GB1120821A — Derivatives of tetracycline antibiotics

USPTO Abstract

The invention comprises tetracycline derivatives of formula <FORM:1120821/C2/1> and their physiologically acceptable salts and complexes, wherein R represents the nucleus of a tetracycline antibiotic RCONH2, selected from tetracycline, or one of the following derivatives thereof: 7-chloro-; 7-bromo-; 5-oxy-; 4-desdimethylamino-; 4-desdimethylamino - 7 - chloro -; 4 - desdimethylamino - 5-oxy-; 6-deoxy-; 6-deoxy-5-oxy-; 6-demethyl-; 6 - demethyl - 7 - chloro -; 6 - deoxy - 6 - demethyl -; 6 - deoxy - 6 - demethyl - 4 - desdimethylamino, metacycline or meclocycline, and <FORM:1120821/C2/2> is the residue of a primary or secondary amine which may be (1) a mono- or di-alkyl-amino or hydroxyalkylamino group, (2) a secondary saturated heterocyclic amino group containing one nitrogen atom, or a carboxy-, alkyl-, hydroxyalkyl-, dialkyl-amino-, or dialkyl-amino alkyl derivative thereof; (3) an N1-substituted piperazino group wherein the N-substituent is alkyl, hydroxyalkyl, or dialkylaminoalkyl, or a carboxymethyl tetracycline group corresponding to the formula <FORM:1120821/C2/3> wherein R is as above; or (4) the residue of a o -aminoalkanoic acid or an a , o -diaminoalkanoic acid, having 3 to 6 carbon atoms, or a suitable salt thereof; "alkyl" refers to such groups having up to 5 carbons. The compounds are prepared by reacting in an inert solvent, at -10 DEG to 60 DEG C., stoichiometric amounts of the tetracycline antibiotic, glyoxylic acid, and the appropriate amine. The product may be formed into a salt, or the reaction carried out in the presence of the appropriate base to give the corresponding salt as the reaction product. Preferred cations are Na, K, Ca, Mg, Al, NH4, or amine groups, possibly being as defined above, or lidocaine or mepivacaine, but preferably tertiary alkylamines. <FORM:1120821/C2/4> may be piperidine, pyrrolidine, morpholine, N - (2 - hydroxyethyl) - piperazine or lysine. The reaction process, which may be performed in, e.g. ketones, lower alkanols, ethers or cyclic ethers, envisages the use of reacting derivatives of the reactants, such as amine or metal salts or lower alkanol hemi-acetals of glyoxylic acid, and acid addition salts of the tetracycline and amine. The product of the reaction may be obtained by cooling and crystallization of the mixture, precipitation with added miscible non-solvents, or by evaporating or lyophilizing off the solvent. As well as the salts of the inventive compounds mentioned above, complexes with calcium or magnesium may be formed, the proportion of complexing metal affecting the aqueous solubility and the stability of the complex. Pharmaceutical oral or parenteral compositions comprise the inventive compounds, together with excipients such as sterile water or tabletting substances, or in capsule form.