GB2273097A - 4-Alkyl and 4-Alkenyl-3-Cephem Sulphones - Google Patents

Description

2273097 4-ALKYL AND 4-ALKENYL DUTA-3-CEPUBM MULEMONES The present

invention relates to new cephem sulphones as potent elastase inhibitors useful in the prevention, control and treatment of inflammation.

According to the invention there are provided cephalosporin sulphones of formula (1) R 0 S ' _,B PN,,- " 2 0 R A (1) wherein A represents:

I) a group -CHR7CH,Y, -CH2CIMYr -CO=CHY wherein Y is nitro, cyano, -COA1, -COOA1, -COSA', -SO2A1, -CONAW, _SO2NA2A7 and R is hydrogen or C1_C,2 alkyl, C,-C,2 alkoxy, Cl-C12 alkylthio, C,-C,2 acylamino, C6-Cj, aryl,, C._C,4 aralkyl, halogen, hydroxy, substituted amino or Y; A% A 2 and A independently are hydrogen or a) C,-C,2 straight or branched alkyl b) C2_C,2 alkenyl C) C2-C,2 alkynyl d) C3_C6 cycloalkyl e) C.,-C, cycloalkenyl f) c6-clo aryl 9) C._C,4 aralkyl, aralkenyl, aralkynyl; h) heterocyclyl,, heterocyclylalkyl, heterocyclylalkenyl; or A2 and A taken together with the nitrogen atom form a azaheterocyclic group; or A and taken together form a azaheterocyclic ring; or A' and taken together form a carbocyclic or heterocyclic ring; II) a group -CH.0A1, -CH20COA1,, -CH20SO2A1# -CH2SA' wherein A' is as defined above; B is hydrogen or -CHIPCHY, -CH2CIMY, -CW=CHY wherein W and Y are as defined above; R' represents (1) a halogen atom (2) A as defined above (3) an ether -0-Al wherein A' is as defined above (4) a thioether, sulphoxide or sulphone -S(O),Al wherein n is either 0, 1 or 2 and A' is as def ined above (5) acyloxy -OCOA1 wherein A' is as defined above (6) sulphonyloxy -OSO.Al wherein A' is as defined above (7) acylamino -NHCOA1 wherein AI is as defined above.

R represents (1) A' as defined above (2) chloro or fluoro (3) an oxy group -OA1, wherein A' is as defined above (4) a sulphenyl, sulphinyl or sulphonyl group -S(O),,Al wherein n and AI are as def ined above (5) an acyl group -COA1,, -CO0A1 wherein A' is as -defined above W, 4 (6) an oxymethyl group -CH20A1 wherein A' is as defined above (7) a thiomethyl group or a derivative thereof of formula -CH2S (0) nAl wherein n and A' are as def ined above (8) an acyloxymethyl group -CH,OCOA' wherein Al is as defined above (9) an aminomethyl group -CH2NAW wherein A' is as defined above and A5, being the same or different, is as defined for A'; or Al and A5 taken together with the nitrogen atom to which they are attached represent a heterocyclic ring (10) ammoniomethyl -CHN+A'AW wherein A' and A are as defined above and k, being the same or different, is as def ined for A', or Al is alkyl and A and k taken together with the nitrogen atom to which they are attached represent 15 a heterocyclic ring; or Al, A5 and k together with the nitrogen atom to which they are attached represent an aromatic heterocyclic ring (11) acylamino -CH2NHCOA' wherein A' is as defined above The term halogen preferably encompasses fluorine, chlorine or bromine.

A C,-C,2 alkyl group is a straight or branched alkyl group, for example a CI-CIO alkyl group, typically a Ci-C6 or Cj-C4 alkyl group. Specific examples of such alkyl groups are methyl, ethyl, n-propyl,isopropyl, nbutyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl groups.

A Ci-C,2 alkoxy group is a straight or branched alkoxy group, for example a CI-CIO alkyl group, typically a CI-C6 or C,-C4 alkyl group. Specific examples of such alkoxy groups - 4 are methoxy, ethoxy, n-propoxy, isopropoxy. n-butoxy, isobutoxy, sec- butoxy, tert-butoxy, n-pentoxy and n-hexyloxy groups.

A C,_% acylamino group is a straight or branched 5 acylamino, group, wherein the acyl moiety is, for example. a Cl-CIO acyl group, typically a C,-Ci or Cl-C4 acyl group. Specific examples of such acylamino groups are formamido, acetamido, propionamido and pivalamido groups.

A Cl-C12 alkylthio group is a straight or branched alkylthio group, for example a Cl-Cl, alkylthio group, typically a Cl-C6 or Cl-C4 alkylthio group. Specific examples of such alkylthio groups are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio. n-pentylthio and n-hexylthio groups.

A C2-C12 alkenyl group is a straight or branched alkenyl group, for example a C2-Clo alkenyl group,, typically a C2-C6 or C2-C4 alkenyl group. Specific examples of such alkenyl groups are vinyl, allyl,, crotyl, propenyl, 2-methyl-l-propenyl, 1-methyl-l-propenyl, butenyl and pentenyl groups.

A C2-C12 alkynyl group is a straight or branched alkynyl group,, for example a C2-cl. alkynyl group, typically a C2-C6 or C2-C4 alkynyl g roup. Specific examples of such alkynyl groups are ethynyl, propargyl, 1-propynyl, 1-butynyl and 2-butynyl groups.

A C3-C6 cycloalkyl group is a saturated carbocyclic group of 3 to 6 carbon atoms. such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

A C,-C, cycloalkenyl group is an unsaturated carbocyclic group, for example a cyclopentenyl or cyclohexenyl group.

A C6-Clo aryl group is a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms, for example phenyl or naphthyl.

A C7-C14 aralkyl group is an alkyl group of 1 to 4 carbon atoms, for example a methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl or secbutyl group, linked to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms, for example phenyl or naphthyl. Examples of such aralkyl groups are benzyl, phenylethyl and naphthylmethyl.

A C,_C14 aralkenyl group is an alkenyl group of 2 to 4 carbon atoms, for example a vinyl, allyl, crotyl, propenyl, 2 -methyl - lpropenyl, 1-methyll-propenyl or butenyl group, linked to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms such as phenyl or naphthyl. Examples of such aralkenyl groups are styryl, 2 -phenyl -1-propenyl, 3-phenyl-2-butenyl and 2-naphtylethenyl.

A C,-CM aralkynyl group is an alkynyl group of 2 to 4 carbon atoms, for example an ethynyl,, propargyl,, 1-propynyl or butynyl group, linked to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms such as phenyl or naphthyl. Examples of such aralkynyl 2-phenylethynyl and 2-naphtylethynyl.

A heterocyclic group is groups are a S- or 6-membered. saturated or unsaturated heterocyclyl ring, containing at least one heteroatom selected from 0,, S and N,, which is optionally fused to a second 5- or 6-membered, saturated or unsaturated heterocyclyl group or to a cycloalkyl group. Examples of saturated and unsaturated heterocyclic groups include pyrazolyl, imidazolyl, pyridyl, pyrazyl, pyrimidyl, pyrrolo, pyridazinyl, morpholino, thiomorpholino,, furyl and thienyl groups; and groups having the following structures:

1/ ("'R.4 NXT- 9R 4 N r--'o wherein R is hydrogen, Cl-C4 alkyl, alkoxy, alkoxycarbonyl; benzyloxycarbonyl, 2-phenylethoxycarbonyl,, chloro,, fluoro, phenyl, p- carboxyphenyl,, acetamido, formamido, benzamido,, carboxy, carbamoyl, hydroxy, cyano or nitro; and groups of the following structgres:

CH3 -eN - 0.,N OP N-N N-N OP CO co- N AN k'12OOP 1 CH3 COOH 1::5, - ,-N p,, N N-N 51,0, 1 '>N r J S0 N # 55 N,j" jN, A N /0 SCH2COOP N N-N N-N N 1 --<S3c) N N Ph & CH CH2COOP c &2 2 2 HCOOP 2 wherein P is hydrogen or straight or branched Cl-C, alkyl, C2-C, alkenyl or aralkyl; When a heterocyclyl group is formed by the following substituents A' and A5; A and A6; A' and A; and A2 and A,, respectively taken together, it is typically a saturated heterocyclyl group, for example one of the saturated heterocyclyl groups listed above.

Other substituents mentioned herein as possibly being a heterocyclyl group are more typically an unsaturated -10 heterocyclyl group, for example one of the unsaturated heterocyclyl groups listed above.

An azaheterocyclic group is a 5- or 6-membered saturated or unsaturated heterocyclyl ring, containing at least one nitrogen and optionally a heteroatom. selected from 0 and S, which is optionally fused to a second 5- or 6-membered, saturated or unsaturated heterocyclyl group or to a cycloalkyl group. Examples of azaheterocyclic groups include those heterocyclic groups specifically mentioned above which contain at least one nitrogen atom.

A heterocyclylalkyl group is an alkyl group of 1 to 4 carbon atoms, for example a methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or sec-butyl group, linked to a heterocyclic group, for example selected from those specifically mentioned above.

A heterocyclylalkenyl group is an alkenyl group of 2 to 4 carbon atoms, for example a vinyl, allyl, crotyl, propenyl, 2-methyl-l-propenyl, 1-methyl-1-propenyl or butenyl group, linked to a heterocyclic group, for example selected from those specifically mentioned above.

A carbocyclic group comprises at least 3 carbon atoms, more typically 5 or more carbon atoms. It may also be a fused ring system. such as a naphthyl group.

The above said alkyl,, alkoxy,, acylamino,, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,, aralkyl, aralkenyl, aralkynyl, heterocyclyl, azaheterocyclyl, heterocyclylalkyl, heterocyclylalkenyl and carbocyclic groups can be either unsubstituted or substituted (or further substituted) by one or more substituents selected from the following ones:

- halo (i.e., fluoro, bromo, chloro or iodo); - hydroxy; - nitro; - azido; - mercapto (-SH); - amino (i. e., -NH2, or -NHR 0 or -NR 0 R where in R 0 and R"", which are the same or different. are Cl-C12 straight or branched alkyl, phenyl or benzyl; - formyl (i.e., -CHO); - cyano; - carboxy(alkyl) (i.e., (CH.)tCOOH or (CH.)tCOOR0) wherein W is as defined above and t is 0, lt 2 or 3; - sulpho -SO3H); - acyl (i.e., -C(O)Rf) wherein RO is as defined above or trifluoroacetyl (i.e., -C(O)CF3); carbamoyl (i.e.. -CONH2); N-methylcarbamoyl (i.e. -CONHCH3) or N- carboxymethylcarbanoyl (i.e.,, -CONHCH.COOH); S i carbamoyloxy (i.e., -OCONH2); acyloxy (i.e., -OC(O)RO) wherein R' is as defined above or formyloxy (i.e. , -OC(O)H); alkoxycarbonyl or benzyloxycarbonyl (i.e., -C(O)OR) 5 wherein R' is as defined above; alkoxycarbonyloxy or benzyloxycarbonyloxy (i.e.,, -OC(O)ORO) wherein RO is as defined above; alkoxy, phenoxy or benzyloxy (i.e., ORO) wherein Rt is as defined above; alkylthio, phenylthio or benzylthio (i.e., -SRI') wherein R,' is as defined above; alkylsulphinyl, phenylsulphinyl or benzy1sulphinyl (i.e., -S(O)RO) wherein RO is as defined above; alkylsulphonyl, phenylsulphonyl or benzy1sulphonyl (i.e., -S(O).RO) wherein RO is as defined above; acylamino (i.e., -NHC(O)Rttt or -NHC(0)0Rtff) wherein W." 'S Cl-C12 straight or branched alkyl, phenyl, benzyl, CH2CH2COOH or CH2CH2CH2COOH; sulphonamido (i.e., NHS02R1) wherein R' is as defined above; guanidino (i.e., -NHC(=NH)NH2); Cl-C4 alkyl, C2-C4 alkenyl or alkynyl; C3-C6 cycloalkyl; substituted methyl selected from chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, aminomethyl, N,N- dimethylaminomethyl, azidomethyl, cyanomethyl, carboxymethyl. sulphomethyl, carbamoylmethyl, carbamoyloxyraethyl, hydroxymethyl, Cl-C, alkoxycarbonylmethyl, - 10 guanidinomethyl.

The carboxyl -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 a 2,2,2-trichoroethyl or a 2,2,2-trifluoroethyl; a lower alkanoyloxyalkyl group such as acetoxymethyl. propionyloximethyl, pivaloyloxymethyl, 1-acetoxyetyl, 1-propionyloxyethyl; a lower alkoxycarbonyloxyalkyl group such as 1-(methoxycarbonyloxy)ethyl, 1(ethoxycarbony-loxy)ethyl, 1- (isopropoxycarbonyloxy) ethyl; a lower alkenyl group such as 2- propenyl, -chloro-2-propenyl, 3-methoxycarbonyl-2-propenyl, 2-iaethyl-2- propenyl, 2-butenyl, cinnanyl; an aralkyl group such as benzyl, p- nethoxybenzyl, 3,4-dinethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl, bis(p-methoxy- phenyl)methyl; a (5-substituted 2-oxo-1, 3-dioxol-4-y1) methyl group such as (5-methyl-2-oxo-1, 3-dioxol-4-y1) methyl; a lower alkylsilyl group such as trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triphenylsilyl; or an indanyl group; a phtalidyl group; a pyranyl group; a metoxy- methyl or methylthiomethyl group; a 2-methoxyethoxymethyl group. Particularly preferred are a tetr-butyl group, a p-nitrobenzyl group, a praethoxybenzyl group. a benzhydryl group,, a tert-butyldinethylsilyl, tert-butyldiphenylsilyl group or a propenyl group.

The hydroxy protecting group may, for example. be a lower alkylsilyl group such as trinethylsilyl,, tert-butyldimethylsilyl. tertbutyldiphenylsilyl; a lower alkoxymethyl group such as methoxymethyl or 2methoxyethoxymethyl, a tetrahydropyranyl group; an aralkyl group such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl, bis(p- methoxyphenyl)methyl, trityl; an acyl group such as formyl or acetyl; a lower alkoxycarbonyl group such as tert-butoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2-iodoethoxycarbonyl; an alkenyloxycarbonyl group such as 2-propenyloxycarbonyl, 2-chloro-2-propenyloxycarbonyl, 3- methoxycarbonyl-2propenyloxycarbonyl, 2-butenyloxycarbonyl.

2-methyl-2-propenyloxycarbonyl, cinnamyloxycarbonyl; an as benzvloxvcarbonvl aralkyloxycarbonyl group such 01 p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl. Particularly preferred are a 2-propenyloxycarbonyl group, a p-nitrobenzyloxycarbonyl a p-methoxybenzyloxycarbonyl group a tert- group, #I butoxycarbonyl group. 2,2,2-trichloroethoxycarbonyl- group, a lower alkylsilyl group such as trimethylsilyl or tertbutyldimethylsilyl, tert- butyldiphenylsilyl group.

The amino, hydroxy or- mercapto protecting groups possibly present may be those usually employed in the chemistry of penicillins and cephalosporins for this kind of functions. They may be. for instance. optionally substituted. especially halo-substituted, acyl groups. e.g.

acetyl,, monochloroacetyl,, dichloroacetyl,, trifluoroacetyl, benzoyl or p-bromophenacyl; triarylmethylgroups. e.g. triphenylmethyl; silyl groups, in particular trimethylsilyl, dimethyl-tert-butylsilyl, diphenyl-tert-butylsilyl,; or also groups such as tert-butoxycarbonyl, pnitrobenzyloxycarbonyl, - 12 2,2,2-tri-chloroethoxycarbonyl, benzyl and pyranyl.

Preferred protecting groups of the hydroxy function are p-nitrobenzy-loxycarbonyl; allyloxycarbonyl; dimethyl-tert-butylsilyl; diphenyl-tert-butylsilyl; trimethylsilyl; 2,2,2-trichloro-ethoxycarbonyl; benzyl; dimethoxybenzyl; p-methoxybenzyl-oxycarbonyl; p-bromophenacyl; triphenylmethyl and pyranyl.

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 especially physiologically tolerable salts, for example alkali metal and alkaline earth metalsalts (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-toluenesulphonic acid). Some compounds of formula (1) which contain a carboxylate and an ammonium group may exist as zwitterions; such salts are also part of the present invention.

The present invention encompasses all the possible stereoisomers, for example epimers, diastereoisomers, geometrical isomers and tautomers,, as well as their racemic or optically active mixtures. However the configurations - 13 depicted in formula (V) are particularly preferred 0 0 R' 51.1. B 0 N R 2 A (10) wherein A represents I) a group -CWCH2Y. -CH2CWY, -CO=CHY wherein Y is nitro, cyano, -COA1, - CO0A1, -SO2A1, -CONAW, -S02NA2A3 and R is a Cl-C4 alkyl, Cl-C4 alkoxy, Cl- C4 alkylthio, Cl-C4 acylamino, C6-C,, aryl, aralkyl, hydroxy or Y; A', A 2 and A each independently are hydrogen, methyl, Cl-Cl, straight or branched alkyl, alkenyl, alkynyl,, C3-C6 cycloalkyl, diphenylmethyl, phenyl, benzyl or 2-phenyl-2 methylpropyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl and benzyl groups are either unsubstituted or substituted by Cl-C4 alkyl, fluoro. chloro. carboxy.

sulpho. Cl-C, alkoxycarbonyl, carbamoyl, carbamoyloxy, sulphamoyl, methyl sulphonyl, hydroxy, methoxy. ethoxy, tert butoxy, benzyloxy,, acetoxy,, pivaloyloxy,, benzoyloxy and phenylacetoxy; or A and A taken together with the nitrogen atom form a part of the heterocyclic groups:

A (' R N- R 4 N q /c) r 0 A wherein R is hydrogen, C,-C, alkyl, alkoxy. alkoxycarbonyl; benzyloxycarbonyl. 2-phenylethoxycarbonyl, chloro. fluoro, phenyl, p- carboxyphenyl, acetamido, formaTaido, benzamido, carboxy.carbamoyl, hydroxy,, cyano, nitro; or A2 and 0 taken together form a azaheterocyclic ring; or Al and 0 taken together form a carbocyclic or heterocyclic ring; II) a group -CH20COAl or -CH2OSO2A' wherein Al is as def ined above; or a group -CH20k or -CH2Sk wherein k is either A' or a heterocyclic group selected from: CH3 ,,N 0 P N OP N-N zz- N x 0 'N N (01 I CH2COOP CH3 COOH N-N __ ki N 1 !-.N N N-N !"' J S' N # kk N, :zt, N N sr /. - SCH2COOP N-N N N-N N s 1 1 ',1 -, --<S.-- N N H2CH2CH2COOP rH.,COOP H2Ph 2 - 15 wherein P is hydrogen or straight or branched C,-C5 alkyl, C 2C, alkenyl, aralkyl; B is hydrogen or -CIMCH2Y, -CH2CIMYi -CR=CHY wherein W and Y are as defined above; R' is (V) chloro. fluoro or bromo (21') Cl-C4 alkyl, Cl-C4 alkenyl,, 1-(hydroxy) ethyl, l(benzyloxy)ethyl, 1-(benzyloxycarbonyloxy)ethyl, 1-(phenylacetoxy)ethyl, 2-fluoro-l- hydroxyethyl, phenyl or benzyl (3,1) methoxy, ethoxy, isopropoxy, phenoxy or benzyloxy (40) nethylthio, ethylthio, isopropylthio (51) formyloxy, acetoxy or phenylacetoxy (61) mesyloxy or tosyloxy (71) formamido, acetamido, fluoroacetamido, trifluoro- acetamido or chloroacetamido R2 is either hydrogen or (1) methyl, chloromethyl, bromomethyl, benzyl, ethyl, propyl, phenyl (2 1) chloro 20 (31) methoxy or benzyloxy (41) methylthio (51) formyl, acetyl, benzoyl, carboxy. methoxycarbonyl. ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl; (60) methoxymethyl, ethoxymethyl. isopropoxymethyl; or benzyloxymethyl, phenoxymethyl, 3-pyridyloxymethyl wherein the phenyl and pyridyl rings are either unsubstituted or substituted by one group or two equal or different groups chosen from hydroxy, carboxy, amino and Cl-C4 alkoxycarbonyl; (7 1) -CH2 (S) nA wherein n is zero, one or two and A is as defined above (80) acetoxymethyl, benzoxymethyl, phenylacetoxymethyl or C,-C6 alkanoyloxymethyl wherein the above groups are either unsubstituted or substituted by one or more groups selected from carboxy. hydroxy, C,-C alkoxy; (90) trialkylammoniomethyl wherein the alkyl group is chosen from methyl, ethyl or propyl; N-methylpyrrolidiniomethyl, N-methylpiperidimiomethyl,, N-methylmorpholiniomethyl; and the pharmaceutically and veterinarily acceptable salts thereof and all the possible stereoisomers e.g.: epimers, diastereoisomers, geometrical isomers. tautomers.

Specific examples of the preferred compounds of the present invention are those listed in Table 1.

is TABLE 1

1 0 \\- S R 2 A n R' R A B 1 Cl CH20COCH3 CH2CH2COCH3 CH2CH2COCH3 2 1, of le H 3 11 CH3 te @B 4 CH20COCH3 CH20H of (1) #I ff 7 11 8 fe 9 11 12 13 14 is 16 17 is is 19 21 CH20COCH3 il Il 0 U 0 le OCH3 " H Il OCH3 CH3 of of il is If we Il CH2S- is OCH3 CH3 of If CH20AC -CH=CH-COOCH3 -CH20COC6H4p-CH3 -CH2CH2CN CH2CH2CN -CH=CH-CO2CH2e il CH2CH2COCH3 Il CH2CH2COCH3 CH2s- il je CH2CH2CN il g# H CH2CH2CN H -CH=CH-CO2CH.Jt H CH2CH2COCH3 CH2CH2COCH31 H H CH2CH2COCH3 go H CH2CH2CN H CH2CH2CN N-N 1 22 91 CH2s- Y3 It H 23 CH2S- CH2CH2CN 0--SCH 2 CH 2 COH 24 11 CH3 CH2CH2COPh CH2CH2COPh 11 el go H - 18 26 " CS, 27 '1 CH3 CH2CH2CO-(D-COOBut H CH2CH2CO-(D-CO2H H CH, N OH "-N-, 28 11 CH2j CH2CH2COPh 29 Il Il Il H N N 11 CH2CH2COPh CH2S'kN'1 CH CH C 02 H 2 2 0- H3 CH:5 '- N.,- N CH 31 Il CH '-%XO CH CH CN CH CH2CN 2S'jz 2 2 2 32 " is Il H Compounds of the formula (1) wherein A represents the groups defined under I) can be prepared by a process which comprises:

z Ia) subjecting a compound of formula (2), - 1 0 0 B YI (2) N, -2 A 00p 1 wherein R1, R, A and B are as def ined above and P, is a carboxy protecting group, to conditions that remove the protecting group P, followed by decarboxylation under mild conditions, Ib) if desired, converting the resulting compound of formula (1) int-9 a pharmaceutically or veterinarily acceptable salt thereof. "Mild conditions" in this context means conditions under which other functional groups present in the compound of formula (2) are unaffected.

The conditions which are appropriate for removal of the carboxy protecting group vary depending on the nature of the protecting group and are well documented in the literature (see e.g. T.W. GREENE: "Protective Groups in organic Synthesis", Wiley (1981) and therein cited references). For example tert-butyl, benzhydryl or p-methoxybenzyl groups can be smoothly removed by treatment 25 with formic or trifluoroacetic acid, the latter often being used with anisole in dichloromethane.

Decarboxylation can occur spontaneously during purification, e.g.: silica gel chromatography or treatment with aqueous sodium bicarbonate solution, or occurs easily in the presence of organic bases in organic solvents. Preferred organic bases are tertiary amines such as triethylamine, N ethyldiisopropylamine, N,N-dimethylaniline, pyridine, lutidine,, collidine, quinoline, N,,N-dimethylaminopiridine, Nmethyluorpholine,, N-methylpirrolidine,, N-methylpiperidine, 1,5diazabicyclo[4.3.0]non-5-ene (DBN).

Preferred organic solvents are either polar or apolar and preferably aprotic, such as acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, ethyl formiate, toluene, benzene, diethyl ether, diisopropylether, 1,2dimethoxyethane, 1,2- dichloroethane, acetone, dimethylformanide, dimethylsulphoxide.

Preferred reaction temperature ranges from -20 OC to room temperature for the base catalyzed decarboxylation, while the thermal decarboxylation is generally carried out at reflux temperature. Compounds of formula (1) wherein A is as def ined under II) can be prepared by a process which comprises: 20 IIa) in any order, converting the carboxyl group -COOH of a compound of formula (3) R S B N R2 00 0 0 H.

wherein R' g, W and B are as def ined above (3) Z into a group -CHW, as represented in f ormula (4) R 1 S -XT - R 2 CH2W (4) wherein W is a group OA1, OCOA1, OS02A1, SA1 wherein A' is as defined above; and oxidizing the sulphur atom at the I-position of the said cephem nucleus to the desired oxidation level IIb) if desired, converting the resulting compound of formula (1) into a pharmaceutically or veterinarily acceptable salt thereof.

In the conversion step the carboxylic moiety of (3) is typically activated as the acyl halide, anhydride, mixed anhydride, thioester or ester thereof and then reacted with a reducing agent to afford 4- hydroxymethylcephem (W=OH).

Suitable reducing agents are sodium borohydride, diisobutylaluminum hydride, tri-tert-butoxyaluminum hydride. Etherification, esterification with carboxylic or sulphonic acids, and thioetherification of the 4hydroxymethyleephem (W=OH) are carried out by following methodologies described or referred to in the major textbooks (see among others: J. MARCH, "Advanced Organic Chemistry", J. Wiley, (1985)).

In the oxidation step, the compounds are oxidized to the corresponding sulphones. Preferred oxidizing agents are peracids in an inert organic or inorganic solvent. Suitable peracids are for example peracetic acid. m-chloroperbenzoic acid (MCPBA), monoperphtalic acid, potassium peroxymonosulphate (OXONE R) ' sodium or potassium or tetrabutylammonium persulphate. tetrabutylammonium peroxymonosulphate; suitable solvents are chloroform, dichloromethane. tetrahydrofuran, ethanol, methanol, acetonitrile, water and mixtures thereof.

It is understood that in the process above any functional group, if needed or desired. can be masked by conventional methods and unmasked at the end or when convenient.

Some compounds of the present invention may also exist as a isomeric mixture formed by A3 isomers like those depicted in the formula (1) and A2 isomers in which the double bond is shifted to the 2 position of the cephem nucleus; the ratio between the two forms is variable depending on the nature of the substituents. Compounds of formula (2) and (3) are known compounds or can be prepared from known compounds by known methodologies. In particular compounds of formula (2) are disclosed in EP 0457381-A2.

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 devoted to the search for inhibitors of human leukocyte 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, 1985; 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, fl-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 leukocyte elastase (HIX). Owing to their high elastaseinhibiting activity and their quite negligible toxicity, (the orientative acute toxicity by i.v., oral or aerosol route is almost always greater than 500 mg/kg in rat) the compounds of the present invention can be used in the treatment of inflammatory and degenerative diseases caused by proteolytic enzymes in mammals including humans. The compounds can be used to make medicaments useful 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, - 24 rheumatoid arthritis, osteoarthritis, infectious arthritis, rheumatic fever,, spondylitis,, gout,, lupus, psoriasis, and the like. Accordingly, the present invention also provides pharmaceutical and veterinary compositions containing a suitable carrier and/or diluent and, as an active principle, a 4-alk(en)ylcephem 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. In particular, 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, flavoring agents, coloring 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 forexample,, inert diluents, such as calcium carbonatei sodium carbonate, lactose,, calcium phosphate or sodium phosphate; - 25 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 admixt ure with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethy1cellulose, 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 coloring agents, one or more flavoring 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 peparation of 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, flavoring and coloring 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, natural ly-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 flavoring 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 flavoring and coloring 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 f ixed oil may be employed including synthetic mono- or diglycerides. In addition fatty 5 acids such as oleic acid f ind 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-irratating 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.

Still a further object of the present invention is to provide a method of controlling inflammatory and degenerative diseases by administering a therapeutically effective amount of one or more of the active compounds encompassed by the formula I in humans or mammalians in need of such treatment.

Daily dose 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 - 29 with the carrier materials to produce a single dosage form will vary depending upon the host treated 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 500mg of active ingredient.

The invention is further illustrated by the following Examples.

ExanDle 1 3-Acetoxymethyl-7a-chloro-4-(3-oxo-l-butyl)-3-cephem 1,1-dioxide p-Methoxybenzyl 3-acetoxymethyl -7a-chloro-4 -(3-oxo-l-butyl)- was immediately separated, ethyl acetate was added and the resulting mixture was vigorously stirred for 10 min. (complete evolution of carbon dioxide). Following drying over Na2SO4, the organic phase was evaporated to afford a - 30 gummy product which was cristallized from diisopropyl ether (440 iag). IR (KBr) 1790, 1725,, 1702 CM". NMR (MC13, 200 MHz) 6 2.08 (3H, s), 2.18 (3H, s), 2.7-3.0 (4Hj, ra),, 3.68 (1H,. br d, J = 18Hz),, 3.94 (1H, d, J = 18Hz), 4.60 (1H, d, J = 13Hz). 4.73 (1H, m), 4.74 (1H, d, J = 13Hz), 5.29 (1H, d, J = 1.9Hz).

Example 2

7a-Chloro-3-methyl-4-(3-oxo-l-butyl)-3-cephem 1,1-dioxide Starting from p-methoxybenzyl 3-acetoxymethyl-7a-chloro4-(3-oxo-l-butyl)2-cephem-4-carboxylate 1,1-dioxide and following the procedure reported in Example 1 the. title product was obtained as a white solid.

IR (KBr) 1790, 1715 cm-1.

NMR (MC1V 200 MHz) 6 2.03 (3H,, s), 2.17 (3H, s),, 2.6-3.2 (4H, m), 3.41 (IH,, d, J = 18Hz), 3.88 (1H, br d, J = 18HZ), 4.67 (IH,, m), 5.25 (1H, dr J = 1.9HZ).

ExamDle 3 3-Acetoxymethyl-7a-chloro-2 25 1,1-dioxide ,4-bis(3-oxo-l-butyl)-3-cephen A solution of p-methoxybenzyl 3-acetoxymethyl-7achloro-214-bis(3-oxo-1- butyl)-2-cephem-4-carboxylate 1,1-dioxide (800 mg) in dichloromethane (5 ml), anisole 1 (0.5 ml) and trifluoroacetic acid (3 ml) was left at room temperature for 30 min. The solvent was removed thoroughly, then acetone was added soon followed by triethylmine (120 pl). After stirring for 10 min. at room temperature the solution was concentrated under reduced pressure and the residue was purified by flash chromatography (cyclohexaneethyl acetate mixtures as eluants). The title product was obtained as a white powder (370 mg).

1 IR (CHC13) 1796, 1743, 1721 cm".

NMR (CDC13, 200 MHz) 6 1.8-2.3 (2H, m),, 2.07 (3H,, s) g, 2.17 (3H, s), 2. 18 (3H, s) f 2.7-3.0 (4Hf m) f 3.54 (1H, dd, J = 7.4 and >2Hz), 4.71 (1H, di J = 12.9Hz), 4.77 (1H, d, J = 2.0Hz), 4.86 (1H, d, J = 12.9Hz), 5.30 (1H, d, J = 12.9Hz).

Examole 4 3-Acetoxymethyl-7a-chloro-4-[E-2-(methoxycarbonyl)ethenyl]3-cephem 1,1dioxide A solution of 3-acetoxymethyl-7a-chloro-4-formyl-3-cephem 1,1-dioxide (92 mg) in dichloromethane (10 ml) at OOC was treated with methyl triphenylphosphoranylidenacetate (100 ng). After 5,1 at 0 0 C the brown solution was washed with 4 % aq. HCl, dried over Na.SO4 and concentrated in vacuo.

Flash chromatography (eluting with EtoAc/cyclohexane mixtures) of the residue afforded a light yellow powder.

1 IR (KBr) 1800. 17301 1710 cm", NMR (CDC'3, 200 MHz) 6 2.13 (3H, s),, 3.83 (3H, s), 3.98 (2H, - 32 ABq,, J = 18.5HZ), 4.75 (2H, s),, 4.81 (1H, M)y 5.34 (lH,, d, J = 1. 9HZ)j 6.46 (1H, d, J = 16.5Hz), 7.51 (1H, d, J = 16.5Hz).

ExamDle 5 3-Acetoxymethyl-7a-chloro-4-hydroxymethyl-3-cephem 1,1dioxide A solution of 3-acetoxymethyl-7a-chloro-4-carboxylic acid 1,,1-dioxide (2 g) in THF (80 ml) was cooled to -200C and treated with oxalyl chloride (1. 1 ml)-. A catalytic amount of DMF (two drops) was added and the mixture was stirred for 1.5h after removal of the cooling device. The solvent was thoroughly removed in vacuo, benzene was added and the mixture was evaporat6d to dryness. The residue was dissolved in THF (60 nl) and cooled to WC. Tri-tert-butoxyaluminum hydride (3.4 g) in THF (40 ml) was dropped in 15 min. while keeping the internal temperature at 0C. Stirring was continued for 5 =in., after which time the reaction mixture was poored into cold EtOAc/4% aqueous HCl, shaking vigorously. The organic phase was then washed with water and aq. NaHCO3. After drying over Na2S04 and removing the solvent, the residue was purified by silica gel chromatography. The title product was obtained as a yellow oil (1. 2 g).

IR (CHC13) 3500-33000 1787, 1741 "'.

1 2 Example 6

3-Acetoxymethyl-7a-chloro-4 (4-methylbenzoyl) oxymethyl-3cephem 1,1dioxide SteD A A solution of 3-acetoxymethyl-7a-chloro-4-carboxylic acid (6.9 g) in THP (100 =l) at OC was treated with DMF (0.2 ml) and oxalyl chloride (4.4 ml) and stirred 2 hours at r.t. After removal of the solvent. the residue was taken up in benzene and evaporated to dryness. The gummy material was dissolved in THF (100 ml). Tri-tert-butoxyaluminum hydride (11 g) in THF (100 ml) was dropped in 20 min. while keeping the temperature at OOC. After additional stirring for 10 min., the mixture wag partitioned between EtOAc and cold 4% hydrochloric acid. Following washings with aq. NaHCO3 and water, the organic phase was dried and evaporated. After silica gel chromatography a colorless oil (2.9 g) was isolated. corresponding to 3-acetoxymethyl-7achloro-4hydroxymethyl-3-cephem.

IR (KBr) 3450, 1760, 1745 cm"l.

NMR (CDC13,, 200 MHz) 6 2.10 (3H,, s), 3.47 (2Hi ABq, J = 18Hz), 4.57 (2H, m), 4.75 (2H, s), 4.81 (2H, s).

SteR- B To a stirred solution of the above described product (500 mg) in dichloromethane (15 ml) at r-t., p-toluic acid (250 mg), triphenylphosphine (800 mg) and diethyl azodi carboxylate (475 Al) were added sequentially. After 10 min.

the solvent was removed and the residue passed through a - 34 silica gel column (eluting with EtOAc/cyclohexane mixtures) thus allowing the isolation of 3-acetoxymethyl-7a-chloro-4 (4methylbenzoyl)oxymethyl-3-cephem (ca. 400 mg).

NMR (CDC13, 200 MHz) 6 2.40 (3H, s), 3.37 (1K, d, J = 1SHz), 3.46 (1H, d, J = 18Hz), 4.73 (1H, d, J = 13.2HZ), 4.74 (1HO, d, J = 1.9Hz), 4.77 (IH, d, J = 1.9Hz), 4.98 (1H, d,, J = 13.2Hz), 5.26 (1H, d, J = 13.2Hz), 5.46 (1H, d, J = 13.2Hz), 7.22 (2H, d, J = 8.2Hz), 7.92 (2H, d, J = 8.2HZ).

Step C A mixture of the above described product (100 Tag) in methanol (8 ml) and water (7 ml) was treated with oxone R (500 mg) and vigorously stirred for 5 hours at r.t.

The mixture was worked-up by pouring into EtoAc/water, separating the organic phase, drying over Na2S04 and removing the solvent under reduced pressure. Flash chromatography of the residue gave the title product as a white powder (60 ng). IR (KBr) 1812, 17330 1714 cm-1.

NMR (CDC13, 200 MHz) 6 2.06 (3H, s) j 2.41 (3H, s), 3.77 (1H, dd, J = 0.9 and 17.8Hz), 3.99 (1H, d, J = 17.8Hz), 4.61 (1H, d, J = 13Hz), 4.78 (1H, m), 4.97 (IHi d, J = 13Hz), 5.20 (1H, d,, J = 13. 6Hz), 5.34 (IH, d, J = 1.9Hz), 5.42 (1H,, d, J 13. 6Hz). 7. 2 5 (2H, d, J = 8. 3HZ), 7. 9 1 (2H, d, J = 8. 3Hz).

ExamDle 7 2a,,4-bis-(2-cyanoethyl)-7a-nethoxy-3-methyl-3-cephem 1,,1dioxide A solution of tert-butyl 7a-methoxy-3-methyl-4- carboxylate 1,1-dioxide (100 ng) in acrylonitrile (8 ml) was treated with triethylamine (0. 05 ml), then left stand at room temperature for 40 hours. After removal of the solvent, the residue was purified by silica gel chromatography, allowing 5 the isolation of tert-butyl 2,,4-bis (2cyanoethyl) -7a-methoxy3-methyl-2-cephem-4-carboxylate 1, 1-dioxide (60 mg). NMR (CDC13, 200 MHz) 6 1.51 (9H,s); 2.00 (3H,s); 2.2-3.2 (SH,m); 3.56 (3H,s); 4.70 (1H,d,1.1Hz); 5.17 (1H,dj=1.1HZ).

A portion of this product (30 mg) was dissolved in dichloromethane (1 M1)r then anisole (0.1 M1) and trifluoroacetic acid (0. 5 ml) were added. The solution was left stand at room temperature for 2 hours, then concentrated to dryness. The residue was taken up in EtOAc (20 ml) and saturated aqueous NaHCO3 and the resulting mixture was vigorously stirred for 2 hours. The organic phase was separated, washed with brine and evaporated. Following silica gel chromatography the title product was obtained as a white powder (15 mg).

NMR (CDC'3, 200 MHz) 6 1.93 (3His); 2.1-2.4 (2H.m); 2.6-2.9 (4H,,m); 3.03.3 (2Him); 3.57 (3His); 4.68 (1H,,d,J=1.8Hz); 5.15 (1H,dj=1.8Hz). UV Inx 253 (e=7650).

Claims (11)

1. A compound of general formula I 0 R \",,-0 S B N 0/) 7N, ,-R 2 A (1) wherein A represents:

I) a group -CHEOCH2Y I -CHPMY, -CO=CHY wherein Y is nitro, cyano, -COA1, -COOA1, -COSA', -SO2A1, -CONAW, _S02NAW and R is hydrogen or C,-C,2 alkyl,, C1_C,2 alkoxy, C,_C12 alkylthio, C,-C,2 acylamino, C6-Cj. aryl, C._C,4 aralkyl,, halogen, hydroxy, substituted amino or Y; A V and A independently are hydrogen or a) C,-C,2 straight or branched alkyl b) C2_C,2 alkenyl C) C.-C,, alkynyl d) e) C3-C6 cycloalkyl C,-C, cycloalkenyl f) C6-Cl. aryl g) C7-C14 aralkyl, aralkenyl,, aralkynyl; h) heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl; or A and A taken together with the nitrogen atom form a azaheterocyclic group; or A and IP taken together form a azaheterocyclic ring; - 37 or A' and R taken together form a carbocyclic or heterocyclic ring; II) a group -CH,0Al. -CH20COA1p -CH20SO2A1, -CH.SA' wherein A' is as def ined above; B is hydrogen or -CMPCH,Y, -CH2CMZY, -CR=CHY wherein R and Y are as defined above; R' represents (1) a halogen atom (2) A as defined above (3) an ether -0-Al where in A' is as def ined above (4) a thioether, sulphoxide or sulphone -S (0) nAl wherein n is either 0, 1 or 2 and A' is as def ined above (5) acyloxy -OCOA1 wherein A' is as def ined above (6) sulphonyloxy -OSO.Al wherein A' is as defined above (7) acylamino -NHCOA1 wherein A' is as def ined above. R2 represents (1) A' as defined above (2) chloro or fluoro (3) an oxy group -0A1, wherein A' is as def ined above (4) a sulphenyl, sulphinyl or sulphonyl group -S (0) nAl wherein n and A' are as def ined above (5) an acyl group -COA1, -CO0A1 wherein A' is as def ined above (6) an oxymethyl group -CH20A1 wherein A' is as def ined 25 above (7) a thiomethyl group or a derivative thereof of formula -CH2S (0) nAl wherein n and A1 are as def ined above (8) an acyloxymethyl group -CH.OCOA1 wherein A' is as defined above (9) an aminomethyl group -CH2NAIAS wherein A' is as defined above and A% being the same or different,, is as defined for A'; or Al and A taken together with the nitrogen 5 atom to which they are attached represent a heterocyclic ring (10) ammoniomethyl -CH2NA'AW wherein Al and V are as defined above and k,, being the same or different,, is as def ined for A', or A' is alkyl and A and k taken together with the nitrogen atom to which they are attached represent a heterocyclic ring; or A% A and k together with the nitrogen atom to wich they are attached represent an aromatic heterocyclic ring (11) acylamino -CH2NHCOA1 wherein Al is as def ined above or a pharmaceutically acceptable salt thereof.

2. A compound according to claim I having the general formula 0 R' \';: ', 0 B 0 R 2 A (11f) wherein A represents I) a group -CILOCHY, -CH2CWY, -CIO=CHY wherein Y is nitro, cyano, -COA', - COOA1, -SO2A1, -CONWA, -S02NVV and Se is a Cl-C4 alkyl, CI-C4 alkoxy, Cj- C4 alkylthio, c I-C4 acylamino, C6-CIO aryl, aralkyl, hydroxy or Y; A% W and A each independently are hydrogen, methyll CI-CIO straight or branched alkyl, alkenyl, alkynyl, C3-C6 cycloalkyl,, diphenylmethyl, phenyl, benzyl or 2-phenyl-2methylpropyl; wherein the alkyl,, alkenyl, alkynyl, cycloalkyl, phenyl and benzyl groups are either unsubstituted or substituted by CI-C4 alkyl, fluoro, chloro, carboxy, sulpho, CI-C4 alkoxycarbonyl, carbamoyl, carbamoyloxy, sulphamoyl, methylsulphonyl, hydroxy, methoxy, ethoxy, tert-butoxy, benzyloxy, acetoxy, pivaloyloxy, benzoyloxy and phenylacetoxy; or A2 and A taken together with the nitrogen atom form a part of the heterocyclic groups:

R a R An 0 NT N wherein R is hydrogen, C,-C4 alkyl, alkoxy, alkoxycarbonyl; 20 benzyloxycarbonyl, 2-phenylethoxycarbonyl, chloro, fluoro,, phenyl,, p- carboxyphenyll acetamido,, formamido,, benzamido,, carboxy, carbamoyl,, hydroxy, cyano, nitro; or A and R taken together form a azaheterocyclic ring; or Al and R taken together form a carbocyclic or heterocyclic 25 ring; II) a group -CH20COAI or -CH20S02A' wherein jO is as def ined above; or a group -CH20k or -m2sk wherein k is either A' or a heterocyclic ring selected from:

CH3 -,I.eN op woN OP N-N N )"'N'4' 0-'N'-O'OCO L'M3 COOH N-N Y kk N 1 COOP H CH2 3 :._N N-N N N N.0>1 i-N SCH, 2COOP N-N N N N-N 1 S N N CH CH COOP CH2Ph LM2 2 2 rH.,COOP 2 1 ir u R wherein P is hydrogen or straight or branched Cl-C, alkyl, C2- C. alkenyl, aralkyl; B is hydrogen or -CWCH2Y, -CH2CWY, -CIP=CHY wherein 0 and Y are as defined above; (V) chloro,, fluoro or bromo (V) Cl-C, alkyl,, C,-C4 alkenyl, 1-(hydroxy) ethyl, 1(benzyloxy)ethyl.

r i 1-(benzyloxycarbonyloxy)ethyl, 1_ (phenylacetoxy)ethyl. benzyl (311) methoxy, ethoxy, isopropoxy, phenoxy or benzyloxy (4 0) methylthio, ethylthio, isopropylthio (511) formyloxy, acetoxy or phenylacetoxy (61) mesyloxy or tosyloxy (71) formamido, acetamido, fluoroacetamido, trifluoroacetamido or Chloroacetamido R is either hydrogen or (11) methyl, chloromethyl, bromomethyl,, benzyl, ethyl, propyl, phenyl (21) chloro (31) methoxy or benzyloxy (41) methylthio (51) formyl, acetyl, benzoyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl; (6 1) methoxymethyl, ethoxymethyl, isopropoxymethyl; or benzyloxymethyl. phenoxymethyl, 3-pyridyloxymethyl wherein the phenyl and pyridyl rings are either unsubstituted or substituted by one group or two equal or different groups chosen from hydroxy, carboxy,, amino and C,-C4 alkoxycarbonyl; (71) -CH2(S)n A wherein n is zero, one or two and A is as defined above (81) acetoxymethyl, benzoxymethyl, phenylacetoxymethyl or C3-C, alkanoyloxymethyl wherein the above groups are either unsubstituted or substituted by one or more groups selected from carboxy, hydroxy, Cl-C alkoxy; (91) trialkylammoniomethyl wherein the alkyl group is 2-fluoro-l-hydroxyethyl, phenyl or chosen from methyl, ethyl or propyl; N-methylpyrrolidiniomethyl,, N- methylpiperidinionethyl,, N-nethylraorpholiniomethyl; or a pharmaceutically or veterinarily acceptable salt or stereoisomer thereof.

3. A compound according to claim 1 or claim 2 in which A represents a 3oxo-l-butyl,, hydroxymethyl,, methoxycarbonylethenyl,, 4methylbenzoyloxymethyl, benzyloxycarbonylethenyl,, cyanoethyl group 2(benzoyl) ethyl or 2-(p-carboxybenzoyl) ethyl group.

4. A compound according to any one of the preceding claims in which R, represents chlorine or a methoxy group.

5. A compound according to any one of the preceding claims in which R. represents an acetoxymethyl, methyl, methyl tetrazolthio-:-methyl thiadiazolthiomethyl or (6hydroxy-5-oxo-2-methyl-2,5-dihydro-1,2,4-Triazin-5-yl)thiomethyl group.

6. A compound according to any one of the preceding claims in which B represents hydrogen or a 3-oxo-l-butyl hydroxymethyl,, nethoxycarbonylethenyl, 4-methylbenzoyl- oxymethyl,, benzyloxycarbonylethenyl, cyanoethyl, 2 (benzoyl)ethyl or 2-(p-carboxybenzoyl)ethyl group.

7. A compound specifically herein mentioned as any one of compounds 1 to 32.

8. A method for the preparation of a compound as defined in claim 1. the method commencing 0 (i) from a compound of the general formula 2 0 N -;, B N 1 R 2 OOP 1 (2) wherein R' and W, A and B are as def ined in claim 1 and P' a carboxy protecting group and comprising the steps of removing the protecting group P' and decarboxylating the resultant 10 compound under mild conditions. or (ii) from a compound of the general formula (3) 1 S N ot:o 2 OOH (3) wherein R' and 10 and B are as def ined above and comprising the steps of converting the carboxy group at the 4-position of the cephem nucleus into a group of the formula CH2W wherein W represents a group of formula 0A1, 0COA1, OSO.Al or SA' wherein A' is as def ined in claim 1 and oxidising the sulphur atom at the 1-position of the cephem nucleus to the sulphone oxidation level, the steps being carried out in either order.

(iii) if desired,, converting the resultant compound of the formula (1) into a pharmaceutically acceptable salt thereof.

- 44

9. A pharmaceutical or veterinary composition comprising a pharmaceutically acceptable diluent or carrier and, as an active principle, a compound as defined in any of the claims 1 to 7.

10. A compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, for use as a human leukocyte elastase (HLE) inhibitor.

11. A compound according to claim 10 for use in the treatment of degenerative or inflammatory disease.

7