CH662558A5 - Salt of 2 ', 4'-Difluoro-4-HYDROXY-3-BIFENILCARBOSSILICO, ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN. - Google Patents

Description

662 558

2

CLAIMS 1. 2 ', 4'-difluoro-4-hydroxy-3-biphenylcarboxylate of imidazole of formula I

0 ©

.eoo

F

2. Process for obtaining the compound according to claim 1, characterized in that the acid is salified

2 ', 4' -difluoro-4-hydroxy-3-biphenylcarboxylic with imidazole in the presence of solvent or solvent mixtures.

3. Process according to claim 2, characterized in that it operates in almost stoichiometric ratios.

4. Pharmaceutical compositions with analgesic, anti-inflammatory, antipyretic activity, containing the compound according to claim 1 as the active principle.

Pharmaceutical compositions according to claim 4, in solid, semi-solid or liquid pharmaceutical forms, for oral, parenteral, rectal or topical administrations intended for human and / or animal therapy.

The object of the invention is the compound 2 ', 4' -difluoro-4 - hydroxy-3-phenylcarboxylate of imidazolium of formula I:

Eous

F

The processes for preparing the compound of formula I, and the pharmaceutical compositions that contain it as an active ingredient, the latter to be used in human and / or animal therapy for oral, parenteral, rectal or topical administration, particularly in the algic, febrile or inflammatory forms.

The 2 ', 4' -difluoro-4-hydroxy-3-biphenyl carboxylic acid, from which the compound of formula I derives, is known and is reported on some patents (US 3 714 226; Fr. 1 522 570; S. Afr. 6 701 021) and on scientific publications (J. Harmah et al .; J. Med. Chem. 21, 1093, 1978. - RN Brodgen et al .; Drugs 19, 84, 1980) and is also known with the Diflunisal denomination.

The preparation of the compound of formula I is carried out by salifying the 2 ', 4' -difluoro-4-hydroxy - 3-biphenyl carboxylic acid in solution with imidazole in almost stoichiometric ratios. The solvent used or the solvent mixtures for obtaining salification have the property of dissolving the two reagents and simultaneously crystallizing the salt.

The pharmacological experiments carried out on the compound object of the present invention, have been able to demonstrate, with respect to other known salts of the 2 ', 4' -difIuoro-4-hydroxy-3-bi-phenylcarboxylic acid, a more intense analgesic, antipyretic effect, anti-inflammatory, together with the absence of gastrolessive effects.

The analgesic, antiphlogistic and antipyretic action of 2 ', 4' -difluoro-4-hydroxy-3-biphenylcarboxylic acid is well known, the intensity of which appears to be greater than that of acetylsalicylic acid or some known derivatives 2-arylpropionics (RN Brodgen and Coli, previously mentioned).

Also for this acid, however, extensive clinical use appears to be limited because of its gastrolesivity.

All nonsteroidal anti-inflammatory drugs present to a greater or lesser extent the ability to produce gastric lesions (B. Scott, Brit. Med. J, 1, 489, 1979). As for the salt of formula I, this new compound appears surprisingly free of gastrolesive effects. Its administration in the animal, even at high dosages, does not cause the appearance of gastric ulcers, not only, but protects from the formation of gastric ulcers those animals that are treated with known ulcerogenic agents such as cortisone or reserpine or are subjected to techniques ulcerogens such as the ligation of the stomach in the rat.

It is to be considered that the compound of formula I participates both in the well-known activity of the 2 ', 4' -difluoro-4-hydroxy-3-be-phenylcarboxylic acid to block the prostaglandin synthesis and that of the imidazole to selectively inhibit tromboxane synthase, as well as selectively inhibiting the synthesis of cyclic GMP. (Maperns P. W., Brit. J. Clin. Pharmacol. Suppl. 1, 4, 15, 1977) Puig Parellada P. and Coli. Pharmacology 10, 161, 1973; Needleman P. and Coli. Proc. Born. Acad. Sci USA 74, 1716, 1977; Moncavada S. e Coll .; Prostaglandins, 13, 611, 1977).

The compound of formula I therefore seems able, to a greater or lesser extent in prostaglandin synthesis, to shift the balance in favor of cytoprotective PGE Prostaglandins.

Confirming the significant anti-inflammatory, analgesic and antipyretic effects of the compound of formula I, it should also be remembered the enhancement that imidazole has on the activities of many anti-inflammatories and in particular on salicylic derivatives and on its ability to inhibit certain precursors of inflammation such as example histamine for its blocking ability on histidinde carboxylase.

In all the experiments carried out on the compound of formula I, however, it has been possible to demonstrate how this salt has an anti-inflammatory, analgesic or antipyretic activity superior to that of its components considered individually and how it also has gastrolytic effects.

Toxicological characteristics

The acute animal toxicity tests have shown that the LD50 of the compound of formula I for oral administration in the rat is equal to 725 mg / kg; while in the mouse, by the same route, it is equal to 860 mg / kg.

Chronic toxicity tests were performed in both the rat and the dog.

In the rat, Wistar strain, 80 mg / kg were administered orally together with the diet for twenty consecutive weeks.

The various tests concerning weight growth and the different blood chemistry parameters have not shown at the end of these tests any alteration indicating a harmful or toxic effect of the compound of formula I.

Particularly at the level of the stomach and intestines of the animals undergoing an autopsy, no mucosal lesions of an ulcerative or hemorrhagic character were revealed.

