2-((2-amino-6-chloro-9H-purin-9-yl)methyl)-3,5-dimethylpyridin-4-ol | 848695-83-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 2-((2-amino-6-chloro-9H-purin-9-yl)methyl)-3,5-dimethylpyridin-4-ol
• 英文别名: 2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol；o-Desmethyl BIIB021；2-[(2-amino-6-chloropurin-9-yl)methyl]-3,5-dimethyl-1H-pyridin-4-one
• CAS: 848695-83-0
• 化学式: C₁₃H₁₃ClN₆O
• 分子量: 304.739
• InChiKey: UBBCAAXVXOVGLY-UHFFFAOYSA-N

物化性质

• 熔点：
  255-270 °C
• 沸点：
  737.4±70.0 °C(Predicted)
• 密度：
  1.62±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  21
• 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：
  98.7
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-碘代丙烷 、 2-((2-amino-6-chloro-9H-purin-9-yl)methyl)-3,5-dimethylpyridin-4-ol 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以40%的产率得到6-chloro-9-(4-isopropoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
  参考文献：
  名称：

  Rationally Designed High-Affinity 2-Amino-6-halopurine Heat Shock Protein 90 Inhibitors That Exhibit Potent Antitumor Activity

  摘要：

  Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. We now report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine (30). These highly potent inhibitors (IC50 of 30 = 0.009 mu M in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumor cell lines (IC50 of 30 = 0.03 mu M in MCF7 cells). Moreover, this class of inhibitors shows higher affinity for the activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. When administered orally to mice, these compounds exhibited potent tumor growth inhibition (> 80%) in an N87 xenograft model, similar to that observed with 17-allylamino-17-desmethoxygeldanamycin (17-AAG), which is a compound currently in phase I/II clinical trials.

  DOI：

  10.1021/jm050752+
• 作为产物：
  描述：

  BIIB 021; 6-氯-9-[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]-9H-嘌呤-2-胺 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 生成 2-((2-amino-6-chloro-9H-purin-9-yl)methyl)-3,5-dimethylpyridin-4-ol
  参考文献：
  名称：

  Rationally Designed High-Affinity 2-Amino-6-halopurine Heat Shock Protein 90 Inhibitors That Exhibit Potent Antitumor Activity

  摘要：

  Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. We now report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine (30). These highly potent inhibitors (IC50 of 30 = 0.009 mu M in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumor cell lines (IC50 of 30 = 0.03 mu M in MCF7 cells). Moreover, this class of inhibitors shows higher affinity for the activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. When administered orally to mice, these compounds exhibited potent tumor growth inhibition (> 80%) in an N87 xenograft model, similar to that observed with 17-allylamino-17-desmethoxygeldanamycin (17-AAG), which is a compound currently in phase I/II clinical trials.

  DOI：

  10.1021/jm050752+

文献信息

• Process Development of an N-Benzylated Chloropurine at the Kilogram Scale
  作者：Xianglin Shi、Hexi Chang、Markus Grohmann、William F. Kiesman、Daw-Iong Albert Kwok

  DOI：10.1021/op5003903

  日期：2015.3.20

  large-scale preparation of 6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-2-amine methanesulfonic acid salt (4) from commercially available starting materials. In the first step, the benzylpurine free base (3) was prepared by benzylation of 6-chloro-9H-purin-2-amine (1) with 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride (2). The benzylpurine free base was then directly

  为大规模制备6-氯-9-（（4-甲氧基-3,5-二甲基吡啶-2-基）甲基）-9 H-嘌呤-2-胺甲烷磺酸开发了两步制药工艺来自市售起始原料的酸盐（4）。第一步，用2-（氯甲基）-4-甲氧基-3,5-二甲基吡啶盐酸盐（6-氯-9 H-嘌呤-2-胺（1）进行苄基化反应制得苄嘌呤游离碱（3）。2）。然后将苄嘌呤游离碱直接转化为甲磺酸盐。有必要将吡啶盐酸盐2分批加入K 2 CO 3的混合物中。（-325目）和氯嘌呤化合物1的二甲基乙酰胺（DMA）。通过过滤除去由N 7苄基化形成的主要的区域异构杂质（6）和无机盐。用MsOH处理DMA滤液，得到的目标盐的降解可忽略不计。在第二步中，尽管产品在溶液中存在水解不稳定性，但通过晶种从DMSO-EtOAc中重结晶粗盐后，结晶API的收率和纯度均很高。
• 2-Aminopurine analogs having HSP90-inhibiting activity
  申请人：Kasibhatla Rao Srinivas

  公开号：US20050113340A1

  公开（公告）日：2005-05-26

  2-Aminopurine analogs are described and demonstrated or predicted to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents in the treatment and prevention of various HSP90 mediated disorders, e.g., proliferative disorders. Method of synthesis and use of such compounds are also described and claimed.

  本文描述了2-氨基嘌呤类似物，并展示或预测其作为热休克蛋白90（HSP90）抑制剂，在治疗和预防各种HSP90介导的疾病，例如增殖性疾病方面具有实用性。还描述和声明了这些化合物的合成方法和使用方法。
• 2-Aminopurine Analogs Having HSP90-Inhibiting Activity
  申请人：Kasibhatla Rao Srinivas

  公开号：US20070185064A1

  公开（公告）日：2007-08-09

  2-Aminopurine analogs are described and demonstrated or predicted to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents in the treatment and prevention of various HSP90 mediated disorders, e.g., proliferative disorders. Method of synthesis and use of such compounds are also described and claimed.

  本文描述了2-氨基嘌呤类似物，并证明或预测其在治疗和预防各种HSP90介导的疾病（如增生性疾病）中作为HSP90抑制剂具有实用价值。还描述和声称了这种化合物的合成方法和使用方法。
• METHODS, COMPOSITIONS AND KITS FOR PROMOTING MOTOR NEURON SURVIVAL AND TREATING AND DIAGNOSING NEURODEGENERATIVE DISORDERS
  申请人：PRESIDENT AND FELLOWS OF HARVARD COLLEGE

  公开号：US20160082015A1

  公开（公告）日：2016-03-24

  Methods, compositions, and kits for promoting motor neuron survival and for treatment and diagnosis of neurodegenerative disorders such as Amyotrophic lateral sclerosis (ALS) and Spinal muscular atrophy (SMA) are described herein.

  本文描述了促进运动神经元存活以及治疗和诊断神经退行性疾病，如肌萎缩侧索硬化症（ALS）和脊髓性肌萎缩症（SMA）的方法、组合物和试剂盒。
• Deazapurine derivatives as HSP90-Inhibitors
  申请人：Conforma Therapeutics Corporation

  公开号：EP2145888A1

  公开（公告）日：2010-01-20

  Heterobicyclic compounds of formula I are described and demonstrated to have utility as Heat Shock Protein 90 (HSP90) inhibiting agent. Method of synthesis and use of such compounds are also described.

  描述并证明了式 I 的杂双环化合物作为热休克蛋白 90（HSP90）抑制剂的实用性。还描述了合成和使用此类化合物的方法。