JPH0566389B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a novel fused 7-membered ring compound useful as a medicine and an antihypertensive/therapeutic agent containing the same. Prior Art and Problems to be Solved by the Invention Although various compounds are known that have angiotensin-converting enzyme inhibitory activity, a compound having a fused 7-membered ring as its basic skeleton was described in European Patent Publication No. 72352. Only things are known. The present inventors have actively searched for compounds that have angiotensin-converting enzyme inhibitory activity and are useful as therapeutic agents for cardiovascular diseases such as hypertension, heart disease, and stroke. The production was successful and the present invention was completed. Means for solving the problems 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 represent tri or tetramethylene, and R ³ and R ⁵ each represent hydrogen , lower alkyl or aralkyl,
R ⁴ represents hydrogen or lower alkyl, R ⁶ represents a fused or non-fused heteroalicyclic group containing at least one N, O or S as a ring atom, A represents an alkylene chain, and n represents 1 or 2. The present invention provides a compound represented by the following formula or 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, butoxy, isobutoxy, sec-butoxy, tert-
Examples include alkoxy groups having about 1 to 4 carbon atoms such as butoxy. Alternatively, 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 , R ³ , R ⁴ or R ⁵ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec
Examples include alkyl groups having about 1 to 4 carbon atoms such as -butyl and tert-butyl. Examples of the aralkyl group represented by R ³ or R ⁵ include benzyl, phenethyl, 3-phenylpropyl group, α-methylbenzyl group, α-ethylbenzyl group, α-methylphenethyl group, β-methylphenethyl group, β-ethylphenethyl group. Examples include phenyl lower (C _1-4 ) alkyl groups having about 7 to 10 carbon atoms. The fused or non-fused heteroalicyclic group represented by R ⁶ and containing at least one N, O or S as a ring constituent atom includes a 4- to 8-membered saturated or partially saturated heterocycle; In the case of a heterocycle containing three or more heteroatoms, the same type of atoms or two or more types of atoms may coexist as ring constituent atoms, such as oxetanyl, thietanyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, oxanyl. (3,4,5,6-tetrahydro-2H-pyranyl), thianyl, piperidyl, oxepanil, thiepanil, perhydroazepinyl, oxocanyl, thiocanyl, perhydroazocinyl, dioxanyl, dithianyl, piperazinyl, morpholinyl, perhydrothiazinyl , oxathianil, perhydrodiazepinyl, oxathiepanil, dioxepanil, dithiepanil, perhydroxazepinyl, perhydrothiazepinyl, perhydroxazocinyl, perhydrothiazosinyl, oxathiocanyl, perhydrodiazosinyl, dithiocanyl, dioxocanyl, chromanil, isochromanil, 3,4-dihydro-2H-1-thianaphthyl, 3,4-dihydro-1H-2-thianaphthyl,
1,2,3,4-tetrahydroquinolyl, 1,
2,3,4-tetrahydroisoquinolyl, 2,3
-dihydrobenzofuryl, 1,3-dihydroisobenzofuryl, 2,3-dihydrobenzo[b]thienyl, 1,3-dihydrobenzo[c]thienyl, indolinyl, isoindolinyl, 2,3,
4,5-tetrahydro-1(1H)-benzazepinyl, 2,3,4,5-tetrahydro-3(1H)
-benzazepinyl, 2,3,4,5-tetrahydro-2(1H)-benzazepinyl, 2,3,4,
5-tetrahydro-1-benzoxepinyl,
1,3,4,5-tetrahydro-2-benzoxepinyl, 1,2,4,5-tetrahydro-3-
Benzoxepinyl, 2,3,4,5-tetrahydro-1-benzothiepinyl, 1,3,4,5-
Tetrahydro-2-benzothiepinyl, 1,2,
4,5-tetrahydro-3-benzothiepinyl,
2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1,4-dithianaphthyl, 1,2,3,4-tetrahydroquinoxalinyl, 3,4-dihydro-2H-1 ,4-benzoxazinyl, 3,4-dihydro-2H-1,4-
Benzothiazinyl, 2,3-dihydro-1,4-
Benzoxatinyl, 3,4-dihydro-2H-
1,5-benzodioxepinyl, 2,3-dihydro-5H-1,4-benzodioxepinyl, 2,
3,4,5-tetrahydro-1H-1,5-benzodiazepinyl, 2,3,4,5-tetrahydro-1H-1,4-benzodiazepinyl, 3,4-
dihydro-2H-1,5-benzodithiepinyl,
2,3-dihydro-5H-1,4-benzodithiepinyl, perhydroindolyl, perhydroisoindolyl, perhydroquinolyl, perhydroisoquinolyl, perhydro-1-thianaphthyl, perhydro-2-thianaphthyl, etc. Examples include monocyclic or bicyclic heteroalicyclic groups. The fused or non-fused heteroalicyclic group has, for example, a lower (C _1-4 ) alkyl group (e.g., methyl, ethyl, propyl, butyl), oxo, lower (C _1-5 ) alkanoyl (e.g., acetyl, propionyl), benzoyl, phenyl-lower (C _1-4 ) alkoxycarbonyl (e.g., benzyloxycarbonyl), lower (C _1-4 ) alkoxycarbonyl (e.g.,
tert-butoxycarbonyl), aryl groups such as phenyl and naphthyl, benzyl,
It may have a phenyl lower (C _1-4 ) alkyl group such as phenethyl, α-methylphenethyl, β-methylphenethyl, etc. as a substituent (one or two). The aryl group or the phenyl group of the phenyl lower alkyl group as the substituent further includes halogens such as fluorine, chlorine, and bromine, and lower (C _1-4 ) groups such as methoxy, ethoxy, propoxy, and butoxy.
It may be substituted with lower (C _1-4 ) alkyl such as alkoxy, methyl, ethyl, propyl, butyl. Such substituted fused or non-fused heteroalicyclic groups include, for example, 1-phenylpiperidyl, 1-benzylpiperidyl, 4-phenylpiperidyl, 4-benzylpiperidyl, 1-acetylpiperidyl, 1-benzoylpiperidyl, 4- Phenylpiperazinyl, 4-acetylpiperazinyl, 4-benzoylpiperazinyl, 1-oxoisoindolinyl, 1,3-dioxoisoindolinyl, 1,2,3,4-tetrahydro-1-oxo Examples include groups such as isoquinolyl and 1,2,3,4-tetrahydro-3-oxoisoquinolyl. Examples of the alkylene chain represented by A include linear or branched alkylene chains having about 1 to 16 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamentylene, Octamethylene, nonamethylene, decamethylene, undecamethylene, dodecamethylene, tridecamethylene, tetradecamethylene, pentadecamethylene,
2 such as hexadecamethylene, propylene, ethylmethylene, 4-propylhexamethylene, 3,3-dimethylhexamethylene, 5,5-diethylhexamethylene, 3,5-dimethylnonamethylene, etc.
Value groups can be mentioned. The alkylene chain may have an unsaturated bond (eg, double bond, triple bond) within the chain. The divalent group represented by CnH ₂ n forms methylene, ethylene or ethylidene, depending on the value of n. Specific examples of the compounds of the present invention include the compounds shown in Table A.

【table】

【table】

【table】

【table】

【table】

【table】

[Table] Although the compound of the present invention () has an asymmetric carbon in the molecule, both the R configuration and the S configuration are included in the present invention. Among these, compounds in which the absolute configuration of the carbon atom represented by the symbol (〓1) is R and the absolute configuration of the carbon atom represented by the symbol (〓2) are S are preferred. 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. Among them, the expression [In the formula, A represents alkylene having 2 to 9 carbon atoms] Compounds represented by the following and pharmacologically acceptable salts thereof are preferred. The compound of the present invention () has the formula It can be produced by subjecting a compound represented by the formula [wherein each symbol has the same meaning as 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 conventional inorganic acids (e.g., hydrogen chloride,
sulfuric acid, nitric acid, hydrogen bromide) to protonate the amino group of the compound (), and then, for example, 2,
Phenols such as 4,5-trichlorophenol, pentachlorophenol, pentafluorophenol, 2-nitrophenol or 4-nitrophenol or N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenztriazole, N-hydroxypiperidine This can be carried out by condensing in the presence of a catalyst such as dicyclohexylcarbodiimide to convert it into an active ester, followed by cyclization. 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.
This can be accelerated by the addition of 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, dimethyl sulfoxide,
Examples include N-methylpyrrolidone, chloroform, and methylene chloride, which may be used alone or as a mixed solvent. Moreover, 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] [In the formula, W ^a represents a halogen or a group represented by R ^a SO ₂ -O- (wherein R ^a represents lower (C _1-4 ) alkyl, trifluoromethyl, phenyl or p-tolyl) , other symbols have the same meanings as above]. The reaction is usually carried out in the presence or absence of water or other organic solvents (e.g., acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, benzene, toluene) alone or in combination, and maintained at a temperature range of about -20 to +150°C. It can be advanced by At this time, a base such as potassium carbonate, sodium hydroxide, sodium bicarbonate, pyridine, triethylamine, etc. may be present in the reaction system for the purpose of accelerating the reaction rate. Moreover, 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] and a compound represented by the formula W ^b -CnH ₂ n-COOR ⁵ () [In the formula, W ^b is halogen or the formula R ^b SO ₂ -O- (in the formula, R ^b represents a group represented by lower (C _1-4 ) alkyl, trifluoromethyl, phenyl or p-tolyl, and other symbols have the same meanings as above]. It can also be manufactured. The reaction is carried out in water or other organic solvents (e.g. acetonitrile, dimethylformamide,
dimethyl sulfoxide, tetrahydrofuran, benzene, toluene) alone or in a mixed solvent, -
The process can be carried out by maintaining the temperature within the range of about 20 to +150°C. At this time, a base such as potassium carbonate, sodium hydroxide, or sodium hydroxide may be present in the reaction system. In the formula (), a compound in which R ⁴ is hydrogen is, for example, a compound with the formula [In the formula, each symbol has the same meaning as above] Compound and formula It can be produced by subjecting a compound represented by the formula [wherein each symbol has the same meaning as above] to a condensation reaction under reductive conditions. The reductive conditions include, for example, catalytic reduction using a metal such as platinum, palladium, or rhodium or a mixture of these with an arbitrary carrier as a catalyst, such as lithium aluminum hydride, lithium boron hydroxide,
Reduction with metal hydride compounds such as lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride, reduction with metal sodium, metal magnesium, etc. and alcohols,
Examples of reaction conditions include reduction of metals such as iron and zinc with acids such as hydrochloric acid and acetic acid, electrolytic reduction, and reduction using reductases. The above reaction is usually carried out in water or in an organic solvent (e.g. methanol, ethanol, ethyl ether, dioxane, methylene chloride,
It is carried out in the presence of chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide), and the reaction temperature varies depending on the reduction means, but is generally preferably about -20°C to +100°C.
Although the purpose of this reaction can be sufficiently achieved at room temperature, the reaction may be carried out under increased pressure or reduced pressure if necessary. In addition, compounds where R ⁴ is hydrogen in formula () are, for example, [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 the formula to hydrolysis or catalytic reduction reaction. In parentheses, all kinds of acyl groups and trityl groups can be used as the protecting group shown by Z that can be removed by hydrolysis, but in particular benzyloxycarbonyl, tert-butoxycarbonyl, trifluoroacetyl, trityl, etc. This is advantageous if the reaction is carried out under mild reaction conditions. Examples of the protecting group represented by Z which can be removed by catalytic reduction include benzyl, diphenylmethy, and benzyloxycarbonyl. The hydrolysis reaction in this method is carried out in water, an organic solvent such as methanol, ethanol, dioxane, pyridine, acetic acid, acetone, methylene chloride, or a mixed solvent thereof, and an acid (e.g. hydrogen chloride, hydrogen bromide,
hydrogen iodide, hydrogen fluoride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid) or bases (e.g., sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium acetate, triethylamine). It can also be carried out by adding. 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 catalyst 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. In addition, compounds where R ⁴ is hydrogen in formula () are, for example, [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 hydride, hydrogen iodide, hydrogen fluoride, sulfuric acid, methanesulfonic acid, p-
It can also be carried out by adding toluenesulfonic acid, trifluoroacetic acid, acidic resin) or a base (eg, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate, sodium acetate, triethylamine). The reaction is usually -20 to +
It is carried out at a temperature of about 150℃. In the compound () of the present invention, when the atom in the group R ⁶ bonded to the group A is a nitrogen atom, for example, the formula [In the formula, each symbol has the same meaning as above] Compound and formula [In the formula, X represents a ring-constituting atomic group, and the formula

It can also be produced by carrying out a condensation reaction of a compound represented by [Formula] in which a group R ⁶ is shown] under reductive conditions. The reductive conditions include, for example, catalytic reduction using metals such as platinum, palladium, and rhodium, or mixtures thereof with arbitrary carriers, such as lithium aluminum hydride, lithium borohydride,
Reduction with metal hydride compounds such as lithium cyanoborohydride, sodium cyanoborohydride, sodium cyanoborohydride, reduction with metal sodium, metal magnesium, etc. and alcohols,
Examples of reaction conditions include reduction of metals such as iron and zinc with acids such as hydrochloric acid and acetic acid, electrolytic reduction, and reduction using reductases. The above reaction is usually carried out in water or in an organic solvent (e.g. methanol, ethanol, ethyl ether, dioxane, methylene chloride,
It is carried out in the presence of chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide), and the reaction temperature varies depending on the reduction means, but is generally preferably about -20°C to +100°C.
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. In addition, in the compound () of the present invention, when the atom in the group R ⁶ bonded to the group A is a nitrogen atom, for example, the compound (XI) and the formula [Wherein, W ^c is a halogen or a group represented by the formula R ^c SO ₂ -O- (wherein R ^c represents lower (C _1-4 ) alkyl, trifluoromethyl, phenyl or p-tolyl). , Y represents a ring-constituting atomic group, and the formula

It can be produced by reacting a compound represented by [Formula] in which a group R ⁶ is shown. The reaction is carried out by combining both in an appropriate solvent or mixed solvent.
The process proceeds by keeping the temperature within the 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. A compound in which R ³ is hydrogen and/or R ⁵ is hydrogen in formula () is a compound in which R ³ is lower alkyl or/and R ⁵ is lower alkyl in formula () by hydrolysis reaction or elimination reaction. It can also be produced by adding the formula ()
Among them, it can also be produced by subjecting a compound in which R ³ is benzyl and/or R ⁵ is benzyl to a catalytic reduction reaction. The hydrolysis or elimination reaction in this method is carried out using water or, for example, methanol, ethanol, ethyl acetate, chloroform,
It is carried out in an organic solvent such as tetrahydrofuran, dioxane, pyridine, acetic acid, acetone, methylene chloride, or a mixed solvent thereof, and an acid (e.g., hydrogen chloride, hydrogen bromide, hydrogen fluoride, hydrogen iodide, sulfuric acid, methanesulfonic acid) , p-toluenesulfonic acid, trifluoroacetic acid) or bases (e.g., sodium hydroxide, potassium hydroxide, potassium carbonate,
It can also be carried out by adding sodium hydrogen carbonate, sodium carbonate, sodium acetate). The above reaction is usually carried out at a temperature of about -20 to +150°C.
The catalytic reduction reaction in this method is carried out in water or an organic solvent such as methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran, or a mixed solvent thereof, such as palladium-
It is carried out in the presence of a suitable catalyst such as carbon. This reaction is carried out at normal pressure or a pressure up to about 150 kg/cm ² and at a temperature of normal temperature to +150°C. In the formula (), a compound in which R ³ is lower alkyl or aralkyl and/or R ⁵ is lower alkyl or aralkyl, in the formula (),
A compound in which R ³ is hydrogen and/or R ⁵ is hydrogen is defined by the formula R ³ ′-OH () or the formula R ⁵ ′-OH () [wherein R ³ ′ and R ⁵ ′ represent lower alkyl or aralkyl] It can be produced by a condensation reaction with a compound represented by: The condensation reaction conditions include, for example, reaction conditions using condensation reagents (e.g., dicyclohexylcarbodiimide, carbonyldiimidazole, diethyl cyanophosphate, diphenyl phosphate azide), or acid catalysts (e.g., hydrogen chloride, hydrogen bromide, p-toluenesulfone). For example, reaction conditions using (acid) can be mentioned. The reaction proceeds in a suitable solvent or mixed solvent, or in the absence of a solvent at a temperature range of about -20 to +150°C. In the formula (), a compound in which R ³ is lower alkyl or aralkyl and/or R ⁵ is lower alkyl or aralkyl, in the formula (),
A compound in which R ³ is hydrogen and/or R ⁵ is hydrogen is defined by the formula R ³ ″−W ^d () or the formula R ⁵ ″−W ^d () [wherein R ³ ″ and R ⁵ ″ are lower alkyl or aralkyl] and W ^d is a halogen or the formula R ^d SO ₂
-O- (wherein R ^d represents a group represented by lower (C _1-4 ) alkyl, trifluoromethyl, phenyl or p-tolyl)] The reaction that can be produced proceeds in a suitable solvent at a temperature range of about -20 to +150°C in the presence of a base (eg, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate). In the compound () of the present invention, when the group R ⁶ has an unsubstituted imino group, the group R ⁶ of formula ()
It can be produced by subjecting a compound having a benzylimino group or an acylimino group therein to a catalytic reduction reaction, an elimination reaction, or a solvolysis reaction. The catalytic reduction reaction in this method is carried out in water or an organic solvent such as methanol, ethyl acetate, ethanol, dioxane, tetrahydrofuran, or a mixed solvent thereof, in the presence of a suitable catalyst such as palladium-carbon. This reaction is carried out at normal pressure or a pressure up to about 150 kg/cm ² and at a temperature of normal temperature to +150°C. In addition, the solvolysis or elimination reaction in this method can be carried out using water or, for example, methanol, ethanol,
The process is carried out in an organic solvent such as ethyl acetate, chloroform, tetrahydrofuran, dioxane, pyridine, acetic acid, acetone, methylene chloride, or a mixed solvent thereof. It can also be carried out by adding sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid) or a base (e.g., sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium acetate). . The above reaction is usually -20 to +
It is carried out at a temperature of about 150℃. lower (C _1-4 ) alkyl in the group R ⁶ in formula (),
A compound having an imino group substituted with aralkyl or acyl is a compound having an unsubstituted imino group in the group R ⁶ in formula () and a compound having the formula R ^{7 −We} (XII) [wherein R ⁷ is lower alkyl or aralkyl] or acyl, W ^e is halogen or formula R ^e SO ₂ −
It represents a group represented by O- (wherein R ^e represents lower (C _1-4 ) alkyl, trifluoromethyl, phenyl or p-tolyl). ] can be obtained 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. On this occasion,
For the purpose of accelerating the reaction rate, a base such as potassium carbonate, sodium hydroxide, sodium bicarbonate, pyridine, triethyleneamine, etc. may be present in the reaction system as a deoxidizing agent. In addition, compounds having an imino group substituted with lower (C _1-4 ) alkyl or aralkyl in the group R ⁶ in formula () are different from compounds having an unsubstituted imino group in the group R ⁶ in formula (). It can also be obtained by condensing (C _1-4 )alkyl aldehyde or aralkyl aldehyde under reductive conditions. The reductive conditions include, for example, catalytic reduction using metals such as platinum, palladium, and rhodium, or mixtures thereof with arbitrary carriers, such as lithium aluminum hydride, lithium borohydride,
Reduction with metal hydride compounds such as lithium cyanoborohydride, sodium cyanoborohydride, sodium cyanoborohydride, reduction with metal sodium, metal magnesium, etc. and alcohols,
Examples of reaction conditions include reduction of metals such as iron and zinc with acids such as hydrochloric acid and acetic acid, electrolytic reduction, and reduction using reductases. The above reaction is usually carried out in water or in an organic solvent (e.g. methanol, ethanol, ethyl ether, dioxane, methylene chloride,
It is carried out in the presence of chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide), and the reaction temperature varies depending on the reduction means, but is generally preferably about -20°C to +100°C.
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. In the case of a compound having an acylimino group in the group R ⁶ of the formula (), a compound having an unsubstituted imino group in the group R ⁶ of the formula () and the formula (R ⁷ ′) ₂ O () [in the formula, It can also be produced by reacting a compound represented by R ⁷ 'represents acyl]. The reaction proceeds in water, a suitable organic solvent, or a mixed solvent thereof by maintaining both 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. A compound in which R ⁴ is lower alkyl in the formula () can also be produced by subjecting a compound in which the group R ⁴ in the formula () is hydrogen to an alkylation reaction. The above alkylation reaction includes, for example, a reductive alkylation reaction in which a lower alkyl (C _1-4 ) aldehyde is reacted with a metal such as platinum, palladium, rhodium, or any other carrier. catalytic reduction with metal hydrides such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, 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 reaction is usually carried out in water or an organic solvent (e.g. methanol,
The reaction temperature varies depending on the reduction method, but is generally around -20°C to +100°C. is preferred. 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. ], or the formula R ⁴ -W ^f () [wherein W ^f is halogen or the formula R ^f SO ₂ -O- (wherein R ^f is lower (C _1-4 ) alkyl, trifluoromethyl, phenyl or (reaction conditions _are : One example is the condition of maintaining the temperature in a range of about +150℃.At this time, a base such as potassium carbonate, sodium hydroxide, sodium hydrogen carbonate, pyridine, triethylamine, etc. is coexisting in the reaction system as a deoxidizing agent to accelerate the reaction rate. ), etc. The salt of compound () can be obtained by the reaction itself for producing compound (), but it can also be produced by adding an acid, alkali, or base as necessary. The object compound (2) of the present invention thus obtained can be separated and purified from the reaction mixture by conventional separation and purification methods such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin film chromatography, etc. can be isolated. Compound () may exist in at least 4 stereoisomers. 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 (),
A single optical isomer of compound () can be obtained by carrying out the above reaction using each single isomer of (), (), (), (), (), () and (XI). If the product is a mixture of two or more isomers, it can be separated using conventional methods such as optically active acids (e.g., camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, etc.);
Optically active bases (e.g., cinchonine, cinchonidine,
It can be separated into its respective isomers by methods such as forming salts with quinine, quinidine, α-methylbenzylamine, dehydroabiethylamine, etc.), various chromatography, fractional recrystallization, and other separation methods. can. Raw material compounds of the present invention (), (), (), ()
,
(), () and (XI) can be easily produced, for example, by the method shown in the following reaction formula. In the above reaction formula, R ⁸ is a halogen or a diazonium group, W ^g is a halogen or the formula R ^g SO ₂ -O-
(In the formula, R ^g represents lower (C _1-4 ) alkyl, trifluoromethyl, phenyl or p-tolyl.) Other symbols have the same meanings as above. To explain in more detail the method for producing the compound () shown in the above reaction formula, cystine (
XI) as a raw material compound to induce cysteine,
Compound () is produced by reacting with compound (XII). The reaction between compounds () and () can be carried out in the same manner as the reaction between compounds () and (). The reaction ()→() is a conventional alkylation reaction, and can be carried out, for example, by reacting a lower alkyl aldehyde corresponding to the group R ⁴ under reducing conditions. By subjecting the compound () to a usual reduction reaction of a nitro group to an amino group, and then an alkylation reaction,
Compound () can be obtained. In the method for producing compound () and (), the amino group of compound () is protected with an appropriate amino group-protecting group (eg, phthaloyl group) to first obtain compound (). This reaction involves combining compound () with a base (e.g.,
It proceeds easily in the presence of sodium carbonate, potassium carbonate, potassium hydrogen carbonate), usually at temperatures 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. Reduction methods include, for example, catalytic reduction using palladium on carbon, palladium using barium sulfate as a carrier, sulfide palladium, platinum, etc., or metal and acid or alkali reduction using zinc, tin, stannous chloride, iron, etc. A reduction reaction is used. The compound thus obtained ()
The dehydration ring closure reaction to form compound () can be advantageously carried out in the presence of a commonly known dehydration condensation agent. Examples of such dehydration condensation agents include dicyclohexylcarbodiimide, carbonyldiimidazole, and diethyl cyanophosphate. Examples of solvents used include dioxane, methylene chloride, acetonitrile, N,N-dimethylformamide, and tetrahydrofuran.
The reaction is usually carried out at a temperature range of about -10 to +100°C. At this time, in order to advance the reaction advantageously,
A base such as triethylamine or pyridine can also be added to the reaction solution as a catalyst. Compound (XI) is usually produced by a condensation reaction between compounds () and () in a solvent such as N,N-dimethylformamide, dimethylsulfoxide, or acetonitrile in the presence of a base such as sodium hydride or potassium carbonate. It can be produced by condensation at a temperature range of about 10 to +100°C. Next, the reaction (XI) → () is carried out with hydrazine hydrate in a solvent such as methanol, ethanol, dioxane, etc. at a temperature range of -10° to +100°C,
Compound () can be produced. The reaction from () to () is a normal alkylation reaction, for example, a method in which a lower alkyl aldehyde corresponding to the group R ⁴ is reacted under reducing conditions, or a method in which compound () is reacted in an appropriate solvent. can give. Compound () can be produced by subjecting compound () to a conventional reduction reaction of a nitro group to an amino group, followed by a dehydration ring-closing reaction. 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 () → () is carried out by preparing the compound () and () in an appropriate solvent from −20 to
The process progresses by maintaining the temperature within a range of approximately +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 ()
Compound () can be obtained according to the known Strecker reaction using () and hydrogen cyanide as starting compounds. In the method for producing compound (XI), compound (
) can be obtained by reacting compounds () and (). As the solvent, acetonitrile, methyl ethyl ketone, acetone, tetrahydrofuran, methylene chloride, dimethyl sulfoxide, dimethyl formamide, etc. are used, and the reaction is usually carried out at a temperature range of about -10 to +150°C. At this time, a base such as triethylamine, pyridine, potassium carbonate, or sodium carbonate, potassium iodide, etc. may be added in order to advantageously advance the reaction. （）→
The reaction () can be carried out in the same way as the reaction () → (), and (
)→(XI) can be carried out in the same manner as the reaction (XI)→(). Compounds () and () used in the production of the compound () of the present invention can be easily produced, for example, by the method shown in the following reaction formula. In the above reaction formula, R ³ ′ and R ³ ″ each represent lower alkyl or aralkyl, and the other symbols have the same meanings as above. Compound (′) is the compound () and (
) in the presence of a base such as sodium ethoxy, followed by heating in the presence of lithium chloride or the like in aqueous dimethyl sulfoxide. Compound(')
can be produced by subjecting compound (') to a known reduction reaction and subjecting the resulting compound (IL) to a known halogenation reaction or sulfonylation reaction. The raw material compound () used here is, for example, the formula [In the formula, W ^h represents a halogen, A' represents A as A'- _CH2 , and other symbols have the same meanings as above] by subjecting the compound to a reduction reaction known per se. can be manufactured. When R ⁶ contains a group that may affect the reaction, the group may be substituted with, for example, lower (C _1-5 ) alkanoyl (e.g. acetyl), benzoyl, phenyl lower (C _1-4 ) alkoxycarbonyl (e.g. , benzyloxycarbonyl, lower (C _1-4 ) alkoxycarbonyl (e.g., tert-butoxycarbonyl). , a compound in which R ₃ is hydrogen can be easily produced by subjecting compounds ('), (IL), and (') to a hydrolysis reaction, respectively. In the formula (), a compound in which R ⁴ is hydrogen, for example, It can also be produced by the method shown by the following reaction formula. The reaction of ()→(L) is (XI)→
This can be done under the same conditions as (). Compound (') is compound (L) and () or ()
, compound () and () or compound ()
It can be produced by reacting under the same reaction conditions as the reaction of and (). 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 circulatory system diseases such as hypertension, heart disease caused by hypertension, and stroke. The compound of the present invention has low toxicity, is well absorbed even when administered orally, has excellent persistence, and has excellent stability. excipients,
It can be mixed with a diluent and safely administered orally or parenterally as a pharmaceutical composition such as a powder, granule, tablet, capsule, or injection. 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 10 mg/Kg for oral administration. , especially 0.02~2
mg/Kg, especially about 0.04 to 0.8 mg/Kg, but for intravenous administration, a single dose is about 0.002 to 1 mg/Kg, especially 0.02 to 1 mg/Kg, especially about 0.02 to 0.2 mg/Kg.
It is preferable to administer these doses about 1 to 3 times a day, especially about 1 to 2 times a day, depending on the symptoms. Examples 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
3-(o-nitrophenyl) when recrystallized from ml
3.6 g of thio-2(R)-phthalimidopropionic acid are obtained as pale yellow needles. Melting point 220-222℃ Elemental analysis value C ₁₇ H ₁₂ N ₂ O ₆ Calculated value: C54.84; H3.25; N7.53 Actual value: C54.46; H3.26; N7.46 [α] ²⁴ _D -79° (c=0.9, in methanol) 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 the mixture was allowed to stand, and the precipitated pale yellow powder crystals were collected to obtain 8.4 g of 3-(o-aminophenyl)thio-2(R)-phthalimidopropionic acid. 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. water in reaction solution
Add 200ml and leave it overnight, remove the precipitated solid and dry. This product was subjected to silica gel column chromatography (dichloromethane: ethyl acetate = 2:
Purification by step 1) yields 3(R)-phthalimide-2,3-
Dihydro-1,5(5H)-benzothiazepine-4
5.4 g of -one are obtained as colorless prismatic crystals.
Melting point 202-205℃ Elemental analysis value C ₁₇ H ₁₂ N ₂ O ₃ S Calculated value: C62.95; H3.73; N8.64 Actual value: C63.15; H4.02; N8.49 [α] ²¹ _D -164° (c=0.9, in methanol) 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 Example 2 was added, and the mixture was stirred for 5 minutes. Further, 2 g of chloroacetic acid tert-butyl ester is 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-
4 g of 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester
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: C63.01; H5.06; N6.39 Actual value: C62.95; H5.10; N6.34 [α] ²⁰ _D −156° (c=0.9, in chloroform) Example 4 4-oxo-3(R)-phthalimide-2,3,4,5-tetrahydro-1,5-benzothiazebin-5- obtained in Example 3 Add 4 g of acetic acid tert-butyl ester and 1.4 g of hydrazine hydrate to 100 ml of ethanol. 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. The resulting oil was crystallized from a mixture of ether and petroleum ether to give 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-
2 g of 1,5-benzothiazepine-5-acetic acid tert-butyl ester are obtained as colorless prismatic crystals. Melting point 86-89℃ Elemental analysis value C ₁₅ H ₂₀ N ₂ O ₃ S Calculated value: C58.42; H6.54; N9.08 Actual value: C58.73; H6.48; N9.13 [α] ²⁰ _D -238° (c=1, in methanol) Example 5-9 Using an o-nitroaniline derivative having a substituent as a raw material, a reaction similar to the case of synthesizing an unsubstituted product (R=H) is carried out. The compounds shown in Table 1 are obtained.

