Patent GB-1282742-A (GB)
Title: Antibacterial penicillin derivatives
IPC: C07D499/00
Filed: 1969-06-12
Abstract: 1282742 Acylureido-penicillins; phenyl glycine derivatives BRISTOL-MYERS CO 12 June 1969 [13 June 1968] 29739/69 Headings C2A and C2C Novel 3-acylureido-substituted penicillanic acids having the Formula I and non-toxic salts thereof, wherein R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are each hydrogen, nitro, di-(lower) alkylamino, lower alkanoylamino, amino, hydroxy, lower alkanoyloxy, lower alkyl, lower alkoxy, sulphamyl, chloro, bromo, iodo, fluoro, or trifluoromethyl, provided that one of R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> is other than hydrogen, and Z is lower alkyl, C 4 -C 7  cycloalkyl, monohalo (lower) alkyl, di. chloromethyl, C 2 -C 6  alkenyl, or one of the following groups: wherein n is 0, 1, 2 or 3 and R<SP>4</SP>, R<SP>5</SP> and R<SP>6</SP> are each hydrogen, nitro, di-(lower) alkylamino, lower alkanoyl-amino, lower alkanoyloxy, lower alkyl, lower alkoxy, sulphamyl, chloro, iodo, bromo, fluoro or trifluoromethyl, and the word " lower " indicates 1 to 6 carbon atoms, are prepared by reacting a penicillin of formula with an isocyanate of formula wherein Z, R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are as defined above, in the presence of a base in an anhydrous inert solvent. In a preferred process an organic solvent (e.g. dimethylformamide, dimethylsulphoxide chloroform tetrahydrofuran, n-pentane or methylene chloride), and the base (e.g. triethylamine, N - methyl - piperidine or pyridine), and the starting penicillin are stirred with a pulverized molecular sieve material to remove traces of water, filtered and then reacted with the isocyanate at - 20 to 50 C. The product may be isolated by precipitation with a non- solvent, during which procedure it may be converted to a salt, e.g. of Na or K. The products may be resolved into the D- and L-diastereoisomers, or a D- or L-form of starting penicillin may be used for the preparation. The substituted α-aminopenicillanic acids used as starting materials may be prepared by condensing an α-amino acid chloride hydrochloride with 6-aminopenicillanic acid. Those exemplified are as follows: 6-(D-α-amino-4- iodophenylacetamido) penicillanic acid; the corresponding 3-iodo compound; 6 - [D - (-) - α - amino - α - (3 - chloro - 4 - hydroxyphenyl)- acetamido] penicillanic acid; the corresponding (3,5 - dichloro - 4 - hydroxyphenyl) compound; 6 - [D - (-) - α - amino - α - (3 - hydroxyphenyl) acetamido] pencillanic acid; 6- [D - (-) - α - amino - α - (3 - chlorophenyl) acetamido] penicillanic acid; and 6 - (D-α- amino - 3 - fluorophenylacetamido) penicillanic acid. Also disclosed in the examples are 6-[D- ( - ) - 2,2 - dimethyl - 4 - (3 - chloro - 4 - hydroxyphenyl) - 5 - oxo - 2 - (H) - 1 - imidazolidinyl] penicillanic acid and the analogous- (3,5-dichloro-4-hydroxyphenyl) compound. Acetyl isocyanate is prepared by treating acetyl chloride with silver cyanate. Other starting materials or intermediates prepared in the examples are as follows: D-α- acetamido-phenylacetic acid; D-α-acetamido-3- and -4-nitro-, -3- and -4-amino-, and -3- and -4-iodo-phenylacetic acids; D-α-amino-3- and -4-iodo-phenylacetic acids, and the hydrochloride salt of the acid chlorides of these latter two compounds; D - (-) - α - ammo - α - (3- chloro - 4 - hydroxyphenyl) - glycine and the corresponding α - (3,5 - dichloro - 4 - hydroxyphenyl) compound; sodium - D - (-) - N - (2- hydroxy - 1 - naphthylmethylene) - α - amino- α - (3 - chloro - 4 - hydroxyphenyl) acetate and the corresponding α - (3,5 - dichloro - 4 - hydroxyphenyl) compound; DL - α - amino-3- methoxyphenylacetic acid and the D-diastereoisomer of this compound; D-α-amino-3- hydroxyphenylacetic acid, and its hydrobromide and hydrochloride; dl - 2 - (p - methoxyphenyl)- glycine; dl - 2 - (p - methoxyphenyl) - N- (chloroacetyl) - glycine and its D-(-) isomer; L - (+) - 2 - (p - methoxyphenyl))-glycine and its D - (-) isomer; D - (-) - 2-(p-hydroxyphenyl)- glycine; D - (-) - 2 - (3,5 - dichloro - 4 - hydroxyphenyl) glycine; D-α-amino-3-and-4-acetamidophenylacetic acids; D - α - amino - 3 - and -4- aminophenylacetic acids; DL-amino-3-chloro- and -3-fluorophenyl acetic acids and the D-( - ) isomers thereof; DL - formamido - 3 - chloro- and -3-fluoro-phenylacetic acids; and D-α- (carbobenzoxyamino) - 3 - fluorophenyl acetic acid. Pharmaceutical compositions having antibacterial activity comprise an acylureidosubstituted penicillanic acid of Formula I above or non-toxic salt thereof together with a pharmaceutically acceptable diluent or carrier.