JPS6314771A - Optically active imidazole derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:(1R)-(+)-4-[1-(2-Methoxyphenyl)-2-(imidazol-1-yl )ethylbenzoic acid expressed by formula I and (1S)-(-)-4-[1-(2-methoxyphenyl)-2-(imidazol-1-yl) ethylthio]benzoic acid expressed by formula II and ester, amide and salt thereof. USE:Capable of inhibiting thromboxane synthetase of blood platelet microsome of mammals including humans and exhibiting powerful and specific thromboxane A2 biosynthesis inhibitory action and useful as a treating and preventing agent for cardiac infraction, cerebrovascular thrombosis and ischemic peripheral angiopathy and treating and preventing agent for post-operative thrombosis and as a promoter for aperture property of transplanted blood vessels. PREPARATION:A racemic compound expressed by formula III (R is protecting group of carboxylic acid) is resolved with an acid based optical resolving agent and converted into a carboxylic acid to afford the aimed compounds expressed by formulas I and II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new oil-active imidazole derivative useful as a therapeutic agent for cardiovascular diseases caused by thromboxane A2 and a method for producing the same.

Thromboxane A2, a stimulator of platelet aggregation (
Hereinafter, it will be abbreviated as TXA 2. ) is used in parallel from prostaglandin endoveroxide PGG2 and PGI2, and T
The balance between XA2 and PGI2 production has been shown to be a regulatory factor in thrombus formation. Therefore, in the treatment or prevention of thromboembolism, PGs that selectively suppress TXA2 synthesis and thereby have antiplatelet aggregation effects are recommended.
It is desirable to promote the expression of I2.

In recent years, imidazole and 1-methylimidazole have been discovered as compounds having such TXA2 biosynthesis inhibitory activity.Kanidolman et al., Prostaglandins, vol. 13, 611 Sada.

(1977), but it has not yet been put into practical use due to its activity and other aspects.

As a result of many years of intensive research into the synthesis and pharmacological activity of compounds with TXA2 biosynthesis inhibitory activity, the present inventors have discovered (1R)-(t)- having the following &' formula (11).
4-[1-(2-methoxyphenyl)-2-(imidazol-1-yl)ethylthio]benzene, and (1S) -(-1-4-[1-(2
-Methoxyphenyl)-2-(imidazol-1-yl)ethylthio]benzoic acid was recognized to have a strong inhibitory activity, and this showed that the compounds (I) and (It) of the present invention The present invention has been completed based on the discovery that the present invention is useful as a treatment for certain diseases.

The object compound of the present invention is an optically active imidazole derivative (1)(1R)-(+)-4-(1-(2-methoxyphenyl)-2-(imidazol-1-yl)ethylthiobenzoin ml (formula (1)).

and (Is)-(-)-4-[1-(2-methoxy7x=#)-2-(4midazol-1-yl)ethylthio]an, Kikam (formula (u)) and its Optimistically acceptable esters, amides and melons.

The compounds CI) and (n) object of the present invention are described in their neutral form or also possess their pharmacologically acceptable Nisder, amides and forms. Pharmacologically recognized esters and amides are esters that are activated in vivo and have favorable pharmacokinetic properties, such as methyl, ethyl, n-propyl, isopropyl,
Lower alkyl groups such as n-butyl and isobutyl; lower alkanoyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, and pivaloyloxymethyl; tip: 1-ethoxycarbonyloxyethyl, 1-n-propoxycarbonyloxy Lower alkoxycarbonyloxyalkyl groups such as ethyl, 1-isoproboxycarbonyloxyethyl; phthalidyl group or (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group; amide group; N- N-substituted abado groups such as methyl oxide; N such as N,N-dimethylamide;

It is an N-disubstituted amide group. Pharmacologically acceptable salts include pyrochloride, hydrobromide, nitrate M salt, and phosphorus rM! Mineral acid salts such as salts, methanesulfonates, benzenesulfonates, sulfonates such as p-)luenesulfone #R salts,
Acetate, trifluoroacetate, aspartate, glutamate, sulfur #1 salt, tartrate, citrate, maleate, fumarate, lactate, salicylate, malonate, succinate Pharmaceutically acceptable acid addition salts such as organic salts, or salts of Muzankinmaki such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, or ammonium salts, cyclohexylammonium salts, diisopropylammonium salts. salts, ammonium salts such as triethylammonium salts, lysine salts,
These are commercially acceptable base addition salts such as basic abanoic acid salts such as arginine salts.

