US 4,668,770 AGranted

Renin inhibitory tripeptides

AssigneeMerck & Co., Inc.

InventorsJoshua S. Boger, Daniel F. Veber, Ben E. Evans

Life of this patent

Estimating the term…

Abstract

Renin inhibitory peptides of the formula ##STR1## and analogs thereof inhibit renin and are useful for treating various forms of renin-associated hypertension and hyperaldosteronism.

Claims3

Dependent claims

A peptide of the formula:

##STR38## wherein:
A is hydrogen;
or ##STR39## where X is --O--;
##STR40## and R.sub.a.sup.2 and R.sub.b.sup.2 may be the same or different and are hydrogen;
Y--(CH.sub.2).sub.n -- or Y--(CH.sub.2).sub.m --CH.dbd.CH--(CH.sub.2).sub.p, where Y is hydrogen;
aryl;
aryl substituted with up to five members independently selected from the group consisting of C.sub.1-8 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
n is 0 to 5;
m is 0 to 2;
and p is 0 to 2;
except that where X is --O--, only one of R.sub.a.sup.2 or R.sub.b.sup.2 is present;
R.sup.1 is hydrogen;
C.sub.1-4 alkyl, provided, that where R.sup.1 is i-propyl, and B is Phe or Tyr, A is other than hydrogen or phenoxyacetyl;
hydroxy C.sub.1-4 alkyl;
aryl;
aryl substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy;
fluorom, chloro, bromo, and iodo;
indolyl;
4-imidazolyl;
amine C.sub.2-4 alkyl;
guanidyl C.sub.2-3 alkyl;
or methylthiomethyl;
R.sup.3 is C.sub.3-6 alkyl;
C.sub.3-7 cycloalkyl;
aryl;
or C.sub.3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, fluoro, chloro, bromo, and iodo;
R.sup.4 is hydrogen;
or ##STR41## where R.sup.2 is hydrogen;
C.sub.1-4 alkyl;
aryl;
aryl C.sub.1-4 alkyl;
or aryl C.sub.1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, fluoro, chloro, bromo, and iodo;
or indolyl;
R.sup.5 is hydrogen;
C.sub.1-4 alkyl;
hydroxy;
or C.sub.3-7 cycloalkyl;
and
B is
(1) --Y--(CH.sub.2).sub.n --R.sup.6
where
Y is --NH-- or --O--;
n is 0 to 5;
and
R.sup.6 is hydrogen;
hydroxy;
C.sub.1-4 alkyl;
C.sub.3-7 cycloalkyl;
aryl;
aryl substituted with up to five members independently selected from the group consisting of C.sub.1-6 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, amino, mono- or di-C.sub.1-4 alkylamino, and halo;
amino;
mono-, di-, or tri-C.sub.1-4 alkylamino;
quanidyl;
pyridyl;
(2) ##STR42## where Y is as defined above;
n is 0 or 1;
k is 0 or 1;
l is 1 to 4;
m is 1 to 4;
and
R.sup.6 and R.sub.a.sup.6 may be the same or different and have the same meaning as R.sup.6 above and R.sub.a.sup.6 may additionally be ##STR43## where R.sup.7 is hydrogen or C.sub.1-3 alkyl;
(3) ##STR44## where Y is as defined above;
n is 0 or 1;
and
Z is
(a) ##STR45## where n is 0 or 1;
and
R.sup.7 is as defined above;
or
(b) ##STR46## where n is 0 or 1;
or ##STR47## D is absent;
glycyl, sarcosyl;
or ##STR48## and E is absent;
OR;
NHR;
or N(R).sub.2, where R may be the same or different and is hydrogen or C.sub.1-4 alkyl;
and
q is 1 to 4;
wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B and D substituents, which may have an S or R configuration;
and a pharmaceutically acceptable salt thereof.

77 more elements

Dependencies are inferred from the claim text.

Facts

Application: 06/608,321Filed 8 May 1984 · continuation in part
Priority: 27 Dec 1982
Granted: 26 May 1987
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07K 5/0227
Containing at least one abnormal peptide link: containing the peptide sequence -Phe-His-NH-2-C-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6…
Y10S 530/86
Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof: renin inhibitors
C07K
Peptides
Y10S
Technical subjects covered by former uspc cross-reference art collections [xracs] and digests

Family

Serial453,250Parent of this continuation-in-part · filed 27 Dec 1982
US 4,668,770 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Renin inhibitory peptides of the formula ##STR1## and analogs thereof inhibit renin and are useful for treating various forms of renin-associated hypertension and hyperaldosteronism.

