methyl (2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl)acetate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶唑类
• 英文名称: methyl (2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl)acetate
• 英文别名: methyl 2-[2-(5-fluoro-2-methylanilino)-1,3-benzoxazol-6-yl]acetate
• 化学式: C₁₇H₁₅FN₂O₃
• 分子量: 314.316
• InChiKey: JYYCJKRLRZMQOZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  64.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl (2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl)acetate 在 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 以97%的产率得到[2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl]acetic acid
  参考文献：
  名称：

  VLA-4 INHIBITORS

  摘要：

  公开号：

  EP1346982B1
• 作为产物：
  描述：

  methyl (4-amino-3-hydroxyphenyl)acetate 、 5-氟-2-甲基苯基异硫氰酸酯 在 mercury(II) oxide 作用下， 以 甲醇 为溶剂， 反应 126.0h， 生成 methyl (2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl)acetate
  参考文献：
  名称：

  Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic Acid: An Orally Active, Selective Very Late Antigen-4 Antagonist

  摘要：

  We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexinecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.

  DOI：

  10.1021/jm901154c

文献信息

• Vla-4 inhibitors
  申请人：——

  公开号：US20040110945A1

  公开（公告）日：2004-06-10

  The present invention relates to a compound represented by the following formula (I): 1 (wherein, W represents W A —A 1 —W B — (in which, W A is substituted or unsubstituted aryl, etc., A 1 is —NR 1 —, single bond, —C(O)—, etc., and W B is substituted or unsubstituted arylene, etc.), R is single bond, —NH—, —OCH 2 —, alkenylene, etc., X is —C(O)—, —CH 2 —, etc., and M is, for example, the following formula: 2 (in which, R 11 , R 12 and R 13 each independently represents hydrogen, hydroxyl, amino, halogen, etc., R 14 is hydrogen or lower alkyl, Y represents —CH 2 —O—, etc., Z is substituted or unsubstituted arylene, etc., A 2 is single bond, etc, and R 10 is hydroxyl or lower alkoxy)), or salt thereof; and a medicament containing the same. This compound or salt thereof selectively inhibits binding of cell adhesion molecules to VAL-4 and exhibits high bioavailability so that it is useful as a preventive and/or remedy for inflammatory diseases, autoimmune diseases, metastasis, bronchial asthma, rhinostenosis, diabetes, and the like.

  本发明涉及以下式(I)所表示的化合物：1（其中，W代表WA-A1-WB-（其中，WA是取代或未取代的芳基等，A1是-NR1-，单键，-C（O）-等，WB是取代或未取代的芳烃基等），R是单键，-NH-，-OCH2-，烯烃基等，X是-C（O）-，-CH2-等，M是例如以下公式：2（其中，R11，R12和R13分别独立地代表氢，羟基，氨基，卤素等，R14是氢或低级烷基，Y代表-CH2-O-等，Z是取代或未取代的芳烃基等，A2是单键等，而R10是羟基或低级烷氧基），或其盐；以及含有该化合物的药物。该化合物或其盐选择性地抑制细胞黏附分子与VAL-4的结合，并表现出高的生物利用度，因此可用作预防和/或治疗炎症性疾病、自身免疫性疾病、转移、支气管哮喘、鼻窦狭窄、糖尿病等。
• VLA-4 INHIBITORS
  申请人：DAIICHI PHARMACEUTICAL CO., LTD.

  公开号：EP1346982B1

  公开（公告）日：2011-09-14
• US7157487B2
  申请人：——

  公开号：US7157487B2

  公开（公告）日：2007-01-02
• Discovery of <i>trans</i>-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4<i>S</i>)-methoxy-(2<i>S</i>)-pyrrolidinylmethoxy]cyclohexanecarboxylic Acid: An Orally Active, Selective Very Late Antigen-4 Antagonist
  作者：Fumihito Muro、Shin Iimura、Yuuichi Sugimoto、Yoshiyuki Yoneda、Jun Chiba、Toshiyuki Watanabe、Masaki Setoguchi、Yutaka Iigou、Keiko Matsumoto、Atsushi Satoh、Gensuke Takayama、Tomoe Taira、Mika Yokoyama、Tohru Takashi、Atsushi Nakayama、Nobuo Machinaga

  DOI：10.1021/jm901154c

  日期：2009.12.24

  We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexinecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.