Pharmaceutical composition for inhibiting platelet aggregation

Abstract: There is disclosed a pharmaceutical composition for inhibiting platelet aggregation comprising 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof and a 1,5-benzothiazepine derivative of the formula: wherein R¹ is a lower alkyl group or a lower alkoxy group, R² is a lower alkanoyl group, R³ and R⁴ are a lower alkyl group and R⁵ is hydrogen atom, a lower alkyl group or a halogen atom, or a pharmaceutically acceptable salt thereof.

Description: This invention relates to a pharmaceutical composition for inhibiting platelet aggregation. It is known that 1,5-benzothiazepine derivatives such as (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine -4(5H)-one (Diltiazem) and the corresponding 8-chloro-compound (Clentiazem) have an antihypertensive, coronary vasodilating and/or platelet aggregation-inhibiting activities (U.S. Patent Nos.3 562 257, 4 567 175 and 4 590 188). It is also known that 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno [3,2-c]pyridine (Ticlopidine) is useful as the platelet aggregation inhibitor [(THE MERCK INDEX, TENTH EDITION, 1351 pages, 9272(1983)]. EP-A-0 255 141 discloses a pharmaceutical composition for enhancing the antithrombotic effect of acetyl salicylic acid by the use therewith of diltiazem or a pharmaceutically acceptable acid addition salt. Further, Recenti Progressi in Medicina Vol.80(1) p.28-32, 1989 describes oral anticoagulants and antiplatelet agents in the prevention of metastases; ticlopidine was found to be effective, and also diltiazem was tested. As a result of the various investigations, the inventors of the present invention have found that inhibitory effects on the platelet aggregation is enhanced in a synergistic manner by means of combined use of ticlopidine and the following 1,5-benzothiazepine derivatives, compared with either agent alone. Thus, according to the present invention, there is provided a pharmaceutical composition for inhibiting platelet aggregation which comprises ticlopidine or a pharmaceutically acceptable salt thereof and a 1,5-benzothiazepine derivative of the formula: wherein R¹ is an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, R² is an alkanoyl group having 2 to 5 carbon atoms, R³ and R⁴ are an alkyl group having 1 to 4 carbon atoms and R⁵ is an alkyl group having 1 to 4 carbon atoms or a halogen atom such as chlorine, bromine and fluorine. According to the present invention there is also provided the use of a pharmaceutical composition comprising ticlopidine and a 1,5-benzothiazepine derivative of formula (I) with the with the additional possible substitution on R⁵ having a hydrogen atom in the preparation of a pharmaceutical formulation for the inhibition of platelet aggregation. Preferred compounds (I) are those wherein R¹ is methyl or methoxy, R² is acetyl, R³ and R⁴ are methyl, and R⁵ is hydrogen atom, methyl or chlorine. Since the 1,5-benzothiazepine derivatives (I) of the present invention has two asymmetric carbon atoms at 2-position and 3-position of benzothiazepine ring, there exist two kinds of stereoisomers [ namely, cis-and trans-isomers ] and four kinds of optical isomers [ namely, (+)-cis-, (-)-cis-, (+)-trans- and (-)-trans-isomers ]. The present invention is inclusive of either of these isomers and their mixtures. Among them, preferred isomers are (-)-cis-isomer of the compounds of the formula (I). The ticlopidine and 1,5-benzothiazepine derivatives (I) of the present invention can be used for medical use of either in free form or in the form of pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of ticlopidine and compound (I) include, for example, inorganic acid addition salt such as hydrochloride, hydrobromide, sulfate and phosphate, and organic acid addition salt such as oxalate, acetate, maleate, fumarate, tartrate and methanesulfonate. A preferred weight ratio of ticlopidine or a pharmaceutically acceptable salt thereof to the 1,5-benzothiazepine derivative (I) or a pharmaceutically acceptable salt thereof is 0.1 - 40 : 1, especially 0.3 - 10 : 1. A preferred daily dose of ticlopidine or a pharmaceutically acceptable salt thereof is 20 to 200 mg, especially 30 to 100 mg, and that of the 1,5-benzothiazepine derivatives (I) or a pharmaceutically acceptable salt thereof is 5 to 200 mg, especially 10 to 100 mg, within the range of above-mentioned ratio. Although the composition of the present invention can be used by way of either oral administration or parenteral administration, oral administration is preferred. In the case of oral administration, the composition of the present invention can be used as a pharmaceutical preparation together with a pharmaceutical carrier suitable for oral administration. The pharmaceutical carriers include, for example, conventional excipients, binders, disintegrators and lubricants (e.g., starch, lactose, glucose, gelatin, sorbitol, tragacanth gum, polyvinylpyrrolidone, sugar, corn starch, polyethylene glycol, talc, potassium phosphate and magnesium stearate). Further, the dosage form may be a solid preparation such as tablets, pills, capsules and suppositories or it may also be a liquid preparation such as solutions, suspensions and emulsions. On the other hand, in the case of parenteral administration, the composition of the present invention may be preferably used as an injection, and as the pharmaceutical carrier for this purpose, for example, distilled water for injection, vegetable oil, propylene glycol, etc., can be suitably used. If required, a dissolving agent, a buffering agent and/or a stabilizing agent may be also employed. As described above, the pharmaceutical composition of the present invention has excellent inhibitory effects on the platelet aggregation, and therefore it can be effectively used for treatment of coronary or cerebrovascular thrombosis, peripheral vascular disease, platelet aggregation disorders and migraine. Furthermore, the pharmaceutical composition of the present invention shows a stronger platelet aggregation-inhibiting activity as compared with single use of each component and exerts an excellent synergistic effect. Namely, the dose of each component can be reduced by means of the combined use of the components in order to obtain an effect equivalent to that obtained by single use. Therefore, the pharmaceutical preparation of the present invention is high in safety and exerts a good effect. EXPERIMENTAL EXAMPLE Inhibitory effect on platelet aggregation (Method) Nine volumes of human blood were mixed with one volume of an aqueous 3.8 % trisodium citrate solution, and the mixture was centrifuged to give platelet-rich plasma (hereinafter referred to as "PRP") as the supernatant solution. The bottom layer was further centrifuged to give platelet-poor plasma (hereinafter referred to as "PPP") as the supernatant solution. PRP was diluted with PPP so that the blood platelet counts were 4X10⁵ / mm³. Then, 175 µl of said diluted PRP were added to a mixture of 25 µl of a solution of the following test compound (A), (B) or (C) and 25 µl of a solution of ticlopidine (D). After the mixture was stirred for 2 minutes at 37 °C, 25 µl of a collagen solution [ Horm®, HORMON-CHEMIE ] was added thereto, and the degree of platelet aggregation was measured by the method of Born [ Nature, 194, page 927 (1962) ]. In the control group, a mixture of 175 µl of diluted PRP, 25 µl of a solution of the test compound (A), (B), (C) or (D) and 25 µl of a physiological saline solution was tested. Further, as a non-medicated control group, a mixture of 175 µl of said diluted PRP and 50 µl of a physiological saline solution was used. Inhibitory effect on platelet aggregation is represented by the relative proportion of platelet aggregation of test compound(s) to that non-medicated control. It is calculated from the following formula. Inhibitory effect on platelet aggregation (%) = Platelet aggregation (%) of non-medicated control - Platelet aggregation (%) of test compound(s) Platelet aggregation (%) of non-medicated control X 100 (Test compounds) (A) (-)-cis-2-(4-methylphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one maleate (R¹, R³, R⁴ and R⁵ = methyl, R² = acetyl. ) (B) (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one maleate (R¹= methoxy, R² = acetyl, R³ and R⁴ = methyl, R⁵ = chlorine. ) (C) (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride (R¹ = methoxy, R² = acetyl, R³ and R⁴ = methyl, R⁵ = hydrogen atom. ) (D) Ticlopidine hydrochloride 〈i.e. 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride〉 (Result) The results are shown in the following TABLE 1

Claims: A pharmaceutical composition for inhibiting platelet aggregation, which comprises 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof and a 1,5-benzothiazepine derivative of the formula: wherein R¹ is an alkyl group having one to four carbon atoms or an alkoxy group having one to four carbon atoms, R² is an alkanoyl group having two to five carbon atoms, R³ and R⁴ are an alkyl group having one to four carbon atoms and R⁵ is an alkyl group having one to four carbon atoms or a halogen atom, or a pharmaceutically acceptable salt thereof. The composition according to claim 1, wherein R¹ is methyl group or methoxy group, R² is acetyl group, R³ and R⁴ are methyl group and R⁵ is methyl group or chlorine atom. The composition according to claim 1, wherein R¹ is methyl group, R² is acetyl group, R³ and R⁴ are methyl group and R⁵ is methyl group. The composition according to claim 1, wherein R¹ is methoxy group, R² is acetyl group, R³ and R⁴ are methyl group and R⁵ is chlorine atom. The composition according to claim 3, wherein said 1,5-benzothiazepine derivative is a (-)-cis-isomer. The composition according to claim 4, wherein said 1,5-benzothiazepine derivative is a (+)-cis-isomer. The composition according to any one of the preceding claims, wherein the weight ratio of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof to the 1,5-benzothiazepine derivative (I) or a pharmaceutically acceptable salt thereof is 0.1 - 40 : 1. The composition according to claim 7, wherein the weight ratio of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof to the 1,5-benzothiazepine derivative (I) or a pharmaceutically acceptable salt thereof is 0.3 - 10 : 1. The composition as claimed in any one of the preceding claims, wherein the composition comprises a pharmaceutical carrier and is suitable for oral or parenteral administration. A use of a pharmaceutical composition, which comprises 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof and a 1,5-benzothiazepine derivative of the formula: wherein R¹ is an alkyl group having one to four carbon atoms or an alkoxy group having one to four carbon atoms, R² is an alkanoyl group having two to five carbon atoms, R³ and R⁴ are an alkyl group having one to four carbon atoms and R⁵ is hydrogen atom, an alkyl group having one to four carbon atoms or a halogen atom, or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical formulation for the inhibition of platelet aggregation. The use according to claim 10, wherein R¹ is methyl group or methoxy group, R² is acetyl group, R³ and R⁴ are methyl group and R⁵ is hydrogen atom, methyl group or chlorine atom. The use according to claim 10, wherein R¹ is methyl group, R² is acetyl group, R³ and R⁴ are methyl group and R⁵ is methyl group. The use according to claim 10, wherein R¹ is methoxy group, R² is acetyl group, R³ and R⁴ are methyl group and R⁵ is hydrogen atom or chlorine atom. The use according to claim 12, wherein said 1,5-benzothiazepine derivative is a (-)-cis-isomer. The use according to claim 13, wherein said 1,5-benzothiazepine derivative is a (+)-cis-isomer. The use according to claim 10, wherein the weight ratio of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable sat thereof to the 1,5-benzothiazepine derivative (I) or a pharmaceutically acceptable salt thereof is 0.1 - 40 : 1. The use according to claim 10, wherein the weight ratio of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof to the 1,5-benzothiazepine derivative (I) or a pharmaceutically acceptable salt thereof is 0.3 - 10 : 1. The use according to claim 10, wherein the daily dose of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof is 20 to 200 mg and the daily dose of the 1,5-benzothiazepine derivative (I) or a pharmaceutically acceptable salt thereof is 5 to 200 mg.

Inventors: MURATA SAKAE, NARITA HIROSHI, ODAWARA AKIO, SASAKI YASUHIKO, MURATA, SAKAE, NARITA, HIROSHI, ODAWARA, AKIO, SASAKI, YASUHIKO
Applicants: TANABE SEIYAKU CO, TANABE SEIYAKU CO., LTD.
Application year: 1993
Main classification: A61K31
IPC codes: A61K31, A61P7, C07D281