Patent FR-2903694-A1 (FR)
Title: Use of imidazole-2-thione compounds, for the preparation of a composition for the treatment and/or prevention of hyperpigmentary disorders, melasma, chloasma, lentigines, senile lentigo and vitiligo
Inventor: SUZUKI ITARU
IPC: A61K31/4164
Filed: 2006-07-11
Abstract: Use of imidazole-2-thione compounds (I), their salts, optical, tautomeric or geometric isomers, for the preparation of a composition for the treatment and/or prevention of hyperpigmentary disorders. Use of imidazole-2-thione compounds of formula (I), their salts, optical, tautomeric or geometric isomers, for the preparation of a composition for the treatment and/or prevention of hyperpigmentary disorders. R 1H, T, T 2 or 3-8C cycloalkyl; R 2-R 4H, alkyl, T 1 or T 2; T : alkyl such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl or n-hexyl; T 1aryl such as phenyl, biphenyl, naphthyl, thiophenyl, pyridinyl, pyrimidinyl, imidazolyl or triazolyl (all optionally substituted by halo e.g. Cl, F, Br or I, -CF 3, T, alkoxy e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, n-pentyloxy or n-hexyloxy, nitro, alkyl ester, nitrile, amide, carboxyl, hydroxyl or amino (optionally substituted by at least one alkyl)); T 2aralkyl such as -(CH 2) n-T 1; and n : 1-6. Independent claims are included for: (1) imidazole-2-thione compounds formula (II); (2) preparation of (II) comprising addition of an aqueous solution of formaldehyde to a peroxy compound (III) of formula (R 7-C(=O)-C(=O)-R 8) in solution in a polar solvent, addition of an aqueous solution of hydroxylamine hydrochloride to the obtained mixture, addition of a solution of hydrochloric acid to the obtained mixture, neutralization and obtaining a precipitate, filtration and drying the obtained precipitate to obtain alcohol compounds of formula (IVa) and/or (IVb) and treatment of obtained compounds with a sulfur donor to obtain (II), or alkylation of (IVa) and/or (IVb) to obtain alkylated imidazole derivatives of formula (Va) and/or (Vb), reduction of (Va) and/or (Vb) to obtain alkoxy imidazole derivative of formula (VIa) and/or (VIb), treatment of (VIa) and/or (VIb) by n-butyl lithium in an organic solvent and with sulfur S8, to obtain (II) or alkylation of (IVa) and/or (IVb) to form (Va) and/or (Vb), reduction of (Va) and/or (Vb) to form (VIa) and/or (VIb), alkylation of (VIa) and/or (VIb), addition of a base and sulfur S8 to the obtained reaction mixture, to obtain (II); and (3) compositions comprising (II) in a medium/carrier. R 5H, T, T 2 or 3-8C cycloalkyl, preferably H; and R 6-R 8H, alkyl, T 1 or T 2, preferably R 6 is H. Provided that: when R 5 is a hydrogen atom then R 6 may represent an optionally substituted phenyl; when R 6 is a hydrogen or methyl and R 7 and R 8 are hydrogen atoms then R 5 is a non-substituted benzyl; when R 5 and R 6 represents a hydrogen atom and R 7 represents a radical phenyl, then R 8 may represent a methyl. [Image] [Image] [Image] ACTIVITY : Dermatological. MECHANISM OF ACTION : Tyrosinase inhibitor. The ability of (I) to inhibit tyrosinase was tested. The results showed that 1-hydroxy-5-(4-methoxy-phenyl)-1,3-dihydro-imidazole-2-thione exhibited an IC 5 0 value of 0.82 mu M.