Patent GB-1290177-A (GB)
IPC: C07C57/34
Filed: 1969-08-29
Abstract: 1290177 Esters of α-carboxy-penicillins; malonic ester derivatives PFIZER Inc 29 Aug 1969 [4 June 1969 (4)] 43239/69 Headings C2A and C2C Novel penicillins having the general Formula (I): and salts thereof, wherein R 1  is thienyl, furyl, pyridyl, phenyl or substituted phenyl in which the substituent is C 1  to C 6  alkyl, C 1  to C 6  alkoxy, di-(C 1  to C 6  alkyl) amino, chloro, bromo or trifluoromethyl ; and R 2  is a group of formula: in which X 1  is Cl, Br, F, C 1  to C 6  alkyl or C 1  to C 6  alkoxy, X2 is Cl or C 1  to C 6  alkyl, X 3  is hydrogen, phenyl, carboxyvinyl, carbo-(C 1  to C 6  alkoxy)- vinyl, carboxy C 1  to C 6  alkyl or carbo-(C 1  to C 6  alkoxy) C 1  to C 6  alkyl, and X 4  is NO 2  or di-(C 1  to C 6  alkyl) amino; or R 2  is mono-substituted phenyl wherein the substituent is phenyl, carboxyvinyl, carbo-(C 1  to C 6  alkoxy) vinyl, carboxy C 1  to C 6  alkyl or carbo-(C 1  to C 6  alkoxy) C 1  to C 6  alkyl; or R 2  is biphenyl, C 1  to C 6  alkynyl, 3-[1- (R 5 -substituted)-piperidyl], or a group of formula -(CH 2 ) m -NR 5 R 6 , -CH 2 -CH(CH 3 )- NR 5 R 6 , or -CH(CH 3 )-CH 2 -NR 5 R 6 , in which m is 2 or 3, R 5  is H, C 1  to C 6  alkyl or benzyl and R 6  is C 1  to C 6  alkyl, C 1  to C 6  alkanoyl, carbo C 1  to C 6  alkoxy, benzyl or phenyl, provided that when R 5  is H then R 6  is carbo C 1  to C 6  alkoxy and when R 5  is C 1  to C 6  alkyl then R 6  is not C 1  to C 6  alkyl ; or R 2  is γ-phenylallyl, γ- (substituted phenyl) allyl in which the substituent is one or more of Cl, Br, F, C 1  to C 6  alkoxy, C 1  to C 6  alkyl, NO 2  or methylenedioxy; or R 2  is γ-phenylpropargyl or γ-(substituted phenyl)- propargyl in which the substituent is Cl, Br, NO 2 , C 1  to C 6  alkoxy or C 1  to C 6  alkyl ; and also penicillins having the general Formula (I) above wherein R 2  may additionally be (C 1  to C 3  alkylene)-Y 1  in which Y 1  is azetitino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N - (C 1  to C 6  alkyl) piperazino, pyrrolo, imidazolo, 2-imidazolino, 2,5-dimethylpyrrolidino, 1,4,5,6-tetrahydropyrimidino, 4-methylpiperidino, 2,6-dimethylpiperidino or a radical of formula in which Z is -(CH 2 ) 3 - or -(CH 2 ) 4 -, which radical may be substituted by -CH 3 , Cl or Br; are prepared by reacting a compound of formula wherein M is H, Na, K or tri-(C 1  to C 6  alkyl)- amino, with an acylating agent of formula wherein X is Cl, Br or -OCOR 4 , in which R 4  is benzyl or C 1  to C 6  alkyl and R 1  and R 2  are as previously defined, in a reaction-inert solvent system at pH 5 to 8 and 0‹ to 50‹ C. α-Carbo-(2-biphenyloxy) phenyl acetic acid is prepared by reacting together phenylmalonic acid, thionyl chloride and o-phenylphenol. The product is converted to the corresponding acid chloride by treatment with thionyl chloride. Pharmaceutical compositions having antibiotic activity against gram-positive and -negative bacteria comprise a penicillin of Formula I as defined above or a non-toxic salt thereof, together with a pharmaceutically acceptable diluent or carrier. Reference has been directed by the Comptroller to Specification 1,133,886.