N¹,N⁶-bis(trifluoroacetyl)-1,6-diamino-3-azahexane | 172657-59-9

• 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: N¹,N⁶-bis(trifluoroacetyl)-1,6-diamino-3-azahexane
• 英文别名: 2,2,2-trifluoro-N-[3-[2-[(2,2,2-trifluoroacetyl)amino]ethylamino]propyl]acetamide
• CAS: 172657-59-9
• 化学式: C₉H₁₃F₆N₃O₂
• 分子量: 309.212
• InChiKey: RYRYTFWDLKZIJP-UHFFFAOYSA-N

物化性质

• 沸点：
  383.8±42.0 °C(Predicted)
• 密度：
  1.341±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  70.2
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N¹,N⁶-bis(trifluoroacetyl)-1,6-diamino-3-azahexane 在 ammonium hydroxide 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 20.0h， 生成 (2-aminoethyl)(3-aminopropyl)carbamic acid tert-butyl ester
  参考文献：
  名称：

  Solution Phase Combinatorial Chemistry. Discovery of Novel Polyazapyridinophanes with Potent Antibacterial Activity by a Solution Phase Simultaneous Addition of Functionalities Approach

  摘要：

  Chemical modification of pre-formed asymmetric polyazaphane scaffolds by simultaneous addition of Functionality (letters) in solution has been developed for the preparation of tertiary nitrogen-based combinatorial chemistry libraries. This approach has some significant advantages over the more commonly employed solid phase bead splitting/resction/mixing procedures for the preparation of libraries. Three novel, asymmetric polyazaphanes 32, 33, and 37 have been synthesized in high yields by an efficient cyclization of 2,6-bis(bronzomethyl)pyridine (31) with new orthogonally protected triamines 29, 30, and 35, respectively. Selective deprotection of 32, 33, and 37 provided mono-t-Boc-protected scaffolds 1-3 suitable for solution phase, simultaneous addition of functionalities. Model studies of small libraries of scaffold 2 using CZE analyses indicated that simultaneous addition of 10 benzylic bromide alkylating functionalities would result in libraries containing approximately equimolar amounts of all possible compounds. Sixteen purified tertiary amine libraries 4-19 (total complexity of 1600 compounds) were generated by this procedure from scaffold 2. A ''fix-last'' combinatorial method was devised to minimize chemical reactions. Several first-round sublibraries of scaffold 2, containing a mixture of 100 compounds, exhibited potent antimicrobial activities. Twenty single compounds 63-82 with uniform functionalities at the combinatorialized sites were synthesized. Some of these pure compounds were more active, while others were less active, compared with the parent mixtures 5 and 10.

  DOI：

  10.1021/ja964153r
• 作为产物：
  描述：

  亚精胺 、 三氟乙酸乙酯 以 水 、 乙腈 为溶剂， 生成 N¹,N⁶-bis(trifluoroacetyl)-1,6-diamino-3-azahexane
  参考文献：
  名称：

  Dibenzosuberyl substituted polyamines and analogs of clomipramine as effective inhibitors of trypanothione reductase; molecular docking, and assessment of trypanocidal activities

  摘要：

  Trypanothione reductase (TR) is an enzyme critical to the maintenance of the thiol redox balance in trypanosomatids, including the genera Trypanosoma and Leishmania that are parasites responsible for several serious diseases. Analogs of clomipramine were prepared since clomipramine is reported to inhibit TR and cure mice infected with trypanosomes, however its psychotropic activity precludes its use as an anti-trypanosomal therapeutic. The clomipramine analogs contained a tricyclic dibenzosuberyl moiety. Additionally a series of polyamines with N-dibenzosuberyl substituents were prepared. All compounds studied were competitive inhibitors of TR and showed trypanocidal activities against Trypanosoma brucei in vitro. The analogs of clomipramine were poor inhibitors of TR, whereas the polyamine derivatives were effective TR inhibitors with the most potent compound, N-4, N-8-bis(dibenzosuberyl) spermine (7), having a K-i value of 0.26 mu M. However, compound (7) did not prolong the lives of mice infected with trypanosomes. Analysis of docking studies indicated: the tricyclic groups of inhibitors bind at four distinct hydrophobic regions in the active site of TR; the importance of the chlorine substituent of clomipramine in binding to TR; and binding of the dibenzosuberyl groups of (7) occur at separate and distinct hydrophobic regions within the active site of TR. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.01.018

文献信息

• Ethyl trifluoroacetate: a powerful reagent for differentiating amino groups
  作者：Daqiang Xu、Kapa Prasad、Oljan Repic、Thomas J. Blacklock

  DOI：10.1016/0040-4039(95)01655-4

  日期：1995.10

  Selective protection of primary amines in the presence of secondary amines and monofunctionalization of symmetric primary and secondary diamines using ethyl trifluoroacetate is described. Effective differentiation of primary, secondary and tertiary alkyl-substituted primary amines from one another by ethyl trifluoroacetate acylation is also demonstrated. These results are explained on the basis of

