.beta.-Lactam antibiotics, their preparation and use

The present invention provides a compound of the formula (I): ##STR1## or a pharmaceutically acceptable salt or in-vivo hydrolyzable ester thereof wherein R.sup.1 is a hydrogen atom, an .alpha.-sulphonato-oxyethyl group, an .alpha.-sulphonato-oxypropyl group or is a group CR.sup.3 R.sup.4 R.sup.5 wherein R.sup.3 is a hydrogen atom or a hydroxy group; R.sup.4 is a hydrogen atom or a C.sub.1-6 alkyl group; and R.sup.5 is a hydrogen atom or a C.sub.1-6 alkyl group, a benzyl group, a phenyl group or is joined to R.sup.4 to form together with the carbon atom to which they are joined a carbocyclic ring of 5 to 7 carbon atoms; R.sup.2 is a pyrimidinyl group substituted by one two or three groups selected from nitro, halo, amino or substituted amino, and in addition may be optionally substituted by one or two C.sub.1-6 alkyl groups as the degree of substitution permits; and x is zero or one. These compounds are antibacterial agents. Their preparation and use are described.

This invention relates to novel carbapenem derivatives and in particular to 
3-substituted thio carbapenem derivatives. This invention further relates 
to processes for their preparation and to compositions containing them. 
European patent application No. 0001627, 0001628, 0008514, 017970 and 
017992 disclose a wide variety of carbapenem derivatives. 
We have discovered a novel class of antibiotics not specifically disclosed 
in any of the aforementioned publications. These compounds have superior 
effiacy, for example antibacterial activity and/or stability, than related 
compounds specifically disclosed in the aforementioned publications. 
Accordingly, the present invention provides a compound of the formula (I): 
##STR2## 
or a pharmaceutically acceptable salt or in-vivo hydrolysable ester 
thereof wherein R.sup.1 is a hydrogen atom, an .alpha.-sulphonato-oxyethyl 
group, an .alpha.-sulphonato-oxypropyl group or is a group CR.sup.3 
R.sup.4 R.sup.5 wherein R.sup.3 is a hydrogen atom or a hydroxy group; 
R.sup.4 is a hydrogen atom or a C.sub.1-6 alkyl group; and R.sup.5 is a 
hydrogen atom or a C.sub.1-6 alkyl group, a benzyl group, a phenyl group 
or is joined to R.sup.4 to form together with the carbon atom to which 
they are joined a carbocyclic ring of 5 to 7 carbon atoms; R.sup.2 is a 
pyrimidinyl group substituted by one two or three groups selected from 
nitro, halo, amino or substituted amino, and in addition may be optionally 
substituted by one or two C.sub.1-6 alkyl groups as the degree of 
substitution permits; and x is zero or one. 
Suitably x is zero. Suitably x is one. 
When used herein "halo" means chloro, bromo or iodo, preferably chloro or 
bromo. "Substituted amino" includes C.sub.1-6 alkylamino such as 
methylamino or ethylamino; C.sub.2-6 alkylamido such as acetamido or 
propionamido; aryl (C.sub.2-6) alkylamido wherein aryl is suitably phenyl 
such as phenylacetamido; aryloxy (C.sub.2-6) alkylamido such as 
phenoxyacetamido; or di (C.sub.1-6) alkylamino such as dimethylamino. 
Suitable examples of C.sub.1-6 alkyl include the methyl and ethyl groups. 
Preferably the pyrimidinyl group R.sup.2 is substituted by one or two 
groups selected from chloro, amino, acetamido and methyl. 
Suitably R.sup.2 is a pyrimidin-2-yl group. Suitably also R.sup.2 is a 
pyrimidin-4-yl group. In one preferred aspect R.sup.2 is a 4-substituted 
pyrimidin-2-yl group. In another preferred aspect R.sup.2 is a 
4,6-disubstituted pyrimidin-2-yl group. 
A favoured group of compounds of this invention is that of the formula 
(II): 
##STR3## 
and pharmaceutically acceptable salts and in-vivo hydrolysable esters 
thereof wherein R.sup.1 is as hereinbefore defined. Suitably the amino 
substituent is in the 5-position of the pyrimidinyl ring. Suitably also 
the amino substituent is in the 4-position of the pyrimidinyl ring. 
A further favoured group of compounds of this invention is that of the 
formula (III): 
##STR4## 
and pharmaceutically acceptable salts and in-vivo hydrolysable esters 
thereof wherein R.sup.1 is as hereinbefore defined. 
Another favoured group of compounds of this invention is that group 
analogous to formula (II) wherein amino is replaced by acetamido. 
Suitably R.sup.1 in the compounds of the formulae (I)-(III) is a hydrogen 
atom. Suitably R.sup.1 in the compounds of the formulae (I)-(III) is a 
CR.sup.3 R.sup.4 R.sup.5 group. Alternatively the group R.sup.1 is an 
.alpha.-sulphonato-oxyethyl or .alpha.-sulphonato-oxypropyl group. 
Suitably R.sup.3 is a hydrogen atom or a hydroxy group. Suitably R.sup.5 is 
a hydrogen atom or a methyl, ethyl, n-propyl or phenyl group. Suitably 
R.sup.4 is a hydrogen atom or a methyl, ethyl or n-propyl group. 
Favourably R.sup.4 is a hydrogen atom or a methyl group. Favourably 
R.sup.5 is a hydrogen atom or a methyl group. 
Favourably the CR.sup.3 R.sup.4 R.sup.5 moiety is a --C(CH.sub.3).sub.2 OH, 
--CH(CH.sub.3)OH or --CH(C.sub.2 H.sub.5)OH group, of these the 
--CH(CH.sub.3)OH group is preferred. 
It is to be realised that compounds of the formulae (I) to (III) wherein 
R.sup.3, R.sup.4 and R.sup.5 have different values may exist in either the 
8R or 8S form (the C-8 carbon atom being that adjacent to the ring 
carbon). If desired these compounds may be presented as mixtures of the 8R 
and 8S forms. 
The compounds of the formulae (I)-(III) may have the cis- or trans- 
configuration about the .beta.-lactam ring, or they may be provided as 
mixtures thereof. 
The compounds of the formulae (I)-(III) may have 5S or 5R stereochemistry 
or may be provided as mixtures thereof. It is believed that the more 
active isomer is that which exemplified in the relation for formula (I) 
has the configuration shown in formula (IV): 
##STR5## 
Suitable esters of the compounds of the formulae (I)-(IV) include those 
cleavable by biological methods and by chemical methods such as 
hydrogenolysis, hydrolysis electrolysis or photolysis. 
Suitably the carboxylic acid is esterified by a group of the sub-formula 
(a), (b), (c), (d), (e) or (f): 
##STR6## 
wherein A.sup.1 is a hydrogen atom, C.sub.1-6 alkanoyl or an alkyl, 
alkenyl or alkynyl group of up to 3 carbon atoms; A.sup.2 is a hydrogen 
atom or a methyl group; A.sup.3 is a phenyl group or a phenyl group 
substituted by a fluorine, chlorine or bromine atom or a nitro, methyl or 
methoxy group; A.sup.4 is a hydrogen atom or a phenyl group or a phenyl 
group substituted by a fluorine, chlorine or bromine atom or a nitro, 
methyl or methoxy group; A.sup.5 is a hydrogen atom or a methyl group; 
A.sup.6 is a C.sub.1-4 alkyl, phenyl or C.sub.1-4 alkoxy group or A.sup.5 
is joined to A.sup.6 to form a phthalidyl, dimethylphthalidyl or 
dimethoxyphthalidyl group; A.sup.7 is a C.sub.1-4 alkyl, phenyl, 
chlorophenyl or nitrophenyl group; A.sup.8 is a C.sub.1-4 alkyl or phenyl 
group; A.sup.9 is a C.sub.1-4 alkyl or phenyl group; A.sup.10 is C.sub.1-4 
alkyl; and A.sup.11 is C.sub.1-4 alkyl: or CHA.sup.1 A.sup.2 is a phenacyl 
or bromophenacyl group. 
Favourably A.sup.1 is a hydrogen atom or a methyl, ethyl, vinyl or ethenyl 
group. Favourably A.sup.2 is a hydrogen atom. Favourably A.sup.3 is a 
phenyl, p-bromophenyl, p-methoxyphenyl or p-nitrophenyl group. Favourably 
A.sup.4 is a hydrogen atom. Favourably A.sup.6 is a methyl, t-butyl or 
ethoxy group or is joined to A.sup.5. Favourably A.sup.7 is a methyl 
group. 
Preferred groups of the sub-formula (a) include the methyl, ethyl and 
acetonyl groups. 
Preferred groups of the sub-formula (b) include the benzyl and 
p-nitrobenzyl groups. 
Preferred groups of the sub-formula (c) include the acetoxymethyl, 
pivaloyloxymethyl, .alpha.-ethoxycarbonyloxymethyl and phthalidyl groups. 
A preferred group of the sub-formula (d) is the methoxymethyl group. 
Preferred groups of the sub-formula (e) include the trimethylsilyl, 
tert-butyldimethylsilyl and tertbutyldiphenylsilyl groups. 
A preferred group of the sub-formula (f) is p-methoxycarbonylbenzyl. 
Particularly preferred esterifying groups are the p-nitrobenzyl and 
phthalidyl groups. 
Pharmaceutically acceptable in-vivo hydrolysable esters are those esters 
which hydrolyse in the human body to produce the parent acid or its salt. 
Such esters may be identified by administration to a test animal such a 
rat or mouse by intravenous administration and thereafter examining the 
test animal's body fluids for the presence of the compound of the formula 
(I) or its salt. 
Suitable esters of this type include those of sub-formula (c) as 
hereinbefore defined. 
Suitable pharmaceutically acceptable salts include those of the alkali and 
alkaline earth metals, of these the sodium and potassium salts are 
preferred. These pharmaceutically acceptable salts may be formed at the 
C-2 carboxy and/or at the C-6 sulphonato-oxyethyl moiety (if present). 
Thus compounds of the formula (I) wherein R.sup.1 contains a OSO.sub.3 H 
group or pharmaceutically acceptable salt thereof, may be in the form of a 
di-salt such as the di-sodium or dipotassium salt, or may be in the form 
of a mono-salt of an in-vivo hydrolysable ester, or may be in the form of 
a monosalt of an acid or may be in the form of a di-acid. 
Non-pharmaceutically acceptable salts of the compounds of the formula (I) 
are also of use as they may be converted to the compound of the formula 
(I) or a pharmaceutically acceptable salt or in-vivo hydrolysable ester 
thereof. 
In a further aspect of this invention there is provided a pharmaceutical 
composition which comprises a compound of the formula (I) or 
pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof and 
a pharmaceutically acceptable carrier. 
The compositions of this invention may be prepared by conventional methods 
of preparing antibiotic compositions and in conventional manner may be 
adapted for oral, topical or parenteral administration. 
Aptly, the compositions of this invention are in the form of a unit-dose 
composition adapted for oral administration. 
Alternatively the compositions of this invention are in the form of a 
unit-dose composition adapted for administration by injection. 
Unit dose forms according to this invention will normally contain from 50 
to 500 mgs of a compound of this invention, for example about 62.5, 100, 
125, 150, 200, 250 or 300 mgs. Such compositions may be administered from 
1 to 6 times a day or more conveniently 2, 3 or 4 times a day so that the 
total daily dose for a 70 kg adult is about 200 to 2000 mgs, for example 
about 400, 600, 750, 1000 or 1500 mgs. 
The compositions of this invention may be used to treat bacterial 
infection, in animals such as mammals including humans, for example 
infections of the respiratory tract, urinary tract or soft tissues, or 
mastitis in cattle. 
The carriers used in the compositions of this invention may include 
diluents, binders, disintegrants, lubricants, colours, flavouring agents 
or preservatives in conventional manner. Thus suitable agents include 
lactose, starch, sucrose, calcium phosphate, sorbitol, 
polyvinylpyrrolidone, acacia, gelatin, tragacanth, potato starch or 
polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate. 
Orally administrable forms of the compositions of this invention are most 
suitably in the form of unit-dose units such as tablets or capsules. 
The present invention also provides synergistic pharmaceutical compositions 
which comprise a pharmaceutical composition as hereinbefore described 
which also contains a penicillin or a cephalosporin. 
Suitable penicillins for inclusion in the compositions of this invention 
include benzyl penicillin, phenoxymethylpenicillin, ampicillin or a 
pro-drug therefor, amoxycillin or a pro-drug therefor, carbenicillin or a 
pro-drug therefor, ticarcillin or a pro-drug therefor, suncillin, 
sulbenicillin, azlocillin or mezlocillin. 
Particularly suitable penicillins for inclusion in orally administrable 
compositions of this invention include ampicillin and its orally 
administrable pro-drugs, amoxycillin and its orally administrable 
pro-drugs and orally administrable pro-drugs of carbenicillin. Thus 
particularly suitable penicillins include ampicillin anhydrate, amicillin 
trihydrate, sodium ampicillin, talampicillin hydrochloride, pivampicillin 
hydrochloride and bacampicillin hydrochloride; amoxycillin trihydrate, 
sodium amoxycillin; and the sodium salts of the phenyl and 5-indanyl 
.alpha.-esters of carbenicillin. 
A preferred penicillin for inclusion in the orally administrable 
compositions of this invention is amoxycillin trihydrate. A further 
preferred penicillin for inclusion in the orally administrable 
compositions of this invention is ampicillin trihydrate. 
Particularly suitable penicillins for inclusion in injectably administrable 
compositions of this invention include injectable salts such as the sodium 
salt of ampicillin, amoxycillin, carbenicillin and ticarcillin. 
A preferred penicillin for inclusion in the injectably administrable 
compositions of this invention is sodium amoxycillin. A further preferred 
penicillin for inclusion in the injectably administrable compositions of 
this invention is sodium ampicillin. 
Particularly suitable cephalosporins for inclusion in the compositions of 
this invention include cephaloridine, cephalexin, cephradine, cefazolin 
and cephalothin. 
A particularly suitable cephalosporin for inclusion in the orally 
administrable compositions of this invention is cephalexin. 
Particularly suitable cephalosporins for inclusion in the injectably 
administrable compositions of this invention include cephaloridine, 
cefazolin and cephradine, generally as their pharmaceutically acceptable 
salt. 
The weight ratio between compound of this invention and penicillin or 
cephalosporin is generally from 10:1 to 1:10, more usually from 5:1 to 1:5 
and normally from 3:1 to 1:3. 
The penicillin or cephalosporin is generally utilised in its conventionally 
administered amount. 
In another aspect the present invention provides a process for the 
preparation of a compound of the formula (I) which process comprises: 
(a) the elimination of O.dbd.PR.sup.6 R.sup.7 R.sup.8 in the ring-closing 
of an ester of the compound of the formula (V): 
##STR7## 
wherein R.sup.1 and R.sup.2 are as hereinbefore defined and R.sup.6, 
R.sup.7 L and R.sup.8 are independently phenyl or methoxyphenyl groups: 
or (b) the reaction of a compound of the formula (VI) 
##STR8## 
wherein R.sup.a is carboxy-blocking group or a hydrogen atom, and R.sup.9 
is an organic group bonded via a carbon atom and is different to the group 
R.sup.2 ; and a compound of the formula (VII): 
EQU R.sup.2 --SH (VII) 
or reactive derivative thereof, wherein R.sup.2 is as hereinbefore defined; 
or (c) the reaction of a compound of the formula (VIII): 
##STR9## 
or reactive derivative thereof wherein R.sup.a is a carboxy-blocking group 
or hydrogen atom, and R.sup.1 is as hereinbefore defined, with a compound 
of the formula (IX): 
EQU X--R.sup.2 (IX) 
wherein X is a displaceable group and R.sup.2 is as hereinbefore defined; 
or (d) the reaction of an ester of a compound of the formula (X): 
##STR10## 
wherein R.sup.1 and R.sup.2 are as hereinbefore defined with a base 
capable of isomerising the double bond: 
and thereafter if necessary: 
(i) removing any carboxy-protecting group R.sup.a, 
(ii) converting the product into a pharmaceutically acceptable salt or 
in-vivo hydrolysable ester, 
(iii) oxidising the sulpur atom to afford an SO group. 
Suitable carboxyl-blocking derivatives for the group --CO.sub.R.sup.a in 
formulae (VI) and (VII) include salts, esters, and anhydride derivatives 
of the carboxylic acid. The derivative is one which may readily be cleaved 
at a later stage of the reaction. The salts need not be pharmaceutically 
acceptable. Suitable salts include inorganic salts, for example metal 
salts such as silver or mercuric salt, or alkali metal salts such as the 
lithium or sodium salt, or tertiary amine salts, such as those with 
tri-lower-alkylamines, n-ethylpiperidine, and dimethylpiperazine. A 
preferred salt is with triethylamine. 
Suitable ester-forming carboxyl-blocking groups are those which may be 
removed under conventional conditions. Such groups for R.sup.a include 
benzyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl, 
3,5-di-t-butyl-4-hydroxybenzyl, benzoylmethyl, p-nitrobenzyl, 
4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, t-butyl, 
t-amyl-diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 
4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, 
pentachlorophenyl, p-toluenesulphonylethyl, methoxymethyl, a silyl, 
stannyl or phosphorus-containing group, an oxime radical of formula 
--N.dbd.CHR.degree. where R.degree. is aryl or heterocyclic, or an in vivo 
hydrolysable ester. 
The carboxyl group may be regenerated from any of the above esters by usual 
methods appropriate to the particular R.sup.a group, for example, 
acid--and base--catalysed hydrolysis, or by enzymically--catalysed 
hydrolysis, or by hydrogenation. The hydrolysis must of course be carried 
out under conditions to which the groups on the rest of the molecule are 
stable. 
When it is desired to produce a compound of formula (I) in the form of a 
free acid or salt by the process of this invention, a compound of formula 
(VI) or (VIII) is generally employed wherein R.sup.a is a 
carboxyl-blocking group. For the preparation of a compound of formula (I) 
in the form of a pharmaceutically acceptable ester, it is convenient to 
employ a compound of formula (VI) or (VIII) wherein R.sup.a represents the 
desired ester group. 
Preferably the process of this invention is performed on a compound of the 
formula (VI) or (VIII) wherein R.sup.a is an ester-forming group. 
Process variant (a) is mormally performed by heating the ester of the 
compound of the formula (V) in an inert solvent, for example temperatures 
of 90.degree. to 120.degree. C. and more suitably 100.degree. to 
110.degree. C. may be employed in a solvent such as toluene, preferably 
under substantially anhydrous conditions. If it is desired to form a 
compound of the formula (I) containing an amino group, it is preferred to 
perform process variant (a) on the corresponding nitrocompound and convert 
the nitro group to an amino group in conventional manner for example by 
hydrogenation. 
Process variant (b) may be performed in any solvent that is substantially 
inert during the reaction, for example tetrahydrofuran, dimethylformamide, 
dioxan, hexamethyl phosphoramide, dimethoxyethane or dimethoxydiethyl 
ether. Of these solvents dimethylformamide is preferred. Alternatively we 
have found it useful to use a phase transfer catalyst. Particularly 
suitable phase transfer catalysts include tetra-n-butyl ammonium bromide, 
cetyl benzyldimethyl ammonium chloride and cetyltriethylammonium chloride; 
suitable solvents include halogenated water-immiscible solvents such as 
chloroform in the presence of water. The reaction is normally performed at 
ambient or a depressed temperature, for example 20.degree. C. to 
-70.degree. C., and preferably between 0.degree. C. and -50.degree. C. 
However when using a phase transfer catalyst it is preferably to conduct 
the reaction between 0.degree. C. and ambient temperature. When the thiol 
of the formula (VII) is used the reaction is normally carried out in the 
presence of a base. Examples of such bases include sodium hydride, sodium 
hydroxide, sodium alkoxide such as the methoxide, ethoxide or butoxide, 
sodium amide, potassium hydroxide, potassium alkoxide such as the 
methoxide, ethoxide or butoxide, potassium. amide, and trialkylamines such 
as triethylamine and tri-n-propylamine. Of these triethylamine is 
preferred. Preferably the base is present in an amount of at least 0.9 
equivalents, more preferably between 1.0 and 1.2 equivalents per mole of 
the thiol compound. Instead of using a base in the reaction a reactive 
derivative of the thiol may be used, preferably the reactive derivative is 
a salt of the thiol, in particular an alkali metal salt such as sodium or 
potassium. The amount of thiol compound of the formula (VII) or reactive 
derivative thereof is generally between 1.0 and 1.5 moles per mole 
equivalent of the compound of the formula (VI). 
Suitably R.sup.9 is an optionally substituted C.sub.1-6 alkyl C.sub.2-6 
alkenyl, C.sub.2-6 alkynyl, aryl (C.sub.1-6) alkyl, C.sub.2-6 alkanoyl, 
aryl (C.sub.2-6) alkanoyl, arylcarbonyl, aryl, heterocyclyl, heterocyclyl 
(C.sub.1-6) alkyl, heteroaryl (C.sub.1-6) alkyl or heteroaryl group. 
Suitably the hetero atom or hetero atoms in the above named heteroaryl 
and/or heterocyclyl moieties are selected from 1 to 4 oxygen, nitrogen or 
sulphur atoms. Suitable optional substituents for R.sup.9 include amino, 
alkanoylamino, mono- and di-alkylamino, hydroxy, alkoxy and carboxy and 
salts and esters thereof. Preferably R.sup.9 is a C.sub.1-6 alkyl, 
C.sub.2-6 alkenyl, aryl, such as phenyl or heteroaryl group, any of such 
groups being optionally substituted. Favourably R.sup.9 is methyl, ethyl, 
alkanoylaminoethyl such as acetamidoethyl, alkanoylaminoethenyl such as 
acetamidoethenyl, aminoethyl, phenyl, pyridyl or pyrimidyl. 
Process variant (c) may be carried out in any solvent that is substantially 
inert during the reaction, for example tetrahydrofuran, dimethylformamide, 
dioxan, dimethoxyethane, dimethoxydiethyl-ether or 
hexamethyl-phosphoramide. Of these solvents dimethylformamide is 
preferred. When the thiol compound of the formula (II) is used, the 
reaction is normally carried out in the presence of an acid acceptor, for 
example a carbonate or bicarbonate such as anhydrous potassium carbonate. 
Alternatively we have found it useful to use a phase transfer catalyst. 
Particularly suitable phase transfer catalysts include tetrabutylammonium 
bromide and cetyl benzyl dimethyl ammonium chloride; suitable solvents 
include halogenated water-immiscible solvents such as chloroform and 
dichloromethane in the presence of an aqueous base such as aqueous sodium 
hydroxide. The reaction is normally performed at a non-extreme 
temperature, for example -30.degree. C. to +60.degree. C., more suitably 
-10.degree. C. to +40.degree. C. and preferably at ambient temperature. 
Suitably X is a halo moiety such as bromo or chloro or is a sulphonate 
ester moiety such as tosylate or mesylate. Of these preferably X is a 
chloro or brommo moiety. Instead of using an acid acceptor in the 
reaction, a reactive derivative of the thiol may be used, preferably the 
reactive derivative is a salt of the thiol, in particular an alkali metal 
salt such as sodium or potassium. 
Process variant (d) may be performed by treating the compound of the 
formula (IX) in a solvent such as dimethylformamide, dimethylsulphoxide, 
diethyl ether, tetrahydrofuran, dimethoxyethane or dichloromethane with a 
strong base such as di-isopropylamine, diazabicyclononene or 
diazabicycloundecene at a temperature of about 0.degree. C. to 25.degree. 
C. 
Compounds of the formula (V) may be prepared via the methods of European 
Patent Application Publication Number 0008514 substituting the substituted 
pyrimidinyl group for the R.sub.1 of the afore-mentioned specification. 
Compounds of the formula (VI) may be prepared by methods of European Patent 
Application Publication Number 0002564. 
Alternatively the compounds of the formula (VI) may be prepared by the 
S-oxidation of a compound of the formula (XI): 
##STR11## 
or salt or ester thereof wherein R.sup.1 and R.sup.9 are as defined in 
relation to formula (VI) with an oxidising agent; and thereafter if 
necessary converting the free acid or salt to an ester. 
Suitable oxidising agents include perbenzoic acid, hydrogenperoxide, 
iodobenzene dichloride/water and sodium metaperiodate. Substituted 
perbenzoic acids such as m-chloroperbenzoic acid are preferred. 
The reaction between the compund of the formula (X) and the oxidising agent 
is conveniently performed in an inert solvent such as methylene chloride, 
chloroform or carbon tetrachloride at an ambient or depressed temperature, 
preferably between -30.degree. C. and +20.degree. C. 
The amount of the oxidising agent used in the oxidation of the compound of 
the formula (XI) can vary widely dependent on the type of oxidising agent, 
reaction conditions, presence of other potentially reactive groups, etc. 
Generally between 1 and 2 molar equivalents of the oxidising agent are 
preferred. 
In a similar manner to the foregoing the compounds of the formula (I) 
wherein X is one may be prepared by the oxidation of a compound of the 
formula (I), Wherein X is zero. 
The compounds of the formulae (VIII) (X) and (XI) may be prepared via the 
methods of European Patent Application Publications Nos. 0001627 and 
0001628. Alternatively the compounds of the formula (VIII) may be prepared 
via the methods of European patent application No. 80302659.0 (Publication 
No. 24832). 
The following Examples serve to illustrate the invention.