211-ASTATINE CONTAINING RADIOTHERAPEUTICS FOR THE TREATMENT OF CANCER

• US 20180162818A1
• Filed: 04/26/2016
• Published: 06/14/2018
• Est. Priority Date: 05/04/2015
• Status: Active Grant

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: PRYMA, Daniel A., LIEBERMAN, Brian p., MAKVANDI, Mehran, MACH, Robert H.
• Granted Patent: US 10,457,642 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 41/0038 Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy radiotherapy per se A61N5/10
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 51/0446 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 51/0455 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 209/44 Iso-indoles; Hydrogenated iso-indoles
• CPC Class Codes: C07D 217/04 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: G21H 5/02 as tracers

Abstract

Described herein is an alpha-emitting radionuclide, ²¹¹At, which has been incorporated into a selective sigma-2 ligand moiety to provide cytotoxic capabilities to a chemical compound. As described herein, a compound of formula (I), wherein R¹-R⁴, m, and n are defined herein, was prepared and utilized in in vitro and in vivo tumor targeting of alpha-emitting sigma-2 ligand in a breast cancer model. In one embodiment, the compound is 5-(²¹¹At)—N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2,3-dimethoxybenzamide.

Claims

1. A compound of formula (I):

2. The compound of claim 1, of formula (II):

3. The compound of claim 1, wherein said halogen is a radioactive isotope.

4. The compound of claim 1, wherein R¹ is C₁ to C₆ fluoroalkoxy.

5. The compound of claim 3, wherein R¹ is O(CH₂)_pF and p is 1 to 10.

6. The compound of claim 1, wherein n is 2 to 4.

7. The compound of claim 1, of formula (III):

8. The compound of claim 1, of formula (IV):

9. The compound of claim 1, of formula (V):

10. The compound of claim 1, of formula (VI):

11. The compound of claim 1, of formula (VII):

12. The compound of claim 1, of formula (VIII):

13. The compound of claim 1, which is:

15. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

16. A method of

preventing or reducing proliferation of cancer cells, or

sensitizing cancer cells to a chemotherapeutic;

said method comprising contacting said cells with a compound of any one of claim 1.

18. The method of claim 16, further comprising administering radiation to said cells.

19. A method of modulating expression of the sigma-2-receptor/progesterone receptor membrane component 1 on a cell, said method comprising contacting said cell with a compound of claim 1.

20. The method of claim 19, further comprising administering radiation to said cell.

21. A method of treating cancer in a patient or sensitizing a patient'"'"'s cancer cells to a chemotherapeutic or administering radiotherapy to a patient, said method comprising administering a compound of claim 1 to said patient.

22. The method of claim 21, wherein said cancer is a neuroendocrine cancer.

23. The method of claim 21, wherein said cancer is of the prostate, head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, bladder, uterus, cervix, breast, ovaries, vagina, testicles, thyroid, blood, lymph nodes, kidney, liver, intestines, pancreas, brain, central nervous system, adrenal gland, neuroendocrine, or skin or a leukemia.

25. The method of claim 21, further comprising administering radiation to said patient.

26. The method of claim 21, wherein said compound is administered to said patient through intravenous, intra-arterial, intraperitoneal or intracavitary injection.

27. The method of claim 21, comprising administering an amount of said compound having from about 0.01 to about 100 Curies of radiation.

14. A compound which is 5-(²¹¹astatine)-N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2,3-dimethoxybenzamide, derivative, salt, or prodrug thereof.

17. (canceled)

24. (canceled)

28-31. -31. (canceled)