Renin inhibitors containing an n-terminal disulfide cycle

Claim 1

A peptide of the formula: ##STR39## wherein: A is hydrogen; or ##STR40## where X is ##STR41## and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) n --where Y is C 1-4 alkyl; hydrogen; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; n is 0 to 5; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR42## where R 5 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and; halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; D is ##STR43## where Z is --(CH 2 ) p --and p is 1 or 2; or --S--; E is absent; or ##STR44## where R 6 is hydrogen; ##STR45## where R 9 is hydrogen, C 1-4 alkyl, hydroxy, or C 3-7 cycloalkyl; or --CH 2 R 10 , where R 10 is 4-imidazolyl, amino-C 2-4 alkyl, 2-, 3- or 4-pyridyl, or guanidyl-C 2-3 alkyl; F is absent; glycyl; sarcosyl; or ##STR46## where R 5 is as defined above; G is OR; NHR; N(R) 2 , where each R may be the same or different and is hydrogen; or C 1-4 alkyl; or, when E and/or F are absent, G may be (1) --Y--(CH 2 ) q --R 7 where Y is --NH-- or --O--; q is 0 to 5; and R 7 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or diC 1-4 alkylamino, and halo; amino; mono-, di- or tri-C 1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl-C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; ##STR47## where Y is as defined above; k is 0 or 1; k' is 0 or 1; k" is 1 to 4; k'" is 1 to 4; and R 7 and R a 7 may be the same or different and have the same meaning as R 7 above and R a 7 may additionally be ##STR48## where R 8 is hydrogen or C 1-3 alkyl; or ##STR49## where Y is as defined above; r is 0 or 1; and Z is ##STR50## where r' is 0 or 1; and R 8 is a defined above; or ##STR51## where r" is 0 or 1; R 2 is hydrogen; C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR52## `where R 11 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 2 is as defined above; and m is 1 or 2; m' is 1 or 2; m" is 1 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B, D, F, and G substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 7

A method of treating renin-associated hypertension comprising administering to a patient in need of such treatment, a therapeutically effective amount of a peptide of the formula: ##STR69## wherein: A is hydrogen; or ##STR70## where X is ##STR71## and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) n -- where Y is C 1-4 alkyl; hydrogen; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; n is 0 to 5; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR72## where R 5 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and; halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; D is ##STR73## where Z is --(CH 2 ) p -- and p is 1 or 2; or --S--; E is absent; or ##STR74## where R 6 is hydrogen; ##STR75## where R 9 is hydrogen, C 1-4 alkyl, hydroxy, or C 3-7 cycloalkyl; or --CH 2 R 10 , where R 10 is 4-imidazolyl, amino-C 2-4 alkyl, 2-, 3- or 4-pyridyl, or guanidyl-C 2-3 alkyl; F is absent; glycyl; sarcosyl; or ##STR76## where R 5 is as defined above; G is OR; NHR; N(R) 2 , where each R may be the same or different and is hydrogen; or C 1-4 alkyl; or, when E and/or F are absent, G may be (1) --Y--(CH 2 ) q --R 7 where Y is --NH-- or --O--; q is 0 to 5; and R 7 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or diC 1-4 alkylamino, and halo; amino; mono-, di- or tri-C 1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl-C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; ##STR77## where Y is as defined above; k is 0 or 1; k' is 0 or 1; k" is 1 to 4; k'" is 1 to 4; and R 7 and R a 7 may be the same or different and have the same meaning as R 7 above and R a 7 may additionally be ##STR78## where R 8 is hydrogen or C 1-3 alkyl; or ##STR79## where Y is as defined above; r is 0 or 1; and Z is ##STR80## where r' is 0 or 1; and R 8 is as defined above; or ##STR81## where r" is 0 or 1; R 2 is hydrogen; C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR82## where R 11 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 2 is as defined above; and m is 1 or 2; m' is 1 or 2; m" is 1 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B, D, F, and G substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 8

A method of treating renin-associated hypertension comprising administering to a patient in need of such treatment, a therapeutically effective amount of a peptide of the formula: ##STR69## wherein: A is hydrogen; or ##STR70## where X is ##STR71## and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) n -- where Y is C 1-4 alkyl; hydrogen; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; n is 0 to 5; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR72## where R 5 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and; halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; D is ##STR73## where Z is --(CH 2 ) p -- and p is 1 or 2; or --S--; E is absent; or ##STR74## where R 6 is hydrogen; ##STR75## where R 9 is hydrogen, C 1-4 alkyl, hydroxy, or C 3-7 cycloalkyl; or --CH 2 R 10 , where R 10 is 4-imidazolyl, amino-C 2-4 alkyl, 2-, 3- or 4-pyridyl, or guanidyl-C 2-3 alkyl; F is absent; glycyl; sarcosyl; or ##STR76## where R 5 is as defined above; G is OR; NHR; N(R) 2 , where each R may be the same or different and is hydrogen; or C 1-4 alkyl; or, when E and/or F are absent, G may be (1) --Y--(CH 2 ) q --R 7 where Y is --NH-- or --O--; q is 0 to 5; and R 7 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or diC 1-4 alkylamino, and halo; amino; mono-, di- or tri-C 1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl-C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; ##STR77## where Y is as defined above; k is 0 or 1; k' is 0 or 1; k" is 1 to 4; k'" is 1 to 4; and R 7 and R a 7 may be the same or different and have the same meaning as R 7 above and R a 7 may additionally be ##STR78## where R 8 is hydrogen or C 1-3 alkyl; or ##STR79## where Y is as defined above; r is 0 or 1; and Z is ##STR80## where r' is 0 or 1; and R 8 is as defined above; or ##STR81## where r" is 0 or 1; R 2 is hydrogen; C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR82## where R 11 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 2 is as defined above; and m is 1 or 2; m' is 1 or 2; m" is 1 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B, D, F, and G substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 10

