(R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione | 202520-49-8

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione
• 英文别名: (R)-3-(3,3-dimethylbutan-2-ylamino)-4-ethoxycyclobut-3-ene-1,2-dione；3-[[(2R)-3,3-dimethylbutan-2-yl]amino]-4-ethoxycyclobut-3-ene-1,2-dione
• CAS: 202520-49-8
• 化学式: C₁₂H₁₉NO₃
• 分子量: 225.288
• InChiKey: YSRUSQVLYQQMCN-SSDOTTSWSA-N

物化性质

• 沸点：
  322.1±52.0 °C(Predicted)
• 密度：
  1.07±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  16
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione 在 oxone 、 sodium ethanolate 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 3-[[(2R)-3,3-dimethylbutan-2-yl]amino]-4-[[2-(pyridin-4-ylamino)pyrimidin-4-yl]amino]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
• 作为产物：
  描述：

  (R)-3,3-二甲基-2-丁胺 、 方酸二乙酯 以 乙醇 为溶剂， 以9.78 g (74%)的产率得到(R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione
  参考文献：
  名称：

  Fluorinated N-arylmethylamino derivatives of cyclobutene-3,4-diones

  摘要：

  通用式（I）的化合物 ##STR1## 其中 R.sub.1 是直链烷基，支链烷基，环烷基，羟基烷基，氟烷基或多氟烷基；R.sub.2 和 R.sub.3 分别是氢或从甲酰基，烷酰基，烯酰基，烷基磺酰基，芳酰基，芳基烯酰基，芳基磺酰基，芳基烷酰基或芳基烷基磺酰基组成的酰基；A 是以下式的取代苯基团：##STR2## 其中 R.sub.4 是 F，1至10个碳原子的全氟烷基或1至10个碳原子的全氟烷氧基；或其药学上可接受的盐使平滑肌放松。

  公开号：

  US05750574A1

文献信息

• Substituted N-arylmethylamino derivatives of cyclobutene-3,4-diones
  申请人：American Home Products Corporation

  公开号：US05763474A1

  公开（公告）日：1998-06-09

  The compounds of the formula: ##STR1## wherein R.sub.1 is straight chain alkyl, branched chain alkyl cycloalkyl, hydroxyalkyl, fluoroalkyl or polyfluoroalkyl; R.sub.2 and R.sub.3 are, independently, hydrogen or an acyl substituent selected from the group consisting of formyl, alkanoyl, alkenoyl, alkoxycarbonyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl, arylalkanoyl or arylalkylsulfonyl; A is a substituted phenyl group of the following formula: ##STR2## wherein R.sub.4 and R.sub.5 are, independently, cyano, nitro, amino, alkyl, perfluoroalkyl, fluoroalkyl, alkoxy, perfluoroalkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, sulfamyl, alkylsulfonamido, arylsulfonamido, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarboxamido, arylcarboxamido, alkylsulfonyl, perfluoroalkylsulfonyl, arylsulfonyl, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl or hydrogen, with the proviso that R.sub.4 and R.sub.5 cannot both be hydrogen; or a pharmaceutically acceptable salt thereof, relaxes smooth muscles.

  该化合物的化学式为：##STR1## 其中R.sub.1是直链烷基，支链烷基，环烷基，羟基烷基，氟代烷基或多氟代烷基; R.sub.2和R.sub.3分别是氢或酰基取代基，所述酰基取代基从以下组中选择：甲酰基，脂肪酰基，烯酰基，烷氧羰基，烷基磺酰基，芳酰基，芳基烯酰基，芳基磺酰基，芳基烷酰基或芳基烷基磺酰基; A是以下公式的取代苯基：##STR2## 其中R.sub.4和R.sub.5分别是氰基，硝基，氨基，烷基，全氟烷基，氟代烷基，烷氧基，全氟烷氧基，氟代烷氧基，氨基，烷基氨基，二烷基氨基，磺酰氨基，烷基磺酰胺基，芳基磺酰胺基，氨基甲酰基，烷基氨甲酰基，二烷基氨甲酰基，烷基羧甲酰基，芳基羧甲酰基，烷基磺酰基，全氟烷基磺酰基，芳基磺酰基，氯，溴，氟，碘，1-咪唑基，羧基或氢，但R.sub.4和R.sub.5不能都是氢; 或其药学上可接受的盐，可以放松平滑肌。
• Substituted N-arylmethylamino derivatives of cyclobutene-3, 4-diones
  申请人：American Home Products Corporation

  公开号：US05780505A1

  公开（公告）日：1998-07-14

  The compounds of the formula: ##STR1## wherein R.sub.1 is straight chain alkyl, branched chain alkyl, cycloalkyl, hydroxyalkyl, fluoroalkyl or polyfluoroalkyl; R.sub.7 and R.sub.8 are, independently, hydrogen or an acyl substituent selected from the group consisting of formyl, alkanoyl, alkenoyl, alkoxycarbonyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl, arylalkanoyl or arylalkylsulfonyl; A is a phenyl group with either two or three substituents of the following formula: ##STR2## wherein the positions of substitution are R.sub.2,R.sub.3 -, R.sub.2,R.sub.4 -, R.sub.2,R.sub.5 -, R.sub.2,R.sub.6 -, R.sub.3,R.sub.4 -, R.sub.3,R.sub.5 -, and R.sub.2,R.sub.4,R.sub.6 - and R.sub.2 is methyl, ethyl, fluoro, chloro, methoxy or trifluoromethyl; R.sub.3 is methyl, ethyl, fluoro, chloro, methoxy or trifluoromethyl; R.sub.4 is methyl, fluoro, bromo, methoxy or cyano; R.sub.5 is methyl, fluoro, chloro, methoxy, cyano or trifluoromethyl; R.sub.6 is methyl, fluoro, chloro, or methoxy; or a pharmaceutically acceptable salt thereof, relax smooth muscles.

  该化合物的配方为：##STR1## 其中R.sub.1是直链烷基，支链烷基，环烷基，羟基烷基，氟烷基或多氟烷基; R.sub.7和R.sub.8分别是氢或酰基取代基，所述酰基取代基被选自以下群组：甲酰基，脂肪酰基，烯酰基，烷氧羰基，烷基磺酰基，芳酰基，芳基烯酰基，芳基磺酰基，芳基烷酰基或芳基烷基磺酰基; A是苯基，其具有以下公式的两个或三个取代基：##STR2## 其中取代位点为R.sub.2，R.sub.3-，R.sub.2，R.sub.4-，R.sub.2，R.sub.5-，R.sub.2，R.sub.6-，R.sub.3，R.sub.4-，R.sub.3，R.sub.5-和R.sub.2，R.sub.4，R.sub.6-，R.sub.2是甲基，乙基，氟，氯，甲氧基或三氟甲基; R.sub.3是甲基，乙基，氟，氯，甲氧基或三氟甲基; R.sub.4是甲基，氟，溴，甲氧基或氰基; R.sub.5是甲基，氟，氯，甲氧基，氰基或三氟甲基; R.sub.6是甲基，氟，氯或甲氧基; 或其药学上可接受的盐，可使平滑肌松弛。
• Design and SAR of Novel Potassium Channel Openers Targeted for Urge Urinary Incontinence. 2. Selective and Potent Benzylamino Cyclobutenediones
  作者：Adam M. Gilbert、Madelene M. Antane、Thomas M. Argentieri、John A. Butera、Gerardo D. Francisco、Chris Freeden、Eric G. Gundersen、Russell F. Graceffa、David Herbst、Bradford H. Hirth、Joseph R. Lennox、Geraldine McFarlane、N. Wesley Norton、Dominick Quagliato、Jeffrey H. Sheldon、Dawn Warga、Alexandra Wojdan、Morgan Woods

  DOI：10.1021/jm9905108

  日期：2000.3.1

  A novel series of benzylamine, potassium channel openers (KCOs) is presented as part of our program toward designing new, bladder-selective compounds for the treatment of urge urinary incontinence (UUI). We have found that the in vitro potency of (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]3-ethyl-benzonitrile 1 in the relaxation of precontracted rat detrusor strips can also be obtained with cyanobenzylamine derivative 4 (IC50 = 0.29 mu M) (Figure 3). Addition of a 2-Cl substituted benzylamine moiety and changing the alkylamino substituent of 4 to a t-Bu amine gives 31 (IC50 = 0.14 mu M)-a compound with similar in vitro potency as 4 as well as relaxant activity on bladder smooth muscle in vivo when administered orally (31, ED50 = 3 mg/kg) in a rodent model of bladder instability. Further modifications, particularly the replacement of the t-Bu amino substituent with a tert-amylamine, gave a similarly active compound 60 (IC50 = 0.10 mu M) which shows excellent in vivo efficacy (ED50 = 0.6 mg/kg). Moreover, 60, 3-(2,4-dichloro-6-methyl-benzylamino)-4- 1,1-dimethylpropylamino)-cyclobut-3-ene-1,2-dione (WAY-151616), shows excellent tissue selectivity for bladder K channels over arterial tissue (60, MAP ED20 = 100 mg/kg; selectivity: MAP ED20/ bladder ED50 = 166). Other manipulations of the benzylamino cyclobutenediones, acylation of the benzylamine, conversion of the benzylamine substituent to a benzamide, homologation of the benzylamine to a phenethylamine, and incorporation of a methyl group at the benzyl carbon, all led to substantial loss of in vitro activity, although some in vivo activity was maintained in the acylated analogues. Compound 60 represents an attractive candidate for development in the treatment of UUI.
• WO2007/140233
  申请人：——

  公开号：——

  公开（公告）日：——
• SUBSTITUTED N-ARYLMETHYLAMINO DERIVATIVES OF CYCLOBUTENE-3,4-DIONES
  申请人：AMERICAN HOME PRODUCTS CORPORATION

  公开号：EP0934257A1

  公开（公告）日：1999-08-11