JPH0125752B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD 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 8 carbon atoms,
Represents a lower alkenyl group, lower alkynyl group or aralkyl 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. BACKGROUND ART 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 platelet aggregation inhibiting activity, 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. Problems to be Solved by the Invention Various studies were conducted to find a new type of platelet aggregation inhibitor that has excellent properties of inhibiting platelet aggregation and low toxicity. Means for Solving the Problems As a result of various studies, the present inventors have discovered that a novel diphenylpyrrolylthiazole derivative represented by the above general formula () satisfies these requirements, and has 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 8 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n- Butyl group, isobutyl group, sec-butyl group, n-pentyl group, isopentyl group, neo-pentyl group, 2-pentyl group, 3-pentyl group, 2
-Methyl-1-butyl group, 3-methyl-2-butyl group, n-hexyl group, n-octyl group, lower alkenyl group such as allyl group, lower alkynyl group such as propargyl group, Examples of aralkyl groups include benzyl groups. The diphenylpyrrolylthiazole derivative () of the present invention can be produced by the methods shown below (Method A, Method B). [Method A] In Method A, the compound () of the present invention is represented by the following formula () The compound shown by and the following formula () (In the formula, R is the same as above. X represents a halogen atom.) It can be produced by reacting with a compound represented by the following formula. That is, the compound () of the present invention can be produced by reacting the compound () with 1 to 1.2 equivalents of the compound () relative to the compound () in the presence of a base or a phase transfer catalyst. When using metallic potassium, metallic sodium, potassium tert-butoxide, etc. as a base, for example, N, N
- React in dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran or dimethoxyethane at room temperature to the boiling point of the solvent for 1 to 24 hours. In addition, when using a quaternary ammonium salt such as tetra-n-butylammonium bromide or methyltrioctylammonium chloride as a phase transfer catalyst, for example, benzene or dichloromethane and a 50% sodium hydroxide or 60% potassium hydroxide aqueous solution are used. The reaction is usually carried out for 1 to 10 minutes in a two-layer solution with a temperature ranging from 0°C to the boiling point of the solvent. The compound () used as a raw material in Method A is a new compound that has not been described in any literature, for example, the following formula () The compound shown by and the following formula () (In the formula, Y represents a bromine atom or a chlorine atom.) It can be produced by reacting with a compound represented by the following formula. That is, 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. It can be manufactured by [Method B] In Method B, the compound () of the present invention is represented by the following formula () It can be produced by reacting a compound represented by the following formula () R-OH () (wherein R is the same as above). That is, in the presence of an acid catalyst, compound () and a large excess of compound () are refluxed, or in the presence of an acid catalyst, 1 to 10 equivalents of compound () to compound () are mixed with benzene, toluene, etc. It can be produced by refluxing while water is distilled off azeotropically. The compound () used as a raw material in method B is, for example, the following formula It can be obtained by alkaline hydrolysis of the compound represented by (compound of Example 2 below) according to a conventional method. The compound of the present invention () exhibits a strong platelet aggregation inhibiting effect as described below, and has low toxicity, and is effective in preventing various diseases caused by platelet aggregation, such as thrombosis, ischemic heart disease, and transient cerebral ischemia. It is useful for treatment, and is further useful for the treatment of diseases associated with enhancement of platelet function, such as diabetes, hypertension, and arteriosclerosis. When the compound of the present invention () is used for the treatment or prevention of various thrombotic diseases caused by platelet aggregation, it is usually used as an orally administered agent. When used as an oral preparation, the compound of the present invention () is formulated into a conventional dosage form. Oral dosage forms include solid preparations such as tablets, granules, powders, fine granules, and hard capsules, as well as syrups,
Includes liquid preparations such as soft capsules. Preparation of such formulations is carried out by conventional methods. For example, solid preparations are formulated using conventional pharmaceutical additives such as lactose, starch, crystalline cellulose, tank, etc. Hard capsules can be obtained by filling fine granules, powders, etc. thus prepared into suitable capsules. A syrup can be obtained by dissolving or suspending the compound of the present invention () in an aqueous solution containing white sugar, carboxymethylcellulose, and the like. Soft capsules contain lipid excipients, such as vegetable oils, oil emulsions,
It can be obtained by filling a suitable soft capsule with the compound of the present invention () prepared using glycols and the like. The dosage of the compound () of the present invention varies depending on the type and severity of the disease, body weight, age, etc., but it is usually 1 to 100 mg per day for adults, administered at once or divided into 2 to 3 doses. Administer. Effects of the Invention 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 compound] (1) 19 compounds obtained in Examples 1 to 19 (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)
I got it. This citrate-added blood was centrifuged at 1700 rpm for 10 minutes, and platelet-rich plasma (PRP) was extracted from the supernatant.
