Pro-Neurogenic Compounds

Abstract

Compounds and methods for stimulating neurogenesis (e.g., post-natal neurogenesis, including post-natal hippocampal and hypothalamic neurogenesis) and/or protecting neuronal cell from cell death are disclosed herein. In vivo activity tests suggest that these compounds may have therapeutic benefits in neuropsychiatric and/or neurodegenerative diseases such as schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, abuse of a neuro-active drug, retinal degeneration, spinal cord injury, peripheral nerve injury, physiological weight loss associated with various conditions, as well as cognitive decline associated with normal aging, chemotherapy, and the like.

What is claimed is: 
     
         1 . A compound or pharmaceutically acceptable salt thereof, for promoting neurogenesis and/or reducing neuronal cell death, the compound having formula (II): 
       
         
           
           
               
               
           
         
         wherein R 1a  is selected from the group consisting of: —CH 2 —C(O)—Z 1a  and —CH 2 —C(R A1 )(R A2 )—CH 2 —Z 2a ; 
         R 3a  and R 4a  are each independently selected from the group consisting of: hydrogen, halo, hydroxyl, C 1-3  alkoxyl, cyano, carboxyl, and formamide; 
         wherein Z 1a  is selected from the group consisting of: hydroxyl; C 1-6  alkoxyl; amine optionally substituted with 1 or more C 1-12  alkyl, C 2-12  alkenyl, C 3-12  cycloalkyl, C 1-12  sulfonyl optionally substituted with 1-6 halo, C 6-12  aryl sulfonyl optionally substituted with 1-6 halo, C 4-12  heteroaryl sulfonyl optionally substituted with 1-6 halo, C 2-12  carbonyl optionally substituted with 1-6 halo, and/or C 2-12  carboxyalkyl optionally substituted with 1-6 halo; C 2-12  heterocyclyl; C 6-12  aryl optionally substituted with 1 or more halo, hydroxyl, C 1-6  alkyl and/or C 1-6  alkoxyl; and C 4-12  heteroaryl optionally substituted with 1 or more halo, hydroxyl, C 1-6  alkyl and/or C 1-6  alkoxyl; 
         wherein one of R A1  and R A2  is hydroxyl, halo, or amine optionally substituted with 1 or more C 1-6  alkyl, C 2-6  alkenyl, C 3-6  cycloalkyl, C 2-6  heterocyclyl, C 6-12  aryl, and/or C 4-12  heteroaryl; and the other of R A1  and R A2  is hydrogen; 
         wherein Z 2a  is selected from the group consisting of: halo, O(R a ), S(R b ) and N(R c )(R d ); 
         wherein R a  and R b  are each independently selected from the group consisting of: C 1-12  alkyl; C 2-12  alkenyl; C 3-12  cycloalkyl; C 2-6  heterocyclyl; C 6-12  aryl optionally substituted with 1 or more halo, hydroxyl, C 1-6  alkyl and/or C 1-6  alkoxyl; and C 4-12  heteroaryl optionally substituted with 1 or more halo, hydroxyl, C 1-6  alkyl and/or C 1-6  alkoxyl; 
         wherein R c  and R d  are each independently selected from the group consisting of: hydrogen; C 1-12  alkyl; C 2-12  alkenyl; C 3-12  cycloalkyl; C 2-6  heterocyclyl; C 6-12  aryl optionally substituted with 1 or more halo, hydroxyl, C 1-6  alkyl and/or C 1-6  alkoxyl; and C 4-12  heteroaryl optionally substituted with 1 or more halo, hydroxyl, C 1-6  alkyl and/or C 1-6  alkoxyl; or wherein R c  and R d  together with the nitrogen they are attached to form a C 4-14  heteroaryl optionally substituted with 1 or more halo, hydroxyl, C 1-6  alkyl and/or C 1-6  alkoxyl. 
       
     
     
         2 . The compound or salt of  claim 1 , wherein R 3a  and R 4a  are both hydrogen or both bromo. 
     
     
         3 . The compound or salt of  claim 1 , wherein Z 1a  is hydroxyl or amine optionally substituted with 1 or more C 1-12  alkyl, C 2-12  alkenyl, and/or C 3-12  cycloalkyl. 
     
     
         4 . The compound or salt of  claim 1 , wherein one of R A1  and R A2  is hydroxyl or halo; and the other of R A1  and R A2  is hydrogen. 
     
     
         5 . The compound or salt of  claim 1 , wherein Z 2a  is O(R a ) or S(R b ). 
     
     
         6 . The compound or salt of  claim 1 , wherein Z 2a  is N(R c )(R d ). 
     
     
         7 . A compound or pharmaceutically acceptable salt thereof, for promoting neurogenesis and/or reducing neuronal cell death, the compound having formula (III): 
       
         
           
           
               
               
           
         
         wherein R 1b  is selected from the group consisting of: hydrogen; C 1-6  alkyl optionally substituted with 1 or more halo, hydroxyl, cyano and/or azide; —CH(R 5 )—C(O)—Z 1b ; and —CH 2 —C(R A1 )(R A2 )—CH 2 —Z 2b ;
 wherein R 5  is hydrogen or C 1-3  alkyl; 
 wherein one of R A1  and R A2  is hydroxyl or halo and the other is hydrogen; 
 wherein Z 1b  is selected from the group consisting of: hydroxyl; C 1-6  alkoxyl; and amine optionally substituted with a hydroxyl, C 1-12  sulfonyl optionally substituted with 1-6 halo, C 6-12  aryl sulfonyl optionally substituted with 1-6 halo, C 4-12  heteroaryl sulfonyl optionally substituted with 1-6 halo, C 2-12  carbonyl optionally substituted with 1-6 halo, and/or C 2-12  carboxyalkyl optionally substituted with 1-6 halo; 
 wherein Z 2b  is selected from the group consisting of: C 1-3  alkyl, azide, and N(R 6 )(R 7 ); 
 wherein R 6  and R 7  are each independently selected from the group consisting of: hydrogen; carboxamide optionally substituted with 1 or more C 1-6  alkyl, C 6-12  aryl and/or C 4-12  heteroaryl; C 6-12  aryl optionally substituted with 1 or more halo, hydroxyl, C 1-6  alkyl and/or C 1-6  alkoxyl; C 1-12  sulfonyl optionally substituted with 1-6 halo; C 6-12  aryl sulfonyl optionally substituted with 1-6 halo; and C 4-12  heteroaryl sulfonyl optionally substituted with 1-6 halo; wherein no more than one of R 6  and R 7  is hydrogen; and 
 
         wherein R 3b  and R 4b  are each independently selected from the group consisting of: hydrogen, halo, hydroxyl, C 1-3  alkoxyl, cyano, carboxyl, and formamide. 
       
     
     
         8 . The compound or salt of  claim 7 , wherein when R 1b  is optionally substituted C 1-6  alkyl, R 1b  is selected from unsubstituted C 1-6  alkyl or C 3-6  alkyl substituted with 1 hydroxyl or C 1-6  alkyl substituted with 1 cyano. 
     
     
         9 . The compound or salt of  claim 8 , wherein when R 1b  unsubstituted C 1-6  alkyl, R 1b  is unsubstituted C 2-6  alkyl. 
     
     
         10 . The compound or salt of  claim 7 , wherein when R 5  is hydrogen, Z 1b  is amine optionally substituted with a hydroxyl, C 1-12  sulfonyl optionally substituted with 1-6 halo, C 6-12  aryl sulfonyl optionally substituted with 1-6 halo, C 4-12  heteroaryl sulfonyl optionally substituted with 1-6 halo, C 2-12  carbonyl optionally substituted with 1-6 halo, and/or C 2-12  carboxyalkyl optionally substituted with 1-6 halo. 
     
     
         11 . The compound or salt of  claim 7 , wherein Z 2b  is azide or N(R 6 )(R 7 ). 
     
