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At least 19 recordsLinked to original sources
PubMed1992

Application of preparative liquid chromatography to the isolation of enantiomers of a benzodiazepinone derivative.

The isolation of milligram amounts of the enantiomers of a benzodiazepinone derivative was performed on an analytical cellulose tribenzoate-based column by multiple repetitive injections. An enantiomeric purity greater than 98% was required. First, an analytical method was developed to maximize the resolution by adjusting the mobile phase composition, flow-rate and most importantly the column temperature. Then the preparative separation was optimized by adjusting the sample size and detecting the sample where its UV absorbance was low. The locations of the cut points were determined by use of detector response levels. The method development, preparative separations and analytical assays of the fractions obtained were all performed on analytical columns.

Benzodiazepinones↗
PubMed2002

Soluble polymer-supported synthesis of benzodiazepinones.

Soluble polymer-supported synthetic method provides a highly efficient route for the construction of biologically important 1,5-benzodiazepin-2-ones. A library of N-substituted benzodiazepinones can be readily assembled utilizing S(N)Ar reaction, reduction of nitro group and one-pot cyclization following N-alkylation as the key step in the synthesis. All reactions in the sequence were performed at room temperature to facilitate the generation of libraries in a parallel fashion. The crude products were obtained in 80-95% yield with 60-96% HPLC purity.

Benzodiazepinones↗
PubMed1978

Structure activity relation for some 1,4-benzodiazepinones: correlation between rate constants for reduction by sodium borohydride and antileptazol ED50.

Significant correlation in 11 different 1,4-benzodiazepinones has been established between log k2 (the second order rate constant for the reduction of the "azepinones" by sodium borohydride) and their ED50 against leptazol-induced seizures in mice. The results suggest a possible involvement of the carobnyl group at the receptor site.

Animals↗
PubMed1982

Quinazolines and 1,4-benzodiazepines. 90. Structure-activity relationship between substituted 2-amino-N-(2-benzoyl-4-chlorophenyl)acetamides and 1,4-benzodiazepinones.

The syntheses of 2-amino-N-(2-benzoyl)-4-chlorophenyl)acetamides are reported. The pharmacological properties of these compounds were compared with data obtained from the corresponding cyclized products [5-(2,6-dichlorophenyl)-1,4-benzodiazepin-2-ones]. Evidence is presented which suggests that the central nervous system activity observed for 1,4-benzodiazepines is inherent only in the closed seven-membered ring and is not due to the ring-opened form.

Acetamides↗
PubMed1993

Determination of the magnitude and enantioselectivity of ligand binding to rat and rabbit serum albumins using immobilized-protein high performance liquid chromatography stationary phases.

Rat, rabbit and human serum albumins were immobilized on an HPLC stationary phase, and the resulting phases were tested for their abilities to determine the extent and enantioselectivity of ligand binding to the respective albumins. A series of achiral and chiral compounds were chromatographed on the phases including benzodiazepinones, non-steroidal anti-inflammatory drugs, amino acids, warfarin and leucovorin. The chromatographic retentions of the benzodiazepinones and one series of nonsteroidal anti-inflammatory agents were compared with protein binding data from ultrafiltration studies. The observed correlation factors (r) were consistently 0.999, indicating that the albumin phases can be used to determine the magnitude of binding to the respective proteins. The enantioselectivity was also investigated, and the results indicate that the stationary phases can be used to determine relative enantioselectivities and intraspecies differences in this stereoselectivity. For example, when R- and S-warfarin were studied, R-warfarin was retained to a greater extent than S-warfarin by the rabbit serum albumin-stationary phase, whereas the opposite enantioselectivity was found for the rat and human albumins. Binding interaction studies were also conducted on the rabbit and rat albumin stationary phases by sequentially adding increasing concentrations of octanoic acid to the chromatographic mobile phase. The octanoic acid reduced the retention of a series of non-steroidal anti-inflammatory agents, and the results of the experiments suggest that the interaction takes place at two or more sites on the albumin molecule and by anti-cooperative allosteric interactions and competitive displacement. The results of this study demonstrate that the immobilized serum albumin columns can be used to quantitate and probe ligand binding interactions.

Animals↗
PubMed1991

Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyridobenzo- and dipyridodiazepinones.

