JPH0374660B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Technical Field) The present invention relates to 1,5-benzothiazepine derivatives useful as pharmaceuticals and a method for producing the same.

(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 for suppressing thrombus formation, there has been 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 so far.

Also, in U.S. Patent No. 3,562,257, 2-(4-methoxyphenyl)-3-hydroxy (or acetoxy)-5-[2-(dimethylamino)ethyl]-7-
7-chloro-1, such as chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one,
Various benzothiazepine derivatives, including 5-benzothiazepine derivatives, have been disclosed, and these benzothiazepine derivatives have been shown to have antidepressant, tranquilizing, and/or coronary vasodilatory effects.

(Object of the invention) An 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, R ² represents a hydrogen atom or lower alkanoyl, and R ³ represents lower alkyl.) The compound () of the present invention or a salt thereof has an excellent platelet aggregation inhibiting effect. ing. For example, in order to suppress the collagen-induced aggregation of human platelets,
When examined in vitro, the compound of the present invention (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-2,3-dihydro- The IC ₅₀ (concentration required to inhibit collagen-induced platelet aggregation by 50%) of 1,5-benzothiazepine-4(5H)-one hydrobromide was 0.3 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 for example in cerebral infarction, cerebral thrombosis, transient cerebral ischemia, myocardial infarction, coronary artery thrombosis, pulmonary embolism, thrombovasculitis, etc. It can be used to treat, alleviate, and prevent diseases such as thrombosis and embolism.

The compound of the present invention is represented by the general formula ()
R ¹ is lower alkyl such as methyl, ethyl, propyl, butyl, R ² is a hydrogen atom or lower alkanoyl such as acetyl, propionyl, butyryl, and R ³ is methyl, ethyl, propyl,
Examples include compounds in which R ¹ is methyl, R ² is a hydrogen atom or acetyl, and R ³ is methyl in the general formula (). can be mentioned.

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 Although there are optical isomers of the species (i.e. (+)-cis, (-)-cis, (+)-trans and (-)-trans isomers), in the present invention these isomers or mixtures thereof It also includes. However, among these compounds, cis isomers are preferred as compounds for pharmaceutical use.

According to the invention, the compound () has the general formula (However, R ¹ and R ² have the same meanings as above.) The compound or its salt and the general formula (However, Q represents a hydrogen atom or a protective group, X represents a halogen atom, and R ³ has the same meaning as above.) By reacting the compound represented by the formula or its salt, (However, R ¹ , R ² , R ³ and Q have the same meanings as above.) When the compound represented by 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.

In addition, among the compounds (), compounds in which R ² is lower alkanoyl, that is, compounds with the general formula (However, R ⁴ represents lower alkanoyl, and R ¹ and R ³ have the same meanings as above.) The compound represented by the general formula (However, R ¹ , R ³ and Q have the same meaning as above.) A compound or a salt thereof with the general formula R ⁴ -OH (V) (However, R ⁴ has the same meaning as above.) By reacting with a compound represented by or a reactive derivative thereof, the general formula (However, R ¹ , R ³ , R ⁴ 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 protected compound is protected from the compound (-a). It can be produced by removing the group.

Furthermore, compounds in which R ² is a hydrogen atom among the compounds (), that is, compounds with the general formula (However, R ¹ and R ³ have the same meanings as above.) The compound represented by the general formula (However, R ¹ , R ³ , R ⁴ and Q have the same meanings as above.) A compound represented by the formula or a salt thereof is deacylated to give the general formula (However, R ¹ , R ³ 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 (-b). It can be manufactured by

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.

The condensation reaction between compound () or its salt and 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 such as sodium salt and potassium salt. Examples of the salt of the compound () include hydrochloride,
Acid addition salts such as hydrobromide salts are included. 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 potassium carbonate and sodium 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., and the condensation reaction
Preferably it is carried out at 100°C, especially from 20 to 80°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,
Ethylene chloride, chloroform, toluene, chlorobenzene, mixtures thereof, and the like can be used. The removal reaction is carried out at a temperature of 0 to 40°C, especially 0 to 40°C.
Preferably it is carried out at 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, compound () is dissolved in acetic acid for 20
The protecting group can be removed by treating with zinc at ~60°C, and when the protecting group is iodoethoxycarbonyl, the compound () can be removed by treating with zinc in methanol at 20~60°C. , the protecting group can be removed.

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.

