6-(chloromethyl)thymine | 430440-92-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 6-(chloromethyl)thymine
• 英文别名: 6-(chloromethyl)-5-methyl-1H-pyrimidine-2,4-dione
• CAS: 430440-92-9
• 化学式: C₆H₇ClN₂O₂
• 分子量: 174.587
• InChiKey: ZHEDAPZVSYSIKS-UHFFFAOYSA-N

物化性质

• 熔点：
  241-244 °C(Solv: water (7732-18-5))
• 密度：
  1.310±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  58.2
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  吡啶 、 6-(chloromethyl)thymine 反应 48.0h， 以40%的产率得到
  参考文献：
  名称：

  Synthesis and enzymatic evaluation of pyridinium-Substituted uracil derivatives as novel inhibitors of thymidine phosphorylase

  摘要：

  A series of water soluble N(1)- and C(6)-substituted uracil pyridinium compounds were prepared as potential inhibitors of thymidine phosphorylase (TP). The C(6)-uracil substituted derivatives were the most active. 1-[(5-Chloro-2,4-dihydroxy-pyrimidin-6-yl)methyl]pyridinium chloride, was identified as the best inhibitor being 5-fold more potent than the known inhibitor, 6-amino-5-bromouracil. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00309-1
• 作为产物：
  描述：

  6-(hydroxymethyl)-2,4-dihydroxy-5-methylpyrimidine 在 盐酸 、 三氯氧磷 作用下， 以 甲醇 为溶剂， 反应 14.0h， 生成 6-(chloromethyl)thymine
  参考文献：
  名称：

  Synthesis and enzymatic evaluation of pyridinium-Substituted uracil derivatives as novel inhibitors of thymidine phosphorylase

  摘要：

  A series of water soluble N(1)- and C(6)-substituted uracil pyridinium compounds were prepared as potential inhibitors of thymidine phosphorylase (TP). The C(6)-uracil substituted derivatives were the most active. 1-[(5-Chloro-2,4-dihydroxy-pyrimidin-6-yl)methyl]pyridinium chloride, was identified as the best inhibitor being 5-fold more potent than the known inhibitor, 6-amino-5-bromouracil. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00309-1

文献信息

• Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2: Optimization of inhibitors of human thymidine phosphorylase and their selectivity with uridine phosphorylase
  作者：Shingo Yano、Hideki Kazuno、Tsutomu Sato、Norihiko Suzuki、Tomohiro Emura、Konstanty Wierzba、Jun-ichi Yamashita、Yukio Tada、Yuji Yamada、Masakazu Fukushima、Tetsuji Asao

  DOI：10.1016/j.bmc.2004.04.046

  日期：2004.7

  A series of novel 6-methylene-bridged uracil derivatives have been optimized for clinical use as the inhibitors of human thymidine phosphorylase (TP). We describe their synthesis and evaluation. Introduction of a guanidino or an amidino group enhanced the in vitro inhibitory activity of TP comparing with formerly reported inhibitor 1. Their selectivity for TP based on uridine phosphorylase inhibitory

  已经优化了一系列新颖的6-亚甲基桥接的尿嘧啶衍生物，以作为人胸苷磷酸化酶（TP）的抑制剂用于临床。我们描述它们的综合和评估。与以前报道的抑制剂1相比，胍基或a基的引入增强了TP的体外抑制活性。还评估了它们基于尿苷磷酸化酶抑制活性对TP的选择性。化合物2（TPI）由于其强大的TP抑制作用和2'-脱氧-5-（三氟甲基）尿苷（F（3）dThd）药代动力学的出色调节作用，已被选择用于临床评估。结果，TAS-102（F（3）dThd和TPI的组合）目前处于1期临床研究中。
• [EN] SOLID STATE FORMS OF 5-CHLORO-6-[(2-IMINOPYRROLIDIN-1-YL)METHYL]PYRIMIDINE-2,4-(1H,3H)-DIONE HYDROCHLORIDE AND THEIR PROCESSES FOR THE PREPARATION THEREOF<br/>[FR] FORMES À L'ÉTAT SOLIDE DE CHLORHYDRATE DE 5-CHLORO-6-[(2-IMINOPYRROLIDIN-1-YL)MÉTHYL]PYRIMIDINE-2,4-(1H,3H)-DIONE ET PROCÉDÉS DE PRÉPARATION ASSOCIÉS
  申请人：MSN LABORATORIES PRIVATE LTD R&D CENTER

  公开号：WO2019049174A1

  公开（公告）日：2019-03-14

  The present invention relates to solid state forms of 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride compound of formula-1a and their processes for the preparation thereof and an improved process for the preparation of 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride. The present inventors also provides an amorphous polymorph of the combination drug consisting of 2'-deoxy-5-(trifluoromethyl) uridine and 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione monohydrochloride and its process for the preparation.

  本发明涉及化合物5-氯-6-[(2-亚胺吡咯啉-1-基)甲基]嘧啶-2,4-(1H,3H)-二酮盐酸盐的固态形式，其化学式为1a，以及其制备方法和改进的制备方法。本发明者还提供了由2'-脱氧-5-(三氟甲基)尿苷和5-氯-6-[(2-亚胺吡咯啉-1-基)甲基]嘧啶-2,4-(1H,3H)-二酮单盐酸组成的组合药物的非晶形态多晶形态及其制备方法。
• Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 1: Discovery of novel orally active inhibitors of human thymidine phosphorylase
  作者：Shingo Yano、Hideki Kazuno、Norihiko Suzuki、Tomohiro Emura、Konstanty Wierzba、Jun-ichi Yamashita、Yukio Tada、Yuji Yamada、Masakazu Fukushima、Tetsuji Asao

  DOI：10.1016/j.bmc.2004.04.036

  日期：2004.7

  prepared as inhibitors of human thymidine phosphorylase (TP). To enhance the in vivo antitumor activity of fluorinated pyrimidine 2'-deoxyribonucleosides such as 2'-deoxy-5-(trifluoromethyl)uridine (F(3)dThd), a potent TP inhibitor preventing their degradation to an inactive compound, has become a target of medicinal chemistry. We present here the synthesis and evaluation of novel human TP inhibitors. Introduction

  已经制备了一系列新型的6-亚甲基桥接的尿嘧啶衍生物作为人胸苷磷酸化酶（TP）的抑制剂。为了增强氟化嘧啶2'-脱氧核糖核苷如2'-脱氧-5-（三氟甲基）尿苷（F（3）dThd）的体内抗肿瘤活性，一种有效的TP抑制剂可防止其降解为惰性化合物。药物化学的目标。我们在此介绍新型人TP抑制剂的合成和评估。与已知的TP抑制剂6-氨基-5-氯尿嘧啶相比，在5-氯尿嘧啶的6-位引入N-取代的氨基甲基侧链具有改善的水溶性和增强的抑制活性。口服给药后，化合物42在小鼠中被合理地很好地吸收。当与F（3）dThd结合使用时，化合物42通过增加前者的最大血浆浓度来发挥其TP抑制作用，这在猴子实验中得到了证明。与单独使用F（3）dThd相比，在携带人肿瘤异种移植物的小鼠中，药代动力学特征的积极变化伴随着该组合体内抗肿瘤活性的增强。生化和药理作用似乎都符合预期的概念。
• URACIL DERIVATIVES, AND ANTITUMOR EFFECT POTENTIATOR AND ANTITUMOR AGENT CONTAINING THE SAME
  申请人：TAIHO PHARMACEUTICAL COMPANY LIMITED

  公开号：EP0763529A1

  公开（公告）日：1997-03-19

  Provided are a uracil derivative represented by the following formula (1): wherein R1 represents a chlorine, bromine or iodine atom or a cyano or lower alkyl group; and R2 represents a 4-8 membered heterocyclic group having 1-3 nitrogen atoms, which may be substituted by one or more lower alkyl, imino, hydroxyl, hydroxymethyl, methanesulfonyloxy, amino or nitro groups; an amidinothio group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group; a guanidino group, one or more of the hydrogen atom(s) on one, two or all of the nitrogen atoms of which may each be substituted by a lower alkyl or cyano group; a (lower alkyl)amidino group; an amino group, one or both of the hydrogen atoms on the nitrogen atom of which may each be substituted by a lower alkyl group; a group -CH2N(Ra)Rb in which Ra and Rb may be the same or different and each represents a hydrogen atom or a lower alkyl group or Ra and Rb may form a pyrrolidine ring together with the nitrogen atom to which Ra and Rb are bonded; a group -NH-(CH2)m-Z in which Z represents an amino group, one or both of the hydrogen atoms on the nitrogen atom of which may each be substituted by a lower alkyl group, or a cyano group, and m stands for an integer of from 0 to 3; a group NRc(CH2)n-OH in which Rc represents a hydrogen atom or a lower alkyl group, and n stands for a natural number of from 1 to 4; a group -X-Y in which X represents S or NH, and Y represents a 2-imidazolin-2-yl, 2-imidazolyl, 1-methylimidazol-2-yl, 1,2,4-triazol-3-yl, 2-pyrimidyl or 2-benzimidazolyl group which may be substituted by one or more lower alkyl groups; or a ureido or thioureido group, one or more of the hydrogen atom(s) on one or both of the nitrogen atoms of which may each be substituted by a lower alkyl group; or a salt thereof; as well as a pharmaceutical, antitumor effect potentiator and antitumor agent containing same as an active ingredient.

  本发明提供了由下式(1)代表的尿嘧啶衍生物： 其中 R1 代表氯、溴或碘原子或氰基或低级烷基；R2 代表具有 1-3 个氮原子的 4-8 位杂环基团，可被一个或多个低级烷基、亚氨基、羟基、羟甲基、甲磺酰氧基、氨基或硝基取代；脒基，其一个或多个氮原子或两个氮原子上的一个或多个氢原子可分别被低级烷基取代；胍基，其中一个、两个或全部氮原子上的一个或多个氢原子可分别被低级烷基或氰基取代； （低级烷基）脒基； 氨基，其中一个或两个氮原子上的氢原子可分别被低级烷基取代；基团-CH2N(Ra)Rb，其中 Ra 和 Rb 可以相同或不同，各自代表一个氢原子或一个低级烷基，或 Ra 和 Rb 可与 Ra 和 Rb 键合的氮原子一起形成一个吡咯烷环；基团-NH-(CH2)m-Z，其中 Z 代表氨基，其氮原子上的一个或两个氢原子可分别被低级烷基或氰基取代，m 代表 0 至 3 的整数； 基团 NRc(CH2)n-OH，其中 Rc 代表氢原子或低级烷基，n 代表 1 至 4 的自然数；基团-X-Y，其中 X 代表 S 或 NH，Y 代表可被一个或多个低级烷基取代的 2-咪唑啉-2-基、2-咪唑基、1-甲基咪唑-2-基、1,2,4-三唑-3-基、2-嘧啶基或 2-苯并咪唑基；或脲基或硫脲基，其中一个或多个氮原子上的氢原子或两个氮原子上的氢原子可分别被一个低级烷基取代；或其盐；以及含有上述物质作为活性成分的药物、抗肿瘤增效剂和抗肿瘤剂。
• CANCEROUS METASTASIS INHIBITORS CONTAINING URACIL DERIVATIVES
  申请人：TAIHO PHARMACEUTICAL COMPANY LIMITED

  公开号：EP0884051A1

  公开（公告）日：1998-12-16

  This invention provides a drug which has inhibitory activities against thymidine phosphorylase and inhibits metastasis of a cancer. Specifically, this invention relates to a cancerous metastasis inhibitor comprising, as an active ingredient, a uracil derivative represented by the following formula (1): wherein R1 represents a chlorine, bromine or iodine atom or a cyano or lower alkyl group and R2 represents a substituted or unsubstituted 4-8 membered heterocyclic group having nitrogen atoms or a substituted or unsubstituted amidinothio, guanidino, (lower alkyl)amidino, amino or like group, or a salt thereof.

  本发明提供了一种对胸苷磷酸化酶具有抑制活性并能抑制癌症转移的药物。具体地说，本发明涉及一种癌症转移抑制剂，其活性成分包括下式（1）所代表的尿嘧啶衍生物： 其中 R1 代表氯、溴或碘原子或氰基或低级烷基，R2 代表取代或未取代的具有氮原子的 4-8 位杂环基团或取代或未取代的脒基、胍基、（低级烷基）脒基、氨基或类似基团，或其盐。