     
         12 . A compound or pharmaceutically acceptable salt thereof, for promoting neurogenesis and/or reducing neuronal cell death, the compound having formula (IV): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1c  is selected from the group consisting of: hydrogen, C 1-6  alkyl, C 1-6  carboxyalkyl, C 1-12  sulfonyl optionally substituted with 1-6 halo, C 6-12  aryl sulfonyl optionally substituted with 1-6 halo and C 4-12  heteroaryl sulfonyl optionally substituted with 1-6 halo; 
         R 2c  is selected from the group consisting of: hydrogen; hydroxyl; cyano; halo; amine optionally substituted with 1 or more C 1-6  alkyl, C 2-6  alkenyl, C 3-6  cycloalkyl, aryl, and/or heteroaryl; and C 1-12  alkoxyl; 
         R 3c  is selected from the group consisting of: carboxyl; C 1-6  alkoxycarbonyl; hydroxyl; C 1-12  alkoxyl; cyano; halo; and amine optionally substituted with 1 or more C 1-6  alkyl, C 2-6  alkenyl, C 3-6  cycloalkyl, aryl, and/or heteroaryl; 
         R 4c  is selected from the group consisting of: hydrogen, halo, hydroxyl, and C 1-3  alkoxyl; and 
         one or both of Q 1  and Q 2  are nitrogen. 
       
     
     
         13 . The compound or salt of  claim 12 , wherein R 2c  is hydrogen; hydroxyl; or C 1-12  alkoxyl. 
     
     
         14 . The compound or salt of  claim 12 , wherein R 3c  is carboxyl; C 1-6  alkoxycarbonyl; hydroxyl; or amine substituted with 1-2 C 1-6  alkyl. 
     
     
         15 . A compound or pharmaceutically acceptable salt thereof, for promoting neurogenesis and/or reducing neuronal cell death, the compound having formula (V): 
       
         
           
           
               
               
           
         
         wherein R 1d  is selected from the group consisting of: hydrogen and CH 2 —C(R A1 )(R A2 )—CH 2 —N(R 6 )(R 7 );
 wherein one of R A1  and R A2  is hydroxyl or halo and the other is hydrogen; and 
 wherein R 6  and R 7  are each independently selected from the group consisting of: hydrogen; C 6-12  aryl optionally substituted with 1 or more halo, hydroxyl, C 1-6  alkyl and/or C 1-6  alkoxyl; and C 4-12  heteroaryl optionally substituted with 1 or more halo, hydroxyl, C 1-6  alkyl and/or C 1-6  alkoxyl; 
 
         wherein R 2d  is selected from the group consisting of: halo, hydroxyl, C 1-12  alkoxyl, cyano, aryl, and heteroaryl; 
         wherein R 3d  is selected from the group consisting of: hydrogen and amine optionally substituted with 1 or more C 1-6  alkyl, C 2-6  alkenyl, C 3-6  cycloalkyl, C 2-6  heterocyclyl, aryl, and/or heteroaryl; and 
         wherein R 4d  is selected from the group consisting of: hydrogen, halo, hydroxyl, and C 1-3  alkoxyl. 
       
     
     
         16 . The compound or salt of  claim 15 , wherein R 2d  is cyano, and R 4d  is hydrogen, bromo or methoxy. 
     
     
         17 . A method of treating a disease, disorder, or condition associated with unwanted neuronal cell death or insufficient neurogenesis, the method comprising administering an effective amount of the compound or salt of  claim 1 . 
     
     
         18 . A method of treating a disease, disorder, or condition associated with unwanted neuronal cell death or insufficient neurogenesis, the method comprising administering an effective amount of the compound or salt of  claim 7 . 
     
     
         19 . A method of treating a disease, disorder, or condition associated with unwanted neuronal cell death or insufficient neurogenesis, the method comprising administering an effective amount of the compound or salt of  claim 12 . 
     
     
         20 . A method of treating a disease, disorder, or condition associated with unwanted neuronal cell death or insufficient neurogenesis, the method comprising administering an effective amount of the compound or salt of  claim 15 .