5-甲基-4,5,6,7-四氢-2H-吲唑-3-羧酸 | 842972-14-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 5-甲基-4,5,6,7-四氢-2H-吲唑-3-羧酸
• 中文别名: 5-甲基-4,5,6,7-四氢-2H-1H-吲唑-3-羧酸
• 英文名称: 5-methyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
• 英文别名: 5-methyl-4,5,6,7-tetrahydro-1(2)H-indazole-3-carboxylic acid；5-Methyl-4,5,6,7-tetrahydro-1(2)H-indazol-3-carbonsaeure；5-Methyl-4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid
• CAS: 842972-14-9
• 化学式: C₉H₁₂N₂O₂
• mdl: MFCD06011086
• 分子量: 180.206
• InChiKey: TYDZWBIBMZLMSH-UHFFFAOYSA-N

物化性质

• 沸点：
  425.0±45.0 °C(Predicted)
• 密度：
  1.284±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.555
• 拓扑面积：
  66
• 氢给体数：
  2
• 氢受体数：
  3

安全信息

• 危险等级：
  IRRITANT
• 危险品标志：
  Xi
• 海关编码：
  2933990090

反应信息

• 作为反应物：
  描述：

  5-甲基-4,5,6,7-四氢-2H-吲唑-3-羧酸 、 Methyl 4-aminobut-2-enoate;2,2,2-trifluoroacetic acid 在 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成
  参考文献：
  名称：

  一种基于片段的方法来发现半胱氨酸蛋白酶的不可逆共价抑制剂

  摘要：

  报道了一种新的基于片段的药物发现方法，该方法不可逆地将类药物片段束缚在催化半胱氨酸上。我们将亲电试剂连接到 100 个片段上，而亲电试剂的反应性没有显着改变。质谱分析发现了半胱氨酸蛋白酶木瓜蛋白酶的三种非肽抑制剂。鉴定出的化合物显示出不可逆抑制剂的特征。不可逆的束缚系统也显示出特异性：三种鉴定出的木瓜蛋白酶抑制剂不与 UbcH7、USP08 或带有 GST 标签的人类鼻病毒 3C 蛋白酶共价反应。

  DOI：

  10.1021/jm500345q
• 作为产物：
  描述：

  alkaline earth salt of/the/ methylsulfuric acid 生成 5-甲基-4,5,6,7-四氢-2H-吲唑-3-羧酸
  参考文献：
  名称：

  v. Auwers et al., Justus Liebigs Annalen der Chemie, 1929, vol. 469, p. 62

  摘要：

  DOI：

文献信息

• Potent and selective inhibitors of receptor-interacting protein kinase 1 that lack an aromatic back pocket group
  作者：Gregory L. Hamilton、Huifen Chen、Gauri Deshmukh、Charles Eigenbrot、Rina Fong、Adam Johnson、Pawan Bir Kohli、Patrick J. Lupardus、Bianca M. Liederer、Sreemathy Ramaswamy、Haowei Wang、Jian Wang、Zhaowu Xu、Yunliang Zhu、Domagoj Vucic、Snahel Patel

  DOI：10.1016/j.bmcl.2019.04.014

  日期：2019.6

  lipophilic aromatic group present in most literature inhibitors that typically occupies a hydrophobic back pocket of the protein active site. Despite not having this ubiquitous feature of many known RIPK1 inhibitors, we were able to obtain compounds with good potency, kinase selectivity, and pharmacokinetic properties in rats. The use of the lipophilic yet metabolically stable pentafluoroethyl group was critical

  受体相互作用蛋白激酶1（RIPK1），细胞坏死病途径的关键组成部分，已被公认是重要的治疗靶点。RIPK1的药理抑制或遗传失活已在动物疾病模型中显示出了希望，这些疾病的范围包括急性缺血性疾病，慢性炎症和神经退行性疾病。我们在这里介绍一类RIPK1抑制剂，其特征是大多数文献中的抑制剂（通常占据蛋白质活性位点的疏水性后口袋）中缺乏亲脂性芳香族基团。尽管没有许多已知的RIPK1抑制剂普遍存在的功能，我们仍能够在大鼠中获得具有良好效价，激酶选择性和药代动力学特性的化合物。
• TETRAHYDROBENZOISOXAZOLE AND TETRAHYDROINDAZOLE DERIVATIVES AS MODULATORS OF THE MITOTIC MOTOR PROTEIN
  申请人：Schiemann Kai

  公开号：US20100022530A1

  公开（公告）日：2010-01-28

  Compounds of the formula (I) in which A 1 , A 2 , R 1 , X 1 , X 2 , X 3 , Y, R 2 , Cy and n have meanings indicated in claim 1 , can be employed, inter alia, for the treatment of tumours.

  公式（I）中A1，A2，R1，X1，X2，X3，Y，R2，Cy和n具有权利要求1中所示的含义的化合物，可以用于治疗肿瘤等疾病。
• Pyrrole and Pyrazole DAAO Inhibitors
  申请人：Fang Q. Kevin

  公开号：US20100016397A1

  公开（公告）日：2010-01-21

  Methods for increasing D-Serine concentration and reducing concentration of the toxic products of D-Serine oxidation, for enhancing learning, memory and/or cognition, or for treating schizophrenia, Alzheimer's disease, ataxia or neuropathic pain, or preventing loss in neuronal function characteristic of neurodegenerative diseases involve administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 and R 2 are independently selected from hydrogen, halo, nitro, alkyl, acyl, alkylaryl, and XYR 5 ; or R 1 and R 2 , taken together, form a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group; X and Y are independently selected from O, S, NH, and (CR 6 R 7 ) n ; R 3 is hydrogen, alkyl or M + ; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc ion or a mixture thereof; Z is N or CR 4 ; R 4 is from selected from hydrogen, halo, nitro, alkyl, alkylaryl, and XYR 5 ; R 5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R 6 and R 7 are independently selected from hydrogen and alkyl; n is an integer from 1 to 6; at least one of R 1 , R 2 and R 4 is other than hydrogen; and at least one of X and Y is (CR 6 R 7 ) n . D-serine or cycloserine may be coadministered along with the compound of formula I.

  增加D-丝氨酸浓度并减少D-丝氨酸氧化产物浓度的方法，以增强学习、记忆和/或认知能力，或治疗精神分裂症、阿尔茨海默病、共济失调或神经病理性疼痛，或预防神经退行性疾病特征性神经元功能损失，包括向需要治疗的受试者施用公式I的化合物或其药学上可接受的盐或溶剂的治疗有效量：其中，R1和R2分别选自氢、卤素、硝基、烷基、酰基、烷基芳基和XYR5；或R1和R2共同形成5、6、7或8成员取代或未取代的碳环或杂环基；X和Y分别选自O、S、NH和（CR6R7）n；R3为氢、烷基或M+；M为铝离子、钙离子、锂离子、镁离子、钾离子、钠离子、锌离子或其混合物；Z为N或CR4；R4选自氢、卤素、硝基、烷基、烷基芳基和XYR5；R5选自芳基、取代芳基、杂芳基和取代杂芳基；R6和R7分别选自氢和烷基；n为1到6的整数；R1、R2和R4中至少有一个不是氢；X和Y中至少有一个是（CR6R7）n。D-丝氨酸或环丝氨酸可以与公式I的化合物一起共同施用。
• PYRROLE AND PYRAZOLE DAAO INHIBITORS
  申请人：FANG Q. Kevin

  公开号：US20110092559A1

  公开（公告）日：2011-04-21

  Methods for increasing D-Serine concentration and reducing concentration of the toxic products of D-Serine oxidation, for enhancing learning, memory and/or cognition, or for treating schizophrenia, Alzheimer's disease, ataxia or neuropathic pain, or preventing loss in neuronal function characteristic of neurodegenerative diseases involve administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 and R 2 are independently selected from hydrogen, halo, nitro, alkyl, acyl, alkylaryl, and XYR 5 ; or R 1 and R 2 , taken together, form a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group; X and Y are independently selected from O, S, NH, and (CR 6 R 7 ) n ; R 3 is hydrogen, alkyl or M + ; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc ion or a mixture thereof; Z is N or CR 4 ; R 4 is from selected from hydrogen, halo, nitro, alkyl, alkylaryl, and XYR 5 ; R 5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R 6 and R 7 are independently selected from hydrogen and alkyl; n is an integer from 1 to 6; at least one of R 1 , R 2 and R 4 is other than hydrogen; and at least one of X and Y is (CR 6 R 7 ) n . D-serine or cycloserine may be coadministered along with the compound of formula I.

  增加D-丝氨酸浓度和减少D-丝氨酸氧化的有毒产物浓度的方法，以增强学习、记忆和/或认知能力，或用于治疗精神分裂症、阿尔茨海默病、共济失调或神经病理性疼痛，或预防神经退行性疾病特征性神经元功能丧失，包括向需要治疗的受试者施用公式I的化合物的治疗有效量，或其药学上可接受的盐或溶剂：其中，R1和R2分别选自氢、卤、硝基、烷基、酰基、烷基芳基和XYR5；或R1和R2一起形成一个5、6、7或8成员的取代或未取代的碳环或杂环基；X和Y分别选自O、S、NH和（CR6R7）n；R3是氢、烷基或M+；M是铝、钙、锂、镁、钾、钠、锌离子或其混合物；Z是N或CR4；R4选自氢、卤、硝基、烷基、烷基芳基和XYR5；R5选自芳基、取代芳基、杂芳基和取代杂芳基；R6和R7分别选自氢和烷基；n是1到6的整数；R1、R2和R4中至少有一个不是氢；X和Y中至少有一个是（CR6R7）n。D-丝氨酸或环丝氨酸可以与公式I的化合物一起共同施用。
• BICYCLIC LACTAMS AS RECEPTOR-INTERACTING PROTEIN-1 (RIP1) KINASE INHIBITORS FOR TREATING E.G. INFLAMMATORY DISEASES
  申请人：F. Hoffmann-La Roche AG

  公开号：EP3760625A1

  公开（公告）日：2021-01-06

  The invention provides compounds having the general formula (I) wherein R1, X, Z1, L, n, the A ring, the B ring, and the C ring are as described herein, pharmaceutical compositions including the compounds and the compounds for use in methods of medical treatment. The present compounds are receptor-interacting protein-1 (RIP1) kinase inhibitors useful for treating e.g. inflammatory diseases, such as e.g. irritable bowel disorders (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of kidneys, liver and lungs, cisplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatits, psoriasis, retinitis pigmentosa, retinal degeneration, chronic kidney diseases, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD). The present description discloses the preparation of exemplary and reference compounds, as well as pharmacological data thereof (e.g. pages 116 to 1221; examples 1 to 793; examples A to C; tables). An exemplary compound is e.g. 5a-methyl-N-((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide (example 1)

  本发明提供具有通式 (I) 的化合物 其中 R1、X、Z1、L、n、A 环、B 环和 C 环如本文所述；包括本发明化合物的药物组合物；以及本发明化合物在医疗方法中的用途。 本化合物是受体相互作用蛋白-1（RIP1）激酶抑制剂，可用于治疗炎症性疾病，例如肠易激综合征 (IBS)、克罗恩病、溃疡性结肠炎、心肌梗塞、中风、脑外伤、动脉粥样硬化、肾脏、肝脏和肺部缺血再灌注损伤、顺铂诱导的肾损伤、败血症、全身性炎症性休克、溃疡性结肠炎等、败血症、全身炎症反应综合征（SIRS）、胰腺炎、银屑病、色素性视网膜炎、视网膜变性、慢性肾脏疾病、急性呼吸窘迫综合征（ARDS）、慢性阻塞性肺病（COPD）。 本说明书公开了示例化合物和参考化合物的制备方法及其药理数据（如第 116 页至第 1221 页；例 1 至例 793；例 A 至例 C；表）。 示例化合物如 5a-甲基-N-((S)-5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]氧氮杂卓-3-基)-1,4,4a,5,5a,6-六氢环丙基[f]吲唑-3-甲酰胺（例 1）