ethyl 4-cyclobutyl-2,4-dioxobutanoate | 1222955-59-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 酮酸及其衍生物
• 英文名称: ethyl 4-cyclobutyl-2,4-dioxobutanoate
• CAS: 1222955-59-0
• 化学式: C₁₀H₁₄O₄
• 分子量: 198.219
• InChiKey: QHIAUQJBVQTXSM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  14
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  60.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 4-cyclobutyl-2,4-dioxobutanoate 在 sodium tetrahydroborate 、 四溴化碳 、 盐酸羟胺 、 三苯基膦 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 3-(bromomethyl)-5-cyclobutyl-1,2-oxazole
  参考文献：
  名称：

  In Vitro Pharmacokinetic Optimizations of AM2-S31N Channel Blockers Led to the Discovery of Slow-Binding Inhibitors with Potent Antiviral Activity against Drug-Resistant Influenza A Viruses

  摘要：

  Influenza viruses are respiratory pathogens that are responsible for both seasonal influenza epidemics and occasional influenza pandemics. The narrow therapeutic window of oseltamivir, coupled with the emergence of drug resistance, calls for the next-generation of antivirals. With our continuous interest in developing AM2-S31N inhibitors as oral influenza antivirals, we report here the progress of optimizing the in vitro pharmacokinetic (PK) properties of AM2-S31N inhibitors. Several AM2-S31N inhibitors, including compound 10b, were discovered to have potent channel blockage, single to submicromolar antiviral activity, and favorable in vitro PK properties. The antiviral efficacy of compound 10b was also synergistic with oseltamivir carboxylate. Interestingly, binding kinetic studies (K-d, K-on, and K-off) revealed several AM2-S31N inhibitors that have similar K-d values but significantly different K-on and K-off values. Overall, this study identified a potent lead compound (10b) with improved in vitro PK properties that is suitable for the in vivo mouse model studies.

  DOI：

  10.1021/acs.jmedchem.7b01536
• 作为产物：
  描述：

  环丁基甲基酮 、 草酸二乙酯 在 sodium ethanolate 作用下， 以 四氢呋喃 为溶剂， 以76 %的产率得到ethyl 4-cyclobutyl-2,4-dioxobutanoate
  参考文献：
  名称：

  N-联苯吡咯啉酮和二苯并呋喃作为 RNA 结合蛋白 LIN28 抑制剂，破坏 LIN28–Let-7 相互作用

  摘要：

  RNA 结合蛋白 LIN28 是 miRNA let-7生物发生的调节因子。鉴于 LIN28 在肿瘤发生和癌症干细胞发育中发挥的核心作用以及 LIN28 与不良临床预后的相关性，LIN28 抑制剂受到高度追捧。尽管已经报道了不同支架的 LIN28 抑制剂，但由于进行的构效关系 (SAR) 研究非常有限，因此大多数 LIN28 抑制小分子的潜力尚未得到充分探索。我们之前将三取代吡咯啉酮确定为一类新的 LIN28 抑制剂，可破坏 LIN28- let-7相互作用。在这里，我们通过评估 95 个小分子进行了广泛的 SAR，并鉴定了具有N-联苯或N-二苯并呋喃取代基的新型三取代吡咯啉酮，推翻了水杨酸部分对于活性必不可少的现有结论。用杂环取代基交换 LIN28 抑制剂中带负电荷的水杨酸部分有利于膜通透性，导致细胞测定中的活性增加，并有可能降低毒性。

  DOI：

  10.1021/acsmedchemlett.3c00341

文献信息

• [EN] 2-AMINO-6-METHYL-4,4a,5,6-TETRAHYDROPYRANO[3,4-d][1,3]THIAZIN-8a(8H)-YL-1,3-THIAZOL-4-YL AMIDES<br/>[FR] AMIDES 2-AMINO-6-MÉTHYL-4,4A,5,6-TÉTRAHYDROPYRANO[3,4-D][1,3]THIAZIN-8A(8H)-YL-1,3-THIAZOL-4-YLE
  申请人：PFIZER

  公开号：WO2015155626A1

  公开（公告）日：2015-10-15

  The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula (I), and the variable R1 is as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  本发明涉及所披露的化合物、互变异构体和药学上可接受的盐，其中所述化合物具有式(I)的结构，变量R1如规范中所定义。还披露了相应的药物组合物、治疗方法、合成方法和中间体。
• [EN] HETEROAROMATIC MACROCYCLIC ETHER CHEMOTHERAPEUTIC AGENTS<br/>[FR] AGENTS CHIMIOTHÉRAPEUTIQUES À BASE D'ÉTHER MACROCYCLIQUE HÉTÉROAROMATIQUE
  申请人：NUVALENT INC

  公开号：WO2021226269A1

  公开（公告）日：2021-11-11

  Disclosed are heterocyclic heteroaromatic macrocyclic ether compounds, pharmaceutically acceptable salts of the compounds and pharmaceutical compositions thereof. Also disclosed are methods of treating or preventing cancer using the heterocyclic heteroaromatic macrocyclic ether compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions thereof.

  揭示了杂环杂芳大环醚化合物，这些化合物的药用盐以及它们的药物组合物。还揭示了使用这些杂环杂芳大环醚化合物、这些化合物的药用盐以及它们的药物组合物来治疗或预防癌症的方法。
• PDE9 inhibitors for treating type 2 diabetes,metabolic syndrome, and cardiovascular disease
  申请人：Pfizer Inc.

  公开号：US20040220186A1

  公开（公告）日：2004-11-04

  The invention provides compounds of Formula (I) 1 the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, wherein A, P, J, x, and R 10 are as defined herein; pharmaceutical compositions thereof; and methods of using the pharmaceutical compositions for the treatment of diseases, including, diabetes, including type 1 and type 2 diabetes, hyperglycemia, dyslipidemia, impaired glucose tolerance, metabolic syndrome, and/or cardiovascular disease.

  该发明提供了公式（I）1的化合物及其立体异构体和前药，以及该化合物、立体异构体和前药的药学上可接受的盐，其中A、P、J、x和R10如本文所定义；其制药组合物；以及使用该制药组合物治疗疾病的方法，包括糖尿病，包括1型和2型糖尿病，高血糖，血脂异常，葡萄糖耐量受损，代谢综合征和/或心血管疾病。
• [EN] 2H-PYRAZOLO [4,3-D]PYRIMIDIN-5-AMINE DERIVATIVES AS H4 HISTAMINE RECEPTOR ANTAGONISTS FOR THE TREATMENT OF ALLERGIC, IMMUNOLOGICAL AND INFLAMMATORY DISEASES<br/>[FR] DÉRIVÉS DE 2H-PYRAZOLO[4,3-D]PYRIMIDIN-5-AMINE UTILISÉS COMME ANTAGONISTES DES RÉCEPTEURS H4 DE L'HISTAMINE POUR LE TRAITEMENT DE MALADIES ALLERGIQUES, IMMUNOLOGIQUES ET INFLAMMATOIRES
  申请人：PALAU PHARMA SA

  公开号：WO2010043633A1

  公开（公告）日：2010-04-22

  Pyrazolopyrimidine derivatives of formula (I), wherein the meaning of the different substituents are those indicated in the description. These compounds are useful as histamine H4 receptor antagonists.

  式（I）的吡唑吡嘧啶衍生物，其中不同取代基的含义如描述中所示。这些化合物可用作组胺H4受体拮抗剂。
• 2-Amino-6-Methyl-4,4a,5,6-Tetrahydropyrano[3,4-d][1,3]Thiazin-8a(8H)-yl-1,3-Thiazol-4-yl Amides
  申请人：Pfizer Inc.

  公开号：US20150291621A1

  公开（公告）日：2015-10-15

  The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula I, and the variable R 1 is as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  本发明涉及公开的化合物、互变异构体和药学上可接受的盐，其中化合物具有公式I的结构，变量R1如规范中所定义。本发明还公开了相应的药物组合物、治疗方法、合成方法和中间体。