JPS58121214A - Inhibitor of blood platelet aggregation - Google Patents

Abstract

PURPOSE:The titled drug useful as an antithrombosis, having low toxicity and inhibitory action on blood platelet aggregation, comprising alpha-(substituted methylene)-gamma-butyrolactone derivative or its salt as an active ingredient. CONSTITUTION:The titled inhibitor comprising an alpha-(substituted methylene)-gamma- butyrolactone derivative shown by the formulaI[R<1> is a group shown by the formula II (R<2> is H, lower alkyl, OH, etc.; R<3> is H, lower alkoxy, or halogen; R<4> is H or OH), a group shown by the formula III (R<5> is lower alkyl, phenyl, etc.), naphthyl, pyridyl, etc.]or its salt as an active ingredient. Blood platelets playing an important role in hemostatic mechanism cause extraordinary adhesion or aggregation particularly in malignant tumor, burn, arteriosclerosis, etc., and they as inducers cause thromosis or thrombus is also caused by the aggregation of blood platelet in artificial organs, transfusion, etc. But the compound shown by the formulaIshows improved inhibitory action on blood platelet aggregation.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to platelet aggregation inhibitors. More specifically, the present invention relates to a phenyl group, a lower cycloalkyl group represented by the general formula (1) (representing a gen atom or a cyano group, BB represents hydrogen, a lower alkoxy group, or a halogen atom, and R4 represents a hydrogen or a hydroxyl group). V group or phenyl group), naphthyl V group, hydroxynaphthyl group, lower alkyl/L/pri V group, pyridyl group or indolyl group. ) A platelet aggregation inhibitor containing a physiologically acceptable α-(substituted methylene)-γ-butyrolactone derivative or a salt-formable salt thereof as an active ingredient.

Platelets, which play an important role in the hemostasis mechanism, are subject to abnormal adhesion and aggregation, particularly in cases of malignant tumors, burns, arteriosclerosis, etc., and this often triggers thrombosis. Furthermore, recently, blood is often handled outside the body in artificial kidneys, heart-lung machines, other artificial organs, and blood transfusions, but it is also necessary to prevent the formation of blood clots caused by platelet aggregation. . In recent years, thrombosis caused by such platelet aggregation has been on the rise, and there is a desire to develop an antithrombotic agent that has an appropriate platelet aggregation inhibitory effect or platelet aggregation inhibiting effect.

As a result of extensive testing of the pharmacological action of α-(#methylene)-γ-butyrolactone derivatives, the inventors found that the general formula (1
The present invention was completed based on the discovery that the compound represented by () and its salt-formable salts have an excellent platelet aggregation inhibiting effect or platelet aggregation inhibiting effect. Namely 1. An object of the invention is to provide a platelet aggregation inhibitor tanning agent.

The platelet aggregation inhibitor according to the present invention is an α-(!i-substituted methylene-γ-butyrolactone derivative represented by the general formula (1) or a salt of a salt-formable salt thereof that is physiologically acceptable). The component represents hydrogen, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a halogen atom, or a cyano group, and R8 represents hydrogen, a lower alkoxy group, or a halogen atom, a lower alkyl group, a lower cycloalkyl group, or a phenyl group. ), a naphthyl group, a hydroxynaphthyl group, a lower alkylfuryl group, a pyridyl group or an indolyl group;
Examples of the lower alkyl group of R2 include methyl group, ethyl group, propyl group, butyl group, hexyl group, etc., and examples of the lower alkoxy group include methoxy group, ethoxy group, propoxy group, ethoxy group, hexyloxy group, etc. , halogen atoms include fluorine, chlorine, bromine, and iodine, and lower alkoxy groups of R3 include methoxy group, nidoxy M, -y''o poxy group, butoxy group, hexy)V
Examples include oxy groups, and halogen atoms include fluorine,
Examples of the lower alkyl group of R5 include chlorine, bromine, and iodine, and examples of the lower alkyl group of R5 include methyl group, ethyl group, propyl group, butyl group,
Examples of the hexyl group include the lower cyfuroa) V-kyl group, such as cyclopropyl group, cyclo7-f-yl group, cyclopentyl group, and cyclohexyl group, and examples of the naphthyl group include l-naphthyl group and 2-naphthyl group. Examples of the hydroxynaphthyl group include 2-hydroxy-1-naphftv group, 1-hydroxy-2-naphthyl group, 3-hydroxy-2-naphthyl group, and lower alkyl
As the furyl group, 5-methyA/-2-furyl group, 5-Z
Examples include f A/ + 2-F IJ/'4, and examples of the pyridyl group include 2-pyridyl group, 3-pyridyl group, and 4-pyridyl group.
Examples of the indolyl group include a pyridyl group, and examples of the indolyl group include a 2-indolyl group, a 3-indolyl group, and a 5-indolyl group. Specific examples of the compound represented by the general formula (1) include the following.

α-(benzylidene)-γ-butyrolactone (hereinafter abbreviated as compound I) α-(p-methylbenzylidene)-γ-butyrolactone (hereinafter abbreviated as compound ■) α-(m-methylbenzylidene)-γ-butyrolactone ( α-(p-isopropylbenzylidene)-γ-butyrolactone (hereinafter referred to as compound ■) α-(p-tert-butylbenzylidene)-γ-butyrolactone (hereinafter referred to as compound V) α -(p-hydroxybenzylidene)-γ-butyrolactone (hereinafter abbreviated as compound ■)
α-(8,4-dihydroxybenzylidene)-γ-butyrolactone (hereinafter abbreviated as compound ■) α-(p-methoxybenzylidene)-γ-butyrolactone (hereinafter abbreviated as compound ■) α-(m-methoxybenzylidene) −γ
-Butyrolactone (hereinafter abbreviated as compound ■) α-(2
-Hydroxy-5-methoxybenzylidene)-γ-butyrolactone (hereinafter abbreviated as compound 3-Ditoxy-4-hydroxy-5-iodobenzylidene)-γ-butyrolactone (hereinafter abbreviated as compound ■) α-(2,6-dichlorobenzylidene)-γ-butyrolactone (hereinafter abbreviated as compound x■) α -(p-cyanobenzylidene)-T-butyrolactone (compound XI under pressure)
abbreviated as V) α-(3,5-ditertiary-butyl-
4-methylaminocarbonyloxybenzylidene)-γ
-Butyrolactone (hereinafter abbreviated as compound xv) α-(
3,5-ditertiary-butyA/-4-ethylaminocarbonyloxybenzylidene)-γ-butyrolactone (
α-(3,5-ditertiary-butyl-4-butylaminocarbonyloxybenzylidene)-γ-butyrolactone (hereinafter referred to as compound X■) α-(3,5-ditertiary-butyl- 4-cyclohexylaminocarbonyloxybenzylidene)-γ
-Butyrolactone (hereinafter abbreviated as compound
(hereinafter abbreviated as compound IN) α-(l-naphthylmethylene)-γ-butyrolactone (hereinafter abbreviated as compound 0) α-(2-hydroxy-1-naphthylmethylene)-γ-
Butyrolactone (hereinafter abbreviated as compound IXI) α-(5-methyl-2-furylmethylene)-γ-butyrolactone (hereinafter abbreviated as compound xx■) a-(8-pyridylmethinone)-γ-butyrolactone (hereinafter abbreviated as compound X
XI[[abbreviated as]α-(3-indolylmethylene)
-γ-butyrolactone (hereinafter abbreviated as compound 01V)
etc.

Among the compounds represented by general formula (1), compounds having a hydroxyl group as a substituent can form a salt with a base. Any compound capable of forming a salt with a hydroxyl group-containing compound can be selected. Examples of specific salts include (1) metal salts, especially salts with alkali metals, alkaline earth metals, and aluminum, (2) ammonium salts, and (3) amine salts, especially methylamine, diamine, and diethylamine. , triethylamine, pyridine, piperidine, morpholine, hexamethyleneimine, aniline, pyridine, etc., and a physiologically acceptable salt may be selected from these salts as the platelet aggregation inhibitor.

The above compounds and their salts also have excellent platelet aggregation inhibiting activity and are low toxicity compounds.

It can be said that this meets the purpose of the present invention. The compound represented by the above general formula (1) can be synthesized by the following method.

(1) Method of G. A. Howie et al. [Journal of Medicine Chemistry, 17.
840 (1974)], the general formula (2) represents an alkyl group, a hydroxyl group, a lower alkoxy group, a 7% rogen atom or a cyano group, R represents hydrogen, a lower alkoxy group or a rogen atom, and R4 represents hydrogen or a hydroxyl group. phenyl group represented by (representing), a group 1 represented by lower cycloalkyl group or phenyl group),
Represents a naphthyl group, a hydroxynaphthyl group, a lower alkylfuryl group, a pyridyl group or an Indian IJA/ group.

) and α-(triarylphosphoranylidene)- represented by the general formula
It is synthesized by reacting with γ-butyrolactones. This method uses the so-called Witzteich reaction, but in addition to the above-mentioned compounds, ylides derived from trialkylphosphines and triphenylarsine can also be used as the ylide to be reacted with the above-mentioned aldehydes.

(2) H. Zimmer et al.'s method [Journal of
Organic Chemistry, Mu, 28 (1959),
1, by condensing an aldehyde represented by the above-mentioned general formula (2) with γ-butyrolactone using a base or an acid as a catalyst. Bases that can be used as catalysts include alkali metal pulchlorates such as sodium methylate and sodium ethylate, alkali metal hydrides such as potassium hydride and sodium hydride, and piperidine.

Amines such as morpholine and ethanolamine; alkali metal hydroxides such as potassium hydroxide and sodium hydroxide;
Examples include alkali metal amides such as lithium diisopropylamide, and alkali metal salts of organic acids such as sodium acetate and potassium acetate. Furthermore, examples of acids that can be used as catalysts include boron trifluoride, titanium tetrachloride, p-toluenesulfonic acid, and benzenesulfonic acid.

(3) The method of S. Tsuboi et al.
Letters, 1825 (1978)), aldehydes represented by the above general formula (2) and 2-acetyl-γ
It is synthesized by reacting -butyrolactone with a base catalyst such as potassium carbonate.

(4) It can be synthesized by reacting the aldehyde represented by the above general formula (2) with the compound shown below.

(R, R, R, R represent an alkyl group) (5) General formula (
Among the compounds represented by 1), the compounds represented by general (R5 represents a lower alkyl group, lower cycloalkyl group, or phenyl group) are α-( 3゜5-diternary petit Iv, -4-hydroxybenzylidene)-γ-butyrolactone and incyanate represented by the general formula R5-NGO (R5 represents a lower alkyl group, a lower cycloalkyl group, or a phenyl group) can be synthesized by reacting with

Platelet aggregation inhibitory action The platelet aggregation inhibitor according to the present invention contains as an active ingredient a compound represented by the above general formula (1) or a salt of a substance capable of forming a salt. The platelet aggregation inhibitory effect and toxicity of these compounds are as shown in the atit example below.
Hiko, the platelet aggregation effect of arachidonic acid is J, B, S.
The method of m1th et al. [The Journal of Clinical Investigation, Dan, 1468 (1978)]
).

Specifically, the platelet aggregation inhibitory effect was tested using the method shown below.

(1) Preparation of platelet-rich plasma (PRP solution) Blood (blood 9W: 1 volume of 8.84 sodium citrate solution) was collected from the carotid artery of a white male rabbit, and 1000 r, p,
Centrifugation was performed for IO minutes, and the supernatant was
It was used as an RP solution.

(2) Preparation of arachidonic acid solution Sodium abquidonate was dissolved in physiological saline to prepare an arachidonic acid 211f/ml solution.

(3) Add 0.9 ml of PRP solution and 0.9 ml of methanol solution of the test compound to the cuvette of the platelet aggregometer. Add O1g/t.

After incubation at 37°C for 1 minute, 0.05 ml of arachidonic acid solution, which is a platelet aggregation-inducing agent, was added. Track changes in permeability associated with platelet aggregation.

The ability of the test compound to inhibit platelet aggregation was measured. Measurements were carried out at various concentrations of the test compound, and the minimum concentration of the test compound required to completely inhibit platelet aggregation was determined.

The results are shown in Table 1. It has been found that the compounds according to the present invention have a strong platelet aggregation inhibiting effect. In addition, the compound numbers shown in Table 1 correspond to the above-mentioned compound numbers.

Table 1 Platelet aggregation inhibitory effect and acute toxicity Acute toxicity ICR female mice (body weight 20-25 g) were used, and each group had 6 mice. Test compound suspended in 2.54 gum arabic aqueous solution! It was administered orally at a rate of fc O,l sg//lOf body weight. General symptoms were observed for two weeks after administration, the number of deaths/number of test cases was calculated, and the lethal dose LD5o (qAg) was estimated. The results are shown in Table 1. It can be seen that all the compounds of the present invention have low toxicity.

Preparation and Dosage Preparations of the platelet aggregation inhibitor according to the present invention include oral,
Either enteral or parenteral administration can be selected. Specific formulations include tablets, capsules, fine granules, syrups, crude drugs, and the like. As carriers for the formulations of platelet aggregation inhibitors according to the invention, organic or inorganic solid or liquid, usually inert, pharmaceutical carrier materials suitable for oral, enteral or oral administration are used. It will be done. Specific examples include crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gums, and polyalkylene glyco-I. The ratio of the platelet aggregation inhibitor according to the invention to the carrier in the formulation is from 0.2 to
The platelet aggregation inhibitor according to the present invention can also contain other platelet aggregation inhibitors and other drugs that are compatible therewith. In this case, the platelet aggregation inhibitor according to the present invention It goes without saying that the aggregation inhibitor does not have to be the main ingredient in the preparation, and the platelet aggregation inhibitor according to the Oki invention is generally administered at a dosage that achieves the desired effect without side effects. Although the specific value should be determined by a doctor's judgment, it is generally administered at IOη to lOf, preferably about 201 g to 5 g, per day for adults. The platelet aggregation inhibitor can be administered as a pharmaceutical preparation with units of IIIP to 5f, preferably 3 Da to lf, as the active ingredient.

