EP0137794A1 - Clavam-derivate - Google Patents

Clavam-derivate

Info

Publication number
EP0137794A1
EP0137794A1 EP84900634A EP84900634A EP0137794A1 EP 0137794 A1 EP0137794 A1 EP 0137794A1 EP 84900634 A EP84900634 A EP 84900634A EP 84900634 A EP84900634 A EP 84900634A EP 0137794 A1 EP0137794 A1 EP 0137794A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
clavam
benzyl
carboxylate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP84900634A
Other languages
English (en)
French (fr)
Inventor
John Barry Harbridge
Irene Stirling
Gordon Bruton
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
Original Assignee
Beecham Group PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB838304954A external-priority patent/GB8304954D0/en
Priority claimed from GB838324961A external-priority patent/GB8324961D0/en
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0137794A1 publication Critical patent/EP0137794A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • This invention relates to novel ⁇ -lactam containing compounds, their preparation and their use, and in particular to a novel class of clavams. These compounds have antibacterial and ⁇ -lactamase inhibitory properties, and therefore are of use in the treatment of bacterial infection either alone or in a synergistic composition with other ⁇ -lactam antibacterial agents, such as penicillins and cephalosporins.
  • Clavulanic acid has the structure:
  • the present invention provides certain 3-carboxyclavam derivatives having a propylidene moiety at the 2-position of the clavam nucleus.
  • the present invention comprises compounds of the formula (II):
  • R is hydrogen or a hydrocarbon group and where X is hydroxy, substituted hydroxy, mercapto, substituted mercapto; azido, cyano, halo, isothiocyanato, substituted amino or X represents the residue of a carbon nucleophile or is an activated aryl or heteroaryl group.
  • Suitable substituted hydroxy groups for X include etherified and acylated hydroxy and suitable substituted mercapto groups include etherified and acylated mercapto.
  • Suitable substituted amino groups for X include alkylated or acylated amino.
  • hydrocarbon' includes groups having up to 18 carbon atoms, suitably up to 10 carbon atoms, conveniently up to 6 carbon atoms. Suitable hydrocarbon groups include C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1 _ 6 )-alkyl, aryl, and aryl (C 1-6 )alkyl .
  • 'aryl' includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, C 1-6 alkyl, phenyl, C 1-6 alkoxy, halo(C 1-6 ) alkyl, hydroxy, amino, nitro, carboxy, C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl-(C 1-6 )-alkyl C 1-6 alkylcarbonyloxy, or C 1-6 alkylcarbonyl groups.
  • X is hydroxy or substituted hydroxy.
  • substituted hydroxy groups include -OR 1 , -OCOR 1 , -OCSR 1 , -OCO 2 R 1 , -OCS 2 R 1 , OCOSR 1 , -OCSOR 1 , -OSO 3 H, -OPO 3 H, -OSO 2 R 1 and -OCONR 2 R 3 wherein R 1 is a substituted or unsubstituted hydrocarbon group of 1 to 20 carbon atoms; and R 2 and R 3 are each independently hydrogen or substituted or unsubstituted hydrocarbon groups of 1 to 20 carbon atoms.
  • R 1 is C 1-10 alkyl, C 2-10 alkenyl, aryl (C 1-6 ) alkyl, heterocyclyl (C 1-6 ) alkyl, aryl (C 2-6 ) alkenyl, heteroaryl (C 1-6 ) alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl or C 3-8 cycloalkyl (C 1-6 ) alkyl, any of such groups being optionally substituted.
  • Suitable optional substituents for the group R 1 include C 1-6 alkyl, amino, C 1 -6 alkanoylamino, mono- and di- (C 1-6 ) alkylamino, hydroxy, C 1-6 alkoxy, mercapto, C 1-6 alkylthio, heteroarylthio, arylthio. oxo, sulphamoyl, carbamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, carboxy and salts and esters thereof, C 1-6 alkanoyloxy, arylcarbonyl and heteroarylcarbonyl.
  • R 2 and R 3 are hydrogen or C 1-6 alkyl.
  • X is C 1-6 alkoxy or benzyloxy optionally substituted by one, two or three halogen atoms, cyano, azido, hydroxy, C 1-6 alkoxy, C 2-6 alkanoyloxy, C 1-4 alkylthio, aryloxy such as phenoxy, amino, C 1-6 alkanoylamino, carboxy or esterified carboxy.
  • X is methoxy
  • X is C 1-6 alkanoyloxy such as acetoxy, C 1-6 alkyl sulphonyloxy such as methanesulphonyloxy or arylsulphonyloxy such as p-toluenesulphonyloxy, or C 1-6 alkylcarbamoyloxy such as methylcarbamoyloxy.
  • X is mercapto or substituted mercapto.
  • substituted mercapto groups include -SCOR 4 , -S-R 4 , -SCSR 4 , -SCO 2 R 4 , -SCS 2 R 4 , -SCOSR 4 , -SCSOR 4 , -SSO 2 R 4 , -SCONR 5 R 6 , -S(O)R 4 , -S(O) 2 R 4 and -S-SR 4 , wherein R 4 , R 5 and R 6 are independently substituted or unsubstituted hydrocarbon groups of 1 to 20 carbon atoms.
  • substituents for R 4 , R 5 and R 6 include those described hereinabove as being suitable as substituents for R 1 .
  • R 4 is a C 1-10 alkyl, C 2-10 alkenyl, aryl (C 1-6 ) alkyl, heterocyclyl (C 1-6 ) alkyl, aryl, (C 2-6 ) alkenyl, C 3-8 cycloalkyl (C 1-6 ) alkyl.
  • X is a group -S(O) n R 7 wherein n is zero, one or two, and R 7 is benzyl, C 1-6 alkyl, C 2-6 alkenyl, aryl or heteroaryl, any of such groups R 7 being optionally substituted by one, two or three halogen atoms, azido, hydroxy, C 1-6 alkoxy, C 2-6 alkanoyloxy, C 1-4 alkylthio, aryloxy such as phenoxy, amino, C 1-6 alkanoylamino, carboxy or esterified carboxy.
  • X is S(O) n R 7 wherein n is zero or two, and R 7 is C 1-6 alkyl such as methyl, benzyl, phenyl or tetrazolyl.
  • X is thiophenyl
  • X is substituted amino.
  • substituted amino groups include -NHR 10 , -NR 10 R 11 , -NR 10 R 11 R 12 , -NHCX 1 R 10 , -NHCX 1 ZR 10 , -NHSO 2 R 10 , -NHCX 1 NR 10 R 11 , -N(CX 1 R 12 )R 13 , -N(CX 1 R 12 )CZR 13 , -N(CX 1 R 12 )ZR 13 , -N(CX 1 ZR 12 )R 13 and -N(CX 1 ZR 12 )CX 1 ZR 13 wherein X 1 and Z are each oxygen or sulphur and R 10 , R 11 , R 12 and R 13 are independently substituted or unsubstituted hydrocarbon groups of 1 to 20 carbon atoms.
  • R 10 - R 13 include those described hereinabove as being suitable as substituents for R 1 .
  • the groups R 10 and R 11 may be joined to form a heterocyclic ring containing from three to ten carbon atoms and not more than four heteroatoms selected from oxygen, nitrogen and sulphur. More suitably R 10 , R 11 , R 12 and R 13 are independently selected from C 1-10 alkyl, C 2-10 alkenyl, aryl (C 1-6 ) alkyl, heterocyclyl (C 1-6 ) alkyl, aryl
  • C 2-6 alkenyl, C 3-8 cycloalkyl (C 1-6 ) alkyl, heterocyclyl, heterocyclyl (C 1-6 ) alkyl, aryl, heteroaryl and heteroaryl (C 1-6 ) alkyl, any of such groups being optionally substituted.
  • X is an amino group substituted by at least one acyl and/or acyloxy group.
  • X is an acetylamino or an N-acetyl- N-acetoxy amino group.
  • X is C 1-6 alkylamino such as methylamino, ethylamino, propylamino and butylamino, di-(C 1-6 ) alkylamino such as diethylamino, benzylamino, C 1-8 alkanoylamino such as acetamido, succinimido or phthalimide, any of such groups being optionally substituted by one, two or three halogen atoms, or by an azido, hydroxy, C 1-6 alkoxy, C 2-6 alkanoyloxy, C 1-4 alkylthio, aryloxy such as phenoxy, amino, C 1-6 alkanoylami no , carboxy or esteri f ied carboxy group .
  • C 1-6 alkylamino such as methylamino, ethylamino, propylamino and butylamino
  • di-(C 1-6 ) alkylamino such as diethylamino
  • X is succinimido.
  • X is C 1-6 alkylamino, benzylamino, C 1-6 alkanoylamino or di-(C 1-6 ) alkylamino.
  • X is an aryl or heteroaryl group bonded to the adjacent -CHR group via a carbon atom, for example phenyl, furyl, pyrrolyl, thienyl and such ring systems fused to a benzene ring, any of such groups being optionally substituted.
  • Other heteroaryl groups for X which can be bonded to the adjacent CHR group by a nitrogen include triazolyl, tetrazolyl and trioxoimidazolidinyl, optionally substituted with C 1-6 alkyl or C 1-6 alkoxycarbonyl.
  • X is triazolyl
  • X is the residue of a carbon nucleophile such as of the sub-formula -CR 14 R 15 R 16 wherein R 14 and R 15 are the same or different and at least one of them represents a group capable of producing a stabilised carbanion, such as an electron withdrawing group, and R 16 is hydrogen or a substituted or unsubstituted hydrocarbon group of 1 to 20 carbon atoms.
  • R 14 and R 15 may be selected from groups -CX 1 R 10 and CX 1 ZR 10 as previously described.
  • R 16 may be defined as for R 10 hereinabove.
  • X is -CH(COOR 1 7 )COR 18 or -CH (COR 17 )COR 18 wherein R 17 and R 18 are independently selected from C 1-10 alkyl, C 3-8 cycloalkyl, aryl such as phenyl, aryl (C 1-6 ) alkyl such as benzyl, any of groups R 17 and R 18 being optionally substituted by one, two or three halogen atoms, C 1-6 alkoxy, C 2-6 alkanoyloxy, C 1-4 alkylthio, aryloxy such as phenoxy, C 1-6 alkanoylamino or esterified carboxy.
  • X is -CH(COCH 3 ) 2 .
  • X is azido or cyano.
  • X is a halo moiety for example iodo, bromo or chloro.
  • Compounds wherein X is azido or halo are of particular interest as useful chemical intermediates.
  • X is iodo.
  • the major use of the compounds of the formulae (II)-(IV) and salts and esters thereof is as pharmaceuticals and accordingly the salts and esters of the compounds of the formulae (II)-(IV) are preferably pharmaceutically acceptable.
  • the compounds of this invention both pharmaceutically acceptable and non-pharmaceutically acceptable may be used as intermediates and also as antibacterial agents or ⁇ -lactamase inhibitors in non-pharmaceutical usage such as a disinfectant or paint additive.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (II)-(IV) include metal salts such as aluminium, alkali metal salts such as sodium and potassium, and alkaline earth metal salts such as calcium or magnesium; and ammonium and substituted ammonium salts, for example those with lower alkylamines such as triethylamine, cycloalkylamines such as bicyclohexylamine, 1-ephenamine, N-ethylpiperidine and N-benzyl- ⁇ -phenethylamine.
  • metal salts such as aluminium, alkali metal salts such as sodium and potassium, and alkaline earth metal salts such as calcium or magnesium
  • ammonium and substituted ammonium salts for example those with lower alkylamines such as triethylamine, cycloalkylamines such as bicyclohexylamine, 1-ephenamine, N-ethylpiperidine and N-benzyl- ⁇ -phenethylamine.
  • Non-pharmaceutically acceptable salts for use as intermediates include the lithium and silver salts.
  • Suitable esters of the compounds of the formulae (II)-(IV) include those cleavable by biological methods such as enzymatic hydrolysis, in vivo hydrolysis, and those cleavable by chemical methods such as hydrogenolysis, hydrolysis, electrolysis or photolysis.
  • the carboxylic acid i s esteri i fied by a group of the sub-formula ( a) , (b ) , (c ) , (d ) , ( e ) or ( f ) are examples of the sub-formula ( a) , (b ) , (c ) , (d ) , ( e ) or ( f ) :
  • a 1 is a hydrogen atom, C 1-6 alkanoyl or an C 1-5 alkyl group optionally substituted by C 1-7 alkoxy or C 1-7 carboxylic acyloxy, or an alkenyl or alkynyl group of up to 5 carbon atoms;
  • a 2 is a hydrogen atom or a methyl group;
  • a 3 is a phenyl group or a phenyl group substituted by a fluorine, chlorine or bromine atom or a nitro, C 1-3 alkyl or C 1-3 alkoxy group;
  • a 4 is a hydrogen atom or a phenyl group or phenyl group substituted by a fluorine, chlorine or bromine atom or a nitro, C 1-3 alkyl or C 1-3 alkoxy group;
  • a 5 is a hydrogen atom or a methyl group;
  • a 6 is a C 1-4 alkyl, phenyl or C 1-4 alkoxy group or A 5 is joined to A
  • Favourably A 1 is a hydrogen atom or a methyl, ethyl, vinyl or ethynyl group.
  • Favourably A 2 is a hydrogen atom.
  • Favourably R 3 is a phenyl, p-bromophenyl, p-methoxyphenyl or p-nitrophenyl group.
  • Favourably A 4 is a hydrogen atom.
  • Favourably A 6 is a methyl, t-butyl or ethoxy group or is joined to A 5 .
  • Favourably A 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 sub-formula (c) include the acetoxymethyl, pivaloyloxymethyl, ⁇ -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, tert-butyldiphenylsilyl groups and tri-isopropylsilyl.
  • a preferred group of the sub-formula (f) is p-methoxycarbonylbenzyl .
  • 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 as a rat or mouse by intravenous administration and thereafter examining the test animal's body fluids for the presence of the compound of the formulae (II)-(IV) or salt.
  • Suitable esters of this type include those of sub-formula (c) as hereinbefore defined.
  • esters include di(C 1-6 ) alkylamino C 1-6 alkyl esters such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl and diethylaminoethyl.
  • Esters of the compounds of the formula (II)-(IV) such as those of the sub-formula (a)-(f) if desired, may be presented in the form of their acid addition salts if an amino group is present in group X.
  • the acid used to form the salt will most suitably be pharmaceutically acceptable, but non-pharmaceutically acceptable acid addition salts are also envisaged, for example as intermediates in the preparation of the pharmaceutically acceptable salts by ion exchange.
  • Suitable pharmaceutically acceptable acid addition salts include those of inorganic and organic acids, such as hydrochloric, phosphoric, sulphuric, methanesulphonic, toluenesulphonic, citric, malic, acetic, lactic, tartaric, propionic and succinic acid.
  • the acid addition salt is provided as a solid and preferably as a crystalline solid.
  • Compounds of this invention when in crystalline form may be solvated, for example hydrated.
  • the present invention provides a process for producing a compound of formula II by reduction of a compound of formula V
  • R is as defined above in relation to formula (II), R a is hydrogen or a carboxy blocking group, Y is tetrazolyl or triazolyl each of which may be optionally substituted and each of which is bonded to the oxazolidene ring via a nitrogen atom, or -O.CO.R b where R b is hydrogen, alkyl, alkenyl, arylalkyl, aryl, cycloalkyl or heterocyclyl, and Z is an oxygen or sulphur atom and thereafter if necessary i) converting a compound of formula II where X is hydroxy or mercapto to a compound of formula (II) wherein X is not hydroxy or mercapto; ii) removing any carboxy blocking group R a , iii) converting the product into a salt or ester.
  • the reduction is effected by conventional methods preferably using one or more mild reducing agetns. Care must be taken not to reduce the CO 2 R a group at the same time.
  • Z is oxygen
  • Y when Y is tetrazolyl or triazolyl, suitable substituents are esterified or salified carboxy, optionally substituted C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, or aryl, azido, isocyano, cyano, nitro, bromo, chloro, or a group of the sub-formula -(CO) n -NR x RY wherein n is zero or one, R x is hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkanoyl, or arylcarbonyl, and R Y is hydrogen, C 1-6 alkyl or C 1-6 alkanoyl, or R x and R Y may be joined to form (with the nitrogen atom to which they are attached) an optionally substituted 4,5 or 6-membered ring.
  • Preferred substituents are optionally substituted C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, or aryl; azido, isocyano, cyano, nitro, bromo, chloro, or a group of the sub-formula -NRxRY wherein R x is hydrogen or optionally substituted C 1-6 alkyl, C 1-6 alkanoyl, or arylcarbonyl, and R Y is hydrogen, C 1-6 alkyl or C 1-6 alkanoyl, or R x and R Y may be joined to form (with the nitrogen atom to which they are attached) an optionally substituted 4,5 or 6-membered ring.
  • alkyl and alkenyl groupsor moieties have from 1 to 6 carbon atoms; aryl groups include those selected from phenyl; phenyl substituted in one or more positions in the ring by one or more of alkyl, alkenyl, alkoxy, halo such as chloro, alkyl substituted by halo such as trifluoromethyl, nitro, amino, mono- or di-alkylamino, carboxy, alkoxycarbonyl, acylamino and like substitutents ; naphthyl, quinolyl each of which may be optionally substituted as defined above in relation to 'phenyl'; and cycloalkyl and heterocyclyl groups have from 3 to 10 atoms selected from C, N, O and S such as pyrrolyl, furyl, thienyl and pyridyl.
  • Y is tetrazolyl or triazolyl, each of which may be optionally substituted by C 1-6 alkyl, C 2-6 alkenyl, bromo or chloro, or -O.CO.R b where R b is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or optionally substituted phenyl.
  • R b is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or optionally substituted phenyl.
  • Y is 2-tetrazolyl, optionally 5-substituted by alkyl; triazolyl; or -O.CO.R b where R b is alkyl or aryl.
  • Y is 2-tetrazolyl, optionally 5-substituted by C 1-4 alkyl; triazolyl; or -O.CO.R b where R b is C 1-4 alkyl or phenyl.
  • R b is C 1-4 alkyl or phenyl.
  • Preferred C 1-4 alkyl groups are methyl and ethyl. An especially preferred C 1-4 alkyl group is methyl.
  • Suitable carboxy-protecting groups for the group -CO 2 R a in formula (V) include ester derivatives of the carboxylic acid.
  • the derivative is preferably one which may readily be cleaved at a later stage of the reaction.
  • Suitable ester-forming carboxy-protecting groups are those which may be removed undr conventional conditions.
  • Such groups for R a include benzyl, p-methoxybenzyl, 2, 4, 6-trimethylbenzyl, 3, 5-di-t-butylbenzyl, 4-pyridylmethyl, allyl, diphenylmethyl, triphenymethyl, 2-benzyloxyphenyl, 4-methylthiophenyl, methoxymethyl, a silyl or a phosphorus-V-containing group, or methyl or ethyl, but especially benzyl.
  • the free carboxylic acid or a salt thereof may be regenerated from any of the above esters by usual methods appropriate to the particular R a group; for example, by base-catalysed hydrolysis, by enzymically-catalysed hydrolysis or by hydrogenation.
  • the reduction of the compound (V) to give compound (II) involves two steps, namely reduction of the moiety and removal of the group Y. These two steps may be performed in one reaction or seperately, depending on the nature of the groups involved. For example, when Y represents a group -O.CO.R b , the process is conveniently carried out in two stages, by initially reducing the compound (V), for example with zinc borohydride to give an allylic alcohol of formula (VI):
  • the group Y may then be removed by further reduction, for example catalytic hydrogenation, preferably after protection of the alcohol group.
  • the alcohol may be protected by silylation to form a protected derivative of formula (VI A):
  • R9 is a hydrocarbon group as defined hereinbefore.
  • Suitable silylating agents include halosilanes or silazanes, particularly trimethylchlorosilane, dimethyl-dichlorosilane or bis(trimethyl silyl) acetamide. This protected intermediate can then be reduced using standard reactions with conventional reducing agents for example hydrogen in the presence of palladium catalyst.
  • the hydrogenation reaction is effected in a solvent inert under reaction conditions such as toluene, tetrahydrofuran, dioxan, ethanol or aqueous ethanol or mixtures thereof.
  • the protecting group is subsequently cleaved after the hydrogenation to yield the free acid, ester or salt of formula (II).
  • the reduction and removal of the Y group to produce a compound of formula II may be effected in one stage using an appropriate reducing agent such as zinc borohydride.
  • This reaction normally takes place in a solvent inert under the reaction conditions such as toluene, dichloromethane, tetrahydrofuran or dioxan, or mixtures thereof, but especially tetrahydrofuran and toluene.
  • the reaction is generally carried out at a depressed or non-elevated temperature, for example -80o to +30oC, and preferably at a depressed temperature, for example -20o to + 20oC, and conveniently at about 0oC.
  • This process may produce isomers of formula II with both Z and E sterochemistry about the double bond.
  • the two isomers can be separated using conventional methods and where required the E isomer can be converted to the Z isomer using ultra violet light.
  • R a and Y are as defined above in relation to formula (V) .
  • a compound of formula (VII) is subjected to ozonolysis to produce an intermediate compound of formula (VIII)
  • R d , R e and R f are each independently C 1-6 alkyl, aryl or aryl (C 1-6 ) alkyl.
  • R d , R e and R f are phenyl.
  • R a is as defined in relation to formula (V) with
  • R 19 and R 20 are each independently C 1-6 alkyl, aryl or aryl(C 1-6 )alkyl;
  • k, 1 and m are each independently 0 or 1
  • R 21 , R 22 and R 23 are each independently C 1-6 alkyl, aryl or aryl(C 1-6 )alkyl.
  • Suitable compounds of formula (XIV) include those wherein R 19 and R 20 are each independently methyl, ethyl, propyl, butyl, phenyl or benzyl. It is generally convenient that R 19 and R 20 represent the same moiety. Particularly suitable compounds of the formula (XIV) include those wherein R 19 and R 20 each represent ethyl, t-butyl or isopropyl, but especially ethyl.
  • Suitable compounds of formula (XV) include those wherein R 21 , R 22 and R 23 are each independently methyl, ethyl, n-propyl, n-butyl, benzyl, phenyl or methoxyphenyl. It is generally convenient that R 21 , R 22 and R 23 each represent the same moiety.
  • Favoured compounds of formula (XV) include tri-arylphosphines and tri-alkylphosphites. Particularly suitable compounds of formula (XV) include triphenylphosphine, trimethylphosphite, triethylphosphite and tri-pmethoxyphenylphosphine, but especially triphenylphosphine.
  • Compounds of formula VIIA can be derived by conventional methods from clavulanic acid of formula (I).
  • the present invention also provides a process for the production of a compound of formula II wherein R is hydrogen by reduction of a compound of formula X
  • R a is as defined hereinbefore in relation to formula (V); and thereafter if necessary
  • a suitable method of reduction utilises a complex hydride such as a borohydride, for example lithium borohydride, sodium cyanoborohydride, di-isobutyl aluminium hydride; or a reagent such as aluminium tri-isopropoxide.
  • a complex hydride such as a borohydride, for example lithium borohydride, sodium cyanoborohydride, di-isobutyl aluminium hydride; or a reagent such as aluminium tri-isopropoxide.
  • Such reaction may be performed in an inert organic solvent such as a hydrocarbon, a chlorinated hydrocarbon or an ether, for example toluene, cyclohexane, diethyl ether, heptane, hexane, dichloromethane or tetrahydrofuran.
  • the reaction may be performed at any non-extreme temperature for example -30oC to +60°C, more suitably 0oC to +30o
  • R a is as defined hereinabove in relation to formula (V).
  • a compound of formula (XI) is treated with a silylating agent.
  • Suitable silylating agents include halosilanes or silazanes.
  • the si lylated i ntermedi ate has the formu la
  • R a and R9 are as defined hereinbefore in relation to formula (V) and (VI A) respectively.
  • This intermediate is not stereospecific with respect to the double bond at the 3 carbon position in the side chain. It is then subjected to a peracid oxidation step to give a second intermediate of formula
  • R h is a residue of carboxylic acid.
  • Suitable peracids include peracetic acid and perbenzoic acid.
  • the second intermediate is reacted with a tetra alkyl ammonium fluoride, for example tetraethyl ammonium fluoride dihydrate which produces a compound of formula XII
  • R a is as defined hereinbefore in relation to formula V.
  • This compound (XIII) is novel and forms part of the invention.
  • the reduction reaction can be carried out by conventional methods.
  • a suitable method of reduction utilizes a complex hydride such as borohydride.
  • borohydride for example lithium borohydride, sodium or potassium borohydride, sodium cyanoborohydride, di-isobutyl aluminium hydride; or a reagent such as aluminium tri-isopropoxide.
  • compounds wherein X is halo may be prepared by reaction with a halogenating agent such as a non-metallic halide for example phosphorus trichloride, phosphorus tribromide, thionyl chloride, thionyl bromide or the halogenating agent may be a hydrocarbonsulphonyl halide generally used in the presence of halide ions, for example an alkanesulphonyl halide such as methanesulphonylchloride or an arylsulphonyl halide such as p-toluenesulphonyl chloride; the source of halide ions may be lithium halide or an amine salt.
  • a halogenating agent such as a non-metallic halide for example phosphorus trichloride, phosphorus tribromide, thionyl chloride, thionyl bromide or the halogenating agent may be a hydrocarbonsulphonyl hal
  • a base is present such as pyridine, and the reaction is preferably performed at a depressed or ambient temperature for example -60oC to +20°C.
  • the compounds of the formula (II) wherein X is iodo are most conveniently prepared by a halogen exchange reaction, reacting the corresponding chloro or bromo compound with a source of iodide ions such as lithium iodide or trimethylphosphi te methiodide.
  • Etherification of -OH or -SH may be effected by the reaction of a diazoalkane in the presence of a Lewis acid catalyst for example boron trifluoride preferably at a depressed or ambient temperature in an inert solvent.
  • Acylation of -OH or -SH may be effected by reaction with an acylating agent e.g. RCY-T or RSO 2 T wherein T is a leaving group displaceable by a nucleophile.
  • T is halo such as chloro or bromo, or a sulphonyloxy moiety, for example C 1-6 alkyl- or aryl- sulphonyloxy such as a mesylate or tosylate, or T is a carboxylate moiety, for example a C 1-6 alkanoyloxy group optionally substituted by 1 to 3 halogen atoms, in particular acetoxy or is an arylcarbonyloxy for example benzoyloxy.
  • halo such as chloro or bromo
  • a sulphonyloxy moiety for example C 1-6 alkyl- or aryl- sulphonyloxy such as a mesylate or tosylate
  • T is a carboxylate moiety, for example a C 1-6 alkanoyloxy group optionally substituted by 1 to 3 halogen atoms, in particular acetoxy or is an arylcarbonyloxy for example benzoyloxy.
  • such reaction is performed in the presence of a base such as an alkali or alkaline earth metal salt, in particular lithium, sodium or potassium carbonates; or an organic base such as amine for example pyridine or a tertiary amine and in particular triethylamine.
  • a base such as an alkali or alkaline earth metal salt, in particular lithium, sodium or potassium carbonates
  • organic base such as amine for example pyridine or a tertiary amine and in particular triethylamine.
  • Suitable solvents include chloroform, dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide and acetone.
  • the acylation reaction is performed at a non-extreme temperature for example at an ambient or slightly depressed temperature, such as -20oC to +20°C.
  • T is a hydroxy group or hydrocarbyloxy for example C 1-6 alkoxy or aryloxy such as phenoxy.
  • T is hydroxy preferably
  • Compounds of the formula (II) wherein X is azido may be prepared by the reaction of an azide with a compound of the formula (II) wherein X is a readily displaceable group such as a halogen atom (chlorine or bromine) or a sulphonyloxy group.
  • the azide is suitably an alkali metal azide such as sodium azide or an organic azide such as tetramethylguanidinuim azide or tetrabutylammonium azide.
  • the reaction is preferably performed in an inert polar organic solvent such as acetonitrile, dimethylsulphoxide, ethyl acetate, dichloromethane, acetone or tetrahydrofuran at a non-extreme temperature.
  • an inert polar organic solvent such as acetonitrile, dimethylsulphoxide, ethyl acetate, dichloromethane, acetone or tetrahydrofuran at a non-extreme temperature.
  • Azide derivatives can also be prepared by the reaction of a compound of formula (II) wherein X is OH with hydrazoic acid in the presence of a compound of formula (XIV) as hereinbefore defined:
  • the reaction is suitably performed in an inert organic solvent such as tetrahydrofuran or benzene, at a non-extreme temperature such as -20°C to +100°C usually at -50°C to 50°C and conveniently at ' ambient temperature.
  • an inert organic solvent such as tetrahydrofuran or benzene
  • Compounds of the formula (II) wherein X is substituted amino may be prepared by the reaction of the corresponding primary amine, for example by alkylation and/or acylation.
  • Primary amines can be produced by reduction of the corresponding nitro compound which is described in European patent publication No. 2319 or by reduction of the corresponding azido compound.
  • acyl and acyloxy amines can be obtained directly from the nitro compound by reaction with an acyl anhydride and zinc in the presence of acetic acid.
  • Alkylation of the primary amine may be effected by reaction with a compound RX' ' wherein X'' is a leaving group to form a secondary amine (-NHR).
  • This secondary amine then may be reacted with another compound RX' ' (which may be the same or different as the first) to form a tertiary amine (-NR 2 ). and subsequently, if desired, a quaternary amine (-NR 3 +) may be prepared, wherein the substituent groups are the same or different.
  • Suitable groups X' ' include halo such as iodo and bromo, or a sulphonate such as a C 1-6 alkyl- or aryl- sulphonate for example methanesulphonate or p-toluenesulphonate.
  • alkylation reactions are conveniently performed in an inert organic solvent such as dimethylformamide, acetonitrile or dichloromethane, preferably in the presence of strong non-nucleophilic organic base at a non-extreme temperature such as -20oC to +50oC, preferably -10°C to +20°C and most conveniently between 0oC and ambient.
  • Suitable organic bases include 1, 5-diazabicyclo [4.3.0]non-5-ene and 1,8-diazabicyclo [5.4.0] undecene .
  • Secondary and tertiary amines also may be prepared by the reaction of a compound of the formula (II) wherein X is a good leaving group, such as tosyloxy with a secondary amine (RNHR o ) to form a tertiary amine.
  • X is a good leaving group, such as tosyloxy
  • RNHR o secondary amine
  • One or both of the groups R and R o may then be removed, for example by hydrogenation to provide a secondary or primary amine.
  • Acylation of the primary amine (-NH 2 ) may be effected by reaction with an acylating agent.
  • Apt acylating agents include any N-acylating compound suitable for the performance of analogous reactions with 6-aminopenicillanic acid or 7-aminocephalosporanic acid or salts or esters thereof , for example an acid halide , an anhydride or mixed anhydride or other reactive derivative, such as that produced by the reaction of an acid with an enzyme or a condensation-promoting agent such as dicyclohexylcarbodi-imide.
  • the acylating agent is of the formula RX' ' where X' ' is a displaceable group, for example halo, sulphonate, carboxylate.
  • the acylating agent also may be a ketene or isocyanate or isothiocyanate or an activated imide.
  • a base for example an inorganic base such as an alkali or alkaline earth metal salt, in particular lithium, sodium or potassium carbonates; or an organic base such as an amine for example triethylamine.
  • the reaction is performed in an aprotic organic solvent such as dimethylformamide, acetonitrile, ethyl acetate, dimethyl sulphoxide; water may be added to aid solubility if necessary.
  • the reaction is suitably performed at a non-extreme temperature, for example between -20oC and 40oC and preferably at ambient temperature.
  • Acylation may be effected on the primary amine (-NH 2 ) once or twice to form the mono-acyl or di-acyl derivatives, in the di-acyl case the acyl groups may be the same or different.
  • acylation may be effected on a secondary amine (-NHR) to form the N-alkyl-N-acyl derivative.
  • Di-acyl derivatives wherein the two acyl groups are joined so as to form a heterocyclic ring are most conveniently prepared by the reaction of a compound of the formula (II) wherein X is OH with a compound of the formula: HNR A R B wherein R A and R B form the heterocyclylic ring system in the presence of an azodicarboxylate compound of the formula (XIV) and (XV) as hereinbefore defined.
  • the reaction is suitably performed in an inert organic solvent such as tetrahydrofuran and benzene, at a non-extreme temperature such as -20°C to +100°C, usually at -50°C to 50°C and conveniently, at ambient temperature.
  • Bis-acyl derivatives can be prepared under similar reaction conditions by the reaction of a compound of formula (II) wherein X is OH with an O-acyl hydroxamic acid derivative of formula R c CO.NH.O.CO R d wherein R c and R d are each independently C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkyl acyl or aryl, in the presence of a compound of formula (XIV) and (XV) as hereinbefore defined.
  • the foregoing reaction may also be used to prepare di-acyl derivatives wherein the two acyl groups are not joined. If one of the two acyl groups are removable for example hydrogenolysable then a mono-acyl derivative may be formed.
  • Such compounds include phenol, phenol substituted by one, two or three atoms or groups selected from hydroxy, halo, C 1-6 alkoxy, C 1-6 alkyl or C 3-8 cycloalkyl; furan optionally substituted by C 1-6 alkyl, thiophene optionally substituted by C 1-6 alkyl, pyrrole optionally substituted by C 1-6 alkyl, or any of the aforementioned ring systems fused to an optionally substituted benzene ring.
  • a catalyst is employed which is one known to catalyst reactions known as Friedel-Crafts reactions.
  • Suitable catalysts include aluminium trichloride, zinc chloride, zinc bromide, antimony pentachloride, ferric chloride, stannic chloride, boron trifluoride etherate and chemical equivalents thereof. Of these boron trifluoride etherate is preferred.
  • the reaction is generally performed in the presence of an inert organic solvent, preferably a non-polar solvent such as a halogenated hydrocarbon for example chloroform, carbon tetrachloride or dichloromethane. Suitable the reaction is performed at a depressed or moderate temperature, i.e. between +50oC and -70°C, preferably between 0oC and -30oC. Preferably the reaction is performed under an inert atmosphere.
  • Compounds of the formula (II) wherein X is the residue of a carbon nucleophile may be prepared from compounds of the formula (II) wherein X is a displaceable group by reaction with a carbon nucleophile.
  • the displaceable group may be halo such as chloro, bromo or iodo or aryl- or C 1-6 alkyl- sulphonyloxy for example p-toluenesulphonyloxy or methanesulphonyloxy.
  • Reaction is suitably performed in an aprotic organic solvent at a depressed or ambient temperature for example -70°C to +25oC, preferably at -20oC to 0oC.
  • Suitable solvents include tetrahydrofuran, dimethylformamide or dimethyl- sulphoxide.
  • the carbon nucleophile may be a compound R-H in which case a base is present, or the carbon nucleophile may be presented as a salt.
  • the cation in such a salt is suitably a metal ion or an ammonium ion, for example sodium, potassium, thallium or a tetra- C 1-6 -alkyl ammonium cation.
  • Suitable salts include both pharmaceutically acceptable and non-pharmaceutically acceptable salts, for example inorganic salts such as metal salts (silver and mercuric), or alkali metal salts (sodium and lithium) and tertiary amine salts.
  • inorganic salts such as metal salts (silver and mercuric), or alkali metal salts (sodium and lithium) and tertiary amine salts.
  • the present invention also provides a pharmaceutical composition which comprises a compound of this invention and a pharmaceutically acceptable carrier.
  • compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of the infection in animals especially mammals including humans.
  • compositions of this invention include tablets, capsules, creams, syrups, suspensions, solutions, reconstitutable powders and sterile forms suitable for injection or infusion.
  • Such compositions may contain conventional pharmaceutically acceptable materials such as diluents, binders, colours, flavours, preservatives, disintegrant and the like in accordance with conventional pharmaceutical practice in the manner well understood by those skilled in the art of formulating antibiotics.
  • the injectable solution of the compound of this invention may be made up in a sterile pyrogen-free liquid such as water, aqueous ethanol or the like.
  • An alternative approach to administering the compounds of this invention is to utilise an injectable suspension.
  • Such suspensions may be made up in sterile water; sterile saline or the like and may also contain suspending agents such as polyvinylpyrrolidone, lecithin or the like.
  • suspending agents such as polyvinylpyrrolidone, lecithin or the like.
  • the zwitterionic compounds of this invention should be in the form of fine particles.
  • compositions of a compound of the invention are particularly suitable as high blood levels of the compound can occur after administration by injection or infusion.
  • one preferred composition aspect of this invention comprises a compound of the invention in sterile form and most suitably in sterile crystalline form.
  • Such compostions may be prepared in an acceptable oil suspending agent such as arachis oil or its equivalent.
  • an acceptable oil suspending agent such as arachis oil or its equivalent.
  • the compounds of this invention should be in the form of fine particles.
  • Unit dose compositions comprising a compound of this invention adapted for oral administration form a further suitable composition aspect of this invention.
  • Unit dose compositions comprising a compound of this invention adapted for topical administration are also presented by this invention.
  • the compound of the formula may be present in the composition as sole therapeutic agent or it may be present together with other therapeutic agents such as, for example, a penicillin or cephalosporin.
  • a penicillin or cephalosporin which shows instability to ⁇ -lactamases since the resulting composition shows enhanced effectiveness (synergy).
  • Suitable penicillins, cephalosporins or other ⁇ -lactam antibiotics for inclusion in such synergistic compositions include not only those known to be highly susceptible to ⁇ -lactamases but also those which have a degree of intrinsic resistance to ⁇ -lactamases.
  • Suitable penicillins for inclusion in the compositions of this invention include benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin, pirbenicillin, azlocillin, mezlocillin, sulbenicillin, pipericillin, and other well known penicillins including pro-drugs thereof such as their in vivo hydrolysable esters such as the acetoxymethyl, pivaloyloxymethyl, ⁇ -ethoxycarbonyloxyethyl or phthalidyl esters of ampicillin benzylpenicillin or amoxycillin, and aldehyde or ketone adducts of penicillins containing a 6- ⁇ -aminoacetamide side chain (such as hetacillin, metampicillin and analogous derivatives of amoxycillin) or ⁇ -esters of carbenicillin or ticarcillin such as
  • Suitable cephalosporins for inclusion in the compositions of this invention include, for example, cefatrizine, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephapirin, cephamandole nafate, cephradine, 4-hydroxycephalexin, cefaparole, cephaloglycin, cefoperazone, and other well known cephalosporins or pro-drugs thereof.
  • Such compounds are frequently used in the form of a salt of hydrate or the like.
  • the composition will be adapted for parenteral administration.
  • Such penicillins may be used as a pharmaceutically acceptable salt such as the sodium salt.
  • the ampicillin or amoxycillin may be used in the form of fine particles of the zwitterionic form (generally as ampicillin trihydrate or amoxycillin trihydrate) for use in an injectable suspension, for example, in the manner hereinbefore described for a compound of this invention.
  • the preferred penicillin for use in the synergistic composition is amoxycillin, for example as its sodium salt or trihydrate.
  • a cephalosporin or penicillin When present together with a cephalosporin or penicillin, the ratio of a compound of the invention to the penicillin or cephalosporin agent may vary over a wide range of ratios, such as from 10:1 to 1:10, for example about 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5 or 1:6 (wt/wt, based on pure free antibiotic equivalent).
  • the total quantity of a compound of the invention in any unit dosage form will normally be between 25 and 1000 mg and will usually be between 50 and 500 mg, for example about 62.5, 100, 125, 150, 200 or 250 mg.
  • compositions of this invention may be used for the treatment of infections of inter alia, the respiratory tract, the urinary tract and soft tissues in humans.
  • the penicillins or cephalosporin in the synergistic composition of this invention will normally be present at approximately the amount at which it is conventionally used which will usually be expected to be from about 62.5 to 3000 mg per dose, more usually about 125, 250, 500 or 1000 mg per dose.
  • One particularly favoured composition of this invention will contain from 150 to 1000 mg of amoxycillin as the trihydrate or sodium salt and from 25 to 500 mg of a compound of this invention.
  • composition of this invention will contain from 150 to 1000 mg of ampicillin or a pro-drug thereof and from 25 to 500 mg of a compound of this invention.
  • this form of composition will contain ampicillin trihydrate, ampicillin anhydrate, sodium ampicillin, hetacillin, pivampicillin, hydrochloride, bacampicillin hydrochloride or talampicillin hydrochloride. Most suitably this form of the composition will contain a zwitterionic compound of the formula (II) when in crystalline form.
  • the preceding composition will contain from 200 to 700 mg of the penicillin component. Most suitably the preceding composition will comprise from 50 to 250 mg of a zwitterionic compound of the formula (II) preferably in crystalline form.
  • compositions may be adapted for oral or parenteral use except when containing an in vivo hydrolysable ester of ampicillin or amoxycillin in which case the compositions will not be adapted for parenteral administration.
  • compositions of this invention will contain from 200 to 2000 mg of carbenicillin, ticarcillin or a pro-drug thereof and from 50 to 500 mg of a compound of this invention.
  • this form of composition will contain di-sodium carbenicillin.
  • this form of the composition will contain di-sodium ticarcillin.
  • this form of the composition will contain from 75 to 250 mg of a zwitterionic compound of the formula (II) preferably in crystalline form.
  • Such compositions containing di-salts of carbenicillin and ticarcillin will be adapted for parenteral administration.
  • the present invention also provides a method of treating bacterial infections in animals, in particular humans or domestic mammals, which comprises the administration of a composition of this invention
  • the infection treated will be due to a strain of Staphylococcus aureus, Klebsiella aerogenes, Escherichia coli , Proteus sp. , Bacteroides fragilis or the like.
  • the organisms believed to be most readily treated by an antibacterially effective amount of a compound of this invention is Staphylococcus aureus.
  • the other organisms named are more readily treated by using a synergistically effective amount of the compound of this invention and a penicillin or cephalosporin.
  • the administration of the two components may take place separately but in general we prefer to use a composition containing both the synergist and the penicillin or cephalosporin.
  • the indications for treatment include respiratory tract and urinary tract infections in humans.
  • Preparation 1a The indications for treatment include respiratory tract and urinary tract infections in humans.
  • Benzyl 2-(tetrazol-2-yl)-2-vinyl clavam-3-carboxylate (4.7 g) in ethyl acetate (about 100 ml) was cooled to -65oC and the solution saturated with ozone (pale blue colour).
  • Triphenylphosphine (3.5 g) was added and the mixture allowed to warm to -10oC.
  • Formylmethylene-triphenylphosphorane (8 g) was slurried with N,N-dimethylformamide (3 x 50 ml portions) , allowing to settle partially each time and then adding the supernatant (and some solid) to the ozonolysis product, the remaining insoluble solid was also added.
  • the mixture was allowed to stir at -10°C to 0°C for 2.5 hours.
  • the insoluble material was filtered off and washed with toluene (1.5 g recovered) .
  • the filtrate was diluted with toluene (30. ml) and poured into water (200 ml) , slightly acidified (pH 5) and separated.
  • the aqueous phase was washed with three further portions of toluene-ethyl acetate (70 ml, 2:5) ; the combined solvent layers were then washed with water (50 ml) and dried over Na 2 SO 4 .
  • the tic then showed three KMnO 4 positive zones and triphenyl phosphine oxide. The fastest running zone was triphenyl phosphine.
  • the solvent phase was collected and evaporated under reduced pressure to an oil, which was subjected to chromatography on silica gel using ethyl acetate-hexane (1:1) . A partial separation was obtained. The fractions containing, the. desired product were combined, evaporated and rechromatographed on silica gel using a reverse gradient: 3:2 ethyl acetate-hexane, graded to 1:1 ratio. The first eluted component was the double-bond E isomer, followed by the title compound (100 mg) with the Z-configuration which had spectral characteristics identical to the material prepared by reduction of the aldehyde of example 3 hereinafter.
  • silyl ether (0.1 g) from Preparation 2d in redistilled tetrahydrofuran (15 ml) containing saturated sodium bicarbonate solution (0.25 ml) and 10% pallatised charcoal (25 mg) was hydrogenated at ambient temperature and pressure until tic showed the virtual absence of starting material.
  • the reaction was filtered through a bed of silica to remove catalyst, and the filtrate diluted with water, adjusted to pH 3 by the addition of "Amberlite" IR 120 (H form) resin. After a few minutes the resin was removed by filtration and the filtrate adjusted to pH 7 with lithium hydroxide.
  • n-pentane 60 ml was added to the reaction. After a further 30 minutes stirring was halted and when a bilayer had formed the n-pentane layer was decanted and evaporated to an oil. This oil was extracted with n-pentane (50 ml) which was filtered through magnesium sulphate and evaporated to give an oil.
  • Benzyl Z-2-(3-oxopropylidene)clavam-3-carboxylate (0.2, 0.665 mmol) was dissolved in dry dimethoxyethane (10 ml) and placed under a slow stream of dry nitrogen before being cooled to -20°C.
  • Sodium borohydride (0.011 g, 0.29 mmol) was added portionwise and after 5 mins. the reaction was diluted with ethyl acetate and washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and brine (2 x) before being dried (MgSO 4 ) and evaporated to an oil, 0.1833 g.
  • Benzyl E-2-(4-oxobutylidene)clavam-3-carboxylate (3.13 g, 9.94 mmol) was dissolved in dry redistilled tetrahydrofuran (30 ml) ; placed under a slow stream of dry nitrogen and cooled to -20°C.
  • Triethylamine (1.52 ml, 10.9 mmol) and trimethylsilyl trifluoromethanesulphonate (1.98 ml, 10.9 mmol) were then added dropwise simultaneously, with vigorous stirring. After 20 minutes n-pentane (50 ml) was added and after a further 30 minutes stirring was halted.
  • n-pentane was decanted, the residue was extracted again with n-pentane (30 ml) at room temperature. The n-pentane extractions were combined and evaporated to a colourless oil which was further extracted with n-pentane (25 ml) . Evaporation of the n-pentane afforded the title ester as a chromatographically labile colourless oil of high purity (>90%) in 32.5% yield as a mixture of enolether olef inic isomers . v max . ( f ilm) , 1 807 ,
  • the title ester may be resolved into pairs of isomers by silica gel cromatography (toluene/ethyl acetate 7:1 as eluent) but with concomitant reduction in yield due to its relative instability towards silica-gel.
  • v max. (film) 3500, 1804, 1748, 1730 and sh 1700 cm -1 .
  • N.M.R. silica gel cromatography
  • Benzyl E-2-(3-hydroxy-4-m-chlorobenzoyloxy-4-trimethylsilyloxybutylidene)clavam-3-carboxylate (1.65 g, 2.95 mmol) was dissolved in dry dimethoxyethane (15 ml) and placed under a stream of dry nitrogen. The reaction was cooled to -20°C and tetraethylamonium fluoride dihydrate (0.593 g, 3.2 mmol) was added portionwise. After 10 mins sodium borohydride (0.041 g, 1 mmol) was added.
  • Lithium Z-2-(3-N-methylcarbatmoyloxypropylidene) clavam-3- carboxylate Lithium Z-2-(3-N-methylcarbatmoyloxypropylidene) clavam-3- carboxylate.
  • the residual solid was crystallised from aqueous acetone to give a 3:1 mixture of lithium Z-2-(3-N-raethylcarbamoyloxypropylidene)clavam-3-carboxylate and E-2-(3-N-methylcarbamoyloxypropylidene)clavam-3-carboxylate as a solid in 68% yield.
  • Benzyl E-2-(3-N-methylcarbamoyloxypropylidene)clavam-3-carboxylate (219 mg; 0.61mmol) was dissolved in dry redistilled tetrahydrofuran (30ml) and hydrogenolysed over 10% palladium on carbon (110mg) for 25 minutes. The catalyst was filtered off and the filtrate was diluted with water (25ml) and the solution neutralised with 1M lithium hydroxide.
  • the reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution and with brine.
  • the solution was dried (MgSO 4 ) and evaporated to a syrup which was chromatographed on silica gel using n-hexane/ethylacetate (2:1) as eluent.
  • the first eluted material was the title ester 73.3mg, 69% yield based on consumed substrate.
  • the second eluted material was the alcohol substrate, 51.8mg.
  • Benzyl 2-(3-hydroxypropylidene)clavam-3-carboxylate (0.13 g; 0.429 mmol) was hydrogenated at room temperature in tetrahydrofuran (7 ml) over 10% palladium on barium sulphate (0.04 g) for 12 min. after which thin layer chromatography showed that all of the starting material had been consumed.
  • the catalyst was filtered off and washed with tetrahydrofuran. An equal volume of water was added to the combined filtrates and the pH adjusted to 7.2 with potassium hydroxide.
  • the less polar isomer from Preparation 16a (4.5 g) was dissolved in ethyl acetate (100 ml), cooled to -65°C and saturated with ozone. Argon was passed through the solution whilst it warmed to -30°C. A solution of triphenylphosphine (2.5 g) in ethyl acetate (15 ml) was added and the mixture allowed to warm to between -20° and 0°C. (T.l.c. was used to monitor the decomposition of oxidants, using a starch-iodide spray to visualize the zones). After about 40 mins .
  • Benzyl 2-acetoxy-2-vinylclavam-3-carboxylate 14 g (more polar isomer) was dissolved in ethyl acetate (250 ml) and saturated with ozone at -65°C.
  • a solution of triphenylphosphine 8 g in ethyl acetate (20 ml) was added and the mixture allowed to warm to -30°C (monitored by t.l.c). After a short time ( ⁇ 1/2 hr) , a solution + suspension of formylmethylenetriphenylphosphorane (25 g) in warm N,N-dimethyl ⁇ formamide (150 ml) wasi added in two portions.
  • the mixture was maintained at between -30° and -5°C for about 1.5 hr, when the reaction appeared to be substantially complete (by t.l.c).
  • the unreacted phosphorane was removed by filtration, the filtrate diluted with toluene (200 ml) and ice-water to a total of about 1 litre.
  • the mixture was agitated gently and then separated.
  • the aqueous phase was washed with toluene, the solvent layers combined, washed with water, dried over Na 2 SO 4 , evaporated and subjected to chromatography on silica gel using ethyl acetatehexane (2:3) as eluent.
  • the aldehyde of Preparation 16e (6 g) was dissolved in 1,2-dimethoxyethane (100 ml) and dry tetrahydrofuran (50 ml). Sodium borohydride (free from lumps, 0.16 g) was added; after 1/2 hr t.l.c showed some unreacted aldehyde so a further 0.12 g of NaBH. was added. T.l.c. then showed the absence of starting material, so the solution was diluted with an equal volume of water and of toluene, titrated to pH 5 with 1M HCl solution (frothing) and then separated.
  • Benzyl 2-(3-hydroxypropylidene)clavam-3-carboxylate (mixture of E and Z isomers, mainly Z) (200 mg) in dry tetrahydrofuran (12 ml) containing triphenylphosphine (200 mg) and succinimide (200 mg) was stirred and cooled to 0°C. Diethyl azodicarboxylate (0.2 ml) was added and the mixture was allowed to warm to ambient temperature during 1/2 hr. It was found by t.l.c. that the reaction was incomplete, so 200 mg portions of phosphine, azodicarboxylate and succinimide were added and the reaction mixture stirred overnight at ambient temperature.
  • Example 17a The product of Example 17a (25 mg) in redistilled tetrahydrofuran (5 ml) was hydrogenated over 10% palladised charcoal (12 mg) at ambient temperature and pressure; about 2 cm 3 of hydrogen was absorbed.
  • the catalyst was removed by filtration, the filtrate diluted with water, titrated to pH .6.8 with dilute lithium hydroxide solution and evaporated to dryness under reduced pressure. After desiccation in vacuo , the residue was triturated with acetone, filtered off, washed with a little acetone and dried in vacuo , to yield a white solid (10 mg) . P.m.r.
  • Benzyl 2-vinyl-2-acetoxyclavam-3-carboxylate (less polar isomer) (4.65 g) in ethyl acetate (100 ml) was cooled to -65°C with stirring and saturated with ozone.
  • the mixture was flushed with argon while the temperature was allowed to rise to -30°C, then triphenylphosphine (3.66 g) was added.
  • the mixture was stirred at 0 to -20°C during 1 hr, then a suspension of acetylmethylene triphenylphosphorane (8.1 g) in N,N-dimethylfor-mamide (30 ml) was added.
  • reaction mixture was diluted with toluene, washed with water, dried over MgSO 4 and evaporated to an oil.
  • Excess benzyl bromide was extracted from the residue with hexane and the insoluble gum chromatographed on silica gel using 2:2:1 cyclohexane-hexane-ethyl acetate, fractions containing the desired product were combined and evaporated to yield 450 mg.
  • the benzyl ester of Example 18 (340 mg) was dissolved in methyl isocyanate (5 ml) and stirred at ambient temperature for 7 days. The excess reagent was evaporated by passing dry air through, and then the residue was dried in vacua . The product was chromatographed on silica gel using 2:2:1 hexanecyclohexane-ethyl acetate to give the product as an oil (395 mg) .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP84900634A 1983-02-23 1984-02-08 Clavam-derivate Withdrawn EP0137794A1 (de)

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GB838304954A GB8304954D0 (en) 1983-02-23 1983-02-23 Antibacterial agents
GB838324961A GB8324961D0 (en) 1983-09-17 1983-09-17 Chemical intermediates
GB8324961 1983-09-17
GB8304954 1983-09-17

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GB1546569A (en) * 1975-07-29 1979-05-23 Beecham Group Ltd 1-oxa-1-dethiapenicillins methods for their preparation and compositions containing them
GB1593275A (en) * 1976-10-22 1981-07-15 Glaxo Lab Ltd Clavam derivatives
EP0002319B1 (de) * 1977-11-29 1981-11-18 Beecham Group Plc Clavulansäurederivate, Verfahren zu ihrer Herstellung und diese enthaltende Zusammensetzungen
GB2045236A (en) * 1979-03-26 1980-10-29 Hoechst Uk Ltd Oxapenem derivatives
EP0080286A1 (de) * 1981-11-25 1983-06-01 Beecham Group Plc Beta-Lactame enthaltende antibakterielle Verbindungen, Verfahren zu ihrer Herstellung und ihre Verwendung
EP0080285A1 (de) * 1981-11-25 1983-06-01 Beecham Group Plc Beta-Lactame enthaltende therapeutische Verbindungen

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