US 6,972,295 B2Granted

Substituted amides

AssigneeMerck & Co., Inc.

InventorsWilliam K. Hagmann, Linus S. Lin, Shrenik K. Shah, Ravindra N. Guthikonda, Hongbo Qi, Linda L. Chang, Ping Liu, Helen M. Armstrong, James P. Jewell, Thomas J. Lanza, Jr.

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Abstract

Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.

A compound of structural fomula I:

or a pharmaceutically acceptable salt thereof, wherein;
R1 is selected from:
(1) aryl, and
(2) aryl-C1-4alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from Ra, and each aryl is optionally substituted with one to four substituents independently selected from Rb;
R2 is selected from:
(1) aryl,
(2) aryl-C1-4alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from Ra, and each aryl is optionally substituted with one to four substituents independently selected from Rb;
R3 is selected from:
(1) hydrogen, and
(2) C1-4alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from Ra;
R4 is selected from:
(1) hydrogen, and
(2) C1-4alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from Ra;
R5 is selected from pyridyloxy and C1-8alkyl substituted with pyridyloxy, wherein alkyl is optionally substituted with one to four substituents independently selected from Ra, and pyridyl is unsubstituted or substituted with one to three substituents selected from Rh,
each Ra is independently selected from:
(1) —ORd,
(2) —NRcS(O)mRd,
(3) halogen,
(4) —SRd,
(5) —S(O)mNRcRd,
(6) —NRcRd,
(7) —C(O)Rd,
(8) —CO2Rd,
(9) —CN,
(10) —C(O)NRcRd,
(11) —NRcC(O)Rd,
(12) —NRcC(O)ORd,
(13) —NRcC(O)NRcRd,
(14) —CF3, and
(15) —OCF3;
each Rb is independently selected from:
(1) Ra,
(2) C1-10alkyl,
(3) oxo,
(4) aryl, and
(5) arylC1-4alkyl;
Rc and Rd are independently selected from:
(1) hydrogen,
(2) C1-10alkyl,
(3) C2-10alkenyl,
(4) cycloalkyl,
(5) cycloalkyl-C1-10alkyl,
(6) aryl, and
(7) aryl-C1-10alkyl,
each Rc and Rd may be unsubstituted or substituted with one to three substituents selected from Rh;
each Rh is independently selected from:
(1) halogen,
(2) C1-10alkyl,
(3) —OC1-4alkyl,
(4) —SC1-4alkyl,
(5) —CN,
(6) —CF3, and
(7) —OCF3,
m is selected from 1 and 2.

55 more elements

Facts

Application

10/387,265Filed 12 Mar 2003 · us provisional application

Priority

12 Mar 2002

Published

US 2004/0058820 A125 Mar 2004

Granted

6 Dec 2005

Term ends

Not estimatedThe source records don’t support an estimate.

Classification81 codes

C07D 213/64
One oxygen atom: attached in position 2 or 6
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/10
Drugs for disorders of the alimentary tract or the digestive system: laxatives
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…

Abstract

Claims20