Hydroxamic acids and acyl hydroxamines as NAALADase inhibitors

Abstract

This invention relates to new compounds, pharmaceutical compositions and diagnostic kits comprising such compounds, and methods of using such 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 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable equivalent of said compound, wherein: 
 X is —(CO)NHOH or —N(OH)CHO;  
 Y is a bond or a divalent linking group having from 1 to 9 carbon atom(s) and from 0 to 5 heteroatom(s) independently selected from the group consisting of oxygen, sulfur and nitrogen;  
 Z is —CR 1 R 2 —, —NR 1 —, —O— or —S—;  
 A 1 , A 2 , A 3 , A 4  and A 5  are independently hydrogen, C 1 -C 9  alkyl, C 2 -C 9  alkenyl, C 2 -C 9  alkynyl, aryl, heteroaryl, carbocycle, heterocycle, C 1 -C 9  alkoxy, C 2 -C 9  alkenyloxy, phenoxy, benzyloxy, hydroxy, halo, nitro, cyano, isocyano, —COOR 3 , —COR 3 , —NR 3 R 4 , —SR 3 , —SOR 3 , —SO 2 R 3 , —SO 2 (OR 3 ), —(CO)NR 3 R 4 , —(CO)NR 3 (CH 2 ) n COOH, —NR 3 (CO)R 4  or —(CH 2 ) n COOH, or any adjacent two of A 1 , A 2 , A 3  and A 4  form with the benzene ring a fused ring that is saturated or unsaturated, aromatic or non-aromatic, and carbocyclic or heterocyclic, said heterocyclic ring containing 1 or 2 oxygen, nitrogen and/or sulfur heteroatom(s);  
 n is 1-3;  
 R 1 , R 2 , R 3  and R 4  are independently hydrogen, C 1 -C 9  alkyl, C 2 -C 9  alkenyl, C 2 -C 9  alkynyl, aryl, heteroaryl, carbocycle or heterocycle; and  
 said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, alkoxy, alkenyloxy, phenoxy, benzyloxy, and fused ring are independently unsubstituted or substituted with one or more substituent(s).  
 
     
     
         2 . A compound according to  claim 1 , wherein: 
 Y is —(CR 5 R 6 ) p —W—(CR 7 R 8 ) q —;    W is —CR 9 R 10 —, —NR 9 —, —O—, —S— or —SO 2 —;    p and q are independently 0-4;    provided that when q is 0 and W is —NR 9 —, —O—, —S— or —SO 2 —, then Z is —CR 1 R 2 —;    R 5 , R 6 , R 7 , R 8 , R 9  and R 10  are independently hydrogen, C 1 -C 9  alkyl, C 2 -C 9  alkenyl, C 2 -C 9  alkynyl, aryl, heteroaryl, carbocycle, heterocycle, halo, hydroxy, sulfhydryl, nitro, amino, cyano, isocyano, thiocyano, isothiocyano, formamido, thioformamido, sulfo, sulfino, C 1 -C 9  alkoxy, C 2 -C 9  alkenoxy, phenoxy or benzyloxy, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, alkoxy, alkenyloxy, phenoxy and benzyloxy are independently unsubstituted or substituted with one or more substituent(s); and    A 1 , A 2  and A 3  are each hydrogen.    
     
     
         3 . A compound according to  claim 2 , wherein: 
 Y is —(CR 5 R 6 ) p —W—(CR 7 R 8 ) q —;    W is —CR 9 R 10 —;    p is 0-4; and    q is 0.    
     
     
         4 . A compound according to  claim 3 , wherein: 
 R 5 , R 6 , R 9  and R 10  are each hydrogen;    A 4  and A 5  are independently hydrogen, —COOR 3 , C 1 -C 9  alkyl, or phenyl.    
     
     
         5 . A compound according to  claim 4 , wherein the compound is in the form of an alkali metal or alkali earth metal salt.  
     
     
         6 . A compound according to  claim 4 , wherein the compound is an enantiomer or part of an enantiomer-enriched mixture.  
     
     
         7 . A compound according to  claim 4 , wherein the compound is:  
       
         
           
           
               
               
           
         
       
     
     
         8 . A method for inhibiting NAALADase enzyme activity, treating a glutamate abnormality, effecting a neuronal activity, treating a prostate disease, treating cancer, inhibiting angiogenesis or effecting a TGF-β activity, comprising administering to a mammal in need of such inhibition, treatment or effect, an effective amount of a compound of  claim 1 .  
     
     
         9 . The method of  claim 8 , wherein said method is for treating a glutamate abnormality selected from the group consisting of a compulsive disorder, stroke, demyelinating disease, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis, anxiety, anxiety disorder, memory impairment and glaucoma.  
     
     
         10 . The method of  claim 8 , wherein said method is for effecting a neuronal activity selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of a neurological disorder.  
     
     
         11 . The method of  claim 10 , wherein the neuronal activity is treatment of a neurological disorder and said neurological disorder is pain, diabetic neuropathy, peripheral neuropathy caused by physical injury or disease state, traumatic brain injury, physical damage to spinal cord, stroke associated with brain damage, a demyelinating disease or a neurological disorder relating to neurodegeneration.  
     
     
         12 . The method of  claim 8 , wherein said method is for treating cancer.  
     
     
         13 . The method of  claim 8 , wherein said method is for inhibiting angiogenesis.  
     
     
         14 . The method of  claim 8 , wherein said method is for treating a TGF-β abnormality selected from the group consisting of neurodegenerative disorder, extra-cellular matrix formation disorder, cell-growth related disease, infectious disease, immune related disease, epithelial tissue scarring, collagen vascular disease, fibroproliferative disorder, connective tissue disorder, inflammation, inflammatory disease, respiratory distress syndrome, infertility, and diabetes.  
     
     
         15 . 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 an effective amount of a compound of  claim 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.    
     
     
         16 . A method for detecting a disease, disorder or condition where NAALADase levels are altered in a mammal, comprising: 
 (i) labeling a compound of  claim 1  with an effective amount of an imaging reagent;    (ii) administering to said mammal an effective amount of the labeled compound;    (iii) allowing said labeled compound to localize and bind to NAALADase present in said mammal; and    (iv) measuring the amount of NAALADase bound to said labeled compound, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.    
     
     
         17 . A diagnostic kit for detecting a disease, disorder or condition where NAALADase levels are altered, comprising a compound of  claim 1  labeled with a marker.  
     
     
         18 . A pharmaceutical composition comprising: 
 (i) an effective amount of a compound of  claim 1;  and    (ii) a pharmaceutically acceptable carrier.    
     
     
         19 . A compound of formula III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable equivalent of said compound, wherein: 
 X is —(CO)NHOH or —N(OH)CHO;  
 Y is a bond or a divalent linking group having from 1 to 9 carbon atom(s) and from 0 to 5 heteroatom(s) independently selected from the group consisting of oxygen, sulfur and nitrogen; and  
 R is hydrogen, C 1 -C 9  alkyl, C 2 -C 9  alkenyl, C 2 -C 9  alkynyl, C 1 -C 9  alkoxy or C 2 -C 9  alkenoxy, wherein said alkyl, alkenyl, alkynyl, alkoxy and alkenoxy are independently unsubstituted or substituted with one or more substituent(s); provided that when Y is methylene, amine or oxygen, then R is not carboxyethyl.  
 
     
     
         20 . A compound according to  claim 19 , wherein the compound is in the form of an alkali metal or alkali earth metal salt.  
     
     
         21 . A compound according to  claim 19 , wherein the compound is an enantiomer or part of an enantiomer-enriched mixture.  
     
     
         22 . A method for inhibiting NAALADase enzyme activity, treating a glutamate abnormality, effecting a neuronal activity, treating a prostate disease, treating cancer, inhibiting angiogenesis or effecting a TGF-β activity, comprising administering to a mammal in need of such inhibition, treatment or effect, an effective amount of a compound of  claim 19 .  
     
     
         23 . 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 an effective amount of a compound of  claim 19 , 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.    
     
     
         24 . A method for detecting a disease, disorder or condition where NAALADase levels are altered in a mammal, comprising: 
 (i) labeling a compound of  claim 19  with an effective amount of an imaging reagent;    (ii) administering to said mammal an effective amount of the labeled compound;    (iii) allowing said labeled compound to localize and bind to NAALADase present in said mammal; and    (iv) measuring the amount of NAALADase bound to said labeled compound, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.    
     
     
         25 . A diagnostic kit for detecting a disease, disorder or condition where NAALADase levels are altered, comprising a compound of  claim 19  labeled with a marker.  
     
     
         26 . A pharmaceutical composition comprising: 
 (i) an effective amount of a compound of  claim 19;  and    (ii) a pharmaceutically acceptable carrier.