Resolvins: Biotemplates for novel therapeutic interventions

• US 7,585,856 B2
• Filed: 08/12/2003
• Issued: 09/08/2009
• Est. Priority Date: 08/12/2002
• Status: Expired due to Term

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Serhan, Charles N.
• Primary Examiner(s): Carr; Deborah D
• Application Number:
  US10/639,714
• Publication Number:
  US 20040116408A1
• Time in Patent Office: 2,219 Days
• Field of Search: 554/35, 554/227, 564/74, 568/38, 568/448, 546/184
• US Class Current: 514/218
• CPC Class Codes: A61K 31/202 having three or more double bonds, e.g. linolenic eicosanoids, e.g. leukotrienes A61K31/557
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 59/42 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 59/48 containing six-membered aromatic rings
• CPC Class Codes: C07C 69/732 of unsaturated hydroxy carboxylic acids
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

The present invention is generally drawn to novel isolated therapeutic agents, termed resolvins, generated from the interaction between a dietary omega-3 polyunsaturated fatty acid (PUFA) such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), cyclooxygenase-II (COX-2) and an analgesic, such as aspirin (ASA). Surprisingly, careful isolation of compounds generated from the combination of components in an appropriate environment provide di- and tri-hydroxy EPA or DHA compounds having unique structural and physiological properties. The present invention therefore provides for many new useful therapeutic di- or tri-hydroxy derivatives of EPA or DHA (resolvins) that diminish, prevent, or eliminate inflammation or PMN migration, for example. The present invention also provides methods of use, methods of preparation, and packaged pharmaceuticals for use as medicaments for the compounds disclosed throughout the specification.

Claims

1. A purified compound having the formula:

2. The compound of claim 1 wherein P₁ and P₂ are hydrogen atoms and Z is carboxylic acid or a carboxylic ester.

7. The compound of claim 1, wherein the C-7 carbon has an S configuration.

8. The compound of claim 1, wherein the C-17 carbon has an R configuration.

9. The compound of claim 1, wherein the C-7 carbon has an S configuration and the C-17 carbon has an R configuration.

10. The compound of claim 7, wherein P₁ is a hydrogen atom.

11. The compound of claim 8, wherein P₂ is a hydrogen atom.

12. The compound of claim 9, wherein P₁ and P₂ are both hydrogen atoms.

20. The compound of claim 1, 3, 5, wherein Z is —

C(O)OR^d, —

C(O)NR^cR^c, —

C(NH)NR^cR^c, —

C(S)OR^d, —

C(S)NR^cR^c, or —

CN.

21. The compound of claim 20, wherein Z is —

C(O)OR^d, —

C(O)NR^cR^c, —

C(NH)NR^cR^c, or —

CN.

22. The compound of claim 20, wherein each R^b is independently selected from ═

O, —

OR^d, (C1-C3) haloalkyloxy, —

OCF₃, ═

S, —

SR^d, ═

NR^d, ═

NOR^d, —

NR^cR^c, halogen, —

CF₃, —

CN, —

NO₂, —

S(O)R^d, —

S(O)₂R^d, —

S(O)₂OR^d, —

S(O)NR^cR^c, —

S(O)₂NR^cR^c, —

OS(O)R^d, —

OS(O)₂R^d, —

OS(O)₂OR^d, —

OS(O)₂NR^cR^c, —

C(O)R^d, —

C(O)OR^d, —

C(O)NR^cR^c, —

C(NH)NR^cR^c, —

C(NR^a)NR^cR^c, —

C(NOH)R^a, —

C(NOH)NR^cR^c, —

OC(O)R^d, —

OC(O)OR^d, —

OC(O)NR^cR^c, —

OC(NH)NR^cR^c, —

OC(NR^a)NR^cR^c, —

[NHC(O)]_nR^d, —

[NR^aC(O)]_nR^d, —

[NHC(O)]_nOR^d, —

[NR^aC(O)]_nOR^d, —

[NHC(O)]_nNR^cR^c, —

[NR^aC(O)]_nNR^cR^c, —

[NHC(NH)]_nNR^cR^c or —

[NR^aC(NR^a)]_nNR^cR^c, and n is 0 or 1.

23. The compound of claim 20, wherein each R^b is independently selected from ═

O, —

OR^d, —

OCF₃, ═

S, —

SR^d, ═

NR^d, —

NR^cR^c, halogen, —

CF₃, —

CN, —

NO₂, —

S(O)R^d, —

S(O)₂R^d, —

S(O)₂OR^d, —

S(O)NR^cR^c, —

S(O)₂NR^cR^c, —

OS(O)R^d, —

OS(O)₂R^d, —

OS(O)₂OR^d, —

OS(O)₂NR^cR^c, —

C(O)R^d, —

C(O)OR^d, —

C(O)NR^cR^c, —

OC(O)R^d, —

OC(O)OR^d, —

OC(O)NR^cR^c, —

[NHC(O)]_nR^d, —

[NR^aC(O)]_nR^d, —

[NHC(O)]_nOR^d, —

[NR¹C(O)]_nOR^d, —

[NHC(O)]_nNR^cR^c, —

[NR^aC(O)]_nNR^cR^c, or —

[NHC(NH)]_nNR^cR^c.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1, 3, or 5.

25. A method of reducing TNF-induced cytokine production, comprising administering to a patient a compound of claim 1, 3, or 5.

26. The method of claim 25, wherein the reduced TNF-induced cytokine production is associated with arterial inflammation, neuronal inflammation, arthritis, psoriasis, urticaria, vasculitis, asthma, ocular inflammation, pulmonary inflammation, pulmonary fibrosis, seborrheic dermatitis, pustular dermatosis, or cardiovascular inflammation.

27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 23.

28. A method of reducing TNF-induced cytokine production, comprising administering to a patient a compound of claim 23.

29. The method of claim 28, wherein the reduced TNF-induced cytokine production is associated with arterial inflammation, neuronal inflammation, arthritis, psoriasis, urticaria, vasculitis, asthma, ocular inflammation, pulmonary inflammation, pulmonary fibrosis, seborrheic dermatitis, pustular dermatosis, or cardiovascular inflammation.

33. A method of reducing PMN transmigration and recruitment, comprising administering to a patient a compound of claim 1, 3, or 5.

34. The method of claim 33, wherein the reduction of the PMN transmigration and recruitment is associated with arterial inflammation, neuronal inflammation, arthritis, psoriasis, urticaria, vasculitis, asthma, ocular inflammation, pulmonary inflammation, pulmonary fibrosis, seborrheic dermatitis, pustular dermatosis, or cardiovascular inflammation.

35. A method of reducing PMN transmigration and recruitment, comprising administering to a patient a compound of claim 23.

36. The method of claim 35, wherein the reduction of PMN transmigration and recruitment is associated with arterial inflammation, neuronal inflammation, arthritis, psoriasis, urticaria, vasculitis, asthma, ocular inflammation, pulmonary inflammation, pulmonary fibrosis, seborrheic dermatitis, pustular dermatosis, or cardiovascular inflammation.

3. A purified compound having the formula:

4. The compound of claim 3, wherein P₁, P₂ and P₃ each are hydrogen atoms and Z is a carboxylic acid or a carboxylic ester.

13. The compound of claim 3, wherein the C-7 carbon has an S configuration.

14. The compound of claim 3, wherein the C-17 carbon has an R configuration.

15. The compound of claim 3, wherein the C-7 carbon has an S configuration and the C-17 carbon has an R configuration.

16. The compound of claim 13, wherein P₁ is a hydrogen atom.

17. The compound of claim 14, wherein P₂ is a hydrogen atom.

18. The compound of claim 15, wherein P₁ and P₂ are both hydrogen atoms.

19. The compound of claim 18, wherein P₃ is a hydrogen atom.

5. A purified compound having the formula:

6. The compound of claim 5, wherein P₁ is a hydrogen atom, X is an oxygen, and Z is a carboxylic acid or a carboxylic ester.

30. A compound having the formula:

31. A compound having the formula:

32. A compound having the formula: