(2S)-6-(5-{[2-(benzyloxy)-3-hydroxypropyl]amino}-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-2-(2-methylphenyl)-3(2H)-pyridazinone | 928345-25-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (2S)-6-(5-{[2-(benzyloxy)-3-hydroxypropyl]amino}-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-2-(2-methylphenyl)-3(2H)-pyridazinone
• 英文别名: 6-[5-{[(2S)-2-(benzyloxy)-3-hydroxypropyl]amino}-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one；6-[5-(4-fluorophenyl)-3-[[(2S)-3-hydroxy-2-phenylmethoxypropyl]amino]-1H-pyrazol-4-yl]-2-(2-methylphenyl)pyridazin-3-one
• CAS: 928345-25-9
• 化学式: C₃₀H₂₈FN₅O₃
• 分子量: 525.582
• InChiKey: BGAWFBPWJBJWQQ-DEOSSOPVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  39
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  103
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (2S)-6-(5-{[2-(benzyloxy)-3-hydroxypropyl]amino}-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-2-(2-methylphenyl)-3(2H)-pyridazinone 在 甲基磺酰氯 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 73.7h， 以88%的产率得到(2S)-6-[6-(benzyloxy)-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)-3(2H)pyridazinone
  参考文献：
  名称：

  Identification, Synthesis, and Biological Evaluation of 6-[(6R)-2-(4-Fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one (AS1940477), a Potent p38 MAP Kinase Inhibitor

  摘要：

  Several p38 MAPK inhibitors have been shown to effectively block the production of cytokines such as IL-1 beta, TNF alpha, and IL-6. Inhibitors of p38 MAP kinase therefore have significant therapeutic potential for the treatment of autoimmune disease. Compound 2a was identified as a potent TNF alpha production inhibitor in vitro but suffered from poor oral bioavailability. Structural modification of 2a led to the discovery of tetrahydropyrazolopyrimidine derivatives, exemplified by compound 3, with an improved pharmacokinetic profile. We found that blocking metabolism at the methyl group of the amine and constructing the tetrahydropyrimidine core were important to obtaining compounds with good biological profiles and oral bioavailability. Pursuing the structure-activity relationships of this series led to the discovery of AS1940477 (3f), with excellent cellular activity and a favorable pharmacokinetic profile. This compound represents a highly potent inhibitor of p38 MAP kinase with regard to in vivo activity in an adjuvant-induced arthritis model.

  DOI：

  10.1021/jm3008008
• 作为产物：
  描述：

  对氟苯甲酸乙酯 在 吡啶 、 盐酸 、 pyridinium hydrobromide perbromide 、 水 、 copper diacetate 、 sodium acetate 、 对甲苯磺酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 溶剂黄146 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 55.33h， 生成 (2S)-6-(5-{[2-(benzyloxy)-3-hydroxypropyl]amino}-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-2-(2-methylphenyl)-3(2H)-pyridazinone
  参考文献：
  名称：

  Identification, Synthesis, and Biological Evaluation of 6-[(6R)-2-(4-Fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one (AS1940477), a Potent p38 MAP Kinase Inhibitor

  摘要：

  Several p38 MAPK inhibitors have been shown to effectively block the production of cytokines such as IL-1 beta, TNF alpha, and IL-6. Inhibitors of p38 MAP kinase therefore have significant therapeutic potential for the treatment of autoimmune disease. Compound 2a was identified as a potent TNF alpha production inhibitor in vitro but suffered from poor oral bioavailability. Structural modification of 2a led to the discovery of tetrahydropyrazolopyrimidine derivatives, exemplified by compound 3, with an improved pharmacokinetic profile. We found that blocking metabolism at the methyl group of the amine and constructing the tetrahydropyrimidine core were important to obtaining compounds with good biological profiles and oral bioavailability. Pursuing the structure-activity relationships of this series led to the discovery of AS1940477 (3f), with excellent cellular activity and a favorable pharmacokinetic profile. This compound represents a highly potent inhibitor of p38 MAP kinase with regard to in vivo activity in an adjuvant-induced arthritis model.

  DOI：

  10.1021/jm3008008

文献信息

• PYRIDAZINONE DERIVATIVES USED FOR THE TREATMENT OF PAIN
  申请人：Yamazaki Hitoshi

  公开号：US20090042856A1

  公开（公告）日：2009-02-12

  A pyridazinone derivative compound shown by the following formula (I): wherein R 1 is selected from hydrogen, etc.; R 2 is selected from substituted or unsubstituted aryl, etc.; R 3 is hydrogen, etc.; p is 0, 1 or 2; R 4 and R 5 , are each hydrogen, etc.; R 6 and R 7 , are taken together to form a group of the formula: wherein R 8 is hydrogen; X is selected from oxygen, etc; R 10 is selected from hydrogen, etc.; R 11 is selected from hydrogen, etc.; R 12 is selected from hydrogen, etc.; R 13 is selected from hydrogen, etc.; R 14 is selected from hydrogen, etc.; m and n are each 0, 1, or 2, or a pharmaceutically acceptable salt thereof, which is useful as a medicament.

