2-pivaloyl-4-oxo-6-ethynylpyrido<2,3-d>pyrimidine | 116387-25-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 2-pivaloyl-4-oxo-6-ethynylpyrido<2,3-d>pyrimidine
• 英文别名: 6-ethynyl-2-(pivaloylamino)-4(3H)-oxopyrido [2,3-d]pyrimidine；2-Pivaloylamino4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine；N-(6-ethynyl-4-oxo-3H-pyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide
• CAS: 116387-25-8
• 化学式: C₁₄H₁₄N₄O₂
• 分子量: 270.291
• InChiKey: KLUNIYXWSVXRCD-UHFFFAOYSA-N

物化性质

• 熔点：
  >250 °C
• 密度：
  1.24±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  83.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-pivaloyl-4-oxo-6-ethynylpyrido<2,3-d>pyrimidine 在 palladium on activated charcoal 吡啶 、 ammonium hydroxide 、 sodium hydroxide 、 copper(l) iodide 、 四(三苯基膦)钯 、 氢气 、 三乙胺 、 4-氯苯基二氯磷酸酯 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 5,10-dideaza-5,6,7,8-tetrahydroaminopterin
  参考文献：
  名称：

  The synthesis and biological activity of a series of 2,4-diaminopyrido[2,3-D]pyrimidine based antifolates as antineoplastic and antiarthritic agents

  摘要：

  A new series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates 1-3 were synthesized through an efficient conversion of 2-pivaloyl-4-oxo-6-ethynylpyrido[2,3-d]pyrimidine 5 to the corresponding 4-amino analog 7 via the activated 1,2,4-triazole intermediate 6. Compound 7 was used as the key intermediate for the preparation of the final products. The detailed biological evaluation of these compounds both as antineoplastic and antiarthritic agents will be discussed. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(98)00683-0
• 作为产物：
  描述：

  2-(pivaloylamino)-4-hydroxy-6-<(trimethylsilyl)ethynyl>pyrido<2,3-d>pyrimidine 生成 2-pivaloyl-4-oxo-6-ethynylpyrido<2,3-d>pyrimidine
  参考文献：
  名称：

  [EN] COMPOUNDS USEFUL AS ANTIPROLIFERATIVE AGENTS AND GARFT INHIBITORS
  [FR] COMPOSES UTILES COMME AGENTS ANTIPROLIFERATIFS ET INHIBITEURS DE L'ENZYME GLYCINAMIDE RIBONUCLEOTIDE FORMYLE TRANSFERASE (GARFT)

  摘要：

  化合物的化学式为(I)，它们与它们的4-羟基互变异构体处于平衡状态，呈现为对映异构体混合物形式，它们的药学可接受盐是有效的GARFT抑制剂。其中，A为S、CH2或Se；Z为取代或未取代的C1-C3烷基、C2-C3烯基、C2-C3炔基或氨基，或S或O；X为取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、-C(O)E，其中E为氢、取代或未取代的C1-C3烷基、取代或未取代的C2-C3烯基、取代或未取代的C2-C3炔基、取代或未取代的OC1-C3烷氧基或NR10R11，其中R10和R11独立选择为氢、取代或未取代的C1-C3烷基、取代或未取代的C2-C3烯基、取代或未取代的C2-C3炔基；NR10R11，其中R10和R11如上所述独立定义；羟基；硝基；SR12，其中R12为氢、取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基或取代或未取代的C2-C6炔基；氰基；或取代或未取代的C1-C3烷氧基；R1和R2独立地为氢或与附加的CO2形成容易水解的酯基。这些化合物及其盐可用作抗增殖剂。该发明还涉及使用这些化合物作为GARFT抑制剂或抗增殖剂的制药组合物和方法。该发明还涉及作为制备这些化合物的中间体的有用化合物及其合成方法。

  公开号：

  WO1996003406A1

文献信息

• Pyridopyrimidines as nonclassical antifolates
  申请人：The Trustees of Princeton University

  公开号：US05786358A1

  公开（公告）日：1998-07-28

  2-Amino-4-hydroxy-4,5,6,7-tetrahydropyrido\x9b2,3-d!pyrimidine derivatives of aromatic amides, such as a benzamide or thienylcarboxamide in which the amino portion of the amide is other than L-glutamic acid are inhibitors of enzymes which utilize folic acid, in particular glycinamide ribonucleotide formyl transferase. A typical embodiment is N-(N-4-\x9b2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido\x9b2,3-d!pyrimidin-6-y l)ethyl!benzoyl}-L-.gamma.-glutamyl)-D-aspartic acid.

  芳香酰胺的2-氨基-4-羟基-4,5,6,7-四氢吡啶\x9b2,3-d!嘧啶衍生物，如苯甲酰胺或噻吩甲酰胺，其中酰胺的氨基部分不同于L-谷氨酸，是利用叶酸的酶的抑制剂，特别是甘胺核糖核苷酸甲酰转移酶。一个典型的实施例是N-(N-4-\x9b2-(2-氨基-4-羟基-5,6,7,8-四氢吡啶\x9b2,3-d!嘧啶-6-基)乙基!苯甲酰}-L-.gamma.-谷氨酰)-D-天冬氨酸。
• Pyrido[2,3-d]pyrimidine derivatives
  申请人：The Trustees of Princeton University

  公开号：US04889859A1

  公开（公告）日：1989-12-26

  Derivatives of N-[2-(5,6,7,8-tetrahydropyrido-[2,3-d]pyrimidin-6-yl)-alkyl]benzoyl-L-glut amic acid are antineoplastic agents. A typical embodiment is N-(2-fluoro-4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido-[2,3-d]pyrimi din-6-yl)ethyl]benzoyl)-L-glutamic acid.

  N-[2-(5,6,7,8-四氢吡啶[2,3-d]嘧啶-6-基)-烷基]苯甲酰-L-谷氨酸的衍生物是抗肿瘤药物。一个典型的实施例是N-(2-氟-4-[2-(2-氨基-4-羟基-5,6,7,8-四氢吡啶[2,3-d]嘧啶-6-基)乙基]苯甲酰)-L-谷氨酸。
• Compounds useful as antiproliferative agents and GARFT inhibitors
  申请人：Agouron Pharmaceuticals, Inc.

  公开号：US05608082A1

  公开（公告）日：1997-03-04

  Compounds of the Formula I, which are in equilibrium with their 4-hydroxy tautomers and are in the form of diastereomeric mixtures, and their pharmaceutically acceptable salts are potent GARFT inhibitors: ##STR1## wherein A, Z, X, and R.sub.1 and R.sub.2 are defined in the specification. These compounds and their salts are useful as antiproliferative agents. The invention also pertains to pharmaceutical compositions and methods employing such compounds as GARFT inhibitors or antiproliferative agents. The invention also relates to compounds useful as intermediates for preparing such compounds, and to their synthesis.

  公式I的化合物与其4-羟基互变异构体处于平衡状态，呈对映异构体混合物形式，并且它们的药用盐是有效的GARFT抑制剂：其中A、Z、X、R1和R2在说明书中有定义。这些化合物及其盐可用作抗增殖剂。本发明还涉及使用这些化合物作为GARFT抑制剂或抗增殖剂的药物组合物和方法。本发明还涉及用于制备这些化合物的中间体化合物，并涉及它们的合成。
• Convergent processes for the synthesis of a GARFT inhibitor containing a methyl substituted thiophene core and intermediates therefor
  申请人：AGOURON PHARMACEUTICALS, INC.

  公开号：US20040266796A1

  公开（公告）日：2004-12-30

  The invention relates to processes for the preparation of a GARFT inhibitor containing a methyl substituted thiophene core having the following structure: 1 wherein each of R 1 and R 2 are independently a hydrogen atom or a moiety that together with the attached CO 2 forms a readily hydrolyzable ester group; from an intermediate of the formula 2 wherein R 3 is a moiety that together with the attached CO 2 forms a readily hydrolyzable ester group; Pg 1 is an amino protecting group; R 4 is H; or Pg 1 can optionally be taken together with R 4 and the nitrogen to which Pg 1 and R 4 are attached to form (i) an imine; or (ii) a fused or bridged bicyclic ring or a spirocyclic ring, wherein said ring is saturated and contains from 5 to 12 carbon atoms in which up to 2 carbon atoms are optionally replaced with a hetero moiety selected from O, S(O) j wherein j is an integer from 0 to 2, and —NR 8 —, provided that two O atoms, two S(O) j moieties, or an O atom and a S(O) j moiety are not attached directly to each other; R 5 is selected from the group consisting of —C≡C— and —CH═CH—; and R 8 is independently H or C 1 -C 6 alkyl; to form the compound of the formula (I) that is optically pure; and to processes for preparing intermediates thereof.

  本发明涉及一种制备含有甲基取代噻吩核心的GARFT抑制剂的过程，其具有以下结构： 其中R1和R2中的每一个独立地是氢原子或者与连接的CO2形成易水解酯基团的基团；从具有以下结构的中间体开始： 其中R3是一个基团，与连接的 一起形成易水解酯基团；Pg1是氨基保护基团；R4是H；或者Pg1可以选择与R4及Pg1和R4连接的氮一起形成(i)亚胺；或者(ii)融合的或者桥接的双环或者螺环，其中所述环是饱和的，含有5至12个碳原子，其中最多有2个碳原子可以选择性地被来自O、S(O)j（其中j是0到2的整数）和—NR8—的杂原子基团替代，前提是两个O原子、两个S(O)j基团，或者一个O原子和一个S(O)j基团不能直接连接在一起；R5选自由—C≡C—和—CH2CH—的基团；R8独立地是H或者C1-C6烷基；形成具有光学纯度的化合物的公式(I)；以及制备其中间体的过程。
• 5,6,7,8-tetrahydropyrido[2,3-D]pyrimidines
  申请人：The Trustees of Princeton University

  公开号：US06066639A1

  公开（公告）日：2000-05-23

  Glutamic acid derivatives in which the amino group is substituted with a 2-amino-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylalkyl-Z-carbonyl group, in which Z is a divalent, five-membered, nitrogen-containing heterocyclic ring system optionally containing a sulfur or nitrogen atom as a second hetero ring member, are antineoplastic agents. A typical embodiment is N-3-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)e thyl]-pyrazol-5-ylcarbonyl}-L-glutamic acid.

  谷氨酸衍生物，其中氨基被2-氨基-5,6,7,8-四氢吡咯[2,3-d]嘧啶-6-基烷基-Z-羰基基团取代，其中Z是二价、五元杂环含氮环系统，可选地包含硫或氮原子作为第二个杂环环成员，是抗肿瘤剂。一个典型的实施例是N-3-[2-(2-氨基-4-羟基-5,6,7,8-四氢吡咯[2,3-d]嘧啶-6-基)乙基]-吡唑-5-基羰基}-L-谷氨酸。