Pentafluorophenyl 4-{N-[(6S/6R)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(propyl-2-ynyl)amino}benzoate | 174487-68-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: Pentafluorophenyl 4-{N-[(6S/6R)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(propyl-2-ynyl)amino}benzoate
• 英文别名: pentafluorophenyl 4-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoate；pentafluorophenyl p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)-amino]benzoate；pentafluorophenyl p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta-[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoate；(2,3,4,5,6-pentafluorophenyl) 4-[(2-methyl-4-oxo-3,6,7,8-tetrahydrocyclopenta[g]quinazolin-6-yl)-prop-2-ynylamino]benzoate
• CAS: 174487-68-4
• 化学式: C₂₈H₁₈F₅N₃O₃
• 分子量: 539.461
• InChiKey: QXYXQLMLEIMZPQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  39
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  71
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  Pentafluorophenyl 4-{N-[(6S/6R)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(propyl-2-ynyl)amino}benzoate 在 1-羟基苯并三唑 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 (S)-4-((R)-2-Benzenesulfonylamino-1-methyl-2-oxo-ethylcarbamoyl)-2-{4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)-prop-2-ynyl-amino]-benzoylamino}-butyric 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：

  N-(4-{N-[(6RS)-2-Methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoyl)-L-glutamic acid 在 吡啶 、 Tris-HCl buffer 、 carboxypeptidase G₂ 、 zinc(II) chloride 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 73.0h， 生成 Pentafluorophenyl 4-{N-[(6S/6R)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(propyl-2-ynyl)amino}benzoate
  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

• [EN] ANTI-CANCER COMPOUNDS CONTAINING CYCLOPENTAQUINAZOLINE RING<br/>[FR] COMPOSES ANTI-CANCER CONTENANT UN NOYAU DE CYCLOPENTAQUINAZOLINE
  申请人：BRITISH TECHNOLOGY GROUP LIMITED

  公开号：WO1995030673A1

  公开（公告）日：1995-11-16

  (EN) Cyclopentaquinazoline of formula (I), wherein R1 is hydrogen, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl or C1-4 fluoroalkyl; wherein R2 is hydrogen, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, C2-4 hydroxyalkyl, C2-4 halogenoalkyl or C1-4 cyanoalkyl; Ar1 is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, C1-4 alkyl and C1-4 alkoxy; and wherein R3 is a group of the formula: -A1-Ar2-A2-Y1, in which A1 is a bond between the $g(a)-carbon atom of the group -CONHCH(CO2H)- and Ar2 or is a C1-2 alkylene group; Ar2 is phenylene, tetrazoldiyl, tiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which in the case of phenylene may optionally bear one or two substituents on the ring selected from halogeno, nitro, C1-4 alkyl and C1-4 alkoxy; A2 is a C1-3 alkylene or C2-3 alkenylene group; and a pharmaceutically acceptable salt or ester thereof are of therapeutic value particularly in the treatment of cancer.(FR) Cyclopentaquinazoline représenté par la formule (I), dans laquelle R1 représente hydrogène, amino, alkyle C1-4, alcoxy C1-4 , hydroxyalkyle C1-4 ou fluoroalkyle C1-4; dans laquelle R2 représente hydrogène, alkyle C1-4, alcényle C3-4, alcynyle C3-4, hydroxyalkyle C2-4, alogénoalkyle C2-4 ou cyanoalkyle C1-4; Ar1 représente phenylène, thiophénediyle, thiazolediyle, pyridinediyle ou pyrimidinediyle pouvant éventuellement porter un ou deux substituants sélectionés à partir de halogéno, hydroxy, amino, nitro, cyano, trifluorométhyle, alkyle C1-4 et alcoxy C1-4; et dans laquelle R3 représente un groupe de formule: -A1-Ar2-A2-Y1, dans laquelle A1 représente une liaison entre l'atome de $g(a)-carbone du groupe -CONHCH(CO2H) et un groupe alkylène C1-2; Ar2 représente phénylène, tétrazoldiyle, tiophénediyle, thiazolediyle, pyridinediyle ou pyrimidinediyle qui, dans le cas de phénylène, peut éventuellement porter un ou deux substituants sur le noyau sélectionnés à partir de halogéno, nitro, alkyle C1-4 et alcoxy C1-4; A2 représente un groupe alkylène C1-3 ou alkénylène C2-3; ainsi qu'un de ses sels ou de ses esters présentant une valeur thérapeutique, en particulier, dans le traitement du cancer.

  (I)式中的环戊喹唑啉，其中R1为氢、氨基、C1-4烷基、C1-4烷氧基、C1-4羟基烷基或C1-4氟代烷基；R2为氢、C1-4烷基、C3-4烯基、C3-4炔基、C2-4羟基烷基、C2-4卤代烷基或C1-4氰基烷基；Ar1为苯基、噻吩二基、噻唑二基、吡啶二基或嘧啶二基，可选地带有一个或两个卤代、羟基、氨基、硝基、氰基、三氟甲基、C1-4烷基和C1-4烷氧基取代基；R3为以下公式的基团：-A1-Ar2-A2-Y1，其中A1为连接基团-CONHCH（CO2H）的$g(a)-碳原子和Ar2之间的键或C1-2烷基链；Ar2为苯基、四唑二基、噻吩二基、噻唑二基、吡啶二基或嘧啶二基，若为苯基，则可选地在环上带有一个或两个卤代、硝基、C1-4烷基和C1-4烷氧基取代基；A2为C1-3烷基链或C2-3烯基链；以及其药学上可接受的盐或酯，特别是在癌症治疗方面具有治疗价值。
• 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.

  式(I)的环戊喹唑啉：##STR1## 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氟代烷基；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是苯撑基，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，所选取代基为卤代，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是式子：--A.sup.1--Ar.sup.2--A.sup.2--Y.sup.1的基团，在其中A.sup.1，A.sub.2，Y.sup.1和Ar.sub.2在权利要求书中被定义；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。
• Marriott, Jonathan H.; Neidle, Stephen; Matusiak, Zbigniew, Journal of the Chemical Society. Perkin transactions I, 1999, # 11, p. 1495 - 1503
  作者：Marriott, Jonathan H.、Neidle, Stephen、Matusiak, Zbigniew、Bavetsias, Vassilios、Jackman, Ann L.、Melin, Camille、Boyle, F. Thomas

  DOI：——

  日期：——
• ANTI-CANCER COMPOUNDS CONTAINING CYCLOPENTAQUINAZOLINE RING
  申请人：BRITISH TECHNOLOGY GROUP LIMITED

  公开号：EP0758328A1

  公开（公告）日：1997-02-19