(2S,3S)-2-amino-3-methylpentanoic acid 2-[(E/Z)-4-(3,3-dimethylbutyrylamino)-3,5-difluorobenzoylimino]thiazol-3-ylmethyl ester hydrochloride | 1262897-91-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S,3S)-2-amino-3-methylpentanoic acid 2-[(E/Z)-4-(3,3-dimethylbutyrylamino)-3,5-difluorobenzoylimino]thiazol-3-ylmethyl ester hydrochloride
• 英文别名: [2-[4-(3,3-dimethylbutanoylamino)-3,5-difluorobenzoyl]imino-1,3-thiazol-3-yl]methyl (2S,3S)-2-amino-3-methylpentanoate;hydrochloride
• CAS: 1262897-91-5
• 化学式: C₂₃H₃₀F₂N₄O₄S*ClH
• 分子量: 533.039
• InChiKey: JQWKGZCWEWEXJD-ZYJMRSDMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.24
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  139
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2S,3S)-2-amino-3-methylpentanoic acid 2-[(E/Z)-4-(3,3-dimethylbutyrylamino)-3,5-difluorobenzoylimino]thiazol-3-ylmethyl ester hydrochloride 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 1.0h， 生成 N-[3-chloromethyl-3H-thiazol-2-(E/Z)ylidene]-4-(3,3-dimethylbutyrylamino)-3,5-difluorobenzamide
  参考文献：
  名称：

  Discovery of Phosphoric Acid Mono-{2-[(E/Z)-4-(3,3-dimethyl-butyrylamino)-3,5-difluoro-benzoylimino]-thiazol-3-ylmethyl} Ester (Lu AA47070): A Phosphonooxymethylene Prodrug of a Potent and Selective hA_2A Receptor Antagonist

  摘要：

  The discovery and structure-activity relationship of a series of hA(2A) receptor antagonists is described. Compound 28 was selected from the series as a potent and selective compound and was shown to be efficacious in an in vivo model of Parkinson's disease. It had acceptable ADME properties; however, the low intrinsic solubility of this compound was limiting for its developability, because the oral bioavailability from dosing in suspension was significantly lower than the oral bioavailability from solution dosage. As a consequence, prodrugs of 28 were prepared with dramatically increased aqueous solubility. The prodrugs efficiently delivered 28 into systemic circulation, with no detectable levels of prodrug in plasma samples. From this investigation, we selected 32 (Lu AA47070), a phosphonooxymethylene prodrug of 28, as a drug candidate.

  DOI：

  10.1021/jm1008659
• 作为产物：
  描述：

  (2-((4-(3,3-dimethylbutanamido)-3,5-difluorobenzoyl)imino)thiazol-3(2H)-yl)methyl (tert-butoxycarbonyl)-L-isoleucinate 在 盐酸 作用下， 以 乙醚 为溶剂， 反应 1.0h， 以100%的产率得到(2S,3S)-2-amino-3-methylpentanoic acid 2-[(E/Z)-4-(3,3-dimethylbutyrylamino)-3,5-difluorobenzoylimino]thiazol-3-ylmethyl ester hydrochloride
  参考文献：
  名称：

  Discovery of Phosphoric Acid Mono-{2-[(E/Z)-4-(3,3-dimethyl-butyrylamino)-3,5-difluoro-benzoylimino]-thiazol-3-ylmethyl} Ester (Lu AA47070): A Phosphonooxymethylene Prodrug of a Potent and Selective hA_2A Receptor Antagonist

  摘要：

  The discovery and structure-activity relationship of a series of hA(2A) receptor antagonists is described. Compound 28 was selected from the series as a potent and selective compound and was shown to be efficacious in an in vivo model of Parkinson's disease. It had acceptable ADME properties; however, the low intrinsic solubility of this compound was limiting for its developability, because the oral bioavailability from dosing in suspension was significantly lower than the oral bioavailability from solution dosage. As a consequence, prodrugs of 28 were prepared with dramatically increased aqueous solubility. The prodrugs efficiently delivered 28 into systemic circulation, with no detectable levels of prodrug in plasma samples. From this investigation, we selected 32 (Lu AA47070), a phosphonooxymethylene prodrug of 28, as a drug candidate.

  DOI：

  10.1021/jm1008659

文献信息

• Pro-drugs of N-thiazol-2-yl-benzamide derivatives
  申请人：Sams Graven Anette

  公开号：US20060264485A1

  公开（公告）日：2006-11-23

  The invention relates to compounds of the formula I A-B-Z   I wherein the variables are as defined in the claims. The compounds are pro-drugs of A 2A -receptor ligands with improved aqueous solubility, and are useful in the treatment of neurological and psychiatric disorders where an A 2A -receptor is implicated.

  本发明涉及IA-B-Z式化合物，其中变量如权利要求所定义。这些化合物是A2A受体配体的前药，具有改善的水溶性，并且在涉及A2A受体的神经和精神障碍的治疗中有用。
• WO2006/114093
  申请人：——

  公开号：——

  公开（公告）日：——
• US7674912B2
  申请人：——

  公开号：US7674912B2

  公开（公告）日：2010-03-09
• Discovery of Phosphoric Acid Mono-{2-[(<i>E</i>/<i>Z</i>)-4-(3,3-dimethyl-butyrylamino)-3,5-difluoro-benzoylimino]-thiazol-3-ylmethyl} Ester (Lu AA47070): A Phosphonooxymethylene Prodrug of a Potent and Selective hA_2A Receptor Antagonist
  作者：Anette G. Sams、Gitte K. Mikkelsen、Mogens Larsen、Morten Langgård、Mark E. Howells、Tenna J. Schrøder、Lise T. Brennum、Lars Torup、Erling B. Jørgensen、Christoffer Bundgaard、Mads Kreilgård、Benny Bang-Andersen

  DOI：10.1021/jm1008659

  日期：2011.2.10

  The discovery and structure-activity relationship of a series of hA(2A) receptor antagonists is described. Compound 28 was selected from the series as a potent and selective compound and was shown to be efficacious in an in vivo model of Parkinson's disease. It had acceptable ADME properties; however, the low intrinsic solubility of this compound was limiting for its developability, because the oral bioavailability from dosing in suspension was significantly lower than the oral bioavailability from solution dosage. As a consequence, prodrugs of 28 were prepared with dramatically increased aqueous solubility. The prodrugs efficiently delivered 28 into systemic circulation, with no detectable levels of prodrug in plasma samples. From this investigation, we selected 32 (Lu AA47070), a phosphonooxymethylene prodrug of 28, as a drug candidate.