JPH05239065A - Tricyclic heterocyclic compounds, method for producing the same and agent used therefor - Google Patents

Abstract

PURPOSE:To provide a new compound exhibiting a lipoperoxide production- inhibiting activity and a lipoxygenase-inhibiting activity and useful as an agent for preventing.treating cancer, arterial sclerosis, hepatic diseases, cerebrovascular diseases, inflammation, etc. CONSTITUTION:A compound of formula I [A is (substituted)1-3C alkylene, bond; The B ring is (substituted)aromatic ring; one of W1, W2 is N, and the other is S; R<1> is H, (substututed)hydrocarbon, (substituted)heterocylic group, (substituted)alkoxycarbonyl; R<2> is H, (substituted)hydrocarbon group, (substituted) heterocyclic ring. (substituted)carboxylic acid, etc.,]. For example, 3- acetylamino-1-phenyl-2,3,4,5-terahydro-1H-[1]benzazepine-2-one. The compound of formula I is obtained e.g. by reacting a compound of formula II (X is releasable group) with a compound of formula III.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel tricyclic heterocycle or a salt thereof, and a pharmaceutical composition containing the same as an active ingredient. More specifically, it relates to a novel lipid peroxide production inhibitor and lipoxygenase inhibitor useful as a preventive / therapeutic agent for various diseases such as cancer, arteriosclerosis, liver disease, cerebrovascular disorder, inflammation and the like.

[0002]

2. Description of the Related Art As it has become clear that the production of lipid peroxide in the body and its accompanying radical reaction have various adverse effects on the living body through membrane damage, enzyme damage, etc. Various attempts have been made to apply a production inhibitor to a medicine. In vivo antioxidant enzymes and their modified derivatives have been reported to be effective in these fields at present, and in vivo antioxidant enzymes and their modified derivatives ("Free radical clinic", Vol. 2, 83-91, Nippon Medical Center, 1
987), the formula

[Chemical 8] Vitamin E and its derivatives ("vitamin", 61 , 383-390, 1987) represented by

[Chemical 9] Vitamin C and its derivatives represented by (Biochemical Pharmacology "Biochem. Pharmacol." 37 , 1
089-1098, 1988), in vivo antioxidants, formulas

[Chemical 10] Quercetin represented by “Quercetin” (phytochemistry “Phytochemistry”, 27 , 969-978,
1988) and other flavonoids and their derivatives, and formulas

[Chemical 11] Natural antioxidants of plant origin, such as curcumin "Curcumin" (phytochemistry, 27 , 969-978, 1988)

[Chemical 12] Ebselen represented by "Ebselen" (Biochemical Pharmacology 36 , 3095-3102, 19
87), the formula

[Chemical 13] Thiazolidine derivative represented by (Proceeding of the National Academic of Sciences of the United States of America “Proc. Natl. Acad. Sci. USA” 79 , 6246
-6249, 1982), formula

[Chemical 14] 21-aminosteroids such as U-74006F represented by (Journal of Biological Chemistry "J. Biol. Chem." 262 , 10438-104
40, 1987), formula

[Chemical 15] [In the formula, R ¹ represents a hydrogen atom or an optionally substituted aliphatic group, a carboxylic acid acyl group or a sulfonic acid acyl group, and R ² represents a hydrogen atom or a substituent group. Represents an optionally substituted aromatic ring group or aliphatic group. ] The compound or its salt represented by these (EP-A-
0,351,856), formula

[Chemical 16] [In the formula, A is a bond or CH ₂ , R ¹ is a hydrogen atom or an optionally substituted aliphatic group, a carboxylic acid acyl group or a sulfonic acid acyl group, and R ² is a hydrogen atom or , Each represents an aromatic ring group or an aliphatic group which may have a substituent. ] The compound or its salt represented by these (EP-A-0,443,588), Formula

[Chemical 17] [Wherein R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent,
R ² is a hydrogen atom, an aliphatic group which may have a substituent,
The carboxylic acid acyl group which may have a substituent or the sulfonic acid acyl group which may have a substituent is represented by R ³ ,
R ⁴ is a hydrogen atom or a hydrocarbon group which may have a substituent, and n is an integer of 0 to 3. ] The condensed thiazoles or salts thereof represented by (Japanese Patent Application No. 03-32
5515) and other synthetic antioxidant / lipid peroxide production inhibitors.

[0003]

However, known in vivo antioxidant enzymes, vitamin E, vitamin C, or derivatives thereof and natural antioxidants of plant origin are used as antioxidant / lipid peroxide production inhibitors. Has not yet been fully developed and is not always satisfactory in practice. In order to widely use antioxidant / lipid peroxide production inhibitors in the field of medicine, antioxidant / lipid peroxide production having properties superior to the above-mentioned known synthetic compounds in terms of action, action time, toxicity, etc. The development of inhibitors is needed. The purpose of the present invention is to
It is an object of the present invention to provide a novel compound having a completely different chemical structure from the known synthetic antioxidant / lipid peroxide production inhibitor. In particular EP-A-0351856, EP-A-044358
8. The compound described in Japanese Patent Application No. 03-325515 has a thiazole ring bicyclic condensed ring, but the present invention is a new tricyclic compound consisting of a thiazole ring tricyclic condensed ring. It is an object of the present invention to provide a novel compound which has a completely different structure in that it has a heterocyclic skeleton, and is further useful as a drug, which has a very useful lipid peroxide production inhibitory action.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to solve the above problems, and as a result, have a formula having a novel tricyclic heterocycle.

[Chemical 18] [Wherein A is an alkylene group or a bond having a chain length of 3 or less, which may have a substituent, B ring is an aromatic ring which may have a substituent, and W ¹ and W ² are one Is a nitrogen atom and the other is a sulfur atom, R ¹ is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent or a substituent which may have a substituent. A good alkoxycarbonyl group,
R ² represents a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a carboxylic acid or a sulfonate acyl group which may have a substituent, respectively. Show. ], And succeeded in synthesizing the tricyclic fused heterocycles represented by the following formula or salts thereof, and these novel compounds have unexpectedly strong inhibitory action on lipid peroxide formation, 12
-Hydroxyheptadecatrienoic acid (hereinafter abbreviated as "HHT") and lipoxygenase inhibitory or inhibitory activity, leukotriene D ₄ (LTD ₄ ) receptor antagonistic activity, etc. were found to be useful as a medicine, and based on these, And completed the present invention.

That is, the present invention provides (1) tricyclic heterocycles [I] or salts thereof, and (2) formula

[Chemical 19] [In the formula, R ³ represents an amino group which may be protected, R ⁴ represents an aromatic ring group which may have a substituent, and A and B rings have the same meanings as described above. ] The compound or its salt represented by these,
Formula (3)

[Chemical 20] [In the formula, X represents a leaving group, and A, B rings and R ² have the same meanings as described above. ] The compound or its salt represented by these, and a formula

[Chemical 21] [In the formula, R ¹ has the same meaning as described above. ] The compound represented by these or its salt is made to react, Formula

[Chemical formula 22] [In the formula, A, B rings, R ¹ and R ² have the same meanings as described above. ]
A method for producing a compound represented by: or a salt thereof, formula (4)

[Chemical formula 23] [In the formula, A, B rings, R ¹ and R ² have the same meanings as described above. ]
A compound represented by or a salt thereof is reacted with a sulfurizing agent,

[Chemical formula 24] [In the formula, A, B rings, R ¹ and R ² have the same meanings as described above. ]
(5) Compound [I] or a salt thereof, wherein (6) A is an alkylene group having a chain length of 3 or less, The present invention relates to the compound [I] or a salt thereof in which R ² is a hydrogen atom or a phenyl group.

In the above formula, the "alkylene group having a chain length of 3 or less" in "the alkylene group having a chain length of 3 or less which may have a substituent" represented by A is a straight chain C _1-3 alkylene. Indicates a group. That is, methylene, ethylene and propylene are shown. Examples of the “substituent” of the “alkylene group having a chain length of 3 or less which may have a substituent” represented by A include, for example, C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) , Halogen atoms (eg,
Fluoro, chloro, bromo, iodo, etc.), nitro group,
Cyano group, hydroxy group, C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, etc.), amino group, mono- or di-C _1-4 alkyl-substituted amino group (eg, methylamino, ethylamino, propylamino) , Dimethylamino, diethylamino, etc.), cyclic amino group (eg, pyrrolidino, piperidino, morpholino, etc.), C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), C _1-4 alkylsulfonyl Amino group (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg, , Methylcal Cycloalkenyl, ethylcarbonyl, etc. propyl carbonyl), a carbamoyl group, mono- or di-C _1-4 alkyl-substituted carbamoyl group (e.g., methylcarbamoyl, ethylcarbamoyl, etc.),
1 to 3 C _1-6 alkylsulfonyl groups (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.) and the like are used. Preferred examples of A include unsubstituted or C _1-4 alkyl groups (eg,
Methylene, ethylene, propylene substituted with (methyl, ethyl, propyl, isopropyl, etc.) are used.
Examples of the “aromatic ring” of the “optionally substituted aromatic ring” represented by ring B include an aromatic carbocycle and an aromatic heterocycle.

As the aromatic carbocycle, for example, a C _6-10 aryl group such as benzene or naphthalene is used. The aromatic heterocycle may be, for example, a nitrogen atom,
1 to 5 heteroatoms such as oxygen atom and sulfur atom,
Preferably, a 5- to 13-membered aromatic monocyclic heterocyclic group or aromatic condensed heterocyclic group containing about 1 to 3 is used. For example, a 5- to 8-membered aromatic monocyclic heterocyclic group such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, or, for example, benzofuran, isobenzofuran Benzo [b] thiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, benzothiazole, 1,2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline, Cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pyrrolo [1,2-
b] 8- to 13-membered aromatic condensed heterocyclic groups such as pyridazine and pyrazolo [1,5-a] pyridine are used. Of these, for example, a 5- or 6-membered aromatic monocyclic heterocyclic group and the like are preferable, and particularly preferable examples include benzene, pyridine, thiophene, pyrrole and the like.

The substituent which the above aromatic ring may have includes, for example, C _1-4 alkyl group (eg, methyl, ethyl, propyl, butyl, etc.), halogen atom (eg, fluoro, chloro, bromo, Iodo, etc.), nitro group, cyano group, hydroxy group, C _1-4 alkoxy group (eg, methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.), C _1-4 alkylthio group (eg, methylthio, ethylthio, Propylthio, isopropylthio, butylthio, etc.), amino group,
Mono or di C _1-4 alkyl-substituted amino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), cyclic amino group (eg, pyrrolidino, piperidino, morpholino, etc.), C
_1-4 alkyl-carbonylamino groups (eg, acetylamino, propionylamino, butyrylamino, etc.),
Aminocarbonyloxy group, mono- or di-C _1-4 alkyl-substituted aminocarbonyloxy group (eg, methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), C _1-4 alkylsulfonylamino group (For example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.), C
_1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl, etc.), carboxyl group, C _1-6
An alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), C
_3-6 cycloalkyl-carbonyl (eg, cyclohexylcarbonyl), carbamoyl group, mono- or di-C _1-4 alkyl-substituted carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutyl) Lucarbamoyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl,
Propylsulfonyl etc.), C _3-6 cycloalkylsulfonyl group (eg cyclopentylsulfonyl, cyclohexylsulfonyl etc.), phenyl which may have 1 to 4 substituents, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl -C _1-4 alkylcarbamoyl, phenyl carbamyl mode yl, phenyl -C _1-4 alkyl - carbonylamino, benzoylamino,-phenyl -C _1-4 alkylsulfonyl, phenylsulfonyl, phenyl--C _1-4 alkylsulfinyl, phenyl -C _1-4 the substituent in alkylsulfonylamino or Fenirusu Ruhoniruamino group (each phenyl group or a naphthyl group, for example methyl, ethyl, propyl, butyl, C _1-4 a such as isopropyl
Alkyl group, methoxy, ethoxy, n-propyloxy,
C _1-4 alkoxy group such as i-propyloxy and n-butyloxy, halogen atom such as chloro, bromo and iodo, hydroxyl group, benzyloxy group, amino group, mono- or di-C _1-4 alkyl-substituted amino as described above. A group, a nitro group, a C _1-6 alkyl-carbonyl group such as those mentioned above and the like are used. ) And the like are used. Particularly, for example, a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.) or a C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, butyloxy, isopropyloxy, etc.) and the like are preferable as the substituent. The number of substituents that these aromatic rings may have is suitably 1 to 3.

The "hydrocarbon group" of the "hydrocarbon group which may have a substituent" represented by R ¹ is, for example, linear, cyclic, saturated, unsaturated, or various combinations thereof. Hydrocarbon groups are used. Examples of the chain saturated hydrocarbon group include straight-chain or branched C
_1-11 alkyl groups, preferably C _1-6 alkyl groups (eg methyl, ethyl, n-propyl, i-propyl, n
-Butyl, i-butyl, tert-butyl, n-pentyl,
n-hexyl etc.) and the like are used. Examples of the chain unsaturated hydrocarbon group include straight chain or branched C
_2-4 alkenyl group (eg, vinyl, allyl, 2-butenyl, 2,4-butadienyl, etc.), linear or branched C _2-4 alkynyl group (eg, propynyl, propargyl, 2-butynyl, etc.) Are used. Examples of the cyclic saturated hydrocarbon group include C _3-7 monocyclic cycloalkyl groups (eg, cyclobutyl, cyclopentyl,
Cyclohexyl), C _8-14 bridged cyclic saturated hydrocarbon group (eg, bicyclo [3.2.1] oct-2-yl, bicyclo [3.3.1] non-2-yl, adamantane-1)
-Yl etc.) is used. Examples of the cyclic unsaturated hydrocarbon group include phenyl, naphthyl, anthryl,
A C _6-14 carbon aromatic ring group such as phenanthryl or acenaphthylenyl is used.

Further, the "hydrocarbon group" of the "hydrocarbon group which may have a substituent" represented by R ¹ is a chain, cyclic, saturated or unsaturated hydrocarbon group exemplified above. Hydrocarbon groups consisting of various combinations of
_7-18 Aralkyl (eg, phenyl-C _1-6 alkyl such as phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, α-naphthylmethyl or naphthyl-C _1-6 alkyl), C _8-18 arylalkenyl (eg, phenyl-C _2-4 alkenyl such as styryl, cinnamyl, 4-phenyl-2-butenyl, 4-phenyl-3-butenyl, etc.), C _8-18 arylalkynyl (eg, phenylethynyl) , 3-phenyl-2-propynyl, phenyl-C _2-4 alkynyl such as 3-phenyl-1-propynyl), C _3-7 monocyclic cycloalkyl-C _1-6 alkyl (eg cyclopropylmethyl, Cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclo Propylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylbutyl,
Cyclobutylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbutyl, cyclopropylpentyl, cyclobutylpentyl, cyclopentylpentyl, cyclohexylpentyl, cycloheptylpentyl, cyclopropylhexyl, cyclobutylhexyl,
Cyclopentylhexyl, cyclohexylhexyl, cycloheptylhexyl, etc.) are used. Preferred examples of the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R ¹ include a linear or branched C _1-6 alkyl group (eg, methyl, ethyl , N
-Propyl, i-propyl, n-butyl, i-butyl,
tert-butyl, n-pentyl, n-hexyl, etc.), phenyl group, phenyl-C _1-6 alkyl group (eg, phenylmethyl, phenylethyl, phenylpropyl, etc.), phenyl-C _1-6 alkenyl group (eg, Styryl, cinnamyl, 4-phenyl-2-butenyl, 4-phenyl-3-butenyl, etc.), phenyl-C _1-6 alkynyl group (eg phenylethynyl, 3-phenyl-2)
-Propynyl, 3-phenyl-propynyl and the like) are used. Furthermore, a linear or branched C _1-3 alkyl group (methyl, ethyl, n-propyl, i-propyl, etc.), a phenyl group phenyl-C _1-3 alkyl (for example, phenylmethyl, phenylethyl, phenylpropyl). Or phenyl-C _1-3 alkenyl (eg,
(Styryl, cinnamyl, etc.) and the like are more preferable as the same “hydrocarbon group”.

The substituent which the chain saturated, chain unsaturated and cyclic saturated hydrocarbon group represented by R ¹ may have is, for example, a halogen atom (for example,
Fluoro, chloro, bromo, iodo, etc.), nitro group,
Cyano group, hydroxy group, C _1-4 alkoxy group (eg, methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.), C _1-4 alkylthio group (eg, methylthio, ethylthio, propylthio, etc.), amino group, Mono or di C _1-4 alkyl substituted ami
Group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), cyclic amino group (eg, pyrrolidino, piperidino, morpholino, etc.), C _1-4 alkyl-carbonylamino group (eg, acetylamino, Propionylamino, butyrylamino, etc.), C _1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl group, C _1-6 alkyl - carbonyl group (e.g., methylcarbonyl, ethylcarbonyl, etc. propyl carbonyl), a carbamoyl group, mono- or di-C _1-4 alkyl-substituted carbamoyl group (e.g., methylcarbamoyl, Such as Chi carbamoyl),
1 to 5 C _1-6 alkylsulfonyl groups (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.) and the like are used.

The substituent of the cyclic unsaturated hydrocarbon group represented by R ¹ is, for example, a C _1-4 alkyl group (eg,
Methyl, ethyl, propyl, butyl etc.), halogen atom (eg fluoro, chloro, bromo, iodo etc.), nitro group, cyano group, hydroxy group, C _1-4 alkoxy group (eg methoxy, ethoxy, propyloxy, Butyloxy, isopropyloxy, etc.), C _1-4
Alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), amino group, mono- or di-C _1-4 alkyl-substituted amino group (eg, methylamino, ethylamino, propylamino,
Dimethylamino, diethylamino, etc.), cyclic amino group (eg, pyrrolidino, piperidino, morpholino, etc.), C _1-4 alkyl-carbonylamino group (eg,
Acetylamino, propionylamino, butyrylamino, etc.), aminocarbonyloxy group, mono- or di-C
_1-4 alkyl-substituted aminocarbonyloxy group (for example, methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), C _1-4 alkylsulfonylamino group (for example, methylsulfonylamino,
Ethylsulfonylamino, propylsulfonylamino, etc.), C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg, methyl) Carbonyl, ethylcarbonyl, butylcarbonyl, etc.), C _3-6 cycloalkyl-carbonyl (eg, cyclohexylcarbonyl), carbamoyl group, mono- or di-C _1-4 alkyl-substituted carbamoyl group (eg,
Methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.), C _3-6 cycloalkylsulfonyl group ( (Eg, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), phenyl optionally substituted with 1 to 4 substituents, naphthyl, phenoxy,
Benzoyl, phenoxycarbonyl, phenyl-C _1-4
Alkylcarbamoyl, phenylcarbamoyl, phenyl-C _1-4 alkyl-carbonylamino, benzoylamino, phenyl-C _1-4 alkylsulfonyl, phenylsulfonyl, phenyl-C _1-4 alkylsulfinyl,
Phenyl-C _1-4 alkylsulfonylamino group or phenylsulfonylamino group (substituents in each phenyl group or naphthyl group include, for example, C _1-4 alkyl group such as methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, etc. , N-propyloxy,
C _1-4 alkoxy group such as i-propyloxy and n-butyloxy, halogen atom such as chloro, bromo and iodo, hydroxyl group, benzyloxy group, amino group, mono or di C _1-4 alkyl-substituted amino group as described above. , A nitro group, and a C _1-6 alkyl-carbonyl group such as those mentioned above are used. ) And the like are used. Particularly, for example, a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.) or a C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, butyloxy, isopropyloxy, etc.) and the like are preferable as the substituent. The number of substitutions of these cyclic unsaturated hydrocarbon groups is suitably 1 to 3.

The substituent of the "hydrocarbon group consisting of various combinations of chain, cyclic, saturated and unsaturated hydrocarbon groups" represented by R ¹ is, for example, a C _1-4 alkyl group (eg methyl group). , Ethyl, propyl, butyl, etc.), halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), nitro group, cyano group, hydroxy group, C _1-4 a
Lucoxy group (eg, methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.), C
_1-4 alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), amino group, mono- or di-C _1-4 alkyl-substituted amino group (eg, methylamino, ethylamino, propylamino, dimethylamino) , Diethylamino etc.), cyclic amino groups (eg pyrrolidino, piperidino, morpholino etc.), C _1-4 alkyl-carbonylamino groups (eg acetylamino, propionylamino, butyrylamino etc.), aminocarbonyloxy groups, mono or di C _1-4 alkyl substituted Aminokaruboni aryloxy group (e.g., methylamino carbonyloxy, ethylamino carbonyloxy, dimethylaminocarbonyloxy, diethylamino carbonyloxy), C _1-4 alkylsulfonyl group (e.g., Chill sulfonylamino,
Ethylsulfonylamino, propylsulfonylamino, etc.), C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg, methyl) Carbonyl, ethylcarbonyl, butylcarbonyl, etc.), C _3-6 cycloalkyl-carbonyl (eg, cyclohexylcarbonyl), carbamoyl group, mono- or di-C _1-4 alkyl-substituted carbamoyl group (eg,
Methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.), C _3-6 cycloalkylsulfonyl group ( (Eg, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), phenyl optionally substituted with 1-4 substituents, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl-C _1-4 alkylcarbamoyl, phenylcarbamoyl, phenyl-
C _1-4 alkyl-carbonylamino, benzoylamino, phenyl-C _1-4 alkylsulfonyl, phenylsulfonyl, phenyl-C _1-4 alkylsulfinyl, phenyl-C _1-4 alkylsulfonylamino or phenylsulfonyl amino groups (respectively Examples of the substituent on the phenyl group or naphthyl group include C _1-4 alkyl groups such as methyl, ethyl, propyl, butyl and isopropyl, methoxy, ethoxy, n-propyloxy,
C _1-4 alkoxy group such as i-propyloxy and n-butyloxy, halogen atom such as chloro, bromo and iodo, hydroxyl group, benzyloxy group, amino group, mono- or di-C _1-4 alkyl-substituted amino as described above Groups, nitro groups, C _1-6 alkylcarbonyl groups such as those mentioned above are used
Can be ) And the like are used.

The "heterocyclic group" of the "optionally substituted heterocyclic group" represented by R ¹ is 1 to 5, preferably 1 to 3 heteroatoms (eg, 1 to 3) in the ring. , N, O, S, etc.) are used, and 5- to 13-membered aromatic or non-aromatic heterocyclic groups are used. Examples of the aromatic heterocycle include 5- to 8-membered aromatic monocyclic heterocyclic groups such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, and pyrazine. Or, for example, benzofuran, isobenzofuran, benzo [b] thiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, benzothiazole, 1,2-benzisothiazole, 1H-. Benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pyrrolo [1,2-
b] Pyridazine, pyrazolo [1,5-a] pyridine, and other 8- to 13-membered fused aromatic heterocyclic groups are used.

Examples of the above non-aromatic heterocyclic group include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl,
Piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrazinyl and the like are used. Among the above "heterocyclic groups", 5- or 6-membered heterocyclic groups are preferable, and examples thereof include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, thiazolyl, thiadiazolyl, thiophenyl. Used. Particularly, pyridine is preferable.

The "substituent" of the "optionally substituted heterocyclic group" represented by R ¹ is, for example, C _1-4
Alkyl group (eg, methyl, ethyl, propyl, butyl, etc.), halogen atom (eg, fluoro, chloro,
Bromo, iodo, etc.), nitro group, cyano group, hydroxy group, C _1-4 alkoxy group (eg, methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.), C _1-4 alkylthio group (eg, methylthio, ethylthio) , Propylthio, isopropylthio, butylthio, etc.), amino group, mono- or di-C _1-4 alkyl-substituted amino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), cyclic amino group (eg, pyrrolidino) , Piperidino, morpholino, etc.), C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), aminocarbonyloxy group, mono- or di-C _1-4 alkyl-substituted aminocarbonyloxy group (eg, Methylamino Le Boniruokishi,
Ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.),
C _1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.), C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl, etc.) , A carboxyl group, a C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), a C _3-6 cycloalkyl-carbonyl (eg, cyclohexylcarbonyl, etc.), a carbamoyl group, a mono- or di-C _{1 -4} alkyl-substituted carbamoyl groups (eg methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl,
Diethylcarbamoyl, dibutylcarbamoyl, etc.),
A C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.), C
_3-6 cycloalkylsulfonyl (eg, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), 1-
Phenyl, naphthyl, which may have 4 substituents,
Phenoxy, benzoyl, phenoxycarbonyl, phenyl-C _1-4 alkylcarbamoyl, phenylcarbamoyl, phenyl-C _1-4 alkyl-carbonylamino,
Benzoylamino, phenyl-C _1-4 alkylsulphonyl, phenylsulphonyl, phenyl-C _1-4 alkylsulfinyl, phenyl-C _1-4 alkylsulphonylamino or phenylsulphonylamino groups (substituents on the respective phenyl or naphthyl groups as is for example methyl, ethyl, propyl, butyl, C _1-4 alkyl groups such as isopropyl, methoxy, ethoxy, n- Puropiruoki shea, i- propyloxy, C _1-4 alkoxyl groups such as n- butyloxy, chloro, A halogen atom such as bromo or iodo, a hydroxyl group, a benzyloxy group, an amino group, a mono- or di-C _1-4 alkyl-substituted amino group as described above, a nitro group, a C _1-6 alkylcarbonyl group as described above, etc. are used. ) Selected from 1 to 3
Individuals are used.

The "alkoxycarbonyl group" of the "alkoxycarbonyl group which may have a substituent" represented by R ¹ is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, i-propoxycarbonyl, butoxycarbonyl, tert. A C _1-6 alkoxy-carbonyl group such as butoxycarbonyl is used. As a preferable example of the above-mentioned alkoxycarbonyl group, for example, a C _1-3 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl is used, and methoxycarbonyl is particularly preferable. The "substituent" of the "alkoxycarbonyl group which may have a substituent" represented by R ¹ may be any substituent as long as it is a substituent usually used in medicine, and specifically, for example, halogen An atom (eg, chloro,
Bromo, fluoro, etc., hydroxy, C _1-3 alkoxy (eg methoxy, ethoxy, n-propoxy, i
-Propoxy etc.), C _6-10 aryloxy (eg
Phenoxy, etc.), C _7-10 aralkyloxy (eg,
Benzyloxy etc.), mercapto, C _1-3 aralkylthio (eg methylthio, ethylthio etc.), C _6-10 arylthio (eg phenylthio etc.), C _7-10 aralkylthio (eg benzylthio etc.), amino, C
_1-3 alkyl-substituted mono- or di-substituted amino (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), cyclic amino (eg, pyrrolidino, morpholino, piperidino, piperazino, etc.), C _2-5 alkoxy Carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), C _1-10 acyl (eg, formyl, acetyl, propionyl, benzoyl etc.), C _2-4 acyloxy (eg, acetoxy, propionyloxy etc.), C _2-10 1 to 5, preferably 1 to 3, selected from an acylamide (eg, acetamide, benzamide, etc.), a carboxyl group, a carbamoyl group, a phenyl group which may have a substituent, or a naphthyl group is used. Examples of the substituent of the phenyl group or naphthyl group include C
_1-4 alkyl groups (eg methyl, ethyl, propyl,
Butyl, etc.), halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), nitro group, cyano group, hydroxy group, C _1-4 alkoxy group (eg, methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.) , C _1-4 alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), amino group, mono- or di-C _1-4
Alkyl-substituted amino groups (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), cyclic amino groups (eg, pyrrolidino, piperidino, morpholino, etc.), C _1-4 alkyl-carbonyl amino groups (eg, acetyl) Amino, propionylamino, butyrylamino, etc.), aminocarbonyloxy group, mono- or di-C _1-4 alkyl-substituted aminocarbo
Nyloxy group (eg, methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), C _1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.) , A C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl, etc.), a carboxyl group, a C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl,
Butylcarbonyl etc.), C _3-6 cycloalkyl-carbonyl (eg cyclohexylcarbonyl etc.),
Carbamoyl group, mono- or di-C _1-4 alkyl-substituted carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl) , Ethylsulfonyl, propylsulfonyl, etc.), C _3-6 cycloalkylsulfonyl (eg, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), phenyl which may have 1 to 4 substituents, naphthyl, phenoxy, benzoyl, Phenoxycarbonyl, phenyl-C _1-4 alkylcarbamoyl, phenylcarbamoyl, phenyl-C _1-4 alkyl-carbonylamino, benzoylamino, phenyl-C _1-4 alkylsulfonyl, phenylsulfur Honyl, Phenyl-C
_1-4 alkylsulfinyl, phenyl-C _1-4 alkylsulphonylamino or phenylsulphonylamino groups (the substituents in the respective phenyl or naphthyl groups include, for example, C _1- , such as methyl, ethyl, propyl, butyl, isopropyl, etc. ₄ alkyl group, methoxy,
Ethoxy, n-propyloxy, i-propyloxy,
C _1-4 alkoxy group such as n-butyloxy, chloro,
Halogen atoms such as bromo and iodo, hydroxyl group, benzyloxy group, amino group, mono- or di-C as above.
_1-4 alkyl substituted amino group, nitro group, C as described above
_{A 1-6} alkylcarbonyl group or the like is used. 1) to about 3) are preferable.

The "hydrocarbon group which may have a substituent (s)" represented by R ² includes, for example, the groups described in the above "hydrocarbon group which may have a substituent (s)" of R ^1. Used. As the “heterocyclic group optionally having substituent (s)” represented by R ² , for example, the groups described in the above “heterocyclic group optionally having substituent (s)” of R ^{1 and} the like can be used.
Examples of the “carboxylic acid acyl group which may have a substituent” represented by R ² include, for example, the formula R ⁵ CO— (in the formula, R ⁵ represents a hydrocarbon group which may have a substituent). Group) and the like are used. "A sulfonate acyl group which may have a substituent" represented by R ²
For example, a group represented by the formula R ⁵ SO ₂ — (wherein R ⁵ has the same meaning as described above) and the like are used. Examples of the "hydrocarbon group which may have a substituent" represented by R ⁵ include the groups described in the "hydrocarbon group which may have a substituent" of R ^{1 and} the like. . Preferable examples of R ⁵ include, for example, a linear or branched C _1-6 alkyl group (eg, methyl, ethyl, n
-Propyl, i-propyl, n-butyl, i-butyl,
tert-butyl etc.), C _2-4 alkenyl group (eg vinyl, allyl, 2-butenyl, 2,4-butadienyl etc.), C _2-4 alkynyl group (eg propargyl, 2
-Butynyl) or a phenyl group.

^One of W ¹ and W ² is a nitrogen atom and the other is a sulfur atom.

[Chemical 25] Forms a thiazole ring. The compound represented by the formula [I] or a salt thereof may give rise to stereoisomers depending on the types of substituents on R ¹ , R ² and the B ring, but not only these isomers alone, Mixtures thereof are also included in the present invention. As the salt of the compound represented by the formula [I], a pharmaceutically acceptable salt is particularly preferable. Examples of such salts include hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid,
Inorganic acids such as hydrobromic acid and organic carboxylic acids (eg formic acid,
Salts with organic acids such as acetic acid, tartaric acid, citric acid, oxalic acid, phthalic acid, fumaric acid, maleic acid), sulfonic acids (eg, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) Used. When the compound [I] has an acidic group such as a carboxyl group as a substituent on the R ¹ and B rings, an alkali metal (eg, sodium, potassium, etc.) or an alkaline earth metal (eg,
Inorganic salts such as magnesium, or organic bases (eg dicyclohexylamine, triethylamine,
An amine such as 2,6-lutidine).

In the above formula [II], the optionally protected amino group represented by R ³ is, for example, one represented by the formula:
A group represented by NHR ³ ′ (wherein R ³ ′ represents a hydrogen atom or a protecting group) and the like are used. The protecting group represented by R ³ ′ includes, for example, an alkylcarbonyl which may have a substituent, preferably C _1-6 alkylcarbonyl (eg, formyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.), a substituent Optionally substituted phenylcarbonyl, optionally substituted alkyloxycarbonyl, preferably C _1-6 alkyl-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), a substituent Optionally having phenyloxycarbonyl, optionally having a C _7-10 aralkyl-carbonyl (eg, benzyloxycarbonyl etc.),
Trityl which may have a substituent, phthaloyl which may have a substituent and the like are used. As the substituent, a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), a C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group, etc. are used. The number of groups is about 1 to 3.

Examples of the "aromatic ring" of the "optionally substituted aromatic ring group" represented by R ⁴ include an aromatic carbocycle and an aromatic heterocycle. As the aromatic carbocycle, for example, a C _6-10 aryl group such as benzene or naphthalene is used. Of these, benzene is preferable.
As the aromatic heterocycle, for example, a 5- to 13-membered aromatic monocyclic heterocycle containing 1 to 5, preferably 1 to 3 heteroatoms such as nitrogen atom, oxygen atom and sulfur atom. A group or a fused aromatic heterocyclic group is used. For example, a 5- to 8-membered aromatic monocyclic heterocyclic group such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, or, for example, benzofuran, isobenzofuran Benzo [b] thiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, benzothiazole, 1,2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline, 8- to 13-membered aromatic heterocyclic groups such as cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pyrrolo [1,2-b] pyridazine, pyrazolo [1,5-a] pyridine Used. Of these, for example, a 5- or 6-membered aromatic monocyclic heterocyclic group and the like are preferable, and particularly preferable examples include pyridine, thiophene, pyrrole and the like. Examples of the substituent that the aromatic ring may have include C _1-4
Alkyl group (eg, methyl, ethyl, propyl, butyl, etc.), halogen atom (eg, fluoro, chloro,
Bromo, iodo, etc.), nitro group, cyano group, hydroxy group, C _1-4 alkoxy group (eg, methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.), C _1-4 alkylthio group (eg, methylthio, Ethylthio, propylthio, isopropylthio,
Butylthio etc.), amino group, mono- or di-C _1-4 alkyl substituted amino group (eg methylamino, ethylamino, propylamino, dimethylamino, diethylamino etc.), cyclic amino group (eg pyrrolidino, piperidino, morpholino etc.) , C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), aminocarbonyloxy group, mono- or di-C _1-4 alkyl-substituted aminocarbonyloxy group (eg, methylaminocarbonyloxy, ethyl Aminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), C
_1-4 alkylsulfonylamino group (for example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.), C _1-4 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, isobutoxycarbonyl etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg methylcarbonyl, ethylcarbonyl, butylcarbonyl etc.), C _3-6 cycloalkyl-carbonyl (eg cyclohexylcarbonyl etc.) ), Carbamoyl group, mono- or di-C _1-4 alkyl-substituted carbamoyl group (for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), C
_1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.),
A C _3-6 cycloalkylsulfonyl group (eg, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.),
Phenyl optionally substituted with 1 to 4 substituents, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl-C _1-4 alkylcarbamoyl, phenylcarbamoyl, phenyl-C _1-4 alkyl-carbonylamino, benzoylamino,-phenyl -C _1-4 alkylsulfonyl, phenylsulfonyl, phenyl--C _1-4 alkylsulfinyl, the substituent on the phenyl -C _1-4 alkylsulfonylamino or Fenirusu Ruhoniruamino group (each phenyl group or a naphthyl group Are, for example, C _1-4 alkyl groups such as methyl, ethyl, propyl, butyl and isopropyl, C _1-4 alkoxy groups such as methoxy, ethoxy, n-propyloxy, i-propyloxy and n-butyloxy, chloro, Halogen atoms such as bromo and iodo Hydroxyl, benzyloxy group, an amino group, the above such mono- or di-C _1-4 alkyl-substituted amino group, a nitro group, above such C _1-6 alkyl -. The carbonyl group is used) and the like. In particular, for example, a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.) or a C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy,
Butyloxy, isopropyloxy, etc.) are preferable as the substituent. The number of substituents which these aromatic ring groups may have is suitably 1 to 3.

As the salt of the compound represented by the formula [II], a pharmaceutically acceptable salt is particularly preferable. Examples of these salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid and organic carboxylic acids (eg, formic acid, acetic acid,
Tartaric acid, citric acid, oxalic acid, phthalic acid, fumaric acid, maleic acid, etc.), sulfonic acid (eg, methanesulfonic acid,
A salt with an organic acid such as benzenesulfonic acid and p-toluenesulfonic acid is used. Also the compound [II]
Has an acidic group such as a carboxyl group as a substituent on the R ⁴ and B rings, an inorganic salt with an alkali metal (eg, sodium, potassium, etc.) or an alkaline earth metal (eg, magnesium, etc.), or an organic base (Eg, dicyclohexylamine, triethylamine,
An amine such as 2,6-lutidine). Next, a method for producing the compound [I] of the present invention or a salt thereof and the compound [II] or a salt thereof will be described.
Hereinafter, the compound represented by the formula [I] or a salt thereof is abbreviated as the compound [I], and the compound represented by the formula [II] or a salt thereof is abbreviated as the compound [II]. Of the compound [I],
Compound [V] in which W ¹ is a sulfur atom and W ² is a nitrogen atom can be obtained by reacting compound [III] or a salt thereof with compound [IV] or a salt thereof. Examples of the leaving group represented by X in the formula [III] include a halogen atom (eg, chloro, bromo, iodo, etc.), C _1-6
Alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, etc.), C _6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) and the like are used. Particularly, a halogen atom or the like is preferable as X.

This reaction is advantageously carried out using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, but alcohols such as methanol, ethanol, propanol and isopropanol are preferable. Reaction temperature is usually 50 to 150
C., preferably 60 to 100.degree. The reaction time is generally 3 to 24 hours, preferably 6 to 12 hours. The amount of compound [IV] or a salt thereof to be used is generally about 1 to 3 mol, preferably about 1 to 1.3 mol, relative to 1 mol of compound [III] or a salt thereof. Compound [III] or a salt thereof can be produced by a method known per se or a method analogous thereto. For example, Journal of
The American Chemical Society “J. Am. Chem. S
oc. ”, 80 , 6233 (1958), Journal of Medicinal Chemistry“ J. Med. Chem. ”, 1
4 , 501 (1971), Helvetica Kimika Acta "Helv. Chim. Acta", 71 , 337 (1988) and the like. In addition, compound [IV]
Alternatively, the salt thereof can be produced by a method known per se or a method analogous thereto. For example, Tetrahedron Letters “Tetrahedron Lett.”, 22 , 1
851 (1981) and the like. As the salts of the compounds [III] and [V], pharmaceutically acceptable salts are particularly preferable. Examples of such salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid and organic carboxylic acids (eg, formic acid, acetic acid, tartaric acid, citric acid, oxalic acid, phthalic acid, fumaric acid, maleic acid). Acids, etc.), sulfonic acids (eg, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and salts with organic acids are used. Further, the compounds [III] and [V] are R ²
And having an acidic group such as a carboxyl group as a substituent on the B ring, an alkali metal (eg, sodium,
A salt may be formed with an inorganic base or organic base (eg, amines such as dicyclohexylamine, triethylamine, 2,6-lutidine, etc.) such as potassium) or an alkaline earth metal (eg, magnesium) etc. As the salt of compound [IV], a pharmaceutically acceptable salt is particularly preferable. Examples of such salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid and organic carboxylic acids (eg, formic acid, acetic acid, tartaric acid, citric acid, oxalic acid, phthalic acid, fumaric acid, maleic acid). Acid, etc.), sulfonic acid (eg,
A salt with an organic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. is used. When the compound [III] has an acidic group such as a carboxyl group as a substituent in R ¹ , an alkali metal (eg, sodium, potassium, etc.) or an alkaline earth metal (eg,
Inorganic or organic bases (eg magnesium, etc.) (eg dicyclohexylamine, triethylamine,
An amine such as 2,6-lutidine).

