Pharmaceutical compositions and methods for treating anxiety, anxiety disorders and memory impairment using NAALADase inhibitors

Abstract

The present invention relates to pharmaceutical compositions and methods of using NAALADase inhibitors for treating glutamate-mediated diseases, disorders and conditions selected from the group consisting of anxiety, anxiety disorders and memory impairment.

We claim:  
     
         1 . A method for treating a glutamate mediated disease, disorder or condition selected from the group consisting of anxiety, anxiety disorder and memory impairment, comprising administering an effective amount of a NAALADase inhibitor to a mammal in need of such treatment.  
     
     
         2 . The method of  claim 1 , wherein the NAALADase inhibitor is an acid containing metal chelator.  
     
     
         3 . The method of  claim 1 , wherein the NAALADase inhibitor is a compound of formula I:  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable equivalent, wherein:  
         Y is CR 3 R 4 , NR 5  or O;  
         R 1  is selected from the group consisting of hydrogen, C 1 -C 9  alkyl, C 2 -C 9  alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, Ar, COOR, NR 6 R 7  and OR, wherein said alkyl, alkenyl, cycloalkyl and cycloalkenyl are unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 9  alkoxy, C 2 -C 9  alkenyloxy, phenoxy, benzyloxy, COOR, NR 6 R 2  and Ar; 
 R 2  is selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, Ar, halo and carboxy, wherein said alkyl, alkenyl, cycloalkyl and cycloalkenyl are unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 9  alkoxy, C 2 -C 9  alkenyloxy, phenoxy, benzyloxy, NR 6 R 7  and Ar;  
 R 3  and R 4  are independently hydrogen or C 1 -C 3  alkyl;  
 R 5  is hydrogen or C 1 -C 3  alkyl;  
 R, R 6  and R 7  are independently selected from the group consisting of hydrogen, C 1 -C 9  alkyl, C 2 -C 9  alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl and Ar, wherein said alkyl, alkenyl, cycloalkyl and cycloalkenyl are unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 9  alkoxy, C 5 -C 9  alkenyloxy, phenoxy, benzyloxy and Ar; and  
 Ar is selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, tetrahydropyranyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  alkoxy, C 2 -C 6  alkenyloxy, phenoxy, benzyloxy, carboxy and NR,R 2 .  
 
       
     
     
         4 . The method of  claim 3 , wherein Y is CH 2 .  
     
     
         5 . The method of  claim 4 , wherein R 2  is —(CH 2 ) 2 COOH.  
     
     
         6 . The method of  claim 5 , wherein R 1  is hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 3 -C 3  cycloalkyl, C 5 -C 7  cycloalkenyl, benzyl, phenyl or OR, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, benzyl and phenyl are unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of carboxy, C 3 -C 3  cycloalkyl, C 5 -C 7  cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  alkoxy, C 2 -C 6  alkenyloxy, phenoxy, benzyloxy, NR 6 R 7 , benzyl and phenyl.  
     
     
         7 . The method of  claim 6 , wherein the compound of formula I is selected from the group consisting of: 
 2-(phosphonomethyl)pentanedioic acid;    2-[[(2-carboxyethyl)hydroxyphosphinyl]methyl]-pentanedioic acid;    2-[(benzylhydroxyphosphinyl)methyl]pentanedioic acid;    2-[(phenylhydroxyphosphinyl)methyl]pentanedioic acid;    2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]-methyl]pentanedioic acid;    2-[(butylhydroxyphosphinyl)methyl]pentanedioic acid;    2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]-pentanedioic acid;    2-[(3-phenylpropylhydroxyphosphinyl)methyl]-pentanedioic acid;    2-[[(4-fluorophenyl)hydroxyphosphinyl]methyl]-pentanedioic acid;    2-[(methylhydroxyphosphinyl)methyl]pentanedioic acid;    2-[(phenylethylhydroxyphosphinyl)methyl]-pentanedioic acid;    2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]-pentanedioic acid;    2-[[(4-fluorobenzyl)hydroxyphosphinyl]methyl]-pentanedioic acid;    2-[[(4-methoxybenzyl)hydroxyphosphinyl]methyl]-pentanedioic acid;    2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]-methyl]pentanedioic acid;    2-[[4-trifluoromethylbenzyl)hydroxyphosphinyl]-methyl]pentanedioic acid;    2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]-pentanedioic acid;    2-[[(2,3,4,5,6-pentafluorobenzyl)hydroxy-phosphinyl]methyl]pentanedioic acid; and    pharmaceutically acceptable equivalents.    
     
     
         8 . The method of  claim 7 , wherein the compound of formula I is 2-[[(2,3,4,5,6-pentafluorobenzyl)-hydroxyphosphinyl]methyl]pentanedioic acid or a pharmaceutically equivalent.  
     
     
         9 . The method of  claim 8 , wherein the compound of formula I is an enantiomer or an enantiomer-enriched mixture.  
     
