4-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-3-hydroxymethyl-5'-(5-methanesulfonyl-pyridin-2-ylamino)-1'-methyl-1'H-[2,3']bipyridinyl-6'-one | 1423130-13-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 4-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-3-hydroxymethyl-5'-(5-methanesulfonyl-pyridin-2-ylamino)-1'-methyl-1'H-[2,3']bipyridinyl-6'-one
• 英文别名: 6-Tert-butyl-8-fluoro-2-[3-(hydroxymethyl)-2-[1-methyl-5-[(5-methylsulfonylpyridin-2-yl)amino]-6-oxopyridin-3-yl]pyridin-4-yl]phthalazin-1-one；6-tert-butyl-8-fluoro-2-[3-(hydroxymethyl)-2-[1-methyl-5-[(5-methylsulfonylpyridin-2-yl)amino]-6-oxopyridin-3-yl]pyridin-4-yl]phthalazin-1-one
• CAS: 1423130-13-5
• 化学式: C₃₀H₂₉FN₆O₅S
• 分子量: 604.662
• InChiKey: DDDRXCYXARZQIL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  43
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  154
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  glutathion 、 4-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-3-hydroxymethyl-5'-(5-methanesulfonyl-pyridin-2-ylamino)-1'-methyl-1'H-[2,3']bipyridinyl-6'-one 在 氧气 作用下， 生成 、
  参考文献：
  名称：

  Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton’s tyrosine kinase (BTK)

  摘要：

  Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a number of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead molecules in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compound 1 has a value of 459 pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation association of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS analysis of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compound 7 (RN941) with significantly reduced covalent binding of 26 pmol/ing protein. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2016.11.092
• 作为产物：
  描述：

  在 甲醇 、 sodium tetrahydroborate 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以54 mg的产率得到4-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-3-hydroxymethyl-5'-(5-methanesulfonyl-pyridin-2-ylamino)-1'-methyl-1'H-[2,3']bipyridinyl-6'-one
  参考文献：
  名称：

  [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE
  [FR] INHIBITEURS DE LA TYROSINE KINASE DE BRUTON

  摘要：

  该应用程序根据通用公式I披露化合物：其中变量如本文所述，并且抑制Btk。本文披露的化合物对调节Btk的活性并治疗与过度Btk活性相关的疾病有用。这些化合物进一步用于治疗与异常B细胞增殖相关的炎症和自身免疫疾病，如类风湿性关节炎。还披露了含有公式I化合物和至少一种载体、稀释剂或赋形剂的组合物。

  公开号：

  WO2013024078A1

文献信息

• INHIBITORS OF BRUTON'S TYROSINE KINASE
  申请人：Brotherton-Pleiss Christine E.

  公开号：US20130045965A1

  公开（公告）日：2013-02-21

  This application discloses compounds according to generic Formula I: wherein the variables are defined as described herein, and which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation, such as rheumatoid arthritis. Also disclosed are compositions containing compounds of Formula I and at least one carrier, diluent or excipient.

  本申请公开了通用式I所示的化合物：其中变量如本文所述，并抑制Btk。本文所披露的化合物有助于调节Btk的活性并治疗与过度Btk活性相关的疾病。此外，这些化合物还有助于治疗与异常B细胞增殖相关的炎症和自身免疫性疾病，如类风湿性关节炎。还披露了含有通用式I化合物和至少一种载体、稀释剂或赋形剂的组合物。
• US8889682B2
  申请人：——

  公开号：US8889682B2

  公开（公告）日：2014-11-18
• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE LA TYROSINE KINASE DE BRUTON
  申请人：HOFFMANN LA ROCHE

  公开号：WO2013024078A1

  公开（公告）日：2013-02-21

  This application discloses compounds according to generic Formula I: wherein the variables are defined as described herein, and which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation, such as rheumatoid arthritis. Also disclosed are compositions containing compounds of Formula I and at least one carrier, diluent or excipient.

  该应用程序根据通用公式I披露化合物：其中变量如本文所述，并且抑制Btk。本文披露的化合物对调节Btk的活性并治疗与过度Btk活性相关的疾病有用。这些化合物进一步用于治疗与异常B细胞增殖相关的炎症和自身免疫疾病，如类风湿性关节炎。还披露了含有公式I化合物和至少一种载体、稀释剂或赋形剂的组合物。
• Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton’s tyrosine kinase (BTK)
  作者：Yan Lou、Francisco Lopez、Yongying Jiang、Xiaochun Han、Chris Brotherton、Roland Billedeau、Steve Gabriel、Shelly Gleason、David M. Goldstein、Ramona Hilgenkamp、Buelent Kocer、Lucja Orzechowski、Jenny Tan、Peter Wovkulich、Bo Wen、David Fry、Paola Di Lello、Lucy Chen、Fang-jie Zhang、Jennifer Fretland、Anjali Nangia、Tian Yang、Timothy D. Owens

  DOI：10.1016/j.bmcl.2016.11.092

  日期：2017.2

  Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a number of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead molecules in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compound 1 has a value of 459 pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation association of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS analysis of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compound 7 (RN941) with significantly reduced covalent binding of 26 pmol/ing protein. (C) 2016 Elsevier Ltd. All rights reserved.