Peptidomimetic inhibitors of PSMA, compounds comprising them, and methods of use

Abstract

Compounds of the formula, A—L—B, wherein A is glutamate or a glutamate analog; L is a phosphoramidate or a phosphoramidate analog; and B is serine or a serine analog are described which are potent inhibitors of prostate-specific membrane antigen (PMSA). Such compounds are useful in treatment of prostate cancer; and when chemically attached to a fluorescent dye, can efficiently and selectively label prostate cancer cells for fluorescent imaging.

1. The  A compound or pharmaceutically acceptable salt thereof, of the formula, 
                 
 
       wherein
 each n is independently 1, 2, 3, 4, 5 or 6;  
 each R 1  and R 2  are independently —C(O)OR 3 , —C(O)N (R 3 ) 2 , —P(O)(OR 3 ) 2 , —OP(O)(OR 3 ) 2 , —S(O) 2 R 3 , —S(O) 2 OR 3 , —S(O) 2 N(R 3 ) 2 , or tetrazolyl;  
 each R 3  is independently —H or C 1 -C 6  alkyl;  
 R 4  is —H, —C(O)OR 3 , —C(O)N(R 3 ) 2 , —P(O)(OR 3 ) 2 , —OP(O)(OR 3 ) 2 , —S(O) 2 R 3 , —S(O) 2 OR 3 , —S(O) 2 N (R 3 ) 2 , or tetrazolyl;  
 L is —P(O)(OR 3 )—, or —P(O)(N(R 3 ) 2 )—;  
 M is —O—, —S—, —N( R   3 )—,  or —CH   2   —;   
 M and T are independentlyT is —O—, —S—, or —N(R 3 )—, or —CH 2 —; ; 
 R 10  is —H, —C 1 -C 6  alkyl, aryl, —C 1 -C 6  alkyl-aryl,  -aryl-aryl, —X—R 6 , —R 7 , —C(O)R 5 , —S(O) 2 R 5 , peptide, dendrimer, or peptide dendrimer, wherein  
 X is —O—, —S—, or —N(R 3 )—; 
 R 5  is —CH(R 51 )N(R 52 ) 2 ; C 1 -C 6  alkyl optionally substituted with 1 to 3 groups which are independently -halogen, COOR 53 , or —N(R 52 ) 2 ; aryl;  or heteroaryl, wherein 
 R 51  is —H, aryl, heteroaryl, C 1 -C 6  alkyl-aryl optionally substituted with —OH; C 1 -C 6  alkyl-heteroaryl, or C 1 -C 6  alkyl optionally substituted with —OR 53 , —SR 53 , —NH 2 , —N(H)C(═NH)NH 2 , —COOR 53 , or —C(O)N(R 53 ) 2 ; and  
 R 52  is —H, C 1 -C 6 alkyl, —C(O)R 53 , C(O)OR 53 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(R 53 ) 2 , —C(O) aryl, or —C(O)heteroaryl; 
 R 53  is —H, C 1 -C 6 alkyl, or C 1 -C 6  alkyl-aryl;  
 
 
 
 R 6  is —H or C 1 -C 6  alkyl;  
 and  
 R 7  is —L 1 —R 8 , wherein 
 L 1  is —C(O)N(R 3 )—, —C(S)N(R 3 )—, —C(O)CH (R 21 )—, —C(O)(O), or —C(O)—L 2 —,  
 wherein 
 R 21  is —H, aryl, heteroaryl, C 1 -C 6  alkyl-aryl optionally substituted with —OH; C 1 -C 6  alkyl-heteroaryl, or C 1 -C 6  alkyl optionally substituted with —OR 23 , —SR 23 , —NH 2 , —N(H)C(═NH)NH 2 , —COOR 23 , or —C(O)N(R 23 ) 2 ; and  
 R 23  is —H, C 1 -C 6 alkyl, or C 1 -C 6  alkyl-aryl;  
 
 L 2  is —C 1 -C 24  alkyl- or -phenyl-C 1 -C 24  alkyl-, wherein 
 each alkyl group is optionally substituted with 1 to 4 groups which are oxo, ═S, or —COOH; and  
 one to six of the methylene groups in each alkyl group is optionally replaced by —O—, —S—, or —N(R 3 )—, provided that no two adjacent methylene groups are both replaced by —O—, —S—, or —N(R 3 )—; and  
 
 
 R 8  is —H, —NH 2 , or —OH; and  
 Q is —O—, —S—, —N(R 3 )—, —N(R 3 )O—, —ON (R 3 )—, —CH 2 —,  or ═NO—.  
 
     
     
       2. The compound or pharmaceutically acceptable salt thereof of  claim 1  of the formula, 
                 
 
     
     
       3. The compound or pharmaceutically acceptable salt thereof of  claim 1  of the formula, 
                 
 
     
     
       4. The compound or pharmaceutically acceptable salt thereof of  claim 3 , wherein each R 1  and R 2  is —C(O)OH. 
     
     
       5. The compound or pharmaceutically acceptable salt thereof of  claim 3 , wherein R 10  is —C(O)-phenyl. 
     
     
       6. The compound or pharmaceutically acceptable salt thereof of  claim 3 , wherein R 10  is R 7 . 
     
     
       7. The compound of  claim 1  which is
 N-{[(2S)-2-(benzoylamino)-2-carboxyethoxy](hydroxy)phosphoryl}-L-glutamic acid; 
 N-[{(2S)-2-[benzoyl(methyl)amino]-2-carboxyethoxy}(hydroxy)phosphoryl]-L-glutamic acid; 
 N-(((   2 S )-   2   -( benzoyl ( methyl ) amino )-   2   - carboxyethoxy )( hydroxy ) phosphoryl )- L - glutamic acid;   
 N-{[2-(benzoylamino)ethoxy](hydroxy)phosphoryl}-L-glutamic acid; 
 N-[{2-[benzoyl(methyl)amino]ethoxy}(hydroxy)phosphoryl]-L-glutamic acid; 
 N-((   2   -( benzoyl ( methyl ) amino ) ethoxy )( hydroxy ) phosphoryl )- L - glutamic acid;   
 N-[(biphenyl-4-ylmethoxy)(hydroxy)phosphoryl]-L-glutamic acid; 
 N-[(2-carboxy-4-phenylbutoxy)(hydroxy)phosphoryl]-L-glutamic acid; 
 N-[hydroxy(4-phenylbutoxy)phosphoryl]-L-glutamic acid; 
 N-{[(2S)-2-{[4-(aminomethyl)benzoyl]amino}-2-carboxyethoxy)(hydroxy)phosphoryl}-L-glutamic acid; 
 N-(((   2 S )-   2   -((   4   -( aminomethyl ) benzoyl ) amino )-   2   - carboxyethoxy )( hydroxy ) phosphoryl )- L - glutamic acid;   
 L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxypropyl]amino}(hydroxy)phosphoryl]-L-serine;  
 L- γ - glutamyl - O -((((   1 S )-   1 , 3   - dicarboxypropyl ) amino )( hydroxy ) phosphoryl )- L - serine;   
 N-{[(2S)-2-amino-2-carboxyethoxy](hydroxy)phosphoryl}-L-glutamic acid; 
 N-(((   2 S )-   2   - amino -   2   - carboxyethoxy )( hydroxy ) phosphoryl )- L - glutamic acid;   
 N-[{[(2S)-20-amino-2-carboxy-4,8-dioxo-6,12,15,18-tetraoxa-3,9-diazaicos-1-yl[oxy}(hydroxy)phosphoryl]-L-glutamic acid; 
 N-((((   2 S )-   20   - amino -   2   - carboxy -   4 , 8   - dioxo -   6 , 12 , 15 , 18   - tetraoxa -   3 , 9   - diazaicos -   1   - yl ) oxy )( hydroxy ) phosphoryl)- L - glutamic acid;   
 
       or a pharmaceutical acceptable salt thereof. 
     