The present invention will be explained below with reference to production examples and examples, but the present invention is not limited thereto.

Production Example 1 Synthesis of Compound V p-tert-butylbenzaldehyde 4.85y1
α-Triphenylphosphoranylidene-γ-butyrolactone lo, 85f, and dimethyl sulfoxide CDMSO
40g/) of the mixture was reacted at 80°C for 2 hours. A 10-fold amount of chloroform was added to the reaction mixture, which was first washed with water, then washed with an aqueous solution of hydrogen sulfite, and further washed twice with water. After drying this chloroform layer over anhydrous sodium sulfate, chloroform was distilled off under reduced pressure, and the resulting residue was dissolved in ethanol and crystallized to obtain 2.221 colorless crystals (yield: 32). From the NMR spectrum and IR spectrum, it was confirmed that this compound was the target compound.

Production Examples 2 to 9 Production Example 1 using the reaction reagents and reaction times shown in Table 2.
The target compound was produced in the same manner as above. Production examples are shown in Table 2.

Preparation Example 1O Synthesis of Compound XXII 5-methyl-2-furfurur/v11. 1g of O and 17.22f of γ-butyrolactone were dissolved in 100yxl of ene, and 10.81ft of sodium methylate was added.
The reaction was carried out at 80°C for 30 minutes without stirring. The reaction mixture was poured into 200 ml of 1O superior sulfuric acid and stirred at room temperature for 1 hour. The generated precipitate was collected and recrystallized from ethyl acetate to obtain yellow crystals of Jl, 311 (yield: 7
．． 8%). From the NMR spectrum and IR spectrum, it was confirmed that this compound was the target compound.

Production Example 11 Synthesis of compound and methyl incyaner) was reacted at 70°C for 5 hours. The formed crystals were separated, washed with a small amount of toluene, and air-dried.

These crystals were recrystallized from ethanol to obtain colorless crystals of 1.65F (yield: 50). It was confirmed from the NMR spectrum and IR spectrum that this was the target compound.

Production Examples 12 to 15 Production Example 1 was prepared using the reaction reagents and reaction times shown in Table 8.
The desired compound was produced in the same manner as in Example 1. Production examples are shown in Table 8.

Example 1 A mixture of 1100 g of the compound, 55 g of lactose, and 41 g of dried potato starch was kneaded with 20 wt1 of water, and then extruded through a 16-mesh screen.

It was dried and granulated at 40°C. Next, the mixture was uniformly mixed with 4 g of magnesium stearate and compressed into tablets by a conventional method to obtain tablets containing 100 jlli' of the compound It in each 20 CIf tablet.

Example 2 Tablets containing 100 caps of compound xv in 200 III g of each tablet were obtained in the same manner as in Example 1 using compound xV instead of compound (1) of Example.

Example 3 After mixing 196f of granules obtained in exactly the same manner as in Example 1 with 4g of magnesium stearate, 200q each of the granules were filled into No. 2 hard capsules, and one capsule was filled with a hard capsule containing compound ■looMy. did.

Example 4 In the same manner as in Example 3, using Compound
It was made into a hard capsule containing 0q.

Example 5 Compound ■ 10. Oflactose
85. Of Crystalline Cellulose 4.5g Magnesium Stearate 15FI The above components were thoroughly mixed to obtain a powder containing 1θ011g of Compound (1) per volume.

Example 6 In place of Compound I in Example 5, Compound XVt- was used in the same manner as in Example 6 to obtain a powder containing 100 Mg of Compound XV in 1 g.

Procedural amendment Ch agent Showa Tuff year/λ month 3rd Director of the Patent Office Kazuo Wakasugi 1, Indication of the case 1983 Patent order No. 20 SO No. 2, Title of the invention Kouyuho Juryan Tushuibei IA3,
Person making an amendment Patent applicant 4, agent related to the case

Claims (1)

[Scope of Claims] (1) A platelet aggregation inhibitor containing an α-(substituted methylene)-5γ4-tyrolactone derivative represented by the following general formula (1) or a physiologically acceptable salt thereof as an active ingredient. 1 Lower-fJV Kyl group, hydroxyl group, lower alkoxy group, halogen atom or cyano group, R is hydrogen, lower alkoxy group, halogen atom group or phenyl group), naphthyl group, hydroxy Represents a naphthyl group, lower alkylfuryl group, pyridyl group or indolyl group. )