(2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoic acid | 928014-62-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoic acid
• 英文别名: (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanoic acid；(2R)-3-(7-methyl-1H-indazol-5-yl)-2-[[4-(2-oxo-1H-quinolin-3-yl)piperidine-1-carbonyl]amino]propanoic acid
• CAS: 928014-62-4
• 化学式: C₂₆H₂₇N₅O₄
• 分子量: 473.531
• InChiKey: QROJAPWIUDLXLJ-JOCHJYFZSA-N

物化性质

• 沸点：
  858.9±65.0 °C(Predicted)
• 密度：
  1.384±0.06 g/cm3(Predicted)
• pKa：
  4.46±0.50 (Predicted,Most Acidic Temp: 25 °C)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  35
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  127
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoic acid 在 palladium 10% on activated carbon 、 甲酸铵 、 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 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-[(2R)-1-[8-(N-methyl-D-alanyl)-2,8-diazaspiro[4.5]dec-2-yl]-3-(7-methyl-1H-indazol- 5-yl)-1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide
  参考文献：
  名称：

  [EN] CGRP RECEPTOR ANTAGONISTS
  [FR] ANTAGONISTES DU RÉCEPTEUR CGRP

  摘要：

  本公开涉及式(I A)的新化合物，其中R1、R2、R3和R4如本文所定义，并其在治疗、预防、改善、控制或减少与CGRP受体功能相关的脑血管或血管疾病中的用途。本公开还涉及到式(IB)的新化合物，其中R1、R2和R3如本文所定义，并其在治疗、预防、改善、控制或减少与CGRP受体功能相关的脑血管或血管疾病中的用途。本公开还涉及到式(IC)的新化合物，其中Ar1和R1如本文所定义，并其在治疗、预防、改善、控制或减少与CGRP受体功能相关的脑血管或血管疾病中的用途。

  公开号：

  WO2018178938A1
• 作为产物：
  描述：

  3-(哌啶-4-基)-3,4-二氢喹唑啉-2(1H)-酮 在 lithium hydroxide monohydrate 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.5h， 生成 (2R)-3-(7-methyl-1H-indazol-5-yl)-2-({[4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl]carbonyl}amino)propanoic acid
  参考文献：
  名称：

  Structure-Based Drug Discovery of N-((R)-3-(7-Methyl-1H-indazol-5-yl)-1-oxo-1-(((S)-1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2′-oxo-1′,2′-dihydrospiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine

  摘要：

  Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 angstrom resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being selected as a clinical candidate for acute treatment of migraine.

  DOI：

  10.1021/acs.jmedchem.0c01003

文献信息

• [EN] CGRP RECEPTOR ANTAGONIST<br/>[FR] ANTAGONISTE DES RÉCEPTEURS CGRP
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2011123232A1

  公开（公告）日：2011-10-06

  The disclosure generally relates to the compound of formula I, (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)pipe ridine-1-carboxamide, including pharmaceutically acceptable salts, which is a CGRP-receptor antagonist. The disclosure also relates to pharmaceutical compositions and methods for using the compound in the treatment of CGRP related disorders including migraine headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cancer.

  该披露通常涉及到式I的化合物，即(R)-N-(3-(7-甲基-1H-吲哚-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙酰基)-4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰胺，包括药学上可接受的盐，它是一种CGRP受体拮抗剂。该披露还涉及到在治疗与CGRP相关的疾病，包括偏头痛、神经源性血管舒张、神经源性炎症、热损伤、循环性休克、与绝经期相关的潮红、哮喘、慢性阻塞性肺病（COPD）和癌症中使用该化合物的药物组合物和方法。
• [EN] INTRANASAL PHARMACEUTICAL COMPOSITIONS OF CGRP INHIBITORS<br/>[FR] COMPOSITIONS PHARMACEUTIQUES INTRANASALES D'INHIBITEURS DE CGRP
  申请人：BIOHAVEN PHARM HOLDING CO LTD

  公开号：WO2021127070A1

  公开（公告）日：2021-06-24

  Provided is pharmaceutical composition for intranasal delivery, wherein the pharmaceutical composition includes a therapeutically active ingredient including a CGRP inhibitor. Also provided is a method for delivering a CGRP inhibitor to a subject, wherein the method includes intranasally administering to the subject a composition including a therapeutically active component including a CGRP inhibitor.

  提供了一种用于鼻内给药的药物组合物，其中该药物组合物包括一种治疗有效成分，该治疗有效成分包括CGRP抑制剂。还提供了一种将CGRP抑制剂递送给主体的方法，该方法包括将包括治疗有效成分的药物组合物鼻内给药给主体，该治疗有效成分包括CGRP抑制剂。
• Selection of an Enantioselective Process for the Preparation of a CGRP Receptor Inhibitor
  作者：Reginald O. Cann、Chung-Pin H. Chen、Qi Gao、Ronald L. Hanson、Daniel Hsieh、Jun Li、Dong Lin、Rodney L. Parsons、Yadagiri Pendri、R. Brent Nielsen、William A. Nugent、William L. Parker、Sandra Quinlan、Nathan P. Reising、Brenda Remy、Justin Sausker、Xuebao Wang

  DOI：10.1021/op3003097

  日期：2012.12.21

  (R)-N-(3-(7-Methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazine-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (1) is a potent calcitonin gene-related peptide (CGRP) receptor antagonist. We have developed a convergent, stereoselective, and economical synthesis of the hydrochloride salt of 1 and demonstrated the synthesis on a multikilogram scale. Two

  （- [R ）- N-（3-（7-甲基-1- ħ -吲唑-5-基）-1-（4-（1-甲基哌啶-4-基）哌嗪-1-基）-1-氧代丙烷-2- -基）-4-（2-氧代-1,2-二氢喹啉-3-基）哌啶-1-甲酰胺（1）是一种有效的降钙素基因相关肽（CGRP）受体拮抗剂。我们开发了一种收敛，立体选择性和经济的1盐酸盐合成方法并以多千克规模展示了该合成方法。利用Rh催化的不对称氢化或生物催化过程来开发单个手性中心的两种不同的手性吲唑基氨基酯亚基途径。讨论了每种工艺路线的优点和缺点，以及最终原料药的组装过程中遇到的挑战。
• CGRP antagonists
  申请人：Han Xiaojun

  公开号：US20070049577A1

  公开（公告）日：2007-03-01

  The present invention encompasses compounds of Formula I which are antagonists of calcitonin gene-related peptide receptors (“CGRP-receptor”), pharmaceutical compositions comprising them, methods for identifying them, methods of treatment using them and their use in therapy for treatment of neurogenic vasodilation, neurogenic inflammation, migraine and other headaches, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP-receptors.

  本发明涵盖了Formula I的化合物，它们是降钙素基因相关肽受体（“CGRP受体”）的拮抗剂，包括它们的药物组合物、鉴定它们的方法、使用它们进行治疗的方法以及它们在治疗神经源性血管舒张、神经源性炎症、偏头痛和其他头痛、热伤、循环性休克、与绝经期潮热相关的潮红、气道炎症性疾病（如哮喘和慢性阻塞性肺疾病（COPD））以及其他可以通过CGRP受体拮抗效应治疗的疾病的治疗中的应用。
• CGRP Receptor Antagonist
  申请人：Chaturvedula Prasad V.

  公开号：US20120059017A1

  公开（公告）日：2012-03-08

  The disclosure generally relates to the compound of formula I, (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide, including pharmaceutically acceptable salts, which is a CGRP-receptor antagonist. The disclosure also relates to pharmaceutical compositions and methods for using the compound in the treatment of CGRP related disorders including migraine headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cancer.

  本公开涉及式I的化合物，即(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-羧酰胺，包括药用可接受的盐，该化合物是CGRP受体拮抗剂。本公开还涉及制备该化合物的药物组合物以及使用该化合物治疗CGRP相关疾病的方法，包括偏头痛、神经源性血管扩张、神经源性炎症、热损伤、循环性休克、与更年期相关的潮红、气道炎症性疾病如哮喘、慢性阻塞性肺疾病（COPD）和癌症。