Novel pyrido[2,3-b][1,4]benzodiazepinones (I), pyrido[2,3-b][1,5]benzodiazepinones (II), and dipyrido[3,2-b:2',3'-e][1,4]diazepinones (III) were found to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in vitro at concentrations as low as 35 nM. In all three series, small substituents (e.g., methyl, ethyl, acetyl) are preferred at the lactam nitrogen, whereas slightly larger alkyl moieties (e.g., ethyl, cyclopropyl) are favored at the other (N-11) diazepinone nitrogen. In general, lipophilic substituents are preferred on the A ring, whereas substitution on the C ring generally reduces potency relative to the corresponding compounds with no substituents on the aromatic rings. Maximum potency is achieved with methyl substitution at the position ortho to the lactam nitrogen atom; however, in this case an unsubstituted lactam nitrogen is preferred. Additional substituents on the A ring can be readily tolerated. The dipyridodiazepinone derivative 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e] [1,4]diazepin-6-one (96, nevirapine) is a potent (IC50 = 84 nM) and and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase, and has been chosen for clinical evaluation.

Antiviral Agents↗
PubMedDate not supplied

Solid-phase synthesis of 7-acylamino-1,4-benzodiazepine-2,5-diones.

A method for the synthesis of polymer-bound 7-acylamino-benzodiazepine-2,5-diones is described. The amino group of an alpha-amino acid is linked to polystyrene or TentaGel resin via reductive amination of polymer-bound 4-alkoxy-2,6-dimethoxybenzaldehyde. Acylation with unprotected 5-nitroanthranilic acid is followed by base-catalyzed ring closure. Reduction of the nitro group yields enantiomerically pure 7-aminobenzodiazepin-2,5-dione attached via the N-4 atom to the resin. Acylation of the amino group on the aromatic ring with acid chlorides in N-methylpyrrolidone (no DMF, no base!) followed by cleavage from the resin using TFA/Me(2)S/water (90:5:5) provides the acylated benzodiazepinones in 52-69% (PS resin) and 41-48% (TG resin) yield (based on the theoretical loading) and >70% purity (HPLC, 210 nm). Using Fmoc-protected tyrosine fluoride in NMP gives the amino acid-coupled benzodiazepinones in 24% (PS resin) and 31% (TG resin) yield.

Benzazepines↗
PubMed1998

Synthesis of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2, 3-benzodiazepin-4-ones as novel and potent noncompetitive AMPA receptor antagonists.

A group of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2, 3-benzodiazepin-4-ones was synthesized and assayed for antagonism of rat brain alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors expressed in Xenopus oocytes. The benzodiazepinones inhibited AMPA-activated membrane current responses in a manner consistent with noncompetitive, allosteric inhibition of the receptor-channel complex. The most potent compound in the series was 1-(4-aminophenyl)-7,8-(methylenedioxy)-3,5-dihydro-4H-2, 3-benzodiazepin-4-one (6), which had an IC50 of 2.7 microM. For comparison, the reference compound GYKI 52466 (2) had an IC50 of 6.9 microM. Compound 6 also had potent anticonvulsant activity in a mouse maximum electroshock-induced seizure (MES) assay: the ED50 was 2.8 mg/kg iv, whereas the ED50 for GYKI 52466 was 4.6 mg/kg iv. In contrast to a previous report, the 7,8-dimethoxy analogue of 6 was a low-potency AMPA antagonist (IC50 >100 microM) and weak anticonvulsant (ED50 >10 mg/kg iv). The benzodiazepinones described herein are potent noncompetitive AMPA receptor antagonists that could have therapeutic potential as anticonvulsants and neuroprotectants.

Allosteric Regulation↗
PubMed1999

Solid-Phase Synthesis of 3,4,5-Substituted 1,5-Benzodiazepin-2-ones.

The preparation of 3,4,5-substituted 8-carboxamido-1,5-benzodiazepin-2-ones using a solid-phase synthetic method is described. 4-Fluoro-3-nitrobenzoic acid is tethered to a solid support via the acid group. Aromatic substitution of the aryl fluoride with either an alpha- or beta-substituted beta-amino ester is carried out in the presence of DIEA in DMF. The reduction of the aryl nitro group is accomplished in the presence of SnCl(2).H(2)O. Hydrolysis of the ester is carried out in the presence of a heterogeneous mixture of 1 N NaOH/THF (1:1). The resulting aniline acid is cyclized to form the benzodiazepinone skeleton with DIC and HOBt. Selective alkylation at the N-5 position of the benzodiazepinone is accomplished with alkyl halides in the presence of K(2)CO(3) in acetone. The desired products are cleaved from solid supports and obtained in 46-98% isolated yields.

Journal Article↗