KR920003580B1 - Prophylactic and curing composition for arteriosclerosis - Google Patents

Abstract

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Description

Atherosclerosis prevention and treatment

The present invention relates to novel arteriosclerosis prophylactic and therapeutic agents, the use of 8-chlorobenzothiazepine compounds for the preparation of the medicaments and the prophylaxis or treatment of arteriosclerosis. 2-4-methoxyphenyl) -3-alkanoyloxy-5- [2- (dialkylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H ) -One is a known compound and is known to have excellent coercive action and / or brain and vasodilatation action (see Japanese Patent Laid-Open No. 225174/1984).

However, the antiarteriosclerosis action of this compound is not known in the prior art.

nkeberg)형 동맥경화증(중막 경화증)및 세동맥 경화증의 3군으로 나뉜다. 아테롬성 동맥경화증은 관상 동맥, 뇌저 동맥, 신장 동맥, 흉곽 대동맥 및 복부 대동맥 등의 내막에 지방 침착이나 플라크 형성이 일어나는 것이다. 묀케베르그형 동맥경화증은 대퇴 동맥과 같은, 중 정도의 크기를 갖는 사지의 동맥에서 호발하고, 중막의 석회화를 초래한다. 아테롬성 동맥경화증은 신장, 부신, 비장, 난소 또는 췌장 등의 세동맥에서 나타나는 경화성 변화이다.Atherosclerosis is pathologically characterized by atherosclerosis, Schönberg (M).

nkeberg) is divided into three groups: atherosclerosis (media in sclerosis) and arteriosclerosis. Atherosclerosis is the formation of fat deposits or plaques in the lining of the coronary, basal artery, renal artery, thoracic aorta and abdominal aorta. Schonberg type atherosclerosis occurs in arteries of moderately sized limbs, such as the femoral artery, and results in calcification of the media. Atherosclerosis is a sclerotic change that occurs in arterioles such as the kidney, adrenal gland, spleen, ovary or pancreas.

In recent years, studies on such atherosclerosis have been conducted, and it has been considered that unlimited proliferation of mesothelial smooth muscle cells in the vascular lining and abnormal accumulation of cholesterol in the cells contribute to such atherosclerosis. The relationship between (PGI ₂ ) is noted. For example, when a rabbit is raised in a high cholesterol diet, it has been known that the arteriosclerosis progresses and the prostacyclin production ability of the rabbit decreases.

It is also known that prostacyclin production is reduced to less than half of normal sites in arteriosclerosis sites (see Gendai Iryo, Vol. 12, p. 909, 1980).

On the other hand, Hajjar et al. Added the prostacyclin to the rabbit aorta in a culture system for thickening smooth muscle cells, which increased the ACEH (acid cholesteryl ester hydrolase) activity of the cells, thereby preventing the deposition of cholesterol in the cells. Inhibited [Journal of Clinical Investigatin. 70, 479 (1982)]. In addition, it has been reported that the vascular mesothelial smooth muscle cells at the site of the atherosclerosis also lowered the cholesterol content of the cells by adding prostacyclin to the culture system [Lancet, Vol. 2, p. 521 (1983). ) Reference].

In light of this situation, the present invention seeks to provide a novel arteriosclerosis prevention and treatment agent having anti-arteriosclerosis action while enhancing the prostacyclin-producing ability of vascular intima smooth muscle cells.

The present invention relates to an agent for preventing and treating atherosclerosis, wherein the active ingredient is an 8-chloro-1,5-benzothiazepine derivative represented by the following general formula (I) or an acid addition salt thereof.

In the above formula, R ¹ , R ² , R ³ and R ⁴ each represent a lower alkyl group.

The invention also relates to the use of a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof for the preparation of the medicament.

In addition, the present invention provides a method for preventing or treating atherosclerosis.

As compound (I) which becomes an active ingredient of this invention, the compound whose R <^1> , R <^2> , R <^3> and R <^4> are lower alkyl groups, such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group in the said general formula, Included.

Since these compounds have two asymmetric carbons in the molecule, either two stereoisomers (ie, cis- and trans-isomers) or four optical isomers (ie, (+)-cis-isomers, (-)- Cis-isomers, (+)-trans-isomers and (-)-trans-isomers] exist in the present invention, including each of these isomers and mixtures thereof.

In general, however, cis-isomers are suitable as medicaments.

Compound (I), which is an active ingredient of the present invention, significantly increases the prostacyclin producing ability of vascular intima smooth muscle cells, and has an excellent anti-arteriosclerosis effect.

For example, in rat aortic smooth muscle cultured cells, (+)-cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2, When 3-dihydro-1,5-benzothiazepin-4 (5H) -one was added to investigate the prostacyclin production ability of these cells, the compound showed excellent prostacyclin production enhancement activity. Also, (+)-cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] against experimental atherosclerosis in rabbits and Schönberg's atherosclerosis in rats. When examining the effect of -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one, the compound showed an excellent improving effect on any atherosclerosis. Therefore, the medicament according to the present invention can be used for the prevention and treatment of various atherosclerosis, for example, atherosclerosis, Schönberg's atherosclerosis (medium sclerosis) and arteriosclerosis.

Compound (I), which is an active ingredient of the medicament according to the present invention, may be used in the form of a free base or a pharmaceutically acceptable acid addition salt thereof. Such pharmaceutically acceptable acid addition salts include, for example, inorganic acid addition salts or oxalates such as hydrochloride, hydrobromide, hydrochloride, perchlorate, sulfate or phosphate, malate, fumarate, succinate, methanesulfonate Or organic acid addition salts such as 2- (4-hydroxybenzoyl) benzoate.

Compound (I) or a pharmaceutically acceptable acid addition salt thereof may be administered orally or parenterally with excipients suitable for oral or parenteral administration. The pharmaceutical agent of the present invention can be formulated into a suitable formulation using a conventionally used pharmaceutical carrier even when taking oral or parenteral dosage forms. Such pharmaceutical carriers include, for example, binders (syrup, gum arabic, gelatin, sorbitol, tragacanth gum, polyvinylpyrrolidone, etc.), excipients (lactose, sucrose, corn starch, calcium phosphate, sorbitol, Glycine etc.), a lubricating agent (magnesium stearate, talc, polyethylene glycol, silica, etc.), a disintegrating agent (potato starch, etc.) and a humectant (such as sodium lauryl sulfate). As the formulation, tablets, pills, powders, capsules or granules may be used. In the case of parenteral administration, for example, distilled water for injection, physiological saline solution, glucose aqueous solution, or the like may be administered as an injection or drop injection, and glycerin, propylene glycol, simple syrup, ethanol, fatty oil, ethylene glycol or It can be administered as a suspension, a dispersion or an emulsion using sorbitol.

The dosage of Compound (I) or acid addition salts thereof, which is an active ingredient of the present invention, varies slightly depending on the age, weight, type and severity of disease, etc., but is generally about 0.05 to 60 mg / kg / day. About 0.05 to 10 mg / kg / day, in particular 0.5 to 10 mg / kg / day for oral administration and about 0.05 to 2 mg / kg / day for parenteral administration.

Compound (I) which is an active ingredient of the present invention can be produced, for example, by the method described in JP-A-225174 / 1984, which corresponds to US Pat. No. 4,567,175.

The term "lower alkyl group" in this specification and claims should be understood to mean an alkyl group having 1 to 6 carbon atoms.

Hereinafter, the present invention will be described in more detail with reference to experimental examples and examples.

Experimental Example 1

Prostacyclin Production-promoting Effect on Aortic Smooth Muscle Cells

Rat aortic smooth muscle cells (hereinafter referred to as SMC) were monolayered in the growth medium for growth, then the growth medium was removed, and cultured at 37 ° C. for 15 minutes with addition of the measurement medium. The medium was then removed and freshly added measuring medium containing the compound under test was incubated at 37 ° C. in 5% CO ₂ -95% air for 24 hours.

를 방사선 면역 분석법에 의해 측정하며 피시험 화합물의 프로스타사이클린 생성 촉징 작용을 조사하였다.After incubation, stable prostacyclin metabolite 6-KetoPGE _{1 in} supernatant

Was measured by radioimmunoassay and the prostacyclin production stimulating action of the compound under test was investigated.

As the compound under test, (+)-cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1 , 5-benzothiazepin-4 (5H) -one maleate was used.

(Note) The composition of each medium used in the experiment is as follows.

Growth medium for growth: Eagle's minimal basal medium 10% fetal bovine serum

Medium for measurement: Eagle's minimum basal medium + 10 mM N-2-hydroxy ethylpiperazine-N-2-ethanesulfonic acid (pH 7.4)

<Result>

The results are shown in Table 1 below. When the test compound was added, it was found that the prostacyclin production ability was increased about 1.8 times compared to the case where the test compound was not added.

TABLE 1

Experimental Example 2

Effect on Atherosclerosis

Rabbits (males, body weight: about 2.4 kg, group 1: 10 rabbits) were kept on high fat diet (usually with 0.5% cholesterol and 3% soybean oil added).

On the other hand, in order to investigate the effect of the compound under test on atherosclerosis of the aorta caused under such experimental conditions, 30 mg / kg of the compound under test was administered as an aqueous solution at the same time once a day at the same time as the start of high fat diet. Administered. Twelve weeks after the start of the experiment, the rabbits were killed under anesthesia (in combination with ether and pentobarbitol), and the percentage of atheromatous lesions occupied on the intima of the cervical and thoracic aorta (the rate of atherosclerosis) was investigated.

As the compound under test, (+)-cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1 , 5-benzothiazepin-4 (5H) -one maleate was used.

<Result>

The results are shown in Table 2 below. It can be clearly seen that the test compound-administered group has a low rate of atheromatous formation by the non-administered group.

The effect in the compound administered group is that atherosclerotic lesions, that is, deposition of blood cholesterol on the vascular wall, atherosclerosis following preliminary vascularization of the vascular lining, and ulcer formation by continuous destruction of the atherosclerosis of the compound according to the present invention. It is inferred to be inhibited by the effect of enhancing prostacyclin production.

TABLE 2

Example 3

Effect on Möckeberg-type atherosclerosis

Spontaneous hypertensive rats (male, age 12 weeks, group 1: 14-15 rats) were fed high fat diet (usually with 3% cholesterol, 7% hardened cotton oil, 0.5% cholic acid and 0.5% thioucil) Breeding for 7 days, the first 4 days were dissolved vitamin D ₂ 8mg / kg in 2ml / kg of olive oil and administered once daily by the gastric tube at a certain time. To investigate the effect of the compound under test on Finkeberg-type atherosclerosis of the aorta caused under these experimental conditions, the compound under test was administered to the gastrointestinal tract 1 hour after and 7 hours after vitamin D ₂ administration. Administration was continued for one day and administration of only the test compound twice daily was continued for the next three days.

Seven days after the start of the experiment, the mice were killed under ether anesthesia to examine the lesions.

As the compound to be tested, (+)-cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1, 5-benzothiazepin-4 (5H) -one maleate was used.

<Result>

The results are shown in Table 3 below. In the group treated with the compound under test, the incidence of lesions was clearly reduced.

TABLE 3

(In the numbers in the table, the denominator represents the number of weeks used in the experiment, and the molecule represents the number of mice in which lesions were identified).

Example 1

refine

(+)-Cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] 8-chloro-2,3-dihydro-1,5-benzothiazepine -4 (5H)-

Whole maleate 45.0 g

20.1 g of corn starch

Lactose 82.4g

3.0 g of polyvinylpyrrolidone

38.0 g of crystalline cellulose

1.5 g magnesium stearate

Total 190.0 g

The drug, lactose and corn starch were mixed with an alcohol solution of polyvinylpyrrolidone, spun granulated by wet granulation and then dried to form granules.

Subsequently, magnesium stearate and crystalline cellulose were added to the granules, and the mixture was compressed to obtain tablets having a diameter of 8 mm and a weight of 190 mg.

Example 2

[Injection]

(+)-Cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothia 10 g of Zepin-4 (5H) -one maleate was dissolved in 2 liters of distilled water for injection. The solution was filtered using a membrane filter having a pore size of 0.22 탆, injected into each 2 ml ampoule by aseptic operation, and then sealed to prepare an injection.

Claims (4)

An agent for preventing and treating atherosclerosis, comprising 8-chloro-1,5-benzothiazepine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

In the above formula, R ¹ , R ² , R ³ and R ⁴ each represent a lower alkyl group. The compound of claim 1, wherein the (+)-cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro- An agent for preventing and treating atherosclerosis, comprising 1,5-benzothiazepine-4 (5H) -one or a pharmaceutically acceptable salt thereof as an active ingredient. The agent for preventing and treating atherosclerosis, Schönberg's atherosclerosis or arteriosclerosis according to claim 1. The agent for preventing and treating atherosclerosis according to claim 1, in a form for oral administration.