A method of treating renin-associated hyperaldosteronism, comprising administering to a patient in need of such treatment, a therapeutically effective amount of a peptide of the formula: ##STR84## wherein: A is hydrogen; or ##STR85## where X is ##STR86## and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) n -- where Y is C 1-4 alkyl; hydrogen; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; n is 0 to 5; except that where X is --O--, only one of R a 1 and R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR87## where R 5 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl; aryl substituted with up to three member selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and; halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; D is ##STR88## where Z is --(CH 2 ) p -- and p is 1 or 2; or --S--; E is absent; or ##STR89## where R 6 is hydrogen; ##STR90## where R 9 is hydrogen, C 1-4 alkyl, hydroxy, or C 3-7 cycloalkyl; or --CH 2 R 10 , where R 10 is 4-imidazolyl, amino-C 2-4 alkyl, 2-, 3- or 4-pyridyl, or guanidyl-C 2-3 alkyl; F is absent; glycyl; sarcosyl; or ##STR91## where R 5 is as defined above; G is OR; NHR; N(R) 2 , where each R may be the same or different and is hydrogen; or C 1-4 alkyl; or, when E and/or F are absent, G may be (1) --Y--(CH 2 ) q --R 7 where Y is --NH-- or --O--; q is 0 to 5; and R 7 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or diC 1-4 alkylamino, and halo; amino; mono-, di- or tri-C 1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl-C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; ##STR92## where Y is as defined above; k is 0 or 1; k' is 0 or 1; k" is 1 to 4; k'" is 1 to 4; and R 7 and R a 7 may be the same or different and have the same meaning as R 7 above and R a 7 may additionally be ##STR93## where R 8 is hydrogen or C 1-3 alkyl; or ##STR94## where Y is as defined above; r is 0 or 1; and Z is ##STR95## where r' is 0 or 1; and R 8 is as defined above; or ##STR96## where r" is 0 or 1; R 2 is hydrogen; C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR97## where R 11 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 2 is as defined above; and m is 1 or 2; m' is 1 or 2; m" is 1 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B, D, F, and G substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 11

A method of treating renin-associated hyperaldosteronism, comprising administering to a patient in need of such treatment, a therapeutically effective amount of a peptide of the formula: ##STR84## wherein: A is hydrogen; or ##STR85## where X is ##STR86## and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) n -- where Y is C 1-4 alkyl; hydrogen; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; n is 0 to 5; except that where X is --O--, only one of R a 1 and R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR87## where R 5 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl; aryl substituted with up to three member selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and; halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; D is ##STR88## where Z is --(CH 2 ) p -- and p is 1 or 2; or --S--; E is absent; or ##STR89## where R 6 is hydrogen; ##STR90## where R 9 is hydrogen, C 1-4 alkyl, hydroxy, or C 3-7 cycloalkyl; or --CH 2 R 10 , where R 10 is 4-imidazolyl, amino-C 2-4 alkyl, 2-, 3- or 4-pyridyl, or guanidyl-C 2-3 alkyl; F is absent; glycyl; sarcosyl; or ##STR91## where R 5 is as defined above; G is OR; NHR; N(R) 2 , where each R may be the same or different and is hydrogen; or C 1-4 alkyl; or, when E and/or F are absent, G may be (1) --Y--(CH 2 ) q --R 7 where Y is --NH-- or --O--; q is 0 to 5; and R 7 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or diC 1-4 alkylamino, and halo; amino; mono-, di- or tri-C 1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl-C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; ##STR92## where Y is as defined above; k is 0 or 1; k' is 0 or 1; k" is 1 to 4; k'" is 1 to 4; and R 7 and R a 7 may be the same or different and have the same meaning as R 7 above and R a 7 may additionally be ##STR93## where R 8 is hydrogen or C 1-3 alkyl; or ##STR94## where Y is as defined above; r is 0 or 1; and Z is ##STR95## where r' is 0 or 1; and R 8 is as defined above; or ##STR96## where r" is 0 or 1; R 2 is hydrogen; C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR97## where R 11 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 2 is as defined above; and m is 1 or 2; m' is 1 or 2; m" is 1 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B, D, F, and G substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof.

Claim 12

A method of determining the presence of renin-associated hypertension in a patient, comprising administering to such a patient, at a hypotensive dosage level as a single dose, a peptide of the formula: ##STR98## wherein: A is hydrogen; or ##STR99## where X 1 is ##STR100## and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) n -- where Y is C 1-4 alkyl; hydrogen; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; n is 0 to 5; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR101## where R 5 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl; aryl substituted with up to three member selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and; halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; D is ##STR102## where Z is --(CH 2 ) p -- and p is 1 or 2; or --S--; E is absent; or ##STR103## where R 6 is hydrogen; ##STR104## where R 9 is hydrogen, C 1-4 alkyl, hydroxy, or C 3-7 cycloalkyl; or --CH 2 R 10 , where R 10 is 4-imidazolyl, amino-C 2-4 alkyl, 2-, 3- or 4-pyridyl, or guanidyl-C 2-3 alkyl; F is absent; glycyl; sarcosyl; or ##STR105## where R 5 is as defined above; G is OR; NHR; N(R) 2 , where each R may be the same or different and is hydrogen; or C 1-4 alkyl; or, when E and/or F are absent, G may be (1) --Y--(CH 2 ) q --R 7 where Y is --NH-- or --O--; q is 0 to 5; and R 7 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or diC 1-4 alkylamino, and halo; amino; mono-, di- or tri-C 1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl-C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; ##STR106## where Y is as defined above; k is 0 or 1; k' is 0 or 1; k" is 1 to 4; k'" is 1 to 4; and R 7 and R a 7 may be the same or different and have the same meaning as R 7 above and R a 7 may additionally be ##STR107## where R 8 is hydrogen or C 1-3 alkyl; or ##STR108## where Y is as defined above; r is 0 or 1; and Z is ##STR109## where r' is 0 or 1; and R 8 is as defined above; or ##STR110## where r" is 0 or 1; R 2 is hydrogen; C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR111## where R 11 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 2 is as defined above; and m is 1 or 2; m' is 1 or 2; m" is 1 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B, D, F, and G substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof; followed by monitoring of said patient's blood pressure.

Claim 13

A method of determining the presence of renin-associated hypertension in a patient, comprising administering to such a patient, at a hypotensive dosage level as a single dose, a peptide of the formula: ##STR98## wherein: A is hydrogen; or ##STR99## where X 1 is ##STR100## and R a 1 and R b 1 may be the same or different and are hydrogen; Y--(CH 2 ) n -- where Y is C 1-4 alkyl; hydrogen; aryl; C 3-7 cycloalkyl; or C 3-7 cycloalkyl or aryl substituted with up to five members independently selected from the group consisting of C 1-8 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; n is 0 to 5; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent; glycyl; sarcosyl; or ##STR101## where R 5 is hydrogen; C 1-4 alkyl; hydroxy C 1-4 alkyl; aryl; aryl substituted with up to three member selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and; halo; indolyl; 4-imidazolyl; amino C 2-4 alkyl; guanidyl C 2-3 alkyl; or methylthiomethyl; D is ##STR102## where Z is --(CH 2 ) p -- and p is 1 or 2; or --S--; E is absent; or ##STR103## where R 6 is hydrogen; ##STR104## where R 9 is hydrogen, C 1-4 alkyl, hydroxy, or C 3-7 cycloalkyl; or --CH 2 R 10 , where R 10 is 4-imidazolyl, amino-C 2-4 alkyl, 2-, 3- or 4-pyridyl, or guanidyl-C 2-3 alkyl; F is absent; glycyl; sarcosyl; or ##STR105## where R 5 is as defined above; G is OR; NHR; N(R) 2 , where each R may be the same or different and is hydrogen; or C 1-4 alkyl; or, when E and/or F are absent, G may be (1) --Y--(CH 2 ) q --R 7 where Y is --NH-- or --O--; q is 0 to 5; and R 7 is hydrogen; hydroxy; C 1-4 alkyl; C 3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, mono- or diC 1-4 alkylamino, and halo; amino; mono-, di- or tri-C 1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C 1-6 alkyl, hydroxy, trifluoromethyl, C 1-4 alkoxy, halo, aryl, aryl-C 1-4 alkyl, amino, and mono- or di-C 1-4 alkylamino; ##STR106## where Y is as defined above; k is 0 or 1; k' is 0 or 1; k" is 1 to 4; k'" is 1 to 4; and R 7 and R a 7 may be the same or different and have the same meaning as R 7 above and R a 7 may additionally be ##STR107## where R 8 is hydrogen or C 1-3 alkyl; or ##STR108## where Y is as defined above; r is 0 or 1; and Z is ##STR109## where r' is 0 or 1; and R 8 is as defined above; or ##STR110## where r" is 0 or 1; R 2 is hydrogen; C 1-4 alkyl; aryl; aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; or indolyl; R 3 is C 3-6 alkyl; C 3-7 cycloalkyl; aryl; or C 3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C 1-4 alkyl, trifluoromethyl, hydroxy, C 1-4 alkoxy, and halo; R 4 is hydrogen; or ##STR111## where R 11 is hydrogen; C 1-4 alkyl; hydroxy; or C 3-7 cycloalkyl; and R 2 is as defined above; and m is 1 or 2; m' is 1 or 2; m" is 1 to 4; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B, D, F, and G substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof; followed by monitoring of said patient's blood pressure.