GB2174699A - Imidazolium salt of 2',4'-difluoro-4-hydroxy-diphenyl-3-carboxylic acid - Google Patents

Abstract

The above novel salt has enhanced analgesic, antiinflammatory and antipyretic activity without gastric toxicity.

Description

SPECIFICATION Salt of 2',4'-difluoro-4-hydroxy-diphenyl-3-carboxylic acid, its preparation and use The present invention relates to a salt of 2',4'-difluoro-4-hydroxy-diphenyl-3-carboxylic acid.

2',4'-Difluoro-4-hydroxy-diphenyl-3-carboxylic acid, from which the compound of the present invention is obtained, is well known and is described both in patents (U.S. 3,714,226; Fr.

1,522,570; S. Afr. 6,701,021) and in scientific publications (J. Harman et aL; J. Med. Chem.

21, 1093, 1978-R.N. Brodgen et al.; Drugs 19, 84, 1980) and goes under the name Diflunisal.

The analgesic, anti-inflammatory and antipyretic activities of 2',4'-difluoro-4-hydroxy-diphenyl-3carboxylic acid are well recognised and higher than those of acetylsalicyclic acid and of some known 2-arylpropionate derivatives (R.N. Brodgen et al., see above). However, even for this compound, extensive use in clinical treatments is limited, due to its gastrolesivity.

All NSAIDs (non-steroidal anti-inflammatory drugs) are, to various degrees, gastrotoxic (B.

Scott, Brit. Med. J. 1,499, 1979).

The present invention relates to 2',4'-difluoro-4-hydroxy-diphenyl-3-carboxylate of imidazole, of the general formula (I).

The present invention relates also to a procedure for preparing the compound of formula (I), and to pharmaceutical compositions which contain it as the active ingredient, to be used in human and/or animal therapy, for oral, parenteral, rectal or topical administration in painful, febrile or inflammatory conditions.

The compound of formula (I) may be prepared by salifying 2',4'-difluoro-4-hydroxy-diphenyl-3carboxylic acid and imidazole in almost stoichiometric ratios. The solvent, or mixture of solvents, used for the reaction suitably can dissolve both reagents and, at the same time, crystallize the salt.

The pharmacological tests carried out proved that the compound of the invention has stronger analgesic, antipyretic and anti-inflammatory effects, when compared with other known salts of 2',4'-difluoro-4-hydroxy-diphenyl-3-carboxylic acid, and does not show any sign of gastric toxicity.

Surprisingly, the salt of formula I showed no sign of gastric ulcerations, and proved also to be able to prevent the appearance of gastric lesions in animals treated with known ulcerogenic agents, such as corticosteroids or reserpine, or subjected to ulcerogenic procedures, such as the iigation of the stomach in the rat.

It should be remembered that the compound having formula (I) has the ability of 2',4'-difluoro4-hydroxydiphenyl-3-carboxylic acid to block PG synthesis and that imidazole to inhibit selectively thrnmboxane synthetase and cyclic GMP (Maperns P.W., Brit. J. Clin. Pharmacol. suppl. 1, 4, 15, 1977; Puig Parellada P. et awl., Pharmacology 10, 161, 1973; Needleman P. et al., Proc. Natl.

Acad. Sci. USA 74, 1716, 1977; Moncavada S. et awl., Prostaglandins, 13, 611, 1977).

The compound of formula (I) appears to shift the balance in favour of PGE cytoprotective prostaglandins.

To confirm the remarkable antiinflammatory, analgesic and antipyretic effects of compound (I), it should be remembered that imidazole increases the activity of many antiinflammatory agents, particularly of salicylate derivatives, and its capacity to inhibit some percursors of inflammation, such as histamine, due to its ability to block histidinedecarboxylase.

In all the tests carried out with compound (I), this salt proved to have antiinflammatory, analgesic and antipyretic activities higher than those of its individual components, and to be devoid of gastrotoxic activity.

TOXICOLOGICAL FEATURES Acute toxicity studies have shown an oral LD50 of 725 mg/kg in the rat and of 860 mg/kg in the mouse.

Chronic toxicity studies have been performed in the rat and in the dog.

In the Wistar rat 80 mg/kg have been given orally with the food for 20 weeks.

All tests relative to weight gain and hematochemical parameters have shown no signs of changes indicative of toxicity for compound (I).

Particularly, neither ulcerative nor hemorrhagic lesions were evidenced at the stomach and intestinal level, in the animals subjected to autopsy. Also the tests effected on Beagle dogs, for 12 consecutive weeks, evidenced neither toxic nor intolerance signs, at the end of the treat ment.

PHA RMA CO-D YNA MIC CHA RA C TERIS TICS Antiinflammatory, analgesic and antipyretic activities were evaluated in the animal, in comparison to equimolecular amounts of 2',4'-difluoro-4-hydroxy-diphenyl-3-carboxylic acid or imidazole.

The carrageenin oedema test in the rat and the adjuvant-induced arthritis test in the rat were, used for the determination of antiinflammatory activity; the phenylquinone writhing test and the hot plate test in the mouse were used for the analgesic activity; whilst the yeast hyperthermia test in the rat was used to evaluate the antipiretic activity.

In each of these tests the activity of the compound (I) was higher than that of 2',4'-difluoro-4hydroxy-diphenyl-3-carboxylic acid. The ED50 was 5 mg/leg in the carrageenin oedema; 8.5 mg/kg in the adjuvant arthritis; 12.5 mg/kg in the writhing test; 17 mg/kg in the hot plate test; and 20 mg/kg in the yeast test, The ulcerogenicity of the compound of the invention has also been evaluated in comparison with that of 2',4'-difluoro-4-hydroxy-diphenyl-3-carboxylic acid (diflunisal). In the rat, with the stomach ligated according to the technique of Schay, the administration of diflunisal (300 mg/kg) increased after 4 hours the number and severity of the ulcerations present by more than 100%, while such increase has not been noted in the rats treated with equimolecular amounts of compound (I).

Moreover 125 mg/kg of compound (I) decreased the severity and number of ulcers produced in the rat by the administration of 2.5 mg/kg reserpine i.v. or of 5 mg/kg indomethacine s.c. In these tests, 2',4'-difluoro-4-hydroxydiphenyl-3-carboxylic acid considerably worsens the ulcerative, hemorrhagic picture produced by both reserpine and indomethacine.

Therefore, toxicological and pharmacological tests of compound (I) have shown that the compound possesses favourable toxicological and pharmacological features, with analgesic, antiinflammatory and antipyretic activities higher than those of diflunisal, from which it is produced. The compound of this invention is also devoid of ulcerogenic or gastrotoxic activity, having instead the ability of protecting against such lesions. On the contrary, diflunisal has a well defined, doserelated ulcerogenic activity.

EXAMPLE 1 Preparation of imidazolium 2', 4'-difluoro-4-hydroxydiphen yI-3-carboxyla te One mole (250.2 g) of 2',4'-difluoro-4-hydroxy-diphenyl-3-carboxylic acid was dissolved in anhydrous acetone, and imidazole (71.5 g; 1.05 moles) diluted in the same solvent was added thereto.

After a few minutes at room temperature, a white abundant crystalline precipitate was formed, which was collected on a filter and washed with fresh acetone. After drying, compound 1 (302.4 g; 0.95 moles; 95% recovery) was obtained, melting at 154-154"C (not corrected).

Elemental analysis: (for C,6H,2F2N20J (318.28) Calculated % C=60.38; H=3.80; N=8.80 Found % C=60.55; H=3.91; N=8.84.

IR. Spectrum (nujol) v max: 2541, 1540, 1480, 1260, 820, 810 cm N. M. R. Spectrum: confirms the structure.

EXAMPLE 2 Preparation of imidazolium 2 $ 4'-difluoro-4-hydroxydiphen yl-3-carboxylate Similarly to Example but using ethanol instead of acetone, a salt which crystallizes by adding petroleum ether was obtained.

The product obtained is identical to that described in Example 1 and has similar chemical and physico-chemical features.

EXAMPLE 3 Tablets containing the imidazolium salt as the active ingredient One thousand tablets, each containing 300 mg of the active ingredient, were prepared: 85.5 g of corn starch, 103 g of microgranular cellulose and 300 g of active ingredient were mixed thoroughly in a fine powder. The mixture was transferred to a mixing machine and 100 g of a 10% solution of gelatin in distilled water were added and then the mixture was granulated.

Thereafter the granulate was dried, sieved and 1.5 g of magnesium stearate were added. After further mixing, 0.5 mg tablets were made by means of either flat or rounded punches. The tablets were thus made up with: 300 mg active ingredient; 103 mg microgranular cellulose; 85.5 mg corn starch; 10 mg gelatin; 1.5 mg magnesium stearate. The rounded tablets can optionally be film-coated.

EXAMPLE 4 Suppositories containing as the active ingredient the imidazolium salt One thousand suppositories were prepared as follows: 1.5 kg of glycerid esters of saturated fatty acids were melted at 70"C, and then cooled to 40"C; at that point 500 g of the active principle as micronized powder were added. After mixing and filtering through stainless steel mesh the compound was dosed in the appropriate containers.

After cooling at 5"C suppositories were obtained with the following composition: 0.5 g active ingredient; 1.5 g glycerid esters of saturated fatty acids.

Claims (7)

1. Imidazolium 2',4'-difluoro-4-hydroxy-diphenyl-3-carboxylate of formula (I)

2. A process for preparing the compound according to claim 1, wherein the imidazolium salt of 2',4'-difluoro-4-hydroxy-diphenyl-3-carboxylic acid is prepared in the presence of a solvent or of a mixture of solvents.

3. A process according to claim 2, wherein the reaction is carried out in almost stoichiometric ratios.

4. Pharmaceutical compositions with analgesic, antiinflammatory and antipyretic activity containing the compound as claimed in claim 1, as the active ingredient.

5. Pharmaceutical compositions according to claim 4, in solid, semi-solid or liquid form, for oral, parenteral, rectal or topical administration in human and/or animal therapy.

6. A process for preparing the compound of formula (I) substantially as described herein.

7. Pharmaceutical composition containing the compound of formula (I) as active ingredient substantially as described herein.