The present invention provides cephalosporin sulphones of formula (I) and the pharmaceutically and veterinarily acceptable salts thereof: ##STR1## wherein n is one or two: A and B are both or each independently hydrogen or an organic radical; PA1 R.sup.1 represents halogen, A, OA, --S(O).sub.m A wherein m is 0-2, --OC(O)A, --OS(O).sub.2 A, --NHC(O)A or --NH--Z wherein Z is a mono, di- or tripeptide and A is as defined above; PA1 R.sup.2 represents a halogen, A, --S(O).sub.m A, --O--A, --C(O)A, --C(O)OA, --CH.sub.2 --OA, --CH.sub.2 S(O).sub.m A, --CH.sub.2 OC(O)A, --CH.sub.2 O--Z, --CH.sub.2 SC(O) A, --CH.sub.2 --N(A)A, --CH.sub.2 N.sup.+ (A)(A')A", --CH.sub.2 NH--C(O)A or --CH.sub.2 NH--Z wherein A and Z are as defined above. The compounds of formula (I) and their salts are elastase inhibitors.

The present invention relates to new cephalosporins, their preparation and 
to pharmaceutical and veterinary compositions containing them. 
The compounds disclosed in the present invention are cephem sulphones or 
sulphoxides featuring the simultaneous presence on the cephem skeleton of 
an acyl group at C-4 and an acyloxy group at C-2. 
According to the invention there are provided cephalosporin sulphones of 
formula (I) and the pharmaceutically and veterinarily acceptable salts 
thereof: 
##STR2## 
wherein n is one or two: A and B are each, independently, hydrogen or an 
organic radical selected from optionally substituted C.sub.1 -C.sub.12 
straight or branched alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 
alkynyl, C.sub.6 -C.sub.14 aryl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 
-C.sub.8 cycloalkenyl, or C.sub.7 -C.sub.18 aralkyl, C.sub.8 -C.sub.18 
aralkenyl, C.sub.8 -C.sub.18 aralkynyl, (cycloalkyl)alkyl, 
(cycloalkyl)alkenyl, heterocyclyl, (heterocyclyl)alkyl and 
(heterocyclyl)alkenyl groups; 
R.sup.1 represents 
(1) a chlorine, fluorine, bromine or iodine atom 
(2) A as defined above 
(3) an ether OA wherein A is as defined above 
(4) a thioether, sulphoxide or sulphone --S(O).sub.m A wherein m is either 
zero, one or two and A is as defined above; 
(5) acyloxy --OC(O)A wherein A is as defined above; 
(6) sulphonyloxy --OS(O).sub.2 A wherein A is as defined above; 
(7) an acylamino group --NHC(O)A wherein A is as defined above or acylamino 
--NH--Z wherein Z is a mono, di- or tripeptide composed of D or L 
.alpha.-aminoacids chosen from Ala, Gly, Val, Leu, Ile and Phe, and in 
which .alpha.-amino acids the terminal amino group is either free or 
acylated by a group --C(O)A or --C(O)OA wherein A is as defined above; 
R.sup.2 represents: 
(1) A as defined above; 
(2) a chlorine or fluorine atom; 
(3) a sulphenyl, sulphinyl or sulfonyl group --S(O).sub.m A wherein A is as 
defined above; 
(4) an oxy group --O--A wherein A is as defined above; 
(5) an acyl group --C(O)A or acyloxy group --C(O)OA wherein A is as defined 
above; 
(6) an oxymethyl group --CH.sub.2 --OA wherein A is as defined above; 
(7) a thiomethyl group or a derivative thereof of formula --CH.sub.2 
S(O).sub.m A wherein m and A are as defined above; 
(8) an acyloxymethyl group --CH.sub.2 OC(O)A or --CH.sub.2 O--Z wherein A 
and Z are as defined above; 
(9) an acylthiomethyl group --CH.sub.2 SC(O)A wherein A is as defined 
above; 
(10) an aminomethyl group --CH.sub.2 --N(A)A' wherein A is as defined above 
and A', being the same or different, is as defined above for A; or A and 
A' taken together with the nitrogen atom to which they are attached 
represent a heterocyclic ring; 
(11) ammoniomethyl --CH.sub.2 N.sup.+ (A)(A')A" wherein A and A' are as 
defined above and A", being the same or different, is as defined for A; or 
A is alkyl and A' and A" together with the nitrogen atom to which they are 
attached represent a heterocyclic ring, or A and A' and A" together with 
the nitrogen atom to which they are attached represent a heterocyclic 
ring; 
(12) an acylaminomethyl group --CH.sub.2 NH--C(O) A or --CH.sub.2 NH--Z 
wherein A and Z are as defined above. 
As referred to herein a C.sub.1 -C.sub.12 alkyl group is straight or 
branched, for instance C.sub.1 -C.sub.10 alkyl, typically C.sub.1 -C.sub.6 
alkyl or C.sub.1 -C.sub.4 alkyl. Examples include methyl, ethyl, n-propyl, 
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and 
so on. 
A C.sub.2 -C.sub.12 alkenyl group is straight or branched, for instance 
C.sub.2 -C.sub.10 alkenyl, typically C.sub.2 -C.sub.6 alkenyl or C.sub.2 
-C.sub.4 alkenyl. Examples include vinyl, allyl, crotyl, 
2-methyl-1-propenyl, 1-methyl-1-propenyl, butenyl, pentenyl and so on. 
A C.sub.2 -C.sub.12 alkynyl group is straight or branched, for instance 
C.sub.2 -C.sub.10 alkynyl, typically C.sub.2 -C.sub.6 alkynyl or C.sub.2 
-C.sub.4 alkynyl. Examples include ethynyl, propargyl, 1-propynyl, 
1-butynyl, 2-butynyl and so on. 
A C.sub.6 -C.sub.14 aryl group is preferably a monocyclic, bicyclic or 
tricyclic aromatic hydrocarbon group of 6 to 14 carbon atoms, such as 
phenyl, naphthyl, phenanthryl or anthryl. 
A C.sub.3 -C.sub.8 cycloalkyl group is preferably a saturated carbocyclic 
group of 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, 
cyclopentyl, cyclohexyl and so on. 
A C.sub.5 -C.sub.8 cycloalkenyl group is preferably an unsaturated 
carbocyclic group such as cyclopentenyl, cyclohexenyl and so on. 
A C.sub.7 -C.sub.18 aralkyl group is preferably an alkyl group of 1 to 4 
carbon atoms linked to a monocyclic, bicyclic or tricyclic aromatic 
hydrocarbon group of 6 to 14 carbon atoms. Examples of aralkyl groups are 
benzyl, phenylethyl, naphthylmethyl, naphthylethyl and anthrylmethyl. 
A C.sub.8 -C.sub.18 aralkenyl group is preferably an alkenyl group of 2 to 
4 carbon atoms linked to a monocyclic, bicyclic or tricyclic aromatic 
hydrocarbon group of 6 to 14 carbon atoms. Examples of aralkenyl groups 
are styryl, 2-phenyl-1-propenyl, 3-phenyl-2-butenyl, 2-naphthylethenyl, 
anthrylethenyl and so on. 
A C.sub.8 -C.sub.14 aralkynyl group is preferably an alkynyl group of 2 to 
4 carbon atoms linked to a monocyclic, bicyclic or tricyclic aromatic 
hydrocarbon group of 6 to 10 carbon atoms. Examples of aralkynyl groups 
are 2-phenylethynyl, 2-naphthylethynyl, anthrylethynyl and so on. 
A (cycloalkyl)alkyl group is preferably an alkyl group of 1 to 4 carbon 
atoms linked to a cycloalkyl group. 
A (cycloalkyl)alkenyl group is preferably an alkenyl group of 2 to 4 carbon 
atoms linked to a cycloalkyl group or to an aryl group. 
A heterocyclyl group is preferably a 3- to 6-membered, saturated or 
unsaturated heterocyclyl ring, containing at least one heteroatom selected 
from O, S and N, which is optionally fused to a second 5- or 6-membered, 
saturated or unsaturated heterocyclyl group or to a cycloalkyl group or to 
an aryl group. 
A (heterocyclyl)alkyl group is preferably an alkyl group of 1 to 4 carbon 
atoms linked to a heterocyclyl group. 
A (heterocyclyl)alkenyl group is preferably an alkenyl group of 2 to 4 
carbon atoms linked to a heterocyclic group. 
The term halogen or halo preferably denotes fluorine, chlorine or bromine. 
The above said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, 
aralkyl, aralkenyl, aralkynyl, (cycloalkyl)alkyl, (cycloalkyl)alkenyl, 
heterocyclyl, (heterocyclyl)alkyl and (heterocyclyl)alkenyl groups can be 
either unsubstituted or substituted by one or more substituents selected 
from: 
halo (e.g., fluoro, bromo, chloro or iodo); 
hydroxy; 
nitro; 
azido; 
mercapto (--SH); 
amino (i.e., --NH.sub.2, or --NHR.sup.i or --NR.sup.i R.sup.ii) wherein 
R.sup.i and R.sup.ii, which are the same or different, are C.sub.1 
-C.sub.12 straight or branched alkyl or phenyl or benzyl; or phenyl 
optionally substituted by one or more halogen atoms or carboxy groups; 
formyl (i.e., --CHO); 
cyano; 
carboxy(alkyl) (i.e., (CH.sub.2).sub.t COOH or (CH.sub.2).sub.t COOR.sup.i) 
wherein R.sup.i is as defined above and t is 0, 1, 2 or 3; 
sulfo (i e., --SO,H); 
acyl (i.e., --C(O)R.sup.i) wherein R.sup.i is as defined above or 
trifluoroacetyl (i.e., --C(O)CF.sub.3); 
carbamoyl (i.e., --CONH.sub.2); N-methylcarbamoyl (i.e., --CONHCH.sub.3) or 
N-carboxymethylcarbamoyl (i.e., --CONHCH.sub.2 COOH); 
carbamoyloxy (i.e., --OCONH.sub.2); 
acyloxy (i.e., --OC(O)R.sup.i) wherein R.sup.i is as defined above or 
formyloxy (i.e., --OC(O)H); 
alkoxycarbonyl or benzyloxycarbonyl (i.e., --C(O)OR.sup.i) wherein R.sup.i 
is as defined above; 
alkoxycarbonyloxy or benzyloxycarbonyloxy (i.e., --OC(O)OR.sup.i) wherein 
R.sup.i is as defined above; 
alkoxy, phenoxy or benzyloxy (i.e., --OR.sup.i) wherein R.sup.i is as 
defined above; 
alkylthio, phenylthio or benzylthio (i.e., --SR.sup.i) wherein R.sup.i is 
as defined above; 
alkylsulfinyl, phenylsulfinyl or benzylsulfinyl (i.e., --S(O)R.sup.i) 
wherein R.sup.i is as defined above; 
alkylsulfonyl, phenylsulfonyl or benzylsulfonyl (i.e., --S(O).sub.2 
R.sup.i) wherein R.sup.i is as defined above; 
acylamino (i.e., --NHC(O)R.sup.iii or --NHC(O)OR.sup.iii) wherein R.sup.iii 
is C.sub.1 -C.sub.12 straight or branched alkyl, phenyl, benzyl, CH.sub.2 
CH.sub.2 COOH or CH.sub.2 CH.sub.2 CH.sub.2 COOH; 
sulfonamido (i.e., --NHSO.sub.2 R.sup.i) wherein R.sup.i is as defined 
above; 
guanidino ( i. e. , --NHC (.dbd.NH) NH.sub.2); 
C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl or alkynyl; 
C.sub.3 -C.sub.6 cycloalkyl; 
substituted methyl selected from chloromethyl, fluoromethyl, 
difluoromethyl, trifluoromethyl, aminomethyl, N,N-dimethylaminomethyl, 
azidomethyl, cyanomethyl, carboxymethyl, sulfomethyl, carbamoylmethyl, 
carbamoyloxymethyl, hydroxymethyl, C.sub.1 -C.sub.4 
alkyloxycarbonylmethyl, guanidinomethyl. 
phthalimido, indolyl, indolinyl, isoindolinyl, 1-oxoisoindolinyl. 
The heterocyclic group may in particular be chosen from: 
##STR3## 
wherein Y is S, O or NH 
Any of the above heterocyclic groups may be totally or partially reduced. 
More preferably, the heterocyclic group is chosen from: 
##STR4## 
wherein R.sup.I is, typically, hydrogen, methyl, allyl or benzyl, or a 
hydroxy protecting group; R.sup.II is hydrogen, methyl, ethyl, propyl, 
phenyl, benzyl, carboxymethyl, 2-carboxyethyl, 3- carboxypropyl, 
3-benzhydryloxycarbonylpropyl, sulphoethyl, 2,2-dimethylaminoethyl and 
R.sup.III is typically hydrogen, methyl, allyl or benzyl or a carboxy 
protecting group. 
The carboxy-protecting group may, for example, be a lower alkyl group such 
as methyl, ethyl, propyl, isopropyl or tert-butyl; a halogenated lower 
alkyl group such as 2,2,2-trichoroethyl or 2,2,2-trifluoroethyl; a lower 
alkanoyloxyalkyl group such as acetoxymethyl, propionyloxymethyl, 
pivaloyloxymethyl, 1-acetoxyethyl, 1-propionyloxyethyl; a lower 
alkoxycarbonyloxyalkyl group such as 1-(methoxycarbonyloxy)ethyl, 
1-(ethoxycarbonyloxy) ethyl, 1-(isopropoxycarbonyloxy)ethyl; a lower 
alkenyl group such as 2-propenyl, 2-chloro-2-propenyl, 
3-methoxycarbonyl-2-propenyl, 2-methyl-2-propenyl, 2-butenyl, cinnamyl; an 
aralkyl group such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, 
o-nitrobenzyl, p-nitrobenzyl, benzhydryl, bis(p-methoxyphenyl)methyl; a 
(5-substituted 2-oxo-1,3-dioxol-4-yl)methyl group such as 
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl; a lower alkylsilyl group such as 
trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 
triphenylsilyl; or an indanyl group; a phthalidyl group; a pyranyl group; 
a methoxymethyl or methylthiomethyl group; a 2-methoxyethoxymethyl group. 
Particularly preferred are a tert-butyl group, a p-nitrobenzyl group, a 
p-methoxybenzyl group, a benzhydryl group, a tert-butyldimethylsilyl, 
tert-butyldiphenylsilyl group or a propenyl group. 
The amino, hydroxy or mercapto protecting groups which may optionally be 
present are any of those usually employed in the chemistry of penicillins 
and cephalosporins for this kind of function. They may be, for instance, 
optionally substituted, especially halo-substituted, acyl groups, e.g. 
acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, benzoyl or 
p-bromophenacyl; triarylmethyl groups, e.g. triphenylmethyl; silyl groups, 
in particular trimethylsilyl, dimethyl-tert-butylsilyl, 
diphenyl-tert-butylsilyl,; or also groups such as tert-butoxycarbonyl, 
p-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyl and 
pyranyl. Preferred protecting groups of the hydroxy function are 
p-nitrobenzyloxycarbonyl; allyloxycarbonyl; dimethyl-tert-butylsilyl; 
diphenyl-tert-butylsilyl; trimethylsilyl; 2,2,2-trichloroethoxycarbonyl; 
benzyl; dimethoxybenzyl; p-methoxybenzyloxycarbonyl; p-bromophenacyl; 
triphenylmethyl, pyranyl, methoxymethyl, benzhydryl, 
2-methoxyethoxymethyl, formyl, acetyl, trichloroacetyl. 
The present invention provides the salts of those compounds of formula (I) 
that have salt-forming groups, especially the salts of the compounds 
having a carboxylic group, a basic group (e.g. an amino or guanidino 
group), or a quaternary ammonium group. The salts are pharmaceutically or 
veterinarily acceptable salts, for example alkali metal and alkaline earth 
metal salts (e.g. sodium, potassium, lithium, calcium and magnesium 
salts), ammonium salts and salts with an appropriate organic amine or 
amino acid (e.g. arginine, procaine salts), and the addition salts formed 
with suitable organic or inorganic acids, for example hydrochloric acid, 
sulphuric acid, carboxylic and sulphonic organic acids (e.g. acetic, 
trifluoroacetic, p-toluensulphonic acid). Some compounds of formula (I) 
which contain a carboxylate and an ammonium group may exist as 
zwitterions; such salts are also part of the present invention. 
Furthermore, physiologically hydrolyzable esters, hydrates and solyates of 
compounds of formula (I) are included within the scope of the present 
invention. The physiologically hydrolyzable esters of the compounds (I) 
may include, for example, methoxycarbonylmethyl, 
1-methoxycarbonyloxy-1-ethyl, indanyl, phthalidyl, methoxymethyl, 
pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl or 
5-methyl-2-oxo-1,3-dioxolan-4-yl esters, and other physiologically 
hydrolyzable esters which have been widely used in the technical fields of 
penicillin and cephalosporin antibiotics: more preferably, 
methoxycarbonyloxymethyl, 1-methoxycarbonyloxy,l-ethyl, methoxymethyl or 
pivaloyloxymethyl; and most preferably, methoxycarbonyloxymethyl or 
methoxymethyl. Typical solvates of the cephalosporin compounds of 
formula(I) may include solyates with water miscible solvents, e.g. 
methanol, ethanol, acetone; or acetonitrile; and more preferably, ethanol. 
The present invention also provides a pharmaceutical composition 
comprising, as an active principle, a compound of formula (I) or salt 
thereof, in association with one or more pharmaceutically acceptable 
carriers, excipients or other additives, if necessary. 
The present invention encompasses all the possible stereoisomers of 
compounds of formula (I) as well as their racemic or optically active 
mixtures. However the configuration depicted in formula (1') is 
particularly preferred 
##STR5## 
wherein n is one or two; A is hydrogen or C.sub.1 -C.sub.12 straight or 
branched alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, 
C.sub.6 -C.sub.10 aryl, C.sub.3 -C.sub.8 cycloalkyl, heterocyclyl, 
2-phenyl-2-propyl, benzyl or diphenylmethyl, wherein the alkyl, alkenyl, 
alkynyl, aryl, cycloalkyl, heterocyclyl and benzyl groups are either 
unsubstituted or substituted by fluoro, chloro, sulfo, carboxy, C.sub.1 
-C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, carbamoyl, sulfamoyl, 
carbamoyloxy, methanesulphonyl, nitro, cyano, diazo, hydroxy, methoxy, 
ethoxy, tert-butoxy, benzyloxy, benzhydryloxy, acetoxy, pivaloyloxy, 
benzoxy, carboxymethyl, carboxyphenyl C.sub.6 H.sub.5 --COOH, 
carboxybenzyl CH.sub.2 --C.sub.6 H.sub.4 --COOH, benzoyl, pivaloyl, amino, 
formamido, acetamido, trifluoroacetamido or pivalamido; 
B is 
(1') a hydrogen atom; 
(2') an optionally substituted C.sub.1 -C.sub.5 straight or branched alkyl 
or alkenyl group or C.sub.3 -C.sub.6 cycloalkyl; 
(3') optionally substituted C.sub.6 -C.sub.14 aryl; 
(4') optionally substituted C.sub.7 -C.sub.15 aralkyl; 
(5') optionally substituted heterocyclyl; 
(6') optionally substituted (heterocyclyl)alkyl; 
the substituents for the groups defined under (1')-(6') being selected from 
fluoro, chloro, bromo, nitro, cyano, sulfo, carboxy, tetrazolyl, C.sub.1 
-C.sub.4 alkoxycarbonyl, carbamoyl,N-carboxyphenylcarbamoyl, 
N-carboxybenzylcarbamoyl, N-carboxymethylphenylcarbamoyl, sulfamoyl, 
carbamoyloxy, methanesulfonyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, 
benzyloxy, benzhydryloxy, phenoxy, p-chlorophenoxy, p-carboxyphenoxy, 
acetoxy, pivaloyloxy, benzoyloxy, methylthio, phenylthio, methanesulfonyl, 
benzenesulfonyl, carboxymethylthio, carboxyphenyl C.sub.6 H.sub.5 --COOH, 
carboxybenzyl CH.sub.2 --C.sub.6 H.sub.5 --COOH, acetyl, trifluoroacetyl, 
benzoyl, pivaloyl, amino, dimethylamino, phenylamino, 
2,6-dichlorophenylamino diethylamino, formamido, acetamido, 
trifluoroacetamido, pivalamido, oxo, phenyl, phthalimido, isoindolinyl, 
1-oxoisoindolinyl and C.sub.1 -C.sub.5 straight or branched alkyl, vinyl 
or allyl, and C.sub.1 -C.sub.4 alkyl substituted by one or more 
substituents selected from chloro, fluoro, difluoro, trifluoro, amino, N,N 
dimethylamino, azido, cyano, carboxy, sulfo, carbamoyl, carbamoyloxy, 
hydroxy, C.sub.1 -C.sub.4 alkyloxycarbonyl, guanidino and a group Y-A'", 
wherein Y is oxygen, sulphur or carbamoyl(oxy) and A'" is an optionally 
substituted C.sub.1 -C.sub.4 alkyl, phenyl, benzyl or heterocyclic group, 
the optional substituents being selected from those defined above for 
groups (1')-(5'); 
R.sup.1 is 
(1') hydrogen or a chlorine, fluorine or bromine atom 
(2') C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, 1-(hydroxy)ethyl, 
1-(benzyloxy)ethyl, 1-(benzyloxycarbonyloxy)ethyl, 1-(phenylacetoxy)ethyl, 
2-fluoro-1-hydroxyethyl, phenyl or benzyl 
(3') methoxy, ethoxy, isopropoxy, phenoxy or benzyloxy 
(4') methylthio, ethylthio, isopropylthio 
(5') formyloxy, acetoxy or phenylacetoxy 
(6') mesyloxy or tosyloxy 
(7') formamido, acetamido, fluoroacetamido, trifluoroacetamido or 
chloroacetamido 
(8') R.sup.iv -Ala-NH, wherein R.sup.iv is acetyl, tert-butoxycarbonyl, 
benzoxycarbonyl or HOOC--CH.sub.2 CH.sub.2 C(O)--; 
(9') R.sup.iv -Val-NH, wherein R.sup.iv is as defined above; 
(10') Val-Pro-NH, LysNH or Ala-Ala-ProNH, wherein the terminal amino group 
of Val, Lys or Ala respectively or the .alpha.-amino group of Lys is 
either free or acylated with a group R.sup.iv as defined above; 
R.sup.2 is either hydrogen or 
(1') methyl, chloromethyl, bromomethyl, benzyl, ethyl, propyl or phenyl 
(2') chloro 
(3') methoxy or benzyloxy 
(4') methylthio 
(5') formyl, acetyl, benzoyl, carboxy, methoxycarbonyl, ethoxycarbonyl, 
tert-butoxycarbonyl or benzyloxycarbonyl; 
(6') methoxymethyl, ethoxymethyl, isopropoxymethyl; or benzyloxymethyl, 
phenoxymethyl, 3-pyridyloxymethyl wherein the phenyl and pyridyl rings are 
either unsubstituted or substituted by one group or two groups which are 
the same or different and are each chosen from hydroxy, carboxy, amino and 
C.sub.1 -C.sub.4 alkoxycarbonyl; 
(7') --CH.sub.2 (S).sub.n A wherein n is zero, one or two and A is as 
defined above; 
(8') acetoxymethyl, benzoyloxymethyl, phenylacetoxymethyl or C.sub.3 
-C.sub.6 alkanoyloxymethyl, which groups are either unsubstituted or 
substituted by one or more groups selected from carboxy, hydroxy and 
C.sub.1 -C.sub.3 alkoxy; 
(9') trialkylammoniomethyl wherein the alkyl group is methyl, ethyl or 
propyl; N-methylpyrrolidiniomethyl, N-methylpiperidimiomethyl or 
N-methylmorpholiniomethyl; 
(10') pyridiniomethyl which is either unsubstituted or substituted on the 
heterocyclic ring by fluoro, chloro, methoxy, hydroxy, carboxy or 
carbamoyl; 
(11') carbamoyloxymethyl; or 
(12') carboxy; 
and the pharmaceutically and veterinarily acceptable salts thereof and all 
the possible isomers, e.g. stereoisomers, epimers, diastereoisomers, 
geometrical isomers, tautomers. 
Still more preferred are compounds of formula (I') wherein n is two; 
A is selected from tert-butyl, phenyl, 1-phenylethyl, 2-phenyl-2-propyl, 
4-benzylphenyl, biphenylyl, naphthyl and tolyl, any of which is optionally 
substituted by a C.sub.1 -C.sub.4 alkyl group or a carboxy group; 
B is 
(1") methyl, ethyl, vinyl, propyl, allyl, isopropyl, n-butyl, s-butyl, 
tert-butyl, pentyl, optionally substituted by a group selected from 
carboxy, sulfo, amino, cyano, methoxy, phenoxy, naphthyloxy, 
p-chlorophenoxy, p-carboxyphenoxy; 
(2") a phenyl group optionally substituted by one or two groups selected 
from fluoro, chloro, bromo, iodo, C.sub.1 -C.sub.5 alkyl, methoxy, 
methylthio, methanesulfonyl, carboxy, tert-butoxycarbonyl, 
benzhydryloxycarbonyl, carboxymethyl, sulfo, sulfomethyl, 
carboxymethylthio, carboxymethoxy, nitro, cyano, amino, dimethylamino, 
phenylamino, 2,3 dimethylphenylamino, dibutylamino, hydroxy, acetamido, 
trifluorocetamido, acetyl, trifluoroacetyl, carbamoyl and sulfamoyl; 
(3") naphthyl, optionally substituted by one or two groups selected from 
fluoro, chloro, bromo, iodo, C.sub.1 -C.sub.4 alkyl, methoxy, methylthio, 
methanesulfonyl, carboxy, tert-butoxycarbonyl, benzhydryloxycarbonyl, 
carboxymethyl, carboxymethylthio, carboxymethoxy, sulfo, sulfomethyl, 
nitro, cyano, amino, dimethylamino, hydroxy, acetamido, trifluorocetamido, 
acetyl, trifluoroacetyl, carbamoyl and sulfamoyl; 
(4") anthryl or phenanthryl, optionally substituted by one or two groups 
selected from fluoro, chloro, bromo, iodo, C.sub.1 -C.sub.4 alkyl, 
methoxy, methylthio, methanesulfonyl, carboxy, tert-butoxycarbonyl, 
benzhydryloxycarbonyl, carboxymethyl, carboxymethylthio, carboxymethoxy, 
sulfo, sulfomethyl, nitro, cyano, amino, dimethylamino, hydroxy, 
acetamido, trifluorocetamido, acetyl, trifluoroacetyl, carbamoyl and 
sulfamoyl; 
(5") biphenyl --C.sub.6 H.sub.4 --C.sub.6 H.sub.5, optionally substituted 
by a carboxy, sulfo, carboxymethyl or sulfomethyl group; 
(6") a heterocycle chosen from thiazole, tetrazole, thiadiazole, triazole, 
isothiazole, oxazole, isoxazole, pyridine, pyrimidine, pyridazine, 
quinoline, isoquinoline, benzothiazole, benzoxazole, furan, thiophene, 
pyrrole, indole, chromane, benzofuran and benzothiophene either 
unsubstituted or substituted by one or two groups selected from fluoro, 
chloro, bromo, iodo, straight or branched C.sub.1 -C.sub.4 alkyl, methoxy, 
methylthio, methanesulfonyl, carboxy, tert-butoxycarbonyl, 
benzhydryloxycarbonyl, carboxymethyl, carboxymethylthio, carboxymethoxy, 
sulfo, sulfomethyl, nitro, cyano, amino, dimethylamino, 
dimethylaminoethyl, hydroxy, acetamido, trifluoroacetamido, acetyl, 
trifluoroacetyl, carbamoyl and sulfamoyl; 
(7") phenyl substituted by t-butyl, N-carboxyphenylcarbamoyl, 
N-carboxybenzylcarbamoyl or N-carboxymethylphenylcarbamoyl or by methyl 
substituted by a group Y--A'", wherein Y is O, S or OCONH and A'" is 
tetrazole, thiadiazole, pyridine, triazole, C.sub.1 -C.sub.4 alkyl, phenyl 
or benzyl either unsubstituted or substituted by one or two groups 
selected from C.sub.1 -C.sub.4 alkyl, methansulfonyl, carboxy, sulfo, 
amino, hydroxy, oxo, acetamido, carboxymethyl and carboxymethylthio; 
(8") phenyl(C.sub.1 -C.sub.4)alkyl or naphthyl(C.sub.1 -C.sub.4)alkyl, with 
yhe phenyl and naphthyl rings optionally substituted by C.sub.1 -C.sub.5 
alkyl, C.sub.1 -C.sub.4 alkoxy, phenoxy, benzoyl, phenylamino, 
2,6-dichlorophenylamino, phenyl, p-chlorophenyl, naphthyl, chloro, fluoro, 
hydroxy, carboxy, nitro, phthalimido, isoindolinyl, 1-oxoisoindolinyl. 
