benzyl 5-[[(4S,6R)-2,2-dimethyl-6-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxan-4-yl]methoxy]-1-(4-fluorophenyl)-4-propan-2-ylpyrazole-3-carboxylate | 906645-40-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: benzyl 5-[[(4S,6R)-2,2-dimethyl-6-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxan-4-yl]methoxy]-1-(4-fluorophenyl)-4-propan-2-ylpyrazole-3-carboxylate
• CAS: 906645-40-7
• 化学式: C₃₃H₄₁FN₂O₇
• 分子量: 596.696
• InChiKey: VGSAYSGYJVYAPC-FTJBHMTQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  43
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  98.1
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  benzyl 5-[[(4S,6R)-2,2-dimethyl-6-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxan-4-yl]methoxy]-1-(4-fluorophenyl)-4-propan-2-ylpyrazole-3-carboxylate 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 以95%的产率得到5-[[(4S,6R)-2,2-dimethyl-6-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxan-4-yl]methoxy]-1-(4-fluorophenyl)-4-propan-2-ylpyrazole-3-carboxylic acid
  参考文献：
  名称：

  Pyrazole inhibitors of HMG-CoA reductase: An attempt to dramatically reduce synthetic complexity through minimal analog re-design

  摘要：

  An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.08.004
• 作为产物：
  描述：

  、 (4R-Cis)-6-羟甲基-2,2-二甲基-1,3-二氧六环-4-乙酸叔丁酯 在 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 为溶剂， 以88%的产率得到benzyl 5-[[(4S,6R)-2,2-dimethyl-6-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxan-4-yl]methoxy]-1-(4-fluorophenyl)-4-propan-2-ylpyrazole-3-carboxylate
  参考文献：
  名称：

  Pyrazole inhibitors of HMG-CoA reductase: An attempt to dramatically reduce synthetic complexity through minimal analog re-design

  摘要：

  An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.08.004

文献信息

• [EN] OXYPYRAZOLE HMG Co-A REDUCTASE INHIBITORS<br/>[FR] INHIBITEURS OXYPYRAZOLE DE L'ENZYME HMG CO-A REDUCTASE
  申请人：WARNER LAMBERT CO

  公开号：WO2006087630A2

  公开（公告）日：2006-08-24

  [EN] Novel compounds and pharmaceutical compositions useful as hypocholesterolemic and hypolipidemic agents are described. More specifically, potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase ("HMG CoA reductase") are described. Method of using such compounds and compositions to treat subjects, including humans, suffering from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, benign prostatic hypertrophy (BPH), diabetes and osteoporosis are also described.
  [FR] L'invention concerne de nouveaux composés et de nouvelles compositions pharmaceutiques qui peuvent servir d'agents hypocholestérolémiants et hypolipidémiants. Cette invention se rapporte de manière plus spécifique à des inhibiteurs puissants de l'enzyme 3-hydroxy-3-méthylglutaryl-coenzyme A réductase ( HMG CoA réductase ). La présente invention concerne par ailleurs des procédés d'utilisation de ces composés et de ces compositions pour traiter des sujets, y compris des êtres humains souffrant d'hyperlipidémie, d'hypercholestérolémie, d'hypertriglycéridémie, d'athérosclérose, de la maladie d'Alzheimer, d'une hypertrophie prostatique bénigne (BPH), de diabète, et d'ostéoporose.
• Pyrazole inhibitors of HMG-CoA reductase: An attempt to dramatically reduce synthetic complexity through minimal analog re-design
  作者：Scott D. Larsen、Toni-Jo Poel、Kevin J. Filipski、Jeffrey T. Kohrt、Jeffrey A. Pfefferkorn、Roderick J. Sorenson、Bradley D. Tait、Valerie Askew、Lisa Dillon、Jeffrey C. Hanselman、Gina H. Lu、Andrew Robertson、Catherine Sekerke、Mark C. Kowala、Bruce J. Auerbach

  DOI：10.1016/j.bmcl.2007.08.004

  日期：2007.10

  An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity. (c) 2007 Elsevier Ltd. All rights reserved.