(4-Chloro-phenyl)-{[(R)-1-(4-chloro-phenyl)-ethyl]-[(E)-(3-phenyl-acryloyl)]-amino}-acetic acid methyl ester | 851664-11-4

• 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: (4-Chloro-phenyl)-{[(R)-1-(4-chloro-phenyl)-ethyl]-[(E)-(3-phenyl-acryloyl)]-amino}-acetic acid methyl ester
• 英文别名: methyl 2-(4-chlorophenyl)-2-[[(1R)-1-(4-chlorophenyl)ethyl]-[(E)-3-phenylprop-2-enoyl]amino]acetate
• CAS: 851664-11-4
• 化学式: C₂₆H₂₃Cl₂NO₃
• 分子量: 468.38
• InChiKey: LHCZCHGVJNVBBF-SKRRQWNUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (4-Chloro-phenyl)-{[(R)-1-(4-chloro-phenyl)-ethyl]-[(E)-(3-phenyl-acryloyl)]-amino}-acetic acid methyl ester 在 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) sodium hydroxide 、 silver trifluoromethanesulfonate 、 氯化铵 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 (3S)-1,3,6,7-tetrahydro-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-phenyl-6-(phenylseleno)-1,4-diazepine-2,5-dione
  参考文献：
  名称：

  Structure-based design, synthesis, and biological evaluation of novel 1,4-diazepines as HDM2 antagonists

  摘要：

  Crystallographic analysis of ligands bound to HDM2 suggested that. 7-substituted 1,4-diazepine-2,5-diones could mimic the alpha-helix of p53 peptide and may represent a promising scaffold to develop HDM2-p53 antagonists. To verify this hypothesis, we synthesized and biologically evaluated 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-7-phenyl-1,4-diazepin-1-yl]valeric acid (10) and 5-[(3S)-7-(2-bromophenyl)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-1,4-diazepin-1-yl]valeric acid (11). Preliminary in vitro testing shows that 10 and 11 substantially antagonize the binding between HDM2 and p53 with an IC50 of 13 and 3.6 mu M, respectively, validating the modeling predictions. Taken together with the high cell permeability of diazepine 11 determined in CACO-2 cells, these results suggest that 1,4-diazepine-2,5-diones may be useful in the treatment of certain cancers. (c) 2005 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2005.02.018
• 作为产物：
  描述：

  (R)-(+)-1-(4-氯苯基)乙胺 在 吡啶 、 四丁基碘化铵 、 potassium carbonate 作用下， 以 氯仿 、 乙腈 为溶剂， 生成 (4-Chloro-phenyl)-{[(R)-1-(4-chloro-phenyl)-ethyl]-[(E)-(3-phenyl-acryloyl)]-amino}-acetic acid methyl ester
  参考文献：
  名称：

  Structure-based design, synthesis, and biological evaluation of novel 1,4-diazepines as HDM2 antagonists

  摘要：

  Crystallographic analysis of ligands bound to HDM2 suggested that. 7-substituted 1,4-diazepine-2,5-diones could mimic the alpha-helix of p53 peptide and may represent a promising scaffold to develop HDM2-p53 antagonists. To verify this hypothesis, we synthesized and biologically evaluated 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-7-phenyl-1,4-diazepin-1-yl]valeric acid (10) and 5-[(3S)-7-(2-bromophenyl)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-1,4-diazepin-1-yl]valeric acid (11). Preliminary in vitro testing shows that 10 and 11 substantially antagonize the binding between HDM2 and p53 with an IC50 of 13 and 3.6 mu M, respectively, validating the modeling predictions. Taken together with the high cell permeability of diazepine 11 determined in CACO-2 cells, these results suggest that 1,4-diazepine-2,5-diones may be useful in the treatment of certain cancers. (c) 2005 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2005.02.018

文献信息

• Substituted 1,4-diazepines and uses thereof
  申请人：——

  公开号：US20040220179A1

  公开（公告）日：2004-11-04

  The present invention is directed to novel 1,4-diazepines, pharmaceutical compositions thereof, and the use thereof as inhibitors of HDM2-p53 interactions. Compounds have Formula I: 1 or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: R 1 , R 2 , R 9 , R 10 , R a , R d and M are defined herein; X is a bivalent radical of: an alkane, a cycloalkane, an optionally-substituted arene, an optionally-substituted heteroarene, an optionally-substituted arylalkane or an optionally-substituted heteroarylalkane; and R 3 is —CO 2 R d , —CO 2 M, —OH, —NHR d , —SO 2 R d , —NHCONHR d , optionally-substituted amidino or optionally-substituted guanidino; or R 3 —X— is hydrogen or an electron pair; R 4 is oxygen or —NR 9 R 10 ; R 5 is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted; and R 6 , R 7 and R 8 are independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkylalkyl, aralkyl or heteroarylalkyl, each of which is optionally substituted; or R 6 and R 7 , together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic ring optionally substituted 1 to 3 times with R a .

  本发明涉及新型1,4-二氮杂环烷化合物，其药物组成物，以及其作为HDM2-p53相互作用抑制剂的用途。化合物具有以下结构式I：1或其溶剂化合物、水合物或药用可接受盐；其中：R1、R2、R9、R10、Ra、Rd和M在此处定义；X是以下结构的双价基团：烷烃、环烷烃、可选取代芳烃、可选取代杂芳烃、可选取代芳基烷烃或可选取代杂芳基烷烃；而R3为—CO2Rd、—CO2M、—OH、—NHRd、—SO2Rd、—NHCONHRd、可选取代酰胺基或可选取代胍基；或者R3—X—为氢或电子对；R4为氧或—NR9R10；R5为环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基，或饱和或部分不饱和的杂环，每种均可选取代；而R6、R7和R8独立地为氢、烷基、环烷基、芳基、杂芳基、饱和或部分不饱和的杂环、环烷基烷基、芳基烷基、杂芳基烷基，每种均可选取代；或者R6和R7，与它们相连的碳原子共同形成一个3至7成员的碳环，可选取代1至3次以Ra。
• Combinational therapy involving a small molecule inhibitor of the MDM2: p53 interaction
  申请人：Lu Tianbao

  公开号：US20050227932A1

  公开（公告）日：2005-10-13

  The present invention is directed to a combinational therapy for treating cancer or other cell proliferative diseases. Such a therapy combines the use of radiation therapy or chemotherapy with the use of a small molecule inhibitor of the MDM2: p53 interaction.

  本发明针对治疗癌症或其他细胞增殖性疾病提供了一种联合治疗方案。这种治疗方案将放射治疗或化疗与使用MDM2：p53相互作用的小分子抑制剂相结合。
• Combinational therapy involving a small molecule inhibitor of the MDM2: P53 interaction
  申请人：Ortho-McNeil Pharmaceutical, Inc.

  公开号：EP1712235A2

  公开（公告）日：2006-10-18

  The present invention is directed to a combinational therapy for treating cancer or other cell proliferative diseases. Such a therapy combines the use of radiation therapy or chemotherapy with the use of a small molecule inhibitor of the MDM2: p53 interaction.

  本发明涉及一种治疗癌症或其他细胞增殖性疾病的组合疗法。这种疗法将放疗或化疗与 MDM2：p53 相互作用的小分子抑制剂结合使用。
• US7115598B2
  申请人：——

  公开号：US7115598B2

  公开（公告）日：2006-10-03
• Structure-based design, synthesis, and biological evaluation of novel 1,4-diazepines as HDM2 antagonists
  作者：Pierre Raboisson、Juan José Marugán、Carsten Schubert、Holly K. Koblish、Tianbao Lu、Shuyuan Zhao、Mark R. Player、Anna C. Maroney、Rolanda L. Reed、Norman D. Huebert、Jennifer Lattanze、Daniel J. Parks、Maxwell D. Cummings

  DOI：10.1016/j.bmcl.2005.02.018

  日期：2005.4

  Crystallographic analysis of ligands bound to HDM2 suggested that. 7-substituted 1,4-diazepine-2,5-diones could mimic the alpha-helix of p53 peptide and may represent a promising scaffold to develop HDM2-p53 antagonists. To verify this hypothesis, we synthesized and biologically evaluated 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-7-phenyl-1,4-diazepin-1-yl]valeric acid (10) and 5-[(3S)-7-(2-bromophenyl)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-2,5-dioxo-1,4-diazepin-1-yl]valeric acid (11). Preliminary in vitro testing shows that 10 and 11 substantially antagonize the binding between HDM2 and p53 with an IC50 of 13 and 3.6 mu M, respectively, validating the modeling predictions. Taken together with the high cell permeability of diazepine 11 determined in CACO-2 cells, these results suggest that 1,4-diazepine-2,5-diones may be useful in the treatment of certain cancers. (c) 2005 Published by Elsevier Ltd.