JPS5879925A - Drug composition having antithrombus action - Google Patents

Abstract

PURPOSE:A drug composition having antithrombus action consisting essentially of 4-oxyimino-1-phenyl-1,2,3,4-tetrahydroquinoline or its halogen-substituted derivative at 6-position or its salt. CONSTITUTION:A preventive and remedy for arterial thrombosis consisting essentially of a compound shown by the formula (X is halogen or H) or its salt, having high safety. Showing more improved effect than aspirin, diphyridamole, ticlopidine, etc., capable of being medicated orally, through the intestine, or by injection. The compound shown by the formula, a main ingredient of the drug composition, is obtained by acylating diphenylamine with an acylating agent such as beta-propiolactone, etc., followed by subjecting the acylated compound to ring formation with an oxidizing agent such as phosphorus pentoxide, etc. The prepared compound is halogenated with an N-halogenosuccinimide, etc. and converted into an oxime with hydroxyamine, etc. to give a compound shown by the formula, a substituted derivative at 6-position.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a pharmaceutical composition having an anti-1r side frame effect, more specifically, the general formula (1): (wherein, X means a halogen atom or a hydrogen atom).

) 4-oximino-1-phenyl-1,
The present invention relates to a pharmaceutical composition having an antithrombotic effect containing 2,3,4-tetrahydroquinoline, its 6-halogen-substituted product, or a salt thereof as a main component.

In recent years, so-called thrombus formation, the formation of blood clots within the lumen of curved canals or within the heart, has been thought to be the cause of many vascular diseases, including cerebrovascular disorders and ischemic heart disease. It's here. In other words, this state of pathological thrombus formation is called thrombosis, and especially in artery 1 (TL thrombosis), because thrombus causes narrowing and occlusion of the lumen of the curved tube, it can cause ischemic lesions in important organs such as the brain, heart, and lungs. It causes the development of infarcts and infarcts, leading to dysfunction of the organs, leading to lesions such as 11+1 heart disease, cerebrovascular disorders, and 1Ilb infarction.In addition, +fn intraluminal coagulation, peripheral circulation disorder, and rust urine. It is also well known that thrombosis is a contributing factor to the development and progression of vascular disorders and arteriosclerosis associated with debris. It has been reported that this arterial thrombosis also plays a role in the occurrence of vascular disease, and thrombosis is once again considered to be extremely important as a fundamental disease of vascular disease.

Therefore, aspirin, diviridamol, and the like are being evaluated as preventive and therapeutic agents for this arterial thrombosis in 1 m beds. Very recently, in Japan, ticlopidine has become available for general clinical use as an anti-1m embolism drug, but there is still no alternative medicine that has the same anti-1m embolism effect, and there are various causes and conditions of the disease. In the treatment of thrombosis, there is a desire for the development of pharmaceuticals that have more abundant and highly safe antithrombotic effects.

The present inventors have conducted intensive research for many years in order to provide the market with a drug having antithrombotic effects, especially anti-arterial thrombotic effects. As a result, the present inventors have found that the compound represented by general formula (1) has a strong antithrombotic effect. The present invention has been completed by discovering that the present invention has an effective effect and is also extremely safe.

4-oximino- which is the main component of the pharmaceutical composition of the present invention
1-Phenyl-1,2,3,4-tetrahydroquinoline and its 6-position halogen-substituted product are known compounds and can generally be produced by the following steps. That is, diphenylamine is converted into an acyl compound with an acyl compound such as .beta.-propiolactone, and this is cyclized with an oxidizing agent such as phosphorus pentoxide. When producing a 6-position substituted product, it is produced by halogenating it with a halogenating reagent such as N-halogenoscunnimide and converting it into an oxime with hydroxylamine or the like.

4-Oxv-1-phenylated thus produced
Table 1 shows the properties of 1,2,3,4-tetrahydroquinoline and its 6-position halogen substituted product.

Table 1 Compound 1, which is the main component of the present invention, will be described below. l, I.

Experimental Example 1 Antithrombotic effect in rats The method of Ashida et al. (Ashida et al.: Thromb
osis Re5e-arch, volume 17, page 663,
(1980). That is, a test compound was orally administered to 10 Winuta male piglets per group, each weighing around 250 g and which had been fasted overnight. Three hours later, under ether anesthesia, a 24 cm long shunt was created between the carotid artery and jugular vein using a polyethylene tubule N013.

After 4 hours, the venous end of the shunt was removed, and the presence or absence of blood flow in the artery and the length of the thrombus within the polyethylene tubule were measured. The total length of thrombus was expressed as 100 for the control, and the appearance rate of thrombus was expressed as a percentage. The results are shown in Table 2.

Table 2 Compounds 1 to V all have antithrombotic effects.

In particular, compounds (1) and (2) exhibited 2 to 3 times more activity than ticlopidine. Furthermore, the effect of aspirin was extremely weak compared to these compounds.

Experimental Example 2 Antithrombotic effect in rabbits Method of Kobayashi et al. (Journal of the Japanese Society of Hematology, Vol. 37, p. 102)
(1976).

4 hours after oral administration of the test compound to 8 rabbits per group,
The femoral artery was exposed and the outer diameter of the blood vessel was Q, 9 mm using a ligature.
A stricture was added so that 10 mg of nilazic acid/animal was injected intravenously. After 24 hours, the thrombus formation rate at the stenosis was measured. The results are shown in Table 6.

Compounds I to ■ in Table 3 all exhibit antithrombotic effects, in particular,
The effects of compounds 1 and 1 were about 10 times that of aspirin.

Experimental Example 3 Acute Toxicity Test A group of 10 ddY male mice weighing approximately 20 g were treated with C.
Compounds 1 to 2 were each suspended in a 10% aqueous gum arabic solution and administered orally, and the Ll) and o values were calculated from the number of deaths over 7 days. The results are shown in Table 4 (-).

LD of compounds I~■. The values are all 5 g,/Kg or more, which is large compared to the amount that exhibits pharmacological effects, and therefore is sufficiently safe.

As is clear from the experimental examples shown in Table 4 and above, all of Compounds I to (1) have a remarkable antithrombotic effect. Moreover, all of these compounds r to V are sufficiently safe. Therefore, compounds 1 to 1 of the present invention are useful for the prevention and treatment of thrombotic diseases.

Table 5 shows the daily doses of Compounds 1 to ■ for adults before treatment.

The doses in Table 5, F, and Tables may be increased or decreased as appropriate depending on the symptoms.

Compounds IV can be prepared into pharmaceutical formulations in a conventional manner with any optional conventional pharmaceutical carriers, bases or excipients.

For oral administration, capsules, tablets, powder suppositories,
As an injection, it is preferable to use a pharmaceutically acceptable dispersion aid, such as a suspension agent using Tween 80 or gum arabic solution Kl, or an emulsion agent using polyoxyethylene sorbitan monooleate.

Next, examples of the present invention will be shown.

Example 1 Capsule Compound 1 500g Lactose 485g Magnesium stearate 15g 1,000g The above components were weighed and mixed uniformly. 500mg of mixed powder in No. 1 hard gelatin capsule
Fill each sample to form capsules.

Example 2 Tablet Compound I+ 500 g Lactose 3
20g potato starch 150g polyvinyl alcohol 15g magnesium stearate 15g1. o o o g After weighing each of the above ingredients, compound ①, lactose and Bote) rR powder are mixed uniformly. An aqueous solution of polyvinyl alcohol is added to this mixture, and granules are prepared by wet granulation. The granules were dried, mixed with magnesium stearate, and compressed into tablets weighing 200 m.
g tablets.

Example 3 Powder Compound El 10og Milk 1kg 890g Magnesium Stearate 10g 1,000g After weighing each of the above components, they were mixed uniformly to give 1
0% powder.

Example 4 Suppository Compound IY 10og Polyethylene Glycol 1500 180g Polyethylene Glycol 4000 720 gl, 000g Compound 1v was well ground in a mortar to form a fine powder, and then
Make a rectal suppository by melting.

Example 5 Injection compound ■ 100g Polyoxyethylene sorbitan monooleate 100g Sodium chloride ate 9g Compound ■ and polyoxyethylene sorbitan monooleate were mixed, and 9g was added to 200 ml of distilled water for injection.
Add a solution of sodium chloride in the solution, and add distilled water for injection to a total volume of 1.000 ml. This mixture was then shaken and then heated to 1.055 kg at 110°C for 20 minutes.
/cm' (gauge) (15 psig) water vapor pressure (
After cooling and treating in an autoclave, 2 ml each is dispensed into ampoules and sealed tightly to prepare an injection.

Patent applicant: Mochida Pharmaceutical Co., Ltd.

Claims (1)

[Claims] General formula (■): 4-oximino-1-phenyl-1, represented by (wherein, X means a halogen atom or a hydrogen atom);
A pharmaceutical composition having an antithrombotic effect, which contains 2,3,4-tetrahydroquinoline, its 6-position halogen-substituted product, or a salt thereof as a main component.