3-N-((tert-butyloxy)carbonylamino)benzyl-4-nitrophenyl carbonate | 188751-44-2

• 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: 3-N-((tert-butyloxy)carbonylamino)benzyl-4-nitrophenyl carbonate
• 英文别名: 3-N-tert-butoxycarbonyl-aminobenzyl-4-nitrophenyl carbonate；Boc-mAZ-ONp；carbonic acid 3-tert-butoxycarbonylamino-benzyl ester 4-nitro-phenyl ester；[3-[(2-Methylpropan-2-yl)oxycarbonylamino]phenyl]methyl (4-nitrophenyl) carbonate
• CAS: 188751-44-2
• 化学式: C₁₉H₂₀N₂O₇
• 分子量: 388.377
• InChiKey: NEQYGMKCFFGRBT-UHFFFAOYSA-N

物化性质

• 沸点：
  507.0±50.0 °C(Predicted)
• 密度：
  1.316±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  120
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-N-((tert-butyloxy)carbonylamino)benzyl-4-nitrophenyl carbonate 在 盐酸 、 1-丙基磷酸酐 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 53.0h， 生成 3-(4-methoxyphenyl)-N-[3-[(1H-pyrrolo[2,3-b]pyridin-4-ylmethylcarbamoylamino)methyl]phenyl]prop-2-ynamide
  参考文献：
  名称：

  [EN] CHEMICAL COMPOUNDS
  [FR] COMPOSÉS CHIMIQUES

  摘要：

  本发明涉及取代的杂芳基衍生物。具体而言，本发明涉及根据公式Q的化合物：其中D、L、M、W、X、Y和Z在此定义。本发明的化合物是DNA甲基转移酶（DNMT）活性的抑制剂，包括DNMT1、DNMT3a或DNMT3b，并且可用于治疗癌症和过度增殖性疾病。因此，本发明进一步涉及包含本发明化合物的药物组合物。本发明还进一步涉及使用本发明的化合物或包含本发明化合物的药物组合物来抑制DNMT活性和治疗相关疾病的方法。

  公开号：

  WO2013062945A1
• 作为产物：
  描述：

  3-氨基苯甲醇 在 吡啶 、 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 17.0h， 生成 3-N-((tert-butyloxy)carbonylamino)benzyl-4-nitrophenyl carbonate
  参考文献：
  名称：

  Discovery of 3-Aminobenzyloxycarbonyl as an N-Terminal Group Conferring High Affinity to the Minimal Phosphopeptide Sequence Recognized by the Grb2-SH2 Domain

  摘要：

  The observation that anthranilic acid as N-terminal group produces a dramatic increase of the binding affinity of the phosphopeptide sequence Glu-pTyr-Ile-Asn for the Grb2-SH2 domain was rationalized by molecular modeling. The model, which invokes a stacking interaction between the N-terminal group and the SH2 domain residue Arg alpha A2, was subsequently used to design the 3-aminobenzyloxycarbonyl N-terminal group. The latter confers high affinity (IC50 = 65 nM in an ELISA assay) to the minimal sequence pTyr-Ile-Asn recognized by the Grb2-SH2 domain.

  DOI：

  10.1021/jm9702185

文献信息

• Structure−Activity Relationships of Small Phosphopeptides, Inhibitors of Grb2 SH2 Domain, and Their Prodrugs
  作者：Wang-Qing Liu、Michel Vidal、Catherine Olszowy、Emmanuelle Million、Christine Lenoir、Hélène Dhôtel、Christiane Garbay

  DOI：10.1021/jm031005k

  日期：2004.2.1

  affinity for the Grb2 SH2 domain, in the 10(-8)-10(-9) range of Kd values. These compounds behave as potent antagonists of the Grb2-Shc interaction. Our results highlight the importance of the doubly negative charge borne by the pY + 1 amino acid in accordance with the interactions observed in the complex crystallized between mAZ-pTyr-(alphaMe)pTyr-Asn-NH2 and the Grb2 SH2 domain. mAZ-pTyr-(alphaMe)pTyr-Asn-NH2

  为开发针对癌症中HER2 / ErbB2过表达的潜在抗肿瘤药，我们设计了受体的磷酸酪氨酸与衔接蛋白Grb2的SH2结构域之间的识别抑制剂。在本文的第一部分中，我们报告了受约束的（α-Me）磷酸酪氨酸残基类似物的合成，例如（α-Me）-4-膦酰基甲基苯丙氨酸（-CH2PO3H2），（α-Me）4-膦酰基二氟甲基苯丙氨酸（- CF2PO3H2）和（α-Me）-4-膦酰基苯丙氨酸（-PO3H2）。这些残基在mAZ-pTyr-Xaa-Asn-NH2系列中的结合提供了对Grb2 SH2域具有非常高亲和力的化合物，其Kd值在10（-8）-10（-9）范围内。这些化合物可作为Grb2-Shc相互作用的有效拮抗剂。我们的结果强调了根据在mAZ-pTyr-（alphaMe）pTyr-Asn-NH2和Grb2 SH2域之间结晶的复合物中观察到的相互作用，由pY +1个氨基酸携带的双负电荷的重要性。mAZ-pT
• Small Peptides Containing Phosphotyrosine and Adjacent αMe-Phosphotyrosine or Its Mimetics as Highly Potent Inhibitors of Grb2 SH2 Domain
  作者：Wang-Qing Liu、Michel Vidal、Nohad Gresh、Bernard P. Roques、Christiane Garbay

  DOI：10.1021/jm9911074

  日期：1999.9.1

  small peptides with the sequence mAZ-pTyr-Xaa-Asn-NH(2), where Xaa denotes alpha-methylphosphotyrosine or its carboxylic mimetics, were synthesized as inhibitors of the Grb2 SH2 domain. Peptide 3 with (alpha-Me)pTyr as Xaa has the highest affinity for Grb2 (K(d) = 3 +/- 1 nM) and exhibits to date the best inhibitory activity (IC(50) = 11 +/- 1 nM) to displace PSpYVNVQN-Grb2 interaction in an ELISA test

  合成了一系列序列为mAZ-pTyr-Xaa-Asn-NH（2）的小肽，其中Xaa表示α-甲基磷酸酪氨酸或其羧基模拟物，作为Grb2 SH2域的抑制剂。具有（aa-Me）pTyr作为Xaa的肽3对Grb2的亲和力最高（K（d）= 3 +/- 1 nM），迄今为止显示出最佳的抑制活性（IC（50）= 11 +/- 1 nM ）以取代ELISA测试中的PSpYVNVQN-Grb2相互作用。具有（alpha-Me）Tyr，（alpha-Me）Phe（4-CO（2）H）或（alpha-Me）Phe（4-CH（2）CO（2）H）的肽的较低亲和力Xaa证明了在pY + 1位置带有双电荷的磷酸基团的重要性。分子建模显示了由（alpha-Me）pTyr残基与Grb2 SH2域提供的其他氢键相互作用。因此，这些结果表明，疏水性pY + 1残基的作用
• Use of 2, 4diamino-3-hydroxycarboxylic acid derivatives as proteasome inhibitors
  申请人：France Dennis

  公开号：US20050026994A1

  公开（公告）日：2005-02-03

  The present invention relates to the new use of 2,4-diamino-3-hydroxycarboxylic acids of formula (I), in which A and B independently represent a bond or an unsubstituted or substituted amino acyl moiety; R 1 represents hydrogen; an amino protecting group; or a group of formula R 5 Y— wherein R 5 represents hydrogen or an unsubstituted or substituted alkyl, alkenyl, alkinyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl group; and Y represents —CO—; —NH—CO—; —NH—CS—; —SO 2 —; —O—CO—; or —O—CS—; R 2 represents the side chain of a natural amino acid; an alkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group; or trimethylsilylmethyl, 2-thienylmethyl or styrylmethyl; R 3 represents halogen, alkyl, alkoxy or hydroxyalkoxy; and R 4 represents 2(R)-hydroxyindan-1(S)-yl; (S)-2-hydroxy-1-phenylethyl; or 2-hydroxy-benzyl unsubstituted or substituted in 4-position by methoxy; in the manufacture of a pharmaceutical composition for the treatment of a proliferative disease, e.g., of a solid tumor; to a method of treatment of warm-blooded animals; and to 2,4-diamino-3-hydroxycarboxylic acids of formula (I*), wherein A and B independently represent an unsubstituted or substituted amino acyl moiety; R 2 represents arylalkyl; R 3 represents halogen, alkyl, alkoxy or hydroxyalkoxy; R 4 represents 2-hydroxy-benzyl unsubstituted or substituted in 4 position by methoxy; and R 5 represents arylalkyl and Y represents —CO—; or R 5 represents alkyl substituted by cycloalkyl, naphthyl, pyridyl or phenyl in which phenyl is substituted by alkyl or amino; and Y represents —O—CO; pharmaceutically acceptable salts thereof; and the use of such compounds of formula (I*) for the therapeutic treatment of the human or animal body, especially the treatment of proliferative diseases.

  本发明涉及式（I）的 2,4-二氨基-3-羟基羧酸的新用途，其中 A 和 B 独立地代表一个键或一个未取代或取代的氨基酰基；R 1 代表氢；氨基保护基；或式 R 5 Y- 其中 R 5 代表氢或未取代或取代的烷基、烯基、炔基、芳基、芳烷基、杂芳基、杂芳烷基、杂环烷基或杂环烷基；且 Y 代表 -CO-；-NH-CO-；-NH-CS-；-SO 2 -；-O-CO-；或-O-CS-； R 2 代表天然氨基酸的侧链；烷基、芳烷基、杂芳烷基或环烷基烷基；或三甲基硅甲基、2-噻吩甲基或苯乙烯甲基； R 3 3 代表卤素、烷基、烷氧基或羟基烷氧基；以及 R 4 代表 2(R)-羟基茚满-1(S)-基；(S)-2-羟基-1-苯基乙基；或未被甲氧基取代或在 4-位被甲氧基取代的 2-羟基苄基； 用于制造治疗增殖性疾病，例如式 (I*) 的 2,4-二氨基-3-羟基羧酸，其中 A 和 B 独立地代表未取代或取代的氨基酰基； R 2 代表芳烷基 3 代表卤素、烷基、烷氧基或羟基烷氧基； R 4 代表未取代的 2-羟基苄基或在 4 位被甲氧基取代的 2-羟基苄基；以及 R 5 代表芳烷基，Y 代表-CO-；或 R 5 代表被环烷基、萘基、吡啶基或苯基取代的烷基，其中苯基被烷基或氨基取代；且 Y 代表 -O-CO；其药学上可接受的盐；以及将式 (I*) 的此类化合物用于人体或动物机体的治疗，尤其是增殖性疾病的治疗。
• N-Terminal carboxyl and tetrazole-containing amides as adjuvants to Grb2 SH2 domain ligand binding
  作者：Terrence R Burke Jr、Zhu-Jun Yao、Yang Gao、Jane X Wu、Xiaofeng Zhu、Juliet H Luo、Ribo Guo、Dajun Yang

  DOI：10.1016/s0968-0896(01)00014-1

  日期：2001.6

  High affinity binding of peptides to Src homology 2 (SH2) domains, often requires the presence of phosphotyrosyl (pTyr) or pTyr-mimicking moieties in the N-terminal position of the binding ligand. Several reports have shown that N-alpha-acylation of the critical pTyr residue can result in increased SH2 domain binding potency. For Grb2 SH2 domains which recognize pTyr-Xxx-Asn-NH2 motifs, significant potency enhancement can be incurred by N-alpha-(3-amino)Z derivatization of tripeptides such as pTyr-Xxe-Asn-NH2. Using ligands based on the high affinity pY-Ac(6)c-Asn-(naphthylpropylamide) motif, (where Ac(6)c = 1-aminocyclohex-anecarboxylic acid), additional reports have shown moderate potentiating effects of N-alpha-oxalyl derivatization. The current study examined variations of the N-alpha-oxalyl theme in the context of a Xxx-Ac(6)c-Asn-(naphthylpropylamide) platform, where Xxx = the hydrolytically stable pTyr mimetics phosphonomethyl phenylalanine (Pmp) or carboxymethyl phenylalanine (Cmf). The effects of N-alpha-(3-amino)Z derivatization were also investigated for this platform, to ascertain whether the large binding enhancement reported for tripeptides such as pTyr-Ile-Asn-NH2 could be observed. In ELISA-based extracellular Grb2 SH2 domain binding assays, it was found for the Pmp-based series, that extending the oxalyl carboxyl out by one methylene unit or replacing carboxyl functionality with a tetrazole isostere, resulted in binding potency greater than the parent N-alpha-acetyl-containing compound, with enhancement approximating that observed for the N-alpha-oxalyl derivative. When Cmf was used as the pTyr mimetic, only modest differences in IC50 values were observed for the series. Examination of the N-alpha-(3-amino)Z derivatized Pmp-Ac(6)c-Asn-(naphthylpropylamide), showed that binding affinity was reduced relative to the parent N-alpha-acetyl analogue, in contrast to the reported significant enhancement of affinity observed with other peptide ligands. Treatment of MDA-453 tumor cells, which are mitogenically driven through erbB-2 tyrosine kinase-dependent pathways, with Pmp-containing inhibitors resulted in growth inhibition, with the N-alpha-oxalyl and N-alpha-malonyl-containing compounds exhibiting IC50 values (4.3 and 4.6 muM, respectively) approximately five-fold lower than the parent N-alpha-acetyl-containing compound. Tetrazole and N-alpha-(3-amino)Z-containing inhibitors were from two- to four-fold less potent than these latter analogues in the growth inhibition assays. (C) 2001 Elsevier Science Ltd. All rights reserved.
• USE OF 2,4-DIAMINO-3-HYDROXYCARBOXYLIC ACID DERIVATIVES AS PROTEASOME INHIBITORS
  申请人：Novartis AG

  公开号：EP1173413B1

  公开（公告）日：2004-06-30