(2S,3S)-3-[[[(1R)-3-methyl-1-[[(3-methylbutyl)amino]carbonyl]butyl]amino]carbonyl]-oxiranecarboxylic acid ethyl ester | 111612-35-2

• 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: (2S,3S)-3-[[[(1R)-3-methyl-1-[[(3-methylbutyl)amino]carbonyl]butyl]amino]carbonyl]-oxiranecarboxylic acid ethyl ester
• 英文别名: ethyl (-)-(2R,3R)-3-<(R)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl>-2-oxiranecarboxylate；ethyl (-)-(2R,3R)-3-[(R)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]-2-oxiranecarboxylate；ethyl (2R,3R)-3-[[(2R)-4-methyl-1-(3-methylbutylamino)-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylate
• CAS: 111612-35-2
• 化学式: C₁₇H₃₀N₂O₅
• 分子量: 342.436
• InChiKey: SRVFFFJZQVENJC-MGPQQGTHSA-N

物化性质

• 沸点：
  538.0±50.0 °C(predicted)
• 密度：
  1.102±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  24
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  97
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S,3S)-3-[[[(1R)-3-methyl-1-[[(3-methylbutyl)amino]carbonyl]butyl]amino]carbonyl]-oxiranecarboxylic acid ethyl ester 在 氢氧化钾 作用下， 以 乙醇 为溶剂， 以99%的产率得到(2S,3S)-3-[[[(1R)-3-methyl-1-[[(3-methylbutyl)amino]carbonyl]butyl]amino]carbonyl]-oxiranecarboxylic acid
  参考文献：
  名称：

  Design, Synthesis and Evaluation of d-Homophenylalanyl Epoxysuccinate Inhibitors of the Trypanosomal Cysteine Protease Cruzain

  摘要：

  The binding modes of E-64c to papain combined with molecular modeling and ligand design using the crystal structure of cruzain have been used to develop new, potent D-Homophenylalanyl epoxysuccinate inhibitors of cruzain, the major cysteine protease of Trypanosoma cruzi. The most potent inhibitor 47 contains an O-benzyl hydroxamate unit and is highly specific for cruzain relative to other cysteine proteases tested. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4020(00)00882-6
• 作为产物：
  描述：

  BOC-D-亮氨酸 在 盐酸 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 乙酸乙酯 为溶剂， 生成 (2S,3S)-3-[[[(1R)-3-methyl-1-[[(3-methylbutyl)amino]carbonyl]butyl]amino]carbonyl]-oxiranecarboxylic acid ethyl ester
  参考文献：
  名称：

  Efficient synthetic method for ethyl (+)-(2S,3S)-3-((S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl)-2-oxiranecarboxylate (EST), a new inhibitor of cysteine proteinases.

  摘要：

  Ethly (+)-(2S, 3S)-3-[(S)-3-甲基-1-(3-甲基丁基氨基甲酰基)丁基氨基甲酰基]-2-环氧羧酸酯（EST；la）预计将作为治疗肌肉萎缩症的口服药物，因为它对与疾病相关的肌纤维蛋白降解中涉及的半胱氨酸蛋白酶具有强大的抑制活性。通过广泛的研究，旨在开发一种适用于工业应用的新合成方法，发现L-精氨酸可以作为新的高效分离剂，用于获得光学纯的L-反-环氧富马酸（3a），而使用对硝基苯酚的活性酯方法在乙基L-反-环氧富马酸（7a）和L-亮氨酸异戊酰胺（8a）之间的偶联反应中非常有效，因为副产物的生成极少。为了检查反-环氧富马酸和亮氨酸部分的立体化学对半胱氨酸蛋白酶抑制活性的贡献，采用类似的方法合成了la的二叠体（lb-d），并测量了la-d对木瓜蛋白酶的灭活速率常数。化合物la，具有L-反-环氧富马酸和L-亮氨酸部分，显示出其中最强的活性。

  DOI：

  10.1248/cpb.35.1098

文献信息

• COMPOSITIONS AND METHODS FOR SYNTHESIZING (2S,3S)-TRANS-EPOXYSUCCINYL-L-LEUCYL-AMIDO-3-METHYLBUTANE ETHYL ESTER
  申请人：AMERICAN LIFE SCIENCE PHARMACEUTICALS, INC.

  公开号：US20170166543A1

  公开（公告）日：2017-06-15

  In alternative embodiments the invention provides methods for synthesizing AB-007 (also called loxistatin, E64d, EST or ((2S,3S)-trans-epoxysuccinyl-L-leucyl-amido-3-methylbutane ethyl ester) and its acid form E64c (loxistatin acid), and various synthetic intermediates, and deuterated forms of these compounds, and stereoisomers thereof. In alternative embodiments the invention provides a tosylate salt of AB-007-4 or a tosylate salt of L-leucine isoamylamine, or equivalents thereof. A synthetic scheme of the invention provides kilogram quantities of AB-007 manufactured according to current good manufacturing practices (cGMP's), consistent with US FDA requirements for human use. In alternative embodiments the invention provides a tosylate salt of AB-007-4 or a tosylate salt of L-leucine isoamylamine, or equivalents thereof.

