N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide | 1619884-67-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide
• 英文别名: N-(3,4-dichlorophenyl)-1-methylindazole-5-carboxamide
• CAS: 1619884-67-1
• 化学式: C₁₅H₁₁Cl₂N₃O
• 分子量: 320.178
• InChiKey: OIDIFCINLNNUKU-UHFFFAOYSA-N

物化性质

• 沸点：
  404.0±40.0 °C(Predicted)
• 密度：
  1.43±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  46.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  1-甲基-1H-吲唑-5-羧酸 、 3,4-二氯苯胺 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 甲醇 为溶剂， 生成 N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide
  参考文献：
  名称：

  甲酰胺与甲胺的关系：（吲唑-5-基）甲胺作为单胺氧化酶B和乙酰胆碱酯酶抑制剂的晶体结构，结合相互作用，光物理研究和生物学评估

  摘要：

  首次进行了一项综合研究，比较了两种与结构相关的物质类别，即吲唑-5-甲酰胺（11 – 16）和（吲唑-5-基）甲亚胺（17 – 22）。这两种化学实体都是有效的，选择性的和可逆的MAO-B抑制剂，因此，可作为开发针对帕金森氏病（PD）和其他神经系统疾病的候选药物的有前途的先导结构。化合物15（K i  = 170 pM，SI = 25907）和17（K i = 270 pM，SI = 16340）是这两个系列中最有效和最具选择性的MAO-B抑制剂。为了研究多靶标抑制活性，进一步筛选了所有化合物对人AChE和BuChE酶的效力。发现化合物15是所有系列中最有效和最具选择性的AChE抑制剂（h AChE IC 50  = 78.3±1.7μM）。而且，如初步细胞毒性筛选所确定的，化合物11和17没有药物引起的肝毒性的风险，并且具有更宽的安全范围。由HYDE分析支持的对人MAO-B酶结合位点的分

  DOI：

  10.1016/j.ejmech.2019.06.041

文献信息

• Crystal structures, binding interactions, and ADME evaluation of brain penetrant N -substituted indazole-5-carboxamides as subnanomolar, selective monoamine oxidase B and dual MAO-A/B inhibitors
  作者：Nikolay T. Tzvetkov、Hans-Georg Stammler、Beate Neumann、Silvia Hristova、Liudmil Antonov、Marcus Gastreich

  DOI：10.1016/j.ejmech.2017.01.011

  日期：2017.2

  N-alkyl-substituted indazole-5-carboxamides, developed as potential drug and radioligand candidates for the treatment and diagnosis of Parkinson's disease (PD) and other neurological disorders, is reported. Recent efforts have been focused on the development of subnanomolar potent, selective MAO-B (N1-alkyl-substituted compounds 12a–14a and 15) and dual active MAO-A/B (N2-methylated compounds 12b–14b) inhibitors

  据报道，对结构优化的N-烷基取代的吲唑-5-羧酰胺类进行了药理和理化分析，已开发出其作为治疗和诊断帕金森氏病（PD）和其他神经系统疾病的潜在药物和放射性配体候选物。最近的努力集中在开发具有纳摩尔浓度的亚纳摩尔有效的选择性MAO-B（N1-烷基取代的化合物12a - 14a和15）和双活性MAO-A / B（N2-甲基化的化合物12b - 14b）抑制剂，具有纳摩尔浓度。分别对MAO-B和MAO-A酶有中等活性。两个系列中最有前途的类药物衍生物是N-（3-氯-4-氟苯基）-1-甲基-1 H-吲唑-5-羧酰胺（13a，NTZ-1441，IC 50 hMAO-B 0.662 nM，相对于MAO-A选择性> 15000倍）和N -（3-氯-4-氟苯基）-2-甲基-2 H-吲唑-5-甲酰胺（13b，NTZ-1442，IC 50 hMAO-B 8.08 nM，IC 50 hMAO-A 0.56μM，SI
• [EN] SUBSTITUTED INDAZOLE OR INDOLE DERIVATIVES AS IN VITRO MAO-B INHIBITORS<br/>[FR] DÉRIVÉS D'INDAZOLE OU D'INDOLE SUBSTITUÉS EN TANT QU'INHIBITEURS DE MAO-B IN VITRO
  申请人：NTZ LAB LTD

  公开号：WO2014107771A1

  公开（公告）日：2014-07-17

  Substituted indazole or imidazole derivatives of formula I as in vitro selective and reversible MAO-B inhibitors and for use in the prevention and treatment of meurodegenerative disorders such as Parkinson's disease, Alzheimer's disase and dementia

  I式中取代的吲唑或咪唑衍生物可作为体外选择性和可逆的MAO-B抑制剂，并用于预防和治疗神经退行性疾病，如帕金森病、阿尔茨海默病和痴呆症。
• SUBSTITUTED INDAZOLE DERIVATIVES AS IN VITRO MAO-B INHIBITORS
  申请人："NTZ LAB" LTD.

  公开号：US20150353504A1

  公开（公告）日：2015-12-10

  Substituted indazole or imidazole derivatives of formula I as in vitro selective and reversible MAO-B inhibitors and for use in the prevention and treatment of meurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and dementia

  公式I中的替代吲唑或咪唑衍生物可作为体外选择性和可逆的MAO-B抑制剂，并用于预防和治疗神经退行性疾病，如帕金森病、阿尔茨海默病和痴呆症。
• Indazole- and Indole-5-carboxamides: Selective and Reversible Monoamine Oxidase B Inhibitors with Subnanomolar Potency
  作者：Nikolay T. Tzvetkov、Sonja Hinz、Petra Küppers、Marcus Gastreich、Christa E. Müller

  DOI：10.1021/jm500729a

  日期：2014.8.14

  Indazole- and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were N-(3,4-dichlorophenyl)-1-methyl-1H-indazole-5-carboxamide (38a, PSB-1491, IC50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (53, PSB-1410, IC50 human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (E)-N-(3,4-dichlorophenyl)-1-(1H-indazol-5-yl)methanimine (58) represents a further novel class of highly potent and selective MAO-B inhibitors (IC50 human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In N-(3,4-difluorophenyl-1H-indazole-5-carboxamide (30, PSB-1434, IC50 human MAO-B 1.59 nM, selectivity versus MAO-A>6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors' interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size.
• SUBSTITUTED INDAZOLE OR INDOLE DERIVATIVES AS IN VITRO MAO-B INHIBITORS
  申请人："NTZ Lab" Ltd.

  公开号：EP2964219B1

  公开（公告）日：2017-05-03