3-(cyclopropylphenylmethyl)-6,7,8,9-tetrahydro-4-hydroxycycloheptapyran-2(5H)-one | 163020-91-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 环庚吡喃类
• 英文名称: 3-(cyclopropylphenylmethyl)-6,7,8,9-tetrahydro-4-hydroxycycloheptapyran-2(5H)-one
• 英文别名: 3-(cyclopropylphenylmethyl)-6,7,8,9-tetrahydro-4-hydroxycyclohepta[b]pyran-2(5H)-one；3-[cyclopropyl(phenyl)methyl]-4-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyran-2-one
• CAS: 163020-91-5
• 化学式: C₂₀H₂₂O₃
• 分子量: 310.393
• InChiKey: ZSSAOBZTABFHRA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 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：

  3-(cyclopropylphenylmethyl)-6,7,8,9-tetrahydro-4-hydroxycycloheptapyran-2(5H)-one 、 alkaline earth salt of/the/ methylsulfuric acid 在 lithium diisopropyl amide 作用下， 生成 9-Cyclopropylmethyl-3-(cyclopropyl-phenyl-methyl)-4-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyran-2-one
  参考文献：
  名称：

  Structure-Based Design of Nonpeptidic HIV Protease Inhibitors from a Cyclooctylpyranone Lead Structure

  摘要：

  Recently, the novel cyclooctylpyranone HIV protease inhibitor 1 was identified in our labs, and an X-ray structure of this inhibitor complexed with HIV-2 protease was obtained. This crystal structure was used to develop two strategies for creating derivatives of 1 with enhanced enzyme inhibitory activity. The first strategy, substitution on the cyclooctyl ring, met with limited success, but provided some interesting information about the conformationally-flexible cyclooctyl ring on the inhibitors. The second strategy, substitution at the meta position of the aryl ring, was far more successful and generated compounds, such as the carboxamide derivatives 41 (K-i = 3.0 +/- 0.4 nM) and 36 (K-i = 4.0 +/- 0.8 nM), which were significantly more active than the corresponding unsubstituted cyclooctylpyranone 2 (K-i = 11.7 +/- 4.7 nM). An X-ray crystal structure of 36 complexed with HIV-1 protease indicated the increase in binding affinity is most likely due to the additional interactions between the amide substituent and the S3 region of the protease.

  DOI：

  10.1021/jm00022a011
• 作为产物：
  描述：

  环庚三烯并[b]吡喃-2(5H)-酮,6,7,8,9-四氢-4-羟基- 、 环丙基苯基碳酸酯 在 3 A molecular sieve 、 对甲苯磺酸 作用下， 以 甲苯 为溶剂， 反应 7.0h， 以69%的产率得到3-(cyclopropylphenylmethyl)-6,7,8,9-tetrahydro-4-hydroxycycloheptapyran-2(5H)-one
  参考文献：
  名称：

  Use of Medium-Sized Cycloalkyl Rings To Enhance Secondary Binding: Discovery of a New Class of Human Immunodeficiency Virus (HIV) Protease Inhibitors

  摘要：

  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).

  DOI：

  10.1021/jm00011a008

文献信息

• 4-HYDROXY-BENZOPYRAN-2-ONES AND 4-HYDROXY-CYCLOALKYL B]PYRAN-2-ONES USEFUL TO TREAT RETROVIRAL INFECTIONS
  申请人：THE UPJOHN COMPANY

  公开号：EP0682663A1

  公开（公告）日：1995-11-22
• [EN] 4-HYDROXY-BENZOPYRAN-2-ONES AND 4-HYDROXY-CYCLOALKYL[B]PYRAN-2-ONES USEFUL TO TREAT RETROVIRAL INFECTIONS<br/>[FR] 4-HYDROXY-BENZOPYRANE-2-ONES ET 4-HYDROXY-CYCLOALKYLE-[B]PYRANE-2-ONES UTILES POUR LE TRAITEMENT DES INFECTIONS RETROVIRALES
  申请人：THE UPJOHN COMPANY

  公开号：WO1994018188A1

  公开（公告）日：1994-08-18

  (EN) The present invention relates to compounds of formula (I) which are 4-hydroxy-benzopyran-2-ones and 4-hydroxy-cycloalkyl[b]pyran-2-ones useful for inhibiting a retrovirus in a mammalian cell infected with said retrovirus. In formula (I) R10 and R20 taken together are formula (II) or formula (III).(FR) Composés de la formule (I) correspondant à des 4-hydroxy-benzopyrane-2-ones et à des 4-hydroxy-cycloalkyle[b]pyrane-2-ones employés pour l'inhibition d'un rétrovirus dans une cellule de mammifère infectée par ledit rétrovirus. Dans la formule (I) R10 et R20 considérés ensemble sont (II) ou (III).
• Structure-Based Design of Nonpeptidic HIV Protease Inhibitors from a Cyclooctylpyranone Lead Structure
  作者：Karen R. Romines、Keith D. Watenpaugh、W. Jeffrey Howe、Paul K. Tomich、Kristine D. Lovasz、Jeanette K. Morris、Musiri N. Janakiraman、Janet C. Lynn、Miao-Miao Horng

  DOI：10.1021/jm00022a011

  日期：1995.10

  Recently, the novel cyclooctylpyranone HIV protease inhibitor 1 was identified in our labs, and an X-ray structure of this inhibitor complexed with HIV-2 protease was obtained. This crystal structure was used to develop two strategies for creating derivatives of 1 with enhanced enzyme inhibitory activity. The first strategy, substitution on the cyclooctyl ring, met with limited success, but provided some interesting information about the conformationally-flexible cyclooctyl ring on the inhibitors. The second strategy, substitution at the meta position of the aryl ring, was far more successful and generated compounds, such as the carboxamide derivatives 41 (K-i = 3.0 +/- 0.4 nM) and 36 (K-i = 4.0 +/- 0.8 nM), which were significantly more active than the corresponding unsubstituted cyclooctylpyranone 2 (K-i = 11.7 +/- 4.7 nM). An X-ray crystal structure of 36 complexed with HIV-1 protease indicated the increase in binding affinity is most likely due to the additional interactions between the amide substituent and the S3 region of the protease.
• 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).