Biphenyl sulfonamides as dual angiotensin endothelin...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S380000, C514S385000, C544S336000, C548S245000, C548S300700

Reexamination Certificate

active

06638937

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to biphenyl sulfonamide compounds which are combined angiotensin and endothelin receptor antagonists, to methods of using such compounds in the treatment of conditions such as hypertension and other diseases, and to pharmaceutical compositions containing such compounds.
SUMMARY OF THE INVENTION
The present invention provides biphenyl sulfonamide compounds of the following formula I, enantiomers (including atropisomers), diastereomers, salts and metabolites thereof:
wherein:
R
2
is hydrogen, halogen, —CHO, alkyl, haloalkyl, (cycloalkyl)alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, aryloxy alkoxyalkoxy, cyano, hydroxy, hydroxyalkyl, nitro, —CH(OR
13
)(OR
14
), —(CH
2
)
w
Y; with the proviso that when R
1
is B, R
2
is not hydrogen, halogen, alkyl, haloalkyl, alkoxy, hydroxyalkyl, nitro, —(CH
2
)
w
NR
19
R
20
or —NHSO
2
R
22
;
R
3
is heteroaryl;
R
4
and R
5
are each independently alkyl, hydroxyalkyl, cycloalkyl, hydroxy substituted cycloalkyl, alkoxyalkyl, or hydroxy substituted alkoxyalkyl, or R
4
and R
5
together form a cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl ring which may be optionally substituted with one or more hydroxy group;
R
6
is alkyl, hydroxyalkyl, haloalkyl, hydroxy substituted haloalkyl, cycloalkyl, hydroxy substituted cycloalkyl, (cycloalkyl)alkyl, hydroxy substituted (cycloalkyl)alkyl, aralkyl, alkoxy, hydroxy substituted alkoxy, alkoxyalkyl, hydroxy substituted alkoxyalkyl, or —NR
16
R
17
;
R
7
is —(CH
2
)
w
—CO
2
R
15
, —(CH
2
)
w
—(C═O)NR
16
R
17
, —(CH
2
)
w
—NR
15
(C═O)NR
16
R
17
, —(CH
2
)
w
—CH
2
OH, —(CH
2
)
w
—(C═O)R
15
, tetrazolyl, oxadiazolyl or triazolyl wherein said tetrazolyl, oxadiazolyl or triazolyl may optionally be substituted with hydrogen, alkyl, hydroxy or halogen;
R
8
, R
9
, R
9a
, R
10
and R
12
are each independently hydrogen, halogen, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, arylalkyl, alkylthioalkyl, alkoxy or alkoxyalkyl, or R
9
and R
9a
together with the carbon atom to which they are bonded form a cycloalkyl ring;
R
11
and R
11a
are each independently hydrogen, alkoxy, or together form a carbonyl;
R
13
and R
14
are alkyl or together form a five to six-membered ring;
R
15
, R
16
and R
17
are independently hydrogen, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, aralkyl, heterocycloalkyl, aryl, heteroaryl or —(CH
2
)
w
Q, or R
16
and R
17
may together form a four to six-membered heterocyclic ring;
n is 1 or 2;
w is 0, 1, or 2;
Y is heteroaryl, —COOH, —COOR
18
, —CONR
19
R
20
, —NR
19
R
20
, —NR
19
—OR
20
, —NR
21
(C═O)R
22
, —NR
21
(C═O)NR
19
R
20
, —N(R
19
)-(alk)—NR
21
(C═O)R
22
, —NR
21
(C═O)OR
18
, —NR
21
SO
2
R
22
, —SO
2
R
22
, Q, R or S;
R
18
, R
19
, R
20
, R
21
and R
22
are each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or R
19
and R
20
may together form a four to seven-membered heterocyclic ring;
R
23
and R
24
are each independently hydrogen, alkyl or cycloalkyl, or may together form a three to seven membered cycloalkyl ring;
Z is oxygen,
x is 2, 3 or 4;
R
25
, R
26
and R
27
are each independently hydrogen, alkyl or cycloalkyl, or R
26
and R
27
may together form a three to seven-membered cycloalkyl ring;
R
101
, R
102
, R
103
, and R
104
are each independently hydrogen, halogen, —CHO, alkyl, haloalkyl, (cycloalkyl)alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, cyano, hydroxy, hydroxyalkyl, nitro, —CH(OR
13
)(OR
14
), or —(CH
2
)
w
Y;
wherein said rings; aryl alone or as part of another group; or heteroaryl alone or as part of another group may each optionally be substituted by one or more hydrogen, halogen, cyano, alkyl, hydroxyalkyl, alkoxy, nitro or trifluoromethyl groups.
The compounds of the formula I and salts thereof may be used as combined endothelin and angiotensin receptor antagonists.
Preferred Compounds
Compounds of the formula I and salts thereof wherein one or more, and especially all, of R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
11a
, R
12
, R
15
, R
16
, R
17
, R
18
, R
19
, R
20
, R
21
,R
22
, R
23
, R
24
, R
25
, R
26
, R
27
, R
101
, R
102
, R
103
, R
104
, n, w, Y, Q, Z, and x are selected from the following definitions, are preferred compounds of the present invention:
R
2
is alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or —(CH
2
)
w
Y, or when R
1
is D, R
2
is hydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or (CH
2
)
w
Y;
R
3
is isoxazolyl, pyridizinyl, pyrazinyl or pyrimidinyl, each optionally substituted with one to three of the following substituents: hydrogen, halogen, cyano, alkyl, alkoxy, trifluoromethyl or nitro;
R
4
and R
5
are each independently alkyl, cycloalkyl, or R
4
and R
5
together form a cyclobutyl, cyclopentyl or cyclohexyl ring;
R
6
is alkyl, haloalkyl, cycloalkyl or alkoxy;
R
7
is —CO
2
R
15
, —(C═O)NR
16
R
17
or —CH
2
OH;
R
8
, R
9
, R
10
and R
12
are each independently hydrogen, halogen, alkyl, cycloalkyl, alkoxy or alkoxyalkyl;
R
11
and R
11a
are each independently hydrogen, alkoxy, or together form a carbonyl;
R
15
, R
16
and R
17
are independently hydrogen, alkyl or cycloalkyl or R
16
and R
17
may together form a four to six-membered heterocyclic ring;
n is 1 or 2;
w is 0, 1, or 2;
Y is —COOR
18
, —NR
21
(C═O)R
22
, —NR
21
(C═O)NR
19
R
20
, —NR
21
(C═O)OR
18
, —NR
21
SO
2
R
22
, —SO
2
R
22
or Q;
Q is
R
18
, R
19
, R
20
, R
21
and R
22
are each independently hydrogen, alkyl, cycloalkyl, or R
19
and R
20
may together form a four to seven-membered heterocyclic ring;
R
23
and R
24
are each independently hydrogen, alkyl or cycloalkyl, or may together form a three to seven membered cycloalkyl ring;
Z is oxygen,
x is 2, 3 or 4;
R
25
, R
26
and R
27
are each independently hydrogen, alkyl or cycloalkyl, or R
26
and R
27
may together form a three to seven-membered cycloalkyl ring;
R
101
, R
102
, R
103
, and R
104
are each independently hydrogen, halogen, alkoxy or alkyl.
Compounds of the formula I and salts thereof wherein one or more, and especially all, of R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
11a
, R
15
, R
16
, R
17
, R
18
, R
19
, R
20
, R
21
, R
22
, R
23
, R
24
, R
25
, R
26
, R
27
, R
101
, R
102
, R
103
, R
104
, n, w, Y, Q, Z, and x are selected from the following definitions, are more preferred compounds of the present invention:
R
2
is alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, hydroxyalkyl, or —(CH
2
)
w
Y; or when R
1
is D, R
2
is hydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkyl, or —(CH
2
)
w
Y;
R
3
is isoxazolyl, optionally substituted with one or two of the following substituents: hydrogen, halogen, cyano, alkyl, alkoxy, trifluoromethyl or nitro;
R
4
and R
5
are each independently alkyl, cycloalkyl, or R
4
and R
5
together form a cyclobutyl, cyclopentyl or cyclohexyl ring;
R
6
is alkyl, haloalkyl, cycloalkyl or alkoxy;
R
7
is —C
2
R
15
or —(C═O)NR
16
R
17
;
R
8
, R
9
and R
10
are each independently hydrogen, halogen, alkyl, cycloalkyl alkoxy or alkoxyalkyl;
R
11
and R
11a
together form a carbonyl;
R
15
, R
16
and R
17
are independently hydrogen, alkyl, or cycloalkyl or R
16
and R
17
may together form a four to six-membered heterocyclic ring;
n is 2;
w is 0, 1, or 2;
Y is —NR
21
(C═O)R
22
, —NR
21
,(C═O)NR
19
R
20
, —NR
21
(C═O)OR
18
, —NR
21
SO
2
R
22
, —SO
2
R
22
or Q;
Q is
R
18
, R
19
, R
20
, R
21
and R
22
are each independently hydrogen, alkyl, cycloalkyl, or R
19
and R
20
may together form a four to seven-membered heterocyclic ring;
R
23
and R
24
are each independently hydrogen, alkyl or cycloalkyl, or may together form a three to seven membered cycloalkyl ring;
Z is oxygen,
x

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