5-Phenyl-6-oxa-12b-aza-naphtho[2,3-e]azulen-4-one | 177578-82-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: 5-Phenyl-6-oxa-12b-aza-naphtho[2,3-e]azulen-4-one
• 英文别名: 8-phenyl-9-oxa-2-azatetracyclo[8.8.0.02,6.012,17]octadeca-1(18),3,5,10,12,14,16-heptaen-7-one
• CAS: 177578-82-4
• 化学式: C₂₂H₁₅NO₂
• 分子量: 325.367
• InChiKey: QKIVMUINKRSFES-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  31.2
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  5-Phenyl-6-oxa-12b-aza-naphtho[2,3-e]azulen-4-one 、 二甲氨基甲酰氯 在 potassium hydride 作用下， 生成 PBOX-5
  参考文献：
  名称：

  吡咯并苯并氮杂庚因衍生物的合成，生物活性和SARs，是一类新的特定的“外围型”苯并二氮杂receptor受体配体。

  摘要：

  据报道，“外周型”苯二氮杂receptor受体（PBR）在许多生物学过程中起作用。为了提供新的受体配体，我们已经合成并测试了基于吡咯并苯并氮杂pine骨架的一系列PBR配体。这些新化合物中的几种被证明对PBR具有高亲和力和选择性配体，而苯并氮杂pine 17f和17j被认为是迄今为止对该受体最有效的配体。本文详述的SAR和分子模型研究描述了改善亲和力所需的许多结构特征。某些配体被用作“分子尺度”，以探究PBR裂隙中亲脂性口袋L1和L3的空间尺寸，并确定L1和L3的占领对亲和力的影响，而其他C-7修饰的类似物提供了有关与推定的受体位点H1进行氢键结合的专门信息。新的吡咯并苯并a庚因在大鼠皮层中进行了测试，该组织表达高密度的线粒体PBR，并通过[3H] PK 11195结合的位移测量，在低纳摩尔或亚纳摩尔范围内表现出IC50和Ki值。还发现最高亲和力配体的子集对大鼠肾上腺线粒体中的[3H] PK

  DOI：

  10.1021/jm960251b
• 作为产物：
  描述：

  3-氨基-2-萘酚 在 sodium hydroxide 、 五氯化磷 、 sodium hydride 、 溶剂黄146 作用下， 以 四氢呋喃 、 乙醇 、 1,2-二氯乙烷 为溶剂， 反应 27.5h， 生成 5-Phenyl-6-oxa-12b-aza-naphtho[2,3-e]azulen-4-one
  参考文献：
  名称：

  Pyrrolobenzothiazepinones and Pyrrolobenzoxazepinones:  Novel and Specific Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors with Antiviral Activity

  摘要：

  Two novel classes of pyrrolobenzothiazepinones and pyrrolobenzoxazepinones were investigated as potential anti-AIDS drugs. These compounds were found to inhibit HIV-1 reverse transcriptase (RT) enzyme in vitro and to prevent HIV-1 cytopathogenicity in T4 lymphocytes, without appreciable activity on HIV-2 cytopathic effects, and against HBV as well as calf-thymus DNA alpha-polymerase. Their potency is influenced by substituents at position 6 and on the fused aromatic ring. Specifically, small lipophilic substituents at C-6 were preferred, whereas substitutions on the benzo-fused ring were found to be detrimental to activity, with respect to the unsubstituted compounds. Modification of the pi-system at C-6 is well tolerated, although the replacement of the benzo-fused with a [2,3]naphtho-fused ring leads to a less active compound. Maximum potency and specificity is achieved with a phenyl and an ethyl group at position 6 of the pyrrolobenzoxazepinone system. In the enzymatic assay the oxazepinone derivative (+/-)-6-ethyl-6-phenylpyrrolo[2,1-d][1,5] 16e (IC50 = 0.25 mu M) was found to be more potent than nevirapine (IC50 = 0.5 mu M), tested in the same experimental conditions using rC . dG as a template-primer. In cell culture assay benzoxazepine 16e was active against HIV-1, both wild type and AZT-sensitive, and HIV-1 (IIIB) strains, but not against HIV-2. In enzyme assay although 16e inhibited HIV-1 RT, it was inactive against the nevirapine-resistant recombinant RT Y181C at 50 mu M. Molecular modeling studies suggest that these derivatives present a 3D pharmacophoric arrangement similar to that of other nonnucleoside inhibitors such as nevirapine.

  DOI：

  10.1021/jm950702c

文献信息

• Synthesis, Biological Activity, and SARs of Pyrrolobenzoxazepine Derivatives, a New Class of Specific “Peripheral-Type” Benzodiazepine Receptor Ligands
  作者：Giuseppe Campiani、Vito Nacci、Isabella Fiorini、Maria P. De Filippis、Antonio Garofalo、Silvia M. Ciani、Giovanni Greco、Ettore Novellino、D. Clive Williams、Daniela M. Zisterer、Margaret J. Woods、Camelia Mihai、Cristina Manzoni、Tiziana Mennini

  DOI：10.1021/jm960251b

  日期：1996.1.1

  affinity, while other C-7 modified analogues provided information specifically on the hydrogen bonding with a putative receptor site H1. The new pyrrolobenzoxazepines were tested in rat cortex, a tissue expressing high density of mitochondrial PBR, and exhibited IC50 and Ki values in the low nanomolar or subnanomolar range, as measured by the displacement of [3H]PK 11195 binding. A subset of the highest

  据报道，“外周型”苯二氮杂receptor受体（PBR）在许多生物学过程中起作用。为了提供新的受体配体，我们已经合成并测试了基于吡咯并苯并氮杂pine骨架的一系列PBR配体。这些新化合物中的几种被证明对PBR具有高亲和力和选择性配体，而苯并氮杂pine 17f和17j被认为是迄今为止对该受体最有效的配体。本文详述的SAR和分子模型研究描述了改善亲和力所需的许多结构特征。某些配体被用作“分子尺度”，以探究PBR裂隙中亲脂性口袋L1和L3的空间尺寸，并确定L1和L3的占领对亲和力的影响，而其他C-7修饰的类似物提供了有关与推定的受体位点H1进行氢键结合的专门信息。新的吡咯并苯并a庚因在大鼠皮层中进行了测试，该组织表达高密度的线粒体PBR，并通过[3H] PK 11195结合的位移测量，在低纳摩尔或亚纳摩尔范围内表现出IC50和Ki值。还发现最高亲和力配体的子集对大鼠肾上腺线粒体中的[3H] PK
• Pyrrolobenzothiazepinones and Pyrrolobenzoxazepinones:  Novel and Specific Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors with Antiviral Activity
  作者：Giuseppe Campiani、Vito Nacci、Isabella Fiorini、Maria P. De Filippis、Antonio Garofalo、Giovanni Greco、Ettore Novellino、Sergio Altamura、Laura Di Renzo

  DOI：10.1021/jm950702c

  日期：1996.1.1

  Two novel classes of pyrrolobenzothiazepinones and pyrrolobenzoxazepinones were investigated as potential anti-AIDS drugs. These compounds were found to inhibit HIV-1 reverse transcriptase (RT) enzyme in vitro and to prevent HIV-1 cytopathogenicity in T4 lymphocytes, without appreciable activity on HIV-2 cytopathic effects, and against HBV as well as calf-thymus DNA alpha-polymerase. Their potency is influenced by substituents at position 6 and on the fused aromatic ring. Specifically, small lipophilic substituents at C-6 were preferred, whereas substitutions on the benzo-fused ring were found to be detrimental to activity, with respect to the unsubstituted compounds. Modification of the pi-system at C-6 is well tolerated, although the replacement of the benzo-fused with a [2,3]naphtho-fused ring leads to a less active compound. Maximum potency and specificity is achieved with a phenyl and an ethyl group at position 6 of the pyrrolobenzoxazepinone system. In the enzymatic assay the oxazepinone derivative (+/-)-6-ethyl-6-phenylpyrrolo[2,1-d][1,5] 16e (IC50 = 0.25 mu M) was found to be more potent than nevirapine (IC50 = 0.5 mu M), tested in the same experimental conditions using rC . dG as a template-primer. In cell culture assay benzoxazepine 16e was active against HIV-1, both wild type and AZT-sensitive, and HIV-1 (IIIB) strains, but not against HIV-2. In enzyme assay although 16e inhibited HIV-1 RT, it was inactive against the nevirapine-resistant recombinant RT Y181C at 50 mu M. Molecular modeling studies suggest that these derivatives present a 3D pharmacophoric arrangement similar to that of other nonnucleoside inhibitors such as nevirapine.