US2023015736A1PendingUtilityA1

Prostate-specific membrane antigen targeted high-affinity agents for endoradiotherapy of prostate cancer

Assignee: UNIV JOHNS HOPKINSPriority: Mar 22, 2016Filed: Aug 22, 2022Published: Jan 19, 2023
Est. expiryMar 22, 2036(~9.7 yrs left)· nominal 20-yr term from priority
C07D 401/12C07B 59/004A61P 35/00A61K 51/0497C07D 257/02A61K 51/0482A61K 51/0402A61P 43/00A61P 13/08C07C 275/16Y02P20/55
75
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Claims

Abstract

Prostate-specific membrane antigen targeted high-affinity agents for endoradiotherapy of prostate cancer are disclosed.

Claims

exact text as granted — not AI-modified
That which is claimed: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 Z is tetrazole or CO 2 Q; 
 Q is H or a protecting group; 
 m is an integer selected from the group consisting of 1, 2, 3, 4, and 5; 
 R is independently H or —CH 2 —R 1 ; 
 R 1  is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; 
 L is a linker selected from the group consisting of C 1 -C 6  alkylene and C 3 -C 6  cycloalkylene, and arylene; 
 W is selected from the group consisting of —NR 2 —(C═O)—, —NR 2 —(C═S)—, —(C═O)—NR 2 —, and —(C═S)—NR 2 —; wherein each occurrence of L and W can be the same or different; 
 R 2  is H or a C 1 -C 4  alkyl; 
 n is an integer selected from the group consisting of 1, 2, and 3; 
 Ch is a chelating agent that can comprise a metal or a radiometal; and pharmaceutically acceptable salts thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein X is independently Br or I. 
     
     
         3 . The compound of  claim 1 , wherein the chelating agent is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein the metal chelating agent comprises a metal selected from the group consisting of: Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho and Sc. 
     
     
         5 . The compound of  claim 4 , wherein the metal is a radiometal and is selected from the group consisting of:  68 Ga,  64 Cu,  86 Y,  90 Y,  89 Zr,  111 In,  99m Tc,  177 Lu,  153 Sm,  186 Re,  188 Re,  67 Cu,  212 Pb,  225 Ac,  213 Bi,  212 Bi,  212 Pb,  67 Ga,  203 Pb,  47 Sc, and  166 Ho. 
     
     
         6 . The compound of  claim 1 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . A method for treating one or more PSMA expressing tumors or cells, the method comprising contacting the one or more PSMA expressing tumors or cells with an effective amount of a compound of formula (I), the compound of formula (I) comprising: 
       
         
           
           
               
               
           
         
       
       wherein:
 Z is tetrazole or CO 2 Q; 
 Q is H or a protecting group; 
 m is an integer selected from the group consisting of 1, 2, 3, 4, and 5; 
 R is independently H or —CH 2 —R 1 ; 
 R 1  is selected from the group consisting of substituted aryl, substituted pyridine, and unsubstituted isoquinoline; 
 L is a linker selected from the group consisting of C 1 -C 6  alkylene and C 3 -C 6  cycloalkylene, and arylene; 
 W is selected from the group consisting of —NR 2 —(C═O)—, —NR 2 —(C═S)—, —(C═O)—NR 2 —, and —(C═S)—NR 2 —; wherein each occurrence of L and W can be the same or different; 
 R 2  is H or a C 1 -C 4  alkyl; 
 n is an integer selected from the group consisting of 1, 2, and 3; 
 Ch is a chelating agent that comprises a radiometal suitable for radiotherapy; and pharmaceutically acceptable salts thereof. 
 
     
     
         8 . The method of  claim 7 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein X is independently Br or I. 
     
     
         9 . The method of  claim 7 , wherein the chelating agent is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 7 , wherein the radiometal is selected from the group consisting of  90 Y,  177 Lu,  211 At,  111 In,  153 Sm,  186 Re,  188 Re,  67 Cu,  212 Pb,  225 Ac,  213 Bi,  212 Bi,  212 Pb, and  67 Ga. 
     
     
         11 . The method of  claim 7 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 7 , wherein the one or more PSMA-expressing tumor or cell is selected from the group consisting of: a prostate tumor or cell, a metastasized prostate tumor or cell, a lung tumor or cell, a renal tumor or cell, a glioblastoma, a pancreatic tumor or cell, a bladder tumor or cell, a sarcoma, a melanoma, a breast tumor or cell, a colon tumor or cell, a germ cell, a pheochromocytoma, an esophageal tumor or cell, a stomach tumor or cell, and combinations thereof. 
     
     
         13 . The method of  claim 7 , wherein the one or more PSMA-expressing tumor or cell is a prostate tumor or cell. 
     
     
         14 . The method of  claim 7 , wherein the one or more PSMA-expressing tumor or cell is in vitro, in vivo, or ex vivo. 
     
     
         15 . The method of  claim 7 , wherein the one or more PSMA-expressing tumor or cell is present in a subject. 
     
     
         16 . The method of  claim 15 , wherein the subject is human. 
     
     
         17 . The method of  claim 7 , wherein the method results in inhibition of the tumor growth.

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