  描述了在仲胺存在下对伯胺的选择性保护以及使用三氟乙酸乙酯对对称伯和仲二胺进行单官能化。还证明了通过三氟乙酸乙酯酰化作用将伯，仲和叔烷基取代的伯胺彼此有效区分。这些结果是基于底物胺的空间和电子效应来解释的。
• Achiral oligoamines as versatile tool for the development of aspartic protease inhibitors
  作者：Andreas Blum、Jark Böttcher、Benedikt Sammet、Torsten Luksch、Andreas Heine、Gerhard Klebe、Wibke E. Diederich

  DOI：10.1016/j.bmc.2008.08.012

  日期：2008.9

  Due to the important role that aspartic proteases play in many patho-physiological processes, they have intensively been targeted by modern drug development. However, up to now, only for two family members, renin and HIV protease, approved drugs are available. Inhibitor development, mostly guided by mimicking the natural peptide substrates, resulted in very potent inhibitors for several targets, but the pharmacokinetic properties of these compounds were often not optimal. Herein we report a novel approach for lead structure discovery of non-peptidic aspartic protease inhibitors using easily accessible achiral linear oligoamines as starting point. An initial library comprising 11 inhibitors was developed and screened against six selected aspartic proteases. Several hits could be identified, among them selective as well as rather promiscuous inhibitors. The design concept was confirmed by determination of the crystal structure of two derivatives in complex with the HIV-1 protease, and represents a promising basis for the further inhibitor development. (C) 2008 Elsevier Ltd. All rights reserved.
• Solution Phase Combinatorial Chemistry. Discovery of Novel Polyazapyridinophanes with Potent Antibacterial Activity by a Solution Phase Simultaneous Addition of Functionalities Approach
  作者：Haoyun An、Lendell L. Cummins、Richard H. Griffey、Ramesh Bharadwaj、Becky D. Haly、Allister S. Fraser、Laura Wilson-Lingardo、Lisa M. Risen、Jacqueline R. Wyatt、P. Dan Cook

  DOI：10.1021/ja964153r

  日期：1997.4.1

  Chemical modification of pre-formed asymmetric polyazaphane scaffolds by simultaneous addition of Functionality (letters) in solution has been developed for the preparation of tertiary nitrogen-based combinatorial chemistry libraries. This approach has some significant advantages over the more commonly employed solid phase bead splitting/resction/mixing procedures for the preparation of libraries. Three novel, asymmetric polyazaphanes 32, 33, and 37 have been synthesized in high yields by an efficient cyclization of 2,6-bis(bronzomethyl)pyridine (31) with new orthogonally protected triamines 29, 30, and 35, respectively. Selective deprotection of 32, 33, and 37 provided mono-t-Boc-protected scaffolds 1-3 suitable for solution phase, simultaneous addition of functionalities. Model studies of small libraries of scaffold 2 using CZE analyses indicated that simultaneous addition of 10 benzylic bromide alkylating functionalities would result in libraries containing approximately equimolar amounts of all possible compounds. Sixteen purified tertiary amine libraries 4-19 (total complexity of 1600 compounds) were generated by this procedure from scaffold 2. A ''fix-last'' combinatorial method was devised to minimize chemical reactions. Several first-round sublibraries of scaffold 2, containing a mixture of 100 compounds, exhibited potent antimicrobial activities. Twenty single compounds 63-82 with uniform functionalities at the combinatorialized sites were synthesized. Some of these pure compounds were more active, while others were less active, compared with the parent mixtures 5 and 10.
• Dibenzosuberyl substituted polyamines and analogs of clomipramine as effective inhibitors of trypanothione reductase; molecular docking, and assessment of trypanocidal activities
  作者：Mary C. O’Sullivan、Timothy B. Durham、Hannah E. Valdes、Kelly L. Dauer、Nicholas J. Karney、Andrew C. Forrestel、Cyrus J. Bacchi、Jerome F. Baker

  DOI：10.1016/j.bmc.2015.01.018

  日期：2015.3

  Trypanothione reductase (TR) is an enzyme critical to the maintenance of the thiol redox balance in trypanosomatids, including the genera Trypanosoma and Leishmania that are parasites responsible for several serious diseases. Analogs of clomipramine were prepared since clomipramine is reported to inhibit TR and cure mice infected with trypanosomes, however its psychotropic activity precludes its use as an anti-trypanosomal therapeutic. The clomipramine analogs contained a tricyclic dibenzosuberyl moiety. Additionally a series of polyamines with N-dibenzosuberyl substituents were prepared. All compounds studied were competitive inhibitors of TR and showed trypanocidal activities against Trypanosoma brucei in vitro. The analogs of clomipramine were poor inhibitors of TR, whereas the polyamine derivatives were effective TR inhibitors with the most potent compound, N-4, N-8-bis(dibenzosuberyl) spermine (7), having a K-i value of 0.26 mu M. However, compound (7) did not prolong the lives of mice infected with trypanosomes. Analysis of docking studies indicated: the tricyclic groups of inhibitors bind at four distinct hydrophobic regions in the active site of TR; the importance of the chlorine substituent of clomipramine in binding to TR; and binding of the dibenzosuberyl groups of (7) occur at separate and distinct hydrophobic regions within the active site of TR. (C) 2015 Elsevier Ltd. All rights reserved.