Catecholamine derivatives for obesity and neurological disorders

Abstract

Novel compounds, compositions, and methods related to the activation of the TrkB receptor are provided. The methods include administering in vivo or in vitro a therapeutically effective amount of a compound containing a catecholamine backbone and pharmaceutically acceptable salts, prodrugs, and derivatives thereof. Specifically, methods, compositions, and compounds for the treatment of disorders including neurological disorders, neuropsychiatric disorders, and metabolic disorders are provided. For example, a first method is provided of treating or reducing the risk of depression, anxiety, or obesity in a subject, which includes administering to the subject a therapeutically effective amount of the described compounds. A further method of promoting neuroprotection in a subject also is provided, which includes administering to the subject a therapeutically effective amount of the described compounds.

1 . A compound of the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         R 1  is hydrogen, —OH, or ═O; 
         R 2  is hydrogen, substituted or unsubstituted C 1-4  alkyl, substituted or unsubstituted C 1-4  heteroalkyl, substituted or unsubstituted C 2-4  alkenyl, substituted or unsubstituted C 2-4  heteroalkenyl, substituted or unsubstituted C 2-4  alkynyl, substituted or unsubstituted C 2-4  heteroalkynyl, or substituted or unsubstituted carbonyl; 
         R 3  and R 4  are each independently selected from hydrogen, substituted or unsubstituted C 1-12  alkyl, substituted or unsubstituted C 3-12  cycloalkyl, substituted or unsubstituted C 1-12  heteroalkyl, substituted or unsubstituted C 2-12  alkenyl, substituted or unsubstituted C 3-12  cycloalkenyl, substituted or unsubstituted C 2-12  heteroalkenyl, substituted or unsubstituted C 2-12  alkynyl, substituted or unsubstituted C 3-12  cycloalkynyl, substituted or unsubstituted C 2-12  heteroalkynyl, substituted or unsubstituted carbonyl; and 
         R 5 , R 6 , and R 7  are each independently selected from hydrogen, halogen, —OH, or alkoxy, wherein one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , or R 7  is not hydrogen; 
         wherein if one of R 3  or R 4  is a saccharide, R 5  is not hydrogen; and 
         wherein if R 1  is —OH, one of R 2 , R 3 , R 4 , R 5 , R 6 , or R 7  is not hydrogen; 
         if R 1  is —OH and one of R 3  or R 4  is —CH 3  or isopropyl, one of R 2 , R 3 , R 4 , R 5 , R 6 , or R 7  is not hydrogen; 
         if R 2  is —COOH, one of R 1 , R 3 , R 4 , R 5 , R 6 , or R 7  is not hydrogen; and 
         if R 2  is —COOH and R 1  is —OH, then one of R 3 , R 4 , R 5 , R 6 , or R 7  is not hydrogen. 
       
     
     
         2 . The compound of  claim 1 , wherein R 2  and NR 4  are combined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein the heteroaryl is not substituted or unsubstituted pyrrole. 
     
     
         3 . The compound of  claim 1 , wherein R 3  and NR 4  are combined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. 
     
     
         4 . The compound of  claim 1 , wherein the halogen is fluorine. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
         wherein R 8  and R 9  are each independently selected from hydrogen, substituted or unsubstituted C 1-4  alkyl, substituted or unsubstituted C 2-4  alkenyl, or substituted or unsubstituted C 2-4  alkynyl. 
       
     
     
         6 . The compound of  claim 1 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         9 . A method of treating or reducing the risk of depression, anxiety, or obesity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         R 1  is hydrogen, —OH, or ═O; 
         R 2  is hydrogen, substituted or unsubstituted C 1-4  alkyl, substituted or unsubstituted C 1-4  heteroalkyl, substituted or unsubstituted C 2-4  alkenyl, substituted or unsubstituted C 2-4  heteroalkenyl, substituted or unsubstituted C 2-4  alkynyl, substituted or unsubstituted C 2-4  heteroalkynyl, or substituted or unsubstituted carbonyl; 
         R 3  and R 4  are each independently selected from hydrogen, substituted or unsubstituted C 1-12  alkyl, substituted or unsubstituted C 3-12  cycloalkyl, substituted or unsubstituted C 1-12  heteroalkyl, substituted or unsubstituted C 2-12  alkenyl, substituted or unsubstituted C 3-12  cycloalkenyl, substituted or unsubstituted C 2-12  heteroalkenyl, substituted or unsubstituted C 2-12  alkynyl, substituted or unsubstituted C 3-12  cycloalkynyl, substituted or unsubstituted C 2-12  heteroalkynyl, substituted or unsubstituted carbonyl; and 
         R 5 , R 6 , and R 7  are each independently selected from hydrogen, halogen, —OH, or alkoxy, wherein one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , or R 7  is not hydrogen; 
         wherein if one of R 3  or R 4  is a saccharide, R 5  is not hydrogen; and 
         wherein if R 1  is —OH, one of R 2 , R 3 , R 4 , R 5 , R 6 , or R 7  is not hydrogen; 
         if R 1  is —OH and one of R 3  or R 4  is —CH 3 , one of R 2 , R 3 , R 4 , R 5 , R 6 , or R 7  is not hydrogen; 
         if R 2  is —COOH, one of R 1 , R 3 , R 4 , R 5 , R 6 , or R 7  is not hydrogen; and 
         if R 2  is —COOH and R 1  is —OH, then one of R 3 , R 4 , R 5 , R 6 , or R 7  is not hydrogen. 
       
     
     
         10 . The method of  claim 9 , further comprising selecting a subject with or at risk of developing depression, anxiety, or obesity. 
     
     
         11 . A method of promoting neuroprotection in a subject, comprising administering to the subject a therapeutically effective amount of the compound of  claim 1  or derivative thereof. 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 11 , wherein the subject has amyotrophic lateral sclerosis. 
     
     
         14 . The method of  claim 11 , wherein the subject has a central nervous system injury. 
     
     
         15 . The method of  claim 14 , wherein the central nervous system injury is a brain injury. 
     
     
         16 . The method of  claim 14 , wherein the central nervous system injury is a spinal cord injury. 
     
     
         17 . The method of  claim 14 , wherein the central nervous system injury is a stroke. 
     
     
         18 - 30 . (canceled)