EP0918770A1 - Derives de pyridyle-piperazinyle-phenyle-oxazolidinone et leur utilisation en tant qu'antibacteriens - Google Patents

Derives de pyridyle-piperazinyle-phenyle-oxazolidinone et leur utilisation en tant qu'antibacteriens

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Publication number
EP0918770A1
EP0918770A1 EP97929405A EP97929405A EP0918770A1 EP 0918770 A1 EP0918770 A1 EP 0918770A1 EP 97929405 A EP97929405 A EP 97929405A EP 97929405 A EP97929405 A EP 97929405A EP 0918770 A1 EP0918770 A1 EP 0918770A1
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EP
European Patent Office
Prior art keywords
formula
compound
fluoro
phenyl
oxooxazolidin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP97929405A
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German (de)
English (en)
Inventor
Michael John Betts
Catherine Jane Midgley
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AstraZeneca AB
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Zeneca Ltd
AstraZeneca AB
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Publication of EP0918770A1 publication Critical patent/EP0918770A1/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. Examples of such strains are 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 are 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 aminoglycosides 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 1 is hydrogen, ( 1 -4C)alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino, dimethylamino or (l-4C)alkyl or R 1 is of the formula
  • R b is hydrogen, methyl or methoxy or R' is of the formula
  • n 0, 1 or 2;
  • R 2 and R J are independently hydrogen or fluoro
  • R 4 and R 5 are independently hydrogen or methyl
  • R 6 is pyridyl 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) neighbor- (wherein n is 0, 1 or 2), (1 -4C)alkoxy. carboxy, hydroxy,
  • (l -4C)alkoxycarbonyl carbamoyl, N-(l -4C)alkylcarbamoyl, di-(N-( l-4C)alkyl)carbamoyI. cyano, nitro, amino, N-( l-4C)alkylamino. di-(N-(l -4C)alkyl)amino or
  • ( l -4C)alkylamino di-(l -4C)alkylamino, (l -4C)alkoxycarbonyl. carbamoyl. N-( l -4C alkylcarbamoyl. di-( ⁇ -( 1 -4C)alkyl)carbamoyl [wherein the ( l -4C)alkyl group or groups in the last two-mentioned carbamoyl substituents is optionally substituted by .
  • alkyl includes straight chained and branched structures.
  • (l - ⁇ C)alkyl includes propyl. isopropyl and tert-butvl.
  • references to individual alkyl groups such as ' ⁇ propyl" 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.
  • Examples of ( l -4C)alkyl include methyl, ethyl, propyl. isopropyl and tert-butvl; examples of halo include fluoro. chloro. bromo and iodo: examples of N-( 1- 4C)alkylcarbamoyl include methylcarbamoyl.
  • 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 (l-4C)alkoxycarbonyl include 2-hydroxyethylaminocarbonyl.
  • examples of (l-4C)aikylS(O) include methylthio. ethylthio. methylsulfinyl. ethylsulfinyl.
  • examples of (l -4C)alkylS(O) : amino include methylsulfonylamino and ethylsulfonylamino: examples of (2-4C)alkenyi 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 (2-4C)alkanoylamino include acetamido and propionylamino
  • examples of N-( 1 -4C)alkylamino include methylamino and ethylamino
  • example of di-(N-( l -4C)alkyl)amino include di-N-methylamino, di-( -ethyl)amino and N-ethyl-N- methylamino
  • examples of ( l-4C)alkoxycarbonyl include methoxycarbonyl . ethoxy carbonyl.
  • examples of (l -4C)alkanesulfonyloxy include methanesulfonyloxy and ethanesulfonyloxy; and examples of ( l -4C alkylaminocarbonyloxy include methvlaminocarbonvloxv and ethvlaminocarbonvloxv.
  • Suitable pharmaceuticall -acceptable salts include acid addition salts such as methanesulfonate. fumarate. hydrochlo ⁇ de. hydrobromide.
  • 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 t ⁇ ethylamine. morpho ne. N- methylpipe ⁇ dine, N-ethylpipe ⁇ dine. procaine. dibenzylamine. N,N-d ⁇ benzyleth ⁇ lamine or amino acids for example lysine There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions ⁇ 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
  • a suitable N-oxide refers to the N-oxides which may be formed on an a ⁇ a ⁇ lable nitrogen atom in either the piperazine ring or in the py ⁇ dine ring R 6
  • a suitable N-oxide ma ⁇ 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. tor 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 toi carboxy include ( l-6C)alkoxymethyl esters for example methyl.
  • (3- 8C)cycloalkoxycarbonyloxy(l-6C)alkyl esters for example l-cyclohexylcarbon ⁇ l ,3-d ⁇ o ⁇ olen-2-onylmethyl esters for example 5-methyl-1.3-dioxolen-2-onylmethyl.
  • ( 1 - 6C)alko. ⁇ ycarbonylo ⁇ yethyl esters for example 1-methoxycarbonyioxyethyl and ma ⁇ be formed at any carboxv group in the compounds of this invention
  • An in-vivo hydrolysable ester of a compound of the formula (I) containing a hydro ⁇ group includes inorganic esters such as phosphate esters and l ethers and related compounds which as a result of the in-vivo hydrolysis of the esler breakdown to give the parent hydro ⁇ > group
  • ⁇ -acyloxyalkyl ethers include aceto ⁇ > methoxy and 2.2-d ⁇ methylprop ⁇ onyloxymethoxy
  • a selection ot in-vivo hydrolvsable ester forming groups for hydroxy include ( l -10C)alkanoyl. benzoyl. phenylacetyl and substituted benzoyl and phenylacetyl. ( l -l OC)alkoxycarbonyl (to give alkyl carbonate esters). di-( l -
  • 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 1 .
  • R 1 is acetamido.
  • the enantiomer depicted above is the 5S enantiomer and when R 1 is hydroxy, the enantiomer depicted above is the 5R enantiomer.
  • the invention relates to all tautomeric forms of the compounds of the formula (I) that possess antibacterial activity.
  • R (> is pyridyl linked via a ring carbon atom and optionally substituted on a ring carbon atom by one.
  • ( l -4C)alkylSO amino. ( 1 -4C)alkanoylamino. carboxy, hydroxy. amino.
  • R b is hydrogen, methyl or methoxy, or R' is of the formula - NHS(0) n ( 1 -4C)alkyl wherein n is 0. 1 or 2.
  • R' is of the formula -NHS(O) embrace( l-4C)aikyl wherein n is 0, i or 2. n is preferably 2.
  • R 1 is acetamido
  • R 1 is hydroxy
  • R 2 and R J are hydrogen and the other is fluoro.
  • At ieast one of R 4 and R J is hydrogen.
  • R 4 and R" are both hydrogen.
  • optional substituents on the pyridyl 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 py ⁇ dyl ring are independent ⁇ selected from ( l-4C)alkyl (optionally substituted by ( l -4C)alkoxy or (2-4C)alkanovlam ⁇ no ).
  • the optional substituents on the py ⁇ dyl ring are independently selected from methyl or ethyl (each optionally substituted by methox> . ethoxy or acetamido). methylthio, ethylthio. chloro. bromo. carboxy. methoxycarbonyl. ethoxycarbonyl and carbamoyl
  • the optional substituents on the py ⁇ dyl ring are independently selected from methyl, ethyl, methoxymethyl. 2-(acetam ⁇ do)ethyl, methylthio. chloro. bromo. carboxN . methoxycarbonyl and carbamoyl
  • the optional substituents on the py ⁇ dyl ring are independently selected from ( l -4C)alkyl (preferably methyl), halo (preferably chloro). nitro. cyano. carbamoyl. N-( 1 -4C)alkylcarbamoyl and d ⁇ -( -( 1 -4C)alkyl 1
  • the pyndyl ring is py ⁇ d ⁇ n-4-yl
  • R' is acetamido.
  • one of R " and R' is hydrogen and the other is fluoro.
  • R 4 and R' are both hydrogen.
  • R° is py ⁇ dine (preferably py ⁇ d ⁇ n-4-yl) optionally substituted by a substituent selected from methyl, chloro. nitro. cyano. carbamoyl. N-( l -4C)alkylcarbamoyl and d ⁇ -(N-( l - 1 )carbamoyl
  • R 1 is acetamido.
  • one of R 1 and R 1 is hydrogen and the other is fluoro.
  • R 4 and R s are both hydrogen.
  • R" is py ⁇ dine (preferably py ⁇ d ⁇ n-4-yl) optionally substituted by a substituent selected from nitro.
  • carbamoN 1.
  • Particular compounds of the present invention include N-[(5S)-3-(3-Fluoro-4-(4-(3-methylpy ⁇ d ⁇ n-2- ⁇ l)p ⁇ peraz ⁇ n- l -yl)phen> l)-2-oxooxazohd ⁇ n-5-yl- meth ⁇ ljacetamide. N-[(5S)-3-(3-Fluoro-4-(4-(4-methylpyridin-2-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-yl methyljacetamide:
  • Further particular compounds of the present invention include : N-[(5S -3-(3-Fluoro-4-(4-(2-methylpyridin-3-yl)piperazin-l-yl)phenyl)-2-oxooxazolidin-5-yl methyl ]acetamide:
  • An especially preferred compound of the invention is N-[(5S)-3-( 3-Fluoro-4-(4-(pyridin-4-yl)piperazin- 1 -yl)phenyl)-2-oxooxazolidin-5-y 1- methyljacetamide: and pharmaceutically-acceptable salts, and suitable N-oxides. thereof.
  • 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 is R°or protected R b nd R"' is R' or protected R' and thereafter if necessary forming a pharmaceutically-acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof.
  • 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).
  • carboxy protecting groups include straight or branched chain ( l-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 alkoxycaroonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl, 1 -ethoxycarbonyloxyethyl); aryl lower alkyl groups (eg rj-methoxybenzyl, o ⁇ nitrobenzyl.
  • l-12C alkyl groups eg isopropyl. tert-butvl
  • lower alkoxy lower alkyl groups eg methoxymethyl. ethoxymethyl. isobutoxy methyl
  • tri(lower alkyl)silyl groups eg trimethylsilyl and tert-butyldimethylsilyl
  • tri(lower alkyl)silyl lower alkyl groups eg trimethylsilylethyl
  • (2-6C)alkenyl groups eg allyl and vinylethyl
  • Methods particularly appropriate for the removal of carboxy! 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-butoxvcarbonvl); lower alkenyloxycarbonyl groups (eg allyloxycarbonyl): aryl lower alkoxycarbonyl groups (eg benzoyloxycarbonyl. r methoxybenzyloxycarbonyl. ⁇ nitrobenzyloxycarbonyl. r nitrobenzyioxycarbonyl): tri lower alkyl/arylsilyl groups (eg trimethylsilyl. tert- butyldimethylsilyl. tert-butvldiphenylsilvl ); aryl lower alkyl groups (eg benzyl) groups: and triaryl lower alkyl groups (eg triphenylmethyl).
  • lower alkenyl groups eg allyl
  • lower alkanoyl groups eg
  • 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. r methoxybenzyloxycarbonyl, o ⁇ nitrobenzyloxycarbonyl.
  • aralkyl groups eg benzyl and substituted benzyl, eg r methoxybenzyl. nitrobenzyl and 2.4-dimethoxybenzyl. and triphenylmethyl
  • di-r anisylmethyl and furylmethyl groups di-r anisylmethyl and furylmethyl groups
  • nitrobenzyloxycarbonyl trialkylsilyl (eg trimethylsilyl and tert-butyldimethylsilvl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups.
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, metal- or enzymically-catalysed hydrolysis, for groups such as ( nitrobenzyloxycarbonyl. 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-butyldimethylsilvl. tert-butvldiphenylsilvl); tri alkyl/arylsilyloxymethyl (eg. tert-butvldimethylsilyloxvmethvl. tert-butvldiphenylsilyloxymethyl); 4-alkoxyphenyl (eg.
  • Aralkoxymethyl. groups may be introduced onto the amide group by reacting the latter group with the appropriate aralkoxymethyl chloride, and removed by catalytic hydrogenation.
  • Alkoxymethyl, tri alkyl/arylsilyl and tri alkyl/silyl groups may be introduced by reacting the amide with the appropriate chloride and removing with acid, or in the case of the silyl containing groups fluoride ions.
  • the 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.
  • protecting groups see one of the many general texts on the subject, for example. "Protective Groups in Organic Synthesis " by Theodora Green (publisher: John Wiley & Sons).
  • R : - R' and R and R l ⁇ are as hereinabove defined.
  • R 12 is mesyloxy or tosyloxy.
  • R 1 ' is ( l - ⁇ C)alkyl or benzyl.
  • R l is ( l-6C)alkyl.
  • R 15 is (l -4C)alkyl or benzyl and L' 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 (see Example 5) or sulfonamido (see Example 6) group, a hydroxy group alkvlated to a methoxy group, a carboxy group converted to a carbamoyl group (see Example 10).
  • a carboxy group converted to an N-( l -4C)alkylcarbamoyl or di-(N-( l -4C)alkyl)carbamoyl group see. for example. Examples 1 1 -15) or a bromo group converted to an alkylthio group.
  • a chloro group may be introduced at an unsubstituted position in R 7 (as for example in Example 7) or a chloro group may be removed from R .
  • Compounds of the formula (I) or (II) wherein R 1 or R 10 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 sulfonyl group.
  • a thio group may be oxidised to a sulfinyl group with a peracid such as m-chioroperoxybenzoic acid and oxidising agents such as potassium permanganate will convert a thio group to a sulfonyl group.
  • a compound of the formula (I) or (II) wherein R 1 or R 10 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 1 " is hydroxy into a or mesyloxN 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.
  • 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.
  • 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 to a compound of the formula
  • R a is ( l -4C)alkyl.
  • 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 1 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 (1) or (II) wherein R' or R 10 is azido. by performing the hydrogenation in the presence of acetic anhydride (for example using similar methods to those used in Example 16).
  • 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 group may be introduced into the amino compound by reacting the latter compound with ( l -4C)alkyl chloro ormate. in the presence of an organic base such as triethvlamine. in an organic solvent such as dichloromethane and in a temperature range of 0°C to ambient temperature.
  • R a is amino.
  • the -CONH : 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 phenyl 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 triethvlamine 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 triethvlamine. 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 : group may be introduced into the amino compound my reacting the latter compound with dimethylcarbamoyl chloride and triethvlamine 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 il> 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'° is ( l -4C)alkylSO : NH- by reacting the former compound with a sulfonyl chloride, for example, mesyl chloride, in a mild base such as pyridine.
  • compounds of the formula (I) or (II) wherein R 1 or R'° is ( 1 - 4C)alkylSO NH- or ( l -4C)alkylSONH- may be prepared by reacting a compound of the formula (1) or (II) wherein R' is amino with a compound of the formula ( l -4C)alkylS0 2 L or (1-4QSOL 2 wherein L 2 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 (( 1 -4C)alkylSCl).
  • a compound of the formula (I) or (II) wherein R 1 or R 10 is fluoro may be prepared by reacting a compound of the formula (I) or (II) wherein R 1 or R'° 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 ild base such as triethvlamine or pyridine.
  • the ( l -4C)alkylaminocarbonyloxy compound may be prepared by reacting the hydroxy compound with ( 1 -4C)alkyl cyanate in an organic solvent such as THF or acetonitrile. in the presence of triethvlamine. in a temperature range of 0°C to 50°C.
  • a compound of the formula (I) or ( II) wherein R' 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' or R 10 is ( 1- 4C)alky lthio 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.
  • a compound of the formula (IV) is conveniently prepared by reacting a chloroformate of the formula (CICOOR 13 ) with a compound of the formula (IV A):
  • catalytic hydrogenation metal reductions or with reducing agents such as sodium hydrosulfite.
  • Suitable catalysts in catalytic hydrogenation include 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 is a leaving group, preferably halo and in particular fluoro.
  • 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.
  • organic or inorganic base such as sodium bicarbonate, potassium carbonate or an amine base such as diisopropylethylamine.
  • 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 ( l-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.
  • Such conversions are well known to the skilled chemist, for example 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 triethvlamine.
  • the reaction is preferably carried out in the temperature range 50°C - 150°C.
  • Suitable leaving groups for this reaction include halo. ( Oalkylthio. ( 1 -4C)alkanesulfinyl. ( 1 -4C)alkanesulfonyl or phenoxy.
  • the leaving group is fluoro. chloro or ( l -4C)alkanesulfonyl such as methanesulfonyl.
  • a compound of the formula (II) wherein R is of the formula -N(C ⁇ 2 R l :> )CO(l -4C)alkyl is conveniently prepared by reacting a compound of the formula (I) and (II) wherein R 1 or R is hydroxy with an amide of the formula HN(CO ⁇ R ⁇ )CO(l-4C)alkyl under Mitsunobu conditions.
  • Mitsunobu conditions For example, in the presence of tri- n-butylphosphine and l.r-(azodicarbonyl)dipiperidine in an organic solvent such as THF, and in the temperature range 0°C - 60°C, but preferably at ambient temperature. Details of analogous Mitsunobu reactions are contained in Tsunoda et al, Tet. Letts.. 34. 1639. ( 1993).
  • Amides of the formula HN(CO 2 R " )CO(l -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 (VIII) may be prepared by reacting a compound of the formula (I) or (II) wherein R 1 or R'° 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 preparared 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).
  • a peracid such as m- chloroperbenzoic acid
  • a suitable solvent such as dioxan or a mixture of water and THF
  • 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 ol 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 of the formula (I) or a pharmaceuticalh -acceptable salt, suitable N-oxide or in-vivo hydrolysable ester thereof and a pharmaceutically-acceptable diluent or carrier
  • compositions of this invention may be administered in standard manner tor 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, (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 aminoglycosides). 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.
  • 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.
  • 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 l OOmg and l g 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 mgkg-1 to 20 mgkg-' 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. pneu ococci and methicillin resistant strains of S. aureus and coagulase negatn e staphylococci
  • the antibacterial spectrum and potency of a particular compound may be determined in a standard test system
  • 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% defib ⁇ nated horse blood, an inoculum of 10 ⁇ CFU/spot and an incubation temperature of 7°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)
  • MRQR methicillin resistant quinolone resistant
  • DMA is N.N-dimethylacetamide
  • DMSO dimethylsulfoxide
  • THF is tetrahydrofuran
  • TFA is trifluoroacetic acid
  • NMP N-methylpyrrolidone dba is dibenzylideneacetone
  • DMPU is N.N-dimethylpropyleneurea.
  • N-[(5S)-3-(3-Fluoro-4-(piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyljacetamide trifluoroacetate salt (90 mg. 0.2 mM) was dissolved in DMF (3 ml). Triethvlamine (58 ⁇ L. 0.42 mM) was stirred in. then 2-chloro-4-methyl-5-nitropyridine (35 mg. 0.2 mM) was added, and the solution heated under argon at 160°C for 5 hours.
  • N-[(5S)-3-(3-Fluoro-4-(4-(5-nitropyridin-2-yl)piperazin-l -yl)phenyl)-2-oxooxazolidin-5- ylmethyljacetamide (229 mg. 0.5 mM) was suspended in ethanol (50 ml), and treated with a solution of hydrogen chloride in diethyl ether (1 M. 2 ml). Palladium catalyst (10% on charcoal. 100 mg) was added, and the mixture hydrogenated at ambient pressure for 20 hours.
  • N-[(5S)-3-(3-Fluoro-4-(piperazin-l -yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (450 mg, 1 mM) was dissolved in DMA ( 15 ml), triethylamine (202 mg. 2 mM) was added, and the whole mixture stirred at ambient temperature under argon for 15 minutes.
  • tert-Butyl 2-chloropyridine-5-carboxylate (214 mg, 1 mM) was added, and the solution heated to 120°C for 6 hours. After cooling, solvent was evaporated, the residue dissolved in dichloromethane, and washed with saturated sodium bicarbonate solution.
  • Example 10 N-
  • Oxalyl chloride (254 mg, 2 mM) was added dropwise at ambient temperature to a stirred suspension of N-[(5S)-3-(3-fluoro-4-(4-(5-carboxypyridin-2-yl)piperazin-l-yl)phenyl)-2- oxooxazolidin-5-ylmethyl]acetamide (457 mg. 1 mM) in dichloromethane (25 ml) under argon. DMF (50 ⁇ L) was added, and the mixture stirred for 16 hours. Solvent was removed, and the residue suspended in dichloromethane (40 ml) under argon. Bistrimethylsilylamine (845 ⁇ L. 4 mM) was added dropwise.
  • Example 1 N-f(5S)-3-(3-Fluoro-4-(4-(5-methylaminocarbonylpyridin-2-yl)piperazin-l- yl)phenyl)-2-oxooxazolidin-5-ylmethyl
  • Carbonyldiimidazole (244 mg. 1.5 mM) was added, and the mixture stirred for 3 hours.
  • Example 12 N-l(5S)-3- 3-Fluoro-4-(4-(5-(2-hvdroxyethvIaminocarbonyl)pyridin-2- yl)niperazin-l-vDphenvD-2-oxooxazolidin-5-ylmethyllacetamide
  • Example 13 N-
  • Example 14 N-[(5S)-3-(3-Fluoro-4-(4-(5-(2-metho ⁇ vethylaminocarbonyl)pyridin-2- yDpiperazin-l-vnphenvD-2-oxooxazolidin-5-ylmethyl1acetam.de
  • Example 15 N-
  • Example 2 Using the same technique as Example 1 1. but replacing the methylamine with glycine methyl ester hydrochloride (376 mg, 3 mM), and adding triethylamine (417 mg, 3 mM). the title product (381 mg) was obtained.
  • Tris(dba)dipalladium (0.74 g. 0.81 mM) was added to a degassed, stirred mixture of 2- bromopyridine (9.48 g, 60 mM), N-benzylpiperazine (7 g. 40 mM). sodium tert-butoxide (5.76 g. 60 mM). and tri- -tolylphosphine ( 1 g, 3.3 mM) in toluene (500 ml) under argon. The mixture was heated to reflux for 18 hours, cooled, filtered through celite. washed with water (100 ml) and dried over magnesium sulfate. After filtration and evaporation to dryness.
  • tert-Butanol 0.717 g. 6.46 mM
  • dry THF 25 ml
  • n-Butyl lithium 1.6 M in /.sohexane. 4.85 ml, 7.75 mM
  • Examples 17-31 (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 18 is a repeat using the Zymark robotic synthesis of Example 2.
  • Ethyl 2-chloropyridine-5-carboxylate (6 g. 32 mM) was dissolved in dry ethanol (25 ml), n- propylamine (5 ml. 61 mM) added, and the mixture allowed to stand at ambient temperature for 17 days. Solvent was removed, and the residue recrystallised from a mixture of diethyl ether and petrol, to give the desired product, mp 109°C-1 10°C (2.8 g).
  • N-[(5S)-3-(3-Fluoro-4-(piperazin-l-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide trifluoroacetate salt (900 mg, 2 mM) was dissolved in a mixture of iso-propylalcohol (1 ml) and xylene (2ml). Triethylamine (0.556 ml. 4 mM) was stirred in and 3-fluoro-4-iodopyridine (Tetrahedron.1993 . p49-64: 0.446 g, 2 mM) was added. The solution was heated under argon at 130°C for 72 hours.
  • Tris(dba)dipalladium (0.74 g, 0.81 mM) was added to a degassed, stirred mixture of 3-bromopyridine (9.48 g, 60 mM). N-benzylpiperazine (7 g, 40 mM). sodium tert-butoxide (5.76 g. 60 mM). and tri-o-tolyiphosphine (1 g. 3.3 mM) in toluene (500 ml) under argon. The mixture was heated to reflux for 8 hours, cooled and evaporated to dryness. The residue was treated with water (250 ml), extracted with dichloromethane (3 x 150 ml) and dried over magnesium sulfate.
  • tert-Butanol 0.355 g. 4.8 mM
  • dry THF 10 ml
  • n-Butyl lithium 1.6 M in isohexane. 2.4 ml, 3.84 mM
  • a solution of 5-benzyloxycarbonyl- amino-2-(4-(pyridin-3-yl)piperazin-l-yl)fluorobenzene (1.3 g, 3.2 mM) dissolved in dry DMPU (20 ml) was added dropwise.
  • 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 indépendamment hydrogène ou fluoro; R4 et R5 représentent indépendamment hydrogène ou méthyle: R6 représente pyridyle, 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, 2), alkyle C1-C4 S(O)2amino, alkanoylamino C1-C4, carboxy, hydroxy, amino, alkylamino C1-C4, di-alkylamino 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.
EP97929405A 1996-07-06 1997-07-01 Derives de pyridyle-piperazinyle-phenyle-oxazolidinone et leur utilisation en tant qu'antibacteriens Withdrawn EP0918770A1 (fr)

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BR0308018A (pt) 2002-02-28 2005-01-04 Astrazeneca Ab Composto ou um seu sal farmaceuticamente aceitável ou um seu éster hidrolisável in vivo, pró-droga, método para produzir um efeito antibacteriano em um animal de sangue quente, uso de um composto ou um seu sal farmaceuticamente aceitável ou um seu éster hirolisável in vivo, composição farmacêutica, e, processo para a preparação de um composto ou um seu sal farmaceuticamente aceitável ou um seu éster hidrolisável in vivo
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