FR2580641A1 - ARYLALCANOIC DERIVATIVES OF IMIDAZOLIUM, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

THE INVENTION RELATES TO MEDICINES. IT CONCERNS ARYLALCANOATE SALTS OF IMIDAZOLIUM RESPONDING TO GENERAL FORMULA 1: (CF DRAWING IN BOPI) IN WHICH AR REPRESENTS A RADICAL PHENYL, NAPHTYL, INDENE OR INDOLE, SUBSTITUTED BY ONE OR MORE RIGHT CHAIN ALKYL GROUPS OR RAMIFIED, ALCOXY, HALOGENO, ARYLCARBONYL, CYCLOALKYL, CHLOROBENZOYL OR BENZYLMETHYLSUFONYL, AND R REPRESENTS A HYDROGEN ATOM, A METHYL GROUP OR AN ETHYL GROUP. USE AS ANALGESIC, ANTIPYRETIC AND ANTI-INFLAMMATORY AGENTS IN THE PHARMACEUTICAL INDUSTRY.

Description

_ 1 -

  The present invention relates to arylalcium salts

  imidazole compounds having the general formula (I): Ar-CH-OO N (I)

R

  In which Ar represents a phenyl or naphthyl radical,

  indole or indole, substituted by one or more groups

  kines with straight or branched chain, alkoxy, halo, aryl-

  carbonyl, cycloalkyl, chlorobenzoyl or benzylmethylsulphonyl

  fonyle, and R represents a hydrogen atom, a group

methyl or an ethyl group.

  The starting acids used to prepare the imidazolium salts are well known. Among these are the

  2- (4-isobutylphenyl) propionic acid (Ibupro-

  FENE); (p-isobutylphenyl) acetic acid (Ibufenac); acid

  2- (3-benzoylphenyl) propionic acid (ketoprofen); acid 1- (p-

  chlorobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid (Indo-

  methacine) and other anti-inflammatory agents well

known (Sulindac, etc.).

  All these acids are endowed with anti-inflammatory

  mat, antipyretic and analgesic that are assorted, as is generally the case with non-inflammatory

  Steroids, of gastrotoxic activity (B. Scott, Brit.

  Med. J., 1, 489, 1979), This gastrotoxic activity can also lead to gastric ulcerations and considerably hinders the therapeutic interest of these acids

  while limiting their clinical use.

  In comparison with the acids from which it is derived

  or with their other known salts, it has been found with

  taking that the salts of general formula (I) have, at equivalent doses, much stronger anti-inflammatory, analgesic and antipyretic effects without concomitant ulcerogenic or gastrotoxic phenomena, and that they can therefore be used clinically with greater safety and efficiency, even for long periods of time. It has also been found that the compounds of

  formula (I) can reduce the number and severity of ul-

  caused in animals by agents such as _2 -

  reserpine and corticosteroids.

  The present invention also relates to processes for preparing the compounds of formula (I), by salifying

  imidazole with the corresponding acid in approximately

  stoichiometric, in the presence of solvents or mixtures of solvents, from which the salt can be separated either

  by spontaneous crystallization, either by progressive extraction

  sive the solution by adding a solvent in which the salt is not soluble, either by evaporation of the solvent

used in the reaction.

  In the context of the present invention,

  pharmaceutical compositions containing, as active ingredients, one or more compounds of formula (I). These compositions may be used in human and / or veterinary therapy in the form of oral, parenteral, rectal or topical preparations, especially in a

  pathology of inflammatory, painful or cerebrile type.

  Toxicological and pharmacological characteristics Examples of the tests carried out on the imidazolium ibuprofen salt, on the imidazolium Naproxen salt and on the imidazolium ketoprofen salt, which are respectively designated by

  "salt A", "salt B", and "salt C", to abbreviate.

  Acute toxicity tests showed, for male as well as female rats, an LD50 of 1205 mg / kg for A; of 780 mg / kg for B, and 915 mg / kg for C. Chronic toxicity tests performed on the rat by oral administration of these salts for 15 weeks at doses of 50 and 100 mg / kg showed a development

  normal and normal values for hematology and

  chemical breakdown of blood. It should be noted that, in these animals, the gastric and intestinal mucosa did not show any of the ulcers or haemorrhages that usually accompany the administration of Ibuprofen, Naproxen

and ketoprofen.

  It has been noted in particular in rats that after

  ligation of the pylorus according to Schay or after injection of

  syrup, administration of Ibuprofen, Naproxen or

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  Cetoprofen increased the number and severity of gastric ulcerations by two to five times; on the contrary, the administration of equimolecular amounts of salts A, B and C reduced the number of lesions caused by these manipulations. Using carrageenin-induced edema in the rat as a measure of anti-inflammatory activity, the hot-plate test in mice provides a measure of analgesic activity, and yeast-induced fever in rats it was found that a comparison of equimolar amounts of the above three acids with their respective salts A, B and C was extremely favorable to the salts, which were found to have anti-inflammatory activities,

  analgesic and antipyretic much larger.

