JPH07116224B2 - Benzolactam compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel benzolactam compound useful as a drug, particularly a brain function improving drug.

[Conventional technology]

JP-A-59-205372, JP-A-60-69076 and JP-A-61-148171 disclose 3- (1-carboxyalkyl) amino-4-oxo-2,3,4,5-tetrahydro having a hypotensive action. −
1,5-benzothiazepine-5-acetic acid derivative is disclosed in JP-A-58-38
Nos. 260 and 61-15875 disclose 3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine derivatives having antihypertensive action or cholecystokinin antagonistic action. There is.

[Problems to be Solved by the Invention]

In order to improve consciousness disorder, memory disorder, cognitive decline, diminished motivation and various dementia caused by cerebral dysfunction or organic organ disorder, conventional consciousness disorder improving drug, antiamnestic drug,
A number of psychotropic drugs called cognitive enhancers or nootropics as well as anti-dementia drugs have been developed. However, none of these drugs are necessarily satisfactory in terms of efficacy, duration of action, and side effects.

An object of the present invention is to provide a novel compound useful as a brain function improving drug.

[Means for Solving the Problems]

As a result of intensive studies to solve such problems, the present inventors have shown that the novel benzolactam compounds show an improving effect in various experimental memory impairment models, that is, exhibiting an anti-amnesia effect. This has led to the completion of the present invention.

That is, the present invention provides (1) the general formula [In the formula, A is a sulfur atom, an oxygen atom, a methylene group, -NR ⁶
-Group (R ⁶ is a hydrogen atom, an alkyl group, benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-
Represents a phenylhexyl or amino protecting group) or represents a carbonyl group. R ¹ is a hydrogen atom, an alkyl group, a cycloalkyl group, benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, halogen on the aromatic ring, tri Phenyl, 1-naphthyl or 2 which may have at least one substituent selected from fluoromethyl, hydroxy, amino, nitro, cyano, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons.
-Naphthyl, halogen on the aromatic ring, amino, 1 to 1 carbon atoms
6 alkyls, thienyl which may have at least one substituent selected from alkoxy having 1 to 6 carbons, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, Benzthiazolyl or indolyl or 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 3-furylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,
2-indolylmethyl and 3-indolylmethyl are shown.
R ² is an alkyl group, a cycloalkyl group, benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-
Substitution selected from phenylhexyl, halogenated alkyl group, alkoxy group, halogen on the aromatic ring, trifluoromethyl, hydroxy, amino, nitro, cyano, alkyl having 1 to 6 carbons, and alkoxy having 1 to 6 carbons. Substituent selected from phenyl, which may have at least one group, 1-naphthyl or 2-naphthyl, halogen, amino, alkyl having 1 to 6 carbons, and alkoxy having 1 to 6 carbons on the aromatic ring. May have at least one of thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,
Thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzthiazolyl or indolyl, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 3-furylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridyl Methyl,
2-indolylmethyl, 3-indolylmethyl or formula [Wherein B is an alkylene group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkylidene group, an alkenylene group, -CH ₂ OCH _2- , -CH ₂ S (O)]
nCH _2- (n represents an integer of 0 to 2), -CH ₂ CON (R ⁸ )-
(R ⁸ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), D is an oxygen atom, a methylene group or -N
(R ⁹ )-(R ⁹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms). The group has at least one substituent selected from halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons on the aromatic ring. Phenyl, 1-naphthyl or 2-naphthyl, or may have at least one substituent selected from halogen, amino, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons on the aromatic ring. May be bound by thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzthiazolyl or indolyl]. R ³ and R ⁴ are the same or different and are a hydrogen atom, an alkyl group or benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-
Alkyl, benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 3 together with adjacent nitrogen atoms which represent phenylhexyl or which are bound to one another
A group forming 1-pyrrolidinyl, piperidino, morpholino and 1-piperazinyl which may be substituted with -phenylpropyl, 4-phenylbutyl, 6-phenylhexyl is shown. R ⁵ represents a hydrogen atom, 1 to 3 halogen atoms, an alkyl group or an alkoxy group (when R ⁵ is 2 to 3, they may be the same or different). ] The benzolactam compound represented by, its isomer or salt, and (2) General formula (In the formula, R _a ¹ is an alkyl group, a cycloalkyl group, benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, or halogen on the aromatic ring. Phenyl optionally having at least one substituent selected from trifluoromethyl, hydroxy, amino, nitro, cyano, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons, 1-naphthyl or 2-naphthyl, thienyl, furyl, pyrrolyl, pyrazolyl which may have at least one substituent selected from halogen, amino, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons on the aromatic ring. , Imidazolyl, thiazolyl, oxazolyl,
Pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzthiazolyl or indolyl or 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl,
3-furylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-indolylmethyl,
3-indolylmethyl is shown, and other symbols have the same meanings as defined in (1) above. ) A benzolactam compound represented by the following formula, its isomer or salt.

The definition of each symbol used in the present specification including the compound of the general formula (I) of the present invention will be explained in more detail. R ¹ , R ² , R ³ ,
The alkyl group for R ⁴ , R ⁵ and R ⁶ includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl,
It is an alkyl group having 1 to 6 carbon atoms such as hexyl, and may further have an unsaturated bond (double bond, triple bond). The cycloalkyl group in R ¹ and R ² is a cycloalkyl group having 5 to 7 carbon atoms such as cyclopentyl, cyclohexyl or cycloheptyl, which may have a double bond in the ring. The alkoxy group for R ¹ , R ² and R ⁵ is an alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, isopentyloxy and hexyloxy. Further, it has at least one substituent selected from halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons on the aromatic ring. It may be optionally substituted with phenyl, 1-naphthyl or 2-naphthyl. Examples of the halogenated alkyl group for R ² include trifluoromethyl, chloromethyl, 2,2,2-trifluoroethyl and the like. formula In the group represented by, B is an alkylene group (methylene, ethylene, trimethylene, propylene, tetramethylene,
Alkylene having 1 to 6 carbon atoms such as hexamethylene,
Further, it may be substituted with an alkyl group having 1 to 4 carbon atoms such as methyl and ethyl), an alkylidene group (propylidene, butylidene, etc.), an alkenylene group (vinylene, propenylene, etc.), —CH ₂ OCH ₂ —, — CH ₂ S (O) nC
H ₂ - (n is an integer of _{0~2), - CH 2 CON (} R 8) - (R
⁸ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), D is an oxygen atom, a methylene group or -N (R ⁹ )-
(R ⁹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms). The group has at least one substituent selected from halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons on the aromatic ring. Phenyl, 1-naphthyl or 2-naphthyl, or at least one substituent selected from halogen, amino, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons on the aromatic ring. It may be attached by a good thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzthiazolyl or indolyl. Examples of the halogen atom in R ¹ , R ² and R ⁵ include fluorine, chlorine and bromine.
The amino protecting group for R ⁶ includes benzyloxycarbonyl, tertiary butoxycarbonyl, trifluoroacetyl and the like. The protecting group for the carboxy group in Q is an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl and tertiary butyl, or an aralkyl group such as benzyl.

Since the compounds of the general formulas (I) and (a) have 1 to 3 asymmetric carbon atoms in the molecule, the number of asymmetric carbon atoms is 1.
If there are two or more of them, optical isomers, racemates thereof, or a mixture thereof exist, and if the number of asymmetric carbons is two or more, optically pure diastereoisomers, racemates of diastereoisomers. , Or a mixture of diastereoisomers may exist. The present invention includes all forms of these stereoisomers.

Further, the compound of the present invention and various isomers thereof can form an acid addition salt with an inorganic acid or an organic acid, and a hydrate (monohydrate, hemihydrate, dihydrate, 3 / 2 hydrate etc.),
It may also exist as a solvate with ethanol, isopropyl alcohol, dimethylformamide and the like. The present invention also includes these.

Preferred compounds of general formula (I) are trans-3
(S)-[γ-butyrolactone-γ (S) -carboxamido] -4-oxo-2 (R) -phenyl-2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-acetamide, trans-3 (R)-[γ-butyrolactone-γ
(S) -Carboxamide] -4-oxo-2 (S) -phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, cis-3- [γ-butyrolactone-γ (S) -Carboxamide] -4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, trans-4-oxo-3-
[5-oxo-2 (S) -pyrrolidicarboxamide]-
2-Phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, trans-3- (2-indolecarboxamido) -4-oxo-2-phenyl-2,3,4 , 5-Tetrahydro-1,5-benzothiazepine-5
-Acetamide, trans-3- (4,5-dihydroorotylamino) -4-oxo-2-phenyl-2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-acetamide, 2-isopropyl-3- (2-indolecarboxamide) -4-oxo-2,3,4,5-tetrahydro-1,5
-Benzothiazepine-5-acetamide, 3 (R)-
[Γ-butyrolactone-γ (S) -carboxamide]-
4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, trans-3- [γ-butyrolactone-γ (S) -carboxamide] -4-oxo-2- ( 2-thienyl) -2,3,4,5-tetrahydro-1,5
-Benzothiazepine-5-acetamide, trans-3
-(2-indolecarboxamide) -4-oxo-2
-(2-thienyl) -2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, trans-3-
(2-indolecarboxamide) -4-oxo-2-
Phenyl-N- (2-phenylethyl) -2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, trans-3- (2-indolecarboxamide)
-2-Phenyl-5- (1-pyrrolidinylcarbonylmethyl) -2,3-dihydro-1,5-benzothiazepine-4
(5H) -one, cis-4-oxo-3 (R)-[5-oxo-2 (S) -pyrrolidinecarboxamide] -2
(R) -Phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, cis-4-oxo-
3 (S)-[5-oxo-2 (S) -pyrrolidinecarboxamide] -2 (S) -phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, cis- 3- [γ-butyrolactone-γ (S) -carboxamide] -8-chloro-4-oxo-2-phenyl-2,3,
4,5-tetrahydro-1,5-benzothiazepine-5-carboxamide, trans-3- [γ-butyrolactone-γ
(S) -Carboxamide] -8-chloro-4-oxo-
2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, cis-3- (2-indolecarboxamido) -2-oxo-4-phenyl-2,
3,4,5-Tetrahydro-1H-1-benzazepine-1-
Acetamide and 3- (2-indolecarboxamide) -2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide, or its isomers and salts.

The compound of the general formula (I) of the present invention is, for example, a compound of the general formula (In the formula, each symbol has the same meaning as defined above.) And a carboxylic acid represented by (In the formula, each symbol has the same meaning as defined above.) Or a compound represented by the general formula (Wherein each symbol has the same meaning as defined above) and a carboxylic acid represented by the general formula R ² COOH (V) (wherein R ² has the same meaning as defined above) or a carboxylic acid thereof. React with a reactive derivative, or (Wherein each symbol has the same meaning as defined above) and the general formula (In the formula, R ³ and R ⁴ are as defined above, X is chlorine,
A halogen atom such as bromine or iodine. ) And a compound represented by

For the above-mentioned amidation reaction, amidation method or peptide synthesis method known per se can be applied correspondingly. For example, when the compound of the general formula (II) or (V) is a free carboxylic acid, the amidation reaction includes dicyclohexylcarbodiimide, phosphorus halide (phosphorus trichloride, phosphorus oxychloride, etc.), diphenylphosphoryl azide, 2 It is carried out in the presence of a condensing agent such as -chloro-N-methylpyridinium iodide-tributylamine system (Mukoyama method) in an inert solvent or without a solvent, under cooling or at room temperature or under heating.

The compound represented by the general formula (II) or (V) is used as a reactive derivative of a carboxylic acid, and is an acid halide (acid chloride, acid bromide, etc.) or mixed acid anhydride (lower alkyl carbonic acid mixed acid anhydride, alkyl phosphoric acid mixed acid anhydride). When an organic base such as triethylamine, pyridine, or dimethylaniline is used, or an inorganic base such as alkali hydrogen carbonate, alkali carbonate, or alkali hydroxide is deoxidized in an inert solvent or without a solvent. It is carried out under cooling to warming in the presence of the agent. Further, as the reactive derivative, lower alkyl ester (methyl ester, ethyl ester, etc.) or so-called active ester (p-nitrophenyl ester, p-nitrobenzyl ester, p-chlorophenyl ester, succinimide ester, benzotriazole ester, etc.) When a) is used, the reaction is carried out in an inert solvent or without a solvent, optionally in the presence of a strong base catalyst such as sodium alkoxide, from room temperature to under heating.

Examples of the inert solvent used in the amidation reaction described above include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran and dioxane, and ethyl acetate. Examples thereof include esters such as acetone, ketones such as acetone, alcohols such as methanol, ethanol and isopropyl alcohol, amides such as dimethylformamide and dimethylacetamide, acetonitrile, dimethylsulfoxide, water and the like, which are appropriately selected depending on the reaction. be able to.

On the other hand, the condensation reaction between the compound of formula (VI) and the compound of formula (VII) is carried out in the presence of a deoxidizing agent in an inert solvent, from cooling to heating. Examples of the deoxidizing agent used here include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, alkali metal hydrides such as sodium hydride and lithium hydride, and sodium. Examples thereof include alkali metal alkoxides such as methoxide, sodium ethoxide, potassium-tert-butoxide, and organic bases such as triethylamine and pyridine. Further, when using a phase transfer catalyst such as tetra-n-butylammonium bromide or benzyltriethylammonium iodide, when the reaction is carried out in a mixed solvent of water and another organic solvent,
It is also possible to use an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.

The novel compounds of the general formulas (II), (IV) and (VI) used in the above-mentioned amidation reaction and condensation reaction are produced, for example, as follows.

That is, the compound of the general formula (II) is obtained by adding the compound of the general formula (VI) to the compound of the general formula XCH ₂ CO ₂ Q (VIII) (wherein each symbol has the same meaning as described above). In the presence of a deoxidizer similar to the above,
General formula after condensation reaction in an inert solvent (Wherein each symbol has the same meaning as defined above), the compound represented by the formula (II ′)
It is obtained by removing the protecting group Q of the carboxy group of the compound of.

The decarboxylation protecting group reaction of the compound of formula (II ′) is treated with an acid (hydrochloric acid, hydrobromic acid, hydrobromic acid-acetic acid, trifluoroacetic acid, etc.) or an alkali (sodium hydroxide, potassium hydroxide, etc.). Alternatively, it is carried out by a method well known in synthetic organic chemistry such as catalytic hydrogenolysis using palladium carbon, platinum oxide or the like as a catalyst.

The compound of general formula (IV) has the general formula (Wherein each symbol has the same meaning as defined above) and the general formula XCH ₂ CO ₂ Q '(VIII') (wherein X has the same meaning as above and Q'is a carboxy group). A compound represented by the formula (1) is a protective group.) Or the R ² CO- group is an amino protecting group (for example, trifluoroacetyl, chloroacetyl, ethoxycarbonyl, Benzyloxycarbonyl,
A general formula (II ′) which is a tertiary butoxycarbonyl etc.
The general formula obtained by selectively deamidating the compound of (In the formula, each symbol has the same meaning as described above.) The compound represented by the formula (III) is reacted to synthesize the compound.

Further, even if the compound of the general formula (I) in which the R ² CO- group is the above-mentioned amino protecting group is converted to a deamino protecting group, the compound of the general formula (I
The compound of V) is obtained.

The amidation reaction between the compound of the general formula (X) and the compound of the general formula (III) essentially consists of the ester compound of the compound of the general formula (II) and the compound of the general formula (III) described above. It is the same as the reaction, and is carried out without solvent or in a suitable solvent under normal pressure or increased pressure, with cooling or with heating.

Further, the deamination protecting group reaction of the compounds of the general formulas (II ′), (I) and (VI) can be carried out by using an acid (hydrofluoric acid, hydrochloric acid, hydrogen chloride-dioxane, hydrobromic acid, hydrobromic acid- It can be easily carried out by a known method such as treatment with acetic acid, trifluoroacetic acid, etc.) or alkali (sodium hydroxide, potassium hydroxide, ammonia, etc.) or catalytic hydrogenolysis using palladium carbon, platinum oxide, etc. as a catalyst. Be seen.

Among the compounds of the general formula (VI) which are the raw material compounds of the present invention, the compound of the general formula (VI) in which A is a sulfur atom, an oxygen atom or a -NR ⁶ -group (R ⁶ is as defined above). Is a general formula synthesized according to a known method. (Wherein R ¹ and R ² have the same meanings as described above, and R ⁷ represents a hydrogen atom or a lower alkyl such as methyl, ethyl or tertiary butyl, or a carboxy protecting group such as trimethylsilyl or benzyl.). The general formula for α-dehydroamino acid derivatives (In the formula, R ⁵ has the same meaning as described above, and A ′ represents a sulfur atom, an oxygen atom or a —NR ⁶ — group (R ⁶ has the same meaning.). General formula (Wherein each symbol has the same meaning as defined above), the compound represented by the formula (XIII)
It is synthesized by subjecting the compound of 1 to a ring closure reaction.

The addition reaction is carried out in the absence of solvent or in a suitable solvent such as alcohol, dimethylformamide, dimethylsulfoxide, tetrahydrofuran or pyridine, without catalyst or in the presence of a base catalyst such as triethylamine, sodium carbonate or potassium carbonate, under cooling or at room temperature. Or proceed under heating.

The ring-closing reaction is carried out in the presence or absence of a dehydration condensation agent,
It is carried out in a solvent-free or inert solvent under cooling or at room temperature or under heating.

Further, the compound of the general formula (VI) is a compound of the general formula (XI) and a compound of the general formula (XII) in the absence of solvent or in a suitable solvent, an inorganic acid such as hydrochloric acid or sulfuric acid, or acetic acid or methanesulfonic acid. Alternatively, it is also synthesized by heating in the presence or absence of an organic acid such as p-toluenesulfonic acid to cause the cycloaddition reaction all at once.

Needless to say, the compound of general formula (VI) can also be produced by subjecting the compound of general formula (IX) and the compound of general formula (V) to the same amidation reaction as described above. Absent.

On the other hand, the compound of the general formula (IX), which is the starting compound of the present invention, has the general formula (VI) in which the R ² CO- group is the aforementioned amino-protecting group.
The compound can be obtained by subjecting it to the above-mentioned deamination protecting group reaction, or can be obtained by the method shown below. That is, the general formula prepared by applying known methods (In the formula, R ¹ and R ⁷ have the same meanings as described above.) [In the formula, R ⁵ has the same meaning as described above, A ″ represents a sulfur atom, an oxygen atom, a methylene group, and a —NR ⁶ group (R ⁶ has the same meaning as described above.) Y represents amino or nitro. ] The compound represented by (Wherein each symbol has the same meaning as defined above), the compound represented by the formula (XVI)
The compound of the general formula (In the formula, each symbol has the same meaning as defined above.). The compounds of the general formulas (XVI) and (XVII) in which Y is nitro can be reduced to the compounds of the general formulas (XVI) and (XVII) in which Y is amino. Then, a compound of the general formula (XVII) in which Y is amino (Wherein each symbol has the same meaning as defined above), and the compound represented by the formula (XVII
The compound of the general formula (I
The compound of X) can be obtained.

The compound of general formula (IX) can also be obtained as follows. That is, by subjecting the compound of general formula (XVII) to a decarboxylation reaction, (In the formula, each symbol has the same meaning as above.). The compound of the general formula (XIX) in which Y is nitro is converted into the compound of the general formula (XIX) in which Y is amino by further reduction reaction. The compound of the general formula (IX) is obtained by subjecting the compound of the general formula (XIX), in which Y is amino, thus obtained, to a ring closure reaction.

The addition reaction of compound (XIV) and compound (XV) can be carried out in the absence of solvent or in a suitable solvent which does not inhibit this reaction, under cooling.
Or proceed to room temperature or under heating. At that time, depending on the properties of the compound (XIV) and the compound (XV), a base such as sodium hydride, lithium diisopropylamide, butyl lithium or sodium alkoxide, or an inorganic acid such as hydrochloric acid or sulfuric acid, acetic acid, methanesulfonic acid, p-
The use of organic acids such as toluene sulfonic acid or Lewis acids such as boron trifluoride, zinc chloride, aluminum chloride, titanium tetrachloride, stannic chloride may give more favorable results.

The amination reaction of compound (XVI) proceeds by using a suitable base and an aminating agent in a solvent that does not inhibit this reaction. The base used is appropriately selected depending on the properties of the compound (XVI), and examples thereof include sodium hydride, lithium diisopropylamide, butyl lithium, sodium alkoxide, sodium hydroxide and the like. As the aminating agent, O-2,4-dinitrophenylhydroxylamine, O-mesitylenesulfonylhydroxylamine, O-mesitoylhydroxylamine and the like can be used.

Compounds (XVI), (XVII) and (XI where Y is nitro
The reduction reaction of (X) is carried out in an appropriate solvent that does not inhibit this reaction,
It is carried out in the presence of a reducing agent. The reducing conditions include platinum,
Catalytic hydrogen reduction catalyzed by metals such as palladium, Raney nickel, rhodium and mixtures thereof with carriers, or reduction by metals such as iron and zinc with acids such as hydrochloric acid and acetic acid, or reduction with stannous chloride, etc. Methods known in organic chemistry can be applied correspondingly. In addition, during the reduction reaction of compound (XVII) or (XIX), the reaction mixture is heated to an appropriate temperature to give a reductant [general formula (XVII) wherein Y is amino].
Alternatively, the compound (XVIII) or (IX) which is a ring-closed compound can be obtained without isolating (XIX)].

The decarboxylation reaction of compound (XVII) and compound (XVIII) is carried out by using a solvent inert to a reaction such as pyridine, dimethylformamide, tetrahydrofuran, toluene, xylene, mesitylene, methyl cellosolve, dioxane, methanol, ethanol, isopropanol, water, or the like. In a solvent obtained by appropriately combining them, using a base such as sodium hydroxide or potassium hydroxide, an acid such as hydrochloric acid or sulfuric acid, or a decarboxylating agent such as lithium iodide, lithium bromide or lithium chloride , 0 ℃ ~ 25
It proceeds at a temperature of 0 ° C.

The ring-closing reaction of compounds (XVII) and (XIX) in which Y is amino is carried out without solvent in the presence or absence of a dehydration condensing agent, or in a suitable solvent such as acetic acid, pyridine, dimethylformamide, tetrahydrofuran, toluene, xylene, Proceed under cooling or at room temperature or under heating.

Needless to say, the compound of the general formula (X) can be obtained by converting the compound of the general formula (II ′) in which R ² CO— is the amino protecting group described above into a deamino protecting group. It can also be obtained by the method. That is, the compound of the general formula (XVI) in which Y is amino is subjected to the ring-closing reaction similar to the above to give the compound of the general formula (Wherein each symbol has the same meaning as defined above), and the compound represented by the formula (VIII)
The condensation reaction similar to the above is performed using the compound of (In the formula, each symbol has the same meaning as described above.) A compound represented by the following general formula can be obtained by subjecting the compound to the same amination reaction as described above. (In the formula, each symbol has the same meaning as described above.) The compound of the general formula (X) can also be obtained by subjecting the compound represented by to the decarboxylation reaction similar to the above.

It goes without saying that the compound of general formula (XXII) can also be obtained by subjecting the compound of general formula (XVIII) and the compound of general formula (VIII) to the same condensation reaction as described above.
In addition, the —CO ₂ R ⁷ groups of the compounds of the general formulas (XX) and (XXI) are subjected to transfer reactions such as Hoffman transfer, Schmidt transfer and Curtius transfer according to known methods to give amino, respectively. Compound (IX) and compound (X) can be obtained.

In addition to the above, the method for producing the compound of formula (I) is as follows. That is, the general formula prepared by applying known methods (In the formula, A ′, R ⁵ and Q have the same meanings as described above.) The compound of the general formula (II) is subjected to the same cycloaddition reaction as described above with the compound of the general formula (XI). ′) Or a compound of the formula (II) and further carrying out the same amidation reaction as described above using the compound of the general formula (III), or the compound of the general formula (XXIII) and the general formula (III) By preliminarily subjecting the compound of (Wherein each symbol has the same meaning as defined above), and subjecting the compound of general formula (XXIV) and the compound of general formula (XI) to the same cycloaddition reaction as described above. The compound of general formula (I) is also produced by

As described above, the separation and purification of the reaction product obtained in each step, particularly various stereoisomers, can be easily performed by using a well-known purification method in synthetic organic chemistry such as recrystallization, column chromatography, and optical resolution. . Further, the compound (I) of the present invention thus obtained or various isomers thereof are prepared by a conventional method from inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, etc.) or organic acids (maleic acid, Fumaric acid,
The corresponding acid addition salt can be obtained by treating with succinic acid, tartaric acid, malic acid, p-toluenesulfonic acid, etc.).

The compounds included in the present invention other than those described in the Examples section are exemplified below.

Cis-3- [5-oxo-2 (S) -pyrrolidinecarbo
Xamide] -2-phenyl-5- (1-pyrrolidinyl cas
Rubonylmethyl) -2,3-dihydro-1,5-benzothiaze
Pin-4 (5H) -one trans-3- [5-oxo-2 (S) -pyrrolidinecarcinone
Ruboxamide] -2-phenyl-5- (1-pyrrolidini
Lucarbonylmethyl) -2,3-dihydro-1,5-benzothi
Azepine-4 (5H) one cis-3- [5-oxo-2 (S) -pyrrolidinecarbo
Xamido] -2-phenyl-5-piperidinocarbonyl
Methyl-2,3-dihydro-1,5-benzothiazepine-4
(5H) -one trans-3- [5-oxo-2 (S) -pyrrolidinecarba
Ruboxamide] -2-phenyl-5-piperidinocarbo
Nylmethyl-2,3-dihydro-1,5-benzothiazepine-
4 (5H) -one cis-N, N-dimethyl-4-oxo-3- [5-oxo
-2 (S) -Pyrrolidinecarboxamide] -2-phenyl
Ru-2,3,4,5-tetrahydro-1,5-benzothiazepine-
5-acetamide trans-N, N-dimethyl-4-oxo-3- [5-o
Xo-2 (S) -pyrrolidinecarboxamide] -2-fu
Phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepi
5-acetamide cis-N, N-diethyl-4-oxo-3- [5-oxo
-2 (S) -Pyrrolidinecarboxamide] -2-phenyl
Ru-2,3,4,5-tetrahydro-1,5-benzothiazepine-
5-acetamide trans-N, N-diethyl-4-oxo-3- [5-o
Xo-2 (S) -pyrrolidinecarboxamide] -2-fu
Phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepi
5-acetoamide cis-4-oxo-3- [5-oxo-2 (S) -pyro
Lysinecarboxamide] -N- (2-phenylethyl)
-2-Phenyl-2,3,4,5-tetrahydro-1,5-benzo
Thiazepine-5-acetamide trans-4-oxo-3- [5-oxo-2 (S)-
Pyrrolidinecarboxamide] -N- (2-phenylethyl
) -2-Phenyl-2,3,4,5-tetrahydro-1,5-be
Nazothiazepine-5-acetamide cis-N-methyl-4-oxo-3- [5-oxo-2
(S) -Pyrrolidinecarboxamide] -2-phenyl-
2,3,4,5-Tetrahydro-1,5-benzothiazepine-5-
Acetamide trans-N-methyl-4-oxo-3- [5-oxo
-2- (S) -Pyrrolidinecarboxamide] -2-fe
Nyl-2,3,4,5-tetrahydro-1,5-benzothiazepine
-5-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -2-phenyl-5- (1-pyrrolidinylcar
Bonylmethyl) -2,3-dihydro-1,5-benzothiazepi
N-4 (5H) -one trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -2-phenyl-5- (1-pyrrolidinyl
Carbonylmethyl) -2,3-dihydro-1,5-benzothia
Zepin-4 (5H) -one cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -2-phenyl-5-piperidinocarbonyl
Cyl-2,3-dihydro-1,5-benzothiazepine-4 (5
H) -one trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -2-phenyl-5-piperidinocarboni
Rumethyl-2,3-dihydro-1,5-benzothiazepine-4
(5H) -one cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -N, N-dimethyl-4-oxo-2-phenyl
-2,3,4,5-Tetrahydro-1,5-benzothiazepine-5
-Acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -N, N-dimethyl-4-oxo-2-phen
Nyl-2,3,4,5-tetrahydro-1,5-benzothiazepine
-5-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -N, N-diethyl-4-oxo-2-phenyl
-2,3,4,5-Tetrahydro-1,5-benzothiazepine-5
-Acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -N, N-diethyl-4-oxo-2-phen
Nyl-2,3,4,5-tetrahydro-1,5-benzothiazepine
-5-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -4-oxo-N- (2-phenylethyl)-
2-phenyl-2,3,4,5-tetrahydro-1,5-benzothi
Azepine-5-acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -4-oxo-N- (2-phenylethyl
) -2-Phenyl-2,3,4,5-tetrahydro-1,5-be
Nzothiazepine-5-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -N-methyl-4-oxo-2-phenyl-2,
3,4,5-Tetrahydro-1,5-benzothiazepine-5-a
Cetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -N-methyl-4-oxo-2-phenyl
-2,3,4,5-Tetrahydro-1,5-benzothiazepine-5
-Acetamide cis-3- (2-indolecarboxamide) -2-fu
Phenyl-5-piperidinocarbonylmethyl-2,3-dihi
Doro-1,5-benzothiazepine-4 (5H) -one trans-3- (2-indolecarboxamide) -2
-Phenyl-5-piperidinocarbonylmethyl-2,3-
Dihydro-1,5-benzothiazepine-4 (5H) -one cis-N, N-dimethyl-3- (2-indolecarboxy
Samido) -4-oxo-2-phenyl-2,3,4,5-teto
Lahydro-1,5-benzothiazepine-5-acetamide trans-N, N-dimethyl-3- (2-indolecal
Voxamide) -4-oxo-2-phenyl-2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-acetoa
Midcis-N, N-diethyl-3- (2-indolecarboxy
Samido) -4-oxo-2-phenyl-2,3,4,5-teto
Lahydro-1,5-benzothiazepine-5-acetamide trans-N, N-diethyl-3- (2-indolecal
Voxamide) -4-oxo-2-phenyl-2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-acetoa
Mid cis-3- (2-cyclopentanonecarboxamide)-
4-oxo-N- (2-phenylethyl) -2-phenyl
Ru-2,3,4,5-tetrahydro-1,5-benzothiazepine-
5-acetamide trans-3- (2-cyclopentanone carboxami
De) -4-oxo-N- (2-phenylethyl) -2-
Phenyl-2,3,4,5-tetrahydro-1,5-benzothiaze
Pin-5-acetamide cis-3- (2-cyclopentanonecarboxamide)-
4-oxo-2-phenyl-2,3,4,5-tetrahydro-
1,5-benzothiazepine-5-acetamide trans-3- (2-cyclopentanone carboxami
De) -4-oxo-2-phenyl-2,3,4,5-tetrahi
Dro-1,5-benzothiazepine-5-acetamide cis-N-benzyl-4-oxo-3- [5-oxo-
2 (S) -Pyrrolidinecarboxamide] -2-phenyl
-2,3,4,5-Tetrahydro-1,5-benzothiazepine-5
-Acetamide trans-N-benzyl-4-oxo-3- [5-oxy
So-2 (S) -pyrrolidinecarboxamide] -2-fe
Nyl-2,3,4,5-tetrahydro-1,5-benzothiazepine
-5-acetamide cis-N-benzyl-3- [γ-butyrolactone-γ
(S) -Carboxamide] -4-oxo-2-phenyl
-2,3,4,5-Tetrahydro-1,5-benzothiazepine-5
-Acetamide trans-N-benzyl-3- [γ-butyrolactone-
γ (S) -carboxamido] -4-oxo-2-phenyl
Ru-2,3,4,5-tetrahydro-1,5-benzothiazepine-
5-acetamide cis-N-benzyl-3- (2-indolecarboxa
Mido) -4-oxo-2-phenyl-2,3,4,5-tetra
Hydro-1,5-benzothiazepine-5-acetamide trans-N-benzyl-3- (2-indolecarbo
Xamido) -4-oxo-2-phenyl-2,3,4,5-te
Trahydro-1,5-benzothiazepine-5-acetami
Cis-N, 2-diphenyl-4-oxo-3- [5-oxy
So-2 (S) -pyrrolidinecarboxamide] -2,3,4,5
-Tetrahydro-1,5-benzothiazepine-5-aceto
Amido trans-N, 2-diphenyl-4-oxo-3- [5-
Oxo-2 (S) -pyrrolidinecarboxamide] -2,3,
4,5-tetrahydro-1,5-benzothiazepine-5-acetate
Toamido cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -N, 2-diphenyl-4-oxo-2,3,4,5-te
Trahydro-1,5-benzothiazepine-5-acetami
Trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -N, 2-diphenyl-4-oxo-2,3,4,5
-Tetrahydro-1,5-benzothiazepine-5-aceto
Amido cis-N, 2-diphenyl-3- (2-indolecarbo
Xamide) -4-oxo-2,3,4,5-tetrahydro-1,5
-Benzothiazepine-5-acetamide trans-N, 2-diphenyl-3- (2-indolecarba
Ruboxamide) -4-oxo-2,3,4,5-tetrahydro
-1,5-benzothiazepine-5-acetamide cis-8-chloro-3- [5-oxo-2 (S) -pyro
Lysinecarboxamide] -2-phenyl-5- (1-pi
Loridinylcarbonylmethyl) -2,3-dihydro-1,5-
Benzothiazepine-4 (5H) -one trans-8-chloro-3- [5-oxo-2 (S)-
Pyrrolidinecarboxamide] -2-phenyl-5- (1
-Pyrrolidinylcarbonylmethyl) -2,3-dihydro-
1,5-benzothiazepine-4 (5H) -one cis-8-chloro-3- [5-oxo-2 (S) -pyro
Lysinecarboxamide] -2-phenyl-5-piperidi
Nocarbonylmethyl-2,3-dihydro-1,5-benzothia
Zepin-4 (5H) -one trans-8-chloro-3- [5-oxo-2 (S)-
Pyrrolidinecarboxamide] -2-phenyl-5-pipe
Lysinocarbonylmethyl-2,3-dihydro-1,5-benzo
Thiazepine-4 (5H) -one cis-8-chloro-N, N-dimethyl-4-oxo-3-
[5-oxo-2 (S) -pyrrolidinecarboxamide]
-2-Phenyl-2,3,4,5-tetrahydro-1,5-benzo
Thiazepine-5-acetamide trans-8-chloro-N, N-dimethyl-4-oxo-
3- [5-oxo-2 (S) -pyrrolidinecarboxami
De] -2-phenyl-2,3,4,5-tetrahydro-1,5-be
Nzothiazepine-5-acetamide cis-8-chloro-N, N-diethyl-4-oxo-3-
[5-oxo-2 (S) -pyrrolidinecarboxamide]
-2-Phenyl-2,3,4,5-tetrahydro-1,5-benzo
Thiazepine-5-acetamide trans-8-chloro-N, N-diethyl-4-oxo-
3- [5-oxo-2 (S) -pyrrolidinecarboxami
De] -2-phenyl-2,3,4,5-tetrahydro-1,5-be
Nazothiazepine-5-acetamide cis-8-chloro-4-oxo-3- [5-oxo-2
(S) -Pyrrolidinecarboxamide] -N- (2-phen
Nylethyl) -2-phenyl-2,3,4,5-tetrahydro
-1,5-benzothiazepine-5-acetamide trans-8-chloro-4-oxo-3- [5-oxo
-2 (S) -Pyrrolidinecarboxamide] -N- (2-
Phenylethyl) -2-phenyl-2,3,4,5-tetrahi
Dro-1,5-benzothiazepine-5-acetamide cis-8-chloro-N-methyl-4-oxo-3- [5
-Oxo-2 (S) -pyrrolidinecarboxamide] -2
-Phenyl-2,3,4,5-tetrahydro-1,5-benzothia
Zepine-5-acetamide trans-8-chloro-N-methyl-4-oxo-3-
[5-oxo-2 (S) -pyrrolidinecarboxamide]
-2-Phenyl-2,3,4,5-tetrahydro-1,5-benzo
Thiazepine-5-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -8-chloro-2-phenyl-5- (1-pyro
Lysinylcarbonylmethyl) -2,3-dihydro-1,5-be
Nzothiazepine-4 (5H) -one trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -8-chloro-2-phenyl-5- (1-
Pyrrolidinylcarbonylmethyl) -2,3-dihydro-1,5
-Benzothiazepine-4 (5H) -one cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -8-chloro-2-phenyl-5-piperidino
Carbonylmethyl-2,3-dihydro-1,5-benzothiaze
Pin-4 (5H) -one trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -8-chloro-2-phenyl-5-piperi
Dinocarbonylmethyl-2,3-dihydro-1,5-benzothi
Azepine-4 (5H) -one cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -8-chloro-N, N-dimethyl-4-oxo-
2-phenyl-2,3,4,5-tetrahydro-1,5-benzothi
Azepine-5-acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -8-chloro-N, N-dimethyl-4-oxy
So-2-phenyl-2,3,4,5-tetrahydro-1,5-ben
Zothiazepine-5-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -8-chloro-N, N-diethyl-4-oxo-
2-phenyl-2,3,4,5-tetrahydro-1,5-benzothi
Azepine-5-acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -8-chloro-N, N-diethyl-4-oxy
So-2-phenyl-2,3,4,5-tetrahydro-1,5-ben
Zothiazepine-5-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -8-chloro-4-oxo-N- (2-phenyl
Ruethyl) -2-phenyl-2,3,4,5-tetrahydro-
1,5-benzothiazepine-5-acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -8-chloro-4-oxo-N- (2-phenyl)
(Phenylethyl) -2-phenyl-2,3,4,5-tetrahydr
1,5-benzothiazepine-5-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -8-chloro-N-methyl-4-oxo-2-
Phenyl-2,3,4,5-tetrahydro-1,5-benzothiaze
Pin-5-acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -8-chloro-N-methyl-4-oxo-
2-phenyl-2,3,4,5-tetrahydro-1,5-benzothi
Azepine-5-acetamide cis-8-chloro-3- (2-indolecarboxami
De) -2-Phenyl-5-piperidinocarbonylmethyl
-2,3-Dihydro-1,5-benzothiazepine-4 (5H)-
On trans-8-chloro-3- (2-indolecarboxy
Samido) -2-phenyl-5-piperidinocarbonyl
Cyl-2,3-dihydro-1,5-benzothiazepine-4 (5
H) -one cis-8-chloro-N, N-dimethyl-3- (2-indo)
Carboxamide) -4-oxo-2-phenyl-2,
3,4,5-Tetrahydro-1,5-benzothiazepine-5-a
Cetamide trans-8-chloro-N, N-dimethyl-3- (2-i
And carboxamide) -4-oxo-2-phenyl
-2,3,4,5-Tetrahydro-1,5-benzothiazepine-5
-Acetamide cis-8-chloro-N, N-diethyl-3- (2-indo
Carboxamide) -4-oxo-2-phenyl-2,
3,4,5-Tetrahydro-1,5-benzothiazepine-5-a
Cetamide trans-8-chloro-N, N-diethyl-3- (2-i
And carboxamide) -4-oxo-2-phenyl
-2,3,4,5-Tetrahydro-1,5-benzothiazepine-5
-Acetamide cis-8-chloro-3- (2-cyclopentanonecarbo
Xamide) -4-oxo-N- (2-phenylethyl)
-2-Phenyl-2,3,4,5-tetrahydro-1,5-benzo
Thiazepine-5-acetamide trans-8-chloro-3- (2-cyclopentanone carbonate
Ruboxamide) -4-oxo-N- (2-phenylethyl)
) -2-Phenyl-2,3,4,5-tetrahydro-1,5-be
Nazothiazepine-5-acetamide cis-8-chloro-3- (2-cyclopentanonecarbo
Xamido) -4-oxo-2-phenyl-2,3,4,5-te
Trahydro-1,5-benzothiazepine-5-acetami
Trans-8-chloro-3- (2-cyclopentanone carbonate
Ruboxamide) -4-oxo-2-phenyl-2,3,4,5
-Tetrahydro-1,5-benzothiazepine-5-aceto
Amido cis-N-benzyl-8-chloro-4-oxo-3-
[5-oxo-2 (S) -pyrrolidinecarboxamide]
-2-Phenyl-2,3,4,5-tetrahydro-1,5-benzo
Thiazepine-5-acetamide trans-N-benzyl-8-chloro-4-oxo-3
-[5-oxo-2 (S) -pyrrolidinecarboxami
De] -2-phenyl-2,3,4,5-tetrahydro-1,5-be
Nzothiazepine-5-acetamide cis-N-benzyl-3- [γ-butyrolactone-γ
(S) -Carboxamide] -8-chloro-4-oxo-
2-phenyl-2,3,4,5-tetrahydro-1,5-benzothi
Azepine-5-acetamide trans-N-benzyl-3- [γ-butyrolactone-
γ (S) -carboxamide] -8-chloro-4-oxo
-2-Phenyl-2,3,4,5-tetrahydro-1,5-benzo
Thiazepine-5-acetamide cis-N-benzyl-3- (2-indolecarboxa
[Mido] -8-chloro-4-oxo-2-phenyl-2,3,
4,5-tetrahydro-1,5-benzothiazepine-5-acetate
Toamido trans-N-benzyl-3- (2-indolecarbo
Xamide] -8-chloro-4-oxo-2-phenyl-
2,3,4,5-Tetrahydro-1,5-benzothiazepine-5-
Acetamide cis-8-chloro-N, 2-diphenyl-4-oxo-3
-[5-oxo-2 (S) -pyrrolidinecarboxami
] -2,3,4,5-Tetrahydro-1,5-benzothiazepine
-5-acetamide trans-8-chloro-N, 2-diphenyl-4-oxo
-3- [5-oxo-2 (S) -pyrrolidinecarboxa
[Mido] -2,3,4,5-tetrahydro-1,5-benzothiazepi
5-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -8-chloro-N, 2-diphenyl-4-oxo
-2,3,4,5-Tetrahydro-1,5-benzothiazepine-5
-Acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -8-chloro-N, 2-diphenyl-4-o
Xo-2,3,4,5-tetrahydro-1,5-benzothiazepine
-5-acetamide cis-8-chloro-N, 2-diphenyl-3- (2-yne
Dolecarboxamide) -4-oxo-2,3,4,5-teto
Lahydro-1,5-benzothiazepine-5-acetamide trans-8-chloro-N, 2-diphenyl-3- (2-
Indolecarboxamide) -4-oxo-2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-acetoa
Midcis-3- [5-oxo-2 (S) -pyrrolidinecarbo
Xamide] -4-phenyl-1- (1-pyrrolidinyl cas
Rubonylmethyl) -1,3,4,5-tetrahydro-1-ben
Zazepine-2 (2H) -one trans-3- [5-oxo-2 (S) -pyrrolidinecarbo
Ruboxamide] -4-phenyl-1- (1-pyrrolidini
Lucarbonylmethyl) -1,3,4,5-tetrahydro-1-
Benzazepine-2 (2H) -one cis-3- [5-oxo-2 (S) -pyrrolidinecarbo
Xamide] -4-phenyl-1-piperidinocarbonyl
Methyl] -1,3,4,5-tetrahydro-1-benzazepi
N-2 (2H) -one trans-3- [5-oxo-2 (S) -pyrrolidinecarcinone
Ruboxamide] -4-phenyl-1-piperidinocarbo
Nylmethyl] -1,3,4,5-tetrahydro-1-benza
Zepin-2 (2H) -one cis-N, N-dimethyl-2-oxo-3- [5-oxo
-2 (S) -Pyrrolidinecarboxamide] -4-phenyl
Ru-2,3,4,5-tetrahydro-1H-1-benzazepine
-1-acetamide trans-N, N-dimethyl-2-oxo-3- [5-o
Xo-2 (S) -pyrrolidinecarboxamide] -4-fu
Phenyl-2,3,4,5-tetrahydro-1H-benzazepine
-1-acetamide cis-N, N-diethyl-2-oxo-3- [5-oxo
-2 (S) -Pyrrolidinecarboxamide] -4-phenyl
Ru-2,3,4,5-tetrahydro-1H-1-benzazepine
-1-acetamide trans-N, N-diethyl-2-oxo-3- [5-o
Xo-2 (S) -pyrrolidinecarboxamide] -4-fu
Phenyl-2,3,4,5-tetrahydro-1H-1-benzase
Pin-1-acetamide cis-N-methyl-2-oxo-3- [5-oxo-2
(S) -Pyrrolidinecarboxamide] -4-phenyl-
2,3,4,5-Tetrahydro-1H-1-benzazepine-1
-Acetamide trans-N-methyl-2-oxo-3- [5-oxo
-2 (S) -Pyrrolidinecarboxamide] -4-phenyl
Ru-2,3,4,5-tetrahydro-1H-1-benzazepine
-1-acetamide cis-N-benzyl-2-oxo-3- [5-oxo-
2 (S) -Pyrrolidinecarboxamide] -4-phenyl
-2,3,4,5-Tetrahydro-1H-1-benzazepine-
1-acetamide trans-N-benzyl-2-oxo-3- [5-oxy
So-2 (S) -pyrrolidinecarboxamide] -4-fe
Nyl-2,3,4,5-tetrahydro-1H-1-benzazepi
1-acetamide cis-2-oxo-3- [5-oxo-2 (S) -pyro
Lysinecarboxamide] -N- (2-phenylethyl)
-4-phenyl-2,3,4,5-tetrahydro-1H-1-be
Indazepine-1-acetamide trans-2-oxo-3- [5-oxo-2 (S)-
Pyrrolidinecarboxamide] -N- (2-phenylethyl
) -4-Phenyl-2,3,4,5-tetrahydro-1H-1
-Benzazepine-1-acetamide cis-N, 4-diphenyl-2-oxo-3- [5-oxy
So-2 (S) -pyrrolidinecarboxamide] -2,3,4,5
-Tetrahydro-1H-1-benzazepine-1-aceto
Amido trans-N, 4-diphenyl-2-oxo-3- [5-
Oxo-2 (S) -pyrrolidinecarboxamide] -2,3,
4,5-Tetrahydro-1H-1-benzazepine-1-a
Cetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -4-phenyl-1- (1-pyrrolidinylcar
Bonylmethyl) -1,3,4,5-tetrahydro-1-benz
Azepine-2 (2H) -one trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -4-phenyl-1- (1-pyrrolidinyl
Carbonylmethyl) -1,3,4,5-tetrahydro-1-be
Indazepine-2 (2H) -one cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -4-phenyl-1-piperidinocarbonyl
Cyl) -1,3,4,5-tetrahydro-1-benzazepine
-2 (2H) -one trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -4-phenyl-1-piperidinocarboni
Lumethyl) -1,3,4,5-tetrahydro-1-benzaze
Pin-2 (2H) -one cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -N, N-dimethyl-2-oxo-4-phenyl
-2,3,4,5-Tetrahydro-1H-1-benzazepine-
1-acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -N, N-dimethyl-2-oxo-4-phen
Nyl-2,3,4,5-tetrahydro-1H-1-benzazepi
1-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -N, N-diethyl-2-oxo-4-phenyl
-2,3,4,5-Tetrahydro-1H-1-benzazepine-
1-acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -N, N-diethyl-2-oxo-4-phen
Nyl-2,3,4,5-tetrahydro-1H-1-benzazepi
1-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -N-methyl-2-oxo-4-phenyl-2,
3,4,5-Tetrahydro-1H-1-benzazepine-1-
Acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -N-methyl-2-oxo-4-phenyl
-2,3,4,5-Tetrahydro-1H-1-benzazepine-
1-acetamide cis-N-benzyl-3- [γ-butyrolactone-γ
(S) -Carboxamide] -2-oxo-4-phenyl
-2,3,4,5-Tetrahydro-1H-1-benzazepine-
1-acetamide trans-N-benzyl-3- [γ-butyrolactone-
γ (S) -carboxamido] -2-oxo-4-phenyl
Ru-2,3,4,5-tetrahydro-1H-1-benzazepine
-1-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -2-oxo-N- (2-phenylethyl)-
4-phenyl-2,3,4,5-tetrahydro-1H-1-ben
Duazepine-1-acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -2-oxo-N- (2-phenylethyl
) -4-Phenyl-2,3,4,5-tetrahydro-1H-1
-Benzazepine-1-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -N, 4-diphenyl-2-oxo-2,3,4,5-te
Trahydro-1H-1-benzazepine-1-acetamy
Trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -N, 4-diphenyl-2-oxo-2,3,4,5
-Tetrahydro-1H-1-benzazepine-1-aceto
Amido cis-3- (2-indolecarboxamide) -2-o
Xoxo-N- (2-phenylethyl) -4-phenyl-2,
3,4,5-Tetrahydro-1H-1-benzazepine-1-
Acetamide trans-3- (2-indolecarboxamide) -2
-Oxo-N- (2-phenylethyl) -4-phenyl
-2,3,4,5-Tetrahydro-1H-1-benzazepine-
1-acetamide trans-3- (2-indolecarboxamide) -2
-Oxo-4-phenyl-2,3,4,5-tetrahydro-1H
-1,5-benzodiazepine-1-acetamide cis-3- (2-indolecarboxamide) -2-o
Xo-4-phenyl-2,3,4,5-tetrahydro-1H-1,5
-Benzodiazepine-1-acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -2-oxo-4-phenyl-2,3,4,5-
Tetrahydro-1H-1,5-benzodiazepine-1-ace
Toamido cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -2-oxo-4-phenyl-2,3,4,5-teto
Lahydro-1H-1,5-benzodiazepine-1-acetoa
Mido trans-2-oxo-3- [5-oxo-2 (S)-
Pyrrolidinecarboxamide] -4-phenyl-2,3,4,5
-Tetrahydro-1H-1,5-benzodiazepine-1-a
Cetamide cis-2-oxo-3- [5-oxo-2 (S) -pyro
Lysinecarboxamide] -4-phenyl-2,3,4,5-te
Trahydro-1H-1,5-benzodiazepine-1-aceto
Amide trans-3- (2-indolecarboxamide) -5
-Methyl-2-oxo-4-phenyl-2,3,4,5-teto
Lahydro-1H-1,5-benzodiazepine-1-acetoa
Mid cis-3- (2-indolecarboxamide) -5-me
Tyl-2-oxo-4-phenyl-2,3,4,5-tetrahi
Doro-1H-1,5-benzodiazepine-1-acetamide trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -5-methyl-2-oxo-4-phenyl
-2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine
-1-acetamide cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -5-methyl-2-oxo-4-phenyl-2,
3,4,5-Tetrahydro-1H-1,5-benzodiazepine-1
-Acetamide trans-5-methyl-2-oxo-3- [5-oxo
-2 (S) -Pyrrolidinecarboxamide] -4-phenyl
Ru-2,3,4,5-tetrahydro-1H-1,5-benzodiazepi
1-acetamide cis-5-methyl-2-oxo-3- [5-oxo-2
(S) -Pyrrolidinecarboxamide] -4-phenyl-
2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine-
1-acetamide trans-3- (2-indolecarboxamide) -4
-Phenyl-1- (2-phenylethylaminocarbonyl
Lumethyl) -1,3,4,5-tetrahydro-1,5-benzodia
Zepin-2 (2H) -one cis-3- (2-indolecarboxamide) -4-ph
Phenyl-1- (2-phenylethylaminocarbonylmethone
Cyl) -1,3,4,5-tetrahydro-1,5-benzodiazepi
N-2 (2H) -one trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -4-phenyl-1- (2-phenylethyl
Luminocarbonylmethyl) -1,3,4,5-tetrahydro
-1,5-benzodiazepine-2 (2H) -one cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -4-phenyl-1- (2-phenylethyla
Minocarbonylmethyl) -1,3,4,5-tetrahydro-1,5
-Benzodiazepine-2 (2H) -one trans-3- [5-oxo-2 (S) -pyrrolidinecarcinone
Ruboxamide] -4-phenyl-1- (2-phenylene
Cylaminocarbonylmethyl) -1,3,4,5-tetrahydr
Ro-1,5-benzodiazepine-2 (2H) -one cis-3- [5-oxo-2 (S) -pyrrolidinecarbo
Xamide] -4-phenyl-1- (2-phenylethyl
Aminocarbonylmethyl) -1,3,4,5-tetrahydro-
1,5-benzodiazepine-2 (2H) -one trans-3- (2-indolecarboxamide] -5
-Methyl-4-phenyl-1- (2-phenylethyla
Minocarbonylmethyl) -1,3,4,5-tetrahydro-1,5
-Benzodiazepine-2 (2H) -one cis-3- (2-indolecarboxamide] -5-me
Cyl-4-phenyl-1- (2-phenylethylamino
Carbonylmethyl) -1,3,4,5-tetrahydro-1,5-be
Nazodiazepine-2 (2H) -one trans-3- [γ-butyrolactone-γ (S) -cal
Voxamide] -5-methyl-4-phenyl-1- (2-
Phenylethylaminocarbonylmethyl) -1,3,4,5-
Tetrahydro-1,5-benzodiazepine-2 (2H) -o
Cis-3- [γ-butyrolactone-γ (S) -carboxy
Samido] -5-methyl-4-phenyl-1- (2-phen
Nylethylaminocarbonylmethyl) -1,3,4,5-teto
Lahydro-1,5-benzodiazepine-2 (2H) -one trans-5-methyl-3- [5-oxo-2 (S)-
Pyrrolidinecarboxamide] -4-phenyl-1- (2
-Phenylethylaminocarbonylmethyl) -1,3,4,5
-Tetrahydro-1,5-benzodiazepine-2 (2H)-
On cis-5-methyl-3- [5-oxo-2 (S) -pyro
Lysinecarboxamide] -4-phenyl-1- (2-phenyl
Phenylethylaminocarbonylmethyl) -1,3,4,5-thene
Trahydro-1,5-benzodiazepin-2 (2H) -one 2-benzyl-3- [γ-butyrolaton-γ (S) -carb
Ruboxamide] -4-oxo-2,3,4,5-tetrahydro
-1,5-benzothiazepine-5-acetamide 3- (γ-butyrolactone-γ (S) -carboxami
] -N, N-Dimethyl-4-oxo-2-phenyl-2,
3,4,5-Tetrahydro-1,5-benzothiazepine-5-a
Cetamide N, N-dimethyl-3- (2-indolecarboxamido
De) -4-oxo-2-phenyl-2,3,4,5-tetrahi
Dro-1,5-benzothiazepine-5-acetamide 3- [γ-butyrolactone-γ (S) -carboxami
] -2-Isopropyl-4-Ocido-2,3,4,5-teto
Lahydro-1,5-benzothiazepine-5-acetamide 2-isopropyl-4-oxo-3- [5-oxo-2
(S) -Pyrrolidinecarboxamide] -2,3,4,5-teto
Lahydro-1,5-benzothiazepine-5-acetamide 2-isopropyl-4-oxo-3- [2 (S) -pyro
Lysinecarboxamide] -2,3,4,5-tetrahydro-1,5
-Benzothiazepine-5-acetamide 3- [γ-butyrolactone-γ (S) -carboxami
De] -4-oxo-2- (3-pyridyl) -2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-acetoa
Mido 3- (2-indolecarboxamide) -4-oxo-
2- (3-pyridyl) -2,3,4,5-tetrahydro-1,5-
Benzothiazepine-5-acetamide 3- (1-methyl-4,5-dihydroorotyl) amino-
4-oxo-2-phenyl-2,3,4,5-tetrahydro-
1,5-benzothiazepine-5-acetamide 3- (1-methyl-4,5-dihydroorotyl) amino-
4-oxo-2- (2-thienyl) -2,3,4,5-tetra
Hydro-1,5-benzothiazepine-5-acetamide 3- [γ-butyrolactone-γ (S) -carboxami
]]-8-Chloro-4-oxo-2-phenyl-2,3,4,
5-tetrahydro-1,5-benzothiazepine-5-aceto
Amide 3- [γ-butyrolactone-γ (S) -carboxami
]]-8-Methyl-4-oxo-2-phenyl-2,3,4,
5-tetrahydro-1,5-benzothiazepine-5-aceto
Amide 3- [γ-butyrolactone-γ (S) -carboxami
De] -8-methoxy-4-oxo-2-phenyl-2,3,
4,5-tetrahydro-1,5-benzothiazepine-5-acetate
Toamido 2- (5-bromo-2-thienyl) -3- [γ-butyro
Lactone-γ (S) -carboxamide] -4-oxo-
2,3,4,5-Tetrahydro-1,5-benzothiazepine-5-
Acetamide 3- [γ-butyrolactone-γ (S) -carboxami
De] -2- (5-methyl-2-thienyl) -4-oxo
-2,3,4,5-Tetrahydro-1,5-benzothiazepine-5
-Acetamide 3- [γ-butyrolactone-γ (S) -carboxami
De] -2- (3-methyl-2-thienyl) -4-oxo
-2,3,4,5-Tetrahydro-1,5-benzothiazepine-5
-Acetamide 2- (5-bromo-2-thienyl) -3- (2-indo)
Carboxamide) -4-oxo-2,3,4,5-tetra
Hydro-1,5-benzothiazepine-5-acetamide 3- [γ-butyrolactone-γ (S) -carboxami
De] -2- (4-imidazolyl) -4-oxo-2,3,4,
5-tetrahydro-1,5-benzothiazepine-5-aceto
Amido 2- (4-imidazolyl) -4-oxo-3- [5-o
Xo-2 (S) -pyrrolidinecarboxamide] -2,3,4,
5-tetridro-1,5-benzothiazepine-5-aceto
Amido 2- (4-imidazolyl) -3- (2-indolecal
Voxamide) -4-oxo-2,3,4,5-tetrahydro-
1,5-benzothiazepine-5-acetamide 2- (2-aminothiazol-4-yl) -3- [γ-
Butyrolactone-γ (S) -carboxamide] -4-o
Xo-2,3,4,5-tetrahydro-1,5-benzothiazepine
-5-acetamide 2- (2-aminothiazol-4-yl) -4-oxo
-3- [5-oxo-2 (S) -pyrrolidinecarboxa
[Mido] -2,3,4,5-tetrahydro-1,5-benzothiazepi
5-Acetamido 2- (2-aminothiazol-4-yl) -3- (2-
Indolecarboxamide) -4-oxo-2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-acetoa
Mido 3- [γ-butyrolactone-γ (S) -carboxami
De] -4-oxo-2-phenyl-2,3,4,5-tetrahi
Dro-1,5-benzoxepin-5-acetamide 3- (2-indolecarboxamide) -4-oxo-
2-phenyl-2,3,4,5-tetrahydro-1,5-benzo
Xepine-5-acetamide 3- [γ-butyrolactone-γ (S) -carboxami
De] -2-oxo-4-phenyl-2,3,4,5-tetrahi
Doro-1H-1,5-benzodiazepine-1-acetamide 3- (2-indolecarboxamide) -2-oxo-
4-phenyl-2,3,4,5-tetrahydro-1H-1,5-ben
Zodiazepine-1-acetamide 3- [γ-butyrolactone-γ (S) -carboxami
De] -2-oxo-4-phenyl-2,3,4,5-tetrahi
Doro-1H-1-benzazepine-1-acetamide 3- (2-indolecarboxamide) -2-oxo-
4-phenyl-2,3,4,5-tetrahydro-1H-1-ben
Zazepine-1-acetamide 3- [γ-butyrolactone-γ (S) -carboxami
De] -2,5-dioxo-4-phenyl-2,3,4,5-tetra
Hydro-1H-1-benzazepine-1-acetamide 3- (2-indolecarboxamide) -2,5-dioki
So-4-phenyl-2,3,4,5-tetrahydro-1H-1-
Benzazepine-1-acetamide When the compound of the present invention is used as the above-mentioned drug,
Alternatively, if appropriate, a pharmacologically acceptable carrier, excipient, rare
Mix with powders, powders, granules, tablets, capsules,
Administered orally or parenterally in the form of injections
You can Dosage depends on target disease, symptoms, or use
Depending on the compound, if given orally, it will last 1 day for an adult.
It is about 1 to 500 mg.

[Action]

Various experimental amnestic models have been used as one of the methods for evaluating the improving effect on consciousness disorder, memory disorder or dementia caused by brain dysfunction or organic disorder. Volume 3, page 127 (1983),
Volume 5, page 1 (1985), Japanese Journal of Pharmacol. (Jap.J.Pharmacol.)
39, 153 (1985), Psychopharmacology, 78, 104 (1982)
Year) etc.].

The benzolactam compound of the present invention shows an improving effect on the experimental amnesia induced by the convulsive shock, prolongs the survival time under hypoxia, has a strong effect even by oral administration, and has low toxicity. It is useful as a therapeutic agent for improving reduced brain function because of its excellent duration of effect.

〔Example〕

Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto. In addition,
In the examples, CDCl ₃ means deuterated chloroform, DMSO means dimethylsulfoxide, DMSO-d ₆ means deuterated dimethylsulfoxide, and KBr means potassium bromide.

Example 1 (i) 30.6 g of o-aminobenzenethiol and N-
66 g of benzyloxycarbonyl-α-dehydro-β-phenylalanine is dissolved in 140 ml of ethanol, and the mixture is stirred and refluxed for 24 hours. After completion of the reaction, the mixture was cooled at room temperature, and the precipitated crystals were filtered to give N-benzyloxycarbonyl-S- (2
57 g of -aminophenyl) -β-phenylcysteine are obtained.

(Ii) N-benzyloxycarbonyl-S- (2-aminophenyl) -β-phenylcysteine (155 g) is mixed with 3.6 l of xylene, and the mixture is stirred and refluxed for 4.5 hours while removing water. After cooling to room temperature, the precipitated crystals were collected by filtration and had a melting point of 235.
52.5 g of trans-3-benzyloxycarboxamido-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one at .about.237 DEG C. are obtained.

On the other hand, the filtrate was concentrated under reduced pressure to about 1, the precipitated crystals were collected by filtration, then separated and purified by silica gel column chromatography (eluent; chloroform: methanol = 20: 1), and recrystallized from isopropyl alcohol. 3 g of cis-3-benzyloxycarboxamido-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one with a melting point of 186 ° -189 ° C. are obtained.

(Iii) 30% bromide in a mixture of trans-3-benzyloxycarboxamido-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one 69.5 g, anisole 180 ml and acetic acid 40 ml. Add 300 ml of hydrogen-acetic acid and stir at room temperature for 1.5 hours. After completion of the reaction, a mixed solvent of ether 1 and 0.5 l of isopropyl ether is added, and the precipitated crystals are collected by filtration. After washing the crystals with ether,
A 10% aqueous solution of sodium carbonate 1 and chloroform (3 l) are added to the mixture to extract the precipitated organic matter. The chloroform layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure.
Phenyl-2,3-dihydro-1,5-benzothiazepine-4
41.5 g of (5H) -one are obtained. Hydrobromide melting point: 27
2-293 ° C (decomposition) NMR spectrum of hydrobromide salt [DMSO-d ₆ , tetramethylsilane (TMS) internal standard (ppm)]: δ = 4.27 (d, 1H, J =
12Hz), 4.78 (d, 1H, J = 12Hz), 7.1 to 7.8 (9H), 10.73
(S, 1H) (iv) trans-3-amino-2-phenyl-2,3-
Dihydro-1,5-benzothiazepin-4 (5H) -one 54.
8 g is dissolved in 700 ml of dimethylformamide, and 8.8 g of 60% sodium hydride is added to this solution under ice cooling. Gradually raise the reaction temperature to room temperature and stir for 1.5 hours. The reaction solution was cooled to about 10 ° C again, and bromoacetic acid ethyl ester 25.5 ml was added.
100 ml of a dimethylformamide solution containing is added dropwise. The reaction temperature is returned to room temperature, stirred for 5 hours, and concentrated under reduced pressure. Ice water and chloroform are poured into the residue, and the organic matter is extracted. After washing the chloroform layer with water and drying, the solvent is distilled off under reduced pressure, and a mixed solution of isopropyl ether and isopropyl alcohol is added to the residue for crystallization. The crystals were collected by filtration to give trans-3-amino-4-oxo-2.
37 g of -phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester are obtained. NMR spectrum (CDCl ₃ ; ppm): δ = 1.31 (t, 3H), 1.58 (brs,
2H), 3.7 ~ 4.4 (5H), 4.93 (d, 1H, J = 17Hz), 6.9 ~ 7.7
(9H) (v) 20 g of trans-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester was dissolved in 600 ml of methanol, Blow ammonia gas under ice cooling until saturated. The reaction temperature is slowly returned to room temperature, and the reaction solution is concentrated under reduced pressure after standing overnight. Isopyropyr alcohol was added to the obtained residue to crystallize, which was collected by filtration to give trans-3-amino-4-oxo-2-phenyl-2,3,4,5.
18 g of tetrahydro-1,5-benzothiazepine-5-acetamide are obtained. Melting point 217-219 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 1.68 (brs, 2H), 3.8
3 (d, 1H, J = 10Hz), 4.19 (d, 1H, J = 10Hz), 4.4 (d, 1H, J
= 16 Hz), 4.74 (d, 1H, J = 16 Hz), 6.8 to 7.8 (9H) (vi) γ-butyrolactone-γ (S) -carboxylic acid succinimide ester obtained by applying a known method 3.
2 g and trans-3-amino-obtained in (v) above
4-oxo-2-phenyl-2,3,4,5-tetrahydro-
3.2 g of 1,5-benzothiazepine-5-acetamide are mixed with 100 ml of dichloromethane and stirred at room temperature for 8.5 hours, and the reaction mixture gradually dissolves. After allowing the reaction solution to stand overnight, 5% aqueous sodium hydrogen carbonate solution was added and the mixture was stirred for a while to precipitate crystals. The crude crystals collected by filtration were recrystallized from methanol to give trans-3 (S)-[γ-butyrolactone-γ (S) -carboxamide] -4-oxo-
1.1 g of 2 (R) -phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide (A isomer) are obtained. On the other hand, chloroform is added to the filtrate and the separated organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. Isopropyl alcohol was added to the residue, and the precipitated crystals were recrystallized from ethanol to give trans-3 (R).
-[Γ-butyrolactone-γ (S) -carboxamide]
1.7 g of -4-oxo-2 (S) -phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide (B isomer) are obtained.

A isomer: melting point 264 to 267 ° C. ¹³ C NMR spectrum (DMSO-d ₆ ; TMS internal standard, ppm); δ =
25.6,26.2,51.6,52.7,54.4,75.6,124.2,124.9,127.5,12
6.8,128.0,131.3,135.6,141,145.7,168.5,169.2,176.5 [α] _D = + 565 ° (c = 0.5%, DMSO) B isomer: melting point 248-250 ° C ¹³ C NMR spectrum (DMSO-d ₆ ; ppm) : Δ = 25.2, 26.4, 51.
7,53.0,53.8,76.1,124.2,124.9,126.8,127.5,128.0,13
1.3,135.7,141.1,145.6,168.7,169,3,176.3 [α] _D = −502 ° (c = 0.5%, DMSO) Example 2 (i) Similar to Example 1 (iii), (I
A mixture of 4.7 g of cis-3-benzyloxycarboxamido-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one obtained in i), 2.5 ml of acetic acid and 1.3 ml of anisole. 20 ml of 30% hydrogen bromide-acetic acid is added to and stirred at room temperature for 1 hour. After the reaction is completed, 150 ml of isopropyl ether is added and decantation is performed, and the oily residue is crystallized with ether. The crystals collected by filtration were further washed with isopropyl ether and dried under reduced pressure to give cis-3-
3.5 g of amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one hydrobromide are obtained. Melting point 253-258 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.25 (d, 1H, J = 7H
z), 5.29 (d, 1H, J = 7 Hz), 7.1 to 7.9 (9H) (ii) In the same manner as in (iv) of Example 1, cis-3-amino-2-phenyl-2,3-dihydro- 3 g of 1,5-benzothiazepin-4 (5H) -one hydrobromide is mixed with 40 ml of dimethylformamide, and 0.72 g of 60% sodium hydride is added to this mixture under ice cooling. Gradually raise the temperature to room temperature and stir for 2 hours. The reaction solution is cooled again to about 10 ° C., and 5 ml of a dimethylformamide solution containing 1.1 ml of ethyl bromoacetate is added dropwise. The reaction temperature is returned to room temperature, stirred for 6 hours, and concentrated under reduced pressure. Ice water and chloroform are poured into the residue, and the organic matter is extracted. Wash the chloroform layer with water,
After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give cis-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5- Benzothiazepine-5-acetic acid ethyl ester
3.0 g are obtained as an oil.

NMR spectrum (CDCl ₃ ; ppm): δ = 1.31 (t, 3H), 1.58
(Brs, 2H), 3.8-5.1 (6H), 7.1-7.8 (9H) (iii) cis-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5- Benzothiazepine-
When 3.0 g of 5-acetic acid ethyl ester was used and the same reaction procedure as in (v) of Example 1 was carried out, cis-3-amino-
4-oxo-2-phenyl-2,3,4,5-tetrahydro-
1.8 g of 1,5-benzothiazepine-5-acetamide are obtained. Melting point 196-200 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 1.44 (brs, 2H), 3.8
7 (d, 1H, J = 8Hz), 4.44 (d, 1H, J = 16Hz), 4.84 (d, 1H, J
= 16Hz), 4.89 (d, 1H, J = 8Hz), 6.9 to 8.0 (10H), 6.05
(Brs, 1H) (iv) Similarly to (vi) of Example 1, 1.3 g of γ-butyrolactone-γ (S) -carboxylic acid succinimide ester
And cis-3-amino-4-oxo-2-phenyl-
2,3,4,5-Tetrahydro-1,5-benzothiazepine-5-
1.13 g of acetamide is mixed with 30 ml of dichloromethane and stirred at room temperature for 25 hours. A 5% aqueous sodium hydrogen carbonate solution is added to the reaction solution, and after stirring for a while, chloroform is added to separate the organic layer. The organic layer was washed with water, dried, and concentrated under reduced pressure. The obtained residue was recrystallized from isopropyl alcohol to give cis-3- [γ-butyrolactone-γ (S)-
Carboxamide] -4-oxo-2-phenyl-2,3,4,
0.9 g of 5-tetrahydro-1,5-benzothiazepine-5-acetamido 1/2 isopropyl alcohol solvate is obtained. Melting point 143-146 ° C. [α] _D = + 20 ° (c = 0.1%, DMSO) Example 3 Trans-3-amino-4 obtained in (v) of Example 1
-Oxo-2-phenyl-2,3,4,5-tetrahydro-1,5
-Benzothiazepine-5-acetamide 3.27 g and L
-Pyroglutamic acid 1.29 g dimethylformamide 70 ml
Dicyclohexylcarbodiimide 2.06
Add g and stir at room temperature for 8 hours. The precipitated crystals are filtered off and the filtrate is concentrated under reduced pressure. Chloroform is added to the concentrated residue, and this organic layer is washed with dilute hydrochloric acid and then with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and isopropyl alcohol was added to the resulting residue to precipitate crystals. The crude crystals collected by filtration were recrystallized from methanol to give trans-4-oxo-3- [5-oxo-2 (S) -pyrrolidinecarboxamide] -2-phenyl-2,3,4,5-
0.9 g of the B isomer of tetrahydro-1,5-benzothiazepine-5-acetamide is obtained as the monohydrate. on the other hand,
The recrystallization mother liquor of methanol is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography. The eluate was concentrated under reduced pressure, and the solid residue was recrystallized from isopropyl alcohol to give trans-4-oxo-3- [5-
Oxo-2 (S) -pyrrolidinecarboxamide] -2-
0.38 g of the A isomer of phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide is obtained as 1/2 isopropyl alcohol solvate. A isomer (as 1/2 isopropyl alcohol solvate): melting point 189-199 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 3.5-4.2 (2H),
4.4-5.1 (3H), 6.9-7.7 (11H), 8.57 (d, 1H) [α] _D = + 520 ° (c = 0.1%, DMSO) B isomer (as monohydrate): melting point 199-204 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 1.1 to 2.2 (4H),
3.5 to 5.1 (5H), 6.9 to 7.8 (11H), 8.43 (d, 1H) [α] _D = −507 ° (c = 0.1%, DMSO) Example 4 Transformer obtained in (v) of Example 1 -3-amino-4
-Oxo-2-phenyl-2,3,4,5-tetrahydro-1,5
-2.0 g of benzothiazepine-5-acetamide, 1.0 g of 2-indolecarboxylic acid and 1.87 g of 2-chloro-N-methylpyridinium iodide were mixed in 80 ml of dichloromethane, and 3.5 ml of tri-n-butylamine was stirred at room temperature.
Add. The reaction mixture is once dissolved and crystals are precipitated again. After stirring for 2 hours, the crystals are filtered off, and chloroform and water are added to the filtrate. The separated organic layer is washed with 10% aqueous hydrochloric acid, brine, aqueous potassium carbonate solution and brine in this order, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, isopropyl ether was added to the resulting residue, and the crystals were collected by filtration.
Trans-3- (2-indolecarboxamide) -4
-Oxo-2-phenyl-2,3,4,5-tetrahydro-1,5
0.95 g of benzothiazepine-5-acetamide are obtained. Melting point 222-225 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 3.9-5.2 (4H),
6.8 to 7.8 (16H), 8.86 (d, 1H) Example 5 1.65 g of 4,5-dihydroorotic acid prepared by a known method,
1.27 g of N-hydroxysuccinimide and 2.27 g of dicyclohexylcarbodiimide were added to 30 m of dimethylformamide.
Mix with l and stir overnight at room temperature. The precipitated crystals were filtered off, and the filtrate was filtered under ice-cooling to give trans-3-amino-4-oxo-2-phenyl-2,3, obtained in (v) of Example 1.
3.27 g of 4,5-tetrahydro-1,5-benzothiazepine-5-acetamide was added, and the mixture was stirred for 6.5 hours while gradually returning the reaction temperature to room temperature. After filtering off the precipitated insoluble matter,
The filtrate is concentrated under reduced pressure, and water is added to the residue to precipitate crystals. The crude crystals collected by filtration were recrystallized from a mixed solvent of dimethylformamide-methanol to give trans-3- (4,
4.1 g of 5-dihydroorotylamino) -4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide hemihydrate are obtained. Melting point 2
68-272 ° C (decomposition) [α] _D = + 45 ° (c = 1%, DMSO) Example 6 5-oxo-3-instead of 4,5-dihydroorotic acid
Carboxyperhydro-1,4-thiazine (1.7 g) was used to carry out the same reaction treatment operation as in Example 5, whereby trans-4-
Oxo-3- (5-oxoperhydro-1,4-thiazine-3-carboxamide) -2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide-1 water 1.5g of Japanese product is obtained. Melting point 259-262 ° C (decomposition) Example 7 trans-3-amino-4 obtained in (v) of Example 1
-Oxo-2-phenyl-2,3,4,5-tetrahydro-1,5
-Benzothiazepine-5-acetamide 2.29 g, nicotinic acid 0.86 g and dicyclohexylcarbodiimide 1.44 g
Is mixed with 30 ml of pyridine and stirred at room temperature for 22 hours.
The precipitated crystals are filtered off and the filtrate is concentrated under reduced pressure. The solid residue obtained was washed with isopropyl ether and recrystallized from ethanol to give trans-3-nicotinamide-4.
-Oxo-2-phenyl-2,3,4,5-tetrahydro-1,5
1.37 g of benzothiazepine-5-acetamide are obtained.

NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.12 (d, 1H, J = 16)
Hz), 4.66 (d, 1H, J = 16Hz), 4.80 (d, 1H, J = 12Hz), 5.0
5 (dd, 1H, J = 8Hz, 12Hz), 7.96 (m, 1H), 8.64 (m, 1H),
8.75 (m, 1H), 9.22 (d, 1H, J = 8Hz) Example 8 (i) A mixture of 17.7 g of N-trifluoroacetyl-α-dehydroleucine and 27 ml of acetic acid was heated to 155 ° C and o
-A mixture of 8.5 ml of aminobenzenethiol and 5 ml of acetic acid is slowly added dropwise with stirring. The reaction solution is heated and stirred for 2 hours, concentrated under reduced pressure, and isopropyl ether is added to the residue. The precipitated crystals are collected by filtration to obtain 10.5 g of 2-isopyrupyr-3-trifluoroacetamido-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one. Melting point 212-215 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 0.72 (d, 3H), 1.0
(D, 3H), 1.72-2.2 (m, 1H), 3.64 (dd, 1H), 4.39 (dd,
1H), 7.0-7.8 (4H) (ii) 2-isopropyl-3-trifluoroacetamido-2,3-dihydro-1,5-benzothiazepine-4 (5
Dissolve 10 g of H) -one in 200 ml of methanol and
Add 75 ml of normal aqueous sodium hydroxide solution. After 2.5 hours, the reaction solution is poured into ice water, and the precipitated organic matter is extracted with chloroform. The chloroform layer is washed with water and dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. Isopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to obtain 5.7 g of 3-amino-2-isopropyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one. Melting point 180-1
83 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 0.74 (d, 3H), 1.0
(D, 3H), 6.9 to 7.7 (4H) (iii) trans-3-amino-2-phenyl-2,3-
3-amino-2-isopropyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one 4 g was used instead of dihydro-1,5-benzothiazepin-4 (5H) -one. A crude oily substance is obtained by carrying out the reaction in the same manner as in (iv) of Example 1. This oil was purified by silica gel column chromatography (eluent; chloroform: methanol = 100: 1) to give 3-amino-2-isopropyl-4-oxo-2,3,4,5-tetrahydro-1,5. 5.7 g of benzothiazepine-5-acetic acid ethyl ester are obtained.

NMR spectrum (CDCl ₃ ; ppm): δ = 0.76 (d, 3H), 1.05
(D, 3H), 1.3 (t, 3H), 1.7 (brs, 2H), 2.36 to 2.68 (m, 1
H), 3.08 (dd, 1H), 3.45 (d, 1H, J = 11Hz), 4.0 (d, 1
H), 4.24 (q, 2H), 4.9 (d, 1H, J = 17Hz), 7.0 to 8.0 (4
H) (iv) 3-amino-2 instead of trans-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester −
Isopyropyr-4-oxo-2,3,4,5-tetrahydro-
1,5-benzothiazepine-5-acetic acid ethyl ester 5.7g
Is carried out in the same manner as in (v) of Example 1,
A crude oil is obtained as a concentrated residue. The oily substance is purified by silica gel column chromatography and the eluate is concentrated to give a solid residue. By washing this with isopropyl ether, 3-amino-2-isopropyl-4-ocio-2,3,4,5-tetrahydro-1,5
2.9 g of benzothiazepine-5-acetamide are obtained. Melting point 227-229 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 0.68 (d, 3H), 0.9
8 (d, 3H), 1.85 (brs, 2H), 3.88 (d, 1H, J = 17Hz), 4.63
(D, 1H, J = 17Hz), 7.0 to 7.7 (6H) (v) 3-amino-2-isopropyl-4-oxo-
2,3,4,5-Tetrahydro-1,5-benzothiazepine-5-
Dissolve 1 g of acetamide and 1 g of 2-indolecarboxylic acid succinimide ester in 35 ml of dimethylformamide, heat to 70 ° C. and stir. After 24 hours, the reaction solution is concentrated under reduced pressure, 50 ml of saturated sodium carbonate and 50 ml of ethyl acetate are added thereto, and the mixture is stirred for a while. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of dimethylformamide-methanol to give 2-isopropyl-3- (2-indolecarboxamido) -4-oxo-2,3,4,5-tetrahydro-1. 0.92 g of 5,5-benzothiazepine-5-acetamide is obtained. Decomposition temperature 300 ℃ or higher NMR spectrum (DMSO-d ₆ ; ppm): δ = 0.73 (d, 3H), 1.0
2 (d, 3H), 1.9 to 2.3 (m, 1H), 3.48 to 3.76 (1H), 4.01
(D, 1H, J = 17Hz), 4.4 to 4.9 (2H), 6.9 to 8.0 (11H), 8.
87 (d, 1H), 11.5 (1H) Example 9 (i) A mixture of 3.4 g of O-methyl-N-2-naphthol-α-dehydrotyrosine methyl ester and 7 ml of acetic acid was added.
Heat to 55 ° C. and slowly add 4 ml of o-aminobenzenethiol to this mixture with stirring. After heating and stirring for 5 hours, the reaction solution is concentrated under reduced pressure, and a mixed solvent of isopropyl ether and ethyl acetate is added to the residue. The precipitated crystals were collected by filtration to give 2-p-methoxyphenyl-3-
(2-Naphthalenecarboxamide) -2,3-dihydro-
1.5 g of 1,5-benzothiazepin-4 (5H) -one are obtained. Melting point 277 to 280 ° C (decomposition) NMR spectrum (DMSO-d ₆ ; ppm): δ = 3.65 (s, 3H), 4.7
~ 5.1 (2H), 6.7 ~ 8.3 (15H), 9.03 (d, 1H), 10.28 (S,
1H) (ii) In the same manner as in (iv) of Example 1, 2-p-methoxyphenyl-3- (2-naphthalenecarboxamide)
-2,3-Dihydro-1,5-benzothiazepine-4 (5H)-
1.5 g of on is dissolved in 30 ml of dimethylformamide, and 0.145 g of 60% sodium hydride is added under ice cooling. After stirring at room temperature for 30 minutes, 5 ml of a dimethylformamide solution containing 0.45 ml of ethyl bromoacetate is added dropwise. After stirring at room temperature for 3 hours, the reaction solution is concentrated under reduced pressure, chloroform and water are added to the residue, and the organic layer is separated. After washing the chloroform layer with water and drying, the solvent was distilled off under reduced pressure, and a mixed solvent of isopropyl alcohol-isopropyl ether was added. The precipitated crystals were collected by filtration to give 2-p-methoxyphenyl-
3- (2-naphthalenecarboxamide) -4-oxo-
2,3,4,5-Tetrahydro-1,5-benzothiazepine-5-
1.8 g of ethyl acetate are obtained. Melting point 183-186 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 1.16 (t, 3H), 3.6
4 (s, 3H), 4.08 (q, 2H), 4.3 to 5.2 (4H), 6.77 (d, 2
H), 7.09 (d, 2H), 7.2 ~ 8.0 (10H), 8.24 (1H), 9.02
(D, 1H) (iii) 2-p-methoxyphenyl-3- (2-naphthalenecarboxamide) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-ethyl acetate 1.8 g of ester is dissolved in 500 ml of methanol, and ammonia gas is blown thereinto for about 1 hour under ice cooling. After standing at room temperature for 3 days,
The reaction solution is concentrated under reduced pressure to about 50 ml to precipitate crystals. The crystals were collected by filtration to give 2-p-methoxyphenyl-3-
(2-naphthalenecarboxamide) -4-oxo-2,3,
1.2 g of 4,5-tetrahydro-1,5-benzothiazepine-5-acetamide are obtained. Melting point 243-245 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 3.64 (s, 3H), 4.0
8 (d, 1H, J = 17Hz), 4.5 to 5.2 (3H), 6.76 (d, 2H), 7.09
(D, 2H), 7.2-8.0 (12H), 8.24 (1H), 9.06 (d, 1H) Example 10 (i) 3 (R) -amino-4-oxo-obtained by applying a known method 32 g of 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester was added to methanol 3
Dissolve in 00 ml and blow ammonia gas under ice cooling until saturated. The reaction temperature was slowly returned to room temperature and left overnight, and the precipitated crystals were collected by filtration to give 3 (R) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-. 28 g of acetamide are obtained. Melting point 223
~ 225 ° C (decomposition) NMR spectrum (DMSO-d ₆ ; ppm): δ = 1.86 (brs, 2H),
3.90 (d, 1H, J = 18Hz), 4.62 (d, 1H, J = 18Hz), 7.1 to 7.7
(6H) (ii) γ-butyrolactone-γ (S) -carboxylic acid succinimide ester 2.6 g and 3 (R) -amino-4
2.3 g of -oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide are mixed with 50 ml of dichloromethane and stirred at room temperature for 4 hours. After leaving the reaction solution overnight,
A 5% aqueous sodium hydrogen carbonate solution is added, and after stirring for a while, chloroform is added to separate the organic layer. The organic layer is washed with water, dried, concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give 3 (R)-
[Γ-butyrolactone-γ (S) -carboxamide]-
1.5 g of amorphous powder of 4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide are obtained.

[Α] _D = −214.3 ° (c = 1.0%, chloroform) NMR spectrum (CDCl ₃ ; ppm): δ = 3.0 (t, 1H), 7.1-
7.8 (4H) Example 11 (i) A mixture of 19 g of N-benzyloxycarbonyl-β- (2-thienyl) -α-dehydroalanine and 30 ml of acetic acid was heated to 150 ° C. to give o-aminobenzenethiol 2
Slowly add 0 ml. The reaction solution is stirred at the same temperature for 5 hours, concentrated under reduced pressure, and a mixed solvent of isopropyl ether and ethyl acetate is added to the residue. The precipitated crystals are collected by filtration to obtain 8.5 g of trans-3-benzyloxycarboxamido-2- (2-thienyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one. Melting point
230-231 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.20 (dd, 1H, J = 1
2Hz, 9Hz), 4.88 (s, 2H), 4.90 (d, 1H, J = 12Hz), 6.7〜
7.7 (12H), 7.92 (d, 1H, J = 9Hz) On the other hand, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give cis-3.
-Benzyloxycarboxamide-2- (2-thienyl) -2,3-dihydro-1,5-benzothiazepine-4 (5
H) -one 1.2 g is obtained. Melting point 201-202 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.50 (dd, 1H, J = 8)
Hz, 7Hz), 4.97 (s, 2H), 5.49 (d, 1H, J = 7Hz), 6.8 to 7.8
(12H) (ii) trans-3-benzyloxycarboxamido-2- (2-thienyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one 14.2 g, anisole 3.7 g and acetic acid To a mixture of 60 ml, 100 ml of 30% hydrobromic acid-acetic acid was added, and the mixture was stirred at room temperature for 1.5 hours. A mixed solvent of 200 ml of ether and 600 ml of isopropyl ether was added, and the precipitated crystals were collected by filtration to give trans-3-amino-2- (2-thienyl) -2,3-dihydro-1,5-benzothiazepine-4.
12.2 g of (5H) -on hydrobromide are obtained. Free base melting point 188-189 ° C Free base NMR spectrum (DMSO-d ₆ ; ppm): δ = 1.80
(S, 2H), 4.57 (d, 1H, J = 10Hz), 6.7 to 7.6 (7H) (iii) trans-3-amino-2- (2-thienyl) -2,3-dihydro-1,5- Benzothiazepine-4 (5
H) -one ・ hydrobromide (12.2 g) in dimethylformamide
Mix to 100 ml and add 2.7 g of 60% sodium hydride to the mixture under ice cooling. Gradually raise the temperature to room temperature and stir for 2 hours. The reaction solution is cooled to about 10 ° C. again, and 5.7 g of ethyl bromoacetate is added dropwise. The reaction temperature is returned to room temperature, stirred overnight, and concentrated under reduced pressure. Ice water and ethyl acetate are poured into the residue, and the organic matter is extracted. The ethyl acetate layer was washed with water and dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give trans-
3-amino-4-oxo-2- (2-thienyl) -2,3,
8.0 g of 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester are obtained as an oil.

NMR spectrum (CDCl ₃ ; ppm): δ = 1.30 (t, 3H), 1.72
(S, 2H), 3.68 (d, 1H, J = 10Hz), 3.9 to 4.5 (4H), 4.88
(D, 1H, J = 18Hz), 6.7 to 7.8 (7H) (iv) trans-3-amino-4oxo-2- (2-
Thienyl) -2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester 8 g was added to methanol 300 ml.
And boil ammonia gas under ice cooling until saturated. The reaction temperature is slowly returned to room temperature, and the reaction solution is concentrated under reduced pressure after standing overnight. Isopropyl alcohol was added to the obtained residue for crystallization, and the crystals were collected by filtration.
7 g of trans-3-amino-4-oxo-2- (2-thienyl) -2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide are obtained. Melting point 207 to 210 ° C. (decomposition) NMR spectrum (DMSO-d ₆ ; ppm): δ = 1.82 (brs, 2H),
3.91 (d, 1H, J = 18Hz), 4.58 (d, 1H, J = 10Hz), 4.67 (d,
1H, J = 18Hz), 6.7 to 7.7 (9H) (v) trans-3-amino-4-oxo-2- (2
-Thienyl) -2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide 4 g and γ-butyrolactone-γ (S) -carboxylic acid succinimide ester 3.3 g
Is dissolved in 50 ml of dimethylformamide and left for 2 days at room temperature. The reaction solution is concentrated under reduced pressure, 50 ml of saturated sodium hydrogen carbonate and 50 ml of ethyl acetate are added thereto, and the mixture is stirred for a while. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of chloroform-methanol to give trans-3- [γ
-Butyrolactone-γ (S) -carboxamide] -4-
2.1 g of the A isomer of oxo-2- (2-thienyl) -2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide are obtained. On the other hand, the ethyl acetate layer of the filtrate is washed with water and dried, the solvent is distilled off under reduced pressure, isopropyl alcohol is added to the residue for crystallization, and the residue is filtered. When recrystallized from ethanol, trans-3- [γ-butyrolactone-γ (S) -carboxamide] -4-oxo-2-
1.5 g of the B isomer of (2-thienyl) -2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide are obtained.

A isomer: melting point 258 to 163 ° C. (decomposition) [α] _D = + 573.7 ° (c = 0.2%, DMSO) NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.07 (d, 1H, J = 17
Hz), 4.4 to 5.1 (4H), 6.7 to 7.8 (9H), 8.93 (d, 1H) B isomer: [α] _D = -497.4 ° (c = 0.2%, DMSO) NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.05 (d, 1H, J = 17
Hz), 4.3 to 4.9 (3H), 5.08 (d, 1H, J = 11Hz), 6.7 to 7.8
(9H), 8.81 (d, 1H) Example 12 Trans-3-amino-4 obtained in Example 11 (iv)
-Oxo-2- (2-thienyl) -2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide 1.6 g
And 1.3 g of 2-indolecarboxylic acid succinimide ester were dissolved in 50 ml of dimethylformamide, and the mixture was stirred at 70 ° C for 8 hours.
Stir for hours. The reaction mixture is concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (50 ml) and ethyl acetate (50 ml) are added to the residue, and the mixture is stirred for a while. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of dimethylformamide-methanol to give trans-3- (2-indolecarboxamide) -4-oxo-2- (2-thienyl) -2,3,4,5. 1.9 g of tetrahydro-1,5-benzothiazepine-5-acetamide are obtained. Decomposition temperature 270 ℃ or higher NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.08 (d, 1H, J = 17)
Hz), 4.4 to 5.3 (3H), 6.6 to 7.7 (14H), 9.0 (d, 1H) Example 13 (i) N-benzyloxycarbonyl-β- (p-chlorophenyl) -α-dehydroalanine ethyl ester
To a mixture of 10 g and 20 ml of acetic acid, 15 ml of o-aminobenzenethiol is added, and the mixture is stirred at 150 ° C for 24 hours. The reaction solution is concentrated under reduced pressure, and a mixed solvent of isopropyl ether and ethyl acetate is added to the residue. When the precipitated crystals are collected by filtration, 2-
(P-Chlorophenyl) -3-benzyloxycarboxamide-2,3-dihydro-1,5-benzothiazepine-4
3 g of (5H) -one are obtained. Melting point 260-263 ° C (decomposition) NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.1-4.7 (2H),
4.84 (s, 2H), 6.9-8.0 (14H) (ii) 2- (p-chlorophenyl) -3-benzyloxycarboxamido-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one To a mixture of 3.5 g, anisole 860 mg and acetic acid 50 ml was added 30% hydrobromic acid-acetic acid 70 ml,
Stir at room temperature for 3 hours. 300 ml of isopropyl ether was added, and the precipitated crystals were collected by filtration to give 3-amino-2- (p
3 g of -chlorophenyl) -2,3-dihydro-1.5-benzothiazepin-4 (5H) -one hydrobromide are obtained.
Melting point 201-203 ° C. (decomposition) NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.28 (d, 1H, J = 11)
Hz), 4.78 (d, 1H, J = 11Hz), 7.0 to 7.7 (8H) (iii) 3-amino-2- (p-chlorophenyl)-
2,3-Dihydro-1,5-benzothiazepine-4 (5H) -one ・ hydrobromide 3 g was mixed with dimethylformamide 50 ml, and this mixture was cooled with ice to give 60% sodium hydride 630 mg.
Add. Gradually raise the temperature to room temperature and stir for 3 hours. The reaction solution was cooled to about 10 ° C again, and bromoacetic acid ethyl ester was added.
Add 1.3 g dropwise. The reaction temperature is returned to room temperature, stirred overnight, and concentrated under reduced pressure. Ice water and chloroform are poured into the residue, and the organic matter is extracted. After washing the chloroform layer with water and drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 3-amino-2-
1.5 g of (p-chlorophenyl) -4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester are obtained.

NMR spectrum (DMSO-d ₆ ; ppm): δ = 1.20 (t, 3H), 1.8
0 (brs, 2H), 3.4 to 4.9 (6H), 6.9 to 7.7 (8H) (iv) 3-amino-2- (p-chlorophenyl) -4
-Oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester 1.5 g methanol 200 ml
And boil ammonia gas under ice cooling until saturated. The reaction temperature is slowly returned to room temperature, left overnight, and the reaction solution is concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the precipitated crystals were collected by filtration to give 3-amino-2- (p-chlorophenyl) -4-oxo-2,3,4,5.
0.9 g of tetrahydro-1,5-benzothiazepine-5-acetamide are obtained. Melting point 217-220 ° C (decomposition) NMR spectrum (DMSO-d ₆ ; ppm): δ = 1.72 (brs, 2H),
3.60 (d, 1H, J = 11Hz), 3.94 (d, 1H, J = 16Hz), 4.30 (d,
1H, J = 11Hz), 4.70 (d, 1H, J = 16Hz), 6.9 to 7.7 (10H) (v) 3-amino-2- (p-chlorophenyl) -4
0.9 g of -oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide and 1.2 g of 2-indolecarboxylic acid succinimide ester were dissolved in 30 ml of dimethylformamide and the mixture was mixed at 65 ° C with 13 Stir for hours. The reaction mixture is concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate are added to the residue, and the mixture is stirred for a while. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of chloroform-methanol to give 2- (p-chlorophenyl) -3- (2-indolecarboxamido) -4-oxo-2,3,4,5-tetrahydro- 1,5-benzothiazepine-5-acetamide 0.8
g is obtained. Melting point 275-290 ° C (decomposition) NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.11 (d, 1H, J = 17)
Hz), 4.4 to 5.2 (3H), 6.8 to 7.8 (15H), 8.95 (d, 1H) Example 14 (i) trans-3-amino-2-phenyl-2,3-
Dihydro-1,5-benzothiazepin-4 (5H) -one 13.
Dissolve 9g in 250ml dimethylformamide and add 6g to this solution.
2.3 g of 0% sodium hydride are added. After stirring at room temperature for 20 minutes, 80 ml of a dimethylformamide solution containing 10 g of tert-butyl bromoacetate is added dropwise. After stirring at room temperature for 3 hours, the mixture is concentrated under reduced pressure. Water is poured into the residue, and the organic matter is extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried, and the solvent was evaporated under reduced pressure to give trans-3-amino-4-oxo-
White crystals of 2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 1
8.6 g are obtained. Melting point 172-174 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 1.50 (s, 9H), 1.60
(Brs, 2H), 3.83 (d, 1H, J = 11Hz), 4.10 (d, 1H, J = 17H
z), 4.15 (d, 1H, J = 11Hz), 4.85 (d, 1H, J = 17Hz), 7.0
To 7.8 (m, 9H) (ii) trans-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tertiary butyl ester 18 g and 12 g of 2-indolecarboxylic acid succinimide ester synthesized by a known method were dissolved in 300 ml of dimethylformamide.
Stir for 33.5 hours at ℃. The reaction solution is poured into ice water and crystals are precipitated by stirring. The crystals were collected by filtration, washed with water and dried to give trans-3- (2-indolecarboxamide).
22 g of -4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester are obtained. Melting point 196-200 ° C (decomposition) NMR spectrum (DMSO-d ₆ ; ppm): δ = 1.34 (s, 9H), 4.5
0 (d, 2H), 4.76 (d, 1H, J = 12Hz), 5.06 (dd, 1H, J = 8Hz,
12Hz), 6.78 ~ 7.78 (14H), 8.86 (d, 1H, J = 8Hz), 11.24
(Brs, 1H) (iii) trans-3- (2-indolecarboxamido) -4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid third 21 g of 30% hydrobromic acid-acetic acid solution is added dropwise while stirring 5 g of butyl butyl ester, 15 ml of acetic acid and 2 ml of anisole at room temperature. After stirring at room temperature for 9 hours, the precipitated crystals were collected by filtration and washed with ethyl acetate to give trans-3- (2-indolecarboxamido) -4-oxo-2-phenyl-2,3,4,5- 3.5 g of tetrahydro-1,5-benzothiazepine-5-acetic acid are obtained. Melting point 260-270 ° C (decomposition) NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.30 (d, 1H, J = 17)
Hz), 4.71 (d, 1H, J = 17Hz), 4.76 (d, 1H, J = 12Hz), 5.1
0 (dd, 1H, J = 10Hz, 12Hz), 6.7 to 7.8 (14H), 8.86 (d, 1
H, J = 10 Hz), 11.24 (brs, 1H), 12.18 (brs, 1H) (iv) trans-3- (2-indolecarboxamido) -4-oxo-2-phenyl-2,3,4,5- Tetrahydro-1,5-benzothiazepine-5-acetic acid 2 g, dichloromethane 20 ml, 2-phenylethylamine 0.2 g and tri-
While stirring 2 g of n-butylamine at room temperature, 1.2 g of 2-chloro-N-methylpyridinium iodide was added, and the mixture was stirred at room temperature for 18 hours. Chloroform was added to the reaction solution, which was washed with 5% aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then dried, and the solvent was distilled off under reduced pressure. The residue is separated and purified by silica gel column chromatography (eluent: chloroform) and recrystallized from ethanol to give trans-
3- (2-indolecarboxamide) -4-oxo-
2-phenyl-N- (2-phenylethyl) -2,3,4,5
0.7 g of tetrahydro-1,5-benzothiazepine-5-acetamide hemihydrate are obtained. Melting point 157-163 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 2.82 (t, 2H, J = 6H
z), 3.59 (m, 2H), 4.41 (d, 1H, J = 12Hz), 4.59 (2H),
5.11 (dd, 1H, J = 8Hz, 12Hz), 6.55 (d, 1H, J = 2Hz), 6.8
~ 7.9 (20H), 8.75 (brs, 1H) Example 15 trans-3- (2-indolecarboxamido) -4-oxo-2-phenyl-2,3,4, obtained in (iii) of Example 14 5-tetrahydro-1,5-benzothiazepine-5
-Acetic acid 0.2 g, dichloroform 2 ml, methylamine hydrochloride 4
5 mg and 0.32 g of tri-n-butylamine under stirring at room temperature 2
0.13 g of -chloro-N-methylpyridinium iodide is added, and the mixture is stirred at room temperature for 23 hours. The solvent was distilled off under reduced pressure, the residue was washed several times with isopropyl ether, and ethyl acetate was added. It was washed with 5% aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give trans-3- (2-
60 mg of indolecarboxamide) -N-methyl-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide are obtained. Melting point 19
5 ° C (decomposition) NMR spectrum (CDCl ₃ ; ppm): δ = 2.82 (d, 3H, J = 6H
z), 4.37 (d, 1H, J = 16Hz), 4.59 (d, 1H, J = 12Hz), 4.9
(D, 1H, J = 16Hz), 5.15 (dd, 1H, J = 8Hz, 12Hz), 6.51
(D, 1H, J = 3Hz), 6.8 to 7.8 (15H), 8.56 (brs, 1H) Example 16 Trans-3- (2-indolecarboxamido) -4-oxo obtained in (iii) of Example 14 -2-Phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5
0.5 g of acetic acid, 10 ml of dimethylformamide, 0.11 g of pyrrolidine and 0.5 g of tri-n-butylamine were stirred at room temperature to give 2-chloro-N-methylpyridinium iodide.
Add 5 g and stir at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure, chloroform was added, the mixture was washed with 5% aqueous hydrochloric acid, saturated sodium hydrogencarbonate and saturated saline, dried, and then the solvent was distilled off under reduced pressure, and recrystallized from a mixed solvent of chloroform-methanol. -3- (2-Indolecarboxamido) -2-phenyl-5- (1-pyrrolidinylcarbonylmethyl) -2,3-dihydro-1,5-benzothiazepine-
0.15 g of 4 (5H) -one is obtained. Melting point 282-284 ° C (decomposition) NMR spectrum (CDCl ₃ ; ppm): δ = 1.5-2.1 (4H), 3.2
~ 3.7 (4H), 4.10 (d, 1H, J = 16Hz), 4.50 (d, 1H, J = 10H
z), 5.00 (d, 1H, J = 16Hz), 5.38 (dd, 1H, J = 8Hz, 10H
z), 6.62 (d, 1H, J = 2Hz), 6.8 to 7.8 (14H), 8.80 (brs,
1H) Example 17 trans-3- (2-indolecarboxamido) -4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoti obtained in (iii) of Example 14 Azepine-5
0.5 g of acetic acid and 20 ml of dimethylformamide, 0.14 g of morpholine and 0.5 g of tri-n-butylamine under stirring at room temperature under stirring with 2-chloro-N-methylpyridinium iodide.
Add 45 g and stir at 45 ° C. for 6 hours. After the solvent was distilled off under reduced pressure, chloroform was added and the mixture was washed with 5% aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of chloroform-methanol to give trans-3- (2-indolecarboxamide) -2-phenyl-5- (morpholinocarbonylmethyl) -2,3-dihydro-1. 0.26 g of 5,5-benzothiazepine-4 (5H) -one monohydrate is obtained. Melting point 274-277 ° C (decomposition) NMR spectrum (CDCl ₃ -CD ₃ OD; ppm): δ = 4.37 (d, 1H, J
= 16Hz), 4,51 (d, 1H, J = 12Hz), 4.97 (d, 1H, J = 16H)
z), 5.29 (dd, 1H, J = 9Hz, 12Hz), 6.8 ~ 7.9 (15H), 8.94
(Brs, 1H) Example 18 (i) 3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-obtained by a known method
11 g of 1-acetic acid ethyl ester is dissolved in 300 ml of methanol, and ammonia gas is blown therein under ice cooling. The reaction solution is left in the refrigerator for 3 days, concentrated under reduced pressure, and isopropyl ether is added to the residue. When the precipitated crystals are filtered, 3-
Amino-2-oxo-2,3,4,5-tetrahydro-1H-1
4.2 g of benzazepine-1-acetamide are obtained.
Melting point 198-200 ° C (decomposition) IRmax (KBr, cm ^-1 ): 3370,3310,3175,1705,1665 (ii) 3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1 -Benzazepine-1-acetamide 2.0 g
And γ-butrolactone-γ (S) -carboxylic acid succinimide ester (2.5 g) are mixed in 70 ml of dichloromethane and stirred at room temperature for 6 hours, the reaction mixture gradually dissolving. After the reaction was completed, 100 ml of saturated aqueous sodium hydrogen carbonate solution
And stir for a while. After filtering the precipitated crystals, the organic layer of the filtrate is separated from the aqueous layer. The organic layer is washed with water and dried, the solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography. Concentrate the eluate under reduced pressure,
Isopropyl ether is added to the obtained residue, and the precipitated crystals are collected by filtration. When recrystallized from the above-obtained crystal together with a mixed solvent of chloroform-isopropyl ether, 3- [γ-butyrolactone-γ (S) -carboxamide] -2-oxo-2,3,4,5-tetrahydro was obtained. -1H-
1-benzazepine-1-acetamide hemihydrate 0.2
5 g are obtained. Melting point 165 to 182 ° C IRmax (KBr, cm ^-1 ): 3400,3330,1790,1660 [α] _D = + 32 ° (c = 0.5%, DMSO) Example 19 cis obtained in Example 2 (iii) -3-amino-4-
Oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-
Using benzothiazepine-5-acetamide (3.27 g) and L-pyroglutamic acid (1.29 g), the same reaction and treatment operations as in Example 3 were carried out to obtain a diastereomer-mixed reaction product. This mixture was separated and purified by silica gel column chromatography (developing solvent: chloroform / methanol = 30: 1) to give cis-4-oxo-3 (R)-[5-oxo-2 (S) as white crystalline powder. -Pyrrolidinecarboxamide] -2 (R) -phenyl-2,3,
400 mg of 4,5-tetrahydro-1,5-benzothiazepine-5-acetamide (B isomer) and cis-4-oxo-3 (S)-[5-oxo-2 (S)-as white crystalline powder.
Pyrrolidinecarboxamide] -2- (S) -phenyl-
2,3,4,5-Tetrahydro-1,5-benzothiazepine-5-
190 mg of acetamide (A isomer) are obtained.

A isomer: NMR spectrum (DMSO-d ₆ ; ppm): δ = 1.43 (m, 1H), 1.8
5 to 2.1 (m, 3H), 4.05 to 4.10 (2H), 4.73 to 4.78 (2H),
5.09 (m, 1H, J = 7.3Hz), 7.27 (1H), 7.36 to 7.42 (6H),
7.56 ~ 7.63 (4H), 7.68 (d, 1H), 7,75 (d, 1H) [α] _D = + 140 ° (c = 0.1%, DMSO) B isomer: melting point 250 ~ 253 ° C (decomposition) ( Recrystallized from ethanol) NMR spectrum (DMSO-d ₆ ; ppm): δ = 1.62 to 1.76 (m, 2
H), 1.86 ~ 1.94 (m, 1H), 2.09 ~ 2.2 (m, 1H), 3.93 (1
H), 4.11 (d, 1H, J = 16.6Hz), 4.72 to 4.79 (2H), 5.11
(D, 1H, J = 7.3Hz), 7.19 (d, 1H, J = 7.3Hz), 7.29 (1
H), 7.37 (6H), 7.61 (2H), 7.65 (1H), 7.76 (d, 1H, J
= 7.3 Hz), 7.94 (s, 1H) [α] _D = -157 ° (c = 0.1%, DMSO) Example 20 Trans-3-amino-4 obtained in Example 1 (v)
-Oxo-2-phenyl-2,3,4,5-tetrahydro-1,5
-Benzothiazepine-5-acetamide 1.64 g and triethylamine 1.4 ml are dissolved in chloroform 30 ml and benzoyl chloride 0.6 ml is added with stirring at room temperature. After stirring for 6 hours, an aqueous sodium hydrogen carbonate solution is added, and the precipitated crystals are collected by filtration. The crystals were recrystallized from methanol to give trans-3-benzamide-4 having a melting point of 246-248 ° C.
-Oxo-2-phenyl-2,3,4,5-tetrahydro-1,5
1.25 g of benzothiazepine-5-acetamide are obtained as a white crystalline powder.

NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.09 (d, 1H, J = 17)
Hz), 4.66 (d, 1H, J = 17Hz), 4.7 to 5.2 (2H), 7.0 to 7.8
(16Hz), 8.92 (d, 1H, J = 8Hz) Example 21 Trans-3-amino-4 obtained in (v) of Example 1
-Oxo-2-phenyl-2,3,4,5-tetrahydro-1,5
When 1.64 g of -benzothiazepine-5-acetamide and 0.67 ml of p-chlorobenzoyl chloride were used and the same reaction and treatment operations as in Example 20 were carried out, the melting point was 272 to 275.
1.6 g of trans-3-p-chlorobenzamide-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide at ℃ are obtained as white crystalline powder. .

NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.08 (d, 1H, J = 17)
Hz), 4.65 (d, 1H, J = 17Hz), 4.7 to 5.2 (2H), 7.0 to 7.7
(16 Hz), 9.03 (d, 1H, J = 8 Hz) Example 22 (i) A mixture of 35 g of ethyl 2-benzyloxycarbonylamino-4-phenyl-2-butenate and 50 ml of acetic acid was heated to 150 ° C., and this mixture was heated. To this is added 17 ml of o-aminobenzenethiol. After heating and stirring for 6 hours, the reaction solution was evaporated under reduced pressure, and isopropyl ether was added to the residue. The precipitated crystals are collected by filtration to obtain 10 g of 2-benzyl-3-benzyloxycarboxamido-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one. Melting point 2
15-216 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 5.00 (s, 2H), 6.9
-7.6 (m, 14H), 8.02 (d, 1H, J = 6Hz) (ii) In the same manner as in (iii) of Example 1, 2-benzyl-3-benzyloxycarboxamide-2,3-dihydro-1 was used. To a mixture of 1,5-benzothiazepin-4 (5H) -one 10.9 g, anisole 2.8 ml and acetic acid 14 ml, 30% under ice cooling.
Add 47 ml of hydrogen bromide-acetic acid and stir for 6 hours. After the reaction is completed, 150 ml of isopropyl ether is added and the crystals are collected by filtration. After further washing the crystals with isopropyl ether,
100 ml of 15% sodium carbonate solution and chloroform 100
Add to 0 ml of mixture and dissolve and extract solids. The chloroform layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 7.1 g of 3-amino-2-benzyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one. can get. Melting point 223-224 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 1.75 (brs, 1H), 2.5
~ 2.9 (1H), 3.1 ~ 3.3 (2H), 3.45 (d, 1H, J = 12Hz), 7.
0-7.7 (9H), 7.85 (brs, 1H) (iii) 3-amino-2-benzyl-2,3-dihydro-
7.1 g of 1,5-benzothiazepin-4 (5H) -one are suspended in 90 ml of dimethylformamide and 1.1 g of 60% sodium hydride is added to this mixture. A solution of 3.05 ml of ethyl bromoacetate and 10 ml of dimethylformamide is added dropwise to the obtained solution over 30 minutes under ice cooling. The reaction temperature is gradually returned to room temperature and after stirring for 7.5 hours, the reaction mixture is concentrated under reduced pressure. Water and chloroform are added to the residue and the organic matter is extracted. The chloroform layer is dried and the oily product obtained by evaporation under reduced pressure is dissolved in 300 ml of methanol, and ammonia gas is blown into the solution under ice cooling to a saturated state. Return the reaction temperature to room temperature,
After standing for two days and nights, the reaction solution is concentrated under reduced pressure. The precipitated white crystals were collected by filtration to give 3-amino-2-benzyl-
4.29 g of 4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide are obtained. Melting point 233 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 1.5 to 1.9 (2H), 2.6
5 (1H), 4.26 (d, 1H, J = 17Hz), 4.80 (d, 1H, J = 17Hz),
5.37 (brs, 1H), 7.05 (brs, 1H), 7.2 to 7.7 (9H) (iv) 1.77 g of 2-indolecarboxylic acid succinimide ester obtained by a known method and 3-obtained by (iii) above Amino-2-benzyl-4-oxo-2,3,4,
2.01 g of 5-tetrahydro-1,5-benzothiazepine-5-acetamide are dissolved in a mixture of 150 ml of dichloromethane and 30 ml of dimethylformamide and heated to 70 ° C. After stirring for 8 hours, isopropyl ether is added to the reaction solution. The crude product obtained by collecting the precipitated solid by filtration was recrystallized from a mixed solvent of dimethylformamide and isopropyl ether to give 2-benzyl-3- (2-indolecarboxamide) -4-oxo-2,3,4, 5-Tetrahydro-1,5-benzothiazepine-5-acetamide ・ 1/2
1.94 g of dimethylformamide adduct are obtained. Melting point 275
℃ NMR spectrum (CDCl ₃ ; ppm): δ = 2.65 (dd, 1H, J = 11H
z, 14Hz), 3.25 (dd, 1H, J = 2.5Hz, 14Hz), 3.83 (ddd, 1H,
J = 2.5Hz, 11Hz, 11Hz), 4.12 (d, 1H, J = 17Hz), 4.58 (d
d, 1H, J = 8Hz, 11Hz), 4.78 (d, 1H, J = 17Hz), 6.59 (brs,
1H), 9.01 (d, 1H, J = 8Hz), 10.77 (brs, 1H) Example 23 (i) 2-amino-5-chlorobenzenethiol 20.5
g and 28.2 g of N-benzyloxycarbonyl-α-dehydro-β-phenylalanine are dissolved in 100 ml of ethanol, and the mixture is refluxed with stirring for 48 hours. After completion of the reaction, the reaction solution is concentrated under reduced pressure, 200 ml of the resulting residual hexylene is added, and the mixture is refluxed with stirring for 6 hours while removing water. After completion of the reaction, the mixture was cooled at room temperature, and the precipitated crystals were filtered and washed with isopropyl alcohol to give 3-benzyloxycarboxamide-8-chloro-2-phenyl-2,3-
Dihydro-1,5-benzothiazepin-4 (5H) -one 20.
0g is obtained.

(Ii) 2-benzyloxycarboxamide-8-chloro-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one 20.0 g was added to dimethylformamide 200
Dissolve in ml and add 1.91 g of 60% sodium hydride to this solution. After stirring for 30 minutes at room temperature, the reaction mixture was ice-cooled and 50 ml of a dimethylformamide solution containing 7.6 g of ethyl bromoacetate.
Is dripped. The reaction solution is returned to room temperature and stirred for 5 hours,
Concentrate under reduced pressure. Pour ice water and chloroform into the residue,
Extract organics. After the chloroform layer was washed with water and dried, the solvent was distilled off under reduced pressure, and it was separated and purified by silica gel column chromatography (eluent: chloroform) to give cis-3.
-Benzyloxycarboxamide-8-chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester 11.0 g and trans-3-benzyloxycarboxamide -8-Chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester 3.3
g is obtained.

Cis NMR spectrum (CDCl ₃ ; ppm): δ = 1.29 (t, 3H), 4.25
(D, 1H), 4.26 (q, 2H), 4.73 (t, 1H), 4.79 (d, 1H), 4.
94 (d, 1H), 5.03 (d, 1H), 5.12 (d, 1H), 5.22 (d, 1H),
7.2-7.5 (m, 12H), 7.72 (d, 1H) trans isomer NMR spectrum (CDCl ₃ ; ppm): δ = 1.27 (t, 3H), 4.1
~ 4.3 (m, 4H), 4.7 ~ 4.9 (m, 4H), 5.57 (d, 1H), 7.1 ~
7.5 (m, 12H), 7.67 (d, 1H) (iii) cis-3-benzyloxycarboxamide-
A mixture of 8-chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester 11.0 g, anisole 2.3 g and acetic acid 11 ml gave a 30% odor. Add 38 ml of hydrogen chloride-acetic acid and stir at room temperature for 3.5 hours. After completion of the reaction, hexane and isopropyl ether are added, and the precipitated crystals are collected by filtration. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained crystals, and the mixture was stirred under ice cooling, the organic layer was separated, washed with water, dried and concentrated under reduced pressure to give cis-3-amino-8-chloro-4-oxo-. 6.9 g of 2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester are obtained.

NMR spectrum (CDCl ₃ ; ppm): δ = 1.34 (t, 3H), 1.58
(Brs, 2H), 3.86 (d, 1H), 4.16 (d, 1H), 4.27 (q, 2H),
4.89 (d, 1H), 4.90 (d, 1H), 7.24 (m, 7H), 7.71 (d, 1
H) (iv) cis-3-amino-8-chloro-4-oxo-
2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester 6.9 g was added to methanol 22
Dissolve in 0 ml, and blow ammonia gas under ice cooling until it becomes saturated. The reaction temperature is slowly returned to room temperature,
After standing overnight, the reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to give cis-3-amino-8-chloro-4-oxo-2.
6.2 g of phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide are obtained.

NMR spectrum (CDCl ₃ ; ppm): δ = 3.85 (d, 1H), 4.46
(D, 1H), 4.67 (d, 1H), 4.89 (d, 1H), 5.95 (brs, 1H),
6.98 (brs, 1H), 7.25 to 7.55 (m, 7H), 7.73 (d, 1H) (v) cis-3-amino-8-chloro-4-oxo-
2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide 5.7 g, γ-butyrolactone-γ (S) -carboxylic acid succinimide ester 4.1 g were mixed with dichloromethane 114 ml. Then, the reaction mixture gradually dissolves when stirred at room temperature for 6 hours. After completion of the reaction, 5% sodium hydrogen carbonate is added, and crystals are precipitated by stirring for a while under ice cooling. The crude crystals obtained by filtration were recrystallized from a mixed solvent of isopropyl alcohol and chloroform to give cis-3- [γ-butyrolactone-γ (S) -carboxamide] -8-chloro-4-oxo-2-phenyl- 2,3,4,5-tetrahydro-1,5-benzothiazepine-5
2.5 g of the B isomer of acetamide, 1/3 chloroform, 1/4 isopropyl alcohol solvate are obtained. On the other hand, chloroform is added to the filtrate, the separated organic layer is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether was added to the residue, and the precipitated crystals were recrystallized from isopropyl alcohol to give cis-3- [γ-butyrolactone-γ (S) -carboxamide] -8-chloro-4-oxo-2-phenyl-2,3 1.5 g of 1,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide A isomer 1/2 isopropyl alcohol solvate are obtained.

A isomer: melting point 125-127 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 2.14 (m, 1H), 2.38
~ 2.49 (m, 3H), 4.45 (d, 1H), 4.58 (t, 1H), 4.65 (d, 1
H), 4.83 (t, 1H), 5.20 (d, 1H), 5.74 (brs, 1H), 6.69
(D, 1H), 6.88 (brs, 1H), 7.32 ~ 7.53 (m, 7H), 7.79
(D, 1H) [α] _D = + 107.8 ° (c = 0.1%, DMSO) B isomer: melting point 198-200 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 1.90-2.01 (m, 2)
H), 2.24 ~ 2.43 (m, 2H), 4.50 (d, 1H), 4.60 ~ 4.64 (m,
2H), 4.83 (t, 1H), 5.23 (d, 1H), 5.66 (brs, 1H), 6.81
(Brs, 1H), 6.89 (d, 1H), 7.31 ~ 7.54 (m, 7H), 7.78
(D, 1H) [α] _D = −96.7 ° (c = 0.1%, DMSO) Example 24 (i) Similar to Example 23 (iii), Example 23 (i
trans-3-benzyloxycarboxamide-8-chloro-4-oxo-2-phenyl-2,3, obtained in i)
4,5-Tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester 3.3 g, anisole 0.68 g and acetic acid 3.3 ml
11.4 ml of 30% hydrogen bromide-acetic acid was added to the mixture of 2.
Stir for 5 hours. After completion of the reaction, hexane and isopropyl ether are added, and the precipitated crystals are collected by filtration. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained crystals, and the mixture was stirred under ice-cooling, the organic layer was separated, washed with water, dried and concentrated under reduced pressure to give trans-3-amino-8.
1.7 g of ethyl chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1.5-benzothiazepine-5-acetic acid are obtained. Melting point 173-175 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 1.32 (t, 3H), 1.59
(Brs, 2H), 3.85 (d, 1H), 4.06 to 4.37 (4H), 4.88 (d, 1
H), 7.04 to 7.62 (8H) (ii) In the same manner as in Example 23 (iv), trans-3-amino-8-chloro-4-oxo-2-phenyl-2,3,4,
1.7 g of 5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester was dissolved in 50 ml of methanol, and under ice cooling,
Blow in ammonia gas until saturated. The reaction temperature was slowly returned to room temperature and, after standing overnight, the reaction solution was concentrated under reduced pressure and the precipitated crystals were collected by filtration to give a melting point of 225 to 228.
C. trans-3-amino-8-chloro-4-oxo-
1.4 g of 2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide are obtained.

NMR spectrum (CDCl ₃ ; ppm): δ = 4.22 (d, 1H), 4.38
(D, 1H), 4.72 (d, 1H), 5.74 (brs, 1H), 6.95 (brs, 1
H), 7.04 to 7.68 (m, 8H) (iii) In the same manner as in (v) of Example 23, trans-3-
Amino-8-chloro-4-oxo-2-phenyl-2,3,
1.4 g of 4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, 0.97 g of γ-butyrolactone-γ (S) -carboxylic acid succinimide ester and 25 m of dichloromethane
The reaction mixture gradually dissolves when mixed with 1 and stirred at room temperature for 6 hours. After completion of the reaction, 5% sodium hydrogen carbonate is added, and crystals are precipitated by stirring for a while under ice cooling. The crude crystals obtained by filtration were recrystallized from a mixed solvent of isopropyl alcohol and chloroform to give trans-3-
[Γ-butyrolactone-γ (S) -carboxamide]-
0.3 g of the A isomer of 8-chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide is obtained. On the other hand, chloroform is added to the filtrate, the separated organic layer is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Isopropyl ether was added to the residue, and the precipitated crystals were recrystallized from isopropyl alcohol to give trans-3- [γ-butyrolactone-γ (S) -carboxamide] -8-chloro-4.
-Oxo-2-phenyl-2,3,4,5-tetrahydro-1,5
0.3 g of the B isomer of benzothiazepine-5-acetamide
Is obtained.

A isomer: melting point 270-276 ° C NMR spectrum (CDCl ₃ + CD ₃ OD; ppm): δ = 1.88 (m, 1
H), 2.23 to 2.49 (m, 3H), 4.27 (d, 1H), 4.55 to 4.64 (2
H), 4.68 (d, 1H), 5.01 (d, 1H), 7.07 to 7.58 (8H) [α] _D = + 370.1 ° (c = 0.1%, DMSO) B isomer: melting point 190-195 ° C NMR Spectrum (CDCl ₃ + CD ₃ OD; ppm): δ = 1.68 to 1.72
(M, 1H), 1.85 to 1.95 (m, 1H), 2.25 to 2.47 (2H), 4.34
(D, 1H), 4.58 ~ 4.62 (3H), 4.99 ~ 5.12 (1H), 7.10 ~
8.00 (8H) [α] _D = -119.0 ° (c = 0.1%, DMSO) Example 25 cis-3-amino-8-chloro-4-oxo-2-phenyl obtained in Example 23 (iv) -2,3,4,5-Tetrahydro-1,5-benzothiazepine-5-acetamide 2.1
g, L-pyroglutamic acid 0.75 g and dicyclohexylcarbodiimide 1.26 g were treated in the same manner as in Example 3 to give cis-8-chloro-4-oxo-3- [5-
Oxo-2 (S) -pyrrolidinecarboxamide] -2-
Phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide A isomer hemihydrate is 0.92
g, B isomer / 1/2 isopropyl alcohol / hemihydrate 0.43 g is obtained.

A isomer: melting point 165-176 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 1.66 (m, 2H), 2.17
(M, 2H), 3.88 (m, 1H), 4.41 (d, 1H), 4.65 (d, 1H), 4.
84 (t, 1H), 5.21 (d, 1H), 5.91 (brs, 1H), 5.97 (brs, 1
H), 6.43 (brs, 1H), 6.91 (brs, 1H), 7.3 ~ 7.5 (m, 7
H), 7.78 (d, 1H) [α] _D = + 116.4 ° (c = 0.1%, DMSO) B isomer: melting point 160-171 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 1.60 (m, 1H), 1.74
(M, 1H), 1.96 (m, 1H), 2.25 (m, 1H), 3.90 (dd, 1H),
4.48 (d, 1H), 4.71 (d, 1H), 4.86 (t, 1H), 5.28 (d, 1
H), 6.91 (d, 1H), 6.95 (brs, 1H), 7.14 (brs, 1H), 7.3
-7.5 (m, 7H), 7.78 (d, 1H) [α] _D = 123.9 ° (c = 0.1%, DMSO) Example 26 Trans-3-amino-8 obtained in Example 24 (ii)
-Chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide
When 1.7 g, L-pyroglutamic acid 0.6 g and dicyclohexylcarbodiimide were used and treated in the same manner as in Example 3, trans-8-chloro-4-oxo-3- [5-
Oxo-2 (S) -pyrrolidinecarboxamide] -2-
Phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide A isomer 1/2 isopropyl alcohol solvate 0.29g, B isomer hemihydrate 0.3g is obtained.

