Methods of treating disorders of trigeminalvascular activation

Abstract

Alpha-aminoamide derivatives useful in the treatment of disorders of trigeminalvascular activation are disclosed.

1 - 15 . (canceled) 
     
     
         16 . A method of treating disorders of trigeminovascular activation comprising administering to a mammal having a disorder of trigeminovascular activation a therapeutically effective amount of an α-aminoamide of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 A is a —(CH 2 ) m — or —(CH 2 ) n —X—, wherein m is 1 or 2; n is zero, 1 or 2; and X is —O—, —S— or —NH—; 
 R is a phenyl ring, unsubstituted or substituted by one or two substituents independently selected from halogen, hydroxy, C 1 -C 4  alkyl, C 1 -C 3  alkoxy and trifluoromethyl; 
 R 1  is hydrogen or C 1 -C 3  alkyl; 
 R 2  is hydrogen or C 1 -C 2  alkyl, unsubstituted or substituted by hydroxy or phenyl; phenyl, unsubstituted or substituted by one or two substituents independently selected from C 1 -C 3  alkyl, halogen, hydroxy, C 1 -C 2  alkoxy or trifluoromethyl; 
 R 3  is hydrogen or C 1 -C 3  alkyl; 
 or an optically active isomer, racemic mixture, or pharmaceutically acceptable derivative thereof. 
 
     
     
         17 . The method of  claim 16 , wherein:
 A is a group selected from —CH 2 —CH 2 —, —CH 2 —O—, —CH 2 —S—, —CH 2 —CH 2 —O—;   R is a phenyl ring, unsubstituted or substituted by one or two substituents independently selected from halogen, C 1 -C 3  alkyl or a methoxy group; or a thienyl ring;   R 1  is hydrogen or C 1 -C 2  alkyl;   R 2  is hydrogen or methyl, unsubstituted or substituted by hydroxy, or phenyl unsubstituted or substituted by C 1 -C 2  alkyl, halogen, hydroxy, methoxy or trifluoromethyl; and   R 3  is hydrogen or C 1 -C 2  alkyl.   
     
     
         18 . The method of  claim 16 , wherein:
 A is —CH 2 —O—, —CH 2 —S— or —CH 2 —CH 2 —;   R is a phenyl ring, unsubstituted or substituted by one or two halogen atoms;   R 1  is hydrogen;   R 2  is hydrogen or methyl, unsubstituted or substituted by hydroxy or phenyl ring, unsubstituted or substituted by a halogen atom; and   R 3  is hydrogen or methyl.   
     
     
         19 . The method of  claim 16 , wherein the α-aminoamide is selected from the group consisting of:
 2-(4-benzyloxybenzylamino)propanamide;   2-[4-(2-fluorobenzyloxy)benzylamino]propanamide;   2-[4-(2-chlorobenzyloxy)benzylamino]propanamide;   2-[4-(3-fluorobenzyloxy)benzylamino]propanamide;   2-[4-(3-chlorobenzyloxy)benzylamino]propanamide;   2-[4-(4-fluorobenzyloxy)benzylamino]propanamide;   2-[4-(2-fluorobenzyloxy)benzylamino]-N-methyl-propanamide;   2-[4-(3-fluorobenzyloxy)benzylamino]-N-methyl-propanamide;   2-[4-(2-fluorobenzyloxy)benzylamino]-3-hydroxy-propanamide;   2-[4-(3-fluorobenzyloxy)benzylamino]-3-hydroxy-propanamide;   2-(4-benzyloxybenzylamino)-3-hydroxy-N-methylpropanamide;   2-[4-(2-fluorobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;   2-[4-(2-chlorobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;   2-[4-(3-fluorobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;   2-[4-(3-chlorobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;   2-[4-(2-(3-fluorophenyl)ethyl)benzylamino)-propanamide;   2-[4-benzylthiobenzylamino)-propanamide;   2-[4-benzyloxybenzylamino]-3-phenyl-N-methylpropanamide;   2-[4-benzyloxybenzylamino]-N-methylbutanamide;   2-[4-benzyloxybenzylamino]-2-phenyl-acetamide;   2-[4-(2-fluorobenzyloxy)benzylamino]-2-phenyl-acetamide   2-[4-(3-fluorobenzyloxy)benzylamino]-2-phenyl-acetamide;   2-[4-(3-chlorobenzyloxy)benzylamino]-2-phenyl-acetamide;   2-[4-(3 fluorobenzyloxy)benzylamino]-2-(2-fluorophenyl)-acetamide;   2-[4-(3-fluorobenzyloxy)benzylamino]-2-(3-fluorophenyl)-acetamide; and   2-[4-(3-chlorobenzyloxy)benzylamino]-2-(3-fluorophenyl)-acetamide;   or an optically active isomer, racemic mixture, or pharmaceutically acceptable derivative thereof.   
     
     
         20 . The method of  claim 16 , wherein the α-aminoamide is selected from the group consisting of:
 (S)-(+)-2 [4-(3-fluorobenzyloxy)benzylamino]-propanamide,   (S)-(+)-2-[4-(2-fluorobenzyloxy)benzylamino]-propanamide and   (S)-(+)-2-[4-(3-chlorobenzyloxy)benzylamino]-propanamide.   
     
     
         21 . The method of  claim 16 , wherein the therapeutically effective amount is from about 0.05 to 20 mg/kg body weight per day. 
     
     
         22 . The method of  claim 16 , wherein the therapeutically effective amount is from about 0.5 to 10 mg/kg day. 
     
     
         23 . The method of  claim 16 , wherein the therapeutically effective amount is from about 0.5 to 5 mg/kg day. 
     
     
         24 . The method of  claim 20 , wherein said α-aminoamide is (S)-(+)-2-[4-(3-fluorobenzyloxy)benzylamino]-propanamide. 
     
     
         25 . The method of  claim 20 , wherein said α-aminoamide is (S)-(+)-2-[4-(2-fluorobenzyloxy)benzylamino]-propanamide. 
     
     
         26 . The method of  claim 20 , wherein said α-aminoamide is (S)-(+)-2-[4-(3-chlorobenzyloxy)benzylamino]-propanamide. 
     
     
         27 . The method of  claim 16 , wherein the mammal is a human. 
     
     
         28 . The method of  claim 16 , wherein the pharmaceutically acceptable derivative is an acid addition salt. 
     
     
         29 . The method of  claim 16 , wherein said administering is by oral administration. 
     
     
         30 . The method of  claim 16 , wherein said administering is by parenteral administration. 
     
     
         31 . The method of  claim 16 , wherein said disorder is a head pain disorder. 
     
     
         32 . The method of  claim 31 , wherein said head pain disorder is a primary or a secondary headache disorder. 
     
     
         33 . The method of  claim 31 , wherein said head pain disorder is headache, hemicrania, or cluster headache. 
     
     
         34 . The method of  claim 33 , wherein said head pain disorder is headache. 
     
     
         35 . The method of  claim 34 , wherein said headache is acute, cluster, evolutive or tension type. 
     
     
         35 . The method of  claim 33 , wherein said head pain disorder is hemicrania. 
     
     
         36 . The method of  claim 35 , wherein said hemicrania is chronic paroxysmal hemicrania. 
     
     
         37 . The method of  claim 33 , wherein said head pain disorder is cluster headache.