NOVEL CHEMICAL COMPOUND HAVING ANTIMYCOTIC, CICATRIZING AND ANTIINFLAMMATORY ACTIVITY

Abstract: The addition compound between econazole and acexa­ mic acid is hereinafter described. The novel compound has valuable properties, which make it suitable for the preparation of pharmaceutical compositions for topical use, particularly for vaginal and urethral use. The compound is useful for human and veterinary formulations.

Description: The present invention relates to the novel addition compound between econazole and acexamic acid, having for­ mula (I) The present invention relates also to processes for preparing compound (I) as well as pharmaceutical composi­ tions containing compound (I) as the active principle, particularly compositions for vaginal and urethral use. Econazole has been known for a long time to be valuable antimycotic drug, particularly useful in the treatment of gynecological diseases (see, e.g., J. Med. Chem. 12 (1969) 784). Econazole is commonly used in therapy for topical use, in form of addition compound with nitric acid. The administration of nitrate compounds for topical route is known to present some dangers, due to possible formation of nitrosamine, which are cancerogenic compounds. The mechanism of formation of nitrosamines seems in fact to involve nitrocompounds and biological amines as well as amines present in pharmaceutical compositions for topical use (such as triethanolamine, etc.). Acexamic acid, or ε-acetamidocaproic acid, is a well known antiinflammatory and cicatrizing drug, due to its favourable effect on connective tissue and epithelia, used in dermatology for healing sores and wounds ("Reper­ torio Terapeutico", 6th Ed.). Compound (I) according to the present invention, while exhibiting a therapeutical action which is substan­ tially superimposable to those of the single components thereof, has the peculiar advantage of a higher therapeu­ tical safety, since any possible production of such cance­ rogenic compounds as nitrosoamines is avoided, which pro­ duction can, on the contrary, occur in case of use of the addition compound between econazole and nitric acid. The novel compound (acenazole) exhibits toxicity and hysto-damaging activity which are equal to or lower than those of its single components. Therefore the novel compound (acenazole) is thera­ peutically useful in the treatment of those mycotic disea­ ses treated with econazole, and also of mycotic diseases in which skin or mucosal lesions and irritative or phlogi­ stic factors are present. Compound I is particularly useful in the treatment of vaginal and urethral mycosis. The compounds of the invention may be administered in form of conventional topical compositions, such as powders, solutions, ointments, gels, creams; impregnated tissues, sanitary towels or napkins; dermatologic milks and soaps; collutoria, otologic-drops, eye-drops; prepara­ tions for scalp mycosis, shampoos, lotions and creams; urethral suppositories, vaginal capsules, creams and gels, vaginal washings, preparations for the direct introduction in vagina by means of cannula supplying devices with ma­ nual or mechanical pressure (spray foam). Said formulations may optionally contain other compounds having pharmacological properties (pharmaceuti­ cal combinations), and pharmaceutically acceptable car­ riers and excipients, such as surfactants, emulsifiers, pH regulating agents, preservers, perfumes, etc. The compound according to the invention may be prepared in various ways, for example by reacting econazo­ le with acexamic acid, in anhydrous or partially hydrated solvents, such as methanol, ethanol, isopropanol, acetone, etc. Econazole and acexamic acid are reacted in equimo­ lecular ratios or in an excess up to 5% of acexamic acid. Temperature is not critical, as it can range from 0 to 100°C, preferably from 20 to 50°C. The compound may be recovered according to conven­ tional techniques, such as crystallization, precipitation by means of non-solvents, evaporation (possibly under va­ cuum) and spray-dry. The following examples further illustrate the in­ vention, without limiting it. EXAMPLE 1 38 Grams (0.1 mol) of econazole were added to 250 ml of 30% aqueous acetone, to obtain a clear solution having pH ∼ 8.5 (Solution A.). 17.3 Grams (0.1 mol) of acexamic acid were added to 250 ml of 30% aqueous acetone, to give a clear solution having pH ∼ 4. The two obtained solutions were mixed to give a mixture having pH ∼ 6. The mixture was concentrated under vacuum to small volume, the residue was taken up in 300 ml of acetone. Solvent was evaporated off, the oily residue was recovered, left to crystallize and dried (air, 30°C). Yield: 55 g; m.p. 60-62°C. TLC analysis and I.R. analysis prove the purity and nature of the obtained compound. EXAMPLE 2 51.9 Grams of acexamic acid were suspended in 250 ml of acetone. A clear solution of 114 g of econazole in 250 ml of acetone was added under strong stirring, at 40°C. After some time a complete solution was obtained, which was filtered. The residue was evaporated under va­ cuum at 50°C in order to remove the solvent. An oily residue was obtained which crystallized upon cooling. The obtained product was dried (air, 30°C) to give 164 g of the desired compound, analytically corresponding to that of Example 1. EXAMPLE 3 Cream for vaginal use (ingredient for 100 g of preparation). To 1.25 g of Compound I, vaseline oil, emulsifier, water and a preserver, q.s. to 100 g, are added. EXAMPLE 4 Ovules for vaginal use (ingredients for one 3 g ovule). The following excipients are added to 0.063 g of Compound I: vaseline oil, thick vaseline. Coating: gelati­ ne, glycerine, zinc oxyde, preservative agent. EXAMPLE 5 Suppositories for urethral use (ingredients for one 2 g suppository). Compound I 0.200 g; excipients and coating agents q.s. EXAMPLE 6 Dermatological powders. Compound I 1.5 g; excipients: rice starch, talc, zinc oxy­ de, q.s. EXAMPLE 7 Dermatological cream (ingredients for 100 g). Compound I 1.25 g; excipients: polyethylene-glycole 1000 monocetyl ester, cetyl alcohol, stearyl alcohol, vaseline, vaseline oil, distilled water q.s.

Claims: 1. The addition compound between econazole and acexamic acid, of formula (I) : 2. A process for preparing compound (I), wherein eco­ nazole is reacted with acexamic acid, in the presence of an anhydrous or partially hydrated solvent, such as metha­ nol, ethanol, acetone, in equimolecular ratios or in an excess of acexamic acid up to 5%, at a temperature ranging from 0° to 100°C, preferably from 20 to 50°C, the solvent is removed by evaporation under vacuum and the formed com­ pound is let crystallize. 3. Pharmaceutical compositions for topical administra­ tion for human and veterinary use, containing compound I as the active principle, optionally in admixture with pharmaceutically acceptable carriers or excipients. CLAIMS FOR CONTRACTING STATE: AT 1. A process for preparing the addition compound between econazole and acexamic acid, of formula (I) : wherein econazole is reacted with acexamic acid, in the presence of an anhydrous or partially hydrated solvent, at a temperature ranging from 0° to 100°C, the solvent is removed by evaporation under vacuum and the formed compound is let crystallize. 2. A process as claimed in claim 1, wherein the solvent is selected from the group comprising methanol, ethanol and acetone. 3. A process as claimed in claims 1-2, wherein econazole and acexamic acid are used in a substantially equimolecular ratio. 4. A process as claimed in claims 1-3, wherein the temperature ranges from 20 to 50°C.

Inventors: DI SCHIENA, MICHELE GIUSEPPE
Applicants: CHINOIN S.P.A.
Application year: 1985
Main classification: C07D233
IPC codes: C07D233, C07C233, C07D521