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Twenty-nine patients referred for oesophageal diagnostic work up prospectively divided into patients with normal (‘controls’) and abnormal motility on the basis of manometric findings underwent oesophageal scintigraphy with and without simultaneous manometry. All patients with abnormal peristalsis had a mean pressure amplitude of less than 30 mmHg andlor simultaneous contractions in the proximal andlor distal half of the oesophagus. For manometry a low compliance perfusion system was used (external diameter of the manometric tube 0.5 cm). Radionuclide oesophageal emptying (%) was measured 12 sec after the beginning of each swallow. Values of >8O% were considered normal. Oesophageal emptying for liquid and semi-solid test-boluses during manometry was compared t o the corresponding values obtained without the manometric tube in place. Oesophageal emptying was reduced during studies with the manometric tube in situ in controls from 97.6 ± 1.2% to 85.9 ± 5.3%, P = 0.018 forliquid boluses, and from 95.3 ± 1.2% to 84.4 ± 4.3%, P = 0.01 for semi-solid boluses. A trend was also seen in patients with abnormal contractility which was not statistically significant (65.6 ± 9.0% vs 56.6 ± 8.5% P = 0.1, 62.4 ± 9.1% vs 56.7 ± 7.6%, p=0.4). Three controls duringliquid studies and four controls during semi-solid studies were falsely classified as pathological by scintigraphy with the tube in situ whereas only one patient with abnormal contractility was classified normal in each of the liquid and semi-solid studies. In conclusion, subjects with normal contractility patterns may show pathological emptying in radionuclide studies if simultaneous manometry is performed. Patients who have reduced oesophageal emptying may be less often falsely classified as normal.

The interesting bronchodilator activity of novel dl-16,16-trimethyleneprostaglandin congeners and their preparation via the conjugate addition of the appropriate vinyl lithiocuprate reagent to several cyclopentenones are described. Also discussed is the preparation of the key intermediate vinyl iodine 7.

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.

The interesting bronchodilator activity of certain dl-11-deoxy-3-thiaprostaglandins and their preparation by the conjugate addition of appropriately substituted (E)-1-alkenyllithio cuprate reagents to requisite cyclopentenones are described.

dl-Erythro-16-methoxy-PGE2, PGA2, PGF2alpha, 11-deoxy PGE1, and 11-deoxy PGF1alpha have been prepared via the cuprate conjugate addition procedure. These congeners are less potent than the parent prostaglandins as stimulators of isolated gerbil colon contractions and as bronchodilators in the guinea pig Konzett assay.

The interesting bronchodilator activity of l-11-deoxy-11 alpha-[(2-hydroxyethyl)thio]prostaglandin E2 methyl ester (3a) is described. The preparation of 3a and its analogues by Michael-type additions to various members of the PGA series or by total synthesis using the lithiocuprate conjugate addition process is also described. Structure-activity relationships in this series are discussed.

1-Jod-E-1-octen-3-ol (Ia) liefert die beiden O-Tritylather (Ib) und (Ic), die mit Butyllithium und Trimethylaluminium zu (IIb) und (IIc) metalliert werden.

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 preparation of a series of 6-chloro-6-dehydro-17-alkylprogesterones, of the 6-fluoro and 6-methyl derivatives of 6-dehydro-17-ethylprogesterone and of 6-chloro-1,6-bisdehydroprogesterone is described. The oral progestational activity of these and other 17-alkyl-progesterone derivatives is discussed.

Treatment of a 16-dehydro, 17-acetoxy, 17-hydroxy or 17-bromopregn-20-one with a liquid ammonia solution of lithium, barium or calcium (and in at least one instance sodium) afforded an intermediate 17-enolate anion, which on reaction with the appropriate alkyl, allyl and benzyl halide furnished the corresponding 17-alkyl, allyl and benzyl-pregn-20-one. A very useful liquid-liquid partition column chromatographic procedure is described.