Heterodimers of glutamic acid
View Patent ↗Compounds of Formula (Ia) wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl or —NR′R′, Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p Z is H or C 1 -C 4 alkyl, R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 6 -C 12 heteroaryl, —NR′R′ or COOZ, which have diagnostic and therapeutic properties, such as the treatment and management of prostate cancer and other diseases related to NAALADase inhibition. Radiolabels can be incorporated into the structure through a variety of prosthetic groups attached at the X amino acid side chain via a carbon or hetero atom linkage.
1. A method of treating a patient with prostate cancer, the method comprising a step of:
administering a therapeutically effective amount of a glutamate-urea-lysine prostate-specific membrane antigen (PSMA)-binding moiety, wherein the glutamate-urea-lysine PSMA-binding moiety comprises a structure:
or a pharmaceutically acceptable salt thereof,
wherein each Z, independently, is H or C 1 -C 4 alkyl.
2. A method of treating a patient with prostate cancer, the method comprising a step of administering a therapeutically effective amount of a glutamate-urea-lysine prostate-specific membrane antigen (PSMA)-binding moiety, wherein the glutamate-urea-lysine PSMA-binding moiety corresponds to a compound of Formula (I):
wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 3 -C 12 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl or —NR′R′;
Q is C(O), O, NR′, S(O) 2 , C(O) 2 , or (CH 2 ) p ;
Y is C(O), O, NR′, S(O) 2 , C(O) 2 , or (CH 2 ) p ;
each Z, independently, is H or C 1 -C 4 alkyl;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1, 2, 3, 4, 5 or 6;
p is 0, 1, 2, 3, 4, 5 or 6; and
R′ independently is H, a C 6 -C 12 substituted or unsubstituted aryl, a C 3 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 6 substituted or unsubstituted alkyl,
when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 3 -C 12 heteroaryl, —NR′R′ or COOZ;
further wherein
at least one of Q and Y comprises a heteroatom selected from the group consisting of O, S, and N; and
(i) at least one of R or R′ is a C 6 -C 12 aryl or C 3 -C 12 heteroaryl substituted with a radiohalogen or
(ii) at least one of R or R′ is a C 3 -C 12 heteroaryl;
or a pharmaceutically acceptable salt of the compound of Formula (I).
3. The method of claim 2 , wherein
n is 0 or 1;
m is 0, 1, 2, 3 or 4;
Q is NR′;
Y is C(O) or CH 2 ; and
R is a C 6 -C 12 substituted or unsubstituted aryl.
4. The method of claim 3 , wherein R is a phenyl moiety substituted with a radiohalogen.
5. The method of claim 2 , wherein the compound is:
wherein the hydrogen of the carboxy groups of any of the above compounds can be substituted with C 1 -C 4 alkyl, and
X is selected from the group consisting of radiohalogen I-123, I-125, I-131, I-124, Br-75, Br-77, and F-18.
6. The method of claim 2 , wherein the compound is:
7. The method of claim 2 , wherein
n is 0 or 1;
m is 0, 1, 2, 3 or 4;
Q is NR′;
Y is C(O) or CH 2 ;
R is a —CH 2 (CH 2 ) 1-4 CHNR′R′; and
R′ independently is a C 1 -C 2 alkyl substituted with a pyridine or carboxy group.
8. A method of treating a patient with prostate cancer, the method comprising the step of:
administering a therapeutically effective amount of a compound of formula (III):
wherein
L is a bond, an optionally substituted C 1 -C 15 alkyl, C 1 -C 15 alkenyl, or C 1 -C 15 alkynyl, or —[(CH 2 ) q O] s —, wherein q and s are independently an integer of 1 to 10;
E is —NR′R′;
Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 , or (CH 2 ) p ;
Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 , or (CH 2 ) p ;
each Z, independently, is H or C 1 -C 4 alkyl;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1, 2, 3, 4, 5 or 6;
n′ is 0, 1, 2, 3, 4, 5 or 6;
p is 0, 1, 2, 3, 4, 5 or 6;
R′ independently is H, a C 6 -C 12 substituted or unsubstituted aryl, a C 3 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C14 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with a radiohalogen, C 3 -C 12 heteroaryl, —NR′R′ or COOZ;
or a pharmaceutically acceptable salt thereof.
9. The method of claim 8 , wherein the compound is:
wherein the hydrogen of the carboxy groups of the above compounds can be substituted with C 1 -C 4 alkyl.
10. The method of claim 2 , wherein the compound is of Formula (Iib):
wherein —Y—R is selected from the group consisting of:
wherein X is H or a radiohalogen selected from the group consisting of: I, Br, Cl, and F.
11. The method of claim 2 , wherein the compound is of the following structure:
wherein the hydrogen of the carboxy groups of the compound or salt can be substituted with C 1 -C 4 alkyl; and
X is selected from a radiohalogen and H.
12. The method of claim 2 , wherein the compound is of the following structure:
wherein the hydrogen of the carboxy groups of the compound or salt can be substituted with C 1 -C 4 alkyl; and
X is selected from a radiohalogen and H.
13. The method of claim 2 , wherein the compound is selected from the group consisting of:
14. The method of claim 2 wherein the compound is selected from the group consisting of:
15. The method of claim 2 , wherein the compound is selected from the group consisting of:
16. The method of claim 10 , wherein X is a radiohalogen of I, Br, Cl or F.
17. The method of claim 10 , wherein the radiohalogen is a therapeutic radiohalogen.
18. The method of claim 10 , wherein the radiohalogen is I-123, I-125, I-131, I-124, Br-75, Br-77, or F-18.
19. The method of claim 2 , wherein the radiohalogen is a therapeutic radiohalogen.
20. The method of claim 2 , wherein the radiohalogen is I-123, I-125, I-131, I-124, Br-75, Br-77, or F-18.
21. The method of claim 8 , wherein n′ is 0.
22. The method of claim 21 , wherein L is an optionally substituted C 1 -C 15 alkyl.
23. The method of claim 22 , wherein n is 0.
24. The method of claim 23 , wherein Q is NR′.
25. The method of claim 22 , wherein Q is NR′ and Y is C(O).
26. The method of claim 24 , wherein R′ independently is H, a C 3 -C 12 substituted or unsubstituted heteroaryl, or a C 1 -C 15 substituted or unsubstituted alkyl.
27. The method of claim 25 , wherein R′ independently is H, a C 3 -C 12 substituted or unsubstituted heteroaryl, or a C 1 -C 15 substituted or unsubstituted alkyl.
28. The method of claim 26 , wherein R′ independently is a C 3 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 15 substituted alkyl, and when substituted, the C 1 -C 15 substituted alkyl is substituted with COOH.
29. The method of claim 27 , wherein R′ independently is a C 3 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 15 substituted alkyl, and when substituted, the C 1 -C 15 substituted alkyl is substituted with COOH.
30. The method of claim 11 , wherein X is a radiohalogen.
31. The method of claim 11 , wherein X is selected from the group consisting of: I, Br, Cl, F, I-123, I-125, I-131, I-124, Br-75, Br-77, and F-18.
32. The method of claim 11 , wherein X is I-123, I-125, I-131, or I-124.
33. The method of claim 11 having the formula:
34. The method of claim 12 , wherein X is a radiohalogen.
35. The method of claim 12 , wherein X is selected from the group consisting of: I, Br, Cl, F, I-123, I-125, I-131, I-124, Br-75, Br-77, and F-18.
36. The method of claim 12 , wherein X is I-123, I-125, I-131, or I-124.
37. The method of claim 12 having the formula:
38. The method of claim 2 , wherein the compound is of the following structure:
wherein the hydrogen of the carboxy groups of the compound or salt can be substituted with C 1 -C 4 alkyl; and
X is selected from a radiohalogen and H.
39. The method of claim 38 , wherein X is selected from the group consisting of: I, Br, Cl, F, I-123, I-125, I-131, I-124, Br-75, Br-77, and F-18.
40. The method of claim 38 , wherein X is I-123, I-125, I-131, or I-124.
41. The method of claim 38 wherein the compound has the formula:
42. A method of treating a patient with prostate cancer, the method comprising the step of:
administering a therapeutically effective amount of a compound having the formula:
wherein X is a radiohalogen selected from the halogen group consisting of: I, Br, Cl, and F; or H;
or a pharmaceutically acceptable salt thereof.
43. The method of claim 42 , wherein X is a radiohalogen of I, Br, Cl or F.
44. The method of claim 42 wherein the compound has the formula:
45. The method of claim 1 , wherein the glutamate-urea-lysine prostate-specific membrane antigen (PSMA)-binding moiety provides an analgesic effect on the patient.
46. The method of claim 2 , wherein the glutamate-urea-lysine prostate-specific membrane antigen (PSMA)-binding moiety provides an analgesic effect on the patient.
47. A method of treating a patient with prostate cancer, the method comprising a step of:
administering a therapeutically effective amount of a glutamate-urea-lysine prostate-specific membrane antigen (PSMA)-binding moiety, wherein the glutamate-urea-lysine PSMA-binding moiety comprises or is derived from:
or a pharmaceutically acceptable salt thereof.