US 5,514,696 A · Phenyl sulfonamide endothelin antagonists

Abstract

Compounds of the formula ##STR1## inhibit the activity of endothelin. The symbols are defined as follows: R.sup.1, R.sup.2 and R.sup.3 are each independently (a) hydrogen, except that R.sup.1 is other than hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3 ; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) --C(O)H or --C(O)R.sup.6 ; (h) --CO.sub.2 H or --CO.sub.2 R.sup.6 ; (i) --SH, --S(O).sub.n R.sup.6, --S(O).sub.m --OH, --S(O).sub.m --OR.sup.6, --O--S(O).sub.m --R.sup.6, --O--S(O).sub.m OH or --O--S(O).sub.m --OR.sup.6 ; (j) --Z.sup.4 --NR.sup.7 R.sup.8 ; or (k) --Z.sup.4 --N(R.sup.11 --Z.sup.5 --NR.sup.9 R.sup.10 ; and the remaining symbols are as defined in the specification.

A compound of the formula ##STR8## wherein:

one of X and Y is N and the other is O;
R.sup.1, R.sup.2 and R.sup.3 are each independently
(a) hydrogen, except that R.sup.1 is other than hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, naphthyl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3 ;
(c) halo;
(d) hydroxyl;
(e) cyano;
(f) nitro;
(g) --C(O)H or --C(O)R.sup.6 ;
(h) --CO.sub.2 H or --CO.sub.2 R.sup.6 ;
(i) --SH, --S(O).sub.n R.sup.6, --S(O).sub.m --OH, --S(O).sub.m --OR.sup.6, --O--S(O).sub.m --R.sup.6, --O--S(O).sub.m OH or --O--S(O).sub.m --OR.sup.6 ;
(j) --Z.sup.4 --NR.sup.7 R.sup.8 ;
or
(k) --Z.sup.4 --N(R.sup.11)--Z.sup.5 --NR.sup.9 R.sup.10 ;
R.sup.4 and R.sup.5 are each independently
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3 ;
(c) halo;
(d) hydroxyl;
(e) cyano;
(f) nitro;
(g) --C(O)H or --C(O)R.sup.6 --;
(h) --CO.sub.2 H or --CO.sub.2 R.sup.6 ;
(i) --SH, --S(O).sub.n R.sup.6, --S(O).sub.m --OH, --S(O).sub.m --OR.sup.6, --O--S(O).sub.m --R.sup.6, --O--S(O).sub.m OH or --O--S(O).sub.m --OR.sup.6 ;
(j) --Z.sup.4 --NR.sup.7 R.sup.8 ;
or
(k) --Z.sup.4 --N(R.sup.11)--Z.sup.5 --NR.sup.9 R.sup.10 ;
or
(l) R.sup.4 and R.sup.5 together are alkylene or alkenylene, either of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached;
R.sup.6 is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl any of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3 ;
R.sup.7 is
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3 ;
(c) cyano;
(d) hydroxyl;
(e) --C(O)H or --C(O)R.sup.6 ;
(f) --CO.sub.2 R.sup.6 ;
or
(g) --SH, --S(O).sub.n R.sup.6, --S(O).sub.m --OH, --S(O).sub.m --OR.sup.6, --O--S(O).sub.m --R.sup.6, --O--S(O).sub.m OH or --O--S(O).sub.m --OR.sup.6, except when Z.sup.4 is --S(O).sub.n --;
R.sup.8 is
(a) hydrogen;
(b) --C(O)H or --C(O)R.sup.6, except when Z.sup.4 is --C(O)-- and R.sup.7 is --C(O)H, --C(O)R.sup.6 or --CO.sub.2 R.sup.6 ;
or
(c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3 ;
or
R.sup.7 and R.sup.8 together are alkylene or alkenylene, either of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3, completing a 3- to 8-membered saturated, unsaturated or aromatic ting together with the nitrogen atom to which they are attached;
R.sup.9 is
(a) hydrogen;
(b) hydroxyl;
(c) --C(O)H or --C(O)R.sup.6 ;
(d) --CO.sub.2 R.sup.6 ;
(e) --SH, --S(O).sub.n R.sup.6, --S(O).sub.m --OH, --S(O).sub.m --OR.sup.6, --O--S(O).sub.m R.sup.6, --O--S(O).sub.m OH or --O--S(O).sub.m --OR.sup.6 ;
or
(f) alkyl, alkenyl , alkynyl , alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3 ;
R.sup.10 is
(a) hydrogen;
(b) --C(O)H or --C(O)R.sup.6, except when Z.sup.5 is --C(O)-- and R.sup.9 is --C(O)H, --C(O)R.sup.6 or --CO.sub.2 R.sup.6 ;
or
(c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3 ;
R.sup.11 is
(a) hydrogen;
(b) hydroxyl;
(c) --C(O)H, --C(O)R.sup.6 or CO.sub.2 R.sup.6 ;
or
(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3 ;
or any two of R.sup.9, R.sup.10 and R.sup.11 together are alkylene or alkenylene, either of which my be substituted with Z.sup.1, Z.sup.2 and Z.sup.3, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;
Z.sup.1, Z.sup.2 and Z.sup.3 ere each independently
(a) hydrogen;
(b) halo;
(c) hydroxy;
(d) alkyl;
(e) alkenyl;
(f) aralkyl;
(g) alkoxy;
(h) aryloxy;
(i) aralkoxy;
(j) --SH, --S(O).sub.n Z.sup.6, --S(O).sub.m --OH, --S(O).sub.m --OZ.sup.6, --O--S(O).sub.m --Z.sup.6, --O--S(O).sub.m OH or --O--S(O).sub.m --OZ.sup.6 ;
(k) oxo;
(l) nitro;
(m) cyano;
(n) --C(O)H or --C(O)Z.sup.6 ;
(o) --CO.sub.2 H or --CO.sub.2 Z.sup.6 ;
(p) --Z.sup.4 --NZ.sup.7 Z.sup.8 ;
(q) --Z.sup.4 --N(Z.sup.11)--Z.sup.5 --Z.sup.6 ;
or
(r) --Z.sup.4 --N(Z.sup.11)--Z.sup.5 --NZ.sup.7 Z.sup.8 ;
Z.sup.4 and Z.sup.5 are each independently
(a) a single bond;
(b) --Z.sup.9 --S(O).sub.n --Z.sup.10 --;
(c) --Z.sup.9 --C(O)--Z.sup.10 --;
(d) --Z.sup.9 --C(S)--Z.sup.10 --;
(e) --Z.sup.9 --O--Z.sup.10 --;
(f) --Z.sup.9 --S--Z.sup.10 --;
or
(g) --Z.sup.9 --O--C(O)--Z.sup.10 --;
Z.sup.6, Z.sup.7 and Z.sup.8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, or Z.sup.7 and Z.sup.8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached;
Z.sup.9 and Z.sup.10 are each independently a single bond, alkylene, alkenylene or alkynylene;
Z.sup.11 is
(a) hydrogen;
(b) hydroxyl;
(c) --C(O)H, --C(O)Z.sup.6 or CO.sub.2 Z.sup.6 ;
or
(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl;
or any two of Z.sup.7, Z.sup.8 and Z.sup.11 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;
m is 1 or 2;
and
n is 0, 1, or 2,
other than N-(5-methyl-3-isoxazolyl)-2-amino-4-trifluoromethylbenzenesulfonamide;
N-(5-methyl-3-isoxazolyl)-4-amino-2-fluoro-benzene-sulfonamide;
and N-(3,4-dimethyl-5-isoxazolyl)-2-amino-4-trifluoromethyl-benzenesulfonamide .

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Phenyl sulfonamide endothelin antagonists

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Phenyl sulfonamide endothelin antagonists

Life of this patent

Abstract

Claims22