R.sup.1 is hydrogen or a chlorine, fluorine or bromine atom, or a methoxy, 
ethoxy, propoxy, isopropoxy, allyloxy, methylthio, ethylthio, 
isopropylthio, formamido, acetamido, trifluoroacetamido, chloroacetamido, 
methyl, ethyl, isopropyl, allyl or hydroxyethyl group; 
R.sup.2 is either hydrogen or methyl, chloromethyl, bromomethyl, 
methoxymethyl, carbamoyloxymethyl, carboxy, phenoxymethyl, 
3-pyridyloxymethyl, acetoxymethyl, benzoyloxymethyl, 
p-carboxybenzoyloxymethyl, aminomethyl, pyridiniomethyl, glycyloxymethyl 
or a --CH.sub.2 --S--Het group wherein Het is a heterocyclic ring 
preferably chosen from 
##STR6## 
and the pharmaceutically and veterinarily acceptable salts thereof, and 
all the possible isomers including stereoisomers such as epimers, 
diastereoisomers, geometrical isomers, tautomers. Possible enolic forms of 
the above described compounds are to be considered tautomers of compounds 
of formula (I') and fall within the scope of the present invention. 
Specific examples of the preferred compounds of the present invention are 
those listed in Table I. 
TABLE 1 
__________________________________________________________________________ 
##STR7## 
n R.sup.1 R.sup.2 A B 
__________________________________________________________________________ 
1 Cl CH.sub.3 t-Bu Ph 
2 CH.sub.3 O 
CH.sub.3 t-Bu Ph 
3 CH.sub.3 O 
CH.sub.3 t-Bu 
##STR8## 
4 CH.sub.3 O 
CH.sub.3 t-Bu 
##STR9## 
5 " " " 
##STR10## 
6 " " " CH.sub.3 
7 " " " CH.sub.2 Ph 
8 " " " CH.sub.2 OPh 
9 " " " CH.sub.2 CH.sub.2 CO.sub.2 H 
10 " " " CH(OH)Ph 
11 " " " 
##STR11## 
12 " " " 
##STR12## 
13 " " " 
##STR13## 
14 " " " 
##STR14## 
15 CH.sub.3 O 
CH.sub.3 t-Bu 
##STR15## 
16 CH.sub.3 O 
CH.sub.2 OCOCH.sub.3 
t-Bu CH.sub.3 
17 CH.sub.3 O 
CH.sub.2 OCOCH.sub.3 
t-Bu Ph 
18 CH.sub.3 O 
CH.sub.2 OCOCH.sub.3 
t-Bu 
##STR16## 
19 CH.sub.3 O 
##STR17## t-Bu Ph 
20 CH.sub.3 O 
##STR18## t-Bu 
##STR19## 
21 CH.sub.3 O 
##STR20## t-Bu CH.sub.3 
22 " " " Ph 
23 CH.sub.3 O 
CH.sub.3 Ph CH.sub.3 
24 " " " Ph 
25 " " " 
##STR21## 
26 " CH.sub.2 OCOCH.sub.3 
" Ph 
27 " 
##STR22## " Ph 
28 CH.sub.3 O 
##STR23## Ph Ph 
29 CH.sub.3 O 
CH.sub.3 
##STR24## Ph 
30 CH.sub.3 O 
CH.sub.3 
##STR25## Ph 
31 CH.sub.2 CHCH.sub.2 
CH.sub.3 t-Bu Ph 
32 " " " 
##STR26## 
33 " " Ph Ph 
34 " " " " 
35 CH.sub.3 CONH 
" " " 
36 CF.sub.3 CONH 
" " " 
37 HCONH " t-Bu " 
38 CH.sub.3 O 
CH.sub.3 t-Bu 
##STR27## 
39 " " Ph " 
40 " " t-Bu 
##STR28## 
41 " " Ph " 
42 " " t-Bu 
##STR29## 
43 " " Ph " 
44 " " t-Bu 
##STR30## 
45 " " Ph " 
46 " " t-Bu 
##STR31## 
47 " " Ph " 
48 " " t-Bu 
##STR32## 
49 " " Ph " 
50 " " t-Bu 
##STR33## 
51 " " Ph " 
52 CH.sub.3 O 
CH.sub.3 t-Bu 
##STR34## 
53 " " Ph " 
54 " " t-Bu 
##STR35## 
55 " " Ph " 
56 " " t-Bu 
##STR36## 
57 " " Ph " 
58 " " t-Bu 
##STR37## 
59 " " Ph " 
60 " " t-Bu 
##STR38## 
61 " " Ph " 
62 " " t-Bu 
##STR39## 
63 " " Ph " 
64 " " t-Bu 
##STR40## 
65 " " Ph " 
66 CH.sub.3 O 
CH.sub.3 t-Bu 
##STR41## 
67 " " Ph " 
68 " " t-Bu 
##STR42## 
69 " " Ph " 
70 " " t-Bu 
##STR43## 
71 " " Ph " 
72 " " t-Bu 
##STR44## 
73 " " Ph " 
74 " " t-Bu 
##STR45## 
75 " " Ph " 
76 " " t-Bu 
##STR46## 
77 " " Ph " 
78 " " t-Bu 
##STR47## 
79 " " Ph " 
80 CH.sub.3 O 
CH.sub.3 t-Bu H 
81 " " t-Bu 
##STR48## 
82 " " Ph " 
83 " " t-Bu 
##STR49## 
84 " " Ph " 
85 " " t-Bu 
##STR50## 
86 " " Ph " 
87 " CH.sub.2 OCOPh 
t-Bu Ph 
88 " " Ph " 
89 " CH.sub.3 Ph 
##STR51## 
90 " " t-Bu 
##STR52## 
91 " " Ph " 
92 " " t-Bu 
##STR53## 
93 " " Ph " 
94 CH.sub.3 O 
CH.sub.3 t-Bu C(CH.sub.3).sub.3 
95 " " Ph " 
96 " " t-Bu CH(C.sub.2 H.sub.5)(CH.sub.2).sub.3 
CH.sub.3 
97 " " " CH.sub.2 NHCOPh 
98 " " " CH.sub.2 CH.sub.2 COPh 
99 " " " C.sub.6 H.sub.5 -4-SO.sub.3 H 
100 
" ` Ph " 
101 
" " " C.sub.6 H.sub.5 -4-CH.sub.2 
SO.sub.3 H 
102 
" " t-Bu " 
__________________________________________________________________________ 
The present invention also provides a process for the preparation of cephem 
sulphones of formula (I), which process comprises: 
(i) reacting a compound of formula (II) 
##STR54## 
wherein either (i.sub.a) n' is 0, 1 or 2; A, R.sup.1 and R.sup.2 are as 
defined above, and X is a leaving group, with a compound of formula (III) 
EQU B--C(O)O--M (III) 
wherein B is as defined above and M is hydrogen or a metal; or 
(i.sub.b) n', A, R.sup.1 and R.sup.2 are as defined above, and X is 
hydrogen, with a compound of formula (IV) 
EQU B--C(O)O--O--W--B' (IV) 
wherein B is as defined above and B' being the same or different is as 
defined above for B and W is either a bond or a group selected from 
--C(O)--, --C(O)O--, --S(O).sub.2 --, --C(O)NR.sup.v -- wherein R.sup.v is 
phenyl or a C.sub.1 -C.sub.4 alkyl group; 
(ii) if needed, when n in the compound of formula (I) is of higher value 
than n' in formula II as above defined, oxidizing the obtained compound to 
a compound of formula (I); and 
(iii) if desired, converting the resulting compound of formula (I) into a 
pharmaceutically or veterinarily acceptable salt thereof, and/or, if 
desired, converting the compound or salt into a stereoisomer, e.g. epimer, 
