Patent ID: 6025472
Filing Date: 2000-02-15
Classification: A61K,A61P,C07C,C07D,C07K

Abstract:
A compound of the formula: ##STR114## wherein (a) X is selected from the group consisting of --S(O).sub.2 --, --N(R')--S(O).sub.2 --, --(C.dbd.O)--, --OC(.dbd.O)--, --NH--C(.dbd.O)--, --P(O)(R"")-- and a direct link, wherein R' is hydrogen, alkyl of 1 to about 4 carbon atoms, aryl of about 6 to about 14 carbon atoms or aralkyl of about 6 to about 16 carbon atoms, and R"" is NR', OR', R', or SR', with the proviso that R"" is not NH, OH, H, or SH, and;(b) R.sub.1 is selected from the group consisting substituted benzyl or substituted naphthyl wherein the substitution is selected from the group consisting of --C(O)OH, --C(O)OZ.sub.1, --S(O).sub.m Z.sub.1, and --CF.sub.3 ;c) R.sub.2 is selected from the group consisting of ##STR115## hydrogen, --CH.sub.2 CH.sub.2 CH.sub.2 NHC(.dbd.NH)NH.sub.2, --CH.sub.2 CH.sub.2 S(O).sub.2 CH.sub.3, --(CH.sub.2).sub.p C(O)Z.sub.5, --(CH.sub.2).sub.p C(O)OZ.sub.6, --(CH.sub.2).sub.p C(O)NHZ.sub.6, --CH.sub.2 S(O).sub.2 (CH.sub.2).sub.p C(O)Z.sub.5, --CH.sub.2 S(O).sub.2 (CH.sub.2).sub.p C(O)OZ.sub.6, --CH.sub.2 S(O).sub.2 (CH.sub.2).sub.p C(O)NR.sub.5 R.sub.6, --CH.sub.2 S(O).sub.2 Z.sub.6, --(CH.sub.2).sub.p NH.sub.2, --(CH.sub.2).sub.p C(O)NR.sub.5 R.sub.6, --(O)Z.sub.6, and ##STR116## wherein p is 1 to 6,Z.sub.5 is --OH, --OCH.sub.3, --OCH.sub.2 CH.sub.3, or --NR.sub.5 R.sub.6,Z.sub.6 is alkyl of 1 to about 4 carbon atoms, aryl of about 6 to about 14 carbon atoms, or aralkyl of about 7 to 16 carbon atoms,R.sub.5 is hydrogen, methyl, or Z.sub.6,R.sub.6 is hydrogen or a cyclic alkyl of 3 to about 15 carbon atoms, an aralkyl of about 7 to about 15 carbon atoms optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, or Y.sub.3, or heteroaryl of 5 to 14 atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and S(O).sub.i, wherein i is 0-2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, or Y.sub.3 ; ##STR117## is 6,7-dimethoxy-1,2,3,4-tetrahydroisoguinolinyl, 4-hydroxy piperidyl, 4-keto piperidyl, N-morpholino, 3,4-methylenedioxybenzyl piperazinyl, 4-phenyl piperazinyl optionally mono-substituted with fluoro, chloro, methoxy, or trifluoromethyl, or 4-benzyl piperazinyl optionally mono-substituted with fluoro, chloro, methoxy, or trifluoromethyl, and pharmaceutically acceptable quaternary ammonium salts thereof;(d) R.sub.3 is selected from the group consisting of(1) hydrogen;(2) alkyl of 1 to about 8 carbon atoms optionally substituted with --OH;(3) cyclic alkyl of about 3 to about 10 carbon atoms;(4) alkyl of 1 to about 3 carbon atoms substituted with cyclic alkyl of about 5 to about 8 carbon atoms;(5) aryl of about 3 to about 10 carbon atoms which is optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3 ;(6) alkyl of 1 to about 3 carbon atoms substituted on the terminal carbon with aryl of about 4 carbon atoms to about 10 carbon atoms which is optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3 ;(7) alkyl of 1 to about 6 carbon atoms with alkyl branching at the alpha, beta, gamma, and delta carbons of 1 to about 6 carbon atoms; and(e) R.sub.4 is selected from the group consisting of hydrogen, alkyl of 1 to about 7 carbon atoms optionally substituted with --OH, and alkyl of 1 to about 3 carbon atoms substituted on the terminal carbon atom with aryl of about 4 carbon atoms to about 10 carbon atoms which is optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3 ;wherein Y.sub.1, Y.sub.2, and Y.sub.3 are(i) independently selected from the group consisting of hydrogen, halogen, cyano, nitro, tetrazolyl, amino, guanidino, amidino, methylamino, methylguanidino, --CF.sub.3, --CF.sub.2 CF.sub.3, --CH(CF.sub.3).sub.2, --C(OH)(CF.sub.3).sub.2, --OCF.sub.3, --OCF.sub.2 CF.sub.3, --OC(O)NH.sub.2, --OC(O)NHZ.sub.1, --OC(O)NZ.sub.1 Z.sub.2, --NHC(O)Z.sub.1, --NHC(O)NH.sub.2, --NHC(O)NZ.sub.1, --NHC(O)NZ.sub.1 Z.sub.2, --C(O)OH, --C(O)OZ.sub.1, --P(O).sub.3 H, --P(O).sub.3 H.sub.2, --P(O).sub.3 (Z.sub.1).sub.2, --S(O).sub.3 H, --S(O).sub.m Z.sub.1, --Z.sub.1, --OZ.sub.1, --OH, --NH.sub.2, --NHZ.sub.1, and --NZ.sub.1 Z.sub.2, wherein m is 0, 1 or 2, and Z.sub.1 and Z.sub.2 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms, or(ii) Y.sub.1 and Y.sub.2 are selected together to be --OC(Z.sub.3)(Z.sub.4)O, wherein Z.sub.3 and Z.sub.4 are independently selected from the group consisting of hydrogen, alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms.