Triptolide analogs for the treatment of autoimmune and inflammatory disorders

• US 6,777,441 B2
• Filed: 10/02/2001
• Issued: 08/17/2004
• Est. Priority Date: 10/02/2000
• Status: Expired due to Term

• Current Assignee: Emory University
• Original Assignee: Emory University
• Inventors: Venkatesan, Hariharan, Snyder, James P., Wang, Susheng, Liotta, Dennis C.
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US09/970,089
• Publication Number:
  US 20030027806A1
• Time in Patent Office: 1,050 Days
• Field of Search: 549/336, 514/475
• 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. A compound of the formula (V):

or its pharmaceutically acceptable salt thereof, wherein;

(a) B, D and E are independently O;

(b) G is OR¹¹, NR¹¹R¹² or SR¹¹;

(c) R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, arylalkyl;

a moiety selected from optionally substituted furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, and imidazole; and

(d) each R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, arylalkyl;

a moiety selected from optionally substituted furyl furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, and imidazole.

2. A pharmaceutical composition for the treatment of an inflammatory disorder in a host comprising an effective treatment amount of a compound according to claim 1 in a pharmaceutically acceptable carrier or diluent.

5. The pharmaceutical composition of claim 2, or 4, wherein the host is a human.

6. The pharmaceutical composition of claim 2, or 4, wherein the compound is in the form of a dosage unit.

7. The pharmaceutical composition according to claim 6, wherein the dosage unit contains 7 to 3000 mg of the compound.

8. The pharmaceutical composition according to claim 6, wherein the dosage unit contains 70 to 1400 mg of the compound.

9. The pharmaceutical composition according to claim 6, wherein the dosage unit contains 50-500 mg of the compound.

27. The compound of claim 1 wherein G is OR¹¹.

28. The compound of claim 1 wherein G is NR¹¹R¹².

29. The compound of claim 1 wherein G is SR¹¹.

30. The compound of claim 1 wherein at least one of R¹, R², R³, R⁴, R⁵ and R⁶ is an alkyl group.

31. The compound of claim 1 wherein at least one of R¹, R², R³, R⁴, R⁵ and R⁶ is an alkenyl group.

32. The compound of claim 1 wherein at least one of R¹, R², R³, R⁴, R⁵ and R⁶ is an alkynyl group.

33. The compound of claim 1 wherein at least one of R¹, R², R³, R⁴, R⁵ and R⁶ is an aryl group.

34. The compound of claim 1 wherein at least one of R¹, R², R³, R⁴, R⁵ and R⁶ is an alkaryl group.

35. The compound of claim 1 wherein at least one of R¹, R², R³, R⁴, R⁵ and R⁶ is an arylalkyl group.

36. The compound of claim 1 wherein R⁷, R⁵, R⁹, R¹⁰, R¹¹ and R¹² are all hydrogen.

37. The compound of claim 1 wherein at least one of R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is an alkyl group.

38. The compound of claim 1 wherein at least one of R⁷, R⁸, R⁹, R¹⁰, R¹¹ and is an alkenyl group.

39. The compound of claim 1 wherein at least one of R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is an alkynyl group.

40. The compound of claim 1 wherein at least one of R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is an aryl group.

41. The compound of claim 1 wherein at least one of R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is an alkaryl group.

42. The compound of claim 1 wherein at least of R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is an arylalkyl group.

3. A compound of formula:

or its pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition for the treatment of an inflammatory disorder in a host comprising an effective treatment amount of a compound of formula:

or its pharmaceutically acceptable salt thereof, wherein;

(a) B, D and E are independently O;

(b) G is OR¹¹, N¹¹R¹² or SR¹¹;

(c) R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, arylalkyl;

a moiety selected from optionally substituted furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, and imidazole and

 

each R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, arylalkyl;

a moiety selected from optionally substituted furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl thiophene, furan, pyrrole, isopyrrole, pyrazole, and imidazole;

in a pharmaceutically acceptable carrier in combination with other anti-inflammatory agents.

10. The pharmaceutical composition according to claim 4, wherein the dosage unit is a tablet or capsule.

11. The pharmaceutical composition according to claim 4, wherein the anti-inflammatory agent is selected from the group consisting of heparin, frusemide, ranitidine, an agent that effects respiratory function, immunosuppressive agents, IV gamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold compounds, platelet activating factor (PAF), leukotriene-D₄-receptor antagonists), Ziflo (zileuton), leukotriene C₁ or C₂ antagonists and inhibitors of leukotriene synthesis, and an inducible nitric oxide synthase inhibitor.

12. The pharmaceutical composition of claim 4, the anti-inflammatory agent is selected from the group consisting β

₂-adrenergic agonist (β

agonists).

