5-Chloracetyl-5,10-dihydro-11H-dibenzo<1,4>diazepin-11-on | 93986-09-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: 5-Chloracetyl-5,10-dihydro-11H-dibenzo<1,4>diazepin-11-on
• 英文别名: 5-(chloroacetyl)-10,11-dihydrodibenzo<1,4>diazepin-11-one；5-(2-chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]-diazepin-11-one；5-Chloracetyl-10.11-dihydro-5H-dibenzo<1.4>diazepinon-(11)；5-(2-chloroacetyl)-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one；5-chloroacetyl-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one；5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one；11-(2-chloroacetyl)-5H-benzo[b][1,4]benzodiazepin-6-one
• CAS: 93986-09-5
• 化学式: C₁₅H₁₁ClN₂O₂
• 分子量: 286.718
• InChiKey: OYGJCGQSFROSHD-UHFFFAOYSA-N

物化性质

• 熔点：
  238.5-240 °C
• 沸点：
  455.9±34.0 °C(Predicted)
• 密度：
  1.365±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  49.4
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  5-Chloracetyl-5,10-dihydro-11H-dibenzo<1,4>diazepin-11-on 在 盐酸 、 potassium carbonate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 20.0~100.0 ℃ 、200.0 kPa 条件下， 反应 10.5h， 生成 5-((4-(4-guanidinobutyl)piperidin-1-yl)acetyl)-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one bis(hydrotrifluoroacetate)
  参考文献：
  名称：

  M2 Subtype preferring dibenzodiazepinone-type muscarinic receptor ligands: Effect of chemical homo-dimerization on orthosteric (and allosteric?) binding

  摘要：

  A series of new dibenzodiazepinone-type muscarinic receptor ligands, including two homo-dimeric compounds, was prepared. Sixteen representative compounds were characterized in equilibrium binding studies with [H-3]N-methylscopolamine ([H-3]NMS) at the muscarinic receptor subtype M-2, and seven selected compounds were additionally investigated at M-1, M-3, M-4 and M-5 with respect to receptor subtype selectivity. The side chain of the known M-2 preferring muscarinic receptor antagonist DIBA was widely varied with respect to chain length and type of the basic group (amine, imidazole, guanidine and piperazine). Most of the structural changes were well tolerated with respect to muscarinic receptor binding, determined by displacement of [H-3]NMS. Compounds investigated at all subtypes shared a similar selectivity profile, which can be summarized as M-2 > M-1 approximate to M-4 > M-3 approximate to M-5 (46, 50, 57, 62-64) and M-2 > M-1 approximate to M-4 > M-3 > M-5 (1, 58). The homo-dimeric dibenzodiazepinone derivatives UNSW-MK250 (63) and UNSW-MK262 (64) exhibited the highest M-2 receptor affinities (pIC(50) = 9.0 and 9.2, respectively). At the M-2 receptor a steep curve slope of -2 was found for the dimeric ligand 63, which cannot be described according to the law of mass action, suggesting a more complex mechanism of binding. In addition to equilibrium binding studies, for selected ligands, we determined pEC(50,diss), an estimate of affinity to the allosteric site of M-2 receptors occupied with [H-3]NMS. Compounds 58 and 62-64 were capable of retarding [H-3]NMS dissociation by a factor > 10 (E-max,E-diss >92%), with highest potency (pEC(50,diss) = 5.56) residing in the dimeric compound 64. As the monomeric counterpart of 64 was 100 times less potent (62: pEC(50),(diss) = 3.59), these data suggest that chemical dimerization of dibenzodiazepinone-type M receptor ligands can enhance allosteric binding. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.01.015
• 作为产物：
  描述：

  2-[(2-氨基苯基)氨基]苯甲酸 在 磷酸 作用下， 以 xylene 为溶剂， 反应 16.0h， 生成 5-Chloracetyl-5,10-dihydro-11H-dibenzo<1,4>diazepin-11-on
  参考文献：
  名称：

  Ruger; Rohnert; Lohmann, Pharmazie, 1990, vol. 45, # 8, p. 555 - 559

  摘要：

  DOI：

文献信息

• Dibenzodiazepinone-type muscarinic receptor antagonists conjugated to basic peptides: Impact of the linker moiety and unnatural amino acids on M2R selectivity
  作者：Corinna. G. Weinhart、David Wifling、Maximilian. F. Schmidt、Eduard Neu、Carina Höring、Timothy Clark、Peter Gmeiner、Max Keller

