WO1997014690A1 - Derives de 5-(acetamidomethyl)-3-aryldihydrofuran-2-one et de tetrahydrofuran-2-one ayant une activite antibiotique - Google Patents

Derives de 5-(acetamidomethyl)-3-aryldihydrofuran-2-one et de tetrahydrofuran-2-one ayant une activite antibiotique Download PDF

Info

Publication number
WO1997014690A1
WO1997014690A1 PCT/GB1996/002504 GB9602504W WO9714690A1 WO 1997014690 A1 WO1997014690 A1 WO 1997014690A1 GB 9602504 W GB9602504 W GB 9602504W WO 9714690 A1 WO9714690 A1 WO 9714690A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
alkyl
ofthe formula
mixture
compound
Prior art date
Application number
PCT/GB1996/002504
Other languages
English (en)
Inventor
Michael Barry Gravestock
Original Assignee
Zeneca Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zeneca Limited filed Critical Zeneca Limited
Priority to JP9515591A priority Critical patent/JPH11513680A/ja
Priority to EP96933552A priority patent/EP0858453A1/fr
Priority to AU72248/96A priority patent/AU7224896A/en
Publication of WO1997014690A1 publication Critical patent/WO1997014690A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide

Definitions

  • the present invention relates to antibiotic compounds and in particular to antibiotic compounds containing a furanone ring. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
  • bacterial pathogens may be classified as either Gram-positive of Gram-negative pathogens.
  • Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity.
  • the compounds of the present invention are regarded primarily as effective against Gram-positive pathogens because of their particularly good activity against such pathogens.
  • Gram-positive pathogens for example Staphylococci, Enterococci Streptococci and mycobacteria. are particularly important because ofthe development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established.
  • MRSA methicillin resistant staphylococcus
  • MRCNS methicillin resistant coagulase negative staphylococci
  • penicillin resistant streptococcus pneumoniae and multiply resistant enterococcus faecium.
  • vancomycin The major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens.
  • the present inventors have discovered a class of antibiotic compounds containing a furanone ring which have useful activity against Gram-positive pathogens including MRSA and MRCNS and, in particular, against various strains exhibiting resistance to vancomycin and against E. faecium strains resistant to both aminoglycosides and clinically used Beta-lactams.
  • the compounds also possess a particularly favourable toxicological profile. Accordingly the present invention provides a compound of the formula (I):
  • R! and R ⁇ are independently hydrogen or fluorine
  • R3 and R ⁇ are independently hydrogen or methyl; D is O, S, SO, SO 2 or of the formula R ⁇ N wherein R ⁇ is hydrogen or benzyl; or R ⁇ is of the formula R 6 CO- or R 6 SO wherein R 6 is amino, (l -4C)alkylamino, di-((l-4C)alkyl)- amino or (l-6C)alkyl optionally substituted by hydroxy, cyano, amino, ( 1 -4C)alkylamino, di-((l-4C)alkyl)amino.
  • R > is ofthe formula R ⁇ C(O)O(l-6C)alkyl wherein R? is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (l- ⁇ C)alkyl, or R*> is of the formula R ⁇ O-, wherein R ⁇ is benzyl or optionally substituted (l -6C)alkyI; or R ⁇ is of the formula R 10 CH(R 9 XCH2) m - wherein is 0 or 1.
  • R 9 is fluoro. cyano.
  • heteroaryl means a 5- or 6-membered aryl ring wherein 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulfur.
  • alkyl includes both straight-chain and branched-chain alkyl groups.
  • references to individual alkyl groups such as “propyl” are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain versions only.
  • An analogous convention applies to other generic terms, for example amino(l-4C)alkyl includes 1 -aminoethyl and 2-aminoethyl.
  • Particular optional substituents for carbon atoms in 5- or 6- membered heteroaryl, phenyl and (l-6C)alkyl in R? include, halo, nitro, amino, hydroxy, cyano, (l-4C)alkyl, (1- 4C)alkoxy and (l-4C)alkylS(O) n (wherein n is 1 or 2).
  • Particular optional substituents for nitrogen atoms which can be substituted without becoming quatemised in 5- or 6- membered heteroaryl rings in R? include (1- 4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and ( 1 -4C)alkanoyl.
  • the compounds ofthe present invention have a chiral centre at the C5-position.
  • the 5(R) enantiomer, as shown in formula (IA), is the pharmaceutically-active enantiomer.
  • the present invention includes the pure 5(R) enantiomer or diastereoisomer and mixtures ofthe 5(R) and 5(S) enantiomers or diastereoisomers, for example a racemic mixture or equal mixtures of diastereoisomers. If a mixture of 5(R) and 5(S) is used, a larger amount (depending on the ratio of the enantiomers or diastereoisomers) will be required to achieve the same effects as the same weight ofthe 5(R) compound.
  • -A-B- is of the formula >CHCH2- (i.e. when the ring is a 3.4- dihyrofuranone ring) there is also a chiral centre at the 3-position.
  • the present invention relates to both the 3R and the 3S diastereoisomers.
  • Suitable values for generic radicals referred to above and hereinafter include those set out below; for (l-6C)alkyl : methyl, ethyl, propyl, isopropyl and tert-butyl: for (l-4C)alkoxy : methoxy.
  • acetyl and propionyl for ( 1 -4C)alkoxycarbonyl : methoxycarbonyl, ethoxycarbonyl and propoxy carbonyl; for amino( 1 -6C)alkanoyl : aminoacetyl and aminopropionyl; for (l-4C)alkylamino(l-6C)alkanoyl : methylaminoacetyl, methylaminopropionyl and ethylaminoacetyl; for di-(( 1 -4C)alkyl)amino( 1 -6C)alkanoyl dimethylaminoacetyl and dimethylaminopropionyl; for hydroxy(l-6C)alkyl : hydroxymethyl, 1 -hydroxethyl,
  • Suitable pharmaceutically-acceptable salts include acid addition salts such as hydrochloride, hydrobromide. citrate, maleate. methanesulfonate. fumarate and salts formed with phosphoric and sulfuric acid.
  • suitable salts are base salts such as sodium, an alkaline earth metal salt for example calcium or magnesium, an ammonium or tetra-(2-hydroxyethyl)ammonium salt, an organic amide salt for example triethylamine, morpholine, M-methylpiperidine, H-ethylpiperidine, procaine, dibenzylamine, M-N-dibenzylethylamine or amino acids for example lysine. There may be more than one or more cation or anion depending on the number of charged functions and the valency ofthe cations or anions.
  • a preferred pharmaceutically-acceptable salt is the sodium salt.
  • salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
  • the compounds ofthe formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound ofthe formula (I).
  • pro-drugs include in-vivo hydrolysable esters of a compound ofthe formula
  • An in-vivo hydrolysable ester of a compound ofthe formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkoxymethyl esters, for example methoxymethyl; (l-6C)alkanoyloxymethyl esters, for example pivaloyloxymethyl; phthalidyl esters; (3-8C)cycloalkylcarbonyloxy-(l -6C)alkyl esters, for example 1- cyclohexylcarbonyloxyethyl; 1.3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3- dioxolen-2-onylmethyl; and ( 1 -6C)alkoxycarbonyloxyethyl esters, for example 1 -methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this invention.
  • An in-vivo hydrolysable ester of a compound ofthe formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent alcohol.
  • the term includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result ofthe in-vivo hydrolysis ofthe ester breakdown to give the parent hydroxy group.
  • Examples of ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropiony loxy methoxy.
  • a selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyi, phenylacetyl, and substituted benzoyi and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-M-alkylcarbamoyl (to give carbamates). dialkylaminoacetyl and carboxy acetyl.
  • optional substituents for phenyl in Rl are amino, ( 1 -4C)alkylamino, di(( 1 - 4C)alkyl)amino, amino(l-6C)alkanoyl, (l-4C)alkylamino(l-6C)alkanoyl, di((l- 2C)alkyl)(l-6C)alkanoyl, hydroxy (l-6C)alkyl, amino( 1 -6C)alkyl, (l-4C)alkylamino(l- 6C)alkyl and di((l-2C)alkyl)amino(l-6C)alkyl.
  • optional substituents for phenyl in R ⁇ are ( 1 -4C)alkylamino( 1 -6C)alkanoyl and hydroxy (l-6C)alkyl.
  • optional substituents for ( 1 -6C)alkyl in R? are hydroxy, cyano. amino.
  • preferred compounds ofthe invention comprise a compound ofthe formula (I) wherein :
  • R* and R ⁇ are independently hydrogen or fluorine
  • R3 and R ⁇ are independently hydrogen or methyl
  • D is O, S, SO, SO 2 or ofthe formula R ⁇ N wherein R ⁇ is benzyl; or R ⁇ is ofthe formula R 6 CO- or R 6 SO 2 - wherein R 6 is amino, ( 1 -4C)alkylamino. di-(( 1 -4C)alkyl)-amino or ( 1 -
  • R 7 C(O)O(l-6C)alkyl wherein R? is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl or optionally substituted (l-6C)alkyl, or R ⁇ is ofthe formula R ⁇ O-. wherein R ⁇ is benzyl or optionally substituted (l-6C)alkyl; or R ⁇ is ofthe formula
  • R 10 CH(R 9 )(CH2) m - wherein m is 0 or 1.
  • R 9 is fluoro. cyano. ( 1 -4C)alkoxy, ( 1 -4C)alkyl- sulfonyl, (l-4C)alkoxycarbonyl or hydroxy, (provided that when m is 0, R 9 is not hydroxy) and RlO is hydrogen or (l-4C)alkyl; and pharmaceutically-acceptable salts thereof; or
  • Rl and R ⁇ are independently hydrogen or fluorine:
  • R3 and R ⁇ are independently hydrogen or methyl;
  • D is O, S, SO, SO 2 or ofthe formula R 5 N wherein R 5 is benzyl; or R 5 is ofthe formula R ⁇ CO- or R 6 SO 2 - wherein R 6 is amino, (l-4C)alkylamino, di-((l-4C)alkyl)-amino or (1- 6C)alkyl optionally substituted by hydroxy, cyano. amino, (l-4C)alkylamino, di-((l- 4C)alkyl)amino, or (l-4C)alkylS(O) n _. wherein n is 1 or 2, or R 6 is ofthe formula
  • Rl and R ⁇ are independently hydrogen or fluorine; R3 and R ⁇ are hydrogen; D is O, S, or ofthe formula R ⁇ N wherein R ⁇ is benzyl, or R ⁇ is of the formula R ⁇ CO- or R 6 SO 2 - wherein R 6 is amino, (l-4C)alkylamino, di-((l-4C)alkyl)-amino or (l-6C)alkyl optionally substituted by hydroxy, cyano, amino, (l-4C)alkylamino, di-((l- 4C)alkyl)amino, or (l-4C)alkylS(O) n _, wherein n is 1 or 2, or R ⁇ is ofthe formula R 7 C(O)O(l-6C)alkyl wherein R 7 is pyridyl or imidazol-1-yl, phenyl optionally substituted by ( 1 -4C)alkylamino( 1 -6C)alkanoyl and hydroxy( 1 -6
  • D is O, S, or ofthe formula R 5 N wherein R 5 is of the formula R 6 CO- or R 6 SO 2 - wherein R 6 is hydroxymethyl or of the formula R 7 C(O)O(l-6C)alkyl wherein R 7 is dimethylamino(l-6C)alkyl: or R ⁇ > is of the formula R ⁇ O-, wherein R ⁇ is (l-6C)alkyl; or R ⁇ is ofthe formula Rl ⁇ CH(R 9 )(CH2) m - wherein m is 0 or 1.
  • R 9 is fluoro or cyano and R ® is hydrogen; and pharmaceutically-acceptable salts thereof; or
  • Rl and R ⁇ are independently hydrogen or fluorine;
  • R3 and R ⁇ are hydrogen;
  • D is S, or ofthe formula R ⁇ N wherein R ⁇ is ofthe formula R ⁇ SO 2 - wherein R*> is (1- 6C)alkyl; and pharmaceutically-acceptable salts thereof.
  • Particular preferred compounds ofthe invention are : 5R-acetamidomethyl-3-(3-fluoro-4-thiomo ⁇ holinophenyl)dihydrofuran-2(3H)-one;
  • Particular especially preferred compounds ofthe invention are:
  • Particular further especially preferred compounds ofthe invention are: 5R-acetamidomethyl-3-(3-fluoro-4-mo ⁇ holinophenyI)furan-2(5H)-one; 5R-acetamidomethyl-3-(3-fluoro-4-thiomo ⁇ holinophenyl)furan-2(5H)-one; or pharmaceutically-acceptable salts thereof.
  • An especially preferred compound ofthe invention is : 5R-acetamidomethyl-3-(3-fluoro-4-thiomo ⁇ holinophenyl)furan-2(5H)-one; or pharmaceutically-acceptable salts thereof.
  • the present invention provides a process for preparing a compound ofthe formula (I) or a pharmaceutically-acceptable salt thereof.
  • the compounds ofthe formula (I) are prepared:
  • -A-B- is >C(OH)-CH 2 -; 1) when D is ofthe formula R 5 N wherein R 5 is hydrogen, by the N-dealkylation of the related compound wherein R is benzyl or ( 1 -4C)alkyl; wherein R 1 , R 2 . R 3 , R 4 . R 6 , R 9 , R 10 .
  • a and B are as hereinabove defined and L. L , L 2 and L 3 are leaving groups and X- is a counter ion: and wherein any functional groups are optionally protected and thereafter if necessary: i) removing any protecting groups; ii) forming a pharmaceutically- acceptable salt.
  • Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of he protecting group in question, such methods being chosen so as to effect removal ofthe protecting group with minimum disturbance of groups elsewhere in the molecule.
  • protecting groups are given below for the sake of convenience, in which "lower” signifies that the group to which it is applied preferable has 1 -4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope ofthe invention.
  • a carboxyl protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (eg isopropyl, tbutyl); lower alkoxy lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl; lower aliphatic acyloxy lower alkyl groups, (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (eg 1 -methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg p-methoxybenzyl, o ⁇ nitrobenzyl, jhnitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsilyl and kbutyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (
  • hydroxyl protecting groups include lower alkenyl groups (eg allyl); lower alkanoyl groups (eg acetyl): lower alkoxycarbonyl groups (eg kbutoxycarbonyl); lower alkenyloxycarbonyl groups (eg ally loxycarbony 1); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, jtmethoxybenzyloxycarbonyl, o_nitrobenzyloxycarbonyl, p__nitrobenzyloxycarbonyl); tri lower alkyl/arylsilyl groups (eg trimethylsilyl, tbutyldimethylsilyl, kbutyldiphenylsilyl); aryl lower alkyl groups (eg benzyl); and triaryl lower alkyl groups (eg triphenylmethyl).
  • lower alkenyl groups eg allyl
  • lower alkanoyl groups eg acetyl
  • amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg p_-methoxybenzyl, nitrobenzyl and 2.4-dimethoxybenzyl, and triphenylmethyl); di-jtanisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg kbutoxycarbonyl); lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl, prmethoxybenzyloxycarbonyl, jtnitrobenzyloxycarbonyl, jtnitrobenzy loxy carbonyl: trialkylsilyl (eg trimethylsilyl and tbutyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups.
  • aralkyl groups eg benzyl and
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, metal- or enzymically-catalysed hydrolysis, for groups such as Qrnitrobenzyloxycarbonyl, photolytically and for groups such as silyl groups, fluoride.
  • aryl lower alkyl eg benzyl
  • triaryl lower alkyl eg triphenylmethyl
  • N-bromosuccinimide either in an inert solvent such as carbon tetrachloride or in acetic acid in the presence of catalytic amounts of 2,2'-azobisobutyronitrile (AIBN).
  • AIBN 2,2'-azobisobutyronitrile
  • Standard oxidising agents are known in the art. One should select an oxidising agent which is capable of oxidising the -SPh group but not other groups in the molecule.
  • Preferred oxidising agents for this reaction include potassium peroxymonosulfate (oxone) and sodium periodate.
  • L may be chloro and the reaction may be performed in the presence of an organic base, such as pyridine or triethylamine, in a temperature range of 0°C to ambient temperature, in an inert organic solvent such as tetrahydrofuran or methylenechloride.
  • organic base such as pyridine or triethylamine
  • CH3COL may be acetic anhydride in which case the reaction may be carried out in the presence of base such as sodium hydroxide under Schotten-Baumann conditions.
  • Suitable reducing agents include triethylamine/hydrogen sulfide, triphenylphosphine or phosphite ester and hydrogen (in the presence of a catalyst). More specifically a compound ofthe formula (XI) may be converted to a compound ofthe formula (IV) by heating them in an aprotic solvent, such as 1 ,2-dimethoxyethane. in the presence of P(OMe)3 and subsequently heating in 6N aqueous hydrochloric acid, or reacting the compound ofthe formula (XI) with palladium on carbon in a protic solvent such as ethanol.
  • a protic solvent such as ethanol
  • the compounds of the formula (X) may be converted to compounds ofthe formula (XI) by reacting it with a source of azide.
  • a source of azide For example, by reacting the compound of the formula (X) with sodium azide in an inert solvent such as DMF in a temperature range of ambient to 100°C, normally in the region of 50 to 85°C.
