3-chloro-2-methylpropylsulfonyl, 5-bromohexylsulfonyl and 5,6-dichlorohexylsulfonyl groups, etc.
As to the aminocarbonyl group which may optionally contain as substituent(s) lower alkyl groups, there may be exemplified aminocarbonyl groups which may optionally contain as a substituent(s) one or two straight chain or branched chain alkyl groups 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 and N-methyl-N-hexylaminocarbonyl groups, etc.
As to the pyridylthio-substituted lower alkoxy group, there may be exemplified pyridylthio-substituted alkoxy groups in which the alkoxy moety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for example, (2-pyridyl)thiomethoxy, (3-pyridyl)thiomethoxy, (4-pyridyl)thiomethoxy, 2-(2-pyridyl)thioethoxy, 2-(3-pyridyl)thioethoxy, 2-(4-pyridyl)thioethoxy, 3-(2-pyridyl)thiopropoxy, 3-(3-pyridyl)thiopropoxy, 3-(4-pyridyl)thiopropoxy, 4-(2-pyridyl)thiobutoxy, 4-(3-pyridyl)thiobutoxy, 4-(4-pyridyl)thiobutoxy, 5-(2-pyridyl)thiopentyloxy, 5-(3-pyridyl)thiopentyloxy, 5-(4-pyridyl)thiopentyloxy, 6-(2-pyridyl)thiohexyloxy, 6-(3-pyridyl)thiohexyloxy, 6-(4-pyridyl)thiohexyloxy, 1,1-dimethyl-2-(2-pyridyl)thioethoxy, 1,1-dimethyl-2-(3-pyridyl)thioethoxy, 1,1-dimethyl-(4-pyridyl)thioethoxy, 2-methyl-3-(2-pyridyl)thiopropoxy, 2-methyl-3-(3-pyridyl)thiopropoxy and 2-methyl-3-(4-pyridyl)thiopropoxy groups, etc.
As to the pyridylsulfinyl-substituted lower alkoxy group, there may be exemplified pyridylsulfinyl-substituted alkoxy groups in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for example, (2-pyridyl)sulfinylmethoxy, (3-pyridyl)sulfinylmethoxy, (4-pyridyl)sulfinylmethoxy, 2-(2-pyridyl)sulfinylethoxy, 2-(3-pyridyl)sulfinylethoxy, 2-(4-pyridyl)sulfinylethoxy, 3-(2-pyridyl)sulfinylpropoxy, 3-(3-pyridyl)sulfinylpropoxy, 3-(4-pyridyl)sulfinylpropoxy, 4-(2-pyridyl)sulfinylbutoxy, 4-(3-pyridyl)sulfinylbutoxy, 4-(4-pyridyl)sulfinylbutoxy, 5-(2-pyridyl)sulfinylpentyloxy, 5-(3-pyridyl)sulfinylpentyloxy, 5-(4-pyridyl)sulfinylpentyloxy, 6-(2-pyridyl)sulfinylhexyloxy, 6-(3-pyridyl)sulfinylhexyloxy, 6-(4-pyridyl)sulfinylhexyloxy, 1,1-dimethyl-2-(2-pyridyl)sulfinylethoxy, 1,1-dimethyl-2-(3-pyridyl)sulfinylethoxy, 1,1-dimethyl-(4-pyridyl)sulfinylethoxy, 2-methyl-3-(2-pyridyl)sulfinylpropoxy, 2-methyl-3-(3-pyridyl)sulfinylpropoxy and 2-methyl-3-(4-pyridyl)sulfinylpropoxy groups, etc.
As to the pyridylsulfonyl-substituted lower alkoxy group, there may be exemplified pyridylsulfonyl-substituted alkoxy groups in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for example, (2-pyridyl)sulfonylmethoxy, (3-pyridyl)sulfonylmethoxy, (4-pyridyl)sulfonylmethoxy, 2-(2-pyridyl)sulfonylethoxy, 2-(3-pyridyl)sulfonylethoxy, 2-(4-pyridyl)sulfonylethoxy, 3-(2-pyridyl)sulfonylpropoxy, 3-(3-pyrfidyl)sulfonylpropoxy, 3-(4-pyridyl)sulfonylpropoxy, 4-(2-pyridyl)sulfonylbutoxy, 4-(3-pyridyl)sulfonylbutoxy, 4-(4-pyridyl)sulfonylbutoxy, 5-(2-pyridyl)sulfonylpentyloxy, 5-(3-pyridyl)sulfonylpentyloxy, 5-(4-pyridyl)sulfonylpentyloxy, 6-(2-pyridyl)sulfonylhexyloxy, 6-(3-pyridyl)sulfonylhexyloxy, 6-(4-pyridyl)sulfonylhexyloxy, 1,1-dimethyl-2-(2-pyridyl)sulfonylethoxy, 1,1-dimethyl-2-(3-pyridyl)sulfonylethoxy, 1,1-dimethyl-(4-pyridyl)sulfonylethoxy, 2-methyl-3-(2-pyridyl)sulfonylpropoxy, 2-methyl-3-(3-pyridyl)sulfonylpropoxy and 2-methyl-3-(4-pyridyl)sulfonylpropoxy groups, etc.
As to the imidazolylthio-substituted lower alkoxy group, there may be exemplified imidazolylthio-substituted alkoxy groups in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for exmaple, (2-imidazolyl)thiomethoxy, 2-(2-imidazolyl)thioethoxy, 1-(2-imidazolyl)thioethoxy, 3-(4-imidazolyl)thiopropoxy, 4-(5-imidazolyl)thiobutoxy, 5-(4-imidazolyl)thiopentyloxy, 6-(2-imidazolyl)thiohexyloxy, 1,1-dimethyl-2-(2-imidazolyl)thioethoxy and 2-methyl-3-(5-imidazolyl)thiopropoxy groups, etc.
As to the imidazolylsulfinyl-substituted lower alkoxy group, there may be exemplified imidazlylsulfonyl-substituted alkoxy groups in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for example, (2-imidazolyl)sulfinylmethoxy, 2-(2-imidazolyl)sulfinylethoxy, 1-(2-imidazolyl)sulfinylethoxy, 3-(4-imidazolyl)sulfinylpropoxy, 4-(5-imidazolyl)sulfinylbutoxy, 5-(4-imidazolyl)sulfinylpentyloxy, 6-(2-imidazolyl)sulfinylhexyloxy, 1,1-dimethyl-2-(2-imidazolyl)sulfinylethoxy and 2-methyl-3-(5-imidazolyl)sulfinylpropoxy groups, etc.
As to the imidazolylsulfonyl-substituted lower alkoxy group, there may be exemplified imidazolylsulfonyl-substituted alkoxy groups in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for example, (2-imidazolyl)sulfonylmethoxy, 2-(2-imidazolyl)sulfonylethoxy, 1-(2-imidazolyl)sulfonylethoxy, 3-(4-imidazolyl)sulfonylpropoxy, 4-(5-imidazolyl)sulfonylbutoxy, 5-(4-imidazolyl)sulfonylpentyloxy, 6-(2-imidazolyl)sulfonylhexyloxy, 1,1-dimethyl-2-(2-imidazolyl)sulfonylethoxy and 2-methyl-3-(5-imidazolyl)sulfonylpropoxy groups, etc.
As to the pyrimidinylthio-substituted lower alkoxy group which may optionally contain a lower alkyl group on the pyrimidine ring, there may be exemplified pyrimidinylthioalkoxy groups which may optionally contain 1 to 3 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms on the pyrimidine ring and in which the alkoxy moiety is a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms; for exmaple, (2-pyrimidinyl)thiomethoxy, 2-(2-pyrimidinyl)thioethoxy, 1-(4-pyrimidinyl)thioethoxy, 3-(5-pyrimidinyl)thiopropoxy, 4-(6-pyrimidinyl)thiobutoxy, 5-(2-pyrimidinyl)thiopentyloxy, 6-(4-pyrimidinyl)thiohexyloxy, 1,1-dimethyl-2-(2-pyrimidinyl)thioethoxy, 2-methyl-3-(4-pyrimidinyl)thiopropoxy, 2-(6-methyl-2-pyrimidinyl)thioethoxy, (4-ethyl-2-pyrimidinyl)thiomethoxy, 1-(5-propyl-4-pyrimidinyl)thioethoxy, 3-(2-butyl-5-pyrimidinyl)thiopropoxy, 4-(6-pentyl-2-pyrimidinyl)thiobutoxy, 5-(5-hexyl-2-pyrimidinyl)thiopentyloxy, 6-(6-methyl-2-pyrimidinyl)thiohexyloxy, 2-(4,6-dimethyl-2-pyrimidinyl)thioethoxy and (4,5,6-trimethyl-2-pyrimidinyl)thiomethoxy groups, etc.
As to the amino-substituted lower alkoxy group which may optionally contain as a substituent a lower alkyl group, there may be exemplified straight chain or branched chain alkoxy groups having 1 to 6 carbon atoms which may optionally contain as substituent(s) 1 to 2 straight chain or branched chain alkyl groups having 1 to 6 carbon atoms; for example, aminomethoxy, 2-aminoethoxy, 1-aminoethoxy, 3-aminopropoxy, 4-aminobutoxy, 5-aminopentyloxy, 6-aminohexyloxy, 6-aminohexyloxy, 1,1-dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, melthylaminomethoxy, 1-ethylaminoethoxy, 2-propylaminoethoxy, 3-isopropylaminopropoxy, 4-isopropylaminobutoxy, 4-butylaminobutoxy, 4-tert-butylaminobutoxy, 5-pentylaminopentyloxy, 6-hexylaminohexyloxy, dimethylaminomethoxy, 2-diethylaminoethoxy, 2-dimethylaminoethoxy, (N-ethyl-N-propylamino)melthoxy and 2-(N-methyl-N-hexylamino)ethoxy groups, etc.
As to the pyrrolidinyl-substituted lower alkyl group, there may be exemplified pyrrolidinylalkyl groups which may optionally contain as substituent(s) 1 to 3 straight chain or branched chain alkyl groups and in which the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms; for example, (2-pyrrolidinyl)methyl, 2-(2-pyrrolidinyl)ethyl, 1-(3-pyrrolidinyl)ethyl, 3-(2-pyrrolidinyl)propyl, 4-(3-pyrrolidinyl)butyl, 5-(2-pyrrolidinyl)pentyl, 6-(3-pyrrolidinyl)hexyl, 1,1-dimethyl-2-(2-pyrrolidinyl)ethyl, 2-methyl-3-(3-pyrrolidinyl)propyl, (5-ethyl-2-pyrrolidinyl)methyl, 2-(1-methyl-2-pyrrolidinyl)ethyl, 1-(3-propyl-2-pyrrolidinyl)ethyl, 3-(1-butyl-2-pyrrolidinyl)propyl, 4-(3-pentyl-5-pyrrolidinyl)butyl, 5-(4-hexyl-3-pyrrolidinyl)pentyl, 6-(2-methyl-4-pyrrolidinyl)hexyl, 1,1-dimethyl-2-(4-methyl-3-pyrrolidinyl)ethyl, 2-methyl-3-(1-methyl-3-pyrrolidinyl)propyl, (1,3-dimethyl-2-pyrrolidinyl)methyl and (1,2,3-trimethyl-4-pyrrolidinyl)methyl groups, etc.
The compounds of the present invention can be produced by various processes. ##STR20##
In the above, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and the bond between the 4- and 5-position carbons of the benzoazepine skeleton are the same as defined above.
The process shown by the reaction formula 1 is a process in which a benzoheterocyclic compound of the general formula (2) is reacted with a carboxylic acid of the general formula (3) according to an ordinary amide-bond-formation reaction. In the amide-bond-formation reaction, the known conditions for amide-bond-formation reaction can be applied easily. The process includes, for example, (a) a mixed acid anhydride process which comprises reacting a carboxylic acid (3) with an alkylhalocarboxylic acid to form a mixed acid anhydride and reacting the anhydride with an amine (2); (b) an active ester process which comprises converting a carboxylic acid (3) into an active ester such as p-nitro-phenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzo-triazole ester or the like and reacting the active ester with an amine (2); a carbodiimide process which comprises subjecting a carboxylic acid (3) and an amine (2) to a condensation reaction in the presence of an activating agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or the like; and other processes. The other processes include, for example, a process which comprises converting a carboxylic acid (3) into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride or the like and reacting the carboxylic acid anhydride with an amine (2); a process which comprises reacting an ester of a carboxylic acid (3) and a lower alcohol with an amine (2) at a high pressure at a high temperature; and a process which comprises reacting an acid halide of a carboxylic acid (3), i.e. a carboxylic acid halide with an amine (2).
The mixed acid anhydride used in the mixed acid anhydride process (a) can be obtained by a general Schotten-Baumann reaction. The anhydride is reacted with an amine (2) generally without being isolated, whereby the compound of the general formula (1) according to the present invention can be produced. The Schotten-Baumann reaction is conducted in the presence of a basic compound. The basic compound is a compound conventionally used in the Schotten-Baumann reaction and includes, for example, organic bases 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) and the like, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate and the like. The reaction is conducted generally at about -20.degree. C. to 100.degree. C., preferably at about 0.degree.-50.degree. C., and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours. The reaction of the resulting mixed acid anhydride with an amine (2) is conducted generally at about -20.degree. C. to 150.degree. C., preferably at about 10.degree.-50.degree. C., and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours. The mixed acid anhydride process (a) is conducted generally in a solvent. The solvent may be any solvent conventionally used in the mixed acid anhydride process, and can be exemplified by halogenated hydrocarbons such as chloroform, dichloro-methane, dichloroethane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dimethoxyethane and the like; esters such as methyl acetate, ethyl acetate and the like; aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphoric triamide and the like; and mixtures thereof. The alkylhalocarboxylic acid used in the mixed acid anhydride process (a) includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate and isobutyl chloroformate. The proportions of the carboxylic acid (3), the alkylhalocarboxylic acid and the amine (2) used in the process are generally equal moles. However, the carboxylic acid (3) and the alkylhalocarboxylic acid may be used each in an amount of about 1-1.5 moles per mole of the amine (2).
The process which comprises reacting a carboxylic acid halide with an amine (2) [this is a process included in the other processes (d)], can be conducted in the presence of a basic compound in an appropriate solvent. The basic compound can be selected from various known basic compounds and can be exemplified by not only the basic compounds usable in the above Schotten-Baumann reaction but also sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride. The solvent can be exemplified by not only the solvents usable in the mixed acid anhydride process (a) but also alcohols (e.g. methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve and methyl cellosolve), pyridine, acetone and water. The proportions of the amine (2) and the carboxylic acid halide used are not particularly restricted and can be appropriately selected from a wide range, but the carboxylic acid halide is used in an amount of generally at least about 1 mole, preferably about 1-5 moles per mole of the amine (2). The reaction is conducted generally at about -20.degree. C. to 180.degree. C., preferably at about 0.degree.-150.degree. C. and is complete generally in about 5 minutes to 30 hours.
The amide-bond-formation reaction shown by the reaction formula 1 can also be carried by a process which comprises reacting a carboxylic acid (3) with an amine (2) in the presence of a phosphorus compound as condensating agent. The phosphorus compound includes triphenylphosphine, diphenylphosphinyl chloride, phenyl N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, diphenyl phosphoric azide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, etc.
The reaction is conducted in the presence of the same solvent and basic compound as used in the above-mentioned process which comprises reacting a carboxylic acid halide with an amine (2), generally at about -20.degree. C. to 150.degree. C., preferably at about 0.degree.-100.degree. C., and is complete generally in about 5 minutes to 30 hours. The amounts of the condensating agent and the carboxylic acid (3) used are each at least about 1 mole, preferably about 1-2 moles per mole of the amine (2). ##STR21##
In the above, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and the bond between the 4- and 5-position carbons of the benzoazepine skeleton are the same as defined above. R.sup.14 is a group represented by the following formula ##STR22## (R.sup.13 and m are the same as defined above), a phenyl-lower alkanoyl group having, on the phenyl ring, 1-3 substituents selected from the group consisting of halogen atoms, lower alkoxy groups, lower alkyl groups and a nitro group, or a group represented by the following formula. ##STR23##
The reaction of the compound (2a) with the compound (4) can be conducted under the same conditions as in the reaction of the reaction formula 1 between the compound (2) and the compound (3). ##STR24##
In the above, R.sup.1, R.sup.2, R.sup.3, R.sup.6 and R.sup.7 are the same as defined above.
The reaction for converting a compound (1c) into a compound (1d) can be conducted by a reduction reaction.
In the reduction reaction, the reduction can be preferably conducted using a hydride as a reducing agent. The hydride as reducing agent includes, for example, lithium aluminum hydride, lithium boron hydride, sodium boron hydride and diborane. The amount of the hydride used is at least 1 mole, preferably 1-15 moles per mole of the raw material. This reduction reaction is conducted generally using an appropriate solvent such as water, lower alcohol (e.g. methanol, ethanol or isopropanol), ether (e.g. tetrahydrofuran, diethyl ether, diisopropyl ether or diglyme) or mixture thereof, generally at about -60.degree. C. to 150.degree. C., preferably at -30.degree. C. to 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 or diglyme.
The reduction for converting a compound (1c) into a compound (1e) is conducted in the absence of any solvent or in the presence of an appropriate solvent, in the presence or absence of a dehydrating agent. The solvent includes, for example, alcohols such as methanol, ethanol, isopropanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; aprotic polar solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone and the like; and mixtures thereof. The dehydrating agent includes, for example, desiccants generally used for solvent dehydration, such as molecular sieve and the like; mineral acids such as hydrochloric acid, sulfuric acid, boron trifluoride and the like; and organic acids such as p-toluenesulfonic acid and the like. The reaction is conducted generally at room temperature to 250.degree. C., preferably at about 50.degree.-200.degree. C. and is complete generally in about 1-48 hours. The amount of the compound (5) used is not particularly restricted but is generally at least equimolar, preferably equimolar to a large excess to the compound (1c). The amount of the dehydrating agent used is generally a large excess when a desiccant is used, and is a catalytic amount when an acid is used.
In the subsequent reduction reaction, various methods can be used. It can be conducted by catalytic hydrogenation in the presence of a catalyst in an appropriate solvent. The solvent includes, for example, water; alcohols such as methanol, ethanol, isopropanol and the like; hydrocarbons such as hexane, cyclohexane and the like; ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, diethyl ether and the like; esters such as ethyl acetate, methyl acetate and the like; aprotic polar solvents such as dimethylformamide and the like; and mixtures thereof. ##STR25##
In the above, R.sup.1, R.sup.2, R.sup.3, R.sup.5 R.sup.6 and the bond between the 4- and 5-position carbons of the benzoazepine skeleton are the same as defined above. R.sup.7a is a lower alkyl group or a lower alkenyl group. R.sup.15 and R.sup.16 are each a hydrogen atom or a lower alkyl group. X is a halogen atom. R.sup.7b is a benzoyl group having halogen substituent(s) on the phenyl ring.
The reaction of the compound (1f) with the compound (6) is conducted generally in an appropriate inactive solvent in the presence or absence of a basic compound.
The inactive solvent includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethylene glycol dimethyl ether and the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and the like; lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol and the like; acetic acid; ethyl acetate; acetone; acetonitrile; pyridine; dimethyl sulfoxide; dimethylformamide; hexamethylphosphoric triamide; and mixtures thereof. The basic compound includes, for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like; metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; sodium hydride; potassium; sodium; sodium amide; metal alcoholates such as sodium methylate, sodium ethylate and the like; and organic bases such as 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) and the like. The proportions of the compound (1f) and the compound (6) are not particularly restricted and can be appropriately selected from a wide range, but the compound (6) is used in an amount of preferably at least about 1 mole, more preferably about 1-10 moles per mole of the compound (1f). The reaction is conducted generally at about 0.degree.-200.degree. C., preferably at about 0.degree.-170.degree. C. and is complete generally in about 30 minutes to 75 hours. In the reaction system may be used an alkali metal halide (e.g. sodium iodide or potassium iodide), etc.
The reaction of the compound (1f) with the compound (7) is conducted in the absence of any solvent or in the presence of an appropriate solvent in the presence of a reducing agent. The solvent can be exemplified by water; alcohols such as methanol, ethanol, isopropanol and the like; acetonitrile; formic acid; acetic acid; ethers such as dioxane, diethyl ether, diglyme, tetrahydrofuran and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; and mixtures thereof. The reducing agent can be exemplified by formic acid; alkali metal salts of fatty acids, such as sodium formate and the like; hydride reducing agents such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride and the like; and catalytic reducing agents such as palladium black, palladium-carbon, platinum oxide, platinum black, Raney nickel and the like.
When formic acid is used as the reducing agent, the appropriate reaction temperature is generally about room temperature to 200.degree. C., preferably about 50.degree.-150.degree. C., and the reaction is complete in about 1-10 hours. The amount of formic acid used is preferably a large excess to the compound (1f).
When a hydride reducing agent is used, the appropriate reaction temperature is generally about -30.degree. C. to 100.degree., preferably about 0.degree.-70.degree. C., and the reaction is complete in about 30 minutes to 12 hours.
The appropriate amount of the reducing agent used is generally about 1-20 moles, preferably about 1-6 moles per mole of the compound (1f). When lithium aluminum hydride is used as the reducing agent, it is preferable to use, as the solvent, an ether (e.g. diethyl ether, dioxane, tetrahydrofuran or diglyme) or an aromatic hydrocarbon (e.g. benzene, toluene or xylene).
When a catalytic reducing agent is used, the reaction is conducted in a hydrogen atmosphere of generally about normal pressure to 20 atm., preferably about normal pressure to 10 atm. in the presence of a hydrogen donor (e.g. formic acid, ammonium formate, cyclohexene or hydrazine hydrate) generally at about -30.degree. C. to 100.degree. C., preferably at about 0.degree.-60.degree. C., and is complete generally in about 1-12 hours. The amount of the catalytic reducing agent used is generally about 0.1-40% by weight, preferably about 1-20% by weight based on the compound (1f).
The reaction of the compound (1f) with the compound (30) can be conducted under the same conditions as in the reaction of the compound (2) with the compound (3) in the reaction formula-1.
The appropriate amount of the compound (7) used is generally at least equimolar, preferably equimolar to a large excess to the compound (1f). ##STR26##
In the above, R.sup.1, R.sup.2, R.sup.3, X, R.sup.5 and the bond between the 4- and 5-position carbons of the benzoazepine skeleton are the same as defined above. R.sup.18 is a lower alkanoyloxy group having halogen substituent(s), or a lower alkoxy-substituted lower alkanoyloxy group. R.sup.19 is a lower alkenyloxy group, a group --O--CO--A--NR.sup.8 R.sup.9 (A, R.sup.8 and R.sup.9 are the same as defined above), a group --OACONR.sup.23 R.sup.24 (A, R.sup.23 and R.sup.24 are the same as defined above), a pyrrolidinylcarbonyl-lower alkoxy group having lower alkoxycarbonyl group(s) on the pyrrolidine ring, a group --OANR.sup.27 R.sup.28 (A, R.sup.27 and R.sup.28 are the same as defined above), a phenylsulfonyloxy group having lower alkyl substituent(s) on the phenyl ring, a hydroxyl group-containing lower alkoxy group, a 1,2,4-triazolyl-substituted lower alkoxy group, a 1,2,3,4-tetrazolyl-substituted lower alkoxy group, a 1,2,3,5-tetrazolyl-substituted lower alkoxy group, a pyridylthio-substituted lower alkoxy group, a pyrimidinylthio-substituted lower alkoxy group which may have lower alkyl group(s) on the pyrimidine ring, an imidazolylthio-substituted lower alkoxy group, a pyridylsulfinyl-substituted lower alkoxy group, a pyridylsulfonyl-substituted lower alkoxy group, an imidazolylsulfinyl-substituted lower alkoxy group or an imidazolylsulfonyl-substituted lower alkoxy group. R.sup.20 is a lower alkenyl group, a group --CO--A--NR.sup.8 R.sup.9 (A, R.sup.8 and R.sup.9 are the same as defined above), a group --ACONR.sup.23 R.sup.24 (A, R.sup.23 and R.sup.24 are the same as defined above), a pyrrolidinylcarbonyl-lower alkyl group having lower alkoxycarbonyl group(s) on the pyrrolidine ring, a group --ANR.sup.27 R.sup.28 (A, R.sup.27 and R.sup.28 are the same as defined above), a phenylsulfonyloxy group having lower alkyl substituent(s) on the phenyl ring, a hydroxyl group-containing lower alkyl group, a 1,2,4-triazolyl-substituted lower alkyl group, a 1,2,3,4-tetrazolyl-substituted lower alkyl group, a 1,2,3,5-tetrazolyl-substituted lower alkyl group, a pyridylthio-substituted lower alkyl group, a pyrimidinylthio-substituted lower alkyl group which may have lower alkyl group(s) on the pyrimidine ring, an imidazolylthio-substituted lower alkyl group, a pyridylsulfinyl-substituted lower alkyl group, a pyridylsulfonyl-substituted lower alkyl group, an imidazolylsulfinyl-substituted lower alkyl group or an imidazolylsulfonyl-substituted lower alkyl group. R.sup.17 is a lower alkanoyl group having halogen substituent(s) or a lower alkoxy-substituted lower alkanoyl group.
The reaction of the compound (1h) with the compound (8) or (9) can be conducted under the same conditions as in the reaction of the compound (1f) with the compound (6) in the reaction formula-4.
The reaction of the compound (1h) with the compound (10) can be conducted under the same conditions as in the reaction of the compound (1f) with the compound (6) in the reaction formula 4.
When the R.sup.18 of the compound (1i) is a lower alkanoyl group having halogen substituent(s), the compound (1i) can be reacted with a compound HNR.sup.8 R.sup.9 (11) (R.sup.8 and R.sup.9 are the same as defined above) under the same conditions as in the reaction of the compound (1f) with the compound (6) in the reaction formula 4, to obtain a compound (1j) wherein the R.sup.19 is a group --O--CO--A--NR.sup.8 R.sup.9 (A, R.sup.8 and R.sup.9 are the same as defined above). ##STR27##
In the above, R.sup.1, R.sup.2 and R.sup.3 are the same as defined above. R.sup.20 is a lower alkoxy group. R.sup.21 is a lower alkoxycarbonyl group, a cyano group or an amino group which may have lower alkyl substituent(s). D is a lower alkylene group. l is 0 or 1.
The reaction of the compound (1c) with the compound (11) is conducted in the presence of a basic compound in an appropriate solvent. The basic compound can be exemplified by inorganic bases such as metallic sodium, metallic potassium, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and the like; metal alcoholates such as sodium methylate, sodium ethylate, potassium tert-butoxide and the like; alkyl- or aryllithiums or lithium amides such as methyllithium, n-butyllithium, phenyllithium, lithium diisopropylamide and the like; and organic bases such as pyridine, piperidine, quinoline, triethylamine, N,N-dimethylaniline and the like. The solvent can be any solvent as long as it gives no adverse effect on the reaction. The solvent includes, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane and the like; amines such as pyridine, N,N-dimethylaniline and the like; aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide and the like; and alcohols such as methanol, ethanol, isopropanol and the like. The appropriate reaction temperature is generally about -80.degree. C. to 150.degree. C., preferably about -80.degree. C. to 120.degree. C. The reaction is complete generally in about 0.5-15 hours.
The reaction for converting the compound (1k) into a compound (1l) is conducted under the same conditions as in the reduction reaction in the reaction formula 3 for converting the compound (1c) into a compound (1e). When hydrogen is used as a reducing agent in the reduction reaction, the addition of a metal halide (e.g. nickel chloride) allows the reaction to proceed favorably.
When the compound (1l) is a compound (1l) wherein the R.sup.21 is a lower alkoxycarbonyl group, the reaction for converting the compound (1l) into a compound (1m) can be carried out in an appropriate solvent or in the absence of any solvent in the presence of an acid or a basic compound. The solvent includes, for example, water; lower alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone and the like; ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and the like; fatty acids such as acetic acid, formic acid and the like; and mixtures thereof. The acid includes, for example, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like; and organic acids such as formic acid, acetic acid, aromatic sulfonic acids and the like. The basic compound includes, for example, metal carbonates such as sodium carbonate, potassium carbonate and the like; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. The reaction favorably proceeds generally at about room temperature to 200.degree. C., preferably at about room temperature to 150.degree. C., and is complete generally in about 10 minutes to 25 hours. ##STR28##
In the above, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.11, R.sup.12, A and the bond between the 4- and 5-position carbons of the benzoazepine skeleton are the same as defined above. R.sup.22 is a carboxy-substituted lower alkyl group.
The reaction of the compound (1n) with the compound (12) can be conducted under the same conditions as in the reaction of the compound (2) with the compound (3) in the reaction formula 1. ##STR29##
In the above, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.10 and the bond between the 4- and 5-position carbons of the benzoazepine skeleton are the same as defined above.
The reaction of the compound (1p) with the compound (13) is conducted in an appropriate solvent in the presence of a basic compound. In the system of the reaction, it is advisable to use a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide or the like. The basic compound and solvent can be any basic compound and solvent used in the reaction of the compound (1f) with the compound (6) in the reaction formula 4. The appropriate amount of the compound (13) used is at least 1 mole, preferably about 1-2 moles per mole of the compound (1p). The reaction is conducted at 0.degree.-100.degree. C., preferably at about 0.degree.-70.degree. C. and is complete in about 1-15 hours.
When the compound (13) is used in the reaction, it is possible to protect the amino group moiety of the amino acid residue of the R.sup.10, with an ordinary amino acid-protecting group such as phenyl-lower alkoxycarbonyl group (e.g. benzyloxycarbonyl group), lower alkoxycarbonyl group (e.g. tert-butoxycarbonyl group) or the like, react the resulting product with a compound (1p) and deprotecting said protecting group by an ordinary deprotection reaction such as catalytic reduction, hydrolysis or the like to obtain a compound (1q).
The compound (2a) as starting material can be produced, for example, by the following reaction formula. ##STR30##
In the above, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and the bond between the 4- and 5-position carbons of the benzoazepine skeleton are the same as defined above.
The reaction of the compound (2) with the compound (14) can be conducted under the same conditions as in the reaction of the compound (2) with the compound (3) in the reaction formula-3.
The reaction for converting the compound (15) into a compound (2a) is conducted, for example, by (1) reducing the compound (15) with a catalytic reduction catalyst in an appropriate solvent or (2) reducing the compound (15) in an appropriate inactive solvent using, as a reducing agent, a mixture between a metal or a metal salt and an acid or a mixture between a metal or a metal salt and an alkali metal hydroxide, a sulfide or an ammonium salt.
In the case (1) using a catalytic reduction catalyst, the solvent includes, for example, water; alcohols such as methanol, ethanol, isopropanol and the like; hydrocarbons such as hexane, cyclohexane and the like; ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether and the like; esters such as ethyl acetate, methyl acetate and the like; aprotic polar solvents such as N,N-dimethylformamide and the like; and mixtures thereof. The catalytic reduction catalyst includes, for example, palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromite and Raney nickel. The appropriate amount of the catalyst used is generally about 0.02-1 time the amount of the starting material. The appropriate reaction temperature is generally about -20.degree. C. to 150.degree. C., preferably about 0.degree.-100.degree. C., the appropriate hydrogen pressure used is generally 1-10 atm. The reaction is complete generally in about 0.5-10 hours. An acid such as hydrochloric acid or the like may be used in the reaction.
In the case (2) using a mixture as a reducing agent, there is used, as the reducing agent, a mixture between iron, zinc, tin or stannous chloride and a mineral acid (e.g. hydrochloric acid or sulfuric acid), or a mixture between iron, ferrous sulfate, zinc or tin and an alkali metal hydroxide (e.g. sodium hydroxide), a sulfide (e.g. ammonium sulfide), ammonia water or an ammonium salt (ammonium chloride). The inert solvent can be exemplified by water, acetic acid, methanol, ethanol and dioxane. The conditions for the reduction reaction can be appropriately selected depending upon the reducing agent used. For example, when stannous chloride and hydrochloric acid are used as a reducing agent, the reaction is preferably conducted at about 0.degree.-80.degree. C. for about 0.5-10 hours. The reducing agent is used in an amount of at least 1 mole, generally 1-5 moles per mole of the raw material compound.
A compound (1) wherein the R.sup.1 is a hydroxyl group, can also be obtained by dealkylating a compound (1) wherein the R.sup.1 is a lower alkoxy group. The dealkylation reaction can be conducted by heat-treating said compound in a mixture between an acid (e.g. hydrobromic acid or hydrochloric acid) and a solvent (e.g. water, methanol, ethanol or isopropyl alcohol) at 30.degree.-150.degree. C., preferably 50.degree.-120.degree. C., or by hydrolyzing said compound. The hydrolysis is conducted in an appropriate solvent the presence of an acid. The solvent includes, for example, water; lower alcohols such as methanol, ethanol, isopropyl alcohol and the like; ethers such as dioxane, tetrahydrofuran and the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and the like; polar solvents such as acetonitrile and the like; and mixtures thereof. The acid includes, for example, mineral acids such as hydrochloric acid, hydrobromic acid and the like; Lewis acids such as boron trifluoride, aluminum chloride, boron tribromide and the like; iodides such as sodium iodide, potassium iodide and the like; and mixtures of said Lewis acid and said iodide. The reaction proceeds favorably generally at room temperature to 150.degree. C., preferably at room temperature to 100.degree. C., and is complete generally in about 0.5-15 hours. ##STR31##
In the above, R.sup.1, R.sup.2, R.sup.3, R.sup.5 R.sup.25, R.sup.26, A, B and the bond between the 4- and 5-position carbons of the benzoazepine skeleton are the same as defined above. R.sup.31 is a hydroxyl group-substituted lower alkyl group.
The reaction of the compound (1r) with the compound (16) is conducted under the same conditions as in the reaction of the compound (1p) with the compound (13) in the reaction formula 8. ##STR32##
In the above, R.sup.1, R.sup.2, R.sup.3, R.sup.5 R.sup.29, R.sup.30, R.sup.31, X and the bond between the 4- and 5-position carbons of the benzoazepine skeleton are the same as defined above. R.sup.32 is a phenylsulfonyl group which may have lower alkyl substituent(s) on the phenyl ring. R.sup.33 is a phenylsulfonyloxy-substituted lower alkyl group which may have lower alkyl substituent(s) on the phenyl ring. R.sup.34 is a group --ANR.sup.29 R.sup.30 (A, R.sup.29 and R.sup.30 are the same as defined above). R.sup.39 is an imidazolyl group, a 1,2,4-triazolyl group, a 1,2,3,4-tetrazolyl group or a 1,2,3,5-tetrazolyl group.
The reaction of the compound (1t) with the compound (17) is conducted under the same conditions as in the reaction of the compound (1f) with the compound (6) in the reaction formula-4. The reaction of the compound (1u) with the compound (18a) or compound (18b) is conducted also under the same conditions as in the reaction of the compound (1f) with the compound (6) in the reaction formula-4. ##STR33##
In the above, R.sup.1, R.sup.2, R.sup.3, R.sup.5 R.sup.27, R.sup.28, X, R.sup.32 and the bond between the 4- and 5-position carbons of the benzoazepine skeleton are the same as defined above. R.sup.35 is a lower alkoxycarbonyl-substituted lower alkyl group or a lower alkoxycarbonyl group. R.sup.36 is a hydroxyl group-containing lower alkoxy group. R.sup.37 is a lower alkoxy group having a phenylsulfonyloxy group which may have lower alkyl substituent(s) on the phenyl ring. R.sup.38 is a group --OANR.sup.27 R.sup.28 (A, R.sup.27 and R.sup.28 are the same as defined above).
The reaction of the compound (1h) with the compound (19) is conducted under the same conditions as in the reaction of the compound (1f) with the compound (6) in the reaction formula 4. The reaction for converting the compound (20) into a compound (1w) is conducted under the same conditions as in the reaction for converting the compound (1c) into a compound (1d) in the reaction formula 3. The reaction of the compound (1w) with the compound (17) is conducted under the same conditions as in the reaction of the compound (1f) with the compound (6) in the reaction formula 4. The reaction of the compound (1x) with the compound (21) is conducted also under the same conditions as in the reaction of the compound (1f) with the compound (6) in the reaction formula-4. ##STR34##
In the above, R.sup.1, R.sup.2, R.sup.3, R.sup.5, X and the bond between the 4- and 5-position carbons of the benzoazepine skeleton are the same as defined above. R.sup.27a is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkinyl group, a lower alkylsulfonyl group, an aminothiocarbonyl group which may have lower alkyl substituent(s), a group ##STR35## [R.sup.41 is a hydrogen atom or a cyano group. R.sup.42 is a lower alkyl group or an amino group which may have lower alkyl substituent(s).], a carbamoyl group, a lower alkoxycarbonyl group, a cycloalkyl group, a phenyl-lower alkyl group which may have halogen substituent(s) on the phenyl ring, a cyano-substituted lower alkyl group, a halogen-substituted lower alkylsulfonyl group or a lower alkyl group having an amino substituent which may have lower alkyl group(s). R.sup.28a is a lower alkyl group, a lower alkenyl group, a lower alkinyl group, a lower alkylsulfonyl group, a lower alkoxycarbonyl group, a cycloalkyl group, a phenyl-lower alkyl group which may have halogen substituent(s) on the phenyl ring, a cyano-substituted lower alkyl group, a halogen-substituted lower alkylsulfonyl group or a lower alkyl group having an amino substituent which may have lower alkyl group(s). R.sup.43 is a lower alkyl group. M is an alkali metal such as sodium, potassium or the like. R.sup.44 is a lower alkoxy group. R.sup.45 and R.sup.46 are each a lower alkylthio group. R.sup.47 is a lower alkylsulfonyl group or a halogen-substituted lower alkylsulfonyl group.
The reaction of the compound (1z) with the compound (22) or the compound (7) can be conducted under the same conditions as in the reaction of the compound (1f) with the compound (6) or the compound (7) in the reaction formula-4. The reaction of the compound (1z) with the compound (23) is conducted in the presence or absence of a basic compound, preferably in the absence of any basic compound, in an appropriate solvent or in the absence of any solvent. The solvent and basic compound can be any solvent and basic compound used in the reaction of the carboxylic acid halide with the amine (2) in the reaction formula-1.
The appropriate amount of the compound (23) used is generally about 1-5 moles, preferably about 1-3 moles per mole of the compound (1z). The reaction is conducted generally at about 0.degree.-200.degree. C., preferably at room temperature to 150.degree. C. generally in about 5 minutes to 30 hours. In the reaction, a boron compound such as boron trifluoride ethyl etherate or the like may be used.
The reaction of the compound (1z) with the compound (24) can be conducted in the presence of an acid in an appropriate solvent. The acid includes, for example, organic acids such as acetic acid, trifluoroacetic acid and the like and mineral acids such as hydrochloric acid, sulfuric acid and the like. The solvent can be any solvent used in the reaction of the carboxylic acid halide with the amine (2) in the reaction formula-1.
The reaction of the compound (1z) with the compound (25) can be conducted under the same conditions as in the above reaction of the compound (1z) with the compound (23).
The reaction of the compound (1z) with the compound (26) can be conducted under the same conditions as in the above reaction of the compound (1z) with the compound (23). The product obtained thereby is reacted with a compound (27) without being isolated, whereby a compound (1ee) can be obtained. The reaction with the compound (27) can be conducted in the same solvent as used in the reaction of the compound (1z) with the compound (26), generally at 0.degree.-150.degree. C., preferably at about 0.degree.-100.degree. C. generally in about 1-10 hours. The appropriate amount of the compound (27) used is at least 1 mole, generally 1-25 moles per mole of the compound (1z).
The reaction of the compound (1z) with the compound (28) can be conducted under the same conditions as in the reaction of the carboxylic acid halide with the amine (2) in the reaction formula-1. ##STR36##
In the above, R.sup.1, R.sup.2, R.sup.3, R.sup.5, M and the bond between the 4- and 5-position carbons of the benzoazepine skeleton are the same as defined above. R.sup.48 is a cyano-substituted lower alkyl group. R.sup.49 is a 1,2,3,4-tetrazolyl-substituted lower alkyl group.
The reaction of the compound (1gg) with the compound (29) can be conducted in an appropriate solvent in the presence of an ammonium halide such as ammonium chloride or the like.
The appropriate amount of the compound (29) used is at least 1 mole, preferably 1-2 moles per mole of the compound (1gg). The reaction is conducted generally at room temperature to 200.degree. C., preferably at room temperature to 150.degree. C. and is complete in about 1-10 hours.
When the compound of the general formula (1) is a compound of the general formula (1) wherein the R.sup.4 is an imidazolylthio-substituted lower alkoxy group or a pyridylthio-substituted lower alkoxy group, the compound can be converted by oxidation into a compound of the general formula (1) wherein the R.sup.4 is an imidazolylsulfinyl-substituted lower alkoxy group or an imidazolylsulfonyl-substituted lower alkoxy group, or a pyridylsulfinyl-substituted lower alkoxy group or a pyridylsulfonyl-substituted lower alkoxy group.
The oxidation reaction for converting the imidazolylthio-substituted lower alkoxy group into an imidazolylsulfinyl-substituted lower alkoxy group, the oxidation reaction for converting the imidazolylsulfinyl-substituted lower alkoxy group into an imidazolylsulfonyl-substituted lower alkoxy group, the oxidation reaction for converting the pyridylthio-substituted lower alkoxy group into a pyridylsulfinyl-substituted lower alkoxy group, and the oxidation reaction for converting the pyridylsulfinyl-substituted lower alkoxy group into a pyridylsulfonyl-substituted lower alkoxy group are conducted in an appropriate solvent in the presence of an oxidizing agent. The solvent can be exemplified by water; organic acids such as formic acid, acetic acid, trifluoroacetic acid and the like; alcohols such as methanol, ethanol and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; and mixtures thereof. The oxidizing agent includes, for example, peracids such as performic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid, o-carboxyperbenzoic acid and the like; hydrogen peroxide; sodium metaperiodate; bichromic acid; bichromates such as sodium bichromate, potassium bichromate and the like; permanganic acid; permanganates such as potassium permanganate, sodium permanganate and the like; and lead salts such as lead tetraacetate and the like. The appropriate amount of the oxidizing agent used is at least 1 mole, preferably 1-2.5 moles per mole of the starting material. In the cases of the oxidation reaction for converting the imidazolylthio-substituted lower alkoxy group into an imidazolylsulfonyl-substituted lower alkoxy group and the oxidation reaction for converting the pyridylthio-substituted lower alkoxy group into a pyridylsulfonyl-substituted lower alkoxy group, the appropriate amount of the oxidizing agent used is at least 2 moles, preferably 2-4 moles per mole of the oxidizing agent. The reaction is conducted generally at 0.degree.-150.degree. C., preferably at about 0.degree.-100.degree. C. and is complete in about 10 minutes to 15 hours.
When the compound of the general formula (1) is a compound of the general formula (1) wherein the R.sup.2 is a lower alkoxy group, can be converted by dealkylation into a compound of the general formula (1) wherein the R.sup.2 is a hydroxyl group.
The dealkylation can be conducted by heating said compound at 30.degree.-150.degree. C. preferably at 50.degree.-120.degree. C. in a mixture of an acid (e.g. hydrobromic acid or hydrochloric acid) and a solvent(e.g. water, methanol, ethanol, isopropyl alcohol or acetic acid). Alternatively, the dealkylation can be conducted by hydrolysis. The hydrolysis is conducted in an appropriate solvent in the presence of an acid. The solvent includes, for example, water; lower alcohols such as methanol, ethanol, isopropanol and the like; ethers such as dioxane, tetrahydrofuran and the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and the like; polar solvents such as acetonitrile and the like; and mixtures thereof. The acid includes, for example, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like; Lewis acids such as boron trifluoride, aluminum chloride, boron tribromide and the like; iodides such as sodium iodide, potassium iodide and the like; and mixtures of said Lewis acid and said iodide. The reaction proceeds favorably generally at room temperature to 150.degree. C., preferably at room temperature to 100.degree. C., and is complete generally in about 0.5-15 hours.
Of the compounds (1) used as an active ingredient in the present invention, those having an acidic group can each form a salt with a pharmacologically acceptable basic compound. The basic compound can be exemplified by metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and the like; alkali metal carbonates or bicarbonates such as sodium carbonate, sodium hydrogencarbonate and the like; and alkali metal alcoholates such as sodium methylate, potassium ethylate and the like. Of the compounds (1) used as an active ingredient in the present invention, those having basicity can easily form a salt with an ordinary phamacologically acceptable acid. The acid can be exemplified by inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid and the like; and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinnic acid, benzoic acid and the like. These salts can also be used as an active ingredient in the present invention, similarly to the compounds (1) of free form. Incidentally, the compounds (1) include stereoisomers and optical isomers and these isomers can also be used as an active ingredient in the present invention.
Each of the intended compounds (1) obtained by the above reaction formulas can be separated from the reaction system by an ordinary means and can further be purified. There can be used, as the separation and purification means, various methods such as distillation, recrystallization, column chromatography, ion-exchange chromatography, gel chromatography, affinity chromatography, preparative thin-layer chromatography, solvent extraction and the like.
Each of the thus obtained active ingredient compounds is effective as a vasopressin antagonist and is used in the form of ordinary pharmaceutical preparation. The pharmaceutical preparation is prepared by using diluents or excipients ordinarily used, such as filler, bulking agent, binder, humectant, disintegrator, surfactant, lubricant and the like. The pharmaceutical preparation can be used in various forms depending upon the purpose of remedy, and the typical forms include tables, pills, a powder, a solution, a suspension, an emulsion, granules, suppositories, an injection (e.g. solution or suspension), etc. In preparing tablets, various carriers conventionally known in the art can be used. The carriers can be exemplified by excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrators such as dry starch, sodium alginate, powdered agar, powdered laminarin, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan-fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and the like; disintegration inhibitors such as white sugar, stearin, cacao butter, hydrogenated oil and the like; absorption promoters such as quaternary ammonium salts, sodium lauryl sulfate and the like; humectants such as glycerine, starch and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid and the like; and lubricants such as refined talc, stearic acid salts, boric acid powder, polyethylene glycol and the like. The tablets can be prepared, as necessary, in the form of ordinary coated tablets, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets or film-coated tablets, or in the form of double-layered tablets or multi-layered tablets. In preparing pills, various carriers conventionally known in the art can be used. The carriers can be exemplified by excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin, talc and the like; binders such as powdered acacia, powdered tragacanth, gelatin, ethanol and the like; and disintegrators such as laminarin, agar and the like. In preparing suppositories, various carriers conventionally known in the art can be used. The carriers can be exemplified by a polyethylene glycol, cacao butter, a higher alcohol, a higher alcohol ester, gelatin and a semi-synthetic glyceride. Capsules can be prepared generally by mixing the active ingredient compound with various carriers shown above and filling the mixture into a hard gelatin capsule or a soft capsule by an ordinary method. In preparing an injection (solution, emulsion or suspension), it is sterilized and is preferably made isotonic to the blood. In preparing the solution, emulsion or suspension, there can be used all of the diluents conventionally used in the art, such as water, ethyl alcohol, polyethylene glycol, propylene glycol, ethoxylated isostearyl alcohol, polyoxy-isostearyl alcohol and polyoxyethylene sorbitan-fatty acid ester. In this case, the injection may contain sodium chloride, glucose or glycerine in an amount sufficient to make the injection isotonic, and may further contain a solubilizing agent, a buffer solution, a soothing agent, etc. all ordinarily used. The pharmaceutical preparation may furthermore contain, as necessary, a coloring agent, a preservative, a perfume, a flavoring agent, a sweetening agent and other drugs.
The amount of the active ingredient compound to be contained in the vasopressin antagonist of the present invention is not particularly restricted and can be appropriately selected from a wide range, but the appropriate amount is generally about 1-70% by weight, preferably about 5-50% by weight in the pharmaceutical preparation.
The method for administering the vasopressin antagonist of the present invention is not particularly restricted. The vasopressin antagonist can be administered in various methods depending upon the form of preparation, the age, sex and other conditions of patient, the disease condition of patient, etc. For example, tablets, pills, a solution, a suspension, an emulsion, granules or capsules are administered orally. An injection is intravenously administered singly or in admixture with an ordianry auxiliary solution of glucose, amino acids or the like, or, as necessary, is singly administered intramuscularly, intradermally, subcutaneously or intraperitoneally. Suppositories are administered intrarectally.
The dose of the vasopressin antagonist of the present invention is appropriately selected depending upon the administration method, the age, sex and other conditions of patient, the disease condition of patient, etc., but the appropriate dose is generally about 0.6-50 mg per kg of body weight per day in terms of the amount of the active ingredient, i,e, the present compound of the general formula (1). The pharmaceutical prepartion contains about 10-1,000 mg of the active ingredient compound in each unit of administration form.

EXAMPLES
The present invention is described in more detail below by showing Preparation Examples for preparing some of the vasopressin antagonists of the present invention, Reference Examples for producing some of the raw materials used for production of the active ingredient compounds to be contained in the vasopressin antagonists of the present invention, Examples for producing said active ingredient compounds, and Test Examples for examining the efficacies of said active ingredient compounds.
______________________________________Preparation Example 1______________________________________7-Hydroxy-5-methylamino-1-[4-(2-chlorobenzoylamino)- 150 gbenzoyl]-2,3,4,5-tetrahydro-1H-benzoazepineAvicel (trade mark for microcrystalline cellulose, 40 gmanufactured by Asahi Chemical Industry Co., Ltd.)Corn starch 30 gMagnesium stearate 2 gHydroxypropyl methyl cellulose 10 gPolyethylene glycol 6,000 3 gCastor oil 40 gEthanol 40 g______________________________________
The active ingredient compound of the present invention, Avicel, corn starch and magnesium stearate are mixed and ground. Then, the mixture is made into tablets using a tablet machine of R 10 mm (sugar coating). The tablets are each covered with a coating film consisting of hydroxypropyl methyl cellulose, polyethylene glycol 6,000, castor oil and ethanol, to prepare film-coated tablets.
______________________________________Preparation Example 2______________________________________5-Dimethylamino-1-[4-(4-carbamoylbenzoyl- 150 gamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepineCitric acid 1.0 gLactose 33.5 gDicalcium phosphate 70.0 gPluronic F-68 30.0 gSodium lauryl sulfate 15.0 gPolyvinylpyrrolidone 15.0 gPolyethylene glycol (Carbowax 1,500) 4.5 gPolyethylene glycol (Carbowax 6,000) 45.0 gCorn starch 30.0 gDry sodium stearate 3.0 gDry magnesium stearate 3.0 gEthanol Appropriate amount______________________________________
The active ingredient compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed.
The mixture is sifted using a No. 60 screen and then wet-pelletized using an alcoholic solution containing polyvinylpyrrolidone, Carbowax 1,500 and Carbowax 6,000. As necesary, the mixture is made into a paste by adding ethanol. Corn starch is added, after which mixing is conducted until uniform particles are formed. The resulting mixture is sifted using a No. 10 screen and placed in a tray. The mixture in the tray is dried in an oven of 100.degree. C. for 12-14 hours. The dried particles are sifted using a No. 16 screen, then mixed with dry sodium lauryl sulfate and dry magnesium stearate, and compressed into desired forms using a tablet-making machine.
The core portion of each of the tablets obtained is treated with a varnish and then covered with talc for prevention of moisture absorption. An undercoating layer is formed on the surface of the core portion. Varnish coating is conducted a plurality of times for internal use. Further, an undercoating layer and smooth coating are applied in order to make completely round and smooth tablets. Color coating is conducted until a desired color is obtained. Then, drying and grinding are conducted in this order to obtain tablets of uniform lustre.
______________________________________Preparation Example 3______________________________________5-Dimethylamino-1-{4-[2-(3-methylphenyl)acetylamino]- 5 gbenzoyl}-2,3,4,5-tetrahydro-1H-benzoazepinePolyethylene glycol (molecular weight = 4,000) 0.3 gSodium chloride 0.9 gPolyoxyethylene sorbitan monooleate 0.4 gSodium metabisulfite 0.1 gMethylparaben 0.18 gPropylparaben 0.02 gDistilled water for injection 10.0 ml______________________________________
The two parabens, sodium metabisulfite and sodium chloride are dissolved in distilled water for injection, of about half of the above amount at 80.degree. C. with stirring. The resulting solution is cooled to 40.degree. C. Therein are dissolved the active ingredient compound of the present invention, polyethylene glycol and polyoxyethylene sorbitan monooleate in this order. To the resulting solution is added the remaining amount of distilled water for injection. The solution is filtered for sterilization using an appropriate filter paper to prepare an injection.
Reference Example 1
38.8 g of potassium carbonate was added to a solution of 50 g of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 400 ml of acetone and 200 ml of water. To the solution was added 40 g of p-nitrobenzoyl chloride with ice-cooling and stirring. The resulting mixture was stirred overnight at room temperature. The reaction mixture was mixed with an appropriate amount of water. The resulting crystals were collected by filtration and dried to obtain 71 g of 5-dimethylamino-1-(4-nitro-benzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine.
A light yellow powder
Melting point: 139.degree.-142.degree. C.
Reference Example 2
5 g of 10% palladium-carbon was dispersed in 500 ml of ethanol. Thereto was added 64.1 g of 5-dimethylamino-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine. The mixture was subjected to catalytic reduction at normal temperature at normal pressure. After the reduction, 10% palladium-carbon was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 56.1 g of 5-dimethylamino-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine.
A white powder
Melting point: 120.degree.-122.degree. C.
Reference Example 3
In 15 ml of chloroform were dissolved 0.7 g of 5-hydroxy-7-chloro-1-[2-methoxy-4-(2methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine, 0.83 g of dimethylaminopyridine and 0.72 g of dimethylaminopyridine hydrochloride. Thereto were added 0.56 g of N-tert-butoxy-carbonyl-L-methionine and 0.93 g of dicyclohexylcarbodi-imide. The mixture was stirred at room temperature for 3 hours. 3 ml of methanol and 0.7 ml of acetic acid were added, and the mixture was stirred at room temperature for 30 minutes. The resulting insolubles were removed by filtration. The filtrate was mixed with a 5% aqueous sodium hydrogensulfate solution, followed by extraction with dichloromethane. The dichloromethane layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution in this order and dried over magnesium sulfate. The resulting dichloromethane solution was concentrated for solvent removal. The residue was purified by silica gel column chromatography [elutant: dichloromethane/methanol=150/1] to obtain 1.27 g of 5-(N-tert-butoxycarbonyl-L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine.
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.29-2.92, 3.35-5.40, 6.09-6.35 (total 30H, m, 1.45(s), 1.47(s)), 6.61-8.00 (12H, m)
The following compounds were obtained in the same manner as in Reference Example 3, using respective starting materials.
5-(N-tert-butoxycarbonyl-L-alanyloxy)-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
.sup.1 H-NMR (CDCl.sub.3) .delta.: 0.95-3.05, 3.29-5.22, 5.95-6.27 (total 23H, m), 6.86-8.17 (13H, m)
5-(N-tert-butoxycarbonyl-glycyloxy)-1-[2-chloro-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.30-3.09, 3.69-5.29, 5.91-6.35 (total 21H, m), 6.77-8.48 (13H, m)
5-(N-tert-butoxycarbonyl-L-methionyloxy-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.05-3.06, 3.25-3.63, 4.01-5.37 (total 26H, m), 5.97-6.28 (1H, m), 6.72-8.72 (13H, m)
Reference Example 4
The following compounds were obtained in the same manner as in Reference Example 1, using respective starting materials.
5-(3-Hydroxypropoxy)-7-chloro-1-(2-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.4-2.6 (7H, m), 2.7-3.0 (1H, m), 3.0-4.1 (7H, m), 4.3-5.1 (2H, m), 6.6-7.0 (2H, m), 7.1-8.0 (4H, m)
5-[3-(p-Toluenesulfonyloxy)propoxy]-7-chloro-1-(2-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.:
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.35-2.65 (9H, m), 2.65-3.0 (1H, m), 3.05-3.95 (5H, m), 3.95-4.45 (2H, m), 4.5-5.05 (2H, m), 6.6-7.05 (2H, m), 7.1-8.05 (8H, m)
5-(2-Hydroxyethoxy)-7-chloro-1-(2-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.35-2.6 (4H, m), 2.7-3.0 (1H, m), 3.0-4.1 (7H, m), 4.35-5.0 (2H, m), 6.6-7.0 (2H, m), 7.1-8.05 (5H, m)
5-[2-(p-Toluenesulfonyloxy)ethoxy]-7-chloro-1-(2-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.35-2.6 (7H, m), 2.65-2.95 (1H,m), 3.0-3.95 (5H, m), 4.1-5.05 (4H, m), 6.55-7.05 (2H, m), 7.05-7.6 (4H, m), 7.65-8.0 (4H, m)
5-Methoxycarbonylmethyl-7-chloro-1-(2-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.2-1.5 (1H, m), 1.5-2.3 (3H, m), 2.6-2.95 (2H, m), 2.95-3.25 (1H, m), 3.3-4.2 (7H, m), 4.45-5.15 (1H, m), 6.65-6.85 (1H, m), 6.85-7.0 (1H, m), 7.02 (1H, d, J=1.8 Hz), 7.1-8.05 (3H, m)
5-Methoxycarbonylmethyl-7-chloro-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A light yellow prism
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.2-1.75 (2H, m), 1.75-2.3 (2H, m), 2.6-3.15 (2H, m), 3.15-3.4 (1H, m), 3.76 (3H, s), 4.05-5.2 (2H, m), 6.54 (1H, d, J=8.3 Hz), 6.92 (1H, dd, J=8.3 Hz, 2.2 Hz), 7.1-7.25 (1H, m), 7.52 (2H, d, J=8.8 Hz), 8.06 (2H, dd, J=8.8 Hz, 2 Hz)
5-[2-(p-Toluenesulfonyloxy)ethyl]-7-chloro-1-(2-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.0-1.4 (1H, m), 1.4-2.15 (4H, m), 2.15-2.4 (1H, m), 2.4-2.55 (3H, m), 2.9-3.3 (2H, m), 3.35-4.5 (6H, m), 6.6-8.0 (10H, m)
5-Cyanomethyl-7-chloro-1-(3-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A white powder
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.38-2.37, 2.66-4.22, 4.41-4.68, 5.03-5.24 [total 12H, m, (3.79(s))], 6.55-8.00 [6H, m, (6.76 (dd, J=1.6 Hz, 8.3 Hz)), [6.92 (d, J=1.4 Hz)], [7.23 (d, J=2.0 Hz))]
5-Ethoxycarbonylmethyl-7-chloro-1-(3-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A white powder
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.25-2.26, 2.61-4.66, 5.01-5.25 [total 17H, m, (1.28 (3H, t, J=7.1 Hz)) (3.83 (3H, s))], 6.57 (1H, d, J=9.5 Hz), 6.85-7.31 (4H, m), 7.63 (1H, d, J=8.3 Hz)
Methyl N-{[7-fluoro-1-(2-chloro-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepin-5-yl]oxymethylcarbonyl}-L-alanate
A yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.37-1.53 (3H, m), 1.54-4.25 (8H, m), 4.40-5.05 (3H, m), 6.65-8.35 (7H, m)
Methyl N-{[7-fluoro-1-(2-chloro-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepin-5-yl]oxymethylcarbonyl}-L-prolinate
A yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.37-4.19 (16H, m), 4.23-5.07 (3H, m), 6.56-8.43 (6H, m)
5-Methoxycarbonylmethyl-7-chloro-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A yellow powder
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.50-2.31 (4H, m), 2.45-5.20 (5H, m), 2.57, 2.61 (3H, s), 3.75 (3H, s), 6.55 (1H, d, J=8.4 Hz), 6.89 (1H, dd, J=2.3 Hz, 8.4 Hz), 7.09 (1H, d, J=2.3 Hz), 7.16 (1H, d, J=8.4 Hz), 7.78 (1H, dd, J=2.2 Hz, 8.4 Hz), 8.00 (1H, d, J=2.2 Hz)
5-Methoxycarbonylmethyl-7-chloro-1-(2-chloro-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A yellow powder
Melting point: 133.degree.-134.degree. C.
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.05-2.28 (4H, m), 2.57-3.05 (2H, m), 3.06-3.32 (1H, m), 3.33-3.85 (1H, m), 3.74 (3H, s), 4.39-4.67 (1H, m), 6.78-7.19 (3H, m), 7.38 (1H, d, J=8.2 Hz), 7.93 (1H, dd, J=8.2 Hz, 2.1 Hz), 8.17 (1H, d, J=2.1 Hz)
5-Methoxycarbonylmethyl-7-chloro-1-(3-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A slightly yellow powder
Melting point: 139.5.degree.-141.degree. C.
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.16-2.31 (4H, m), 2.61-3.09 (2H, m), 3.12-3.40 (1H, m), 3.41-5.23 (2H, m), 3.72 (3H, s), 3.83 (3H, s), 6.58 (1H, d, J=8.3 Hz), 6.85-7.24 (4H, m), 7.63 (1H, d, J=8.3 Hz)
5-[2-(p-Toluenesulfonyloxy)ethoxy]-7-chloro-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.12-5.14 (17H, m), 6.50 (1H, dd, J=16 Hz, 8.4 Hz), 6.91 (1H, d, J=8.4 Hz), 7.10-8.45 (8H, m)
5-[3-(p-Toluenesulfonyloxy)propoxy]-7-chloro-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Slightly yellow and amorphous
.sup.1 H-NMR (CDCl;.sub.3) .delta.: 1.09-3.08 (13H, m), 3.09-5.18 (6H, m), 6.50 (1H, dd, J=17.8 Hz, 8.4 Hz), 6.84-8.42 (9H, m)
5-(2-Methoxyacetyloxy)-7-chloro-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.7-3.2 (5H, m), 3.36, 3.46 (total 3H, s), 4.10, 4.29 (total 2H, s), 4.7-5.2 (1H, m), 6.1-6.2 (1H, m), 6.57 (1H, d, J=8.3 Hz), 6.9-7.1 (1H, m), 7.2-7.5 (1H, m), 7.5-7.6 (2H, m), 8.0-8.2 (2H, m)
5-Methoxycarbonylmethyl-7-fluoro-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A light yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.22-1.70 (2H, m), 1.77-2.23 (2H, m), 2.65-3.04 (2H, m), 3.12-3.30 81H, m), 3.75 (3H, s), 4.07-4.35 (1H, m), 4.40-5.18 (1H, m), 6.44-6.70 (2H, m), 6.80-7.05 (1H, m), 7.40-7.60 (2H, m), 7.95-8.10 (2H, m), 8.15-8.28 (1H, m)
5-Hydroxy-7-fluoro-1-(2-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.52-2.36 (4H, m), 2.68-2.95 (1H, m), 3.12 (3H, brs), 3.44-4.03 (3H, m), 4.65-5.17 (2H, m), 6.50-6.76 (2H, m), 6.80-8.03 (4H, m)
5-(3-Morpholinopropoxy)-7-fluoro-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.43-2.62 (11H, m), 2.53, 2.59 (3H, s), 2.72-3.03 (1H, m), 3.10-3.83 (7H, m), 4.36-5.07 (2H, m), 6.46-6.71 (2H, m), 6.86-8.20 (4H, m)
5-[3-(1-Imidazolyl)propoxy]-7-fluoro-1-(2-methyl-4-nitro-benzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A light yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.37-2.63 (6H, m), 2.52, 2.59, 2.60 (total 3H, s), 2.73-3.05 (1H, m), 3.10-3.80 (2H, m), 3.96-5.07 (4H, m), 6.46-6.72 (2H, m), 6.85-7.20 (4H, m), 7.26-8.23 (3H, m)
5-Methoxycarbonylmethyl-7-fluoro-1-(2-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.19-2.26 (4H, m), 2.57-2.90 (2H, m), 2.95-3.20 (1H, m), 3.35-4.27 (4H, m), 3.75 (3H, s), 4.48-5.12 (1H, m), 6.52-6.67 (1H, m), 6.71-8.02 (5H, m)
5-[2-(p-Toluenesulfonyloxy)ethoxy]-7-fuoro-1-(2-methoxy-4-nitrobenzoyl)-2,3,4,5-1H-benzoazepine
A lighty yellow oil
H-NMR (CDCl.sub.3) .delta.: 1.34-1.88 (2H, m), 1.95-2.38 (2H, m), 2.40, 2.43, 2.45 (total 3H, s), 2.70-2.91 (1H, m), 3.43-4.00 (5H, m), 4.13-4.47 (2H, m), 4.56-5.03 (2H, m), 6.54-7.96 (10H, m)
5-(3-Hydroxypropoxy)-7-fluoro-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.38-2.67 (8H, m), 2.53, 2.59 (total 3H, s), 2.72-3.08 (1H, m), 3.14-3.93 (5H, m), 4.25-5.11 (2H, m), 6.47-6.73 (2H, m), 6.86-8.18 (4H, m)
5-[3-(p-Toluenesulfonyloxy)propoxy]-7-fluoro-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) 1.38-2.63 (6H, m), 2.42, 2.44 (total 3H, s), 2.52, 2.57, 2.58 (total 3H, s), 2.73-3.03 (1H, m), 3.10-3.83 (2H, m), 4.05-5.03 (4H, m), 6.45-6.70 (2H, m), 6.86-8.19 (8H, m)
5-[3-(1-Pyrrolidinyl)propoxy]-7-fluoro-1-(2-methyl-4-nitro-benzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine hydroiodide
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.40-1.90 (2H, m), 1.95-2.63 (7H, m), 2.53, 2.58, 2.59 (total 3H, s), 2.75-3.90 (10H, m), 4.42-4.98 (2H, m), 5.22 (1H, brs), 6.47-6.68 (2H, m), 6.92-7.38 (2H, m), 7.56-8.32 (2H, m)
5-(2-Hydroxyethoxy)-7-fluoro-1-(2-ethyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A light yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.38-2.63 (5H, m), 2.53, 2.58, 2.59 (total 3H, s), 2.76-3.93 (4H, m), 4.40-5.00 (2H, m), 6.49-8.18 (6H, m)
5-Hydroxy-7-fluoro-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A light yellow powder
.sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.40-2.31 (4H, m), 2.49, 2.54, 2.55 (total 3H, s), 2.62-3.43 (1H, m), 4.55-5.06 (2H, m), 5.77 (1H, brs), 6.66-6.98 (2H, m), 7.10-7.50 (2H, m), 7.60-8.36 (2H, m)
7-Hydroxymethyl-7-fluoro-1-(2-methoxy-4-nitrobenzoyl)-2,3,4,5,-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.13-1.40 (1H, m), 1.46-2.31 (3H, m), 2.40-3.50 (2H, m), 2.66 (1H, brs), 3.55-4.13 (5H, m), 4.53-5.03 (1H, m), 6.57 (1H, dt, J=8.5 Hz, 2.8 Hz), 6.67-7.18 (2H, m), 7.28-8.03 (3H, m)
5-(2-Hydroxyethyl)-7-chloro-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
White and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.38-2.35 (7H, m), 2.36-4.00 (7H, m), 4.30-4.53 (1H, m), 6.57 (1H, d, J=8.3 Hz), 6.89 (1H, dd, J=2.2 Hz, 8.3 Hz), 7.03 (1H, d, J=8.3 Hz), 7.13 (1H, d, J=2.2 Hz), 7.67-7.82 (1H, m), 7.91-8.08 (1H, m)
5-[2-(p-Toluenesulfonyloxy)ethyl]-7-chloro-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A white powder
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.07-2.78 [13H,m (2.46, s)], 2.79-3.38 (2H, m), 3.97-4.48 (2H, m), 6.56 (1H, d, J=8.2 Hz), 6.90 (1H, dd, J=2.2 Hz, 8.2 Hz), 7.02 (1H, d, J=2.2 Hz), 6.93 (1H, d, J=8.4 Hz), 7.20-7.64 (2H, m), 7.72-7.91 (3H, m), 7.98 (1H, d, J=2.1 Hz)
Reference Example 5
The following compounds were obtained in the same manner as in Reference Example 2, using respective starting materials.
5-[3-(p-Toluenesulfonyloxy)propoxy]-7-chloro-1-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Pink and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.3-2.35 (6H, m), 2.44 (3H, s), 2.55-4.0 (8H, m), 4.25 (2H, t, J=6 Hz), 4.5-5.15 (2H, m), 5.93 (1H, s), 6.1-6.45 (1H, m), 6.66 (1H, d, J=8.4 Hz), 6.88 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.99 (1H, d, J=8 Hz), 7.29 (1H, s), 7.35 (2H, d, J=8.2 Hz), 7.81 (2H, d, J=8.3 Hz)
5-[2-(p-Toluenesulfonyloxy)ethoxy]-7-chloro-1-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.3-2.35 (4H, m), 2.45 (3H, s), 2.65-2.95 (1H, m), 3.05-4.0 (7H, m), 4.0-5.1 (4H, m), 5.90 (1H, brs), 6.05-6.4 (1H, m), 6.64 (1H, d, J=8.3 Hz), 6.75-7.15 (2H, m), 7.15-7.55 (3H, m), 7.83 (2H, d, J=8.2 Hz)
5-Methoxycarbonylmethyl-7-chloro-1-(2-methoxy-4-amino-benzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.15-2.3 (4H, m), 2.55-3.25 (3H, m), 3.3-4.05 (9H, m), 4.1-4.7 (1H, m), 5.85-6.45 (2H, m), 6.65-6.8 (1H, m), 6.8-7.4 (3H, m)
5-Methoxycarbonylmethyl-7-chloro-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A colorless prism (recrystallized from ethanol)
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.15-2.3 (4H, m), 2.5-3.05 (2H, m), 3.05-3.3 (1H, m), 3.3-4.3 (6H, m), 4.35-5.3 (1H, m), 6.43 (2H, d, J=8.5 Hz), 6.61 (1H, d, J=8.4 Hz), 6.85-7.0 (1H, m), 7.0-7.4 (3H, m)
5-[2-(p-Toluenesulfonyloxy)ethyl]-7-chloro-1-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.0-2.4 (6H, m), 2.46 (3H, s), 2.5-4.4 (10H, m), 5.85-7.25 (6H, m), 7.3-7.5 (2H, m), 7.65-7.9 (2H, m)
5-Cyanomethyl-7-chloro-1-(3-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A white powder
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.21-2.33, 2.40-4.70, 5.05-5.39 (total 14H, m), 6.38-7.42 (4H, m), 6.43 (1H, d, J=8.1H), 7.04 (1H, dd, J=2.3 Hz, 8.4 Hz)
5-Ethoxycarbonylmethyl-7-chloro-1-(3-methoxy-4-amino-benzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.11-2.28 [7H, m, (1.27 (t, J=7.1 Hz))], 2.49-4.61, 5.01-5.35 (total 12H, 3.68(s)), 6.40 (1H, d, J=8.0 Hz), 6.49-7.44 (4H, m), 6.95 (1H, dd, J=2.3 Hz, 8.3 Hz)
5-Methoxycarbonylmethyl-7-chloro-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
White and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 0.83-2.47 (4H, m), 2.37 (3H, s), 2.48-5.25 (7H, m), 3.72 (3H, s), 6.16 (1H, d, J=8.3 Hz), 6.41 (1H, s), 6.54 (1H, d, J=8.3 Hz), 6.64 (1H, d, J=8.2 Hz), 6.90 (1H, d, J=8.2 Hz), 7.00-7.42 (1H, m)
Methyl N-{[7-fluoro-1-(2-chloro-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepin-5-yl]oxymethylcarbonyl}-L-alanate
Slightly yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.35-1.51 (3H, m), 1.51-5.14 (15H, m), 6.10-7.42 (7H, m)
Methyl N-{[7-fluoro-1-(2-chloro-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepin-5-yl]oxymethylcarbonyl}-L-prolinate
Slightyly yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.33-2,64 (8H, m), 2.64-3.00 (1H, m), 3.01-4.44 (9H, m), 4.45-5.13 (3H, m), 6.12-7.46 (6H, m)
5-Methoxycarbonylmethyl-7-chloro-1-(2-chloro-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.09-2.36 (4H, m), 2.45-5.19 (7H, M), 3.71 (3H, s), 6.12-7.50 (2H, m), 6.27 (1H, dd. J=2.1 Hz. 8.3 Hz), 6.54 (1H, d, J=2.1 Hz), 6.92 (1H, d, J=2.1 Hz), 7.05 (1H, dd, J=2.1 Hz, 6.1 Hz)
5-Methoxycarobnylmethyl-7-chloro-1-(3-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Slightly yellow and amorphous
.sup.1 -NMR (CDCl.sub.3) .delta.: 1.01-2.29 (4H, m), 2.44-3.31 (3H, m), 3.32-5.29 (4H, m), 3.68 (3H, s), 3.71 (3H, s), 6.41 (1H, d, J=8.0 Hz), 6.50-6.78 (2H, m), 6.79-6.91 (1H, m), 6.95 (1H, d, J=8.4 Hz), 7.04-7.24 (1H, m)
5-[2-(p-Toluenesulfonyloxy)ethoxy]-7-chloro-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.01-2.52 (4H, m), 2.32 (3H, s), 2.43 (3H, s), 2.53-4.78 (9H, m), 5.86-8.03 (10H, m)
5-[3-(p-Toluenesulfonyloxy)propoxy]-7-chloro-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Slightly yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.13-3.03 (7H, m), 2.33, 2.43 (6H, each s), 3.04-5.18 (8H, m), 5.98-8.07 (10H, m)
5-(2-Methoxyacetyloxy)-7-chloro-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A white powder
Melting point: 166.degree.-169.degree. C. (recrystallized from dichloromethane-diethyl ether)
5-Methoxycarbonylmethyl-7-fluoro-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A light yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.06-2.20 (4H, m), 2.40-3.22 (3H, m), 3.26-4.28 (3H, m), 3.71 (3H, s), 4.35-5.30 (1H, m), 6.23-6.45 (2H, m), 6.53-6.72 (2H, m), 6.75-7.20 (3H, m)
5-(3-Morpholinopropoxy)-7-fluoro-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.; 1.41-2.63 (10H, m), 2.33 (3H, s), 2.75-3.00 (1H, m), 3.32-3.92 (8H, m), 4.27-5.16 (2H, m), 5.98-6.75 (4H, m), 6.80-7.38 (2H, m)
5-[2-(p-Toluenesulfonyloxy)ethoxy]-7-fluoro-1-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A light yellow oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.29-2.30 (4H, m), 2.45 (3H, s), 2.62-2.88 (1H, m), 2.96-3.97 (4H, m), 3.46 (3H, s), 4.08-4.43 (2H, m), 4.52-5.07 (2H, m), 5.86-6.00 (1H, m), 6.06-6.38 (1H, m), 6.47-6.75 (2H, m), 6.90-7.40 (2H, m), 7.36 (2H, d, J=8.2 Hz), 7.82 (2H, d, J=8.2 Hz)
5-[3-(1-Pyrrolidinyl)propoxy]-7-fluoro-1-(2-methyl-4-amino-benzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.40-2.70 (16H, m), 2.33 (3H, s), 2.73-2.96 (1H, m), 3.30-3.86 (4H, m), 4.28-5.14 (2H, m), 6.00-6.25 (1H, m), 6.30-6.72 (4H, m), 6.75-7.35 (1H, m)
5-[2-(1,3-Dioxo-1,2,3,4,5,6,7-octahydroisoindol-2-yl)ethoxy]-7-fluoro-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A colorless oil
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.30-2.47 (13H, m), 2.33 (3H, s), 2.66-4.01 (8H, m), 4.32-5.13 (2H, m), 6.04-6.26 (4H, m), 6.80-7.36 (2H, m)
5-Methoxycarbonylmethyl-7-fluoro-1-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Light yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.41-2.15 (4H, m), 2.57-3.14 (3H, m), 3.35-4.31 (3H, m), 3.59 (3H, s), 3.74 (3H, s), 4.45-5.15 (1H, m), 5.88-6.17 (2H, m), 6.51-7.07 (4H, m)
5-[2-(p-Toluenesulfonyloxy)ethyl]-7-chloro-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Yellow and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.10-2.53 [13H, m (2.31, 2.45, each 3H, each s)], 2.54-4.46 (6H, m), 5.95-6.70 (3H, m), 6.71-7.56 [5H, m (7.36, 2H, d, J=8.1 Hz)], 7.80 (2H, d, J=8.1 Hz]
Reference Example 6
The following compound was obtained in the same manner as in Reference Example 1, using appropriate starting materials.
5-Ethoxycarbonylmethoxy-7-chloro-1-(2-methoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A light yellow powder
Melting point: 123.degree.-124.degree. C.
Reference Example 7
The following compounds were obtained in the same manner as in Reference Example 2, using respective starting materials.
5-(2-Chloroanilino)carbonylmethyl-7-chloro-1-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.ppm: 1.09-2.31 (5H, m), 2.32-5.74 (6H, m), 3.84 (3H, s), 5.80-8.82 (11H, m)
5-Methoxycarbonylmethoxy-7-chloro-1-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.ppm: 1.17-2.59 (4H, m), 2.60-5.19 (13H, m), 5.83-7.55 (6H, m)
5-Carboxymethyl-7-chloro1-1-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.ppm: 1.08-2.24 (5H, m), 2.42-4.67 (6H, m), 3.52 (3H, s), 5.78-7.46 (7H, m)
5-(2-Chlorobenzoyl)amino-7-chloro-1-[2-methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
A brown powder
Melting point: 205.degree.-206.degree. C. (recrystallized from acetone-n-hexane)
Example 1
38.8 g of potassium carbonate was added to a solution of 50 g of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 400 ml of acetone and 200 ml of water. To the mixture was added 66.5 g of 4-[2-(2-chloro-phenyl)acetylamino]benzoyl chloride with ice-cooling and stirring. The mixture was stirred overnight at room temperature. The reaction mixture was mixed with water, followed by extraction with dichloromethane. The dichloromethane layer was dried over magnesium sulfate and then subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography and then recrystallized from methanol to obtain 99.3 g of 5-dimethylamino-1-{4-[2-(2-chlorophenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine.
A white powder
Melting point: 187.degree.-189.degree. C.
Example 2
15 ml of thionyl chloride was added to 0.44 g of 2-chlorophenylacetic acid. The mixture was stirred at room temperature for 2 hours. The reaction mixture was subjected to distillation to remove the remaining thionyl chloride and then to azeotropy with toluene twice to completely remove the thionyl chloride. The residue was dissolved in 10 ml of dichloromethane. 0.36 ml of triethylamine was added, with ice-cooling, to a dichloromethane solution containing 0.40 g of 5-dimethylamino-1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine. Thereto was dropwise added the above obtained 2-(2-chlorophenyl)acetyl chloride solution. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was water-washed twice, then dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elutant: chloroform/methanol=200/1) and then recrystallized from methanol-diethyl ether to obtain 0.29 g of 5-dimethylamino-1-{4-[2-(2-chlorophenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine.
A white powder
Melting point: 187.degree.-189.degree. C.
Tables 1 to 42 (Examples 3 to 85) and their NMR data appear here.
The following compounds were obtained in the same manner as in Examples 1 and 2, using respective raw materials.
TABLE 1______________________________________ ##STR37##Example 3Structure: ##STR38## ##STR39##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 153-154.5.degree. C.Form: free______________________________________
TABLE 2______________________________________Example 4Structure: ##STR40## ##STR41##Crystal form: white powderRecrystallization solvent: diethyl etherMelting point: 226-231.degree. C.Form: freeExample 5Structure: ##STR42## ##STR43##Crystal form: white powderRecrystallization solvent: ethanol-n-hexaneMelting point: 224-229.degree. C.Form: free______________________________________
TABLE 3______________________________________Example 6Structure: ##STR44## ##STR45## ##STR46##Crystal form: white powderRecrystallization solvent: ethanol-diethyl etherMelting point: 179-181.degree. C.Form: hydrochlorideExample 7Structure: ##STR47## ##STR48##Crystal form: colorless and amorphousForm: freeNMR: 1)______________________________________
TABLE 4______________________________________Example 8Structure: ##STR49## ##STR50##Crystal form: colorless and amorphousForm: freeNMR: 2)Example 9Structure: ##STR51## ##STR52## ##STR53##Crystal form: colorless and amorphousForm: freeNMR: 3)______________________________________
TABLE 5______________________________________Example 10Structure: ##STR54## ##STR55##Crystal form: colorless and amorphousForm: freeNMR: 4)Example 11Structure: ##STR56## ##STR57##Crystal form: colorless and amorphousForm: freeNMR: 5)______________________________________
TABLE 6______________________________________Example 12Structure: ##STR58## ##STR59## ##STR60##Crystal form: colorless and amorphousForm: freeNMR: 6)Example 13Structure: ##STR61## ##STR62##Crystal form: colorless and amorphousForm: freeNMR: 7)______________________________________
TABLE 7______________________________________Example 14Structure: ##STR63## ##STR64##Crystal form: colorless and amorphousForm: freeNMR: 8)Example 15Structure: ##STR65## ##STR66##Crystal form: colorless and amorphousForm: freeNMR: 9)______________________________________
TABLE 8______________________________________Example 16Structure: ##STR67## ##STR68##Crystal form: colorless and amorphousForm: freeNMR: 10)Example 17Structure: ##STR69## ##STR70##Crystal form: colorless and amorphousForm: freeNMR: 11)______________________________________
TABLE 9______________________________________Example 18Structure: ##STR71## ##STR72##Crystal form: colorless and amorphousForm: freeNMR: 12)Example 19Structure: ##STR73## ##STR74##Crystal form: colorless and amorphousForm: freeNMR: 13)______________________________________
TABLE 10______________________________________Example 20Structure: ##STR75## ##STR76##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 189.5-191.degree. C.Form: freeExample 21Structure: ##STR77## ##STR78##Crystal form: colorless and amorphousForm: freeNMR: 14)______________________________________
TABLE 11______________________________________Example 22Structure: ##STR79## ##STR80##Crystal form: colorless and amorphousForm: freeNMR: 15)Example 23Structure: ##STR81## ##STR82##Crystal form: colorless and amorphousForm: freeNMR: 16)______________________________________
TABLE 12______________________________________Example 24Structure: ##STR83## ##STR84##Crystal form: colorless and amorphousForm: freeNMR: 17)Example 25Structure: ##STR85## ##STR86##Crystal form: colorless and amorphousForm: freeNMR: 18)______________________________________
TABLE 13______________________________________Example 26Structure: ##STR87## ##STR88##Crystal form: colorless and amorphousForm: freeNMR: 19)Example 27Structure: ##STR89## ##STR90##Crystal form: colorless and amorphousForm: freeNMR: 20)______________________________________
TABLE 14______________________________________Example 28Structure: ##STR91## ##STR92##Crystal form: colorless and amorphousForm: freeNMR: 21)Example 29Structure: ##STR93## ##STR94##Crystal form: colorless and amorphousForm: freeNMR: 22)______________________________________
TABLE 15______________________________________Example 30Structure: ##STR95## ##STR96##Crystal form: colorless and amorphousForm: freeNMR: 23)Example 31Structure: ##STR97## ##STR98##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 192.5-194.5.degree. C.Form: free______________________________________
TABLE 16______________________________________Example 32Structure: ##STR99## ##STR100##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 210-21.degree. C.Form: freeExample 33Structure: ##STR101## ##STR102##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 221-222.degree. C.Form: free______________________________________
TABLE 17______________________________________Example 34Structure: ##STR103## ##STR104##Crystal form: colorless and amorphousForm: freeNMR: 24)Example 35Structure: ##STR105## ##STR106##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 175-176.degree. C.Form: free______________________________________
TABLE 18______________________________________Example 36Structure: ##STR107## ##STR108##Crystal form: white powderRecrystallization solvent: methanol-solvent etherMelting point: 212-215.degree. C.Form: freeExample 37Structure: ##STR109## ##STR110##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 210-211.degree. C.Form: free______________________________________
TABLE 19______________________________________Example 38Structure: ##STR111## ##STR112##Crystal form: white powderRecrystallization solvent: methanolMelting point: 217-218.degree. C.Form: freeExample 39Structure: ##STR113## ##STR114##Crystal form: white powderRecrystallization solvent: methanolMelting point: 245-247.degree. C.Form: free______________________________________
TABLE 20______________________________________Example 40Structure: ##STR115## ##STR116##Crystal form: colorless and amorphousForm: freeNMR: 25)Example 41Structure: ##STR117## ##STR118##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 214-216.degree. C.Form: free______________________________________
TABLE 21______________________________________Example 42Structure: ##STR119## ##STR120##Crystal form: colorless and amorphousRecrystallization solvent: methanolMelting point: 208.5-209.degree. C.Form: freeExample 43Structure: ##STR121## ##STR122##Crystal form: white powderRecrystallization solvent: methanolMelting point: 184-186.degree. C.Form: free______________________________________
TABLE 22______________________________________Example 44Structure: ##STR123## ##STR124##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 195-196.degree. C.Form: freeExample 45Structure: ##STR125## ##STR126##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 214-215.degree. C.Form: free______________________________________
TABLE 23______________________________________Example 46Structure: ##STR127## ##STR128##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 145-146.5.degree. C.Form: freeExample 47Structure: ##STR129## ##STR130##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 241-241.5.degree. C.Form: free______________________________________
TABLE 24______________________________________Example 48Structure: ##STR131## ##STR132##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 119-120.degree. C.Form: freeExample 49Structure: ##STR133## ##STR134##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 142.5-146.5.degree. C.Form: free______________________________________
TABLE 25______________________________________Example 50:Structure: ##STR135## ##STR136##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 145-146.degree. C.Form: freeExample 51Structure: ##STR137## ##STR138##Crystal form: colorless and amorphousForm: freeNMR: 26)______________________________________
TABLE 26______________________________________Example 52Structure: ##STR139## ##STR140##Crystal form: colorless and amorphousForm: freeNMR: 27)Example 53Structure: ##STR141## ##STR142##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 199-202.degree. C.Form: free______________________________________
TABLE 27______________________________________Example 54Structure: ##STR143## ##STR144##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 171-172.degree. C.Form: freeExample 55Structure: ##STR145## ##STR146##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 243.5-245.degree. C.Form: free______________________________________
TABLE 28______________________________________Example 56Structure: ##STR147## ##STR148##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 239-240.degree. C.Form: freeExample 57Structure: ##STR149## ##STR150##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 162-163.degree. C.Form: free______________________________________
TABLE 29______________________________________Example 58Structure: ##STR151## ##STR152##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 134-135.degree. C.Form: freeExample 59Structure: ##STR153## ##STR154##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 177-178.degree. C.Form: free______________________________________
TABLE 30______________________________________Example 60Structure: ##STR155## ##STR156##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 168-169.degree. C.Form: freeExample 61Structure: ##STR157## ##STR158## ##STR159##Crystal form: colorless and amorphousForm: freeNMR: 28)______________________________________
TABLE 31______________________________________Example 62Structure: ##STR160## ##STR161## ##STR162##Crystal form: colorless and amorphousForm: freeNMR: 29)Example 63Structure: ##STR163## ##STR164##Crystal form: colorless and amorphousForm: freeNMR: 30)______________________________________
TABLE 32______________________________________Example 64Structure: ##STR165## ##STR166##Crystal form: colorless and amorphousForm: freeNMR: 31)Example 65Structure: ##STR167## ##STR168##Crystal form: colorless and amorphousForm: freeNMR: 32)______________________________________
TABLE 33______________________________________Example 66Structure: ##STR169## ##STR170##Crystal form: colorless and amorphousForm: freeNMR: 33)Example 67Structure: ##STR171## ##STR172##Crystal form: colorless and amorphousForm: freeNMR: 34)______________________________________
TABLE 34______________________________________Example 68Structure: ##STR173## ##STR174##Crystal form: colorless and amorphousForm: freeNMR: 35)Example 69Structure: ##STR175## ##STR176##Crystal form: colorless and amorphousForm: freeNMR: 36)______________________________________
TABLE 35______________________________________Example 70Structure: ##STR177## ##STR178##Crystal form: colorless and amorphousForm: freeNMR: 37)Example 71Structure: ##STR179## ##STR180## ##STR181##Crystal form: colorless and amorphousForm: freeNMR: 38)______________________________________
TABLE 36______________________________________Example 72Structure: ##STR182## ##STR183## ##STR184##Crystal form: colorless and amorphousForm: freeNMR: 39)Example 73Structure: ##STR185## ##STR186##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 128-130.degree. C.Form: free______________________________________
TABLE 37______________________________________Example 74Structure: ##STR187## ##STR188## ##STR189##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 139-140.degree. C.Form: freeExample 75Structure: ##STR190## ##STR191## ##STR192##Crystal form: colorless and amorphousForm: freeNMR: 40)______________________________________
TABLE 38______________________________________Example 76Structure: ##STR193## ##STR194## ##STR195##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 194-196.degree. C.Form: freeExample 77Structure: ##STR196## ##STR197## ##STR198##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 241-243.degree. C.Form: free______________________________________
TABLE 39______________________________________Example 78Structure: ##STR199## ##STR200## ##STR201##Crystal form: white powderRecrystallization solvent: dichloromethane-diethyl etherMelting point: 129.5-131.5.degree. C.Form: freeExample 79Structure: ##STR202## ##STR203## ##STR204##Crystal form: white powderRecrystallization solvent: dichloromethane-diethyl etherMelting point 136-138.degree. C.Form: free______________________________________
TABLE 40______________________________________Example 80Structure: ##STR205## ##STR206## ##STR207##Crystal form: white powderRecrystallization solvent: methanol-diethyl etherMelting point: 178-179.degree. C.Form: freeExample 81Structure: ##STR208## ##STR209## ##STR210##Crystal form: colorless and amorphousForm: freeNMR: 41)______________________________________
TABLE 41______________________________________Example 82Structure: ##STR211## ##STR212## ##STR213##Crystal form: colorless and amorphousForm: freeNMR: 42)Example 83Structure: ##STR214## ##STR215## ##STR216##Crystal form: colorless and amorphousForm: freeNMR: 43)______________________________________
TABLE 42______________________________________Example 84Structure: ##STR217## ##STR218## ##STR219##Crystal form: colorless and amorphousForm: freeNMR: 44)Example 85Structure: ##STR220## ##STR221## ##STR222##Crystal form: colorless and amorphousForm: freeNMR: 45)______________________________________
1) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.41-1.72 (2H, m), 1.86-2.13 (1H, m), 2.19-2.48 (1H, m), 2.64-3.18 (4H, m), 4.20-4.83 (2H, m), 6.44-7.10 (3H, m), 7.17-8.15 (7H, 9.32 (1H, brs), 9.91 (1H, s), 10.72 (1H, s)
2) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.40-3.20 (11H, m), 3.27-5.05 (2H, m), 6.38-8.37 (11H, m)
3) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.40-3.30 (14H, m), 3.30-5.20 (2H, m), 6.70-8.60 (11H, m)
4) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.47-5.16 (7H, m), 6.30-8.23 (11H, m) 8.90-9.10 (1H, m), 10.10-10.55 (1H, m)
5) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.30-5.28 (9H, m), 6.19-8.13 (11H, m), 9.44-9.60 (1H, m), 10.56-10.94 (1H, m)
6) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.46-5.10 (21H, m), 6.43-8.44 (11H, m)
7) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.00-2.55 (10H, m), 2.33 (3H, s), 2.57-3.14 (1H, m), 3.39-3.78 (1H, m), 3.61 (2H, s), 3.84-5.20 (1H, m), 6.40-7.71 (12H, m)
8) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.05-2.57 (10H, m), 2.35 (3H, s), 2.57-3.15 (1H, m), 3.30-3.82 (1H, m), 3.63 (2H, s), 3.89-5.19 (1H, m), 6.42-7.70 (12H, m)
9) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.10-3.18 (11H, m), 3.32-3.80 (1H, m), 3.57 (2H, s), 3.95-5.20 (1H, m), 6.43-7.68 (12H, m), 8.13-8.44 (1H, m)
10) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.06-3.21 (11H, m), 3.313.90 (1H, m), 3.54 (2H, s), 3.90-5.18 (1H, m), 6.38-7.65 (12H, m), 8.26-8.62 (1H, m)
11) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.10-3.14 (11H, m), 3.34-3.75 (1H, m), 3.65 (2H, s), 3.89 (3H, s), 3.95-5.20 (1H, 6.45-7.70 (12H, m), 7.72-8.05 (1H, m)
12) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.09-3.16 (11H, m), 3.35-5.20 (2H, m), 3.61 (2H, s), 3.78 (3H, s), 6.38-7.64 (12H, m), 7.70 (1H, s)
13) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.10-3.25 (11H, m), 3.36-3.71 (3H, m), 3.75-3.90 (3H, m), 3.95-5.20 (1H, m), 6.42-7.68 (12H, m)
14) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.08-3.21 (11H, m), 3.36-3.79 (1H, m), 3.59 (2H, s), 3.91-5.19 (1H, m), 6.45-7.65 (12H, m), 8.04-8.35 (1H, m)
15) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.08-3.20 (11H, m), 3.34-3.79 (1H, m), 3.58 (2H, s), 3.90-5.19 (1H, m), 6.43-7.65 (12H, m), 7.91-8.20 (1H, m)
16) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.11-3.13 (11H, m), 3.35-3.72 (1H, m), 3.61 (2H, s), 3.86 (3H, s), 3.88 (3H, s), 3.94-5.20 (1H, m), 6.45-7.69 (11H, m)
17) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.10-3.27 (11H, m), 3.36-3.75 (1H, m), 3.49 (2H, s), 3.90-5.20 (1H, m), 6.41-7.84 (11H, m), 8.81-9.59 (1H, m)
18) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.10-3.20 (11H, m), 3.35-3.66 (1H, m), 3.73 (2H, s), 3.91-5.20 (1H, m), 6.48-7.65 (11H, m), 7.68-7.94 (1H, m)
19) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.08-3.21 (11H, m), 3.38-3.68 (1H, m), 4.00 (2H, s), 3.95-5.20 (1H, m), 6.45-7.70 (11H, m), 8.15 (1H, s)
20) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.08-3.25 (11H, m), 3.36-3.69 (1H, m), 3.91 (2H, s), 3.88-5.20 (1H, m), 6.45-7.72 (11H, m), 7.85-8.13 (1H, m), 8.85 (1H, s)
21) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.10-3.30 (11H, m), 3.39-3.95 (3H, m), 3.95-5.20 (1H, m), 6.45-7.82 (10H, m), 7.94-8.36 (2H, m), 8.82-9.17 (1H, m)
22) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.06-3.11 (11H, m) 3.35-3.70 (1H, m), 3.62 (2H, s), 3.74 (3H, s), 3.86 (3H, s), 3.92-5.20 (1H, m), 6.45-7.67 (11H, m), 7.81-8.16 (1H, m)
23) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.04-5.10 (17H, m), 5.96-6.17 (1H, m), 6.52-7.86 (11H, m)
24) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.41-1.89 (2H, m), 1.90-2.24 (2H, m), 2.31 (3H, s), 2.47-2.89 (2H, m), 3.45 (3H, s), 3.69 (2H, s), 4.57-5.13 (2H, m), 6.39-6.76 (2H, m), 6.78-6.95 (1H, m), 6.95-7.41 (7H, m), 7.41-7.65 (1H, m)
25) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.45-1.92 (2H, m), 1.92-2.28 (2H, m), 2.50-2.96 (2H, m), 3.45 (3H, s), 3.81 (2H, s), 4.64-5.20 (2H, m), 6.28-7.12 (3H, m), 7.13-7.50 (5H, m), 7.50-7.64 (1H, m), 7.65-7.99 (1H, m)
26) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.52-2.54 (2H, m), 2.27 (3H, s), 2.70-2.98 (2H, m), 2.98-5.52 (2H, m), 3.65 (2H, s), 6.56-6.87 (1H, m), 6.97-7.43 (8H, m), 7.78 (1H, d, J=2.4 Hz), 7.91-8.15 (1H, m)
27) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.76-2.40 (2H, m), 2.29 (3H, s), 2.86 (2H, t, J=6.0 Hz), 3.00-5.32 (2H, m), 3.69 (2H, s), 6.46-8.05 (10H, m)
28) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.47-2.92, 3.44-4.11 (total 21H, m), 4.66-5.12 (1H, m), 5.85-6.30 (1H, m), 6.61-8.10 (11H, m) [.alpha.].sub.D.sup.24 =+90.degree. (methanol, c=0.2) (measured for hydrochloride)
29) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.48-2.88, 3.45-4.09 (total 21H, m), 4.60-5.05 (1H, m), 5.85-6.31 (1H, m), 6.62-7.78 (10H, m), 7.92-8.41 (1H, m) [.alpha.].sub.D.sup.24 =-107.degree. (methanol, c=0.2) (measured for hydrochloride)
30) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.21-3.06, 3.40-3.87 (total 14H, m), 4.54-5.05 (1H, m), 5.88-6.22 (1H, m), 6.83-8.09, 8.33-8.59, 8.82-9.03 (total 12H, m) [.alpha.].sub.D.sup.24 =+90.degree. (methanol, c=0.2) (measured for hydrochloride)
31) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.50-3.22, 3.54-3.99 (total 16H, m), 4.41-4.90 (1H, m), 5.88-6.22 (1H, m), 6.79-8.04 (11H, m), 9.05-9.63 (1H, m) [.alpha.].sub.D.sup.24 =+54.degree. (methanol, c=0.2) (measured for hydrochloride)
32) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.51-4.12 (16H, m), 4.60-5.17 (1H, m), 5.89-5.29 (1H, m), 6.71-8.50, 9.85-10.36 (total 12H, m) [.alpha.].sub.D.sup.24 =-68.degree. (methanol, c=0.2) (measured for hydrochloride)
33) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.04-4.63 (20H, m), 6.42-7.74 (11H, m)
34) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.08-2.23 (4H, m), 2.23-2.55 (6H, m), 2.55-3.00 (2H, m), 3.00-5.10 (3H, m), 6.68-7.90 (10H, m), 10.13-10.50 (1H, m)
35) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49-2.43 (3H, m), 2.43-2.61 (6H, m), 2.61-2.92 (2H, m), 2.92-3.99 (3H, m), 4.48-4.97 (1H, m), 5.80 (1H, brs), 6.44 (1H, brs), 6.53-7.83 (11H, m)
36) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.43-2.38 (3H, m), 2.38-2.77 (8H, m), 2.77-3.33 (8H, m), 3.33-5.10 (2H, m), 6.36-8.04 (11H, m)
37) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.43-2.13 (2H, m), 3.13-2.63 (7H, m), 2.63-3.75 (2H, m), 3.75-4.82 (4H, m), 4.97-5.50 (2H, m), 5.83-6.15 (1H, m), 6.51-7.73 (11H, m)
38) Isomer A; colorless and amorphous .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.95-4.18, 4.61-5.18 (total 19H, m), 5.85-6.29 (1H, m), 6.90-8.35 (12H, m)
Isomer B; colorless and amorphous .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.94-4.33, 4.61-5.23 (total 19H, m), 5.84-6.28 (1H, m), 6.76-7.91 (11H, m), 9.25-9.76 (1H, m)
39) Isomer A; colorless and amorphous .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.46-2.98, 3.22-4.05 (total 21H, m), 4.67-5.19 (1H, m), 5.79-6.22 (1H, m), 6.50-7.81 (11H, m)
[.alpha.].sub.D.sup.24 =+112.degree. (methanol, C=0.2) (measured for hydrochloride)
Isomer B; colorless and amorphous .sup.1 H-NMR (CDCl.sub.3) 1.42-2.98, 3.30-4.01 (total 21H, m), 4.58-5.20 (1H, m), 5.85-6.21 (1H, m), 6.43-8.14 (11H, m)
[.alpha.].sub.D.sup.24 --143.degree. (methanol, C=0.2) (measured for hydrochloride)
40) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.30-2.30 (4H, m), 2.31 (3H, s), 2.95-3.54 (3H, m), 2.71 (2H, s), 2.80-4.60 (2H, m), 5.01-5.39 (2H, m), 5.70-6.05 (1H, m), 6.41-6.63 (1H, m), 6.80-7.43 (9H, m), 7.50-7.67 (1H, m)
41) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.49-1.97 (2H, m), 2.02-2.30 (2H, m), 2.30-2.61 (12H, m), 2.68-2.95 (1H, m), 3.11-3.49 (2H, m), 3.62-3.86 (2H, m), 4.68-5.15 (1H, m), 5.90-6.19 (1H, m), 6.41-6.60 (1H, m), 6.60-7.02 (3H, m), 7.05-7.40 (6H, m), 7.40-7.52 (1H, m)
42) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.55-1.94 (2H, m), 1.95-2.59 (14H, m), 2.60-2.91 (1H, m), 2.91-3.47 (2H, m), 3.75 (2H, s), 4.60-5.20 (1H, m), 5.90-6.22 (1H, m), 6.40-6.66 (1H, m), 6.72-7.41 (9H, m), 7.77-8.04 (1H, m)
43) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.53-1.94 (2H, m), 2.0-2.25 (2H, m), 2.25-2.52 (9H, m), 2.58-2.92 (1H, m), 3.07-3.41 (2H, m), 3.53 (3H, s), 3.60-3.91 (2H, m), 4.66-5.13 (1H, m), 6.39-7.55 (10H, m), 7.60-7.80 (1H, m)
44) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.62-1.98 (2H, m), 1.98-2.58 (11H, m), 2.64-2.98 (1H, m), 2.99-3.44 (2H, m), 3.44-3.60 (3H, m), 3.72 (2H, s), 4.60-5.21 (1H, m), 5.91-6.28 (1H, m), 6.44-7.120 (4H, m), 7.10-7.49 (5H, m), 7.72 (1H, s), 8.00-8.36 (1H, m)
45) Isomer A; Colorless and amorphous .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.67-3.62, 4.67-5.20 (total 22H, m), 5.87-6.31 (1H, m), 6.49-7.85 (11H, m)
[.alpha.].sub.D.sup.24 =-133.degree. (methanol, C=0.2) (measured for hydrochloride)
Isomer B; Colorless and amorphous .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.81-3.65, 4.65-5.18 (total 22H, m), 5.86-6.28 (1H, m), 6.44-8.03 (11H, m)
[.alpha.].sub.D.sup.24 =+126.degree. (methanol, C=0.2) (measured for hydrochloride)
Example 86
0.85 g of 60% sodium hydride was added to 200 ml of tetrahydrofuran. Thereto was dropwise added 4.68 ml of ethyl diethylphosphonoacetate with ice-cooling and stirring. The mixture was stirred for 10 minutes with ice-cooling. To the reaction mixture was added 2.10 g of 5-oxo-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetra-hydro-1H-benzoazepine. The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 200 ml of ice water. The resulting mixture was subjected to extraction with 300 ml of ethyl acetate. The extract was washed with 300 ml of an aqueous sodium chloride solution, then dried over magnesium sulfate, and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: ethyl acetate/n-hexane=1/2) to obtain 2.22 g of 5-ethoxy-carbonylmethylidene-7-chloro-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine as a mixture of the E form and the Z form.
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.04-5.10 (17H, m), 5.96-6.17 (1H, m), 6.52-7.86 (11H, m)
Example 87
In 30 ml of a 1:1 mixture of tetrahydrofuran and methanol were dissolved 0.30 g of 5-ethoxycarbonylmethylidene-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and 0.55 g of nickel chloride hexahydrate. Thereto was slowly added 0.26 g of sodium borohydride with ice-cooling and stirring. The mixture was stirred for 10 minutes with ice-cooling. The resulting insolubles were removed by filtration with Celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography (elutant: ethyl acetate/n-hexane=1/1) to obtain 0.13 g of 5-ethoxycarbonylmethyl-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.04-4.63 (20H, m), 6.42-7.74 (11H, m)
Example 88
672 mg of N-benzyloxycarbonyl-L-valine and 1.42 g of dicyclohexylcarbodiimide were added to a solution of 1.0 g of 5-hydroxy-7-chloro-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine, 1.26 g of dimethylaminopyridine and 1.10 g of dimethylaminopyridine hydrochloride dissolved in 20 ml of chloroform. The mixture was stirred at room temperature for 7 hours. Thereto were added 3 ml of methanol and 0.7 ml of acetic acid, and the mixture was stirred at room temperature for 30 minutes. The resulting insolubles were removed by filtration. To the filtrate was added a 5% aqueous sodium hydrogensulfate solution. The mixture was subjected to extraction with dichloromethane. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution in this order, then dried over magnesium sulfate, and subjected to vacuum distillation to remove the solvent to obtain 2.0 g of crude 5-N-benzyl-oxycarbonyl-L-valyloxy-7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine. This crude product was dissolved in a mixed solvent consisting of 15 ml of acetic acid and 15 ml of ethyl acetate. To the solution was added 0.3 g of 5% Pd-C. The mixture was subjected to hydrogenolysis at normal temperature at normal pressure. Then, the catalyst was removed by filtration. The filtrate was concentrated. The residue was purified by silica gel column chromatography (elutant: ethyl acetate) to obtain 0.48 g of an isomer A and 0.47 g of an isomer B both of 5-L-valyloxy-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Isomer A
Rf value: 0.3 (developer: ethyl acetate/methanol=10/1)
.sup.1 H-NMR (CDCl.sub.3) .delta.: 0.67-3.62, 4.67-5.20 (total 22H, m), 5.87-6.31 (1H, m), 6.49-7.85 (11H, m)
[.alpha.].sub.D.sup.24 =-133.degree. (methanol, c=0.2) (measured for hydrochloride)
Isomer B
Rf value: 0.4 (developer: ethyl acetate/methanol=10/1)
.sup.1 H-NMR (CDCl.sub.3) .delta.: 0.81-3.65, 4.65-5.18 (total 22H,m), 5.86-6.28 (1H, m), 6.44-8.03 (11H, m)
[.alpha.].sub.D.sup.24 =+126.degree. (methanol, c=0.2) (measured for hydrochloride)
Example 89
A uniform solution of 1.27 g of 5-(N-tert-butoxycarbonyl-L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine, 2.5 ml of trifluoroacetic acid and 0.6 ml of anisole was stirred at room temperature for 2 hours. The most part of trifluoroacetic acid was removed by distillation under reduced pressure. To the residue was added a 0.2N aqueous sodium hydroxide solution to make the residue alkaline. The mixture was subjected to extraction with dichloromethane. The dichloromethane layer was water-washed, then dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elutant: ethyl acetate) to obtain 0.34 g of an isomer A and 0.35 g of an isomer B both of 5-(L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Isomer A
Colorless and amorphous
Rf value: 0.5 (developer: ethyl acetate/methanol=10/1)
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.47-2.92, 3.44-4.11 (total 21H, m), 4.66-5.12 (1H, m), 5.85-6.30 (1H, m), 6.61-8.10 (11H, m)
[.alpha.].sub.D.sup.24 =+96.degree. (methanol, c=0.2) (measured for hydrochloride)
Isomer B
Colorless and amorphous
Rf value: 0.4 (developer: ethyl acetate/methanol=10/1)
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.48-2.88, 3.45-4.09 (total 21H, m), 4.60-5.05 (1H, m), 5.85-6.31 (1H, m), 6.62-7.78 (10H, m), 7.92-8.41 (1H, m)
[.alpha.].sub.D.sup.24 =-107.degree. (methanol, c=0.2) (measured for hydrochloride)
Tables 43 to 109 (Examples 90 to 221) and their NMR data appear here.
The following compounds were obtained in the same manner as in Examples 1 and 2, using respective raw materials.
TABLE 43______________________________________ ##STR223##Example 90Structure: ##STR224## ##STR225## ##STR226##Crystal form: colorless and amorphousForm: dihydrochlorideNMR: 46)______________________________________
TABLE 44______________________________________Example 91Structure: ##STR227## ##STR228## ##STR229##Crystal form: colorless and amorphousForm: freeNMR: 47)Example 92Structure: ##STR230## ##STR231## ##STR232##Crystal form: colorless and amorphousForm: freeNMR: 48)______________________________________
TABLE 45______________________________________Example 93Structure: ##STR233## ##STR234## ##STR235##Crystal form: colorless and amorphousForm: freeNMR: 49)Example 94Structure: ##STR236## ##STR237## ##STR238##Crystal form: colorless and amorphousForm: freeNMR: 50)______________________________________
TABLE 46______________________________________Example 95Structure: ##STR239## ##STR240## ##STR241##Crystal form: slightly yellow and amorphousForm: freeNMR: 51)Example 96Structure: ##STR242## ##STR243## ##STR244##Crystal form: slightly yellow and amorphousForm: freeNMR: 52)______________________________________
TABLE 47______________________________________Example 97Structure: ##STR245## ##STR246## ##STR247##Crystal form: white powderRecrystallization solvent: dichloromethane-diethyl etherMelting point: 149-152.degree. C.Form: freeExample 98Structure: ##STR248## ##STR249## ##STR250##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 53)______________________________________
TABLE 48______________________________________Example 99Structure: ##STR251## ##STR252## ##STR253##Crystal form: colorless and amorphousForm: freeNMR: 54)Example 100Structure: ##STR254## ##STR255## ##STR256##Crystal form: colorless and amorphousRecrystallization solvent: ethanol-diethyl ether-n-hexaneMelting point: 182-184.degree. C.Form: free______________________________________
TABLE 49______________________________________Example 101Structure: ##STR257## ##STR258##Crystal form: colorless and amorphousForm: freeNMR: 55)Example 102Structure: ##STR259## ##STR260##Crystal form: colorless prismRecrystallization solvent: ethanolMelting point: 191-193.degree. C.Form: free______________________________________
TABLE 50______________________________________Example 103Structure: ##STR261## ##STR262## ##STR263##Crystal form: colorless and amorphousForm: dihydrochlorideNMR: 56)Example 104Structure: ##STR264## ##STR265## ##STR266##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 57)______________________________________
TABLE 51______________________________________Example 105Structure: ##STR267## ##STR268##Crystal form: white powderRecrystallization solvent: ethyl acetateMelting point: 243.5-244.5.degree. C.Form: freeExample 106Structure: ##STR269## ##STR270##Crystal form: colorless needleRecrystallization solvent: ethanol-diethyl etherMelting point: 164-166.degree. C.Form: free______________________________________
TABLE 52______________________________________Example 107Structure: ##STR271## ##STR272##Crystal form: colorless prismForm: freeNMR: 58)Example 108Structure: ##STR273## ##STR274##Crystal form: colorless needleRecrystallization solvent: methanol-diethyl etherMelting point: 141-144.degree. C.Form: free______________________________________
TABLE 53______________________________________Example 109Structure: ##STR275## ##STR276## ##STR277##Crystal form: yellow and amorphousForm: hydrochlorideNMR: 59)Example 110Structure: ##STR278## ##STR279## ##STR280##Crystal form: yellow and amorphousForm: hydrochlorideNMR: 60)______________________________________
TABLE 54______________________________________Example 111Structure: ##STR281## ##STR282## ##STR283##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 61)Example 112Structure: ##STR284## ##STR285##Crystal form: colorless and amorphousForm: freeNMR: 62)______________________________________
TABLE 55______________________________________Example 113Structure: ##STR286## ##STR287##Crystal form: white powderRecrystallization solvent: ethanol-chloroformMelting point: 254-258.degree. C.Form: freeExample 114Structure: ##STR288## ##STR289##Crystal form: white powderRecrystallization solvent: ethanolMelting point: 258-261.degree. C.Form: free______________________________________
TABLE 56______________________________________Example 115Structure: ##STR290## ##STR291##Crystal form: colorless and amorphousForm: freeNMR: 63)Example 116Structure: ##STR292## ##STR293##Crystal form: colorless and amorphousForm: freeNMR: 64)______________________________________
TABLE 57______________________________________Example 117Structure: ##STR294## ##STR295## ##STR296##Crystal form: colorless and amorphousForm: freeNMR: 65)Example 118Structure: ##STR297## ##STR298##Crystal form: colorless and amorphousForm: freeNMR: 66)______________________________________
TABLE 58______________________________________Example 119Structure: ##STR299## ##STR300##Crystal form: white powderRecrystallization solvent: ethanol-waterMelting point: 260-263.degree. C. (decomposed)Form: freeExample 120Structure: ##STR301## ##STR302##Crystal form: colorless and amorphousForm: freeNMR: 67)______________________________________
TABLE 59______________________________________Example 121Structure: ##STR303## ##STR304## ##STR305##Crystal form: colorless and amorphousForm: freeNMR: 68)Example 122Structure: ##STR306## ##STR307##Crystal form: colorless and amorphousForm: freeNMR: 69)______________________________________
TABLE 60______________________________________Example 123Structure: ##STR308## ##STR309## ##STR310##Crystal form: colorless and amorphousForm: freeNMR: 70)Example 124Structure: ##STR311## ##STR312## ##STR313##Crystal form: light yellow and amorphousForm: hydrochlorideNMR: 71)______________________________________
TABLE 61______________________________________Example 125Structure: ##STR314## ##STR315## ##STR316##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 72)Example 126Structure: ##STR317## ##STR318## ##STR319##Crystal form: colorless prismRecrystallization solvent: ethanol-dichloromethaneMelting point: 213-215.5.degree. C.Form: free______________________________________
TABLE 62______________________________________Example 127Structure: ##STR320## ##STR321## ##STR322##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 73)Example 128Structure: ##STR323## ##STR324## ##STR325##Crystal form: colorless and amorphousForm: dihydrochlorideNMR: 74)______________________________________
TABLE 63______________________________________Example 129Structure: ##STR326## ##STR327## ##STR328##Crystal form: slightly yellow and amorphousForm: hydrochlorideNMR: 75)Example 130Structure: ##STR329## ##STR330## ##STR331##Crystal form: slightly yellow and amorphousForm: hydrochlorideNMR: 76)______________________________________
TABLE 64______________________________________Example 131Structure: ##STR332## ##STR333## ##STR334##Crystal form: colorless and amorphousForm: freeNMR: 77)Example 132Structure: ##STR335## ##STR336## ##STR337##Crystal form: colorless and amorphousForm: freeNMR: 78)______________________________________
TABLE 65______________________________________Example 133Structure: ##STR338## ##STR339## ##STR340##Crystal form: colorless needleRecrystallization solvent: dichloromethane-methanolForm: freeMelting point: 202.5-203.5.degree. C.Example 134Structure: ##STR341## ##STR342## ##STR343##Crystal form: colorless needleRecrystallization solvent: ethyl acetate-diethyl etherForm: freeMelting point: 164-167.degree. C.______________________________________
TABLE 66______________________________________Example 135Structure: ##STR344## ##STR345## ##STR346##Crystal form: light yellow and amorphousForm: hydrochlorideNMR: 79)Example 136Structure: ##STR347## ##STR348## ##STR349##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 80)______________________________________
TABLE 67______________________________________Example 137Structure: ##STR350## ##STR351## ##STR352##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 81)Example 138Structure: ##STR353## ##STR354## ##STR355##Crystal form: colorless and amorphousForm: freeNMR: 82)______________________________________
TABLE 68______________________________________Example 139Structure: ##STR356## ##STR357## ##STR358##Crystal form: white powderRecrystallization solvent: ethanol-waterMelting point: 260-261.degree. C.Form: freeExample 140Structure: ##STR359## ##STR360## ##STR361##Crystal form: colorless and amorphousForm: freeNMR: 83)______________________________________
TABLE 69______________________________________Example 141Structure: ##STR362## ##STR363## ##STR364##Crystal form: colorless and amorphousForm: freeNMR: 84)Example 142Structure: ##STR365## ##STR366## ##STR367##Crystal form: colorless and amorphousForm: freeNMR: 85)______________________________________
TABLE 70______________________________________Example 143Structure: ##STR368## ##STR369## ##STR370##Crystal form: colorless and amorphousForm: dihydrochlorideNMR: 86)Example 144Structure: ##STR371## ##STR372## ##STR373##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 87)______________________________________
TABLE 71______________________________________Example 145Structure: ##STR374## ##STR375## ##STR376##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 88)Example 146Structure: ##STR377## ##STR378## ##STR379##Crystal form: light yellow and amorphousForm: hydrochlorideNMR: 89)______________________________________
TABLE 72______________________________________Example 147Structure: ##STR380## ##STR381## ##STR382##Crystal form: light yellow and amorphousForm: hydrochlorideNMR: 90)Example 148Structure: ##STR383## ##STR384## ##STR385##Crystal form: colorless and amorphousForm: dihydrochlorideNMR: 91)______________________________________
TABLE 73______________________________________Example 149Structure: ##STR386## ##STR387## ##STR388##Crystal form: white powderRecrystallization solvent: dichloromethane-diethyl etherMelting Point: 190-193.degree. C.Form: freeExample 150Structure: ##STR389## ##STR390## ##STR391##Crystal form: colorless prismRecrystallization solvent: ethanol-hexaneMelting Point: 168-175.degree. C.Form: freeNMR: 92)______________________________________
TABLE 74______________________________________Example 151Structure: ##STR392## ##STR393## ##STR394##Crystal form: colorless prismRecrystallization solvent: ethyl acetate-diethyl etherMelting Point: 153-155.degree. C.Form: freeExample 152Structure: ##STR395## ##STR396## ##STR397##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 93)______________________________________
TABLE 75______________________________________Example 153Structure: ##STR398## ##STR399## ##STR400##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 94)Example 154Structure: ##STR401## ##STR402## ##STR403##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 95)______________________________________
TABLE 76______________________________________Example 155Structure: ##STR404## ##STR405## ##STR406##Crystal form: colorless and amorphousForm: freeNMR: 96)Example 156Structure: ##STR407## ##STR408## ##STR409##Crystal form: colorless and amorphousForm: freeNMR: 97)______________________________________
TABLE 77______________________________________Example 157Structure: ##STR410## ##STR411## ##STR412##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 98)Example 158Structure: ##STR413## ##STR414## ##STR415##Crystal form: colorless needleRecrystallization solvent: ethanol-diethyl etherMelting point: 99-102.degree. C.Form: free______________________________________
TABLE 78______________________________________Example 159Structure: ##STR416## ##STR417## ##STR418##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 99)Example 160Structure: ##STR419## ##STR420## ##STR421##Crystal form: slightly yellow and amorphousForm: hydrochlorideNMR: 100)______________________________________
TABLE 79______________________________________Example 161Structure: ##STR422## ##STR423## ##STR424##Crystal form: white powderRecrystallization solvent: ethyl acetate-diethyl etherMelting point: 227.degree. C.Form: freeNMR: 101)Example 162Structure: ##STR425## ##STR426## ##STR427##Crystal form: white powderRecrystallization solvent: ethyl acetate-n-hexaneMelting point: 231-232.degree. C.Form: freeNMR: 102)______________________________________
TABLE 80______________________________________Example 163Structure: ##STR428## ##STR429## ##STR430##Crystal form: colorless and amorphousForm: freeNMR: 103)Example 164Structure: ##STR431## ##STR432## ##STR433##Crystal form: colorless and amorphousForm: freeNMR: 104)______________________________________
TABLE 81______________________________________Example 165Structure: ##STR434## ##STR435## ##STR436##Crystal form: colorless and amorphousForm: freeNMR: 105)Example 166Structure: ##STR437## ##STR438## ##STR439##Crystal form: colorless and amorphousForm: freeNMR: 106)______________________________________
TABLE 82______________________________________Example 167Structure: ##STR440## ##STR441## ##STR442##Crystal form: colorless and amorphousForm: freeNMR: 107)Example 168Structure: ##STR443## ##STR444## ##STR445##Crystal form: colorless and amorphousForm: freeNMR: 108)______________________________________
TABLE 83______________________________________Example 169Structure: ##STR446## ##STR447## ##STR448##Crystal form: white powderRecrystallization solvent: ethanol-diethyl etherMelting point: 196.degree. C.Form: hydrochlorideExample 170Structure: ##STR449## ##STR450## ##STR451##Crystal form: colorless and amorphousForm: freeNMR: 109)______________________________________
TABLE 84______________________________________Example 171Structure: ##STR452## ##STR453## ##STR454##Crystal form: white powderRecrystallization solvent: ethanol-diethyl etherMelting point: 182-183.degree. C.Form: hydrochlorideExample 172Structure: ##STR455## ##STR456## ##STR457##Crystal form: colorless prismRecrystallization solvent: ethanol-diethyl etherMelting point: 193-195.degree. C. (decomposed)Form: hydrochloride______________________________________
TABLE 85______________________________________Example 173Structure: ##STR458## ##STR459## ##STR460##Crystal form: colorless prismRecrystallization solvent: ethanol-diethyl etherMelting point: 190-193.degree.C. (decomposed)Form: hydrocholorideExample 174Structure: ##STR461## ##STR462## ##STR463##Crystal form: white powderRecrystallization solvent: ethanol-diethyl etherMelting point: 208-209.degree.C.Form: hydrochloride______________________________________
TABLE 86______________________________________Example 175Structure: ##STR464## ##STR465## ##STR466##Crystal form: white powder ##STR467##Melting point: 215-217.degree.C.Form: hydrochlorideExample 176Structure: ##STR468## ##STR469## ##STR470##Crystal form: colorless needleRecrystallization solvent: ethanol-diethyl etherMelting point: 222-224.degree.C.Form: dihydrochloride______________________________________
TABLE 87______________________________________Example 177Structure: ##STR471## ##STR472## ##STR473##Crystal form: colorless needleRecrystallization solvent: ethanol-diethyl etherMelting point: 214-216.degree.C.Form: dihydrochlorideExample 178Structure: ##STR474## ##STR475## ##STR476##Crystal form: white powderRecrystallization solvent: ethanol-diethyl etherMelting point: 254-256.degree.C.Form: hydrochloride______________________________________
TABLE 88______________________________________Example 179Structure: ##STR477## ##STR478## ##STR479##Crystal form: colorless needleRecrystallization solvent: ethanol-diethyl etherMelting point: 148-150.degree.C.Form: freeExample 180Structure: ##STR480## ##STR481## ##STR482##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 110)______________________________________
TABLE 89______________________________________Example 181Structure: ##STR483## ##STR484## ##STR485##Crystal form: colorless and amorphousForm: freeNMR: 111)Example 182Structure: ##STR486## ##STR487## ##STR488##Crystal form: colorless and amorphousForm: freeNMR: 112)______________________________________
TABLE 90______________________________________Example 183Structure: ##STR489## ##STR490## ##STR491##Crystal form: white powderRecrystallization solvent: ethanol-diethyl etherMelting point: 186-188.degree.C.Form: hydrochlorideExample 184Structure: ##STR492## ##STR493## ##STR494##Crystal form: white powder ##STR495##Melting point: 239.5-240.5.degree.C.Form: free______________________________________
TABLE 91______________________________________Example 185Structure: ##STR496## ##STR497## ##STR498##Crystal form: white powder ##STR499##Melting point: 253-255.degree.C.Form: freeExample 186Structure: ##STR500## ##STR501## ##STR502##Crystal form: colorless and amorphousForm: freeNMR: 113)______________________________________
TABLE 92______________________________________Example 187Structure: ##STR503## ##STR504## ##STR505##Crystal form: colorless and amorphousForm: freeNMR: 114)Example 188Structure: ##STR506## ##STR507## ##STR508##Crystal form: colorless and amorphousForm: freeNMR: 115)______________________________________
TABLE 93______________________________________Example 189Structure: ##STR509## ##STR510## ##STR511##Crystal form: white powder ##STR512##Melting point: 185-187.5.degree.C.Form: freeExample 190Structure: ##STR513## ##STR514## ##STR515##Crystal form: light yellow oilForm: freeNMR: 116)______________________________________
TABLE 94______________________________________Example 191Structure: ##STR516## ##STR517## ##STR518##Crystal form: light yellow and amorphousForm: freeNMR: 117)Example 192Structure: ##STR519## ##STR520## ##STR521##Crystal form: light yellow and amorphousForm: freeNMR: 118)______________________________________
TABLE 95______________________________________Example 193Structure: ##STR522## ##STR523## ##STR524##Crystal form: colorless and amorphousForm: freeNMR: 119)Example 194Structure: ##STR525## ##STR526## ##STR527##Crystal form: white powderMelting point: 145-147.degree.C.Form: free______________________________________
TABLE 96______________________________________Example 195Structure: ##STR528## ##STR529## ##STR530##Crystal form: colorless and amorphousForm: freeNMR: 120)Example 196Structure: ##STR531## ##STR532## ##STR533##Crystal form: colorless and amorphousForm: freeNMR: 121)______________________________________
TABLE 97______________________________________Example 197Structure: ##STR534## ##STR535## ##STR536##Crystal form: light yellow and amorphousForm: freeNMR 122)Example 198Structure: ##STR537## ##STR538## ##STR539##Crystal form: colorless and amorphousForm: freeNMR: 123)______________________________________
TABLE 98______________________________________Example 199Structure: ##STR540## ##STR541## ##STR542##Crystal form: colorless and amorphousForm: freeNMR: 124)Example 200Structure: ##STR543## ##STR544## ##STR545##Crystal form: white powderForm: freeNMR: 125)______________________________________
TABLE 99______________________________________Example 201Structure: ##STR546## ##STR547## ##STR548##Crystal form: colorless and amorphousForm: freeNMR: 126)Example 202Structure: ##STR549## ##STR550## ##STR551##Crystal form: colorless and amorphousForm: freeNMR: 127)______________________________________
TABLE 100______________________________________Example 203Structure: ##STR552## ##STR553## ##STR554##Crystal form: colorless and amorphousForm: freeNMR: 128)Example 204Structure: ##STR555## ##STR556## ##STR557##Crystal form: colorless and amorphousForm: freeNMR: 129)______________________________________
TABLE 101______________________________________Example 205:Structure: ##STR558## ##STR559## ##STR560##Crystal form: colorless and amorphousform: freeNMR: 130)Example 206Structure: ##STR561## ##STR562## ##STR563##Crystal form: colorless and amorphousForm: freeNMR: 131)______________________________________
TABLE 102______________________________________Example 207Structure: ##STR564## ##STR565## ##STR566##Crystal form: colorless and amorphousForm: freeNMR: 132)Example 208Structure: ##STR567## ##STR568## ##STR569##Crystal form: colorless and amorphousForm: freeNMR: 133)______________________________________
TABLE 103______________________________________Example 209Structure: ##STR570## ##STR571## ##STR572##Crystal form: colorless and amorphousForm freeNMR: 134)Example 210Structure: ##STR573## ##STR574## ##STR575##Crystal form: colorless and amorphousForm: freeNMR: 135)______________________________________
TABLE 104______________________________________Example 211Structure: ##STR576## ##STR577## ##STR578##Crystal form: colorless and amorphousForm: freeNMR: 136)Example 212Structure: ##STR579## ##STR580## ##STR581##Crystal form: colorless and amorphousForm: freeNMR: 137)______________________________________
TABLE 105______________________________________Example 213Structure: ##STR582## ##STR583## ##STR584##Crystal form: colorless and amorphousForm: freeNMR: 138)Example 214Structure: ##STR585## ##STR586## ##STR587##Crystal form: colorless and amorphousForm: freeNMR: 139)______________________________________
TABLE 106______________________________________Example 215Structure: ##STR588## ##STR589## ##STR590##Crystal form: colorless and amorphousForm: freeNMR: 140)Example 216Structure: ##STR591## ##STR592## ##STR593##Crystal form: colorless and amorphousForm: freeNMR: 141)______________________________________
TABLE 107______________________________________Example 217Structure: ##STR594## ##STR595## ##STR596##Crystal form: colorless and amorphousForm: freeNMR: 142)Example 218Structure: ##STR597## ##STR598## ##STR599##Crystal form: colorless and amorphousForm: freeNMR: 143)______________________________________
TABLE 108______________________________________Example 219Structure: ##STR600## ##STR601## ##STR602##Crystal form: colorless and amorphousForm: freeNMR: 144)Example 220Structure: ##STR603## ##STR604## ##STR605##Crystal form: colorless and amorphousForm: freeNMR: 145)______________________________________
TABLE 109______________________________________Example 221Structure: ##STR606## ##STR607##R.sup.2 : 2-CH.sub.3 ##STR608##Crystal form: white and amorphousForm: freeNMR: 146)______________________________________
46) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.35-2.45 (12H, m), 2.55-2.95 (3H, m), 3.1-4.0 (4H, m), 4.05-4.45 (1H, m), 4.5-4.8 (1H, m), 5.95-6.3 (1H, m), 6.89 (1H, d, J=8.6 Hz), 7.05-7.8 (9H, m ), 8.17 (3H, brs), 8.90 (3H, brs), 10.25-10.60 (1H, m)
47) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.47-2.17 (3H, m), 2.32-2.92 (8H, m), 2.92-4.57 (6H, m), 5.17 (1H, brs), 5.76 (1H, brs), 6.17-8.14 (12H, m)
48) .sup.1 H-MNR (CDCl.sub.3) .delta.: 1.22-2.52 (10H, m), 2.70-3.05 (1H, m), 3.30-5.10 (8H, m), 6.60-8.05 (12H, m)
49) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.21-2.46 (7H, m), 2.70-2.95 (1H, m), 2.95-5.60 (7H, m), 6.60-8.32 (11H, m), 8.60-9.40 (1H, m)
50) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.35-2.52 (10H, m), 2.70-3.02 (1H, m), 3.02-5.05 (8H, m), 6.60-7.85 (11H, m), 7.85-8.23 (1H, m)
51) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.44-2.51 (11H, m), 2.67-3.77 (7H, m), 3.88-5.00 (4H, m), 6.66-9.05 (11H, m)
52) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.02-1.43 (3H, m), 1.43-4.98 (10H, m), 6.80-8.25 (11H, m), 10.35-10.72 (1H, m), 12.37-13.00 (1H, m)
53) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.2-2.2 (3H, m), 2.35 (3H, s), 2.83 (6H, s), 2.7-3.2 (1H, m), 3.3-3.6 (3H, m), 4.29 (2H, s), 4.2-5.1 (2H, 6.80 (1H, d, J=8.2 Hz), 7.0-7.8 (10H, 10.4-10.6 (1H, m), 10.6-10.9 (1H, br)
54) .sup.1 Hs-NMR (CDCl.sub.3) .delta.: 1.15-5.30 {20H, m [1.28 (3H, t, J=7.1 Hz), 2.50 (s), 3.73 (3H, s)]}, 6.50-7.61 (9H, m), 8.32 (1H, brs), 8.34 (1H, d, J=8.1 Hz)
55) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.21-5.34 {15H, m [2.50 (s), 3.78 (s)]}, 5.91-8.78 {13H, m [6.56 (1H, d, J=8.3 Hz)])}
56) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.22-3.04, 3.15-3.89 (total 25H, m), 4.65-5.21 (1H, m), 5.86-6.33 (1H, m), 6.49-7.78 (8H, m), 8.01-8.52 (2H, m)
57) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.06-4.66, 5.02-5.26, 5.54-5.79 (total 25H, m [2.48(s), 2.56(s), 3.98(s)]}, 6.61-7.64, 8.04-8.39, 8.57-5.76 8total 12H, m)
58) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.23-3.23 (7H, m), 2.35 (3H, m), 4.64-5.01 (1H, m), 6.32 (6H, dd, J=2.6 Hz, 8.4 Hz), 6.50 (1H, d, J=8.4 Hz), 6.66 (6H, d, J=2.6 Hz), 7.08 (2H, d, J=8.6 Hz), 7.14-7.80 (4H, m), 7.54 (2H, d, J=8.4 Hz), 9.40 (1H, brs), 10.32 (1H, s)
59) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.26-4.82 (19H, m), 5.68 (1H, t, J=7.1 Hz), 6.64-7.47 (9H, m), 7.80-8.30 (2H, m)
60) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.26-4.68 (19H, m), 5.58 (1H, t, J=6.9 Hz), 6.63-8.50 (11H, m)
61) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.02-2.04 (4H, m), 2.33, 2.40 (total 3H, s), 2.50-4.22 (14H, m), 2.75, 2.77 (total 3H, s), 4.29-4.68 (2H, m), 6.73-7.78 (10H, m), 10.30, 10.50 (total 1H, brs), 11.50 (1H, brs)
62) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.0-1.4 (1H, m), 1.4-2.25 (3H, m), 2.25-3.3 (12H, m), 3.35-4.15 (4H, m), 4.3-4.95 (1H, m), 6.6-8.0 (10H, m), 8.6-9.25 (1H, m)
63) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.25-3.36 (1.1H, m), 2.31 (6H, s), 2.40 (3H, s), 3.92 (2H, t, J=5.0 Hz), 4.77-5.00 (1H, m), 6.42 (1H, dd, J=2.1 Hz, 6.9 Hz), 6.52 (1H, d, J=6.9 Hz), 6.75 (1H, d, J=2.1 Hz), 6.98-7.61 (8H, m), 8.42 (1H, s)
64) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.35-3.16 (9H, m), 1.91 (3H, s), 2.43 (3H, m), 3.25-3.58 (2H, m), 3.76-4.12 (2H, m), 4.80-5.09 (1H, m), 5.06 (1H, brs), 6.42 (1H, dd, J=2.2 Hz, 6.8 Hz), 6.56 (1H, d, J=6.8 Hz), 6.74 (1H, d, J=2.2 Hz), 6.98-7.64 (8H, m), 7.96 (1H, s)
65) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.20-3.18 (11H, m), 2.33 (3H, s), 2.47 (3H, s), 2.48 (3H, s), 3.20-5.12 (6H, m), 6.40-7.93 (11H, m)
66) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.21-2.22 (2H, m), 2.35-3.21 (3H, m), 2.46 (3H, s), 2.48 (3H, s), 2.98 (3H, s), 3.15 (3H, s), 3.45-4.63 (4H, m), 6.47-7.83 (11H, m)
67) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.42-2.95 (16H, m), 2.40 (3H, s), 2.46 (3H, s), 3.35-4.45 (3H, m ), 4.50-5.03 (2H, m), 6.51-8.02 (11H, m)
68) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.43-2.96 (12H, m), 7.42 (3H, s), 2.47 (3H, s), 3.36-3.83 (7H, m), 4.32-5.08 (2H, m), 6.51-7.76 (11H, m)
69) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.42-2.60 (9H, m), 2.45 (3H, s), 2.66-3.83 4H, m), 4.03-5.13 (3H, m), 6.50-8.39 (14H, m)
70) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.2-2.35 (6H, m), 2.35-2.6 (6H, m), 2.6-2.95 (1H, m), 3.1-4.05 (5H, m), 4.05-4.45 (2H, m), 4.45-5.1 (2H, m), 6.55-6.8 (1H, m), 6.8-7.55 (11H, m), 7.6-7.95 (3H, m)
71) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.3-2.45 (9H, m), 2.6-2.85 (1H, m), 2.9-4.1 (14H, m), 4.4-4.8 (2H, m), 6.88 (1H, d, J=8.4 Hz), 7.0-7.75 (10H, m), 10.25-10.55 (1H, m), 11.01 (1H, brs)
72) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.2-2.45 (8H, m), 2.6-2.85 (1H, m), 3.2-4.0 (6H, m), 4.2-4.8 (4H, m), 6.87 (1H, d, J=8.4 Hz), 7.0-8.0 (11H, m), 9.05-9.3 (1H, m), 10.2-10.55 (1H, m)
73) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.10-2.4 (12H, m), 2.65-4.10 (13H, m), 4.48-5.00 (2H, m), 6.58-7.22 (2H, m), 7.22-7.86 (8H, m), 10.29, 10.45 (total 1H, brs), 11.07 (1H, brs)
74) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.24-1.82 (3H, m), 1.82-2.48 (9H, m), 2.66-3.94 (3H, m), 4.22-4.93 (2H, m), 6.63-7.98 (14H, m), 9.08, 9.18 (total 1H, brs), 10.29, 10.44 (total 1H, brs)
75) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.2-2.45 (13H, m), 2.6-2.8 (1H, m), 2.8-3.8 (10H, m), 3.83 (1H, d, J=7.2 Hz), 4.4-4.8 (2H, m), 6.88 (1H, d, J=8.4 Hz), 7.0-7.75 (9H, m), 10.2-10.8 (2H, m)
76) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 0.96-2.63 (19H, m), 2.63-4.04 (6H, m), 4.07-4.95 (2H, m), 6.57-7.99 (11H, m), 10.29, 10.44 (total 1H, brs), 10.49 (1H, brs)
77) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.44-2.59 (10H, m), 2.60-5.25 (3H, m), 6.42-8.33 (11H, m)
78) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.06-2.54 (8H, m), 2.33 (3H, s), 2.45 (3H, s), 2.57-5.02 (12H, m), 6.53-8.38 (11, m)
79) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.2-2.3 (9H, m), 2.3-2.45 (3H, m), 2.6-2.8 (1H, m), 2.8-3.9 (14H, m), 3.9-4.15 (1H, m), 4.3-3.8 (2H, m), 6.88 (1H, d, J=8.4 Hz), 6.95-7.7 (9H, m), 10.2-10.5 (1H, m), 10.95 (1H, brs)
80) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 0.97-2.62 {15H, m [2.07(3H, s)]}, 2.63-4.19 (13H, m), 4.31-5.01 (2H, m), 6.54-8.07 (10H, m), 10.30, 10.46 (total 1H, brs), 10.98 (1H, brs)
81) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.02-2.15 (4H, m), 2.15-2.48 (6H, m), 2.80 (3H, s), 2.64-3.88 {10H, m [2.80 (3H, s-like)]}, 3.95-4.78 (3H, m), 6.45-8.12 (10H, m), 10.26, 10.47 (total 1H, brs), 11.30 (1H, brs)
82) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.3-1.8 (2H, m), 1.85-2.35 (2H, m), 2.35-2.6 (6H, m), 2.65-2.9 (1H, m), 3.35-4.0 (5H, m), 4.1-5.05 (4H, m), 6.5-6.8 (1H, m), 6.8-7.6 (10H, m), 7.6-8.05 (4H, m)
83) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.10-1.38 (1H, m), 1.23 (6H, d, J=5.6 Hz), 1.53-2.09 (3H, m), 2.13-3.46 (3H, m), 2.53 (3H, s), 3.56-4.52 (6H, m), 6.32-8.21 (12H, m)
84) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.45-2.10 (3H, m), 2.13-3.40 (4H, m), 2.39 (3H, d, J=4.7 Hz), 2.53 (3H, s), 3.42-4.68 (5H, m), 6.38-7.59 (10H, m), 7.79 (1H, brs), 8.16 (1H, brs)
85) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.13-2.21 (3H, m), 2.41-3.24 82H, m), 2.45 (3H, s), 2.99, 3.14 (total 6H, s), 3.47-4.65 (4H, m), 6.53-8.14 (11H, m)
86) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.25-2.45 (9H, m), 2.55-2.85 (1H, m), 2.9-4.1 (15H, m), 4.3-4.8 (2H, m), 6.88 (1H, d, J=8.4 Hz), 7.0-7.8 (9H, m), 9.84 (2H, brs), 10.15-10.55 (1H, m), 12.02 (1H, brs)
87) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.3-2.15 (3H, m), 2.15-2.45 (4H, m), 2.6-2.85 (1H, m), 3.0-4.25 (15H, m), 4.45-4.9 (2H, m), 6.89 (1H, d, J=8.4 Hz), 7.0-7.75 (9H, m), 10.25-10.6 (1H, m), 11.05-11.65 (1H, m)
88) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.15-2.2 (4H, m), 2.25-2.4 (3H, m), 2.6-2.85 (1H, m), 3.0-3.95 (4H, m), 3.95-4.15 (1H, m), 4.35-4.8 (4H, m), 6.6-6.95 (1H, m), 6.95-8.0 (12H, m), 9.15-9.45 81H, m), 10.25-10.6 (1H, m)
89) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.3-2.2 (7H, m), 2.2-2.45 (4H, m), 2.55-2.85 (1H, m), 2.85-4.25 (11H, m), 4.25-4.85 (5H, m), 6.89 (1H, d, J=8.4 Hz), 7.0-7.8 (9H, m), 10.25-10.6 (1H, m), 11.45-12.0 (1H, m)
90) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.3-2.2 (7H, m), 2.2-2.45 (4H, m), 2.55-2.9 (1H, m), 2.9-4.15 (11H, m), 4.4-4.9 (2H, m), 6.8-7.0 (1H, m), 7.0-7.8 (9H, m), 10.2-10.7 (1H, m), 10.88 (1H, brs)
91) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.3-2.1 (3H, m), 2.15-2.45 (4H, m), 2.55-2.85 (1H, m), 2.9-4.25 (15H, m), 4.4-4.85 (2H, m), 6.75-7.0 (1H, m), 7.0-7.9 (9H, m), 9.90 (2H, brs), 10.2-10.55 (1H, m), 11.65-12.50 (1H, m)
92) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 0.91-2.16 (4H, m), 2.22-4.98 (8H, m), 6.61-7.85 (12H, m), 10.35-10.81 (1H, m)
93) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 0.94-2.05 (4H, m), 2.45-4.90 (22H, m), 2.77 (3H, s), 6.80 (1H, d, J=8.6 Hz), 6.94-7.77 (9H, m), 10.52, 10.72 (total 1H, brs), 11.47 (1H, brs)
94) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.0-2.3 (8H, m), 2.4-3.2 (1H, m), 3.2-4.2 (6H, m), 4.2-4.8 (2H, m), 6.80 (1H, d, J=8.4 Hz), 6.95-7.8 (9H, m), 10.5-10.75 (1H, m), 10.86 (1H, brs)
95) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 0.9-1.3 (1H, m), 1.3-2.0 (3H, m), 2.05-2.45 (3H, m), 2.55-3.3 (6H, m), 3.3-4.55 (10H, m), 6.8-7.8 (10H, m), 9.51 (2H, brs), 10.2-10.6 (1H, m)
96) .sup.1 H -NMR (CDCl.sub.3) .delta.: 1.42-2.36 (14H, m), 2.36 (3H, s), 2.46 (3H, s), 2.86-3.96 (5H, m), 4.43-5.03 (1H, m), 6.52-8.33 (11H, m), 6.54-7.58 (10H, m), 7.80 (1H, brs)
97) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.37-2.90 (15H, m), 2.33 (3H, s), 2.47 (3H, s), 3.38-3.99 (5H, m), 4.31-5.08 (2H, m), 6.56-7.98 (11H, m)
98) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 0.75-2.25 (10H, m), 2.25-4.4 (13H, m), 6.79 (1H, d, J=8.2 Hz), 6.9-7.9 (14H, m), 8.25-8.8 (1H, m), 10.45-10.85 (1H, m), 10.85-11.35 (1H, m)
99) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.07-2.10 (4H, m), 2.19-2.62 (3H, m), 2.62-4.72 (16H, m), 6.60-7.84 (10H, m), 10.48, 10.68 (total 1H, brs), 11.32 (1H, brs)
100) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.04-2.68 {[13H, m [2.08 (3H, s)]], 2.68-4.24 (13H, m), 4.32-5.00 (2H, m), 6.54-7.91 (10H, m), 10.29, 10.44 (total 1H, brs), 11.14 (1H, brs)
101) .sup.1 H-NMR (CDCl.sub.3 +DMSO-d.sub.6) .delta.: 1.00-2.21 (4H, m), 2.54-2.99 (2H, m), 2.42, 2.49 (3H, each s), 3.00-5.14 (3H, m), 6.78-8.23 (11H, m), 10.04, 10.29 (1H, each s)
102) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.06-2.14 (4H, m), 2.39 (3H, s), 2.48-3.65 (4H, 4.21-4.50 (1H, m), 6.75 (1H, d, J=8.2 Hz), 6.94 (1H, d, J=8.2 Hz), 7.07 (1H, dd, J=2.2 Hz, 8.2 Hz), 7.14-7.82 (7H, m), 10.44, 10.64 (1H, each s), 12.42 (1H, brs)
103) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.20-2.81 (9H, m), 2.33 (3H, s), 2.47 (3H, s), 2.85-3.93 (7H, m), 4.43-5.21 (1H, m), 6.53-6.87 (3H, m), 7.15-7.86 (9H, m)
104) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.22-2.21 (4H, m), 2.42-3.24 (3H, m), 2.47 (3H, s), 2.98 (3H, s), 3.15 (3H, s), 3.58-4.03 (1H, m), 4.40-5.22 (1H, m), 6.53-6.72 (3H, m), 7.13-7.67 (9H, m)
105) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.21-2.23 (8H, m), 2.40-4.10 (7H, m), 2.47 (3H, s), 4.35-5.22 (2H, m), 6.53-6.85 (3H, m), 7.13-7.70 (9H, m)
106) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.08-2.63 (9H, m), 2.32, 2.34 (total 3H, s), 2.63-4.11 (10H, m), 4.35-5.06 (1H, m), 6.53-8.24 (11H, m)
107) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.11-2.28 (4H, m), 2.45-3.23 (3H, m), 3.01 (3H, s), 3.16 (3H, s), 3.45-4.15 (4H, m), 4.38-5.07 (1H, m), 6.53-8.16 (11H, m)
108) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.06-2.23 (8H, m), 2.50-4.12 (7H, m), 3.76 (3H, s), 4.34-5.10 (2H, m), 6.52-8.23 (11H, m)
109) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.02-2.59 {16H, m [2.09 (3H, s-like)]}, 2.59-3.83 (9H, m), 3.87-4.63 (2H, m), 6.56-8.12 (10H, m), 10.27, 10.45 (total 1H, brs), 11.00 (1H, brs)
110) .sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.38-5.08 [25H, m (2.36, s-like)], 6.60-9.20 (12H, m), 10.29, 10.43 (total 1H, brs)
111) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.04-2.10 (8H, m), 2.16-3.25 (6H, m), 2.28 (3H, s), 2.30 (3H, s), 2.44, 2.51 (total 3H, s), 3.36-4.18 (5H, m), 4.32-5.02 (2H, m), 6.50-7.90 (10H, m), 8.32, 8.64 (total 1H, brs)
112) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.06-2.17 (10H, m), 2.45, 2.51 (total 3H, s), 2.47-3.06 (2H, m), 3.13-4.06 (8H, m), 4.30-5.00 (2H, m), 6.52-7.82 (10H, m), 8.36, 8.72 (total 1H, brs)
113) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.12-2.20 (8H, m), 1.91, 1.93 (total 3H, s), 2.34-3.41 (5H, m), 2.44 (3H, m), 3.55-4.13 (3H, m), 4.32-5.25 (2H, m), 5.96-7.55 (11H, m), 8.16, 8.23 (total 1H, brs), 8.52 (1H, brs)
114) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.06-2.20 (8H, m), 1.92, 1.93 (total 3H, s), 2.36-3.30 (5H, m), 2.43, 2.52 (total 3H, m), 3.46-4.09 (6H, m), 4.35-5.03 (1H, m), 6.00-7.58 8.25 (1H, brs), 8.44 (1H, brs)
115) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.06-2.25 (8H, m), 1.90 (3H, s), 2.35-3.30 (5H, m), 3.36-4.07 (7H, m), 4.30-4.97 (1H, m), 6.23-7.92 (10H, m), 8.83 (1H, brs), 9.90 (1H, brs)
116) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.34 (3H, t, J=5.6 Hz), 1.55-2.3 (3H, m), 2.46 (3H, s), 2.8-3.9 (6H, m), 4.24 (2H, q, J=5.6 Hz), 5.96 (1H, s), 6.6-7.6 (10H, m), 8.10 (1H, s)
117) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.3-2.6 (28H, m), 2.6-2.9 (1H, m), 3.0-4.0 (5H, m), 4.3-5.1 (2H, m), 6.6-7.6 (10H, m), 7.70 (1H, brs)
118) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.1-2.25 (4H, m), 2.55-3.15 (3H, m), 3.3-4.0 (7H, m), 4.05-5.1 (1H, m), 6.7-7.9 (10H, m), 8.3-8.75 (1H, m)
119) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.3-2.9 (23H, m), 3.25-4.0 (9H, m), 4.3-5.1 (2H, m), 6.6-7.55 (10H, m), .7.6-7.95 (1H, m)
120) .sup.1 -NMR (CDCl.sub.3) .delta.: 1.15-2.2 (4H, m), 2.5-3.3 (3H, m), 3.4-3.9 (4H, m), 4.3-5.25 (1H, m), 6.45-6.7 (1H, m), 6.8-7.05 (1H, m), 7.05-7.6 (8H, m), 7.6-7.8 (1H, m), 8.1-8.4 (1H, m)
121) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.2-2.5 (7H, m), 2.55-3.25 (3H, m), 3.3-3.85 (4H, m), 4.35-5.2 (1H, m), 6.59 (1H, d, J=6.7 Hz), 6.95 (1H, dd, J=6.7 Hz, 1.6 Hz), 7.11 (1H, d, J=1.7 Hz), 7.15-8.05 (9H, m)
122) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.95-2.35 (6H, m), 2.35-2.6 (6H, m), 2.6-3.3 (2H, m), 3.35-5.05 (6H, m), 6.55-6.8 (1H, m), 6.8-8.15 (14H, m)
123) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.2-2.2 (4H, m), 2.35 (3H, s), 2.55-3.05 (2H, m), 3.05-3.25 (1H, m), 3.45-3.75 (1H, m), 4.2-5.15 (1H, m), 6.45-6.6 (1H, m), 6.75-6.95 (1H, m), 7.0-8.05 (9H, m), 8.15-8.45 (1H, m)
124) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.2-2.2 (4H, m), 2.5-3.0 (2H, m), 3.0-3.25 (1H, m), 3.3-3.75 (1H, m), 4.2-5.2 (1H, m), 6.45-6.65 (1H, m), 6.8-7.0 (1H, m), 7.0-7.5 (8H, m), 7.55 (1H, d, J=6.9 Hz), 8.4-8.6 (1H, m)
125) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.15-1.45 (1H, m), 1.45-2.4 (5H, m), 2.4-2.7 (3H, m), 3.05-3.35 (2H, m), 3.45-4.1 (5H, m), 4.35-5.2 (1H, m), 6.6-7.6 (10H, m), 7.6-7.8 (3H, m), 7.8-8.05 (2H, m)
126) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.23-2.30, 2.56-3.98, 4.27-5.65 [total 16H, 2.47 (3H, s), 3.72 (3H, s)], 6.61 (1H, d, J=8.3Hz), 6.18-7.57 (8H, m), 8.15 (1H, s), 8.31 (1H, d, J=8.1Hz)
127) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.56-5.10 (6H, m), 2.50 (3H, s), 3.80 (3H, s), 5.59 (1H, s), 6.51-6.86 (2H, m), 6.91-7.06 (1H, m), 7.13 (1H, dd, J=2.4Hz, 8.4Hz), 7.19-7.58 (5H, m), 8.15 (1H, s), 8.32 (1H, d, J=8.4Hz)
128) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.88-4.12 (16H, m), 1.44, 1.46, 1.48 (9H, each s), 2.45, 2.51 (6H, each s), 4.31-4.62 (1H, m), 6.58 (1H, d, J=8.2Hz), 6.78-8.31 (10H, m)
129) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.81-2.98 (5H, m), 2.35, 2.37, 2.43, 2.49 (9H, each s), 3.02-4.75 (6H, m), 6.61 (1H, dd, J=18Hz, 8.4Hz), 4.93 (1H, d, J=8.4Hz, 2.3Hz), 7.08-8.40 (9H, m)
130) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.33-3.00 (7H, m), 2.41, 2.43, 2.46 (9H, each s), 3.05-5.14 (6H, m), 6.57 (1H, d, J=8.2Hz), 6.71 (1H, d, J=8.2Hz), 6.82-8.28 (13H, m)
131) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.83-2.52 (4H, m), 2.42, 2.45 (3H, each s), 2.56-5.18 (5H, m), 3.72 (3H, s), 6.57 (1H, d, J=8.3Hz), 6.87 (1H, d, J=8.3Hz), 7.06 (1H, dd, J=5.7Hz, 2.3Hz), 6.67-8.49 (8H, m)
132) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.05-2.23 (4H, m), 2.24-5.07 (5H, m), 2.43, 2.49 (3H, each s), 3.71 (3H, s), 6.75-9.00 (11H, m)
133) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.78-2.31 (4H, m), 2.48-3.35 (3H, m), 3.36-5.39 (2H, m), 3.73 (3H, s), 3.75 (3H, s), 6.61 (1H, d, J=8.3Hz), 6.35-7.93 (8H, m), 8.35 (1H, d, J=8.4Hz), 8.61, 8.86 (1H, each s)
134) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.03-2.28 (4H, m), 2.50-3.33 (3H, m), 3.34-5.48 (2H, m), 3.73 (3H, s), 3.75 (3H, s), 6.62 (1H, d, J=8.3Hz), 6.43-7.82 (8H, m), 8.18-8.70 (2H, m)
135) .sup.1 H -NMR (CDCl.sub.3) .delta.: 1.02-2.30 (4H, m), 2.49-3.40 (3H, m), 3.41-5.42 (2H, m), 3.73 (3H, s), 6.61 (1H, d, J=8.2Hz), 6.34-7.99 (8H, m), 8.33 (1H, d, J=8.3Hz), 8.61, 8.86 (1H, each s)
136) .sup.1 H-NMR (CDCl.sub.3) .delta.: 0.98-2.35 (4H, m), 2.36-5.47 (5H, m), 3.72 (3H, s), 6.61 (1H, d, J=8.2Hz), 6.47-7.91 (9H, m), 8.12-8.72 (1H, m)
137) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.28-2.55 (12H, m), 2.34 (3H, s), 2.42 (3H, s), 2.65-2.94 (2H, m), 3.03-3.98 (5H, m), 4.35-5.03 (2H, m), 6.50-8.54 (11H, m)
138) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.17-2.17 (4H, m), 2.43 (3H, s), 2.53-3.21 (3H, m), 3.31-3.82 (1H, m), 3.71 (3H, s), 4.31-5.20 (1H, m), 6.50-6.73 (2H, m), 6.77-7.53 (8H, m), 7.99, 8.00, 8.08 (total 1H, brs)
139) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.18-2.15 (4H, m), 2.34 (3H, s), 2.52-3.27 (3H, m), 3.47-3.73 (1H, m), 4.22-5.18 (1H, m), 6.50-6.72 (2H, m), 6.78-6.94 (1H, m), 7.07-7.50 (7H, m), 8.45 (2H, brs)
140) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.11-2.23 (7H, m), 2.45 (3H, s), 2.46 (3H, s), 2.63-3.82 (4H, m), 4.10-5.20 (3H, m), 6.55-7.83 (10H, m)
141) .sup.1 H-NMR (CDCl.sub.1) .delta.: 1.13-2.09 (4H, m), 2.36 (6H, s), 2.56-3.68 (4H, m), 4.28-5.13 (1H, m), 5.92 (1H, brs), 6.55-7.66 (10H, m), 8.17 (1H, brs)
142) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.12-1.41 (4H, m), 1.43-2.18 (3H, m), 2.28-3.03 (3H, m), 2.44 (3H, s), 3.32-3.90 (1H, m), 3.60 (3H, s), 4.02-4.96 (3H, m), 6.55-7.56 (10H, m), 8.53 (1H, brs)
143) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.10-2.12 (4H, m), 2.53-3.03 (3H, m), 3.34-3.95 (1H, m), 4.27-4.95 (1H, m), 6.53-7.70 (10H, m), 8.57, 8.59, 8.86 (total 1H, brs)
144) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.13-2.13 (4H, m), 2.45 (3H, s), 2.53-3.14 (3H, m), 3.27-4.10 (4H, m), 4.30-5.02 (1H, m), 6.52-7.05 (5H, m), 7.07-7.53 (5H, m), 8.70 (1H, brs), 9.13 (1H, brs)
145) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.08-2.15 (4H, m), 2.50-3.12 (3H, m), 3.25-4.02 (4H, m), 4.28-5.00 (1H, m), 6.52-7.05 (5H, m), 7.11-7.67 (5H, m), 8.91 (1H, brs), 9.13 (1H, brs)
146) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.12-2.75 (16H, m), 2.76-3.92 (3H, m), 3.93-4.42 (1H, m), 6.32-8.25 (15H, m)
Example 222
0.41 g of dimethylaminopyridine and 0.35 g of dimethylaminopyridine hydrochloride were added to a solution of 0.4 g of 5-hydroxymethyl-7-chloro-1-[4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 10 ml of chloroform. The mixture was heated and made into a solution. To the solution were added 0.15 g of N,N-dimethylglycine hydrochloride and 0.46 g of dicyclohexyl-carbodiimide in this order at room temperature with stirring. The mixture was stirred overnight at room temperature. Thereto were added 1.3 ml of methanol and 0.4 ml of acetic acid, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with dichloromethane. The extract was dried over magnesium sulfate and subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: methyl acetate) and then mixed with hydrochloric acid-methanol. The mixture was stirred at room temperature for 1 hour to form a hydrochloride and obtain 0.36 g of 5-[(2-dimethylaminoacetyloxy)methyl]-7-chloro-1-[4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine hydrochloride.
Colorless and amorphous
.sup.1 H-NMR (DMSO-d.sub.6) .delta.: 1.2-2.2 (3H, m), 2.35 (3H, s), 2.83 (6H, s), 2.7-3.2 (1H, m), 3.3-3.6 (3H, m), 4.29 (2H, s), 4.2-5.1 (2H, m), 6.80 (1H, d, J=8.2 Hz), 7.0-7.8 (10H, m), 10.4-10.6 (1H, m), 10.6-10.9 (1H, br)
Example 223
0.28 g of lithium borohydride was added to a solution of 2.2 g of 5-ethoxycarbonylmethoxy-7-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine dissolved in 50 ml of tetrahydrofuran, at room temperature with stirring. The mixture was refluxed for 30 minutes. The reaction mixture was poured into a diluted hydrochloric acid. The mixture was subjected to extraction with dichloromethane. The extract was dried over magnesium sulfate and subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=100/1.fwdarw.50/1) and then recrystallized from dichloromethane-diethyl ether to obtain 1.6 g of 5-(2-hydroxyethoxy)-7-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
A white powder
Melting point: 185.degree.-187.5.degree. C.
Example 224
In 10 ml of dimethylformamide were dispersed 0.4 g of 5-[2-(p-toluenesulfonyloxy)ethoxy]-7-fluoro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine, 0.38 ml of N-methylpiperazine and 0.3 g of sodium iodide. The dispersion was stirred at room temperature for 3 days. The reaction mixture was concentrated. The residue was mixed with water and the mixture was subjected to extraction with ethyl acetate. The extract was dried over sodium carbonate and purified by silica gel column chromatography (elutant: dichloromethane/-methanol=10/1) to obtain 1.15 g of 5-[2-(4-methyl-1-piperazinyl)ethoxy]-7-fluoro-1-[2-methoxy-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.37-2.90 (15H, m), 2.33 (3H, s), 2.47 (3H, s), 3.38-3.99 (5H, m), 4.31-5.08 (2H, m), 6.56-7.98 (11H, m)
Example 225
0.178 g of sodium iodide and 0.152 g of 4-acetyl-piperazine were added to a solution of 0.25 g of 5-[2-(p-toluenesulfonyloxy)ethyl]-7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 20 ml of dry dimethylformamide. The mixture was stirred at room temperature for 1 hour and heated at 50.degree. C. for 2 hours and at 60.degree. C. for 3 hours. The reaction mixture was mixed with 1N hydrochloric acid and diethyl ether. The aqueous layer was separated, then neutralized with a saturated aqueous sodium bicarbonate solution, and subjected to extraction with dichloromethane. The dichloromethane layer was washed with water, then dried and subjeced to distillation to remove the solvent. The resiude was mixed with hydrochloric acid-ethanol to form a hydrochloride and obtain 150 mg of 5-[2-(4-acetyl-1-piperazinyl)ethyl]-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine hydrochloride.
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.: 1.02-2.59 [16H, m (2.09, 3H, s-like)], 2.59-3.83 (9H, m), 3.87-4.63 (2H, m), 6.56-8.12 (10H, m), 10.27, 10.45 (total 1H, brs), 11.00 (1H, brs)
Tables 110 to 154 (Examples 226 to 314) and their NMR data appear here.
The following compounds were obtained in the same manner as in Examples 1 and 2, using respective raw materials.
TABLE 110______________________________________ ##STR609##Example 226Structure: ##STR610## ##STR611## ##STR612##Crystal form: white powder ##STR613##Melting point: 183-185.degree. C. Form: free______________________________________
TABLE 111______________________________________Example 227Structure: ##STR614## ##STR615## ##STR616##Crystal form: white powder ##STR617##Melting point: 200-201.5.degree. C.Form: freeExample 228Structure: ##STR618## ##STR619## ##STR620##Crystal form: colorless needleForm: freeNMR: 147)______________________________________
TABLE 112______________________________________Example 229Structure: ##STR621##R.sup.2 : 3-OCH.sub.3 ##STR622##Crystal form: colorless and amorphousForm: freeNMR: 148)Example 230Structure: ##STR623##R.sup.2 : 3-OCH.sub.3 ##STR624##Crystal form: colorless needle ##STR625##Melting point: 158-160.degree. C.Form: free______________________________________
TABLE 113______________________________________Example 231Structure: ##STR626## ##STR627## ##STR628##Crystal form: colorless and amorphousForm: freeNMR: 149)Example 232Structure: ##STR629## ##STR630##R.sup.2 : 2-CH.sub.3 ##STR631##Crystal form: colorless and amorphousForm: freeNMR: 150)______________________________________
TABLE 114______________________________________Example 233Structure: ##STR632## ##STR633##R.sup.2 : 2-CH.sub.3 ##STR634##Crystal form: colorless and amorphousForm: freeNMR: 151)Example 234Structure: ##STR635## ##STR636##R.sup.2 : 2-CH.sub.3 ##STR637##Crystal form: colorless and amorphousForm: freeNMR: 152)______________________________________
TABLE 115______________________________________Example 235Structure: ##STR638## ##STR639##R.sup.2 : 2-CH.sub.3 ##STR640##Crystal form: colorless and amorphousForm: freeNMR: 153)Example 236Structure: ##STR641## ##STR642##R.sup.2 : 2-OCH.sub.3 ##STR643##Crystal form: colorless and amorphousForm: freeNMR: 154)______________________________________
TABLE 116______________________________________Example 237Structure: ##STR644## ##STR645##R.sup.2 : 2-OCH.sub.3 ##STR646##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 155)Example 238Structure: ##STR647## ##STR648##R.sup.2 : 2-OCH.sub.3 ##STR649##Crystal form: white powderRecrystallization solvent: ethyl acetate-diethyl etherMelting point: 214-216.degree. C.Form: free______________________________________
TABLE 117______________________________________Example 239Structure: ##STR650## ##STR651##R.sup.2 : 2-OCH.sub.3 ##STR652##Crystal form: white powderRecrystallization solvent: acetone-n-hexaneForm: freeExample 240Structure: ##STR653## ##STR654##R.sup.2 : 2-OCH.sub.3 ##STR655##Crystal form: white powderRecrystallization solvent: acetone-diethyl etherMelting point: 263-264.degree. C.Form: free______________________________________
TABLE 118______________________________________Example 241Structure: ##STR656## ##STR657##R.sup.2 : 2-OCH.sub.3 ##STR658##Crystal form: white powderRecrystallization solvent: ethanol-diethyl etherMelting point: 218-218.5.degree. C.Form: freeExample 242Structure: ##STR659## ##STR660##R.sup.2 : 3-OCH.sub.3 ##STR661##Crystal form: colorless and amorphousForm: freeNMR: 156)______________________________________
TABLE 119______________________________________Example 243Structure: ##STR662## ##STR663##R.sup.2 : 3-OCH.sub.3 ##STR664##Crystal form: colorless and amorphousForm: freeNMR: 157)Example 244Structure: ##STR665## ##STR666##R.sup.2 : 3-OCH.sub.3 ##STR667##Crystal form: colorless and amorphousForm: freeNMR: 158)______________________________________
TABLE 120______________________________________Example 245Structure: ##STR668## ##STR669##R.sup.2 : 2-CH.sub.3 ##STR670##Crystal form: colorless and amorphousForm: freeNMR: 159)Example 246Structure: ##STR671## ##STR672##R.sup.2 : 2-OCH.sub.3 ##STR673##Crystal form: white powderRecrystallization solvent: acetone-diethyl etherMelting point: 205-208.degree. C.Form: free______________________________________
TABLE 121______________________________________Example 247Structure: ##STR674## ##STR675##R.sup.2 : 2-OCH.sub.3 ##STR676##Crystal form: colorless and amorphousForm: freeNMR: 160)Example 248Structure: ##STR677## ##STR678##R.sup.2 : 2-OCH.sub.3 ##STR679##Crystal form: white powderRecrystallization solvent: acetone-n-hexaneMelting point: 209-209.5.degree. C.Form: free______________________________________
TABLE 122______________________________________Example 249Structure: ##STR680## ##STR681##R.sup.2 : 2-OCH.sub.3 ##STR682##Crystal form: colorless and amorphousForm: freeNMR: 161)Example 250Structure: ##STR683## ##STR684##R.sup.2 : 2-OCH.sub.3 ##STR685##Crystal form: colorless and amorphousForm: freeNMR: 162)______________________________________
TABLE 123______________________________________Example 251Structure: ##STR686## ##STR687##R.sup.2 : 2-OCH.sub.3 ##STR688##Crystal form: colorless and amorphousForm: freeNMR: 163)Example 252Structure: ##STR689## ##STR690##R.sup.2 : 3-OCH.sub.3 ##STR691##Crystal form: colorless and amorphousForm: freeNMR: 164)______________________________________
TABLE 124______________________________________Example 253Structure: ##STR692## ##STR693##R.sup.2 : 3-OCH.sub.3 ##STR694##Crystal form: colorless and amorphousForm: freeNMR: 165)Example 254Structure: ##STR695## ##STR696##R.sup.2 : 3-OCH.sub.3 ##STR697##Crystal form: colorless and amorphousForm: freeNMR: 166)______________________________________
TABLE 125______________________________________Example 255Structure: ##STR698## ##STR699##R.sup.2 : 3-OCH.sub.3 ##STR700##Crystal form: colorless and amorphousForm: freeNMR: 167)Example 256Structure: ##STR701## ##STR702## ##STR703##Crystal form: colorless and amorphousForm: freeNMR: 168)______________________________________
TABLE 126______________________________________Example 257Structure: ##STR704## ##STR705##R.sup.2 : 2-OCH.sub.3 ##STR706##Crystal form: white powderRecrystallization solvent: ethanol-diethyl etherMelting point: 223.5-224.degree. C.Form: freeExample 258Structure: ##STR707## ##STR708##R.sup.2 : 2-OCH.sub.3 ##STR709##Crystal form: white powderRecrystallization solvent: ethanol-n-hexaneMelting point: 212-213.degree. C.Form: hydrochloride______________________________________
TABLE 127______________________________________Example 259Structure: ##STR710## ##STR711## ##STR712##Crystal form: colorless needleRecrystallization solvent: dichloromethane-ethanolMelting point: 211-213.degree. C.Form: freeExample 260Structure: ##STR713## ##STR714##R.sup.2 : 2-CH.sub.3 ##STR715##Crystal form: colorless and amorphousForm: freeNMR: 169)______________________________________
TABLE 128______________________________________Example 261Structure: ##STR716## ##STR717##R.sup.2 : 2-CH.sub.3 ##STR718##Crystal form: light yellow and amorphousForm: hydrochlorideNMR: 170)Example 262Structure: ##STR719## ##STR720## ##STR721##Crystal form: colorless and amorphousForm: freeNMR: 171)______________________________________
TABLE 129______________________________________Example 263Structure: ##STR722## ##STR723## ##STR724##Crystal form: colorless and amorphousForm: freeNMR: 172)Example 264Structure: ##STR725## ##STR726## ##STR727##Crystal form: colorless and amorphousForm: freeNMR: 173)______________________________________
TABLE 130______________________________________Example 265Structure: ##STR728## ##STR729## ##STR730##Crystal form: colorless and amorphousForm: freeNMR: 174)Example 266Structure: ##STR731## ##STR732## ##STR733##Crystal form: colorless and amorphousForm: freeNMR: 175)______________________________________
TABLE 131______________________________________Example 267Structure: ##STR734## ##STR735## ##STR736##Crystal form: colorless and amorphousForm: freeNMR: 176)Example 268Structure: ##STR737## ##STR738##R.sup.2 : 2-CH.sub.3 ##STR739##Crystal form: colorless and amorphousForm: freeNMR: 177)______________________________________
TABLE 132______________________________________Example 269Structure: ##STR740## ##STR741##R.sup.2 : 2-CH.sub.3 ##STR742##Crystal form: colorless and amorphousForm: freeNMR: 178)Example 270Structure: ##STR743## ##STR744##R.sup.2 : 2-CH.sub.3 ##STR745##Crystal form: colorless and amorphousForm: freeNMR: 179)______________________________________
TABLE 133______________________________________Example 271Structure: ##STR746## ##STR747## ##STR748##Crystal form: white powderRecrystallization solvent: acetone-n-hexaneMelting point: 163-165.degree. C.Form: freeExample 272Structure: ##STR749## ##STR750## ##STR751##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 180)______________________________________
TABLE 134______________________________________Example 273Structure: ##STR752## ##STR753## ##STR754##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 181)Example 274Structure: ##STR755## ##STR756## ##STR757##Crystal form: colorless and amorphousForm: freeNMR: 182)______________________________________
TABLE 135______________________________________Example 275Structure: ##STR758## ##STR759## ##STR760##Crystal form: colorless and amorphousForm: freeNMR: 183)Example 276Structure: ##STR761## ##STR762## ##STR763##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 184)______________________________________
TABLE 136______________________________________Example 277Structure: ##STR764## ##STR765## ##STR766##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 185)Example 278Structure: ##STR767## ##STR768## ##STR769##Crystal form: white powderRecrystallization solvent:dichloromethane-n-hexaneMelting point: 185-187.degree. C. (decomposed)Form: hydrochloride______________________________________
TABLE 137______________________________________Example 279Structure: ##STR770## ##STR771## ##STR772##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 186)Example 280Structure: ##STR773## ##STR774## ##STR775##Crystal form: white powderRecrystallization solvent:acetone-n-hexaneMelting point: 266.5-267.degree. C.Form: free______________________________________
TABLE 138______________________________________Example 281Structure: ##STR776## ##STR777## ##STR778##Crystal form: white powderRecrystallization solvent: acetoneMelting point: 255-257.degree. C.Form: freeExample 282Structure: ##STR779## ##STR780## ##STR781##Crystal form: white powderRecrystallization solvent:acetone-n-hexaneMelting point: 263.5-264.degree. C.Form: free______________________________________
TABLE 139______________________________________Example 283Structure: ##STR782## ##STR783## ##STR784##Crystal form: white powderRecrystallization solvent: ethanolMelting point: 240-241.5.degree. C.Form: freeExample 284Structure: ##STR785## ##STR786## ##STR787##Crystal form: colorless and amorphousForm: freeNMR: 187)______________________________________
TABLE 140______________________________________Example 285Structure: ##STR788## ##STR789## ##STR790##Crystal form: white powderRecrystallization solvent: diethyl etherMelting point: 159-163.degree. C. (decomposed)Form: freeExample 286Structure: ##STR791## ##STR792## ##STR793##Crystal form: colorless and amorphousForm: freeNMR: 188)______________________________________
TABLE 141______________________________________Example 287Structure: ##STR794## ##STR795## ##STR796##Crystal form: colorless and amorphousForm: freeNMR: 189)Example 288Structure: ##STR797## ##STR798## ##STR799##Crystal form: colorless and amorphousForm: freeNMR: 190)______________________________________
TABLE 142______________________________________Example 289Structure: ##STR800## ##STR801## ##STR802##Crystal form: colorless and amorphousForm: freeNMR: 191)Example 290Structure: ##STR803## ##STR804## ##STR805##Crystal form: whire powderRecrystallization solvent:dichloromethane-diethyl etherMelting point: 247-248.degree. C.Form: free______________________________________
TABLE 143______________________________________Example 291Structure: ##STR806## ##STR807## ##STR808##Crystal form: colorless and amorphousForm: freeNMR: 192)Example 292Structure: ##STR809## ##STR810## ##STR811##Crystal form: white powderRecrystallization solvent:acetone-diethyl etherMelting point: 192.5-194.degree. C.Form: free______________________________________
TABLE 293______________________________________Example 293Structure: ##STR812## ##STR813## ##STR814##Crystal form: white powderRecrystallization solvent:dichloromethane-diethyl etherMelting point: 171-172.degree. C.Form: freeExample 294Structure: ##STR815## ##STR816## ##STR817##Crystal form: colorless and amorphousForm: freeNMR: 193)______________________________________
TABLE 145______________________________________Example 295Structure: ##STR818## ##STR819## ##STR820##Crystal form: colorless and amorphousNMR: 194)Form: freeExample 296Structure: ##STR821## ##STR822## ##STR823##Crystal form: colorless and amorphousNMR: 195)Form: free______________________________________
TABLE 146______________________________________Example 297Structure: ##STR824## ##STR825## ##STR826##Crystal form: colorless and amorphousForm: freeNMR: 196)Example 298Structure: ##STR827## ##STR828## ##STR829##Crystal form: colorless and amorphousForm: freeNMR: 197)______________________________________
TABLE 147______________________________________Example 299Structure: ##STR830## ##STR831## ##STR832##Crystal form: colorless and amorphousForm: freeNMR: 198)Example 300Structure: ##STR833## ##STR834## ##STR835##Crystal form: colorless and amorphousNMR: 199)Form: free______________________________________
TABLE 148______________________________________Example 301Structure: ##STR836## ##STR837## ##STR838##Crystal form: colorless and amorphousForm: freeNMR: 200)Example 302Structure: ##STR839## ##STR840## ##STR841##Crystal form: colorless and amorphousNMR: 201)Form: free______________________________________
TABLE 149______________________________________Example 303Structure: ##STR842## ##STR843## ##STR844##Crystal form: white powderRecrystallization solvent:ethanol-n-hexaneMelting point: 214-215.degree. C.Form: freeExample 304Structure: ##STR845## ##STR846## ##STR847##Crystal form: white powderRecrystallization solvent:acetone-diethyl etherMelting point: 193-195.degree. C.Form: hydrochloride______________________________________
TABLE 150______________________________________Example 305Structure: ##STR848## ##STR849## ##STR850##Crystal form: colorless and amorphousForm: hydrochlorideNMR: 202)Example 306Structure: ##STR851## ##STR852## ##STR853##Crystal form: white powderRecrystallization solvent: acetone-n-hexaneMelting point: 211-212.degree. C.Form: free______________________________________
TABLE 151______________________________________Example 307Structure: ##STR854## ##STR855## ##STR856##Crystal form: colorless and amorphousForm: freeNMR: 203)Example 308Structure: ##STR857## ##STR858## ##STR859##Crystal form: colorless and amorphousForm: freeNMR: 204)______________________________________
TABLE 152______________________________________Example 309Structure: ##STR860## ##STR861## ##STR862##Crystal form: colorless and amorphousForm: freeNMR: 205)Example 310Structure: ##STR863## ##STR864## ##STR865##Crystal form: colorless needleRecrystallization solvent:dichloromethane-diethyl etherMelting point: 153-156.degree. C.Form: free______________________________________
TABLE 153______________________________________Example 311Structure: ##STR866## ##STR867## ##STR868##Crystal form: colorless and amorphousForm: freeNMR: 206)Example 312Structure: ##STR869## ##STR870## ##STR871##Crystal form: colorless and amorphousForm: freeNMR: 207)______________________________________
TABLE 314______________________________________Example 313Structure: ##STR872## ##STR873## ##STR874##Crystal form: colorless oilForm: freeNMR: 208)Example 314Structure: ##STR875## ##STR876## ##STR877##Crystal form: colorless and amorphousForm: freeNMR: 209)______________________________________
147) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.36-2.23 (4H, m), 2.25-3.20 (5H, m), 3.66 (3H, s), 4.00-4.27 (4H, m), 4.87-5.19 (1H, m), 6.52-7.23 (8H, m), 7.24 (1H, d, J=2.4Hz), 7.31-7.55 (2H, m), 8.18 (1H, dd, J=1.8Hz, 7.8Hz), 8.47 (1H, d, J=8.4Hz), 9.90-10.05 (total 1H, each s)
148) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.12-4.32 (28H, m), 4.73-5.12 (1H, m), 6.04 (1H, d, J=7.8Hz), 6.45-7.47 (8H, m), 8.15 (1H, dd, J=1.7Hz, 7.8Hz), 8.38 (1H, d, J=7.8Hz), 10.19, 10.28 (total 1H, each s)
149) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.20-3.29, 3.51-4.52, 4.95-5.19 (total 14H, m), 6.37-7.85 (13H, m), 8.54-8.79, 8.91-9.19 (total 1H, m)
150) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.15-4.03, 4.12-4.47, 4.91-5.14 (total 22H, m), 2.02 (3H, s), 6.40-7.78 (10H, m), 8.45, 8.69 (total 1H, each s)
151) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.40-3.02, 3.09-3.94, 4.27-5.15 (total 25H, m), 6.40-6.83, 7.05-7.78 (total 9H, m), 6.94 (1H, dd, J=2.2Hz, 8.4Hz), 8.56, 8.73, 8.86 (total 1H, each s)
152) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.31-3.18, 3.35-3.97, 4.30-4.77, 4.86-5.13 (total 26H, m), 5.49-6.02, 6.18-6.40 (total 1H, m), 6.41-7.00, 7.06-7.84 (total 10H, m), 8.25-8.63 (1H, m)
153) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.12-3.91, 4.16-4.92, 4.87-5.11 (total 23H, m), 1.87 (3H, s), 5.85-6.18 (1H, m), 6.35-6.99, 7.04-7.78 (total 10H, m), 8.45-8.96 (1H, m)
154) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.00-2.25 (5H, m), 1.28 (3H, t, J=7.1Hz), 2.26-5.08 (17H, m), 4.20 (2H, q, J=7.1Hz), 6.61-7.92 (10H, m), 8.25, 8.47 (total 1H, each brs)
155) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.75-1.01 (3H, m), 1.05-2.04 (13H, m), 2.62-4.69 (17H, m), 6.79-7.78 (10H, m), 10.54, 10.76 (total 1H, each brs), 11.17 (1H, brs)
156) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.22-1.67 (2H, m), 1.71-3.34 (16H, m), 2.49 (3H, s), 3.53-4.08 (1H, m), 3.64, 3.70 (total 3H, s), 4.37-5.21 (1H, m), 6.55-7.53 (9H, m), 8.03-8.44 (2H, m)
157) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.12-4.13 (17H, m), 2.49 (3H, s), 4.37-5.25 (1H, m), 6.54-7.58 (9H, m), 8.04-8.46 (2H, m)
158) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.20-4.02 (21H, m), 2.49 (3H, s), 4.40-5.23 (1H, m), 6.53-7.58 (9H, m), 8.03-8.47 (2H, m)
159) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.31-4.70, 4.87-5.14 (total 14H, m), 6.48-7.84 (13H, m), 9.15, 9.31, 9.53 (total 1H, each s)
160) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.10-5.05 (22H, m), 5.57-5.88 (1H, m), 6.68-7.89 (10H, m), 8.29, 8.50 (total 1H, each brs)
161) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.88-2.72 (6H, m) 2.32 (3H, s), 2.46 (3H, s), 3.28-3.97 (10H, m), 4.58-4.82 (1H, m), 5.90-6.18 (1H, m), 6.58-7.56 (10H, m), 8.06, 8.28 (total 1H, brs)
162) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 2.03-2.68 (2H,m), 2.45 (3H, s), 2.99 (3H, s), 3.10 (3H, s), 3.32-3.55 (1H, m), 3.72 (3H, s), 4.57-4.78 (1H, m), 5.88-6.16 (1H, m), 6.57-7.56 (10H, m), 8.25, 8.51 (total 1H, brs)
162) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 2.03-2.68 (2H, m), 2.45 (3H, s), 2.99 (3H, s), 3.10 (3H, s), 3.32-3.55 (1H, m), 3.72 (3H, s), 4.57-4.78 (1H, m), 5.88-6.16 (1H, m), 6.57-7.56 (10H, M), 8.25, 8.51 (total 1H, brs)
163) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.44-1.82 (6H, m), 2.16-2.69 (2H, m), 2.46 (3H, s), 3.18-3.93 (7H, m), 3.74 (3H, s), 4.58-4.82 (1H, m), 5.87-6.17 (1H, m), 6.56-7.57 (10H, m), 8.24, 8.51 (total 1H, brs)
164) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.21-2.23 (4H, m), 2.56-3.37 (9H, m), 3.57-4.05 (1H, m), 3.64, 3.71 (total 3H, s), 4.37-5.23 (1H, m), 6.52-7.76 (9H, m), 8.23-8.58 (2H, m)
165) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.19-2.25 (10H,m), 2.54-4.02 (15H, m), 4.34-5.23 (1H, m), 6.54-7.73 (9H, m), 8.22-8.55 (2H, m)
166) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.23-2.27 (4H, m), 2.55-3.37 (9H, m), 3.58-3.99 (1H, m), 3.65, 3.72 (total 3H, s), 4.37-5.23 (1H, m), 6.53-6.68 (1H, m), 6.77-7.93 (8H, m), 8.30-8.95 (2H, m)
167) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.18-2.27 (10H, m), 2.52-3.98 (15H, m), 4.35-5.26 (1H, m), 6.52-7.48 (9H, m), 8.29-8.47 (1H, m), 8.60, 8.87 (total 1H, brs)
168) .sup.1 H-NMR (DMSO-d.sub.6) .delta. ppm: 0.73-2.03 (16H, m), 2.62-4.68 (17H, m), 6.78-7.75 (10H, m), 10.54, 10.76 (total 1H, each brs), 11.17 (1H, brs)
169) .sup.1 H-NMR (CDCl.sub.3) .delta.: 1.40-3.05, 3.14-4.06 (total 20H, m), 4.31-4.75, 4.82-5.11 (total 2H, m), 6.41-6.82, 7.08-7.80 (total 9H, m), 6.93 (1H, dd, J=2.4Hz, 8.4Hz), 8.22, 8.37, 8.55 (total 1H, each s).
170) .sup.1 H-NMR (DMSO-d.sub.6) .delta. ppm: 1.35-4.15 (20H, m), 4.46-5.08 (2H, m), 6.55-6.98, 7.04-7.21, 7.22-7.84 (total 10H, m), 10.25-10.91 (2H, m)
171) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.88-1.18 (6H, m), 2.05-3.98 (16H, m), 2.46 (3H, s), 3.73 (3H, s), 4.58-4.83 (1H, 5.93-6.23 (1H, m), 6.55-7.58 (10H, m) 7.93, 8.01 (total 1H, brs)
172) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.18-4.02 (23H, m), 2.47 (3H, s), 4.68-4.87 (1H, m), 6.03-6.26 (1H, m), 6.57-8.12 (11H, m)
173) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.81-4.07 (25H, m), 3.69, 3.73 (total 3H, s), 4.32-5.23 (1H, m), 6.52-6.66 (1H, m), 6.67-7.72 (8H, m), 8.19-8.54 (2H, m)
174) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.93-4.13 (17H, m), 2.32 (3H, s), 2.36 (3H, s), 3.70, 3.73 (total 3H, s), 4.35-5.23 (1H, m), 6.53-6.70 (1H, m), 6.72-7.74 (8H, m), 8.26-8.57 (2H, m)
175) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.78-4.13 (25H, m), 3.70, 3.75 (total 3H, s), 4.32-5.23 (1H, m), 6.51-6.74 (1H, m), 6.88-7.58 (7H, m), 7.65-7.88 (1H, m), .8.26-8.94 (2H, m)
176) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.93-4.13 (17H, m), 2.32 (3H, s), 2.36 (3H, s), 3.71, 3.73 (total 3H, s), 4.36-5.23 (1H, m), 6.52-6.75 (1H, m), 6.80-7.57 (7H, m), 7.65-7.90 (1H, m), 8.27-8.92 (2H, m)
177) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.35-4.71, 4.84-5.14 (total 14H, m), 6.41-6.80, 6.80-7.79 (total 10H, m), 7.91, 7.98, 8.04, 8.15, 8.20 (total 2H, each s), 8.46, 8.86 (total 1H, each s)
178) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.32-5.12 (14H, m), 6.42-7.88 (10H, m), 8.42-8.57, 8.70, 8.77, 8.83 (total 2H, each s)
179) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.31-5.11 (14H, m, 2.35, 2.42 (each s)), 6.41-7.83 (10H, m), 8.32, 8.47, 8.50, 8.57, 8.85 (total 2H, each s)
180) .sup.1 H-NMR (DMSO-d.sub.6) .delta. ppm: 0.68-2.49 (13H, m), 2.35, 2.41 (total 1H, each s), 2.50-5.09 (8H, m), 6.56-8.08 (10H, m), 10.52, 10.69 (total 1H, each brs), 10.81 (1H, brs)
181) .sup.1 H-NMR (DMSO-d.sub.6) .delta. ppm: 1.00-2.49 (11H, m), 2.35, 2.41 (total 3H, each s), 2.51-5.13 (8H, m), 6.53-7.82 (10H, m), 10.54 10.71 (total 1H, each brs), 10.73 (1H, brs)
182) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.13-3.32 (10H, m), 3.42-5.10 (3H, m), 4.62 (1H, t, J=7Hz), 6.45-7.93 (10H, m), 8.67-9.26 (2H, m)
183) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.02-3.35 (10H, m), 3.37-5.12 (3H, m), 4.83 (1H, t, J=6.6Hz), 6.47-7.89 (10H, m), 8.42-9.11 (2H, m)
184) .sup.1 H-NMR (DMSO-d.sub.6) .delta. ppm: 1.01-2.52 (10H, m), 2.53-5.06 (9H, m), 5.38-5.73 (2H, m), 5.83-6.24 (1H, m), 6.54-7.82 (10H, m), 10.51, 10.69 (total 1H, each brs), 11.10 (1H, brs)
185) .sup.1 H-NMR (DMSO-d.sub.6) .delta. ppm: 1.00-2.57 (10H, m), 2.58-5.06 (6H, m), 5.15-5.63 (2H, m), 5.82-6.18 (1H, m), 6.52-8.08 (10H, m), 9.15-9.74 (2H, br), 10.51, 10.68 (total 1H, brs)
186) .sup.1 H-NMR (DMSO-d.sub.6) .delta. ppm: 1.04-2.59 (10H, m), 2.60-5.08 (7H, m), 6.53-7.88 (10H, m), 9.70 (2H, brs), 10.52, 10.68 (total 1H, (each brs)
187) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.16-2.63 (5H, m), 2.36, 2.47, 2.52 (total 6H, s), 2.66-3.32 (2H, m), 3.36-5.22 (4H, m), 6.44-8.15 (14H, m)
188) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.14-3.92 (18H, m), 2.40 (3H, s), 2.46 (3H, s), 4.23-5.18 (1H, m), 6.41-6.98 (3H, 7.02-7.90 (8H, m)
189) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.13-3.92 (13H, m), 2.41 (3H, s), 4.27-5.14 (1H, m), 5.10-5.23 (2H, m), 5.78-6.05 (1H, 6.43-8.35 (11H, m)
190) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.12-3.87 (18h, m), 2.07 (3H, s), 2.42 (3H, s), 4.28-5.16 (1H, m), 6.46-8.22 (11H, m)
191) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.17-3.40 (18H, m), 2.43 (3H, s), 4.30-5.17 (1H, m), 6.45-8.13 (11H, m)
192) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.79-5.21 (11H, m), 2.38, 2.44 (total 3H, each s), 6.50-8.30 (13H, m)
193) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.14-3.92 (18H, m), 2.04 (3H, s), 2.46 (3H, s), 4.23-5.08 (1H, m), 6.78-8.35 (11H, m)
194) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.82-4.01 (30H, m), 4.44-5.06 (1H, m), 6.68-7.80 (10H, m), 8.24, 8.48 (total 1H, brs)
195) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.07-4.12 (21H, m), 2.38, 2.41 (total 3H, s), 4.43-5.03 (1H, m), 6.71-7.87 (10H, m), 8.36, 8.58 (total 1H, brs)
196) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.13-4.12 (9H, m), 3.92 (3H, brs), 4.25-4.47 (2H, m), 6.45-6.85 (2H, m), 6.88-7.52 (8H, m), 7.56-7.96 (2H, m), 8.27-8.56 (2H, m), 8.23, 9.03 (total 1H, brs)
197) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.06-4.08 (15H, m), 4.37-5.03 (1H, m), 6.65-8.56 (16H, m)
198) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.14-2.12 (4H, m), 2.28-5.06 (10H, m), 6.51-7.89 (14H, m), 8.28-8.75 (2H, m)
199) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.56-2.17 (4H, m), 2.33-3.52 (4H, m), 3.76-4.17 (4H, m), 6.98-7.55 (10H, m), 7.63-7.97 (2H, m), 8.22 (2H, dd, J=4.9Hz, 1.5Hz), 8.68-9.16 (2H, m)
200) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.14-3.93 (18H, m), 4.25-5.14 (1H, m), 5.08-5.29 (2H, m), 5.78-6.02 (1H, m), 6.44-7.78 (10H, m), 7.96, 8.21 (total 1H, brs)
201) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.10-1.40 (1H, m), 1.50-4.00 (22H, m), 4.50-5.10 (1H, m), 6.40-7.05 (3H, m), 7.10-7.90 (8H, m)
202) .sup.1 H-NMR (DMSO-d.sub.6) .delta. ppm: 1.05-2.52 (4H, m), 2.53-2.82 (1H, m), 3.01-4.12 (10H, m), 4.48-4.89 (2H, m), 6.76-7.76 (10H, m), 9.68 (2H, brs), 10.59, 10.75 (total 1H, each brs)
203) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 0.78-2.45 (5H, m), 2.46-5.95 (9H, m), 3.02 (3H, s), 6.67-7.92 (10H, m), 8.27, 8.60 (total 1H, each brs)
204) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.51-2.59 (4H, m), 2.65-3.07 (1H, m), 3.81 (3H, s), 4.04-5.29 (6H, m), 6.50-6.78, 6.88-7.10, 7.12-8.01 (total 11H, m)
205) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.37-3.08 (5H, m), 3.95-5.25 (6H, m), 5.65-6.27 (2H, m), 6.42-6.73, 6.77-7.10, 7.10-8.08 (total 10H, m)
206) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.11 (3H, t, J=7.4Hz), 1.50-3.06 (11H, m), 3.35-3.85 (4H, m), 4.07-5.29 (6H, m), 6.46-6.73, 6.86-7.14, 7.14-7.69 (total 8H, m), 7.78 (2H, d, J=8.3Hz), 7.89 (1H, d, J=8.1Hz)
207) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.50-3.02 (5H, m), 3.11 (2H, t, J=6.3Hz), 3.78 (3H, s), 3.94 (2H, t, J=6.3Hz), 4.04-5.23 (4H, m), 6.62 (1H, d, J=8.1Hz), 7.02 (1H, d, J=7.9Hz), 7.07-7.80 (8H, m), 8.11 (1H, d, J=7.5Hz)
208) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.45-3.32 (7H, m), 3.59-5.22 (6H, m), 6.62 (1H, d, J=8.1Hz), 6.87-7.75 (10H, m), 8.07 (1H, d, J=6.3Hz)
209) .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.10 (3H, t, J=7.1Hz), 1.50-3.22 (13H, m), 3.32-3.79 (4H, m), 3.94 (2H, t, J=6.2Hz), 4.04-5.25 (4H, m), 6.53-6.75 (1H, m), 6.87-7.67 (9H, m), 8.11 (1H, d, J=7.4Hz)
The compounds shown in Table 155 were obtained in the same manner as in Examples 1 and 2, using respective starting materials.
Table 155 (Examples 315 to 429) and their NMR data appear here.
TABLE 155 - ##STR878## ##STR879## ##STR880## ##STR881## ##STR882## ##STR883## 315 ##STR884## ##STR885## Colorless andamorphous (-) 316 ##STR886## ##STR887## Colorless andamorphous (-) 317 ##STR888## ##STR889## Colorless andamorphous (-) 318 ##STR890## ##STR891## Colorless andamorphous (HCl) 319 ##STR892## ##STR893## White powder(Acetone-n-hexane) 206-207(-) 320 ##STR894## ##STR895## Colorless andamorphous (-) 321 ##STR896## ##STR897## White powder(Acetone-n-hexane) 192-193(-) 322 ##STR898## ##STR899## Colorless andamorphous (HCl) 323 ##STR900## ##STR901## White powder(Acetone-ethylacetate-n-hexane) 194-195.5(-) 324 ##STR902## ##STR903## White powder(Acetone-n-hexane) 198-199(decomposed)(-) 325 ##STR904## ##STR905## White powder(Acetone-n-hexane) 199-200(-) 326 ##STR906## ##STR907## White powder(Acetone-n-hexane) 228-229.5(-) 327 ##STR908## ##STR909## White powder(Acetone-n-hexane) 138-139(-) 328 ##STR910## ##STR911## Colorless andamorphous (-) 329 ##STR912## ##STR913## Colorless andamorphous (-) 330 ##STR914## ##STR915## White powder(Ethyl acetate-n-hexane) 192-193.5(-) 331 ##STR916## ##STR917## White powder(Acetone-ethylacetate-n-hexane) 206-207(decomposed)(-) 332 ##STR918## ##STR919## White powder(Acetone-diethylether) 247-248(-) 333 ##STR920## ##STR921## Colorless andamorphous (-) 334 ##STR922## ##STR923## Colorless andamorphous (-) 335 ##STR924## ##STR925## Colorless andamorphous (-) 336 ##STR926## ##STR927## Colorless andamorphous (-) 337 ##STR928## ##STR929## White powder(Acetone-n-hexane) 169-171(-) 338 ##STR930## ##STR931## White powder(Acetone-diethylether) 142-144(-) 339 ##STR932## ##STR933## White powder(Ethyl acetate-diethyl ether) 161-163.5(-) 340 ##STR934## ##STR935## Colorless andamorphous (-) 341 ##STR936## ##STR937## White powder 152.5-153(-) 342 ##STR938## ##STR939## White powder(Acetone-n-hexane) 199.5-222(decomposed)(-) 343 ##STR940## ##STR941## White powder(Ethyl acetate-n-hexane) 177-178(-) 344 ##STR942## ##STR943## Yellow plate 140-142.5(-) 345 ##STR944## ##STR945## Colorless andamorphous (-) 346 ##STR946## ##STR947## Yellow plate(Acetone-n-hexane) 183-184.5(-) 347 ##STR948## ##STR949## Colorless andamorphous (-) 348 ##STR950## ##STR951## Colorless andamorphous (-) 349 ##STR952## ##STR953## Colorless andamorphous (-) 350 ##STR954## ##STR955## Colorless andamorphous (-) 351 ##STR956## ##STR957## Colorless andamorphous (-) 352 ##STR958## ##STR959## Colorless andamorphous (-) 353 ##STR960## ##STR961## Colorless andamorphous (-) 354 ##STR962## ##STR963## Colorless andamorphous (-) 355 ##STR964## ##STR965## Colorless andamorphous (-) 356 ##STR966## ##STR967## Colorless andamorphous (-) 357 ##STR968## ##STR969## Colorless andamorphous (-) 358 ##STR970## ##STR971## Colorless needle(Ethanol-diethylether) (-) 359 ##STR972## ##STR973## Colorless andamorphous (-) 360 ##STR974## ##STR975## Colorless andamorphous (-) 361 ##STR976## ##STR977## Colorless andamorphous (-) 362 ##STR978## ##STR979## Colorless andamorphous (-) 363 ##STR980## ##STR981## Colorless andamorphous (-) 364 ##STR982## ##STR983## Colorless andamorphous (-) 365 ##STR984## ##STR985## Colorless andamorphous (-) 366 ##STR986## ##STR987## Colorless andamorphous (-) 367 ##STR988## ##STR989## Colorless andamorphous (-) 368 ##STR990## ##STR991## Colorless andamorphous (-) 369 ##STR992## ##STR993## Colorless andamorphous (-) 370 ##STR994## ##STR995## Light orangepowder(Diethyl ether) 182-183(-) 371 ##STR996## ##STR997## Light yellowpowder(Diethyl ether) 172-173(-) 372 ##STR998## ##STR999## White powder(Diethyl ether) 233-235(-) 373 ##STR1000## ##STR1001## White powder(Diethyl ether) 162-164(-) 374 ##STR1002## ##STR1003## White powder(Diethyl ether) 193-196(-) 375 ##STR1004## ##STR1005## Colorless andamorphous (-) 376 ##STR1006## ##STR1007## Colorless andamorphous (-) 377 ##STR1008## ##STR1009## Colorless andamorphous (-) 378 ##STR1010## ##STR1011## Colorless andamorphous (-) 379 ##STR1012## ##STR1013## Colorless andamorphous (-) 380 ##STR1014## ##STR1015## White powder(Acetone-n-hexane) 152-153(-) 381 ##STR1016## ##STR1017## Colorless andamorphous (-) 382 ##STR1018## ##STR1019## Colorless andamorphous (-) 383 ##STR1020## ##STR1021## Colorless andamorphous (-) 384 ##STR1022## ##STR1023## Colorless andamorphous (-) 385 ##STR1024## ##STR1025## Colorless andamorphous (-) 386 ##STR1026## ##STR1027## White powder(Acetone-n-hexane) 269-270(-) 387 ##STR1028## ##STR1029## White powder(Diethyl ether) 162-165(-) 388 ##STR1030## ##STR1031## White powder(Diethyl ether) 168-171(-) 390 ##STR1032## ##STR1033## Colorless andamorphous (-) 391 ##STR1034## ##STR1035## Colorless andamorphous (-) 392 ##STR1036## ##STR1037## Colorless andamorphous (-) 393 ##STR1038## ##STR1039## Colorless andamorphous (-) 394 ##STR1040## ##STR1041## White powder(Diethyl ether) 191-192(-) 395 ##STR1042## ##STR1043## White powder(Diethyl ether) 181-182(-) 396 ##STR1044## ##STR1045## White powder(Diethyl ether) 139-142(decomposed)(-) 397 ##STR1046## ##STR1047## White powder(Diethyl ether) 149-152(-) 398 ##STR1048## ##STR1049## Light brown andamorphous (-) 399 ##STR1050## ##STR1051## Colorless andamorphous (-) 400 ##STR1052## ##STR1053## Colorless oil (-) 401 ##STR1054## ##STR1055## White powder(Diethyl ether) 146-150(-) 402 ##STR1056## ##STR1057## White powder(Diethyl ether) 86-88(-) 403 ##STR1058## ##STR1059## White powder(Diethyl ether) 99-102(-) 404 ##STR1060## ##STR1061## Light yellow andamorphous (-) 405 ##STR1062## ##STR1063## Light yellow andamorphous (-) 406 ##STR1064## ##STR1065## White powder(Diethyl ether) 141-143(decomposed(-) 407 ##STR1066## ##STR1067## White powder(Diethyl ether) 140-142(-) 408 ##STR1068## ##STR1069## Colorless andamorphous (-) 409 ##STR1070## ##STR1071## Colorless andamorphous (-) 410 ##STR1072## ##STR1073## Colorless andamorphous (-) 411 ##STR1074## ##STR1075## Colorless andamorphous (-) 412 ##STR1076## ##STR1077## Colorless andamorphous (-) 413 ##STR1078## ##STR1079## Colorless andamorphous (-) 414 ##STR1080## ##STR1081## Colorless andamorphous (-) 415 ##STR1082## ##STR1083## Colorless andamorphous (-) 416 ##STR1084## ##STR1085## Colorless andamorphous (-) 417 ##STR1086## ##STR1087## Colorless andamorphous (-) 418 ##STR1088## ##STR1089## Colorless andamorphous (-) 419 ##STR1090## ##STR1091## Colorless andamorphous (-) 420 ##STR1092## ##STR1093## Colorless andamorphous (-) 421 ##STR1094## ##STR1095## Colorless andamorphous (-) 422 ##STR1096## ##STR1097## Colorless andamorphous (-) 423 ##STR1098## ##STR1099## Colorless andamorphous (-) 424 ##STR1100## ##STR1101## Colorless andamorphous (-) 425 ##STR1102## ##STR1103## Colorless andamorphous (-) 426 ##STR1104## ##STR1105## Colorless andamorphous (-) 427 ##STR1106## ##STR1107## White powder 188-189(-) 428 ##STR1108## ##STR1109## Colorless andamorphous (-) 429 ##STR1110## ##STR1111## White powder 175-177(-) Example .sup.1 H-NMR .delta. ppm 315 (CDCl.sub.3): 1.05-4.82(17H, m), 6.16-8.42(13H, m) 316 (CDCl.sub.3): 0.82-2.15(9H, m), 2.18-4.65(14H, m), 2.26, 2.33(total 6H, S), 6.68-7.05(3H, m), 7.05-8.73(8H, m) 317 (CDCl.sub.3): 0.97-2.11(4H, m), 2.13-3.43(5H, m), 2.38, 2.49(Total 3H, S), 3.46-4.67(2H, m), 3.65, 3.90(total 3H, brs), 6.64-7.42(11H, m), 8.03-8.56(2H, m), 8.66, 8.92(total 1H, brs) 318 (DMSO-d.sub.6): 1.08-2.48(4H, m), 2.26(3H, S), 2.57-4.10, 4.41-4.89( total 10H, m), 6.65-7.82(10H, m), 8.97, 9.45, 9.96(each 1H, each brs), 10.63, 10.78(total 1H, each brs) 320 (CDCl.sub.3): 1.01-5.18(12H, m), 6.48-7.98(11H, m), 8.44, 8.50(total 1H, each brs) 322 (CDCl.sub.3 +DMSO-d.sub.6): 0.58-5.05(22H, m), 6.57-7.95(10H, m), 9.38-10.32(3H, m) 329 (CDCl.sub.3): 1.12-2.21(4H, m), 2.52-5.01(7H, m), 3.62(3H, S), 6.58-7.91(12H, m), 8.23, 8.35(total 1H, each brs), 8.75-9.02(2H, m) 333 (CDCl.sub.3): 0.82-5.11(19H, m), 2.80(3H, S), 6.64-7.93(10H, m), 8.12-8.48(1H, m) 334 (CDCl.sub.3): 1.03-5.14(22H, m), 1.27(3H, t, J=7.12Hz), 4.14(2H, q, J=7.12Hz), 6.62-7.92(10H, m), 7.93-8.82(1H, m) 328 (CDCl.sub.3): 1.1-4.7, 4.9-5.1(total 29H, m with S at 2.35), 6.6-7.4, 7.6-8.2(total 9H, m), 9.90, 10.05(total 1H, each s) 364 (CDCl.sub.3): 2.04, 2.05(total 3H, each S), 2.05-2.80(10H, m), 3.40-3.70(5H, m), 3.81, 3.91(total 3H, each S), 4.60-4.75(1H, m), 6.13(1H, t, J=6.3Hz), 6.70-6.95(4H, m), 7.30-7.50(5H, m), 7.68(1H, d, J=6.4Hz), 8.27, 8.45(total 1H, each S) 391 (CDCl.sub.3): 1.20-2.20(4H, m), 2.50-3.30(3H, m), 3.40-3.80(1H, m), 4.25-4.50, 5.05-5.30(total 1H, m), 5.30-6.20(1H, br), 6.40-6.80(3H, m), 7.00-7.40(6H, m), 7.62(1H, d, J=6.2Hz). 8.08(1H, s) 335 (CDCl.sub.3): 0.85-5.17(26H, m), 6.65-8.01(10H, m), 8.77-9.24(1H, m) 336 (CDCl.sub.3): 1.34-2.48(4H, m), 2.49-4.94(13H, m)2.83(3H, d, J=4.86Hz), 5.19-6.23(2H, m), 6.55-8.04(10H, m), 8.30-8.58(1H, m) 340 (CDCl.sub.3): 1.19-2.52(4H, m), 2.53-5.12(10H, m), 3.61(3H, s), 6.40-7.88(14H, m), 7.93-8.34(1H, m) 345 (CDCl.sub.3): 1.03(6H, t, J=7.12H), 1.39-5.08(25H, m), 6.56-7.87(10H , m), 8.03-8.46(1H, m) 347 (CDCl.sub.3): 1.03(6h, t, J=7.12Hz), 0.75-5.07(22H, m), 3.65(3H, S), 6.60-7.90(10H, m), 8.12-8.49(1H, m) 348 (CDCl.sub.3): 1.03(6H, t, J=7.1Hz), 0.79-5.13(27H, m), 6.58-7.88(10H , m), 7.97-8.25(1H, m) 349 (CDCl.sub.3): 0.95-2.14(4H, m), 2.23-3.18(5H, m), 3.01, 3.06(total 3H, S), 3.42-4.07(3H, m), 4.45-5.08(1H, m), 6.68-7.80(13H, m), 8.02-8.68( 2H, m) 350 (CDCl.sub.3): 1.02-2.36(6H, m), 2.43-3.13(4H, m), 3.21-4.65(3H, m), 3.49, 3.56(total 3H, S), 3.94(3H, brs), 5.75-6.12(2H, m), 6.45-7.53(10H, m), 7.63-7.94(2H, m), 8.15, 8.44(total 1H, brs) 351 (CDCl.sub.3): 0.71-4.64(20H, m), 2.20, 2.21(total 3H, S), 3.94(3H, brs), 6.37-6.93(2H, m), 6.98-7.53(7H, m), 7.61-7.92(2H, m), 8.36(1H, brs) 352 (CDCl.sub.3): 0.91-3.23(13H, m), 1.06(6H, t, J=7.1Hz), 2.99, 3.18(total 3H, S), 3.26-5.08(4H, m), 3.72, 3.93(total 3H, brs), 6.67-7.05 (3H, m), 7.11-7.83(7H, m), 8.05-8.43(1H, m) 353 (CDCl.sub.3): 1.22-2.27(4H, m), 2.62-2.97(2H, m), 3.07-4.08(4H, m), 5.66(3H, S), 4.14-5.25(3H, m), 6.53-6.72(1H, m), 6.77-7.87(12H, m), 8.18-8.87(3H, m) 354 (CDCl.sub.3): 1.16-2.11(4H, m), 2.46-2.82(3H, m), 2.86-4.12(9H, m), 4.35-5.23(1H, m), 6.52-6.67(1H, m), 6.75-7.86(11H, m), 8.27-8.86(3H, m) 355 (CDCl.sub.3): 1.06-2.13(5H, m), 2.35-3.32(8H, m), 3.41-5.23(6H, m), 6.48(1H, m), 6.73-7.52(9H, m), 7.56-7.92(2H, m), 8.24-8.93(3H, m) 356 (CDCl.sub.3): 0.85, 1.09, 1.32(total 9H, t, J=7.0Hz), 1.22-1.67(2 H, m), 1.74-2.42(3H, m), 2.47-4.14(13H, m), 3.70, 3.74(total 3H, S), 4.35-5.22(1H, m), 6.52-6.68(1H, m), 6.72-7.57(7H, m), 7.67-7.93(1H, m), 8.27-8.93(2H, m) 357 (CDCl.sub.3): 0.83-4.11(20H, m), 2.34, 2.39(total 3H, S), 3.71, 3.99(total 3H, S), 6.47-6.72(1H, m), 6.77-7.57(7H, m), 7.65-7.91(1H, m), 8.14-8.88(2H, m) 358 (CDCl.sub.3): 1.1-4.0, 4.3-4.6, 4.95-5.2(total 20H, m with two S at 2.20 and 2.33), 6.57(1H d, J=8.3Hz), 6.8-7.7(9H, m), 7.83(2H, d, J=6.8Hz), 8.42, 8.60(total 1H, each S) 359 (CDCl.sub.3): 1.18-2.27(4H, m), 2.34-2.98 82H, m), 2.49(3H, S), 3.04-4.07(2H, m), 3.64(3H, S), 4.14-5.23(4H, m), 6.47-7.73(12H, m), 7.97-8.73(3H, m) 360 (CDCl.sub.3): 1.14-2.24(5H, m), 2.32-3.35(3H, m), 2.49(3H, S), 3.00(2H, J, J=6.0Hz), 3.40-5.22(4H, m), 3.69(3H, S), 6.47-7.22(12H, m), 8.03-8.77(3H, m) 361 (CDCl.sub.3): 1.07-2.26(4H, m), 2.33-3.34(5H, m), 2.50(3H, S), 2.96, 3.06(total 3H, S), 3.44-5.23(4H, m), 3.69, 3.72(total 3H, S), 6.48-6.66(1H, m), 6.71-7.73(11H, m), 8.03-8.69(3H, m) 362 (CDCl.sub.3): 0.73-1.67(11H, m), 1.74-2.13(2H, m), 2.24-5.23(15H, m), 2.49, 2.50(total 3H, S), 3.68, 3.74(total 3H, S), 6.53-6.67(1H, m), 6.83-7.55(7H, m), 8.05-8.46(2H, m) 363 (CDCl.sub.3): 0.64-4.10(19H, m), 2.33, 2.38(total 3H, S), 2.49(3H, S), 3.69, 3.97(total 3H, S), 4.13-5.22(1H, m), 6.51-6.73(1H, m), 6.75-7.65(9H, m), 8.05-8.76(2H, m) 365 (CDCl.sub.3): 1.21-2.32(4H, m), 2.53-3.02(2H, m), 3.05-5.26(5H, m), 6.59(1H, d, J=8.4Hz), 6.87-8.02(14H, m), 8.39-8.63(1H, m) 366 (CDCl.sub.3): 1.16-2.18(5H, m), 2.23-3.87(4H, m), 2.99(2H, t, J=6.1Hz), 3.70(2H, t, J=6.1Hz), 4.13-5.18(1H, m), 6.48-6.73(1H, m), 6.88-7.93(13H, m), 8.04-8.57(2H, m) 367 (CDCl.sub.3): 1.04-3.23(9H, m), 2.96, 3.05(total 3H, S), 3.38-4.08(3 H, m), 4.28-5.17(1H, m), 6.55(1H, t, J=7.8Hz), 6.82-7.73(13H, m), 8.34-8.73(2H, m) 368 (CDCl.sub.3): 0.75-2.22(13H, m), 2.25-3.95(16H, m), 4.32-5.20(1H, m), 6.49-6.63(1H, m), 6.84-7.12(2H, m), 7.15-7.75(8H, m), 8.32-8.73(1H, m) 369 (CDCl.sub.3): 0.91-3.88(20H, m), 2.30, 2.37(total 3H, S), 4.07-5.18( 1H, m), 6.48-7.43(11H, m), 8.29, 8.53(total 3H, brs) 375 (CDCl.sub.3): 1.10-5.05(13H, m), 2.33, 2.40(total 6H, S), 2.98, 3.17(total 3H, S), 3.70, 3.91(total 3H, brs), 6.68-7.83(10H, m), 8.27-8.72(1H, m) 376 (CDCl.sub.3): 0.94-1.37(7H, m), 1.51-2.12(3H, m), 2.13-3.16(8H, m), 3.25-4.12(8H, m), 4.28-5.06(1H, m), 6.65-7.52(8H, m), 7.55-7.98(2H, m) 377 (CDCl.sub.3): 0.97-2.13(10H, m), 2.38-4.65(18H, m), 6.43-7.98(10H, m), 8.34-8.57(1H, m) 378 (CDCl.sub.3): 1.17-3.15(20H, m), 3.23-4.64(4H, m), 3.74, 3.95(total 3H, brs), 6.64-8.01(10H, m), 8.10-8.31(1H, m) 379 (CDCl.sub.3): 1.10-2.22(8H, m), 2.26-5.12(17H, m), 3.16(2H, S), 3.73(3H, brs), 6.72-7.04(3H, m), 7.08-8.88(7H, m), 8.29, 8.53(total 1H, brs) 381 (CDCl.sub.3): 1.08-2.14(4H, m), 2.28-3.28(3H, m), 2.46, 2.52(total 3H, S), 3.32-4.65(4H, m), 3.70, 3.92(total 3H, S), 6.52-7.72(14H, m), 7.76, 8.08(total 1H, S), 8.33-8.57(1H, m) 382 (CDCl.sub.3): 1.07-2.76(9H, m), 2.45, 2.53(total 3H, m), 2.83-4.58(8 H, m), 6.65-7.87(13H, m), 7.97, 8.22(total 1H, S), 8.38-8.55(1H, m) 383 (CDCl.sub.3): 0.93-2.17(4H, m), 2.24-3.18(5H, m), 2.49, 2.53(total 3H, S), 3.00, 3.06(total 3H, S), 3.44-4.06(6H, m), 4.07-5.08(1 H, m), 6.63-7.75(14H, m), 8.43-8.66(1H, m) 384 (CDCl.sub.3): 0.92-1.35(9H, m), 1.45-2.24(6H, m), 2.38-2.83(10H, m), 2.89-4.73(9H, m), 6.64-7.04(3H, m), 7.12-7.90(8H, m) 385 (CDCl.sub.3): 0.97-4.56(20H, m), 2.24, 2.25(total 3H, S), 2.52, 2.65(total 3H, S), 3.92(3H, brs), 6.37-7.58(9H, m), 7.79(1H, brs), 8.13-8.53(1H, m) 389 (CDCl.sub.3): 1.05-2.39(5H, m), 2.44-4.98(15H, m), 6.68-7.02(2H, m), 7.05-7.83(8H, m), 8.47-8.73(1H, m) 390 (CDCl.sub.3): 1.43-2.13(6H, m), 2.13-4.65(18H, m), 6.65-7.53(9H, m), 7.55-7.92(2H, m), 8.56-9.05(1H, m) 392 (CDCl.sub.3): 0.74-1.33(12H, m), 1.45-3.57(11H, m), 3.52-4.63(2H, m), 3.70, 394(total 3H, brs), 6.34-7.55(9H, m), 7.61-8.02(2H, m), 8.25, 8,48(total 1H, brs) 393 (CDCl.sub.3): 0.86-1.33(7H, m), 1.42-2.23(4H, m), 2.28-3.24(11H, m), 2.99, 3.17(total 3H, S), 3.28-5.07(7H, m), 6.61-7.05(3H, m), 7.07-7.57(7H, m), 7.58-7.83(1H, m) 398 (CDCl.sub.3): 1.12-4.03(31H, m), 2.00(3H, S), 2.35(3H, S), 4.03-4.35 (2H, m), 4.35-5.19(1H, m), 5.98-7.66(10H, m), 7.87-8.28(1H, m), 9.96-10.1 3(1H, m) 399 (CDCl.sub.3): 1.2-2.5(8H, m), 2.6-3.2(3H, m), 3.90(2H, d, J=6.6Hz), 3.97(2H, d, J=6.6Hz), 4.8-5.15(1H, m), 6.4-7.7(13H, m), 9.31(1H, S) 400 (CDCl.sub.3): 1.3-2.25(8H, m with S at 2.06), 2.25-3.2(9H, m), 3.45(2H, t, J=5Hz), 3.59(2H, t, J=5Hz), 3.98(2H, t, J=6Hz), 4.8-5.2(1H, m), 8.58(1H, d, J=8.3Hz), 8.92(1H, dd, J=3.3Hz, 8.8Hz), 7.05-7.4(5H, m), 7.48(1H, d, J=8.5Hz), 8.25(1H, S) 404 (CDCl.sub.3): 1.17-2.22(14H, m), 2.01(3H, S), 2.43(2H, d, J=7.3Hz), 2.56-3.26(5H, m), 2.80, 2.94, 3.01, 3,18(total 6H, S), 3.56-3.94(2H, m), 4.05-4.32(2H, m), 4.48-5.21(1H, m), 6.11-6.33(1H, m), 6.52-6.67(1H, m), 6.87-7.62(9H, m), 8.17-8.26(1H, m), 9.92-10.06(total 1H, brs) 405 (CDCl.sub.3): 1.18-3.05(12H, m), 2.38, 2.44(total 3H, S), 3.08-5.22( 10H, m), 6.60(1H, d, J=8.3Hz), 6.75-7.17(4H, m), 7.26-7.50(2H, m), 7.50-7.73(2H, m), 8.24-8.56(2H, m) 408 (CDCl.sub.3): 1.2-3.2, 3.6-4.2, 4.8-5.2(total 28H, m with S at 1.92 and two t at 2.37(J=7Hz)and 3.97(J=6Hz), 5.75(1H, d, J=8.1Hz), 8.57(1H, d, J=8.3Hz), 6.8-7.4(7H, m), 7.49(1H, d, J-8.4Hz), 2.61(1H, S) 409 (CDCl.sub.3): 1.16-5.26(13H, m), 2.26, 2.36(total 6H, m), 2.94, 3.18(total 3H, m), 3.70(3H, S), 6.59(1H, d, J=8.3Hz), 6.72-7.75(8H, m), 8.25-8.55(2H, m) 410 (CDCl.sub.3): 1.13-2.86(11H, m), 2.14, 2.28(total 6H, S), 3.03-5.23( 4H, m), 3.66, 3.70(total 3H, S), 6.60(1H, d, J=8.3Hz), 6.76-7.77(9H, m), 8.24-8.75(2H, m) 411 (CDCl.sub.3): 1.18-2.83(18H, m), 2.88-5.23(5H, m), 3.66, 3.70(total 3H, S), 6.32-7.05(4H, m), 7.08-7.53(4H, m), 7.56-7.76(2H, m), 8.23-8.73(2 H, m) 412 (CDCl.sub.3): 1.13-2.85(12H, m), 2.98-5.23(12H, m), 6.17-6.83(2H, m), 6.83-7.05(2H, m), 7.05-7.52(4H, m), 7.52-7.78(2H, m), 8.23-8.76(2H, m) 413 (CDCl.sub.3): 1.03-1.46(3H, m), 1.52-2.63(6H, m), 2.26(6H, S), 2.68-3.93(5H, m), 3.70, 3.80(total 3H, brs), 3.98-5.21(4H, m), 6.52-7.18( 4H, m), 7.22-7.50(5H, m), 8.18-8.53(2H, m) 414 (CDCl.sub.3): 1.53-2.64(6H, m), 2.24(6H, S), 2.67-4.03(6H, m), 2.97, 3.05(total 3H, S), 4.07-5.25(4H, m), 6.52-7.20(4H, m), 7.26-7.72(5H , m), 8.22-8.57(2H, m) 415 (CDCl.sub.3): 1.52-3.13(14H, m), 3.23-5.25(8H, m), 3.68, 3.80(total 3H, S), 6.54-7.21(4H, m), 7.24-7.75(5H, m), 8.25-8.57(2H, m) 416 (CDCl.sub.3): 1.01-2.62(11H, m), 2.24(6H, S), 2.67-5.32(9H, m), 3.67, 3.81(total 3H, brs), 6.53-7.22(4H, m), 7.24-7.73(5H, m), 8.24-8.53( 2H, m) 417 (CDCl.sub.3): 0.82-1.15(6H, m), 1.55-2.18(4H, m), 2.22-3.07(7H, m), 3.13-3.58(2H, m), 3.75(3H, S), 3.93-4.27(2H, m), 4.38-5.23(2H, m), 6.57-7.17(4H, m), 7.23-7.73(6H, m), 8.24-8.56(2H, m) 418 (CDCl.sub.3): 1.32-3.12(17H, m), 3.16-4.32(4H, m), 3.75(3H, S), 4.36-5.24(2H, m), 6.53-7.18(4H, m), 7.22-7.73(6H, m), 8.24-8.55(2H, m) 419 (CDCl.sub.3): 1.55-3.07(11H, m), 3.13-4.33(11H, m), 4.38-5.25(2H, m), 6.55-7.53(8H, m), 7.53-7.75(2H, m), 8.25-8.54(2H, m) 420 (CDCl.sub.3): 0.83-2.31(12H, m), 2.33-5.22(13H, m), 2.93, 3.19(total 3H, S), 3.72, 3.76(total 3H, S), 6.59(1H, d, J=8.3Hz), 6.86-7.14(4H, m), 7.25-7.73(4H, m)8.22-8.56(2H, m) 421 (CDCl.sub.3): 0.86-1.23(6H, m), 1.47-2.18(4H, m), 2.22-5.23(18H, m), 5.80(3H, S), 6.52-7.18(4H, m), 7.24-7.75(6H, m), 8.34(2H, brs) 422 (CDCl.sub.3): 0.78-1.67(11H, m), 1.70-5.23(17H, m), 2.95, 3.20(total 3H, S), 6.59(1H, dd, J=8.3, 2.5Hz), 6.73-7.56(6H, m), 7.56-7.73(2H, m), 8.28-8.58(2H, m) 423 (CDCl.sub.3): 0.92-1.65(5H, m), 1.67-5.21(18H, m)2.30, 2.36(total 6H, S), 6.53-6.68(1H, m), 6.68-7.22(3H, m), 7.22-7.49(3H, m), 7.57-7.75(2 H, m), 8.26-8.55(2H, m) 424 (CDCl.sub.3): 0.84-2.24(13H, m), 2.24-3.12(8H, m), 3.12-5.25(4H, m), 6.15-7.56(8H, m), 7.56-7.82(2H, m), 8.26-8.76(2H, m) 425 (CDCl.sub.3): 1.28(3H, t, J=6.9Hz), 1.22-2.18(6H, m), 2.20-5.23(15H, m), 2.53(3H, S), 6.60(1H, d, J=8.3Hz), 6.75-7.15(4H, m), 7.26-7.58(2H, m), 7.58-7.42(2H, m), 8.28-8.57(2H, m) 426 (CDCl.sub.3): 1.25-(3H, t, J=7.13), 1.41-2.92(5H, m), 2.93-5.04(6H, m), 3.64(3H, S), 6.63-7.91(10H, m), 8.14, 8.23, 8.38(total 1H, each brs) 428 (CDCl.sub.3): 1.09-5.06(23H, m), 6.62-8.14(10H, m), 8.68-9.28(1H, m)
Example 430
0.13 ml of methyl isothiocyanate was added to 20 ml of a suspension of 0.5 g of 5-(2-aminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine in ethanol. The mixture was refluxed for 3 hours. The reaction mixture was subjected to vacuum distillation to remove ethanol. The residue was mixed with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and then subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol =50/1) to obtain 0.46 g of 5-(2-methylaminothiocarbonylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.ppm: 1.05-4.82 (17H, m), 6.16-8.42 (13H, m)
Example 431
0.129 g of ethyl acetoimidate hydrochloride was added to 15 ml of a suspension of 0.5 g of 5-(2-amino-ethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine in ethanol with ice-cooling. The mixture was stirred overnight at room temperature. Then, 0.163 g of ethyl acetoimidate hydrochloride was further added. The mixture was stirred at 50.degree. C. for 7 hours and then refluxed for 3 hours. After cooling, the reaction mixture was subjected to filtration to remove insolubles. The filtrate was concentrated. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=30/1) to obtain 0.2 g of 5-[2-(1-iminoethyl)aminoethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine hydrochloride.
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.ppm: 1.08-2.48 (4H, m), 2.26 (3H, s), 2.57-4.10, 4.41-4.89 (total 10H, m), 6.65-7.82 (10H, m), 8.79, 9.45, 9.96 (each 1H, each brs), 10.63, 10.78 (total 1H, each brs)
Example 432
0.12 g of sodium cyanate and 0.22 ml of trifluoro-acetic acid were added to a solution of 0.5 g of 5-(2-amino-ethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 15 ml of dry dimethylformamide. The mixture was stirred at 80.degree. C. for 1 hour. After cooling, the reaction mixture was mixed with slight amounts of a saturated aqueous sodium hydrogen-carbonate solution and hexane, followed by extraction with ethyl acetate. The organic layer was water-washed, then dried over magnesium sulfate and subjected to vacuum distillation to remove the solvent. The resiude was recrystallized from acetone-n-hexane to obtain 0.41 g (76%) of 5-(2-ureidoethoxy)-7-chloro-1-[2-methoxy-4-(2-chloro-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
A white powder
Melting point: 206.degree.-207.degree. C.
Example 433
0.14 g of ammonium chloride and 0.17 g of sodium azide were added to a solution of 0.7 g of 5-cyanomethyl-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 10 ml of dry dimethylformamide. The mixture was stirred at 100.degree. C. for 2 hours. To the reaction mixture was added hydrochloric acid to control the pH of the mixture at about 2, followed by extraction with ethyl acetate. The organic layer was water-washed, then dried and subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol =30/1) to obtain 0.52 g of 5-(1-methyl-1,2,3,4-tetrazol-5-yl)methyl-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.ppm: 1.01-5.18 (12H, m), 6.48-7.98 (11H, m), 8.44, 8.50 (total 1H, each brs)
Example 434
An aqueous solution containing 0.27 g of sodium metaperiodate was added, at room temperature, to a suspension of 0.33 g of 5-[2-(4-pyridyl)thioethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine in 20 ml of methanol. The mixture was stirred at 70.degree. C. for 2 hours. The reaction mixture was subjected to vacuum distillation to remove methanol. The residue was mixed with a saturated aqueous sodium chloride solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=50/1) and recrystallized from ethyl acetate-n-hexane to obtain 0.18 g of 5-[2-(4-pyridyl)sulfinylethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl-2,3,4,5-tetrahydro-1H-benzoazepine.
A white powder
Melting point: 192.degree.-193.5.degree. C.
The above-mentioned compound of Example 331 was obtained in the same manner as in Example 434 using appropriate starting materials.
Example 435
0.33 g of sodium metaperiodate was added to a suspension of 0.3 g of 5-[2-(4-pyridyl)thioethoxy]-7-chloro-1-[-2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine in 20 ml of methanol. The mixture was refluxed for 5 hours. The reaction mixture was subjected to vacuum distillation to remove methanol. The residue was mixed with a saturated aqueous sodium chloride solution, followed by extraction with dichloromethane. The extract was dried over anhydrous magnesium sulfate and then subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol =50/1) to obtain 0.28 g of 5-[2-(4-pyridyl)sulfonylethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine.
