3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione | 201012-44-4

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione
• 英文别名: 3-Butoxy-4-(1,1-dimethylpropylamino)-cyclobut-3-ene-1,2-dione；3-butoxy-4-(2-methylbutan-2-ylamino)cyclobut-3-ene-1,2-dione
• CAS: 201012-44-4
• 化学式: C₁₃H₂₁NO₃
• 分子量: 239.315
• InChiKey: AONBEDNGWLEBOY-UHFFFAOYSA-N

物化性质

• 沸点：
  343.3±52.0 °C(Predicted)
• 密度：
  1.05±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  17
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.69
• 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：

  2,4-二甲基苄胺 、 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione 以 四氢呋喃 为溶剂， 以45%的产率得到3-[(2,4-Dimethylphenyl)methylamino]-4-(2-methylbutan-2-ylamino)cyclobut-3-ene-1,2-dione
  参考文献：
  名称：

  Design and SAR of Novel Potassium Channel Openers Targeted for Urge Urinary Incontinence. 2. Selective and Potent Benzylamino Cyclobutenediones

  摘要：

  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.

  DOI：

  10.1021/jm9905108
• 作为产物：
  描述：

  叔戊基胺 、 方酸二正丁酯 以 四氢呋喃 为溶剂， 反应 19.5h， 以86%的产率得到3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione
  参考文献：
  名称：

  Design and SAR of Novel Potassium Channel Openers Targeted for Urge Urinary Incontinence. 2. Selective and Potent Benzylamino Cyclobutenediones

  摘要：

  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.

  DOI：

  10.1021/jm9905108

文献信息

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

  公开号：US05872139A1

  公开（公告）日：1999-02-16

  The compounds of the formula: ##STR1## wherein R.sub.1 and R.sub.2 are, independently, hydrogen, straight chain alkyl, branched chain alkyl, cycloalkyl, bicycloalkyl or aralkyl, wherein the aromatic moiety of the aralkyl group may be optionally substituted with one to three straight chain alkyl, halogen, nitro, cyano, alkoxy, alkoxycarbonyl, trifluoromethyl or trifluoromethoxy groups; R.sub.3 is hydrogen, formyl, alkanoyl, alkenoyl, alkylsulfonyl, aroyl, arylalkenoyl, arylsulfonyl, arylalkanoyl or arylalkylsulfonyl; A is selected from the group consisting of: ##STR2## wherein n is 0 or 1; R.sub.4, R.sub.5 and R.sub.6 are, independently, cyano, nitro, amino, alkyl, perfluoroalkyl, alkoxy, perfluoroalkoxy, alkylamino, dialkylamino, sulfamyl, alkylsulfonamido, arylsulfonamido, alkylcarboxamido, arylcarboxamido, alkanoyl, alkylsulfonyl, perfluoroalkylsulfonyl, arylsulfonyl, chloro, bromo, fluoro, iodo, 1-imidazolyl, carboxyl or hydrogen; or a pharmaceutically acceptable salt thereof, relax smooth muscles.

  该化合物的公式为：##STR1## 其中R.sub.1和R.sub.2分别是氢、直链烷基、支链烷基、环烷基、双环烷基或芳基烷基，其中芳基烷基群的芳香基团可以选择性地被一个到三个直链烷基、卤素、硝基、氰基、烷氧基、烷氧羰基、三氟甲基或三氟甲氧基基团取代；R.sub.3是氢、甲酰、烷酰、烯酰、烷基磺酰、芳酰、芳基烯酰、芳基磺酰、芳基烷酰或芳基烷基磺酰；A选自以下组合之一：##STR2## 其中n为0或1；R.sub.4、R.sub.5和R.sub.6分别是氰基、硝基、氨基、烷基、全氟烷基、烷氧基、全氟烷氧基、烷基氨基、二烷基氨基、磺胺基、烷基磺酰胺、芳基磺酰胺、烷基羧酰胺、芳基羧酰胺、烷酰、烷基磺酰、全氟烷基磺酰、芳基磺酰、氯、溴、氟、碘、1-咪唑基、羧基或氢；或其药学上可接受的盐，用于放松平滑肌。
• [EN] METHOD OF TREATING URINARY INCONTINENCE<br/>[FR] PROCEDE DE TRAITEMENT DE L'INCONTINENCE URINAIRE
  申请人：AMERICAN HOME PRODUCTS CORPORATION

  公开号：WO1998011888A1

  公开（公告）日：1998-03-26

  (EN) This invention provides a method of treating urinary incontinence in a female mammal which comprises administering to said mammal an effective amount of an anti-incontinent agent intravaginally or rectally.(FR) La présente invention concerne un procédé de traitement de l'incontinence urinaire chez un mammifère femelle, qui consiste à administrer audit mammifère, par voie vaginale ou rectale, une dose suffisante d'un agent anti-incontinence.

  该发明提供了一种治疗雌性哺乳动物尿失禁的方法，包括通过阴道或直肠给该哺乳动物注射有效剂量的抗失禁药物。
• 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。
• HETEROCYCLYLMETHYLAMINO DERIVATIVES OF CYCLOBUTENE-3,4-DIONES AS POTASSIUM CHANNEL MODULATORS
  申请人：AMERICAN HOME PRODUCTS CORPORATION

  公开号：EP0906282A1

  公开（公告）日：1999-04-07
• METHOD OF TREATING URINARY INCONTINENCE
  申请人：AMERICAN HOME PRODUCTS CORPORATION

  公开号：EP0927034A1

  公开（公告）日：1999-07-07