2,4-二氯-6-甲基烟醛 | 91591-72-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 2,4-二氯-6-甲基烟醛
• 英文名称: 2,4-dichloro-6-methylpyridine-3-carbaldehyde
• 英文别名: 2,4-dichloro-6-methylnicotinaldehyde
• CAS: 91591-72-9
• 化学式: C₇H₅Cl₂NO
• mdl: MFCD08272074
• 分子量: 190.029
• InChiKey: QUHJCWDZCMZQFW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.142
• 拓扑面积：
  30
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2,4-二氯-6-甲基烟醛 在 四丙基高钌酸铵 、 4 A molecular sieve 、 N-甲基吗啉氧化物 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， 反应 18.5h， 生成 5-chloro-7-methyl-1-(1-propylbutyl)-2,3-dihydro-1H-[1,6]naphthyridin-4-one
  参考文献：
  名称：

  Potent, Orally Active Corticotropin-Releasing Factor Receptor-1 Antagonists Containing a Tricyclic Pyrrolopyridine or Pyrazolopyridine Core

  摘要：

  Two new classes of tricyclic-based corticotropin-releasing factor (CRF1) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF1 receptor (K-i = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC50 = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t(1/2) = 6.3, 12 h) and penetrate the rat brain ([brain]/[plasma] = 0.27, 0.52) but tend toward large volumes of distribution (V-D = 38, 44 L kg(-1)) and rapid clearances (CL = 70, 43 mL min(-1) kg(-1)). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84-86% were observed for 30 mg kg(-1) doses.

  DOI：

  10.1021/jm050070m
• 作为产物：
  描述：

  2,4-二氯-6-甲基吡啶-3-甲酸乙酯 在 lithium aluminium tetrahydride 、 pyridinium chlorochromate 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 38.0h， 生成 2,4-二氯-6-甲基烟醛
  参考文献：
  名称：

  发现 4-乙氧基-6-氯-5-氮杂吲唑作为新型 PDE4 抑制剂，用于治疗酒精使用障碍和酒精性肝病

  摘要：

  酒精使用障碍 (AUD) 每年导致大量残疾和约 300 万人死亡，主要由酒精性肝病 (ALD) 引起。磷酸二酯酶 IV (PDE4) 已成为 AUD 和 ALD 新疗法的有吸引力的分子靶点。在这项研究中，我们描述了 5-氮杂吲唑类似物作为 AUD 和 ALD 的 PDE4 抑制剂的鉴定。系统优化研究发现ZL40 (IC 50 = 37.4 nM) 具有显着的口服生物利用度 ( F = 94%)、令人满意的安全性以及比已批准的 PDE4 抑制剂罗氟司特和阿普司特更低的致吐效力。令人鼓舞的是， ZL40通过减少酒精摄入量和改善急性酒精引起的镇静和运动障碍而表现出 AUD 治疗效果。同时， ZL40在 NIAAA 小鼠模型中显示出减轻酒精性肝损伤和减轻炎症的潜力。这些结果表明， ZL40是一种有前景的化合物，可用于未来治疗酒精相关疾病的药物开发。

  DOI：

  10.1021/acs.jmedchem.3c02087

文献信息

• [EN] PYRAZOLOPYRIDINES AS INHIBITORS OF THE KINASE LRRK2<br/>[FR] PYRAZOLOPYRIDINES EN TANT QU'INHIBITEURS DE LA KINASE LRRK2
  申请人：MEDICAL RES COUNCIL TECHNOLOGY

  公开号：WO2011141756A1

  公开（公告）日：2011-11-17

  A compound of formula la or formula lb, or a pharmaceutically acceptable salt or ester thereof, wherein R1 is selected from: aryl; heteroaryl; -NHR3; fused aryl-C4-7-heterocycloalkyl; - CONR4R5; -NHCOR6; -C3-7-cycloalkyl; -0-C3-7-cycloalkyl; -NR3R6; and optionally substituted -C1-6 alkyl; wherein said aryl, heteroaryl, fused aryl-C4-7-heterocycloalkyl and C4-7- heterocycloalkyl are each optionally substituted; Q is CN, halogen, or is selected from C1-6-alkyl, C3-7-cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted with one or more substituents A; R2 is selected from hydrogen, aryl, C1-6-alkyl, C2-6-alkenyl,C3-7-cycloalkyl, heteroaryl, C4-7 heterocycloalkyl and halogen, wherein said C1-6-alkyl,, Cz-B-alkenyl, aryl, heteroaryl and C4-7-heterocycloalkyl are each optionally substituted;R3 is selected from aryl, heteroaryl, C4-7-heterocycloalkyl, C3-7- cycloalkyl, fused aryl-C-heterocycloalkyl and C1-6-alkyl, each of which is optionally substituted; R4 and R5 are each independently hydrogen, or optionally substituted C3-7- cycloalkyl, aryl, heteroaryl, C1-6-alkyl or C3-6-heterocycloalkyl; or R4 and R5 together with the N to which they are attached form a C3-6-heterocycloalkyl ring; each R6 is independently selected from C1-6-alkyl, C3-7 cycloalkyl, C-heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted; each R7 is selected from hydrogen, optionally substituted C1-6-alkyl and C3-7-cycloalkyl; each of R8 and R9 is independently hydrogen or optionally substituted C1-6-alkyl; or R8 and R9 together with the N to which they are attached form a C4-6-heterocycloalkyl; each R10 is selected from C3-7- cycloalkyl and optionally substituted C1-6-alkyl; each R11 is independently selected from C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkyl-C3-7-cycloalkyl, C4-7-heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted; A is selected from halogen, - NR4S02R5, -CN, -OR6, -NR4R5, -NR7R11, hydroxyl, -CF3, -CONR4R5, -NR4COR5, -NR7(CO)NR4R5, -N02, -C02H, -C02R6, -S02R6, -S02NR4R5, -NR4COR5 ,-NR4COOR5, 6-alkyl and -COR6. Further aspects relate to pharmaceutical compositions, therapeutic uses and process for preparing compounds of formulae la and lb.

  一种具有化学式la或化学式lb的化合物，或其在药学上可接受的盐或酯，其中R1选择自：芳基；杂环芳基；-NHR3；融合芳基-C4-7-杂环烷基；-CONR4R5；-NHCOR6；-C3-7-环烷基；-0-C3-7-环烷基；-NR3R6；以及可选择地取代的-C1-6烷基；其中所述的芳基、杂环芳基、融合芳基-C4-7-杂环烷基和C4-7-杂环烷基均可选择地取代；Q选择自CN、卤素，或选择自C1-6-烷基、C3-7-环烷基、杂环烷基、芳基和杂环芳基，每种均可选择地取代一个或多个取代基A；R2选择自氢、芳基、C1-6-烷基、C2-6-烯烃基、C3-7-环烷基、杂环芳基、C4-7-杂环烷基和卤素，其中所述的C1-6-烷基、C2-6-烯烃基、芳基、杂环芳基和C4-7-杂环烷基均可选择地取代；R3选择自芳基、杂环芳基、C4-7-杂环烷基、C3-7-环烷基、融合芳基-C-杂环烷基和C1-6-烷基，每种均可选择地取代；R4和R5各自独立地为氢，或可选择地取代的C3-7-环烷基、芳基、杂环芳基、C1-6-烷基或C3-6-杂环烷基；或R4和R5与其连接的N一起形成一个C3-6-杂环烷基环；每个R6独立地选择自C1-6-烷基、C3-7-环烷基、C-杂环烷基、芳基和杂环芳基，每种均可选择地取代；每个R7选择自氢、可选择地取代的C1-6-烷基和C3-7-环烷基；每个R8和R9各自独立地为氢或可选择地取代的C1-6-烷基；或R8和R9与其连接的N一起形成一个C4-6-杂环烷基；每个R10选择自C3-7-环烷基和可选择地取代的C1-6-烷基；每个R11独立地选择自C1-6-烷基、C3-7-环烷基、C1-6-烷基-C3-7-环烷基、C4-7-杂环烷基、芳基和杂环芳基，每种均可选择地取代；A选择自卤素、-NR4S02R5、-CN、-OR6、-NR4R5、-NR7R11、羟基、-CF3、-CONR4R5、-NR4COR5、-NR7(CO)NR4R5、-N02、-C02H、-C02R6、-S02R6、-S02NR4R5、-NR4COR5、-NR4COOR5、6-烷基和-COR6。进一步涉及到具有化学式la和lb的化合物的制药组合物、治疗用途和制备过程。
• HETEROAROMATIC COMPOUNDS AND THEIR USE AS DOPAMINE D1 LIGANDS
  申请人：PFIZER INC.

  公开号：US20140128374A1

  公开（公告）日：2014-05-08

  The present invention provides, in part, compounds of Formula I: and pharmaceutically acceptable salts thereof and N-oxides of the foregoing; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds, salts or N-oxides, and their uses for treating D1-mediated (or D1-associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), ADHD, impulsivity, compulsive gambling, overeating, autism spectrum disorder, MCI, age-related cognitive decline, dementia, RLS, Parkinson's disease, Huntington's chorea, anxiety, depression, MDD, TRD, and bipolar disorder.

  本发明在一定程度上提供了以下式I的化合物：以及这些化合物的药用盐和其N-氧化物；用于制备这些化合物的工艺；用于制备中间体；以及含有这些化合物、盐或N-氧化物的组合物，并且它们用于治疗D1介导（或D1相关）的疾病，包括但不限于精神分裂症（例如其认知和消极症状）、认知障碍（例如与精神分裂症、阿尔茨海默病、帕金森病或药物治疗相关的认知障碍）、注意力缺陷多动障碍（ADHD）、冲动性、强迫性赌博、过度进食、自闭症谱系障碍、轻度认知障碍、年龄相关认知衰退、痴呆症、不宁腿综合征、帕金森病、亨廷顿舞蹈症、焦虑、抑郁症、抑郁障碍、难治性抑郁症和躁郁症。
• Design and synthesis of a novel tyrosine kinase inhibitor template
  作者：P. Jake Slavish、Qin Jiang、Xiaoli Cui、Stephan W. Morris、Thomas R. Webb

  DOI：10.1016/j.bmc.2009.03.046

  日期：2009.5

  We report the design and synthesis of an insulin receptor kinase family-targeted inhibitor template using the inhibitor conformation observed in an IGF1R/inhibitor co-crystal complex by application of a novel molecular design approach that we have recently published. The synthesis of the template involves a one pot Opatz cyclization reaction that provides a versatile indole ester in good yields. We

  我们通过应用我们最近发表的新型分子设计方法，使用在 IGF1R/抑制剂共晶复合物中观察到的抑制剂构象来设计和合成胰岛素受体激酶家族靶向抑制剂模板。模板的合成涉及单锅 Opatz 环化反应，该反应以良好的产率提供多功能吲哚酯。我们还开发了所需的化学反应，用额外的取代基精心制作这个模板，并使用这种化学反应制备了一些显示对间变性淋巴瘤激酶 (ALK) 选择性抑制的初始化合物。
• CRF receptor antagonists and methods relating thereto
  申请人：Neurocrine Biosciences, Inc.

  公开号：US06531475B1

  公开（公告）日：2003-03-11

  CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, such as stroke. The CRF receptor antagonists of this invention have the following structure: including stereoisomers and pharmaceutically acceptable salts thereof, wherein n, m, A, B, C, R, R1, R2 and Ar are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same

  本发明披露了CRF受体拮抗剂，其在治疗各种疾病中具有用途，包括治疗在温血动物中表现为CRF过度分泌的疾病，如中风。本发明的CRF受体拮抗剂具有以下结构：包括其立体异构体和药学上可接受的盐，其中n、m、A、B、C、R、R1、R2和Ar的定义如本文所述。还披露了含有CRF受体拮抗剂与药学上可接受的载体结合的组合物，以及使用相同的方法。
• [EN] TOSYLACETATE BASED COMPOUNDS AND DERIVATIVES THEREOF AS PHGDH INHIBITORS<br/>[FR] COMPOSÉS À BASE DE TOSYLACÉTATE ET DÉRIVÉS DE CEUX-CI UTILISÉS EN TANT QU'INHIBITEURS DE PHGDH
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2018167019A1

  公开（公告）日：2018-09-20

  The present invention encompasses compounds of formula (I), wherein the groups R1 to R, A1 to A4 and n have the meanings given in the claims and specification, their use as inhibitors of PHGDH, pharmaceutical compositions which contain compounds of this kind and their use as medicaments, especially as agents for treatment and/or prevention of oncological diseases.

  本发明涵盖了公式（I）的化合物，其中基团R1到R，A1到A4和n的含义如权利要求和说明书中所述，它们作为PHGDH的抑制剂的用途、含有这种化合物的制药组合物以及它们作为药物的用途，特别是作为治疗和/或预防肿瘤疾病的药物。