  The following nonlimiting examples illustrate

further the present invention.

Example 1

  Salt A One mole of ibuprofen is dissolved in 1000 ml of anhydrous acetone. To this solution is added 1.05 moles of imidazole dissolved in 500 ml of anhydrous acetone. After mixing thoroughly, the solvent is evaporated to dryness under reduced pressure. We obtain an oily mass, a little hygroscopic

  presenting the chemical-physical characteristics and

  following tests: Basic analysis:

C H N

  Calculated (%): 66.19 7.64 9.65 Found (%): 66.25 7.79 9.48

  IR spectrum: conform to the structure.

NMR Srectre: confirms the structure.

Example 2

  Imidazolium 2- (6-methoxy-2-naphthyl) propionate One mole of 2- (6-methoxy-2-naphthyl) acid is dissolved

  propionic in 1000 ml of anhydrous ethanol. To this solution

  1.05 moles of imidazole dissolved in 500 ml of anhydrous acetone are added. After carefully mixing and heating at 500C for about 20 minutes, the mixture is cooled

  solution and add petroleum ether until

  slight cloudiness, then leave the crystal mixture

  to read during a cold night. The salt is obtained in the form of crystals that are collected, washed on filter paper

  and dry; melting point between 143 and 14600 (uncorrected).

  Elemental Analysis: a H N Calculated (%): 68.44 6.08 9.39 Found (%) 68.38 6.22 9.37

  IR spectrum: conform to the structure.

NMR spectrum: confirms the structure.

Example 3

  Imidazolium 2- (3-benzoylphenyl) propionate With the same molar proportions as in Example 1 between 2- (3-benzoylphenyl) propionic acid and imidazole,

  the salt is obtained in the form of a semi-solid hygro-

  scopic, having the following characteristics z Elemental analysis s

0 H N

  Calculated (%): 70.79 5.63 8.69 Found (%) 70.84 5.67 8.71

  IR spectrum: conform to the structure.

NMR spectrum: confirms the structure.

Example 4-

  Tablets containing 2- (6-methoxy-2-naphthyl) propionate

  imidazoltum as an active ingredient.

  A thousand tablets each containing 330 mg of the active ingredient are prepared. 83.5 g of corn starch, 75 g of microgranular cellulose and 330 g are thoroughly mixed together.

  of active ingredient in micronized powder form. We trans-

  The mixture is then added to a blender and 100 g of a 10% solution of gelatin in deionized water is added and the mixture is granulated. After drying and sieving

  the aggregates are added 1.5 g of magnesium stearate.

  After mixing again, 0.5 g tablets are prepared using flat or round punches. Tablets

2580641

  have the following composition: 330 mg of active ingredient; mg of microgranular cellulose; 83.5 mg starch

  but; 10 mg of gelatin; 1.5 mg of magnesium stearate.

  The rounded tablets may optionally be coated with a film.

Example 5

  Suppositories containing imidazolium 2- (3-benzoyl-phenyl) propionate as an active ingredient A thousand suppositories are prepared as follows: 1870 g of saturated fatty acid glycerides are melted at 70 ° C. and then brought back at 40 °, after which 130 g of the active ingredient are added. After mixing and filtering through a sieve of stainless steel, the preparation is dosed into containers

appropriate.

  After cooling to 5 ° C., the suppositories obtained have the following composition: 130 mg of ingredient

  active; 1870 mg of saturated fatty acid glycerides.

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Claims (8)

  1. Compounds characterized in that they are arylalkanoate salts of imidazolium corresponding to the general formula (I): Ar-CH-CO () H wherein Ar represents a phenyl, naphthyl,   of indene or indole, substituted by one or more groups   straight or branched cat kyles, alkoxy, halo, aryl-   carbonyl, cycloalkyl, chlorobenzoyl or benzylmethylsulphonyl   fonyle, and R represents a hydrogen atom, a group methyl or an ethyl group.   2. Compound according to claim 1, characterized in that it is 2 (4-isobutylphenyl) propionate imidazolium.   3. Compound according to claim 1, characterized in that it is imidazolium 2 (6-methoxy-2-naphthyl) propionate. 4. Compound according to claim 1, characterized in that it is 2- (3-benzoylphenyl) propionate imidazolium.   5. A process for preparing a compound such as   dique in claim 1, characterized in that the salt of the acid with imidazole is prepared in the presence of a solvent or a mixture of solvents, from which the salt can be separated either by spontaneous crystallization or   by evaporation, or by addition of a non-solvent.   6. Process according to claim 5, characterized in that the reaction is carried out with almost   stoichiometric acid and imidazole.   7. Pharmaceutical composition with anti-activity   inflammatory, analgesic and antipyretic, characterized in that it contains, as an active ingredient, one or   several of the compounds as claimed in the claims 1 to 4. -7-   8. Pharmaceutical composition according to the   7, characterized in that it is in a form intended for oral, parenteral,   rectal or topical in human and / or veterinary therapy.