bis-o-tolyl N-hydroxyoxime | 108714-78-9

• 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: bis-o-tolyl N-hydroxyoxime
• 英文别名: 2,2'-dimethyl-benzophenone oxime；2,2'-Dimethyl-benzophenon-oxim；Methanone, bis(2-methylphenyl)-, oxime；N-[bis(2-methylphenyl)methylidene]hydroxylamine
• CAS: 108714-78-9
• 化学式: C₁₅H₁₅NO
• 分子量: 225.29
• InChiKey: BJYDQNYKCCLENM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  32.6
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  bis-o-tolyl N-hydroxyoxime 在 氨 、 sodium 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以66%的产率得到2,2'-dimethylbenzhydrylamine
  参考文献：
  名称：

  Design, Synthesis, and Activity of a Series of Pyrrolidine-3-carboxylic Acid-Based, Highly Specific, Orally Active ET_B Antagonists Containing a Diphenylmethylamine Acetamide Side Chain

  摘要：

  The endothelin (ET)-B receptor subtype is expressed on vascular endothelial and smooth muscle cells and mediates both vasodilation and vasoconstriction. On the basis of the pharmacophore of the previously reported ETA-specific antagonist 1, (ABT-627), we are reporting the discovery of a novel series of highly specific, orally active ETB receptor antagonists. Replacing the dibutylaminoacetamide group of 1 with a diphenylmethylaminoacetamide group resulted in antagonist 2 with a complete reversal of receptor specificity. Structure-activity relationship studies revealed that ortho-alkylation of the phenyl rings could further increase ETB affinity and also boost the ETA/ETB activity ratio of the resulting antagonists. A similar antagonism selectivity profile could also be achieved when one of the phenyl rings of the acetamide side chain was replaced with an alkyl group, preferably a tert-butyl group,(10h). Combining these features with modification of the a-aryl group of the pyrrolidine core, we have identified a potent antagonist (9k, A-308165) with over 27 000-fold selectivity favoring the ETB receptor and an acceptable pharmacokinetic profile (F = 24%) in rats.

  DOI：

  10.1021/jm990171i
• 作为产物：
  描述：

  2,2'-二甲基二苯甲酮 在 氢氧化钾 、 羟胺 作用下， 生成 bis-o-tolyl N-hydroxyoxime
  参考文献：
  名称：

  Grignard; Bellet; Courtot, Annales de Chimie (Cachan, France), 1919, vol. <9> 12, p. 382

  摘要：

  DOI：

文献信息

• Synthesis of Novel GABA Uptake Inhibitors. 3. Diaryloxime and Diarylvinyl Ether Derivatives of Nipecotic Acid and Guvacine as Anticonvulsant Agents
  作者：Lars J. S. Knutsen、Knud Erik Andersen、Jesper Lau、Behrend F. Lundt、Rodger F. Henry、Howard E. Morton、Lars Nærum、Hans Petersen、Henrik Stephensen、Peter D. Suzdak、Michael D. B. Swedberg、Christian Thomsen、Per O. Sørensen

  DOI：10.1021/jm981027k

  日期：1999.9.1

  (3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-buteny] acid 1(tiagabine, Gabitril) is a potent and selective gamma-aminobutyric acid (GABA) uptake inhibitor with proven anticonvulsant efficacy in humans. This drug, which has a unique mechanism of action among marketed anticonvulsant agents, has been launched for add-on treatment of partial seizures with or without secondary generalization in patients > 12 years of age. Using this new agent as a benchmark, we have designed two series of novel GABA uptake inhibitors of remarkable potency, using a putative new model of ligand interaction at the GABA transporter type 1 (GAT-1) uptake site. This model involves the postulated interaction of an electronegative region in the CABA uptake inhibitor with a positively charged domain in the protein structure of the GAT-1 site. These two novel series of anticonvulsant agents contain diaryloxime or diarylvinyl ether functionalities linked to cyclic amino acid moieties and were derived utilizing the new model, via a series of design steps from the known 4,4-diarylbutenyl GABA uptake inhibitors. The new compounds are potent inhibitors of [H-3]-GABA uptake in rat brain synaptosomes in vitro, and their antiepileptic potential was demonstrated in vivo by their ability to protect against seizures induced by the benzodiazepine receptor inverse agonist methyl 4-ethyl-6,7-dimethoxy-beta-carboline-3-carboxylate (DMCM) in mice. From structure-activity studies of these new GABA uptake inhibitors, we have shown that insertion of an ether oxygen in conjugation with the double bond in tiagabine (K-i = 67 nM) improves in vitro potency by 5-fold to 14 nM.

  (3R)-1-[4,4-双(3-甲基-2-噻吩基)-3-丁炔基]乙酸（丙戊酸钠，商品名：Gabitril）是一种强效且选择性的γ-氨基丁酸（GABA）摄取抑制剂，在人类中已被证实具有抗惊厥效果。这种药物在已上市的抗惊厥药物中具有独特的作用机制，目前已被批准用于12岁以上患者的部分性癫痫发作的辅助治疗，无论是否伴有继发性全面性发作。 以此新型药物作为参考，我们设计了两个系列的新型GABA摄取抑制剂，这些抑制剂展现出显著的 potency。我们采用了GABA转运蛋白类型1（GAT-1）摄取位点上的一种新型配体相互作用模型。该模型假设GABA摄取抑制剂中的一个带负电的区域与GAT-1位点蛋白质结构中的一个带正电的区域发生相互作用。 这两个系列的新型抗癫痫药物包含 diaryloxime 或 diarylvinyl醚功能基团，并与环状氨基酸部分相连。它们是从已知的4,4-二芳基-1-丁烯基GABA摄取抑制剂出发，利用新模型并通过一系列设计步骤衍生而来的。 实验表明，这些新化合物在体外对大鼠脑突触体中的[H-3]-GABA摄取表现出强效抑制作用，且在体内通过保护小鼠免受苯二氮卓受体反向激动剂——甲基4-乙基-6,7-二甲氧基-β-咔啉-3-羧酸酯（DMCM）引起的癫痫发作，进一步证明了它们的抗癫痫潜力。 通过这些新型GABA摄取抑制剂的构效关系研究，我们发现：在丙戊酸钠的骨架中引入与双键共轭的醚氧键（Ki = 67 nM）可使体外活性提高5倍，达到14 nM的效力。
• Grignard; Bellet; Courtot, Annales de Chimie (Cachan, France), 1919, vol. <9> 12, p. 382
  作者：Grignard、Bellet、Courtot

  DOI：——

  日期：——
• Kerr,D.A.; Wilson,D.A., Journal of the Chemical Society C: Organic, 1970, p. 1718 - 1725
  作者：Kerr,D.A.、Wilson,D.A.

  DOI：——

  日期：——
• Synthesis and GABA uptake inhibitory properties of 6-aryl iminoxymethyl substituted nipecotic acids
  作者：Victor N'Goka、Tine B. Stenbøl、Povl Krogsgaard-Larsen、Gilbert Schlewer

  DOI：10.1016/j.ejmech.2004.07.003

  日期：2004.10

  Nipecotic acid derivatives bearing an aryl iminoxymethyl side chain at the position 6 were synthesised and tested for their GABA uptake inhibitory properties. Contrarily to the N-substituted derivatives 2, 3 the introduction of the oxime function in the side chain of analogues of the active nipecotic derivative 4 does neither increase, nor maintain the activity. (C) 2004 Elsevier SAS. All rights reserved.
• Design, Synthesis, and Activity of a Series of Pyrrolidine-3-carboxylic Acid-Based, Highly Specific, Orally Active ET_B Antagonists Containing a Diphenylmethylamine Acetamide Side Chain
  作者：Gang Liu、Natasha S. Kozmina、Martin Winn、Thomas W. von Geldern、William J. Chiou、Douglas B. Dixon、Bach Nguyen、Kennan C. Marsh、Terry J. Opgenorth

  DOI：10.1021/jm990171i

  日期：1999.9.1

  The endothelin (ET)-B receptor subtype is expressed on vascular endothelial and smooth muscle cells and mediates both vasodilation and vasoconstriction. On the basis of the pharmacophore of the previously reported ETA-specific antagonist 1, (ABT-627), we are reporting the discovery of a novel series of highly specific, orally active ETB receptor antagonists. Replacing the dibutylaminoacetamide group of 1 with a diphenylmethylaminoacetamide group resulted in antagonist 2 with a complete reversal of receptor specificity. Structure-activity relationship studies revealed that ortho-alkylation of the phenyl rings could further increase ETB affinity and also boost the ETA/ETB activity ratio of the resulting antagonists. A similar antagonism selectivity profile could also be achieved when one of the phenyl rings of the acetamide side chain was replaced with an alkyl group, preferably a tert-butyl group,(10h). Combining these features with modification of the a-aryl group of the pyrrolidine core, we have identified a potent antagonist (9k, A-308165) with over 27 000-fold selectivity favoring the ETB receptor and an acceptable pharmacokinetic profile (F = 24%) in rats.