Mineralocorticoid receptor antagonists
The present invention is directed to compounds of the Formula (I) as well as pharmaceutically acceptable salts thereof, that are aldosterone receptor antagonists which might be useful for treating aldosterone-mediated diseases. The invention furthermore relates to processes for preparing compounds of the Formula (I), to their possible use for the treatment of the abovementioned diseases and for preparing pharmaceuticals for this purpose, and to pharmaceutical compositions which comprise compounds of the Formula (I).
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
X is NH or O;
each R 1 is independently halo, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or OR, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF 3 , CF 2 H, or CN;
each R is independently H, C 1 -C 6 alkyl, CF 3 , or C 3 -C 10 cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OH, OC 1 -C 6 alkyl, OCF 3 , OC 3 -C 10 cycloalkyl, CF 2 H, CF 3 , or CN;
each R 3 is independently halo, OR, C 1 -C 6 alkyl, CF 3 , C 3 -C 10 cycloalkyl, C(O)OR, (CR c ) 0-3 -heteroaryl, (CR c ) 0-3 -heterocyclyl, NR 6 S(O) 2 R 7 , CN, C(O)NR 6 R 7 , or (CR c ) 0-3 -aryl,
where said alkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four groups selected from OR, halo, CF 2 H, CF 3 , C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl;
R 4 is H, C 1 -C 6 alkyl, aryl, C 3 -C 10 cycloalkyl or heterocyclyl, where said alkyl, aryl, cycloalkyl, or heterocyclyl, is optionally substituted with one to four groups selected from C 1 -C 6 alkyl, halo, CF 3 , or OR;
R 5 is H, CF 2 H, CF 3 , C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl;
each R 6 is independently H, CF 2 H, CF 3 , C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl;
each R 7 is independently C 1 -C 6 alkyl, (CR d 2 ) t -aryl, C 3 -C 10 cycloalkyl, or (CR d 2 ) t -heteroaryl, where said alkyl, aryl, cycloalkyl, or heteroaryl is optionally substituted with one to four groups selected from OR, halo, or aryl;
each R a is independently H, C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF 2 H, CF 3 , or CN;
each R b is independently H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or aryl, wherein said alkyl, cycloalkyl and aryl are optionally substituted with one to three groups selected from halo, OR, CF 2 H, CF 3 , or CN;
each R c is independently H or C 1 -C 6 alkyl;
each R d is independently H or C 1 -C 6 alkyl;
m is 0, 1, 2 or 3;
n is 0, 1, 2, 3 or 4;
p is 0,1, 2 or 3; and
t is 0 or 1.
2. The compound of claim 1 , wherein
each R 1 is independently halo, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or OR, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF 3 , or CN;
each R 3 is independently halo, OR, C 1 -C 6 alkyl, CF 3 , C 3 -C 6 cycloalkyl, C(O)OR, (CR c ) 0-3 -heteroaryl, (CR c ) 0-3 -heterocyclyl, NR 6 S(O) 2 R 7 , CN, C(O)NR 6 R 7 , or (CR c ) 0-3 aryl,
where said alkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four groups selected from OR, halo, CF 2 H, CF 3 , C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl;
R 4 is
C 1 -C 6 alkyl,
aryl, where aryl is selected from phenyl, indenyl, naphthyl, dihydroindenyl, or tetrahydronaphthalenyl, or
C 3 -C 6 cycloalkyl,
where said alkyl, aryl, or cycloalkyl is optionally substituted with one to four groups selected from C 1 -C 6 alkyl, halo, CF 3 , or OR; and
m is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , as illustrated by structural Formula II:
or a pharmaceutically acceptable salt thereof, wherein
each R 1 is independently halo or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one to three groups selected from halo, OR, CF 3 , CF 2 H, or CN;
each R is independently H, C 1 -C 6 alkyl, CF 3 , or C 3 -C 10 cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OH, OC 1 -C 6 alkyl, OCF 3 , OC 3 -C 10 cycloalkyl, CF 2 H, CF 3 , or CN;
each R a is independently H or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one to three groups selected from halo, OR, CF 2 H, CF 3 , or CN;
each R b is independently H or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one to three groups selected from halo, OR, CF 2 H, CF 3 , or CN;
each R 3 is independently halo, OR, C 1 -C 6 alkyl, CF 3 , (CR c ) 0-3 -heteroaryl, (CR c ) 0-3 -heterocyclyl, NR 6 S(O) 2 R 7 , CN, or C(O)NR 6 R 7 , where said alkyl, heteroaryl or heterocyclyl is optionally substituted with one to four groups selected from OR, halo, CF 2 H, CF 3 , C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl;
R 4 is
C 1 -C 6 alkyl,
aryl, where aryl is selected from phenyl, indenyl, naphthyl, dihydroindenyl, or tetrahydronaphthalenyl, or
C 3 -C 6 cycloalkyl,
where said alkyl, aryl, or cycloalkyl is optionally substituted with one to four groups selected from C 1 -C 6 alkyl, halo, CF 3 , or OR;
R 5 is H, CF 2 H, CF 3 , C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl;
each R 6 is independently H, CF 2 H, CF 3 , C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl;
each R 7 is independently C 1 -C 6 alkyl, where said alkyl is optionally substituted with one to four groups selected from OR, halo, or aryl;
each R c is independently H or C 1 -C 6 alkyl;
each R d is independently H or C 1 -C 6 alkyl;
m is 0, 1 or 2;
n is 0, 1 or 2; and
p is 0, 1 or 2.
4. A compound which is
Compound
Number
IUPAC Name
1
(5R)-5-Benzyl-5-(5-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-(4-
fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione
2
(5R)-5-Benzyl-5-(5-fluoro-1H-benzimidazol-2-yl)-3-[(1R)-1-(4-
fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione
3
(5R)-5-(1H-Benzimidazol-2-yl)-5-benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-
1,3-oxazolidine-2,4-dione
4
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[5-(trifluoromethoxy)-
1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
5
Methyl 2-{(5R)-5-benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-2,4-dioxo-1,3-
oxazolidin-5-yl}-1H-benzimidazole-5-carboxylate
6
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[6-(1H-tetrazol-1-yl)-
1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
7
(5R)-5-Benzyl-5-(4,5-difluoro-1H-benzimidazol-2-yl)-3-[(1R)-1-(4-
fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione
8
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[5-(trifluoromethyl)-1H-
benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
9
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-(5-morpholin-4-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
10
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[5-(morpholinylmethyl)-
1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
11
(5R)-5-Benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-[1-(4,4-
difluorocyclohexyl)ethyl]-1,3-oxazolidine-2,4-dione
12
(5R)-5-Benzyl-5-(5-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-
cyclohexylethyl]-1,3-oxazolidine-2,4-dione
13
(5R)-5-Benzyl-5-(5-chloro-1H-benzimidazol-2-yl)-3-[(1R)-2,3-dihydro-
1H-inden-1-yl]-1,3-oxazolidine-2,4-dione
14
N-(2-{(5R)-5-benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-2,4-dioxo-1,3-
oxazolidin-5-yl}-1H-benzimidazol-7-yl)methanesulfonamide
15
(5R)-5-Benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-(3,4-
difluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione
16
N-(2-{(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-2,4-dioxo-1,3-
oxazolidin-5-yl}-1H-benzimidazol-6-yl)ethanesulfonamide
17
5-(6-Chloro-1H-benzimidazol-2-yl)-3-[(1R)-2,3-dihydro-1H-inden-1-yl]-5-
(4-fluorobenzyl)-1,3-oxazolidine-2,4-dione
18
2-{3-[(1R)-1-Cyclohexylethyl]-5-(4-fluorobenzyl)-2,4-dioxo-1,3-
oxazolidin-5-yl}-1H-benzimidazole-5-carbonitrile
19
(5R)-5-Benzyl-5-(4,6-dichloro-1H-benzimidazol-2-yl)-3-[(1R)-1-(4-
fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione
20
5-Benzyl-5-(4-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-(4-
fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione
21
Methyl 2-{(5R)-5-benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-2,4-dioxo-1,3-
oxazolidin-5-yl}-1H-benzimidazole-5-carboxamide
22
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-(5-pyrimidin-5-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
23
(5R)-5-Benzyl-5-[5-(3,5-dimethylisoxazol-4-yl)-1H-benzimidazol-2-yl]-3-
[(1R)-1-(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione
24
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[5-(1-methyl-1H-
pyrazol-4-yl)-1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
25
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-(5-pyridin-3-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
26
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[5-(1H-pyrazol-4-yl)-
1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
27
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[5-(1H-pyrazol-5-yl)-
1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
28
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[5-(5-fluoro-pyridin-3-
yl)-1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
29
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[5-(4-chloro-pyridin-3-
yl)-1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
30
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-(4-isoxazol-4-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
31
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[4-(1-methyl-1H-
pyrazol-4-yl)-1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
32
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[4-(1-methyl-1H-
pyrazol-5-yl)-1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
33
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[4-(2-methoxypyridin-3-
yl)-1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
34
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-(4-pyridin-4-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
35
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-(4-pyrimidin-5-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
36
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-(4-pyridin-3-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
37
(5R)-5-Benzyl-5-(5,6-difluoro-1-methyl-1H-benzimidazol-2-yl)-3-[(1R)-1-
(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione or
38
(5R)-5-Benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-
phenylethyl]imidazolidine-2,4-dione
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 which is
Compound
Number
IUPAC Name
9
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-(5-morpholin-4-yl-
1H-benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
11
(5R)-5-Benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-[1-(4,4-
difluorocyclohexyl)ethyl]-1,3-oxazolidine-2,4-dione
12
(5R)-5-Benzyl-5-(5-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-
cyclohexylethyl]-1,3-oxazolidine-2,4-dione
13
(5R)-5-Benzyl-5-(5-chloro-1H-benzimidazol-2-yl)-3-[(1R)-2,3-dihydro-
1H-inden-1-yl]-1,3-oxazolidine-2,4-dione
14
N-(2-{(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-2,4-dioxo-1,3-
oxazolidin-5-yl}-1H-benzimidazol-7-yl)methanesulfonamide
23
(5R)-5-Benzyl-5-[5-(3,5-dimethylisoxazol-4-yl)-1H-benzimidazol-2-
yl]-3-[(1R)-1-(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione
24
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[5-(1-methyl-1H-
pyrazol-4-yl)-1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
25
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-(5-pyridin-3-yl-1H-
benzimidazol-2-yl)-1,3-oxazolidine-2,4-dione
26
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[5-(1H-pyrazol-4-
yl)-1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
28
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[5-(5-fluoro-pyridin-
3-yl)-1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione or
29
(5R)-5-Benzyl-3-[(1R)-1-(4-fluorophenyl)ethyl]-5-[5-(4-chloro-pyridin-
3-yl)-1H-benzimidazol-2-yl]-1,3-oxazolidine-2,4-dione
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprised of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 6 further comprising one or more additional pharmaceutically active agents.
8. A method of treating cardiovascular disease, heart failure, hypertension, atherosclerosis or primary hyperaldosteronism or a related condition in a human patient in need of, comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
9. A method of treating metabolic syndrome in a mammal in need of such treatment, comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
10. A method of treating a physiological or pathologic disease, selected from Conn's Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic/diastolic), arrhythmias, myocardial fibrosis, myocardial infarction and Bartter' s Syndrome in a human patient in need of, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
11. A method of treating renal failure in a human patient in need of such treatment comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
12. A method for antagonizing aldosterone receptor (MR) and increasing aldosterone levels in a mammal which comprises administering to said mammal a therapeutically effective amount of the compound of claim 1
or a pharmaceutically acceptable salt thereof.