(2R,3R)-2-((3-carbamoyl-6-phenylpyrrolo[1,2-b] pyridazin-4-yl)amino)-3-hydroxybutyl dihydrogen phosphate | 1400878-19-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: (2R,3R)-2-((3-carbamoyl-6-phenylpyrrolo[1,2-b] pyridazin-4-yl)amino)-3-hydroxybutyl dihydrogen phosphate
• 英文别名: (2R,3R)-2-((3-Carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3-hydroxybutyl dihydrogen phosphate；[(2R,3R)-2-[(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-yl)amino]-3-hydroxybutyl] dihydrogen phosphate
• CAS: 1400878-19-4
• 化学式: C₁₈H₂₁N₄O₆P
• 分子量: 420.362
• InChiKey: RPXQUVSAJYVOTC-IAQYHMDHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  159
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2R,3R)-2-((3-carbamoyl-6-phenylpyrrolo[1,2-b] pyridazin-4-yl)amino)-3-hydroxybutyl dihydrogen phosphate 在 碳酸氢钠 作用下， 以 甲醇 、 水 为溶剂， 以4.05 g的产率得到
  参考文献：
  名称：

  Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis

  摘要：

  The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.

  DOI：

  10.1021/acsmedchemlett.8b00508
• 作为产物：
  描述：

  4-溴-1H-吡咯-2-羧酸甲酯 在 四氮唑 、 potassium phosphate 、 硫酸 、 10 wt% Pd(OH)2 on carbon 、 氢气 、 palladium diacetate 、 sodium hydride 、 N,N-二异丙基乙胺 、 2-二环己基磷-2,4,6-三异丙基联苯 、 三氯氧磷 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 N,N-二甲基甲酰胺 、 异丙醇 、 mineral oil 为溶剂， 反应 70.25h， 生成 (2R,3R)-2-((3-carbamoyl-6-phenylpyrrolo[1,2-b] pyridazin-4-yl)amino)-3-hydroxybutyl dihydrogen phosphate
  参考文献：
  名称：

  Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis

  摘要：

  The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.

  DOI：

  10.1021/acsmedchemlett.8b00508

文献信息

• [EN] PYRROLOPYRIDAZINE JAK3 INHIBITORS AND THEIR USE FOR THE TREATMENT OF INFLAMMATORY AND AUTOIMMUNE DISEASES<br/>[FR] INHIBITEURS DE JAK3 DE TYPE PYRROLOPYRIDAZINE ET LEUR UTILISATION POUR TRAITER LES MALADIES INFLAMMATOIRES ET AUTO-IMMUNES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2012125887A1

  公开（公告）日：2012-09-20

  Disclosed are compounds of formula (I) and pharmaceutically acceptable salts thereof. The compounds of formula (I) inhibit tyrosine kinase activity of JAK3, thereby making them useful for the treatment of inflammatory and autoimmune diseases.

  揭示了式（I）的化合物及其药用盐。式（I）的化合物抑制JAK3的酪氨酸激酶活性，因此它们可用于治疗炎症和自身免疫性疾病。
• PYRROLOPYRIDAZINE JAK3 INHIBITORS AND THEIR USE FOR THE TREATMENT OF INFLAMMATORY AND AUTOIMMUNE DISEASES
  申请人：Wrobleski Stephen T.

  公开号：US20140005146A1

  公开（公告）日：2014-01-02

  Disclosed are compounds of formula (I) and pharmaceutically acceptable salts thereof. The compounds of formula (I) inhibit tyrosine kinase activity of JAK3, thereby making them useful for the treatment of inflammatory and autoimmune diseases.

  本发明揭示了式(I)化合物及其药学上可接受的盐。式(I)化合物抑制JAK3的酪氨酸激酶活性，因此它们可用于治疗炎症和自身免疫性疾病。
• US9221826B2
  申请人：——

  公开号：US9221826B2

  公开（公告）日：2015-12-29
• Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis
  作者：Steven H. Spergel、Michael E. Mertzman、James Kempson、Junqing Guo、Sylwia Stachura、Lauren Haque、Jonathan S. Lippy、Rosemary F. Zhang、Michael Galella、Sidney Pitt、Guoxiang Shen、Aberra Fura、Kathleen Gillooly、Kim W. McIntyre、Vicky Tang、John Tokarski、John S. Sack、Javed Khan、Percy H. Carter、Joel C. Barrish、Steven G. Nadler、Luisa M. Salter-Cid、Gary L. Schieven、Stephen T. Wrobleski、William J. Pitts

  DOI：10.1021/acsmedchemlett.8b00508

  日期：2019.3.14

  The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.