Compounds of formula ##STR1## wherein R is hydrogen atom or C.sub.1 -C.sub.4 alkyl group optionally substituted from halogen atom or hydroxy group optionally protected, A is a Z, Z--O--C--O-- or Z--C)-- residue, wherein Z is phenylene, naphthylene, heterocyclediyl, C.sub.1 -C.sub.7 alkylene, C.sub.2 -C.sub.4 alkenylene, alkynylene, ##STR2## C.sub.3 -C.sub.8 cycloalkylene, aralkylene radical optionally substituted, and O.sup.(+) represents a group +NR.sub.1 R.sub.2 R.sub.3, wherein R.sub.1, R.sub.2 and R.sub.3 are each either: PA0 (i) a optionally substituted alkyl, aralkyl or aryl radical or PA0 (ii) R.sub.1 is as defined above under (i) and R.sub.2 and R.sub.3, taken together, represent an optionally substituted or fused heterocyclic radical, or PA0 (iii) R.sub.1, R.sub.2 and R.sub.3, taken together, represent an optionally substituted azonia-bicyclo or tricyclo radical, or PA0 (iv) R.sub.1, R.sub.2 and R.sub.3, taken together, represent an optionally substituted or fused pyridinium, pyrazinium, pyrazolium or pyridazinium radical, and the pharmaceutically or veterinarily acceptable salts thereof, are disclosed. A method of preparation is also provided. The compounds show high antibacterial activity.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to penem compounds, to processes for their 
preparation, and to pharmaceutical and veterinary compositions containing 
penem compounds. 
2. Description of the Background 
Penem compounds are antibiotics. There is a continuing need for new 
antibiotics because the continued wide scale use of these compounds gives 
rise to resistant strains of pathogens. Accordingly, there is no constant 
effectiveness for any given antibiotic. Additionally, known antibiotics 
suffer from the disadvantage of being effective against only certain types 
of microorganisms. 
There is thus a strongly felt need for new antibiotics which do not suffer 
from the above disadvantages. 
SUMMARY OF THE INVENTION 
Accordingly, it is an object of this invention to provide a novel class of 
antibiotics. 
It is another object of this invention to provide a novel class of 
antibiotics which are useful in human therapy. 
It is another object of this invention to provide a novel class of 
antibiotics which are useful in animal therapy. 
It is another object of this invention to provide a novel class of 
antibiotics which are potent antibacterial agents. 
It is another object of this invention to provide a novel class of 
antibiotics which are broad spectrum antibacterial agents. 
It is another object of this invention to provide a novel class of 
antibiotics which are imbued with increased activity against Gram-positive 
strains. 
It is another object of this invention to provide a novel class of 
antibiotics which are imbued with increased activity against Gram-negative 
strains. 
It is another object of this invention to provide a novel class of 
antibiotics which have prolonged plasma levels. 
It is another object of this invention to provide a novel class of 
antibiotics which display a very high degree of therapeutic effectiveness 
in treating infections caused by both Gram-positive and Gram-negative 
bacteria. 
It is another object of this invention to provide a novel class of 
antibiotics having negligible toxicity. 
It is another object of this invention to provide a novel class of 
antibiotic compounds which are useful in the treatment of respiratory 
tract infections; e.g., bronchitis, bronchopneumonia or pleuritis. 
It is another object of this invention to provide a novel class of 
antibiotic compounds which are useful in the treatment of hepatobiliary or 
abdominal infections. 
It is another object of this invention to provide a novel class of 
antibiotic compounds which are useful in the treatment of septicemia. 
It is another object of this invention to provide a novel class of 
antibiotic compounds which are useful in the treatment of urinary tract 
infections; e.g., pyelonephritis or cystitis. 
It is another object of this invention to provide a novel class of 
antibiotic compounds which are useful in the treatment of obstetrical and 
gynecological infections; e.g., cervicitis or endometritis. 
It is another object of this invention to provide a novel class of 
antibiotic compounds which are useful in the treatment of ear, nose and 
throat infections; e.g., otitis, sinusitis or parotitis. 
It is another object of this invention to provide a novel method for the 
treatment of respiratory tract infections, hepatobiliary and abdominal 
infections, septicemia, urinary tract infections, obstetrical and 
gynecological infections, or ear, nose and throat infections. 
The inventors have now discovered a novel class of penem antibiotics which 
surprisingly satisfy all of the above objects of this invention as well as 
other objects which will become apparent from the description of this 
invention given hereinbelow. The present invention thus relates to new 
penem compounds, to processes for their preparation, and to pharmaceutical 
and veterinary compositions containing them. 
The compounds of the invention are quaternary ammonium carboxylates of the 
following formula (I) and their pharmaceutically or veterinarily 
acceptable salts 
##STR3## 
wherein 
R is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group which may be either 
unsubstituted or substituted by one or more substituents chosen from free 
or protected hydroxy groups and halogen atoms; 
A is a Z, Z--O--CO-- or --Z--CO-- residue, wherein Z represents (a) an 
unsubstituted or substituted phenylene or naphthylene group; (b) an 
unsubstituted or substituted heterocyclediyl radical where the hetero ring 
is mono or bicyclic, saturated or unsaturated, and contains at least one 
heteroatom selected from the group of oxygen, sulphur and nitrogen atoms; 
(c) an unsubstituted or substituted linear or branched C.sub.1 -C.sub.7 
alkylene radical; (d) a C.sub.2 -C.sub.4 alkenylene or alkynylene group or 
a group of formula 
##STR4## 
or (e) an unsubstituted or substituted C.sub.3 -C.sub.8 cycloalkylene 
ring; (f) an aralkylene radical of formula 
##STR5## 
wherein n is 1, 2 or 3, and Q(+) represents a +NR.sub.1 R.sub.2 R.sub.3 
group, wherein (i) R.sub.1, R.sub.2 and R.sub.3 are each independently an 
unsubstituted or substituted alkyl, aralkyl or aryl radical; or (ii) 
R.sub.1 is as defined above under (i) and R.sub.2 and R.sub.3 taken 
together with the nitrogen atom to which they are both bound represent an 
unsubstituted or substituted heterocyclic or fused heterocyclic radical; 
or (iii) R.sub.1, R.sub.2 and R.sub.3 taken together with the nitrogen 
atom to which they are all bound represent an unsubstituted or substituted 
azoniabicyclo or azoniatricyclo radical; or (iv) R.sub.1, R.sub.2 and 
R.sub.3 taken together with the nitrogen atom to which they are all bound 
represent an unsubstituted or substituted pyridinium, pyrazinium, 
pyrazolium, or pyridazinium radical, or an unsubstituted or substituted 
pyridinium, pyrazinium, pyrazolium, or pyridazinium radical fused with one 
phenyl ring or with a 5 to 7 membered, saturated or unsaturated 
cycloaliphatic or heterocyclic ring. 
The present invention includes all the possible geometrical and optical 
isomers of the compounds of formula (I). They may be in the form of 
isomeric mixtures or in the form of the individual separated isomers. 
Preferably, the compounds of formula (I) have a (5R, 6S) configuration. 
The preferred R group is an (.alpha.-hydroxy)ethyl radical. This radical 
preferably has a (1R) configuration, i.e., a R configuration at the 
.alpha.-carbon atom of the ethyl group. 
As noted above the pharmaceutically or veterinarily acceptable salts of the 
compounds of formula (I) are included within the scope of this invention. 
These salts may be both salts with (1) acids; any pharmaceutically or 
veterinarily acceptable inorganic or organic acids such as, e.g., 
hydrochloric, hydrobromic, sulfuric, or phosphoric acid, or acetic, 
citric, tartaric, fumaric or methanesulphonic acid, and salts with (2) any 
pharmaceutically or veterinarily acceptable bases; either inorganic bases 
such as, e.g., alkali or alkaline-earth metal hydroxides, in particular 
sodium and potassium hydroxides, or organic bases such as, e.g., 
triethylamine, pyridine, benzylamine or collidine, including aminoacids 
such as, e.g., lysine or procaine. The invention includes also inner 
salts, i.e., zwitterions. In the present specification, the term "halogen" 
encompasses fluorine, chlorine, bromine and iodine atoms, preferably 
fluorine and chlorine atoms. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The alkyl groups, including the aliphatic moieties of the alkoxy, alkylthio 
and alkanoyl groups, may be branched or straight chain. Preferably, the 
alkyl and aralkyl radicals under definition (i) for Q are unsubstituted or 
substituted C.sub.1 -C.sub.4 alkyl and C.sub.7 -C.sub.11 aralkyl radicals. 
In the definitions of Z, R.sub.1, R.sub.2 and R.sub.3, the substituents 
for the mentioned alkyl, aralkyl, aryl, azoniabicyclo, azoniatricyclo, 
pyridinium, pyrazinium, pyrazolium, pyridazinium, cycloalkylene, alkylene, 
phenylene, naphthylene and heterocyclediyl radicals are preferably 
selected from the group consisting of: (a) halogens; (b) hydroxy; (c) 
C.sub.1 -C.sub.4 alkoxys; (d) C.sub.1 -C.sub.4 alkylthios; (e) a group 
--NR.sub.4 R.sub.5, wherein R.sub.4 and R.sub.5 is, independently, a 
hydrogen atom or a C.sub.1 -C.sub.4 alkyl groups; (f) sulfos; (g) 
--CO.sub.2 R.sub.4 groups, wherein R.sub.4 is as defined above; (h) --CN; 
(i) dimethylformimidino; (j) --CO--NR.sub.4 R.sub.5, groups wherein 
R.sub.4 and R.sub.5 are as defined above; (k) hydroxycarbamoyl or 
carbamoyloxy groups; (l) hydroxyiminomethyl (HO--N.dbd.CH--) or 
methoxyiminomethyl (CH.sub.3 O--N.dbd.CH--) groups, hydroxyimino 
(.alpha.-methyl)methyl (HO--N.dbd.C(CH.sub.3)--) groups; (m) formamido or 
acetamido groups; (n) formyloxy or acetoxy groups; (o) C.sub.1 -C.sub.4 
alkanoyl groups; (p) aryl groups; (q) saturated or unsaturated 
heterocyclic rings; (r) a nitro group; (s) a mesyloxy group; (t) oxo 
groups; and (u) C.sub.1 -C.sub.4 alkyl groups which may be either 
unsubstituted or substituted by a substituent chosen from (a) to (t) 
above. 
A C.sub.1 -C.sub.4 alkyl group is, preferably, a methyl or an ethyl group. 
A heterocyclediyl radical is, preferably, a furanediyl, a 
1,3-thiadiazolediyl, a thiophenediyl or a pyridinediyl group. 
A C.sub.1 -C.sub.7 alkylene radical is preferably a methylene, an ethylene, 
a propylene or a butylene group. 
A C.sub.3 -C.sub.8 cycloalkylene ring is, preferably, a cyclobutylene, a 
cyclopentylene or a cyclohexylene group. 
A C.sub.2 -C.sub.4 alkenylene group is, preferably, a 1,2-ethenylene group. 
A C.sub.2 -C.sub.4 alkynylene group is, preferably, an ethynylene group. 
The term "aryl" encompasses, preferably, phenyl and naphthyl groups. The 
heterocyclic rings may be saturated or unsaturated. They may have from 4 
to 7 members. And they may contain from 1 to 4 heteroatoms selected from 
oxygen, nitrogen and sulphur atoms. 
A C.sub.1 -C.sub.4 alkoxy group is, preferably, a methoxy or an ethoxy 
group. 
A C.sub.1 -C.sub.4 alkylthio group is, preferably, a methylthio or an 
ethylthio group. 
A C.sub.1 -C.sub.4 alkanoyl group is, preferably, an acetyl or a propionyl 
group. 
A protected hydroxy group may be a hydroxy group protected by a protecting 
group chosen from for instance, an unsubstituted or substituted, 
especially halo-substituted, acyl group, e.g., acetyl, monochloroacetyl, 
dichloroacetyl, trifluoroacetyl, benzoyl or p-bromophenacyl; a 
triarylmethyl group, in particular triphenylmethyl; a silyl group, in 
particular trimethylsilyl, dimethyl-tert-butylsilyl, diphenyl-tert-butyl 
silyl; or also a group such as tert-butoxycarbonyl, 
p-nitro-benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 
allyloxycarbonyl, benzyl, and pyranyl. 
