JPH0427213B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a pharmaceutical composition comprising a novel 1,5-benzothiazepine derivative as an active ingredient. (Prior art) U.S. Pat. No. 3,562,257 describes 2-(4-methoxyphenyl)3-hydroxy (or acetoxy)-5
7-chloro-1,5- such as -[2-(dimethylamino)ethyl]-7-chloro-2,3-dihydroxy-1,5-benzothiazepin-4(5H)-one
Various benzothiazepine derivatives, including benzothiazepine derivatives, have been shown to have antidepressant, tranquilizing, and/or coronary vasodilatory effects. (Object of the Invention) The present invention provides an antihypertensive, cerebral/coronary vasodilator and/or platelet aggregation inhibitor containing a 1,5-benzothiazepine derivative as an active ingredient. (Structure and Effects of the Invention) The pharmaceutical composition of the present invention contains an antihypertensive, cerebral/coronary vasodilator and/or platelet aggregation inhibitor as a new 1,5-benzothiazepine derivative as an active ingredient, and its effectiveness. The component is a 1,5-benzothiazepine derivative represented by the following general formula or a pharmacologically acceptable acid addition salt thereof. (However, R ¹ is a lower alkyl group or lower alkoxy group, R ² is a hydrogen atom or a lower alkanoyl group,
Both R ³ and R ⁴ represent a lower alkyl group, and R ⁵ represents a lower alkyl group, a lower alkoxy group, or a benzyloxy group. ) The 1,5-benzothiazepine derivative () or its pharmacologically acceptable acid addition salt contained as an active ingredient in the pharmaceutical composition of the present invention has an excellent antihypertensive effect,
It has cerebral/coronary vasodilator effect and/or platelet aggregation inhibitory effect. The pharmaceutical composition of the present invention exhibits a strong and sustained antihypertensive effect, a cerebral/coronary vasodilator effect, and an excellent platelet aggregation inhibiting effect, and has low toxicity; therefore, it is effective against hypertension;
It is useful as a prophylactic, ameliorating, or therapeutic agent for cerebral diseases such as cerebral vasospasm, cerebral infarction, and stroke, and heart diseases such as angina pectoris, arrhythmia, and myocardial infarction. As the active ingredient of the pharmaceutical composition of the present invention, in the general formula (), R ¹ is a methyl group, an ethyl group,
Lower alkyl groups such as propyl group, butyl group, lower alkoxy groups such as methoxy group, ethoxy group, propoxy group, butoxy group, R ² is a hydrogen atom or lower alkanoyl group such as acetyl group, propionyl group, butyryl group, R ³ and R ⁴ is a lower alkyl group such as methyl, ethyl, propyl, or butyl, and R ⁵ is a lower alkyl group such as methyl, ethyl, propyl, or butyl, methoxy, ethoxy, or propoxy. , a lower alkoxy group such as a butoxy group, or a benzyloxy group. In addition, more preferable compounds from a therapeutic standpoint include, in the general formula (), R ¹ is a methyl group or a methoxy group, R ² is a hydrogen atom or an acetyl group, R ³ and R ⁴ are both a methyl group, and R ⁵ is a methyl group;
A compound in which R ¹ is a methoxy or methyl group, R ² is an acetyl group, R ³ and R ⁴ are both a methyl group, and R ⁵ is a methyl or methoxy group. It is a certain compound. The active ingredient 1,5-benzothiazepine derivative () has two asymmetric carbon atoms at the 2- and 3-positions of the benzothiazepine skeleton, so it has two stereoisomers (i.e., cis and trans isomers). ) or four optical isomers (i.e. (+)-cis, (-)-
cis, (+)-trans and (-)-trans isomers] or mixtures thereof. However, for pharmaceutical applications, the cis isomer is particularly preferred. 1,5- which is the active ingredient of the pharmaceutical composition of the present invention
Benzothiazepine derivatives () can be used both as free bases and as their pharmacologically acceptable acid addition salts. Examples of pharmacologically acceptable acid addition salts include hydrochloride, hydrobromide,
Inorganic acid addition salts such as hydroiodide, perchlorate, sulfate, phosphate; organic acid addition salts such as oxalate, maleate, fumarate, tartrate, methanesulfonate, etc. Can be mentioned. These salts can be easily obtained, for example, by treating compound () with an acid. The active ingredient 1,5-benzothiazepine derivative () or its pharmacologically acceptable acid addition salt can be administered orally or parenterally, and is a pharmaceutical suitable for oral or parenteral administration. It can be used as a pharmaceutical formulation mixed with excipients. As such excipients, for example, starch, lactose, glucose, potassium phosphate, corn starch, gum arabic, magnesium stearate, and other common pharmaceutical excipients can be suitably used. Pharmaceutical preparations may be solid preparations such as tablets, pills, capsules, and suppositories, or liquid preparations such as solutions, suspensions, and emulsions.
Furthermore, when administered parenterally, this pharmaceutical preparation can also be used as an injection. The daily dosage of the 1,5-benzothiazepine derivative () or its pharmacologically acceptable salt varies depending on the administration method, age, weight, condition, and type of disease of the patient, but is usually about 0.05～10mg/Kg
is preferably about 0.5 to 10 mg/Kg for oral administration, and about 0.05 to 2 mg/Kg for parenteral administration (e.g., intravenous injection).
Especially preferred is mg/Kg. The 1,5-benzothiazepine derivative () which is the active ingredient of the present invention has the general formula (However, R ¹ , R ² and R ⁵ have the same meanings as above.) N-unsubstituted benzothiazepine compound or its salt and the general formula (However, X represents a halogen atom, and R ³ and R ⁴
has the same meaning as above. ) It can be produced by carrying out a condensation reaction with an aminoethyl halide compound or a salt thereof. In addition, 1,5-benzothiazepine derivatives ()
General formula (However, R ⁶ represents a lower alkanoyl group, R ¹ ,
R ³ , R ⁴ and R ⁵ have the same meanings as above. ) The 3-alkanoyloxy-1,5-benzothiazepine derivative represented by the general formula (However, R ¹ , R ³ , R ⁴ and R ⁵ have the same meanings as above.) A 3-hydroxy-1,5-benzothiazepine derivative or a salt thereof represented by the general formula R ⁶ -OH () (However, R ⁶ has the same meaning as above.) It can be produced by reacting the lower fatty acid shown below or its reactive derivative. The condensation reaction between the N-unsubstituted benzothiazepine compound () or its salt and the aminoethyl halide compound () or its salt can be carried out in a suitable solvent in the presence or absence of an alkaline reagent. Examples of the salt of the compound () include alkali metal salts. When compound () is used in free form, the condensation reaction is preferably carried out in the presence of an alkaline reagent. As the alkali reagent, for example, alkali metal hydroxide, alkali metal carbonate, alkali metal hydride, etc. can be suitably used. As the solvent, it is preferable to use, for example, acetone, ethyl acetate, dimethyl sulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, etc., and the condensation reaction is preferably carried out at 0 to 100°C, particularly 20 to 70°C. The reaction between the 3-hydroxy-1,5-benzothiazepine derivative (-a) or its salt and the reactive derivative of lower fatty acid () is carried out in a suitable solvent in the presence or absence of an acid absorber. be able to. Examples of the salt of compound (-a) include acid addition salts such as hydrochloride and hydrobromide. As reactive derivatives of lower fatty acids (),
Examples include acid anhydrides and acid halides.
Examples of the deoxidizer include pyridine, triethylamine, N-methylpyridine, N-methylmorpholine, N-methylpyrrolidine, N-ethyl-N,
Examples include N-diisopropylamine. As the solvent, it is preferable to use, for example, acetic acid, chloroform, dichloromethane, dimethylformamide, tetrahydrofuran, or the like. In the reaction, when excess acetic anhydride is used as the reactive derivative of the lower fatty acid (), the use of a solvent is not necessarily required. The reaction is preferably carried out at 50 to 140°C when an acid anhydride is used as the reactive derivative of the lower fatty acid (), and at -10 to 100°C when an acid halide is used. On the other hand, when lower fatty acid () is used in the form of a free acid, the condensation reaction between the compound and compound (-a) or a salt thereof can be carried out in a suitable solvent in the presence of a condensing agent. Examples of condensing agents include N,N'-dicyclohexylcarbodiimide, N,
N'-carbonyldiimidazole, 1-methyl-
Examples include 2-halopyridinium iodo salt, methoxyacetylene, triphenylphosphine-carbon tetrachloride, and the like. Examples of the solvent include methylene chloride, 1,2-dichloroethane, chloroform, benzene, toluene, tetrahydrofuran,
It is preferable to use dioxane or the like. This reaction is preferably carried out at a temperature of 0 to 50°C, particularly 0 to 20°C. Since all of the above reactions proceed without racemization, compounds () and (-
By using the optically active substance of a), the corresponding optically active compounds () and (-b) can be obtained, respectively. Note that the raw material compound () of the present invention is a new compound, for example, according to the reaction formula below,
It can be produced according to the method described in No. 9383, No. 46-8982, and No. 46-43785. (However, R ⁰ represents lower alkyl, and R ¹ , R ⁵ and R ⁶ have the same meanings as above.) In (Method A), compound (-a) is a stereoisomer (i.e. cis and trans isomer). When obtained as a mixture of optically active 1- It is also possible to resolve each optical isomer using an optical resolution agent such as (2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride. On the other hand, if intermediate products () are also required, optically active p
Optical isomers can be separated using an optical resolving agent such as -hydroxyphenylglycine alkyl ester. In the present specification, lower alkyl group, lower alkoxy group and lower alkanoyl group each have 1 carbon number.
It represents an alkyl group having ~4, an alkoxy group having 1 to 4 carbon atoms, and an alkanoyl group having 2 to 4 carbon atoms. In addition, in this specification, "threo" refers to the hydroxyl group substituted at the 2- and 3-positions of propionic acid and the formula:

[Formula] (wherein, R ⁵ has the same meaning as above) and the substituted aminophenylthio group have a threo configuration (i.e., the two substituents are on opposite sides of the main chain in the Fischer projection). (located). Experimental Example 1 (Antihypertensive effect) A sample dissolved or suspended in water (dose: 30 or 100 mg/Kg) was orally administered to spontaneously hypertensive rats (group 1: 3 rats) that had been fasted overnight. Systolic blood pressure in rats was measured using plethysmograph method.
Medicine. , Vol. 78, p. 957 (1971)). The antihypertensive effect of the sample was determined 1 hour and 4 hours after administration. The results are shown in Table 1 below.

[Table] Experimental Example 2 (Cerebral vasodilatory effect) Male dogs (body weight: 11-14 kg) were treated with pentobarbital sodium salt (intravenous administration, dose: 30 mg/
Anesthetized with Kg). The blood flow in the vertebral artery was measured using an electromagnetic flowmeter under artificial respiration. 5% of the sample
It was dissolved in an aqueous glucose solution and the solution was injected into the vertebral artery. The cerebral vasodilatory effect of the sample was determined as the efficacy ratio to papaverine calculated from the dose-effect curve. The results are shown in Table 2 below.

【table】

[Table] Experimental Example 3 (Acute Toxicity) The compounds listed in Table 2 above were administered intraperitoneally to ddY male mice (5 to 6 weeks old) at a rate of 100 mg/Kg.
Although the animals were observed for 3 days, there were no deaths. Experimental Example 4 (Coronary Vasodilation Effect) The effect on coronary blood flow in the isolated heart of a guinea pig (weight: approximately 280 g) was investigated using the Langendorff method. Rabbit blood from which fibrin has been removed from the excised heart 2
% Loklinger solution (saturated with a gas mixture of 95% oxygen and 5% carbon dioxide).
The perfusion pressure was maintained at 40 cm water column. The specimens were dissolved in 5% glucose solution and injected into the perfusate in a volume of 0.1 ml per heart. The outflow perfusate was measured using a drip counter and was defined as coronary blood flow. The compounds listed below increase coronary blood flow at doses that increase coronary blood flow.
It was 10 μg/heart and 0.5 ml/min or more. On the other hand, in the above experiment, papaverine increased coronary blood flow by 0.5 ml/min or more at a dose of 100 μg/heart.

【table】

[Table] Experimental Example 5 (Platelet aggregation inhibitory effect) Blood was collected from the abdominal aorta of SD-strain male rats anesthetized with ether. 9 volumes of rat blood
3.8w/v% citric acid trisodium salt aqueous solution 1
platelet-suspended plasma (PRP) was prepared by centrifuging the mixture. The remaining blood was further centrifuged to prepare platelet-free plasma (PPP). PRP platelet count in PPP is 0.8 to 1×10 ⁶ /mm ³
Adjusted to. Diluted PRP 200μ and sample solution 25μ
(Final concentration of specimen: 100 μg/ml)
After stirring for 2 minutes at ℃, the collagen solution [Biochimica e Biofidica Acta. , Volume 186, No.
p. 254 (1969)] 25μ was added to induce platelet aggregation. Platelet aggregation ability was measured by the method of Born [Nature, Vol. 194, p. 927 (1962)] to determine the platelet aggregation inhibitory effect of the sample. The compound shown below is acetylsalicylic acid (100μg/ml)
showed an inhibitory effect on platelet aggregation equivalent to or greater than that of

【table】

[Table] Production example 1 (±)-cis-2-(4-methylphenyl)-3
-Hydroxy-5-[2-(dimethylamino)ethyl]-8-methoxy-2,3-dihydro-1,5
-A mixture of 0.9 g of benzothiazepine-4(5H)-one and 10 ml of acetic anhydride is stirred at 110°C for 4 hours.
After cooling, the solvent is distilled off from the mixture under reduced pressure, benzene is added to the residue, and the solvent is further distilled off under reduced pressure. By converting the residue into oxalate and recrystallizing it from a mixture of chloroform, ethanol and ether,
(±)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]
-8-methoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one oxalate
Obtain 1.15g. Mp 209-211°C (decomposition) Production Examples 2-4 The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in Production Example 1.

[Table]
*) Production example of recrystallization from ethanol 5 (±)-cis-2-(4-methylphenyl)-3
-Hydroxy-5-[2-dimethylamino)ethyl]-8-methyl-2,3-dihydro-1,5-
By treating benzothiazepin-4(5H)-one in the same manner as in Production Example 1, (±)-cis-2-
(4-methylphenyl)-3-acetoxy-5-
[2-(dimethylamino)ethyl]-8-methyl-
2,3-dihydro-1,5-benzothiazepine-
4(5H)-one hydrochloride is obtained. Mp 184-186℃ (recrystallized from a mixture of isopropanol and ether) Production example 6 (±)-cis-2-(4-methoxyphenyl)-
3-hydroxy-5-[2-(dimethylamino)ethyl]-7-methoxy-2,3-dihydro-1,
A mixture of 1 g of 5-benzothiazepine-4(5H)-one hydrochloride, 1.5 ml of acetic anhydride, and 1.5 ml of acetic acid was added.
Stir at 110°C for 4 hours. After cooling, the solvent is distilled off from the mixture under reduced pressure, benzene is added to the residue, and the solvent is further distilled off under reduced pressure. By recrystallizing the residue from a mixture of ethanol and ether, (±)-
Cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-7
0.87 g of -methoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride 1/2 hydrate is obtained. Mp 216-218°C Production Examples 7 and 8 The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in Production Example 6.

[Table] Production example 9 (+)-cis-2-(4-methoxyphenyl)-
3-hydroxy-5-[2-dimethylamino)ethyl]-8-methyl-2,3-dihydro-1,5
A mixture of 5.05 g of -benzothiazepine-4(5H)-one, 2 ml of acetic anhydride and 0.1 ml of pyridine is stirred at 110°C for 4 hours. After cooling, the solvent is distilled off from the mixture under reduced pressure, benzene is added to the residue, and the solvent is further distilled off under reduced pressure. The residue was made into a hydrobromide salt and recrystallized from a mixture of ethanol and ether to give (+)-cis-2-(4-methoxyphenyl).
-3-acetoxy-5-[2-(dimethylamino)
ethyl]-8-methyl-2,3-dihydro-1,
6.374 g of 5-benzothiazepine-4(5H)-one hydrobromide are obtained. Mp 151-152°C (decomposition) [α] ²⁰ _D +82.5° (C=0.308, methanol) Production Examples 10-15 The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in Production Example 9.

[Table] Production example 16 (±)-cis-2-(4-methoxyphenyl)-
3-Hydroxy-6-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one
2.81g, dimethylaminoethyl chloride hydrochloride
A mixture of 1.35 g of potassium carbonate, 2.7 g of potassium carbonate, and 40 ml of acetone is heated under reflux for 16 hours. After cooling, inorganic substances are filtered off and washed with chloroform. The filtrate and washing liquid were combined, the solvent was distilled off, the residue was converted into a hydrochloride salt, and then recrystallized from a mixture of ethanol and ether to give (±)-cis-2-(4-
methoxyphenyl)-3-hydroxy-5-[2-
(dimethylamino)ethyl]-6-methyl-2,3
-dihydro-1,5-benzothiazepine-4
2.93 g of (5H)-one hydrochloride 3/4 hydrate is obtained. Mp 112-115°C Production Examples 17-21 The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in Production Example 16.

[Table] Production Examples 22-24 The following compounds were obtained by treating the corresponding raw material compounds in the same manner as in Production Example 16.

[Table] Production Examples 25-30 The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in Production Example 16.

[Manufacture of raw material compounds]

Reference example 1 2-amino-4-methoxythiophenol 13g
A mixture of 17.6 g of (±)-trans-3-(4-methoxyphenyl)glycidic acid methyl ester is heated at 160° C. for 16 hours under an argon atmosphere.
After cooling, add ethanol to the mixture, collect the precipitated crystals by filtration, and recrystallize from chloroform.
(±)-cis-2-(4-methoxyphenyl)-3-
Hydroxy-7-methoxy-2,3-dihydro-
1,5-benzothiazepine-4(5H)-one 4.52
get g. Mp 220-222°C Reference Examples 2-7 The following compounds are obtained by treating the corresponding raw material compounds in the same manner as in Reference Example 1.

【table】

[Table] Reference Examples 8 to 10 The following compounds were obtained by treating the corresponding raw material compounds in the same manner as in Reference Example 1.

[Table] Reference example 11 (a) 2-amino-5-methyl-thiophenol
29.1g, (±)-trans-3-(4-methoxyphenyl)glycidic acid methyl ester 47.8g
and 300 ml of toluene are heated to 60-65°C for 3 days and then to 70-80°C for 2 days. After the reaction, the solvent is distilled off from the mixture under reduced pressure, benzene is added to the residue, and the mixture is extracted with hydrochloric acid (concentrated hydrochloric acid diluted 1:1 with water). The extract is neutralized with potassium carbonate and further extracted with benzene. Wash the extract with water,
After drying, benzene is distilled off. The residue was purified by silica gel chromatography [solvent: benzene-ethyl acetate (10:1), and recrystallized from a mixture of ethanol and isopropyl ether to give (±)-threo-2-hydroxy-3-
(2-amino-5-methylphenylthio)-3-
15.8 g of (4-methoxyphenyl)propionic acid methyl ester are obtained. Mp 110-112℃ 2-amino-4-methyl-thiophenol and (±)-trans-3-(4-methoxyphenyl)glycidic acid methyl ester at 60-70℃
(±)-threo-2-hydroxy-3-(2-amino-4-methylphenylthio)-3-(4-methoxyphenyl ) to obtain propionic acid methyl ester. Mp 107～108℃ (b) (±)-threo-2-hydroxy-3-(2-
Amino-5-methylphenylthio)-3-(4-
A mixture of 5 g of methoxyphenyl) propionic acid methyl ester, 50 ml of 5% aqueous sodium hydroxide solution and 50 ml of methanol is stirred at room temperature for 2 hours. After the reaction, 10% hydrochloric acid is added to the mixture under ice cooling to adjust the pH to between 3 and 5. The precipitated crystals were collected by filtration, washed with water, dried, and then recrystallized from methanol to obtain (±)-threo-2-hydroxy-3.
-(2-amino-5-methylphenylthio)-3
-(4-methoxyphenyl)propionic acid 4.3g
get. Mp190～193℃ (±)-threo-2-hydroxy-3-(2-
Amino-4-methylphenylthio)-3-(4-
(±)-threo-2 methoxyphenyl)propionate methyl ester was treated in the same manner as above except for recrystallization from ethanol.
-Hydroxy-3-(2-amino-4-methylphenylthio)-3-(4-methoxyphenyl)
Obtain propionic acid. Mp168～170℃ (c) 45.3g of L-(p-hydroxyphenyl)glycine methyl ester hydrochloride in 1000ml of methanol
Dissolve in ml. A solution of 11.7 g of potassium hydroxide in 100 ml of methanol is added to the solution under ice cooling, and the precipitate (potassium chloride) is filtered off. (±) -Threo-
37.8 g of 2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid was added to the filtrate, the mixture was heated at 50°C, and Methanol 900ml
Add to make a solution. The solvent is distilled off from the solution under reduced pressure at a temperature below 50°C. Add 200 ml of ethanol to the residue and refrigerate overnight. The precipitated crystals are collected by filtration (the filtrate is referred to as mother liquor) and recrystallized from ethanol (the mother liquor is referred to as mother liquor). By further recrystallizing the crystals from ethanol, (+)-threo-2-hydroxy-3-(2-amino-5-
Methylphenylthio)-3-(4-methoxyphenyl)propionic acid L-(p-hydroxyphenyl)glycine methyl ester salt [Mp164
~167°C, 20.7 g of [α] ²⁰ _D +255.8° (C=0.655, methanol) was obtained. 15.3g of the compound obtained above was mixed with methanol.
Suspend in a mixture of 240 ml and 200 ml of water, add 27 ml of cation exchange resin to the suspension, and stir overnight at room temperature. Filter off the resin and wash the resin with methanol. The filtrate and washing liquid were combined, and the solvent was distilled off under reduced pressure. Water was added to the residue, the precipitated crystals were collected by filtration, and recrystallized from ethanol to give (±)-threo-2-hydroxy-3-(2-amino-5-
7 g of methylphenylthio)-3-(4-methoxyphenyl)propionic acid are obtained. Mp158-160°C [α] ²⁰ _D +296.0° (C=0.290, methanol) The above mother liquor and mother liquor are combined, 13 ml of concentrated hydrochloric acid is added thereto, and the solvent is distilled off under reduced pressure. Add water to the residue and filter the precipitated crystals. 15.5g of the crystal, D
-(p-hydroxyphenyl)glycine methyl ester hydrochloride 20.3g and potassium hydroxide
By treating 5.2 g of the mixture in the same manner as above, (-)-threo-2-hydroxy-3-
(2-amino-5-methylphenylthio)-3-
(4-methoxyphenyl)propionic acid D-
12.9 g of (p-hydroxyphenyl)glycine methyl ester salt [M.p 164-167°C (recrystallized from ethanol), [α] ²⁰ _D -254.8° (C=0.949, methanol)] was obtained. 15.3 g of the compound obtained above was treated in the same manner as above to obtain a free acid (-)-threo-2-hydroxy-3-(2-amino-5-
6.5 g of methylphenylthio)-3-(4-methoxyphenyl)propionic acid are obtained. Mp158-160℃ (recrystallized from ethanol) [α] ²⁰ _D -265.3゜ (C = 0.331, methanol) (±)-threo-2-hydroxy-3-(2-amino-4 -Methylphenylthio)-3-(4-methoxyphenyl)propionic acid can be optically resolved into the following compounds by treating in the same manner as above. (+)-threo-2-hydroxy-3-(2-
Amino-4-methylphenylthio)-3-(4-
methoxyphenyl)propionic acid: Mp 168-170℃ (recrystallized from ethanol) [α] ²⁰ _D +360.3° (C = 0.342, methanol) (-)-threo-2-hydroxy-3-(2-
Amino-4-methylphenylthio)-3-(4-
methoxyphenyl)propionic acid: Mp173-176℃ (recrystallized from ethanol) [α] ²⁰ _D -360.5° (C = 0.352, methanol) (d) (+)-threo-2-hydroxy-3-(2-
Amino-5-methylphenylthio)-3-(4-
A mixture of 9 g of methoxyphenyl)propionic acid and 350 ml of xylene is refluxed for 24 hours. After cooling,
By distilling off the xylene and recrystallizing the residue from ethyl acetate, (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-methoxy-2,3-dihydro-1, 7.8 g of 5-benzothiazepine-4(5H)-one are obtained. Mp223-226°C (decomposition) [α] ²⁰ _D +123.8° (C=0.707, dimethylformamide) The following compound is obtained by treating the corresponding raw material compound in the same manner as above.

[Table] Reference example 12 (a) (±)-cis-2-(4-methoxyphenyl)
-3-hydroxy-8-methoxy-2,3-dihydro-1,5-benzothiazepine-4 (5H)
A mixture of 4 g of -one, 13 ml of pyridine and 5 ml of methylene chloride is cooled with ice water. Add (s)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride [(s)-1-
(2-naphthylsulfonyl)pyrrolidine-2-
Prepared from carboxylic acid and oxalyl chloride in anhydrous benzene. ] Add 4g and stir at room temperature.
Stir for an hour. After the reaction, water and a mixture of ethyl acetate and chloroform (1:1) are added to the mixture, and the organic layer is separated. The organic layer was treated with 10% hydrochloric acid,
It is washed successively with water, a 5% aqueous sodium hydrogen carbonate solution, and water, and after drying, the solvent is distilled off. Dissolve the residue in benzene and precipitate crystals [3.7g, Mp148-150
°C (recrystallized from ethyl acetate) [α] ²⁰ _D -28.5° (C
= 0.755, chloroform)] (the filtrate is called the mother liquor). 3.6 g of crystals obtained above, 5 ml of chloroform,
A mixture of 50 ml of ethanol and 50 ml of 5% aqueous sodium hydroxide solution is stirred at room temperature for 1 hour. After the reaction, the mixture was washed with water, dried, the solvent was distilled off, and the residue was recrystallized from ethyl acetate to give (-)-cis-2-(4-methoxyphenyl).
-3-hydroxy-8-methoxy-2,3-dihydro-1,5-benzothiazepine-4 (5H)
- Obtain 1.46 g of on. Mp187-189℃ [α] ²⁰ _D -98.7゜(C=0.290, dimethylformamide) (b) The solvent is distilled off from the above mother liquor (benzene solution), and the residue is purified by silica gel chromatography to form an oil. Object {[α] ²⁰ _D −68.5゜(C
= 0.539, chloroform)}3.4g was obtained. 3.3 g of the above oil, 5 ml of chloroform, 50 ml of ethanol, and 50 ml of 5% aqueous sodium hydroxide solution
By processing ml in the same way as in (a) above, (+)
-cis-2-(4-methoxyphenyl)-3-hydroxy-8-methoxy-2,3-dihydro-
1,5-benzothiazepine-4(5H)-one 1.3
get g. Mp187-190°C (recrystallized from ethyl acetate) [α] ²⁰ _D +99.0° (C = 0.257, dimethylformamide)

Claims (1)

[Claims] 1. General formula (However, R ¹ is a lower alkyl group or lower alkoxy group, R ² is a hydrogen atom or a lower alkanoyl group,
Both R ³ and R ⁴ represent a lower alkyl group, and R ⁵ represents a lower alkyl group, a lower alkoxy group, or a benzyloxy group. ) or a pharmacologically acceptable acid addition salt thereof as an active ingredient. 2 General formula (However, R ¹ is a lower alkyl group or lower alkoxy group, R ² is a hydrogen atom or a lower alkanoyl group,
Both R ³ and R ⁴ represent a lower alkyl group, and R ⁵ represents a lower alkyl group, a lower alkoxy group, or a benzyloxy group. ) A cerebral/coronary vasodilator comprising a 1,5-benzothiazepine derivative or a pharmacologically acceptable acid addition salt thereof as an active ingredient. 3 General formula (However, R ¹ is a lower alkyl group or lower alkoxy group, R ² is a hydrogen atom or a lower alkanoyl group,
Both R ³ and R ⁴ represent a lower alkyl group, and R ⁵ represents a lower alkyl group, a lower alkoxy group, or a benzyloxy group. ) A platelet aggregation inhibitor comprising a 1,5-benzothiazepine derivative or a pharmacologically acceptable acid addition salt thereof as an active ingredient.