  • the hydroxy group in compounds of the formula (XII) is converted to a tosyloxy or mesyloxy group by standard methods known in the art. such as reacting the compounds of the formula (XII) with a tosyl chloride or mesyl chloride group in the presence of a mild base such as triethylamine or pyridine.
  • the protecting group. Rl4. in compounds ofthe formula (XIII) is removed using standard methods known in the art. For example, when R' 4 is benzyl with palladium on carbon.
  • Compounds ofthe formula (XIII) may be prepared by cyclising a compound of the formula (XIV) in a lactone-forming reaction, for example, by heating the compound of the formula (XIII) in aqueous acid in a suitable co-solvent such as THF. DMF or by using a biphasic system.
  • Compounds ofthe formula (XIV) may be formed by reacting together compounds ofthe formulae (XV) and (XVI) in the presence of a strong base, such as lithium diisopropylamide, in an aprotic solvent such as THF in a temperature range of -78°C to
  • compounds ofthe formula (XII) may be prepared by reacting a compound ofthe formula (XV) with a compound ofthe formula (XVII).
  • Suitable values for R *> include iodo. bromo, mesyloxy and tosyloxy.
  • the compounds ofthe formula (XX) may be converted into compounds ofthe formula (XIX) by dissolving the former compound in aqueous sodium hydrogen carbonate and subsequently adding iodine in an inert solvent which is miscible with water, such as
  • THF in a temperature range of -20°C to ambient, normally at 0°C.
  • the compounds ofthe formula (XX) are prepared by deprotonating a compound ofthe formula (XXI) with a strong base, such as lithium diisopropylamide in an aprotic solvent, such as THF and reacting this deprotonated compound with allyl bromide.
  • a strong base such as lithium diisopropylamide
  • an aprotic solvent such as THF
  • the deprotonation is carried out at low temeprature. often -78°C: the temperature being allowed to increase after the addition of allyl bromide.
  • the saturated heterocyclic group is introduced, for example, by reacting the compound ofthe formula (XXIII) with a compound ofthe formula (XXII):
  • L 4 is a leaving group.
  • Suitable conditions for this reaction include heating the reagents in an inert organic solvent such as acetonitrile or DMF, in a temperature range of 80-150°C.
  • Suitable values for L 4 include mesyl, tosyl and fluoro.
  • Preferably L 4 is fluoro.
  • the acetyl group may be converted to a carboxymethyl group by reaction with mo ⁇ holine, in the presence of sulfur, in a temperature range of 100°C-200°C, preferably at reflux. Preferablv the reaction is carried out in the absence of solvent.
  • This forms a mo ⁇ holinothioacetyl group which may be converted to the carboxymethyl group by treatment with an aqueous base, such as aqueous potassium hydroxide or a strong acid such as concentrated hydrochloric acid, in a temperature range of 80-120°C.
  • reaction between compounds ofthe formulae (VI) and R ⁇ COl is 5 conveniently carried out using similar conditions to those described for the reaction between compounds ofthe formulae (IV) and (V).
  • L ⁇ is halo and in particular chloro.
  • R 6 is of the formula R 8 O- then R 6 COL J is a suitable formate, preferably a chloroformate (i.e. L is preferably chloro), and the reaction with a compound ofthe formula (VI) is conveniently carried out in the presence of a suitable formate, preferably a chloroformate (i.e. L is preferably chloro), and the reaction with a compound ofthe formula (VI) is conveniently carried out in the presence of a suitable formate, preferably a chloroformate (i.e. L is preferably chloro), and the reaction with a compound ofthe formula (VI) is conveniently carried out in the presence of a suitable
  • Compounds ofthe formula (VII) may be reduced using agents such as sodium borohydride or sodium cyanoborohydride.
  • iminium salt formation and reduction in silu may be carried out in a water-miscible solvent such as ethanol or tetrahydrofuran, in the presence of a reducing agent such as sodium cyanoborohydride (NaCNBH3) under acidic conditions (Synthesis 135, 1975: Org. Prep. Proceed. Int. 11, 201. 1979).
  • Compounds of the formula (VI) may be prepared from appropriate intermediates using similar methods to those described in scheme I and scheme II and other processes for the preparation of compounds ofthe formula (I).
  • the piperazine group can be introduced by reacting the appropriate intermediate with a compound of the formula (XXII) wherein D is nitrogen or protected nitrogen. If a protecting group is used it may be removed at a convenient stage later in the reaction sequence.
  • Compounds of the formula (IX) may be oxidised to compounds ofthe formula
  • D is SO or SO2-
  • Suitable oxidising agents for the conversion of D to SO include potassium metaperiodate and peracids such as metachloroperoxybenzoic acid. Stronger oxidising agents, such as oxone may be used to convert D to SO2.
  • dehydration may be achieved by use of suitable acidic conditions, such as the use of toluene-4-sulfonic acid in glacial acetic acid, or the use of phosphorous tribromide in an inert solvent under base-catalysed conditions using a base such as pyridine.
  • Compounds in which -A-B- is >C(OH)CH2_ are conveniently prepared by reacting the compound of formula (I) in which -A-B- is >CHCH2_ with a suitable oxidizing agent.
  • a suitable oxidizing agent which is capable of oxidizing the >CHCH2- group to the >C(OH)CH2- group, but not other groups in the molecule.
  • a preferred oxidizing agent for this reaction is an oxaziridine. such as (lS)(+)(10-camphorsulfonyl)oxaziridine, in the presence of a suitable base, such as potassium bis(trimethylsilyl)amide.
  • N-dealkylation of a compound ofthe formula (I) wherein D is R N and R 5 is benzyl or ( 1 -4C)alkyl is conveniently achieved by use of a reagent such as 1- chloroethylchloroformate.
  • the reaction is conveniently performed in an inert solvent such as dichloromethane at a temperature in the range 0-40°C.
  • Compounds ofthe formula (IV) and related intermediates can be prepared as a mixture of (R) and (S) enantiomers or diastereoisomers as appropriate, and resolved and/or separated into the desired enantiomer or diastereoisomer using standard methods known in the art.
  • the pure enantiomer or diastereoisomer can be used to prepared compounds ofthe formula (I).
  • compounds ofthe formula (I) can be prepared as the pure (R) form from a compound ofthe formula (XVI) in the form of the pure (S) enantiomer depicted below:
  • an optically active form of a compound of the formula (I) When an optically active form of a compound of the formula (I) is required, it may be obtained, by carrying out one of the above procedures using an optically active starting material or by resolution of a racemic form ofthe compound or intermediate using a standard procedure.
  • a compound ofthe formula I. or a pharmaceutically-acceptable salt thereof for use in a method of treatment ofthe human or animal body by therapy.
  • a method for producing an antibacterial effect in a warm-blooded animal, such as man. in need of such treatment which comprises administering to said animal an effective amount of a compound of the present invention. or a pharmaceutically-acceptable salt thereof.
  • the invention also provides the use of a compound ofthe present invention, or a pharmacetuically-acceptable salt thereof, in the manufacture of a novel medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.
  • a compound of the formula (I) or a pharmaceutically-acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition which comprises a compound ofthe formula (I) or a pharmaceutically- acceptable salt thereof and a pharmaceutically-acceptable diluent or carrier.
  • the pharmaceutical compositions of this invention may be administered in the standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration.
  • the compounds of this invention may be formulated by means known in the art into the form of. for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, dispersible powders, suppositories and sterile injectable aqueous or oily solutions or suspensions.
  • the pharmaceutical composition of this invention may also contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents (for example ⁇ - lactams or aminoglycosides). These may include penicillins, for example oxacillin or flucloxacillin and carbapenems, for example meropenem or imipenem, to improve therapeutic effectiveness against methicillin-resistant staphylococci.
  • drugs of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein product (BPI) or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between lOOmg and lg ofthe compound of this invention.
  • composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of 5 mgkg-I to 20 mgkg-I ofthe compound of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • the pharmaceutically-acceptable compounds ofthe present invention are useful antibacterial agents having a good spectrum of activity in vitro against standard Gram-positive organisms, which are used to screen for activity against pathogenic bacteria.
  • the pharmaceutically-acceptable compounds ofthe present invention show activity against enterococci. pnenumococci and methicillin resistant strains of S. aureus and coagulase negative staphylococci.
  • the antibacterial spectrum and potency of a particular compound may be determined in a standard test system.
  • the antibacterial properties ofthe compounds ofthe invention may also be demonstrated in vivo in conventional tests.
  • Staphylococci were tested on agar. using an inoculum of IO 4 cfu/spot and an incubation temperature of 37°C for 24 hours - standard test conditions for the expression of methicillin resistance. Streptococci and enterococci were tested on agar supplemented with 5% defibrinated horse blood, an inoculum of IO 4 CFU/spot and an incubation temperature of 37°C in an atmosphere of 5% carbon dioxide for 48 hours - blood is required for the growth of some ofthe test organisms.
  • MRQS methicillin resistant quinolone sensitive
  • MRQR methicillin resistant quinolone resistant
  • MR methicillin resistant
  • DMF is dimethylformamide
  • THF is tetrahydrofuran
  • DME is 1.2 -dimethoxyethane
  • LDA is lithium diisopropylamide
  • HCl is hydrochloric acid
  • DMPU is M,N-dimethylpropylene urea
  • MS is mass spectroscopy
  • Methanesulfonyl chloride (2.5g) was added dropwise to a solution of a 1 :1 mixture of cis:trans isomers of 5R-hydroxymethyl-3-(3-fluoro-4-thiomo ⁇ holinophenyl)dihydrofuran- 2(3H)-one (5.3g) in pyridine (50ml) whilst maintaining the temperature at 0°C-5°C.
  • the mixture was stirred at 0°C-5°C for a further 30 minutes, and then allowed to warm to ambient temperature over 1 hour. The mixture was then stirred for a further 1 hour before being drowned into ice-cold water (125ml).
  • Trimethylphosphite (2g) was added dropwise at 50°C to a solution of a 5: 1 mixture of cis:trans isomers of 5R-azidomethyl-3-(3-fluoro-4-thiomo ⁇ holino-phenyl)- dihydrofuran-2(3H)-one (4.6g) in 1.2 -dimethoxyethane (70ml).
  • the mixture was refluxed for 3 hours and then cooled to 60°C. 6N HCl (5ml) and water (5ml) were added, the mixture refluxed for a further 5 hours, and then allowed to cool overnight.
  • 3,4-Difluoroacetophenone ( 16 g) was added to a suspension of anhydrous piperazine (30 g) in acetonitrile (160 ml), and the mixture stirred under argon at reflux for 5 hours. The mixture was evaporated, and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate. and the solvent evaporated to give 3-fluoro-4- ( 1 -piperazinyl)acetophenone as a solid (20 g) which was used without further purification.
  • a solution of LDA was prepared by the dropwise addition of n-butyl lithium (18.3 ml, 1.2M solution in hexane) to a stirred solution of diisopropylamine (3.08 ml) in dry THF (20 ml) at 0°C .
  • the solution of LDA was added to a stirred solution of
  • NMR fCDCty 2.20 (broad. IH); 2.34-2.48 (m. IH); 2.57-2.72 (m. IH); 3.04 (t. 4H); 3.67 (t + m, 5H); 3.86 (dd. 0.5H): 3.92-4.05 (m. 1.5H): 4.56-4.65 ( . 0.5H); 4.56-4.75 (m, 0.5H): 5.14 (s, 2H); 6.89-7.05 (m. 3H); 7.35 (m, 5H).
  • Trimethylphosphite 1 g was added slowly at 50°C to a solution of a 1:1 3R:3S mixture of isomers of 5R-azidomethyl-3-(3-fluoro-4-mo ⁇ holinophenyl)-dihydrofuran-2-(3H)-one (2.2g) in 1 ,2-dimethoxyethane (40ml). The mixture was refluxed for 2 hours and then cooled back to 50°C before carefully adding 6N HCl (2.4 ml) and water (2ml). The mixture was refluxed overnight, and then evaporated down to an oily residue, which was taken up in a 1 :1 mixture of THF and water (80ml).
  • the mixture was cooled to 0°C-5°C and sodium hyrdrogencarbonate (6g) added to adjust pH to 8-9.
  • Acetic anhydride (2 ml) was added and mixture stirred at 0°C-5°C for 15 minutes.
  • the mixture was allowed to rise to ambient temperature and stirred for a further 15 minutes.
  • the pH ofthe mixture was re-adjusted to 8 and extracted with ethyl acetate, which was then evaporated to yield an oil.
  • the oil was purified by silica gel column chromatography using as eluant a mixture of methanol (10%) and dichloromethane.
  • Mo ⁇ holine (34g) and elemental sulfur (12.4g) were added to 3-fluoro-4- mo ⁇ holinoacetophenone (66.6g) and the mixture refluxed for 3 hours. After cooling to 50°C a 1 :1 mixture of ethyl acetate and iso-hexane (200ml) was added and the mixture refluxed for 10 minutes before cooling to ambient temperature and stirring for 30 minutes. The resulting solid was filtered and washed with 1 : 1 mixture of ethyl acetate and iso ⁇ hexane before being dried to give M-[2-(3-fluoro-4-mo ⁇ holinophenyl)-l- thioxojethylmo ⁇ holine (80g, 83% yield).
  • M-il ESP+ (M+H) 325.3
  • M-[2-(3-Fluoro-4-mo ⁇ holinophenyl)-l-thioxo]ethylmo ⁇ holine (79g) was refluxed overnight in 5N HCl (300ml). The mixture was then cooled to ambient temperature and the pH adjusted to 10. The aqueous solution was extracted with dichloromethane (3 x 75 ml) and the organic phases discarded. The aqueous phase was then reacidified to pH 4 with concentrated HCl and the resulting solid filtered and dried to give 3-fluoro-4- mo ⁇ holinophenylacetic acid (25g, 43% yield).
  • N.N 1 -dimethy lpropylene urea (DMPU) (5ml) was added to a stirred suspension of 3- fluoro-4-mo ⁇ holinophenylacetic acid (12.5g) in THF (150ml) and the mixture cooled to - 78°C.
  • a 1.5M solution of LDA (77ml) was added dropwise below
  • DMSO-D6. 62.15 (m. 1 H (cis)). ⁇ ca.2.45 (m. 2H (trans)). 62.58 (m. 1 H (cis)). 62.98 (t. 4H). 6 ca.2.65 (m. IH). 63.75 (t. 4H), 64.05 (m,l H). 64.5-4.7 (m. IH). ⁇ ca.5.1 (broad, IH), 66.98-67.18 (m. 3H).
  • Methanesulfonyl chloride ( 1.4g) was added at 0°C -5°C to a solution of a 1 :1 3R:3S mixture of isomers of 5R-hydroxymethyl-3-(3-fluoro-4-mo ⁇ holino- phenyl)dihydrofuran-2-(3H)-one (2.8g) in pyridine (50ml). The mixture was allowed to come to room temperature and stirred for 3 hours before being poured into ice-cold water (100ml). The resulting solid was filtered off, and the filtrate evaporated down to an oil, which was triturated with a 1 : 1 mixture of ethyl acetate and iso-hexane.
  • Potassium carbonate (1.5g) and diphenyl disulfide (0.68g) were added to a solution of a 1 :2 3R:3S mixture of isomers of 5R-acetamidomethyl-3-(3-fluoro-4- mo ⁇ holinophenyl)dihydrofuran-2-(3H)-one (Example 3) (0.7g) in 1 ,2-dimethoxyethane (50ml), and the mixture refluxed for 5 hours. More potassium carbonate (1.5g) was then added and the refluxing continued for a further 48 hours. The mixture was cooled and poured into 0.5N HCl (44ml) whilst maintaining the temperature below 15°C.
  • Example 5 Toluene-4-sulfonic acid (0.4g) was added to a solution of a 1 :2 3R:3S mixture of isomers of 5(R)-acetamidomethyl-3-hydroxy-3-(4- ⁇ 4-benzylpiperazin- 1 -yl ⁇ -phenyl)dihydrofuran- 2(3H)-one (0.8g) in glacial acetic acid (15ml). and the mixture refluxed for 30 minutes. The acetic acid was removed under reduced pressure and the residue dissolved in a mixture of ethyl acetate and saturated sodium hydrogencarbonate solution. The mixture was stirred for 5 minutes, and the organic phase separated.
  • the mixture was stirred over a weekend whilst allowing to warm to ambient temperature.
