2-(methylthio)thieno[2,3-d]pyrimidin-4-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: 2-(methylthio)thieno[2,3-d]pyrimidin-4-amine
• 英文别名: 2-methylsulfanylthieno[2,3-d]pyrimidin-4-amine
• 化学式: C₇H₇N₃S₂
• 分子量: 197.285
• InChiKey: WAWBMSKFZIYOSU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(methylthio)thieno[2,3-d]pyrimidin-4-amine 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 噻吩-2-甲酸亚铜(I) 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 54.0h， 生成 tetraethyl (((2-(3-(phenylcarbamoyl)phenyl)thieno[2,3-d]pyrimidin-4-yl)amino)methylene)bis(phosphonate)
  参考文献：
  名称：

  Unraveling the Prenylation–Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors

  摘要：

  Post-translational prenylation of the small GTP-binding proteins (GTPases) is vital to a plethora of biological processes, including cellular proliferation. We have identified a new class of thienopyrimidine-based bisphosphonate (ThP-BP) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) that block protein prenylation in multiple myeloma (MM) cells leading to cellular apoptosis. These inhibitors are also effective in blocking the proliferation of other types of cancer cells. We confirmed intracellular target engagement, demonstrated the mechanism of action leading to apoptosis, and determined a direct correlation between apoptosis and intracellular inhibition of hGGPPS. Administration of a ThP-BP inhibitor to a MM mouse model confirmed in vivo down regulation of Rap 1A geranylgeranylation and reduction of monoclonal immunoglobulins (M-protein, a biomarker of disease burden) in the serum. These results provide the first proof-of-principle that hGGPPS is a valuable therapeutic target in oncology and more specifically for the treatment of multiple myeloma.

  DOI：

  10.1021/acs.jmedchem.8b00886
• 作为产物：
  描述：

  硫氰酸甲酯 、 2-氨基噻吩-3-甲腈 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 24.0h， 以80%的产率得到2-(methylthio)thieno[2,3-d]pyrimidin-4-amine
  参考文献：
  名称：

  [EN] SUBSTITUTED BICYCLIC PYRIMIDINE-BASED COMPOUNDS AND COMPOSITIONS AND USES THEREOF
  [FR] COMPOSÉS BICYCLIQUES SUBSTITUÉS À BASE DE PYRIMIDINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES

  摘要：

  已经制备了Formula I的新型C-2取代双环化合物，并发现它们作为hGGPPS的有效抑制剂，通过抑制蛋白质的戊二烯基酰基化和抑制GGPP的生物合成而被发现是有用的。该申请涉及这些化合物，包括这些化合物的组合物，以及它们的用途，特别是作为用于治疗癌症和其他可通过抑制人类戊二烯基酰基化焦磷酸盐hGGPPS活性的药物。

  公开号：

  WO2018137036A1

文献信息

• Thienopyrimidine derivatives, their preparation and their medical use
  申请人：SANKYO COMPANY LIMITED

  公开号：EP0082023A2

  公开（公告）日：1983-06-22

  Compounds of formula (I): [wherein R1 represents a variety of aliphatic diamino or triami- no groups, a 6- or 7- membered heterocyclic ring containing two nitrogens, one of which is optionally substituted or a tetrahydro-1,4-thiazin-4-yl group; R2 represents an optionally mono- or di- alkyl-substituted amino group, a mono- or di-(2-hydroxyethyl)-substituted amino group or an optionally mono- or di- alkyl-substituted aminoethylamino group; and R3 and R4 each represents hydrogen or C1-C4 alkyl or together represent tri- to penta- methylene] and salts thereof may be prepared by reacting an equivalent compound, but in which the groups R1 and R2 are replaced by leaving groups, with compounds R'H (in which free amino groups are optionally protected) and R2H. Various of the compounds have one or more of the following activities: hypoglycaemic activity; the ability to inhibit aggregation of blood platelets; hypotensive activity; or diuretic activity. They can be used in the treatment or prophylaxis of thrombosis, hyperglycaemia, hypertension or oedema and may be formulated as compositions with conventional pharmaceutical carriers or diluents.

  式(I)化合物： [其中 R1 代表各种脂肪族二氨基或三氨基、含有两个硝基（其中一个被任选取代）的 6-或 7-成员杂环或四氢-1,4-噻嗪-4-基；R2 代表任选的单-或二-烷基取代的氨基、单-或二-（2-羟乙基）取代的氨基或任选的单-或二-烷基取代的氨基乙氨基；R3和R4各自代表氢或C1-C4烷基，或共同代表三亚甲基至五亚甲基]及其盐类可通过将等效化合物（但其中基团R1和R2被离去基团取代）与化合物R'H（其中游离氨基可任选被保护）和R2H反应制备。这些化合物具有以下一种或多种活性：降血糖活性；抑制血小板聚集的能力；降血压活性；或利尿活性。它们可用于治疗或预防血栓形成、高血糖、高血压或水肿，并可与常规药物载体或稀释剂配制成组合物。
• Substituted bicyclic pyrimidine-based compounds and compositions and uses thereof
  申请人：Tsantrizos Youla S.

  公开号：US11279719B2

  公开（公告）日：2022-03-22

  Novel C-2-substituted bicyclic compounds of Formula I have been prepared and found to be useful as inhibitors of by inhibiting geranylgeranylation of proteins. The application is directed to these compounds, to compositions comprising these compounds and to their use, in particular as medicaments to cancer and other conditions treatable by inhibiting human geranylgeranylation pyrophosphate hGGPPS activity.

  制备出了新颖的 C-2 取代的式 I 双环化合物，并发现这些化合物可通过抑制蛋白质的香叶木苷酸化而成为有用的抑制剂。 本申请涉及这些化合物、包含这些化合物的组合物及其用途，特别是作为可通过抑制人叶愈创木酚酰化焦磷酸 hGGPPS 活性来治疗癌症和其他疾病的药物。
• [EN] SUBSTITUTED BICYCLIC PYRIMIDINE-BASED COMPOUNDS AND COMPOSITIONS AND USES THEREOF<br/>[FR] COMPOSÉS BICYCLIQUES SUBSTITUÉS À BASE DE PYRIMIDINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
  申请人：THE ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL UNIV

  公开号：WO2018137036A1

  公开（公告）日：2018-08-02

  Novel C-2-substituted bicyclic compounds of Formula I have been prepared and found to be useful as potent inhibitors of hGGPPS by inhibiting geranylgeranylation of proteins and inhibiting the biosynthesis of GGPP. The application is directed to these compounds, to compositions comprising these compounds, and to their use, in particular as medicaments for use in the treatment of cancer and other conditions which are treatable by inhibiting human geranylgeranylation pyrophosphate hGGPPS activity.

  已经制备了Formula I的新型C-2取代双环化合物，并发现它们作为hGGPPS的有效抑制剂，通过抑制蛋白质的戊二烯基酰基化和抑制GGPP的生物合成而被发现是有用的。该申请涉及这些化合物，包括这些化合物的组合物，以及它们的用途，特别是作为用于治疗癌症和其他可通过抑制人类戊二烯基酰基化焦磷酸盐hGGPPS活性的药物。
• Unraveling the Prenylation–Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors
  作者：Cyrus M. Lacbay、Daniel D. Waller、Jaeok Park、Mònica Gómez Palou、Félix Vincent、Xian Fang Huang、Viviane Ta、Albert M. Berghuis、Michael Sebag、Youla S. Tsantrizos

  DOI：10.1021/acs.jmedchem.8b00886

  日期：2018.8.9

  Post-translational prenylation of the small GTP-binding proteins (GTPases) is vital to a plethora of biological processes, including cellular proliferation. We have identified a new class of thienopyrimidine-based bisphosphonate (ThP-BP) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) that block protein prenylation in multiple myeloma (MM) cells leading to cellular apoptosis. These inhibitors are also effective in blocking the proliferation of other types of cancer cells. We confirmed intracellular target engagement, demonstrated the mechanism of action leading to apoptosis, and determined a direct correlation between apoptosis and intracellular inhibition of hGGPPS. Administration of a ThP-BP inhibitor to a MM mouse model confirmed in vivo down regulation of Rap 1A geranylgeranylation and reduction of monoclonal immunoglobulins (M-protein, a biomarker of disease burden) in the serum. These results provide the first proof-of-principle that hGGPPS is a valuable therapeutic target in oncology and more specifically for the treatment of multiple myeloma.