Triptolide Analogs for the Treatment of Autoimmune and Inflammatory Disorders

• US 20090234000A1
• Filed: 05/29/2009
• Published: 09/17/2009
• Est. Priority Date: 10/02/2000
• Status: Active Grant

• Current Assignee: Dennis C. Liotta, Hariharan Venkatesan, James P. Snyder, Susheng Wang
• Original Assignee: Dennis C. Liotta, Hariharan Venkatesan, James P. Snyder, Susheng Wang
• Inventors: Venkatesan, Hariharan, Snyder, James P., Liotta, Dennis C., Wang, Susheng
• Granted Patent: US 8,193,249 B2
• Time in Patent Office: Days
• US Class Current: 514/475
• 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 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 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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 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: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 37/002 : by transformation of a functional group, e.g. oxo, carboxyl
• CPC Class Codes: C07C 39/11 : Alkylated hydroxy benzenes containing also acyclically bound hydroxy groups, e.g. saligenol
• CPC Class Codes: C07C 39/17 : containing other rings in addition to the six-membered aromatic rings , e.g. cyclohexylphenol
• CPC Class Codes: C07C 45/46 : Friedel-Crafts reactions
• CPC Class Codes: C07C 47/565 : all hydroxy groups bound to the ring
• CPC Class Codes: C07D 303/04 : containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
• CPC Class Codes: C07D 303/14 : by free hydroxyl radicals
• CPC Class Codes: C07D 303/32 : by aldehydo- or ketonic radicals
• CPC Class Codes: C07D 493/10 : Spiro-condensed systems

Abstract

The present invention provides synthetic methods and compositions for treatment of autoimmune and anti-inflammatory disorders comprising administering an effective amount of a derivative of triptolide alone or in combination or alternation with other anti-autoimmune or anti-inflammatory compounds.

Claims

1-22. -22. (canceled)

23. A compound of the formula (II), (IV) or (III):

or its pharmaceutically acceptable salt or prodrug thereof, wherein;

(a) the dotted line indicates the presence of either a single or double bond, wherein the valences of a single bond are completed by hydrogens;

(b) A, B, D and E are O; and

R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, alkaryl, arylalkyl.

24. The compound of claim 23, wherein the compound has the formula (II).

25. The compound of claim 23, wherein the compound has the formula (IV).

26. The compound of claim 23, wherein the compound has the Formula (III).

27. The compound of claim 23, wherein the compound has the formula (II);

and

R¹ is t-butyl, isopentyl, neopentyl, isohexyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, cycloalkyl, aryl, alkylaryl or arylalkyl.

28. The compound of claim 23, wherein the compound has the formula (IV);

and

R¹ is t-butyl, isopentyl, neopentyl, isohexyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, cycloalkyl, aryl, alkylaryl or arylalkyl.

29. The compound of claim 23, wherein the compound has the formula (III);

and

R¹ is t-butyl, isopentyl, neopentyl, isohexyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, cycloalkyl, aryl, alkylaryl or arylalkyl.

30. The compound of claim 23 wherein R⁵ and R⁶ are independently hydrogen, or alkyl.

31. The compound of claim 23 wherein R² is hydrogen or alkyl.

32. The compound of claim 23 wherein R¹ and R⁴ are independently alkyl, alkenyl or alkynyl.

33. The compound of claim 23 wherein alkyl is substituted with hydroxyl, alkoxy, carboxyl, acyl, acyloxy, amino, amido, alkylamino, dialkylamino, thiol, sulfonyl, sulfate or phosphate.

34. The compound of claim 23, wherein alkyl is substituted with hydroxyl or amino.

35. The compound of claim 23 wherein:

R¹, R², R³ and R⁴ are independently hydrogen or alkyl; and

R⁵ and R⁶ are hydrogen.

36. The compound of claim 35, wherein R² and R³ are hydrogen.

37. The compound of claim 35, wherein R² is alkyl and R³ is hydrogen.

38. The compound of claim 35, wherein R¹ and R⁴ are alkyl;

and R₂ and R₃ are hydrogen.

39. The compound of claim 35, wherein R¹, R² and R⁴ are alkyl;

and R₃ is hydrogen.

40. The compound of claim 35, wherein R¹ t-butyl;

R⁴ is methyl; and

R² and R³ are hydrogen or methyl.

41. A pharmaceutical composition comprising the compound of claim 23 in combination with a pharmaceutically acceptable carrier.

42. The pharmaceutical composition of claim 41 in combination with another active agent.