New bicyclic lactone glutamate receptor modulators for treating cerebral ischemia, cranial/brain trauma, pain or CNS-mediated spasms

摘要

Bicyclic lactones of formula (I) and their salts are new: A = CH2, CO, CR<4>(OH), (CH2)a-CHR<5> or 2-6C alkanediyl, alkenediyl or alkynediyl; a = 0-4; R<4> = H or 1-4C alkyl; R<5> = phenyl; R<1> = H, 3-6C cycloalkyl, Het<1>, Het<2>, a group of formula (i)-(vi): or 6-10C aryl, where all rings are optionally substituted by one or more of (a) halogen, CN, NO2, CF3, OH and 1-6C alkoxy, (b) 3-6C cycloalkyl, phenyl, phenoxy, benzyloxy and Het<3>, all optionally substituted by CN or halogen, and/or (c) 1-6C alkyl and 2-6C alkenyl optionally substituted by halogen, 6-10C aryl, SR<8>, OR<9>, NR<10>R<11> or 4-oxopiperidino; Het<1> = 5- or 6-membered heterocyclyl containing 1-3 heteroatoms selected from S, O, N and NR<6>; Het<2> = benzo-fused 5- or 6-membered heterocyclyl containing 1-2 heteroatoms selected from S, O, N and NR<7>; R<6> and R<7> = H or Me; b and c = 1 or 2; Het<3> = 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from S, N and O; R<8> = 1-6C alkyl or phenyl; R<9> = H or 1-6C alkyl; R<10> and R<11> = H, phenyl, or 1-6C alkyl optionally substituted by phenyl optionally substituted by halogen, NO2, OH, and/or 1-6C alkoxy, or R<10>+R<11> = CH2CH2GCH2CH2; G = O, CH2 or NR<12>; R<12> = H, phenyl, benzyl, 1-6C alkyl, 2-7C alkoxycarbonyl or Het<4>; Het<4> = 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from S, N and O, optionally substituted by COOR<13>, NR<14>R<15>, NR<16>COR<17>, NR<18>COOR<19> and CONR<20>R<21>; R<13> = (a) H, (b) 1-9C alkyl or 2-9C alkenyl optionally substituted by 6-10C aryl, Het<5> or groups of formula (vii)-(x): or (c) 6-10C aryl optionally substituted by phenyl optionally substituted by CN or halogen; d = 1 or 2; Het<5> = 5- to 7-membered heteroaryl containing 1-3 heteroatoms selected from S, N and O; R<14> and R<15> = H, 3-6C cycloalkyl, phenyl, or 1-6C alkyl optionally substituted by 3-6C cycloalkyl or phenyl optionally substituted by halogen, OH and/or 1-6C alkoxy; R<16> = H or 1-6C alkyl; R<17> = H, adamantyl, 3-6C cycloalkyl, 2-6C alkenyl, or 1-12C alkyl optionally substituted by adamantyl, 3-6C cycloalkyl, 6-10C aryl, phenoxy or Het<6>, where aryl and Het<6> are optionally substituted by 1-6C alkyl, 1-6C alkoxy, OH, NO2 and/or halogen, and/or alkyl is optionally substituted by OR<22> or OCOR<22>; Het<6> = 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from S, N and O; R<22> = (a) 1-6C alkyl optionally substituted by halogen, NO2, OH and/or 1-6C alkoxy; (b) 6-10C aryl or Het<7> optionally substituted by 1-6C alkoxy, 1-6C alkyl, OH, NO2 and/or halogen; (c) a group of formula (xi): or (d) NR<23>R<24>; Het<7> = 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from S, N and O; L and M = H or halogen; R<23> and R<24> = groups as defined for R<10> and R<11>; R<18> = a group as defined for R<16>; R<19> = (a) 3-8C cycloalkyl or (b) 1-8C alkyl or 2-5C alkenyl optionally substituted by halogen, phenyl, OH, morpholinyl, 3-8C cycloalkyl and SiR<25>R<26>R<27>; R<25>-R<27> = 1-6C alkyl; R<20> and R<21> = (a) H, adamantyl, 3-8C cycloalkyl, phenyl, phenoxyphenyl or Het<8>, (b) 2-8C alkenyl, 1-12C alkyl or 2-6C alkynyl optionally substituted by OH,, 3-6C cycloalkyl, 1-6C alkoxy, halogen, OH, CF3 or Ar<1>, (c) 1-12C alkyl optionally substituted by SCF3, 4-oxopiperidino, bicyclo2.2.1hept-2-yl, 8-methoxy-2,3-dihydro-2-benzopyranyl or NR<28>R<29>, or (d) 1-R<30>-4-piperidyl; or R<20>+R<21> = (CH2)3 or CH2CH2G'CH2CH2; Het<8> = 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from S, N and O; Ar<1> = phenyl or Het<8> optionally substituted by 1-2 of 1-6C alkoxy, 2-7C alkoxycarbonyl, halogen, phenoxy, OH and 1-6C alkyl; R<28> and R<29> = H or 1-6C alkyl; R<30> = a group as defined for R<12>; G' = a group as defined for G; R<2> and R<3> = H or 1-6C alkyl; D+E = a group of formula (xii)-(xiv): R<31>-R<38> = H, phenyl or 1-6C alkyl.