IP Library Granted Patent US 8,076,359
Granted Patent B2
US 8,076,359 · App. 12/312,454 · Granted Dec 13, 2011

Renin inhibitors

Assignee: Merck Canada Inc.
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Quick Facts
Patent No.
US 8,076,359
App. No.
12/312,454
Granted
Dec 13, 2011
Kind
B2
Abstract

The present invention relates to disubstituted piperidinyl renin inhibitor compounds having the structure (Formula I) and their use in treating cardiovascular events and renal insufficiency.

Claims (51)

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein

X is N or CH;

Y is O, CH 2 , or a bond;

R 1 is

—(CH 2 ) 1-3 OR 4 , or

—O(CH 2 ) 1-2 OR 4 ;

R 2 is selected from the group consisting of

—(CH 2 ) 1-5 OR 4 ,

—O(CH 2 ) 2-4 OR 4 ,

—C(O)R 4 ,

—OR 4 ,

—O(CH 2 ) 2-4 O—(C 3 -C 8 cycloalkyl), wherein cycloalkyl is unsubstituted or substituted with C 1 -C 4 alkyl or C 1 -C 4 alkanol,

—O(CH 2 ) 2-4 NR 4 R 5 ,

R 4 and R 5 are independently C 1 -C 6 alkyl unsubstituted or substituted with —OH or CF 3 .

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —(CH 2 ) 3 OCH 3 , —(CH 2 ) 2 OCH 3 or —O(CH 2 ) 2 OCH 3 .

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is O.

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 2 is selected from the group consisting of

—(CH 2 ) 3 OR 4 ,

—O—(CH 2 ) 2 OR 4 ,

—C(O)R 4 ,

—OR 4 ,

—O(CH 2 ) 2 O—(C 3 -C 8 cycloalkyl), wherein cycloalkyl is unsubstituted or substituted with C 1 -C 4 alkyl or C 1 -C 4 alkanol,

—O(CH 2 ) 2 NR 4 R 5 , and

5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 2 is selected from the group consisting of

—(CH 2 ) 3 OCH 3 ,

—O(CH 2 ) 2 OCH 3 ,

—C(O)CH 3 ,

—OCH 2 C(CH 3 ) 2 OH,

—O(CH 2 ) 2 OCH 2 CF 3 ,

—O(CH 2 ) 2 OCH 3 ,

—O(CH 2 ) 2 N(CH 3 ) 2 ,

6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 4 and R 5 are independently selected from the group consisting of —CH 3 , —CH 2 CF 3 , and —(CH 2 )C(CH 3 ) 2 OH.

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

(3R,4S)-N-Cyclopropyl-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-N-[3-(2-methoxyethoxy)-5-(3-methoxypropyl)benzyl]piperidine-3-carboxamide,

(3R,4S)-N-Cyclopropyl-4-{6-2-[2,6-dichloro-4-methylphenoxy)ethoxy]pyridin-3-yl}-N-[3-(2-methoxyethoxy)-5-(3-methoxypropyl)benzyl]piperidine-3-carboxamide,

(3R,4S)-N-Cyclopropyl-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-N-[3-[2-(dimethylamino)ethoxy]-5-(3 -methoxypropyl)benzyl]piperidine-3-carboxamide,

(3R,4S)-N-Cyclopropyl-N-[3-[2-(cyclopropyloxy)ethoxy]-5-(3 -methoxypropyl)-benzyl]-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxamide,

(3R,4S)-N-Cyclopropyl-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-N-{3-3-methoxypropyl)-5-[2-(2,2,2-trifluoroethoxy)ethoxy]benzyl}piperidine-3-carboxamide,

(3R,4S)-N-Cyclopropyl-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-N-[3-(2-hydroxy-2-methylpropoxy)-5-(3-methoxypropyl)benzyl]piperidine-3-carboxamide,

(3R,4S)-N-[3-{[1-(Cyanomethyl)cyclopropyl]methoxy}-5 -(3-methoxypropyl)benzyl]-N-cyclopropyl-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxamide,

(3R,4S)-N-Cyclopropyl-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-N-[3-{[(1R,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxypropyl)benzyl]-piperidine-3 -carboxamide,

(3R,4S)-N-[3-Acetyl-5-(3-methoxypropyl)benzyl]-N-cyclopropyl-4-{4-[2-(2,6-di-chloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxamide,

(3R,4S)-N-Cyclopropyl-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-N-[3-(2-methoxyethoxy)-5-(2-methoxyethyl)benzyl]piperidine-3-carboxamide,

(3R,4S)-N-[3 ,5-Bis(3-methoxypropyl)benzyl]-N-cyclopropyl-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxamide, and

(3R,4S)-N-[3,5-Bis(2-methoxyethoxy)benzyl]-N-cyclopropyl-4- {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxamide.

8. 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.

9. A method for the treatment of hypertension, comprising the administration to a patient of a pharmaceutically active amount of a compound according to claim 1 .

Assignments (3)
CHANGE OF NAME Recorded Jul 26, 2011
From: MERCK FROSST CANADA LTD.
To: MERCK CANADA INC.
Reel/Frame 026649/0605 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 11, 2011
From: DUBE, DANIEL; GALLANT, MICHEL; GRIMM, ERICH; JUTEAU, HELENE; LALIBERTE, SEBASTIEN; WU, TOM YAO-HSIANG
To: MERCK FROSST CANADA LTD
Reel/Frame 026570/0791 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 16, 2010
From: DUBE, DANIEL; GALLANT, MICHEL; GRIMM, ERIC; JUTEAU, HELENE; LALIBERTE, SEBASTIEN; WU, TOM YAO-HSIANG
To: MERCK FROSST CANADA LTD.
Reel/Frame 025513/0130 →
Continuity (2)
Provisional Application 60859914 · Nov 17, 2006
Related Publication 20100063091A1 · Mar 11, 2010