环庚三烯并[b]吡喃-2(5H)-酮,6,7,8,9-四氢-4-羟基- | 102654-30-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 中文名称: 环庚三烯并[b]吡喃-2(5H)-酮,6,7,8,9-四氢-4-羟基-
• 英文名称: 6,7,8,9-Tetrahydro-4-hydroxycycloheptapyran-2(5H)-on
• 英文别名: 4-Hydroxy-5,6-pentandiyl-2H-pyran-2-on；4-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyran-2-one；4-Hydroxcyclohepta-2-pyron；4-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyran-2-one
• CAS: 102654-30-8
• 化学式: C₁₀H₁₂O₃
• 分子量: 180.203
• InChiKey: ZZZWCTDUVJKZGU-UHFFFAOYSA-N

物化性质

• 熔点：
  181-183 °C
• 沸点：
  343.9±42.0 °C(Predicted)
• 密度：
  1.25±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  环庚三烯并[b]吡喃-2(5H)-酮,6,7,8,9-四氢-4-羟基- 在 potassium tert-butylate 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.5h， 生成 2,5-Dioxo-(2H,5H)-cycloheptapyrano<2,3-c>pyran-3-carbonsaeureethylester
  参考文献：
  名称：

  Eine breit anwendbare Synthese fluoreszierender kondensierter ?-Pyrone

  摘要：

  DOI：

  10.1007/bf00938720
• 作为产物：
  描述：

  环庚烯-1-氧基(三甲基)硅烷 、 丙二酰氯 以 乙醚 为溶剂， 反应 2.0h， 以85%的产率得到环庚三烯并[b]吡喃-2(5H)-酮,6,7,8,9-四氢-4-羟基-
  参考文献：
  名称：

  Effenberger, Franz; Ziegler, Thomas; Schoenwaelder, Karl-Heinz, Chemische Berichte, 1986, vol. 119, # 11, p. 3394 - 3404

  摘要：

  DOI：

文献信息

• Structure-Based Design of Nonpeptidic HIV Protease Inhibitors:  The Sulfonamide-Substituted Cyclooctylpyranones
  作者：Harvey I. Skulnick、Paul D. Johnson、Paul A. Aristoff、Jeanette K. Morris、Kristine D. Lovasz、W. Jeffrey Howe、Keith D. Watenpaugh、Musiri N. Janakiraman、David J. Anderson、Robert J. Reischer、Theresa M. Schwartz、Lee S. Banitt、Paul K. Tomich、Janet C. Lynn、Miao-Miao Horng、Kong-Teck Chong、Roger R. Hinshaw、Lester A. Dolak、Eric P. Seest、Francis J. Schwende、Bob D. Rush、Gina M. Howard、Lisa N. Toth、Karen R. Wilkinson、Thomas J. Kakuk、Carol W. Johnson、Serena L. Cole、Renee M. Zaya、Gail L. Zipp、Peggy L. Possert、Robert J. Dalga、Wei-Zhu Zhong、Marta G. Williams、Karen R. Romines

  DOI：10.1021/jm960441m

  日期：1997.3.1

  substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a

  最近，具有间甲酰胺取代基（例如2c）的环辛基吡喃酮衍生物被确定为有效的非肽类HIV蛋白酶抑制剂，但这些化合物在细胞培养中缺乏显着的抗病毒活性。然而，在间位取代磺酰胺基团会产生具有出色的HIV蛋白酶结合亲和力和抗病毒活性的化合物。在基于迭代结构的药物设计过程的指导下，我们已经准备并评估了许多此类衍生物，这些衍生物可通过七步合成轻松获得。进一步评估了一些最有效的化合物在大鼠和狗中的药代动力学和毒性等特性。通过这项工作，对氰基苯基磺酰胺衍生物35k成为有前途的抑制剂，被选择用于进一步开发，并进入了I期临床试验。
• Cycloalkylpyranones and Cycloalkyldihydropyrones as HIV Protease Inhibitors:  Exploring the Impact of Ring Size on Structure−Activity Relationships
  作者：Karen R. Romines、Jeanette K. Morris、W. Jeffrey Howe、Paul K. Tomich、Miao-Miao Horng、Kong-Teck Chong、Roger R. Hinshaw、David J. Anderson、Joseph W. Strohbach、Steve R. Turner、Steve A. Mizsak

  DOI：10.1021/jm960296c

  日期：1996.1.1

  3-(1-phenylpropyl) derivatives with various cycloalkyl ring sizes, the cyclooctyl analog was the most potent. We became interested in exploring the influence of other structural changes, such as substitution on the phenyl ring and saturation of the 5,6-double bond, on the cycloalkyl ring size structure-activity relationship (SAR). Saturation of the 5,6-double bond in the pyrone ring significantly impacts the SAR

  以前，已证明3-取代的环烷基吡喃酮，例如2d，是HIV蛋白酶的有效抑制剂。在具有各种环烷基环大小的3-（1-苯基丙基）衍生物的初始系列中，环辛基类似物是最有效的。我们开始研究其他结构变化的影响，例如对苯环的取代和5,6-双键的饱和度对环烷基环尺寸结构-活性关系（SAR）的影响。吡喃环中的5,6-双键饱和会严重影响SAR，从而将最佳环的大小从八改变为六。在苯环的间位取代磺酰胺可显着提高这些抑制剂的效能，但无论在环烷基吡喃酮或环烷基二氢吡喃酮系列中，都不会改变最佳的环大小。这项工作已导致鉴定出对HIV蛋白酶具有极佳结合亲和力的化合物（Ki值在10-50 pM范围内）。此外，环烷基二氢吡喃酮类在细胞培养中显示出优异的抗病毒活性，ED50值低至1 microM。
• Effenberger, Franz; Ziegler, Thomas, Chemische Berichte, 1987, vol. 120, p. 1339 - 1346
  作者：Effenberger, Franz、Ziegler, Thomas

  DOI：——

  日期：——
• Use of Medium-Sized Cycloalkyl Rings To Enhance Secondary Binding: Discovery of a New Class of Human Immunodeficiency Virus (HIV) Protease Inhibitors
  作者：Karen R. Romines、Keith D. Watenpaugh、Paul K. Tomich、W. Jeffrey Howe、Jeanette K. Morris、Kristine D. Lovasz、Anne M. Mulichak、Barry C. Finzel、Janet C. Lynn

  DOI：10.1021/jm00011a008

  日期：1995.5

  A unique strategy for the enhancement of secondary binding of an inhibitor to an enzyme has been demonstrated in the design of new human immunodeficiency virus (HIV) protease inhibitors. When the planar benzene ring of a 4-hydroxycoumarin lead compound (1a, K-1 = 0.800 mu M) was replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl rings, the enzyme inhibitory activity of the resulting compounds was dramatically improved, and inhibitors with more than 50-fold better binding (e.g., 5d, K-i = 0.015 mu M) were obtained. X-ray crystal structures of these inhibitors complexed with HIV protease indicated the cycloalkyl rings were able to fold into the S1' pocket of the enzyme and fill it much more effectively than the rigid benzene ring of the 4-hydroxycoumarin compound. This work has resulted in the identification of a promising lead structure for the design of potent, deliverable HIV protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life (4.9 h), and ease of synthesis (three steps).
• WOLFBEIS O. S.; ZIEGLER E.; KNIERZINGER A.; WIPFLER H.; TRUMMER I., MONATSH. CHEM., 1980, 111, NO 1, 93-112
  作者：WOLFBEIS O. S.、 ZIEGLER E.、 KNIERZINGER A.、 WIPFLER H.、 TRUMMER I.

  DOI：——

  日期：——