3,4-bis(benzyloxy)-5-fluorobenzyl cyanide | 104716-77-0

• 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: 3,4-bis(benzyloxy)-5-fluorobenzyl cyanide
• 英文别名: 3,4-Dibenzyloxy-5-fluorobenzylcyanide；2-[3-fluoro-4,5-bis(phenylmethoxy)phenyl]acetonitrile
• CAS: 104716-77-0
• 化学式: C₂₂H₁₈FNO₂
• 分子量: 347.389
• InChiKey: XSFHLRXDFQNPEY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  42.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3,4-bis(benzyloxy)-5-fluorobenzyl cyanide 在 sodium tetrahydroborate 、 硼烷四氢呋喃络合物 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 113.0h， 生成 8-fluoro-6,7-bis(phenylmethoxy)-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  5-Fluoro- and 8-fluorotrimetoquinol: selective .beta.2-adrenoceptor agonists

  摘要：

  The 5-fluoro and 8-fluoro analogues of trimetoquinol, TMQ, have been synthesized and evaluated for beta 2- and beta 1-adrenoceptor activity in guinea pig trachea and atria, respectively. The fluoro analogues of TMQ maintained potent beta 2-adrenoceptor agonist activity but had reduced beta 1-adrenoceptor agonist activity. The changes in beta 1-activity of these compounds were correlated to differences in phenolic pKa's. The beta 1- and beta 2-adrenoceptor actions of 2 and 3 were blocked in a competitive manner by propranolol. The enhanced beta 2/beta 1 selectivity for the analogues was found to be 8-fluoro analogue 3 greater than 5-fluoro analogue 2 greater than trimetoquinol (1).

  DOI：

  10.1021/jm00384a015
• 作为产物：
  描述：

  3-methoxy-4-hydroxy-5-fluorobenzyl cyanide 在 三溴化硼 、 potassium carbonate 、 potassium iodide 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 22.0h， 生成 3,4-bis(benzyloxy)-5-fluorobenzyl cyanide
  参考文献：
  名称：

  5-Fluoro- and 8-fluorotrimetoquinol: selective .beta.2-adrenoceptor agonists

  摘要：

  The 5-fluoro and 8-fluoro analogues of trimetoquinol, TMQ, have been synthesized and evaluated for beta 2- and beta 1-adrenoceptor activity in guinea pig trachea and atria, respectively. The fluoro analogues of TMQ maintained potent beta 2-adrenoceptor agonist activity but had reduced beta 1-adrenoceptor agonist activity. The changes in beta 1-activity of these compounds were correlated to differences in phenolic pKa's. The beta 1- and beta 2-adrenoceptor actions of 2 and 3 were blocked in a competitive manner by propranolol. The enhanced beta 2/beta 1 selectivity for the analogues was found to be 8-fluoro analogue 3 greater than 5-fluoro analogue 2 greater than trimetoquinol (1).

  DOI：

  10.1021/jm00384a015

文献信息

• Synthesis and .alpha.2-adrenoceptor effects of substituted catecholimidazoline and catecholimidazole analogs in human platelets
  作者：Duane D. Miller、Akihiko Hamada、Michael T. Clark、Adeboye Adejare、Popat N. Patil、Gamal Shams、Karl J. Romstedt、Sung U. Kim、Urusa Intrasuksri

  DOI：10.1021/jm00166a009

  日期：1990.4

  with alpha 1- and alpha 2-adrenoceptors are different. New analogues of desoxycatecholimidazoline (1), desoxycatecholimidazole (3), benzylic hydroxyl substituted imidazole (4), and the aromatic fluorine substitution analogues of 1 at the 2 (5), 5 (6), and 6 (7) positions, and a set of asymmetric 4-substituted catecholimidazolines, S-8 and R-8, were prepared and tested for interaction with alpha 2-adrenoceptors

  已知儿茶酚胺和儿茶酚酰咪唑啉与α1和α2肾上腺素受体相互作用的空间要求是不同的。Deoxycatecholimidazoline（1），desoxycatecholimidazole（3），苄基羟基取代的咪唑（4）的新类似物以及在2（5），5（6）和6（7）位置处的芳族氟取代类似物1和制备一组不对称的4-取代的儿茶酚咪唑啉S-8和R-8，并测试与人血小板中的α2-肾上腺素受体的相互作用。除3外，所有化合物均对人血小板中α-肾上腺素受体介导的反应具有选择性。在咪唑啉1中引入双键以生成咪唑3或在3中引入苄基羟基，如在图4中所示：降低了对血小板凝集的抑制，等级效力为1大于3大于4。2位，5位或6位的氟原子取代仅轻微改变了1的抑制活性。每个类似物（1、3 -7）产生α2介导的对血小板腺苷酸环化酶的抑制作用，可以归类为部分激动剂。S-8和R-8对肾上腺素诱导的聚集反应的抑制力有很大不同，只有R-8和
• 5-fluoro-and 8-fluoro-trimetoquinol compounds and the processes for
  申请人：Ohio State University Research Foundation

  公开号：US04737504A1

  公开（公告）日：1988-04-12

  The present invention relates to novel 5-fluoro- and 8-fluoro-trimetoquinol compounds of the general formula I wherein X.sub.1 =F,X.sub.2 =H or X.sub.1 =H,X.sub.2 =F ##STR1## The present invention also relates to a process for making the 5-fluoro- and 8-fluoro-trimetoquinol compounds by condensation of an appropriately substituted phenethylamine to afford an appropriately substituted phenethylacetamide compound. The amides are cyclized to give appropriately substituted intermediate dihydroisoquinolines. Without isolation, the dihydroisoquinolines are reduced to give appropriately substituted tetrahydroisoqinolines. The hydrochloride salts of tetrahydroisoqinolines are prepared and subjected to hydrogenolysis, to give the fluorine substituted trimetoquinol compounds of the present invention. The present invention also encompasses the preparation of the phenethylamines by reducing appropriately substituted benzylcyanides and to the preparation of an intermediate benzylcyanide compound by converting a fluorine substituted methoxyphenol compound, under aminomethylation conditions into a N, N-dimethyl-4-hydroxy-3-methoxy-5-fluorobenzylamine. The benzylamine is converted to benzylnitrile and a functional group shuffle is carried out which yields the appropriately substituted benzylcyanide compound. In a composition aspect, the present invention encompasses novel pharmaceutical compositions comprising a compound of the formula I, together with a physiologically acceptable carrier or excipient, in an amount sufficient to increase .beta..sub.2 -adrenergic and antithrombotic activities while simultaneously decreasing the .beta..sub.1 -adrenergic activity in mammals, including humans. The compounds of the invention are useful in the treatment of pulmonary, cardiovascular or thromboembolic disorders.

  本发明涉及一种新的5-氟和8-氟三甲氧喹酮化合物，其通式为I，其中X.sub.1 =F，X.sub.2 =H或X.sub.1 =H，X.sub.2 =F。本发明还涉及一种制备5-氟和8-氟三甲氧喹酮化合物的方法，通过将适当取代的苯乙胺缩合以得到适当取代的苯乙酰胺化合物。酰胺环化得到适当取代的中间二氢异喹啉。在没有分离的情况下，将二氢异喹啉还原得到适当取代的四氢异喹啉。四氢异喹啉的盐酸盐被制备并经氢解，得到本发明的氟取代三甲氧喹酮化合物。本发明还涵盖了通过还原适当取代的苄基氰化物制备苯乙胺，以及通过将氟取代的甲氧基苯酚化合物在氨甲基化条件下转化为N，N-二甲基-4-羟基-3-甲氧基-5-氟苄胺制备中间苄基氰化合物。苄胺转化为苯乙腈，并进行功能基转移，得到适当取代的苄基氰化合物。在组合方面，本发明涵盖了包含通式I化合物的新型药物组合物，与生理上可接受的载体或赋形剂一起使用，用量足以增加哺乳动物，包括人类的β2-肾上腺素能和抗血栓活性，同时减少β1-肾上腺素能活性。本发明的化合物在治疗肺部、心血管或血栓性疾病中有用。
• 5-fluoro- and 8-fluoro-trimetoquinol compounds and the processes for
  申请人：Ohio State University Research Foundation

  公开号：US04855476A1

  公开（公告）日：1989-08-08

  The present invention relates to novel 5-fluoro- and 8-fluoro-trimetoquinol compounds of the general formula I wherein X.sub.1 =F, X.sub.2 =H or X.sub.1 =H, X.sub.2 =F ##STR1## The present invention also relates to a process for making the 5-fluoro- and 8-fluoro-trimetoquinol compounds by condensation of an appropriately substituted phenethylamine to afford an appropriately substituted phenlethylacetamide compound. The amides are cyclized to give appropriately substituted intermediate dihydroisoquinolines. Without isolation, the dihydroisoquinolines are reduced to give appropriately substituted tetrahydroisoquinolines. The hydrochloride salts of tetrahydroisoquinolines are prepared and subjected to hydrogenolysis, to give the fluorine substituted trimetoquinol compounds of the present invention. The present invention also encompasses the preparation of the phenethylamines by reducing appropriately substituted benzylcyanides and to the preparation of an intermediate benzylcyanide compound by converting a fluorine substituted methoxyphenol compound, under aminomethylation conditions into a N-N-dimethyl-4-hydroxy-3-methoxy-5-fluorobenzylamine. The benzylamine is converted to benzylnitrile and a functional group shuffle is carried out which yields the appropriately substituted benzylcyanide compound. In a composition aspect, the present invention encompasses novel pharmaceutical compositions comprising a compound of the formula I, together with a physiologically acceptable carrier or excipient, in an amount sufficient to increase .beta..sub.2 -adrenergic and antithrombotic activities while simultaneously decreasing the .beta..sub.1 -adrenergic activity in mammals, including humans. The compounds of the invention are useful in the treatment of pulmonary, cardiovascular or thromboembolic disorders.

  本发明涉及一种新型5-氟和8-氟三甲氧喹啉化合物，其通式为I，其中X.sub.1 = F，X.sub.2 = H或X.sub.1 = H，X.sub.2 = F ##STR1## 本发明还涉及一种制备5-氟和8-氟三甲氧喹啉化合物的方法，通过适当取代的苯乙胺缩合以得到适当取代的苯乙基乙酰胺化合物。酰胺环化形成适当取代的中间二氢异喹啉。在不分离的情况下，将二氢异喹啉还原为适当取代的四氢异喹啉。四氢异喹啉的盐酸盐制备并经过氢解作用，得到本发明的氟取代三甲氧喹啉化合物。本发明还包括通过还原适当取代的苄基氰化物制备苯乙胺以及通过将氟取代的甲氧基酚化合物在氨甲基化条件下转化为N- N-二甲基-4-羟基-3-甲氧基-5-氟苄胺来制备中间苄基氰化合物。苄胺转化为苄腈并进行功能基洗牌，得到适当取代的苄基氰化合物。在组成方面，本发明涵盖了包含式I化合物的新型制药组合物，以及与生理学上可接受的载体或赋形剂一起使用，其量足以在哺乳动物中，包括人类中提高β2-肾上腺素能和抗血栓活性，同时降低β1-肾上腺素能活性。本发明的化合物在治疗肺部、心血管或血栓栓塞性疾病方面是有用的。
• MILLER, DUANE D.;FELLER, DENNIS R.;CLARK, MICHAEL T.;ADEJARE, ADEBOYE;ROM+
  作者：MILLER, DUANE D.、FELLER, DENNIS R.、CLARK, MICHAEL T.、ADEJARE, ADEBOYE、ROM+

  DOI：——

  日期：——
• MILLER, DUANE D.;HAMADA, AKIHIKO;CLARK, MICHAEL T.;ADEIARE, ADEBOYE;PATIL+, J. MED. CHEM., 33,(1990) N, C. 1138-1144
  作者：MILLER, DUANE D.、HAMADA, AKIHIKO、CLARK, MICHAEL T.、ADEIARE, ADEBOYE、PATIL+

  DOI：——

  日期：——