phenyl(methoxydimethylglycinyl) phosphorochloridate | 261909-35-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: phenyl(methoxydimethylglycinyl) phosphorochloridate
• 英文别名: phenyl (methyl 2-amino-2-methylpropanoate) phosphorochloridate；methyl 2-(chloro(phenoxy)phosphorylamino)-2-methylpropanoate；methyl 2-(chloro(phenoxy)phosphorylamino)-2-methylpropionate；Methyl 2-[[chloro(phenoxy)phosphoryl]amino]-2-methylpropanoate
• CAS: 261909-35-7
• 化学式: C₁₁H₁₅ClNO₄P
• 分子量: 291.671
• InChiKey: LSXKEJBWQUEBHF-UHFFFAOYSA-N

物化性质

• 沸点：
  362.2±44.0 °C(Predicted)
• 密度：
  1.282±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  阿巴卡韦 、 phenyl(methoxydimethylglycinyl) phosphorochloridate 在 叔丁基氯化镁 作用下， 以 四氢呋喃 为溶剂， 反应 96.0h， 以193.7 mg的产率得到methyl 2-[[[(1S,4R)-4-[2-amino-6-(cyclopropylamino)purin-9-yl]cyclopent-2-en-1-yl]methoxy-phenoxy-phosphoryl]amino]-2-methyl-propanoate
  参考文献：
  名称：

  Application of Phosphoramidate Pronucleotide Technology to Abacavir Leads to a Significant Enhancement of Antiviral Potency

  摘要：

  We report the first application of pronucleotide (ProTide) technology to the antiviral agent abacavir (Ziagen), used for the treatment of HIV infection. The phenylmethoxyalaninyl phosphoramidate of abacavir was prepared in good yield in one step. Also prepared was the corresponding phosphoramidate of the guanine nucleoside analogue "carbovir". The antiviral profile of each of the parent nucleosides was compared to that of the phosphoramidate ProTides. A significant (28- to 60-fold) increase in anti-HIV potency was noted for the ProTide of abacavir but not for that of carbovir. These findings were in agreement with the markedly higher (ca. 37-fold) levels of carbovir triphosphate that are formed in CEM cells upon response to the abacavir ProTide compared with the parent abacavir compound. In contrast the anti-HBV potency of both abacavir and carbovir were improved (10- and 20-fold, respectively) by ProTide formation. As in CEM cells, the abacavir ProTide provided significantly enhanced carbovir triphosphate levels in HepG2 2.2.15 cells over that of the parent nucleoside. On the basis of these data, a series of phosphoramidate analogues with structural variation in the ester and amino acid regions were prepared and their antiviral profiles described. In addition, the pharmacokinetic disposition of the abacavir phenylethoxyalaninyl phosphoramidate was evaluated in Cynomolgus monkeys.

  DOI：

  10.1021/jm0491400
• 作为产物：
  描述：

  2-氨基异丁酸甲酯盐酸盐 、 二氯磷酸苯酯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 phenyl(methoxydimethylglycinyl) phosphorochloridate
  参考文献：
  名称：

  氨基磷酸酯ProTide技术的应用显着提高了碳环腺苷衍生物的抗病毒效力。

  摘要：

  我们报告了氨基磷酸酯原核苷酸（ProTide）技术在抗病毒剂碳环L-d4A（L-Cd4A）中的应用。L-Cd4A的苯基甲基丙氨酸基母体ProTide是通过格利雅（Grignard）介导的磷酰氯反应制备的，得到的化合物具有显着改善的抗HIV（2600倍）和HBV活性。我们描述了ProTide的芳基，酯和氨基酸区域的修饰，以及这些变化如何影响抗病毒活性和代谢稳定性。注意到针对HIV和HBV的SAR分别且不同。另外，由D-核苷D-Cd4A和双脱氧类似物L-CddA和D-CddA制备ProTide。与母体药物相比，这些化合物显示出更适度的效能改善。综上所述，当将ProTide方法应用于L-Cd4A时，在体外的效价提高了9000倍，非常成功，抗HIV的能力提高了。为了临床前候选人的选择，我们使用食蟹猴肝脏和肠道S9馏分进行了代谢稳定性研究。

  DOI：

  10.1021/jm060776w

文献信息

• [EN] URACYL SPIROOXETANE NUCLEOSIDES<br/>[FR] NUCLÉOSIDES DE SPIROOXÉTANE D'URACILE
  申请人：CENTOCOR ORTHO BIOTECH PRODUCT

  公开号：WO2010130726A1

  公开（公告）日：2010-11-18

  Compounds of the formula (I) including any possible stereoisomers thereof, wherein: R4 is a monophosphate, diphosphate or triphosphate ester; or R4 is formula (II) or formula (III), R7 is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted indolyl; R8 and R8 are hydrogen, C1-C6alkyl, benzyl, or phenyl; or R8 and R8 form C3-C7cycloalkyl; R9 is C1-C10alkyl, C3-C7cycloalkyl, phenyl or phenyl-C1-C6alkyl, wherein the phenyl moiety in phenyl or phenyl-C1-C6alkyl is optionally substituted; or a pharmaceutically acceptable salt or solvate thereof; pharmaceutical formulations and the use of compounds I as HCV inhibitors.

  化合物的公式（I）及其可能的立体异构体，其中：R4是单磷酸酯、二磷酸酯或三磷酸酯；或R4是公式（II）或公式（III），R7是可选择取代的苯基、可选择取代的萘基或可选择取代的吲哚基；R8和R8是氢、C1-C6烷基、苄基或苯基；或R8和R8形成C3-C7环烷基；R9是C1-C10烷基、C3-C7环烷基、苯基或苯基-C1-C6烷基，其中苯基或苯基-C1-C6烷基中的苯基部分可选择取代；或其药学上可接受的盐或溶剂；药物配方和将化合物I用作HCV抑制剂。
• [EN] SPIROCYCLIC NUCLEOSIDE ANALOGUES FOR THE TREATMENT OF HEPATITIS E<br/>[FR] ANALOGUES NUCLÉOSIDIQUES SPIROCYCLIQUES POUR LE TRAITEMENT DE L'HÉPATITE E
  申请人：JANSSEN SCIENCES IRELAND UNLIMITED CO

  公开号：WO2021209427A1

  公开（公告）日：2021-10-21

  The present disclosure is directed toward spirocyclic nucleoside analogs, compositions comprising these compounds, and their use for treating hepatitis E infections.

  本公开涉及螺环核苷类似物、包含这些化合物的组合物，以及它们用于治疗甲型肝炎感染的用途。
• Uracyl Spirooxetane Nucleosides
  申请人：Jonckers Tim Hugo Maria

  公开号：US20120065156A1

  公开（公告）日：2012-03-15

  Compounds of the formula I: including any possible stereoisomers thereof, wherein: R 4 is a monophosphate, diphosphate or triphosphate ester; or R 4 is R 7 is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted indolyl; R 8 and R 8′ are hydrogen, C 1 -C 6 alkyl, benzyl, or phenyl; or R 8 and R 8′ form C 3 -C 7 cycloalkyl; R 9 is C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, phenyl or phenyl-C 1 -C 6 alkyl, wherein the phenyl moiety in phenyl or phenyl-C 1 -C 6 alkyl is optionally substituted; or a pharmaceutically acceptable salt or solvate thereof; pharmaceutical formulations and the use of compounds I as HCV inhibitors.

  化合物I的公式，包括其任何可能的立体异构体，其中： R4是单磷酸酯、二磷酸酯或三磷酸酯；或R4是R7，R7是可选取代的苯基、可选取代的萘基或可选取代的吲哚基； R8和R8'是氢、C1-C6烷基、苄基或苯基；或R8和R8'形成C3-C7环烷基； R9是C1-C10烷基、C3-C7环烷基、苯基或苯基-C1-C6烷基，其中苯基或苯基-C1-C6烷基中的苯基基团是可选的； 或其药学上可接受的盐或溶剂； 化合物I作为HCV抑制剂的药物配方和用途。
• Chemical compounds
  申请人：NuCana BioMed Limited

  公开号：EP2955190A2

  公开（公告）日：2015-12-16

  Phosphoramidate derivatives of nucleotides and their use in the treatment of cancer are described. The base moieties of, for example, each of deoxyuridine, cytarabine, gemcitabine and citidine may be substituted at the 5-position. The phosphoramidate moiety has attached to the P atom an aryl-O moiety and an α-amino acid moiety. The α-amino acid moiety may correspond to or be derived from either a naturally occurring or a non-naturally occurring amino acid.

  本文介绍了核苷酸的磷酰胺衍生物及其在治疗癌症中的应用。例如，脱氧尿苷、阿糖胞苷、吉西他滨和枸橼酸的碱基可在 5 位被取代。磷酰胺基团的 P 原子上连接有一个芳基-O 基团和一个α-氨基酸基团。α-氨基酸分子可以是天然氨基酸或非天然氨基酸，也可以来自天然氨基酸。
• CHEMICAL COMPOUNDS
  申请人：NuCana plc

  公开号：EP3486251A1

  公开（公告）日：2019-05-22

  Phosphoramidate derivatives of nucleotides and their use in the treatment of cancer are described. The base moieties of, for example, each of deoxyuridine, cytarabine, gemcitabine and citidine may be substituted at the 5-position. The phosphoramidate moiety has attached to the P atom an aryl-O moiety and an α-amino acid moiety. The α-amino acid moiety may correspond to or be derived from either a naturally occurring or a non-naturally occurring amino acid.

  本文介绍了核苷酸的磷酰胺衍生物及其在治疗癌症中的应用。例如，脱氧尿苷、阿糖胞苷、吉西他滨和枸橼酸的碱基可在 5 位被取代。磷酰胺基团的 P 原子上连接有一个芳基-O 基团和一个α-氨基酸基团。α-氨基酸分子可以是天然氨基酸或非天然氨基酸，也可以来自天然氨基酸。