Patent ID: 6207710
Filing Date: 2001-03-27
Classification: A61K,C07K

Abstract:
A compound represented by formula: ##STR12##wherein R.sup.1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;R.sup.2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;each R.sup.3 is independently selected from the group consisting of hydrogen and methyl and R.sup.3 together with R.sup.4 can be fused to form a cyclic structure of from 3 to 8 atoms which is optionally fused with an aryl or heteroaryl group;each R.sup.4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms;X is selected from the group consisting of --C(O)Y and --C(S)Y where Y is selected from the group consisting of(a) alkyl or cycloalkyl,(b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include .alpha.-haloalkyl, .alpha.-diazoalkyl, .alpha.-OC(O)alkyl, or .alpha.-OC(O)aryl groups,(c) alkoxy or thioalkoxy,(d) substituted alkoxy or substituted thioalkoxy,(e) hydroxy,(f) aryl,(g) heteroaryl,(h) heterocyclic,(i) --NR'R"" where R' and R"" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R"" is hydroxy or alkoxy, and where R' and R"" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups,(j) --NHSO.sub.2 --R.sup.8 where R.sup.8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic,(k) --NR.sup.9 NR.sup.10 R.sup.10 where R.sup.9 is hydrogen or alkyl, and each R.sup.10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and(l) --ONR.sup.9 [C(O)O].sub.z R.sup.10 where z is zero or one, R.sup.9 and R.sup.10 are as defined above;X can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, phthalimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,X' is hydrogen, hydroxy or fluoro;X"" is hydrogen, hydroxy or fluoro, or X' and X"" together form an oxo group,Z is selected from the group consisting of a bond covalently linking R.sup.1 to --CX'X""--, oxygen and sulfur; andn is an integer equal to 1 or 2;with the proviso that:A. when R.sup.1 is phenyl or 3-nitrophenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is --CH(OH)CH.sub.3, R.sup.5 is hydrogen, X' and X"" are hydrogen, Z is a bond, and n is 1, then X is not --C(O)OH;B. when R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is --CH(OH)CH.sub.3 derived from D-threonine, R.sup.5 is hydrogen, X' and X"" are hydrogen, Z is a bond, and n is 1, then X is not --C(O)OH or --C(O)OCH.sub.3 ;C. when R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.4 is benzyl, R.sup.5 is hydrogen, X is methoxycarbonyl, X' and X"" are hydrogen, Z is a bond, and n is 1, then R.sup.3 is not methyl;D. when R.sup.1 is iso-propyl, R.sup.2 is --CH.sub.2 C(O)NH.sub.2, R.sup.3 is hydrogen, R.sup.4 is iso-butyl, R.sup.5 is hydrogen, X' and X"" are hydrogen, Z is a bond, and n is 1, then X is not --C(O)OCH.sub.3 ;E. when R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.5 is hydrogen, X is --C(O)OCH.sub.3, X' and X"" are hydrogen, Z is a bond, and n is 1, then R.sup.3, the nitrogen atom attached to R.sup.3, and R.sup.4 do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl;F. when R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.5 is hydrogen, X is --C(O)OCH.sub.3, X' and X"" are hydrogen, Z is a bond, and n is 1, then R.sup.4 is not 4-amino-n-butyl;G. when R.sup.1 is 3-nitrophenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is --CH(OH)CH.sub.3, R.sup.5 is hydrogen, X' and X"" are hydrogen, Z is a bond, and n is 1, then X is not --C(O)NH.sub.2 or --CH.sub.2 OH;H. when R.sup.1 is phenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.5 is hydrogen, X is --CH.sub.2 OCH.sub.3, X' and X"" are hydrogen, Z is a bond, and n is 1, then R.sup.4 is not benzyl or ethyl;I. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl, R.sup.3 is methyl, R.sup.4 is methyl, R.sup.5 is hydrogen, X' and X"" are hydrogen, Z is a bond, and n is 1, then X is not --CHOH.phi.;J. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is phenyl derived from D-phenylglycine, R.sup.5 is hydrogen, X' and X"" are hydrogen, Z is a bond, and n is 1, then X is not --CHOH.phi. or --CH.sub.2 OH;K. when R.sub.1 is N-(2-pyrrolidinonyl), R.sub.2 is methyl, R.sub.3 is hydrogen, R.sub.4 is benzyl, R.sup.5 is hydrogen, X' and X"" are hydrogen, Z is a bond, and n is 1, then X is not --C(O)OCH.sub.3 ;L. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl derived from D-alanine, R.sup.3 is hydrogen, R.sup.4 is phenyl derived from D-phenylglycine, R.sup.5 is hydrogen, X' and X"" are hydrogen, Z is a bond, and n is 1, then X is not --C(O)NH-benzyl;M. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is hydrogen, R.sup.5 is hydrogen, X' and X"" are hydrogen, Z is a bond, and n is 1, then X is not --CH.sub.2 OH;N. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is 4-phenylphenyl, R.sup.5 is hydrogen, X' and X"" are hydrogen, Z is a bond, and n is 1, then X is not --C(O)NHC(CH.sub.3).sub.3 ; andO. when R.sup.1 is 3,5-difluorophenyl, R.sup.2 is methyl, R.sup.3 is hydrogen, R.sup.4 is phenyl derived from D-phenylglycine, R.sup.5 is hydrogen, X' and X"" are hydrogen, Z is a bond, and n is 1, then X is not --C(O)NHCH(CH.sub.3).phi.;with the further proviso that the compounds of formulas I-IV below are excluded: ##STR13##wherein R.sup.1 is selected from the group consisting of:(a) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and heteroaryl,(b) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and heteroaryl,(c) cycloalkenyl,(d) substituted alkyl provided that the substituent is not aryl and/or heteroaryl groups,(e) substituted alkenyl provided that the substituent is not aralkenyl or heteroaralkenyl,(f) substituted alkynyl provided that the substituent is not aralkynyl or heteroaralkynyl, and(h) heterocyclic;R.sup.2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;each R.sup.4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms;X is --C(O)Y or --C(S)Y where Y is selected from the group consisting of(a) alkyl or cycloalkyl,(b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include .alpha.-haloalkyl, .alpha.-diazoalkyl, .alpha.-OC(O)alkyl or .alpha.-OC(O)aryl groups,(c) alkoxy or thioalkoxy,(d) substituted alkoxy or substituted thioalkoxy,(e) hydroxy,(f) aryl,(g) heteroaryl,(h) heterocyclic,(i) --NR'R"" where R' and R"" are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R"" is hydroxy or alkoxy, and where R' and R"" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups,(j) --NHSO.sub.2 --R.sup.8 where R.sup.8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic,(k) --NR.sup.9 NR.sup.10 R.sup.10 where R.sup.9 is hydrogen or alkyl, and each R.sup.10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and(l) --ONR.sup.9 [C(O)O].sub.z R.sup.10 where z is zero or one, R.sup.9 and R.sup.10 are as defined above;X can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, phthalimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,X' is hydrogen, hydroxy or fluoro;X"" is hydrogen, hydroxy or fluoro, or X' and X"" together form an oxo group, andn is an integer equal to 1 or 2;with the proviso excluding the following known compound:when R.sup.1 is o-fluorophenyl, R.sup.2 is 3,4-dichlorophenyl or ethyl, R.sup.4 and R.sup.5 are hydrogen, X' and X"" are hydrogen, then X is not --C(O)OCH.sub.3 ; ##STR14##whereinR.sup.1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;R.sup.2 is selected from the group consisting of(a) substituted alkyl provided that such substituted alkyl groups do not include aryl or heteroaryl substituted alkyl, or a side-chain of a naturally occurring amino acid,(b) substituted alkenyl provided that such substituted alkenyl groups do not include aryl or heteroaryl substituted alkenyl,(c) substituted alkynyl provided that such substituted alkynyl groups do not include aryl or heteroaryl substituted alkynyl,(d) heterocyclic,(e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, and heteroaryl, and(f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that if there is an alkyl substituent on the substituted heteroaryl group then there is at least one other substituent which is not alkyl;each R.sup.4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms;X is --C(O)Y or --C(S)Y where Y is selected from the group consisting of(a) alkyl or cycloalkyl,(b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include .alpha.-haloalkyl, .alpha.-diazoalkyl, .alpha.-OC(O)alkyl or .alpha.-OC(O)aryl groups,(c) alkoxy or thioalkoxy,(d) substituted alkoxy or substituted thioalkoxy,(e) hydroxy,(f) aryl,(g) heteroaryl,(h) heterocyclic,(i) --NR'R"" where R' and R"" are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R"" is hydroxy or alkoxy, and where R' and R"" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups,(j) --NHSO.sub.2 --R.sup.8 where R.sup.8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic,(k) --NR.sup.9 NR.sup.10 R.sup.10 where R.sup.9 is hydrogen or alkyl, and each R.sup.10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and(l) --ONR.sup.9 [C(O)O].sub.z R.sup.10 where z is zero or one, R.sup.9 and R.sup.10 are as defined above;X can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,X' is hydrogen, hydroxy or fluoro;X"" is hydrogen, hydroxy or fluoro, or X' and X"" together form an oxo group, andn is an integer equal to 1 or 2; ##STR15##whereinR.sup.1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;R.sup.2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;R.sup.4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl provided that at least one R.sup.4 is selected to be:(a) substituted alkyl provided that such substituted alkyl groups do not include aryl or heteroaryl substituted alkyl, or a side-chain of a naturally occurring amino acid,(b) substituted alkenyl provided that such substituted alkenyl groups do not include aryl or heteroaryl substituted alkenyl,(c) substituted alkynyl provided that such substituted alkynyl groups do not include aryl or heteroaryl substituted alkynyl,(d) heterocyclic,(e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, and heteroaryl, and(f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that if there is an alkyl substituent on the substituted heteroaryl group then there is at least one other substituent which is not alkyl;each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms;X is --C(O)Y or --C(S)Y where Y is selected from the group consisting of(a) alkyl or cycloalkyl,(b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include .alpha.-haloalkyl, .alpha.-diazoalkyl, .alpha.-OC(O)alkyl or .alpha.-OC(O)aryl groups,(c) alkoxy or thioalkoxy,(d) substituted alkoxy or substituted thioalkoxy,(e) hydroxy,(f) aryl,(g) heteroaryl,(h) heterocyclic,(i) --NR'R"" where R' and R"" are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R"" is hydroxy or alkoxy, and where R' and R"" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups,(j) --NHSO.sub.2 --R.sup.8 where R.sup.8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic,(k) --NR.sup.9 NR.sup.10 R.sup.10 where R.sup.9 is hydrogen or alkyl, and each R.sup.10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and(l) --ONR.sup.9 [C(O)O].sub.z R.sup.10 where z is zero or one, R.sup.9 and R.sup.10 are as defined above;X can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,X' is hydrogen, hydroxy or fluoro;X"" is hydrogen, hydroxy or fluoro, or X' and X"" together form an oxo group, andn is an integer equal to 1 or 2; and ##STR16##wherein R.sup.1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;R.sup.2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;each R.sup.4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms;X is selected from the group consisting of(a) --C(O)-alkyl,(b) --C(O)-substituted alkoxy or substituted thioalkoxy provided that the substituted alkoxy groups do not include benzyl and phenethyl,(c) --C(O)-aryl wherein the aryl group is substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl,(d) --C(O)-heteroaryl wherein the heteroaryl group is substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy(e) --C(O)--NR'R"" where R' and R"" are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R"" is hydroxy or alkoxy, and where R' and R"" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, andX can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of amino, thiol, alkoxy, phthalimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,provided that R' and R"" are not both independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl;X' is hydrogen, hydroxy or fluoro;X"" is hydrogen, hydroxy or fluoro, or X' and X"" together form an oxo group, andn is an integer equal to 1 or 2;with the proviso that:when R.sup.1 is iso-propyl, R.sup.2 is phenyl, R.sup.4 is methyl, R.sup.5 is hydrogen, X' and X"" are hydrogen, n is 2, and the second R.sup.4 at the carboxy terminus is methyl, then X is not --C(O)NH-pNO.sub.2 -.phi..