JPS63183565A - Imidazole derivative - Google Patents

Abstract

NEW MATERIAL:The imidazole derivative of formula I (A is -CO- or -SO2-; R is phenyl which may have substituent group; n is 2-6) or its acid addition salt. EXAMPLE:1-(4-Chlorobenzoyl)-4-[3-(1-imidazolyl)propyl]piperazine. USE:A remedy and preventive for phlebothrombosis, coronary occlusion in myocardial infraction, pulmonary embolism, cerebral thrombosis and embolism, etc. It has strong platelet coagulation inhibiting action. PREPARATION:The imidazole derivative of formula I can be produced e.g. by reacting a 1,4-substituted piperazine of formula II with an imidazole derivative of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel imidazole derivatives, and more particularly to imidazole derivatives useful as pharmaceuticals.

[Conventional technology and its problems]

It has been known that some imidazole derivatives have an inhibitory effect on platelet aggregation, for example, 1-(7
-carpoxyhezotyl)imidazole hydrochloride, 4-(
2-(I-imidazolyl)ethoxy]benzoic acid hydrochloride, etc. have been reported. However, the platelet aggregation inhibiting effects of these compounds are not necessarily sufficient, and there has been a demand for compounds with even better effects.

[Failure to solve the problem]

The present inventor synthesized an imidazole derivative having a biperazone ring and searched for its pharmacological action. The inventors found that a new compound represented by formula (I) below has an extremely strong inhibitory effect on platelet aggregation, and inhibits thrombus formation. The present invention was completed based on the discovery that the present invention is useful for the treatment of associated circulatory system diseases.

That is, the present invention relates to the following general formula (I) (wherein A represents -C〇- or -802-, R represents a phenyl group which may have a substituent, and n is 2 to 6 The present invention provides an imidazole derivative represented by the following formula (indicating an integer of ) and an acid addition salt thereof.

In the compound (I) of the present invention, the phenyl group which may have a substituent represented by R includes a phenyl group, a halectuphenyl group, an alkylphenyl group, a substituted alkylphenyl group, an arylphenyl group, and a hydroxyphenyl group. , alkoxyphenyl group, alkoxycargenylphenyl group, carboxyphenyl group, aminophenyl group, substituted aminophenyl group, mercazotophenyl group, alkylthiophenyl group, sulfoxyphenyl group, substituted sulfonylphenyl group, nitrophenyl group, Examples include acyloxyphenyl group, acylphenyl group, cyanophenyl group, and the like.

Compound (I) of the present invention can be produced, for example, by any of the following methods.

Method 1: According to the following reaction formula, 1,4-substituted biperazone (I) is reacted with imidazole (E) to form an imidazole derivative (I
).

@ ■ (In the formula, X represents a leaving group such as a halogen atom, tosyloxy group, mesyloxy group, etc., and A, R.

(n has the same meaning as above) This reaction is carried out using 1 to 3 moles of (e) to 1 mole of (n) and stirring for 1 to 24 hours at room temperature or the reflux temperature of the solvent used. be done. Examples of the solvent include diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and dimethylformamide. Note that a base such as sodium hydride may be added to accelerate the reaction. After the reaction is complete,
In order to obtain the compound (I) of the present invention, the solvent may be distilled off and recrystallized by a conventional method, or if necessary, it may be purified by chromatography or the like.

Method 2: According to the following reaction formula, 1-substituted piperazino (2) is reacted with the imidazole derivative (2) to form the imidazole derivative (I).
get.

■M (In the formula, X represents a leaving group such as a halogen atom, tosyloxy group, mesyloxy group, etc., and A, R.

(n has the same meaning as above) This reaction is carried out by using 1 mol of M per 1 mol of hood and reacting in a solvent at room temperature to 120°C for 1 to 24 hours in the presence of a base. As a solvent, for example, dimethylformamide or water and dioxane in a ratio of 1:1.
A mixed solvent of , etc. is preferred. As the base, for example, potassium carbonate, sodium carbonate, pyricine, triethylamine, etc. can be used.

After the reaction is completed, the solvent is distilled off and recrystallized by a conventional method, or
Alternatively, the target compound (I) can be obtained in a pure form by purifying by chromatography or the like, if necessary.

Method 3: Imidanol derivative (I) is produced by reacting carboxylic acid chloride or sulfonic acid chloride (b) with 1-substituted viperacin (b) according to the following reaction formula.

(B) (B) (In the formula, A, R and n have the same meanings as above) In this reaction, 1 mole of (■) is used per 1 mole of (B),
The reaction is carried out in a solvent at room temperature for 1 to 24 hours in the presence of a base.

As the solvent, for example, diethyl ether, tetrahydrofuran, dioxane, acetone, etc. are preferable. As the base, for example, triethylamine, tri-n-butylamine, bilysin, 4-dimethylaminopyridine, hydrogen carbonate, etc. can be used. After the reaction is completed, the solvent is distilled off and recrystallized by a conventional method, or if necessary, purified by chromatography etc.,
The target product (I) can be obtained in pure form.

The imidazole derivative (I) of the present invention thus obtained can be further treated with an inorganic salt such as a hydrochloride, a hydrobromide, a sulfate, or a maleate or a fumarate by a conventional method, if necessary. , tartrate, citrate, methanesulfonate, and other organic acid salts.

[Effect]

Regarding the compound (I) of the present invention obtained as described above,
The results of testing its pharmacological effects are as follows.

Platelet aggregation inhibitory effect: Citrated blood was collected from a male rabbit (body weight 3 Kt) and platelet rich plasma (PRP) was prepared by centrifugation. investigated. The test compound was dissolved in physiological saline, and the pH was adjusted to around 7 with a 1N aqueous sodium hydroxide solution, and then PRP was added 2 minutes before adding the flocculant.
Added inside.

