N,N-Didemethyladinazolam | 37115-34-7

• 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: N,N-Didemethyladinazolam
• 英文别名: N,N-didesmethyladinazolam；C-(8-chloro-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-1-yl)-methylamine；8-chloro-1-(aminomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine；Desmethyladinazolam；(8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl)methanamine
• CAS: 37115-34-7
• 化学式: C₁₇H₁₄ClN₅
• 分子量: 323.785
• InChiKey: IITNCTOGXYNNRY-UHFFFAOYSA-N

物化性质

• 熔点：
  167.5-172.5 °C
• 沸点：
  541.9±60.0 °C(Predicted)
• 密度：
  1.45±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  69.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N,N-Didemethyladinazolam 、 聚合甲醛 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 水 、 乙腈 为溶剂， 反应 1.75h， 以64.3%的产率得到阿地唑仑
  参考文献：
  名称：

  药理学上重要的1-取代的6-苯基-4 H - s-三唑并[4,3- a ] [1,4]苯并二氮杂s的新颖合成

  摘要：

  几种6-苯基-4 H - s-三唑并[4,3- a ] [1,4]苯并二氮杂pine在实验动物和人类中均具有有用的生物学活性。该手稿描述了从不具有预先形成的苯并二氮杂ring环系统的中间体新颖合成这些化合物的方法。

  DOI：

  10.1002/jhet.5570170331
• 作为产物：
  描述：

  7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 在 氨 、 potassium iodide 作用下， 以 四氢呋喃 、 甲醇 、 溶剂黄146 为溶剂， 反应 19.91h， 生成 N,N-Didemethyladinazolam
  参考文献：
  名称：

  1-（氨基烷基）-6-芳基-4-Hs-三唑并[4,3-a] [1,4]苯并二氮杂卓具有抗焦虑和抗抑郁活性。

  摘要：

  已经制备了一系列的1-（氨基烷基）-6-芳基-4H-s-三唑并[4，3-a] [1，4]苯并二氮杂并评估中枢神经系统活性。我们发现该系列的成员在旨在检测抗焦虑和抗抑郁活性的药理学测试系统中具有活性。每种类型的活性可以通过适当的取代基选择独立地变化。

  DOI：

  10.1021/jm00178a009

文献信息

• Intermediates and process for the production of certain
  申请人：The Upjohn Company

  公开号：US03947466A1

  公开（公告）日：1976-03-30

  A multi-step process for the preparation of 1-[(amino - or substituted amino)methyl]-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepines of the formula VI: ##SPC1## wherein R' is hydrogen or alkyl of 1 to 3 carbon atoms, inclusive, and wherein the rings A and B are unsubstituted or substituted by one or two substituents selected from the group consisting of chloro, fluoro, bromo, nitro, and trifluoromethyl, which comprises: treating a compound of the formula I: ##SPC2## wherein rings A and B are defined as above, with acetic anhydride and formic acid to obtain compound II: ##SPC3## wherein A and B rings have the significance as above, treating compound II with sufficient formaldehyde to produce compound III, the 3,5-bis(hydroxymethyl)derivative of II; treating III with phthalimide, triphenylphosphine and diethyl azodicarboxylate to give compound IV, the 3,5-bis(phthalimidomethyl) derivative of II; and treating IV with hydrazine hydrate to obtain a compound of formula V ##SPC4## wherein rings A and B are defined, as herein above. Compound V can then be alkylated in known manner to give those compounds of formula VIa which corresponds to formula VI when R' is desired to be alkyl. The compounds of formula VI have antidepressant and antianxiety effects in mammals and birds.

  一种用于制备公式VI中1-[(氨基或取代氨基)甲基]-6-苯基-4H-s-三唑并[4,3-a][1,4]苯二氮杂平的多步骤过程：其中R'是氢或含有1至3个碳原子的烷基，环A和环B未取代或取代为来自氯、氟、溴、硝基和三氟甲基的一个或两个取代基，包括以下步骤：将公式I的化合物：用乙酸酐和甲酸处理以获得化合物II；将化合物II与足够的甲醛处理以产生化合物III，II的3,5-双(羟甲基)衍生物；将III与邻苯二甲酰亚胺、三苯基膦和双乙酰双氨基甲酸酯处理以给出化合物IV，II的3,5-双(邻苯二甲酰亚胺基)衍生物；将IV与水合肼处理以获得公式V的化合物，其中A和B环如上定义。然后，可以以已知方式烷基化化合物V，以给出当R'需要是烷基时对应于公式VI的公式VIa的那些化合物。公式VI的化合物在哺乳动物和鸟类中具有抗抑郁和抗焦虑作用。
• Kinetic Characterization and Identification of the Enzymes Responsible for the Hepatic Biotransformation of Adinazolam and <i>N</i>-Desmethyladinazolam in Man
  作者：Karthik Venkatakrishnan、Lisa L Von Moltke、Su Xiang Duan、Joseph C Fleishaker、Richard I Shader、David J Greenblatt

  DOI：10.1111/j.2042-7158.1998.tb06859.x

  日期：2011.4.12

  The kinetics of the N-demethylation of adinazolam to N-desmethyladinazolam (NDMAD), and of NDMAD to didesmethyladinazolam (DDMAD), were studied with human liver microsomes using substrate concentrations in the range 10–1000 μm. The specific cytochrome P450 (CYP) isoforms mediating the biotransformations were identified using microsomes containing specific recombinant CYP isozymes expressed in human lympho-blastoid cells, and by the use of CYP isoform-selective chemical inhibitors.

  Adinazolam was demethylated by human liver microsomes to NDMAD, and NDMAD was demethylated to DDMAD; the substrate concentrations, Km, at which the reaction velocities were 50% of the maximum were 92 and 259 μm, respectively. Another metabolite of yet undetermined identity (U) was also formed from NDMAD (Km 498 μm). Adinazolam was demethylated by cDNA-expressed CYP 2C19 (Km 39 μm) and CYP 3A4 (Km 83 μm); no detectable activity was observed for CYPs 1A2, 2C9, 2D6 and 2E1. Ketoconazole, a relatively specific CYP 3A4 inhibitor, inhibited the reaction; the concentration resulting in 50% of maximum inhibition, IC50, was 0·15 μm and the inhibition constant, Ki, was &lt; 0·04 μm in five of six livers tested. Troleandomycin, a specific inhibitor of CYP 3A4, inhibited adinazolam N-demethylation with an IC50 of 1·96 μm. The CYP 2C19-inhibitor omeprazole resulted in only partial inhibition (IC50 21 μm) and sulphaphenazole, α-naphthoflavone, quinidine and diethyldithiocarbamate did not inhibit the reaction. NDMAD was demethylated by cDNA-expressed CYP 3A4 (Km 220 μm, Hill number A 1·21), CYP 2C19 (Km 187 μm, Hill number A 1·29) and CYP 2C9 (Km 1068 μm). Formation of U was catalysed by CYP 3A4 alone. Ketoconazole strongly inhibited NDMAD demethylation (IC50 0·14 μm) and formation of U (IC50 &lt; 0·1 μm) whereas omeprazole and sulphaphenazole had no effect on reaction rates.

  These results show that CYP 3A4 is the primary hepatic CYP isoform mediating the N-demethylation of adinazolam and NDMAD. Co-administration of adinazolam with CYP 3A4 inhibitors such as ketoconazole or erythromycin might lead to reduced efficacy, since adinazolam by itself has relatively weak benzodiazepine agonist activity, with much of the pharmacological activity of adinazolam being attributable to its active metabolite NDMAD.

  摘要：使用人类肝微粒体，以10-1000μm的底物浓度研究了阿地那唑的N-去甲基化反应生成N-去甲基阿地那唑（NDMAD）以及NDMAD的去甲基化反应生成二去甲基阿地那唑（DDMAD）的动力学。通过使用含有在人类淋巴母细胞中表达的具体重组CYP同工酶的微粒体，并通过使用CYP同工酶选择性化学抑制剂，确定了介导生物转化的特定细胞色素P450（CYP）同工酶。阿地那唑被人类肝微粒体去甲基化生成NDMAD，NDMAD被去甲基化生成DDMAD；反应速率达到最大值时的底物浓度Km分别为92和259μm。另一个未确定身份的代谢物（U）也从NDMAD（Km 498μm）中形成。阿地那唑被cDNA表达的CYP 2C19（Km 39μm）和CYP 3A4（Km 83μm）去甲基化，对于CYPs 1A2、2C9、2D6和2E1没有检测到活性。相对特异性的CYP 3A4抑制剂酮康唑抑制了反应，导致50％最大抑制的浓度IC50在测试的六个肝脏中为0.15μm，抑制常数Ki为<0.04μm。特异性CYP 3A4抑制剂三唑巴胺以IC50为1.96μm抑制阿地那唑的N-去甲基化。CYP 2C19抑制剂奥美拉唑仅导致部分抑制（IC50 21μm），而磺胺苯并咪唑、α-萘酚、奎尼丁和二乙硫氨酸不抑制反应。NDMAD被cDNA表达的CYP 3A4（Km 220μm，Hill数A 1.21）、CYP 2C19（Km 187μm，Hill数A 1.29）和CYP 2C9（Km 1068μm）去甲基化。仅CYP 3A4催化U的形成。酮康唑强烈抑制NDMAD的去甲基化（IC50 0.14μm）和U的形成（IC50 <0.1μm），而奥美拉唑和磺胺苯并咪唑对反应速率没有影响。这些结果表明，CYP 3A4是介导阿地那唑和NDMAD的N-去甲基化的主要肝脏CYP同工酶。与CYP 3A4抑制剂如酮康唑或红霉素联用阿地那唑可能导致疗效降低，因为阿地那唑本身具有相对较弱的苯二氮平激动剂活性，其药理活性的大部分归因于其活性代谢物NDMAD。
• HESTER J. B.; RUDZIK A. D.; VOIGTLANDER P. F. VON, J. MED. CHEM., 1980, 23, NO 4, 392-402
  作者：HESTER J. B.、 RUDZIK A. D.、 VOIGTLANDER P. F. VON

  DOI：——

  日期：——
• HESTER J. B. JR., J. HETEROCYCL. CHEM., 1980, 17, NO 3, 575-581
  作者：HESTER J. B. JR.

  DOI：——

  日期：——
• TREATMENT OF PREMENSTRUAL SYNDROMES USING TRIAZOLOBENZODIAZEPINES
  申请人：THE UPJOHN COMPANY

  公开号：EP0219541A1

  公开（公告）日：1987-04-29