After collecting the PRP, it was further centrifuged at 3000 rpm for 10 minutes, and platelet-poor plasma (PPP) was obtained from the supernatant. The thus obtained PRP450μ was incubated at 37°C for 3 minutes and used as a coagulant.
After adding 50μ of 1.0mM sodium arachidonate, the 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) × 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,
A test similar to the above was conducted using 50 μg of 100 μg/ml collagen as an aggregating agent. [Test Results] These are shown in Table 1 along with the following acute toxicity test results. 2. Acute toxicity [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 1.

【table】

[Table] Based on the above pharmacological test results, compounds of the present invention ()
has a superior platelet aggregation inhibitory effect compared to the known platelet aggregation inhibitors ticlopidine hydrochloride, aspirin, and the compounds A, B, and C described in the above-mentioned prior literature, and has low toxicity and is effective against platelet aggregation. It is useful for the prevention and treatment of various diseases caused by thrombosis, ischemic heart disease, and transient cerebral ischemia, as well as for the treatment of diseases associated with enhanced platelet function such as diabetes, hypertension, and arteriosclerosis. is also clearly useful. EXAMPLES Next, the present invention will be described in more detail with reference to reference examples and examples. Reference example 1 4,5-bis-(4-methoxyphenyl)-2-
Pyrrole-2-yl)thiazole: Pyrrole-2-carbothioamide [J.Org.
Chem., 38 667 (1973)] 1.51 g (12 mmol) and α-bromo-4,4'-dimethoxydeoxybenzoin [Aust. J. Chem., 8 , 385 (1955)
Reference] 4.02g (12 mmol) of acetonitrile
The mixture was dissolved in 120 ml and stirred at 60°C for 50 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and chloroform and an aqueous sodium carbonate solution were added to the resulting residue, which was then shaken. Next, the chloroform layer was separated, and the aqueous layer was extracted with chloroform and combined. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from ligroin to give 4,5-bis-(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole.
3.74g was obtained (yield 86%). Melting point: 131.5-134.0℃ NMR (CDCl ₃ , δppm): 3.7 (6H), 6.1 (1H,
dd), 6.5~6.9 (6H), 7.1~7.5 (4H), 9.4~9.8
(1H). Elemental analysis value (as C ₂₁ H ₁₈ N ₂ O ₂ S): Calculated value (%) C, 69.56; H, 5.01; N, 7.73 Actual value (%) C, 70.06; H, 4.90; N, 7.68 Reference example 2 2-[4,5-bis-(4-methoxyphenyl)
Thiazol-2-yl]pyrrol-1-yl acetic acid: 2-[4,5-bis-(4-methoxyphenyl)
3.59 g (8 mmol) of ethyl thiazol-2-yl]pyrrol-1-yl acetate (see Example 2),
0.90 g (16 mmol) of potassium hydroxide was refluxed in 80 ml of ethanol for 50 minutes. Ethanol was distilled off under reduced pressure, and the resulting residue was dissolved in water. 10% hydrochloric acid was added to this aqueous solution, and the precipitated crystals were collected by filtration and dried to obtain 3.20 g of crude crystals. By recrystallizing from benzene, 2.69 g of 2-[4,5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-yl acetic acid was obtained (yield: 80%). Melting point: 197.5-200.5℃ NMR (DMSO-d6, δppm): 3.75 (3H, s),
3.8 (3H, s), 5.25 (2H, s), 6.15 (1H, dd),
6.75 (1H, dd), 6.8~7.1 (5H), 7.2~7.55 (4H),
12.3-13.1 (1H). Elemental analysis value (as C ₂₃ H ₂₀ N ₂ O ₄ S): Calculated value (%) C, 65.70; H, 4.79; N, 6.66 Actual value (%) C, 65.75; H, 4.74; N, 6.48 Example 1 2-[4,5-bis-(4-methoxyphenyl)
Thiazol-2-yl]pyrrol-1-ylmethyl acetate (Method A): 4.5-bis-(4-methoxyphenyl)-2-pyrrol-2-yl)thiazole (see Reference Example 1)
1.81g (5 mmol), 0.84g methyl bromoacetate
(5.5 mmol) and 0.16 g (0.5 mmol) of tetra-n-butylammonium bromide in dichloromethane.
The mixture was stirred vigorously for 2 minutes at room temperature in a bilayer solution of 20 ml and 20 ml of 50% aqueous sodium hydroxide solution. Next, water and dichloromethane were added and shaken while cooling on ice. The dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane and combined. After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [developing solvent: dichloromethane:
cyclohexane (1:1)], then n
-2-[4,
Methyl 5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-yl acetate 1.31
g (60% yield). Melting point: 171.5-174.5°C NMR (CDCl ₃ , δppm): 3.7 (3H, s), 3.8
(6H), 5.25 (2H, s), 6.25 (1H, dd), 6.7~6.95
(6H), 7.2-7.5 (4H). Elemental analysis value (as C ₂₄ H ₂₂ N ₂ O ₄ S): Calculated value (%) C, 66.34; H, 5.10; N, 6.45 Actual value (%) C, 66.41; H, 4.99; N, 6.43 Example 2 2-[4,5-bis-(4-methoxyphenyl)
Ethyl thiazol-2-yl]pyrrol-1-yl acetate (method A): 4,5-bis-(4-methoxyphenyl)-2-
(pyrrol-2-yl)thiazole (see Reference Example 1) 3.62 g (10 mmol), ethyl bromoacetate
1.67 g (10 mmol) and 0.32 g (1 mmol) of tetra-n-butylammonium bromide were refluxed for 2 minutes with vigorous stirring in a bilayer solution of 40 ml of dichloromethane and 40 ml of 50% aqueous sodium hydroxide solution.
Next, water and dichloromethane were added and shaken while cooling on ice. The dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane and combined. After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ligroin to obtain 3.64 g of ethyl 2-[4,5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-yl acetate (yield: 81%). Melting point: 132.5-135.5°C NMR (CDCl ₃ , δppm): 1.2 (3H, t), 3.8
(6H), 4.15 (2H, quartet), 5.25 (2H, s), 6.25
(1H, dd), 6.7-6.95 (6H), 7.2-7.55 (4H). Elemental analysis value (as C ₂₅ H ₂₄ N ₂ O ₄ S): Calculated value (%) C, 66.95; H, 5.39; N, 6.25 Actual value (%) C, 67.17; H, 5.40; N, 6.19 Example 3 2-[4,5-bis-(4-methoxyphenyl)
Thiazol-2-yl]pyrrol-1-yl n-propyl acetate (method B): 2-[4,5-bis-(4-methoxyphenyl)
2.10 g (5 mmol) of thiazol-2-yl]pyrrol-1-yl acetic acid (see Reference Example 2), concentrated sulfuric acid
100 mg was refluxed in 100 ml of n-probanol for 20 minutes. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent: dichloromethane), and then recrystallized from cyclohexane to give 2-[4,5-bis-(4-
1.40 g of n-propyl (methoxyphenyl)thiazol-2-yl]pyrrol-1-yl acetate was obtained (yield: 61%). Melting point: 94.0~97.0℃ NMR ( _CDCl3 , δppm): 0.8 (3H, t), 1.4~
1.75 (2H), 3.8 (6H), 4.05 (2H, t), 5.25 (2H,
s), 6.25 (1H, dd), 6.65-6.9 (6H), 7.2-7.5
(4H). Elemental analysis values (as C ₂₆ H ₂₆ N ₂ O ₄ S): Calculated value (%) C, 67.51; H, 5.67; N, 6.06 Actual value (%) C, 67.75; H, 5.48; N, 6.20 Example 4 2-[4,5-bis-(4-methoxyphenyl)
Isopropyl thiazol-2-yl]pyrrol-1-yl acetate (Method B): 2-[4, 5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrole-1
-1.40 g of isopropyl acetate was obtained (yield: 61
%). Melting point: 130.0-133.0°C NMR (CDCl ₃ , δppm): 1.15 (6H, d), 3.8
(6H), 4.8-5.15 (1H), 5.25 (2H, s), 6.25
(1H, dd), 6.65-6.9 (6H), 7.2-7.5 (4H). Elemental analysis value (as C ₂₆ H ₂₆ N ₂ O ₄ S): Calculated value (%) C, 67.51; H, 5.67; N. 6.06 Actual value (%) C, 67.78; H, 5.64; N, 6.10 Example 5 2-[4,5-bis-(4-methoxyphenyl)
Thiazol-2-yl]pyrrol-1-yl n-butyl acetate (method B): 2-[4,5-bis-(4-methoxyphenyl)
1.68 g (4 mmol) of thiazol-2-yl]pyrrol-1-yl acetic acid (see Reference Example 2), 0.30 g (4 mmol) of n-butanol, and 95 mg (0.5 mmol) of p-toluenesulfonic acid in 50 ml of benzene.
The mixture was refluxed for 8 hours while water was distilled off azeotropically. After cooling, benzene was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent;
2-[4,5-bis-(4-methoxyphenyl)thiazole-2-
1.20 g of n-butyl pyrrol-1-yl acetate
was obtained (yield 63%). Melting point: 98.0-101.0°C NMR (CDCl ₃ , δppm): 0.85 (3H, t), 1.1-
1.7 (4H), 3.85 (6H), 4.1 (2H, t), 5.3 (2H,
s), 6.25 (1H, dd), 6.7-6.95 (6H), 7.2-7.5
(4H). Elemental analysis value (as C ₂₇ H ₂₈ N ₂ O ₄ S): Calculated value (%) C, 68.04; H, 5.92; N, 5.88 Actual value (%) C, 68.19; H, 6.03; N, 5.99 Example 6 2-[4,5-bis-(4-methoxyphenyl)
Isobutyl thiazol-2-yl]pyrrol-1-yl acetate (method A): 4,5-bis-(4-methoxyphenyl)-2-
(pyrrol-2-yl)thiazole (see Reference Example 1) 1.81 g (5 mmol), isobutyl bromoacetate 1.07 g (5.5 mmol), and tetra-n-butylammonium bromide 0.16 g (0.5 mmol) in 20 ml of dichloromethane, 50 % sodium hydroxide aqueous solution 20ml
was stirred vigorously for 2 minutes at room temperature. Next, water and dichloromethane were added and shaken while cooling on ice. The dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane and combined. After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [developing solvent: dichloromethane:cyclohexane (1:1)], and then recrystallized from n-hexane.
