JPH0512350B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel diphenylpyrrolylthiazole derivative, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient. For more details, see the general formula () (In the formula, R is an alkyl group having 1 to 4 carbon atoms,
Alkenyl group having 2 to 4 carbon atoms, 2 carbon atoms
~4 alkynyl group or 2,2,2-trifluoroethyl group. ) The present invention relates to a diphenylpyrrolylthiazole derivative represented by the following, a method for producing the same, and a platelet aggregation inhibitor containing the compound as an active ingredient. Conventionally, various compounds such as ticlopidine hydrochloride and aspirin have been clinically used as platelet aggregation inhibitors. By the way, U.S. Patent No. 4168315 and J.Med.
Chem. 24 , 1507 (1981) discloses 4,5-diphenyl-2-substituted or unsubstituted alkylthiazoles having a platelet aggregation inhibitory effect, and among them, 4,5-bis(4 -methoxyphenyl)-2-trifluoromethylthiazole (compound A) is exemplified as a representative compound. Furthermore, U.S. Pat. No. 4,322,428 discloses 4,5-bis-(4-methoxyphenyl)-2-(4-halophenyl)thiazole as an anti-inflammatory agent and platelet aggregation inhibitor, and it has platelet aggregation inhibitory effect. Although specific pharmacological test results have not been described, a representative compound is 4,5-bis-(4-methoxyphenyl)-2-
(4-fluorophenyl)thiazole (compound B)
is exemplified. On the other hand, European Patent No. 77024 has 4,
5-bis-(4-methoxyphenyl)-2-pyrrorylimidazole derivatives are disclosed as anti-inflammatory agents, and are 4,5-bis-(4-methoxyphenyl)-2-( 1-methylpyrrole-2
-yl)imidazole (compound C) is exemplified. The present inventors have conducted intensive research to obtain a new type of platelet aggregation inhibitor that has excellent platelet aggregation inhibitory effects and low toxicity, and as a result, a novel diphenylpyrrolylthiazole derivative represented by the general formula () has been obtained. The inventors have discovered that the present invention satisfies such requirements, and have completed the present invention. An object of the present invention is to provide a novel diphenylpyrrolylthiazole derivative that exhibits a strong inhibitory effect on platelet aggregation, has low toxicity, and is useful for the prevention and treatment of various thrombotic diseases caused by platelet aggregation. It is in. Another object of the present invention is to provide a method for producing novel diphenylpyrrolylthiazole derivatives. Another object of the present invention is to provide a platelet aggregation inhibitor containing a novel diphenylpyrrolylthiazole derivative as an active ingredient. Among the groups defined by R in the diphenylpyrrolylthiazole derivative () of the present invention, examples of the alkyl group having 1 to 4 carbon atoms include ethyl group, n-propyl group, isopropyl group, and isobutyl group. Examples of the alkenyl group having 2 to 4 atoms include allyl group, and examples of the alkynyl group having 2 to 4 carbon atoms include propargyl group and 2,2,2-trifluoroethyl group. The diphenylpyrrolylthiazole derivative () of the present invention can be produced by the methods shown below (Method A, Method B). [Method A] (In the formula, R is the same as above. X represents a bromine atom or a chlorine atom.) In method A, first, 0.5
Compound () is prepared by bubbling hydrogen sulfide gas into compound () in the presence of ~5 equivalents of base, for example in dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or pyridine at 0-40°C for 3-24 hours. get. As the base, tertiary amines such as triethylamine are preferably used. Next, compound () and an equivalent amount of compound () to compound () are reacted for 10 minutes to 4 hours in an alcohol such as acetonitrile, DMF, DMSO or ethanol at 50°C to the boiling point temperature of the solvent. The compound () of the present invention can be obtained by this method. For example, the compound () used as a raw material in Method A has the following formula: (In the formula, R is the same as above.) According to the conventional method, the compound () is converted into an oxime (), and then the oxime () is heated in acetic anhydride (see Reference Examples below). ). [Method B] (In the formula, R and X are the same as above. Y is a bromine atom,
Represents a chlorine atom, an iodine atom, or a p-toluenesulfonyloxy group. ) In method B, first, pyrrole-2-carbothioamide () and compound () are reacted in the same manner as in the case of compound () and compound () in method A. Intermediate 4,5
-bis-(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole () is obtained. Next, the compound () of the present invention can be obtained by reacting the production intermediate () with the compound () in the presence of a base. When metallic potassium, metallic sodium, potassium tert-butoxide, etc. are used as a base, the production intermediate () and an excess amount of the compound () relative to the production intermediate () are mixed with, for example, DMF, DMSO, tetrahydrofuran or The reaction is carried out in dimethoxyethane at room temperature to the boiling point temperature of the solvent for 1 to 24 hours. The reaction between the production intermediate () and the compound () can be carried out using a quaternary ammonium salt such as tetra-n-butylammonium bromide or methyltrioctylammonium chloride as a phase transfer catalyst, for example, with benzene or dichloromethane. , 50% sodium hydroxide or 60% potassium hydroxide aqueous solution in a two-layer solution at 0° C. to the boiling point of the solvent for several minutes to 24 hours. The compound of the present invention () exhibits a strong platelet aggregation inhibitory effect, has low toxicity, and is useful for the prevention and treatment of various diseases caused by platelet aggregation, such as thrombosis, ischemic heart disease, and transient cerebral ischemia. Moreover, it is also useful in the treatment of diseases associated with enhancement of platelet function, such as diabetes, hypertension, and arteriosclerosis. The test results of the platelet aggregation inhibitory effect and acute toxicity of the compound of the present invention () are shown below. 1. Platelet aggregation inhibitory effect [test compounds] (1) Seven compounds obtained in Examples 1 to 7 (compounds of the present invention) (2) Compounds A, B, and C (comparative compounds...each described in the above patent publication) (compound) (3) Ticlopidine hydrochloride (comparison compound) (4) Aspirin (comparison compound) [Test method] Hartley guinea pigs fasted overnight (body weight
Each test compound was dissolved or suspended in corn oil-10% gum arabic emulsion and administered orally to 300 to 350 g (3 animals per group), and 3 hours later, blood was collected from the abdominal aorta and citrated blood was added. (1/10 volume of 3.8% sodium citrate aqueous solution: 9/10 volume of blood) was obtained. This citrate-added blood was centrifuged at 1700 rpm for 10 minutes, and platelet-rich plasma (PRP) was obtained from the supernatant.
After collecting PRP, centrifuge at 3000 rpm for 10 minutes.
Platelet poor plasma (PPP) was obtained from the supernatant. 450 μl of PRP obtained in this way was heated at 37℃ for 3 minutes.
Incubate for 1 minute and use as a flocculant.
After adding 50 μl of 1.0 mM sodium arachidonate,
Platelet aggregation rate was measured using a platelet aggregation profiler (Bio Data Corp Model PAP-3) using the above PPP as a blank. As a control, the aggregation rate of a group to which no drug was administered was measured in the same manner. The platelet aggregation inhibition rate was calculated using the following formula. Platelet aggregation inhibition rate (%) = (1 - aggregation rate of test compound administration group/aggregation rate of control group) x 100 Next, calculate the dose (ED50) at which the platelet aggregation inhibition rate is 50% using the regression formula. I asked for it. Also, instead of sodium arachidonic acid,
The same test as above was conducted using 50 μl of 100 μg/ml collagen as an aggregating agent. [Test Results] The results are shown in Table 1.

