4-<2-(2,4-Diaminopyrrolo<2,3-d>pyrimidin-5-yl)ethyl>benzoic acid | 149010-53-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: 4-<2-(2,4-Diaminopyrrolo<2,3-d>pyrimidin-5-yl)ethyl>benzoic acid
• 英文别名: 4-[2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid；4-[2-(2,4-diamino-7H-pyrrolo [2,3-d]pyrimidin-5-yl)ethyl]benzoic acid
• CAS: 149010-53-7
• 化学式: C₁₅H₁₅N₅O₂
• 分子量: 297.316
• InChiKey: LYDPRAUTBLAGMK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  131
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-<2-(2,4-Diaminopyrrolo<2,3-d>pyrimidin-5-yl)ethyl>benzoic acid 在 盐酸 、 三乙胺 、 焦碳酸二乙酯 作用下， 以 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.33h， 生成 methyl (2S)-2-[[4-[2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]-5-[[(E)-4-methoxy-4-oxobut-2-enoyl]amino]pentanoate
  参考文献：
  名称：

  非谷氨酸型吡咯并[2,3-d]嘧啶类抗叶酸药。三，N（Ω）掩蔽鸟氨酸类似物的合成和生物学性质。

  摘要：

  N- [4- [3-（2,4-二氨基-7H-吡咯并[2,3-d]嘧啶-5-基）丙基]苯甲酰基] -Lg谷氨酸的谷氨酸部分（1b，TNP-351 ）和相关化合物（1a）替换为各种N（ω）-酰基-，磺酰基-，氨基甲酰基-和芳基-2，ω-二氨基链烷酸，以及所得产物的抑制作用（9、11、14分别在二氢叶酸还原酶（DHFR）上检测了18、21、23、25、30、36），小鼠纤维肉瘤Meth A细胞和耐甲氨蝶呤的人CCRF-CEM细胞的生长。通过偶合吡咯并[2,3-d]嘧啶羧酸（7a，b）和N（ω）-邻苯二甲酰基2，ω-二氨基链烷酸甲酯（6a-）有效地合成了被半邻苯二甲酰基化的化合物（9a-f） c）和随后的水解。其他N（ω）-酰基和磺酰基-鸟氨酸类似物（21，23，25）通过酰化衍生自叔丁氧基羰基鸟氨酸类似物（17a，b）的游离氨基中间体（19a，b）而合成。游离鸟氨酸类似物（18）不能强烈抑制Meth

  DOI：

  10.1248/cpb.48.1270
• 作为产物：
  描述：

  对乙氧基甲酰苯丙醛 在 三乙胺 、 3-ethylbenzothiazolium bromide sodium hydroxide 、 4 A molecular sieve 、 水 、 sodium ethanolate 、 三乙胺 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 98.0h， 生成 4-<2-(2,4-Diaminopyrrolo<2,3-d>pyrimidin-5-yl)ethyl>benzoic acid
  参考文献：
  名称：

  WO2008/89390

  摘要：

  公开号：

文献信息

• Non-glutamate Type Pyrrolo(2,3-d)pyrimidine Antifolates. II. Synthesis and Antitumor Activity of N5-Substituted Glutamine Analogs.
  作者：Fumio ITOH、Yoshio YOSHIOKA、Koichi YUKISHIGE、Sei YOSHIDA、Megumi WAJIMA、Koichiro OOTSU、Hiroshi AKIMOTO

  DOI：10.1248/cpb.44.1498

  日期：——

  cross resistance to the analog (4Oa) having a tetrazole moiety as a substituent of glutamine, which exhibited potent antitumor activities. These results demonstrate that the antifolate analogs (4) with N5-substituted glutamine in place of glutamic acid are novel potent DHFR inhibitors with activity against MTX-resistant tumors. The potent antitumor activity of these analogs (4) may result from their

  N- [4- [3-（2,4-二氨基-7H-吡咯并[2，3-d]嘧啶-5-基）丙基]苯甲酰基] -L-谷氨酸的谷氨酸部分（1b，TNP- 351）和相关化合物被一些N5取代的谷氨酰胺代替。通过将吡咯并[2,3-d]嘧啶羧酸（11a，b）与一些经过适当保护的N5取代的谷氨酰胺衍生物（10A-S）偶联来有效制备抗叶酸剂（4A-S），这是通过偶联Boc-Glu制备的使用合适的缩合试剂将-OMe（7）与各种胺（8A-S）结合，然后进行水解。检查了所得产物对培养物中二氢叶酸还原酶（DHFR），胸苷酸合成酶（TS）和鼠类纤维肉瘤Meth A细胞生长的抑制作用。所有N5取代的谷氨酰胺类似物（4A-S）对DHFR的抑制作用都比TNP-351强得多，并且某些类似物对Meth A细胞的生长抑制作用与TNP-351相同。还检查了一些典型的类似物（4Bb，4Db，4F，4Oa）对培养物中抗甲氨蝶呤（MTX）的人C
• Pyrrolopyrimidinyalglutaminate derivatives and their use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US05403843A1

  公开（公告）日：1995-04-04

  A condensed pyrimidine derivative of the formula (I): ##STR1## wherein the ring A stands for an optionally substituted 5-membered ring; B stands for an optionally substituted divalent 5- or 6-membered homo- or hetero-cyclic group; X stands for, among others, amino group; Y stands for, among others, hydrogen atom, halogen atom or amino group; Z stands for a divalent aliphatic group having five or less atoms forming straight chain, optionally having nitrogen, whose chain portion may optionally have a hetero-atom; W stands for, among others, --NH--CO-- or --CO--NH--; R.sup.1 stands for an optionally substituted cyclic or chain-like group; COOR.sup.2 stands for an optionally esterified carboxyl group; and p denotes an integer of 1 to 4, provided that when --W--R.sup.1 denotes a moiety represented by the formula: ##STR2## wherein COOR.sup.16 and COOR.sup.17 are, independently, an optionally esterified carboxyl group and n denotes an integer of 1 to 5, p denotes 1, 3 or 4, or a salt thereof, exhibiting highly specific toxicities to various tumor cells and excellent therapeutic effects on methotrexate-resistant tumor cells as well.

  化合物的简化嘧啶衍生物，其化学式为（I）：##STR1## 其中，环A代表可选取代的5成员环；B代表可选取代的二价5-或6成员同系或异系环基；X代表氨基等；Y代表氢原子、卤素原子或氨基等；Z代表直链形成的具有五个或更少原子的二价脂肪基，其中可以有氮，其链部分可以可选地具有杂原子；W代表--NH--CO--或--CO--NH--等；R.sup.1代表可选取代的环状或链状基团；COOR.sup.2代表可选的酯化羧基；p表示1到4的整数，但当--W--R.sup.1表示由式子表示的基团时：##STR2## 其中，COOR.sup.16和COOR.sup.17分别代表可选的酯化羧基，n表示1到5的整数，p表示1、3或4，或其盐，对各种肿瘤细胞表现出高度特异性毒性，并且对甲氧苄氨甲酸耐药性肿瘤细胞具有优异的治疗效果。
• Condensed pyrimidine derivatives, their production and use as antitumor agents
  申请人：TAKEDA CHEMICAL INDUSTRIES, LTD.

