Antibacterial activity is exhibited by 2-azetidinones activated in the 1-position with an --SO.sub.3 H group and having in the 3-position an acylamino group of the formula ##STR1##

BRIEF DESCRIPTION OF THE INVENTION 
Compounds having the formula 
##STR2## 
and pharmaceutically acceptable salts thereof, have antibacterial 
activity. In formula I, and throughout the specification, the symbols are 
as defined below. 
R.sub.1 is phenyl, substituted phenyl, 2-amino-4-thiazolyl, 
5-amino-3-(1,2,4-thiadiazolyl), 2-amino-4-oxazolyl, 2-amino-4-imidazolyl, 
or 2-amino-6-pyridyl; 
R.sub.2 and R.sub.3 are the same or different and each is hydrogen, alkyl, 
alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or 
7-membered heterocycle (hereinafter referred to as R.sub.a), or one of 
R.sub.2 and R.sub.3 is hydrogen and the other is azido, halomethyl, 
dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 
2-phenylethynyl, carboxyl, --CH.sub.2 X.sub.1 [wherein X.sub.1 is azido, 
amino (--NH.sub.2), hydroxy, carboxyl, alkoxycarbonyl, alkanoylamino, 
phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, 
phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted 
phenyl, cyano, 
##STR3## 
--S--X.sub.2, or --O--X.sub.2 (wherein A, X.sub.2, X.sub.6 and X.sub.7 are 
as hereinafter defined)], --S--X.sub.2 or --O--X.sub.2 [wherein X.sub.2 is 
alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, 
(substituted phenyl)alkyl, alkanoyl, phenylalkanoyl, (substituted 
phenyl)alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, or 
heteroarylcarbonyl], 
##STR4## 
[wherein one of X.sub.3 and X.sub.4 is hydrogen and the other is hydrogen 
or alkyl, or X.sub.3 and X.sub.4 when taken together with the carbon atom 
to which they are attached form a cycloalkyl group; and X.sub.5 is formyl, 
alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, 
phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, 
alkoxycarbonyl, aminocarbonyl 
##STR5## 
(substituted amino)carbonyl, or cyano (-Cs.tbd.N)], or 
##STR6## 
wherein A is --CH.dbd.CH--, --(CH.sub.2).sub.m --, --(CH.sub.2).sub.m 
--O--, --(CH.sub.2).sub.m --NH--, or --CH.sub.2 --S--CH.sub.2 --, m is 0, 
1 or 2, and X.sub.6 and X.sub.7 are the same or different and each is 
hydrogen, alkyl, phenyl or substituted phenyl, or X.sub.6 is hydrogen and 
X.sub.7 is amino, substituted amino, alkanoylamino or alkoxy, or X.sub.6 
and X.sub.7 when taken together with the nitrogen atom to which they are 
attached form a 4, 5, 6 or 7-membered heterocycle]; 
R.sub.4 and R.sub.5 are the same or different and each is hydrogen or alkyl 
or R.sub.4 and R.sub.5 together with the carbon atom to which they are 
attached are cycloalkyl; and 
n is 0 or 1. 
Listed below are definitions of various terms used to describe the 
.beta.-lactams of this invention. These definitions apply to the terms as 
they are used throughout the specification (unless they are otherwise 
limited in specific instances) either individually or as part of a larger 
group. 
The terms "alkyl" and "alkoxy" refer to both straight and branched chain 
groups. Those groups having 1 to 10 carbon atoms are preferred. 
The term "cycloalkyl" refers to cycloalkyl groups having 3,4,5,6 or 7 
carbon atoms. 
The term "substituted alkyl" refers to alkyl groups substituted with one or 
more (preferably 1, 2 or 3) azido, amino (--NH.sub.2), halogen, hydroxy, 
carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, 
phenyloxy, (substituted phenyl)oxy, R.sub.a -oxy, mercapto, alkylthio, 
phenylthio, (substituted phenyl)thio, alkylsulfinyl, or alkylsulfonyl 
groups. 
The terms "alkanoyl", "alkenyl", and "alkynyl" refer to both straight and 
branched chain groups. Those groups having 2 to 10 carbon atoms are 
preferred. 
The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and 
iodine. 
The term "substituted phenyl" refers to a phenyl group substituted with 1, 
2 or 3 amino (--NH.sub.2), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 
to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), alkanoyloxy, 
aminocarbonyl, or carboxy groups. 
The expression "a 4,5,6 or 7-membered heterocycle" (referred to as "R.sub.a 
") refers to substituted and unsubstituted, aromatic and non-aromatic 
groups containing one or more (preferably 1, 2 or 3) nitrogen, oxygen or 
sulfur atoms. Exemplary substituents are oxo (.dbd.0), halogen, hydroxy, 
nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 
to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 
2-furfurylideneamino 
##STR7## 
benzylideneamino and substituted alkyl groups (wherein the alkyl group has 
1 to 4 carbons). One type of "4,5,6 or 7-membered heterocycle" is the 
"heteroaryl" group. The term "heteroaryl" refers to those 4,5,6 or 
7-membered heterocycles which are aromatic. Exemplary heteroaryl groups 
are substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl, 
1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, 
pyrimidinyl, oxazolyl, triazinyl, and tetrazolyl. Exemplary nonaromatic 
heterocycles (i.e., fully or partially saturated heterocyclic groups) are 
substituted and unsubstituted azetidinyl, oxetanyl, thietanyl, 
piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, 
tetrahydropyrimidinyl, dihyrothiazolyl and hexahydroazepinyl. Exemplary of 
the substituted 4,5,6 or 7-membered heterocycles are 1-alkyl-3-azetidinyl, 
2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-1-imidazolidinyl, 
3-benzylideneamino-2-oxo-1-imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl, 
3-phenyl (or substituted phenyl)-2-oxo-1-imidazolidinyl, 
3-benzyl-2-oxo-1-imidazolidinyl, 3-(2-aminoethyl)-2-oxo-1-imidazolidinyl, 
3-amino-2-oxo-1-imidazolidinyl, 
3-[(alkoxycarbonyl)amino]-2-oxo-1-imidazolidinyl, 
3-[2-[(alkoxycarbonyl)-amino]ethyl]-2-oxo-1-imidazolidinyl, 
2-oxo-1-pyrrolidinyl, 2-oxo-3-oxazolidinyl, 
4-hydroxy-6-methyl-2-pyrimidinyl, 2-oxo-1-hexahydroazepinyl, 
2-oxo-3-pyrrolidinyl, 2-oxo-3-tetrahydrofuranyl, 2,3-dioxo-1-piperazinyl, 
2,5-dioxo-1-piperazinyl, 4-alkyl-2,3-dioxo-1-piperazinyl, and 
4-phenyl-2,3-dioxo-1-piperazinyl. 
The term "substituted amino" refers to a group having the formula--NX.sub.8 
X.sub.9 wherein X.sub.8 is hydrogen, alkyl, phenyl, substituted phenyl, 
phenylalkyl or (substituted phenyl)alkyl, and X.sub.9 is alkyl, phenyl, 
substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, 
cyano, alkoxy, phenylalkoxy, or amino (--NH.sub.2). 
The compounds of this invention form basic salts with inorganic and organic 
bases which are also within the scope of this invention. Such salts 
include ammonium salts, alkali metal salts, alkaline earth metal salts, 
and salts with organic bases such as dicyclohexylamine, benzathine, 
N-methyl-D-gluccamine, hydrabamine and the like. 
The compounds of this invention are pictured as acids. They can also exist, 
however, as zwitterions (internal or inner salts), and these are also 
included within the language "pharmaceutically acceptable salts" and the 
scope of this invention. 
DETAILED DESCRIPTION OF THE INVENTION 
The .beta.-lactams of formula I, and pharmaceutically acceptable salts 
thereof, have activity against gram-positive and gram-negative organisms. 
Of particular interest is the good antipseudomonal activity exhibited by 
the compounds of this invention. The compounds of this invention can be 
used as agents to combat bacterial infections (including urinary tract 
infections and respiratory infections) in mammalian species, such as 
domesticated animals (e.g., dogs, cats, cows, horses, and the like) and 
humans. 
For combating bacterial infections in mammals, a compound of this invention 
can be administered to a mammal in need thereof in an amount of about 1.4 
mg/kg/day to about 350 mg/kg/day, preferably about 14 mg/kg/day to about 
100 mg/kg/day. All modes of administration which have been used in the 
past to deliver penicillins and cephalosporins to the site of the 
infection are also contemplated for use with .beta.-lactams of this 
invention. Such methods of administration include oral, intravenous, 
intramuscular, and as a suppository. 
The compounds of this invention wherein n is 1 can be prepared by coupling 
a compound having the formula 
##STR8## 
with a nucleophile having the formula 
##STR9## 
The coupling reaction can be run using procedures well known in the art. 
Exemplary of such procedures are the dicyclohexylcarbodiimide coupling and 
the dicyclohexylcarbodiimide/N-hydroxybenzotriazole coupling. 
The compounds of this invention wherein n is 0 or 1 can be prepared by 
condensing a glyoxylic acid having the formula 
##STR10## 
with an alkoxylamine having the formula 
##STR11## 
The condensation reaction can be run in water, an organic solvent, or a 
mixed organic solvent-water system. 
Another procedure for preparing the compounds of this invention wherein n 
is 0 or 1 comprises coupling a carboxylic acid having the formula 
##STR12## 
with a .beta.-lactam having the formula 
##STR13## 
The reaction proceeds most readily if the carboxylic acid is in an 
activated form. Activated forms of carboxylic acids are well known in the 
art and include acid halides, acid anhydrides (including mixed 
anhydrides), activated acid amides and activated acid esters. 
The .beta.-lactams of formulas II, IV and VII can be prepared using the 
methodology described in United Kingdom patent application No. 2,071,650, 
published Sept. 23, 1981. 
The starting material of formula III (i.e., 
2-(aminomethyl)-5-hydroxy-4-oxo-1,4-dihydropyridine) can be prepared from 
2-(hydroxymethyl)-5-hydroxy-4H-pyran-4-one using the methodology set forth 
in parts A-E of Exmaple 1, infra. 
A starting material of formula V can be prepared by first reacting a 
phthalimide having the formula 
##STR14## 
wherein Y is a halogen or hydroxyl group, with a compound of formula III 
or the compound having the formula 
##STR15## 
When Y is hydroxyl, the reaction proceeds best in the presence of a 
coupling agent such as dicyclohexylcarbodiimide. The phthalimide 
protecting group is then removed using hydrazine or methylhydrazine. Amine 
protecting groups other than the phthalimide group can also be used in 
preparing a compound of formula V. 
The compound of formula IX (i.e., 
2-amino-5-hydroxy-4-oxo-1,4-dihydropyridine) can be prepared from 
5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one using the methodology set 
forth in parts A-F of Example 2, infra. 
A carboxylic acid reactant of formula VI can be prepared by reacting a 
compound having the formula 
##STR16## 
with a compound of formula III or IX. Alternatively, a glyoxylic having 
the formula 
##STR17## 
can be reacted with a compound of formula V to yield the desired reactant 
of formula VI. As used above, the symbol "Z" represents a carboxylic acid 
protecting group and "Z'" represents hydrogen or a carboxylic acid 
protecting group. The carboxylic acids of formula VI are an integral part 
of this invention. 
In the above reactions, if the R.sub.1 group contains an amino substituent, 
it may be protected; exemplary protecting groups are the triphenylmethyl 
and formyl groups. Also, the hydroxyl group on the pyridinone nucleus (or 
hydroxyl groups on the tautomer) can be protected. Exemplary protecting 
groups are the trimethylsilyl, benzyl and benzyhydryl groups. 
Those compounds of formula I wherein R.sub.1 is 2-amino-4-thiazolyl are 
preferred. In the case of R.sub.4 and R.sub.5, methyl is in the preferred 
alkyl group. 
The compounds of formula I contain at least one chiral center--the carbon 
atom (in the 3-position of the .beta.-lactam nucleus) to which the amino 
or acylamino substituent is attached. This invention is directed to those 
.beta.-lactams which have been described above, wherein the 
stereochemistry at the chiral center in the 3-position of the 
.beta.-lactam nucleus is the same as the configuration at the carbon atom 
in the 6-position of naturally occurring penicillins (e.g., penicillin G) 
and as the configuration at the carbon atom in the 7-position of naturally 
occurring cephamycins (e.g., cephamycin C). 
Compounds of formula I exists as tautomeric mixtures. The two forms are as 
shown below: 
##STR18## 
The tautomeric products are obtained in relative amounts that differ from 
compound to compound. Both forms are included within the scope of 
structural formula I. 
The compounds of formula I have the imino substituent 
##STR19## 
and can, therefore, exist as the syn or anti isomer or as a mixture of 
isomers. All of these isomeric forms are within the scope of this 
invention. In general, however, the syn isomer of a compound of formula I 
has the greatest activity. 
Exemplary of the compounds falling within the scope of this invention are: 
[3S-[3.alpha.(Z),4.beta.]]-3-[[(2-amino-4-thiazolyl)[[2-[[(1,4-dihydro-5-hy 
droxy-4-oxo-2-pyridinyl)methyl]amino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl 
]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid 
[3S-[3.alpha.(Z),4.beta.]]-3-[[(2-amino-4-thiazolyl)[[2-[[(1,4-dihydro-5-hy 
droxy-4-oxo-2-pyridinyl)methyl]amino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl 
]amino]-4-[[(carbamoyl)oxy]methyl]-2-oxo-1-azetidinesulfonic acid 
[3S(Z)]-3-[[(2-amino-4-thiazolyl)[[2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyrid 
inyl)methyl]amino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-2-oxo-1-aze 
tidinesulfonic acid 
[3S-[3.alpha.(Z),4.alpha.]]-3-[[(2-amino-4-thiazoly)[[2-[[(1,4-dihydro-5-hy 
droxy-4-oxo-2-pyridinyl)methyl]amino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl 
]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid 
[3S-[3.alpha.(Z),4.beta.]]-3-[[(2-amino-4-thiazolyl)[[2-[(1,4-dihydro-5-hyd 
roxy-4-oxo-2-pyridinyl)amino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]- 
4-methyl-2-oxo-1-azetidinesulfonic acid 
[3S-[3.alpha.(Z),4.beta.]]-3-[[(2-amino-4-thizolyl)[[2-[(1,4-dihydro-5-hydr 
oxy-4-oxo-2-pyridinyl)amino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-4 
-[[(carbamoyl)oxy]methyl]-2-oxo-1-azetidinesulfonic acid 
[3S(Z)]-3-[[(2-amino-4-thiazolyl)[[2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridi 
nyl)amino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-2-oxo-1-azetidinesu 
lfonic acid 
[3S-[3.alpha.(Z),4.alpha.]]-3-[[(2-amino-4-thiazolyl)[[2-[(1,4-dihydro-5-hy 
droxy-4-oxo-2-pyridinyl)amino]-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino] 
-4-methyl-2-oxo-1-azetidinesulfonic acid 
The following examples are specific embodiments of this invention.