(4-aminosulfonylpyrimidin-5-yl)(5-fluoro-2-methoxyphenyl)methanone | 741712-83-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (4-aminosulfonylpyrimidin-5-yl)(5-fluoro-2-methoxyphenyl)methanone
• 英文别名: (4-Amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone；(4-amino-2-ethylsulfonylpyrimidin-5-yl)-(5-fluoro-2-methoxyphenyl)methanone
• CAS: 741712-83-4
• 化学式: C₁₄H₁₄FN₃O₄S
• 分子量: 339.347
• InChiKey: SNUUKTSRPVYOEO-UHFFFAOYSA-N

物化性质

• 沸点：
  625.7±65.0 °C(Predicted)
• 密度：
  1.397±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  121
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (4-aminosulfonylpyrimidin-5-yl)(5-fluoro-2-methoxyphenyl)methanone 在 三氟乙酸 作用下， 以 二氯甲烷 、 异丙醇 为溶剂， 反应 4.5h， 生成 [4-amino-2-(piperidin-4-ylamino)pyrimidin-5-yl](5-fluoro-2-methoxyphenyl)methanone
  参考文献：
  名称：

  Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), A Potent and Selective Cyclin-Dependent Kinase Inhibitor with Significant in Vivo Antitumor Activity

  摘要：

  The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K-i > 10 AM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K-i = 0.001, 0.003, and 0.001 AM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC50 = 0.08 mu M). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.

  DOI：

  10.1021/jm0606138
• 作为产物：
  描述：

  4-氨基-2-(乙基硫代)-N-甲氧基-N-甲基-5-嘧啶羧酰胺 在 正丁基锂 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 正己烷 、 氯仿 为溶剂， 反应 1.34h， 生成 (4-aminosulfonylpyrimidin-5-yl)(5-fluoro-2-methoxyphenyl)methanone
  参考文献：
  名称：

  Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), A Potent and Selective Cyclin-Dependent Kinase Inhibitor with Significant in Vivo Antitumor Activity

  摘要：

  The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K-i > 10 AM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K-i = 0.001, 0.003, and 0.001 AM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC50 = 0.08 mu M). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.

  DOI：

  10.1021/jm0606138

文献信息

• 4-aminopyrimidine-5-one derivatives
  申请人：——

  公开号：US20040162303A1

  公开（公告）日：2004-08-19

  Novel 4-aminopyrimidine-5-one derivatives are disclosed. These compounds inhibit cyclin-dependent kinases, in particular cyclin-dependent kinase 4 (Cdk4). These compounds and their pharmaceutically acceptable salts and esters have antiproliferative activity and are useful in the treatment or control of cancer, in particular solid tumors. This invention is also directed to pharmaceutical compositions containing such compounds and to methods of treating or controlling cancer, most particularly the treatment or control of breast, lung, colon and prostate tumors. Also disclosed are intermediates useful in the preparation of these novel 4-aminopyrimidine-5-one derivatives.

  本发明揭示了新型4-氨基嘧啶-5-酮衍生物。这些化合物抑制细胞周期蛋白依赖性激酶，特别是细胞周期蛋白依赖性激酶4（Cdk4）。这些化合物及其药学上可接受的盐和酯具有抗增殖活性，并可用于治疗或控制癌症，特别是实体瘤。本发明还涉及含有这些化合物的制药组合物以及治疗或控制癌症的方法，尤其是乳腺、肺、结肠和前列腺肿瘤的治疗或控制。此外，还揭示了制备这些新型4-氨基嘧啶-5-酮衍生物的中间体。
• 4-Aminopyrimidine-5-one derivatives
  申请人：Hoffmann-La Roche Inc.

  公开号：US07157455B2

  公开（公告）日：2007-01-02

  Novel 4-aminopyrimidine-5-one derivatives are disclosed. These compounds inhibit cyclin-dependent kinases, in particular cyclin-dependent kinase 4 (Cdk4). These compounds and their pharmaceutically acceptable salts and esters have antiproliferative activity and are useful in the treatment or control of cancer, in particular solid tumors. This invention is also directed to pharmaceutical compositions containing such compounds and to methods of treating or controlling cancer, most particularly the treatment or control of breast, lung, colon and prostate tumors. Also disclosed are intermediates useful in the preparation of these novel 4-aminopyrimidine-5-one derivatives.

  本发明披露了新型4-氨基嘧啶-5-酮衍生物。这些化合物抑制细胞周期依赖性激酶，特别是细胞周期依赖性激酶4（Cdk4）。这些化合物及其药学上可接受的盐和酯具有抗增殖活性，并且在治疗或控制癌症，特别是实体瘤方面非常有用。本发明还涉及含有这些化合物的制药组合物以及治疗或控制癌症的方法，特别是乳腺癌、肺癌、结肠癌和前列腺癌的治疗或控制方法。还披露了在制备这些新型4-氨基嘧啶-5-酮衍生物过程中有用的中间体。
• 4-AMINOPYRIMIDINE-5-ONE
  申请人：F.HOFFMANN-LA ROCHE AG

  公开号：EP1628619A2

  公开（公告）日：2006-03-01
• US7157455B2
  申请人：——

  公开号：US7157455B2

  公开（公告）日：2007-01-02
• US7615634B2
  申请人：——

  公开号：US7615634B2

  公开（公告）日：2009-11-10