Patent EP-1589007-A2 (EP)
Inventor: CHABRIER DE LASSAUNIERE PIERRE
IPC: A61P1/00
Filed: 2000-10-10
Abstract: 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> 0>R 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> 3>R 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> 6>R 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> 3>R 2> 4>, phenyl (optionally substituted by halogen, OH, CN, NO 2, alkyl, alkoxy, -NR 1> 0>R 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> 7>R 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> 0>R 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> 4>R 3> 5>, or - -CHR 3> 6>R 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> 0>R 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 1>R 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 2>R 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> 2>R 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 3>R 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> 6>R 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 4>R 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 5>R 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> 8>R 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 7>R 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 8>R 6> 3>,or -(CH 2) k-COR 6> 4>); R 6> 1> : H, alkyl, allenyl, allenyl alkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy or -NR 6> 5>R 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> 8>R 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.