BACKGROUND OF THE INVENTION 
Cephalosporins having a ureido acyl side chain are disclosed in U.S. Pat. 
Nos. 3,673,183; 3,708,479; 3,833,568; and 3,860,591. Cephalosporins 
substituted in the 3-position with -CH.sub.2 -S-hetero groups and in the 
7-position with 
##STR3## 
GROUPS ARE DISCLOSED AS POSSESSING ANTI-BACTERIAL ACTIVITY IN U.S. Pat. 
Nos. 3,641,021; 3,759,904; 3,813,388; 3,878,204; 3,796,801 (method of 
treating Enterobacter infections), etc. Also disclosed as useful 
intermediates are cephalosporins substituted in the 3-position with 
-CH.sub.2 -S-hetero groups and in the 7-position with a 
##STR4## 
U.S. Pat. No. 3,819,621. 
SUMMARY OF THE INVENTION 
This invention relates to new cephalosporins of the formula 
##STR5## 
R.sub.1 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, 
cycloalkadienyl, phenyl, phenyl-lower alkyl or substituted phenyl and 
phenyl-lower alkyl; R.sub.2 represents hydrogen or lower alkyl, and 
R.sub.3 represents hydrogen, lower alkyl, phenyl-lower alkyl, 
diphenyl-lower alkyl, substituted phenyl-lower alkyl, tri(lower 
alkyl)stannyl, tri(lower alkyl)silyl, a salt forming ion, or the group 
##STR6## 
wherein R is lower alkyl, phenyl, phenyl-lower alkyl, or substituted 
phenyl and phenyl-lower alkyl; and R.sub.4 represents certain heterocyclic 
groups. 
DETAILED DESCRIPTION OF THE INVENTION 
The various groups represented by the symbols have the meaning defined 
below and these definitions are retained throughout this specification. 
The lower alkyl groups referred to throughout this specification include 
straight or branched chain hydrocarbon groups containing 1 to 8 carbon 
atoms, preferably 1 to 4 carbons. Examples of the type of groups 
contemplated are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc. 
The lower alkoxy groups include such lower alkyl groups attached to an 
oxygen, e.g., methoxy, ethoxy, propoxy, etc. The phenyl-lower alkyl and 
diphenyl-lower alkyl groups include such lower alkyl groups attached to a 
phenyl, e.g., benzyl, phenethyl, diphenylmethyl, etc. 
Cycloalkyl refers to groups having 3 to 7 carbons in the ring, i.e., 
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The 
term cycloalkenyl also represents rings having 3 to 7 carbons with one 
double bond, i.e., cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. The 
term cycloalkadienyl represents a ring having 6 or 7 carbons with two 
double bonds located at various positions such as 1,4-cyclohexadienyl 
which is preferred. 
The substituted phenyl and substituted phenyl-lower alkyl groups 
representing R.sub.1, R.sub.3, or R include one or two (preferably only 
one) simple substituents selected from halogen (preferably chlorine or 
bromine), lower alkyl and lower alkoxy, e.g. 2-, 3- or 4-chlorophenyl, 2-, 
3- or 4-bromophenyl, 3,4-dichlorophenyl, 2-methylphenyl, 4-ethoxyphenyl, 
2-, 3-, or 4-chlorobenzyl, 2-, 3- or 4-ethylphenethyl, etc. Also, in the 
case of R.sub.1, the phenyl substituent can be a hydroxyl group. 
The salt forming ions represented by R.sub.3 may be metal ions, e.g., 
aluminum, alkali metal ions such as sodium or potassium, alkaline earth 
metal ions such as calcium or magnesium, or an amine salt ion, of which a 
number are known for this purpose, for example, phenyl-lower alkylamines 
such as dibenzylamine, N,N-dibenzylethylenediamine, lower alkylamines such 
as methylamine, triethylamine, and N-lower alkylpiperidines such as 
N-ethylpiperidine. 
The heterocyclic groups represented by R.sub.4 are 
##STR7## 
wherein R.sub.5 is hydrogen or alkyl of 1 to 4 carbons. 
Preferred embodiments of this invention are as follows: 
R.sub.1 is phenyl, benzyl, phenethyl, substituted phenyl, benzyl or 
phenethyl, cyclohexenyl or 1,4-cyclohexadienyl. 
R.sub.2 is hydrogen or lower alkyl of 1 to 4 carbons. 
R.sub.3 is hydrogen, lower alkyl of 1 to 4 carbons, benzyl, phenethyl, 
diphenylmethyl, trimethylsilyl, trimethylstannyl, aluminum, alkaline earth 
metal, alkali metal, or 
##STR8## 
R is lower alkyl of 1 to 4 carbons, phenyl, benzyl, or phenethyl. 
The most preferred embodiments are: 
R.sub.1 is phenyl or 4-hydroxyphenyl, especially phenyl. 
R.sub.2 is hydrogen or methyl, especially hydrogen. 
R.sub.3 is hydrogen, sodium or potassium, especially hydrogen. 
##STR9## 
especially 5-methyl-1,3,4-thiadiazol-2-yl and 1-methyl-1H-tetrazol-5-yl. 
Compounds of formula I are obtained by reacting an .alpha.-ureido compound 
of the formula 
##STR10## 
with a 3-heterothio-7-amino substituted cephalosporin of the formula 
##STR11## 
wherein R.sub.3 is preferably diphenylmethyl or t-butyl or other ester 
protecting groups. 
This reaction is carried out by converting the .alpha.-ureido compound of 
formula II to a mixed carbonic or other anhydride by treating a solution 
of the .alpha.-ureido compound in an organic solvent containing a 
tri(lower alkyl)amine with an anhydride forming agent, i.e., a lower alkyl 
chloroformate, an aryl chloroformate, or an acyl halide, at reduced 
temperatures of from about 0.degree. C to about -20.degree. C. 
Alternatively, the .alpha.-ureido compound of formula II can be converted 
to an activated ester by reacting with a carboxyl group activating agent 
such as dicyclohexylcarbodiimide or bisimidazole carbonyl. In some cases 
the carboxyl group may be activated by conversion to an acid halide, e.g. 
the chloride, or to an azide. 
The methods of preparing the .alpha.-ureido compounds of formula II are 
known to those skilled in the art. 
The compounds of formula I can also be prepared by acylating the compound 
of formula III with an acid chloride of formula 
##STR12## 
or an .alpha.-(substituted)amino acid of the formula 
##STR13## 
wherein Y is a protecting group such as 
##STR14## 
or 
##STR15## 
to yield after removal of the protecting group the intermediate of formula 
##STR16## 
Various intermediates of formula VI where R.sub.1 is phenyl are disclosed 
in U.S. Pat. Nos. 3,813,388; 3,641,021; 3,759,904; and 3,796,801. 
The intermediates of formula VI are converted to the final products of 
formula I by treatment with an isocyanate of the formula 
EQU R.sub.2 -N.dbd.C.dbd.O (VII) 
or when R.sub.2 is hydrogen an alkali or alkaline earth cyanate such as 
potassium cyanate in solution at a pH of from about 7 to about 8. 
The final products of formula I can also be prepared by reacting the 
compound of formula II with 7-ACA preferably in the presence of 
dicyclohexylcarbodiimide to yield the compound of formula VIII (as 
disclosed in U.S. Pat. No. 3,673,183) 
##STR17## 
followed by treatment with the compound of the formula 
EQU R.sub.4 -S-H (IX) 
in solution at a pH of from about 7.8 to about 8.0. 
Similarly, the final products of formula I can be prepared by reacting the 
compounds of formula IV or V with an ester of 7-ACA preferably in the 
presence of dicyclohexylcarbodiimide followed by treatment with an acid 
(HX), preferably trifluoroacetic acid in the presence of anisole, to yield 
the salt of formula 
##STR18## 
The salt of formula X is treated with the isocyanate of formula VIII (or 
the alkali or alkaline earth cyanate where R.sub.2 is hydrogen) followed 
by treatment with the compound of formula IX to yield the final product of 
formula I. 
The compounds of formula I wherein R.sub.3 is lower alkyl, phenyl-lower 
alkyl, substituted phenyl-lower alkyl, diphenyl-lower alkyl, or the 
acyloxymethyl group 
##STR19## 
may be obtained by reacting the 3-heterothio-7-amino substituted 
cephalosporin of formula III or the 7-ACA either before or after the 
acylation of the 7-amino substituent with one or two moles of a compound 
of the formula 
EQU halo-R.sub.3 (XI) 
or 
EQU R.sub.3 .dbd.N.sup.+ .dbd.N.sup.- (XII) 
wherein halo is preferably chlorine or bromine in an inert solvent such as 
dimethylformamide, acetone, dioxane, benzene, or the like at about ambient 
temperature or below. 
Similarly, the compounds of formula I wherein R.sub.3 is tri(lower 
alkyl)stannyl or tri(lower alkyl)silyl are obtained by introducing such 
groups onto the 3-heterothio cephalosporanic acid moiety either before or 
after the acylation reaction. 
The carboxylate salts of the compound of formula I are formed by reacting 
the carboxyl group of the cephalosporanic acid moiety, i.e., R.sub.3 is 
hydrogen, with any of the salt forming ions described above. 
It will be appreciated that the compounds of formula I are optically active 
due to the presence of an asymmetric carbon atom in the 7-position side 
chain. By selection of the appropriate starting material it is possible to 
obtain the compounds of formula I as a mixture of optically active isomers 
or isolated as a single isomer. The various isomers as well as their 
mixtures are within the scope of this invention. 
The compounds of formula I have a broad spectrum of antibacterial activity 
against both gram positive and gram negative organisms such as 
Staphylococcus aureus, Salmonella schottmuelleri, Klebsiella pneumoniae, 
Proteus rettgeri, Escherichia coli, Streptococcus pyogenes, etc. In 
particular, it has been found that the L-isomer of the compounds of 
formula I wherein R.sub.2 is hydrogen are surprisingly active against 
beta-lactamase producing organisms such as Enterobacter, indole-positive 
Proteus, resistant Escherichia coli, and Serratia. 
The compounds of formula I can be used as antibacterial agents in a 
prophylactic manner, e.g., in cleaning or as surface disinfecting 
compositions, or otherwise to combat infections due to organisms such as 
those named above, and in general may be utilized in a manner similar to 
cephalothin and other cephalosporins. For example, a compound of formula I 
or a physiologically acceptable salt thereof may be used in various animal 
species in an amount of about 1 to 100 mg./kg., daily, orally or 
parenterally, in single or two to four divided doses to treat infections 
of bacterial origin, e.g., 5.0 mg./kg. in mice. 
Up to about 600 mg. of a compound of formula I or a physiologically 
acceptable salt thereof may be incorporated in an oral dosage form such as 
tablets, capsules or elixirs or in an injectable form in a sterile aqueous 
vehicle prepared according to conventional pharmaceutical practice. 
They may also be used in cleaning or disinfecting compositions, e.g., for 
cleaning barns or dairy equipment, at a concentration of about 0.2 to 1% 
by weight of such compounds admixed with, suspended or dissolved in 
conventional inert dry or aqueous carriers for application by washing or 
spraying. 
They are also useful as nutritional supplements in animal feeds. 
Illustrative process details are provided in the examples for the various 
reactions. All temperatures are on the centigrade scale.