公开(公告)号：US4737504A

公开(公告)日：1988-04-12

申请号：US890490

申请日：1986-07-25

申请人： Duane D. Miller ,  Dennis R. Feller ,  Michael T. Clark ,  Adeboye Adejare ,  Karl J. Romstedt ,  Gamal Shams

发明人： Duane D. Miller ,  Dennis R. Feller ,  Michael T. Clark ,  Adeboye Adejare ,  Karl J. Romstedt ,  Gamal Shams

IPC分类号： C07D217/20 ,  A61K31/47

CPC分类号： C07D217/20

摘要： 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.

摘要翻译： 本发明涉及通式I的新的5-氟 - 和8-氟 - 三甲基喹诺酮化合物，其中X1 = F，X2 = H或X1 = H，X2 = F。本发明还涉及一种 通过适当取代的苯乙胺的缩合制备5-氟 - 和8-氟 - 三甲基喹啉化合物，得到适当取代的苯乙基乙酰胺化合物。 使酰胺环化，得到适当取代的中间体二氢异喹啉。 不分离，将二氢异喹啉还原，得到适当取代的四氢异喹啉。 制备四氢异喹啉的盐酸盐并进行氢解，得到本发明的氟取代的三甲基喹诺酮化合物。 本发明还包括通过在氨基甲基化条件下将氟取代的甲氧基苯酚化合物转化成N，N-二甲基-4-羟基-3-甲氧基的方法，通过还原适当取代的苄基氰化物和制备中间体苄基氰化合物来制备苯乙胺 -5-氟苄胺。 将苄胺转化为苄基腈，进行官能团混洗，产生适当取代的苄基氰化合物。 在组合物方面，本发明包括新颖的药物组合物，其包含式I化合物以及生理上可接受的载体或赋形剂，其量足以增加β2-肾上腺素能和抗血栓形成活性，同时降低β1-肾上腺素能 哺乳动物，包括人类的活动。 本发明的化合物可用于治疗肺，心血管或血栓栓塞障碍。

公开(公告)号：US4855476A

公开(公告)日：1989-08-08

申请号：US167336

申请日：1988-03-14

申请人： Duane D. Miller ,  Dennis R. Feller ,  Michael T. Clark ,  Adeboye Adejare ,  Karl J. Romstedt ,  Gamal Shams

发明人： Duane D. Miller ,  Dennis R. Feller ,  Michael T. Clark ,  Adeboye Adejare ,  Karl J. Romstedt ,  Gamal Shams

IPC分类号： C07D217/20

CPC分类号： C07D217/20

摘要： 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.

摘要翻译： 本发明涉及通式I的新的5-氟 - 和8-氟 - 三甲基喹诺酮化合物，其中X1 = F，X2 = H或X1 = H，X2 = F。本发明还涉及一种 通过适当取代的苯乙胺的缩合制备5-氟 - 和8-氟 - 三甲基喹啉化合物，得到适当取代的苯乙酰基乙酰胺化合物。 使酰胺环化，得到适当取代的中间体二氢异喹啉。 不分离，将二氢异喹啉还原，得到适当取代的四氢异喹啉。 制备四氢异喹啉的盐酸盐并进行氢解，得到本发明的氟取代的三甲基喹诺酮化合物。 本发明还包括通过将氨基甲基化条件下的氟取代的甲氧基苯酚化合物转化成N-二甲基-4-羟基-3-甲氧基-5 - 氟苄胺。 将苄胺转化为苄基腈，进行官能团混洗，产生适当取代的苄基氰化合物。 在组合物方面，本发明包括新颖的药物组合物，其包含式I化合物以及生理上可接受的载体或赋形剂，其量足以增加β2-肾上腺素能和抗血栓形成活性，同时降低β1-肾上腺素能 哺乳动物，包括人类的活动。 本发明的化合物可用于治疗肺，心血管或血栓栓塞障碍。