  以下为化学式（I）所示的吡啶并咪唑酮衍生物化合物：其中R1选择氢等；R2选择取代或未取代的芳基等；R3选择氢等；p为0、1或2；R4和R5均为氢等；R6和R7相互结合形成下式的基团：其中R8为氢；X选择氧等；R10选择氢等；R11选择氢等；R12选择氢等；R13选择氢等；R14选择氢等；m和n均为0、1或2，或其药学上可接受的盐，用作药物。
• [EN] PYRIDAZINONE DERIVATIVES USED FOR THE TREATMENT OF PAIN<br/>[FR] NOUVEAUX COMPOSES
  申请人：ASTELLAS PHARMA INC

  公开号：WO2007026950A1

  公开（公告）日：2007-03-08

  [EN] A pyridazinone derivative compound shown by the following formula (I): wherein R₁ is selected from hydrogen, etc.; R₂ is selected from substituted or unsubstituted aryl, etc.; R₃ is hydrogen, etc.;p is 0, 1 or 2; R₄ and R₅ are each hydrogen, etc.; R₆ and R₇ are taken together to form a group of the formula: wherein R₈ is hydrogen; X is selected from oxygen, etc; R₁₀ is selected from hydrogen, etc.; R₁₁ is selected from hydrogen, etc.; R₁₂ is selected from hydrogen, etc.; R₁₃ is selected from hydrogen, etc.; R₁₄ is selected from hydrogen, etc.; m and n are each 0, 1, or 2, or a pharmaceutically acceptable salt thereof, which is useful as a medicament.
  [FR] L'invention concerne un dérivé de pyridazinone représenté par la formule (I), dans laquelle R₁ est sélectionné dans le groupe comprenant hydrogène, etc., R₂ est sélectionné dans le groupe comprenant aryle substitué ou non substitué, etc., R₃ représente hydrogène, etc., p représente 0, 1 ou 2, R₄ et R₅ représentent chacun hydrogène, etc., R₆ et R₇ sont pris ensemble pour former un groupe représenté par la formule dans laquelle R₈ représente hydrogène, X est sélectionné dans le groupe comprenant oxygène, etc., R₁₀ est sélectionné dans le groupe comprenant hydrogène, etc., R₁₁ est sélectionné dans le groupe comprenant hydrogène, etc., R₁₂ est sélectionné dans le groupe comprenant hydrogène etc., R₁₃ est sélectionné dans le groupe comprenant hydrogène, etc., R₁₄ est sélectionné dans le groupe comprenant hydrogène, etc., m et n représentent chacun 0, 1, ou 2, ou un sel pharmaceutiquement acceptable de celui-ci. Ce dérivé est utile en tant que médicament.
• Identification, Synthesis, and Biological Evaluation of 6-[(6<i>R</i>)-2-(4-Fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-<i>a</i>]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2<i>H</i>)-one (AS1940477), a Potent p38 MAP Kinase Inhibitor
  作者：Toru Asano、Hitoshi Yamazaki、Chiyoshi Kasahara、Hirokazu Kubota、Toru Kontani、Yu Harayama、Kazuki Ohno、Hidekazu Mizuhara、Masaharu Yokomoto、Keiji Misumi、Tomohiko Kinoshita、Mitsuaki Ohta、Makoto Takeuchi.

  DOI：10.1021/jm3008008

  日期：2012.9.13

  Several p38 MAPK inhibitors have been shown to effectively block the production of cytokines such as IL-1 beta, TNF alpha, and IL-6. Inhibitors of p38 MAP kinase therefore have significant therapeutic potential for the treatment of autoimmune disease. Compound 2a was identified as a potent TNF alpha production inhibitor in vitro but suffered from poor oral bioavailability. Structural modification of 2a led to the discovery of tetrahydropyrazolopyrimidine derivatives, exemplified by compound 3, with an improved pharmacokinetic profile. We found that blocking metabolism at the methyl group of the amine and constructing the tetrahydropyrimidine core were important to obtaining compounds with good biological profiles and oral bioavailability. Pursuing the structure-activity relationships of this series led to the discovery of AS1940477 (3f), with excellent cellular activity and a favorable pharmacokinetic profile. This compound represents a highly potent inhibitor of p38 MAP kinase with regard to in vivo activity in an adjuvant-induced arthritis model.