2-(3-nitrophenyl)-5-tert-butyl-2H-pyrazol-3-yl-amine | 476637-05-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-(3-nitrophenyl)-5-tert-butyl-2H-pyrazol-3-yl-amine
• 英文别名: 3-tert-Butyl-1-(3-nitrophenyl)-1H-pyrazol-5-amine；5-tert-butyl-2-(3-nitrophenyl)pyrazol-3-amine
• CAS: 476637-05-5
• 化学式: C₁₃H₁₆N₄O₂
• 分子量: 260.296
• InChiKey: FJUBBFVKESGGSK-UHFFFAOYSA-N

物化性质

• 沸点：
  425.4±40.0 °C(Predicted)
• 密度：
  1.26±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  89.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(3-nitrophenyl)-5-tert-butyl-2H-pyrazol-3-yl-amine 在 10percent Pd/C ammonium formate 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 13.0h， 生成 1-[1-(3-aminophenyl)-3-tert-butyl-1H-pyrazol-5-yl]-3-phenylurea
  参考文献：
  名称：

  Pyrazole Urea-Based Inhibitors of p38 MAP Kinase:  From Lead Compound to Clinical Candidate

  摘要：

  We report on a series of N-pyrazole, N'-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5'-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure-activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.

  DOI：

  10.1021/jm020057r
• 作为产物：
  描述：

  新戊酰基乙腈 、 3-硝基苯肼 在 盐酸 作用下， 以 水 为溶剂， 反应 2.0h， 生成 2-(3-nitrophenyl)-5-tert-butyl-2H-pyrazol-3-yl-amine
  参考文献：
  名称：

  Synthesis, Structural Characterization, and In Vitro and In Silico Antifungal Evaluation of Azo-Azomethine Pyrazoles (PhN2(PhOH)CHN(C3N2(CH3)3)PhR, R = H or NO2)

  摘要：

  R1-N=N-R2-CH=N-R3是一类活性药物配体，被广泛应用于抗真菌、抗菌和抗肿瘤药物。本研究合成了四种新的azo-azomethines，其中R1 = Ph，R2 = 酚，R3 = pyrazol-Ph-R'（R = H或NO2），并使用X射线、红外、核磁共振和紫外-可见技术进行了结构表征，评估了它们对已认证的白色念珠菌和新生隐球菌菌株的抗真菌活性。抗真菌测试表明，这些化合物对两种菌株均具有高到中等的抑制活性，该活性与芳香环中硝基的存在和位置相关。这些生物学试验进一步通过分子对接研究来补充，针对每个真菌菌株的三个不同分子靶点进行了分子动力学模拟和结合自由能计算。发现硝基化合物在“间位”和“对位”的活性位点上具有更好的亲和力，使它们成为开发具有高抗真菌活性的新席夫碱的有前途的构建模块。

  DOI：

  10.3390/molecules26247435

文献信息

• [EN] 7H-PYRROLO[2,3-d]PYRIMIDINE DERIVATIVES, AS WELL AS THEIR THERAPEUTICALLY ACCEPTABLE SALTS, PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND PROCESS FOR PRODUCTION THE ACTIVE AGENT<br/>[FR] DERIVES DE 7H-PYRROLO[2,3-D]PYRIMIDINE ET LEURS SELS ACCEPTABLES D'UN POINT DE VUE THERAPEUTIQUE, PREPARATIONS PHARMACEUTIQUES LES CONTENANT ET PROCEDE DE PRODUCTION DE L'AGENT ACTIF
  申请人：SZOLCSANYI JANOS

  公开号：WO2005105804A1

  公开（公告）日：2005-11-10

  The invention relates to new 7H-pyrrolo[2,3-d]pyrimidine derivatives, as well as their therapeutically acceptable salts, pharmaceutical preparations containing them and process for producing the active agent. The pharmaceutical preparation is adventageously antiphlogistic and analgetic one, a preparation reducing neuropathic hyperalgesia and rheumatic arthritis, a preparation for hindering destruction of bones chondrus, being applicable for treatment of other diseases, which may be connected with other inflammatory processes e.g. asthma, eczema or psoriasis.

  这项发明涉及新的7H-吡咯[2,3-d]嘧啶衍生物，以及它们的治疗可接受的盐、含有它们的药物制剂和生产活性剂的过程。药物制剂具有抗炎和镇痛的优势，可减少神经病性过敏和类风湿性关节炎，可用于阻止骨骨软骨的破坏的制剂，适用于治疗可能与其他炎症过程相关的其他疾病，例如哮喘、湿疹或牛皮癣。
• Synthesis and antifungal activity of nitrophenyl-pyrazole substituted Schiff bases
  作者：Andrés Restrepo-Acevedo、Nicolas Osorio、Luis E. Giraldo-López、Richard F. D'Vries、Susana Zacchino、Rodrigo Abonia、Ronan Le Lagadec、Fernando Cuenú-Cabezas

  DOI：10.1016/j.molstruc.2021.132289

  日期：2022.4

  electrophilic character and the reactivity of the Schiff bases. The relative position of the nitro group plays an important role on the antifungal activity against C. albicans as compound bearing the 2-nitrophenyl substituent (2a) was considerably more active than the other derivatives. In contrast, all three isomers presented a similar, limited, activity against C. neoformans. Molecular docking simulations

  使用无溶剂和微波辅助程序等环保技术，以几乎定量的产率制备了三种新的带有 2-、3- 或 4-硝基苯基取代基的吡唑基偶氮甲碱异构体 ( 2a-c )。这些化合物通过标准分析方法进行了充分表征，包括对三种合成化合物中的两种进行单晶 X 射线衍射晶体学。计算出的 HOMO 和 LUMO 的分子轨道分布表明，可以通过在吡唑部分添加硝基苯基来调节带隙能量，从而调节 Schiff 碱的亲电特性和反应性。硝基的相对位置对白色念珠菌的抗真菌活性起重要作用作为带有 2-硝基苯基取代基 ( 2a ) 的化合物，其活性比其他衍生物高得多。相比之下，所有三种异构体都表现出类似的、有限的针对新型隐球菌的活性。分子对接模拟表明，活性最强的化合物2a与 3PVK 模型蛋白的结合能最低。
• 7H-Pyrrolo[2,3-D]Pyrimidine Derivatives, As Well As Their Therapeutically Acceptable Salts, Pharmaceutical Preparations Containing Them And Process For Production The Active Agent
  申请人：Szolcsanyi Janos

  公开号：US20080214583A1

  公开（公告）日：2008-09-04

  The invention relates to new 7H-pyrrolo[2,3-d]pyrimidine derivatives, as well as their therapeutically acceptable salts, pharmaceutical preparations containing them and process for producing the active agent. The pharmaceutical preparation is adventageously antiphlogistic and analgetic one, a preparation reducing neuropathic hyperalgesia and rheumatic arthritis, a preparation for hindering destruction of bones chondrus, being applicable for treatment of other diseases, which may be connected with other inflammatory processes e.g. asthma, eczema or psoriasis.

  本发明涉及新的7H-吡咯并[2,3-d]嘧啶衍生物及其治疗上可接受的盐、含有它们的制药制剂和活性剂的生产过程。该制药制剂具有抗炎和镇痛作用，可减轻神经病性疼痛和风湿性关节炎，防止软骨破坏，可用于治疗其他可能与其他炎症过程相关的疾病，例如哮喘、湿疹或牛皮癣。
• Structure−Activity Relationships of the p38α MAP Kinase Inhibitor 1-(5-<i>tert</i>-Butyl-2-<i>p</i>-tolyl-2<i>H</i>-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796)
  作者：John Regan、Alison Capolino、Pier F. Cirillo、Thomas Gilmore、Anne G. Graham、Eugene Hickey、Rachel R. Kroe、Jeffrey Madwed、Monica Moriak、Richard Nelson、Christopher A. Pargellis、Alan Swinamer、Carol Torcellini、Michele Tsang、Neil Moss

  DOI：10.1021/jm030121k

  日期：2003.10.1

  We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH2 interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degreesC translating into K-d values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.
• Hybrid Compound Design To Overcome the Gatekeeper T338M Mutation in cSrc
  作者：Matthäus Getlik、Christian Grütter、Jeffrey R. Simard、Sabine Klüter、Matthias Rabiller、Haridas B. Rode、Armin Robubi、Daniel Rauh

  DOI：10.1021/jm9002928

  日期：2009.7.9

  The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.