tert-butyl N-[(1S)-1-[[3-(trifluoromethyl)phenyl]carbamoyl]hex-5-enyl]carbamate | 1528755-68-1

• 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: tert-butyl N-[(1S)-1-[[3-(trifluoromethyl)phenyl]carbamoyl]hex-5-enyl]carbamate
• 英文别名: tert-butyl N-[(2S)-1-oxo-1-[3-(trifluoromethyl)anilino]hept-6-en-2-yl]carbamate
• CAS: 1528755-68-1
• 化学式: C₁₉H₂₅F₃N₂O₃
• 分子量: 386.414
• InChiKey: NTQBLLFUAHCUET-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  27
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  67.4
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl N-[(1S)-1-[[3-(trifluoromethyl)phenyl]carbamoyl]hex-5-enyl]carbamate 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 甲醇 、 palladium 10% on activated carbon 、 氢气 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 20.0 ℃ 、100.0 kPa 条件下， 反应 16.33h， 生成 (2S)-N'-benzyloxy-2-[[(2R)-5-oxopyrrolidin-2-carbonyl]amino]-N-[3-(trifluoromethyl)phenyl]octanediamide
  参考文献：
  名称：

  [EN] HYDROXAMATE DERIVATIVES BEARING AMIDE-LACTAMS AS POTENT HDAC INHIBITORS AND THEIR USES AS MEDICAMENTS
  [FR] DÉRIVÉS D'HYDROXAMATE PORTANT DES AMIDE-LACTAMES À TITRE DE PUISSANTS INHIBITEURS D'HDAC ET LEURS UTILISATIONS À TITRE DE MÉDICAMENTS

  摘要：

  本发明涉及式(I)的新酰胺化合物，及其用作抗肿瘤和促凋亡剂的应用。该发明包括将此类化合物用于医学领域，与癌症以及其他抑制HDAC有响应的疾病的治疗相关，以及包含此类化合物的药物组合物。

  公开号：

  WO2014122222A1
• 作为产物：
  描述：

  间氨基三氟甲苯 、 (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tert-butyl N-[(1S)-1-[[3-(trifluoromethyl)phenyl]carbamoyl]hex-5-enyl]carbamate
  参考文献：
  名称：

  [EN] HYDROXAMATE DERIVATIVES BEARING AMIDE-LACTAMS AS POTENT HDAC INHIBITORS AND THEIR USES AS MEDICAMENTS
  [FR] DÉRIVÉS D'HYDROXAMATE PORTANT DES AMIDE-LACTAMES À TITRE DE PUISSANTS INHIBITEURS D'HDAC ET LEURS UTILISATIONS À TITRE DE MÉDICAMENTS

  摘要：

  本发明涉及式(I)的新酰胺化合物，及其用作抗肿瘤和促凋亡剂的应用。该发明包括将此类化合物用于医学领域，与癌症以及其他抑制HDAC有响应的疾病的治疗相关，以及包含此类化合物的药物组合物。

  公开号：

  WO2014122222A1

文献信息

• [EN] HYDROXAMATE DERIVATIVES BEARING AMIDE-LACTAMS AS POTENT HDAC INHIBITORS AND THEIR USES AS MEDICAMENTS<br/>[FR] DÉRIVÉS D'HYDROXAMATE PORTANT DES AMIDE-LACTAMES À TITRE DE PUISSANTS INHIBITEURS D'HDAC ET LEURS UTILISATIONS À TITRE DE MÉDICAMENTS
  申请人：SIGMA TAU IND FARMACEUTI

  公开号：WO2014122222A1

  公开（公告）日：2014-08-14

  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)的新酰胺化合物，及其用作抗肿瘤和促凋亡剂的应用。该发明包括将此类化合物用于医学领域，与癌症以及其他抑制HDAC有响应的疾病的治疗相关，以及包含此类化合物的药物组合物。
• ST7612AA1, a Thioacetate-ω(γ-lactam carboxamide) Derivative Selected from a Novel Generation of Oral HDAC Inhibitors
  作者：Giuseppe Giannini、Loredana Vesci、Gianfranco Battistuzzi、Davide Vignola、Ferdinando M. Milazzo、Mario Berardino Guglielmi、Marcella Barbarino、Mosè Santaniello、Nicola Fantò、Marco Mor、Silvia Rivara、Daniele Pala、Maurizio Taddei、Claudio Pisano、Walter Cabri

  DOI：10.1021/jm5008209

  日期：2014.10.23

  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.
• Hydroxamic acid based histone deacetylase inhibitors with confirmed activity against the malaria parasite
  作者：Giuseppe Giannini、Gianfranco Battistuzzi、Davide Vignola

  DOI：10.1016/j.bmcl.2014.12.051

  日期：2015.2

  Recent studies have highlighted a key role in regulating gene transcription, in both eukaryotes and prokaryotes, by enzymes that control the acetylation and deacetylation of histones. In particular, inhibitors of histone deacetylases (HDAC-Is) have been shown effective in controlling the development of many parasites, such as the plasmodium of malaria. Here we report the results of a study aimed at evaluating antiparasitic effect of two classes of HDAC-Is bearing different zinc binding group (hydroxamic acid vs thiol). The study showed that only the hydroxamic acid based HDAC inhibitors were active, with Plasmodium falciparum being the most sensitive parasite, having from low double-digit to single-digit nanomolar range in vitro activities. Among three derivatives evaluated also in vivo, ST8086AA1 (8) effectively inhibited 88% of the development of Plasmodium falciparum. (C) 2014 Elsevier Ltd. All rights reserved.
• 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.