Triazine based radiopharmaceuticals and radioimaging agents
View Patent ↗Compounds according to Formula I and Formula II are potent inhibitors of PSMA. Pharmaceutical compositions may include a complex of a radionuclide and a Formula I compound or a Formula II compound. Methods include using the radionuclide complex of a Formula I compound or a Formula II compound for treating or diagnosis of a disease or a condition associated with PSMA activity.
1. A compound according to formula I
wherein:
A is (CHR 1 ) m or C(O);
W is —C(O)—(CH 2 ) p —; —C(O)[—CH 2 —CH 2 —O] n , —[CH 2 —CH 2 —O], —(CH 2 ) 2 —, —C(O)—[CH(R 3 ) t ] q —, —(CH 2 ) m —O—(CH 2 ) n —, —(CH 2 ) m —S—(CH 2 ) n —, —(CH 2 ) m —S(O)—(CH 2 ) n —, —(CH 2 ) m —S(O) 2 —(CH 2 ) n , or —(CH 2 ) m —NR a —(CH 2 ) n —,
Y is —NH—, —NR 2 —, or
X is —(C 1 -C 10 )alkylene-(C 3 -C 10 )arylene, —(C 3 -C 10 )arylene, —(C 3 -C 10 )arylene-(C 1 -C 10 )alkylene-, phenylene, —(C 1 -C 10 )alkylene-(C 3 -C 10 )cycloalkylene, —(C 3 -C 10 )cycloalkylene, or —(C 3 -C 10 )cycloalkylene-(C 1 -C 10 )alkylene-;
R 1 and R 2 are each independently H, —C(O)—(C 1 -C 10 )alkyl, benzyl, —(C 3 -C 10 )cycloalkyl, or —(C 3 -C 10 )aryl;
R a and R b are each independently H, —OH, —(C 1 -C 10 )alkyl, —[CH 2 —CH 2 —O] n —(CH 2 ) 2 -T, —C(O)—(C 1 -C 10 )alkyl, —(C 1 -C 10 )alkylene-C(O)—, —(C 1 -C 10 )alkylene-C(O)—Z, benzyl, —(C 3 -C 10 )cycloalkyl, —(C 3 -C 10 )aryl-(C 1 -C 10 )alkylene, —(C 3 -C 10 )aryl, halo-(C 1 -C 10 )alkyl, hydroxy-(C 1 -C 10 )alkyl, —NH—(C 1 -C 10 )alkyl, or —(C 1 -C 10 )alkylene-NR d R e —, or R a and R b together with the nitrogen to which they are bonded form a (C 3 -C 6 )-heteroaryl or (C 3 -C 6 )-heterocycloalkyl;
Z is —OH, —O(C 1 -C 10 )alkyl,
R c is —OH, —O(C 1 -C 10 )alkyl, —Obenzyl, —O(C 3 -C 10 )cycloalkyl, —O(C 3 -C 10 )aryl, —O—(C 1 -C 10 )alkylene-(C 3 -C 10 )aryl, or —O—(C 1 -C 10 )alkylene-(C 3 -C 10 )cycloalkyl,
R 3 is H, halogen, —OH, —NH 2 , —(CH 2 ) p —COOH, or —(CH 2 ) p —NH 2 ;
T is —H, —OH, —COOH, or —NR d R e ;
R d and R e are each independently H, bond, —OH, —(C 1 -C 10 )alkyl, or —(C 3 -C 10 )heteroaryl-(C 1 -C 10 )alkylene;
m, n, p, q, t and r are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8 9, or 10; and
wherein any alkyl, alkylene, aryl, arylene, heteroaryl, heteroarylene, cycloalkyl, cycloalkylene, heterocycloalkyl, or heterocycloalkylene is optionally substituted with 1, 2, or 3 substituent groups selected from the group consisting of —(C 1 -C 10 )alkyl, —(C 1 -C 10 )haloalkyl, —(C 1 -C 10 ) aminoalkyl, —(C 1 -C 10 )alkylene-COOH, —(C 1 -C 10 )hydroxyalkyl, —OH, halogen, —NH 2 , —COOH, —C(O)—(C 1 -C 10 )alkyl, —(C 1 -C 10 )alkylene-C(O)—, —(C 1 -C 10 )alkylene-C(O)—X, —NH—(C 1 -C 10 )alkyl, and —(C 1 -C 10 )alkylene-NR d R e , and —NR d R e .
2. The compound of claim 1 , wherein X is phenylene, r is 1 and D is
3. The compound of claim 2 , wherein the compound is a compound according to Formula II
wherein:
A is (CHR 1 ) m or C(O);
W is selected from the group consisting of —C(O)—(CH 2 ) p —; —C(O)[—CH 2 —CH 2 —O] n —, —[CH 2 —CH 2 —O] n —(CH 2 ) 2 —, —C(O)—[CH(R 3 ) t ] q , —(CH 2 ) m —O—(CH 2 ) n —, —(CH 2 ) m —S—(CH 2 ) n —, —(CH 2 ) m —S(O)—(CH 2 ) n —, —(CH 2 ) m —S(O) 2 —(CH 2 ) n —, and —(CH 2 ) m —NR a —(CH 2 ) n ,
Y is selected from —NH—, —NR 2 — or
R 1 and R 2 are each independently selected from H, —(C 1 -C 10 )alkyl, —C(O)—(C 1 -C 10 )alkyl, benzyl, —(C 3 -C 10 )cycloalkyl, or —(C 3 -C 10 )aryl;
R a and R b are each independently selected from the group consisting of H, —OH, —(C 1 -C 10 )alkyl, —[CH 2 —CH 2 —O] n —(CH 2 ) 2 -T, —C(O)—(C 1 -C 10 )alkyl, —(C 1 -C 10 )alkylene-C(O)—, —(C 1 -C 10 )alkylene-C(O)—Z, benzyl, —(C 3 -C 10 )cycloalkyl, —(C 3 -C 10 )aryl-(C 1 -C 10 )alkylene, —(C 3 -C 10 )aryl, halo-(C 1 -C 10 )alkyl, hydroxy-(C 1 -C 10 )alkyl, —NH—(C 1 -C 10 )alkyl, and —(C 1 -C 10 )alkylene-NR d R e , or R a and R b together with the nitrogen to which they are bonded form a (C 3 -C 6 )-heteroaryl or (C 3 -C 6 )-heterocycloalkyl;
Z is selected from —OH, —O(C 1 -C 10 )alkyl,
R c is selected from —OH, —O(C 1 -C 10 )alkyl, —Obenzyl, —O(C 3 -C 10 )cycloalkyl, —O(C 3 -C 10 )aryl, —O—(C 1 -C 10 )alkylene-(C 3 -C 10 )aryl, or —O—(C 1 -C 10 )alkylene-(C 3 -C 10 )cycloalkyl,
R 3 is selected from H, halogen, —OH, —NH 2 , —(CH 2 ) p —COOH, or —(CH 2 ) p —NH 2 ;
T is selected from —H, —OH, —COOH, or —NR d R e ;
R d and R e are each independently selected from H, bond, —OH, —(C 1 -C 10 )alkyl, or —(C 3 -C 10 )heteroaryl-(C 1 -C 10 )alkylene;
m, n, p, q, t and x are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8 9, or 10;
wherein any alkyl, alkylene, aryl, arylene, heteroaryl, heteroarylene, cycloalkyl, cycloalkylene, heterocycloalkyl, or heterocycloalkylene is optionally substituted with 1, 2, or 3 substituent groups selected from the group consisting of —(C 1 -C 10 )alkyl, —(C 1 -C 10 )haloalkyl, aminoalkyl, —(C 1 -C 10 )alkylene-COOH, —(C 1 -C 10 )hydroxyalkyl, —NH 2 , —COOH, —C(O)—(C 1 -C 10 )alkyl, —(C 1 -C 10 )alkylene-C(O)—, —(C 1 -C 10 )alkylene-C(O)—X, —NH—(C 1 -C 10 )alkyl, and —(C 1 -C 10 )alkylene-NR d R e —, and —NR d R e .
4. The compound of claim 3 , wherein A is (CHR 1 ) m , and W is —C(O)—(CH 2 ) p —.
5. The compound of claim 4 , wherein W is —C(O)—(CH 2 ) 7 — or —C(O)—(CH 2 ) 10 —.
6. The compound of claim 4 , wherein R 1 is hydrogen and m is 2.
7. The compound of claim 3 , wherein Y is —NH— or
8. The compound of claim 7 , wherein Y is
9. The compound of claim 3 , wherein R a and R b are each independently hydrogen or methyl and R c is —OH.
10. The compound of claim 3 , wherein R a and R b together with the nitrogen to which they are bonded form a (C 3 -C 6 )-heterocycloalkyl.
11. The compound of claim 10 , wherein the (C 3 -C 6 )-heterocycloalkyl is selected from piperidine, piperazine, morpholine, thiomorpholine, isothiazolidine, isoxazolidine, pyrrolidine, immidazolidine, thiazolidine or oxazolidine.
12. The compound of claim 11 , wherein the (C 3 -C 6 )-heterocycloalkyl is piperidine or 4-(piperidin-4-yl)butanoic acid.
13. The compound of claim 10 , wherein R a is —H and R b is
14. The compound according to claim 10 , wherein R d and R e are each independently —(C 3 -C 10 )heteroaryl-(C 1 -C 10 )alkylene.
15. The compound of claim 10 , wherein R d and R e are each independently
16. The compound of claim 3 , which is selected from the following compounds:
or a pharmaceutically acceptable salt, solvate, or ester thereof.
