Use of selective gaba a alpha 5 negative allosteric modulators for the treatment of central nervous system conditions

Abstract

The present invention relates to the pharmaceutical use of selective GABA A α5 negative allosteric modulators for the treatment, prevention and/or delay of progression of central nervous system (CNS) conditions related to excessive GABAergic inhibition in the brain.

1 . A method of treating or delaying the progression of CNS conditions related to excessive GABAergic inhibition in the cortex and hippocampus comprising administering to a subject having such condition a therapeutically effective amount of a GABA A α5 negative allosteric modulator of formula (I) or formula (II) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen, halo, alkyl, haloalkyl, or cyano; 
         R 2  is hydrogen, halo, alkyl, haloalkyl, or cyano; 
         R 3  is hydrogen, alkyl, or heterocycloalkylalkyl, wherein heterocycloalkylalkyl is optionally substituted with one or more hydroxy, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, halo, or cyano; 
         R 4  is aryl or heteroaryl, each optionally substituted by one, two or three halo; 
         R 5  is hydrogen, alkyl, haloalkyl or hydroxyalkyl; 
         R 6  is —C(O)—NR 7 R 8    
         R 7  is hydrogen; 
         R 8  is alkyl; 
         or R 7  and R 8  together with the nitrogen to which they are bound form a heterocycloalkyl, or a heteroaryl, each optionally substituted with one or more hydroxy, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, halo, or cyano; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the excessive GABAergic inhibition in the cortex and hippocampus is caused by neurodevelopmental defects. 
     
     
         3 . The method of  claim 1 , wherein the CNS conditions are caused by neurodevelopmental defects which result in excessive GABAergic inhibition in the cortex and hippocampus. 
     
     
         4 . The method of  claim 1 , wherein said CNS condition is selected from cognitive deficits in Down Syndrome, cognitive deficits in autism and cognitive deficits in neurofibromatosis type I. 
     
     
         5 . The method of  claim 4 , wherein said CNS condition is cognitive deficits in Down Syndrome. 
     
     
         6 . The method of  claim 4 , wherein said CNS condition is cognitive deficits in autism. 
     
     
         7 . The method of  claim 4 , wherein said CNS condition is cognitive deficits in neurofibromatosis type I. 
     
     
         8 . The method of  claim 1 , wherein said CNS condition is cognitive deficits after stroke. 
     
     
         9 . The method of  claim 1 , wherein said GABA A α5 negative allosteric modulator binds to human GABA A α5β3γ2 receptor subtype with a binding selectivity of a factor of 10 or more as compared to binding affinities to human GABA A α1β2/3γ2, α2β3γ2 and α3β3γ2 receptor subtypes. 
     
     
         10 . The method of  claim 1 , wherein said GABA A α5 negative allosteric modulator exhibits a functional selectivity by acting as inverse agonist at human GABA A α5β3γ2 receptor subtype by reducing the effect of GABA by more than 30% and in addition affecting the effect of GABA at human GABA A α1β2/3γ2, α2β3γ2 and α3β3γ2 receptor subtypes by less than 15%. 
     
     
         11 . The method of  claim 1 , wherein said GABA A α5 negative allosteric modulator is selected from a compound of formula (I) or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method of  claim 11 , wherein R 1  is hydrogen, halo, haloalkyl, or cyano; R 2  is halo, or haloalkyl; R 3  is hydrogen, alkyl, or heterocycloalkylalkyl substituted with one oxof. 
     
     
         13 . The method of  claim 12 , wherein said GABA A α5 negative allosteric modulator is selected from
 3-Fluoro-10-fluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine; 
 3-Bromo-10-difluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine; 
 3-Cyano-10-difluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine; 
 10-Difluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine; 
 3-Chloro-10-fluoromethyl-6-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine; 
 10-Chloro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine; 
 3,10-Dichloro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine; 
 10-Chloro-3-cyano-6-methyl-9H-imidazo[1,5-d][1,2,4]triazolo[1,5-d][1,4]benzodiazepine; 
 10-Chloro-3-difluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine; 
 3-Bromo-10-chloro-6-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine; 
 10-Bromo-3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine; and 
 3-Bromo-10-methyl-6-(2-oxo-pyrrolidin-1-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         14 . The method of  claim 1 , wherein said GABA A α5 negative allosteric modulator is selected from a compound of formula (II) or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 14 , wherein R 4  is aryl or heteroaryl, each optionally substituted by one halo; R 5  is alkyl; R 6  is C(O)—NR 7 R 8 ; R 7  is hydrogen and R 8  is alkyl; or R 7  and R 8  together with the nitrogen to which they are bound form a heterocycloalkyl optionally substituted with one or two oxo, or form a heteroaryl. 
     
     
         16 . The method of  claim 15 , wherein said GABA A α5 negative allosteric modulator is selected from:
 N-Isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide; 
 (5,6-Dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]methanone; 
 [6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone; 
 (1,1-Dioxo-1,6-thiomorpholin-4-yl)-{6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]pyridin-3-yl}-methanone; 
 {6[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]pyridin-3-yl}-morpholin-4-yl-methanone; 
 [6-(5-Methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy-pyridin-3-yl]-morpholin-4-yl-methanone; 
 6-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]isopropyl-nicotinamide; 
 (1,1-Dioxo-1,6-thiomorpholin-4-yl)-{6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone; and 
 {6-[3-(5-Chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-thiomorpholin-4-yl-methanone; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         17 . The method of  claim 16 , wherein said GABA A α5 negative allosteric modulator is (1,1-Dioxo-1,6-thiomorpholin-4-yl)-{6[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method of  claim 1 , wherein said GABA A α5 negative allosteric modulator is used separately, sequentially or simultaneously in combination with a second active pharmaceutical compound.