(1S,2S,3R)-(2,5-dihydroxy-1-isobutyl-4-methyl-pentyl)carbamic acid tert-butyl ester | 169057-41-4

• 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: (1S,2S,3R)-(2,5-dihydroxy-1-isobutyl-4-methyl-pentyl)carbamic acid tert-butyl ester
• 英文别名: tert-butyl N-[(4S,5S,7R)-5,8-dihydroxy-2,7-dimethyloctan-4-yl]carbamate
• CAS: 169057-41-4
• 化学式: C₁₅H₃₁NO₄
• 分子量: 289.415
• InChiKey: PPAXJNPSIXZPFB-AGIUHOORSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  20
• 可旋转键数：
  9
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.93
• 拓扑面积：
  78.8
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1S,2S,3R)-(2,5-dihydroxy-1-isobutyl-4-methyl-pentyl)carbamic acid tert-butyl ester 在 N-morpholine oxide 、 4 Angstroem MS 、 n-Prop₄RuO₄ 作用下， 以 二氯甲烷 为溶剂， 生成 (3R,5S)-5-[(1'S)-1-(N-Boc-amino)-3-methylbutyl]-3-methyl-dihydrofuran-2(3H)-one
  参考文献：
  名称：

  羟乙烯二肽等排体的一般立体控制合成

  摘要：

  羟基亚乙基二肽电子等排体是由源自高烯丙基醇的立体控制合成硼氢化顺保护aminoepoxides然后将所得伯醇的化学选择性氧化。

  DOI：

  10.1016/0040-4039(95)00357-i
• 作为产物：
  描述：

  dimethyl <(3S)-5-methyl-3-<(tert-butoxycarbonyl)amino>-2-oxohexyl>phosphonate 在 palladium on activated charcoal sodium tetrahydroborate 、 lithium aluminium tetrahydride 、 正丁基锂 、 氢气 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 为溶剂， 生成 (1S,2S,3R)-(2,5-dihydroxy-1-isobutyl-4-methyl-pentyl)carbamic acid tert-butyl ester
  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

• Structure-Based Design, Synthesis, and Memapsin 2 (BACE) Inhibitory Activity of Carbocyclic and Heterocyclic Peptidomimetics
  作者：Stephen Hanessian、Hongying Yun、Yihua Hou、Gaoqiang Yang、Malken Bayrakdarian、Eric Therrien、Nicolas Moitessier、Silvio Roggo、Siem Veenstra、Marina Tintelnot-Blomley、Jean-Michel Rondeau、Christian Ostermeier、André Strauss、Paul Ramage、Paolo Paganetti、Ulf Neumann、Claudia Betschart

  DOI：10.1021/jm050142+

  日期：2005.8.1

  BACE led to the design and synthesis of a series of constrained P(1)' analogues. A cyclopentane ring was incorporated in 1 spanning the P(1)' Ala methyl group and the adjacent methylene carbon atom of the chain. Progressive truncation at the P(2)'-P(4)' sites led to a potent truncated analogue 5 with good selectivity over Cathepsin D. Using the same backbone replacement concept, a series of cyclopentane

  基于BACE的Tang-Ghosh七肽抑制剂1（OM99-2）的X射线晶体结构的分子建模，导致设计和合成了一系列受约束的P（1）'类似物。1个环戊烷环结合在P（1）'Ala甲基和该链的相邻亚甲基碳原子上。在P（2）'-P（4）'位点的逐步截短导致有效的截短的类似物5，对组织蛋白酶D具有良好的选择性。使用相同的骨架替换概念，一系列环戊烷，环戊酮，四氢呋喃，吡咯烷和吡咯烷酮合成的类似物在P和P'位点有相当大的变化。环戊酮和2-吡咯烷酮类似物45和57显示出较低的nM BACE抑制作用。
• Aspartyl protease inhibitors
  申请人：——

  公开号：US20040147454A1

  公开（公告）日：2004-07-29

  The present invention provides compounds having the formula: 1 wherein R 1 , R′, R 2 , R 3 , R 3′ , R 4 , X 1 , X 2 and X 3 are as defined herein, and pharmaceutical compositions thereof. The present invention also provides methods of inhibiting proteases, more specifically aspartyl proteases. In certain embodiments, compounds inhibit BACE (&bgr;-site APP-cleaving enzyme), and thus are useful in the treatment or prevention of a disease characterized by &bgr;-amyloid deposits in the brain (including, but not limited to, Alzheimer's Disease). The present invention also provides methods for preparing compounds of the invention.

  本发明提供具有以下公式的化合物：1其中R1、R′、R2、R3、R3′、R4、X1、X2和X3如本文所定义，以及其药物组合物。本发明还提供抑制蛋白酶的方法，更具体地是抑制天冬氨酸蛋白酶。在某些实施方式中，这些化合物抑制BACE（β-APP剪切酶），因此在治疗或预防大脑中存在β-淀粉样沉积的疾病（包括但不限于阿尔茨海默病）方面是有用的。本发明还提供制备本发明化合物的方法。
• [EN] ASPARTYL PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE L'ASPARTYL-PROTEASE
  申请人：SUNESIS PHARMACEUTICALS INC

  公开号：WO2003106405A1

  公开（公告）日：2003-12-24

  The present invention provides compounds having formula (I): wherein R’, R0, R1, X1, R2, R3, R3’, X2, X3, and R4 are as defined herein, and pharmaceuticals compositions thereof. The present invention also provides methods of inhibiting proteases, more specially aspartyl proteases. In certain embodiments, compounds inhibit BACE (β-site APP-cleaving enzyme), and thus are useful in the treatment or prevention of a disease characterized by β-amyloid deposits in the brain (including, but not limited to, Alzheimer’s Disease). The present invention also provides methods for preparing compounds of the invention.

  本发明提供具有以下结构的化合物（I）：其中R'、R0、R1、X1、R2、R3、R3'、X2、X3和R4如本文所定义，并且其药物组合物。本发明还提供抑制蛋白酶的方法，更具体地是天冬氨酸蛋白酶。在某些实施例中，这些化合物抑制BACE（β-APP裂解酶），因此可用于治疗或预防大脑中存在β-淀粉样沉积的疾病（包括但不限于阿尔茨海默病）。本发明还提供了制备本发明化合物的方法。
• A general stereocontrolled synthesis of hydroxyethylene dipeptide isosteres
  作者：Laurent Pégorier、Marc Larchevêque

  DOI：10.1016/0040-4039(95)00357-i

  日期：1995.4

  Hydroxyethylene dipeptide isosteres were synthesized by stereocontrolled hydroboration of homoallylic alcohols derived from syn protected aminoepoxides followed by chemoselective oxidation of the resulting primary alcohols.

  羟基亚乙基二肽电子等排体是由源自高烯丙基醇的立体控制合成硼氢化顺保护aminoepoxides然后将所得伯醇的化学选择性氧化。
• 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.