Compositions and methods for treating neoplastic diseases

• US 20070225350A1
• Filed: 12/02/2005
• Published: 09/27/2007
• Est. Priority Date: 12/03/2004
• Status: Abandoned Application

• Current Assignee: Triphase Research and Development I Corp
• Original Assignee: Triphase Research and Development I Corp
• Inventors: Anderson, Kenneth, Chauhan, Dharminder
• Application Number:
  US11/293,354
• Publication Number:
  US 20070225350A1
• Time in Patent Office: Days
• US Class Current: 514/412
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Disclosed herein are compositions and methods for treating neoplastic diseases. Included are compositions and methods that are effective against multiple myeloma cells resistant to conventional and bortezomib treatment. Furthermore, combination treatment with two different proteosome inhibitors is shown to be synergistic for treating multiple myeloma.

Claims

1. A method of treating a neoplastic disease, comprising:

administering to a patient inflicted with the neoplastic disease a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof;

wherein X is selected from the group consisting of fluorine, chlorine, bromine or iodine, and

wherein the neoplastic disease is susceptible to resistance to at least one other chemotherapeutic agent.

2. The method of claim 1, wherein X is chlorine.

3. The method of claim 1, wherein the compound of formula (I) has the structure of formula (II):

4. The method of claim 1, wherein the neoplastic disease is cancer.

5. The method of claim 4, wherein the cancer is selected from the group consisting of breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer.

6. The method of claim 5, wherein the cancer is selected from the group consisting of multiple myeloma, colorectal carcinoma, prostate carcinoma, breast adenocarcinoma, non-small cell lung carcinoma, and an ovarian carcinoma or melanoma.

7. The method of claim 6, wherein the cancer is a multiple myeloma.

8. The method of claim 1, wherein the patient is a human.

9. The method of claim 1, wherein the other chemotherapeutic agent is selected from the group consisting of dexamethasone, doxorubicin, and thalidomide.

10. The method of claim 1, wherein the other chemotherapeutic agent is a proteosome inhibitor.

11. The method of claim 10, wherein the other chemotherapeutic agent is bortezomib.

12. A method of treating a neoplastic disease, comprising administering to a patient inflicted with the neoplastic disease a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof:

wherein X is selected from the group consisting of fluorine, chlorine, bromine or iodine, in combination with at least one additional chemotherapeutic agent.

13. The method of claim 12, wherein X is chlorine.

14. The method of claim 12, wherein the compound of formula (I) has the structure of formula (II):

15. The method of claim 12, wherein the neoplastic disease is cancer.

16. The method of claim 15, wherein the cancer is selected from the group consisting of breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer.

17. The method of claim 16, wherein the cancer is selected from the group consisting of multiple myeloma, colorectal carcinoma, prostate carcinoma, breast adenocarcinoma, non-small cell lung carcinoma, and an ovarian carcinoma or melanoma.

18. The method of claim 17, wherein the cancer is a multiple myeloma.

19. The method of claim 12, wherein the patient is a human.

20. The method of claim 12, wherein the other chemotherapeutic agent is selected from the group consisting of dexamethasone, doxorubicin, and thalidomide.

21. The method of claim 12, wherein the other chemotherapeutic agent is a proteosome inhibitor.

22. The method of claim 21, wherein the other chemotherapeutic agent is bortezomib.

23. The method of claim 12, wherein the combination is synergistic.

24. The method of claim 12, wherein the combination is additive.

25. A pharmaceutical composition, comprising:

a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof;

wherein X is selected from the group consisting of fluorine, chlorine, bromine or iodine; and

at least one additional chemotherapeutic agent.

26. The composition of claim 25, wherein X is chlorine.

27. The composition of claim 25, wherein the compound of formula (I) has the structure of formula (II):

28. The composition of claim 25, wherein the other chemotherapeutic agent is selected from the group consisting of dexamethasone, doxorubicin, and thalidomide.

29. The composition of claim 25, wherein the other chemotherapeutic agent is a proteosome inhibitor.

30. The composition of claim 29, wherein the other chemotherapeutic agent is bortezomib.

31. A method of treating a neoplastic disease, comprising administering to a patient inflicted with the neoplastic disease a synergistic combination of at least two proteosome inhibitors.

32. The method of claim 31, wherein the neoplastic disease is cancer.

33. The method of claim 32, wherein the cancer is selected from the group consisting of breast cancer, sarcoma, leukemia, ovarian cancer, uretal cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, melanoma, angioma, and brain or central nervous system (CNS) cancer.

34. The method of claim 33, wherein the cancer is selected from the group consisting of multiple myeloma, colorectal carcinoma, prostate carcinoma, breast adenocarcinoma, non-small cell lung carcinoma, and an ovarian carcinoma or melanoma.

35. The method of claim 34, wherein the cancer is a multiple myeloma.

36. The method of claim 31, wherein the patient is a human.

37. The method of claim 31, wherein at least one of the proteosome inhibitors is selected from the group consisting of bortezomib and the compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof:

wherein X is selected from the group consisting of fluorine, chlorine, bromine or iodine.