     
         10 . The method of  claim 1 , wherein the NAALADase inhibitor is a compound of formula II  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable equivalent, wherein: 
 X is a moiety of formula III, IV or V  
                     
  m and n are independently 0, 1, 2, 3 or 4;  
 Z is SR 13 , SO 3 R 13 , SO 2 R 13 , SOR 13 , SO(NR 13 )R 14  or S(NR 13 R 14 ) 2 R 15 ;  
 B is N or CR 16 ;  
 A is O, S, CR 17 R 18  or (CR 17 R 18 ) m S;  
 R 9  and R 13  are hydrogen;  
 R 8 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17  and R 18  are independently hydrogen, C 1 -C 9  straight or branched chain alkyl, C 2 -C 9  straight or branched chain alkenyl, C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, Ar 1 , hydroxy, carboxy, carbonyl, amino, amido, cyano, isocyano, nitro, sulfonyl, sulfoxy, thio, thiocarbonyl, thiocyano, formanilido, thioformamido, sulfhydryl, halo, haloalkyl, trifluoromethyl or oxy, wherein said alkyl, alkenyl, cycloalkyl and cycloalkenyl are independently unsubstituted or substituted with one or more substituent(s); and  
 Ar 1  is a carbocyclic or heterocyclic moiety, which is unsubstituted or substituted with one or more substituent (s)  
 provided that when X is a moiety of formula III and A is O, then n is 2, 3 or 4; when X is a moiety of formula III and A is S, then n is 2, 3 or 4; and when X is a moiety of formula III and A is (CR 17 R 18 ) m S, then n is 0, 2, 3 or 4.  
 
       
     
     
         11 . The method of  claim 10 , wherein the NAALADase inhibitor is a compound of formula VI  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable equivalent, wherein: 
 n is 0, 1, 2 or 3;  
 Z is SH, SO 3 R 13 , SO 2 R 13 , SOR 13  or S(NR 13 R 14 ) 2 R 15 ; and  
 A is O, S or CR 17 R 18 .  
 
       
     
     
         12 . The method of  claim 11 , wherein Z is SH.  
     
     
         13 . The method of  claim 12 , wherein R 8  is —(CH 2 ) 2 COOH.  
     
     
         14 . The method of  claim 12 , wherein the compound of formula VI is selected from the group consisting of: 
 2-(2-sulfanylethyl)pentanedioic acid;    3-(2-sulfanylethyl)-1,3,5-pentanetricarboxylic acid;    2-(2-sulfanylpropyl)pentanedioic acid;    2-(2-sulfanylbutyl)pentanedioic acid;    2-(2-sulfanyl-2-phenylethyl)pentanedioic acid;    2-(2-sulfanylhexyl)pentanedioic acid;    2-(2-sulfanyl-1-methylethyl)pentanedioic acid;    2-[1-(sulfanylmethyl)propyl]pentanedioic acid;    2-(3-sulfanylpentyl)pentanedioic acid;    2-(3-sulfanylpropyl)pentanedioic acid;    2-(3-sulfanyl-2-methylpropyl)pentanedioic acid;    2-(3-sulfanyl-2-phenylpropyl)pentanedioic acid;    2-(3-sulfanylbutyl)pentanedioic acid;    2-[3-sulfanyl-2-(phenylmethyl)propyl]pentanedioic acid;    2-[2-(sulfanylmethyl)butyl]pentanedioic acid;    2-[2-(sulfanylmethyl)pentyl]pentanedioic acid;    2-(3-sulfanyl-4-methylpentyl)pentanedioic acid; and    pharmaceutically acceptable equivalents.    
     
     
         15 . The method of  claim 14 , wherein the compound of formula VI is selected from the group consisting of 2-(2-sulfanylethyl)pentanedioic acid, 2-(2-sulfanylpropyl)pentanedioic acid, 2-(3-sulfanylpropyl)pentanedioic acid and pharmaceutically acceptable equivalents.  
     
     
         16 . The method of  claim 15 , wherein the compound of formula VI is an enantiomer or an enantiomer-enriched mixture.  
     
     
         17 . The method of  claim 1 , wherein the NAALADase inhibitor is administered in combination with at least one additional therapeutic agent.  
     
     
         18 . The method of  claim 1 , wherein the glutamate mediated disease, disorder or condition is an anxiety disorder selected from the group consisting of panic attack, agoraphobia, panic disorder, acute stress disorder, chronic stress disorder, specific phobia, simple phobia, social phobia, substance induced anxiety disorder, organic anxiety disorder, obsessive compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and anxiety disorder NOS.  
     
     
         19 . The method of  claim 1 , wherein the glutamate mediated disease, disorder or condition is memory impairment.  
     
     
         20 . A pharmaceutical composition comprising: 
 (i) an effective amount of a NAALADase inhibitor for treating a glutamate mediated disease, disorder or condition selected from the group consisting of anxiety, anxiety disorder and memory impairment; and    (ii) a pharmaceutically acceptable carrier.