diastereoisomer, geometrical isomer or tautomer thereof. 
In step (i.sub.a) the leaving group X is typically a halogen, preferably 
bromine, chlorine or iodine. When M in formula (III) is hydrogen the 
acyloxylation reaction is usually performed in the presence of an 
inorganic or organic base. These external bases are generally not required 
when M of formula (III) is a metal, e.g an alkaline metal or a heavy 
metal, preferably a halophylic metal such as silver, copper, mercury or 
lead. The reaction (i.sub.a) can be carried out in a wide range of organic 
solvents such as acetonitrile, N,N-dimethylformamide, dichloromethane, 
tetrahydrofuran, dioxane, ethyl acetate, chloroform, benzene, carbon 
tetrachloride, diethyl ether, dimethoxyethane, sulpholane, 
dimethylsulphoxide, hexamethylphosphoramide, N-methyl pyrrolidone, 
acetone, water and mixtures of any of these. Reaction temperatures range 
between -50.degree. C. and +120.degree. C., preferably between -20.degree. 
C. and +80.degree. C. Preferred external bases are tertiary organic bases 
either aliphatic or aromatic or alicyclic such as triethylamine, 
diisopropylethylamine, aniline, pyridine, lutidine, collidine, quinoline, 
N-methylmorpholine, N-methylpyrrolidine, diazabicyclooctane (DABCO); or 
inorganic bases such as alkaline bicarbonates, or carbonates, e.g. sodium 
bicarbonate, calcium carbonate, cesium carbonate, potassium carbonate. A 
beneficial effect has often been observed upon addition of alkaline metal 
salts such as sodium iodide or potassium iodide and additives such as 
molecular sieves, alumina or calcium oxide. The reaction can also be 
carried out in the presence of heavy metal salts such as silver nitrate, 
silver perchlorate, silver triflate, copper nitrate, mercury nitrate. 
Step (i.sub.b) is usually performed in the presence of tertiary aliphatic 
or aromatic organic bases such as 1,5-diazabicyclo[4,3,0]non-5-ene, 
1,8-diazabicyclo[5,4,0]undec-7-ene, 1,1,3,3-tetramethylguanidine, 
1,4-diazabicyclo [2,2,2]octane, N,N-diisopropylethylamine, 
N-methylmorpholine, N-methylpyrrolidine, triethylamine, pyridine, 
lutidine, collidine, quinoline. The reaction can be carried out in a wide 
range of non-protic organic solvents such as acetonitrile, 
N,N-dimethylformamide, tetrahydrofuran, dioxane, benzene, sulpholane, 
N,N-dimethylacetamide, hexamethylphosphoramide, N-methyl pyrrolidone or 
mixtures thereof. Temperatures for reaction (i.sub.b) range between 
-60.degree. C. and +40.degree. C., preferably between -30.degree. C. and 
room temperature. 
If needed, the oxidation reaction mentioned in step (ii) is performed with 
organic or inorganic peracids or salts thereof, preferably peracetic acid, 
metachloroperbenzoic acid, permaleic acid, perphthalic acid, oxone, sodium 
or potassium persulphate in suitable organic solvents or mixtures of 
organic solvents with water. Preferred reaction temperatures range between 
-40.degree. C. and +40.degree. C. 
It is understood that in the process above any functional group, if needed 
or desired can be masked by a conventional method and unmasked at the end 
or when convenient. It is also understood that the groups R.sup.1, 
R.sup.2, A and B can be converted by conventional methods into different 
groups included within those previously defined, if desired, at the end or 
at any stage of the process above. This conversion or masking/unmasking of 
the protecting groups are well known in the cephalosporin area (see, e.g. 
"Cephalosporins and Penicillins", E. H. Flynn Ed.). 
Compounds of formula (II) are known or can be prepared from known compounds 
as described in EP-A-0337704. Compounds of formulae (III) and (IV) are 
known.compounds or can be prepared from known compounds by known methods. 
The potential of protease inhibitor therapy in the treatment of conditions 
resulting from the destruction of connective tissues has recently received 
particular attention. Much effort has been deveted to the search for 
inhibitors of human leucocyte elastase (HLE), which is the primary 
destructive agent in pulmonary emphysema and is probably involved in 
rheumatoid arthritis (J. C. Power, Am. Rev. Resp. Diseases 127, S54-S58, 
1983; C. H. Hassal et al, FEBS Letters, 183, n. 2, 201, 1985, G. Weinbaum 
and V. V. Damiano, TIPS, 8, 6, 1987; M. Velvart, Rheumatol. Int. 1, 121, 
1981). Low molecular weight inhibitors appear to have a number of 
advantages over natural high molecular weight protease inhibitors from 
either plant or animal sources: 1) they can be obtained in quantities; 2) 
they can be rationally designed or optimised; 3) they are not antigenic; 
and 4) they may be used orally or in aerosols. Many low molecular weight 
elastase inhibitors discovered so far contain reactive functional groups 
(chloromethyl ketones, isocyanates, etc); they may react with functional 
groups of proteins, and therefore they may be quite toxic. In this 
respect, .beta.-lactam compounds are of potential interest because, though 
reactive towards serine protease, they are, as it is known, non-toxic at 
very high concentrations. 
