Patent GB-763534-A (GB)
Title: Tetra-substituted alkylene diamines and penicillin salts thereof
IPC: C07D499/24
Filed: 1954-09-10
Abstract: The invention comprises salts of penicillin with N-substituted diamines having the general formula <FORM:0763534/IV(b)/1> wherein R and R2 represent alkyl or aralkyl groups, R1 and R3 represent aralkyl groups and Alk represents an alkylene radical, straight or branched, having 2 to 6 carbon atoms.  The aryl of the aralkyl group may contain 1 to 3 substitutents which are alkyl, alkoxy, alkylenedioxy, halogen, nitro, amino, oxo or hydroxy groups, or combinations thereof. Penicillin, or a salt thereof, is reacted with the diamine, or a salt thereof, in the presence of a solvent.  The reaction of water-soluble salts in aqueous solution is preferred.  Specified salts of penicillin are the alkali metal, alkaline earth metal and organic amine salts including those of copending Specification 745,414.  Specified salts of the diamines are (a) inorganic e.g. hydrochloric, sulphuric, phosphoric, nitric and hydrobromic, and (b) organic, especially aliphatic monocarboxylic acids of 1 to 6 C atoms, e.g. formic, acetic, propionic, butyric, isovaleric, glycolic, lactic, glyconic, amino-acetic, and crotonic; aliphatic dicarboxylic acids of 3 to 6 C atoms, e.g. malonic, succinic, glutaric, adipic, malic, tartaric, glutamic, maleic and fumaric acids; and aliphatic tricarboxylic acids, e.g. citric, isocitric and aconitic acids.  The penicillin may be any penicillin, e.g. penicillin G, dihydro F, O, X or K.  Examples describe the preparation of the following diamines, their salts with certain acids and their salts with penicillin:  (a) N,N,N1,N1 - tetrabenzyl trimethylenediamine; (b) N,N,N1,N1 - tetrabenzyl hexamethylenediamine; (c) N,N,N1,N1-tetrabenzylpropylenediamine; (d) N,N1 - dimethyl - N,N1 - di - (omega - phenyl - tertiary butyl) - trimethylenediamine; (e) N,N1-dimethyl-N,N1-di-(omegaphenyl-tert.-butyl) trimethylene diamine; (f) N,N1-dibenzyl - N,N1 - dipiperonyl ethylenediamine; (g) N,N,N1,N1-[tetra-(p-chlorobenzyl)] - ethylenediamine; (h) N,N,N1,N1 - tetra-(2 - phenylethyl) - trimethylenediamine; (i) N,N,N1,N1 - tetracinnamyl ethylenediamine; (j) N,N1 - dibenzyl - N,N1 - dimethylethylenediamine; (k) N,N,N1,N1-tetrabenzyl ethylenediamine. The penicillin salts are employed in the purification of penicillin salts are employed in the purification of penicillin and also in therapeutic preparations (see Group VI).  The tetrasubstituted alkylene diamines are prepared by (a) reacting an alkylene diamine with an excess of aralkyl halide in the presence of an alcohol as solvent, or (b) reacting an alkylene dihalide with a secondary amine in a solvent under refluxing conditions.  Specification 716,556 also is referred to.ALSO:Salts of penicillin with N-substituted diamines having the general formula <FORM:0763534/VI/1> wherein R and R2 represent alkyl or aralkyl groups, R1 and R3 represent aralkyl groups and alk represents an alkylene radical, straight or branched, having 2 to 6 carbon atoms (see Group IV(b)) are employed in oral or parenteral medicaments along with a carrier.  Specified carriers are (a) spreading agents such as hyaluronidase; (b) aqueous media containing a gum such as pectin or gelatin, alumina gel or a water-soluble cellulose e.g. carboxymethylcellulose; (c) vegetable oil with or without the further addition of aluminium monostearate gel.  Optional ingredients are more-soluble penicillin salts and sulphonamides.