4-氨基-5-氟-1-[(2R,4S,5R)-4-羟基-5-(羟基甲基)-3-亚甲基四氢呋喃-2-基]嘧啶-2-酮 | 129531-96-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 4-氨基-5-氟-1-[(2R,4S,5R)-4-羟基-5-(羟基甲基)-3-亚甲基四氢呋喃-2-基]嘧啶-2-酮
• 英文名称: 2'-deoxy-2'-methylidene-5-fluorocytidine
• 英文别名: 4-amino-5-fluoro-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-3-methylideneoxolan-2-yl]pyrimidin-2-one
• CAS: 129531-96-0
• 化学式: C₁₀H₁₂FN₃O₄
• 分子量: 257.221
• InChiKey: CBFZRLQZSOMINR-BKPPORCPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.7
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  108
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,3-二棕榈酰-Sn-甘油-1-磷酰胆碱 、 4-氨基-5-氟-1-[(2R,4S,5R)-4-羟基-5-(羟基甲基)-3-亚甲基四氢呋喃-2-基]嘧啶-2-酮 在 sodium acetate buffer 、 Dianion WK-20 resin (Na⁽¹⁺⁾ form) 、 phospholipase D 作用下， 生成 5'-phosphatidyl-5-fluoro-2'-deoxy-2'-methylenecytidine
  参考文献：
  名称：

  Nucleosides and nucleotides. 155. synthesis, antitumor effects, and possible enzymatic activation mechanism of 5′-phosphatidyl-2′-deoxy-2′-methylenecytidine (DMDC)

  摘要：

  2'-Deoxy-2'-methylenecytidine (DMDC, 1) and its 5-fluoro congener (5-F-DMDC, 2), potent antitumor nucleosides developed by us, were efficiently converted to their 5'-phosphatidyl derivatives bearing palmitoyl residues (3 and 4, respectively) as novel antitumor phospholipids by phospholipase D-catalyzed trans-phosphatidylation. These phospholipids 3 and 4, administered i.p., remarkably prolonged the life-span of mice which were i.p.-inoculated with M5076 sarcoma, and the effects were clearly superior to that of DMDC. Compound 3 was a good substrate for phospholipase A(2) from bovine pancreas as well as phospholipase D from Streptomyces, while it was slightly hydrolyzed by phospholipase C from Bacillus cereus. Copyright (C) 1996 Elsevier Science Ltd

  DOI：

  10.1016/0960-894x(96)00389-7
• 作为产物：
  描述：

  3',5'-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-2'-deoxy-2'-methylidene-5-fluorouridine 在 吡啶 、 ammonium hydroxide 、 4-氯苯基二氯磷酸酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 53.5h， 生成 4-氨基-5-氟-1-[(2R,4S,5R)-4-羟基-5-(羟基甲基)-3-亚甲基四氢呋喃-2-基]嘧啶-2-酮
  参考文献：
  名称：

  各种2'-和3'-亚甲基取代的核苷类似物的合成及其抗癌和抗病毒活性以及2'-脱氧-2'-亚甲基吡啶盐酸盐的晶体结构。

  摘要：

  已经合成了各种2'-和3'-亚甲基取代的核苷类似物，并将其评估为潜在的抗癌剂和/或抗病毒剂。在这些化合物中，2'-脱氧-2'-亚甲基-5-氟胞苷（22）和2'-脱氧-2'-亚甲基胞苷（23）不仅在培养中表现出对鼠L1210和P388白血病，肉瘤180的有效抗癌活性。 ，人CCRF-CEM淋巴母细胞性白血病，其ED50值分别为1.2和0.3 microM，0.6和0.4 microM，1.5和1.5 microM，0.05和0.03 microM，但在小鼠L1210白血病中也有活性。在所有测试的药物剂量水平（分别为25、50和75 mg / kg）中，化合物23没有毒性死亡，而化合物22在最高剂量水平下仅产生一个毒性死亡。相反，在同一项研究中，1-β-D-阿拉伯呋喃糖基胞嘧啶（ara-C）分别导致2 / 5、5 / 5和5/5毒性死亡。化合物22和23均显示出比ara-C更好的抗癌活性，产生更高的T

  DOI：

  10.1021/jm00112a040

文献信息

• Nucleosides and nucleotides. 97. Synthesis of new broad spectrum antineoplastic nucleosides, 2'-deoxy-2'-methylidenecytidine (DMDC) and its derivatives
  作者：Akira Matsuda、Kenji Takenuki、Motohiro Tanaka、Takuma Sasaki、Tohru Ueda

  DOI：10.1021/jm00106a049

  日期：1991.2

  A new type of antineoplastic nucleoside, 2'-deoxy-2'-methylidenecytidine (DMDC) has been synthesized from the corresponding 2'-keto pyrimidine nucleosides 3 and 8 by the Wittig reaction. During the course of the reaction, we found that an intermediate betaine could pick a proton from the excess triphenylphosphonium bromide to form the 2'-phosphonium salts 5 and 10, which could be further converted

  通过Wittig反应，由相应的2'-酮嘧啶核苷3和8合成了一种新型的抗肿瘤核苷2'-脱氧-2'-亚甲基胞苷（DMDC）。在反应过程中，我们发现中间体甜菜碱可以从过量的三苯基溴化pick中挑出质子形成2'-on盐5和10，并可以进一步转化为2'-脱氧-2'-亚甲基通过氢化钠处理得到核苷4和9。还从相应的5-取代的尿苷12a-f，h合成了各种5-取代的DMDC衍生物19a-e，h及其尿嘧啶同类物16a-h。其中，DMDC以及2'-脱氧-2'-亚甲基-5-氟胞苷（19a）对培养的鼠L1210细胞显示出有效的抗白血病活性。还检查了与1-β-D-阿拉伯呋喃糖基胞嘧啶胞嘧啶和5-氟尿嘧啶相比，DMDC和19a对培养的各种人类肿瘤细胞的活性。还描述了DMDC对L1210的体内抗肿瘤活性。
• 2'-Methylidenepyrimidin nucleoside compounds, their use and method for production thereof.
  申请人：YOSHITOMI PHARMACEUTICAL INDUSTRIES, LTD.

  公开号：EP0360018A1

  公开（公告）日：1990-03-28

  2′-Methylidenepyrimidine nucleoside compounds of the general formula : wherein R¹ stands for amino or hydroxy group; R² stands for a halogen or a lower alkyl when R¹ is amino or R² stands for an alkyl having 2 to 4 carbon atoms, an alkynyl having 2 to 4 carbon atoms or a haloalkyl when R¹ is hydroxy group; and R³ stands for hydrogen or a phosphoric acid residue, or salts thereof, anticancer compositions containing one or more of these compounds and methods for production of these compounds. Said compounds and salts thereof exhibit noticeable antitumor activities and are useful as anticancers.

  通式为...的2′-亚甲基嘧啶核苷化合物 其中R¹代表氨基或羟基；当R¹为氨基时，R²代表卤素或低级烷基；当R¹为羟基时，R²代表具有2至4个碳原子的烷基、具有2至4个碳原子的炔基或卤代烷基；R³代表氢或磷酸残基，或其盐、含有一种或多种这些化合物的抗癌组合物以及生产这些化合物的方法。 上述化合物及其盐类具有明显的抗肿瘤活性，可用作抗癌剂。
• Pyrimidine 2'-methylidene nucleoside compounds
  申请人：YAMASA SHOYU CO., LTD.

  公开号：EP0373485A1

  公开（公告）日：1990-06-20

  Pyrimidine 2′-deoxy-2′-methylidene nucleoside compounds : wherein R¹ represents amino, hydroxy, silylamino, silyloxy, acylamino or acyloxy; R² represents hydrogen, halogen, a lower alkyl, a lower alkenyl, a lower alkynyl or haloalkyl; R³ and R⁴ represent the same or different hydrogen, silyl, acyl or aminoacyl, or a pharmaceutically acceptable salt or hydrate thereof, except that R¹ is amino or hydroxy, and both of R³ and R⁴ are hydrogen. Said compounds possess excellent antitumor and antiviral activities, thus providing novel anticancer and antiviral agent.

  嘧啶 2′-脱氧-2′-亚甲基核苷化合物 ： 其中，R¹代表氨基、羟基、水硅烷基、水硅烷氧基、酰氨基或酰氧基；R²代表氢、卤素、低级烷基、低级烯基、低级炔基或卤代烷基；R³和R⁴代表相同或不同的氢、水硅烷基、酰基或氨基酰基，或其药学上可接受的盐或水合物，但R¹为氨基或羟基，R³和R⁴均为氢。 上述化合物具有优异的抗肿瘤和抗病毒活性，从而提供了新型抗癌剂和抗病毒剂。
• 2'-Methylidenepyrimidine Nucleoside Compounds, their use and method for production thereof
  申请人：YOSHITOMI PHARMACEUTICAL INDUSTRIES, LTD.

  公开号：EP0566162A1

  公开（公告）日：1993-10-20

  2'-Methylidenepyrimidine nucleoside compounds of the general formula : wherein R¹ stands for amino or hydroxy group; R² stands for a halogen or a lower alkyl when R¹ is amino or R² stands for an alkyl having 2 to 4 carbon atoms, an alkynyl having 2 to 4 carbon atoms or a haloalkyl when R¹ is hydroxy group; and R³ stands for hydrogen or a phosphoric acid residue, or salts thereof, anticancer compositions containing one or more of these compounds and methods for production of these compounds. Said compounds and salts thereof exhibit noticeable antitumor activities and are useful as anticancers.

  通式为...的 2'-亚甲基嘧啶核苷化合物 其中R¹代表氨基或羟基；R²代表卤素或低级烷基（当R¹为氨基时），或R²代表具有2至4个碳原子的烷基、具有2至4个碳原子的炔基、或卤代烷基（当R¹为羟基时）；以及R³代表氢或磷酸残基，或它们的盐、含有一种或多种这些化合物的抗癌组合物以及生产这些化合物的方法。 上述化合物及其盐类具有明显的抗肿瘤活性，可用作抗癌剂。
• NOVEL 2'-METHYLIDENENUCLEOTIDE COMPOUND, PROCESS FOR PRODUCING THE SAME, AND PHARMACEUTICAL USE THEREOF
  申请人：Matsuda, Akira

  公开号：EP0690068A1

  公开（公告）日：1996-01-03

  A novel 2'-methylidenenucleotide compound represented by general formula (I) or a salt thereof, a process for producing the same, and a pharmaceutical use thereof. In said formula, R represents hydrogen or halogen; R¹ and R² represent each independently a fatty acid residue or a hydrocarbon residue; and R³ and R⁴ represent each independently hydrogen, halogen or alkyl. The compound and salts thereof have an excellent antitumor activity against mammals. More specifically, they have a remarkable activity of inhibiting growth of mouse tumors, cultured human tumor cells or human tumors transplanted to nude mice, and hence are efficacious in curing or inhibiting the recurrence of mammalian pulmonary cancer, digestive cancer, mamary cancer, head and neck cancers, gynecologic cancer, urologic cancer, leukemia, melanoma, lymphatic metastatic tumor, and so forth. Also they are useful as an antitumor drug because they have an increased bioavailability and are lowly toxic. Further they have the effects of persistent and increased activities.

  一种由通式(I)代表的新型 2'-亚甲基烯核苷酸化合物或其盐，一种生产该化合物的工艺及其药物用途。在所述式中，R 代表氢或卤素；R¹ 和 R² 各自独立地代表脂肪酸残基或烃残基；R³ 和 R⁴ 各自独立地代表氢、卤素或烷基。该化合物及其盐类对哺乳动物具有极佳的抗肿瘤活性。更具体地说，它们具有抑制小鼠肿瘤、培养的人类肿瘤细胞或移植到裸鼠身上的人类肿瘤生长的显著活性，因此在治疗或抑制哺乳动物肺癌、消化系统癌症、乳腺癌、头颈部癌症、妇科癌症、泌尿系统癌症、白血病、黑色素瘤、淋巴转移性肿瘤等方面具有疗效。此外，它们还可作为抗肿瘤药物，因为它们具有更高的生物利用度和低毒性。此外，它们还具有持续和增强活性的作用。