WO2002080841A2 - Antibacterial oxazolidinones with a cyclic sulphilimine or sulphoximine - Google Patents

Antibacterial oxazolidinones with a cyclic sulphilimine or sulphoximine Download PDF

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Publication number
WO2002080841A2
WO2002080841A2 PCT/GB2002/001615 GB0201615W WO02080841A2 WO 2002080841 A2 WO2002080841 A2 WO 2002080841A2 GB 0201615 W GB0201615 W GB 0201615W WO 02080841 A2 WO02080841 A2 WO 02080841A2
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Prior art keywords
alkyl
ring
oxo
optionally substituted
phenyl
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PCT/GB2002/001615
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French (fr)
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WO2002080841A3 (en
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Michael John Betts
Michael Lingard Swain
Neil James Hales
Hoan Khai Huynh
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to AU2002308000A priority Critical patent/AU2002308000A1/en
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Publication of WO2002080841A3 publication Critical patent/WO2002080841A3/en

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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
    • C07D413/10—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 carbon chain containing aromatic rings
    • 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
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to antibiotic compounds and in particular to antibiotic compounds containing a substituted 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 as effective against both Gram-positive and certain Gram-negative pathogens.
  • Gram-positive pathogens for example Staphylococci, Enterococci, and Streptococci 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 f aecium.
  • MRSA methicillin resistant staphylococcus
  • MRCNS methicillin resistant coagulase negative staphylococci
  • penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus f aecium.
  • the major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing.
  • antibacterial compounds containing an oxazolidinone ring have been 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, 1156-1165).
  • Such antibacterial oxazolidinone compounds with a 5-acetamidomethyl sidechain may be subject to mammalian peptidase metabolism.
  • bacterial resistance to known antibacterial agents may develop, for example, by (i) the evolution of active binding sites in the bacteria rendering a previously active pharmacophore less effective or redundant, and/or (ii) the evolution of means to chemically deactivate a given pharmacophore. Therefore, there remains an ongoing need to find new antibacterial agents with a favourable pharmacological profile, in particular for compounds containing new pharmacophores.
  • the present invention provides a compound of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof,
  • T is selected from the groups in (TA) & (TB) below (wherein ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a and CY are defined hereinbelow);
  • TA T is selected from the following groups (TA1) and (TA2) :-
  • TA1 (TA2) wherein : in (TA1), Q ⁇ i is 0 or 1 and represents a chain of carbon atoms (optionally substituted as defined for ARl) of length Oi and M is a bond joining the adjacent carbon atoms, or M represents one or two carbon atoms, and defines a 4- to 7-membered monocyclic ring, which ring may optionally have one of:
  • (TB) T is selected from the following groups (TB 1) to (TB3) :-
  • (TB3) wherein ()m, ()oi, ()nr, () ⁇ r, ()p ⁇ and ()pr represent chains of carbon atoms (optionally substituted as defined for ARl hereinafter) of length ni, Oi, n , Or, pi and p respectively, and are independently 0-2, with the proviso that in (TBl) and (TB2) the sum of n 1; oi, nr and o v does not exceed 8 (giving a maximum ring size of 14 in (TBl) and 11 in (TB2)), and in (TB3) the sum of ni, 01 , n , o ⁇ , i and pr does not exceed 6 (giving a maximum ring size of 12);
  • R s and R s are independently selected from : (i) hydrogen (except where E is -SO 2 -or -O-CO-), or
  • (l-6C)alkyl ⁇ optionally substituted by one or more (l-4C)alkanoyl groups (including geminal disubstitution) and/or optionally monosubstituted by cyano, cyano-imino, (l-4C)alkoxy, trifluoromefhyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as defined for ARl hereinafter), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) hereinafter, (l-4C)alkylS(O)q- (q is 0, 1 or 2); and/or (with the proviso that where R 2s is -SO 2 or -O-CO- not on the first carbon atom of the (1-6C) alkyl chain) optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and
  • (l-4C)alkoxycarbonyl trifluoromethyl, ethenyl, 2-(l-4C)alkylethenyl, 2-cyanoethenyl, 2- cyano-2-((l-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((l-4C)alkyl)ethenyl, 2-((l- 4C)alkylaminocarbonyl)ethenyl, 2-((l-4C)alkoxycarbonyl)ethenyl, 2-(ARl)ethenyl, 2- (AR2)ethenyl, or 2-(AR2a)ethenyl; wherein Re is selected from groups (Rcl) to (Rc5) :-
  • (Rcl) (l-6C)alkyl ⁇ optionally substituted by one or more (l-4C)alkanoyl groups (including geminal disubstitution) and/or optionally monosubstituted by cyano, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for ARl defined hereinafter), (l-4C)alkylS(O)q- (q is 0, 1 or 2); or, on any but the first carbon atom of the (1- 6C)alkyl chain, optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally monosubstituted by oxo, -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamin
  • Rc2b hydrogen, (l-4C)alkoxycarbonyl, trifluoromethyl, -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], ethenyl, 2-(l-4C)alkylethenyl, 2- cyanoethenyl, 2-cyano-2-((l-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((l-4C)alkyl)ethenyl, 2-((l-4C)alkylaminocarbonyl)ethenyl, 2-((l-4C)alkoxycarbonyl)ethenyl, 2-(ARl)ethenyl, 2- (AR2)ethenyl, 2-(AR2a)ethenyl;
  • 4C)alkyl group being optionally substituted by (l-4C)alkoxycarbonyl or by carboxy), benzyloxy-(l-4C)alkyl or (l-lOC)alkyl ⁇ optionally substituted as defined for (Rc2c) ⁇ ; (Rc2e) R 15 O- wherein R 15 is benzyl, (l-6C)alkyl ⁇ optionally substituted as defined for
  • AR2b and Rj is hydrogen or (l-6C)alkyl
  • ARl is an optionally substituted phenyl or optionally substituted naphthyl
  • AR2 is an optionally substituted 5- or 6-membered, fully unsaturated (i.e with the maximum degree of unsaturation) monocyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O-O, O-S or S-S bonds), and linked via a ring carbon atom, or a ring nitrogen atom if the ring is not thereby quaternised;
  • AR2a is a partially hydrogenated version of AR2 (i.e. AR2 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom if the ring is not thereby quaternised;
  • AR2b is a fully hydrogenated version of AR2 (i.e. AR2 systems having no unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom;
  • AR3 is an optionally substituted 8-, 9- or 10-membered, fully unsaturated (i.e with the maximum degree of unsaturation) bicyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O-O, O-S or S-S bonds), and linked via a ring carbon atom in either of the rings comprising the bicyclic system;
  • AR3a is a partially hydrogenated version of AR3 (i.e. AR3 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not thereby quaternised, in either of the rings comprising the bicyclic system;
  • AR3b is a fully hydrogenated version of AR3 (i.e. AR3 systems having no unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom, in either of the rings comprising the bicyclic system;
  • AR4 is an optionally substituted 13- or 14-membered, fully unsaturated (i.e with the maximum degree of unsaturation) tricyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O-O, O-S or S-S bonds), and linked via a ring carbon atom in any of the rings comprising the tricyclic system;
  • AR4a is a partially hydrogenated version of AR4 (i.e. AR4 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not thereby quaternised, in any of the rings comprising the tricyclic system;
  • CY is an optionally substituted cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl ring;
  • (HET)AR is a 5-6 membered aromatic or heteroaromatic ring
  • a 5-membered ring this may be a thiophene ring, comprising a single sulphur atom sited ortho to the nitrogen atom on the adjacent oxazolidinone ring, such a ring may have a single optional substituent Rl as hereinafter defined sited ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring
  • Rl substituent
  • when a 6-membered ring this may be a phenyl ring or comprise a single nitrogen atom sited ortho to the nitrogen atom on the adjacent oxazolidinone ring
  • such ring may be optionally substituted at one or both positions ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring by Rl, where each
  • Rl is independently selected from hydrogen, halogen, methyl and methoxy, ethyl and ethoxy;
  • Y is -NH- ;
  • Z is hydrogen, -COR5 or -CSR5, wherein R5 is selected from:
  • (l-6C)alkyl (optionally substituted with 1-4 halogen atoms), cyclopropyl, -O-(l-6C)alkyl, NH2 or NH-(l-6C)alkyl or N-di((l-6C)alkyl).
  • (l-6C)alkyl includes propyl, isopropyl and tert-butyl.
  • 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.
  • a similar convention applies to other radicals, for example halo(l-4C)alkyl includes 1-bromoethyl and 2-bromoethyl.
  • a C5-C6 heteroaromatic ring means a 5- or 6-membered aryl ring wherein (unless stated otherwise) 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulfur. Unless stated otherwise, such rings are fully aromatic.
  • Particular examples of 5- or 6- membered heteroaryl ring systems are furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.
  • halogen when present as an aromatic ring substituent is selected from any one of bromine, chlorine or fluorine, as an aliphatic substituent from chlorine or fluorine.
  • substituents for alkyl, phenyl (and phenyl containing moieties ) and naphthyl groups and ring carbon atoms in heteroaryl (mono or bicyclic) rings include halo, (l-4C)alkyl , hydroxy, nitro, carbamoyl, (l-4C)alkylcarbamoyl, di-((l-4C)alkyl)carbarnoyl, cyano, trifluoromethyl, trifluoromethoxy, amino, (l-4C)alkylamino, di((l-4C)alkyl)amino, (l-4C)alkyl S(O) - (q is 0,
  • phenyl and naphthyl groups and heteroaryl (mono- or bicyclic) rings may be mono- or di-substituted on ring carbon atoms with substituents independently selected from the above list of particular optional substituents, or on ring nitrogen atoms provided the ring is not thereby quaternised.
  • 5-membered heteroaryl rings containing 2 or 3 heteroatoms independently selected from N, O and S are pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, and also in an alternative embodiment, isothiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole or 1,2,3-thiadiazole.
  • Examples of (l-4C)alkyI and (l-5C)alkyl include methyl, ethyl, and propyl and isopropyl; examples of (l-6C)aIkyl include methyl, ethyl, propyl, isopropyl, pentyl and hexyl; examples of (l-lOC)a ⁇ ky ⁇ include methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyl and nonyl; examples of (l-4C)alkanoylamino-(l-4C)alkyl include formamidomethyl, acetamidomethyl and acetamidoethyl; examples of hydroxy(l-4C)alkyl and hydroxy(l- 6C)alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of (l-4C)alkoxycarbonyl include me
  • 4C)alkyl)amino include dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N- propylamino and dipropylamino; examples of halo groups include fluoro, chloro and bromo; examples of (l-4C)alkyIsu ⁇ fonyI include methylsulfonyl and ethylsulfonyl; examples of (1- 4C)alkoxy-(l-4C)alkoxy and (l-6C)alkoxy-(l-6C)alkoxy include methoxymethoxy, 2- methoxyethoxy, 2-ethoxyethoxy and 3-methoxypropoxy; examples of (l-4C)alkoxy-(l- 4C)alkoxy-(l-4C)alkoxy include 2-(methoxymethoxy)ethoxy,
  • examples of (l-4C)alkylS(O) 2 amino include methylsulfonylamino and ethylsulfonylamino; examples of (l-4C)aIkanoylamino and (l-6C)alkanoyla ino include formamido, acetamido and propionylamino; examples of (l-4C)a!koxycarbonyIamino include methoxycarbonylamino and ethoxycarbonylamino; examples of N-(l-4C)alkyl-N-(l- 6C)alkanoylamino include N-methylacetamido, N-ethylacetamido and N- methylpropionamido; examples of (l-4C)alkylS(O)pNH- wherein p is 1 or 2 include methyls
  • Particular values for AR2 include, for example, for those AR2 containing one heteroatom, furan, pyrrole, thiophene; for those AR2 containing one to four N atoms, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3- & 1,2,4-triazole and tetrazole; for those AR2 containing one N and one O atom, oxazole, isoxazole and oxazine; for those AR2 containing one N and one S atom, thiazole and isothiazole; for those AR2 containing two N atoms and one S atom, 1,2,4- and 1,3,4-thiadiazole.
  • AR2a include, for example, dihydropyrrole (especially 2,5- dihydropyrrol-4-yl) and tetrahydropyridine (especially l,2,5,6-tetrahydropyrid-4-yl).
  • AR2b include, for example, tetrahydrofuran, pyrrolidine, morpholine (preferably morpholino), thiomorpholine (preferably thiomorpholino), piperazine (preferably piperazino), imidazoline and piperidine, l,3-dioxolan-4-yl, l,3-dioxan-4-yl, 1,3- dioxan-5-yl and l,4-dioxan-2-yl.
  • Particular values for AR3 include, for example, bicyclic benzo-fused systems containing a 5- or 6-membered heteroaryl ring containing one nitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen, sulfur and nitrogen.
  • ring systems include, for example, indole, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, quinoline, quinoxaline, quinazoline, phthalazine and cinnoline.
  • AR3 include 5/5-, 5/6 and 6/6 bicyclic ring systems containing heteroatoms in both of the rings.
  • Specific examples of such ring systems include, for example, purine and naphthyridine.
  • AR3 include bicyclic heteroaryl ring systems with at least one bridgehead nitrogen and optionally a further 1-3 heteroatoms chosen from oxygen, sulfur and nitrogen.
  • ring systems include, for example, 3H-pyrrolo[l,2-a]pyrrole, pyrrolo[2,l-b]thiazole, lH-imidazo[l,2-a]pyrrole, lH-imidazo[l,2-a]imidazole, lH,3H- ⁇ yrrolo[l,2-c]oxazole, lH-imidazo[l,5-a]pyrrole, pyrrolo[l,2-b]isoxazole, imidazo[5,l-b]thiazole, imidazo[2,l-b]thiazole, indolizine, imidazo[l,2-a]pyridine, imidazo[l,5-a]pyridine, pyrazolo[l,5-a]pyridine, pyrrolo[l,
  • ring systems include, for example, [lH]-pyrrolo[2,l-c]oxazine, [3H]- oxazolo[3,4-a]pyridine, [6H]-pyrrolo[2,l-c]oxazine and pyrido[2,l-c][l,4]oxazine.
  • 5/5- bicyclic ring systems are imidazooxazole or imidazothiazole, in particular imidazo[5,l-b]thiazole, imidazo[2,l-b]thiazole, imidazo [5, 1-b] oxazole or imidazo[2,l-b]oxazole.
  • AR3a and AR3b include, for example, indoline, l,3,4,6,9,9a-hexahydropyrido[2,lc][l,4]oxazin-8-yl, 1,2,3,5,8,8a- hexahydroimidazo[l,5a]pyridin-7-yl, l,5,8,8a-tetrahydrooxazolo[3,4a]pyridin-7-yl, l,5,6,7,8,8a-hexahydrooxazolo[3,4a]pyridin-7-yl, (7aS)[3H,5H]-l,7a- dihydropyrrolo[l,2c]oxazol-6-yl, (7aS)[5H]-l,2,3,7a-tetrahydropyrrolo[l,2c]imidazol-6-yl, (7aR)[3H,5H]-l,7a-dihydropyrrol
  • Particular values for AR4 include, for example, pyrrolo[a]quinoline, 2,3-pyrroloisoquinoline, pyrrolo[a]isoquinoline, lH-pyrrolo[l,2-a]benzimidazole, 9H-imidazo[l,2-a]indole, 5H-imidazo[2,l-a]isoindole, lH-imidazo[3,4-a]indole, imidazo[l,2-a]quinoline, imidazo[2,l-a]isoquinoline, imidazo [l,5-a]quinoline and imidazo[5,l-a]isoquinoline.
  • CY are (on an available carbon atom) up to three substituents independently selected from (1- 4C)alkyl ⁇ optionally substituted by (preferably one) substituents selected independently from hydroxy, trifluoromethyl, (l-4C)alkyl S(O)q- (q is 0, 1 or 2) (this last substituent preferably on ARl only), (l-4C)alkoxy, (l-4C)alkoxycarbonyl, cyano, nitro, (l-4C)alkanoylamino, - CONRvRw or -NRvRw ⁇ , trifluoromethyl, hydroxy, halo, nitro, cyano, thiol, (l-4C)alkoxy, (1- 4C)alkanoyloxy, dimethylaminomethyleneaminocarbonyl, di(N-(l- 4C)alkyl)aminomethylimino, carboxy, (l-4C)alkoxycarbonyl, (l-4C)alkanoyl, (1- 4C
  • substituents on ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a and CY are up to three substituents independently selected from trifluoromethoxy, benzoylamino, benzoyl, phenyl ⁇ optionally substituted by up to three substituents independently selected from halo, (l-4C)alkoxy or cyano ⁇ , furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyimino(l-4C)alkyl, (l-4C)alkoxyimino(l-4C)alkyl, halo-(l-4C)alkyl, (1- 4C)alkanesulfonamido,
  • Preferable optional substituents on Ar2b as l,3-dioxolan-4-yl, l,3-dioxan-4-yl, 1,3- dioxan-5-yl or l,4-dioxan-2-yl are mono- or disubstitution by substituents independently selected from (l-4C)alkyl (including geminal disubstitution), (l-4C)alkoxy, (l-4C)alkylthio, acetamido, (l-4C)alkanoyl, cyano, trifluoromethyl and phenyl] .
  • Preferable optional substituents on C Y are mono- or disubstitution by substituents independently selected from (l-4C)aIkyl (including geminal disubstitution), hydroxy, (1- 4C)alkoxy, (l-4C)alkylthio, acetamido, (l-4C)alkanoyl, cyano, and trifluoromethyl.
  • Suitable substituents on AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4 and AR4a are (on an available nitrogen atom, where such substitution does not result in quaternization) (l-4C)alkyl, (l-4C)alkanoyl ⁇ wherein the (l-4C)alkyl and (l-4C)alkanoyl groups are optionally substituted by (preferably one) substituents independently selected from cyano, hydroxy, nitro, trifluoromethyl, (l-4C)alkyl S(O)q- (q is 0, 1 or 2), (l-4C)alkoxy, (1- 4C)alkoxycarbonyl, (l-4C)alkanoylamino, -CONRvRw or -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl] ⁇ , (2-4C)alkenyl, (2-4C)alkynyl, (1- 4
  • suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, citrate, maleate, tartrate and (less preferably) hydrobromide. Also suitable are 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, tris-(2-hydroxyethyl)amine, N-methyl D- glucamine and amino acids such as lysine.
  • a preferred pharmaceutically-acceptable salt is the sodium salt.
  • salts of the sulfoximine NH residue are envisaged, by way of non - limiting example sulphonic acid derivatives, methane sulfonate, hydrochloride and hydrobromide salts.
  • salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
  • 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).
  • a prodrug may be used to alter or improve the physical and/or pharmacokinetic profile of the parent compound and can be formed when the parent compound contains a suitable group or substituent which can be derivatised to form a prodmg.
  • pro-drugs include in- vivo hydrolysable esters of a compound of the formula (I) or a pharmaceutically-acceptable salt thereof.
  • prodrugs are known in the art, for examples see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H.
  • An in- vivo hydrolysable ester of a compound of the formula (I) or a pharmaceutically- acceptable salt thereof containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkoxymethyl esters for example methoxymethyl, (l-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, (3-8C)cycloalkoxycarbonyloxy(l- 6C)alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolan-2-onylmethyl esters for example 5-methyl-l,3-dioxolan-2-ylmethyl; and (l-6C)alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
  • An in-vivo hydrolysable ester of a compound of the formula (I) or a pharmaceutically- acceptable salt thereof containing a hydroxy group or groups includes inorganic esters such as phosphate esters (including phosphoramidic cyclic 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/s.
  • the sulphoximine residue may be derivatised by a convenient biologically labile group to give a derivative suitable for use as a solubilising pro- drug.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy.
  • a selection of in-vivo hydrolysable ester forming groups for hydroxy include (l-lOC)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)alkylaminoacetyl and carboxyacetyl.
  • substituents on benzoyl and phenylacetyl include chloromethyl or aminomethyl, (l-4C)alkylaminomethyl and di-((l- 4C)alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4-position of the benzoyl ring.
  • Suitable in-vivo hydrolysable esters of a compound of the formula (I) are described within the definitions listed in this specification, for example esters described by the definition (Rc2d), and some groups within (Rc2c).
  • Suitable in-vivo hydrolysable esters of a compound of the formula (I) are described as follows.
  • a 1,2-diol may be cyclised to form a cyclic ester of formula (PD1) or a pyrophosphate of formula (PD2) :
  • (PD1) (PD2) Particularly interesting are such cyclised pro-drugs when the 1,2-diol is on a (l-4C)alkyl chain linked to a carbonyl group in a substituent of formula Re borne by a nitrogen atom in structures (TA1) or (TA2).
  • Esters of compounds of formula (I) wherein the HO- function/s in (PD1) and (PD2) are protected by (l-4C)alkyl, phenyl or benzyl are useful intermediates for the preparation of such pro-drugs.
  • hydrolysable esters include phosphoramidic esters, and also compounds of formula (I) in which any free hydroxy group, or sulfoxime group, independently forms a phosphoryl (npd is 1) or phosphiryl (npd is 0) ester of the formula
  • npd is independently 0 or 1 for each oxo group :
  • phosphono is -P(O)(OH) 2
  • (l-4C)alkoxy(hydroxy)- phosphoryl is a mono-(l-4C)alkoxy derivative of -O-P(O)(OH) 2
  • di-(l- 4C)alkoxyphos ⁇ horyl is a di-(l-4C)alkoxy derivative of -O-P(O)(OH) .
  • Useful intermediates for the preparation of such esters include compounds containing a group/s of formula (PD3) in which either or both of the -OH groups in (PD3) is independently protected by (l-4C)alkyl (such compounds also being interesting compounds in their own right), phenyl or phenyl-(l-4C)alkyl (such phenyl groups being optionally substituted by 1 or 2 groups independently selected from (l-4C)alkyl, nitro, halo and (1- 4C)alkoxy).
  • PD3 group/s of formula (PD3) in which either or both of the -OH groups in (PD3) is independently protected by (l-4C)alkyl (such compounds also being interesting compounds in their own right), phenyl or phenyl-(l-4C)alkyl (such phenyl groups being optionally substituted by 1 or 2 groups independently selected from (l-4C)alkyl, nitro, halo and (1- 4C)alkoxy).
  • prodrugs containing groups such as (PD1), (PD2) and (PD3) may be prepared by reaction of a compound of formula (I) containing suitable hydroxy group/s with a suitably protected phosphorylating agent (for example, containing a chloro or dialkylamino leaving group), followed by oxidation (if necessary) and deprotection.
  • a suitably protected phosphorylating agent for example, containing a chloro or dialkylamino leaving group
  • Prodrags containing a group such as (PS1) may be obtained by analogous chemistry.
  • a compound of formula (I) contains a number of free hydroxy group
  • those groups not being converted into a prodrug functionality may be protected (for example, using a t-butyl-dimethylsilyl group), and later deprotected.
  • enzymatic methods may be used to selectively phosphorylate or dephosphorylate alcohol functionalities.
  • esters include, for example, those in which Re is defined by, for example, R 14 C(O)O(l-6C)alkyl-CO- (wherein R 14 is for example, benzyloxy-(l-4C)alkyl, or phenyl).
  • Suitable substituents on a phenyl group in such esters include, for example, 4-(l-4C)piperazino-(l-4C)alkyl, piperazino-(l-4C)alkyl and morpholino-(l-4C)alkyl.
  • salts of an in-vivo hydrolysable ester may be formed this is achieved by conventional techniques.
  • compounds containing a group of formula (PD1), (PD2) and/or (PD3) may ionise (partially or fully) to form salts with an appropriate number of counter-ions.
  • an in-vivo hydrolysable ester prodrug of a compound of formula (I) contains two (PD3) groups, there are four HO-P- functionalities present in the overall molecule, each of which may form an appropriate salt (i.e. the overall molecule may form, for example, a mono-, di-, tri- or tetra- sodium salt).
  • 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 (I):
  • the present invention includes the pure enantiomer depicted above or mixtures of the R and S 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. For the avoidance of doubt the enantiomer depicted above is the R enantiomer.
  • the compounds of the formula (I) may have other chiral centres, for example certain sulfoxime compounds may be chiral at the sulfur atom. It is to be understood that the invention encompasses all such optical and diastereo-isomers, and racemic mixtures, that possess antibacterial activity. It is well known in the art how to prepare optically-active forms (for example by resolution of the racemic form by recrystallisation techniques, by chiral synthesis, by enzymatic resolution, by biotransformation or by chromatographic separation) and how to determine antibacterial activity as described hereinafter.
  • the invention relates to all tautomeric forms of the compounds of the formula (I) that possess antibacterial activity.
  • Particularly preferred compounds of the invention comprise a compound of formula (I), or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein the substituents HET, T and other substituents mentioned above have values disclosed hereinbefore, or any of the following values (which may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore or hereinafter):
  • compounds of formula (I) in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (I), and in a further alternative embodiment are provided in-vivo hydrolysable esters of compounds of formula (I).
  • T is selected from (TA2) and (TB).
  • T is (TAlb).
  • (TAl) when the ring has an optional double bond between any two ring carbon atoms, the ring is preferably linked via an sp carbon atom of the double bond.
  • (TAl) is (TAla) or (TAlb), and preferably (TA2) is (TA2a) :-
  • TAlb TAlb
  • TAlb TAlb
  • R 2s is preferably selected from : (i) hydrogen, a (l-6C)alkyl group ⁇ optionally monosubstituted by (l-4C)alkanoyl group, cyano, cyano-imino, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for ARl defined herein), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein, (l-4C)alkylS(O)q- (q is 0, 1 or 2); or optionally substituted by one or more fluoro groups (including geminal disubstitution); or optionally substituted by one or more hydroxy groups (excluding geminal disubstitution), and/or optionally further substituted, by no more than one of each of, oxo, -NRv
  • R 2s is most preferably selected from : (i) hydrogen, (l-6C)alkyl ⁇ optionally monosubstituted by (l-4C)alkoxy, trifluoromethyl, (l-4C)alkylS(O)q- (q is 0, 1 or 2); or optionally substituted by one or more fluoro-groups (including geminal disubstitution); or optionally substituted by one or more hydroxy groups (excluding geminal disubstitution) ⁇ ; or
  • E is preferably -CO- or -SO - and R s is preferably selected from : (i) (l-6C)alkyl ⁇ optionally monosubstituted by cyano, cyano-imino, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for ARl defined herein), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein, (l-4C)alkylS(O) q - (q is 0, 1 or 2); and or (with the proviso that where R 2s is -SO 2 - or -O-CO- not on the first carbon atom of the (1-6C) alkyl chain) optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy
  • E is preferably -CO- or -SO 2 - and R 2s is most preferably selected from : (i) (l-6C)alkyl ⁇ optionally monosubstituted by (l-4C)alkoxy, trifluoromethyl, (1- 4C)alkylS(O)q- (q is 0, 1 or 2); or optionally substituted by one or more fluoro groups (including geminal disubstitution); or optionally substituted by one or more hydroxy groups (excluding geminal disubstitution) ⁇ , (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamino.
  • optional substituents are selected from (preferably one of) hydroxy, trifluoromethyl, (l-4C)alkyl S(O)q- (q is 0, 1 or 2), (l-4C)alkoxy, (l-4C)alkoxycarbonyl, cyano, nitro, (l-4C)alkanoylamino, -CONRvRw or- NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl].
  • HET(AR) is a 5 membered aromatic or heteroaromatic ring as defined herein and optionally substituted as defined herein. In another embodiment HET(AR) is a 6 membered aromatic or heteroaromatic ring as defined herein and optionally substituted as defined herein. Preferably HET(AR) is phenyl. In a further embodiment, HET(AR) is not phenyl.
  • HET(AR) is substituted at both positions ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring by Rl as defined herein. In an another aspect HET(AR) is substituted at one such position.
  • Rl is hydrogen or halogen. Most preferably Rl is hydrogen or fluorine.
  • Z is hydrogen or -COR5 or -CSR5, wherein R5 is CH3, NH2, OCH3, OEt, or CHC12. In one embodiment, preferably Z is -COR5 wherein R5 is CH3. In another embodiment, preferably Z is hydrogen.
  • Re is R 13 CO- and preferably R 13 is (l-4C)alkoxycarbonyl, hydroxy(l-4C)alkyl, (l-4C)alkyl (optionally substituted by one or two hydroxy groups, or by an (l-4C)alkanoyl group), (l-4C)alkylamino, dimethylamino(l-4C)alkyl, (l-4C)alkoxymethyl, (l-4C)alkanoylmethyl, (l-4C)alkanoyloxy(l-4C)alkyl, (l-5C)alkoxy or 2-cyanoethyl.
  • R 13 is 1,2-dihydroxyethyl, l,3-dihydroxyprop-2-yl,
  • R 13 is 1,2-dihydroxyethyl, l,3-dihydroxyprop-2-yl or 1,2,3-trihydroxyprop-l-yl.
  • R 13 is hydrogen, (l-lOC)alkyl [optionally substituted by one or more hydroxy] or R 1 C(O)O(l-6C)alkyl.
  • preferred values for Re are those in group (Rc2) when present in any of the definitions herein containing Re.
  • R 2s is preferably selected from (i) hydrogen, a (l-6C)alkyl group ⁇ optionally monosubstituted by (l-4C)alkanoyl group, cyano, cyano-imino, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for ARl defined herein), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein, (l-4C)alkylS(O)q- (q is 0, 1 or 2); or optionally substituted by one or more fluoro groups (including geminal disubstitution); or optionally substituted by one or more hydroxy groups (excluding geminal disubstitution
  • R2 F and R F are independently selected from: (i) hydrogen (except where E is SO2 or O-CO-), a (l-6C)alkyl group ⁇ optionally substituted by one or more (l-4C)alkanoyl groups (including geminal disubstitution) and/or optionally monosubstituted by cyano, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for AR defined herein after, heteroaryl(optionally substituted and defined as below),(l-4C)alkylS(O)q- (q is 0, 1 or 2); or (with the proviso that where R2 F is SO2 or O-CO- not on the first carbon atom of the (1-6C) alkyl chain) optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally monosubstituted by oxo, -NRvRw [where
  • W is a bond joining the adjacent carbon atoms or represents one or two carbon atoms (each -CH2- or -CH-), the heterocyclic ring comprising W therefore has 5-7 ring atoms and may optionally have one or more of (i) one double bond between ring carbon atoms, (ii) a Cl- C3 bridge connecting two ring carbon atoms and optionally containing a heteroatom selected from oxygen or nitrogen, and (iii) a C2-C5 cyclic moiety around a ring carbon atom;
  • (HET)AR is a 5-6 membered aromatic or heteroaromatic ring
  • a 5-membered ring this may be a thiophene ring, comprising a single sulphur atom sited ortho to the nitrogen atom on the adjacent oxazolidinone ring, such a ring may have a single optional substituent R1 F as hereinafter defined sited ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring
  • R1 F as hereinafter defined sited ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring
  • a 6-membered ring this may be a phenyl ring or comprise a single nitrogen atom sited ortho to the nitrogen atom on the adjacent oxazolidinone ring
  • such ring may be optionally substituted at one or both positions ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring by R1 F , where each
  • RI F is independently selected from hydrogen, halogen, methyl, methoxy, ethyl and ethoxy;
  • Y is -NH-
  • a C5-C6 heteroaromatic ring means a 5- or 6-membered aryl ring wherein (unless stated otherwise) 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulfur. Unless stated otherwise, such rings are fully aromatic.
  • Particular examples of 5- or 6-membered heteroaryl ring systems are furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.
  • substituents for alkyl, phenyl (and phenyl containing moieties ) and naphthyl groups and ring carbon atoms in heteroaryl (mono or bicyclic) rings include halo, (l-4C)alkyl , hydroxy, nitro, carbamoyl, (l-4C)alkylcarbamoyl, di- ((l-4C)alkyl)carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, amino, (l-4C)alkylamino, di((l-4C)alkyl)amino, (l-4C)alkyl S(O) - (q is 0, 1 or 2), carboxy, (l-4C)alkoxycarbonyl, (2-
  • phenyl and naphthyl groups and heteroaryl (mono- or bicyclic) rings may be mono- or di-substituted on ring carbon atoms with substituents independently selected from the above list of particular optional substituents, or on ring nitrogen atoms provided the ring is not thereby quaternised.
  • ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a and CY are understood to be as hereinbefore defined for formula I.
  • Z is COR5 or CSR5, wherein R5 is CH3, NH2, OCH3, OEt, or CHC12. More particular values are as follows:
  • Rl is halogen
  • R2 and R are independently hydrogen (except where E is SO2 or O-CO-), an alkyl, cycloalkyl, alkenyl or alkynyl group [especially cyclopropyl, or cyclobutyl, ethyl or methyl], all being optionally substituted by one or more of hydroxy, O-alkyl, alkanoyl (including geminal disubstitution), CN, SO2CH3, fluorine, chlorine, trifluoromethyl, COOH, COO- alkyl, CONH2, CONH-alkyl, or CON-dialkyl; and wherein any group has up to 6, such as up to 4 carbon atoms, the O-alkyl and alkanoyl groups may be further substituted by any convenient substituent such as for example trifluoromethyl; Z is COCH3.
  • in-vivo hydrolysable esters are preferred where appropriate, especially phosphoryl esters (as defined by formula (PD3) with npd as 1, or of formula (PS1)).
  • Particularly preferred compounds of the present invention include the compounds described in the following examples. Therefore the present invention also provides a compound described in any one of the following examples, or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof (and in particular compounds and salts thereof); and their use as a medicament (as herein described).
  • the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof. It will be appreciated that during certain of the following processes certain substituents may require protection to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.
  • 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).
  • 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.
  • reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. Resins may also be used as a protecting group.
  • a compound of the formula (I), or a pharmaceutically-acceptable salt or an in vivo hydrolysable ester thereof may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the formula (I), or a pharmaceutically-acceptable salt or an in vivo hydrolysable ester thereof, are provided as a further feature of the invention and are illustrated by the following representative examples. Necessary starting materials may be obtained by standard procedures of organic chemistry (see, for example, Advanced Organic Chemistry (Wiley- Interscience), Jerry March). The preparation of such starting materials is described within the accompanying non-limiting Examples.
  • necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • Information on the preparation of necessary starting materials or related compounds may also be found in the following Patent and Application Publications, the contents of the relevant process sections of which are hereby incorporated herein by reference : WO99/02525; WO98/54161; WO97/37980; WO97/30981 (& US5,736,545); WO97/21708 (& US5,719,154); WO97/10223; WO97/09328; WO96/35691; WO96/23788; WO96/15130; WO96/13502; WO95/25106 (& US5,668,286); WO95/14684 (& US5,652,238); WO95/07271 (& US5,688,792); WO94/13649; WO94/01110; WO93/23384 (& US5,547,950 & US
  • an appropriate aminomethyl side chain oxazolidinone is acylated to give an appropriate corresponding acylamide product.
  • a preformed sulfilimine or sulfoximine ring-containing intermediate is coupled to an aryloxazolidinone.
  • LG represents a convenient leaving group
  • the present invention also provides that compounds of the formulae (I) and pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof, can be prepared by a process (a) to (1) as follows (wherein the variables are as defined above unless otherwise stated) :
  • LG is a displaceable group (which may be (i) generated in-situ, for example under Mitsunobu conditions, or (ii) preformed, such as chloro or mesylate) with a compound of the formula (III): Y-Z (HD wherein heterocyclic compound Y-Z is appropriately derivatised for coupling with a compound of formula (II); or
  • Suitable aminating agents include mesitylenesulfonyl hydroxylamine, sodium azide and polyphosphoric acid, and chloramine-T (T as defined by (TA2) or (TB)); suitable oxygenating agents include peracids and osmium tetroxide - amine N-oxide mixtures; or
  • Z is a (thio)acyl group as hereinabove defined; or with a related compound of formula (XI) where the hydroxy group at the internal C-atom is optionally conventionally protected e.g. with an acetyl group and where the leaving group LG(f) at the terminal C-atom is a conventional leaving group e.g. a chloro- or mesyloxy- group;
  • an alkylthio group may be oxidised to an alkylsulfinyl or alkylsulfonyl group, a cyano group reduced to an amino group, a nitro group reduced to an amino group, a hydroxy group alkylated to a methoxy group, a hydroxy group converted to an arylthiomethyl or a heteroarylthiomethyl group (see, for example, Tet.Lett, 585, 1972), a carbonyl group converted to a thiocarbonyl group (eg. using Lawsson's reagent) or a bromo group converted to an alkylthio group. It is also possible to convert one R2 group into another R2 group as a final step in the preparation of a compound of the formula (I).
  • Convenient methods for functionalised sulfilimines and sulfoximines include those in which a sulfilimine or sulfoximine is (i) alkylated, (ii) acylated or (iii) arylated.
  • a sulfilimine or sulfoximine is (i) alkylated, (ii) acylated or (iii) arylated.
  • sulfoximine chemistry is provided by Michael Reggelin and Cornelia Zur in Synthesis, 2000, 1, 1-64. Further references include Reggelin et al, Tetrahedron Letters, 1992, 33 (46), 6959 - 6962; Reggelin et al, Tetrahedron Letters, 1992, 36 (33), 5885 - 5886; and Gage et al, Tetrahedron Letters, 2000, 41, 4301 - 4305.
  • reactions (b)(ii) are performed conveniently in the presence of a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide or hydroxide, for example sodium carbonate or potassium carbonate, or, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo-[5.4.0]undec-7-ene, the reaction is also preferably carried out in a suitable inert solvent or diluent, for example methylene chloride, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide, NN-dimethylacetamide, N-methylpyrrolidin- 2-one or dimethylsulfoxide at and at a temperature in the range 25-60°C.
  • a suitable base such as, for example, an alkali or al
  • the compound of the formula (IT) may be formed by reacting a compound of the formula (II) wherein Y is hydroxy (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.
  • a compound of the formula (II) wherein Y is chloro or iodo may also be prepared from a compound of the formula (II) wherein Y is mesylate or tosylate, by reacting the latter compound with lithium chloride or lithium iodide and crown ether, in a suitable organic solvent such as THF, in a temperature range of ambient temperature to reflux
  • the compound (II) may be prepared by reacting the hydroxy compound with (l-4C)alkanesulfonyl chloride or tosyl chloride in the presence of a mild base such as triethylamine or pyridine.
  • a mild base such as triethylamine or pyridine.
  • Y is a phosphoryl ester (such as Ph ⁇ 2 -P(O)-O-) or Ph 2 -P(O)-O- the compound
  • (JJ) may be prepared from the hydroxy compound under standard conditions.
  • compounds of the formula (HI) may be prepared by procedures which are selected from standard chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the procedures described in the Examples.
  • standard chemical techniques are as described in Houben Weyl.
  • the general method is illustrated in Scheme 2.
  • One compound of formula (I) may be converted into another compound of formula (I) by reacting a compound of formula (I) in which a substituent is halo with a suitable compound to form another compound.
  • a substituent for example, halo may be displaced by suitable vinyl, aromatic, tropolone and nitrogen-linked systems by reaction using known Pd(0) coupling techniques.
  • an optically active form of a compound of the formula (I) When an optically active form of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using an optically active starting material (formed, for example, by asymmetric induction of a suitable reaction step), or by resolution of a racemic form of the compound or intermediate using a standard procedure, or by chromatographic separation of diastereoisomers (when produced). Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates.
  • a pure regioisomer of a compound of the formula (I) when required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by separation of a mixture of the regioisomers or intermediates using a standard procedure.
  • a compound of the formula (I), or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester or amide thereof for use in a method of treatment of the human or animal body by therapy.
  • a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof.
  • the invention also provides a compound of the formula (I), or a pharmaceutically- acceptable salt, or in-vivo hydrolysable ester thereof, for use as a medicament; and for use as an antibacterial agent; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically-acceptable salt, 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.
  • an in-vivo hydrolysable ester or a pharmaceutically-acceptable salt thereof, including a pharmaceutically-acceptable salt of an in-vivo hydrolysable ester (hereinafter in this section relating to pharmaceutical composition "a compound of this invention") for the therapeutic (including prophylactic) treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), an in-vivo hydrolysable ester or a pharmaceutically-acceptable salt thereof, including a pharmaceutically-acceptable salt of an in-vivo hydrolysable ester, and a pharmaceutically-acceptable diluent or carrier.
  • 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, topical 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, aerosols (or sprays), drops and sterile injectable aqueous or oily solutions or suspensions.
  • the pharmaceutical composition of this invention may also contain or be co-administered (simultaneously, sequentially or separately) with one or more known drugs selected from other clinically useful antibacterial agents (for example, ⁇ -lactams or aminoglycosides) and/or other anti-infective agents (for example, an antifungal triazole or amphotericin).
  • drugs selected from other clinically useful antibacterial agents (for example, ⁇ -lactams or aminoglycosides) and/or other anti-infective agents (for example, an antifungal triazole or amphotericin).
  • drugs for example, ⁇ -lactams or aminoglycosides
  • other anti-infective agents for example, an antifungal triazole or amphotericin
  • carbapenems for example meropenem or imipenem, to broaden the therapeutic effectiveness.
  • Compounds of this invention may also contain or be co-administered with bactericidal/permeability-
  • 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 lmg and lg of a compound of this invention, preferably between lOOmg and lg of a compound. Especially preferred is a tablet or capsule which contains between 50mg and 800mg of a compound of this invention, particularly in the range lOOmg to 500mg.
  • a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection, for example an injection which contains between 0.1% w/v and 50% w/v (between lmg/ml and 500mg/ml) of a compound of this invention.
  • Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of 0.5 mgkg-1 to 20 mgkg-1 of a compound of this invention, the composition being administered 1 to 4 times per day.
  • a daily dose of 5 mgkg-1 to 20 mgkg-1 0 f a compound of this invention is administered.
  • 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 may receive a daily oral dose which may be approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • a pharmaceutical composition to be dosed intravenously may contain advantageously
  • a suitable bactericide for example to enhance stability
  • antioxidant or reducing agent for example to enhance stability
  • sequestering agent for example to enhance stability
  • 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, methicillin resistant strains of S.aureus and coagulase negative staphylococci, haemophilus and moraxella strains.
  • 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 and assessed in-vivo in conventional tests, for example by oral and/or intravenous dosing of a compound to a warm-blooded mammal using standard techniques.
  • Streptococci were tested in Mueller-Hinton broth supplemented with 2.5% clarified lake horse blood with an innoculum of 10 ⁇ CFU/well and an incubation temperature of 37°C aerobically for 24 hours.
  • MSQS methicillin sensitive and quinolone sensitive
  • MRQR methicillin resistant and quinolone resistant
  • CDC1 3 is deuterated chloroform; MS is mass spectroscopy; ESP is electrospray; THF is tetrahydrofuran; TFA is trifluoroacetic acid; NMP is N-methylpyrrolidone; 0 HOBT is 1-hydroxy-benzotriazole; EtOAc is ethyl acetate; MeOH is methanol; phosphoryl is (HO) 2 ⁇ P(O)-Os phosphiryl is (HO) 2 -P-O-; EDC is l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (hydrochloride); PTSA is para-toluenesulfonic acid.
  • the crude product was purified on a 300 g silica sinter column , eluting with a gradient from 0% to 100% ethyl acetate in dichloromethane. Relevant fractions were combined, reduced to a small volume, and diluted with an excess of ⁇ hexane to precipitate the desired product
  • 3,5-Difluoroaniline (12.9 g, 0.1 M) was reacted with tetrahydrothiopyran-4-one under essentially the following conditions (except that n-butyllithium was used to generate both anions): dissolved in dry tetrahydrofuran (400 ml), stirred under nitrogen, and cooled to -78°.
  • H-Butyllithium (1.6M in hexanes, 131 ml, 0.21 M) was run in over 15 minutes, keeping the temperature below -65°, and the mixture then stirred a further 30 minutes at -70°.
  • Chlorotrimethylsilane (22.8 g, 0.21 M) in tetrahydrofuran (100 ml) was added dropwise over 15 minutes, keeping the temperature below -65°, after which the temperature was allowed to rise to ambient, and stirring continued for 40 minutes to complete the silylation.
  • the mixture was then recooled to -78°, and seobutyllithium (1.3M in cyclohexane, 84.3 ml, 0.11 M) added dropwise, and stirring continued at this temperature for 5 hours.
  • the intermediate for Example 4 was prepared as follows:
  • the intermediate for Example 5 was prepared as follows:
  • the intermediate for Example 7 was prepared as follows:
  • Example 11 N- 5S)- ⁇ 3- r3,5-Difluoro-4- (IRS- 1- (5-isoxazolecarboximino)- l-o ⁇ o-3,6- dihvdrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethyl ⁇ 1-acetamide:
  • Example 12 N-r(5S)- ⁇ 3-r3-Fiuoro-4-qRS-l-((ethoxycarbonyl)imino)-l-oxo-3.6- dihvdrothiopyran-4-vi)-phenvn-2-oxo-oxazolidin-5-yImethyl ⁇ ]-acetamide:
  • Example 14 N-r(5S)- ⁇ 3-r3-Fluoro-4- RS-l-(((ethylamino)carbonyl)imino)-l-oxo-3,6- dihvdrothiopyran-4-yl)-pheny ⁇ -2-oxo-oxazolidin-5-ylmethyI ⁇ 1-acetamide:
  • Example 15 The above compound (Example 15) (13mg, 0.028mmol) was dissolved in ethanol followed by the addition of hydroxylamine water solution (30%, lOeq), the reaction mixture was stirred for 2 hr at room temperature. Solvent was removed under vacuum and the residue was purified by HPLC(C-18) with acetonitrile/water containing 1% TFA to give 10 mg of the title compound.
  • Example 17 N-r(55)- ⁇ 3-r3-Fluoro-4- RS-l-((prop-2-ene-l-o ⁇ ycarbonyl)imino)-l-oxo- 3,6-dihvdrothiopyran-4-yl)-phenvn-2-oxo-oxazolidin-5-ylmethyl ⁇ 1-acetamide:
  • Example 18 N-r(55)- ⁇ 3-r3-Fluoro-4-qR5-l-(2-propenylimino)-l-oxo-3,6- dihvdrothiopyran-4-yl)-phenyll-2-oxo-oxazolidin-5-ylmethv 1-acetamide:
  • Example 1 N-[(5S)- ⁇ 3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl ⁇ ]-acetamide (Example 1) (50 mg, 0.13 mmol), allyl bromide (24 mg, 0.20mmol) and sodium carbonate (excess) were mixed in 10 ml of anhydrous acetonitrile, followed by the addition of silver triflate ( 33 mg, 0.13mmol).
  • Example 1 N-[(5S)- ⁇ 3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl ⁇ ]-acetamide (Example 1) as its mesitylene sulfonate salt (0.3 g, 0.52 mmol) was reacted with isopropyl-isocyanate (66mg, 0.77 mmol) following the procedure outlined for Example 3 to give 0.267 g of the title compound.
  • Example 22 N-r(5S)- ⁇ 3-r3.5-Difluoro-4- R5-l-(acetylimino)-l-oxo-3.6- dihydrothiopyran-4-yl)-phenyIl-2-oxo-oxazolidin-5-ylmethyl ⁇ l-acetamide:
  • Example 23 N-r(5S)- ⁇ 3-r3-Fluoro-4- RS-l-(((methylamino)carbonyl)imino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethvU1-acetamide:
  • Example 24 N-r(55)- ⁇ 3-r3-Fluoro-4-qR5-l-(2-propylsulfonylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyll-2-oxo-oxazoIidin-5-ylmethvI
  • Example 25 N-r(55)- ⁇ 3-r3.5-Difluoro-4- RS-l-(2-hvdroxyacetylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenvn-2-oxo-oxazolidin-5-ylmethyl ⁇ 1-acetamide:
  • Example 26 N-r(55)- ⁇ 3-r3-Fluoro-4-qRS-l-((2-methylprop-l-yl-oxycarbonyl)imino)-l- oxo-3,6-dihvdrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethyll1-acetamide:
  • Example 27 N-[(5S)- ⁇ 3-r3-Fluoro-4- R5-l-(((2-methoxy)ethoxycarbonyl)imino)-l-oxo- 3,6-dihvdrothiopyran-4-yl)-phenvn-2-oxo-oxazolidin-5-ylmethyl>1-acetamide:
  • Example 1 N-[(5S)- ⁇ 3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl ⁇ ]-acetamide (Example 1) as its mesitylene sulfonate salt (0.3 g, 0.52 mmol) was reacted with 2-methylethylchloroformate (0.144 g, 1.04 mmol) following the procedure outlined for Example 3 to give 0.231 g of the title compound.
  • Example 28 N-r(5S)- ⁇ 3-r3-Fluoro-4-qRS-l-((2S)-2-hvdroxy-3-(l-oxa- butoxy)propylimino)-l-oxo-3,6-dihvdrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5- ylmethvDI-acetamide:
  • reaction mixture was stirred at 70°C for 24 hours, diluted with water, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated to dryness. This residue was purified by flash chromatography with 5% methanol in dichloromethane to give 0.2 g of the title compound as a white solid.
  • Example 29 N-r(55)- ⁇ 3-r3-Fluoro-4-qR5-l-((2R)-2-hvdroxy-3-(l-oxa- butoxy))propylimino)-l-oxo-3,6-dih.ydrothiopyran-4-yl)-phenyn-2-oxo-oxazoIidin-5- ylmethvUI-acetamide:
  • the reaction mixture was stirred at 70°C for 24 hours, then diluted with water, extracted with dichloromethane, the organic phase was dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was purified by flash chromatography with 5% methanol in dichloromethane to give 0.704 g of the title compound as a white solid.
  • Example 30 N-r(5S)- ⁇ 3-r3-Fluoro-4- RS-l-(((2R)-2,3-dihvdroxy)propylimino)-l-oxo- 3,6dihvdrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethyl ⁇ 1-acetamide:
  • Example 31 N-r(55)-13-r3-Fluoro-4- RS-l-(((25)-2.3-dihvdroxy)propylimino)-l-oxo- 3,6-dihydrothiopyran-4-yl)-phenvI1-2-oxo-oxazolidin-5-ylmethy l-acetamMe:
  • the tube was then sealed and the reaction mixture was stirred at 50°C for 24 hours. It was diluted with water, extracted with dichloromethane and the organic phase was dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was purified by flash chromatography with 5% methanol in dichloromethane to give 71 mg of the title compound as a white solid.

Abstract

Compounds of formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein, for example; T is selected, for example, from a group of formula (TA1) or (TA2), wherein, for example, X1m is O= and X2m is R2s-(E)ms-N-; wherein E is an electron withdrawing group, for example, -SO2- or -CO-; and, for example, R2s is hydrogen or (1-6C)alkyl; and, for example, HET(AR) is a 5 or 6 membered aromatic or heteroaromatic ring; and Y is NH and , for example, Z is hydrogen or -COR5 or CSR5, wherein R5 is, for example (1-6C)alkyl; are useful as pharmaceutical agents; and processes for their manufacture and pharmaceutical compositions containing them are described.

Description

CHEMICAL COMPOUNDS
The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing a substituted 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.
The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, 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 as effective against both Gram-positive and certain Gram-negative pathogens.
Gram-positive pathogens, for example Staphylococci, Enterococci, and Streptococci 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 f aecium. The major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens. There is also now increasing resistance appearing towards agents such as β- lactams, quinolones and macrolides used for the treatment of upper respiratory tract infections, also caused by certain Gram negative strains including Hinfluenzae and M.catarrhalis.
Certain antibacterial compounds containing an oxazolidinone ring have been 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, 1156-1165). Such antibacterial oxazolidinone compounds with a 5-acetamidomethyl sidechain may be subject to mammalian peptidase metabolism. Furthermore, bacterial resistance to known antibacterial agents may develop, for example, by (i) the evolution of active binding sites in the bacteria rendering a previously active pharmacophore less effective or redundant, and/or (ii) the evolution of means to chemically deactivate a given pharmacophore. Therefore, there remains an ongoing need to find new antibacterial agents with a favourable pharmacological profile, in particular for compounds containing new pharmacophores.
We have discovered a new class of antibiotic compounds containing an aryl substituted oxazolidinone ring in which the aryl ring is itself substituted by certain novel sulfilimine and sulfoximine-containing rings. These compounds have useful activity against Gram-positive pathogens including MRS A and MRCNS and, in particular, against various strains exhibiting resistance to vancomycin and against E. faecium strains resistant to both aminoglycosides and clinically used β-lactams, but also to fastidious Gram negative strains such as Hinfluenzae, M.catarrhalis, mycoplasma spp. and chlamydial strains.
Accordingly the present invention provides a compound of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof,
Figure imgf000003_0001
(I) wherein: T is selected from the groups in (TA) & (TB) below (wherein ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a and CY are defined hereinbelow); (TA) T is selected from the following groups (TA1) and (TA2) :-
Figure imgf000003_0002
(TA1) (TA2) wherein : in (TA1), Qθi is 0 or 1 and represents a chain of carbon atoms (optionally substituted as defined for ARl) of length Oi and M is a bond joining the adjacent carbon atoms, or M represents one or two carbon atoms, and defines a 4- to 7-membered monocyclic ring, which ring may optionally have one of:
(i) one double bond between any two ring carbon atoms; or (ii) a C1-C3 bridge connecting any two appropriate, non-adjacent ring carbon atoms, which bridge may optionally contain one heteroatom selected from oxygen or >NRc; or (iii) a C2-C5 cyclic moiety including a ring carbon atom to define a spiro C2-C5 ring system, which ring may optionally contain one heteroatom selected from oxygen or >NRc; or (iv) a C1-C4 bridge connecting adjacent carbon atoms to define a fused ring, wherein a C2- C4 bridge may optionally contain one heteroatom selected from oxygen or >NRc; wherein Re is as defined hereinafter; wherein in (TA2), ()ni and ()θi are independently 0, 1 or 2 and represent chains of carbon atoms (optionally substituted as defined for ARl) of length n] and O respectively, and define a 4- to 8-membered monocyclic ring, which ring may optionally have one of (i) a C1-C3 bridge connecting any two appropriate, non-adjacent ring carbon atoms, which bridge contains one heteroatom selected from oxygen or >NRc; or
(ii) a C2-C5 cyclic moiety including a ring carbon atom to define a spiro C2-C5 ring system, which ring may optionally contain one heteroatom selected from oxygen or >NRc; or (iii) a C1-C4 bridge connecting adjacent carbon atoms to define a fused ring, wherein a C2-C4 bridge may optionally contain one heteroatom selected from oxygen or >NRc; wherein Re is as defined hereinafter; or
(TB) T is selected from the following groups (TB 1) to (TB3) :-
Figure imgf000004_0001
(TB1) (TB2)
Figure imgf000004_0002
(TB3) wherein ()m, ()oi, ()nr, ()θr, ()pι and ()pr represent chains of carbon atoms (optionally substituted as defined for ARl hereinafter) of length ni, Oi, n , Or, pi and p respectively, and are independently 0-2, with the proviso that in (TBl) and (TB2) the sum of n1; oi, nr and ov does not exceed 8 (giving a maximum ring size of 14 in (TBl) and 11 in (TB2)), and in (TB3) the sum of ni, 01, n , o^, i and pr does not exceed 6 (giving a maximum ring size of 12); Xim and X2m taken together represent R2s-(E)ms-N=; or Xim is O= and X2m is R s-(E)ms-N-, and vice versa; wherein E is an electron withdrawing group selected from -SO2-, -CO-, -O-CO-, -CO-O-, - CS-, -CON(Rs>, -SO2N(Rs)-, or E may represent a group of the formula R3s-C(=N-O-R3s)- C(=O)-, wherein R3s is H or as defined in R s at (i) below; or, when E is -CON(Rs)- or -SO2N(Rs)-, R2s and Rs may link together to form a carbon chain which defines a 5- or 6-membered saturated, unsaturated or partially unsaturated ring linked via the N atom in E, which ring is optionally further substituted by an oxo substituent, and which ring may be optionally fused with a phenyl group to form a benzo-fused system, wherein the phenyl group is optionally substituted by up to three substituents independently selected from halo, cyano, (l-4C)alkyl and (l-4C)alkoxy; ms is O or l; except, wherein in (TA1) (other than as defined in (i) - (iv) above), in (TA2) (other than as defined in (i) - (iii) above), or in (TBl) when TBl is TBlb:
Figure imgf000005_0001
TBlb and Xlm is O= and X2m is R s-(E)ms-N-, or vice versa,
R2s-(E)ms- may not be hydrogen, (l-4C)alkyl (optionally substituted as defined for Rp below), -C(=O)(l-4C)alkyl (optionally substituted as defined for Rp below), -C(=O)O(l-4C)alkyl (optionally substituted as defined for Rp below), -C(=O)NHRp, -C(=S)NHRP, or para-toluene sulphonyl, wherein Rp is hydrogen, (l-4C)alkyl (optionally substituted with one or more halo, cyano, nitro, phenyl, (3-6C)cycloalkyl, ORp2> C(=O)Rp2, OC(=O)Rp2, C(=O)ORp2, S(=O)mpRp2, S(=O)mpNRp2Rp2, NRp2SO2Rp2, NRp2NSO2Rp2Rp2, NRp2C(=O)Rp2, C(=O)NRp2Rp2, NRp2Rp2, oxo or oxime) or phenyl, wherein Rp2 is hydrogen, (l-4C)alkyl or phenyl, wherein at each occurrence phenyl is optionally substituted with one or more halo, cyano, nitro, phenyl, (3-6C)cycloalkyl, ORp2, C(=O)Rp2, OC(=O)Rp2, C(=O)ORp2, S(=O)mpRp2, S(=O)mpNRp2Rp2, NRp2SO2Rp2, NRp2NSO2Rp2Rp2, NRp2C(=O)Rp2, C(=O)NRp2Rp2, or NRp2Rp2, and mp is 0, 1 or 2;
R s and Rs are independently selected from : (i) hydrogen (except where E is -SO2-or -O-CO-), or
(l-6C)alkyl {optionally substituted by one or more (l-4C)alkanoyl groups (including geminal disubstitution) and/or optionally monosubstituted by cyano, cyano-imino, (l-4C)alkoxy, trifluoromefhyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as defined for ARl hereinafter), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) hereinafter, (l-4C)alkylS(O)q- (q is 0, 1 or 2); and/or (with the proviso that where R2s is -SO2 or -O-CO- not on the first carbon atom of the (1-6C) alkyl chain) optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally further substituted, by no more than one of each of, oxo, - NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (1-
6C)alkanoylamino, (l-4C)alkoxycarbonylamino, N-(l-4C)alkyl-N-(l-6C)alkanoylamino, (1- 4C)alkylS(O)pNH- or (l-4C)alkylS(O)p.((l-4C)alkyl)N- (p is 1 or 2)}; or (ii) an optionally substituted aryl or optionally substituted heteroaryl group of the formula ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) hereinafter; or (where ms is 0 only);
(iii) cyano, -CO-NRvRw, -CO-NRv Rw', -SO2-NRvRw, -SO2-NRv Rw' [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl; Rw' is phenyl (optionally substituted as defined for ARl hereinafter), or a heteroaryl group selected from AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a (optionally substituted as defined hereinafter)],
(l-4C)alkoxycarbonyl, trifluoromethyl, ethenyl, 2-(l-4C)alkylethenyl, 2-cyanoethenyl, 2- cyano-2-((l-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((l-4C)alkyl)ethenyl, 2-((l- 4C)alkylaminocarbonyl)ethenyl, 2-((l-4C)alkoxycarbonyl)ethenyl, 2-(ARl)ethenyl, 2- (AR2)ethenyl, or 2-(AR2a)ethenyl; wherein Re is selected from groups (Rcl) to (Rc5) :-
(Rcl) (l-6C)alkyl {optionally substituted by one or more (l-4C)alkanoyl groups (including geminal disubstitution) and/or optionally monosubstituted by cyano, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for ARl defined hereinafter), (l-4C)alkylS(O)q- (q is 0, 1 or 2); or, on any but the first carbon atom of the (1- 6C)alkyl chain, optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally monosubstituted by oxo, -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamino, N-(l-4C)alkyl-N-(l- 6C)alkanoylamino, (l-4C)alkylS(O)pNH- or (l-4C)alkylS(O)p.((l-4C)alkyl)N- (p is 1 or 2)}; (Rcl) RI3CO- , R13SO2- or R13CS~ wherein R13 is selected from (Rc2a) to (Rc2e) :- (Rc2a) ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a and CY;
(Rc2b) hydrogen, (l-4C)alkoxycarbonyl, trifluoromethyl, -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], ethenyl, 2-(l-4C)alkylethenyl, 2- cyanoethenyl, 2-cyano-2-((l-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((l-4C)alkyl)ethenyl, 2-((l-4C)alkylaminocarbonyl)ethenyl, 2-((l-4C)alkoxycarbonyl)ethenyl, 2-(ARl)ethenyl, 2- (AR2)ethenyl, 2-(AR2a)ethenyl;
(Rc2c) (l-lOC)alkyl {optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy, (l-lOC)alkoxy, (l-4C)alkoxy-(l- 4C)alkoxy, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxy, (l-4C)alkanoyl, carboxy, phosphoryl [- O-P(O)(OH)2, and mono- and di-(l-4C)alkoxy derivatives thereof], phosphiryl [-O-P(OH)2 and mono- and di-(l-4C)alkoxy derivatives thereof], and amino; and/or optionally substituted by one group selected from phosphonate [phosphono, -P(O)(OH)2, and mono- and di-(l- 4C)alkoxy derivatives thereof], phosphinate [-P(OH)2 and mono- and di-(l-4C)alkoxy derivatives thereof], cyano, halo, trifluoromethyl, (l-4C)alkoxycarbonyl, (l-4C)alkoxy-(l- 4C)alkoxycarbonyl, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxycarbonyl, (l-4C)alkylamino, di((l-4C)alkyl)amino, (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamino, N-(l-4C)alkyl-N- (l-6C)alkanoylamino, (l-4C)alkylaminocarbonyl, di((l-4C)alkyl)aminocarbonyl, (1- 4C)alkylS(O)pNH-, (l-4C)alkylS(O)p-((l-4C)alkyl)N-, fluoro(l-4C)alkylS(O)pNH-, fluoro(l- 4C)alkylS(O)p((l-4C)alkyl)N-, (l-4C)alkylS(O)q- [the (l-4C)alkyl group of (1- 4C)alkylS(O)q- being optionally substituted by one substituent selected from hydroxy, (1- 4C)alkoxy, (l-4C)alkanoyl, phosphoryl [-O-P(O)(OH)2, and mono- and di-(l-4C)alkoxy derivatives thereof], phosphiryl [-O-P(OH)2 and mono- and di-(l-4C)alkoxy derivatives thereof], amino, cyano, halo, trifluoromethyl, (l-4C)alkoxycarbonyl, (l-4C)alkoxy-(l- 4C)alkoxycarbonyl, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxycarbonyl, carboxy, (1- 4C)alkylamino, di((l-4C)alkyl)amino, (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamino, N- (l-4C)alkyl-N-(l-6C)alkanoylamino, (l-4C)alkylaminocarbonyl, di((l- 4C)alkyl)aminocarbonyl, (l-4C)alkylS(O)pNH-, (l-4C)alkylS(O)p-((l-4C)alkyl)N-, (1- 4C)alkylS(O)q-, ARl-S(O)q- , AR2-S(O)q- , AR3-S(O)q- and also AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3 containing groups], CY, ARl, AR2, AR3, AR1-O-, AR2-O- , AR3-O-, ARl-S(O)q- , AR2-S(O)q- , AR3-S(O)q- , AR1-NH-, AR2-NH-, AR3-NH- (p is 1 or 2 and q is 0, 1 or 2), and also AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3 containing groups}; (Rc2d) R14C(O)O(l-6C)alkyl wherein R14 is ARl , AR2, (l-4C)alkylamino (the (1-
4C)alkyl group being optionally substituted by (l-4C)alkoxycarbonyl or by carboxy), benzyloxy-(l-4C)alkyl or (l-lOC)alkyl {optionally substituted as defined for (Rc2c)}; (Rc2e) R15O- wherein R15 is benzyl, (l-6C)alkyl {optionally substituted as defined for
(Rc2c)}, CY or AR2b; (Rc3) hydrogen, cyano, 2-cyanoethenyl, 2-cyano-2-((l-4C)alkyl)ethenyl, 2-((l-
4C)alkylaminocarbonyl)ethenyl, 2-((l-4C)alkoxycarbonyl)ethenyl, 2-nitroethenyl, 2-nitro-2- ((l-4C)alkyl)ethenyl, 2-(ARl)ethenyl, 2-(AR2)ethenyl, or of the formula (Rc3a)
Figure imgf000008_0001
(Rc3a) wherein X00 is -OR17, -SR17, -NHR17and -N(R17)2 ; wherein R17 is hydrogen (when X00 is -NHR17and -N(R17)2), and R17 is (l-4C)alkyl, phenyl or AR2 (when X00 is -OR17, -SR17 and -NHR17); and R16 is cyano, nitro, (l-4C)alkylsulfonyl, (4- 7C)cycloalkylsulfonyl, phenylsulfonyl, (l-4C)alkanoyl and (l-4C)alkoxycarbonyl; (Rc4) trityl, ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b; (Rc5) RdOC(Re)=CH(C=O)-, RfC(=O)C(=O)-, RgN=C(Rh)C(=O)- or
RiNHC(Rj)=CHC(=O wherein Rd is (l-6C)alkyl; Re is hydrogen or (l-6C)alkyl, or Rd and Re together form a (3-4C)alkylene chain; Rf is hydrogen, (l-6C)alkyl, hydroxy(l-6C)alkyl, (1- 6C)alkoxy(l-6C)alkyl, -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, hydroxy(2-6C)alkoxy, (1- 4C)alkylamino(2-6C)alkoxy, di-(l-4C)alkylamino(2-6C)alkoxy; Rg is (l-6C)alkyl, hydroxy or (l-6C)alkoxy; Rh is hydrogen or (l-6C)alkyl; Ri is hydrogen, (l-6C)alkyl, ARl, AR2, AR2a,
AR2b and Rj is hydrogen or (l-6C)alkyl; wherein
ARl is an optionally substituted phenyl or optionally substituted naphthyl; AR2 is an optionally substituted 5- or 6-membered, fully unsaturated (i.e with the maximum degree of unsaturation) monocyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O-O, O-S or S-S bonds), and linked via a ring carbon atom, or a ring nitrogen atom if the ring is not thereby quaternised;
AR2a is a partially hydrogenated version of AR2 (i.e. AR2 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom if the ring is not thereby quaternised;
AR2b is a fully hydrogenated version of AR2 (i.e. AR2 systems having no unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom;
AR3 is an optionally substituted 8-, 9- or 10-membered, fully unsaturated (i.e with the maximum degree of unsaturation) bicyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O-O, O-S or S-S bonds), and linked via a ring carbon atom in either of the rings comprising the bicyclic system;
AR3a is a partially hydrogenated version of AR3 (i.e. AR3 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not thereby quaternised, in either of the rings comprising the bicyclic system;
AR3b is a fully hydrogenated version of AR3 (i.e. AR3 systems having no unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom, in either of the rings comprising the bicyclic system; AR4 is an optionally substituted 13- or 14-membered, fully unsaturated (i.e with the maximum degree of unsaturation) tricyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O-O, O-S or S-S bonds), and linked via a ring carbon atom in any of the rings comprising the tricyclic system;
AR4a is a partially hydrogenated version of AR4 (i.e. AR4 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not thereby quaternised, in any of the rings comprising the tricyclic system;
CY is an optionally substituted cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl ring;
For the avoidance of doubt in the definition of (TA1) & (TA2) and (TB), it is to be understood that when R2s and Rs are independently selected from
(ii) (l-6C)alkyl {optionally substituted, for example, by no more than one of each of oxo and -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], to avoid duplication with the substituent -CO-NRvRw provided in section (iii) of the definition for R2s and Rs , then oxo and -NRvRw are not to be both selected together when (l-6C)alkyl is methyl;
(HET)AR is a 5-6 membered aromatic or heteroaromatic ring, (i) when a 5-membered ring this may be a thiophene ring, comprising a single sulphur atom sited ortho to the nitrogen atom on the adjacent oxazolidinone ring, such a ring may have a single optional substituent Rl as hereinafter defined sited ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring, (ii) when a 6-membered ring this may be a phenyl ring or comprise a single nitrogen atom sited ortho to the nitrogen atom on the adjacent oxazolidinone ring, such ring may be optionally substituted at one or both positions ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring by Rl, where each
Rl is independently selected from hydrogen, halogen, methyl and methoxy, ethyl and ethoxy;
Y is -NH- ; Z is hydrogen, -COR5 or -CSR5, wherein R5 is selected from:
H, (l-6C)alkyl (optionally substituted with 1-4 halogen atoms), cyclopropyl, -O-(l-6C)alkyl, NH2 or NH-(l-6C)alkyl or N-di((l-6C)alkyl).
For the avoidance of doubt, in the above definitions of TA1, TA2 and TB, ()nι, ()oi, ()nr, ()or, Opt and ()p indicate (-CH2-)m, (-CH2-)0l, (-CH2-)m\ (-CH2)0l\ (-CH2-)pl and (-CH2-)pi' respectively.
In this specification the term 'alkyl' includes straight chained and branched structures. For example, (l-6C)alkyl includes propyl, isopropyl and tert-butyl. However, 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. A similar convention applies to other radicals, for example halo(l-4C)alkyl includes 1-bromoethyl and 2-bromoethyl. The term "a C5-C6 heteroaromatic ring" means a 5- or 6-membered aryl ring wherein (unless stated otherwise) 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulfur. Unless stated otherwise, such rings are fully aromatic. Particular examples of 5- or 6- membered heteroaryl ring systems are furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.
In general "halogen" when present as an aromatic ring substituent is selected from any one of bromine, chlorine or fluorine, as an aliphatic substituent from chlorine or fluorine.
Particular optional substituents for alkyl, phenyl (and phenyl containing moieties ) and naphthyl groups and ring carbon atoms in heteroaryl (mono or bicyclic) rings (such as set out hereinafter in groups ARl to CY inclusive) include halo, (l-4C)alkyl , hydroxy, nitro, carbamoyl, (l-4C)alkylcarbamoyl, di-((l-4C)alkyl)carbarnoyl, cyano, trifluoromethyl, trifluoromethoxy, amino, (l-4C)alkylamino, di((l-4C)alkyl)amino, (l-4C)alkyl S(O) - (q is 0,
1 or 2), carboxy, (l-4C)alkoxycarbonyl, (2-4C)alkenyl, (2-4C)alkynyl, (l-4C)alkanoyl, (1- 4C)alkoxy, (l-4C)alkylS(O)2amino, (l-4C)alkanoylamino, benzoylamino, benzoyl, phenyl (optionally substituted by up to three substituents selected from halo, (l-4C)alkoxy or cyano), furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyimino(l-4C)alkyl, (l-4C)alkoxyimino(l- 4C)alkyl, hydroxy-(l-4C)alkyl, halo-(l-4C)alkyl, nitro(l-4C)alkyl, amino(l-4C)aιkyl, cyano(l-4C)alkyl, (l-4C)alkanesulfonamido, aminosulfonyl, (l-4C)alkylaminosulfonyl and di-((l-4C)alkyl)aminosulfonyl. The phenyl and naphthyl groups and heteroaryl (mono- or bicyclic) rings may be mono- or di-substituted on ring carbon atoms with substituents independently selected from the above list of particular optional substituents, or on ring nitrogen atoms provided the ring is not thereby quaternised.
Particular examples of 5-membered heteroaryl rings containing 2 or 3 heteroatoms independently selected from N, O and S (with the proviso that there are no O-O, O-S or S-S bonds) are pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, and also in an alternative embodiment, isothiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole or 1,2,3-thiadiazole. There follow particular and suitable values for certain substituents and groups referred to in this specification. These values may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore, or hereinafter. For the avoidance of doubt each stated species represents a particular and independent aspect of this invention.
Examples of (l-4C)alkyI and (l-5C)alkyl include methyl, ethyl, and propyl and isopropyl; examples of (l-6C)aIkyl include methyl, ethyl, propyl, isopropyl, pentyl and hexyl; examples of (l-lOC)aϊkyΙ include methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyl and nonyl; examples of (l-4C)alkanoylamino-(l-4C)alkyl include formamidomethyl, acetamidomethyl and acetamidoethyl; examples of hydroxy(l-4C)alkyl and hydroxy(l- 6C)alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of (l-4C)alkoxycarbonyl include methoxycarbonyl, efhoxycarbonyl and propoxycarbonyl; examples of 2-((l-4C)aIkoxycarbonyI)ethenyI include 2-
(methoxycarbonyl)ethenyl and 2-(ethoxycarbonyl)ethenyl; examples of 2-cyano-2-((l- 4C)alkyl)ethenyl include 2-cyano-2-methylethenyl and 2-cyano-2-ethylethenyl; examples of 2-nitro-2-((l-4C)alkyl)ethenyl include 2-nitro-2-methylethenyl and 2-nitro-2-ethylethenyl; examples of 2-((l-4C)alkylaminocarbonyl)ethenyl include 2-(methylaminocarbonyl)ethenyl and 2-(ethylarninocarbonyl)efhenyl; examples of (2-4C)alkenyl include allyl and vinyl; examples of (2-4C)alkynyl include ethynyl and 2-propynyl; examples of (l-4C)alkanoyI include formyl, acetyl and propionyl; examples of (l-4C)aIkoxy include methoxy, ethoxy and propoxy; examples of (l-6C)alkoxy and (l-lOC)alkoxy include methoxy, ethoxy, propoxy and pentoxy; examples of (l-4C)alkylthio include methylthio and ethylthio; examples of (1- 4C)alkylamino include methylamino, ethylamino and propylamino; examples of di-((l-
4C)alkyl)amino include dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N- propylamino and dipropylamino; examples of halo groups include fluoro, chloro and bromo; examples of (l-4C)alkyIsuϊfonyI include methylsulfonyl and ethylsulfonyl; examples of (1- 4C)alkoxy-(l-4C)alkoxy and (l-6C)alkoxy-(l-6C)alkoxy include methoxymethoxy, 2- methoxyethoxy, 2-ethoxyethoxy and 3-methoxypropoxy; examples of (l-4C)alkoxy-(l- 4C)alkoxy-(l-4C)alkoxy include 2-(methoxymethoxy)ethoxy,
2-(2-methoxyethoxy)ethoxy; 3-(2-methoxyethoxy)propoxy and 2-(2-ethoxyethoxy)ethoxy; examples of (l-4C)alkylS(O)2amino include methylsulfonylamino and ethylsulfonylamino; examples of (l-4C)aIkanoylamino and (l-6C)alkanoyla ino include formamido, acetamido and propionylamino; examples of (l-4C)a!koxycarbonyIamino include methoxycarbonylamino and ethoxycarbonylamino; examples of N-(l-4C)alkyl-N-(l- 6C)alkanoylamino include N-methylacetamido, N-ethylacetamido and N- methylpropionamido; examples of (l-4C)alkylS(O)pNH- wherein p is 1 or 2 include methylsulfinylamino, methylsulfonylamino, ethylsulfinylamino and ethylsulfonylamino; examples of (l-4C)alkylS(O)p((l-4C)aIkyl)N- wherein p is 1 or 2 include methylsulfinylmethylamino, methylsulfonylmethylamino, 2-(ethylsulfinyl)ethylamino and 2- (ethylsulfonyl)ethylamino; examples of fluoro(l-4C)alkylS(O)pNH- wherein p is 1 or 2 include trifluoromethylsulfinylamino and trifluoromethylsulfonylamino; examples of fluoro(l-4C)alkylS(0)p((l-4C)alkyl)NH- wherein p is 1 or 2 include trifluoromethylsulfinylmethylamino and trifluoromethylsulfonylmethylamino examples of (1- 4C)alkoxy(hydroxy)phosphoryl include methoxy(hydroxy)phosphoryl and ethoxy(hydroxy)phosphoryl; examples of di-(l-4C)alkoxyphosphoryl include di- methoxyphosphoryl, di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl; examples of (l-4C)alkylS(O)q- wherein q is 0, 1 or 2 include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; examples of pheήylS(O)q and naphthylS(O)q- wherein q is 0, 1 or 2 are phenylthio, phenylsulfinyl, phenylsulfonyl and naphthylthio, naphthylsulfinyl and naphthylsulfonyl respectively; examples of benzy!oxy-(l- 4C)alkyl include benzyloxymethyl and benzyloxyethyl; examples of a (3-4C)aϊkylene chain are trimethylene or tetramethylene; examples of (l-6C)alkoxy-(l-6C)alkyl include methoxymethyl, ethoxymethyl and 2-methoxyethyl; examples of hydroxy- (2-6C)alkoxy include 2-hydroxyethoxy and 3-hydroxypropoxy; examples of (l-4C)alkylamino-(2- 6C)alkoxy include 2-methylaminoethoxy and 2-ethylaminoethoxy; examples of di-(l- 4C)aIkylamino-(2-6C)aIkoxy include 2-dimethylaminoethoxy and 2-diethylaminoethoxy; examples of phenyl(l-4C)alkyl include benzyl and phenethyl; examples of (1- 4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl; examples of di((l- 4C)alkyl)carbamoyl include di(methyl)carbamoyl and di(ethyl)carbamoyl; examples of hydroxyimino(l-4C)alkyl include hydroxyiminomethyl, 2-(hydroxyimino)ethyl and 1- (hydroxyimino)ethyl; examples of (l-4C)alkoxyimino-(l-4C)alkyl include methoxyiminomethyl, ethoxyiminomethyl, l-(methoxyimino)ethyl and 2- (methoxyimino)ethyl; examples of halo(l-4C)alkyl include, halomethyl, 1-haloethyl, 2- haloethyl, and 3-halopropyl; examples of nitro(l-4C)alkyl include nitromethyl, 1-nitroethyl, 2-nitroethyl and 3-nitroρropyl; examples of amino(l-4C)alkyl include aminomethyl, 1- aminoethyl, 2-aminoethyl and 3-aminopropyl; examples of cyano(l-4C)alkyl include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; examples of (1- 4C)alkanesulfonamido include methanesulfonamido and ethanesulfonamido; examples of (l-4C)alkylaminosulfonyl include methylaminosulfonyl and ethylaminosulfonyl; and examples of di-(l-4C)alkyIaminosulfonyl include dimethylaminosulfonyl, diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl; examples of (1- 4C)aIkanesuIfonyIoxy include methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy; examples of (l-4C)alkanoyloxy include acetoxy; examples of (l-4C)aIkylaminocarbonyl include methylaminocarbonyl and ethylaminocarbonyl; examples of di((l- 4C)aIkyl)aminocarbonyl include dimethylaminocarbonyl and diethylaminocarbonyl; examples of (3-6C)cycloalkyl and (3-8C)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; examples of (4-7C)cycloalkyl include cyclobutyl, cyclopentyl and cyclohexyl; examples of di(N-(l-4C)alkyl)aminomethylimino include dimethylaminomethylimino and diethylaminomethylimino.
Particular values for AR2 include, for example, for those AR2 containing one heteroatom, furan, pyrrole, thiophene; for those AR2 containing one to four N atoms, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3- & 1,2,4-triazole and tetrazole; for those AR2 containing one N and one O atom, oxazole, isoxazole and oxazine; for those AR2 containing one N and one S atom, thiazole and isothiazole; for those AR2 containing two N atoms and one S atom, 1,2,4- and 1,3,4-thiadiazole.
Particular examples of AR2a include, for example, dihydropyrrole (especially 2,5- dihydropyrrol-4-yl) and tetrahydropyridine (especially l,2,5,6-tetrahydropyrid-4-yl).
Particular examples of AR2b include, for example, tetrahydrofuran, pyrrolidine, morpholine (preferably morpholino), thiomorpholine (preferably thiomorpholino), piperazine (preferably piperazino), imidazoline and piperidine, l,3-dioxolan-4-yl, l,3-dioxan-4-yl, 1,3- dioxan-5-yl and l,4-dioxan-2-yl. Particular values for AR3 include, for example, bicyclic benzo-fused systems containing a 5- or 6-membered heteroaryl ring containing one nitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen, sulfur and nitrogen. Specific examples of such ring systems include, for example, indole, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, quinoline, quinoxaline, quinazoline, phthalazine and cinnoline. Other particular examples of AR3 include 5/5-, 5/6 and 6/6 bicyclic ring systems containing heteroatoms in both of the rings. Specific examples of such ring systems include, for example, purine and naphthyridine.
Further particular examples of AR3 include bicyclic heteroaryl ring systems with at least one bridgehead nitrogen and optionally a further 1-3 heteroatoms chosen from oxygen, sulfur and nitrogen. Specific examples of such ring systems include, for example, 3H-pyrrolo[l,2-a]pyrrole, pyrrolo[2,l-b]thiazole, lH-imidazo[l,2-a]pyrrole, lH-imidazo[l,2-a]imidazole, lH,3H-ρyrrolo[l,2-c]oxazole, lH-imidazo[l,5-a]pyrrole, pyrrolo[l,2-b]isoxazole, imidazo[5,l-b]thiazole, imidazo[2,l-b]thiazole, indolizine, imidazo[l,2-a]pyridine, imidazo[l,5-a]pyridine, pyrazolo[l,5-a]pyridine, pyrrolo[l,2-b]pyridazine, pyrrolo[l,2-c]pyrimidine, pyrrolo[l,2-a]pyrazine, pyrrolo[l,2-a]pyrimidine, pyrido[2,l-c]-s-triazole, s-triazole[l,5-a]pyridine, imidazo[l,2-c]pyrimidine, imidazo[l,2-a]pyrazine, imidazo[l,2-a]pyrimidine, imidazo[l,5-a]pyrazine, imidazo [l,5-a]pyrimidine, imidazo[l,2-b]-pyridazine, s-triazolo[4,3-a]pyrimidine, imidazo [5, 1-b] oxazole and imidazo[2,l-b]oxazole. Other specific examples of such ring systems include, for example, [lH]-pyrrolo[2,l-c]oxazine, [3H]- oxazolo[3,4-a]pyridine, [6H]-pyrrolo[2,l-c]oxazine and pyrido[2,l-c][l,4]oxazine. Other specific examples of 5/5- bicyclic ring systems are imidazooxazole or imidazothiazole, in particular imidazo[5,l-b]thiazole, imidazo[2,l-b]thiazole, imidazo [5, 1-b] oxazole or imidazo[2,l-b]oxazole.
Particular examples of AR3a and AR3b include, for example, indoline, l,3,4,6,9,9a-hexahydropyrido[2,lc][l,4]oxazin-8-yl, 1,2,3,5,8,8a- hexahydroimidazo[l,5a]pyridin-7-yl, l,5,8,8a-tetrahydrooxazolo[3,4a]pyridin-7-yl, l,5,6,7,8,8a-hexahydrooxazolo[3,4a]pyridin-7-yl, (7aS)[3H,5H]-l,7a- dihydropyrrolo[l,2c]oxazol-6-yl, (7aS)[5H]-l,2,3,7a-tetrahydropyrrolo[l,2c]imidazol-6-yl, (7aR)[3H,5H]-l,7a-dihydropyrrolo[l,2c]oxazol-6-yl, [3H,5H]-pyrrolo[l,2-c]oxazol-6-yl, [5H]-2,3-dihydropyrrolo[l,2-c]imidazol-6-yl, [3H,5H]-pyrrolo[l,2-c]thiazol-6-yl, [3H,5H]-l,7a-dihydropyrrolo[l,2-c]thiazol-6-yl, [5H]-pyrrolo[l,2-c]imidazol-6-yl, [lH]-3,4,8,8a-tetrahydropyrrolo[2,l-c]oxazin-7-yl, [3H]-l,5,8,8a-tetrahydrooxazolo[3,4- a]pyrid-7-yl, [3H]-5,8-dihydroxazolo[3,4-a]pyrid-7-yl and 5,8-dihydroimidazo[l,5-a]pyrid-7- yi-
Particular values for AR4 include, for example, pyrrolo[a]quinoline, 2,3-pyrroloisoquinoline, pyrrolo[a]isoquinoline, lH-pyrrolo[l,2-a]benzimidazole, 9H-imidazo[l,2-a]indole, 5H-imidazo[2,l-a]isoindole, lH-imidazo[3,4-a]indole, imidazo[l,2-a]quinoline, imidazo[2,l-a]isoquinoline, imidazo [l,5-a]quinoline and imidazo[5,l-a]isoquinoline.
The nomenclature used is that found in, for example, "Heterocyclic Compounds (Systems with bridgehead nitrogen), W.L.Mosby (Intercsience Publishers Inc., New York), 1961, Parts 1 and 2.
Where optional substituents are listed such substitution is preferably not geminal disubstitution unless stated otherwise. If not stated elsewhere suitable optional substituents for a particular group are those as stated for similar groups herein. Suitable substituents on ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a and
CY are (on an available carbon atom) up to three substituents independently selected from (1- 4C)alkyl {optionally substituted by (preferably one) substituents selected independently from hydroxy, trifluoromethyl, (l-4C)alkyl S(O)q- (q is 0, 1 or 2) (this last substituent preferably on ARl only), (l-4C)alkoxy, (l-4C)alkoxycarbonyl, cyano, nitro, (l-4C)alkanoylamino, - CONRvRw or -NRvRw}, trifluoromethyl, hydroxy, halo, nitro, cyano, thiol, (l-4C)alkoxy, (1- 4C)alkanoyloxy, dimethylaminomethyleneaminocarbonyl, di(N-(l- 4C)alkyl)aminomethylimino, carboxy, (l-4C)alkoxycarbonyl, (l-4C)alkanoyl, (1- 4C)alkylSO2amino, (2-4C)alkenyl {optionally substituted by carboxy or (1- 4C)alkoxycarbonyl}, (2-4C)alkynyl, (l-4C)alkanoylamino, oxo (=O), thioxo (=S), (1- 4C)alkanoylamino {the (l-4C)alkanoyl group being optionally substituted by hydroxy}, (1- 4C)alkyl S(O)q- (q is 0, 1 or 2) {the (l-4C)alkyl group being optionally substituted by one or more groups independently selected from cyano, hydroxy and (l-4C)alkoxy}, -CONRvRw or -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl].
Further suitable substituents on ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a and CY (on an available carbon atom), and also on alkyl groups (unless indicated otherwise) are up to three substituents independently selected from trifluoromethoxy, benzoylamino, benzoyl, phenyl {optionally substituted by up to three substituents independently selected from halo, (l-4C)alkoxy or cyano}, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyimino(l-4C)alkyl, (l-4C)alkoxyimino(l-4C)alkyl, halo-(l-4C)alkyl, (1- 4C)alkanesulfonamido, -SO2NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl]. Preferable optional substituents on Ar2b as l,3-dioxolan-4-yl, l,3-dioxan-4-yl, 1,3- dioxan-5-yl or l,4-dioxan-2-yl are mono- or disubstitution by substituents independently selected from (l-4C)alkyl (including geminal disubstitution), (l-4C)alkoxy, (l-4C)alkylthio, acetamido, (l-4C)alkanoyl, cyano, trifluoromethyl and phenyl] ._ Preferable optional substituents on C Y are mono- or disubstitution by substituents independently selected from (l-4C)aIkyl (including geminal disubstitution), hydroxy, (1- 4C)alkoxy, (l-4C)alkylthio, acetamido, (l-4C)alkanoyl, cyano, and trifluoromethyl.
Suitable substituents on AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4 and AR4a are (on an available nitrogen atom, where such substitution does not result in quaternization) (l-4C)alkyl, (l-4C)alkanoyl {wherein the (l-4C)alkyl and (l-4C)alkanoyl groups are optionally substituted by (preferably one) substituents independently selected from cyano, hydroxy, nitro, trifluoromethyl, (l-4C)alkyl S(O)q- (q is 0, 1 or 2), (l-4C)alkoxy, (1- 4C)alkoxycarbonyl, (l-4C)alkanoylamino, -CONRvRw or -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl]}, (2-4C)alkenyl, (2-4C)alkynyl, (1- 4C)alkoxycarbonyl or oxo (to form an N-oxide).
For certain optional substituents, suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, citrate, maleate, tartrate and (less preferably) hydrobromide. Also suitable are salts formed with phosphoric and sulfuric acid. In another aspect 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, tris-(2-hydroxyethyl)amine, N-methyl D- glucamine and amino acids such as 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. A preferred pharmaceutically-acceptable salt is the sodium salt.
In addition certain salts of the sulfoximine NH residue are envisaged, by way of non - limiting example sulphonic acid derivatives, methane sulfonate, hydrochloride and hydrobromide salts.
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. 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). A prodrug may be used to alter or improve the physical and/or pharmacokinetic profile of the parent compound and can be formed when the parent compound contains a suitable group or substituent which can be derivatised to form a prodmg. Examples of pro-drugs include in- vivo hydrolysable esters of a compound of the formula (I) or a pharmaceutically-acceptable salt thereof.
Various forms of prodrugs are known in the art, for examples see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al, Chem Pharm Bull, 32, 692 (1984). An in- vivo hydrolysable ester of a compound of the formula (I) or a pharmaceutically- acceptable salt thereof containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkoxymethyl esters for example methoxymethyl, (l-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, (3-8C)cycloalkoxycarbonyloxy(l- 6C)alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolan-2-onylmethyl esters for example 5-methyl-l,3-dioxolan-2-ylmethyl; and (l-6C)alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention. An in-vivo hydrolysable ester of a compound of the formula (I) or a pharmaceutically- acceptable salt thereof containing a hydroxy group or groups includes inorganic esters such as phosphate esters (including phosphoramidic cyclic 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/s. In addition the sulphoximine residue may be derivatised by a convenient biologically labile group to give a derivative suitable for use as a solubilising pro- drug. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include (l-lOC)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)alkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl and phenylacetyl include chloromethyl or aminomethyl, (l-4C)alkylaminomethyl and di-((l- 4C)alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4-position of the benzoyl ring.
Certain suitable in-vivo hydrolysable esters of a compound of the formula (I) are described within the definitions listed in this specification, for example esters described by the definition (Rc2d), and some groups within (Rc2c). Suitable in-vivo hydrolysable esters of a compound of the formula (I) are described as follows. For example, a 1,2-diol may be cyclised to form a cyclic ester of formula (PD1) or a pyrophosphate of formula (PD2) :
Figure imgf000019_0001
(PD1) (PD2) Particularly interesting are such cyclised pro-drugs when the 1,2-diol is on a (l-4C)alkyl chain linked to a carbonyl group in a substituent of formula Re borne by a nitrogen atom in structures (TA1) or (TA2). Esters of compounds of formula (I) wherein the HO- function/s in (PD1) and (PD2) are protected by (l-4C)alkyl, phenyl or benzyl are useful intermediates for the preparation of such pro-drugs. Further in-vivo hydrolysable esters include phosphoramidic esters, and also compounds of formula (I) in which any free hydroxy group, or sulfoxime group, independently forms a phosphoryl (npd is 1) or phosphiryl (npd is 0) ester of the formula
(PD3) or (PS1), wherein npd is independently 0 or 1 for each oxo group :
Figure imgf000019_0002
HO (PD3)
Figure imgf000020_0001
(PS1)
For the avoidance of doubt, phosphono is -P(O)(OH)2; (l-4C)alkoxy(hydroxy)- phosphoryl is a mono-(l-4C)alkoxy derivative of -O-P(O)(OH)2; and di-(l- 4C)alkoxyphosρhoryl is a di-(l-4C)alkoxy derivative of -O-P(O)(OH) .
Useful intermediates for the preparation of such esters include compounds containing a group/s of formula (PD3) in which either or both of the -OH groups in (PD3) is independently protected by (l-4C)alkyl (such compounds also being interesting compounds in their own right), phenyl or phenyl-(l-4C)alkyl (such phenyl groups being optionally substituted by 1 or 2 groups independently selected from (l-4C)alkyl, nitro, halo and (1- 4C)alkoxy).
Thus, prodrugs containing groups such as (PD1), (PD2) and (PD3) may be prepared by reaction of a compound of formula (I) containing suitable hydroxy group/s with a suitably protected phosphorylating agent (for example, containing a chloro or dialkylamino leaving group), followed by oxidation (if necessary) and deprotection. Prodrags containing a group such as (PS1) may be obtained by analogous chemistry.
When a compound of formula (I) contains a number of free hydroxy group, those groups not being converted into a prodrug functionality may be protected (for example, using a t-butyl-dimethylsilyl group), and later deprotected. Also, enzymatic methods may be used to selectively phosphorylate or dephosphorylate alcohol functionalities.
Other interesting in-vivo hydrolysable esters include, for example, those in which Re is defined by, for example, R14C(O)O(l-6C)alkyl-CO- (wherein R14is for example, benzyloxy-(l-4C)alkyl, or phenyl). Suitable substituents on a phenyl group in such esters include, for example, 4-(l-4C)piperazino-(l-4C)alkyl, piperazino-(l-4C)alkyl and morpholino-(l-4C)alkyl.
Where pharmaceutically-acceptable salts of an in-vivo hydrolysable ester may be formed this is achieved by conventional techniques. Thus, for example, compounds containing a group of formula (PD1), (PD2) and/or (PD3) may ionise (partially or fully) to form salts with an appropriate number of counter-ions. Thus, by way of example, if an in-vivo hydrolysable ester prodrug of a compound of formula (I) contains two (PD3) groups, there are four HO-P- functionalities present in the overall molecule, each of which may form an appropriate salt (i.e. the overall molecule may form, for example, a mono-, di-, tri- or tetra- sodium salt).
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 (I):
Figure imgf000021_0001
(I)
The present invention includes the pure enantiomer depicted above or mixtures of the R and S 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. For the avoidance of doubt the enantiomer depicted above is the R enantiomer.
Furthermore, the compounds of the formula (I) may have other chiral centres, for example certain sulfoxime compounds may be chiral at the sulfur atom. It is to be understood that the invention encompasses all such optical and diastereo-isomers, and racemic mixtures, that possess antibacterial activity. It is well known in the art how to prepare optically-active forms (for example by resolution of the racemic form by recrystallisation techniques, by chiral synthesis, by enzymatic resolution, by biotransformation or by chromatographic separation) and how to determine antibacterial activity as described hereinafter.
Furthermore, some compounds of the formula (I), for example certain sulfoxime compounds may exist as cis- and trans-isomers. It is to be understood that the invention encompasses all such isomers, and mixtures thereof, that possess antibacterial activity.
The invention relates to all tautomeric forms of the compounds of the formula (I) that possess antibacterial activity.
It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess antibacterial activity.
It is also to be understood that certain compounds of the formula (I) may exhibit polymorphism, and that the invention encompasses all such forms which possess antibacterial activity.
As stated before, we have discovered a range of compounds that have good activity against a broad range of Gram-positive pathogens including organisms known to be resistant to most commonly used antibiotics, together with activity against fastidious Gram negative pathogens such as Hinfluenzae, M.catarrhalis, Mycoplasma and Chlamydia strains. They have good physical and/or pharmacokinetic properties in general, and favourable toxicological profiles.
Particularly preferred compounds of the invention comprise a compound of formula (I), or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein the substituents HET, T and other substituents mentioned above have values disclosed hereinbefore, or any of the following values (which may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore or hereinafter):
In one embodiment of the invention are provided compounds of formula (I), in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (I), and in a further alternative embodiment are provided in-vivo hydrolysable esters of compounds of formula (I).
In one embodiment is provided a compound of formula (I), or in-vivo hydrolysable ester or pharmaceutically acceptable salt thereof, as defined herein wherein T is selected from (TA2) and (TB). In another embodiment is provided a compound of formula (I), or in-vivo hydrolysable ester or pharmaceutically acceptable salt thereof, as defined herein wherein T is (TAl). In a further embodiment, is provided a compound of formula (I), or in-vivo hydrolysable ester or pharmaceutically acceptable salt thereof, as defined herein wherein T is (TAlb).
In a further embodiment is provided a compound of formula (I), or in-vivo hydrolysable ester or pharmaceutically acceptable salt thereof, as defined herein wherein T is selected from (TAl), (TA2) and (TB) and wherein when T is (TAl) the ring contains one of : (i) one double bond between any two ring carbon atoms; or
(ii) a C1-C3 bridge connecting any two appropriate, non-adjacent ring carbon atoms, which bridge may optionally contain one heteroatom selected from oxygen or >NRc; or (iii) a C2-C5 cyclic moiety including a ring carbon atom to define a spiro C2-C5 ring system, which ring may optionally contain one heteroatom selected from oxygen or >NRc; or (iv) a C1-C4 bridge connecting adjacent carbon atoms to define a fused ring, wherein a C2- C4 bridge may optionally contain one heteroatom selected from oxygen or >NRc; wherein Re is as defined hereinbefore or hereinafter; and wherein when T is (TA2), ()m and ()θi are independently 0, 1 or 2 and represent chains of carbon atoms (optionally substituted as defined for ARl) of length ni and oi respectively, and define a 4- to 8-membered monocyclic ring, which ring contains one of (i) a C1-C3 bridge connecting any two appropriate, non-adjacent ring carbon atoms, which bridge contains one heteroatom selected from oxygen or >NRc; or
(ii) a C2-C5 cyclic moiety including a ring carbon atom to define a spiro C2-C5 ring system, which ring may optionally contain one heteroatom selected from oxygen or >NRc; or (iii) a C1-C4 bridge connecting adjacent carbon atoms to define a fused ring, wherein a C2-C4 bridge may optionally contain one heteroatom selected from oxygen or >NRc; wherein Re is as defined hereinbefore or hereinafter; and wherein when T is (TB), T may not be (TBlb) .
In (TAl), when the ring has an optional double bond between any two ring carbon atoms, the ring is preferably linked via an sp carbon atom of the double bond. Preferably (TAl) is (TAla) or (TAlb), and preferably (TA2) is (TA2a) :-
Figure imgf000023_0001
(TAla) (TAlb) (TA2a) wherein Xlm and X2m are as defined above, and hereinafter. More preferably (TAl) is (TAlb).
In (TBl) to (TB3), preferably ni = oi & nχ> = o (most preferably all are 1); pi = p (most preferably both are 0); and further preferred values for the groups defined in (TB) are defined by formulae (TBla, b), (TB2a) and (TB3a) :-
Figure imgf000023_0002
(TBla) (TBlb)
Figure imgf000024_0001
(TB2a) (TB3a) wherein Xlm and X2m are as defined above, and hereinafter.
When (TA) is (TAla) or (TA2a), preferably Xlm and X2m together are represent R2s- (E)ms-N=, wherein R s and -(E)ms are as defined above, and hereinafter.
When (TB) is (TBlb) preferably Xlm and X2m together are represent R s-(E)ms-N=, wherein R2s and -(E)ms are as defined above, and hereinafter.
In one embodiment, preferably Xlm is O= and X m is R s-(E)ms-N-, and vice versa. In another embodiment, preferably Xlm and X m together are represent R s-(E)ms-N=; wherein in either embodiment, R2s and -(E)ms are as defined above, and hereinafter. When ms is 0, R2s is preferably selected from : (i) hydrogen, a (l-6C)alkyl group {optionally monosubstituted by (l-4C)alkanoyl group, cyano, cyano-imino, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for ARl defined herein), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein, (l-4C)alkylS(O)q- (q is 0, 1 or 2); or optionally substituted by one or more fluoro groups (including geminal disubstitution); or optionally substituted by one or more hydroxy groups (excluding geminal disubstitution), and/or optionally further substituted, by no more than one of each of, oxo, -NRvRw [wherein Rv is hydrogen or (1- 4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamino, N-(l-4C)alkyl-N-(l-6C)alkanoylamino, (l-4C)alkylS(O)pNH- or (l-4C)alkylS(O)p.((l- 4C)alkyl)N- (p is 1 or 2)}; or
(ii) an optionally substituted aryl or optionally substituted heteroaryl group of the formula ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein; or (iii) cyano, -CO-NRvRw, -CO-NRv Rw', -SO2-NRvRw, -SO2-NRv Rw' [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl; Rw' is phenyl (optionally substituted as for ARl defined herein), or a heteroaryl group selected from AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a (optionally substituted as defined herein)], (l-4C)aIkoxycarbonyl, trifluoromethyl.
When ms is 0, R2s is most preferably selected from : (i) hydrogen, (l-6C)alkyl {optionally monosubstituted by (l-4C)alkoxy, trifluoromethyl, (l-4C)alkylS(O)q- (q is 0, 1 or 2); or optionally substituted by one or more fluoro-groups (including geminal disubstitution); or optionally substituted by one or more hydroxy groups (excluding geminal disubstitution)}; or
(iii) -CO-NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], -CO-NRv Rw' [wherein Rv is hydrogen or (l-4C)alkyl; Rw' is phenyl (optionally substituted as for ARl defined herein)], (l-4C)alkoxycarbonyl.
When ms is 1, E is preferably -CO- or -SO - and R s is preferably selected from : (i) (l-6C)alkyl {optionally monosubstituted by cyano, cyano-imino, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for ARl defined herein), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein, (l-4C)alkylS(O)q- (q is 0, 1 or 2); and or (with the proviso that where R2s is -SO2- or -O-CO- not on the first carbon atom of the (1-6C) alkyl chain) optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally monosubstituted by -NRvRw [wherein Rv is hydrogen or (1- 4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamino, N-(l-4C)alkyl-N-(l-6C)alkanoylamino, (l-4C)alkylS(O)pNH- or (l-4C)alkylS(O)p_((l- 4C)alkyl)N- (p is l or 2)}; or
(ii) an optionally substituted aryl or heteroaryl group of the formula ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein.
When ms is 1, E is preferably -CO- or -SO2- and R2s is most preferably selected from : (i) (l-6C)alkyl {optionally monosubstituted by (l-4C)alkoxy, trifluoromethyl, (1- 4C)alkylS(O)q- (q is 0, 1 or 2); or optionally substituted by one or more fluoro groups (including geminal disubstitution); or optionally substituted by one or more hydroxy groups (excluding geminal disubstitution)}, (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamino.
In (TB) and (TA2), where ()nl5 Qoi, ()nr, ()or, ()pi and ()pr represent chains of carbon atoms optionally substituted as defined for ARl herein, preferable optional substituents are selected from (preferably one of) hydroxy, trifluoromethyl, (l-4C)alkyl S(O)q- (q is 0, 1 or 2), (l-4C)alkoxy, (l-4C)alkoxycarbonyl, cyano, nitro, (l-4C)alkanoylamino, -CONRvRw or- NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl]. Most preferably, ()nj, ()oi, ()nr, ()or, ()pi and ()pr represent unsubstituted chains of carbon atoms. Preferable values for other substituents (which may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore or hereinafter) are :-
(a) In one embodiment, HET(AR) is a 5 membered aromatic or heteroaromatic ring as defined herein and optionally substituted as defined herein. In another embodiment HET(AR) is a 6 membered aromatic or heteroaromatic ring as defined herein and optionally substituted as defined herein. Preferably HET(AR) is phenyl. In a further embodiment, HET(AR) is not phenyl.
(b) In one aspect preferably HET(AR) is substituted at both positions ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring by Rl as defined herein. In an another aspect HET(AR) is substituted at one such position.
(c) Preferably Rl is hydrogen or halogen. Most preferably Rl is hydrogen or fluorine.
(d) Preferably Z is hydrogen or -COR5 or -CSR5, wherein R5 is CH3, NH2, OCH3, OEt, or CHC12. In one embodiment, preferably Z is -COR5 wherein R5 is CH3. In another embodiment, preferably Z is hydrogen. (f) Preferably Re is R13CO- and preferably R13 is (l-4C)alkoxycarbonyl, hydroxy(l-4C)alkyl, (l-4C)alkyl (optionally substituted by one or two hydroxy groups, or by an (l-4C)alkanoyl group), (l-4C)alkylamino, dimethylamino(l-4C)alkyl, (l-4C)alkoxymethyl, (l-4C)alkanoylmethyl, (l-4C)alkanoyloxy(l-4C)alkyl, (l-5C)alkoxy or 2-cyanoethyl. (g) More preferably R13 is 1,2-dihydroxyethyl, l,3-dihydroxyprop-2-yl,
1,2,3-trihydroxyprop-l-yl, methoxycarbonyl, hydroxymethyl, methyl, methylamino, dimethylaminomethyl, methoxymethyl, acetoxymethyl, methoxy, methylthio, naphthyl, tert-butoxy or 2-cyanoethyl. (h) Particularly preferred as R13 is 1,2-dihydroxyethyl, l,3-dihydroxyprop-2-yl or 1,2,3-trihydroxyprop-l-yl.
(i) In another aspect preferably R13 is hydrogen, (l-lOC)alkyl [optionally substituted by one or more hydroxy] or R1 C(O)O(l-6C)alkyl. For compounds of formula (I) preferred values for Re are those in group (Rc2) when present in any of the definitions herein containing Re.
In the definition of (Rc2c) the AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3 containing groups are preferably excluded. Especially preferred compounds of the present invention are of the formula (IB):
Figure imgf000027_0001
(IB) wherein Y is NH and Z is -COMe; each Ri is independently hydrogen or fluoro; T is selected from (TAl), (TA2) and (TBl) to (TB3) wherein Xlm and X2m together represent R2s-(E)ms-N= (as defined hereinbefore or hereinafter); or in-vivo hydrolysable esters or pharmaceutically acceptable salts thereof.
Further especially preferred compounds of the invention are of the formula (IB) wherein Y is NH and Z is hydrogen; each Ri is independently hydrogen or fluoro; T is selected from (TAl), (TA2) and (TBl) to (TB3) wherein Xim and X2m together represent R2s- (E)ms-N= (as defined hereinbefore or hereinafter) or Xlm is O= and X m is R2s-(E)ms-N-, and vice versa; or in-vivo hydrolysable esters or pharmaceutically acceptable salts thereof.
Further especially preferred compounds of the invention are of the formula (IB) wherein Y is NH and Z is hydrogen or -COMe; each Ri is independently hydrogen or fluoro;
T is (TAlb); wherein Xlm is O= and X2m is R2s-(E)ms-N-, and vice versa (as defined hereinbefore or hereinafter); or in-vivo hydrolysable esters or pharmaceutically acceptable salts thereof.
Further especially preferred compounds of the invention are of the formula (IB) wherein Y is NH and Z is hydrogen or -COMe; each Ri is independently hydrogen or fluoro;
T is selected from TBl to TB3 (but excluding (TBlb)) wherein Xlm is O= and X2m is R2s- (F-Jms-N-, and vice versa (as defined hereinbefore or hereinafter); or in-vivo hydrolysable esters or pharmaceutically acceptable salts thereof.
In the above aspects and preferred compounds of formula (IB), in (TAl), (TA2) and (TBl) to (TB3) when ms is 0, R2s is preferably selected from (i) hydrogen, a (l-6C)alkyl group {optionally monosubstituted by (l-4C)alkanoyl group, cyano, cyano-imino, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for ARl defined herein), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein, (l-4C)alkylS(O)q- (q is 0, 1 or 2); or optionally substituted by one or more fluoro groups (including geminal disubstitution); or optionally substituted by one or more hydroxy groups (excluding geminal disubstitution), and/or optionally further substituted, by no more than one of each of, oxo, -NRvRw [wherein Rv is hydrogen or (1- 4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamino, N-(l-4C)alkyl-N-(l-6C)alkanoylamino, (l-4C)alkylS(O)pNH- or (l-4C)alkylS(O)p.((l- 4C)alkyl)N- (p is 1 or 2)}; or
(ii) an optionally substituted aryl or optionally substituted heteroaryl group of the formula ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein; or (where ms is 0 only), (iii) cyano, -CO-NRvRw, -CO-NRv Rw', -SO2-NRvRw, -SO2-NRv Rw' [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl; Rw' is phenyl (optionally substituted as for ARl defined herein), or a heteroaryl group selected from AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a (optionally substituted as defined herein)], (1 -4C)alkoxycarbonyl, trifluoromethyl; and when ms is 1, E is preferably -CO- or -SO - and R s is preferably selected from : (i) (l-6C)alkyl {optionally monosubstituted by cyano, cyano-imino, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for ARl defined herein), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein, (l-4C)alkylS(O)q- (q is 0, 1 or 2); and/or (with the proviso that where R2s is -SO2- or -O-CO- not on the first carbon atom of the (1-6C) alkyl chain) optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally monosubstituted by -NRvRw [wherein Rv is hydrogen or (1- 4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamino, N-(l-4C)alkyl-N-(l-6C)alkanoylamino, (l-4C)alkylS(O)pNH- or (l-4C)alkylS(O)p.((l-
4C)alkyl)N- (p is 1 or 2)}; or
(ii) an optionally substituted aryl or heteroaryl group of the formula ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein.
In a further aspect of the invention, is provided a compound of formula (I) wherein T is (TAl) as hereinbefore defined; and therefore provides a compound of the formula (IC), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof,
Figure imgf000029_0001
(IC) wherein:
XI and X2 taken together represent R2F-(E)m-N=, wherein E is an electron withdrawing group selected from SO2-, CO-, O-CO-, CO-O-, CS-, CON(RF)-, SO2N(RF)-, or E may represent a group of the formula R3F -C(=N-O-R3 F)-C(=O)-, wherein R3F is H or as defined in R2F (i) below; or XI is O= and X2 is R2F -(E)m-N-, and vice versa; and R2F and RF may be linked as a 5- or 6-membered unsaturated or partially unsaturated ring; m is O or 1;
R2F and RF are independently selected from: (i) hydrogen (except where E is SO2 or O-CO-), a (l-6C)alkyl group {optionally substituted by one or more (l-4C)alkanoyl groups (including geminal disubstitution) and/or optionally monosubstituted by cyano, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for AR defined herein after, heteroaryl(optionally substituted and defined as below),(l-4C)alkylS(O)q- (q is 0, 1 or 2); or (with the proviso that where R2F is SO2 or O-CO- not on the first carbon atom of the (1-6C) alkyl chain) optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally monosubstituted by oxo, -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (l-6C)alkanoylamino, (1- 4C)alkoxycarbonylamino, N-(l-4C)alkyl-N-(l-6C)alkanoylamino, (l-4C)alkylS(O)pNH- or (l-4C)alkylS(O)p_((l-4C)alkyl)N- (p is 1 or 2)}; or
(ii) an optionally substituted aryl or heteroaryl group of the formula ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, or CY all as hereinbefore defined, or where m=0 only,
(iii) cyano (l-4C)alkoxycarbonyl, trifluoromethyl, ethenyl, 2-(l-4C)alkylethenyl, 2- cyanoethenyl, 2-cyano-2-((l-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((l-4C)alkyl)ethenyl, 2-((l-4C)alkylaminocarbonyl)ethenyl, 2-((l-4C)alkoxycarbonyl)ethenyl, 2-(ARl)ethenyl, 2- (AR2)ethenyl, or 2-(AR2a)ethenyl;
W is a bond joining the adjacent carbon atoms or represents one or two carbon atoms (each -CH2- or -CH-), the heterocyclic ring comprising W therefore has 5-7 ring atoms and may optionally have one or more of (i) one double bond between ring carbon atoms, (ii) a Cl- C3 bridge connecting two ring carbon atoms and optionally containing a heteroatom selected from oxygen or nitrogen, and (iii) a C2-C5 cyclic moiety around a ring carbon atom;
(HET)AR is a 5-6 membered aromatic or heteroaromatic ring, (i) when a 5-membered ring this may be a thiophene ring, comprising a single sulphur atom sited ortho to the nitrogen atom on the adjacent oxazolidinone ring, such a ring may have a single optional substituent R1F as hereinafter defined sited ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring, (ii) when a 6-membered ring this may be a phenyl ring or comprise a single nitrogen atom sited ortho to the nitrogen atom on the adjacent oxazolidinone ring, such ring may be optionally substituted at one or both positions ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring by R1F, where each
RIF is independently selected from hydrogen, halogen, methyl, methoxy, ethyl and ethoxy;
Y is -NH-;
Z is hydrogen ,-COR5 or-CSR5, wherein R5 is selected from: H, (l-6C)alkyl (optionally substituted with 1-4 halogen atoms), cyclopropyl, -O-(l-6C)alkyl, NH2 orNH-(l-6C)alkyl orN-di(l-6C)alkyl); except that (other than when the heterocyclic ring comprising M is optionally substituted as defined in (i) - (iii) above), when Xi is O= and X2 is R2r^(E)m-N-, or vice versa, R2p-(E)m- may not be hydrogen, (l-4C)alkyl (optionally substituted as defined for Rp below), -C(=O)(l-4C)alkyl (optionally substituted as defined for Rp below), -C(=O)O(l-4C)alkyl (optionally substituted as defined for Rp below), -C(=O)NHRp, or -C(=S)NHRP, wherein Rp is hydrogen, (l-4C)alkyl (optionally substituted with one or more halo, cyano, nitro, phenyl, (3-6C)cycloalkyl, ORp2> C(=O)Rp2, OC(=O)Rp2, C(=O)ORp2, S(=O)mpRp2, S(=O)mpNRp2Rp2, NRp2SO2Rp2, NRp2NSO2RP2RP2, NRp2C(=O)Rp2, C(=O)NRp2Rp2, NRp2Rp2, oxo or oxime) or phenyl, wherein RP2 is hydrogen, (l-4C)alkyl or phenyl, wherein at each occurrence phenyl is optionally substituted with one or more halo, cyano, nitro, phenyl, (3-6C)cycloalkyl, ORp2, C(=O)Rp2, OC(=O)Rp2, C(=O)ORp2, S(=O)mpRp2, S(=O)mpNRp2RP2, NRp2SO2Rp2, NRp2NSO2Rp2RP2, NRp2C(=O)Rp2, C(=O)NRp2Rp2, or NRp2Rp2, mp is 0, 1 or 2;
For compounds of the formula (IC) the term "a C5-C6 heteroaromatic ring" means a 5- or 6-membered aryl ring wherein (unless stated otherwise) 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulfur. Unless stated otherwise, such rings are fully aromatic. Particular examples of 5- or 6-membered heteroaryl ring systems are furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.
For compounds of the formula (IC), particular optional substituents for alkyl, phenyl (and phenyl containing moieties ) and naphthyl groups and ring carbon atoms in heteroaryl (mono or bicyclic) rings (such as set out hereinbefore in groups ARl to AR4a and CY inclusive) include halo, (l-4C)alkyl , hydroxy, nitro, carbamoyl, (l-4C)alkylcarbamoyl, di- ((l-4C)alkyl)carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, amino, (l-4C)alkylamino, di((l-4C)alkyl)amino, (l-4C)alkyl S(O) - (q is 0, 1 or 2), carboxy, (l-4C)alkoxycarbonyl, (2-
4 4C)alkenyI, (2-4C)alkynyl, (l-4C)alkanoyl, (l-4C)alkoxy, (l-4C)alkylS(O)2amino, (1- 4C)alkanoylamino, benzoylamino, benzoyl, phenyl (optionally substituted by up to three substituents selected from halo, (l-4C)alkoxy or cyano), furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyimino(l-4C)alkyl, (l-4C)alkoxyimino(l-4C)alkyl, hydroxy-(l-4C)alkyl, halo-(l- 4C)alkyl, nitro(l-4C)alkyl, amino(l-4C)alkyl, cyano(l-4C)alkyl, (l-4C)alkanesulfonamido, aminosulfonyl, (l-4C)alkylaminosulfonyl and di-((l-4C)alkyl)aminosulfonyl. The phenyl and naphthyl groups and heteroaryl (mono- or bicyclic) rings may be mono- or di-substituted on ring carbon atoms with substituents independently selected from the above list of particular optional substituents, or on ring nitrogen atoms provided the ring is not thereby quaternised. ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a and CY are understood to be as hereinbefore defined for formula I.
