15-Deoxy-16-hydroxy prostaglandins

It should be noted that the various 15-deoxy-16-hydroxy-prostaglandins prepared in the course of our studies consisted of two racemates ( 1 1 by NMR) epimeric at Cje which were not separable by TLC or HPLC. However, introduction of an allylic double bond (A or 16-vinyl) frequently made separation feasible. A 17-methyl group (4 racemates) also allowed separation into two components. Of necessity, the compounds were tested as the racemic mixture, although it is likely that biological activity largely resides with only one of the four diastereomers (40.56). 

The only other bronchodilator information available concerning this series of carboxylic acid equivalents is a report that PGEj and other carbinols (XV) (50,51) and 15-deoxy-16-hydroxy-prostaglandin carbinols will relax ginea pig trachea (131a). 

The same compound has also been used to prepare 11-deoxy-lla-hydroxy-methyl prostaglandin Es 239). 

Misoprostol, /la,13EH )-H,t6-Dihydroxy-16-methyl-9-oxoprost-13-en-I-oic acid methyl ester ( )-methyl -(1ft, 2 R, 3R)-3-hydroxy-2-[(E)-(4RS) -4 -hydroxy -4-methyl-1 octenyi]-5-oxocyclopentaneheptanoate ( )-15-deoxy (]6RS)-16-hydroxy.16-methy]-PGE] methyl ester SC 29333 Cytotec, C H Oj mol wt 332.54. C 69.08%, H 10.01%, O 20.91%. Cy to protective prostaglandin PGE, analog comprised of four stereoisomers in approximately equal proportions (the (+)- and (—)-enantiomers of Ihe I6R- and 16S-forms). Prepn P. W. Collins, R. Pappo,... 

The significance of the 11- and/or 15-hydroxy functions for bronchodilator activity is demonstrated in Table VI. Substantial activity clearly obtains in the 11-deoxy series, but the 15a-hy-droxy group apparently is an essential feature, although this requirement can be satisfied by a hydroxy group at Cje see section VIII F. Nevertheless it is noteworthy, that in the Konzett as well as other assays, even a primitive prostaglandin such as 11,15-bisdeoxy-PGEi produces a real PG-like effect, albeit with much diminished potency. 

The isosteric relationship of sulfur and vinylene has often been recognized, and on occasion an exchange of one for the other has provided analogs of interest. However, this concept has not proven useful in the prostaglandin series, the 13-thia derivatives (see Scheme 35) having less than 1% the activity of the parent A -15-deoxy-16-hydroxy (or A 3 i5 hy(jroxy) compound (91). 

BRONCHODILATOR ACTIVITY OF 15-DEOXY-16-HYDROXY-16-SUBSTITUTED PROSTAGLANDINS... 

The corresponding ll- -hydroxymethyl compound [113], as well as the 12-hydroxymethyl- [114], 9-hydroxymethyl- [115], and 9,11-dihydroxymethyl-[116], analogues have also been prepared and other ring substituted analogues include 10-hydroxy- [117,118], 10-hydroxy-11-deoxy- [119,120], 8-methoxy-carbonyl- [121] 10,11-methylene- [122] 10,11-ethylene- [123], 10-and 11-methyl- [124-126]. Many 11-substituted prostaglandins have also been syndie-sized from prosta andins obtained from the Gorgonian Coral source [127]. 

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