Phenyl sulfonamide endothelin antagonists

Details Phenyl sulfonamide endothelin antagonists Phenyl sulfonamide endothelin antagonists

2000-04-19

2004-01-06

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S380000

Reexamination Certificate

active

06673824

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to endothelin antagonists useful, inter alia, for treatment of hypertension.
BRIEF DESCRIPTION OF THE INVENTION
Compounds of the formula
and pharmaceutically acceptable salts thereof are endothelin receptor antagonists useful, inter alia, as antihypertensive agents. 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
and R
3
are each independently
(a) hydrogen, except that R
1
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 Z
1
, Z
2
and Z
3
;
(c) halo;
(d) hydroxyl;
(e) cyano;
(f) nitro;
(g) —C(O)H or —C(O)R
6
;
(h) —CO
2
H or —CO
2
R
6
;
(i) —SH, —S(O)
n
R
6
, —S(O)
m
—OH, —S(O)
m
—OR
6
, —O—S(O)
m
—R
6
, —O—S(O)
m
OH or —O—S(O)
m
—OR
6
;
(j) —Z
4
—NR
7
R
8
; or
(k) —Z
4
—N(R
11
)—Z
5
—NR
9
R
10
;
R
4
and R
5
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
6
;
(h) —CO
2
H or —CO
2
R
6
;
(i) —SH, —S(O)
n
R
6
, —S(O)
m
—OH, —S(O)
m
—OR
6
; —O—S(O)
m
—R
6
, —O—S(O)
m
OH or —O—S(O)
m
—OR
6
;
(j) —Z
4
—NR
7
R
8
;
(k) —Z
4
—N(R
11
)—Z
5
—NR
9
R
10
; or
(l) R
4
and R
5
together are 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
6
is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z
1
, Z
2
and Z
3
;
R
7
is
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z
1
, Z
2
and Z
3
;
(c) cyano;
(d) hydroxyl;
(e) —C(O)H or —C(O)R
6
;
(f) —CO
2
R
6
;
(g) —SH, —S(O)
n
R
6
, —S(O)
m
—OH, —S(O)
m
—OR
6
, —O—S(O)
m
—R
6
, —O—S(O)
m
OH or —O—S(O)
m
—OR
6
, except when Z
4
is —S(O)
n
—;
R
8
is
(a) hydrogen;
(b) —C(O)H or —C(O)R
6
, except when Z
4
is —C(O)— and R
7
is —C(O)H, —C(O)R
6
or —CO
2
R
6
;
(c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z
1
, Z
2
and Z
3
; or
R
7
and R
8
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, unsaturated or aromatic ring together with the nitrogen atom to which they are attached;
R
9
is
(a) hydrogen;
(b) hydroxyl;
(c) —C(O)H or —C(O)R
6
;
(d) —CO
2
R
6
;
(e) —SH, —S(O)
n
R
6
, —S(O)
m
—OH, —S(O)
m
—OR
6
, —O—S(O)
m
R
6
, —O—S(O)
m
OH or —O—S(O)
m
—OR
6
;
(f) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z
1
, Z
2
and Z
3
;
R
10
is
(a) hydrogen;
(b) —C(O)H or —C(O)R
6
, except when Z
5
is —C(O)— and R
9
is —C(O)H, —C(O)R
6
or —CO
2
R
6
; or
(c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z
1
, Z
2
and Z
3
;
R
11
is
(a) hydrogen;
(b) hydroxyl;
(c) —C(O)H, —C(O)R
6
or CO
2
R
6
; or
(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z
1
, Z
2
and Z
3
;
or any two of R
9
, R
10
and R
11
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, unsaturated or aromatic ring together with the atoms to which they are attached;
Z
1
, Z
2
and Z
3
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)
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
;
(k) oxo;
(l) nitro;
(m) cyano;
(n) —C(O)H or —C(O)Z
6
;
(o) —CO
2
H or —CO
2
Z
6
;
(p) —Z
4
—NZ
7
Z
8
;
(q) —Z
4
—N(Z
11
)—Z
5
—Z
6
; or
(r) —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
—; or
(g) —Z
9
—O—C(O)—Z
10
—;
Z
6
, Z
7
and Z
8
are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, or Z
7
and Z
8
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;
Z
9
and Z
10
are each independently a single bond, alkylene, alkenylene or alkynylene;
Z
11
is
(a) hydrogen;
(b) hydroxyl;
(c) —C(O)H, —C(O)Z
6
or —CO
2
Z
6
;
(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, 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, 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.
For coumpound I, it is preferred that:
R
1
is phenyl or phenoxy, optionally substituted with one or more alkyl, alkoxy, —NZ
7
Z
8
, halo and hydroxy;
R
2
and R
3
are each independently hydrogen, alkyl or —NR
7
R
8
;
R
4
and R
5
are alkyl; and
R
7
, R
8
, Z
7
and Z
8
are each independently hydrogen, alkyl or —C(O)alkyl.
Most preferred compounds are those wherein:
R
1
is phenyl or phenoxy, optionally substituted with alkyl, alkoxy, amino, alkylamino, dialkylamino, alkanoylamino or hydroxy;
R
2
and R
3
are each independently hydrogen, alkyl of 1 to 4 carbon atoms, amino, alkylamino, dialkylamino or alkanoylamino; and
R
4
and R
5
are alkyl of 1 to 4 carbon atoms, especially methyl.
DETAILED DESCRIPTION OF THE INVENTION
Listed below are definitions of terms used in this specification. These definitions apply to the terms as used throughout this specification, individually or as part of another group, unless otherwise limited in specific instances.
The terms “alkyl” and “alkoxy” refer to straight or branched chain hydrocarbon groups having 1 to 10 carbon atoms. The terms “lower alkyl” and “lower alkoxy” refer to groups of 1 to 4 carbon atoms, which are preferred.
The term “aryl” or “ar-” refers to phenyl, naphthyl and biphenyl.
The term “alkenyl” refers to straight or branched chain hydrocarbon groups of 2 to 10 carbon atoms having at least one double bond. Groups of two to four carbon atoms are preferred.
The term “alkynyl” refers to straight or branched chain groups of 2 to 10 carbon atoms having at least one triple bond. Groups of two to four carbon atoms are preferred.
The term “alkylene” refers to a straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., —(CH
2
)
x
— wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.
The term “alkenylene” refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkenylene groups are —CH═CH—CH═CH—, —CH
2
—CH═CH—, —CH
2
—CH═CH—CH
2
—, —C(CH
3
)
2
CH═CH— and —CH(C
2
H
5
)—CH═CH.
The term “alkynylene” refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by singe bonds, and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkynylene groups are —C≡C—, —CH
2
—C≡C—, —CH(CH
3
)—C≡C— and —C≡C—CH(C
2
H
5
)CH
2
—.
The term “alkanoyl” refers to groups of the formula —C(O)alkyl.
The terms “cycloalkyl” and “cycloalkenyl” refer to cyclic hydrocarbon groups of 3 to 8 carbon atoms.
The terms “

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