NMDA NR2B antagonists for treatment

Abstract

The invention provides new methods for treating certain disorders resulting from neurodegeneration and for treating depression which comprise administration of NR2B subunit selective NMDA antagonists. The disorders that can be treating by the invention include hearing loss, vision loss, neurodegeneration caused by epileptic seizures, neurotoxin poisoning, Restless Leg Syndrome, multi-system atrophy, non-vascular headache, and depression.

What is claimed is:  
     
         1 . A method of treating sensorineural hearing loss in a mammal, which method comprises administering to the mammal an amount of an NR2B subunit selective NMDA antagonist, which amount is effective in treating sensorineural hearing loss.  
     
     
         2 . A method according to  claim 1 , wherein the method is treating sensorineural hearing loss that is aminoglycoside-induced and/or of a genetic origin.  
     
     
         3 . A method according to  claim 1 , wherein the sensorineural hearing loss is sound-induced.  
     
     
         4 . A method according to  claim 1 , wherein the NR2B subunit selective NMDA receptor antagonist is a compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable acid addition salt thereof, wherein: 
 (a) R 2  and R 5  are taken separately and R 1 , R 2 , R 3  and R 4  are each independently hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , OH or OR 7  and R 5  is methyl or ethyl; or  
 (b) R 2  and R 5  are taken together and are  
                     
 forming a chroman-4-ol ring, and R 1 , R 3  and R 4  are each independently hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , OH or OR 7 ;  
 R 6  is  
                     
 R 7  is methyl, ethyl, isopropyl or n-propyl;  
 R 8  is phenyl optionally substituted with up to three substituents independently selected from the group consisting of (C 1 -C 6 ) alkyl, halo and CF 3 ;  
 X is O, S or (CH 2 ) n ; and  
 n is 0, 1, 2, or 3.  
 
     
     
         5 . A method according to  claim 1 , wherein the NR2B subunit selective NMDA receptor antagonist is 
 (+)-(1S,2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol;    (1S,2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol;    (3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chroman-4,7-diol;    a pharmaceutically-acceptable acid addition salt of one of said compounds; or    (1R*,2R*)-1-(4-hydroxy-3-methylphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol-mesylate.    
     
     
         6 . A method of treating neurological damage caused by epileptic seizures in a mammal, which method comprises administering to the mammal an amount of an NR2B subunit selective NMDA antagonist, which amount is effective in inhibiting neurological damage.  
     
     
         7 . A method according to  claim 6 , wherein said NR2B subtype selective NMDA receptor antagonist is a compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable acid addition salt thereof, wherein: 
 (a) R 2  and R 5  are taken separately and R 1 , R 2 , R 3  and R 4  are each independently hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , OH or OR 7  and R 5  is methyl or ethyl; or  
 (b) R 2  and R 5  are taken together and are  
                     
 forming a chroman-4-ol ring, and R 1 , R 3  and R 4  are each independently hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , OH or OR 7 ;  
                     
 R 7  is methyl, ethyl, isopropyl or n-propyl;  
 R 8  is phenyl optionally substituted with up to three substituents independently selected from the group consisting of (C 1 -C 6 ) alkyl, halo and CF 3 ;  
 X is O, S or (CH 2 ) n ; and  
 n is 0, 1, 2, or 3.  
 
     
     
         8 . A method according to  claim 6 , wherein the NR2B subunit selective NMDA receptor antagonist is (+)-(1S, 2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol; 
 (1S,2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol;    (3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chroman-4,7-diol;    a pharmaceutically-acceptable acid addition salt of one of said compounds; or (1R*,2R*)-1-(4-hydroxy-3-methylphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol-mesylate.    
     
     
         9 . A method of treating neurological damage caused by neurotoxin poisoning in a mammal, which method comprises administering to the mammal an amount of an NR2B subunit selective NMDA antagonist, which amount is effective in inhibiting neurological damage.  
     
     
         10 . A method according to  claim 9 , wherein the NR2B subunit selective NMDA receptor antagonist is a compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable acid addition salt thereof, wherein: 
 (a) R 2  and R 5  are taken separately and R 1 , R 2 , R 3  and R4 are each independently hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , OH or OR 7  and R 5  is methyl or ethyl; or  
 (b) R 2  and R 5  are taken together and are  
                     
 forming a chroman-4-ol ring, and R 1 , R 3  and R 4  are each independently hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , OH or OR 7 ;  
 R 6  is  
                     
 R 7  is methyl, ethyl, isopropyl or n-propyl;  
 R 8  is phenyl optionally substituted with up to three substituents independently selected from the group consisting of (C 1 -C 6 ) alkyl, halo and CF 3 ;  
 X is O, S or (CH 2 ) n ; and  
 n is 0, 1, 2, or 3.  
 
     
     
         11 . A method according to  claim 9 , wherein the NR2B subunit selective NMDA receptor antagonist is (+)-(1S, 2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy4-phenylpiperidino)-1-propanol; 
 (1S,2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol;    (3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chroman-4,7-diol;    a pharmaceutically-acceptable acid addition salt of one of said compounds; or (1R*,2R*)-1-(4-hydroxy-3-methylphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol-mesylate.    
     
