tert-butyl (5'-chloro-3-methyl-2,2',5-trioxospiro[imidazolidine-4,3'-indol]-1'(2'H)-yl)acetate | 1262426-98-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: tert-butyl (5'-chloro-3-methyl-2,2',5-trioxospiro[imidazolidine-4,3'-indol]-1'(2'H)-yl)acetate
• 英文别名: tert-butyl 2-(5'-chloro-1-methyl-2,2',4-trioxospiro[imidazolidine-5,3'-indole]-1'-yl)acetate
• CAS: 1262426-98-1
• 化学式: C₁₇H₁₈ClN₃O₅
• 分子量: 379.8
• InChiKey: BPKIXJNOGOXKAB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  96
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl (5'-chloro-3-methyl-2,2',5-trioxospiro[imidazolidine-4,3'-indol]-1'(2'H)-yl)acetate 在 盐酸 、 碳酸氢钠 、 potassium iodide 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 32.0h， 生成 [5'-chloro-1-[(1,3-diphenyl-1H-pyrazol-4-yl)methyl]-3-methyl-2,2',5-trioxospiro[imidazolidine-4,3'-indol]-1'(2'H)-yl]acetic acid
  参考文献：
  名称：

  Optimization of the Central Core of Indolinone–Acetic Acid-Based CRTH2 (DP2) Receptor Antagonists

  摘要：

  New spiroindolinone antagonists of CRTH2 are described. Following identification of insufficient stability in human plasma as an important liability of the lead compounds, replacement of the spirosuccinimide core with a spirohydantoin or spiropyrrolidinone structure has yielded a compound that is fully stable in human plasma and with good potency in a human whole blood assay (IC(50) = 69 nM) but shows a much lower oral bioavailability (6-9% in rodents) than the earlier compounds. Successive optimization aimed at restoring an acceptable oral bioavailability has yielded compound (S)-17a, which exhibits both stability in human plasma and a good oral bioavailability in rat (37%) and mouse (39%). This compound is also active in a mouse model of ovalbumin-induced lung inflammation following oral dosing at 30 mg/kg.

  DOI：

  10.1021/ml2001196
• 作为产物：
  描述：

  tert-butyl (5-chloro-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate 在 水 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 9.83h， 生成 tert-butyl (5'-chloro-3-methyl-2,2',5-trioxospiro[imidazolidine-4,3'-indol]-1'(2'H)-yl)acetate
  参考文献：
  名称：

  Optimization of the Central Core of Indolinone–Acetic Acid-Based CRTH2 (DP2) Receptor Antagonists

  摘要：

  New spiroindolinone antagonists of CRTH2 are described. Following identification of insufficient stability in human plasma as an important liability of the lead compounds, replacement of the spirosuccinimide core with a spirohydantoin or spiropyrrolidinone structure has yielded a compound that is fully stable in human plasma and with good potency in a human whole blood assay (IC(50) = 69 nM) but shows a much lower oral bioavailability (6-9% in rodents) than the earlier compounds. Successive optimization aimed at restoring an acceptable oral bioavailability has yielded compound (S)-17a, which exhibits both stability in human plasma and a good oral bioavailability in rat (37%) and mouse (39%). This compound is also active in a mouse model of ovalbumin-induced lung inflammation following oral dosing at 30 mg/kg.

  DOI：

  10.1021/ml2001196

文献信息

• [EN] TRICYCLIC INDOLE-DERIVED SPIRO DERIVATIVES AS CRTH2 MODULATORS<br/>[FR] DÉRIVÉS SPIRO ISSUS D'INDOLE TRICYCLIQUE COMME MODULATEURS DE CRTH2
  申请人：MERCK SERONO SA

  公开号：WO2011006936A1

  公开（公告）日：2011-01-20

  The present invention relates to compounds of formula (I) for use as pharmaceutical active compounds, as well as pharmaceutical formulations containing the same, for the treatment of allergic diseases. The compounds according to Formula (I) are suitable as modulators of CRTH2. The invention provides spiro derivatives according to Formula (I) and related formulae that are useful in the treatment and/or prevention of diseases selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, and inflammatory dermatoses such as atopic dermatitis, contact hypersensitivity, allergic contact dermatitis, chronic urticaria/chronic idiopathic/autoimmune urticaria, drag-induced exanthems (e.g. toxic epidermal necrolysis or Lyell's syndrome/Stevens-Johnson syndrome/drug hypersensitivity syndrome), photodermatosis or polymorphous light eruption (e.g. photo-irritant contact dermatitis, photoallergy contact dermatitis, chronic actinic dermatitis), and myositis neurodegenerative disorders such as neuropatic pain and other diseases with an inflammatory component such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD).

  本发明涉及式（I）的化合物作为药用活性化合物的用途，以及含有该化合物的药物配方，用于治疗过敏性疾病。根据式（I）的化合物适用作为CRTH2的调节剂。本发明提供了根据式（I)的螺环衍生物及相关公式，可用于治疗和/或预防选择自过敏性疾病的疾病，如过敏性哮喘、过敏性鼻炎、过敏性结膜炎和炎症性皮肤病，如特应性皮炎、接触性过敏性皮炎、慢性荨麻疹/慢性特发性/自身免疫性荨麻疹、药物诱发性皮疹（如毒性表皮坏死松解症或李尔综合征/史蒂文斯-约翰逊综合征/药物过敏综合征）、光敏性皮炎或多形性光疹（如光致刺激性接触性皮炎、光过敏接触性皮炎、慢性日光性皮炎）和肌炎神经退行性疾病，如神经性疼痛和其他具有炎症成分的疾病，如类风湿性关节炎、多发性硬化、骨关节炎和炎症性肠病（IBD）。
• TRICYCLIC INDOLE-DERIVED SPIRO DERIVATIVES AS CRTH2 MODULATORS
  申请人：Crosignani Stefano

  公开号：US20120115895A1

  公开（公告）日：2012-05-10

  The present invention relates to compounds of formula (I) for use as pharmaceutical active compounds, as well as pharmaceutical formulations containing the same, for the treatment of allergic diseases. The compounds according to Formula (I) are suitable as modulators of CRTH2. The invention provides Spiro derivatives according to Formula (I) and related formulae that are useful in the treatment and/or prevention of diseases selected from allergic diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, and inflammatory dermatoses such as atopic dermatitis, contact hypersensitivity, allergic contact dermatitis, chronic urticaria/chronic idiopathic/autoimmune urticaria, drag-induced exanthems (e.g., toxic epidermal necrolysis or Lyell's syndrome/Stevens-Johnson syndrome/drug hypersensitivity syndrome), photodermatosis or polymorphous light emption (e.g., photoirritant contact dermatitis, photoallergy contact dermatitis, chronic actinic dermatitis), and myositis neurodegenerative disorders such as neuropatic pain and other diseases with an inflammatory component such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, and inflammatory bowel disease (IBD).

  本发明涉及式（I）的化合物作为药物活性化合物的用途，以及含有该化合物的药物制剂，用于治疗过敏性疾病。根据式（I）的化合物适用于CRTH2的调节剂。本发明提供了根据式（I）及相关式的螺环衍生物，其在过敏性疾病（如过敏性哮喘、过敏性鼻炎、过敏性结膜炎）以及炎症皮肤病（如特应性皮炎、接触性超敏性、过敏性接触性皮炎、慢性荨麻疹/慢性特发性/自身免疫性荨麻疹、药物诱发性皮疹（如毒性表皮坏死症或Lyell综合征/史蒂文斯-约翰逊综合征/药物过敏综合征）、光敏皮肤病或多形性光敏反应（如光致刺激性接触性皮炎、光致过敏接触性皮炎、慢性光性皮炎））以及肌炎神经退行性疾病（如神经病性疼痛）和其他具有炎症成分的疾病（如类风湿性关节炎、多发性硬化症、骨关节炎和炎症性肠病（IBD））的治疗和/或预防中有用。