JPS59225174A - Benzothiazepine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:8-Chloro-1,5-benzothiazepine of formula I (R<1> is H, lower alkyl or R<4>CO-; R<2> and R<3> are lower alkyl; R<4> is H or lower alkyl). EXAMPLE:( + )-cis-2-( 4-Methoxyphenyl )-3-hydroxy-5-[2-( dimethylamino )-ethyl]- 8- chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. USE:It has hypotensive and/or cerebral and coronary vasodilating activities, and is useful as a drug. It has no side effect and low toxicity. It is useful e.g. for the prevention and remedy for hypertension, cerebral infarction, stenocardia, arrhythmia, myocardial infarction, etc. PREPARATION:The compound of formula I can be prepared by condensing the benzothiazepine derivative of formula II (R<5> is H or R<4>CO-) with the compound of formula III (X is halogen), and if necessary, converting the product to an acid addition salt.

Description

Detailed Description of the Invention (Technical Field) The present invention provides novel 8-chloro-1,
This field relates to 5-benzothiazepine derivatives and their production method.

(Prior Art) U.S. Pat. No. 3,562,257 describes 2-(4-methoxyphenyl)-3-hydroxy (or acetoxy)-5
-[2-(dimethylamino)ethyl]-7-chloro2
,3-dihydro-1,5-benzothiazepine-4 (3H
A variety of benzothiazepine derivatives have been disclosed, including 7-chloro-1,5-penzothiazepine derivatives such as It has been shown to have an effect.

(Objective of the invention) The present invention aims to provide a novel 8-chloro-1,5-benzothiazepine derivative that has superior antihypertensive effect and/or cerebral/coronary vasodilatory effect compared to known compounds. It is something.

(Structure and Effects of the Invention) The novel 8-chloro-1,5-benzothiazepine derivative of the present invention is represented by the following general formula (I).

(However, R1 is a hydrogen atom, a lower alkyl group, or a group represented by rt-, and R2 and R3 are lower alkyl groups.

R4 represents a hydrogen atom or a lower alkyl group. ) The compound (I) of the present invention or a salt thereof has superior properties as an antihypertensive agent and/or cerebral/coronary vasodilator compared to known compounds. In particular, the compound (1) of the present invention has the excellent feature of having a strong and sustained hypotensive effect. For example, when a sample is orally administered to spontaneously hypertensive rats (SHR), the ←)-cis-2-(4-methoxyphenyl)-3-
Acetoxy-5-[2-(dimethylamino)ethyl]-
8-chloro 2,3-dihydro-1,5-benzothiazepine-4(3H)-one maleate (dosage: 3
0 m#/kg) is the blood pressure of the SHR after administration of the sample.
Approximately 86 mmHg at the 4th hour, approximately 68 mmHg at the 4th hour
lower.

Furthermore, the compound (I) of the present invention has an excellent cerebral or coronary vasodilator effect. For example, when a sample is intraarterially administered to an anesthetized dog and the vertebral artery blood flow is measured to examine the cerebral vasodilatory effect, 1. 5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-
1,5-benzothiazepin-4(3H)-one hydrochloride and (t)-cis-2-(4-methoxyphenyl)-3
-propionyloxy-5-[2-(dimethylamino)
[ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepine-4(3H)-one succinate exhibits a cerebral vasodilatory effect that is approximately 24 to 25 times more potent than bapaverine; is a known compound (t)-cis-2-(
4-methoxyphenyl)-3-acetoxy-5-[2-
(dimethylamino)ethyl]-7-chloro-2,3-dihydro-1,5-benzothiazepine-4(3H)-one hydrochloride is about 5 times more potent. On the other hand, when the coronary vasodilator effect was investigated using the Langendor 7 method using a single guinea pig isolated heart.

←)-cis-2-(4-methoxyphenyl)- of the present invention
3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro2,3-dihydro-1°5-benzothiazepin-4(3H)-one hydrochloride is about 10 times more potent than papaverine. Shows significant coronary vasodilator effect.

Furthermore, the compound (I) of the present invention not only has antihypertensive effects, but also
Regarding the effect of increasing cerebral and coronary blood flow, (,+)-cis-2-(
4-methoxyphenyl)-3-acetoxy-5-[2-
(Dimethylamino)ethyl]-7-chloro-2,3-dihydro-1,5-penzothiacepin-4(3H)-one has a more excellent duration of action.

In addition, the compound (I) of the present invention also has an excellent platelet aggregation inhibiting effect. Furthermore, compound (I) has weak side effects (eg, central nervous system effects) and at the same time low toxicity.

For example, 2 of the present invention (t)-cis-2=(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro2,3-dihydro-1,5
- Acute toxicity of pensothiacepin-4(3H)-one hydrochloride (LD50: Max, oral administration) is 1000 q
/kg or more.

The compound of the present invention is represented by general formula (I).

For example, R1 is a hydrogen atom: a lower alkyl group having 1 to 5 carbon atoms such as a ethyl group, an ethyl group, a propyl group, a butyl group, a pentyl group; or a group represented by the formula R'CO-; R4
is a hydrogen atom or a methyl group, an ethyl group, a propyl group,
It is a lower alkyl group having 1 to 5 carbon atoms such as butyl group and pentyl group: R2 and R3 each have 1 carbon number such as methyl group, ethyl group, propyl group, butyl group, and pentyl group.
-5 lower alkyl groups are mentioned. Of these.

Preferred compounds are represented by general formula (I).

Examples include compounds in which R1 is a hydrogen atom, a methyl group, a formyl group, an acetyl group, a mesolobionyl group, a butyryl group, or a valeryl group, and R2 and R3 are each an alkyl group having 1 to 3 carbon atoms. More preferred compounds include general formula (I) in which R1 is a hydrogen atom, a methyl group,
Formyl group, acetyl group or propionyl group R
Examples include compounds in which 2 and R3 are each a methyl group or an ethyl group. Other preferred compounds include those represented by general formula (I).

Examples include compounds in which R1 is a hydrogen atom. Further examples include compounds which are child or lower alkyl groups.

Further, more preferred compounds include those in which R1 is an acetyl group or a propionyl group in the general formula (I);
is a methyl group and R3 is a methyl group or an ethyl group. Even more preferred compounds include compounds in the general formula (I) in which R1 is an acetyl group or a propionyl group, and R2 and R3 are methyl groups. Particularly preferred compounds include l:> in which R1 is an acetyl group in the general formula (I).
, R2 is a methyl group.

Examples include compounds in which R3 is a methyl group or an ethyl group.

Compound (I) of the present invention has two asymmetric carbon atoms in the molecule, so it forms two stereoisomers (i.e.

cis and trans isomers) or four optical isomers (
That is, there are (+)-cis, 0-cis, (→-trans and (→-trans isomers)), and in the present invention, these isomers or compounds for use as concentrates include these compounds. Among these, the cis isomer is preferred, especially the (ho)-cis isomer.

This is the real deal! According to 11rc, in compound (I) R
A compound in which 1 is a hydrogen atom or a group represented by the formula R'C0- (wherein R4 has the same meaning as above), that is, a group represented by the general formula (similarly R5 is a hydrogen atom or a group represented by S-).

H2, R3 and R4 have the same meaning as above. ) The compound represented by the general formula (OAL, R' has the same meaning as above) or its salt and the general formula (where, X is a halogen atom, R2 and R3 have the same meaning as above) It can be produced by a total condensation reaction with the compound shown in (1) or a salt thereof.

Further, in compound (I), R1 is of the formula R'C0- (provided that

R4 has the same meaning as above), i.e., a compound represented by the general formula (however,
R'', R3 and R4 have the same meanings as above) is a compound represented by the general formula (however, 82 and R3 have the same meanings as above) or a salt thereof and the general formula % formula It can also be produced by condensation reaction of a compound represented by % ( ) (wherein R4 has the same meaning as above) or a reacted derivative thereof.

Furthermore, a compound in which R1 of compound (I) is a lower alkyl group, that is, a compound represented by the general formula (wherein H6 is a lower alkyl group, and R2 and R3 have the same meanings as above), is the compound (I). -b) If the salt is a salt of the general formula % (), however, X' is a reactive residue and R6 has the same meaning as above. ) It can be produced by reacting with the compound shown below.

The condensation reaction between compound (El) or its salt and compound (11) or its salt can be carried out in a suitable solvent. Preferred examples of the salt of compound (II) include alkali metal salts such as sodium salt and potassium salt. When compound (b) is used in free form, the binding reaction is preferably carried out in the presence of an alkaline reagent.

As an alkaline reagent.

For example, alkali metal hydroxides (e.g. potassium hydroxide,
Examples include sodium hydroxide), alkali metal carbonates (eg, potassium carbonate, sodium carbonate), and alkali metal hydrides (eg, sodium hydride). Compound(
Preferred examples of the salts of Ill) include acid addition salts such as hydrochloride and hydrobromide. As the solvent, for example, acetone, ethyl acetate, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, etc. are preferably used. This reaction can be carried out at 0°C to 100°C, particularly the condensation reaction, in a suitable solvent in the presence or absence of a deoxidizing agent. Preferred examples of the salt of compound (■-b) include acid addition salts such as hydrochloride and hydrobromide. As a reactive derivative of compound GV), 2
For example, mixed acid anhydrides (e.g., formic acid and acetic acid anhydrides)
, lower saturated fatty acid anhydrides (eg, acetic anhydride, propionic anhydride), lower alkanoyl halides (eg, acetyl chloride, propionyl chloride, bunaryl chloride, valeryl chloride), and the like.

Examples of deoxidizers include pyridine, triethylamine,
Examples include N-methylpiperidine, N-methylmorpholine, N-methylpyrrolidine, N-ethyl-N, and N-diisopropylamine. Examples of solvents include acetic acid,
Preferably, chloroform, dichloromethane, dimethylformamide, tetrahydrofuran, etc. are used. In the reaction, when excess acetic anhydride is used as the reactive derivative of compound (mV), it is not necessarily necessary to use another solvent because the acetic anhydride also acts as a solvent. When carrying out the reaction, compound (IV)
When a lower saturated fatty acid anhydride is used as the reactive derivative, the reaction is preferably carried out at 20°C to 140°C, and when a mixed acid anhydride or lower alkanoyl halide is used as the reactive derivative, the reaction is carried out at 10°C to 100°C. It is preferable to do so.

On the other hand, when compound (ff) is used in the form of free acid.

The condensation reaction between the compound and compound (1-b) or a salt thereof can be carried out in a suitable solvent in the presence of a condensing agent. Examples of condensing agents include dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole, 1-
Methyl-2-halopyridinicum iodo salt (e.g. 1
-Methyl-2-gromopyridinicum iodo salt), methoxyacetylene.

Examples include triphenylphosphine-carbon tetrachloride. As a solvent, for example, methylene chloride.

1.2-Citaloethane, chloroform, benzene.

Preferably, toluene, tetrahydrofuran, dioxane, etc. are used. This reaction was carried out at 0°C to 50°C.

It is preferable to carry out the reaction at a temperature of 0°C to 20°C.

The reaction between compound (I-b) or a salt thereof and compound (D) can be carried out in a suitable solvent in the presence of a deoxidizing agent. ), lower alkyl halides (e.g., methyl iocdide, ethyl iocdide), etc. Examples of deoxidizing agents include sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, etc. As the solvent, it is preferable to use, for example, benzene, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, etc. This reaction is carried out at 20°C to 100°C, especially at 20°C.
Preferably, it is carried out at 0°C to 60°C.

The starting material compound (II) or Fi(I-b) of the present invention has two asymmetric carbon atoms at the 2 and 3 positions of the benzothiazepine skeleton, and therefore has four types of isomers (namely, (+)-cis).

(→-cis, (+)-trans and (→-trans isomers) exist, but all the above reactions proceed without racemization, so compound (b) or (
If the optically active form of 1-b) is used, compound (I) of the present invention can be obtained.
)'! It can be easily obtained as a z-optically active substance.

The compound in which R1 is a hydrogen atom in the raw material compound (b) of the present invention J is a new compound and can be produced, for example, according to the following reaction formula.

(4) Law (■) (v…) (II-a) (B) Law (M) (Vll) (Rho a) (C) Law (X) (Vl) (XI) (Xll) (
■) (U-a) (However, in the above formula, R7 represents a lower alkyl group.) According to method (a), Ibi compound (II-a) is 2-amino-5-talolothiophenol ( U and 3-(p-methoxyphenyl)
It can be produced by reacting with glycidic acid ester (■).

(6) According to the method, the compound ([1-a) is (1)2-
Amino-5-talolothiophenol (Vi) and 3-(p
-methoxyphenyl) glycidate (Vll)
to form a propionic acid ester compound,
(ii) If necessary, it can be produced by hydrolyzing the compound (Vl) to form a propionic acid compound (■), and then (iii) subjecting compound (VIII) or (ff) to intramolecular ring closure.

According to method (C), compound (II'-a) is
Nitro 5-talolothiophenol (X) and 3-(p-
methoxyphenyl) glycidic acid ester (■) to form a propionic acid ester & compound (Xl),
(II) Compound (XI) is hydrolyzed to form compound (Xl
), and (it) reduce the compound (Xll) to obtain a compound (IK), :L.

Then, 0v) can be produced by intramolecular ring closure of the U compound (IK).

(a) The reaction of the method, that is, the compound (Vl) and the compound (V
The reaction between compound (Vl) and compound (Vll)
This can be carried out by heating a mixture with 150°C to 160°C. This reaction can be carried out without a solvent (for example, xylene, diphenyl ether, p-cymene). Due to the reaction.

When compound (U-a) is obtained as a mixture of two stereoisomers (i.e. cis and trans isomers), these mixtures may contain lower alkanols (e.g.

It is possible to separate each isomer by fully utilizing the difference in solubility in a solvent such as ethanol) or by column chromatography.

The first step of the CB) method, that is, compound (41) and compound (■),! The reaction of: is carried out by adding a mixture of compound (Vl) and Vl) in a suitable solvent at 40°C to 110°C in a convenient manner.
This can be carried out by heating at 0°C to 110°C. As the solvent, it is preferable to use, for example, toluene, benzene, ayatonitrile, dioxane, or the like. In the reaction, trans-5-(4-methoxyphenyl) glycidic acid lower alkyl ester is used as the starting compound (Vll).

Compound 01fl) is obtained as the threoisomer.

Hydrolysis of compound (■) r/i can be carried out by treating the chemical compound with an alkaline reagent in a suitable solvent. Examples of alkaline reagents include potassium hydroxide, sodium hydroxide, and potassium carbonate.

Preferred examples include sodium carbonate. As the solvent, it is preferable to use, for example, alkanols (eg methanol, ethanol) or mixtures of these alkanols and water. This reaction is carried out at 0°C to 100°C, especially at 25°C.
Preferably, the reaction is carried out at a temperature of 100°C to 100°C.

Compound (IX) I/i thus obtained, if necessary p-
By using an optically active form of hydroxyphenylglycine ester, an optical resolving agent such as cinchonidine, each optically active isomer can be obtained. For example, (±)
The optical resolution of -threo-2-hydroxy-5-(2-amino-5-chlorophenylthio)-3-(4-methoxyphenyl)propionic acid is performed to separate the compound from the optically active p-hydroxyenylglycine methyl ester. It can be separated into each component by reacting to form diastereomers of the compound, then fractionally crystallizing the diastereomers, crystallizing the poorly soluble salts, and collecting each easily soluble salt from the solution. . More specifically, if L-p-hydroxyphenylglycine methyl ester is used as a resolving agent, (th)-threo-2-hydroxy-5-(
If 2-amino-5-chlorophenylthio)-3-(4-methoxyphenyl)propionic acid forms a poorly soluble diastereomer and D-p-hydroxyphenylglycine methyl ester is used as the 9-resolving agent, (−)−
Threo-2-hydroxy-5-(2-amino-5-chlorophenylthio)-3-(4-methoxyphenyl)propionic acid forms a sparingly soluble salt.

Fractional crystallization can be carried out by recrystallizing a mixture of two diastereomers from a solvent such as a lower alkanol (eg, methanol, ethanol). After optical resolution, optically active compound (IX) can be obtained by treating the obtained diastereomer with an acid (e.g., hydrochloric acid).
e can be obtained in free form.

The compound thus obtained (Will) or ([)
The intramolecular ring closure of the racemic or optically active form of
-cymene, acetic acid) or by heating without a solvent. This reaction is preferably carried out at 100°C to 160°C, particularly under reflux. In addition, the compound (■
) can also be carried out in the presence of dimethylsulfinyl carbanion (CHsSOCH; ) in dimethylsulfoxide (prepared from dimethylsulfoxide and sodium hydride) at θ°C to 50°C. Furthermore, the intramolecular ring closure of compound (]IX can also be carried out in a suitable solvent in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide alone or dicyclohexylcarbodiimide and 1-hydroxybenzotriazole; 4-dimethylaminopyridine.

N-Hydroxyphthalimide. Combinations with N-hydroxysuccinimide, trichlorophenol, p-nitrophenol or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine can be used. Also, carbonyldiimidazole, ethoxyacetylene, 1-methyl-2-halobiridiniumolide (for example).

1-Methyl-2-taloloviridinicum iodo salt.

1-methyl-2-glomoviridinicum iodo salt) can also be used as the condensing agent. Furthermore, 1-methyl-2-halobyridinicumnolide can be used as the condensing agent in combination with a base such as triethylamine or tributylamine. Solvents include taloloform, dimethylformamide, carbon tetrachloride, cycloo/
It is preferable to use ethane, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, and the like. This reaction is preferably carried out at -10°C to 70°C.

(C) The first step of method, i.e. compound (X) and compound (
The reaction with (2) can be carried out in an appropriate solvent in the presence or absence of a catalyst. Examples of catalysts include zinc acetate, zinc iodide, zinc chloride, stannous chloride, stannous octylate, and stannic chloride.

Lewis acids such as stannic octylate, stannous stearate, fluorine trifluoride, sulfuric acid, perchloric acid, etc.
! Other Lewis acids described in European Patent Application No. 0059335 can also be suitably used as catalysts. Examples of solvents include toluene, benzene, xylene, dioxane, tetrahydrofuran, acetonitrile, and carbon tetrachloride.

Preferably, chloroform, ether, etc. are used. This reaction is preferably carried out at 20°C to 100°C, particularly 25°C to 60°C. In the reaction, the starting compound (
If trans-5-(4-methoxyphenyl)glycidic acid lower alkyl ester is used as [), compound (n) can be obtained as a threo isomer.

Hydrolysis of compound (X[) can be carried out by treating the compound with an alkaline reagent in a suitable solvent. Examples of alkaline reagents include sodium hydroxide, potassium hydroxide, and sodium carbonate.

Examples include potassium carbonate. As a solvent.

For example, it is preferable to use a mixture of water and a lower alkanol (eg, methanol, ethanol, propatool), dimethyl sulfoxide or dimethyl formamide. This reaction is carried out at 0°C to 80°C, especially at 20°C to 40°C.
Preferably, it is carried out at .degree.

The compound (■) thus obtained can be converted into each optically active isomer by using an optically resolving agent such as an optically active form of lysine, if necessary.

Example, t ha, ←)-threo-2-hydroxy-5-(2
What is the optical resolution of -ditro-5-chlorophenylthio)-3-(4-methoxyphenyl)propionic acid?

By reacting the compound with optically active lysine to form a diastereomer of the compound, and then fractionally crystallizing the diastereomer to crystallize the poorly soluble salt and collect the easily soluble salt from the solution, It can be separated into each component. More specifically, if all L-lysine is used as a resolving agent, ←)-threo-2-hydroxy-5-(2
0-threo-2- Hydroxy-5-(2-nitro-
5-chlorophenylthio)-3-(4-methoxyphenyl)propionic acid forms a sparingly soluble salt. The fractionated crystal is 2
This can be accomplished by recrystallizing a mixture of diastereomers from a solvent such as dimethylformamide or a lower alkanol (eg, methanol). After optical resolution, the resulting cyaste and omers are converted into acids (e.g.

By treating with hydrochloric acid, sulfuric acid), optically active compounds (
XI) can be obtained in free form.

The racemic or optically active form of the compound (■) thus obtained can be reduced by catalytic reduction of the compound or by treatment with a metal or a metal salt and an acid. Catalytic reduction of compound (■) can be carried out in a suitable solvent in a hydrogen gas stream in the presence of a catalyst.

Examples of the catalyst include palladium carbon, palladium black, Raney nickel, and Raney cobalt. Examples of solvents include lower alkanols (eg, methanol, ethanol, propatool), and acetic acid.

It is preferable to use tetrahydrofuran, dioxane or a mixed solvent thereof. This reaction is preferably carried out at 20°C to 50°C under 1 to 20 atmospheres. On the other hand, when compound (XI) is treated with a metal or metal salt and an acid, the treatment can be carried out in a suitable solvent. Examples of metal salts include tin, zinc, iron, ferrous chloride, and ferric sulfate. Examples of acids include hydrochloric acid.

Examples include hydrobromic acid, acetic acid, and propionic acid. As the solvent, for example, water, methanol, ethanol, acetic acid, ether, tetrahydrofuran, or a mixed solvent thereof is preferably used.

This reaction is preferably carried out at 20°C to 80°C.

The intramolecular ring closure of the compound (ff) thus obtained is CB)
It can be implemented in the same way as the law.

On the other hand, in the starting compound (■), R1 is of the formula R'C0-
(However, R4 has the same meaning as above.) The compound represented by the group is also a new compound. It can be produced by acylation with a compound represented by formula 5 R'COOH (wherein R4 has the same meaning as above) or a reactive conductor thereof.

All of the above reactions can be carried out without racemization.

Compound (1) of the present invention When used as a medicine.

It can be used both as the free compound and as its pharmacologically acceptable acid addition salt. Examples of pharmacologically acceptable acid addition salts include hydrochloride.

Hydrobromide, Hydroioccide, Perchlorate, Sulfate,
Inorganic acid addition salts such as phosphates: succinates.

Examples include organic acid addition salts such as maleate, fumarate, tartrate, and methanesulfonate.

These salts can be easily obtained (for example, by treating compound (I) with an acid). Compound (I) or a pharmacologically acceptable acid addition salt thereof can be administered either orally or parenterally.

When the compound (I) of the present invention or a pharmacologically acceptable acid addition salt thereof is used as a medicine, the compound (I)
can be used as a pharmaceutical formulation mixed with pharmaceutical excipients suitable for oral or parenteral administration. Such excipients include, for example, starch, lactose, glucose, potassium phosphate.

Corn starch, gum arabic, stearic acid, and other common pharmaceutical excipients can be suitably used. Pharmaceutical formulations may be solid forms such as tablets, pills, capsules, suppositories, or still in solution.

Liquid preparations such as suspensions and emulsions may also be used. Furthermore, when administered parenterally, this pharmaceutical preparation can also be used as an injection solution.

As mentioned above, the compound (I) of the present invention has excellent antihypertensive effects, cerebral or coronary vasodilatory effects, and platelet aggregation, and is useful for the treatment, improvement, or prevention of heart diseases such as angina pectoris, arrhythmia, or myocardial infarction. be. Especially.

The compound (I) of the present invention is a compound 2 described in U.S. Pat.
-[2-(dimethylamino)ethyl]-7-chloro2
．． 3-dihydro-1,5-benzothiazepine-4 (3H
)-ON, etc.), it not only has superior therapeutic effects (lower blood pressure, cerebral/coronary vasodilation, etc.), but also
It exhibits excellent duration of action and low toxicity, and is therefore an even better antihypertensive agent and/or brain therapy agent than the above-mentioned 7-chloro compound.
It is a coronary vasodilator.

The daily dosage of the compound (I) of the present invention or a pharmacologically acceptable salt thereof is determined by the administration method, the age and weight of the patient,
Although it varies depending on the condition and type of disease, the daily dosage is usually about 0.05 to 10 m1j/kg, and especially for oral administration, FJo, 5 to 10 tr is preferred.
q; 1/kg, preferably about 0.05 to 2 my/kg for parenteral administration (for example, intravenous injection).

9 In this specification, lower alkyl groups, lower alkyl/yl groups, and lower saturated fatty acids each have 1 to 5 carbon atoms.
straight-chain or branched alkyl group.

It represents a straight chain or branched alkanoyl group having 2 to 6 carbon atoms and a straight chain or branched saturated fatty acid having 2 to 6 carbon atoms.

In this specification, 'threo' refers to the hydroxy group substituted at the 2- and 3-positions of propionic acid and the 2-amino-5-talolophenylthio (also 2-nitro-5-chlorophenylthio) group. has a threaded arrangement (i.e.
This means that the two groups are located on opposite sides in the Fischer projection.

Example (antihypertensive effect) Sample dissolved or suspended in water (dose: 3°”f/k
g) spontaneously hypertensive rats (SH
R) (group 1: 3 animals) was orally administered. Plethysmograph 7 method for measuring systolic blood pressure in rats (The Journal of Laboratory and Clinical Medicine, No. 78)
Vol., p. 957 (1971)). The antihypertensive effect of the sample was determined 1 hour and 4 hours after administration, and judged based on the following index.

(-): l Blood pressure drop below OmmHg (+):
Blood pressure decrease of 10 m+nHg or more and less than 20ml/g (+
+): 20 mmHg or more 40 mmHg * Full blood pressure drop (+++): 40 mmHg or more 60 m
Blood pressure decrease below mHg (+++++): Blood pressure decrease by 60 g or more The results are shown in Table 1 below.

Table 1 Examples (Cerebral vasodilatory effect) Bendoparbital natrichum salt (intravenous administration, dose = 30 mg) to a large male (body weight = 10-20 kg)
/ kg). The blood flow in the vertebral artery was measured using an electromagnetic flowmeter under artificial respiration. The specimen was dissolved in a 5% glucose aqueous solution, and the solution was injected into the vertebral artery.

The cerebral vasodilatory effect of the specimen was determined as the efficacy ratio to pavaperine calculated from the dose-effect curve. The results are shown in Table 2 below.

Table 2 Examples Male dogs (body weight: 20-24 9. Group: 2 dogs) were treated with bendoparbital sodium salt (intravenous injection).

The animals were anesthetized with a dose of 35 my/kg). The blood flow in the vertebral artery was measured over time using an electromagnetic flowmeter under artificial respiration. Analyte ((+)-cis-2-(4-methoxyphenyl)-3-acetoxy-3-(2-(dimethylamino)ethyl)-8-chloro2,3-dihydro-1,5
- benzothiazepine-4(3H)-one hydrochloride) in saline at a dose of 200 μI/kg into the femoral vein.
Injected with. The cerebral vasodilatory effect of the sample was calculated from the formula below.

Increase in vertebral artery blood flow (Δvnl/min) = [Blood flow after injection of test compound] - [Blood flow immediately before injection of test compound] The results are shown in Table 3 below.

Table 3 Examples (Coronary Vasodilation Effect) The effect on the coronary blood flow of the isolated heart of a guinea pig (body weight: approximately 280 g) was investigated using the Langendor 7 method. The isolated heart was perfused with Lockringer's solution (saturated with a gas mixture consisting of 95% oxygen and 5% carbon dioxide) containing 2% rabbit blood from which fibrin had been removed. Perfusion pressure was maintained at 40ffi water column. Specimen I/i was dissolved in 5% glucose solution and injected into the perfusate in a volume of 0.1, nl per heart. The outflow perfusate was measured using a drip counter and was defined as coronary blood flow.

The coronary vasodilator effect of the specimen was determined based on the following index.

(±) Two-pair blood flow increase is 0 at dose 1100P/heart
Less than 54/min (+): Increase in coronary blood flow at a dose of 100P
f/0.54 min or more in the heart (++): Increase in coronary blood flow is 0.5 m//min or more in the heart at a dose of 30 μV (+++)
: Increase in coronary blood flow is U, 5 at doses below 10 μV cardiac.
rnl/min or more The results are shown in Table 4 below.

Table 4 Examples (Platelet aggregation inhibitory effect) Blood was collected from the abdominal aorta of SD-strain male rats anesthetized with ether. 3.8 W/V for 9 volumes of blood in the throat
Platelet-suspended plasma (PRP) was prepared by mixing with 1 volume of % citric acid/trisodium salt aqueous solution and centrifuging the mixture. The remaining blood is further centrifuged to obtain platelet-free plasma (
PPP) was prepared. PRP platelet count is 0.0 with PPP.
It was adjusted to 8 to 1 x 1 oyw. Diluted PRP200P
/ and 25 μl of sample solution (final concentration of sample: ]00#/m
After stirring the mixture with q at 37°C for 2 minutes, add a collagen solution [Biochimica, Kogyo, Biofijiyoku, Acta 8. 18th
6, p. 254 (1969)] was added to cause platelet aggregation. Platelet aggregation ability was measured using Born's method [
Nature, Volume 194, Page 927 (1962)
], the platelet aggregation inhibition rate was determined, and the platelet aggregation inhibition effect of the sample was determined based on the following index.

(-): Sample platelet aggregation inhibition rate is less than 10% (+):
The platelet aggregation inhibition rate of the sample is 10% or more, but lower than the inhibition rate of acetylsalicylic acid (100 μg/-) (
+ Platelet aggregation inhibition rate of ten houses samples is 1L of acetylsalicyl
The results are shown in Table 5 below.

Table 5 Example 1 (t)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1-5-benzothiazepin-4(3H)-one 6 .8g.

2-(dimethylamino)ethyl chloride hydrochloride 3,o
2y, potassium carbonate 6.1g and acetone 150
The mixture of - is heated under reflux for 20 hours. After the reaction is completed, insoluble matter is filtered off and washed with ethanol. The solution 6 and the washing solution are combined, and the solution is concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate, the solution was washed with water, and the solvent was distilled off after drying. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give (-+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethyl Amino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(3H)-one 7.1
3 f/ is obtained as colorless needles.

M, 9.122-124°C (decomposition) [α column + 144.6° (C = 0.85. methanol) ice crystal succinate: M, 9.201-203°C (decomposition) (chloroform, ethanol and Recrystallization from a mixture of ether) [α paste + 78.4° (C = 0.74.dimethylformamide) Example 2 (→-cis-2-(4-methoxyphenyl)-3-hydroxy-3-(2=( dimethylamino)ethyl]-8-
Chloro-2,3-dihydro-1,5-benzothiazepin-4(3H)-one 6.4. f, a mixture of 65-acetic anhydride and 0.7-pyridine is stirred at 110°C for 3 hours. After completion of the reaction, the two reaction mixtures were subjected to Ka&f under reduced pressure and the solvent was distilled off. By converting the residue into hydrochloride and recrystallizing it from a mixture of acetone and ethanol, (+)-cis-2-
(4-methoxyphenyl)-3-ayatoxy5-(2
-(dimethylamino)ethyl)-8-chloro-2,3-
4.7 g of dihydro-1,5-benzothiazepine-4(3H)-one hydrochloride was obtained.

M, p, 127-131℃ (decomposed) [α capture + 92.2° (C = 0.796. Ethanol) Elemental analysis value: C2□H,,50,N2S Cl・HC
I・'AHzO calculation value: C, 53,44; H, 5,5
0:N, 5.67, CI, 14.34 Experimental value:
C, 53, 11, H, 5, 38, N, 5.60. C.I.
, 13.98 Wood maleate: Needle crystals (recrystallized from ethanol) M, P, 158-160°C [α + 75.4° (C = 1.0.methanol) 7 malic acid of ice crystals Acute: Needle crystals (recrystallized from a mixture of ethanol and ether) M
, l), i99~201℃ (decomposition) Ice crystal methanesulfonate Niprism crystal (recrystallized from a mixture of ethanol and ether) M, 9.147~149℃ Elemental analysis values: C23H2,O,N252C1・H ,0
Calculated value: C, 49,05: H, 5,55; N, 4.6
2;S, 11.38:C1,6,29 Experimental value: C,48,88:H,5,42:N, 5.0
3;S, 11.38:C1,6,38 Example 3 (→-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1°5-benzothiazepine -4(3H)-one 6.4Q.

2-(dimethylamino)ethyl chloride hydrochloride 3,O
A mixture of 5.8 g of potassium carbonate and 150 g of acetone is treated in the same manner as in Example 1. By recrystallizing the obtained crude product from a mixture of ethyl acetate and n-hexane, (-)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-5-[2-(dimethylamino)ethyl]
6.93 f of -8-chloro-2°3-dihydro-1,5-benzothiazepin-4(3H)-one is obtained as colorless needles.

M-1), 121-123°C (decomposed) [α at -142,7° (C = 1.04. methanol) Crystal succinate: M, p, 202-204°C (decomposed) (chloroform, ethanol (recrystallized from a mixture of 2-(4-methoxyphenyl)-3=hydroxy-5-[2 -(dimethylamino)ethyl]-8-
A mixture of 6.359 m of chloro-2,3-dihydro-1,5-benzothiazepin-4(3H)-one, 64 M of acetic anhydride and 7 mt of pyridine is treated as in Example 2. The product was converted into a hydrochloride salt and recrystallized from acetone to give (→-cis-2-(4-methoxyphenyl)-
3-acetoxy-5-['2-(dimethylamino)ethyl]-8-chloro2,3-dihydro-1,5-'C
Nzothiazepine-4(5H)-one hydrochloride 4.28
get g.

M, 9.128-132°C (decomposition) [α pasting -93.3° (c=o, s 72. ethanol)
Elemental analysis value: C112H2504N2S C1-HC
l・'AHz0 calculated value: C, 53, 44; H, 5, 5
0:N, 5.67:C1, 14,34 Experimental value: C,5
3,17, H, 5,45, N, 5.59, CI,
14.28 Example 5 ←)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1°5-benzothiazepin-4(3H)-one6. 72g.

Potassium hydroxide 2.589 and dimethyl sulfoxide 9
Stir the 0- mixture at room temperature for 1 hour. 2- to the mixture
(dimethylamino)ethyl chloride hydrochloride 3.169
is added and the mixture is stirred at room temperature for 16 hours. The reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration and washed with water. Dissolve the crystals in concentrated hydrochloric acid.

The solution is washed with ethyl acetate and then made alkaline with potassium carbonate. This solution is extracted with chloroform. The extract was washed with water, dried, and the solvent was distilled off under reduced pressure. By converting the price into hydrochloride and recrystallizing from ethanol, (±)
-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-talolo 2,3-dihydro-1,5-benzothiazepine-4
6.65 g' of (3H)-one hydrochloride are obtained. The crystal is chloroform.

When recrystallized from a mixture of ethanol and ether, it becomes prismatic crystals.

M, p, 136-139'C Elemental analysis value: C2oHzs03N2SCI ・HCI
-V2CzHsOH calculation value: C, 53, 96:H,
5,82:N, 5.99; C1, 15,17 experimental value: C, 53,61:H, 5,94:N, 6.00:C
1, 15, 31 Example 6 (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-3-(2-(dimethylamino)ethyl]-8
-Chloro-2,3-dihydro-1,5-benzothiazepine-j(5H)-one hydrochloride 1 g.

A mixture of acetic anhydride 2- and acetic acid 2- is stirred at 110°C for 4 hours. The reaction mixture was concentrated under reduced pressure and the solvent was distilled off. By adding ether to the residue and filtering the precipitated crystals, cis)-cis-2-(4-methoxyphenyl)-3
-acetoxy-5-[2-(dimethylamino)ethyl]
-8-10 rho2°3-dihydro-1,5-benzothiazepine-4'(5H)-one hydrochloride 1.08 f is obtained. When crystals are recrystallized from a mixture of chloroform, ethanol, and ether, they become needle-shaped crystals.

M, 9.159-161℃ Elemental analysis value 2C2□H25N, 04SCI -HCI
-C2)1. OH calculation value: C, 54, 23;)l,
5.8B, N, 5.27, C1, 13,34 Experimental value: C, 53,99; H, 5,70; N, 5.47:
C1, 13, 45 Example 7 (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1°5-benzothiazepine-4(3H)- On 3g and 2-(N-
Methyl-N-ethylamino)ethyl chloride hydrochloride 1
．． 7g is treated in the same manner as in Example 5. The product was taken as a hydrochloride salt and recrystallized from a mixture of ethanol and nitrate to give (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-3-(2-(N-methyl). -N-ethylamino)ethyl]-8-chloro2,3-dihydro-1,5-benzothiazepin-4(3H)-one hydrochloride 3.19 g is obtained as colorless needles.

M, 9.132-135℃ (decomposition) Elemental analysis value "C21H2503N2SC1-HCl
-V2H20 calculated value: C, 54,07; H, 5,84
,N,6.01 :C1,15,20 Experimental value: C,5
4,32:H,5,88;N,5.76:C1,15,
31 Example 8 (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-ethylamino)ethyl]-8-chloro2,3-dihydro- 1,5-
Benzothiazepine-4(3H)-one hydrochloride 0.99
．． A mixture of acetic anhydride 5- and acetic acid 5- is treated analogously to Example 6. The obtained crude product was recrystallized from a mixture of chloroform, ethanol and ether to give (±
)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methyl-N-ethylamino)ethyl]-8-chloro2,3-dihydro-1,5-benzothi 0.9 g of azepin-4(3H)-one hydrochloride is obtained as needles.

M, p, 229-232℃ (decomposition) Elemental analysis value "C23H27N2045 C1・HCI
-'AH20 calculated value: C, 54, 22, H, 5, 7
5,'N, 5.51. CI, 13.95 experimental value: C,
53,97:H, 5,82:N, 5.87:C1,13
, 73 Example 9 (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1°5-benzothiazepin-4(3H)-one 2f and 2- (N
-/+/l/-N 1.13 f of n-propylamino)ethyl chloride hydrochloride is treated in the same manner as in Example 5. (±)-cis-2-(4-methoxyphenyl)=3-hydroxy-
5-[2-(N-methyl-N-n-propylamino)ethyl]-8-chloro-2゜3-dihydro-1,5-benzothiazepin-4(3H)-one hydrobromide 2.1
g is obtained as colorless prismatic crystals.

M, p, 82-83°C (decomposition) Example 10)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-n-propylamino) ethyl]-8-chloro-2,3-dihydro-1,
5-benzothiazepine-4(3H)-one 0.829.
A mixture of one part of acetic anhydride and one part of pyridine is stirred at 100°C for 3 hours. The reaction mixture is concentrated under reduced pressure to remove the solvent. By recrystallizing the remaining residue as succinic acid salt from a mixture of chloroform and ethanol, (±)−
cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methyl-N-n-propylamino)
ethyl]-8-chloro2,3-dihydro-1゜5-benzothiazepine-4(3H)-one succinate 0.7
5 II is obtained as colorless needles.

M-p, 197-198°C (decomposition) Example 11 (t)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1°5-benzothiazepine -4(3H)-one 3.4 g.

2-(dimethylamino)ethyl chloride hydrochloride i, s
A mixture of p, potassium 3.231 carbonate and acetone 80 is treated as in Example 1. product.

(+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8 by converting it into a hydrochloride and recrystallizing it from a mixture of acetone and ethanol. -chloro-2゜3-dihydro-1,
5-Benzothiazepine-4(3H)-one hydrochloride3.
Get 75 F.

M-1), 127-131℃ (decomposition) [α packed +92.4° (c=o, si, ethanol)
Example 12 (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1°5-benzothiazepin-4(3H)-one 3.29° Example 1 A mixture of 1.46 g of 2-(dimethylamino)ethyl chloride hydrochloride, 3f of potassium carbonate, and 75% of acetone was prepared.
Process in the same way as . The product was diluted with hydrochloric acid and recrystallized from a mixture of chloroform, ethanol and hyethyl to give (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethyl Amino)ethyl]-8-chloro2,3-dihydro-1,5-pentthiazepin-4(3H)-one hydrochloride 3.4 II
get.

M, p, 159-161°C Example 13 (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1°5-benzothiazepine-4( 3H)-one 1 g, 2-(N-methyl-N-ethylamino)ethyl chloride hydrochloride 0.
A mixture of 5f, 0.959 g of potassium carbonate and 20 g of acetone is treated as in Example 1. The product was converted into a hydrochloride salt and recrystallized from a mixture of chloroform, ethanol and ether to give C+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methyl). -N-ethylamino)ethyl]-8-chloro-2,3
-dihydro-1,5-benzothiazepine-4 ('5I(
)-one hydrochloride 1.03 y is obtained.

M, p, 229-232°C (decomposition) Example 14 (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1°5-benzothiazepine -4(3H)-one 19,2-(N-methyl-N-n-propylami/)ethyl chloride hydrochloride 0.559. Potassium carbonate 0.95g and acetone 2
The mixture of 0rn1 is treated as in Example 1. (±)-cis-2-(4-
methoxyphenyl)-3-acetoxy-5-[2-(N
-Methyl-N-n-7'rovira3])ethyl]-8-
1.1 g of 10 rho-2,3-dihydro-1,5-benzothiazepine-4(3H)-one cissulfate are obtained as colorless needles.

M, p, 197-198°C (decomposition) Example 15 (t)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1°5-benzothiazepine -4(3H)-one 2.5 g.

A mixture of 1.3j' of 2-"(N-methyl-N-ethylamide/)ethyl chloride hydrochloride, 3.01 f of potassium carbonate, and 35" of acetone is heated under reflux for 21 hours. Insoluble materials are filtered off, and The solvent is distilled off by concentrated MJ under reduced pressure.The residue is made into a perchlorate and recrystallized from methanol to give (+)-cis-2-(4-methoxyphenyl)-'3- Hydroxy-5-[2-(N-methyl-N-
ethyl amino)-8-talolo 2,3-dihydro-1,5-benzothiazepine-4(3B)-one perchlorate 3.241 is obtained.

M-p, 197-201°C [α pasting +80.6° (C = 0.5. methanol)
Example 16 (t)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-ethylamino)ethyl]-8-chloro-2,3-dihydro- 1,5-
A mixture of benzothiazepin-4(3B)-one 2.7'4F, acetic anhydride 25- and 12 drops of pyridine is stirred at 100°C for 3 hours. The mixture was evaporated under reduced pressure to remove all the solvent. Dissolve the residue in ether and extract the solution with dilute hydrochloric acid. The extract is washed with ether, made alkaline with 10% sodium hydroxide solution, and then extracted with chloroform.

After washing the extract with water and drying, the solvent was distilled off under reduced pressure.

The residue was converted into L-tartrate and recrystallized from ethanol to give (F)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methyl-N-
ethylamino)ethyl]-8-chloro2,3-dihydro-1,5-benzothiazepine-4(3H)-one L
- 3.28 f of tartrate are obtained.

M-1), 128-133°C (decomposition) [α+84.0° (C=1.0.ethanol) Example 17 (→-cis-2-(4-methoxyphenyl)-3-hydroxy-8- Chloro-2,3-dihydro?-1゜5-benzothiazepin-4(3H)-one 1.019゜2-(diethylamino)ethyl chloride hydrochloride 0.57 m',
A mixture of 1.24 f potassium carbonate and 30 f/acetone is treated analogously to Example 15. The product was made into the 7-malate salt and recrystallized from ethanol to give (→-cis-2-(4-methoxyphenyl)-3-hydroxy-
5-[2-(,diethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepine-4(
1.2211 of 3H)-one 7 malate salt is obtained.

M, p, 146-147.5°C [α capture +91.0° (c = i, o, methanol) Example 18 (→-cis-2-(4'-methoxyphenyl)-3-hydroxyphenyl)-3-hydroxy 5-[ 2-(diethylamino)ethyl]-8
-chloro-2,3-dihydro-1,5-benzothiazepine-4(3H)-one 0.6751. Acetic anhydride 7rnl
and 2 drops of pyridine are treated as in Example 16. The product was made into a succinate salt and recrystallized from ethanol to give (→-cis-2-(4-methoxyphenyl)-3
-acetoxy-5-[2-(diethylamino)ethyl]
-8-chloro-2,3-dihydro-1,5-benzothiazepine-4(3H)-one succinic acid, salt 0.634
Get y.

M, p, 183-184.5°C (decomposition) [α capture +86.
6° (C==1.0. Methanol) Example 19 (→-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-
Chloro 2,3-dihydro-1,5-benzothiazepin-4(3H)-one 0.8 g, formic acid 9-1 acetic anhydride 3-
and pyridine 1- is stirred at room temperature for 3 days.

The reaction mixture is concentrated under reduced pressure to remove the solvent. The remaining amount is treated as succinate.

By recrystallization from a mixture of ethanol and ether, (+)-cis-2-(4-methoxy7enyl)-3
-Formyloxy-3-(2-(dimethylamino)ethyl E-8-chloroZ, a-dihydro-1,5-benzothiazepine-4(3H)-one succinate 0.725
Get II.

M, p, iso ~ 183°C (decomposition) [α piece + 117.8° (C = 1.0. dimethylformamide) Example 20 (→-cis-2-(4-methoxyphenyl)-3-hydroxy-5- [2-(dimethylamino)ethyl]-8-
Chloro-2,3-dihydro-1,5-benzothiazepine-4(3H)-one Ig, propionyl chloride 0
．． The mixture of 47F and pyridine 2o- was stirred for 2 hours at room temperature. The reaction mixture was condensed under reduced pressure and the solvent was distilled off. The residue was converted into succinate and recrystallized from acetone to give (+)-cis-2-(4-methoxyphenyl)-3-glopionyloxy-5-[2-(dimethylamino)ethyl]-8 -chloro-2,3-dihydro-1
, 0.9471 of 5-benzothiazepine-4(3H)-one succinate is obtained.

M, p, 130°C (decomposition) [α+85.82° (C = 1.dimethylformamide) Example 21 (→-cis-2-(4-methoxyphenyl)-3-hydroxy-3-42-(dimethyl amino)ethyl]-8-
Example 2 A mixture of 900 μg of chloro-2,3-dihydro-1,5-benzothiazepin-4(3H)-one, 300 μg of n-butyryl chloride, and 1+ng of pyridine was prepared.
Process in the same way as 0. By converting the product into a sequate salt and recrystallizing it from ethanol, (+)-cis-2-
(4-methoxyphenyl)-3-n-butyryloxy-
5-[2-(dimethylamino)ethyl E-8-90 rho 2,3-dihydro-1,5-benzothiazepine-4(3
H)-one succinate 1.216F is obtained.

M, p, 140-142°C [α paste +61.28° (C = 0.320. Ethanol) Example 22 ←)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2- (dimethylamino)ethyl]-8-
A mixture of 900 rng of chloro 2,3-dihydro-1,5-benzothiazepin-4(3H)-one, 30 ON of n-valeryl chloride and 1-pyridine is treated analogously to Example 20. By converting the product into succinate and recrystallizing it from ethanol, (+)-cis-2-(4-
methoxyphenyl)-3-n-valeryloxy-5-[
2-(dimethylamino)ethyl)-8-chloro-2,3
-dihydro-1,5-benzothiazepine-4(3H)-
1.21 B y of on-succinate is obtained.

M-p, 167-169°C [α pasting +56.4° (C = 0.328. methanol)
Example 23 ←)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[,2-(dimethylamino)ethyl]-8
-chloro-2,3-dihydro-1,5-benzothiazepin-4(3H)-one 1.5 g, sodium hydride ('
62.2% oily dispersion oily 0.2211 and benzene 4
5- Heat the mixture under reflux for 1 hour.

[Stir at 50°C for 3 hours. The reaction mixture was washed with 10-thiosodium hydroxide solution and water, dried, and concentrated under reduced pressure to remove the solvent. The residue was removed using silica gel chromatography as CM medium, chloroform:ethanol = 9:1
). The purified product was converted into hydrochloride, and ethanol was added.
By recrystallizing from a mixture with ether, (+)
-cis-2-(4-methoxyphenyl)-3-methoxy-5-[2-(dimethylamino)ethyl]-8-chloro2,3-dihydro-1,5'-benzothiazepine-4
0.7 g of (3H,)-one hydrochloride is obtained.

M, p, 212-216°C [α +89.16° (C = 1.0. Dimethylformamide) Preparation of raw material compound Production example 1 2-amino-5-talolothiophenol 20.3f and (t) A mixture of 26.49 -trans-5-(4-methoxyphenyl)glycidic acid methyl ester is stirred at 160° C. for 16 hours under a stream of argon gas. From now on, ethanol is added to the mixture and the precipitated crystals are collected by filtration. By washing the crystals with ethanol, (±)-cis-2-(4
-methoxyphenyl)-3'-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepine-4(
3H)-one 11.3'9k is obtained. When ice crystals are recrystallized from dimethylformamide, they become needle-shaped crystals.

M, p, 230-232°C The mother liquor (ethanol solution) is concentrated under reduced pressure to remove the solvent. The residue is dissolved in ethyl acetate, and the solution is washed successively with 10% hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and water. After drying the ethyl acetate solution, the solvent was distilled off under reduced pressure.

