3-nitro-5-(trifluoromethyl)benzohydrazide | 22227-34-5

• 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: 3-nitro-5-(trifluoromethyl)benzohydrazide
• 英文别名: 3-Nitro-5-trifluoromethyl-benzoic acid hydrazide
• CAS: 22227-34-5
• 化学式: C₈H₆F₃N₃O₃
• 分子量: 249.149
• InChiKey: VXKMHWFQNXKKGE-UHFFFAOYSA-N

物化性质

• 密度：
  1.535±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-nitro-5-(trifluoromethyl)benzohydrazide 在 palladium on activated charcoal 、 氢气 、 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 25.0 ℃ 、241.32 kPa 条件下， 反应 26.0h， 生成 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide
  参考文献：
  名称：

  [EN] PYRIDINE DERIVATIVES AS REARRANGED DURING TRANSFECTION (RET) KINASE INHIBITORS
  [FR] DÉRIVÉS PYRIDINE UTILISÉS COMME INHIBITEURS DE LA KINASE RÉARRANGÉE AU COURS DE LA TRANSFECTION (RET)

  摘要：

  这项发明涉及一种新型化合物，它们是重排基因转位（RET）激酶的抑制剂，包括含有它们的药物组合物，它们的制备方法，以及它们在治疗中的使用，单独或结合使用，用于规范胃肠敏感性、蠕动和/或分泌以及/或腹部紊乱或疾病的治疗，或与与RET功能障碍相关的疾病相关的治疗，或者调节RET活性可能具有治疗益处的治疗，包括但不限于所有分类的肠易激综合征（IBS），包括以腹泻为主、以便秘为主或交替排便模式、功能性腹胀、功能性便秘、功能性腹泻、未特指的功能性肠道障碍、功能性腹痛综合征、慢性特发性便秘、功能性食管障碍、功能性胃十二指肠障碍、功能性肛门疼痛、炎症性肠病、非小细胞肺癌、肝细胞癌、结肠癌、髓样甲状腺癌、滤泡性甲状腺癌、间变性甲状腺癌、乳头状甲状腺癌、脑肿瘤、腹腔癌、实体肿瘤、其他肺癌、头颈癌、神经胶质瘤、神经母细胞瘤、冯·希普-林道综合征和肾肿瘤、乳腺癌、输卵管癌、卵巢癌、移行细胞癌、前列腺癌、食管和胃食管交界处癌症、胆道癌、腺癌，以及任何具有增加RET激酶活性的恶性肿瘤。

  公开号：

  WO2014141187A1
• 作为产物：
  描述：

  3-三氟甲基苯甲酸 在 硫酸 、 硝酸 、 一水合肼 作用下， 以 乙醇 为溶剂， 反应 53.0h， 生成 3-nitro-5-(trifluoromethyl)benzohydrazide
  参考文献：
  名称：

  S-取代的3,5-二硝基苯基1,3,4-恶二唑-2-硫醇和四唑-5-硫醇作为高效的抗结核药

  摘要：

  两类新的抗结核药，即5-烷基硫烷基-1-（3,5-二硝基苯基）-1 H-四唑和2-烷基硫烷基-5-（3,5-二硝基苯基）-1,3,4-恶二唑，和描述了它们的结构-活性关系。这些化合物对结核分枝杆菌具有出色的活性，包括临床分离的多药（MDR）和广泛耐药性（XDR）菌株，与一线或二线抗结核药物无交叉耐药性。最有前途的化合物的最小抑菌浓度（MIC）值达到0.03μM。此外，这些化合物具有高度选择性的抗分枝杆菌作用，因为它们对4克阳性和4克阴性细菌以及8种真菌菌株完全没有活性，并且体外活性低对四种哺乳动物细胞系（包括肝细胞系HepG2和HuH7）具有毒性。尽管结构-活性关系研究表明，两个硝基的存在对分枝杆菌的活性非常有利，但具有三氟甲基而不是硝基之一的类似物仍具有很高的分枝杆菌活性，这表明进一步优化结构的可能性这类抗结核药。

  DOI：

  10.1016/j.ejmech.2016.11.041

文献信息

• Discovery of a First-in-Class Gut-Restricted RET Kinase Inhibitor as a Clinical Candidate for the Treatment of IBS
  作者：Hilary Schenck Eidam、John Russell、Kaushik Raha、Michael DeMartino、Donghui Qin、Huiping Amy Guan、Zhiliu Zhang、Gong Zhen、Haiyu Yu、Chengde Wu、Yan Pan、Gerard Joberty、Nico Zinn、Sylvie Laquerre、Sharon Robinson、Angela White、Amanda Giddings、Ehsan Mohammadi、Beverly Greenwood-Van Meerveld、Allen Oliff、Sanjay Kumar、Mui Cheung

  DOI：10.1021/acsmedchemlett.8b00035

  日期：2018.7.12

  to the discovery of a first-in-class, gut-restricted RET kinase inhibitor, 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (15, GSK3179106), as a clinical candidate for the treatment of IBS. GSK3179106 is a potent, selective, and gut-restricted pyridone hinge binder small molecule RET kinase inhibitor with a RET IC50 of

  腹痛和排便习惯异常是肠易激综合症（IBS）患者治疗不当的主要症状。尽管IBS的病因尚不完全清楚，但胃肠道（GI）的许多功能是由肠神经系统（ENS）调节的。炎症或应激诱导的生长因子或细胞因子的表达可能导致胃肠道内脏传入神经元过度神经支配，并有助于IBS的病理生理。转染（RET）期间重新排列的神经元生长因子受体酪氨酸激酶对ENS的发展至关重要，例如Hirschsprung患者携带RET功能丧失突变且缺乏正常的结肠神经支配导致结肠梗阻。相似地，成人ENS中的RET信号通过促进突触形成，信号传递和神经元可塑性来维持神经元功能。ENS中RET的抑制代表了一种新的神经元功能和IBS患者症状正常化的治疗策略。本文中，我们描述了我们的筛选工作以及随后的结构-活性关系（SAR），以优化该系列的效价，选择性和诱变性，从而发现了首屈一指的肠道限制性RET激酶抑制剂2- （4-（4-乙氧基-6-氧代-1,6-二氢
• NOVEL COMPOUNDS AS REARRANGED DURING TRANSFECTION (RET) INHIBITORS
  申请人：GlaxoSmithKline Intellectual Property Development Limited

  公开号：US20160271123A1

  公开（公告）日：2016-09-22

  This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.

  本发明涉及一种新型化合物，其为重排转录因子（RET）激酶的抑制剂，以及含有它们的制药组合物，其制备过程和其在治疗中的使用，单独或联合使用，用于正常化胃肠敏感性、运动性和/或分泌以及腹部紊乱或疾病和/或与RET功能障碍相关的治疗或调节RET活性可能具有治疗效益的疾病，包括但不限于所有分类的肠易激综合症（IBS），包括腹泻型、便秘型或交替排便模式，功能性腹胀、功能性便秘、功能性腹泻、未特指的功能性肠道疾病、功能性腹痛综合征、慢性特发性便秘、功能性食管障碍、功能性胃十二指肠障碍、功能性肛门疼痛、炎症性肠病、非小细胞肺癌、肝细胞癌、结直肠癌、髓样甲状腺癌、滤泡性甲状腺癌、间变性甲状腺癌、乳头状甲状腺癌、脑肿瘤、腹腔癌、实体肿瘤、其他肺癌、头颈癌、胶质瘤、神经母细胞瘤、Von Hippel-Lindau综合征和肾肿瘤、乳腺癌、输卵管癌、卵巢癌、移行细胞癌、前列腺癌、食管和胃食管连接处的癌症、胆道癌、腺癌以及任何RET激酶活性增加的恶性肿瘤。
• PYRIDINE DERIVATIVES AS REARRANGED DURING TRANSFECTION (RET) KINASE INHIBITORS
  申请人：GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LIMITED

  公开号：US20160002215A1

  公开（公告）日：2016-01-07

  This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.

  本发明涉及一种新型化合物，其为重排转录因子（RET）激酶的抑制剂，以及包含它们的制药组合物、其制备方法和它们在治疗中的使用，单独或结合使用，用于正常化胃肠敏感性、运动性和/或分泌以及/或腹部紊乱或疾病和/或与RET功能障碍相关的治疗或调节RET活性可能有治疗益处的疾病，包括但不限于所有分类的肠易激综合征（IBS），包括以腹泻为主导、以便秘为主导或交替的大便模式、功能性腹胀、功能性便秘、功能性腹泻、未特定功能性肠道疾病、功能性腹痛综合征、慢性特发性便秘、功能性食管障碍、功能性胃十二指肠障碍、功能性肛门疼痛、炎症性肠病、增殖性疾病，如非小细胞肺癌、肝细胞癌、结直肠癌、髓样甲状腺癌、滤泡性甲状腺癌、间叶甲状腺癌、乳头状甲状腺癌、脑肿瘤、腹腔癌、实体瘤、其他肺癌、头颈癌、胶质母细胞瘤、神经母细胞瘤、Von Hippel-Lindau综合征和肾肿瘤、乳腺癌、输卵管癌、卵巢癌、移行细胞癌、前列腺癌、食管和胃食管交界处癌、胆道癌、腺癌以及任何具有增加RET激酶活性的恶性肿瘤。
• Pyridine derivatives as rearranged during transfection (RET) kinase inhibitors
  申请人：GlaxoSmithKline Intellectual Property Development Limited

  公开号：US09382238B2

  公开（公告）日：2016-07-05

  This invention relates to novel compounds which are inhibitors of the Rearranged during Transfection (RET) kinase, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination, for the normalization of gastrointestinal sensitivity, motility and/or secretion and/or abdominal disorders or diseases and/or treatment related to diseases related to RET dysfunction or where modulation of RET activity may have therapeutic benefit including but not limited to all classifications of irritable bowel syndrome (IBS) including diarrhea-predominant, constipation-predominant or alternating stool pattern, functional bloating, functional constipation, functional diarrhea, unspecified functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorders, functional gastroduodenal disorders, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, brain tumors, peritoneal cavity cancer, solid tumors, other lung cancer, head and neck cancer, gliomas, neuroblastomas, Von Hippel-Lindau Syndrome and kidney tumors, breast cancer, fallopian tube cancer, ovarian cancer, transitional cell cancer, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary cancer, adenocarcinoma, and any malignancy with increased RET kinase activity.

  本发明涉及新型化合物，其为重排转录（RET）激酶的抑制剂，涉及含有它们的制药组合物，制备它们的过程，以及它们在治疗中的使用，单独或联合使用，用于规范胃肠敏感性、动力和/或分泌以及/或腹部疾病或疾病相关的治疗，包括但不限于所有分类的肠易激综合症（IBS），包括腹泻型、便秘型或交替排便模式，功能性腹胀、功能性便秘、功能性腹泻、未指定的功能性肠道疾病、功能性腹痛综合征、慢性特发性便秘、功能性食管障碍、功能性胃十二指肠障碍、功能性肛门疼痛、炎症性肠病、增殖性疾病，如非小细胞肺癌、肝细胞癌、结直肠癌、髓样甲状腺癌、滤泡性甲状腺癌、间变性甲状腺癌、乳头状甲状腺癌、脑肿瘤、腹膜腔癌、实体肿瘤、其他肺癌、头颈癌、胶质瘤、神经母细胞瘤、Von Hippel-Lindau综合症和肾肿瘤、乳腺癌、输卵管癌、卵巢癌、移行细胞癌、前列腺癌、食管和胃食管交界处癌、胆管癌、腺癌以及任何具有增加RET激酶活性的恶性肿瘤。
• Development of 3,5-Dinitrophenyl-Containing 1,2,4-Triazoles and Their Trifluoromethyl Analogues as Highly Efficient Antitubercular Agents Inhibiting Decaprenylphosphoryl-β-<scp>d</scp>-ribofuranose 2′-Oxidase
  作者：Galina Karabanovich、Jan Dušek、Karin Savková、Oto Pavliš、Ivona Pávková、Jan Korábečný、Tomáš Kučera、Hana Kočová Vlčková、Stanislav Huszár、Zuzana Konyariková、Klára Konečná、Ondřej Jand’ourek、Jiřina Stolaříková、Jana Korduláková、Kateřina Vávrová、Petr Pávek、Věra Klimešová、Alexandr Hrabálek、Katarína Mikušová、Jaroslav Roh

  DOI：10.1021/acs.jmedchem.9b00912

  日期：2019.9.12

  We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis strains, including clinically isolated multidrug-resistant strains. Thorough structure activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosis H(37)Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosis were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 mu M, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-beta-D-ribofuranose 2'-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.