JPH0374661B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD This invention relates to 1,5-benzothiazepine derivatives useful as pharmaceutical compounds. (Prior Art) The main cause of thrombus formation is said to be the interaction between blood components, particularly platelets, blood coagulation factors, etc., and blood vessel walls. For example, when damage occurs to the blood vessel wall, platelets in the bloodstream aggregate in the exposed subendothelial tissue of the blood vessel, such as collagen. A substance that aggregates platelets is released from this aggregate, and the growth of the platelet aggregate is promoted. Furthermore, the aggregates thus formed are stabilized by fibrin, leading to the formation of a thrombus. Therefore, as one of the drugs that suppress thrombus formation, there is a demand for a drug that suppresses platelet aggregation during the above-mentioned thrombus formation process, and aspirin and the like have been used as platelet aggregation inhibitors. OBJECTS OF THE INVENTION One object of the present invention is to provide novel 1,5-benzothiazepine derivatives. (Structure and Effects of the Invention) The target compound of the present invention is a 1,5-benzothiazepine derivative or a salt thereof represented by the following general formula. (However, R ¹ represents lower alkyl, lower alkoxy or hydroxy, R ² represents a hydrogen atom, lower alkanoyl, benzyl or benzoyl,
R ³ represents lower alkyl, and R ⁴ and R ⁵ are: A) When R ¹ is lower alkyl or lower alkoxy, one is lower alkyl, lower alkoxy, fluorine atom, benzyloxy, hydroxy or lower alkylthio; B) When R ¹ is hydroxy, one is lower alkyl, fluorine atom, hydroxy or lower alkylthio, and the other is hydrogen atom. represents an atom, or both represent lower alkoxy. ) The compound () of the present invention or a salt thereof has an excellent platelet aggregation inhibiting effect. For example, when investigating the inhibitory effect on collagen-induced aggregation of human platelets, the compound of the present invention (-)-cis-
2-(4-methylphenyl)-3-hydroxy-5
-[2-(N-Methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride half hydrate IC ₅₀
(Concentration required to inhibit collagen-induced platelet aggregation by 50%) was 0.003 to 0.03 μg/ml. Incidentally, the IC ₅₀ of aspirin (chemical name: acetylsalicylic acid), which is known to have a similar effect, was approximately 20 μg/ml. As described above, since the compound () of the present invention has an excellent platelet aggregation inhibiting effect, it can be used to prevent, for example, cerebral infarction, cerebral thrombosis, transient cerebral ischemia, myocardial infarction, coronary artery thrombosis, pulmonary artery infarction, peripheral vascular embolism. , treatment for various thrombosis such as thrombovasculitis, embolism and other diseases,
It can be used for palliation and prevention. In the compound of the present invention, in the general formula (), R ¹ is lower alkyl such as methyl, ethyl, propyl, or butyl; lower alkoxy such as methoxy, ethoxy, propoxy, or butoxy, or hydroxy, and R ² is a hydrogen atom or acetyl. , lower alkanoyl such as propylonyl, butyryl, isobutyryl; benzyl or benzoyl;
When R ³ is lower alkyl such as methyl, ethyl, propyl, butyl ^, and R ⁴ and R ⁵ are lower alkyl or lower alkoxy, one is lower alkyl such as methyl, ethyl, propyl, butyl. Alkyl; lower alkoxy such as methoxy, ethoxy, propoxy, butoxy; fluorine atom, benzyloxy, hydroxy or lower alkylthio such as methylthio, ethylthio, propylthio, butylthio, and the other is a hydrogen atom, or both are methoxy, ethoxy B) When R ¹ is hydroxy, one is lower alkyl such as methyl, ethyl, propyl, butyl, fluorine atom, hydroxy or methylthio, ethylthio, propylthio, butylthio. lower alkylthio such as, and the other is a hydrogen atom, or both are methoxy, ethoxy,
Lower alkoxy such as propoxy and butoxy can be mentioned. Among these, preferred compounds are those in which R ¹ is methyl, methoxy or hydroxy, R ² is a hydrogen atom, acetyl, propionyl, butyryl, isobutyryl, benzyl or benzoyl, and R ³ is methyl. Yes, R ⁴
and R ⁵ is A) When R ¹ is methyl or methoxy,
one is methyl, methoxy, fluorine atom, benzyloxy, hydroxy or methylthio and the other is hydrogen atom, or both are methoxy; B) When R ¹ is hydroxy, one is methyl, fluorine Atom, hydroxy or methylthio, and the other is a hydrogen atom, or both are methoxy.More preferable compounds include those in the general formula () in which R ¹ is methyl or methoxy and R ² is a hydrogen atom or acetyl, R ³ is methyl, one of R ⁴ and R ⁵ is methyl, methoxy or hydroxy, and the other is a hydrogen atom. Since the compound () of the present invention has two asymmetric carbon atoms at the 2- and 3-positions of the 1,5-benzothiazepine skeleton, it can form two stereoisomers (i.e., cis and trans isomers) or There are optical isomers of the species [i.e. (+)-cis, (-)-cis, (+)-trans and (-)-trans isomers], and in the present invention these isomers and mixtures thereof It also includes. However, among these compounds, the cis isomer, especially the (-)-cis isomer, is preferred as a compound for pharmaceutical use. According to the present invention, the compound () is prepared by the following [Method A] ~
It can be manufactured according to [Method F]. [Method A] Among the compounds (), the general formula (However, R ⁶ represents lower alkyl or lower alkoxy, and one of R ⁷ and R ⁸ is lower alkyl, lower alkoxy, fluorine atom, benzyloxy, or lower alkylthio, and the other is hydrogen atom, or both are It represents lower alkoxy, and R ² and R ³ have the same meanings as above.) The compound represented by the general formula (However, R ² , R ⁶ , R ⁷ and R ⁸ have the same meanings as above.) A compound represented by or a salt thereof and the general formula (However, Q represents a hydrogen atom or a protective group, and X ¹
represents a halogen atom, and R ³ has the same meaning as above. ) or a salt thereof to form the general formula (However, R ² , R ³ , R ⁶ , R ⁷ , R ⁸ and Q have the same meanings as above.) When a compound represented by the formula is prepared and the substituent Q is a protecting group, the compound It can be produced by removing the protecting group from (). [Method B] General formula of compound () (However, R ⁹ represents lower alkyl or phenyl, and R ³ , R ⁶ , R ⁷ and R ⁸ have the same meanings as above.) The compound represented by the general formula (However, R ³ , R ⁶ , R ⁷ , R ⁸ and Q have the same meaning as above.) A compound represented by the formula or a salt thereof and the general formula R ⁹ COOH () (However, R ⁹ has the same meaning as above. ) or its reactive derivative to form the general formula (However, R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and Q have the same meanings as above.) When a compound represented by the formula is prepared and the substituent Q is a protecting group, the compound It can be produced by removing the protecting group from (). [Method C] Among the compounds (), the general formula (However, R ³ , R ⁶ , R ⁷ and R ⁸ have the same meanings as above.) The compound represented by the formula (However, R ³ , R ⁶ , R ⁷ , R ⁸ and Q have the same meanings as above.) When a compound represented by the formula is prepared and the substituent Q is a protecting group, from the compound () It can be produced by removing the protecting group. [Method D] Among the compounds (), the general formula (However, R ¹¹ represents a hydrogen atom, lower alkanoyl or benzoyl, R ¹² and R ¹³ represent that one is lower alkyl, fluorine atom, hydroxy or lower alkylthio, and the other is a hydrogen atom, and R ³ is has the same meaning as above.) The compound represented by the general formula (However, R ¹⁰ represents lower alkyl, R ³ , R ¹¹ ,
R ¹² and R ¹³ have the same meanings as above. ) It can be produced by dealkylating the compound represented by or a salt thereof. [Method E] Among the compounds (), the general formula (However, R ³ , R ⁶ , R ⁷ and R ⁸ have the same meanings as above.) The compound represented by () or its salt and the general formula (However, X ² represents a halogen atom) by reacting with the compound represented by the general formula (However, R ³ , R ⁶ , R ⁷ , R ⁸ and Q have the same meanings as above.) When a compound represented by the formula is prepared and the substituent Q is a protecting group, the compound (XI) It can be produced by removing the protecting group. [Method F] Among the compounds (), the general formula (However, R ³ , R ⁶ and R ¹¹ have the same meanings as above.) The compound represented by the general formula (However, R ³ , R ⁶ , R ¹¹ and Q have the same meanings as above.) The compound represented by the formula or a salt thereof is debenzylated to give the general formula (However, R ³ , R ⁶ , R ¹¹ and Q have the same meanings as above.) When a compound represented by the formula is prepared and the substituent Q is a protecting group, the protecting group is removed from the compound (). It can be manufactured by removing it. Examples of the protecting group used in the method of the present invention include benzyloxycarbonyl, p-
Substituted or unsubstituted benzyloxycarbonyl such as methoxybenzyloxycarbonyl; substituted or unsubstituted lower alkoxycarbonyl such as tert.-butoxycarbonyl, β,β,β-trichloroethoxycarbonyl, iodoethoxycarbonyl; benzyl, p-methoxybenzyl, Mention may be made of the conventional protecting groups for amino groups such as substituted or unsubstituted phenyl-lower alkyl such as 3,4-dimethoxybenzyl. Further, as the salt of the compound () which is the raw material compound of the method of the present invention, an alkali metal salt such as a sodium salt or a potassium salt can be used, while the compound (), (), (), () and (XII
)
Salts include addition salts of inorganic acids such as hydrochloride, hydrobromide, perchlorate, hydroiodide, and oxalate, maleate, fumarate, succinate, methanesulfonic acid. Addition salts of organic acids such as salts can be used. The reactions of [Method A] to [Method F] will be explained in detail below. [Method A] The condensation reaction between the compound () or its salt and the compound () or its salt can be carried out in a suitable solvent in the presence or absence of an alkaline reagent.
When compound () is used in free form, the condensation reaction is preferably carried out in the presence of an alkaline reagent. As the alkaline reagent, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal hydrides such as sodium hydride can be suitably used. As the solvent, it is preferable to use, for example, acetone, ethyl acetate, dimethyl sulfoxide, dimethyl formamide, dioxane, etc.
Preferably it is carried out at 100°C, especially between 25 and 70°C. When the substituent Q in the compound () produced in this manner is a protecting group, a conventional method can be applied to remove the protecting group. For example, when the protecting group is substituted or unsubstituted benzyloxycarbonyl, the protecting group can be removed by treating the compound () with an acid in a suitable solvent. As the acid, it is preferable to use hydrogen bromide, hydrogen chloride, trifluoroacetic acid, etc., and as the solvent, acetic acid,
Benzene, ethyl acetate, methylene chloride, 1,
2-dichloroethane, chloroform, toluene,
Chlorobenzene etc. can be used. The removal reaction is preferably carried out at a temperature of 0 to 40°C, particularly 0 to 25°C. When the protecting group is tert.-butoxycarbonyl, the protecting group can be removed by treating the compound () with an acid in a suitable solvent. As the acid, it is preferable to use hydrogen bromide, hydrochloric acid, trifluoroacetic acid, formic acid, etc., and as the solvent, acetic acid,
Water etc. can be used. The removal reaction is −10
Preference is given to carrying out the reaction at a temperature of -50°C, especially 0-40°C. When the protecting group is β,β,β-trichloroethoxycarbonyl, the protecting group can be removed by treating compound () with zinc-acetic acid at 20 to 60°C, and the protecting group is In the case of ethoxycarbonyl, the protecting group can be removed by treating compound () with zinc-methanol at 20 to 60°C. Furthermore, when the protecting group is substituted or unsubstituted phenyl-lower alkyl, the protecting group can be converted to a substituent that can be removed by acid treatment (for example, benzyloxycarbonyl, etc.), and then acid treatment can be performed. , the protecting group can be removed.
For example, the conversion of substituted or unsubstituted phenyl-lower alkyl to benzyloxycarbonyl can be performed by converting the compound () (Q = substituted or unsubstituted phenyl-lower alkyl) and benzyloxycarbonyl halide (e.g., benzyloxycarbonyl chloride)
This can be carried out by reacting them in an appropriate solvent. As the solvent, benzene, toluene, xylene, dioxane, tetrahydrofuran, etc. can be used, and the conversion is carried out at 50 to 130 °C,
It is particularly preferable to carry out the reaction at 80 to 100°C.
For the subsequent removal of benzyloxycarbonyl, the above-mentioned method for removing the protecting group can be applied. [Method B] The reaction between the compound () or a salt thereof and the reactive derivative of the compound () can be carried out in an appropriate solvent in the presence or absence of a deoxidizing agent. Reactive derivatives of compound () include acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, benzoic anhydride; acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, benzoyl chloride; Examples include acid halides such as. Examples of the deoxidizing agent include pyridine, triethylamine, N-methylpiperidine, N-methylmorpholine, N-methylpyrrolidine, and N-ethyl-N,N-diisopropylamine. As the solvent, for example, pyridine, benzene, dioxane, tetrahydrofuran, toluene, methylene chloride, acetic acid, etc. are preferably used. In the reaction, when excess acetic anhydride is used as the reactive derivative of compound (), it is not necessarily necessary to use another solvent because the acetic anhydride also acts as a solvent. When carrying out the reaction, if an acid anhydride is used as a reactive derivative of compound (), 20
It is preferable to carry out the reaction at a temperature of -130°C, and when an acid halide is used as the reactive derivative, it is preferably carried out at a temperature of 20 - 60°C. On the other hand, the compound () or its salt and the compound ()
The reaction with can be carried out in a suitable solvent in the presence of a condensing agent. Examples of the condensing agent include N,
N'-dicyclohexylcarbodiimide, N,
N'-carbonyldiimidazole, 1-methyl-
2-halopyridinium iodo salt (e.g. 1-
methyl-2-bromopyridinium iodo salt),
Methoxyacetylene, triphenylphosphine
Examples include carbon tetrachloride. As the solvent, methylene chloride, 1,2-dichloroethane, chloroform, benzene, toluene, tetrahydrofuran, dioxane, etc. are preferably used. The reaction is preferably carried out at a temperature of 0 to 80°C, especially 10 to 40°C. When the substituent Q in the compound () produced in this manner is a protecting group, the protecting group removal method in [Method A] can be applied to remove the protecting group. In addition, the raw material compound () in the above method is [A
This corresponds to the case where R ² is a hydrogen atom among the intermediate products ( ) in [method]. [Method C] The deacylation reaction of the compound () or a salt thereof can be carried out by treating the compound with an acid or alkaline reagent in a suitable solvent. As the acid, for example, hydrochloric acid or hydrobromic acid can be used, and as the alkaline reagent, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide,
Alkali metal carbonates such as sodium carbonate and potassium carbonate can be used. As a solvent,
Alkanols such as methanol and ethanol,
Preference is given to using water and mixtures thereof. The reaction is carried out at 0 to 100°C, especially when using an acid.
It is preferable to carry out at a temperature of 20 to 60°C, and when using an alkaline reagent, a temperature of 0 to 100°C, especially 10 to 50°C.
Preferably, the reaction is carried out at .degree. When the substituent Q in the compound () produced in this manner is a protecting group, the protecting group removal method in [Method A] can be applied to remove the protecting group. [Method D] The dealkylation reaction of the compound () or a salt thereof can be carried out by treating the compound with a boron trihalide such as boron tribromide in a suitable solvent. As the solvent, it is preferable to use methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene, etc. The reaction is preferably carried out at -50 to 25°C, especially at -10 to 25°C. [Method E] The reaction between compound () or a salt thereof and compound () can be carried out in a suitable solvent in the presence of a deoxidizing agent. Examples of deoxidizing agents include alkali metal hydrides such as sodium hydride, alkali metal amides such as sodium amide, and the like. As the solvent, it is preferable to use, for example, dimethylformamide, dimethylsulfoxide, benzene, tetrahydrofuran, dioxane, or the like. The reaction is 0
