IP Library Granted Patent US 8,063,090
Granted Patent B2
US 8,063,090 · App. 12/532,031 · Granted Nov 22, 2011

Mineralocorticoid receptor modulators

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Quick Facts
Patent No.
US 8,063,090
App. No.
12/532,031
Granted
Nov 22, 2011
Kind
B2
Abstract

The present invention relates to diphenylmethyl imidazole mineralocorticoid receptor modulators compounds having the structure and their use in treating cardiovascular events.

Claims (53)

1. A compound of formula I,

and pharmaceutically acceptable salts thereof, or an optical isomer thereof, wherein

Z is selected from the group consisting of

1) an aryl ring,

2) a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of:

a) a 5-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S,

b) a 6-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and

c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and

3) a 4-6 membered saturated heterocyclic ring with 1, 2 or 3 heteroatom ring atoms selected from the group consisting of N, O and S, wherein the point of attachment to the heterocyclic ring is a carbon atom,

said aryl, heteroaryl, saturated heterocyclic ring is unsubstituted, mono-substituted with R 4 , disubstituted with groups independently selected from R 4 , trisubstituted with groups independently selected from R 4 , or tetrasubstituted with groups independently selected from R 4 , and wherein any stable S or N heteroaryl or heterocyclic ring atom is unsubstituted or substituted with oxo, said heteroaryl ring R 4 substitutions being on one or more heteroaryl ring carbon atoms;

R 1 and R 2 are selected from the group consisting of hydrogen and C 1 -C 6 alkyl,

or R 1 and R 2 , together with the carbon atoms to which they are attached, form a benzimidazole ring substituted at the 1- and 2-positions;

R 3 and R 5 are selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, and CN;

R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, NO 2 , NH 2 , CF 3 , SCF 3 , NHC(O)R 7 , OH, CN, NR a R b , CONR a R b , CO2Ra, C(O)0-2R a , SO2NR a R b , where R a and R b are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or R a and R b , together with the N atom to which they are attached, form a 3-8-membered ring containing the N atom and 1-3 heteroatoms selected from the group consisting of N, O and S;

R 6 and R 9 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

R 7 is selected from the group consisting of

1) an aryl ring,

2) a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of:

a) a 5-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S,

b) a 6-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and

c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and

3) C 1 -C 6 alkyl,

wherein said aryl ring, heteroaryl ring, and C 1 -C 6 alkyl is unsubstituted, mono-substituted with R 8 , disubstituted with groups independently selected from R 8 , trisubstituted with groups independently selected from R 8 , or tetrasubstituted with groups independently selected from R 8 , and wherein any stable S or N heteroaryl ring atom is unsubstituted or substituted with oxo, said heteroaryl ring R 8 , substitutions being on one or more heteroaryl ring carbon atoms; and

R 8 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, CN and halogen.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is selected from the group consisting of an aryl ring and 9-membered unsaturated heteroaryl bicyclic ring with 1 or 2 heteroatom ring atoms, wherein the heteroatom is O, wherein said aryl or heteroaryl bicyclic ring is unsubstituted, mono-substituted with R 4 , disubstituted with groups independently selected from R 4 , trisubstituted with groups independently selected from R 4 , or tetrasubstituted with groups independently selected from R 4 , said heteroaryl ring R 4 substitutions being on one or more heteroaryl ring carbon atoms.

3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of CH 3 , OCH 3 , halogen, NO 2 , NH 2 , CF 3 , SCF 3 , Cl, Br, I, and NHC(O)R 7 .

4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 7 is aryl, either unsubstituted, mono-substituted with CH 3 or Cl, or independently di-substituted with a substituent selected from the group consisting of CH 3 and Cl.

5. A compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein Z is selected from the group consisting of

6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are selected from the group consisting of hydrogen and CH 3 , or R 1 and R 2 , together with the carbon atoms to which they are attached, form a benzimidazole ring substituted at the 1- and 2-positions.

7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 5 are hydrogen.

8. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of hydrogen and CH 3 .

9. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

2-(diphenylmethyl)-1-(1-phenylethyl)-1H-imidazole,

2-(diphenylmethyl)-1-[1-(3-iodophenyl)ethyl]-1H-imidazole,

2-(diphenylmethyl)-1-(4-methoxybenzyl)-1H-imidazole,

2-(diphenylmethyl)-1-[3-(trifluoromethyl)benzyl]-1H-imidazole,

2-(diphenylmethyl)-1-{3-[(trifluoromethyl)thio]benzyl}-1H-imidazole,

1-{1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(diphenylmethyl)-1H-imidazole,

1-[3,5-bis(trifluoromethyl)benzyl]-2-(diphenylmethyl)-1H-imidazole,

2-(diphenylmethyl)-1-(3-iodobenzyl)-1H-imidazole,

2-(diphenylmethyl)-1-(3-methylbenzyl)-1H-imidazole,

2-(diphenylmethyl)-1-(3-nitrobenzyl)-1H-imidazole,

3-{[2-(diphenylmethyl)-1H-imidazol-1-yl]methyl}aniline, 1-[1-(3,5-dichlorophenyl)ethyl]-2-(diphenylmethyl)-1H-imidazole,

1-(5-bromo-2-methoxybenzyl)-2-(diphenylmethyl)-1H-imidazole,

1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-2-(diphenylmethyl)-1H-imidazole,

N-(3-{[2-(diphenylmethyl)-1H-imidazol-1-yl]methyl}phenyl)-3,5-dimethoxybenzamide,

3,5-dichloro-N-(3-{[2-(diphenylmethyl)-1H-imidazol-1-yl]methyl}phenyl)benzamide,

1-benzyl-2-(diphenylmethyl)-4,5-dimethyl-1H-imidazole,

2-(diphenylmethyl)-1H-benzimidazole,

1-benzyl-2-(diphenylmethyl)-1H-benzimidazole, and

2-(diphenylmethyl)-1-(1-phenylethyl)-1H-benzimidazole.

10. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. A method for the treatment of hypertension or heart failure, comprising administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

Assignments (4)
CHANGE OF NAME Recorded Aug 29, 2012
From: SCHERING CORPORATION
To: MERCK SHARP & DOHME CORP.
Reel/Frame 028866/0511 →
MERGER Recorded Aug 27, 2012
From: MERCK SHARP & DOHME CORP.
To: SCHERING CORPORATION
Reel/Frame 028850/0515 →
CHANGE OF NAME Recorded Jan 27, 2010
From: MERCK & CO., INC.
To: MERCK SHARP & DOHME CORP.
Reel/Frame 023852/0595 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 21, 2009
From: BRANDISH, PHILIP E., MR.; HERSHEY, JAMES C., MR.; FRALEY, MARK E., MR.; STEEN, JUSTIN T., MR.
To: MERCK & CO., INC.
Reel/Frame 023257/0481 →