3-(2-脱氧-beta-D-赤式-呋喃戊糖基)-6-(4-戊基苯基)呋喃并[2,3-d]嘧啶-2(3H)-酮 5'-L-缬氨酸酯 | 956483-02-6

• 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
• 中文名称: 3-(2-脱氧-beta-D-赤式-呋喃戊糖基)-6-(4-戊基苯基)呋喃并[2,3-d]嘧啶-2(3H)-酮 5'-L-缬氨酸酯
• 中文别名: 3-(2-脱氧-beta-D-赤式-呋喃戊糖基)-6-(4-戊基苯基)呋喃并[2,3-d]嘧啶-2(3H)-酮5'-L-缬氨酸酯；3-(2-脱氧-BETA-D-赤式-呋喃戊糖基)-6-(4-戊基苯基)呋喃并[2,3-D]嘧啶-2(3H)-酮5'-L-缬氨酸酯
• 英文名称: FV-100
• 英文别名: 3-(2'-deoxy-5'-valyl-β-D-ribofuranosyl)-6-(p-pentylphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one；(S)-((2R,3S,5R)-(3-hydroxy-5-(2-oxo-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-3(2H)-yl)-tetrahvdrofuran-2-yl))methyl 2-amino-3-methylbutanoate；Valnivudine；[(2R,3S,5R)-3-hydroxy-5-[2-oxo-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-3-yl]oxolan-2-yl]methyl (2S)-2-amino-3-methylbutanoate
• CAS: 956483-02-6
• 化学式: C₂₇H₃₅N₃O₆
• 分子量: 497.591
• InChiKey: FJRRWJMFUNGZBJ-RBVMOCNTSA-N

物化性质

• 沸点：
  667.3±65.0 °C(Predicted)
• 密度：
  1.33±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  124
• 氢给体数：
  2
• 氢受体数：
  7

制备方法与用途

valnivudine（FV-100自由基）是CF-1743的前药，是一种口服有效的抗带状疱疹(HZ)核苷类似物。CF-1743是一种双环核苷类似物(BCNA)，对水痘带状疱疹病毒(VZV)具有高度特异性的抗病毒活性。在体内，valnivudine能够迅速广泛地转化为CF-1743。

反应信息

• 作为反应物：
  描述：

  3-(2-脱氧-beta-D-赤式-呋喃戊糖基)-6-(4-戊基苯基)呋喃并[2,3-d]嘧啶-2(3H)-酮 5'-L-缬氨酸酯 以Quant.的产率得到(S)-((2R,3S,5R)-(3-hydroxy-5-(2-oxo-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-3(2H)-yl)-tetrahydrofuran-2-yl))methyl 2-amino-3-methylbutanoate hydrochloride
  参考文献：
  名称：

  ANTI-VIRAL PYRIMIDINE NUCLEOSIDE DERIVATIVES

  摘要：

  一种用于治疗或预防病毒感染的化合物，例如由水痘-带状疱疹病毒引起的水痘或带状疱疹，所述化合物具有通式（II）：其中X为O、S、NH或CH2，Y为O、S或NH，Z为O、S或CH2，R1为C1-6烷基，优选为正烷基，如正戊基或正己基，且R2和R3中的一个为OH，另一个为中性、非极性氨基酸基团，或其药学上可接受的盐或水合物。所述中性、非极性氨基酸基团R2或R3可以是（IV）：其中R4、R5、R6和R7各自独立地为H或C1-2烷基。在优选实施例中，R2或R3中的一个为缬氨酸、亮氨酸、异亮氨酸或丙氨酸，特别是缬氨酸。

  公开号：

  US20150072948A1
• 作为产物：
  描述：

  (S)-((2R,3S,5R)-3-(2-chloroacetoxy)-5-(2-oxo-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-3(2H)-yl)-tetrahydrofuran-2-yl)methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methylbutanoate 在 sodium carbonate 、 硫脲 、 哌啶 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 4.0h， 生成 3-(2-脱氧-beta-D-赤式-呋喃戊糖基)-6-(4-戊基苯基)呋喃并[2,3-d]嘧啶-2(3H)-酮 5'-L-缬氨酸酯
  参考文献：
  名称：

  [EN] METHOD OF PREPARATION OF ANTIVIRAL COMPOUNDS AND USEFUL INTERMEDIATES THEREOF
  [FR] PROCÉDÉ DE PRÉPARATION DE COMPOSÉS ANTIVIRAUX ET INTERMÉDIAIRES UTILES DE CEUX-CI

  摘要：

  公开号：

  WO2012048202A3

文献信息

• COMPOSITIONS FOR THE TREATMENT OR PROPHYLAXIS OF VIRAL INFECTIONS
  申请人：Balzarini Jan

  公开号：US20100256087A1

  公开（公告）日：2010-10-07

  A compound of the general formula (III): wherein X is O, S, NH or CH 2 ; Y is O, S or NH; Z is O, S or CH 2 ; R 1 is C 1-8 alkyl, especially C 1-6 alkyl, preferably n-alkyl, e.g., n-pentyl or n-hexyl; at least one of R 2 and R 3 is H—[R 4 -R 5 ] n —R 6 —, in which: H—[R 4 -R 5 ] n — comprises an oligopeptide, R 4 being an amino acid and R 5 being an amino acid selected from proline, alanine, hydroxyproline, dihydroxyproline, thiazolidinecarboxylic acid (thioproline), dehydroproline, pipecolic acid (L-homoproline), azetidinecarboxylic acid, aziridinecarboxylic acid, glycine, serine, valine, leucine, isoleucine and threonine, R 6 is a neutral, non-polar amino acid moiety that is bonded to R 5 by a peptide bond, and n is 1, 2, 3, 4 or 5; and the other of R 3 and R 2 is H—[R 4 -R 5 ]n-R 6 — or H; or a pharmaceutically acceptable salt thereof.

  通式（III）的化合物：其中X为O、S、NH或CH2；Y为O、S或NH；Z为O、S或CH2；R1为C1-8烷基，特别是C1-6烷基，最好是n-烷基，例如n-戊基或n-己基；R2和R3中至少一个为H—[R4-R5]n—R6—，其中：H—[R4-R5]n—包括寡肽，R4为氨基酸，R5为从脯氨酸、丙氨酸、羟脯氨酸、二羟脯氨酸、噻唑烷羧酸（硫代脯氨酸）、去氢脯氨酸、吡咯烷羧酸（L-异脯氨酸）、氮杂环丙氨酸、氮杂环丙氨酸、甘氨酸、丝氨酸、缬氨酸、亮氨酸、异亮氨酸和苏氨酸中选择的氨基酸，R6是通过肽键与R5结合的中性、非极性氨基酸基团，n为1、2、3、4或5；R3和R2中的另一个为H—[R4-R5]n-R6—或H；或其药学上可接受的盐。
• Dipeptidyl Peptidase IV Dependent Water-Soluble Prodrugs of Highly Lipophilic Bicyclic Nucleoside Analogues
  作者：Alberto Diez-Torrubia、Jan Balzarini、Graciela Andrei、Robert Snoeck、Ingrid De Meester、María-José Camarasa、Sonsoles Velázquez

  DOI：10.1021/jm101624e

  日期：2011.3.24

  upon selective conversion by purified DPPIV/CD26 and by soluble DPPIV/CD26 present in bovine, murine, and human serum. Vildagliptin, a specific inhibitor of DPPIV/CD26, was able to completely block the hydrolysis of the prodrugs in the presence of purified DPPIV/CD26 human, murine, and bovine serum. Several novel prodrugs showed remarkable increases in water solubility (up to more than 3 orders of magnitude)

  我们提出基于二肽基肽酶IV（DPPIV / CD26）的前药方法在含羟基药物衍生物中的首次报道。特别是，我们将此策略应用于双环呋喃并嘧啶核苷类似物（BCNA）的高度亲脂性抗病毒药物家族，以改善其理化和药代动力学特性。我们的稳定性数据表明，通过纯化的DPPIV / CD26和存在于牛，鼠和人血清中的可溶性DPPIV / CD26的选择性转化，前药可有效释放母体BCNA药物。维达列汀，一种DPPIV / CD26的特异性抑制剂，在纯化的DPPIV / CD26人，鼠和牛血清的存在下能够完全阻断前药的水解。与难溶性母体药物相比，几种新颖的前药显示出水溶性的显着提高（最高超过3个数量级）。我们还证明了与小鼠母体药物相比，前药的口服生物利用度显着提高。
• Anti-viral pyrimidine nucleoside analogues
  申请人：——

  公开号：US20030148967A1

  公开（公告）日：2003-08-07

  A compound having the formula (I) wherein Ar is an, optionally substituted, aromatic ring system, the aromatic ring system comprising one six-membered aromatic ring or two fused six-membered aromatic rings; R 8 and R 9 are each independently selected form the group comprising hydrogen, alkyl, cycloalkyl, halogens, amino, alkylamino, dialkylamino, nitro, cyano, alkyoxy, aryloxy, thiol, alkylthiol, arythiol, aryl; Q is selected from the group comprising O, S and CY 2 , where Y may be the same or different and is selected from H, alkyl and halogens; X is selected from the group comprising O, NH, S, N-alkyl, (CH 2 ) m where m is 1 to 10, and CY 2 where Y may be the same or different and is selected from hydrogen, alkyl and halogens; Z is selected from the group comprising O, S, NH, and N-alkyl; U″ is H and U′ is selected from H and CH 2 T, or U′ and U″ are joined so as to form a ring moiety including Q wherein U′—U″ together is respectively selected from the group comprising —CTH—CT′T″- and —CT=CT- and —CT′=CT′-, so as to provide ring moieties selected from the group comprising (a), (b) wherein: T is selected from the group comprising OH, H, halogens, O-alkyl, O-acyl, O-aryl, CN, NH 2 and N 3 ; T′ is selected from the group comprising H and halogens and, where more than one T′ is present, they may be the same or different; T″ is selected from the group comprising H and halogens; and W is selected from the group comprising H, a phosphate group and a pharmacologically acceptable salt, derivative or pro-drug thereof; with the proviso that when T is OAc and T′ and T″ are present and are H, Ar is not 4-(2-benzoxazolyl)phenyl. C 1 to C 10 alkyl and alkoxy substituents on the aromatic ring system of Ar are preferred. Compounds show anti-viral activity, for example with respect to varicella zoster virus.

  一种化合物的化学式为（I），其中Ar是一个可选择取代的芳香环系统，该芳香环系统包括一个六元芳香环或两个融合的六元芳香环；R8和R9各自独立地选自羟基，烷基，环烷基，卤素，氨基，烷基氨基，二烷基氨基，硝基，氰基，烷氧基，芳基氧基，硫醇，烷硫基，芳硫基，芳基；Q选自O，S和CY2的群，其中Y可以相同或不同，选自氢，烷基和卤素；X选自O，NH，S，N-烷基，（CH2）m，其中m为1到10，以及CY2，其中Y可以相同或不同，选自氢，烷基和卤素；Z选自O，S，NH和N-烷基；U″为H，U′选自H和CH2T，或U′和U″结合形成包括Q的环基，其中U′—U″分别选自—CTH—CT′T″-和—CT=CT-和—CT′=CT′-，从而提供选自（a），（b）的环基，其中：T选自OH，H，卤素，O-烷基，O-酰基，O-芳基，CN，NH2和N3；T′选自H和卤素，当存在多个T′时，它们可以相同或不同；T″选自H和卤素；W选自H，磷酸盐基团和药理学上可接受的盐，衍生物或前药；但是，当T为OAc且T′和T″存在且为H时，Ar不是4-（2-苯并噻唑基）苯基。偏好在Ar的芳香环系统上具有C1到C10的烷基和烷氧基取代基。该化合物表现出抗病毒活性，例如对带状疱疹病毒的活性。
• Method of Preparation of Antiviral Compounds and Useful Intermediates Thereof
  申请人：Wang Yanling

  公开号：US20130331561A1

  公开（公告）日：2013-12-12

  The invention is directed to processes for synthesizing bicyclic nucleoside antiviral compounds and for synthesizing the intermediates used in the process. The invention is also directed to novel intermediate compounds useful in the process. The anti-viral compounds are useful in the treatment of herpes zoster (i.e., varicella zoster virus, VZV, shingles) and for the prevention of post herpetic neuralgia (PHN) resulting from this viral infection.

  该发明涉及合成双环核苷类抗病毒化合物的过程以及用于该过程的中间体的合成。该发明还涉及在该过程中有用的新型中间体化合物。这些抗病毒化合物可用于治疗带状疱疹（即水痘-带状疱疹病毒，VZV，带状疱疹）并预防由该病毒感染引起的后遗神经痛（PHN）。
• Method of preparation of antiviral compounds and useful intermediates thereof
  申请人：Wang Yanling

  公开号：US09260469B2

  公开（公告）日：2016-02-16

  The invention is directed to processes for synthesizing bicyclic nucleoside antiviral compounds and for synthesizing the intermediates used in the process. The invention is also directed to novel intermediate compounds useful in the process. The antiviral compounds are useful in the treatment of herpes zoster (i.e., varicella zoster virus, VZV, shingles) and for the prevention of post herpetic neuralgia (PHN) resulting from this viral infection.

  本发明涉及合成双环核苷类抗病毒化合物的过程，以及用于该过程的中间体的合成。本发明还涉及在该过程中有用的新型中间体化合物。这些抗病毒化合物可用于治疗带状疱疹（即水痘带状疱疹病毒，VZV，带状疱疹）并预防由该病毒感染引起的后遗神经痛（PHN）。