(3aR,3bR,4aS,5S,5aS)-2,2-dimethylhexahydrocyclopropa[3,4]-cyclopenta[1,2-d][1,3]dioxol-5-ol | 1078503-71-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (3aR,3bR,4aS,5S,5aS)-2,2-dimethylhexahydrocyclopropa[3,4]-cyclopenta[1,2-d][1,3]dioxol-5-ol
• 英文别名: (1S,2R,3S,4S,5S)-2,3-O-(isopropylidene)-2,3,4-trihydroxybicyclo[3.1.0]hexane；(1R,2R,3S,4S,5S)-2,3-O-isopropylidene-2,3,4-trihydroxybicyclo[3.1.0]hexane；(+)-(1S,2S,3S,4R,5R)-3,4-O-isopropylidenebicycle[3.1.0]hexa-2-ol；(3AR,3bR,4aS,5S,5aS)-2,2-dimethylhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxol-5-ol；(1R,2R,4S,5S,6S)-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-ol
• CAS: 1078503-71-5
• 化学式: C₉H₁₄O₃
• 分子量: 170.208
• InChiKey: MAQPKLNGHGQJGE-YMVPXFTJSA-N

物化性质

• 沸点：
  270.2±20.0 °C(Predicted)
• 密度：
  1.222±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  38.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (3aR,3bR,4aS,5S,5aS)-2,2-dimethylhexahydrocyclopropa[3,4]-cyclopenta[1,2-d][1,3]dioxol-5-ol 在 吡啶 、 氯化亚砜 、 sodium azide 、 sodium methylate 、 三乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 12.17h， 生成 (-)-(1S,2S,3S,4R,5R)-4-azido-bicyclo[3.1.0]hexane-2,3-O-sulphite
  参考文献：
  名称：

  Regio- and stereoselective synthesis of truncated 3′-aminocarbanucleosides and their binding affinity at the A3 adenosine receptor

  摘要：

  描述了截断的 3′-氨基羟苷 4a–d 的立体选择性合成，通过对二醇 9 进行立体和区域选择性的转化为溴乙酸酯 11a，以及它们对人类 A3 腺苷受体的结合亲和力。

  DOI：

  10.1039/c1ob05853c
• 作为产物：
  描述：

  (3AS,4S,6AR)-2,2-二甲基-3A,6A-二氢-4H-环戊[D][1,3]二噁酚-4-醇 在 二碘甲烷 、 diethylzinc 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 以70%的产率得到(3aR,3bR,4aS,5S,5aS)-2,2-dimethylhexahydrocyclopropa[3,4]-cyclopenta[1,2-d][1,3]dioxol-5-ol
  参考文献：
  名称：

  Synthesis and Anti-Renal Fibrosis Activity of Conformationally Locked Truncated 2-Hexynyl-N⁶-Substituted-(N)-Methanocarba-nucleosides as A₃ Adenosine Receptor Antagonists and Partial Agonists

  摘要：

  Truncated N-6-substituted-(N)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4'-thioadenosines. Hydrophobic N-6 and/or C2 substituents were tolerated in A(3)AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high hA(2A)AR affinity. A small hydrophobic alkyl (4b and 4c) or N-6-cycloalkyl group (4d) showed excellent binding affinity at the hA(3)AR and was better than an unsubstituted free amino group (4a). A(3)AR affinities of 3-halobenzylamine derivatives 4f-4i did not differ significantly, with K-i values of 7.8-16.0 nM. N-6-Methyl derivative 4b (K-i = 4.9 nM) was a highly selective, low efficacy partial A(3)AR agonist. All compounds were screened for renoprotective effects in human TGF-beta 1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-beta 1-induced collagen I upregulation, and their A(3)AR binding affinities were proportional to antifibrotic effects; 4b was most potent (IC50 = 0.83 mu M), indicating its potential as a good therapeutic candidate for treating renal fibrosis.

  DOI：

  10.1021/jm4015313

文献信息

• [EN] COMPOUNDS AND COMPOSITIONS USEFUL FOR TREATING DISORDERS RELATED TO NTRK<br/>[FR] COMPOSÉS ET COMPOSITIONS UTILES POUR TRAITER DES TROUBLES ASSOCIÉS AU GÈNE NTRK
  申请人：BLUEPRINT MEDICINES CORP

  公开号：WO2017035354A1

  公开（公告）日：2017-03-02

  This invention relates to inhibitors of NTRK that are active against wild-type NTRK and its resistant mutants.

