diethyl (S)-2-(4-nitrophthalimido)glutarate | 139988-43-5

• 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: diethyl (S)-2-(4-nitrophthalimido)glutarate
• 英文别名: diethyl(S)-2-(4-nitrophthalimido)glutarate；diethyl (2S)-2-(5-nitro-1,3-dioxoisoindol-2-yl)pentanedioate
• CAS: 139988-43-5
• 化学式: C₁₇H₁₈N₂O₈
• 分子量: 378.339
• InChiKey: QLFHNYHWNXXKBF-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  27
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  136
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  diethyl (S)-2-(4-nitrophthalimido)glutarate 在 palladium on activated charcoal 盐酸 、 氢气 、 sodium cyanoborohydride 、 溶剂黄146 、 锌 作用下， 以 乙醇 、 水 为溶剂， -40.0~-10.0 ℃ 、344.73 kPa 条件下， 反应 30.5h， 生成 diethyl 2-(S)-[5-methylamino-2,3-dihydro-1-oxo-2(1H)-isoindolyl]glutarate
  参考文献：
  名称：

  Benzo[f]quinazoline Inhibitors of Thymidylate Synthase: Methyleneamino-Linked Aroylglutamate Derivatives

  摘要：

  Syntheses of several new inhibitors of thymidylate synthase (TS) structurally related to folic acid are described in which the pterin portion of the folate molecule is replaced by a benzo[f]quinazoline moiety, but which retain the natural methyleneamino link to the benzoylglutamate side chain. The effect on enzyme activity and cytotoxicity of various changes in the structure of the (p-aminobenzoyl)glutamate side chain are reported. Replacement of the benzamide portion of the (p-aminobenzoyl)glutamate moiety with 2-fluorobenzamido, 2-isoindolinyl, 1,2-benzisothiazol-2-yl, and 2-thenamido moieties varied in effect from a 9-fold diminution of TS activity to a 5-fold enhancement, while cytotoxic potency on SW-480 and MCF-7 tumor lines showed increases ranging from 3.6-to 450-fold. The detrimental effect on enzyme activity and cytotoxicity of alkyl substitution on the PABA nitrogen is confirmed for these compounds, in contrast with several series of previously reported quinazoline antifolates (2). Substitution of a C3-methyl substituent for 3-amino had little effect on TS activity but was beneficial in terms of solubility and cytotoxicity. The excellent combination of TS inhibitory activity, FPGS substrate activity, and affinity for the reduced folate transport system in the most potent of these derivatives, 3e, resulted in IC50 values of 0.2-0.8 nM against these tumor lines.

  DOI：

  10.1021/jm00032a019
• 作为产物：
  描述：

  4-硝基邻苯二甲酸酐 、 L-谷氨酸二乙酯盐酸盐 在 N,N-二异丙基乙胺 作用下， 以 甲苯 为溶剂， 生成 diethyl (S)-2-(4-nitrophthalimido)glutarate
  参考文献：
  名称：

  Pharmaceutical compounds

  摘要：

  本发明涉及新型苯并喹唑嘧啶酸甲脱氧胸苷合成酶抑制剂，以及含有它们的药物配方和它们在医学上的应用。

  公开号：

  US05405851A1

文献信息

• Pharmaceutical compounds
  申请人：Burroughs Wellcome Co.

  公开号：US05405851A1

  公开（公告）日：1995-04-11

  The present invention relates to novel benzoquinazoline thymidylate synthase inhibitors, to pharmaceutical formulations containing them and to their use in medicine.

  本发明涉及新型苯并喹唑嘧啶酸甲脱氧胸苷合成酶抑制剂，以及含有它们的药物配方和它们在医学上的应用。
• Combination of benzoquinazoline antifolates and protecting agents
  申请人：SmithKline Beecham Corporation

  公开号：US06358952B1

  公开（公告）日：2002-03-19

  The use of a protecting agent, for example a folate derivative such as folic acid or leucovorin, in combination with a non-competitive folic acid analogue, for example benzoquinazoline derivatives, for use in reducing the side effects associated with the administration of such non-competitive folic acid analogues, and pharmeceutical formulations comprising such combinations are disclosed.

  本发明涉及使用保护剂，例如叶酸衍生物，如叶酸或亚叶酸，与非竞争性叶酸类似物，例如苯并喹唑啉衍生物的组合物，用于减少与这些非竞争性叶酸类似物的给药相关的副作用，并且揭示了包含这些组合物的制药配方。
• Novel combination of benzoquinazoline antifolates and protecting agents
  申请人：——

  公开号：US20030203924A1

  公开（公告）日：2003-10-30

  The use of a protecting agent, for example a folate derivative such as folic acid or leucovorin, in combination with a non-competitive folic acid analogue, for example benzoquinazoline derivatives, for use in reducing the side effects associated with the administration of such non-competitive folic acid analogues, and pharmaceutical formulations comprising such combinations are disclosed.

  本发明揭示了一种保护剂的使用，例如叶酸衍生物，如叶酸或亚叶酸，与一种非竞争性叶酸类似物，例如苯并喹唑啉衍生物的结合使用，用于减少与此类非竞争性叶酸类似物的给药相关的副作用，并揭示了包含此类组合物的制药组合物。
• Treatment of cancer with pharmaceutically active benzoquinazoline
  申请人：Glaxo Wellcome Inc.

  公开号：US05661155A1

  公开（公告）日：1997-08-26

  The present invention relates to bezoquinazoline thymidylate synthase inhibitors, to pharmaceutical formulations containing them and to their use in medicine.

  本发明涉及苯二氮杂喹嗪嘧啶酸合成酶抑制剂，含有它们的制药配方以及它们在医学上的使用。
• Dithiolan derivatives, their preparation and their therapeutic effect
  申请人：Sankyo Company Limited

  公开号：EP1070710A2

  公开（公告）日：2001-01-24

  Compounds of formula (I): [in which: one of m and n is 0, and the other is 0, 1 or 2; k is 0 or an integer of from 1 to 12; A is a single bond, an oxygen atom, a carbonyl group or a group of formula         -N(R2)CO-, -N(R2)CS-, -N(R2)SO2-, -CON(R2)N(R3)CO-,         -CON(R2)CO-, -CON(R2)CS -, -O-CO-, -ON(R2)CO-,         -ON(R2)SO2-, -O-CON(R2)N(R3)CO-, -O-CON(R2)CO-,         -O-CON(R2)SO2-, -CO-O-, -CO-CO-, -CO-CON(R2)N(R3)CO-,         -CO-CON(R2)CO-, -CO-CON(R2)SO2-, -N(R2)O-, -N(R2)COCO-,         -N(R2)N(R3)CO-, -N(R2)N(R3)SO2-, -N(R2)CON(R3)N(R4)CO-,         -N(R2)CON(R3)CO-, -N(R2)CON(R3)SO2- or         -N(R2)CON(R3)SO2N(R4)CO- in which R2, R3 and R4 are the same or different and each is hydrogen, alkyl, aralkyl, acyl or one of substituents α; B is a single bond, or a group of formula -N(R5)- or -N(R6)N(R5)- in which R5 and R6 are the same or different and each is hydrogen, alkyl, aralkyl, acyl or one of substituents α, or R5, together with R1 and the nitrogen atom to which they are bonded, may form a heterocyclic ring having from 5 to 7 ring atoms; R1 is hydrogen, one of substituents α, or optionally substituted alkyl, or, where A is a group of formula -N(R2)CO-, -N(R2)CS-, -CON(R2)N(R3)CO-, -CON(R2)CO-, -CON(R2)CS-, -O-CO-, -ON(R2)CO-, -O-CON(R2)N(R3)CO-, -O-CON(R2)CO-, -CO-CON(R2)N(R3)CO-, -CO-CON(R2)CO-, -N(R2)N(R3)CO-, -N(R2)CON(R3)N(R4)CO- or -N(R2)CON(R3)CO- [in which R2, R3 and R4 are as defined above] and B is a single bond, R1 may represent a group of formula -OR7 in which R7 is alkyl, alkenyl, aralkyl, or one of substituents α ; or, where A is a group of formula -ON(R2)SO2-, -O-CON(R2)SO2-, -CO-CO-, -CO-CON(R2)SO2-, -N(R2)COCO-, -N(R2)N(R3)SO2- or -N(R2)CON(R3)SO2- [in which R2 and R3 are as defined above] and B is a single bond, or, where A is not an oxygen atom, a group of formula -CO-O- or -N(R6)O- and B is -N(R5)- [in which R5 is as defined above], R1 may represent a hydroxy group or a group of formula -OR7 (in which R7 is as defined above) and said substituents α are selected from aryl groups and heterocyclic groups]; and pharmaceutically acceptable salts thereof have an excellent ability to enhance the activity of glutathione reductase and can therefore be used for the treatment and prevention of a variety of diseases including cataracts.

  式(I)化合物： 其中 m 和 n 中的一个为 0，另一个为 0、1 或 2；k 为 0 或 1 至 12 的整数；A 为单键、氧原子、羰基或式（I）的基团。 -n(r2)co-、-n(r2)cs-、-n(r2)so2-、-con(r2)n(r3)co、 -con(r2)co，-con(r2)cs-，-o-co，-on(r2)co、 -on(r2)so2-，-o-con(r2)n(r3)co，-o-con(r2)co、 -o-con(r2)so2-，-co-o-，-co-co-，-co-con(r2)n(r3)co、 -co-con(r2)co、-co-con(r2)so2-、-n(r2)o-、-n(r2)coco、 -n(r2)n(r3)co-，-n(r2)n(r3)so2-，-n(r2)con(r3)n(r4)co-、 -N（R2）CON（R3）COPY，-N（R2）CON（R3）SO2- 或 -n(r2)con(r3)so2n(r4)co-或 其中 R2、R3 和 R4 相同或不同，且各自为氢、烷基、芳基、酰基或取代基 α 之一；B 为单键，或为式 -N(R5)- 或 -N(R6)N(R5)- 的基团，其中 R5 和 R6 相同或不同，且各自为氢、烷基、芳基、酰基或取代基 α 之一，或 R5 与 R1 及其键合的氮原子可形成具有 5 至 7 个环原子的杂环；R1 是氢、取代基 α 之一或任选取代的烷基，或者，其中 A 是式-N(R2)CO-、-N(R2)CS-、-CON(R2)N(R3)CO-、-CON(R2)CO-、-CON(R2)CS-、-O-CO-、-ON(R2)CO-、-O-CON(R2)N(R3)CO-、-O-CON(R2)CO-、-CO-CON(R2)N(R3)CO-的基团、-CO-CON(R2)CO-、-N(R2)N(R3)CO-、-N(R2)CON(R3)N(R4)CO-或-N(R2)CON(R3)CO-[其中 R2、R3 和 R4 如上定义]且 B 为单键，R1 可代表式 -OR7 的基团，其中 R7 为烷基、烯基、芳基或取代基 α 之一；或，其中 A 是式-ON(R2)SO2-、-O-CON(R2)SO2-、-CO-CO-、-CO-CON(R2)SO2-、-N(R2)COCO-、-N(R2)N(R3)SO2-或-N(R2)CON(R3)SO2-的基团[其中 R2 和 R3 如上定义]，B 是单键，或，其中 A 不是氧原子、式-CO-O-或-N(R6)O-的基团，且 B 为-N(R5)-[其中 R5 如上定义]，R1 可代表羟基或式-OR7（其中 R7 如上定义）的基团，且所述取代基 α 选自芳基和杂环基团]；及其药学上可接受的盐类具有极佳的增强谷胱甘肽还原酶活性的能力，因此可用于治疗和预防包括白内障在内的多种疾病。