     
         12 . A method of treating vision loss caused by neurodegeneration of the visual pathway in a mammal, which method comprises administering to the mammal an amount of an NR2B subunit selective NMDA antagonist, which amount is effective in treating vision loss caused by neurodegeneration of the visual pathway.  
     
     
         13 . A method according to  claim 12 , wherein the neurodegeneration is caused by a stroke in the visual pathway.  
     
     
         14 . A method according to  claim 13 , wherein the stroke is in the retina, optic nerve, and or occipital lobe.  
     
     
         15 . A method according to  claim 12 , wherein the neurodegeneration is caused by a neurodegenerative disease, such as macular degeneration.  
     
     
         16 . A method according to  claim 15 , wherein the neurodegeneration comprises retinal degeneration caused by glaucoma.  
     
     
         17 . A method according to  claim 12 , wherein the NR2B subunit selective NMDA receptor antagonist is a compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable acid addition salt thereof, wherein: 
 (a) R 2  and R 5  are taken separately and R 1 , R 2 , R 3  and R 4  are each independently hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , OH or OR 7  and R 5  is methyl or ethyl; or  
 (b) R 2  and R 5  are taken together and are  
                     
 forming a chroman-4-ol ring, and R 1 , R 3  and R 4  are each independently hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , OH or OR 7 ;  
                     
 R 7  is methyl, ethyl, isopropyl or n-propyl;  
 R 8  is phenyl optionally substituted with up to three substituents independently selected from the group consisting of (C 1 -C 6 ) alkyl, halo and CF 3 ;  
 X is O, S or (CH 2 ) n ; and  
 n is 0, 1, 2, or 3.  
 
     
     
         18 . A method according to  claim 12 , wherein the NR2B subunit selective NMDA receptor antagonist is 
 (+)-(1S,2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol;    (1S,2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol;    (3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chroman-4,7-diol;    a pharmaceutically-acceptable acid addition salt of one of said compounds; or    (1R*,2R*)-1-(4-hydroxy-3-methylphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol-mesylate.    
     
     
         19 . A method of treating multi-system atrophy in a mammal, which method comprises administering to the mammal an amount of an NR2B subunit selective NMDA antagonist, which amount is effective in treating multi-system atrophy.  
     
     
         20 . A method according to  claim 19 , wherein the NR2B subunit selective NMDA receptor antagonist is a compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable acid addition salt thereof, wherein: 
 (a) R 2  and R 5  are taken separately and R 1 , R 2 , R 3  and R 4  are each independently hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , OH or OR 7  and R 5  is methyl or ethyl; or  
 (b) R 2  and R 5  are taken together and are  
                     
 forming a chroman-4-ol ring, and R 1 , R 3  and R 4  are each independently hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , OH or OR 7 ;  
 R 6  is  
                     
 R 7  is methyl, ethyl, isopropyl or n-propyl;  
 R 8  is phenyl optionally substituted with up to three substituents independently selected from the group consisting of (C 1 -C 6 ) alkyl, halo and CF 3 ;  
 X is O, S or (CH 2 ) n ; and  
 n is 0, 1, 2, or 3.  
 
     
     
         21 . A method according to  claim 19 , wherein the NR2B subunit selective NMDA receptor antagonist is (+)-(1S, 2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol; 
 (1S,2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol;    (3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chroman-4,7-diol;    a pharmaceutically-acceptable acid addition salt of one of said compounds; or    (1R*,2R*)-1-(4-hydroxy-3-methylphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol-mesylate.    
     
     
         22 . A method of treating non-vascular headache in a mammal, which method comprises administering to the mammal an amount of an NR2B subunit selective NMDA antagonist, which amount is effective in treating non-vascular headache.  
     
     
         23 . A method according to  claim 22 , wherein the NR2B subunit selective NMDA receptor antagonist is a compound of the formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable acid addition salt thereof, wherein: 
 (a) R 2  and R 5  are taken separately and R 1 , R 2 , R 3  and R 4  are each independently hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , OH or OR 7  and R 5  is methyl or ethyl; or  
 (b) R 2  and R 5  are taken together and are  
                     
 forming a chroman-4-ol ring, and R 1 , R 3  and R 4  are each independently hydrogen, (C 1 -C 6 ) alkyl, halo, CF 3 , OH or OR 7 ;  
                     
 R 7  is methyl, ethyl, isopropyl or n-propyl;  
 R 8  is phenyl optionally substituted with up to three substituents 15 independently selected from the group consisting of (C 1 -C 6 ) alkyl, halo and CF 3 ;  
 X is O, S or (CH 2 ) n ; and  
 n is 0, 1, 2, or 3.  
 
     
     
         24 . A method according to  claim 22 , wherein the NR2B subunit selective NMDA receptor antagonist is (+)-(1S, 2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy4-phenylpiperidino)-1-propanol; 
 (1S,2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol;    (3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-chroman-4,7-diol;    a pharmaceutically-acceptable acid addition salt of one of said compounds; or    (1R*,2R*)-1-(4-hydroxy-3-methylphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol-mesylate.