2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole | 224435-07-8

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole
• 英文别名: 5-[(5-ethyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-amine
• CAS: 224435-07-8
• 化学式: C₉H₁₁N₃OS₂
• 分子量: 241.338
• InChiKey: HFSUOEOQZXTYLK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  119
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-吡啶乙酸 、 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以49%的产率得到2-Amino-5-thio-substituted thiazole 47
  参考文献：
  名称：

  Discovery of Aminothiazole Inhibitors of Cyclin-Dependent Kinase 2:  Synthesis, X-ray Crystallographic Analysis, and Biological Activities

  摘要：

  High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC50 values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase alpha (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2.

  DOI：

  10.1021/jm0201520
• 作为产物：
  描述：

  (2-acetylamino-thiazol-5-ylmercapto)-acetic acid 在 sodium hydroxide 、 硫酸 、 乙酸酐 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 2-amino-5-[[(5-ethyl-2-oxazolyl)methyl]thio]-thiazole
  参考文献：
  名称：

  Discovery of Aminothiazole Inhibitors of Cyclin-Dependent Kinase 2:  Synthesis, X-ray Crystallographic Analysis, and Biological Activities

  摘要：

  High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC50 values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase alpha (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2.

  DOI：

  10.1021/jm0201520

文献信息

• Aminothiazole inhibitors of cyclin dependent kinases
  申请人：Bristol-Myers Squibb Company

  公开号：US06040321A1

  公开（公告）日：2000-03-21

  Compounds of the formula ##STR1## and pharmaceuticaly acceptable salts thereof. As used in formula I, and throughout the specification, the symbols have the following meanings: R.sub.1 and R.sub.2 are independently hydrogen, fluorine or alkyl; R.sub.3 is aryl or heteroaryl R.sub.4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; or CO-alkyl, CONH-alkyl, COO-alkyl, SO.sub.2 -alkyl, C(NCN)NH-alkyl, C(NNO.sub.2)NH-alkyl, C(NH)NH-alkyl, C(NH)NHCO-alkyl, C(NOR.sub.6)NH-alkyl, R.sub.5 is hydrogen or alkyl; R.sub.6 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylakyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; m is an integer of 0 to 2; and n is an integer of 1 to 3. The compounds of formula I are protein kinase inhibitors and are useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.

  公式##STR1##的化合物及其药用盐。在公式I中使用时，以及在说明书中，符号具有以下含义：R.sub.1和R.sub.2独立地是氢、氟或烷基；R.sub.3是芳基或杂环芳基；R.sub.4是氢、烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂环芳基、杂环芳基烷基、杂环烷基、杂环烷基烷基；或CO-烷基、CONH-烷基、COO-烷基、SO.sub.2-烷基、C(NCN)NH-烷基、C(NNO.sub.2)NH-烷基、C(NH)NH-烷基、C(NH)NHCO-烷基、C(NOR.sub.6)NH-烷基；R.sub.5是氢或烷基；R.sub.6是氢、烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂环芳基、杂环芳基烷基、杂环烷基或杂环烷基烷基；m是0到2的整数；n是1到3的整数。公式I的化合物是蛋白激酶抑制剂，可用于治疗和预防增殖性疾病，例如癌症、炎症和关节炎。它们也可能对治疗神经退行性疾病如阿尔茨海默病、心血管疾病、病毒性疾病和真菌性疾病有益。
• AMINOTHIAZOLE INHIBITORS OF CYCLIN DEPENDENT KINASES
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP1042307A1

  公开（公告）日：2000-10-11
• EP1042307A4
  申请人：——

  公开号：EP1042307A4

  公开（公告）日：2003-01-29
• US6040321A
  申请人：——

  公开号：US6040321A

  公开（公告）日：2000-03-21
• US6262096B1
  申请人：——

  公开号：US6262096B1

  公开（公告）日：2001-07-17