N-benzyl (+)-isofagomine | 215724-77-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: N-benzyl (+)-isofagomine
• 英文别名: (+)-N-Benzylisofagomine；(3R,4R,5R)-1-benzyl-5-(hydroxymethyl)piperidine-3,4-diol；(3R,4R,5R)-1-Benzyl-5-hydroxymethyl-3,4-piperidinediol
• CAS: 215724-77-9
• 化学式: C₁₃H₁₉NO₃
• 分子量: 237.299
• InChiKey: SGPVIQCAOCSXHN-JHJVBQTASA-N

物化性质

• 沸点：
  433.6±24.0 °C(Predicted)
• 密度：
  1.259±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  63.9
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-benzyl (+)-isofagomine 在 palladium dihydroxide 氢气 作用下， 以 乙醇 为溶剂， 20.0 ℃ 、517.1 kPa 条件下， 反应 10.0h， 以95%的产率得到(3R,4R,5R)-5-(羟基甲基)哌啶-3,4-二醇盐酸盐
  参考文献：
  名称：

  A Novel Approach to Both the Enantiomers of Potent Glycosidase Inhibitor Isofagomine via PET-Promoted Cyclization of 1-[Benzyl(trimethylsilyl-methyl)amino]-1,4,5-trideoxy-2,3-O-(1-methylethylidene)-threo-pent-4-ynitol

  摘要：

  在合成 1-N-iminosugar 型糖苷酶抑制剂时，利用 PET 生成的δ-三甲基硅甲胺自由基阳离子环化到系链炔基的方法解决了在立体中心旁生成氨基甲基的问题。(+)- 和 (-)-isofagomine 的合成证明了这一方法的成功，isofagomine 是一种极其有效的 1-N-iminosugar 类δ-糖苷酶抑制剂。

  DOI：

  10.1055/s-2001-15063
• 作为产物：
  描述：

  槟榔碱 在 氢氧化钾 、 锂硼氢 、 1-氯乙基氯甲酸酯 、 三乙基硼氢化锂 、 三乙胺 、 间氯过氧苯甲酸 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 二氯甲烷 、 甲苯 为溶剂， 反应 7.58h， 生成 N-benzyl (+)-isofagomine
  参考文献：
  名称：

  Iminosugars: potential inhibitors of liver glycogen phosphorylase

  摘要：

  The first synthesis of the single isomers (3R,4R,5R); (3S,4S,5S); (3R,4R,5S) and (3S,4S,5R) of 5-hydroxymethyl-piperidine-3,4-diol from Arecolin is reported, including the synthesis of a series of N-substituted derivatives of the (3R,4R,5R)-isomer (Isofagomine). The inhibitory effect of these isomers as well as of a series of N-substituted derivatives of the (3R,4R,SR)-isomer and selected hydroxypiperidine analogues on liver glycogen phosphorylase (GP) showed that the (3R,4R,5R) configuration was essential for obtaining an inhibitory effect at submicromolar concentration. The results also showed that all three hydroxy groups should be present and could not be substituted, nor were extra OH groups allowed if sub-micromolar inhibition should be obtained. Some inhibitory effect was retained for N-substituted derivatives of Isofagagomine; however, N-substitution always resulted in a loss of activity compared to the parent compound, IC50 values ranging from 1 to 100 muM were obtained for simple alkyl, arylalkyl and benzoylmethyl substituents. Furthermore, we found that it was not enough to assure inhibitory effect to have the (R,,R) configuration. Fagomine, the (2R,3R,4R)-2-hydroxymethylpiperidine-3,4-diol analogue, showed an IC50 value of 200 muM compared to 0.7 muM for Isofagomine. In addition, Isofagomine was able to prevent basal and glucagon stimulated glycogen degradation in cultured hepatocytes with IC50 values of 2-3 muM. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00291-1

文献信息

• METHOD FOR THE TREATMENT OF NEUROLOGICAL DISORDERS BY ENHANCING THE ACTIVITY OF BETA-GLUCOCEREBROSIDASE
  申请人：Wustman Alan Brandon

  公开号：US20080009516A1

  公开（公告）日：2008-01-10

  Provided is a method of increasing the stability of wild-type β-glucocerebrosidase. Also provided are methods of treating and/or preventing an individual having a neurological disease in which increased expression or activity of β-glucocerebrosidase in the central nervous system would be beneficial. This method comprises administering an effective amount of a pharmacologic chaperone for β-glucocerebrosidase, with the proviso that the individual does not have a mutation in the gene encoding β-glucocerebrosidase. Further provided are β-glucocerebrosidase inhibitors which have been identified as specific pharmacologic chaperones and which have been shown to increase activity of β-glucocerebrosidase in vivo in the central nervous system.

  提供了一种增加野生型β-葡萄糖苷酶稳定性的方法。同时，提供了一种治疗和/或预防神经系统疾病的方法，其中在中枢神经系统中增加β-葡萄糖苷酶的表达或活性将有益。该方法包括给予β-葡萄糖苷酶的药理伴侣的有效剂量，但前提是该个体没有β-葡萄糖苷酶编码基因的突变。进一步提供了β-葡萄糖苷酶抑制剂，这些抑制剂已被确定为特定的药理伴侣，并已被证明在中枢神经系统内增加β-葡萄糖苷酶的活性。
• Method for the Treatment of Neurological Disorders by Enhancing the Activity of Beta-Glucocerebrosidase
  申请人：Amicus Therapeutics, Inc.

  公开号：US20150025109A1

  公开（公告）日：2015-01-22

  Provided is a method of increasing the stability of wild-type β-glucocerebrosidase. Also provided are methods of treating and/or preventing an individual having a neurological disease in which increased expression or activity of β-glucocerebrosidase in the central nervous system would be beneficial. This method comprises administering an effective amount of a pharmacologic chaperone for β-glucocerebrosidase, with the proviso that the individual does not have a mutation in the gene encoding β-glucocerebrosidase. Further provided are β-glucocerebrosidase inhibitors which have been identified as specific pharmacologic chaperones and which have been shown to increase activity of β-glucocerebrosidase in vivo in the central nervous system.

  提供了一种增加野生型β-葡萄糖苷酶稳定性的方法。还提供了治疗和/或预防神经系统疾病的方法，其中在中枢神经系统中增加β-葡萄糖苷酶的表达或活性将有益。该方法包括给予β-葡萄糖苷酶药理伴侣的有效剂量，前提是个体没有β-葡萄糖苷酶编码基因的突变。此外，还提供了已被确定为特定药理伴侣并已被证明能够在中枢神经系统中增加β-葡萄糖苷酶活性的β-葡萄糖苷酶抑制剂。
• Method for the treatment of neurological disorders by enhancing the activity of β-glucocerebrosidase
  申请人：Amicus Therapeutics, Inc.

  公开号：US10064851B2

  公开（公告）日：2018-09-04

  Provided is a method of increasing the stability of wild-type β-glucocerebrosidase. Also provided are methods of treating and/or preventing an individual having a neurological disease in which increased expression or activity of β-glucocerebrosidase in the central nervous system would be beneficial. This method comprises administering an effective amount of a pharmacologic chaperone for β-glucocerebrosidase, with the proviso that the individual does not have a mutation in the gene encoding β-glucocerebrosidase. Further provided are β-glucocerebrosidase inhibitors which have been identified as specific pharmacologic chaperones and which have been shown to increase activity of β-glucocerebrosidase in vivo in the central nervous system.

  本文提供了一种提高野生型β-葡糖脑苷脂稳定性的方法。还提供了治疗和/或预防神经系统疾病患者的方法，在这种疾病中，增加中枢神经系统中β-葡糖脑苷脂的表达或活性是有益的。该方法包括施用有效量的β-葡糖脑苷脂药理伴侣，但前提是个体没有β-葡糖脑苷脂编码基因的突变。此外，还提供了β-葡糖脑抑制剂，这些抑制剂已被确定为特异性药理合剂，并已被证明能提高β-葡糖脑在体内中枢神经系统中的活性。
• METHODS FOR PREVENTING AND/OR TREATING LYSOSOMAL STORAGE DISORDERS
  申请人：Amicus Therapeutics, Inc.

  公开号：EP2416656B1

  公开（公告）日：2015-12-23
• A general strategy towards the synthesis of 1-N-iminosugar type glycosidase inhibitors: demonstration by the synthesis of d- as well as l-glucose type iminosugars (isofagomines)
  作者：Ganesh Pandey、Manmohan Kapur

  DOI：10.1016/s0040-4039(00)01553-7

  日期：2000.11

  Both enantiomers of isofagomine, the potent glycosidase inhibitor of a type 1-N-iminosugar have been synthesized by the intramolecular cyclization of the PET generated alpha -trimethylsilylmethylamine radical cation with the appropriate tethered acetylene moiety. (C) 2000 Published by Elsevier Science Ltd.