Preferably it is carried out at a temperature of -80°C, especially 25-60°C. When the substituent Q in compound (XI) thus produced is a protecting group, the protecting group removal method in [Method A] can be applied to remove the protecting group. [Method F] The debenzylation reaction of compound (XII) or a salt thereof can be carried out by a conventional method such as treating the compound with an acid in a suitable solvent. Hydrogen bromide is preferably used for the acid treatment, and the solvents include acetic acid, methylene chloride, benzene, ethyl acetate,
It is preferable to use a mixture of these. The reaction is preferably carried out at -10 to 40°C, especially at 0 to 20°C. In addition, among compounds (XII), when the substituent Q is substituted or unsubstituted benzyloxycarbonyl or substituted or unsubstituted lower alkoxycarbonyl, the protecting group can be simultaneously removed by the above reaction. When the substituent Q in the compound () produced in this manner is a protecting group, the protecting group removal method in [Method A] can be applied to remove the protecting group. Raw material compounds of the present invention (), (), (), ()
and (XII) is 2 of the 1,5-benzothiazepine skeleton.
Because it has two asymmetric carbon atoms at the position and 3 position,
Four optical isomers [i.e. (+)-cis, (-)-cis, (+)-trans and (-)-trans isomers]
However, since all of the above reactions proceed without racemization, optically active forms of compounds (), (), (), (), or (XII) can be used as starting compounds. Compound (-
a), (-b), (-c), (-d), (-e
)
or (-f) can be obtained. Compound (), which is the raw material compound of the present invention, can be produced, for example, by the following [method a], [method b], etc. (However, R ¹⁴ represents lower alkyl, R ¹⁵ represents lower alkanoyl, benzyl or benzoyl, and R ⁶ , R ⁷ and R ⁸ have the same meanings as above.) According to [method a], the compound ( ) is a compound (
) and compound () to react to form compound (
-a), and if necessary, acylates or benzylates the compound to obtain compound (-b). According to [method b], the compound () is the compound (
) and compound () to react to form compound (
), if necessary, hydrolyze the compound to form the compound (), then intramolecularly close the compound () or the compound () to form the compound (-
The compound (-b) can be produced by preparing the compound (a) and, if necessary, acylating or benzylating the compound to obtain the compound (-b). The first step in [method a] is the compound (
) and compound () is the reaction between compound ()
and compound () in a suitable solvent (e.g., xylene, diphenyl ether, p-cymene, etc.) or without a solvent, by heating the mixture to 150 to 165°C, and the reaction is carried out in an inert state. It is preferable to carry out the reaction in a gas (eg, argon gas, nitrogen gas, etc.). In this reaction, the compound (
If compound () is formed together with -a) and if compound (-a) is obtained as a mixture of two stereoisomers (i.e. cis and trans isomers), their separation can be carried out using a suitable solvent ( for example,
This can be carried out by fractional crystallization using the difference in solubility in ethanol, ethyl acetate, etc.) or by subjecting it to column chromatography. The first step in [method b] is the compound (
) and compound () is the reaction between compound ()
and compound () in a suitable solvent (e.g., toluene, acetonitrile, benzene, dioxane, xylene, etc.) or without a solvent, at a concentration of 20 to 110
It can be carried out at ℃. If the trans isomer is used as the starting compound () in the reaction, the compound () will be obtained primarily as the threo isomer. Hydrolysis of the compound (), which is a subsequent optional step, involves dissolving the compound in a suitable solvent (for example, methanol,
It can be carried out by treatment with an alkaline reagent (e.g., potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, etc.) in an alkanol such as ethanol, water, a mixed solvent thereof, etc. at 0 to 100°C. can. The compound () thus obtained can be separated into each optically active substance by using an optically resolving agent such as optically active p-hydroxyphenylglycine alkyl ester, if necessary. The intramolecular ring-closing reaction of the compound () or the racemic or optically active form of the compound () obtained in this way is carried out by dissolving these compounds in a suitable solvent (for example, xylene, toluene, diphenyl ether,
p-cymene, acetic acid, etc.) or without solvent, 110-160
This can be carried out by heating to °C.
In addition, the intramolecular ring-closing reaction of compound () was carried out in dimethyl sulfoxide in the presence of methylsulfinyl carbanion (prepared from CH ₃ SOCH ₂ , dimethyl sulfoxide and sodium hydride) at 0 to 50°C.
It can also be carried out. On the other hand, the acylation reaction of compound (-a), which is an optional step in [method a] and [method b], is similar to the acylation of compound ().
The benzylation reaction of compound (-a) can be carried out by reacting compound (-a) with compound () or a reactive derivative thereof. ) can be carried out by reacting with When used as a medicament, the compound of the present invention () can be used as a free base or as a pharmacologically acceptable acid addition salt thereof. Examples of pharmacologically acceptable acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, and phosphate; oxalate; maleate, fumarate, 2-(4-
Examples include organic acid addition salts such as hydroxybenzoyl) benzoate, succinate, and methanesulfonate. These salts can be used, for example, in the compound ()
can be easily obtained by treating with acid. Compound () or its pharmacologically acceptable acid addition salt can be administered either orally or parenterally. When the compound () of the present invention or its pharmacologically acceptable acid addition salt is used as a medicine, the compound () is used as a pharmaceutical preparation by mixing it with a pharmaceutical excipient suitable for oral or parenteral administration. I can do it. As such excipients, for example, starch, lactose, glucose, potassium phosphate, corn starch, gum arabic, stearic acid, and other common pharmaceutical excipients can be suitably used. Pharmaceutical preparations include tablets, pills,
It may be a solid preparation such as a capsule or suppository, or a liquid preparation such as a solution, suspension, or emulsion. Furthermore, when administered parenterally, this pharmaceutical preparation can also be used as an injection. The daily dosage of the compound () of the present invention or a pharmacologically acceptable acid addition salt thereof is determined by the administration method,
Although it varies depending on the patient's age, weight, condition, and type of disease, it is usually about 0.05 to 50 mg/Kg, preferably about 0.5 to 20 mg/Kg for oral administration, and about 0.5 to 20 mg/Kg for parenteral administration (e.g., intravenous injection). Particularly preferred is about 0.05-10 mg/Kg. In addition, in this specification, lower alkyl, lower alkylthio, lower alkoxy, and lower alkanoyl are alkyl having 1 to 4 carbon atoms, and 1 to 4 carbon atoms, respectively.
4 alkylthio, alkoxy having 1 to 4 carbon atoms, and alkanoyl having 2 to 5 carbon atoms. In this specification, "threo" means that the hydroxyl group and the substituted phenylthio group substituted at the 2- and 3-positions of propionic acid have a threo-type arrangement (i.e., in the Fischer projection, the two substituents are in the main chain). located on the opposite side of ). Hereinafter, the present invention will be further explained in detail by giving experimental examples, examples, and manufacturing examples. Experimental Example 1 (Inhibitory effect on rat and human platelet aggregation in vitro) Nine volumes of blood collected from rats or humans were mixed with 3.8
Platelet-suspended plasma (PRP) was prepared by mixing with 1 volume of % (W/V) trisodium citrate aqueous solution and centrifuging the mixture. The remaining blood was further centrifuged to prepare platelet-free plasma (PPP).
Rat PRP platelet count is 0.8 to 1 including PPP.
The platelet count of human PRP was adjusted to 4× ^{10 5 /} mm ³ by adding PPP ^. dilution
After stirring a mixture of 200μ PRP and 25μ sample solution at 37°C for 2 minutes, a collagen solution [Biochimica
E. biofisica acta. , Vol. 186, p. 254 (1969)] was added to cause platelet aggregation. Platelet aggregation ability was determined by Born's method [Nature. ，
Vol. 194, p. 927 (1962)] to determine the platelet aggregation inhibitory effect of the sample. The platelet aggregation inhibitory effect of the test compound was expressed as IC ₅₀ (concentration required to inhibit collagen-induced platelet aggregation by 50%). The results are shown in Tables 1 and 2 below.

[Table] It was warm in ml.

[Table] It was warm in ml.
Experimental Example 2 (ex vivo rat platelet aggregation inhibitory effect) An aqueous sample solution (sample dose: 10 mg/Kg) was orally administered to SD male rats that had been fasted for about 20 hours.
After 3 hours, blood is collected from the abdominal aorta. Platelet-suspended plasma (PRP) was prepared by mixing 9 volumes of this blood with 1 solution of 3.8% (W/V) trisodium citrate aqueous solution and centrifuging the mixture. The remaining blood was further centrifuged to prepare platelet-free plasma (PPP). The platelet count of PRP was adjusted to 0.8 to 1×10 ⁶ /mm ³ by adding PPP. dilution
Platelet aggregation was caused by adding 25μ of a collagen solution (prepared according to the method described in Experimental Example 1) to 225μ of PRP. Platelet aggregation ability was measured by Born's method to determine the platelet aggregation inhibitory effect of the sample. The compounds shown in Table 3 below had a platelet aggregation inhibition rate of 50% or more.

[Table] Example 1 (1) (±)-cis-2-(4-methoxyphenyl)
-3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-
A mixture of 2 g of powdered potassium hydroxide, 0.42 g of powdered potassium hydroxide, and 15 ml of dimethyl sulfoxide is stirred at 50° C. for 30 minutes. After the reaction, 2-(N-benzyloxycarbonyl-N-methylamino) was added to the mixture.
A solution of 2.64 g of ethyl chloride in 5 ml of dimethyl sulfoxide is added and the mixture is stirred at 50° C. for 3 days. The mixture is poured into ice water and extracted with ethyl acetate. The extract was washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. By purifying the residue with silica gel column chromatography [solvent: chloroform-ethyl acetate (10:1)],
(±)-cis-2-(4-methoxyphenyl)-3
-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8
2.95 g of -methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil. (2) (±)-cis-2-(4-methoxyphenyl)
-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]
A mixture of 2.49 g of -8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 15 ml of acetic anhydride and 5 ml of pyridine is stirred at 100 DEG C. for 2 hours. After cooling, acetic anhydride and pyridine are distilled off from the mixture under reduced pressure. Furthermore, by repeating the operation of adding toluene to the residue and distilling off the solvent under reduced pressure twice, (±)-cis-2-
(4-methoxyphenyl)-3-acetoxy-5
-[2-(N-benzyloxycarbonyl-N-
methylamino)ethyl]-8-methyl-2,3
-dihydro-1,5-benzothiazepine-4
3.08 g of (5H)-one are obtained as an oil. (3) (±)-cis-2-(4-methoxyphenyl)
-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]
-8-Methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one 3.08 g, acetic acid
A mixture of 10 ml and 5 ml of 25% hydrogen bromide-acetic acid is stirred at room temperature for 2 hours. After the reaction, the solvent is distilled off from the mixture under reduced pressure. Toluene is added to the residue, and the precipitated crystals are collected by filtration and washed with ether. The crystals (hydrobromide) were converted into a free base, further converted into a hydrochloride, and then recrystallized from ethanol to obtain (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5. -[2-(N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-
Obtain 1.2 g of 1/2 ethanol hydrochloride 1/2 hydrate. Mp 154-156℃ Examples 2-6 The following compounds are obtained by treating the corresponding starting compounds in the same manner as in Example 1-(1), (2) and (3).

【table】

[Table] Examples 7 and 8 The following compounds are obtained by treating the corresponding starting compounds in the same manner as in Example 1-(1), (2) and (3).

