Heterodimers of glutamic acid

Abstract

Compounds of Formula (Ia) wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl or —NR′R′, Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p Z is H or C 1 -C 4 alkyl, R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 6 -C 12 heteroaryl, —NR′R′ or COOZ, which have diagnostic and therapeutic properties, such as the treatment and management of prostate cancer and other diseases related to NAALADase inhibition. Radiolabels can be incorporated into the structure through a variety of prosthetic groups attached at the X amino acid side chain via a carbon or hetero atom linkage.

1 - 67 . (canceled) 
     
     
         68 . A method of tumor detection in a patient suffering from a disease, disorder, or condition, comprising administering a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R is a C 3 -C 12  heteroaryl substituted with a halogen; 
         each Z is independently hydrogen or C 1 -C 4  alkyl; 
         Q is NH; 
         Y is C(O), S(O) 2 , C(O) 2 , or (CH 2 ) p ; 
         m is 4; 
         n is 0; and 
         p is 0, 1, 2, 3, 4, 5 or 6; and 
         wherein the compound of Formula (I) is prepared via an intermediate having the formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         69 . The method of  claim 68 , wherein the disease, disorder, or condition is painful and sensory diabetic neuropathy, neuronal damage, prostate cancer, schizophrenia, colorectal cancer, inflammation, amyotrophic lateral sclerosis, or diabetic neuropathy. 
     
     
         70 . The method of  claim 69 , wherein the disease, disorder, or condition is colorectal cancer or prostate cancer. 
     
     
         71 . The method of  claim 70 , wherein the disease, disorder, or condition is prostate cancer. 
     
     
         72 . The method of  claim 68 , wherein Y is C(O). 
     
     
         73 . The method of  claim 72 , wherein R is pyridinyl substituted with halogen. 
     
     
         74 . The method of  claim 73 , wherein the halogen is a radiohalogen. 
     
     
         75 . The method of  claim 74 , wherein the radiohalogen is selected from the group consisting of: I-123, I-124, I-125, I-131, Br-75, Br-77, and F-18. 
     
     
         76 . The method of  claim 75 , wherein each Z is hydrogen. 
     
     
         77 . The method of  claim 75 , wherein each Z is C 1 -C 4  alkyl. 
     
     
         78 . The method of  claim 77 , wherein each Z is independently selected from t-butyl and methyl. 
     
     
         79 . The method of  claim 75 , wherein the radiohalogen is F-18. 
     
     
         80 . The method of  claim 79 , wherein the radiohalogen is at a position para to variable Y. 
     
     
         81 . The method of  claim 68 , wherein the method comprises obtaining an image of one or more organs or tissues or both in the patient. 
     
     
         82 . The method of  claim 81 , further comprising determining from the image an amount of PSMA which is present in the one or more organs or tissues or both in the patient. 
     
     
         83 . The method of  claim 82 , wherein the one or more organs or tissues or both includes prostate tissue, kidney tissue, brain tissue, vascular tissue, or tumor tissue. 
     
     
         84 . A method of inhibiting prostate-specific membrane antigen (PSMA) in a subject suffering from a disease, disorder, or condition, comprising administering a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R is a C 3 -C 12  heteroaryl substituted with a halogen; 
         each Z is independently hydrogen or C 1 -C 4  alkyl; 
         Q is NH; 
         Y is C(O), S(O) 2 , C(O) 2 , or (CH 2 ) p ; 
         m is 4; 
         n is 0; and 
         p is 0, 1, 2, 3, 4, 5 or 6; and 
         wherein the compound of Formula (I) is prepared via an intermediate having the formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         85 . The method of  claim 84 , wherein the disease, disorder, or condition is painful and sensory diabetic neuropathy, neuronal damage, prostate cancer, schizophrenia, colorectal cancer, inflammation, amyotrophic lateral sclerosis, or diabetic neuropathy. 
     
     
         86 . The method of  claim 85 , wherein the disease, disorder, or condition is colorectal cancer or prostate cancer. 
     
     
         87 . The method of  claim 86 , wherein the disease, disorder, or condition is prostate cancer. 
     
     
         88 . The method of  claim 84 , wherein Y is C(O). 
     
     
         89 . The method of  claim 88 , wherein R is pyridinyl substituted with halogen. 
     
     
         90 . The method of  claim 89 , wherein the halogen is a radiohalogen. 
     
     
         91 . The method of  claim 90 , wherein the radiohalogen is selected from the group consisting of: I-123, I-124, I-125, I-131, Br-75, Br-77, and F-18. 
     
     
         92 . The method of  claim 84 , wherein each Z is hydrogen. 
     
     
         93 . The method of  claim 84 , wherein each Z is C 1 -C 4  alkyl. 
     
     
         94 . The method of  claim 93 , wherein each Z is independently selected from t-butyl and methyl. 
     
     
         95 . The method of  claim 91 , wherein the radiohalogen is F-18. 
     
     
         96 . The method of  claim 95 , wherein the radiohalogen is at a position para to variable Y.