  在另一种实施方案中，本发明提供了合成AB-007（也称为loxistatin、E64d、EST或((2S，3S)-trans-epoxysuccinyl-L-leucyl-amido-3-methylbutane ethyl ester）及其酸性形式E64c（loxistatin acid）以及各种合成中间体，以及这些化合物的氘代形式和立体异构体的方法。在另一种实施方案中，本发明提供AB-007-4的对甲苯磺酸盐或L-亮氨基异戊胺的对甲苯磺酸盐，或它们的等效物。本发明的合成方案提供了按照当前良好制造规范（cGMP）制造的千克级AB-007，符合美国FDA对人类使用的要求。在另一种实施方案中，本发明提供AB-007-4的对甲苯磺酸盐或L-亮氨基异戊胺的对甲苯磺酸盐，或它们的等效物。
• COMPOSITIONS AND METHODS FOR TREATING BETA-AMYLOID RELATED DISEASES
  申请人：TERNANSKY Robert J.

  公开号：US20110105603A1

  公开（公告）日：2011-05-05

  In alternative embodiments the invention provides compositions and methods for ameliorating diseases and conditions having a beta-amyloid component, including Alzheimer's disease (AD), Vascular Dementia (VD), dementia, pre-dementia, Cognitive Dysfunction Syndrome (CDS) and loss of cognition in humans and in non-human animal. In alternative embodiment the invention provides analogs of AB-007 and its acid form E64c (loxistatin), their preparation, and pharmaceutical compositions thereof and methods of making and using same. In alternative embodiments compositions of the invention are deuterated analogs of AB-007 (or E64d) and E64c (or loxistatin). In alternative embodiments compositions of the invention are metabolically blocked forms as compared to AB-007 and loxistatin. In alternative embodiments compositions of the invention are used to ameliorate (including treat, slow, reverse or prevent) a disease or condition which can be ameliorated by partial or complete inhibition of a cysteine protease, e.g., AD, VD, CDS. The invention also provides alternative dosage forms and formulations for AB-007 and loxistatin, and for compounds of this invention, which can be used e.g., to treat AD, VD and CDS, in humans and in non-human animals.

  在另一种实施方案中，本发明提供了用于改善具有β-淀粉样成分的疾病和病况的组合物和方法，包括阿尔茨海默病（AD），血管性痴呆（VD），痴呆，前痴呆，认知功能障碍综合征（CDS）和人类和非人类动物的认知丧失。在另一种实施方案中，本发明提供了AB-007的类似物及其酸性形式E64c（loxistatin），它们的制备，以及其制备和使用的药物组合物和方法。在另一种实施方案中，本发明的组合物是AB-007（或E64d）和E64c（或loxistatin）的氘代类似物。在另一种实施方案中，本发明的组合物是与AB-007和loxistatin相比代谢阻滞的形式。在另一种实施方案中，本发明的组合物用于改善（包括治疗，减缓，逆转或预防）可以通过部分或完全抑制半胱氨酸蛋白酶（例如AD，VD，CDS）改善的疾病或病况。本发明还提供了AB-007和loxistatin的另一种剂型和配方，以及本发明化合物的剂型和配方，可用于治疗人类和非人类动物的AD，VD和CDS等疾病和病况。
• Compositions and methods for treating beta-amyloid related diseases
  申请人：American Life Science Pharmaceuticals, Inc.

  公开号：US10022418B2

  公开（公告）日：2018-07-17

  In alternative embodiments the invention provides compositions and methods for ameliorating diseases and conditions having a beta-amyloid component, including Alzheimer's disease (AD), Vascular Dementia (VD), dementia, pre-dementia, Cognitive Dysfunction Syndrome (CDS) and loss of cognition in humans and in non-human animal. In alternative embodiment the invention provides analogs of AB-007 and its acid form E64c (loxistatin), their preparation, and pharmaceutical compositions thereof and methods of making and using same. In alternative embodiments compositions of the invention are deuterated analogs of AB-007 (or E64d) and E64c (or loxistatin). In alternative embodiments compositions of the invention are metabolically blocked forms as compared to AB-007 and loxistatin. In alternative embodiments compositions of the invention are used to ameliorate (including treat, slow, reverse or prevent) a disease or condition which can be ameliorated by partial or complete inhibition of a cysteine protease, e.g., AD, VD, CDS. The invention also provides alternative dosage forms and formulations for AB-007 and loxistatin, and for compounds of this invention, which can be used e.g., to treat AD, VD and CDS, in humans and in non-human animals.

  在另一个实施方案中，本发明提供了用于改善具有β-淀粉样蛋白成分的疾病和病症的组合物和方法，包括阿尔茨海默病（AD）、血管性痴呆（VD）、痴呆、痴呆前期、认知功能障碍综合征（CDS）以及人类和非人类动物的认知能力丧失。在另一个实施方案中，本发明提供了AB-007及其酸形式E64c（loxistatin）的类似物、它们的制备及其药物组合物以及制造和使用方法。在另一个实施方案中，本发明的组合物是AB-007（或E64d）和E64c（或loxistatin）的氚代类似物。在另一个实施方案中，本发明的组合物与AB-007和loxistatin相比是代谢受阻的形式。在其他实施方案中，本发明的组合物用于改善（包括治疗、减缓、逆转或预防）可通过部分或完全抑制半胱氨酸蛋白酶（如AD、VD、CDS）来改善的疾病或病症。本发明还提供了AB-007和loxistatin以及本发明化合物的替代剂型和制剂，可用于治疗人类和非人类动物的AD、VD和CDS等。
• Efficient synthetic method for ethyl (+)-(2S,3S)-3-((S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl)-2-oxiranecarboxylate (EST), a new inhibitor of cysteine proteinases.
  作者：MASAHARU TAMAI、CHIHIRO YOKOO、MITSUO MURATA、KIYOSHI OGUMA、KAORU SOTA、EISUKE SATO、YUICHI KANAOKA

  DOI：10.1248/cpb.35.1098

  日期：——

  Ethly (+)-(2S, 3S) -3- [(S) -3-methyl-1- (3-methylbutylcarbamoyl) butylcarbamoyl] -2- oxirane-carboxylate (EST ; la) is expected to be useful as an oral therapeutic agent for muscular dystrophy on the basis of its potent inhibitory activities against the cysteine proteinases involved in the myofibrillar protein degradation that occurs in the disease. Through extensive investigations aimed at developing a new synthetic method for la that would be suitable for industrial application, it has been found that L-arginine can be used as a new, efficient resolving agent to obtain optically pure L-trans-epoxysuccinic acid (3a), and the active ester method using p-nitrophenol is very effective in the coupling reaction of ethyl L-trans-epoxysuccinate (7a) and L-leucine isoamylamide (8a) because of the extremely low formation of by-products. To examine the contribution of the stereochemistry of the trans-epoxysuccinic acid and leucine moieties to the inhibitory activity against cysteine proteinases, the diastereomers (lb-d) of la were synthesized by a similar method and the rate constants of inactivation of papain by la-d were measured. Compound la, having L-trans-epoxysuccinic acid and L-leucine moieties, showed the most potent activity among them.

  Ethly (+)-(2S, 3S)-3-[(S)-3-甲基-1-(3-甲基丁基氨基甲酰基)丁基氨基甲酰基]-2-环氧羧酸酯（EST；la）预计将作为治疗肌肉萎缩症的口服药物，因为它对与疾病相关的肌纤维蛋白降解中涉及的半胱氨酸蛋白酶具有强大的抑制活性。通过广泛的研究，旨在开发一种适用于工业应用的新合成方法，发现L-精氨酸可以作为新的高效分离剂，用于获得光学纯的L-反-环氧富马酸（3a），而使用对硝基苯酚的活性酯方法在乙基L-反-环氧富马酸（7a）和L-亮氨酸异戊酰胺（8a）之间的偶联反应中非常有效，因为副产物的生成极少。为了检查反-环氧富马酸和亮氨酸部分的立体化学对半胱氨酸蛋白酶抑制活性的贡献，采用类似的方法合成了la的二叠体（lb-d），并测量了la-d对木瓜蛋白酶的灭活速率常数。化合物la，具有L-反-环氧富马酸和L-亮氨酸部分，显示出其中最强的活性。
• Design, Synthesis and Evaluation of d-Homophenylalanyl Epoxysuccinate Inhibitors of the Trypanosomal Cysteine Protease Cruzain
  作者：William R Roush、Alejandro Alvarez Hernandez、James H McKerrow、Paul M Selzer、Elizabeth Hansell、Juan C Engel

  DOI：10.1016/s0040-4020(00)00882-6

  日期：2000.12

  The binding modes of E-64c to papain combined with molecular modeling and ligand design using the crystal structure of cruzain have been used to develop new, potent D-Homophenylalanyl epoxysuccinate inhibitors of cruzain, the major cysteine protease of Trypanosoma cruzi. The most potent inhibitor 47 contains an O-benzyl hydroxamate unit and is highly specific for cruzain relative to other cysteine proteases tested. (C) 2000 Elsevier Science Ltd. All rights reserved.