methyl 4-[(4S)-fluoro-1-[2-(2-methylphenylamino)-6-benzoxazolylacetyl]-(2S)-pyrrolidinylmethoxy]butanoate | 441713-99-1

• 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 4-[(4S)-fluoro-1-[2-(2-methylphenylamino)-6-benzoxazolylacetyl]-(2S)-pyrrolidinylmethoxy]butanoate
• 英文别名: methyl 4-((2S,4S)-4-fluoro-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-2-pyrrolidinylmethoxy)-n-butyrate；methyl 4-[[(2S,4S)-4-fluoro-1-[2-[2-(2-methylanilino)-1,3-benzoxazol-6-yl]acetyl]pyrrolidin-2-yl]methoxy]butanoate
• CAS: 441713-99-1
• 化学式: C₂₆H₃₀FN₃O₅
• 分子量: 483.54
• InChiKey: KGFBOUKAZFUHCG-PMACEKPBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  35
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  93.9
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl 4-[(4S)-fluoro-1-[2-(2-methylphenylamino)-6-benzoxazolylacetyl]-(2S)-pyrrolidinylmethoxy]butanoate 在 sodium hydroxide 、 水 、 盐酸 作用下， 以 四氢呋喃 为溶剂， 反应 17.0h， 以27%的产率得到4-[(4S)-fluoro-1-[2-(2-methylphenylamino)-6-benzoxazolylacetyl]-(2S)-pyrrolidinylmethoxy]butanoic acid
  参考文献：
  名称：

  A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid

  摘要：

  During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-( 2- methylphenylamino) benzoxazole moiety which mimics the diphenylurea structure. However, this modi. cation resulted in a significant decrease ( 3, IC(50) = 19 nM) in VLA-4 inhibitory activity compared to 1 ( IC(50) = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC(50) = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties ( CL = 3.3ml/min/ kg, F = 51%) in rats. (c) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.12.026
• 作为产物：
  描述：

  2-(2-methylphenylamino)-6-benzoxazolylacetic acid 、 methyl 4-[(4S)-fluoro-(2S)-pyrrolidinylmethoxy]butanoate 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 以78%的产率得到methyl 4-[(4S)-fluoro-1-[2-(2-methylphenylamino)-6-benzoxazolylacetyl]-(2S)-pyrrolidinylmethoxy]butanoate
  参考文献：
  名称：

  A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid

  摘要：

  During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-( 2- methylphenylamino) benzoxazole moiety which mimics the diphenylurea structure. However, this modi. cation resulted in a significant decrease ( 3, IC(50) = 19 nM) in VLA-4 inhibitory activity compared to 1 ( IC(50) = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC(50) = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties ( CL = 3.3ml/min/ kg, F = 51%) in rats. (c) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.12.026

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
• A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid
  作者：Fumihito Muro、Shin Iimura、Yoshiyuki Yoneda、Jun Chiba、Toshiyuki Watanabe、Masaki Setoguchi、Gensuke Takayama、Mika Yokoyama、Tohru Takashi、Atsushi Nakayama、Nobuo Machinaga

  DOI：10.1016/j.bmc.2008.12.026

  日期：2009.2

  During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-( 2- methylphenylamino) benzoxazole moiety which mimics the diphenylurea structure. However, this modi. cation resulted in a significant decrease ( 3, IC(50) = 19 nM) in VLA-4 inhibitory activity compared to 1 ( IC(50) = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC(50) = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties ( CL = 3.3ml/min/ kg, F = 51%) in rats. (c) 2008 Elsevier Ltd. All rights reserved.