New imino- or pyridyl-substituted lipoic acid derivatives, as nitrogen monoxide synthase inhibitors and antioxidant regenerating agents, useful e.g. for treating nervous system or cerebrovascular disorders or cancer

摘要

Imino- or pyridyl-substituted lipoic acid derivatives (Ia) or (Ib) are new. Imino- or pyridyl-substituted lipoic acid derivatives of formulae (Ia) or (Ib) and their salts are new. [Image] R 1, R 2H or D'; or R 1+ R 2direct bond; D' : 1-6C alkyl; A : (CH 2) mN(R 3)CO(CH 2) n, (CH 2) mCON(R 3)(CH 2) n, (CH 2) mN(R 3)(CH 2) n, (CH 2) mCON(R 3)(CH 2) p-N(R 4)(CH 2) n, (CH 2) mN(R 3)CON(R 4)(CH 2) nor (CH 2) m; m, n : 0-6; p : 2-6; R 3, R 4H or D'; X : phenylene or phenylene-alkylene group of formula -C 6H 3(R 5)-T-; or (CH 2) q; T : (CH 2) i, T being attached to Y'; R 5H, D', -(CH 2) mQ or 5- or 6-membered heterocycle (containing O, N(R 6) or S); i, q : 0-6; Q : halo, OH, CN, NH 2, alkoxy, alkylthio, alkylamino or dialkylamino; R 6H, D' or the bond to the phenyl ring; Y' : -N=C(B)-NH 2or R 7-substituted 2-aminopyridinyl; B' : D', NR 8R 9, SR 10or 5- or 6-membered aryl or 5-or 6-membered heteroaryl (containing 1-4 O, S and N, especially thiophene, furan, pyrrole or thiazole), both optionally substituted by D', 2-6C alkenyl or OD'; R 8R 9H or D'; or NR 8R 95- or 6-membered non-aromatic heterocycle in which the ring members are CH 2, NH, O or S; R 7, R 10H or D'. Independent claims are included for the preparation of (Ia) or (Ib). ACTIVITY : Neuroprotective; antiparkinsonian; analgesic; cerebroprotective; antiaddictive; antialcoholic; vasotropic; antiinfertility; nootropic; antiinflammatory; antidepressant; tranquilizer; neuroleptic; anticonvulsant; hypnotic; antimigraine; antithrombotic; antiemetic; antibacterial; immunosuppressive; cytostatic. MECHANISM OF ACTION : Nitrogen monoxide (NO) synthase inhibitor; antioxidant regenerating agent. N-(4-(((2-Thienyl) (imino)methyl)-amino)-phenyl)-1,2-dithiolane-3-pentanamide (Iaa) had IC 50less than 4.5 MicroM for inhibition of rat cerebellar neuronal constitutive NO synthase and EC 50less than 30 MicroM for inhibiting the effects of glutamate-induced oxidative stress on cultured HT-22 cells.