Use of docosatrienes, resolvins and their stable analogs in the treatment of airway diseases and asthma

• US 7,872,152 B2
• Filed: 08/09/2007
• Issued: 01/18/2011
• Est. Priority Date: 08/12/2002
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Levy, Bruce D., Serhan, Charles N.
• Primary Examiner(s): Puttlitz; Karl J
• Application Number:
  US11/836,460
• Publication Number:
  US 20080096961A1
• Time in Patent Office: 1,258 Days
• Field of Search: None
• US Class Current: 560/205
• CPC Class Codes: A61K 31/202 having three or more double bonds, e.g. linolenic eicosanoids, e.g. leukotrienes A61K31/557
• CPC Class Codes: A61K 31/275 Nitriles; Isonitriles
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/537 spiro-condensed or forming part of bridged ring systems
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory 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: C07C 59/42 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 59/48 containing six-membered aromatic rings
• 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 resolving, 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. An isolated compound of the formula:

2. The compound of claim 1, wherein Z is a carboxylic acid, ester, amide, thiocarbamate, carbamate, thioester, thiocarboxamide, or a nitrile.

3. The compound of claim 1, wherein the configuration at C10 is (R/S).

4. The compound of claim 3, wherein P₁ is —

CH₃.

5. The compound of claim 1, wherein the configuration at C17 is (S).

6. The compound of claim 1, wherein the double bond configurations are 4Z,7Z,11E,13,15E,19Z.

7. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

8. A method of treating an individual suffering from or susceptible to a disease or condition characterized by inflammation, comprising the step of administering to the individual in need thereof a composition of claim 7.

17. The compound of claim 1, wherein P₁ and P₂ are each H.

19. The compound of claim 1, wherein Z is COOR^a, wherein R^a is hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, or (C6-C16) arylalkyl.

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

23. The compound of claim 1, wherein the C-10 carbon atom has an S configuration and the carbon atom at C-17 has an S configuration.

25. The compound of claim 1, wherein the C-10 carbon atom has an R configuration and the carbon atom at C-17 has an S configuration.

27. The compound of claim 1, wherein the compound has the structure:

9. A compound of the formula:

10. The compound of claim 9, wherein Z is a carboxylic ester, amide, thiocarbamate, carbamate, thioester, thiocarboxamide, or a nitrile.

11. The compound of claim 9, wherein the configuration at C10 is (R/S).

12. The compound of claim 11, wherein P₁ is —

CH₃.

13. The compound of claim 9, wherein the configuration at C17 is (S).

14. The compound of claim 9, wherein the double bond configurations are 4Z,7Z,11E,13,15E,19Z.

15. A composition comprising a compound of claim 9 and a pharmaceutically acceptable carrier.

16. A method of treating an individual suffering from or susceptible to a disease or condition characterized by inflammation, comprising the step of administering to the individual in need thereof a composition of claim 15.

18. The compound of claim 9, wherein P₁ and P₂ are each H.

20. The compound of claim 9, wherein Z is COOR^a, wherein R^a is (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, or (C6-C16) arylalkyl.

22. The compound of claim 9, wherein the carbon atom at C-17 has an R configuration.

24. The compound of claim 9, wherein the C-10 carbon atom has an S configuration and the carbon atom at C-17 has an S configuration.

26. The compound of claim 9, wherein the C-10 carbon atom has an R configuration and the carbon atom at C-17 has an S configuration.