A peptide of the formula:

##STR38## wherein:
A is hydrogen;
or ##STR39## where X is --O--;
##STR40## and R.sub.a.sup.2 and R.sub.b.sup.2 may be the same or different and are hydrogen;
Y--(CH.sub.2).sub.n -- or Y--(CH.sub.2).sub.m --CH.dbd.CH--(CH.sub.2).sub.p, where Y is hydrogen;
aryl;
aryl substituted with up to five members independently selected from the group consisting of C.sub.1-8 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, and halo;
n is 0 to 5;
m is 0 to 2;
and p is 0 to 2;
except that where X is --O--, only one of R.sub.a.sup.2 or R.sub.b.sup.2 is present;
R.sup.1 is hydrogen;
C.sub.1-4 alkyl, provided, that where R.sup.1 is i-propyl, and B is Phe or Tyr, A is other than hydrogen or phenoxyacetyl;
hydroxy C.sub.1-4 alkyl;
aryl;
aryl substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy;
fluorom, chloro, bromo, and iodo;
indolyl;
4-imidazolyl;
amine C.sub.2-4 alkyl;
guanidyl C.sub.2-3 alkyl;
or methylthiomethyl;
R.sup.3 is C.sub.3-6 alkyl;
C.sub.3-7 cycloalkyl;
aryl;
or C.sub.3-7 cycloalkyl or aryl substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, fluoro, chloro, bromo, and iodo;
R.sup.4 is hydrogen;
or ##STR41## where R.sup.2 is hydrogen;
C.sub.1-4 alkyl;
aryl;
aryl C.sub.1-4 alkyl;
or aryl C.sub.1-4 alkyl or aryl where the aryl portion is substituted with up to three members selected from the group consisting of C.sub.1-4 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, fluoro, chloro, bromo, and iodo;
or indolyl;
R.sup.5 is hydrogen;
C.sub.1-4 alkyl;
hydroxy;
or C.sub.3-7 cycloalkyl;
and
B is
(1) --Y--(CH.sub.2).sub.n --R.sup.6
where
Y is --NH-- or --O--;
n is 0 to 5;
and
R.sup.6 is hydrogen;
hydroxy;
C.sub.1-4 alkyl;
C.sub.3-7 cycloalkyl;
aryl;
aryl substituted with up to five members independently selected from the group consisting of C.sub.1-6 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, amino, mono- or di-C.sub.1-4 alkylamino, and halo;
amino;
mono-, di-, or tri-C.sub.1-4 alkylamino;
quanidyl;
pyridyl;
(2) ##STR42## where Y is as defined above;
n is 0 or 1;
k is 0 or 1;
l is 1 to 4;
m is 1 to 4;
and
R.sup.6 and R.sub.a.sup.6 may be the same or different and have the same meaning as R.sup.6 above and R.sub.a.sup.6 may additionally be ##STR43## where R.sup.7 is hydrogen or C.sub.1-3 alkyl;
(3) ##STR44## where Y is as defined above;
n is 0 or 1;
and
Z is
(a) ##STR45## where n is 0 or 1;
and
R.sup.7 is as defined above;
or
(b) ##STR46## where n is 0 or 1;
or ##STR47## D is absent;
glycyl, sarcosyl;
or ##STR48## and E is absent;
OR;
NHR;
or N(R).sub.2, where R may be the same or different and is hydrogen or C.sub.1-4 alkyl;
and
q is 1 to 4;
wherein all of the asymmetric carbon atoms have an S configuration, except for those in the A, B and D substituents, which may have an S or R configuration;
and a pharmaceutically acceptable salt thereof.

77 more elements

Facts

Application

06/608,321Filed 8 May 1984 · continuation in part

Priority

27 Dec 1982

Granted

26 May 1987

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07K 5/0227
Containing at least one abnormal peptide link: containing the peptide sequence -Phe-His-NH-2-C-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6…
Y10S 530/86
Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof: renin inhibitors
C07K
Peptides
Y10S
Technical subjects covered by former uspc cross-reference art collections [xracs] and digests