Heterodimers of glutamic acid

• US 8,487,129 B2
• Filed: 11/11/2011
• Issued: 07/16/2013
• Est. Priority Date: 11/08/2006
• Status: Active Grant

• Current Assignee: Molecular Insight Pharmaceuticals Incorporated (Lantheus Holdings, Inc.)
• Original Assignee: Molecular Insight Pharmaceuticals Incorporated (Lantheus Holdings, Inc.)
• Inventors: Babich, John W., Zimmerman, Craig N., Maresca, Kevin P.
• Primary Examiner(s): VALENROD, YEVGENY
• Application Number:
  US13/294,677
• Publication Number:
  US 20120208988A1
• Time in Patent Office: 613 Days
• Field of Search: None
• US Class Current: 562/439
• CPC Class Codes: A61K 39/385 Haptens or antigens, bound to carriers
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 59/001 Acyclic or carbocyclic compounds
• CPC Class Codes: C07C 275/16 being further substituted by carboxyl groups
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 275/30 being further substituted by halogen atoms, or by nitro or nitroso groups
• CPC Class Codes: C07C 311/19 to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom

Abstract

Compounds of Formula (Ia)

wherein R is a C₆-C₁₂ substituted or unsubstituted aryl, a C₆-C₁₂ substituted or unsubstituted heteroaryl, a C₁-C₆ 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 C₁-C₄ alkyl,
• R′ is H, C(O), S(O)₂, C(O)₂, a C₆-C₁₂ substituted or unsubstituted aryl, a C₆-C₁₂ substituted or unsubstituted heteroaryl or a C₁-C₆ substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C₆-C₁₂ 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.

Claims

1. A 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 CH₂ ; and

R is a C₆-C₁₂ 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:

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 CH₂;

R is a —

CH₂(CH₂)_1-4CHNR′

R′

; and

R′

independently is a C₁-C₂ alkyl substituted with a pyridine or carboxy group.

12. The compound or salt of claim 1, wherein the compound is of the Formula (II):

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.

18. The compound or salt of claim 1, wherein the compound is of Formula Iib:

19. The compound or salt of claim 1, wherein the compound is of the following structure:

20. The compound or salt of claim 1, wherein the compound is of the following structure:

21. The compound or salt of claim 1, selected from the group consisting of:

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.

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.

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:

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:

8. A compound of formula III:

9. The compound or salt of claim 8, wherein the compound is

10. The compound or salt of claim 8, wherein the compound is

11. A compound or salt of claim 8, wherein the compound is:

28. A radionuclide chelate complex comprising the compound or salt of claim 8 and a radionuclide.

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 C₁-C₁₅ 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 C₃-C₁₂ substituted or unsubstituted heteroaryl, or a C₁-C₁₅ substituted or unsubstituted alkyl.

38. The compound or salt of claim 36, wherein R′

independently is H, a C₃-C₁₂ substituted or unsubstituted heteroaryl, or a C₁-C₁₅ substituted or unsubstituted alkyl.

39. The compound or salt of claim 37, wherein R′

independently is a C₃-C₁₂ substituted or unsubstituted heteroaryl or a C₁-C₁₅ substituted alkyl, and when substituted, the C₁-C₁₅ substituted alkyl is substituted with COOH.

40. The compound or salt of claim 38, wherein R′

independently is a C₃-C₁₂ substituted or unsubstituted heteroaryl or a C₁-C₁₅ substituted alkyl, and when substituted, the C₁-C₁₅ substituted alkyl is substituted with COOH.

17. A radionuclide chelate complex, wherein the radionuclide chelate complex is

54. A compound having the formula:

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: