WO1987000525A1 - Penemes de 6-alkylidene - Google Patents

Penemes de 6-alkylidene Download PDF

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Publication number
WO1987000525A1
WO1987000525A1 PCT/GB1986/000428 GB8600428W WO8700525A1 WO 1987000525 A1 WO1987000525 A1 WO 1987000525A1 GB 8600428 W GB8600428 W GB 8600428W WO 8700525 A1 WO8700525 A1 WO 8700525A1
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penem
preparation
ring
compound
group
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PCT/GB1986/000428
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English (en)
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Nigel John Perryman Broom
Peter David Edwards
Neal Frederick Osborne
Steven Coulton
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Beecham Group P.L.C.
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Publication of WO1987000525A1 publication Critical patent/WO1987000525A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2

Definitions

  • This invention relates to ⁇ -lactam compounds and in particular to a class of 6-alkylidene penems which have I3-lactamase inhibitory and antibacterial properties.
  • the compounds are therefore useful in the treatment of antibacterial infections in humans or animals, either alone or in combination with other antibiotics.
  • EP 0 041 768 A (Beecham; published 16 December 1981; corresponding to U.S. Patent No 4485 110) discloses
  • each of R a and R b denotes hydrogen or an optionally substituted hydrocarbon or heterocyclic group
  • R c denotes hydrogen or an organic group.
  • EP 0 120 613 A discloses a sub-group of compounds within the general formula (A) which have better activity than other compounds of the general formula (A). That sub-group consists of compounds of the general formula (B):
  • R c denotes hydrogen or an organic group
  • R d and R e denotes hydrogen
  • R d and R e denotes a group of the sub-formula (C):
  • R f denotes a substituent group
  • X denotes an oxygen atom, a sulphur atom or an >NRg group
  • Rg denotes hydrogen, hydrocarbon or a nitrogen-protecting group
  • n denotes 0, 1, 2 or 3.
  • R 1 and R 2 denotes hydrogen
  • R 1 and R 2 denotes an unsubstituted or substituted fused bicyclic hetero-aromatic group bonded through a carbon atom thereof and having five or six atoms in each ring
  • R 3 denotes hydrogen or an organic group.
  • bicyclic hetero-aromatic group' as used herein means a group comprising two fused rings together having aromatic character at least one of which rings contains a non-carbon atom (i.e. a hetero-atom) as a ring member and at least one of which rings contains a carbon-bonded free valency by which the group is bonded to the remainder of the molecule.
  • Each ring of the fused bicyclic hetero-aromatic group R 1 or R 2 may contain 5 or 6 ring atoms (including ring junction atoms - also referred to as bridgehead atoms - constituting members of both rings) and the hetero-aromatic group may consist of two fused rings both of the same size or it may consist of one 5-membered ring fused to one 6-membered ring.
  • the fused bicyclic hetero-aromatic group R 1 or R 2 is bonded to the remainder of the molecule through a carbon atom of one of the rings.
  • the said bond may be from either ring.
  • the fused bicyclic hetero-aromatic group R 1 or R 2 may comprise two fused 5-membered rings, two fused 6-membered rings, or one 5-membered ring and one 6-membered ring fused together (in which last-mentioned case, the bond to the remainder of the molecule may be from either the 5-membered ring or the 6-membered ring).
  • the bicyclic hetero-aromatic group may be based on a bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, or bicyclo[4.4.0]decyl ring system.
  • the fused bicyclic hetero-aromatic group may contain one or more hetero-atoms selected from nitrogen, oxygen and sulphur atoms.
  • at least one hetero-atom is present in at least one of the rings (which may be a 5-membered ring or a 6-membered ring), it is not necessary for both rings to contain a hetero-atom: one ring may contain no hetero-atoms or both rings may each contain one or more hetero-atoms depending on the type of hetero-atoms.
  • the ring through which the hetero-aromatic group is bonded to the remainder of the molecule should contain at least one non-bridgehead carbon atom for attachment of the bond.
  • the hetero-aromatic group may contain one bridgehead nitrogen atom at the ring fusion without losing its aromaticity (see, for example, M.J. Cook et al, 'Aromaticity of heterocycles', Advances in heterocyclic chemistry, Academic Press, 1974, 17 , 255ff.).
  • a substituent in at least one of the rings may contribute to the aromaticity of the hetero-aromatic group (see, for example, A.R. Katritzky and J.M. Lagowski, 'Protopic tautomerism of heteroaromatic compounds', Advances in heterocyclic chemistry, Academic Press, 1963, 1, 311, 339; 2 , 1, 27; Supplement 1).
  • such a substituent may be essential to the aromaticity of the ring system.
  • hetero-aromatic groups containing an sp 2 -hydridized substituent include chromonyl groups and coumarinyl groups.
  • the fused bicyclic hetero-aromatic group R 1 or R 2 may suitably comprise two fused rings together constituting an aromatic system and each selected from:
  • a six-membered heterocyclic ring containing one hetero-atom selected from oxygen, sulphur and substituted nitrogen, containing one carbon atom carrying an sp 2 -hydridized substituent in conjugation with the said hetero-atom, and optionally also containing up to three, advantageously not more than two, and preferably not more than one, additional ring nitrogen atoms, the remaining ring atoms being carbon atoms;
  • At least one of said rings is a heterocyclic ring
  • the ring fusion is at a carbon-carbon bond or a carbon-nitrogen bond
  • one of said rings contains a carbon atom through which the hetero-aromatic group is bonded to the remainder of the molecule.
  • 'ring nitrogen atom' as used herein means a nitrogen atom all three bonds of which are attached to other ring atoms, either through a double bond to one adjacent ring atom and a single bond to another adjacent ring atom or, in the case of a bridgehead nitrogen atom, through three single bonds to an adjacent atom in each ring and to the other bridgehead atom.
  • Examples of 'ring nitrogen atoms' are the nitrogen atoms in the following structures:
  • 'substituted nitrogen atom' as used herein means a nitrogen atom forming part of a heterocyclic ring and having two bonds attached to other ring atoms and one bond attached to an atom or group outside the ring (including a hydrogen atom).
  • Such a 'substituted nitrogen atom' may, for example, be denoted by -N(R°)-, in which R° is defined as below.
  • Examples of 'substituted nitrogen atoms' are those in the following structures:
  • bridgehead atom' as used herein means one of the two atoms at a ring fusion junction which are common to both rings.
  • the bridgehead atoms may both be carbon atoms or may be one carbon atom and one nitrogen atom, as in the following structures:
  • one of the bridgehead atoms may be a nitrogen atom.
  • fused bicyclic hetero-aromatic groups R 1 or R 2 include the following groups:
  • each of X 1 and X 2 which may be identical or different, denotes -O-, -S-, or -N(R°)-, R° denotes a hydrogen atom or an unsubstituted or substituted hydrocarbon group, and
  • X 1 is defined as above, and
  • pyrroloimidazolyl imidazoimidazolyl, pyrrolo- pyrazolyl, pyrazolopyrazolyl, imidazopyrazolyl, pyrrolotriazolyl, imidazotriazolyl, pyrazolo- triazolyl, pyrrolotetrazolyl, imidazotetrazolyl, and pyrazolotetrazolyl groups; pyrrolo-oxazolyl, imidazo-oxazolyl, pyrazolo-oxazolyl, oxazolo- triazolyl, oxazolo-tetrazolyl, pyrrolo- oxadiazolyl, imidazo-oxadiazolyl, pyrazolo- oxadiazolyl, triazolo-oxadiazolyl, pyrrolo- oxatriazolyl, imidazo-oxatriazolyl, and pyrazolo- oxa
  • X 1 and X 2 are defined as above
  • Z denotes an sp 2 -hybridized substituent.
  • Such groups include: benzofuryl, benzothienyl, benzopyrrolyl (indolyl), benzopyrazolyl, benzoimidazolyl, benzo-oxazolyl, benzoisoxazolyl, benzothiazolyl, benzo- isothiazolyl, benzo-oxadiazolyl, benzo- thiadiazolyl, benzotriazolyl, furopyridyl, thienopyridyl, pyrrolopyridyl, pyrazolopyridyl, imidazoypyridyl, triazolopyridyl, oxazolopyridyl, isoxazolopyridyl, thiazolopyridyl, and isothiazolopyridyl groups, the pyrazinyl, pyrimidinyl and pyridazinyl derivatives corresponding to the above-mentioned pyridyl ring systems, oxadiazol
  • X 1 is defined as above, and
  • Examples of such groups include the following: cyclopentapyranyl, cyclopentaoxazinyl, cyclopenta- oxadiazinyl, cyclopentaoxatriazinyl, pyrano- pyrrolyl, pyranopyrazolyl, pyranoimidazolyl, pyrano-triazolyl, pyrrolo-oxazinyl, pyrazolo- oxazinyl, imidazo-oxazinyl, and pyrrolo- oxadiazinyl groups, and the thia derivatives corresponding to the above mentioned pyran and other oxa ring systems, the 1H-cyclopentapyridyl group and corresponding derivatives in which up to three additional ring-nitrogen atoms are present in either ring, in all of which above-mentioned groups the free valency (by which the group is attached to the remainder of the molecule) may extend from a carbon atom of either
  • (v) A group consisting of a five-membered ring and a six-membered ring fused together with one bridgehead atom being a carbon atom and the other bridgehead atom being a nitrogen atom, the five-membered ring optionally containing one, two or three ring-nitrogen atoms (additional to the bridgehead nitrogen atom), and the six-membered ring optionally containing up to four ring-nitrogen atoms (additional to the bridgehead nitrogen atom), with the proviso that the total number of ring-nitrogen atoms does not exceed five, preferably not exceeding four, inclusive of the bridgehead nitrogen atom, or the six-membered ring optionally containing one hetero-atom selected from oxygen, sulphur and substituted nitrogen, and also containing an sp 2 -hybridized substituent in conjugation with the said hetero-atom, and also optionally containing one or two ring-nitrogen atoms (additional to the bridgehead nitrogen
  • ⁇ 1 and Z are defined as above.
  • Examples of such groups include the indolizinyl group, as well as corresponding derivatives containing up to three additional ring-nitrogen atoms in either ring, for example pyrazolo- [1,5-a]pyridine, imidazo[l,2-a]pyrazinyl, and also corresponding derivatives in which the six- membered ring includes an additional hetero-atom selected from oxygen, sulphur and substituted nitrogen and carries an sp 2 -hydridised substitutent ortho or para to the said hetero-atom, in all of which above-mentioned groups the free valency (by which the group is attached to the remainder of the molecule) may extend from a carbon atom of either ring (excluding the bridgehead carbon atom). All isomeric forms of the above-mentioned groups are included.
  • X 1 , X 2 and Z are defined as above.
  • Such groups may be represented by the formula
  • the above listed hetero-aromatic groups are examples only of possible groups R 1 and R 2 . Further examples include groups listed above carrying substituents listed below on a carbon atom or on a substituted nitrogen atom.
  • hetero-aromatic group R 1 or R 2 include the benzo[b]furyl group:
  • N-substituted derivatives thereof for example N-(p-methoxyphenylsulphonyl)-indolyl, and the benzotriazolyl group.
  • the fused bicyclic hetero-aromatic group may be unsubstituted or may be substituted on one or both rings by one or more substituents bonded to the respective ring at a carbon atom.
  • substituents should not of course destroy the aromatic character of the hetero-aromatic group.
  • the hetero- aromatic group may be unsubstituted or may carry one or two substituents.
  • the fused bicyclic hetero-aromatic group R 1 or R 2 may include a substituent other than hydrogen at a substituted nitrogen atom.
  • the nitrogen substituent may, for example, be a hydrocarbon group or a nitrogen-protecting group.
  • substituents which may be present in the hetero-aromatic group R 1 or R 2 include (C 1-6 )alkanoyl, (C 1-6 )alkanoyloxy, heterocyclyl, amino, (C 1-6 )alkanoylamino, (mono or di)-(C 1-6 )alkylamino, hydroxy, (C 1-6 ) alkoxy, sulpho, mercapto, (C 1-6 )alkylthio, (C 1-6 ) alkylsulphinyl, (C 1-6 )alkyl- s ⁇ lphonyl, heterocyclylthio, arylthio, sulphamoyl, carbamoyl, amidino, guanidino, nitro, halogen, carboxy, carboxy salts, carboxy esters, arylcarbonyl, and heterocyclylcarbonyl, groups, and also unsubstituted or substituted (C 1-6 ) alkyl, (C 1-6
  • Examples of suitable optional substituents for the above-mentioned (C 1-6 ) alkyl, (C 2-6 ) alkenyl, (C 2-6 )alkynyl, aryl and aryl (C 1-6 ) alkyl substitutents include (C 1-6 )alkanoyl, (C 1-6 )alkanoyloxy, heterocyclyl, amino, (C 1-6 )alkanoylamino, (mono or di)-(C 1-6 )alkylamino, hydroxy, (C 1-6 )alkylsulphinyl, (C 1-6 )alkylsulphonyl, heterocyclylthio, arylthio, sulphamoyl, carbamoyl, amidino, guanidino, nitro, halogen, carboxy, carboxy salts, carboxy esters, arylcarbonyl and heterocyclylcarbonyl groups.
  • hetero-aromatic group R 1 or R 2 includes a carboxy salt or carboxy ester substituent, that substituent is suitably a pharmaceutically acceptable salt or pharmaceutically acceptable ester.
  • substituent is suitably a pharmaceutically acceptable salt or pharmaceutically acceptable ester.
  • the hetero-aromatic group R 1 or R 2 is or includes a basic moiety, the compound according to the invention may exist in zwitterionic form.
  • heterocyclyl' as used herein includes aromatic and non-aromatic, single and fused, rings containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by up to three groups selected from halogen, (C 1-6 )alkyl, (C 1-6 )alkoxy, halo(C 1-6 )alkyl, hydroxy, amino, carboxy, (C 1-6 )alkoxycarbonyl, (C 1-6 )alkoxycarbonyl(C 1-6 )alkyl, aryl, (C 1-6 )alkylthio, arylthio, mercapto and oxo groups.
  • 'aryl' as used herein includes phenyl and naphthyl, which may be unsubstituted or substituted by 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, (C 1-6 )alkylcarbonyl, (C 1-6 )alkylthio, arylthio, and mercapto groups.
  • hydrocarbon' as used herein 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.
  • R 3 represents hydrogen or an organic group, which may suitably be linked through a sulphur or carbon atom.
  • R 3 may represent hydrogen or a group of formula -R 4 or -SR 4 , where R 4 denotes an unsubstituted or substituted (C 1-10 )hydrocarbon or heterocyclyl group.
  • R 3 represents hydrogen, (C 1-10 )alkyl or (C 1- 10 )alkylthio, or substituted (C 1 -10 )alkyl or substituted ( C 1-1 0 ) - alkylthio, wherein the substituent may be hydroxy, (C 1-6 ) alkoxy, (C 1-6 )alkanoyloxy, halogen, mercapto, (C 1-6 )alkylthio, heterocyclylthio, amino, (mono or di)-(C 1-6 )alkylamino, (C 1-6 )alkanoylamino, carboxy, or (C 1-6 )alkoxycarbonyl.
  • suitable organic groups R 3 include methyl, ethyl, propyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, hydroxymethyl, methoxymethyl, ethoxymethyl, acetoxymethyl, (1 or 2)-acetoxyethyl, aminomethyl, 2-aminoethyl, acBtamidomethyl, 2-acetamidoethyl, carboxymethyl, 2-hydroxyethylthio, methoxymethylthio, 2-methoxyethylthio, acetoxymethylthio, 2-aminoethylthio, acetamidomethylthio, 2;-acetamidoethylthio, carboxymethylthio, 2-carboxyethylthio, aryl (especially phenyl), arylthio (especially phenylthio), pyridyl, pyrimidyl, isoxazolyl
  • R 3 may denote a group of the formula -OR 7 or -R 8 , in which R 7 denotes an unsubstituted or substituted phenyl, naphthyl, thienyl, pyridyl, quinolyl or isoquinolyl group, and R 8 denotes a nitrogen-containing heterocyclyl ring bonded through a ring-nitrogen atom.
  • R 7 and R 8 examples of groups denoted by R 7 and R 8 , and also examples of suitable substituents for the aryl or heterocyclyl rings denoted by R 7 , are given in GB 2 102 798 A (Hoechst), EP 0 099 059 A (Hoechst), and EP 0 148 128 A (Ciba-Geigy; corresponding to AU 84/37236).
  • Pharmaceutically acceptable in vivo hydrolysable esters (also referred to as 'metabolisable esters') of the compounds of the general formula I are those esters which hydrolyse in the human body to produce the parent acid or its salt. Such esters may be identified by oral or intravenous administration to a test animal, and subsequent examination of the test animal's body fluids for the presence of the compound of the formula I or a salt thereof.
  • the in vivo hydrolysable ester moiety may constitute a link between two different active ingredient moieties, one of which is a compound according to the invention and the other of which may be another therapeutically active compound, such that on in vivo hydrolysis of the ester moiety, the ester link breaks to give the two separate active compounds.
  • the linked entity may be referred to as a 'mutual pro-drug'.
  • Suitable in vivo hydrolysable ester groups include those of part-formulae (a), (b) and (c):
  • a 1 denotes hydrogen, methyl, or phenyl
  • a 2 denotes (C 1-6 )alkyl, (C 1-6 )alkoxy or phenyl; or
  • a 1 and A 2 together denote 1, 2-phenylene, which may be unsubstituted or substituted by one or two methoxy groups;
  • a 3 denotes (C 1-6 )alkylene, which may be unsubstituted or substituted by a methyl or ethyl group;
  • each of A 4 and A 5 which may be identical or different, denotes (C 1-6 )alkyl;
  • a 6 denotes (C 1-6 ) alkyl.
  • suitable in vivo hydrolysable ester groups include acetoxymethyl, pivaloyloxymethyl, ⁇ -acetoxyethyl, ⁇ -acetoxybenzyl, ⁇ -pivaloyloxyethyl, ethoxycarbonyloxymethyl, ⁇ -ethoxycarbonyloxyethyl, dimethylaminomethyl, diethylaminomethyl, phthalidyl and dimethoxyphthalidyl groups.
  • Suitable pharmaceutically acceptable salts of the 3-carboxylic acid group of the compound of formula I include metal salts, e.g. aluminium salts, alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts), ammonium salts, and substituted ammonium salts, for example those with lower alkylamines (e.g.triethylamine),hydroxy-lower alkylamines (e.g. 2-hydroxyethylamine), di(2-hydroxyethyl) amine or tri (2-hydroxyethyl) amine), eyeloalkylamines (e.g.
  • metal salts e.g. aluminium salts, alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts), ammonium salts, and substituted ammonium salts, for example those with lower alkylamines (e.g.triethylamine
  • dicyclohexylamine or with procaine, and also dibenzylamine, N,N-dibenzylethylenediamine, 1-ephenamine, N-ethylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine,
  • N,N'-bishydroabietylethylene-diamine bases of the pyridine type (e.g. pyridine, collidine and quinoline), and other amines which have been or can be used to form salts with penicillins.
  • bases of the pyridine type e.g. pyridine, collidine and quinoline
  • other amines which have been or can be used to form salts with penicillins.
  • the compounds of the general formula I and their salts may exist in hydrated or non-hydrated form.
  • the compounds of the general formula I and also the salts and esters thereof may exist in two optically active forms and it is to be understood that both such forms as well as racemic mixtures thereof are embraced by the present invention. It is believed that the more active form is that of structure IA:
  • R 1 , R 2 and R 3 are defined as above.
  • R 1 denotes the hetero-aromatic group and that R 2 denotes a hydrogen atom.
  • Examples of individual compounds according to the invention include:
  • a compound of the general formula I, or a salt or ester thereof, may be prepared by eliminating the elements of a compound of the general formula XIII:
  • R 1 and R 2 are defined as above, and
  • X o denotes a hydroxy group or a leaving group
  • the compound of the general part-formula XIV may suitably be a compound of the general part-formula XIVA:
  • XIVA in which R 1 , R 2 and X o are defined as above. More especially it may be a compound of the general formula XIVB:
  • R 1 , R 2 and X o are defined as above,
  • R 10 denotes (C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, (C 1-6 )alkylthio, arylthio, hetero-aromatic-thio, acyl (for example, (C 1-6 ) alkylcarbonyl, especially acetyl), ( C 2-6 ) alkenyl (especially vinyl ) , or aryl(C 2-6 )alkenyl, all of which may optionally be substituted, and
  • R 11 denotes hydrogen or an N-protecting group
  • R 10 and R 11 together denote the remainder of a penem nucleus, which may be substituted and/or may optionally carry a protecting group.
  • R 10 and R 11 in general formula XIVB together denote the remainder of a penem nucleus, they may suitably together denote the sub-formula XVI:
  • R 12 denotes the hydrogen atom or organic group R 3 or a group convertible into R 3 during the preparation of a penem of the general formula I or salt or ester thereof, and
  • R x denotes hydrogen or a carboxyl-blocking group.
  • penem or penem intermediate of the general part-formula XIV is of the general formula XIVD given below.
  • a carboxyl-blocking group R x (also referred to as a carboxyl-protecting group) is suitably a group that can readily be removed at a later stage of the penem preparation process.
  • Examples of suitable carboxyl-blocking derivatives that may form the group -CO 2 R x include salt, ester, and anhydride derivatives of the carboxylic acid.
  • the salts may be organic or inorganic and need not be pharmaceutically acceptable.
  • suitable salt-forming groups R x include inorganic salts, for example alkali metal atoms (e.g. lithium and sodium), other metal atoms, tertiary amino groups (e.g. tri-lower-alkylamino, N-ethylpiperidino, and dimethylpiperazino groups).
  • a preferred salt-forming group R x is the triethylamino group.
  • ester-forming group R x is advantageously one that can be removed under conventional conditions.
  • suitable ester-forming groups R x include benzyl, 3 ,5-di-t-butyl-4-hydroxy-benzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2, 2,2-trichloroethyl, 2,2,2-tribromoethyl, allyl, acetonyl, t-butyl, t-amyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, p-toluene-sulphonylethyl, and methoxymethyl groups, and also silyl, stannyl and phosphorus-containing groups, and oxime radicals of formula -N
  • the free carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular R x group, for example, by acid-catalysed, base-catalysed or enzymically-catalysed hydrolysis, or by hydrogenation.
  • the hydrolysis must of course be carried out under conditions in which the groups on the rest of the molecule are stable.
  • the process step according to the invention involves the elimination of the elements of a compound H-X o from a penem or penem intermediate of the general part-formula XIV, in which X o denotes a hydroxy group or a leaving group.
  • the compound of the formula H-X o being eliminated is water and the elimination reaction is a dehydration reaction, which may suitably be carried out by treating a compound of the general part-formula XIV with a compound of the general formula XVII:
  • each of R 13 and R 14 which may be identical or different, denotes aryl, (C 1-6 )alkyl or aryl(C 1-6 ) alkyl,
  • each of R 15 , R 16 and R 17 which may be identical or different, denotes aryl, (C 1-6 )alkyl or aryl (C 1-6 )alkyl.
  • R 13 and R 14 are preferably selected from methyl, ethyl, propyl, butyl, phenyl, and benzyl, the ethyl and isopropyl groups being preferred.
  • R 13 and R 14 may be identical.
  • a preferred compound of the general formula XVII is diethyl azodicarboxylate.
  • Preferred compounds of the general formula XVIII include triarylphosphines and trialkylphosphites.
  • Preferred groups R 15 , R 16 and R 17 include methyl, ethyl, n-propyl, n-butyl, benzyl, phenyl and methoxyphenyl.
  • R 15 , R 16 and R 17 are all identical.
  • a preferred compound of the general formula XVIII is triphenylphosphine.
  • the dehydration reaction may suitably be carried out at a non-extreme temperature, for example a temperature of from -20°C to +100°C. It may be convenient to begin the reaction at a depressed temperature, for example
  • the reaction may suitably be carried out in an inert aprotic organic solvent.
  • suitable solvents include tetrahydrofuran, dioxane, ethyl acetate, benzene, and dichloromethane.
  • X 01 in general formula XIV, denotes a leaving group, which will hereinafter be referred to as X 01 , it may suitably be a halogen atom or a group of one of the formulae
  • n denotes 0 or 1
  • R 18 denotes (C 1-6 )alkyl, aryl or aryl (C 1-6 )alkyl,
  • R 19 denotes (C 1-6 )alkyl or aryl.
  • Preferred groups of formula XIXB are those in which n denotes zero and R 18 denotes (C 1-6 )alkyl, especially the acetoxy group.
  • Suitable bases for that purpose include, for example, powdered inorganic bases, for example alkali metal carbonates, bicarbonates, hydroxides, and hydrides (e.g. powdered potassium carbonate), and also organic bases of low nucleophilicity, for example 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • Suitable solvents for use as the aprotic medium in this reaction include, for example, dimethylformamide, hexamethylphosphor- amide, dichloromethane, and tetrahydrofuran.
  • the elimination may suitably be effected at a low temperature, for example a temperature of from -70°C to +70°C, advantageously from -40°C to 0°C.
  • the compounds of the general formula XIV in which X o denotes a leaving group X 01 may suitably be prepared from the corresponding compound in which X o denotes a hydroxy group by replacing the hydroxy group by a leaving group X 01 .
  • the leaving group X 01 may be introduced into the molecule at an earlier stage in the synthesis of the penem nucleus.
  • a group ⁇ 01 of the formula XIXA or XIXB may be introduced at the beginning of, or at any stage during, the synthesis of the penem.
  • the group X 01 may suitably be introduced by replacing a hydroxyl group in known manner.
  • the dehydration or other elimination reaction of the process according to the invention may be carried out at any suitable stage during the preparation of the penem of the general formula I or salt or ester thereof, suitably at an early stage or late stage in the manufacturing process.
  • the dehydration or other elimination reaction may be carried out on a compound of the general formula XIVC: XIVC
  • R 1 , R 2 and X o are defined as above,
  • R 20 denotes (C 1-6 ) alkyl, aryl, aryl(C 1-6 )alkyl, (C 1-6 )alkylthio, arylthio, hetero-aromatic-thio, acyl (for example, (C 1-6 )alkylcarbonyl, especially acetyl), (C 2-6 )alkenyl (especially vinyl), or aryl(C 1-6 )alkenyl, all of which may optionally be substituted, and
  • R 21 denotes hydrogen or an N-protecting group
  • R 1 , R 2 , R 20 and R 21 are defined as above, which may then subsequently be converted to a penem of the general formula I or salt or ester thereof in known manner, suitably by a conventional penem preparation method.
  • R 1 , R 2 , R 12 and R x are defined as above, and thereafter, if necessary or desired: (a) removing any carboxyl-blocking group R x , and/or
  • the conversion of a compound of the general formula XVC to the desired penem may suitably proceed via a compound of the general formula XVD, according to known penem preparation methods.
  • a compound of the general formula XIVD especially one in which X o denotes a leaving group X 01 , may conveniently be prepared from a compound of the general formula XIVC, especially one in which X o denotes a leaving group X 01 , according to known penem preparation methods.
  • R 10 or R 20 may suitably denote a triphenylmethyl group.
  • R 10 or R 20 may suitably denote a triphenylmethyl group.
  • N-protecting groups, R 11 or R 21 include silyl groups, for example t-butyldimethylsilyl groups.
  • the group R 12 may be a group convertible into R 3 during the penem preparation process.
  • One particular example of such a group which may conveniently be used in the preparation of a group R 3 of the formula -SR 4 (in which R 4 is defined as above), is the group of the formula XX: XX
  • R 22 denotes an organic radical different from the group R 4 .
  • a sulphoxide compound of the general formula XIVD or XVD in which R 12 denotes a group of the formula XX may be reacted with a thiol of the general formula XXI:
  • R 4 is defined as above, or a reactive derivative thereof, to give a compound of the general formula XIVD or XVD in which R 12 denotes a group of the formula XXII:
  • R 4 is defined as above.
  • reaction of the sulphoxide with the thiol may be carried out as described in European Patent Publication No. EP 0 046 363A.
  • a sulphoxide compound of the general formula XIVD or XVD in which R 12 denotes a sulphoxide group of the formula XIX above may be prepared by S-oxidation of a compound of the general formula XIVD or XVD, respectively, in which R 12 denotes a group of the formula -S-R 22 .
  • the S-oxidation may be effected using a mild oxidising agent, for example a perbenzoic acid, hydrogen peroxide, selenium dioxide or sodium metaperiodate.
  • Perbenzoic acids for example m-chloroperbenzoic acid, are preferred.
  • the present invention also provides a process for the preparation of a compound of the general formula I in which R 3 denotes a group of the formula -SR 4 (in which R 4 is defined as above), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, which comprises reacting a compound of the general formula XXIII:
  • R 1 , R 2 , R 22 and R x are defined as above,
  • the compounds of the general formulae XIVC and XVC are novel intermediates and also constitute subjects of the present invention.
  • the compounds of the general formula XIVD, in particular those in which R 12 denotes R 3 or a sulphoxide group of the formula XIX, are also novel intermediates and form a further subject of the present invention.
  • the compounds of the general formula XVD in which R 12 denotes a sulphoxide group of the formula XIX are further novel intermediates and constitute a yet further subject of the present invention.
  • the compounds according to the invention have ⁇ -lactamase inhibitory and antibacterial properties, and are useful for the treatment of infections in animals, especially mammals, including humans, in particular in humans and domesticated (including farm) animals.
  • the compounds may be used, for example, for the treatment of infections of, inter alia, the respiratory tract, the urinary tract, and soft tissues, especially in humans.
  • the compounds may be used for the treatment of infections caused by strains of, for example, Staphylococcus aureus, Klebsiella aerogenes, Escherichia coli, Proteus sp., and Bacteroides fragilis. It is generally advantageous to use a compound according to the invention in admixture or conjunction with a penicillin, cephalosporin or other ⁇ -lactam antibiotic and that can often result in a synergistic effect, because of the ⁇ -lactamase inhibitory properties of the compounds according to the invention. In such cases, the compound according to the invention and the other ⁇ -lactam antibiotic can be administered separately or in the form of a single composition containing both active ingredients as discussed in more detail below.
  • the compounds according to the invention are suitably provided in substantially pure form, for example at least 50% pure, advantageously at least 75% pure, preferably at least 95% pure, especially at least 98% pure, all percentages being calculated as weight/weight.
  • An impure or less pure form of a compound according to the invention may, for example, be used in the preparation of a more pure form of the same compound or of a related compound (for example, a corresponding salt, ester or free acid) suitable for pharmaceutical use.
  • the purity of any compound used as an intermediate may be less critical than that of a compound used as a final product, for example one used directly for pharmaceutical use (for example in a composition according to the invention as described below), nevertheless such an intermediate compound is advantageously provided in substantially pure form. It is generally advantageous to provide the compounds according to the invention in crystalline form.
  • the free acids and salts according to the invention may be in hydrated or non-hydrated form.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention that is to say, a compound of the general formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides a method of treating bacterial infections in animals, especially in humans and in domesticated mammals (including farm mammals), which comprises administering a compound or composition according to the invention to the animal. Such administration may advantageously be effected in conjunction with the prior, simultaneous pr subsequent administration of a penicillin, cephalosporin or other ⁇ -lactam antibiotic.
  • compositions of the invention may be in a form adapted for oral, topical or parenteral use and may be used for the treatment of infection in animals especially mammals, including humans, in particular in humans and domesticated animals (including farm animals).
  • compositions of the invention may, for example, be made up in the form of tablets, capsules, creams, syrups, suspensions, solutions, reconstitutable powders, and sterile forms suitable for injection or infusion.
  • Such compositions may contain conventional pharmaceutically acceptable materials, for example diluents, binders, colours, flavours, preservatives, and disintegrants, in accordance with conventional pharmaceutical practice in manner well understood by those skilled in the art of formulating antibiotics.
  • a compound according to the invention is present in sterile form, including in sterile crystalline form.
  • a further preferred form of the composition according to the invention is one in which the composition is in injectable or infusable form.
  • One injectable or infusable form of the composition according to the invention is an injectable or infusable solution, which suitably comprises a solution of a compound according to the invention in a sterile pyrogen-free liquid, for example water or aqueous ethanol.
  • a sterile pyrogen-free liquid for example water or aqueous ethanol.
  • a further injectable or infusable form of the composition according to the invention is an injectable or infusable suspension, in which case the compound according to the invention is advantageously present in finely particulate form.
  • the suspension may be an aqueous suspension in, for example, sterile water or sterile saline, which may additionally include a suspending agent, for example polyvinylpyrrolidone.
  • the suspension may be an oily suspension in a pharmaceutically acceptable oil suspending agent, for example arachis oil.
  • a composition according to the invention may be in unit dosage form, for example unit dosage form for oral administration, topical administration, or parenteral administration (including administration by injection or infusion).
  • a composition according to the invention may comprise a compound according to the invention as the sole active ingredient or therapeutic agent, or it may also comprise one or more additional active ingredients or therapeutic agents, for example a penicillin, cephalosporin or other ⁇ -lactam antibiotic, or pro-drug thereof.
  • a composition comprising a compound according to the invention and another active ingredient or therapeutic agent, especially a penicillin, cephalosporin or other ⁇ -lactam antibiotic, or pro-drug thereof, can show enhanced effectiveness, and in particular can show a synergistic effect.
  • Penicillins, cephalosporins and other ⁇ -lactam antibiotics suitable for co-administration with the compounds according to the invention - whether by separate administration or by inclusion in the compositions according to the invention - include both those known to show instability to or to be otherwise susceptible to ⁇ -lactamases and also those known to have a degree of resistance to ⁇ -lactamases.
  • penicillins suitable for co-administration with the compounds according to the invention include benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin, pirbenicillin, azlocillin, mezlocillin, sulbenicillin, piperacillin, and other known penicillins.
  • the penicillins may be used in the form of pro-drugs thereof, for example as in vivo hydrolysable esters, for example the acetoxymethyl, pivaloyloxymethyl, ⁇ -ethoxycarbonyloxyethyl and phthalidyl esters of ampicillin, benzylpenicillin and amoxycillin; as aldehyde or ketone adducts of penicillins containing a 6 ⁇ -aminoacetamido side chain (for example hetacillin, metampicillin and analogous derivatives of amoxycillin); and as ⁇ -esters of carbenicillin and ticarcillin, for example the phenyl and indanyl ⁇ -esters.
  • pro-drugs thereof for example as in vivo hydrolysable esters, for example the acetoxymethyl, pivaloyloxymethyl, ⁇ -ethoxycarbonyloxyethyl and phthalidyl esters of ampicillin, benzyl
  • cephalosporins examples include, cefatrizine, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephapirin, cephamandole nafate, cephradine, 4-hydroxycephalexin, cephaloglycin, cefoperazone, cefsulodin, ceftazidime, cefuroxime, cefmetazole, cefotaxime, ceftriaxone, and other known cephalosporins, all of which may be used in the form of pro-drugs thereof.
  • ⁇ -lactam antibiotics other than penicillins and cephalosporins examples include aztreonam, latamoxef (Moxalactam - Trade Mark), and other known ⁇ -lactam antibiotics, all of which may be used in the form of pro-drugs thereof.
