HU191627B - Process for preparing imidazole derivatives and salts thereof futher pharmaceutical compositions containing such compounds as active substances - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to novel imidazole derivatives of formula (I) wherein R is halogen, W is carboxyl or (C1-C4) alkoxycarbonyl, A is C1-C3 alkylene, and B is C1-C3 alkyl; means a straight or branched chain alkyl group having 2-3 carbon atoms and a physiologically acceptable acid addition salt thereof. The compounds of the present invention have inhibitory effects on TXA2 synthesis. -1-

Description

Thromboxane A ₂ (TXA ₂ ), which is formed from PGG and PGH ₂ prostaglandin endo peroxides, has a platelet aggregation stimulating effect, whereas prostacyclin (PCI,), which is also formed from PGG ₂ and PGH, is an anti-platelet agent. aggregation effect. The balance between TXA ₂ and PGI ₂ formation was found to be critical for thrombus formation. Consequently, it would be desirable to selectively inhibit the formation of TXA _{2 in} the treatment or prevention of thrombo-embolic diseases, while favoring the formation of PGI with anti-aggregating properties.

Imidazole derivatives substituted in position 1 with a variety of organic groups such as aliphatic, aryl, aryl aliphatic or heterocyclic groups are known to inhibit thromboxane synthesis (2,008,089 A, 2,006,752 A, 2,010,813). A, 2,018,136 A and 2,044,259 A). In order to achieve optimal therapeutic effect, high potency and high selectivity of TXA ₂ synthesis inhibitors are required, i.e., they inhibit TXA synthesis but are ineffective in the formation of PGI ₂ . Long duration of action is also desirable.

It has now been found that the imidazole derivatives of the formula (I) and their physiologically acceptable salts (hereinafter referred to as "active compounds") produced by the process of the present invention have an advantageous TXA ₂ synthesis inhibitory activity.

In the compounds of formula (I) according to the invention, R is halogen,

W is carboxyl or (C1-C4) -alkoxycarbonyl

A is a C 1-3 alkylene group and B is a straight or branched C 2 -C 3 alkenylene group.

In the compounds of formula I, A is preferably a straight-chained C 1-3 alkylene group such as methylene or ethylene, halogen is fluorine, chlorine bromine or iodine, preferably chlorine or bromine, and W is preferably carboxyl. The R substituent is at any position on the phenyl ring, although the R substituent is preferably in the 2 position and the (B) W substituent is preferably in the 4 position. Particularly preferred are compounds of formula I wherein B is CH = CH and W is carboxyl.

Particularly preferred compounds are 3- / 3-chloro-4- (1H-imidazolylmethyl) -phenyl / -prop-2-enoic acid and its ethyl ester and 3- / 3-bromo-4- (1H-imidazolylmethyl). phenyl-prop-2-enoic acid and its ethyl ester.

It has now been found that the compounds of formula (I) produced by the process of the invention have a high inhibitory effect on TXA ₂ synthesis in vitro and a long duration of action in vivo.

The physiologically acceptable salts of the compounds of formula (I) prepared according to the process of the present invention include acid addition salts such as oxalic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salts with tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid.

Where the compounds of formula (I) contain an asymmetric carbon atom, the optically active stereoisomers as well as the racemic mixtures are included within the scope of the present invention. If desired, the optically active stereoisomers may be resolved in known manner, for example by fractional crystallization of diastereoisomeric salts. The geometric isomers of the compounds of formula (I) are also within the scope of the invention.

In the process of the present invention, the compounds of formula I are prepared by reacting an imidazole or a salt thereof with a compound of formula II wherein A, B, R and W are as defined above and Z is a leaving group.

In the process of the invention, imidazole or a salt thereof, for example an alkali metal such as sodium or silver, is reacted with a compound of formula II. This reaction is well known in the art and the leaving group may be a variety of substituents, in particular halogen, preferably chlorine or boron, arylsulfonyloxy, preferably paratoluenesulfonyloxy, alkanesulfonyloxy or arylalkylsulfonyloxy. Further, Z may also be a trialkylammonium cation, such as a trimethylammonium cation, linked to the appropriate anion. The reaction is preferably carried out in the presence of an acid scavenger such as an alkali metal alkoxide such as sodium methoxide or potassium tert-butoxide, usually in a solvent medium such as alkanol or Ν, Ν-dimethylformamide. In some cases, it is preferable to carry out the reaction in the presence of a crown ether such as 18-crown-6, preferably in an ether solvent. When Z is halogen, the reaction is carried out in the presence of a copper catalyst (such as in the Ullmann reaction). The cleavage group can also be prepared in situ (Z = OH) by reaction with hydrogen halide (e.g., hydrochloric acid or Lewis acid, such as aluminum chloride) and the resulting compound directly without isolation. with imidazole.

Intermediates of the reactions described above may also be prepared according to known procedures.

The physiologically acceptable acid addition salts of the compounds of formula (I) of the present invention may also be prepared according to known methods, for example by treating the parent imidazole with the appropriate acid or by anion exchange.

The imidazoles of formula (I) of the present invention may be used in combination with phosphodiesterases such as theophylline or dipyridamole, whereby, by another means, inhibition of platelet aggregation is achieved.

The active compounds of the present invention are particularly useful for the treatment and prevention of thrombo-embolic diseases in mammals, including humans, which include any disease associated with platelet aggregation.

The active compounds of the invention are useful in all cases where inhibition of platelet aggregation and / or reduction of platelet adhesive properties are desirable, such as for the prevention or treatment of Jrombus formation in mammals (including humans). Thus, for example, myocardial infarction, cerebrovascular thrombosis, and ischemic peripheral vascular disease can be used to treat and prevent postoperative thrombosis and to enhance the effects of vascular transplantation.

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The active compounds of the invention may be used as additives to blood, blood substitutes, or any fluid used for artificial circulation or perfusion of detached body parts, such as limbs or organs, whether or not associated with the original body or prepared for transplantation. The active compounds are also used in laboratory experiments in animals, such as cats, dogs, rabbits, monkeys and rats, to develop new methods for organ and limb transplantation.

The active compounds also have certain vasodilatory effects and can be used in the treatment of hypertension in mammals, including humans.

The active compounds may also be used to treat and prevent angina pectoris, to treat and delay the onset of shock, and to treat migraine and asthma.

The amount of active compound to be used will depend on the route of administration and the conditions of treatment. For mammals, including humans, a suitable dose is 0.1 to 300 mg, preferably 0.5 to 10 mg (e.g. 8 mg) per kg body weight. In the case of oral administration to adults, the dose is 50 to 1800 mg, preferably 200 to 900 mg, especially 300 to 700 mg, for example 550 mg, three times a day.

Although the active compounds of the invention may be administered alone, administration in the form of a pharmaceutical composition is preferred. The human or veterinary pharmaceutical compositions of the present invention contain the above active compounds. These compositions are formulated for use in both human and veterinary use by admixing the above active compounds with pharmaceutically acceptable carriers and optionally other compatible therapeutic agents. The formulations are in a unit dose of 60 mg and

They may contain between 1.5 g of active compound. The compositions may be administered orally, rectally, vaginally or parenterally. Preferred compositions are tablets, capsules, elixirs and injectable suspensions or solutions.

The formulations are formulated in conventional unit dosage forms. In general, the active compounds (as the parent compound or its physiologically acceptable salt) are uniformly and well mixed with the desired carrier (liquid or finely divided solid carrier) and then formulated to the desired form.

The following examples illustrate the process of the invention in more detail. In the examples, all temperatures are given in ° C.

Example 1 Preparation of 1- (4-Carboxy-2-chlorobenzyl) imidazole

a) Preparation of 4-Bromomethyl-3-chlorobenzonitrile

5.0 g (0.033 mole) of 3-chloro-4-methylbenzonitrile, 5.87 g (0.033 mole) of N-bromosuccinimide and 0.08 g of 2,2-azobis (2-methylpropio) nitrile. It is stirred in anhydrous carbon tetrachloride (2 ml) and stirred for 2 hours under reflux and illumination with a tungsten filament lamp. The reaction mixture was then filtered hot, concentrated under reduced pressure and the resulting brown oil was solidified by cooling. Petroleum ether (f.p.

