2-amino-4-cyclohexylmethoxy-6-di(4-methoxybenzyl)amino-5-pyrimidine carbaldehyde | 244288-48-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-amino-4-cyclohexylmethoxy-6-di(4-methoxybenzyl)amino-5-pyrimidine carbaldehyde
• 英文别名: 2-amino-4-[bis[(4-methoxyphenyl)methyl]amino]-6-(cyclohexylmethoxy)pyrimidine-5-carbaldehyde
• CAS: 244288-48-0
• 化学式: C₂₈H₃₄N₄O₄
• 分子量: 490.602
• InChiKey: DUEKTGIJNPCETP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  99.8
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-amino-4-cyclohexylmethoxy-6-di(4-methoxybenzyl)amino-5-pyrimidine carbaldehyde 在 三氟乙酸 作用下， 生成 NU6055
  参考文献：
  名称：

  4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2

  摘要：

  The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC50 vs cdk1/cyclinB1 = 2.9 +/- 0.1 muM and IC50 vs cdk2/cyclinA3 = 2.2 +/- 0.6 muM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy- or cycloalkoxy-groups at the O-4-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC50 vs cdk1/cyclinB1 = 12 +/- 2 muM and cdk2/cyclinA3 = 13 +/- 4 muM) retaining significant activity. Substitutions at the N-6 position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC50 vs cdk1/cyclinB1 = 35 +/- 3 muM and cdk2/cyclinA3=43 +/- 3 muM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3 Angstrom resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)00884-3
• 作为产物：
  描述：

  2-氨基-4,6-二氯嘧啶-5-甲醛 在 sodium hydride 、 三乙胺 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 生成 2-amino-4-cyclohexylmethoxy-6-di(4-methoxybenzyl)amino-5-pyrimidine carbaldehyde
  参考文献：
  名称：

  4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2

  摘要：

  The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC50 vs cdk1/cyclinB1 = 2.9 +/- 0.1 muM and IC50 vs cdk2/cyclinA3 = 2.2 +/- 0.6 muM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy- or cycloalkoxy-groups at the O-4-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC50 vs cdk1/cyclinB1 = 12 +/- 2 muM and cdk2/cyclinA3 = 13 +/- 4 muM) retaining significant activity. Substitutions at the N-6 position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC50 vs cdk1/cyclinB1 = 35 +/- 3 muM and cdk2/cyclinA3=43 +/- 3 muM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3 Angstrom resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)00884-3

文献信息

• Cyclin dependent kinase inhibitors
  申请人：Cancer Research Campaign Technology Limited

  公开号：US06677345B1

  公开（公告）日：2004-01-13

  A range is disclosed of pyrimidine derivatives (I) which can act as inhibitors of cyclin dependent kinases (CDK's) and which thereby can provide useful therapeutic compounds for use in treatment of tumours or other cell proliferation disorders. The compounds of this invention bind to CDK molecules in a manner that appears to differ from that of known CDK inhibitors such as olomoucine and roscovitine. In formula (I), X is O, S or CHRx where Rx is H or C1-4 alkyl; D is H or NZ1Z2 where Z1 and Z2 are each independently H, C1-4 alkyl, C1-4 hydroxyalkyl, optionally substituted aryl or optionally substituted aralkyl; A is selected from H, C1-4 alkyl, C1-4 alkoxy, hydroxy, CH2(CH2)nOH (n=1-4), and NRa1Ra2 where Ra1 and Ra2 are each independently H or C1-4 alkyl; Y is or includes an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; D′ is H or NZ3Z4 where Z3 and Z4 are each independently H, C1-4 alkyl, C1-4 hydroxyalkyl, optionally substituted aryl or optionally-substituted aralkyl; E is selected from NO, NO2, N═N—Ar where Ar is an optionally substituted aryl or optionally substituted aralkyl, NRe1Re2 or Nre1Nre2Re3 (Re1, Re2 and Re3 each being independently H, C1-4 alkyl, C1-4 hydroxyalkyl, an optionally substituted aryl or an optionally substituted aralkyl), C(Re)═U (Re being hydrogen, C1-4 alkyl or substituted alkyl, e.g. hydroxyalkyl, or an unsubstituted or substituted aryl or aralkyl, e.g. benzyl, and U being selected from O, Nre′, NORe′ and N—NRe′Re″ where Re′ and Re″ are each independently H, C1-4 alkyl or CONH2), T, CH2T, CHT2 and CT3, where T is a halide I, Br, Cl or F.

  本发明公开了一系列嘧啶衍生物(I)，可以作为细胞周期依赖性激酶（CDK's）的抑制剂，并因此可以提供用于治疗肿瘤或其他细胞增殖障碍的有用治疗化合物。本发明的化合物以一种似乎与已知的CDK抑制剂（如olomoucine和roscovitine）不同的方式结合到CDK分子上。在式(I)中，X是O、S或CHRx，其中Rx是H或C1-4烷基；D是H或NZ1Z2，其中Z1和Z2分别独立地是H、C1-4烷基、C1-4羟基烷基、可选取代芳基或可选取代芳基烷基；A从H、C1-4烷基、C1-4烷氧基、羟基、CH2(CH2)nOH（n=1-4）和NRa1Ra2中选择，其中Ra1和Ra2分别独立地是H或C1-4烷基；Y是或包括一个可选取代的4-至8-成员碳环或杂环；D′是H或NZ3Z4，其中Z3和Z4分别独立地是H、C1-4烷基、C1-4羟基烷基、可选取代芳基或可选取代芳基烷基；E从NO、NO2、N═Ar（其中Ar是可选取代的芳基或可选取代的芳基烷基）、NRe1Re2或Nre1Nre2Re3（Re1、Re2和Re3分别独立地是H、C1-4烷基、C1-4羟基烷基、可选取代芳基或可选取代芳基烷基）、C(Re)═U（Re为氢、C1-4烷基或取代烷基，例如羟基烷基，或未取代或取代的芳基或芳基烷基，例如苄基，U从O、Nre′、NORe′和N—NRe′Re″中选择，其中Re′和Re″分别独立地是H、C1-4烷基或CONH2）、T、CH2T、CHT2和CT3中选择，其中T是卤素I、Br、Cl或F。
• 4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2
  作者：Veronique Mesguiche、Rachel J Parsons、Christine E Arris、Johanne Bentley、F.Thomas Boyle、Nicola J Curtin、Thomas G Davies、Jane A Endicott、Ashleigh E Gibson、Bernard T Golding、Roger J Griffin、Philip Jewsbury、Louise N Johnson、David R Newell、Martin E.M Noble、Lan Z Wang、Ian R Hardcastle

  DOI：10.1016/s0960-894x(02)00884-3

  日期：2003.1

  The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC50 vs cdk1/cyclinB1 = 2.9 +/- 0.1 muM and IC50 vs cdk2/cyclinA3 = 2.2 +/- 0.6 muM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy- or cycloalkoxy-groups at the O-4-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC50 vs cdk1/cyclinB1 = 12 +/- 2 muM and cdk2/cyclinA3 = 13 +/- 4 muM) retaining significant activity. Substitutions at the N-6 position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC50 vs cdk1/cyclinB1 = 35 +/- 3 muM and cdk2/cyclinA3=43 +/- 3 muM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3 Angstrom resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series. (C) 2002 Elsevier Science Ltd. All rights reserved.