Preferred protecting groups of the hydroxy function are 
p-nitro-benzyloxycarbonyl; dimethyl-tert-butyl-silyl; 
diphenyl-tert-butyl-silyl; trimethyl silyl; allyloxy-carbonyl; benzyl; 
p-bromophenacyl; triphenylmethyl and pyranyl. 
Preferred classes of compounds under this invention include compounds of 
formula (I) wherein: 
R is an (.alpha.-hydroxy)ethyl group; 
Z is one of the following residues: 
##STR6## 
(c') a methylene, an ethylene, a n-propylene or a tetramethylene group 
(d') a 1,2-ethenediyl group 
##STR7## 
(f') para, meta or ortho 
##STR8## 
Q.sup.(+) is +NR.sub.1 R.sub.2 R.sub.3, wherein (i') R.sub.1, R.sub.2 and 
R.sub.3 are each independently a methyl, an ethyl, a n-propyl, an 
i-propyl, a dimethylaminomethyl, or cyanomethyl, a cyanoethyl, a 
carbamoylmethyl, a 2-hydroxyethyl, a 2-cloroethyl, a carboxymethyl, an 
ethoxycarboxylmethyl, a carboxyethyl, a 2-methyl-2-cyanoethyl, a 
3-oxobutyl or a dimethylformimidino group --C(NMe.sub.2).dbd.NH; or (ii') 
R.sub.1 is as defined above under (i'), still preferably a methyl, an 
ethyl, a chloroethyl, a cyanomethyl, a cyanoethyl, a hydroxyethyl or an 
aminoethyl, and R.sub.2 and R.sub.3, taken together with the nitrogen atom 
to which they are bound, represent one of the following heterocyclyl 
ammonium radicals 
##STR9## 
The above heterocyclic rings maybe unsubstituted or substituted. When 
they are substituted, the substituted are one or more, preferably one or 
two substituents, which may be the same or different and selected form the 
group (a), (b), (e), (g), (h), (i), (q), (t) and (u) as defined above; or 
(iii') R.sub.1, R.sub.2 and R.sub.3, taken together with the nitrogen atom 
to which they are all bound, represent one of the following radicals 
##STR10## 
wherein the quinuclidine ring may be substituted by an oxo, hydroxy or 
methoxy group; or (iv') R.sub.1, R.sub.2 and R.sub.3, taken together with 
the nitrogen atom to which they are all bound, represent one of the 
following radicals 
##STR11## 
wherein R.sub.6 and R.sub.7 are independently a hydrogen atom; a C.sub.1 
-C.sub.4 alkyl, which may be unsubstituted or substituted with a cyano, a 
hydroxy, a sulfo, a hydroxyimino group; a methylsulphonyl; a carbamoyl; a 
hydroxy; a methylthio; a methoxy; a formamido; a formyl; a 
hydroxycarbamoyl or an amino group, and the pharmaceutically or 
veterinarily acceptable salts thereof. 
Specific examples of preferred compounds of the invention are listed in the 
following table: 
__________________________________________________________________________ 
##STR12## 
COMPOUND 
A Q.sup..sym. 
__________________________________________________________________________ 
##STR13## 
##STR14## 
2 
##STR15## 
##STR16## 
3 
##STR17## .sup..sym. NMe.sub.3 
4 
##STR18## .sup..sym. NEt.sub.3 
5 
##STR19## 
##STR20## 
6 
##STR21## 
##STR22## 
7 
##STR23## 
##STR24## 
8 
##STR25## 
##STR26## 
9 
##STR27## 
##STR28## 
10 
##STR29## 
##STR30## 
11 
##STR31## 
##STR32## 
12 
##STR33## 
##STR34## 
13 
##STR35## 
##STR36## 
14 
##STR37## 
##STR38## 
15 
##STR39## 
##STR40## 
16 
##STR41## 
##STR42## 
17 
##STR43## 
##STR44## 
18 
##STR45## N.sup..sym.Me.sub.3 
19 
##STR46## .sup..sym.NEt.sub.3 
20 
##STR47## 
##STR48## 
21 
##STR49## 
##STR50## 
22 
##STR51## 
##STR52## 
23 
##STR53## 
##STR54## 
24 
##STR55## N.sup..sym.Me.sub.3 
25 
##STR56## 
##STR57## 
26 
##STR58## 
##STR59## 
27 
##STR60## .sup..sym.NEt.sub.3 
28 
##STR61## 
##STR62## 
29 CH.sub.2 CH.sub.2 
##STR63## 
30 CH.sub.2 CH.sub.2 
##STR64## 
31 CH.sub.2 CH.sub.2 
##STR65## 
32 CH.sub.2 CH.sub.2 
.sup..sym.NMe.sub.3 
33 CH.sub.2 CH.sub.2 CH.sub.2 
##STR66## 
34 CH.sub.2 CH.sub.2 CH.sub.2 
##STR67## 
35 CH.sub.2 CH.sub.2 CH.sub.2 
##STR68## 
36 
##STR69## .sup..sym.N(CH.sub.3).sub.3 
37 
##STR70## 
##STR71## 
38 
##STR72## 
##STR73## 
39 
##STR74## 
##STR75## 
40 
##STR76## 
##STR77## 
41 
##STR78## 
##STR79## 
42 
##STR80## 
##STR81## 
43 
##STR82## 
##STR83## 
44 
##STR84## 
##STR85## 
45 
##STR86## 
##STR87## 
46 
##STR88## 
##STR89## 
47 
##STR90## 
##STR91## 
48 
##STR92## 
##STR93## 
49 
##STR94## 
##STR95## 
50 
##STR96## 
##STR97## 
51 
##STR98## 
##STR99## 
52 
##STR100## 
##STR101## 
53 
##STR102## 
##STR103## 
54 
##STR104## 
##STR105## 
55 
##STR106## 
##STR107## 
55/a 
##STR108## 
##STR109## 
56 
##STR110## 
##STR111## 
57 
##STR112## 
##STR113## 
58 
##STR114## 
##STR115## 
59 
##STR116## 
##STR117## 
60 
##STR118## 
##STR119## 
61 
##STR120## 
##STR121## 
62 
##STR122## 
##STR123## 
63 
##STR124## 
##STR125## 
64 
##STR126## 
##STR127## 
65 
##STR128## 
##STR129## 
66 
##STR130## 
##STR131## 
67 
##STR132## 
##STR133## 
68 
##STR134## 
##STR135## 
69 
##STR136## 
##STR137## 
70 
##STR138## 
##STR139## 
71 
##STR140## 
##STR141## 
72 
##STR142## 
##STR143## 
73 
##STR144## 
##STR145## 
74 
##STR146## 
##STR147## 
75 
##STR148## 
##STR149## 
76 
##STR150## 
##STR151## 
__________________________________________________________________________ 
The compounds of formula (I) can be prepared by a process comprising 
reacting a compound of formula (II) 
##STR152## 
wherein R.sub.1, R.sub.2 and R.sub.3 are as defined above, with a penem 
intermediate of formula (III) 
##STR153## 
wherein R and A are as defined above, Z' is a carboxy protecting group, 
and L is a leaving group susceptible to nucleophilic displacement by the 
amine of formula (II). The protecting groups present are then removed and, 
if desired, a mixture of isomers obtained is separated into the single 
isomers. 
The leaving group L in the compound of formula (III) may be, for example, a 
sulphonyloxy group --OSO.sub.2 R', wherein R' is an unsubstituted or 
substituted alkyl group or an aryl group; or a halogen atom such as 
iodine, bromine or chlorine. A particularly preferred sulphonyloxy group 
is trifluoromethanesulphonyloxy, --OSO.sub.2 CF.sub.3. A particularly 
preferred halogen atom is iodine. 
A carboxy protecting group Z' may be any group which, together with the 
--CO.sub.2 -- moiety, forms an esterified carboxy group. Examples of 
carboxy protecting groups are, in particular, C.sub.1 -C.sub.6 alkyl 
groups, for instance methyl, ethyl or tert-butyl; halosubstituted C.sub.1 
-C.sub.6 alkyl groups, for example 2,2,2-trichloroethyl; C.sub.2 -C.sub.4 
alkenyl groups, for example allyl; unsubstituted or substituted aryl 
groups, for example phenyl and p-nitro-phenyl; unsubstituted or 
substituted aryl C.sub.1 -C.sub.6 alkyl groups, for example benzyl, 
p-nitro-benzyl and p-methoxy-benzyl; aryloxy-C.sub.1 -C.sub.6 alkyl 
groups, for example phenoxy-ethyl; or groups such as benzhydryl, 
o-nitro-benzhydryl, acetonyl, trimethylsilyl, diphenyl-tert-butyl-silyl, 
and dimethyl-tert-butyl-silyl, or groups such as pivaloyloxy methyl or 
phthalidyl. 
Particularly preferred carboxy protecting groups are allyl, p-nitrobenzyl, 
trimethylsilyl, dimethyl- tert-butyl-silyl, and trichloroethyl. 
When in the compound of formula (III) R is a C.sub.1 -C.sub.3 alkyl group 
substituted by hydroxy, the hydroxy is preferably protected, and a 
particularly preferred protecting group is dimethyl-tert-butyl-silyl. 
The reaction between a compound of formula (II) and a compound of formula 
(III), may be performed in a suitable organic, preferably aprotic, 
solvent. Such a solvent may be, for instance, tetrahydrofuran, 
dimethylformamide, acetone or a halogenated hydrocarbon such as, e.g., 
dichloromethane. 
The reaction temperature may, preferably, vary between about -100.degree. 
C. and about +40.degree. C., preferably between -70.degree. C. and 
+15.degree. C. 
A compound of formula (III), wherein L is a sulphonyloxy group, may be 
prepared by reacting, according to known and conventional procedures, a 
carbinol precursor of formula (IV) 
##STR154## 
wherein R, A and Z' are as defined above, with the appropriate sulphonyl 
anhydride or sulphonyl halide, preferably triflic anhydride or triflic 
chloride, in the presence of a non-nucleophilic acid acceptor which may 
be, for instance, an inorganic base such as, e.g., calcium or lithium 
carbonate or calcium oxide, or an organic base such as, e.g., 
2,6-lutidine, or also the same compound of formula (II) to be reacted in 
the subsequent step. 
Indeed, according to a preferred procedure of the invention the compound of 
formula (IV) is made to react with the suitable sulphonyl anhydride or 
sulphonyl halide in the presence of an excess, usually an amount equal to 
or greater than 2 molar equivalents, of the desired compound of formula 
(II). In this situation the compound of formula (III) is not even isolated 
from the reaction mixture because it reacts in situ with the compound of 
formula (II). This preferred procedure is preferably carried out using dry 
dichloromethane as a solvent, at temperatures of from about -70.degree. C. 
to +25.degree. C. 
When a compound of formula (II) is reacted with a compound of formula (III) 
wherein L is halogen, the presence of a silver salt, particularly if it is 
soluble in the media, e.g., AgClO.sub.4, may be beneficial. 
A compound of formula (III) wherein L is halogen, may be prepared from the 
corresponding carbinol precursor of formula (IV) according to a modified 
Mitsunobu reaction. Where this carbinol is allowed to react with an 
organic amine hydrohalide, such as, for instance, methoxyamine 
hydrochloride, pyridine hydrochloride, pyridine hydrobromide and the 
preformed complex obtained from diethylazodicarboxylate and 
triphenylphosphine. The reaction is carried out, e.g., in tetrahydrofuran 
or methylene chloride, preferably at a temperature around room 
temperature. 
Alternatively, in the above modified Mitsunobu reaction a zinc halide, such 
as zinc chloride, zinc bromide or zinc iodide, can be substituted for the 
organic amine hydrohalide, under conditions substantially similar to those 
reported in J. Org. Chem., 1984, 49, 3027. 
Alternatively, a compound of formula (III) wherein L is halogen may be 
obtained from the carbinol of formula (IV) according to the more 
conventional procedures, entailing reaction with an inorganic acid halide 
such as SOCL.sub.2, PCl.sub.5, PCl.sub.3, PBr.sub.3, POCl.sub.3, 
POBr.sub.3 and the like. 
