GB2143816A

GB2143816A - Benzothiazepine derivatives

Info

Publication number: GB2143816A
Application number: GB08416421A
Authority: GB
Inventors: Tsutomu Katakami; Nobuyuki Fukazawa; Hajime Iizuka; Takashi Nishina; Isao Shirakawa; Michihiko Miyamoto
Original assignee: Mitsui Toatsu Chemicals Inc
Current assignee: Mitsui Toatsu Chemicals Inc
Priority date: 1983-06-29
Filing date: 1984-06-28
Publication date: 1985-02-20
Also published as: IT1176345B; DE3423743A1; GB8416421D0; FR2548184A1; IT8421645A0; IT8421645A1

Abstract

Compounds of the general formula <IMAGE> (where K is hydrogen or a -CH2COOR2 group where R2 is hydrogen or a lower alkyl group, Z is hydrogen or phenyl, and Y is hydrogen, a -CHR3-COOR1 group, an alkanoyl group or a -COO(CH2)nR4 group where R1 is hydrogen or a lower alkyl group, R3 is hydrogen, an alkyl group, an alkylphenyl group or an aryl-lower alkyl group, R4 is an aryl group and n is 1 to 10) and their salts are useful for the treatment of hypertension and other cardiovascular diseases and as intermediates for coronary dilators and psychotropic drugs.

Description

SPECIFICATION Benzothiazepine derivatives and their methods of preparation Background of the invention 1) Field of the invention This invention relates to novel benzothiazepine derivatives and their various methods of preparation.

2) Description of the prior art It is generally known that angiotensin present in the blood acts on the smooth muscle of blood vessels to cause an intense contraction thereof and hence a marked rise in blood pressure. There are two forms of angiotensin: angiotensin I and angiotensin II. Renin, which is secreated by the kidneys, acts on angiotensinogen to form angiotensin I. By the action of the angiotensin converting enzyme present in blood plasma and tissues, angiotensin I is converted into angiotensin 11. It is angiotensin II that has biological activities.

Arise in blood pressure could be checked by inhibiting the angiotensin converting enzyme from acting on angiotensin I. With attention focused on this idea, the developement of compounds which are useful as drugs for the treatment of hypertension and other cardiovascular diseases has hitherto been carried on.

However, there have been obtained no compounds that are entirely satisfactory from the viewpoints of efficacy, side effects, toxicity and the like. Therefore, it would be still desirable to develop such compounds.

Moreover, pharmaceutical applications require that the desired compounds can be consistently produced in high yield and readily separated from by-products and the like.

Summary of the invention It is an object of the present invention to provide novel compounds which have an inhibitory effect on the activity of angiotensin while exhibiting little toxicity.

it is another object of the present invention to provide novel compounds which are useful as drugs for the treatment of hypertension and other cardiovascular diseases.

It is still another object of the present invention to provide several processes for preparing such compounds.

According to the present invention, there are provided benzothiazepine derivatives of the general formula

where K is hydrogen or a -CH2COOR2 group where R2 is hydrogen or a lower alkyl group, Z is hydrogen or phenyl, and Y is hydrogen, a -CHR3-COOR, group, an alkanoyl group or a -COO(CH2)nR4 group where R1 is hydrogen or a lower alkyl group, R3 is hydrogen, an alkyl group, an alkylphenyl group or an aryl-lower alkyl group, R4 is an aryl group and n is a whole number of 1 to 10.

Detailed description of the invention The benzothiazepine derivatives of the present invention will be more fully described hereinbelow.

In the general formula (I), the lower alkyl groups represented by R1 and R2 are selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl and the like. The alkanoyl group represented by Y is selected from the group consisting of formyl, acetyl, propanoyl, butanoyl, pivaloyl and the like. The alkyl group represented by R3 is preferably a straight-chain or branched alkyl group having 1 to 10 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. In benzothiazepine dericatives as claimed in claim 5, a straight-chain or branched alkyl group having 5 to 10 carbon atoms is most preferably used as the alkyl group represented by R3.The alkylphenyl group represented by R3 has the formula

and, among such alkylphenyl groups, those in which m is 1 or 2 (i.e., benzyl and phenetyl) are particularly preferred. The aryl-lower alkyl group represented by R3 is selected from the group consisting of tolylmethyl, tolylethyl, tolylpropyl, tolylbutyl, xylylmethyl, xylylethyl, xylylpropyl, xylylbutyl and the like. As the -COO(CH2)nR4 group represented by Y, those in which n is a whole number of 1 to 5 are particularly preferred.

Specific examples thereof include benzyloxycarbonyl, phenetyloxycarbonyl, phenyl propyloxycarbonyl, phenylbutyloxycarbonyl, phenylpentyloxycarbonyl, tolylmethoxycarbonyl, tolylethoxycarbonyl, tolylpropoxyca rbonyl, tolylbutoxycarbonyl, tolylpentyloxycarbonyl, xylyl methoxycarbonyl, xylylethoxycarbonyl, xylylpropoxycarbonyl, xylylbutoxycarbonyl, xylylpentyloxycarbonyl and the like.

Typical benzothiazepine derivative falling within the scope of the present invention include: 3-amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 3-acetylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 3-benxyloxycarbonylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 3-amino-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 3-benzyloxycarbonylamino-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 3-amino-5-ethoxycarbonylmethyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 3-a mi no-5-t-butoxycarbonyl methyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-ca rboxymethyl-3-carboxymethylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-carboxymethyl-3-ethoxycarbonylmethylam ino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 3-ethoxycarbonyl methylam ino-5-t-butoxy-carbonylmethyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-carboxymethyl-3-( 1 -carboxyethyla m ino)-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-carboxymethyl-3-( 1 -carboxynonyl am no)-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-carboxymethyl-3-( 1 -ethoxycarbonylethylamino)-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-carboxymethyl-3-( 1 -ethoxyca rbonyl nonylam ino)-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-t-butoxycarbonylmethyl-3(1 -ethoxycarbonylethylamino)-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 3-(1 -ethoxyCarbonyinonylamino)-5-t-butoxywarbonylmethyl-2,3-dihydro-1 ,5-benzoth iazepin-4(5H)-one, 3-(1 -carboxy-3-ph enylpropylamino)-5-carboxymethyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-carboxymethyl-3-(1 -ethoxycarbonyl-3-phenylpropylamino)-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 3-(1 -ethoxycarbonyl-3-phenyl propylamino)-5-ethoxyca rbonyl methyl-2,3-dihydro-1 ,5-benzothiazepin4(5H)-one, 3-amino-5-t-butoxycarbonylmethyl-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-carboxymethyl-3-ca rboxymethylamino-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-carboxymethyl-3-ethoxycarbonylmethylam ino-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-t-butoxycarbonylmethyl-3-ethoxycarbonyl methylam ino-2-phenyl-2,3-dihyd ro-1 ,5-benzothiazepin-4(5H)one, 5-carboxymethyl-3-(1 -carboxynonylam ino)-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-carboxymethyl-3-(1 -ethoxycarbonylnonylamino)-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin-44(5H)-one, 5-t-butoxycarbonyl methyl-3-(1 -ethoxycarbonylnonylamino)-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin4(5H)-one, 3-(1 -carboxy-3-phenylpropylamino)-3-carboxymethyl-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-carboxymethyl-3-( 1 -ethoxyca rbonyl methyl-3-phenylpropylamino)-2-phenyl-2,3-dihydro-1 ,5- benzothiazepin-4(5H)-one, 5-t-butoxycarbonyl methyl-3-(1 -ethoxycarbonyl-3-phenyl propylamino)-2-phenyl-2,3-dihydro-1 ,5- benzothiazepin-4(5H)-one and the like.

The compounds of the present invention can be prepared according to any one of the following processes.

where Z is hydrogen or phenyl, Xis a halogen, Y2 is an alkanoyl group, -COO(CH2)nR4 group where R4 is a aryl group and n is a whole number of 1 to 10, or an ordinary amino-protecting group, B5 is hydrogen or a lower alkyl group, Y' is hydrogen, an alkanoyl group, a -COO(CH2)nR4 group where R4 is an aryl group and n is a whole number of 1 to 10, or an ordinary amino-protecting group.

The term "ordinary amino-protecting group" as used herein comprehends urethane type protecting groups such as p-methoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 3,5 dimethoxybenzyloxyca rbonyl, 3,4,5-tri methoxybenzyloxycarbonyl, t-butoxycarbonyl, etc.; and acyl type protecting groups such as trifluoroacetyl, trichloroacetyl, benzoyl, etc.

Specifically, a compound of the general formula (II) or (Ill) is reacted with 2-amino-benzenethiol at a temperature ranging from 0 C to the boiling of the reaction mixture, for a period of several hours. This reaction may be carried out in the absence of solvent or in the presence of a solvent selected from the group consisting of alcohols (such as methanol, ethanol, propanol, etc.). Thus, there can preferably be obtained a compound of the general formula

Then, the compound of the general formula (IV) can preferably be converted into a compound of the general formula (V), by heating the former alone or in a suitable solvent such as benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, ethylene glycol, diphenyl ether or the like.The same purpose can be accomplished by using a dehydrating agent, such as dicyclohexylcarbodiimide or the like, suitable for cyclizing the compound of the general formula (IV) to form the compound of the general formula (V).

After the compound of the general formula (IV) has been cyclized, the alkanoyl, benzyloxycarbonyl or other amino-protecting group may be eliminated from the compound of the general formula (V), if desired, according to an ordinary procedure for the removal of protecting groups. Thus, there can be obtained a compound of the general formula (V) in which Y' is hydrogen.For example, where Y2 is benzyloxycarbonyl, this group can be removed by treating the compound with hydrogen bromide-acetic acid, hydrogen bromide-trifluoroacetic acid, hydrogen fluoride or the like, or by dissolving the compound in a suitable solvent such as ethanol, methanol, acetic acid or the like and hydrogenating it at a hydrogen pressure ranging from atmospheric pressure to 100 kg/cm2, in the presence of a noble metal catalyst commonly used for hydrogenation, such as palladium-carbon, platinum-carbon, platinum oxide or the like.

If desired, the compound of the general formula (V) thus obtained may be combined with hydrochloric acid, hydrobromic acid and the like to form their salts.

The compound of the general formula (V) in accordance with the present invention contains two asymmetric carbon atoms in the molecule and, therefore, has various optical isomers. It is to be understood that all of such optical isomers fall within the scope of the present invention.

where X, Z, Y2, B5 and Y' are as previously defined.

Specifically, a compound of the general formula (VI) and a compound of the general formula (VII) are dissolved in a suitable solvent. Specific examples of useful solvents include water and organic solvents such as methanol, ethanol, dimethylformamide, dimethyl sulfoxide, chloroform, benzene, etc., and these solvents may be used alone or in combination. Then, under an atmosphere of nitrogen, these compounds are reacted in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, triethylamine, cyclohexylamine, pyridine, lutidine and the like. This reaction may be carried out at a temperature ranging from 0"C to the boiling point, for a period of several hours.Thus, there can preferably be obtained a compound of the general formula

As the compound of the general formula (VI) used in this reaction, that in which Xis fluorine is most preferred. However, the reaction proceeds even if X is chlorine, bromine or iodine. The cysteine derivative of the general formula (VII) may be prepared according to any of various well-known methods [W. Foye and M. Verderame, J. Am. Pharm. Assoc. Sci. Ed., 46, 273(1957); L. Zervas and I. Photaki, J. Am. Chem. Soc., 84,3887(1962); and the like]. If the L- or D-isomer of the cysteine derivative is used, the corresponding L-or D-isomer of the compound of the general formula (VIII) can be obtained selectively.Then, the compound of the general formula (VIII) is reduced to form a compound of the general formula (IV). This can be accomplished by dissolving the former in a suitable solvent such as water, alcohols, acetic acid and a mixture thereof, and then reacting it with an acid such as acetic acid, hydrochloric acid, sulfuric acid or the like, in the presence of a metallic powder such as powdered iron, powdered tin, powdered zinc or the like.

This reduction may be carried out at a temperature ranging from 0 C to the boiling point of the reaction mixture, for a period of time ranging from several hours to several tens of hours. As occasion demands, this reduction may be carried out by dissolving the compound of the general formula (VIII) in a suitable solvent such as water, ethanol, methanol, ethyl acetate, acetic acid or the like, and then hydrogenating it at a hydrogen pressure ranging from atmospheric pressure to 100 kg/cm2, in the presence of a noble metal catalyst commonly used for hydrogenation, such as palladium-carbon, platinum-carbon, platinum oxide or the like.

The compound of the general formula (IV) thus obtained can be converted into a compound of the general formula (V) by treating the former in the same manner as previously described.

where X and Z are as previously defined, R1 is hydrogen or a lower alkyl group, B2 is hydrogen or a lower alkyl group, and B3 is hydrogen, an alkyl group, an alkylphenyl group or an aryl-lower alkyl group.

Specifically, a compound of the general formula (X) is reacted with a compound of the general formula (IX) in a solvent such as benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide or the like, in the presence of a suitable desalting agent such as sodium, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide or the like. This reaction may be carried out at a temperature ranging from -5 C to the boiling point of the reaction mixture, for a period of time ranging from about 0.5 to 5 hours.Thus, there can be obtained a compound of the general formula

where B2 is a lower alkyl group, the compound of the general formula (Xl) can be converted into the corresponding carboxylic acid by hydrolyzing the former according to a suitable procedure (for example, saponification by means of alkali). Moreover, where B2 is t-butyl, the compound of the, general formula (Xl) can also be converted into the corresponding carboxylic acid by reacting the former with an unprotecting agent commonly used for the synthesis of peptides, such as hydrogen chloride-dioxane, hydrogen bromide-acetic acid or the like.

The benzothiazepine derivative of the general formula (X) which is used as one of the starting materials in this process may be prepared according to either of the above-described processes (A) and (B).

Then, the compound of the general formula (Xl) is reacted with a compound of the general formula (XII) in the presence of a suitable reducing agent to form a compound of the general formula (XIII).

More specifically, this reaction is carried out as follows: Under cooling with ice or at a temperature up to 80"C, the compound of the general formula (Xl) and the compound of the general formula (XII) are mixed in a solvent selected from the group consisting of aliphatic or cyclic ethers (such as diethyl ether, dioxane, tetrahydrofuran, etc.), alcohols (such as methanol, ethanol, isopropyl alcohol, diethylene glycol, etc.), water and mixtures thereof. Then, these compounds are reduced with a reducing agent to form a compound of the general formula (XIII). Suitable reducing agents are complex metal hydrides such as diborane, sodium boron hydride, sodium boron cyanide hydride and the like.The same purpose can be accomplished by hydrogenating the compounds in the presence of a catalyst commonly used for hydrogenation, such as palladium-carbon, platinum-carbon, Raney nickel, Raney copper or the like. In this case, the hydrogenation may be carried out at a hydrogen pressure ranging from 1 to 300 atmospheres and a temperature ranging from room temperature to 1 50"C. There may be used any of solvents commonly used for hydrogenation, such as water, alcohols (such as methanol, ethanol, etc.), acetic acid, ethyl acetate and the like.

Where R1 or R2 is an alkyl group, the compound of the general formula (XIII) can be converted into the corresponding carboxylic acid by hydrolyzing the former according to an ordinary procedure (for example, treatment with an alkali). Moreover, where R1 or B2 is t-butyl, the compound of the general formula (XIII) can also be converted into the corresponding carboxylic acid, simply by exposing the former to an ordinary reagent for the cleavage of t-butyl esters, such as hydrogen chloride-dioxane, hydrogen bromide-acetic acid or the like.

The compound of the general formula (Xlil) in accordance with the present invention contains three asymmetric carbon atoms in the molecule and, therefore, has various stereoisomers. It is to be understood that all of such stereoisomers fall within the scope of the present invention.

The compound of the general formula (XIII) thus obtained may contain one or two carboxyl groups in the molecule. In this case, the compound of the general formula (XIII) can be combined with various inorganic or organic bases to form its salts. Specific examples of such salts include metallic salts such as sodium potassium, calcium, magnesium and like salts; and salts formed with organic bases such as lysine, dicyclohexylamine and like salts. Moreover, the compound of the general formula (XIII) contains an amino group that can combine with various acids to form salts. For example, the compound of the general formula (XIII) can be combined with inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, tartaric acid, maleic acid and the like, to form its salts.

The benzothiazepine derivatives of the present invention, including their salts formed as above, have a powerful inhibitory effect on the angiotensin converting enzyme and exert a marked depressor effect in such models of hypertension as spontaneously occuring hypertensive rats and the like, so that they are useful as drugs for the treatment of hypertension and other cardiovascular diseases. In addition, these compounds are also useful as intermediates for the synthesis of coronary dilators, psychotropic drugs and the like.

The present invention is further illustrated by the following examples. However, these examples are not to be construed to limit the scope of the invention.

EXAMPLE 1 Preparation ofN-acetyl-S-(2-aminophenyl) cysteine: A mixture consisting of 8.6 g of a-acetyl-aminoacrylic acid, 20 g of 2-aminobenzenethiol and 50 ml of ethanol was heated for an hour. After the ethanol was distilled off, ether was added to the residue so as to cause crystallization. Upon recrystallization from ethanol, there was obtained 8.9 g of the desired product. Its melting point (m.p.) was 143-144"C.

EXAMPLE 2 Preparation of N-benzyloxycarb onyl-S-12-aminoph eny-cysteine methyl ester: 2.72 g of N-benzyloxycarbonyl-p-chloroalanine methyl ester was dissolved in 10 ml of ether, and 1.0 g of triethylamine was added thereto.

