Patent GB-1132057-A (GB)
Title: 6-amino penicillanic acid derivatives
IPC: C07D499/76
Filed: 1966-01-28
Abstract: 1,132,057. 2-Pyridyl-penicillins. J. R. GEIGY A.G. 28 Jan., 1966 [29 Jan., 1965], No. 3851/66. Headings C2A and C2C. The invention relates to 2-pyridyl penicillins, of the formula wherein X is oxygen or sulphur and R is a straight-chain C 1  to C 4  alkyl or alkenyl radical; and to the non-toxic salts thereof with organic or inorganic bases. These penicillins are prepared by reacting 6-amino-penicillanic acid or a salt thereof with a compound introducing the acyl radical of an acid of formula wherein X and R are as before, and optionally converting the product into a salt; suitable such compounds being: (1) the free acid, in the presence of a water binding agent (e.g. dicyclohexyl carbodiimide); (2) a halide, anhydride, or mixed anhydride of the acid, in the presence of an acid binding agent (e.g. sodium or potassium bicarbonate, carbonate, or hydroxide or a tertiary organic base); or (3) an azide or activated ester of the acid, such as the p-nitrophenyl ester. The reaction using (2) above is performed in organic solvent when the acid binding agent is an organic base, and in aqueous-organic medium when this agent is an alkali metal compound. Examples are given for the preparation of the following penicillins: methoxy-; ethoxy-; n-propoxy-; n-butoxy-; allyloxy-; methylthio-; ethylthio-; n-propylthio-; and allylthio-2-pyridyl penicillin. Examples are also given for preparing starting materials, as follows: (1) 3-n-butoxy-picolinyl chloride is prepared by refluxing the corresponding acid with thionyl chloride in benzene, in the presence of dimethyl-formamide; (2) 3- n-butoxypicolinic acid is prepared by hydrolysis with HCl at elevated temperature, of the corresponding acid amide; (3) 3-n-butoxy picoline amide is prepared by reacting 3-hydroxy picoline amide with n-butyl bromide in dimethyl formamide, in the presence of K 2 CO 3 ; (4) the corresponding 3-methoxy and 3-n-propoxy picoline amides, chlorides and acids are analogously prepared; (5) 3-ethylthiopicolinic acid is prepared by reducing dithio-3,3<SP>1</SP>-dipyridyl-2,2<SP>1</SP>- dicarbonic acid to 3-mercapto-picolinic acid, and reacting the latter with ethyl iodide. Pharmaceutical compositions comprise the inventive penicillins or their non-toxic salts and an inert carrier, in conventional forms for oral, rectal, local, or parenteral administration. Salts may be those of Na, K, NH 4 , Mg, Ca, or alkyl- and alkanolamines, heterocyclic bases, and procaine, benzylamine, dibenzylamine, or 1- phenyl-2-propylamine. Oral dosage units may take the form of tablets or dragee cores, with conventional excipients, and dragee coatings. Rectal forms comprise suppositories with a fusible fatty carrier or rectal gelatine capsules containing the active agent in a suitable polyethylene glycol carrier. Dry ampoules for preparing aqueous parenterally administrable solutions contain a sterile water-soluble salt of the penicillin, optionally with solid soluble stabilizers and buffers. Locally applicable compositions may be ointments or powders of the penicillins or their salts, with conventional excipients.