Novel neuromodulatory compounds

Abstract

Provided herein are novel neuromodulatory compounds and compositions thereof. In other embodiments, provided herein are methods of treatment, prevention, or amelioration of a variety of medical disorders such as, for example, migraine and Parkinson's disease, using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of agonizing receptors such as, for example, the 5-HT 1D and/or the 5-HT 1B receptor, without agonizing the 5-HT 2B receptor using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of antagonizing or inhibiting activity at receptors such as, for example, the adrenergic alpha 2A and/or the alpha 2B receptors using the compounds and compositions disclosed herein. In other embodiments, provided herein are methods of agonizing dopaminergic D 2 receptors and/or antagonizing or inhibiting activity of receptors such as the 5-HT 2 receptors using the compounds and compositions disclosed herein.

What is claimed is: 
     
         1 . A compound of Formula (I) or (II): 
       
         
           
           
               
               
           
         
         or ion pairs, metabolites, polymorphs, salts, hydrates or solvates thereof, wherein: 
         R 1  is hydrogen, (C 1 -C 4 ) alkyl, substituted (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkyl substituted with one or more fluorine atoms; 
         R 2  is alkyl, substituted alkyl, acyl, substituted acyl, halo, heteroalkyl, substituted heteroalkyl, —NO 2 , —N 3 , —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO 2 R 106  or —O 2 CR 107 ; 
         R 3  is hydrogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) substituted alkyl, (C 1 -C 4 ) alkyl substituted with one or more fluorine atoms; arylalkyl or substituted arylalkyl; 
         R 4  and R 5  are independently hydrogen, (C 1 -C 4 ) alkyl, substituted (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkyl substituted with one or more fluorine atoms, heteroalkyl, substituted hetereoalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl or R 4  and R 5  together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
         R 11  is hydrogen, (C 1 -C 3 ) alkyl or (C 1 -C 3 ) alkyl substituted with one or more fluorine atoms; 
         R 12  is hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted hetereoalkyl, substituted heteroarylalkyl or —S(O) m R 108 ; 
         R 100 -R 108  are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted hetereoalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; 
         m and k are independently 0, 1 or 2; and 
         n is 0, 1, 2 or 3; 
         provided that at least one of R 4  or R 5  is substituted with fluorine unless R 4  and R 5  together with the nitrogen atom to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. 
       
     
     
         2 . The compound of  claim 1 , wherein R 4  and R 5  are not both —CH 2 CH 3 . 
     
     
         3 . A composition comprising the compound of  claim 1  and a vehicle. 
     
     
         4 . A method of treating a migraine in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
         5 . A method of treating a migraine in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the composition of  claim 3 . 
     
     
         6 . A method of treating one or more symptoms of Parkinson's disease in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
         7 . A method of treating one or more symptoms of Parkinson's disease in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the composition of  claim 3 . 
     
     
         8 . A method of agonizing the D 2  receptor in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
         9 . A method of agonizing the 5-HT 1D  receptor in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
         10 . A method of selectively agonizing the 5-HT 1D  receptor over the 5-HT 1B  receptor in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
     
     
         11 . A method of providing functional antagonist activity at the 5-HT 2B  receptor in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound of  claim 1 .