Back to results
US 6,673,824 B1Granted
Phenyl sulfonamide endothelin antagonists
AssigneeBristol-Myers Squibb Company
InventorsNatesan Murugesan, John T. Hunt, Philip D. Stein
Life of this patent
Estimating the term…
Abstract
Compounds of the formula inhibit the activity of endothelin. The symbols are defined as follows: R1, R2 and R3 are each independently (a) hydrogen, except that R1 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 Z1, Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) —C(O)H or —C(O)R6; (h) —CO2H or —CO2R6; (i) —SH, —S(O)nR6, —S(O)m—OH, —S(O)m—OR6, —O—S(O)m—R6, —O—S(O)mOH or —O—S(O)m—OR6; (j) —Z4—NR7R8; or (k) —Z4—N(R11)—Z5—NR9R10; and the remaining symbols are as defined in the specification.
Claims4
A pharmaceutical composition comprising at least one endothelin antagonist in combination with at least one additional therapeutic agent selected from ECE inhibitors, PAF antagonists, AII receptor antagonists, renin inhibitors, ACE inhibitors, NEP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, bile acid sequestrants, calcium channel blockers, potassium channel activators, beta-adrenergic agents, antiarrhythmic agents, diuretics, and thrombolytic agents wherein said endothelin antagonist is selected from compounds of formula I
- wherein:
- one of X and Y is N and the other is O;
- R1, R2 and R3 are each independently
- (a) hydrogen, except that R1 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 Z1, Z2 and Z3;
- (c) halo;
- (d) hydroxyl;
- (e) cyano;
- (f) nitro;
- (g) —C(O)H or —C(O)R6;
- (h) —CO2H or —CO2R6;
- (i) —SH, —S(O)nR6, —S(O)m—OH, —S(O)m—OR6, —O—S(O)m—R6, —O—S(O)mOH or —O—S(O)m—OR6;
- (j) —Z4—NR7R8;
- or
- (k) —Z4—N(R11)—Z5—NR9R10;
- wherein at least one of R1, R2 or R3 is phenyl or biphenyl which may be substituted with Z1, Z2 and Z3;
- R4 and R5 are each independently
- (a) hydogen;
- (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1, Z2 and Z3;
- (c) halo;
- (d) hydroxyl;
- (e) cyano;
- (f) nitro;
- (g) —C(O)H or —C(O)R6;
- (h) —CO2H or —CO2R6;
- (i) —SH, —S(O)nR6, —S(O)m—OH, —S(O)m—OR6, —O—S(O)m—R6, —O—S(O)mOH or —O—S(O)m—OR6;
- (j) —Z4—NR7R8;
- or
- (k) —Z4—N(R11)—Z5—NR9R10;
- or
- (l) R4 and R5 together are alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached;
- R6 is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkyalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
- R7 is
- (a) hydrogen;
- (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
- (c) cyano;
- (d) hydroxyl;
- (e) —C(O)H or —C(O)R6;
- (f) —CO2R6;
- or
- (g) —SH, —S(O)nR6, —S(O)m—OH, —S(O)m—OR6, —O—S(O)m—R6, —O—S(O)mOH or —O—S(O)m—OR6, except when Z4 is —S(O)n—;
- R8 is
- (a) hydrogen;
- (b) —C(O)H or —C(O)R6, except when Z4 is —C(O)— and R7 is —C(O)H, —C(O)R6 or —CO2R6;
- or
- (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
- or
- R7 and R8 together are alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached;
- R9 is
- (a) hydrogen;
- (b) hydroxyl;
- (c) —C(O)H or —C(O)R6;
- (d) —CO2R6;
- (e) —SH, —S(O)nR6, —S(O)m—OH, —S(O)m—OR6, —O—S(O)m—R6, —O—S(O)mOH or —O—S(O)m—OR6;
- or
- (f) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
- R10 is
- (a) hydrogen;
- (b) —C(O)H or —C(O)R6, except when Z5 is —C(O)— and R9 is —C(O)H, —C(O)R6 or —CO2R6;
- or
- (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
- R11 is
- (a) hydrogen;
- (b) hydroxyl;
- (c) —C(O)H, —C(O)R6 or CO2R6;
- or
- (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
- or any two of R9, R10 and R11 together are alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;
- Z1, Z2 and Z3 are each independently
- (a) hydrogen;
- (b) halo;
- (c) hydroxy;
- (d) alkyl;
- (e) alkenyl;
- (f) aralkyl;
- (g) alkoxy;
- (h) aryloxy;
- (i) aralkoxy;
- (j) —SH, —S(O)nZ6, —S(O)m—OH, —S(O)m—OZ6, —O—S(O)m—Z6, —O—S(O)mOH or —O—S(O)m—OZ6;
- (k) oxo;
- (l) nitro;
- (m) cyano;
- (n) —C(O)H or —C(O)Z6;
- (o) —CO2H or —CO2Z6;
- (p) —Z4—NZ7Z8;
- (q) —Z4—N(Z11)—Z5—Z6;
- or
- (r) —Z4—N(Z11)—Z5—NZ7Z8;
- Z4 and Z5 are each independently
- (a) a single bond;
- (b) —Z9—S(O)n—Z10—;
- (c) —Z9—C(O)—Z10—;
- (d) —Z9—C(S)—Z10—;
- (e) —Z9—O—Z10—;
- (f) —Z9—S—Z10—;
- or
- (g) —Z9—O—C(O)—Z10—;
- Z6, Z7 and Z8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, or Z7 and Z8 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;
- Z9 and Z10 are each independently a single bond, alkylene, alkenylene or alkynylene;
- Z11 is
- (a) hydrogen;
- (b) hydroxyl;
- (c) —C(O)H, —C(O)Z6 or —CO2Z6;
- or
- (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl;
- or any two of Z7, Z8 and Z11 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,
- or a pharmaceutically acceptable salt thereof.
107 more elements
A method of treating hypertension comprising administering to a patient in need thereof an effective amount of at least one endothelin antagonist in combination with an effective amount of at least one additional therapeutic agent selected from ECE inhibitors, PAP antagonists, angiotensin II receptor antagonists, renin inhibitors, ACE inhibitors, NEP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, bile acid sequestrants, calcium channel blockers, potassium channel activators, beta-adrenergic agents, antiarrhythmic agents, diuretics, and thrombolytic agents wherein said endothelin antagonist is selected from compounds of formula I
- wherein:
- one of X and Y is N and the other is O;
- R1, R2 and R3 are each independently
- (a) hydrogen, except that R1 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 Z1, Z2 and Z3;
- (c) halo;
- (d) hydroxyl;
- (e) cyano;
- (f) nitro;
- (g) —C(O)H or —C(O)R6;
- (h) —CO2H or —CO2R6;
- (i) —SH, —S(O)nR6, —S(O)m—OH, —S(O)m—OR6, —O—S(O)m—R6, —O—S(O)mOH or —O—S(O)m—OR6;
- (j) —Z4—NR7R8;
- or
- (k) —Z4—N(R11)—Z5—NR9R10;
- wherein at least one of R1, R2 or R3 is phenyl or biphenyl which may be substituted with Z1, Z2 and Z3;
- R4 and R5 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 Z1, Z2 and Z3;
- (c) halo;
- (d) hydroxyl;
- (e) cyano;
- (f) nitro;
- (g) —C(O)H or —C(O)R6;
- (h) —CO2H or —CO2R6;
- (i) —SH, —S(O)nR6, —S(O)m—OH, —S(O)m—OR6, —O—S(O)m—R6, —O—S(O)mOH or —O—S(O)m—OR6;
- (j) —Z4—NR7R8;
- or
- (k) —Z4—N(R11)—Z5—NR9R10;
- or
- R6 is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
- R7 is
- (a) hydrogen;
- (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
- (c) cyano;
- (d) hydroxyl;
- (e) —C(O)H or —C(O)R6;
- (f) —CO2R6;
- (g) —SH, —S(O)nR6, —S(O)m—OH, —S(O)m—OR6, —O—S(O)m—R6, —O—S(O)mOH or —O—S(O)m—OR6, except when Z4 is —S(O)n—;
- R8 is
- (a) hydrogen;
- (b) —C(O)H or —C(O)R6, except when Z4 is —C(O)— and R7 is —C(O)H, —C(O)R6 or —CO2R6;
- (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
- or
- R7 and R8 together are alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached;
- R9 is
- (a) hydrogen;
- (b) hydroxyl;
- (c) —C(O)H or —C(O)R6;
- (d) —CO2R6;
- (e) —SH, —S(O)nR6, —S(O)m—OH, —S(O)m—OR6, —O—S(O)mR6, —O—S(O)mOH or —O—S(O)m—OR6;
- (f) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
- R10 is
- (a) hydrogen;
- (b) —C(O)H or —C(O)R6, except when Z5 is —C(O)— and R9 is —C(O)H, —C(O)R6 or —CO2R6;
- or
- (c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
- R11 is
- (a) hydrogen;
- (b) hydroxyl;
- (c) —C(O)H, —C(O)R6 or CO2R6;
- or
- (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
- or any two of R9, R10 and R11 together are alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;
- Z1, Z2 and Z3 are each independently
- (a) hydrogen;
- (b) halo;
- (c) hydroxy;
- (d) alkyl;
- (e) alkenyl;
- (f) aralkyl;
- (g) alkoxy;
- (h) aryloxy;
- (i) aralkoxy;
- (j) —SH, —S(O)nZ6, —S(O)m—OH, —S(O)m—OZ6, —O—S(O)m—Z6, —O—S(O)mOH or —O—S(O)m—OZ6;
- (k) oxo;
- (l) nitro;
- (m) cyano;
- (n) —C(O)H or —C(O)Z6;
- (o) —CO2H or —CO2Z6;
- (p) —Z4—NZ7Z8;
- (q) —Z4—N(Z11)—Z5—Z6;
- or
- (r) —Z4—N(Z11)—Z5—NZ7Z8;
- Z4 and Z5 are each independently
- (a) a single bond;
- (b) —Z9—S(O)n—Z10—;
- (c) —Z9—C(O)—Z10—;
- (d) —Z9—C(S)—Z10—;
- (e) —Z9—O—Z10—;
- (f) —Z9—S—Z10—;
- or
- (g) —Z9—O—C(O)—Z10—;
- Z6, Z7 and Z8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, or Z7 and Z8 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;
- Z9 and Z10 are each independently a single bond, alkylene, alkenylene or alkynylene;
- Z11 is
- (a) hydrogen;
- (b) hydroxyl;
- (c) —C(O)H, —C(O)Z6 or —CO2Z6;
- or
- (d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl;
- or any two of Z7, Z8 and Z11 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,
- or a pharmaceutically acceptable salt thereof.
103 more elements
Dependencies are inferred from the claim text.