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Prostaglandin congeners wherein the 15-hydroxy group is moved to the C16, C17, or C20 position or is replaced by a hydroxymethyl group were prepared via the 1,4-addition of a lithium trialkyl-trans-alkenyl alanate to an appropriate cyclopentenone. Several of the 16-hydroxy derivatives showed significant activity as constrictors of the isolated gerbil colon and in bronchodilator and anti-secretory assays.

Simplified prostaglandin analogs were prepared and tested for inhibition of gastric acid secretion. An alkyl moiety of 1-8 carbon atoms was substituted for the C-13 to C-20 chain of the PG's. Analog variations included shortened and lengthened acid side chains, beta-oxidation blockage, beta-ketol, Falpha-hydroxyl, and cyclohexanone substitution. Maximal inhibitory activity was obtained with the shorter alkyl moieties.

A new route for the synthesis of 2-amino-5-(l-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole (1) is described. This route was based upon the preparation of 2-amino-5-halomethyl-1,3,4-thiadiazoles by condensation of haloacetic acids with thiosemicarbazide. One of these intermediates, 2-acetamido-5-dichloromethyl-1,3,4-thiadiazole (4), was hydrolyzed to the corresponding 5-amino-2-carboxaldehyde 6, which was trapped as its oxime 5. 5-Acetamido-1,3,4-thiadiazole-2-carbonitrile (7), formed upon dehydration of 5, was then converted into 2-amino-5-(2-imidazolyl)-1,3,4-thiadiazole (11) by a route based on the Pinner amidine synthesis. Methylation and nitration of the imidazole moiety then completed the preparation of 1.

The preparation of prostaglandin E 1 , 15-deoxyprostaglandin E 1 , and 11-deoxyprostaglandin E 1 via conjugate addition of an appropriate trans -1-alkenylalanate to cyclopentenone I or II is described. Diisobutylaluminum hydride adds in a trans -manner to 3- t -butoxy-1-octyne, but in the required cis -manner to 3-trityloxy-1-octyne.

d1-Prostaglandin E1 and d1-11-deoxyprostaglandin E1 are conveniently synthesized via the copper (I) catalyzed conjugate addition of the Grignard reagent prepared from 3-trityloxy-trans-1-octenyl bromide to the appropriate cyclopentenone precursor. The Grignard reagent also afforded the synthesis of a novel structure, d1-15-hydroxy-9-oxo-13-cis-prostenoic acid.

Treatment of ethyl 3-quinuclidinone-2-carboxyIate (III) with appropriate reagents gave 2,3-fused heterocycles including pyrazolol, aminopyrimidinone, and aminopyridazinone types. The thiourea derivative of III could not be cyclized. Triazoline, pyrazoline, and isoxazoline derivatives were prepared by 1,3-dipolar cycloadditions to the 2- and 3-positions of methyl 2,3-dehydroquinuclidine-3-carboxylate (XIIIa). Such facile formation of cycloaddition products was not possible with 2,3-dehydroquinuclidine, which reacted only with phenylazide (in poor yield). Structural assignments for the products of cycloaddition were made by analogy, but alternative structures could not be ruled out by the nmr or mass spectra.

The synthesis of dl-11-doxy-15- or 16-alkylprostaglandins by the conjugate addition of appropriately substituted lithium alanate or lithium cuprate reagents to several cyclopentenones is described as is the preparation of the requisite intermediate (E)-1-iodo-1-alkenyl compounds 4, 22, 23, and 31. The bronchodilator activity of these prostaglandin congeners is presented.

Simplified prostaglandin analogs were prepared and tested for inhibition of gastric acid secretion. An alkyl moiety of 1-8 carbon atoms was substituted for the C-13 to C-20 chain of the PG's. Analog variations included shortened and lengthened acid side chains, beta-oxidation blockage, beta-ketol, Falpha-hydroxyl, and cyclohexanone substitution. Maximal inhibitory activity was obtained with the shorter alkyl moieties.