tert-butyl (S,Z)-6-(benzyloxy)-3-(5-(chloro(hydroxyimino)methyl)-4-cyclopropylisoxazol-3-yl)hexanoate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyl (S,Z)-6-(benzyloxy)-3-(5-(chloro(hydroxyimino)methyl)-4-cyclopropylisoxazol-3-yl)hexanoate
• 英文别名: tert-butyl (3S)-3-[5-[(Z)-C-chloro-N-hydroxycarbonimidoyl]-4-cyclopropyl-1,2-oxazol-3-yl]-6-phenylmethoxyhexanoate
• 化学式: C₂₄H₃₁ClN₂O₅
• 分子量: 462.974
• InChiKey: BQVGTIDZFKUIBW-RHGYLGJDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  32
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  94.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl (S,Z)-6-(benzyloxy)-3-(5-(chloro(hydroxyimino)methyl)-4-cyclopropylisoxazol-3-yl)hexanoate 在 potassium carbonate 、 戴斯-马丁氧化剂 、 三氟乙酸 、 [双(2-甲氧基乙基)胺]三氟化硫 作用下， 以 二氯甲烷 、 氯仿 、 水 、 甲苯 为溶剂， 反应 4.0h， 生成 (S)-6-benzyloxy-3-[4'-cyclopropyl-5-(1,1-difluoro-2,2-dimethyl-propyl)[3,5']biisoxazolyl-3'-yl]hexanoic acid
  参考文献：
  名称：

  Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold

  摘要：

  Starting from a previously reported ROR gamma inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation ROR gamma inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.

  DOI：

  10.1021/acs.jmedchem.8b01567
• 作为产物：
  描述：

  5-苄氧基戊酸 在 4-二甲氨基吡啶 、 bis-triphenylphosphine-palladium(II) chloride 、 potassium phosphate 、 N-氯代丁二酰亚胺 、 lithium hydroxide monohydrate 、 盐酸羟胺 、 双氧水 、 sodium hexamethyldisilazane 、 二异丁基氢化铝 、 potassium carbonate 、 1-羟基苯并三唑 、 戴斯-马丁氧化剂 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 氯仿 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 33.5h， 生成 tert-butyl (S,Z)-6-(benzyloxy)-3-(5-(chloro(hydroxyimino)methyl)-4-cyclopropylisoxazol-3-yl)hexanoate
  参考文献：
  名称：

  Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold

  摘要：

  Starting from a previously reported ROR gamma inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation ROR gamma inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.

  DOI：

  10.1021/acs.jmedchem.8b01567

文献信息

• TRIAZOLE-ISOXAZOLE COMPOUND AND MEDICAL USE THEREOF
  申请人：JAPAN TOBACCO INC.

  公开号：US20160137639A1

  公开（公告）日：2016-05-19

  A compound represented by Formula [I]: or pharmaceutically acceptable salt thereof, wherein each symbol is as defined in the description.

  由式[I]表示的化合物： 或其药学上可接受的盐，其中每个符号如描述中所定义。
• Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold
  作者：Masayuki Kotoku、Takaki Maeba、Shingo Fujioka、Masahiro Yokota、Noriyoshi Seki、Keisuke Ito、Yoshihiro Suwa、Taku Ikenogami、Kazuyuki Hirata、Yasunori Hase、Yoshiaki Katsuda、Naoki Miyagawa、Kojo Arita、Kota Asahina、Masato Noguchi、Akihiro Nomura、Satoki Doi、Tsuyoshi Adachi、Paul Crowe、Haiyan Tao、Scott Thacher、Hiromasa Hashimoto、Takayoshi Suzuki、Makoto Shiozaki

  DOI：10.1021/acs.jmedchem.8b01567

  日期：2019.3.14

  Starting from a previously reported ROR gamma inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation ROR gamma inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.