Heterocyclic compounds for the treatment of migraine

Abstract

Described herein are compounds useful in the treatment of migraine, which have the general formula: wherein: W is a CH group or a N atom; Z is N or C-R4; B and D are selected independently from CH and N, with the proviso that at least one of B and D is CH and with the further proviso that one of B and D can represent N only when W and Z are both other than N; A is a group of Formula II, III or IV, such that group A contains at least 1 N atom; NR7 is either —NH— or —N═ is a single or double bond; X is a N atom, a CH group or a C(OH) group when is a single bond; or, when is a double bond, a C atom; Y is an NH, N-alkyl, N-benzyl or CH 2 group; U and V each represent a N atom or a CH group, with the proviso that both cannot be N; a and b are, independently, 0 or 1; c is an integer from 0 to 3; d is an integer from 1 to 3; e is an integer from 1 to 2; f is an integer from 0 to 3; g is an integer from 3 to 6 and h is an integer from 2 to 3; such that the sum of c and d is at least 2 and the sum of e and f is at least 2; R 1 is selected from the group consisting of H, alkyl, alkyloxy, alkanoyl, aminoalkylenyl, alkylaminoalkylenyl, a hydroxyalkylenyl group, an alkyloxyalkylenyl group, a cycloalkyl group, a cycloalkylalkylenyl group, a heterocycloalkyl group, a heterocycloalkylalkylenyl group, an aryl group, a heterocycloaryl group, an amido group, a thioamido group, an arylcarbonyl group and an arylsulfonyl group; R 2 and R 3 are independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl and optionally-substituted benzyl; or R 2 and R 3 , together with the nitrogen atom to which they are attached, may form a mono- or bi-cyclic group containing up to 10 carbon atoms and which, in addition, may contain a second heteroatom selected from the group consisting of N, S and O, and which may contain one or more substituents selected from the group consisting of alkyl, hydroxy, hydroxymethyl, alkyloxymethyl, amino and substituted amino; R 4 is selected from the group consisting of H, alkyl and cycloalkyl; CR 5 represents a group selected from —CH2—, CH(OH)—, —C(O)—, —CH(alkyl)- and —CH(alkyloxy)-; R6 is selected from the group consisting of H, alkyl, aryl, halogen, hydroxy, alkyloxy, amino, monoalkylamino and di-substitutedalkylamino; and salts and solvates thereof

We claim:  
     
         1 . A compound selected from the group consisting of a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 W is a CH group or a N atom;  
 Z is N or C;  
 B and D are selected independently from CH and N, with the provisio that at least one of B and D is CH and with the further provisio that one of B and D can represent N only when W and Z are both other than N;  
 A is a group of Formula II, such that group A contains at least 1 N atom; 
 —(CR 5 ) h —NR 2 R 3   Formula II 
 R 1  is selected from the group consisting of H, alkyl including C(1-12)alkyl, alkyloxy, alkanoyl, aminoalkylenyl, alkylaminoalkylenyl, a hydroxyalkylenyl group, an alkyloxyalkylenyl group, a cycloalkyl group, a cycloalkylalkylenyl group, a heterocycloalkyl group, a heterocycloalkylenyl group, an aryl group, a heteroaryl group, an amido group, a thioamido group, an arylcarbonyl group and an arylsulfonyl group;  
 R 2  and R 3  are independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl and optionally-substituted benzyl; or R 2  and R 3 , together with the nitrogen atom to which they are attached, may form a mono- or bi-cyclic group containing up to 10 carbon atoms and which, in addition, may contain a second heteroatom selected from the group consisting of N, S and O, and which may contain one or more substituents selected from the group consisting of alkyl, hydroxy, hydroxymethyl, alkyloxymethyl, amino and substituted amino;  
 R 4  is selected from the group consisting of H, alkyl and cycloalkyl;  
 CR 5  represents a group selected from —CH2—, CH(OH)—, —C(O)—, —CH(alkyl)- and —CH(alkyloxy)-;  
 R 6  is selected from the group consisting of H, alkyl, aryl, halogen, hydroxy, alkyloxy, amino, monoalkylamino and di-substitutedalkylamino;  
 and salts and solvates thereof.  
 
     
     
         2 . A compound according to  claim 1  wherein R 1  is an aryl group.  
     
     
         3 . A compound according to  claim 1  wherein R 1  is a heterocycloalkyl group.  
     