1.31 g of isobutyl 2-[4,5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-yl acetate was obtained (yield 55%). Melting point: 105.5-108.5°C NMR (CDCl ₃ , δppm): 0.8 (6H, d), 1.7-
2.0 (1H), 3.5-3.95 (8H), 5.3 (2H, s), 6.25
(1H, dd), 6.7-6.95 (6H), 7.2-7.5 (4H). Elemental analysis value (as C ₂₇ H ₂₈ N ₂ O ₄ S): Calculated value (%) C, 68.04; H, 5.92; N, 5.88 Actual value (%) C, 67.72; H, 5.87; N, 5.92 Example 7 2-[4,5-bis-(4-methoxyphenyl)
sec-butyl thiazol-2-yl]pyrrol-1-yl acetate (method A): Bromoacetic acid instead of isobutyl bromoacetate
2-[4,5-bis-(4
1.67 g of sec-butyl (methoxyphenyl)thiazol-2-yl]pyrrol-1-yl acetate was obtained (yield 70%). Melting point: 102.5-105.5°C NMR (CDCl ₃ , δppm): 0.75 (3H, t), 1.05
(3H, d), 1.3-1.65 (2H), 3.8 (6H), 4.85 (1H,
quartet), 5.3 (2H, s), 6.2 (1H, dd), 6.65~
6.9 (6H), 7.2~7.5 (4H). Elemental analysis value (as C ₂₇ H ₂₈ N ₂ O ₄ S): Calculated value (%) C, 68.04; H, 5.92; N, 5.88 Actual value (%) C, 68.13; H, 5.95; N, 5.99 Example 8 2-[4,5-bis-(4-methoxyphenyl)
Thiazol-2-yl]pyrrol-1-yl n-pentyl acetate (Method B): 2-[4,5-bis-(4-methoxyphenyl)
2.10 g (5 mmol) of thiazol-2-yl]pyrrol-1-yl acetic acid (see Reference Example 2), 1.76 g (20 mmol) of n-pentanol, and 200 mg of concentrated sulfuric acid were azeotroped with water in 50 ml of benzene. The mixture was refluxed for 2 hours while being distilled off. After cooling, benzene was distilled off under reduced pressure, the resulting residue was subjected to silica gel column chromatography [developing solvent: dichloromethane], and then recrystallized from n-hexane to obtain 2.
-[4,5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetic acid n-
1.14 g of pentyl was obtained (yield 46%). Melting point: 101.0~104.0℃ NMR ( _CDCl3 , δppm): 0.85 (3H, t), 1.1~
1.7 (6H), 3.8 (6H), 4.1 (2H, s), 5.3 (2H,
s), 6.25 (1H, dd), 6.7-6.95 (6H), 7.2-7.5
(4H). Elemental analysis value (as C ₂₈ H ₃₀ N ₂ O ₄ S): Calculated value (%) C, 68.55; H, 6.16; N, 5.71 Actual value (%) C, 68.61; H, 6.02; N, 5.76 Example 9 2-[4,5-bis-(4-methoxyphenyl)
Isopentyl thiazol-2-yl]pyrrol-1-yl acetate (method B): isopentanol instead of n-pentanol
2-[4,5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrole-1-
1.13 g of isopentyl yl acetate was obtained (yield 46%). Melting point: 98.5-101.5°C NMR (CDCl ₃ , δppm): 0.8 (6H, d), 1.3-
1.7 (3H), 3.8 (6H), 4.1 (2H, t), 5.3 (2H,
s), 6.25 (1H, dd), 6.7-6.95 (6H), 7.2-7.5
(4H). Elemental analysis value (as C ₂₈ H ₃₀ N ₂ O ₄ S): Calculated value (%) C, 68.55; H, 6.16; N, 5.71 Actual value (%) C, 68.29; H, 6.17; N, 5.81 Example 10 2-[4,5-bis-(4-methoxyphenyl)
thiazol-2-yl]pyrrol-1-yl neo-pentyl acetate (method A): Bromoacetic acid instead of isobutyl bromoacetate
2-[4,5-bis-
(4-methoxyphenyl)thiazol-2-yl]
1.72 g of neo-pentyl pyrrol-1-yl acetate was obtained (yield 70%). Melting point: 114.5-117.5°C NMR (CDCl ₃ , δppm): 0.8 (9H, s), 3.8
(6H), 5.35 (2H, s), 6.25 (1H, dd), 6.7~6.95
(6H), 7.2-7.5 (4H). Elemental analysis values (as C ₂₈ H ₃₀ N ₂ O ₄ S): Calculated value (%) C, 68.55; H, 6.16; N, 5.71 Actual value (%) C, 68.45; H, 6.32; N, 5.64 Example 11 2-[4,5-bis-(4-methoxyphenyl)
thiazol-2-yl]pyrrol-1-yl-2-methyl-1-butyl acetate (method B): 2-methyl-1-in place of n-pentanol
2-[4,5-bis-(4-
methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate-2-methyl-1-butyl
0.83g was obtained (yield 34%). Melting point: 81.5~84.5℃ NMR ( _CDCl3 , δppm): 0.7~0.9 (6H), 1.0~
1.8 (3H), 3.8 (6H), 3.85~4.05 (2H), 6.3 (2H,
s), 6.25 (1H, dd), 6.7~. 6.95 (6H), 7.2~7.5
(4H). Elemental analysis value (as C ₂₈ H ₃₀ N ₂ O ₄ S): Calculated value (%) C, 68.55; H, 6.16; N, 5.71 Actual value (%) C, 68.20; H, 6.10; N, 5.83 Example 12 2-[4,5-bis-(4-methoxyphenyl)
thiazol-2-yl]pyrrol-1-yl-2-pentyl acetate (method B): 2-pentanol instead of n-pentanol
1.64 g of 2-pentyl 2-[4,5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-yl acetate was prepared in the same manner as in Example 8, except that 1.76 g (20 mmol) was used. was obtained (yield 67%). Melting point: 81.0~84.0℃ NMR ( _CDCl3 , δppm): 0.65~0.9 (3H), 1.0~
1.65 (7H), 3.85 (6H), 4.75~5.1 (1H), 5.3 (2H,
s), 6.25 (1H, dd), 6.7-6.95 (6H), 7.2-7.55
(4H). Elemental analysis value (as C ₂ ⁸ H ₃₀ N ₂ O ₄ S): Calculated value (%) C, 68.55; H, 6.16; N, 5.71 Actual value (%) C, 68.81; H, 6.33; N, 5.85 Implemented Example 13 2-[4,5-bis-(4-methoxyphenyl)
3-pentyl thiazol-2-yl]pyrrol-1-yl acetate (method B): 3-pentanol instead of n-pentanol
2-[4,5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrole-1-
1.69 g of 3-pentyl ylacetate was obtained (yield 69%). Melting point: 94.0~97.0°C NMR ( _CDCl3 , δppm): 0.75 (6H, t), 1.3~
1.65 (4H), 3.85 (6H), 4.9 (1H, quintet), 5.4
(2H, s), 6.25 (1H, dd), 6.7-6.95 (6H), 7.2
~7.55 (4H). Elemental analysis value (as C ₂₈ H ₃₀ N ₂ O ₄ S): Calculated value (%) C, 68.55; H, 6.16; N, 5.71 Actual value (%) C, 68.80; H, 6.25; N, 5.76 Example 14 2-[4,5-bis-(4-methoxyphenyl)
Thiazol-2-yl]pyrrol-1-yl 3-methyl-2-butyl acetate (B) method: 3-methyl-2-yl instead of n-pentanol
2-[4,5-bis-(4-
3-Methyl-2-butyl (methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate 0.71
g (yield 29%). Melting point: 88.5-91.5°C NMR (CDCl ₃ , δppm): 0.75 (6H, d), 1.0
(3H, d), 1.5-1.9 (1H), 3.85 (6H), 4.65-4.9
(1H), 5.35 (2H, s), 6.25 (1H, dd), 6.7-6.95
(6H), 7.2-7.55 (4H). Elemental analysis value (as C ₂₈ H ₃₀ N ₂ O ₄ S): Calculated value (%) C, 68.55; H, 6.16; N, 5.71 Actual value (%) C, 68.37; H, 6.26; N, 5.72 Example 15 2-[4,5-bis-(4-methoxyphenyl)
n-hexyl thiazol-2-yl]pyrrol-1-yl acetate (method A): n-bromoacetate instead of isobutyl bromoacetate
2-[4,5-bis-(4
2.12 g of n-hexyl (-methoxyphenyl)thiazol-2-yl]pyrrol-1-yl acetate was obtained (yield 76%). Melting point: 102.0~105.0℃ NMR ( _CDCl3 , δppm): 0.85 (3H), 1.1~1.65
(8H), 3.8 (6H), 4.1 (2H, t), 5.25 (2H, s),
6.25 (1H, dd), 6.7~6.95 (6H), 7.2~7.5 (4H). Elemental analysis values (as C ₂₉ H ₃₂ N ₂ O ₄ S): Calculated value (%) C, 69.02; H, 6.39; N, 5.55 Actual value (%) C, 69.20; H, 6.28; N, 5.71 Example 16 2-[4,5-bis-(4-methoxyphenyl)
n-octyl thiazol-2-yl]pyrrol-1-yl acetate (method B): n-octanol instead of n-pentanol
2-[4,5-bis-4-methoxyphenyl)thiazol-2-yl]pyrrole-1-
Obtained 1.15 g of n-octyl ylacetate (yield 43%) Melting point: 84.5-87.5°C NMR (CDCl ₃ , δppm): 0.9 (3H), 1,1-1.7
(12H), 3.85 (3H, s), 3.9 (3H, s), 4.1 (2H,
t), 5.3 (2H), 6.25 (1H, dd), 6.7-6.95 (6H),
7.2-7.55 (4H). Elemental analysis value (as C ₃₁ H ₃₆ N ₂ O ₄ S): Calculated value (%) C, 69.90; H, 6.81; N, 5.26 Actual value (%) C, 70.01; H, 7.02; N, 5.30 Example 17 2-[4,5-bis-(4-methoxyphenyl)
Allyl thiazol-2-yl]pyrrol-1-yl acetate (method A): 2-[4, 1.66 g of allyl 5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-yl acetate was obtained (yield 72%). Melting point: 97.0~100.0℃ NMR ( _CDCl3 , δppm): 3.85 (6H), 4.55~4.65
(2H), 5.1~5.35 (4H), 5.6~. 6.0 (1H), 6.25
(1H, dd), 6.7-6.95 (6H), 7.2-7.55 (4H). Elemental analysis value (as C ₂₆ H ₂₄ N ₂ O ₄ S): Calculated value (%) C, 67.81: H, 5.25; N, 6.08 Actual value (%) C, 67.89; H, 5.32; N, 6.32 Example 18 2-[4,5-bis-(4-methoxyphenyl)
Thiazol-2-yl]pyrrol-1-yl propargyl acetate (method A): 4,5-bis-(4-methoxyphenyl)-2-
After stirring 2.19 g (6 mmol) of (pyrrol-1-yl)thiazole (see Reference Example 1) and 0.71 g (6.3 mmol) of potassium tert-butoxide in 10 ml of DMF at room temperature, propargyl bromoacetate was added.
1.17 g (6.6 mmol) was added, and the mixture was stirred at room temperature all day and night. Next, water and ethyl acetate were added, and the ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography [developing solvent;
2-[4,5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrole-1-
1.62 g of propargyl yl acetate was obtained (yield 59%) Melting point: 100.0-103.0°C NMR (CDCl ₃ , δppm): 2.45 (1H, t), 3.8
(6H), 4.65 (2H, d), 5.3 (2H, s), 6.25 (1H,
dd), 6.65-6.9 (6H), 7.2-7.5 (4H). Elemental analysis value (as C ₂₆ H ₂₂ N ₂ O ₄ S): Calculated value (%) C, 68.10; H, 4.84; N, 6.11 Actual value (%) C, 68.29; H, 4.70; N, 6.05 Example 19 2-[4,5-bis-(4-methoxyphenyl)
Benzyl thiazol-2-yl]pyrrol-1-yl acetate (method A): 2-[4, 0.92 g of benzyl 5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-yl acetate was obtained (yield: 36
%). Melting point: 152.0-154.5℃ NMR (CDCl ₃ , δppm): 3.80 (3H, s), 3.85
(3H, s), 5.1 (2H, s), 5.3 (2H, s), 6.25
(1H, dd), 6.7-6.9 (6H), 7.15-7.5 (9H). Elemental analysis value (as C ₃₀ H ₂₆ N ₂ O ₄ S): Calculated value (%) C, 70.57; H, 5.13; N, 5.49 Actual value (%) C, 70.49; H, 5.02; N, 5.41 Example 20, 21, 22, 23 The following compounds were synthesized according to Example 8. (Method B) 2-[4,5-bis-(4-methoxyphenyl)
Thiazol-2-yl]pyrrol-1-yl isobutyl acetate (yield 34%) 2-[4,5-bis-(4-methoxyphenyl)
Thiazol-2-yl]pyrrol-1-yl acetic acid
sec-butyl (yield 41%) 2-[4,5-bis-(4-methoxyphenyl)
Thiazol-2-yl]pyrrol-1-yl acetic acid
neo-pentyl (yield 22%) 2-[4,5-bis-(4-methoxyphenyl)
n-hexyl thiazol-2-yl]pyrrol-1-yl acetate (yield 46%) The above-obtained compounds exhibited the same physical properties as the corresponding compounds described in the examples above. Example 24 Formulation example (tablet) One tablet contains 2-[4,5-bis-
(4-methoxyphenyl)thiazol-2-yl]
Compressed tablets containing 2 mg of allyl pyrrol-1-yl acetate (compound of Example 17) were prepared according to the following formulation. [Formulation] Ingredients Total amount (g) Compound of Example 17...40 Crystalline cellulose...1580 Lactose...1600 Carboxymethyl cellulose Calcium...120 Talc...40 Magnesium stearate...20 Each of the above ingredients Mix uniformly and add 1 according to the usual method.
It was compressed into tablets of 170 mg. Example 25 Formulation example (powder) 2-[4,5-bis-
(4-methoxyphenyl)thiazol-2-yl]
n-propyl pyrrol-1-yl acetate (Example 3)
A powder containing 2 mg of the compound) was prepared according to the following formulation. [Formulation] Ingredients Total amount (g) Compound of Example 3...2 Lactose...598 Starch...400 The above ingredients were thoroughly mixed to form a uniform powder. Example 26 Formulation example (hard capsule) One capsule contains 2-[4,5-
Bis-(4-methoxyphenyl)thiazole-2
-yl]pyrrol-1-yl isobutyl acetate (compound of Example 6) 2 mg hard capsules were prepared according to the following formulation. [Formulation] Ingredients Total amount (g) Compound of Example 6...40 Crystalline cellulose...880 Lactose...2000 Talc...60 Magnesium stearate...20 Thoroughly mix the above ingredients to form a homogeneous mixture. Powder and
Each 150 mg of this was filled into No. 3 hard capsules. Example 27 Formulation example (soft capsule) One capsule contains 2-[4,5-
Bis-(4-methoxyphenyl)thiazole-2
-yl]pyrrol-1-yl propargyl acetate (compound of Example 18) 2 mg soft capsules were prepared according to the following formulation. [Formulation (1)] Total amount of ingredients (g) Compound of Example 18...40 Corn oil...1960 [Formulation (2)] Total amount of ingredients (g) Gelatin...2000 Glycerin...660 Paraoxy Methyl benzoate...4 Paraoxypropyl benzoate...1 Purified water...1600 A gelatin film prepared by dissolving the compound of Example 18 in corn oil according to recipe (1) and then preparing it according to recipe (2) Soft capsules were obtained.

Claims (1)

[Claims] 1. The following formula (In the formula, R is an alkyl group having 1 to 8 carbon atoms,
Represents a lower alkenyl group, lower alkynyl group or aralkyl group. ) A diphenylpyrrolylthiazole derivative represented by 2 Below formula The compound shown by and the formula below (In the formula, R is an alkyl group having 1 to 8 carbon atoms,
It represents a lower alkenyl group, a lower alkynyl group or an aralkyl group, and X represents a halogen atom. ) 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 diphenylpyrrolylthiazole derivative represented by the following. 3 Below formula A compound represented by the following formula R-OH (wherein R is an alkyl group having 1 to 8 carbon atoms,
Represents a lower alkenyl group, lower alkynyl group or aralkyl 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 diphenylpyrrolylthiazole derivative represented by the following. 4 Below formula (In the formula, R is an alkyl group having 1 to 8 carbon atoms,
Represents a lower alkenyl group, lower alkynyl group or aralkyl group. ) A platelet aggregation inhibitor containing a diphenylpyrrolylthiazole derivative as an active ingredient.