(1R,3R,5R)-1-acetoxy-3-[(tert-butyldimethylsilyl)oxy]-6-oxa-bicyclo[3.2.1]octane-4,7-dione | 766529-88-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 英文名称: (1R,3R,5R)-1-acetoxy-3-[(tert-butyldimethylsilyl)oxy]-6-oxa-bicyclo[3.2.1]octane-4,7-dione
• 英文别名: (1R,3R,5R)-3-(tert-butyldimethylsilyloxy)-4,7-dioxo-6-oxabicyclo[3.2.1]octan-1-yl acetate；[(1R,3R,5R)-3-[tert-butyl(dimethyl)silyl]oxy-4,7-dioxo-6-oxabicyclo[3.2.1]octan-1-yl] acetate
• CAS: 766529-88-8
• 化学式: C₁₅H₂₄O₆Si
• 分子量: 328.437
• InChiKey: GRVQVONDDBHRPF-UEKVPHQBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.97
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  78.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (1R,3R,5R)-1-acetoxy-3-[(tert-butyldimethylsilyl)oxy]-6-oxa-bicyclo[3.2.1]octane-4,7-dione 在 2,6-二甲基吡啶 、 sodium tetrahydroborate 、 sodium periodate 、 正丁基锂 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 为溶剂， 生成 methyl-2-((3R,5R)-3,5-bis(tertbutyldimethylsilyloxy)-4-methylenecyclohexylidene)acetate
  参考文献：
  名称：

  Synthesis of VS-105: A novel and potent vitamin D receptor agonist with reduced hypercalcemic effects

  摘要：

  We have synthesized a novel vitamin D receptor agonist VS-105 ((1R,3R)-5-((E)-2-((3 alpha S,7 alpha S)-1-((R)-1-((S)-3-hydroxy-2,3-dimethylbutoxy)ethyl)-7 alpha-methyldihydro-1H-inden-4(2H,5H,6H,7H,7 alpha H)-ylidene) ethylidene)-2-methylenecyclohexane-1,3-diol). Preparation of a-ring phenylphosphine oxide 11, followed by Wittig-Horner coupling of 11 with the protected 25-hydroxy Grundmann's ketone 22 generated the precursor 12. Deprotection of the TBDMS groups of 12 produced the target compound VS-105. The biological profiles of VS-105 were evaluated using in vitro assays (VDR receptor binding, VDR reporter gene and HL-60 differentiation) in comparison to calcitriol (the endogenous hormone) or paricalcitol. Furthermore, the PTH suppressing potency and hypercalcemic side effects of VS-105 were evaluated in the 5/6 nephrectomized uremic rats in comparison to paricalcitol. Combining various changes at 20-epi, 22-oxa, 24-methyl, and 2-methylene yielded VS-105 that not only is highly potent in inducing functional responses in vitro, but also effectively suppresses PTH in a dose range that does not affect serum calcium in the 5/6 nephrectomized uremic rats. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.08.076
• 作为产物：
  描述：

  (1R,3R,5R)-3-[(tert-butyldimethylsilyl)oxy]-1-hydroxy-6-oxa-bicyclo[3.2.1]octane-4,7-dione 以85.1的产率得到(1R,3R,5R)-1-acetoxy-3-[(tert-butyldimethylsilyl)oxy]-6-oxa-bicyclo[3.2.1]octane-4,7-dione
  参考文献：
  名称：

  Vitamin D Receptor Agonists and Uses Thereof

  摘要：

  本发明公开了一种式（I）的化合物，其中R1、R2、R3、R4、R5、R6、X和a如本文所定义，或其药学上可接受的盐。本发明还公开了一种包括式（I）的化合物或其盐的制药组合物，以及一种治疗需要调节维生素D受体的疾病的方法，例如骨疾病、心血管疾病、与肾脏疾病相关的心血管并发症、内皮功能障碍、甲状旁腺功能亢进、低钙血症、免疫紊乱、左心室肥厚、增生性疾病、蛋白尿、肾脏疾病和血栓形成等疾病。

  公开号：

  US20120115824A1

文献信息

• [EN] SYNTHESIS AND BIOLOGICAL ACTIVITY OF 2-METHYLENE ANALOGS OF CALCITRIOL AND RELATED COMPOUNDS<br/>[FR] SYNTHÈSE ET ACTIVITÉ BIOLOGIQUE D'ANALOGUES 2-MÉTHYLÈNE DU CALCITRIOL ET DE COMPOSÉS APPARENTÉS
  申请人：WISCONSIN ALUMNI RES FOUND

  公开号：WO2017023617A1

  公开（公告）日：2017-02-09

  Disclosed are 2-methylene analogs of vitamin D3 and related compounds, their biological activities, and various pharmaceutical uses for these analogs. Particularly disclosed are 1α-hydroxy-2-methylene-vitamin D3, (20S)-1α-hydroxy-2-methylene- vitamin D3, and (5E)- 1α,25-dihydroxy-2-methylene- vitamin D3, their biological activities, and various pharmaceutical uses for these compounds including methods of treating and/or preventing bone diseases and disorders.

  公开了维生素D3的2-亚甲基类似物及相关化合物，它们的生物活性以及这些类似物的各种药用用途。特别公开了1α-羟基-2-亚甲基-维生素D3、(20S)-1α-羟基-2-亚甲基-维生素D3和(5E)-1α,25-二羟基-2-亚甲基-维生素D3，它们的生物活性以及这些化合物的各种药用用途，包括治疗和/或预防骨骼疾病和失调的方法。
• Synthesis and Biological Activity of 2-Methylene Analogues of Calcitriol and Related Compounds
  作者：Izabela K. Sibilska、Marcin Szybinski、Rafal R. Sicinski、Lori A. Plum、Hector F. DeLuca

  DOI：10.1021/acs.jmedchem.5b01295

  日期：2015.12.24

  In an attempt to prepare vitamin D analogues that are superagonists, (20R)- and (20S)-isomers of 1α-hydroxy-2-methylenevitamin D3 and 1α,25-dihydroxy-2-methylenevitamin D3 have been synthesized. To prepare the desired A-ring dienyne fragment, two different approaches were used, both starting from the (−)-quinic acid. The obtained derivative was subsequently coupled with the C,D-ring enol triflates

  在试图制备维生素d类似物是超级激动剂，（20 - [R ）-和（20小号）1α-羟基-2- methylenevitamin d的-异构体3和1α，25-二羟基-2- methylenevitamin d 3已被合成。为了制备所需的A环二烯炔片段，使用了两种不同的方法，均从（-）-奎尼酸开始。随后使用Sonogashira反应将获得的衍生物与衍生自相应的Grundmann酮的C，D-环烯醇三氟甲磺酸酯偶联。此外，（20 R）-和（20 S）-1α，25-二羟基-2-亚甲基维生素D 3化合物具有（5 E）-构型是通过碘催化的异构化制备的。天然激素的所有四个2-亚甲基类似物都具有很高的体外活性。如预期的那样，25-脱氧类似物的效力要低得多。在合成的化合物中，发现两个化合物1α，25-二羟基-2-亚甲基维生素D 3及其C-20差向异构体的活性几乎与2-亚甲基-19- nor- （20 S）-1α相同，骨骼上有25-二羟基维生素D
• 2-methylene-vitamin D analogs and their uses
  申请人：Wisconsin Alumni Research Foundation

  公开号：US08410080B1

  公开（公告）日：2013-04-02

  This invention discloses 2-methylene-vitamin D analogs, and specifically (20S)-1α,25 -dihydroxy-2-methylene-vitamin D3 as well as (5E)-(20S)-1α,25-dihydroxy-2 -methylene-vitamin D3 and (20R)-1α,25-dihydroxy-2-methylene-vitamin D3, as well as pharmaceutical uses therefor. These compounds exhibit relatively high binding activity and pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as an anti-cancer agent especially for the treatment or prevention of osteosarcoma, leukemia, colon cancer, breast cancer, skin cancer or prostate cancer. These compounds also have relatively high calcemic activities evidencing use in the treatment of bone diseases.

