JPS6317045B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a platelet aggregation inhibitor, and more specifically to a platelet aggregation inhibitor of the general formula (However, R ¹ and R ² represent that R ¹ is a methyl group and R ² is a hydrogen atom or a methyl group, or R ¹ is a hydrogen atom and R ² is a methyl group.) The present invention relates to a platelet aggregation inhibitor containing a thiazepine derivative or a pharmacologically acceptable acid addition salt thereof as an active ingredient. It is said that the interaction between the blood vessel wall and blood components, particularly platelets and plasma coagulation factors, plays a central role in thrombus formation in thrombosis. In other words, when the blood vessel wall suffers some sort of damage, platelets in the bloodstream come into contact with the exposed subendothelial tissue of the blood vessel, and at this time, the platelets adhere to the subendothelial layer of the blood vessel, especially collagen, and release substances that promote platelet aggregation into the cells. The action of this substance causes platelets in the bloodstream to aggregate and form a platelet clot at the injured site of the blood vessel wall.Furthermore, this platelet clot is stabilized by the action of fibrin, forming a thrombus. It is said that it will develop into Substances that inhibit the above-mentioned processes are platelet aggregation inhibitors, which have recently attracted attention as antithrombotic agents. The present inventors have conducted various studies under such circumstances and have found that the benzothiazepine derivative represented by the above general formula [] has an excellent platelet aggregation inhibiting effect and is useful as an antithrombotic agent. ,
The present invention has now been completed. Specific examples of the benzothiazepine derivatives [] of the present invention include 2-(4-methoxyphenyl)-3
-Hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 2-(4-methoxyphenyl)-3-hydroxy- 5-[2-(methylamino)ethyl]-2,3-dihydro-1,5-
Benzothiazepine-4(5H)-one, 2-(4-
methoxyphenyl)-3-hydroxy-5-[2
-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5H)-one, 2-(4-hydroxyphenyl)-3-hydroxy-5-[2-(dimethyl amino) ethyl]
Examples include -2,3-dihydro-1,5-benzothiazepine-4(5H)-one. Although the above-mentioned compound of the present invention is known [Chemical & Pharmaceutical Bulletin, 19 , 1546 (1971)], its platelet aggregation inhibiting action is not known at all. All of the compounds [ ] of the present invention exhibit excellent platelet aggregation inhibiting activity. For example, when the inhibitory effect of the specimen on human platelet collagen-induced aggregation was investigated, the compound of the present invention [] exhibited a platelet aggregation inhibition rate of 64 to 78% at a concentration of 50 μg/ml. By the way, aspirin (chemical name: acetylsalicylic acid), which is known to have a similar effect, has a 100μ
It showed only 60% platelet aggregation inhibition rate at a concentration of g/ml. Moreover, the compound [ ] of the present invention has low toxicity. For example, 2-(4-methoxyphenyl)
-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5H)-one [dl-cis form] and 2-(4-hydroxy phenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]
The maximum tolerated dose (mouse, ip administration) of -2,3-dihydro-1,5-benzothiazepine-4(5H)-one [dl-cis form] was 300 mg/Kg. The compound [] of the present invention has an excellent platelet aggregation inhibiting effect as described above, and is therefore useful as an antithrombotic agent, such as peripheral arterial thrombosis, pulmonary embolism, coronary artery occlusion, myocardial infarction, cerebral infarction, It is useful for the prevention and treatment of various thromboses such as transient cerebral ischemia. When the compound of the present invention [ ] is used as a medicine, it can be used either as a free base or as a pharmacologically acceptable acid addition salt thereof. Acid addition salts include, for example, inorganic acid salts such as hydrochloride, sulfate, hydrobromide, phosphate, or oxalate, tartrate, fumarate, maleate, methanesulfonate, citrate. Examples include organic acid salts such as acid salts. The compound of the present invention [ ] can be administered orally or parenterally, and can also be used in combination with a suitable pharmaceutical carrier. As a pharmaceutical carrier,
For example, sugars such as lactose and mannitrate, starches, crystalline cellulose, calcium citrate, secondary
Examples include calcium phosphate, gelatin, dextrin, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, stearic acid and its magnesium salt or calcium salt, talc, and the like. In addition, the dosage forms include tablets,
It may be a solid agent such as a powder or a capsule,
It may also be a liquid preparation such as a solution or suspension.
Furthermore, when administered parenterally, it can also be used as an injection. Dose of the compound of the present invention [ ] Although it varies depending on the administration route, type of disease, patient's age, weight, severity of symptoms, etc., it is usually 0.5 to 50 mg/Kg per day for oral administration, especially 1-20 mg/Kg, for intravenous administration 0.1-10 mg/Kg, especially 0.5-5
mg/Kg is preferred. The compound of the present invention [] is published in Chemical and Pharmaceutical Bulletin, 19 , 595.
