2,6-dichloro-9-(3,5-difluorophenyl)-9H-purine | 1199523-48-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2,6-dichloro-9-(3,5-difluorophenyl)-9H-purine
• 英文别名: 2,6-Dichloro-9-(3,5-difluorophenyl)purine
• CAS: 1199523-48-2
• 化学式: C₁₁H₄Cl₂F₂N₄
• 分子量: 301.082
• InChiKey: CFINFFNFMMVSKT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  43.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,2-二氟乙胺 、 2,6-dichloro-9-(3,5-difluorophenyl)-9H-purine 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 2-chloro-N-(2,2-difluoroethyl)-9-(3,5-difluorophenyl)purin-6-amine
  参考文献：
  名称：

  Identification and Optimization of Inhibitors of Trypanosomal Cysteine Proteases: Cruzain, Rhodesain, and TbCatB

  摘要：

  Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas' disease and African sleeping sickness, respectively. Both parasites rely oil essential cysteine proteases for survival: cruzain for T. cruzi and TbCatB/rhodesain for T. brucei. A recent quantitative high-throughput screen of cruzain identified triazine nitriles. which are known inhibitors of other cysteine proteases, its reversible inhibitors of the enzyme. Structural modifications detailed herein, including core scaffold modification from triazine to purine, improved the in vitro potency against both cruzain and rhodesain by 350-fold, while also gaining activity against T. brucei parasites. Selected compounds were screened against it panel of human cysteine and serine proteases to determine selectivity, and it cocrystal was obtained of our most potent analogue bound to cruzain.

  DOI：

  10.1021/jm901069a
• 作为产物：
  描述：

  2,6-二氯嘌呤 、 3,5-二氟苯硼酸 在 copper diacetate 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以21%的产率得到2,6-dichloro-9-(3,5-difluorophenyl)-9H-purine
  参考文献：
  名称：

  [EN] SUBSTITUTED TRIAZINE AND PURINE COMPOUNDS, METHODS OF INHIBITING CRUZAIN AND RHODESAIN AND METHODS OF TREATING CHAGAS DISEASE AND AFRICAN TRYPANOSOMIASIS
  [FR] COMPOSÉS DE TRIAZINE ET DE PURINE SUBSTITUÉES, MÉTHODES D'INHIBITION DE CRUZAÏNE ET DE RHODÉSAÏNE ET MÉTHODES DE TRAITEMENT DE LA MALADIE DE CHAGAS ET DE LA TRYPANOSOMIASE AFRICAINE

  摘要：

  这项发明提供了一种新型的三嗪和嘌呤化合物（II），可用于治疗和预防哺乳动物原生动物疾病，包括非洲锥虫病和充血性心脏病。

  公开号：

  WO2010059418A1

文献信息

• Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties
  作者：Mathieu Bibian、Ronald J. Rahaim、Jun Yong Choi、Yoshihiko Noguchi、Stephan Schürer、Weimin Chen、Shima Nakanishi、Konstantin Licht、Laura H. Rosenberg、Lin Li、Yangbo Feng、Michael D. Cameron、Derek R. Duckett、John L. Cleveland、William R. Roush

  DOI：10.1016/j.bmcl.2013.05.075

  日期：2013.8

  The development of a series of potent and highly selective casein kinase 1δ/ε (CK1δ/ε) inhibitors is described. Starting from a purine scaffold inhibitor (SR-653234) identified by high throughput screening, we developed a series of potent and highly kinase selective inhibitors, including SR-2890 and SR-3029, which have IC50 ⩽ 50 nM versus CK1δ. The two lead compounds have ⩽100 nM EC50 values in MTT

  描述了一系列有效且高度选择性的酪蛋白激酶 1δ/ε (CK1δ/ε) 抑制剂的开发。从通过高通量筛选鉴定的嘌呤支架抑制剂 (SR-653234) 开始，我们开发了一系列强效且高激酶选择性的抑制剂，包括 SR-2890 和 SR-3029，与 CK1δ 相比，其 IC 50  ⩽ 50 nM。这两种先导化合物在针对人 A375 黑色素瘤细胞系的 MTT 测定中具有 ⩽100 nM EC 50值，并且具有适合用于针对人癌细胞系的原理动物异种移植研究的物理、体外和体内 PK 特性。
• Development of dual casein kinase 1δ/1ε (CK1δ/ε) inhibitors for treatment of breast cancer
  作者：Andrii Monastyrskyi、Napon Nilchan、Victor Quereda、Yoshihiko Noguchi、Claudia Ruiz、Wayne Grant、Michael Cameron、Derek Duckett、William Roush

  DOI：10.1016/j.bmc.2017.12.020

  日期：2018.2

  Casein kinase 1δ/ε have been identified as promising therapeutic target for oncology application, including breast and brain cancer. Here, we described our continued efforts in optimization of a lead series of purine scaffold inhibitors that led to identification of two new CK1δ/ε inhibitors 17 and 28 displaying low nanomolar values in antiproliferative assays against the human MDA-MB-231 triple negative

  酪蛋白激酶1δ/ε已被确定为包括乳腺癌和脑癌在内的肿瘤学应用的有希望的治疗靶标。在这里，我们描述了我们在优化嘌呤支架抑制剂前导系列方面的持续努力，该系列试验导致鉴定出两种新的CK1δ/ε抑制剂17和28在针对人MDA-MB-231三阴性乳腺癌的抗增殖试验中显示出较低的纳摩尔值。细胞系具有物理，体外和体内药代动力学特性，适合用于证明针对人类癌症的动物异种移植的原理研究。
• [EN] SUBSTITUTED TRIAZINE AND PURINE COMPOUNDS, METHODS OF INHIBITING CRUZAIN AND RHODESAIN AND METHODS OF TREATING CHAGAS DISEASE AND AFRICAN TRYPANOSOMIASIS<br/>[FR] COMPOSÉS DE TRIAZINE ET DE PURINE SUBSTITUÉES, MÉTHODES D'INHIBITION DE CRUZAÏNE ET DE RHODÉSAÏNE ET MÉTHODES DE TRAITEMENT DE LA MALADIE DE CHAGAS ET DE LA TRYPANOSOMIASE AFRICAINE
  申请人：GOVERNMENT OF THE U S A AS REP

  公开号：WO2010059418A1

  公开（公告）日：2010-05-27

  The invention provides for novel triazine and purine compounds ( II ) that are useful for the treatment and prevention of mammalian protozoal diseases, including Af rican trypanosomiasis and Chagas disease.

  这项发明提供了一种新型的三嗪和嘌呤化合物（II），可用于治疗和预防哺乳动物原生动物疾病，包括非洲锥虫病和充血性心脏病。
• Identification and Optimization of Inhibitors of Trypanosomal Cysteine Proteases: Cruzain, Rhodesain, and TbCatB
  作者：Bryan T. Mott、Rafaela S. Ferreira、Anton Simeonov、Ajit Jadhav、Kenny Kean-Hooi Ang、William Leister、Min Shen、Julia T. Silveira、Patricia S. Doyle、Michelle R. Arkin、James H. McKerrow、James Inglese、Christopher P. Austin、Craig J. Thomas、Brian K. Shoichet、David J. Maloney

  DOI：10.1021/jm901069a

  日期：2010.1.14

  Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas' disease and African sleeping sickness, respectively. Both parasites rely oil essential cysteine proteases for survival: cruzain for T. cruzi and TbCatB/rhodesain for T. brucei. A recent quantitative high-throughput screen of cruzain identified triazine nitriles. which are known inhibitors of other cysteine proteases, its reversible inhibitors of the enzyme. Structural modifications detailed herein, including core scaffold modification from triazine to purine, improved the in vitro potency against both cruzain and rhodesain by 350-fold, while also gaining activity against T. brucei parasites. Selected compounds were screened against it panel of human cysteine and serine proteases to determine selectivity, and it cocrystal was obtained of our most potent analogue bound to cruzain.