(1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-21-[[(2R)-2-methylpyrrolidin-2-yl]methoxy]-20-(5-pyridin-4-yl-1,2,4-triazol-1-yl)-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid | 1207754-40-2

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: (1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-21-[[(2R)-2-methylpyrrolidin-2-yl]methoxy]-20-(5-pyridin-4-yl-1,2,4-triazol-1-yl)-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid
• CAS: 1207754-40-2
• 化学式: C₄₃H₆₃N₅O₄
• 分子量: 714.004
• InChiKey: XQJBAZVVFSSTDB-RLMQNPQRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  52
• 可旋转键数：
  8
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  聚合甲醛 、 (1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-21-[[(2R)-2-methylpyrrolidin-2-yl]methoxy]-20-(5-pyridin-4-yl-1,2,4-triazol-1-yl)-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 以47%的产率得到(1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-21-[[(2R)-1,2-dimethylpyrrolidin-2-yl]methoxy]-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-20-(5-pyridin-4-yl-1,2,4-triazol-1-yl)-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid
  参考文献：
  名称：

  Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase

  摘要：

  Orally bioavailable inhibitors of beta-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.05.031
• 作为产物：
  描述：

  (1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-20-acetyloxy-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-21-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid 在 甲醇 、 硫酸 、 三氟化硼乙醚 、 sodium hydride 、 potassium carbonate 、 一水合肼 、 溶剂黄146 、 苯甲醚 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-21-[[(2R)-2-methylpyrrolidin-2-yl]methoxy]-20-(5-pyridin-4-yl-1,2,4-triazol-1-yl)-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid
  参考文献：
  名称：

  Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase

  摘要：

  Orally bioavailable inhibitors of beta-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.05.031

文献信息

• Antifungal agents
  申请人：Greenlee Mark L.

  公开号：US20100113439A1

  公开（公告）日：2010-05-06

  Novel derivatives of enfumafungin are disclosed herein, along with their pharmaceutically acceptable salts, hydrates and prodrugs. Also disclosed are compositions comprising such compounds, methods of preparing such compounds and methods of using such compounds as antifungal agents and/or inhibitors of (1,3)-β-D-glucan synthase. The disclosed compounds, their pharmaceutically acceptable salts, hydrates and prodrugs, as well as compositions comprising such compounds, salts, hydrates and prodrugs, are useful for treating and/or preventing fungal infections and associated diseases and conditions.

  本文披露了恩福马富金的新型衍生物，以及它们的药用盐、水合物和前药。还公开了包含这些化合物的组合物、制备这些化合物的方法以及将这些化合物用作抗真菌剂和/或(1,3)-β-D-葡聚糖合酶抑制剂的方法。这些公开的化合物、它们的药用盐、水合物和前药，以及包含这些化合物、盐、水合物和前药的组合物，可用于治疗和/或预防真菌感染及相关疾病和病况。
• US8188085B2
  申请人：——

  公开号：US8188085B2

  公开（公告）日：2012-05-29
• Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase
  作者：Brian H. Heasley、Gregory J. Pacofsky、Ahmed Mamai、Hao Liu、Kingsley Nelson、Ghjuvanni Coti、Michael R. Peel、James M. Balkovec、Mark L. Greenlee、Paul Liberator、Dongfang Meng、Dann L. Parker、Robert R. Wilkening、James M. Apgar、F. Racine、Ming Jo Hsu、Robert A. Giacobbe、Jennifer Nielsen Kahn

  DOI：10.1016/j.bmcl.2012.05.031

  日期：2012.11

  Orally bioavailable inhibitors of beta-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein. (C) 2012 Elsevier Ltd. All rights reserved.