  DOI：10.1016/j.ejmech.2021.113159

  日期：2021.3

  continuation of our work on dualsteric dibenzodiazepinone-type M2R antagonists, a series of M2R ligands containing a dibenzodiazepinone pharmacophore linked to small basic peptides was synthesized (64 compounds). The linker moiety was varied with respect to length, number of basic nitrogens (0-2) and flexibility. Besides proteinogenic basic amino acids (Lys, Arg), shorter homologues of Lys and Arg, containing

  人类毒蕈碱型乙酰胆碱受体（MRs）家族的特征是五个亚型（M 1 R-M 5 R）之间具有高度的序列同源性，这是缺乏亚型选择性MR配体的原因。在继续研究双空间二苯并二氮杂醌型M 2 R拮抗剂时，一系列M 2合成了含有与小碱性肽连接的二苯并二氮杂酮药效团的R配体（64种化合物）。接头部分的长度，碱性氮原子数（0-2）和柔韧性有关。除了蛋白原性碱性氨基酸（Lys，Arg）之外，还掺入了分别含有三个和两个亚甲基的Lys和Arg的较短同源物，以及D-构型氨基酸。接头的类型对M 2 R亲和力有显着影响，并且还影响了M 2 R选择性。相反，碱性肽的结构比M 2 R亲和力决定了M 2 R选择性。例如，至多M 2 - [R选择性化合物（UR-CG188，89与皮摩尔M）2 R亲和力（p K i 9.60），表现出更高的M 2 R选择性（K i M 1 R / M 2 R / M 3 R / M 4 R / M
• Condensed diazepinones, their compositions and methods of use as
  申请人：Dr. Karl Thomae GmbH

  公开号：US04550107A1

  公开（公告）日：1985-10-29

  Disclosed are novel condensed diazepinones of formula I ##STR1## wherein B is a fused ring selected from ##STR2## X is --CH-- or, when B is ortho-phenylene, X can also be nitrogen; A.sub.1 is C.sub.1 -C.sub.2 alkylene; A.sub.2 is C.sub.1 -C.sub.2 when it is in the 2-position relative to the saturated heterocyclic ring nitrogen or a single bond or methylene when it is in the 3- or 4-position; R.sub.1 is C.sub.1 -C.sub.3 alkyl; R.sub.2 is C.sub.1 -C.sub.7 alkyl, optionally hydroxy-substituted on at least one of its second to seventh carbon, or C.sub.3 -C.sub.7 cycloalkyl, optionally hydroxy substituted, or C.sub.3 -C.sub.7 cycloalkylmethyl; or R.sub.1 and R.sub.2 can, together with the nitrogen therebetween, be a 4- to 7-membered saturated monocyclic, heterocyclic ring which can optionally include an oxygen or N--CH.sub.3 ; R.sub.3 is hydrogen, chlorine, or methyl; R.sub.4 is hydrogen or C.sub.1 -C.sub.4 alkyl, R.sub.5 is hydrogen, chlorine or C.sub.1 -C.sub.4 alkyl; and Z is a single bond, oxygen, methylene or 1,2-ethylene; and NR.sub.1 R.sub.2 --N oxides and nontoxic, pharmaceutically acceptable addition salts thereof. Also disclosed are pyrrolobenzodiazepinone intermediates, pharmaceutical compositions containing the condensed diazepinones and methods of using them to treat cardiovascular disorders, particularly bradycardia and bradyarrhythmia.

  揭示了式I的新型缩合二氮杂环酮##STR1##其中B是从##STR2##中选择的融合环；X是--CH--或者当B是邻苯二甲烷时，X也可以是氮；A.sub.1是C.sub.1-C.sub.2烷基；A.sub.2是C.sub.1-C.sub.2，当它相对于饱和杂环环氮位于2位时，或者是单键或亚甲基，当它位于3位或4位时；R.sub.1是C.sub.1-C.sub.3烷基；R.sub.2是C.sub.1-C.sub.7烷基，其至少在第二到第七碳上可选择地被羟基取代，或者是C.sub.3-C.sub.7环烷基，可选择地被羟基取代，或者是C.sub.3-C.sub.7环烷基甲基；或者R.sub.1和R.sub.2可以与其之间的氮一起形成一个4到7成员的饱和单环杂环，可选择地包括氧或N--CH.sub.3；R.sub.3是氢、氯或甲基；R.sub.4是氢或C.sub.1-C.sub.4烷基，R.sub.5是氢、氯或C.sub.1-C.sub.4烷基；Z是单键、氧、亚甲基或1,2-乙烯基；以及NR.sub.1 R.sub.2 --N氧化物和其无毒、药学上可接受的加合盐。还揭示了吡咯苯二氮杂环酮中间体、含有缩合二氮杂环酮的药物组合物以及使用它们治疗心血管疾病，特别是心动过缓和心动过缓性心律失常的方法。
• Universal Template Approach to Drug Design:  Polyamines as Selective Muscarinic Receptor Antagonists
  作者：Maria L. Bolognesi、Anna Minarini、Roberta Budriesi、Silvia Cacciaguerra、Alberto Chiarini、Santi Spampinato、Vincenzo Tumiatti、Carlo Melchiorre

  DOI：10.1021/jm981038d

  日期：1998.10.1

  The concept that polyamines may represent a universal template in the receptor recognition process is embodied in the design of new selective muscarinic ligands. Tetraamines 4-7 and 16-20 and diamine diamides 8-15 were synthesized, and their pharmacological profiles at muscarinic receptor subtypes were assessed by functional experiments in isolated guinea pig left atrium (M2) and ileum (M3) and by

  在新的选择性毒蕈碱配体的设计中体现了多胺可能在受体识别过程中代表通用模板的概念。合成了四胺4-7和16-20以及二胺二酰胺8-15，并通过在分离的豚鼠左心房（M2）和回肠（M3）中进行的功能实验以及在大鼠中的结合试验评估了毒蕈碱受体亚型的药理学特征皮层（M1），心脏（M2），上颌下腺（M3）和NG 108-15细胞（M4）。已经证实，四胺模板的末端氮上的适当取代基可以调节对毒蕈碱受体的亲和力和选择性。与其他亚型相比，新型四胺C-三苯胺（17）能够明显地区分M1和M2受体，此外，它的亲脂性是铅化合物三苯丙胺的100倍。其中四胺主链被转化为二胺二酰胺的化合物14（三甲酰胺），对毒蕈碱型亚型保持高亲和力，在质量上显示出与三甲胺类似的结合亲和力分布（M2> M1> M4> M3）。这两种配体由于相对于曲普他明和甲基辛特拉明改善了亲脂性，因此可以用作研究中枢神经系统胆碱能功能的工具。此外，尽管最高亲
• Condensed diazepinones, processes for preparing them and pharmaceutical
  申请人：——

  公开号：US05002943A1

  公开（公告）日：1991-03-26

  Novel condensed diazepinones of general formula I ##STR1## wherein B represents one of the divalent groups ##STR2## and X, A.sup.1, A.sup.2 and R.sup.1 -R.sup.10 are as defined herein. The condensed diazepinones are suitable as vagal pacemakers for the treatment of bradycardia and bradyarrhythmia and they have spasmolytic effects on peripheral organs, particularly the colon, bladder and bronchi.

  新型缩合二氮杂卓酮，其通式为I ##STR1## 其中B代表二价基团之一 ##STR2## 且X、A.sup.1、A.sup.2 和 R.sup.1 -R.sup.10 如本文所定义。这些缩合二氮杂卓酮适用于治疗心动过缓和心搏徐缓性心律失常的迷走神经起搏器，并对周围器官，特别是结肠、膀胱和支气管具有解痉作用。
• Synthesis and structure-activity relationship of some 5-[[[(dialkylamino)alkyl]-1-piperidinyl]acetyl]-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11-ones as M2-selective antimuscarinics
  作者：Victor I. Cohen、Jesse Baumgold、Biyun Jin、Rosanna De la Cruz、Waclaw J. Rzeszotarski、Richard C. Reba

  DOI：10.1021/jm00053a021

  日期：1993.1

  as potential M2-selective ligands. The compounds were evaluated for their affinity and selectivity for the muscarinic cholinergic receptor. The best M2-selective antimuscarinic agent studied is 5-[[4-[4-diethylamino)butyl]-1- piperidinyl]acetyl]-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-11- one, which is approximately 10 times more potent at M2 receptors than previously known compounds such as 11-

  制备了一系列5-[[[[（二烷基氨基）烷基] -1-哌啶基]乙酰基] -10,11-二氢-5H-二苯并[b，e] [1,4]-二氮杂-11-酮M2选择性配体。评价化合物对毒蕈碱胆碱能受体的亲和力和选择性。研究的最好的M2选择性抗毒蕈碱剂是5-[[4- [4-二乙基氨基）丁基] -1-哌啶基]乙酰基] -10,11-二氢-5H-二苯并[b，e] [1,4]二氮杂ze -11-，在M2受体上的效力比以前已知的化合物（例如11-[[4- [4-（二乙基氨基）丁基] -1-哌啶基]乙酰基] -5,11-二氢-6H）强约10倍-吡啶基[2，3-b] [1，4]苯并二氮杂-1-酮（AQ-RA 741）。