  这项发明涉及对NTRK的抑制剂，对野生型NTRK及其耐药突变体具有活性。
• Functionalized Congeners of A₃ Adenosine Receptor-Selective Nucleosides Containing a Bicyclo[3.1.0]hexane Ring System
  作者：Dilip K. Tosh、Moshe Chinn、Andrei A. Ivanov、Athena M. Klutz、Zhan-Guo Gao、Kenneth A. Jacobson

  DOI：10.1021/jm900426g

  日期：2009.12.10

  (N)-Methanocarba nucleosides containing bicyclo[3.1.0]hexane replacement of the ribose ring previously demonstrated selectivity as A3 adenosine receptor (AR) agonists (5′-uronamides) or antagonists (5′-truncated). Here, these two series were modified in parallel at the adenine C2 position. N6-3-Chlorobenzyl-5′-N-methyluronamides derivatives with functionalized 2-alkynyl chains of varying length terminating

  (N)-Methanocarba 核苷含有双环 [3.1.0] 己烷取代核糖环，先前证明选择性作为 A 3腺苷受体 (AR) 激动剂（5'-糖醛酰胺）或拮抗剂（5'-截短）。在这里，这两个系列在腺嘌呤 C2 位置并行修改。N 6 -3-Chlorobenzyl-5'- N - methyluronamides 衍生物具有不同长度的官能化 2-炔基链，末端为反应性羧酸盐、酯或胺基团，是完整的、有效的人类 A 3 AR 激动剂。链取代的灵活性允许与荧光花青染料 (Cy5) 和生物素结合，导致结合K i值分别为 17 和 36 nM。链的远端通过同源建模预测以结合在A 3 AR 细胞外区域。相应的l-核苷在 AR 结合中几乎没有活性。在 5'-截断的核苷系列中，2-Cl 类似物在 A 3 AR 上比 2-H 和 2-F 更有效，腺苷酸环化酶抑制的功能功效各不相同，2-炔基链的引入大大降低了亲和力。两个系列之间的
• Selective A3 adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system
  作者：Artem Melman、Ben Wang、Bhalchandra V. Joshi、Zhan-Guo Gao、Sonia de Castro、Cara L. Heller、Soo-Kyung Kim、Lak Shin Jeong、Kenneth A. Jacobson

  DOI：10.1016/j.bmc.2008.08.007

  日期：2008.9

  We have prepared 50-modified derivatives of adenosine and a corresponding (N)-methanocarba nucleoside series containing a bicyclo[3.1.0]hexane ring system in place of the ribose moiety. The compounds were examined in binding assays at three subtypes of adenosine receptors (ARs) and in functional assays at the A3 AR. The H-bonding ability of a group of 9-riboside derivatives containing a 50-uronamide

  我们已经制备了 50 种修饰的腺苷衍生物和相应的 (N)-methanocarba 核苷系列，其中含有双环 [3.1.0] 己烷环系统代替核糖部分。在三种亚型腺苷受体 (AR) 的结合试验和 A3 AR 的功能试验中检查了这些化合物。NH 的修饰降低了一组含有 50-尿醛酰胺部分的 9-核苷衍生物的 H 键合能力；然而，这些衍生物没有显示出作为选择性 A3 AR 拮抗剂所需的活性，如 50-N,N-二甲基脲酰胺所发生的那样。然而，缺乏 40-羟甲基的截短的 (N)-methanocarba 类似物是人类 A3 AR 的高效选择性拮抗剂。这些化合物是使用 50-羧基中间体的还原性自由基脱羧从 D-核糖合成的。一种效率较低的合成方法始于 L-核糖，它类似于 (N)-methanocarba A3AR 激动剂的已发表合成。化合物 33b-39b（N6-3-卤代苄基和相关的芳烷基衍生物）是有效的 A3AR
• ADENOSINE RECEPTOR AGONISTS, PARTIAL AGONISTS, AND ANTAGONISTS
  申请人：Jacobson Kenneth A.

  公开号：US20120252823A1

  公开（公告）日：2012-10-04

  Disclosed are A 3 adenosine receptor antagonists and/or partial agonists and A 1 adenosine receptor agonists and/or partial agonists of formula (I): wherein R 1 to R 5 are as described herein, as well as pharmaceutical compositions thereof and methods of use thereof. The A 3 AR antagonists or partial agonists find use in treating a number of diseases such as cancer, glaucoma, and inflammatory diseases, as well as in preventing cardiac ischemia. Also disclosed are radiolabeled compounds of formula (I) and the use thereof in diagnostic imaging of tissues and organs. The A 1 AR agonists and partial agonists find use in treating diseases such as seizures, convulsion, stroke, diabetes, pain, arrhythmias, depression, and anxiety and in cardioprotection or neuroprotection.

  本发明涉及式(I)的A3腺苷受体拮抗剂和/或部分激动剂以及A1腺苷受体激动剂和/或部分激动剂，其中R1至R5如本文所述，以及其制药组合物和使用方法。A3AR拮抗剂或部分激动剂可用于治疗诸如癌症、青光眼和炎症性疾病等多种疾病，以及预防心脏缺血。本发明还涉及式(I)的放射性标记化合物及其在组织和器官的诊断成像中的应用。A1AR激动剂和部分激动剂可用于治疗癫痫、惊厥、中风、糖尿病、疼痛、心律失常、抑郁症和焦虑症以及心脏保护或神经保护。
• Compounds and compositions useful for treating disorders related to NTRK
  申请人：BLUEPRINT MEDICINES CORPORATION

  公开号：US10017512B2

  公开（公告）日：2018-07-10

  This disclosure relates to inhibitors of NTRK that are active against wild-type NTRK and its resistant mutants, such as compounds of Formula (I):

  本公开涉及对野生型 NTRK 及其抗性突变体有活性的 NTRK 抑制剂，如式 (I) 化合物：