【table】

[Table] Example 9 (1) (-)-cis-2-(4-methoxyphenyl)
-3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-
A mixture of 6.3 g of 2-(N-benzyl-N-methylamino)ethyl chloride hydrochloride, 4.65 g of potassium carbonate, 7.2 g of potassium carbonate, and 80 ml of acetone is refluxed for 20 hours. After cooling, insoluble materials are removed by filtration, and the solvent is distilled off from the filtrate under reduced pressure. The residue is made into perchlorate,
By recrystallizing from methanol, (-)-
cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothi Azepine-4(5H)-
Obtain 10.8 g of perchlorate. Mp 178-181℃ [α] ²⁰ _D −86.1゜(C=0.18, methanol) (2) (−)-cis-2-(4-methoxyphenyl)
-3-hydroxy-5-[2-(N-benzyl-
N-methylamino)ethyl]-8-methyl-2,
3-dihydro-1,5-benzothiazepine-4
(5H)-one perchlorate (10.7 g) as the free base, the compound was mixed with 80 ml of acetic anhydride and 1 ml of pyridine.
Add and heat to 100℃ for 4 hours. After cooling, acetic anhydride and pyridine are distilled off from the mixture under reduced pressure. By adding benzene to the residue and distilling off the solvent under reduced pressure, (-)-cis-2-(4-
methoxyphenyl)-3-acetoxy-5-[2
-(N-benzyl-N-methylamino)ethyl]
10.37 g of -8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil. (3) (−)-cis-2-(4-methoxyphenyl)
-3-acetoxy-5-[2-(N-benzyl-
N-methylamino)ethyl]-8-methyl-2,
3-dihydro-1,5-benzothiazepine-4
A solution of 9 g of benzyloxycarbonyl chloride in 25 ml of benzene was added dropwise to a mixture of 10.37 g of (5H)-one and 125 ml of benzene under reflux over 30 minutes, and the mixture was refluxed for 4 hours. After cooling, the solvent was distilled off under reduced pressure from the mixture to give (-)-cis-2
-(4-methoxyphenyl)-3-acetoxy-
5-[2-(N-benzyloxycarbonyl-N
-methylamino)ethyl]-8-methyl-2,
3-dihydro-1,5-benzothiazepine-4
11.8 g of (5H)-one are obtained as an oil. (4) (−)-cis-2-(4-methoxyphenyl)
-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]
-8-Methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one 11.8 g, 25%
A mixture of 25 ml of hydrogen bromide-acetic acid and 50 ml of acetic acid is stirred at room temperature for 2 hours. 800 ml of anhydrous ether is added to the mixture, and the insoluble powder is filtered off and dissolved in acetone. Ether is added to the solution, and the precipitated insoluble powder is collected by filtration and dissolved in water. The solution is made alkaline with aqueous ammonia and extracted with chloroform. After washing the extract with water and drying, the solvent was distilled off under reduced pressure. By converting the residue into oxalate and recrystallizing it from ethanol, (-)-cis-
2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methylamino)ethyl]-8
-Methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one oxalate 8.4g
get. Mp 166-168℃ [α] ²⁰ _D -79.4゜(C=0.36, methanol) Examples 10-15 (However, in compound Nos., i to v, R ¹ represents methoxy, and in compound No. vi, R ¹ represents methyl.) The corresponding raw material compound was treated in the same manner as in Example 9-(1). By doing so, the following compound is obtained.

【table】

(However, in Examples No. 10 to 14, R ¹ represents methoxy, and in Example No. 15, R ¹ represents methyl.) The corresponding raw material compounds were converted to Example 9-(2), (3) ) and (4) to obtain the following compound.

[Table] Example 16 (1) (±)-cis-2-(4-methylphenyl)-
3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 5.96 g, 2-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride 5.89
A mixture of 1.68 g of potassium hydroxide and 85 ml of dimethyl sulfoxide was treated in the same manner as in Example 1-(1), and the crude product was subjected to silica gel chromatography [solvent: benzene-ethyl acetate (9:1)].
(±)-cis-2-(4
-methylphenyl)-3-hydroxy-5-[2
-(N-Benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepine-4 (5H)
7.89 g of -one are obtained as an oil. (2) (±)-cis-2-(4-methylphenyl)-
3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-
A mixture of 1.6 g of 8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.69 g of benzoyl chloride, 5 ml of pyridine and 2 ml of benzene is stirred at room temperature for 2 hours. After the reaction, the mixture is poured into ice water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure to obtain (±)-cis-2-(4-methylphenyl)-3-benzoyloxy-5-[2-
(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-
2.14 g of on are obtained as an oil. (3) (±)-cis-2-(4-methylphenyl)-
3-benzoyloxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5
- 2.14 g of benzothiazepine-4(5H)-one,
A mixture of 2 ml of 25% hydrogen bromide-acetic acid and 2 ml of acetic acid is stirred at room temperature for 2 hours. After the reaction, ether is added to the mixture and the precipitated crystals are collected by filtration. After thoroughly washing the crystals with ether, water is added to the crystals. The mixture is made alkaline by adding ammonia water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure, and the residue was converted into an oxalate salt, which was then recrystallized from a mixture of dimethylformamide and ethanol to obtain (±)-cis-2-(4-methylphenyl). -3-benzoyloxy-5-[2-(N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5
-0.85 g of benzothiazepine-4(5H)-one oxalate is obtained. Mp 212-213.5℃ Example 17 (±)-cis-2-(4-methylphenyl)-3
-Hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1.38 g, A mixture of 0.45 g of isobutyryl chloride, 5 ml of pyridine and 2 ml of benzene was treated in the same manner as in Example 16-(2) to obtain the product (±)-cis-2-(4-methylphenyl)-3.
-isobutyryloxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]
By treating -8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in the same manner as in Example 16-(3), (±)-cis-2-
(4-methylphenyl)-3-isobutyryloxy-5-[2-(N-methylamino)ethyl]-8-
0.40 g of methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one oxalate is obtained. Mp 188.5-190.5℃ (decomposition) Example 18 (±)-cis-2-(4-methylphenyl)-3
-Hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1.35 g, A mixture of 0.44 g of n-butyryl chloride, 5 ml of pyridine and 2 ml of benzene was treated in the same manner as in Example 16-(2) to obtain the product (±)-cis-2-(4-methylphenyl)-3.
-n-butyryloxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]
By treating -8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in the same manner as in Example 16-(3), (±)-cis-2-
(4-methylphenyl)-3-n-butyryloxy-5-[2-(N-methylamino)ethyl]-8-
0.43 g of methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one oxalate is obtained. Mp 185.5-186℃ Example 19 (±)-cis-2-(4-methylphenyl)-3
-Hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1.46 g, A mixture of 0.42 g of propionyl chloride, 5 ml of pyridine and 2 ml of benzene was treated in the same manner as in Example 16-(2) to obtain the product (±)-cis-2-(4-methylphenyl)-3.
-Propionyloxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]
By treating -8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in the same manner as in Example 16-(3), (±)-cis-2-
(4-methylphenyl)-3-propionyloxy-5-[2-(N-methylamino)ethyl]-8-
Methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one 1/2 oxalate 0.45
get g. Mp 128-132℃ Example 20 (1) (±)-cis-2-(4-methoxyphenyl)
-3-hydroxy-8-benzyloxy-2,
3-dihydro-1,5-benzothiazepine-4
(5H)-one 5g, 2-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride
(±)-cis-2-(4-
methoxyphenyl)-3-hydroxy-5-[2
-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-benzyloxy-2,
3-dihydro-1,5-benzothiazepine-4
3.75 g of (5H)-one are obtained as an oil. (2) (±)-cis-2-(4-methoxyphenyl)
-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]
-8-benzyloxy-2,3-dihydro-
1,5-benzothiazepine-4(5H)-one
(±)-cis-2-(4-methoxyphenyl)
-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]
-8-benzyloxy-2,3-dihydro-
1,5-benzothiazepine-4(5H)-one
4.18 g are obtained as an oil. (3) (±)-cis-2-(4-methoxyphenyl)
-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]
-8-benzyloxy-2,3-dihydro-
1,5-benzothiazepine-4(5H)-one
2.31g, 25% hydrogen bromide-acetic acid 3.5ml and acetic acid 7
ml of the mixture is stirred for 1 hour at room temperature. Ether is added to the mixture and the precipitated crystals are collected by filtration. After washing the crystals with ether, they are suspended in water and an aqueous sodium bicarbonate solution is added. The suspension is extracted with chloroform (the aqueous layer is referred to as the aqueous layer), the extract is washed with water and dried, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel chromatography [solvent: chloroform-ethanol (9:1)],
(±)-cis-2-(4-methoxyphenyl) was obtained by converting 0.29 g of the obtained oil into a hydrochloride and recrystallizing it from a mixture of ethanol and ether.
-3-acetoxy-5-[2-(N-methylamino)ethyl]-8-benzyloxy-2,3-
Dihydro-1,5-benzothiazepine-4
0.21 g of (5H)-one hydrochloride is obtained. Mp 175-178°C (decomposition) An aqueous sodium bicarbonate solution is added to the aqueous layer obtained above, and the mixture is extracted with chloroform. After washing the extract with water and drying, the solvent is distilled off under reduced pressure. The residue was made into a hydrochloride salt and recrystallized from ethanol to give (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methylamino)ethyl]-8 -Hydroxy-2,3
-dihydro-1,5-benzothiazepine-4
Obtain 0.22 g of (5H)-one hydrochloride 1/2 hydrate. Mp 242-245℃ (decomposition) Example 21 (±)-cis-2-(4-methoxyphenyl)-
3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-
A mixture of 1.97 g of benzyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 3.6 ml of 25% hydrogen bromide-acetic acid and 7 ml of acetic acid is stirred at room temperature for 3 hours. After the reaction, ether is added to the mixture and the precipitated crystals are collected by filtration. The crystals are washed with ether and dissolved in water. The solution is made alkaline with aqueous ammonia and extracted with chloroform. After washing the extract with water and drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography [solvent: chloroform-ethanol (9:1)]. 0.58 g of the resulting oil was converted into a hydrochloride and purified from ethanol. By recrystallization, (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N
-methylamino)ethyl]-8-hydroxy-2,
3-dihydro-1,5-benzothiazepine-4
0.54 g of (5H)-one hydrochloride is obtained. The physical property values of this compound matched those of the compound obtained in Example 20-(3). Example 22 (±)-cis-2-(4-methoxyphenyl)-
3-acetoxy-5-[2-(N-methylamino)
ethyl]-8-methyl-2,3-dihydro-1,
1.1 g of 5-benzothiazepine-4(5H)-one hydrobromide, 10 ml of 5% aqueous sodium hydroxide solution
and 5 ml of ethanol are stirred at room temperature for 3 hours. After the reaction, water is added to the mixture and extracted with ethyl acetate. The extract is washed with brine, dried, and the solvent is distilled off under reduced pressure. The residue was made into a hydrochloride salt and recrystallized from ethanol to give (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-8 −
0.46 g of methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride is obtained. Mp 230-232℃ (decomposition) Examples 23-26 The following compound is obtained by treating the corresponding raw material compound in the same manner as in Example 22.

【table】

[Table] Examples 27-33 The following compound is obtained by treating the corresponding raw material compound in the same manner as in Example 22.

【table】

[Table] Example 34 (1) (-)-cis-2-(4-methylphenyl)-
3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 0.90 g, 2-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride 1.03
(-)-cis-2-(4-methylphenyl)-3-hydroxy-5-[ 2-
(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-
Obtain 0.62 g of onion as an oil. (2) (-)-cis-2-(4-methylphenyl)-
3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-
Example 1 A mixture of 0.73 g of 8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 5 ml of acetic anhydride, and 0.1 ml of pyridine was prepared.
- By treating in the same manner as (2), (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-
N-methylamino)ethyl]-8-methyl-2,
3-dihydro-1,5-benzothiazepine-4
0.92 g of (5H)-one is obtained as an oil. (3) (-)-cis-2-(4-methylphenyl)-
3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-
A mixture of 0.92 g of 8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 2 ml of 25% hydrogen bromide-acetic acid and 2 ml of acetic acid is stirred at room temperature for 2 hours. After the reaction, the solvent is distilled off from the mixture under reduced pressure, toluene is added to the residue, and the solvent is further distilled off under reduced pressure. Ether is added to the residue, and the precipitated crystals are collected by filtration and washed with ether. A mixture of the crystals, 2 ml of ethanol and 2 ml of 5% aqueous sodium hydroxide solution is stirred at room temperature for 2 hours. The mixture was brought to pH 8 with acetic acid and extracted with chloroform. After washing the extract with water and drying, the solvent is distilled off under reduced pressure. After converting the residue into a hydrochloride, it was recrystallized from isopropanol to form (-)-cis-
2-(4-methylphenyl)-3-hydroxy-
5-[2-(N-methylamino)ethyl]-8-
0.32 g of methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride 1/2 hydrate is obtained. Mp 128-145℃ [α] ²⁰ _D −103.8゜(C=0.29, methanol) (4) (−)-cis-2-(4-methylphenyl)-
3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-
An equal mixture of 8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 25% hydrogen bromide-acetic acid is stirred at room temperature for 2 hours. After the reaction, the solvent is distilled off from the mixture, toluene is added to the residue, and the solvent is further distilled off. Ether is added to the residue, and the precipitated crystals are collected by filtration and washed with ether. The product was made into a fumarate salt and recrystallized from a mixture of acetone and ethyl acetate to give (-)-cis-2-(4-methylphenyl)-
3-acetoxy-5-[2-(N-methylamino)ethyl]-8-methyl-2,3-dihydroxy-1,5-benzothiazepine-4(5H)-
Get on. Mp 167.5-170℃ (decomposition) [α] ²⁰ _D -81.6゜ (C=0.50, methanol) Example 35 (+)-cis-2-(4-methylphenyl)-3
-Hydroxy-8-methyl-2,3-dihydro-
By treating 1,5-benzothiazepin-4(5H)-one in the same manner as in Example 34-(1), (2) and (3), (+)-cis-2-(4-methylphenyl) -3
-Hydroxy-5-[2-(N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5
-Benzothiazepine-4(5H)-one hydrochloride
A hemihydrate is obtained. Mp 130-147°C (recrystallized from isopropanol) [α] ²⁰ _D +103.84° (C = 0.182, methanol) Example 36 A solution of 6.34 g of boron tribromide in 50 ml of methylene chloride is cooled to -50°C. Add (-) to the solution at the same temperature.
-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]
A solution of 1.89 g of -8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in 50 ml of methylene chloride was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 30 minutes. do. After the reaction, the solvent is distilled off under reduced pressure, chloroform is added to the residue, the mixture is poured into ice water, made alkaline by adding an aqueous sodium bicarbonate solution, and the chloroform layer is separated.
After washing and drying the chloroform layer, the solvent was distilled off under reduced pressure, and the residue was converted into 2-(4-hydroxybenzoyl)benzoate, which was recrystallized from a mixture of acetone and ether to give (-)-cis-2. -(4-
hydroxyphenyl)-3-hydroxy-5-[2
-(N-methylamino)ethyl]-8-methyl-
2,3-dihydro-1,5-benzothiazepine-
1.77 g of 4(5H)-one 2-(4-hydroxybenzoyl)benzoate monohydrate are obtained. Mp 170-174℃ (decomposition) [α] ²⁰ _D -73.14゜ (C = 0.35, methanol) Example 37 (1) 2-(tert.-butoxycarbonylthio)-4,
0.78 g of 6-dimethylpyrimidine was converted into (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-
Add to 10 ml of a dioxane solution containing 1.21 g of 8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one under ice cooling. After stirring the mixture at room temperature for 4 hours, water was added to the mixture,
Extract with ethyl acetate. The extract is washed with 10% hydrochloric acid and brine, dried, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel chromatography [solvent: benzene-ethyl acetate (5:1)] to give (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2 -(N-
tert.-Butoxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one
1.29 g are obtained as an oil. (2) Sodium hydride (63% oil dispersion) 0.21
g to (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-tert.-
Butoxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5
-Add to a solution of 1.25 g of benzothiazepine-4(5H)-one in 10 ml of dimethyl sulfoxide. After stirring at room temperature for 1.5 hours, a solution of 0.37 g of benzyl chloride in 2 ml of dimethyl sulfoxide was added to the mixture, and the mixture was further stirred at room temperature for 1 hour. After the reaction, the mixture is poured into ice water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure and the residue was washed with n-hexane to obtain (±)-cis-2-(4-methoxyphenyl).
-3-benzyloxy-5-[2-(N-tert.-
Butoxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5
1.31 g of -benzothiazepine-4(5H)-one are obtained as an oil. (3) (±)-cis-2-(4-methoxyphenyl)
-3-benzyloxy-5-[2-(N-tert.-
Butoxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5
A mixture of 0.54 g of -benzothiazepine-4(5H)-one and 5 ml of formic acid is stirred at room temperature for 1 hour. Ice water is added to the mixture, made alkaline by adding sodium bicarbonate, and extracted with chloroform. After drying the extract, the solvent was distilled off under reduced pressure,
By converting the residue into oxalate and recrystallizing it from a mixture of ethanol and ether, (±)-
cis-2-(4-methoxyphenyl)-3-benzyloxy-5-[2-(N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,
0.21 g of 5-benzothiazepine-4(5H)-one oxalate 1/3 hydrate is obtained. Mp 131-134℃ Example 38 (±)-cis-2-(4-methoxyphenyl)-
3-Hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-
2.1 g of methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 7 ml of benzene and
A mixture of 7 ml of 25% hydrogen bromide-acetic acid is stirred at room temperature for 2 hours. The solvent was distilled off from the mixture under reduced pressure at room temperature, ether was added to the residue, and the precipitated crystals were collected by filtration.
Wash with ether. The crystals (hydrobromide) were converted into a free base, further converted into a hydrochloride salt, and then recrystallized from ethanol to form (±)-cis-2-
(4-methoxyphenyl)-3-hydroxy-5-
0.8 g of [2-(N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride is obtained. Mp 230-232℃ (decomposition) Example 39 (1) (±)-cis-2-(4-methylphenyl)-
2 g of 3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.4 g of potassium hydroxide, 15 ml of dimethyl sulfoxide and 2-(N-benzyloxycarbonyl-N -methylamino)ethyl chloride
By treating 2.58 g of the mixture in the same manner as in Example 1-(1), (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-
Benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one
2.6 g are obtained as an oil. (2) (±)-cis-2-(4-methylphenyl)-
3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-
Example 38: 2.5 g of 8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one
By processing in the same manner as (±)-cis-2
-(4-methylphenyl)-3-hydroxy-5
1.1 g of -[2-(N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride is obtained. Mp 238-243℃ (recrystallized from dimethylformamide) Production example 1 2-amino-5-methyl-thiophenol 18.2
A mixture of 25.45 g of g and (±)-trans-3-(4-methylphenyl)glycidic acid methyl ester is heated to 160° C. for 16 hours under an argon atmosphere.
After cooling, ethanol was added to the mixture, the precipitated crystals were collected by filtration, and recrystallized from a mixture of dimethylformamide and ethanol to give (±)-cis-2-
5.15 g of (4-methylphenyl)-3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained. Mp 182.5-184.5°C The following compound is obtained by treating the corresponding raw material compound in the same manner as above.

