Theoretical study of the interaction between benzodiazepine derivatives and water by use of AMYR calculations

AMYR is computer software for calculation of molecular associations using Fraga’s pairwise atom–atom potential. The interaction energy is evaluated by use of a 1/R expansion. A pairwise dispersion energy term is included in the potential and corrected by use of a damping function. The software performs energy minimization by use of variable metric methods. The new version enables stationary point analysis of the intermolecular potential by means of the Hessian eigenvalues. The AMYR model has been used for the first time for calculation of the interactions of benzodiazepine molecules, specifically benzodiazepine, 3-chlorobenzodiazepine, and 3-methylbenzodiazepine, with water molecules. Intermolecular interaction energies have been obtained and the stable conformation was determined in each case. Changes of conformation were considered for the C–N–C angle α when the solute molecules were surrounded by n water molecules (1 ≤ n ≤ 6).     

Substituent effects on the stability of 1,4‐benzodiazepin‐2‐one tautomers: A density functional study

The relative stability of 1,4‐benzodiazepin‐2‐one tautomers in the gas phase and model solvents was calculated at the M06 and ωB97XD levels of theory. The two density functionals were benchmarked earlier and demonstrated as excellent models to study tautomerism in a vast array of chemical systems. A number of commercially available 1,4‐benzodiazepin‐2‐ones were investigated computationally for the first time. In addition, some biologically active and newly devised benzodiazepines were considered, which may be important in designing structures with desired (bio)chemical features. Special attention was paid to determine substituent effects on the Gibbs free energies of keto, enol, and iminol forms for each respective benzodiazepine. It was demonstrated that (i) the replacement of the benzene ring by the heterocyclic ring in the benzodiazepine system may stabilize the iminol tautomer, and (ii) the electron‐withdrawing substituent at the C3‐position of the respective benzodiazepine may stabilize the enol tautomer relative to the parent keto form. It is concluded that substituent effects may govern the chemical reactivity and biological properties of selected benzodiazepines.     

The mass spectral fragmentation of 1a,3-disubstituted 4-benzoyl-1a,2,3,4- tetrahydrooxazirino

The mass spectrometric behaviour of four 1a,3-disubstituted 4-benzoyl-1a,2,3,4-tetrahydrooxazirino[2,3-a][1,5]benzodiazepines has been studied with the aid of mass-analyzed ion kinetic energy spectrometry and accurate mass measurements under electron impact ionization. All compounds show a tendency to eliminate a neutral oxygen atom, or oxygen atom plus benzoyl or aryl radicals, or oxygen atom plus CO molecule to yield 2,3-dihydro-1H-1,5-benzodiazepine derivative ions, or 1-benzoyl-2,3-dihydro-1H-1,5-benzodiazepine ions, which could further lose benzoyl to give 2,3-dihydro-1H-1,5-benzodiazepine ions. All compounds also show a tendency to eliminate a benzoyl radical to produce 1a,2,3,4-tetrahydrooxazirino[2,3-a][1,5]benzodiazepine ions. Both oxazirino[2,3-a][1,5]benzodiazepine ions and 2,3-dihydro-1H-1,5-benzodiazepine ions can undergo diazepine ring contraction rearrangement to yield benzimidazole ions by loss of propene or styrenes and other small fragments. The oxazirino[2,3-a][1,5]benzodiazepine ions [M(+)-PhCO] also undergo rearrangement reactions to form benzoxazole ions and benzimidazole ions. Copyright 1999 John Wiley & Sons, Ltd.     

Imidazo[1,2-b]pyridazines: Syntheses and interaction with central and peripheral-type (mitochondrial) benzodiazepine receptors

The fundamental chemistry of pyridazines, the syntheses of substituted irnidazo[1,2-b]pyridazines (1) (and some related compounds) and the interaction of the products with central benzodiazepine receptors (CBR) and peripheral-type (mitochondrial) benzodiazepine receptors (PBR) are described. Some of these imidazo[1,2-b]pyridazines had high selective affinity for the central benzodiazepine receptors and others had high selectivity for the peripheral-type (mitochondrial) benzodiazepine receptors. The results of structure-activity studies and molecular modeling will be reported. In vivo tests of some compounds which interacted strongly with the central benzodiazepine receptors revealed reasonably potent anticonvulsant/anticonflict activity, and some of those which bind selectively to the peripheral-type (mitochondrial) benzodiazepine receptors are being examined as possible radiopharmaceuticals for imaging of tumors (and other disease states).     