  • compositions according to the invention the compound according to the invention and the penicillin, cephalosporin or other ⁇ -lactam antibiotic may be linked by means of an in vivo hydrolysable ester group, in the form of a mutual pro-drug.
  • compositions according to the invention may not be suitable for oral administration, in which case the composition will be in a form suitable for parenteral or topical administration.
  • penicillins for co-administration with the compounds according to the invention include ampicillin, amoxycillin, carbenicillin, piperacillin, azl ⁇ cillin, mezlocillin, and ticarcillin.
  • Such penicillins may be used in the form of their pharmaceutically acceptable salts, for example their sodium salts.
  • 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 or infusable suspension, for example, in the manner hereinbefore described in relation to the compounds according to the invention.
  • Amoxycillin for example in the form of its sodium salt or the trihydrate, is particularly preferred for use in synergistic compositions according to the invention.
  • cephalosporins for co-administration with the compounds according to the invention include cephaloridine, cefoperazone and cefazolin, which may be used in the form of their pharmaceutically acceptable salts, for example their sodium salts.
  • a compound according to the invention may be administered to the. patient in an antibacterially effective amount or, when a compound according to the invention is being used in conjunction with a penicillin, cephalosporin, or other ⁇ -lactam antibiotic, it may be used in a synergistically effective amount.
  • the compounds according to the invention may suitably be administered to the patient at a daily dosage of from 0.7 to 50 mg/kg of body weight.
  • a daily dosage for an adult human (of approximately 70 kg body weight), from 50 to 3000 mg, preferably from 100 to 1000 mg, of a compound according to the invention may be adminstered daily, suitably in from 1 to 6, preferably from 2 to 4, separate doses. Higher or lower dosages may, however, be used in accordance with clinical practice.
  • each unit dose may suitably comprise from 25 to 1000 mg, preferably from 50 to 500 mg, of a compound according to the invention.
  • Each unit dose may, for example, be 62.5, 100, 125, 150, 200 or 250 mg of a compound according to the invention.
  • the ratio of the amount of the compound according to the invention to the amount of the other ⁇ -lactam antibiotic may vary within a wide range.
  • the said ratio may, for example, be from 100:1 to 1:100; more particularly, it may, for example, be from 2:1 to 1:30.
  • the amount of penicillin or cephalosporin or other ⁇ -lactam antibiotic in a synergistic composition according to the invention will normally be approximately similar to the amount in which it is conventionally used per se, for example from about 50 mg, advantageously from about 62.5 mg, to about 3000 mg per unit dose, more usually about 125, 250, 500 or 1000 mg per unit dose.
  • compositions according to the invention are one comprising from 150 to 1000 mg, preferably from 200 to 700 mg, of amoxycillin or ampicillin or a pro-drug thereof, in admixture or conjunction with from 5 to 500 mg, preferably from 20 to 250 mg, of a compound according to the invention, per unit dose.
  • the amoxycillin may suitably be in the form of its trihydrate or sodium salt;
  • the ampicillin may suitably be in the form of ampicillin trihydrate, ampicillin anhydrate, sodium ampicillin, hetacillin, pivampicillin hydrochloride, bacampicillin hydrochloride or talampicillin hydrochloride; and the compound according to the invention may most suitably be in crystalline form.
  • Such composition may be in a form suitable for oral or parenteral use, except when it comprises an in vivo hydrolysable ester of ampicillin or amoxycillin in which case the composition should not normally be intended for parenteral administration.
  • a further example of a particularly suitable composition according to the invention is one comprising from 200 to 2000 mg of carbenicillin or ticarcillin or a pro-drug thereof, in admixture or conjunction with from 5 to 500 mg, preferably from 25 to 250 mg, of a compound according to the invention, per unit dose.
  • the carbenicillin or ticarcillin may most suitably be in the form of its di-sodium salt, and the compound according to the invention may most suitably be in crystaline form.
  • the composition contains the carbenicillin or ticarcillin in the form of a di-salt, it is most suitably presented in a form suitable for parenteral administration.
  • the azetidinone-alcohol (3) (isomer II) from Preparation 1(b) (0.156g) was dissolved in methanol: dichloromethane (1:1; 10 ml). The solution was cooled to -20°C and potassium fluoride (0.016g) added. After stirring at room temperature for 0.5 h, tic showed that all of the starting material had been consumed. The reaction mixture was evaporated to a yellow solid which was redissolved in dichloromethane (20 ml). The organic phase was washed with saturated brine (3x) and dried (MgSO 4 ).
  • the azetidinone (4) from Preparation 1(c) (1.22g) was dissolved in dry dichloromethane (80 ml). The solution was cooled in an ice bath and 4-dimethylaminopyridine (0.27g) and triethylamine (0.4 ml) added. After stirring at ice bath temperature for 5 minutes, acetic anhydride (0.3 ml) was added. The mixture was stirred at ice bath temperature for 0.5 h, then washed with saturated brine (100 ml); dilute citric acid solution (100 ml); saturated brine (100 ml); saturated sodium bicarbonate solution (100 ml) and saturated brine (3 x 100 ml).
  • azetidinone (5) (0.272g) from Preparation -1(d) and p-nitrobenzylglyoxylate monohydrate (0.128g) were heated in refluxing benzene (18 ml) with provision for azeotropic removal of water (Dean and Stark apparatus containing molecular sieves 4A) for 1 hour.
  • the mixture was cooled to room temperature and treated with triethylamine (5.2 mg). After stirring at room temperature for 2.25 h the reaction mixture was evaporated to yield the crude hydroxy ester (6); ⁇ max (CHCI 3 ) 3500, 1770 and 1750 cm -1 .
  • the penem ester (11) (0.02g) from Example 1(a) was dissolved in a mixture of dioxan (8 ml) and water (2 ml). 5% Palladium on carbon (30 mg) was added and the mixture hydrogenated at room temperature for 20 min. A 1% w/v sodium bicarbonate solution (0.37 ml) was added and the mixture filtered through celite, the residue was washed with water. The combined filtrates were evaporated to a gum which was chromatographed on Biogel P2 using water as eluent.
  • the ketone (14) from Preparation 2(a) (3g; 3.89 mmol) was dissolved in dimethoxyethane (25 ml) at 0°C under argon and treated with sodium borohydride (310 mg initially) in portions until t.l.c. showed no starting material present.
  • the mixture was treated with citric acid until effervescence ceased, then extracted with ethyl acetate (200 ml). The extracts were washed several times with brine, dried (anhydrous magnesium sulphate) and evaporated to an oil. This crude mixture was chromatographed on silica, eluting with ethyl acetate:cyclohexane (1:2).
  • Methyl 3,4-diaminobenzoate was reacted with aqueous acetic acid and sodium nitrite according to the method of F.R. Benson et al, J. Am. Chem. Soc, 74, (1952), 4917, and the title compound (24) isolated in 60% yield, as a crystalline solid, m.p. 170°C (ethyl acetate); v max (Nujol) 3200 - 2200 (b) and 1720 cm -1 ; ⁇ ppm [(CD 3 ) 2 SO] 3.96 (3H, s); 7.80 -8.30 (2H, m); 8.65 (1H, m); 11.77 (1H, s).
  • 5-Methoxycarbonylbenzotriazole (24) (0.88g) was dissolved in dry N,N-dimethyl formamide (20 ml), potassium carbonate (0.35 g) and methyl iodide (0.62 ml) were added and the reaction mixture stirred under an atmosphere of argon in a stoppered flask at ambient temperature for 1 hour.
  • the ketone (26) from Preparation 3(a) (104 mg) was dissolved in dioxan (3 ml) containing pH 7.0 phosphate buffer (0.3 ml) and the solution chilled to 0°C.
  • Sodium borohydride (16 mg) was added in portions with stirring over 2.5 hours after which time the reaction mixture was allowed to warm to room temperature.
  • the solution was diluted with ethyl acetate and brine (ca. 40 ml).
  • the organic phase was separated, washed with brine, dried (MgSO 4 ) and evaporated.
  • the azetidinone (28) from Preparation 3(c) (2.40 g) was partially dissolved/suspended in dry dichloromethane (MDC) (200 ml) and this partial solution chilled to 0°C. 4-Dimethylaminopyridine (0.64 g) was added, followed by the dropwise addition of a solution of acetic anhydride (0.53 ml) in MDC (20 ml). The reaction mixture was stirred at 0°C for 2 hours and then allowed to warm to room temperature.
  • MDC dry dichloromethane
  • the silver thiolate (33) (308 mg) from Preparation 3(f) was dissolved in dry MDC (4 ml) and the solution chilled to 0°C. 4-Dimethylaminopyridine (47 mg) and acetic formic anhydride (0.28 ml) were added followed by triethylamine hydrochloride (240 mg). The mixture was stirred for 5 minutes at 0°C when a precipitate formed. The cooling bath was removed and stirring continued for 30 minutes. The mixture was diluted with ethyl acetate (50 ml) and the precipitate removed by filtration and washed well with ethyl acetate.
  • the penem (34) from Preparation 3(g) (297 mg) was dissolved in dry MDC (20 ml) and the solution chilled to -40°C under an atmosphere of argon.
  • a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.107 ml) in dry MDC (2 ml) was added dropwise and the reaction stirred 0.5 hours at -30°C.
  • the reaction mixture was diluted with MDC (2 ml), washed with dilute citric acid (10 ml), sodium bicarbonate solution (2 x 10 ml), saturated brine (10 ml) and dried (MgSO4).
  • the penem ester (35) from Example 3(a) (120 mg) was dissolved in a mixture of dioxane (40 ml) and water (12 ml). 5% Palladium on carbon (150 mg) was added and the mixture hydrogenated at room temperature for 30 minutes. A 1% w/v sodium bicarbonate solution (2.24 ml) was added, the mixture filtered through celite and the pad washed thoroughly with water. The filtrate was concentrated under reduced pressure to a small volume (ca. 5 ml) and chromatographed on Biogel P2 using water as eluent.
  • Methyl 1H-thieno[2,3-d]triazole-5-carboxylate Methyl 3-(4-methoxybenzyl) thieno[3,2-d]triazole-5- carboxylate (37) (0.5g) was suspended in trifluoroacetic acid (14.0ml) and warmed in an oil bath at 80°C with stirring. After 3.5 hours, when very little starting material remained (the reaction being monitored by h.p.l.c.) the solution was cooled and the trifluoroacetic acid evaporated.
  • azetidinone (41) (isomer II) from Preparation 4(b) (790mg) was dissolved in a mixture of methanol (30ml) and methylene dichloride (MDC) (30ml) and the solution chilled to -15°C. Potassium' fluoride (90mg) in methanol (3ml) was added dropwise and the reaction mixture stirred at -10°C for 1 hour followed by a further 0.5h to 0°C.
  • the azetidinone (42) from Preparation 4(c) (563mg) was dissolved in dry THF (30ml) and this solution chilled to 0°C. 4-Dimethylaminopyridine (147mg) was added, followed by the dropwise addition of a solution of acetic anhydride (0.122ml) in MDC (4ml). The reaction mixture was stirred for 1 hour at 0°C followed by 1 hour to room temperature. The reaction was diluted with MDC (200ml) and washed with 1N HCl (50ml), water (50ml), saturated sodium bicarbonate solution (50ml), brine (50ml) and dried (MgSO 4 ).
  • the azetidinone (43) (422mg) from Preparation 4(d) and p-nitrobenzylglyoxylate monohydrate (190mg) were heated in refluxing benzene (25ml) with the provision for the azeotropic removal of water (Dean and Stark apparatus containing 4A molecular, sieves) for 1 hour.
  • the mixture was cooled to room temperature and treated with triethylamine (15mg). After stirring at room temperature for 1 hour the reaction mixture was evaporated to yield the crude hydroxy ester (44); v max (CHCI 3 ) 3530, 1770 and 1750cm -1 .
  • 2,6-Lutidine (0.133ml) was then added and the mixture stirred under an atmosphere of argon for 12 hours at 50°C. After addition of ethyl acetate (120ml) the organic phase was washed with saturated brine, 1N hydrochloric acid, saturated brine, saturated sodium bicarbonate solution, saturated brine and dried
  • the silver thiolate (47) (1.42g) from Preparation 4(f) was dissolved in dry MDC (17ml) and the solution chilled to 0°C. 4-Dimethylaminopyridine (0.217g) and acetic formic anhydride (1.30ml) were added, followed by triethylamine hydrochloride (1.12g). The mixture was stirred for 5 minutes at 0°C when a precipitate formed. The cooling bath was removed and stirring continued for 30 minutes. The mixture was diluted with ethyl, acetate (150ml), and the precipitate removed by filtration and washed well with ethyl acetate.
  • the penem (48) from Preparation 4(g) (100mg) was dissolved in dry MDC (40ml) and the solution chilled to -40°C under an atmosphere of argon.
  • a solution of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) (0.035ml) in dry MDC (1ml) was added and the reaction stirred 0.5 hours at -30°C.
  • the reaction mixture was diluted with MDC (40ml), washed with dilute citric acid (10ml), sodium bicarbonate solution (10ml), saturated brine (10ml) and dried (MgSO 4 ).
  • the penem ester (49) from Example 4(a)(260mg) was dissolved in a mixture of dioxan (150ml) and water (20ml). 5% Palladium on carbon (340mg) was added and the mixture hydrogenated at room temperature for 40 minutes. A 5% w/v sodium bicarbonate solution (0.95ml) was added, the mixture filtered through a celite pad and the pad washed thoroughly with water. The filtrate was concentrated under reduced pressure to a small volume (ca 5ml) and chromatographed on Biogel P2 using water as eluent. The appropriate fractions, as determined by u.v.
  • the ketone (52) from Preparation 5(a)(0.90g) was dissolved in dioxan (30ml) containing pH7.0 phosphate buffer (3.0ml) and the solution chilled to 0°C.
  • Sodium borohydride (0.14g) was added in portions with stirring over 1.5 hours after which time the reaction mixture was allowed to warm to room temperature.
  • the solution was diluted with ethyl acetate and brine (ca.400ml).
  • the organic phase was separated, washed with brine, dried (MgS04) and evaporated to yield a two component mixture.
  • the azetidinone (54) from Preparation 5(c)(1.73g) was suspended in dry methylene dichloride (MDC) (120ml). 4-Dimethylaminopyridine (0.51g) was added and the mixture chilled to 0°C. A solution of acetic anhydride (0.39ml) in MDC (10ml) was added dropwise to the stirred suspension and stirring continued for 1.0 hour at 0°C, followed by 0.5 hour to room temperature. The reaction was diluted with MDC (120ml) and washed with 1N HCl(50ml), water (50ml), brine (50ml) and dried (MgS ⁇ 4).
  • MDC dry methylene dichloride
  • the azetidinone (55)(1.85g) from Preparation 5(d) and p-nitrobenzylglyoxylate monohydrate (0.95g) were heated in refluxing benzene (80ml) with provision for the azeotropic removal of water (Dean and Stark apparatus containing 4A molecular sieves) for 1.5 hour.
  • the mixture was cooled to room temperature and treated with triethylamine (90mg). After stirring at room temperature for 1 hour the reaction mixture was evaporated to yield the crude hydroxy ester (56); ⁇ m ax (CHCI 3 ) 3530, 1760cm -1 .
  • the phosphorane (58)(1.93g) from Preparation 5(e) was dissolved in a mixture of methanol (13ml) and dry MDC (20ml) and the solution treated with pyridine (0.20ml). A solution of silver nitrate in methanol (0.15M, 15.6ml) was then added dropwise with stirring. After 1.0 hour at room temperature followed by 1.0 hour at 0°C the reaction was concentrated to approximately one quarter volume and dry ether (approx. 10ml) added.
  • the silver thiolate (59)(1.51g) from Preparation 5(f) was dissolved in dry MDC (18ml) and the solution chilled to 0°C. 4-Dimethylaminopyridine (0.24g) and acetic-formic anhydride (1.42ml) were added followed by triethylamine hydrochloride (1.22g). The mixture was stirred for 5 minutes at 0°C when a precipitate formed. The cooling bath was removed and stirring continued for 30 minutes. The mixture was diluted with ethyl acetate (150ml) and the precipitate removed by filtration and washed well with ethyl acetate.
  • the penem (60) from Preparation 5(g)(96mg) was dissolved in dry MDC (20ml) and the solution chilled to -40°C with stirring under an atmosphere of argon.
  • a solution of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) (0.035ml) in dry MDC (1ml) was added and the reaction stirred 0.5 hours at -30°C.
  • the reaction mixture was diluted with MDC (40ml), washed with dilute citric acid (10ml), sodium bicarbonate solution (10ml), saturated brine (10ml) and dried (MgS ⁇ 4).
  • the penem ester (61) from Example 5(a)(205mg) was dissolved in 20% aqueous dioxan (120ml) and hydrogenolysed at atmospheric pressure in the presence of 5% palladium on carbon (215mg) for 0.5 hour.
  • the reaction mixture was then treated with sodium bicarbonate solution (0.88ml of a 5% w/v aqueous solution) and filtered through a celite pad.
  • the pad was washed thoroughly with water (150ml) and the filtrate concentrated under reduced pressure to a volume of approximately 5ml. This concentrated solution was chromatographed on Biogel P2, eluting with water. Appropriate fractions, as determined by u.v.