Furthermore, esters and amides that undergo metabolic activation in vivo and have favorable pharmacokinetic properties can also be converted into the aforementioned acid addition salts.

The compounds having the formulas (1) and (1) of the present invention are:
It can be manufactured by the method shown below.

In the above formula, R is a protecting group for carboxylic acid, such as preferably methyl, ethyl, propyl, butyl, tert
- A rectangular or branched button-like alkyl group with a carbon age of 1 to 4, such as butyl; an alkenyl group with ash e3 to 4, such as allyl, 2-butenyl, and an aralkyl group, such as benzyl and p-nitrobenzyl. or benzhydryl group.

In this method, a racemic compound having the general formula (iu) is resolved using an acid-based optical resolving agent by a prior crystallization method to obtain an optically Y old acid addition salt, which is then treated with a base. This is accomplished by deprotecting the optically active esters represented by general formulas (N) and (V).

Suitable acid-based optical resolution agents used in the method of the present invention include (+)-dibenzoyl-D-tartaric acid,
(-)-dibenzoyl-L-hetatalic acid.

L-(+)-tartaric acid, D-(-)-tartaric acid + i'
(+)-mandelic acid, D-(-)-mandelic acid, L-
(-)-camphor-10-sulfonic acid, D-(+)-
Camphor-10-sulfone l'W, D-camphoric acid, D-malic acid, L-malic acid, (+)-di-p-toluoyl-D-tartaric acid, (-)-di-p-toluoyl-L
Particularly preferred are L-(-)- or D-(+)-camphor-10-sulfonic acids in which -tartaric acid or the like can be opened or the optically active acid addition group is obtained in crystalline form. The optically active acid used as a resolving agent is used to resolve the racemic compound (
01 to 3 times the mole of Ill), preferably 0.4 to 1.2
Use twice the molar amount. Solvents used for optical resolution include water, lower alcohols such as methanol, ethanol, and isopropanol, halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane, ketones such as acetone and methyl ethyl ketone, diisopropyl ether, ether, and dioxane. ethers such as benzene, toluene, aromatic hydrocarbons such as xylene, saturated hydrocarbons such as hexane, pentane, cyclohexane, nitriles such as acetonitrile, ethyl formate,
Ester M such as ethyl acetate, NtN-dimethylformamide, amides such as N,N-dimethylacetamide, dimethyl sulfoxide, nitromethane or a mixed solvent of these organic solvents or mixed bath with water or heating. Dissolve them uniformly, cool after dissolution,
The acid addition salt of the compound represented by the general formula (N) or (V) is taken out as a crystal.

If a vertical seed crystal is added during direct cooling to precipitate crystals, a product with even better optical purity can be obtained. The optically active compound (II/) or (l
Isolation is carried out by treatment with a base. For example, it can be isolated by treatment with an alkaline aqueous solution such as sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate, etc., and extraction with an organic bath agent. A neglected optically active compound (N) or an alkyl ester (where l is a linear chain such as methyl ester, ethyl ester, etc.) in which the protecting group of the carboxyl group is removed by methods known in the art of fractionation, It is removed by alkaline hydrolysis and the tert-butyl ester is removed by trifluoroacetic acid. When the holding group of carboxylic acid is allyl or 2-butenyl group, a palladium complex is used.8, W, Mc Combie (J, Org.

Chem, 47.587 (1982)). In the case of carboxylic acid retention groups, benzy/lz, aralkyl groups such as p-nitrobenzyl, or benzhydryl groups, this is achieved by contacting with a reducing agent. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it is not involved in this reaction, alcohols such as methanol and ethanol, ethers such as tetrahydrofura/dioxane, and Mixed solvents of these organic solvents and water are suitable for debonding with alkali or reducing agents, and halogenated hydrocarbons such as dichloromethane and chloroform, and esters such as ethyl formate and ethyl acetate are suitable for use with acids or palladium. Suitable for deprotection using a complex. The reaction temperature is usually around 0'C to 100C, and the reaction time varies depending on the type of koji-protecting group, but is usually 5 minutes to 24 hours.

After completion of the reaction, the target compound of the carboxyl protecting group removal reaction is collected from the reaction mixture according to a conventional method. For example, in the case of deprotection with alkali or acid, the solvent is distilled off, the residue is neutralized, extracted with an organic solvent, washed with water,
It can be obtained by drying and distilling off the solvent.
In the case of reduction or deprotection using a palladium complex, it can be obtained by removing insoluble matter precipitated from the reaction mixture, washing the organic solvent layer with water, drying, and distilling off the solvent.

The target compound thus obtained can be further prepared by conventional methods, such as column chromatography or recrystallization, if necessary. Furthermore, the optically active compounds (I) and (1) having a carboxylic acid can be prepared by using techniques known in this field to obtain a pharmacologically acceptable compound that exhibits similar W activity in vivo and has favorable pharmacokinetic properties.
12] Can be converted into compatible esters, amides and salts.

Effects of the Invention (1) (1R) − covered by the above formula (I) of the present invention
(+)-4-(1-(2-methoxyphenyl)-2-(
imidazol-1-yl)ethylthio]benzoic acid and (Ig)-(-)-4-CI represented by the above formula (U)
-(2-methoxyphenyl)-2-(imidazole-1
-yl)ethylthio]benzoic acid is a novel compound that has not been described in any literature, and it inhibits thromboxane synthetase in platelet microseams of mammals including humans, and has a strong and specific TXA2 biosynthesis inhibitory effect. shows. That is, the compounds of the present invention can be combined with, for example, 10-8 mol of TXA at a time.

It inhibits biosynthesis by 50%, but inhibition of cyclooxygenase and prostacyclin synthetase is extremely effective. In addition, in vivo experiments have shown that oral administration of the compounds of the present invention is effective in preventing death of rabbits and mice caused by direct injection of arachidonic acid.

Therefore, the optically active imidazole visiting conductor of the present invention is TXA
It is useful as a therapeutic system for diseases caused by 2, such as inflammation, hypertension, thrombosis, cerebral hemorrhage, and asthma, and is particularly useful for the treatment and/or prevention of facet thrombosis in mammals including humans. be. For example, the compounds of the invention are useful in the treatment and prevention of myocardial infarction, cerebrovascular thrombosis, and ischemic peripheral vascular disease; in the treatment and prevention of post-surgical thrombosis; and in promoting the patency of graft blood vessels after surgery. It is.

The dose of the compound of the present invention required for the therapeutic or preventive effect on the above-mentioned diseases may vary depending on the mode of administration, age, type of symptoms to be treated, etc. Oral administration for adults is usually divided into three doses per day. 50 to 1800 ■.

Although the compounds of the invention can be administered neat, it is usually preferable to present them as a pharmaceutical formulation. The formulation can be in oral dosage forms such as tablets, capsules, powders, and syrups, or parenteral dosage forms such as suppositories, subcutaneous or intravenous injections.

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

Example 1 Racemic methyl 4-CI-(2-methoxyphenyl)-2-(imidazol 1-yl)ethylthio]benzoate (5.53 g) was dissolved in ethanol (25 ml), commonly known as W-I, D-(+ )-camphor-10-sulfone (H(
3,481) was added. Ether (83 ml) was added slowly and the mixture was heated overnight.

The precipitated deposited salt crystals were dried for P weeks and recrystallized 2 to 3 times from ethanol-ether (1:2) to obtain the target compound (R form) (3,o8F).

R body-salt mp 135-138℃ [α': l, =, +117.3° (c=1.0
; CH30H) t, ff1 (3,0g) of this R form
Add saturated carbonated water, purple sodium water (60g+/) and purchase o11
Add edible water (40 g/) and add ethyl acetate-ether (3
:1), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, a small amount of ether was added to the residue for crystallization, and P was separated to obtain the target compound (1,6119).

mp 110~81℃ [α:] Tongue 3: +154.4° (c=t, 0; C
H30H) Example 2 Powdered left-handed melon (6,6
7f) was added with 70 ml of saturated aqueous sodium carbonate (C) and 40 ml of Japanese brine (C), extracted with ethyl acetate, washed with saturated, zero-negative water, and dried over anhydrous magnesium sulfate. When the bath agent was distilled off, a left-handed oil (4,349) was obtained. This oil (404 g) was dissolved in ethanol (165 t) and L-(-)-camphor 10-sulfonic acid (2,5481) was added. ether (62
Add waste/) slowly and set aside overnight. The precipitated salt crystals were filtered, dried, and recrystallized two to three times with ethanol-ether (1:3) to obtain the salts (2,502'l) of the target compounds (8 compounds). Ta.

Father, this thing is 4-(1-(2-methoxyphenyl)-
Racemic methyl 2-(imidazol-1-yl)ethylthio]benzoate (500μ) was dissolved in ethanol (1'N
L-(-)-camphor-10-sulfonic acid (315 μm) was added to the solution, ether was added, and the mixture was incubated overnight. The precipitated salt was filtered once and dried. , also obtained by recrystallization with ethanol-ether (1:3) (14811 g).

8 bodies - Tolerance mp 135-136℃ [α]D”” 120.1° ((=l, Q; CH
30H) These eight bodies (2,4211) were treated with saturated sodium carbonate water (50ml) and saturated saline (40ytl).
) was added thereto, and the mixture was extracted with a mixed solvent of ethyl acetate and ether (3:f), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, a small amount of ether was added to the residue to crystallize it, and after P separation, the target compound (1,1891) was obtained.
or obtained. Recrystallization with ether yielded crystals used for X-ray crystallography.

rr:p 130-81°C [α], j3=-155,8° (c=1.0;
cH3oH) X-ray crystallography of this showed S coordination.

Example 3 Methyl ruthio]benzoate (1) (1R) -(+) -4-[1-(2-methoxyphe-/')-2-(imida7''-ru-1-yl)ethylthio]benzoate ( 210η) to methanol (
2.3 ml) and IN-sodium hydroxide (1
, 14 ml) and stirred at room temperature for 16 hours.

The reaction solution was neutralized using 1N hydrochloric acid (114 ml), and a Rover column (Merck, Ricroprep RP-
8, Size B), and the target compound (198%) in the form of a colorless powder was obtained from the portion eluted with 60% methanol water.

mp 77~19℃ [α) Otsu'= 1141.1° (c=1.o; C
H30H) Example 4 Methyl(18)-(-)-4-[1-(2-methoxyphenyl)-2-(iotasol-1-yl)ethylthio]benzoate (1S08g) was dissolved in methanol (2s+t). and IN-sodium hydroxide (0,1177 ml
) and stirred at room temperature for 16 hours.

The reaction solution was treated and purified in the same manner as in Example 3 to obtain the target compound (1631'9) as a colorless powder.

mp74-76℃ [α], = -145,7'(C=1.0;
CH,OH) Example 5゜(1)(1R) = (+) -4-[1-(2-Methoxyphenyl) Prepared by scaling up Example 1 (1)(
1R)-(+)-4-(1-(2-methoxyphenyl)-2-(imidazol-1-yl)ethelthio] methyl Andichiroate (5,751) was dissolved in methanol (70g+/)
1N sodium hydroxide (31.2 L) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction solution was distilled off under reduced pressure,
1N sodium hydroxide (20m/) was added to the residue, extracted with ether, and the aqueous layer was acidified (pa 2-3) using concentrated hydrochloric acid.
The resulting crystalline product was collected, washed with a small amount of cold water, and dried to obtain the target compound (6,3f).

