GB2174698A - Compounds with antiinflammatory, antipyretic and analgesic activity, their preparation and drugs which contain them - Google Patents

Abstract

This invention deals with imidazolium salts of arylalkanoid acids variously substituted. These salts have been found to possess anti-inflammatory, antipyretic and analgesic activity and are devoid of gastric toxicity. The invention includes also the procedures for their preparation and the pharmacological compounds which contain them as the active principle.

Description

SPECIFICATION Compounds with antiinflammatory, antipyretic and analgesic activity, their preparation and drugs which contain them The invention relates to derivatives of arylalkanoic acids which have been found to have antiinflammatory antipyretic and analgesic activity.

The starting arylalkanoic acids used to prepare the compounds of the invention are well known. Among these are: 2-(4-isobutylphenyl)propionic acid (Ibuprofen); (p-isobutylphenyl)acetic acid (Ibufenac); 2-(3-benzoylphenyl)propionic acid (Ketoprofen); 1-(p-chlorobenzoyl)-5-methoxy-2- methyl-3-indolylacetic acid (Indomethacin) and other well known anti-inflammatory agents (Sulindac, etc.).

All these acids possess anti-inflammatory antipyretic and analgesic activity, which is accompanied, as is generally the case for all NSAIDs (non-steroidal anti-inflammatory drugs), by gastric toxicity (B. Scott, Brit. Med. J. 1, 489, 1979). This gastro-toxic activity can lead also to gastric ulcerations and greatly hinders the therapeutic usefulness of these acids and limits their clinical use.

The present invention relates to arylalkanoids of imidazole of general formula (I)

The salts of general formula (I) have surprisingly shown, when compared with the acids from which they are dervied or with their other known salts, at equivalent doses, a much stronger antiinflammatory, analgesic and antipyretic effect, without concomitant ulcerogenic or gastrotoxic phenomena, and can, therefore, be clinically used more safely and effectively even for long periods of time. It has also been found that compounds (I) can reduce the number and the severity of ulcers produced in the animal by agents such reserpine and corticosteroids.

This invention also relates to the procedures for the preparation of compounds (I), by salifying imidazole with the corresponding acid in almost stoichiometric ratios, in the presence of solvents or mixtures of solvents, from which the salt can be recovered either by spontaneous crystallization or by gradual removal from the solution through adding a solvent in which the salt is not soluble or by evaporation of the solvent used in the reaction.

included in the invention are also pharmaceutical compositions containing as the active ingredients one or more compounds (I). Said compositions can be used in human and/or animal therapy as oral, parenteral, rectal or topical preparations particularly in pathology of the inflammatory, painful or febrile type.

TOXICOLOGICAL AND PHARMACOLOGICAL FEATURES We quote as examples tests carried out on the Ibuprofen imidazolium salt, on the Naproxen imidazolium salt, and on the Ketoprofen imidazolium salt, from here on indicated as "salt A", "salt B", and "salt C" for sake of shortness.

Acute toxicity tests showed a LD50 for both male and female rats of 1205 mg/kg for A; of 780 mg/kg for B; and of 915 mg/kg for C.

Chronic toxicity tests carried out in the rat by oral administration of said salts for 15 weeks at doses of 50 and 100 mg/kg showed normal growth and normal hematological and blood chemistry values. It should be noted that in these animals gastric and intestinal mucosa did not show any ulcers or hemorrhages which usually accompany administration of Ibuprofen, Naproxen, and Ketoprofen.

Particularly it was noted that in the rat after ligation of the pilorus according to Schay or after injection with reserpine, administration of Ibuprofen, Naproxen and Ketoprofen increased two to five times the number and the severity of the gastric ulcerations produced; on the contrary, administration of equimolecular amounts of salts A, B and C reduced the number and severity of the lesions induced by those manipulations.

Using the carrageenin-induced oedema in the rat as a measure of antiinflammatory activity, the hot plate test in the mouse as a measure of analgesic activity and the yeast-induced fever in the rat, it was noted that a comparison of equimoiecular amounts of the three acids above with their respective salts A, B and C was extremely favourable to the salts, which proved to be endowed with a much greater.antiinflammatory, analgesic and antipyretic activity.

The following non-limiting examples, illustrate further the invention.

EXAMPLE 1 Salt A One mole of Ibuprofen was dissolved in 1000 ml of anhydrous acetone. To this solution 1.05 moles of imidazole dissolved in 500 ml of anhydrous acetone was added. After thoroughly stirring, the solvent was evaporated to dryness underreduced pressure. An oily mass, somewhat hygroscopic, was obtained, having the following chemico-physical and analytical features: Elemental analysis: C H N Calculated % 66.19 7.64 9.65 Found % 66.25 7.79 9.48.

I.R. Spectrum: according to the structure.

N. M. R. Spectrum: confirms the structure.

EXAMPLE 2 Imidazolium 2-(6-methoxy-2-naphthyl)propionate One mole of 2-(6-methoxy-2-naphthyl)propionic acid was dissolved in 1000 ml of anhydrous ethanol. To this solution 1.05 moles of imidazole dissolved in 500 ml of anhydrous acetone was added. After thoroughly stirring and heating at 50"C for about 20 minutes, the solution was cooled and petroleum ether was slowly added until slight turbidity, then the mixture was left to crystaliize overnight in the cold. The salt was obtained as a crystal, which was collected, washed on filter paper and dried: melting point between 143 and 146"C (non corrected).

Elemental analysis: C H N Calculated % 68.44 6.08 9.39 Found % 68.38 6.22 9.37.

I.R. Spectrum: according to the structure.

N. M. R. Spectrum: confirms the structure.

EXAMPLE 3 Imidazolium 2- (3-benzo ylphenyl)propionate With the same molar ratios as in Example 1 between 2-(3-benzoylphenyl)propionic acid and imidazole, the salt was obtained as a semi-solid, hygroscopic mass, with the following features: Elemental analysis: C H n Calculated % 70.79 5.63 8.69 Found % 70.84 5.67 8.71.

I.R. Spectrum: according to the structure.

N. M. R. Spectrum: confirms the structure.

EXAMPLE 4 Tablets containing as the active ingredient imidazolium 2-(6-methoxy-2-naphthyl)propionate One thousand tablets were prepared, containing each 330 mg of the active ingredient: 83.5 g of corn starch, 75 g of microgranular cellulose and 330 g of active ingredient as a micronized powder were mixed thoroughly. The mixture was then transferred to a mixing machine and 100 g of a 10% solution of gelatin in demineralized water were added and then the mixture was granulated. Thereafter the granulate was dried, sieved and 1.5 g of magnesium stearate was added. After further mixing, 0.5 g tablets were prepared by means of either flat or rounded punches. The tablets were thus made up with: 330 mg active ingredient; 75 mg microgranular cellulose; 83.5 mg corn starch; 10 mg gelatin; 1.5 mg magnesium stearate. The rounded tablets could optionally be film-coated.

EXAMPLE 5 Suppositories containing as the active ingredient imidazolium 2-(3-benzoyl-phenyl)propionate One thousand suppositories were prepared as follows: 1870 g of glycerid esters of saturated fatty acids were melted at 70"C, then cooled to 40"C, after that 130 g of the active ingredient were added. After mixing and filtering through stainless steel mesh, the preparation was dosed in the appropriate containers.

After cooling at 5"C, suppositories were obtained with the following composition: 130 mg active ingredient; 1870 mg glycerid esters of saturated fatty acids.

Claims (11)

1. Imidazolium arylalkanoids of general formula (I)

where Ar represents phenyl, naphthyl, indenyl or indolyl, substituted with one or more groups selected from straight or branched alkyl, alkoxy, halogen, arylcarbonyl, cycloalkyl, chlorobenzoyl and benzylmethylsulphonyl, and R represents a hydrogen atom, a methyl or ethyl group.

2. Imidazolium 2-(4-isobutylphenyl)propionate.

3. Imidazolium 2-(6-methoxy-2-naphthyl)propionate.

4. Imidazolium 2-(3-benzoylphenyl)propionate.

5. A process for the preparation of a compound as claimed in claim 1, wherein the salt of the acid with the imidazole is prepared in the presence of a solvent or a mixture of solvents, from which the salt can be recovered either by spontaneous crystallization or by evaporation or by addition of a non-solvent.

6. A process as claimed in claim 5, wherein the reaction is carried out with almost stoichiometric ratios of acid and imidazole.

7. Pharmaceutical compositions with antiinflammatory, analgesic and antipyretic activity, containing, as the active ingredient, one or more compounds as claimed in any one of claims 1 to 4.

8. Pharmaceutical compositions as claimed in claim 7, in solid, semi-solid or liquid form, for oral, parenteral, rectal or topical administration in human and/or animal therapy.

9. A compound of general formula (I) substantially as described herein.

10. A process according to claim 5 substantially as described herein and exemplified.

11. A pharmaceutical composition according to claim 7, substantially as described herein.