A isomer: melting point 176-190 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 1.35 (m, 1H), 2.04
(M, 3H), 3.91 (m, 1H), 4.19 (d, 1H), 4.60 (d, 1H), 4.
65 (d, 1H), 5.00 (dd, 1H), 6.70 (brs, 1H), 7.1 ~ 7.7
(M, 10H), 8.34 (brs, 1H) [α] _D = + 407.9 ° (c = 0.1%, DMSO) B isomer: melting point 183-205 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 1.08 (M, 1H), 2.06
(M, 2H), 2.37 (m, 1H), 3.82 (d, 1H), 3.95 (m, 1H), 4.
70 (d, 1H), 4.72 (d, 1H), 5.28 (dd, 1H), 6.09 (brs, 1
H), 6.85 (brs, 1H), 7.2 ~ 7.4 (m, 6H), 7.46 (d, 1H),
7.71 (d, 1H), 7.90 (d, 1H), 8.47 (d, 1H) [α] _D = −413.6 ° (c = 0.1%, DMSO) Example 27 The cis obtained in Example 23 (iv) -3-Amino-8-chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide 0.3 g
And 0.5 g of 2-indolecarboxylic acid succinimide ester were treated in the same manner as in (v) of Example 13, to give cis-8-chloro-3- (2-indolecarboxamido) -4-oxo-2-. Phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide
0.2g is obtained. Melting point 174-178 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 4.60 (m, 2H), 5.10
(T, 1H), 5.28 (d, 1H), 6.49 (1H), 7.1 to 7.6 (m, 15
H), 7.8 (1H) Example 28 Trans-3-amino-8 obtained in Example 24 (ii)
-Chloro-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide
When 0.3 g and 0.5 g of 2-indolecarboxylic acid succinimide ester were treated in the same manner as in (v) of Example 13, trans-8-chloro-3- (2-indolecarboxamido) -4-oxo- 2-phenyl-2,3,4,
0.17 g of 5-tetrahydro-1,5-benzothiazepine-5-acetamide is obtained. Melting point 274-278 ° C NMR spectrum (CDCl ₃ + CD ₃ OD; ppm): δ = 4.18 (d, 1
H), 4.70 (d, 1H), 4.84 (d, 1H), 5.15 (d, 1H), 6.9 to 7.
6 (m, 13H) Example 29 (i) 51.0 g of 2- [2- (2-nitrophenyl) -1-phenylethyl] propanedicarboxylic acid dimethyl ester obtained by a known method was dried with 1 ml of methanol. Dissolve in 550 ml of tetrahydrofuran, add 6.86 g of 60% sodium hydride with stirring and heat to 40 ° C. After the generation of hydrogen gas has subsided, O- (2,
28.4 g of 4-dinitrophenyl) hydroxylamine is added under water cooling and stirred for 2 hours. After adding 600 ml of chloroform to the red-yellow solid obtained by distilling off the solvent and stirring well,
The insoluble matter is filtered off. The filtrate was concentrated, isopropyl ether and hexane were added to the residue, and the precipitated solid was collected by filtration to give 2-amino-2- [2- (2-nitrophenyl).
36.7 g of dimethyl ester of -1-phenylethyl] propanedicarboxylic acid are obtained. Melting point 114 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 2.20 (brs, 2H), 3.5
2 (s, 3H), 3.80 (s, 3H), 6.9 to 7.4 (8H), 7.6 to 7.8 (1
H) (ii) 42.45 g of 2-amino-2- [2- (2-nitrophenyl) -1-phenylethyl] propanedicarboxylic acid dimethyl ester was dissolved in 1000 ml of acetic acid, and 70
Add 55.6g zinc at ~ 85 ° C. After stirring for a further 2 hours, 750 ml of acetic acid are added and the precipitate is filtered off. The filtrate is concentrated under reduced pressure, saturated aqueous potassium carbonate solution is added, and the organic matter is extracted with chloroform. After drying and concentrating the chloroform layer,
Isopropyl ether and hexane were added, the precipitated crystals were collected by filtration, and 3-amino-3-methoxycarbonyl-4-
22.1 g of phenyl-1,3,4,5-tetrahydro-1-benzazepin-2 (2H) -one are obtained. Melting point 201 ° C NMR spectrum (CDCl ₃ ; ppm): δ = 3.12 (dd, 1H, J = 3H
z, 16Hz), 3.37 (dd, 1H, J = 3Hz, J = 10Hz), 3.56 (s, 3
H), 4.00 (dd, 1H, J = 10Hz, 16Hz), 6.9 ~ 7.4 (9H), 8.10
(Brs, 1H) (iii) 3-amino-3-methoxycarbonyl-4-
Phenyl-1,3,4,5-tetrahydro-1-benzazepin-2 (2H) -one 17.98 g, lithium iodide trihydrate 2
A mixture of 1.76 g and 400 ml of dry pyridine is stirred under reflux for 2 days. To the residue obtained by concentrating the reaction solution under reduced pressure, an aqueous solution of potassium carbonate, an aqueous solution of sodium thiosulfate and chloroform are added to extract an organic substance. The residue obtained by drying and concentrating the chloroform layer is subjected to silica gel column chromatography (eluent; chloroform: methanol =
20: 1), cis-3-amino-4-phenyl-1,3,
4,5-Tetrahydro-1-benzazepine-2 (2H)-
On 5.6 g and trans-3-amino-4-phenyl-
1,3,4,5-tetrahydro-1-benzazepine-2 (2
H) -one 5.44 g is obtained.

Cis NMR spectrum (CDCl ₃ ; ppm): δ = 1.30 (brs, 2H), 2.7
~ 3.3 (2H), 3.5 to 3.9 (2H), 6.9 to 7.6 (9H), 8.20 (br
s, 2H) Trans NMR spectrum (CDCl ₃ ; ppm): δ = 2.1 (2H), 2.66 (d,
1H, J = 13Hz), 3.1 to 3.6 (2H), 3.76 (d, 1H, J = 11Hz),
6.8 to 7.5 (10H) (iv) cis-3-amino-4-phenyl-1,3,4,5-
Tetrahydro-1-benzazepin-2 (2H) -one 5.
Dissolve 55 g in 100 ml of dry dimethylformamide at room temperature
Add 0.97 g of 60% sodium hydride. After stirring for 30 minutes, a solution of 2.7 ml of ethyl bromoacetate and 10 ml of dimethylformamide is added dropwise over 30 minutes under ice cooling. The reaction temperature is gradually returned to room temperature, and after stirring for 15 hours, the reaction mixture is concentrated under reduced pressure, water and chloroform are added to the residue, and organic matter is extracted. The chloroform layer was dried and the oily product obtained by evaporation under reduced pressure was subjected to silica gel column chromatography (eluate;
Chloroform: methanol = 20: 1) and cis-3-
0.6 g of amino-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid ethyl ester are obtained.

NMR spectrum (CDCl ₃ ; ppm): δ = 1.28 (t, 3H, J = 7H
z), 1.47 (brs, 2H), 2.7 ~ 3.1 (1H), 3.4 ~ 3.9 (3H),
4.23 (q, 2H, J = 7Hz), 4.21 (d, 1H, J = 16Hz), 4.88 (d, 1
H, J = 16 Hz), 7.0 to 7.5 (9H) (v) cis-3-amino-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-
When 6.3 g of 1-acetic acid ethyl ester was dissolved in 250 ml of methanol and the same reaction operation as in (v) of Example 1 was carried out, cis-3-amino-2-oxo-4-phenyl-2,3,4,5 was obtained. −
5.5 g of tetrahydro-1H-1-benzazepine-1-acetamide are obtained.

NMR spectrum (CDCl ₃ ; ppm): δ = 1.48 (brs, 2H), 2.7
~ 3.8 (4H), 4.34 (d, 1H, J = 16Hz), 4.68 (d, 1H, J = 16H
z), 5.70 (br, 1H), 6.25 (br, 1H), 7.0 to 7.5 (9H) (vi) cis-3-amino-2-oxo-4-phenyl-2,3,4,5-tetrahydro- 1-benzazepine-5-
Acetamide (0.2 g) and 2-indolecarboxylic acid succinimide ester (0.18 g) were dissolved in dimethylformamide (5 ml), the same reaction procedure as in Example 12 was performed, and recrystallization from a mixed solvent of ethanol and isopropyl alcohol gave cis-3- ( 2-indolecarboxamide)-
2-oxo-4-phenyl-2,3,4,5-tetrahydro-1
0.18 g of H-1-benzazepine-1-acetamide (1/2 isopropyl alcohol adduct) is obtained. Melting point 204 ~
216 ° C NMR spectrum (DMSO-d ₆ ; ppm): δ = 2.19 (m, 1H), 4.3
6 (d, 1H, J = 17Hz), 4.66 (d, 1H, J = 17Hz), 6.55 (1H) Example 30 (i) Trans-3-obtained in Example 29 (iii)
Amino-4-phenyl-1,3,4,5-tetrahydro-1-
When benzazepin-2 (2H) -one (5.3 g) and bromoacetic acid ethyl ester were treated by the same reaction procedure as in Example 29 (iv), trans-3-amino-2-oxo-4-
0.55 g of phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid ethyl ester are obtained.

NMR spectrum (CDCl ₃ ; ppm): δ = 1.27 (t, 3H, J = 7H
z), 1.84 (brs, 2H), 2.58 (d, 1H, J = 14Hz), 3.25 (dd, 1)
H, J = 8Hz, 11Hz), 3.78 (d, 1H, J = 11Hz), 3.83 (dd, 1H, J
= 8Hz, 14Hz), 4.19 (q, 2H, J = 7Hz), 4.41 (d, 1H, J = 17H
z), 4.78 (d, 1H, J = 17Hz), 6.8 to 7.5 (9H) (ii) trans-3-amino-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1 When 4.8 g of -benzazepine-1-acetic acid ethyl ester was dissolved in 200 ml of methanol and the same reaction operation as in (v) of Example 1 was performed,
Trans-3-amino-2-oxo-4-phenyl-2,
3,4,5-Tetrahydro-1H-1-benzazepine-1-
2.63 g of acetamide are obtained.

NMR spectrum (CDCl ₃ ; ppm): δ = 1.63 (2H), 2.59
(D, 1H, J = 13Hz), 3.1 to 3.8 (2H), 3.80 (d, 1H, J = 11H
z), 4.23 (d, 1H, J = 15Hz), 4.71 (d, 1H, J = 15Hz), 5.7
(Br, 1H), 6.4 (br, 1H), 6.8 to 7.5 (9H) (iii) trans-3-amino-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1- When benzazepine-1-acetamide (0.2 g) and 2-indolecarboxylic acid succinimide ester (0.18 g) were dissolved in dimethylformamide (5 ml) and the same reaction procedure as in Example 12 was performed, trans-3- (2-indolecarboxamide) was obtained.
0.2 g of 2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide is obtained. Melting point 280-283 ° C (decomposition) NMR spectrum (DMSO-d ₆ ; ppm): δ = 4.28 (d, 1H, J = 17)
Hz), 4.67 (d, 1H, J = 17Hz), 8.63 (d, 1H, J = 8Hz) Example 31 cis-3-amino-2-oxo-4-phenyl obtained in (v) of Example 29 -2,3,4,5-tetrahydro-1H-1
When 2.42 g of -benzazepine-1-acetamide and 1.9 g of γ-butyrolactone-γ (S) -carboxylic acid succinimide ester were dissolved in 50 ml of dichloromethane and the same reaction procedure as in (vi) of Example 1 was carried out, cis -3- [γ-butyrolactone-γ (S) -carboxamide] -2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-
2.53 g of benzazepine-1-acetamide are obtained.

NMR spectrum (CDCl ₃ ; ppm): δ = 1.7 to 2.5 (4H), 2.9
(1H), 3.65 (1H), 4.0 (1H), 4.4 to 4.8 (4H), 7.2 to 7.
4 (9H) Example 32 Trans-3-amino-2 obtained in (ii) of Example 30
-Oxo-4-phenyl-2,3,4,5-tetrahydro-1H
-1-benzazepine-1-acetamide 1.70 g and γ-
When 1.33 g of butyrolactone-γ (S) -carboxylic acid succinimide ester was dissolved in 35 ml of dichloromethane and the same reaction procedure as in (vi) of Example 1 was carried out, trans-3-
[Γ-butyrolactone-γ (S) -carboxamide]-
2-oxo-4-phenyl-2,3,4,5-tetrahydro-1
1.65 g of H-1-benzazepine-1-acetamide are obtained.

NMR spectrum (CDCl ₃ -DMSO-d ₆ ; ppm): δ = 1.7 to 2.5
(4H), 2.7 (1H), 3.6 (1H), 3.8 (1H), 4.3 to 5.0 (4
H), 6.3 (1H), 6.9-7.9 (11H) Example 33 cis-3-amino-2-oxo-4-phenyl-2,3,4,5-tetrahydro obtained in (v) of Example 29 -1H-1
-Benzazepine-1-acetamide 2.53 g and L-
Pyroglutamic acid (1.06 g) was dissolved in dimethylformamide (50 ml) and treated by the same reaction procedure as in Example 3 to give cis-2-oxo-3- [5-oxo-2].
(S) -Pyrrolidinecarboxamide] -4-phenyl-
2,3,4,5-Tetrahydro-1H-1-benzazepine-1
2.41 g of acetamide are obtained.

NMR spectrum (CDCl ₃ ; ppm): δ = 1.5 to 2.3 (4H), 2.9
(1H), 3.5 (1H), 3.8 to 4.0 (2H), 4.3 to 4.7 (3H), 5.8
-6.8 (4H), 7.1-7.5 (9H) Example 34 Trans-3-amino-2 obtained in (ii) of Example 30
-Oxo-4-phenyl-2,3,4,5-tetrahydro-1H
-1-benzazepine-1-acetamide (1.00 g) and L-pyroglutamic acid (0.42 g) were added to dimethylformamide (20 m).
It was dissolved in l and treated by the same reaction procedure as in Example 3 to give trans-2-oxo-3- [5-oxo-2 (S) -pyrrolidinecarboxamido] -4-phenyl-2,3,4. 0.41 g of A isomer and B isomer of 5,5-tetrahydro-1H-1-benzazepine-1-acetamide
0.42 g is obtained.

A isomer NMR spectrum (CDCl ₃ ; ppm): δ = 1.9 to 2.2 (4H), 2.6
6 (d, 1H, J = 14Hz), 3.6 (2H), 3.96 (1H), 4.19 (d, 1H,
J = 17Hz), 4.69 (d, 1H, J = 17Hz), 4.88 (1H), 6.5 (br,
1H), 6.9 to 7.4 (11H), 7.9 (br, 1H) [α] _D = + 217.6 ° (c = 0.1%, DMSO) B isomer NMR spectrum (CDCl ₃ ; ppm): δ = 1.45 (1H ), 2.1 to 2.
3 (3H), 2.75 (d, 1H, J = 14Hz), 3.52 (dd, 1H, J = 9Hz, 14
Hz), 3.67 (dd, 1H, J = 9Hz, 12Hz), 3.98 (1H), 4.04 (d,
1H, J = 17Hz), 4.70 (d, 1H, J = 17Hz), 5.12 (dd, 1H, J = 9
Hz, 12Hz), 6.1 (1H), 6.8 (1H), 7.1 ~ 7.4 (9H), 7.7
(1H), 8.1 (d, 1H, J = 9Hz) [α] _D = −119 ° (c = 0.1%, DMSO) Formulation Example When the compound of the present invention is used as a brain function improving drug, for example, The composition can be formulated.

(A) Tablet The present compound 30 mg Lactose 150 mg Crystalline cellulose 50 mg Carboxymethyl cellulose 7 mg Calcium magnesium stearate 3 mg Total 240 mg The tablet can be coated with a film, which is usually used, and can be further coated with sugar.

(B) Granule tablets This compound 30 mg Polyvinylpyrrolidone 25 mg Lactose 385 mg Hydroxypropylcellulose 50 mg Talc 10 mg Total 500 mg (c) Powder This compound 30 mg Lactose 300 mg Starch 440 mg Colloidal silica 30 mg Total (d) Capsule This compound 30 mg Lactose 102 mg Crystalline cellulose 56 mg Colloidal silica 2 mg Total 190 mg (e) Injectable drug Contain 1 to 30 mg of this compound in 1 ml of an aqueous solution (pH 6.5 to 7.0). The preparation process is performed aseptically.

[Effects of the Invention] Experimental Example Effect on Experimental Amnesia The experiment is based on Psychopharmacologi.
a) Sara (Sar) described in Volume 36, Page 59 (1974)
It was performed according to the method of a) et al.

Using male ddY mice weighing 23 to 26 g as a group of 20 mice,
A step-through type passive avoidance behavior training box consisting of a light box and a dark box was used as the experimental device.
As a trial of acquisition, animals were placed in a light box and given a foot shock immediately after entering the dark box. Experimental amnesia was induced by loading with electric shock convulsion shock (ECS) immediately after the acquisition trial. As a test trial, the animal was placed in a light box 3 hours after the acquisition trial, and the time until entering the dark box (reaction latency) was measured up to 600 seconds. The test compound was intraperitoneally (ip) administered immediately after ECS loading.

To evaluate the effect, antagonism against shortening of response latency induced by ECS load was examined. Table 1 shows the minimum effective dose that shows a significant antagonism as compared with the control group.

Claims (2)

[Claims] 1. A general formula [In the formula, A is a sulfur atom, an oxygen atom, a methylene group, -NR ⁶
-Group (R ⁶ is a hydrogen atom, an alkyl group, benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-
Represents a phenylhexyl or amino protecting group) or represents a carbonyl group. R ¹ is a hydrogen atom, an alkyl group, a cycloalkyl group, benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, halogen on the aromatic ring, tri Phenyl, 1-naphthyl or 2 which may have at least one substituent selected from fluoromethyl, hydroxy, amino, nitro, cyano, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons.
-Naphthyl, halogen on the aromatic ring, amino, 1 to 1 carbon atoms
6 alkyls, thienyl which may have at least one substituent selected from alkoxy having 1 to 6 carbons, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, Benzthiazolyl or indolyl or 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 3-furylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,
2-indolylmethyl and 3-indolylmethyl are shown.
R ² is an alkyl group, a cycloalkyl group, benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-
Substitution selected from phenylhexyl, halogenated alkyl group, alkoxy group, halogen on the aromatic ring, trifluoromethyl, hydroxy, amino, nitro, cyano, alkyl having 1 to 6 carbons, and alkoxy having 1 to 6 carbons. Substituent selected from phenyl, which may have at least one group, 1-naphthyl or 2-naphthyl, halogen, amino, alkyl having 1 to 6 carbons, and alkoxy having 1 to 6 carbons on the aromatic ring. May have at least one of thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,
Thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzthiazolyl or indolyl, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 3-furylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridyl Methyl,
2-indolylmethyl, 3-indolylmethyl or formula [Wherein B is an alkylene group which may be substituted with an alkyl group having 1 to 4 carbon atoms, an alkylidene group, an alkenylene group, -CH ₂ OCH _2- , -CH ₂ S (O)]
nCH _2- (n represents an integer of 0 to 2), -CH ₂ CON (R ⁸ )-
(R ⁸ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), D is an oxygen atom, a methylene group or —N (R ⁹ ).
-(R ⁹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms). The group has at least one substituent selected from halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons on the aromatic ring. Phenyl, 1-naphthyl or 2-naphthyl, or at least one substituent selected from halogen, amino, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons on the aromatic ring. Optionally thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzthiazolyl or indolyl]. R ³ and R ⁴ are the same or different and each is a hydrogen atom, an alkyl group or benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 3
Alkyl, benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, or together with adjacent nitrogen atoms bonded to each other. A group forming 1-pyrrolidinyl, piperidino, morpholino, and 2-piperazinyl which may be substituted with -phenylbutyl or 6-phenylhexyl is shown. R ⁵ represents a hydrogen atom, or 1 to 3 halogen atoms, an alkyl group or an alkoxy group (R
^{When 5} is 2-3, they may be the same or different). ] The benzolactam compound represented by these, its isomer, or salt. 2. General formula (In the formula, R _a ¹ is an alkyl group, a cycloalkyl group, benzyl, diphenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, or halogen on the aromatic ring. Phenyl optionally having at least one substituent selected from trifluoromethyl, hydroxy, amino, nitro, cyano, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons, 1-naphthyl or 2-naphthyl, thienyl, furyl, pyrrolyl, pyrazolyl which may have at least one substituent selected from halogen, amino, alkyl having 1 to 6 carbons and alkoxy having 1 to 6 carbons on the aromatic ring. , Imidazolyl, thiazolyl, oxazolyl,
Pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzthiazolyl or indolyl or 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl,
3-furylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-indolylmethyl,
3-indolylmethyl is shown, and other symbols have the same meanings as defined in claim 1. ) A benzolactam compound represented by :, an isomer or salt thereof.