New 4-(alkyl, alkenyl or alkynyl)-cyclohexylamine derivatives, are ORL1 receptor ligands useful e.g. for treating anxiety, depression, epilepsy, senile dementia, withdrawal symptoms or especially pain

摘要

1-Substituted 4-(omega -substituted alkyl, alkenyl or alkynyl)-cyclohexylamine derivatives (I) are new. Cyclohexylamine derivatives of formula (I), optionally in the form of racemates, pure stereoisomers (especially enantiomers or diastereomers) or their mixtures in all proportions, including free bases, free acids, salts (specifically acid or base addition salt) or solvates (specifically hydrates), are new. [Image] ----- : optional bond; R 1, R 2H, Alk, Cyc, Ar, Het, -Q 1-Ar, -Q 1-Cyc' or -Q 1-Het; or NR 1R 2morpholino, 4-(R 6)-piperazino, azetidino, pyrrolidino, piperidino or homopiperidino; Alk : optionally unsaturated, optionally mono- or polysubstituted 1-8C alkyl; Cyc : optionally unsaturated, optionally mono- or polysubstituted 3-8C cycloalkyl; Cyc' : optionally mono- or polysubstituted 3-8C cycloalkyl; Ar : optionally mono- or polysubstituted aryl; Het : optionally mono- or polysubstituted heteroaryl; Q 11-3C alkylene; R 6as for R 1; R 3Alk, Cyc, Ar, Het, -Q 2-Ar, -Q 2-Cyc' or -Q 2-Het ; Q 2optionally unsaturated, optionally substituted 1-4C alkylene; R 4H or optionally protected hydroxy; n : 0 or 1; R 5Cyc', Ar, Het, -CH 2R 12, -(CH 2) 2R 12or -(CH 2) 3R 12; R 12Cyc', Ar or Het. Independent claims are also included for the preparation of (I). ACTIVITY : Analgesic; tranquilizer; antidepressant; anticonvulsant; neuroprotective; nootropic; antiaddictive; antialcoholic; vasotropic; cardiant; hypotensive; hypertensive; auditory; antipruritic; antimigraine; laxative; anorectic; antidiarrheic; immunomodulator; uropathic; relaxant; anesthetic; diuretic. The least polar diastereomer of dimethyl-(1-phenyl-4-(2-p-tolyl-vinyl)-cyclohexylamine hydrochloride (Ia) gave 100% inhibition at a dose of 10 mg/kg i.v. in the mouse writhing test for analgesic activity. MECHANISM OF ACTION : Nociceptin/ORL1 receptor (opioid receptor like-receptor 1) system modulator; ORL1 receptor ligand; mu -opiate receptor ligand. The least polar diastereomer of (Ia) had K ivalues of 200 nM and 42 mu M respectively in ORL1 and mu -receptor binding assays.