Novel 5-HT 3 receptor modulators are disclosed. These compounds are used in the treatment of various disorders, including chemotherapy-induced nausea and vomiting, post-operative nausea and vomiting, and irritable bowel syndrome. Methods of making these compounds are also described in the present invention.
1. A compound having the following formula:
wherein:
X is CH or N;
each R 1 is independently selected from the group consisting of H, halogen, —OR 4 , or C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 7 , —NR 7 R 8 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 7 , or —NR 7 R 8 ;
R 2 is H;
R 4 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 6 , phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;
R 6 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or phenyl;
R 7 and R 8 are each independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 6 , phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
n is 1 or 2; and
p is 0, 1, 2, or 3;
or an oxide thereof or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 in the (S) configuration.
3. The compound according to claim 1 in the (R) configuration.
4. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
5. A method of treating irritable bowel syndrome comprising:
selecting a patient with irritable bowel syndrome; and
administering to the patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
6. The method according to claim 5 further comprising:
administering to the patient a therapeutically effective amount of a second serotonin 5-HT 3 receptor modulator or a serotonin 5-HT 4 receptor modulator.
7. The method according to claim 6 , wherein the second serotonin 5HT 3 receptor modulator or serotonin 5HT 4 receptor modulator is selected from the group consisting of Alosetron, renzapride, cilansetron, Tegaserod, Prucalopride, ondansetron, somatostatin analogs, muscarinic receptor antagonists, laxatives, antispasmodics, antidepressants, antidiarrheal agents, prokinetic agents, peripheral opiate narcotic antagonists, and combinations thereof.
8. A method of treating emesis comprising:
selecting a patient with emesis; and
administering to the patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
9. The method according to claim 8 further comprising:
administering to the patient a therapeutically effective amount of one or more other anti-emetic compounds.
10. The method according to claim 9 , wherein the one or more other anti-emetic compounds are selected from the group consisting of dexamethasone, alosetron, alprazolam, aprepitant, dimenhydrinate, diphenhydramine, dolasetron, tetrahydrocannabinol, nabilone, dronabinol, droperidol, granisetron, haloperidol, lorazepam, metoclopramide, midazolam, olanzapine, ondansetron, palonosetron, proclorperazine, promethazine, tropisetron, and combinations thereof.