US 6,271,248 B1Granted

Substituted biphenysulfonamide endothelin antagonists

AssigneeBristol-Myers Squibb Company

InventorsNatesan Murugesan, Joel C. Barrish, John Lloyd

Life of this patent

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Abstract

Compounds of the formula wherein X, Y, R1, R2, R3, R4 and R5 are as described herein, inhibit the activity of endothelin.

Claims25

Dependent claims

A compound of the formula

an enantiomer, diastereomer or pharmaceutically acceptable salt thereof,
wherein:
one of X and Y is N and the other is O;
R1 is
R2 and R3 are each independently
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be independently substituted with one or more of Zl, 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;
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 independently substituted with one or more of Zl, 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;
(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, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be independently substituted with one or more of Z1, Z2 and Z3;
R7, R8, R9, R10 and R11 are each independently
(a) hydrogen;
or
(b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be independently substituted with one or more of Zl, Z2 and Z3;
R7 and R8 together may be alkylene or alkenylene, either of which may be independently substituted with one or more of Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;
any two of R9, R10 and R11 together may be alkylene or alkenylene, either of which may be independently substituted with one or more of Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
G1 is
(a) hydrogen;
or
(b) alkyl;
G2 is
—(CH2)m-NR12R13 where R12 and R13 together are alkylene which may be independently substituted with one or more of Z1, Z2 and Z3, completing a 3- to 8-membered saturated ring together with the nitrogen atom to which they are attached, or, together with the nitrogen atom to which they are attached form
R14 is lower alkyl substituted with 1, 2 or 3 halogen atoms;
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—H;
(r) —Z4—N(Z11)—Z5—Z6;
or
(s) —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—;
(g) —Z9—O—C(O)—Z10—;
or
(h) —Z9—C(O)—O—Z10—;
Z6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl;
Z7 and Z8 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated 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;
or
(b) alkyl, 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 or unsaturated ring together with the atoms to which they are attached;
each m is independently 1 or 2;
and
each n is independently 0, 1, or 2.

84 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/488,506Filed 20 Jan 2000 · division
Priority: 11 Oct 1995
Granted: 7 Aug 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 413/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 3/08
Drugs for disorders of the metabolism: for glucose homeostasis
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

Application60/007,032Us provisional application · filed 11 Oct 1995
Application08/728,238Parent of this division · filed 8 Oct 1996
US 6,080,774 AParent of this division
US 6,271,248 B1This patent

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

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A compound of the formula

an enantiomer, diastereomer or pharmaceutically acceptable salt thereof,
wherein:
one of X and Y is N and the other is O;
R1 is
R2 and R3 are each independently
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be independently substituted with one or more of Zl, 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;
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 independently substituted with one or more of Zl, 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;
(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, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be independently substituted with one or more of Z1, Z2 and Z3;
R7, R8, R9, R10 and R11 are each independently
(a) hydrogen;
or
(b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be independently substituted with one or more of Zl, Z2 and Z3;
R7 and R8 together may be alkylene or alkenylene, either of which may be independently substituted with one or more of Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;
any two of R9, R10 and R11 together may be alkylene or alkenylene, either of which may be independently substituted with one or more of Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
G1 is
(a) hydrogen;
or
(b) alkyl;
G2 is
—(CH2)m-NR12R13 where R12 and R13 together are alkylene which may be independently substituted with one or more of Z1, Z2 and Z3, completing a 3- to 8-membered saturated ring together with the nitrogen atom to which they are attached, or, together with the nitrogen atom to which they are attached form
R14 is lower alkyl substituted with 1, 2 or 3 halogen atoms;
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—H;
(r) —Z4—N(Z11)—Z5—Z6;
or
(s) —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—;
(g) —Z9—O—C(O)—Z10—;
or
(h) —Z9—C(O)—O—Z10—;
Z6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl;
Z7 and Z8 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated 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;
or
(b) alkyl, 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 or unsaturated ring together with the atoms to which they are attached;
each m is independently 1 or 2;
and
each n is independently 0, 1, or 2.

84 more elements

Facts

Application

09/488,506Filed 20 Jan 2000 · division

Priority

11 Oct 1995

Granted

7 Aug 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 413/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 3/08
Drugs for disorders of the metabolism: for glucose homeostasis
A61P 9/00
Drugs for disorders of the cardiovascular system