Claims
- 1. A compound having the formula:
- 2. A compound or form thereof according to claim 1, wherein R1 is selected from:
(a) hydrogen and halogen; and (b) groups of the formula: 56wherein:
(i) G is a bond, —NH—, —N(RB)—, —O— or —C(═O)—; and (ii) RA and each RB are independently selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, piperidinyl, piperazinyl, morpholinyl, thienyl, pyridyl, pyrimidyl, pyrazolyl, thiazolyl and pyrazinyl, each of which is substituted with from 0 to 4 substituents independently selected from halogen, hydroxy, cyano, amino, C1-C2alkyl, and C1-C2alkoxy.
- 3. A compound according to claim 2, wherein R1 is:
(a) hydrogen or halogen; or (b) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, thienyl, pyridyl, pyrazolyl, thiazolyl or pyrimidinyl, each of which is unsubstituted or substituted with hydroxy or C1-C2alkoxy.
- 4. A compound or form thereof according to any one of claims 1-3, wherein R2 is hydrogen or C1-C4alkyl.
- 5. A compound or form thereof according to claim 4, wherein R2 is hydrogen or C1-C4alkyl.
- 6. A compound or form thereof according to any one of claims 1-5, wherein R3 is hydrogen, halogen, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C2-C6alkyl ether, C2-C6haloalkyl ether or mono- or di-(C1-C6alkyl)amino.
- 7. A compound or form thereof according to claim 6, wherein R3 is hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or mono- or di-(C1-C4alkyl)amino.
- 8. A compound or form thereof according to any one of claims 1-7, wherein R4 represents 0, 1 or 2 substituents independently chosen from halogen, hydroxy, methyl, ethyl, methoxy and trifluoromethyl.
- 9. A compound or form thereof according to claim 8, wherein R4 represents 0 substituents.
- 10. A compound or form thereof according to any one of claims 1-9, wherein Ar represents phenyl or a 5- or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently selected from halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C7cycloalkyl(C0-C6alkyl), C3-C7cycloalkyl(C1-C6alkoxy), 3- to 7-membered heterocycloalkyl(C0-C8alkyl), C1-C8aminoalkyl, C1-C6hydroxyalkyl, and mono- and di-(C1-C6alkyl)amino(C0-C6alkyl).
- 11. A compound or form thereof according to claim 10, wherein Ar represents phenyl, thiazolyl, pyrimidyl or pyridyl, each of which is substituted with from 0 to 4 substituents independently selected from halogen, hydroxy, cyano, amino, C1-C4alkyl, C1-C4alkenyl, C1-C4alkynyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy and mono- and di-(C1-C4alkyl)amino(C0-C4alkyl).
- 12. A compound or form thereof according to claim 11, wherein Ar represents phenyl, thiazolyl, or pyridyl, each of which is substituted with from 0 to 3 substituents independently chosen from chloro, fluoro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, C1-C2alkylamino, C1-C2haloalkyl and C1-C2haloalkoxy.
- 13. A compound or form thereof according to claim 12, wherein Ar represents phenyl or 2-pyridyl, each of which is substituted with 1, 2 or 3 substituents independently chosen from fluoro, chloro, cyano, trifluoromethyl and methyl.
- 14. A compound or form thereof according to claim 1, wherein:
R1 is:
(a) hydrogen or halogen; or (b) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, thienyl, pyridyl, pyrazolyl, thiazolyl or pyrimidinyl, each of which is unsubstituted or substituted with halogen, hydroxy or C1-C2alkoxy; R2 is hydrogen, halogen or C1-C4alkyl; R3 is hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, or mono- or di-(C1-C4alkyl)amino; R4 represents 0, 1 or 2 substituents independently chosen from halogen, hydroxy, methyl, ethyl, methoxy and trifluoromethyl; and Ar represents phenyl, thiazolyl, or pyridyl, each of which is substituted with from 0 to 3 substituents independently chosen from chloro, fluoro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, C1-C2alkylamino, C1-C2haloalkyl and C1-C2haloalkoxy.
- 15. A compound or form thereof according to claim 1, wherein the compound has the formula:
- 16. A compound or form thereof according to claim 15, wherein R1 is hydrogen, halogen, methyl or methoxy.
- 17. A compound or form thereof according to claim 15, wherein R1 is pyridyl, pyrazolyl or thiazolyl.