[Table] Example 10-13 S-(2-nitrophenyl) obtained in Example 5-8
When the -L-cysteine derivative is reacted with N-ethoxycarbonylphthalimide in the same manner as in Example 1, the compounds shown in Table 2 are obtained.

[Table] Examples 14-17 When the phthalimide derivatives obtained in Examples 10-13 are reacted in the same manner as in Example 2, the compounds shown in Table 3 are obtained.

[Table] Examples 18-21 When the phthalimidobenzothiazepine derivatives obtained in Examples 14-17 are reacted in the same manner as in Example 3, the compounds shown in Table 4 are obtained.

[Table] Example 22-25 The phthalimidobenzothiazepine acetic acid tert-butyl ester derivative obtained in Example 18-21 was added to Example 4.
When reacted in the same manner as above, the compounds shown in Table 5 are obtained.

[Table] Example 26 5.3 g of S-(2-nitro-4-trifluoromethylphenyl)-L-cysteine obtained in Example 9 was
Add to 67ml of 0.25N 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 C ₁₈ H ₁₅ F ₃ N ₂ O ₆ Calculated value: C48.65; H3.40; N6.30 Actual value: C48.68 ;H3.41;N6.27 Example 27 4.3 g of S-(2-nitro-4-trifluoromethylphenyl)-N-benzyloxycarbonyl-L-cysteine obtained in Example 26 and 4 g of zinc powder were dissolved in acetic acid. Add to a mixture of 50ml and water 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, a solution of 1.83 g of diethyl cyanophosphate in 5 ml of dimethylformamide was added dropwise over 5 minutes.
Add a solution of 0.78 g of triethylamine in 5 ml of dimethylformamide. Stir on ice for 30 minutes, then at room temperature for 2.5 hours. 200ml of water to the reaction solution
was added, extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The obtained oil was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1 to 2:1) to yield 3(R)-benzyloxycarbonylamino-7-trifluoromethyl-2,3-dihydro -1,5(5H)-benzothiazepine-4-one 1.3
g is obtained as a colorless powder crystal. Melting point 120-123℃ [α] _D −161° (in methanol) Elemental analysis value C ₁₈ H ₁₅ F ₃ N ₂ O ₃ Calculated value: C54.54; H3.81; N7.07 Actual value: C54. 79; H3.90; N7.09 Example 28 3(R)-benzyloxycarbonylamino-7-trifluoromethyl-2,3-dihydro-1,5(5H)-benzothiazepine obtained in Example 27 -4-
Dissolve 1.1g of On in 20ml of dimethylformamide,
Add 0.46 g of chloroacetic acid tert-butyl ester, 0.42 g of potassium carbonate, and 0.1 g of potassium iodide,
Stir at room temperature for 4.5 hours. Add 100 ml of water to the reaction solution and extract with 100 ml of ethyl acetate. extract liquid
After washing with 0.1N hydrochloric acid, an aqueous sodium bicarbonate solution, and water in this order, drying over anhydrous magnesium sulfate, and distilling under reduced pressure, 3(R)-benzyloxycarbonylamino-4-oxo-7-trifluoromethyl-2,
1.4 g of 3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester are obtained as a colorless lozenge. IRν ^nujol _nax cm ^-1 : 1680 (amide), 1710 (urethane)
,
1740 (ester) *IR: (infrared absorption spectrum: same below) Example 29 3(R)-benzyloxycarbonylamino-4-oxo-7-trifluoromethyl-2,3,4, obtained in Example 28 5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 1.4
Dissolve g in 5 ml of acetic acid and make a 30% hydrogen bromide-acetic acid solution.
Add 10ml and leave at room temperature for 4 hours. Add 100 ml of petroleum ether to the reaction solution, mix well, and then remove the supernatant liquid 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. Addition of petroleum ether to the residue yields 3(R)-amino-4-oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid/hydrogen bromide. 0.75 g of the acid salt precipitates as crystals.
Melting point 176-180℃ Elemental analysis value C ₁₂ H ₁₁ F ₃ N ₂ O ₃ S・HBr・H ₂ O Calculated value: C34.38; H3.37; N6.68 Actual value: C34.40; H3.60 ;N6.66 Example 30 3(R)-amino-4-oxo- obtained in Example 4
1 g of 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester
Dissolve in 20ml of methanol and add potassium cyanide.
Add 0.32 g, N-(4-formylbutyl)phthalimide 1.1 g and acetic acid 0.3 g, and stir overnight at room temperature. The reaction solution was dried under reduced pressure to give 3(R)-(1-cyano-5-phthalimidobentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothi as a crude product. azepine-5-acetic acid
A tert-butyl ester is obtained. This product is used as a raw material in Example 31 without being purified. Example 31 3(R)-(1-cyano-5-phthalimidopentyl)amino-4-oxo-2, obtained in Example 30
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, and add 20 ml of ethanolic hydrochloric acid (11N) to
After stirring for a while, leave it at room temperature overnight. Ethanol was distilled off under reduced pressure, and 50 ml of ethanol and 10 g of Amberlyst 15 ion exchange resin were added to the residue.
Reflux with stirring for 7 hours. After cooling, the resin portion was treated with a 5% pyridine-ethanol solution, and 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 subjected to silica gel column chromatography (hexane:acetone=
2:1), 3(R)-(1-ethoxycarbonyl-5-phthalimidopentyl)amino-
4-oxo-2,3,4,5-tetrahydro-
0.9 g of 1,5-benzothiazepine-5-acetic acid ethyl ester is obtained as a colorless oil. IRν ^neat _nax cm ^-1 : 1770, 1740, 1720, 1710 (phthalimide and ester), 1670 (amide) Mass spectrum (m/e): 567 (M ⁺ ) Example 32 3(R) obtained in Example 2 -phthalimide-2,3-
Dihydro-1,5(5H)-benzothiazepine-4
Dissolve 6.48 g of -one in 25 ml of dimethylformamide, 6.27 g of 2-bromopropionic acid tert-butyl ester, 5.5 g of potassium carbonate and 0.5 g of potassium iodide.
Add g and stir overnight at room temperature. water in reaction solution
Add 200ml and extract with 300ml of ethyl acetate. After washing the extract with 200ml of 0.5N hydrochloric acid and 100ml of saturated sodium bicarbonate solution,
Dry over anhydrous magnesium sulfate and evaporate under reduced pressure. The obtained oil was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:1 to 2:1).
7.8 g of 3(R)-phthalimido-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-α-methylacetic acid tert-butyl ester was obtained as a colorless powder. It will be done. IRν ^neat _nax cm ^-1 : 1770, 1730, 1720, 1680 (C=0) Elemental analysis value C ₂₄ H ₂₄ N ₂ O ₅ S・1/2H ₂ O Calculated value: C62.46; H5.46; N6 .07 Actual value: C62.62; H5.14; N6.13 Example 33 3(R)-phthalimido-4-oxo-2,3,4,5-tetrahydro-1,5- obtained in Example 32 When 7.6 g of benzothiazepine-5-α-methylacetic acid tert-butyl ester was treated with hydrazine hydrate in the same manner as in Example 4, 3(R)-amino-4-oxo-2,3,4,5-tetrahydro 5.4 g of -1,5-benzothiazepine-5-α-methylacetic acid tert-butyl ester are obtained as a pale yellow oil. IRν ^neat _nax cm ^-1 : 1730, 1670 (C=0) [α] _D −223° (c=0.5, in methanol) Mass spectrum (m/e): 322 (M ⁺ ) Example 34 In Example 4 The obtained 3(R)-amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 3.08
Dissolve g in 20 ml of dimethylformamide and add ethyl 2-bromo-6-phthalimidohexanoate.
7.36g, potassium carbonate 2.76g and potassium iodide
Add 1.66g and stir overnight at room temperature. Furthermore, 3.68 g of bromoester 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. To the obtained oil, add 5 g of oxalic acid and 30 ml of ethyl acetate, dissolve it, and add 120 g of petroleum ether.
Add ml 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. The obtained oil was subjected to silica gel column chromatography (hexane:acetone=
4:1), the first fraction is 3(R)-[1
1.75 g of (R)-ethoxycarbonyl-5-phthalimidobentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester as an oil. can get. IRν ^neat _nax cm ^-1 : 3330 (NH), 1780, 1740, 1720,
1680 (C=O) Mass spectrum (m/e): 595 (M ⁺ ) 3(R)-[1(S)-ethoxycarbonyl-5-phthalimidopentyl]amino-4- as the second fraction
Oxo-2,3,4,5-tetrahydro-1,5
2.5 g of benzothiazepine-5-acetic acid tert-butyl ester are obtained as an oil. IRν ^neat _nax cm ^-1 : 3330 (NH), 1770, 1740, 1720,
1680 (C=O) Mass spectrum (m/e): 595 (M ⁺ ) [α] _D -119° (c=0.3, in methanol) Example 35 3(R)-[1 obtained in Example 34 (S)-Ethoxycarbonyl-5-phthalimidopentyl]amino-4-
Oxo-2,3,4,5-tetrahydro-1,5
-Dissolve 0.2 g of benzothiazepine-5-acetic acid tert-butyl ester in 5 ml of 5N hydrogen chloride-ethyl acetate solution and leave 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)-ethoxycarbonyl-5-phthalimidopentyl]amino-4-oxo-2,3,4 was obtained. ,5-tetrahydro-
1,5-benzothiazepine-5-acetic acid hydrochloride
0.13 g is obtained as a colorless powder. Elemental analysis value C ₂₇ H ₂₉ N ₃ O ₇ S・HCl1/2H ₂ O Calculated value: C55.42; H5.34; N7.18 Actual value: C55.09; H5.12; N7.15 [α] _D −114° (c=0.5, in methanol) Example 36 3(R)-[1(R)-ethoxycarbonyl-5-phthalimidopentyl]amino-4- obtained in Example 34
Oxo-2,3,4,5-tetrahydro-1,5
-Dissolve 1.6 g of benzothiazepine-5-acetic acid tert-butyl ester in 20 ml of ethanol, add 0.8 g of 85% hydrazine hydrate, and let stand overnight at room temperature.
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)-[5-amino-1(R)-ethoxycarbonylpentyl ]Amino-4-oxo-2,3,4,5-tetrahydro-
An ethyl acetate solution of 1,5-benzothiazepine-5-acetic acid tert-butyl ester is obtained. 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 subjected to silica gel column chromatography (hexane:
When purified with acetone = 4:1), 3(R)-[5-
tert-Ptoxycarbonylamino-1(R)-ethoxycarbonylpentyl]amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 1.4 g
is obtained as a colorless oil. IRν ^neat _nax cm ^-1 : 3350 (NH), 1740, 1710, 1680 (C
=O) Mass spectrum (m/e): 565 (M ⁺ ) Example 37 3(R)-[1(S)-ethoxycarbonyl-5-phthalimidopentyl]amino-4- obtained in Example 34
Oxo-2,3,4,5-tetrahydro-1,5
- 2.6 g of benzothiazepine-5-acetic acid tert-butyl ester was treated with hydrazine in the same manner as in Example 36,
When reacted with di-tert-butyl dicarbonate and purified by silica gel column chromatography, 3(R)-[5-tert-butoxycarbonylamino-
1(S)-Ethoxycarbonylpentyl]amino-4
-oxo-2,3,4,5-tetrahydro-1,
1.87 g of 5-benzothiazepine-5-acetic acid tert-butyl ester are obtained as a colorless oil. IRν ^neat _nax cm ^-1 : 3350 (NH), 1740, 1710, 1670 (C
=O) Mass spectrum (m/e): 565 (M ⁺ ) [α] _D −136° (c = 0.8, in methanol) Example 38 3(R)-[5-tert- Butoxycarbonylamino-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester (0.6 g) and 40 ml of methanol
Dissolve in a mixture of 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, made weakly acidic with phosphoric acid,
Extract 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,
0.37 g of 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester is obtained as a colorless lozenge. 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: C58.08; H7.31; N7.82 Actual value: C58.11; H7.22; N7.73 IRν ^nujol _nax cm ^-1 : 3350 (NH), 1730, 1700, 1680 (C
=O) Example 39 3(R)-Amino-4-oxo- obtained in Example 4
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 5g
and 17.9 g of ethyl 2-bromo-6-phthalimidohexanoate were dissolved in 200 ml of acetonitrile,
Add 2.46 g of triethylamine and reflux for 45 hours. Distill the acetonitrile under reduced pressure and add water to the residue.
Add 200ml and 300ml of ethyl acetate and extract. 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 obtained in Example 34, 3(R)-[1(R)-ethoxycarbonyl-
5-phthalimidopentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 3.9
g and 3(R)-[1(S)-ethoxycarbonyl-5-phthalimidopentyl]amino-4-oxo-2,
4.1 g of 3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester are obtained as a colorless oil. Example 40-42 3(R)-amino-4-oxo-2,3,4,5-
Tetrahydro-1,5-benzothiazepine-5-
When acetic acid tert-butyl ester is reacted with the α-bromo ester shown in Table 6 in the same manner as in Example 39, the following benzothiazepine derivatives are obtained.

[Table] *Diastereomer mixture examples 43-45 When the benzothiazepine derivatives obtained in Examples 40-42 are treated with a hydrogen chloride ethyl acetate solution in the same manner as in Example 35, the compounds shown in Table 7 are obtained. .

[Table] *Diastereomer mixture examples 46-48 After treating the benzothiazepine derivatives obtained in Examples 40-42 with hydrazine in the same manner as in Example 36,
Reaction with di-tert-butyl dicarbonate gives the compounds shown in Table 8.

[Table] *Diastereomer mixture Example 49 3(R)-(1-ethoxycarbonyl-5-phthalimidopentyl)amino-4-oxo-2,3,4,5-tetrahydro-1 obtained in Example 31 ,5-
Benzothiazepine-5-acetic acid ethyl ester 0.7
Dissolve g in 20 ml of ethanol and add 0.3 g of 85% hydrazine hydrate. 85% hydrazine hydrate 0.3g 1
After adding it after 1 hour and 2 hours, leave it overnight.
Ethanol was distilled off under reduced pressure, 50 ml of water was added to the residue, salt was added to saturate it, and ethyl acetate was added.
Extract 3 times with 100ml. 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 ml of 5N hydrogen chloride ethyl acetate solution to the obtained ethyl acetate solution, evaporate under reduced pressure, and add ethyl ether to the residue to obtain 3(R)-(5-amino-1-ethoxycarbonylpentyl)amino-4. -oxo-2,3,4,
5-tetrahydro-1,5-benzothiazepine-
0.13 g of 5-acetic acid ethyl ester dihydrochloride is obtained as a colorless powder. Elemental analysis value C ₂₁ H ₃₁ N ₃ O ₅ S・2HCl・H ₂ O Calculated value: C47.73; H6.67; N7.95 Actual value: C47.81; H6.53; N7.83 Mass spectrum ( m/e): 437 (M ⁺ ) Example 50 3(R)-(5-amino-1-ethoxycarbonylpentyl)amino-4-oxo-2,3,4,5-tetrahydro- obtained in Example 49 1,5-benzothiazepine-5-acetic acid ethyl ester dihydrochloride
Dissolve 50mg in a mixture of 30ml ethyl acetate and 10ml water,
Add 0.15 ml of benzyloxycarbonyl chloride and 0.3 g of sodium bicarbonate and stir at room temperature for 2.5 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-
55 mg of 1,5-benzothiazepine-5-acetic acid ethyl ester hydrochloride is obtained as a colorless powder. Mass spectrum (m/e): 571 (M ⁺ ) Example 51 3(R)-(5-benzyloxycarbonylamino-1-ethoxycarbonylpentyl)amino-4-oxo-2,3 obtained in Example 50 , 55 mg of 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid ethyl ester hydrochloride with 3 ml of ethanol.
Dissolve in 2 ml of 1N aqueous sodium hydroxide solution,
Leave at room temperature for 1 hour. After adding 50 ml of water to the reaction solution and extracting with 20 ml of ethyl ether, the aqueous layer was adjusted to pH 4 with 1N hydrochloric acid. After adding ammonium chloride to a saturated solution, the aqueous layer was diluted with 20 ml of ethyl acetate for 10 min.
Extract times. After washing the extract with a small amount of water, it was dried over anhydrous magnesium sulfate and evaporated under reduced pressure.
3(R)-(5-benzyloxycarbonylamino-
1-carboxypentyl)amino-4-oxo-
40 mg of 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid are obtained as a colorless powder. Mass spectrum (m/e): 515 (M ⁺ ) Example 52 3(R)-(5-benzyloxycarbonylamino-1-carboxypentyl)amino-4-oxo-2,3, obtained in Example 51 Dissolve 40 mg of 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid in 1 ml of acetic acid, add 1 ml of 30% hydrogen bromide acetic acid solution, and let stand 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, the mixture was allowed to stand, the supernatant liquid was removed by decanting, and the precipitate was collected and dried to give 3(R)-(5-amino-1 -carboxypentyl)amino-4-oxo-2,
33 mg of 3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide are obtained as a colorless powder. SIMS spectrum (m/e): 382 (MH ⁺ ); KI addition 420 (M+K) ⁺ Examples 53, 54 When the benzothiazepine derivatives obtained in Examples 36 and 37 are treated with hydrogen chloride in the same manner as in Example 35, The compound of Table 9 is obtained as colorless crystals.

