JPH0621071B2 - Platelet aggregation inhibitor - Google Patents

Description

TECHNICAL FIELD The present invention relates to a platelet aggregation inhibitor.

(Prior Art) It is said that the main cause of thrombus formation is the interaction between blood components, especially platelets, blood coagulation factors, etc., and the blood vessel wall. In order to suppress thrombus formation, conventional aspirin etc. suppresses platelet aggregation. It has been used as an agent.

(Object, Structure and Effect of the Invention) The present invention relates to a platelet aggregation inhibitor comprising a novel 1,5-benzothiazepine derivative represented by the following general formula or a pharmacologically acceptable acid addition salt thereof as an active ingredient.

(However, R ¹ is a lower alkyl group or a lower alkoxy group, R ²
Represents a hydrogen atom or a lower alkanoyl group, R ³ represents a lower alkyl group, and R ⁴ represents a lower alkyl group or a lower alkoxy group. The compound (I) or a pharmaceutically acceptable acid addition salt thereof which is an active ingredient of the present invention has an excellent inhibitory effect on platelet aggregation, and therefore a platelet aggregation inhibitor comprising the compound as an active ingredient is a cerebral infarction. , Cerebral thrombosis, transient cerebral ischemia, myocardial infarction, coronary artery thrombosis, pulmonary artery thrombosis, thrombosis such as thromboangiitis, and treatment, alleviation and prevention of diseases such as embolism.

Furthermore, the compound (I), which is the active ingredient of the present invention, has low toxicity, and for example, (±) -cis-2- (4-methylphenyl) -3-hydroxy-5- [2- (N-methylamino) Ethyl] -8-methyl-2,3-dihydro-1,5
The maximum tolerated dose of benzothiazepine-4 (5H) -one.hydrochloride (rat, ip administration) was 300 mg / kg.

The compound (I), which is the active ingredient of the present invention, can be used as a free base or a pharmaceutically acceptable acid addition salt thereof. Examples of the pharmaceutically acceptable acid addition salt include, for example, hydrochloride, hydrobromide, hydroiodide,
Inorganic acid addition salts such as sulfates and phosphates; organic acid addition salts such as oxalates, fumarates, 2- (4-hydroxybenzoyl) benzoates, succinates and methanesulfonates To be These salts can be easily obtained, for example, by treating the compound (I) with an acid.

A platelet aggregation inhibitor containing compound (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient can be administered orally or parenterally, and is suitable for oral or parenteral administration. It can also be used as a pharmaceutical preparation mixed with a excipient. As such an excipient, for example, den powder, lactose, glucose, potassium phosphate, corn starch, gum arabic, stearic acid, and other usual pharmaceutical excipients can be preferably used. The pharmaceutical preparation may be solid preparations such as tablets, capsules, microcapsules and suppositories, and liquid preparations such as solutions and emulsions. Furthermore, when administered parenterally, this pharmaceutical preparation can be used as an injection.

The dose of the platelet aggregation inhibitor of the present invention depends on the administration method; age, body weight, condition of the patient, and type of disease, but the compound (I) as its active ingredient or a pharmacologically acceptable acid addition thereof. The dose of salt is usually about 0.05 to 50 mg per day
/ Kg, especially about 0.5 to 50 mg / kg for oral administration, about 0.05 to 10 for parenteral administration (eg, intravenous injection)
It is preferably used in the range of mg / kg.

As the compound which is the active ingredient of the present invention, in the general formula (I), R ¹ is a lower alkyl group having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, butyl group, methoxy group, ethoxy group, A lower alkoxy group having 1 to 4 carbon atoms such as a propoxy group and a butoxy group, R ² is a hydrogen atom or an acetyl group, a propionyl group, a butyryl group, an isobutyryl group,
A lower alkanoyl group having 2 to 5 carbon atoms such as a valeryl group;
R ³ is a lower alkyl group having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group and butyl group, R ⁴ is a lower alkyl group having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group and butyl group Examples of the group include a lower alkoxy group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group.

The compound (I), which is the active ingredient of the present invention, has two asymmetric carbon atoms at the 2- and 3-positions of the 1,5-benzothiazepine skeleton, and therefore has two stereoisomers (ie, cis and trans). Isomer) or four optical isomers [that is, (+)-
Cis, (−)-cis, (+)-trans and (−)-trans isomers, but in the present invention, all of these isomers and mixtures thereof are used as the active ingredient of the platelet aggregation inhibitor. be able to. However,
Of these compounds, it is preferable to use the cis isomer, especially the (−)-cis isomer, as an active ingredient.

The compound (I), which is the active ingredient of the present invention, can be prepared, for example, by the general formula (Provided that R ¹ and R ⁴ have the same meanings as described above) and the general formula (Wherein Q represents a protecting group, X represents a halogen atom, and R ³ has the same meaning as described above). (However, R ¹ , R ³ , R ⁴ and Q have the same meanings as described above), and if necessary, lower alkanoyl the 3-position hydroxyl group of the compound, It can be produced by subjecting it to a removal reaction.

Starting compound (II) or its salt (for example, sodium salt)
The condensation reaction of the aminoethyl halide compound (III) or a salt thereof (for example, hydrochloride) can be carried out in a suitable solvent in the presence of an alkaline reagent (for example, potassium hydroxide). The lower alkanoylation reaction of the 3-position hydroxyl group of the product (IV) or a salt thereof (for example, hydrochloride) can be carried out by using the compound (IV) and a reactive derivative of lower saturated fatty acid (for example, acid anhydride), if necessary. It can be carried out by reacting in a suitable solvent. Protecting group Q from the intermediate product (eg, benzyloxycarbonyl group, tert.-
The butoxycarbonyl group, benzyl group) can be removed by a method known per se.

Since all of the above reactions proceed without racemization, if the optically active substance is used as the starting compound, the desired product can be obtained as the optically active substance.

In the present specification, "threo" means that the hydroxyl groups substituted at the 2- and 3-positions of propionic acid and the substituted phenylthio group have a threo configuration (that is, in the Fisher projection view, the 2 substituents are the main chains). Located on the opposite side of.

Experimental Example 1 (Inhibitory action of rat and human platelet aggregation in vitro) 9% of blood collected from rat or human was 3.8% (W /
V) The mixture was mixed with 1 volume of trisodium citrate aqueous solution, and the mixture was centrifuged to prepare platelet-suspended plasma (PRP). The remaining blood is further centrifuged to remove platelet-free plasma (P
PP) was prepared. Rat PRP platelet count is PPP
Was diluted to 0.8 to 1 × 10 ⁶ / mm ³ , while the platelet count of human PRP was diluted to 4 × 10 ⁵ / mm ³ by adding PPP. A mixture of 200 μL of diluted PRP and 25 μL of a sample solution was stirred at 37 ° C. for 2 minutes, and then a collagen solution [Biokimica E. biophysica Acta. , Volume 186, Second
54 (1969)] 25 μm was added to cause platelet aggregation. The platelet aggregation ability was measured by the method of Bourne [Nature, Vol. 194, p. 927 (1962)], and the platelet aggregation inhibitory action of the specimen was determined. The inhibitory action on platelet aggregation of the test compound was represented by IC ₅₀ (concentration required to inhibit 50% of platelet aggregation induced by collagen). The results are shown in Tables 1 and 2 below.

Experimental Example 2 (In vivo inhibition of rat platelet aggregation) SD male rats that have been fasted for about 20 hours are orally administered with an aqueous sample solution (sample dose: 10 mg / kg), and blood is collected from the abdominal aorta 3 hours later. 9% of this blood and 3.8% (W / V)
Platelet suspended plasma (PRP) is obtained by mixing 1 volume of trisodium citrate aqueous solution and centrifuging the mixture.
Was prepared. The residual blood was further centrifuged to prepare platelet-depleted plasma (PPP). The platelet count of PRP was diluted to 0.8 to 1 × 10 ⁶ / mm ³ by adding PPP. Diluted PRP2
25 μ of collagen solution (prepared by the method described in Experimental Example 1) was added to 25 μ to cause platelet aggregation. The platelet aggregation ability was measured by the method of Bourne, and the inhibitory effect on platelet aggregation of the sample was determined. The compounds shown in Table 3 below all had a platelet aggregation inhibitory rate of 50% or more.

Production Example 1 (1) (±) -cis-2- (4-methoxyphenyl) -3
-Hydroxy-8-methyl-2,3-dihydro-1,5
-Benzothiazepin-4 (5H) -one 2g, powdered potassium hydroxide 0.42g and dimethylsulfoxide 15ml.
The mixture of is stirred at 50 ° C. for 30 minutes. After the reaction, a solution of 2.64 g of 2- (N-benzyloxycarbonyl-N-methylamino) ethyl chloride in 5 ml of dimethyl sulfoxide was added to the mixture, and the mixture was stirred at 50 ° C. for 3 days. The mixture is poured into ice water and extracted with ethyl acetate. The extract is washed with saturated brine, dried and the solvent is evaporated under reduced pressure. By purifying the residue by 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) A mixture of 2.49 g of the product of (1) above, 15 ml of acetic anhydride and 5 ml of pyridine is stirred at 100 ° C. for 2 hours. After cooling, acetic anhydride and pyridine are distilled off under reduced pressure from the mixture. Toluene was further added to the residue and the solvent was distilled off under reduced pressure twice to obtain (±) -cis-
2- (4-methoxyphenyl) -3-acetoxy-5-
[2- (N-benzyloxycarbonyl-N-methylamino) ethyl] -8-methyl-2,3-dihydro-1,
3.08 g of 5-benzothiazepin-4 (5H) -one is obtained as an oil.

