Compounds of the formula ##STR1## wherein A is ##STR2## R is hydrogen, lower alkyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, tri(lower alkyl)silyl, lower alkoxymethyl, 2,2,2-trichloroethyl, ##STR3## Y is halogen or lower alkoxy; R.sub.1 is lower alkyl, phenyl, or substituted phenyl; and X is hydrogen, lower alkanoyloxy, ##STR4## or certain heterothio groups; R.sub.4 is hydrogen or lower alkyl; R.sub.5 is lower alkyl; are disclosed. These compounds, particularly the free acids, possess the useful pharmacological property of inhibiting .beta.-lactamase enzymes as well as being useful as intermediates, particularly where R is a readily cleavable ester, in the preparation of antibacterially active 6.alpha.-methoxy penicillins and 7.alpha.-methoxy cephalosporins.

BACKGROUND OF THE INVENTION 
Welch, J. Org. Chem., Vol. 41, p. 2220-2222, discloses reacting 
6-aminopenicillanic acid (6-APA) with an arylsulfenyl chloride under 
aqueous conditions to yield a mixture of an aryl sulfenamide and a 
diarylsulfenimide 6-substituted penicillin. 
Nudelman in U.S. Pat. No. 3,907,788 discloses reacting 
7-aminocephalosporanic acid (7-ACA) with an equimolar amount of a sulfenyl 
derivative to yield a 7-sulfenamido cephalosporin. 
The combination of an active antibacterial agent and an agent having 
.beta.-lactamase inhibition are taught in U.S. Pat. Nos. 3,624,225, 
3,867,538, and 3,952,094. 
Various acylated 7.alpha.-methoxy cephalosporins and 6.alpha.-methoxy 
penicillins are disclosed as possessing useful antibacterial activity as 
note for example U.S. Pat. Nos. 3,775,410, 3,780,031, 3,780,033, 
3,780,037, 3,843,641, 3,920,639, 3,960,845, 3,978,651, etc. 
Also, 7-amino-7-substituted thio-cephalosporins and 6-amino-6-substituted 
thio-penicillins are disclosed in U.S. Pat. Nos. 3,840,533 and 3,855,233. 
SUMMARY OF THE INVENTION 
This invention relates to new thiooxime cephalosporin and penicillin 
derivatives of the formula 
##STR5## 
A represents 
##STR6## 
R represents hydrogen, lower alkyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, 
diphenylmethyl 2,2,2-trichloroethyl, tri(lower alkyl)silyl, lower 
alkoxymethyl, 
##STR7## 
Y is halogen or lower alkoxy. 
R.sub.1 represents lower alkyl, phenyl, or substituted phenyl. 
X represents hydrogen, lower alkanoyloxy, 
##STR8## 
or certain heterothio groups. 
R.sub.4 is hydrogen or lower alkyl. 
R.sub.5 is lower alkyl. 
Also disclosed are methods of converting the compounds of formula I to 
antibacterially active 7-acyl-7.alpha.-methoxy cephalosporins and 
6-acyl-6.alpha.-methoxy penicillins. 
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 4 carbon 
atoms. Examples of the type of groups contemplated are methyl, ethyl, 
n-propyl, isopropyl, t-butyl, etc. The lower alkoxy groups include such 
lower alkyl groups attached to an oxygen, e.g., methoxy, ethoxy, propoxy, 
etc. 
The term halogen employed in the definition of the variable Y is meant to 
include the four common halogens, e.g. chlorine, bromine, fluorine or 
iodine, with chlorine being preferred. 
The substituted phenyl groups include a single substituent selected from 
halogen (preferably chlorine or bromine), lower alkyl of 1 to 4 carbons 
(preferably methyl or ethyl), and lower alkoxy of 1 to 4 carbons 
(preferably methoxy or ethoxy). 
Lower alkanoyloxy refers to a group of the formula 
##STR9## 
alkyl wherein lower alkyl is of 1 to 4 carbons, preferably wherein lower 
alkyl is methyl. 
The heterothio groups are 
##STR10## 
wherein R.sub.2 is hydrogen or lower alkyl of 1 to 4 carbons (preferably 
methyl or ethyl) and R.sub.3 is hydrogen, lower alkyl of 1 to 4 carbons 
(preferably methyl or ethyl), methoxy, hydroxy, or halogen (preferably 
chlorine). 
The compounds of formula I wherein A, Y, and R.sub.1 are as defined above; 
X is hydrogen, lower alkanoyloxy, 
##STR11## 
or heterothio; and R is hydrogen, lower alkyl, benzyl, p-methoxybenzyl, 
p-nitrobenzyl, diphenylmethyl, tri(lower alkyl)silyl, lower alkoxymethyl 
or 2,2,2-trichloroethyl; are prepared by reacting a 6-aminopenicillin or 
7-aminocephalosporin of the formula 
##STR12## 
with a halosulfenyl compound of the formula 
EQU halo--S--R.sub.1 (III) 
wherein halo is preferably chlorine or bromine. This reaction is performed 
in an inert non-aqueous solvent such as methylene chloride, chloroform, 
ethyl acetate, dimethylformamide, tetrahydrofuran, etc., with at least a 
molar excess, preferably 2 to 4 equivalents, of the sulfenyl compound of 
formula III. The reaction is performed at a temperature of from about 
-30.degree. C to about 30.degree. C for from about 1 to about 24 hours. 
Preferably one or more acid scavengers such as propylene oxide, butylene 
oxide, pyridine, tri(lower alkyl)-amine, or crushed molecular sieves are 
employed in the reaction and the reaction is performed under an inert 
atmosphere, e.g. argon or nitrogen. When R is hydrogen, the compound of 
formula II is preferably converted to its trimethylsilyl ester before 
reaction with the sulfenyl compound. 
The compounds of formula I wherein X is pyridinium or carbamoyl substituted 
pyridinium are prepared by reacting a compound of the formula (or its 
sodium salt) 
##STR13## 
with pyridine or carbamoyl substituted pyridine in a polar solvent such as 
water and in the presence of a catalyst such as an alkali metal 
thiocyanate. U.S. Pat. No. 3,792,047 and German Offenlegungsschrift No. 
2,234,280 both disclose methods for reacting a cephalosporin so as to 
replace an acetoxy group with a pyridinium group. 
Also, the compounds of formula I wherein X is heterothio can be prepared by 
reacting the compound of formula Ia with a mercaptan of the formula 
EQU hetero--S--H (IV) 
or an alkali metal (preferably sodium) mercaptan salt of the formula 
EQU hetero--S--alkali metal. (V) 
methods for displacing the acetoxy group of a cephalosporin by a heterothio 
group are taught in various U.S. Pat. Nos. including 3,855,213; 3,890,309; 
3,892,737; etc. 
The compounds of formula I wherein R is 
##STR14## 
may be obtained by treating the compound of formula II wherein R is 
hydrogen either before or after the reaction with the sulfenyl compound 
with one or two moles of a compound of the formula 
##STR15## 
wherein halo is chlorine or bromine in an inert solvent such as 
dimethylformamide at or below ambient temperature. 
Similarly, the compounds of formula I wherein R is 
##STR16## 
are prepared by treating the compound of formula II wherein R is hydrogen 
either before or after the reaction with the sulfenyl compound of formula 
III with a compound of the formula 
##STR17## 
as taught by Ferres et al. in U.S. Pat. No. 3,860,579. 
The thiooxime compounds of formula I particularly wherein R is a readily 
cleavable ester group such as t-butyl, benzyl, p-methoxybenzyl, 
p-nitrobenzyl, diphenylmethyl, and 2,2,2-trichloroethyl are valuable as 
intermediates in the preparation of various antibacterially active 
7-acyl-7.alpha.-methoxy cephalosporins and 6-acyl-6.alpha.-methoxy 
penicillins by several routes. 
For example, the thiooxime compound of formula I can be reacted with a 
tri(lower alkyl)phosphine, a tri(phenyl) or a tri(substituted 
phenyl)phosphine, preferably triphenylphosphine, followed by treatment 
with an acid catalyst such as silica gel to yield the 
7.beta.-amino-7.alpha.-substituted thio cephalosporin or 
6.beta.-amino-6.alpha.-substituted thio penicillin of the formula 
##STR18## 
wherein R.sub.1 and A are as defined above. The reaction between the 
thiooxime of formula I and the phosphine is performed in an inert solvent 
such as methylene chloride, chloroform, ethylacetate, dimethylformamide, 
tetrahydrofuran, etc., at about 0.degree. to about 80.degree. C for from 
about 1 to about 24 hours. The reaction is preferably performed under an 
inert atmosphere such as nitrogen or argon. 
The resulting compound of formula VIII can then be acylated according to 
known procedures to yield the compounds of the formula 
##STR19## 
which are then treated with a metal salt such as mercuric acetate, 
mercuric chloride, silver tetrafluoroborate, etc., in the presence of 
methanol as taught in German Offenlegungsschrift No. 2,360,945 of Dolfini 
et al. and by Applegate et al. in J. Org. Chem., Vol. 39, p. 2794-2796 to 
yield the corresponding acylated 7.alpha.-methoxy cephalosporins or 
6.alpha.-methoxy penicillins. The ester protecting group (i.e. R is 
t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, 
2,2,2-trichloroethyl) can then be removed according to known methods to 
yield the final compounds in the free acid form. 
Alternatively, the compound of formula VIII can be treated with a metal 
salt such as mercuric chloride in the presence of methanol as taught in 
Belgium Pat. No. 811,314 and by Jen et al. in J. Org. Chem., Vol. 38, p. 
2857-2859 to yield the corresponding 7.beta.-amino-7.alpha.-methoxy 
cephalosporin or 6.beta.-amino-6.alpha.-methoxy penicillin of the formula 
##STR20## 
Acylation followed by the removal of the ester protecting group according 
to known procedures yields the desired final products. 
Also, it has been discovered that the thiooximes of formula I can be 
reacted so as to yield the compound of formula X directly thus obviating 
the need to proceed via the intermediate of formula VIII. This reaction 
can be performed by forming a solution of the thiooxime of formula I in an 
inert solvent such as methylene chloride, ethyl acetate, chloroform, 
dimethylformamide, tetrahydrofuran, etc., and adding under an inert 
atmosphere a tri(lower alkyl)phosphine, or a tri(phenyl)phosphine, or a 
tri(substituted phenyl)phosphine, preferably triphenylphosphine. The 
reaction mixture is kept at a temperature of from about 0.degree. to about 
80.degree. C for from about 1 to about 24 hours with stirring. A metal 
catalyst such as mercuric acetate, mercuric chloride, silver 
tetrafluoroborate, silver acetate, silver nitrate, silver perchlorate, 
lead acetate, or thallium acetate, preferably mercuric acetate, mercuric 
chloride, or silver tetrafluoroborate, and methanol are added to the 
reaction mixture. After about 1 to about 4 hours, the reaction mixture is 
concentrated and the product of formula X is either isolated by 
conventional procedures or acylated directly to yield the desired 
6-acyl-6.alpha.-methoxy penicillin or 7-acyl-7.alpha.-methoxy 
cephalosporin. Alternatively, the thiooxime solution, phosphine, metal 
catalyst and methanol can be combined into a reaction mixture at one time. 
After about 4 to about 8 hours at from about 0.degree. to about 
80.degree., the reaction mixture is concentrated and the product of 
formula X is either isolated or acylated directly. 
The thiooxime compounds of formula I particularly those wherein R is 
hydrogen, lower alkoxymethyl, 
##STR21## 
especially those wherein R is hydrogen, possess the useful pharmacological 
property of inhibiting .beta.-lactamase enzymes. Thus, these compounds can 
be combined with known antibacterial agents which are susceptible to 
attack by .beta.-lactamase enzymes and enhance the antibacterial activity 
of these known agents. Examples of such known antibacterial agents include 
penicillins such as penicillin G, penicillin V, ampicillin, amoxycillin, 
and epicillin, preferably ampicillin, and cephalosporins such as 
cephradine, cephalexin, cefazolin, cefoxitin, cefaloridine, cephaloglycin, 
and cefamandole, preferably cephradine. The thiooxime is present at from 
about 1% to about 90% by weight of the antibacterial combination. Since a 
unit dose of most antibacterial agents for a 70 kg. mammal contains from 
about 250 mg. to about 2 g. of active ingredient, the thiooxime will be 
present at from about 2.5 mg. to about 1.8 g. in the unit dose. 
The thiooxime and active antibacterial agent are formulated into a 
composition along with a pharmaceutically acceptable carrier and other 
ingredients according to accepted pharmaceutical practice. The composition 
is formulated so as to be administered orally or parenterally depending 
upon the mode of administration best suited for the particular active 
antibacterial agent. Thus, a suitable injectable composition is a dry 
blend of the antibacterial agent, thiooxime, and sodium carbonate which is 
then reconstituted with water prior to administration. 
The following examples are illustrative of the invention. All temperatures 
are expressed in degrees centigrade.