2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-6,13-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-5-one | 554430-43-2

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 异黄酮类化合物
• 英文名称: 2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-6,13-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-5-one
• 英文别名: 2,8-bis-(tert-butyl-dimethyl-silyloxy)-11,12-dihydro-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-one；5,11-Bis{[tert-butyl(dimethyl)silyl]oxy}-1,2-dihydro-8H-[1]benzopyrano[4,3-d][1]benzoxepin-8-one；5,15-bis[[tert-butyl(dimethyl)silyl]oxy]-8,18-dioxatetracyclo[9.8.0.02,7.012,17]nonadeca-1(11),2(7),3,5,12(17),13,15-heptaen-19-one
• CAS: 554430-43-2
• 化学式: C₂₉H₄₀O₅Si₂
• 分子量: 524.805
• InChiKey: CFJGXVWWKCTOPU-UHFFFAOYSA-N

物化性质

• 沸点：
  556.6±50.0 °C(Predicted)
• 密度：
  1.10±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  8.16
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  54
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-6,13-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-5-one 在 盐酸 、 正丁基锂 、 二异丁基氢化铝 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 水 为溶剂， 反应 6.66h， 生成 1-(2-{4-[2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-5H-6,13-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-5-yl]phenoxy}ethyl)piperidine
  参考文献：
  名称：

  四环杂化合物的合成作为选择性雌激素受体调节剂。第2部分。放大2,5,8取代的11,12- Dihydro- 5 H -6,13-​​dioxabenzo [3,4]环庚-[1,2- a ]萘衍生物的工艺改进

  摘要：

  一种改进的，可重现的非色谱方法，用于大规模合成2,5,8-取代的11,12-二氢-5 H -6,13-​​二氧杂苯并[3,4]环庚[1,2- a ]萘衍生物描述了雌激素受体调节剂（SERM）。经过九个连续的合成步骤，以9-21％的总收率制备了标题化合物，具有较高的化学纯度（> 97％）。

  DOI：

  10.1021/op700061x
• 作为产物：
  描述：

  3-(2,4-Dimethoxy-phenyl)-7-methoxy-4-(2-methoxy-ethyl)-chromen-2-one 在 三溴化硼 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 2,8-bis(tert-butyldimethylsilyloxy)-11,12-dihydro-6,13-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene-5-one
  参考文献：
  名称：

  受限制的色烯对映异构体对的意外当量效价，该对映体通过与雌激素受体α配合的共晶结构合理化。

  摘要：

  尽管在了解ERα信号通路和获得许多治疗药物的认可方面取得了巨大进展，但ER +乳腺癌仍然是女性癌症死亡的主要原因。我们着手发现具有双重作用机制的化合物，其中它们不仅与雌二醇竞争与ERα的结合，而且还可以诱导ERα蛋白本身的降解。我们被包含四环苯并吡喃并苯并xepine支架的约束色酮所吸引，据报道它们是有效的选择性雌激素受体调节剂（SERMs）。氟甲基氮杂环丁烷侧链的掺入产生了高效且有效的选择性雌激素受体降解剂（SERD），例如16aa，并且还令人惊讶地是其对映体对16ab。

  DOI：

  10.1016/j.bmcl.2019.01.036

文献信息

• Novel heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators
  申请人：——

  公开号：US20040259915A1

  公开（公告）日：2004-12-23

  The present invention is directed to novel heteroatom containing tetracyclic derivatives, pharmaceutical compositions containing them, their use in the treatment and/or prevention of disorders mediated by one or more estrogen receptors and processes for their preparation. The compounds of the invention are useful in the treatment and/or prevention of disorders associated with the depletion of estrogen such as hot flashes, vaginal dryness, osteopenia and osteoporosis; hormone sensitive cancers and hyperplasia of the breast, endometrium, cervix and prostate; endometriosis, uterine fibroids, osteoarthritis and as contraceptive agents, alone or in combination with a progestogen or progestogen antagonist.

  本发明涉及新颖的含杂原子四环衍生物、含有它们的药物组合物、它们在治疗和/或预防由一个或多个雌激素受体介导的疾病中的应用，以及它们的制备方法。本发明的化合物在治疗和/或预防与雌激素耗竭相关的疾病中具有用途，例如热潮红、阴道干燥、骨量减少和骨质疏松症；激素敏感性癌症以及乳腺、子宫内膜、宫颈和前列腺的增生；子宫内膜异位症、子宫肌瘤、骨关节炎，以及作为避孕剂，单独使用或与孕激素或孕激素拮抗剂联合使用。
• Heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators
  申请人：Janssen Pharmaceutica N.V.

  公开号：US07329654B2

  公开（公告）日：2008-02-12

  The present invention is directed to novel heteroatom containing tetracyclic derivatives, pharmaceutical compositions containing them, their use in the treatment and/or prevention of disorders mediated by one or more estrogen receptors and processes for their preparation. The compounds of the invention are useful in the treatment and/or prevention of disorders associated with the depletion of estrogen such as hot flashes, vaginal dryness, osteopenia and osteoporosis; hormone sensitive cancers and hyperplasia of the breast, endometrium, cervix and prostate; endometriosis, uterine fibroids, osteoarthritis and as contraceptive agents, alone or in combination with a progestogen or progestogen antagonist.

  本发明涉及新颖的含杂原子的四环衍生物，包含它们的制药组合物，以及它们在治疗和/或预防由一个或多个雌激素受体介导的疾病中的使用和制备过程。本发明的化合物在治疗和/或预防与雌激素耗竭相关的疾病方面具有用途，如潮热，阴道干燥，骨质疏松症；激素敏感性癌症和乳腺，子宫内膜，宫颈和前列腺的增生；子宫内膜异位症，子宫肌瘤，骨关节炎以及作为避孕剂，单独或与孕激素或孕激素拮抗剂联合使用。
• Identification and Structure−Activity Relationships of Chromene-Derived Selective Estrogen Receptor Modulators for Treatment of Postmenopausal Symptoms
  作者：Nareshkumar Jain、Jiayi Xu、Ramesh M. Kanojia、Fuyong Du、Guo Jian-Zhong、Emmanuel Pacia、Muh-Tsann Lai、Amy Musto、George Allan、Michael Reuman、Xun Li、DoWon Hahn、Martin Cousineau、Sean Peng、David Ritchie、Ronald Russell、Scott Lundeen、Zhihua Sui

  DOI：10.1021/jm900146e

  日期：2009.12.10

  As part of it program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line its well in Ishikawa cell line with IC50 values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and file SERM raloxifene, 7-(R) wits found to be it potent SERM that behaved its antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were Significantly improved compared to those of the phase 2 development compound 9-(R).
• Unexpected equivalent potency of a constrained chromene enantiomeric pair rationalized by co-crystal structures in complex with estrogen receptor alpha
  作者：Birong Zhang、James R. Kiefer、Robert A. Blake、Jae H. Chang、Steven Hartman、Ellen Rei Ingalla、Tracy Kleinheinz、Vidhi Mody、Michelle Nannini、Daniel F. Ortwine、Yingqing Ran、Amy Sambrone、Deepak Sampath、Maia Vinogradova、Yu Zhong、Jerome C. Nwachukwu、Kendall W. Nettles、Tommy Lai、Jiangpeng Liao、Xiaoping Zheng、Hai Chen、Xiaojing Wang、Jun Liang

  DOI：10.1016/j.bmcl.2019.01.036

  日期：2019.4

  containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex

  尽管在了解ERα信号通路和获得许多治疗药物的认可方面取得了巨大进展，但ER +乳腺癌仍然是女性癌症死亡的主要原因。我们着手发现具有双重作用机制的化合物，其中它们不仅与雌二醇竞争与ERα的结合，而且还可以诱导ERα蛋白本身的降解。我们被包含四环苯并吡喃并苯并xepine支架的约束色酮所吸引，据报道它们是有效的选择性雌激素受体调节剂（SERMs）。氟甲基氮杂环丁烷侧链的掺入产生了高效且有效的选择性雌激素受体降解剂（SERD），例如16aa，并且还令人惊讶地是其对映体对16ab。
• Synthesis of Tetracyclic Heterocompounds as Selective Estrogen Receptor Modulators. Part 2. Process Improvement for Scale-Up Of 2,5,8-Substituted 11,12-Dihydro-5<i>H</i>-6,13-dioxabenzo[3,4]cyclohepta-[1,2-<i>a</i>]naphthalene Derivatives
  作者：Xun Li、Michael Reuman、Ronald K. Russell、Scott Youells、Sandra Beish、Zhiyong Hu、Shawn Branum、Nareshkumar Jain、Zhihua Sui

  DOI：10.1021/op700061x

  日期：2007.7.1

  An improved, reproducible nonchromatographic process for scale-up synthesis of 2,5,8-substituted 11,12-dihydro-5H-6,13-dioxabenzo[3,4]cyclohepta[1,2-a]naphthalene derivatives as selective estrogen receptor modulators (SERMs) is described. The titled compounds were prepared in 9−21% overall yield with high chemical purity (>97%) after nine consecutive synthetic steps.

  一种改进的，可重现的非色谱方法，用于大规模合成2,5,8-取代的11,12-二氢-5 H -6,13-​​二氧杂苯并[3,4]环庚[1,2- a ]萘衍生物描述了雌激素受体调节剂（SERM）。经过九个连续的合成步骤，以9-21％的总收率制备了标题化合物，具有较高的化学纯度（> 97％）。