Trihydroxy polyunsaturated eicosanoid derivatives
The invention features methods for the preparation of naturally occurring trihydroxy polyunsaturated eicosanoids and their structural analogs. The invention further provides new derivatives and analogs of trihydroxy polyunsaturated eicosanoids that can be prepared according to these methods. The invention also provides compositions and methods using trihydroxy polyunsaturated eicosanoid derivatives for the prevention, amelioration and treatment of a variety of diseases or conditions associated with inflammation or inflammatory response, autoimmune diseases, rheumatoid arthritis, cardiovascular diseases, or abnormal cell proliferation or cancer.
1. A method of ameliorating or treating a disease or condition associated with inflammation or an inflammatory response, the method comprising administering to a subject an effective amount of a compound having a structure of general formula 46:
wherein:
A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, or —OM, where M is a cation selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn;
R a and R b are independently selected from hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;
R 2 is hydrogen, alkyl, perfluoroalkyl, aryl or heteroaryl;
R 5 is selected from i)-iv) as follows:
i) CH 2 CH(R 6 )CH 2 , where R 6 is hydrogen, alkyl, perfluoroalkyl, aryl, heteroaryl, fluoro, hydroxy or alkoxy;
ii) CH 2 C(R 6 R 7 )CH 2 , where R 6 and R 7 are each independently alkyl, perfluoroalkyl, aryl, or fluoro, or R 6 and R 7 are connected together to form a carbocyclic or heterocyclic ring;
iii) CH 2 OCH 2 , CH 2 C(O)CH 2 , or CH 2 CH 2 ; and
iv) a carbocyclic, heterocyclic, aryl or heteroaryl ring; and
R 8 and R 9 are independently selected from hydrogen, alkyl, perfluoroalkyl, alkoxy, aryl and heteroaryl, or R 8 and R 9 are connected together to form a carbocyclic or heterocyclic ring.
2. The method of claim 1 , wherein R a and R b are independently selected from hydrogen, acyl, alkoxyacyl and aminoacyl.
3. The method of claim 1 , wherein the compound has a structure of general formula 44.
4. The method of claim 3 , wherein R a and R b are independently selected from hydrogen, acyl, alkoxyacyl and aminoacyl.
5. The method of claim 3 , wherein the compound has a structure of general formula 29,
6. The method of claim 5 , wherein R a and R b are each hydrogen and A is hydroxyl or alkoxy.
7. A method of ameliorating or treating a disease or condition associated with, inflammation or an inflammatory response, the method comprising administering to a subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having a structure of general formula 46:
wherein:
A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, or —OM, where M is a cation selected from ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn;
R a and R b are independently selected from hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;
R 2 is hydrogen, alkyl, perfluoroalkyl, aryl or heteroaryl;
R 5 is selected from i)-iv) as follows:
i) CH 2 CH(R 6 )CH 2 , where R 6 is hydrogen, alkyl, perfluoroalkyl, aryl, heteroaryl, fluoro, hydroxy or alkoxy;
ii) CH 2 C(R 6 R 7 )CH 2 , where R 6 and R 7 are each independently alkyl, perfluoroalkyl, aryl, or fluoro, or R 6 and R 7 are connected together to form a carbocyclic or heterocyclic ring;
iii) CH 2 OCH 2 , CH 2 C(O)CH 2 , or CH 2 CH 2 ; and
iv) a carbocyclic, heterocyclic, aryl or heteroaryl ring; and
R 8 and R 9 are independently selected from hydrogen, alkyl, perfluoroalkyl, alkoxy, aryl and heteroaryl, or R 8 and R 9 are connected together to form a carbocyclic or heterocyclic ring.
8. The method of claim 7 , wherein R a and R b are independently selected from hydrogen, acyl, alkoxyacyl and aminoacyl.
9. The method of claim 7 , wherein the compound has a structure of general formula 44,
10. The method of claim 9 , wherein R a and R b are independently selected from hydrogen, acyl, alkoxyacyl and aminoacyl.
11. The method of claim 9 , wherein the compound has a structure of general formula 29,
12. The method of claim 11 , wherein R a and R b are each hydrogen and A is hydroxyl or alkoxy.
13. The method of claim 12 , wherein A is hydroxyl.
14. The method of claim 12 , wherein A is alkoxy.
15. The method of claim 14 , wherein the alkyl group of the alkoxy is a branched chain alkyl group.
16. A method of ameliorating or treating a disease or condition associated with inflammatory response, the method comprising administering to a subject an effective amount of a compound having a structure of general formula 25,
wherein:
R a , R b , R 1 and R 2 are each hydrogen;
Q is —C(O)-A, where A is hydroxyl or alkoxy; and
Y and Z are carbon chains of up to 20 carbon atoms.
17. The method of claim 16 , wherein A is hydroxyl.
18. The method of claim 16 , wherein A is alkoxy.
19. The method of claim 18 , wherein the alkyl group of the alkoxy is a branched chain alkyl group.
20. The method of claim 16 , wherein Z is —CH 2 —.
21. The method of claim 16 , wherein Y is —CH 2 CH 2 CH 2 —.
22. The method of claim 16 , wherein A is hydroxyl; Z is —CH 2 —; and Y is —CH 2 CH 2 CH 2 —.
23. The method of claim 16 , wherein A is alkoxy; Z is —CH 2 —; and Y is —CH 2 CH 2 CH 2 —.
24. The method of claim 23 , wherein the alkyl group of the alkoxy is a branched chain alkyl group.
25. A method of ameliorating or treating a disease or condition associated with inflammation or an inflammatory response, the method comprising administering to a subject an effective amount of a compound having a structure of general formula 25:
wherein:
R a , R b , R 1 and R 2 are each hydrogen;
Q is —C(O)-A, where A is hydroxyl or alkoxy; and
Y and Z are carbon chains of up to 20 carbon atoms.
26. The method of claim 25 , wherein A is hydroxyl.
27. The method of claim 25 , wherein A is alkoxy.
28. The method of claim 27 , wherein the alkyl group of the alkoxy is a branched chain alkyl group.
29. The method of claim 25 , wherein Z is —CH 2 —.
30. The method of claim 25 , wherein Y is —CH 2 CH 2 CH 2 —.
31. The method of claim 25 , wherein A is hydroxyl; Z is —CH 2 —; and Y is —CH 2 CH 2 CH 2 —.
32. The method of claim 26 , wherein A is alkoxy; Z is —CH 2 —; and Y is —CH 2 CH 2 CH 2 —.
33. The method of claim 32 , wherein the alkyl group of the alkoxy is a branched chain alkyl group.
34. A method of ameliorating or treating a disease or condition associated with, inflammation or an inflammatory response, the method comprising administering to a subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having a structure of general formula 25:
wherein:
R a , R b , R 1 and R 2 are each hydrogen;
Q is —C(O)-A, where A is hydroxyl or alkoxy; and
Y and Z are carbon chains of up to 20 carbon atoms.
35. The method of claim 34 , wherein A is hydroxyl.
36. The method of claim 34 , wherein A is alkoxy.
37. The method of claim 36 , wherein the alkyl group of the alkoxy is a branched chain alkyl group.
38. The method of claim 34 , wherein Z is —CH 2 —.
39. The method of claim 34 , wherein Y is —CH 2 CH 2 CH 2 —.
40. The method of claim 34 , wherein A is hydroxyl; Z is —CH 2 —; and Y is —CH 2 CH 2 CH 2 —.
41. The method of claim 35 , wherein A is alkoxy; Z is —CH 2 —; and Y is —CH 2 CH 2 CH 2 —.
42. The method of claim 41 , wherein the alkyl group of the alkoxy is a branched chain alkyl group.