Imidazo[1,2-a]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto

Patent metadata

Field	Value
Publication number	US-9567327-B2
Application number	US-67346308-A
Country	US
Kind code	B2
Filing date	Aug 14, 2008
Priority date	Aug 15, 2007
Publication date	Feb 14, 2017
Grant date	Feb 14, 2017

Abstract

rmidazo[1,2-α]pyridine derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the 5-HT 2A serotonin receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of insomnia, dyssomnia, parasomnia and related sleep disorders, platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, thrombosis, asthma or symptoms thereof, agitation or symptoms thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de Ia Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like. The present invention also relates to methods for the treatment of 5-HT 2A serotonin receptor mediated disorders in combination with other pharmaceutical agents administered separately or together.

First claim

What is claimed is:

1. A compound selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of H, C 1 -C 6 acyl, C 1 -C 6 acyloxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonylamino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 2 -C 8 dialkylamino, C 1 -C 6 alkylcarboxamide, C 1 -C 6 alkylsulfonamide, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylureyl, amino, aryl, aryl-C 1 -C 4 -alkylenyl, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 2 -C 6 dialkylcarboxamide, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 haloalkylsulfonyl, halogen, heteroaryl, heterocyclyl, hydroxyl, nitro and sulfonamide;
R 6 and R 7 are each independently selected from the group consisting of H, C 1 -C 6 acyl, C 1 -C 3 alkyl, aryl, carboxamide, carboxy, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, heteroaryl and heterocyclyl;
R 8 and R 9 are each independently selected from the group consisting of H, C 1 -C 6 acyl, C 1 -C 3 alkyl, aryl, carboxamide, C 1 -C 3 alkoxy, carboxy, cyano, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen and hydroxyl; or
R 8 and R 9 taken together form oxo; or
R 8 and R 9 together with the atom to which they are both bonded form a C 3 -C 7 cycloalkyl ring; and
R 10 , R 11 , R 12 , R 13 and 14 are each independently selected from the group consisting of H, C 1 -C 6 acyl, C 1 -C 6 acyloxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonylamino, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonamide, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylureyl, amino, carbo-C 1 -C 6 alkoxy, carboxamide, carboxy, cyano, C 3 -C 6 cycloalkyl, C 3 -C 7 cycloalkylcarbonyl, C 2 -C 8 dialkylamino, C 2 -C 6 dialkylcarboxamide, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 haloalkylsulfonyl, halogen, heteroaryl, heterocyclyl, hydroxyl, nitro, phenyl, sulfonamide and sulfonic acid; wherein said phenyl group is optionally substituted with 1, 2 or 3 halogens.

2. The compound according to claim 1 , wherein R 1 and R 2 are each independently selected from the group consisting of H, C 1 -C 6 acyloxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, aryl, aryl-C 1 -C 4 -alkylenyl, carbo-C 1 -C 6 alkoxy, carboxy, cyano, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heterocyclyl and hydroxyl.

3. The compound according to claim 2 , wherein R 1 and R 2 are each independently selected from the group consisting of H, methyl, t-butyl, phenyl, cyano, trifluoromethyl, chloro and bromo.

4. The compound according to claim 3 , wherein R 1 is H; and R 2 is cyano, chloro or bromo.

5. The compound according to claim 3 , wherein R 1 and R 2 are both H.

6. The compound according to claim 1 , wherein R 3 , R 4 and R 5 are each independently selected from the group consisting of H, methyl, methoxy and bromo.

7. The compound according to claim 6 , wherein R 3 , R 4 and R 5 are each H.

8. The compound according to claim 1 , wherein R 6 and R 7 are each independently selected from the group consisting of H and methyl.

9. The compound according to claim 8 , wherein R 6 and R 7 are both H.

10. The compound according to claim 1 , wherein:
R 8 and R 9 are each independently selected from the group consisting of H, C 1 -C 3 alkyl, aryl, C 1 -C 3 alkoxy, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen and hydroxyl; or
R 8 and R 9 taken together form oxo; or
R 8 and R 9 together with the atom to which they are both bonded form a C 3 -C 7 cycloalkyl ring.

11. The compound according to claim 10 , wherein R 8 and R 9 are both H.

12. The compound according to claim 10 , wherein R 8 and R 9 together form oxo.

13. The compound according to claim 1 , wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of H, C 1 -C 6 acyloxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 2 -C 8 dialkylamino, C 1 -C 6 alkylcarboxamide, C 1 -C 6 alkylsulfonamide, C 1 -C 6 alkylsulfonyl, amino, carboxamide, carboxy, cyano, C 3 -C 6 cycloalkyl, C 2 -C 6 dialkylcarboxamide, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heterocyclyl, hydroxyl, nitro, phenyl, sulfonamide and sulfonic acid; wherein said phenyl group is optionally substituted with 1, 2 or 3 halogens.

14. The compound according to claim 13 , wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of H, methyl, methoxy, dimethylamino, —NHSO 2 CH 3 , methylsulfonyl, carboxamide, carboxy, cyano, cyclohexyl, fluoro, chloro, trifluoromethoxy, difluoromethoxy, trifluoromethyl, morpholin-4-yl, pyrrolidin-1-yl, thien-2-yl, hydroxyl, nitro, phenyl and sulfonic acid.

15. The compound according to claim 14 , wherein:
R 10 and R 12 are both F; and
R 11 , R 13 and R 14 are each H.

16. The compound according to claim 1 , selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates or hydrates thereof:

wherein:
R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, aryl and C 1 -C 6 haloalkyl;
R 2 is selected from the group consisting of H, cyano and halogen;
R 8 and R 9 are each independently selected from the group consisting of H and halogen; or
R 8 and R 9 together form oxo; and
R 12 and R 14 are each independently selected from the group consisting of H and halogen.

17. The compound according to claim 1 , selected from compounds of Formula (Ic) and pharmaceutically acceptable salts, solvates or hydrates thereof:

wherein:
R 1 is selected from the group consisting of H, methyl, t-butyl, phenyl and trifluoromethyl;
R 2 is selected from the group consisting of H, cyano, chloro and bromo;
R 8 and R 9 are each independently selected from the group consisting of H and F; or R 8 and R 9 together form oxo; and
R 12 and R 14 are each independently selected from the group consisting of H, fluoro and chloro.

18. The compound according to claim 1 , selected from compounds of Formula (Ie) and pharmaceutically acceptable salts, solvates or hydrates thereof:

wherein:
R 6 and R 7 are each independently selected from the group consisting of H and C 1 -C 3 alkyl;
R 8 and R 9 are each independently selected from the group consisting of H and halogen; or
R 8 and R 9 together form oxo; and
R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 2 -C 8 dialkylamino, C 1 -C 6 alkylsulfonamide, C 1 -C 6 alkylsulfonyl, carboxamide, carboxy, cyano, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, heteroaryl, halogen, heterocyclyl, hydroxyl, nitro, phenyl and sulfonic acid.

Assignees

• Xiong Yifeng
• Feichtinger Konrad
• Ren Albert S
• Ullman Brett
• Arena Pharm Inc

Inventors

• Xiong Yifeng
• Feichtinger Konrad
• Ren Albert S
• Ullman Brett

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title