5-fluoro-and 8-fluoro-trimetoquinol compounds and the processes for their preparation

摘要

The present invention relates to novel 5-fluoro- and 8-fluoro-trimetoquinol compounds of the general formula I wherein X1=F,X2=H or X1=H,X2=F <IMAGE> 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 2-adrenergic and antithrombotic activities while simultaneously decreasing the beta 1-adrenergic activity in mammals, including humans. The compounds of the invention are useful in the treatment of pulmonary, cardiovascular or thromboembolic disorders.