(+)-(R)-3-(1,2,2-trimethyl-propylamino)-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (+)-(R)-3-(1,2,2-trimethyl-propylamino)-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione
• 英文别名: 3-[[(2R)-3,3-dimethylbutan-2-yl]amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
• 化学式: C₁₅H₁₉N₃O₂
• 分子量: 273.335
• InChiKey: IQNOGQGSOHNMCL-SECBINFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  71.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (R)-3,3-二甲基-2-丁胺 在 sodium ethanolate 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 (+)-(R)-3-(1,2,2-trimethyl-propylamino)-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione
  参考文献：
  名称：

  Hit to Lead optimization of a novel class of squarate-containing polo-like kinases inhibitors

  摘要：

  A high throughput screening (HTS) hit, 1 (Plk1 K-i = 2.2 mu M) was optimized and evaluated for the enzymatic inhibition of Plk-1 kinase. Molecular modeling suggested the importance of adding a hydrophobic aromatic amine side chain in order to improve the potency by a classic kinase H-donor-acceptor binding mode. Extensive SAR studies led to the discovery of 49 (Plk1 K-i = 5 nM; EC50 = 1.05 mu M), which demonstrated moderate efficacy at 100 mpk in a MiaPaCa tumor model, with no overt toxicity. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.10.009

文献信息

• Design and SAR of Novel Potassium Channel Openers Targeted for Urge Urinary Incontinence. 1. <i>N</i>-Cyanoguanidine Bioisosteres Possessing in Vivo Bladder Selectivity
  作者：John A. Butera、Madelene M. Antane、Schuyler A. Antane、Thomas M. Argentieri、Chris Freeden、Russell F. Graceffa、Bradford H. Hirth、Douglas Jenkins、Joseph R. Lennox、Edward Matelan、N. Wesley Norton、Dominick Quagliato、Jeffrey H. Sheldon、Walter Spinelli、Dawn Warga、Alexandra Wojdan、Morgan Woods

  DOI：10.1021/jm9905099

  日期：2000.3.1

  5'-triphosphate-sensitive potassium (K(ATP)) channel openers is described. As part of our efforts directed toward identifying novel, bladder-selective potassium channel openers (KCOs) targeted for urge urinary incontinence (UUI), we found that bioisosteric replacement of the N-cyanoguanidine moiety of pinacidil (1, Figure 1) with a diaminocyclobutenedione template afforded squaric acid analogue 2, the prototype

  描述了结构上新颖的一系列腺苷5'-三磷酸敏感性钾（K（ATP））通道开放剂。作为我们致力于鉴定针对尿急性尿失禁（UUI）的新型膀胱选择性钾通道开放剂（KCO）的工作的一部分，我们发现用二氨基环丁烯二酮生物置换了Pinacidil的N-氰基胍部分（图1，图1）。模板提供了方酸类似物2，它是一系列新颖的K（ATP）通道开放剂的原型，对体内的膀胱平滑肌具有独特的选择性。进一步修饰杂环以得到取代的芳基衍生物（3），提供了有效的KCO，当口服给药时，其具有所需的逼尿肌选择性。使用离体大鼠逼尿肌条体外研究了这些钾通道激动剂对膀胱收缩功能的影响。在膀胱不稳的大鼠模型中，对体内有效的松弛剂进行了评估。同时在血压正常的大鼠中评估铅化合物对平均动脉血压（MAP）和心率的影响，以作为体内膀胱选择性的量度。（R）-4- [3,4-二氧-2-（1,2,2-三甲基-丙基氨基）-环丁-1-烯基氨基] -3-乙基-苯甲腈
• DIAMINOCYCLOBUTENE-3,4-DIONES
  申请人：AMERICAN HOME PRODUCTS CORPORATION

  公开号：EP0796243B1

  公开（公告）日：1999-01-27
• US5512585A
  申请人：——

  公开号：US5512585A

  公开（公告）日：1996-04-30
• [EN] DIAMINOCYCLOBUTENE-3,4-DIONES<br/>[FR] DIAMINOCYCLOBUTENE-3,4-DIONES
  申请人：AMERICAN HOME PRODUCTS CORPORATION

  公开号：WO1996015103A1

  公开（公告）日：1996-05-23

  (EN) The compound of formula (I), wherein R1 and R2 are, independent from each other, hydrogen, C1-10 straight chain alkyl, C1-10 branched alkyl, or C3-10 cyclic or bicyclic alkyl; R3 is an acyl substituent selected from the group consisting of formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms; A is selected from the group consisting of (a), wherein R4 is hydrogen, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkoxy, C1-6 perfluoroalkoxy, amino, C1-6 alkylamino, C2-12 dialkylamino, C1-6 alkylsulfonamido, alkylcarboxamido containing 2 to 7 carbon atoms, nitro, cyano, carboxyl; or, A is a phenyl group of formula (b), wherein R5 and R6, independent from each other, are selected from the following: cyano, nitro, amino, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkoxy, C1-6 perfluoroalkoxy, C1-6 alkylamino, C2-12 dialkylamino, sulfamyl, C1-6 alkylsulfonamido, C6-12 arylsulfonamido, alkylcarboxamido containing 2 to 7 carbon atoms, arylcarboxamido containing 7 to 13 carbon atoms, C2 to C6 alkanoyl, C1-6 alkylsulfonyl, C1-6 perfluoroalkylsulfonyl, C6-12 arylsulfonyl, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl or hydrogen; or a pharmaceutically acceptable salt thereof, are smooth muscle relaxants.(FR) On décrit un composé de formule (I), où R1 et R2 représentent indépendamment hydrogène, C1-10 alkyle à chaîne droite ou ramifiée, ou C3-10 alkyle cyclique ou bicyclique; R3 représente un substituant acyle choisi dans le groupe consistant en formyle, alcanoyle à 2 à 7 atomes de carbone, alcénoyle à 3 à 7 atomes de carbone alkylsulfonyle à 1 à 7 atomes de carbone, aroyle à 7 à 12 atomes de carbone, arylalcénoyle à 9 à 20 atomes de carbone, arylsulfonyle à 6 à 12 atomes de carbone, arylalcanoyle à 8 à 12 atomes de carbone ou arylalkylsulfonyle à 7 à 12 atomes de carbone; A est sélectionné dans le groupe consistant en (a), où R4 représente hydrogène, C1-6 alkyle, C1-6 perfluoroalkyle, C1-6 alcoxy, C1-6 perfluoroalcoxy, amino, C1-6 alkylamino, C2-12 dialkylamino, C1-6 alkylsulfonamido, alkylcarboxamido contenant 2 à 7 atomes de carbone, nitro, cyano, carboxyle; ou bien A représente un groupe phényle de la formule (b), où R5 et R6 sont indépendamment choisis parmi: cyano, nitro, amino, C1-6 alkyle perfluoroalkyle, C1-6 alcoxy, C1-6 perfluoroalcoxy, C1-6 alkylamino, C2-12 dialkylamino, sulfamyle, C1-6 alkylsulfonamido, C6-12 arylsulfonamido, alkyl carboxamido contenant 2 à 7 atomes de carbone, arylcarbonamido contenant 7 à 13 atomes de carbone, C2-6 alcanoyle, C1-6 alkylsulfonyle, C1-6 perfluoroalkylsulfonyle, C6-12 arylsulfonyle, chloro, bromo, fluoro, iodo, 1-imidazolyle, carboxyle ou hydrogène. Ce composé, ou un de ses sels pharmaceutiquement acceptables, constitue un dépresseur des muscles lisses.
• [EN] SQUARATE KINASE INHIBITORS<br/>[FR] INHIBITEURS DE LA SQUARATE KINASE
  申请人：WYETH CORP

  公开号：WO2009012375A2

  公开（公告）日：2009-01-22

  The present application provides compounds of Formula (I): and pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof, wherein Het, R4, R9, and R10 are defined herein. Compounds of formula (I) are useful as inhibitors of MAP kinase activated protein kinase 2 (MK2).