Substituted biphenysulfonamide endothelin antagonists

Details Substituted biphenysulfonamide endothelin antagonists Substituted biphenysulfonamide endothelin antagonists

2000-01-20

2001-08-07

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S378000, C514S380000, C548S221000, C548S245000, C548S246000, C540S484000, C546S184000, C546S348000

Reexamination Certificate

active

06271248

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
its enantiomers and diastereomers, 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
2
and R
3
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
; 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 -C
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, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z
1
, Z
2
and Z
3
;
R
7
, R
8
, R
9
, R
10
and R
11
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
;
R
7
and R
8
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;
any two of R
9
, R
10
and R
11
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 atoms to which they are attached;
G
1
is
(a) hydrogen; or
(b) alkyl;
G
2
is
(a) hydroxyalkyl;
(b) -(CH
2
)
m
OR
6
; or
(c) -(CH
2
)
m
-NR
12
R
13
;
(d) mono-to hexa-halo substituted alkyl (i.e., alkyl substituted with one, two, three, four, five or six halogen atoms); or
(e) -(CH
2
)
n
OR
14
;
R
12
and R
13
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 P R
12
and R
13
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, together with the nitrogen atom to which they are attached form
R
14
is lower alkyl substituted with 1, 2 or 3 halogen atoms;
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
-H;
(r) —Z
4
-N(Z
11
)-Z
5
-Z
6
; or
(s) —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, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl;
Z
7
and Z
8
are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl-alkyl, 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, 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;
each m is independently 1 or 2; and
each n is independently 0, or 2.
For compound I, it is preferred that:
R
2
and R
3
are each independently hydrogen or alkyl;
R
4
and R
5
are each independently alkyl; and
R
12
and R
13
, together with the nitrogen atom to which they are attached, form
Most preferred compounds are those wherein:
R
2
and R
3
are each hydrogen; and
R
4
and R
5
are each 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 term “alkyl” or “alk-” refers to straight or branched chain hydrocarbon groups having 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms. The expression “lower alkyl” refers to alkyl groups of 1 to 4 carbon atoms.
The term “alkoxy” refers to alkyl-o-. The expression “lower alkoxy” refers to lower alkyl-o-.
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 single 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 term “hydroxyalkyl” refers to an alkyl group including one or more hydroxy radicals such as —CH
2
CH
20
H, —CH
2
CH
2
OHCH
2
OH, -CH(CH
2
OH)
2
and the like.
The terms “halogen” and “halo” refer to fluorine, chlorine, bromine and iodine.
Throughout the specification, groups and substituents thereof are chosen to provide stable moieties and compounds.
The compounds of formula I form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g, in isolating or purifying the compounds of this invention.
The compounds of formula I may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as

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