Radiolabeled prostate specific membrane antigen inhibitors

• US 9,388,144 B2
• Filed: 11/25/2014
• Issued: 07/12/2016
• Est. Priority Date: 08/05/2011
• 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, Joyal, John L., Lu, Genliang
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): SAMALA, JAGADISHWAR RAO
• Application Number:
  US14/553,157
• Publication Number:
  US 20150078998A1
• Time in Patent Office: 595 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 49/0002 General or multifunctional contrast agents, e.g. chelated agents
• CPC Class Codes: A61K 51/0402 carboxylic acid carriers, fatty acids amino acids A61K51/0406
• CPC Class Codes: A61K 51/0478 complexes from non-cyclic ligands, e.g. EDTA, MAG3
• CPC Class Codes: A61K 51/0482 chelates from cyclic ligands, e.g. DOTA
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 255/02 not condensed with other rings
• CPC Class Codes: C07D 257/02 not condensed with other rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07F 5/003 without C-Metal linkages

Abstract

Compounds according to Formula I and Formula II are potent inhibitors of PSMA activity:

Pharmaceutical compositions may include a complex of a radionuclide and a compound of Formula I or Formula II.

Claims

1. A compound represented by formula I

2. The compound of claim 1, wherein X is (CHR¹)_m, Y is C(O), W is hydrogen and k is 5.

3. The compound of claim 1, wherein L is —

C(O)CH₂— and

T is hydrogen.

4. The compound of claim 1, wherein R¹ is hydrogen and m is 2.

5. The compound of claim 1, wherein L is —

C(O)—

[(CH₂)_p—

V]_n—

(CH₂)_q—

C(O)—

U or —

C(O)—

(C₁-C₁₀)alkylene.

6. The compound of claim 5, wherein L is —

C(O)methylene.

7. The compound of claim 5, wherein L is —

C(O)—

[(CH₂)_p—

V]_n—

(CH₂)_q—

C(O)—

U and T is hydrogen.

8. The compound of claim 7, wherein V is NR², n is 2 and q is 1.

9. The compound of claim 7, wherein U is NR²R³.

10. The compound of claim 9, wherein R² is hydrogen and R³ is —

(CH₂)₂—

NH—

C(O)—

(CH₂)—

.

11. The compound of claim 1, wherein L is OR⁶-benzylene and T is —

(C₅-C₁₄)heteroaryl-(C₁-C₁₀)alkylene.

12. The compound of claim 11, wherein the heteroaryl is an imidazole, further substituted with the group —

(C₁-C₁₀)alkylene-C(O)—

U.

13. The compound of claim 11, wherein T is selected from the group consisting of

14. The compound of claim 1, wherein T is.

15. The compound of claim 14, wherein each R′

″

is independently

16. The compound of claim 4, wherein W is —

(CH₂)—

COOH, k is 1, L is —

[C(O)—

(CH(Z)_d)—

NH]_j—

NR²R³ and T is hydrogen.

17. The compound of claim 16, wherein R² is hydrogen, R³ is —

C(O)CH₂— and

j is 4.

18. The compound of claim 4, wherein W and T are hydrogen, k is 5, and L is [C(O)—

CH(Z)_d—

NH]_t—

C(O)—

(CHR¹)_m—

(CH₂)_p—

U.

19. The compound of claim 18, wherein Z is —

(CH₂)₄—

NR²R³ and U is —

NR⁴R⁵.

20. The compound of claim 18, wherein m and t are 1, p is 4 and R¹ is —

NH₂.

21. The compound of claim 19, wherein R⁴ is hydrogen and R⁵ is C(O)methylene.

22. The compound of claim 19, wherein R² and R³ are each independently —

(CH₂)_p—

(C₅-C₁₄)heteroaryl.

23. The compound of claim 18, wherein p is 1 and the heteroaryl is an imidazole, further substituted with the group —

(C₁-C₁₀)alkylene-C(O)—

U.

24. The compound of claim 1, which is:

25. A metal complex comprising a radionuclide and the compound of claim 1.

26. The metal complex of claim 25, wherein the radionuclide is selected from the group consisting of ¹¹¹In, ⁹⁰Y, ⁶⁸Ga, ⁶⁴Cu ¹⁵³Gd, ¹⁵⁵Gd, ¹⁵⁷Gd, ¹⁵⁷Fe and ¹⁷⁷Lu.

27. The metal complex of claim 25, which is:

28. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or ester thereof;

and a pharmaceutically acceptable carrier.

29. A pharmaceutical composition comprising the metal complex of claim 25, or a pharmaceutically acceptable salt or ester thereof;

and a pharmaceutically acceptable carrier.