JPH07223958A - Agent for suppressing thickening of blood vessel - Google Patents

Abstract

PURPOSE:To obtain an agent for suppressing the thickening of blood vessel after the coronary blood flow reconstruction operation by using a staurosporine compound as an active component. CONSTITUTION:This agent contains a compound of formula (X is NH or O) or its salt, e.g. 6-deaza-6-oxostaurosporine as an active component. The compound of formula is effective for preventing the restenosis of blood vessel in the remote period after the coronary blood flow reconstruction operation such as percutaneous coronary vasodilating operation using a balloon catheter and suppressing the thickening of the endosporium of blood vessel. The daily administration rate for adult is 0.3-1mg/kg for staurosporine and 10-30mg/kg for 6- deaza-6oxostaurosporine by oral administration.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an agent for suppressing vascular hypertrophy after coronary revascularization surgery.

[0002]

2. Description of the Related Art In percutaneous coronary dilatation, a catheter having a small balloon is inserted at the tip of the stenotic portion of the coronary artery, and the balloon is inflated several times to expand the lumen of the blood vessel to reduce the stricture. It is a well-established treatment method that is extremely safe in the treatment of ischemic heart disease (Modern Medicine, 25, 147). However, this method still has a big problem. It is 3 after surgery
Restenosis in the remote period occurs in 0 to 40% of cases (J. Am. Coll. Cardiol. 12, 114).
9).

In the general formula (1) described below, staurosporine in which X is NH is a known substance found as an antibiotic AM-2282 (Japanese Patent Publication No. 57-53076 and Japanese Patent Laid-Open No. 3-244387). ). This substance has a strong inhibitory effect on platelet aggregation (Japanese Patent Publication 1-5
2369), a strong vasorelaxant effect (JP-A-2-9819), and an antitumor activity (JP-A-60-185719).

In the general formula (1) described below, X is O.
It is already known that 6-deaza-6-oxostaurosporine has a strong platelet aggregation inhibitory action (JP-A-4-145085, WO93 / 1877).
1 International specification).

[0005]

The cause of distant restenosis has been shown to be the formation of intimal thickening of blood vessels after surgery. Therefore, the development of this intimal thickening inhibitor has been desired as a powerful method for preventing restenosis, but an effective therapeutic agent has not been developed yet.

[0006]

Means for Solving the Problems The present inventor has conducted earnest research on a drug having an intimal thickening suppressing action to solve the above problems, and as a result, the following general formula (1)

[0007]

[Chemical 2] The present invention was completed by finding that staurosporine and 6-deaza-6-oxostaurosporine represented by the formula (wherein X represents NH or O) have an excellent intimal thickening suppressing action.

That is, the present invention provides a vascular hyperplasia inhibitor characterized by containing a staurosporine compound represented by the general formula (1) or a non-toxic salt thereof as an active ingredient.

The active ingredient of the present invention can be produced and obtained by a known method. That is, staurosporine is described in J. Antibiotics, 30, 275 (1
977), Japanese Patent Publication No. 57-53076, and JP-A-3-
It can be manufactured according to the method described in Japanese Patent No. 244387. Further, 6-deaza-6-oxostaurosporine can be produced according to the method described in JP-A-4-145085.

The above-mentioned non-toxic salts are pharmaceutically acceptable salts, for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, succinic acid, malic acid, citric acid, Glycolic acid, fumaric acid, methanesulfonic acid, p
-Salts with organic acids such as toluenesulfonic acid, aspartic acid, glutamic acid and the like can be mentioned.

The acute toxicity value (LD ₅₀ value) of a single administration of this active ingredient in mice was 3 mg /% of staurosporine.
40 kg of 6-deaza-6-oxostaurosporine
It is 0 mg / kg or more, and is a substance that can be used as a medicine. When this active ingredient is used as a blood vessel thickening inhibitor, it is administered alone or in combination with a pharmaceutically acceptable carrier. The composition is determined by the administration route, administration schedule and the like. The dose of the active ingredient of the present invention varies depending on the type of the active ingredient, but usually, in the case of oral administration, staurosporine is 0.3 to 1 mg / kg / day in an adult, 6
-Deaza-6-oxostaurosporine is 10-30m
g / kg / day.

The vascular hyperplasia inhibitor of the present invention can be selected from either oral or parenteral preparations. Specific examples include tablets, powders, granules, capsules, suppositories, injections and the like. As the excipient or auxiliary agent used in the preparation, an organic or inorganic inert carrier suitable for oral or parenteral administration is used. Specific examples thereof include lactose, starch, vegetable or animal fats and oils. The ratio of the present active ingredient to the carrier in the preparation is 0.
It can be appropriately changed between 1% and 100%.

The effect of the present active ingredient on inhibiting vascular hypertrophy can be confirmed, for example, by the following animal experiments. Intimal thickening, such as that seen in restenosis after percutaneous coronary artery dilatation, can be created in a vascular endothelial cell detachment model in animal experiments. Therefore, the balloon catheter method (Jpn.JP
armacol. 52, 541) to extensively exfoliate the vascular endothelial cells of the rabbit carotid artery to prepare an intimal thickening model blood vessel, and a section of this model blood vessel was stained with fungizone (Zentralbl.A11g.Patho).
l. Anat. 9, 289) to measure the areas of the intima and media of the blood vessel, calculate the ratio of the intimal area to the media area as the thickening degree, and determine the inhibitory effect on the thickening degree when this active ingredient is administered. be able to.

[0014]

EXAMPLES Next, examples of the present invention will be described in detail, but the present invention is not limited thereto. Example 1 Preparation of tablets 6-deaza-6-oxostaurosporine 10 mg Light anhydrous silicic acid 100 mg Crystalline cellulose 50 mg Carboxymethyl cellulose calcium 25 mg Talc 4 mg Lactose 69 mg Magnesium stearate 2 mg The above ingredients were mixed and granulated, and compression molded. Then, one tablet of 260 mg was produced.

Example 2 Production of Tablet In Example 1, staurosporine 1 was used as an active ingredient.
Using mg, it was mixed with a carrier having the same composition ratio, formed into granules, and compression-molded to produce tablets.

Example 3 Inhibitory Effect of Staurosporine on Intimal Thickening In the experiment, a 10-week-old (body weight: about 2.5 to 3.0 kg) healthy male rabbit was used. An intimal thickening model blood vessel was anesthetized with rabbits under pentobarbital, and a balloon catheter (air volume of about 0.155 ml, diameter of about 2.5 mm) was inserted into the right carotid artery, and endothelial cells were transferred by reciprocating the balloon once to the subclavian artery. It was made by peeling. Staurosporine was fed immediately after balloon treatment (0.3 mg and 1.0 mg).
mg / kg / day). The left and right common carotid arteries were extracted 3 weeks after the endothelial cell detachment surgery. The excised blood vessels were cut at a distance of about 2 mm from 1 to 2 cm below the balloon insertion port. The obtained section was subjected to fungizone staining, and the ratio of the intimal area to the media area of the blood vessel was determined as the degree of thickening. The left carotid artery was used as a control normal vessel.

The results are shown in FIG. 1 (the effect of staurosporine on the formation of intimal thickening of blood vessels), and 25.7% of the intimal thickening was formed by the balloon treatment. 6.2% each by administering 0.3 mg and 1.0 mg / kg / day of porin, respectively
And decreased to 9.5%.

Example 4 Inhibitory Effect of 6-Deaza-6-oxostaurosporine on Intimal Hyperplasia A healthy male rabbit of 10 weeks old (body weight: about 2.5 to 3.0 kg) was used in the experiment. An intimal thickening model blood vessel was anesthetized with rabbits under pentobarbital, and a balloon catheter (air volume of about 0.155 ml, diameter of about 2.5 mm) was inserted into the right carotid artery, and endothelial cells were transferred by reciprocating the balloon once to the subclavian artery. It was made by peeling. 6-deaza-6-oxostaurosporine was fed (3 mg, 10 mg and 30 mg / kg / day) immediately after the balloon treatment.

The left and right common carotid arteries were excised 6 weeks after the endothelial cell detachment operation. 1-2 cm from the balloon insertion port
It was cut from the bottom at intervals of about 2 mm. The obtained section was subjected to fungizone staining, and the ratio of the intimal area to the media area of the blood vessel was determined as the degree of thickening. The left carotid artery was used as a control normal vessel.

The results are shown in FIG. 2 (6 for intimal hyperplasia formation).
-Action of deaza-6-oxostaurosporine), and 56.9% of intimal thickening was formed by balloon treatment, and the degree of intimal thickening was 6-deaza-6-oxostaurosporine. 10 mg and 30 mg /
27.4% and 1 each by administration of kg / day
It decreased to 1.2%.

[0021]

Industrial Applicability As described above, the present active ingredient exhibits an excellent inhibitory effect on vascular hyperplasia after coronary artery revascularization, and can provide a useful vascular hyperplasia inhibitor.

[Brief description of drawings]

FIG. 1 shows the effect of staurosporine on the formation of intimal hyperplasia in the rabbit carotid artery after balloon vascular endothelial cell detachment.

FIG. 2 shows the effect of 6-deaza-6-oxostaurosporine on the formation of intimal hyperplasia after detachment of vascular endothelial cells by balloon catheterization in the rabbit carotid artery.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Satoshi Omura 5-12-7 Seta, Setagaya-ku, Tokyo

Claims (1)

[Claims] 1. A compound represented by the general formula (1): A vascular thickening inhibitor comprising a staurosporine compound represented by the formula (wherein X represents NH or O) or a non-toxic salt thereof as an active ingredient.