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.ppm: 1.12-2.21 (4H, m), 2.52-5.01 (7H, m), 3.62 (3H, s), 6.58-7.91 (12H, m), 8.23, 8.35 (total 1H, each brs), 8.75-9.02 (2H, m)
The above-mentioned compound of Example 332 was obtained in the same manner as in Example 435 using appropriate starting materials.
Example 436
0.18 g of m-chloroperbenzoic acid was added, with ice-cooling, to a suspension of 0.32 g of 5-[2-(2-imidazolyl)thioethoxy]-7-chloro-1-[2-methoxy-4-(2-chloro-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine in 10 ml of dichloromethane. The mixture was stirred at room temperature for 15 minutes. The reaction mixture was mixed with a saturated aqueous sodium chloride solution, followed by extraction with dichloromethane. The extract was washed with a saturated aqeuous sodium hydrogencarbonate solution, then dried over anhydrous magnesium sulfate, and subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: ethyl acetate/methanol=100/1) and recrystallized from acetone-diethyl ether to obtain 0.27 g of 5-[2-(2-imidazolyl)sulfonylethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine.
A white powder
Melting point: 247.degree.-248.degree. C.
The above-mentioned compound of Example 329 was obtained in the same manner as in Example 436 using appropriate starting materials.
Example 437
An ethanol solution containing 0.174 g of dimethyl cyanodithioimidocarbonate was added to a solution of 0.6 g of 5-(2-aminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chloro-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 30 ml of ethanol. The mixture was stirred overnight at room temperature. Thereto was added 1.76 ml of a methanol solution containing 40% of methylamine. The mixture was stirred at 40.degree.-50.degree. C. for 3 hours. The reaction mixture was subjected to vacuum distillation to remove ethanol. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=100/1) to obtain 0.46 g of 5-[2-(3-methyl-2-cyanoguanidino)ethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.ppm: 1.34-2.48 (4H, m), 2.49-4.94 (13H, m), 2.83 (3H, d, J=4.86Hz), 5.19-6.23 (2H, m), 6.55-8.04 (10H, m), 8.30-8.58 (1H, m)
Example 438
0.64 ml of trifluoromethanesulfonic acid anhydride was dropwise added, with ice-cooling, to a solution of 0.4 g of 5-(2-aminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chloro-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazpine dissolved in 10 ml of pyridine. The mixture was stirred for 1.5 hours at the same temperature. Thereto was added 10% hydrochloric acid, followed by extraction with ethyl acetate. The extract was water-washed, dried and subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=100/1) to obtain 0.18 g of 5-(2-trifluoromethanesulfonylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
A yellow plate
Melting point: 140.degree.-142.5.degree. C.
Example 439
0.01 ml of chloroacetonitrile, 0.22 ml of triethylamine and 0.24 ml of sodium iodide were added to 50 ml of a solution of 0.7 g of 5-(2-aminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in dimethylformamide. The mixture was stirred at 60.degree. C. for 2 hours. The reaction mixture was mixed with water, followed by extraction with ethyl acetate-n-hexane (10:1). The organic layer was water-washed, dried and subjected to vacuum distilation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=50/1) and crystallized from acetone-n-hexane to obtain 0.5 g of 5-(2-cyanomethylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine.
A white powder
Melting point: 152.5.degree.-153.degree. C.
The above-mentioned compounds of Examples 321, 322, 337, 338, 340 and 343-349 were obtained in the same manner as in Example 439 using respective starting materials.
Example 440
9.1 ml of 98% boron tribromide was dropwise added, at -10.degree. C. with stirring, to a solution of 10 g of 5-carboxymethyl-7-chloro-1-[2-methoxy-4-(2-chloro-benzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 400 ml of dichloromethane. The mixture was slowly returned to room temperature and stirred overnight at the same temperature. The reaction mixture was mixed with water, followed by extraction with dichloromethane. The extract was water-washed, then dried over anhydrous magnesium sulfate, and subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography to obtain 9.08 g of 5-carboxymethyl-7-chloro-1-[2-hydroxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Colorless and amorphous
.sup.1 H-NMR (CDCl.sub.3) .delta.ppm: 1.20-2.20 (4H, m ), 2.50-3.30 (3H, m), 3.40-3.80 (1H, m), 4.25-4.50, 5.05-5.30 (total 1H, m), 5.30-6.20 (1H, br), 6.40-6.80 (3H, m), 7.00-7.40 (6H, m), 7.62 (1H, d, J=6.2Hz ), 8.08 (1H, s)
Pharmacological Tests
Test compound No.
1. 5-Dimethylamino-1-[4-(3-carbamoylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
2. 5-Dimethylamino-1-{4-[2-(2-methylphenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
3. 5-Dimethylamino-1-{4-[2-(2-chlorophenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
4. 5-Dimethylamino-1-{4-[2-(2-methoxyphenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
5. 5-Dimethylamino-1-{4-[-2-(2-fluorophenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
6. 5-Dimethylamino-1-(4-[2-(2,6-dichlorophenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
7. 5-Dimethylamino-1-{4-[4-(2-nitrophenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
8. 5-Dimethylamino-7-hydroxy-1-[2-chloro-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
9. 5-(L-Alanyloxy)-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
10. 5-(L-Methionyloxy)-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
11. 5-Dimethylamino-7-acetyloxy-1-[2-chloro-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
12. 5-(L-Prolyloxy)-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride (Example 64)
13. 5-(L-Methionyloxy)-7-chloro-1-[2-methoxy-4-(2methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine-hydrochloride (Example 61)
14. 5-(L-Methionyloxy)-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride (Isomer A of Example 72)
15. 5-(L-Valyloxy)-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine hydrochloride (Isomer A of Example 86)
16. 5-Hydroxy-7-chloro-1-{2-methyl-4-[2-(2-methylphenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
17. 5-(2-Morpholinoacetyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
18. 5-Hydroxy-7-chloro-1-{2-methoxy-4-[2-(2-methylphenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
19. 5,7-Dihydroxy-5-hydroxymethyl-1-[2-chloro-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
20. 5-Dimethylamino-7-dimethylaminocarbonylmethoxy-1-[2-chloro-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
21. 5-Ethoxycarbonylmethylaminocarbonylmethoxy-7-fluoro-1-[2-chloro-4-[2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
22. 5-Carboxymethylaminocarbonylmethoxyl-7-fluoro-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
23. 5-[(2-.beta.-Methoxycarbonyl)-1-pyrrolidinylcarbonylmethoxy]-7-fluoro-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
24. 5-(2-Methoxyacetyloxy)-7-chloro-1-[4-(2-methyl-4-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
25. 5-{[2-(Dimethylaminoacetyloxy)methyl}-7-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepineohydrochloride
26. 5-Ethoxycarbonylmethyl-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
27. 5-[(4-Methyl-1-piperazinyl)carbonylmethyl-7-chloro-1-[3-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
28. 5-Carbamoylmethoxy-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydro-1H-benzoazepine
29. 5-(L-Lysyloxy)-7-chloro-1-[2-methoxyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
30. 5-[(4-Piperidinyl)aminocarbonylmethyl-7-chloro-1-[3-methoxy-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
31. 5-Carboxymethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
32. 5-Dimethylaminocarbonylmethyl-7-chloro-1-[3-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
33. 5-(3-Dimethylaminopropylidene)-7-fluoro-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
34. 5-[2-(1-Pyrrolidinyl)ethoxy]-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
35. 5-(3-Morpholinopropoxy)-7-fluoro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
36. 5-[3-(1-Imidazolyl)propoxy]-7-fluoro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
37. 5-[3-(p-Toluenesulfonyloxy)propoxy]-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
38. 5-Cyano-7-chloro-1-[3-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
39. 5-Cyanomethyl-7-chloro-1-[3-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
40. 5-[2-(4-Acetyl-1-piperazinyl)ethoxy-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
41. 5-[(4-Methyl-1-piperazinyl)carbonylmethyl]-7-chloro-1-[2-methyl-4-(methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
42. 5-Methylaminocarbonylmethyl-7-fluoro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
43. 5-[2-(1-Piperazinyl)ethoxy]-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.dihydrochloride
44. 5-[(4-Methyl-1-piperazinyl)carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
45. 5-[(4-Dimethylamino-1-piperidinyl)carbonylmethyl-7-chloro-1-[2-methoxy-4-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
46. 5-[(4-Methyl-1-piperazinyl)methyl]-7-fluoro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
47. 5-[2-(4-Methyl-1-1-piperazinyl)ethoxy]-7-fluoro-1-[2-methoxy-4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
48. 5-[(1-Benzyl-4-piperidinyl)aminocarbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
49. 7-Chloro-1-[2-methoxy-4-{2-[4-(4-acetyl-1-piperazinyl)butoxy]benzoylamino}benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
50. 5-[(1-Pyrrolidinyl)carbonylmethyl]-7-fluoro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
51. 5-Dimethylaminocarbonylmethyl-7-fluoro-1-[2-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
52. 5-[(1-Piperazinyl)-carbonylmethyl]-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
53. 5-[2(1-Acetyl-1-piperazinyl)ethyl]-7-chloro-1-[2-metheyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
54. 5-[2-(4-Dimethyl-1-piperidinyl)ethyl]-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.dihydrochloride
55. 5-[2-(4-Methyl-1-piperazinyl)ethyl]-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepin.cndot.hydrochloride
56. 7-Chloro-1-[3-methoxy-4-{2-[4-(4-acetyl-1-piperazinyl)butoxy]benzoylamino}benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
57. 7-Chloro-5-[(4-piperidinyl)aminocarbonylmethoxy]-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
58. 5-[(1-Piperidinyl)carbonylmethyl-7-fluoro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
59. 5-[(1-Methyl-4-piperidinyl)aminoarbonylmethoxy]-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
60. 5-[(4-Acetylamino-1-piperidinyl)carbonylmethyl]-7-fluoro-1-[2-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
61. 5-(2-Hydroxyethoxy)-7-chloro-1-[4-(2-methylbenzoyamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
62. 5-(Carbonylmethylaminocarbonylmethyl)-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
63. 5-[(4-Methyl-1-piperazinyl)carbonylmethyl]-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
64. 5-Allyloxy-7-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
65. 5-Ethoxycarbonylmethylidene-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
66. 5-Methylamino-7-chloro-1-{2-chloro-4-[2-(2methylphenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
67. 5-Allylamino-7-chloro-1-{4-[2-(2-methylphenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
68. 5-(2-Dimethylaminoacetyloxy)-7-chloro-1-{2-methoxy-4-[2-(2-methylphenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
69. 5-[2-(1,3-Dioxo-4a,4,5,6,7,7a-hexahydro-isoindolyn-1-yl)ethoxy]-7-fluoro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
70. 5-(2-Chloroethyl)-7-chloro-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
71. 7-Chloro-1-[3-methoxy-4-{2-[3-(1-imidazoyl)propoxy]benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
72. 7-Chloro-1-[3-methoxy-4-{2-[3-(4-acetylamino-1-piperidinyl)propoxy]benzoylamino}benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
73. 7-Chloro-1-[3-methoxy-4-{2-[3-(1,2,4-triazol-1-yl)-propoxy]benzoylamino}benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
74. 5-[2-(1-Imidazoyl)ethyl]-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
75. 5-[2-(4-Acetylamino-1-piperidinyl)ethoxy]-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
76. 5-[2-(4-Acetylamino-1-piperidinyl)ethyl]-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
77. 5-(4-Ethoxycarbonylmethyl-1-piperazinyl)carbonyl-methyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
78. 5-(4-Ethyl-1-piperazinyl)carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
79. 5-[4-(4-Chlorophneyl)-1-piperazinyl]carbonyl-methyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
80. 5-(4-Cyanomethyl-1-piperazinyl)carbonylmethyl 7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
81. 5-(4-Allyl-1-piperazinyl)carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
82. 5-(1-Piperidinyl)carbonylmethyl-7-fluoro-[3-methoxy-4-(2-methylbenzoylamino)benzoyl-2,3,4,5-tetrahydro-1H-benzoazepine
83. 5-(4-Oxiranyl-1-piperazinyl)carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-carbonylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
84. 5-(4-Carbonylmethyl-1-piperazinyl)carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
85. 5-[4-(2-Hydroxyethyl)-1-piperazinyl]-carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
86. 5-(4-Methyl-1-piperazinyl)carbonylmethyl-7-fluoro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,-dihydro-1H-benzoazepine
87. 5-[4-(2-Hydroxy-3-isopropylaminopropyl)-1-piperazinyl]carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
88. 5-[N-Methyl-N-(2-hydroxyethyl)amino]-carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydo-1H-benzoazepine
89. 5-(2-Dimethylaminoethylamino)carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
90. 7-Chloro-1-(3-methoxy-4-[2-(3-[N'-methoxyureido]propoxy)benzoylamino]benzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
91. 5-[N-Methyl-N-(2-diethylaminoethyl)amino]-carbonylmethyl-7-chloro-1-[3-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
92. 5-[2-1,2,4-Triazol-1-yl)ethoxy]-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
93. 5-[2-(1,2,3,4-Tetrazol-1-yl)ethoxy]-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
94. 5-[2-(1,2,3,4-Tetrazol-1-yl)ethoxy-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
95. 5-(2-Morpholinoethyl)-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl-2,3,4,5-tetrahydro-1H-benzoazepine
96. 5-[2-(1-Piperidinyl)ethyl]-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
97. 5-[2-(1-Pyrrolidinyl)ethyl]-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
98. 5-[2-(1,2,3,4-Tetrazol-1-yl)ethyl]-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl-2,3,4,5-tetrahydro-1H-benzoazepine
99. 5-[2-(1,2,3,5-Tetrazol-1-yl)ethyl]-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl-2,3,4,5-tetrahydro-1H-benzoazepine
100. 5-[2-(N-Methyl-N-allylamino)ethyl]-7-chloro 1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
101. 5-(2-Allylaminoethyl)-7-fluoro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
102. 5-(2-Cyclopropylaminoethyl)-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
103. 5-(2-Propargylaminoethyl)-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
104. 5-[2-(1-Imidazolyl)ethyl]-7-chloro-1-[2-methyl-4-(methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
105. 5-[2-(1,2,4-Triazol-1-yl)ethyl]-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
106. 5-Hydroxy-7-chloro-1-{4-[2-(2-methylphenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
107. 5-(L-Lysyloxy)-7-chloro-1-[3-methoxy-4-(2methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.dihydrochloride
108. 5-(4-Methyl-1-piperazinyl)carbonylmethyl-7-chloro-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
109. 5-(4-Methyl-1-piperazinyl)carbonylmethyl-7-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
110. 5-(4-Dimethylamino-1-piperidinyl)carbonylmethyl-7-fluoro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
111. 5-Dimethylaminocarbonylmethyl-7-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
112. 5-Carbamoylmethyl-7-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
113. 5-(2-Hydroxyethoxy)-7-chloro-1-[4-(2chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
114. 5-(1-Pyrrolidinyl)carbonylmethyl-7-fluoro-1-[2-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
115. 5-(1-Piperazinyl)carbonylmethyl-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
116. 5-(4-Methyl-1-piperazinyl)carbonylmethyl-7-chloro-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
117. 5-(4-Methyl-1-piperazinyl)carbonylmethyl-7-chloro-1-[3-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochlorid
118. 5-(4-Dimethylamino-1-piperidinyl)carbonylmethyl-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
119. 5-(4-Methyl-1-piperazinyl)carbonylmethyl-7-chloro-1-[3-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
120. 5-Dimethylaminocarbonylmethyl-7-chloro-1-[3-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
121. 5-(2-Allylaminoethyl)-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
122. 5-Methylaminocarbonylmethyl-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
123. 5-Carbamoylmethyl-7-chloro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl-2,3,4,5-tetrahydro-1H-benzoazepine
124. 5-Morpholinoethyl-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
125. 5-(4-Methyl-1-homopiperazinyl)carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
126. 5-(2-Pyridylmethyl)aminocarbonylmethyl-7-chlor-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
127. 5-(4-Pyridyl)aminocarbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
128. 5-(4-Ethyl-1-piperazinyl)carbonylmethoxy-7-chloro-1-[4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
129. 5-[2-(N-Allyl-N-methylamino)ethyl]-7-fluoro-1-[2-methyl-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
130. 5-[2-(2-Pyridyl)ethyl]aminocarbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
131. 5-(2-Diethylaminoethoxy)-7-chloro-1-[4-(1-oxoisoindolin-2-yl)benzoyl]-2,3,4,5-tetrahydro-1H-bezoazepine
132. 5-(4-Ethyl-1-piperazinyl)carbonylethoxy-7-chloro-1-[4-(1-oxoisoindolin-2-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
133. 5-(2-Methylaminothiocarbonylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
134. 5-(5-Methyl-2-pyrazinyl)methylaminocarbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
135. 5-[2-(1-Iminoethyl)aminoethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
136. 5-(2-Ureidoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
137. 5-(2-Ethoxycarbonylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
138. 5-(2-Cyclopropylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
139. 5-[2-(4-Pyridyl)thioethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
140. 5-[2-(6-Methyl-2-pyrimidinyl)thioethoxy-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
141. 5-[2-(2-Imidazolyl)thioethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
142. 5-[2-(4-Pyridyl)sulfonylethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
143. 5-[2-(4-Pyridyl)sulfinylethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
144. 5-[2-(2-Imidazolyl)sulfinylethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]
2,3,4,5-tetrahydro-1H-benzoazepine
145. 5-[2-(2-Imidazolyl)sulfonylethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
146. 5-[2-(4-Methanesulfonyl-1-piperazinyl)ethyl]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
147. 5-[2-(4-Ethoxycarbonyl-1-piperazinyl)ethyl]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
148. 5-[2-(4-Methylaminocarbonyl-1-piperazinyl)ethyl]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
149. 5-[2-(3-Methyl-2-cyanogianidino)ethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
150. 5-(2-Benzylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
151. 5-(2-Cyanomethylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylaminobenzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
152. 5-(2-Trifluoromethylsulfonylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
153. 5-[2-(3-Diethylaminopropyl)aminoethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
154. 5-[2-(1-Methyl-2-pyrrolyl)ethyl]aminocarbonyl-methyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
155. 5-[2-(1-Methyl-2-pyrrolidinyl)ethyl]-aminocarbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
156. 5-[2-(1-Piperidinyl)ethyl]aminocarbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
157. 5-{4-[(1-Pyrrolidynyl)carbonylmethyl]-1-piperazinyl}carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
158. 5-(2-Chloroanilino)carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
159. 5-(2-Chlorobenzoylamino)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
160. 5-{2-[N-(2-Hydroxyethyl)-N-methylamino]ethyl}-aminocarbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
161. 5-Carboxymethyl-7-chloro-1-[2-hydroxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
162. 5-Dimethylaminocarbonylmethyl-7-chloro-1-{4-[2-(4-isopropylaminobutoxy)benzoylamino]-benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
163. 5-[N-(2-Dimethylaminoethyl)-N-methylamino]-carbonylmethyl-7-chloro-1-[3-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
164. 5-(2-Morpholinoethyl)aminocarbonylmethyl-7-chlorolo-[3-methoxy-4-(2-bromobenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
165. 5-[N-(2-Dimethylaminoethyl)-N-ethylamino]-carbonylmethoxy-7-chloro-[3-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
166. 5-(4-Methyl-1-homopiperazinyl)carbonylmethoxy-7-chloro-1-[3-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
167. 5-[2-(1-Piperidinyl)ethyl]aminocarbonylmethoxy-7-chloro-1-[3-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
168. 5-(2-Morpholinoethyl)aminocarbonylmethoxy-7-chloro-1-[3-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
169. 5-(2-Allylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
170. 5-(2-Propargylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.cndot.hydrochloride
171. 5-[2-(1-Imidazolyl)ethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
172. 5-(2-Methanesulfonylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
173. 5-Carbamoylmethyl-7-chloro-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
174. 5-[2-(4-Acetyl-1-piperazinyl)ethyl]-7-chloro-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
175. 5-[N-(2-Diethylaminoethyl)-N-ethylamino]-carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
176. 5-[2-(1,2,4-Triazol-1-yl)ethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
177. 5-(2-Cyclopentylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
178. 5-(4-Methyl-1-piperazinyl)carbonylmethyl-7-chloro-1-(4-benzoylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine
179. 5-[2-(4-Acetyl-1-piperazinyl)ethyl]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,-dihydro-1H-benzoazepine
180. 5-[2-(4-Methyl-1-homopiperazinyl)ethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
181. 5-[4-(2-Chlorophenyl)-1-piperazinyl]-carbonylmethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
182. 5-Dimethylaminocarbonylmethyl-7-chloro-1-{4-[2-(4-tert-butylaminobutoxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
183. 5-(4-Methyl-1-piperazinyl)carbonylmethyl-7-chloro-1-{2-methoxy-4-[(2,3-dihydro-4H-chromen-8-yl)carbonylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine
184. 7-Chloro-1-[4-{3-[4-(4-Acetylamino-1-piperidinyl)butoxy]-6-chlorobenzoylamino}benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
185. 5-(4-Methyl-1-homopiperazinyl)carbonylmethyl-7-chloro-1-[3-methoxy-4-(2-bromobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine
Test-1: V.sub.1 Recepter binding assay
By using rat liver plasma membrane preparations prepared according to Ichiraha's method [by Akira Ichihara: J. Bio. Chem., 258, 9283 (1983)], the plasma membrane (50,000 dpm, 2.times.10.sup.-10 M) of [.sup.3 H]-Arg-vasopressin and a test compound (60 .mu.g, 10.sup.-8 to 10.sup.-4 M) were incubated at 37.degree. C. for 10 minutes in 250 .mu.l (in total volume) of 100 mM Tris-HCl buffer (pH=8.0), containing 5 mM MgCl.sub.2, 1 mM EDTA and 0.1% BSA. After the incubation, the mixture was filtered three times by using a glass filter (GF/F) so as to separate the membrane preparation by combining with vasopressin and then washed with the buffer (5 ml). This glass filter was taken out and mixed with a liquid of scintillation cocktail. The amount of [.sup.3 H]-vasopressin combining with the membrane was measured by liquid scintillation counter and the rate of inhibitory effect of the test compound was calculated according to the following equation:
Rate of inhibitory
effect (%)=100-[(C.sub.1 -B.sub.1)/(C.sub.0 -B.sub.1)].times.100
wherein,
C.sub.1 : the amount of [.sup.3 H]-vasopressin combining with the membrane in the presence of the test compound of a known amount,
C.sub.0 : the amount of [.sup.3 H]-vasopressin combining with the membrane in the absence of the test compound,
B.sub.1 : the amount of [.sup.3 H]-vasopressin combining with the membrane in the presence of the excess amount of vasopressin (10.sup.-6 M).
The results are expressed as IC.sub.50 value, which is the concentration of the test compound required to achieve the inhitory effect in the rate of 50% and are shown in the following Table 156.
TABLE 156______________________________________Test compound IC.sub.50 Test compound IC.sub.50No. (.mu.M) No. (.mu.M)______________________________________ 64 0.045 70 0.13 71 0.025 70 0.13 73 0.007 72 0.0012 80 0.016 77 0.029 82 0.057 79 0.065 84 0.019 81 0.023 87 0.007 83 0.025 89 0.009 85 0.016 91 0.0026 88 0.010126 0.024 90 0.0055128 0.014 125 0.008131 0.032 127 0.023133 0.020 130 0.018135 0.018 132 0.090137 0.017 134 0.012139 0.12 136 0.037141 0.056 138 0.005143 0.013 140 0.28145 0.091 142 0.098147 0.039 144 0.055149 0.09 146 0.054151 0.046 148 0.054153 0.036 150 0.016155 0.007 152 0.041157 0.016 154 0.021159 0.28 156 0.0055162 0.0092 158 0.031164 0.0026 160 0.006166 0.0048 163 0.0018168 0.01 165 0.0036170 0.024 167 0.0055172 0.005 169 0.007 171 0.11______________________________________
Test 2: V.sub.2 Recepter binding assay
By using rat kidney plasma membrane preparations prepared according to Hechter's method [by O. Hechter: J. Bio. Chem., 2.53, 3211 (1978)], the plasma membrane (100,000 dpm, 4.times.10.sup.-10 M) of [.sup.3 H]-Arg-vasopressin and a test compound (0.6 mg, 10.sup.-10 to 10.sup.-5 M) were incubated at 4.degree. C. for 3 hours in 250 .mu.l (in total volume) of 100 mM Tris-HCl buffer (pH=8.0), containing, 5 mM MgCl.sub.2, 1 mM EDTA and 0.1% BSA. After the incubation, the mixture, the mixture was filtered by using a glass filter (GF/F) so as to separate the membrane preparation combining with vasopressin, then washed twice with the buffer (5 ml). This glass filter was taken out and mixed with liquid scintillation cocktail. The amount of [.sup.3 H]-vasopressin combining with the membrane was measured by a liquid scintillation counter and the rate of inhibitory effect of the test compound was calculated according to the following equation: Rate of the inhibitory
effect (%)=100-[(C.sub.1 -B.sub.1)/(C.sub.0 -B.sub.1)].times.100
wherein,
C.sub.1 : the amount of [.sup.3 H]-vasopressin combining with the membrane in the presence of the testcompound of a known amount,
C.sub.0 : the amount of [.sup.3 H]-vasopressin combining with the membrane in the absence of the test compound,
B.sub.1 : the amount of [.sup.3 H]-vasopressin combining with the mebrane in the presence of the excess amount of of vasopressin (10.sup.-6 M).
The results are expressed as IC.sub.50 value, which is the concentration of the test compound required to achieve the inhibitory effect in the rate of 50%, and are shown in the following Table 157.
TABLE 157______________________________________Test compound IC.sub.50 Test compound IC.sub.50No. (.mu.M) No. (.mu.M)______________________________________ 70 0.015 69 0.024 72 0.074 71 0.28 74 0.032 73 0.080 76 0.014 75 0.032 80 0.009 77 0.022 84 0.005 79 0.15 86 0.059 81 0.010 88 0.002 83 0.007 90 0.14 85 0.008 92 0.0074 87 0.002 94 0.014 89 0.0025 96 0.009 91 0.0035 98 0.009 93 0.014100 0.0047 95 0.017102 0.0071 97 0.0072104 0.009 99 0.012125 0.004 101 0.007127 0.004 103 0.008129 0.012 105 0.0075131 0.17 126 0.005133 0.049 128 0.013135 0.0049 130 0.004137 0.005 132 0.12139 0.012 134 0.004141 0.0076 136 0.0043143 0.022 138 0.003145 0.014 140 0.046147 0.014 142 0.038149 0.045 144 0.0099151 0.008 146 0.01153 0.005 148 0.005155 0.0019 150 0.009157 0.0073 152 0.061159 0.025 154 0.012163 0.008 156 0.003165 0.0043 158 0.014167 0.0085 160 0.0033169 0.0056 162 0.13171 0.015 164 0.0085 166 0.01 168 0.019 170 0.007 172 0.0039______________________________________
Test-3: Vasopressin antagonistic activity in vivo
In order to test the vasopressin antagonistic activity of the compound of the present invention when admistered orally to rats under awaking, the following experiment was conducted. Cannulas were inserted into the aorta abdominalis and the carotid arteries of male SD-rats (body weight: 300-450 g) under pentobarbital-anesthetization. A few days thereafter, vasopressin (30 mU/kg) was administered intravenously to the rats under awaking with measuring the blood pressure at the cannula inserted into the arorta abdominalis by a piezo-electric transducer. The test compound was dissolved in polyethylene glycol or water, or suspended in 5% gum arabic solution, and orally administered by force to the rats.
The increase in the diastolic pressure of the rat was periodically mesured at 30 minutes' interval after the administration of vasopressin for 8 hours. The rate of inhibitory effect (%) of the test compound on the increase in the diastolic pressure caused by vasopressin (30 mU/kg) was calculated based on the increase in the diastolic pressure when vasopressin (30 mU/kg) was intravenously administered without a test compound.
The test result is expressed as ID50 value, which is the oral dose of the test compound required to achieve the inhibitory effect in the rate of 50% and is shown in Table 158 as follows:
TABLE 158______________________________________Test compound ID.sub.50No. (mg/kg)______________________________________63 3.4______________________________________
Test-4: Anti-antiduretic water diuretic/activity in vivo
The test compound of the present invention was dissolved in polyethylene glycol 400 or water or suspended in 5% gum arabic aqueous solution, and the mixture was orally administered by force to male SD-rats (body weight: 300 to 400 g) under untreated and unrestrained. After administration the rats were kept in a metabolism cage and the amount of urine spontaneously excreted by the rats was measured at 2 hours' interval, during which the rats could freely be given feed and water.
In the cotrol group, a solvent was administered instead of a test compound solution (or suspension).
The test results are expressed as ED.sub.3, which is the oral dose of the test compound which is required to increase the amount of the urine excreted from the rat in the test compound-treated group for the first 2 hours by time based on the amount of urine excreted from the rat for the first 2 hours in the control group. The results are shown in Table 159 as follows:
TABLE 159______________________________________Test compound ED.sub.3No. (mg/kg)______________________________________41 1.463 3.2______________________________________
Test-5 Oxytocin receptor binding assay
In accordance with Chan's method [by W. Y. Chan, et al.: Endocrinology, 126, 2095-2101 (1990)], the uterin muscle benn injected subcutaneously with diethylstilbe-sterol (DES) the day before and was homogenized, which was used as a membrane prepara tion. The membrane preparation (0.2 mg), [.sup.3 H]-oxytocin (100,000 dpm, 10.sup.-9 M), a test compound (10.sup.-9 to 10.sup.-5 M) were incubated at 25.degree.. for one hour 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. The mixture was filtered through a glass filter (GF/F) so as to separate the membrane preparation combining with [.sup.3 H]-oxytocin, then, was washed twicw with the buffer (5 ml). The glass filter was put into a vial and mixed with Aquasole (a liquid scintillation cocktail). The amount of [.sup.3 H]-oxytocin combining w ith the membrane was measured by a liquid scintillation counter. The rate of the inhibitory effect of the test compound was calculated according to the equation as follows:
Rate of the inhibitory
effect (%)=100-[(C.sub.1 -B)/(C.sub.0 -B)].times.100
wherei,
C.sub.1 : the amount of [.sup.3 H]-oxytocin combining with the membrane in the presence of a test compound (in known amount),
C.sub.0 : the amount of [.sup.3 H]-oxytocin combinig with the membrane in the absence of a test compound,
B: the amount of [.sup.3 H]-oxytocin combining with the membrane in the presence of the excess amount of oxytocin (5.times.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 Table 160 as follows:
TABLE 160______________________________________Test compound IC.sub.50 Test compound IC.sub.50No. (.mu.M) No. (.mu.M)______________________________________ 17 0.046 29 0.11 32 0.61 47 1.6 53 1.9 54 0.30 57 2.7 58 0.094 59 1.9 60 0.099 61 0.23 68 0.23 80 0.084 81 0.10 83 0.076 84 0.045 85 0.094 87 0.070 88 0.058 96 4.4 97 4.066 99 2.8100 4.045 101 5.3102 2.9 103 3.0104 1.6 106 0.60107 1.3 108 1.9109 0.36 110 0.22111 0.25 112 0.28113 0.25 114 0.17115 2.1 116 0.38117 0.32 118 3.2119 0.27 120 0.19121 2.3 122 2.2123 2.2 124 2.8125 0.037 126 0.073127 0.032 128 0.095130 0.115 131 1.790132 0.478 133 0.072134 0.096 135 0.146136 0.151 137 0.451138 0.233 139 1.003140 4.288 141 0.193142 1.132 143 0.200144 0.354 145 0.849146 0.154 147 0.504148 0.225 150 0.471152 1.643 153 0.248154 0.197 155 0.055156 0.070 157 0.047158 0.130 159 1.696160 0.084 164 0.041167 0.177 168 0.085169 0.147 170 0.416171 0.317 172 0.133173 2.187 174 1.055175 0.013 176 0.387177 0.258 178 0.969179 2.604 180 0.284181 0.606 182 4.710183 4.409 184 3.669185 0.162______________________________________

Number	Name	Date
3516987	Charles et al.	Jun 1970
3542760	Charles et al.	Nov 1970
5258510	Ogawa et al.	Nov 1993

Benzoheterocyclic compounds and vasopressin antagonist and oxytocin antagonist compositions containing a benzoheterocyclic compound

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