3-Substituted 1,4-benzodiazepin-2-ones

Abstract

The preparation of a number of 1,4-benzodiazepines substituted in the 3 position is described. The rearrangement of 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one 4-oxide with diacetyl sulfide yields largely the 3-acetylthio compound. Amines, ethers, and sulfides were prepared through the chloro intermediate. A 3-carbethoxybenzodiazepine was prepared and converted into oxazepam. The pharmacological test data of new and previously published compounds are given.

Design of potent, orally effective, nonpeptidal antagonists of the peptide hormone cholecystokinin.

“…3-Alkyl and 3-amido substituents are reported (23,(32)(33)(34)40) to be detrimental to anti-anxiety activity. Our results are consistent with these reports.…”

Water-Soluble Derivatives of 3-Oxy-substituted 1,4-Benzodiazepines

“…When an excess of chloroacetyl chloride was used, an additional product, XVI (derived from diacylation), was obtained. When the analogous N -oxide rearrangement of XV with methyl chloroformate was carried out, a mixture of the carbonate XVII and the chloro Compound XVIII (1) was obtained. The carbonate, uncontaminated with XVIII, could be prepared from the 3-hydroxy Compound I1 upon treatment with methyl chloroformate.…”

“…Recent efforts (1) in the area of 3-hydroxy-1,4-benzodiazepines have been directed to the preparation of water-soluble derivatives suitable for parenteral administration. Aqueous 1,4-benzodiazepine solutions would be expected to have the distinct advantage of diminishing the incidence of pain and the subsequent venous inflammation often encountered with injectable formulations of water-insoluble 1,4-benzodiaze pines.…”

Acid‐catalyzed stereoselective heteronucleophilic substitution and racemization of 3‐O‐methyloxazepam and 3‐O‐ethyloxazepam

“…Since the reaction rate of MeOX in EtOH was higher than that of EtOX in MeOH, the results in Figures 4 and 5 (numerical values in Table 1) suggested that the nucleophilicity of the leaving nucleophile played a more important role than that of the attacking nucleophile in determining the reaction rates. A more definitive answer regarding the relative contribution of nucleophilicity of attacking and leaving nucleophiles on the acid-catalyzed heteronucleophilic substitution reaction rate may be obtained by (1) comparing reaction rates of a 3-akoxy-1,4-benzodiazepine in a series of alcohols such as methanol, ethanol, n-propanol, n-butanol, and n-pentanol, and (2) comparing reaction rates of several different 3-akoxy-1,4-benzodiazepines (such as MeOX, EtOX, 3-0-n-propoxyoxazepam, 3-O-n-butoxyoxazepam, and 3-0-n-pentoxyoxazepam) in a single alcoholic solvent. These studies are being planned in our laboratory.…”