  公开号：EP0530537A1

  公开（公告）日：1993-03-10

  A condensed pyrimidine derivative of the formula (I): wherein the ring A stands for an optionally substituted 5-membered ring; B stands for an optionally substituted divalent 5- or 6-membered homo- or hetero-cyclic group; X stands for, among others, amino group; Y stands for, among others, hydrogen atom, halogen atom or amino group; Z stands for a divalent aliphatic group having five or less atoms forming straight chain, optionally having nitrogen, whose chain portion may optionally have a hetero-atom; W stands for, among others, -NH-CO-or -CO-NH-; R¹ stands for an optionally substituted cyclic or chain-like group ; COOR² stands for an optionally esterified carboxyl group; and p denotes an integer of 1 to 4, provided that when -W-R¹ denotes a moiety represented by the formula: wherein COOR¹⁶ and COOR¹⁷ are, independently, an optionally esterified carboxyl group and n denotes an integer of 1 to 5, p denotes 1, 3 or 4, or a salt thereof, exhibiting highly specific toxicities to various tumor cells and excellent therapeutic effects on methotrexate-resistant tumor cells as well.

  式 (I) 的缩合嘧啶衍生物： 其中，环 A 代表任选取代的 5 元环；B 代表任选取代的二价 5 元或 6 元同环或杂环基团；X 代表氨基；Y 代表氢原子、卤素原子或氨基；Z 代表二价脂肪族基团，该基团具有 5 个或更少原子，形成直链，可任选具有氮，其链部分可任选具有杂原子；W 表示-NH-CO-或-CO-NH-；R¹ 表示任选取代的环状或链状基团；COOR² 表示任选酯化的羧基；p 表示 1 至 4 的整数，条件是当 -W-R¹ 表示由式表示的分子时： 其中 COOR¹⁶和 COOR¹⁷分别为任选酯化的羧基，n 表示 1 至 5 的整数，p 表示 1、3 或 4，或其盐，对各种肿瘤细胞具有高度特异性毒性，对甲氨蝶呤耐药的肿瘤细胞也有极好的治疗效果。
• Analogues of 4-[(7-Bromo-2-methyl-4-oxo-3<i>H</i>-quinazolin-6-yl)methylprop-2-ynylamino]-<i>N</i>-(3-pyridylmethyl)benzamide (CB-30865) as Potent Inhibitors of Nicotinamide Phosphoribosyltransferase (Nampt)
  作者：Jeffrey W. Lockman、Brett R. Murphy、Daniel F. Zigar、Weston R. Judd、Paul M. Slattum、Zhong-Hua Gao、Kirill Ostanin、Jeremy Green、Rena McKinnon、Ryan T. Terry-Lorenzo、Tracey C. Fleischer、J. Jay Boniface、Mark Shenderovich、J. Adam Willardsen

  DOI：10.1021/jm101145b

  日期：2010.12.23

  We have shown previously that the target of the potent cytatoxic agent 4-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino]-N-(3-pyridylmethyl)benzamide (CB38065, 1) is nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known we sought to optimize the biochemical and cellular Nampt activity of 1 as well as its cytotoxicity. It was found that a 3-pyridyl-methylamide substituent in the A region was critical to cellular Nampt activity and cytotoxicity, although other aromatic substitution did yield compounds with submicromolar enzymatic inhibition. Small unsaturated groups worked best in the D-region of the molecule, with 3,3-dimethylallyl providing optimal potency. The E region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for activity, and many substituents were tolerated at C(2) of the quinazolin-4-one. The best compounds showed subnanomolar inhibition of Nampt and low nanomolar cytotoxicity in cellular assays.
• A novel synthetic approach to pyrrolo[2,3-d]pyrimidine antifolates
  作者：Tetsuo Miwa、Takenori Hitaka、Hiroshi Akimoto

  DOI：10.1021/jo00059a016

  日期：1993.3

  A novel and efficient synthetic method for the synthesis of pyrrolo[2,3-d]pyrimidine antifolates is described. The key reaction of this method is the photo-initiated free radical addition of bromomalononitrile or ethyl bromocyanoacetate to an enol ether to afford the backbone skeleton of the targeted antifolate molecule. The key intermediates 3 or 4 are smoothly converted to the pyrrolo[2,3-d]pyrimidine antifolates 1 or 2 in three steps and in high overall yield.