The residue was purified by silica gel chromatography (eluent: chloroform) to obtain
methoxyphenyl)-3-hydroxy-8-chloro-2
,3-dihydro-1,5-benzothiazepine-4 (3H
)-one (cis-isomer) o, s g and (±)-trans-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiacebin-4 (5H)-one (trans-isomer) 1
．． Get 5 II.

Cis isomer: M, p, 230-232°C Trans-isomer: Needle crystals (recrystallized from a mixture of ethyl acetate and n-hexane) M, p, 183-185°C Production example 2 (1) 2- 7 E/-5-talolothiophenol 63.1 y, (+,)-trans-5-(4
-methoxyphenyl) glycidic acid methyl ester 90
．． 4 A mixture of y and toluene 600°C at 65-70℃
Stir for 40 hours. From now on, the precipitated crystals will be collected by filtration. Get an F. When the ice crystals are recrystallized from a mixture of ethyl acetate and n-hexane, they become needle-shaped crystals.

M, p, 131-132°C (2) -Threo-2-hydroxy-5-(2-asanino-5-talolophenylthio)-3-(4-methoxyphenyl)propionic acid methyl ester 23. 5N, 5%
Sodium hydroxide aqueous solution 150- and methanol 150-
- Stir the mixture at room temperature for 2 hours. The reaction mixture was adjusted to pH 4 with liquid dilute hydrochloric acid, and the precipitated crystals were collected by filtration. By washing the crystals with water and recrystallizing them from a mixture of dimethylformamide and ethanol, the product (threo-2-hydroxy-5-(2-amino-5-chlorophenylthio)-) was obtained.
3-(4-methoxyphenyl)propionic acid 17.59
is obtained as needle crystals.

M, p, 189-191°C (decomposition) +31 (J:)-threo-2-hydroxy-5-(
2-7E /-5-chlorophenylthio)-3-(4-
methoxyphenyl °) propionic acid 2 g and xylene 1
The mixture of 50 and 50-g was heated under reflux for 25 hours while removing water using a dehydrator. From now on, I will collect the precipitated crystals by filtration.

By recrystallization from dimethylformamide.

1.6 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(3H)-one are obtained.

M, p, 230-232°C Production Example 3 (±)-threo-2-hydroxy-5-(2-amino-
5-Chlorophenylthio)-3-(4-methoxyphenyl)propionic acid methyl ester (450 rng) was dissolved in 1.5 ml of dimethyl sulfoxide, and the solution was dimethylsulfinyl carbanion solution (dimethyl sulfoxide 3-
and (prepared from 103q of oily dispersion of sodium 60 dihydride) at 15°C or lower. The mixture is stirred at room temperature for 40 minutes.

The mixture is poured into 1901 ng of acetic acid and ice. The precipitated crystals were collected by filtration, washed with water, dried, and recrystallized from dimethylformamide to give υ, cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro- 300 fng of 1,5-benzothiazepin-4(3H)-one are obtained.

The physicochemical properties of the ice crystals matched those of the specimen obtained in Production Example 2 (3).

Production Example 4 fl) Dissolve 30.51 of L-p-hydroxyphenylglycine methyl ester hydrochloride in 600 - of methanol, and add 7.85 g of potassium hydroxide and 11 methanol to the solution.
50- Add the solution. Filter off the insoluble matter and transfer to the liquid ←)-threo-2-hydroxy-5-(2-7minor-5-chlorophenylthio)-3'-(4-methoxyphenyl)propionic acid 24.79 methanol 900 rn! Add solution. The mixture is concentrated under reduced pressure at below 60° C. to remove methanol.

The remaining residue was dissolved in 500 rnl of ethanol, and insoluble matter was filtered off. After leaving the filtrate at room temperature overnight, insoluble matter is filtered off. The filtrate is concentrated under reduced pressure to remove the solvent. By recrystallizing the remainder from ethanol (the mother liquor is referred to as mother liquor (I)) and further recrystallizing the obtained crystals from ethanol, (
h)-threo-2-hydroxy-5-(2-amino-5
-chlorophenylthio)-3-(4-methoxyphenyl)propionic acid L-p-hydroxyphenylglycine methyl ester salt 14.3y is obtained.

M, p, 169-172°C (decomposition) [α degree + 316.7° (C = 1.14. dimethylformamide) 10 dihydrochloric acid was added to 14.3 fl of the salt obtained above.

The mixture is concentrated under reduced pressure to remove the solvent. Add water to the residue and filter the precipitated crystals. By washing with crystal gold water and drying, (+)-threo-2-hydroxy-5-
(2-Asanino-5-talolophenylthio)-3-(4-
7.89% of methoxyphenyl)propionic acid is obtained.

M, p, 173-175°C (decomposition) [α + 325.0° (C = 0.73.IN sodium hydroxide) The mother liquor (I) obtained above is concentrated under reduced pressure and the solvent is distilled off. . Add 10% hydrochloric acid and water to the remaining residue, and filter the precipitated crystals. Obtained crystal 15.5y, potassium hydroxide 4.
By treating 92 g and D-p-hydroxyphenylchrysine methyl ester hydrochloride i 9.1 y in the same manner as above, (-)-meno-2-hydroxy-5-
(2-amino-5-chlorophenylthio)-3-(4-
13.9 y of methoxyphenyl)propionic acid D-p-hydroxyphenylglycine methyl ester salt is obtained.

M, p, 168-171°C (decomposition) [α paste -316,5° (C = 1.342. dimethylformamide) 13.9 liters of the salt obtained above was treated with 10% hydrochloric acid in the same manner as above. By processing to the free acid.

(→-threo-2-hydroxy-5-(2-amino-5
-chlorophenylthio)-3-(4-methoxyphenyl)propionic acid 7.39 k are obtained.

M, p, 172-174℃ (decomposition) Amino-5-chlorophenylthio)-3
A mixture of 10 g of -(4-methoxyphenyl)propionic acid and 600 g of xylene is heated under reflux for 20 hours. From now on, (+)-cis-2-(
4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepine-4(
3H)-one 6.9f is obtained.

M, p, 236-239°C (decomposition) [α capture +92.10 (C= to 2. dimethylformamide) (2-b) (-)-threo-2-hydroxy-5-(2-amino-5- By treating a mixture of 9 g of chlorophenylthio)-3-(4-methoxyphenyl)propionic acid and 500 g of xylene in the same manner as in (2-a) above, (-)-cis-2-(4-methoxyphenyl) -3-hydroxy-8-chloroCl-2゜3
-dihydro-1,5-benzothiazepine-4(3H)-
Obtain 6.5 g of on.

M, p, 23.5-237℃ (decomposition) [α] 9-9
2. o° (C=1.06. Dimethylformamide) Production Example 5 (1-a) 5-chloro-2-nitrothiopheno-/l'
19.75. and (+) -trans-3-(4-/
Toxyphenyl) glycidic acid methyl ester 27゜6
f' toluene 200. Suspend ZK and add 500 liters of zinc acetate dihydrate to the suspension. Mixture at room temperature
After stirring for an hour, the mixture was concentrated under reduced pressure to remove the solvent. Add isopropyl ether to the price.

Filter the precipitated crystals. After washing the crystals with water and isopropyl ether, the crystals were recrystallized from a mixture of benzene and isopropyl ether.
Chloro-2-nitrophenylthio)-2-hydroxy-
5-(4-methoxyphenyl)propionic acid methyl ester 27.66 fi k obtained as needles.

M, p, 141-143°C (1-b) 5-chloro-2-nitrothiophenol 1.7 g, (e)-trans-5-(4-methoxyphenyl) glycidic acid methyl ester 1.7 g, toluene 17 - and anhydrous stannic chloride 0.05 i'e above (17
If the button is processed in the same way as a), it will be seven years old, (g)-threo-5.
-(5-90rho-2-nitrophenylthio)-2-hydroxy-5-(,4-methoxyphenyl)propionic acid methyl ester 2.21F is obtained.

M, 9.141-143°C (1-c) 5-chloro-2-nitrothiophenol 1.
7 g, (±)-trans-5-(4-methoxyphenyl) glycidic acid methyl ester 2.38 g.

70 tons of toluene and 30 tons of stannous chloride were added to the above (1
-By processing in the same way as a), ←)-Threo-5
1.933 fl of -(5-chloro-2-nitrophenylthio)-2-hydroxy-5-(4-methoxyphenyl)propionic acid methyl ester are obtained.

