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US 2014/0275133 A1Published application
Mineralocorticoid receptor antagonists
AssigneeMerck Sharp & Dohme Corp.
InventorsHong Shen, Jason M. Cox, Hong Dong Chu
Life of this patent
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Abstract
The present invention is directed to compounds of the Formula (I) as well as pharmaceutically acceptable salts thereof that are possible 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 above mentioned diseases and for preparing pharmaceuticals for this purpose, and to pharmaceutical compositions which comprise compounds of the Formula (I).
Claims14
A compound of Formula I:
- or a pharmaceutically acceptable salt thereof, wherein
- X is NH or O;
- Each R1 is independently halo, CF3, C1-C6 alkyl, C3-C10 cycloalkyl, or OR, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF3, or CN;
- Each R is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, or CF3 wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OH, C1-C6 alkoxy, CF3, or CN;
- Each Ra is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, or CF3 wherein said alkyl, cycloalkyl and aryl are optionally substituted with one to three groups selected from halo, OR, CF3, or CN;
- Each Rb is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, CF3, or aryl, wherein said alkyl, cycloalkyl and aryl are optionally substituted with one to three groups selected from halo, OR, CF3, or CN;
- R2 is triazolyl, oxadiazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl or oxazolyl, where triazolyl, oxadiazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl or oxazolyl is optionally substituted with one to two groups from R5;
- R4 is H, C1-C6 alkyl, aryl, or C3-C10 cycloalkyl, where said alkyl, aryl, or cycloalkyl is optionally substituted with one to four groups selected from halo or OR;
- Each R5 is independently OR, (CRc2)0-3—CF3, C1-C6 alkyl, (CRc2)0-3—C3-C10 cycloalkyl, (CRc2)0-3-aryl, (CRc2)0-3-heteroaryl, or (CRc2)0-3-halo, where said alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one to three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, OR, halo, CF3 or NH2;
- and wherein said optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl are optionally substituted one to four times by halo, CF3, NH2 or OR.
- Each Rc is independently H, C1-C6 alkyl, or C3-C10 cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF3, or CN;
- m is 0, 1, 2 or 3;
- and
- p is 0, 1, 2 or 3.
11 more elements
A compound which is
- Compound
- Number
- IUPAC Name
- 1
- 5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-3-
- [(1R)-1-(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione
- 2
- (5R)-5-Benzyl-5-[5-(3,5-dimethoxybenzyl)-1,3,4-oxadiazol-
- 2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione
- 3
- (5R)-5-Benzyl-5-(5-benzyl-1,3,4-oxadiazol-2-yl)-3-
- [(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione
- 4
- (5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-
- 2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione
- 5
- (5R)-5-Benzyl-5-[5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-
- 2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione
- 6
- (5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(3-phenyl-1,2,4-
- oxadiazol-5-yl)-1,3-oxazolidine-2,4-dione
- 7
- (5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-pyridin-4-
- yl-1,3,4-oxadiazol-2-yl)-1,3-oxazolidine-2,4-dione
- 8
- (5R)-5-Benzyl-5-[5-(4,6-dimethoxypyrimidin-2-yl)-1,3,4-oxadiazol-
- 2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione
- 9
- (5R)-5-Benzyl-5-{5-[1-(3,5-difluorophenyl)cyclopropyl]-1,3,4-oxadiazol-
- 2-yl}-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione
- 10
- (5R)-5-[5-(3-Amino-5-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-
- 5-benzyl-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione
- 11
- (5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-[5-(2,2,2-trifluoroethyl)-
- 1,3,4-oxadiazol-2-yl]-1,3-oxazolidine-2,4-dione
- 12
- (5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-{5-[1-(trifluoromethyl)
- cyclopropyl]-1,3,4-oxadiazol-2-yl}-1,3-oxazolidine-2,4-dione
- 13
- (5R)-5-Benzyl-5-[5-(cyclopropylmethyl)-1,3,4-oxadiazol-
- 2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione
- 14
- (5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-[5-(1-pyridin-4-ylcyclopropyl)-
- 1,3,4-oxadiazol-2-yl]-1,3-oxazolidine-2,4-dione
- 15
- (5R)-5-Benzyl-5-[4-(3,5-dimethoxyphenyl)-1H-imidazol-
- 2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione
- 16
- (5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-phenyl-
- 1H-imidazol-2-yl)-1,3-oxazolidine-2,4-dione
- 17
- (5R)-5-Benzyl-5-(5-benzyl-1H-imidazol-2-yl)-3-
- [(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione
- 18
- (5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(4-phenyl-
- 1,3-oxazol-2-yl)-1,3-oxazolidine-2,4-dione
- 19
- (5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-phenyl-
- 1,3-oxazol-2-yl)-1,3-oxazolidine-2,4-dione
- 20
- (5R)-5-Benzyl-5-(5-benzyl-1,3-oxazol-2-yl)-3-
- [(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione
- 21
- (5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(3-phenyl-
- 1H-1,2,4-triazol-5-yl)-1,3-oxazolidine-2,4-dione
- 22
- (5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-
- 2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione
- or a pharmaceutically acceptable salt thereof.
67 more elements
A method for antagonizing aldosterone receptor (MR) and increasing aldosterone levels in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I:
- or a pharmaceutically acceptable salt thereof, wherein
- X is NH or O;
- Each R1 is independently halo, CF3, C1-C6 alkyl, C3-C10 cycloalkyl, or OR, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF3, or CN;
- Each R is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, or CF3 wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OH, C1-C6 alkoxy, CF3, or CN;
- Each Ra is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, or CF3 wherein said alkyl, cycloalkyl and aryl are optionally substituted with one to three groups selected from halo, OR, CF3, or CN;
- Each Rb is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, CF3, or aryl, wherein said alkyl, cycloalkyl and aryl are optionally substituted with one to three groups selected from halo, OR, CF3, or CN;
- R2 is triazolyl, oxadiazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl or oxazolyl, where triazolyl, oxadiazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl or oxazolyl is optionally substituted with one to two groups from R5;
- R4 is H, C1-C6 alkyl, aryl, or C3-C10 cycloalkyl, where said alkyl, aryl, or cycloalkyl is optionally substituted with one to four groups selected from halo or OR;
- Each R5 is independently OR, (CRc2)0-3—CF3, C1-C6 alkyl, (CRc2)0-3—C3-C10 cycloalkyl, (CRc2)0-3-aryl, (CRc2)0-3-heteroaryl, or (CRc2)0-3-halo, where said alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one to three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, OR, halo, CF3 or NH2;
- and wherein said optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl are optionally substituted one to four times by halo, CF3, NH2 or OR.
- Each Rc is independently H, C1-C6 alkyl, or C3-C10 cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF3, or CN;
- m is 0, 1, 2 or 3;
- and
- p is 0, 1, 2 or 3.
11 more elements
Dependencies are inferred from the claim text.