Heterodimers of glutamic acid

• US 10,640,461 B2
• Filed: 03/14/2016
• Issued: 05/05/2020
• 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): Sznaidman, Marcos L
• Assistant Examiner(s): Rodriguez, Rayna
• Application Number:
  US15/068,841
• Publication Number:
  US 20160279235A1
• Time in Patent Office: 1,513 Days
• Field of Search: 514138, 424 165, 424 185, 424 91
• 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 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;

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.

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):

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 CH₂; and

R is a C₆-C₁₂ 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:

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 CH₂;

R is a —

CH₂(CH₂)_1-4CHNR′

R′

; and

R′

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

10. The method of claim 2, wherein the compound is of Formula (Iib):

11. The method of claim 2, wherein the compound is of the following structure:

12. The method of claim 2, wherein the compound is of the following structure:

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.

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:

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:

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.

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);

9. The method of claim 8, wherein the compound is:

21. The method of claim 8, wherein n′

is 0.

22. The method of claim 21, wherein L is an optionally substituted C₁-C₁₅ 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 C₃-C₁₂ substituted or unsubstituted heteroaryl, or a C₁-C₁₅ substituted or unsubstituted alkyl.

27. The method of claim 25, wherein R′

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

28. The method of claim 26, 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.

29. The method of claim 27, 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.

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;

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:

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;