Method of treating inflammatory arthritis

• US 20070027203A1
• Filed: 07/26/2006
• Published: 02/01/2007
• Est. Priority Date: 01/12/2004
• Status: Active Grant

• Current Assignee: Natrogen Therapeutics International, Inc.
• Original Assignee: Natrogen Therapeutics International, Inc.
• Inventors: Liu, Xiao Mei, Wang, Longgui, Chen, Ruihuan, Tsao, Allen, Mencher, Simon
• Granted Patent: US 7,855,223 B2
• Time in Patent Office: Days
• US Class Current: 514/414
• 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 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 25/16 : Anti-Parkinson drugs
• 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 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/14 : Decongestants or antiallergics
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/08 : for leprosy
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention is directed to a method for treating inflammatory arthritis in a mammal. The method typically comprises administering to an animal a therapeutically effective amount of at least one compound selected from indigo, isoindigo, indirubin or derivatives thereof, such as NATURA-α or NATURA. The present invention is further directed to pharmaceutical compositions that include a therapeutically effective amount of at least one compound of the invention, an anti-inflammatory arthritis agent and a pharmaceutically acceptable carrier.

Claims

1. A method of treating inflammatory arthritis comprising administering to an animal a therapeutically effective amount of at least one compound selected from the group consisting of:

indigo, isoindigo, indirubin or a derivative thereof, wherein the derivative thereof is formula (I), (II) or (III)

2. The method of claim 1, wherein the inflammatory arthritis involves inflammation of at least one joint in the animal.

3. The method of claim 2, wherein the arthritis is selected from the group consisting of:

rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and osteoarthritis.

4. The method of claim 3, wherein the arthritis is juvenile rheumatoid arthritis.

5. The method of claim 1, wherein the compound is administered prior to or during the induction phase of the inflammatory arthritis.

6. The method of claim 1, wherein the animal is diagnosed with inflammatory arthritis and the compound is administered in conjunction with an anti-inflammatory arthritis agent during the induction or later phase of the inflammatory arthritis.

7. The method of claim 6, wherein the anti-inflammatory arthritis agent is selected from the group consisting of:

an analgesic, a COX-2 inhibitor, a corticosteroid, non-steroidal anti-inflammatory drug (NSAID);

a disease modifying anti-rheumatic drug (DMARD); and

a biologic disease modifying anti-rheumatic drug (biologic DMARD).

8. The method of claim 7, wherein the anti-inflammatory arthritis agent is an analgesic selected from the group consisting of:

acetaminophen, aspirin, codeine, propoxyphene, fentanyl, palladone, morphine, morphine sulfate, oxycontin, aspirin, pentazocine, tramadol, hydrocodon, naproxen, indomethacin, ibuprofen, fenoprofen, ketorolac tromethamine, choline magnesium trisalicylate, and combinations thereof.

9. The method of claim 6, wherein the anti-inflammatory arthritis agent is selected from the group consisting of:

rofecoxib, valdecoxib, parecoxib, etoricoxib, celecoxib, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, salicylate, arylalkanoic acid, 2-arylpropionic acid, N-arylanthranilic acid, oxiam, coxib, sulphonanilide, hydroxychloroquine, chloroquine, leflunomide, methotrexate, sulfasalazine, gold, gold thiomalate, aurothioglucose, auranofin, azathioprine, cyclophosphamide, anti-TNF, etanercept, infliximab, and adalimumab, anti-IL-1, anti-CD20, anakinra, or combinations thereof.

10. The method of claim 1, wherein the animal is a human and the compound is administered orally, mucosally, parenterally, topically, or transdermally.

11. The method according to claim 10, wherein at least R₁ or R₂ is a tri-acetylated monosaccharide or a methyl group and administration of the compound is in an amount of 5 to 100 mg/day.

12. The method of claim 1, wherein administration of the compound is in an amount of 5 to 100 mg/kg/day in an oral formulation for a period of at least 45 days.

13. The method according to claim 1, the compound is selected from the group consisting of:

formulas (IV), (V), and (VI) respectively;

14. The method of claim 1, wherein the compound is N-methyl-Δ

3,3′

-dihydroindole-2,2′

diketone or 1-(β

-D-O-triacetyl-xylopranosyl)-isoindigo.

15. The method according to claim 1, wherein at least two compounds are administered concurrently or sequentially in an extended release formulation.

16. The method according to claim 1, wherein the compound is administered in a pharmaceutical composition comprising the compound, an anti-inflammatory arthritis agent, and a pharmaceutically acceptable carrier.

17. The method according to claim 1, wherein the compound is administered at a concentration sufficient to inhibit at least one cytokine selected from the group consisting of IL-1α

, β

, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, TNF-α

, LT, LIF, Oncostatin, or IFNc1α

, β

, γ

;

or stimulate expression of at least one cytokine selected from the group consisting of IL-4, IL-10, IL-11, W-13 or TGFβ

.

18. The method of claim 1, wherein the compound is administered in an amount sufficient to modulate cytokines TNF-α

, IL-1β

, IL-6, and IL-10.

19. The method of claim 1, wherein the compound is administered in an amount sufficient to modulate a humoral response in the animal being treated, resulting in a change in total IgG antibody in the animal.

20. The method of claim 19, wherein the modulation of total IgG antibody includes modulation of IgG2a, and IgG1 isotypes.

21. The method of claim 1, wherein the compound is administered in an amount sufficient to cause a shift in TH1 cell response to a TH2 cell response in the animal and the compound is administered for a period of at least 45 days.

22. The method of claim 1, wherein the compound is in an amount sufficient to modulate regulatory T cells.

23. The method of claim 22, wherein the regulatory T cell is a CD4+ CD25+Foxp3+ cell.

24. The method of claim 23, wherein the CD4+ CD25+Foxp3+ cell is in the spleen and/or the peripheral blood.

25. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group:

indigo, isoindigo, indirubin or derivatives thereof, an anti-inflammatory arthritis agent and a pharmaceutically acceptable carrier, wherein the derivative thereof is selected from formula (I), (II) or (III)

26. The composition of claim 25, wherein the anti-inflammatory arthritis agent is selected from the group consisting of:

an analgesic, a corticosteroid, non-steroidal anti-inflammatory drug (NSAID);

a disease modifying anti-rheumatic drug (DMARD); and

a biologic disease modifying anti-rheumatic drug (biologic DMARD).

27. The composition of claim 26, wherein the anti-inflammatory arthritis agent is selected from the group consisting of:

acetaminophen, aspirin, codeine, propoxyphene, fentanyl, palladone, morphine, morphine sulfate, oxycontin, aspirin, pentazocine, tramadol, hydrocodon, naproxen, indomethacin, ibuprofen, fenoprofen, ketorolac tromethamine, choline magnesium trisalicylate, rofecoxib, valdecoxib, parecoxib, etoricoxib, celecoxib, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, salicylate, arylalkanoic acid, 2-arylpropionic acid, N-arylanthranilic acid, oxiam, coxib, sulphonanilide, hydroxychloroquine, chloroquine, leflunomide, methotrexate, sulfasalazine, gold, gold thiomalate, aurothioglucose, auranofin, azathioprine, cyclophosphamide, anti-TNF, etanercept, infliximab, and adalimumab, anti-IL-1, anti-CD20, anakinra, or combinations thereof.

28. The composition of claim 25, wherein the compound is N-methyl-Δ

3,3′

-dihydroindole-2,2′

diketone or 1-(β

-D-O-Triacetyl-xylopranosyl)-isoindigo.