17. A metal complex comprising a radionuclide and a compound of claim 1 .
18. The metal complex of claim 17 , wherein the compound is
wherein:
A is (CHR 1 ) m or C(O);
W is selected from the group consisting of —C(O)—(CH 2 ) p —; —C(O)[—CH 2 —CH 2 —O] n —, —[CH 2 —CH 2 —O] n —(CH 2 ) 2 —, —C(O)—[CH(R 3 ) t ] q —, —(CH 2 ) m —O—(CH 2 ) n —, —(CH 2 ) m —S—(CH 2 ) n —, —(CH 2 ) m —S(O)—(CH 2 ) n —, —(CH 2 ) m —S(O) 2 —(CH 2 ) n —, and —(CH 2 ) m —NR a —(CH 2 ) n —,
Y is selected from —NH—,
R 1 and R 2 are each independently selected from H, —(C 1 -C 10 )alkyl, —C(O)—(C 1 -C 10 )alkyl, benzyl, —(C 3 -C 10 )cycloalkyl, or —(C 3 -C 10 )aryl;
R a and R b are each independently selected from the group consisting of H, —OH, —(C 1 -C 10 )alkyl, —[CH 2 —CH 2 —O] n —(CH 2 ) 2 -T, —C(O)—(C 1 -C 10 )alkyl, —(C 1 -C 10 )alkylene-C(O)—, —(C 1 -C 10 )alkylene-C(O)—Z, benzyl, —(C 3 -C 10 )cycloalkyl, —(C 3 -C 10 )aryl-(C 1 -C 10 )alkylene, —(C 3 -C 10 )aryl, halo-(C 1 -C 10 )alkyl, hydroxy-(C 1 -C 10 )alkyl, —NH—(C 1 -C 10 )alkyl, and —(C 1 -C 10 )alkylene-NR d R e , or R a and R b together with the nitrogen to which they are bonded form a (C 3 -C 6 )-heteroaryl or (C 3 -C 6 )-heterocycloalkyl;
Z is selected from —OH, —O(C 1 -C 10 )alkyl,
R c is selected from —OH, —O(C 1 -C 10 )alkyl, —Obenzyl, —O(C 3 -C 10 )cycloalkyl, —O(C 3 -C 10 )aryl, —O—(C 1 -C 10 )alkylene-(C 3 -C 10 )aryl, or —O—(C 1 -C 10 )alkylene-(C 3 -C 10 )cycloalkyl,
R 3 is selected from H, halogen, —OH, —NH 2 , —(CH 2 ) p —COOH, or —(CH 2 ) p —NH 2 ;
T is selected from —H, —OH, —COOH, or —NR d R e ;
R d and R e are each independently selected from H, bond, —OH, —(C 1 -C 10 )alkyl, or —(C 3 -C 10 )heteroaryl-(C 1 -C 10 )alkylene;
m, n, p, q, t and x are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8 9, or 10;
wherein any alkyl, alkylene, aryl, arylene, heteroaryl, heteroarylene, cycloalkyl, cycloalkylene, heterocycloalkyl, or heterocycloalkylene is optionally substituted with 1, 2, or 3 substituent groups selected from the group consisting of —(C 1 -C 10 )alkyl, —(C 1 -C 10 )haloalkyl, —(C 1 -C 10 ) aminoalkyl, —(C 1 -C 10 )alkylene-COOH, —(C 1 -C 10 )hydroxyalkyl, —NH 2 , —COOH, —C(O)—(C 1 -C 10 )alkyl, —(C 1 -C 10 )alkylene-C(O)—, —(C 1 -C 10 )alkylene-C(O)—X, —NH—(C 1 -C 10 )alkyl, and —(C 1 -C 10 )alkylene-NR d R e —, and —NR d R e ; and
the radionuclide is selected from the group consisting of 111 In, 90 Y, 68 Ga, 64 Cu 153 Gd, 155 Gd, 157 Gd, 59 Fe, 225 Ac, 212 Bi, 213 Bi, 55 Co, 67 Cu, 165 Dy, 166 Ho, 192 Ir, 223 Ra, 186 Re, 188 Re 105 Rh, 212 Pb, 213 Pb, 149 Tb, 227 Th, 153 Sm, 89 Sr, 117 Sn, 169 Yb, 90 Y, 86 Y, 89 Zr and 177 Lu.
19. The metal complex of claim 18 , which is:
or a pharmaceutically acceptable salt or solvate thereof.
20. A pharmaceutical composition comprising the compound of claim 3 , or a pharmaceutically acceptable salt, solvate, or ester thereof; and a pharmaceutically acceptable carrier.
21. A pharmaceutical composition comprising the metal complex of claim 18 , or a pharmaceutically acceptable salt, solvate, or ester thereof; and a pharmaceutically acceptable carrier.
22. The metal complex of claim 18 , which is:
or a pharmaceutically acceptable salt or solvate thereof.
23. The metal complex of claim 18 , which is:
or a pharmaceutically acceptable salt or solvate thereof.