Substituted amides
View Patent ↗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.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof, wherein;
R 1 is selected from:
(1) aryl,
(2) aryl-C 1-4 alkyl,
(3) heteroaryl,
(4) heteroaryl-C 1-4 alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from R a , and each aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R b ;
R 2 is benzyl, unsubstituted or substituted with halogen, cyano, trifluoromethyl or methoxy;
R 3 is selected from:
(1) hydrogen, and
(2) C 1-4 alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from R a ;
R 4 is selected from:
(1) hydrogen, and
(2) C 1-4 alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from R a ;
R 5 is selected from:
(1) C 1-8 alkyl substituted with —OR d or NR c R d ,
(2) C 2-8 alkenyl substituted with OR d or NR c R d , and
(3) phenyl-C 1-8 alkyl wherein phenyl is substituted with one to three R b substitutents;
R 6 is selected from:
(1) C 1-4 alkyl,
(2) C 2-4 alkenyl,
(3) C 2-4 alkynyl,
(4) halogen, and
(5) —CN,
wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R a ;
each R a is independently selected from:
(1) —OR d ,
(2) —NR c S(O) m R d ,
(3) halogen,
(4) —S(O) m R d ,
(5) —S(O) m NR c R d ,
(6) —NR c R d ,
(7) —C(O)R d ,
(8) —CO 2 R d ,
(9) —CN,
(10) —C(O)NR c R d ,
(11) —NR c C(O)R d ,
(12) —NR c C(O)OR d ,
(13) —NR c C(O)NR c R d ,
(14) —CF 3 ,
(15) —OCF 3 , and
(16) cycloheteroalkyl;
each R b is independently selected from:
(1) R a ,
(2) C 1-10 alkyl,
(3) oxo,
(4) aryl,
(5) arylC 1-4 alkyl,
(6) heteroaryl, and
(7) heteroarylC 1-4 alkyl;
R c and R d are independently selected from:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 2-10 alkenyl,
(4) cycloalkyl,
(5) cycloalkyl-C 1-10 alkyl;
(6) cycloheteroalkyl,
(7) cycloheteroalkyl-C 1-10 alkyl;
(8) aryl,
(9) heteroaryl,
(10) aryl-C 1-10 alkyl, and
(11) heteroaryl-C 1-10 alkyl, or
R c and R d together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R g ,
each R c and R d may be unsubstituted or substituted with one to three substituents selected from R h ;
each R g is independently selected from: C 1-10 alkyl, and —C(O)R c ;
each R h is independently selected from:
(1) halogen,
(2) C 1-10 alkyl,
(3) —O C 1-4 alkyl,
(4) —S (O) m C 1-4 alkyl,
(5) —CN,
(6) —CF 3 , and
(7) —OCF 3 ; and
m is selected from 0, 1 and 2.
2. The compound according to claim 1 , wherein R 4 is selected from:
(1) hydrogen, and
(2) methyl;
and pharmaceutically acceptable salts thereof.
3. The compound according to claim 2 , wherein R 4 is hydrogen;
and pharmaceutically acceptable salts thereof.
4. The compound according to claim 2 , wherein R 3 is selected from hydrogen, methyl and ethyl; and pharmaceutically acceptable salts thereof.
5. The compound according to claim 3 , wherein R 3 is methyl; and pharmaceutically acceptable salts thereof.
6. The compound according to claim 4 , wherein R 1 is selected from:
(1) phenyl,
(2) phenyl-C 1-4 alkyl,
(3) pyridyl, and
(4) pyridyl-C 1-4 alkyl,
wherein each phenyl and pyridyl is optionally substituted with one or two substituents selected from halogen, methyl, trifluoromethyl, cyano and methoxy, and each pyridyl is optionally present as the N-oxide;
and pharmaceutically acceptable salts thereof.
7. The compound according to claim 5 , wherein R 1 is phenyl, unsubstituted or substituted with a halogen or cyano substituent; and pharmaceutically acceptable salts thereof.
8. The compound according to claim 7 , wherein R 2 is 4-chlorobenzyl, and pharmaceutically acceptable salts thereof.
9. The compound according to claim 8 , wherein R 6 is selected from:
(1) methyl,
(2) halogen, and
(3) —CN;
and pharmaceutically acceptable salts thereof.
10. The compound according to claim 1 , wherein R 5 is:
and pharmaceutically acceptable salts thereof.
11. The compound according to claim 1 , selected from:
(1) N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-1,2-dimethyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,
(2) N-{[3-(4-chlorophenyl)-2-cyano-2-phenyl-1-methyl]propyl}-2-(5-trifluoromethyl-2pyridyloxy)-2-methylpropanamide,
(3) N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-fluoro-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,
(4) N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-2-(5-triflouromethyl-2-pyridyloxy)-2-methylpropanamide,
(5) N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1,2-dimethyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,
(6) 1-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-3-[2-(phenyl)ethyl)urea, and
(7) N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-fluoro-1(S)-methyl]propyl}-1-ethyl-cyclobutanecarboxamide,
and pharmaceutically acceptable salts thereof.
12. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.