4-amino-2-(pyridin-3-ylmethyl)-isoindole-1,3-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 4-amino-2-(pyridin-3-ylmethyl)-isoindole-1,3-dione
• 英文别名: 4-Amino-2-(pyridin-3-ylmethyl)isoindole-1,3-dione
• 化学式: C₁₄H₁₁N₃O₂
• 分子量: 253.26
• InChiKey: CAGQWGBEEJVXTG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  76.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  对叔丁基苯磺酰氯 、 4-amino-2-(pyridin-3-ylmethyl)-isoindole-1,3-dione 在 吡啶 作用下， 反应 24.0h， 生成 4-(tert-butyl)-N-(1,3-dioxo-2-(pyridin-3-ylmethyl)isoindolin-4-yl)benzene sulfonamide
  参考文献：
  名称：

  A New Series of Orally Bioavailable Chemokine Receptor 9 (CCR9) Antagonists; Possible Agents for the Treatment of Inflammatory Bowel Disease

  摘要：

  Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule. We wish to describe work aimed at producing new, orally active CCR9 antagonists based on the 1,3-dioxoisoindoline skeleton. This study led to a number of compounds that were potent in the nanomolar range and which, on optimization, resulted in several possible preclinical development candidates with excellent PK properties.

  DOI：

  10.1021/acs.jmedchem.5b01840
• 作为产物：
  描述：

  3-硝基邻苯二甲酸酐 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 、 溶剂黄146 为溶剂， 反应 36.0h， 生成 4-amino-2-(pyridin-3-ylmethyl)-isoindole-1,3-dione
  参考文献：
  名称：

  A New Series of Orally Bioavailable Chemokine Receptor 9 (CCR9) Antagonists; Possible Agents for the Treatment of Inflammatory Bowel Disease

  摘要：

  Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule. We wish to describe work aimed at producing new, orally active CCR9 antagonists based on the 1,3-dioxoisoindoline skeleton. This study led to a number of compounds that were potent in the nanomolar range and which, on optimization, resulted in several possible preclinical development candidates with excellent PK properties.

  DOI：

  10.1021/acs.jmedchem.5b01840

文献信息

• New anti-inflammatory N-pyridinyl(alkyl)phthalimides acting as tumour necrosis factor-α production inhibitors
  作者：Xavier Collin、Jean-Michel Robert、Gaétane Wielgosz、Guillaume Le Baut、Christine Bobin-Dubigeon、Nicole Grimaud、Jean-Yves Petit

  DOI：10.1016/s0223-5234(01)01254-5

  日期：2001.8

  This paper describes the synthesis of N-pyridinyl(alkyl)phthalimides related to N-phenyl-4,5,6,7-tetrafluorophthalimides known to be inhibitors of tumour necrosis factor-alpha (TNF alpha) production. Pharmacomodulation at the phthalimidic nitrogen led to the selection of two pharmacophoric fragments (2,4-lutidinyl and beta -picolyl), allowing significant inhibition of TNF alpha production (compounds 12 and 17). Variation of the substituents linked to the homocycle of their phthalimide scaffold indicated that high (TNF alpha production) inhibitory potency could be achieved, notably by 5-fluoro, 4- or 5-nitro, 5-amino and especially tetrafluoro substitution. The most active compound, N-(pyridin-3-ylmethyl)-4,5,6,7-tetrafluorophthalimide (32) (84% inhibition at 10 muM), also produced an anti-oedematous effect in the PMA-induced mouse-ear swelling test. Although less active than dexamethasone, it exerted a marked reduction in ear thickness after oral administration (63% vs. 85% for dexamethasone at 0.2 mM kg(-1)) and remained efficient after topical application (46% vs. 96% for the dexamethasone). It also induced potent inhibition in the rat carrageenan foot oedema test with an ID50 (0.14 muM kg(-1)) comparable with that of N-(2,6-diisopropylphenyl)phthalimide (4) (0.15 muM kg(-1)). (C) 2001 Editions scientifiques et medicales Elsevier SAS.
• [EN] COMPOUNDS USEFUL AS CCR9 MODULATORS<br/>[FR] COMPOSÉS UTILES EN TANT QUE MODULATEURS DU CCR9
  申请人：NORGINE BV

  公开号：WO2015097121A9

  公开（公告）日：2015-09-03
• COMPOUNDS USEFUL AS CCR9 MODULATORS
  申请人：Norgine BV

  公开号：EP3087069A1

  公开（公告）日：2016-11-02
• US9969687B2
  申请人：——

  公开号：US9969687B2

  公开（公告）日：2018-05-15
• A New Series of Orally Bioavailable Chemokine Receptor 9 (CCR9) Antagonists; Possible Agents for the Treatment of Inflammatory Bowel Disease
  作者：S. Barret Kalindjian、Sanjay V. Kadnur、Christopher A. Hewson、Chandregowda Venkateshappa、Suresh Juluri、Rajendra Kristam、Bheemashankar Kulkarni、Zainuddin Mohammed、Rohit Saxena、Vellarkad N. Viswanadhan、Jayashree Aiyar、Donna McVey

  DOI：10.1021/acs.jmedchem.5b01840

  日期：2016.4.14

  Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule. We wish to describe work aimed at producing new, orally active CCR9 antagonists based on the 1,3-dioxoisoindoline skeleton. This study led to a number of compounds that were potent in the nanomolar range and which, on optimization, resulted in several possible preclinical development candidates with excellent PK properties.