  • Azetidinone (1)(0.92g) was condensed with methyl thieno [3,2-b]furan-2-carboxylate (63)(0.36g) in the manner described in Preparation 5(a). Chromatography of the crude product (silica gel eluted with hexane:ethyl acetate, 4:1) gave the title azetidinone (64) as a crisp foam (0.77g); v max (CHCI 3 ) 1750, 1660cm -1 ; ⁇ ppm (CDCI 3 ) 0.36 (3H, s), 0.38 (3H, s), 0.98 (9H, s), 4.13 (1H, d, J 1.5Hz), 5.00 (1H, d, J 1.5Hz), 6.88-7.60 (18H, m); (Found [MNa] + 632).
  • the azetidinone (64) from preparation 6(a) (0.76g) was reduced to a mixture of alcohols using the method described in Preparation 5(b). This two component mixture was separated by chromatography (silica gel eluted with ethyl acetate/ n-hexane) to give the more polar azetidinone (65) as the major isomer (0.56g); Rf(hexane: ethyl acetate, 4:1) 0.1; v max (CHCI 3 ) 1735, 1600cm -1 ; ⁇ ppm (CDCI 3 ) -0.08, 0.03 (each 3H, s), 0.78(9H, s), 2.77 (1H, broad d, J 9Hz, exchanges on addition of D2O), 3.81 (1H, dd, J 6.7 and 1.9Hz), 4.03 (1H, m, sharpens to a doublet on addition of D 2 O, J 6.7Hz), 4.10 (1H, d,
  • azetidinone (65) from Preparation 6(b) (0.56g) was deprotected in the manner described in Preparation 5(c) to give the title azetidinone (66) as a cream coloured solid (0.42g); v max (CHCl 3 ) 3400, 1765cm -1 .
  • the penem ester (71)(120mg) from Example 6(a) was hydrogenolysed using the conditions described in Example 5(b) and the title penem sodium salt (72) isolated as a freeze-dried solid (50mg); V max (KBr) 1750, 1660 and 1600cm -1 ; ⁇ max (H 2 O) 359nm ( ⁇ 19,200); ⁇ ppm (D 2 O) 6.54 (1H, s), 6.94 (1H, s), 6.97 (1H, s)7.08 (1H, d, J 5.3Hz), 7.13 (1H, s), 7.53 (1H, d, J 5.3Hz).
  • Methyl imidazo[2,1-b]thiazole-6-carboxylate (0.4g) (British Patent Publication GB 1493048) was condensed with the azetidinone (l)(0.92g) in the manner described in Preparation 5(a).
  • the azetidinone (73) from Preparation 7(a)(0.85g) was dissolved in a mixture of dioxan (30ml) and ethanol (30ml) and the solution treated, portionwise, with sodium borohydride (75mg). Reaction was continued for one hour and the reaction mixture then concentrated to 50% volume. A further quantity of sodium borohydride (75mg) was added and reaction continued until no starting material remained, as shown by t.l.c. Ethyl acetate (150ml) and saturated brine solution (30ml) were added to the reaction with thorough mixing and the phases separated.
  • the major product (74) was the more polar isomer (0.45g); Rf (ethyl acetate) 0.3; v max (CHCI 3 ) 1730cm -1 ; ⁇ ppm (CDCI 3 ) -0.03, 0.02 (each 3H, s), 0.72 (9H, s), 2.75 (1H, broad d, J 8.5Hz, exchanges on addition of D 2 O), 3.74 (1H, dd, J 6.0Hz and 1.5Hz), 4.10 (1H, m, sharpens to a doublet on addition of D 2 O, J 6.0Hz), 4.43 (1H, d, J 1.5Hz), 6.70-7.60 (18H, m); (Found [MNa] + 634).
  • Azetidinone (74) (450mg) from Preparation 7(b) was dissolved in dry MDC (20ml) and 4-dimethyl- aminopyridine (97mg) added. This solution was chilled to 5°C and a solution of acetic anhydride (80 ⁇ l) in dry MDC (2ml) added. After 0.5 hours at 5°C the cooling bath was removed and acetic anhydride (40 ⁇ l) was added. Reaction was continued at room temperature for 0.5 hour when a further quantity of acetic anhydride (80 ⁇ l) was added.
  • reaction mixture was diluted with MDC (40ml) and washed with 1N HCl (30ml), water (30ml), saturated sodium bicarbonate solution (2x30ml), saturated brine (30ml), dried
  • the azetidinone (75)(440mg) from Preparation 7(c) was dissolved in dry THF (20ml) and the solution chilled to 5°C.
  • Anhydrous potassium fluoride (78mg) followed by 18-crown-6 (39mg) dissolved in dry THF (5ml) were added. After 0.5 hour at 5°C the cooling bath was removed and the reaction stirred at ambient temperature overnight. The reaction mixture was then diluted with ethyl acetate (125ml), washed with brine (3 x 30ml), dried (MgSO 4 ) and evaporated.
  • azetidinone (76)(1.45g) isolated as described in Preparation 7(d) was converted to the title phosphorane in the manner described in Preparation 5(e). Chromatography of the crude phosphorane ( silica gel eluted with a gradient of 66% to 100% ethyl acetate in hexane gave the title azetidinone (77)(1.28g), v max (CHCl 3 ) 1750, 1620 and 1605cm -1 .
  • acetoxy penem (79)(268mg) from Preparation 7(g) was reacted in the manner described in Example 5(a) to give a single isomer as shown by t.l.c, Rf(hexane:ethyl acetate, 1:3) 0.37; Rf(5% ethyl acetate/MDC) 0.20; Rf (10% ethyl cetate/MDC)0.32.
  • the penem ester (80) (60mg) from Example 7(a) was dissolved in a mixture of dioxan (50ml) and water (8ml). A 5% w/v solution of sodum bicarbonate (230 ⁇ l) was added followed by 5% palladium on carbon (100mg) and the mixture hydrogenated at room temperature for 20 minutes. The mixture was then filtered on a celite pad, and the pad washed thoroughly with water. The filtrate was concentrated under reduced pressure to a small volume ( ca 5ml) and chromatographed on Biogel P2 using water as eluent.
  • Azetidinone (1)(0.92g) was condensed with methyl quinoxaline-2-carboxylate (0.50g) using the conditions described in Preparation 4(a). Chromatography (silica gel eluted with ethyl acetate :hexane, 1:1) gave the title azetidinone (82) as a yellow foam (1.14g); v max (CHCl 3 ) 1745, 1685cm -1 ; ⁇ ppm (CDCI 3 ) 0.44 (6H, s), 1.06 (9H, s), 5.03 (1H, d, J2Hz), 5.40(1H, d, J2Hz), 6.70-8.40 (19H, m), 9.28 (1H, s).
  • azetidinone (82) (1.10g) from Preparation 8(a) was reacted as described in Preparation 4(b) and the crude product, as a two component mixture, was subjected to chromatography (silica gel eluted with ethyl acetate/hexane).
  • azetidinone (84) from Preparation 8(c)(820mg) was reacted as described in preparation 4(d) and the crude product when subjected to chromatography (silica gel eluted with ethyl acetate:n-hexane, 1:1) gave the title azetidinone (85) as a cream coloured solid (830mg); % ⁇ ax (CHCI 3 ) 3400, 1775cm -1 ; ⁇ ppm(CDCl 3 ) 2.20 (3H, s), 4.02 (1H, dddd, J 5.4Hz, 2.8Hz, and 1.0Hz), 4.18 (1H, broad s), 4.62 (1H, d, J 2.8Hz), 6.40 (1H, d, J 5.4Hz), 7.10-7.50 (15H, m), 7.85 (1H, m), 8.20 (1H, m), 8.88 (1H, s); (Found CMH] + 546).
  • azetidinone (90)(2.16g) from Preparation 9(a) was reacted as described in Preparation 4(b) and the crude product as a three component mixture, was subjected to chromatography (silica gel eluted with ethyl acetate). The most polar component gave the title azetidinone (91)(0.86g); v max (CHCI 3 ) 3350 (broad), 1730cm -1 ; ⁇ ppm (CDCI 3 ) -0.08 and 0.02 (each 3H, s), 0.67 (9H, s),
  • the azetidinone (91) from Preparation 9(b) (820mg) was dissolved in dry MDC (40ml) and this solution chilled to 5°% and treated with dimethylaminpyridine (49mg), triethylamine (0.19ml), and the dropwise addition of a solution of acetic anhydride (0.4ml) dissolved in dry MDC (5ml). Reaction was continued for 1 hour at 5°C to ambient temperature then diluted with MDC (150ml) and washed with 1N HCl (50ml), water (50ml), saturated NaHCO 3 solution (50ml), brine (50ml), dried (MgSO 4 ) and evaporated.
  • the azetidinone (92)(620mg) from Preparation 9(c) was dissolved in dry THF (40ml) and the solution chilled to 5°C.
  • Anhydrous potassium fluoride (260mg) followed by 18-crown-6 (120mg) dissolved in dry THF (4ml) were added. After 0.5 hours at 5°C the cooling bath was removed and the reaction stirred at ambient temperature for 3 days after which time t.l.c indicated complete reaction.
  • the reaction mixture was then diluted with ethyl acetate (150ml), washed with brine (3 x 50ml) dried (MgSO 4 ) and evaporated.
  • azetidinone (93) (480mg) isolated as described in Preparation 9(d) was converted to the title phosphorane in the manner described in Preparation 5(e). Chromatography of the crude phosphorane (silica gel eluted with ethyl acetate) gave the title azetidinone (94)(560mg); v max (CHCI 3 ) 1750, 1615 and 1605cm -1 .
  • the phosphorane (94)(525mg) from Preparation 9(e) was converted to the title silver salt as described in Preparation 5(f) to give the thiolate (95) as a cream coloured solid (360mg); ⁇ max (KBr) 1750 (broad), 1600 (broad) cm -1 .
  • reaction was continued at -30°C for 1 hour after which time the reaction mixture was washed with 5% citric acid solution (50ml), saturated NaHCO 3 solution (2 x 50ml) brine (50ml), dried (MgSO 4 ) and evaporated.
  • the penem ester (96)(53mg) from Example 9(a) was dissolved in a mixture of dioxan (60ml) and water (6ml) containing sodium bicarbonate (10mg). 5% Palladium on carbon (75mg) was added and the mixture hydrogenated at room temperature for 25 minutes. The mixture was then filtered on a celite pad and the pad washed thoroughly with water. The filtrate was concentrated under reduced pressure to a small volume (ca 3ml) and chromatographed on Biogel P2 using water as eluent.
  • the following table summarises the ⁇ -lactamase inhibitory activity of selected compounds according to the invention, as identified by Example numbers, against selected micro-organisms.
  • the data is given in the form of the minimum inhibitory concentration (MIC) of amoxycillin in ⁇ g/ml when used in conjunction with 5 ⁇ g/ml of the respective compound according to. the invention.
  • the MIC values for amoxycillin alone against the same organisms, and also an MIC values for the compounds according to the invention alone (given in brackets), are given for comparison purposes.
  • Table 'NT' means 'not tested'.

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Abstract

Composés de formule générale (I) ainsi que leurs sels pharmaceutiquement acceptables et esters hydrolysables in vivo, formule dans laquelle un parmi R1 et R2 représente de l'hydrogène, l'autre représentant un groupe hétéroaromatique bicyclique fondu substitué ou non et lié à travers l'un de ces atomes de carbone et possédant cinq ou six atomes dans chaque cycle, et R3 représente de l'hydrogène ou un groupe organique. Ces nouveaux composés possèdent des propriétés anti-bactériennes et inhibitrices de la beta-lactamase.
PCT/GB1986/000428 1985-07-22 1986-07-21 Penemes de 6-alkylidene WO1987000525A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994010178A1 (fr) * 1992-10-29 1994-05-11 Smithkline Beecham P L C Penemes 6-(methylene substitue) et intermediaires
WO1995017184A1 (fr) * 1993-12-23 1995-06-29 Smithkline Beecham Plc Compositions pharmaceutiques contenant de la ceftriaxone ainsi que des penemes
US5776455A (en) * 1994-04-25 1998-07-07 Smithkline Beecham P.L.C. Pharmaceutical formulations
US6472383B1 (en) 1994-04-25 2002-10-29 Smithkline Beecham P.L.C. Pharmaceutical formulations
WO2003093280A1 (fr) * 2002-05-01 2003-11-13 Wyeth Derives d'heterotricyclyl 6-alkylidene-penemes en tant qu'inhibiteurs de beta-lactamase
WO2003093279A1 (fr) * 2002-05-01 2003-11-13 Wyeth PENEMES 6-ALKYLIDENE BICYCLIQUES UTILISES EN TANT QU'INHIBITEURS DE ss-LACTAMASES
WO2003093277A1 (fr) * 2002-05-01 2003-11-13 Wyeth Procede de preparation de derives de 6-alkylidene penem
WO2006130588A1 (fr) * 2005-06-01 2006-12-07 Wyeth 6-alkylidene-penemes bicycliques utilises comme inhibiteurs de $g(b)-lactamases de classe d
US8871201B2 (en) 2004-08-13 2014-10-28 Wyeth Llc Stabilizing formulations

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Publication number Priority date Publication date Assignee Title
EP0120613A1 (fr) * 1983-03-02 1984-10-03 Beecham Group Plc Dérivés de pénème et précurseurs
EP0150781A1 (fr) * 1984-01-26 1985-08-07 Beecham Group Plc 6-Alkylidène-pénèmes, leur préparation et application ainsi que des intermédiaires

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0120613A1 (fr) * 1983-03-02 1984-10-03 Beecham Group Plc Dérivés de pénème et précurseurs
EP0150781A1 (fr) * 1984-01-26 1985-08-07 Beecham Group Plc 6-Alkylidène-pénèmes, leur préparation et application ainsi que des intermédiaires

Cited By (26)

* Cited by examiner, † Cited by third party
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US6037469A (en) * 1992-10-29 2000-03-14 Smithkline Beecham Plc 6-(substituted methylene) penems and intermediates
AP438A (en) * 1992-10-29 1995-11-24 Smithkline Beecham Plc "6-(Substituted-methylene) penems and derivatives thereof and their use in pharmaceutical compositions".
US5602250A (en) * 1992-10-29 1997-02-11 Smithkline Beecham P.L.C. 6-(substituted methylene)penems and intermediates
AU687365B2 (en) * 1992-10-29 1998-02-26 Smithkline Beecham Plc 6-(substituted methylene) penems and intermediates
US6600035B1 (en) 1992-10-29 2003-07-29 Smithkline Beecham P.L.C. 6-(substituted methylene) penems and intermediates
WO1994010178A1 (fr) * 1992-10-29 1994-05-11 Smithkline Beecham P L C Penemes 6-(methylene substitue) et intermediaires
CN1044247C (zh) * 1992-10-29 1999-07-21 史密丝克莱恩比彻姆有限公司 新的青霉烯类衍生物及其制法与用途
CN1102595C (zh) * 1992-10-29 2003-03-05 史密丝克莱恩比彻姆有限公司 青霉烯类化合物及其衍生物
WO1995017184A1 (fr) * 1993-12-23 1995-06-29 Smithkline Beecham Plc Compositions pharmaceutiques contenant de la ceftriaxone ainsi que des penemes
US5911985A (en) * 1994-04-25 1999-06-15 Smithkline Beecham P.L.C. Pharmaceutical formulations containing a β-lactamase inhibiting penem in combination with β-lactam antibiotic and their use in the treatment of bacterial infections
US6472383B1 (en) 1994-04-25 2002-10-29 Smithkline Beecham P.L.C. Pharmaceutical formulations
US5939066A (en) * 1994-04-25 1999-08-17 Smithkline Beecham P.L.C. Pharmaceutical formulations
US5776455A (en) * 1994-04-25 1998-07-07 Smithkline Beecham P.L.C. Pharmaceutical formulations
US7112582B2 (en) 2002-05-01 2006-09-26 Wyeth Bicyclic 6-alkylidene-penems as β-lactamase inhibitors
WO2003093279A1 (fr) * 2002-05-01 2003-11-13 Wyeth PENEMES 6-ALKYLIDENE BICYCLIQUES UTILISES EN TANT QU'INHIBITEURS DE ss-LACTAMASES
WO2003093277A1 (fr) * 2002-05-01 2003-11-13 Wyeth Procede de preparation de derives de 6-alkylidene penem
JP2005533017A (ja) * 2002-05-01 2005-11-04 ワイス β−ラクタマーゼ阻害剤としての二環式６−アルキリデン−ペネム
US7018997B2 (en) 2002-05-01 2006-03-28 Wyeth Tricyclic 6-alkylidene-penems as β-lactamase inhibitors
WO2003093280A1 (fr) * 2002-05-01 2003-11-13 Wyeth Derives d'heterotricyclyl 6-alkylidene-penemes en tant qu'inhibiteurs de beta-lactamase
EP1988093A1 (fr) 2002-05-01 2008-11-05 Wyeth a Corporation of the State of Delaware 6-alkylidene-penems bicycles en tant qu'inhibiteurs beta-lactamases
US7691842B2 (en) 2002-05-01 2010-04-06 Wyeth Llc Tricyclic 6-alkylidene-penems as β-lactamase inhibitors
CN1649883B (zh) * 2002-05-01 2010-05-26 惠氏公司 作为内酰胺酶抑制剂的二环6-亚烷基-表霉烯
SG162614A1 (en) * 2002-05-01 2010-07-29 Wyeth Corp Bicyclic 6-alkylidene-penems as beta-lactamases inhibitors
US7812014B2 (en) 2002-05-01 2010-10-12 Wyeth Llc Bicyclic 6-alkylidene-penems as β-lactamase inhibitors
US8871201B2 (en) 2004-08-13 2014-10-28 Wyeth Llc Stabilizing formulations
WO2006130588A1 (fr) * 2005-06-01 2006-12-07 Wyeth 6-alkylidene-penemes bicycliques utilises comme inhibiteurs de $g(b)-lactamases de classe d

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