[Table] Production example 2 2-amino-5-fluorothiophenol
20.66 g and (±)-trans-3-(4-methylphenyl)glycidic acid methyl ester 27.45 g
The mixture is stirred at 150-160°C for 16 hours. After cooling, the mixture is poured into benzene and further 18% hydrochloric acid is added. The organic layer is separated, washed with water and an aqueous sodium bicarbonate solution, dried, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel chromatography [solvent: chloroform-ethyl acetate (10:1)] and recrystallized from ethanol.
(±)-cis-2-(4-methylphenyl)-3-hydroxy-8-fluoro-2,3-dihydro-
1,5-benzothiazepine-4(5H)-one 3.19
get g. Mp 210-213℃ 2-amino-4-methyl-thiophenol
22.66 g and (±)-trans-3-(4-methylphenyl)glycidic acid methyl ester 30.97 g
By treating the mixture of
(±)-cis-2-(4-methylphenyl)-3-hydroxy-7-methyl-2,3-dihydro-1,
2.21 g of 5-benzothiazepine-4(5H)-one are obtained. Mp 204-205℃ Production example 3 (1) 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. The solvent was distilled off from the mixture under reduced pressure, benzene was added to the residue, and the mixture was extracted with hydrochloric acid (concentrated hydrochloric acid diluted 1:1 with water). The extract is neutralized with potassium carbonate and further extracted with benzene. After washing the extract with water and drying,
Benzene was distilled off under reduced pressure, 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 obtain (±)-threo-2. -hydroxy-3-(2
-amino-5-methylphenylthio)-3-(4
15.8 g of -methoxyphenyl)propionic acid methyl ester are obtained. Mp 110-112℃ By treating 2-amino-5-methyl-thiophenol and (±)-trans-3-(4-methylphenyl)glycidic acid methyl ester in the same manner as above, (±)-threo-2 -Hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methylphenyl)propionic acid methyl ester is obtained. Mp 114-114.5℃ (recrystallized from isopropyl ether) (2) (±)-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, the mixture was adjusted to pH3 with 10% hydrochloric acid under cooling rice.
Adjust to ~5. By filtering the precipitated crystals, washing with water, drying, and recrystallizing from methanol, (±)-
threo-2-hydroxy-3-(2-amino-
4.3 g of 5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid are obtained. Mp 190～193℃ (±)-threo-2-hydroxy-3-(2-
Amino-5-methylphenylthio)-3-(4-
(±)-threo-2-hydroxy-3-(2-amino-5
-methylphenylthio)-3-(4-methylphenyl)propionic acid is obtained. Mp 168-172℃ (3-a) 45.3g of L-p-hydroxyphenylglycine methyl ester hydrochloride in methanol
Dissolve in 1000ml. 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-2-hydroxy-3-(2
-amino-5-methylphenylthio)-3-
(4-methoxyphenyl)propionic acid 37.8
Add g. The mixture is heated to 50°C and 900ml of methanol is added to form a solution. The solvent is distilled off from the solution under reduced pressure at a temperature below 50°C, 200 ml of ethanol is added to the residue, and the mixture is refrigerated overnight. The precipitated crystals are collected by filtration (the filtrate is referred to as the mother liquor), and recrystallized from ethanol (the mother liquor is referred to as the mother liquor).
Further, by recrystallizing the crude product from ethanol, (±)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid. L-p-hydroxyphenylglycine methyl ester salt [Mp164-167°C, [α] ²⁰ _D +255.8° (C = 0.66, methanol)]
Obtain 20.7g. 15.3g of the salt obtained above in methanol
After suspending the suspension in a mixture of 240 ml and 200 ml of water, adding 27 ml of cation exchange resin and stirring at room temperature overnight, the resin was filtered off and washed 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-
7 g of 5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid are obtained. Mp 158-160°C [α] ²⁰ _D +296.0° (C=0.29, methanol) Combine the mother liquor obtained above, add 13 ml of concentrated hydrochloric acid, and evaporate the solvent under reduced pressure. Add water to the residue and filter the precipitated crystals. 15.5 g of the crystals, 20.3 g of D-p-hydroxyphenylglycine methyl ester hydrochloride
By treating a mixture of 5.2 g of potassium hydroxide and potassium hydroxide in the same manner as above, (-)-threo-
2-Hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid/D-p-hydroxyphenylglycine methyl ester salt [Mp 164-167°C, ethanol Recrystallized from [α] ²⁰ _D −254.8°C = 0.95, methanol)]
Obtain 12.9g. 15.3 g of the salt obtained above was treated in the same manner as above to obtain the free acid (-)-threo-2-hydroxy-3-(2-amino-
6.5 g of 5-methylphenylthio)-3-(4-methoxyphenyl)propionic acid are obtained. Mp 158-160℃ (recrystallized from ethanol) [α] ²⁰ _D −265.3゜ (C=0.33, methanol) (3-b) Potassium hydroxide 0.71g methanol 10ml
Add the solution to 2.74 g of L-p-hydroxyphenylglycine methyl ester hydrochloride in methanol.
Add to 70ml solution. Insoluble matter is filtered off and washed with methanol. Combine the filtrate and wash and add (±)-threo-2-hydroxy-3-
(2-amino-5-methylphenylthio)-3
-(4-methylphenyl)propionic acid 2g
Add. Methanol was distilled off from the mixture under reduced pressure, 20 ml of ethanol was added to the residue, and the mixture was left at 0°C overnight. By filtering the precipitated crystals and recrystallizing them twice from ethanol, (+)-threo-2-hydroxy-3-(2-amino-5
0.41 g of -methylphenylthio)-3-(4-methylphenyl)propionic acid L-p-hydroxyphenylglycine methyl ester salt is obtained. Mp 170-172℃ [α] ²⁰ _D +308.64゜ (C = 0.61, methanol) 2.65g of the salt obtained above and 10% hydrochloric acid 10
ml of the mixture, the solvent is distilled off under reduced pressure, water is added to the residue, and the solvent is distilled off from the mixture under reduced pressure. Add water to the residue again, filter out the precipitated crystals,
After washing with water and drying, by recrystallizing from methanol, (+)-threo-2-hydroxy-3
-(2-amino-5-methylphenylthio)-
3-(4-methylphenyl)propionic acid
Obtain 0.93g. Mp 166-168℃ [α] ²⁰ _D +356.7゜ (C = 0.52, dimethylformamide) Potassium hydroxide 2.75g, D-p-hydroxyphenylglycine methyl ester hydrochloride
By treating 10.65 g and (±)-threo-2-hydroxy-3-(2-amino-5-methylphenylthio)-3-(4-methylphenyl)propionic acid 7.77 g in the same manner as above, ( -)-threo-2-hydroxy-3-
(2-amino-5-methylphenylthio)-3
-(4-methylphenyl)propionic acid D
1.21 g of -p-hydroxyphenylglycine methyl ester salt is obtained. Mp 170-172°C (recrystallized from ethanol) [α] ²⁰ _D -320.61° (C = 0.41, methanol) By treating 1.18 g of the salt obtained above in the same manner as above to obtain a free acid, ( -)-threo-2-hydroxy-3-(2-amino-
0.39 g of 5-methylphenylthio)-3-(4-methylphenyl)propionic acid is obtained. Mp 166-168°C (recrystallized from methanol) [α] ²⁰ _D -356.23° (C = 0.63, dimethylformamide) (4) (+)-threo-2-hydroxy-3-(2-
Amino-5-methylphenylthio)-3-(4-
Reflux for 24 hours while removing water to form a mixture of 9 g of methoxyphenyl)propionic acid and 350 ml of xylene. After the reaction, xylene was distilled off from the mixture under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-methyl-2. , 7.8 g of 3-dihydro-1,5+benzothiazepin-4(5H)-one are obtained. Mp 223-226°C (decomposition) [α] ²⁰ _D +123.8° (C=0.71, dimethylformamide) The following compound is obtained by treating the corresponding raw material compound in the same manner as above.

