JP2515114B2 - Platelet aggregation inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the following general formula (I), which is useful as a medicine. (In the formula, R represents a hydrogen atom or a lower alkyl group, and n
Represents an integer of 0 to 3) and relates to a platelet aggregation inhibitor containing as an active ingredient a piperazine derivative represented by or a non-toxic salt thereof.

A thrombus is a state in which blood is solidified in a blood vessel, and if there is damage or inflammation on the vascular endothelium, platelets attach to it and cause aggregation, forming a white thrombus mainly composed of platelets.
Further progresses to a red thrombus that also contains strong red blood cells with a fibrin mesh. A condition in which a thrombus has occurred is thrombosis, which significantly impedes the blood flow beyond the site of the thrombus and causes serious damage to tissues.

Therefore, the most convenient way to treat thrombosis is to suppress the adhesion and aggregation of platelets, which is an early stage of thrombus formation.

Therefore, the inventors of the present invention have conducted extensive studies to find a compound having an inhibitory effect on platelet aggregation. as a result,
The present invention has been completed by finding that the compound represented by the general formula (1) has an excellent inhibitory effect on platelet aggregation.

Therefore, an object of the present invention is to provide a platelet aggregation inhibitor containing a compound represented by the general formula (I) or a non-toxic salt thereof as an active ingredient.

It is known by the present inventors that the compound represented by the general formula (I) has already been effective in an experimental model of myocardial infarction by coronary artery ligation and is useful as a preventive and therapeutic agent for myocardial infarction. (JP-A-57-169478, JP-A-5
8-126879) Examples of the case where R in the general formula (I) is a lower alkyl group include a methyl group, an ethyl group, a propyl group, an isobutyl group, an n-butyl group and a sec-butyl group.

The non-toxic salts include sodium, potassium, calcium, magnesium, trialkylamine, dibenzylamine, N-lower alkylpiperidine,
Non-toxic salts such as α-phenethylamine, 1- (1-naphthyl) ethylamine, N-benzyl-β-phenethylamine, or non-toxic with hydrochloric acid, hydrobromic acid, formic acid, sulfuric acid, fumaric acid, maleic acid, tartaric acid, etc. Examples include salt.

The compound represented by the general formula (I) can be obtained, for example, by the following method.

(In the formula, R and n have the same meanings as described above, and X represents an amino-protecting group.) Specific examples of the compound represented by formula (I) include
The following can be mentioned.

(2R, 3R) -3 [(s) -1- {4- (4-methoxyphenylmethyl) piperazin-1-ylcarbonyl}-
3-Methylbutylcarbamoyl] oxirane-2-carboxylic acid, (2R, 3R) -3-[(s) -1- {4- (3,4-dimethoxyphenylmethyl) pyrazin-1-ylcarbonyl} -3 -Methylbutylcarbamoyl] oxirane-2
-Carboxylic acid, (2R, 3R) -3-[(s) -3-methyl-1- {4-
(2,3,4-Trimethoxyphenylmethyl) piperazine-
1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid, (2R, 3R) -3-[(s) -3-methyl-1- {4-
(3,4,5-Trimethoxyphenylmethyl) piperazine-
1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid, (2R, 3R) -3-[(s) -1- (4-benzylpiperazin-1-ylcarbonyl) -3-methylbutylcarbamoyl] oxirane- 2-carboxylic acid, (2S, 3S) -3-[(s) -1- {4- (4-methoxyphenylmethyl) piperazin-1-ylcarbonyl}
-3-Methylbutylcarbamoyl] oxirane-2-carboxylic acid, (2S, 3S) -3-[(s) -1- {4- (3,4-dimethoxyphenylmethyl) piperazin-1-ylcarbonyl}- 3-Methylbutylcarbamoyl] oxirane-2
-Carboxylic acid, (2S, 3S) -3-[(s) -3-methyl-1- {4-
(2,3,4-Trimethoxyphenylmethyl) piperazine-
1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid, (2S, 3S) -3-[(s) -3-methyl-1- {4-
(3,4,5-Trimethoxyphenylmethyl) piperazine-
1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid, (2S, 3S) -3-[(s) -1- (4-benzylpiperazin-1-ylcarbonyl) -3-methylbutylcarbamoyl] oxirane- 2-carboxylic acid.

Esters or non-toxic salts of these compounds are also the active ingredients of the present invention.

The usefulness of the compound represented by the general formula (I) and its non-toxic salt in the present invention as a platelet aggregation inhibitor is that of ADP (adenosine diphosphate), collagen and PAF (platelet activating factor). Test substance “(2R, 3R) -3 due to platelet aggregation by stimulant”
-[(S) -3-Methyl-1- {4- (2,3,4-trimethoxyphenylmethyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid ethyl 1/2 sulfate It became clear by observing the effect of ".

That is, the test drug inhibited the in vitro aggregation of human platelets by 10 μM of ADP at 80 μg / ml or more,
The aggregation of μg / ml collagen was suppressed at 40 μg / ml or more, and the aggregation by collagen at 2.5 μg / ml, which is near the threshold for inducing platelet aggregation, was suppressed at 10 μg / ml or more.

On the other hand, the test drug also significantly suppressed the aggregation by 10 ^-9 M PAF using rabbit platelets.

Further, the compound represented by the general formula (I), which is the active ingredient of the present invention, is found to be a highly safe substance for the living body by the acute toxicity test in mice.

The dose of the compound of the general formula (I) and the non-toxic salt thereof according to the present invention varies depending on the kind of the compound and the degree of symptoms such as thrombotic disease, but usually about 10 mg to 1 g per day is administered to a patient. Good.

