N-(benzyloxycarbonyl)-N-methyl-L-glutamic acid | 42417-69-6

• 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: N-(benzyloxycarbonyl)-N-methyl-L-glutamic acid
• 英文别名: N-Benzyloxycarbonyl-N-methylglutaminsaeure；α-N-Z-L-MeGlu；(2S)-2-[methyl(phenylmethoxycarbonyl)amino]pentanedioic acid
• CAS: 42417-69-6
• 化学式: C₁₄H₁₇NO₆
• 分子量: 295.292
• InChiKey: HPBMLBGBAOGMJU-NSHDSACASA-N

物化性质

• 沸点：
  494.1±45.0 °C(Predicted)
• 密度：
  1.332±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  21
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(benzyloxycarbonyl)-N-methyl-L-glutamic acid 在 palladium on activated charcoal 硫酸 、 氢气 、 三乙胺 、 焦碳酸二乙酯 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 41.58h， 生成 (S)-2-[((S)-4-Carboxy-4-{4-[(2,7-dimethyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-methyl-amino]-benzoylamino}-butyryl)-methyl-amino]-pentanedioic acid
  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 、 氯甲酸苄酯 在 碳酸氢钠 作用下， 反应 2.0h， 以75%的产率得到N-(benzyloxycarbonyl)-N-methyl-L-glutamic acid
  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

• Thymidylate synthase inhibiting quinazolinones
  申请人：British Technology Group Limited

  公开号：US05561133A1

  公开（公告）日：1996-10-01

  Quinazolines of the formula ##STR1## wherein R.sup.1 is typically methyl, hydrogen or amino; R.sup.2 is typically methyl or propargyl; Ar is typically phenylene or 2'-fluorophenylene; R.sup.3 is the residue of a dipeptide substituted, typically by methyl, at position (a), (b) or (c), shown in the following partial formula: ##STR2## R.sup.4, R.sup.5, R.sup.6 and R.sup.8 are typically hydrogen, R.sup.7 is typically hydrogen or methyl; or a pharmaceutically acceptable salt, ester or amide thereof are of value in the treatment of cancer.

  式##STR1##中的喹唑啉，其中R.sup.1通常是甲基、氢或氨基；R.sup.2通常是甲基或丙炔基；Ar通常是苯基或2'-氟苯基；R.sup.3是二肽残基，通常在位置(a)、(b)或(c)处被甲基等取代，如下部分式所示：##STR2##R.sup.4、R.sup.5、R.sup.6和R.sup.8通常是氢，R.sup.7通常是氢或甲基；或其药学上可接受的盐、酯或酰胺在癌症治疗中具有价值。
• [EN] 4-IMIDAZOLIDINONES AS KV1.5 POTASSIUM CHANNEL INHIBITORS<br/>[FR] 4-IMIDAZOLIDINONES UTILISÉS COMME INHIBITEURS DES CANAUX POTASSIQUES KV1.5
  申请人：WYETH CORP

  公开号：WO2009079624A1

  公开（公告）日：2009-06-25

  The present teachings relate to 4-imidazolidinones of Formula (I) Insert formula here as it appears in written form in the specification (I) which are useful as Kv1.5 potassium channel inhibitors providing atrial-selective antiarrhythmic activity. The present teachings further relate to compositions and methods for treating atrial-selective antiarrhythmia.

  本教导涉及到公式(I)中的4-咪唑啉酮。这些化合物可作为Kv1.5钾通道抑制剂，提供房性选择性抗心律失常活性。本教导还涉及治疗房性选择性抗心律失常的组合物和方法。
• <i>N</i>-Methylamino Acids in Peptide Synthesis. II. A New Synthesis of <i>N</i>-Benzyloxycarbonyl, <i>N</i>-Methylamino Acids
  作者：John R. McDermott、N. Leo Benoiton

  DOI：10.1139/v73-286

  日期：1973.6.15

  Reaction of N-benzyloxycarbonyl derivatives of aliphatic amino acids, and threonine, aspartic, and glutamic acids whose side-chains were protected with the t-butyl group, gave the corresponding N-methylamino acid derivatives in good yields. The methionine derivative could be obtained by using only one mol of methyl iodide. Derivatives of threonine, and aspartic and glutamic acids whose side-chains were not protected could not be methylated. Analysis of the crude products of methylation in three cases showed that they contained 0–1% of racemized material.

  N-苄氧羰基衍生物与保护有叔丁基侧链的脂肪族氨基酸、苏氨酸、天冬氨酸的反应，产生相应的N-甲基氨基酸衍生物，收率较高。甲硫氨酸衍生物可以仅使用一摩尔的碘甲烷获得。苏氨酸、天冬氨酸的衍生物，其侧链未受保护的情况下无法进行甲基化。对三种情况下甲基化的粗产品进行分析显示，含有0-1%的消旋杂质。
• SULPHOSTIN ANALOGUES AND PROCESSES FOR THE PREPARATION OF SULPHOSTIN AND ANALOGUES THEREOF
  申请人：ZAIDAN HOJIN BISEIBUTSU KAGAKU KENKYU KAI

  公开号：EP1184388B1

  公开（公告）日：2003-07-30
• DIPEPTIDYLQUINAZOLONES AS ANTI-CANCER AGENTS
  申请人：BRITISH TECHNOLOGY GROUP LIMITED

  公开号：EP0631576A1

  公开（公告）日：1995-01-04