Patent ID: 6235760
Filing Date: 2001-05-22
Classification: A61K,A61P

Abstract:
A method of treating a CNS injury to the brain, in a mammal in need of such treatment, which method comprises administering to said mammal an effective amount of a compound of formula (I) ##STR3##wherein:R.sub.1 is 4-pyridyl, pyrimidinyl, quinazolin-4-yl, quinolyl, isoquinolinyl, 1-imidazolyl or 1-benzimidazolyl which is optionally substituted with one or two substituents each of which is independently selected from C.sub.1-4 alkyl, halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, NH.sub.2, mono- or di-C.sub.1-6 -alkylamino or N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR.sub.22 ;R.sub.2 is hydrogen, (CR.sub.10 R.sub.20).sub.n OR.sub.12, heterocyclyl, heterocyclylC.sub.1-10 alkyl, C.sub.1-10 alkyl, halo-substituted C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-10 alkyl, C.sub.5-7 cycloalkenyl, aryl, arylC.sub.1-10 alkyl, heteroaryl, heteroarylC.sub.1-10 alkyl, (CR.sub.10 R.sub.20).sub.n' OR.sub.13, (CR.sub.10 R.sub.20).sub.n' S(O).sub.m R.sub.25, (CR.sub.10 R.sub.20).sub.n' NHS(O).sub.2 R.sub.25, (CR.sub.10 R.sub.20).sub.n' NR.sub.8 R.sub.9, (CR.sub.10 R.sub.20).sub.n' NO.sub.2, (CR.sub.10 R.sub.20).sub.n' CN, (CR.sub.10 R.sub.20).sub.n' SO.sub.2 R.sub.25, (CR.sub.10 R.sub.20).sub.n' S(O).sub.m NR.sub.8 R.sub.9, (CR.sub.10 R.sub.20).sub.n' C(Z)R.sub.13, (CR.sub.10 R.sub.20).sub.n' C(Z)OR.sub.13, (CR.sub.10 R.sub.20).sub.n' C(Z)NR.sub.8 R.sub.9, (CR.sub.10 R.sub.20).sub.n' C(Z)NR.sub.13 OR.sub.12, (CR.sub.10 R.sub.20).sub.n' NR.sub.10 C(Z)R.sub.13, (CR.sub.10 R.sub.20).sub.n' NR.sub.10 C(Z)NR.sub.8 R.sub.9, (CR.sub.10 R.sub.20).sub.n' N(OR.sub.21)C(Z)NR.sub.8 R.sub.9, (CR.sub.10 R.sub.20).sub.n' N(OR.sub.21)C(Z)R.sub.13, (CR.sub.10 R.sub.20).sub.n' C(.dbd.NOR.sub.21)R.sub.13, (CR.sub.10 R.sub.20).sub.n' NR.sub.10 C(.dbd.NR.sub.27)NR.sub.8 R.sub.9, (CR.sub.10 R.sub.20).sub.n' OC(Z)NR.sub.8 R.sub.9, (CR.sub.10 R.sub.20).sub.n' NR.sub.10 C(Z)NR.sub.8 R.sub.9, (CR.sub.10 R.sub.20).sub.n' NR.sub.10 C(Z)OR.sub.10, 5-(R.sub.25)-1,2,4-oxadizaol-3-yl or 4-(R.sub.12)-5-(R.sub.18 R.sub.19)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl moieties may be optionally substituted;n is 0, or an integer from 1 to 10;n' is an integer having a value of 1 to 10;m is 0, or the integer having a value of 1 or 2;m' is an integer having a value of 1 or 2;m"" is an integer having a value of 1 or 2;m'"" is 0, or an integer of 1;v is 0, or an integer having a value of 1 to 5;t is a number having a value of 1, 2 or 3;R.sub.3 is X.sub.a P(Z)(X.sub.b R.sub.13).sub.2 or Q--(Y.sub.1).sub.t ;Q is an aryl or heteroaryl group;X.sub.a is --NR.sub.8 --, --O--, --S-- or a C.sub.1-10 alkylene chain optionally substituted by C.sub.1-4 alkyl and optionally interrupted by --NR.sub.8 --, --O-- or --S--;X.sub.b is --(CR.sub.10 R.sub.20).sub.n, --NR.sub.8 --, --O-- or --S--;Z is oxygen or sulfur;Y.sub.1 is independently selected from hydrogen, C.sub.1-5 alkyl, halo-substituted C.sub.1-5 alkyl, halogen, X.sub.a --P(Z)--(X.sub.b R.sub.13).sub.2 or (CR.sub.10 R.sub.20).sub.n Y.sub.2 ;Y.sub.2 is OR.sub.8, NO.sub.2, S(O).sub.m"" R.sub.11, SR.sub.8, S(O).sub.m"" OR.sub.8, S(O).sub.m NR.sub.8 R.sub.9, --NR.sub.8 R.sub.9, O(CR.sub.10 R.sub.20).sub.n' NR.sub.8 R.sub.9, C(O)R.sub.8, CO.sub.2 R.sub.8, CO.sub.2 (CR.sub.10 R.sub.20).sub.n' CONR.sub.8 R.sub.9, ZC(O)R.sub.8, CN, C(Z)NR.sub.8 R.sub.9, NR.sub.10 C(Z)R.sub.8, C(Z)NR.sub.8 OR.sub.9, NR.sub.10 C(Z)NR.sub.8 R.sub.9, NR.sub.10 S(O).sub.m"" R.sub.11, N(OR.sub.21)C(Z)NR.sub.8 R.sub.9, N(OR.sub.21)C(Z)R.sub.8, C(.dbd.NOR.sub.21)R.sub.8, NR.sub.10 C(.dbd.NR.sub.15)SR.sub.11, NR.sub.10 C(.dbd.NR.sub.15)NR.sub.8 R.sub.9, NR.sub.10 C(.dbd.CR.sub.14 R.sub.24)SR.sub.11, NR.sub.10 C(.dbd.CR.sub.14 R.sub.24)NR.sub.8 R.sub.9, NR.sub.10 C(O)C(O)NR.sub.8 R.sub.9, NR.sub.10 C(O)C(O)OR.sub.10 --C(.dbd.NR.sub.13)NR.sub.8 R.sub.9, C(.dbd.NOR.sub.13)NR.sub.8 R.sub.9, C(.dbd.NR.sub.13)ZR.sub.11, OC(Z)NR.sub.8 R.sub.9, NR.sub.10 S(O).sub.m"" CF.sub.3, NR.sub.10 C(Z)OR.sub.10, 5-(R.sub.18)-1,2,4-oxadizaol-3-yl or 4-(R.sub.12)-5-(R.sub.18 R.sub.19)-4,5-dihydro-1,2,4-oxadiazol-3-yl;R.sub.4 is phenyl, naphth-1-yl or naphth-2-yl which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substituent, is halo, cyano, C(Z)NR.sub.7 R.sub.17, C(Z)OR.sub.23, (CR.sub.10 R.sub.20).sub.m'"" COR.sub.36, SR.sub.5, SOR.sub.5, OR.sub.36, halo-substituted-C.sub.1-4 alkyl, C.sub.1-4 alkyl, ZC(Z)R.sub.36, NR.sub.10 C(Z)R.sub.23, or (CR.sub.10 R.sub.20).sub.m'"" NR.sub.10 R.sub.20 and which, for other positions of substitution, is halo, cyano, C(Z)NR.sub.16 R.sub.26, C(Z)OR.sub.8, (CR.sub.10 R.sub.20).sub.v COR.sub.8, S(O).sub.m R.sub.8, OR.sub.8, halo-substituted-C.sub.1-4 alkyl, C.sub.1-4 alkyl, (CR.sub.10 R.sub.20).sub.v NR.sub.10 C(Z)R.sub.8, NR.sub.10 S(O).sub.m' R.sub.11, NR.sub.10 S(O).sub.m' NR.sub.7 R.sub.17 ZC(Z)R.sub.8 or (CR.sub.10 R.sub.20).sub.m' NR.sub.16 R.sub.26 ;R.sub.5 is hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl or NR.sub.7 R.sub.17, excluding the moieties SR.sub.5 being SNR.sub.7 R.sub.17 and SOR.sub.5 being --SOH;R.sub.6 is C.sub.1-4 alkyl, halo-substituted-C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl or C.sub.3-5 cycloalkyl;R.sub.7 and R.sub.17 is each independently selected from hydrogen or C.sub.1-4 alkyl or R.sub.7 and R.sub.17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR.sub.22 ;R.sub.8 is hydrogen, heterocyclyl, heterocyclylalkyl or R.sub.11 ;R.sub.9 is hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or R.sub.8 and R.sub.9 may together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR.sub.12 ;R.sub.10 and R.sub.20 is each independently selected from hydrogen or C.sub.1-4 alkyl;R.sub.11 is C.sub.1-10 alkyl, halo-substituted C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;R.sub.12 is hydrogen, --C(Z)R.sub.13 or optionally substituted C.sub.1-4 alkyl, optionally substituted aryl, optionally substituted arylC.sub.1-4 alkyl, or S(O).sub.2 R.sub.25 ;R.sub.13 is hydrogen, C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, heterocyclyl, heterocyclylC.sub.1-10 alkyl, aryl, arylC.sub.1-10 alkyl, heteroaryl or heteroaryl C.sub.1-10 alkyl;R.sub.14 and R.sub.24 is each independently selected from hydrogen, alkyl, nitro or cyano;R.sub.15 is hydrogen, cyano, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl;R.sub.16 and R.sub.26 is each independently selected from hydrogen or optionally substituted C.sub.1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C.sub.1-4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR.sub.12 ;R.sub.18 and R.sub.19 is each independently selected from hydrogen, C.sub.1-4 alkyl, substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl or together denote a oxygen or sulfur;R.sub.21 is hydrogen, a pharmaceutically acceptable cation, C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, aryl, aryl C.sub.1-4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or C.sub.1-10 alkanoyl;R.sub.22 is R.sub.10 or C(Z)--C.sub.1-4 alkyl;R.sub.23 is C.sub.1-4 alkyl, halo-substituted-C.sub.1-4 alkyl, or C.sub.3-5 cycloalkyl;R.sub.36 is hydrogen or R.sub.23 ;R.sub.25 is C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C.sub.1-10 alkyl, heteroaryl or heteroarylalkyl;R.sub.27 is hydrogen, cyano, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, or aryl;or a pharmaceutically acceptable salt thereof.