M, p, 141-143°C (1-d) 5-chloro-2-nitrothiophenol 1.7f, (±)-trans-5-(4-methoxyphenyl)gly7-t acid methyl ester 1 .7f, toluene 20- and tin octylate 0.05- to the above (1
-a) (!- By the same treatment, (5-C5-90-2-nitrophenylthio)-2
-Hydroxy-5-(4-methoxyphenyl)propionic acid methyl ester 2.14 ytm.

M, p, 141-143°C (2) (±)-threo-5-(5-chloroc1-2-nitrophenylthio)-2-hydroxy-5-(4-methoxyphenyl)propionic acid methyl ester 22 , Oj'
, 120% aqueous sodium hydroxide solution and 400% methanol are stirred at room temperature for 5 hours. The reaction mixture was made acidic with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water, dried, and then recrystallized from methanol to yield (±)-threo-5-C5-chloro-2-nitrophenylthio)-2-hydroxy-5-(4-methoxyphenyl)propionic acid 17. Obtained by plate crystallization of 49y.

M, 9.179-182°C Dissolve in a mixture of /-ru 5- and acetic acid 5-, and add 10% palladium carbon 40 to the solution. The mixture was shaken in a stream of hydrogen gas at room temperature and normal pressure for 6 hours. After the reaction is completed, insoluble matter is filtered off, and the filtrate is reduced to 11 M and the solvent is distilled off. By recrystallizing the residue from a mixture of dimethylformamide and ethanol, (±)-threo-5-(5-chloro-2
-aminophenylthio)-2-hydroxy-5-(4-
269 ml of methoxyphenyl)propionic acid are obtained.

The physicochemical properties of ice crystals l'i corresponded to the specimen obtained in Production Example 2 (2).

Production Example 6 (1) (±)-Threo-5-(5-chloro-2-nitrophenylthio)-2-hydroxy-5-(4-methoxyphenyl)propionic acid 8.04 II f Dissolved in 110 rnl of methanol Then, add L-lysine hydrochloride 3 to the solution.
．． Add 85 f k. IN hydroxide methanol solution 21rn1 was added to the mixture under ice cooling.

Leave the mixture at room temperature. The precipitated crystals are collected by filtration (the mother liquor is referred to as mother liquor (I)). (+)-threo-5-(5-chloro-2-
Nitrophenylf)-2-hydroxy-5-(4-methoxyphenyl)propionic acid L-lysine salt 4.29
Get y.

M, p, 244-246°C (decomposition) 4.29 f of the salt obtained above is suspended in water, and the suspension is made acidic with dilute hydrochloric acid. The mixture is extracted with chloroform. After washing all of the extract with water and drying, the solvent is distilled off under reduced pressure. When the remaining gold is recrystallized from kol in improno, from K,
Nitrophenyl f-A-)-2-hydroxy-5-(4
-Methoxyphenyl) fibrobionic acid 3.36 f are obtained.

M, 9.93-97℃ [α + 138.7° (C = 0.623. Chloroform) elemental analysis value” 018H1406NSCI-C
3HtOH calculation value: C,51,41:H,4,99:
N, 3.16:S, 7.22CI, 7.99 Experimental value: C, 51,25:H, 4,81:N, 3.3
0; S, 7.21 CI, 7.87 The mother liquor (I) obtained above and 01) are combined, and the solution is concentrated under reduced pressure to remove the solvent. Filter the precipitated crystals.

By recrystallizing from a mixture of ethanol and water (1:1), 0-threo-5-(5-chloro-2-nitrophenylthio)-2-hydroxy-5-(4-methoxyphenyl ) Propionic acid L-lysine salt 3.611 is obtained.

M-p, 229-231°C (decomposition) The salt 3.61 f' obtained above was made into a free acid using dilute hydrochloric acid and recrystallized from Improper Tool.
(-)-threo-5-(5-chloro-2-nitrophenylthio)-2-hydroxy-5-(4-methoxybuenyl)propion WR2,80y is obtained.

M, p, 92-97°C [α sugar -120.2° (C = 0.323. Chloroform) elemental analysis value: C,, H□406NSCI -
C3H,OH calculation value: c, si, 4x, H, 4,9
9, N, 3. '16: S, 7.22 CI, 7.99 Experimental value: C, 51, 12, H, 4, 64, N, 3.6
8. S, 7.63CI, 8.32 (2-a) (t)-threo-5-(5-chloro-2
-nitrophenylthio)-2-hydroxy-5-(4-
362 ml of methoxyphenyl)propionic acid was treated in the same manner as in Preparation Example 5 (3). By recrystallizing the obtained crude product from methanol, ←)-threo-5-(5-
Chloro-2-aminophenylthio)-2-hydroxy-
5-(4-methoxyphenyl)propionic acid 301 m
Get yt.

The physicochemical properties of the ice crystals matched those of the specimen obtained in Production Example 4, +11.

(2-b) (-)-threo-5-(5-chloro-2
-nitrophenylthio)-2-hydroxy-5-(4-
3501 ngk of methoxyphenyl)propionic acid was treated in the same manner as in (3) of Production Example 5. By recrystallizing the obtained crude product from methanol, 0-threo-5-(5
-Chloro-2-aminophenylthio)-2-hydroxy-5-(4-methoxyphenyl)propionic acid 260■
tflru.

The physicochemical properties of the ice crystals matched those of the specimen obtained in Production Example 4 (1).

Production Example 7 (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1°5-benzothiazepin-4(3H)-one 1.8711 Dissolve in pyridine 10- and add 0.5 acetyl chloride to the solution.
Drop 2 fl. The mixture is stirred at room temperature for 1 hour. After the reaction is completed, chloroform is added to the mixture, the mixture is washed with 10% hydrochloric acid, and after drying, the solvent is removed under reduced pressure. By recrystallizing the residual from chloroform, C+
)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(3H)-one 1.4 f f colorless needles get as.

M, p, 220-223°C Production Example 8 ←)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1°5-benzothiazepine-4(3H )-one 3N, acetyl chloride 0.77 fl and pyridine 20- are treated in the same manner as in Preparation Example 7. The resulting crude product is recrystallized from a mixture of ether and n-hexane. ! 7. (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-8
-Chloro-2,3-dihydro-1,5-benzothiazepine-4(3H)-one 1°61f obtained as colorless needles.

M, p, 120-122℃

Claims (1)

[Claims] 1. Represented by the general formula (where R1 is a hydrogen atom, lower alkyl is a group represented by R'C O-, R2 and R3 are lower alkyl, R4 is a hydrogen atom or a lower alkyl group) 8-chloro-1,5-benzothiazepine derivative or a pharmacologically acceptable acid addition salt thereof. 2. Benzothiazepine derivatives or salts thereof represented by the general formula (similarly R5 is a hydrogen atom or a group represented by 2R4CO-; R4 represents a hydrogen atom or a lower alkyl group). (However, R5 is a hydrogen atom or a group represented by the formula R'CO-. R4 is a hydrogen atom or a lower alkyl group.) A benzothiazepine derivative or its salt represented by the general formula (However, R2 and R3 are (lower alkyl group, X represents a halogen atom) or a salt thereof, and if necessary, the product is converted into a pharmacologically acceptable acid addition salt thereof. (However, R", R3 and R5 have the same meanings as above.) A method for producing an 8-chloro-1,5-benzothiazepine derivative or a pharmacologically acceptable acid addition salt thereof. 4. General A benzothiazepine derivative or its salt represented by the formula (where R2 and R3 represent a lower alkyl group) and the general formula % (similarly, R4 represents a hydrogen atom or a lower alkyl group). compound or a reactive derivative thereof, and optionally convert the product into its pharmacologically acceptable acid addition salt (!) (wherein R2, R3 and R4 are A method for producing an 8-chloro-1,5-benzothiazepine derivative or a pharmacologically acceptable acid addition salt thereof, represented by the following formula (with the same meaning as 1) (where R2 and R3 represent a lower alkyl group). ) is reacted with a compound represented by the general formula % (where R6 is a lower alkyl group and XI represents a reactive residue), and if necessary, the product is 8-chloro-1,5-benzothi represented by the general formula (R'', RJ and R6 have the same meanings as above), which is characterized by being converted into a pharmacologically acceptable acid addition salt. A method for producing an azepine derivative or a pharmacologically acceptable acid addition salt thereof.