(1971) and 26 , 2889 (1978). In addition, since the compound of the present invention [ ] has two asymmetric carbon atoms,
There are two types of stereoisomers (cis form, trans form), and each stereoisomer has two types of optically active forms (d
(1-isomer, l-isomer) exist, and any of these can be used in the present invention. By the way,
The physical constants of the compound [] (dl-cis form) are as follows. (1) Compound A [R ¹ = CH ₃ , R ² = CH ₃ ] Free base: Mp101 to 103°C (reconsolidated from isopropyl ether) IRνnudiol max (cm ^-1 ): 3460, 1660, 1605,
1580 NMR (CDCl ₃ ) δ: 2.26 (6H, s), 3.79 (3H, s), 4.26
(1H, d, J=7Hz), 4.89 (1H, d,
J=7Hz), 6.79-7.77 (8H, m) Mass m/e: 372 (M ⁺ ) Hydrochloride: Mp220-221.5℃ (decomposition) (reconsolidation from ethanol) (2) Compound B [R ¹ = CH ₃ , R ² = H) Free base: Mp124-125℃ (decomposition) (reconsolidation from isopropyl ether) IRν Nudiol max (cm ^-1 ): 3300, 1665, 1605,
1575 NMR (CDCl ₃ ) δ: 2.40 (3H, s), 3.80 (3H, s), 4.29
(1H, d, J=7Hz), 4.90 (1H, d,
J=7Hz), 6.79-7.79 (8H, m) Mass m/e: 358 (M ⁺ ) Hydrochloride: Mp208-209℃ (decomposition) (reconsolidation from ethanol) (3) Compound C [R ¹ = H , R ² = CH ₃ ] Free base: Mp135-138℃ (decomposed) (reconsolidated from ethanol) IRν Nudiol max (cm ^-1 ): 3400, 1665, 1615,
1595, 1580 NMR (CDCl ₃ ) δ: 2.31 (6H, s), 4.29 (1H, d, J = 7
Hz), 4.88 (1H, d, J = 7Hz), 6.65~
7.75 (8H, m) Mass m/e: 358 (M ⁺ ) Hydrochloride: Mp235-237℃ (decomposition) (reconsolidation from ethanol) Experimental example 1 (Experimental method) Forearm of a healthy adult male (28-38 years old) SD male rats (body weight 250
Blood was collected from the abdominal aorta of ~300g), 9 volumes of the blood was mixed with 1 volume of 3.8% trisodium citrate aqueous solution, and platelet-suspended plasma (PRP) was prepared by centrifugation (250 x g, 5 minutes). did. The remaining blood was further centrifuged (500×g, 10 minutes) to prepare platelet-free plasma (PPP). The platelet count of PRP is 3-4x for humans when diluted with PPP.
The density was adjusted to 10 ⁵ /mm ³ , and in the case of rats to 8 to 10×10 ⁵ /mm ³ . PRP 200μ prepared above and sample solution 25μ were placed in the cell of an agglutinometer (Cienco, DP-247E model).
After stirring for 2 minutes, apply the method from Holmsen [Biochimica e Biofijica Acta,
186, 254 (1969)] was added to induce platelet aggregation. The aggregation ability was measured at 37° C. and 1100 rpm according to the Born method [Nature, 194 , 927 (1962)], and the platelet aggregation inhibition rate was calculated using the following formula. Inhibition rate = [1-Agglutination rate when sample is added/Aggregation rate when sample is not added] x 100 (sample) A: 2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino) ) Ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5H)-one (dl-cis form) B:2-(4-methoxyphenyl)-3-hydroxy-5-[2 -(Methylamino)ethyl]
-2,3-dihydro-1,5-benzothiazepine-4(5H)-one (dl-cis form) C:2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethyl Amino)ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5H)-one (dl-cis form) ASA: Acetylsalicylic acid (Results) The results are as shown in Tables 1 to 3 below. [Table] [Table] [Table] Example 1 (Tablet) 2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-
2,3-dihydro-1,5-benzothiazepine
A mixture of 50 g of 4(5H)-one (dl-cis form), 90 g of lactose, and 33.5 g of corn starch was made into granules using 5 g of hydroxypropyl cellulose as a binder, then 1.5 g of magnesium stearate was added, and the mixture was made into granules with a diameter of 8 mm using a tablet machine. Example 2 (Powder) 2-(4-methoxyphenyl)-3-hydroxy-5-[2-(methylamino)ethyl]-2,
3-dihydro-1,5-benzothiazepine-4
After thoroughly mixing 100 g of (5H)-one (dl-cis form) and 900 g of corn starch, it was sieved through a 42-mesh sieve (350 μm opening) to form a powder (10%
(dispersed). Example 3 (Injection) 2-(4-hydroxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5 to about 8 g of distilled water for injection
-Benzothiazepine-4(5H)-one hydrochloride (dl
- Add 500 g of cis form and 400 g of D-sorbitol, stir and dissolve, then dilute the total amount with distilled water for injection to 10 g.
shall be. This solution is filtered through a membrane filter with a pore size of 0.22 μm, dispensed into 2 ml ampoules, sealed, and sterilized by heat in the usual manner to obtain an injection.

Claims (1)

[Claims] 1. General formula (However, R ¹ and R ² represent that R ¹ is a methyl group and R ² is a hydrogen atom or a methyl group, or R ¹ is a hydrogen atom and R ² is a methyl group.) A platelet aggregation inhibitor containing an azepine derivative or a pharmacologically acceptable acid addition salt thereof as an active ingredient. 2 2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-
2,3-dihydro-1,5-benzothiazepine
The platelet aggregation inhibitor according to claim 1, which contains 4(5H)-one or a pharmacologically acceptable acid addition salt thereof as an active ingredient. 3 2-(4-methoxyphenyl)-3-hydroxy-5-[2-(methylamino)ethyl]-
2,3-dihydro-1,5-benzothiazepine
The platelet aggregation inhibitor according to claim 1, which contains 4(5H)-one or a pharmacologically acceptable acid addition salt thereof as an active ingredient. 4 2-(4-hydroxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]
The platelet aggregation inhibitor according to claim 1, which contains -2,3-dihydro-1,5-benzothiazepine-4(5H)-one or a pharmacologically acceptable acid addition salt thereof as an active ingredient. .