(2R,3S,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyrrole 1-oxide | 1105054-49-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2R,3S,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyrrole 1-oxide
• 英文别名: (2R,3S,4R)-1-oxido-3,4-bis(phenylmethoxy)-2-(phenylmethoxymethyl)-3,4-dihydro-2H-pyrrol-1-ium
• CAS: 1105054-49-6
• 化学式: C₂₆H₂₇NO₄
• 分子量: 417.505
• InChiKey: FYVRCXABOYBHKY-CYXNTTPDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  56.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2R,3S,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyrrole 1-oxide 在 氢气 、 palladium(II) hydroxide 作用下， 以 甲醇 为溶剂， 反应 24.0h， 以79%的产率得到(2R,3S,4R)-2-羟甲基四氢吡咯-3,4-二醇
  参考文献：
  名称：

  [EN] TREATMENT OF FABRY DISEASE
  [FR] TRAITEMENT DE LA MALADIE DE FABRY

  摘要：

  本文揭示了聚羟基吡咯烷的新用途，用于制造治疗法布里病（FD）的药物。因此，本公开提供了一种治疗患有或疑似患有FD的受试者的方法。该方法包括步骤，向受试者施用化合物I式，其盐、酯或溶剂化物的治疗有效量，其中：R1是H，或C1-3胺，可选地取代为-COR2；R2是烷基或烯烃，可选地取代为环烷基或苯基，其至少有一个取代基选自卤素，烷基，卤代烷基和烷氧基的群体；以缓解、减轻和/或预防与FD相关的症状。根据本公开的优选实施例，化合物I式是人类溶酶体α-半乳糖苷酶A（α-Gal A）的突变体的伴侣蛋白。

  公开号：

  WO2017222881A1
• 作为产物：
  描述：

  C₂₆H₂₉NO₅ 在 咪唑 、 叔丁基二苯基氯硅烷 、 甲基磺酰氯 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 以1.1 g的产率得到(2R,3S,4R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyrrole 1-oxide
  参考文献：
  名称：

  Rapid preparation of (3R,4S,5R) polyhydroxylated pyrrolidine-based libraries to discover a pharmacological chaperone for treatment of Fabry disease

  摘要：

  The rapid discovery of a pharmacological chaperone toward human alpha-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 x 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue alpha-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other alpha-Gal A mutants in COS7 cells. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.10.004

文献信息

• First total synthesis of (+)-broussonetine W: glycosidase inhibition of natural product & analogs
  作者：Ying-Ying Song、Kyoko Kinami、Atsushi Kato、Yue-Mei Jia、Yi-Xian Li、George W. J. Fleet、Chu-Yi Yu

  DOI：10.1039/c6ob00720a

  日期：——

  The first total synthesis of (+)-broussonetine W (4), a naturally-occurring pyrrolidine iminosugar isolated from the traditional Chinese medical plant Broussonetia kazinoki SIEB (Moraceae), has been completed through a concise synthetic route starting from the readily available D-arabinose derived cyclic nitrone 10 in 11 steps and 31% overall yield, with regioselective installation of the α,β-unsaturated

  （+）-布洛西汀W（4）的第一个全合成方法是从简便的D-化合物开始的简洁合成路线，该方法是从传统中药厂Broussonetia kazinoki SIEB（桑科）中分离得到的天然存在的吡咯烷亚氨基糖。阿拉伯糖衍生的环硝酮10分11个步骤，总收率31％，关键步骤是通过从α-溴代酮中消除HBr选择性地安装α，β-不饱和酮官能团。（+）-布罗尼汀W（4的多个类似物）具有可变的侧链长度，也已经准备了不同的多羟基吡咯烷核构型或饱和的环己酮以探索糖苷酶的抑制作用以及这种有趣的化合物的初步结构与活性之间的关系。糖苷酶抑制研究确定了天然产物（+）-布洛涅汀W（4）是β-半乳糖苷酶的选择性和强效抑制剂（IC 50 = 0.03μM），而其对映异构体是α-葡萄糖苷酶的选择性和强效抑制剂（IC 50= 0.047μM）。发现多羟基化的吡咯烷环的构型对其糖苷酶抑制活性起关键作用。侧链的长度和α，β-不饱和酮官能团也对其糖苷酶抑制有一定影响。
• Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition
  作者：Xin Yan、Yuna Shimadate、Atsushi Kato、Yi-Xian Li、Yue-Mei Jia、George W. J. Fleet、Chu-Yi Yu

  DOI：10.3390/molecules25071498

  日期：——

  of pyrrolidine analogues of pochonicine and its stereoisomers have been synthesized from four enantiomeric pairs of polyhydroxylated cyclic nitrones. Among the ten N-acetylamino pyrrolidine analogues, only compounds with 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and pochonicine (1) configurations showed potent inhibition of β-N-acetylhexosaminidases (β-HexNAcases); while 1-amino analogues lost almost all

  由四对多羟基化环硝酮对映体合成了十对 Pochonicine 的吡咯烷类似物及其立体异构体。在十种 N-乙酰氨基吡咯烷类似物中，只有具有 2,5-二脱氧-2,5-亚氨基-d-甘露醇 (DMDP) 和 Pochonicine (1) 构型的化合物显示出对 β-N-乙酰己糖胺酶 (β-HexNAcases) 的有效抑制作用;而1-氨基类似物几乎失去了对测试酶的所有抑制作用。测定结果揭示了 N-乙酰氨基的重要性以及此类抑制剂所需的吡咯烷环可能的正确构型。
• Nanomolar β-glucosidase and β-galactosidase inhibition by enantiomeric α-1-C-alkyl-1,4-dideoxy-1,4-imino-arabinitol derivatives
  作者：Dong Zi、Ying-Ying Song、Tian-Tian Lu、Maki Kise、Atsushi Kato、Jun-Zhe Wang、Yue-Mei Jia、Yi-Xian Li、George W.J. Fleet、Chu-Yi Yu

  DOI：10.1016/j.ejmech.2022.115056

  日期：2023.2

  but greatly improved their inhibitions of bovine liver β-glucosidase and β-galactosidase. Furthermore, epimerization of C-1′ configurations of compounds 18a-e clearly lowered their inhibition potency of bovine liver β-glucosidase and β-galactosidase. Notably, some of the α-1-C-alkyl DAB derivatives were also found to have potent human lysosome β-glucosidase inhibitions. In contrast, enantiomers of compounds

  一系列具有芳基的α-1- C-烷基DAB（1,4-二脱氧-1,4-亚氨基-d-阿拉伯糖醇）和LAB（1,4-二脱氧-1,4-亚氨基-l-阿拉伯糖醇）衍生物取代基被设计为 broussonetine W ( 12 ) 的类似物，并作为糖苷酶抑制剂进行了测定。虽然 α-1- C-烷基 DAB 衍生物16的抑制谱与 broussonetine W ( 12 ) 的抑制谱具有良好的相关性，但在端芳基 ( 17a-f ) 或 C-1' 位置的羟基上引入取代基烷基链 ( 18a-e) 降低了它们的 α-葡萄糖苷酶抑制作用，但大大提高了它们对牛肝 β-葡萄糖苷酶和 β-半乳糖苷酶的抑制作用。此外，化合物18a-e的 C-1' 构型的差向异构化明显降低了它们对牛肝 β-葡萄糖苷酶和 β-半乳糖苷酶的抑制效力。值得注意的是，还发现一些 α-1- C6-烷基 DAB 衍生物具有有效的人溶酶体 β-葡萄糖苷酶抑制作用。相反，化合物18a-e和1'-
• Treatment of Fabry disease
  申请人：Academia Sinica

  公开号：US10995067B2

  公开（公告）日：2021-05-04

  Disclosed herein are novel uses of a polyhydroxylated pyrrolidine for the manufacture of a medicament for treating Fabry disease (FD). Accordingly, the present disclosure provides a method of treating a subject having or suspected of having FD. The method includes the step of, administering to the subject a therapeutically effective amount of a compound of formula (I), a salt, an ester or a solvate thereof, wherein: R1 is H, or C1-3 amine optionally substituted with —COR2; R2 is alkyl or alkene optionally substituted with cycloalkyl or phenyl having at least one substituent selected from the group consisting of, halo, alkyl, haloalkyl, and alkoxyl; so as to ameliorate, alleviate mitigate and/or prevent symptoms associated with the FD. According to preferred embodiments of the present disclosure, the compound of formula (I) is a chaperon of a mutated human lysosomal α-galactosidase A (α-Gal A).

  本文公开了一种聚羟基吡咯烷的新用途，用于制造治疗法布里病（FD）的药物。因此，本公开提供了一种治疗法布里病或疑似法布里病受试者的方法。该方法包括以下步骤：向受试者施用治疗有效量的式(I)化合物、其盐、酯或溶液，其中：R1是H，或任选被-COR2取代的C1-3胺；R2是烷基或烯基，任选被环烷基或苯基取代，环烷基或苯基具有至少一个选自由卤代、烷基、卤代烷基和烷氧基组成的组的取代基；从而改善、减轻和/或预防与FD相关的症状。根据本公开的优选实施方案，式（I）化合物是突变的人溶酶体 α-半乳糖苷酶 A（α-Gal A）的合子。
• A convenient approach toward the synthesis of enantiopure isomers of DMDP and ADMDP
  作者：En-Lun Tsou、Yao-Ting Yeh、Pi-Hui Liang、Wei-Chieh Cheng

  DOI：10.1016/j.tet.2008.10.096

  日期：2009.1

  A practical method for the synthesis of five-membered iminocyclitols, pyrrolidine alkaloids bearing multiple hydroxyl substituents, has been developed. All of the eight key intermediates, enantiopure tri-O-benzyl cyclic nitrones, are prepared from four cheap, readily available D-aldopentoses. The nucleophilic addition of cyclic nitrones with vinyl magnesium chloride and TMSCN shows high 2,3-trans stereoselectivity. To construct the 2,3-cis configurations, inversion of the C-2 nitrile group is achieved via an elimination-reduction sequence. Using this approach, five isomers of DMDP and six isomers of ADMDP are prepared efficiently. In the biological evaluation, iminocyclitol 27 is a new and potent inhibitor against beta-hexosaminidase with an IC50 value of 0.2 mu M. (C) 2008 Elsevier Ltd. All rights reserved.