(S)-2-Amino-4-methylcarbamoyl-butyric acid tert-butyl ester | 166169-80-8

• 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: (S)-2-Amino-4-methylcarbamoyl-butyric acid tert-butyl ester
• 英文别名: tert-butyl (2S)-2-amino-5-(methylamino)-5-oxopentanoate
• CAS: 166169-80-8
• 化学式: C₁₀H₂₀N₂O₃
• 分子量: 216.28
• InChiKey: PIXBTJVXWBKSAQ-ZETCQYMHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  15
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  81.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-2-Amino-4-methylcarbamoyl-butyric acid tert-butyl ester 在 diethyl cyanophosphoridate 、 三乙胺 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 (S)-4-Methylcarbamoyl-2-{4-[(2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-prop-2-ynyl-amino]-benzoylamino}-butyric acid
  参考文献：
  名称：

  The Synthesis and Thymidylate Synthase Inhibitory Activity of L-.gamma.-L-Linked Dipeptide and L-.gamma.-Amide Analogs of 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)

  摘要：

  Sixteen gamma-linked dipeptide and four L-Glu-gamma-amide analogues of 2-desamino-2-methyl-N-10-propargyl-5,8-dideazafolic acid (ICI 198583) have been synthesized and evaluated as inhibitors of thymidylate synthase (TS). Z-blocked L-Glu-gamma-L-linked dipeptides and L-Glu-gamma-amides were prepared by condensing alpha-tert-butyl-N-(benzyloxycarbonyl)-L-glutamic acid with the appropriate tert-butyl-protected L-amino acid or amine. The Z group was removed by catalytic hydrogenolysis, and the resulting dipeptides or L-Glu-gamma-amides were condensed with the appropriate pteroic acid analogue trifluoroacetate salt using diethyl cyanophosphoridate as coupling reagent. Deprotection with trifluoroacetic acid in the final step gave the desired quinazoline gamma-linked dipeptides and L-Glu-gamma-amides as their trifluoroacetate salts. Nearly all the dipeptide analogues were potent inhibitors of TS, the best being ICI 198583-gamma-L-2-aminoadipate (IC50 = 2 nM). Several of these dipeptides were found to be susceptible to enzymatic hydrolysis in mice. The quinazoline monocarboxylate L-Glu-gamma-amides, lacking an alpha'-carboxyl group, are less active against TS and L1210 cell growth but are also not susceptible to enzymatic hydrolysis in mice.

  DOI：

  10.1021/jm00046a014
• 作为产物：
  描述：

  Z-谷安酸叔丁基酯 在 palladium on activated charcoal N-甲基吗啉 、 氢气 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 为溶剂， -20.0 ℃ 、101.33 kPa 条件下， 反应 4.33h， 生成 (S)-2-Amino-4-methylcarbamoyl-butyric acid tert-butyl ester
  参考文献：
  名称：

  The Synthesis and Thymidylate Synthase Inhibitory Activity of L-.gamma.-L-Linked Dipeptide and L-.gamma.-Amide Analogs of 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)

  摘要：

  Sixteen gamma-linked dipeptide and four L-Glu-gamma-amide analogues of 2-desamino-2-methyl-N-10-propargyl-5,8-dideazafolic acid (ICI 198583) have been synthesized and evaluated as inhibitors of thymidylate synthase (TS). Z-blocked L-Glu-gamma-L-linked dipeptides and L-Glu-gamma-amides were prepared by condensing alpha-tert-butyl-N-(benzyloxycarbonyl)-L-glutamic acid with the appropriate tert-butyl-protected L-amino acid or amine. The Z group was removed by catalytic hydrogenolysis, and the resulting dipeptides or L-Glu-gamma-amides were condensed with the appropriate pteroic acid analogue trifluoroacetate salt using diethyl cyanophosphoridate as coupling reagent. Deprotection with trifluoroacetic acid in the final step gave the desired quinazoline gamma-linked dipeptides and L-Glu-gamma-amides as their trifluoroacetate salts. Nearly all the dipeptide analogues were potent inhibitors of TS, the best being ICI 198583-gamma-L-2-aminoadipate (IC50 = 2 nM). Several of these dipeptides were found to be susceptible to enzymatic hydrolysis in mice. The quinazoline monocarboxylate L-Glu-gamma-amides, lacking an alpha'-carboxyl group, are less active against TS and L1210 cell growth but are also not susceptible to enzymatic hydrolysis in mice.

  DOI：

  10.1021/jm00046a014

文献信息

• Heterocyclic inhibitors of farnesyl protein transferase
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0618221A2

  公开（公告）日：1994-10-05

  Inhibition of farnesyl protein transferase is effected by compounds of the formula its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs or solvates thereof, wherein:    A₁ and A₂ are each independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl;    G₁ is S or O;    G₂ is H, -C(O)OH, -C(O)NH₂, 5-tetrazolyl, -C(O)N(R₇)OH or -CH₂OH;    X is O or R₈N;    Y and Z are each independently -CH₂- or -C(O)-;    R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are each independently H or alkyl;    R₁ may also be alkanoyl,    R₁ and A₁ taken together may be -(CH₂)m;    R₈ is H, alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl or -C(O)R₉;    R₉ is H, alkyl, phenyl, phenylalkyl, substituted phenyl or (substituted phenyl)alkyl;    m is 3 or 4;    n is 0, 1 or 2;    p is 0, 1 or 2; and    q is 0 or 1, with the proviso that when p is 0, then q is also 0.

  式中的化合物可抑制法尼基蛋白转移酶的作用 其对映体、非对映体、药学上可接受的盐、原药或溶液，其中 A₁ 和 A₂ 各自独立地为 H、烷基、取代烷基、环烷基、取代环烷基、苯基或取代苯基； G₁ 是 S 或 O； G₂ 是 H、-C(O)OH、-C(O)NH₂、5-四唑基、-C(O)N(R₇)OH 或 -CH₂OH； X 是 O 或 R₈N； Y 和 Z 各自独立地为 -CH₂- 或 -C(O)-； R₁、R₂、R₃、R₄、R₅、R₆ 和 R₇ 各自独立地为 H 或烷基； R₁ 也可以是烷酰基、 R₁ 和 A₁ 合在一起可以是-(CH₂)m； R₈ 是 H、烷基、苯基、苯基烷基、取代苯基、（取代苯基）烷基或 -C(O)R₉； R𠢙 是 H、烷基、苯基、苯基烷基、取代苯基或（取代苯基）烷基； m 是 3 或 4 n 是 0、1 或 2 p 是 0、1 或 2；以及 q 为 0 或 1，但条件是当 p 为 0 时，q 也为 0。
• The Synthesis and Thymidylate Synthase Inhibitory Activity of L-.gamma.-L-Linked Dipeptide and L-.gamma.-Amide Analogs of 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)
  作者：Graham M. F. Bisset、Vassilios Bavetsias、Timothy J. Thornton、Krzysztof Pawelczak、A. Hilary Calvert、Leslie R. Hughes、Ann L. Jackman

  DOI：10.1021/jm00046a014

  日期：1994.9

  Sixteen gamma-linked dipeptide and four L-Glu-gamma-amide analogues of 2-desamino-2-methyl-N-10-propargyl-5,8-dideazafolic acid (ICI 198583) have been synthesized and evaluated as inhibitors of thymidylate synthase (TS). Z-blocked L-Glu-gamma-L-linked dipeptides and L-Glu-gamma-amides were prepared by condensing alpha-tert-butyl-N-(benzyloxycarbonyl)-L-glutamic acid with the appropriate tert-butyl-protected L-amino acid or amine. The Z group was removed by catalytic hydrogenolysis, and the resulting dipeptides or L-Glu-gamma-amides were condensed with the appropriate pteroic acid analogue trifluoroacetate salt using diethyl cyanophosphoridate as coupling reagent. Deprotection with trifluoroacetic acid in the final step gave the desired quinazoline gamma-linked dipeptides and L-Glu-gamma-amides as their trifluoroacetate salts. Nearly all the dipeptide analogues were potent inhibitors of TS, the best being ICI 198583-gamma-L-2-aminoadipate (IC50 = 2 nM). Several of these dipeptides were found to be susceptible to enzymatic hydrolysis in mice. The quinazoline monocarboxylate L-Glu-gamma-amides, lacking an alpha'-carboxyl group, are less active against TS and L1210 cell growth but are also not susceptible to enzymatic hydrolysis in mice.