Methods for the preparation of biphenyl isoxazole sulfonamides

Details Methods for the preparation of biphenyl isoxazole sulfonamides Methods for the preparation of biphenyl isoxazole sulfonamides

1998-08-27

2003-02-04

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06515136

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to 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.
BRIEF DESCRIPTION OF THE INVENTION
The present methods allow preparation of biphenyl sulfonamides 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, preferably pharmaceutically acceptable salts, thereof. Preferred substituent groups for the biphenyl group include those groups R
11
to R
14
described herein and especially, when the biphenyl group is a 2-biphenyl group, the group
in the 4′-position. Preferred methods of the present invention allow preparation of compounds of the following formula Ia:
enantiomers and diastereomers, and salts, preferably pharmaceutically acceptable salts, thereof. Throughout this specification, the above symbols are defined as follows:
one of X and Y is N and the other is O;
R
1
, R
2
, R
3
and R
4
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 aralkoxy, any of which may be substituted with Z
1
, Z
2
and Z
3
;
(c) halo;
(d) hydroxyl;
(e) cyano;
(f) nitro;
(g) —C(O)H or —C(O)R
5
;
(h) —CO
2
H or —CO
2
R
5
;
(i) —Z
4
—NR
6
R
7
;
(j) —Z
4
—N(R
10
)—Z
5
—NR
8
R
9
; or
(k) R
3
and R
4
together may also be alkylene or alkenylene, either of which may be substituted with Z
1
, Z
2
and Z
3
, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached;
R
5
is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z
1
, Z
2
and Z
3
;
R
6
, R
7
, R
8
, R
9
and R
10
are each independently
(a) hydrogen; or
(b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z
1
, Z
2
and Z
3
; or
R
6
and R
7
together may be alkylene or alkenylene, either of which may be substituted with Z
1
, Z
2
and Z
3
, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; or any two of R
8
, R
9
and R
10
together are alkylene or alkenylene, either of which may be substituted with Z
1
, Z
2
and Z
3
, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
R
11
, R
12
, R
13
and R
14
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
1
, Z
2
and Z
3
,
(c) heterocycle, substituted heterocycle or heterocyclooxy;
(d) halo;
(e) hydroxyl;
(f) cyano;
(g) nitro;
(h) —C(O)H or —C(O)R
5
;
(i) —CO
2
H or —CO
2
R
5
;
(j) —SH, —S(O)
n
R
5
, —S(O)
m
—OH, —S(O)
m
—OR
5
, —O—S(O)m—OR
5
, —O—S(O)
m
OH or —O—S(O)
m
—OR
5
;
(k) —Z
4
—NR
6
R
7
; or
(l) —Z
4
—N(R
10
)—Z
5
—NR
8
R
9
;
Z
1
, Z
2
and Z
3
are each independently
(a) hydrogen;
(b) halo;
(c) hydroxy;
(d) alkyl;
(e) alkenyl;
(f) aryl;
(g) aralkyl;
(h) alkoxy;
(i) aryloxy;
(j) aralkoxy;
(k) heterocycle, substituted heterocycle or heterocyclooxy;
(l) —SH, —S(O)
n
Z
6
, —S(O)
m
—OH, —S(O)
m
—OZ
6
, —O—S(O)
m
—Z
6
, —O—S(O)
m
OH or —O—S(O)
m
—OZ
6
;
(m) oxo;
(n) nitro;
(o) cyano;
(p) —C(O)H or —C(O)Z
6
;
(q) —CO
2
H or —CO
2
Z
6
;
(r) —Z
4
—NZ
7
Z
8
;
(s) —Z
4
—N(Z
11
)—Z
5
—H;
(t) —Z
4
—N(Z
11
)—Z
5
—Z
6
; or
(u) —Z
4
—N(Z
11
)—Z
5
—NZ
7
Z
8
;
Z
4
and Z
5
are each independently
(a) a single bond;
(b) —Z
9
—S(O)
n
—Z
10
—;
(c) —Z
9
—C(O)—Z
10
—;
(d) —Z
9
—C(s)—Z
10
—;
(e) —Z
9
—O—Z
10
—;
(f) —Z
9
—S—Z
10
—;
(g) —Z
9
—O—C(O)—Z
10
—; or
(h) —Z
9
—C(O)—O—Z
10
—;
Z
6
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;
Z
7
and Z
8
are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, or Z
7
and Z
8
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;
Z
9
and Z
10
are each independently a single bond, alkylene, alkenylene or alkynylene;
Z
11
is
(a) hydrogen; or
(b) alkyl, alkyl substituted with one, two or three halogens, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl;
or any two of Z
7
, Z
8
and Z
11
together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
J is O, S, N or NR
15
;
K and L are N or C, provided that at least one of K or L is C;
R
15
is hydrogen, alkyl, hydroxyethoxy methyl or methoxyethoxy methyl;
each m is independently 1 or 2;
each n is independently 0, 1 or 2; and
p is 0 or an integer from 1 to 2.
In accordance herewith, a compound of the formula I or salt thereof may be prepared by a method 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, such as with one or more groups described for the groups R
11
to R
14
herein, with a halophenyl compound of the formula III or salt thereof:
where the phenyl ring of said formula III may be further substituted, such as with one or more groups described for the groups R
11
to R
14
herein, and especially, when the biphenyl group of said compound of the formula I or salt thereof is a 2-biphenyl, the group
para to the halo group, in the presence of a palladium(0) catalyst and, preferably, a base, to form a nitrogen-protected 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.
“Prot”, as used in formula II and throughout this specification, denotes a nitrogen-protecting group, which may be any suitable nitrogen-protecting group such as 2-ethoxyethyl, 2-methoxypropyl, methoxyethoxymethyl or those described in European Patent Application Publication No. 569;193 (1993), incorporated herein by reference, and is preferably methoxyethoxymethyl (“MEM”). The halo group in formula III is preferably bromo or iodo, most preferably iodo.
In a preferred embodiment, a compound of the formula Ia or salt thereof may be prepared by a method comprising the steps of:
(a) contacting a pinacol ester of the formula IIa or salt thereof:
 with a halophenyl compound of the formula IIIa or salt thereof:
 in the presence of a palladium(0) catalyst and, preferably, a base, to form a nitrogen-protected compound of the formula IVa or salt thereof:
(b) deprotecting the nitrogen of said formula IVa compound or salt thereof to form said compound of the formula Ia or salt thereof.
The present methods for preparing a compound of the formula I or salt thereof are advantageous in that they provide high yields with minimal or no formation of impurities.
Further provided herewith are novel intermediates of the present methods, and novel methods for preparing such intermediates.
De

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