3-<<(1,1-dimethylethoxy)carbonyl>amino>-12-oxo-2,4,11-triaza-tetradec-2-enedioic acid, 1-<1,1-dimethyl ester> | 170367-34-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-<<(1,1-dimethylethoxy)carbonyl>amino>-12-oxo-2,4,11-triaza-tetradec-2-enedioic acid, 1-<1,1-dimethyl ester>
• 英文别名: 3-[[(1,1-dimethylethoxy)carbonyl]amino]-12-oxo-2,4,11-triazateteadec-2-enedioic acid 1-(1,1-dimethylethyl ester)；3-[6-[Bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]hexylamino]-3-oxopropanoic acid
• CAS: 170367-34-7
• 化学式: C₂₀H₃₆N₄O₇
• 分子量: 444.528
• InChiKey: OUXXCTJBLOQCNQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  31
• 可旋转键数：
  15
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  155
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-<<(1,1-dimethylethoxy)carbonyl>amino>-12-oxo-2,4,11-triaza-tetradec-2-enedioic acid, 1-<1,1-dimethyl ester> 在 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 [21-[[(1,1-dimethylethoxy)carbonyl]amino]-1,25,25-trimethyl-10,12,23-trioxo-4-(phenylmethyl)-24-oxa-4,9,13,20,22-pentaaza-21-hexacosen-1-yl]carbamic acid, 1,1-dimethylethyl ester (S)
  参考文献：
  名称：

  Structure−Immunosuppressive Activity Relationships of New Analogues of 15-Deoxyspergualin. 2. Structural Modifications of the Spermidine Moiety

  摘要：

  A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Various substitutions of the spermidine "D" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. Various positions of methylation were first investigated leading to the discovery of the monomethylated malonic derivative 56h in which the pro-R hydrogen of the methylene a to the primary amine of the spermidine moiety has been replaced by a methyl group. Synthesis of the similarly methylated analogue of the previously reported glycolic derivative LF 08-0299 afforded 60e which demonstrated a powerful activity at a dose as low as 0.3 mg/kg in the GVHD model and was much more potent than DSG in the demanding heart allotransplantation model in rats. The improvement of in vivo activity was supposed to be related to an increase of the metabolic stability of the methylated analogues compared to the parent molecules. Due to its very low active dose, compatible with a subcutaneous administration in humans, and its favorable pharmacological and toxicological profile, 60e was selected as a candidate for clinical evaluation.

  DOI：

  10.1021/jm991043x
• 作为产物：
  描述：

  N,N'-bis-Boc-S-methyl-isothiourea 在 sodium hydroxide 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 乙二醇二甲醚 为溶剂， 反应 17.5h， 生成 3-<<(1,1-dimethylethoxy)carbonyl>amino>-12-oxo-2,4,11-triaza-tetradec-2-enedioic acid, 1-<1,1-dimethyl ester>
  参考文献：
  名称：

  Structure−Immunosuppressive Activity Relationships of New Analogues of 15-Deoxyspergualin. 1. Structural Modifications of the Hydroxyglycine Moiety

  摘要：

  A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent currently commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Using the general concept of bioisosteric replacement, variations of the hydroxyglycine central "C" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. By this way, the malonic derivative 13a was discovered as the first example of a new series of potent immunosuppressive agents encompassing a retro-amide bond linked to the hexyl-guanidino moiety. Structure-activity relationships of this series were studied by synthesizing compounds 13g-i and 13k-s. Variation of the "right-amide" of 13a led to the urea 19a and the carbamates 23 and 27a which proved to be equally active as DSG in our GVHD model. Finally 27a was found to be the most potent derivative, being slightly more active than DSG in a heart allotransplantation model in rats. Due to the absence of chiral center in its structure and to its improved chemical stability compared to DSG, 27a was selected as a candidate for clinical evaluation.

  DOI：

  10.1021/jm980431g

文献信息

• US5637613A
  申请人：——

  公开号：US5637613A

  公开（公告）日：1997-06-10
• Structure−Immunosuppressive Activity Relationships of New Analogues of 15-Deoxyspergualin. 1. Structural Modifications of the Hydroxyglycine Moiety
  作者：Luc Lebreton、Jocelyne Annat、Philippe Derrepas、Patrick Dutartre、Patrice Renaut

  DOI：10.1021/jm980431g

  日期：1999.1.1

  A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent currently commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Using the general concept of bioisosteric replacement, variations of the hydroxyglycine central "C" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. By this way, the malonic derivative 13a was discovered as the first example of a new series of potent immunosuppressive agents encompassing a retro-amide bond linked to the hexyl-guanidino moiety. Structure-activity relationships of this series were studied by synthesizing compounds 13g-i and 13k-s. Variation of the "right-amide" of 13a led to the urea 19a and the carbamates 23 and 27a which proved to be equally active as DSG in our GVHD model. Finally 27a was found to be the most potent derivative, being slightly more active than DSG in a heart allotransplantation model in rats. Due to the absence of chiral center in its structure and to its improved chemical stability compared to DSG, 27a was selected as a candidate for clinical evaluation.
• Structure−Immunosuppressive Activity Relationships of New Analogues of 15-Deoxyspergualin. 2. Structural Modifications of the Spermidine Moiety
  作者：Luc Lebreton、Eric Jost、Bertrand Carboni、Jocelyne Annat、Michel Vaultier、Patrick Dutartre、Patrice Renaut

  DOI：10.1021/jm991043x

  日期：1999.11.1

  A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Various substitutions of the spermidine "D" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. Various positions of methylation were first investigated leading to the discovery of the monomethylated malonic derivative 56h in which the pro-R hydrogen of the methylene a to the primary amine of the spermidine moiety has been replaced by a methyl group. Synthesis of the similarly methylated analogue of the previously reported glycolic derivative LF 08-0299 afforded 60e which demonstrated a powerful activity at a dose as low as 0.3 mg/kg in the GVHD model and was much more potent than DSG in the demanding heart allotransplantation model in rats. The improvement of in vivo activity was supposed to be related to an increase of the metabolic stability of the methylated analogues compared to the parent molecules. Due to its very low active dose, compatible with a subcutaneous administration in humans, and its favorable pharmacological and toxicological profile, 60e was selected as a candidate for clinical evaluation.