4(S)-<valyl>amino>-5-phenyl-2(E)-pentenoic acid ethyl ester | 148743-44-6

• 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(S)-<valyl>amino>-5-phenyl-2(E)-pentenoic acid ethyl ester
• 英文别名: ethyl (E,4S)-4-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]-5-phenylpent-2-enoate
• CAS: 148743-44-6
• 化学式: C₂₆H₃₂N₂O₅
• 分子量: 452.55
• InChiKey: OEEPBCGPZPRTFQ-ZMNDGBDXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  33
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  93.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4(S)-<valyl>amino>-5-phenyl-2(E)-pentenoic acid ethyl ester 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 120.0h， 生成 (2S,3R,4S)-4-<valyl>amino>-2,3-epoxy-5-phenylpentanoic acid ethyl ester 、 (2R,3S)-3-[(S)-1-((S)-2-Benzyloxycarbonylamino-3-methyl-butyrylamino)-2-phenyl-ethyl]-oxirane-2-carboxylic acid ethyl ester
  参考文献：
  名称：

  Inhibitors of HIV-1 Proteinase Containing 2-Heterosubstituted 4-Amino-3-hydroxy-5-phenylpentanoic Acid: Synthesis, Enzyme Inhibition, and Antiviral Activity

  摘要：

  A convenient procedure for the synthesis of 2-heterosubstituted statine derivatives as novel building blocks in HN-protease inhibitors has been developed. The synthesis starts with protected L-phenylalaninols, which were converted to gamma-amino alpha,beta-unsaturated esters in a one-pot procedure. A highly diastereoseletive epoxidation of the N-protected (E)-enoates, followed by regioselective ring opening of the corresponding 2,3-epoxy esters with a variety of heteronucleophiles, resulted in 2-heterosubstituted statine derivatives. The overall stereochemical outcome of the transformations meets the required configuration of HIV-protease inhibitors. The short, synthetically flexible, and highly diastereoselective synthesis of 2-heterosubstituted statines has enabled a broad derivation, covering the S3, S2, and S1'-S3' sites of the enzyme. In a series of 46 derivatives, several potent inhibitors were obtained with K-i values as low as 3.4 nM and antiviral activity in the lower nanomolar-range. The structural parameters of the compounds which determine the potency of inhibition and selectivity for the viral enzyme are discussed.

  DOI：

  10.1021/jm00045a013
• 作为产物：
  描述：

  L-苯丙氨醇 在 草酰氯 、 三乙胺 作用下， 以 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 74.0h， 生成 4(S)-<valyl>amino>-5-phenyl-2(E)-pentenoic acid ethyl ester
  参考文献：
  名称：

  Inhibitors of HIV-1 Proteinase Containing 2-Heterosubstituted 4-Amino-3-hydroxy-5-phenylpentanoic Acid: Synthesis, Enzyme Inhibition, and Antiviral Activity

  摘要：

  A convenient procedure for the synthesis of 2-heterosubstituted statine derivatives as novel building blocks in HN-protease inhibitors has been developed. The synthesis starts with protected L-phenylalaninols, which were converted to gamma-amino alpha,beta-unsaturated esters in a one-pot procedure. A highly diastereoseletive epoxidation of the N-protected (E)-enoates, followed by regioselective ring opening of the corresponding 2,3-epoxy esters with a variety of heteronucleophiles, resulted in 2-heterosubstituted statine derivatives. The overall stereochemical outcome of the transformations meets the required configuration of HIV-protease inhibitors. The short, synthetically flexible, and highly diastereoselective synthesis of 2-heterosubstituted statines has enabled a broad derivation, covering the S3, S2, and S1'-S3' sites of the enzyme. In a series of 46 derivatives, several potent inhibitors were obtained with K-i values as low as 3.4 nM and antiviral activity in the lower nanomolar-range. The structural parameters of the compounds which determine the potency of inhibition and selectivity for the viral enzyme are discussed.

  DOI：

  10.1021/jm00045a013

文献信息

• 4-AMINO-3-HYDROXYCARBOXYLIC ACID DERIVATIVES
  申请人：SANDOZ LTD.

  公开号：EP0594656A1

  公开（公告）日：1994-05-04
• [EN] 4-AMINO-3-HYDROXYCARBOXYLIC ACID DERIVATIVES
  申请人：SANDOZ LTD.

  公开号：WO1993001166A1

  公开（公告）日：1993-01-21

  (EN) The invention concerns the compounds of formula (I) wherein A and B independently are a bond or optionally substituted aminoacyl; R1 is hydrogen; an amino protecting group; or a group of formula R6Y- wherein R6 is hydrogen or an optionally substituted alkyl, alkenyl, alkinyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl group; and Y is -CO-; -NHCO-; NHCS-; -SO2-; -O-CO-; or -O-CS-; R2 is the side chain of a natural amino acid; an alkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group; or trimethylsilylmethyl, 2-thienylmethyl or styrylmethyl; R3 is an optionally substituted alkyl, alkenyl, alkinyl, cyloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group; R4 is a group of formula -OR7 or -NHR7 wherein R7 has the significance indicated above for R6; and X is -S- or -NR5- wherein R5 is hydrogen, methyl, formyl or acetyl; in free form and, where such forms exist, in salt form. They can be obtained by a process comprising epoxide ring opening, appropriate substitution and/or deprotection or saponification. They have antiviral activity, particularly HIV-1 proteinase inhibiting activity, and are thus indicated for use in the treatment of retroviral diseases.(FR) Composés répondant à la formule (I), dans laquelle A et B représentent, indépendamment l'un de l'autre, une liaison ou aminoacyle éventuellement substitué; R1 représente hydrogène; un groupe protecteur amino; ou un groupe répondant à la formule R6Y- dans laquelle R6 représente hydrogène ou un groupe alkyle, alcényle, alcynyle, aryle, arylalkyle, hétéroaryle, hétéroarylalkyle, hétérocyclyle ou hétérocyclylalkyle éventuellement substitué; et Y représente -CO-; -NHCO-; -NHCS-; -SO2-; -O-CO-; ou -O-CS-; R2 représente la chaîne latérale d'un acide aminé naturel; un groupe alkyle, arylalkyle, hétéroarylalkyle ou cycloalkylalkyle; ou triméthylsilylméthyle, 2-thiènylméthyle ou styrylméthyle; R3 représente un groupe alkyle, alcényle, alcynyle, cycloalkyle, aryle, arylalkyle, hétéroaryle ou hétéroarylalkyle éventuellement substitué; R4 représente un groupe répondant à la formule -OR7 ou -NHR7 dans laquelle R7 a la même notation que R6; et X représente -S- ou -NR5- où R5 représente hydrogène, méthyle, formyle ou acétyle; sous forme libre et, lorsque de telles formes existent, sous forme de sel. On peut les obtenir à l'aide d'un procédé comportant l'ouverture du cycle époxyde, une substitution appropriée et/ou la déprotection ou la saponification. Ils présentent une activité antivirale, notamment une activité d'inhibition de la protéinase du VIH-1, et sont de ce fait indiqués pour l'utilisation lors du traitement des maladies rétrovirales.
• Inhibitors of HIV-1 Proteinase Containing 2-Heterosubstituted 4-Amino-3-hydroxy-5-phenylpentanoic Acid: Synthesis, Enzyme Inhibition, and Antiviral Activity
  作者：Dieter Scholz、Andreas Billich、Brigitte Charpiot、Peter Ettmayer、Philipp Lehr、Brigitte Rosenwirth、Erwin Schreiner、Hubert Gstach

  DOI：10.1021/jm00045a013

  日期：1994.9

  A convenient procedure for the synthesis of 2-heterosubstituted statine derivatives as novel building blocks in HN-protease inhibitors has been developed. The synthesis starts with protected L-phenylalaninols, which were converted to gamma-amino alpha,beta-unsaturated esters in a one-pot procedure. A highly diastereoseletive epoxidation of the N-protected (E)-enoates, followed by regioselective ring opening of the corresponding 2,3-epoxy esters with a variety of heteronucleophiles, resulted in 2-heterosubstituted statine derivatives. The overall stereochemical outcome of the transformations meets the required configuration of HIV-protease inhibitors. The short, synthetically flexible, and highly diastereoselective synthesis of 2-heterosubstituted statines has enabled a broad derivation, covering the S3, S2, and S1'-S3' sites of the enzyme. In a series of 46 derivatives, several potent inhibitors were obtained with K-i values as low as 3.4 nM and antiviral activity in the lower nanomolar-range. The structural parameters of the compounds which determine the potency of inhibition and selectivity for the viral enzyme are discussed.