Particular values for XI and X2 are as follows: (i) XI is O= and X2 is R2-(E)m-N-, wherein m = 0 and vice versa, (ii) XI is O= and X2 is R2-(E)m-N-, wherein m is 1 and vice versa (iii) XI and X2 taken together represent R2-(E)m-N=, wherein E is -SO2- and m is 0 (iv) XI and X2 taken together represent R2-(E)m-N=, wherein E is -SO2- and m is 1 (v) XI and X2 taken together represent R2-(E)m-N=, wherein E is -CO- and m is 0 (vi) XI and X2 taken together represent R2-(E)m-N=, wherein E is -CO- and m is 1 (vii) XI and X2 taken together represent R2-(E)m-N=, wherein E is -O-CO- and m is 0 (viii) XI and X2 taken together represent R2-(E)m-N=, wherein E is -O-CO- and m is 1 (ix) XI and X2 taken together represent R2-(E)m-N=, wherein E is -CO-O- and m is 0 (x) XI and X2 taken together represent R2-(E)m-N=, wherein E is -COO— and m is 1 (xi) XI and X2 taken together represent R2-(E)m-N=, wherein E is -CS- and m is 0 (xii) XI and X2 taken together represent R2-(E)m-N=, wherein E is -CS- and m is 1 (xiii) XI and X2 taken together represent R2-(E)m-N=, wherein E is -CON(R)- and m is 0 (xiv) XI and X2 taken together represent R2-(E)m-N=, wherein E is -CON(R)- and m is 1 (xv) XI and X2 taken together represent R2-(E)m-N=, wherein E is -SO2N(R)- and m is 0 (xvi) XI and X2 taken together represent R2-(E)m-N=, wherein E is -SO2N(R)- and m is 1 Rl is hydrogen or halogen; R2 and R are independently hydrogen (except where E is SO2 or O-CO-), a (1- 6C)alkyl group {optionally substituted by one or more (l-4C)alkanoyl groups (including geminal disubstitution) and/or optionally monosubstituted by cyano, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for AR defined hereinafter, heteroaryl(optionally substituted and defined as below),(l-4C)alkylS(O)q- (q is 0, 1 or 2); or, optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally monosubstituted by oxo, -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (1- 6C)alkanoylamino, (l-4C)alkoxycarbonylamino, N-(l-4C)alkyl-N-(l-6C)alkanoylamino, (1- 4C)alkylS(O)pNH- or (l-4C)alkylS(O)p.((l-4C)alkyl)N- (p is 1 or 2)}; m is 1;
Z is COR5 or CSR5, wherein R5 is CH3, NH2, OCH3, OEt, or CHC12. More particular values are as follows:
Rl is halogen;
R2 and R are independently hydrogen (except where E is SO2 or O-CO-), an alkyl, cycloalkyl, alkenyl or alkynyl group [especially cyclopropyl, or cyclobutyl, ethyl or methyl], all being optionally substituted by one or more of hydroxy, O-alkyl, alkanoyl (including geminal disubstitution), CN, SO2CH3, fluorine, chlorine, trifluoromethyl, COOH, COO- alkyl, CONH2, CONH-alkyl, or CON-dialkyl; and wherein any group has up to 6, such as up to 4 carbon atoms, the O-alkyl and alkanoyl groups may be further substituted by any convenient substituent such as for example trifluoromethyl; Z is COCH3.
In all of the above aspects and preferred compounds of formula (IB) and (IC), in-vivo hydrolysable esters are preferred where appropriate, especially phosphoryl esters (as defined by formula (PD3) with npd as 1, or of formula (PS1)).
In all of the above definitions the preferred compounds are as shown in formula (I), ie the pharmaceutically active enantiomer.
Particularly preferred compounds of the present invention include the compounds described in the following examples. Therefore the present invention also provides a compound described in any one of the following examples, or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof (and in particular compounds and salts thereof); and their use as a medicament (as herein described).
Process section:
In a further aspect the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof. It will be appreciated that during certain of the following processes certain substituents may require protection to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.
For examples of 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). 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.
Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. Resins may also be used as a protecting group.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. A compound of the formula (I), or a pharmaceutically-acceptable salt or an in vivo hydrolysable ester thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the formula (I), or a pharmaceutically-acceptable salt or an in vivo hydrolysable ester thereof, are provided as a further feature of the invention and are illustrated by the following representative examples. Necessary starting materials may be obtained by standard procedures of organic chemistry (see, for example, Advanced Organic Chemistry (Wiley- Interscience), Jerry March). The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. Information on the preparation of necessary starting materials or related compounds (which may be adapted to form necessary starting materials) may also be found in the following Patent and Application Publications, the contents of the relevant process sections of which are hereby incorporated herein by reference : WO99/02525; WO98/54161; WO97/37980; WO97/30981 (& US5,736,545); WO97/21708 (& US5,719,154); WO97/10223; WO97/09328; WO96/35691; WO96/23788; WO96/15130; WO96/13502; WO95/25106 (& US5,668,286); WO95/14684 (& US5,652,238); WO95/07271 (& US5,688,792); WO94/13649; WO94/01110; WO93/23384 (& US5,547,950 & US 5,700,799); WO93/09103 (& US5,565,571, US5,654,428, US5,654,435, US5,756,732 & US5,801,246); US5,231,188; US5,247,090; US5,523,403; WO97/27188; WO97/30995; WO97/31917; WO98/01447; WO98/01446; WO99/10342; WO99/10343; WO99/11642; European Patent Application Nos. 0,359,418 and 0,609,905; 0,693,491 Al (& US5,698,574); 0,694,543 Al (& AU 24985/95); 0,694,544 Al (& CA 2,154,024); 0,697,412 Al (& US5,529,998); 0,738,726 Al (& AU 50735/96); 0,785,201 Al (& AU 10123/97); German Patent Application Nos. DE 195 14 313 Al (& US5,529,998); DE 196 01 264 Al (& AU
10098/97); DE 196 01 265 Al (& AU 10097/97); DE 196 04 223 Al (& AU 12516/97); DE
196 49 095 Al (& AU 12517/97).
The following Patent and Application Publications may also provide useful information and the contents of the relevant process sections are hereby incorporated herein by reference :
FR 2458547; FR 2500450(& GB 2094299, GB 2141716 & US 4,476,136); DE 2923295 (&
GB 2028306, GB 2054575, US4,287,351, US4,348,393, US4,413,001, US4,435,415 &
US4,526,786), DE 3017499 (& GB 2053196, US4,346,102 & US4,372,967); US4,705,799; European Patent Application Nos. 0,312,000; 0,127,902; 0,184,170; 0,352,781;
0,316,594.
Information on the preparation of necessary starting materials or related compounds
(which may be adapted to form necessary starting material) may also be found in WO
01/46185. The skilled organic chemist will be able to use and adapt the information contained and referenced within the above references to obtain necessary starting materials.
In particular we refer to our PCT patent applications WO-99/64417 and WO-00/21960 wherein detailed guidance is given on convenient methods for preparing oxazolidinone compounds. Convenient methods include those in which as a last step;
(i) a sulfoxide is converted into a sulfoximine;
(ii) a sulfilimine is oxidised to the corresponding sulfoximine
(iii) an appropriate aminomethyl side chain oxazolidinone is acylated to give an appropriate corresponding acylamide product. (iv) a preformed sulfilimine or sulfoximine ring-containing intermediate is coupled to an aryloxazolidinone.
Such methods are shown by way of non-limiting illustration below wherein LG represents a convenient leaving group:
Figure imgf000037_0001
Figure imgf000037_0002
Figure imgf000037_0003
The present invention also provides that compounds of the formulae (I) and pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof, can be prepared by a process (a) to (1) as follows (wherein the variables are as defined above unless otherwise stated) :
(a) by modifying a substituent in or introducing a substituent into another compound of formula (I); or
(b) by reaction of a compound of formula (II) :
Figure imgf000037_0004
(H) wherein LG is a displaceable group (which may be (i) generated in-situ, for example under Mitsunobu conditions, or (ii) preformed, such as chloro or mesylate) with a compound of the formula (III): Y-Z (HD wherein heterocyclic compound Y-Z is appropriately derivatised for coupling with a compound of formula (II); or
(c) by oxidation (i) with an aminating agent of a lower valent sulfur compound (TV), or an analogue thereof, which is suitable to give a T substituent as defined by (TA2), or a bi-, or tri-cyclic ring analogue of (IV) which is suitable to give a T substituent as defined by (TB); or (ii) with an oxygenating agent of a lower valent sulfur compound (V), or an analogue thereof, which is suitable to give a T substituent as defined by (TA2), or a bi-, or tri-cyclic ring analogue of (V) which is suitable to give a T substituent as defined by (TB);
Figure imgf000038_0001
(IV) (V) where n = 0 or 1 and ()x and ()x' are chains of length x and x'.
Suitable aminating agents include mesitylenesulfonyl hydroxylamine, sodium azide and polyphosphoric acid, and chloramine-T (T as defined by (TA2) or (TB)); suitable oxygenating agents include peracids and osmium tetroxide - amine N-oxide mixtures; or
(d) (i) by coupling, using catalysis by transition metals such as palladium(O), of a compound of formula (VI) :
Figure imgf000038_0002
(VI) wherein Y-Z is as hereinbefore defined, LG is a replaceable substituent - such as chloride, bromide, iodide, or trifluoromethylsulfonyloxy; with a compound of the formula (VII), or an analogue thereof, which is suitable to give a T substituent as defined by (TAl), in which the link is via an sp2 carbon atom, or (TA2), or a bi- or tri-cyclic ring analogue of (VTJ) which is suitable to give a T substituent as defined by (TB);
Figure imgf000039_0001
(vπ) where n = 0 or 1 and ()x and ()x' are chains of length x and x'; D is NH or CH=C-LG where LG is a leaving group such as chloride, bromide, iodide, or trifluoromethylsulfonyloxy; or (d) (ii) by coupling, using catalysis by transition metals such as palladium(O), of a compound of formula (Vm):
Figure imgf000039_0002
(vm) wherein Y-Z is as hereinbefore defined, with a compound [Aryl]-LG, where LG is a replaceable substituent such as chloride, bromide, iodide, or trifluoromethylsulfonyloxy or an analogue thereof; or
(e) by reduction of a compound formed by process (d) in which the T substituent (as defined by (TAl)) is linked via an sp2 carbon atom, to form the saturated analogue; or (f) by reaction of a compound of the formula (IX) :
T-Q-Z(f)
(IX) wherein Z(f) is an isocyanate, amine or urethane group with an epoxide of the formula (X):
C> H
(X)
wherein Z is a (thio)acyl group as hereinabove defined; or with a related compound of formula (XI) where the hydroxy group at the internal C-atom is optionally conventionally protected e.g. with an acetyl group and where the leaving group LG(f) at the terminal C-atom is a conventional leaving group e.g. a chloro- or mesyloxy- group;
Figure imgf000040_0001
(XI)
General guidance on reaction conditions and reagents may be obtained in Advanced
Organic Chemistry, 4th Edition, Jerry March (publisher : J.Wiley & Sons), 1992. Necessary starting materials may be obtained by standard procedures of organic chemistry, such as described in this process section, in the Examples section or by analogous procedures within the ordinary skill of an organic chemist. Certain references are also provided (see above) which describe the preparation of certain suitable starting materials, for particular example see International Patent Application Publication No. WO 97/37980, the contents of which are incorporated here by reference.
Processes analogous to those described in the references may also be used by the ordinary organic chemist to obtain necessary starting materials. Methods for converting substituents into other substituents are known in the art. For example an alkylthio group may be oxidised to an alkylsulfinyl or alkylsulfonyl group, a cyano group reduced to an amino group, a nitro group reduced to an amino group, a hydroxy group alkylated to a methoxy group, a hydroxy group converted to an arylthiomethyl or a heteroarylthiomethyl group (see, for example, Tet.Lett, 585, 1972), a carbonyl group converted to a thiocarbonyl group (eg. using Lawsson's reagent) or a bromo group converted to an alkylthio group. It is also possible to convert one R2 group into another R2 group as a final step in the preparation of a compound of the formula (I).
Convenient methods for functionalised sulfilimines and sulfoximines include those in which a sulfilimine or sulfoximine is (i) alkylated, (ii) acylated or (iii) arylated. A detailed review of sulfoximine chemistry is provided by Michael Reggelin and Cornelia Zur in Synthesis, 2000, 1, 1-64. Further references include Reggelin et al, Tetrahedron Letters, 1992, 33 (46), 6959 - 6962; Reggelin et al, Tetrahedron Letters, 1992, 36 (33), 5885 - 5886; and Gage et al, Tetrahedron Letters, 2000, 41, 4301 - 4305.
The general method for introducing or refunctionalizing sulfimines or sulfoximines in the final step is illustrated in Scheme 1. (b)(i) Reaction (b)(i) (in which Y is initially hydroxy) is performed under Mitsunobu conditions, for example, in the presence of tri-n-butylphosphine and diethyl azodicarboxylate (DEAD) in an organic solvent such as THF, and in the temperature range 0°C - 60°C, but preferably at ambient temperature. Details of Mitsunobu reactions are contained in Tet. Letts., 31, 699, (1990); The Mitsunobu Reaction, D.L.Hughes, Organic Reactions, 1992, Vol.42, 335-656 and Progress in the Mitsunobu Reaction, D.L.Hughes, Organic Preparations and Procedures International, 1996, Vol.28, 127-164. The general method is illustrated in Scheme 2. (b)(ii) Reactions (b)(ii) are performed conveniently in the presence of a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide or hydroxide, for example sodium carbonate or potassium carbonate, or, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo-[5.4.0]undec-7-ene, the reaction is also preferably carried out in a suitable inert solvent or diluent, for example methylene chloride, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide, NN-dimethylacetamide, N-methylpyrrolidin- 2-one or dimethylsulfoxide at and at a temperature in the range 25-60°C.
When Y is chloro, the compound of the formula (IT) may be formed by reacting a compound of the formula (II) wherein Y is hydroxy (hydroxy compound) with 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. A compound of the formula (II) wherein Y is chloro or iodo may also be prepared from a compound of the formula (II) wherein Y is mesylate or tosylate, by reacting the latter compound with lithium chloride or lithium iodide and crown ether, in a suitable organic solvent such as THF, in a temperature range of ambient temperature to reflux
When Y is (l-4C)alkanesulfonyloxy or tosylate the compound (II) may be prepared by reacting the hydroxy compound with (l-4C)alkanesulfonyl chloride or tosyl chloride in the presence of a mild base such as triethylamine or pyridine. When Y is a phosphoryl ester (such as Phθ2-P(O)-O-) or Ph2-P(O)-O- the compound
(JJ) may be prepared from the hydroxy compound under standard conditions.
If not commercially available, compounds of the formula (HI) may be prepared by procedures which are selected from standard chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the procedures described in the Examples. For example, standard chemical techniques are as described in Houben Weyl. The general method is illustrated in Scheme 2.
(c) Convenient methods for aminating thioethers or sulfoxides are indicated in Michael Reggelin and Cornelia Zur in Synthesis, 2000, 1, 1-64. For substrates containing nucleophilic nitrogen atoms such as tertiary arylamines it is advantageous to use an acidic reaction mixture such as sodium azide in polyphosphoric acid to reduce the amount of amination on nitrogen. Sulfoximines may be made either by oxidizing thioethers first to the corresponding sufoxides and then to the sulfoximines or by oxidizing thioethers first to the corresponding sulfilimines (sulfimines) and then to the sulfoximine. The general method for aminating thiethers or sulfoxides and for oxidizing sulfimines is illustrated in Scheme 1.
(d) The cyclic sulfoxides and sulfimines used in reaction (d) may be obtained by oxidation of the corresponding cyclic aminothioethers as illustrated in Scheme 1.
(e) The reduction of a compound formed by process (d) in which the T substituent (as defined by (TAl)) is linked via an sp2 carbon atom, to form the saturated analogue, may be performed using standard hydrogenation. For example, a dihydrothiopyran may be reduced to produce the tetrahydrothiopyran analogue.
The following Schemes illustrate process chemistry which allows preparation of compounds of the formula (I); wherein A and R are values suitable to provide the compounds of formula (I) defined herein. The Schemes may be genericised by the skilled man to apply to compounds within the present specification which are not specifically illustrated in the Schemes (for example to HET as a 6-membered ring as defined herein).
Figure imgf000043_0001
Figure imgf000043_0002
Figure imgf000043_0003
Scheme 1
(I) Amination with sodium azide/polyphosphoric acid or mesitylenesulfonylhydroxylamine; (JJ) 1 equivalent m-chloroperoxybenzoic acid; (III) alkylation, arylation, or acylation according to reaction (a).
Figure imgf000043_0004
Figure imgf000043_0005
Figure imgf000044_0001
Scheme 2
Figure imgf000044_0002
Scheme 3
One compound of formula (I) may be converted into another compound of formula (I) by reacting a compound of formula (I) in which a substituent is halo with a suitable compound to form another compound. Thus, for example, halo may be displaced by suitable vinyl, aromatic, tropolone and nitrogen-linked systems by reaction using known Pd(0) coupling techniques. Further examples of converting substituents into other substituents are contained in the accompanying non-limiting Examples.
Certain compounds may be prepared by the skilled chemist, for example as described in International Patent Application Publication Nos. WO95/07271, WO97/27188, WO
97/30995, WO 98/01446 and WO 98/01447, the contents of which are hereby incorporated by reference, and by analogous processes. The removal of any protecting groups, the formation of a pharmaceutically-acceptable salt and or the formation of an in vivo hydrolysable ester are within the skill of an ordinary organic chemist using standard techniques. Furthermore, details on the these steps, for example the preparation of in-vivo hydrolysable ester prodrugs has been provided in the section above on such esters, and in certain of the following non-limiting Examples.
Certain novel intermediates utilised in the above processes are provided as a further feature of the invention.
When an optically active form of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using an optically active starting material (formed, for example, by asymmetric induction of a suitable reaction step), or by resolution of a racemic form of the compound or intermediate using a standard procedure, or by chromatographic separation of diastereoisomers (when produced). Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates. Similarly, when a pure regioisomer of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by separation of a mixture of the regioisomers or intermediates using a standard procedure.
According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester or amide thereof for use in a method of treatment of the human or animal body by therapy.
According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof.
The invention also provides a compound of the formula (I), or a pharmaceutically- acceptable salt, or in-vivo hydrolysable ester thereof, for use as a medicament; and for use as an antibacterial agent; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically-acceptable salt, 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.
In order to use a compound of the formula (I), an in-vivo hydrolysable ester or a pharmaceutically-acceptable salt thereof, including a pharmaceutically-acceptable salt of an in-vivo hydrolysable ester, (hereinafter in this section relating to pharmaceutical composition "a compound of this invention") for the therapeutic (including prophylactic) 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), an in-vivo hydrolysable ester or a pharmaceutically-acceptable salt thereof, including a pharmaceutically-acceptable salt of an in-vivo hydrolysable ester, 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, topical or parenteral administration. For these purposes 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, aerosols (or sprays), drops and sterile injectable aqueous or oily solutions or suspensions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain or be co-administered (simultaneously, sequentially or separately) with one or more known drugs selected from other clinically useful antibacterial agents (for example, β-lactams or aminoglycosides) and/or other anti-infective agents (for example, an antifungal triazole or amphotericin). These may include carbapenems, for example meropenem or imipenem, to broaden the therapeutic effectiveness. Compounds of this invention may also contain or be co-administered with bactericidal/permeability- increasing protein (BPI) products or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents. A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between lmg and lg of a compound of this invention, preferably between lOOmg and lg of a compound. Especially preferred is a tablet or capsule which contains between 50mg and 800mg of a compound of this invention, particularly in the range lOOmg to 500mg. In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection, for example an injection which contains between 0.1% w/v and 50% w/v (between lmg/ml and 500mg/ml) of a compound of this invention. Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of 0.5 mgkg-1 to 20 mgkg-1 of a compound of this invention, the composition being administered 1 to 4 times per day. In another embodiment a daily dose of 5 mgkg-1 to 20 mgkg-1 0f a compound of this invention is administered. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
Alternatively the intravenous dose may be given by continuous infusion over a period of time.
Alternatively each patient may receive a daily oral dose which may be approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day. A pharmaceutical composition to be dosed intravenously may contain advantageously
(for example to enhance stability) a suitable bactericide, antioxidant or reducing agent, or a suitable sequestering agent.
In the above other, pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments of the compounds of the invention described herein also apply.
Antibacterial Activity :
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. Notably, the pharmaceutically-acceptable compounds of the present invention show activity against enterococci, pneumococci, methicillin resistant strains of S.aureus and coagulase negative staphylococci, haemophilus and moraxella strains. 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 and assessed in-vivo in conventional tests, for example by oral and/or intravenous dosing of a compound to a warm-blooded mammal using standard techniques.
The following results were obtained on a standard in-vitro test system. The activity is described in terms of the minimum inhibitory concentration (MIC) determined by the broth-dilution technique with an inoculum size of 5x10^ CFU/spot. Typically, compounds are active in the range 0.01 to 256 μg/ml. Staphylococci were tested in broth using an inoculum of 5x10^ CFU/spot and an incubation temperature of 37°C for 16-24hours.
Streptococci were tested in Mueller-Hinton broth supplemented with 2.5% clarified lake horse blood with an innoculum of 10^ CFU/well and an incubation temperature of 37°C aerobically for 24 hours.
Fastidious Gram negative organisms were tested in Mueller-Hinton broth supplemented with hemin and NAD, grown aerobically for 24h at 37°C, and with an innoculum of 5x10^ CFU/well.
