JPS60222481A - Novel diphenylpyrrolylthiazole derivative, its preparation, and drug composition comprising it as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R is lower alkyl, lower alkenyl, lower alkynyl, or 2,2,2-trifluoroethyl). EXAMPLE:4,5-Bis-( 4-methoxyphenyl )-2-( 1-ethylpyrrol-2-yl )thiazole. USE:An inhibitor of blood platelet aggregation. Having low toxicity, useful for preventing and remedying various thrombotic diseases caused by blood platelet aggregation. PREPARATION:A compound shown by the formula II is reacted with a hydrogen sulfide gas in the presence of 0.5-5 equivalent base in DMF, DMSO, etc., to give a compound shown by the formula III. Then, this compound is an equivalent amount of a compound shown by the formula IV (X is Cl, or Br) to give a compound shown by the formula I. The compound shown by the formula I is usually used as an oral drug in order to remedy and to prevent various thrombotic diseases caused by blood platelet aggregation.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel diphenylpyrrolylthiazole derivatives,
The present invention relates to a method for producing the same and a pharmaceutical composition containing the same as an active ingredient. More specifically, diphenylpyrrolylthiazole derivatives represented by the general formula CI) (wherein R represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a 2,2,2-trifluoroethyl group); The present invention relates to a production method 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, US Pat. No. 4,188,315 and J.

Med, Che+s, 24.1507 (1981)
contains 4,5-diphenyl- which has platelet aggregation inhibiting effect.
2-substituted or unsubstituted alkylthiazoles are disclosed, and among them, 4,5-bis-(4-methoxyphenyl)-2-trifluoromethylthiazole (compound A) represented by the following formula is a representative compound. Illustrated.

(Compound A) Also, in U.S. Patent No. 4,322,428, 4,5-
Bis-(4-methoxyphenyl)-2-(4-halophenyl)thiazole has been disclosed as an anti-inflammatory agent and a platelet aggregation inhibitor, and no specific pharmacological test results regarding its platelet aggregation inhibitory effect have been described. One representative compound is 4,5-bis-(4-methoxyphenyl)-2-(4-fluorophenyl)thiazole (compound B) shown by the following formula.

(Compound B) On the other hand, European Watch No. 77.024 contains 4.
A 5-bis-(4-methoxyphenyl)-2-pyrrorylimidazole derivative is disclosed as an anti-inflammatory agent, and is represented by the following formula: 4,5-bis-(4-methoxyphenyl)
-2-(1-methylpyrrol-2-yl)imidazole (compound C) is exemplified.

(Compound C) The present inventors have conducted extensive research to obtain a new type of platelet aggregation inhibitor that has excellent platelet aggregation inhibitory action and low toxicity, and as a result, we have found a novel diphenyl compound represented by the general formula (I). The inventors have discovered that pyrrolylthiazole derivatives satisfy these 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. 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 (1) of the present invention, examples of lower alkyl groups include ethyl group, n-propyl group, isopropyl group, and isobutyl group, and examples of lower alkenyl groups include, for example. Examples of the allyl group and lower alkynyl group include propargyl group and 2,2,2-trifluoroethyl group.

The diphenylpyrrolylthiazole derivative (I) of the present invention can be produced by the methods shown below (Method A, Method B).

[Method A]

(X) (I) (I) (In the formula, R is the same as above. X represents a bromine atom or a chlorine atom.) In method A, first, 0.5 ~
Hydrogen sulfide gas is added to compound (II) in the presence of 5 equivalents of base, for example in dimethylformamide (DMF), dimethylsulfoxide (DMSO) or pyridine, at 0-40°C.
Compound (III
). As the base, tertiary amines such as triethylamine are preferably used.

Next, compound (III) and an equivalent amount of compound (rV) to compound (In), for example, acetonitrile,
The compound (I) of the present invention can be obtained by reacting in an alcohol such as DNF, DMSO or ethanol at a temperature ranging from 50° C. to the boiling point temperature of the solvent for 10 minutes to 4 hours.

Compound (II) used as a raw material in Method A is:
For example, according to the following formula (wherein R is the same as above), compound (V) is converted into oxime (Vl) by a conventional method.
It can be obtained by heating the oxime (Vl) in acetic anhydride (see Reference side below).

(Vtechr) (VIII (n) (wherein R,
) In method B, first, virol-2-carbothioamide (■) and compound (IV) are reacted in the same manner as in the case of compound (ITI) and compound (TV) in method A. to obtain the production intermediate 4,5-bis-(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole (Vl).

Next, in the presence of a base, the production intermediate ([) and the compound (IX
) The compound (I) of the present invention can be obtained by reacting with When metallic potassium, metallic sodium, potassium tert-butoxide, etc. are used as the base, the production intermediate (Vl) and the compound (IX) in an excess amount with respect to the production intermediate (Vl) are mixed with, for example, DMF, DMSO. , tetrahydrofuran or dimethoxyethane at room temperature to the boiling point temperature of the solvent for 1 to 24 hours.

The reaction between this production intermediate ([) and compound (IK) can be carried out using a quaternary ammonium salt such as tetra-n-butylammonium bromide or methyltrioctylammonium chloride as a phase transfer catalyst, such as benzene or It can also be carried out by reacting in a two-layer solution of dichloromethane and a 5 oz* sodium oxide or 80 ml potassium hydroxide aqueous solution at a temperature ranging from 0° C. to the boiling point of the solvent for several minutes to 24 hours.

The compound CI) of the present invention exhibits a strong platelet aggregation inhibitory effect,
Moreover, it has low toxicity and is effective against various diseases caused by platelet aggregation.
For example, it is useful for the prevention and treatment of thrombosis, ischemic heart disease, and transient cerebral ischemia, and is also useful for the treatment of diseases involving 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 (I) of the present invention are shown below.

1. Platelet aggregation inhibitory effect [test compounds] (1) Seven types of compounds obtained in Examples 1 to 7 (compounds of the present invention) (2) Compounds A, B, and C (comparative compounds...each).

Compound described in the above patent publication) (3) Ticlopidine fillate (comparative compound) (0 Aspirin (comparative compound) [Test method] - Hartley guinea pigs fasted at night (body weight 300-3
Each test compound was added to corn oil-1 (50 g, 3 animals per group).
It is dissolved or suspended in 0% gum arabic emulsion and administered orally. After 3 hours, blood is collected from the abdominal aorta and citrate surface solution (3.8% sodium citrate aqueous solution 1/1
0 volume: blood 9/lO volume) was obtained. This citrate surface solution was centrifuged at 1700 rpm for 10 minutes, platelet rich plasma (PPP) was obtained from the supernatant, and after collecting PPP, it was further centrifuged for 30 min.
After centrifugation at 00 rpm for 10 minutes, platelet-poor plasma (ppp) was obtained from the supernatant.

The PRP450 pu thus obtained was incubated at 37 °C for 3 min and 1.0 m
After adding 50 ILl of sodium arachidonate of M, platelet-aggregation profiler (Bio
The platelet aggregation rate was measured using Data Carp 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.

Next, - administration t (at which the platelet aggregation inhibition rate is 50%) (
ED50) was determined using a regression equation.

Also, instead of sodium arachidonic acid, 100μg/
A test similar to the above was conducted using 50 ILl of aQ collagen as an aggregating agent.

〔Test results〕

Table 1 2. Acute toxicity [Test compound] Same as "platelet aggregation inhibition effect" above.

[Test method] ddY male mice (body weight 18-23g, 5 mice per group)
After overnight fasting, each test compound was suspended in a 1% gum arabic solution and administered orally. The acute toxicity value (LD50) was calculated from the number of deaths 10 days after administration using the fill method.

〔Test results〕

The pharmacological test results shown in Table 2 and above show that the compound (I) of the present invention exhibits superior platelet aggregation compared to known platelet aggregation inhibitors such as ticlopidine hydrochloride, aspirin, and compounds A, B, and C described in the above-mentioned prior documents. It has an inhibitory effect and is low in toxicity, making it useful for the prevention and treatment of various diseases caused by platelet aggregation, such as thrombosis, ischemic heart disease, and transient cerebral ischemia.In addition, diabetes, It is clear that it is also useful in the treatment of diseases associated with the nine-dimensional platelet function, such as hypertension and arteriosclerosis.

When using the compound (I) of the present invention 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 (I) of the present invention is formulated into a conventional dosage form. As an oral dosage form,
In addition to solid preparations such as tablets, granules, powders, fine granules, and hard capsules, liquid preparations such as syrups and soft capsules are included. 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, and talc. 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 (I) of the present invention in an aqueous solution containing white sugar, carboxymethylcellulose, and the like. Soft capsules can be obtained by filling suitable soft capsules with the compound (I) of the present invention prepared using a lipid excipient such as vegetable oil, oil emulsion, glycols, etc.

The dosage of the compound (1) of the present invention varies depending on the type and severity of the disease, body weight, age, etc., but it is usually 1-100 g/Kg per day for adults, and this is administered at once or twice to a day.
Administer in 3 divided doses.

Next, the present invention will be explained in more detail with reference to Reference Examples and Examples.

Reference example 1 1-ethylpyrrole-2-carbonitrile structure: 1-ethylpyrrole-2-carbaldehyde (J.

Che + w, Soc, (C) 2583 (1970) reference 37.4 g (flO mmol), hydroxylamine hydrochloride 4.8 g (69 mmol), sodium acetate trihydrate 9.4 g (89 mmol), water 30- After mixing and stirring at room temperature for 20 minutes, the mixture was left in a cool place overnight. The precipitated oxime was collected by filtration, dried, refluxed in 25@Q acetic anhydride for 20 minutes, and allowed to cool to room temperature. Next, the mixture was poured into ice water, stirred for 2 hours, neutralized with sodium carbonate, and extracted twice with ether. After drying the ether layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure to obtain l-ethylpyrrole-2-carbonitrile 5.
．． 25g was obtained (yield 73z).

Temperature near 1-74℃/emmHg NMR (CDGI!3, δ ppm): 1.4 (3
H,t), 4.1(28,q).

, 8.1 (IH, dd), 8.8-7.0 (2H).

Reference example 2 1-isopropylvirol-2-carponi, SuL2MJ
t: l-isopropylpyrrole-2-carbaldehyde (J,
(See Chem, Soc. (C) 2563 (1970))
8.2 g (Go mmol), hydroxylamine hydrochloride 4.8 g (89 mmol), sodium acetate trihydrate 9
．． 4 g (H mmol).

30 d of water was mixed, stirred at 70°C for 1.5 hours, cooled to room temperature, and extracted twice with ether. After drying the ether layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the oxime as an oil. Next, the oxime was refluxed in anhydrous vinegar @ 251Q for 20 minutes, cooled to room temperature, poured into ice water, stirred for 2 hours, neutralized with sodium carbonate, and extracted twice with ether. After drying the ether layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure to obtain 5.7 g of l-isopropylpyrrole-2-carbonitrile (yield: 71
%).

Boiling temperature 8-81°C 15.5mmHg NMR (CDCQ-1,8Pp) = 1.5 (8) 1.
d), 4.5(it(), 8°1(IH, dd), B,
? (18, dd), 6. ! If (IH, dd).

Reference example 3 l-n-propylpyrrole-2-carbonitrile (8N)
: 1-n-propylpyrrole-2-carbaldehyde (Can, J, C:hem, 55.4112 (1977
) was synthesized according to the method described in (boiling point near 2-75℃
15mmHg). ) 8.2 g (80 mmol) was used, and 1-n-propylpyroyl- Obtained 3.6 g of 2-carbonitrile (yield: 45
%).

NMR (CDCQ3, δppm): 0.9 (3H,
t), 1.5-2.1 (2H), 3.9 (2H, t)
, 6.1 (lH, dd), 8.8-6.9 (2H).

Reference example 4 1-isobutylpyrofury 2-carbonitri
[Structure: 1-inbutylpyrrole-2-carbaldehyde (j
,Agr,Food,Chem, ,22.279(1
974)) 1-Inbunalbyrol-2-
8.6 g of carbonitrile was obtained (yield 74z).

Boiling point 284-87°O 15 layers mHg NMR (CD3, δPPM): 0.9 (8) 1.
d), 1.7 to 2.0 (IH), 3.8 (2H, d)
, 6.1 (IH, dd), 8.8-8.9 (28).

Reference Example 5 ■-Preparation of -allylpyrrole-2-carbonitrile: 1-allylpyrrole-dehyde (Gan. J. Ghem. 55.4112 (19
7? ) Synthesized according to the method of Nikizo [boiling point 280-8
3℃77mmHg). ] 8. Reference Example 2 except that 1 g (mmol Go) was used and separation and purification were performed by silica gel column chromatography (developing elution: cyclohexane: diglormethane; 3:1) instead of vacuum distillation.
In the same manner as above, 4.0 g of l-allylpyrrole-2-carbonitrile was obtained (yield: 5 oz).

NMR (GOOl!yo, δpp■): 4.5-4.7 (
2H), 4.8-5, 4(2H), 5. El~8.0
(IH), 8.2 (IH.dd), 8.8-6.

8 (2H1.

Example 1 4 5-bis-(4-methoxyphenyl-2-l-
Ethylpyrrol-2-yl Azold: 3.0 g (25 mmol) of l-ethylpyrrole-2-carbonitrile obtained in Reference Example 1 was mixed with 12.5 g (125 mmol) of triethylamine and 13 g of pyridine.
Hydrogen sulfide was blown into the solution at 20° C. for 8 hours. Next, 300-m water was added to the reaction solution, the precipitated crystals were collected by filtration, dried, and recrystallized from ligroin to obtain 1-
2.5 g of ethylpyrrole-2-carbothioamide was obtained (yield: 65z).

Melting point near 1.5-74.5℃ (2) 4,5-bis-(4-methoxyphenyl)
=2-(1-ethylpyrrol-2-yl)thiazole: , 1-ethylpyrrole-2-carbothioamide 1 of L
．． 85 g (12 mmol) and α-brome-4.

4'-dimethoxydeoxybenzoin (Aust.

J. Ghem. , 8.385 (1955)) 4.
02g (12 mmol) in acetonitrile 120m, Q
and stirred at 80°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 obtained residue was recrystallized from n-hexane to obtain 3.8 g of 4,5-bis-(4-methoxyphenyl)-2-(1-ethylpyrrol-2-yl)thiazole (yield: 77z). ).

Melting point 778.5-79.5°C NMR (CDCQi, δppm): 1.5 (3H,
t), 3.8 (EIH), 4°55 (2H, (1),
8.15 (IH, dd), 8.85 (IH, dd),
8.75-8.95 (5H), 7.2-7.8 (4H)
.

Elemental analysis value (as C23H22N202S): Calculated value (%) C, 70,74: H, 5,613; N, 7.
1? Actual value (%) C,? 0.84. )1,5.80:
N, 7.11 Example 2 4.5-bis-4-methoxyphenyl-2-1-inpropylpyrrole-2-l thia-1-ethylpyrrole-
l- obtained in Reference Example 2 instead of 2-carbonitrile
Isopropylpyrrole-2-carbonitrile 3.35g
1-isopropylpyrrole-2-carbothioamide (
Melting point: 87.5-100.5°C) 3.85g (yield 82z) was obtained, followed by 4.5-bis-(4-methoxyphenyl)-2-(1-isopropylpyrrol-2-yl)thiazole 3.30 g was obtained (yield 88z).

Melting point near 2.5-75.5°C NMR (CDCQi, δppm): 1.5 (EIH,
d), 3.8 (6H), 5°7 (IH), 111.2
(IH, dd) , 8.85 (IH, dd) , 8.7
5-7.05 (5H), 7.2-7.8 (4H).

Elemental analysis value (as C24H2, N202S).

Calculated value (%) C, 71, 2B, H, 5, 98, N, 6
．． 93 actual value (%) C, 71,54: H, 8,03:
N, 7.02 Example 3 Support i Futami Muni standing (2 “■ Yota” 3-speed Uni” -1-n-
Propylpyrrole-2-l Al-ethylpyrrole-2
-1-n obtained in Reference Example 3 instead of carbonitrile
-Propylpyrrole-2-carbonitrile 3.35g (
3.35 g of 1-n-propylpyrrole-2-carbothioamide (melting point: 88-91°C) was obtained in the same manner as in Example 1, except that 25 mmol) was used (yield 80%, -bis-(4-methoxyphenyl) -2-(
2.42 g of 1-n-propylpyrrol-2-yl)thiazole was obtained (yield 50%).

Melting point = 77-80°C NMR (CD3, apPm): 0.95 (3H
,t), 1.7-2.1(2H), 3.8(6)1),
4.4 (2H, t), 6.1 (lH, dd), 8.5~
6°! 35 (lllH), 7.1-7.6 (4H).

Elemental analysis fit (C24H24N 202 S): Calculated value (%) C, 71,213; H, 5, 1
38, N, 8.113 Actual value (%) C,? 1.19;
H, 6,05:N, 6.97 Example 4 45-bis-4-methoxyphenyl-2-l-inbutylpyrrol-2-yl A1-ethylpyrrole-2-
l-isobutylpyrrole, -2- Carbothioamide (melting point: 1
25.5-128.5℃) 4.05g was obtained (yield 88z
), 2.588 of 5-bis-(4-methoxyphenyl)-2-(1-isobutylpyrrol-2-yl)thiazole was obtained (yield: 511).

Melting point near 6-78℃ NMR (C11Gla, apPm): 0.85 (1
3)1. d), 2.1-2.55 (IH), 3.8 (O
H) , 4.3 (2H, d) , 8.15 (IH, dd
), 6.8-6.95(OH), 7.2-7.8(
4H).

Elemental analysis value (as C25H28N 202 S) Calculated value (%) 0.71.74 HJ, 2B, NJ, 8
11 Actual 811 value (%) C,? 2.00;H,e,3[
1;N, l11.13B Example 5 45-bis-4-mexiphenyl-2- l-allylpyrrol-2-yl azole l-ethylpyrrole- l-allylpyrrole-2- obtained in Reference Example 5 1-allylpyrrole-2-
Carbothioamide (melting point: 80.5-83, 0°O)2
．． Obtained 45g (yield 59z), next item 4, 5 -
3.04 g of his-(4-methoxyphenyl)-2-(1-allylpyrrol-2-yl)thiazole was obtained (yield E13%).

Melting point: 57-60°C NMR (CDCQ3, δppm): 3.8 (OH)
, 4.9-5.3(48), 5.9-e. l(IH
), 6.2 (IH, dd), 8.7 (IH. dd),
e.

75~8.95 (5H), 7.2~? ．． El(4)1
).

Elemental analysis value (as C24H22N202S) Two calculated values (%) C, 71.82:) 1, 5.51: N, 6.
! 3B actual measurement value (%) G,? 1.89; H, 5.48,
N. 6.91 Example 6 4,5-bis-4-methoxyphenyl-2-1-
Propargylpyrrole-2-lua (1) 4,
5-bis-(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole: pyrrole-2-carbothioamide (J. Org. Ghes, I, fi87 (197
3)) 1.51 g (12 mmol) and α-b, 4,4'-dimethoxydeoxybenzoin 4.
02 g (12 mmol) was dissolved in 120 d of acetonitrile 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. By recrystallizing the obtained residue from ligroin, 4.5-bis-
74 g of (4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole 3 was obtained (yield: 86z).

