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 5 -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 (CH2)p
Y is C(O), O, NR′, S(O) 2 , C(O) 2 , or (CH2)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
R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 5 -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 5 -C 12 heteroaryl, —NR′R′ or COOZ,
wherein at least one of Q and Y comprises a heteroatom selected from the group consisting of O, S, and N,
further wherein
(i) at least one of R or R′ is a C 6 -C 12 aryl or C 5 -C 12 heteroaryl substituted with a halogen or
(ii) at least one of R or R′ is a C 5 -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, I-123, I-125, I-131, I-124, Br-75, Br-77, or F-18.
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 4 , wherein the compound is:
wherein the hydrogen in 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 4 , wherein the compound is:
7. The compound or salt of claim 1 , wherein
n is 0 or 1
m is 0, 2, 3 or 4
Q is NR′
Y is C(O) or CH 2 and
R is a —CH 2 (CH 2 ) 1-4 CHNR′R′ and
R′ is a C 1 -C 2 alkyl substituted with a pyridine or carboxy group, wherein at least one R′ is a C 1 -C 2 alkyl substituted with a pyridine.
8. The compound or salt of claim 1 , wherein the compound is
wherein the hydrogen in the carboxy groups of any of the above compounds can be substituted with C 1 -C 4 alkyl.
9. The compound or salt of claim 1 , wherein
n is 0 or 1
m is 0
Q is CH 2
Y is CH 2 and
R is —NR′R′ and
R′ is a C 1 -C 2 alkyl substituted with a pyridine or carboxy group, wherein at least one R′ is a C 1 -C 2 alkyl substituted with a pyridine.
10. The compound or salt of claim 9 , wherein the compound is
wherein the hydrogen in 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 1 , wherein the compound is:
wherein R′ is a C 6 -C 12 aryl or C 5 -C 12 heteroaryl, and wherein the hydrogen in 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 compounds is of the Formula (II):
13. A radionuclide chelate complex comprising the compound or salt of claim 1 .
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. A radionuclide chelate complex comprising a compound of Formula (I), or a pharmaceutically acceptable salt of the compound of Formula (I), and a radionuclide:
wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 5 -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 , or (CH2)p
Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 , or (CH2)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
R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 5 -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 5 -C 12 heteroaryl, —NR′R′ or COOZ,
further wherein
(i) at least one of R or R′ is a C 6 -C 12 aryl or C 5 -C 12 heteroaryl substituted with a halogen or
(ii) at least one of R or R′ is a C 5 -C 12 heteroaryl;
wherein the radionuclide is a (technetium-99m)Tc(CO) 3 chelate complex or (rhenium-186/188) Re(CO) 3 chelate complex.
17. The radionuclide chelate complex of claim 16 , wherein the radionuclide is
wherein the hydrogen in the carboxy groups of any of the above compounds can be substituted with C 1 -C 4 alkyl.
18. A glutamate-urea-lysine PSMA-binding moiety having Formula (I) of claim 1 , and whose IC 50 inhibition of PSMA is less than 20 nM, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH 2 or β-NH 2 groups, wherein the PSMA-binding moiety is one of:
wherein X is one of: I, Br, Cl, F, and H.
19. A compound comprising the PSMA-binding moiety of claim 18 conjugated to a radio-imaging moiety in which the PSMA-binding moiety and the radio-imaging moiety are conjugated via an amide, ester, amine, or ether linkage.
20. A compound of Formula (Ia)
wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 5 -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 , or (CH2)p
Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 , or (CH2)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 1, 2, 3, 4, 5 or 6
is 0, 1, 2, 3, 4, 5 or 6
R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 5 -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 5 -C 2 heteroaryl, —NR′R′ or COOZ,
further wherein
(i) at least one of R or R′ is a C 6 -C 12 aryl or C 5 C 12 heteroaryl substituted with at least a halogen or
(ii) at least one of R or R′ is a substituted or unsubstituted C 5 -C 12 heteroaryl,
or a pharmaceutically acceptable salt of the compound of Formula (Ia).
21. The compound or salt of claim 20 , wherein the halogen is a radiohalogen, I-123, I-125, I-131, I-124, Br-75, Br-77, or F-18.
22. The compound or salt of claim 20 , wherein
n is or 1
n′ is 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.
23. The compound or salt of claim 22 , wherein R is a phenyl moiety substituted with a halogen.
24. The compound or salt of claim 20 , wherein
n is 0 or 1
n′ is 1
m is 0, 1, 2, 3 or 4
Q is NR′
Y is C(O) or CH 2 and
R is a —CH 2 (CH 2 ) 1-4 CHNR′R′ and
R′ is a C 1 -C 2 alkyl substituted with a pyridine or carboxy group, wherein at least one R′ is a C 1 -C 2 alkyl substituted with a pyridine.
25. The compound or salt of claim 24 , wherein the compound is
wherein the hydrogen in the carboxy groups of any of the above compounds can be substituted with C 1 -C 4 alkyl.
26. The compound or salt of claim 20 , wherein
n is 0 or 1
n′ is 1
m is 0, 1, 2, 3 or 4
Q is CH 2
Y is CH 2 and
R is —NR′R′ and
R′ is a C 1 -C 2 alkyl substituted with a pyridine or carboxy group, wherein at least one R′ is a C 1 -C 2 alkyl substituted with a pyridine.
27. The compound or salt of claim 26 , wherein the compound is
wherein the hydrogen in the carboxy groups of any of the above compounds can be substituted with C 1 -C 4 alkyl.
28. The compound or salt of claim 20 , wherein the compounds is of the Formula (Iia):
29. A radionuclide chelate complex comprising the compound or salt of claim 20 .
30. The radionuclide chelate complex of claim 29 , wherein the radionuclide is an imaging radionuclide.
31. The radionuclide chelate complex of claim 29 , wherein the radionuclide is a therapeutic radionuclide.
32. A radionuclide chelate complex comprising a compound of Formula (ha), or a pharmaceutically acceptable salt of the compound of Formula (Ia), and a radionuclide:
wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 5 -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 , or (CH2)p
Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 , or (CH2)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′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 5 - 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 5 -C 12 heteroaryl, —NR′R′ or COOZ,
further wherein
(i) at least one of R or R′ is a C 6 -C 12 aryl or C 5 -C 12 heteroaryl substituted with at least a halogen or
(ii) at least one of R or R′ is a substituted or unsubstituted C 5 -C 12 heteroaryl;
wherein the radionuclide is a (technetium-99m)Tc(CO) 3 chelate complex or (rhenium-186/188) Re(CO) 3 chelate complex.
33. A compound or a pharmaceutically acceptable salt thereof, 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, CI, F, and H.
34. The compound or salt of claim 33 , wherein the compound is of the following structure:
wherein X is selected from the group consisting of:
35. The compound or salt of claim 33 , wherein the compound is of the following structure:
wherein X is selected from the group consisting of:
36. The compound or salt of claim 33 selected from the group consisting of:
(S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)pentanedioic acid,
(S,S)-2-{3-[1-Carboxy-5-(2-chloro-benzylamino)-pentyl]-ureido}-pentanedioic acid,
(S,S)-2-{3-[1-Carboxy-5-(3-chloro-benzylamino)-pentyl]- ureido-}-pentanedioic acid,
(S,S)-2-{3-[1-Carboxy-5-(4-chloro-benzylamino)-pentyl]- ureido}-pentanedioic acid,
(S)-2-(3-((R)-5-(benzylamino)-1-carboxypentyl)ureido)pentanedioic acid,
2-(3-{1-Carboxy-5[-3-(phenyl)-ureido]-pentyl}-ureido)-pentanedioic acid,
2-(3-{1-Carboxy-5-[3(4-bromo-phenyl)-ureido]-pentyl}-ureido)-pentanedioic acid;
2-(3-{1-Carboxy-5-[3(4-chloro-phenyl)-ureidol]-pentyl}-ureido)-pentanedioic acid;
(S)-2-(3-((R)-1-carboxy-5-(□opyridine-1-ylmethylamino)pentyl)ureido)pentanedioic acid; and
2-( 3 -{1-Carboxy-5-[3-(3-iodo-benzyl)-ureido]-pentyl}-ureido)-pentanedioic acid.
37. The compound or salt according to claim 1 , wherein the compound is selected from the group consisting of:
38. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
39. A radionuclide chelate complex comprising the compound or salt of claim 33 .
40. The radionuclide chelate complex of claim 39 , wherein the radionuclide is an imaging radionuclide.
41. The radionuclide chelate complex of claim 39 , wherein the radionuclide is a therapeutic radionuclide.
42. The radionuclide chelate complex of claim 39 , wherein the radionuclide is a (technetium-99m)Tc(CO) 3 chelate complex or (rhenium-186/188)Re(CO) 3 chelate complex.
43. A compound of formula III:
wherein
L is a bond, an optionally substituted alkyl, alkenyl, or alkynyl of C 1 -C 15 , 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 1 )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′ is independently H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 5 -C l2 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 5 -C 12 heteroaryl, —NR′R′ or COOZ,
or a pharmaceutically acceptable salt thereof.
44. A radionuclide chelate complex comprising the compound or salt of claim 43 .
45. The compound or salt of claim 43 , wherein the compound is of the following structure:
wherein n is an integer of 0 to 9.
46. The compound or salt of claim 45 , wherein n is 9 and the compound is (19S,23S)-2-(4-iodobenzyl)-1-(4-iodophenyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-19,23,25-tricarboxylic acid.
47. The compound or salt of claim 43 , wherein the compound is of the following structure:
wherein n is 2, 4, or 8.
48. A radionuclide chelate complex comprising the compound or salt of claim 47 of the following structure:
wherein n is 2, 4 or 8.
49. The radionuclide chelate complex of claim 48 of the following structure:
[Re(CO) 3 {(17R,21S)-11,19-dioxo-1-(yridine-2-yl)-2-(yridine-2-ylmethyl)-5,8-dioxa-2,12,18,20-tetraazatricosane-17,21,23-tricarboxylic acid})][Br];
[Re(CO) 3 {(23R,27S)-17,25-dioxo-1-(pyridin-2-yl)-2-(pyridin-2-ylmethyl)-5,8,11,14—tetraoxa-2,18,24,26-tetraazanonacosane-23,27,29-tricarboxylic acid}][Br]; and
[Re(CO) 3 {(35R,39S)-29,37-dioxo-1-(yridine-2-yl)-2-(yridine-2-ylmethyl)-5,8,11,14,17,20,23,26-octaoxa-2,30,36,38-tetraazahent- etracontane-35,39,41-tricarboxylic acid}][Br]; or a pharmaceutically acceptable salt thereof.
50. The compound or salt of claim 43 of the following structure:
51. A radionuclide chelate complex comprising a salt form of the compound of claim 50 of the following structure:
[Re(CO) 3 {(19R,23S)-13,21-dioxo-2-(yridine-2-ylmethyl)-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylic acid}].
52. A radionuclide chelate complex comprising a compound of Formula (I), or a pharmaceutically acceptable salt of the compound of Formula (I), and a radionuclide:
wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 5 -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 , or (CH2)p
Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 , or (CH2)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
R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 5 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 5 -C 12 heteroaryl, —NR′R′ or COOZ,
further wherein
(i) at least one of R or R′ is a C 6 -C 12 aryl or C 5 -C 12 heteroaryl substituted with a halogen or
(ii) at least one of R or R′ is a C 5 -C 12 heteroaryl;
wherein the radionuclide is a radio copper.
53. A radionuclide chelate complex comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt of the compound of Formula (Ia), and a radionuclide:
wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 5 -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 , or (CH2)p
Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 , or (CH2)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′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 5 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 5 C 12 heteroaryl, —NR′R′ or COOZ,
further wherein
(i) at least one of R or R′ is a C 6 -C 12 aryl or C 5 -C 12 heteroaryl substituted with at least a halogen or
(ii) at least one of R or R′ is a substituted or unsubstituted C 5 -C 12 heteroaryl;
wherein the radionuclide is a radio copper.
54. A radionuclide chelate complex comprising a compound or a pharmaceutically acceptable salt thereof and a radionuclide, 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, CI, F, and H;
wherein the radionuclide is a radio copper.
55. A radionuclide chelate complex comprising the compound or salt of claim 20 selected from the following structures: