4-{[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 英文名称: 4-{[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide
• 英文别名: 4-{[(1R,2s,3S,5s,7s)-5-hydroxy-2-adamantyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide
• 化学式: C₁₈H₂₂N₄O₂
• 分子量: 326.398
• InChiKey: DREIJXJRTLTGJC-ZKVNVPQCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.01
• 重原子数：
  24.0
• 可旋转键数：
  3.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  104.03
• 氢给体数：
  4.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  4-{[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide 在 氢溴酸 作用下， 以 乙醇 、 水 为溶剂， 以161 kg的产率得到4-{[(1R,2s,3S,5s,7s)-5-hydroxy-2-adamantyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrobromide
  参考文献：
  名称：

  CRYSTAL OF FUSED PYRIDINE COMPOUND SALT

  摘要：

  提供了一种在固态中高度稳定且作为制备药物产品的大块材料有用的化合物的盐或晶体。解决方法为：4-{[(1R,2s,3S,5s,7s)-5-羟基-2-重氮基]氨基}-1H-吡咯并[2,3-b]吡啶-5-羧酰胺琥珀酸盐，4-{[(1R,2s,3S,5s,7s)-5-羟基-2-重氮基]氨基}-1H-吡咯并[2,3-b]吡啶-5-羧酰胺溴化物，以及4-{[(1R,2s,3S,5s,7s)-5-羟基-2-重氮基]氨基}-1H-吡咯并[2,3-b]吡啶-5-羧酰胺盐酸盐及其晶体可作为制备固体制剂，特别是固体分散制剂的大块材料。此外，溴化物的晶体在固态中具有优异的稳定性，并可作为制备药物产品的大块材料。

  公开号：

  US20130102628A1
• 作为产物：
  描述：

  4-aminoadamantan-1-ol 在 N-甲基吡咯烷酮 、 三正丁胺 、 氢气 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 10.5h， 生成 4-{[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide
  参考文献：
  名称：

  Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor

  摘要：

  Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assays. Chemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the1H-pyrrolo [2,3-b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.

  DOI：

  10.1016/j.bmc.2018.08.005

文献信息

• CRYSTAL OF FUSED PYRIDINE COMPOUND SALT
  申请人：Kikuchi Takashi

  公开号：US20130102628A1

  公开（公告）日：2013-04-25

  [Problem] A salt or crystal of a compound which is highly stable in a solid state and useful as a bulk material for the preparation of a pharmaceutical product is provided. [Means for Solution] 4-[(1R,2s,3S,5s,7s)-5-Hydroxy-2-adamantyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide succinate, 4-[(1R,2s,3S,5s,7s)-5-hydroxy-2-adamantyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrobromide, and 4-[(1R,2s,3S,5s,7s)-5-hydroxy-2-adamantyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrochloride and crystals thereof are useful as a bulk material for the preparation of a solid preparation, in particular, a solid dispersion preparation. Furthermore, the crystal of the hydrobromide has excellent stability in a solid state and is useful as a bulk material for the preparation of a pharmaceutical product.

  提供了一种在固态中高度稳定且作为制备药物产品的大块材料有用的化合物的盐或晶体。解决方法为：4-[(1R,2s,3S,5s,7s)-5-羟基-2-重氮基]氨基}-1H-吡咯并[2,3-b]吡啶-5-羧酰胺琥珀酸盐，4-[(1R,2s,3S,5s,7s)-5-羟基-2-重氮基]氨基}-1H-吡咯并[2,3-b]吡啶-5-羧酰胺溴化物，以及4-[(1R,2s,3S,5s,7s)-5-羟基-2-重氮基]氨基}-1H-吡咯并[2,3-b]吡啶-5-羧酰胺盐酸盐及其晶体可作为制备固体制剂，特别是固体分散制剂的大块材料。此外，溴化物的晶体在固态中具有优异的稳定性，并可作为制备药物产品的大块材料。
• PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION
  申请人：Astellas Pharma Inc.

  公开号：EP2979698A1

  公开（公告）日：2016-02-03

  A pharmaceutical composition containing, as the active ingredient, 4-[(1R,2s,3S,5s,7s)-5-hydroxy-2-adamantyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, of which the solubility in an acidic pH region is different from that in a neutral pH region, with rapid disintegration property and rapid drug dissolution property as well as the expectation of a good drug dosing compliance, is provided. The pharmaceutical composition for oral administration of the present invention contains 4-[(1R,2s,3S,5s,7s)-5-hydroxy-2-adamantyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof, and a hydrophilic lubricant, and is useful as a pharmaceutical composition for oral administration with rapid disintegration property and rapid drug dissolution property as well as the expectation of a good drug dosing compliance.

  本发明提供了一种含有 4-[(1R,2s,3S,5s,7s)-5-羟基-2-金刚烷基]氨基}-1H-吡咯并[2,3-b]吡啶-5-甲酰胺作为活性成分的药物组合物，该药物组合物在酸性 pH 值区域的溶解度不同于在中性 pH 值区域的溶解度，具有快速崩解特性和快速药物溶解特性，并有望实现良好的药物剂量依从性。本发明的口服药物组合物含有 4-[(1R,2s,3S,5s,7s)-5-羟基-2-金刚烷基]氨基}-1H-吡咯并[2,3-b]吡啶-5-甲酰胺或其药学上可接受的盐，以及亲水性润滑剂，可作为口服药物组合物使用，具有快速崩解特性和快速药物溶出特性，以及良好的药物剂量依从性。
• US8779140B2
  申请人：——

  公开号：US8779140B2

  公开（公告）日：2014-07-15
• US9408835B2
  申请人：——

  公开号：US9408835B2

  公开（公告）日：2016-08-09
• [EN] CRYSTAL OF FUSED PYRIDINE COMPOUND SALT<br/>[FR] CRISTAL D'UN SEL D'UN COMPOSÉ DE PYRIDINE FUSIONNÉ
  申请人：ASTELLAS PHARMA INC

  公开号：WO2011162300A1

  公开（公告）日：2011-12-29

  【課題】優れた固体状態での安定性を有し、医薬品の製造原料として有用な化合物の塩もしくは結晶を提供する。 【解決手段】4-[(1R,2s,3S,5s,7s)-5-ヒドロキシ-2-アダマンチル]アミノ}-1H-ピロロ[2,3-b]ピリジン-5-カルボキサミドコハク酸塩、4-[(1R,2s,3S,5s,7s)-5-ヒドロキシ-2-アダマンチル]アミノ}-1H-ピロロ[2,3-b]ピリジン-5-カルボキサミド臭化水素酸塩、及び、4-[(1R,2s,3S,5s,7s)-5-ヒドロキシ-2-アダマンチル]アミノ}-1H-ピロロ[2,3-b]ピリジン-5-カルボキサミド塩酸塩、並びにこれらの結晶は、固体製剤殊に固体分散体製剤の製造に有用である。また、臭化水素酸塩の結晶は、固体状態の安定性に優れ、医薬品の製造原体として有用である。