Tryptamine sulfonamides as 5-HT
View Patent ↗Novel compounds of the structural formula (I) are antagonists of the 5-HT 6 receptor and are useful in the treatment, prevention and suppression of diseases mediated by the 5-HT 6 receptor. The compounds of the present invention are useful in the treatment of obesity, diabetes, metabolic disorder, cognitive disorders, age related cognitive disorder, depression, mania, bipolar disorders, schizophrenia, anxiety, generalized anxiety disorder, panic disorder, and obsessive compulsive disorder, epilepsy, convulsions, migraine, substance withdrawal from substances including but not limited to opiates, nicotine, tobacco products, alcohol, benzodiazepines, sedatives, and the like, sleep disorders, attention deficit/hyperactivity disorder, and Alzheimer's disease.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of:
(1) —O—,
(2) —NH—,
(3) —S—,
(4) —SO 2 —,
(5) —CH 2 —,
(6) —CHF—,
(7) —CF 2 —,
(8) —CH(OH)—,
(9) —CO—,
(10) —NHCO—,
(11) —CONH—, and
(12) —CO 2 —;
R 1 is selected from the group consisting of:
(1) -hydrogen, and
(2) —C 1-3 alkyl;
R 2 is selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —C 3-7 cycloalkyl,
(3) —C 2-6 cycloheteroalkyl,
(4) phenyl,
(5) naphthyl, and
(6) heteroaryl,
wherein each alkyl, cycloalkyl, cycloheteroalkyl, phenyl, naphthyl and heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents selected from —C 1-6 alkyl, —C 3-7 cycloalkyl, halogen, —CF 3 , —OCF 3 , —CN, —SO 2 R 7 , —CO 2 R 8 , phenyl, —C 2-6 cycloheteroalkyl, —OR 7 , —SR 7 , —CONHR 8 , —NHSO 2 R 7 , and —NHCOR 7 ;
R 3 and R 4 are each independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl,
(4) —OC 1-6 alkyl,
(5) —CN,
(6) —OR 7 ,
(7) —SO 2 R 7 ,
(8) —SR 7 ,
(9) —N(R 8 ) 2 ,
(10) —CONHR 8 ,
(11) —NHSO 2 R 7 , and
(12) —NHCOR 7 ,
wherein each alkyl is unsubstituted or substituted on each carbon with 1, 2 or 3 substituents selected from halogen, —C 1-6 alkyl, —C 3-7 cycloalkyl, —CF 3 , —OCF 3 , —CN, —SO 2 R 7 , —CO 2 R 8 , phenyl, —C 2-6 cycloheteroalkyl, —OR 7 , —SR 7 , —CONHR 8 , —NHSO 2 R 7 , and —NHCOR 7 ;
R 5 is selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —C 1-6 alkenyl,
(3) phenyl, and
(4) benzyl,
wherein each alkyl, alkenyl, phenyl and benzyl is unsubstituted or substituted on each carbon with 1, 2 or 3 substituents selected from: halogen, —C 1-6 alkyl, —C 3-7 cycloalkyl, —CF 3 , —OCF 3 , —CN, —SO 2 R 7 , —CO 2 R 8 , phenyl, —C 2-6 cycloheteroalkyl, —OR 7 , —SR 7 , —CONHR 8 , —NHSO 2 R 7 , and —NHCOR 7 ;
R 6 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-4 alkyl;
R 7 is selected from the group consisting of:
(1) —C 1-6 alkyl, and
(2) —C 3-6 cycloalkyl; and
R 8 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —C 3-6 cycloalkyl.
2. The compound according to claim 1 , wherein R 1 and R 6 are hydrogen; or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 , wherein X is —O—; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 , wherein R 3 is selected from the group consisting of:
(1) hydrogen,
(2) fluoro,
(3) chloro,
(4) bromo,
(5) —CF 3 ,
(6) —OCF 3 ,
(7) —CN,
(8) —OR 7 ,
(9) —SO 2 R 7 , and
(10) —SR 7 ;
or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 4 , wherein R 4 is selected from the group consisting of:
(1) hydrogen,
(2) fluoro, and
(3) chloro;
or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5 , wherein R 3 is fluoro and R 4 is hydrogen; or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 , wherein R 2 is selected from:
(1) methyl,
(2) ethyl,
(3) isopropyl, and
(4) phenyl,
wherein phenyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, CF 3 , OCF 3 and —OCH 3 ; or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1 , wherein R 5 is C 2-4 alkyl, wherein each alkyl carbon is unsubstituted or substituted with 1, 2 or 3 fluoro substituents; or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 , wherein R 5 is —CH 2 CF 2 CHF 2 ; or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 of structural formula IC:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from:
(1) methyl,
(2) ethyl,
(3) isopropyl, and
(4) phenyl,
wherein phenyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, CF 3 , OCF 3 and —OCH 3 ; and
R 5 is C 2-4 alkyl, wherein each alkyl carbon is unsubstituted or substituted with 1, 2 or 3 fluoro substituents.
11. The compound according to claim 1 , selected from:
or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1 , selected from:
or a pharmaceutically acceptable salt thereof.
13. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
14. A composition comprising a compound according to claim 1 and a compound selected from simvastatin, taranabant, ezetimibe and sitagliptin; and a pharmaceutically acceptable carrier.
15. A method of treating obesity in a patient in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 1 .