[Table] Example 55 3(R)-[5-amino-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5 obtained in Example 54 Add 0.2 g of benzothiazepine-5-acetic acid dihydrochloride to 4 ml of 1N aqueous sodium hydroxide 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). After concentrating the effluent under reduced pressure, lyophilization yields 3(R)-[5-amino-1(S)-carboxypentyl].
Amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid 0.1
g is obtained as a colorless powder. Elemental analysis value C ₁₇ H ₂₃ N ₃ O ₅ S・H ₂ O Calculated value: C51.12; H6.31; N10.52 Actual value: C50.87; H5.83; N10.34 [α] _D − 149° (c=0.3, in 1N hydrochloric acid) SIMS spectrum (m/e): 382 (MH ⁺ ); KI addition 420 (M+K) ⁺ Example 56 3(R)-[5-tert obtained in Example 38 -butoxycarbonylamino-1(S)-carboxypentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-
When 0.32 g of butyl ester was treated with hydrogen chloride as in Example 35, 3(R)-[5-amino-1(S)
-carboxypentyl]amino-4-oxo-
0.26 g of 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride is obtained as a colorless powder crystal. Elemental analysis value C ₁₇ H ₂₃ N ₃ O ₅ S・2HCl・CH ₃ COOC ₂ H ₅ Calculated value: C46.49; H6.13; N7.75 Actual value: C46.12; H6.16; N7.52 Dissolve 0.15 g of this product in 2 ml of water, add 0.5 ml of 1N sodium hydroxide aqueous solution, and then add 0.5 ml of acetic acid.
Amberlight XAD-2 in the same manner as Example 55
The same educt as obtained in Example 55 when purified with
0.096g is obtained. Examples 57-59 When the benzothiazepine derivatives obtained in Examples 46-48 are treated with a hydrogen chloride ethyl acetate solution in the same manner as in Example 35, the compounds shown in Table 10 are obtained.

[Table] *Diastereomer mixture example 60 Dissolve 0.43g of sodium in 10ml of ethanol,
Ethyl 3-(1-benzyloxycarbonyl-4
Add 5 g of -piperidyl)propionate and 2.75 g of diethyl oxalate, and evaporate under reduced pressure while heating on a water bath at 60-70°C for 45 minutes. After cooling, add 200 ml of water to the resulting brown candy and make it slightly acidic with concentrated hydrochloric acid.
Extract with 300 ml of ethyl acetate, dry the extract over anhydrous magnesium sulfate, and evaporate under reduced pressure. 50 ml of 10% hydrated dimethyl sulfoxide and 0.73 g of lithium chloride were added to the obtained yellow oil, and the mixture was heated at 100°C for 30 minutes at 120° C.
Stir at -130°C for 30 minutes and then at 140°C for 45 minutes. After cooling the reaction solution, add 300ml of water and add ethyl acetate.
After extraction with 300ml, the extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give ethyl 4-(1-benzyloxycarbotyl-4-piperidyl)-2-oxobutyrate as a pale brown oil.
4.5g is obtained. IRν ^neat _nax cm ^-1 : 1730, 1700 (C=O) Mass spectrum (m/e): 347 (M ⁺ ) Examples 61, 62 Using the propionic acid ethyl ester derivatives shown in Table 11 as raw materials, Example 60 and When similar reactions are carried out, corresponding α-keto esters are obtained.

[Table] Example 63 3(R)-amino-4-oxo- obtained in Example 4
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 2g
Dissolved in 50ml of ethanol, 0.43g of acetic acid, Example
Ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-oxobutyrate obtained in step 60
Add 4.5g and 10g of Molecular Sieve 3A. After stirring this mixture at room temperature for 1 hour, a solution of 0.4 g of sodium cyanoborohydride in 30 ml of ethanol was added dropwise over 2.5 hours while stirring at room temperature. Furthermore, a solution of 0.5 g of sodium cyanoborohydride in 20 ml of ethanol was added dropwise over 3 hours and left overnight. The reaction solution was distilled off under reduced pressure, and 300 ml of water and 300 ml of ethyl acetate were added to the residue, and the mixture was shaken. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Add 50 ml of ethyl ether to the residue, and add 50 ml of a solution of 1 g of oxalic acid in ethyl ether. After adding 200 ml of petroleum ether and shaking well, let it stand, remove the supernatant liquid by decanting, and add 100 ml of petroleum ether again to the precipitated part and shake. After removing the petroleum ether layer by tilting, 50 ml of water and 200 ml of ethyl acetate were added to the precipitate.
Add excess baking soda while stirring to neutralize. After washing the ethyl acetate with water, it is dried over anhydrous magnesium sulfate and distilled off under reduced pressure to obtain an oily substance. When this product was separated and purified by silica gel column chromatography (hexane:ethyl acetate = 2:1 to 4:3), it was first separated and purified by 3(R)-[3-(1-benzyloxycarbonyl-4-piperidyl)-1( R)-Ethoxycarbonylpropyl]amino-4-oxo-2,3,
0.6 g of 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester is obtained as a colorless oil. IRν ^neat _nax cm ^-1 : 3320 (NH), 1740, 1700, 1680 (C
=O) Mass spectrum (m/e): 639 (M ⁺ ) From the following fractions, 3(R)-[3-(1-benzyloxycarbonyl-4-piperidyl)1(S)-ethoxycarbonylpropyl]amino-4 -oxo-2,
1.3 g of 3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester are obtained as a colorless oil. IRν ^neat _nax cm ^-1 : 3320 (NH), 1740, 1700, 1690,
1670 (C=O) Mass spectrum (m/e): 639 (M ⁺ ) Examples 64, 65 3(R)-amino in the same manner as in Example 63 using the α-ketoester obtained in Examples 61 and 62 -4-oxo-
Upon reaction with 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester, the compounds shown in Table 12 are obtained as oils.

[Table] Example 66 3(R)-[3-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpropyl]amino-4-oxo- obtained in Example 63
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 0.3g
Dissolve in 20 ml of 5N hydrogen chloride ethyl acetate solution and leave at room temperature for 3 hours. Petroleum ether 200% in the reaction solution
ml of 3(R)-[3-1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpropyl]amino-4-oxo-2,
3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride is precipitated. After removing the supernatant by decanting and drying, 0.22 g of colorless powder is obtained. Elemental analysis value C ₃₀ H ₃₇ N ₃ O ₇ S・HCl・H ₂ O Calculated value: C56.46; H6.32; N6.58 Actual value: C56.29; H6.31; N6.57 [α] _D -91° (c=0.6, in methanol) Examples 67-70 When the benzothiazepine derivatives obtained in Examples 64 and 65 were treated with hydrogen chloride in the same manner as in Example 66, the table
The compound shown in 13 is obtained.

[Table] Example 71 3(R)-[3-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpropyl]amino-4-oxo- obtained in Example 63
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 0.6g
Dissolve in 2 ml of acetic acid and add 2 ml of 30% hydrogen bromide acetic acid solution.
Add and leave at room temperature for 1 hour. After adding 150 ml of ethyl ether to the reaction solution and allowing it to stand, the supernatant liquid was removed by decanting. After washing the precipitate with ethyl ether and drying, 3(R)-[1(R)-ethoxycarbonyl-3-(4-piperidyl)propyl]
Amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid 2
0.5 g of hydrobromide is obtained as a colorless powder. Elemental analysis value C ₂₂ H ₃₁ N ₃ O ₅ S・2HBr・H ₂ O Calculated value: C41.98; H5.60; N6.68 Actual value: C41.43; H5.39; N6.30 [α] ²² _D -106° (c=0.6, in methanol) Example 72 3(R)-[3-1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpropyl] obtained in Example 63 Amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid tert-butyl ester 0.4g
When treated with hydrogen bromide as in Example 71,
3(R)-[1(S)-ethoxycarbonyl-3-(4-piperidyl)propyl]amino-4-oxo-2,
0.35 g of 3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide is obtained as a colorless powder. Elemental analysis value C ₂₂ H ₃₁ N ₃ O ₅ S・2HBr・H ₂ O Calculated value: C40.81; H5.76; N6.49 Actual value: C40.47; H5.32; N6.28 [α] _D −86° (c=0.6, in methanol) Example 73 3(R)-[1(S)ethoxycarbonyl-3-(4-piperidyl)propyl]amino- obtained in Example 72
4-oxo-2,3,4,5-tetrahydro-
Add 0.15 g of 1,5-benzothiazepine-5-acetic acid dihydrobromide to 4 ml of 1N aqueous sodium hydroxide solution.
Dissolve in and leave at room temperature for 2 hours. After adding 1 ml of acetic acid to make it slightly acidic, add Amberlite XAD-2.
Column chromatography (methanol: water =
1:1). After concentration under reduced pressure and lyophilization, 3(R)-[1(S)-carboxy-3-(4-piperidyl)propyl]amino-4-oxo-2,3,
0.06 g of 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid is obtained as a colorless powder. Elemental analysis value C ₂₀ H ₂₇ N ₃ O ₅ S・H ₂ O Calculated value: C54.65; H6.65; N9.56 Actual value: C54.05; H6.17; N9.21 Mass spectrum (m/ e): 422 (MH ⁺ ); KI addition, 460 (M + K) ⁺ [α] _D -128° (c = 0.1, methanol + water) Examples 74, 75 Benzothiazepine derivatives obtained in Examples 68, 70 is hydrolyzed with a 1N aqueous sodium hydroxide solution in the same manner as in Example 73, and purified by Amberlite XAD-2 column chromatography to obtain the compounds shown in Table 14 as colorless powders.

〔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, based on the inhibition rate of hippuric acid production when the compound of the present invention is added to the amount of hippuric acid produced by ACE using hipuryl-L-histidyl-L-leucine (HHL) as a substrate,
ACE100μ (protein concentration
A solution of the compound of the present invention dissolved in 0.02 to 0.5% dimethyl sulfoxide in 100 mM boric acid-hydrochloric acid buffer (PH 8.3, containing 300 mM sodium chloride) was added to 100 μl of 1.25 mM HHL (20 mg/ml). As a control, a boric acid-hydrochloric acid buffer containing dimethyl sulfoxide at the same concentration as the sample solution was provided. Add this solution to 37
After heating at ℃ for 1 hour, 150μ of 1N hydrochloric acid was added to stop the reaction, and 0.8ml of ethyl acetate was added.
Centrifuged at 11.500 rpm for 2 minutes. Ethyl acetate layer 0.5
ml, dry under nitrogen gas at below 40℃, add 4.5 ml of distilled water to the residue, mix well, and add this.
Colorimetric determination was performed at a wavelength of 228 nm. [Experimental Results] The experimental results regarding the compounds of the present invention were as shown in Table 15.

〔experimental method〕

Weight 300-400g, bred with ad libitum access to food and water.
using male rats (Sprague-Dawley).
The day before the experiment, pentobarbital sodium (50
After the rats were anesthetized by intraventricularly injecting 2 mg/Kg), polyethylene tubes were inserted and fixed into the femoral artery for blood pressure measurement and the femoral vein for injecting angiotensin and angiotensin. On the day of the experiment, the mean 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 RM-45). Thereafter, 300 ng/Kg of angiotensin and then 100 ng/Kg of angiotensin were injected into the femoral vein to examine their pressor effect. Next, 300μ of the compound of the present invention
g/Kg was administered intravenously as a physiological saline solution, and angiotensin was repeatedly injected 5, 10, 30, 60, 90, and 120 minutes after administration to monitor the pressor response. In calculating the inhibition rate for the pressor action of angiotensin, the inhibition rate was corrected based on the temporal variation of the angiotensin pressor response. [Experimental Results] The experimental results regarding the compounds of the present invention were as shown in Table 16.

[Table] Experimental Example 3 Acute toxic effect of the compound of the present invention [Experimental method] The present invention was suspended in a 5% gum arabic aqueous solution in 4-week-old male Jcl: ICR mice and 5-week-old male Jcl: Wistar rats. the compound is administered orally, 2
We conducted weekly observations. [Experimental Results] Table 17 shows the acute toxic effects (LD ₅₀ ) of the compounds of the present invention.
Shown below.

[Table] Preparation Example When the compound of the present invention () is used, for example, as a therapeutic agent for hypertension, it can be used, for example, in the following formulation. 1 Tablet (1) 3(R)-[1(S)-carboxy-3-(4-piperidyl)propyl]amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid 10g (2) Lactose 90g (3) Corn starch 29g (4) Magnesium stearate 1g 130g Ingredients (1), (2) and Mix 17g of ingredient (3) and
granulate together with the paste made from component (3) in g, add and mix 5 g of component (3) and component (4) to the granules, and compress the mixture with a compression tablet machine to form tablet 1.
7mm diameter tablet containing 10mg of ingredient (1) per tablet
Manufacture 1000 pieces. 2 Injection (1) 3(R)-[1(S)-carboxy-3-(4-piperidyl)propyl]amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid 10g (2) Sodium chloride 9g Dissolve components (1) and (2) in 1000ml of distilled water, and add 1ml to 1000 brown ampoules. Dispense in portions, replace with nitrogen gas, and seal. The entire process is performed under sterile conditions. 3 Tablets (1) 3(R)-[1(S)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid 10g (2) Lactose 90g (3) Corn starch 29g (4) Magnesium stearate 1g 130g Ingredients (1), (2) and Mix 17g of ingredient (3) and
granulate together with the paste made from component (3) in g, add and mix 5 g of component (3) and component (4) to the granules, and compress the mixture with a compression tablet machine to form tablet 1.
7mm diameter tablet containing 10mg of ingredient (1) per tablet
Manufacture 1000 pieces. 4 Injection (1) 3(R)-[1(S)-carboxy-5-(4-piperidyl)bentyl]amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid 10g (2) Sodium chloride 9g Dissolve components (1) and (2) in 1000ml of distilled water, and add 1ml to 1000 brown ampoules. Dispense in portions, replace with nitrogen gas, and seal. The entire process is performed under sterile conditions.

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 represent tri or tetramethylene, and R ³ and R ⁵ each represent hydrogen , lower alkyl or aralkyl,
R ⁴ represents hydrogen or lower alkyl, R ⁶ represents a fused or non-fused heteroalicyclic group containing at least one N, O or S as a ring atom, A represents an alkylene chain, and n represents 1 or 2. ] or its salt. 2. The compound according to claim 1, wherein R ¹ and R ² are hydrogen. 3. The compound according to claim 1, wherein R ³ and R ⁵ are each hydrogen or lower alkyl. 4. The compound according to claim 1, wherein R ³ and R ⁵ are hydrogen. 5. The compound according to claim 1, wherein R ⁴ is hydrogen. 6 R ⁶ is a substituent lower alkyl, oxo,
A fused or non-fused heteroalicyclic group containing at least one N, O or S as a ring atom which may have one substituent among lower alkanoyl, benzoyl, aralkyloxycarbonyl or lower alkoxycarbonyl; A compound according to claim 1. 7 R ⁶ is a substituent lower alkyl, oxo,
The compound according to claim 1, which is oxanyl, thianyl or piperidyl optionally having lower alkanoyl, benzoyl, aralkyloxycarbonyl or lower alkoxycarbonyl. 8 R ⁶ as a substituent is lower alkyl, oxo,
The compound according to claim 1, which is piperidyl optionally having lower alkanoyl, benzoyl, aralkyloxycarbonyl or lower alkoxycarbonyl. 9. The compound according to claim 8, wherein the piperidyl group is 4-piperidyl. 10. The compound according to claim 1, wherein ^R6 is 4-piperidyl. 11. A compound according to claim 1, wherein the group C _o H _2o is methylene. 12. The compound according to claim 1, wherein A is alkylene having 2 to 9 carbon atoms. 13. The compound according to claim 1, wherein A is tetramethylene. 14. The compound according to claim 1, wherein R ⁶ is 1,3-dioxoisoindolinyl. 15 formula [In the formula, A represents alkylene having 2 to 9 carbon atoms] The compound according to claim 1, which is represented by the following formula. 16. The compound according to claim 15, wherein 16A is alkylene having 2 to 6 carbon atoms. 17. The compound according to claim 15, wherein A is tetramethylene. 18 formula [In the formula, R ¹ and R ² each represent hydrogen, halogen, trifluoromethyl, lower alkyl, or lower alkoxy, or both are linked to represent tri or tetramethylene, and R ³ and R ⁵ each represent hydrogen , lower alkyl or aralkyl,
R ⁴ represents hydrogen or lower alkyl, R ⁶ represents a fused or non-fused heteroalicyclic group containing at least one N, O or S as a ring atom, A represents an alkylene chain, and n represents 1 or 2. ] A preventive/therapeutic agent for hypertension containing a compound represented by or a salt thereof.