Improved synthetic routes to the novel thromboxane receptor antagonist ICI 192605: activity of synthetic 1,3-dioxane intermediates.
A study of the synthetic routes to the thromboxane receptor antagonist ICI 192605 4(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl) hexenoic acid is described which led to an improvement in overall synthetic yield from 20 to 55%. Invitro thromboxane receptor antagonist data are reported for the novel 1,3-dioxane synthetic intermediates. These data indicated that shortening of the side chain in an appropriately substituted 2,2-dimethyl-1,3-dioxane (e.g. ICI 180080) from a heptenoic acid, to a hexenoic acid, had little effect on thromboxane receptor antagonist potency (pA2 = 7.5 rabbit thoracic aorta for the heptenoic acid ICI 180080 and pA2 = 6.9 for the corresponding hexenoic acid. Human platelet aggregation pA2 values were 6.7 and 7.0, respectively).
Brown
G R
GR
ICI Pharmaceuticals, Macclesfield, Cheshire, UK.
Foubister
A J
AJ
Hudson
J A
JA
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004146:Dioxanes / Q000138:chemical synthesis*; D004147:Dioxins / Q000138:chemical synthesis*; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D011817:Rabbits; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D017482:Receptors, Thromboxane
D004146:Dioxanes; D004147:Dioxins; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C057498:ICI 192605; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid