(3R,4R)-dihydro-2,2-dimethyl-4-amino-3-hydroxy-1-benzopyran6-carbonitrile | 205312-11-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (3R,4R)-dihydro-2,2-dimethyl-4-amino-3-hydroxy-1-benzopyran6-carbonitrile
• 英文别名: (3R,4R)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydrochromene-6-carbonitrile
• CAS: 205312-11-4
• 化学式: C₁₂H₁₄N₂O₂
• 分子量: 218.255
• InChiKey: APHWBGUCQBONMO-GHMZBOCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  79.3
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (3R,4R)-dihydro-2,2-dimethyl-4-amino-3-hydroxy-1-benzopyran6-carbonitrile 在 potassium carbonate 、 苯硫酚 、 三乙胺 、 sodium iodide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 72.5h， 生成 (4aR,10bR)-5,5-dimethyl-1,2,3,4a,5,10b-hexahydro-[1]benzopyrano[3,4-b][1,4]oxazine-9-carbonitrile
  参考文献：
  名称：

  N -Acyl-1,2,3,4a,5,10b-hexahydro-[1]benzopyrano-[3,4- b ][1,4]oxazine-9-carbonitriles as bladder-selective potassium channel openers

  摘要：

  Optically active N-acyl-5,5-dimethyl-1,2,3,4a,5,10b-hexahydro-[1]benzopyrano[3,4-b][1,4]oxazine-9-carbonitriles 2-22 were synthesized as rigid analogues of cromakalim. The (4aR,10br)-N-benzoyl derivative (-)-11 was identified as a bladder-selective KCO (IC50, (bladder) = 82 muM, IC50, (portal vein) = 34.5 muM). Among the analogues of 11 with substitution on the benzoyl moiety, the 3-methyl analogue (-)-14 showed highly potent and selective activity at portal vein (IC50, (bladder) = 279 muM, IC50, (portal vein) = 0.54 muM). The 4-bromo analogue (-)-19 (IC50, (bladder) = 2.0 muM, IC50, (portal vein) = 8.1 muM) and the 4-hydroxy analogue (-)-21 (IC50, (bladder) = 3.8 muM, IC50, portal vein = 75 muM) showed enhanced activity at the bladder, while maintaining unprecedented bladder selectivity in vitro. The N-benzenesulfonyl analogue (-)-22, a bioisoster of (-)-11, showed similar activity at the bladder with enhanced selectivity (IC50, bladder = 116 muM, IC50, portal vein = 120 muM) (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00260-1
• 作为产物：
  描述：

  (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile 在 二乙胺基三氟化硫 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 0.5h， 生成 (3R,4R)-dihydro-2,2-dimethyl-4-amino-3-hydroxy-1-benzopyran6-carbonitrile
  参考文献：
  名称：

  N -Acyl-1,2,3,4a,5,10b-hexahydro-[1]benzopyrano-[3,4- b ][1,4]oxazine-9-carbonitriles as bladder-selective potassium channel openers

  摘要：

  Optically active N-acyl-5,5-dimethyl-1,2,3,4a,5,10b-hexahydro-[1]benzopyrano[3,4-b][1,4]oxazine-9-carbonitriles 2-22 were synthesized as rigid analogues of cromakalim. The (4aR,10br)-N-benzoyl derivative (-)-11 was identified as a bladder-selective KCO (IC50, (bladder) = 82 muM, IC50, (portal vein) = 34.5 muM). Among the analogues of 11 with substitution on the benzoyl moiety, the 3-methyl analogue (-)-14 showed highly potent and selective activity at portal vein (IC50, (bladder) = 279 muM, IC50, (portal vein) = 0.54 muM). The 4-bromo analogue (-)-19 (IC50, (bladder) = 2.0 muM, IC50, (portal vein) = 8.1 muM) and the 4-hydroxy analogue (-)-21 (IC50, (bladder) = 3.8 muM, IC50, portal vein = 75 muM) showed enhanced activity at the bladder, while maintaining unprecedented bladder selectivity in vitro. The N-benzenesulfonyl analogue (-)-22, a bioisoster of (-)-11, showed similar activity at the bladder with enhanced selectivity (IC50, bladder = 116 muM, IC50, portal vein = 120 muM) (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00260-1

文献信息

• Benzopyran derivatives and heterocyclic analogs thereof as antiischemic agents
  申请人：E.R. SQUIBB & SONS, INC.

  公开号：EP0462761A2

  公开（公告）日：1991-12-27

  A new method for the treatment of ischemic conditions and arrhythmia is disclosed. The method uses compounds of the formula wherein A can be -CH₂-, -O-, -NR₉-, -S-, -SO-, -SO₂-; X can be oxygen or sulfur; Y can be -NR₈, -O-, -S-, -CH₂- and the R groups are as defined herein. Novel compounds within the definition of formula I are also disclosed.

  本研究公开了一种治疗缺血性疾病和心律失常的新方法。该方法使用式 其中 A 可以是-CH₂-、-O-、-NR₉-、-S-、-SO-、-SO₂-；X 可以是氧或硫；Y 可以是-NR₈、-O-、-S-、-CH₂-，R 基团如本文所定义。还公开了符合式 I 定义的新型化合物。
• Cardioselective Antiischemic ATP-Sensitive Potassium Channel Openers. 2. Structure-Activity Studies on Benzopyranylcyanoguanidines; Modification of the Benzopyran Ring
  作者：Karnail S. Atwal、Gary J. Grover、Francis N. Ferrara、Syed Z. Ahmed、Paul G. Sleph、Steven Dzwonczyk、Diane E. Normandin

  DOI：10.1021/jm00011a016

  日期：1995.5

  The ATP-sensitive potassium channel (K-ATP) openers are of considerable interest as myocardial protecting agents. However, there exists a narrow window of safety for the use of first-generation compounds as antiischemic agents due to their powerful peripheral vasodilating effects, which can result in underperfusion of the area already at risk. We have recently disclosed the discovery of benzopyranylcyanoguanidine type K-ATP openers (BMS-180448) which are more selective for the ischemic myocardium compared to the first-generation compounds. This publication deals with structure-activity relationships for the antiischemic activity of the lead compound 8. The presence of an electron-withdrawing group at C6, an sp(3) center at C4, and a gem-dimethyl group at C2 appears to be essential for antiischemic activity. Cyanoguanidine can be replaced with a urea moiety. The results reported here support the hypothesis that distinct structure-activity relationships exist for antiischemic and vaso:relaxant activities of compounds related to 8 and cromakalim. The trifluoromethyl analog 10 is 550-fold more selective in vitro for the ischemic myocardium compared to the first-generation agent cromakalim. The reasons for the selectivity of these compounds for the ischemic myocardium are not clear at the present time. They may be related to the existence of receptor subtypes in smooth muscle and the myocardium.
• Synthesis of 2,3,4a,11b-tetrahydro-oxazino[2,3-c]benzopyran-9-carbonitriles as ATP-sensitive potassium channel openers
  作者：Chen-Yu Cheng、Hsin-I Chiu、Ming-Jyh Chang、Yen-Chung Lin、Ming-Cheng Tsai、Hon-Cheng Yu

  DOI：10.1016/s0960-894x(98)00046-8

  日期：1998.3

  A series of optically active tetrahydro-oxazino[2,3-c]benzopyran derivatives have been synthesized and evaluated for potassium channel opening activity. (4aR,11bR)-1-Benzoyl-5,5-dimethyl-2,3,4a,11b-tetrahydro-oxazino[2,3-c]benzopyran-9-carbonitrile ((-)-11e) was identified as a bladder-selective potassium channel opener (IC50,bladder = 8.15 mu M, IC50,portal vein = 34.5 mu M). (C) 1998 Elsevier Science Ltd. All rights reserved.
• Chromanol derivatives
  申请人：BEECHAM GROUP PLC

  公开号：EP0139992B1

  公开（公告）日：1988-12-28
• US4687779A
  申请人：——

  公开号：US4687779A

  公开（公告）日：1987-08-18