An additional methodology well-known in the literature, namely the reaction 
with PPh.sub.3 in CCl.sub.4, can be exploited for the preparation of 
compounds of formula (III) where L is chloride. A compound of formula 
(III) where L is iodine can be prepared by a halide exchange reaction from 
a compound of formula (III) wherein L is chlorine or bromine and sodium 
iodide. This reaction is preferably carried out in acetone at temperatures 
ranging from 0.degree. C. to +60.degree. C. (reflux temperature). Some 
intermediates of formula (III), preferably when L is chlorine, and the 
intermediates of formula (IV), either as such or as their protected 
derivatives, are known compounds or can be prepared from known compounds 
by following known general methodologies. 
These include, for example: 
(A) the thermal cyclization of a compound of formula (V) 
##STR155## 
wherein R, A and Z' are as defined above, X represents sulphur or oxygen, 
and W is a free or a protected OH, or halogen, preferably chlorine, 
according to the method described, for example, in J. Am. Chem. Soc., 
1978, 100, 8214 and Chem. Pharm. Bull., 1981, 29, 3158; 
(B) the thermal cyclization of a compound of formula (VI) 
##STR156## 
wherein R, X, A and Z' are as defined above, and W' is a free or a 
protected OH. The cyclization is performed in the presence of an organic 
phosphite, preferably trimethyl or triethyl phosphite, according to the 
method described, for example in Chem. Pharm. Bull., 1983, 31, 768 and 
Tetrahedron Lett., 1984, 25, 2395; or 
(C) the reaction of a compound of formula (VII) 
##STR157## 
wherein R, X, Z and Z' are as defined above, with a carboxylic acid of 
formula (VIII), or an activated derivative thereof 
##STR158## 
wherein W is as defined above, according to the method described, for 
example, in our British Patent Application No. 2,118,181--A-- which is 
hereby incorporated by reference. 
In particular, method C may be used to obtain intermediates of formula 
(III) and (Iv) wherein -A represents a group --Z--O--CO--. Method B may be 
used to obtain compounds of formula (IV). And method A may be used to 
obtain intermediates of the formula (III) or (IV). 
Removal of the protecting groups can be effected by known per se 
procedures; e.g., silyl groups can be removed under mild acidic 
conditions, or by fluoride ions, e.g., with tetrabutylammonium fluoride; 
p-nitrobenzyl groups can be removed by reduction, e.g., by catalytic 
hydrogenation, or with metals, such as Fe and Zn; allyl carboxylates can 
be cleved by transallylation with an organic acid or a salt thereof, such 
as acetic acid, 2-ethylhexanoic acid or their sodium and potassium salts, 
this reaction being catalyzed by a triphenylphosphine-palladium complex, 
preferably by tetrakis-triphenylphosphine-Pd(o). 
The optional salification of an obtained compound and the separation of a 
mixture of isomers into the single isomers may be carried out following 
known and conventional procedures. 
Compounds of formula (II), (V), (VI), (VII), (VIII) are known compounds or 
can be prepared from known compounds according to known methods. 
The compounds of formula (I) provided by the present invention are potent, 
broad spectrum antibacterial agents. In comparison to other penem 
compounds, e.g., the sodium salts derived from penems of formula (IV), or 
compounds of formula (I) wherein Q is an amine instead of quaternary 
ammonium, they usually show markedly increased in vitro activity against 
both Gram-positive and Gram-negative strains. 
Moreover, in comparison with other penem compounds, they show unusually 
prolonged plasma levels. And when tested in vivo after parenteral 
administration, they displayed a very high degree of therapeutic 
effectiveness in treating infections caused by both Gram-positive and 
Gram-negative bacteria. Their toxicity, on the other hand, is quite 
negligible. 
Table I shows the in vitro activity of a typical compound of formula (I), 
the compound 5 of the previous examples, in comparison with a classical 
penem of relevance, FCE 21420 (J. Antibiotics, 1982, 35, 1248) and the 
third generation cephalosporin Cefotaxime. 
Table II shows "in vivo" the activity of compound 5. 
TABLE I 
__________________________________________________________________________ 
In-Vitro Antibacterial Activity (.gamma./ml) 
Against Gram-positive And Gram-negative bacteria 
As Determined By The Agar Dilution Technique 
Organism Compound 5.sup.(1) 
FCE 21420.sup.(2) 
Cefotaxime 
__________________________________________________________________________ 
Staphylococcus aureus Smith 
0.011 0.046 0.77 
S. Aureus 209 P 0.005 0.046 1.56 
S. Epidermidis 0.19 0.76 6.25 
Streptococcus faecalis 
0.06 0.1 10 
(4 Strains) 
S. pyogenes ATCC 12384 
0.011 0.046 1.25 
Klebsiella aerogenes 1522 E 
0.38 1.55 0.095 
K. aerogenes 1082 E 
0.38 0.76 6.25 
Escherichia coli 026:B6 
0.19 0.76 0.38 
E. coli 026:B6 cef R (IV) 
0.38 3.12 1.25 
Proteus morganii ATCC 25830 
0.38 1.52 0.037 
P. rettgeri ATCC 9250 
0.38 1.52 0.018 
Citrobacter Freundii 
0.19 1.52 -- 
ATCC 8090 
Serratia marcescens 
0.76 3.12 -- 
ATCC 2902 
Pseudomonas aeruginosa 2598 
25 100 25 
__________________________________________________________________________ 
.sup.(1) Compound 5: 
##STR159## 
.sup.(2) FCE 21420: 
##STR160## 
- 
TABLE II 
______________________________________ 
In-vivo data for "Compound 5" 
t1/2 .alpha. 
t1/2 .beta. 
(minutes) 
______________________________________ 
Plasma half-life.sup.(1) 
5 15 
______________________________________ 
Experimental infections in mice.sup.(2) 
Strain ED.sub.50 (mg/kg, cumulative dose) 
______________________________________ 
Staphylococcus aureus Smith 
0.06 
Escherichia coli G 
0.5 
Klebsiella pneumoniae FI 5724 
0.8 
______________________________________ 
.sup.(1) Determined after a single intravenous dose (10 mg/kg) in the 
mouse; the plasma concentration vs. time data were best described 
according to a two compartments open model with the tabulated 
.sup.(2) Intraperitoneal infection in mice with a 3 .times. LD.sub.50 
challenge; treatments at 30 minutes after infection for S. aureus and 30, 
90, 360 minutes for E. coli and K. pneumoniae. 
Because of their high antibacterial activity, the compounds of the 
invention are useful, for example, in the treatment of respiratory tract 
infections, for example, bronchitis, bronchopneumonia or pleuritis; 
hepatobiliary and abdominal infections; septicemia; urinary tract 
infections, for example, pyelonephritis or cystitis; obstetrical and 
gynecological infections, for instance, cervicitis or endometritis; ear, 
nose and throat infections, for instance otitis, sinusitis or parotitis. 
The compounds of the invention may be administered, either to humans or to 
animals, in a variety of dosage forms, e.g., orally in the form of 
tablets, capsules, drops or syrups; rectally in the form of suppositories; 
parenterally, e.g., intravenously or intramuscularly (as solutions or 
suspensions). Intravenous administration being preferred in emergency 
situations; by inhalation in the form of areosols or solutions for 
nebulizers; intravaginally in the form, e.g., of bougies; or topically in 
the form of lotions, creams and ointments. The pharmaceutical or 
veterinary compositions containing the compounds of formula (I), which are 
also within the scope of the invention, may be prepared in a conventional 
way by employing the conventional carriers or diluents used for e.g., 
cephalosporins. 
Conventional carriers or diluents are, for example, water, gelatine, 
lactose, starches, magnesium stearate, talc, vegetable oils, cellulose and 
the like. Daily doses in the range of about 0.5 to about 100 mg per kg of 
body weight may be used, in various animal species. The exact dose depends 
on the age, weight and condition of the subject to be treated and on the 
frequency and route of administration. 
A preferred way of administration of the compounds of the invention is 
parenteral administration. In this case the compounds may be administered, 
for example to adult humans, in an amount ranging from about 250 mg to 
about 1000 mg pro dose, preferably about 500 mg pro dose, 1-4 times a day, 
dissolved in a suitable solvent, such as, for example, sterile water of 
lidocaine hydrochloride solution for intramuscular injections, and sterile 
water, physiological saline solution, dextrose solution or the 
conventional intravenous fluids or electrolytes, for intravenous 
injections. Furthermore, the compounds of the invention may be used as 
antibacterial agents in a prophylactic manner, e.g., in cleaning or as 
surface disinfecting compositions, for example, 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.