WO1998001446A1 - Derives substitues de piperazinyle-phenyle-oxazolidinone et leur utilisation en tant qu'agents antibacteriens - Google Patents

Derives substitues de piperazinyle-phenyle-oxazolidinone et leur utilisation en tant qu'agents antibacteriens Download PDF

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Publication number
WO1998001446A1
WO1998001446A1 PCT/GB1997/001767 GB9701767W WO9801446A1 WO 1998001446 A1 WO1998001446 A1 WO 1998001446A1 GB 9701767 W GB9701767 W GB 9701767W WO 9801446 A1 WO9801446 A1 WO 9801446A1
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formula
compound
phenyl
fluoro
piperazin
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PCT/GB1997/001767
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English (en)
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Michael John Betts
Catherine Jane Midgley
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Zeneca Limited
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Priority to EP97929403A priority Critical patent/EP0918769A1/fr
Priority to AU33520/97A priority patent/AU3352097A/en
Priority to JP10504900A priority patent/JP2000514083A/ja
Publication of WO1998001446A1 publication Critical patent/WO1998001446A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to antibiotic compounds and in particular to antibiotic compounds containing an oxazolidinone 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 or 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 of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established.
  • strains examples include methicillin resistant staphylococcus (MRSA). methicillin resistant coagulase negative staphylococci (MRCNS). penicillin resistant streptococcus pneumoniae and multiply resistant Enterococcus faecium.
  • MRSA methicillin resistant staphylococcus
  • MRCNS methicillin resistant coagulase negative staphylococci
  • penicillin resistant streptococcus pneumoniae and multiply resistant Enterococcus faecium examples of such strains.
  • 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 an oxazolidinone ring which has 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 aminogiycosides and clinically used ⁇ -lactams.
  • the compounds In comparison with compounds described in the art (for example Walter A. Gregory et al in J.Med.Chem. 1990. 33. 2569-2578 and Chung-Ho Park et al in J.Med.Chem. 1992. 35. 1 156-1 165) the compounds also possess a favourable toxicological profile.
  • R 1 is hydroxy. chloro. fluoro, ( l-4C)alkanesulfonyloxy. amino. azido, ( l -4C)alkoxy.
  • R" and R are independently hydrogen or fluoro:
  • R 4 and R 5 are independently hydrogen or methyl:
  • R 6 is a 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms as the only ring heteroatoms. linked via a ring carbon atom and optionally substituted on a ring carbon atom by one. two or three substituents independently selected from ( l -4C)alkyl (optionally substituted by trifluoromethyl, ( l-4C)alkylS(O) potentially- (wherein n is 0. 1 or 2), ( 1 -4C)alkoxy, carboxy. hydroxy.
  • ( l -4C)alkylS(O) just- (wherein n is 0. 1 or 2).
  • di-(N-( l-4C)alkyl)carbamoyl [wherein the (l-4C)alkyl group or groups in the last two- mentioned carbamoyl substituents is optionally substituted by hydroxy, ( l -4C)alkox or ( l-4C)alkoxycarbonyl], (2-4C)alkenyl (optionally substituted by carboxy or ( 1 -4C)alkoxycarbonyl), ( 1 -4C)alkoxy.
  • cyano or nitro pharmaceutically-acceptable salts thereof: and suitable N-oxides thereof.
  • alkyl includes straight chained and branched structures.
  • (l-6C)alkyl includes propyl. isopropyl and tert-butvl.
  • references to individual alkyl groups such as "propyr are specific for the straight chained version only, and references to individual branched chain alkyl groups such as ' "isopropyl” are specific for the branched chain version only.
  • a 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms as the only ring heteroatoms includes pyrimidine.
  • pyridazine pyrazine. 1.2.3-triazine. 1.2.4-triazine and 1.3.5-triazine.
  • Examples of ( l-4C)alkyl include methyl, ethyl, propyl. isopropyl and tert-butvl: examples of halo include fluoro. chloro. bromo and iodo: examples ofN-( l - 4C .alkylcarbamoyl include methyicarbamoyl.
  • examples of di-(N-( l -4C alkyl)carbamoyl include di-(methyl)carbamoyl and di-(ethyl)carbamoyl: examples of the ( l -4C)alkyl group or groups in N-(l-4C)alkylcarbamoyl and di-(N-( l -4C)alkyl)carbamoyl being optionally substituted by hydroxy.
  • ( l-4C)alkoxy or ( 1 -4C)alkoxycarbonyl include 2-hydroxyethylaminocarbonyl.
  • examples of (l-4C)alkylS(O) n include methylthio, ethylthio. methylsulfinyl.
  • examples of ( 1 -4C a_kylS(O)-,amino include methylsulfonylamino and ethylsulfonylamino:
  • examples of (2-4C)alkenyl include allyl and vinyl:
  • examples of (l-4C)alkoxy include methoxy, ethoxy and propoxy:
  • examples of (l -4C)alkanoylamino include formamido.
  • examples of (2-4C)alkanoylamino include acetamido and propionylamino: examples of N-( l-4C)alkylamino include methylamino and ethylamino: examples of di-(N-( l - 4C)alkyl (amino include di-N-methylamino. di-(N-ethyl)amino and N-ethyi-N-methylamino: examples of ( l-4C)alkoxycarbonyl include methoxycarbonyl. ethoxycarbonyl.
  • examples of ( l-4C)alkanesulfonyloxy include methanesulfonyloxy and ethanesulfonyloxy: and examples of (l-4C)alkylaminocarbonyloxy include methylaminocarbonyloxy and ethylaminocarbonyloxy.
  • Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate. fumarate. hydrochloride. hydrobromide. citrate, maleate and salts formed with phosphoric and sulfuric acid.
  • suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine. morpholine. N- methylpiperidine. N-ethylpiperidine. procaine. dibenzylamine. N.N-dibenzylethylamine or amino acids for example lysine.
  • a preferred pharmaceutically-acceptable salt is the sodium salt. However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
  • a suitable N-oxide refers to the N-oxides which may be formed on an available nitrogen atom in either the piperazine ring or in the heteroaryl ring R".
  • a suitable N-oxide may be optionally in the form of a pharmaceutically-acceptable salt.
  • the compounds of the 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 of the formula (I).
  • pro-drugs include in-vivo hydrolysable esters of a compound of the formula (I).
  • An in-vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is.
  • esters for carboxy include (l-6C)alkoxymethyl esters for example methoxymethyl. ( I -6C)alkanoyloxymethyl esters for example pivaloyloxymethyl. phthalidyl esters.
  • (3- 8C)cycloalkoxycarbonyloxy(l-6C)alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1.3-dioxoten-2-onylmethyl esters for example 5-methyl-1.3-dioxolen-2-onylmethyi: and (1 - 6C)alkoxycarbonyloxyethyi 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 of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2.2-dimethylpropionyloxymethoxy.
  • a selection of in-vivo hydrolysable ester forming groups for hydroxy include ( 1 - 10C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, (l-lOC)alkoxycarbonyl (to give alkyl carbonate esters). di-( l- 4C)alkylcarbamoyl and N-(di-(l-4C)alkylaminoethyl)-N-( l-4C)alkylcarbamoyl (to give carbamates). di-(l-4C)alkylaminoacetyI and carboxyacetyl.
  • substituents on benzoyl include morpholino or piperazino linked from a ring nitrogen atom via methylamino to the 3- or 4- position of the benzoyl ring.
  • the compounds of the present invention have a chiral centre at the C-5 position of the oxazolidinone ring.
  • the pharmaceutically active enantiomer is of the formula (IA):
  • the present invention includes the pure enantiomer depicted above or mixtures of the 5R and 5S enantiomers. for example a racemic mixture. If a mixture of enantiomers is used, a larger amount (depending upon the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer.
  • the enantiomer depicted above could be either 5R or 5S depending upon the value of R .
  • R is acetamido.
  • the enantiomer depicted above is the 5S enantiomer and when R is hydroxy, the enantiomer depicted above is the 5R enantiomer.
  • some compounds of the formula (I) may have other chiral centres. It is to be understood that the invention encompasses all such optical and diastereo-isomers that possess antibacterial activity.
  • the invention relates to all tautomeric forms of the compounds of the formula (I) that possess antibacterial activity.
  • R 2 and R are independently hydrogen or fluoro
  • R 4 and R' are independently hydrogen or methyl
  • R 6 is a 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms as the ring heteroatoms. linked via a ring carbon atom and optionally substituted on a ring carbon atom by one. two or three substituents independently selected from (l -4C)alkyl [optionally substituted by trifluoromethyl. (l -4C)alkylS(O)neig- (wherein n is 0, 1 or 2), ( l -4C alkoxy. carboxy. hydroxy.
  • (l -4C)alkylS(O) possibly- (wherein n is 0. 1 or 2).
  • N-( 1 -4C alkylcarbamoyl and di-(N-(l -4C)alkyl)carbamoyl substituents with the ( l -4C)alkyl group or groups substituted by hydroxy, (l-4C)alkoxy or ( l-4C)alkoxycarbonyl. are excluded: and the number of optional substituents on R 6 is restricted to one or two.
  • suitable N-oxides are optionally excluded.
  • R 1 is of the formula -NHS(O),,( 1 -4C)alkyl wherein n is 0. 1 or 2.
  • n is preferably 2.
  • R 1 is acetamido
  • R 1 is hydroxy
  • R 2 and R' are hydrogen and the other is fluoro.
  • R 4 and R 3 is hydrogen.
  • R 4 and R 5 are both hydrogen.
  • heteroaryl ring in R 6 is pyrimidine. pyridazine or pyrazine.
  • heteroaryl ring in R" is pyrimidine or pyrazine.
  • heteroaryl ring in R 6 is pyrimidin-2-yl or pyrazin-2-yl.
  • heteroaryl ring in R 6 is pyrimidin-2-yl.
  • substituents on the heteroaryl ring are not positioned in the 2- position relative to the ring carbon atom which is attached to the piperazine ring.
  • the optional substituents on the heteroaryl ring are independently selected from ( l-4C)alkyI (optionally substituted by ( l-4C)alkoxy or (2-4C)alkanoylamino).
  • the optional substituents on the heteroaryl ring are independently selected from methyl or ethyl (each optionally substituted by methoxy. ethoxy or acetamido). methylthio. ethylthio. chloro, bromo, carboxy, methoxycarbonyl. ethoxycarbonyl and carbamoyl. (r) Yet more preferably the optional substituents on the heteroaryl ring are independently selected from methyl, ethyl, methoxymethyl, 2-(acetamido)ethyl. methylthio. chloro. bromo. carboxy. methoxycarbonyl and carbamoyl.
  • the optional substituents on the heteroaryl ring are independently selected from ( l -4C)alkyl (preferably methyl), halo (preferably chloro). nitro. cyano. carbamoyl.
  • heteroaryl ring is unsubstituted or substituted by one substituent.
  • especially preferred compounds of the formula (I), or a pharmaceutically - acceptable salt or suitable N-oxide thereof are those defined above wherein R 1 is acetamido. one of R 2 and R is hydrogen and the other is fluoro. R 4 and R' are both hydrogen. R 6 is pyrimidine or pyrazine and the optional substituents on the heteroaryl ring are independently selected from methyl, chloro. nitro. cyano. carbamoyl.
  • N-( l -4C alkylcarbamoyl and di-(N-( l -4C)alkyl)carbamoyl are particularly useful as compounds of the present invention.
  • Particular compounds of the present invention include :
  • Further particular compounds of the present invention include :
  • the present invention provides a process for preparing a compound of the formula (I), a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof.
  • the compounds of the formula (I), a pharmaceuticalh -acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof may be prepared by deprotecting a compound, containing at least one protecting group, of the formula (II).
  • a pharmaceutically- acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof :
  • R 2 , R 3 , R 4 and R 5 are as hereinabove defined.
  • R 7 is R 6 or protected R 6 and R 10 is R 1 or protected R' and thereafter if necessary forming a pharmaceutically-acceptable salt, suitable N- oxide or in-vivo hydrolysable ester.
  • 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 the protecting group in question, such methods being chosen so as to effect removal of the 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 preferably 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 of the invention.
  • a carboxy 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).
  • Examples of carboxy protecting groups include straight or branched chain ( ! -12C)alkyl groups (eg isopropyl. tert-butvl); lower alkoxy lower alkyl groups (eg methoxymethyl. ethoxymethyl. isobutoxy methyl: lower aliphatic acyloxy lower alkyl groups, (eg acetoxymethyl. propionyloxymethyl. butyryloxymethyl, pivaloyloxymethyl): lower alkoxycarbonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl.
  • aryl lower alkyl groups eg g-methoxybenzyl, ⁇ nitrobenzyl, r nitrobenzyl.
  • benzhydryl and phthalidyl tri(lower alkyDsilyl groups (eg trimethylsilyl and tert-butvldimethylsilyl); triOower alkyl)silyl lower alkyl groups (eg trimethylsilylethyl): and (2-6C)alkenyl groups (eg allyl and vinylethyl).
  • Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, metal- or enzymically-catalysed hydrolysis.
  • hydroxy protecting groups include lower alkenyl groups (eg allyl): lower alkanoyl groups (eg acetvl); lower alkoxycarbonyl groups (eg tert-butoxvcarbonyl ); lower alkenyloxycarbonyl groups (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, r methoxybenzyloxycarbonyl, ( nitrobenzyloxycarbonyl. r nitrobenzyloxycarbonyl): tri lower alkyl/arylsilyl groups (eg trimethylsilyl. tert- butyldimethylsilyl. tert-butvldiphenvlsilyl); aryl lower alkyl groups (eg benzyl) groups: and triaryl lower alkyl groups (eg triphenylmethyl).
  • lower alkenyl groups eg allyl
  • lower alkanoyl groups eg ace
  • amino protecting groups include formyl. aralkyl groups (eg benzyl and substituted benzyl, eg r methoxybenzyl. nitrobenzyl and 2.4-dimethoxybenzyl. and triphenylmethyl); di-r anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg tert- butoxycarbonyl); lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl.
  • aralkyl groups eg benzyl and substituted benzyl, eg r methoxybenzyl. nitrobenzyl and 2.4-dimethoxybenzyl. and triphenylmethyl
  • di-r anisylmethyl and furylmethyl groups eg tert- butoxycarbonyl
  • lower alkenyloxycarbonyl eg allyloxycarbonyl
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, metal- or enzymically-catalysed hydrolysis, for groups such as o_-nitrobenzyioxycarbonyl. photolytically and for groups such as silyl groups, fluoride.
  • protecting groups for amide groups include aralkoxymethyl (eg. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (eg. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (eg. trimethylsilyl. tert-butvldimethylsilyl.
  • alkoxyphenyl and alkoxybenzyl groups are conveniently introduced by arylation or alkylation with an appropriate halide and removed by oxidation with eerie ammonium nitrate.
  • alk-1-enyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid.
  • R 1 or R ,0 is of the formula - NHS(O) n ( l-4C)alkyl. wherein n is 1 or 2. by oxidising a compound of the formula (I) wherein n is 0 or. when n is 2 by oxidising a compound of the formula (I) or (II) wherein n is 1 ;
  • R 12 is mesvloxy or tosyloxy.
  • R ⁇ is (l-6C)alkyl or benzyl.
  • R l4 is (l-6C)alkyl.
  • R 15 is (l-4C)alkyl or benzyl and L 1 is a leaving goup and thereafter if necessary: i) removing any protecting groups; ii) forming a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester.
  • an alkylthio group may be oxidised to an alkylsulfinyl or alkysulfonyl group, a cyano group reduced to an amino group, a nitro group reduced to an amino group, an amino group converted to an acetamido or sulfonamido group, a hydroxy group alkylated to a methoxy group, a carboxy group converted to a carbamoyl group, an N-(l-4C)alkyicarbamoyl or di-(N-( 1 -4C)alkyl)carbamoyl group, or a bromo group converted to an alkylthio group.
  • a chloro group may be introduced at an unsubstituted position in R . or a chloro group may be removed from R 7 (by, for example, hydrogenation as in Examples 9 and 31 ).
  • Compounds of the formula (I) or (II) wherein R 1 or R'° is -NHS(O) groove ( l-4C)alkyl can be prepared by oxidising a compound of the formula (I) or (II) with standard reagents known in the art for the oxidation of a thio group to a sulfinyl or suifonyl group.
  • a thio group may be oxidised to a sulfinyl group with a peracid such as m-chloroperoxybenzoic acid and oxidising agents such as potassium permanganate w ill convert a thio group to a sulfonyl group.
  • a compound of the formula (I) or (II) wherein R' or R l() is azido may be prepared. for example, by reacting a compound of the formula (III) with sodium azide in an inert solvent such as DMF in a temperature range of ambient to 100°C. normally in the region of 75°C - 85°C.
  • a compound of the formula (III) may be prepared by converting the hydroxy group in a compound of the formula (I) or (II) wherein R' or R'° is hydroxy into a tosyloxy or mesvloxy group by standard methods known in the art. For example, by reacting the compound of the formula (I) or (II) with tosyl chloride or mesyl chloride in the presence of a mild base such as triethylamine. or pyridine.
  • a mild base such as triethylamine. or pyridine.
  • Suitable reducing agents for reducing azido to amino in a compound of the formula (I) or (II) include triethylamine/hydrogen sulfide. triphenylphosphine or phosphite ester, or hydrogen in the presence of a catalyst. More specifically the reduction of the azido group may be carried out by heating it in an aprotic solvent, such as 1,2-dimethoxyethane. in the presence of P(OMe), and subsequently heating in 6N aqueous hydrochloric acid, or reacting it with hydrogen in the presence of palladium on carbon in a solvent such as DMF or ethyl acetate.
  • aprotic solvent such as 1,2-dimethoxyethane. in the presence of P(OMe)
  • 6N aqueous hydrochloric acid or reacting it with hydrogen in the presence of palladium on carbon in a solvent such as DMF or ethyl acetate.
  • the azido compound may be reduced and converted
  • the amino group may be acetylated to give an acetamido group using the Schotten-Baumann procedure i.e. reacting the compound of the formula (I) or (II) wherein R' or R 10 is amino with acetic anhydride in aqueous sodium hydroxide and THF in a temperature range of 0°C to ambient temperature.
  • the acylation is carried out in situ following the catalytic hydrogenation of a compound of the formula (I) or (II) wherein R 1 or R ⁇ c ⁇ is azido. by performing the hydrogenation in the presence of acetic anhydride (for example using similar methods to those used in Example 15).
  • R a is hydrogen
  • the -CHO group may be introduced into the compound of the formula (I) or (II) wherein R' or R 10 is amino (amino compound) by reacting the latter compound with formic acetic anhydride, in an inert organic solvent such as THF. in a temperature range of 0°C to ambient temperature, or by reacting it with ethyl formate in an inert organic solvent in the temperature range of 50-100°C.
  • the -COO( l-4C)alkyl group may be introduced into the amino compound by reacting the latter compound with ( l-4C)alkyl chloroformate. in the presence of an organic base such as triethylamine. in an organic solvent such as dichloromethane and in a temperature range of 0°C to ambient temperature.
  • the -CONH 2 group may be introduced into the amino compound by reacting the latter compound either with potassium cyanate in aqueous acid (eg hydrochloric acid) in a temperature range of ambient temperature to 40°C or with phenyi carbamate in glyme at reflux.
  • aqueous acid eg hydrochloric acid
  • R a is chloromethyl. dichloromethyl. cyanomethyl or methoxymethyl.
  • the acid chloride may be prepared from the appropriate acid.
  • R a is acetylmethyl
  • the amino compound may be reacted with the appropriate acid anhydride, in dichloromethane or THF, in the presence of an organic base such as triethylamine and in a temperature range of 0°C to ambient temperature, or the amino compound may be reacted with the appropriate acid in the presence of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an organic base such as triethylamine, in an organic solvent such as dichloromethane, in a temperature range of 0°C to ambient temperature.
  • the -CONHMe group may be introduced into the amino compound by reacting the latter compound with methyl isocyanate in an organic solvent such as THF or acetonitrile. in a temperature range of 0°C to ambient temperature.
  • the -CONMe 2 group may be introduced into the amino compound my reacting the latter compound with dimethylcarbamoyl chloride and triethylamine in an organic solvent such as THF or acetonitrile. in a temperature range of 0°C to ambient temperature.
  • Standard reaction conditions for the conversion of a compound of the formula (I) or (II) wherein R 1 or R 10 is amino to a compound of the formula (I) or (II) wherein R or R 10 is sulfonamido are known in the art.
  • a compound of the formula (I) or (II) wherein R 1 or R'° is amino could for example be converted to a compound of the formula (I) or (II) wherein R 1 or R" J is ( 1 -4C)alkylSO,NH- by reacting the former compound with a sulfonyl chloride, for example, mesyl chloride, in a mild base such as pyridine.
  • a sulfonyl chloride for example, mesyl chloride
  • NH- or (l-4C)alkylSONH- may be prepared by reacting a compound of the formula (I) or (II) wherein R 1 is amino with a compound of the formula ( l-4C)alkylSO .L 2 or (1 -4C)SOL 2 wherein L is a phthalimido group.
  • the phthalimido compound may be prepared by oxidising a compound of the formula (IX):
  • Compounds of the formula (IX) can be prepared by reacting phthalimide with an alkylthiochloride (( l -4C)alkylSCl).
  • a compound of the formula (I) or (II) wherein R' or R'° is fluoro may be prepared by reacting a compound of the formula (I) or (II) wherein R 1 or R l ⁇ is hydroxy (hydroxy compound) with a fluorinating agent such as diethylaminosulfur trifluoride in an organic solvent such as dichloromethane in the temperature range of 0°C to ambient temperature.
  • a fluorinating agent such as diethylaminosulfur trifluoride
  • organic solvent such as dichloromethane
  • the compound of the formula (I) or (II) may be formed by reacting the hydroxy compound with a chlorinating agent.
  • a chlorinating agent for example, by reacting the hydroxy compound with thionyl chloride in a temperature range of ambient temperature to reflux, optionally in a chlorinated solvent such as dichloromethane or by reacting the hydroxy compound with carbon tetrachloride/triphenyl phosphine in dichloromethane. in a temperature range of 0°C to ambient temperature.
  • the ( l -4C)alkanesulfonyloxy compound may be prepared by reacting the hydroxy compound with (l -4C)alkanesulfonyl chloride in the presence of a mild base such as triethylamine or pyridine.
  • the ( l -4C)al ylaminocarbonyloxy compound may be prepared by reacting the hydroxy compound with (l-4C)alkyl cyanate in an organic solvent such as THF or acetonitrile. in the presence of triethylamine, in a temperature range of 0°C to 50°C.
  • a compound of the formula (I) or (II) wherein R 1 or R 10 is chloro may also be prepared from a compound of the formula (III), by reacting the latter compound with lithium chloride and crown ether, in a suitable organic solvent such as THF. in a temperature range of ambient temperature to reflux.
  • a compound of the formula (I) or (II) wherein R 1 or R'° is (1 - 4C)alkylthio or ( l-4C)alkoxy may be prepared by reacting the compound of the formula (III) with sodium thio( l-4C)alkoxide or sodium (l -4C)alkoxide respectively, in an alcohol or THF. in a temperature range of 0°C to reflux.
  • Suitable values for R 13 include ethyl and benzyl and suitable values for R' 4 include ethyl and n-propyl, preferably n-propyl.
  • a compound of the formula (IV) is conveniently prepared by reacting a chloroformate of the formula (ClCOOR n ) with a compound of the formula (IVA):
  • reaction is conveniently carried out in the presence of an inorganic or organic base such as sodium bicarbonate or an amine base such as dimethylaniline.
  • an inorganic or organic base such as sodium bicarbonate or an amine base such as dimethylaniline.
  • the former in a solvent such as acetone/water and the latter in an organic solvent such as THF. toluene. DMF or acetonitrile.
  • a compound of the formula (IVA) may be prepared by reducing a compound of the formula (IVB):
  • Raney nickel, platinum metal and its oxide, rhodium, palladium-on-charcoal and Wilkinson ' s catalyst RhCl (Ph,P) Catalyst hydrogenation is conveniently carried out in the temperature range 0°C - 150°C. but preferably at ambient temperature at slightly above atmospheric pressure.
  • a compound of the formula (IVB) is conveniently prepared by reacting together compounds of the formulae (X) and (IVC):
  • R 2 - R " and R are as hereinabove defined and L is a leaving group, preferably halo and in particular fluoro.
  • the reaction between compounds of the formulae (X) and (IVC) is carried out in the presence of an organic or inorganic base such as sodium bicarbonate, potassium carbonate or an amine base such as diisopropylethylamine. in an inert solvent such as acetonitrile. DMF. DMPU or N-methylpyrrolidone. in a temperature range of 50°C - 150°C.
  • a compound of the formula (IVB) may be formed by reacting the appropriate piperazine ring in which one of the ring nitrogen atoms is protected (with for example a ( 1 -4C)alkoxycarbonyl group) with a compound of the formula (IVC). The ring nitrogen-protecting group may then be removed and R 7 introduced onto the ring nitrogen by reacting the product of the deprotection with a compound of the formula (VII).
  • Compounds of the formula (VII) may be prepared by introducing substituents into or modifying substituents in a known optionally substituted heteroaryl ring.
  • a cyano group may be hydrolysed to a carboxy group which in turn may be converted to a carbamoyl or alkoxycarbonyl group or reduced to a hydroxymethyl group; an amino group may be acylated to an alkanoylamino group: a thio group may be alkylated to an alkylthio group which in turn may be oxidised to an alkylsulfinyl or alkylsulfonyl group and a hydroxyalkyl group may be alkylated to an alkoxyalkyl group.
  • the reaction between compounds of the formulae (VI) and (VII) is conveniently carried out in the presence of a base, in an aprotic polar solvent; preferably one with a high boiling point, such as acetonitrile or dimethylformamide.
  • Suitable bases include amine bases such as triethylamine.
  • the reaction is preferably carried out in the temperature range 50°C - 150°C.
  • Suitable leaving groups for this reaction include halo. ( l-4C)alkylthio. ( l -4C)alkanesuIf ⁇ nyl. ( l-4C)alkanesulfonyl or phenoxy.
  • the leaving group is fluoro. chloro or ( 1 -4C)alkanesulfonyl such as methanesulfonyl.
  • Amides of the formula HN CO2R )CO(I-4C)alkyl may be prepared by standard procedures of organic chemistry which are within the ordinary skill of an organic chemist.
  • the compound of the formula (VIJI) may be prepared by reacting a compound of the formula (I) or (II) wherein R 1 or R l ⁇ is amino with formaldehyde and sodium borohydride or sodium cyanoborohydride. in an alcholic solvent such as ethanol or isopropanol. in a temperature range of 0°C to ambient temperature.
  • Suitable N-oxides of compounds of the formula (I) or (II) may be prepared directly from a corresponding parent compound of the formula (I) or (II) using techniques well known to the ordinary skilled organic chemist, such as, for example, using a peracid (such as m- chloroperbenzoic acid) or perphthaiic acid in a suitable solvent (such as dioxan or a mixture of water and THF) at a suitable temperature (such as ambient temperature).
  • Example 36 also illustrates possible suitable reagents and conditions for preparing suitable N-oxides. The preparation of suitable N-oxides by assembly from suitable N-oxide starting materials and the use of the processes described in this specification is within the skill of the ordinary skilled organic chemist, and is illustrated by. for example.
  • a method for producing an antibacterial effect in a warm blooded animal which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof.
  • the invention also provides a compound of the formula (I), or a pharmaceutically- acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof, for use as a medicament: and the use of a compound of the formula (I) of the present invention, or a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof, in the manufacture of a medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.
  • suitable N-oxide or in-vivo hydrolysable ester 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. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof and a pharmaceutically-acceptable diluent or carrier.
  • the pharmaceutical compositions of this invention may be administered in 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, tableis. capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • tableis capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops 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 aminogiycosides). These may include penicillins, for example oxacillin or flucloxacillin and carbapenems. for example meropenem or imipenem. to broaden the therapeutic effectiveness against methicillin-resistant staphylococci.
  • Compounds 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.
  • BPI bactericidal/permeability-increasing protein product
  • 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 of the 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 rngkg-* to 20 mgkg-1 of the 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 of the 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 of the present invention show activity against enterococci. pneumococci 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 of the compounds of the invention may also be demonstrated in-vivo in conventional tests. No overt toxicity or other untoward effects are observed when compounds of the formula I are so tested at conventional daily dose levels.
  • Staphylococci were tested on agar. using an inoculum of 10 ⁇ 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 10 ⁇ 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 of the test organisms.
  • Organism MIC (ug/ml)
  • Kieselgel silica (Art. 9385) unless otherwise stated:
  • DMF is N.N-dimethylformamide
  • DMA is N.N-dimethylacetamide
  • TLC thin layer chromatography
  • DMSO is dimethylsulfoxide
  • CDCI3 is deuterated chloroform
  • MS mass spectroscopy
  • ESP electrospray
  • THF is tetrahydrofuran
  • TFA is trifluoroacetic acid
  • NMP is N-methylpyrrolidone dba is dibenzylideneacetone
  • DMPU is N.N-dimethylpropyleneurea.
  • N-[(5S)-3-(3-Fluoro-4-(piperazin-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (6.73 g, 15 mM) was dissolved in DMA ( 100 ml). Triethylamine (4.37 ml. 31.4 mM) was added, and the whole mixture stirred at ambient temperature under argon for 10 minutes. 2,5-Dichloropyrimidine (2.23 g, 15 mM) was added, and the solution heated to 100°C for 8 hours. After cooling, solvent was evaporated, and the residue slurried with water for 1 hour.
  • N-[(5S)-3-(3-Fluoro-4-(piperazin-l-yl)phenyl)-2-oxooxazolidin-5- lmethyl]acetamide trifluoroacetate salt (90 mg, 0.2 mM) was dissolved in DMA (3 ml). Triethylamine (58 ⁇ L. 0.42 mM) was stirred in, then 2-chloro-4.6-dimethylpyrimidine (28.5 mg. 0.2 mM ) was added, and the solution heated under argon at 160°C for 5 hours.
  • N-[(5S)-3-(3-Fluoro-4-(piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (0.9 g, 2 M) was dissolved in NMP (25 ml), triethylamine (0.28 ml. 2 mM) and 3.6-dichloropyridazine (298 mg. 2 mM) were added, and the solution heated to 1 10°C for 24 hours.
  • Example 8 N-[(5S)-3-(3-Fluoro-4-(4-(6-/ ⁇ -butyloxycarbonylyridazin-3-yl)Diperazin-l- yl)phenyl)-2-oxooxazolidin-5-ylmethv_)acetan ⁇ idc Using the method and scale of Example 7. but replacing the 3-chloropyridazine-6- carboxamide with n-butyl 3-chloropyridazine-6-carboxylate (PCT patent application WO 96/03380; 108 mg, 0.5 mM), the title product (162 mg) was obtained after chromatography as in Example 7.
  • Triethylamine (2 mM) was added to a stirred solution of N-[(5S)-3-(3-fluoro-4-(piperazin-l - yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (450 mg, 1 mM) in DMA (20 ml) under argon.
  • the resultant mixture was stirred at room temperature for 15 minutes, and the appropriate halo-heterocycle ( 1 mM) added.
  • the mixture was heated with stirring at 1 10°C for 6 hours. After cooling the solvent was removed by centrifugal evaporation. The residue was mixed with water and the solid filtered.
  • n-Butyl 3-chioropyridazine-6-carboxylate (429 mg. 2 mM) was dissolved in ethanol (10 ml). and a solution of methylamine in ethanol (2M. 4 ml) added. The mixture was stirred at ambient temperature for 1 hour, and solvent removed. The residue was chromatographed on a
  • n-Butyl 3-chloropyridazine-6-carboxylate (429 mg, 2 mM) was dissolved in ethanol ( 10 ml). and 2-methoxyethylamine ( 150 mg. 2 mM) added. The mixture was stirred at ambient temperature for 48 hours, and solvent then removed. The residue was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0% to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired halo-heterocycle product (76 mg).
  • Example 12 N-[(5S)-3-(3-Fluoro-4-(4-(6-(2-hvdroxyethylaminocarbonyl)pyridazin-3- yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethvHacetamide MS (ESP): 502 (MH + ) for C 21 H 28 FN 7 O 5
  • n-Butyl 3-chloropyridazine-6-carboxylate (858 mg, 4 mM) was dissolved in ethanol (20 ml), and 2-hydroxyethylamine (488 mg, 8 mM) added. The mixture was stirred at ambient temperature for 48 hours, and solvent removed. The residue was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired halo- heterocycle product (637 mg).
  • n-Butyl 3-chloropyridazine-6-carboxylate (858 mg. 4 mM) was dissolved in ethanol (20 ml), and bis-(2-hydroxyethyl)amine (488 mg, 8 mM) added. The mixture was stirred at ambient temperature for 48 hours, and solvent removed. The residue was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired halo-heterocycle product (637 mg).
  • n-Butyl 3-chloropyridazine-6-carboxylate (858 mg, 4 mM) was dissolved in ethanol (20 ml), and glycine methyl ester hydrochloride (1 g. 8 M), and triethylamine (808 mg. 8 mM) added. The mixture was stirred at ambient temperature for 18 hours, and solvent removed. The residue was chromatographed on a 20 g silica Mega Bond EluttB column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired halo-heterocycle product (85 mg). NMR (DMSO-D6) ⁇ : 3.65 (s. 3H); 4.08 (d. 2H); 8.13 (d. I H) 8.23 (d. I H): 9.58 (brt. I H).
  • Tris(dba)dipalladium (1.0 g, 1.09 mM) was added to a degassed, stirred solution of 5- bromopyrimidine (12.19 g, 77 mM), jV-benzylpiperazine (40.5 g, 0.23 M), and tri-o- tolylphosphine ( 1.29 g. 4.24 mM) in toluene (500 ml) under argon.
  • a solution of lithium bis(trimethylsilylamide) (1M in THF, 230 ml) was added dropwise with stirring at ambient temperature. The mixture was then heated with stirring at 100°C for 5 hours.
  • tert-Butanol 0.354 g. 3.19 mM
  • dry THF 25 ml
  • n-Butyl lithium 1.6 M in zsohexane. 2.39 ml, 3.83 mM
  • a solution of 5-benzyloxycarbonyl- amino-2-(4-(pyrimid-5-yl)piperazin-l -yl)fluorobenzene 1.3 g, 3.19 mM
  • dry DMPU 20 ml
  • Examples 16-26 (all of which are (5S) chiral compounds are summarised in Table 1 below) were prepared using the following procedure which employed a Zymark robotic system for multiple parallel synthesis :-
  • Triethylamine (2 mM) was added to a stirred solution of N-[(5S)-3-(3-fluoro-4-(piperazin-l - yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (450 mg, 1 mM) in DMA ( 15 ml) under argon. The resultant mixture was stirred at room temperature for 10 minutes. This solution was then added to the appropriate halo-heterocycle (1 mM) and the mixture heated with stirring at 1 10°C for 6 hours. After cooling the solvent was removed by centrifugal evaporation (SAVANT AES2000) with radiant heating for 5 hours.
  • SAVANT AES2000 centrifugal evaporation
  • Impure materials were dissolved in a mixture of dichloromethane and methanol and purified by silica Mega Bond Elut® chromatography. using a suitable mixture of the two solvents, as determined from the TLC. The relevant fractions were combined and the solvent removed by centrifugal evaporation (SAVANT AES2000 ) on medium heat for 3 hours. Compounds so prepared were generally characterised by the presence of the correct molecular ion for MH * in their electrospray mass spectra, and by their HPLC retention time (in minutes), using the following system and elution parameters.
  • Example 27 N-[(5S)-3-(3-Fluoro- -(4-(6-(/>/s(2-hvdroxyethylamino)carbonyl)pyridazin-
  • n-Butyl 3-chloropyridazine-6-carboxylate (858 mg, 4 mM) was dissolved in ethanol (20 ml), and bis(2-hydroxyethyl)amine (841 mg, 8 mM) added. The mixture was stirred at ambient temperature for 24 hours, and solvent removed. The residue was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient from 0% to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired haloheterocycle product (896 mg).
  • Example 29 N-((5S)-3-(3-Fluoro-4-(4-(4-ehloro-6-methylpyrimidin-2-yl)piperazin-l- yl)phenyl)-2-oxooxazolidin-5-ylmethyl
  • Example 29B Using the same technique as Example 31, but starting with N-[(5S)-3-(3-Fluoro-4-(4-(2- chloro-6-methylpyrimidin-4-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (Example 29B. 692 mg. 1.5 mM) the title product was obtained (470mg). MS (ESP): 429 (MH ⁇ ) for C 21 H 2 FN ⁇ O,
  • Example 30 Using the same technique as Example 31. but starting with N-[(5S)-3-(3-Fluoro-4-(4-(2- methyl-6-chloropyrimidin-4-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (Example 30. 1.34 g. 2.69 mM) the title product was obtained (690mg). MS (ESP): 429 (MH + ) for C :1 H 25 FKA NMR . DMSO-D6. ⁇ : 1.82 (s. 3H); 2.36 (s, 3H): 3.00 (t. 4H); 3.37 (t. 2H); 3.68 (dd. I H); 3.72 (t.
  • Triethylamine (0.5 ml. 3.6 mM) was added to a stirred solution of N-[(5S)-3-(3-fluoro-4- (piperazin-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt ( 157 mg, 0.34 M) in acetonitrile (5 ml), and 3-methylsulfinyl-1.2.4-triazine (50 mg, 0.34 mM) added. The resultant mixture was heated with stirring at 75°C for 18 hours.
  • the 3-methylsulf ⁇ nyl-1.2.4-triazine used as starting material was prepared as follows :-
  • Triethylamine (0.21 ml. 1.5 mM) was added to a stirred solution of N-[(5S)-3-(3-fluoro-4- (piperazin-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (450 mg. 1 mM) in 1.4-dioxane (20 ml), and 2-phenoxy -1.3.5-triazine (J. Amer. Chem. Soc. 1975. 97. 1851 : 173 mg. 1 mM) added. The resultant mixture was heated to reflux for 4 hours.
  • Example 36 N-[(5SK3-(3-Fluoro-4-(l-oxo-4-(pyrimidin-2-vhpiperazin-l-vDphenvD-2- oxooxazolidin-5-ylmethyl
  • Example 37 N-f(5S)-3-(3-Fluoro-4-(4-(2-chloro-5-methylpyrimidin-4-vDpiperazin-l- yl)Dhenyl -2-oxooxazolidin-5-ylmethyllacetamide and N-f(5S)-3-(3-Fluoro-4-(4-(4- chloro-5-methylpyrimidin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl
  • N-[(5S)-3-(3-Fluoro-4-(piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide trifluoroacetate salt (900 mg, 2 mM) was dissolved in DMA (20 ml), and triethylamine (610 mg. 6 mM) added.
  • 2.4-Dichloro-5-methyipyrimidine (326 mg, 2 mM) was added and the mixture heated to 100°C for 18 hours. Solvent was evaporated, and the residue partitioned between dichloromethane (40 ml) and water (20 ml). The organic layer was dried over magnesium sulfate and evaporated.
  • Buffers such as polyethylene glycol, polypropylene glycol. glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ cyclodextrin may be used to aid formulation.
  • the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
  • the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

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Abstract

L'invention concerne un composé représenté par la formule (I) dans laquelle, par exemple: R1 représente la formule -NHC(=O)Ra dans laquelle Ra représente, par exemple, alkyle C¿1?-C4; R?2 et R3¿ représentent hydrogène ou fluoro; R4 et R5 représentent indépendamment hydrogène ou méthyle; R6 représente une chaîne hétéroaryle à 6 éléments contenant 2 ou 3 atomes d'azote en tant que seuls hétéroatomes de chaîne, et éventuellement substitué par des substituants sélectionnés dans alkyle C¿1?-C4 (éventuellement substitué), halo, trifluorométhyle, alkyle C1-C4 S(O)n- (dans laquelle n est 0, 1 ou 2), alkyle C1-C4 S(O)2amino, alkanoylamino C1-C4, carboxy, hydroxy, amino, alkylamino C1-C4, dialkylamino C1-C4, alkoxycarbonyle C1-C4, carbamoyle, N-alkylcarbamoyle C1-C4, di-(N-alkyle C1-C4)carbamoyle [dans laquelle le ou les groupes alkyle C1-C4 dans les deux derniers substituants de carbamoyle sont éventuellement substitués par hydroxy, alkoxy C1-C4 ou alkoxycarbonyle C1-C4], alkényle C2-C4 (éventuellement substitué par carboxy ou alkoxycarbonyle C1-C4), alkoxy C1-C4, cyano ou nitro; ses sels acceptables sur le plan pharmaceutique, ses N-oxydes appropriés et ses esters hydrolysables in-vivo; leurs procédés de préparation; des compositions pharmaceutiques les contenant et leur utilisation en tant qu'agents antibactériens.
PCT/GB1997/001767 1996-07-06 1997-07-01 Derives substitues de piperazinyle-phenyle-oxazolidinone et leur utilisation en tant qu'agents antibacteriens WO1998001446A1 (fr)

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EP97929403A EP0918769A1 (fr) 1996-07-06 1997-07-01 Derives substitues de piperazinyle-phenyle-oxazolidinone et leur utilisation en tant qu'agents antibacteriens
AU33520/97A AU3352097A (en) 1996-07-06 1997-07-01 Substituted piperazinyl-phenyl-oxazolidinone derivatives and their use as anti-bacterial agents
JP10504900A JP2000514083A (ja) 1996-07-06 1997-07-01 置換ピペラジニル―フェニル―オキサゾリジノン誘導体および抗菌剤としてのその利用

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WO2005082899A1 (fr) * 2004-01-28 2005-09-09 Ranbaxy Laboratories Limited Derives d'oxazolidinones utilises en tant qu'antimicrobiens
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EP2138178A1 (fr) 2008-06-28 2009-12-30 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones pour le traitement de maladie pulmonaire obstructive chronique (MPOC) et/ou de l'asthme
EP2140866A1 (fr) 2008-07-04 2010-01-06 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones pour le traitement d'états inflammatoires du tractus gastro-intestinal
US7767702B2 (en) 2001-06-20 2010-08-03 Bayer Schering Pharma Aktiengesellschaft Substituted oxazolidinones for combinational therapy
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US7829712B2 (en) * 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
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US9402851B2 (en) 2003-11-27 2016-08-02 Bayer Intellectual Property Gmbh Process for the preparation of a solid, orally administrable pharmaceutical composition
US9539218B2 (en) 2005-01-31 2017-01-10 Bayer Intellectual Property Gmbh Prevention and treatment of thromboembolic disorders
WO2023061617A1 (fr) * 2020-12-21 2023-04-20 F. Hoffmann-La Roche Ag Composés de sulfonylpipérazinyle pour le traitement d'infections bactériennes

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WO2006043121A1 (fr) * 2004-10-20 2006-04-27 Ranbaxy Laboratories Limited Derives d'oxazolidinone servant d'antimicrobiens
US9539218B2 (en) 2005-01-31 2017-01-10 Bayer Intellectual Property Gmbh Prevention and treatment of thromboembolic disorders
US7919484B2 (en) * 2005-02-09 2011-04-05 Xenon Pharmaceuticals Inc. Combination therapy
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
US7932278B2 (en) 2005-09-23 2011-04-26 Bayer Schering Pharma Aktiengesellschaft 2-aminoethoxyacetic acid derivatives and their use
US8188270B2 (en) 2005-10-04 2012-05-29 Bayer Schering Pharma Aktiengesellschaft Polymorphous form of 5-chloro-N-({(5S)-2-oxo-3[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophene carboxamide
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US8785625B2 (en) 2006-03-31 2014-07-22 Research Foundation Itsuu Laboratory Compound having heterocyclic ring
EP2181993A1 (fr) * 2006-03-31 2010-05-05 Research Foundation Itsuu Laboratory Dérivés d'oxazolidinone antimicrobiens
EP2009012A4 (fr) * 2006-03-31 2009-08-12 Res Found Itsuu Lab Nouveau composé ayant un hétérocycle
DE102007018662A1 (de) 2007-04-20 2008-10-23 Bayer Healthcare Ag Oxazolidinone zur Behandlung und Prophylaxe von pulmonaler Hypertonie
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EP2140866A1 (fr) 2008-07-04 2010-01-06 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones pour le traitement d'états inflammatoires du tractus gastro-intestinal
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