JP2658783B2 - Anti-atherosclerotic agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an anti-atherosclerotic agent.

[0002]

2. Description of the Related Art Cis-2- (4-lower alkylphenyl) -3-lower alkanoyloxy (or hydroxy)
-5- [2- {mono (or di) lower alkylamino} ethyl] -8-lower alkyl-2,3-dihydro-1,5
It is known that a benzothiazepine derivative or a pharmaceutically acceptable acid addition salt thereof has an antihypertensive action, a cerebral / vasodilatory action and an inhibitory action on platelet aggregation (Japanese Patent Application Laid-Open No. 60-1985).
Nos. 202871 and 60-231669).

[0003] However, heretofore, no anti-atherogenic effect of these compounds has been known at all.

[0004] Atherosclerosis is pathologically classified into three groups: atherosclerosis, Monkeberg-type arteriosclerosis (media sclerosis), and arteriosclerosis. Atherosclerosis results in fat deposits and plaque formation in the intima of the coronary artery, basilar artery, renal artery, thoracic and abdominal aorta, and ischemic heart disease, cerebral infarction, renal failure and aortic aneurysm It has been pointed out that there is a connection with such. On the other hand, Monkeberg-type arteriosclerosis frequently occurs in arteries of moderate extremity in limbs such as femoral arteries, and causes calcification of the media. In addition, arteriosclerosis is a sclerotic change seen in arterioles such as kidney and adrenal gland, spleen, ovary, and pancreas [Internal Medicine Series 20, all of arteriosclerosis,
Nankodo (1975)].

In recent years, studies on these arteriosclerosis have progressed, and it is thought that unrestricted proliferation of medial smooth muscle cells in the intima of the blood vessel and abnormal accumulation of intracellular cholesterol may be the cause. In particular, the proliferation of medial smooth muscle cells in the intima of arteries is an important change in the pathogenesis of arteriosclerosis [N. Engl. J. Med. 314, 488 pages (1
986)].

[0006] Therefore, if the proliferation of smooth muscle cells in the intima of arteries can be prevented, arteriosclerosis can be prevented and treated.

[0007]

SUMMARY OF THE INVENTION The present invention provides an anti-atherosclerotic agent having an inhibitory action on the intimal growth of vascular medial smooth muscle cells.

[0008]

According to the present invention, there is provided a compound represented by the general formula [I]:

[0009]

Embedded image

[0010] (wherein, R ^1, R ³ and R ⁵ is a lower alkyl group, R ² represents lower alkanoyl group, R ⁴ represents a lower alkyl group.) Represented by 1,5-benzothiazepine derivative or An anti-atherosclerotic agent containing the pharmaceutically acceptable acid addition salt as an active ingredient.

As specific examples of the 1,5-benzothiazepine derivative which is the active ingredient of the present invention, in the above general formula [I], R ¹ , R ³ and R ⁵ are methyl, ethyl, propyl, a such lower alkyl groups butyl group, R ²
Is a hydrogen atom or an acetyl group, a lower alkanoyl group such as a propionyl group, R ⁴ is a hydrogen atom or a methyl group,
Compounds which are lower alkyl groups such as ethyl group and propyl group are exemplified.

The 1,5-benzothiazepine derivative which is the active ingredient of the present invention has four isomers based on two asymmetric carbon atoms in the molecule (namely, (+)-cis, (-)- Cis,
(+)-Trans and (-)-trans isomers) and mixtures thereof, especially the cis isomer or (-)
The -cis isomer is preferred.

The pharmacologically acceptable acid addition salts of the 1,5-benzothiazepine derivative [I] as the active ingredient of the present invention include hydrochloride, hydrobromide, hydroiodide, Inorganic acid addition salts such as chlorate, sulfate, phosphate; oxalate, maleate, fumarate, tartrate, 2- (4
Organic acid addition salts such as -hydroxybenzoyl) benzoate and methanesulfonate.

The anti-atherosclerotic agent of the present invention can be administered orally or parenterally, and can be administered together with excipients suitable for oral and parenteral administration.

[0015] The anti-atherosclerotic agent of the present invention can be made into an appropriate preparation using a pharmaceutical carrier usually used for oral and parenteral administration. Such pharmaceutical carriers include, for example,
Binders (eg, syrup, gum arabic, gelatin,
Sorbitol, tragacanth, polyvinylpyrrolidone), excipients (eg, lactose, sugar, corn starch, potassium phosphate, sorbite, glycine), lubricants (eg, magnesium stearate, talc, polyethylene glycol, silica), disintegrants (eg, , Potato starch),
Wetting agents (eg, sodium lauryl sulfate) and the like can be mentioned.

These pharmaceutical preparations can be administered as a solid preparation such as tablets, capsules and granules when administered orally, while they can be administered as a suspension or the like when administered parenterally. They can be administered as liquids such as dispersions and emulsions.

The dose of the 1,5-benzothiazepine derivative or the pharmaceutically acceptable acid addition salt thereof, which is the active ingredient of the present invention, depends on the administration route, age, weight, condition of the patient, type of disease and the like. Different, but generally 0.05-100
mg / kg / day, preferably 0.05-10 mg / kg
/ Day, when administered orally, 0.5 to 10 mg
/ Kg / day, for parenteral administration, 0.05-2 m
It is preferably in the range of g / kg / day.

The 1,5-benzothiazepine derivative [I], which is an active ingredient of the present invention, is described in, for example, JP-A-60-1985.
Nos. 202871, 60-231669 and JP-A-1
It can be produced by the method described in JP-A-186875.

In the present specification, a lower alkyl group and a lower alkanoyl group have 1 to 6 carbon atoms, respectively.
Preferably an alkyl group having 1 to 4 carbon atoms and 2 to 2 carbon atoms
6, preferably an alkanoyl group having 2 to 4 carbon atoms.

Experimental Example 1 (Effect on atherosclerosis) Male Wistar rats (8 weeks old, 10 rats per group) were fed a high-fat diet (2% cholesterol and 0.5% sodium cholate in a normal diet). After breeding for 1 week, the endothelium of the left common carotid artery was peeled off using a balloon catheter. Before endothelium detachment 3
At 0 minutes and from the next day to the day before the sacrifice, once a day, a sample aqueous solution (100 mg / kg) was administered to the sample administration group and the same amount of water was administered to the non-administration group using a gastric tube. After the endothelial detachment, the rats were kept on a high-fat diet. Three weeks after the start of the experiment, the rats were sacrificed, and the intimal thickening rate of the carotid artery cross section was calculated according to the following equation. The results are as shown in Table 1.

[0021]

(Equation 1)

[0022]

[Table 1]

(Note) Sample 1: (-)-cis-2- (4-methylphenyl)-
3-acetoxy-5- [2- (dimethylamino) ethyl] -8-methyl-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one fumarate Experimental Example 2 (Inner membrane Effect on thickening) male Wistar rats (9
The left common carotid artery endothelium of a 10-week old group (10 per group) was peeled off using a balloon catheter. Once a day, 30 minutes before endothelial detachment and from the next day to the day before sacrifice, a sample aqueous solution (100 mg / kg) was administered to the specimen administration group, and the same amount of water was administered to the non-administration group using a gastric tube. Two weeks after the start of the experiment, the rats were sacrificed under ether anesthesia, and the intimal hyperplasia rate of the carotid artery cross section was calculated as in Experimental Example 1. The results are as shown in Table 2.

[0024]

[Table 2]

(Note) Specimen 1: Same as the specimen described in Experimental Example 1. Experimental Example 3 (Inhibitory effect on proliferation of aortic intimal smooth muscle cells) Wistar strain bred for 1 week on a high fat diet (addition of 2% cholesterol and 0.5% sodium cholate to a normal diet) The aortic endothelium of a male rat (9 weeks old) was detached with a balloon catheter, and kept on a high-fat diet for another 2 weeks to develop atherosclerosis of the aorta. The intimal smooth muscle cells isolated and cultured from the intima of the affected area (using a separation medium prepared by adding 20% fetal bovine serum to Eagle's minimum essential medium (MEM)) were used to prepare a medium containing an analyte compound [Eagle 10% fetal bovine serum in the minimum essential medium (MEM)
And production) at 37 ° C. in 5% carbon dioxide-95% air under humid conditions. The medium was replaced with a fresh medium containing the test compound once every two to three days, and the number of surviving cells was counted 13 days later. The results are as shown in Table 3.

[0026]

[Table 3]

(Note) Specimen 1: Same as the specimen described in Experimental Example 1.

Sample 2: (-)-cis-2- (4-methylphenyl) -3-hydroxy-5- [2- (methylamino) ethyl] -8-methyl-2,3-dihydro-1,5
-Benzothiazepine-4 (5H) -one hydrochloride Sample 3: (±) -cis-2- (4-methylphenyl)-
3-acetoxy-5- [2- (dimethylamino) ethyl] -8-methyl-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one maleate Sample 4: (±) -Cis-2- (4-methylphenyl)-
3-hydroxy-5- [2- (methylamino) ethyl]
-8-Methyl-2,3 dihydro-1,5-benzothiazepine-4 (5H) -one sulfate

[0029]

EFFECT OF THE INVENTION Since the anti-atherosclerotic agent of the present invention remarkably inhibits the proliferation of vascular medial smooth muscle cells in the intima, the anti-atherosclerotic agent of the present invention is useful for various arteriosclerosis, It can be used effectively for the prevention and treatment of atherosclerosis, Monkeberg-type arteriosclerosis (media sclerosis) and arteriosclerosis.

The active ingredient of the present invention, 1,5-
Benzothiazepine derivatives have low toxicity, such as (±)
-Cis-2- (4-methylphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-methyl-2,3-dihydro-1,5-benzothiazepine-4
Mice were intraperitoneally administered with (5H) -one maleate at a rate of 100 mg / kg, and no death was observed when observed for 3 days.

 ──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-63-107925 (JP, A) JP-A-59-157021 (JP, A) JP-A-64-9981 (JP, A) JP-A 63-10781 275572 (JP, A) JP-A-62-174019 (JP, A) JP-A-60-231669 (JP, A) JP-A-3-157378 (JP, A)

Claims (4)

(57) [Claims] 1. A compound of the general formula [I] (Wherein, R ^1, R ³ and R ⁵ is a lower alkyl group, R ² represents lower alkanoyl group, R ⁴ represents. A lower alkyl group) 1,5-benzothiazepine derivative or a pharmaceutically represented by An anti-atherosclerotic agent containing an acid addition salt which is acceptable to the active ingredient as an active ingredient. 2. R ¹ , R ³ , R ⁴ and R ⁵ are methyl groups, R ²
Is an acetyl group. 3. Anti-arteriosclerotic agent according to claim 1 or 2, wherein an active ingredient 1,5-benzothiazepine derivative is a cis form. 4. The 1,5-benzothiazepine derivative which is an active ingredient is a cis-form levorotatory optically active substance .
4. The anti-atherosclerotic agent according to 2 or 3 .