Imidazo-pyrimidines and triazolo-pyrimidines: benzodiazepine receptor ligands

Abstract

Compounds of Formula I are provided, as are methods for their preparation. The variables Z 1 , Z 2 , Z 3 , R 4 , R 5 , R 6 , R 7 , R 8 and Ar in the above formula are defined herein. Such compounds may be used to modulate ligand binding to GABA A receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting GABA A receptors (e.g., receptor localization studies).

1 - 45 . (canceled) 
     
     
         46 . A pharmaceutical composition comprising 7-[[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine in combination with a physiologically acceptable carrier or excipient. 
     
     
         47 . The pharmaceutical composition of  claim 46 , wherein the pharmaceutical composition is formulated as an injectible fluid, an aerosol, a cream, a gel, a tablet, a capsule, a syrup or a transdermal patch. 
     
     
         48 . The pharmaceutical composition of  claim 47  wherein the pharmaceutical composition is formulated as a tablet or a capsule. 
     
     
         49 . A method for inducing sleep in a patient, said method comprising administering to the patient an effective amount of 7-[[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine. 
     
     
         50 . The method of  claim 49  wherein the patient is a healthy patient. 
     
     
         51 . The method of  claim 49  wherein the 7-[[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine is administered orally. 
     
     
         52 . The method of  claim 49  wherein the 7-[[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine is formulated as an injectible fluid, an aerosol, a capsule, a tablet, a syrup, an elixir, or a transdermal patch. 
     
     
         53 . A method for altering the signal-transducing activity of GABA A  receptor, said method comprising contacting a cell expressing GABA A  receptor, under conditions suitable for binding of Flumazenil to the receptor, with a concentration of 7-[[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine sufficient to modulate GABA A  receptor. 
     
     
         54 . A method of preparing 7-[[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine, said method comprising drying 7-[[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine in vacuo. 
     
     
         55 . A method of preparing 7-[[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine, said method comprising the step of subjecting a 1,2,4-triazolo[4,3-c]pyrimidine intermediate to a Dimroth rearrangement. 
     
     
         56 . A GABA A  receptor to which 7-[[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine is bound. 
     
     
         57 . A method for the treatment of anxiety comprising administering to a patient in need of such treatment a therapeutically effective amount of 7-[[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine. 
     
     
         58 . A method of potentiating the antidepressant activity of a selective serotonin reuptake inhibitor, said method comprising co-administering a therapeutically effective amount of 7-[[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine in combination with a therapeutically effective amount of the selective serotonin reuptake inhibitor. 
     
     
         59 . A body fluid containing 7-[[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl]-2-methyl-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidine.