(3-hydroxypyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}methanone | 1259403-96-7

• 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: (3-hydroxypyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}methanone
• 英文别名: ((S)-3-hydroxypyrrolidin-1-yl)((3R,4R)-4-methyl-3-(methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methanone；[(3S)-3-hydroxypyrrolidin-1-yl]-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]methanone
• CAS: 1259403-96-7
• 化学式: C₁₈H₂₆N₆O₂
• 分子量: 358.443
• InChiKey: RDGVREXPTVNIOZ-IPYPFGDCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  88.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3-hydroxypyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}methanone 、 3,3'-二羟基二苯二硫醚 在 Oxone 、 三丁基膦 作用下， 以 四氢呋喃 、 水 、 异丙醇 、 甲苯 为溶剂， 反应 4.0h， 生成 ((R)-3-((3-hydroxyphenyl)sulfonyl)pyrrolidin-1-yl)((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methanone
  参考文献：
  名称：

  Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin

  摘要：

  By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization; of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.

  DOI：

  10.1021/acs.jmedchem.6b01634
• 作为产物：
  描述：

  N-甲基-N-((3R,4R)-4-甲基哌啶-3-基)-7H-吡咯并[2,3-D]嘧啶-4-胺 、 (S)-4-nitrophenyl 3-hydroxypyrrolidine-1-carboxylate 在 三乙胺 作用下， 以 叔丁醇 为溶剂， 反应 48.0h， 以33%的产率得到(3-hydroxypyrrolidin-1-yl)-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}methanone
  参考文献：
  名称：

  Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant Rejection

  摘要：

  There is a critical need for safer and more convenient treatments for organ transplant rejection and autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved in the signaling of multiple cytokines important for various T cell functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimidine-based series of inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast proliferation assay. Select compounds were evaluated in rodent efficacy models of allograft rejection and destructive inflammatory arthritis. Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for treatment of autoimmune diseases and organ transplant rejection.

  DOI：

  10.1021/jm1004286