Benzenedicarboxylic acid derivatives

Abstract

New benzenedicarboxylic acid derivative compounds; pharmaceutical compositions, diagnostic methods, and diagnostic kits that include those compounds; and methods of using those compounds for inhibiting NAALADase enzyme activity, detecting diseases where NAALADase levels are altered, effecting neuronal activity, effecting TGF-β activity, inhibiting angiogenesis, and treating glutamate abnormalities, neuropathy, pain, compulsive disorders, prostate diseases, cancers, and glaucoma.

1 - 7 . (canceled)  
     
     
         8 . A method for treating a glutamate abnormality in a mammal, comprising administering to said mammal an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable equivalent, wherein: 
 X is —W-Z;  
 W is a bond or a linking group;  
 Z is a terminal group; and  
 Y is —COOH oriented meta or para relative to C-1.  
 
     
     
         9 . The method of  claim 8 , wherein the glutamate abnormality is compulsive disorder, stroke, demyelinating disease, schizophrenia, Parkinson's disease, ALS, anxiety, anxiety disorder, or memory impairment.  
     
     
         10 . The method of  claim 9 , wherein the glutamate abnormality is alcohol dependence.  
     
     
         11 . The method of  claim 9 , wherein the glutamate abnormality is nicotine dependence.  
     
     
         12 . The method of  claim 9 , wherein the glutamate abnormality is cocaine dependence.  
     
     
         13 . A method for effecting a neuronal activity in a mammal, comprising administering to said mammal an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable equivalent, wherein: 
 X is —W-Z;  
 W is a bond or a linking group;  
 Z is a terminal group; and  
 Y is —COOH oriented meta or para relative to C-1.  
 
     
     
         14 . The method of  claim 13 , wherein the neuronal activity is stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration, or treatment of a neurological disorder.  
     
     
         15 . The method of  claim 14 , wherein the neuronal activity is treatment of a neurological disorder that is pain, neuropathy, traumatic brain injury, physical damage to spinal cord, stroke associated with brain damage, demyelinating disease, or a neurological disorder relating to neurodegeneration.  
     
     
         16 . The method of  claim 15 , wherein the method is treating peripheral neuropathy.  
     
     
         17 . The method of  claim 16 , wherein the peripheral neuropathy is caused by Type I or Type II diabetes, HIV, vitamins, or non-vitamin chemicals.  
     
     
         18 . The method of  claim 15 , wherein the method is treatment of neuropathic pain.  
     
     
         19 . The method of  claim 18 , wherein the neuropathic pain is caused by Type I or Type II diabetes, HIV, vitamins, or non-vitamin chemicals.  
     
     
         20 . The method of  claim 18 , wherein the compound of formula I is administered in combination with an effective amount of morphine.  
     
     
         21 . The method of  claim 15 , wherein the neuronal activity is treatment of Parkinson's disease or ALS.  
     
     
         22 . A method for treating a prostate disease in a mammal, comprising administering to said mammal an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable equivalent, wherein: 
 X is —W-Z;  
 W is a bond or a linking group;  
 Z is a terminal group; and  
 Y is —COOH oriented meta or para relative to C-1.  
 
     
     
         23 . The method of  claim 22 , wherein the prostate disease is prostate cancer.  
     
     
         24 . A method for treating cancer in a mammal, comprising administering to said mammal an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable equivalent, wherein: 
 X is —W-Z;  
 W is a bond or a linking group;  
 Z is a terminal group; and  
 Y is —COOH oriented meta or para relative to C-1.  
 
     
     
         25 . The method of  claim 24 , wherein the cancer is of the brain, kidney, or testis.  
     
     
         26 . A method for inhibiting angiogenesis in a mammal, comprising administering to said mammal an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable equivalent, wherein: 
 X is —W-Z;  
 W is a bond or a linking group;  
 Z is a terminal group; and  
 Y is —COOH oriented meta or para relative to C-1.  
 
     
     
         27 . A method for treating a TGF-β abnormality in a mammal, comprising administering to said mammal an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable equivalent, wherein: 
 X is —W-Z;  
 W is a bond or a linking group;  
 Z is a terminal group; and  
 Y is —COOH oriented meta or para relative to C-1.  
 
     
     
         28 . A method for inhibiting NAALADase in a mammal, comprising administering to said mammal an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable equivalent, wherein: 
 X is —W-Z;  
 W is a bond or a linking group;  
 Z is a terminal group; and  
 Y is —COOH oriented meta or para relative to C-1.  
 
     
     
         29 . A method for treating nervous insult in a mammal, comprising administering to said mammal an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable equivalent, wherein: 
 X is —W-Z;  
 W is a bond or a linking group;  
 Z is a terminal group; and  
 Y is —COOH oriented meta or para relative to C-1.  
 
     
     
         30 . The method of  claim 29 , wherein the nervous insult comprises a cognitive disorder.  
     
     
         31 - 38 . (canceled)  
     
     
         39 . A method for detecting a disease, disorder, or condition where NAALADase levels are altered, comprising: 
 (i) contacting a sample of bodily tissue or fluid with a compound of formula I,                           or a pharmaceutically acceptable equivalent, wherein: 
 X is —W-Z;  
 W is a bond or a linking group;  
 Z is a terminal group; and  
 Y is —COOH oriented meta or para relative to C-1, 
 wherein said compound binds to any NAALADase in said sample; and  
 
   (ii) measuring the amount of any NAALADase bound to said sample, wherein the amount of NAALADase is diagnostic for said disease, disorder, or condition.    
     
     
         40 . A method for detecting a disease, disorder, or condition where NAALADase levels are altered in an animal or a mammal, comprising: 
 (i) labeling a compound of formula I,                           a pharmaceutically acceptable equivalent, with an imaging reagent, wherein: 
 X is —W-Z;  
 W is a bond or a linking group;  
 Z is a terminal group; and  
 Y is —COOH oriented meta or para relative to C-1,  
   (ii) administering to said animal or mammal an effective amount of the labeled compound;    (i) allowing said labeled compound to localize and bind to NAALADase present in said animal or mammal; and    (ii) measuring the amount of NAALADase bound to said labeled compound, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.    
     
     
         41 . A diagnostic kit for detecting a disease, disorder or condition where NAALADase levels are altered, comprising a compound of formula I, or a pharmaceutically acceptable equivalent, labeled with a marker,  
       
         
           
           
               
               
           
         
         wherein: 
 X is —W-Z;  
 W is a bond or a linking group;  
 Z is a terminal group; and  
 
         Y is —COOH oriented meta or para relative to C-1.