ditert-butyl (2S)-2-[methyl(phenylmethoxycarbonyl)amino]pentanedioate | 158804-93-4

• 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: ditert-butyl (2S)-2-[methyl(phenylmethoxycarbonyl)amino]pentanedioate
• CAS: 158804-93-4
• 化学式: C₂₂H₃₃NO₆
• 分子量: 407.507
• InChiKey: AZASMNRUNQISRU-KRWDZBQOSA-N

物化性质

• 沸点：
  485.0±45.0 °C(Predicted)
• 密度：
  1.096±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  29
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  82.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ditert-butyl (2S)-2-[methyl(phenylmethoxycarbonyl)amino]pentanedioate 在 palladium on activated charcoal 氢气 作用下， 以 乙酸乙酯 为溶剂， 反应 3.0h， 以98%的产率得到ditert-butyl (2S)-2-(methylamino)pentanedioate
  参考文献：
  名称：

  Folate-Based Inhibitors of Thymidylate Synthase:  Synthesis and Antitumor Activity of γ-Linked Sterically Hindered Dipeptide Analogues of 2-Desamino-2-methyl-N¹⁰-propargyl-5,8-dideazafolic Acid (ICI 198583)

  摘要：

  In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N-10-propargyl-5 ,8-dideazafolic acid (ICI 198583) was prepared. A methyl, ethyl, or propargyl group was incorporated into the gamma-glutamyl amide bond of gamma-linked L,L dipeptide derivatives of ICI 198583, such as ICI 198583-gamma-L-Glu. In addition, steric bulk was introduced on either side of the gamma-glutamyl bond of ICI 198583-gamma-L-Glu or ICI 198583-gamma-L-Ala. The resulting dipeptide analogues, e.g., ICI 198583-gamma-MeGlu and ICI 198583-gamma-Aib, were apparently stable to in vivo hydrolysis but poorer inhibitors of TS and L1210 cell growth. However, introduction of 7-Me, 2'-F substitution into the quinazoline nucleus gave significant improvement in the inhibitory activity against thymidylate synthase. Compounds 28-30, the 7-Me, 2'-F derivatives of ICI 198583-gamma-MeGlu, ICI 198583-gamma-EtGlu, and ICI 198583-gamma-PgGlu, respectively, were potent inhibitors of TS (Ki(iapp) = 0.21-1.1 nM) and L1210 cell growth (IC50 = 0.05-0.34 mu M) and were similar to that seen with the most potent gamma-linked L,D dipeptide derivatives of ICI 198583 previously synthesized. Furthermore, the low cross-resistance ratios for the L1210:R-D1694/L1210 cell line indicated that 28-30 do not undergo polyglutamation.

  DOI：

  10.1021/jm960878u
• 作为产物：
  描述：

  N-methyl-L-glutamic acid 在 硫酸 、 碳酸氢钠 作用下， 以 二氯甲烷 为溶剂， 反应 30.0h， 生成 ditert-butyl (2S)-2-[methyl(phenylmethoxycarbonyl)amino]pentanedioate
  参考文献：
  名称：

  Folate-Based Inhibitors of Thymidylate Synthase:  Synthesis and Antitumor Activity of γ-Linked Sterically Hindered Dipeptide Analogues of 2-Desamino-2-methyl-N¹⁰-propargyl-5,8-dideazafolic Acid (ICI 198583)

  摘要：

  In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N-10-propargyl-5 ,8-dideazafolic acid (ICI 198583) was prepared. A methyl, ethyl, or propargyl group was incorporated into the gamma-glutamyl amide bond of gamma-linked L,L dipeptide derivatives of ICI 198583, such as ICI 198583-gamma-L-Glu. In addition, steric bulk was introduced on either side of the gamma-glutamyl bond of ICI 198583-gamma-L-Glu or ICI 198583-gamma-L-Ala. The resulting dipeptide analogues, e.g., ICI 198583-gamma-MeGlu and ICI 198583-gamma-Aib, were apparently stable to in vivo hydrolysis but poorer inhibitors of TS and L1210 cell growth. However, introduction of 7-Me, 2'-F substitution into the quinazoline nucleus gave significant improvement in the inhibitory activity against thymidylate synthase. Compounds 28-30, the 7-Me, 2'-F derivatives of ICI 198583-gamma-MeGlu, ICI 198583-gamma-EtGlu, and ICI 198583-gamma-PgGlu, respectively, were potent inhibitors of TS (Ki(iapp) = 0.21-1.1 nM) and L1210 cell growth (IC50 = 0.05-0.34 mu M) and were similar to that seen with the most potent gamma-linked L,D dipeptide derivatives of ICI 198583 previously synthesized. Furthermore, the low cross-resistance ratios for the L1210:R-D1694/L1210 cell line indicated that 28-30 do not undergo polyglutamation.

  DOI：

  10.1021/jm960878u

文献信息

• DIPEPTIDYLQUINAZOLONES AS ANTI-CANCER AGENTS
  申请人：BRITISH TECHNOLOGY GROUP LIMITED

  公开号：EP0631576A1

  公开（公告）日：1995-01-04
• US5561133A
  申请人：——

  公开号：US5561133A

  公开（公告）日：1996-10-01
• [EN] DIPEPTIDYLQUINAZOLONES AS ANTI-CANCER AGENTS
  申请人：BRITISH TECHNOLOGY GROUP LTD

  公开号：WO1993019051A1

  公开（公告）日：1993-09-30

  (EN) Quinazolines of formula (I) wherein R1 is hydrogen or amino, or R1 is alkyl, alkoxy or alkylthio each of up to 6 carbon atoms; or R1 is aryl or aryloxy each of up to 10 carbon atoms; or R1 is halogeno, hydroxy or mercapto; or R1 is alkyl of up to 3 carbon atoms which bears one or more substituents selected from halogeno, hydroxy and alkanoylamino each of up to 6 carbon atoms; or R1 is alkoxy of up to 3 carbon atoms which bears one or more substituents selected from hydroxy and alkoxy of up to 6 carbon atoms; wherein R2 is hydrogen or alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, mercaptoalkyl, alkylthioalkyl, halogenoalkyl, cyanoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkanoylalkyl, carboxyalkyl, carbamoylalkyl or alkanoyl each of up to 6 carbon atoms; wherein Ar is phenylene or heterocyclene which is unsubstituted or which bears one or more substituents selected from halogeno, cyano, nitro, hydroxy, amino and carbamoyl and alkyl, alkoxy, halogenoalkyl, alkanoylamino, alkylthio and alkoxycarbonyl each of up to 6 carbon atoms; R3 is the residue of a dipeptide in which the first, N-terminal amino acid residue thereof attached to the carbonyl group of COR3 is an amino acid residue (a) in which A is a carbon-carbon single bond or an alkylene group of up to 5 carbon atoms and V and V' are each separately hydrogen, or alkyl, alkenyl or alkynyl each of up to 6 carbon atoms; and the second amino acid residue is of an $g(a)-amino acid or a pharmaceutically-acceptable salt, ester or amide thereof are of therapeutic value, particularly in the treatment of cancer.(FR) L'invention décrit des quinazolines selon la formule (I) dans laquelle R1 représente l'hydrogène ou un amino, ou R1 représente un alkyle, un alcoxy ou un thioalkyle chacun ayant jusqu'à 6 atomes de carbone; ou R1 représente une aryle ou un aryloxy chacun ayant jusqu'à 10 atomes de carbone; ou R1 représente un halogéno, un hydroxy ou un mercapto; ou R1 représente un alkyle ayant jusqu'à 3 atomes de carbone qui porte un ou plusieurs substituants sélectionnés parmi un halogéno, un hydroxy et un aminoalkanoyle chacun ayant jusqu'à 6 atomes de carbone; ou R1 représente un alcoxy ayant jusqu'à 3 atomes de carbone qui porte un ou plusieurs substituants sélectionnés parmi un hydroxy et un alcoxy ayant jusqu'à 6 atomes de carbone; dans laquelle R2 représente l'hydrogène ou un alkyle, alcényle, alcynyle, hydroxyalkyle, alcoxyalkyle, mercaptoalkyle, alkylthioalkyle, halogénoalkyle, cyanoalkyle, aminoalkyle, alkylaminoalkyle, dialkylaminoalkyle, alcanoylalkyle, carboxyalkyle, carbamoylalkyle ou alcanoyle ayant chacun jusqu'à 6 atomes de carbone; dans laquelle Ar représente un phénylène ou un hétérocyclène qui est non substitué ou qui porte un ou plusieurs substituants selectionnés parmi un halogéno, cyano, nitro, hydroxy, amino et carbamoyle et alkyle, alcoxy, halogénoalkyle, aminoalcanoyle, thioalkyle, et alcoxycarbonyle, ayant chacun jusqu'à 6 atomes de carbone; R3 représente le résidu d'un dipeptide dans lequel la première terminaison N de résidu d'acide aminé reliée au groupe carbonyle de COR3 est un résidu d'acide aminé (a) dans lequel A représente une liaison simple carbone-carbone ou un groupe alkylène ayant jusqu'à 5 atomes de carbone et V et V' représentent chacun séparément l'hydrogène, ou un alkyle, alcényle ou alcynyle ayant chacun jusqu'à 6 atomes de carbone; et le second résidu d'acide aminé est un acide amino-$g(a). L'invention décrit également un sel, ester ou amide de ces composés, pharmaceutiquement acceptable. Ces composés sont particulièrement utiles thérapeutiquement dans le traitement du cancer.
• Folate-Based Inhibitors of Thymidylate Synthase:  Synthesis and Antitumor Activity of γ-Linked Sterically Hindered Dipeptide Analogues of 2-Desamino-2-methyl-<i>N</i>¹⁰-propargyl-5,8-dideazafolic Acid (ICI 198583)
  作者：Vassilios Bavetsias、Ann L. Jackman、Jonathan H. Marriott、Rosemary Kimbell、William Gibson、F. Thomas Boyle、Graham M. F. Bisset

  DOI：10.1021/jm960878u

  日期：1997.5.1

  In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N-10-propargyl-5 ,8-dideazafolic acid (ICI 198583) was prepared. A methyl, ethyl, or propargyl group was incorporated into the gamma-glutamyl amide bond of gamma-linked L,L dipeptide derivatives of ICI 198583, such as ICI 198583-gamma-L-Glu. In addition, steric bulk was introduced on either side of the gamma-glutamyl bond of ICI 198583-gamma-L-Glu or ICI 198583-gamma-L-Ala. The resulting dipeptide analogues, e.g., ICI 198583-gamma-MeGlu and ICI 198583-gamma-Aib, were apparently stable to in vivo hydrolysis but poorer inhibitors of TS and L1210 cell growth. However, introduction of 7-Me, 2'-F substitution into the quinazoline nucleus gave significant improvement in the inhibitory activity against thymidylate synthase. Compounds 28-30, the 7-Me, 2'-F derivatives of ICI 198583-gamma-MeGlu, ICI 198583-gamma-EtGlu, and ICI 198583-gamma-PgGlu, respectively, were potent inhibitors of TS (Ki(iapp) = 0.21-1.1 nM) and L1210 cell growth (IC50 = 0.05-0.34 mu M) and were similar to that seen with the most potent gamma-linked L,D dipeptide derivatives of ICI 198583 previously synthesized. Furthermore, the low cross-resistance ratios for the L1210:R-D1694/L1210 cell line indicated that 28-30 do not undergo polyglutamation.