Micellar enhancement of benzodiazepine fluorescence

The interactions that exist between benzodiazepines and surfactants provide micellar enhancement factors for their fluorimetric determination in the range 1.2-6.5, depending on the nature of both the benzodiazepine and the surfactant. A series of benzodiazepines and anionic surfactants were treated topologically to determine the influence of each benzodiazepine substituent on the basic benzodiazepine structure and the influence of both the hydrophobic moiety of the surfactant and its counter ion on the sensitisation process. Sensitisation parameters were used to quantify the effect of the chemical structures of both surfactants and drugs on their interaction.     

一个取代的三环1,5-苯并二氮杂卓的晶体结构和构 象分析2

用单晶X射线衍射方法测定了6-苯甲酰基-5-(邻氯苯基)-2,3,3a,4,5,6-六氢-3a-苯基-(1,2,3-三乙酸乙酯基)-1H-吡咯啉[1,2-a][1,5-]苯并二氮杂卓的晶体结构。单斜晶系,空间群P2~1/c,a=1.3235(5)nm,b=1.7142(6)nm,c=1.6204(6)nm,β=100.49(3)°,Z=4,最终偏离因子R=0.062,R~w=0.075。晶体结构测定结果表明分子中二氮杂卓七元环采取船式构象,动力学模拟退火计算结果的最低能量构象为椅式,两者的能量差不大,表明这种船式<－>椅式的变化是非常容易发生的。     

Kinetic evaluation of pharmacological effects based on allosteric coupling of the benzodiazepine/gamma-aminobutyric acidA receptor in the brain.

A mathematical allosteric coupling model has been proposed to describe the process by which binding to the benzodiazepine/gamma-aminobutyric acid (GABA) receptor complex initiates a biological response. The model states that the first receptors (benzodiazepine receptors) can diffuse independently in the plane of the membrane and reversibly associate with the second receptors (GABA receptors) to regulate their activity (induction of increased chloride ion flux due to the opening of the chloride ion channel). The ratio of agonist-bound to total GABA receptor density was defined to be directly proportional to the biological response in the model. The analysis makes the following assumptions: i) the binding affinity of agonists (muscimol or benzodiazepine) to the benzodiazepine receptor/GABA receptor complex is much greater than that to each receptor alone; ii) the double receptor-single agonist (benzodiazepine, muscimol or GABA) ternary complex binds to the other agonist with a high binding affinity as compared with that of each agonist to an agonist-free receptor complex; iii) benzodiazepine receptor-GABA receptor interaction is enhanced in the presence of each agonist; iv) the GABA receptor is desensitized after the binding of GABA agonist (GABA or muscimol) to the receptor. The modeling exercise shows that the benzodiazepine concentration required for half-maximal biological response is lower than that required for half-maximal receptor binding. In the case of the GABA agonist, a linear relationship between receptor occupancy and biological response was observed. The degree of discrepancy between the two profiles (receptor occupancy and biological response) concerning benzodiazepine concentration dependency and time dependency increased with a decrease in the dissociation constants based on the benzodiazepine receptor-GABA receptor interaction.(ABSTRACT TRUNCATED AT 250 WORDS)     

2 - 芳基 -4- 苯基 -2, 3- 二氢 -1, 5- 苯并二氮杂卓与重氮乙酸乙酯反应机 理和 立体化学的研究

2-芳基-4-苯基-2,3-二氢-1,5-苯并二氮杂卓与重氮乙酸乙酯在铜粉催化下反应,得到环加成产物吖丙啶并苯并二氮杂卓I外,还得到一个非预期的五员环产物吡咯并苯并二氮杂卓II。改变反应条件可以使化合物II的收率达到50%。通过研究反应过程中分离出的副产物反丁烯酸二乙酯III和4,5-二氢吡唑-3,4,5-三羧酸乙酯IV,初步提出了反应经过乙氧羰基甲基化苯并二氮杂卓翁中间体V再发生环加成反应的机制。通过X-射线单晶衍射分析和NMR分析研究了它们的立体化学,发现为立体专一性反应。     

Synthesis of 1,5‐Benzodiazepine Derivatives Containing 1,2,3‐Triazole Moiety via 1,3‐Dipolar Cycloaddition Reaction

A series of 1,5‐benzodiazepine derivatives were synthesized by the reaction of 1,5‐benzodiazepine containing 1,2,3‐triazole moiety with benzohydroximinoyl chlorides at room temperature. The structural identities of these novel compounds were confirmed on the basis of IR, ¹H NMR, mass spectral and elemental analysis data, and by X‐ray crystallographic analysis of a typical example of the new class of 1,5‐benzodiazepine analogs.     

Optimizing the size and configuration of combinatorial libraries

This paper addresses a major issue in library design, namely how to efficiently optimize the library size (number of products) and configuration (number of reagents at each position) simultaneously with other properties such as diversity, cost, and drug-like physicochemical property profiles. These objectives are often in competition, for example, minimizing the number of reactants while simultaneously maximizing diversity, and thus present difficulties for traditional optimization methods such as genetic algorithms and simulated annealing. Here, a multiobjective genetic algorithm (MOGA) is used to vary library size and configuration simultaneously with other library properties. The result is a family of solutions that explores the tradeoffs in the objectives. This is achieved without the need to assign relative weights to the objectives. The user is then able to make an informed choice on an appropriate compromise solution. The method has been applied to two different virtual libraries: a two-component aminothiazole library and a four-component benzodiazepine library.     

Vibrational spectra and normal coordinate analysis of diazepam, phenytoin and phenobarbitone

Vibrational spectroscopy is an important tool for the structural investigation of the organic molecules. In the present investigation, a normal coordinate analysis has been carried out on some anti-epileptic drugs, viz. diazepam, phenytoin and phenobarbitone. Diazepam is a derivative of benzodiazepine, phenytoin is a derivative of hydanation and pheonobarbitone is a barbiturate. The infrared spectra of the compounds are recorded in the region 4000-400 cm(-1) and Raman spectra are recorded in the region 3500-50 cm(-1). From the structural point of view, diazepam, phenytoin and phenobarbitone have been assumed to C(s) point group. A systematic set of symmetry coordinates has been constructed for these compounds and Wilson's FG matrix method has been applied for the normal coordinate analysis using general quadratic valance force field. The potential energy distribution is also calculated to check the vibrational band assignments.     

Synthesis of 1,2-dihydroindolo [1,7-AB] [1,5] benzodiazepines and related structures. A new heterocyclic ring system

The synthesis of the novel 1,2-dihydroindolo [1,7-ab][1,5]benzodiazepine ring system 4 is described. Condensation of 2-fluoronitrobenzene with indoline provided the starting material for the synthesis, 1-(2-nitrophenyl)indoline (1a) in high yield. The nitro group was reduced catalytically and the resulting amino function was acylated to afford the heterocycle percursor amide 3. Refluxing this amide in phosphorus oxychloride brought about a Bischler-Napieralski type cyclodehydration to form the target 1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine ring system. Dehydrogenation of the latter led to the fully aromatic indolo[1,7-ab][1,5]benzodiazepine structure 5, while reduction with sodium borohydride provided the 1,2,6,7-tetrahydroindolo[1,7-ab]-[1,5]benzodiazepine tetracycle 6.     

An homologous series of benzodiazepine retention index standards for gas chromatography

An homologous series of benzodiazepine retention index standards (the R-series) has been synthesized and the gas chromatographic behavior of the series investigated on NB-54 and NB-1701 capillary columns. The compounds were stable, exhibited symmetrical peak shapes, and fairly linear retention behavior was observed on both columns. The series can be coinjected with every sample to enable the high precision analysis of toxicological samples; screening for 20 benzodiazepine drugs was possible in 23 minutes (including cooling). The R-series method was compared with a retention index method based on a series of benzodiazepine drugs as standards and with a method employing relative retention times. The precision of the R-series method was found to be generally better than that of the two other methods in both long- and short-term studies.     

Quantitation of Benzodiazepine Hydrolysis Products in Urine Using Solid-Phase Extraction and High Performance Liquid Chromatography

Abstract

Solid-phase extraction and high performance liquid chromatography (HPLC) were used to indirectly (via products of acid hydrolysis) confirm the presence of benzodiazepine metabolites in the urine of patients who had received overdoses of these compounds. The use of solid-phase extraction method for quantitation of benzodiazepine hydrolysis products in urine offers numerous advantages in comparison to extraction with chloroform. The chromatograms of urine extracts were free of interferences. The recoveries of the benzodiazepine hydrolysis products and the internal standard were greater than 96%, which makes this method highly reliable for quantitative analytical purposes.     

Palladium catalyzed synthesis of quinazolino [1,4] benzodiazepine alkaloids and analogous

A concise synthesis of enantiopure quinazolino [1,4] benzodiazepine was accomplished by palladium-catalyzed N-arylation of amidines with o-bromobenzoates followed by intra molecular cyclization. The strategy was successfully applied to the total synthesis of pyrrolo quinazolino [1,4] benzodiazepine alkaloids such as circumdatin H, J and other analogues.     

Non-isotopic receptor assay for benzodiazepines using a biotin-labeled ligand and biotin-immobilized microtiter plate.

A non-isotopic receptor assay for benzodiazepine drugs was developed using a biotin-labeled ligand, biotin-1012S. Biotinylated bovine serum albumin (biotin-BSA) was immobilized onto the wall of microtiter plate wells by simple adsorption. Avidin peroxidase conjugate could be extracted from solution owing to its strong interaction with biotin. The amount of avidin peroxidase taken up on the wall was then determined by measuring the enzyme activity. The competition between immobilized biotin on the wall and free biotin for avidin provided the basis for a solid-phase avidin-biotin binding assay. By this binding assay, not only biotin but also biotin-1012S could be measured sensitively. Because 1012S is a ligand with high affinity to benzodiazepine receptors, biotin-1012S could be utilized as a probe ligand for a non-isotopic receptor assay. Based upon the competition between biotin-1012S and various benzodiazepine drugs for the receptor binding sites, a non-isotopic receptor assay was demonstrated.     

Expedient Protocols for the Installation of 1,5‐Benzoazepino‐Based Privileged Templates on the 2‐Position of 1,4‐Benzodiazepine Through a Phenoxyl Spacer

An efficient novel strategy for the hetero‐annulation of 2‐chloro‐1,4‐benzodiazepine ring, substituted on its 5‐position with a carboxamido group ( 5 ), has been developed to allow the incorporation of 1,5‐benzodiazepine, 1,5‐benzothiazepine, and 1,5‐benzoxazepine ( 8 , 9 , 10 , 11 , 12 , 13 ) rings through their dimethylaminomethylene ketone intermediate ( 7 ).     

Parallel synthesis of 1,3-dihydro-1,4-benzodiazepine-2-ones employing catch and release

An efficient solid-phase method has been developed for the parallel synthesis of 1,3-dihydro-1,4-benzodiazepine-2-one derivatives. A key step in this procedure involves catching crude 2-aminobenzoimine products 4 on an amino acid Wang resin 10. Mild acidic conditions then promote a ring closure and in the same step cleavage from the resin to give pure benzodiazepine products 12. The 2-aminobenzoimines 4 can be synthesized from either 2-aminobenzonitriles 1 and Grignard reagents 2 or from iodoanilines 5 and nitriles 7 allowing a range of diversification. Further diversification can be introduced to the benzodiazepine products by N-alkylation promoted by a resin bound base and alkylating agents 13.     

1,2,3-Triazolodiazepines. I. Preparation and benzodiazepine receptor binding of 1-benzyl- and 1-phenethyl-1,2,3-triazolo-[4,5-b][1,4]diazepines

Several new 1,2,3-triazolo[4,5-b][1,4]diazepines were prepared starting from 1-benzyl-1 and 1-phenethyl-4,5-diamino-1,2,3-triazole 2 (Scheme 1), by condensation reactions with β-diketones (Scheme 2), β-ketoesters (Scheme 3), and diethyl malonates (Scheme 4). In the first case we obtained compounds 3 and 4 with basic properties, while the ester function condensations gave cyclic amide derivatives 7, 8, 10, 12 and 13 with acid properties. Some N-methyl derivatives 11, 14 and 15 were obtained from the cyclic amide compounds. Most of compounds were tested for their ability to displace [³H]flunitrazepam from bovine brain membranes but no compound showed benzodiazepine receptor binding affinity.