  • the mixture was then poured into ice-cold water (100ml). and then 5N hydrochloric (200ml) added.
  • the mixture was stirred overnight.
  • the pH ofthe solution was adjusted to 7 with 5N sodium hydroxide solution at below 10°C, and then extracted with dichloromethane which was evaporated down to an oil.
  • the oil was purified by silica gel column chromatography using a mixture of methanol (10%) and dichloromethane as eluant.
  • Methanesulfonyl chloride (2.6ml) was added at 0°C-5°C to a stirred solution of a 1 :1 3R:3S mixture of isomers of 5R-3-(4- ⁇ 4-benzylpiperazin-l-yl ⁇ phenyl)-5- hydroxymethyldihydro-2(3H)-furanone (9.4g) in pyridine (100ml). The mixture was stirred for 30 minutes before allowing to rise to ambient temperature and stirring for a further 90 minutes. The mixture was then poured into ice-cold water (250ml) and extracted with dichloromethane. The dichloromethane solution was evaporated down to an oil (lOg).
  • Trimethylphosphite (2.55g) was added at 50°C to a stirred solution of a 5:7 3R:3S mixture of isomers of 5(R)-azidomethyl-3-(4- ⁇ 4-benzylpiperazin-l-yl ⁇ phenyl)dihydro-2(3H)- furanone (6.7g) in 1 ,2-dimethoxyethane ( 100ml), and the mixture refluxed for 2 hours. The mixture was cooled to 50°C and 6N HCl (5ml) added carefully. The mixture was refluxed for a further six hours and then evaporated down to an oil, which was then taken up in water (50ml) and cooled to 0°-5°C.
  • a solution ( 15 wt.%) of potassium bis(trimethylsilyl)amide (26ml) in toluene was added dropwise at below -70°C to a stirred solution of a 2:3 3R:3S mixture of isomers of 5R- acetamidomethyl-3-(4- ⁇ 4-benzylpiperazin-l-yl ⁇ phenyl)- dihydrofuran-2-(5H)-one (6.97g) in THF (100ml).
  • the mixture was stirred at -78°C for 30 minutes and then (1S)(+)(10- camphorsulfonyl)oxaziridine (4.08g) was added and the mixture stirred for a further 1 hour.
  • Example 7 1 -Chloroethylchloroformate ( 1.1 g) was added at 0°C -5°C to a stirred solution of 5R- acetamidomethyl-3-(3-fluoro-4- ⁇ 4-benzylpiperazin-l-yl ⁇ phenyl)furan-2-(5H)-one (3g) and the mixture allowed to warm to ambient temperature over 15 minutes. The mixture was then refluxed for 30 minutes. The dichloromethane was removed under reduced pressure and the residue dissolved in methanol and refluxed for a further 90 minutes.
  • Methanesulfonyl chloride (2.98g) was added dropwise over 5-10 minutes at 0°C -5°C to a stirred solution of a 3:4 3R:3S mixture of isomers of 5R-3-(4- ⁇ 4-benzylpiperazin-l-yl ⁇ -3- fluorophenyl)-5-hydroxymethyldihydro-2(3H)-furanone (7.7g) in pyridine (75ml). The mixture was stirred for 15 minutes and then allowed to rise to ambient temperature. The mixture was stirred at ambient temperature for a further 2.5 hours, and then poured into ice-cold water ( 100ml).
  • Trimethylphosphite (2.6ml) was added dropwise at 60°C to a solution of a 2:3 3R:3S mixture of isomers of 5R-azidomethyl-3-(4- ⁇ 4-benzylpiperazin-l -yl ⁇ -3- fluorophenyl)dihydro-2(3H)-furanone (7.25g) in 1.2-dimethoxyethane (75ml). The mixture was refluxed for 30 minutes and then cooled to 50°C. 6N hydrochloric acid ( 12ml) was added dropwise and the mixture refluxed for 1 hour. The mixture was then cooled overnight and the dimethoxyethane removed under reduced pressure.
  • Toluene-4-sulfonic acid (1.6g) was added to a stirred solution of a 3:8 3R:3S mixture of isomers of 5R-acetamido-methyl-3-(3-fluoro-4- ⁇ 4-benzylpiperazin-l-yl ⁇ phenyl)-3-
  • Example 7 Sodium hydrogencarbonate (208mg) was added at 0°-5°C to a stirred solution of the 0 hydrochloride salt of 5R-acetamidomethyl-3-(3-fluoro-4-piperazino-phenyl)furan-2-(5H)- one (Example 7) (208mg) in a 1 : 1 mixture of acetone and water ( 15ml). The mixture was stirred for 5 minutes and then methanesulfonyl chloride (0.08g) was added. The mixture was stirred for a further 30 minutes and then brine ( 15ml) was added.
  • Example 9 Acetic anhydride (0.12ml) was added at O°C-5°C to a solution of a 1 :1 3R:3S mixture of isomers of 5R-aminomethyl-3-(4- ⁇ 4-benzyloxycarbonyl-piperazin-l - yl ⁇ phenyl)dihydrofuran-2-(3H)-one (0.46g) in acetonitrile (15ml), and the mixture allowed to warm to ambient temperature. The mixture was stirred for 30 minutes before being evaporated down. The residue was purified by silica gel column chromatography using a mixture of methanol (3%) and ethyl acetate as eluant.
  • the mixture of isomers of 5R-aminomethyl-3-(4- ⁇ 4-benzyloxycarbonyl-piperazin-l- yl ⁇ phenyl)dihydrofuran-2-(3H)-one used as starting material was obtained as follows:- A solution of di-I ⁇ Q-butyl dicarbonate (66g) in dichloromethane (100ml) was added dropwise at below 10°C to a stirred solution of 4-piperazinoacetophenone (62g) in dichloromethane (500ml). and the mixture stirred for 1 hour at 10°C. The mixture was poured into water (300ml) and the organic phase separated and re-washed twice with water, and then brine.
  • the product was extracted into ethyl acetate which was then evaporated down to an oil.
  • the oil was taken up in water (300ml) and the pH again modified to 10 and mixture extracted with ethyl acetate.
  • the ethyl acetate was discarded and the pH ofthe aqueous phase was then brought back to 4.
  • the product was extracted into ethyl acetate, which was evaporated down to a solid.
  • the solid was recrystallised from a mixture of iso ⁇ hexane and ethyl acetate to give 4-(4-benzy loxycarbony lpiperazin- 1-yl)- phenylacetic acid (16.6g, 38% yield).
  • DMPU methyl 4-(4-benzyloxy-carbonylpiperazin- l-yl)phenylacetate
  • THF 180ml
  • a 1.5M solution of LDA in n-hexane (15.5ml) was added dropwise at below or equal to -70°C, and the mixture stirred for 20 minutes before being allowed to rise to 0°C.
  • Methanesulfonyl chloride (0.9g) was added slowly at 0°-5°C to a solution of a 1 : 1 3R:3S mixture of isomers of 5R-hydroxymethyl-3-(4- ⁇ 4-benzyloxycarbonyl-piperazin- 1 - yl ⁇ phenyl)dihydrofuran-2(3H)-one (2.7g) in pyridine (25ml), and the mixture stirred for 1 hour. The mixture was then allowed to rise to ambient temperature and stirred overnight. At the end of this period ice-cold water (30ml) was added and extracted with dichloromethane.
  • Triphenylphosphine (0.6g) was added to a solution of a 3:4 3R:3S mixture of isomers of 5R-azidomethyl-3-(4- ⁇ 4-benzyloxycarbonylpiperazin-l-yl ⁇ phenyl)dihydrofuran-2(3H)-one (0.9g) in THF (25ml). The mixture was stirred at 50°C for 4 hours and then at ambient temperature over a weekend. The THF was removed under reduced pressure and the residue purified by silica gel column chromatography using a mixture of methanol (15%) and dichloromethane as eluant.
  • Example 13 H-Hydroxysuccinimide (73mg), 4-dimethylaminopyridine ( 1 Omg) and 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (123mg) were added to a stirred suspension of H,N-dimethylglycine (66mg) in pyridine (15ml). The mixture was stirred for 15 minutes at ambient temperature and then at 50°C for another 15 minutes. The hydrochloride salt of 5R-acetamidomethyl-3-(4-piperazinophenyl)furan-2-(5H)-one (Example 1 1 ) (150mg) was added and the mixture stirred at ambient temperature ovemight.
  • Example 14 A catalytic quantity of pyridine (3 drops) was added to a stirred solution of a 3:1 3R:3S mixture of isomers of 5R-acetamidomethyl-3RS-hydroxy-3-(3-fluoro-4- thiomo ⁇ holinophenyl)dihydrofuran-2(3H)-one (0.46g) in chloroform (15ml) and the mixture cooled to -5°C. Phosphorous tribromide (300mg) was added and the mixture stirred for 4 hours at -5°C. At the end of this period saturated sodium hydrogencarbonate solution was added until pH 7-8 was reached. The mixture was extracted with chloroform and ethyl acetate and the combined organic phases evaporated.
  • Finely ground potassium carbonate (1.96g) and phenyl disulphide (0.8g) were added to a solution of a 3:1 3R:3S mixture of isomers of 5R-acetamidomethyl-3-(3-fluoro-4-thio- mo ⁇ holinophenyl)dihydrofuran-2(3H)-one (lg) in 1 ,2-dimethoxyethane (40ml).
  • the mixture was refluxed for two days, cooled and drowned out into 0.6N hydrochloric acid (30ml).
  • the mixture was extracted with ethyl acetate (3 x 50ml), the ethyl acetate layers separated and evaporated down.

Abstract

Cette invention concerne un composé correspondant à la formule (I) où -A-B- correspond à la formule ⊃C=CH- ou ⊃CHCH2; R1 et R2 représentent indépendamment hydrogène ou fluor; R3 et R4 représentent indépendamment hydrogène ou méthyle; et D représente O, S, SO, SO¿2? ou correspond à la formule R?5N. R5¿ représente hydrogène ou benzyle, ou correspond encore à la formule R6CO- ou R6SO2 dans lesquelles R6 représente, par exemple, amino ou correspond à la formule R7C(O)O(1-6C)alkyle, R7 représentant, par exemple, un phényle éventuellement substitué ou un (1-6C)alkyle éventuellement substitué. R6 peut également correspondre à la formule R?8O- où R8¿ représente benzyle ou un (1-6C)alkyle éventuellement substitué. R5 peut, quant à lui, également correspondre à la formule R?10CH(R9)(CH¿2)m- où m représente 0 ou 1, R9 représente, par exemple, fluoro et R10 représente hydrogène ou (1-4C)alkyle. Cette invention concerne également les sels de ce composé acceptables sur le plan pharmaceutique, des procédés de fabrication de ces derniers, des solutions les contenant ainsi que leur utilisation en qualité d'agents antibactériens.
PCT/GB1996/002504 1995-10-20 1996-10-15 Derives de 5-(acetamidomethyl)-3-aryldihydrofuran-2-one et de tetrahydrofuran-2-one ayant une activite antibiotique WO1997014690A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP9515591A JPH11513680A (ja) 1995-10-20 1996-10-15 抗生物質活性を有する５−（アセトアミドメチル）−３−アリールジヒドロフラン−２−オンおよびテトラヒドロフラン−２−オン誘導体
EP96933552A EP0858453A1 (fr) 1995-10-20 1996-10-15 Derives de 5-(acetamidomethyl)-3-aryldihydrofuran-2-one et de tetrahydrofuran-2-one ayant une activite antibiotique
AU72248/96A AU7224896A (en) 1995-10-20 1996-10-15 5-(acetamidomethyl)-3-aryldihydrofuran-2-one and tetrahydrofuran-2-one derivatives with antibiotic activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9521508.3 1995-10-20
GBGB9521508.3A GB9521508D0 (en) 1995-10-20 1995-10-20 Chemical compounds

