US 6,639,082 B2Granted

Methods for the preparation of biphenyl isoxazole sulfonamides

AssigneeBristol-Myers Squibb Company

InventorsRichard P. Polniaszek, Xuebao Wang, John K. Thottathil, Theodor Denzel

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Abstract

Methods for the preparation of biphenyl isoxazole sulfonamides and intermediates thereof. The present invention also relates to the novel intermediates prepared by these methods. The biphenyl isoxazole sulfonamides prepared by the present methods are endothelin antagonists useful, inter alia, for the treatment of hypertension.

Claims13

Dependent claims

A method for the preparation of a biphenyl sulfonamide of the following formula I

where the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups,
enantiomers and diastereomers, and salts thereof,
wherein
one of X and Y is N and the other is O;
R3 and R4 are each directly bonded to a ring carbon and are each independently
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aryloxy, 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)R5;
(h) —CO2H or —CO2R5;
(i) —Z4—NR6R7;
—Z4—N(R10)—Z5—NR8R9;
or
(k) R3 and R4 together may also be 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;
R5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
R6, R7, R8, R9 and R10 are each independently
(a) hydrogen;
or
(b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
or
R6 and R7 together may be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;
or any two of R8, R9 and R10 together are alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated 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) aryl;
(g) aralkyl;
(h) alkoxy;
(i) aryloxy;
(j) aryloxy;
(k) heterocycle, substituted heterocycle or heterocyclooxy;
(l) —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;
(m) oxo;
(n) nitro;
(o) cyano;
(p) —C(O)H or —C(O)Z6;
(q) —CO2H or —CO2Z6;
(r) —Z4—NZ7Z8;
(s) —Z4—N(Z11)—Z5—H;
(t) —Z4—N(Z11)—Z5—Z6;
or
(u) —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;
alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy;
alkenyl;
alkynyl;
cycloalkyl;
cycloalkyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkoxyaryl;
cycloalkyl to which is fused a benzene ring;
aryloxy substituted with one or two halogens;
cycloalkylalkyl;
cycloalkenyl;
cycloalkenylalkyl;
aryl;
aryl substituted with methylenedioxy or one to four groups selected from alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy and trihaloalkoxy;
or heterocycle or substituted heterocycle;
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, alkyl substituted with one, two or three halogens, cycloalkyl, cycloalkylalkyl, 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;
comprising the steps of
(a) contacting a pinacol ester of the formula II or salt thereof
where the phenyl ring of said formula II may be further substituted, and where “prot” denotes an alkoxymethyl nitrogen-protecting group,
with a compound of the formula III or salt thereof
where R16 is halogen or a group —O—Q where Q is —SO2CF3, —SO2CH3, or
and where the phenyl ring of said formula
III may be further substituted, in the presence of a palladium(0) catalyst and, optionally, a base, to form a compound of the formula IV or salt thereof
where the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups;
and
(b) deprotecting the nitrogen of said compound of the formula IV or salt thereof to form said compound of the formula I or salt thereof.

89 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/967,387Filed 28 Sep 2001 · us provisional application
Priority: 17 Oct 2000
Published: US 2002/0132838 A119 Sep 2002
Granted: 28 Oct 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 413/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives
C07D 261/16
Nitrogen atoms: benzene-sulfonamido isoxazoles
C07F 5/025
Boron compounds: boronic and borinic acid compounds

Family

Application60/240,902Us provisional application · filed 17 Oct 2000
US 2002/0132838 A1Pre-grant publication · published 19 Sep 2002
US 6,639,082 B2This patent

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

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Abstract

A method for the preparation of a biphenyl sulfonamide of the following formula I

where the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups,
enantiomers and diastereomers, and salts thereof,
wherein
one of X and Y is N and the other is O;
R3 and R4 are each directly bonded to a ring carbon and are each independently
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aryloxy, 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)R5;
(h) —CO2H or —CO2R5;
(i) —Z4—NR6R7;
—Z4—N(R10)—Z5—NR8R9;
or
(k) R3 and R4 together may also be 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;
R5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
R6, R7, R8, R9 and R10 are each independently
(a) hydrogen;
or
(b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
or
R6 and R7 together may be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached;
or any two of R8, R9 and R10 together are alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated 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) aryl;
(g) aralkyl;
(h) alkoxy;
(i) aryloxy;
(j) aryloxy;
(k) heterocycle, substituted heterocycle or heterocyclooxy;
(l) —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;
(m) oxo;
(n) nitro;
(o) cyano;
(p) —C(O)H or —C(O)Z6;
(q) —CO2H or —CO2Z6;
(r) —Z4—NZ7Z8;
(s) —Z4—N(Z11)—Z5—H;
(t) —Z4—N(Z11)—Z5—Z6;
or
(u) —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;
alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy;
alkenyl;
alkynyl;
cycloalkyl;
cycloalkyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkoxyaryl;
cycloalkyl to which is fused a benzene ring;
aryloxy substituted with one or two halogens;
cycloalkylalkyl;
cycloalkenyl;
cycloalkenylalkyl;
aryl;
aryl substituted with methylenedioxy or one to four groups selected from alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy and trihaloalkoxy;
or heterocycle or substituted heterocycle;
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, alkyl substituted with one, two or three halogens, cycloalkyl, cycloalkylalkyl, 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;
comprising the steps of
(a) contacting a pinacol ester of the formula II or salt thereof
where the phenyl ring of said formula II may be further substituted, and where “prot” denotes an alkoxymethyl nitrogen-protecting group,
with a compound of the formula III or salt thereof
where R16 is halogen or a group —O—Q where Q is —SO2CF3, —SO2CH3, or
and where the phenyl ring of said formula
III may be further substituted, in the presence of a palladium(0) catalyst and, optionally, a base, to form a compound of the formula IV or salt thereof
where the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups;
and
(b) deprotecting the nitrogen of said compound of the formula IV or salt thereof to form said compound of the formula I or salt thereof.

89 more elements

Facts

Application

09/967,387Filed 28 Sep 2001 · us provisional application

Priority

17 Oct 2000

Published

US 2002/0132838 A119 Sep 2002

Granted

28 Oct 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 413/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives
C07D 261/16
Nitrogen atoms: benzene-sulfonamido isoxazoles
C07F 5/025
Boron compounds: boronic and borinic acid compounds