  本发明公开了2-亚甲基-维生素D类似物，特别是(20S)-1α,25-二羟基-2-亚甲基-维生素D3以及(5E)-(20S)-1α,25-二羟基-2-亚甲基-维生素D3和(20R)-1α,25-二羟基-2-亚甲基-维生素D3，以及它们的药物用途。这些化合物表现出相对较高的结合活性和显著抑制未分化细胞增殖并诱导其向单核细胞分化的活性，因此可作为抗癌剂，特别用于治疗或预防骨肉瘤、白血病、结肠癌、乳腺癌、皮肤癌或前列腺癌。这些化合物还具有相对较高的升高血钙活性，可用于治疗骨骼疾病。
• [EN] VITAMIN D RECEPTOR AGONISTS AND USES THEREOF<br/>[FR] AGONISTES DU RÉCEPTEUR DE LA VITAMINE D ET UTILISATIONS CORRESPONDANTES
  申请人：VIDASYM LLC

  公开号：WO2010120698A1

  公开（公告）日：2010-10-21

  Disclosed is a compound of Formula (I), in which R1, R2, R3, R4, R5, R6, X, and a are defined herein, or a pharmaceutically acceptable salt thereof. Also disclosed are a pharmaceutical composition comprising a compound or salt therof of Formula (I) and a method of treating a disease which benefits from the modulation of the vitamin D receptor, such as a bone disorder, cardiovascular disease, a cardiovascular complication associated with renal disease, endothelial dysfunction, hyperparathyroidism, hypocalcemia, an immune disorder, left ventricular hypertrophy, a proliferative disease, proteinuria, renal disease, and thrombosis.

  揭示的是化合物Formula (I)，其中R1、R2、R3、R4、R5、R6、X和a在此处定义，或其药用可接受盐。还揭示了一种包含Formula (I)的化合物或其盐的制药组合物，以及一种治疗受益于调节维生素D受体的疾病的方法，如骨骼疾病、心血管疾病、与肾脏疾病相关的心血管并发症、内皮功能障碍、甲状旁腺功能亢进、低钙血症、免疫障碍、左心室肥厚、增殖性疾病、蛋白尿、肾脏疾病和血栓形成。
• New 2-Alkylidene 1α,25-Dihydroxy-19-norvitamin D₃ Analogues of High Intestinal Activity:  Synthesis and Biological Evaluation of 2-(3‘-Alkoxypropylidene) and 2-(3‘-Hydroxypropylidene) Derivatives
  作者：Agnieszka Glebocka、Rafal R. Sicinski、Lori A. Plum、Margaret Clagett-Dame、Hector F. DeLuca

  DOI：10.1021/jm051082a

  日期：2006.5.1

  elaborated that comprised Julia coupling of sulfones 39a and 39b with the cyclohexanone derivative 23. The binding of all synthesized vitamins to the full-length rat recombinant vitamin D receptor (VDR) is either similar to or within one log of 1alpha,25(OH)(2)D(3). The in vivo tests have revealed that the calcemic activity of all analogues in the E-series (5a, 6a, 6b) is considerably higher than that of

  在寻找具有潜在治疗价值的新型维生素D化合物，1α，25-二羟基-2-（3'-羟丙叉基）-19-正维生素D（3）的E-和Z-异构体及其衍生物有效地制备了在C-2具有3'-（甲氧基甲氧基）亚丙基取代基的前一化合物。所有维生素均以收敛合成方式获得，从（-）-奎尼酸和受保护的25-羟基Grundmann酮开始。将奎宁酸转化为酮内酯11，并通过Wittig反应连接一个取代的羟丙基亚基，生成成对的异构体化合物12、13和14、15。然后，将这些烯烃产物转化为氧化膦32-34，将其氧化为Lythgoe型Wittig-Horner与C，D片段35a和35b耦合。还详细说明了另一种方法，包括砜39a和39b与环己酮衍生物23的朱莉娅偶联。所有合成维生素与全长大鼠重组维生素D受体（VDR）的结合与1alpha相似或在1log内，25（OH）（2）D（3）。体内试验表明，E系列（5a，6a，6b）中所有类似物的钙化活性均明显高于天然激素。