methyl (2S)-2-[N-(benzyloxycarbonyl)amino]-5-(methylsufonyloxy)pentanoate | 174488-13-2

• 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: methyl (2S)-2-[N-(benzyloxycarbonyl)amino]-5-(methylsufonyloxy)pentanoate
• 英文别名: Methyl (2S)-2[N-(benzyloxycarbonyl)amino]-5-(methylsulphonyloxy)-pentanoate；methyl (2S)-5-methylsulfonyloxy-2-(phenylmethoxycarbonylamino)pentanoate
• CAS: 174488-13-2
• 化学式: C₁₅H₂₁NO₇S
• 分子量: 359.4
• InChiKey: KNVTZPUAHVOJQH-ZDUSSCGKSA-N

物化性质

• 沸点：
  555.1±50.0 °C(predicted)
• 密度：
  1.277±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  24
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  116
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl (2S)-2-[N-(benzyloxycarbonyl)amino]-5-(methylsufonyloxy)pentanoate 在 10percent Pd/C sodium hydroxide 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢气 、 三乙胺 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 作用下， 以 甲醇 、 乙醇 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 122.0h， 生成 (S)-2-{4-[(2-Methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)-prop-2-ynyl-amino]-benzoylamino}-5-(1H-[1,2,4]triazole-3-sulfonyl)-pentanoic acid
  参考文献：
  名称：

  Design and Synthesis of Cyclopenta[g]quinazoline-Based Antifolates as Inhibitors of Thymidylate Synthase and Potential Antitumor Agents^,

  摘要：

  Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors of TS that are associated with decreased/altered folylpolyglutamate synthetase (FPGS) expression and/or an impaired RFC. Examination of a computer graphics model of the humanized Escherichia coli TS enzyme with quinazoline inhibitors of TS, such as 1 bound in the active site of the enzyme, suggested that conformational restriction introduced by bridging the C9 with C7 to form a pentacycle may be beneficial for binding to TS. That led to the synthesis of a series of potent cyclopenta[g]quinazoline-based inhibitors of the enzyme in which the glutamyl residue associated with classical antifolates was replaced with a variety of glutamate-derived ligands; the most potent inhibitor being the L-Glu-gamma-D-GluT(alpha) derivative 7j. In the mouse L1210:1565 cell line (mutant RFC), the majority of these compounds had activity equal or only slightly greater compared with the parental L1210 cell line, indicating a reduced dependence on the RFC for cellular uptake in the L1210 cell line.

  DOI：

  10.1021/jm991119p
• 作为产物：
  描述：

  Z-L-GluOMe 在 sodium tetrahydroborate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 1.42h， 生成 methyl (2S)-2-[N-(benzyloxycarbonyl)amino]-5-(methylsufonyloxy)pentanoate
  参考文献：
  名称：

  Design and Synthesis of Cyclopenta[g]quinazoline-Based Antifolates as Inhibitors of Thymidylate Synthase and Potential Antitumor Agents^,

  摘要：

  Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors of TS that are associated with decreased/altered folylpolyglutamate synthetase (FPGS) expression and/or an impaired RFC. Examination of a computer graphics model of the humanized Escherichia coli TS enzyme with quinazoline inhibitors of TS, such as 1 bound in the active site of the enzyme, suggested that conformational restriction introduced by bridging the C9 with C7 to form a pentacycle may be beneficial for binding to TS. That led to the synthesis of a series of potent cyclopenta[g]quinazoline-based inhibitors of the enzyme in which the glutamyl residue associated with classical antifolates was replaced with a variety of glutamate-derived ligands; the most potent inhibitor being the L-Glu-gamma-D-GluT(alpha) derivative 7j. In the mouse L1210:1565 cell line (mutant RFC), the majority of these compounds had activity equal or only slightly greater compared with the parental L1210 cell line, indicating a reduced dependence on the RFC for cellular uptake in the L1210 cell line.

  DOI：

  10.1021/jm991119p

文献信息

• Anti-cancer compounds
  申请人：British Technology Group Limited

  公开号：US05747499A1

  公开（公告）日：1998-05-05

  Cyclopentaquinazoline of the formula (I): ##STR1## wherein R.sup.1 is hydrogen, amino, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 hydroxyalkyl or C.sub.1-4 fluoroalkyl; wherein R.sup.2 is hydrogen, C.sub.1-4 alkyl, C.sub.3-4 alkenyl, C.sub.3-4 alkynyl, C.sub.2-4 hydroxyalkyl, C.sub.2-4 halogenoalkyl or C.sub.1-4 cyanoalkyl; Ar.sup.1 is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, C.sub.1-4 alkyl and C.sub.1-4 alkoxy; and wherein R.sup.3 is a group of the formula: --A.sup.1 --Ar.sup.2 --A.sup.2 --Y.sup.1 in which A.sup.1, A.sub.2, Y.sup.1 and Ar.sub.2 are defined in claim 1; or a pharmaceutically acceptable salt or ester there of are of therapeutic value particularly in the treatment of cancer.

  公式（I）的环戊喹唑啉：其中R.sup.1是氢，氨基，C.sub.1-4烷基，C.sub.1-4烷氧基，C.sub.1-4羟基烷基或C.sub.1-4氟烷基；其中R.sup.2是氢，C.sub.1-4烷基，C.sub.3-4烯基，C.sub.3-4炔基，C.sub.2-4羟基烷基，C.sub.2-4卤代烷基或C.sub.1-4氰基烷基；Ar.sup.1是苯基，噻吩二基，噻唑二基，吡啶二基或嘧啶二基，可以选择性地带有一个或两个取代基，所述取代基选自卤素，羟基，氨基，硝基，氰基，三氟甲基，C.sub.1-4烷基和C.sub.1-4烷氧基；其中R.sup.3是以下式的基团：--A.sup.1--Ar.sup.2--A.sup.2--Y.sup.1，其中A.sup.1，A.sub.2，Y.sup.1和Ar.sub.2如权利要求1中定义；或其药学上可接受的盐或酯在治疗癌症方面具有治疗价值。
• Design and Synthesis of Cyclopenta[<i>g</i>]quinazoline-Based Antifolates as Inhibitors of Thymidylate Synthase and Potential Antitumor Agents^,
  作者：Vassilios Bavetsias、Jonathan H. Marriott、Camille Melin、Rosemary Kimbell、Zbigniew S. Matusiak、F. Thomas Boyle、Ann L. Jackman

  DOI：10.1021/jm991119p

  日期：2000.5.1

  Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors of TS that are associated with decreased/altered folylpolyglutamate synthetase (FPGS) expression and/or an impaired RFC. Examination of a computer graphics model of the humanized Escherichia coli TS enzyme with quinazoline inhibitors of TS, such as 1 bound in the active site of the enzyme, suggested that conformational restriction introduced by bridging the C9 with C7 to form a pentacycle may be beneficial for binding to TS. That led to the synthesis of a series of potent cyclopenta[g]quinazoline-based inhibitors of the enzyme in which the glutamyl residue associated with classical antifolates was replaced with a variety of glutamate-derived ligands; the most potent inhibitor being the L-Glu-gamma-D-GluT(alpha) derivative 7j. In the mouse L1210:1565 cell line (mutant RFC), the majority of these compounds had activity equal or only slightly greater compared with the parental L1210 cell line, indicating a reduced dependence on the RFC for cellular uptake in the L1210 cell line.