Method of preparation of compounds of the series of tetracyclines to oxygen bridge between the carbon at 4 and 6

摘要

The invention relates to derivatives of the hypothetical compound termed "tetracycloxide," to which is assigned the formula FORM:1034934/C2/1 in which derivatives the hydrogen atom shown is replaced by a dimethylamino or a hydroxyl group. These derivatives are obtained by treating an appropriately substituted tetracycline with an oxidizing agent. Specified oxidizing agents are oxygen, an alkali-metal chlorate and hydrochloric acid, mercuric acetate, cupric acetate, alkali-metal periodates, potassium permanganate, N-chlorosuccinimide, alkali-metal peroxides and ferric salts. Oxidation under anhydrous conditions favours the formation of the dimethylamino derivatives and oxidation under aqueous conditions favours the formation of the hydroxyl derivative. Examples are given of the preparation of 4-hydroxytetracycloxide and 4 - dimethylaminotetracycloxide from 6-demethyltetracycline and of 7-chloro-4-hydroxytetracycloxide and 7-chloro-4 - dimethylaminotetracycloxide from 6-demethyl - 7 - chlorotetracycline. Products specifically claimed are 4 - hydroxytetracycloxide, 7-chloro, 7-bromo- and 7-iodo-4-hydroxytetracycloxide, 4 - dimethylaminotetracycloxide and 7-chloro-, 7-bromo- and 7-iodo-4-dimethylaminotetracycloxide. The products are useful in the synthesis of 4-di-(lower alkyl)amino-6-demethyltetracyclines. Thus, a 4-hydroxytetracycloxide may be treated with a mono (lower alkyl) amine under reductive amination conditions to yield a 4-dedimethylamino - 4 - mono - (lower alkyl)amino - 6 - demethyltetracycline, which in turn may be treated with a lower alkanol under similar conditions to yield a 4-dedimethylamino-4-di-(lower alkyl)amino - 6 - demethyltetracycline. These properties have bactericidal properties, and in this connection a comparison is made between the properties of 4-dedimethylamino-4 - methylethylamino - 6 - demethyltetracycline and those of 6-demethyltetracycline hydrochloride.