The results are shown in Table 1.

As is clear from the results, the compound of the present invention exhibited a strong inhibitory effect on platelet aggregation induced by arachidonic acid.
.

〔Effect of the invention〕

As mentioned above, the compounds of the present invention have a strong platelet aggregation inhibitory effect, and therefore can be used to treat various circulatory system complications caused by thrombus formation, such as venous thrombosis, coronary artery occlusion in myocardial values, pulmonary embolism, cerebral thrombus, and embolism. It is useful for the treatment and prevention of etc.

〔Example〕

Next, the present invention will be further explained with reference to Examples.

Example 1 l-(4-chlorobenzoyl)-4-[3-(I-imidazolyl)propylcopiperazine (compound number 1): 136 μm of imidazole was dissolved in 3 m/d of dimethylformamide, and hydrogenated under water cooling and stirring. Sodium 60Qk was added little by little and stirred at room temperature for 30 minutes. Then under stirring 4
908 g of 1-(4-chlorobenzoyl)-4-(3-
A solution of chlorzolopyl)piperazine dissolved in 7-dimethylformamide was added dropwise, and the mixture was further stirred at 100°C for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, and dried by adding anhydrous sodium sulfate. After further distilling off the solvent under reduced pressure, the residue was subjected to column chromatography using silica dal, and 434 g of a colorless transparent oil, which was the desired product, was obtained from the 95% chloroform-5 methanol eluate.

NMRδppm (CDCl5) 1.90 (m, 2H), 2.30 (m, 6
H), 3.48 (m, 4H).

3.90 (t, 2H), 6.70 (br,
IH), 6.82 (br, IH).

7.12 (s, 4H), 7.23 (br, IH)ea
t IRνcm-'' 1630 ax The above oily substance was dissolved in anhydrous ether, and ethanol-hydrochloric acid was added dropwise while stirring while cooling with water, and the precipitated colorless crystal hydrochloride was collected as F.

Melting point 221-226°C Example 2 l-(4-chlorobenzoyl)-4-(4-(I-imidazolyl)butyl)viverazone (compound number 2): 1-(4-chlorobenzoyl)piperazine 750 Q and 1- Chlor-4-(I-imidazolyl)butane 530
m+1? The mixture was dissolved in e-sometherformamide 15-, and 3548 g of sodium carbonate was further added thereto, followed by stirring at 120°C for 4 hours. Next, the solvent was distilled off under reduced pressure, water was added to the residue, extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off.

Furthermore, it was subjected to silica dull column chromatography, and 9
The desired pale yellow clear autumn product 81289 was obtained from the 5% chloroform-5% methanol eluate.

Biδppm (CDCA13) 1.70 (m, 4H), 2.39 (m, 6H), 3
．． 55 (m, 4H).

3.95 (t, 2H), 6.90 (br,
IH), 7.05 (br, IH).

7.35 (s, 4H), 7.45 (br,
IH) eat IRv sub-" 1630 aX The above oily substance was dissolved in ether, ethanol-hydrochloric acid was added dropwise while stirring on water cooling, and the solvent was distilled off under reduced pressure to obtain a hydrochloride.

Examples 3 to 11 The compounds shown in Table 2 were obtained in the same manner as in Example 1 or 2.

Below margin 16-Example 12 1-(4-Toluenesulfonyl)-4-(3-(I-imidazolyl)zolopyl)biperazone hydrochloride (compound number 12): 1-(3-(I-imidazolyl)flopyl) 8,301 g of biperazone was dissolved in 15 ffl/tetrahydrofuran, triethylamine 2- was added thereto, and 4-toluenesulfonyl chloride i, o s was added while cooling with water and stirring.
A small amount -t' of t' was added, after which stirring was continued for 18 hours at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform, washed with water, and dried by adding anhydrous sodium sulfate. After further distilling off the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel to obtain a 95%-
A chloropho compound was obtained.

The shim-5% methanol eluate was distilled off under reduced pressure to obtain 1.34 f of a colorless viscous liquid, which was the desired product.

NMRδppm (CDCIs) 1.97 (m, 2H), 145 (m, 6H),
2.50 (s, 3H).

3.05 (m, 4H), 3.98 (t, 2H)
, 6.85 (br, IH).

7.02 (br, IH), 7.35 (d, 2
H), 7.40 (br, IH).

7.67 (d, 2H) IRν"atcfn-11345,1165aX The above viscous liquid was dissolved in anhydrous ether, and ethanol-hydrochloric acid was added dropwise with stirring while cooling with water, and the precipitated colorless crystal hydrochloride was collected.

Melting point 204-207°C Examples 13-17 Compound shown in Table 3 in the same manner as Example 13 Written amendment for margin procedure below (voluntary) December 14, 1985 Kunio Ogawa, Commissioner of the Patent Office 1X1, Indication of the case Showa 1962 Patent Application No. 24392 2, Name of the invention: Imidazole derivative 3, Relationship with the case of the person making the amendment Applicant name: Nisnis Pharmaceutical Co., Ltd. 4, Agent 6, "Detailed description of the invention" of the specification to be amended Column 7 Contents of the amendment (I) In the specification, page 21, bottom line of Table 3: “...
. . . 0 indicating that it was measured in KBr" Next, change the line and insert the following sentence.

Examples 18-20 The compounds shown in Table 4 were obtained in the same manner as in Example 1 or 2.

Claims (1)

[Claims] 1. The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, A represents -CO- or -SO_2-, and R has a substituent. represents a phenyl group which may be substituted, and n is 2 to 6
(representing an integer of ) or an acid addition salt thereof.