Norman Whittaker

Hydantoin prostaglandin analogues, potent and selective inhibitors of platelet aggregation

A series of biologically very active hydantoin prostaglandin analogues has been synthesised for which the relationship between potency and absolute stereochemistry has been elucidated.

Heterocyclic prostaglandin analogues. Part 3. The relationship of configuration to biological activity for some hydantoin prostaglandin analogues

The enantiomers of the two diastereoisomers of 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin have been synthesised. Potent inhibition of platelet aggregation in this series is associated with the configuration corresponding to that in the natural inhibitors, such as prostaglandins E1 and D2.

Heterocyclic prostaglandin analogues. Part 2. Hydantoins and other imidazole analogues

The stable hydantoin prostaglandin analogues (2b) and (3b) have been synthesised as racemic compounds. The less polar diastereoisomer of (2b) is a potent inhibitor of platelet aggregation in human platelet-rich plasma and its cyclohexyl analogue (22, R = C6H11) has ca. 14 times the potency of prostaglandin E1 in this test coupled with selectivity of biological action. Other structural modifications such as introduction of a 15-methyl group and insertion of the m-phenylene or m-oxaphenylene moieties into the acid side-chain of (2b) led to a reduction in anti-aggregatory potency. Synthesis of the imidazole (41) is described.

Heterocyclic prostaglandin analogues. Part 4. Piperazine-2,5-diones, pyrazolidine-3,5-diones, 1,2,4-triazolidinediones, 1,3,4-oxadiazolidinediones and 1,3,4-thiadiazolidinediones

Piperazinedione prostaglandin analogues (10) have been prepared from the previously described di-substituted glycine esters (8). The corresponding pyrazolidinediones (27) and triazolidinediones (30) were obtained by multi-step synthesis from ethyl carbazate (19)via the common intermediates (23). An oxadiazolidinedione (37) and a thiadiazolidinedione (40b) are also described. The piperazinedione (10c) and the triazolidinedione (30c) have ca. one-tenth of the anti-aggregatory potency of prostaglandin E1. Some structure–activity relationships have emerged.