WAY-151616 | 202520-55-6

• 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: WAY-151616
• 英文别名: 3-Cyclobutene-1,2-dione, 3-(((2,4-dichloro-6-methylphenyl)methyl)amino)-4-((1,1-dimethylpropyl)amino)-；3-[(2,4-dichloro-6-methylphenyl)methylamino]-4-(2-methylbutan-2-ylamino)cyclobut-3-ene-1,2-dione
• CAS: 202520-55-6
• 化学式: C₁₇H₂₀Cl₂N₂O₂
• 分子量: 355.264
• InChiKey: GSAHJOWJMPIJOB-UHFFFAOYSA-N

物化性质

• 沸点：
  471.8±55.0 °C(Predicted)
• 密度：
  1.28±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  58.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  丁酸酐 、 WAY-151616 在 sodium hydride 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 13.0h， 以53%的产率得到N-[(2,4-dichloro-6-methylphenyl)methyl]-N-[2-(2-methylbutan-2-ylamino)-3,4-dioxocyclobuten-1-yl]butanamide
  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 、 alkaline earth salt of/the/ methylsulfuric acid 以 乙醇 为溶剂， 反应 72.0h， 生成 WAY-151616
  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

• [EN] ONE-POT SYNTHESIS OF SQUARAMIDES<br/>[FR] SYNTHÈSE MONOTOPE DE SQUARAMIDES
  申请人：UNIV ZARAGOZA

  公开号：WO2016005407A1

  公开（公告）日：2016-01-14

  The present invention refers to the first one-pot synthesis of squaramides. The one-pot synthesis of squaramides described herein is an easy and straightforward procedure to obtain squaramide derivatives which saves energy, avoids time consuming purification steps, reduces costs and provides better yields as compared with those squaramides obtained through the traditional "stop-and-go" approach. Moreover, the authors of the present invention herein demonstrate the efficiency of this one-pot process with the synthesis of three biologically active structures, improving in most of the cases the results of the previous stepwise syntheses.

  本发明涉及对方酰胺的首次一锅合成。本文描述的方酰胺一锅合成是一种简单直接的程序，可获得方酰胺衍生物，节省能源，避免耗时的纯化步骤，降低成本，并提供比通过传统的“停-继续”方法获得的方酰胺更好的产率。此外，本发明的作者在这里展示了这种一锅过程的效率，通过合成三种具有生物活性的结构，在大多数情况下改善了以前逐步合成的结果。
• Substituted N-arylmethylamino derivatives of cyclobutene-3, 4-diones
  申请人：AMERICAN HOME PRODUCTS CORPORATION

  公开号：EP1151990A1

  公开（公告）日：2001-11-07

  The compounds of the formula: wherein R1, R2, R3 and A are as defined herein are useful, via potassium channel modulation, in the treatment of disorders associated with smooth muscle contraction. Such disorders include, but are not limited to, urinary incontinence, hypertension, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina and cerebral vascular disease.

  式中的化合物 其中 R1、R2、R3 和 A 如本文所定义，通过调节钾通道，可用于治疗与平滑肌收缩有关的疾病。这些疾病包括但不限于尿失禁、高血压、哮喘、早产、肠易激综合征、充血性心力衰竭、心绞痛和脑血管疾病。
• Compositions of a cyclooxygenase-2 selective inhibitor and a potassium ion channel modulator for the treatment of central nervous system damage
  申请人：Stephenson T. Diane

  公开号：US20050009733A1

  公开（公告）日：2005-01-13

  The present invention provides compositions and methods for the treatment of central nervous system damage in a subject. More particularly, the invention provides a combination therapy for the treatment of a central nervous system ischemic condition or a central nervous system traumatic injury comprising the administration to a subject of a potassium ion channel modulator in combination with a cyclooxygenase-2 selective inhibitor.

  本发明提供了治疗受试者中枢神经系统损伤的组合物和方法。更具体地说，本发明提供了一种用于治疗中枢神经系统缺血性疾病或中枢神经系统创伤性损伤的组合疗法，包括向受试者施用钾离子通道调节剂与环氧合酶-2 选择性抑制剂。
• 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
• Intranasal administration of modulators of hypothalamic ATP-sensitive potassium channels
  申请人：Herlands Louis

  公开号：US20070026079A1

  公开（公告）日：2007-02-01

  Provided are methods of increasing K ATP channel activity in the hypothalamus of a mammal, methods of reducing glucose production in a mammal, methods of reducing peripheral glucose levels in a mammal, methods of reducing triglyceride levels in a mammal, methods of reducing very low density lipoprotein (VLDL) levels in a mammal, methods of methods of reducing gluconeogenesis in the liver of a mammal, methods of treating metabolic disorders such as diabetes, hyperglycemia, insulin resistance, glucose intolerance, metabolic syndrome and/or obesity, and methods of increasing glucose production and peripheral glucose levels in a mammal. Also provided are methods of treating heart failure, ischemia, coronary heart disease, familial lipoprotein lipase deficiency, hypopituitarism, hyperlipidemia, hypertriglyceridemia, hyperVLDLemia, atherosclerosis, hypercholesterolemia, hypertension, polycystic ovary syndrome, gonadotropin deficiency and/or amenorrhea.