1-[4-(氨基磺酰基)苯基]-5-(4-氯苯基)-1H-吡唑-3-羧酸 | 170571-19-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 1-[4-(氨基磺酰基)苯基]-5-(4-氯苯基)-1H-吡唑-3-羧酸
• 中文别名: 5-(4-氯苯基)-1-(4-氨磺酰苯基)-1H-吡唑-3-羧酸
• 英文名称: 5-(4-chlorophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylic acid
• 英文别名: 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid；5-(4-Chlorophenyl)-1-(4-sulfamoylphenyl)pyrazole-3-carboxylic acid；1-(4-sulfamoylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid
• CAS: 170571-19-4
• 化学式: C₁₆H₁₂ClN₃O₄S
• 分子量: 377.808
• InChiKey: NHAUQESLCOSREJ-UHFFFAOYSA-N

物化性质

• 沸点：
  654.9±65.0 °C(Predicted)
• 密度：
  1.56±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  124
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-[4-(氨基磺酰基)苯基]-5-(4-氯苯基)-1H-吡唑-3-羧酸 在 硼烷四氢呋喃络合物 、 三乙胺 、 对甲苯磺酰氯 、 lithium chloride 作用下， 以 四氢呋喃 为溶剂， 反应 32.0h， 生成 4-[5-(4-chlorophenyl)-3-(chloromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  参考文献：
  名称：

  Synthesis and Biological Evaluation of the 1,5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors:  Identification of 4-[5-(4-Methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib)

  摘要：

  A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of ii (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.

  DOI：

  10.1021/jm960803q
• 作为产物：
  描述：

  4-肼基苯磺酰胺 在 甲醇 、 sodium methylate 、 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 24.0h， 生成 1-[4-(氨基磺酰基)苯基]-5-(4-氯苯基)-1H-吡唑-3-羧酸
  参考文献：
  名称：

  Discovery of novel sulfonamide-containing aminophosphonate derivatives as selective COX-2 inhibitors and anti-tumor candidates

  摘要：

  As an essential enzyme with a variety of physiological functions, Cyclooxygenase-2 (COX-2) is also closely related to carcinoma due to the observed overexpression. In this work, a novel series of sulfonamide-containing aminophosphonate derivatives (A1-A25) were developed as selective COX-2 inhibitors and anti-cancer candidates. The top hit compound A23 presented applicative COX-2 inhibitory activity (IC₅₀ = 0.28 µM) and anti-proliferative capability against several cancer cell lines (IC₅₀ = 2.34-16.43 µM for HeLa, MCF-7, HCT116 and HepG2 cells). Among them, A23 has the most significant inhibitory effect on HCT116 cells, which were comparable with that of the positive controls respectively (eg: IC₅₀ = 8.73 µM for HCT116). The binding pattern of A23 was inferred by the molecular docking simulation. Moreover, A23 could induce the apoptosis via a mitochondrion-dependent mode and cause the arrest of the cell-cycle in G1 stage. A further investigation in the checkpoints of apoptosis indicated that the node Bcl-2 might connect the selective COX-2 inhibition and the anti-tumor activity. Therefore, this work brought new information for developing COX-2 inhibitors in anti-tumor therapies in future.

  DOI：

  10.1016/j.bioorg.2020.104390

文献信息

• Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
  申请人：——

  公开号：US20010041726A1

  公开（公告）日：2001-11-15

  The present invention describes novel nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) inhibitors and novel compositions comprising at least one nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or optionally, at least one therapeutic agent, such as, steroids, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4 (LTB 4 ) receptor antagonists, leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) inhibitors, H antagonists, antineoplastic agents, antiplatelet agents, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof. The present invention also provides novel compositions comprising at least one parent COX-2 inhibitor and at least one nitric oxide donor, and, optionally, at least one therapeutic agent. The present invention also provides kits and methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 inhibitors; for facilitating wound healing; for treating and/or preventing renal toxicity; and for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2.

  本发明描述了新颖的硝化和/或亚硝化环氧合酶2（COX-2）抑制剂以及包含至少一种硝化和/或亚硝化环氧合酶2（COX-2）抑制剂的新型组合物，以及可选地，至少一种捐赠、转移或释放一氧化氮、刺激内源性一氧化氮合成、提高内源性内皮源性舒张因子水平或是一氧化氮合酶底物的化合物，和/或可选地，至少一种治疗剂，如类固醇、非甾体抗炎化合物（NSAID）、5-脂氧合酶（5-LO）抑制剂、白三烯B4（LTB4）受体拮抗剂、白三烯A4（LTA4）水解酶抑制剂、5-HT激动剂、3-羟基-3-甲基戊二酰辅酶A（HMGCoA）抑制剂、H受体拮抗剂、抗肿瘤药物、抗血小板药物、解充血剂、利尿剂、镇静或非镇静抗组胺药、诱导型一氧化氮合酶抑制剂、阿片类药物、镇痛剂、幽门螺杆菌抑制剂、质子泵抑制剂、异前列腺素抑制剂以及其混合物。本发明还提供了包含至少一种母体COX-2抑制剂和至少一种一氧化氮供体的新型组合物，以及可选地，至少一种治疗剂。本发明还提供了用于治疗炎症、疼痛和发热的工具和方法；用于治疗和/或改善COX-2抑制剂的胃肠道特性；用于促进伤口愈合；用于治疗和/或预防肾毒性；以及用于治疗和/或预防由于环氧合酶-2水平升高而导致的其他疾病的工具和方法。
• Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX
  作者：Fa-Qian Shen、Zhong-Chang Wang、Song-Yu Wu、Shen-Zhen Ren、Ruo-Jun Man、Bao-Zhong Wang、Hai-Liang Zhu

  DOI：10.1016/j.bmcl.2017.07.020

  日期：2017.8

  In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition

  在我们先前的研究中，我们设计了一系列吡唑衍生物作为新型COX-2抑制剂。为了获得新型的COX-2和5-LOX双重抑制剂，我们在此设计并合成了20种化合物，方法是将吡唑与取代的香豆素杂交，据报道，该香豆素具有5-LOX抑制作用，并使用包括选择性抑制在内的充分生物学试验依次选择有效的化合物。 COX-2和5-LOX的表达，体外抗增殖，细胞凋亡和细胞周期。其中，最有效的化合物11g（ COX-2的IC 50 = 0.23±  0.16μM，5-LOX的IC 50 = 0.87±0.07μM， 针对A549的IC 50 = 4.48±0.57μM）与阳性对照相比具有初步优势。控制塞来昔布（ 对于COX-2，IC 50 = 0.41± 0.28μM， 对于A549 ，IC 50 = 7.68± 0.55μM）和Zileuton（ 对于5-LOX，IC 50 = 1.35± 0.24μM）。进一步的研
• Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
  申请人：Pharmacia Corporation

  公开号：US20020058810A1

  公开（公告）日：2002-05-16

  This invention is in the field of antiinflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating disorders mediated by cyclooxygenase-2 or 5-lipoxygenase, such as inflammation.

  这项发明属于抗炎药物代理领域，具体涉及用于治疗由环氧合酶-2或5-脂氧合酶介导的疾病的化合物、组合物和方法，如炎症。
• Inhibitors of P2X3
  申请人：Brotherton-Pleiss E. Christine

  公开号：US20070037974A1

  公开（公告）日：2007-02-15

  Compounds of formula 1 are modulators of P2X3 useful for the treatment of pain and genito-urinary, gastrointestinal, and respiratory disorders: wherein R 1 is —C(═S)CH 3 , pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, furyl, furylcarbonyl, acetyl, or carbamoyl; R 2a and R 2b are independently H, methyl, or ethyl; R 3 is H or methyl; Y is a bond, —(CR 4 R 5 ) n — or —CR 4 ═CR 5 —; wherein R 4 and R 5 are each independently H or methyl and n is 1 or 2; X is N or CH; A is phenyl, 5-membered heterocyclyl, or 6-membered heterocyclyl; R 6 , R 7 and R 8 are each independently H, halo, lower alkyl, cycloalkyl, alkylthio, alkylthio-lower alkyl, alkylsulfonyl-lower alkyl, di(lower alkyl)amino-lower alkyl, morpholinyl-lower alkyl, 4-methyl-piperazinyl-methyl, trifluoromethyl, pyridyl, tetrazolyl, thiophenyl, phenyl, biphenyl, or benzyl (where thiophenyl, phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoromethyl, lower alkoxy or lower alkylthio) or R 6 and R 7 together form a 5-membered or 6-membered carbocyclic or heterocyclic ring substituted with 0-3 substituents selected from the group consisting of lower alkyl, lower alkoxy, oxo, halo, thiophenyl-lower alkyl, phenyl, benzyl (where phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoro-methyl, lower alkoxy, lower alkylthio, amino-lower alkyl, lower alkylamino-lower alkyl, or di(lower alkyl)amino-lower alkyl); and pharmaceutically acceptable salts thereof; wherein when R 1 is pyrimidin-2-yl, X is N, Y is a bond and A is oxazol-5-yl the carbon atom at position 4 in said oxazol-5-yl is not substituted by propyl when the carbon atom at position 2 in said oxazol-5-yl is substituted by substituted phenyl and the carbon atom at position 4 in said oxazol-5-yl is not substituted by phenyl when the carbon atom at position 2 is substituted by unsubstituted or substituted phenyl.

  式1的化合物是P2X3的调节剂，用于治疗疼痛和泌尿生殖、胃肠和呼吸系统疾病： 其中 R 1 为—C(═S)CH 3 ，吡啶基，嘧啶基，吡嗪基，噻唑基，呋喃基，呋喃甲酰基，乙酰基或氨基甲酰基；R 2a 和R 2b 独立地为H，甲基或乙基；R 3 为H或甲基；Y为键，—(CR 4 R 5 ) n —或—CR 4 ═CR 5 —；其中R 4 和R 5 各自独立地为H或甲基，n为1或2；X为N或CH；A为苯基，5-成员杂环基或6-成员杂环基；R 6 ，R 7 和R 8 各自独立地为H，卤素，低碳基，环烷基，烷基硫醚，烷基硫醚-低碳基，烷基磺酰基-低碳基，二(低碳基)氨基-低碳基，吗啉基-低碳基，4-甲基哌嗪基-甲基，三氟甲基，吡啶基，四唑基，噻吩基，苯基，联苯基或苄基（其中噻吩基，苯基和苄基被0-3个低碳基，卤素，磺酰胺基，三氟甲基，低烷氧基或低烷硫基取代）或R 6 和R 7 一起形成一个被0-3个取自由低碳基，低烷氧基，氧代基，卤素，噻吩基-低碳基，苯基，苄基（其中苯基和苄基被0-3个低碳基，卤素，磺酰胺基，三氟甲基，低烷氧基，低烷硫基，氨基-低碳基，烷基氨基-低碳基或二(低碳基)氨基-低碳基取代）的5-成员或6-成员碳环或杂环取代环；及其药学上可接受的盐；其中当R 1 为嘧啶-2-基时，X为N，Y为键，A为噁唑-5-基时，所述噁唑-5-基中位置4的碳原子在所述噁唑-5-基中位置2的碳原子被取代的苯基取代时不被丙基取代，且所述噁唑-5-基中位置4的碳原子在位置2被取代的苯基取代时不被苯基取代。
• Discovery of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor: Scaffold hopping approach
  作者：István Ledneczki、Pál Tapolcsányi、Eszter Gábor、András Visegrády、Márton Vass、János Éles、Patrik Holm、Anita Horváth、Anikó Pocsai、Sándor Mahó、István Greiner、Balázs Krámos、Zoltán Béni、János Kóti、Anna E. Káncz、Márta Thán、Sándor Kolok、Judit Laszy、Ottilia Balázs、Gyula Bugovits、József Nagy、Mónika Vastag、Ágota Szájli、Éva Bozó、György Lévay、Balázs Lendvai、Zsolt Némethy

  DOI：10.1016/j.ejmech.2021.113189

  日期：2021.3

  The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (α7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new

  本文重点研究基于支架跳跃的发现和表征参考分子（A-867744）周围的新型烟碱α7受体正调节剂（α7nAChR PAM）配体。首先，进行了大量努力以评估各种药效基团对化学修饰的体外效价（SAR评估）的重要性。随后，合成并表征了具有多功能杂芳族中心核的几种新衍生物。确定了一种有前途的，含吡唑的新化学型，具有良好的物理化学和体外参数。还进行了基于同源性建模的回顾性分析。除具有良好的体外特性外，最先进的衍生物图69还显示了在啮齿动物认知模型中的体内功效（在小鼠位置识别测试中东pol碱引起的失忆）和可接受的药代动力学特性。根据体内数据，所得具有先进药物样特征的分子有可能在生物学相关剂量范围内改善认知能力，从而进一步增强了α7nACh受体在认知过程中的支持作用的观点。