2-aminobenzoxazole carboxamides as 5HT3 modulators
View Patent ↗Compounds of formulae I, II and III: are disclosed as 5-HT3 inhibitors. The compounds are useful in treating CINV, IBS-D and other diseases and conditions.
1. A compound of formula I, II or III:
wherein R 1 , R 2 and R 3 are independently selected from hydrogen, halogen, cyano, alkyl or aryl sulfoxide, alkyl or aryl sulfone, amino, alkylamino, dialkylamino, acylamino, morpholinyl, —O-loweralkyl, hydroxy, loweralkyl, fluoroloweralkyl, O lowerfluoroalkyl, methylenedioxy, ethylenedioxy, alkoxy-loweralkyl and hydroxyloweralkyk;R 4 is a group chosen from:
(i) a saturated nitrogen heterocycle or methyl-substituted saturated nitrogen heterocycle, in which said nitrogen is tertiary, said heterocycle containing at least one 5 or 6-membered ring; and
(ii) an imidazolylalkyl residue wherein the imidazole of said imidazolylalkyl is optionally substituted with up to three groups chosen from halogen, (C 1 -C 4 )alkyl, substituted (C 1 -C 4 )alkyl and NH 2 ; and
R 10 is chosen from the group consisting of
(i) hydrogen;
(ii) (C 1 -C 10 )alkyl;
(iii) substituted (C 1 -C 10 )alkyl;
(iv) heterocyclyl;
(v) substituted heterocyclyl;
(vi) aryl; and
(vii) substituted aryl;
R 11 is chosen from the group consisting of hydrogen and (C 1 -C 10 )alkyl; or
taken together R 10 , R 11 and the nitrogen to which they are attached form a nitrogenous heterocyle or substituted nitrogenous heterocycle, with the proviso that, when R 10 , R 11 and nitrogen form a morpholine ring, the compound is not endo-N-(3,9-dimethyl-3,9-diazabicyclo[3.3.1] nonan-7-yl)-2morpholinobenzoxazole-4-carboxamide.
2. A compound according to claim 1 of formula Ia or Ib:
3. A compound according to claim 1 of formula IIa or IIb:
4. A compound according to claim 1 of formula IIIa or IIIb:
5. A compound according to claim 1 wherein R4 is chosen from:
and
wherein
m is 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
Q is N(CH 3 ) or —O—; and
R 5 is hydrogen or methyl.
6. A compound according to claim 1 wherein R 4 is chosen from quinuclidine, tropane, azabicyclo[3.3.1]nonane, methyl azabicyclo[3.3.1]nonane, dimethyl diazabicyclo[3.3.1]nonane, methylpiperidine and methyl-3-oxa-9-azabicyclo[3.3.1]nonane.
7. A compound according to claim 1 wherein R 1 , R 2 and R 3 are hydrogen.
8. A compound according to claim 1 wherein one of R 1 , R 2 and R 3 is halogen.
9. A compound according to claim 1 wherein R 10 is chosen from the group consisting of hydrogen and (C 1 to C 3 )alkyl.
10. A compound according to claim 3 wherein R 11 is H or CH 3 .
11. A compound according to claim 1 , wherein R 10 is chosen from the group consisting of phenyl, substituted phenyl, (C 1 -C 6 )alkyl, 4 to 7-membered monocyclic nitrogenous heterocycle, 4 to 10 carbon bicyclic nitrogenous heterocycle, 4 to 7-membered monocyclic nitrogenous heterocycle substituted with one or more (C 1 -C 6 )alkyl, 4 to 10 carbon bicyclic nitrogenous heterocycle substituted with one or more (C 1 -C 6 )alkyl, dimethylamino(C 1 -C 6 )alkyl, 4 to 7-membered monocyclic nitrogenous heterocyclyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, and dialkylaminocarbonyl(C 1 -C 6 )alkyl.
12. A compound according to claim 3 , wherein R 10 and R 11 , taken together, form a nitrogenous heterocycle or substituted nitrogenous heterocycle.
13. A compound according to claim 10 , wherein R 10 and R 11 , taken together, form a morpholine, piperazine, piperidine, diazepam, tetrahydroquinoxaline, triazolopyrazine, azabicyclo[3.3.1]nonane, diazabicyclo[2.2.1]heptane, or any of the foregoing substituted with one, two or three substituents chosen independently from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy phenyl and heteroaryl.
14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 .
15. A pharmaceutical composition according to claim 14 additionally comprising a second antiemetic agent.
16. A pharmaceutical composition according to claim 15 , wherein said second antiemetic agent is a neurokinin antagonist.
17. A pharmaceutical composition according to claim 14 additionally comprising a corticosteroid.
18. A method of treating irritable bowel syndrome, emesis, post-operative nausea or vomiting, a psychological disorder, obesity, substance abuse disorders, dementia associated with a neurodegenerative disease, cognition deficits, pain or pain management, fibromyalgia syndrome, chronic fatigue syndrome, bronchial asthma, bulimia nervosa, sleep apnea, pruritis, radiation-induced nausea and vomiting, or epilepsy, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 .
19. A method according to claim 18 , wherein said disorder is irritable bowel syndrome.
20. A method according to claim 18 for treating emesis.
21. A method according to claim 18 for treating post-operative nausea or vomiting.
22. A method according to claim 18 for treating a psychological disorder.
23. A method according to claim 22 , wherein said psychological disorder is chosen from depression, psychosis, schizophrenia, anxiety and appetite disorder.
24. A method according to claim 18 for treating obesity.
25. A method according to claim 18 for treating substance abuse disorders.
26. A method according to claim 25 , wherein said substance abuse disorder is chosen from chemical dependency, cocaine addiction, alcohol dependence and amphetamine addiction.
27. A method according to claim 18 for treating dementia associated with a neurodegenerative disease.
28. A method according to claim 18 for treating cognition deficits.
29. A method according to claim 18 for treating pain or for pain management.
30. A method according to claim 18 for treating fibromyalgia syndrome.
31. A method according to claim 18 for treating chronic fatigue syndrome.
32. A method according to claim 18 for treating or preventing bronchial asthma.
33. A method according to claim 18 for treating bulimia nervosa.
34. A method according to claim 18 for treating sleep apnea.
35. A method according to claim 18 for treating pruritis.
36. A method according to claim 18 for treating radiation-induced nausea and vomiting.
37. A method according to claim 18 for treating epilepsy.