After the addition of 1.5 g of 2-aminobenzenethiol, the resulting mixture was allowed to stand at room temperature for a day. The precipitated crystals were filtered off and the mother liquor was concentrated under pressure. The residue was subjected to silica gel column chromatography. Elution with chloroform gave 1.5 g of N-benzyloxycarbonyl-S-(2-aminophenyl)cysteine methyl ester. When analyzed by thin-layer chromatography (TLC) using an Art 5715 plate (Merck & Co., In.; for purposes of TLC, ART 5715 plates were used in all of the following examples) and chloroform (CHC13) as the developing solvent, the Nbenzyloxycarbonyl-S-(2-aminophenyl)-cysteine methyl ester exhibited an Value of 0.2.

This N-benzyloxycarbonyl-S-(2-aminophenyl)-cysteine methyl ester was cyclized to form 3 benzyloxycarbonylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one.

Then, 15 ml of a 25% solution of hydrogen bromide in acetic acid was added to 3.0 g of the 3-benzyloxycarbonylamono-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one and the resulting mixture was stirred at room temperature for an hour. After the solvent was distilled off under reduced pressure, ether was added to the residue. The precipitated crystals were separated by filtration to obtain 3-amino-2,3-dihydro-1,5benzothiazepin-4(5H)-one.

EXAMPLE 3 Preparation ofN-benzyloxycarbonyl-S-(2-aminophenyl)-cysteine 2.4 g of N-benzyloxycarbonyl-p-chloroalanine methyl ester and 611 mg of potassium carbonate were suspended in 20 ml of methanol. After the addition of 1.22 g of 2-aminobenzenethiol, the resulting mixture was stirred at room temperature for 24 hours. The insoluble matter was filtered off and the mother liquor was concentrated under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with water. After drying, the solvent was distilled off and the residue was dissolved in 10 ml of ethanol. After the addition of 10 ml of 1 N NaOH, the resulting mixture was stirred at room temperature for 3 hours. This mixture was extracted with ethyl acetate and the extract was washed with water. After drying, the solvent was distilled off.The residue was washed with ether several times to obtain 520 mg of N-benzyloxycarbonyl-S-(2-aminophenyl) cysteine.

The N-benzyloxycarbonyl-S-(2-aminophenyl)-cysteine thus obtained had a melting point of 150-151 C.

In the same manner as described in Example 2, the N-benzyloxycarbonyl-S-(2-aminophenyl) cysteine was cyclized to form 3-benzyloxycarbonylamino-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one. Then, 3-amino-2,3- dihydro-1 ,5-benzothiazepin-4(5H)-one could be obtained in the same manner as described in Example 2.

EXAMPLE 4 Preparation ofN-benzyloxycarbonyl-S-(2-aminophenyl)-cysteine: 23 g of a-benzyloxycarbonylaminoacrylic acid and 30 g of 2-aminobenzenethiol were dissolved in 20 ml of ethanol, and the resulting mixture was stirred at room temperature for an hour. After the solvent was distilled off, ether was added to the residue so as to cause crystallization. The precipated crystals were separated by filtration and washed with ether to obtain 17.8 g of the desired compound. Its melting point was 150-151"C.

EXAMPLE 5 Preparation ofN-benzyloxycarbonyl-S-(2-aminophenyl)-cysteine: 5.0 g of N-benzyloxycarbonyl- -bromoalanine and 2.5 g of 2-aminobenzenethiol were dissolved in 50 ml of methanol. In a stream of nitrogen gas, 3.4 g of triethylamine was added dropwise thereto at room temperature. After the mixture was allowed to stand overnight, the solvent was distilled off under reduced pressure and the residue was dissolved in an aqueous solution of sodium hydrogen carbonate. The solution was washed with ether and then acidified by the addition of hydrochloric acid under cooling with ice. The precipitated crystals were separated by filtration to obtain 3.5 g of N-benzyloxycarbonyl-S-(2aminophenyl)cysteine.

The N-benzyloxycarbonyl-S-(2-aminophenyl)-cysteine thus obtained had a melting point of 150"C.

In the same manner as described in Example 2, the N-benzyloxycarbonyl-S-(2-aminophenyl)cysteine was cyclized to form 3-benzyloxycarbonylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one. Then, 3-amino-2,3dihydro-1,5-benzothiazepin-4(5H)-one could be obtained in the same manner as described in Example 2.

EXAMPLE 6 Preparation of 3-acetylamino-2,3-dihydro- l,5-benzothiazepin-4(5H)-one: 1.2 g of N-acetyl-S-(2-aminophenyl)cysteine was disssolved in 20 ml of xylene and the resulting solution was heated under reflux for 2 hours. After cooling, the precipitated crystals were separated and washed with methanol to obtain 0.8 g of the desired compound, or 3-acetylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)one. Its melting point was 283-286"C.

EXAMPLE 7 Preparation of 3-acetylamino-2,3-dih ydro- 1,5-benzothiazepin-4{5H)-one: 16.6 g of N-acetyl-ss-chloroalanine and 12.5 g of 2-aminobenzenthiol were dissolved in 50 ml of ethanol. In a stream of nitrogen gas, 10.1 g of triethylamine was added dropwise thereto at room temperature. After the mixture was allowed to stand overnight, the ethanol was distilled off and the residue was dissolved in an aqueous solution of sodium hydrogen carbonate. The solution was washed with ether and acidified by the addition of concentrated hydrochloric acid under cooling with ice. The precipitated crystals were separated by filtration and recrystallized from ethanol to obtain 13.5 g of N-acetyl-S-(2-aminophenyl)cysteine.

The N-acetyl-S-(2-aminophenyl)cysteine thus obtained had a melting point of 143-144"C.

1.2 g of the N-acetyl-S-(2-aminophenyl)cysteine was dissolved in 20 ml of xylene and the resulting solution was heated under reflux for 2 hours. After cooling, the precipitated crystals were separated by filtration and washed with methanol to obtain 0.8 g of 3-acetylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one.

The 3-acetylamino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one thus obtained has a melting point of 283-286"C.

EXAMPLE 8 Preparation of3-benzyloxycarbonylamino-2,3-dihydro- l,5-benzothiazepin-4(5H)-one: 17.8 g of N-benzyloxycarbonyl-S-(2-aminophenyl)cysteine was dissolved in 250 ml of xylene and the resulting solution was heated under reflux for 4 hours. After the solvent was distilled off under reduced pressure, ether was added to the residue. The precipitated crystals were separated to obtain 12.1 g of the desired compound, or 3-benzyloxycarbonylamino-2,3-dihydro-1 ,5 benzothiazepin-4(5H)-one. Its melting point was 149-1510C.

EXAMPLE 9 Preparation of 3-(L)-amino-2,3-dihydro- 1, 5-benzothiazepin-4(5H)-one: 420 g of N-benzyloxycarbonyl-p-chloro-L-alanine and 247 g of 2-aminobenzenethiol were dissolved in 2 liters of methanol. In a stream of nitrogen gas, 340 g of triethylamine was added dropwise thereto at room temperature. After the mixture was allowed to stand overnight, about 1 g of iodine was added thereto. Then, the methanol was distilled off under reduced pressure and the residue was dissolved in an aqueous solution of sodium hydrogen carbonate. The solution was washed with ether and then acidified by the addition of concentrated hydrochloric acid under cooling with ice. The precipitated crystals were separated by filtration and recrystallized from ethanol to obtain 385 g of N-benzyloxycarbonyl-S-(2-aminophenyl)-L-cysteine.

Physical properties of the N-benzyloxycarbonyl-S-(2-aminophenyl)-L-cysteine thus obtained were as follows: m.p.167-169 C.

[o]2D8 = -18.9 (C=1.1 where C is the sample concentration in g/dl and hereinafter the same; solvent, AcOH).

17.8 g of the N-benzyloxycarbonyl-S-(2-aminophenyl)-L-cysteine was dissolved in 200 ml of xylene and the resulting solution was heated under reflux for 4 hours. After the solvent was distilled off under reduced pressure, ether was added to the residue. The precipitate was washed with ether to obtain 12.6 g of 3-(L)-benzyloxyCarbonylamino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. Physical properties of the 3-(L) benzyloxycarbonylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one thus obtained were as follows: m.p.184-185 C.

[tX]D7 = -230.8 (C=0.63; solvent, MeOH).

Then, 15 ml of a 25% solution of hydrogen bromide in acetic acid was added to 3.0 g of the 3-(L)-benzyloxycarbonylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one and the resulting mixture was stirred at room temperature for an hour. After the solvent was distilled off under reduced pressure, ether was added to the residue. The precipitated crystals were separated by filtration to obtain 2.45 g of 3-(L)-amino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one hydrobromide. Physical properties of the 3-(L)-amino 2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one hydrobromide thus obtained were as follows: m.p. 260"C or above.

{"YD7 = -235.90C (C=0.54; solvent, MeOH).

When racemic N-benzyloxycarbonyl-p-chloroalanine was used as the starting material, there was obtained racemic N-benzyloxycarbonyl-S-(2-aminophenyl)cysteine which, in turn, was treated in the same manner as described above to form racem ic racemic 3-benzyloxycarbonylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one. The racemic 3-benzyloxycarbonylamino2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one thus obtained had a melting pointof 149-151 C.

EXAMPLE 10 Preparation of 3-benzyloxycarb onylamino-2,3-dihydro- 1, 5-benzothiazepin-4(511)-one: 14.1 g of o-fluoronitrobenzene and 25.5 g of N-benzyloxycarbonyl-cysteine were dissolved in 100 ml of ethanol. After the addition of 20 g of triethylamine, the resulting mixture was heated under reflux for 20 hours. After the solvent was distilled off, 200 ml of ethyl acetate was added to the residue and the insoluble matter was filtered off. The mother liquor was washed with weak hydrochloric acid and then with an aqueous solution of sodium chloride. After drying, the solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography using a 5:1 mixture of benzene and acetic acid as the eluent. Thus, there was obtained 3.8 g of N-benzyloxycarbonyl-S-(2-nitrophenyl)cysteine.

When analyzed by thin-layer chromatography using a 3:1 mixture of benzene and acetic acid as the developing solvent, the N-benzyloxycarbonyl-S-(2-nitrophenyl)cysteine exhibited an Rf value of 0.45.

3.0 g of the N-benzyloxyxcarbonyl-S-(2-nitrophenyl)cysteine was dissolved in 30 ml of ethanol, and 3.0 g of powdered iron was added thereto. After the addition of 1 ml of acetic acid and 10 ml of water, the resulting reaction mixture was heated under reflux for 5 hours. The insoluble matter was filtered off and the mother liquor was concentrated under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with water. After drying, the solvent was distilled off and the residue was dissolved in an aqueous solution of sodium hydrogen carbonate. The resulting solution was washed with ether, acidified by the addition of hydrochloric acid under cooling with ice, and then extracted with ethyl acetate.After the extract was washed with water and dried, the solvent was distilled off and the residue was recrystallized from ethanol to obtain 1.2 g of N-benzyloxycarbonyl-S-(2-aminophenyl)cysteine.

The N-benzyloxycarbonyl-S-(2-aminophenyl)-cysteine thus obtained had a melting point of 149-151"C.

3.46 g of the N-benzyloxycarbonyl-S-(2-aminophenyl)cysteine was dissolved in 50 ml of chloroform. Under cooling with ice, 1.15 g of N-hydroxysuccinimide and 2.06 g of dicyclohexylcarbodiimide were added to the solution and the resulting mixture was allowed to stand overnight. After the precipitated urea was filtered off, the solvent was distilled off. Then, ether was added to the residue and the resulting precipitate was washed with water and then with ether to obtain 2.9 g of 3-benzyloxycarbonylamino-2,3-dihydro-1,5- benzothiazepin-4(5H)-one.

N-benzyloxycarbonyl-S-(2-aminophenyl)cysteine could also be obtained by reducing the N benzyloxywarbonyl-S-(2-nitrophenyl)cysteine according to the following procedure: 3.0 g of the N-benzyloxycarbonyl-S-(2-nitrophenyl)cysteine was dissolved in 50 ml of methanol After the addition of 500 mg of 5% palladium sulfidecarbon, the resulting mixture was hydrogenated at atmospheric pressure and ordinary temperature for 20 hours. After the catalyst was filtered off, the methanol was distilled off and the residue was dissolved in an aqueous solution of sodium hydrogen carbonate. The resulting solution was washed with ether and then acidified by the addition of hydrochloric acid under cooling with ice. The precipitated crystals were recrystallized from ethanol to obtain 2.2. g of N-benzyloxycarbonyl-S-(2aminophenyl)cysteine.

The N-benzyloxycarbonyl-S-(2-aminophenyl)-cysteine thus obtained had a melting point of 150-151"C.

When o-fluoronitrobenzene and N-benzyloxycarbonyl-L-cysteine were used as the starting materials, there was obtained N-benzyloxycarbonyl-S-(2-nitrophenyl)-L-cysteine which, in turn, was treated in the same manner as described above to form N-benzyloxycarbonyl-S-(2-aminophenyl)-L-cysteine. Then, the latter was cyclized to obtain 3-(L)-benzyloxycarnobylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one. The 3-(L)-benzyloxycarbonylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one thus obtained had a melting point of 184-185 C.

EXAMPLE 11 Preparation of3-amino-2,3-dihydro- 1, 5-b enzothiazepin-4(5H)-one: 14 ml of a 25% solution of hydrogen bromide in acetic acid was added to 3.0 g of 3-benzyloxy carbonylamino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and the resulting mixture was stirred at room temperature for an hour. After the addition of ether, the precipitated crystals were separated by filtration to obtain 2.45 g of the hydrobromide of the desired compound, or3-amino-2,3-dihydro-1,5-benzothiazepin- 4(5H)-one. Its melting point was 290"C or above.

1.0 g of this hydrobromide was dissolved in water and the solution was alkalified by the addition of an aqueous solution of sodium carbonate. The precipitated crystals were separated by filtration to obtain 0.7 g of 3-amino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one. When heated to determine its melting point, it decomposed at 182"C.

EXAMPLE 12 Preparation of3-amino-2,3-dihydro- 1,5-benzothiazepin-465H)-one: 1.0 g of 3-benzyloxycarbonylamino-2,3-dihydrn-1,5-benzothiazepinA(5H)-one was dissolved in 20 ml of methanol and then hydrogenated at atmospheric pressure in the presence of 50 mg of 5% palladium-carbon.

Thus, there was obtained the desired compound, or 3-amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.

EXAMPLE 13 Preparation of N-benzZloxycarbonyl-S-r2-aminophenyl)-ss-phenylcrsteine: 20 g of ol-benzyloxycarbonylamino-p-phenyl-acryl acid and 10 g of o-aminobenzenethiol were mixed with 40 ml of ethanol and the resulting mixture was heated under reflux for 20 hours. After cooling to room temperature, the precipitated crystalline component was separated by filtration and washed with ethanol to obtain 2.7 g of crystals. This product decomposed at 198"C.

EXAMPLE14 Preparation of 3-benzZloxycarbonylamino-2-phenyl-2,3-dEhydro-1,5-benzothiazepin-4{5H)-one: 2.7 g of the N-benzyloxycarbonyl-S-(2-aminophenyl)-ss-phenylcysteine obtained in Example 13 was suspended in 60 ml of xylene and the resulting suspension was heated under reflux for 3 hours. Thereafter, the apparatus was cooled to room temperature. The precipitated crystals were separated by filtration and washed with ethanol to obtain 1.9 g of the desired compound.

This compound had a melting point of 246-248"C.

EXAMPLE 15 Preparation of 3-amino-2-phenyl-2,3-dihydro- 1, 5-b enzo thiazepin -4(511)-one hydrobromide: 5.4 g of the compound obtained in Example 14 was dissolved in a 25% solution of hydrogen bromide in acetic acid. After the lapse of 2 hours, 15 ml of acetic acid was added to the solution and the resulting mixture was stirred for an hour. After the addition of ether, the precipitated crystals were separated by filtration and washed with ether to obtain 4.0 g of the desired compound.

This compound had a melting point of 300"C or above.

Its infrared (IR) absorption spectrum (as measured in a KBrtablet) exhibited an absorption band characteristic of C=0 at 1670 cm-1.

EXAMPLE 16 Preparation of 3-amino-2-phenyl-2,3-dihydro- 1,5-benzothiazepin-4(SHJ-one: 1.5 g of the compound obtained in Example 14 was dissolved in 70ml of methanol and then hydrogenated at atmospheric pressure in the presence of 100 mg of 5% palladium-carbon.

After the absorption of hydrogen stopped, the catalyst was filtered off and the resulting methanol solution was concentrated to obtain the desired compound, or 3-amino-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin 4(5H)-one. To this compound were added a 25% solution of hydrogen bromide in acetic acid and then ether.

The precipitated crystals were separated by filtration and washed with ether to obtain 3-amino-2-phenyl-2,3 dihydro-l ,5-benzothiazepi n-4(5H)-one hydrobromide. The infrared spectrum and melting point of this product agreed with those of the compound obtained in Example 15.

EXAM PLE17 Preparation of 3-benzyloxycarbonylamino-2-phenyl-Z3-dihydro- 1, 5-b enzo thiazep in -4(511)-one: The compound obtained in Example 14 was prepared according to an alternative procedure.

