US 5,430,022 A · Peptide compound and its preparation

Abstract

Peptide compounds of the formula (I') ##STR1## in which R.sup.1 is acyl, R.sup.2 is lower alkyl, cyclo(lower)alkyl(lower)alkyl or optionally substituted heterocyclic(lower)alkyl, R.sup.3 is optionally substituted heterocyclic(lower)alkyl or optionally substituted ar(lower)alkyl, R.sup.4 is lower alkyl, amino(lower)alkyl, protected amino(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl or optionally substituted heterocyclic(lower)alkyl, R.sup.5 is carboxy, protected carboxy, carboxy(lower)alkyl or protected carboxy(lower)alkyl, R.sup.6 is hydrogen, lower alkyl, C.sub.6-10 ar(lower)alkyl amino(lower)alkyl, protected amino(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, or heterocyclic(lower)alkyl, R.sup.7 is hydrogen or lower alkyl, and A is --O--, --NH--, lower alkylimino or lower alkylene, or a pharmaceutically acceptable salt thereof are disclosed. The compounds can be used to treat and prevent endothelin mediated diseases such as hypertension. The preparation of such peptides is also disclosed.

Claims12

Dependent claims

A peptide compound having the formula (I') ##STR10## or a pharmaceutically acceptable salt thereof in which R.sup.1 is acyl,

R.sup.2 is lower alkyl, cyclo(lower)alkyl(lower)alkyl or optionally substituted heterocyclic(lower)alkyl,
R.sup.3 is optionally substituted heterocyclic(lower)alkyl or optionally substituted ar(lower)alkyl,
R.sup.4 is lower alkyl, amino(lower)alkyl, protected amino(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl or optionally substituted heterocyclic(lower)alkyl,
R.sup.5 is carboxy, protected carboxy, carboxy(lower)alkyl or protected carboxy(lower)alkyl,
R.sup.6 is hydrogen, lower alkyl, C.sub.6-10 ar(lower)alkyl amino(lower)alkyl, protected amino(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, or heterocyclic(lower)alkyl,
R.sup.7 is hydrogen or lower alkyl, and
A is --O--, --NH--, lower alkylimino or lower alkylene.

4 more elements

A process for the preparation of a peptide compound having the formula (I') ##STR11## or a pharmaceutically acceptable salt thereof in which R.sup.2 is acyl,

R.sup.2 is lower alkyl, cyclo(lower)alkyl(lower)alkyl or optionally substituted heterocyclic(lower)alkyl,
R.sup.3 is optionally substituted heterocyclic(lower)alkyl or optionally substituted ar(lower)alkyl,
R.sup.4 is lower alkyl, amino(lower)alkyl, protected amino(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl or optionally substituted heterocyclic(lower)alkyl,
R.sup.5 is carboxy, protected carboxy, carboxy(lower)alkyl or protected carboxy(lower)alkyl,
R.sup.6 is hydrogen, lower alkyl, C.sub.6-10 ar(lower)alkyl amino(lower)alkyl, protected amino(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, or heterocyclic(lower)alkyl,
R.sup.7 is hydrogen or lower alkyl, and
A is --O--, --NH--, lower alkylimino or lower alkylene, which comprises
(a) reacting a compound of the formula:
##STR12## wherein R.sup.1, R.sup.2 and A are each as defined above or its reactive derivative at the carboxy group or a salt thereof, with a compound of the formula:
##STR13## wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each as defined above, or its reactive derivative at the amino group, or a salt thereof, to give a compound of the formula:
##STR14## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, or a salt thereof;
or
(b) reacting a compound of the formula:
##STR15## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, or its reactive derivative at the amino group, or a salt thereof, with a compound of the formula:
R.sub.C.sup.1 --OH (IV)
wherein R.sub.C.sup.1 is acyl, or its reactive derivative at the carboxy group, or a salt thereof, to give a compound of the formula:
##STR16## wherein R.sub.C.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above or a salt thereof;
or
(c) reacting a compound of the formula:
##STR17## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.7 and A are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof, with a compound of the formula:
##STR18## wherein R.sup.4, R.sup.5 and R.sup.6 are each as defined above, or its reactive derivative at the amino group, or a salt thereof, to give a compound of the formula:
##STR19## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above or a salt thereof;
or
(d) subjecting a compound of the formula:
##STR20## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.a.sup.5 is protected carboxy or protected carboxy(lower)alkyl, or a salt thereof, to a removal reaction of the carboxy-protective group to give a compound of the formula:
##STR21## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7 and A are as defined above, and R.sub.b.sup.5 is carboxy or carboxy(lower)alkyl,
(e) subjecting a compound of the formula:
##STR22## in which R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.a.sup.2 is protected imino containing heterocyclic(lower)alkyl optionally substituted by suitable substituent(s), or a salt thereof, to removal reaction of the imino-protective group in R.sub.a.sup.2 to give a compound of the formula:
##STR23## in which R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.b.sup.2 is imino containing heterocyclic(lower)alkyl optionally substituted by suitable substituent(s), or a salt thereof;
or
(f) subjecting a compound of the formula:
##STR24## in which R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.a.sup.1 is acyl substituted by a protected amino group, or a salt thereof, to removal reaction of the amino-protective group to give a compound of the formula:
##STR25## in which R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.b.sup.1 is acyl substituted by an amino group, or a salt thereof;
or
(g) reacting a compound of the formula:
##STR26## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.c.sup.5 is esterified carboxy, or its reactive derivative at the carboxy group, or a salt thereof, with an optionally substituted amine, or a salt thereof to give a compound of the formula:
##STR27## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.d.sup.5 is amidated carboxy, or a salt thereof, or
(h) acylating the amino group in R.sub.b.sup.1 of a compound of the formula:
##STR28## in which R.sup.1.sub.b, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, or a salt thereof, to give a compound of the formula:
##STR29## in which R.sub.a.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, or a salt thereof;
or
(i) subjecting a compound of the formula:
##STR30## in which R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.c.sup.4 is protected carboxy(lower)alkyl, or a salt thereof, to a removal reaction of the carboxy-protective group in R.sup.4.sub.c to give a compound of the formula:
##STR31## in which R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.d.sup.4 is carboxy(lower)alkyl, or a salt thereof,
(j) subjecting a compound of the formula:
##STR32## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.a.sup.3 is protected imino containing heterocyclic(lower)alkyl optionally substituted by suitable substituent(s), or a salt thereof, to a removal reaction of the imino-protective group in R.sub.a.sup.3 to give a compound of the formula:
##STR33## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.b.sup.3 is imino containing heterocyclic(lower)alkyl optionally substituted by suitable substituent(s),
(k) subjecting a compound of the formula:
##STR34## in which R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.a.sup.4 is protected amino(lower)alkyl or protected imino containing heterocyclic(lower)alkyl optionally substituted by suitable substituent(s), or a salt thereof, to removal reaction of the amino or imino-protective group in R.sub.a.sup.4 to give a compound of the formula:
##STR35## in which R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7 and A are each as defined above, and R.sub.b.sup.4 is amino(lower)alkyl or imino containing heterocyclic(lower)alkyl optionally substituted by suitable substituent(s), or a salt thereof.

47 more elements

Dependencies are inferred from the claim text.

Peptide compound and its preparation

Life of this patent

Peptide compound and its preparation

Life of this patent

Abstract

Claims12