When the compound [V] in which R ² of the compound [V] is a hydrogen atom (hereinafter referred to as the compound [V] (R ² ═H)) or a salt thereof can be obtained by the above-mentioned method, known means, For example, it can be isolated and purified by concentration, liquid conversion, phase transfer, solvent extraction, fractional distillation, distillation, crystallization, recrystallization, chromatography, etc., but the reaction mixture can be used as an aliphatic group without isolation. A compound [V] or a salt thereof in which R ² is other than a hydrogen atom can also be obtained by subjecting it to an introduction reaction, a carboxylic acid acylation reaction, a sulfonic acid acylation reaction, or the like. Specifically, a compound in which R ² is a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent or an sulfonate acyl group which may have a substituent. [V] or a salt thereof is, for example, a compound [V] (R
² = H) or a salt thereof and a formula R ² ′ -Y [VIII] [wherein, R ² ′ is a hydrocarbon group which may have a substituent or a heterocyclic ring which may have a substituent]. A group or a sulfonate acyl group which may have a substituent, and Y represents a leaving group. ] It can manufacture also by making it react with the compound represented by this. Examples of the leaving group represented by Y include a halogen atom (eg, chloro, bromo,
Iodo, etc.), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, etc.), C _6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) and the like are used. A halogen atom is particularly preferable as Y. "A hydrocarbon group which may have a substituent", "a heterocyclic group which may have a substituent" and "a sulfonic acid acyl group which may have a substituent" represented by R ² ' Are, for example, “hydrocarbon group which may have a substituent”, “heterocyclic group which may have a substituent” and “which may have a substituent” described in R ² above. A good acyl sulfonate group ”or the like is used.

When carrying out the reaction for introducing a hydrocarbon group or a heterocyclic group, the amount of the starting compound [VIII] used is the compound [V]
It is about 1 to 2 mol per mol of (R ² = H) or a salt thereof. This reaction may be allowed to proceed in the presence of an inorganic base such as potassium carbonate, sodium carbonate or sodium hydride or an organic base such as triethylamine or pyridine. The base is preferably used in an equimolar amount to the compound [V] (R ² = H) or a salt thereof. This reaction can be advantageously carried out in a solvent, and the solvent used is not particularly limited as long as the reaction proceeds, but for example, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide and the like are preferably used. The reaction is usually carried out under ice-cooling to heating, and the range of about 30 ° to 100 ° C is suitable. The reaction time is usually 30 minutes to 8 hours, preferably 30 minutes to 3 hours. When carrying out the reaction for introducing an acyl sulfonate group, the amount of the compound [VIII] used is about 1 to 3 mol per 1 mol of the compound [V] (R ² = H) or a salt thereof. This reaction is
Usually, it is advantageous to carry out in the presence of an amine such as triethylamine, pyridine or 4-dimethylaminopyridine. The amount of amine used is about 1 to 3 mol per 1 mol of compound [V] (R ² = H) or a salt thereof. This reaction can be carried out in a solvent, and any solvent may be used as long as it is inert to the reaction. For example, acetone, dioxane, dimethylformamide, tetrahydrofuran, chloroform, methylene chloride and the like are preferably used. Be done. Further, the reaction may be carried out using pyridine as a solvent. The reaction usually proceeds smoothly at 0 ° C. to room temperature (room temperature in the following description of the production method specifically means 5 to 35 ° C.). Reaction time is usually 30
Minutes to 12 hours, preferably 30 minutes to 5 hours.

In order to obtain the compound [V] or a salt thereof in which R ² is a carboxylic acid acyl group which may have a substituent, for example, a compound [V] (R ² = H) or a salt thereof is used. Formula R ⁵ COOH [IX] [In the formula, R ⁵ has the same meaning as described above. ] You may react with the carboxylic acid represented by these or its reactive derivative.
Examples of the reactive derivative of the carboxylic acid include acid halides (eg, acid chlorides and acid bromides), acid amides (eg, imidazolides), acid anhydrides, acid azides, active esters (eg, N-phthalimide ester). , N-oxysuccinimide ester, etc.) are used. Further, instead of using the activated ester, the carboxylic acid may be directly reacted with the compound [V] (R ² = H) or a salt thereof. In that case, the reaction is preferably allowed to proceed in the presence of a coupling reagent such as N, N'-dicyclohexylcarbodiimide or 1-hydroxybenzotriazole. The carboxylic acid [IX] or its reactive derivative is generally used in an amount of 1 to 3 mol, preferably about 1 to 1.2 mol, per 1 mol of the compound [V] (R ² = H) or a salt thereof.
Compound [V] (R ² = H) or its salt and carboxylic acid [I
When directly reacting with X], carboxylic acid [IX] is usually added to 1 mol of compound [V] (R ² = H) or a salt thereof.
Usually about 1 to 3 mol is used, preferably about 1 to 1.2 mol is used.
At this time, the reaction can be advantageously carried out in the presence of 1 to 1.2 mol of the coupling reagent with respect to 1 mol of the compound [V] (R ² = H) or a salt thereof. Reaction is usually 0
It progresses smoothly at ℃ ~ room temperature. This reaction is preferably carried out in a solvent, and any solvent may be used as long as it is inert to the reaction, for example, chloroform, methylene chloride, tetrahydrofuran, dioxane, dimethylformamide and the like. When an acid halide is used as a reactive derivative of carboxylic acid [IX], it is desirable to add an amine such as triethylamine, pyridine or 4-dimethylaminopyridine in the reaction system. While the reaction time varies depending on the reagent and solvent to be used, it is generally 30 min-12 hr, preferably 30 min-2 hr.

Furthermore, Compound Compound R ² is a hydrocarbon group which may have a substituent [V] or a salt thereof, R ² is a good carboxylic acyl group which may have a substituent It can also be obtained by reducing [V] or a salt thereof. The reduction can be carried out by a method known per se or a method analogous thereto, but reduction with a reducing agent such as lithium aluminum hydride or diborane is suitable. At this time, ether, tetrahydrofuran, dioxane or the like is used as a solvent, and the reaction may be allowed to proceed under reflux. When R ² of the compound [V] is an acyl carboxylate or an acyl sulfonate, the compound [V] having R ² = H is obtained by hydrolysis with an acid by a method known per se. In addition, in each of the above reactions, when the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent in R ¹ and R ^2, a protecting group commonly used in peptide chemistry or the like is added to these groups. It may be introduced, and the target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino group-protecting group include optionally substituted C _1-6 alkylcarbonyl (eg, formyl, methylcarbonyl, ethylcarbonyl, etc.), phenylcarbonyl, C
_1-6 alkyl-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl (eg, benzoxycarbonyl, etc.),
C _7-10 aralkyl-carbonyl (eg benzyloxycarbonyl etc.), trityl, phthaloyl etc. are used. These substituents include halogen atoms (eg, fluoro, chloro, bromo, iodo, etc.), C _1-6
Alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like are used, and the number of substituents is about 1 to 3.

As the protecting group for the carboxyl group, for example, C _1-6 alkyl _optionally having a substituent (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.) , Phenyl, trityl, silyl and the like are used. These substituents include halogen atoms (eg, fluoro, chloro, bromo, iodo, etc.), C _1-6 alkylcarbonyl (eg, formyl,
(Methyl carbonyl, ethyl carbonyl, butyl carbonyl, etc.), nitro group and the like are used, and the number of substituents is about 1 to 3. Examples of the hydroxyl-protecting group include optionally substituted C _1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.), phenyl, C
_7-10 aralkyl (eg, benzyl), C _1-6 alkylcarbonyl (eg, formyl, methylcarbonyl, ethylcarbonyl nad), phenyloxycarbonyl (eg, benzoxycarbonyl), C _7-10 aralkyl-carbonyl ( For example, benzyloxycarbonyl etc.), pyranyl, furanyl, silyl and the like are used. These substituents include halogen atoms (eg, fluoro, chloro, bromo, iodo, etc.), C _1-6
Alkyl, phenyl, C _7-10 aralkyl, nitro group and the like are used, and the number of substituents is about 1 to 4. Further, as a method for removing the protective group, a method known per se or a method analogous thereto can be used, and examples thereof include acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, A method of treating with palladium acetate or the like is used. The compound [V] obtained by the above method can be isolated and purified by a usual separation means such as recrystallization, distillation and chromatography. When the compound [V] thus obtained is obtained as a free form, it can be converted into a salt by a method known per se or a method analogous thereto (for example, neutralization etc.),
Conversely, when it is obtained as a salt, it can be converted into a free form or another salt by a method known per se or a method analogous thereto.

Next, in the compound [I], W ¹ is a nitrogen atom,
Compound [VII] or a salt thereof in which W ² is a sulfur atom can be obtained by reacting compound [VI] or a salt thereof with a sulfiding agent. The compound other than the aromatic carbocyclic group or aromatic heterocyclic group in which R ² may have a substituent in the starting compound [VI] or a salt thereof can be produced by a method known per se or a method analogous thereto. it can. For example, the expression

[Chemical formula 26] [In the formula, rings A and B have the same meanings as described above. R ² ′ is a compound represented by the above R ² excluding an aromatic carbocyclic group and an aromatic heterocyclic group which may have a substituent] or a salt thereof, and a compound of the formula R ¹ COOH (XI) R ¹ has the same meaning as described above. ] It is obtained by reacting with a carboxylic acid represented by or a reactive derivative thereof. The reaction method is as follows: Compound [V] (R ² = H) or a salt thereof is reacted with Compound [IX] or a reactive derivative thereof, and R ² is a carboxylic acyl group which may have a substituent. This is the same as when obtaining a certain compound [V] or a salt thereof. The compound [VI] in which R ² is an optionally substituted aromatic carbocyclic group or aromatic heterocyclic group, or a salt thereof is a compound [VI] obtained by the above method, wherein R ² is a hydrogen atom. ] (Compound [VI] (R ² = H)) or a salt thereof, by introducing an aromatic ring. That is, the compound [VI] (R ² = H) or a salt thereof and the formula R ⁴ —Z (XII) [R ⁴ has the same meaning as described above, and Z represents a leaving group. ) It can manufacture by reacting with the compound represented by. Compound [X] or a salt thereof can be produced by a method known per se or a method analogous thereto. For example, Archives of Biochemistry and Biophysics “Arch. Biochem. Biophys.”,
102 , 48 (1963), Journal of Organic Chemistry "J.Org.Chem.", 50 , 340.
8 (1985), Helvetic Kimika Actor "He
lv.Chim.Acta. ”, 71 , 337 (1988), etc. The leaving group represented by Z is, for example, a halogen atom (eg, chloro, bromo,
Iodo, etc.), C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, etc.), C _6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) and the like are used. A halogen atom is particularly preferable as Z. The aromatic ring introduction reaction is usually carried out in a solvent in the presence of a copper catalyst and a base. As a copper catalyst,
For example, copper powder, cuprous chloride, cuprous bromide, cuprous oxide, cupric chloride, cupric bromide, cupric oxide, etc. may be used singly or in a plural number. A combination of cuprous is particularly preferred. At this time, as the base, for example, potassium acetate,
Sodium acetate, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and the like are used. The copper catalyst used is usually about 1 to 3 times the molar amount of the compound [VI] (R ² = H) or its salt. The solvent used in the reaction may be any as long as it is inert to the reaction,
For example, dimethylacetamide, dimethylformamide,
Nitrobenzene and naphthalene are common. Particularly, dimethylacetamide, dimethylformamide and the like are preferable as the solvent. The reaction is usually under heating (80-200).
C.) and is preferably about 100 to 140.degree. The reaction usually requires 2 to 24 hours. The compound [VI] and its salt thus obtained can be obtained by a method known per se,
That is, it can be purified by means of liquid conversion, phase transfer, extraction, fractional distillation, distillation, crystallization, recrystallization, chromatography and the like. The compound [VI] or a salt thereof in which R ² is an aromatic carbocyclic group or an aromatic heterocyclic group can be prepared by combining, for example, deprotection of the acyl group R ¹ —CO— on the amino group or introduction of a new protective group. The compound [II] can be easily obtained. As a method for deprotecting and introducing a protecting group, a method known per se can be used.

The compound [VI] or a salt thereof thus obtained can be converted to a compound [VII] or a salt thereof by reacting with a sulfurizing agent such as phosphorus pentasulfide or Lawesson's reagent. The amount of the sulfurizing agent used at this time is generally about 1 to 3 mol per 1 mol of the compound [VI] or a salt thereof,
Usually, it is preferably about equimolar to the compound [VI] or a salt thereof. The reaction solvent is not particularly limited, but an organic solvent such as pyridine is preferable. Reaction is usually 50
C. to 150.degree. C., preferably about 80.degree. C. to 120.degree.
The time required for the reaction varies depending on the reaction temperature, but is usually 3 to 12 hours, preferably 3 to 6 hours. More specifically, for example, if the reaction is performed at about 100 to 120 ° C., the reaction is completed within about 5 hours. The compound [VI
I] or a salt thereof can be obtained by a means known per se, such as concentration, liquid conversion, phase transfer, solvent extraction, fractional distillation, distillation, crystallization,
It can be isolated and purified by recrystallization, chromatography and the like. When the compound [VII] (R ² = H) or a salt thereof in which R ² is a hydrogen atom is obtained by the above method, R ² is a hydrogen atom or an aromatic group which may have a substituent, if necessary. To a compound [VII] other than a carbocyclic group or an aromatic heterocyclic group which may have a substituent or a salt thereof,
If the R ² is a good carboxylic acyl group which may have a substituent compound [VII] or salts thereof obtained is a hydrocarbon group which may have a R ² substituted by reduction When a compound [VII] or a salt thereof, wherein R ² is an optionally substituted carboxylic acid acyl group or sulfonic acid acyl group, is obtained, R ² is hydrolyzed. ² = compound of H [VII]
Alternatively, it can be converted into a salt thereof, and these conversion reactions are the same as in the case of the compound [V] or a salt thereof. At the time of these conversion reactions, the amino group, the carboxyl group, the hydroxyl group and the like, which are present as a substituent, if necessary, can be combined with introduction of a protecting group and deprotection to proceed the reaction, and the object can be achieved. These methods can be performed in the same manner as in the case of compound [V] or a salt thereof. As the salts of the compounds [VI] and [VII], pharmaceutically acceptable salts are particularly preferable. Examples of such salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid and organic carboxylic acids (eg, formic acid, acetic acid, tartaric acid, citric acid, oxalic acid, phthalic acid, fumaric acid, maleic acid). Acids, etc.), sulfonic acids (eg, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and salts with organic acids are used. Compounds [VI] and [V
II] has an acidic group such as a carboxyl group as a substituent in R ¹ , R ² and B ring, it is an inorganic substance such as alkali metal (eg, sodium, potassium) or alkaline earth metal (eg, magnesium) A salt may be formed with a base or an organic base (eg, amines such as dicyclohexylamine, triethylamine, 2,6-lutidine, etc.). As the salt of the compound [X], a pharmaceutically acceptable salt is particularly preferable. Examples of such salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid and organic carboxylic acids (eg, formic acid, acetic acid, tartaric acid, citric acid, oxalic acid, phthalic acid, fumaric acid, maleic acid). Acids, etc.), sulfonic acids (eg, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and salts with organic acids are used. Further, the compound [X] is R ² ′ and B
When having an acidic group such as a carboxyl group as a substituent in the ring, an alkali metal (eg, sodium, potassium, etc.) or an alkaline earth metal (eg, magnesium, etc.)
A salt may be formed with an inorganic base or an organic base (eg, amines such as dicyclohexylamine, triethylamine, 2,6-lutidine, etc.).

When the compound [I] is an optically active substance,
It can be separated into a d body and an l body by a usual optical dividing means. The compound [I] of the present invention is for improving the metabolism of polyunsaturated fatty acids (linoleic acid, γ-linolenic acid, α-linolenic acid, arachidonic acid, dihomo-γ-linolenic acid, eicosapentaenoic acid), especially lipid peroxide. 5-lipoxygenase-based metabolites [eg, leukotrienes, 5-hydroperoxyeicosatetraenoic acid (HPETE), 5-hydroxyeicosatetraenoic acid (HETE), lipoxin] , Leukotoxins, etc.], thromboxane A ₂ synthase inhibition, prostaglandin I ₂ synthase retention promotion, LTD ₄ receptor antagonism, elimination of active enzyme species, etc. Has an improving effect and an anti-allergic effect. Among the above-mentioned actions, the compound [I] of the present invention remarkably exhibits a lipid peroxide production reaction inhibitory action (antioxidant action).

Compound [I] has low toxicity and side effects. Therefore, the compound [I] of the present invention is a thrombosis due to platelet aggregation in mammals (mouse, rat, rabbit, dog, monkey, human etc.), contraction of arterial vascular smooth muscle or vascular spasm in heart, lung, brain and kidney. Ischemic diseases due to atrophy (eg myocardial infarction, stroke), neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, Lu Gehrig's disease, muscular dystrophy), functional disorders associated with central injury such as head injury, spinal cord injury, memory impairment And affective disorders (disorders associated with nerve cell necrosis caused by oxygen deficiency, brain injury, stroke, cerebral infarction, cerebral thrombosis, etc.), stroke, post-cerebral infarction and brain surgery,
Convulsions and epilepsy, lung failure, following head trauma
Bronchial asthma, inflammation (eg nephritis, hepatitis, acute hepatitis, hypersensitivity pneumonitis, etc.), arteriosclerosis, atherosclerotic arteriosclerosis, cirrhosis, immunodeficiency, enzymes due to reactive oxygen species (superoxide, hydroxyl radical, etc.), It has a therapeutic and prophylactic effect on various diseases such as cardiovascular diseases (myocardial infarction, stroke, cerebral edema, etc.), tissue fibrosis phenomenon and cancer caused by disorders of living tissues, cells, etc. , Anti-vasoconstrictor, anti-asthma agent, anti-allergic agent, heart and brain circulatory system improver, nephritis remedy, hepatitis remedy, tissue fibrosis inhibitor, active oxygen species eliminator, arachidonic acid cascade substance control It is useful as a medicine such as an improving agent. The compound [I] is orally or non-orally as a pharmaceutical composition (eg, tablet, capsule, solution, injection, suppository) as it is or mixed with a pharmaceutically acceptable carrier, excipient or the like known per se. It can be safely administered orally. Although the dose varies depending on the administration subject, administration route, symptoms, etc., for example, when it is orally administered as a therapeutic agent to adult patients with cardiovascular disease, it is usually about 0.1 to 20 mg / dose. kg body weight, preferably 0.5-10
Administer approximately mg / kg body weight 1 to 3 times a day.

[0033]

EXAMPLES Reference examples and examples will be described below, but the present invention is not limited thereto. Reference Example 1 3-Acetylamino-2,3,4,5-tetrahydro-1
H- [1] benzazepin-2-one 3-amino-2,3,4,5-tetrahydro-1H-
Acetyl chloride (2.0 g) was gradually added dropwise while ice-cooling a solution of [1] benzazepin-2-one (4.0 g) and triethylamine (4.6 g) in DMF (30 ml). After stirring at room temperature for 2 hours, aqueous sodium hydrogen carbonate was added and the organic matter was extracted with a methanol / chloroform mixed solvent.
The extract layer was washed with water and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel and recrystallized from a mixed solvent of ethanol / ethyl acetate to give the title compound (yield 4.0 g, yield 81%). Melting point 259-261 ° C (recrystallized from ethanol / ethyl acetate) NMR (d ₆ -DMSO) δ: 1.81 (3H, s), 2.01 (1H, m),
2.24 (1H, m), 2.69 (2H, m), 4.19 (1H, m), 6.95-7.30 (4H, m),
8.08 (1H, d, J = 8.4Hz), 9.78 (1H, s). Elemental analysis value: Calculated as C ₁₂ H ₁₄ N ₂ O ₂ : C, 66.04; H, 6.47; N, 12.84. Measured value: C, 65.89; H, 6.29; N, 12.48.

Reference Example 2 3-isobutyrylamino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one By the same method as in Reference Example 1, 3-amino-2,3, 4,
5-Tetrahydro-1H- [1] benzazepine-2-
The title compound was obtained from on and isobutyryl chloride (yield 87%). Melting point 214-215 ° C (recrystallized from hexane / ethyl acetate) NMR (d ₆ -DMSO) δ: 1.13 (6H, m), 1.92 (1H, m),
2.39 (1H, m), 2.60-3.05 (3H, m), 4.53 (1H, m), 6.52 (1H, br
d, J = 6.1Hz), 6.99 (1H, m), 7.13-7.30 (3H, m), 7.65 (1H, br
s). Elemental analysis: Calculated as C ₁₄ H ₁₈ N ₂ O ₂ : C, 68.27; H, 7.37; N, 11.37. Found: C, 68.59; H, 7.26; N, 11.20.

Reference Example 3 3-methoxycarbonylcarbonylamino-2,3,4,
5-Tetrahydro-1H- [1] benzazepine-2-
On By the same method as in Reference Example 1, 3-amino-2,3,4,
5-Tetrahydro-1H- [1] benzazepine-2-
The title compound was obtained from on and methyl oxalyl chloride (yield 83%). Melting point 240-242 ° C (recrystallized from ethanol) NMR (d ₆ -DMSO) δ: 2.20-2.45 (2H, m), 2.60-2.
85 (2H, m), 3.78 (3H, s), 4.19 (1H, m), 7.00-7.36 (4H, m), 8.8
7 (1H, d, J = 7.4Hz), 9.97 (1H, s) Elemental _{analysis: C 13 H 14 N 2 O} 4 Calculated:.. C, 59.54; H , 5.38; N, 10.68 Found: C, 59.76; H, 5.46; N, 10.80.

Reference Example 4 3-Phenylacetylamino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one By the same method as in Reference Example 1, 3-amino-2,3,4. ,
5-Tetrahydro-1H- [1] benzazepine-2-
The title compound was obtained from on and phenylacetyl chloride (yield 79%). Melting point 215 to 217 ° C (recrystallized from ethanol) NMR (d ₆ -DMSO) δ: 1.94-2.40 (2H, m), 2.60-2.
80 (2H, m), 3.45 (2H, s), 4.21 (1H, m), 6.96-7.30 (9H, m), 8.3
. 2 (1H, d, J = 8.5Hz), 9.80 (1H, s) Elemental _{analysis: C 18 H 18 N 2 O} 2 Calculated:. C, 73.45; H, 6.16; N, 9.52 Found: C, 73.13; H, 6.06; N, 9.33.

Reference Example 5 3-Cinnamoylamino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one By the same method as in Reference Example 1, 3-amino-2,3,4. ,
5-Tetrahydro-1H- [1] benzazepine-2-
The title compound was obtained from on and cinnamoyl chloride (yield 72%). Melting point 209 to 211 ° C. (recrystallized from ethyl acetate) NMR (d ₆ -DMSO) δ: 2.04 (1 H, m),
2.69 (1H, m), 2.83-3.10 (2H,
m), 4.68 (1H, m), 6.47 (1H, d, J
= 15.8 Hz), 6.81 (1H, d, J = 7.3H)
z), 7.00-7.54 (9H, m), 7.57 (1
H, d, J = 15.8 Hz), 7.88 (1H, s). Elemental analysis value: C ₁₉ H ₁₈ N ₂ O ₂ calculated value: C, 74.49; H, 5.92; N, 9.14. Measured value: C, 74.05; H, 5.85; N, 9.17.

Reference Example 6 3-Benzoylamino-2,3,4,5-tetrahydro-
1H- [1] benzazepin-2-one By the same method as in Reference Example 1, 3-amino-2,3,4,
5-Tetrahydro-1H- [1] benzazepine-2-
The title compound was obtained from on and benzoyl chloride (yield 84%). Melting point 217 to 219 ° C (recrystallized from ethanol / ethyl acetate) NMR (d ₆ -DMSO) δ: 2.34 (2H, m), 2.76 (2H, m),
4.44 (1H, m), 7.00-7.60 (7H, m), 7.87 (2H, dd, J = 1.5Hz, 7.9H
. z), 8.53 (1H, d, J = 8.1Hz), 9.85 (1H, s) Elemental _{analysis: C 17 H 16 N 2 O} 2 Calculated: C, 72.84; H, 5.75 ; N, 9.99. Found: C, 72.47; H, 5.97; N, 9.90.

Reference Example 7 3- (4-methoxybenzoyl) amino-2,3,4,5
-Tetrahydro-1H- [1] benzazepin-2-one By the same method as in Reference Example 1, 3-amino-2,3,4,
5-Tetrahydro-1H- [1] benzazepine-2-
The title compound was obtained from on and p-anisoyl chloride (yield 75%). Melting point 232-234 ° C (recrystallized from ethyl acetate / ethanol) NMR (d ₆ -DMSO) δ: 2.20-2.40 (2H, m), 2.66-2.
85 (2H, m), 3.81 (3H, s), 4.43 (1H, m), 6.98 (2H, d, J = 8.9Hz),
7.00-7.36 (4H, m), 7.85 (2H, d, J = 8.9Hz), 8.37 (1H, d, J = 8.1
. Hz) Elemental analysis: Calculated _{C 18 H 18 N 2 O 3} : C, 69.66; H, 5.85; N, 9.03. Found: C, 69.44; H, 5.83; N, 9.08.

Reference Example 8 3- (2,3-dimethoxybenzoyl) amino-2,3,
4,5-Tetrahydro-1H- [1] benzazepine-
2-one 2,3-dimethoxybenzoic acid (3.4 g) in THF (1
5 ml) solution was added with N, N'-carbonyldiimidazole (3.0 g) and stirred at room temperature for 30 minutes. Next, to this reaction solution, 3-amino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (3.0 g) was added.
DMF (10 ml) solution of was added dropwise and stirred at room temperature for 2 hours, aqueous sodium hydrogen carbonate was added, and the organic matter was extracted with a methanol / chloroform mixed solvent. After washing the extract layer with water and drying,
The solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel and recrystallized from a mixed solvent of ethanol / ethyl acetate to give the title compound (yield 4.5 g, yield 77).
%). Melting point 192-195 ° C (recrystallized from ethyl acetate / ethanol) NMR (d ₆ -DMSO) δ: 2.06 (1H, m), 2.50-2.85 (3
H, m), 3.83 (3H, s), 3.84 (3H, s), 4.42 (1H, m), 7.00-7.40 (7
H, m), 8.80 (1H, d, J = 7.3Hz), 10.01 (1H, s). Elemental analysis value: C ₁₉ H ₂₀ N ₂ O ₄ Calculated value: C, 67.05; H, 5.92; N, 8.23. Found: C, 67.07; H, 5.98; N, 8.24.

Reference Example 9 3- (4-Nitrobenzoyl) amino-2,3,4,5-
Tetrahydro-1H- [1] benzazepin-2-one By the same method as in Reference Example 1, 3-amino-2,3,4,
5-Tetrahydro-1H- [1] benzazepine-2-
The title compound was obtained from on and 4-nitrobenzoyl chloride (yield 63%). Melting point 238-241 ° C (recrystallized from ethanol) NMR (d ₆ -DMSO) δ: 2.28-2.46 (2H, m), 2.70-2.
90 (2H, m), 4.45 (1H, m), 7.02-7.38 (4H, m), 8.10 (2H, d, J = 8.
. 9Hz), 8.33 (2H, d, J = 8.9Hz), 8.94 (1H, d, J = 8.1Hz) Elemental _{analysis: C 17 H 15 N 3 O} 4 Calculated: C, 62.76; H, 4.65 N, 12.92. Found: C, 62.37; H, 4.57; N, 12.62.

Reference Example 10 3-Benzoylamino-7-methoxy-2,3,4,5-
Tetrahydro-1H- [1] benzazepin-2-one By the same method as in Reference Example 1, 3-amino-7-methoxy-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one was obtained. The title compound was obtained from benzoyl chloride (yield 85%). Melting point 239-241 ° C (recrystallized from ethyl acetate / hexane) NMR (d ₆ -DMSO) δ: 2.31 (2H, m), 2.73 (2H, m),
3.76 (3H, s), 4.44 (1H, m), 6.84 (1H, dd, J = 2.8Hz, 8.5Hz), 6.
91 (1H, d, J = 2.8Hz), 6.98 (1H, d, J = 8.5Hz), 7.40-7.60 (3H,
. m), 7.86 (2H, m), 8.48 (1H, d, J = 8.3Hz), 9.64 (1H, s) Elemental analysis: Calculated _{C 18 H 18 N 2 O 3} : C, 69.66; H , 5.85; N, 9.03. Found: C, 69.41; H, 5.77; N, 8.88.

Reference Example 11 3-Acetylamino-3,4-dihydrocarbostyryl 3-Aminohydrocarbostyryl hydrochloride (15.0 g)
Acetic anhydride (10.0 g) was added dropwise to a pyridine (50 ml) solution of with stirring under ice-cooling, and then the reaction solution was added to 100%.
The mixture was heated and stirred at 0 ° C for 45 minutes. After cooling the reaction solution, aqueous sodium hydrogen carbonate was added, and the organic matter was extracted with chloroform. The extract layer was washed with water and dried, and then the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the title compound (yield 14.5 g, 94% yield). Melting point 249-251 ° C (recrystallized from ethanol) NMR (d ₆ -DMSO) δ: 1.91 (3H, s), 2.77-3.10 (2
H, m), 4.38 ~ 4.54 (1H, m), 6.82 ~ 7.00 (2H, m), 7.10 ~ 7.22 (2
H, m), 8.20 (1H, d, J = 8.0Hz), 10.3 (1H, s). Elemental analysis value: Calculated as C ₁₁ H ₁₂ N ₂ O ₂ C: 64.69; H, 5.92; N, 13.72.Actual value: C, 64.36; H, 5.70; N, 13.64.

Reference Example 12 3- (2,3-dimethoxycinnamoyl) amino-2,
3,4,5-Tetrahydro-1H- [1] benzazepin-2-one By the same method as Reference Example 8, 2,3-dimethoxycinnamic acid, N, N′-carbonyldiimidazole and 3-amino-2 were used. The title compound was obtained from 3,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (yield 65%). Melting point 234 to 236 ° C (recrystallized from ethanol / ethyl acetate) NMR (d ₆ -DMSO) δ: 1.97 to 2.24 (2H, s), 2.60 to
2.83 (2H, m), 3.37 (3H, s), 4.36 (1H, m), 6.78 (1H, d, J = 1
5.9Hz), 7.00 ~ 7.35 (7H, m), 7.58 (1H, d, J = 15.9Hz), 8.35
. (1H, d, J = 8.1Hz), 9.85 (1H, s) Elemental analysis: Calculated _{C 21 H 22 N 2 O 4} :. C, 68.84; H, 6.05; N, 7.65 Found: C , 68.50; H, 6.05; N, 7.64.

Example 1 3-Acetylamino-1-phenyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one 3-Acetylamino-2,3,4,5-tetrahydro- 1
H- [1] benzazepin-2-one (3.2 g), powdered copper (2.9 g), cuprous chloride (0.15 g), potassium acetate (2.9 g) and bromobenzene (8.0 g) were added. It was suspended in dimethylacetamide (30 ml), and this reaction solution was heated with stirring at 130 to 140 ° C. for 8 hours. After cooling
Aqueous sodium hydrogen carbonate was added to the reaction solution, and the organic matter was extracted with a mixed solvent of methanol / chloroform. The extract layer was washed with water and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel and recrystallized from a mixed solvent of ethanol / ethyl acetate to give the title compound (yield 2.6 g, yield 61).
%). Melting point 181 to 183 ° C. (recrystallized from ethanol / ethyl acetate) NMR (d ₆ -DMSO) δ: 1.84 (3H, s), 1.95-2.40 (2
H, m), 2.75-3.10 (2H, m), 4.36 (1H, m), 6.80-6.90 (1H, m), 7.
10-7.48 (8H, m), 8.23 (1H, d, J = 7.7Hz) Elemental _{analysis: C 18 H 18 N 2 O} 2 Calculated:.. C, 73.45; H , 6.16; N, 9.52 Found Values: C, 73.27; H, 6.19; N, 9.55.

Example 2 3-Acetylamino-1- (2-chlorophenyl)-
2,3,4,5-Tetrahydro-1H- [1] benzazepin-2-one By the same method as in Example 1, 3-acetylamino-
The title compound was obtained from 2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one and powdered copper, cuprous chloride, potassium acetate and 2-bromochlorobenzene (yield 49%). Melting point 199-200 ° C (recrystallized from ethanol / ethyl acetate) NMR (d ₆ -DMSO) δ: 1.83 (3H, s), 2.00-2.40 (2
H, m), 2.78-2.90 (1H, m), 2.98-3.35 (1H, m), 4.33-4.58 (1H,
m), 6.68-6.72 (1H, m), 7.10-7.67 (8H, m), 8.18-8.35 (1H,
m). Elemental analysis value: calculated as C ₁₈ H ₁₇ N ₂ O ₂ Cl: C, 65.75; H, 5.21; N, 8.52; Cl, 10.
78. Found: C, 65.71; H, 5.28; N, 8.50; Cl, 10.
73.

Example 3 3-Phenylacetylamino-1-phenyl-2,3,
4,5-Tetrahydro-1H- [1] benzazepine-
2-one By the same method as in Example 1, 3-phenylacetylamino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one and powdered copper, cuprous chloride, potassium acetate and The title compound was obtained from bromobenzene (yield 65%). Melting point 154-156 ° C (recrystallized from hexane / ethyl acetate) NMR (d ₆ -DMSO) δ: 2.00-2.40 (2H, m), 2.75-3.
10 (2H, m), 3.47 (2H, s), 4.35 (1H, m), 6.80-6.90 (1H, m), 7.1
0-7.47 (13H, m), 8.49 (1H, d, J = 7.8Hz). Elemental analysis value: C ₂₄ H ₂₂ N ₂ O ₂ calculated value: C, 77.81; H, 5.99; N, 7.56. Values: C, 77.39; H, 5.94; N, 7.13.

Example 4 3- (4-Methoxybenzoyl) amino-1-phenyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one By the same method as in Example 1, 3 -(4-Methoxybenzoyl) amino-2,3,4,5-tetrahydro-1H-
[1] The title compound was obtained from benzazepin-2-one and powdered copper, cuprous chloride, potassium acetate and bromobenzene (yield 81%). Melting point 222-224 ° C (recrystallized from ethyl acetate) NMR (d ₆ -DMSO) δ: 2.20-2.50 (2H, m), 2.80-3.
12 (2H, m), 3.81 (3H, s), 4.56 (1H, m), 6.83-6.92 (1H, m), 6.9
9 (2H, d, J = 8.9Hz), 7.12-7.48 (8H, m), 7.88 (2H, d, J = 8.9H
z), 8.54 (1H, d, J = 7.7Hz). Elemental analysis value: C ₂₄ H ₂₂ N ₂ O ₃ calculated value: C, 74.59; H, 5.74; N, 7.25. Measured value: C, 74.29; H, 5.84; N, 7.24.

Example 5 3- (4-Nitrobenzoyl) amino-1-phenyl-
2,3,4,5-Tetrahydro-1H- [1] benzazepin-2-one By the same method as in Example 1, 3- (4-nitrobenzoyl) amino-2,3,4,5-tetrahydro-1H −
[1] The title compound was obtained from benzazepin-2-one, powdered copper, cuprous chloride, potassium acetate and bromobenzene (yield 79%). Melting point 259-261 ° C (recrystallized from chloroform / ethanol) NMR (d ₆ -DMSO) δ: 2.30-2.52 (2H, m), 2.84-3.
17 (2H, m), 4.58 (1H, m), 6.86-6.96 (1H, m), 7.12-7.50 (8H,
m), 8.13 (2H, d, J = 8.9Hz), 8.33 (2H, d, J = 8.9Hz), 9.11 (1H,
. d, J = 7.3Hz) Elemental _{analysis: C 23 H 19 N 3 O} 4 Calculated:. C, 68.82; H, 4.77; N, 10.47 Found: C, 68.70; H, 4.71 ; N, 10.22 .

Example 6 2-Methyl-9,10-dihydro-4H-thiazolo [4,5-b] [1] benzazepine 3-bromo-2,3,4,5-tetrahydro-1H-
[1] Benzazepin-2-one (1.0 g) and thioacetamide (470 mg) were added to ethanol (10 ml), and the mixture was heated under reflux for 5 hours. After cooling, sodium bicarbonate water was added, and the organic matter was extracted with chloroform. The extract layer is washed with water and dried,
The solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel and recrystallized from ethyl acetate / hexane to give the title compound (yield 360 mg, 40% yield). Melting point 115-117 ° C. (recrystallized from ethyl acetate / hexane) NMR (CDCl ₃ ) δ: 2.55 (3H, s), 2.95-3.10 (4H, m),
6.61 (1H, br s), 6.76-6.93 (2H, m), 7.05-7.17 (2H, m). Elemental analysis value: Calculated as C ₁₂ H ₁₂ N ₂ S: C, 66.63; H, 5.59; N , 12.95; S, 14.82. Found: C, 66.30; H, 5.44; N, 12.70; S, 14.91.

Example 7 2-Isopropyl-9,10-dihydro-4H-thiazolo [4,5-b] [1] benzazepine hydrochloride In the same manner as in Example 6, 3-bromo-2,3,3.
4,5-Tetrahydro-1H- [1] benzazepine-
The product obtained from 2-one and thioisobutyramide was neutralized with hydrogen chloride to obtain the title compound (yield 46%). Melting point 119 to 122 ° C. (recrystallized from ethanol / diethyl ether) NMR (d ₆ -DMSO) δ: 1.27 (3H, s), 1.31 (3H, s), 2.
94 (4H, s), 3.12 (1H, m), 5.76 (1H, br s), 6.77 (1H, m), 7.00-
7.14 (3H, m). Elemental analysis: Calculated as C ₁₄ H ₁₆ N ₂ S.HCl: C, 59.88; H, 6.10; N, 9.98; S, 11.42;
Cl, 12.62. Found: C, 59.80; H, 6.08; N, 9.97; S, 11.37;
Cl, 12.70.

Example 8 2-Benzyl-9,10-dihydro-4H-thiazolo [4,5-b] [1] benzazepine By the same method as in Example 6, 3-bromo-2,3,3.
4,5-Tetrahydro-1H- [1] benzazepine-
The title compound was obtained from 2-one and thiobenzylamide (yield 46%). Melting point 130-132 ° C. (recrystallized from ethyl acetate / hexane) NMR (CDCl ₃ ) δ: 3.01 (4H, m), 4.14 (2H, s), 6.62 (1
H, br s), 6.76-6.92 (2H, m), 7.05-7.16 (2H, m), 7.25-7.37
. (5H, m) Elemental analysis: C ₁₈ H ₁₆ N ₂ S Calculated:. C, 73.94; H, 5.52; N, 9.58; S, 10.97 Found: C, 74.02; H, 5.62 ; N, 9.57; S, 10.95.

Example 9 2-Phenyl-9,10-dihydro-4H-thiazolo [4,5-b] [1] benzazepine By the same method as in Example 6, 3-bromo-2,3,3.
4,5-Tetrahydro-1H- [1] benzazepine-
The title compound was obtained from 2-one and thiobenzamide (yield 58%). Melting point 129 to 130 ° C. (recrystallized from ethyl acetate / hexane) NMR (CDCl ₃ ) δ: 3.11 (4H, s), 6.76 (1H, br s), 6.8
2-6.96 (2H, m), 7.10-7.20 (2H, m), 7.35-7.47 (3H, m), 7.78-
7.88 (2H, m) Elemental analysis: C ₁₇ H ₁₄ N ₂ S Calculated:.. C, 73.35; H , 5.07; N, 10.06; S, 11.52 Found: C, 73.23; H, 4.88 ; N , 9.92; S, 11.74.

Example 10 2- (4-Methoxyphenyl) -9,10-dihydro-
4H-thiazolo [4,5-b] [1] benzazepine By the same method as in Example 6, 3-bromo-2,3,3.
4,5-Tetrahydro-1H- [1] benzazepine-
The title compound was obtained from 2-one and 4-methoxythiobenzamide (yield 69%). Melting point 173 to 176 ° C. (recrystallized from ethyl acetate) NMR (CDCl ₃ ) δ: 3.09 (4H, s), 3.84 (3H, s), 6.72 (1
H, br s), 6.80-6.98 (4H, m), 7.12 (2H, d, J = 8.9Hz), 7.76 (2
H, d, J = 8.9Hz). Elemental analysis value: Calculated as C ₁₈ H ₁₆ N ₂ OS: C, 70.10; H, 5.23; N, 9.08; S, 10.40. Measured value: C, 70.13; H, 5.18; N, 8.88; S, 10.37.

Example 11 2- (4-chlorophenyl) -9,10-dihydro-4
H-thiazolo [4,5-b] [1] benzazepine By the same method as in Example 6, 3-bromo-2,3,3.
4,5-Tetrahydro-1H- [1] benzazepine-
The title compound was obtained from 2-one and 4-chlorothiobenzamide (yield 48%). Melting point 165 to 167 ° C. (recrystallized from ethyl acetate / hexane) NMR (CDCl ₃ ) δ: 3.10 (4H, s), 6.74 (1H, br s), 6.8
3-6.95 (2H, m), 7.10-7.20 (2H, m), 7.37 (2H, d, J = 8.7Hz), 7.
76 (2H, d, J = 8.7Hz) Elemental analysis: C ₁₇ H ₁₃ N ₂ ClS Calculated:. C, 65.27; H, 4.19; N, 8.96; Cl, 11.33;
S, 10.25. Found: C, 65.15; H, 4.26; N, 8.89; Cl, 11.51;
S, 10.44.

Example 12 2- (4-Pyridyl) -9,10-dihydro-4H-thiazolo [4,5-b] [1] benzazepine By the same method as in Example 6, 3-bromo-2,3. ，
4,5-Tetrahydro-1H- [1] benzazepine-
The title compound was obtained from 2-one and thioisonicotinamide (yield 45%). Melting point 182-184 ° C (recrystallized from ethyl acetate / hexane) NMR (CDCl ₃ ) δ: 3.13 (4H, s), 6.82 (1H, br s), 6.9
0 (2H, m), 7.16 (2H, m), 7.68 (2H, dd, J = 1.6,4.6Hz), 8.66 (2
H, dd, J = 1.6,4.6Hz). Elemental analysis value: Calculated as C ₁₆ H ₁₃ N ₃ S: C, 68.79; H, 4.69; N, 15.04; S, 11.48. Actual value: C, 68.65; H, 4.47; N, 15.00; S, 11.59.

Example 13 2-Methyl-9,10-dihydro-4H-thiazolo [5,4-b] [1] benzazepine 3-acetylamino-2,3,4,5-tetrahydro-1
H- [1] benzazepin-2-one (3.6 g) and phosphorus pentasulfide (3.7 g) were suspended in pyridine to give 10
The mixture was heated and stirred at 0 ° C for 2.5 hours. After cooling, aqueous sodium hydrogen carbonate was added and the organic matter was extracted with a methanol / chloroform mixed solvent. The extract layer was washed with water and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel and recrystallized from a mixed solvent of ethyl acetate / hexane to give the title compound (amount 1.8 g, yield 50%). Melting point 182-184 ° C (recrystallized from ethyl acetate / hexane) NMR (CDCl ₃ ) δ: 2.51 (3H, s), 3.
00-3.20 (4H, m), 5.90 (1H, br
s), 6.77 (1H, dd, J = 1.2Hz, 7.9)
Hz, 6.92 (1H, dt, J = 1.3 Hz, 7.
4 Hz), 7.06-7.20 (2H, m). Elemental analysis value: Calculated as C ₁₂ H ₁₂ N ₂ S: C, 66.63; H, 5.59; N, 12.95; S, 14.
82. Found: C, 66.49; H, 5.55; N, 12.83; S, 14,
79.

Example 14 2-Methyl-4-phenyl-9,10-dihydro-4H
-Thiazolo [5,4-b] [1] benzazepine 3-acetylamino-1-phenyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (2.4 g) and Lawesson's reagent (3.3 g) was suspended in pyridine, and heated and stirred at 100 ° C. for 3 hours. After cooling, aqueous sodium hydrogen carbonate was added and the organic matter was extracted with a methanol / chloroform mixed solvent. The extract layer was washed with water and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel and recrystallized from a mixed solvent of ethyl acetate / hexane to give the title compound (yield 1.7 g, yield 73%). Melting point 126-128 ° C (recrystallized from ethyl acetate / hexane) NMR (CDCl ₃ ) δ: 2.60 (3H, s), 2.83-2.94 (2H, m),
2.96-3.08 (2H, m), 6.79-6.90 (3H, m), 7.11-7.40 (6H, m) Elemental analysis: C ₁₈ H ₁₆ N ₂ S Calculated:. C, 73.94; H, 5.52; N, 9.58; S, 10.9
7. Found: C, 73.87; H, 5.51; N, 9.50; S, 10,8.
3.

Example 15 2-Isopropyl-9,10-dihydro-4H-thiazolo [5,4-b] [1] benzazepine hydrochloride In the same manner as in Example 13, 3-isobutyrylamino-2 was prepared. The title compound was obtained by purifying the compound obtained from 3,3,4,5-tetrahydro-1H- [1] benzazepin-2-one and phosphorus pentasulfide and then neutralizing it with hydrogen chloride (yield 86 %). Melting point 172 to 175 ° C. (recrystallized from diethyl ether / ethanol) NMR (CDCl ₃ ) δ: 1.34 (6H, d, J = 6.9 Hz), 3.00 (2H,
m), 3.09 (2H, m), 3.36 (1H, m), 6.86-7.21 (4H, m), 9.67 (1H,
s). Elemental analysis value: calculated as C ₁₄ H ₁₆ N ₂ S · HCl: C, 59.88; H, 6.10; N, 9.98; S, 11.4
2; Cl, 12.62. Found: C, 59.73; H, 6.11; N, 9.89; S, 11,5.
8; Cl, 12.66.

Example 16 2- (N-tert-butoxycarbonyl-piperidine-3
-Yl) -9,10-dihydro-4H-thiazolo [5,
4-b] [1] Benzazepine By the same method as in Reference Example 8, N-tert-butoxycarbonylpiperidine-3-carboxylic acid, N, N′-carbonyldiimidazole and 3-amino-2,3,4,5. The compound obtained from -tetrahydro-1H- [1] benzazepin-2-one was purified and treated with Lawesson's reagent in the same manner as in Example 14 to give the title compound (yield 73%). Melting point 177 to 178 ° C. (recrystallized from ethyl acetate) NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.50-1.80 (4H, m),
2.13 (1H, m), 2.75-3.00 (2H, m), 3.02-3.20 (4H, m), 4.00 (1
H, m), 4.22 (1H, m), 5.92 (1H, s), 6.79 (1H, d, J = 7.7Hz), 6.94
(1H, t, J = 7.7Hz), 7.06-7.20 (2H, m). Elemental analysis value: Calculated as C ₂₁ H ₂₇ N ₃ O ₂ S: C, 65.42; H, 7.06; N, 10.90; S 8.3
2. Measured value: C, 65.47; H, 6.99; N, 10.86; S, 8.4
Five.

Example 17 2- (Piperidin-3-yl) -9,10-dihydro-
4H-thiazolo [5,4-b] [1] benzazepine
Dihydrochloride 2- (N-tert-butoxycarbonyl-piperidine-3
-Yl) -9,10-dihydro-4H-thiazolo [5,
4-b] [1] benzazepine (4.96 g) in ethanol (150 ml) was added with hydrochloric acid-ethyl acetate (70 ml).
The solution was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of ethyl acetate / ethanol to give the title compound (yield 4.5 g, yield 97%). Melting point 231 to 234 ° C (recrystallized from ethyl acetate / ethanol) NMR (d ₆ -DMSO) δ: 1.65-2.00 (3H, m), 2.10 (1
H, m), 2.83-3.18 (6H, m), 3.20-3.60 (3H, m), 6.80-7.00 (2H,
m), 7.04-7.20 (2H, m). Elemental analysis value: calculated as C ₁₆ H ₁₉ N ₃ S · 2HCL: C, 53.63; H, 5.91; N, 11.73; S, 8.9
5; Cl, 19.79. Found: C, 53.47; H, 5.89; N, 11.55; S, 8.8.
7; Cl, 19.70.

Example 18 2-Methoxycarbonyl-9,10-dihydro-4H-
Thiazolo [5,4-b] [1] benzazepine By the same method as in Example 14, 3-methoxycarbonylcarbonylamino-2,3,4,5-tetrahydro-1.
The title compound was obtained from H- [1] benzazepin-2-one and Lawesson's reagent (yield 53%). Melting point 199-201 ° C (recrystallized from ethyl acetate) NMR (CDCl ₃ ) δ: 3.02-3.14 (2H, m), 3.12-3.21 (2
H, m), 3.94 (3H, s), 6.67 (1H, br s), 6.81-7.22 (4H, m). Elemental analysis value: Calculated as C ₁₃ H ₁₂ N ₂ O ₂ S: C, 59.98; H, 4.65; N, 10.76; S, 12.
32. Found: C, 59.90; H, 4.62; N, 10.65; S, 12.
35.

Example 19 2-Benzyl-9,10-dihydro-4H-thiazolo [5,4-b] [1] benzazepine By the same method as in Example 14, 3-phenylacetylamino-2,3,4. The title compound was obtained from 5,5-tetrahydro-1H- [1] benzazepin-2-one and Lawesson's reagent (yield 70%). Melting point 157-159 ° C (recrystallized from ethyl acetate) NMR (CDCl ₃ ) δ: 3.00-3.10 (2H, m), 3.11-3.21 (2
H, m), 4.13 (2H, s), 5.80 (1H, br s), 6.72 (1H, d, J = 7.8Hz),
6.87-6.97 (1H, m), 7.02-7.19 (2H, m), 7.21-7.37 (5H, m). Elemental analysis value: Calculated as C ₁₈ H ₁₆ N ₂ S: C, 73.94; H, 5.52; N, 9.58; S, 10.9
7. Measured value: C, 73.95; H, 5.51; N, 9.29; S, 11.0
0.

Example 20 2-Benzyl-4-phenyl-9,10-dihydro-4
H-thiazolo [5,4-b] [1] benzazepine By the same method as in Example 14, 3-phenylacetylamino-1-phenyl-2,3,4,5-tetrahydro-
The title compound was obtained from 1H- [1] benzazepin-2-one and Lawesson's reagent (yield 58%). Melting point 115-116 ° C NMR (CDCl ₃ ) δ: 2.83-2.93 (2H, m), 3.00-3.10 (2
H, m), 4.19 (2H, s), 6.77-6.87 (3H, m), 7.10-7.40 (11H, m). Elemental analysis value: Calculated as C ₂₄ H ₂₀ N ₂ S: C, 78.23; H , 5.47; N, 7.60; S, 8.7
0. Found: C, 77.96; H, 5.57; N, 7.42; S, 8.6.
Five.

Example 21 2-Styryl-9,10-dihydro-4H-thiazolo [5,4-b] [1] benzazepine By the same method as in Example 14, 3-cinnamoylamino-2,3,4. The title compound was obtained from 5,5-tetrahydro-1H- [1] benzazepin-2-one and Lawesson's reagent (yield 69%). Mp 162-164 ° C. (recrystallized from ethyl _{acetate) NMR (CDCl 3) δ:} 3.05-3.28 (4H,
m), 6.11 (1H, br s), 6.81 (1H,
d, J = 8.0 Hz), 6.90-7.50 (11H,
m). Calculated: C, 74.97; H, 5.30; N, 9.20;
S, 10.53. Found: C, 74.78; H, 5.35; N, 9.43; S, 10.4.
3.

Example 22 2-Phenyl-9,10-dihydro-4H-thiazolo [5,4-b] [1] benzazepine By the same method as in Example 13, 3-benzoylamino-2,3,4, The title compound was obtained from 5-tetrahydro-1H- [1] benzazepin-2-one and phosphorus pentasulfide (yield 74%). Melting point 182 to 184 ° C. (recrystallized from ethyl acetate / hexane) NMR (CDCl ₃ ) δ: 3.11 (2H, m), 3.27 (2H, m), 6.08
(1H, br s), 6.81 (1H, dd, J = 1.0Hz, 7.8Hz), 6.95 (1H, dt, J =
1.3Hz, 7.3Hz), 7.09-7.20 (2H, m), 7.30-7.42 (3H, m), 7.60
(2H, m). Elemental analysis value: C ₁₇ H ₁₄ N ₂ S Calculated value: C, 73.35; H, 5.07; N, 10.06; S, 11.
52. Found: C, 73.34; H, 5.04; N, 10.14; S, 11.
36.

Example 23 2- (4-methoxyphenyl) -9,10-dihydro-
4H-thiazolo [5,4-b] [1] benzazepine By the same method as in Example 14, 3- (4-methoxybenzoyl) amino-2,3,4,5-tetrahydro-1H
The title compound was obtained from-[1] benzazepin-2-one and Lawesson's reagent (yield 66%). Mp 217-219 ° C (recrystallized from ethyl acetate / ethanol) NMR (CDCl ₃ ) δ: 3.05-3.17 (2H, m), 3.18-3.30 (2
H, m), 3.83 (3H, s), 6.03 (1H, br s), 6.76-7.00 (2H, m), 3.90
(2H, d, J = 8.9Hz ), 7.08-7.20 (2H, m), 7.69 (2H, d, J = 8.9Hz) Elemental _{analysis:. C 18 H 16 N 2} OS Calculated: C, 70.10 H, 5.23; N, 9.08; S, 1
0.40. Found: C, 69.84; H, 5.20; N, 9.04;
S, 10.36.

Example 24 2- (4-methoxyphenyl) -4-phenyl-9,1
0-Dihydro-4H-thiazolo [5,4-b] [1] benzazepine By a method similar to that in Example 14, 3- (4-methoxybenzoyl) amino-1-phenyl-2,3,4,5-tetrahydro was prepared. The title compound was obtained from -1H- [1] benzazepin-2-one and Lawesson's reagent (yield 53%). Melting point 157-159 ° C (recrystallized from ethyl acetate) NMR (CDCl ₃ ) δ: 2.90-3.00 (2H, m), 3.06-3.16 (2
H, m), 3.85 (3H, s), 6.80-6.98 (5H, m), 7.15-7.45 (6H, m), 7.
79 (2H, d, J = 8.8Hz). Elemental analysis value: Calculated as C ₂₄ H ₂₀ N ₂ OS: C, 74.97; H, 5.24; N, 7.29; S, 8.3
4. Measured value: C, 74.81; H, 5.28; N, 7.18; S, 8.2
6.

Example 25 2- (2,3-Dimethoxyphenyl) -9,10-dihydro-4H-thiazolo [5,4-b] [1] benzazepine By the same method as in Example 13, 3- (2 , 3-Dimethoxybenzoyl) amino-1-phenyl-2,3,4,5
The title compound was obtained from -tetrahydro-1H- [1] benzazepin-2-one and phosphorus pentasulfide (yield 65
%). Melting point 154-156 ° C. (recrystallized from hexane / ethyl acetate) NMR (CDCl ₃ ) δ: 3.11 (2H, m), 3.28 (2H, m), 3.90
(3H, s), 3.92 (3H, s), 6.11 (1H, br s), 6.77-6.98 (3H, m), 7.
03-7.20 (3H, m), 7.79 (1H, dd, J = 1.4Hz, 8.1Hz). Elemental analysis value: Calculated as C ₁₉ H ₁₈ N ₂ O ₂ S: C, 67.43; H, 5.36; N , 8.28; S, 9.4
7. Found: C, 67.40; H, 5.55; N, 8.21; S, 9.4.
Five.

Example 26 2- (4-Nitrophenyl) -9,10-dihydro-4
H-thiazolo [5,4-b] [1] benzazepine By a method similar to that in Example 14, 3- (4-nitrobenzoyl) amino-2,3,4,5-tetrahydro-1H-
The title compound was obtained from [1] benzazepin-2-one and Lawesson's reagent (yield 56%). Melting point 223-226 ° C. (recrystallized from chloroform / ethanol) NMR (CDCl ₃ ) δ: 3.10-3.19 (2H, m), 3.25-3.34 (2
H, m), 6.26 (1H, br s), 6.85 (1H, d, J = 7.8Hz), 7.03 (1H, dt, J
= 1.2Hz, 7.4Hz), 7.12-7.25 (2H, m), 7.89 (2H, d, J = 9.1Hz),
8.23 (2H, d, J = 9.1Hz) Elemental _{analysis: C 17 H 13 N 3 O} 2 S Calculated:. C, 63.14; H, 4.05; N, 12.99; S, 9.
92. Found: C, 62.95; H, 4.11; N, 12.74; S, 10.
20.

Example 27 2- (4-Nitrophenyl) -4-phenyl-9,10
-Dihydro-4H-thiazolo [5,4-b] [1] benzazepine By a method similar to that in Example 14, 3- (4-nitrobenzoyl) amino-1-phenyl-2,3,4,5-tetrahydro- The title compound was obtained from 1H- [1] benzazepin-2-one and Lawesson's reagent (yield 47%). Melting point 230-233 ° C (recrystallized from chloroform / ethyl acetate) NMR (CDCl ₃ ) δ: 2.94-3.05 (2H, m), 3.10-3.20 (2
H, m), 6.88-7.01 (3H, m), 7.19-7.45 (6H, m), 8.00 (2H, d, J =
. 9.0Hz), 8.26 (2H, d, J = 9.0Hz) Elemental _{analysis: C 23 H 17 N 3 O} 2 S Calculated: C, 69.15; H, 4.29 ; N, 10.52; S, 8.0
3. Found: C, 68.92; H, 4.21; N, 10.31; S, 7.8.
2.

Example 28 7-Methoxy-2-phenyl-9,10-dihydro-4
H-thiazolo [5,4-b] [1] benzazepine By a method similar to that in Example 13, 3-benzoylamino-7-methoxy-2,3,4,5-tetrahydro-1H-
[1] The title compound was obtained from benzazepin-2-one and phosphorus pentasulfide (yield 50%). Melting point 205-207 ° C. (recrystallized from ethanol / ethyl acetate) NMR (CDCl ₃ ) δ: 3.10 (2H, br s), 3.24 (2H, br s),
3.79 (3H, s), 5.83 (1H, brs), 6.05-6.80 (3H, m), 7.30-7.43
(3H, m), 7.70-7.80 (2H, m). Elemental analysis value: Calculated as C ₁₈ H ₁₆ N ₂ OS: C, 70.10; H, 5.23; N, 9.08; S, 10.4
0. Found: C, 70.10; H, 5.17; N, 8.99; S, 10.3
7.

Example 29 2-Styryl-9,10-dihydro-4H-thiazolo [4,5-b] [1] benzazepine By the same method as in Example 6, 3-bromo-2,3,3.
4,5-Tetrahydro-1H- [1] benzazepine-
The title compound was obtained from 2-one and thiocinnamamide (yield 37%). Melting point 202-204 ° C (recrystallized from methanol / ethyl acetate) NMR (CDCl ₃ ) δ: 3.09 (4H, s), 6.73 (1H, br s),
6.82 ~ 6.97 (2H, m), 7.07 (1H, d, J = 16.2Hz), 7.10-7.20 (2
H, m), 7.37-7.43 (4H, m), 7.48-7.55 (2H, m). Elemental analysis value: calculated as C ₁₉ H ₁₆ N ₂ S · 0.5H ₂ O: C, 72.81; H, 5.47; N, 8.94; S, 10.2
3. Found: C, 73.15; H, 5.32; N, 8.78; S, 10.1
9.

Example 30 2- (2,3-Dimethoxystyryl) -9,10-dihydro-4H-thiazolo [5,4-b] [1] benzazepine By the same method as in Example 14, 3- (2 , 3-Dimethoxycinnamoyl) amino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one and Lawesson's reagent gave the title compound (yield 70%). Melting point 202-203 ° C (recrystallized from ethanol / ethyl acetate) NMR (CDCl ₃ ) δ: 3.05-3.28 (4H, m), 3.86 (3H, s),
3.88 (3H, s), 6.18 (1H, brs), 6.77-7.40 (9H, m). Elemental analysis: C ₂₁ H ₂₀ N ₂ O ₂ S Calculated: C, 69.21; H, 5.53; N, 7.69; S, 8.8
0. Found: C, 69.36; H, 5.64; N, 7.62; S, 8.9.
8.

Example 31 1-Phenyl-3-acetylamino-3,4-dihydrocarbostyril By the same method as in Example 1, 3-acetylamino-
The title compound was obtained from 3,4-dihydrocarbostyril and powdered copper, cuprous chloride, potassium acetate and bromobenzene (yield 42%). Melting point 209 to 211 ° C. (recrystallized from ethanol / ethyl acetate) NMR (d ⁶ -DMSO) δ: 1.92 (3H, s), 3.11 (2H, d, J =
9.9Hz), 4.65 ~ 4.82 (1H, m), 6.23 (1H, dd, J = 1.0,7.9Hz),
6.89 ~ 7.17 (2H, m), 7.23 ~ 7.38 (3H, m), 7.40 ~ 7.60 (3H, m),
8.32 (1H, br d, J = 6.2Hz) Elemental _{analysis: C 17 H 16 N 2 O} 2 S Calculated:.. C, 72.84; H , 5.57; N, 9.99 Found: C, 72.76; H , 5.79; N, 9.98.

Example 32 2-Methyl-4-phenyl-4,9-dihydro-4H-
Thiazolo [5,4-b] quinoline By a method similar to that in Example 14, the title compound was obtained from 1-phenyl-3-acetylamino-3,4-dihydrocarbostyril and Lawesson's reagent (yield 20%). . 3. Melting point 104-107 ° C (recrystallized from hexane / ethyl acetate) NMR (CDCl ₃ ) δ: 2.51 (3H, s), 4.
40 (2H, s), 6.35 (1H, dd, J = 1.
4Hz, 7.9Hz), 6.84 ~ 7.02 (2H,
m), 7.15-7.22 (1H, m), 7.34
￣ 7.60 (5H, m). Elemental _{analysis: C 17} H ₁₆ N ₂ S Calculated: C, 73.35; H, 5.07 ; N, 10.06; S, 11.5
2 Found: C, 73.64; H, 5.09; N, 9.88; S, 11.3
8

Formulation Example 1 Each component was uniformly mixed to obtain a powder for direct compression. This was molded into a tablet having a diameter of 6 mm and a weight of 100 mg with a rotary tableting machine.

[0078]

[Action]

Test example Lipid peroxide production inhibitory effect Rat liver microsome (S-9) (0.3 mg Protein / 40
mM Tris-malate buffer (pH 7.4) 2.4 ml)
DMF solution (0.025 m) of test compound was added to (2.4 ml).
l), FeSO ₄ (0.25 mM) and NADPH (3 mM) 1:
The mixture (1) (0.1 ml) was added and shaken well. 37 ° C
0.2% Butylated hydroxytoluene
/ EtOH (0.125 ml) was added and shaken well.
0.05M 2-Thiobarbituric acid and 20% Trichlo
A 2: 1 mixture of roacetic acid (2.3 ml) was added, and the mixture was shaken well and left at 95 ° C. for 15 minutes. After standing in ice water for 5 minutes or more, the mixture was centrifuged at 2400 rpm for 10 minutes. The absorbance of the supernatant was measured at a wavelength of 532 nm.
Here, instead of the test compound, DMF (0.025 m
l) was used as a control. Butylated hydroxyt was added to the DMF solution (0.025 ml) of the test compound.
oluene / EtOH (0.125 ml), Rat liver microsom
e (S-9) (0.3 mg Protein / 40 mM Tris-malate
buffer (pH 7.4) 2.4 ml) (2.4 ml), water (0.1 m)
l) and 0.05M 2-Thiobarbituric acid and 20% Tr
A 2: 1 mixture of ichloroacetic acid (2.3 ml) was added in this order, and the following operation was performed according to the above-mentioned operation method: blank of test compound, DMF instead of test compound
What added (0.025 ml) was used as the control blank. [Inhibition rate calculation method] The inhibition rate at each concentration was calculated by the following formula. Inhibition rate (%) = (1- (Esa-Esb) / (Eco-Ecb)) x
100 (Esa: A ₅₃₂ with test compound, Esb: A ₅₃₂ of the blank test compound, Eco: A ₅₃₂ in the control, Ecb: shows the A ₅₃₂ of the blank control) [Calculation of IC _50] IC _{50 = (50 (X 2 -X} 1) - (X 2 Y 1 -X 1 Y 2)) / (Y 2 -
Y ₁ ) (Y ₁ : inhibition rate of less than 50%, X ₁ : concentration at Y ₁ , Y ₂ : 50
% Inhibition rate, concentration at X ₂ : Y ₂ )

[0079]

[Table 1] * Sample concentration (M) From the above results, it is understood that the compound of the present invention inhibits the production of lipid peroxide even at a low concentration.

[0080]

INDUSTRIAL APPLICABILITY The compound [I] of the present invention has excellent lipid peroxide production inhibitory and antioxidant effects. Therefore, it can be used for the prevention / treatment of cardiovascular diseases and allergic diseases in mammals and the like, and a useful medicine can be provided.

Claims (6)

[Claims] 1. The formula: [Wherein A is an alkylene group or a bond having a chain length of 3 or less, which may have a substituent, B ring is an aromatic ring which may have a substituent, and W ¹ and W ² are one Is a nitrogen atom and the other is a sulfur atom, R ¹ is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent or a substituent which may have a substituent. A good alkoxycarbonyl group,
R ² represents a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a carboxylic acid or a sulfonate acyl group which may have a substituent, respectively. Show. ] The tricyclic condensed heterocycle represented by these, or its salt. 2. The formula: [In the formula, R ³ represents an amino group which may be protected, R ⁴ represents an aromatic ring group which may have a substituent, and A and B rings have the same meanings as in claim 1. ] The compound or its salt represented by these. 3. The formula: [In the formula, X represents a leaving group, and A, B rings and R ² have the same meanings as in claim 1. ] Or a salt thereof, and a compound of the formula: [In the formula, R ¹ has the same meaning as in claim 1. ] The compound represented by the formula or a salt thereof is reacted with the compound represented by the formula: [In the formula, A, B rings, R ¹ and R ² have the same meanings as described above. ]
A method for producing the compound represented by or a salt thereof. 4. The formula: [In the formula, A, B rings, R ¹ and R ² have the same meanings as described in claim 1. ] The compound represented by the formula or a salt thereof is reacted with a sulfiding agent. [In the formula, A, B rings, R ¹ and R ² have the same meanings as described above. ]
A method for producing the compound represented by or a salt thereof. 5. A lipid peroxide production inhibitor comprising the compound according to claim 1. 6. The compound according to claim 1, wherein A is an alkylene group having a chain length of 3 or less, and R ² is a hydrogen atom or a phenyl group.