Claims
- 1. 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.
- 2. A compound according to claim 1, wherein the substitution is meta or ortho.
- 3. A compound of the formula: ##STR118## 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 of:
- (1) alkyl of 1 to about 12 carbon atoms,
- (2) alkyl of 1 to about 3 carbon atoms substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (3) cyclic alkyl of 3 to about 15 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (4) heterocycloalkyl of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.1, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl, or alkyl of 1 to about 3 carbons, amino, guanidino or amidino,
- (5) heterocyclo of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl or alkyl of 1 to about 3 carbons, amino, guanidino, or amidino,
- (6) alkenyl of about 3 to about 6 carbon atoms which is optionally substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring carbons with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (7) aryl of about 6 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (8) 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (9) aralkyl of about 7 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (10) heteroaralkyl of 6 to 11 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (11) aralkenyl of about 8 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (12) heteroaralkenyl of 7 to 12 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively, ##STR119## (17) perfluoroalkyl of 1 to about 12 carbon atoms, (18) perfluoroaryl of about 6 to about 14 carbon atoms,
- (19) perfluoroaralkyl of about 7 to about 15 carbon atoms,
- (20) hydrogen, and
- (21) ##STR120## is a 5 to 7 member heterocycle of 3 to 6 ring carbon atoms, where V is --CH.sub.2 --, --O--, --S(.dbd.O)--, --S(O).sub.2 -- or --S--, 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, and 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.i, --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, 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,
- (c) R.sub.2 is selected from the group consisting of ##STR121## 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)Z.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 ##STR122## 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 aralykyl 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, as defined above, 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, as defined above; ##STR123## is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinyl, 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, or Y.sub.3 ;
- with the proviso that when R.sub.2 is hydrogen or --CH.sub.2 -pyridine, R.sub.3 is hydrogen and R.sub.4 is hydrogen or methyl, then R.sub.1 X-- is not aminoiminomethyl, .alpha.-aminoacetyl, substituted or unsubstituted naphthyl-sulfonyl, quinoline, dialkylamino substituted quinoline, tetrahydro quinoline sulfonyl or dialkylamino substitued quinoline sufonyl.
- 4. A compound of the formula: ##STR124## 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 cyclohexyl or cyclohexylmethyl;
- (c) R.sub.2 is selected from the group consisting of ##STR125## 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 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 ##STR126## 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 ; ##STR127## 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 torabout 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms.
- 5. A compound of the formula: ##STR128## 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 SRI, with the proviso that R" is not NH, OH, H, or SH, and
- (b) R.sub.1 is selected from the group consisting of:
- (1) alkyl of 1 to about 12 carbon atoms,
- (2) alkyl of 1 to about 3 carbon atoms substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (3) cyclic alkyl of 3 to about 15 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (4) heterocycloalkyl of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl, or alkyl of 1 to about 3 carbons, amino, guanidino or amidino,
- (5) heterocyclo of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl or alkyl of 1 to about 3 carbons, amino, guanidino, or amidino,
- (6) alkenyl of about 3 to about 6 carbon atoms which is optionally substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring carbons with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (7) aryl of about 6 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (8) 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (9) aralkyl of about 7 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (10) heteroaralkyl of 6 to 11 atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, Initrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (11) aralkenyl of about 8 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (12) heteroaralkenyl of 7 to 12 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively, ##STR129## (17) perfluoroalkyl of 1 to about 12 carbon atoms, (18) perfluoroaryl of about 6 to about 14 carbon atoms,
- (19) perfluoroaralkyl of about 7 to about 15 carbon atoms,
- (20) hydrogen, and
- (21) ##STR130## is a 5 to 7 member heterocycle of 3 to 6 ring carbon atoms, where V is --CH.sub.2 --, --O--, --S(.dbd.O)--, --S(O).sub.2 -- or --S--, 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, and 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,
- (c) R.sub.2 is selected from the group consisting of --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 S(O).sub.2 (CH.sub.2).sub.p C(O)Z.sub.5, (CH.sub.2).sub.p C(O)NR.sub.5 R.sub.6, and ##STR131## 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 aralykyl 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, as defined above, 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, as defined above; ##STR132## 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, or Y.sub.3.
- 6. A compound according to claim 5, wherein R.sub.2 is selected from the group consisting of
- --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, and --(CH.sub.2).sub.n C(O)NR.sub.5 R.sub.6.
- 7. A compound according to claim 6, wherein R.sub.2 is --CH.sub.2 CH.sub.2 CH.sub.2 NHC(.dbd.NH)NH.sub.2.
- 8. A compound of the formula: ##STR133## 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 of:
- (1) alkyl of 1 to about 12 carbon atoms,
- (2) alkyl of 1 to about 3 carbon atoms substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (3) cyclic alkyl of 3 to about 15 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (4) heterocycloalkyl of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl, or alkyl of 1 to about 3 carbons, amino, guanidino or amidino,
- (5) heterocyclo of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl or alkyl of 1 to about 3 carbons, amino, guanidino, or amidino,
- (6) alkenyl of about 3 to about 6 carbon atoms which is optionally substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring carbons with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (7) aryl of about 6 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (8) 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (9) aralkyl of about 7 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (10) heteroaralkyl of 6 to 11 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (11) aralkenyl of about 8 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (12) heteroaralkenyl of 7 to 12 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively, ##STR134## (17) perfluoroalkyl of 1 to about 12 carbon atoms, (18) perfluoroaryl of about 6 to about 14 carbon atoms,
- (19) perfluoroaralkyl of about 7 to about 15 carbon atoms,
- (20) hydrogen, and
- (21) ##STR135## is a 5 to 7 member heterocycle of 3 to 6 ring carbon atoms, where V is --CH.sub.2 --, --O--, --S(.dbd.O)--, --S(O).sub.2 -- or --S--, 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, and 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) Yi 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,
- (c) R.sub.2 is selected from the group consisting of ##STR136## 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) --(CH.sub.2).sub.p C(O)Z.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)Z.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 ##STR137## 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 aralykyl of about 7 to 16 carbon atoms, R.sub.5 is hydrogen,
- 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, as defined above, or heteroaryl of 5 to 14 atoms 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, as defined above; ##STR138## 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, or Y.sub.3 ;
- with the proviso that when R.sub.2 is hydrogen or --CH.sub.2 -pyridine, R.sub.3 is hydrogen and R.sub.4 is hydrogen or methyl, then R.sub.1 X-- is not aminoiminomethyl, .alpha.-aminoacetyl, substituted or unsubstituted naphthyl-sulfonyl, quinoline, dialkylamino substituted quinoline, tetrahydro quinoline sulfonyl or dialkylamino substitued quinoline sulfonyl.
- 9. A compound of the formula: ##STR139## 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 of:
- (1) alkyl of 1 to about 12 carbon atoms,
- (2) alkyl of 1 to about 3 carbon atoms substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (3) cyclic alkyl of 3 to about 15 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (4) heterocycloalkyl of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl, or alkyl of 1 to about 3 carbons, amino, guanidino or amidino,
- (5) heterocyclo of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl or alkyl of 1 to about 3 carbons, amino, guanidino, or amidino,
- (6) alkenyl of about 3 to about 6 carbon atoms which is optionally substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring carbons with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (7) aryl of about 6 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (8) 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (9) aralkyl of about 7 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (10) heteroaralkyl of 6 to 11 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (11) aralkenyl of about 8 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (12) heteroaralkenyl of 7 to 12 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively, ##STR140## (17) perfluoroalkyl of 1 to about 12 carbon atoms, (18) perfluoroaryl of about 6 to about 14 carbon atoms,
- (19) perfluoroaralkyl of about 7 to about 15 carbon atoms,
- (20) hydrogen, and
- (21) ##STR141## wherein is a 5 to 7 member heterocycle of 3 to 6 ring carbon atoms, where V is --CH.sub.2 --, --O--, --S(.dbd.O)--, --S(O).sub.2 -- or --S--, 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, and 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,
- (c) R.sub.2 is selected from the group consisting of ##STR142## 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)Z.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 ##STR143## 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 aralykyl of about 7 to 16 carbon atoms,
- R.sub.5 is hydrogen, methyl, or Z.sub.6,
- R.sub.6 is selected from the group consisting of 3-(R)-quinuclidine, 3-(S)-quinuclidine, 4-trifluoromethyl-7-yl-coumarin, 4-methyl-7-yl-coumarin, 7-yl-coumarin, 3-yl-2-ethyl-4(3H)-quinazolinone, 2-yl-benzothiazole, 3-yl-benzoic acid, 3-yl-4-hydroxybenzoic acid, 4-hydroxy-1-methyl-6-phenyl-3-yl-2(1H)-pyridone, and 1-adamantyl, or ethyl morpholine, ethyl piperidine, 2-(2-ethyl)pyridine, 4-hydroxyphenethyl, (R)-alpha-methylbenzyl, (S)-alpha-methylbenzyl, ((1S,2S)-(N-methyl-N-(1-ethyl))benzyl alcohol), ((1S,2R)-(N-methyl-N-(1-ethyl))benzyl alcohol), ((1S, 2S)-(N-methyl-N-(1-ethyl))benzyl alcohol), and (4-(methyl)-5-hydroxy-6-methyl-3-pyridine methanol); and ##STR144## 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, or Y.sub.3 ;
- with the proviso that when R.sub.2 is hydrogen or --CH.sub.2 -pyridine, R.sub.3 is hydrogen and R.sub.4 is hydrogen or methyl, then R.sub.1 X-- is not aminoiminomethyl, .alpha.-aminoacetyl, substituted or unsubstituted naphthyl-sulfonyl, quinoline, dialkylamino substituted quinoline, tetrahydro quinoline sulfonyl or dialkylamino substitued quinoline sulfonyl.
- 10. A compound of the formula: ##STR145## wherein (a) X is selected from the group consisting of --S(H).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 of:
- (1) alkyl of 1 to about 12 carbon atoms,
- (2) alkyl of 1 to about 3 carbon atoms substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (3) cyclic alkyl of 3 to about 15 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alk6xyl or alkyl each of 1 to about 3 carbon atoms,
- (4) heterocycloalkyl of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl, or alkyl of 1 to about 3 carbons, amino, guanidino or amidino,
- (5) heterocyclo of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl or alkyl of 1 to about 3 carbons, amino, guanidino, or amidino,
- (6) alkenyl of about 3 to about 6 carbon atoms which is optionally substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring carbons with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (7) aryl of about 6 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (8) 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (9) aralkyl of about 7 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (10) heteroaralkyl of 6 to 11 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (11) aralkenyl of about 8 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (12) heteroaralkenyl of 7 to 12 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively, ##STR146## (17) perfluoroalkyl of 1 to about 12 carbon atoms, (18) perfluoroaryl of about 6 to about 14 carbon atoms,
- (19) perfluoroaralkyl of about 7 to about 15 carbon atoms,
- (20) hydrogen, and
- (21) ##STR147## is a 5 to 7 member heterocycle of 3 to 6 ring carbon atoms, where V is --CH.sub.2 --, --O--, --S(.dbd.O)--, --S(O).sub.2 -- or --S--, 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, and 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,
- (c) R.sub.2 is selected from the group consisting of ##STR148## 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) C(O)Z.sub.6, --(CH.sub.2).sub.p C(O)NHZ.sub.6, --CH.sub.2 S(O).sub.2 (CH.sub.2)DC(O)Z.sub.5, --CH.sub.2 S(O).sub.2 (CH.sub.2) C(O)OZ.sub.6, --CH.sub.2 S(O).sub.2 (CH.sub.2)S(O) NR.sub.5 R.sub.6, --CH.sub.2 (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 ##STR149## 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 aralykyl 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, as defined above, 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, as defined above; ##STR150## is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinyl, 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 alkyl groups of 1 to about 7 carbon atoms optionally substituted with --OH on a terminal carbon atom, methyl, cyclohexylmethyl, phenyl, and benzyl; 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, or Y.sub.3.
- 11. A compound according to claim 10, wherein R.sub.3 is methyl or cyclohexyl.
- 12. A compound according to claim 11, wherein R.sub.4 is hydrogen or alkyl groups of 1 to about 7 carbon atoms optionally substituted with --OH on a terminal carbon atom.
- 13. A compound according to claim 12, wherein R.sub.4 is hydrogen.
- 14. A compound of the formula: ##STR151## wherein (a) X is --S(O).sub.2 --;
- (b) R.sub.1 is aralkyl of about 7 to about 15 carbon atoms which is optionally mono-, di- or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively
- (c) R.sub.2 is --CH.sub.2 CH.sub.2 CH.sub.2 NHC(.dbd.NH)NH.sub.2 ;
- (d) R.sub.3 is methyl; and
- (e) R.sub.4 is hydrogen, 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, and 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) Yi 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.
- 15. A compound of the formula: ##STR152## wherein (a) X is --S(O).sub.2 --;
- (b) R.sub.1 is aralkyl of about 7 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2 and/or Y.sub.3, respectively;
- (c) R.sub.2 is --CH.sub.2 CH.sub.2 CH.sub.2 NHC(.dbd.NH)NH.sub.2 ;
- (d) R.sub.3 is cyclohexyl; and
- (e) R.sub.4 is hydrogen;
- 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, and 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.i, --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, --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 carbon atoms, 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 and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms.
- 16. A compound according to claim 15, wherein R.sub.1 is substituted or unsubstituted benzyl.
- 17. A compound selected from the group consisting of D-camphorsulfonyl cysteinesulfone-acetic acid sarcosine-arginine aldehyde, (2-carbomethoxy)benzenesulfonyl-(D)-argininyl-sarcosine-argininal, N-benzylsulfonyl-(D)-methioninylsulfone sarcosine argininal, benzylsulfonylmethioninyl(sulfone)N-cyclohexylglycinylargininal, (D)-camphorsulfonyl aspartyl sarcosine arginine aldehyde, (D)-camphorsulfonyl-3-(3-pyridyl)-alanine sarcosine arginine aldehyde, benzylsulfonyl-3-(3-pyridyl)-alanine sarcosine arginine aldehyde, and (D)-camphorsulfonyl-glycine-sarcosine-arginine aldehyde, ##STR153##
- 18. A compound of the formula: 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 of:
- (1) alkyl of 1 to about 12 carbon atoms,
- (2) alkyl of 1 to about 3 carbon atoms substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (3) cyclic alkyl of 3 to about 15 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (4) heterocycloalkyl of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl, or alkyl of 1 to about 3 carbons, amino, guanidino or amidino,
- (5) heterocyclo of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl or alkyl of 1 to about 3 carbons, amino, guanidino, or amidino,
- (6) alkenyl of about 3 to about 6 carbon atoms which is optionally substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring carbons with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (7) aryl of about 6 to about 14 carbon atoms which is mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (8) 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, 1 or 2, which is mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (9) aralkyl of about 7 to about 15 carbon atoms which is mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (10) heteroaralkyl of 6 to 11 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, 1 or 2, which is mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (11) aralkenyl of about 8 to about 15 carbon atoms which is mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (12) heteroaralkenyl of 7 to 12 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, 1 or 2, which is optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively, ##STR154## (17) perfluoroalkyl of 1 to about 12 carbon atoms, (18) perfluoroaryl of about 6 to about 14 carbon atoms,
- (19) perfluoroaralkyl of about 7 to about 15 carbon atoms,
- (20) hydrogen, and
- (21) ##STR155## is a 5 to 7 member heterocycle of 3 to 6 ring carbon atoms, where V is --CH.sub.2 --, --O--, --S(.dbd.O)--, --S(O).sub.2 -- or --S--, 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, and 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) --S(O).sub.3 H, --S(O).sub.m Z.sub.1, --Z.sub.1, --OZ, --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, and
- wherein R.sub.1 is mono-, di-, or tri-substituted with Y.sub.1, Y.sub.2 and/or Y.sub.3 and Y.sub.1, Y.sub.2 and/or Y.sub.3 are independently selected from --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 ##STR156## 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)Z.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 --(H)NH.sub.2, --(CH.sub.2).sub.p C(O)NR.sub.5 R.sub.6, --(O)Z.sub.6, and ##STR157## 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 aralykyl 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, as defined above, 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, as defined above; ##STR158## 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, or Y.sub.3 ;
- with the proviso that when R.sub.2 is hydrogen or --CH.sub.2 -pyridine, R.sub.3 is hydrogen and R.sub.4 is hydrogen or methyl, then R.sub.1 X-- is not aminoiminomethyl, .alpha.-aminoacetyl, substituted or unsubstituted naphthyl-sulfonyl, quinoline, dialkylamino substituted quinoline, tetrahydro quinoline sulfonyl or dialkylamino substitued quinoline sulfonyl.
- 19. A compound according to claim 7 wherein X is --S(O).sub.2 --.
- 20. A compound according to claim 19 wherein R.sub.1 is alkyl, aryl or aralkyl.
- 21. A compound according to claim 20 wherein R.sub.1 is mono-, di-, or tri-substituted with Y.sub.1, Y.sub.2 and/or Y.sub.3 and Y.sub.1, Y.sub.2 and/or Y.sub.3 are independently selected from --C(O)OH, --C(O)OZ.sub.1, --S(O).sub.m Z.sub.1, and --CF.sub.3.
- 22. A compound according to claim 20 wherein R.sub.1 is unsubstituted naphthyl, substituted naphthyl, unsubstituted phenyl, substituted phenyl, unsubstituted benzyl or substituted benzyl.
- 23. A compound according to claim 22 wherein R.sub.1 is benzyl.
- 24. A compound according to claim 20 wherein R.sub.1 is cyclohexyl or cyclohexylmethyl.
- 25. A compound of the formula: ##STR159## 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 of:
- (1) alkyl of 1 to about 12 carbon atoms,
- (2) alkyl of 1 to about 3 carbon atoms substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (3) cyclic alkyl of 3 to about 15 carbon atoms, which optionally is substituted in the ring atoms with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (4) heterocycloalkyl of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl, or alkyl of 1 to about 3 carbons, amino, guanidino or amidino,
- (5) heterocyclo of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, optionally substituted in the ring carbons with hydroxyl, alkoxyl or alkyl of 1 to about 3 carbons, amino, guanidino, or amidino,
- (6) alkenyl of about 3 to about 6 carbon atoms which is optionally substituted with cyclic alkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring carbons with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbon atoms,
- (7) aryl of about 6 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (8) 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (9) aralkyl of about 7 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (10) heteroaralkyl of 6 to 11 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (11) aralkenyl of about 8 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively,
- (12) heteroaralkenyl of 7 to 12 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, 1 or 2, optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3, respectively, ##STR160## (17) perfluoroalkyl of 1 to about 12 carbon atoms, (18) perfluoroaryl of about 6 to about 14 carbon atoms,
- (19) perfluoroaralkyl of about 7 to about 15 carbon atoms,
- (20) hydrogen, and
- (21) ##STR161## is a 5 to 7 member heterocycle of 3 to 6 ring carbon atoms, where V is --CH.sub.2 --, --O--, --S(.dbd.O)--, --S(O).sub.2 -- or --S--, 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, and 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, --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, 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,
- (c) R.sub.2 is is CH.sub.2 CH.sub.2 S(O).sub.2 CH.sub.3 ;
- (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, or Y.sub.3.
- 26. A compound according to claim 25 wherein X is --S(O).sub.2 -- and R.sub.1 is aralkyl.
- 27. A compound according to claim 31 wherein Rl is mono-, di-, or tri-substituted with Y.sub.1, Y.sub.2 and/or Y.sub.3 and Y.sub.1, Y.sub.2 and/or Y.sub.3 are independently selected from --C(O)OH, --C(O)OZ.sub.1, --S(O).sub.m Z.sub.1, and --CF.sub.3.
- 28. A compound of the formula: ##STR162## wherein (a) X is --S(O).sub.2 ;
- (b) R.sub.1 is aralkyl of about 7 to 15 carbon atoms which is optionally mono-, di- or tri-substituted in the aryl ring with Y.sub.1, Y.sub.2 and/or Y.sub.3, respectively;
- (c) R.sub.2 is ##STR163## (d) R.sub.3 is methyl, cyclohexylmethyl, phenyl or benzyl; and (e) R.sub.4 is hydrogen;
- 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, and 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, 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.
- 29. A compound according to claim 28 wherein R.sub.1 is unsubstituted benzyl or substituted benzyl.
- 30. A compound according to claim 29 wherein Y.sub.1 and Y.sub.2 are independently selected from --C(O)OH, --C(Q)OZ.sub.1, --S(O).sub.m Z.sub.1, and --CF.sub.3.
CROSS REFERENCE TO RELATED APPLICATION
This application is a Continuation-in-Part of U.S. Ser. No. 08/361,794, filed Dec. 21, 1994, now U.S. Pat. No. 5,696,231 the disclosure of which is incorporated herein by reference.
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
4883863 |
Abe et al. |
Nov 1989 |
|
5380713 |
Balasubramanian et al. |
Jan 1995 |
|
Foreign Referenced Citations (6)
Number |
Date |
Country |
0185390 |
Dec 1985 |
EPX |
0672659 |
Mar 1995 |
EPX |
9204371 |
Mar 1992 |
WOX |
9413693 |
Jun 1994 |
WOX |
9413693 |
Jun 1994 |
WOX |
9528420 |
Oct 1995 |
WOX |
Non-Patent Literature Citations (1)
Entry |
Szelke et al., "Synthetic inhibitors of tissue kallikrein: effects in vivo in a model of allergic inflammation," Brazilian J. Med. Biol. Res. 27:1943-1947 (1994). |
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
361794 |
Dec 1994 |
|