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 compound of the general formula
wherein:
A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, or -OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, Na, K, Mg, and Zn; and
R a and R b are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, silyl, alkoxyacyl and aminoacyl;
R 2 is hydrogen, alkyl, perfluoroalkyl, aryl and heteroaryl;
R 5 is selected from the group consisting of (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) R 5 is a carbocyclic, heterocyclic, aryl or heteroaryl ring; and
R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, perfluoroalkyl, alkoxy, aryl and heteroaryl, or R 8 and R 9 are connected together to form a carbocyclic or heterocyclic ring.