Melting point: 131.5-134.0°C NMR (CDα3, δPPM): 3.7 (8H), 8
．． 1 (IH.dd), Ill, 5-6.9 (8) 1),
? ．． 1 ~ 7.5 (4H),! 3.4 ~! 3.8(
IH).

Elemental analysis value (as C2, H18N202S): Calculated value (%) C, 139.59; H. 5.01:N,? ．． 7
3 Actual value (%) C, 70.06; H. 4.90,N,
7.811(2) 4,5-bis-(4-methoxyphenyl)-2-(l-propargylpyrrol-2-yl)thiatool: 4,5-bis-(4-methoxyphenyl)-2- as above
(Pyrrol-2-yl)thiazole 1.

81 g (5 mmol), propargyl bromide 1.
18 g (10 mmol), tetra-n-butylammonium bromide O. 16g (0.5 mmol) in dichloromethane 20ml 9.50% sodium hydroxide aqueous solution 20I
The biphasic solution of ILQ was refluxed for 5 minutes with vigorous stirring. Then, cool with water. Dichloromethane was added and shaken. The dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane and combined. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from n-hexane to obtain 1.50 g of 4.5-bis=(4-methoxyphenyl)-2-(1-propargylpyrrol-2-yl)thiazole (
Yield 75z).

Melting point: 101.5-toa. 5°C NMR (CDGli, δPPM): 2.45 (IH
, t), 3.85 (8H).

5, 45 (28, d), 6.25 (IH, dd),
8.7 (IH, dd), 8.75-E1. l]5(5
H), 7.2-7.8 (4H).

Elemental analysis value (C2, H 20 N 2 0 2
S): Calculated value (%) G,? 1.97; H, 5.
03. N, 7.00 Actual value (%) C, 72.1? ．． !
(, 5.04.N, 7.09 Example 7 4.5-bis-(
1.81 g (5 mmol) of 4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole.

2, 2.2-1 Lifluoroethyl-p-toluenesulfonate 1.27 g (5 mmol), tetra-bromide
0.18 g (0.5 mmol) of n-butylammonium was dissolved in benzene 2 (ld), 50 g of aqueous sodium hydroxide solution 2.

Refluxed in a bilayer solution of m9 for 16 hours. Next, water and benzene were added and shaken while cooling with water. The benzene layer was separated, and the aqueous layer was extracted with benzene and combined. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an oil. The oil was subjected to silica gel column chromatography (developing solvent: benzene) and then recrystallized from n-hexane to obtain 4,5-bis-(4-
methoxyphenyl)-2-(1-(2,2,2-trifluoroethyl)pyrrol-2-yl]thiazole 0.8
0 g was obtained (yield 36z).

Melting point: 108.5-111.5°C NMR (CD■3.δppm) = 3.8 (f3H),
5.45 (2H, q), 8.25 (IH, dd), 8
．． E15~B,! 35 (8H), 7.2-7.55 (
48) Elemental analysis value (as C23H1, N202SF3): Calculated value (%) G, 82.15; H, 4, 31, N
, 6.30 actual value (%) G, 82.13. H, 4, 3
1; N, 6.45 Example 8 4.5-bis-(4-methoxyphenyl)-2-(1-
Inbutylpyrrol-2-yl thiazole B: 4,5-bis-(
4-methoxyphenyl)-2-(pyrrol-2-yl)
Thiazole 1.81 g (5 mmol).

After stirring 0.22 g (5.5 mmol) of metallic potassium in 40 mmol of dimethoxyethane at room temperature for 1 hour, 2.74 g (20 mmol) of isobutyl bromide was added and the mixture was refluxed for 2 hours. Next, the solvent was distilled off under reduced pressure, and dichloromethane and water were added to the resulting residue, followed by shaking. The dichloromethane layer was separated, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent: dichloromethane:cyclohexane: l:l), and then recrystallized from methanol to obtain 4,5-bis-(4-methoxyphenyl)-2-(1 0.33 g of -isobutylpyrrol-2-yl)thiazole was obtained (yield: 1 ft%).

The obtained compound showed the same physical property values as the compound described in Example 4 above.

Examples 9.10, 11.12 The following compounds were synthesized according to Example 6 (B
law).

4.5-bis-(4-methoxyphenyl)-2-(1-
Ethylpyrrol-2-yl)thiazole (yield 45z) 4.5-bis-(4-methoxyphecol)-2-(1-
Isopropylpyrrol-2-yl)thiazo-1 (yield: 32z) 4.5-bis-(4-methoxyphenyl)-2-(1-
n-propylpyrrol-2-yl)thiazole (yield 3
3z) 4.5-bis-(4-methoxyphenyl)-2-(l-
Allylpyrrol-2-yl)thiazole (yield: 5 oz) The obtained compounds exhibited the same physical properties as the corresponding compounds described in the examples above.

Example 13 Formulation example (tablet) One tablet contains 2 mg of 4.5-bis-(4-methoxyphenyl)-2-(1-isopropylpyrrol-2-yl)thiazole (compound of Example 2) as an active ingredient. Compressed tablets were prepared according to the following formulation.

[Placement]

Compounds of Example 2 40 Crystalline cellulose 1580 Lactose 1600 Carboxymethylcellulose Calcium 120 Talc 40 Magnesium stearate 20 Each of the above Mix the ingredients uniformly and take 1 tablet 170 ml according to the usual method.
It was compressed into tablets in mg.

Example 14 Formulation example (powder) 1 g contains 2 mg of 4,5-bis-(4-methoxyphenyl)-2-(1-allylpyrrol-2-yl)thiazole (compound of Example 5) as an active ingredient. A powder was prepared according to the following formulation.

[Placement]

・　-11L”1-Kaikol Compound of Example 5...2 Lactose 598 Starch 400 The above components were thoroughly mixed to form a uniform powder.

Example 15 Formulation example (hard capsule) 4.5-bis-(4-methoxyphenyl)-2-(1-n-propylpyrrole-
Hard capsules containing 1 g of 2-yl)thiazole (compound of Example 3) 2I were prepared according to the following formulation.

[Placement]

) '-Compound of Example 3 40 Crystalline cellulose 880 Lactose 2000 Talc 60 Magnesium sdiaphosphate 20 Thoroughly mix each of the above components to make a uniform powder.
50 mg each was filled into No. 3 hard capsules.

Example 1B Formulation example (soft capsule) A, s-bis-(4-methoxyphenyl)-2-(1-n-propylpyrrole-
Soft capsules containing 2 mg of 2-yl)thiazole (compound of Example 3) were prepared according to the following formulation.

[Formulation (1)] 1-jL" L-formation 0 Compound of Example 3 40 Corn oil
1960 [Processing power (2)], -w, gelatin resistance 2000 Glycerin 660 Methyl paraoxybenzoate 4 Propyl paraoxybenzoate 1 Purified water 1600 Example according to prescription (1) Compound No. 3 was dissolved in corn oil, and then wrapped in a gelatin film prepared according to formulation (2) to obtain soft capsules.

Procedural amendment (voluntary) 1. Indication of the case Patent Application No. 79824 of 1982 2. Name of the invention Novel diphenylpyrrolylthiazole derivative, method for producing the same, and pharmaceutical composition containing the same as an active ingredient 3. Amendments made Patent applicant address: 5-17-4 Sumida, Sumida-ku, Tokyo 5-90 Tomobuchi-cho 1-chome, Bejima-ku, Osaka 534 Patent Department 5, Kanebo Co., Ltd. Number of inventions increased by amendment None 6. Column 7 of “Detailed Description of the Invention” of the specification to be amended, contents of the amendment qm * Page 21, line 12 (7) r 1-100 mg
/Kg! Wow, rl ~100mgJ correction.

The above hand ft, Neiichi IE (spontaneous) May 23, 1985 Patent Application No. 79924 of 1988 2, Title of Invention: New diphenylpyrrolylthiazole derivative, method for its production, and its use as an active ingredient. Pharmaceutical composition 3, relationship with the case of the person making the amendment Patent applicant address: 5-17-4 Sumida, Sumida-ku, Tokyo 1-5-90 Tomobuchi-cho, Bejima-ku, Osaka 534 Japan Patent Department, Kanebo Co., Ltd. Telephone (08) E121-1251 4. Date of amendment order (voluntary) 5. Number of inventions increased by amendment None 6. "Claims" column and "Detailed description of the invention" of the specification to be amended Column 7, Contents of amendment (1) The "Claims" of the specification will be corrected as shown in the attached sheet.

(2) "rp-) luenesulfonyl group" in lines 3 to 2 from the bottom of No. 12 of the specification "Fpi ruenesulfonyloxy group"
I am corrected.

Above 2, Claim (1) Diphenylpyrrolyl represented by the following formula (wherein R represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a 2,2,2-trifluoroethyl group) Thiazole derivative.

(2) A compound represented by the following formula (wherein R represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a 2,2,2-trifluoroethyl group) is reacted with hydrogen sulfide.

A compound represented by the following formula (wherein R is the same as above) is prepared, and then the above compound is reacted with a compound represented by the following formula (wherein, X represents a bromine atom or a chlorine atom). A method for producing a novel diphenylpyrrolylthiazole derivative represented by the following formula (wherein R is the same as above), characterized by:

(3) Production intermediate 4.5- produced by reacting pyrrole-2-carbothioamide represented by the following formula with a compound represented by the following formula (wherein, X represents a bromine atom or a chlorine atom) bis-(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole, and then the production intermediate and the following formula (wherein, R is the same as above, Y is a bromine atom, a chlorine atom, an iodine atom, or -j-)Lt17Z)Iy Represents the soil j. ) A method for producing a novel diphenylpyrrolylthiazole derivative represented by the following formula (wherein R is the same as above), characterized by reacting the compound represented by:

Platelets containing a diphenylpyrrolylthiazole derivative represented by the following formula (wherein R represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a 2,2,2-trifluoroethyl group) as an active ingredient. Aggregation inhibitor.

Claims (4)

[Claims] (1) A diphenylpyrrolyl thiazole derivative represented by the following formula (wherein R represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a 2,2,2-trifluoroethyl group). (2) A compound represented by the following formula (wherein R represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a 2,2,2-trifluoroethyl group) is reacted with hydrogen sulfide, and the compound represented by the following formula is (wherein R is the same as above), and then the above compound is reacted with a compound represented by the following formula (wherein, X represents a bromine atom or a chlorine atom). (wherein R is the same as above) A method for producing a novel diphenylpyrrolylthiazole derivative. (3) Pyrrole-2-carbothioamide represented by the following formula is reacted with a compound represented by the following formula (wherein, X represents a bromine atom or a chlorine atom) to produce a production intermediate 4 represented by the following formula, 5-bis-(4-methoxyphenyl)-2-(virol-2-yl)thiazole, and then the production intermediate and the following formula (wherein, R is the same as above, Y is a bromine atom, a chlorine atom, an iodine atom, Represents an atom or P-)luenesulfonyl group. ) A method for producing a novel diphenylpyrrolylthiazole derivative represented by the following formula (wherein R is the same as above), characterized by reacting the compound represented by: (4) The active ingredient is a diphenylpyrrolylthiazole derivative represented by the following formula (wherein R represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a 2,2,2-trifluoroethyl group). Platelet aggregation inhibitor.