Imidazopyridines as serotonergic 5-HT.sub.3 -antagonists

• US 5,591,749 A
• Filed: 04/19/1995
• Issued: 01/07/1997
• Est. Priority Date: 03/07/1991
• Status: Expired due to Fees

• Current Assignee: GD Searle LLC (Pfizer Inc.)
• Original Assignee: GD Searle LLC (Pfizer Inc.)
• Inventors: Nosal, Roger, Flynn, Daniel L., Becker, Daniel P., Moormann, Alan E., Villamil, Clara I.
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): HUANG, EVELYN MEI
• Application Number:
  US08/424,934
• Time in Patent Office: 629 Days
• Field of Search: 546/121, 514/300
• US Class Current: 514/300
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The imidazopyridines compounds of the present invention are serotonergic 5-HT₃ antagonists. As such they are useful for the treatment of humans and animals wherein antagonism of 5-HT₃ receptors is beneficial. Therapy is indicated for, but not limited to, the treatment of anxiety, psychoses, depression (especially depression accompanied by anxiety), cognitive disorders, substance abuse dependence and withdrawal, gastrointestinal motility disturbances (including esophageal reflux, dyspepsia, gastric stasis, irritable bowel syndrome), emesis caused by chemotherapeutic agents, and visceral pain. Additionally, the compounds of the present invention may find utility as enhancers of nasal absorption of bioactive compounds.

Claims

1. A compound of the formula ##STR40## the stereoisomers and pharmaceutically acceptable salts thereof wherein R_l is selected from the group consisting of H and C_1-6 alkyl;

R₂ is selected from the group consisting of H and halogen;

Y is selected from the group consisting of NH and O;

d is 0 or 1; and

R'"'"'₅ is C_1-7 alkyl C_3-8 cycloalkyl C_3-8 cycloalkyl-C_1-2 -alkyl, C_2-7 alkenyl, C_2-7 alkenyl-C_1-4 -alkyl or phenyl-C_1-6 alkyl.

2. A compound according to claim 1 wherein

R, is H₁ and R₂ is H or halo,

Y is NH, and

wherein d is 0 or 1 and R'"'"'₅ is C_1-7 alkyl.

3. A compound of claim 2 wherein R₂ is chloro.

4. A pharmaceutical composition for the treatment of anxiety, psychoses, depression, substance abuse, cognitive disorders, gastrointestinal motility disturbances or conditions responsive to 5-HT₃ antagonists comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

5. A pharmaceutical composition of claim 4

wherein R₁ is H and R₂ is H or halo,

Y is NH, and

wherein d is 0 or 1 and R'"'"'₅ is C_1-7 alkyl.

6. A method of treating anxiety, psychoses, depression or gastrointestinal motility disturbances comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1.

7. The method of claim 6 wherein R₁ is H and R₂ is H or halo,

Y is NH, and

wherein d is 0 or 1 and R'"'"'₅ is C_1-7 alkyl.

8. The method of claim 7 wherein R₂ is chloro.

9. A compound according to claim 1 selected from the group consisting of

(endo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-6-chloroimidazo[1,2-a]pyridine-8-carboxamide, dihydrochloride);

(endo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)imidazo[1,2-a]pyridine-8-carboxamide, hydrochloride); and

(exo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)imidazo[1,2-a]pyridine-8-carboxamide, hydrochloride).

10. A pharmaceutical composition according to claim 4 wherein the compound is selected from the group consisting of:

(endo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-6-chloroimidazo[1,2 -a]pyridine-8 -carboxamide, dihydrochloride);

(endo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)imidazo[1,2-a]pyridine-8-carboxamide, hydrochloride); and

(exo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)imidazo[1,2-a]pyridine-8-carboxamide, hydrochloride).

11. The method of claim 6 wherein the compound is selected from the group consisting of:

(endo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-6-chloroimidazo[1,2-a]pyridine-8-carboxamide, dihydrochloride);

(endo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)imidazo[1,2-a]pyridine-8-carboxamide, hydrochloride); and

(exo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)imidazo[1,2-a]pyridine-8-carboxamide, hydrochloride).