5,6-dichloro-2-isopropylamino-1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)benzimidazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 5,6-dichloro-2-isopropylamino-1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)benzimidazole
• 英文别名: 2-Isopropylamino-5,6-dichloro-1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)benzimidazole；(2R,3R,4R,5R)-5-[5,6-dichloro-2-(propan-2-ylamino)benzimidazol-1-yl]-4-fluoro-2-(hydroxymethyl)oxolan-3-ol
• 化学式: C₁₅H₁₈Cl₂FN₃O₃
• 分子量: 378.231
• InChiKey: AADWXNSPSUHKKF-AAVRWANBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  79.5
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2'-氟-2'-脱氧尿苷 在 吡啶 、 citrate buffer 、 N-溴代丁二酰亚胺(NBS) 、 N-deoxyribofuranosyl transferase 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 为溶剂， 反应 35.17h， 生成 5,6-dichloro-2-isopropylamino-1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)benzimidazole
  参考文献：
  名称：

  Synthesis of Fluorosugar Analogues of 2,5,6-Trichloro-1-(β-d-ribofuranosyl)benzimidazole as Antivirals with Potentially Increased Glycosidic Bond Stability

  摘要：

  The metabolic instability in vivo of the glycosidic bond of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) prompted us to design and synthesize the hitherto unreported fluorinated benzimidazole nucleosides 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole, 2,5,6-trichloro-1-(3-deoxy-3-fluoro-beta-D-ribofuranosyl)benzimidazole, and 2-bromo-5,6-dichloro-1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)benzimidazole. TCRB was converted into the 2',5'-ditrityl and 3'5'-dinitryl derivatives, which were fluorinated with DAST and deprotected to yield 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) and 2,5,6-trichloro-1(3-deoxy-3-fluoro-beta-D-xylofuranosyl)benzimidazole. The resulting low over yield (5%) of 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole encouraged us to develop an alternative route. The heterocycle 2,5,6-trichlorobenzimidazole was condensed with 1-bromo-3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose to give, after deprotection, 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole in a 50% overall yield. The 2'-deoxy-2'-fluoro-beta-D-ribofuranosyl compounds were prepared using 2'-deoxy-2'-fluorouridine, N-deoxyribofuranosyl transferase, and 5,6-dichlorobenzimidazole. Functionalization of the C2 position then gave the desired derivatives. Antiviral and cytotoxicity testing revealed that the deoxy fluoro arabinofuranosyl, xylofuranosyl, and ribofuranosyl derivatives were less active against human cytomegalovirus and more cytotoxic than TCRB.

  DOI：

  10.1021/jm990219s

文献信息

• MODIFIED BENZIMIDAZOLE NUCLEOSIDES AS ANTIVIRAL AGENTS
  申请人：THE REGENTS OF THE UNIVERSITY OF MICHIGAN

  公开号：EP1019425A1

  公开（公告）日：2000-07-19
• US5840743A
  申请人：——

  公开号：US5840743A

  公开（公告）日：1998-11-24
• [EN] MODIFIED BENZIMIDAZOLE NUCLEOSIDES AS ANTIVIRAL AGENTS<br/>[FR] NUCLEOSIDES DE BENZIMIDAZOLE MODIFIES UTILISES COMME AGENTS ANTIVIRAUX
  申请人：THE REGENTS OF THE UNIVERSITY OF MICHIGAN

  公开号：WO1997027204A1

  公开（公告）日：1997-07-31

  (EN) This invention pertains to nucleoside analogs which have antiviral activity and improved metabolic stability. More specifically, this invention pertains to modified sugar benzimidazole nucleosides, as exemplified by compounds such as benzimidazole nucleosides possessing a fluorinated sugar-like moiety (for example, a 2'-fluoro-furanosyl moiety or a 3'-fluoro-furanosyl moiety), and may be represented by formula (I) wherein R1 is a fluorinated sugar-like moiety; and R2, R4, R5, R6 and R7 are benzimidazole substituents, such as -H, halogens (e.g., -F, -C1, -Br, -I), -NO2, -NR2 (where R is independently -H or an alkyl group having 1-6 carbon atoms), -OR (where R is -H or an alkyl group having 1-6 carbon atoms), -SR (where R is -H or a hydrocarbyl of 1-10 carbon atoms), and -CF3. In one embodiment, R1 is 2'-fluoro-furanosyl or 3'-fluoro-furanosyl; R2 is -H, -F, -C1, -Br, -I, or -NR2, wherein R is independently -H or an alkyl group having 1-6 carbon atoms; R4, R5, R6 and R7 are independently -H, -F, -C1, -Br, or -I.(FR) L'invention concerne des analogues de nucléosides ayant une activité antivirale et une stabilité métabolique améliorée. Plus spécifiquement, elle concerne des nucléosides de benzimidazole à sucres modifiés, tels que des nucléosides de benzimidazole possédant une fraction de type sucre fluoré (par exemple, une fraction 2'-fluoro-furanosyle ou une fraction 3'-fluoro-furanosyle), qui peuvent être représentés par la formule suivante (I), où R1 est une fraction de type sucre fluoré; et R2, R3, R4 et R5 sont des substituants benzimidazole, tels que -H, halogènes (par exemple F, Cl, Br, I), NO2, NR2 (où R est indépendamment -H ou un groupe alkyle contenant 1 à 6 atomes de carbone), -OR (où R est -H ou un groupe alkyle contenant 1 à 6 atomes de carbone), SR (où R est -H ou hydrocarbyle contenant 1 à 10 atomes de carbone) et -CF3. Dans un mode de réalisation, R1 est 2'-fluoro-furanosyle ou 3'-fluoro-furanosyle; R2 est -H, -F, -Cl, -Br, -I ou -NR2, où R est indépendamment -H ou un groupe alkyle contenant 1 à 6 atomes de carbone; R4, R5, R6 et R7 sont indépendamment -H, -F, -Cl, -Br ou -I.
• Synthesis of Fluorosugar Analogues of 2,5,6-Trichloro-1-(β-<scp>d</scp>-ribofuranosyl)benzimidazole as Antivirals with Potentially Increased Glycosidic Bond Stability
  作者：Kristjan S. Gudmundsson、George A. Freeman、John C. Drach、Leroy B. Townsend

  DOI：10.1021/jm990219s

  日期：2000.6.1

  The metabolic instability in vivo of the glycosidic bond of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) prompted us to design and synthesize the hitherto unreported fluorinated benzimidazole nucleosides 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole, 2,5,6-trichloro-1-(3-deoxy-3-fluoro-beta-D-ribofuranosyl)benzimidazole, and 2-bromo-5,6-dichloro-1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)benzimidazole. TCRB was converted into the 2',5'-ditrityl and 3'5'-dinitryl derivatives, which were fluorinated with DAST and deprotected to yield 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) and 2,5,6-trichloro-1(3-deoxy-3-fluoro-beta-D-xylofuranosyl)benzimidazole. The resulting low over yield (5%) of 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole encouraged us to develop an alternative route. The heterocycle 2,5,6-trichlorobenzimidazole was condensed with 1-bromo-3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose to give, after deprotection, 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole in a 50% overall yield. The 2'-deoxy-2'-fluoro-beta-D-ribofuranosyl compounds were prepared using 2'-deoxy-2'-fluorouridine, N-deoxyribofuranosyl transferase, and 5,6-dichlorobenzimidazole. Functionalization of the C2 position then gave the desired derivatives. Antiviral and cytotoxicity testing revealed that the deoxy fluoro arabinofuranosyl, xylofuranosyl, and ribofuranosyl derivatives were less active against human cytomegalovirus and more cytotoxic than TCRB.