EP0135521A1 - Clavam derivatives - Google Patents

Clavam derivatives

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Publication number
EP0135521A1
EP0135521A1 EP19840900628 EP84900628A EP0135521A1 EP 0135521 A1 EP0135521 A1 EP 0135521A1 EP 19840900628 EP19840900628 EP 19840900628 EP 84900628 A EP84900628 A EP 84900628A EP 0135521 A1 EP0135521 A1 EP 0135521A1
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EP
European Patent Office
Prior art keywords
formula
compound
group
salt
ester
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.)
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Application number
EP19840900628
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German (de)
French (fr)
Inventor
John Barry Harbridge
Gerald Brooks
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Beecham Group PLC
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Beecham Group PLC
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Publication of EP0135521A1 publication Critical patent/EP0135521A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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

Abstract

Composé de formule (I), son sel ou son ester où X est un groupe facultativement 1,2,4 triazolyl substitué fixé par l'un de ces atomes d'azote. Procédés de production de ces composés et compositions les contenant.Compound of formula (I), its salt or its ester where X is an optionally 1,2,4 substituted triazolyl group attached by one of these nitrogen atoms. Processes for producing these compounds and compositions containing them.

Description

CLAVAM DERIVATIVES
This invention relates to novel β-lactam containing compounds, their preparation and their use, and in particular to a novel class of clavams. These compounds have antibacterial and β-lactamase inhibitory properties, and therefore are of use in the treatment of bacterial infections in humans and animals either alone or in a synergistic composition with other β-lactam antibacterial agents, such as penicillins and cephalosporins.
UK Patent Publication No. 2 006 769 A discloses a compound with antibiotic activity having the formula
where R is a carboxyl or esterified carboxyl group and Rx and Ry are each independently hydrogen, substituted or unsubstituted alkyl, aralkyl, aryl, cyano, formyl, nitro, carboxyl, esterified carboxyl, etherified thiol or a sulphone derivative thereof, acyl, etherified hydroxyl, carbamoyl, substituted carbamoyl, sulphamoyl, substituted sulphamoyl, hydrazinocarbonyl or protected hydrazinocarbonyl group and carboxyl salts thereof. According to the present invention there is provided a compound of formula I
or a salt or ester thereof wherein X is an optionally substituted 1,2,4 triazolyl group, attached via a nitrogen atom thereof.
The group X may be a group (A) or (B):
Wherein R1 and R2 are each independently hydrogen, an optionally substituted hydrocarbon group or a functional group.
The term '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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Cl-6)-alkyl, aryl, and aryl(C1-6) alkyl. When R1 and R2 is hydrocarbon, suitable optional substituents include C1-6 alkyl, heterocyclic, amino, C1-6 alkanoylamino, mono, di- and tri- (C1-6) alkylamino, hydroxy, C1-6 alkoxy, C1-6 alkoxy carbonyl, mercapto, C1-6 alkylthio, heterocyclyl-thio, arylthio, carbamoyl, amidino, quanidino, nitro, chloro, bromo, fluoro, halo-(C1-6)-alkyl, carboxy and salts and esters thereof, C1-6 alkanoyloxy, aryl, aryl-carbonyl, heterocyclylcarbonyl, oxo, C1-6 alkoxycarbonyl-(C1-6) -alkyl, C1-6 alkylcarbonyloxy, and C1-6 alkylcarbonyl groups.
Suitable functional groups include halo, cyano, formyl, nitro, carboxyl, esterified carboxyl, etherified thiol or a sulphone derivative thereof, acyl, acylamino, etherified hydroxyl, carbamoyl or substituted carbamoyl.
When R1 and/or R2 are esterified carboxyl, acyl, amide, etherified hydroxy, etherified thiol or a sulphone derivative thereof, they may be represented by the formulae -COOR3, -COR3, -NH COR3, -OR3, -SR3 and SO2R3 respectively where R3 is a substituted or unsubstituted alkyl, aralkyl, aryl or heterocyclic group.
When R1 and R2 are carbamoyl or substituted carbamoyl, they may be represented by the formulae -CONR4R5, where R4 and R5 are each independently hydrogen, a substituted or unsubstituted alkyl, aralkyl or aryl group or R4 and R5 in combination with the nitrogen atom to which they are attached form a 5 - 7 member heterocyclic ring which is optionally substituted.
Suitable optional substituents for the groups R3, R4 and R5 include those listed above for R1 and R2 when these are hydrocarbon. Preferably R1 and R2 are both hydrogen.
As used, herein, the term 'alkyl' includes straight or branched chain alkyl groups containing, for example, up to 12 carbon atoms, suitably from 1 to 6 carbon atoms. In particular the group may be substituted methyl, ethyl, n-, or iso-propyl, or n-, sec-, iso- or tert-butyl.
As used, herein, the term 'heterocyclic' includes single or fused rings comprising up to four hetero atoms in the ring selected from oxygen, nitrogen and sulphur.
When used herein the 'aryl' includes phenyl and naphthyl.
As used herein the term 'aralkyl' includes groups having up to six carbon atoms in the alkyl portion and is desirably carbocyclic and more preferably monocyclic e.g. benzyl.
Suitably the compounds are of formula II
or a salt or ester thereof;
wherein R6 is hydrogen or an optionally substituted hydrocarbon group as hereinbefore defined in relation to R1 and R2. Suitably R6 is an unsubstituted hydrocarbon group such as C1-6 alkyl or aryl.
Preferably R6 is methyl.
Since compounds of formulae I or II are pharmaceutically active the salts and esters thereof are suitably pharmaceutically acceptable.
Suitable pharmaceutically acceptable salts of the compounds of formulae I or II include metal salts, e.g. aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, ethylenediamine, or bases of the pyridine type such as pyridine, collidine or quinoline.
Suitable esters of the compounds of the formula (I) or (II) 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.
Suitably the carboxylic acid is esterified by a group of the sub-formula (a), (b), (c), (d), (e) or (f):
wherein A1 is a hydrogen atom, C1-6 alkanoyl or an C1-5 alkyl group optionally substituted by C1-7 alkoxy or C1-7 carboxylic acyloxy, or an alkenyl or alkynyl group of up to 5 carbon atoms; A2 is a hydrogen atom or a methyl group; A3 is a phenyl group or a phenyl group substituted by a fluorine, chlorine or bromine atom or a nitro, C1-8 alkyl or C1-3 alkoxy group; A4 is a hydrogen atom or a phenyl group or phenyl group substituted by a fluorine, chlorine or bromine atom or a nitro, C1-3 alkyl or C1-3 alkoxy group; A5 is a hydrogen atom or a methyl group; A6 is a C1-4 alkyl, phenyl or C1-4 alkoxy group or A5 is joined to A6 to form a phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl group; A7 is a C1-4 alkyl, phenyl, chlorophenyl or nitrophenyl group; A8 is a C1-4 alkyl or phenyl group; A9 is a C1-4 alkyl or phenyl group; A10 is C1-4 alkyl;. and A11 is C1-4 alkyl: or CHA1A2 is a phenacyl or bromophenacyl group.
Favourably A1 is a hydrogen atom or a methyl, ethyl, or ethenyl group. Favourably A2 is a hydrogen atom. Favourably A3 is a phenyl, p-bromophenyl, p-methoxyphenyl or p-nitrophenyl group. Favourably A4 is a hydrogen atom. Favourably A6 is a methyl, t-butyl or ethoxy group or is joined to A5. Favourably A7 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, α-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-butyidimethylsilyl, tertbutyldiphenylsilyl groups and tri-isopropylsilyl.
A preferred group of the sub-formula (f) is p-methoxycarbonylbenzyl. Particularly preferred esterifying groups are benzyl, 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 (I) or (II) or salt thereof;
Suitable esters of this type include those of sub-formula (c) as hereinbefore defined.
Further suitable esters include di(C1-6) alkylamino C1-6 alkyl esters such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl and diethylaminoethyl.
The present invention also provides a process for producing a compound of formula I or a salt or ester thereof; which process comprises reacting a compound of formula III
where R8 is a carboxy protecting group, with
i) a compound of formula IV
where one of Ra or Rb represents a group R1 the other represents a group R2, wherein R1 and R2 are as defined with respect to formula I;
ii) a compound of formula V
R9OCON=NCOOR10 (V)
where R9 and R10 are each independently C1-6 alkyl, aryl or aryl (C1-6) alkyl; and
iii) a compound of formula VI
l, m and n are each independently 0 or 1 and R11, R12 and R13 are each independently C1-6 alkyl, aryl or aryl (C1-6) alkyl;
and thereafter where necessary carry out one or more of the following steps:
i) removing the carboxy-protecting group R8, ii) converting one group R1 or R2 to a different such group; and/or
iii) converting a salt to the free carboxylic acid of formula (I) or to an ester, or to a different salt.
If desired, isomers of formula I where X is of sub-formula (A) or (B) can be separated subsequently by conventional methods.
Suitable compounds of formula V include those wherein R9 and R10 are each independently methyl, ethyl, propyl, butyl, phenyl or benzyl. It is generally convenient that R9 and R10 represent the same moiety. Particularly suitable compounds of the formula V include those wherein R9 and R10 each represent ethyl, t-butyl or isopropyl.
Suitable compounds of formula VI include those where R11, R12 and R13 are each independently methyl, ethyl, n-propyl, n-butyl, benzyl, phenyl or methoxyphenyl. It is generally convenient that R11, R12 and R13 each represent the same moiety. Favoured compounds of formula VI include tri-arylphosphines and tri-alkylphosphites. Particularly suitable compounds of formula VI include triphenylphosphine and tri-pmethoxyphenylphosphine, but especially triphenyl-phosphine.
Suitable carboxy-protecting groups for the group -CO2R8 in formula (III) 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 under conventional conditions. Such groups for R8 include benzyl, p-methoxybenzγl, 2,4,6-trimethylbenzyl, 3,5-di-t-butylbenzyl, 4-pyridylmethyl, allyl, diphenylmethyl, triphenylmethyl, 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 R8 group; for example, by base-catalysed hydrolysis, by enzymically-catalysed hydrolysis or by hydrogenation.
Acidic or significantly basic groups present in the compound of formula IV are preferably protected prior to the reaction. Such groups include carboxyl when R1 and/or R2 and consequently Ra and/or Rb is carboxyl, and hydroxy, carboxyl and mercapto where R1 and/or R2 and consequently Ra and/or Rb includes one or more of these groups as a substituent.
Suitable carboxyl protecting groups are those described above for R8. These groups can be removed by similar methods to those described for R8.
Hydroxy or mercapto substituents are preferably protected by a group which can subsequently be easily removed by conventional methods in step (i). Such groups include ester groups, preferably hydrogenolysable ester groups, in particular benzyloxycarbonyl or p-nitrobenzyloxycarbonyl groups. The reaction between the compounds of formulae III - VI normally takes place in a solvent inert under the reaction conditions such as toluene, dichloromethane, tetrahydrofuran or dioxane.
The reaction is generally carried out at a depressed or non-elevated temperature, for example -80° to +30°C, and preferably at a depressed temperature, for example -40º to 0ºC, and conveniently at about -10ºC.
Preferably, the compounds of formulae (V) and (VI) are not mixed together with the compound of formula (III) in the absence of nucleophile. More preferably, the compound of formula (V) is added rapidly to the reaction mixture as the last ingredient.
Further according to the present invention there is provided a process for preparing a compound of formula
(II) or a salt or ester thereof, which process comprises reacting a compound of formula VII
wherein R6 is as defined in relation to formula II; R8 is as defined in relation to formula (III) and Y is a halogen atom; with a compound of formula (VIII)
H2NNHCHO (VIII)
in the presence of a strong non-nucleophilic base, and thereafter where necessary carrying out one or more of the following steps: i) removing the carboxy-protecting group R8,
ii) converting one group R6 to a different such group; and/or
iii) converting a salt to a free carboxylic acid of formula (II) or to an ester, or to a different salt.
The reaction is suitably performed in an inert organic solvent such as dichloromethane, dichloroethane or chloroform.
The reaction may be carried out at a non-extreme temperature such as from -20°C to +40°C, preferably from -10°C to ambient temperature and most preferably at about 0ºC.
Suitable non-nucleophilic strong bases for use in the reaction include tetramethylguanidine,
1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), and
1, 5-diazabicyclo [5.4.0]undec-5-ene (DBU).
Preferably Y is a chlorine atom.
Compounds of formula VII can be prepared by reacting a compound of formula IX
wherein R6 as defined in relation to formula II and R8 is as defined in relation to formula III, with a chlorinating agent in the presence of a base.
Suitable chlorinating agents include phosphorus pentachloride, thionyl chloride, phosgene and phosphorus oxychloride.
Suitable bases include pyridine.
The reaction is suitably carried out in an inert chlorinated organic solvent such as dichloromethane, dichloroethane or chloroform.
The reaction may be carried out at a non-extreme temperature such as from -20°C to +40°C preferably from -10°C to ambient temperatures and most preferably at about 0°C.
When R6 is hydrocarbon substituted with a group which is unstable to chlorination, such as hydroxy, mercapto or amino, this group is preferably protected prior to the chlorination reaction. The protecting groups can be removed subsequently. Suitable protecting groups are conventional groups such as benzyloxycarbonyl.
Preferably the compound of formula VII is prepared and converted in situ to the compound of formula II.
Compounds of formula IX can be prepared by methods described in Belgian Patent No. 860042 and UK Patent No. 1,603,208 (equivalent to Belgian Patent No. 866,496 and US Patent No. 4,258,050).
The present invention provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof in combination with a pharmaceutically acceptable carrier. The 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 mammals including humans.
Tablets and capsules for administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone: fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine, tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulsoe, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monoleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents. For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parental suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compound of formula I may be the sole therapeutic agent in the composition or it may be employed in a synergistic combination with a penicillin or cephalosporin.
Suitable penicillins for inclusion in the compoisitions of this invention incoude benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin, azlocillin, mezlocillin, sulbenicillin, piperacillin, and other well known penicillins including pro-drugs thereof such as their in vivo hydrolysable esters thereof such as the acetoxymethyl, pivaloyloxymethyl, α-ethoxycarbonyloxyethyl or phthalidyl esters of ampicillin, benzylpenicillin or amόxycillin, and aldehyde or ketone adducts of penicillins containing a 6-αaminocetamide side chain (such as hetacillin, metampicillin and analogous derivatives of amoxycillin) or α-esters of carbenicillin or ticarcillin such as their phenyl or indanyl α-esters.
Suitable cephalosporins for inclusion in the compositions of this invention include, for example, cefatrizine, cephaloridine, cephalothin, cefazolin, cephalexin, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephapirin, cephamandole nafate, cephradine, 4-hydroxycephalexin, cefaparole, cephaloglycin, cefoperazone, and other well known cephalosporins or pro-drugs thereof.
Naturally if the penicillin or cephalosporin present in the composition is not suitable for oral administration then the composition will be adapted for parenteral administration.
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. Normally for adult (70kg) human treatment between 50 and 3000 mg of the compounds of the invention will be administered each day of treatment. This corresponds to a dosage of 0.7 to 50 mg/kg per day. More usually between 100 and 1000 mg of the compounds of the invention will be administered per day, for example at 1-6 doses, more usually as 2, 3 or 4 doses. However for the treatment of more severe systemic infections or infections of particularly intransigent organisms higher doses may be used in accordance with clinical practice.
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.
A further particularly favoured 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.
Thus the present invention also provides a method of treating bacterial infection in humans or animals which method comprises administration of a composition of the invention.
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 following Examples illustrate the preparation of compounds of this invention .
Example 1
Benzyl 9-(1',2',4'-triazol-1'-yl)-9-deoxyclavulanate and benzyl 9-(1',2',4'-triazol -4'-yl)-9-deoxyclavulanate
A solution of benzyl clavulanate (10 g) , triphenylphosphine (10.9 g) and 1,2,4-triazole (6.9 g) in distilled tetrahydrofuran (250 ml) was stirred vigorously and cooled to -10°C. Diethylazodicarboxylate (6.8 ml) was added and the mixture was stirred for 30 minutes without external cooling. The solution was evaporated under reduced pressure and the residue was dissolved in dichloromethane (30 ml). This solution was applied to a silica column and the mixture was eluted first with ethyl acetate. Fractions which contained a mixture (mixture A) of three main components were collecte and combined: these three compounds were triphenylphosphine oxide and two β-lactam containing compounds which were a little more polar than triphenylphosphine oxide on silica tic (eluted with ethyl aσetate/hexane 3:1, viewed under ultra violet light and then sprayed with dilute potassium permanganate solution). The column was further eluted with ethyl acetate/ethanol 2:1. Fractions containing a more polar β-lactam containing compound together with non-β-lactam compounds were combined and evaporated under reduced pressur to provide mixture B.
Mixture A was rechromatographed on silica, eluting with ethyl acetate/hexane (1:1, then 2:1 and finally 3:1). Fractions containing the less polar of the two major β-lactam containing compounds (silica tic eluted with ethyl acetate/hexane 3:1) were collected and combined. The solution was evaporated under reduced pressure to provide benzyl 9-(1', 2 ',4'-triazol-1'-yl)-9-deoxyclavulanate (400 mg as a gum. vmaχ (CHCl3) 1800, 1750, 1695 cm-1. δ(CDCl3) 3.06 (1H, d, J 17Hz) , 3.50 (1H, dd, J 17 and 2.5 Hz) , 4.7 - 5.0 (3H, m) , 5.0 - 5.4 (3H, m) , 5.73 (1H, d, J 2.5 Hz), 7.31 (5H, s) , 7.90 (1H, s) , 7.96 (1H, s) . m/e 340.1169 (M+) : C17H16N4O4 requires 340.1169.
Mixture B was rechromatographed on silica, eluting with methyl acetate. Appropriate fractions were combined and evaporated under reduced pressure to provide benzyl 9-(1',2',4'-triazol-4'-yl)-9-deoxyclavulanate (125 mg) as a gum. vmax (CHCl3) 1805, 1750, 1695 cm-1, δ (CDCl3) 3.06 (1H, d, J 17 Hz), 3.54 (1H, dd, J 17 and 2.5 Hz), 4.5 - 5.0 (3H, m) , 5.0 - 5.4 (3H, m) , 5.75 (1H, d, J 2.5 Hz), 7.32 (5H, s) , 8.05 (2H, s) . m/e 340.1180 (M+) : C17H16N4O4 requires 340.1169.
Example 2
Lithium 9-(1',2',4'-triazol-1,-yl)-9-deoxyclavulanate
A solution of benzyl 9-(1',2',4'-triazol-1'-yl)-9-deoxyclavulanate (155 mg) in distilled tetrahydrofuran (10 ml) was treated with 10% Pd/C (100 mg) and shaken under hydrogen at atmospheric pressure for 1½ hours. The mixture was filtered through celite and the filtrate evaporated to approximately 2 ml. To this solution was added water (5 ml) and 0.5 N aqueous lithium hydroxide solution until the pH reached 7.5. The solution was washed with ethyl acetate (20 ml) and freeze dried to provide lithium 9-(1', 2 ',4'-triazol-1'-yl)-9-deoxyclavulanate (94 mg) as a pale yellow solid. vmax (KBr)
1775 , 1705 , 1695 , 1620 cm-1. δ(D2O : Me CN=2 . 0 δ ) 3 . 03
(1H, d, J 17 Hz) , 3 .52 ( IH, dd, J 17 and 2 .5 Hz ) , 4 .7 - 5 .2 (4H, m) , 5 .71 ( 1H, d, J 2.5 Hz) , 7 . 97 ( 1H, s) , 8.36 (1H, s) . Example 3 Lithium 9-(1',2',4'-triazol-4'-yl)-9-deoxyclavulanate
A solution of benzyl 9-(1',2',4'-triazol-4'-yl)-9- deoxyclavulanate (90 mg) in distilled tetrahydrofuran
(5 ml) was treated with 10% Pd/C (80 mg) and shaken under hydrogen at atmospheric pressure for 2 hours.
To the resulting suspension was added water (10 ml) and
0.5 N aqueous lithium hydroxide solution until the pH reached 7.5. The suspension was filtered through celite and the filtrate was washed with ethyl acetate.
Organic solvent was removed. under reduced pressure and the remaining aqueous solution was freeze dried to provide lithium 9-(1',2',4'-triazol-4'-yl)- 9-deoxyclavulanate (42 mg) as a pale yellow solid. vmax (KBr)
1780, 1700, 1630 cm-1. δ (D2O:HOD=4.60δ) 3.02 (1H, d, J 17Hz, 3.51 (1H, dd, J 17 and 2.5 Hz), 4.5 - 5.1 (m including HOD), 5.69 (1H, d, J 2.5 Hz), 8.36 (2H, s).
Preparation 1
Benzyl 9-acetamido-9-deoxyclavulanate
Benzyl-9-azido-9-deoxyclavulanate (2 g) was dissolved in tetrahydrofuran (40 ml) /water (20 ml) and the solution ice cooled and stirred vigorously. Zinc powder (5 g) was added in small quantities over 1% hours, while maintaining the pH of the solution between 3 and 4 by dropwise addition of 2N HCl. When benzyl 9-azido-9-deoxyclavulanate could no longer be detected in the solution (silica tic, eluent ethyl acetate/petroleum ether 1:2), the pH was adjusted to 6 with 1N aqueous sodium bicarbonate and the solution filtered. The filtrate was saturated with NaCl and extracted with ethyl acetate (3 x 30 ml). The combined ethyl acetate extract were dried over MgSO4 and evaporated under reduced pressure to ca. 50 ml to provide a solution containing benzyl 9-amino- 9-deoxyclavulanate. This solution was treated with acetic anhydride (1.0 ml) and pyridine (0.52 ml), stirred 1 hour at room temperature, washed with 0.1 N HCl (50 ml), 1N aqueous sodium bicarbonate solution (50 ml) and water (50 ml), dried over MgSO4 and evaporated under reduced pressure.
The residue was chromatographed on silica to provide the title compound.
Example 4
Benzyl 9-(3'-methyl-1',2',4'-triazol-4'-yl)-9-deoxyclavulanate
A stirred, ice-cooled solution of benzyl 9-acetamido-9-deoxyclavulanate (330 mg) in dichloromethane (10 ml) was treated with pyridine (0.16 ml) and phosphorus pentachloride (220 mg) and left 30 minutes. The resulting solution (at 0 - 5°C) was treated with a solution of formic acid hydrazide (180 mg) and tetramethylguanidine (375 mg) in dichloromethane (5 ml). After stirring for 30 minutes the solution was applied to a silica column (made up in ethyl acetate). The mixture was eluted first with ethylacetate and then with ethylacetate/ethanol 3:2. Appropriate fractions were combined and the solvent removed under reduced pressure to provide benzyl 9-(3'-methyl-1',2',4'-triazol-4'-yl)-9-deoxyclavulanate as a colourless gum (140 mg) . v max (CHCl3) 1805, 1750 and 1695 cm-1, δ (CDCl3) 2.30 (3H, s) , 3.03 (1H, d, J 17 Hz), 3.52 (1H, dd, J 17 and 2.5 Hz), 4.4 - 4.9 (3H, m) , 5.0 - 5.4 (3H, m) , 5.73 (1H, d, J 2.5 Hz), 7.30 (5H, s) , 7.96 (1H, s). Example 5
Sodium 9-(3'-methyl-1',2',4'-triazol-4'-yl)-9-deoxy- clavulanate
Benzyl 9-(3'-methyl-1',2',4'-triazol-4'-yl)-9-deoxyclavulanate (125 mg) was dissolved in distilled tetrahydrofuran (7 ml) and treated with 10% palladium on carbon (100 mg) . The suspension was shaken under hydrogen at atmospheric pressure for 2½ hours, treated with water (20 ml) and then dropwise with 0.5N sodium hydroxide solution until the pH reached 7.5. The suspension was filtered and the filtrate evaporated under reduced pressure. The residue was chromatographed on silica (2 cm. long column), eluting with n-butanol/ethanol/water 4:1:1. Appropriate fractions were combined and evaporated under reduced pressure. Water (20 ml) was added and partially evaporated to remove all organic solvents. The remaining aqueous solution (5 ml) was freeze-dried to provide sodium 9-(3'-methyl-1',2',4'-triazol-4'-yl)-9-deoxyclavulanate (85 mg) as a pale yellow solid. v max. (KBr) 1775, 1690 and 1615 cm-1. δ (D2O: HOD = 4.605) 2.33 (3H, s) , 2.99 (1H, d, J 17 Hz), 3.52 (1H, dd, J 17 and 2.5 Hz), 4.8 - 5.0 (2H, m) , 5.67 (1H, d, J 2.5 Hz), 8.27 (1H, s) .
Antibacterial activity of 1' ,2',4'-triazoles
MIC (μg/ml)

Claims

1) A compound of formula I
or a salt or ester thereof wherein
X is an optionally substituted 1, 2, 4 triazolyl group attached via a nitrogen atom thereof.
2) A compound according to claim 1 wherein X is a group of sub-formula (A) or (B)
wherein R1 and R2 are each independently hydrogen, an optionally substituted hydrocarbon group or a functional group.
3) A compound according to claim 2 wherein R1 and R2 are hydrogen. 4) A compound according to claim 1 of formula II
or a salt or ester thereof; wherein R6 is hydrogen or an optionally substituted hydrocarbon group.
5) A compound selected from
Benzyl 9-(1',2',4'-triazol-1'-yl)-9- deoxyclavulanate;
Benzyl 9-(1',2',4'-triazol-4'-yl)-9- deoxyclavulanate;
Lithium 9-(1',2',4'-triazol-l'-yl)-9- deoxyclavulanate;
Lithium 9-(1',2',4'-triazol-4'-yl)-9- deoxyclav-lanate;
Benzyl 9-(3'methyl-1',2',4'-triazol-4'-yl)-9- deoxyclavulanate; and
Sodium 9-(3'-methyl-1',2',4'-triazol-4'-yl)-9- deoxyclavulanate.
6) A process for preparing a compound of formula I as defined in Claim 1 or a salt or ester thereof; which process comprises reacting a compound of formula III
where R8 is a carboxy protecting group, with i) a compound of formula IV
where one of Ra or Rb represents a group R1 the other represents a group R2, wherein R1 and R2 are as defined with respect to formula I;
ii) a compound of formula V
R9OCON=NCOOR10 (V)
where R9 and R10 are each independently C1-6 alkyl, aryl or aryl (C1-6) alkyl; and
iii) a compound of formula VI
1, m and n are each independently 0 or 1 and R11, R12 and R13 are each independently C1-6 alkyl, aryl or aryl (C1-6) alkyl;
and thereafter where necessary carrying out one or more of the following steps:
i) removing the carboxy-protecting group R8,
ii) converting one group R1 or R2 to a different such group; and/or
(iii) converting a salt to the free carboxylic acid of formula (I) or to an ester, or to a different salt. 7) A process for preparing a compound of formula II as defined in claim 4 or a salt or ester thereof, which process comprises reacting a compound of formula VII
wherein
R6 is as defined in claim 4, R8 is as defined in claim 6 and Y is a halogen atom with a compound of formula VIII
H2NNHCHO VIII
in the presence of a strong non-nucleophilic base and thereafter where necessary carying out one or more of the following steps;
i) removing the carboxy-protecting group R8 ii) converting one group R1 or R2 to a different such group; and/or iii) converting a salt to the free carboxylic acid of formula (II) or to an ester, or to a different salt.
8) A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a salt or ester thereof and a pharmaceutically acceptable carrier.
9) A composition according to claim 8 which further comprises a penicillin or cephalosporin.
10) A compound of formula I as defined in claim 1 or a salt or ester thereof for use in the treatment of bacterial infections in humans or animals.
EP19840900628 1983-02-10 1984-01-31 Clavam derivatives Ceased EP0135521A1 (en)

Applications Claiming Priority (2)

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GB8303649 1983-02-10
GB838303649A GB8303649D0 (en) 1983-02-10 1983-02-10 Beta-lactam compounds

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BE (1) BE900322A (en)
GB (1) GB8303649D0 (en)
WO (1) WO1984003092A1 (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0001516A1 (en) * 1977-10-10 1979-04-18 Glaxo Group Limited Beta-Lactam compounds, processes for their preparation, pharmaceutical compositions containing them and intermediates of use in their preparation
NZ199061A (en) * 1980-12-09 1984-10-19 Beecham Group Ltd 9-(n-tetrazolyl)-deoxyclavulanic acids,salts,esters,and pharmaceutical compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8403092A1 *

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JPS60500620A (en) 1985-05-02
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WO1984003092A1 (en) 1984-08-16

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