JPH0564144B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a novel fused seven-membered ring compound useful as a medicine and a preventive/therapeutic agent for hypertension containing the same. PRIOR TECHNOLOGY Although various compounds are known that have angiotensin-converting enzyme inhibitory action, the only compound that has this action and has a fused 7-membered ring as its basic skeleton is the one described in European Patent Publication No. 72352. unknown. Problems to be Solved by the Invention Currently, compounds useful as therapeutic agents for circulatory disorders such as hypertension, heart disease, and stroke are desired. Means for Solving the Problems The present inventors have conducted an intensive search for compounds that have angiotensin-converting enzyme inhibitory activity and are useful as therapeutic agents for circulatory disorders. The present invention was completed by successfully producing a fused 7-membered ring compound with completely different characteristics. That is, the present invention is based on the formula [In the formula, R ¹ and R ² each represent hydrogen, halogen, trifluoromethyl, lower alkyl, or lower alkoxy, or both are linked to form tri or tetramethylene, and R ³ is hydrogen, lower alkyl, or represents aralkyl, R ⁴ represents an alkyl group having 5 to 16 carbon atoms which may be substituted with hydroxy, lower alkoxy, mercapto, lower alkylthio, amino, mono- or di-lower alkylamino, acylamino or cycloalkylamino, and X represents represents a group represented by S(O)n (in the formula, n represents an integer of 0 to 2), and Y is carboxyl, lower alkoxycarbonyl, aralkyloxycarbonyl, or a carboxyl group protected by lower alkyl or aralkyl; The present invention provides a compound represented by the following formula: carboxyl amidated with a good α-amino acid, m represents 1 or 2], a salt thereof, and a preventive/therapeutic agent for hypertension containing the same. Regarding the above formula (), examples of the halogen represented by R ¹ or R ² include fluorine, chlorine, bromine, and iodine, and examples of the lower alkoxy group represented by R ¹ or R ² include methoxy, ethoxy, and propoxy. , isopropoxy, poxy, isoptoxy, sec-butoxy, tert-
Examples include alkoxy groups having about 1 to 4 carbon atoms such as butoxy. Further, R ¹ and R ² may be linked together to form an alkylene bridge, and examples thereof include alkylene bridges such as trimethylene and tetramethylene. Examples of the lower alkyl group represented by R ¹ , R ² or R ³ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
Examples include alkyl groups having about 1 to 4 carbon atoms such as tert-butyl. The alkyl group represented by R ⁴ is a linear or branched alkyl group having 5 to 16 carbon atoms (e.g.
pentyl, isopentyl, hexyl, heptyl,
Octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,
hexadecyl), and these groups can have substituents such as hydroxy, lower (C _1-4 ) alkoxy (e.g., methoxy, ethoxy, propoxy,
butoxy), mercapto, lower (C _1-4 ) alkylthio (e.g., methylthio, ethylthio, propylthio, butylthio), amino, mono- or di-lower (C _1-4 ) alkylamino (e.g., methylamino, dimethylamino, ethylamino) , propylamino,
Isopropylamino, butylamino, isobutylamino, dimethylamino, methylethylamino,
methylpropylamino, methylbutylamino, diethylamino, ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino, dibutylamino), lower alkanoylamino having 5 or less carbon atoms (e.g., formamide, acetamide, propionamide, butylamino, parelamide, pivalamide) and benzamide, _C3-8 cycloalkylamino (e.g., cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino). It's okay. When R ⁴ is such a substituted alkyl group, it has 5 to 9 carbon atoms.
is preferably an alkyl group. Examples of the aralkyl group represented by R ³ include carbon atoms such as benzyl, phenethyl, 3-phenylpropyl, α-methylbenzyl, α-ethylbenzyl, α-methylphenethyl, β-methylphenethyl, and β-ethylphenethyl groups. number 7
~10 phenyl lower (C _1-4 ) alkyl groups, and the phenyl and alkyl groups in the phenyl lower alkyl group contain 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine),
Lower (C _1-4 ) alkyl group (e.g., methyl group, ethyl group, propyl group, butyl group, etc.), lower (C _1-4 )
Alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylenedioxy, etc.) may be substituted with amino, nitro, hydroxyl, or the like.
Examples of such substituted phenyl lower alkyl groups include 2-(4-chlorophenyl)ethyl group, 2-(4-hydroxyphenyl)ethyl group,
2-(4-methoxyphenyl)ethyl group, 2-
(3,4-dimethoxyphenyl)ethyl group, 2-
(3,4,5-trimethoxyphenyl)ethyl group,
2-(3,4-methylenedioxyphenyl)ethyl group, 2-(p-tolyl)ethyl group, 3,4-dimethoxybenzyl group, 3,4-methylenedioxybenzyl group, 3,4,5- Examples include trimethoxybenzyl group, 4-ethylbenzyl group, 4-chlorobenzyl group, α-aminophenethyl group, β-aminophenethyl group, and the like. The group represented by X forms sulfide, sulfoxide, or sulfone depending on its oxidation state. Examples of the esterified carboxyl group represented by Y include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,
Lower (C _1-4 ) alkoxycarbonyl groups such as tert-butoxycarbonyl, benzyloxycarbonyl, α-phenethyloxycarbonyl, β-phenethyloxycarbonyl, phenylpropyloxycarbonyl, phenylbutyloxycarbonyl, etc. Examples include phenyl lower (C _1-4 ) alkoxycarbonyl groups, and amidated carboxyl groups include α-amino acids such as valine, leucine, isoleucine, threonine, N-lysine, methionine, phenylalanine, and tryptophan. Examples include carboxyl groups amidated with amino groups, and the hydrogen atom of the carboxyl group of these α-amino acids is lower (C _1-4 ) alkyl (e.g., methyl, ethyl, propyl, butyl, tert-butyl) or phenyl. Lower (C _1-4 ) alkyl (e.g., benzyl, phenethyl, phenylpropyl,
phenylbutyl). Groups represented by C _n H _2n include CH ₂ [methylene],
Examples include CH ₂ CH ₂ [ethylene] and CH (CH ₃ ) [ethylidene]. The compounds of the present invention are specifically disclosed below: 3(R)-[1-ethoxycarbonyl-4-methylpentyl]amino-4-oxo-2,3,4,
5-tetrahydro-1,5-benzothiazepine-
5-acetic acid and its tert-butyl ester, 3(R)-[1-ethoxycarbonylnonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid and its tert-butyl ester, 3(R)-[6-amino-1(S)-carboxyhexyl]amino-4-oxo-2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-
Acetic acid, 3(R)-[6-amino-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,
4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, 3(R)-[7-amino-1(S)-carboxyheptyl]amino-4-oxo-2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-
Acetic acid, 3(R)-[7-amino-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,
4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid and its hydrochloride, 3(R)-[8-amino-1(S)-carboxyoctyl]amino-4-oxo-2,3, 4,5-
Tetrahydro-1,5-benzothiazepine-5-
Acetic acid, 3(R)-[8-amino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,
4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, 3(R)-[9-amino-1(S)-carboxynonyl]amino-4-oxo-2,3,4,5- Tetrahydro-1,5-benzothiazepine-5-acetic acid, 3(R)-[9-amino-1(S)-ethoxycarbonylnonyl]amino-4-oxo-2,3,
4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, 3(R)-[10-amino-1(S)-carboxydecyl]amino-4-oxo-2,3,4,5- Tetrahydro-1,5-benzothiazepine-5-acetic acid, 3(R)-[10-amino-1(S)-ethoxycarbonyldecyl]amino-4-oxo-2,3,
Examples include compounds such as 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid and its hydrochloride. Examples of salts of compound () include hydrochloride,
Inorganic acid salts such as hydrobromide, sulfate, nitrate, phosphate, organic salts such as acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate acid salt,
Pharmacologically acceptable salts such as, for example, metal salts such as sodium, potassium, calcium, aluminum salts; salts with bases such as triethylamine, guanidine, ammonium, hydrazine, quinine, cinchonine salts; I can give you salt. The compound of the present invention () has the formula [In the formula, each symbol has the same meaning as above. ] Compounds and formulas represented by [In the formula, R ³ and R ⁴ have the same meanings as above. It can be produced by subjecting the compound represented by the following formula to a condensation reaction under reductive conditions. The reductive conditions include, for example, catalytic reduction using a metal such as platinum, palladium, Raney nickel, or rhodium, or a mixture of these with an arbitrary carrier as a catalyst, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, Reduction with metal hydride compounds such as sodium borohydride and sodium cyanoborohydride;
Reduction of metallic sodium, metallic magnesium, etc. with alcohols, metals such as iron, zinc, and hydrochloric acid,
Examples of reaction conditions include reduction with an acid such as acetic acid, electrolytic reduction, and reduction with a reductase.
The above reaction is usually carried out in water or in an organic solvent (e.g. methanol, ethanol, ethyl ether, dioxane,
The reaction temperature varies depending on the reduction method, but is generally between -20℃ and +100℃.
The temperature is preferably about ℃. Although the purpose of this reaction can be sufficiently achieved at normal pressure, the reaction may be carried out under increased pressure or reduced pressure if necessary. Furthermore, the compound of the present invention () can be expressed by, for example, the formula [In the formula, each symbol has the same meaning as above. ] It can also be produced by subjecting the compound represented by the above to a dehydration ring closure reaction. The dehydration ring closure reaction can be carried out, for example, by an amide bond forming reaction in a conventional peptide. That is, peptide-forming reagents such as dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole, diphenylphosphate azide, and diethyl cyanophosphate are used alone, or common inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid) are used alone. ) to protonate the amino group of compound (), and then, for example, 2,4,5-trichlorophenol, pentachlorophenol, pentafluorophenol,
Phenols such as 2-nitrophenol or 4-nitrophenol or N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenztriazole, and N-hydroxypiperidine are condensed in the presence of a catalyst such as dicyclohexylcarbodiimide to form an active compound. This can be carried out by converting into an ester form and then cyclizing it. The cyclization reaction, whether converting compound () as such or into an activated ester of compound (), is preferably carried out using an organic base, such as a quaternary ammonium salt or tertiary amines (e.g. triethylamine, N- methylpiperidine).
The reaction temperature is usually -20 to +50°C, preferably around room temperature, and commonly used solvents include dioxane, tetrahydrofuran, acetonitrile, pyridine, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, Examples include N-methylpyrrolidone, chloroform, and methylene chloride, which may be used alone or as a mixed solvent. Compounds of the invention may also be used, for example, with the formula [In the formula, Z represents a protecting group that can be removed by hydrolysis or catalytic reduction, and the other symbols have the same meanings as above. It can also be produced by subjecting the compound represented by ] to hydrolysis or catalytic reduction reaction. In (), the protecting group represented by Z that can be removed by hydrolysis includes all kinds of acyl groups and trityl groups. Among these, benzyloxycarbonyl, tert-butoxycarbonyl, trifluoroacetyl, trityl, etc. are particularly advantageous when the reaction is carried out under relatively mild reaction conditions. Examples of the protecting group represented by Z which can be removed by catalytic reduction include benzyl, diphenylmethyl, and benzyloxycarbonyl. The hydrolysis reaction in this method is carried out in water or an organic solvent such as methanol, ethanol, dioxane, pyridine, acetic acid, acetone, methylene chloride, or a mixed solvent thereof. Hydrohydric acid, hydriodic acid, hydrofluoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid) or bases (e.g., sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, It can also be carried out by adding sodium acetate, triethylamine). The above reaction is usually −20~
It is carried out at a temperature of approximately +150℃. In addition, the catalytic reduction reaction in this method is performed in water or an organic solvent such as methanol, ethanol, dioxane, tetrahydrofuran, or a mixed solvent thereof.
For example, it is carried out in the presence of a suitable catalyst such as platinum, palladium-carbon or the like. This reaction is carried out at normal pressure or at 150 °C.
The reaction is carried out under a pressure of up to about Kg/cm ² and at a temperature of room temperature to +150°C, but the reaction generally proceeds satisfactorily at room temperature and normal pressure. Compounds of the invention () can also be used, for example, with the formula [In the formula, each symbol has the same meaning as above. In the compound represented by ], it can also be produced by solvolyzing the cyano group. The above solvolysis reaction is carried out in water or an organic solvent such as methanol, ethanol, dioxane, pyridine, acetic acid, acetone, methylene chloride, or a mixed solvent thereof. Hydrogen acid, hydriodic acid, hydrofluoric acid, sulfuric acid, methanesulfonic acid, p
-toluenesulfonic acid, trifluoroacetic acid) or a base (eg, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium acetate, triethylamine). The reaction is usually carried out at a temperature of about -20 to +150°C. Compound () or compound () with the formula [In the formula, R ³ and R ⁴ have the same meanings as above, and W represents a halogen or a group represented by the formula R ⁵ SO ₂ —O— (R ⁵ represents lower alkyl, phenyl or p-tolyl). ] It can also be produced by reacting a compound represented by: The reaction proceeds by maintaining both in a suitable solvent at a temperature range of about -20 to +150°C. At this time, a base such as potassium carbonate, sodium hydroxide, sodium bicarbonate, pyridine, triethylamine, etc. may be present in the reaction system as a deoxidizing agent for the purpose of accelerating the reaction rate. Compounds of the invention () can also be used, for example, with the formula [In the formula, each symbol has the same meaning as above. ] to the compound represented by the formula W'-C _n H _2n -Y () [where W' is halogen or the formula R ⁵ 'SO ₂ -O
- represents a group (R ⁵ ' represents lower alkyl, phenyl or p-tolyl), and Y has the same meaning as above. ] It can also be produced by reacting a compound represented by: The reaction proceeds by maintaining both in a suitable solvent at a temperature range of about -20 to +150°C. At this time, for example, a base such as potassium carbonate, sodium hydroxide, or sodium hydride may be present in the reaction system. In the compound (), R ³ is hydrogen or /
and when Y is carboxyl, the ester compound in which R ³ is lower (C _1-4 ) alkyl and/or Y is lower (C _1-4 ) alkoxycarbonyl can be subjected to hydrolysis or elimination reaction. Therefore, R ³ is also benzyl or/and Y
The compound () can also be produced by catalytic reduction of a benzyl ester compound in which is benzyloxycarbonyl. Also, in compound (), R ³ is lower (C _1-4 )
When alkyl or/and Y is lower (C _1-4 ) alkoxycarbonyl, R ³ is hydrogen,
Alternatively, it can also be produced by subjecting a compound in which Y is carboxyl to an esterification reaction. In addition, when Y is an esterified or amidated carboxyl in the compound (), for example, the formula [In the formula, each symbol has the same meaning as above. ] The compound represented by the formula R ⁶ −H () [wherein R ⁶ is an α-amino acid whose carboxyl group may be protected by a lower alcohol residue, a phenyl lower alcohol residue, a lower alkyl, or a phenyl lower alkyl Residues are shown. It can also be produced by subjecting a compound represented by the following formula to a condensation reaction. Furthermore, the formula obtained by the above condensation reaction [In the formula, R ⁶ is lower alkyl or α whose carboxyl group is protected with phenyl lower alkyl.
- Indicates amino acid residue; other symbols have the same meanings as above. ] By subjecting the compound represented by, for example, to a hydrolysis reaction, an elimination reaction, or a catalytic reduction reaction,
formula [In the formula, R ⁶ ' represents an α-amino acid residue, and the other symbols have the same meanings as above. ] It is also possible to obtain a compound represented by: When X in compound () is sulfoxide or sulfone, it can also be produced by oxidizing the corresponding sulfide compound.
The oxidation reaction may be carried out using, for example, an organic peracid (e.g., metachloroperbenzoic acid, peracetic acid) or an inorganic oxidizing agent (e.g.,
This is done by applying hydrogen peroxide, periodic acid). The above reaction is usually carried out in the presence of water or an organic solvent (e.g. methanol, ethanol, dioxane, dichloromethane), and is usually -20 to +
It is carried out in a temperature range of 100℃. When using a compound that has a group that may interfere with the reaction [e.g., compounds () and ()
or () reaction] The group is protected with a protecting group known per se (e.g., benzyloxycarbonyl, tert-butoxycarbonyl, chloroacetyl, phthalimide, succinimide) and subjected to the reaction, and after the reaction, a deprotection reaction known per se is carried out. The desired compound can also be obtained. For example, the expression [In the formula, A is a linear or branched carbon number 5
~16 alkylene, Ra and Rb are respectively,
A compound represented by hydrogen, lower (C _1-4 ) alkyl, acyl, or cycloalkyl, and other symbols have the same meanings as above can be produced, for example, as follows. compound () and formula [In the formula, Wa is halogen or the formula ReSO ₂ −O
A group represented by - (in the formula, Re is lower alkyl,
phenyl or p-tolyl), one of Rc and Rd represents hydrogen and the other represents a protecting group (e.g. benzoyl, acetyl), or both together with adjacent nitrogen atoms represent phthalimide, succinimide, and other symbols is the same meaning as above] is reacted to form the formula After obtaining a compound represented by [wherein each symbol has the same meaning as above], compound (Ia') is subjected to a deprotection reaction to form an amino compound (Ia) in which Ra and Rb are hydrogen ( Ib) is obtained. In formula (Ia), a compound in which Ra and/or Rb are lower alkyl or cycloalkyl can be prepared, for example, by mixing the corresponding aldehyde or ketone with compound (Ib), usually in water or an organic solvent (e.g., alcohol,
ether, tetrahydrofuran, dimethylformamide, acetonitrile) or a mixed solvent thereof at a temperature range of about -20 to +100°C under reductive conditions. The reductive conditions include, for example, catalytic reduction using a metal such as platinum or palladium or a mixture of these with an arbitrary carrier as a catalyst, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride. , reduction with metal hydrogen compounds such as sodium cyanoborohydride, reduction with alcohols such as metal sodium and metal magnesium, reduction with metals such as iron and zinc and acids such as hydrochloric acid and acetic acid,
Examples of reaction conditions include electrolytic reduction and reduction using a reductase. In addition, in formula (Ia), a compound in which Ra or/and Rb are acyl can be prepared by combining an activated organic acid derivative such as an acid anhydride or an acid halide with compound (Ib), usually in water or in an organic solvent (e.g., ethyl acetate, ethyl chloride, ether, benzene, toluene, triethylamine, dimethylformamide) or a mixed solvent thereof, -20
It can be produced by reacting at a temperature range of about 150°C to +150°C. At this time, an organic base (eg, triethylamine, picoline, pyridine) or an inorganic base (eg, sodium hydrogen carbonate) may be added to accelerate the reaction rate. The object compound (I) of the present invention thus obtained can be separated and purified from the reaction mixture using conventional means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography, etc. It can be isolated by Compound (I) may exist in at least two stereoisomers depending on the type of substituent represented by R ⁴ . Both of these individual isomers and mixtures thereof are naturally included within the scope of the present invention, and these isomers can also be produced individually if desired. For example, the raw material compound (), (),
By carrying out the above reaction using a single isomer of each of (), () and (), a single optical isomer of compound (I) can be obtained, and two types of products can be obtained. In the case of mixtures of the above isomers, they can be separated using conventional separation methods, such as optically active acids (e.g., camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, etc.), optically active bases (e.g., cinchonine, cinchonidine, quinine, quinidine, α −
It can also be separated into each isomer by a method of forming a salt with methylbenzylamine, dehydroapiethylamine, etc.), various chromatography, fractional recrystallization, and other separation means. Raw material compounds of the present invention (), (), (), ()
and () can be easily produced, for example, by the method shown in the following reaction formula. In the above reaction formula, R ⁷ represents a halogen or a diazonium group, Q represents a halogen or a group represented by the formula R ⁸ SO ₂ --O- (R ⁸ represents lower alkyl, phenyl or p-tolyl), and other Symbols have the same meanings as above. To explain in more detail the method for producing the compound ( ) shown by the above reaction formula, L
- Using cystine () as a raw material compound, compound () is derived, and then, if necessary, the amino group is protected with an appropriate amino group-protecting group (eg, phthaloyl group) to obtain compound (). This reaction proceeds easily in an aqueous solution of compound () in the presence of N-carboethoxyphthalimide () and a base such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, etc., usually at a temperature of about 0 to +100°C.
The reaction ()→() is a reduction reaction of a nitro group to an amino group, and a commonly known reduction method can be used. That is, reduction methods include, for example, palladium-carbon, palladium using barium sulfate as a carrier, sulfide palladium,
Catalytic reduction using catalysts such as platinum, or zinc,
Reduction reactions between metals such as tin, stannous chloride, and iron and acids or alkalis are used.
The compound () of the thus obtained compound ()
) can be advantageously carried out in the presence of a commonly known dehydration condensation agent. Examples of such dehydration condensation agents include dicyclohexycarbodiimide, carbonyldiimidazole, and diethyl cyanophosphate. As the solvent, for example, dioxane, methylene chloride, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, etc. are used, and usually -10 to +
The reaction takes place in a temperature range of about 100°C. At this time, in order to advantageously advance the reaction, a base such as triethylamine or pyridine may be added as a catalyst to the reaction solution. The production of compound () by a condensation reaction between compounds () and () is usually performed using N,N-
dimethylformamide, dimethyl sulfoxide,
It can be produced by condensation in a solvent such as acetonitrile at a temperature range of about -10 to +100°C. Next, the reaction () → (') can be carried out with hydrazine hydrate in a solvent such as methanol, ethanol, dioxane, etc. at a temperature range of about -10°C to +100°C to produce compound ('). . When X in compound () is sulfoxide or sulfone, it can be produced by oxidizing compound ('). The oxidation reaction is carried out, for example, by the action of an organic peracid (eg, metachloroperbenzoic acid, peracetic acid) or an inorganic oxidizing agent (eg, hydrogen peroxide, periodic acid). The above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, dioxane, dichloromethane), and is usually carried out at a temperature range of -20 to +100°C. The oxidation reaction can also be performed on compounds (), (), (), () or (
) to convert each sulfide group into a sulfoxide or sulfone, and then subjected to a series of reactions to produce compound (). When X is a sulfide in compound (), compound () can also be produced by subjecting compound (') to a reaction to produce compound (). In addition, in the method for producing compound (), (
) → () reaction is () → ()
It can be carried out by a reaction similar to that of . Compound (') can be produced by subjecting compound () to a conventional reduction reaction of a nitro group to an amino group and then to an alkylation reaction. When X in compound () is sulfoxide or sulfone, it can be produced by subjecting it to a reaction similar to the reaction of (')→(). When X is a sulfide in compound (), compound () can also be produced by reacting compound (') as compound (). Alternatively, compound () can be produced by subjecting compound () to the oxidation reaction to convert the sulfide group to sulfoxide or sulfone, and then subjecting it to a reaction for producing compound (). In the method for producing compound (), compound (
) can be produced by subjecting compound () to a known amino group protection reaction of an amino acid. The reaction ()→() proceeds by maintaining both in an appropriate solvent at a temperature range of about -20 to +150°C. At this time, a base such as potassium carbonate, sodium hydroxide, sodium bicarbonate, pyridine, triethylamine, etc. may be present in the reaction system as a deoxidizing agent for the purpose of accelerating the reaction rate. In the method for producing compound (), compound (),
() and hydrogen cyanide as raw material compounds,
Compound () can be obtained according to the known Strecker reaction. In the method for producing compound (), ()→
The reaction () can proceed in a similar manner to the reaction () → ('). Compound(
) and compound () in the presence of a metal hydride such as sodium cyanoborohydride to produce compound ('). When compound () is a sulfoxide or sulfone, it can be produced by subjecting it to a reaction similar to the reaction of (')→(). When compound () is a sulfide, compound (') is subjected to the reaction as compound (),
Compound () can also be produced. In the method for producing the above compound () and its intermediates, the compound used in the reaction may be an inorganic acid salt, such as a hydrochloride, a hydrobromide, a sulfate, a nitrate, a phosphate, etc., as long as it does not interfere with the reaction. organic acid salts such as acetates, tartrates, citrates, fumarates, maleates, toluenesulfonates, methanesulfonates, metal salts such as sodium, potassium, calcium, aluminum salts; For example, it may be used in the form of a salt such as a salt with a base such as a triethylamine salt, a guanidine salt, an ammonium salt, a hydrazine salt, a quinine salt, and a cinchonine salt. Effect The compound of the present invention, that is, the fused 7-membered ring compound represented by formula () and its salt, has angiotensin-converting enzyme inhibitory effect on animals, especially mammals (e.g., humans, dogs, cats, rabbits, guinea pigs, rats). Bradykinin degrading enzyme (kininase)
It exhibits suppressive effects and is useful as a diagnostic, preventive, or therapeutic agent for, for example, hypertension and circulatory disorders caused by hypertension (eg, heart disease, stroke). The compound of the present invention has low toxicity, is well absorbed even when administered orally, has excellent persistence, and is highly safe. It can be mixed with excipients and diluents and safely administered orally or parenterally in the form of pharmaceutical compositions such as powders, granules, tablets, capsules, and injections. The dosage varies depending on the condition of the target disease and the route of administration, but for example, when administered to adult patients for the purpose of treating renal or essential hypertension, a single dose is usually about 0.02 to 20 mg/Kg for oral administration. , especially about
About 0.02 to 2 mg/Kg, especially about 0.04 to 0.8 mg/Kg, but for intravenous administration, the daily dose is about 0.002 to 1 mg/Kg,
Especially about 0.002 to 0.2 mg/Kg, especially about 0.02 to 0.2
The dosage is preferably about mg/Kg, and it is desirable to administer these doses about 1 to 5 times a day, preferably about 1 to 3 times, particularly about 1 to 2 times a day, depending on the symptoms. Further, among the intermediates, compound (Ia') has an angiotensin-converting enzyme inhibitory effect, and like compound (), it can be applied as a diagnostic, prophylactic, and therapeutic agent for hypertension. Reference Example 1 S-(o-nitrophenyl)-L-cysteine
Dissolve 2.9 g in a 1.4 g aqueous solution (200 ml) of sodium carbonate, and add 3.5 g of N-ethoxycarbonylphthalimide while stirring. After stirring at room temperature for 5 hours, insoluble matter was removed by filtration, and the mixture was made weakly acidic with concentrated hydrochloric acid. Take the precipitated crystals and add 30% ethanol
When recrystallized from ml, S-(o-nitrophenyl)
Thio-2(R)-phthalimidopropionic acid 3.6g
is obtained as pale yellow needle crystals. Melting point 220-222℃ Elemental analysis value C ₁₇ H ₁₂ N ₂ O ₆ Calculated value as S: C 54.84; H 3.25; N 7.53 Actual value: C 54.46; H 3.26; N 7.46 [α] ²⁴ _D -79° (c = 0.9 in methanol) Reference example 2 10 g of 3-(o-nitrophenyl)thio-2(R)-phthalimidopropionic acid in 300 ml of methanol
Catalytic reduction is carried out at room temperature and pressure using 5% palladium on carbon as a catalyst. After the calculated amount of hydrogen has been absorbed, the catalyst is removed and the methanol is distilled off under reduced pressure.
Ether and petroleum ether were added to the residue and left to stand, and the precipitated pale yellow powder crystals were removed to obtain 3-
8.4 g of (o-aminophenyl)thio-2(R)-phthalimidopropionic acid are obtained. Dissolve 8.4 g of this product in 50 ml of dimethylformamide, and add 5.5 g of diethyl cyanophosphate dropwise while stirring under ice cooling. After the addition is complete, stir for 5 minutes, and then add 2.28 g of triethylamine dropwise while cooling on ice. Stir on ice for 30 minutes, then at room temperature for 1 hour. Add 200 ml of water to the reaction solution, leave it overnight, remove the precipitated solid, and dry. When this product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 2:1), 5.4 g of 3(R)-phthalimido-2,3-dihydro-1,5(5H)-benzothiazepin-4-one was obtained. is obtained as colorless prismatic crystals. Melting point 202-205℃ Elemental analysis value C ₁₇ H ₁₂ N ₂ O ₃ Calculated value as S: C 62.95; H 3.73; N 8.64 Actual value: C 63.15; H 4.02; N 8.49 [α] ²¹ _D -164° (c = 0.9 in methanol) Reference Example 3 Add 0.5 g of sodium hydride (60% oily) to 50 ml of dimethylformamide and stir under ice cooling. Under ice cooling, 4 g of 3(R)-phthalimido-2,3-dihydro-1,5(5H)-benzothiazepin-4-one obtained in Reference Example 2 was added, and the mixture was stirred for 5 minutes. Further, 2 g of chloroacetic acid and tert-butyl ester are added under ice cooling. After stirring for 15 minutes under ice-cooling, add ice water (200 ml) to the reaction mixture to collect precipitated crystals. After drying, purification by silica gel column chromatography (hexane:ethyl acetate = 3:1) yields 4-oxo-3(R)-phthalimide.
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, tert-butyl ester 4
g is obtained as colorless crystals. When a portion is recrystallized from ethyl ether, it becomes colorless prismatic crystals.
Melting point 181-184℃ Elemental analysis value C ₂₃ H ₂₂ N ₂ O ₅ Calculated value as S: C 63.01; H 5.06; N 6.39 Actual value: C 62.95; H 5.10; N 6.34 [α] ²⁰ _D -156° (c =0.9, in chloroform) Reference Example 4 4-oxo-3(R)-phthalimide-2,3,4,5-tetrahydro-1,5- obtained in Reference Example 3
Benzothiazepine-5-acetic acid, 4 g of tert-butyl ester and 1.4 g of hydrazine hydrate in 100 ml of ethanol.
Add to ml. The mixture is heated to reflux with stirring for 1 hour. Concentrate the reaction solution under reduced pressure, add 300 ml of ethyl acetate and 100 ml of water to the residue, and mix well. The ethyl acetate layer was washed successively with diluted sodium hydroxide and water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. When the obtained oil is crystallized from a mixture of ether and petroleum ether, 3(R)
-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid
2 g of tert-butyl ester are obtained as colorless prismatic crystals. Melting point 86-89℃ Elemental analysis value Calculated value as C ₁₅ H ₂₀ N ₂ O ₃ S: C 58.42; H 6.54; N 9.08 Actual value: C 58.73; H 6.48; N 9.13 [α] ²⁰ _D −238° (c = 1 in methanol) Reference example 5 Dissolve 4.5 g of sodium in 100 ml of ethanol,
3-cyclohexylpropionic acid ethyl ester
Add 30g and 29g of diethyl oxalate and heat to approximately 70℃.
Heat on a hot water bath for 30 minutes. Subsequently, it was distilled off under reduced pressure at 70°C for 30 minutes to remove the low boiling point portion. After cooling, add 500 ml of water, 200 ml of ether, and 100 ml of petroleum ether to the resulting brown candy and shake well. The aqueous layer is separated, made slightly acidic with sulfuric acid, and extracted with 200 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. 10 to the resulting oil
Add 110 ml of % hydrated dimethyl sulfoxide and 10 g of common salt, and stir at 140°C for 25 hours. After cooling the reaction solution, add 1 portion of water and extract with 500 ml of ethyl acetate.
The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The resulting brown oil was distilled off under reduced pressure to give ethyl 4-cyclohexyl-2-
18 g of oxobutyrate are obtained as a pale yellow oil. Boiling point 105-110℃ (1.5mmHg) Reference example 6 to 10 Using an o-nitroaniline derivative with a substituent as a raw material, the same reaction as in the case of synthesizing an unsubstituted product (R=H) results in Table 1. The compound shown is obtained.

[Table] Reference Example 11-14 S-(2-nitrophenyl) obtained in Reference Example 6-9
When the -L-cysteine derivative is reacted with N-ethoxycarbonylphthalimide in the same manner as in Reference Example 1, the compounds shown in Table 2 are obtained.

[Table] Reference Examples 15-18 When the phthalimide derivatives obtained in Reference Examples 11-14 are reacted in the same manner as in Reference Example 2, the compounds shown in Table 3 are obtained.

[Table] Reference Examples 19-22 When the phthalimidobenzothiazepine derivatives obtained in Reference Examples 15-18 are reacted in the same manner as in Reference Example 3, the compounds shown in Table 4 are obtained.

[Table] Reference Examples 23-26 When the phthalimidobenzothiazepine acetic acid tert-butyl ester derivative obtained in Reference Examples 19-22 is reacted in the same manner as in Reference Example 4, the compounds shown in Table 5 are obtained.

[Table] Reference Examples 27-30 When the same reaction as in Reference Example 5 is carried out using the carboxylic acid ethyl esters shown in Table 6 as raw materials, the corresponding α-keto esters are obtained.

[Table] Reference Example 31 5.3 g of S-(2-nitro-4-trifluoromethylphenyl)-L-cysteine obtained in Reference Example 10 was
Add to 67ml of 2.5N sodium hydroxide solution and stir at room temperature for 30 minutes, then add 2.7ml of benzyloxycarbonyl chloride and 1N sodium hydroxide solution under ice cooling.
Drop 19ml simultaneously over 30 minutes. After stirring at room temperature for 2.5 hours, the reaction solution is extracted with ethyl ether, and the aqueous solution is made weakly acidic with 1N hydrochloric acid. After extraction with ethyl acetate, the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Ethyl ether was added to the resulting residue to obtain S-(2-nitro-4-
5.5 g of (trifluoromethylphenyl)-N-benzyloxycarbonyl-L-cysteine precipitated as pale yellow crystals. Melting point 150-153℃ [α] _D +20° (in methanol) Elemental analysis value Calculated value as C ₁₈ H ₁₅ F ₃ N ₂ O ₆ S: C 48.65; H 3.40; N 6.30 Actual value: C 48.68; H 3.41; N 6.27 Reference Example 32 Mix 4.3 g of S-(2-nitro-4-trifluoromethylphenyl)-N-benzyloxycarbonyl-L-cysteine obtained in Reference Example 31 and 4 g of zinc powder with 50 ml of acetic acid and 50 ml of water. Add to the mixture and stir at room temperature for 50 minutes. Add 150 ml of water and 150 ml of ethyl acetate to remove insoluble matter. The aqueous layer is further extracted twice with 100 ml of ethyl acetate, the ethyl acetate layers are combined, washed with water, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. When the residue was dissolved in 50 ml of ethyl ether and 5 ml of hydrogen chloride-ethyl acetate solution (5N) was added, S
-(2-amino-4-trifluoromethylphenyl)
3.4 g of -N-benzyloxycarbonyl-L-cysteine hydrochloride is obtained as a pale yellow powder.
Dissolve this product in 30 ml of dimethylformamide, and while stirring under ice-cooling, add a solution of 0.78 g of triethylamine in 5 ml of dimethylformamide dropwise over 10 minutes. Furthermore, 5 ml of dimethylformamide containing 1.83 g of diethyl cyanophosphate was added dropwise over 5 minutes, followed by 5 ml of dimethylformamide containing 0.78 g of triethylamine.
Add solution. Stir on ice for 30 minutes, then at room temperature for 2.5 hours. Add 200 ml of water to the reaction solution, extract with ethyl acetate, dry the extract over anhydrous magnesium sulfate, and evaporate under reduced pressure. The obtained oil was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1 to 2:1) to obtain 3(R)-benzyloxycarbonylamino-
7-trifluoromethyl-2,3-dihydro-
1,5(5H)-benzothiazepine-4-one 1.3g
is obtained as a colorless powder crystal. Melting point 120-123℃ [α] _D -161° (in methanol) Elemental analysis value Calculated value as C ₁₈ H ₁₅ F ₃ N ₂ O ₃ S: C 54.54; H 3.81; N 7.07 Actual value: C 54.79; H 3.90 ;N 7.09 Reference Example 33 3(R)-benzyloxycarbonylamino-7-trifluoromethyl-2,3- obtained in Reference Example 32
Dihydro-1,5(5H)-benzothiazepine-4
Dissolve 1.1 g of -one in 20 ml of dimethylformamide, 0.46 g of chloroacetic acid tert-butyl ester,
Add 0.42 g of potassium carbonate and 0.1 g of potassium iodide, and stir at room temperature for 4.5 hours. 100% water in reaction solution
ml and extracted with 100 ml of ethyl acetate. The extract was washed with 0.1N hydrochloric acid, an aqueous sodium bicarbonate solution, and water in that order, and dried over anhydrous magnesium sulfate.
Distillation under reduced pressure yields 3(R)-benzyloxycarbonylamino-4-oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester.
1.4 g is obtained as a colorless candy. IR υ ^nujol _nax cm ^-1 : 1680 (amide), 1710 (urethane),
1740 (ester) *IR: (Infrared absorption spectrum: same below) Reference example 34 3(R)-benzyloxycarbonylamino-4-oxo-7-trifluoromethyl-2,3,4, obtained in Reference example 33 Dissolve 1.4 g of 5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester in 5 ml of acetic acid, add 10 ml of 30% hydrogen bromide-acetic acid solution, and let stand at room temperature for 4 hours. After adding 100ml of petroleum ether to the reaction solution and shaking well,
Remove the supernatant by decanting. After adding petroleum ether again and carrying out the same operation, the residue was dissolved in a mixture of ethyl acetate and benzene and dried under reduced pressure. Adding petroleum ether to the residue gives 3(R)-amino-4-
Oxo-7-trifluoromethyl-2,3,4,
5-tetrahydro-1,5-benzothiazepine-
0.75 g of 5-acetic acid hydrobromide precipitates as crystals. Melting point 176-180℃ Elemental analysis value C ₁₂ H ₁₁ F ₃ N ₂ O ₃ Calculated value as S・HBr・H ₂ O: C 34.38; H 3.37; N 6.68 Actual value: C 34.40; H 3.60; N 6.66 Reference example 35 3(R)-Amino-4-oxo- obtained in Reference Example 4
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 2
Dissolve 1.6 g of benzyl bromide in 20 ml of ethanol.
g and 1 g of triethylamine are added and left at room temperature for 3 days. Add 100ml of water and 200ml of ethyl acetate to the reaction solution.
The extract is extracted by adding the following ingredients, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
Purification by step 1) yields 3(R)-benzylamino-4
-oxo-2,3,4,5-tetrahydro-1,
2 g of 5-benzothiazepine 5-acetic acid tert-butyl ester are obtained as a colorless oil. This product
Dissolve 1.7g in 30ml of dimethylformamide, add potassium carbonate (1.7g) and ethyl bromoacetate (1ml).
After adding and heating at 80℃ for 2 hours, add 4 ml of ethyl bromoacetate and 3 g of potassium carbonate.
Heat at 100℃ for 8 hours. Add 300 ml of water and 400 ml of ethyl acetate to the reaction solution for extraction, dry the extract over anhydrous magnesium sulfate, and then evaporate under reduced pressure. The obtained oil was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to yield 3(R)-(N-benzyl-N-ethoxycarbonylmethylamino)-4-oxo-2,3 ,4,
5-tetrahydro-1,5-benzazepine-5
-1.6 g of acetic acid tert-butyl ester are obtained as a colorless oil. 3(R)-
(N-benzyl-N-ethoxycarbonylmethylamino)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid.
0.8 g of hydrochloride is obtained as a colorless powder. Elemental analysis value C ₂₂ H ₂₄ N ₂ O ₅ Calculated value as S・HCl: C 56.83; H 5.42; N 6.03 Actual value: C 56.61; H 5.59; N 6.07 [α] _D −164° (in methanol) Mass spectrum (m/e): 428 (M ⁺ ) Reference example 36 3(R)-amino-4-oxo- obtained in Reference example 4
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 1
Dissolve g in 20 ml of methanol and add potassium cyanide.
Add 0.32 g, 1.1 g of N-(4-formylbutyl)phthalimide and 0.3 g of acetic acid, and stir overnight at room temperature. The reaction solution was dried under reduced pressure to give 3(R)-(1-cyano-5-phthalimidopentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine as a crude product. -5-acetic acid tert-butyl ester is obtained. This product is used as a raw material for Reference Example 37 without being purified. Reference Example 37 3(R)-(1-cyano-5-phthalimidopentyl)amino-4-oxo-2, obtained in Reference Example 36
Add 20 ml of ethanolic hydrochloric acid (11N) to 2 g of 3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester, stir under ice cooling for 6 hours, and then leave at room temperature overnight. do. Distill the ethanol under reduced pressure and add 50ml of ethanol to the residue.
Add 10 g of Amberlyst 15 ion exchange resin and reflux with stirring for 7 hours. After cooling, the resin part was treated with a 5% pyridine-ethanol solution,
The ethanol portions were combined and evaporated under reduced pressure. The resulting oil is dissolved in 300 ml of ethyl acetate and washed with 0.1N hydrochloric acid and water. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:acetone = 2:1) to obtain 3(R)-(1-ethoxycarbonyl-5). -phthalimidopentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester 0.9 g is obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 1770, 1740, 1720, 1710 (phthalimide and ester) 1670 (amide) Mass spectrum (m/e): 567 (M ⁺ ) Reference example 38 3 (R) obtained in Reference example 4 -amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 1
g and 2(S)-benzyloxycarbonylamino-
Dissolve 1 g of 3-phenylpropionaldehyde in 20 ml of methanol, add 0.35 g of potassium cyanide and 0.3 g of acetic acid, and stir overnight at room temperature. Furthermore, 2(S)-benzyloxycarbonylamino-3-
Add 0.4 g of phenylpropionaldehyde, 0.2 g of potassium cyanide and 0.2 g of acetic acid and stir for 3 days. The reaction solution was dried under reduced pressure to give 3(R)-[2(S)-benzyloxycarboniamino-1-cyano-3-phenylpropyl]amino-4-oxo-2,3,4 as a crude product. ,5-tetrahydro-
1,5-benzothiazepine-5-acetic acid tert-butyl ester is obtained. This product is used as a raw material for Reference Example 39 without being purified. Reference Example 39 3(R)-[2(S)-benzyloxycarbonylamino-1-cyano-3-phenylpropyl]amino-4-oxo-2,3,4, obtained in Reference Example 38
5-tetrahydro-1,5-benzothiazepine-
Add 5-acetic acid tert-butyl ester to 20 ml of 11N ethanolic hydrochloric acid and stir overnight at room temperature. The reaction solution was dried under reduced pressure, 50 ml of ethanol and Amberlyst 15 ion exchange resin (10 g) were added to the residue, and the mixture was refluxed with stirring for 9 hours. After filtration, the resin portion is eluted with ethanol containing ammonia (ammonia water:ethanol=1:9). After removing ethanol by distillation under reduced pressure, 100 ml of ethyl acetate, 50 ml of water, and 1 g of potassium carbonate are added to the residue, and 1 ml of benzyloxycarbonyl chloride is added dropwise while stirring at room temperature. After stirring for 1.5 hours,
The ethyl acetate layer was washed with water and evaporated under reduced pressure. The obtained oil was subjected to silica gel column chromatography.
When purified with (hexane:acetone = 3:1 to 1:1), 3(R)-[2(S)-benzyloxycarbonylamino-1-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2 ,3,
0.22 g of 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester is obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3350 (NH) 1720, 1680 (C=O). Mass spectrum (m/e): 619 (M ⁺ ) Reference example 40 3(R)-phthalimide-2,3 obtained in Reference example 2
-dihydro-1,5(5H)-benzothiazepine-
Dissolve 6.48 g of 4-one in 25 ml of dimethylformamide, add 6.27 g of 2-bromopropionic acid tert-butyl ester, 5.5 g of potassium carbonate and 0.5 g of potassium iodide, and stir overnight at room temperature. Add 200 ml of water to the reaction solution and extract with 300 ml of ethyl acetate. Add the extract to 200ml of 0.5N hydrochloric acid and 100ml of saturated sodium bicarbonate solution.
After washing with water, it is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained oil was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:1).
~2:1) to give 3(R)-phthalimido-4-oxo-2,3,4,5-tetrahydro-
1,5-benzothiazepine-5-α-methylacetic acid
7.8 g of tert-butyl ester are obtained as a colorless powder. IR υ ^neat _nax cm ^-1 : 1770, 1730, 1720, 1680 (C=O). Elemental analysis value C ₂₄ H ₂₄ N ₂ O ₅ Calculated value as S・1/2H ₂ O: C 62.46; H 5.46; N 6.07 Actual value: C 62.62; H 5.14; N 6.13 Reference example 41 Obtained in reference example 40 3(R)-phthalimido-4-oxo-2,3,4,5-tetrahydro-1,5-
Benzothiazepine-5-α-methylacetic acid tert-
When 7.6 g of butyl ester was treated with hydrazine hydrate in the same manner as in Reference Example 4, 3(R)-amino-4-
Oxo-2,3,4,5-tetrahydro-1,5
5.4 g of -benzothiazepine-5-α-methylacetic acid tert-butyl ester are obtained as a pale yellow oil. IR υ ^neat _nax cm ^-1 : 1735, 1670 (C=O). [α] _D −223° (c=0.5, in methanol) Mass spectrum (m/e): 322 (M ⁺ ) Reference example 42 3(R)-amino-4-oxo- obtained in Reference example 4
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester
Dissolve 3.08 g in 20 ml of dimethylformamide, add 7.36 g of ethyl 2-bromo-6-phthalimidohexanoate, 2.76 g of potassium carbonate and 1.66 g of potassium iodide, and stir overnight at room temperature. Furthermore, 3.68 g of promoester and 1.38 g of potassium carbonate are added and stirred for 3 days. Add 100 ml of water and 300 ml of ethyl acetate to the reaction solution for extraction, wash the extract with water, and then evaporate under reduced pressure. Add 5 g of oxalic acid and 30 ml of ethyl acetate to the resulting oil, dissolve, and dissolve in petroleum ether.
Add 120ml and mix well. After standing still, the supernatant liquid was removed by decanting, and the residue was subjected to the same treatment four times, then extracted with 100 ml of saturated sodium bicarbonate solution and 300 ml of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. It is then distilled off under reduced pressure. When the obtained oil was purified by silica gel column chromatography (hexane:acetone=4:1), 3(R) was obtained as the first fraction.
-[1(R)-ethoxycarbonyl-5-phthalimidopentyl]amino-4-oxo-2,3,
1.75 g of 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester are obtained as an oil. IR υ ^neat _nax cm ^-1 : 3330 (NH), 1780, 1740, 1720, 1680 (C = 0). Mass spectrum (m/e): 595 (M ⁺ ) 3(R)-[1(S)-ethoxycarbonyl-5-phthalimidopentyl]amino-
4-oxo-2,3,4,5-tetrahydro-
2.5 g of 1,5-benzothiazepine-5-acetic acid tert-butyl ester are obtained as an oil. IR υ ^neat _nax cm ^-1 : 3330 (NH), 1770, 1740, 1720, 1680 (C = 0). Mass spectrum (m/e): 595 (M ⁺ ) [α] _D -119° (c = 0.3, in methanol) Reference example 43 3(R)-[1(S)-ethoxycarbonyl obtained in Reference example 42 -5-phthalimidopentyl]amino-
4-oxo-2,3,4,5-tetrahydro-
0.2 g of 1,5-benzothiazepine-5-acetic acid tert-butyl ester is dissolved in a 5N hydrogen chloride-ethyl acetate solution and left at room temperature for 3 hours. When 50 ml of ethyl ether was added to the reaction solution and the precipitate was washed with 100 ml of ethyl ether, 3(R)-[1(S)-
0.13 g of ethoxycarbonyl-5-phthalimidopentylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride is obtained as a colorless powder. Elemental analysis value C ₂₇ H ₂₉ N ₃ O ₇ S・HCl・1/2H ₂ O
Calculated value: C 55.42; H 5.34; N 7.18 Actual value: C 55.09; H 5.12; N 7.15 [α] _D −114° (c=0.5, in methanol) Reference example 44 3(R )-[1(R)-ethoxycarbonyl-5-phthalimidopentyl]amino-
4-oxo-2,3,4,5-tetrahydro-
Dissolve 1.6 g of 1,5-benzothiazepine-5-acetic acid tert-butyl ester in 20 ml of ethanol,
Add 0.8 g of 85% hydrazine hydrate and leave at room temperature overnight. 200 ml of ethyl acetate and 200 ml of water were added to the reaction solution for extraction, and the ethyl acetate portion was washed with a 0.1N aqueous sodium hydroxide solution and then with water to obtain 3(R)-
An ethyl acetate solution of [5-amino-1(R)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester is can get. Add 1.6 g of sodium bicarbonate and 50 ml of water to this solution, and dropwise add a solution of 0.9 g of di-tert-butyl dicarbonate in 5 ml of ethyl acetate while stirring at room temperature.
After stirring for 30 minutes, the ethyl acetate layer is separated and dried over anhydrous magnesium sulfate. The oil obtained after distillation under reduced pressure was purified by silica gel column chromatography (hexane:acetone = 4:1) to yield 3(R)-[5-tert-butoxycarbonylamino-1(R)-ethoxycarbonylpentyl ]Amino-4-oxo-2,3,4,5-tetrahydro-
1.4 g of 1,5-benzothiazepine-5-acetic acid tert-butyl ester are obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3350 (NH), 1740, 1710, 1680 (C=0). Mass spectrum (m/e): 565 (M ⁺ ) Reference example 45 3(R)-[1(S)-ethoxycarbonyl-5-phthalimidopentyl]amino- obtained in Reference example 42
4-oxo-2,3,4,5-tetrahydro-
2.6 g of 1,5-benzothiazepine-5-acetic acid tert-butyl ester was treated with hydrazine in the same manner as in Reference Example 44, reacted with di-tert-butyl dicarbonate, and purified by silica gel column chromatography to obtain 3(R). -[5-tert-butoxycarbonylamino-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid
1.87 g of tert-butyl ester are obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3350 (NH), 1740, 1710, 1670 (C=0). Mass spectrum (m/e): 565 (M ⁺ ) [α] _D -136° (c = 0.8, in methanol) Reference example 46 3(R)-[5-tert-butoxycarbonylamino obtained in Reference example 45 -1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5
-tetrahydro-1,5-benzothiazepine-5
- Acetic acid tert-butyl ester 0.6g in methanol
Dissolve in a mixture of 40 ml and 25 ml of 1N sodium hydroxide, add 10 ml of water, and stir at room temperature for 2 hours. Methanol is distilled off under reduced pressure, the mixture is made weakly acidic with phosphoric acid, and extracted with ethyl acetate. After drying the extract over anhydrous magnesium sulfate and distilling it off under reduced pressure, 3(R)
-[5-tert-butoxycarbonylamino-1
(S)-Carboxypentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester
0.37 g is obtained as a colorless candy. When this product is treated with ethyl acetate, it becomes a colorless powder crystal. melting point
134-135℃ Elemental analysis value C ₂₆ H ₃₉ N ₃ O ₇ Calculated value as S: C 58.08; H 7.31; N 7.82 Actual value: C 58.11; H 7.22; N 7.73 IR υ ^nujol _nax cm ^-1 : 3350 (NH ), 1730, 1700, 1680 (C=0). Reference example 47 3(R)-amino-4-oxo- obtained in reference example 4
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 5
17.9 g of ethyl 2-bromo-6-phthalimidohexanoate are dissolved in 200 ml of acetonitrile, 2.46 g of triethylamine is added, and the mixture is refluxed for 45 hours. Acetonitrile is distilled off under reduced pressure, and 200 ml of water and 300 ml of ethyl acetate are added to the residue for extraction. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained oil was subjected to silica gel column chromatography (hexane:acetone=4:
1), the same product as obtained in Reference Example 42, 3(R)-[1(R)-ethoxycarbonyl-5-phthalimidopentyl]amino-4
-oxo-2,3,4,5-tetrahydro-1,
3.9 g of 5-benzothiazepine-5-acetic acid tert-butyl ester and 3(R)-[1(S)-ethoxycarbonyl-5-phthalimidopentyl]amino-4
-oxo-2,3,4,5-tetrahydro-1,
4.1 g of 5-benzothiazepine-5-acetic acid tert-butyl ester are obtained as a colorless oil. Reference example 48-50 3(R)-amino-4-oxo-2,3,4,5
-tetrahydro-1,5-benzothiazepine-5
- Acetic acid tert-butyl ester is reacted with the α-promo ester shown in Table 7 in the same manner as in Reference Example 47, resulting in the following benzothiazepine derivative.

【table】

[Table] *Diastereomer mixture obtained. Reference Examples 51-53 When the benzothiazepine derivatives obtained in Reference Examples 48-50 are treated with a hydrogen chloride ethyl acetate solution in the same manner as in Reference Example 43, the compounds shown in Table 8 are obtained.

[Table] * Diastereomer mixture reference examples 54-56 After treating the benzothiazepine derivatives obtained in Reference examples 48-50 with hydrazine in the same manner as in Reference example 44,
Reaction with di-tert-butyl dicarbonate gives the compounds shown in Table 9.

[Table] * Diastereomer mixture reference example 57 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5- was prepared in the same manner as in Reference example 47.
2 g of benzothiazepine-5-acetic acid tert-butyl ester and 7.1 g of ethyl 2-promo-11-phthalimidoundecanate are reacted. The obtained product was subjected to silica gel column chromatography.
When separated and purified using (hexane:ethyl acetate=3:1), the first fraction was 3(R)-[1(R)-ethoxycarbonyl-10-phthalimidodecyl]amino-4-oxo-2,3,4 ,5-tetrahydro-
1.2 g of 1,5-benzothiazepine-5-acetic acid tert-butyl ester are obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3320 (NH), 1770, 1740, 1710, 1680 (C=0) [α] _D −104° (c=0.5 in methanol) 3(R)-[ as second fraction 1(S)-Ethoxycarbonyl-10-phthalimidodecyl]amino-4
-oxo-2,3,4,5-tetrahydro-1,
1.2 g of 5-benzothiazepine-5-acetic acid tert-butyl ester are obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3320 (NH), 1770, 1740, 1710, 1670 (C = 0) [α] _D -113° (c = 0.5 in methanol) Reference example 58 3 (R) - [1 ( S)-ethoxycarbonyl-10-
Phthalimidodecyl]amino-4-oxo-2,
After treating 0.5 g of 3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester with hydrazine in the same manner as in Reference Example 44, di-
When reacted with tert-butyl dicarbonate and purified by silica gel column chromatography (hexane:ethyl acetate = 2:1), 3(R)-[10-
tert-Butoxycarbonylamino-1(S)-ethoxycarbonyldecyl]amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester
0.35 g is obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3400 (NH), 1740, 1710, 1670 (C = 0) [α] _D -127° (c = 0.7 in methanol) Reference example 59 3 (R) obtained in Reference example 4 -amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 1.5
Dissolve g in 50 ml of ethanol, 0.3 g of acetic acid, 4.2 g of ethyl 2-oxo-4-phenylbutyrate,
Add 8g of Molecular Sheep 4A. After stirring this mixture at room temperature for 30 minutes, a solution of 0.6 g of sodium cyanoborohydride in 40 ml of ethanol was added dropwise over 2 hours while stirring at room temperature. After stirring overnight at room temperature, 2.1 g of ethyl 2-oxo-4-phenylbutyrate was added, and a solution of 1.3 g of sodium cyanoborohydride in 40 ml of ethanol was added dropwise over 2 hours. The reaction solution was distilled off under reduced pressure, and water was added to the residue.
Add 100ml and 200ml of ethyl acetate and mix.
The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Add 50 ml of ethyl ether and 2 g of cylic acid to the residue, shake well, then add 300 ml of petroleum ether and leave overnight. Remove the solution portion by decanting, add 50 ml of water and 300 ml of ethyl acetate to the precipitate portion, and neutralize by adding excess sodium bicarbonate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to obtain an oil. This product was subjected to silica gel column chromatography (hexane: ethyl acetate =
5:1 to 10:3), first 3(R)
-[1(S)-Ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5
-tetrahydro-1,5-benzothiazepine-5
-0.55 g of acetic acid tert-butyl ester are obtained as an oil. IR υ ^neat _nax cm ^-1 : 3320 (NH), 1730 (ester),
1670 (amide) Elemental analysis value C ₂₇ H ₃₄ N ₂ O ₅ Calculated value as S: C 65.04; H 6.87; N 5.62 Actual value: C 65.36; H 6.91; N 5.61 From the following fractions, the above 3(R)-[ 1(R)-Ethoxycarbonyl-3-phenylpropyl]amino-
4-oxo-2,3,4,5-tetrahydro-
1,5-benzothiazepine-5-acetic acid tert-butyl ester and the following 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-
4-oxo-2,3,4,5-tetrahydro-
A mixture of 1,5-benzothiazepine-5-acetic acid tert-butyl ester, 0.4 g of the fraction in which the diastereomers could not be separated, is obtained as an oil. The mixing ratio is approximately 1:1. As a subsequent fraction, pure 3(R)-[1(S)
-ethoxycarbonyl-3-phenylpropyl]
Amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid
0.75 g of tert-butyl ester is obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3320 (NH), 1740 (ester),
1670 (amide) Elemental analysis value C ₂₇ H ₃₄ N ₂ O ₅ Calculated value as S: C 65.04; H 6.87; N 5.62 Actual value: C 64.90; H 6.63; N 5.66 Reference example 60 Same as Reference example 59, 3(R)-amino-4-
Oxo-2,3,4,5-tetrahydro-1,5
A reaction was carried out using 1.5 g of benzothiazepine-5-acetic acid tert-butyl ester and 5 g of ethyl 4-cyclohexyl-2-oxobutyrate obtained in Reference Example 5, and silica gel column chromatography (hexane:ethyl acetate= 4:1), the first fraction contains 3(R)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzothiazepine-5-acetic acid tert
-0.3 g of butyl ester are obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3320 (NH), 1730 (ester),
1670 (amide) Subsequently, as a second fraction, 3(R)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5 -benzothiazepine-5-acetic acid
0.45 g of tert-butyl ester is obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3320 (NH), 1730 (ester),
1670 (amide) Reference example 61 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 1 g, acetic acid 0.4 in 50 ml of ethanol g, 3.6 g of ethyl 4-(p-methylphenyl)-2-oxobutyrate, and 5 g of Molecular Sheep 4A were sequentially added thereto, and the mixture was stirred at room temperature for 1 hour. Add 0.5 g of 5% palladium on carbon to the mixed solution and perform catalytic reduction at room temperature and pressure. After reacting for 7 hours, the catalyst was removed, evaporated under reduced pressure, and treated with cyanic acid in the same manner as in Reference Example 59. The resulting oil was purified by silica gel column chromatography to yield 3(R)-[1-ethoxycarbonyl-3
-(p-Tolyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester
0.3 g is obtained as a colorless oil. This product is a mixture of two diastereomers (mixing ratio approximately 1:1). IR υ ^neat _nax cm ^-1 : 3320 (NH), 1730 (ester),
1670 (amide) Reference example 62 3(R)-amino-4-oxo-2,3,4,5
-tetrahydro-1,5-benzothiazepine-5
-When a reaction is carried out in the same manner as in Reference Example 61 using 1 g of acetic acid tert-butyl ester and 4 g of isobutyl 2-oxo-3-phenylbutyrate, 3(R)-
[1-Isoptoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-
0.45 g of acetic acid tert-butyl ester is obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3330 (NH), 1730 (ester),
1670 (amide) Reference example 63 3(R)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4- obtained in Reference example 59
Oxo-2,3,4,5-tetrahydro-1,5
-Benzothiazepine-5-acetic acid tert-butyl ester (0.5 g) was dissolved in 5 ml of 5N hydrogen chloride ethyl acetate solution and left overnight at room temperature. Add ether to the reaction solution
20ml and 100ml of petroleum ether were added, and the precipitated colorless powder was taken. 3(R)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4
-oxo-2,3,4,5-tetrahydro-1,
5-Benzothiazepine-5-acetic acid hydrochloride 0.42g
is obtained. Elemental analysis value C ₂₃ H ₂₆ N ₂ O ₅ Calculated value as S・HCl: C 57.68; H 5.68; N 5.85 Actual value: C 57.53; H 5.76; N 5.70 [α] ²² _D −173° (c=1, (in methanol) Reference Example 64-69 When the 1,5-benzothiazepine-5-acetic acid tert-butyl ester derivative obtained in Reference Example 59-62 was treated with hydrogen chloride in the same manner as Reference Example 63, the compounds shown in Table 10 were obtained. can get.

【table】

[Table] * Diastereomer mixture reference example 70 3(R)-[1-(R)-ethoxycarbonyl-3-phenylpropyl]amino-4 obtained in Reference Example 63
-oxo-2,3,4,5-tetrahydro-1,
5-benzothiazepine-5-acetic acid hydrochloride 0.1g
was dissolved in a mixture of 1 ml of ethanol and 3 ml of 1N aqueous sodium hydroxide solution, left at room temperature for 10 minutes, and then left in the refrigerator for 30 minutes. When the precipitated colorless flakes were collected, 3(R)-[1(R)-carboxy-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5 -Benzothiazepine-5-acetic acid disodium salt 0.05
g is obtained. Melting point 215-220℃ IR υ ^neat _nax cm ^-1 : 1660 (amide), 1600 (carboxylate) Elemental analysis value C ₂₁ H ₂₀ N ₂ O ₅ Calculated value as S・5/2H ₂ O: C 50.10; H 5.00 ;N 5.56 Actual value: C 50.28; H 5.29; N 5.91 Reference example 71 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4- obtained in Reference example 65
Oxo-2,3,4,5-tetrahydro-1,5
-Dissolve 0.2 g of benzothiazepine-5-acetic acid in 2 ml of ethanol and 6 ml of 1N aqueous sodium hydroxide solution. After standing at room temperature for 30 minutes, the solution was distilled off under reduced pressure at room temperature to make a liquid volume of approximately 1 ml. Neutralize with acetic acid to make it weakly acidic, and remove the precipitated colorless prism crystals.
3(R)-[1(S)-carboxy-3-phenylpropyl]amino-4-oxo-2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-
0.134 g of acetic acid monosodium salt is obtained. Melting point 166−169℃ IR υ ^neat _nax cm ^-1 : 1720 (carboxylic acid), 1670 (amide),
1640 (carboxylate) [α] ²² _D −122° (c = 0.2 (methanol: water = 1:
1)] Reference example 72-75 Reference example using the aminobenzothiazepine acetic acid tert-butyl ester derivative obtained in Reference examples 23-26
When reacted with ethyl 2-oxo-4-phenylbutyrate in the same manner as No. 59, the compound in Table 11 is obtained as an oil.

【table】

[Table] * Diastereomer mixture reference example 76-82 1-ethoxycarbonyl obtained in reference example 72-75
When a 3-phenylpropylaminobenzothiazepine derivative is treated with hydrogen chloride in the same manner as in Reference Example 63, the table
The compound shown in 12 is obtained as a colorless powder.

[Table] * Diastereomer mixture reference example 83-87 3(R)-amino-4-oxo- obtained in Reference example 4
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester and the α-ketoester obtained in Reference Example 27-30 or ethyl pyruvate were reacted in the same manner as in Reference Example 59. When this is done, the compounds shown in Table 13 are obtained as oils.

[Table] * Diastereomer mixture reference example 88-93 When the 1,5-benzothiazepine-5-acetic acid tert-butyl ester derivative obtained in Reference example 83-87 is treated with hydrogen chloride in the same manner as in Reference example 63, The compounds shown in Table 14 are obtained as colorless powders.

[Table] * Diastereomer mixture reference example 94 3(R)-amino-4-oxo- obtained in Reference example 34
Dissolve 0.65 g of 7-trifluoromethyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid/hydrobromide in 50 ml of ethanol, 0.2 g of sodium acetate, and 0.19 g of acetic acid. , 1.67 g of ethyl 2-oxo-4-phenylbutyrate,
Add 5 g of Molecular Sieve 4A and stir at room temperature for 1 hour. An ethanol solution of 0.56 g of sodium cyanoborohydride was added dropwise to this mixed solution over 2 hours. Distill the solvent under reduced pressure and add 50 ml of water and 150 ml of ethyl acetate.
ml was added, insoluble materials were removed, the ethyl acetate layer was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. When the residue is dissolved in a mixture of ether and petroleum ether and a hydrogen chloride-ethyl acetate solution is added, 3(R)-[1
-ethoxycarbonyl-3-phenylpropyl]
Amino-4-oxo-7-trifluoromethyl-
0.7 g of 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride is precipitated as a colorless powder. [α] _D -95° (in methanol) Mass spectrum: m/e510 (M ⁺ ) Reference example 95 3(R)-[1(S)-ethoxylcarbonyl-3-phenylpropyl] obtained in Reference example 65 Amino
4-oxo-2,3,4,5-tetrahydro-
1,5-benzothiazepine-5-acetic acid hydrochloride
Dissolve 0.3 g in 10 ml of dimethylformamide, add 1 g of sodium hydrogen carbonate and 0.15 g of benzyl bromide, and stir overnight at room temperature. 100ml of water to the reaction solution
was added, extracted with 200 ml of ethyl acetate, washed with water, aqueous sodium bicarbonate, water, 0.1N hydrochloric acid, and water in that order, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the resulting oil was diluted with ether.
Dissolve in 30ml hydrogen chloride-ethyl acetate solution (5N)
When 0.5ml is added dropwise, 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4
-oxo-2,3,4,5-tetrahydro-1,
0.25 g of 5-benzothiazepine-5-acetic acid benzyl ester hydrochloride precipitates as a colorless powder. Elemental analysis value C ₃₀ H ₃₂ N ₂ O ₅ Calculated value as S・HCl: C 63.31; H 5.84; N 4.92 Actual value: C 63.02; H 5.82; N 5.19 Mass spectrum (m/e): 532 (M ⁺ ) [α] _D -90° (in methanol) Reference example 96 3(R)-[1(S)-ethoxylcarbonyl-3
-phenylpropyl]amino-4-oxo-2,
3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, benzyl ester, hydrochloride
Dissolve 0.1g in 10ml of ethanol and use 0.2g of 10% palladium on carbon (50% water content) as a catalyst at room temperature.
Catalytic reduction is carried out under normal pressure. remove the catalyst,
When the liquid was distilled off under reduced pressure and a mixture of ether and petroleum ether was added to the liquid, 3, which was the same as that obtained in Reference Example 65, was obtained.
(R)-[1(S)-ethoxylcarbonyl-3-phenylpropyl]amino-4-oxo-2,3,
0.05 g of 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride is obtained as a colorless powder. Reference Example 97 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4- obtained in Reference Example 65
Oxo-2,3,4,5-tetrahydro-1,5
-Dissolve 0.5 g of benzothiazepine-5-acetic acid hydrochloride in 50 ml of methylene chloride, and while stirring at room temperature, add 0.5 g of m-chloroperbenzoic acid little by little.
Add in 2.5 hours. After stirring for 1 hour at room temperature,
Extract by adding 200ml of water and 50ml of methylene chloride,
The methylene chloride layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. When the residue was dissolved in 100 ml of ethyl ether and 0.5 ml of hydrogen chloride-ethyl acetate solution (5N) was added, 3(R)-[1(S)-
Ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid S-
0.3 g of oxide/hydrochloride precipitates as a colorless powder. Elemental analysis value C ₂₃ H ₂₆ N ₂ O ₆ Calculated value as S・HCl・H ₂ O: C 53.85; H 5.70; N 5.46 Actual value: C 54.24; H 5.70; N 5.27 Mass spectrum (m/e): 458 (M ⁺ ) [α] _D −80° (in methanol) Reference example 98 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4- obtained in Reference example 65
Oxo-2,3,4,5-tetrahydro-1,5
-Benzothiazepine-5-acetic acid hydrochloride 0.5g and L-phenylalanine tert-butyl ester 0.3
g was dissolved in 10 ml of dimethylformamide, and a solution of 0.23 g of diethyl cyanophosphate in 2 ml of dimethylformamide was added dropwise under ice cooling. After stirring for 10 minutes,
A solution of 0.23 g of triethylamine in 2 ml of dimethylformamide was added dropwise, and the mixture was stirred for 30 minutes under ice cooling. Add 200ml of ethyl acetate and 100ml of water to the reaction solution for extraction, and add the ethyl acetate layer to 0.02N hydrochloric acid and 0.05N
The mixture is washed with an aqueous sodium hydroxide solution and then with water, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. The residue was dissolved in petroleum ether and 1 ml of hydrogen chloride-ethyl acetate solution (5N) was added to give 3(R)-[1(S)-
Ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl-N-
0.63 g of acetyl-L-phenylalanine tert-butyl ester hydrochloride precipitates as a colorless powder. Elemental analysis value C ₃₆ H ₄₃ N ₃ O ₆ S・HCl・1/2H ₂ O
Calculated value: C 62.55; H 6.56; N 6.08 Actual value: C 62.61; H 6.77; N 5.89 Mass spectrum (m/e): 645 (M ⁺ ) [α] _D -79° (in methanol) Reference example 99 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino- obtained in Reference Example 98
4-oxo-2,3,4,5-tetrahydro-
Dissolve 0.45 g of 1,5-benzothiazepin-5-yl-N-acetyl-L-phenylalanine tert-butyl ester hydrochloride in 5 ml of hydrogen chloride-ethyl acetate solution (5N) and leave at room temperature for 3 hours. After that,
Distill under reduced pressure. When a mixture of ethyl acetate and ethyl ether is added to the residue, 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-
0.26 g of 1,5-benzothiazepin-5-yl-N-acetyl-L-phenylalanine hydrochloride is obtained as colorless crystals. Melting point 153-157℃ Elemental analysis value C ₃₂ H ₃₅ N ₃ O ₆ Calculated value as S・HCl: C 61.38; H 5.79; N 6.71 Actual value: C 61.21; H 5.78; N 6.66 Mass spectrum (m/e): 589 (M ⁺ ) [α] _D -96° (in methanol) Reference example 100 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4- obtained in Reference example 59
Oxo-2,3,4,5-tetrahydro-1,5
-Dissolve 1 g of benzothiazepine-5-acetic acid tert-butyl ester in 100 ml of methylene chloride,
Add 0.51 g of m-chloroperbenzoic acid and stir for 30 minutes. Furthermore, after adding 0.15 g of m-chloroperbenzoic acid and stirring for 30 minutes, 50 ml of 1N aqueous sodium hydroxide solution was added, and the methylene chloride layer was separated.
After washing with water, evaporate under reduced pressure. Product 3(R)-[1(S)
-ethoxycarbonyl-3-phenylpropyl]
Amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid
Tert-butyl ester 1-oxide is a mixture of two stereoisomers, and when separated by silica gel column chromatography, the pre-flow fraction is 0.3
g, and 0.5 g as a backflow fraction were obtained as a colorless oil, both of which showed a molecular ion peak of 514 in the mass spectrum. Reference Example 101 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4- obtained in Reference Example 59
Oxo-2,3,4,5-tetrahydro-1,5
-Dissolve 0.8 g of benzothiazepine-5-acetic acid tert-butyl ester in 6 ml of ethanol, add 3 ml of 1N aqueous sodium hydroxide solution, and stir at room temperature for 2 hours. Add 200 ml of water to the reaction solution, extract with 100 ml of ethyl ether, and make the aqueous layer weakly acidic with 1N hydrochloric acid to obtain 3(R)-[1(S)-carboxy-3-phenylpropyl]amino-4-oxo. -2,3,
0.5 g of 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester is obtained as colorless crystals. Melting point 165-167℃ [α] _D -101° (in methanol) Elemental analysis value Calculated value as C ₂₅ H ₃₀ N ₂ O ₅ S: C 63.81; H 6.43; N 5.95 Actual value: C 63.69; H 6.38; 5.87 Reference Example 102 3(R)-[1(S)-carboxy-3-phenylpropyl]amino-4-oxo- obtained in Reference Example 101
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 0.3
Dissolve g in 10 ml of dimethylformamide, add 0.5 g of sodium bicarbonate and 0.15 g of benzyl bromide, and stir overnight at room temperature. Water (100ml) to the reaction solution
and ethyl acetate (200ml) for extraction, and the extract was washed with 0.1N hydrochloric acid and water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 3(R)-[1(S)-
Benzyloxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid
0.35 g of tert-butyl ester is obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3330 (NH), 1740 (ester),
1680 (amide) Mass spectrum (m/e): 560 (M ⁺ ) Reference example 103 3(R)-[1(S)-benzyloxycarbonyl-3-phenylpropyl]amino-4 obtained in Reference example 102 -oxo-2,3,4,5-tetrahydro-
When 0.35 g of 1,5-benzothiazepine-5-acetic acid tert-butyl ester was treated with hydrogen chloride in the same manner as in Example 5, 3(R)-[1(S)-benzyloxycarbonyl-3-phenylpropyl ]Amino-4-oxo-2,3,4,5-tetrahydro-
1,5-benzothiazepine-5-acetic acid hydrochloride
0.25 g is obtained as a colorless powder. Elemental analysis value C ₂₈ H ₂₈ N ₂ O ₅ Calculated value as S・HCl: C 62.16; H 5.40; N 5.18 Actual value: C 61.77; H 5.44; N 4.96 [α] _D −82° (in methanol) Mass spectrum (m/e): 504 (M ⁺ ) Reference example 104 3(R)-amino-4-oxo- obtained in Reference example 4
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 2
Dissolve g in 20 ml of ethanol and add ethyl bromoacetate.
Add 1.6 g and 1 g of triethylamine and leave at room temperature overnight. The reaction solution was dried under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:
When purified with ethyl acetate = 2:1), 3(R)-ethoxycarbonylmethylamino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 1.8
g is obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3330 (NH), 1740 (ester),
1670 (amide) Mass spectrum (m/e): 394 (M ⁺ ) Reference example 105 3(R)-ethoxycarbonylmethylamino-4-oxo-2,3,4,5-tetrahydro- obtained in Reference example 104 1.8 g of 1,5-benzothiazepine-5-acetic acid tert-butyl ester is dissolved in 15 ml of hydrogen chloride-ethyl acetate solution (5N) and left at room temperature for 3 hours. When 50 ml of ethyl ether was added to the reaction solution, 3(R)-ethoxycarbonylmethylamino-
4-oxo-2,3,4,5-tetrahydro-
1,5-benzothiazepine-5-acetic acid hydrochloride
1.6 g is obtained as colorless prismatic crystals. Melting point 223-225° (decomposition) Elemental analysis value C ₁₅ H ₁₈ N ₂ O ₅ Calculated value as S・HCl: C 48.06; H 5.11; N 7.47 Actual value: C 47.99; H 5.11; N 7.25 [α] _D − 193° (in methanol) Mass spectrum (m/e): 338 (M ⁺ ) Reference example 106 3(R)-(N-benzyl-N-
Dissolve 0.5 g of ethoxycarbonylmethylamino)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride in 20 ml of ethanol, and dissolve 0.5 g of 10% palladium-carbon (50 %
A catalytic reduction reaction is carried out at room temperature and pressure using 0.5g of water-containing water as a catalyst. When hydrogen absorption stops, the catalyst is removed and the liquid is distilled off under reduced pressure to precipitate crystals. When ethyl acetate is added, 3(R)-ethoxycarbonylmethylamino-4-oxo-2,
0.3 g of 3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid is obtained as colorless prismatic crystals. Melting point 223-226℃ [α] _D -171° (in methanol) Mass spectrum (m/e): 338 (M ⁺ ) Reference example 107 3(R)-Ethoxycarbonylmethylamino-4- obtained in Reference example 105 Add 0.5 g of oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride to 5 g of 1N aqueous sodium hydroxide solution.
ml and leave at room temperature for 3 hours. After neutralizing with 1N hydrochloric acid, adsorb onto Amberlite IR-45. After draining the target product with 1% ammonia water and drying it under reduced pressure, a mixture of ethanol and ether was added and the precipitated powder was taken to obtain 3(R)-carboxymethylamino-4-oxo-2,3,4. ,5-
Tetrahydro-1,5-benzothiazepine-5-
0.25 g of acetic acid is obtained. Elemental analysis value Calculated value as C ₁₃ H ₁₄ N ₂ O ₅ S・2H ₂ O: C 45.09; H 5.24; N 8.09 Actual value: C 45.19; H 4.94; N 8.03 [α] _D −196° (in water) Reference Example 108 3(R)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro- obtained in Reference Example 67
1,5-benzothiazepine-5-acetic acid hydrochloride
Dissolve 0.1 g in 2 ml of methanol, add 1.5 ml of 1N aqueous sodium hydroxide solution, and leave at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure at 40°C or below to a volume of approximately 1 ml, and make it weakly acidic with 1N hydrochloric acid to obtain 3(R).
-[1(S)-carboxy-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-
0.067 g of acetic acid is obtained as colorless prismatic crystals.
Melting point 207-210℃ Elemental analysis value C ₂₁ H ₂₈ N ₂ O ₅ Calculated value as S・H ₂ O: C 57.52; H 6.89; N 6.39 Actual value: C 57.20; H 6.91; N 6.42 [α] _D −137 ° (c=1, in methanol) Reference example 109 3(R)-(1-ethoxylcarbonyl-5-phthalimidopentyl)amino-4 obtained in Reference example 37
-oxo-2,3,4,5-tetrahydro-1,
Dissolve 0.7 g of 5-benzothiazepine-5-acetic acid ethyl ester in 20 ml of ethanol, and add 0.3 g of 85% hydrazine hydrate. 85% hydrazine hydrate 0.3
After adding g after 1 hour and 2 hours, leave it for one night. Ethanol is distilled off under reduced pressure, and water is added to the residue.
Add 50 ml, add salt to saturate, and extract three times with 100 ml of ethyl acetate. The extract is washed with 50 ml of 0.1N aqueous sodium hydroxide solution, followed by 100 ml of water, and dried over anhydrous magnesium sulfate. Add 0.5 N hydrogen chloride ethyl acetate solution to the obtained ethyl acetate solution.
ml and evaporated under reduced pressure, and ethyl ether was added to the residue to give 3(R)-(5-amino-1-ethoxycarbonylpentyl)amino-4-oxo-2,
3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester dihydrochloride
0.13 g is obtained as a colorless powder. Elemental analysis value C ₂₁ H ₃₁ N ₃ O ₅ Calculated value as S・2HCl・H ₂ O: C 47.73; H 6.67; N 7.95 Actual value: C 47.81; H 6.53; N 7.83 Mass spectrum (m/e): 437 (M ⁺ ) Reference Example 110 1 3(R)-(5-amino-1-
ethoxycarbonylpentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5
-Dissolve 50 mg of benzothiazepine-5-acetic acid ethyl ester dihydrochloride in a mixture of 30 ml of ethyl acetate and 10 ml of water, and dissolve benzyloxycarbonyl chloride.
Add 0.15 ml and 0.3 g of sodium bicarbonate and stir at room temperature for 25 hours. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained oil was dissolved in a mixture of 20 ml of ethyl ether and 20 ml of petroleum ether, and 0.2 ml of 5N hydrogen chloride ethyl acetate solution was added to give 3(R)-(5
-benzyloxycarbonylamino-1-ethoxycarbonylpentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester.
55 mg of hydrochloride are obtained as a colorless powder. Mass spectrum (m/e): 571 (M ⁺ ) 2 3(R)-(5-benzyloxycarbonylamino-1-ethoxycarbonylpentyl)amino-4-oxo-2 obtained in Reference Example 110-(1) ,3,
4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester hydrochloride 55 mg
Dissolve in a mixture of 3 ml of ethanol and 2 ml of 1N aqueous sodium hydroxide solution, and leave at room temperature for 1 hour. Add 50ml of water to the reaction solution and add 20ml of ethyl ether.
After extraction, the aqueous layer is adjusted to pH 4 with 1N hydrochloric acid.
After adding ammonium chloride to a saturated solution, the aqueous layer is extracted 10 times with 20 ml of ethyl acetate. The extract was washed with a small amount of water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
(R)-(5-benzyloxycarbonylamino-1-carboxypentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-
40 mg of benzothiazepine-5-acetic acid are obtained as a colorless powder. Mass spectrum (m/e): 515 (M ⁺ ) 3 3(R)-(5-benzyloxycarbonylamino-1-carboxypentyl)amino-4-oxo-2, obtained in Reference Example 110-(2) 3,4,5-
Tetrahydro-1,5-benzothiazepine-5
- Dissolve 40 mg of acetic acid in 1 ml of acetic acid, add 1 ml of 30% hydrogen bromide acetic acid solution, and leave at room temperature for 1 hour. After adding 80 ml of ethyl ether and 20 ml of petroleum ether to the reaction solution and stirring, let it stand, remove the supernatant liquid by decanting, collect the precipitate, and dry it.
3(R)-(5-amino-1-carboxypentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-
33 mg of acetic acid dihydrobromide are obtained as a colorless powder. SIMS spectrum (m/e): 382 (MH ⁺ ); KI addition 420 (M+K) ⁺ Reference example 111 3(R)-[2(S)-benzyloxycarbonylamino-1-ethoxycarbonyl obtained in Reference example 39 -3-phenylpropyl]amino-4-oxo-
When 0.22 g of 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester was treated with hydrogen bromide in the same manner as in Reference Example 110-(3), 3(R)-[2 (S)-amino-1-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-
Benzothiazepine-5-acetic acid ethyl ester
0.18 g of dihydrobromide is obtained as a colorless powder. Elemental analysis value C ₂₅ H ₃₁ N ₃ O ₅ Calculated value as S・2HBr・H ₂ O: C 45.12; H 5.30; N 6.31 Actual value: C 45.11; H 5.28; N 6.27 Mass spectrum (m/e): 485 (M ⁺ ) Reference Example 112 3(R)-[2(S)-amino-1 obtained in Reference Example 111
-ethoxycarbonyl-3-phenylpropyl]
Mix 0.15 g of amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester dihydrobromide with 5 ml of methanol and 5 ml of 1N sodium hydroxide. Dissolve in and leave at room temperature for 1 hour. Distill the methanol under reduced pressure, add 10ml of water, and add Amberlite XAD.
Purify by -2 column chromatography (methanol:water = 1:1). The effluent was concentrated under reduced pressure and then lyophilized to give 3(R)-[2(S)-amino-
1-Carboxy-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-
37 mg of 1,5-benzothiazepine-5-acetic acid disodium salt are obtained as a colorless powder. Elemental analysis value C ₂₁ H ₂₁ N ₃ Na ₂ O ₅ S・32H ₂ O Calculated value: C 50.40; H 4.83; N 8.40 Actual value: C 50.42; H 5.08; N 8.53 SIMS spectrum (m/e): 474 (MH ⁺ ), 452, 430. KI addition: 506, 468, 430. Reference example 113 3(R)-amino-4-oxo- obtained in Reference example 41
Ethyl
When reacted with 4-cyclohexyl-2-oxobutyrate and purified by silica gel column chromatography (hexane: ethyl acetate = 4:1), the first
As a fraction, 3(R)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-
Oxo-2,3,4,5-tetrahydro-1,5
-benzothiazepine-5-α-methylacetic acid tert
-Butyl ester is obtained as an oil. Mass spectrum (m/e): 518 (M ⁺ ) Then, as the second fraction, 3(R)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]
0.28 g of amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-α-methylacetic acid tert-butyl ester is obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 1740, 1670 (C=0) [α] ²³ _D −222° (c=0.4 in methanol) Mass spectrum (m/e): 518 (M ⁺ ) Reference example 114, 115 Reference 1,5-Benzothiazepine obtained in Example 113
When the 5-α-methyl-acetic acid tert-butyl ester derivative was treated with hydrogen chloride in the same manner as in Reference Example 63, the following
The compound shown in 15 is obtained.

[Table] Reference Examples 116, 117 When the benzothiazepine derivatives obtained in Reference Examples 44 and 45 are treated with hydrogen chloride in the same manner as in Reference Example 63, the compounds shown in Table 16 are obtained as colorless crystals.

[Table] Reference Example 118 3(R)-[5-amino-1(S) obtained in Reference Example 117
-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-
Benzothiazepine-5-acetic acid dihydrochloride 0.2g
Add to 4 ml of 1N sodium hydroxide aqueous solution and stir at room temperature for 1.5 hours. The reaction solution was made weakly acidic by adding 1 ml of acetic acid, and then purified by Amberlite XAD-2 column chromatography (methanol:water = 3:7). The effluent was concentrated under reduced pressure and then lyophilized to give 3(R)-[5-amino-1(S)-carboxypentyl]amino-4-oxo-2,3,4,5
-tetrahydro-1,5-benzothiazepine-5
-0.1 g of acetic acid is obtained as a colorless powder. Elemental analysis value C ₁₇ H ₂₃ N ₃ O ₅ Calculated value as S・H ₂ O: C 51.12; H 6.31; N 10.52 Actual value: C 50.87; H 5.83; N 10.34 [α] _D −149° (c=0.3 in 1N hydrochloric acid) SIMS spectrum (m/e): 382 (MH ⁺ ); KI addition 420 (M+K) ⁺ Reference example 119 3(R)-[5-tert-butoxycarbonylamino-1 ( S)-carboxypentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid
When 0.32 g of tert-butyl ester was treated with hydrogen chloride in the same manner as in Reference Example 63, 3(R)-[5-amino-1(S)-carboxypentyl]amino-4
-oxo-2,3,4,5-tetrahydro-1,
5-Benzothiazepine-5-acetic acid dihydrochloride 0.26
g is obtained as a colorless powder crystal. Elemental analysis value C ₁₇ H ₂₃ N ₃ O ₅ S・2HCl・CH ₃
Calculated value as COOC ₂ H ₅ : C 46.49; H 6.13; N 7.75 Actual value: C 46.12; H 6.16; N 7.52 Dissolve 0.15 g of this product in 2 ml of water, add 0.5 ml of 1N aqueous sodium hydroxide solution, and then add 0.5 ml of acetic acid. After adding Amberlight XAD in the same manner as Reference Example 118
-2 gives 0.096 g of the same educt as obtained in Example 60. Reference Examples 120-122 When the benzothiazepine derivatives obtained in Reference Examples 54-56 are treated with a hydrogen chloride ethyl acetate solution in the same manner as in Reference Example 63, the compounds shown in Table 17 are obtained.

[Table] * Diastereomer mixture reference example 123 3(R)-[1(S)-ethoxycarbonyl-5-phthalimidopentyl] obtained in Reference example 42 or 47
Amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid
When 0.5 g of tert-butyl ester was treated with hydrazine in the same manner as in Reference Example 44 and then reacted with benzoyl chloride, 3(R)-[5-benzoylamino-1(S)-ethoxycarbonylpentyl]amino-4- Oxo-2,3,4,5-tetrahydro-
0.14 g of 1,5-benzothiazepine-5-acetic acid tert-butyl ester is obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3350 (NH), 1740 (ester),
1660 (amide) Reference example 124 3(R)-[1(S)-ethoxycarbonyl-5-
Phthalimidopentyl amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 0.5
When g was treated with hydrazine in the same manner as in Reference Example 44 and then reacted with acetyl chloride, 3(R)-[5-acetylamino-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4 , 0.25 g of 5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester are obtained as a colorless oil. IR υ ^neat _nax cm ^-1 : 3320 (NH), 1730 (ester),
1660 (Amide) Reference Examples 125, 126 When the benzothiazepine derivatives obtained in Reference Examples 123 and 124 are treated with a hydrogen chloride ethyl acetate solution in the same manner as in Reference Example 63, the compounds shown in Table 18 are obtained.

[Table] Reference Example 127 3(R)-[5-amino-1(S) obtained in Reference Example 117
-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-
Dissolve 0.2 g of benzothiazepine-5-acetic acid dihydrochloride in 10 ml of ethanol, and add 2 g of cyclohexanone.
and 0.3g of sodium cyanoborohydride,
Leave at room temperature overnight. After distilling off the ethanol under reduced pressure, add 4 ml of 1N aqueous sodium hydroxide solution to the residue.
Add and stir at room temperature for 1 hour. 20% water to reaction solution
ml and extracted three times with 20 ml of ethyl acetate. After adding 1 ml of acetic acid to the aqueous layer to make it slightly acidic, it was purified by Amberlite XAD-2 column chromatography (methanol:water = 1:1), and the effluent was concentrated and freeze-dried. ) [1(S)-carboxy-5-cyclohexylaminopentyl]amino-
4-oxo-2,3,4,5-tetrahydro-
0.12 g of 1,5-benzothiazepine-5-acetic acid is obtained as a colorless powder. Elemental analysis value C ₂₃ H ₃₃ N ₃ O ₅ Calculated value as S・H ₂ O: C 57.36; H 7.32; N 8.72 Actual value: C 56.86; H 7.48; N 8.34 [α] _D −117° (c=0.5 in methanol) SIMS spectrum (m/e): 464 (MH ⁺ ) KI addition 502 (M+K) ⁺ , 464 Reference example 128, 129 3(R)-[5-amino-1(S) obtained in Reference example 117
-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-
Reference example: benzothiazepine-5-acetic acid dihydrochloride
In the same manner as 127, the benzothiazepine derivatives shown below are obtained by reacting with the carbonyl compounds shown in Table 19 and then hydrolyzing them.

〔experimental method〕

The method of Cushman et al. (Biochemical
The experiment was conducted using a method modified from Pharmacology, Vol. 20, p. 1637, 1971). That is, from the hippuric acid production inhibition rate when the present compound is added to the amount of hippuric acid produced by ACE using hipuryl-L-histidyl-L-leucine (HHL) as a base,
The ACE inhibitory effect was determined. ACE100μl (protein concentration 20
mg/ml), 0.02-0.5% dimethyl sulfoxide in 100μl of 1.25mMHHL in 100mM boric acid-hydrochloric acid buffer (PH
8.3, a solution of the compound of the present invention dissolved in a solution (containing 300 mM common salt) was added. As a control, a boric acid-hydrochloric acid buffer containing dimethyl sulfoxide at the same concentration as the sample solution was provided. After heating this solution at 37°C for 1 hour, 150 μl of 1N hydrochloric acid was added to stop the reaction, 0.8 ml of ethyl acetate was added, and the mixture was heated at 11,500 rpm.
Minute centrifugation. Take 0.5 ml of ethyl acetate layer and add 40
The mixture was dried under nitrogen gas at a temperature below .degree. C., and 4.5 ml of distilled water was added to the residue, mixed well, and the mixture was colorimetrically determined at a wavelength of 228 nm. [Experimental Results] The experimental results regarding the compounds of the present invention were as shown in Table 20.

〔experimental method〕

Breeding with free access to food and water, weight 250-350
G male rats (Sprague Dawley) were used.
The day before the experiment, pentobarbital sodium (50
After the rats were anesthetized by intraperitoneal injection of 2 mg/kg), polyethylene tubes were inserted and fixed into the femoral artery for blood pressure measurement and the femoral vein for injecting angiotensin I and angiotensin I, respectively. On the day of the experiment, the average blood pressure during the control period was measured using an electric sphygmomanometer (NEC-Sanei, MPU-0.5-290-0-) and recorded with a polygraph (NEC-Sanei, model 365 or Nihon Kohden, model RM-45). After that, 300 ng/Kg of angiotensin I and then 100 ng/Kg of angiotensin were injected into the femoral vein to examine their pressor effect. Next, compound 3 of the present invention and
10 mg/Kg was orally administered as an aqueous solution or gum arabic suspension, and angiotensin I was repeatedly injected 20, 60, and 120 minutes after administration to monitor the pressor response. In calculating the inhibition rate for the pressor action of angiotensin I, the inhibition rate was corrected based on the temporal fluctuation of the angiotensin pressor response. [Experimental Results] The experimental results regarding the compounds of the present invention were as shown in Table 21.

[Experimental results]

The experimental results regarding the compounds of the present invention were as shown in Table 22.

【table】

Claims (1)

[Claims] 1 formula [In the formula, R ¹ and R ² each represent hydrogen, halogen, trifluoromethyl, lower alkyl, or lower alkoxy, or both are linked to form tri or tetramethylene, and R ³ is hydrogen, lower alkyl, or Indicates aralkyl, R ⁴ is C5-16 alkyl optionally substituted with hydroxy, lower alkoxy, mercapto, lower alkylthio, amino, mono- or di-lower alkylamino, acylamino or cycloalkylamino , and X is S(O)n (where n is 0 to
2), and Y represents carboxyl, lower alkoxycarbonyl, aralkyloxycarbonyl, or carboxyl amidated with an α-amino acid in which the carboxyl group may be protected with lower alkyl or aralkyl. , m represents 1 or 2] or a salt thereof. 2 R ¹ and R ² are hydrogen, halogen,
The compound according to claim 1, which represents trifluoromethyl, lower alkyl, or lower alkoxy, or the two are linked to form trimethylene. 3. The compound according to claim 1, wherein R ¹ and R ² are both hydrogen. 4. The compound according to claim 1, wherein R ³ is hydrogen or lower alkyl. 5. The compound according to claim 1, wherein R ³ is hydrogen or ethyl. 6 ^C5-16 alkyl substituted with amino, mono- or di-lower alkylamino, cycloalkylamino or acylamino The compound according to claim 1, which is 7. The compound according to claim 1, wherein ^R4 is alkyl having 5 to 9 carbon atoms substituted with amino, mono- or di-lower alkylamino, cycloalkylamino, lower alkanoylamino or benzamide. 8 R ⁴ is substituted with amino and has 5 or 6 carbon atoms
The compound according to claim 1, which is an alkyl of 9. The compound according to claim 1, wherein R ⁴ is aminohexyl. 10 Claim 1 in which n is 0 or 1
Compounds described in Section. 11. The compound according to claim 1, wherein n is 0. 12. The compound according to claim 1, wherein Y is carboxyl. A compound according to claim 1, wherein 13 C _n H _2n is methylene or ethylidene. The compound according to claim 1, wherein 14 C _n H _2n is methylene. 15 R ₄ Hydroxy, lower alkoxy, mercapto, lower alkylthio, amino or C5-16 alkyl optionally substituted with mono- or di-lower alkylamino and C _n
2. A compound according to claim 1, wherein H _2n is methylene or ethylene. 16 R ¹ and R ² are hydrogen, halogen,
trifluoromethyl, lower alkyl or lower alkoxy, or both linked to form trimethylene, and R ₄ is Hydroxy, lower alkoxy,
C5-16 alkyl optionally substituted with mercapto, lower alkylthio, amino or mono- or di-lower alkylamino The compound according to claim 1, wherein m is 1 and n is 0 or 1. 17 R ¹ and R ² are both hydrogen, R ³ is hydrogen or lower alkyl, and R ⁴ may be substituted with amino, mono- or di-lower alkylamino, cycloalkylamino, lower alkanoylamino or benzamide is alkyl having 5 to 16 carbon atoms, Y is carboxyl, and m is 1
The compound according to claim 1, wherein n is 0. 18 Claim 17, wherein R ⁴ is alkyl having 5 to 9 carbon atoms substituted with amino, mono- or di-lower alkylamino, cycloalkylamino, lower alkanoylamino, or benzamide.
Compounds described in Section. 18. The compound according to claim 17, wherein 19 R ⁴ is alkyl having 5 to 9 carbon atoms substituted with amino. 20. The compound according to claim 19, wherein R ⁴ is alkyl having 5 or 6 carbon atoms substituted with amino. 21. The compound according to claim 17, wherein R ⁴ is aminohexyl. 22 formula [In the formula, R ¹ and R ² each represent hydrogen, halogen, trifluoromethyl, lower alkyl, or lower alkoxy, or both are linked to form tri or tetramethylene, and R ³ is hydrogen, lower alkyl, or Indicates aralkyl, R ⁴ is C5-16 alkyl optionally substituted with hydroxy, lower alkoxy, mercapto, lower alkylthio, amino, mono- or di-lower alkylamino, acylamino or cycloalkylamino , and X is S(O)n (where n is 0 to
2), and Y represents carboxyl, lower alkoxycarbonyl, aralkyloxycarbonyl, or carboxyl amidated with an α-amino acid in which the carboxyl group may be protected with lower alkyl or aralkyl. , m represents 1 or 2] or a salt thereof.