Claims for Patent: 8,487,129

Summary for Patent: 8,487,129

Title:	Heterodimers of glutamic acid
Abstract:	Compounds of Formula (Ia) ##STR00001## wherein R is a C.sub.6-C.sub.12 substituted or unsubstituted aryl, a C.sub.6-C.sub.12 substituted or unsubstituted heteroaryl, a C.sub.1-C.sub.6 substituted or unsubstituted alkyl or --NR'R', Q is C(O), O, NR', S, S(O).sub.2, C(O).sub.2 (CH2)p Y is C(O), O, NR', S, S(O).sub.2, C(O).sub.2 (CH2)p Z is H or C.sub.1-C.sub.4 alkyl, R' is H, C(O), S(O).sub.2, C(O).sub.2, a C.sub.6-C.sub.12 substituted or unsubstituted aryl, a C.sub.6-C.sub.12 substituted or unsubstituted heteroaryl or a C.sub.1-C.sub.6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C.sub.6-C.sub.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.
Inventor(s):	Babich; John W. (Cambridge, MA), Zimmerman; Craig N. (Cambridge, MA), Maresca; Kevin P. (Cambridge, MA)
Assignee:	Molecular Insight Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	13/294,677
Patent Claims:	1. A compound of Formula (I) ##STR00054## wherein R is a C.sub.6-C.sub.12 substituted or unsubstituted aryl, a C.sub.3-C.sub.12 substituted or unsubstituted heteroaryl, a C.sub.1-C.sub.6 substituted or unsubstituted alkyl or --NR'R', Q is C(O), O, NR', S(O).sub.2, C(O).sub.2, or (CH.sub.2).sub.p, Y is C(O), O, NR', S(O).sub.2, C(O).sub.2, or (CH.sub.2).sub.p, Z is H or C.sub.1-C.sub.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.sub.6-C.sub.12 substituted or unsubstituted aryl, a C.sub.3-C.sub.12 substituted or unsubstituted heteroaryl or a C.sub.1-C.sub.6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C.sub.3-C.sub.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.sub.6-C.sub.12 aryl or C.sub.3-C.sub.12 heteroaryl substituted with a halogen or (ii) at least one of R or R' is a C.sub.3-C.sub.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.sub.2 ; and R is a C.sub.6-C.sub.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: ##STR00055## ##STR00056## ##STR00057## wherein the hydrogen of the carboxy groups of any of the above compounds can be substituted with C.sub.1-C.sub.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: ##STR00058## ##STR00059## 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.sub.2; R is a --CH.sub.2(CH.sub.2).sub.1-4CHNR'R'; and R' independently is a C.sub.1-C.sub.2 alkyl substituted with a pyridine or carboxy group. 8. A compound of formula III: ##STR00060## wherein L is a bond, an optionally substituted C.sub.1-C.sub.15 alkyl, C.sub.1-C.sub.15 alkenyl, or C.sub.1-C.sub.15 alkynyl, or --[(CH.sub.2).sub.qO].sub.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).sub.2, C(O).sub.2, or (CH.sub.2).sub.p; Y is C(O), 0, NR', S, S(O).sub.2, C(O).sub.2, or (CH.sub.2).sub.p; Z is H or C.sub.1-C.sub.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.sub.6-C.sub.12 substituted or unsubstituted aryl, a C.sub.3-C.sub.12 substituted or unsubstituted heteroaryl or a C.sub.1-C.sub.14 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C.sub.3-C.sub.12 heteroaryl, --NR'R' or COOZ; or a pharmaceutically acceptable salt thereof. 9. The compound or salt of claim 8, wherein the compound is ##STR00061## wherein the hydrogen of the carboxy groups of any of the above compounds can be substituted with C.sub.1-C.sub.4 alkyl. 10. The compound or salt of claim 8, wherein the compound is ##STR00062## wherein the hydrogen of the carboxy groups of any of the above compounds can be substituted with C.sub.1-C.sub.4 alkyl. 11. A compound or salt of claim 8, wherein the compound is: ##STR00063## wherein the hydrogen of the carboxy groups of the above compounds can be substituted with C.sub.1-C.sub.4 alkyl. 12. The compound or salt of claim 1, wherein the compound is of the Formula (II): ##STR00064## 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).sub.3 chelate complex or a (rhenium-186/188)Re(CO).sub.3 chelate complex. 17. A radionuclide chelate complex, wherein the radionuclide chelate complex is ##STR00065## ##STR00066## wherein the hydrogen of the carboxy groups of any of the above compounds can be substituted with C.sub.1-C.sub.4 alkyl. 18. The compound or salt of claim 1, wherein the compound is of Formula Iib: ##STR00067## wherein --Y--R is selected from the group consisting of: ##STR00068## 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: ##STR00069## wherein the hydrogen of the carboxy groups of the compound or salt can be substituted with C.sub.1-C.sub.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: ##STR00070## wherein the hydrogen of the carboxy groups of the compound or salt can be substituted with C.sub.1-C.sub.4 alkyl; and X is selected from halogen and H. 21. The compound or salt of claim 1, selected from the group consisting of: ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## and ##STR00078## 22. The compound or salt of claim 1 selected from the group consisting of: ##STR00079## 23. The compound or salt of claim 1, selected from the group consisting of: ##STR00080## 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.sub.1-C.sub.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.sub.3-C.sub.12 substituted or unsubstituted heteroaryl, or a C.sub.1-C.sub.15 substituted or unsubstituted alkyl. 38. The compound or salt of claim 36, wherein R' independently is H, a C.sub.3-C.sub.12 substituted or unsubstituted heteroaryl, or a C.sub.1-C.sub.15 substituted or unsubstituted alkyl. 39. The compound or salt of claim 37, wherein R' independently is a C.sub.3-C.sub.12 substituted or unsubstituted heteroaryl or a C.sub.1-C.sub.15 substituted alkyl, and when substituted, the C.sub.1-C.sub.15 substituted alkyl is substituted with COOH. 40. The compound or salt of claim 38, wherein R' independently is a C.sub.3-C.sub.12 substituted or unsubstituted heteroaryl or a C.sub.1-C.sub.15 substituted alkyl, and when substituted, the C.sub.1-C.sub.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: ##STR00081## 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: ##STR00082## 49. The compound or salt of claim 1, wherein the compound is of the following structure: ##STR00083## wherein the hydrogen of the carboxy groups of the compound or salt can be substituted with C.sub.1-C.sub.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: ##STR00084## 54. A compound having the formula: ##STR00085## 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: ##STR00086##