ethyl 5,6-dihydro-5-(2,4-dimethoxybenzyl)-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate | 78755-91-6

• 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: ethyl 5,6-dihydro-5-(2,4-dimethoxybenzyl)-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
• 英文别名: ethyl 5-[(2,4-dimethoxyphenyl)methyl]-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
• CAS: 78755-91-6
• 化学式: C₂₃H₂₃N₃O₅
• 分子量: 421.453
• InChiKey: ZSIFYYNYXVBIQG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  82.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 5,6-dihydro-5-(2,4-dimethoxybenzyl)-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate 在 ammonium chloride 、 氨 、 potassium carbonate 作用下， 以 N-甲基乙酰胺 、 甲醇 、 水 、 三氟乙酸 为溶剂， 生成 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide
  参考文献：
  名称：

  Imidazodiazepine derivatives

  摘要：

  咪唑二氮杂环己烯衍生物的公式为##STR1##其中A与两个碳原子α和β一起从##STR2##中选择，虚线代表(a)和(b)中存在的双键，D为>C.dbd.O或>C.dbd.S，R.sup.1从氰基，较低的烷酰基和公式--COOR.sup.4的基团中选择，R.sup.4从甲基，乙基，异丙基和2-羟乙基中选择，R.sup.5从氢，三氟甲基和卤素中选择，R.sup.6从氢，三氟甲基，卤素和较低烷基中选择，R.sup.2为氢，R.sup.3为氢或较低烷基，或者R.sup.2和R.sup.3一起为三甲亚基或丙烯亚基，所述的碳原子γ具有S-或R,S-构型，及其药学上可接受的盐，用于对抗具有镇静活性的1,4-苯二氮杂环己烷的中枢抑制、肌肉松弛、共济失调、降低血压和呼吸抑制特性。它们可以用作例如，在过量摄入具有镇静活性的1,4-苯二氮杂环己烷的中毒情况下的解毒剂，或者缩短由这些1,4-苯二氮杂环己烷引起的麻醉。它们还可用于抑制其他适应领域中使用的1,4-苯二氮杂环己烷对中枢神经系统的活性，例如对于片尾蚴活性的1,4-苯二氮杂环己烷，如(+)-5-(邻氯苯基)-1,3-二氢-3-甲基-7-硝基-2H-1,4-苯二氮杂环己烷-2-酮。还提供了生产咪唑二氮杂环己烯衍生物及其中间体的方法。

  公开号：

  US04316839A1
• 作为产物：
  描述：

  2,4-二甲氧基苯甲醛 在 sodium hydroxide 盐酸 、 sodium chloride 、 溶剂黄146 作用下， 以 N-甲基乙酰胺 、 甲醇 、 水 、 二甲基亚砜 为溶剂， 生成 ethyl 5,6-dihydro-5-(2,4-dimethoxybenzyl)-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
  参考文献：
  名称：

  Imidazodiazepine derivatives

  摘要：

  咪唑二氮杂环己烯衍生物的公式为##STR1##其中A与两个碳原子α和β一起从##STR2##中选择，虚线代表(a)和(b)中存在的双键，D为>C.dbd.O或>C.dbd.S，R.sup.1从氰基，较低的烷酰基和公式--COOR.sup.4的基团中选择，R.sup.4从甲基，乙基，异丙基和2-羟乙基中选择，R.sup.5从氢，三氟甲基和卤素中选择，R.sup.6从氢，三氟甲基，卤素和较低烷基中选择，R.sup.2为氢，R.sup.3为氢或较低烷基，或者R.sup.2和R.sup.3一起为三甲亚基或丙烯亚基，所述的碳原子γ具有S-或R,S-构型，及其药学上可接受的盐，用于对抗具有镇静活性的1,4-苯二氮杂环己烷的中枢抑制、肌肉松弛、共济失调、降低血压和呼吸抑制特性。它们可以用作例如，在过量摄入具有镇静活性的1,4-苯二氮杂环己烷的中毒情况下的解毒剂，或者缩短由这些1,4-苯二氮杂环己烷引起的麻醉。它们还可用于抑制其他适应领域中使用的1,4-苯二氮杂环己烷对中枢神经系统的活性，例如对于片尾蚴活性的1,4-苯二氮杂环己烷，如(+)-5-(邻氯苯基)-1,3-二氢-3-甲基-7-硝基-2H-1,4-苯二氮杂环己烷-2-酮。还提供了生产咪唑二氮杂环己烯衍生物及其中间体的方法。

  公开号：

  US04316839A1

文献信息

• Discovery of the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine scaffold as a novel, potent and selective GABAA α5 inverse agonist series
  作者：Guido Achermann、Theresa M. Ballard、Francesca Blasco、Pierre-Emmanuel Broutin、Bernd Büttelmann、Holger Fischer、Martin Graf、Maria-Clemencia Hernandez、Peter Hilty、Frédéric Knoflach、Andreas Koblet、Henner Knust、Anke Kurt、James R. Martin、Raffaello Masciadri、Richard H.P. Porter、Heinz Stadler、Andrew W. Thomas、Gerhard Trube、Jürgen Wichmann

  DOI：10.1016/j.bmcl.2009.07.153

  日期：2009.10

  Through iterative design cycles we have discovered a number of novel new classes where the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine was deemed the most promising GABAA α5 inverse agonist class with potential for cognitive enhancement. This class combines a modest subtype binding selectivity with inverse agonism and has the most favourable molecular properties for further lead optimisation

  通过迭代设计周期，我们发现了许多新颖的新类，其中咪唑并[1,5- a ] [1,2,4]-三唑并[1,5- d ] [1,4]苯并二氮杂被认为是最有前途的GABA一个α5反相激动剂类的认知提高的潜力。此类具有适度的亚型结合选择性和反向激动作用，并具有最有利的分子特性，可进一步优化针对中枢神经系统（CNS）的药物。
• Synthesis and structure-activity relationships of 3,5-disubstituted 4,5-dihydro-6H-imidazo[1,5-a][1,4]benzodiazepin-6-ones at diazepam-sensitive and diazepam-insensitive benzodiazepine receptors
  作者：Subramaniam Ananthan、Sarah D. Clayton、Steven E. Ealick、Garry Wong、Gary E. Evoniuk、Phil Skolnick

  DOI：10.1021/jm00056a008

  日期：1993.2

  Introduction of chlorine at the 7-position enhances ligand affinity at DS BzR while chlorine at the 8-position decreases affinity (IC50: 11f, 9.3 nM; 11h, 2.4 nM; 11i, 37.8 nM). In contrast, chlorine substitution at the 7- as well as the 8-position increases affinity at DI BzR (Ki: 11f, 112 nM; 11h, 20.2 nM; 11i, 10.9 nM). Compound 11 is among the few described high affinity DI-site ligands with a selectivity

  合成了一系列在3和5位具有不同取代基的咪唑并苯并二氮杂6-1，并评估了它们在大鼠皮质和小脑中对地西epa敏感（DS）和对地西epa不敏感（DI）苯并二氮杂（受体（BzR）的亲和力膜。用氨基甲酸酯，乙酰氨基，甲酰基氨基，异硫氰酸根合，2-恶唑啉基，2-苯并恶唑基或对甲苯磺酰基取代3-位的酯取代基会导致DS和DI BzR的亲和力降低> 100倍。用丙基，烯丙基或苯乙基取代5-位氮上的甲基也导致两种BzR同工型的亲和力显着降低。但是，结合苄基会产生在DS BzR上具有中等至高亲和力的配体（11f，h，i和14a-c），提示在受体位点存在疏水口袋。在7位引入氯会增强DS BzR的配体亲和力，而在8位引入氯会降低亲和力（IC50：11f，9.3 nM； 11h，2.4 nM； 11i，37.8 nM）。相反，在7位和8位的氯取代增加了DI BzR的亲和力（Ki：11f，112 nM； 11h，20.2
• Process for preparing imidazodiazepines
  申请人：Hoffmann-La Roche Inc.

  公开号：US04363762A1

  公开（公告）日：1982-12-14

  Imidazodiazepine derivatives of the formula ##STR1## wherein A together with the two carbon atoms denoted as .alpha. and .beta. is selected from the group consisting of: ##STR2## the dotted line represents the double bond present in groups (a) and (b), D is >C.dbd.O or >C.dbd.S, R.sup.1 is selected from the group consisting of cyano, lower alkanoyl and a group of the formula --COOR.sup.4, R.sup.4 is selected from the group consisting of methyl, ethyl, isopropyl and 2-hydroxyethyl, R.sup.5 is selected from the group consisting of hydrogen, trifluoromethyl and halogen and R.sup.6 is selected from the group consisting of hydrogen, trifluoromethyl, halogen and lower alkyl and either R.sup.2 is hydrogen and R.sup.3 is hydrogen or lower alkyl or R.sup.2 and R.sup.3 together are trimethylene or propenylene and the carbon atom denoted as .gamma. has the S- or R,S-configuration, and pharmaceutically acceptable salts thereof are presented and have utility for antagonising the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquillising activity. They can be used, for example, as antidotes in the case of intoxications in which excessive intake of 1,4-benzodiazepines which have tranquillising participates, or for shortening an anaesthesia induced by such 1,4-benzodiazepines. They can also be used for suppressing the activities on the central nervous system of 1,4-benzodiazepines used in other fields of indication, for example of schistosomicidally-active 1,4-benzodiazepines such as (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2 -one. Also presented are processes to produce the imidazodiazepine derivatives and intermediates therefor.

  本发明涉及式（I）的咪唑二氮杂苯衍生物，其中A与表示为α和β的两个碳原子一起从以下组中选择：##STR2##其中虚线表示(a)和(b)中存在的双键，D是>C.dbd.O或>C.dbd.S，R.sup.1从以下组中选择：氰基，低烷酰基和公式--COOR.sup.4的基团，R.sup.4从甲基，乙基，异丙基和2-羟乙基的组中选择，R.sup.5从氢，三氟甲基和卤素的组中选择，R.sup.6从氢，三氟甲基，卤素和低烷基的组中选择，且R.sup.2为氢且R.sup.3为氢或低烷基，或者R.sup.2和R.sup.3一起为三亚甲基或丙烯亚甲基，表示为γ的碳原子具有S-或R，S-构型。还提供了其药学上可接受的盐，并具有对具有镇静作用的1,4-苯二氮䓬类化合物的中枢抑制、肌肉松弛、共济失调、降低血压和呼吸抑制特性的拮抗作用。例如，在过量摄入具有镇静作用的1,4-苯二氮䓬类药物的中毒情况下，它们可以用作解毒剂，或者用于缩短由这些1,4-苯二氮䓬类药物引起的麻醉。它们还可用于抑制用于其他适应症领域的1,4-苯二氮䓬类药物对中枢神经系统的活性，例如对血吸虫杀虫活性的1,4-苯二氮䓬类药物，如(+)-5-(o-氯苯基)-1,3-二氢-3-甲基-7-硝基-2H-1,4-苯二氮䓬啶-2-酮。还提供了制备咪唑二氮杂苯衍生物及其中间体的方法。
• Thienodiazepinone and benzodiazepinone intermediates
  申请人：Hoffmann-La Roche Inc.

  公开号：US04346033A1

  公开（公告）日：1982-08-24

  Imidazodiazepine derivatives of the formula ##STR1## wherein A together with the two carbon atoms denoted as .alpha. and .beta. is selected from the group consisting of ##STR2## the dotted line represents the double bond present in groups (a) and (b), D is >C.dbd.O or >C.dbd.S, R.sup.1 is selected from the group consisting of cyano, lower alkanoyl and a group of the formula --COOR.sup.4, R.sup.4 is selected from the group consisting of methyl, ethyl, isopropyl and 2-hydroxyethyl, R.sup.5 is selected from the group consisting of hydrogen, trifluoromethyl and halogen and R.sup.6 is selected from the group consisting of hydrogen, trifluoromethyl, halogen and lower alkyl and either R.sup.2 is hydrogen and R.sup.3 is hydrogen or lower alkyl or R.sup.2 and R.sup.3 together are trimethylene or propenylene and the carbon atom denoted as .gamma. has the S- or R,S-configuration, and pharmaceutically acceptable salts thereof are presented and have utility for antagonizing the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquillizing activity. They can be used, for example, as antidotes in the case of intoxications in which excessive intake of 1,4-benzodiazepines which have tranquillizing participates, or for shortening an anaesthesia induced by such 1,4-benzodiazepines. They can also be used for suppressing the activities on the central nervous system of 1,4-benzodiazepines used in other fields of indication, for example of schistosomicidally-active 1,4-benzodiazepines such as (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2 -one. Also presented are processes to produce the imidazodiazepine derivatives and intermediates therefor.

  本发明提供了公式## STR1 ##的咪唑二氮杂环衍生物，其中A与表示为α和β的两个碳原子一起从以下组中选择## STR2 ##点线代表(a)和(b)组中存在的双键，D是> C.dbd.O或> C.dbd.S，R.sup.1选择从氰基，低烷酰基和公式--COOR.sup.4的群中选择，其中R.sup.4选择从甲基，乙基，异丙基和2-羟乙基的群中选择，R.sup.5选择从氢，三氟甲基和卤素的群中选择，R.sup.6选择从氢，三氟甲基，卤素和低烷基的群中选择，R.sup.2为氢且R.sup.3为氢或低烷基，或R.sup.2和R.sup.3一起为三亚甲基或丙烯亚甲基，表示为γ的碳原子具有S-或R，S-构型，以及其药学上可接受的盐，用于拮抗具有镇静作用的1,4-苯二氮平具有中枢抑制，肌肉松弛，共济失调，降低血压和呼吸抑制特性。例如，它们可用作中毒情况下的解毒剂，在这种情况下，过量摄入具有镇静作用的1,4-苯二氮平参与，或用于缩短由这种1,4-苯二氮平引起的麻醉。它们还可用于抑制用于其他适应症领域的1,4-苯二氮平对中枢神经系统的活性，例如对于血吸虫杀虫作用的1,4-苯二氮平，如（+）-5-（o-氯苯基）-1,3-二氢-3-甲基-7-硝基-2H-1,4-苯二氮平-2-酮。还提供了制备咪唑二氮杂环衍生物及其中间体的过程。
• Process for preparing imidazodiazepine derivatives
  申请人：Hoffmann-La Roche Inc.

  公开号：US04346036A1

  公开（公告）日：1982-08-24

  Imidazodiazepine derivatives of the formula ##STR1## wherein A together with the two carbon atoms denoted as .alpha. and .beta. is selected from the group consisting of ##STR2## the dotted line represents the double bond present in groups (a) and (b), D is >C.dbd.O or >C.dbd.S, R.sup.1 is selected from the group consisting of cyano, lower alkanoyl and a group of the formula --COOR.sup.4, R.sup.4 is selected from the group consisting of methyl, ethyl, isopropyl and 2-hydroxyethyl, R.sup.5 is selected from the group consisting of hydrogen, trifluoromethyl and halogen and R.sup.6 is selected from the group consisting of hydrogen, trifluoromethyl, halogen and lower alkyl and either R.sup.2 is hydrogen and R.sup.3 is hydrogen or lower alkyl or R.sup.2 and R.sup.3 together are trimethylene or propenylene and the carbon atom denoted as .gamma. has the S- or R,S-configuration, and pharmaceutically acceptable salts thereof are presented and have utility for antagonising the central-depressant, muscle relaxant, ataxic, blood pressure-lowering and respiratory-depressant properties of 1,4-benzodiazepines which have tranquillizing activity. They can be used, for example, as antidotes in the case of intoxications in which excessive intake of 1,4-benzodiazepines which have tranquillizing participates, or for shortening an anaesthesia induced by such 1,4-benzodiazepines. They can also be used for suppressing the activities on the central nervous system of 1,4-benzodiazepines used in other fields of indication, for example of schistosomicidally-active 1,4-benzodiazepines such as (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2 -one. Also presented are processes to produce the imidazodiazepine derivatives and intermediates therefor.

  该专利介绍了公式为##STR1##的咪唑二氮杂苯并二氮䓬衍生物，其中A连同α和β表示的两个碳原子被选自以下组合：##STR2## 虚线代表(a)和(b)组中存在的双键，D为>C.dbd.O或>C.dbd.S，R.sup.1被选自氰基、低级脂肪酰基和式为--COOR.sup.4的基团，R.sup.4被选自甲基、乙基、异丙基和2-羟乙基，R.sup.5被选自氢、三氟甲基和卤素，R.sup.6被选自氢、三氟甲基、卤素和低级烷基，R.sup.2为氢，R.sup.3为氢或低级烷基，或R.sup.2和R.sup.3一起为三亚甲基或丙烯亚甲基，表示为γ的碳原子具有S-或R,S-构型，并且其药学上可接受的盐具有拮抗1,4-苯二氮䓬酮的中枢抑制、肌肉松弛、共济失调、降低血压和呼吸抑制等性质的功效，这些化合物可以用作拮抗具有镇静作用的1,4-苯二氮䓬酮中毒的解毒剂，或者缩短由这些1,4-苯二氮䓬酮诱导的麻醉时间。它们还可以用于抑制其他领域中使用的1,4-苯二氮䓬酮对中枢神经系统的活动，例如对血吸虫活性的1,4-苯二氮䓬酮（如(+)-5-(o-氯苯基)-1,3-二氢-3-甲基-7-硝基-2H-1,4-苯二氮䓬酮-2-酮）的活性。此外，还介绍了制备咪唑二氮杂苯并二氮䓬衍生物及其中间体的方法。