     
       8. The  A compound or pharmaceutically acceptable salt thereof, of the formula, 
                 
 
       wherein
 each n is independently 1, 2, 3, 4, 5 or 6;  
 each R 1  and R 2  are independently —C(O)OR 3 , —C(O)N (R 3 ) 2 , —P(O)(OR 3 ) 2 , —OP(O)(OR 3 ) 2 , —S(O) 2 R 3 , —S(O) 2 OR 3 , —S(O) 2 N(R 3 ) 2 , or tetrazolyl;  
 each R 3  is independently —H or C 1 -C 6  alkyl;  
 R 4  is —H, —C(O)OR 3 , —C(O)N(R 3 ) 2 , —P(O)(OR 3 ) 2 , —OP(O)(OR 3 ) 2 , —S(O) 2 R 3 , —S(O) 2 OR 3 , —S(O) 2 N (R 3 ) 2 , or tetrazolyl;  
 L is —P(O)(OR 3 )—,  or —P(O)(N(R 3 ) 2 )—;  
 M is —O—, —S—, —N( R   3 )—,  or —CH   2   —;   
 M and T are independentlyT is —O—, —S—, or —N(R 3 )—, or —CH 2 — ;  
 R 7  is —X—R 8  or —L 1 —R 8 , wherein 
 X is —O—, —S—, or —N(R 3 )—;  
 L 1  is —C(O)N(R 3 )—, —C(S)N(R 3 )—, —C(O)CH (R 21 )—, —C(O)(O)—, —C(O)—L 2 —, a peptide, dendrimer, or peptide dendrimer, wherein 
 R 21  is —H, aryl, heteroaryl, C 1 -C 6  alkyl-aryl optionally substituted with —OH; C 1 -C 6  alkyl-heteroaryl, or C 1 -C 6  alkyl optionally substituted with —OR 23 , —SR 23 , —NH 2 , —N(H)C(═NH)NH 2 , —COOR 23 , or —C(O)N(R 23 ) 2 ; and  
 R 23  is —H, C 1 -C 6 alkyl, or C 1 -C 6  alkyl-aryl;  
 L 2  is —C 1 -C 24  alkyl- or -phenyl-C 1 -C 24  alkyl-, 
 wherein  
 each alkyl group is optionally substituted with 1 to 4 groups which are oxo, ═S, or —COOH; and  
 one to six of the methylene groups in each alkyl group is optionally replaced by —O—, —S—, or —N(R 3 )—, provided that no two adjacent methylene groups are both replaced by —O—, —S—, or —N(R 3 )—; and  
 
 
 R 8  is a therapeutic agent, detectable label, or biomolecular anchor linked to a solid support; and  
 
 Q is —O—, —S—, —N(R 3 )—, —N(R 3 )O—, —ON (R 3 )—, —CH 2 —,  or ═NO—.  
 
     
     
       9. The compound or pharmaceutically acceptable salt thereof of  claim 8 , of the formula, 
                 
 
     
     
       10. The compound or pharmaceutically acceptable salt thereof of  claim 9 , wherein R 8  is a therapeutic agent. 
     
     
       11. The compound or pharmaceutically acceptable salt thereof of  claim 10 , wherein R 8  is a steroidal group optionally substituted with 1 to 5 groups selected from the group consisting of C 1 -C 10  alkyl, oxo, hydroxy, or halogen. 
     
     
       12. The compound or pharmaceutically acceptable salt thereof of  claim 8  of the formula, 
                 
 
       wherein
 R 7  is —O—R 8 , wherein 
 R 8  is a steroidal group optionally substituted with 1 to 5 groups selected from the group consisting of C 1 -C 10  alkyl, oxo, hydroxy, or halogen.  
 
 
     
     
       13. The compound or pharmaceutically acceptable salt thereof of  claim 9 , wherein R 8  is a detectable label. 
     
     
       14. The compound or pharmaceutically acceptable salt thereof of  claim 13 , wherein R 8  is a fluorescent label. 
     
     
       15. The compound or pharmaceutically acceptable salt thereof of  claim 14 , wherein R 8  is a fluorescein or fluorescein derivative. 
     
     
       16. The compound or pharmaceutically acceptable salt thereof of  claim 9 , wherein R 8  is a chelating agent. 
     
     
       17. The compound or pharmaceutically acceptable salt thereof of  claim 16 , wherein R 8  is R 9 , wherein
 R 9  is C 1 -C 6  alkyl, aryl, or C 1 -C 6  alkyl-aryl, wherein R 9  is substituted with one to three groups which are independently —COOH or N(R 91 ) 2 , wherein 
 each R 91  is independently —H or C 1 -C 6  alkyl substituted with 1 to 3 groups which are independently —COOH or —N(R 92 ) 2  wherein 
 each R 92  is independently —H or C 1 -C 6  alkyl substituted with 1 to 3 COOH.  
 
 
 
     
     
       18. The compound according to  claim 8  which is
 N-{[(2S)-2-carboxy-2-({4-[({3-[(2-{[3-carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl) phenyl]amino}-2-oxoethyl)thio]propanoyl}amono)methyl]benzoyl}amino) ethoxy](hydroxy)phosphoryl}-L-glutamic acid; 
 N-(((   2 S )-   2   -carboxy-   2   -((   4   -(((   3   -((   2   -((   3   - carboxy-     4   -(   6   - hydroxy -   3   - oxo -   9 , 9 a - dihydro -   3 H - xanthen -]   9   - yl )  phenyl ) amino )-   2   - oxoethyl ) thio ) propanoyl ) amino ) methyl ) benzoyl ) amino )  ethoxy )( hydroxy ) phosphoryl )- L - glutamic acid;   
 N-[{(2S)-2-carboxy-2-[(4-{[(6-}[3-carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-H-xanthen-9-yl) benzoyl]amino}hexanoyl)amino]methyl}benzoyl)amino]ethoxy}(hydroxy)phosphoryl]-L-glutamic acid; 
 N-(((   2 S )-   2   - carboxy -   2   -((   4   -(((   6   -((   3   - carboxy -   4   -(   6   - hydroxy -   3   - oxo -   9 , 9 a - dihydro -   3 H - xanthen -   9   - yl ) benzoyl ) amino ) hexanoyl ) amino ) methyl ) benzoyl ) amino ) ethoxy )( hydroxy )  phosphoryl )- L - glutamic acid;   
 N-{3-[(2-{[3-carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)phenyl]amino}-2-oxoethyl) thio]propanoyl}-L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxypropyl]amino}(hydroxy)phosphoryl]-L-serine;  
 N-(   3   -((   2   -((   3   -carboxy-   4   -(   6   - hydroxy -   3   - oxo -   9 , 9 a - dihydro -   3 H - xanthen -   9   - yl ) phenyl ) amino )-   2   - oxoethyl )  thio]propanoyl )- L - γ - glutamyl - O -((((   1 S )-   1 , 3   - dicarboxypropyl ) amino ) ( hydroxy ) phosphoryl )- L - serine;   
 N-(6-{[3-carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)benzoyl]amino}hexanoyl)-L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxypropyl]amino}(hydroxy)phosphoryl]-L-serine;  
 N-(   6   -((   3   - carboxy -   4   -(   6   - hydroxy -   3   - oxo -   9 , 9 a - dihydro -   3 H - xanthen -   9   - yl ) benzoyl ) amino ) hexanoyl )- L - γ - glutamyl - O -((((   1 S )-   1 , 3   - dicarboxypropyl ) amino ) ( hydroxy ) phosphoryl )- L - serine;   
 N-[{(2S)-2-carboxy-2-[({[3-carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl) phenyl]amino}carbonothioyl)amino]ethoxy}(hydroxy)phosphoryl]-L-glutamic acid; 
 N((((   2 S )-   2   - carboxy -   2   -((((   3   - carboxy -   4   -(   6   - hydroxy -   3   - oxo -   9 , 9 a - dihydro -   3 H - xanthen -]   9   - yl )  phenyl ) amino ) carbonothioyl ) amino ) ethoxy )( hydroxy ) phosphoryl )- L - glutamic acid;   
 N-{[(4-{2-[bix(carboxymethyl)amino]-3-[{2-[bix(carboxymethyl)amino]ethyl}(carboxymethyl) amino]propyl}phenyl)amino]carbonothioyl}-L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxypropyl]amino}(hydroxy)phosphoryl]-L-serine;  
 N-((((   4   -(   2   -( bis ( carboxymethyl ) amino )-   3   -((   2   -( bis ( carboxymethyl ) amino ) ethyl )( carboxymethyl )  amino ) propyl ) phenyl ) amino ) carbonothioyl )- L - γ - glutamyl - o -((((   1 S )-   1 , 3   - dicarboxypropyl ) amino )( hydroxy ) phosphoryl )- L - serine;   
 N-{6-[(6-{[5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl]amino}hexanoyl) amino]hexanoyl}-L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxypropyl]amino}(hydroxy)phosphoryl]-L-serine;  
 N-(   6   -((   6   -((   5   -(   2   - oxohexahydro -   1 H - thieno (   3 , 4   - d ) imidazol -   4   -yl) pentanoyl ) amino )( hexanoyl ) amino )  hexanoyl )- L - γ-   glutamyl - O -((((   1 S )-   1 , 3   - dicarboxypropyl ) amino )(i hydroxy) phosphoryl )- L - serine;   
 N-{[(2S)-2-carboxy-2-({4-[({6-[6-{[5-(2-oxohexahydro-1H-thienol[3,4-d]imidazol-4-yl)pentanoyl]amino}hexanoyl)amino]hexanoyl}amino)methyl]benzoyl}amino)ethoxy](hydroxy)phosphoryl}-L-glutamic acid; 
 N-(((   2 S )-   2   - carboxy -   2   -((   4   -(((   6   -((   6   -((   5   -(   2   - oxohexahydro -   1 H - thieno (   3 , 4   - d ) imidazol -   4   - yl )  pentanoyl ) amino ) hexanoyl ) amino ) hexanoyl ) amino ) methyl ) benzoyl ) amino ) ethoxy ) ( hydroxy ) phosphoryl )- L - glutamic acid;   
 N-[{3-[(3β,8ξ,9ξ,14ξ,17ξ,20ξ)-cholestan-3-yloxy]propoxy}(hydroxy)phosphoryl]-L-glutamic acid;  
 N-((   3   -((   3 β, 8 ξ, 9 ξ, 14 ξ, 17 ξ, 20 ξ )- cholestan -] 3 - yloxy ) propoxy )( hydroxy ) phosphoryl )- L - glutamic acid;   
 N-[hydroxy(3-{[(3β,8ξ,9ξ,14ξ)-17-oxoandrostan-3-yl]oxy}propoxy)phosphoryl]-L-glutamic acid;  
 N-( hydroxy (   3   -(((   3 β, 8 ξ, 9 ξ, 14 ξ )-   17   - oxoandrostan -   3   - yl ) oxy ) propoxy ) phosphoryl )- L - glutamic acid;   
 N-{[(3β,8ξ,9ξ,14ξ,17ξ,20ξ)-cholestan-3-yloxy](hydroxy)phosphoryl}-L-glutamic acid;  
 N-(hydroxy{[(3β,8ξ,9ξ,14ξ)-17-oxoandrostan-3-yl]oxy}phosphoryl)-L-glutamic acid;  
 N-(hydroxy(3-{[17-oxoestra-1(10),2,4-trien-3-yl]oxy}propoxy)phosphoryl]-L-glutamic acid; 
 N-( hydroxy (   3   -((   17   - oxoestra -   1   (   10   ),   2 , 4   - trien -   3   - yl ) oxy ) propoxy ) phosphoryl )- L - glutamic acid;   
 N-[(3-{[3-(benzoyloxy)estra-1(10),2,4-trien-17-yl]oxy}propoxy)(hydroxy)phosphoryl]-L-glutamic acid; 
 N-((   3   -((   3   -( benzoyloxy ) estra -   1   (   10   ),   2 , 4   - trien -   17   - yl ) oxy ) propoxy )( hydroxy ) phosphoryl )- L - glutamic acid;   
 
       or a pharmaceutical acceptable salt thereof. 
     
     
       19. A composition comprising a compound according to  claim 8  and a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
       20. A diagnostic kit comprising a compound of  claim 8 . 
     
     
       21. A compound that is
   N -((   2 S )-   2   -( benzoylamino )-   2   - carboxyethoxy )( hydroxy ) phosphoryl )- L - glutamic acid;        N -((   2   -( benzoylamino )( ethoxy )( hydroxy ) phosphoryl )- L - glutamic acid;        N -((   2   - carboxy -   4   - phenylbutoxy )( hydroxy ) phosphoryl )- L - glutamic acid;        N -( hydroxy (   4   - phenylbutoxy ) phosphoryl )- L - glutamic acid;        N -(( biphenyl -   4   - ylethoxy )( hydroxy ) phosphoryl )- L - glutamic acid;        or a pharmaceutically acceptable salt thereof.     
     
     
       22. A compound that is
   N -(( biphenyl -   4   - ylmethoxy )( hydroxy ) phosphoryl )- L - glutamic acid;        N -(((   3 β, 8 ξ, 9 ξ, 14 ξ, 17 ξ, 20 ξ )- cholestan -   3   - yloxy )( hydroxy ) phosphoryl )- L - glutamic acid;        N -( hydroxy (((   3 β, 8 ξ, 9 ξ, 14 ξ )-   17   - oxoandrostan -   3   - yl ) oxy ) phosphoryl )- L - glutamic acid;        or a pharmaceutically acceptable salt thereof.     
     
     
       23. A compound that is
   L -γ- glutamyl - O -((((   1 S )-   1 , 3   - dicarboxypropyl ) amino )( hydroxy ) phosphoryl )- L - serine, or a pharmaceutically acceptable salt thereof.