     
         4 . A compound according to  claim 3  wherein R 1  is tetrahydropyranyl.  
     
     
         5 . A compound according to  claim 1  wherein R 1  is a cycloalkyl group.  
     
     
         6 . A compound according to  claim 1  wherein R 1  is a alkyl group.  
     
     
         7 . A compound according to  claim 6  wherein R 1  is isopropyl.  
     
     
         8 . A compound according to  claim 1 , wherein A is a group selected from a (mono- or di-) substituted aminoalkylenyl, an N-cycloalkyl and an N-cycloalkylalkylenyl.  
     
     
         9 . A compound according to  claim 8 , wherein A is N,N-dimethylaminoethyl, N,N-diethylaminoethyl, N-methyl-N-ethylaminoethyl, N-isopropylaminoethyl, N,N-dipropylaminoethyl, N-cyclopropylaminoethyl, N-cyclopropylmethylaminoethyl, N-methyl-N-cyclopropylamino, pyrrolidinoethyl, pyrrolinoethyl, piperidinoethyl, morphilinoethyl, thiomorpholinoethyl or piperazinoethyl.  
     
     
         10 . A compound according to  claim 1 , wherein the ring system formed by selection of B, D, W and Z is a ring system selected from indole, indoline, indazole, benzotriazole, benzimidazole, 7-aza-indole, and 5-aza-indole.  
     
     
         11 . A compound according to  claim 10 , wherein R6 is selected from H and alkyl, and R4 is H.  
     
     
         12 . A compound according to  claim 11 , wherein the ring system formed by selection of B, D, W and Z, R 4  and R 6  is a ring system selected from indole and indazole.  
     
     
         13 . A compound according to  claim 11 , wherein said ring system is indole.  
     
     
         14 . A compound according to  claim 1 , selected from the group consisting of: 
 6-(2-(N,N-Dimethylamino)ethyl)-1H-indole;    6-(2-(N,N-Dimethylamino)ethyl)-1-isopropyl-indole;    6-(2-(N,N-Diethylamino)ethyl)-indole;    6-(2-(N,N-Diethylamino)ethyl)-1-isopropyl-indole;    6-(2-(N,N-Diethylamino)ethyl)-1-dimethylaminocarbonyl-indole;    6-(2-(N,N-Dimethylamino)ethyl)-1-(tetrahydrothiopyran-4-yl)-indole;    6-(2-(N,N-Dimethylamino)ethyl)-1-(tetrahydropyran-4-yl)-indole;    6-(2-(N,N-Dimethylamino)ethyl)-1-isopropyl-1H-indazole;    6-(2-(N,N-Dimethylaminoethyl)-1-(3-pyridinyl)-indole;    6-(2-(N,N-Dimethylaminoethyl)-1-(3-thienyl)-indole; and    6-(2-(N,N-Dimethylaminoethyl)-1-(4-fluorophenyl)-indole.    
     
     
         15 . A compound according to  claim 14 , selected from the group consisting of: 
 6-(2-(N,N-Dimethylamino)ethyl)-1H-indole;    6-(2-(N,N-Dimethylamino)ethyl)-1-isopropyl-indole;    6-(2-(N,N-Diethylamino)ethyl)-1-isopropyl-indole;    6-(2-(N,N-Diethylamino)ethyl)-1-dimethylaminocarbonyl-indole;    6-(2-(N,N-Di methylamino)ethyl)-1-(tetrahydrothiopyran-4-yl)-indole;    6-(2-(N,N-Dimethylamino)ethyl)-1-(tetrahydropyran-4-yl)-indole;    6-(2-(N,N-Dimethylamino)ethyl)-1-(3-pyridinyl)-indole;    6-(2-(N,N-Dimethylamino)ethyl)-1-(3-thienyl)-indole; and    6-(2-(N,N-Dimethylamino)ethyl)-1-(4-fluorophenyl)-indole.    
     
     
         16 . A composition comprising a therapeutically effective amount of a compound according to  claim 1 , and a pharmaceutically acceptable carrier.  
     
     
         17 . A method for treating a patient having a medical condition for which stimulation of the 5-HT 1D  receptor is indicated, comprising the step of administering to the patient a pharmaceutical composition as defined in  claim 16 .  
     
     
         18 . A method according to  claim 17 , wherein the medical condition is migraine.