Five-membered heterocycles having monoamine oxidase inhibiting, lipidic peroxidation inhibiting and sodium channel modulating activity for the treatment of e.g. central and peripheral nervous disorders

摘要

Five-membered heterocycles (III) in racemic or enantiomeric form, and their mixtures and their salts are new. Five-membered heterocycles of formula (III) in racemic or enantiomeric form, and their mixtures and their salts are new: [Image] Het : 5-membered heterocycle with 2 heteroatoms, such that (III) is of formula (IIIa) - (IIId); A : alkyl, cycloalkyl, cycloalkylalkyl or a group of formula (A1), (A2), (A3), (A4) or (A5); R 3 : H, OH, alkoxy, or alkyl; R 4 - R 8 : H, halogen, OH, alkyl, alkoxy, CN, NO 2, or NR 1 0R 1 1; R 1 0 and R 1 : H, alkyl, or -COR 1 2, or together with the N atom they form a 4-7 membered heterocycle with 1-3 heteroatoms; R 1 2 : H, alkyl, alkoxy or NR 1 3R 1 4; R 1 3 and R 1 4 : H, alkyl; or R 1 3 and R 1 4 together with N atom : 4-7 membered heterocycle with 1-3 heteroatoms; R 9 : H, alkyl, or -COR 1 5; R 1 5 : H, alkyl, alkoxy, or -NR 1 6R 1 7; R 1 6 and R 1 7 : H, alkyl, or together with the N atom they form a 4-7 membered heterocycle with 1-3 heteroatoms; W' is either not present or it : a bond, -O-, -S-, or -NR 1 8-; R 1 8 : H or alkyl; Q : H, -OR 2 2, -SR 2 2, -NR 2 3R 2 4, phenyl (optionally substituted by halogen, OH, CN, NO 2, alkyl, alkoxy, -NR 1 0R 1 1, methylene dioxy or ethylene dioxy), or -COPh, -SO 2Ph, -CH 2Ph (these being optionally substituted on the aromatic ring by alkyl, alkoxy or halogen); R 2 2 : H, alkyl, or aryl (optionally substituted by alkyl, OH, halogen, NO 2, or alkoxy); R 2 3 and R 2 4 : H, alkyl, or -COR 2 5; R 2 5 : alkyl; R 1 9, R 2 0 and R 2 1 : H, halogen, OH, -SR 2 6, alkyl, cycloalkyl, alkenyl, alkoxy, CN, NO 2, -SO 2-NHR 4 9, -CONHR 5 5, -S(O) q-R 5 6, -NH(CO)R 5 7, -CF 3, -OCF 3, or -NR 2 7R 2 8; R 2 6 : H or alkyl; R 2 7 and R 2 8 : H, alkyl, -COR 2 9, or together with the N atom they form a 4-7 membered heterocycle with 1-3 heteroatoms; R 4 9 and R 5 0 : H, alkyl or alkylcarbonyl; q : 0, 1, or 2; R 5 6 and R 5 7 : H, alkyl or alkoxy; R 2 9 : H, alkyl, alkoxy or -NR 3 0R 3 1; R 3 0 and R 3 1 : H, alkyl, or together with the N atom they form a 4-7 membered heterocycle with 1-3 heteroatoms; R 3 2 : H or alkyl; T' : methylene or ethylene; R 3 3 : H, alkyl, - -NR 3 4R 3 5, or - -CHR 3 6R 3 7; : 1-6C alkylene; R 3 4 and R 3 5 : H or alkyl; R 3 6 and R 3 7 : H, carbocyclic or heterocyclic aryl, (optionally substituted by alkyl, OH, halogen, NO 2, alkoxy, or NR 1 0R 1 1); X : S or -NR 3 8; R 3 8 : H, alkyl, cyanoalkyl, aralkyl, alkylcarbonyl, or aralkylcarbonyl; Y' : O or S; R 1 : H, alkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethyl alkyl, alkenyl, allenyl, allenylalkyl, allynyl, cyanoalkyl, -(CH 2) g-Z 1R 3 9, -(CH 2) g-COR 4 0, -(CH 2) g-NHCOR 70, aryl, aralkyl, arylcarbonyl, heteroaryl alkyl, aralkylcarbonyl, (aryl groups in these being optionally substituted by alkyl, halogen, alkoxy, nitro, CN, cyanoalkyl, amino, alkylamino, dialkylamino, -(CH 2) k-Z 2R 3 9 or -(CH 2) k-COR 4 0); and R 2 : H, alkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, trifluoromethyl alkyl, -(CH 2) g-NHCOR 7 1 (aryl and heteroaryl groups being optionally substituted by halogen, alkyl, alkoxy, OH, CN, NO 2, amino, mono- or dialkylamino); or R 1 and R 2 may together form : a 3-7 membered carbocycle; Z 1 and Z 2 : a bond, -O-, -NR 4 1-, or -S-; R 3 9 and R 4 1 : H, alkyl, alkenyl, alkynyl, or cyanoalkyl; R 4 0 : H, alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy, or -NR 4 2R 4 3; R 4 2 and R 4 3 : H, alkyl, allenyl, allenylalkyl, alkenyl, alkynyl, or cyanoalkyl; R 7 0 and R 7 1 : alkyl or alkoxy; B' : H, alkyl, -(CH 2) g-Z 3R 4 4, or a carbocyclic aryl group that may be substituted 1-3 times by halogen, alkyl, alkoxy, OH, CN, NO 2, amino, alkylamino, dialkylamino or carbocyclic aryl; Z 3 : bond, -O-, -NR 4 5-, or -S-; R 4 4 and R 4 5 : H, alkyl, alkenyl, alkynyl, allenyl, allenyl alkyl, or cyanoalkyl; L* : NR 4 6R 4 7 or -OR 4 8; R 4 6 and R 4 7 : H, alkyl, cycloalkyl, alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl, -(CH 2) g-Z 4R 5 0, -(CH 2) k-COR 5 1, -(CH 2) k-COOR 5 1, -(CH 2) k-CONHR 5 1, -SO 2R 5 1, aryl, aralkyl, aryloxyalkyl, arylcarbonyl, arylimino, aralkyl carbonyl, or heteroaryl (the aryl and heteroaryl groups being optionally substituted by halogen, alkyl, alkoxy, OH, CN, NO 2, cyanoalkyl, amino, mono- or dialkylamino), -(CH 2) k-Z 5R 5 0, -(CH 2) k-COR 5 1, or -(CH 2) k-COOR 5 1) or R 4 6 and R 4 7 taken together with the N atom form a 4-8 membered non-aromatic heterocycle (optionally interupted by -CH(R 53)-, -NR 54-, -O-, -S- or -CO); Z 4 and Z 5 : a bond, -O-, -NR 5 2- or -S-; R 50 and R 52 : H, alkyl, alkenyl, alkynyl, allenyl, allenylalkyl, or cyanoalkyl; R 5 1 : H, cycloalkyl, cycloalkylalkyl, alkyl, alkenyl, alkynyl, allenyl, allenylalkyl, cyanoalkyl, alkoxyalkyl, NR 5 8R 5 9, aryl, or aralkyl; R 5 8 and R 5 9 : H, alkyl, alkenyl, alkynyl, allenyl, allenylalkyl, or cyanoalkyl; R 5 3 and R 5 4 : H, -(CH 2) k-Z 7R 6 0 or -CH 2) k-COR 6 1; Z 7 : a bond, -NR 6 2-, or -S-; R 6 0 and R 6 2 : H, alkyl, alkenyl, allenyl, allenyl alkyl, alkynyl, or cyanoalkyl, aryl, aralkyl, arylcarbonyl, aralkylcarbonyl, pyridinyl, pyridinylalkyl, pyridinylcarbonyl, (aryl and pyridinyl groups being optionally substituted by halogen, alkyl, alkoxy, cyanoalkyl, -(CH 2) k-Z 8R 6 3,or -(CH 2) k-COR 6 4); R 6 1 : H, alkyl, allenyl, allenyl alkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy or -NR 6 5R 6 6; R 6 5 and R 6 6 : H, alkyl, allenyl, allenyl alkyl, alkenyl, alkynyl, or cyanoalkyl; Z 8 : -O-, -S- or -NR 6 7-; R 6 3 and R 6 7 : H, alkyl, allenyl, allenyl alkyl, alkenyl, alkynyl, or cyanoalkyl; R 6 4 : H, alkyl, allenyl alkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy or -NR 6 8R 6 9; R 6 8 and R 6 9 : H, alkyl, allenyl, allenyl alkyl, alkenyl, alkynyl, or cyanoalkyl; R 4 8 : H, alkyl, alkynyl, or cyanoalkyl; g, p : 1 - 6; k, n : 0 - 6 [Image] Provisos apply, please see DEFINITIONS An independent claim is included for the use of (III), with the proviso that when (III) is (IIIA) then A is 4-hydroxy-2,3-di-tertiary butyl phenyl, B, R 1 and R 2 are H, and L* = OH, to make pharmaceutical compositions. ACTIVITY : Antiviral; antiinflammatory; analgesic; anticonvulsant, antiparkinsonian; cerebroprotective; hemostatic; nootropic; neuroprotective; neuroleptic; antimigraine; anabolic; anti-HIV, antidiabetic; cytostatic; dermatological; immunosuppressive. MECHANISM OF ACTION : Monoamine oxidase inhibitor; lipidic peroxidation inhibitor; sodium channel modulator.