Thiolactones

Abstract

This invention provides 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, inhibiting angiogenesis, effecting a TGF-β activity or a neuronal activity, and treating a glutamate abnormality, a compulsive disorder, neuropathy, pain, a prostate disease, cancer, Huntington's disease, diabetes, a retinal disorder or glaucoma.

1 . A compound of formula I, II or III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable equivalent, an optical isomer or a mixture of isomers of the compound, wherein: 
 X is C 1 -C 4  alkylene, C 2 -C 4  alkenylene, C 2 -C 4  alkynylene, C 3 -C 8  cycloalkylene, C 5 -C 7  cycloalkenylene or Ar, wherein the alkylene, alkenylene, alkynylene, cycloalkylene or cycloalkenylene is unsubstituted or substituted with one or more substituent(s);  
 L is a bond, —CR 1 R 2 —, —O—, —S—, —SO 2 — or —NR 1 —;  
 Y is —O—, —S—, —CR 3 R 4 — or —NR 3 —;  
 Z is —(CR 5 R 6 ) n —;  
 n is 1, 2, 3 or 4;  
 Ar is a bivalent aryl or heteroaryl radical that is unsubstituted or substituted with one or more substituent(s);  
 R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently hydrogen, C 1 -C 4  alkyl or C 2 -C 4  alkenyl, wherein the alkyl or alkenyl is unsubstituted or substituted with one or more substituent(s);  
 R 7  is hydrogen, phenyl, phenylethyl or benzyl wherein the phenyl, phenylethyl or benzyl is unsubstituted or substituted with one or more substituent(s); and  
 R 8 , R 9 , R 10  and R 11  are independently hydrogen, carboxy, hydroxy, halo, nitro, cyano, C 1 -C 4  alkyl or C 1 -C 4  alkoxy;  
 provided that when the compound is of formula I, L is a bond and X is ethyl, then Y is not —CR 3 R 4 —; and  
 provided that when the compound is of formula I, and Y is —CR 3 R 4 —, then n is 1, 3 or 4.  
 
     
     
         2 . The compound of  claim 1 , wherein the compound is of formula I.  
     
     
         3 . The compound of  claim 2 , wherein: 
 Y is —CR 3 R 4 —; and    n is 1.    
     
     
         4 . The compound of  claim 3 , wherein: 
 L is—CR 1 R 2 —, —O—, —S— or NH;    X is C 1 -C 2  alkylene or Ar; and    Ar is phenylene, biphenylene, benzylene or naphthylene, wherein the phenylene, biphenylene, benzylene or naphthylene is unsubstituted or substituted with one or more substituent(s) independently selected from carboxy, halo, nitro, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, phenyl, phenoxy and benzyloxy.    
     
     
         5 . (canceled)  
     
     
         6 . The compound of  claim 1 , wherein the compound is of formula II.  
     
     
         7 . The compound of  claim 6 , wherein: 
 L is a bond, —CR 1 R 2 — or —O—; and    n is 2.    
     
     
         8 . The compound of  claim 7 , wherein: 
 X is C 1 -C 4  alkylene or Ar; and    Ar is phenylene, biphenylene or benzylene that is unsubstituted or substituted with one or more substituent(s) independently selected from carboxy, halo, nitro, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, phenoxy and benzyloxy.    
     
     
         9 . The compound of  claim 8 , which is: 
 3-(1-oxo-isothiochroman-8-yl)-benzoic acid;    3-(1-oxo-isothiochroman-8-yloxymethyl)-benzoic acid; or    a pharmaceutically acceptable equivalent, an optical isomer or a mixture of isomers thereof.    
     
     
         10 . The compound of  claim 1 , wherein the compound is of formula III.  
     
     
         11 . The compound of  claim 10 , wherein: 
 R 8 , R 9 , R 10 l and R   11  are independently hydrogen or carboxy.    
     
     
         12 . The compound of  claim 1   1 , wherein: 
 R 7  is phenyl or benzyl substituted with one or more substituent(s) independently selected from carboxy, halo, C 1 -C 4  alkyl and C 1 -C 4  alkoxy.    
     
     
         13 . The compound of  claim 12  which is 3-(1-oxo-3,4-dihydro-1H-2-thia-9-aza-fluoren-9-yl)-benzoic acid.  
     
     
         14 . A method for inhibiting NAALADase enzyme activity, treating a glutamate abnormality, effecting a neuronal activity, treating a prostate disease, treating cancer, inhibiting angiogenesis, effecting a TGF-β activity, treating Huntington's disease, treating diabetes, treating a retinal disorder or treating glaucoma, comprising administering to a mammal in need of such inhibition, treatment or effect, an effective amount of a compound of formula I, II or III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable equivalent, an optical isomer or a mixture of isomers of the compound, wherein: 
 X is C 1 -C 4  alkylene, C 2 -C 4  alkenylene, C 2 -C 4  alkynylene, C 3 -C 8  cycloalkylene, C 5 -C 7  cycloalkenylene or Ar, wherein the alkylene, alkenylene, alkynylene, cycloalkylene or cycloalkenylene is unsubstituted or substituted with one or more substituent(s);  
 L is a bond, —CR 1 R 2 —, —O—,—S—, —SO 2 — or —NR 1 —;  
 Y is —O—, —S—, —CR 3 R 4 — or —NR 3 —;  
 Z is —(CR 5 R 6 ) n —;  
 n is 1, 2, 3 or 4;  
 Ar is a bivalent aryl or heteroaryl radical that is unsubstituted or substituted with one or more substituent(s);  
 R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently hydrogen, C 1 -C 4  alkyl or C 2 -C 4  alkenyl, wherein the alkyl or alkenyl is unsubstituted or substituted with one or more substituent(s);  
 R 7  is hydrogen, phenyl, phenylethyl or benzyl wherein the phenyl, phenylethyl or benzyl is unsubstituted or substituted with one or more substituent(s); and  
 R 8 , R 9 , R 10  and R 11  are independently hydrogen, carboxy, hydroxy, halo, nitro, cyano, C 1 -Calkyl or C 1 -C 4  alkoxy.  
 
     
     
         15 . The method of  claim 14 , wherein the method is for treating a glutamate abnormality selected from compulsive disorder, stroke, demyelinating disease, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), anxiety, anxiety disorder, memory impairment and glaucoma.  
     
     
         16 . The method of  claim 15 , wherein the glutamate abnormality is a compulsive disorder that is alcohol, nicotine, cocaine or opioid dependence.  
     
     
         17 . The method of  claim 14 , wherein the method is for effecting a neuronal activity selected from stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of a neurological disorder.  
     
     
         18 . The method of  claim 17 , wherein the neuronal activity is treatment of a neurological disorder that is pain, diabetic neuropathy, peripheral neuropathy, traumatic brain injury, physical damage to spinal cord, stroke associated with brain damage, a demyelinating disease or a neurological disorder relating to neurodegeneration, provided that when the compound is of formula I, Y is —CR 3 R 4 —, and n is 2, then the neuronal activity is treatment of a neurological disorder that is pain, diabetic neuropathy, traumatic brain injury, physical damage to spinal cord, stroke associated with brain damage, a demyelinating disease or a neurological disorder relating to neurodezeneration.  
     
     
         19 . The method of  claim 18 , wherein the peripheral neuropathy is HIV-, chemical- or vitamin-induced.  
     
     
         20 . The method of  claim 18 , wherein the pain is diabetic neuropathic pain.  
     
     
         21 . The method of  claim 20 , wherein the compound is administered in combination with an effective amount of morphine.  
     
     
         22 . The method of  claim 18 , wherein the neurological disorder relating to neurodegeneration is Parkinson's disease.  
     
     
         23 . The method of  claim 18 , wherein the neurological disorder relating to neurodegeneration is amyotrophic lateral sclerosis (ALS).  
     
     
         24 . The method of  claim 14 , wherein the method is for treating a prostate disease that is prostate cancer.  
     
     
         25 . The method of  claim 14 , wherein the method is for treating cancer.  
     
     
         26 . The method of  claim 25 , wherein the cancer is of the brain, kidney or testis.  
     
     
         27 . The method of  claim 14 , wherein the method is for inhibiting angiogenesis.  
     
     
         28 . The method of  claim 14 , wherein the method is for effecting a TGF-β activity.  
     
     
         29 . The method of  claim 28 , wherein the effecting a TGF-β activity is increasing, reducing or regulating TGF-β levels, or treating a TGF-β abnormality.  
     
     
         30 . The method of  claim 29 , wherein the TGF-β abnormality is 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 or diabetes.  
     
     
         31 . The method of  claim 14 , wherein the method is for treating Huntington's disease.  
     
     
         32 . The method of  claim 14 , wherein the method is for treating diabetes that is type I or type II diabetes mellitis.  
     
     
         33 . The method of  claim 14 , wherein the method is for treating a retinal disorder that is diabetic retinopathy.  
     
     
         34 . The method of  claim 14 , wherein the method is for treating a retinal disorder that is age-related macular degeneration.  
     
     
         35 . The method of  claim 14 , wherein the method is for treating glaucoma.  
     
     
         36 . 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 formula I, II or III                          or a pharmaceutically acceptable equivalent, an optical isomer or a mixture of isomers of the compound, wherein:    X is C 1 -C 4  alkylene, C 2 -C 4  alkenylene, C 2 -C 4  alkynylene, C 3 -C 8  cycloalkylene, C 5 -C 7  cycloalkenylene or Ar, wherein the alkylene, alkenylene, alkynylene, cycloalkylene or cycloalkenylene is unsubstituted or substituted with one or more substituent(s);    L is a bond, —CR 1 R 2 —, —O—, —S—, —SO 2 — or —NR 1 —;    Y is —O—, —S—, —CR 3 R 4 — or —NR 3 —;    Z is —(CR 5 R 6 ) n —;    n is 1, 2, 3 or 4;    Ar is a bivalent aryl or heteroaryl radical that is unsubstituted or substituted with one or more substituent(s);    R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently hydrogen, C 1 -C 4  alkyl or C 2 -C 4  alkenyl, wherein the alkyl or alkenyl is unsubstituted or substituted with one or more substituent(s);    R 7  is hydrogen, phenyl, phenylethyl or benzyl wherein the phenyl, phenylethyl or benzyl is unsubstituted or substituted with one or more substituent(s);    R 8 , R 9 , R 10  and R 11  are independently hydrogen, carboxy, hydroxy, halo, nitro, cyano, C 1 -C 4  alkyl or C 1 -C 4  alkoxy; and    the compound binds to any NAALADase in the sample; and    (ii) measuring the amount of any NAALADase bound to the sample, wherein the amount of NAALADase is diagnostic for the disease, disorder or condition.    
     
     
         37 . A method for detecting a disease, disorder or condition where NAALADase levels are altered in a mammal, comprising: 
 (i) labeling a compound of formula I, II or III                          or a pharmaceutically acceptable equivalent, an optical isomer or a mixture of isomers of the compound, wherein:    X is C 1 -C 4  alkylene, C 2 -C 4  alkenylene, C 2 -C 4  alkynylene, C 3 -C 8  cycloalkylene, C 5 -C 7  cycloalkenylene or Ar, wherein the alkylene, alkenylene, alkynylene, cycloalkylene or cycloalkenylene is unsubstituted or substituted with one or more substituent(s);    L is a bond, —CR 1 R 2 —, —O—, —S—, —SO 2 — or —NR 1 —;    Y is —O—, —S—, —CR 3 R 4 — or —NR 3 —;    Z is —(CR 5 R 6 ) n —;    n is 1, 2, 3 or 4;    Ar is a bivalent aryl or heteroaryl radical that is unsubstituted or substituted with one or more substituent(s);    R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently hydrogen, C 1 -C 4  alkyl or C 2 -C 4  alkenyl, wherein the alkyl or alkenyl is unsubstituted or substituted with one or more substituent(s);    R 7  is hydrogen, phenyl, phenylethyl or benzyl wherein the phenyl, phenylethyl or benzyl is unsubstituted or substituted with one or more substituent(s); and    R 8 , R 9 , R 10  and R 11  are independently hydrogen, carboxy, hydroxy, halo, nitro, cyano, C 1 -C 4  alkyl or C 1 -C 4  alkoxy;    with an effective amount of an imaging reagent;    (ii) administering to the mammal an effective amount of the labeled compound;    (iii) allowing the labeled compound to localize and bind to NAALADase present in the mammal; and    (iv) measuring the amount of NAALADase bound to the labeled compound, wherein the amount of NAALADase is diagnostic for the disease, disorder or condition.    
     
     
         38 . A diagnostic kit for detecting a disease, disorder or condition where NAALADase levels are altered, comprising a compound of formula I, II or III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable equivalent, an optical isomer or a mixture of isomers of the compound, wherein: 
 X is C 1 -C 4  alkylene, C 2 -C 4  alkenylene, C 2 -C 4  alkynylene, C 3 -C 8  cycloalkylene, C 5 -C 7  cycloalkenylene or Ar, wherein the alkylene, alkenylene, alkynylene, cycloalkylene or cycloalkenylene is unsubstituted or substituted with one or more substituent(s);  
 L is a bond, —CR 1 R 2 —, —O—, —S—, —SO 2 — or —NR 1 —;  
 Y is —O—, —S—, —CR 3 R 4 — or —NR 3 —;  
 Z is —(CR 5 R 6 ) n —;  
 n is 1, 2, 3 or 4;  
 Ar is a bivalent aryl or heteroaryl radical that is unsubstituted or substituted with one or more substituent(s);  
 R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently hydrogen, C 1 -C 4  alkyl or C 2 -C 4  alkenyl, wherein the alkyl or alkenyl is unsubstituted or substituted with one or more substituent(s);  
 R 7 is hydrogen, phenyl, phenylethyl or benzyl wherein the phenyl, phenylethyl or benzyl is unsubstituted or substituted with one or more substituent(s);  
 R 8 , R 9 , R 10  and R 11  are independently hydrogen, carboxy, hydroxy, halo, nitro, cyano, C 1 -C 4  alkyl or C 1 -C 4  alkoxy; and  
 the compound is labeled with a marker.  
 
     
     
         39 . A pharmaceutical composition comprising: 
 (i) an effective amount of a compound of formula I, II or III                          or a pharmaceutically acceptable equivalent, an optical isomer or a mixture of isomers of the compound, wherein:    X is C 1 -C 4  alkylene, C 2 -C 4  alkenylene, C 2 -C 4  alkynylene, C 3 -C 8  cycloalkylene, C 5 -C 7  cycloalkenylene or Ar, wherein the alkylene, alkenylene, alkynylene, cycloalkylene or cycloalkenylene is unsubstituted or substituted with one or more substituent(s);    L is a bond, —CR 1 R 2 —, —O—, —S—, —SO 2 — or —NR 1 —;    Y is —O—, —S—, —CR 3 R 4 — or —NR 3 —;    Z is —(CR 5 R 6 ) n —;    n is 1, 2, 3 or 4;    Ar is a bivalent aryl or heteroaryl radical that is unsubstituted or substituted with one or more substituent(s);    R 1 , R 2 , R 3 , R 4 , R 5  and R 6 are independently hydrogen, C 1 -C 4  alkyl or C 2 -C 4  alkenyl, wherein the alkyl or alkenyl is unsubstituted or substituted with one or more substituent(s);    R 7  is hydrogen, phenyl, phenylethyl or benzyl wherein the phenyl, phenylethyl or benzyl is unsubstituted or substituted with one or more substituent(s); and    R 8 , R 9 , R 10  and R 11  are independently hydrogen, carboxy, hydroxy, halo, nitro, cyano, C 1 -C 4  alkyl or C 1 -C 4  alkoxy;    provided that when the compound is of formula I, and Y is —CR 3 R 4 —, then n is 1, 3 or 4: and    (ii) a pharmaceutically acceptable carrier.    
     
     
         40 . (canceled)  
     
     
         41 . A method for inhibiting NAALADase enzyme activity, treating a glutamate abnormality, effecting a neuronal activity, treating a prostate disease, treating cancer, inhibiting angiogenesis, effecting a TGF-β activity, treating Huntington's disease, treating diabetes, treating a retinal disorder or treating glaucoma, comprising administering to a mammal in need of such inhibition, treatment or effect, an effective amount of  3 -(2-oxo-tetrahydrothiopyran-3-yl)-propionic acid.  
     
     
         42 . (canceled)