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 New Tetraheterocyclic Systems by the Mixed Condensation Reactions on [1,2,4]Triazolo[4,3‐a][1,5]benzodiazepines

We report here a one step synthesis of a new series of bis‐[1,2,4‐triazolo][4,3‐a:3′,4′‐d][1,5]benzodiazepines 3a–e and [1,2,4]oxadiazolo[5,4‐d][1,2,4]triazolo[4,3‐a][1,5]benzodiazepines 5a–c by the condensation reactions of diarylnitrilimines and arylonitrile oxides. This 1,3‐dipolar cycloaddition is completely regioselective. The structure of these products has been confirmed by ¹H, ¹³C NMR and mass spectroscopic.     

一个取代的三环1,5-苯并二氮杂的晶体结构和构象分析.Ⅱ

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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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.     

一个取代的1,5-苯并二氮杂的晶体结构及构象研究

用X射线衍射方法测定了4-苯甲酰基-3-(邻氯苯基)-1-乙酸乙酯基-1a-苯基-1,1a,2,3-四氢化-4H-环丙胺-[1,2-a][1,5」-苯并二氯化合物的晶体结构,晶体结构测定结果表明分子核心骨架二氮杂为类船式构象.用动力学模拟退火(Simulated Annealing)方法对分子进行了构象分析,结果表明分子中的二氮杂七元环具有三种较稳定的构象,其中以船式构象为最稳定,并存在着明显的芳环堆积作用.分子中七元环同时并接苯环和三元环,且环中的N(2)—C(12)—C(11)—N(1)有π键成分,大大限制了七元环构象的相互转换.     

Crystal structure and pseudosymmetry analysis of the triclinic prodrug cloxazolam (Z′ = 4)

The prodrug cloxazolam [systematic name: 13‐chloro‐2‐(2‐chlorophenyl)‐3‐oxa‐6,9‐diazatricyclo[8.4.0.0^2,6]tetradeca‐1(10),11,13‐trien‐8‐one], C₁₇H₁₄Cl₂N₂O₂, crystallizes in the triclinic space group P, with four chemically identical independent molecules in the asymmetric unit. However, in order to facilitate the analysis of the striking pseudosymmetry relating the four independent molecules, the structure has been analysed and reported in the nonconventional centred B space‐group setting. Pseudosymmetry is an eminently local property, valid only in the realm of the unit‐cell boundary and not propagating to the whole crystal structure. It has been analyzed using the MP procedure described in the preceding article [Baggio (2019). Acta Cryst. C 75 , 837–850]. The molecules consist of a rigid core made up of three rings (five‐, six‐ and seven‐membered) and an extra six‐membered ring joined to the latter group by a single C—C bond, together with a clamping intramolecular C—H…O interaction preventing free rotation and providing additional rigidity. The four molecules in the asymmetric unit pair into dimers with almost exact twofold pseudosymmetry, further linked into (001) slabs as the building bricks of the structure. Interpenetration of slabs finally leads to a three‐dimensional structure of unusual compactness for an organic structure, with a Kitaigorodskii packing index of ca 0.71.     

Development of a unique 3D interaction model of endogenous and synthetic peripheral benzodiazepine receptor ligands

Different classes of Peripheral-type Benzodiazepine Receptor (PBR) ligands were examined and common structural elements were detected and used to develop a rational binding model based on energetically allowed ligand conformations. Two lipophilic regions and one electrostatic interaction site are essential features for high affinity ligand binding, while a further lipophilic region plays an important modulator role. A comparative molecular field analysis, performed over 130 PBR ligands by means of the GRID/GOLPE methodology, led to a PLS model with both high fitting and predictive values (r² = 0.898, Q² = 0.761). The outcome from the 3D QSAR model and the GRID interaction fields computed on the putative endogenous PBR ligands DBI (Diazepam Binding Inhibitor) and TTN (Tetracontatetraneuropeptide) was used to identify the amino acids most probably involved in PBR binding. Three amino acids, bearing lipophilic side chains, were detected in DBI (Phe49, Leu47 and Met46) and in TTN (Phe33, Leu31 and Met30) as likely residues underlying receptor binding. Moreover, a qualitative comparison of the molecular electrostatic potentials of DBI, TTN and selected synthetic ligands indicated also similar electronic properties. Convergent results from the modeling studies of synthetic and endogenous ligands suggest a common binding mode to PBRs. This may help the rational design of new high affinity PBR ligands.     

外周苯二氮受体示踪剂的合成和评价

合成了用作外周苯二氮受体潜在的选择性配体的N,N-二乙基-2-(4-碘苯基)-6-三氟甲基-咪唑并[1,2-a]吡啶-3-乙酰胺(ITFZOL). 其放射性标记物[125I]ITFZOL通过碘脱锡化反应制备, 放化得率75%~85%, 比活度大于76 GBq/μmol. 小鼠尾静脉注射[125I]ITFZIOL后, 放射性集中分布于肾上腺、肺、肾、心、嗅球和小脑等外周苯二氮受体高密度区域. 预先给与外周苯二氮受体选择性配体PK11195明显减少外周苯二氮受体高密度区域放射性分布, 提示[125I]ITFZOL对外周苯二氮受体具有较高的特异亲和性. 生物活性数据表明, [125I]ITFZO是一种潜在的选择性外周苯二氮受体单光子放射性配体.     

1,5-苯并二氮杂的合成及其生物活性研究

采用两种方法: 以三氧化铝为载体邻苯二胺与查尔酮为原料的无溶剂合成法和以PPA(多聚磷酸)为催化剂邻苯二胺与苯乙酮的一锅合成法, 合成了1,5-苯并二氮杂, 产物收率为53.7%～74.5%. 通过¹H NMR, ¹³C NMR, MS, IR, 元素分析等手段对所合成的化合物进行了结构确定, 并测试了它们对菌和乙酰胆碱酶的抑制活性.