Publications (1)

Publication Number Publication Date
WO1997014690A1 true WO1997014690A1 (fr) 1997-04-24

Family

ID=10782620

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1996/002504 WO1997014690A1 (fr) 1995-10-20 1996-10-15 Derives de 5-(acetamidomethyl)-3-aryldihydrofuran-2-one et de tetrahydrofuran-2-one ayant une activite antibiotique

Country Status (5)

Country Link
EP (1) EP0858453A1 (fr)
JP (1) JPH11513680A (fr)
AU (1) AU7224896A (fr)
GB (1) GB9521508D0 (fr)
WO (1) WO1997014690A1 (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054161A1 (fr) * 1997-05-30 1998-12-03 Pharmacia & Upjohn Company Agents antibacteriens oxazolidinone ayant une fonctionnalite thiocarbonyle
US5981528A (en) * 1996-02-24 1999-11-09 Zeneca Limited Antibiotic oxazolidinone derivatives
US6069145A (en) * 1996-01-27 2000-05-30 Zeneca Limited Piperazinonephenyloxazolidinone derivatives and their use as antibacterial agents
US6110936A (en) * 1996-05-11 2000-08-29 Zeneca Limited 3-phenyl-furan-(5H)-2-one and dihydrofuran-2-one derivatives as antibacterial agents
US6194441B1 (en) 1997-08-22 2001-02-27 Zeneca Ltd. Oxazolidinone derivatives and their use as antibacterial agents
EP1107756A1 (fr) * 1998-08-24 2001-06-20 Bristol-Myers Squibb Company Nouveaux agents antibacteriens a base d'isoxazolinone
US6255304B1 (en) 1997-05-30 2001-07-03 Pharmacia & Upjohn Company Oxazolidinone antibacterial agents having a thiocarbonyl functionality
WO2002006278A1 (fr) * 2000-07-17 2002-01-24 Ranbaxy Laboratories Limited Derives d'oxazolidinone utilises en tant qu'antimicrobiens
US6420349B1 (en) 1998-08-24 2002-07-16 Bristol-Myers Squibb Company Isoxazolinone antibacterial agents
US6465456B2 (en) 2000-06-29 2002-10-15 Bristol-Myers Squibb Company Isoxazolinone antibacterial agents
US6495551B1 (en) 1997-11-29 2002-12-17 Michael John Betts Substituted phenyloxazolidinones and their use as antibiotics
US6605630B1 (en) 1997-08-22 2003-08-12 Syngenta Limited Antibiotic oxazolidinone derivatives
EP1409464A1 (fr) * 2001-07-16 2004-04-21 Ranbaxy Laboratories, Ltd. Derives d'oxazolidinone utilises comme antimicrobiens potentiels
WO2005090339A1 (fr) * 2004-03-09 2005-09-29 Orchid Chemicals Pharmaceuticals Ltd Nouveaux agents antibacteriens
US6956040B2 (en) 2001-07-16 2005-10-18 Ranbaxy Laboratories Limited Oxazolidinone piperazinyl derivatives as potential antimicrobials
US7022705B2 (en) 2001-10-25 2006-04-04 Astrazeneca Ab Isoxazoline derivatives useful as antimicrobials
WO2006040614A1 (fr) * 2004-10-11 2006-04-20 Ranbaxy Laboratories Limited Derives d'oxazolidinone substitues
US7081538B1 (en) 1999-12-03 2006-07-25 Astrazeneca Ab Substituted isoxazolines and their use as antibacterial agents
US7141583B2 (en) 2000-04-25 2006-11-28 Astrazeneca Ab Oxazolidinone derivatives with antibiotic activity
US7199143B2 (en) 2002-02-28 2007-04-03 Astrazeneca Ab Chemical compounds
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US7473699B2 (en) 2002-02-28 2009-01-06 Astrazeneca Ab 3-cyclyl-5-(nitrogen-containing 5-membered ring)methyl-oxazolidinone derivatives and their use as antibacterial agents