The reaction between compound (-b) or a salt thereof and a reactive derivative of compound () can be carried out in a suitable solvent in the presence or absence of an acid absorbing agent. Examples of the salt of compound (-b) include acid addition salts such as hydrochloride and hydrobromide. Reactive derivatives of compound () include acid anhydrides such as acetic anhydride, propionic anhydride, and butyric anhydride; acetyl chloride, propionyl chloride,
Examples include acid halides such as butyryl chloride. Examples of deoxidizers include pyridine,
Triethylamine, N-methylpiperidine, N-
Methylmorpholine, N-methylpyrrolidine, N-
Examples include ethyl-N,N-diisopropylamine. As the solvent, it is preferable to use, for example, pyridine, dioxane, benzene, toluene, tetrahydrofuran, ethyl acetate, methylene chloride, 1,2-dichloroethane, chloroform, dimethylformamide, and the like. 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, it is preferable to carry out the reaction at 20 to 130°C when an acid anhydride is used as the reactive derivative of compound (), and at 20 to 60°C when using an acid halide as the reactive derivative.
Preferably, the reaction is carried out at .degree.

On the other hand, when compound () is used in free form,
The condensation reaction between the compound and compound (-b) can be carried out in a suitable solvent in the presence of a condensing agent. Examples of condensing agents include N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-
N'-morpholinocarbodiimide, N-ethyl-
Examples include N'-(3-dimethylaminopropyl)carbodiimide, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine-carbon tetrachloride, and the like. As the solvent, it is preferable to use tetrahydrofuran, dioxane, benzene, toluene, etc. The reaction is carried out at temperatures between 0 and 80°C, especially at 20°C.
Preferably it is carried out at ~40°C.

When the substituent Q in the compound (-a) produced in this way is a protecting group, the above-mentioned removal method can be applied to remove the protecting group.

The deacylation reaction of compound (-a) or a salt thereof can be carried out by treating compound (-a) with an acid or alkaline reagent in a suitable solvent. Examples of the salt of compound (-a) include hydrochloride,
Mention may be made of acid addition salts such as hydrobromide. As the acid, for example, hydrochloric acid or hydrobromic acid can be used, and as the alkaline reagent, for example, alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, alkali metal carbonate such as sodium carbonate and potassium carbonate, aqueous ammonia etc. can be used. As the solvent, it is preferable to use alkanols such as methanol and ethanol, water, mixtures thereof, and the like. The reaction is suitably carried out at 0 to 100°C, particularly 20 to 60°C, when an acid is used, and at 0 to 100°C, especially 10 to 50°C, when an alkaline reagent is used.

When the substituent Q in the compound (-b) produced in this way is a protecting group, the above-mentioned removal method can be applied to remove the protecting group.

Raw material compounds (), (-a) and (
-b) has two asymmetric carbon atoms at the 2- and 3-positions of the 1,5-benzothiazepine skeleton, so it has four optical isomers [i.e., (+)-cis, (-)-cis ,
(+)-trans and (-)-trans isomers], but since all of the above reactions proceed without racemization, the compound (),
By using the optically active form of (-a) or (-b), optically active compound (), (-b) or (-a) can be obtained.

Among the raw material compounds of the present invention, compound (-a)
Compound (-b) corresponds to the case where R ² is a lower alkanoyl in the compound (), and compound (-b) corresponds to the case where R ² is a hydrogen atom in the compound (). It can be produced by the reaction of On the other hand, the compound () is a chemical and pharmaceutical bulletin (Chemical & Pharmaceutical Bulletin).
Pharmaceutical Bulletin) Volume 18 2028-2037
(1970).

When the compound () produced by the method of the present invention is used as a medicine, it 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, phosphate, and nitrate; oxalic acid; Examples include organic acid addition salts such as salts, maleates, fumarates, tartrates, and methanesulfonates. These salts can be easily obtained, for example, by treating compound () with an acid. Compound () or a pharmaceutically acceptable oxidized salt thereof 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 this specification, lower alkyl and lower alkanoyl represent alkyl having 1 to 4 carbon atoms and alkanoyl having 2 to 4 carbon atoms, respectively.

Hereinafter, the present invention will be further explained in detail with reference to Examples.

