28533-42-8Relevant articles and documents
The ortho effect on the acidic and alkaline hydrolysis of substituted formanilides
Desai, Salil Dileep,Kirsch, Lee E.
, p. 471 - 488 (2015/06/30)
The kinetics of formanilides hydrolysis were determined under first-order conditions in hydrochloric acid (0.01-8 M, 20-60°C) and in hydroxide solutions (0.01-3 M, 25 and 40°C). Under acidic conditions, second-order specific acid catalytic constants were used to construct Hammett plots. The ortho effect was analyzed using the Fujita-Nishioka method. In alkaline solutions, hydrolysis displayed both first- and second-order dependence in the hydroxide concentration. The specific base catalytic constants were used to construct Hammett plots. Ortho effects were evaluated for the first-order dependence on the hydroxide concentration. Formanilide hydrolyzes in acidic solutions by specific acid catalysis, and the kinetic study results were consistent with the AAC2 mechanism. Ortho substitution led to a decrease in the rates of reaction due to steric inhibition of resonance, retardation due to steric bulk, and through space interactions. The primary hydrolytic pathway in alkaline solutions was consistent with a modified BAC2 mechanism. The Hammett plots for hydrolysis of meta- and para-substituted formanilides in 0.10 M sodium hydroxide solutions did not show substituent effects; however, ortho substitution led to a decrease in rate constants proportional to the steric bulk of the substituent.
(3R)-N-(1-(tert-butylcarbonylmethyl)-2,3-dihydro-2-oxo-5-(2-pyridyl)- 1H-1,4-benzodiazepin-3-yl)-N'-(3-(methylamino)phenyl)urea (YF476): A potent and orally active gastrin/CCK-B antagonist
Semple, Graeme,Ryder, Hamish,Rooker, David P.,Batt, Andrzej R.,Kendrick, David A.,Szelke, Michael,Ohta, Mitsuaki,Satoh, Masato,Nishida, Akito,Akuzawa, Shinobu,Miyata, Keiji
, p. 331 - 341 (2007/10/03)
A number of new 1,4-benzodiazepin-2-one-based gastrin/CCK-B receptor antagonists related to the archetypal analogue L-365,260, and more closely to the recently reported compound YM022, have been synthesized and evaluated for biological activity. The compounds were screened for their ability to inhibit the binding of [125I]CCK-8 to gastrin/CCK-B receptors prepared from rat brains and that of [3H]L-364,718 to CCK-A receptors from rat pancreas, and were shown to be potent and selective ligands for the gastrin/CCK-B receptor. Functional studies in vivo demonstrated the compounds to be antagonists of the receptor as evidenced by their ability to inhibit pentagastrin-induced gastric acid secretion in anesthetized rats. More extensive evaluation in viva included determination of ED50 values in the rat acid secretion model for selected compounds and an examination of the effect of these compounds on pentagastrin-induced gastric acid secretion in Heidenhain pouch dogs following oral and intravenous administration. Two compounds, i.e. (3R)-N- [1-[(tert-butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4- benzodiazepin-3-yl]-N'-[3-(methylamino)phenyl]urea, 15c (YF476), and (3R)-N- [1-[(tert-Butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4- benzodiazepin-3-yl]-N'-[3-(dimethylamino)phenyl]urea hydrochloride, 15d, showed potent dose-dependent effects in both models with the former showing excellent oral bioavailability and an ED50 of 21 nmol/kg po in dogs. 15e is currently under clinical investigation for the treatment of gastro-oesophagal reflux disease (GORD).