[Test compound]

Same as "platelet aggregation inhibition effect" above. [Test method] Ddy male mice (weight 18-23g, 5 mice per group)
were fasted overnight, and each test compound was suspended in a 1% gum arabic solution and administered orally. The acute toxicity value (LD50) was calculated using the Weil method from the number of deaths 10 days after administration. [Test Results] The results are shown in Table 2.

[Prescription]

Ingredient blending amount (g) Compound of Example 5...2 Lactose...598 Starch...400 The above ingredients were thoroughly mixed to form a uniform powder. Example 15 Formulation example (hard capsule) 4,5-bis- as an active ingredient in one capsule
Capsules containing 2 mg of (4-methoxyphenyl)-2-(1-n-propylpyrrol-2-yl)thiazole (compound of Example 3) were prepared according to the following formulation. [Formulation] Component blending amount (g) Compound of Example 3... 40 Crystalline cellulose... 880 Lactose... 2000 Talc... 60 Magnesium stearate... 20 The above ingredients are thoroughly mixed to form a uniform powder. year,
Each 150 mg of this was filled into No. 3 hard capsules. Example 16 Formulation example (soft capsule) One capsule contains 4,5-bis-
Soft capsules containing 2 mg of (4-methoxyphenyl)-2-(1-n-propylpyrrol-2-yl)thiazole (compound of Example 3) were prepared according to the following formulation. [Formulation (1)] Ingredient blending amount (g) Compound of Example 3... 40 Corn oil... 1960 [Formulation (2)] Ingredient blending amount (g) Gelatin... 2000 Glycerin... 660 Paraoxybenzoic acid Methyl... 4 Propyl paraoxybenzoate... 1 Purified water... 1600 The compound of Example 3 was dissolved in corn oil according to recipe (1), and then wrapped in a gelatin film prepared according to recipe (2) and softened. Capsules were obtained.

Claims (1)

[Claims] 1. The following formula (In the formula, R is an alkyl group having 1 to 4 carbon atoms,
Alkenyl group having 2 to 4 carbon atoms, 2 carbon atoms
~4 alkynyl group or 2,2,2-trifluoroethyl group. ) A diphenylpyrrolylthiazole derivative represented by 2 Below formula (In the formula, R is an alkyl group having 1 to 4 carbon atoms,
Alkenyl group having 2 to 4 carbon atoms, 2 carbon atoms
~4 alkynyl group or 2,2,2-trifluoroethyl group. ) is reacted with hydrogen sulfide to form the following formula (In the formula, R is the same as above.) Then, the above compound and the following formula (In the formula, X represents a bromine atom or a chlorine atom.) (In the formula, R is the same as above.) A method for producing a novel diphenylpyrrolylthiazole derivative. 3 Below formula Pyrrole-2-carbothioamide represented by the following formula (In the formula, X represents a bromine atom or a chlorine atom.) By reacting with a compound represented by the following formula The production intermediate 4,5-bis-(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole represented by the following formula is prepared, and then the production intermediate and the following formula RY (wherein, R is carbon an alkyl group having 1 to 4 atoms,
Alkenyl group having 2 to 4 carbon atoms, 2 carbon atoms
~4 alkynyl group or 2,2,2-trifluoroethyl group. Y represents a bromine atom, a chlorine atom, an iodine atom or a p-toluenesulfonyloxy group. ) The following formula is characterized by reacting with a compound represented by (In the formula, R is the same as above.) A method for producing a novel diphenylpyrrolylthiazole derivative. 4 Below formula (In the formula, R is an alkyl group having 1 to 4 carbon atoms,
Alkenyl group having 2 to 4 carbon atoms, 2 carbon atoms
~4 alkynyl group or 2,2,2-trifluoroethyl group. ) A platelet aggregation inhibitor containing a diphenylpyrrolylthiazole derivative as an active ingredient.