ethyl 8-bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate | 69585-94-0

• 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 8-bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate
• 英文别名: 8-Bromo-6-(2-pyridyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, ethyl ester；ethyl 8-bromo-6-pyridin-2-yl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
• CAS: 69585-94-0
• 化学式: C₁₉H₁₅BrN₄O₂
• 分子量: 411.258
• InChiKey: BGQCASOBECYAIS-UHFFFAOYSA-N

物化性质

• 沸点：
  581.6±50.0 °C(Predicted)
• 密度：
  1.55±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  69.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 8-bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate 在 四丁基氟化铵 、 palladium diacetate 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 水 、 乙腈 为溶剂， 反应 15.5h， 生成 8-乙炔基-6-吡啶-2-基-4H-咪唑[1,5-a] [1,4]苯并二氮杂-3-羧酸乙酯
  参考文献：
  名称：

  改进的抗焦虑，抗惊厥和抗伤害感受性α2/α3-GABA（A）受体亚型选择性配体的合成，有望成为治疗焦虑症，癫痫病和神经性疼痛的有希望的药物。

  摘要：

  摘要 改进的抗焦虑，抗惊厥和抗伤害感受性化合物的合成：Hz-166及其生物等排体1,2,4-恶二唑（MP-III-080）和1,3-恶唑（KRM-II-81）的合成无需柱色谱分析，就可以实现更高的收率，并具有更便捷的纯化方法（结晶等），以克数计。在KRM-II-81的合成中，使用了选择性还原剂二异丁基叔丁氧基氢化铝钾（PDBBA）的另一种方法，在没有N（5）的情况下制备了所需的C（3）-醛。 –C（6）可减少20克规模的亚胺的高收率。 改进的抗焦虑，抗惊厥和抗伤害感受性化合物的合成：Hz-166及其生物等排体1,2,4-恶二唑（MP-III-080）和1,3-恶唑（KRM-II-81）的合成无需柱色谱分析，就可以实现更高的收率，并具有更便捷的纯化方法（结晶等），以克数计。在KRM-II-81的合成中，使用了选择性还原剂二异丁基叔丁氧基氢化铝钾（PDBBA）的另一种方法，在没有N（5）的情况下制备了所需的C（3）-醛。

  DOI：

  10.1055/s-0037-1610211
• 作为产物：
  描述：

  溴西泮 在 potassium tert-butylate 作用下， 以 四氢呋喃 为溶剂， 反应 15.75h， 生成 ethyl 8-bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate
  参考文献：
  名称：

  Imidazodiazepine Anticonvulsant, KRM-II-81, Produces Novel, Non-diazepam-like Antiseizure Effects

  摘要：

  The need for improved medications for the treatment of epilepsy and chronic pain is essential. Epileptic patients typically take multiple antiseizure drugs without complete seizure freedom, and chronic pain is not fully managed with current medications. A positive allosteric modulator (PAM) of alpha 2/3-containing GABA(A) receptors (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-alpha][1,4]diazepin-3-yl) oxazole or KRM-II-81 (8) is a lead compound in a series of imidazodiazepines. We previously reported that KRM-II-81 produces broad-based anticonvulsant and antinociceptive efficacy in rodent models and provides a wider margin over motoric side effects than that of other GABA(A) receptor PAMs. The present series of experiments was designed to fill key missing gaps in prior preclinical studies assessing whether KRM-II-81 could be further differentiated from nonselective GABA(A) receptor PAMs using the anticonvulsant diazepam (DZP) as a comparator. In multiple chemical seizure provocation models in mice, KRM-II-81 was either equally or more efficacious than DZP. Most strikingly, KRM-II-81 but not DZP blocked the development of seizure sensitivity to the chemoconvulsants cocaine and pentylenetetrazol in seizure kindling models. These and predecessor data have placed KRM-II-81 into consideration for clinical development requiring the manufacture of kilogram amounts of good manufacturing practice material. We describe here a novel synthetic route amenable to kilogram quantity production. The new biological and chemical data provide key steps forward in the development of KRM-II-81 (8) as an improved treatment option for patients suffering from epilepsy.

  DOI：

  10.1021/acschemneuro.0c00295

文献信息

• Synthesis of imidazo[1,5-a]diazepine-3-carboxylates
  申请人：Hoffmann-La Roche Inc.

  公开号：US04118386A1

  公开（公告）日：1978-10-03

  A process to produce diazepine-3-carboxylates of the formula ##STR1## is selected from the group consisting of ##STR2## R.sub.6 is selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, and lower alkanoyl; R.sub.4 is lower alkyl; R.sub.3 is selected from the group consisting of phenyl, mono-substituted phenyl, disubstituted phenyl, pyridyl and mono-substituted pyridyl; and R.sub.2 is hydrogen or lower alkyl which comprises reacting a compound of the formula ##STR3## wherein R.sub.1 is of the formula ##STR4## AND R.sub.5 is lower alkyl with a compound of the formula N.dbd.C-CH.sub.2 --COOR.sub.4 in the presence of a base sufficiently strong to generate the anion of the isocyanoacetate.

  选取一种生产式为##STR1##的二氮杂环己酸酯的方法，所述方法选自下列组合之一：##STR2##其中R.sub.6选自氢、卤素、硝基、氰基、三氟甲基、低烷基和低烷酰基；R.sub.4为低烷基；R.sub.3选自苯基、单取代苯基、双取代苯基、吡啶基和单取代吡啶基；R.sub.2为氢或低烷基，包括以下步骤：将式为##STR3##的化合物（其中R.sub.1为式##STR4##，R.sub.5为低烷基）与式为N.dbd.C-CH.sub.2 --COOR.sub.4的化合物在足够强的碱存在下反应，以生成异氰乙酸酯的负离子。
• GABAERGIC AGENTS TO TREAT MEMORY DEFICITS
  申请人：Cook M. James

  公开号：US20060258643A1

  公开（公告）日：2006-11-16

  The present invention provides molecules and methods for the prevention and/or treatment of memory deficit related conditions and/or enhancement of cognizance. In a preferred embodiment, the invention includes compounds, salts and prodrugs thereof for the prevention and/or treatment of these conditions.

  本发明提供了分子和方法，用于预防和/或治疗与记忆缺陷相关的疾病和/或提高认知能力。在一个首选实施例中，该发明包括化合物、盐和前药，用于预防和/或治疗这些疾病。
• SELECTIVE ANTICONVULSANT AGENTS AND THEIR USES
  申请人：Cook James M.

  公开号：US20100261711A1

  公开（公告）日：2010-10-14

  In preferred embodiments, the present invention provides methods of treatment and pharmaceutical compositions for the suppression, alleviation and prevention of seizures. The preferred embodiments of the present invention further relate to methods of treatment and pharmaceutical compositions using benzodiazepine derivatives that provide suppression, alleviation and prevention of seizures with reduced sedative and ataxic side effects.

  在优选实施方式中，本发明提供了用于抑制、缓解和预防癫痫发作的治疗方法和药物组合物。本发明的优选实施方式进一步涉及使用苯二氮䓬类衍生物的治疗方法和药物组合物，该类衍生物在减少镇静和共济失调副作用的同时提供了抑制、缓解和预防癫痫发作的效果。
• [EN] GABAERGIC LIGANDS AND THEIR USES<br/>[FR] LIGANDS GABAERGIQUES ET LEURS UTILISATIONS
  申请人：UWM RES FOUND INC

  公开号：WO2016154031A1

  公开（公告）日：2016-09-29

  Described herein are α3 or α2 or α2/α3 GABAergic receptor subtype selective ligands, pharmaceutical compositions, and methods of use of such ligands and compositions in treatment of anxiety disorders, epilepsy and schizophrenia with reduced sedative and ataxic side effects. In embodiments, such as α3 or α2 or α2/α3 GABAergic receptor subtype selective ligands lack ester linkages and may be thus relatively insensitive to hydrolysis by esterases.

  本文描述了α3或α2或α2/α3 GABA能受体亚型选择性配体、药物组合物以及使用这些配体和组合物治疗焦虑症、癫痫和精神分裂症的方法，且具有减少镇静和共济失调副作用。在某些实施例中，如α3或α2或α2/α3 GABA能受体亚型选择性配体缺乏酯键，因此相对不容易被酯酶水解。
• [EN] STEREOSPECIFIC ANXIOLYTIC AND ANTICONVULSANT AGENTS WITH REDUCED MUSCLE-RELAXANT, SEDATIVE-HYPNOTIC AND ATAXIC EFFECTS<br/>[FR] AGENTS ANXIOLYTIQUES ET ANTICONVULSIFS STEREOSPECIFIQUES PRESENTANT DES EFFETS MYORELAXANTS, SEDATIFS-HYPNOTIQUES ET ATAXIQUES REDUITS
  申请人：WISYS TECHNOLOGY FOUND INC

  公开号：WO2006004945A1

  公开（公告）日：2006-01-12

  The present invention provides compositions and methods of using stereospecific benzodiazepine derivatives, their salts and prodrugs for the treatment of anxiolytic or convulsant disorders having the side effects of reduced alcohol craving in human alcoholics and a concomitant reduced sedative, hypnotic, muscle relaxant and ataxic side-effects. The invention further provides pharmaceutical compositions for treatment of anxiolytic and convulsant disorders in subjects in need thereof, comprising a compound, prodrug or a salt having a chemical structure represented by any one of Formula I-XXI and a pharmaceutically-acceptable carrier.

  本发明提供了使用立体特异性苯二氮平衍生物、它们的盐和前药治疗焦虑或惊厥性疾病的组合物和方法，其副作用为减少酒精成瘾，同时减少镇静、催眠、肌肉松弛和共济失调的副作用。本发明还提供了制药组合物，用于治疗需要的患有焦虑和惊厥性疾病的受试者，包括具有化学结构的化合物、前药或盐，该化学结构由公式I-XXI中的任何一个表示，并且具有药学上可接受的载体。