15- deoxy-16-hydroxy

Misoprostol (Cytotec) (+)(16RS)-15-deoxy-16-hydroxy-16-methy 1-PGE i, methyl ester... 

Syntheses for the p-chain precursors required for the preparation of the 15-deoxy-16-hydroxy, 17-hydroxy, 20-hydroxy or 15-hydroxymethyl derivatives are shown in Scheme 31 (33). The 15-deoxy-13-hydroxy analogs were obtained by a benzophen-one sensitized photo-addition of 1-octanol to the appropriate cyclopentenone as illustrated in Scheme 32 (90). 

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). 

Several carboxylic acid derivatives of ll-deoxy-13,14-dihy-dro-PGEi (237) were prepared via the acid chloride 258 and are listed in Table V. In addition the decyl ester 264 and the dimethylaminoethyl ester 265 of 15-deoxy-16-hydroxy-PGE2 were obtained by the mixed anhydride method (111.112). 

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 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). 

In the 15-deoxy-16-hydroxy series we have noted a loss of potency on homologation of the p-chain, although in the unsubstituted 16-hydroxy series this was manifested only with the 20-propyl derivative (see below). Abbreviation of the chain by one carbon (20-nor congener) in the 16,16 trimethylene series did not effect the activity (46). 

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

Figure 4. Bronchodilator activity of (A) dl-15-deoxy-16-hydroxy-PGEs (B) dl-IS-deoxy-lB-hydroxy lT-methyl-PGEi (C) d -lS-deoxy-16-hydroxy-16-meihyl-PGE, and (D) dl-15-deoxy-16-hydroxy-16-vimjl-PGEg in pilocarpine-bronchoconstricted dogs (aerosol) O 160 pg (n = 3) (A) 16 pg (n = 3) (A) 1.6 pg (n -= 3) ( ...

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