1.0 g of N-benzyloxycarbonyl-S-(2-aminophenyl)-ss-phenylcysteine was mixed with 0.5 g of dicyclohexy carbodiimide and 15ml of N,N-dimethyl-formamide and the resulting mixture was stirred for 5 hours. After the mixture was concentrated under reduced pressure, 20 ml of ethyl acetate was added to the residue and the insoluble matter was removed. Thereafter, the solution was concentrated to obtain the desired compound, or 3-benzyloxycarbonylamino-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one. The physical properties of this product agreed with those of the compound obtained in Example 14.

EXAMPLE 18 Preparation of 3-amino-5-ethoxycarb on ylmeth yl-2,3-dih ydro- 1,5-benzo thiazepin-4/5Hl-one hydrochloride: 2.0 g of 3-amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide was dissolved in 30 ml of dimethylformamide, and 600 mg of sodium hydride (in the form of a 60% suspension in oil) was added thereto. After the mixture was stirred at 50"C for 15 minutes, a solution of 1.21 g of ethyl bromoacetate in 5 ml of dimethylformamide was added thereto and the resulting mixture was stirred at 50"C for 3 hours. After the solvent was distilled off, benzene was added to the residue and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure and the resulting oily material was dissolved in ether.

Then, hydrogen chloride-ether was added to the solution so as to cause crystallization. Thus there was obtained 1.97 g of the desired compound. When heated to determine its melting point, this compound decomposed at 218 C.

EXAMPLE 19 Preparation of 3-amino-5-t-butoxycarbonylmethyl-2,3-dihydro- 1, 5-b enzo th iazepin -4(511)-one: In the same manner as described in Example 18, t-butyl bromoacetate was reacted with the corresponding benzothiazepine to obtain the desired compound, or 3-amino-5-t-butoxycarbonylmethyl-2,3-dihydro-1,5- benzothiazepin-4(5H)-one. Its melting point was 97-99"C.

EXAMPLE 20 Preparation of 3- ( 1-carb oxy-3-ph en ylprop ylamino)-5-carboxym eth yl-2, 3-dihydro- 7,5-benzo thiazepin-415H)- one: 1.2 g of 3-(1 ethoxycarbonyl3phenylprnpylamino)-S-ethoxycarbonylmethyl-2,3-dihydrn-1 ro-1.5- benzothiazepin-4(5H)-one was dissolved in 15 ml of ethanol, and 6 ml of 1 N NaOH was added thereto. The resulting mixture was stirred at room temperature, so that white crystals were precipitated. After 1.5 hours, the ethanol was distilled off under reduced pressure and water was added to the residue. After a small amount of insoluble matter was filtered off, the filtrate was adjusted to pH 3-4 with 6N hydrochloric acid.The precipitated crystals were separated by filtration and washed with cold water and then with ether to obtain 650 mg of the desired compound.

The infrared spectrum of this compound exhibited the following characteristic absorption bands: IRBa,, cm-1: 3440,1740,1690,1400, 1220,760,710.

EXAMPLE 21 Preparation of3-( 3-(l-ethoxycarbon yl-2-phen ylprop ylamino)-5-efhoxycarbon ylmethyl- 3-dihydro- 1,5 benzothiazepin-4(511)-one: 1.8 g of 3-amino-5-ethoxycarbonylmethyl-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one hydrochloride was mixed with 2.5 g of ethyl benzylpyruvate and 30 ml of ethanol, and the resulting mixture was adjusted to pH 5-7 with a saturated aqueous solution of sodium carbonate. After the mixture was allowed to stand for 2 hours, a solution of 0.7 g of sodium boron cyanide hydride in 10 ml of ethanol was added dropwise thereto over a period of one hour. To this mixture were added 5 ml of acetic acid and then 2.5 g of ethyl benzylpyruvate. After 2 hours, 2.0 g of ethyl benzylpyruvate was added and the mixture was allowed to stand overnight.After the ethanol was distilled off, 5ml of concentrated hydrochloric acid was added to the residue and the resulting mixture was stirred for an hour. After the addition of 80 ml of water, the mixture was extracted with ether. 5 ml of hydrogen chloride-ether was added to the ether extract and the separated oily material was isolated. Further, 10 ml of 6N hydrochloric acid was added to the ether layer, and the resulting mixture was stirred for a while and then allowed to stand. The lower layer was isolated and combined with the previously obtained oily material, followed by washing with ether. The aqueous layer was adjusted to pH 2-3 with a sodium hydroxide solution and then extracted with ether.After drying over anhydrous sodium sulfate, the product was concentrated to obtain 1.28 g of the desired compound in the form of an oily material.

The infrared spectrum (as measured between NaCI plates) of this compound exhibited the following characteristic absorption bands: lRNmAaxI, cm1:1760, 1690, 1490, 1210, 1040, 880, 710.

EXAMPLE 22 Preparation of 5-carboxymethyl-3-(7-ethoxycarbonyl-3-phenylpropylamino)-2,3-dihydro- 1, 5-benzo thiazepin- 4(511)-one hydrochloride: The compound obtained in Example 19 was reacted with ethyl benzylpyruvate in the same manner as described in Example 21. Thus, there was obtained 5-t-butoxycarbonylmethyl-3-(1 -ethoxycarbonyl-3- phenyl propylamino)-2,3-dihydro-l ,5-benzothiazepin-4(5H )-one in the form of an oily material.

15 ml of a solution of hydrogen chloride in dioxane was added to 4.5 g of the above diester and the resulting mixture was stirred for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and ether was added to the residue so as to cause crystallization. The precipitated crystals were separated by filtration and washed with ether to obtain 1.65 g of the desired compound, or 5-carboxymethyl-3-(1 -ethoxycarbonyl-3-phenylpropylamino)-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one hydrochloride. Its infrared spectrum exhibited the following principal absorption bands: IRBa,, cm-1: 3440,1750,1690,1480, 1390,1220,760,710.

EXAMPLE 23 Preparation of5-t-butox ycarb on ylmeth yl-3-(l-eth ox y-ca rb on yleth ylamin o)-2, 3-dih ydro- 1,5-benzothiazepin 4(511)-one: 1.5 g of 3-amino-5-t-butoxycarbonylmethyl-2,3-dihydro-1 ,S-benzothiazepin-4(5H )-one and 2.0 g of ethyl pyruvate were dissolved in 15 ml of ethanol. After the addition of 0.3 ml of acetic acid, the resulting mixture was stirred for 2 hours. Then, a solution of 420 mg of sodium boron cyanide hydride in 8 ml of ethanol was slowly added dropwise thereto. After this mixture was allowed to stand overnight, the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed with water, dried and then concentrated. The residue was purified by silica gel column chromatography using a 3:1 mixture of benzene and ethyl acetate as the eluent. Thus, there was obtained 1.0 g of the desired compound in the form of an oily material.

When analyzed by thin-layer chromatography using a 3:1 mixture of benzene and ethyl acetate as the developing solvent, this compound gave two spots having Rf values of 0.5 and 0.6.

EXAMPLE 24 Preparation of5-carb of ymeth yl-3-(l-eth ox 7with oxycaron yl-eth ylamino)-2,3-dih ydro- l,5-benzothiazepin-4(511)-one hydrochloride: 0.9 g of the 5-t-butoxycarbonylmethyl-3-(1 -ethoxycarbonylethylamino)-2,3-dihydro-1 ,5-benzothiazepin- 4(5H)-one obtained in Example 23 was dissolved in 10 ml of a 6N solution of hydrogen chloride in dioxane and then reacted at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, ether was added thereto so as to cause crystallization. The precipitated crystals were purified by silica gel column chromatography using a 50:3:5 mixture of chloroform, methanol and acetic acid as the eluent. Thus, there was obtained 400 mg of the desired compound.

The results of its analysis by infrared spectroscopy, nuclear magnetic resonance (N MR) spectroscopy and thin-layer chromatography using a 50:3:5 mixture of chloroform, methanol and acetic acid as the developing solvent were as follows: IRmBarX, cm-1: 3440,1740,1680,1480, 1230,1010.

N MB(DMSO- D6), ppm:1.0-1 .4(6H), 3.2-3.4(2H), 3.7A.3(SH), 4.6-4.8(1 H), 7.2-7.7(4H).

TLC: Rf = 0.65.

EXAMPLE 25 Preparation of 5carboxymeth yl-3-I I-carboxyeth ylamin 0)-2,3-dih ydro- l,5-benzothiazepin-4(511)-one hydrochloride: 200 mg of the S-carboxymethyl-3-( 1 -ethoxy-ca rboxynylethylam ino)-2,3-di hydro-1 ,5-benzothiazepin-4(SH)- one hydrochloride obtained in Example 24 was dissolved in 5 ml of water and 1.5 ml of a 1 N aqueous solution of sodium hydroxide and then reacted at room temperature for an hour. Thereafter, the solution was adjusted to pH 1-2 with hydrochloric acid and concentrated to dryness under reduced pressure. Ethanol was added to the residue and the insoluble matter was removed by filtration. After the filtrate was concentrated, ether was added thereto so as to cause crystallization.Thus, there was obtained 150 mg of the desired compound.

The results of its analysis by infrared spectroscopy and nuclear magnetic resonance (NMR) spectroscopy were as follows: lBKmBax,cm1: 3420,1740,1670,1480, 1220,1110,770.

NMR(DMSO-D6), ppm:1.3-1 .5(3H);3.7-4.3(5H), 4.6-4.8(1H), 7.3-7.7(4H).

EXAMPLE 26 Preparation of 3-ethoxycarbonylmethylamino-5-t-butoxy-2,3-dEhydro- 1,5-benzothiazepin-4r5H)-one: 1.2 g of 3-amino-5-t-butoxycarbonylmethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 5.0 g of ethyl glyoxylate were dissolved in 20 ml of ethanol. After the addition of 0.3 ml of acetic acid, the resulting mixture was stirred for 3 hours. Then, a solution of 400 mg of sodium boron cyanide hydride in 7 ml of ethanol was slowly added dropwise thereto. After this mixture was allowed to stand overnight, it was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water, dried and then concentrated. The residue was purified by silica gel column chromatography using a 3:1 mixture of benzence and ethyl acetate as the eluent.Thus, there was obtained 1.25 g of the desired compound in the form of an oily material.

When analyzed by thin-layer chromatography using a 3:1 mixture of benzene and ethyl acetate as the developing solvent, this compound exhibited an Rf value of 0.45.

EXAMPLE 27 Preparation of 5-ca rb ox ymeth yl-3-eth ox ycarb on yl-m eth ylamino-2, 3- dih ydro- 1, 5-b enzo th iazep in -4 (511)one hydrochloride: 1.25 g of the 3-ethoxyCarbonylmethylamino-5-t-butoxy-2,3-dihydro-1,5-benziothiazepin-4(5H)-one obtained in Example 26 was dissolved in 10 ml of a 6N solution of hydrogen chloride in dioxane and then reacted at room temperature for an hour. After this solution was concentrated under reduced pressure, ether was added thereto so as to cause crystallization. Thus, there was obtained 720 mg of the desired compound.

When heated to determine its melting point, this compound decomposed at 248"C.

The results of its analysis by infrared spectroscopy, nuclear magnetic resonance spectroscopy and thin-layer chromatography using a 3:1:1 mixture of n-butanol, acetic acid and water as the developing solvent were as follows: IRmBrirX, cm-1: 3060,2740, 1760, 1680, 1390, 1260, 1030,780.

NMR(DMSO-D6), ppm: 1.1-1.3(3H), 3.2-4.8(9H), 7.2-7.8(4H).

TLC: Rf = 0.7.

EXAMPLE 28 Preparation of 5-carboxymethyl-3-carboxymethylamino-2,3-dihydro- 1, 5-b enzothiazepin -4(511)-one hydroch chloride: 420 mg of the 5-ca rboxymethyl-3-ethoxyca rbonyl methylamino.2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one hydrochloride obtained in Example 27 was dissolved in 5 ml of water, 3 ml of ethanol and 3.5 ml of a 1 N aqueous solution of sodium hydroxide and then reacted for 2 hours. Thereafter, the solution was adjusted to pH 1-2 with hydrochloric acid and concentrated to dryness under reduced pressure. Ethanol was added to the residue and the insoluble matter was filtered off. After the filtrate was concentrated, ether was added thereto so as to cause crystallization. Thus, there was obtained 350 mg of the desired compound.

The results of its analysis by infrared spectroscopy and thin-layer chromatography using a 3:1:1 mixture of n-butanol, acetic acid and water as the developing solvent were as follows: IRKmBjx, cm-1: 3440,2980,1750,1680, 1480,1400, 1220,780.

TLC: Rf = 0.4.

EXAMPLE 29 Prepararion of3-(1-ethoxycarbonylnonylamino)-5-t-butoxycarbonylmethyl-2,3-dihydro- 1,5- benzothiazepin4(511)-one: 1.3 g of 3-amino-5-t-butoxyCarbonylmethyi-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 3.0 g of ethyl 2-ketodecanoate were dissolved in 10 ml of ethanol. After the addition of 0.3 ml of acetic acid, the resulting mixture was stirred for 3 hours. Then, a solution of 420 mg of sodium boron cyanide hydride in 7 ml of ethanol was added dropwise thereto. After this mixture was allowed to stand overnight, it was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water, dried and then concentrated. The residue was purified by silica gel column chromatography using a 7:1 mixture of benzence and ethyl acetate as the eluent.Thus, there was obtained 1.8 g of the desired compound in the form of an oily material.

When analyzed by thin-layer chromatography using a 6:1 mixture of benzene and ethyl acetate as the developing solvent, this compound exhibited an Rf value of 0.65.

EXAMPLE 30 Preparation of 5-carboxymethyl-3-(l-theoxycarbonylnonylamino)-2,3-dihydro- l,5-benzothiazepin-4(511)- one: 1.7 g of the 3-(1 -ethoxycarbonylnonylamino)-5-t-butoxycarbonyl methyl-2,3-dihydro-1 ,5-benzothiazepin- 4(5H)-one obtained in Example 29 was dissolved in 12 ml of a 6N solution of hydrogen ch!oride in dioxane and then reacted at room temperature for an hour. After this solution was concentrated under reduced pressure, 0.6 ml of triethylamine was added to the residue. This product was purified by silica gel column chromatography using a 5:2 mixture of benzene and acetic as the eluent. Thus, there was obtained 1.1 g of the desired compound in the form of a colorless, transparent oily material.

The results of its analysis by infrared spectroscopy, nuclear magnetic resonance spectroscopy and thin-layer chromatography using a 10:3 mixture of benzene and acetic acid as the developing solvent were as follows: IR86,, cm-': 2940, 1750, 1690, 1600,1490, 1400, 1220, 1030.

NMR(DMSO- D6), ppm: 0.7-1 .6(20H), 2.6-3.5(4H), 3.8-4.2(3H), 4.5-4.8(1 H), 7.2-7.7(4H).

TLC: Rf = 0.8.

EXAMPLE 31 Preparation of5-carboxymethyl-3-( l-carboxyonylamino)-2,3-dihydro- 1, 5-b enzo th iazepin -4(511)-one: 690 mg of the 5-carboxymethyl-3-(l -ethoxycarbonyl nonylamino)-2,3-dihydro-l ,5-benzothiazepin-4(5H)- one obtained in Example 30 was dissolved in 10 ml of ethanol and 4 ml of a 1N aqueous solution of sodium hydroxide and then reacted at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in 5 ml of water. This solution was adjusted to pH 2 with hydrochloric acid. The precipitated white crystals were separated by filtration and washed thoroughly with water to obtain 600 mg of the desired compound.

The results of its analysis by infrared spectroscopy, nuclear magnetic resonance spectroscopy and thin-layer chromatography using a 3:1:1 mixture of n-butanol, acetic acid and water as the developing solvent were as follows: IRKBarX, cm-1: 3440,2960, 1740, 1690, 1480, 1400, 1230,770.

NMR(DMSO- D6), ppm: 0.7-1 .0(3H), 1.0-1.6(1 4H), 2.8-3.2(2H), 3.2-3.6(2H), 4.0-4.3(1 H), 4.6-4.9(1 H), 7.1 -7.7(4H).

TLC: Rf = 0.85.

EXAMPLE 32 Preparation of3-amino-5-t-butoxycarbonylmethyl-2-phenyl-2,3-dihydro- I, 5-benzothiazepin-4/5H-one : 4.8 g of 3-amino-2-phenyl-2,3-dihydro-1-5-benzothiazepin-4(5H)-one hydrobromide was dissolved in 80 ml of N, N-dimethylformamide. After the addition of 1.2 g of sodium hydride (in the form of a 60% suspension in oil), the resulting mixture was stirred at 50"C for an hour. Then, a solution of 2.7 g of t-butyl bromoacetate in 10 ml of N,N-dimethylformamide was added and the mixture was stirred at 50"C for an additional hour. After the solvent was distilled off under reduced pressure, hexane was added to the residue so as to cause crystallization. The product was separated by filtration and washed with ether, with water and then with ether to obtain 4.0 g of the desired compound. This compound had a melting point of 178-180 C, EXAMPLE 33 Preparation of 5-t-butoxycarbonylmethyl-3-r1-ethoxyCarbonyl-3-phenylpropylamino)-2-phenyl-2,3-dEhydro- 1,5-benzothiazepin-4r5H)-one: 1.2 g of compound obtained in Example 32 was mixed with 2.0 g of ethyl benzylpyruvate, 20 ml of ethanol and 1 ml of acetic acid and dissolved therein by warming to 40"C. The resulting reaction mixture was stirred for 3 hours. Thereafter, a solution of 400 mg of sodium boron cyanide hydride in 10 ml of ethanol was slowly added dropwise to the reaction mixture, which was then allowed to stand overnight.After the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate. The resulting solution was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure.

The concentrate was fractionated and purified by silica gel column chromatography using a 9:1 mixture of benzene and ethyl acetate as the eluent. Thus, there was obtained 1.66 g of the desired compound.

When analyzed by thin-layer chromatography using a 7:1 mixture of benzene and ethyl acetate as the developing solvent, this compound exhibited an Rf value of 0.7.

EXAMPLE 34 Preparation of dcarboxymerh y/-3-( I-ethoxycarbon yl-3-phen ylprop ylamino)-2-phen yl-2,3-dihydro- 1,5 benzothiazepin-4(511)-one hydrochloride: 1.66 g of the compound obtained in Example 33 was dissolved in 10 ml of a 6N a solution of hydrogen chloride in dioxane, and the resulting solution was stirred at room temperature for an hour. Then, ether was added thereto so as to cause crystallization. The precipitated crystals were separated by filtration and washed with ether to obtain 1.1 g of the desired compound.

The infrared absorption characteristics and nuclear magnetic resonance characteristics of this compound were as follows: lRmKSax, cm-': 1730, 1670, 1470, 1450, 1210, 1020, 700.

NMR(DMSO-D6), ppm: 0.9-1 .2(3H), 1.3-2.1 (4H).

When analyzed by thin-layer chromatography using a 10:3 mixture of benzene and acetic acid as the developing solvent, this compound gave two spots having Rf values in the vicinity of 0.8.

The above compound is a mixture of diastereomers, which can be separated, if desired.

EXAMPLE 35 Preparation of 3-(7-carb oxy-3-phenylprolylmin ol-dcarboxymeth yl-2-phen yl-2,9-dihydro- 1, 5-benzothiazepin 485H)-one: 400 mg of the compound obtained in Example 34 was dissolved in a mixture consisting of 5 ml of ethanol and 2.9 ml of a 1 N aqueous solution of sodium hydroxide, and the resulting solution was stirred for 4 hours.

After the reaction mixture was concentrated under reduced pressure, it was dissolved in 40 ml of water and a small amount of insoluble matter was removed. Then, the aqueous solution was adjusted to pH 2 with concentrated hydrochloric acid. The precipitated crystals were separated by filtration and washed with water to obtain 280 mg of the desired compound.

The infrared absorption characteristics of this compound were as follows: IRKBar, cm1:1730, 1710, 1670, 1470, 1390, 1200, 700.

When analyzed by thin-layer chromatography using a 3:1:1 mixture of n-butanol, water and acetic acid as the developing solvent, this compound gave two spots having Rf values of 0.65 and 0.8, which corresponded to its diastereomers. These diastereomers can be separated, if desired.

EXAMPLE 36 Preparation of 5-t-butoxycarbonylmethyl-3-ethoxy-carbonylmethylamino-2-phenyl-2,3-dihydro- 1, 5 benzothiazep in -4(511)-one: The procedure of Example 33 was repeated except that 1.2 g of the 3-amino-5-t-butoxycarbonylmethyl-2phenyl-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one obtained in Example 32 was reacted with 3.0 g of ethyl glyoxylate.

The resulting concentrate was fractionated and purified by silica gel column chromatography using a 4:1 mixture of benzene and ethyl acetate as the eluent. Thus, there was obtained 1.2 g of the desired compound in the form of an oily material.

When analyzed by thin-layer chromatography using a 4:1 mixture of benzene and ethyl acetate as the developing solvent, this compound exhibited an Bf value of 0.5.

EXAMPLE 37 Preparation of dcarboxymeth yl-3ethoxycarb on ylmethylamino-2-phen yl-2,3-dih ydro- 1,5-benzothiazepin 4(511)-one hydrochloride: 1.2 g of the compound obtained in Example 36 was dissolved in 10 ml of a 6N a solution of hydrogen chloride in dioxane, and the resulting solution was stirred at room temperature for 2 hours. Then, ether was added thereto so as to cause crystallization. The precipitated crystals were separated by filtration and washed with ether to obtain 1.0 g of the desired compound.

The melting point of this compound could not be determined because it decomposed at 202-205"C.

The infrared absorption characteristics of this compound and the result of its analysis by thin-layer chromatography using a 10:3 mixture of benzene and acetic acid were as follows: lRKmEarx, cm-1: 1740,1670,1380,1230, 1020,850,770.

TLC: Rf = 0.25.

EXAMPLE 38 Preparation of 5-carboxymethyl-3-carboxymethylamino-2-phenyl-2,3-dihydro- 1,5-benzothiazepin-4(511)-one hydrochloride: 410 mg of the compound obtained in Example 37 was dissolved in a mixture consisting of 3.5 ml of a 1N aqueous solution of sodium hydroxide and 5 ml of ethanol, and the resulting solution was stirred for 30 minutes. Then the solution was adjusted to pH 1-2 with concentrated hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in ethanol and the insoluble matter was filtered off. After the filtrate was concentrated, ether was added thereto so as to cause crystallization. The precipitated crystals were separated by filtration and washed with ether to obtain 330 mg of the desired compound.

When heated to determine its melting point, this compound began to decompose gradually in the vicinity of 100 C.

The infrared absorption characteristics of this compound and the result of its analysis by thin-layer chromatography using a 3:1:1 mixture of n-butanol, water and acetic acid were as follows: IRIBa,, cm-': 1730,1670,1470, 1450,1400,1320, 1200,770.

TLC: Rf = 0.4.

EXAMPLE 39 Preparation of 5-t-butoxycarbonylmethyl-3-r1-ethoxycarbonyinonylamino)-2-phenyl-2,3-dEhydro- 1,5 benzothiazepin-4(511)-one: 1.1 g of the compound obtained in Example 32 was reacted with 3.0 g of ethyl 2-ketodecanoate in the same manner as described in Example 33. The reaction product was fractionated and purified by silica gel column chromatography using a 9:1 mixture of benzene and ethyl acetate as the eluent. Thus, there was obtained 1.3 g of the desired compound in the form of an oily material.

When analyzed by thin-layer chromatography using a 8:1 mixture of benzene and ethyl acetate as the developing solvent, this compound gave two spots having Rf values of 0.92 and 0.88, which corresponded to its diastereomers. These diastereomers can be separated, if desired.

EXAMPLE 40 Preparation of 5-carboxymethyl-3-{1-ethoxycarbonyinonylamino)-2-phenyl-2,3-dEhydro-1,5-benzothiazepin- 4(511)-one hydrochloride: 1.3 g of the oily material obtained in Example 39 was dissolved in 10 ml of a 6N solution of hydrogen chloride in dioxane, and the resulting solution was stirred at room temperature for an hour. Then, ether was added thereto so as to cause crystallization. The precipitated crystals were separated by filtration and washed with ether to obtain 800 mg of the desired compound.

The infrared absorption characteristics of this compound were as follows: IRKmBarx, cm-': 2920,2860,1730,1670, 1470,1450,1200,1020.

When analyzed by thin-layer chromatography using a 10:1 mixture of benzene and acetic acid as the developing solvent, this compound gave two spots having Rf values of 0.45 and 0.55, which corresponded to its diastereomers. These diastereomers can be separated, if desired.

EXAMPLE 41 Preparation of 5-carb oxymeth yl-3-(l-carb oxyn onylamino)-2-phen yl-2,3-dih ydro- 7, 5-benzothiazepin-4(5H)- one: 300 mg of the compound obtained in Example 40 was dissolved in a mixture consisting of 1.6 ml of a 1 N aqueous solution of sodium hydroxide and 1 ml of ethanol. The resulting solution was stirred at room temperature for 3 hours and then at 60"C for an hour. After the addition of ethanol, the precipitated crystals were separated by filtration and washed with ethanol. These crystals were dissolved in a small amount of water and the solution was adjusted to pH 2 with concentrated hydrochloric acid. The precipitated crystals were separated by filtration and washed with water to obtain 170 mg of the desired compound.

The infrared absorption characteristics of this compound were as follows: IRKBarxl cm-': 2920,2860,1730,1710,1680,1470,1450,1390,1320,1210; When analyzed by thin-layer chromatography using a 10:3 mixture of benzene and acetic acid as the developing solvent, this compound gave two spots having Rf values of 0.15 and 0.25, which corresponded to its diastereomers, These diastereomers can be separated, if desired.

EXAMPLE 42 Pharmacological testing of typical compounds of the invention: The efficacy of the compounds of the present invention can be tested by evaluating their inhibitory effects on the angiotensin converting enzyme (ACE). Using ACE isolated from rabbit lungs, in vitro evaluation of inhibitory effects on ACE activity was carried out according to the method of Kushman [Biochem.

Pharmacol.,20, 1637(1971).

When used at concentrations of 0.1 pM and 0.01 FM, the compound of Example 20 inhibited ACE activity by 77.8% and 14.8%, respectively. Some of the compounds obtained in the other examples were also tested by in vitro evaluation of inhibitory effects on ACE activity and the results thus obtained are summarized in Table 1.

TABLE 1 Example No. IC50 ( > M) 24 7.0 25 0.47 27 > 100 28 8.2 30 0.16 31 0.010 The compounds of the present invention can also be tested by evaluating their depressor effects. Such evaluation was carried out by using spontaneously occurring hypertensive rats (SHR). Male rats, aged 20 weeks or more, were fasted for 17 hours. Then, under an unanesthetized condition, the systolic blood pressure of their caudal artery was nonsurgically measured before medication as well as 2,4,6 and 24 hours after medication. Test compounds were orally administered to groups of 3-5 rats showing a systolic blooc pressure of 180 mmHg or above.

When the compound of Example 22 was orally administered in a dose of 50 mg/kg, the blood pressure was reduced by 26, 34 and 46 mmHg after the lapse of 2, 4 and 6 hours, respectively. This depressor effect was found to persist even after 24 hours.

Thus, the compounds of the present invention have an ibhibitory effect on ACE and a depressor effect, so that they are useful as antihypertensive agents.

Claims

1. A benzothiazepine derivative of the general formula

where K is hydrogen or a -CH2COOR2 group where R2 is hydrogen or a lower alkyl group, Z is hydrogen or phenyl, and Y is hydrogen, a -CHR3-COOR1 group, an alkanoyl group or a -COO(CH2)nR4 group where R1 is hydrogen or a lower alkyl group, B3 is hydrogen, an alkyl group, an alkylphenyl group or an aryl-lower alkyl group, R4 is an aryl group and n is a whole number of 1 to 10.

2. A benzothiazepine derivative as claimed in claim 1 wherein, in the general formula (I), K and Z are each hydrogen and Y is hydrogen, a -CHR3-COOR1 group, an alkanoyl group or a -COO(CH2)nR4 group where R1, R3, R4 and n are as previously defined.

3. A benzothiazepine derivative as claimed in claim 1 wherein, in the general formula (I), K is hydrogen, Z is phenyl and Y is hydrogen, a -CHB3-COOR1 group, an alkanoyl group or a -COO(CH2)nR4 group where R1, R3, R4 and n are as previously defined.

4. A benzothiazepine derivative as claimed in claim 1 wherein, in the general formula (I), K is a -CH2COOR2 group where R2 is as previously defined, Z is hydrogen and Y is hydrogen, a -CHR3-COOR1 group, an alkanoyl group or a -COO(CH2)nR4 group where R1, R3, R4 and n are as previously defined.

5. A benzothiazepine derivative as claimed in claim 1 wherein, in the general formula (I), K is a -CH2COOR2 group where R2 is as previously defined, Z is phenyl and Y is hydrogen, a -CHR3-COOR1 group, an alkanoyl group or a -COO(CH2)nR4 group where R1, R3, R4 and n are as previously defined.

6. A benzothiazepine derivative as claimed in claim 2 which is 3-amino-2,3-dihydro-1,5-benzothiazepin 4(5H)-one, 3-acetylamino-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one or 3-benzyloxycarbonylamino-2, 3 dihydro-1,5-benzothiazepin-4(5H)-one.

7. A benzothiazepine derivative as claimed in claim 3 which is 3-amino-2-phenyl-2,3-dihydro-1,5benzothiazepin-4(5H)-one or 3-benzyloxyCarbonylamino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)- one.

8. A benzothiazepine derivative as claimed in claim 4 which is 3-amino-5-ethoxycarbonylmethyl-2,3dihydro-1,5-benzothiazepin-4(5H)-one, 3-amino-5-t-butoxyca rbonylmethyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-carboxymethyl-3-ca rboxymethylamino-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one, 5-carboxymethyl-3-ethoxycarbonylmethylamino-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 3-ethoxycarbonyl methylamino-5-t-butoxycarbonyl methyl-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one, 5-carboxymethyl-3-( 1 -carboxyethylamino)-2,3-dihydrn-1 ,S-benzothiazepin-4(SH)-one, 5-carboxymethyl-3-(1 -carboxynonylamino)-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one, S-carboxymethyl-3-(1 -ethoxycarbonylethylamino)-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one, 5-carboxymethyl-3-(1 -ethoxycarbonylnonylamino)-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one, 5-t-butoxycarbonylmethyl-3-( 1 -ethoxycarbonylethylamino)-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 3-1 -ethoxycarbonyl nonylam ino)-5-t-butoxycarbonyl methyl-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one 3-(1 -carboxy-3-phenyl propylamino)-5-carboxymethyl-2,3-dihydro ,5-benzothiazepin-4(SH)-one, 5-carboxymethyl-3-(1 -ethoxycarbonyl-3-phenylropylamino)-2,3-dihydro-1 ,S-benzothiazepin-4(5H)-one or 3-(1 -ethoxywarbonyl-3-phenyipropylamino)-5-ethoxycarbonylmethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)- one

9. A benzothiazepine derivative as claimed in claim 5 which is 3-amino-S-t-butoxycarbonylmethyl-2- phenyl-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one, 5-carboxymethyl-3-carboxymethylamino-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin-4(SH)-one, 5-carboxymethyl-3-ethoxycarbonyl methylamino-2-phenyl-2,3-dihydro-l ,5-benzothiazepin-4(SH)-one, 5-t-butoxycarbonyl methyl-3-ethoxycarbonyl methylam ino-2-phenyl-2,3-dihydro-l ,5-benzothiazepin-4(5H)- one, 5-carboxymethyl-3-(1 -carboxynonylam ino)-2-phenyl-2,3-dihydro-l ,5-benzothiazepin-4(SH)-one, 5-carboxymethyl-3-(1 -ethoxycarbonylnonylamino)-2-phenyl-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 5-t-butoxycarbonyl methyl-3-( 1 -ethoxycarbonyinonylamino)-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)- one, 3(1 -carboxy-3-phenyl propylamino)-3-carboxymethyl-2-phenyl-2,3-dihydro-1 ,S-benzothiazepin-4(SH)-one, 5-carboxymethyl-3-(1 -ethoxycarbonylmethyl-3-phenyl propylamino)-2-phenyl-2,3-dihydro-1 ,5- benzothiazepin-4(5H)-one or 5-t-butoxycarbonylmethyl-3-( 1 -ethoxycarbonyl-3-phenyl propylamino)-2-phenyl-2,3-dihydro-1 5- benzothiazepin-4(5H)-one.

10. A process for preparing benzothiazepine derivatives of the general formula

where Z is hydrogen or phenyl and Y' is hydrogen, an alkanoyl group, a -COO(CH2)R4 group where R4 is an aryl group and n is a whole number of 1 to 10, or an ordinary amino-protecting group, which comprises reacting a compound of the general formula

I where Z is as previously defined, Xis a halogen, Y2 iS an alkanoyl group, a -COO(CH2)nR4 group where R4 is an aryl group and n is a whole number of 1 to 10, or an ordinary amino-protecting group, and B5 is hydrogen or a lower alkyl group, with 2-aminobenzenethiol to form a compound of the general formula

where Z, Y2 and B5 are as previously defined; and then cyclizing the compound of the general formula (IV) with or without subsequent elimination of theY2 group.

11. A process for preparing benzothiazepine derivatives of the general formula

where Z is hydrogen or phenyl and Y' is hydrogen, an alkanoyl group, a -COO(CH2)nR4 group where R4 is an aryl group and n is a whole number of 1 to 10, or an ordinary amino-protecting group, which comprises reacting a compound of the general formula

where X is a halogen, with a compound of the general formula

where Z is hydrogen or phenyl, Y2 iS an alkanoyl group, a -COO(CH2)nR4 group where R4 is an aryl group and n is a whole number of 1 to 10, or an ordinary amino-protecting group, and B5 is hydrogen or a lower alkyl group to form a compound of the general formula

where Z, Y2 and R5 are as previously defined; reducing the compound of the general formula formula (VIII) to form a compound of the general formula

12. A process for preparing benzothiazepine derivatives of the general formula

where Z is hydrogen or phenyl, R1 is hydrogen or a lower alkyl group, R2 is hydrogen or a lower alkyl group, and R3 is hydrogen, an alkyl group, an alkylphenyi group or an aryl-lower alkyl group, which comprises reacting a compound of the general formula XCH2COOR2 (IX) where Xis a halogen and R2 is as previously defined, with

where Z is as previously defined, to form a compound of the general formula

where Z and B2 are as previously defined; and then reacting the compound of the general formula (Xl) with a compound of the general formula R3COCOOR1 (Xll) where R and B3 are as previously defined, in the presence of a reducing agent or with subsequent reduction by means of a reducing agent.