(S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole hydrochloride | 2244899-62-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: (S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole hydrochloride
• 英文别名: (S)-6-Chloro-7-methyl-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole hydrochloride；5-chloro-4-methyl-2-[(2S)-2-methylpyrrolidin-2-yl]-1H-benzimidazole;hydrochloride
• CAS: 2244899-62-3
• 化学式: C₁₃H₁₆ClN₃*ClH
• 分子量: 286.204
• InChiKey: OSFVHBSKNUZBTN-ZOWNYOTGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.55
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  40.7
• 氢给体数：
  3
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid 、 (S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole hydrochloride 在 盐酸 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 16.0h， 生成 (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride
  参考文献：
  名称：

  寻求治疗失眠症的最佳双食欲素受体拮抗剂（daridorexant）。

  摘要：

  自 1998 年被发现以来，食欲素系统一直是研究界感兴趣的潜在治疗靶点，用于治疗睡眠/觉醒障碍、压力和焦虑障碍、成瘾或饮食障碍。它由两种 G 蛋白偶联受体（orexin 1 和orexin 2 受体）和两种具有激动作用的神经肽（orexin A 和orexin B 肽）组成。在此，我们描述了我们的努力，导致确定一组有前途的双食欲素受体拮抗剂 (DORA)，随后通过基于生理学的药代动力学和药效学建模> [1]并最终选择了目前处于 3 期临床的 daridorexant治疗失眠障碍的试验。

  DOI：

  10.1002/cmdc.202000453
• 作为产物：
  描述：

  (S)-tert-butyl 2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-2-methylpyrrolidine-1-carboxylate 在 盐酸 、 溶剂黄146 作用下， 以 1,4-二氧六环 为溶剂， 反应 4.5h， 生成 (S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole hydrochloride
  参考文献：
  名称：

  [EN] CRYSTALLINE SALT FORM OF (S)-(2-(6-CHLORO-7-METHYL-1 H-BENZO[D]IMIDAZOL-2-YL)-2-METHYLPYRROLIDIN-1 -YL)(5-METHOXY-2-(2H-1,2,3-TRIAZOL-2-YL)PHENYL)METHANONE AS OREXIN RECEPTOR ANTAGONIST
  [FR] FORME DE SEL CRISTALLINE DE (S)-(2-(6-CHLORO-7-MÉTHYL-1 H-BENZO[D]IMIDAZOL- 2-YL)-2-MÉTHYLPYRROLIDIN-1-YL)(5-MÉTHOXY-2-(2H-1,2,3-TRIAZOL-2-YL)PHÉNYL)MÉTHANONE COMME ANTAGONISTE DES RÉCEPTEURS À L'ORÉXINE

  摘要：

  本发明涉及(S)-(2-(6-氯-7-甲基-1 H-苯并[d]咪唑-2-基)-2-甲基吡咯烷-1-基)(5-甲氧基-2-(2H-1,2,3-三唑-2-基)苯基)甲酮盐酸盐的晶体形态，其制备过程，含有所述晶体形态的制药组合物以及其作为药物的用途，特别是作为促进睡眠的药物受体拮抗剂。

  公开号：

  WO2015083071A1

文献信息

• [EN] USE OF BENZIMIDAZOLE-PROLINE DERIVATIVES<br/>[FR] UTILISATION DE DÉRIVÉS DE BENZIMIDAZOLE-PROLINE
  申请人：ACTELION PHARMACEUTICALS LTD

  公开号：WO2015083094A1

  公开（公告）日：2015-06-11

  The present invention relates to compounds of the formula (I), wherein Ar1 and Ar2 are as described in the description and to their use as pharmaceuticals for the treatment of sundown syndrome. The invention also relates to the preparation of such compounds and of pharmaceutically acceptable salts thereof.

  本发明涉及式(I)的化合物，其中Ar1和Ar2如描述中所述，并且它们作为治疗日落综合征的药物的用途，该发明还涉及制备这种化合物及其药用盐的方法。
• The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468
  作者：Alexander Treiber、Ruben de Kanter、Catherine Roch、John Gatfield、Christoph Boss、Markus von Raumer、Benno Schindelholz、Clemens Muehlan、Joop van Gerven、Francois Jenck

  DOI：10.1124/jpet.117.241596

  日期：2017.9

  The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX1 and OX2) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX2 receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met.

  由于特定疾病的要求，如快速起效、在整个夜间的主要时间段保持睡眠状态以及次日无残留影响等，确定新的睡眠药物给药物发现带来了特殊的挑战。因此，估算药物在人脑中含量的可靠工具是成功发现药物的关键。对于在受体药理学或药代动力学方面没有物种差异的药物，动物模型是一个合适的选择。当种间差异突出时，向人体转化就变得更具挑战性。本报告介绍了通过在药物发现早期应用基于生理学的药代动力学和药效学（PBPK-PD）模型，从一类结构相关的化合物中发现了奥曲肽受体 1 和 2（OX1 和 OX2）双重拮抗剂 ACT-541468。虽然所有候选药物在大鼠睡眠模型中都表现出相似的靶受体效力和疗效，但在决定药代动力学特征的关键因素上却表现出巨大的种间差异。根据体外代谢和理化数据建立了人体 PK 模型，然后用于预测 OX2 受体在大脑中的占据时间过程。根据另外两种奥曲肽拮抗剂（almorexant 和 suvorexant）的临床数据得出的约 65% 的 OX2 受体占据阈值，估算出 ACT-541468 的有效剂量为 25 毫克。在对健康受试者进行的单次升剂量试验中，ACT-541468 的人体模型预测结果基本得到了证实。因此，当需要满足特定的药代动力学和药效学要求时，在药物发现的早期应用 PBPK-PD 建模在协助确定药物分子方面具有巨大的潜力。
• [EN] CRYSTALLINE FORM OF (S)-(2-(6-CHLORO-7-METHYL-1H-BENZO[D]IMIDAZOL-2-YL)-2-METHYLPYRROLIDIN-1 -YL)(5-METHOXY-2-(2H-1,2,3-TRIAZOL-2-YL)PHENYL)METHANONE AND ITS USE AS OREXIN RECEPTOR ANTAGONISTS<br/>[FR] FORME CRISTALLINE DE (S)-(2-(6-CHLORO-7-METHYL-1H-BENZO[D]IMIDAZOL-2-YL)-2-METHYLPYRROLIDIN-1 -YL)(5-METHOXY-2-(2H-1,2,3-TRIAZOL-2-YL)PHENYL)METHANONE ET UTILISATION DE CELLE-CI EN TANT QU'ANTAGONISTES DES RECEPTEURS DE L'OREXINE
  申请人：ACTELION PHARMACEUTICALS LTD

  公开号：WO2015083070A1

  公开（公告）日：2015-06-11

  The invention relates to crystalline forms of (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2- yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone, processes for the preparation thereof, pharmaceutical compositions containing such crystalline forms, pharmaceutical compositions prepared from such crystalline forms, and their use as a medicament, especially as orexin receptor antagonists.

  本发明涉及(S)-(2-(6-氯-7-甲基-1H-苯并[d]咪唑-2-基)-2-甲基吡咯烷-1-基)(5-甲氧基-2-(1,2,3-三唑-2-基)苯基)甲酮的晶体形式，其制备方法，含有这种晶体形式的制药组合物，由这种晶体形式制备的制药组合物，以及它们作为药物的用途，特别是作为促进睡眠药物的奥雷昔康受体拮抗剂。
• USE OF BENZIMIDAZOLE-PROLINE DERIVATIVES
  申请人：ACTELION PHARMACEUTICALS LTD

  公开号：US20170001985A1

  公开（公告）日：2017-01-05

  The present invention relates to compounds of the formula (I), wherein Ar 1 and Ar 2 are as described in the description and to their use as pharmaceuticals for the treatment of sundown syndrome. The invention also relates to the preparation of such compounds and of pharmaceutically acceptable salts thereof.

  本发明涉及式(I)化合物，其中Ar1和Ar2如说明书所述，并且它们的用途是作为治疗日落综合症的药物。本发明还涉及这种化合物的制备以及其药学上可接受的盐的制备。
• Crystalline salt form of (S)-(2-(6 chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone as orexin receptor antagonist
  申请人：IDORSIA PHARMACEUTICALS LTD

  公开号：US10023560B2

  公开（公告）日：2018-07-17

  The invention relates to a crystalline form of (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride, processes for the preparation thereof, pharmaceutical compositions containing said crystalline form, and its use as medicament, especially as orexin receptor antagonist.

  本发明涉及(S)-(2-(6-氯-7-甲基-1H-苯并[d]咪唑-2-基)-2-甲基吡咯烷-1-基)(5-甲氧基-2-(2H-1,2,3-三唑-2-基)苯基)甲酮盐酸盐的结晶形式、其制备工艺、含有所述结晶形式的药物组合物及其作为药物，特别是作为奥曲肽受体拮抗剂的用途。