When the compound represented by the general formula (I) or a salt thereof is used as a platelet aggregation inhibitor, it is usually in the form of a pharmaceutical composition together with a pharmaceutical carrier. As a carrier,
Diluents or excipients such as fillers, binders, disintegrants, lubricants and the like, which are usually used for preparing a drug depending on the form of use, are used.

The dosage form may be any of injections, powders, capsules, granules, tablets and the like.

When used in the form of tablets, as a carrier, for example, lactose, sucrose, sodium chloride, glucose solution, starch, calcium carbonate, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, glucose, starch solution, gelatin solution , Carboxymethyl cellulose, methyl cellulose, binders such as potassium phosphate, dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, stearic acid monoglyceride, starch, lactose and other disintegrants, stearate salt, boric acid powder, Lubricants such as solid polyethylene glycol that are widely used in this field can be used.
Further, if necessary, sugar-coated tablets, gelatin-coated tablets, film-coated tablets, etc. can be used.

When prepared as an injection, examples of the diluent include water, ethyl alcohol, propylene glycol, polyoxyethylene sorbit, sorbitan ester and the like. At this time, salt, glucose or glycerin may be contained in an amount sufficient to prepare an isotonic solution, and a usual solubilizing agent, buffer, soothing agent, preservative, etc. are required. You may make it contain according to it.

As described above, the perazine derivative represented by the general formula (I) or a nontoxic salt thereof has an excellent inhibitory effect on platelet aggregation and is useful as a prophylactic and therapeutic agent for thrombosis or a thrombus formation inhibitor. Is.

Next, in the present invention, a compound of the general formula (I) and a non-toxic salt thereof, which are used as active ingredients, are useful as a platelet aggregation inhibitor and are highly safe, and a compound of the general formula (I) The present invention will be specifically described with reference to Examples showing the formulation examples.

Example 1. Inhibition of Platelet Aggregation by ADP or Collagen Test Method According to a conventional method, sodium citrate was collected from 5 human cubital veins, centrifuged, and then Platelet Rich Plasma.
(PRP) and Platelet Poor Plasma (PPP) were prepared and used for the experiment. Platelet aggregation tracer (Nikko Bioscience, PAT-4
It was measured according to A). PRP 180μ and test solution 10μ 37
After preincubation at 1 ° C for 1 minute, ADP (adenosine diphosphate) solution or collagen solution was added to induce aggregation. Table 1 shows the results.

Experimental result Test drug: (2R, 3R) -3-[(s) -3-methyl-1
-{4- (2,3,4-Trimethoxyphenylmethyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid ethyl 1/2 sulfate As shown in Table 1, the test drug was human. AD using platelets
An excellent inhibitory effect on platelet aggregation by P or collagen was observed.

Example 2 Inhibition of Platelet Aggregation by PAF Test Method Male Japanese White rabbits were anesthetized with pentobarbital, sodium citrate blood was collected from the carotid artery, and PR was performed according to a conventional method.
P and PPP were adjusted and used for the experiment. The platelet aggregation was measured with a platelet aggregation tracer (Nikko Bioscience PAT-4A).
After adding 10μ of the test drug solution adjusted to 180μ diluted PRP, add 10μ of PAF solution (final concentration of PAF 10
^-9 M), which caused platelet aggregation. A physiological saline solution containing 0.25% bovine serum albumin was used to prepare the PAF solution, and a physiological saline solution was used to prepare the test drug solution.

 The results are shown in Table 2.

result As shown in Table 2, the test drug was also found to have an excellent inhibitory effect on PAF-induced platelet aggregation.

Example 3. Acute toxicity test Male ddN mice having a body weight of 20 to 28 g were used. The drug was administered through the tail vein. As a result, as shown in Table 3, it was confirmed that the drug of the present invention has high safety.

Example 4 Formulation example (tablet) A film-coated tablet containing the following components in 1 tablet (220 mg).

(2R, 3R) -3-[(s) -3-methyl-1- {4-
(2,3,4-Trimethoxyphenylmethyl) piperazine-
1-ylcarbonyl} butylcarbamoyl] oxiran-2-carboxylate 50 mg Lactose 100 mg Crystalline cellulose 50 mg Magnesium stearate 1 mg Hydroxypropyl methylcellulose 15 mg Hydroxypropyl cellulose 4 mg Other compounds used as active ingredients in the present invention also have the same formulation. It can be a coated tablet.

Example 5 Formulation Example (Granule) The following components are contained in 1 g of granules.

(2R, 3R) -3-[(s) -3-methyl-1- {4-
(2,3,4-Trimethoxyphenylmethyl) piperazine-
1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid ethyl 1/2 sulfate 200 mg lactose 500 mg corn starch 300 mg Other compounds used as active ingredients in the present invention can be granulated by the same formulation. .

Example 6 Formulation example (injection) a) 1 ampoule contains the following components.

(2R, 3R) -3-[(s) -3-methyl-1- {4-
(2,3,4-Trimethoxyphenylmethyl) piperazine-
1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid ethyl 1/2 sulfate 20 mg Aseptic distilled water is added to the above ingredients to a volume of 10 ml.

B) One ampoule contains the following ingredients.

(2S, 3S) -3-[(s) -3-methyl-1- {4-
(2-Pyriminidyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylate sodium 100 mg Phosphate-potassium hydrogen buffer solution (0.4 M solution) 1 ml Aseptic distilled water is added to the above components to a volume of 10 ml.

Other compounds used as active ingredients in the present invention can be made into injections by the similar formulation.

Claims (1)

(57) [Claims] (1) a general formula, (In the formula, R represents a hydrogen atom or a lower alkyl group, and n
Represents an integer of 0 to 3) A platelet aggregation inhibitor containing a piperazine derivative represented by the formula or a non-toxic salt thereof as an active ingredient.