[Table] *: Recrystallized from ethyl acetate **: Recrystallized from ethanol Production Example 4 (1) The following compound is obtained by treating the corresponding raw material compound in the same manner as in Production Example 3-(1). (±)-threo-2-hydroxy-3-(2-
Amino-5-methylphenylthio)-3-(4-
Methoxyphenyl) propionic acid methyl ester Mp 114-116℃ (recrystallized from ethanol) (±)-threo-2-hydroxy-3-(2-
Amino-4-methylthiophenylthio)-3-
(4-methoxyphenyl) propionic acid methyl ester Mp 130-132℃ (recrystallized from ethanol) (2) Sodium hydride (63% oil dispersion) 1.5
A mixture of g and 25 ml of dimethyl sulfoxide is heated to 70° C. for 50 minutes under an argon atmosphere. (±)-Threo-2-hydroxy-3-
(2-amino-5-methylthiophenylthio)-
3-(4-methoxyphenyl)propionic acid methyl ester 7g dimethyl sulfoxide 12ml
The solution is added dropwise under cooling and stirred at room temperature for 20 minutes. After the reaction, the mixture was poured into ice water, the precipitated crystals were collected by filtration, washed with water, dried, and then recrystallized from a mixture of dimethylformamide and ethanol.
(±)-cis-2-(4-methoxyphenyl)-3
-Hydroxy-8-methylthio-2,3-dihydro-1,5-benzothiazepine-4(5H)-
On 6.7g. Mp 183-184°C The following compound is obtained by treating the corresponding raw material compound in the same manner as above. (±)-cis-2-(4-methoxyphenyl)
-3-hydroxy-7-methylthio-2,3-
Dihydro-1,5-benzothiazepine-4
(5H)-one Mp 211-214℃ (recrystallized from a mixture of dimethylformamide and ethanol) (±)-cis-2-(4-methoxyphenyl)
-3-hydroxy-9-fluoro-2,3-dihydro-1,5-benzothiazepine-4 (5H)
-On Mp 217-220℃ (recrystallized from a mixture of dimethylformamide and ethanol)

Claims (1)

[Claims] 1. General formula (However, R ¹ represents lower alkyl, lower alkoxy or hydroxy, R ² represents a hydrogen atom, lower alkanoyl, benzyl or benzoyl,
R ³ represents lower alkyl, and R ⁴ and R ⁵ are: A) When R ¹ is lower alkyl or lower alkoxy, one is lower alkyl, lower alkoxy, fluorine atom, benzyloxy, hydroxy or lower alkylthio; B) When R ¹ is hydroxy, one is lower alkyl, fluorine atom, hydroxy or lower alkylthio, and the other is hydrogen atom. represents an atom, or both represent lower alkoxy. ) A 1,5-benzothiazepine derivative or a salt thereof.