mp120 ~ 124 C Cα):' = +141.8° (c = 1.0; C
H30H) Example 6 Thio]benzoic acid hydrochloride (18)-(-
) -4-C1-(2-methoxyphenyl)-2-(indazol-1-yl)ethylthio]benzoic acid me? #
(8,30fl)'? c' / II / - le (1
00g+/) and 1N-sodium hydroxide (45g+/).
ml) and stirred at room temperature for 16 hours. When the reaction solution was treated and purified in the same manner as in Example 5, the target compound (816f
l) was obtained.

mp120~124°C [a]o 1413° (C=1.0; C
H30H) Reference Example 1 Methyl 4-mercaptobenzoate (StS ll9) was dissolved in dry N,N-dimethylformamide (6 ml), and after adding 5596 sodium hydroxide (231 ml) under water cooling, The mixture was stirred at room temperature for 30 minutes. 1-[2
-Chloro-2-(2-methoxyfe=A/) x
A solution of tilcoimidazole (1,171) dissolved in dry N,N-dimethylformamide (6 ml) was added and heated in 6O-7 (It) for 5.5 hours. After the reaction,
The reaction solution was poured into brine, extracted with ether, washed with water, dried over anhydrous potassium carbonate, and the solvent was distilled off. The residue was purified by column chromatography using silica gel (developing solvent: ethyl acetate nitriethylamine: 40:1).
An oily target compound (1,26f) was obtained. This product was crystallized with a small amount of ether and collected as colorless crystals.

mp T5. ~T6. S°C Infrared absorption spectrum S NuJ01cIa-1=ax 1715.1595,1560. 1505 nuclear magnetic resonance spectrum (eDcJ3) δppm: 3.76 (3
H, 8), 3.84 (3H# B)s 4.3G
(2H, d.

J-T, 0Hz), 5.02 (IH, t, J=7.
0Hz), 6.60-7.38 (9H, m), T
-80 (2H, d, J=8, GHz) Reference example 2゜ test 1 methyl 4-mercaptoamne, @ methyl frate (sya Mg) and 1
- [To a mixture of 2-hydroxy-2-(2-methoxyphenyl)ethyl coimidazole (50011 g) was added trifluoroacetic acid (8.3 L) under ice cooling, and the mixture was heated at 0-5"C.
The mixture was stirred at room temperature for 27 hours and at room temperature for 25 hours. After the reaction, trifluoroacetic acid was distilled off, and aqueous sodium monocarbonate solution was added to the residue, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to column chromatography using silica gel (developing solvent
Purification with ethyl acetate:methanol (15:1) gave the desired product (691) as a colorless oil. This product was crystallized with a small amount of ether and was obtained as colorless crystals by f-fraction, and the melting point, infrared absorption spectrum, and nuclear magnetic resonance spectrum were identical to those obtained in Examination Example 1.

For patents, applicant: Sankyo Co., Ltd.

Claims (3)

[Claims] (1) (1R)-(+) or (1S)-(-)-4-
[1-(2-methoxyphenyl)-2-(imidazol-1-yl)ethylthio]benzoic acid and its pharmacologically acceptable esters, amides and salts. (2) A racemic compound of an imidazole derivative represented by the general formula▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, R represents a protecting group for carboxylic acid) is optically resolved using an acid-based optical resolving agent. (1R)-(+) or (1S)-(-
)-4-i-(2-methoxyphenyl)-2-(imidazol-1-yl)ethylthio]benzoic acid and a method for producing pharmacologically acceptable esters, amides and salts thereof. (3) The production method according to claim 2, wherein R is methyl and the optical resolving agent is D-(+)-amino-10-sulfonic acid or L-(-)-amino-10-sulfonic acid. .