The compounds of the present invention are characterized by high inhibitory 
activity on elastases, especially human leucocyte elastase (HLE). In 
particular, the introduction of the acyloxy group O--C(O)--B, wherein B is 
as above described, at the C-2 position of the cephem nucleus, resulted in 
an unpredictable enhancement of inhibitory activity, relative to the 
corresponding C-2 unsubstituted compounds (formula (II)), which are 
disclosed in U.S. Pat. No. 5,077,286 (Dec. 31, 1991), while retaining good 
chemical stability. 
When tested as inhibitors of human leucocyte elastase (HLE), compounds of 
formula (I) showed high "potency" (low value of apparent dissociation 
constant of HLE-inhibitors complex at steady rate K.sub.i.sup.SS) and high 
"efficiency" (high rate of formation of the HLE-inhibitor complex, K.sub.5 
/K.sub.i): 
##STR55## 
wherein E=enzyme (HLE) 
S=substrate (see Protocol) 
P=product (see Protocol) 
I=inhibition 
EI=Michaelis complex 
EI*=covalent complex (inactivated enzyme) 
I*=inactivated inhibitor 
To illustrate this point, Table 2 reports such parameters for a 
representative compound within the present invention (compound No.2 in 
Table 1), in comparison with the corresponding compound of formula (II) 
lacking the acyloxy group at the C-2 position. Table 2 incorporates, as a 
meaningful reference, the corresponding data obtained for L-659,286, 
another .beta.-lactam compound which was recently reported to undergo 
preclinical studies for the treatment and control of pulmonary emphysema 
(Am. Rev. Respir. Dis. 1988, 137, 204; Agents and Actions, 1988, 25, 60; 
Journal of Cellular Biochemistry 1989, 39, 47-53; J.Med. Chem. 1992, 35 
3731-3744, compound 11f, in text and tables), which was independently 
synthesized in our laboratories. In addition, Table 3 reports the 
corresponding data for other compounds of the present invention, showing 
that excellent or superb potency is in general a common feature of this 
novel class of cephem derivatives. As a matter of fact, inhibition 
parameters were sometimes outside the determination limits of our 
experimental protocol (K.sub.i.sup.SS less than 2 nanomolar, K.sub.5 
/K.sub.I more than 2,000,000 M.sup.-1 sec.sup.-1). 
TABLE 2 
__________________________________________________________________________ 
Kinetic parameters for HLE-inhibition (see Protocol below) by a 
representative compound of 
the present invention (Compound No. 2 in Table I), the corresponding 
previous art compound, and a 
reference cephem sulphone selected as a particularly interesting HLE 
inhibitor (Merck S & D) 
Compound Potency K.sub.i.sup.SS (nM) 
"Efficacy" K.sub.5 /K.sub.i (M.sup.-1 s.sup.-1) 
__________________________________________________________________________ 
Present invention.sup.1 
&lt;2 1.5 .sup. 10.sup.6 
Previous art.sup.2 
1300 0.6 .sup. 10.sup.2 
Reference 75 9.2 .multidot. 10.sup.3 
__________________________________________________________________________ 
1) Structure 
##STR56## FCE 28204 (Table 1, Compound No. 2) 
2) Structure 
##STR57## FCE 25500 (Compd in U.S. Pat. No. 
5,077,286, Example 2) 
3) Structure 
##STR58## Merck S & D L-659,286 (see above for 
references) 
__________________________________________________________________________ 
TABLE 3 
______________________________________ 
Kinetic parameters for HLE inhibitors (see Protocol below) by 
some representative compounds of the present invention 
Compound # 
"Efficacy" K.sub.5 /K.sub.1 (M.sup.-1 sec.sup.-1) 
"Potency" K.sub.i .sup.33 (nM) 
______________________________________ 
6 4 6.5 10.sup.4 
11 &lt;2* &gt;2* 10.sup.6 
19 &lt;2* &gt;2* 10.sup.6 
24 8 ND 
25 29 3.4 10.sup.4 
38 &lt;2* 7.0 10.sup.5 
80 600 1.4 10.sup.3 
83 2 5.0 10.sup.5 
87 &lt;2* 1.6 10.sup.6 
94 &lt;2* 1.5 10.sup.6 
96 &lt;2* &gt;2*10.sup.6 
98 &lt;2* 3.0 10.sup.5 
______________________________________ 
(*) Values outside the determination limits allowed by the experimental 
protocol 
ND: Not determined 
Protocol 
Kinetic parameters of HLE (Calbiochem) were determined at 37.degree. C., 
0.027M pH 7.4 phosphate buffer, 1% DMSO, 1% MeCN, NaCl (I=0.15), by 
monitoring the release of 7-amino-4-methylcoumarin (fluorescence 
detection) from 
N-methoxysuccinyl-alanyl-prolyl-valyl-7-amido-4-methylcoumarin as the 
substrate, according to the equations: 
##EQU1## 
wherein [P], [I], [S]=product, inhibitor, and substrate concentration 
V.sub.s =steady state rate 
V.sub.z =zero time rate 
V.sub.o =rate at [I]=0 
K.sub.m =Michaelis constant for the enzyme substrate pair (independently 
determined under the same experimental conditions). Full details of the 
Experimental Protocol are reported in M. Alpegiani et al., Eur. J. Med. 
Chem. 1992, 27, 875-890. 
The compounds of formula (I) and their salts have high elastase-inhibiting 
activity and quite negligible toxicity (the orientative acute toxicity by 
i.v., oral or aerosol route is almost always greater than 500 mg/kg in 
rat). A patient is treated according to the present invention by a method 
comprising administering to the patient a therapeutically effective amount 
of a compound of formula (I) or a salt thereof. In this way the compounds 
and salts of the present invention can be used in the treatment of 
inflammatory and degenerative diseases caused by proteolytic enzymes in 
mammals including humans. For example, the compounds and their salts can 
be used to prevent or arrest the progression of diseases caused by 
proteolytic degradation of lungs and connective tissues, reduce 
inflammation and fever, and relieve pain. Such diseases are emphysema, 
acute respiratory distress syndrome, bronchial inflammation, rheumatoid 
arthritis, osteoarthritis, infectious arthritis, rheumatic fever, 
spondylitis, gout, lupus, psoriasis, and the like. The condition of the 
patient may thus be improved. 
The present invention also provides a compound of formula (I), or a 
pharmaceutically or veterinarily acceptable salt thereof, for use as an 
elastase inhibitor. The invention further provides pharmaceutical and 
veterinary compositions containing a suitable carrier and/or diluent and, 
as an active principle, a 2-acyloxycephem sulphone of formula (I) or a 
pharmaceutically or veterinarily acceptable salt thereof. The 
pharmaceutical or veterinary compositions containing a compound of formula 
I or salt thereof may be prepared in a conventional way by employing 
conventional non-toxic pharmaceutical carriers or diluents in a variety of 
dosage forms and ways of administration. 
The compounds of formula I can be administered: 
A) Orally, for example, as tablets, troches, lozenges, aqueous or oily 
suspensions, dispersible powders or granules, emulsions, hard or soft 
capsules, or syrups or elixirs. Compositions intended for oral use may be 
prepared according to any method known in the art for the manufacture of 
pharmaceutical compositions and such compositions may contain one or more 
agents selected from the group consisting of sweetening agents, flavouring 
agents, colouring agents and preserving agents in order to provide 
pharmaceutically elegant and palatable preparations. Tablets contain the 
active ingredient in admixture with non-toxic pharmaceutically acceptable 
excipients which are suitable for the manufacture of tablets. These 
excipients may be for example, inert diluents, such as calcium carbonate, 
sodium carbonate, lactose, calcium phosphate or sodium phosphate; 
granulating and disintegrating agents, for example, maize starch, or 
alginic acid; binding agents, for example starch, gelatin or acacia, and 
lubricating agents, for example magnesium stearate, stearic acid or talc. 
The tablets may be uncoated or they may be coated by known techniques to 
delay disintegration and adsorption in the gastrointestinal tract and 
thereby provide a sustained action over a longer period. For example, a 
time delay material such as glyceryl monostearate or glyceryl distearate 
may be employed. Formulation for oral use may also be presented as hard 
gelatin capsules wherein the active ingredient is mixed with an inert 
solid diluent, for example, calcium carbonate, calcium phosphate or 
kaolin, or as soft gelatin capsules wherein the active ingredient is mixed 
with water or an oil medium, for example, peanut oil, liquid paraffin, or 
olive oil. Aqueous suspensions contain the active materials in admixture 
with excipients suitable for the manufacture of aqueous suspensions. Such 
excipients are suspending agents, for example, sodium 
carboxymethylcellulose, methylcellulose, hydroxy propylmethylcellulose, 
sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia; 
dispersing or wetting agents may be naturally-occurring phosphatides, for 
example lecithin, or condensation products of an alkylene oxide with fatty 
acids, for example polyoxyethylene stearate, or condensation products of 
ethylene oxide with long chain aliphatic alcohols, for example 
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide 
with partial esters derived from fatty acids and a hexitol such as 
polyoxyethylene sorbitol monooleate, or condensation products of ethylene 
oxide with partial esters derived from fatty acids and hexitol anhydrides, 
for example polyoxyethylene sorbitan monooleate. The said aqueous 
suspensions may also contain one or more preservatives, for example, ethyl 
or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more 
flavouring agents, or one or more sweetening agents, such as sucrose or 
saccharin. Oily suspension may be formulated by suspending the active 
ingredient in a vegetable oil, for example arachis oil, olive oil, sesame 
oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily 
suspensions may contain a thickening agent, for example beeswax, hard 
paraffin or cetyl alcohol. Sweetening agents, such as those set forth 
above, and flavouring agents may be added to provide a palatable oral 
preparation. These compositions may be preserved by the addition of an 
antioxidant such as ascorbic acid. Dispersible powders and granules 
suitable for preparation or an aqueous suspension by the addition of water 
provide the active ingredient in admixture with a dispersing or wetting 
agent, a suspending agent and one or more preservatives. Suitable 
dispersing or wetting agents and suspending agents are exemplified by 
those already mentioned above. Additional excipients, for example 
sweetening, flavouring and colouring agents, may also be present. The 
pharmaceutical compositions of the invention may also be in the form of 
oil-in-water emulsions. The oily phase may be a vegetable oil, for example 
olive oil or arachis oils, or a mineral oil, for example liquid paraffin 
or mixtures of these. Suitable emulsifying agents may be 
naturally-occurring gums, for example gum acacia or gum tragacanth, 
naturally-occurring phosphatides, for example soy bean, lecithin, and 
esters or partial esters derived from fatty acids and hexitol anhydrides, 
for example sorbitan mono-oleate, and condensation products of the said 
partial esters with ethylene oxide, for example polyoxyethylene sorbitan 
monooleate. The emulsion may also contain sweetening and flavouring 
agents. Syrups and elixirs may be formulated with sweetening agents, for 
example glycerol, sorbitol or sucrose. Such formulations may also contain 
a demulcent, a preservative and flavouring and colouring agents. 
B) Parenterally, either subcutaneously, or intravenously, or 
intramuscularly, or intrasternally, or by infusion techniques, in the form 
of sterile injectable aqueous or olagenous suspensions. The pharmaceutical 
compositions may be in the form of a sterile injectable aqueous or 
olagenous suspension. 
This suspension may be formulated according to the known art using those 
suitable dispersing of wetting agents and suspending agents which have 
been mentioned above. The sterile injectable preparation may also be a 
sterile injectable solution or suspension in a non-toxic 
parenterally-acceptable diluent or solvent, for example as a solution in 
1,3-butane diol. Among the acceptable vehicles and solvents that may be 
employed are water, Ringer's solution and isotonic sodium chloride 
solution. In addition, sterile, fixed oils are conventionally employed as 
a solvent or suspending medium. 
For this purpose any bland fixed oil may be employed including synthetic 
mono- or diglycerides. In addition fatty acids such as oleic acid find use 
in the preparation of injectables; 
C) By inhalation, in the form of aerosols or solutions for nebulizers; 
D) Rectally, in the form of suppositories prepared by mixing the drug with 
a suitable non-irritating excipient which is solid at ordinary temperature 
but liquid at the rectal temperature and will therefore melt in the rectum 
to release the drug. Such materials are cocoa butter and poly-ethylene 
glycols; 
E) Topically, in the form of creams ointments, jellies, solutions or 
suspensions. 
The present invention further provides a method for controlling 
inflammatory and degenerative diseases by administering a therapeutically 
effective amount of one or more of the active compounds of formula I, or a 
pharmaceutically or veterinarily acceptable salt thereof, to humans or 
mammalians in need of such treatment. 
Daily doses are in the range of about 0.1 to about 50 mg per kg of body 
weight, according to the activity of the specific compound, the age, 
weight and conditions of the subject to be treated, the type and severity 
of the disease, and the frequency and route of administration; preferably, 
daily dosage levels for humans are in the range of 20 mg to 2 g. The 
amount of active ingredient that may be combined with the carrier 
materials to produce a single dosage form will vary depending upon the 
host treated, for example his or her age, weight and condition, and the 
particular mode of administration. For example, a formulation intended for 
the oral administration to humans, may contain from 5 mg to 2 g of active 
agent compounded with an appropriate and convenient amount of carrier 
material which may vary from about 5 to about 95 percent of the total 
composition. Dosage unit forms will generally contain between from about 5 
mg to about 500 mg of active ingredient. 
The following examples further illustrate the invention.