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 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 ,
Z 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 halogen 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).
2. The compound or salt of claim 1 , wherein the halogen is a radiohalogen.
3. The compound or salt of claim 1 , 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 compound or salt of claim 3 , wherein R is a phenyl moiety substituted with a halogen.
5. The compound or salt of claim 1 , 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 halogen, radiohalogen, I-123, I-125, I-131, I-124, Br-75, Br-77, and F-18.
6. The compound or salt of claim 1 , wherein the compound is:
7. The compound or salt of claim 1 , 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 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), 0 , NR′, S, S(O) 2 , C(O) 2 , or (CH 2 ) p ;
Z 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 -C 14 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 3 -C 12 heteroaryl, —NR′R′ or COOZ;
or a pharmaceutically acceptable salt thereof.
9. The compound or salt of claim 8 , 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.
10. The compound or salt of claim 8 , 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.
11. A compound or salt 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.
12. The compound or salt of claim 1 , wherein the compound is of the Formula (II):
wherein R, Q, Y, Z, m and n are as defined in claim 1 .
13. A radionuclide chelate complex comprising the compound or salt of claim 1 and a radionuclide.
14. The radionuclide chelate complex of claim 13 , wherein the radionuclide is an imaging radionuclide.
15. The radionuclide chelate complex of claim 13 , wherein the radionuclide is a therapeutic radionuclide.
16. The radionuclide chelate complex of claim 13 , wherein the radionuclide chelate complex is a (technetium-99m)Tc(CO) 3 chelate complex or a (rhenium-186/188)Re(CO) 3 chelate complex.
17. A radionuclide chelate complex, wherein the radionuclide chelate complex is
wherein the hydrogen of the carboxy groups of any of the above compounds can be substituted with C 1 -C 4 alkyl.
18. The compound or salt of claim 1 , wherein the compound is of Formula Iib:
wherein —Y—R is selected from the group consisting of:
wherein X is selected from the group consisting of: I, Br, Cl, F, and H.
19. The compound or salt of claim 1 , 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 halogen and H.
20. The compound or salt of claim 1 , 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 halogen and H.
21. The compound or salt of claim 1 , selected from the group consisting of:
and
22. The compound or salt of claim 1 selected from the group consisting of:
23. The compound or salt of claim 1 , selected from the group consisting of:
24. The compound or salt of claim 18 , wherein X is a radiohalogen of I, Br, Cl or F.
25. The compound or salt of claim 24 , wherein the radiohalogen is an imaging radiohalogen.
26. The compound or salt of claim 24 , wherein the radiohalogen is a therapeutic radiohalogen.
27. The compound or salt of claim 24 , wherein the radiohalogen is I-123, I-125, I-131, I-124, Br-75, Br-77, or F-18.
28. A radionuclide chelate complex comprising the compound or salt of claim 8 and a radionuclide.
29. The compound or salt of claim 2 , wherein the radiohalogen is an imaging radiohalogen.
30. The compound or salt of claim 2 , wherein the radiohalogen is a therapeutic radiohalogen.
31. The compound or salt of claim 2 , wherein the radiohalogen is I-123, I-125, I-131, I-124, Br-75, Br-77, or F-18.
32. The compound or salt of claim 8 , wherein n′ is 0.
33. The compound or salt of claim 32 , wherein L is an optionally substituted C 1 -C 15 alkyl.
34. The compound or salt of claim 33 , wherein n is 0.
35. The compound or salt of claim 34 , wherein Q is NR′.
36. The compound or salt of claim 33 , wherein Q is NR′ and Y is C(O).
37. The compound or salt of claim 35 , wherein R′ independently is H, a C 3 -C 12 substituted or unsubstituted heteroaryl, or a C 1 -C 15 substituted or unsubstituted alkyl.
38. The compound or salt of claim 36 , wherein R′ independently is H, a C 3 -C 12 substituted or unsubstituted heteroaryl, or a C 1 -C 15 substituted or unsubstituted alkyl.
39. The compound or salt of claim 37 , 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.
40. The compound or salt of claim 38 , 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.
41. The compound or salt of claim 19 , wherein the halogen is a radiohalogen.
42. The compound or salt of claim 19 , 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, and H.
43. The compound or salt of claim 19 , wherein X is I-123, I-125, I-131, or I-124.
44. The compound or salt of claim 19 having the formula:
45. The compound or salt of claim 20 , wherein the halogen is a radiohalogen.
46. The compound or salt of claim 20 , 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, and H.
47. The compound or salt of claim 20 , wherein X is I-123, I-125, I-131, or I-124.
48. The compound or salt of claim 20 having the formula:
49. The compound or salt of claim 1 , 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 halogen and H.
50. The compound or salt of claim 49 , wherein the halogen is a radiohalogen.
51. The compound or salt of claim 49 , 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, and H.
52. The compound or salt of claim 49 , wherein X is I-123, I-125, I-131, or I-124.
53. The compound or salt of claim 49 having the formula:
54. A compound having the formula:
wherein X is selected from the group consisting of: I, Br, Cl, F, and H;
or a pharmaceutically acceptable salt thereof.
55. The compound or salt of claim 54 , wherein X is a radiohalogen of I, Br, Cl or F.
56. The compound or salt of claim 54 having the formula: