1-(1,3-二氢-3-氧代-1-异苯并呋喃基)-5-氟-2,4(1H,3H)-嘧啶二酮 | 81820-68-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 中文名称: 1-(1,3-二氢-3-氧代-1-异苯并呋喃基)-5-氟-2,4(1H,3H)-嘧啶二酮
• 中文别名: 1-苯甲基-3,5-二甲基苯
• 英文名称: 1-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil
• 英文别名: 1-(1,3-dihydro-3-oxoisobenzofuran-1-yl)-5-fluorouracil；1-(3-phthalidyl)-5-fluorouracil；N1-phthalidyl-5-fluorouracil；1-phthalidyl 5-fluorouracil；1-Phthalidyl-5-fluorouracil；5-fluoro-1-(3-oxo-1H-2-benzofuran-1-yl)pyrimidine-2,4-dione
• CAS: 81820-68-0
• 化学式: C₁₂H₇FN₂O₄
• 分子量: 262.197
• InChiKey: JADGCGSQDUSAED-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  75.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(1,3-二氢-3-氧代-1-异苯并呋喃基)-5-氟-2,4(1H,3H)-嘧啶二酮 生成 N1-phthalidyl-N3-o-toluyl-5-fluorouracil
  参考文献：
  名称：

  KIGASAWA, KAZUO;HIIRAGI, MINEHARU;WAKISAKA, KIKUO;ICHIKAWA, KEIKO;NAKAZAT+

  摘要：

  DOI：
• 作为产物：
  描述：

  -N,N,N-triethyl N-phthalidylammonium bromide 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 15.0h， 生成 1-(1,3-二氢-3-氧代-1-异苯并呋喃基)-5-氟-2,4(1H,3H)-嘧啶二酮
  参考文献：
  名称：

  Studies of antitumor-active 5-fluorouracil derivatives. I. Synthesis of N-phthalidyl 5-fluorouracil derivatives.

  摘要：

  合成了几种5-氟尿嘧啶衍生物，其中苯并二氢呋喃酮（1,3-二氢-3-氧异苯并呋喃-1-基）基团在其苯环上适当取代，并在N(1)或N(3)位或两个位置上进行取代，并评估了它们的抗肿瘤活性。在这些化合物中，1-(1,3-二氢-3-氧异苯并呋喃-1-基)-5-氟尿嘧啶（3a，590-S）显示出对几种实验性肿瘤系统有显著的活性。研究了几种简单高效的3a大规模制备方法。通过5-氟尿嘧啶与3-溴邻苯二甲酰亚胺的季铵盐在碱存在下缩合，最有效地实现了3a的大规模制备。还描述了(+)-和(-)-3a的合成。

  DOI：

  10.1248/cpb.33.3160

文献信息

• Production of 1-phthalidyl-5-fluorouracil derivatives
  申请人：Shionogi & Co., Ltd.

  公开号：US04605738A1

  公开（公告）日：1986-08-12

  Highly selective and high yield process for producing antitumor agent 1-phthalidyl-5-fluorouracil derivatives of formula (I) which comprises reacting a phthalidyl compound (II) with an amine (III) to yield the quaternary ammonium salts (IV), and reacting the latter with 5-fluorouracil. ##STR1## [wherein X is leaving group; ##STR2## is triethylamine, N-methylmorpholine, N-ethylmorpholine, and the like; R.sup.4 and R.sup.5 each is hydrogen, trialkylsilyloxy, alkoxy, nitro, cyano, carboxy, or alkoxycarbonyl].

  生产抗肿瘤药物1-邻苯二甲酰基-5-氟尿嘧啶衍生物的高选择性和高产率过程，包括将邻苯二甲酰基化合物(II)与胺(III)反应，生成季铵盐(IV)，然后将后者与5-氟尿嘧啶反应。[其中X是离去基团；##STR2##是三乙胺、N-甲基吗啉、N-乙基吗啉等；R.sup.4和R.sup.5分别是氢、三烷基硅氧基、烷氧基、硝基、氰基、羧基或烷氧羰基]。
• Polysacchocride prodrug of 5-fluorouracil (5-FU) with enhanced target specificity for galectin-3 expressing cancers
  申请人：Tam C. Joemy

  公开号：US20080004237A1

  公开（公告）日：2008-01-03

  This application discloses embodiments of a novel prodrug and its method of synthesis. The prodrug comprises a galactose-containing polysaccharide covalently linked to 5-fluorouracil (5-FU). The galactose residues that are part of the backbone of the galactose-containing polysaccharide mediate the binding between the prodrug and the lectin galectin-3 which is expressed in various cancers. The galactose-containing polysaccharide is isolated from various plant material and covalently bonded to 5-FU. Various formulations (parenteral, or other local or systemic forms) can be used to administer this 5-FU-releasing prodrug to target galectin-3 expressing cancers.