Example 1 (1) (±)-cis-2-(4-methylphenyl)-
3-hydroxy-2,3-dihydro-1,5-
Benzothiazepine-4(5H)-one 0.97g, potassium hydroxide 0.23g and dimethyl sulfoxide
Stir 15 ml of the mixture at 50° C. for 30 hours. 2-(N-benzyloxycarbonyl-
A solution of 1.16 g of N-methylamino)ethyl chloride in 5 ml of dimethyl sulfoxide is added, and the mixture is stirred at 50°C for 3 days. After the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract is washed with saturated brine, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography [solvent: chloroform-ethyl acetate (5:1)] to give (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2- (N-
1.18 g of benzyloxycarbonyl-N-methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil. Yield: 73% (2) (±)-cis-2-(4-methylphenyl)-
3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-
1.6 g of 2,3-dihydro-1,5-benzothiazepine-4(5H)-one, 3.5 ml of benzene and 25%
A mixture of 2.9 ml of hydrogen bromide-acetic acid is stirred at room temperature for 2 hours. After the reaction, the reaction solution was diluted with ether, the precipitated crystals were collected by filtration, and recrystallized from ethanol to give (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N -methylamino)ethyl]-2,3-dihydro-1,
956 mg of 5-benzothiazepine-4(5H)-one hydrobromide is obtained as prismatic crystals. Yield: 67% Mp 212-213°C Example 2 (1) (±)-cis-2-(4-methylphenyl)-
3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-
A mixture of 1.2 g of 2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 5 ml of acetic anhydride and 1 drop of pyridine is heated to 100 DEG C. for 2 hours.
After the reaction, acetic acid, acetic anhydride and pyridine were distilled off from the reaction solution, and toluene was added to the residue.
By repeating the operation of distilling off the solvent twice, (±)-cis-2-(4-methylphenyl)-
3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-
1.1 g of 2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil. Yield: 85% (2) (±)-cis-2-(4-methylphenyl)-
3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-
A mixture of 1.1 g of 2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 5 ml of acetic acid and 10 ml of 25% hydrogen bromide-acetic acid is stirred at room temperature for 2 hours. After the reaction, the mixture is concentrated under reduced pressure, toluene is added, and the solvent is distilled off. The precipitated crystals were collected by filtration, washed with ether, and then recrystallized from isopropanol to give (±)-cis-2-
(4-methylphenyl)-3-acetoxy-5-
[2-(N-methylamino)ethyl]-2,3-
Dihydro-1,5-benzothiazepine-4
0.7 g of (5H)-one hydrobromide is obtained as prismatic crystals. Yield: 71% Mp 222-224°C Example 3 (±)-cis-2-(4-methylphenyl)-3
-acetoxy-5-[2-(N-methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrobromide 0.8 g, 5
% sodium hydroxide aqueous solution 10ml and ethanol 5
ml of the mixture is stirred for 1 hour at room temperature. After the reaction,
The reaction solution was diluted with water and extracted with chloroform.
The extract is washed with saturated brine, dried, and the solvent is distilled off. The residue was made into a hydrobromide salt and recrystallized from ethanol to give (±)-cis-2-(4-
methylphenyl)-3-hydroxy-5-[2-
(N-methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5H)-one.
0.58 g of hydrobromide is obtained as prismatic crystals. Yield: 79% Mp 212-213°C Example 4 (±)-cis-2-(4-ethylphenyl)-3
-Hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was treated in the same manner as in Example 1-(1) and (2) to produce (±)-cis-2-( 4-ethylphenyl)-3-hydroxy-5-[2-(N
-methylamino)ethyl]-2,3-dihydro-
1,5-benzothiazepin-4(5H)-one is obtained.

mp207-210℃ (recrystallized from chloroform-ethanol) Example 5 (±)-cis-2-(4-ethylphenyl)-3
-Hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in Example 1-(1),
Example 2 - Treated in the same manner as (1) and (2) to obtain (±)-cis-2-(4-ethylphenyl)-3-acetoxy-5-[2-(N-methylamino)ethyl]-2 ，
3-dihydro-1,5-benzothiazepine-4
(5H)-on is obtained.

mp201-203℃ (decomposition) (recrystallized from chloroform-ethanol) Reference example 2-aminothiophenol and ethyl 3-(4-ethylphenyl)glycidate are heated and stirred to form (±)-cis-2-(4- ethyl phenyl)-3
-Hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained.

m.p.204−206℃

Claims (1)

[Claims] 1. General formula (However, R ¹ represents lower alkyl, R ² represents a hydrogen atom or lower alkanoyl, and R ³ represents lower alkyl.) A 1,5-benzothiazepine derivative or a salt thereof.