Use of chloroquine and clemizole compounds for treatment of inflammatory and cancerous conditions

• US 10,688,083 B2
• Filed: 06/30/2016
• Issued: 06/23/2020
• Est. Priority Date: 06/30/2015
• Status: Active Grant

• Current Assignee: Eiger Group International, Inc.
• Original Assignee: Eiger Group International, Inc.
• Inventors: Glenn, Jeffrey S., Pham, Edward A.
• Primary Examiner(s): Valenrod, Yevgeny
• Application Number:
  US15/738,827
• Publication Number:
  US 20180200228A1
• Time in Patent Office: 1,454 Days
• Field of Search: 514313
• 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 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/4706 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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: C07D 215/46 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
• CPC Class Codes: C07D 235/14 Radicals substituted by nitrogen atoms by nitro radicals C07D235/10

Abstract

Disclosed herein are methods for use of R-chloroquine or clemizole or combinations of R-chloroquine and clemizole for the treatment of a subject in need thereof. Uses include methods of treating inflammatory′ conditions, treating liver cancer or reducing the risk of developing liver cancer in a subject. Uses also include methods of treating non-alcoholic steatohepatitis in a subject.

Claims

1. A method of treating a subject who has been diagnosed with liver cancer, comprising:

administering to the subject an effective amount of clemizole, a deuterated analog of clemizole, or a clemizole metabolite; and

a chemotherapeutic agent.

2. The method of claim 1, wherein the liver cancer is hepatocellular carcinoma.

3. The method of claim 1, wherein the result of the treatment is shrinking the tumor, inhibiting growth of the tumor, increasing time to progression of the tumor, prolonging disease-free survival of the subject, decreasing metastases, increasing the progression-free survival of the subject, or increasing overall survival of the subject.

4. The method of claim 1, further comprising administering to the subject an effective amount of an anti-viral drug, wherein the anti-viral drug is an interferon, a nucleoside analog, a direct acting antiviral, interferon alfa-2b, Peginterferon alfa-2a, entecavir, lamivudine, adefovir, telbivudine, tenofovir, sofosbuvir, ledipasvir, ombitasvir, paritaprevir, ritonavir, dasabuvir, grazoprevir, elbasvir, asunaprevir, daclatasvir, or beclabuvir.

5. The method of claim 1, further comprising administering an effective amount of an inhibitor of CYP3A4.

6. The method of claim 1, wherein the chemotherapeutic agent is selected from the group consisting of:

an alkylating agent, an anti-metabolite, an immunotherapy, a cancer vaccine, an antibody, a kinase inhibitor, an angiogenesis inhibitor, an anti-tumor antibiotic, a topoisomerase inhibitor, a hormonal therapy, a mitotic inhibitor, a nitrogen mustard, a tyrosine kinase inhibitor, an anti-microtubule agent, a histone deacetylase inhibitor, a proteasome inhibitor, and a photodynamic therapy agent.

37. The method of any one of claim 1, 7, 18, or 19, wherein the subject is administered clemizole.

7. A method of treating a subject who has been diagnosed with liver cancer, comprising:

administering to the subject an effective amount of clemizole, a deuterated analog of clemizole, or a clemizole metabolite,

wherein the effective amount is 200-500 mg administered once daily, twice daily, or thrice daily.

8. The method of claim 7, wherein the liver cancer is hepatocellular carcinoma.

9. The method of claim 7, wherein the result of the treatment is shrinking the tumor, inhibiting growth of the tumor, increasing time to progression of the tumor, prolonging disease-free survival of the subject, decreasing metastases, increasing the progression-free survival of the subject, or increasing overall survival of the subject.

10. The method of claim 7, further comprising administering to the subject an effective amount of an anti-viral drug, wherein the anti-viral drug is an interferon, a nucleoside analog, a direct acting antiviral drug, interferon alfa-2b, Peginterferon alfa-2a, entecavir, lamivudine, adefovir, telbivudine, tenofovir, sofosbuvir, ledipasvir, ombitasvir, paritaprevir, ritonavir, dasabuvir, grazoprevir, elbasvir, asunaprevir, daclatasvir, or beclabuvir.

11. The method of claim 7, wherein the effective amount is at least 200 mg administered once daily, twice daily, or thrice daily.

12. The method of claim 7, wherein the effective amount is at least 300 mg administered once daily, twice daily, or thrice daily.

13. The method of claim 7, wherein the effective amount is at least 400 mg administered once daily, twice daily, or thrice daily.

14. The method of claim 7, wherein the effective amount is at least 500 mg administered once daily or no more than thrice daily.

15. The method of claim 7, wherein clemizole, the deuterated analog of clemizole, or the clemizole metabolite is administered for greater than 2 months.

16. The method of claim 7, wherein clemizole, the deuterated analog of clemizole, or the clemizole metabolite is administered for greater than 3 months.

17. The method of claim 7, wherein clemizole, the deuterated analog of clemizole, or the clemizole metabolite is administered for greater than 4 months.

18. A method of treating a subject who has been diagnosed with liver cancer, comprising:

administering to the subject an effective amount of clemizole, a deuterated analog of clemizole, or a clemizole metabolite.

19. A method of preventing liver cancer development in a subject at risk for developing liver cancer, comprising:

administering to the subject an effective amount of clemizole, a deuterated analog of clemizole, or a clemizole metabolite,

wherein the subject has been diagnosed with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), Hepatitis B infection, or cirrhosis of the liver.

20. The method of claim 19, wherein said liver cancer is hepatocellular carcinoma.

21. The method of claim 19, wherein the subject has been diagnosed with NASH.

22. The method of claim 19, wherein the subject has been diagnosed with NAFLD.

23. The method of claim 19, wherein the result of said prevention is prolonging the period of cancer-free survival or overall survival.

24. The method of claim 19, further comprising administering to said subject an effective amount of an anti-viral drug, wherein the anti-viral drug comprises an interferon, a nucleoside analog, a direct acting antiviral, interferon alfa-2b, Peginterferon alfa-2a, entecavir, lamivudine, adefovir, telbivudine, tenofovir, sofosbuvir, ledipasvir, ombitasvir, paritaprevir, ritonavir, dasabuvir, grazoprevir, elbasvir, asunaprevir, daclatasvir, or beclabuvir.

25. The method of claim 19, wherein the effective amount is 200-500 mg administered once daily, twice daily, or thrice daily.

26. The method of claim 19, wherein the effective amount is at least 200 mg administered once daily, twice daily, or thrice daily.

27. The method of claim 19, wherein the effective amount is at least 300 mg administered once daily, twice daily, or thrice daily.

28. The method of claim 19, wherein the effective amount is at least 400 mg administered once daily, twice daily, or thrice daily.

29. The method of claim 19, wherein the effective amount is at least 500 mg administered once daily, twice daily, or thrice daily.

30. The method of claim 19, wherein clemizole, the deuterated analog of clemizole, or the clemizole metabolite is administered for greater than 2 months.

31. The method of claim 19, wherein clemizole, the deuterated analog of clemizole, or the clemizole metabolite is administered for greater than 3 months.

32. The method of claim 19, wherein clemizole, the deuterated analog of clemizole, or the clemizole metabolite is administered for greater than 4 months.

33. The method of claim 19, wherein clemizole, the deuterated analog of clemizole, or the clemizole metabolite is administered for greater than 5 months.

34. The method of claim 19, further comprising administering an effective amount of an inhibitor of CYP3A4.

35. The method of claim 19, wherein the subject has been diagnosed with Hepatitis B infection.

36. The method of claim 19, wherein the subject has been diagnosed with cirrhosis of the liver.