Patent GB-1030630-A (GB)
Title: Antibacterial derivatives of 7-aminocephalosporanic acid
Inventor: ARKLEY VINCENT
IPC: C07D501/46
Filed: 1962-12-14
Abstract: Derivatives of 7-aminocephalosporanic acid have the formula <FORM:1030630/C2/1> where Z is C1-6 alkyl, carbamoyl (excepting a single carbamoyl group in 4-position), N-mono-C1-6-alkyl carbamoyl (excepting a single methylcarbamoyl in 3-position), N,N-dimethyl-carbamoyl, C1-6-alkoxycarbonyl, hydroxy C1-6-alkyl, N-(hydroxy C1-6-alkyl) carbamoyl or carbamoyl C1-6-alkyl and p is 0, 1, 2 or 3. Typical compounds are N-(7-21-thienylacetamido -ceph - 3 - em - 3 - yl methyl) pyridinium-4-carboxylate and N-(7-21-thienylacetamidoceph -3 - em - 3 - yl methyl) - 211 -methylpyridinium-4-carboxylate.  The compounds are prepared by reacting a compound of formula <FORM:1030630/C2/2> where R is hydrogen or a thienylacetyl group or a water-soluble salt thereof, in a strongly polar medium with a nucleophile of formula <FORM:1030630/C2/3> where Z and p have the meanings defined above, the resulting compound where R is hydrogen being thienylacetylated. It is preferred to react the above nucleophile with a compound of formula <FORM:1030630/C2/4> Compounds (III) are prepared by reacting 7-aminocephalosporanic acid with a thienylacetylating agent, e.g. thienylacetyl halides or mixed anhydrides, preferably in the presence of an acid-binding agent, e.g. NaHCO3, at pH 5 to 7 in an aqueous medium. Alternatively, cephalosporin C may be reacted with nucleophilic compound (IV) to form a compound of formula <FORM:1030630/C2/5> which is converted to compounds of formula <FORM:1030630/C2/6> by methods known for the conversion of cephalosporin C to 7-ACA. Compound V may be thienylacetylated to compounds (II). Preferably excess compound (IV) is reacted with compound (III) in water, unreacted components are removed by (a) solvent extraction and (b) percolation through ion-exchange resin, and the residual solution is concentrated and freezedried.  The compounds are broad spectrum antibiotics effective against penicillin-resisting strains of micro-organisms and possessing low toxicity and high water-solubility (see Division A5).ALSO:A pharmaceutical formulation for human or veterinary use comprises a 7-aminocephalosporanic acid derivative of general formula <FORM:1030630/A5-A6/1> where z is a lower alkyl, carbamoyl (excepting a single carbomoyl group in the 4- position), N-monoalkylcarbamoyl (excepting a single methylcarbamoyl in the 3-position), N,N-diloweralkylcarbamoyl, lower alkoxycarbonyl, hydroxy lower alkyl, N-(hydroxy lower alkyl) carbamoyl or carbomoyl lower alkyl group; p is 0, 1, 2 or 3 and lower alkyl or alkoxy means 1-6 and preferably 1-2 carbon atoms.  Typical compounds are (a)N-(7-21-thienylacetamido-ceph-3-em-3 ylmethyl pyridinium-4-carboxylate (b) N-7-21-thienylacetamido-3-em-3 yl methyl 211-methylpyridinium-4-carboxylate and 10) N-(7-21-thienylacetamidoceph-3-em-3-yl methyl)-311-carbamoyl pyridinum-4-carboxylate.  The formulations may be for oral, parenteral or topical administration e.g. tablets, capsules, solutions or suspensions for oral or parenteral use, lotions, ointments and creams.  A veterinary formulation may be in the form of a veterinary cerate.  Optional ingredients are other antibacterial antibiotics such as penicillins and/or tetracyclines.  The compounds are broad spectrum antibiotics, effective against penicillin-resistent micro-organisms and having low toxicity and high solubility in water.