GB1153421A - Cephalosporin Derivatives - Google Patents

Abstract

1,153,421. Cephalosporin derivatives. GLAXO LABORATORIES Ltd. 6 May, 1966 [19 May, 1965], No. 47183/64. Headings C2A and C2C. The invention relates to derivatives of 7- aminocephalosporanic acid, having the formula wherein R<SP>2</SP> is phenylthio, halogenophenyl, aminophenyl, halogenophenoxy, lower-alkylphenoxy, lower-alkylphenyl, lower-alkanoyloxyphenyl, di-lower-alkoxyphenyl, phenoxy, loweralkoxycarbonamidophenyl-lower-alkylthio, diphenylamino, cycloalkylthio, lower-alkoxyphenyl-lower-alkylthio,lower-alkylphenyl-loweralkylthio, nitrophenyl-lower-alkylthio, aminophenyl-lower-alkylthio, naphthyl, naphthylthio, or C 5 to C 7 cycloalkyl; and R is an alkene or alkenylene group, or else R<SP>2</SP> is phenyl, loweralkylthio, or thienyl and R is an alkene or alkenylene group containing at least 2 carbon atoms, and salts thereof with pharmaceutically acceptable cations. " Lower " is defined as meaning C 1 to C 8 , and substituted phenyl groups may contain more than one of the stated moieties. The compounds may be prepared by reacting a compound of formula or a water-soluble salt thereof, where Z is hydrogen or an acyl group of formula where R<SP>2</SP> and R have the meanings given above, with an ammonium or metal azide in a strongly polar medium, e.g. water, optionally containing a minor proportion of miscible organic solvent, and when Z is hydrogen, acylating the product to the required inventive compound. When R<SP>2</SP> contains a reactive amino group (i.e. when R<SP>2</SP> is aminophenyl oraminophenyl-lower-alkylthio), the amino group must be protected with a group such as a trityl or lower-alkoxycarbonyl group prior to acylation. An alternative method of preparation is to react cephalosporin C with an appropriate azide to give the 3-azidomethyl derivative thereof, which is converted to a compound of Formula III wherein Z is hydrogen by removal of the α-aminoadipoyl side chain of the cephalosporin C compound to give the corresponding 7-amino-cephalosporanic acid derivative, which compound is then acylated. The following starting materials are prepared: Styrylacetyl chloride; #-(p-chlorophenyl) propionyl chloride; and 2-methylthiopentanoyl chloride, by treatment of the corresponding acids with thionyl chloride (Examples 5, 6 and 7). 2 - Methylthiopentanoic acid is prepared by refluxing 2-bromopentanoic acid with sodium methylmercaptide in xylene (Example 28). p - N - Tritylaminophenylacetic acid is prepared by tritylating ethyl-p-aminophenylacetate with triphenyl methyl chloride in the presence of triethylamine and hydrolysing the ethyl ester with aqueous NaOH in propylene glycol (Example 29). S - (p. - tert. - butoxycarbonamidobenzyl)- mercapto-acetic acid is prepared from methyl-s- (p-aminobenzyl)-mercaptoacetate hydrochloride via the isocyanate, reaction with tert. butanol and selective hydrolysis of the methyl ester with with one equivalent of NaOH in aqueous dioxan (Example 36). Pharmaceutical compositions for topical, oral or parenteral administration comprise a 3- azidomethyl cephalosporin as above together with a pharmaceutical excipient or carrier.