Highly selective sigma receptor ligands

Abstract

Compounds having the general formula II, III, or IV wherein R 1 can be a radical of an optionally substituted C-4 to C-7 N-containing heterocycle or a radical of an optionally substituted cyclic or acyclic tertiary amine or isoindoline-1,3-dione: R 2,3,4,5,6 can each independently be any one or combinations of the following moieties, cyano, nitro, acyl, alkyl, amido, azido, isothiocyanate, isocyanate, optionally substituted anilino, halogens, ethers, sulfonamides, thioacyl, nitro, aromatic, heterocyclic, olefinic, acetylene, deuterium, or tritium; Y can be either CH, CH 2 , O, S, OCH 2 , N—R, N—Ar, C—R, C—Ar; Z can be either H, O, S, S—R or NR. R groups can be either H, aryls, alkyls, or cycloalkyls; “n” can be 1 to 5 carbons in length and stereoisomers, functional analogs, and pharmaceutically acceptable salts thereof and wherein the moiety bridging R 1 and N can be a substituted alkylene, optionally substituted alkenylene or optionally substituted alkynylene and where the alkylene group can include an inserted C 3 -C 5 cycloalkyl group, aromatic, and hetercocyclic group; wherein X′ is halogen, or C 1 -C 4 haloalyl; wherein the R x is a C 1 -C 5 straight chain or branched chain alkyl or a C 1 -C 4 straight chain or branched chain haloalkyl.

1 . Compounds having the general formula II, III, or IV 
       
         
           
           
               
               
           
         
         wherein R 1  can be an optionally substituted piperidine, an optionally substituted tetrahydropiperidine, an optionally substituted piperazine, an optionally substituted tetrahydropyridine, an optionally substituted azepane or an optionally substituted tetrahydroisoquinoline in which the optional substituents are on the aromatic moiety or a radical of an optionally substituted cyclic or acyclic tertiary amine or isoindoline-1,3-dione: R 2,3,4,5,6  can each independently be any one or combinations of the following moieties, hydrogen, cyano, nitro, acyl, alkyl, amido, azido, isothiocyanate, isocyanate, optionally substituted anilino, halogens, ethers, sulfonamides, thioacyl, nitro, aromatic, heterocyclic, olefinic, acetylene, deuterium, or tritium; wherein when R 2,3,4,5  is a halogen, the halogen is fluorine, bromine or iodine; “n” can be 1 to 5 carbons in length; wherein the moiety bridging R 1  and N can be optionally substituted alkylene, optionally substituted alkenylene or optionally substituted alkynylene group; wherein X′ is halogen, or C 1 -C 4  haloalyl; and wherein the following compounds are excluded: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and stereoisomers, and pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The compounds of  claim 1 , having the formula VI 
       
         
           
           
               
               
           
         
         wherein n=1-5. 
       
     
     
         3 . The compounds of  claim 1 , having the formula VIII 
       
         
           
           
               
               
           
         
         where n=1-5. 
       
     
     
         4 . The compounds of  claim 1 , having the formula X 
       
         
           
           
               
               
           
         
         where n=1-5. 
       
     
     
         5 . The compounds of  claim 1 , having the formula XII 
       
         
           
           
               
               
           
         
         wherein n=1-5. 
       
     
     
         6 . The compounds of  claim 1 , wherein Y=O and Z=O. 
     
     
         7 . The compounds of  claim 1 , wherein Y=S and Z=S. 
     
     
         8 . The compounds of  claim 1 , where Y=CH 2  or Y=CH. 
     
     
         9 . The compounds of  claim 1 , where R 1  is optionally substituted 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compounds of  claim 1 , wherein X is fluoro. 
     
     
         11 . The compounds of  claim 1 , wherein X is trifluoromethyl. 
     
     
         12 . The compounds of  claim 1 , wherein the alkylene bridging moiety is substituted by methyl or trifluoromethyl. 
     
     
         13 . A method of treating a subject for alleviation of affects in the subject resulting from drug intake or drug abuse by the subject comprising administering to the subject a therapeutically effective amount of at least one compound according to  claim 1 . 
     
     
         14 . A method according to  claim 10  wherein the drug abuse or drug intake results from methamphetamine intake or methamphetamine abuse by the subject. 
     
     
         15 . A method according to  claim 10  wherein the drug intake or drug intake results from cocaine abuse or cocaine intake by the subject. 
     
     
         16 . A method of treating a subject having a need for therapy involving sigma receptors comprising administering to the subject an effective amount of at least one compound of  claim 1 . 
     
     
         17 . A method of treating a subject to prevent neurotoxic effects resulting from drug abuse or drug intake by the subject comprising administering to the subject a therapeutically effective amount of at least one compound according to  claim 1 . 
     
     
         18 . A radioligand composition comprising at least one compound according to  claim 1  wherein at least one compound contains a radioactive element. 
     
     
         19 . A pharmaceutical composition comprising at least one compound according to  claim 1  and an acceptable carrier or excipient. 
     
     
         20 . Compounds of the following formula V: 
       
         
           
           
               
               
           
         
         wherein R 2,3,4,5,6  can each independently be any one or combinations of the following moieties, such as, for example, hydrogen, cyano, nitro, acyl, alkyl, amido, azido, isothiocyanate, isocyanate anilino (unsubstituted or substituted), halogens (such as fluorine, chlorine, bromine and iodine), ethers, sulfonamides, thioacyl, nitro, aromatic, heterocyclic, olefinic, acetylenic, deuterium, or tritium; Y can be either CH, CH 2 , O, S, OCH 2 , N—R, N—Ar, C—R, C—Ar where Ar is an optionally substituted aryl. Z can be either H, O, S, S—R or NR. R groups can be either H, aryls, alkyls, or cycloalkyls. “n” can be 1 to 5 carbons in length and stereoisomers, analogs, and pharmaceutically acceptable salts thereof as well as compositions comprising said compounds. The R 1  bridging moiety in the formula V can be an optionally substituted C 1 -C 6  alkylene, C 1 -C 6  alkenylene or C 1 -C 6  alkynylene group wherein the alkylene group can have inserted into its chain a C 3 -C 5  cycloalkyl group, aromatic, and heterocyclic group. 
       
     
     
         21 . A compound having the formula XIV 
       
         
           
           
               
               
           
         
       
     
     
         22 . A method of treating a subject for alleviation of affects in the subject resulting from drug intake or drug abuse by the subject comprising administering to the subject a therapeutically effective amount of the compound according to  claim 21 . 
     
     
         23 . A method according to  claim 22  wherein the drug abuse or drug intake results from methamphetamine intake or methamphetamine abuse by the subject. 
     
     
         24 . A method according to  claim 22  wherein the drug intake or drug intake results from cocaine abuse or cocaine intake by the subject. 
     
     
         25 . A method of treating a subject having a need for therapy involving sigma receptors comprising administering to the subject an effective amount of the compound of  claim 21 . 
     
     
         26 . A method of treating a subject to prevent neurotoxic effects resulting from drug abuse or drug intake by the subject comprising administering to the subject a therapeutically effective amount of the compound according to  claim 21 . 
     
     
         27 . A pharmaceutical composition comprising the compound according to  claim 21  and an acceptable carrier or excipient.