Even the tests performed in the Beagle dog, for twelve consecutive weeks (50 mg / kg orally pro die) did not show any intolerance or toxic reaction at the end of the treatment.

Dynamic drug characteristics

The anti-phlogistic, analgesic and antipyretic activity of the compound of formula I was evaluated in the animal in comparison with equimolecular doses of 2 ', 4' -difluoro-4-hydroxy-3-bife-nylcarboxylic acid or imidazole.

The test of carrageenan-induced rat paw and ar5 was used for the tests of anti-phlogistic activity

10

15

20

25

30

35

40

45

50

55

60

65

mince as an adjuvant in the rat; for tests of analgesic activity, the Phenylquinone Writhing test and that of the hot plate in the mouse, while the beer yeast hyperthermia test was used for the tests of antipyretic activity.

In all the tests carried out, the activity of the compound of formula I proved to be higher than that of the 2 ', 4' -difluoro-4 - hydroxy-3-biphenylcarboxylic acid. His ED50 was 5 mg / kg in the carrageenan test; 8.5 mg / kg in adjuvant arthritis; of 12.5 mg / kg and 17 mg / kg respectively in the two analgesia tests and 20 mg / kg in yeast hyperthermia.

The ulcerogenic activity of the compound object of the invention was also evaluated in comparison with that of 2 ', 4' -difluoro-4-hydroxy-3-biphenyl carboxylic acid. In rats with pyloric ligation to Schay, the administration of the aforementioned acid (300 mg / kg) increases after four hours the number and severity of ulcers present by more than 100%, while no increase in the number of ulcers is found in treated rats with the compound of formula I in equimolecular quantities.

In addition, the compound of formula I (mg 125 / kg) has been shown to decrease the severity and number of ulcer lesions induced in the rat by the administration of reserpine (2.5 mg / kg intravenously) or indomethacin (5 mg / kg subcutaneously). In these tests the 2 ', 4' -difluoro-4-hydroxy-3-biphenylcarboxylic acid considerably aggravates the hemorrhagic ulcerative picture induced by both reserpine and indomethacin.

The toxicological and pharmacological tests carried out with the compound of formula I, show that the product has favorable toxicological characteristics and demonstrates an analgesic, anti-inflammatory and antipyretic activity higher than that carried out by the acid 2 ', 4' -difluoro-4-hydroxy- 3-biphenycarboxylic from which it derives. Furthermore, the compound object of the present invention has proven to be free of ulcerogenic and gastrolesive activities and indeed capable of reducing those experimentally induced. The 2 ', 4' -difluoro-4 ~ hydroxy-3-biphenyl carboxylic acid in these tests, on the other hand, demonstrates a clearly identifiable ulcerogenic action whose intensity is proportional to the dose administered.

Example 1

Preparation of 2,4 '-difluoro-4-hydroxy-3-biphenylcarboxylate di.imidazolium.

In anhydrous acetone, 2 ', 4'-difluoro-4 - hydroxy-3-biphenylcarboxylic acid (250.2 g; 1 mole) is dissolved, to which is added by stirring an imidazole solution (71.5 g; 1 , 05 moles) in the same solvent.

After a few minutes, at room temperature, an abundant crystalline white precipitate is formed which is collected on the buchner and washed on the filter with fusco acetone. After drying the product is obtained (302.4 g; 0.95 moles; 95% yield) with m.p. 153-4 ° C) not corr.)

662 558

Elemental analysis: for C16H12F2N2O3 (318,28)

Calc.% C = 60.38; H = 3.80; N = 8.80;

Found.% C = 60.55; H = 3.91; N = 8.84.

IR spectrum (nujol) vmax: 2541, 1540, 1480, 1260, 820, 810 cm "1

Spectrum 1HNMR: confirms the structure.

Example 2

Preparation of 2 ', 4' -difluoro-4-hydroxy-3-biphenylcarboxylate of imidazolium

Operating analogously as described in Example 1, but using ethanol instead of acetone, salt is obtained which crystallizes by adding petroleum ether.

The product obtained is identical to that described in Example 1 and has the same chemical and chemical-physical characteristics.

Example 3

Tablets containing 2', 4 '-difluoro-4-hydroxy-3-biphenyl carboxylate of imidazolium as the active substance.

1000 tablets are prepared, each containing 300 mg of active ingredient: 85.5 g of corn starch and 103 g of microgranular cellulose and 300 g of fine powder active ingredient are intimately mixed. The mixture is transferred to a mixer and 100 g of a 10% solution of gelatin are added in distilled water and the mixture is granulated. After drying the granulate, it is sieved and 1.5 g of magnesium steaate added. After mixing, it is compressed with flat or rounded punches, producing tablets of 0.5 g each. The composition is: active ingredient 300 mg; microgranular cellulose 103 mg; corn starch 85.5 mg; jelly 10 mg; magnesium stearate 1.5 mg.

The rounded shaped tablets can be subjected to a filming treatment.

Example 4

Suppositories containing 2', 4 '-difluoro-4-hydroxy-3-biphenylcarboxylate of imidazolium as the active substance.

1000 suppositories are prepared as follows: 1.5 kg of saturated fatty acid glyceride esters are melted at 70 ° C; it is left to cool down to 40 ° C, then 500 g of active ingredient in micromized powder are added. After mixing and filtering through a stainless steel mesh, it is dosed in the appropriate containers.

After cooling to + 5 ° C the suppositories are obtained, each with the following composition: active principle, 0.5 g; glyceride esters of saturated fatty acids 1.5 g.

3

5

10

15

20

25

30

35

40

45

50

V