tert-butyl (1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate | 527676-98-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 英文名称: tert-butyl (1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate
• 英文别名: tert-butyl N-[(1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxooxolan-2-yl]butyl]carbamate
• CAS: 527676-98-8
• 化学式: C₁₅H₂₇NO₄
• 分子量: 285.384
• InChiKey: JFBUIGVEJCZHGO-GRYCIOLGSA-N

物化性质

• 沸点：
  417.5±18.0 °C(Predicted)
• 密度：
  1.031±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.87
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl (1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate 在 palladium on activated charcoal 咪唑 、 盐酸 、 lithium aluminium tetrahydride 、 sodium azide 、 jones' reagent 、 氢气 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙二醇二甲醚 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 生成 N-[(1S,2S,4R)-2-Amino-4-((S)-1-benzylcarbamoyl-2-methyl-propylcarbamoyl)-1-isobutyl-pentyl]-N',N'-dipropyl-isophthalamide
  参考文献：
  名称：

  Aminoethylenes:  A Tetrahedral Intermediate Isostere Yielding Potent Inhibitors of the Aspartyl Protease BACE-1

  摘要：

  A series of novel beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure-activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/ P3, P1, and P2' substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors.

  DOI：

  10.1021/jm0509142
• 作为产物：
  描述：

  dimethyl <(3S)-5-methyl-3-<(tert-butoxycarbonyl)amino>-2-oxohexyl>phosphonate 在 palladium on activated charcoal sodium tetrahydroborate 、 正丁基锂 、 氢气 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 tert-butyl (1S)-3-methyl-1-[(2R,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate
  参考文献：
  名称：

  Aminoethylenes:  A Tetrahedral Intermediate Isostere Yielding Potent Inhibitors of the Aspartyl Protease BACE-1

  摘要：

  A series of novel beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure-activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/ P3, P1, and P2' substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors.

  DOI：

  10.1021/jm0509142

文献信息

• [EN] NOVEL SULFONE AMIDE DERIVATIVES CAPABLE OF INHIBITING BACE<br/>[FR] NOUVEAUX DERIVES SULFONAMIDE CAPABLES D'INHIBER BACE
  申请人：LG LIFE SCIENCES LTD

  公开号：WO2005030709A1

  公开（公告）日：2005-04-07

  The present invention relates to novel derivatives of sulfone amide of Formula 1 as defined in this disclosure which inhibit the activity of BACE (or beta-secretase). These sulfone amide derivatives are useful for the treatment and prevention of Alzheimer's disease and related diseases caused by production of beta-amyloid, by inhibiting the activity of BACE.

  本发明涉及本公开中定义的式1的磺酰脒衍生物，该衍生物抑制BACE（或β-分泌酶）的活性。这些磺酰脒衍生物可用于治疗和预防由β-淀粉样蛋白产生引起的阿尔茨海默病及相关疾病，通过抑制BACE的活性。
• COMPOUNDS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND METHODS OF USE THEREOF
  申请人：GHOSH Arun K.

  公开号：US20100267609A1

  公开（公告）日：2010-10-21

  Compounds inhibit memapsin 2 β-secretase activity and selectively inhibit memapsin 2 β-secretase activity relative to memapsin 1 β-secretase activity. The compounds are employed in methods to inhibit memapsin 2 β-secretase activity, in the treatment of Alzheimer's disease, in the inhibition of hydrolysis of a β-secretase site of a β-amyloid precursor protein and to decrease β-amyloid protein in in vitro samples and in mammals. Proteins of memapsin 2 associated with compounds of the invention are crystallized.
• Aminoethylenes:  A Tetrahedral Intermediate Isostere Yielding Potent Inhibitors of the Aspartyl Protease BACE-1
  作者：Wenjin Yang、Wanli Lu、Yafan Lu、Min Zhong、Jian Sun、Anila E. Thomas、Jennifer M. Wilkinson、Raymond V. Fucini、Melissa Lam、Mike Randal、Xiao-Ping Shi、Jeffrey W. Jacobs、Robert S. McDowell、Eric M. Gordon、Marcus D. Ballinger

  DOI：10.1021/jm0509142

  日期：2006.2.1

  A series of novel beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure-activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/ P3, P1, and P2' substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors.