1-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid | 1236188-71-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid
• 英文别名: 1-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)-azetidine-3-carboxylic acid；1-[[4-[5-[5-(2-Methylpropyl)-4-(trifluoromethyl)-1,2-oxazol-3-yl]-1,2,4-oxadiazol-3-yl]phenyl]methyl]azetidine-3-carboxylic acid
• CAS: 1236188-71-8
• 化学式: C₂₁H₂₁F₃N₄O₄
• 分子量: 450.417
• InChiKey: KKZAKGKOIPIRBJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  106
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  methyl 5-isobutylisoxazole-3-carboxylate 在 吡啶 、 N-碘代丁二酰亚胺 、 copper(l) iodide 、 三聚氟氰 、 lithium hydroxide monohydrate 、 氟磺酰基二氟乙酸甲酯 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 甲醇 、 六甲基磷酰三胺 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 、 三氟乙酸 为溶剂， 反应 48.0h， 生成 1-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid
  参考文献：
  名称：

  Potent and Selective Agonists of Sphingosine 1-Phosphate 1 (S1P₁): Discovery and SAR of a Novel Isoxazole Based Series

  摘要：

  Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P(1-5)) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P(1), in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P(1). Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.

  DOI：

  10.1021/acs.jmedchem.6b00089

文献信息

• [EN] SUBSTITUTED OXADIAZOLE DERIVATIVES AS S1P AGONISTS IN THE TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISEASES<br/>[FR] DÉRIVÉS D'OXADIAZOLE SUBSTITUÉS COMME AGONISTES DE S1P DANS LE TRAITEMENT DE MALADIES AUTO-IMMUNES ET INFLAMMATOIRES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2010085581A1

  公开（公告）日：2010-07-29

  Disclosed are compounds of Formula (I) [INSERT CHEMICAL STRUCTURE HERE] (I) or pharmaceutically acceptable salts thereof, wherein Q is [INSERT CHEMICAL STRUCTURE HERE] or [INSERT CHEMICAL STRUCTURE HERE]; R1 is alkyl or aryl, said aryl optionally substituted with one to five substituents independently selected from C1 to C6 alkyl, C1 to C4 haloalkyl, OR4, and/or halogen; and R2, R3, R4, and n are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

  揭示了化合物的结构式 (I) [在此插入化学结构] (I) 或其药学上可接受的盐，其中 Q 是 [在此插入化学结构] 或 [在此插入化学结构]；R1 是烷基或芳基，所述芳基可选择性地取代一个至五个取代基，独立选择自 C1 至 C6 烷基、C1 至 C4 卤代烷基、OR4 和/或卤素；而 R2、R3、R4 和 n 在此有定义。还揭示了将这些化合物用作 G 蛋白偶联受体 S1P1 的选择性激动剂的方法，以及包含这些化合物的药物组合物。这些化合物在治疗、预防或减缓多种治疗领域的疾病或疾病进展方面具有用途，如自身免疫疾病和血管疾病。
• SUBSTITUTED ISOXAZOLE COMPOUNDS
  申请人：Watterson Scott Hunter

  公开号：US20110300165A1

  公开（公告）日：2011-12-08

  Disclosed are compounds of Formula (I) or pharmaceutically acceptable salts thereof, wherein Q is R 1 is alkyl or aryl, said aryl optionally substituted with one to five substituents independently selected from C 1 to C 6 alkyl, C 1 to C 4 haloalkyl, —OR 4 , and/or halogen; and R 2 , R 3 , R 4 , and n are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P 1 , and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

  本发明涉及公式（I）化合物或其药学上可接受的盐，其中Q是R1是烷基或芳基，所述芳基可选择性地被1到5个独立选择的取代基所取代，所述取代基选择自C1到C6烷基，C1到C4卤代烷基，-OR4和/或卤素; R2、R3、R4和n在此被定义。本发明还涉及使用这些化合物作为G蛋白偶联受体S1P1的选择性激动剂的方法，以及包含这些化合物的制药组合物。这些化合物在多种治疗领域中有用，例如自身免疫性疾病和血管疾病的治疗、预防或减缓疾病或障碍的进展。
• SUBSTITUTED OXADIAZOLE DERIVATIVES AS S1P AGONISTS IN THE TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISEASES
  申请人：Bristol-Myers Squibb Company

  公开号：EP2382212A1

  公开（公告）日：2011-11-02
• US8354398B2
  申请人：——

  公开号：US8354398B2

  公开（公告）日：2013-01-15