4-(3,3-dimethylbutanamido)-3,5-difluoro-N-(thiazol-2-yl)benzamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-(3,3-dimethylbutanamido)-3,5-difluoro-N-(thiazol-2-yl)benzamide
• 英文别名: 4-(3,3-dimethylbutyrylamino)-3,5-difluoro-N-thiazol-2-ylbenzamide；4-(3,3-dimethyl-butyrylamino)-3,5-difluoro-N-thiazol-2-yl-benzamide；Benzamide, 4-[(3,3-dimethyl-1-oxobutyl)amino]-3,5-difluoro-N-2-thiazolyl-；4-(3,3-dimethylbutanoylamino)-3,5-difluoro-N-(1,3-thiazol-2-yl)benzamide
• 化学式: C₁₆H₁₇F₂N₃O₂S
• 分子量: 353.393
• InChiKey: KEUJAGGJGBWRFC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  99.3
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-(3,3-dimethylbutanamido)-3,5-difluoro-N-(thiazol-2-yl)benzamide 在 磷酸 、 sodium hydride 、 N,N-二异丙基乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 、 乙腈 、 mineral oil 为溶剂， 反应 3.0h， 生成 Lu AA47070
  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：

  (2S,3S)-2-amino-3-methylpentanoic acid 2-[(E/Z)-4-(3,3-dimethylbutyrylamino)-3,5-difluorobenzoylimino]thiazol-3-ylmethyl ester hydrochloride 生成 4-(3,3-dimethylbutanamido)-3,5-difluoro-N-(thiazol-2-yl)benzamide
  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

• Effective Palladium-Catalyzed Hydroxycarbonylation of Aryl Halides with Substoichiometric Carbon Monoxide
  作者：Signe Korsager、Rolf H. Taaning、Troels Skrydstrup

  DOI：10.1021/ja3114032

  日期：2013.2.27

  A protocol for the Pd-catalyzed hydroxycarbonylation of aryl iodides, bromides, and chlorides has been developed using only 1-5 mol % of CO, corresponding to a p(CO) as low as 0.1 bar. Potassium formate is the only stoichiometric reagent, acting as a mildly basic nucleophile and a reservoir of CO. The substoichiometric CO could be delivered to the reaction from an acyl-Pd(II) precatalyst, which provides

  已开发出一种用于芳基碘化物、溴化物和氯化物的 Pd 催化羟基羰基化的方案，仅使用 1-5 mol% 的 CO，对应于低至 0.1 bar 的 ap(CO)。甲酸钾是唯一的化学计量试剂，作为温和的碱性亲核试剂和 CO 的储库。亚化学计量的 CO 可以从酰基-Pd(II) 预催化剂输送到反应中，提供 CO 和活性催化剂，和从而避免了处理有毒气体的需要。
• [EN] N-THIAZOL-2-YL-BENZAMIDE DERIVATIVES<br/>[FR] DERIVES DE N-THIAZOLE-2-YLE-BENZAMIDE
  申请人：LUNDBECK & CO AS H

  公开号：WO2005039572A1

  公开（公告）日：2005-05-06

  The invention relates to N-thiazol-2-yl-benzamide derivatives of the formula I in the description wherein the variables are as defined in the claims. The compounds are A2A-receptor ligands, such as antagonists, agonists, reverse agonists or partial agonists, and are useful in the treatment of neurological and psychiatric disorders where an A2A-receptor is implicated.

  该发明涉及描述中的式I的N-噻唑-2-基苯甲酰衍生物，其中变量如索权中所定义。这些化合物是A2A受体配体，如拮抗剂、激动剂、反向激动剂或部分激动剂，并且在治疗神经和精神障碍中具有用处，其中A2A受体被牵涉其中。
• N-thiazol-2-yl-benzamide derivatives
  申请人：Sams Graven Anette

  公开号：US20060154974A1

  公开（公告）日：2006-07-13

  The invention relates to compounds of the formula I wherein the variables are as defined in the claims. The compounds are A 2A -receptor ligands, such as antagonists, agonists, reverse agonists or partial agonists, and are useful in the treatment of neurological and psychiatric disorders where an A 2A -receptor is implicated.

  本发明涉及公式I的化合物，其中变量如权利要求所定义。该化合物是A2A受体配体，如拮抗剂，激动剂，反向激动剂或部分激动剂，并且在治疗涉及A2A受体的神经和精神障碍方面有用。
• N-THIAZOL-2-YL-BENZAMIDE DERIVATIVES
  申请人：Sams Anette Graven

  公开号：US20090247593A1

  公开（公告）日：2009-10-01

  The invention relates to compounds of the formula I wherein the variables are as defined in the claims. The compounds are A 2A -receptor ligands, such as antagonists, agonists, reverse agonists or partial agonists, and are useful in the treatment of neurological and psychiatric disorders where an A 2A -receptor is implicated.

  本发明涉及式I的化合物，其中变量如权利要求所定义。这些化合物是A2A受体配体，例如拮抗剂、激动剂、反向激动剂或部分激动剂，并且在治疗神经系统和精神障碍中，其中涉及到A2A受体时具有用处。
• 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。