((S)-5-((R)-2-氨基-3-(3,5-二溴-4-羟基苯基)丙酰胺基)-6-氧代-6-( | 204693-44-7

• 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: ((S)-5-((R)-2-氨基-3-(3,5-二溴-4-羟基苯基)丙酰胺基)-6-氧代-6-(
• 英文名称: 1-[N²-(3,5-dibromo-D-tyrosyl)-N⁶-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine
• 英文别名: 1-[N2-(3,5-dibromo-D-tyrosyl)-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine；1-[N2-[3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine；tert-Butyl ((S)-5-((R)-2-amino-3-(3,5-dibromo-4-hydroxyphenyl)propanamido)-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexyl)carbamate；tert-butyl N-[(5S)-5-[[(2R)-2-amino-3-(3,5-dibromo-4-hydroxyphenyl)propanoyl]amino]-6-oxo-6-(4-pyridin-4-ylpiperazin-1-yl)hexyl]carbamate
• CAS: 204693-44-7
• 化学式: C₂₉H₄₀Br₂N₆O₅
• 分子量: 712.482
• InChiKey: BIIQEMGIHKZLOH-RPWUZVMVSA-N

物化性质

• 沸点：
  856.8±65.0 °C(Predicted)
• 密度：
  1.455±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  42
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  150
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  ((S)-5-((R)-2-氨基-3-(3,5-二溴-4-羟基苯基)丙酰胺基)-6-氧代-6-( 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 7.0h， 生成 1-[N²-[3,5-dibromo-N-[[4-[2(3H)-oxobenzoxazol-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)piperazine bis(trifluoroacetate)
  参考文献：
  名称：

  Development of Human Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonists. 1. Potent and Selective Small Molecule CGRP Antagonists. 1-[N²-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1- piperidinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)piperazine:  The First CGRP Antagonist for Clinical Trials in Acute Migraine

  摘要：

  Although the triptans have greatly improved the acute treatment of migraine headache, there are yet many shortcomings. Therefore, new strategies for the treatment of migraine are needed which offer advantages over current therapy, e.g. triptans. Our novel approach was based on the hypothesis that the release of calcitonin gene-related peptide (CGRP) could play a causative role in migraine headache. Thus we initiated a program aimed at the design and synthesis of small molecule CGRP receptor antagonists. High throughput screening led to the identification of (R)-Tyr-(S)-Lys dipeptide-like compounds that showed weak but unequivocal binding to the human CGRP receptor. Lead optimization afforded highly potent CGRP antagonists, the prototype being compound 19 (BIBN4096). This compound exhibiting a favorable biological profile was selected for initial clinical trials. A proof of concept study indicated that intravenous application of 19 was effective in the treatment of acute migraine headache. This finding strongly supports our initial working hypothesis that CGRP plays an important role in the pathophysiology of migraine.

  DOI：

  10.1021/jm0490641
• 作为产物：
  描述：

  Nε-Boc-Nα-Cbz-L-赖氨酸 在 palladium on activated charcoal potassium hydrogensulfate 、 氢气 、 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 二乙胺 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 20.0~60.0 ℃ 、300.0 kPa 条件下， 反应 5.0h， 生成 ((S)-5-((R)-2-氨基-3-(3,5-二溴-4-羟基苯基)丙酰胺基)-6-氧代-6-(
  参考文献：
  名称：

  Development of Human Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonists. 1. Potent and Selective Small Molecule CGRP Antagonists. 1-[N²-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1- piperidinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)piperazine:  The First CGRP Antagonist for Clinical Trials in Acute Migraine

  摘要：

  Although the triptans have greatly improved the acute treatment of migraine headache, there are yet many shortcomings. Therefore, new strategies for the treatment of migraine are needed which offer advantages over current therapy, e.g. triptans. Our novel approach was based on the hypothesis that the release of calcitonin gene-related peptide (CGRP) could play a causative role in migraine headache. Thus we initiated a program aimed at the design and synthesis of small molecule CGRP receptor antagonists. High throughput screening led to the identification of (R)-Tyr-(S)-Lys dipeptide-like compounds that showed weak but unequivocal binding to the human CGRP receptor. Lead optimization afforded highly potent CGRP antagonists, the prototype being compound 19 (BIBN4096). This compound exhibiting a favorable biological profile was selected for initial clinical trials. A proof of concept study indicated that intravenous application of 19 was effective in the treatment of acute migraine headache. This finding strongly supports our initial working hypothesis that CGRP plays an important role in the pathophysiology of migraine.

  DOI：

  10.1021/jm0490641

文献信息

• Modified amino acids, pharmaceuticals containing these compounds and method for their production
  申请人：——

  公开号：US20010036946A1

  公开（公告）日：2001-11-01

  The present invention relates to modified amino acids of general formula 1 wherein A, Z, X, n, m, R, R 2 , R 3 , R 4 and R 11 are defined as in claims 1 to 5 , their tautomers, their diastereomers, their enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for preparing them as well as their use for the production and purification of antibodies and as labelled compounds in RIA- and ELISA assays and as diagnostic or analytical aids in neurotransmitter research.

  本发明涉及一般式1的改良氨基酸，其中A、Z、X、n、m、R、R2、R3、R4和R11如权利要求1至5中所定义，它们的互变异构体、对映异构体、混合物及其盐，特别是其与无机或有机酸或碱的生理上可接受的盐，含有这些化合物的药物组合物，其用途以及用于制备它们的过程，以及它们在抗体的生产和纯化中的用途，以及在RIA和ELISA测定中作为标记化合物以及在神经递质研究中作为诊断或分析辅助工具的用途。
• Synthesis of tritium-labelled BIBN4096, an experimental h-CGRP-antagonist
  作者：V. P. Shevchenko、I. Yu. Nagaev、N. F. Myasoedov、A. B. Susan、K.-H. Switek、H. Braunger

  DOI：10.1002/jlcr.1061

  日期：2006.4

  Synthesis of tritium labelled BIBN 4096 – 1-piperidine-3H-carboxamide, N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2 H)-quinazolinyl)-, [R-(R*,S*)]-, – a h-CGRP-antagonist for the treatment of migraine is described. Selective tritiation of a heterocyclic aromatic fragment in the presence of aromatic

  氚标记的 BIBN 4096 的合成 – 1-哌啶-3H-甲酰胺，N-[2-[[5-氨基-1-[[4-(4-吡啶基)-1-哌嗪基]羰基]戊基]氨基]-1 -[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-, [R-(R* ,S*)]-, – 描述了一种用于治疗偏头痛的 h-CGRP 拮抗剂。使用固态催化交换方法成功地在 BIBN4096 前体中存在芳环的情况下对杂环芳族片段进行了选择性氚化。随后完成合成序列得到最终的[3H]BIBN4096，其比活性>170 Ci/mmol。版权所有 © 2006 John Wiley & Sons, Ltd.
• Modified aminoacids, pharmaceuticals containing these compounds and method for their production
  申请人：——

  公开号：US20030069231A1

  公开（公告）日：2003-04-10

  The present invention relates to modified amino acids of general formula 1 wherein A, Z, X, n, m, R, R 2 , R 3 , R 4 and R 11 are defined as in claims 1 to 5, their tautomers, their diastereomers, their enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for preparing them as well as their use for the production and purification of antibodies and as labelled compounds in RIA- and ELISA assays and as diagnostic or analytical aids in neurotransmitter research.

  本发明涉及一般式1的改性氨基酸，其中A、Z、X、n、m、R、R2、R3、R4和R11如权利要求1至5所定义，它们的互变异构体、对映异构体、混合物和盐，特别是它们与无机或有机酸或碱的生理上可接受的盐，含有这些化合物的制药组合物，其使用和制备过程，以及它们在抗体的生产和纯化中的使用，作为RIA和ELISA测定中的标记化合物，以及在神经递质研究中作为诊断或分析辅助工具的使用。
• Abgewandelte Aminosäuren, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
  申请人：Boehringer Ingelheim Pharma GmbH & Co.KG

  公开号：EP1440976A1

  公开（公告）日：2004-07-28

  Die vorliegende Erfindung betrifft abgewandelte Aminosäuren der allgemeinen Formel in der A, Z, X, n, m, R, R2, R3, R4 und R11 wie in den Ansprüchen 1 bis 5 definiert sind, deren Tautomere, deren Diastereomere, deren Enantiomere, deren Gemische und deren Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren oder Basen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung sowie deren Verwendung zur Erzeugung und Reinigung von Antikörpern und als markierte Verbindungen in RIA- und ELISA-Assays und als diagnostische oder analytische Hilfsmittel in der Neutrotransmitter-Forschung.

  本发明涉及通式如下的改性氨基酸 其中 A、Z、X、n、m、R、R2、R3、R4 和 R11 如权利要求 1 至 5 所定义，它们的同分异构体、非对映异构体、对映体、混合物和它们的盐，特别是它们与无机或有机酸或碱的生理相容盐、含有这些化合物的药品，它们的用途和制备工艺，以及它们在抗体生产和纯化中的用途，在 RIA 和 ELISA 检测中作为标记化合物，以及在中性粒细胞递质研究中作为诊断或分析辅助剂。
• Switek, K.-H.; Braunger, H., Journal of labelled compounds and radiopharmaceuticals, 2002, vol. 45, # 13, p. 1175 - 1176
  作者：Switek, K.-H.、Braunger, H.

  DOI：——

  日期：——