IMPROVEMENTS IN OR RELATING TO ANTIBIOTICS

摘要

1279402 Cephalosporanic acids GLAXO LABORATORIES Ltd 30 May 1969 [14 June 1968] 28528/68 Heading C2A Novel cephalosporanic acids having the Formula I: and salts, esters or anhydrides thereof, wherein Y is -CH 2 - or -CO- and R is bromo, azido or an aliphatic, carbocyclic aromatic, heterocyclic aromatic having 1 or 2 hetero atoms, araliphatic or cycloaliphatic group, and the group RYCO has an atomic weight sum of at least 120 when R is a carbocyclic aromatic group, m is 0 or 1, and R2 is hydrogen or,C 1 -C 3 alkyl which may be substituted by carboxy, carboalkoxy or mercapto, provided that when m is 0 and R2 is methyl the group Y is -CO-, are prepared by (a) acylating a correspondingly 3-substituted 7-aminocephalosporanic acid or acid-addition or base salt or easily hydrolysable ester thereof with an acylating agent corresponding to the acid RYCOOH, or (b) reacting a correspondingly N - acylated cephalosporanic acid, salt or ester having a group -CH 2 P at the 3-position, P being a group replaceable by the group -S(O) m R2, with a thioetherifying agent corresponding to the latter group and, if desired, in (a) or (b) subsequently oxidizing a 3-CH 2 SR2 group to a 3-CH 2 SOR2 group. Suitable acylating agents are the acid halide, anhydride or mixed anhydride, an active ester or azide of the acid, or the acid itself together with a condensing agent. The group P may be an acetoxy group, in which case the thioetherifying agent is an appropriate thiol. Alternatively the starting material may be a 3-hydroxymethyl compound which is first converted to a compound having a group -CH 2 X at position 3, X being a group (e.g. halogen) such that the acid HX has a pKa of not more than 4À0 in water at 25‹ C., and then the 3-CH 2 X compound is reacted with a thiol so that the thiol residue replaces X by nucleophilic displacement. A catalyst, e.g. a salt of Hg, Ag or Au, is often helpful in this replacement reaction. The sulphinyl compounds (i.e. wherein m is 1) may be prepared by nucleophilic displacement as described above, using a sulphenic acid R2SOH in place of the thiol, or by oxidation of the 3-thio-ether, e.g. with chromic oxide, sodium periodate, dibenzoyl peroxide, peracetic acid, or oxygen in a tetrahydrofuran medium containing peroxide. Pharmaceutical compositions having antibiotic activity against gram-positive and -negative bacteria comprise a cephalosporanic acid of Formula I as defined above except that the proviso need not apply, or a non-toxic salt or ester thereof, together with a pharmaceutical carrier or excipient. The compositions may be in oral, topical or injectable forms or in the form of an intra-mammary preparation for veterinary use. Reference has been directed by the Comptroller to Specification 1,104,937.