US 5,965,732 AGranted

Sulfonamide endothelin antagonists

AssigneeBristol-Myers Squibb Company

InventorJohn T. Hunt

Life of this patent

Estimating the term…

Abstract

Compounds of the formula ##STR1## inhibit endothelin, wherein: R is phenyl, naphthyl or biphenyl, each of which may be substituted.

Claims14

Dependent claims

A compound of the formula ##STR11## or a pharmaceutically acceptable salt thereof, wherein:

R is naphthyl or biphenyl, each of which may be substituted with R.sup.1, R.sup.2 and R.sup.3 ;
R.sup.1, R.sup.2 and R.sup.3 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(C).sub.m --OH, --S(O).sub.m --OR.sup.6, --O--S(O).sub.m --R.sup.6, --OS(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, R.sup.5 and R.sup.12 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 ;
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 --OR.sup.6, --O--S(O).sub.m --R.sup.6 or --O--S(O).sub.m --OR.sup.6, except in the group --Z.sup.4 --NR.sup.7 R.sup.8 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 in the group --Z.sup.4 --NR.sup.7 R.sup.8 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 ;
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 --OR.sup.6, --O--S(O).sub.m --R.sup.6 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 or --CO.sub.2 R.sup.6, except when one of R.sup.9 and R.sup.10 is hydroxyl or --CO.sub.2 R.sup.6 ;
(c) --C(O)H or --C(O)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 ;
Z.sup.1, Z.sup.2 and Z.sup.3 are each independently
(a) hydrogen;
(b) halo;
(c) hydroxy;
(d) alkyl, alkenyl, aralkyl, alkoxy, aryloxy or aralkoxy;
(e) --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 ;
(f) oxo;
(g) nitro;
(h) cyano;
(i) --C(O)H or --C(O)Z.sup.6 ;
(j) --CO.sub.2 H or --CO.sub.2 Z.sup.6 ;
or
(k) --Z.sup.4 --NZ.sup.7 Z.sup.8, --Z.sup.4 --N(Z.sup.11)--Z.sup.5 Z.sup.6 or --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) m--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 ;
(g) --Z.sup.9 --O--C(O)--Z.sup.10 ;
or
(h) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3 ;
Z.sup.6, Z.sup.7 and Z.sup.8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl;
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, provided that when Z.sup.11 is --CO.sub.2 Z.sup.6, Z.sup.6 is other than hydrogen;
or
(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl;
m is 1 or 2;
and
n is 0, 1 or 2.

92 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/114,251Filed 30 Aug 1993
Granted: 12 Oct 1999
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 237/20
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives

Family

No related US applications are recorded in the indexed filing history.

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A compound of the formula ##STR11## or a pharmaceutically acceptable salt thereof, wherein:

R is naphthyl or biphenyl, each of which may be substituted with R.sup.1, R.sup.2 and R.sup.3 ;
R.sup.1, R.sup.2 and R.sup.3 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(C).sub.m --OH, --S(O).sub.m --OR.sup.6, --O--S(O).sub.m --R.sup.6, --OS(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, R.sup.5 and R.sup.12 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 ;
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 --OR.sup.6, --O--S(O).sub.m --R.sup.6 or --O--S(O).sub.m --OR.sup.6, except in the group --Z.sup.4 --NR.sup.7 R.sup.8 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 in the group --Z.sup.4 --NR.sup.7 R.sup.8 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 ;
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 --OR.sup.6, --O--S(O).sub.m --R.sup.6 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 or --CO.sub.2 R.sup.6, except when one of R.sup.9 and R.sup.10 is hydroxyl or --CO.sub.2 R.sup.6 ;
(c) --C(O)H or --C(O)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 ;
Z.sup.1, Z.sup.2 and Z.sup.3 are each independently
(a) hydrogen;
(b) halo;
(c) hydroxy;
(d) alkyl, alkenyl, aralkyl, alkoxy, aryloxy or aralkoxy;
(e) --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 ;
(f) oxo;
(g) nitro;
(h) cyano;
(i) --C(O)H or --C(O)Z.sup.6 ;
(j) --CO.sub.2 H or --CO.sub.2 Z.sup.6 ;
or
(k) --Z.sup.4 --NZ.sup.7 Z.sup.8, --Z.sup.4 --N(Z.sup.11)--Z.sup.5 Z.sup.6 or --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) m--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 ;
(g) --Z.sup.9 --O--C(O)--Z.sup.10 ;
or
(h) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3 ;
Z.sup.6, Z.sup.7 and Z.sup.8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, or aralkyl;
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, provided that when Z.sup.11 is --CO.sub.2 Z.sup.6, Z.sup.6 is other than hydrogen;
or
(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl;
m is 1 or 2;
and
n is 0, 1 or 2.

92 more elements

Facts

Application

08/114,251Filed 30 Aug 1993

Granted

12 Oct 1999

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 237/20
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives