A Rearrangement of 5-Aryl-1,3-dihydro-2H-1,4-benzodiazepine-2-one 4-Oxides<sup>1</sup>

Bell, Stanley C.; Childress, Scott J.

doi:10.1021/jo01052a049

Cited by 123 publications

(44 citation statements)

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“…3-Amidobenzodiazepines (compounds 14-16, 18, 19, and 21) were obtained by acylation of the 3-amino derivatives. The latter were prepared from the 3-hydroxy compounds using published procedures (26)(27)(28) (24).…”

mentioning

confidence: 99%

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

Evans¹,

Bock²,

Rittle³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

285

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We describe the design and synthesis of nonpeptidal antagonists of the peptide hormone cholecystokinin. Several of these compounds have high specificity and nanomolar binding affinity and are active after oral administration. To our knowledge, the design of such agents has not previously been accomplished for any peptide hormone. The structural similarities between these synthetic compounds and the anxiolytic 1,4-benzodiazepines are noted, and the potential of this structural feature for future design of ligands for other peptide hormone receptors is discussed.selective nonpeptidal antagonist of CCK in vitro and in vivo (7). However, asperlicin has liabilities as a pharmacological or potential therapeutic agent, including lack of oral bioavailability, modest potency, and poor water solubility (7, 42).Many important drugs such as ivermectin (18)

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mentioning

confidence: 99%

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

Evans¹,

Bock²,

Rittle³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

285

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“…3-0-Acyloxazepam was prepared from demoxepam according to Bell and Childress. 16 Racemic MeOX and EtOX (recrystallized in MeOH and EtOH, respectively; purity ~9 9 . 9 % ) were prepared by acid-catalyzed methanolysis and ethanolysis of 3-0-acyloxazepam, respectively.…”

Section: Methodsmentioning

confidence: 99%

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

Yang

1994

Chirality

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Enantiomers of 3-O-methyloxazepam (MeOX) and 3-O-ethyloxazepam (EtOX) were resolved by chiral stationary phase high-performance liquid chromatography (CSP-HPLC). Reaction kinetics and deuterium isotope effects of acid-catalyzed racemization of enantiomeric MeOX in ethanol and enantiomeric EtOX in methanol were studied by spectropolarimetry. The acid-catalyzed heteronucleophilic substitution reactions of racemic MeOX in ethanol and racemic EtOX in methanol were studied by reversed-phase HPLC. Thermodynamic parameters involved in the reactions were obtained by temperature-dependent reaction rates. The effects of solvent's dielectric constant on the heteronucleophilic substitution reactions were also determined. A nucleophilically solvated and transient C3 carbocation intermediate resulting from an N4-protonated enantiomer, derived from a 1,4-benzodiazepine either in M (minus) or P (plus) conformation, is proposed to be an intermediate and responsible for the acid-catalyzed stereoselective nucleophilic substitution and the resulting racemization.

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“…3-Acetoxy-l, 4-benzodiazepines were prepared with acetic anhydride by rearrangement of the corresponding 4-oxides (8).…”

Section: Methodsmentioning

confidence: 99%

Structural parameters in the microsomal hydrolysis of 3-acyloxy-l, 4-benzodiazepines and the multiplicity of the esterases involved

Maksay

Tegyey

Simon‐Trompler

et al. 1980

European Journal of Drug Metabolism and Pharmacokinetics

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The biotransformation of several prodrug-type esters of centrally acting 1, 4-benzodiazepines was studied. Their rates of hydrolysis catalyzed by the hepatic microsomal fraction of mice were measured by pH-stat. The heterogeneity of the microsomal esterases was investigated with induction by phenobarbital and with inhibition by DFP. The resulting changes in esterase activity indicated that the phenyl-substituted esters separate from the homogenous sets of oxazepam and lorazepam esters. Regression analysis of the relative hydrolysis rates of the homogenous ester sets revealed a similar dependence on the steric ES the polar sigma* and hydrophobic deltaRM terms of the acyl moiety. The role of the polar term shows that a nucleophilic attack of the acyl moiety determines the hydrolysis. The role of hydrophobicity can be attributed to its interrelation with the steric parameter. The common equations for the aliphatic sters of oxazepam and larazepam suggest the similar nature of the esterases in question and the same catalytic mechanism. Different 3-acetoxy-1, 4-benzodiazepines were also synthetised and their maximal hydrolysis rates were quite different. This excludes the possibility that the deacylation step of the enzymes is rate-determining. Instead, our data suggest that acylation of the microsomal esterases is rate-limiting for the hydrolysis of the aliphatic esters of 3-OH-benzodiazepines.

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A Rearrangement of 5-Aryl-1,3-dihydro-2H-1,4-benzodiazepine-2-one 4-Oxides¹

Cited by 123 publications

References 0 publications

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

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

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

Structural parameters in the microsomal hydrolysis of 3-acyloxy-l, 4-benzodiazepines and the multiplicity of the esterases involved

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A Rearrangement of 5-Aryl-1,3-dihydro-2H-1,4-benzodiazepine-2-one 4-Oxides1

Cited by 123 publications

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

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

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

Structural parameters in the microsomal hydrolysis of 3-acyloxy-l, 4-benzodiazepines and the multiplicity of the esterases involved

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A Rearrangement of 5-Aryl-1,3-dihydro-2H-1,4-benzodiazepine-2-one 4-Oxides¹