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 composition comprising a compound of structural formula I:
or a pharmaceutically acceptable salt thereof, 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 oresent as the N-oxide;
R 2 is selected from:
(1) cyclopropylmethyl,
(2) cyclobutylmethyl,
(3) cyclopentylmethyl,
(4) cyclohexylmethyl,
(5) phenyl,
(6) benzyl,
(7) phenylethyl,
(8) 3-phenylpropyl,
(9) 2-phenylpropyl, and
(10) pyridylmethyl,
wherein each cycloalkyl, aryl and heteroaryl is optionally substituted with one or two R b substituents selected from halogen, trifluoromethyl, cyano, methoxycarbonyl, and 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 1-10 alkyl,
(2) C 2-10 alkenyl,
(3) C 3-10 cycloalkyl,
(4) C 3-10 cycloalkyl-C 1-10 alkyl,
(5) cycloheteroalkyl-C 1-10 alkyl,
(6) aryl-C 1-10 alkyl,
(7) diaryl-C 1-10 alkyl,
(8) aryl-C 2-10 alkenyl,
(9) heteroaryl-C 1-10 alkyl,
wherein alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl are optionally substituted with one to four substituents independently selected from R a and cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R b , provided that R 5 is not —CH═CH—COOH;
R 6 is selected from:
(1) —OR d , and
(2) —NR c R d ;
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) —OC 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;
and a pharmaceutically acceptable carrier.
2. The composition according to claim 1 , wherein in the compound of structural formula I or pharmaceutically acceptable salt thereof, R 4 is selected from:
(1) hydrogen, and
(2) methyl.
3. The composition according to claim 2 , wherein in the compound of structural formula I or pharmaceutically acceptable salt thereof, R 4 is hydrogen.
4. The composition according to claim 2 , wherein in the compound of structural formula I or pharmaceutically acceptable salt thereof, R 3 is selected from hydrogen, methyl and ethyl.
5. The composition according to claim 3 , wherein in the compound of structural formula I or pharmaceutically acceptable salt thereof, R 3 is methyl.
6. The composition according to claim 5 , wherein in the compound of structural formula I or pharmaceutically acceptable salt thereof, R 1 is phenyl, unsubstituted or substituted with a halogen or cyano substituent.
7. The composition according to claim 6 , wherein in the compound of structural formula I or pharmaceutically acceptable salt thereof, R 2 is 4-chlorobenzyl.
8. The composition according to claim 7 , wherein in the compound of structural formula I or pharmaceutically acceptable salt thereof, R 6 is hydroxyl.
9. The composition according to claim 7 , wherein in the compound of structural formula I or pharmaceutically acceptable salt thereof, R 5 is selected from:
(1) C 1-8 alkyl,
(2) C 2-8 alkenyl,
(3) cycloheteroalkyl-C 1-8 alkyl,
(4) aryl-C 1-8 alkyl,
(5) diaryl-C 1-4 alkyl,
(6) aryl-C 2-8 alkenyl, and
(7) heteroaryl-C 1-8 alkyl,
wherein each alkyl or alkenyl is optionally substituted with one or two substituents independently selected from R a , and each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is each optionally substituted with one to three substituents independently selected from R b and wherein cycloheteroalkyl is selected from pyrrolidinyl, 2H-phthalazinyl, azabicyclo[2.2.1]heptanyl, benzoxapinyl, morpholinyl, piperazinyl, dihydroimidazo[2,1-b]thiazolyl, and piperidinyl; aryl is selected from phenyl and naphthyl; and heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, benzothiazolyl, benzoxazolinyl, isoxazolyl, indolyl and thiazolyl.
10. The composition according to claim 8 , wherein in the compound of structural formula I or pharmaceutically acceptable salt thereof, 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.
11. The composition according to claim 10 , wherein in the compound of structural formula I or pharmaceutically acceptable salt thereof, R 5 is:
12. The composition according to claim 1 , wherein the compound of structural formula I is selected from:
(1) N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,
(2) N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridytoxy)-2-methylpropanamide,
(3) N-{[3-(4-chlorophenyl)-2-(3-bromophenyl)-2-hydroxy-1(R)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropananiide,
(4) N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-phenylbutanamide,
(5) N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-1-phenyl-cyclobutanecarboxamide,
(6) N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-phenyl-butanamide,
(7) N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(S)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,
(8) N-{[3-(4-chlorophenyl)-2-(3-cyanophenyl)-2-hydroxy-1(R)-methyl]propyl}-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,
or a pharmaceutically acceptable salt thereof.
13. The composition according to claim 1 comprising the compound:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.