  该应用程序披露了一种新型前药及其合成方法的实施方式。该前药包括一个含半乳糖的多糖，与5-氟尿嘧啶（5-FU）共价连接。作为半乳糖多糖骨架的一部分的半乳糖残基介导了前药与在各种癌症中表达的凝集素galectin-3之间的结合。这种含半乳糖的多糖是从各种植物材料中分离出来并与5-FU共价结合。可以使用各种配方（全身或局部形式）来向靶向表达galectin-3的癌症患者管理这种释放5-FU的前药。
• Novel polysaccharide pro-drug 5-fluorouracil (5-FU) with enhanced target specificity for colorectal cancer and its preparation methods
  申请人：Tam C. Joemy

  公开号：US20080085871A1

  公开（公告）日：2008-04-10

  This invention describes a novel polysaccharide prodrug of 5-fluorouracil (5-FU) with enhanced target specificity for colorectal cancer treatment, and its preparation methods. The prodrug is synthesized by chemically linking anti-cancer drug 5-fluorouracil (5-FU) with a specially selected polysaccharide with molecular weight of 10 5 ˜10 7 Da containing galactose residues. Its distinctive characteristics are that it is a prodrug synthesized by chemically linking polysaccharides with 5-FU through different bridge links for the targeted treatment of colorectal cancer; that the polysaccharides in the chemical compound contain galactose residues; and that these polysaccharides are prepared from natural gums or plant materials. Due to these unique characteristics, as an oral preparation, the polysaccharide component of this novel prodrug can protect the active agent 5-FU from absorption (or metabolism) in the upper gastrointestinal tract and deliver a high concentration of the 5-FU to the colorectal area. Upon reaching the colorectal area, the 5-FU-galactose portion of the prodrug will bind to galectin-3, a-galactoside-binding protein implicated in tumor progression by interactions with its ligands, such as TF (Thomsen-Friedenreich, Galb3GalNAc), Tn (GalNAcaThr/Ser), and Sialy-Tn with galactose residues, which are highly expressed among colorectal cancer cells. Finally, the active 5-FU component will be released locally from the polysaccharide via enzymatic hydrolysis from the local bacterial flora, allowing it to actively kill the colorectal cancer cells. In summary, this novel target-specific prodrug can enhance the selectivity of 5-FU and increase its therapeutic effects in the treatment of colorectal cancer. In addition, with this enhanced target specificity, it is possible to maximize the 5-FU efficacy in cancer patients by having either less toxicity with the same or higher therapeutic dose, and/or administer a lower dosage (if so desired) to achieve the same therapeutic effects, but with much less toxicity. Multiple examples of various approaches to synthesize this novel prodrug are enclosed herein along with several animal model experiments to substantiate the claims as stated above.

  这项发明描述了一种新型的多糖前药5-氟尿嘧啶（5-FU），具有增强的靶向特异性，用于结直肠癌治疗，以及其制备方法。该前药是通过化学连接抗癌药物5-氟尿嘧啶（5-FU）与分子量为105˜107Da、含有半乳糖残基的特选多糖进行合成的。其独特特点在于，它是通过不同的桥接链将多糖与5-FU化学连接而合成的前药，用于靶向治疗结直肠癌；化合物中的多糖含有半乳糖残基；这些多糖是从天然树胶或植物材料中制备的。由于这些独特特点，作为口服制剂，这种新型前药的多糖成分可以保护活性成分5-FU不被上消化道吸收（或代谢），并将高浓度的5-FU传递到结直肠区域。到达结直肠区域后，前药的5-FU-半乳糖部分将与半乳糖结合蛋白galectin-3结合，后者通过与其配体的相互作用，如TF（Thomsen-Friedenreich，Galb3GalNAc）、Tn（GalNAcaThr/Ser）和带有半乳糖残基的Sialy-Tn，参与了肿瘤进展，在结直肠癌细胞中高表达。最终，活性的5-FU成分将通过局部细菌群的酶水解从多糖中释放出来，从而能够主动杀死结直肠癌细胞。总之，这种新型靶向特异性前药可以增强5-FU的选择性，并增加其在结直肠癌治疗中的治疗效果。此外，通过增强的靶向特异性，可以通过减少毒性或使用相同或更高的治疗剂量来最大化癌症患者的5-FU疗效，或者以更低剂量（如果需要）来达到相同的治疗效果，但毒性更小。本文附有多种合成这种新型前药的方法示例，以及几个动物模型实验，以证实上述声明。
• Phthalidylammonium compounds and their production, and their use in the production of 1-phthalidyl-5-fluorouracil derivatives and formulations containing such derivatives
  申请人：SHIONOGI & CO., LTD.

  公开号：EP0112067A2

  公开（公告）日：1984-06-27

  Novel phthalidylammonium compounds (IV) are intermediates in a highly selective and high yield process for producing 1-phthalidyl-5-fluorouracil derivatives of formula (I) which are antitumour agents. The process comprises reacting a phthalidyl compound (II) with an amine (III) to yield the quaternary ammonium salts (IV), and then reacting the latter with 5-fluorouracil as follows: in which X is a leaving group; R1, R2 and R3 each independently represents alkyl or R' represents alkyl and R2 and R3 taken together with the adjacent nitrogen atom form a saturated 5- or 6-membered ring which may contain oxygen or represents quinuclidine; and R4 and R5 each independently represents hydrogen, trialkylsilyloxy, alkoxy, nitro, cyano, carboxy or alkoxycarbonyl.

  新型酞铵化合物（IV）是一种高选择性和高产率工艺的中间体，可用于生产抗肿瘤剂式（I）的 1-酞酰基-5-氟尿嘧啶衍生物。该工艺包括将邻苯二甲酰基化合物（II）与胺（III）反应生成季铵盐（IV），然后将后者与 5-氟尿嘧啶反应如下： 其中 X 是离去基团；R1、R2 和 R3 各自独立地代表烷基或 R' 代表烷基，R2 和 R3 与相邻的氮原子一起形成饱和的 5 或 6 元环，该环可能含有氧或 代表奎宁环；以及 R4 和 R5 各自独立地代表氢、三烷基硅氧基、烷氧基、硝基、氰基、羧基或烷氧羰基。
• A composition for increasing the anti-cancer activity of an anti-cancer compound
  申请人：OTSUKA PHARMACEUTICAL CO., LTD.

  公开号：EP0180188A2

  公开（公告）日：1986-05-07

  A composition for increasing the anti-cancer activity of an anti-cancer compound selected from among 5-fluorouracil and a compound capable of producing 5-fluorouracil in vivo, the composition comprising an effective amount of a pyridine derivative represented by the formula wherein R1 is hydroxy or acyloxy, R2 and R4 are each hydrogen, halogen, amino, carboxyl, carbamoyl, cyano, nitro, lower alkyl, lower alkenyl or lower alkoxycarbonyl, R3 and R are each hydrogen, hydroxy or acyloxy; when at least one of R1, R3 and R5 is hydroxy, the structure of 1-position on the pyridine rina can be duetothe due to the keto-enol tautomerism, said hydrogen attached to nitrogen being optionally substituted with a substituent selected from the group consisting of lower alkyl, tetrahydrofuranyl, tetrahydropyranyl, lower alkoxy-lower alkyl, phthalidyl, carbamoyl, lower alkoxycarbonyl-lower alkylcarbamoyl, phenyl-lower alkoxy-lower alkyl, phenylcarbamoyl which may have a substituent on the phenyl ring, lower alkylcarbamoyl, carboxy-lower alkylcarbamoyl, lower alkylthio-lower alkyl and lower alkenyl, provided that the compound having the following formula is excluded, wherein a is hydrogen, lower alkyl, tetrahydrofuranyl, tetrahydropyranyl, lower alkoxy-lower alkyl, lower alkylcarbamoyl, lower alkylthio-lower alkyl or lower alkenyl.

  一种提高选自5-氟尿嘧啶和一种能在体内产生5-氟尿嘧啶的化合物的抗癌活性的组合物，该组合物包括有效量的由式表示的吡啶衍生物 其中 R1 是羟基或酰氧基，R2 和 R4 分别是氢、卤素、氨基、羧基、氨基甲酰基、氰基、硝基、低级烷基、低级烯基或低级烷氧基羰基，R3 和 R 分别是氢、羟基或酰氧基；当 R1、R3 和 R5 中至少有一个是羟基时，吡啶里纳上 1 位的结构可以是 当 R1、R3 和 R5 中至少有一个是羟基时，吡啶里纳上 1 位的结构可以是酮烯醇同分异构，所述连接到氮上的氢可选择被选自低烷基、四氢呋喃基、四氢吡喃基、低烷氧基低烷基、邻苯二甲酰基、氨基甲酰基、低烷氧基羰基低烷基氨基甲酰基组成的取代基取代、苯基-低级烷氧基-低级烷基、苯基氨基甲酰基（苯基环上可能有取代基）、低级烷基氨基甲酰基、羧基-低级烷基氨基甲酰基、低级烷硫基-低级烷基和低级烯基，但具有下式的化合物除外、 其中 a 为氢、低级烷基、四氢呋喃基、四氢呋喃基、低级烷氧基低级烷基、低级烷基氨基甲酰基、低级烷硫基低级烷基或低级烯基。