(4R)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-4-羟基-N,N-二甲基-L-脯氨酰胺 | 439687-69-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: (4R)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-4-羟基-N,N-二甲基-L-脯氨酰胺
• 英文名称: Nelivaptan
• 英文别名: SSR149415；(2S,4R)-1-[(3R)-5-chloro-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-methoxyphenyl)-2-oxoindol-3-yl]-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide
• CAS: 439687-69-1
• 化学式: C₃₀H₃₂ClN₃O₈S
• 分子量: 630.118
• InChiKey: NJXZWIIMWNEOGJ-WEWKHQNJSA-N

物化性质

• 沸点：
  799.7±70.0 °C(Predicted)
• 密度：
  1.414±0.06 g/cm3(Predicted)
• 溶解度：
  63.01mg/ml，溶于DMSO； 63.01mg/ml 乙醇溶液

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  43
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  134
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (4R)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-4-羟基-N,N-二甲基-L-脯氨酰胺 、 异丁酰氯 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 36.0h， 生成 (3R,5S)-1-[(3R)-5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl 2-methyl propanoate
  参考文献：
  名称：

  Acyloxypyrrolidine derivatives, preparation thereof and application thereof in therapeutic

  摘要：

  本发明涉及一般式（I）的酰氧吡咯烷衍生物： 其中：R1表示氢原子、（C1-C6）烷基、（C3-C6）环烷基、—CH2CH2COOH基团或—NR2R3基团； R2和R3各自独立地表示氢原子或（C1-C6）烷基。本发明还公开和要求该化合物的制备方法和其在治疗学中的应用。

  公开号：

  US20050192335A1
• 作为产物：
  描述：

  2,4-二甲氧基苯磺酰氯 、 (2S,4R)-1-((R)-5-chloro-3-(2-methoxyphenyl)-2-oxoindolin-3-yl)-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.05h， 以100%的产率得到(4R)-1-[(3R)-5-氯-1-[(2,4-二甲氧基苯基)磺酰基]-3-(2-甲氧基苯基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-4-羟基-N,N-二甲基-L-脯氨酰胺
  参考文献：
  名称：

  Synthesis of [11C]SSR149415 and preliminary imaging studies using positron emission tomography

  摘要：

  SSR149415 was the first non-peptide vasopressin-(V-1b) receptor antagonist reported. It has been used to probe the role of V-1b receptors in animal models of depression, aggression, and stress-anxiety, and was progressed to clinical trials for the treatment of depression. Due to the interest in V-1b receptors as a therapeutic target and the growing use of SSR149415 in preclinical research, we developed a method to label SSR145419 with carbon-11 and have studied its pharmacokinetics in non-human primates using positron emission tomography. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.03.108

文献信息

• Method for predicting a treatment response to a CRHR1 antagonist and/or a V1B antagonist in a patient with depressive and/or anxiety symptoms
  申请人：MAX-PLANCK-GESELLSCHAFT ZUR FÖRDERUNG DER WISSENSCHAFTEN E.V.

  公开号：US10190168B2

  公开（公告）日：2019-01-29

  The present invention relates to a method for predicting a treatment response to a corticotropin releasing hormone receptor type 1 (CRHR1) antagonist and/or a vasopressin receptor 1B (V1B) antagonist in a patient with depressive and/or anxiety symptoms. The present invention furthermore relates to a V1B receptor antagonist and/or CRHR1 antagonist for use in the treatment of depressive symptoms and/or anxiety symptoms in a patient. Also, kits, diagnostic compositions, devices and microarrays allowing the determination of the presence or absence of at least one polymorphic variant in the AVPR1B gene in combination with the presence or absence of at least one polymorphic variant in the patient's genome excluding the AVPR1B gene in the nucleic acid sample are described.

  本发明涉及一种预测抑郁和/或焦虑症状患者对促肾上腺皮质激素释放激素受体1型（CRHR1）拮抗剂和/或血管加压素受体1B（V1B）拮抗剂的治疗反应的方法。本发明还涉及用于治疗患者抑郁症状和/或焦虑症状的V1B受体拮抗剂和/或CRHR1拮抗剂。此外，本发明还描述了试剂盒、诊断组合物、装置和微阵列，这些试剂盒、诊断组合物、装置和微阵列可结合核酸样本中患者基因组中排除 AVPR1B 基因的至少一种多态变体的存在与否来确定 AVPR1B 基因中至少一种多态变体的存在与否。
• V1B receptor antagonist for use in the treatment of patients having an elevated AVP level and/or an elevated copeptin level
  申请人：B.R.A.H.M.S GMBH

  公开号：US10857129B2

  公开（公告）日：2020-12-08

  The present invention relates to a vasopressin receptor 1B (V1B) antagonist for use in the treatment of depressive symptoms and/or anxiety symptoms in patients showing an elevated arginine vasopressin (AVP) level and/or an elevated copeptin level. The present invention further relates to a method for predicting the treatment response to a V1B antagonist in patients with depressive symptoms and/or anxiety symptoms.

  本发明涉及一种血管加压素受体1B（V1B）拮抗剂，用于治疗显示精氨酸血管加压素（AVP）水平升高和/或 copeptin 水平升高的患者的抑郁症状和/或焦虑症状。本发明还涉及一种预测抑郁症状和/或焦虑症状患者对V1B拮抗剂治疗反应的方法。
• Potent and selective oxindole-based vasopressin 1b receptor antagonists with improved pharmacokinetic properties
  作者：Thorsten Oost、Gisela Backfisch、Swati Bhowmik、Marcel M. van Gaalen、Hervé Geneste、Wilfried Hornberger、Wilfried Lubisch、Astrid Netz、Liliane Unger、Wolfgang Wernet

  DOI：10.1016/j.bmcl.2011.03.012

  日期：2011.6

  Herein we report the discovery of a novel series of vasopressin 1b (V1b) receptor antagonists, starting from potent but metabolically labile oxindole SSR149415. Masking the proline N,N-dimethyl amide moiety as an oxazole and attaching a benzylic amine moiety to the northern phenyl ring resulted in potent and selective V1b receptor antagonists with improved metabolic stability and improved pharmacokinetic properties in rat. Compound 18c was found to be efficacious in a rat model of anti-depressant activity. (C) 2011 Elsevier Ltd. All rights reserved.
• Bioo. Med. Chem. Lett. 2010, 20, 3103-3106
  作者：

  DOI：——

  日期：——
• V1B RECEPTOR ANTAGONIST FOR USE IN THE TREATMENT OF PATIENTS HAVING AN ELEVATED AVP LEVEL AND/OR AN ELEVATED COPEPTIN LEVEL
  申请人：HOLSBOERMASCHMEYER NEUROCHEMIE GMBH

  公开号：US20150150846A1

  公开（公告）日：2015-06-04

  The present invention relates to a vasopressin receptor 1B (V 1B ) antagonist for use in the treatment of depressive symptoms and/or anxiety symptoms in patients showing an elevated arginine vasopressin (AVP) level and/or an elevated copeptin level. The present invention further relates to a method for predicting the treatment response to a V 1B antagonist in patients with depressive symptoms and/or anxiety symptoms.