13. The pharmaceutical composition of claim 12, wherein the β

agonist is selected from the group consisting of albuterol (salbutamol, Proventil, Ventolin), terbutaline, Maxair (pirbuterol), Serevent (salmeterol), epinephrine, metaproterenol (Alupent, Metaprel), Brethine (Bricanyl, Brethaire, terbutaline sulfate), Tornalate (bitolterol), isoprenaline, ipratropium bromide, bambuterol hydrochloride, bitolterol meslyate, broxaterol, carbuterol hydrochloride, clenbuterol hydrochloride, clorprenaline hydrochloride, efirmoterol fumarate, ephedra (source of alkaloids), ephedrine (ephedrine hydrochloride, ephedrine sulfate), etafedrine hydrochloride, ethylnoradrenaline hydrochloride, fenoterol hydrochloride, hexoprenaline hydrochloride, isoetharine hydrochloride, isoprenaline, mabuterol, methoxyphenamine hydrochloride, methylephedrine hydrochloride, orciprenaline sulphate, phenylephrine acid tartrate, phenylpropanolamine (phenylpropanolamine polistirex, phenylpropanolamine sulphate), pirbuterol acetate, procaterol hydrochloride, protokylol hydrochloride, psuedoephedrine (psuedoephedrine polixtirex, psuedoephedrine tannate, psuedoephedrine hydrochloride, psuedoephedrine sulphate), reproterol hydrochloride, rimiterol hydrobromide, ritodrine hydrochloride, salmeterol xinafoate, terbutaline sulphate, tretoquinol hydrate and tulobuterol hydrochloride.

14. The pharmaceutical composition according claim 4, wherein the anti-inflammatory agent is selected from the group consisting of a corticosteroid, antihistamine (H₁ receptor antagonists), xanthines and methylxanthines, anticholinergic agents (antimuscarinic agents), and phosphodiesterase inhibitors.

15. A pharmaceutical composition for the treatment of an inflammatory disorder in a host comprising an effective treatment amount of a compound of formula:

or its pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier or diluent.

17. The pharmaceutical composition of claim 15 or 16, wherein the compound is in the form of a dosage unit.

18. The pharmaceutical composition of claim 17, wherein the dosage unit contains 7 to 3000 mg of the compound.

19. The pharmaceutical composition of claim 17, wherein the dosage unit contains 70 to 1400 mg of the compound.

20. The pharmaceutical composition of claim 17, wherein the dosage unit contains 50-500 mg of the compound.

21. The pharmaceutical composition of claim 17, wherein the dosage unit is a tablet or capsule.

26. The pharmaceutical composition of any one of claims 15 or 38, wherein the host is a human.

16. A pharmaceutical composition for the treatment of an inflammatory disorder in a host comprising an effective treatment amount of a compound of formula:

or a pharmaceutically acceptable salt thereof;

in a pharmaceutically acceptable carrier, in combination with another anti-inflammatory agent.

22. The pharmaceutical composition of claim 16, wherein the anti-inflammatory agent is selected from the group consisting of heparin, frusemide, ranitidine, an agent that effects respiratory function, immunosuppressive agents, IV gamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold compounds, platelet activating factor (PAF), leukotriene-D₄-receptor antagonists), Ziflo (zileuton), leukotriene C₁ or C₂ antagonists and inhibitors of leukotriene synthesis, and an inducible nitric oxide synthase inhibitor.

23. The pharmaceutical composition of claim 16, wherein the anti-inflammatory agent is selected from the group consisting β

₂-adrenergic agonist (β

agonists).

24. The pharmaceutical composition of claim 23, wherein the β

agonist is selected from the group consisting of albuterol (salbutamol, Proventil, Ventolin), terbutaline, Maxair (pirbuterol), Serevent (salmeterol), epinephrine, metaproterenol (Alupent, Metaprel), Brethine (Bricanyl, Brethaire, terbutaline sulfate), Tornalate (bitolterol), isoprenaline, ipratropium bromide, bambuterol hydrochloride, bitolterol meslyate, broxaterol, carbuterol hydrochloride, clenbuterol hydrochloride, clorprenaline hydrochloride, efirmoterol fumarate, ephedra (source of alkaloids), ephedrine (ephedrine hydrochloride, ephedrine sulfate), etafedrine hydrochloride, ethylnoradrenaline hydrochloride, fenoterol hydrochloride, hexoprenaline hydrochloride, isoetharine hydrochloride, isoprenaline, mabuterol, methoxyphenamine hydrochloride, methylephedrine hydrochloride, orciprenaline sulphate, phenylephrine acid tartrate, phenylpropanolamine (phenylpropanolamine polistirex, phenylpropanolamine sulphate), pirbuterol acetate, procaterol hydrochloride, protokylol hydrochloride, psuedoephedrine (psuedoephedrine polixtirex, psuedoephedrine tannate, psuedoephedrine hydrochloride, psuedoephedrine sulphate), reproterol hydrochloride, rimiterol hydrobromide, ritodrine hydrochloride, salmeterol xinafoate, terbutaline sulphate, tretoquinol hydrate and tulobuterol hydrochloride.

25. The pharmaceutical composition of claim 16, wherein the anti-inflammatory agent is selected from the group consisting of a corticosteroid, antihistamine (H₁ receptor antagonists), xanthines and methylxanthines, anticholinergic agents (antimuscarinic agents), and phosphodiesterase inhibitors.