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4705799A (en) * 1983-06-07 1987-11-10 E. I. Du Pont De Nemours And Company Aminomethyl oxooxazolidinyl benzenes useful as antibacterial agents
WO1993009103A1 (fr) * 1991-11-01 1993-05-13 The Upjohn Company Aryl- et heteroarylphenyloxazolidinones substituees, utilisees comme agents antibacteriens
WO1995007271A1 (fr) * 1993-09-09 1995-03-16 The Upjohn Company Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4705799A (en) * 1983-06-07 1987-11-10 E. I. Du Pont De Nemours And Company Aminomethyl oxooxazolidinyl benzenes useful as antibacterial agents
WO1993009103A1 (fr) * 1991-11-01 1993-05-13 The Upjohn Company Aryl- et heteroarylphenyloxazolidinones substituees, utilisees comme agents antibacteriens
WO1995007271A1 (fr) * 1993-09-09 1995-03-16 The Upjohn Company Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
A.D. BORTHWICK ET AL.: "5-(Acetamidomethyl)-3-aryldihydrofuran-2-ones, and 5-(Acetamidomethyl)-3-aryltetrahydrofuran-2-ones, two new classes of antibacterial agents", MEDICINAL CHEMISTRY RESEARCH, vol. 6, no. 1, January 1996 (1996-01-01), pages 22 - 27, XP000614544 *
DENIS A ET AL: "5-ARYL-BETA,GAMMA BUTENOLIDE, A NEW CLASS OF ANTIBACTERIAL DERIVED FROM THE N-ARYL OXAZOLIDINONE DUP 721", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 4, no. 16, 1 January 1994 (1994-01-01), pages 1925 - 1930, XP000567437 *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6069145A (en) * 1996-01-27 2000-05-30 Zeneca Limited Piperazinonephenyloxazolidinone derivatives and their use as antibacterial agents
US6638955B2 (en) 1996-02-24 2003-10-28 Syngenta Limited Antibiotic oxazolidinone derivatives
US5981528A (en) * 1996-02-24 1999-11-09 Zeneca Limited Antibiotic oxazolidinone derivatives
US6365751B1 (en) 1996-02-24 2002-04-02 Zeneca Ltd. Antibiotic oxazolidinone derivatives
US6271383B1 (en) 1996-02-24 2001-08-07 Zeneca Limited Antibiotic oxazolidinone derivatives
US6110936A (en) * 1996-05-11 2000-08-29 Zeneca Limited 3-phenyl-furan-(5H)-2-one and dihydrofuran-2-one derivatives as antibacterial agents
US6350775B1 (en) 1996-05-11 2002-02-26 Zeneca Limited 3-phenyl-furan-(5H)-2-one and dihydrofuran-2-one derivatives as antibacterial agents
US6218413B1 (en) 1997-05-30 2001-04-17 Pharmacia & Upjohn Company Oxazolidinone antibacterial agents having a thiocarbonyl functionality
US6255304B1 (en) 1997-05-30 2001-07-03 Pharmacia & Upjohn Company Oxazolidinone antibacterial agents having a thiocarbonyl functionality
US6342513B1 (en) 1997-05-30 2002-01-29 Pharmacia And Upjohn Company Oxazolidinone antibacterial agents having a thiocarbonyl functionality
US6362189B1 (en) 1997-05-30 2002-03-26 Pharmacia And Upjohn Company Oxazolidinone antibacterial agents having a thiocarbonyl functionality
WO1998054161A1 (fr) * 1997-05-30 1998-12-03 Pharmacia & Upjohn Company Agents antibacteriens oxazolidinone ayant une fonctionnalite thiocarbonyle
US6537986B2 (en) 1997-05-30 2003-03-25 Pharmacia & Upjohn Company Oxazolidinone antibacterial agents having a thiocarbonyl funtionality
US6194441B1 (en) 1997-08-22 2001-02-27 Zeneca Ltd. Oxazolidinone derivatives and their use as antibacterial agents
US6605630B1 (en) 1997-08-22 2003-08-12 Syngenta Limited Antibiotic oxazolidinone derivatives
US6495551B1 (en) 1997-11-29 2002-12-17 Michael John Betts Substituted phenyloxazolidinones and their use as antibiotics
EP1107756A4 (fr) * 1998-08-24 2003-02-26 Bristol Myers Squibb Co Nouveaux agents antibacteriens a base d'isoxazolinone
US6420349B1 (en) 1998-08-24 2002-07-16 Bristol-Myers Squibb Company Isoxazolinone antibacterial agents
EP1107756A1 (fr) * 1998-08-24 2001-06-20 Bristol-Myers Squibb Company Nouveaux agents antibacteriens a base d'isoxazolinone
US7081538B1 (en) 1999-12-03 2006-07-25 Astrazeneca Ab Substituted isoxazolines and their use as antibacterial agents
US7141583B2 (en) 2000-04-25 2006-11-28 Astrazeneca Ab Oxazolidinone derivatives with antibiotic activity
US6465456B2 (en) 2000-06-29 2002-10-15 Bristol-Myers Squibb Company Isoxazolinone antibacterial agents
WO2002006278A1 (fr) * 2000-07-17 2002-01-24 Ranbaxy Laboratories Limited Derives d'oxazolidinone utilises en tant qu'antimicrobiens
US6734307B2 (en) 2000-07-17 2004-05-11 Ranbaxy Laboratories Limited Oxazolidinone derivatives as antimicrobials
EP1409465A2 (fr) * 2001-07-16 2004-04-21 Ranbaxy Laboratories, Ltd. Derives d'oxazolidinone comme antimicrobiens
US6956040B2 (en) 2001-07-16 2005-10-18 Ranbaxy Laboratories Limited Oxazolidinone piperazinyl derivatives as potential antimicrobials
EP1409464A4 (fr) * 2001-07-16 2005-11-02 Ranbaxy Lab Ltd Derives d'oxazolidinone utilises comme antimicrobiens potentiels
EP1409465A4 (fr) * 2001-07-16 2005-11-02 Ranbaxy Lab Ltd Derives d'oxazolidinone comme antimicrobiens
EP1409464A1 (fr) * 2001-07-16 2004-04-21 Ranbaxy Laboratories, Ltd. Derives d'oxazolidinone utilises comme antimicrobiens potentiels
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US7022705B2 (en) 2001-10-25 2006-04-04 Astrazeneca Ab Isoxazoline derivatives useful as antimicrobials
US7199143B2 (en) 2002-02-28 2007-04-03 Astrazeneca Ab Chemical compounds
US7473699B2 (en) 2002-02-28 2009-01-06 Astrazeneca Ab 3-cyclyl-5-(nitrogen-containing 5-membered ring)methyl-oxazolidinone derivatives and their use as antibacterial agents
WO2005090339A1 (fr) * 2004-03-09 2005-09-29 Orchid Chemicals Pharmaceuticals Ltd Nouveaux agents antibacteriens
WO2006040614A1 (fr) * 2004-10-11 2006-04-20 Ranbaxy Laboratories Limited Derives d'oxazolidinone substitues

Also Published As

Publication number Publication date
EP0858453A1 (fr) 1998-08-19
GB9521508D0 (en) 1995-12-20
AU7224896A (en) 1997-05-07
JPH11513680A (ja) 1999-11-24

Similar Documents

Publication Publication Date Title
EP0858453A1 (fr) Derives de 5-(acetamidomethyl)-3-aryldihydrofuran-2-one et de tetrahydrofuran-2-one ayant une activite antibiotique
US5981528A (en) Antibiotic oxazolidinone derivatives
EP0882041B1 (fr) Derives de piperazinonephenyloxazolidinone et leur utilisation en tant qu'agents antibacteriens
KR101826371B1 (ko) 신규 히드록삼산 유도체
US6110936A (en) 3-phenyl-furan-(5H)-2-one and dihydrofuran-2-one derivatives as antibacterial agents
US5041567A (en) Antibacterial monic acid derivatives
KR100380875B1 (ko) 펜타사이클릭화합물
EP1385844B1 (fr) Oxazolidinones contenant un groupe sulfonimide en tant qu'antibiotique
US6605630B1 (en) Antibiotic oxazolidinone derivatives
JP2007505890A (ja) オキサゾリジノン類のアシルオキシメチルカルバメートプロドラッグ
JPH06507171A (ja) 抗炎症剤としての２−および５−アルキルおよびフェニル置換４−（１−ヒドロキシ、１−アシルオキシまたは１−カルバモイルオキシ）−５ヒドロキシ−２（５ｈ）−フラノン
GB2156350A (en) Active thioesters
JP2006520774A (ja) 抗菌性１，３−オキサゾリジン−２−オン誘導体
EP0123378B1 (fr) Dérivés de 1-normonyl, procédés et usages
EP0399645B1 (fr) Dérivés de tétrahydropyranne, procédé pour leur préparation et compositions pharmaceutiques et vétérinaires les contenant
JP2006520775A (ja) 抗菌性オキサリジノン類
AU655882B2 (en) Anti-inflammatory furanone compounds
WO2024043334A1 (fr) Nouveau dérivé de pipérazine ou sel de celui-ci et composition pharmaceutique
US4505905A (en) Cyclobutanone antibacterials
JPH06100445A (ja) 抗腫瘍剤
JPH04178389A (ja) 三環性カルバペネム化合物
WO1987000527A1 (fr) Composes antibacteriens, leur utilisation et procede de preparation
KR20050108567A (ko) 베타-메틸카바페넴 유도체 및 그의 제조방법
JPS5810560A (ja) ９−デオキシ−９−メチレン−６−ケト−ｐｇｅ型化合物
JPH0426688A (ja) ２‐アルケニルカルバペネム誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1996933552

Country of ref document: EP

ENP Entry into the national phase

Ref country code: JP

Ref document number: 1997 515591

Kind code of ref document: A

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 1996933552

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1996933552

Country of ref document: EP