Recrystallization from ether (40-60 ° C) gave the desired 4-bromomethyl-3-chlorobenzonitrile as a yellow crystal, m.p. 80-83 ° C.

b)] / 2-Chloro-4-cyanobenzyl) imidazole

0.04 g (0.15 mmol) of 1,4,7,10,13,16-hexaoxycyclooctadecane (18-crown-6) and 0.15 g (1.34 mmol) of tert-butoxide and anhydrous ether (0.08 g, 1.18 mmol) and imidazole (0.08 g, 1.18 mmol) and 4-bromomethyl-3-chloro (0.03 g, 1.3 mmol) in anhydrous ether (5 mL) were added dropwise. benzoritrile was added and stirring was continued for a further 3 hours and allowed to stand overnight. The next day, water (8 mL) was added and the organic phase was separated, the aqueous phase was extracted with ether (3 x 15 mL), the combined organic extracts washed with brine (10 mL) and dried over magnesium sulfate. This gave a brown solid, which was purified by chromatography, eluting with 9: 1 isoform / methanol. After concentration of the fractions, the product was obtained as pale yellow crystals.

Preparation of 1- (4-Carboxy-2-chlorobenzyl) imidazole hydrochloride

1- (2-Chloro-4-cyanobenzyl) imidazole (0.2 g, 0.92 mmol) and 6M hydrochloric acid (3 mL) were stirred at reflux for 3 hours, then cooled and concentrated under reduced pressure. To the resulting white crystalline material was added 10 ml of ethanol and the mixture was concentrated again. This operation was repeated three times and the resulting solid was recrystallized from ethyl acetate-petroleum ether (b.p. 40-60 ° C). 1- (4-Carboxy-2-chlorobenzyl) imidazole hydrochloride is obtained in the form of a white plate, m.p. 265-269 ° C.

Example 2

Preparation of ethyl (E ') -3,3-chloro-4- (imidazol-1-ylmethyl) phenyl / prop-2-enoate

a) Preparation of copper cyanide

A vigorously stirred solution of copper sulfate pentahydrate (1080 g, 4.33 mol) and water (3000 ml) was heated to 60 ° C while acidifying the solution dropwise with 2 M hydrochloric acid with a conical red indicator. A solution of 276.15 g (1.453 mol) of sodium metabisulphite in 870 ml of water is added at 50-60 ° C, vigorously stirred and 602.4 g (4.64 mol) of potassium cyanide in 870 ml are added at 60 ° C. water. The reaction mixture was then stirred for an additional half hour at 60 ° C, filtered and the residue was washed well with warm water.

b) Preparation of 3-chloro-4-methylbenzonitrile

A mixture of 3-chloro-4-methylaniline (515.01 g, 3.64 mol), concentrated hydrochloric acid (930 ml) and water (930 ml) was suctioned to 0 ° C, followed by dropwise addition of 259.77 g (0-5 ° C). 3,665 moles of sodium mitrite) in 540 ml of water. Then, according to step a) was dissolved in sodium cyanide solution rézcianidot (421.98 g NaCN in 1350 ml water), the solution was heated at 70 ° C ^ö and cold diazonium salt solution was prepared as previously described by dropwise at 60-70 ° C is added to the vigorously stirred solution of copper cyanide and stirred for another half hour. 3000 ml of ether were added to the reaction mixture, which was filtered. The ethereal phase is separated off and washed first with 1500 ml of 2M hydrochloric acid and then with 1500 ml of water. The ethereal solution was dried over magnesium sulfate and concentrated under reduced pressure. The brown solid thus obtained3

The residue was distilled under reduced pressure to give the desired product

3-chloro-4-methyl-benzonitrile (ja-bp 120-126 C / ² mmHg 21,3.10 °) as a yellow solid. After recrystallization from aqueous ethanol, the product is a white crystalline solid, m.p. 46.5-47.5 ° C.

c) Preparation of 3-chloro-4-methylbenzaldehyde

A mixture of 4.0 g (26.39 mmol) of 3-chloro-4-methylbenzonitrile, 72 ml of 75% formic acid and 4.8 g of 50/50 nickel aluminum alloy was stirred at reflux for 2 hours, then filter hot (Hyflo filter) and wash well with warm ethanol. The filtrate was then concentrated under reduced pressure and the resulting viscous solid was evaporated. This yields the desired 3-chloro-4-methyl-benzaldehyde, as colorless oil, bp: 73-74 ° C / l, 06xl0 ² torr.

d) Preparation of Ethyl 3- (3-chloro-4-methylphenyl) -prop-2-enoate (0.93 g, 19.35 mmol, 50% in oily dispersion), sodium nitrite and 30 mL of anhydrous 1 The mixture of 2-dimethoxyethane was treated with a solution of 4.35 g (19.4 mmol) of phosphoric acid triethyl ester in 10 ml of anhydrous 1,2-dimethoxyethane in a dry nitrogen atmosphere and stirred for a further 1 hour after the addition was complete. . A solution of 3-chloro-4-methylbenzaldehyde (g, 19.41 mmol) in dry 1,2-dimethoxyethane (10 mL) was added dropwise and stirring was continued at ambient temperature for 1.5 hours. The reaction mixture was poured into ice water (50 ml), the resulting oil was separated and the aqueous solution was extracted with ethyl acetate (3 x 50 ml), the organic layers were combined and dried over magnesium sulfate. After concentration of the organic solution under reduced pressure, the brown oil obtained is distilled off to give ethyl 3- (3-chloro-4-methylphenyl) prop-2-enoate as a colorless oil, m.p. 98-104 ° C. / 0.565 x 10 ² Pa.

e) Preparation of ethyl 3- (4-bromomethyl-3-chlorophenyl) prop-2-enoate

10.0 g (44.5 mmol) of ethyl 3- (3-chloro-4-methylphenyl) prop-2-enoate, 31.7 g (178.1 mmol) of N-bromosuccinimide and 0, A mixture of 1 g of 2,2'-azabis (2-methylpropionitrile) and 100 ml of carbon tetrachloride was stirred for 5 hours under reflux and illumination with a tungsten filament lamp. A further 1.0 g of 2,2'-azabis (2-methylpropionitrile) was added and the mixture was lit for a further 6.5 hours. The reaction mixture was filtered while hot, the filtrate was concentrated under reduced pressure and the resulting dark brown oil was chromatographed on a silica gel column eluting with petroleum ether / chloroform (7/3). The desired ethyl 3- (4-bromomethyl-3-chlorophenyl) -prop-2-enoate is obtained in the form of a colorless oil, m.p. 263-265 ° C.

f) Preparation of ethyl 3- (3-chloro (4-imidazol-1-ylmethyl) phenyl) prop-2-enoate

Imidazole (0.078 g, 1.14 mol) was added to a solution of 18-crown-6 ether (0.03 g, 1.14 mmol) and potassium t-butoxide (0.15 g, 1.34 mmol) in anhydrous ether (5 mL). After stirring at room temperature for 1 hour, a solution of ethyl 3- (4-bromomethyl-3-chlorophenyl) -prop-2-enoate (0.4 g, 1.32 mmol) in anhydrous ether (3 mL) was added. and the mixture is stirred overnight at room temperature. Water (1 mL) was added and the organic layer was separated and the aqueous layer was extracted with ether (3 x 5 mL). The organic solutions were combined, washed with 10 mL of saturated brine and dried over magnesium sulfate. Concentration of the organic solution gave a yellow crystalline solid which was recrystallized from aqueous ethanol to give the product as a yellow plate, mp 112-114 ° C.

Example 3 Preparation of (E) -3- [3-Chloro-4- (imidazol-1-ylmethyl) -phenyl] -prop-2-enoic acid hydrochloride

A mixture of 0.1 g (0.31 mmol) of ethyl] - (E ') - 3- [3-chloro-4- (1H-imidazolylmethyl) -phenyl] -prop-2-enoate and 2 ml of 6M hydrochloric acid was added. while stirring for one hour. The reaction mixture was then concentrated under reduced pressure, then ethanol (4 mL) was added and concentrated again. This operation was repeated four times to give a white solid, which was recrystallized from ethanol / petroleum ether (b.p. 40-60-9) to afford (E) -3- [3-chloro- (4-imidazol-1-yl) methyl] - of phenyl-prop-2-enoic acid as a white solid, m.p. 218-220 ° C.

Example 4

Preparation of ethyl 3- (3-bromo-4- (imidazol-1-ylmethyl) -phenyl] -prop-2enoate

a) Preparation of 3-Bromo-4-methylbenzaldehyde

This compound was prepared according to the procedure of Eizember and Ammons (Organic Preparations and Procedures Int. 1974 (5), 251). The product is beige crystalline, m.p. 47-49 ° C.

b) Preparation of ethyl 3β-bromo-4-methylphenyl) prop-2-enoate

To a mixture of 10.84 g (0.226 mol) (as a 50% oily dispersion) of sodium hybrid and 240 ml of anhydrous 1,2-dimethoxyethane was added dropwise a solution of 60 ml of anhydrous 1,2-dimethoxyethane under stirring in a dry nitrogen atmosphere. 6 g (0.226 mmol) of phosphoric acid triethyl ester are added. After completion of the addition, the reaction mixture was stirred at ambient temperature for 1 hour, then 45 g (0.226 mol) of 3-bromo-4-methylbenzaldehyde in 60 ml of anhydrous 1,2-dimethoxyethane was added dropwise over 1.5 hours and the mixture is stirred at ambient temperature overnight. The next day, the material was heated to reflux for 1.5 hours with stirring and then cooled. The material was then poured into stirred ice water and the resulting oil was extracted with ethyl acetate (3 x 300 mL). The ethyl acetate extracts were then combined, dried over magnesium sulfate and concentrated. Distillation of the resulting yellow oil affords the desired ethyl 3- (3-bromo-4-methylphenyl) prop-2-enoate as a white solid, m.p. 124-126 ° C / 0.19 x 10 ² Pa

c) Preparation of ethyl 3- [3-bromo-4- (bromomethyl) phenyl] -prop-2-enoate g (0.015 mol) of ethyl 3- (3-bromo-4-methylphenyl) -prop A mixture of -2-enoate, 5.34 g (0.03 mol) of N-bromosuccinimide and 0.2 g of 2,2'-azabis (2-methylpropionitrile) in 25 ml of anhydrous carbon tetrachloride Stir for 14 hours under a light of a filament lamp and leave to stand at ambient temperature overnight. The next day, the reaction mixture was again heated to spinning, filtered hot and the filtrate was concentrated under reduced pressure. The resulting brown oil was purified by chromatography (chloroform: methanol = 9: 1). The product was obtained as ethyl 3- (3-bromo-4- (bromomethyl) phenyl) -prop-2-enoate as a white solid.

d) 0.25 g (3.67 mmol) of imidazole, 0.42 g (3.75 mmol) of potassium tert-butoxide, 1.29 g (3.7 mmol) of ethyl 3- [3-bromo-4292]. 627

A mixture of -4-bromomethylphenyl-prop-2-enoate and 0.1 g of 18-crown-6-ether was stirred in anhydrous ether for 72 hours at room temperature. Water (5 mL) was added, the aqueous phase was extracted with ether (3 x 50 mL), the ether solutions were combined, dried over magnesium sulfate and concentrated. The resulting yellow oil is chromatographed using chloroform / methanol 9: 1 as eluent. The product fractions were combined, dried over magnesium sulfate and concentrated. The desired ethyl 3- [3-bromo-imidazol-1-ylmethyl] -phenyl] -prop-2-enoate is thus swallowed as a white solid. NMR of the product confirmed the desired structure.

Example 5

Preparation of hydrochloride of 3- (3-bromo-4- (imidazol-1-yl) phenyl) -prop-2-enoic acid

A mixture of 0.12 g of ethyl 3- [3-bromo-4- (imidazol-1-ylmethyl) -phenyl] -prop-2-enoate and 2 ml of 6M hydrochloric acid was heated under reflux for 2 hours. The reaction mixture was then concentrated under reduced pressure, toluene (5 mL) was added and then concentrated again. The resulting white solid was recrystallized from ethanol / ether to give the hydrochloride of 3- [3-bromo-4- (imidazol-1-ylmethyl) -phenyl] -prop-2-enoic acid. 244-249 ° C as a white solid.

Example d

Preparation of 3- (3-Chloro-4- (imidazol-1-ylmethyl) -phenyl] -prop-2-ene-ethyl ester

a) Preparation of ethyl 3- [3-chloro-4- (2,2-bis (methoxyethyl) aminomethyl) phenyl] prop-2-enoate

0.21 g of 2,2-dimethoxyethylamine, 0.61 g of ethyl 3- (4-bromomethyl-3-chlorophenyl) prop-2-enoate, 0.75 ml of triethylamine, A mixture of 0.03 g of 4-dimethylaminopyridine and 5 ml of dichloromethane was stirred at ambient temperature for 72 hours. Water (5 mL) was added and the organic layer was separated. The aqueous layer was washed with ether (2 x 10 mL), the combined organic extracts dried over magnesium sulfate, and then concentrated. The oily product was chromatographed, eluting with chloroform / methanol 9: 1. The product fractions are combined and concentrated to give the desired ethyl 3- / 3-chloro-4- (2,2-bis (methoxyethyl) aminomethyl) phenyl] prop-2-enoate which is purified without further purification. employed.

b) 0.31 g of ethyl 3- [3-chloro-4- (2,2-bis (methoxyethyl) -aminomethyl) -phenyl] -prop-2-enoate, 0.097 g of caustic thiocyanate, A mixture of 1 ml of water and 5 ml of ethanol was treated with 1 drop of 12M hydrochloric acid, heated at 100 ° C for 16 hours, and then 5 ml of ethanol and 5 ml of water were added successively. 40 ml of ammonia solution (S.G. 0.88) are then added to the reaction mixture and the mixture is concentrated under reduced pressure. After addition of 100 ml of acetone, the mixture was stirred for 0.25 hours, filtered and the filtrate was purified by concentration after concentration. The desired ethyl 3- [3-chloro-4- (2-thioimidazol-1-ylmethyl) -phenyl] -prop-2-enoate is obtained which is used without further purification.

c) A mixture of 0.05 g of ethyl 3- [3-chloro-4- (2-thioimidazol-1-ylmethyl) -phenyl] -prop-2-enoate, 10 ml of water and 10 ml of ethanol in 2 ml of ammonia solution. (SG 0.88) and Raney nickel (0.5 g, W2), heated at reflux for 2 hours and filtered. The residue was washed with warm ethanol, the filtrates were combined and concentrated under reduced pressure. The resulting gummy material was mixed with ethanol and the resulting solid was recrystallized from ethanol / petroleum ether. The desired ethyl 3- [3-chloro-4- (imidazol-1-ylmethyl) -phenyl] -prop-2-enoate is obtained, m.p. 111-113 [deg.] C.

Example 7

Preparation of 3- (3-Chloro-4- (itnidazol-1-ylmethyl) -phenyl] -prop-2-enoic acid

A mixture of 0.5 g of ethyl 3- (3-chloro-4- (imidazol-1-ylmethyl) -phenyl) -prop-2-enoate and 0.25 g of sodium hydroxide in 10 ml of water was refluxed for 3 hours. while stirring. The resulting sodium salt solution was then adjusted to pH 6 with glacial acetic acid and the mixture was evaporated to dryness. The residue was taken up in 10 ml of ethanol, boiled and filtered. The filtrate was concentrated and the residue was recrystallized from ethanol / ether. The desired 3- [3-chloro-4- (imidazol-1-ylmethyl) -phenyl] -prop-2-enoic acid is obtained, m.p. 227-229 ° C.

Preparation Examples

Example A)

Preparation of tablet formulation

Composition: Imidazole compound of formula I (Example 3) 150 mg starch 25 mg polyvinylpyrrolidone 2 mg magnesium stearate 3 mg

The imidazole or its salt is ground to a fine powder, mixed with starch and granulated with an aqueous solution of polyvinylpyrrolidone. The granulate was sieved through a 1000 lum sieve, dried, sieved again, and magnesium stearate was added. The mixture is then compressed into tablets.

Example B)

Preparation of tablet formulation

The tablets were prepared as described in the previous example using the following formula:

Imidazole Compound (Example 2) 150 mg lactose 100 mg starch 30 mg polyvinylpyrrohdone 2 mg magnesium stearate 3 mg

Example C)

Preparation of tablet formulation

The tablets are prepared as described in Example A, with the following composition:

Imidazole Compound (Example 3) 100 mg sodium starch glycollate 10 mg polyvinylpyrrolidone 2 mg magnesium stearate 3 mg

Example D)

Preparation of tablet formulation

The tablets are prepared as described in Example A except that pregelatinized starch is used and mixed with the starch and the active ingredient prior to granulation.

Composition: Imidazole Compound (Example 3) 150 mg starch 25 mg pregelatinized starch 5 mg magnesium stearate 3 mg

Example E)

Preparation of injection preparation

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Composition: Imidazole Compound of Formula 1 (Example 7) 15.0 g of lactic acid B.P. Make up to pH 3 with water (B.P. for injection) per 100 ml

The above compound is suspended in 3/4 of water, then enough lactic acid is added to bring the pH to 3 and the remaining water is added. The solution is then sterilized by passing through a membrane filter having a pore size of 0.22 µm and is also added under sterile conditions into sterile 1 ml ampoules. Every ampoule

It contains 150 mg of active substance.

Example F)

Preparation of injection preparation

Composition: Imidazole Compound of Formula I (Example 7) Chlorcresol 0.1 g of water (for injection, B.P.) per 100 ml of 15.0 g of citric acid at pH 3.

The above compound is suspended in 1/2 of water, 10% citric acid solution is added to dissolve the solution to pH 3 and then diluted with the remaining water to the desired volume. Sterilization is accomplished by passing through a membrane filter with a pore diameter of 0.22 µm. The resulting formulation is also added under sterile conditions into sterile 25 ml vials, sealed with a sterile rubber stopper and sealed with an aluminum cap. Each ml of the preparation contains 50 mg of active ingredient.

Determination of inhibition of thromboxane Aβ synthesis

A solution of the test compound is prepared in mg / ml in a suitable solvent and 20 µl is added to 0.8 ml of 100 mM Tris buffer (ph = 7.5).

ml of horse PRP platelets are centrifuged and resuspended in 100 µl of Tris buffer. After sonication or freezing and re-thawing, the platelet suspension is added to the drug solution and allowed to stand at room temperature for 5 minutes. Then 300 ng (50 nCi) (1-14C) arachidonic acid dissolved in 100 µl of buffer solution was added and the mixture was incubated for 30 minutes at 37 ° C.

The reaction was then quenched by addition of 50 µl of 2N hydrochloric acid, and the resulting product was extracted with 1.5 volumes of ethyl acetate and centrifuged for 30 seconds. 1 ml of saturated sodium chloride is then added to the aqueous phase to prevent formation of an emulsion. The organic phase is removed, dried under nitrogen and the product is dissolved in 50 µl of chloroform / methanol and quantitatively transferred to TLC plates for desired analysis.

Plates were developed with 90: 8: 1: 0.8 chloroform: n-ethanol: acetic acid: water, dried and monitored by autoradiography for 2-3 days.

After development, autoradiograms were tested for selective inhibitory activity by the active compound, the radioactive TXB, PGD ₂ , PGE ₂ and PGF ₂ zones were separated and their radioactivity was determined by scintillation counting.

The concentration of active compound required to reduce the activity of the enzyme by 50% (ED _J0 ) is summarized in the following table.

The table

Example number ED _J0 Qug / ml)

6.6

0.5

0.05

0.08

0,015

0.35

Duration of inhibition of thromboxane 4 ₂ synthesis inhibitors in vivo

Weighing 2.5 kg N.Z. male rabbits were anesthetized with sodium pentabarbitone and chloral and cannulated into one of the carotid arteries. Through this, 1 ml of blood samples were taken, two as a control, one to which 10 µg of indomethacin was added to a blank.

The test compound was then orally administered with the active compound of the invention and further blood samples were collected at half-hour intervals for 5-8 hours.

Control samples and blood samples containing the active compound were suspended in a glass tube by incubation at 37 ° C for 45 minutes, indomethacin was added, the serum was separated by centrifugation, pelleted, and thromboxane A ₂ concentration determined by RIA analysis.

The time at which the inhibitor reduced the concentration of Thromboxane A was then determined. According to our studies, the effect of the compound of Example 1 at a dose of 160 mg / kg lasted for at least 5 hours, while that of the compound of Example 3 lasted more than 7 hours.

Claims (3)

Claims A process for the preparation of a novel imidazole derivative of formula (I): wherein: R is halogen, W is carboxyl or (1-4C) alkoxycarbonyl; A is C 1 -C 3 alkylene and B is a straight or branched C 2 -C 3 alkylene group and their physiologically acceptable acid addition salts, characterized in that imidazole or a salt thereof is a compound of formula II, wherein A, B, R and W is as defined above and Z is a leaving group, and if desired the resulting compound is converted into its acid addition salt. 2. A process according to claim 1 wherein the starting compound of formula II is wherein A, B, R and W are as defined in claim 1 and Z is halogen. 3. A process for the preparation of a pharmaceutical composition, wherein a compound of the formula (I) according to claim 1, wherein R, W, A, and B are as defined in claim 1, is prepared. -6191 627, or a physiologically acceptable acid addition salt thereof, with a pharmaceutically acceptable carrier and / or other excipient and converting the mixture into a pharmaceutical composition.