Synthesis and gastric antisecretory properties of 15-deoxy-16-hydroxyprostaglandin E analogs

Abstract

The preparation and gastric antisecretory activity of a series of 15-deoxy-16-hydroxyprostaglandin analogues are described. The compounds were tested intravenously in histamine-stimulated Heidenhain pouch dogs in relation to the reference standards PGE1 and PGE1 methyl ester (PGE1ME). The parent compound of this seris, (+/-)-15-deoxy-16alpha,beta-hydroxyprostaglandin E1 methyl ester (3), was found to be equipotent to the reference standard PGE1ME. Methylation at C-16 of 3 produced 8 which was found to be some 40 times more potent than PGE1. In sharp contrast, addition of two methyl groups to 3 at C15 or C17 markedly reduced the antisecretory action. The 16-ethyl analogue of 3 also showed reduced potency. Removal or epimerization of the C-11 hydroxy group of 8 reduced the activity. Likewise, hydrogenation or changing the stereochemistry of the 13,14 double bond from trans to cis decreased the activity. On the other hand, omega-homologation of 8 or the introduction of a cis-5,6 double bond did not affect the potency. From these studies, it appears that 8, 16, and 17 possess optimum gastric antisecretory effects in this series.

Pharmaceuticals

“…The cyclopentenone is finally obtained by reduction of the enol ether with Red-Al at low temperature. [224] The original access to the fully functionalised ω-side-chain involved addition of DIBAlH to silyl-protected 4-methyloct-1-yn-4-ol, which was prepared by a mercury(II)chloride-activated Grignard reaction. Further reaction with iodine and then with butyllithium and pent-1-ynyl-copper formed a copper complex, which selectively transfers the ω-side-chain to the cyclopentenone.…”

Synthesis of ethyl (±)-(13,15-dideoxy)-16-methyl-9-oxoprosta-13(E,Z),15(E)-dienoate

“…The mixture was boiled for 4 h till the disappearance of the initial enone (TLC monitoring). Ethanol was evaporated, the residue was treated with CHCl 3 (3 × 20 ml), the extract was washed with the saturated solution of NH 4 Ethyl 7-(2,2-diethoxymethyl-5-oxocyclopentyl) heptanoate (VIII). Into a solution of 1 g (3.34 mmol) of nitrocompound VII in 15 ml of anhydrous ethanol was added 0.3 g (4.5 mmol) of sodium ethylate at -5°C.…”

“…For racemic C 16 -epimeric misoprostol (I) these are mainly 8,12-and 13,14-cis-isomers, and also the products of dehydration, compaction, etc. [4,5].…”

“…The reaction mixture was stirred for 2 h at the same temperature. Then it was warmed to 20°C, and a saturated NH 4 Cl water solution was added. The solvent was distilled off, the SYNTHESIS OF ETHYL (±)-(13,15-DIDEOXY)-16-METHYL-9-... reaction products were extracted into CH 2 Cl 2 , the extract was washed with water (3 × 3 ml), and with brine.…”

Misoprostol—a Logical Therapeutic Approach to Gastroduodenal Mucosal Injury Induced by Non-Steroidal Anti-Inflammatory Drugs?

“…Stability was achieved through methylation of carbon 15 or 16 to block the metabolic oxidation of the 15-hydroxy group. T h e resulting analogues were orally active with prolonged gastric antisecretory effect (38,39). Specificity for parietal cell receptors was achieved by transposing the hydroxy group in PGE from position 15 to 16. T h e resulting compound (15-deoxy, 16-hydroxy PGE, methyl ester) was approximately equipotent with its parent compound, PGE, methyl ester, in its gastric antisecretory action.…”