Methods for treating depression, neurodegeneration, inhibiting amyloid beta deposition, delaying senescence, and extending life spans with heterocyclic compounds

Abstract

Disclosed is an antidepressant, neuroprotectant, amyloid β deposition inhibitor, or age retardant composition containing a heterocyclic compound having the general formula (I):

1 . A method of treating or preventing depression, manic depressive psychoses, obsessive-compulsive disorder, panic disorder, or anxiety disorder in a mammal in need thereof, comprising administering to the mammal an effective amount of a heterocyclic compound having the general formula (I):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, wherein:  
         in the general formula (I), the structural unit having the general formula (II):  
         
           
             
             
                 
                 
             
           
         
         is one or more structural units selected from multiple types of structural units having the general formula (III):  
         
           
             
             
                 
                 
             
           
         
         in the general formula (I),  
         R 1  and R 2  each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, C 1 -C 6  alkyl group, C 1 -C 6  alkoxy group, and —O—(CH 2 ) n —R 5 , wherein R 5  is a vinyl group, C 3 -C 6  cycloalkyl group, or phenyl group, and n is 0 or 1;  
         R 3  and R 4  each are one or more functional groups independently selected from the group consisting of a hydrogen atom, C 1 -C 6  alkyl group, C 3 -C 8  cycloalkyl group, and —CH(R 7 )—R 6 ; alternatively, R 3  and R 4  together forms a spiro ring having the general formula (IV):  
         
           
             
             
                 
                 
             
           
         
         said R 6  is one or more functional groups selected from the group consisting of a vinyl group;  
         ethinyl group; phenyl optionally substituted by a C 1 -C 6  alkyl group, C 1 -C 6  alkoxy group, hydroxy group, 1 or 2 halogen atoms, di C 1 -C 6  alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group;  
         said R 7  is a hydrogen atom or C 1 -C 6  alkyl group;  
         in the general formula (IV), the structural unit B is one or more structural units selected from multiple types of structural units having the general formula (V):  
         
           
             
             
                 
                 
             
           
         
         said structural unit B binds at a position marked by * in the general formula (V) to form a spiro ring; and  
         R 8  is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, C 1 -C 6  alkoxy group, cyano group, and trifluoromethyl group.  
       
     
     
         2 . The method according to  claim 1  wherein said heterocyclic compound is one or more heterocyclic compounds selected from the group consisting of: 
 3,3-dibenzylimidazo[1,2-a]pyridin-2(3H)-one,    spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan],    3,3-dipropylimidazo[1,2-a]pyridin-2(3H)-one, 3,3-dibutylimidazo[1,2-a]pyridin-2(3H)-one,    5,5-dibenzylimidazo[2,1-b]thiazol-6(5H)-one, 3,3-dibenzylimidazo[1,2-a]pyrimidin-2(3H)-one,    spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-(4′-fluoroindan)],    spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-(5′-methoxyindan)],    spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-(4′-cyanoindan)],    spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,2′-indan],    spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-((1,2,5-thiadiazo)[4,5-c]indan)],    spiro[imidazo[1,2-a]pyrimidin-2(3H)-one-3,2′-indan],    spiro[imidazo[2,1-a]isoquinolin-2(3H)-one-3,4′-(1′-cyclopentene)],    3,3-bis(4-chlorobenzyl)imidazo[1,2-a]pyridin-2(3H)-one,    8-cyclopropylmethyloxy-3,3-diallylimidazo[1,2-a]pyridin-2(3H)-one,    spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-(4′-hydroxyindan)],    spiro[8-hydroxy-imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan],    spiro[8-methoxyimidazo[1,2-a]pyridin-2(3H)-one-3,4′-(1′-cyclopentene)], and    spiro[8-cyclopropylmethyloxyimidazo[1,2-a]pyridin-2(3H)-one-3,4′-(1′-cyclopentene)].    
     
     
         3 . The method according to  claim 1  or  2  wherein said administration is oral.  
     
     
         4 . The method according to  claim 1  or  2  wherein said method is for treating depression.  
     
     
         5 . A method of reducing or preventing neurodegeneration in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound having the general formula (I):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, wherein:  
         in the general formula (I), the structural unit having the general formula (II):  
         
           
             
             
                 
                 
             
           
         
         is one or more structural units selected from multiple types of structural units having the general formula (III):  
         
           
             
             
                 
                 
             
           
         
         in the general formula (I),  
         R 1  and R 2  each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, C 1 -C 6  alkyl group, C 1 -C 6  alkoxy group, and —O—(CH 2 )n-R 5 , wherein R 5  is a vinyl group, C 3 -C 6  cycloalkyl group, or phenyl group, and n is 0 or 1;  
         R 3  and R 4  each are one or more functional groups independently selected from the group consisting of a hydrogen atom, C 1 -C 6  alkyl group, C 3 -C 8  cycloalkyl group, and —CH(R 7 )—R 6 ; alternatively, R 3  and R 4  together form a spiro ring having the general formula (IV):  
         
           
             
             
                 
                 
             
           
         
         said R 6  is one or more functional groups selected from the group consisting of a vinyl group; ethinyl group; phenyl optionally substituted by a C 1 -C 6  alkyl group, C 1 -C 6  alkoxy group, hydroxy group, 1 or 2 halogen atoms, di C 1 -C 6  alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group;  
         said R 7  is a hydrogen atom or C 1 -C 6  alkyl group;  
         in general formula (IV), the structural unit B is one or more structural units selected from multiple types of structural units having the general formula (V):  
         
           
             
             
                 
                 
             
           
         
         said structural unit B binds at a position marked by * in the general formula (V) to form a spiro ring; and  
         R 8  is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, C 1 -C 6  alkoxy group, cyano group, and trifluoromethyl group.  
       
     
     
         6 . The method according to  claim 5  wherein said heterocyclic compound is spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan].  
     
     
         7 . The method according to  claim 5  or  6  wherein said administration is oral.  
     
     
         8 . The method according to  claim 5 , wherein said neurodegeneration is the result of one or more cerebrovascular disorders selected from the group consisting of transient ischemic attack, cerebral hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage, cerebral infarct, and hypertensive encephalopathy.  
     
     
         9 . A method of inhibiting amyloid β deposition in an mammal in need thereof, comprising administering to the mammal an effective amount of a compound having the general formula (I):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, wherein:  
         in the general formula (I), the structural unit having the general formula (II):  
         
           
             
             
                 
                 
             
           
         
         is one or more structural units selected from multiple types of structural units having the general formula (III):  
         
           
             
             
                 
                 
             
           
         
         in the general formula (I),  
         R 1  and R 2  each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, C 1 -C 6  alkyl group, C 1 -C 6  alkoxy group, and —O—(CH 2 )n-R 5 , wherein R 5  is a vinyl group, C 3 -C 6  cycloalkyl group, or phenyl group, and n is 0 or 1;  
         R 3  and R 4  each are one or more functional groups independently selected from the group consisting of a hydrogen atom, C 1 -C 6  alkyl group, C 3 -C 8  cycloalkyl group, and —CH(R 7 )—R 6 ; alternatively, R 3  and R 4  together form a spiro ring having the general formula (IV):  
         
           
             
             
                 
                 
             
           
         
         said R 6  is one or more functional groups selected from the group consisting of a vinyl group; ethinyl group; phenyl optionally substituted by a C 1 -C 6  alkyl group, C 1 -C 6  alkoxy group, hydroxy group, 1 or 2 halogen atoms, di C 1 -C 6  alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group;  
         said R 7  is a hydrogen atom or C 1 -C 6  alkyl group;  
         in the general formula (IV), the structural unit B is one or more structural units selected from multiple types of structural units having the general formula (V):  
         
           
             
             
                 
                 
             
           
         
         said structural unit B binds at a position marked by * in the general formula (V) to form a spiro ring; and  
         R 8  is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, C 1 -C 6  alkoxy group, cyano group, and trifluoromethyl group.  
       
     
     
         10 . The method according to  claim 9  wherein said heterocyclic compound is spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan].  
     
     
         11 . The method according to  claim 9  or  10  wherein said administration is oral.  
     
     
         12 . The method according to  claim 9  or  10  wherein said amyloid β deposition is associated with one or more amyloid-related pathologies selected from the group consisting of amyloidosis, cerebral amyloid angiopathy, cataract, glaucoma, the progression of glaucoma, age-related macular degeneration, rheumatism, osteoporosis, metabolic syndrome, wrinkles, and hair loss.  
     
     
         13 . An method of delaying senescence is an animal in need thereof, comprising administering to the animal an effective amount of a heterocyclic compound having the general formula (I):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, wherein:  
         in the general formula (I), the structural unit having the general formula (II):  
         
           
             
             
                 
                 
             
           
         
         is one or more structural units selected from multiple types of structural units having the general formula (III):  
         
           
             
             
                 
                 
             
           
         
         in the general formula (I),  
         R 1  and R 2  each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, C 1 -C 6  alkyl group, C 1 -C 6  alkoxy group, and —O—(CH 2 )n-R 5 , wherein R 5  is a vinyl group, C 3 -C 6  cycloalkyl group, or phenyl group, and n is 0 or 1;  
         R 1  and R 4  each are one or more functional groups independently selected from the group consisting of a hydrogen atom, C 1 -C 6  alkyl group, C 3 -C 8  cycloalkyl group, and —C H(R 7 )—R 6 ; alternatively, R 3  and R 4  together form a spiro ring having the general formula (IV):  
         
           
             
             
                 
                 
             
           
         
         said R 6  is one or more functional groups selected from the group consisting of a vinyl group; ethinyl group; phenyl optionally substituted by a C 1 -C 6  alkyl group, C 1 -C 6  alkoxy group, hydroxy group, 1 or 2 halogen atoms, di C 1 -C 6  alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group;  
         said R 7  is a hydrogen atom or C 1 -C 6  alkyl group;  
         in the general formula (IV), the structural unit B is one or more structural units selected from multiple types of structural units having the general formula (V):  
         
           
             
             
                 
                 
             
           
         
         said structural unit B binds at a position marked by * in the general formula (V) to form a spiro ring; and  
         R 8  is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, C 1 -C 6  alkoxy group, cyano group, and trifluoromethyl group.  
       
     
     
         14 . The method according to  claim 13  wherein said heterocyclic compound is spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan].  
     
     
         15 . The method according to  claim 13  or  14  wherein said administration is oral.  
     
     
         16 . A method of extending the life span of a mammal in need thereof, comprising administering to the mammal an effective amount of a compound having the general formula (I):  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, wherein:  
         in the general formula (I), the structural unit having the general formula (II):  
         
           
             
             
                 
                 
             
           
         
         is one or more structural units selected from multiple types of structural units having the general formula (III):  
         
           
             
             
                 
                 
             
           
         
         in the general formula (I),  
         R 1  and R 2  each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, C 1 -C 6  alkyl group, C 1 -C 6  alkoxy group, and —O—(CH 2 )n-R 5 , wherein R 5  is a vinyl group, C 3 -C 6  cycloalkyl group, or phenyl group, and n is 0 or 1;  
         R 3  and R 4  each are one or more functional groups independently selected from the group consisting of a hydrogen atom, C 1 -C 6  alkyl group, C 3 -C 8  cycloalkyl group, and —CH(R 7 )—R 6 ; alternatively, R 3  and R 4  together form a spiro ring having the general formula (IV):  
         
           
             
             
                 
                 
             
           
         
         said R 6  is one or more functional groups selected from the group consisting of a vinyl group; ethinyl group; phenyl optionally substituted by a C 1 -C 6  alkyl group, C 1 -C 6  alkoxy group, hydroxy group, 1 or 2 halogen atoms, di C 1 -C 6  alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group;  
         said R 7  is a hydrogen atom or C 1 -C 6  alkyl group;  
         in the general formula (IV), the structural unit B is one or more structural units selected from multiple types of structural units having the general formula (V):  
         
           
             
             
                 
                 
             
           
         
         said structural unit B binds at a position marked by * in the general formula (V) to form a spiro ring; and  
         R 8  is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, C 1 -C 6  alkoxy group, cyano group, and trifluoromethyl group.  
       
     
     
         17 . The method according to  claim 16  wherein said heterocyclic compound is spiro[imidazo[1,2-a]pyridin-2(3H)-one-3,2′-indan].  
     
     
         18 . The method according to  claim 16  or  17  wherein said administration is oral.