Psma ligands for imaging and endoradiotherapy

Abstract

The present invention relates to compounds which bind and/or inhibit prostate-specific membrane antigen (PSMA) comprising at least one group electron dense substituent (EDS), and at least one moiety which is amenable to radiolabeling; and therapeutic and diagnostic uses thereof.

1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         m is an integer of 2 to 6; 
         n is an integer of 2 to 6; 
         R 1L  is CH 2 , NH or O; 
         R 2L  is C or P(OH); 
         R 3L  is CH 2 , NH or O; 
         X 1  is selected from an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge, and an amine bond; 
         L 1  is a divalent linking group with a structure selected from an oligoamide, an oligoether, an oligothioether, an oligoester, an oligothioester, an oligourea, an oligo(ether-amide), an oligo(thioether-amide), an oligo(ester-amide), an oligo(thioester-amide), oligo(urea-amide), an oligo(ether-thioether), an oligo(ether-ester), an oligo(ether-thioester), an oligo(ether-urea), an oligo(thioether-ester), an oligo(thioether-thioester), an oligo(thioether-urea), an oligo(ester-thioester), an oligo(ester-urea), and an oligo(thioester-urea),
 which linking group may carry a group EDS; 
 
         X 2  is selected from an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge, and an amine bond; 
         R 2  is an optionally substituted aryl group or an optionally substituted aralkyl group, which aryl group or aralkyl group may be substituted on its aromatic ring with one or more substituents selected from halogen and —OH; 
         R 3  is an optionally substituted aryl group or an optionally substituted aralkyl group, which aryl group or aralkyl group may be substituted on its aromatic ring with one or more substituents selected from halogen and —OH; 
         r is 0 or 1; 
         p is 0 or 1; 
         q is 0 or 1; 
         R 4  is selected from an optionally substituted aryl group and a group EDS, which aryl group may be substituted on its aromatic ring with one or more substituents selected from halogen, —OH and —NH 2 ; 
         X 3  is selected from an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge, an amine bond, and a group of the formula 
       
       
         
           
           
               
               
           
         
       
       wherein the marked bond at the carbonyl group attaches X 3  to R M  and the other marked bond attaches X 3  to the remainder of the compound of formula (I);
 R M  is a marker group which comprises a chelating group optionally containing a chelated non-radioactive or radioactive cation; 
 
       and wherein the group EDS is contained at least once in the compound of formula (I) and has a structure selected from 
       (E-1A), (E-1B), (E-2A) and (E-2B): 
       
         
           
           
               
               
           
         
       
       wherein 
          marks the bond which attaches the group EDS, to the remainder of the compound of formula (I); 
       s is 1, 2 or 3, preferably 1 or 2, and more preferably 1; 
       t is 1, 2 or 3, preferably 1 or 2, and more preferably 2; 
       R 5A  is, independently for each occurrence for s>1, an electron withdrawing substituent, which is preferably selected from —NO 2  and —COOH, and which is more preferably —COOH, and wherein the bond between R 5A  and the phenyl ring indicates that the s groups R 5A  replace s hydrogen atoms at any position on the phenyl ring; 
       R 5B  is, independently for each occurrence for s>1, a substituent carrying an electron lone pair at the atom directly attached to the phenyl ring shown in formula (E-1B), which substituent is preferably selected from —OH and —NH 2 , and which is more preferably —NH 2 , and wherein the bond between R 5B  and the phenyl ring indicates that the s groups R 5B  replace s hydrogen atoms at any position on the phenyl ring; 
       R 6A  is, independently for each occurrence for t>1, an electron withdrawing substituent, which is preferably selected from —NO 2  and —COOH, and which is more preferably —COOH, and wherein the bond between R 6A  and the phenyl ring indicates that the t groups R 6A  replace t hydrogen atoms at any position on the phenyl ring; and 
       R 6B  is, independently for each occurrence for t>1, a substituent carrying an electron lone pair at the atom directly attached to the phenyl ring shown in formula (E-1B), which substituent is preferably selected from —OH and —NH 2 , and which is more preferably —OH, and wherein the bond between R 6B  and the phenyl ring indicates that the t groups R 6B  replace t hydrogen atoms at any position on the phenyl ring. 
     
     
         2 . The compound or salt of  claim 1 , wherein m is 2, n is 2 or 4, R 1L  is NH, R 2L  is C, and R 3L  is NH. 
     
     
         3 . The compound or salt of  claim 1 , wherein L 1  is a divalent linking group with a structure selected from an oligoamide which comprises a total of 1 to 5, more preferably a total of 1 to 3, and most preferably a total of 1 or 2 amide bonds within its backbone, and an oligo(ester-amide) which comprises a total of 2 to 5, more preferably a total of 2 to 3, and most preferably a total of 2 amide and ester bonds within its backbone, which linking group may carry a group EDS. 
     
     
         4 . The compound or salt of  claim 2 , wherein the moiety —X 2 -L 1 -X 1 — in formula (I) has a structure selected from:
   *—C(O)—NH—R 7 —NH—C(O)—R 8 —C(O)—NH—  (L-1),
 
   *—C(O)—NH—R 9A —NH—C(O)—R 10A —C(O)—NH—R 11A —NH—C(O)—  (L-2A), and
 
   *—C(O)—NH—R 9B —C(O)—NH—R 10B —C(O)—NH—R 11B —NH—C(O)—  (L-2B);
 
 wherein the amide bond marked with * is attached to the carbon atom carrying R 2  in formula (I), and wherein 
 R 7 , R 8 , R 9A , R 9B , R 11A  and R 11B  are independently selected from optionally substituted C2 to C10 alkanediyl, which alkanediyl groups may each be substituted by one or more substituents independently selected 
 from —OH, —OCH 3 , —COOH, —COOCH 3 , —NH 2 , —NHC(NH)NH 2 , and a group EDS, and 
 R 10A  and R 10B  are selected from optionally substituted C2 to C10 alkanediyl, and optionally substituted C6 to C10 arenediyl, which alkanediyl and arenediyl group may each be substituted by one or more substituents independently selected 
 from —OH, —OCH 3 , —COOH, —COOCH 3 , —NH 2 , —NHC(NH)NH 2 , and a group EDS. 
 
     
     
         5 . The compound or salt of  claim 4 , wherein the moiety —X 2 -L 1 -X 1 — has a structure selected from:
   *—C(O)—NH—CH(COOH)—R 12 —NH—C(O)—R 13 —C(O)—NH—  (L-3),
 
   *—C(O)—NH—CH(COOH)—R 14 —NH—C(O)—R 15 —C(O)—NH—R 16 —CH(COOH)—NH—C(O)—   (L-4), and
 
   *—C(O)—NH—CH(COOH)—R 17 —C(O)—NH—R 18 —C(O)—NH—R 19 —CH(COOH)—NH—C(O)—   (L-5);
 
 wherein the bond marked with * is attached to the carbon atom carrying R 2  in formula (I), 
 R 12  and R 14  are independently selected from linear C2 to C6 alkanediyl, 
 R 13  is a linear C2 to C10 alkanediyl, 
 R 15  and R 16  are independently selected from linear C2 to C6 alkanediyl, 
 and wherein each of R 13  and R 15  may carry one group EDS as a substituent, 
 R 17  is a linear C2 to C6 alkanediyl, 
 R 18  is a phenylene group, and 
 R 19  is a linear C2 to C6 alkanediyl. 
 
     
     
         6 . The compound or salt of  claim 1 , wherein R 2  is an optionally substituted aralkyl group selected from optionally substituted —CH 2 -phenyl and optionally substituted —CH 2 -naphthyl, wherein the phenyl and the naphthyl group are optionally substituted with a substituent selected from halogen, preferably I, and —OH. 
     
     
         7 . The compound or salt of  claim 1 , wherein R 3  is an optionally substituted aralkyl group selected from optionally substituted —CH 2 -phenyl and optionally substituted —CH 2 -naphthyl, wherein the phenyl and the naphthyl group are optionally substituted with a substituent selected from halogen and —OH. 
     
     
         8 . The compound or salt of  claim 1 , wherein r is 1, and wherein R 4  is selected from optionally substituted phenyl, optionally substituted naphthyl, and a group EDS, which phenyl group and naphthyl group are optionally substituted with a substituent selected from halogen, —OH and —NH 2 . 
     
     
         9 . The compound or salt of  claim 1 , wherein X 3  is an amide bond or a group of the formula 
       
         
           
           
               
               
           
         
       
       wherein the marked bond at the carbonyl group attaches X 3  to R M  and the other marked bond attaches X 3  to the remainder of the molecule. 
     
     
         10 . The compound or salt of  claim 1 , wherein R M  is a chelating group optionally containing a chelated non-radioactive or radioactive cation. 
     
     
         11 . The compound or salt of  claim 1 , wherein the compound of formula (I) either contains one group EDS which is carried by the linking group L 1 , or contains two groups EDS, one being represented by R 4  and one being carried by L 1 . 
     
     
         12 . The compound or salt of  claim 1 , which contains a group EDS which has the formula (E-2A): 
       
         
           
           
               
               
           
         
         wherein   marks the bond which attaches the group EDS to the remainder of the compound of formula (I); and 
         t is 1 or 2, and R 6A  is selected from —NO 2  and —COOH. 
       
     
     
         13 . (canceled) 
     
     
         14 . A pharmaceutical or diagnostic composition comprising or consisting of one or more compounds or salts in accordance with  claim 1 . 
     
     
         15 . (canceled) 
     
     
         16 . A method for imaging or treating prostate-specific membrane antigen (PSMA)-associated cancer in a subject, comprising administering to the subject an effective amount of the composition of  claim 14 . 
     
     
         17 . The method of  claim 16 , wherein the chelated cation is  177 Lu. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 16 , wherein the PSMA-associated cancer is glioma, lung cancer, or prostate cancer. 
     
     
         21 . (canceled) 
     
     
         22 . A method for treating prostate cancer in a subject, comprising administering to the subject an effective amount of a composition of  claim 14 .