(3) 3.08 g of the product of (2) above, 10 ml of acetic acid and 2
A mixture of 5% 5% hydrogen bromide-acetic acid is stirred for 2 hours at room temperature. After the reaction, the solvent is distilled off under reduced pressure from the mixture. Ether is added to the residue, and the precipitated crystals are collected by filtration and washed with ether. The crystals (hydrobromide salt) were converted to the free base, further to the hydrochloride, and then recrystallized from ethanol to give
(±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (N-methylamino) ethyl]-
8-Methyl-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one ・ hydrochloride ・ hemihydrate ・ 1 /
1.2 g of 2 ethanol are obtained.

Mp 154 to 156 ° C. Production Examples 2 to 18 Corresponding raw material compounds were produced in Production Example 1 [the same Production Examples (1) and (3)].
Alternatively, the following compound is obtained by treating in the same manner as in Production Examples (1), (2) and (3)].

Reference Example 1 (1) 2-Amino-5-methyl-thiophenol 29.1
g, (±) -trans-3- (4-methoxylphenyl) glycidic acid methyl ester (47.8 g) and toluene (300 ml) at 60-65 ° C. for 3 days, then 7
Heat to 0-80 ° C for 2 days. 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 is diluted 1: 1 with water). Neutralize the extract with potassium carbonate and extract with benzene. The extract was washed with water and dried, benzene was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography [solvent: benzene-ethyl acetate (10: 1)].
And then recrystallized from a mixture of ethanol and isopropyl ether to give (±) -threo-2-hydroxy-3- (2-amino-5-methylphenylthio).
15.8 g of -3- (4-methoxyphenyl) propionic acid methyl ester are obtained.

Mp 110 to 112 ° C. (2) A mixture of 5 g of the product of (1) above, 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 is adjusted to pH 3-5 with 10% hydrochloric acid under ice cooling. The precipitated crystals were collected by filtration, washed with water, dried, and recrystallized from methanol to give (±) -threo-
4.3 g of 2-hydroxy-3- (2-amino-5-methylphenylthio) -3- (4-methoxyphenyl) propionic acid are obtained.

Mp 190 to 193 ° C. (3) 45.3 g of Lp-hydroxyphenylglycine methyl ester / hydrochloride is dissolved in 1000 ml of methanol. A solution of 11.7 g of potassium hydroxide in 100 ml of methanol was added to the solution under ice cooling to precipitate (potassium chloride).
Remove it. 37.8 g of the product of (2) above is added to the filtrate. The mixture is warmed to 50 ° C. and 900 ml of methanol are added to form a solution. The solvent was distilled off under reduced pressure from the solution at 50 ° C. or lower, 200 ml of ethanol was added to the residue, and the mixture was refrigerated overnight. Precipitated crystals were collected by filtration (the filtrate was referred to as mother liquor I), recrystallized from ethanol (mother liquor was referred to as mother liquor II), and the crude product was recrystallized from ethanol to give (+)
-Threo-2-hydroxy-3- (2-amino-5-methylphenylthio) -3- (4-methoxyphenyl) propionic acid / Lp-hydroxyphenylglycine methyl ester salt [Mp164-167 ° C, ▲ [ α] ²⁰ _D ▼ + 255.8 ° (C = 0.66, methanol)] 20.7 g is obtained.

15.3 g of the salt obtained above is suspended in a mixed solution of 240 ml of methanol and 200 ml of water, 27 ml of a cation exchange resin is added and the mixture is stirred overnight at room temperature, then the resin is filtered off and washed with methanol. The filtrate and washings are combined and the solvent is distilled off under reduced pressure. Water was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give (+)-threo-2-hydroxy-3- (2-amino-5-methylphenylthio).
7 g of -3- (4-methoxyphenyl) propionic acid are obtained.

Mp 158 to 160 ° C ▲ [α] ²⁰ _D ▼ + 296.0 ° (C = 0.29, methanol) (4) A mixture of 9 g of the product of the above (3) and 350 ml of xylene is refluxed for 24 hours while removing water. To do.
After the reaction, xylene was distilled off from the mixture under reduced pressure, and the residue was recrystallized from ethyl acetate to give (+)-cis-2.
-(4-Methoxyphenyl) -3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepine-
7.8 g of 4 (5H) -one are obtained.

Mp 223 to 226 ° C. (decomposition) ▲ [α] ²⁰ _D ▼ 123.8 ° (C = 0.71, dimethylformamide) Reference Examples 2 to 10 Corresponding raw material compounds were prepared according to the following reaction formulas in Reference Example 1 [the same Reference Example. (1), (2), (3) and (4) or the same reference examples (1), (2) and (4)] are treated to obtain the following compound.

(However, R ¹ and R ⁴ have the same meaning as described above.)

Continuation of the front page (56) References JP-A-56-156217 (JP, A) Chemical Abstracts, vol. 99, no. 7, abstra ct no. 47687p

Claims (1)

[Claims] 1. A general formula (However, R ¹ is a lower alkyl group or a lower alkoxy group, R ²
Represents a hydrogen atom or a lower alkanoyl group, R ³ represents a lower alkyl group, and R ⁴ represents a lower alkyl group or a lower alkoxy group. ] A platelet aggregation inhibitor comprising a 1,5-benzothiazepine derivative or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.