2-[(dimethylamino)methyl]-8-bromo[1]benzothieno[3,2-d]pyrimidin-4(3H)-one | 1036380-83-2

• 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-[(dimethylamino)methyl]-8-bromo[1]benzothieno[3,2-d]pyrimidin-4(3H)-one
• 英文别名: 8-bromo-2-dimethylaminomethyl-3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-one；Benzothienopyrimidinone deriv., 8；8-bromo-2-[(dimethylamino)methyl]-3H-[1]benzothiolo[3,2-d]pyrimidin-4-one
• CAS: 1036380-83-2
• 化学式: C₁₃H₁₂BrN₃OS
• 分子量: 338.228
• InChiKey: NNXJGFIMOCXDNA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  72.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-[(dimethylamino)methyl]-8-bromo[1]benzothieno[3,2-d]pyrimidin-4(3H)-one 、 3-氟苯基硼酸 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium carbonate 作用下， 以 乙二醇二甲醚 、 乙醇 、 水 为溶剂， 反应 0.17h， 生成 2-[(dimethylamino)methyl]-8-(3-fluorophenyl)[1]benzothieno[3,2-d]pyrimidin-4(3H)-one
  参考文献：
  名称：

  Discovery of 3H-Benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective, and Orally Bioavailable Inhibitors of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (PIM) Kinases

  摘要：

  Pim-1, Pim-2, and Pim-3 are a family of serine/threonine kinases which have been Found to be overexpressed in a variety of hematopoietic malignancies and solid tumors. Benzothienopyrimidinones were discovered as a novel class of Pim inhibitors that potently inhibit all three Pim kinases with subnanomolar to low single-digit nanomolar K-i values and exhibit excellent selectivity against a panel of diverse kinases. Protein crystal structures of the bound Pim-1 complexes of benzothienopyrimidinones 3b (PDB code 3JYA), 6e (PDB code 3JYO), and 12b (PDB code 3JXW) were determined and used to guide SAR studies. Multiple compounds exhibited potent antiproliferative activity in K562 and MV4-11 cells with submicromolar EC50 values. For example, compound 14j inhibited the growth of K562 cells with an EC50 value of 1.7 mu M and showed K-i values of 2, 3, and 0.5 nM against Pim-1, Pim-2, and Pim-3, respectively. These novel Pim kinase inhibitors efficiently interrupted the phosphorylation of Bad in both K562 and LnCaP-Bad cell lines, indicating that their potent biological activities are mechanism-based. The pharmacokinetics of 14j was studied in CD-1 mice and shown to exhibit bioavailability of 76% after oral dosing. ADME profiling of 14j suggested a long half-life in both human and mouse liver microsomes, good permeability, modest protein bin-ling, and no CYP inhibition below 20 mu M concentration.

  DOI：

  10.1021/jm900943h
• 作为产物：
  描述：

  methyl 3-(1-amino-2-chloroethylideneamino)-5-bromobenzo[b]thiophene-2-carboxylate hydrochloride 、 二甲胺 以 甲醇 为溶剂， 生成 2-[(dimethylamino)methyl]-8-bromo[1]benzothieno[3,2-d]pyrimidin-4(3H)-one
  参考文献：
  名称：

  Discovery of 3H-Benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective, and Orally Bioavailable Inhibitors of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (PIM) Kinases

  摘要：

  Pim-1, Pim-2, and Pim-3 are a family of serine/threonine kinases which have been Found to be overexpressed in a variety of hematopoietic malignancies and solid tumors. Benzothienopyrimidinones were discovered as a novel class of Pim inhibitors that potently inhibit all three Pim kinases with subnanomolar to low single-digit nanomolar K-i values and exhibit excellent selectivity against a panel of diverse kinases. Protein crystal structures of the bound Pim-1 complexes of benzothienopyrimidinones 3b (PDB code 3JYA), 6e (PDB code 3JYO), and 12b (PDB code 3JXW) were determined and used to guide SAR studies. Multiple compounds exhibited potent antiproliferative activity in K562 and MV4-11 cells with submicromolar EC50 values. For example, compound 14j inhibited the growth of K562 cells with an EC50 value of 1.7 mu M and showed K-i values of 2, 3, and 0.5 nM against Pim-1, Pim-2, and Pim-3, respectively. These novel Pim kinase inhibitors efficiently interrupted the phosphorylation of Bad in both K562 and LnCaP-Bad cell lines, indicating that their potent biological activities are mechanism-based. The pharmacokinetics of 14j was studied in CD-1 mice and shown to exhibit bioavailability of 76% after oral dosing. ADME profiling of 14j suggested a long half-life in both human and mouse liver microsomes, good permeability, modest protein bin-ling, and no CYP inhibition below 20 mu M concentration.

  DOI：

  10.1021/jm900943h

文献信息

• PIM KINASE INHIBITORS AS CANCER CHEMOTHERAPEUTICS
  申请人：Penning Thomas D.

  公开号：US20080161559A1

  公开（公告）日：2008-07-03

  Inhibitors of Pim kinases, ways to make them and methods of treating patients using them are disclosed.

  抑制Pim激酶的抑制剂，制备方法以及利用它们治疗患者的方法被披露。
• US8148384B2
  申请人：——

  公开号：US8148384B2

  公开（公告）日：2012-04-03
• [EN] PIM KINASE INHIBITORS AS CANCER CHEMOTHERAPEUTICS<br/>[FR] INHIBITEURS DE LA PIM KINASE COMME AGENTS CHIMIOTHÉRAPEUTIQUES DESTINÉS À LUTTER CONTRE LE CANCER
  申请人：ABBOTT LAB

  公开号：WO2008082839A2

  公开（公告）日：2008-07-10

  [EN] Inhibitors of Pim kinases, ways to make them and methods of treating patients using them are disclosed.
  [FR] La présente invention concerne des inhibiteurs des Pim kinases, des manières pour les fabriquer et des procédés de traitement de patients les utilisant.
• [EN] PIM KINASE INHIBITORS AS CANCER CHEMOTHERAPEUTICS<br/>[FR] INHIBITEURS DE LA PIM KINASE UTILISÉS COMME AGENTS CHIMIOTHÉRAPEUTIQUES CONTRE LE CANCER
  申请人：ABBOTT LAB

  公开号：WO2008082840A1

  公开（公告）日：2008-07-10

  [EN] Inhibitors of Pim kinases of formula (I), ways to make them and methods of treating patients using them are disclosed wherein X, A₁ -A₃ are as defined in the claims.
  [FR] La présente invention concerne des inhibiteurs des Pim kinases de formule (I), des manières pour les fabriquer et des procédés de traitement de patients les utilisant. Dans ladite formule, X, A₁ -A₃ sont tels que définis dans les revendications.