Synthesis of new pyrrolo [1,2-c] thiazole derivatives as potent and specific PAF-antagonists

PROSTAGLANDINS

SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP OF 2,5-DIARYLTETRAHYDROFURANS AS PAF ANTAGONISTS

Biftu. T., Chabala, J.C., Acton, J., Beattie, T., Brooker, D., Bugianesi, R., Chang, M.N., Chiang, P.C., Gamble, N., Girotra, N., Graham, D., Kuo, C.H., Ponpipom, M., Sahoo, S., Shen, T.Y., Thompson, K.L., Yang, S.S., Hwang, S.-B., and Doebber, T. Merck and Co.,P.O.Box 2000, Rahway,

NJ 07065

The natural product veraguensin 1 was found to inhibit the binding of ‘H-PAF to a specific receptor site on rabbit platelet membrane preparations UC50 1.1 uM). This led to the synthesis of all possible isomers of veraguensin and new analogs of 2,5diaryltetrahydrofurans such as L-652,731 2 UC50 19 nM). Further investigation led to the preparation of additional new unsymmetrical analogs such as L-659,989 3 UC nM). The synthesis and structure-activity relationship of these compounds wrl fob: discussed.

r

SYNTHESIS OF REW PYRROUI fi,2-c7

2 R=OCH , Rl=CH 1 R=S02C&3, R1=Ch2CH2CH3

THIAZOLE DERIVATIVES AS POTENT AND SPECIFIC

PAF-ANTAGONISTS. La& D. , James C., Fabre J.L., Floch A. et Robaut C., RhBnePoulenc San&, Centre de Recherches de Vitry, 13, quai Jules Guesde, HP14, 94403, Vitry-sur-Seine Cedex, France. Following the discovery of the anti-PAF activity of 48 740 RP, more potent and specific PAF antagonists were prepared in this pyrrolo fi,Z-c1 thiazole series. 52770 RP was synthetised and its 3H-labelled derivative was characterised as a ligand for PAF-receptor sites. Moreover, structure-activity relationshdiips:led us to the design of a new very potent and specific PAF antagonist, 59227 RP [(+)-N-(3_benzoylphenyl)3-(3-pyridinyl) lH,3H-pyrrolo 0,2-c-7 thiazole-7-carboxamide].

48740

RP

4)

52770

RP

(*)

59227

RP

(+I

-R=-H

CONH-R

846

MAY

1988 VOL.

35 NO. 5