3,4-dihydroisoquinolin-4-ol-3-spirocyclohexane N-oxide | 184376-07-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氢异喹啉
• 英文名称: 3,4-dihydroisoquinolin-4-ol-3-spirocyclohexane N-oxide
• 英文别名: 2-oxidospiro[4H-isoquinolin-2-ium-3,1'-cyclohexane]-4-ol
• CAS: 184376-07-6
• 化学式: C₁₄H₁₇NO₂
• 分子量: 231.294
• InChiKey: WEOPEQDYGKXYHA-UHFFFAOYSA-N

物化性质

• 沸点：
  430.8±55.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  17
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  49
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3,4-dihydroisoquinolin-4-ol-3-spirocyclohexane N-oxide 在 草酰氯 、 二甲基亚砜 作用下， 以 二氯甲烷 为溶剂， 反应 0.25h， 以74%的产率得到3,4-dihydro-3H-isoquinolin-4-one-3-spirocyclohexane N-oxide
  参考文献：
  名称：

  Cyclic Nitrone Free Radical Traps:  Isolation, Identification, and Synthesis of 3,3-Dimethyl-3,4-dihydroisoquinolin-4-ol N-Oxide, a Metabolite with Reduced Side Effects

  摘要：

  A C-4 hydroxylated metabolite (2, 3,3-dimethyl-3,4-dihydroisoquinolin-4-ol N-oxide) of the previously described cyclic nitrone free radical trap 1 (3,3-dimethyl-3, 4-dihydroisoquinoline N-oxide, a cyclic analog of phenyl-tert-butylnitrone (PBN)) was isolated, identified, and synthesized. The metabolite (2), though a less potent antioxidant than 1 in an in vitro lipid peroxidation assay, showed greatly reduced acute toxicity and sedative properties. Several analogs of 2 were prepared in attempts to improve on its weak antioxidant activity while retaining the desirable side effect profile. Effective structural changes included replacement of the gem-dimethyl moiety with spirocycloalkane groups and/or oxidation of the alcohols to the corresponding ketones. All of the analogs were more lipophilic (log K'(w)) and more active in the standard lipid peroxidation assay than 2. In addition, some of the compounds were able to protect cerebellar granule cells against oxidative damage (an in vitro model of oxidative brain injury) with IC50 values well below the value of the lead compound 1. The ketones, as predicted, were much more potent than 2 (and 1) in both of the above assays (up to ca. 200-fold). However, only compounds with a hydroxyl or an acetate group at C-4 displayed significantly reduced acute toxicity and sedative properties relative to those of 1. Importantly, the diminishment of toxicity and sedation were not the result of a lack of brain penetration as both 2 and the corresponding ketone (3,3-dimethyl-3,4-dihydro-3H-isoquinolin-4-one N-oxide) achieved equal or greater brain levels than those of 1 when administered to rats ip.

  DOI：

  10.1021/jm960244n
• 作为产物：
  描述：

  硝基环己烷 在 盐酸 、 Oxone 、 aluminum amalgam 、 水 、 sodium methylate 、 potassium carbonate 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 甲苯 为溶剂， 反应 36.25h， 生成 3,4-dihydroisoquinolin-4-ol-3-spirocyclohexane N-oxide
  参考文献：
  名称：

  Cyclic Nitrone Free Radical Traps:  Isolation, Identification, and Synthesis of 3,3-Dimethyl-3,4-dihydroisoquinolin-4-ol N-Oxide, a Metabolite with Reduced Side Effects

  摘要：

  A C-4 hydroxylated metabolite (2, 3,3-dimethyl-3,4-dihydroisoquinolin-4-ol N-oxide) of the previously described cyclic nitrone free radical trap 1 (3,3-dimethyl-3, 4-dihydroisoquinoline N-oxide, a cyclic analog of phenyl-tert-butylnitrone (PBN)) was isolated, identified, and synthesized. The metabolite (2), though a less potent antioxidant than 1 in an in vitro lipid peroxidation assay, showed greatly reduced acute toxicity and sedative properties. Several analogs of 2 were prepared in attempts to improve on its weak antioxidant activity while retaining the desirable side effect profile. Effective structural changes included replacement of the gem-dimethyl moiety with spirocycloalkane groups and/or oxidation of the alcohols to the corresponding ketones. All of the analogs were more lipophilic (log K'(w)) and more active in the standard lipid peroxidation assay than 2. In addition, some of the compounds were able to protect cerebellar granule cells against oxidative damage (an in vitro model of oxidative brain injury) with IC50 values well below the value of the lead compound 1. The ketones, as predicted, were much more potent than 2 (and 1) in both of the above assays (up to ca. 200-fold). However, only compounds with a hydroxyl or an acetate group at C-4 displayed significantly reduced acute toxicity and sedative properties relative to those of 1. Importantly, the diminishment of toxicity and sedation were not the result of a lack of brain penetration as both 2 and the corresponding ketone (3,3-dimethyl-3,4-dihydro-3H-isoquinolin-4-one N-oxide) achieved equal or greater brain levels than those of 1 when administered to rats ip.

  DOI：

  10.1021/jm960244n

文献信息

• Cyclic Nitrone Free Radical Traps:  Isolation, Identification, and Synthesis of 3,3-Dimethyl-3,4-dihydroisoquinolin-4-ol <i>N</i>-Oxide, a Metabolite with Reduced Side Effects
  作者：Craig E. Thomas、Patrick Bernardelli、S. Marc Bowen、Stephen F. Chaney、Dirk Friedrich、David A. Janowick、Bryan K. Jones、Frederick J. Keeley、John H. Kehne、Bert Ketteler、David F. Ohlweiler、Leo A. Paquette、David J. Robke、Thomas L. Fevig

  DOI：10.1021/jm960244n

  日期：1996.1.1

  A C-4 hydroxylated metabolite (2, 3,3-dimethyl-3,4-dihydroisoquinolin-4-ol N-oxide) of the previously described cyclic nitrone free radical trap 1 (3,3-dimethyl-3, 4-dihydroisoquinoline N-oxide, a cyclic analog of phenyl-tert-butylnitrone (PBN)) was isolated, identified, and synthesized. The metabolite (2), though a less potent antioxidant than 1 in an in vitro lipid peroxidation assay, showed greatly reduced acute toxicity and sedative properties. Several analogs of 2 were prepared in attempts to improve on its weak antioxidant activity while retaining the desirable side effect profile. Effective structural changes included replacement of the gem-dimethyl moiety with spirocycloalkane groups and/or oxidation of the alcohols to the corresponding ketones. All of the analogs were more lipophilic (log K'(w)) and more active in the standard lipid peroxidation assay than 2. In addition, some of the compounds were able to protect cerebellar granule cells against oxidative damage (an in vitro model of oxidative brain injury) with IC50 values well below the value of the lead compound 1. The ketones, as predicted, were much more potent than 2 (and 1) in both of the above assays (up to ca. 200-fold). However, only compounds with a hydroxyl or an acetate group at C-4 displayed significantly reduced acute toxicity and sedative properties relative to those of 1. Importantly, the diminishment of toxicity and sedation were not the result of a lack of brain penetration as both 2 and the corresponding ketone (3,3-dimethyl-3,4-dihydro-3H-isoquinolin-4-one N-oxide) achieved equal or greater brain levels than those of 1 when administered to rats ip.