- 18. A compound or form thereof according to claim 1, wherein the compound is selected from:
{6-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidin-4-yl}-dimethyl-amine; 2-[1-(6-methyl-5-propyl-pyrimidin-4-ylmethyl)-1H-imidazol-2-yl]-nicotinonitrile; 2-[1-(6-methyl-5-propyl-pyrimidin-4-ylmethyl)-1H-imidazol-2-yl]-thiazole-4-carbonitrile; 3-[1-(5-ethyl-6-methyl-pyrimidin-4-ylmethyl)-1H-imidazol-2-yl]-benzonitrile; 4-[2-(2,5-difluoro-phenyl)-imidazol-1-ylmethyl]-5-ethyl-6-methyl-pyrimidine; 4-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-2-methyl-5-propyl-pyrimidine; 4-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-6-pyrazol-1-yl-pyrimidine; 4-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-6-pyrazin-2-yl-pyrimidine; 4-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-6-pyridin-4-yl-pyrimidine; 4-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-6-pyridin-3-yl-pyrimidine; 4-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-6-pyridin-2-yl-pyrimidine; 4-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-6-thiazol-2-yl-pyrimidine; 4-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine; 4-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-6-isopropoxy-5-propyl-pyrimidine; 4-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-6-methyl-5-propyl-pyrimidine; 4-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine; 4-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-6-methoxy-5-propyl-pyrimidine; 4-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-6-methyl-5-propyl-pyrimidine; 4-chloro-6-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-2-methyl-5-propyl-pyrimidine; 4-chloro-6-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine; 4-chloro-6-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-2-methyl-5-propyl-pyrimidine; 4-methyl-5-propyl-6-[2-(6-trifluoromethyl-pyridin-2-yl)-imidazol-1-ylmethyl]-pyrimidine; 5-(3-fluoro-propyl)-4-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-pyrimidine; 5-(3-fluoro-propyl)-4-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-6-methyl-pyrimidine; 6-[1-(5-propyl-pyrimidin-4-ylmethyl)-1H-imidazol-2-yl]-pyridine-2-carbonitrile; 6-[1-(6-methyl-5-propyl-pyrimidin-4-ylmethyl)-1H-imidazol-2-yl]-pyridine-2-carbonitrile; 6-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidin-4-ylamine; ethyl-{6-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidin-4-yl}-amine; and methyl-{6-[2-(3-methylamino-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidin-4-yl}-amine.
- 19. A compound or form thereof according to claim 1, wherein the compound exhibits a Ki of 1 micromolar or less in an assay of GABAA receptor binding.
- 20. A compound or form thereof according to claim 1, wherein the compound exhibits a Ki of 100 nanomolar or less in an assay of GABAA receptor binding.
- 21. A compound or form thereof according to claim 1, wherein the compound exhibits a Ki of 10 nanomolar or less in an assay of GABAA receptor binding.
- 22. A pharmaceutical composition comprising a compound or form thereof according to claim 1 in combination with a physiologically acceptable carrier or excipient.
- 23. A pharmaceutical composition according to claim 22, wherein the pharmaceutical composition is formulated as an injectible fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermal patch.
- 24. A method for the treatment of anxiety, depression, a sleep disorder, attention deficit disorder, or Alzheimer's dementia, comprising administering to a patient in need of such treatment a GABAA receptor modulatory amount of a compound or form thereof according to claim 1.
- 25. A method for potentiating a therapeutic effect of a CNS agent, comprising administering to a patient a CNS agent and a compound or form thereof according to claim 1.
- 26. A method for improving short term memory in a patient, comprising administering to a patient a GABAA receptor modulatory amount of a compound or form thereof according to claim 1.
- 27. A method for determining the presence or absence of GABAA receptor in a sample, comprising the steps of:
(a) contacting a sample with a compound or form thereof according claim 1, under conditions that permit binding of the compound to GABAA receptor; (b) removing the compound or form thereof that is not bound to GABAA receptor; and (c) detecting a level of the compound or form thereof bound to GABAA receptor; and therefrom determining the presence or absence of GABAA receptor in the sample.
- 28. A method according to claim 27, wherein the presence or absence of bound compound is detected using autoradiography.
- 29. A method for altering the signal-transducing activity of GABAA receptor, comprising contacting a cell expressing GABAA receptor with a compound or form thereof according claim 1 in an amount sufficient to detectably alter the electrophysiology of the cell, and thereby altering GABAA receptor signal-transducing activity.
- 30. A method according to claim 29, wherein the cell recombinantly expresses a heterologous GABAA receptor, and wherein the alteration of the electrophysiology of the cell is detected by intracellular recording or patch clamp recording.
- 31. A packaged pharmaceutical preparation comprising a pharmaceutical composition according to claim 22 in a container and instructions for using the composition to treat a patient suffering from anxiety, depression, a sleep disorder, attention deficit disorder, Alzheimer's dementia, or short-term memory loss.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application 60/424,945, filed Nov. 8, 2002.
Provisional Applications (1)
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Number |
Date |
Country |
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60424945 |
Nov 2002 |
US |