((S)-1-phenylcarbamoyl-hex-5-enyl)-carbamic acid tert-butyl ester

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ((S)-1-phenylcarbamoyl-hex-5-enyl)-carbamic acid tert-butyl ester
• 英文别名: tert-butyl N-[(2S)-1-anilino-1-oxohept-6-en-2-yl]carbamate
• 化学式: C₁₈H₂₆N₂O₃
• 分子量: 318.416
• InChiKey: VLHYFWUAMXDMRP-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  23
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  67.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ((S)-1-phenylcarbamoyl-hex-5-enyl)-carbamic acid tert-butyl ester 在 偶氮二异丁腈 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三乙胺 、 sodium thiomethoxide 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 (R)-5-oxo-pyrrolidine-2-carboxylic acid ((S)-6-mercapto-1-phenylcarbamoyl-hexyl)-amide
  参考文献：
  名称：

  ST7612AA1, a Thioacetate-ω(γ-lactam carboxamide) Derivative Selected from a Novel Generation of Oral HDAC Inhibitors

  摘要：

  A systematic study of medicinal chemistry aimed at identifying a new generation of HDAC inhibitors, through the introduction of a thiol zinc-binding group (ZBG) and of an amide-lactam in the ?-position of the polyethylene chain of the vorinostat scaffold, allowed the selection of a new class of potent pan-HDAC inhibitors (pan-HDACis). Simple, highly versatile, and efficient synthetic approaches were used to synthesize a library of these new derivatives, which were then submitted to a screening for HDAC inhibition as well as to a preliminary in vitro assessment of their antiproliferative activity. Molecular docking into HDAC crystal structures suggested a binding mode for these thiol derivatives consistent with the stereoselectivity observed upon insertion of amide-lactam substituents in the ?-position. ST7612AA1 (117), selected as a drug candidate for further development, showed an in vitro activity in the nanomolar range associated with a remarkable in vivo antitumor activity, highly competitive with the most potent HDAC inhibitors, currently under clinical trials. A preliminary study of PK and metabolism is also illustrated.

  DOI：

  10.1021/jm5008209
• 作为产物：
  描述：

  苯胺 、 (S)-2-((叔丁氧羰基)氨基)庚-6-烯酸 在 N,N-二异丙基乙胺 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.33h， 以85%的产率得到((S)-1-phenylcarbamoyl-hex-5-enyl)-carbamic acid tert-butyl ester
  参考文献：
  名称：

  NEW THIO DERIVATIVES BEARING LACTAMS AS POTENT HDAC INHIBITORS AND THEIR USES AS MEDICAMENTS

  摘要：

  本发明涉及式（I）的新型酰胺化合物，以及它们作为抗肿瘤和促凋亡剂的用途。该发明涉及这些化合物在医学上的应用，与癌症以及其他需要抑制HDAC的疾病有关，以及含有这些化合物的药物组合物。

  公开号：

  US20140200205A1

文献信息

• [EN] NEW THIO DERIVATIVES BEARING LACTAMS AS POTENT HDAC INHIBITORS AND THEIR USES AS MEDICAMENTS<br/>[FR] NOUVEAUX DÉRIVÉS THIO PORTANT DES LACTAMES EN TANT QU'INHIBITEURS PUISSANTS D'HDAC, ET LEURS UTILISATIONS EN TANT QUE MÉDICAMENTS
  申请人：SIGMA TAU IND FARMACEUTI

  公开号：WO2013041480A1

  公开（公告）日：2013-03-28

  The present invention relates to novel amide compounds of Formula (I), and their use as anti-tumoral and pro-apoptotic agents. The invention includes the use of such compounds in medicine, in relation to cancer disease as well as other diseases where an inhibition of HDAC is responsive, and the pharmaceutical composition containing such compounds.

  本发明涉及一种新型酰胺化合物（式I），以及其作为抗肿瘤和促凋亡剂的用途。该发明包括在医学上使用这些化合物，涉及癌症疾病以及其他需要抑制HDAC的疾病，以及含有这些化合物的药物组合物。
• NEW THIO DERIVATIVES BEARING LACTAMS AS POTENT HDAC INHIBITORS AND THEIR USES AS MEDICAMENTS
  申请人：SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A.

  公开号：US20140200205A1

  公开（公告）日：2014-07-17

  The present invention relates to novel amide compounds of Formula (I), and their use as anti-tumoral and pro-apoptotic agents. The invention includes the use of such compounds in medicine, in relation to cancer disease as well as other diseases where an inhibition of HDAC is responsive, and the pharmaceutical composition containing such compounds.

  本发明涉及式（I）的新型酰胺化合物，以及它们作为抗肿瘤和促凋亡剂的用途。该发明涉及这些化合物在医学上的应用，与癌症以及其他需要抑制HDAC的疾病有关，以及含有这些化合物的药物组合物。
• Thio derivatives bearing lactams as potent HDAC inhibitors and their uses as medicaments
  申请人：SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A.

  公开号：US08927533B2

  公开（公告）日：2015-01-06

  The present invention relates to novel amide compounds of Formula (I), and their use as anti-tumoral and pro-apoptotic agents. The invention includes the use of such compounds in medicine, in relation to cancer disease as well as other diseases where an inhibition of HDAC is responsive, and the pharmaceutical composition containing such compounds.

  本发明涉及一种新的酰胺化合物（I）及其作为抗肿瘤和促凋亡剂的用途。该发明包括在医学上使用这种化合物，与癌症以及其他需要抑制HDAC的疾病相关，并且包含这种化合物的制药组合物。
• Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors
  作者：Maurizio Taddei、Elena Cini、Luca Giannotti、Giuseppe Giannini、Gianfranco Battistuzzi、Davide Vignola、Loredana Vesci、Walter Cabri

  DOI：10.1016/j.bmcl.2013.11.072

  日期：2014.1

  A series of SAHA-like molecules were prepared introducing different lactam-carboxyamides in position 7 of the suberoylanilide skeleton. The activity against different HDAC isoforms was tested and the data compared with the corresponding linear products, without substituent in position 7. In general, this modification provided an effective reinforcement of in vitro activity. While the lactam size or the CO/NH group orientation did not strongly influence the inhibition, the contemporary modification of the suberoylamide fragment gave vary active variants in the lactam series, with compound 28 (ST8078AA1) that showed IC50 values between 2 and 10 nM against all Class I HDAC isoforms, demonstrating it to be a large spectrum pan-inhibitor. This strong affinity with HDAC was also confirmed by the value of IC50 = 0.5 mu M against H460 cells, ranking 28 as one of the most potent HDAC inhibitors described so far. (C) 2013 Elsevier Ltd. All rights reserved.
• US8927533B2
  申请人：——

  公开号：US8927533B2

  公开（公告）日：2015-01-06