18f-labeled triazole containing psma inhibitors

Abstract

The present technology is directed to compounds, intermediates thereof, compositions thereof, medicaments thereof, and methods related to the imaging of mammalian tissue overexpressing PSMA. The compounds are of Formula I or a pharmaceutically acceptable salt thereof, wherein one of R 1 , R 2 , and R 3 is and of Formula IV or a pharmaceutically acceptable salt thereof.

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 P 1 , P 2 , and P 3  are each independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl; 
 W 1  is —C(O)— or —(CH 2 ) n —NH—C(O)—; 
 one of R 1 , R 2 , and R 3  is 
 
       
       
         
           
           
               
               
           
         
         
           
             N and the remaining two of R 1 , R 2 , and R 3  are each H; 
           
           X 1  is absent, O, S, or NH; 
           m is 0, 1, 2, or 3; 
           n is 1 or 2; 
           p is 0, 1, 2, or 3, provided that when p is 0 then X 1  is absent; and 
           q is 1 or 2. 
         
       
     
     
         2 . The compound of  claim 1 , wherein P 1 , P 2 , and P 3  are each independently H or tert-butyl. 
     
     
         3 . The compound of  claim 1 , wherein P 1 , P 2 , and P 3  are each independently H. 
     
     
         4 . An intermediate for preparing a compound of  claim 1 , wherein the intermediate is of Formula II 
       
         
           
           
               
               
           
         
         wherein
 P 4 , P 5 , and P 6  are each independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl; 
 W 2  is —C(O)— or —(CH 2 —NH—C(O)—; 
 one of R 4 , R 5 , and R 6  is 
 
       
       
         
           
           
               
               
           
         
         
           
             and the remaining two of R 4 , R 5 , and R 6  are each H; 
           
           X 2  is absent, 0, S, or NH; 
           r is 0, 1, 2, or 3; 
           s is 1 or 2; and 
           t is 0, 1, 2, or 3, provided that when t is 0 then X 2  is absent. 
         
       
     
     
         5 . A composition comprising a compound of  claim 3  and a pharmaceutically acceptable carrier. 
     
     
         6 . A pharmaceutical composition for detecting mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), the composition comprising an effective amount of the compound of  claim 3  and a pharmaceutically acceptable carrier. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the mammalian tissue comprises one or more of glioma, cervical carcinoma, vulvar carcinoma, endometrial carcinoma, primary ovarian carcinoma, metastatic ovarian carcinoma, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary, gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer. 
     
     
         8 . A method comprising
 administering a compound of  claim 3  to a subject; and   subsequent to the administering, detecting one or more of positron emission, gamma rays from positron emission and annihilation, and Cerenkov radiation due to positron emission.   
     
     
         9 . The method of  claim 8 , wherein the method comprises administering an effective amount of the compound to the subject. 
     
     
         10 . The method of  claim 8 , wherein the subject is suspected of suffering from a mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”). 
     
     
         11 . The method of  claim 10 , wherein the mammalian tissue comprises one or more of glioma, cervical carcinoma, vulvar carcinoma, endometrial carcinoma, primary ovarian carcinoma, metastatic ovarian carcinoma, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary, gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer. 
     
     
         12 . The method of  claim 8 , wherein the administering the compound comprises parenteral administration. 
     
     
         13 . A compound of Formula IV 
       
         
           
           
               
               
           
         
         wherein
 P 7 , P 8 , and P 9  are each independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl; 
 w is 1 or 2; 
 x is 0, 1, 2, or 3; and 
 y is 1 or 2. 
 
       
     
     
         14 .- 15 . (canceled) 
     
     
         16 . An intermediate for preparing a compound of  claim 13 , wherein the intermediate is of Formula V 
       
         
           
           
               
               
           
         
         wherein
 P 10 , P 11 , and P 12  are each independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl; 
 b is 1 or 2; and 
 d is 0, 1, 2, or 3. 
 
       
     
     
         17 . A composition comprising a compound of claim  15  and a pharmaceutically acceptable carrier. 
     
     
         18 . A pharmaceutical composition for detecting a mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), the composition comprising an effective amount of the compound of claim  15  and a pharmaceutically acceptable excipient. 
     
     
         19 . A method comprising
 administering a compound of claim  15  to a subject; and   subsequent to the administering, detecting one or more of positron emission, gamma rays from positron emission and annihilation, and Cerenkov radiation due to positron emission.   
     
     
         20 . The method of  claim 19 , wherein the method comprises administering an effective amount of the compound to the subject. 
     
     
         21 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The intermediate of  claim 4 , wherein the intermediate is