N-(benzyloxycarbonyl)-N'-(tert-butyloxycarbonyl)-D-lysine methyl ester | 84559-78-4

• 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: N-(benzyloxycarbonyl)-N'-(tert-butyloxycarbonyl)-D-lysine methyl ester
• 英文别名: N^α-Cbz-N^ε-Boc-D-Lys-OMe；methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-6-[[(tert-butoxy)carbonyl]amino]hexanoate；Z-D-Lys(boc)-ome；methyl (2R)-6-[(2-methylpropan-2-yl)oxycarbonylamino]-2-(phenylmethoxycarbonylamino)hexanoate
• CAS: 84559-78-4
• 化学式: C₂₀H₃₀N₂O₆
• 分子量: 394.468
• InChiKey: ZJWQKFBUQSKZOS-MRXNPFEDSA-N

物化性质

• 熔点：
  61-62 °C
• 沸点：
  544.7±50.0 °C(Predicted)
• 密度：
  1.130±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  28
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  103
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(benzyloxycarbonyl)-N'-(tert-butyloxycarbonyl)-D-lysine methyl ester 在 palladium on activated charcoal 吡啶 、 盐酸 、 氢气 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 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 82.0h， 生成 N-(benzyloxycarbonyl)-cyclo(D-glutamyl-D-lysyl) methyl ester
  参考文献：
  名称：

  Synthesis of a novel class of peptides: dilactam-bridged tetrapeptides

  摘要：

  DOI：

  10.1021/jo00233a006
• 作为产物：
  描述：

  N-苄氧羰基-N'-叔丁氧羰基-L-赖氨酸 、 碘甲烷 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 N-(benzyloxycarbonyl)-N'-(tert-butyloxycarbonyl)-D-lysine methyl ester
  参考文献：
  名称：

  [EN] FACTOR XIIa INHIBITORS
  [FR] INHIBITEURS DE FACTEUR XIIA

  摘要：

  本发明提供了一种化合物I的化合物和包含一种或多种所述化合物的药物组合物，以及使用所述化合物用于治疗或预防血栓形成、栓塞、高凝血性或纤维化变化的方法。这些化合物是选择性的凝血因子XIIa抑制剂。

  公开号：

  WO2018093716A1

文献信息

• Plasmin-activated prodrugs for cancer chemotherapy. 1. Synthesis and biological activity of peptidylacivicin and peptidylphenylenediamine mustard
  作者：Prasun K. Chakravarty、Philip L. Carl、Michael J. Weber、John A. Katzenellenbogen

  DOI：10.1021/jm00359a003

  日期：1983.5

  Many tumors contain elevated levels of plasminogen activator and thus produce elevated levels of the protease plasmin in the milieu of the tumor. We have hypothesized, therefore, that it should be possible to prepare peptidyl prodrug derivatives of anticancer drugs that would be locally activated by tumor-associated plasmin. As an initial test of this hypothesis, we synthesized the peptidyl prodrugs of the anticancer drugs (alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin, AT-125) and N,N-bis(2-chloroethyl)-p-phenylenediamine (phenylenediamine mustard) by mixed anhydride coupling of the parent drug with the protected tripeptide, Boc-D-Val-Leu-Lys(Boc)-OH, followed by deprotection with trifluoroacetic acid. The prodrugs showed an increased selective in vitro cytotoxicity for Rous sarcoma virus transformed chicken embryo fibroblasts (which produce elevated levels of plasminogen activator) compared to nontransformed fibroblasts (which produce low levels of plasminogen activator). In the presence of the plasmin inhibitor, p-nitrophenyl p'-guanidinobenzoate at 2 micrograms/mL, the selectivity of the phenylenediamine mustard prodrug was reduced, but there was no effect on the cytotoxicity of the free drug. Furthermore, the prodrug analogue D-valylleucyl-D-lysylphenylenediamine mustard (in which L-Lys has been replaced by D-Lys) was inactive. Finally, the prodrug derivative of acivicin did not display selective toxicity for transformed cells when the cells were cultured in plasminogen-free medium. These results suggest that plasmin hydrolysis is necessary for the activation of the prodrugs. The prodrugs were tested in vivo for antitumor activity. The prodrug of acivicin, like acivicin itself, was inactive against the B16 melanoma, a murine tumor that produces high levels of plasminogen activator. This prodrug was active against the M5076 carcinoma, a tumor that displays only moderate levels of plasminogen activator; however, despite the fact that the prodrug was 2- to 3-fold less toxic on a molar basis than acivicin, there was no evidence of an increased therapeutic index. The prodrug of phenylenediamine mustard was also slightly less toxic than the parent drug, but again there was no evidence for an improved therapeutic index against the B16 tumor.
• MANESIS, NICK J.;GOODMAN, MURRAY, J. ORG. CHEM., 52,(1987) N 24, 5331-5341
  作者：MANESIS, NICK J.、GOODMAN, MURRAY

  DOI：——

  日期：——
• Synthesis of a novel class of peptides: dilactam-bridged tetrapeptides
  作者：Nick J. Manesis、Murray Goodman

  DOI：10.1021/jo00233a006

  日期：1987.11
• [EN] FACTOR XIIa INHIBITORS<br/>[FR] INHIBITEURS DE FACTEUR XIIA
  申请人：MERCK SHARP & DOHME

  公开号：WO2018093716A1

  公开（公告）日：2018-05-24

  The present invention provides a compound of Formula I and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses, embolisms, hypercoagulability or fibrotic changes. The compounds are selective Factor XIIa inhibitors.

  本发明提供了一种化合物I的化合物和包含一种或多种所述化合物的药物组合物，以及使用所述化合物用于治疗或预防血栓形成、栓塞、高凝血性或纤维化变化的方法。这些化合物是选择性的凝血因子XIIa抑制剂。