GB1108310A — Derivatives of 6-methylene-tetracycline and process for their preparation

USPTO Abstract

Novel 6-methylene tetracycline derivatives of the general formula <FORM:1108310/C2/1> wherein X is H or Cl, B is H or Cl and X1 is H or OH, X and X1 being H when B is Cl, and R is amino, o -carboxy (lower, i.e. up to 6 carbon atoms) alkylamino, o -amino-o -carboxy (lower) alkylamino, o - carboxamido (lower) alkylamino, o -amino-o -carboxamido (lower) alkyl amino or NR1R2 wherein R1 is alkyl of 1-17 carbon atoms, benzyl, phenethyl, cyclohexyl, hydroxyalkyl of 2-4 carbon atoms, o -amino (lower) alkyl, o (lower) dialkylamino (lower) alkyl; R2 is H or R1; R1 and R2 in combination with the amino group are piperidino, pyrrolidino, morpholino, piperazino, N - methylpiperazino, 2,6 - dimethylmorpholino, N - (b -hydroxyethyl) piperazino or <FORM:1108310/C2/2> and their acid addition and base salts are prepared by reacting a compound of formula <FORM:1108310/C2/3> wherein X, B and X1 are as above defined either with a compound having the formula ZR or its acid addition salt, in which R is as above defined, and Z is H or H2NCH2- in the presence of formaldehyde or paraformaldehyde or, with an addition product of formaldehyde or paraformaldehyde and the compound ZR, and, if desired, forming an acid or a base salt of the product with an inorganic or organic acid or base. The reaction may be carried out in an aqueous medium to which a water-soluble organic solvent may be added at a temperature from 0 DEG to 30 DEG C., the reactants being present in equimolar proportions. Salts of the tetracyclines may be formed with HCl, H2SO4, H3PO4, CH3CO2H, butyric, palmitic, oleic, citric, gluconic, lactic, tartaric, ascorbic or pantothenic acids, penicillins, succinic half ester of D-(-)-threo-2-dichloroacetamino-1-p-nitrophenyl-1,3-propanediol, phytic and maleic acids and also with inorganic or organic bases e.g. alkali metal, alkaline earth metal, ammonium or organic amine salts. The novel 6-demethylene tetracycline derivatives of general Formula I and salts thereof may be formulated into pharmaceutical compositions. Reference has been directed by the Comptroller to Specification 995,031.