4-amino-5-hydroxy-1-isobutyl-2-[5-(2-phosphono)furanyl]benzimidazole | 213197-94-5

• 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: 4-amino-5-hydroxy-1-isobutyl-2-[5-(2-phosphono)furanyl]benzimidazole
• 英文别名: 5-(4-amino-5-hydroxy-1-isobutyl-1H-benzo[d]imidazol-2-yl)furan-2-ylphosphonic acid；[5-[4-amino-5-hydroxy-1-(2-methylpropyl)benzimidazol-2-yl]furan-2-yl]phosphonic acid
• CAS: 213197-94-5
• 化学式: C₁₅H₁₈N₃O₅P
• 分子量: 351.299
• InChiKey: FJALYWCEZCEUMO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  135
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  diethyl [5-(1-isobutyl-4-amino-5-methoxy-1H-benzoimidazol-2-yl)-furan-2-yl]-phosphonate 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以12%的产率得到4-amino-5-hydroxy-1-isobutyl-2-[5-(2-phosphono)furanyl]benzimidazole
  参考文献：
  名称：

  Fructose-1,6-bisphosphatase Inhibitors. 2. Design, Synthesis, and Structure−Activity Relationship of a Series of Phosphonic Acid Containing Benzimidazoles that Function as 5′-Adenosinemonophosphate (AMP) Mimics

  摘要：

  Efforts to enhance the inhibitory potency of the initial purine series of fructose-1,6-bisphosphatase (FBPase) inhibitors led to the discovery of it series of benzirniclazole analogues with hurnan FBPase IC50S < 100 nM. I nhibitor 4.4 emerged as a lead compound based on its potent inhibition of hurnan liver FBPase (IC5() = 55 ilM) and significant glucose lowering in nornial fasted rats. Intravenous administration of 4.4 to Zucker diabetic fatty rats led to rapid and robust glucose lowering, thereby providing the first evidence that FBPase inhibitors could improve glycernia in animal models of type 2 diabetes.

  DOI：

  10.1021/jm901420x

文献信息

• Benzimidazole inhibitors of fructose 1,6-biphosphatase
  申请人：Metabasis Therapeutics, Inc.

  公开号：EP1402895A1

  公开（公告）日：2004-03-31

  Novel benzimidazole compounds of structure (1) and their use as fructose-1,6-bisphosphatase inhibitors is described wherein A, E, and L are selected from the group consisting of -NR82, -NO2, -H, -OR7, -SR7, -C(O)NR42, halo, -COR11, -SO2R3, guanidine, amidine, -NHSO2R5, -SO2NR42, -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloakolxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A and L form a cyclic group, or together L and E form a cyclic group, or together E and J from a cyclic group including aryl, cyclic alkyl, and heterocyclic; J is selected from the group consiting -NR82, -NO2, -H, -OR7, -SR7, -C(O)NR42, halo, -C(O)R11, -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl, and aralkyl, or together with Y forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl; X is selected from the group consisting of alkylamino, alkyl(hydroxy), alkyl(carboxyl), alky(phosphonate), alkyl, alkenyl, alkynyl, alkyl(sulfonate), aryl, carbonylalkyl, 1,1-dihaloalkyl, aminocarbonylamino, alkylaminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylthio, alkylaminocarbonyl, alkylcarbonylamino, alicyclic, aralkyl, and alkylaryl, all optionally substituted; or together with Y form a cyclic group including aryl, cyclic alkyl, and heterocyclic; Y is selected from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C(O)R3, -S(O)2,R3, -C(O)-R11, -CONHR3, -NR22, and-OR3, all except H are optionally substituted; or together with X form a cyclic group including aryl, cyclic alkyl, and heterocyclic; and pharmaceutically acceptable prodrugs and salts thereof.

  描述了结构(1)的新型苯并咪唑化合物及其作为果糖-1,6-二磷酸酶抑制剂的用途，其中A、E和L选自由-NR82、-NO2、-H、-OR7、-SR7、-C(O)NR42、卤素、-COR11、-SO2R3、胍、脒、-NHSO2R5、-SO2NR42、-CN、亚砜、全卤酰基、全卤烷基、全卤醇基、C1-C5 烷基、C2-C5 烯基、C2-C5 炔基和低级脂环族，或 A 和 L 共同组成一个环状基团，或 L 和 E 共同组成一个环状基团，或 E 和 J 共同组成一个包括芳基、环状烷基和杂环在内的环状基团；J选自由-NR82、- 、-H、-OR7、-SR7、-C(O)NR42、卤代、-C(O)R11、-CN、磺酰基、亚砜、全卤烷基、羟基烷基、全卤烷氧基、烷基、卤代烷基、氨基烷基、烯基、炔基、脂环基、芳基和芳烷基组成的基团，或与Y一起形成包括芳基、环烷基和杂环烷基在内的环状基团；X 选自烷基氨基、烷基（羟基）、烷基（羧基）、烷基（膦酸盐）、烷基、 烯基、炔基、烷基（磺酸盐）、芳基、羰基烷基、1,1-二卤代烷基、氨基羰基氨基、烷基氨基烷基、烷氧基烷基、烷硫基烷基、烷硫基、烷基氨基羰基、烷基羰基氨基、脂环族、芳基和烷芳基，均可选择被取代；或与 Y 一起形成环状基团，包括芳基、环烷基和杂环基；Y 选自-H、烷基、烯基、炔基、芳基、脂环族、芳烷基、芳氧基烷基、烷氧基烷基、-C(O)R3、-S(O)2,R3、-C(O)-R11、-CONHR3、-NR22 和-OR3 组成的组，除 H 外，所有均被任选取代；或与 X 一起形成一个环状基团，包括芳基、环烷基和杂环基；及其药学上可接受的原药和盐。
• NOVEL BENZIMIDAZOLE INHIBITORS OF FRUCTOSE-1,6-BISPHOSPHATASE
  申请人：Metabasis Therapeutics, Inc.

  公开号：EP0970095B1

  公开（公告）日：2003-10-29
• US6110903A
  申请人：——

  公开号：US6110903A

  公开（公告）日：2000-08-29
• US6399782B1
  申请人：——

  公开号：US6399782B1

  公开（公告）日：2002-06-04
• [EN] NOVEL BENZIMIDAZOLE INHIBITORS OF FRUCTOSE-1,6-BISPHOSPHATASE<br/>[FR] NOUVEAUX INHIBITEURS DE BENZIMIDAZOLE DE FRUCTOSE-1,6-BISPHOSPHATASE
  申请人：——

  公开号：WO1998039343A1

  公开（公告）日：1998-09-11

  [EN] Novel benzimidazole compounds of structure (1) and their use as fructose-1,6-bisphosphatase inhibitors is described wherein A, E, and L are selected from the group consisting of -NR<8>2, -NO2, -H, -OR<7>, -SR<7>, -C(O)NR<4>2, halo, -COR<11>, -SO2R<3>, guanidine, amidine, -NHSO2R<5>, -SO2NR<4>2, -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloakolxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A and L form a cyclic group, or together L and E form a cyclic group, or together E and J form a cyclic group including aryl, cyclic alkyl, and heterocyclic; J is selected from the group consisting -NR<8>2, -NO2, -H, -OR<7>, -SR<7>, -C(O)NR<4>2, halo, -C(O)R<11>, -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl, and aralkyl, or together with Y forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl; X is selected from the group consisting of alkylamino, alkyl(hydroxy), alkyl(carboxyl), alkyl(phosphonate), alkyl, alkenyl, alkynyl, alkyl(sulfonate), aryl, carbonylalkyl, 1,1-dihaloalkyl, aminocarbonylamino, alkylaminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylthio, alkylaminocarbonyl, alkylcarbonylamino, alicyclic, aralkyl, and alkylaryl, all optionally substituted; or together with Y form a cyclic group including aryl, cyclic alkyl, and heterocyclic; Y is selected from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C(O)R<3>, -S(O)2R<3>, -C(O)-R<11>, -CONHR<3>, -NR<2>2, and -OR<3>, all except H are optionally substituted; or together with X form a cyclic group including aryl, cyclic alkyl, and heterocyclic; and pharmaceutically acceptable prodrugs and salts thereof.
  [FR] L'invention concerne de nouveaux composés de benzimidazole de structure (1), ainsi que leur utilisation en tant qu'inhibiteurs de fructose-1,6-bisphosphatase: dans laquelle: A, E et L sont choisis dans le groupe composé de -NR<8>2, -NO2, -H, -OR<7>, -SR<7>, -C(O)NR<4>2, halo, -COR<11>, -SO2R<3>, guanidine, amidine, -NHSO2R<5>, -SO2NR<4>2, -CN, sulfoxyde, perhaloacyle, perhaloalkyle, perhaloalkoxy, alkyle en C1-C5, alkényle en C2-C5, alkynyle en C2-C5, et alicyclique inférieur; ou A et L forment un groupe cyclique, ou L et E forment un groupe cyclique, ou E et J forment un groupe cyclique renfermant aryle, alkyle cyclique, et hétérocyclique; J est choisi dans le groupe composé de -NR<8>2, -NO2, -H, -OR<7>, -SR<7>, -C(O)NR<4>2, halo, -C(O)R<11>, -CN, sulfuryle, sulfoxyde, perhaloalkyle, hydroxyalkyle, perhaloalkoxy, alkyle, haloalkyle, aminoalkyle, alkényle, alkynyle, alicyclique, aryle, et aralkyle, ou forme avec Y un groupe cyclique renfermant aryle, alkyle cyclique et alkyle hétérocyclique; X est choisi dans le groupe composé de alkylamino, alkylehydroxy), alkyle(carboxyle), alkyle(phosphonate), alkyle, alkényle, alkynyle, alkyle(sulfonate), aryle, carbonylalkyle, 1,1-dihaloalkyle, aminocarbonylamino, alkylaminoalkyle, alkoxyalkyle, alkylthioalkyle, alkylthio, alkylaminocarbonyle, alkylcarbonylamino, alicyclique, aralkyle, et alkylaryle, tous éventuellement substitués, ou forme avec Y un groupe cyclique renfermant aryle, alkyle cyclique, et hétérocyclique; Y est choisi dans le groupe composé de -H, alkyle, alkényle, alkynyle, aryle, alicyclique, aralkyle, aryloxyalkyle, alkoxyalkyle, -C(O)R<3>, -S(O)2R<3>, -C(O)R<11>, -CONHR<3>, -NR<2>2, et -OR<3>, tous sauf H étant éventuellement substitués, ou forme avec X un groupe cyclique renfermant aryle, alkyle cyclique, et hétérocyclique. L'invention concerne également les promédicaments pharmaceutiquement acceptables et les sels de ces composés.