1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo[3,2-d]pyrimidin-6-ylmethyl)pentan-2-ol | 875415-02-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo[3,2-d]pyrimidin-6-ylmethyl)pentan-2-ol
• CAS: 875415-02-4
• 化学式: C₂₀H₂₁F₄N₃O₂
• 分子量: 411.399
• InChiKey: RIPQLOCNIOPCFT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  71
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo[3,2-d]pyrimidin-6-ylmethyl)pentan-2-ol 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 60.0h， 以68%的产率得到4-fluoro-2-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(5H-pyrrolo[3,2-d]pyrimidin-6-ylmethyl)butyl]phenol
  参考文献：
  名称：

  Identification of Highly Efficacious Glucocorticoid Receptor Agonists with a Potential for Reduced Clinical Bone Side Effects

  摘要：

  Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.

  DOI：

  10.1021/jm4019178
• 作为产物：
  描述：

  1,1,1-三氟-4-(5-氟-2-甲氧基苯基)-4-甲基戊-2-酮 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 potassium tert-butylate 、 三乙胺 作用下， 以 N-甲基吡咯烷酮 、 乙醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 47.0h， 生成 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo[3,2-d]pyrimidin-6-ylmethyl)pentan-2-ol
  参考文献：
  名称：

  Identification of Highly Efficacious Glucocorticoid Receptor Agonists with a Potential for Reduced Clinical Bone Side Effects

  摘要：

  Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.

  DOI：

  10.1021/jm4019178

文献信息

• Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
  申请人：Bekkali Younes

  公开号：US20050176706A1

  公开（公告）日：2005-08-11

  Compounds of Formula (IA), (IB), (IC), and (ID) wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as respectively defined herein for Formula (IA), (IB), (IC), and (ID), or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.

  化合物的公式为（IA），（IB），（IC）和（ID），其中R1，R2，R3，R4，R5和R6分别定义为公式（IA），（IB），（IC）和（ID）中所述，或其互变异构体，前药，溶剂化物或盐; 包含这些化合物的药物组合物以及使用这些化合物调节糖皮质激素受体功能的方法和治疗由糖皮质激素受体功能介导或以炎症，过敏或增生过程为特征的疾病状态或病情的方法。
• COMPOSITIONS AND METHODS FOR TREATING, CONTROLLING, REDUCING, OR AMELIORATING INFLAMMATORY PAIN
  申请人：Ward Keith W.

  公开号：US20120316199A1

  公开（公告）日：2012-12-13

  A composition for treating, controlling, reducing, or ameliorating inflammatory pain comprises a dissociated glucocorticoid receptor agonist (“DIGRA”), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof. The composition can comprise an additional anti-inflammatory agent and can be formulated for topical application, injection, or implantation. It may be used in a method of managing post-surgical ocular pain such that it has lower risk of eliciting adverse side effects seen with other therapeutic agents.

  用于治疗、控制、减轻或改善炎症性疼痛的组合物包括解离型糖皮质激素受体激动剂（“DIGRA”）、其前药、其药学上可接受的盐或其药学上可接受的酯。该组合物可以包含额外的抗炎药物，并可制成局部应用、注射或植入剂。它可以用于管理术后眼部疼痛的方法，从而降低与其他治疗剂产生的不良副作用风险。
• Compositions and methods for treating, controlling, reducing, or ameliorating infections and sequelae thereof
  申请人：BAUSCH & LOMB INCORPORATED

  公开号：EP2364707A2

  公开（公告）日：2011-09-14

  A composition for treating, controlling, reducing, ameliorating, or alleviating infections and their inflammatory sequelae comprises a dissociated glucocorticoid receptor agonist ('DIGRA') and an anti-infective agent, such as an antibacterial, antiviral, antifungal, antiprotozoal agent, or a combination thereof. The composition can be formulated for topical application, injection, or implantation.

  一种用于治疗、控制、减少、改善或减轻感染及其炎症后遗症的组合物包含一种解离糖皮质激素受体激动剂（"DIGRA"）和一种抗感染剂，如抗菌剂、抗病毒剂、抗真菌剂、抗原虫剂或其组合。该组合物可配制成外用、注射或植入剂。
• Compositions and methods for treating or preventing glaucoma or progression thereof
  申请人：BAUSCH & LOMB INCORPORATED

  公开号：EP2397140A1

  公开（公告）日：2011-12-21

  A composition for treating or preventing glaucoma or its progression comprises a dissociated glucocorticoid receptor agonist ("DIGRA"), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof. The composition can comprise an additional anti-inflammatory agent and can be formulated for topical application, injection, or implantation. It may be used in combination with another therapy directed to reducing intraocular pressure.

  一种用于治疗或预防青光眼或青光眼进展的组合物包含一种离体糖皮质激素受体激动剂（"DIGRA"）、其原药、其药学上可接受的盐或其药学上可接受的酯。该组合物可包含一种额外的抗炎剂，并可配制成外用、注射或植入剂。它可与另一种降低眼内压的疗法联合使用。
• TREATING INFECTIONS AND SEQUELAE THEREOF WITH COMBINED DISSOCIATED GLUCOCORTICOID RECEPTOR AGONISTS AND ANTI-INFECTIVE AGENTS
  申请人：Bausch & Lomb Incorporated

  公开号：EP2049112B1

  公开（公告）日：2012-03-14