Organism MIC (wε/ml Example 1
Staphylococcus aureus:
MSQS 2
MRQR 4 Streptococcus pneumoniae 1
Streptococcus pyogenes 2
Haemophilus influenzae 2
Moraxella catarrhalis 4
MSQS = methicillin sensitive and quinolone sensitive MRQR = methicillin resistant and quinolone resistant
The invention is now illustrated but not limited by the following Examples in which unless otherwise stated :- i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration;
(ii) operations were carried out at ambient temperature, that is typically in the range
18-26°C and in air unless otherwise stated, or unless the skilled person would otherwise work under an inert atmosphere; (iii) column chromatography (by the flash procedure) was used to purify compounds and was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated;
(iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the structure of the end-products of the formula (I) were generally confirmed by NMR and mass spectral techniques [proton magnetic resonance spectra were generally determined in DMSO-D6 unless otherwise stated using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz, or a Bruker AM250 spectrometer operating at a field strength of 5 250 MHz; chemical shifts are reported in parts per million downfield from tetramethysilane as an internal standard (δ scale) and peak multiplicities are shown thus: s, singlet; d, doublet; AB or dd, doublet of doublets; t, triplet, m, multiplet; fast-atom bombardment (FAB) mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were 0 collected];
(vi) intermediates were not generally fully characterised and purity was in general assessed by thin layer chromatographic, infra-red (IR), mass spectral (MS) or NMR analysis; and (vii) in which the following abbreviations may be used :- ®is a Trademark; DMFis N,N-dimethylformamide; DMA is N,N-dimethylacetamide;TLC is 5 thin layer chromatography; HPLC is high pressure liquid chromatography; MPLC is medium pressure liquid chromatography; DMSO is dimethylsulfoxide; DMSO-d6 is deuterated DMSO;
CDC13 is deuterated chloroform; MS is mass spectroscopy; ESP is electrospray; THF is tetrahydrofuran; TFA is trifluoroacetic acid; NMP is N-methylpyrrolidone; 0 HOBT is 1-hydroxy-benzotriazole; EtOAc is ethyl acetate; MeOH is methanol; phosphoryl is (HO)2~P(O)-Os phosphiryl is (HO)2-P-O-; EDC is l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (hydrochloride); PTSA is para-toluenesulfonic acid.
Examples
Example 1: N-r(5S)-13-r3-Fluoro-4- RS-l-imino-l-oxo-3.6-dihvdrothiopyran-4-yl)- phenyn-2-oxo-oxazolidin-5-ylmethyl|1-acetamide
Figure imgf000050_0001
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5- ylmethyl}]-acetamide, 1.05 g, 2.9 mmol) was dissolved/ suspended in dichloromethane (10 ml) at ambient temperature. O-Mesitylenesulfonylhydroxylamine (0.77 g, 3.6 mmol, see Synthesis, 1972, 140), in dichloromethane (10 ml) was added dropwise, and the mixture stirred at ambient temperature for 18 hours. The solvent was evaporated in vacuo and the reaction mixture taken up in dry ethanol (10 ml). The resulting precipitate was collected by filtration and recrystallized from water (10 ml), to give the desired product (0.93 g) as its mesitylene sulfonate salt. MS (APCD: 382 (MFf1") for Cι7H20FN3O4S 1H-NMR (DMSO-d6_) δ: 1.85 (s, 3H); 2.19 (s, 3H); 2.51 (s, 6H); 3.06 (m, 2H); 3.44 (m, 2H); 3.76 (dd, IH); 3.93 (m, IH); 4.01 (m, IH); 4.15 (dd, IH); 4.50 (m, 2H); 4.77 (m, IH); 5.92(dd, IH); 6.76 (s, 2H); 7.36 (dd, IH); 7.42 (dd, IH); 7.55 (dd, IH); 8.27 (dd, IH); 2 exchangeables not seen.
The intermediates for this compound were prepared as follows:
N-r(55)-{3-r3-FIuoro-4-(-fR5-l-oxo-3,6-dihydrothiopyran-4-vI)-phenvn-2-oxo-oxazolidin- 5-yImethylYl-acetamide
Figure imgf000050_0002
N-[(5S)-{3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5- ylmethyl}]-acetamide (1.25 g, 3.6 mmol) was stirred in a mixture of methanol and ethyl acetate (1: 1, 50 ml) at ambient temperature. Sodium periodate (0.95 g, 4.4 mmol) in water (10 ml) was added dropwise, and the mixture stirred for 18 hours. Brine (100 ml) was added, and the mixture extracted with ethyl acetate (8x 100 ml). The organic phase was separated, dried (magnesium sulfate), filtered and evaporated. The residue was chromatographed on silica gel, washing with 25% acetone in dichloromethane, then eluting with 5 to 7% methanol in dichloromethane to give the title product (1.215 g). MS (ESP): 367 (MΗ+) for C17H19FN2O4S 1H-NMR (DMSO-d ) δ: 1.85 (s, 3H); 2.58 (m, IH); 2.94 (m, 2H); 3.13 (m, IH); 3.40 (m,
IH); 3.43 (m, 2H); 3.67 (m, IH); 3.76 (dd, IH); 4.15 (dd, IH); 4.76 (m, IH); 5.84 (m, IH); 7.33 (dd, IH); 7.41 (dd, IH); 7.52 (dd, IH); 8.27 (dd, IH).
(5S)-{3-r4-(3,6-dihvdro-2H-thiopyran-4-yl)-3-fluorophenyn-2-oxo-oxazolidin-5- ylmethyl}] -acetamide
Figure imgf000051_0001
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-azidomethyl-2-oxazolidinone (2 g, 5.7 mmol) was dissolved in thiolacetic acid (5 ml) and it was stirred at room temperature under nitrogen for 5 hours. The solvent was evaporated in vacuo and the residue subjected to chromatography on silica gel eluting with 25% acetone in dichloromethane to give the title compound (1.50 g).
MS (ESP): 351 (MΗ+) for C17Η19FN2O3S
1H-NMR (DMSO-dή) δ: 1.85 (s, 3H); 2.56 (m, 2H); 2.83 (dd, 2H); 3.31 (m, 2H); 3.43 (dd,
2H); 3.75 (dd, IH); 4.14 (dd, IH); 4.75 (m, IH); 6.06(m, IH); 7.30 (dd, IH); 7.35 (dd, IH); 7.48 (dd, IH); 8.26 (dd, IH).
(5R -3-r4-(3,6-dihvdro-2H-thiopyran-4-yl)-3-fluorophenvIl-5-azidomethyl-2- oxazolidinone
Methanesulfonic acid (5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo- oxazolidin-5-ylmethyl ester (8 g, 19.7 mmol) and sodium azide (4 g, 61.5 mmol) were heated in N,N-dimethylformamide (75 ml) at 80°C for 2 hours. It was cooled to room temperature, diluted with ethyl acetate, washed with potassium phosphate buffer (pΗ 7) and with water and dried over sodium sulfate. After evaporation of the solvent the title product was obtained as a brown oil (~7 g, crude). 1H-NMR (DMSO-d^) δ: 2.56 (m, 2Η); 2.83 (dd, 2H); 3.31 (m, 2H); 3.71 (dd, IH); 3.80
(dd, IH); 3.81 (dd, IH); 4.17 (dd, IH); 4.92 (m, IH); 6.06(m, IH); 7.34 (m, 2H); 7.50 (m, IH). (No MS)
Methanesulfonic acid (5R)-3-[4-(3,6-dihvdro-2H-thiopyran-4-yl)-3-fluorophenvn-2-oxo- oxazolidin-5-ylmethyl ester
Figure imgf000052_0002
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-hydroxymethyl-2-oxazolidinone (14 g, 45.3 mmol) was dissolved in dichloromethane (300 ml) and triethylamine (8.8 ml, 63.3 mmol) was added. It was cooled to -20°C and methanesulfonyl chloride (4.22 ml, 54.4 mmol), dissolved in dichloromethane (50 ml), was added dropwise. The reaction mixture was allowed to warm to room temperature and was quenched with potassium phosphate buffer (pΗ 7). Dichloromethane was removed under vacuum and it was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The title compound (16.9 g) was precipitated from dichloromethane by addition of hexane. 1H-NMR (DMSO-d^ δ: 2.56 (m, 2H); 2.83 (dd, 2H); 3.28 (s, 3H); 3.32 (m, 2H); 3.85 (dd,
IH); 4.21 (dd, IH); 4.48 (dd, IH); 4.53 (dd, IH); 5.04 (m, IH); 6.07 (m, IH); 7.33 (dd, IH); 7.36 (dd, IH); 7.50 (dd, IH). (No MS)
(5R)-3-r4-(3,6-dihydro-2H-thiopyran-4-yl -3-fluorophenyn-5-hydroxymethyl-2- oxazolidinone
Figure imgf000053_0001
4-(2-Fluoro-4-benzyloxycarbonylaminophenyl)-3,6-dihydro-2H-thiopyran (15.3 g, 44.6 mM) was dissolved on dry tetrahydrofuran (175ml) and stirred under nitrogen at -70. /z-Butyllithium (1.6M in hexanes, 30ml, 175 mM) was run in over 20 minutes, keeping the temperature below -60°, and the mixture then stirred a further 10 minutes at -70°. A solution of (R)-glycidyl butyrate (6.42 g, 44.62 mM) dissolved in dry tetrahydrofuran (10 ml) was added dropwise over 10 minutes keeping temperature below -60°, and the mixture left to warm to ambient temperature over 18 hours. Methanol (29ml) was added, and the mixture stirred for 10 minutes only. Saturated aqueous sodium bicarbonate (200 ml) was added, and the mixture extracted with ethyl acetate (400 ml). The extract was washed with saturated aqueous sodium bicarbonate (100ml), brine (100ml), dried (magnesium sulfate). Filtered and evaporated. The crude product was purified on a 300 g silica sinter column , eluting with a gradient from 0% to 100% ethyl acetate in dichloromethane. Relevant fractions were combined, reduced to a small volume, and diluted with an excess of ωσhexane to precipitate the desired product
(11-3 g).
MS (ESP): 310 (MΗ+) for C15Η16FNO3S
NMR (DMSO-d δ: 2.52 (m overlapped by DMSO, ~2H); 2.78 (t, 2H); 3.27 (m, 2H); 3.52 (m, IH); 3.65 (m, IH); 3.80 (dd, IH); 4.06 (dd, IH); 4.65 (m, IH); 5.19 (t, IH); 6.01 (s, IH); 7.28 ( , 2H); 7.47 (dd, IH). 4-(2-Fluoro-4-benzyloxycarbonylaminophenyl)-3.ι6-dihvdro-2H-thiopyran
Figure imgf000054_0001
4-(2-Fluoro-4-aminophenyl)-3,6-dihydro-2H-thiopyran (9.8 g, 46.8 mM) was dissolved in dry dichloromethane (196ml), pyridine (6.23g, 79.1 mM) added, and the mixture stirred under nitrogen at -20°. A solution of benzyl chloroformate (9.54g, 53.9 mM) dissolved in dry dichloromethane (25 ml) was added dropwise, and the mixture left to warm to ambient temperature over 18 hours. The mixture was washed with 1M hydrochloric acid (200 ml), then brine (100 ml), dried (magnesium sulfate), filtered and evaporated to a small volume. The addition of wohexane (300 ml) precipitated the desired product (15.5 g). MS (Negative ESP): 342 (M-Η") for C19Η18FNO2S NMR (DMSO-d ) δ: 2.50 (s, 2H); 2.79 (t, 2H); 3.26 (m, 2H); 5.15 (s, 2H); 5.99 (s, IH);
7.18 (m, 2H); 7.38 (m, 6H); 10.01 (s, IH).
4-(2-Fluoro-4-aminophenyl)-3,6-dihvdro-2H-thiopyran
Figure imgf000054_0002
4-Hydroxy-4-(2-fluoro-4-aminophenyl)tetrahydrothiopyran (11.35 g, 50 mM) and butylated hydroxytoluene (50 mg) as antioxidant were suspended in a mixture of concentrated hydrochloric acid (37%, 200 ml) and water (50 ml), and stirred at 80° under nitrogen for 18 hours. Glacial acetic acid (150 ml) was added, and reaction continued at 80° for a further 5 hours. After cooling, the reaction was made basic by the cautious addition of concentrated ammonia and ice. The mixture was extracted with diethyl ether (400 ml), the extract washed with water (100 ml), brine (100 ml), dried (magnesium sulfate), filtered and evaporated to give the title product (10 g) as a dark oil.
NMR (CDCM δ: 2.59 (m, 2H); 2.72 (t, 2H); 3.30 (m, 2H); 3.80 (br, 2H); 5.93 (m, IH); 6.35 (dd, IH); 6.39 (dd, IH); 6.97 (t, IH). No MS Example 2: N-r(5S)-{3-r3,5-Difluoro-4- RS-l-imino-l-oxo-3.6-dihydrothiopyran-4-yl)- phenyll -2-oxo-oxazolidin-5- ylmethylYl -acetamide
Figure imgf000055_0001
N-[(55)-{3-[3,5-Difluoro-4-(iRS-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin- 5-ylmethyl}]-acetamide, 0.425 g, 1.1 mmol) was dissolved in dichloromethane (20 ml) at ambient temperature. O-Mesitylenesulfonylhydroxylamine (297 mg, 1.4 mmol, see Synthesis, 1972, 140), in dichloromethane (3 ml) was added dropwise, and the mixture stirred at ambient temperature for 12 hours. The resulting precipitate was filtered, washed with dichloromethane and dried to give the desired product (0.6 g) as its mesitylene sulfonate salt. MS (ESP): 400 (MH+) for C17H19F2N3O4S
NMR (DMSO-d^) δ: 1.85 (s, 3H); 2.19 (s, 3H); 2.51 (overlapped by DMSO, ~6H); 2.95
(m, 2H); 3.40-3.50 (2H, overlapping with HDO); 3.75 (m, IH); 3.96 (m, IH); 4.07 (m, IH); 4.14 (dd, IH); 4.56 ( , 2H); 4.79 (m, IH); 5.88 (m, IH); 6.76 (s, 2H); 7.38 (d, 2H); 8.27 (m, IH). 2 exchangeables not seen; complex spectrum resulting from diastereomeric mixture.
The intermediates for this compound were prepared as follows:
N-r(5S)-{3-r3,5-Difluoro-4- RS-l-oxo-3,6-dihvdrothiopyran-4-yl)-phenyll-2-oxo- oxazolidin-5-ylmethylVl-acetamide
Figure imgf000055_0002
N-[(5S)-{3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluoro-phenyl]-2-oxo-oxazolidin-5- ylmethyl}]-acetamide (0.72 g, 2.0 mmol) was stirred in a mixture of methanol and ethyl acetate (1:1, 20 ml) at ambient temperature. Sodium periodate (0.44 g, 2.1 mmol) in water (10 ml) was added dropwise, and the mixture stirred for 3 hours. Precipitated salts were removed by filtration and washed with ethyl acetate. The filtrate was washed with brine, dried over magnesium sulfate and concentrated to dryness. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title product (0.65 g). MS (ESP): 385.2 (MH+) for C17H18F2N2O4S 1H-NMR (DMSO-dg) δ: 1.85 (s, 3H); 2.44 (m, lH); 2.80 ( m, lH); 3.00 (m, lH); 3.13 (m,
IH); 3.40 ( m, lH); 3.44 (m, 2H); 3.70 (m, IH); 3.81 (m, IH); 4.14 (dd, IH); 4.80 (m, IH); 5.78 (brs, IH); 7.36 (d, 2H); 8.45 (m, IH).
(55)-{3-r4-(3,6-dihvdro-2H-thiopyran-4-yl)-3,5-difluorophenvn-2-oxo-oxazolidin-5- ylmethvUI-acetamide
Figure imgf000056_0001
Methanesulfonic acid (5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo- oxazolidin-5-ylmethyl ester (1.1 g, 2.7 mmol) and sodium azide (0.35 g, 5.4 mmol) were heated in N,N-dimethylformamide (5 ml) at 60°C for 18 hours. It was cooled to room temperature, diluted with ethyl acetate, washed with water and dried over magnesium sulfate.
The solvent was removed in vacuo and the residue (containing crude intermediate azide, not characterized) taken up in thiolacetic acid (10 ml). It was stirred at room temperature for 4 hours, then concentrated in vacuo and subjected to chromatography on silica gel eluting with
5% methanol in dichloromethane to give the title compound (0.73 g).
MS (ESP): 369 (MΗ+) for C17Hι8F2N2O3S
1H-NMR (CDC ) δ: 2.05 (s, 3H); 2.54 (brs, 2H); 2.88 (m, 2H); 3.35 (m, 2H); 3.70 (m,
2H); 3.78 (m, IH); 4.04 (dd, IH); 4.82 (m, IH); 5.96 (m, IH); 6.31 (m, IH); 7.12 (d, 2H).
Methanesulfonic acid (5R)-3-[4-(3-,6-dihydro-2H-thiopyran-4-yl)-3.,5-difluorophenyn-2- oxo-oxazoIidin-5-ylmethyl ester
Figure imgf000057_0001
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-hydroxymethyl-2-oxazolidin one (4.0 g, 12.2 mmol) was dissolved in dichloromethane (50 ml) and triethylamine (1.85 g, 18.3 mmol) was added. Methanesulfonyl chloride (1.68 g, 14.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. It was washed with saturated aqueous sodium hydrogencarbonate solution, then with brine and dried over sodium sulfate. The solvent was removed under vacuum and the title compound (5.0 g) was precipitated from dichloromethane by addition of hexanes. NMR (DMSO-dfi) δ: 2.44 (m, 2Η); 2.84 (dd, 2H); 3.28 (s, 3H); 3.31 (m, 2H); 3.86 (dd, IH); 4.20 (dd, IH); 4.50 (m, 2H); 5.10 (m, lH); 5.99 (m, IH); 7.36 (d, 2H). (No MS)
(5R)-3-r4-(3,6-dihvdro-2H-thiopyran-4-yl)-3,5-difluorophenvn-5-hydroxymethyl-2- oxazolidinone
Figure imgf000057_0002
4-(2,6-Difluoro-4-benzyloxycarbonylaminophenyl)-3,6-dihydiO-2H-thiopyran (22 g, 61 mM) was reacted with (R)-glycidyl butyrate under essentially the following conditions: material was dissolved in dry tetrahydrofuran (150 ml), and stirred under nitrogen at -70°. ft-Butyllithium (1.6M in hexanes, 26 ml, 41.6 mM) was run in over 20 minutes, keeping the temperature below -60°, and the mixture then stirred a further 10 minutes at -70°. A solution of (R)-glycidyl butyrate (5.59 g, 38.8 mM) dissolved in dry tetrahydrofuran (10 ml) was added dropwise over 10 minutes keeping temperature below -60°, and the mixture left to warm to ambient temperature over 18 hours. Methanol (25 ml) was added, and the mixture stirred for 10 minutes only. Saturated aqueous sodium bicarbonate (200 ml) was added, and the mixture extracted with ethyl acetate (400 ml). The extract was washed with saturated aqueous sodium bicarbonate (100 ml), brine (100 ml), dried (magnesium sulfate), filtered and evaporated. Crude product from the final extraction was precipitated from dichloromethane by i-rohexane, then recrystallised from isopropanol to give the desired product (16.2 g). MS (ESP): 328 (MFf") for C15Hι5F2NO3S
NMR (DMSO-dg) δ: 2.40 (m, 2H); 2.81 (t, 2H); 3.28 (m, 2H); 3.53 (m, IH); 3.67 (m, IH); 3.82 (dd, IH); 4.08 (t, IH); 4.70 (m, IH); 5.21 (t, IH); 5.95 (s, IH); 7.33 (d, 2H).
4-(2,6-Difluoro-4-benzyloxycarbonylaminophenyl)-3.,6-dihydro-2H-thiopyran
Figure imgf000058_0001
4-(2,6-Difluoro-4-aminophenyl)-3,6-dihydro-2H-thiopyran (15 g, 66 mM) was treated with benzyl chloroformate under essentially the following conditions: material was dissolved in dry dichloromethane (175 ml), pyridine (5.57 g, 70.6 mM) added, and the mixture stirred under nitrogen at -20°. A solution of benzyl chloroformate (8.52 g, 49.9 mM) dissolved in dry dichloromethane (20 ml) was added dropwise, and the mixture left to warm to ambient temperature over 18 hours. The mixture was washed with 1M hydrochloric acid (200 ml), then brine (100 ml), dried (magnesium sulfate), filtered and evaporated to a small volume. The addition of isohexane (300 ml) precipitated the desired product. Similar treatment of the mother liquors from filtration gave more material; total yield (22.5 g). MS (Negative ESP): 360 (M-FT) for C19Η17F2NO2S
NMR (DMSO-ds) 8: 2.37 (br, 2H); 2.78 (t, 2H); 3.24 (m, 2H); 5.16 (s, 2H); 5.89 (m, IH); 7.17 (d, 2H); 7.38 (m, 5H); 10.18 (s, IH).
4-(2-,6-Difluoro-4-aminophenyl)-3,6-dihydro-2H-thiopyran
Figure imgf000058_0002
4-Hydroxy-4-(2,6-difluoro-4-aminophenyl)tetrahydrothiopyran (16.7 g, 68 mM) was treated with concentrated hydrochloric acid under essentially the following conditions: butylated hydroxytoluene (50 mg) used as antioxidant, materials were suspended in a mixture of concentrated hydrochloric acid (37%, 200 ml) and water (50 ml), and stirred at 80° under nitrogen for 18 hours. Glacial acetic acid (150 ml) was added, and reaction continued at 80° for a further 5 hours. After cooling, the reaction was made basic by the cautious addition of concentrated ammonia and ice. The mixture was extracted with diethyl ether (400 ml), the extract washed with water (100 ml), brine (100 ml), dried (magnesium sulfate), filtered and evaporated to give the title product (15.2 g) as a cream solid. MS (ESP): 228 (MH+) for CnHnFaNS NMR (CDCI δ: 2.48 (m, 2H); 2.83 (t, 2H); 3.30 (m, 2H); 3.80 (br, 2H); 5.87 (m, IH); 6.16 (d, 2H).
4-Hydroxy-4-(2,6-difluoro-4-aminophenyl)tetrahydrothiopyran
Figure imgf000059_0001
3,5-Difluoroaniline (12.9 g, 0.1 M) was reacted with tetrahydrothiopyran-4-one under essentially the following conditions (except that n-butyllithium was used to generate both anions): dissolved in dry tetrahydrofuran (400 ml), stirred under nitrogen, and cooled to -78°. H-Butyllithium (1.6M in hexanes, 131 ml, 0.21 M) was run in over 15 minutes, keeping the temperature below -65°, and the mixture then stirred a further 30 minutes at -70°. Chlorotrimethylsilane (22.8 g, 0.21 M) in tetrahydrofuran (100 ml) was added dropwise over 15 minutes, keeping the temperature below -65°, after which the temperature was allowed to rise to ambient, and stirring continued for 40 minutes to complete the silylation. The mixture was then recooled to -78°, and seobutyllithium (1.3M in cyclohexane, 84.3 ml, 0.11 M) added dropwise, and stirring continued at this temperature for 5 hours. A solution of tetrahydrothiopyran-4-one (12.5 g, 0.107 M) in tetrahydrofuran (80 ml) was added dropwise below -70°, and the temperature of the mixture allowed to come to ambient over 18 hours. After cooling in an ice-bath, the reaction was acidified with 1M hydrochloric acid to a pH <1 (-500 ml), stirred 15 minutes, diethyl ether (1 L) added, and the phases separated. The organic layer was washed with 1M hydrochloric acid (200 ml), the combined aqueous layers washed with diethyl ether (200 ml), then made basic with 880 ammonia plus a little ice, then re-extracted with diethyl ether (600 ml). The organic extract was washed with brine (300 ml), dried (magnesium sulfate), filtered and evaporated. Crude product was dissolved in hot dichloromethane (400 ml), evaporated to a low volume, then diluted with iso exane (300 ml). The desired product was precipitated from dichloromethane by zsohexane to give a white solid (17.4 g).
MS (Negative ESP): 244 ( -HT) for CπHι3F2NOS
NMR (CDCI3 δ: 2.26 (d, 2H); 2.39 (t, 4H); 2.65 (t, IH); 3.27 (t, 2H); 3.82 (br, 2H); 6.17 (d, 2H).
Example 3: N-r(55)-l3-[3-Fluoro-4- R5-l-(acetylimino)-l-oxo-3,6-dihvdrothiopyran-4- yl)-phenyI1-2-oxo-oxazolidin-5-ylmethyl}1-acetamide:
Figure imgf000060_0001
N-[(5S)-{ 3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.25 g, 0.43 mmol) was dissolved in pyridine (0.3 ml), dichloromethane (2 ml) was added and it was cooled to -20°C. Acetyl chloride (61 μl, 0.86 mmol) dissolved in dichloromethane (2 ml) was added dropwise and it was stirred for 1 h. It was quenched with phosphate buffer pH 7, extracted with ethyl acetate, washed with water (2 times) and dried over sodium sulfate. Chromatography on silica gel with 5% methanol in dichloromethane gave 0.161 g of the title compound.
MS (ESP): 423.82 (MET) for C19H22FN3O5S 1H-NMR (DMSO-dfi) δ: 8.27 (dd, IH); 7.53 (dd, IH); 7.42 (dd, IH); 7.34 (dd, IH); 5.87 (m, IH); 4.76 (m, IH); 4.40 (m, IH); 4.24 (m, IH); 4.15 (dd, IH); 3.76 (dd, IH); 3.71 (m, 2H); 3.43 (m, 2H); 2.96 (m, 2H); 1.99 (s, 3H); 1.85 (s, 3H).
Example 4; N-r(5S)-{3-r3-Fluoro-4- RS-l-(2-hydroxyacetylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyn-2-oxo-oxazolidm-5-ylmethyl>1-acetamide:
Figure imgf000061_0001
N-[(5S)-{ 3-[3-Fluoro-4-(2RS- l-(2-(acetyloxy)acetylimino)- l-oxo-3 ,6-dihydrothioρyran-4-yl)- phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide (0.22 g, 0.46 mmol) was dissolved in dry methanol (5 ml) and potassium carbonate (0.36 mmol) was added and it was stirred for 2 h at room temperature. It was neutralized over Amberlite CG-50-II weakly acidic ion exchange resin (FT1" -form), filtered and evaporated to dryness. Chromatography on silica gel with acetone gave 0.095 g of the title compound. MS (ESP): 440.2(MH+) for C19H22FN3O6S
1H-NMR (DMSO-d6) δ: 8.26 (dd, IH); 7.53 (dd, IH); 7.41 (dd, IH); 7.34 (dd, IH); 5.88 (m, IH); 4.82 (dd, IH); 4.75 (m, IH); 4.43 (m, IH); 4.29 (m, IH); 4.14 (dd, IH); 3.92 (d, 2H); 3.75 (m, 3H); 3.43 (m, 2H); 2.97 (m, 2H); 1.84 (s, 3H).
The intermediate for Example 4 was prepared as follows:
N-r(5S)-|3-r3-Fluoro-4- R5-l-(2-(acetoxy)acetylimino)-l-oxo-3,6-dihvdrothiopyran-4- yl)-phenvn-2-oxo-oxazolidin-5-yImethyl}1-acetamide:
Figure imgf000061_0002
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.27 g, 0.46 mmol) was reacted with 2-(acetoxy)acetyl chloride (92 μl, 0.86 mmol) following the procedure outlined for Example 3. Chromatography on silica gel with 5% methanol in dichloromethane gave 0.22 g of the title compound.
MS (ESP): 481.83 (MF ) for C2ιH24FN3O7S 1H-NMR (DMSO-dfi) δ: 8.26 (dd, IH); 7.53 (dd, IH); 7.42 (dd, IH); 7.34 (dd, IH); 5.86
(m, IH); 4.76 (m, IH); 4.53 (d, 2H); 4.40 (m, IH); 4.30 (m, IH); 4.15 (dd, IH); 3.80-3.74
(m, 3H); 3.43 (dd, 2H); 2.97 (m, 2H); 2.08 (s, 3H); 1.84 (s, 3H). Example 5; N-r(55)-{3-r3-Fluoro-4- RS-l-(2-hvdroχy-2-methylpropionvIimino)-l-oxo- 3,6-dihvdrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethyl}1-acetamide:
Figure imgf000062_0001
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(2-acetoxy-2-methylpropionylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide (Example 6) (0.283 g, 0.55 mmol) was converted to the title compound following the procedure described for
Example 4. Chromatography on silica gel with acetone/hexane 2:1 to acetone gave 0.119 g of the title compound.
MS (ESP): 468.3 (MFT) for C2ιH26FN3O6S
1H-NMR (DMSO-d6) δ: 8.25 (dd, IH); 7.52 (dd, IH); 7.38 (dd, IH); 7.34 (dd, IH); 5.84
(m, IH); 4.75 (m, IH); 4.52 (s, IH); 4.46 (m, IH); 4.29 (m, IH); 4.14 (dd, IH); 3.78-3.70
(m, 3H); 3.43 (dd, 2H); 2.98 (m, 2H);' 1.85 (s, 3H); 1.28 (s, 3H); 1.27 (s, 3H).
The intermediate for Example 5 was prepared as follows:
Example 6: N-r(55)-{3-r3-Fluoro-4-(JR5-l-(2-acetoxy-2-methylpropionylimino)-l-oxo- 3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazoIidin-5-ylmethyl}]-acetamide
Figure imgf000062_0002
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothioρyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.45 g, 0.77 mmol) was reacted with 1-chlorocarbonyl-l-methyl-ethylacetate (200 μl, 1.38 mmol) following the procedure outlined for Example 3. Chromatography on silica gel with acetone/hexane 2:1 gave 0.308 g of the title compound. MS (ESP): 510.2 (MH÷) for C23H28FN3O7S
1H-NMR (DMSO-d/Λ δ: 8.26 (dd, IH); 7.52 (dd, IH); 7.41 (dd, IH); 7.34 (dd, IH); 5.82 (m, IH); 4.75 (m, IH); 4.34 (m, IH); 4.24 (m, IH); 3.81-3.70 (m, 3H); 3.43 (dd, 2H); 2.96 (m, 2H); 1.93 (s, 3H); 1.85 (s, 3H); 1.46 (s, 3H); 1.45 (s, 3H).
Example 7: N-r(55)-{3-r3-Fluoro-4- R5-l-((25)-2-hydroxy-propionylimino)-l-oxo-3,6- dihvdrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethyin-acetamide
Figure imgf000063_0001
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-((2S)-2-acetoxy-propionylimino)-l-oxo-3,6-dihydrothiopyran- 4-yl)-ρhenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide (Example 8) (0.292 g, 0.59 mmol) was converted to the title compound following the procedure described for Example 4. Chromatography on silica gel with acetone/hexane 2:1 to acetone gave 0.194 g of the title compound.
MS (ESP): 454.24 (MH1") for C20H24FN3O6S
1H-NMR (DMSO-dfi) δ: 8.25 (dd, 2H); 7.52 (dd, 2H); 7.39 (dd, 2H); 7.34 (dd, 2H); 5.85 (m, 2H); 4.76 (m, 2H); 4.73 (dd, 2H); 4.48 (m, IH); 4.40 (m, IH); 4.29 (m, 2H); 4.14 (dd, 2H); 4.02 (m, 2H); 3.82-3.71 (m, 6H); 3.43 (dd, 4H); 3.03-2.90 (m, 4H); 1.85 (s, 6H); 1.24 (d, 3H); 1.22 (d, 3H). (The two diastereomers did show some differences in chemical shifts; integration indicated a 1:1 ratio).
The intermediate for Example 7 was prepared as follows:
Example 8; N-r(55)-{3-r3-Fluoro-4- RS-l-((2S)-2-acetoxy-propionylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethyl}1-acetamide
Figure imgf000064_0001
N-[(5S)-{3-[3-Fluoro-4-(2RS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.46 g, 0.79 mmol) was reacted with S-2-acetoxypropionylchloride (200 μl, 1.58 mmol) following the procedure outlined for Example 3. Chromatography on silica gel with acetone/hexane 2:1 gave 0.316 g of the title compound. MS (ESP): 495.81 (MFf") for C22H26FN3O7S
1H-NMR (DMSO-dfi) δ: 8.26 (dd, 2H); 7.53 (dd, 2H); 7.40 (m, 2H); 7.34 (dd, 2H); 5.83 (m, 2H); 4.86 (m, 2H); 4.76 (m, 2H); 4.45 (m, IH); 4.37-4.24 (m, 3H); 4.14 (dd, 2H); 3.88-3.74 (m, 6H); 3.43 (dd, 4H); 3.03-2.90 (m, 4H); 2.04 (s, 3H); 2.03 (s, 3H); 1.85 (s, 6H); 1.38 (d, 3H); 1.37 (d, 3H). (The two diastereomers did show some differences in chemical shifts; integration indicated a 1:1 ratio).
Example 9: N-r(5S)-{3-r3-Fluoro-4-(iRS-l-((<2?R)-α-formyloxy-benzeneacetimino)-l-oxo- 3,6-dihvdrothiopyran-4-yl)-phenyn-2-oxo-oxazolidin-5-ylmethyin-acetamide
Figure imgf000064_0002
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-ρhenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.40 g, 0.69 mmol) was reacted with R-(-)-O-formylmandeloyl chloride (273 μl, 1.75 mmol) following the procedure outlined for Example 3. Chromatography on silica gel with acetone/hexane 2:1 gave 0.370 g of the title compound.
MS (ESP): 544.2 (MH+) for C26H26FN3O7S 1H-NMR (DMSO-dr.) δ: 8.39 (d, IH); 8.38 (d, IH); 8.27 (dd, 2H); 7.54-7.46 (m, 6H); 7.36-
7.31 (m, 8H); 7.22 (m, 2H); 5.91 (s, IH); 5.90 (s, IH); 5.77 (m, 2H); 4.76 (m, 2H); 4.45- 4.25 (m, 4H); 4.15 (2xdd, 2H); 3.85-3.74 ( , 6H); 3.44 (dd, 4H); 2.92-2.63 (m, 4H); 1.85 (s, 6H). (The two diastereomers did show some differences in chemical shifts; integration indicated a 1:1 ratio).
Example 10; N-r(55)-{3-r3.5-Difluoro-4-qR5-l-(methylsulfonylimino)-l-oxo-3,6- dihvdrothiopyran-4-yl)-phenyll-2-oxo-oxazolidin-5-ylmethyl}l-acetamide:
Figure imgf000065_0001
N-[(5S)-{3-[3,5-Difluoro-4-(2RS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 2) as its mesitylene sulfonate salt (0.94 g, 1.57 mmol) was reacted with methanesulfonyl chloride (155 μl, 2.0 mmol) following the procedure outlined for Example 3. Purification by RP-HPLC with acetonitrile/water containing 1% TFA gave 0.256 g of the title compound.
MS (ESP): 478.0 (MH+) for C18H21F2N3O6S2 1H-NMR (DMSO-dfi) δ: 8.25 (dd, IH); 7.38 (m, 2H); 5.84 (m, IH); 4.78 (m, IH); 4.55 (m,
IH); 4.40 (m, lH); 4.14 (dd, IH); 3.85 (m, 2H); 3.75 (dd, IH); 3.43 (m, 2H); 3.06 (s, 3H);
2.92 (m, 2H); 1.85 (s, 3H).
Example 11 : N- 5S)-{3- r3,5-Difluoro-4- (IRS- 1- (5-isoxazolecarboximino)- l-oχo-3,6- dihvdrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethyl}1-acetamide:
Figure imgf000065_0002
N-[(5S)- { 3- [3 ,5-Difluoro-4-(7RS- 1 -imino- l-oxo-3 ,6-dihydrothioρyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.493 g, 0.82 mmol) was reacted with isoxazole-5-carbonylchloride (0.13 g, 0.97mmol) following the procedure outlined for Example 3. The crude product was recrystallized from ethylacetate/ dichloromethane/ hexane to give 0.169 g of the title compound as a slightly off white solid. MS (ESP : 495.2 (MH*) for C2ιH20F2N4O6S
1H-NMR (DMSO-dfi) δ: 8.74 (d, IH); 8.25 (dd, IH); 7.36 (m, 2H); 7.03 (d, IH); 5.85 (m, IH); 4.78 (m, IH); 4.65 (m, IH); 4.55 (m, IH); 4.12 (dd, IH); 3.94 (m, 2H); 3.74 (dd, IH); 3.43 (m, 2H); 2.94 (m, 2H); 1.85 (s, 3H).
Example 12: N-r(5S)-{3-r3-Fiuoro-4-qRS-l-((ethoxycarbonyl)imino)-l-oxo-3.6- dihvdrothiopyran-4-vi)-phenvn-2-oxo-oxazolidin-5-yImethyl}]-acetamide:
Figure imgf000066_0001
N- [(5S)- { 3 - [3 -Fluoro-4-( RS- 1 -imino- 1 -oxo-3 ,6-dihydrothiopyran-4-yl)-phenyl] -2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) (120mg, 0.32 mmol) was reacted with ethyl chloridocarbonate (45mg, 0.42mmol) following the procedure outlined for Example 3 to give 159mg of the title compound as a slightly off-white solid. MS (ESP): 454.2(MH+) for C20H24FN3O6S
1H-NMR (CDC1 δ: 7.51 (dd, IH); 7.26 (dd, IH); 7.20 (dd, IH); 5.95 (dd, IH); 5.82 (dd, IH); 4.82 (m, IH); 4.45 (m, IH); 4.19 (m, 2H); 4.10 (m, 2H); 3.82 (m, IH); 3.6-3.80 (m, 3H); 3.55 (m, IH); 3.10 (m, 2H); 2.05 (s, 3H); 1.34 (t, 3H).
Example 13; N-r(55)-{3-r3-Fluoro-4- RS-l-(4-(3,5-dimethylisoxazole)-sulfonylimino)-l- oxo-3,6-dihvdrothiopyran-4-yl)-phenvn-2-oxo-oxazolidin-5-ylmethy l-acetamide
Figure imgf000066_0002
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.26 g, 0.45 mmol) was reacted with 3,5-dimethylisoxazole-4-sulfonyl chloride (0.105 g, 0.53 mmol) following the procedure outlined for Example 3 to give 0.078 g of the title compound as a slightly yellowish solid. MS (ESP): 422.4(MH+) for C22H25FN4O7S2
1H-NMR (DMSO-dfi) δ: 8.25 (dd, IH); 7.55 (dd, IH); 7.40 (m, 2H); 5.89 (m, IH); 4.76 (m, IH); 4.45 (m, 2H); 4.10 (m, IH); 3.89 (m, 2H); 3.76 (m, IH); 3.44 (m, 2H); 3.05 (m, 2H); 2.60 (s, 3H); 2.37 (s, 3H); 1.85(s, 3H).
Example 14: N-r(5S)-{3-r3-Fluoro-4- RS-l-(((ethylamino)carbonyl)imino)-l-oxo-3,6- dihvdrothiopyran-4-yl)-phenyπ-2-oxo-oxazolidin-5-ylmethyI}1-acetamide:
Figure imgf000067_0001
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothioρyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.36 g, 0.62 mmol) was reacted with ethyl-isocyanate (53mg, 0.74 mmol) following the procedure outlined for Example 3 to give 0.27 g of the title compound.
MS (ESP): 453.4(MH+) for C20H25FN4O5S
1H-NMR (DMSO-d6) δ: 7.53 (dd, IH); 7.40 (m, IH); 7.33 (dd, IH); 6.77 (m, IH); 5.88 (m, IH); 4.76 (m, IH); 4.45 (m, IH); 4.10 (m, 2H); 3.76 (m, IH); 3.65 (m, 2H); 3.43 (m, 2H);
3.0 (m, 2H); 2.94 (m, 2H); 1.85(s, 3H); 1.01 (t, 3H).
Example 15: N-r(5S)-l3-r3-Fluoro-4-qRS-l-(ethenesulfonylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenvI1-2-oxo-oxazoIidin-5-ylmethylH-acetamide:
Figure imgf000067_0002
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.73 g, 1.26 mmol) was reacted with 2-chloroethanesulfonyl chloride (0.266 g, 1.63 mmol) following the procedure outlined for Example 3 to give 0.556 g of the title compound. MS (ESP): 472.2(MH+) for C19H22FN3O6S2
1H-NMR (GDCW) δ: 7.51 (dd, IH); 7.26 (dd, IH); 7.20 (dd, IH); 6.82 (dd, IH); 6.35 (d, IH); 6.22 (m, IH); 5.90 (d, IH); 5.82 (m, IH); 4.82 (m, IH); 4.45 (m, IH); 4.10 (m, 2H); 3.55-3.85 (m, 5H); 3.25 (m, IH); 3.12 (m, IH); 2.05 (s, 3H).
Example 16: N-r(5S)-{3-r3-Fluoro-4-(lR5-l-((2-amino)-ethanesulfonylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethyl>]-acetamide:
Figure imgf000068_0001
The above compound (Example 15) (13mg, 0.028mmol) was dissolved in ethanol followed by the addition of hydroxylamine water solution (30%, lOeq), the reaction mixture was stirred for 2 hr at room temperature. Solvent was removed under vacuum and the residue was purified by HPLC(C-18) with acetonitrile/water containing 1% TFA to give 10 mg of the title compound.
MS (ESP): 489.2 (MH÷) for C19H25FN4O6S2
1H-NMR (DMSO-dg) δ: 8.26 (dd, IH); 7.53 (dd, IH); 7.42 (dd, IH); 7.35 ( dd, IH); 5.92 (m, IH); 4.76 (m, IH); 4.50 (m, IH); 4.40 (m, IH); 4.15 (dd, IH); 3.89 (m, 2H); 3.76 (dd, IH); 3.7-3.40 (m, 6H) (overlapping with H2O in DMSO); 3.44 (m, 2H); 3.06 (m, 2H); 1.85 (s, 3H).
Example 17: N-r(55)-{3-r3-Fluoro-4- RS-l-((prop-2-ene-l-oχycarbonyl)imino)-l-oxo- 3,6-dihvdrothiopyran-4-yl)-phenvn-2-oxo-oxazolidin-5-ylmethyl}1-acetamide:
Figure imgf000069_0001
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.5 g, 0.86 mmol) was reacted with allyl chloridocarbonate (0.155 g, 1.29 mmol) following the procedure outlined for Example 3 to give 0.394 g of the title compound. MS (ESP): 466.4(MH+) for C2iH24FN3O6S
1H-NMR (CDC1 δ: 7.51 (dd, IH); 7.26 (dd, IH); 7.20 (dd, IH); 5.98 (m, IH); 5.95 (m, IH); 5.83 (dd, IH); 5.40 (dd,lH); 5.24 (dd,lH); 4.82 (m, IH); 4.65 (m, 2H); 4.45 (m, IH); 4.10 (m, 2H); 3.82 (m, IH); 3.6-3.80 (m, 3H); 3.55 (m, IH); 3.13 (m, 2H); 2.05 (s, 3H).
Example 18: N-r(55)-{3-r3-Fluoro-4-qR5-l-(2-propenylimino)-l-oxo-3,6- dihvdrothiopyran-4-yl)-phenyll-2-oxo-oxazolidin-5-ylmethv 1-acetamide:
Figure imgf000069_0002
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) (50 mg, 0.13 mmol), allyl bromide (24 mg, 0.20mmol) and sodium carbonate (excess) were mixed in 10 ml of anhydrous acetonitrile, followed by the addition of silver triflate ( 33 mg, 0.13mmol). The mixture was refluxed for 48 hours, cooled down to room temperature, filtered through celite and concentrated to give a residue which was further purified by chromatography with 5% methanol in dichloromethane to give 35 mg of the title compound. MS (ESP): 422.4(MH+) for C2oH24FN3O4S
1H-NMR (DMSO-dfi) δ: 8.25 (dd, IH); 7.55 (dd, IH); 7.40 (dd, IH); 7.32 (dd, IH); 5.90 (m, 2H); 5.35 (dd, IH); 5.15 (dd, IH); 4.76 (m, IH); 4.45 (m, 3H); 4.10 (dd, 2H); 3.89 (m, 2H); 3.76 (m, IH); 3.45 (m, 2H); 3.0 (m, 2H); 1.83(s, 3H).
Example 19: N-r(5S)-13-r3-FIuoro-4- RS-l-(((2-propylamino)carbonyI)imino)-l-oxo-3,6- dihvdrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethyl>1-acetamide:
Figure imgf000070_0001
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.3 g, 0.52 mmol) was reacted with isopropyl-isocyanate (66mg, 0.77 mmol) following the procedure outlined for Example 3 to give 0.267 g of the title compound.
MS (ESP): 467.36(MH+) for C2ιH27FN4O5S
1H-NMR (DMSO-dg) δ: 8.25 (dd, IH); 7.53 (dd, IH); 7.40 (m, IH); 7.33 (dd, IH); 6.77 (m, IH); 5.88 (m, IH); 4.76 (m, IH); 4.45 (m, IH); 4.10 (m, 2H); 3.76 (m, IH); 3.65 (m,
3H); 3.38 (m, 2H); 2.95 (m, 2H); 1.85(s, 3H); 1.04 (d, 6H).
Example 20: N-r(5S)-|3-r3-Fluoro-4-qRS-l-(methylsulfonylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethylH-acetamide:
Figure imgf000070_0002
N-[(5S)-{3-[3-FluoiO-4-(iRS-l-irnino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.25 g, 0.43 mmol) was reacted with methanesulfonyl chloride (98.5mg, 0.86 mmol) following the procedure outlined for Example 3 to give 0.165 g of the title compound. MS (ESP): 459.9(MH+) for Cι8H22FN3O6S2 1H-NMR (CDC1 δ: 7.51 (dd, IH); 7.27 (dd, IH); 7.21 (dd, IH); 5.95 (dd, IH); 5.82 (dd, IH); 4.82 (m, lH); 4.45 (m, IH); 4.10 (m, 2H); 3.55-3.83 (m, 5H); 3.22 (m, 2H); 3.20 (m, 3H); 2.05 (s, 3H).
Example 21: N-r(55)-{3-r3-Fluoro-4- R5-l-(ethylsulfonylimino)-l-oxo-3.6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazoIidin-5-ylmethyl)1-acetamide:
Figure imgf000071_0001
N-[(5S)-{3-[3-Fluoro-4-(2RS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Examplel) as its mesitylene sulfonate salt (0.26 g, 0.45 mmol) was reacted with ethanesulfonyl chloride (68mg, 0.53 mmol) following the procedure outlined for Example 3 to give 0.2 g of the title compound. MS (ESP): 474.3(MH+) for Cι9H24FN3O6S2 1H-NMR (CDCh) δ: 7.51 (dd, IH); 7.26 (dd, IH); 7.20 (dd, IH); 6.07 (dd, IH); 5.82 (dd, IH); 4.82 (m, IH); 4.45 (m, IH); 4.10 (m, 2H); 3.55-3.85 (m, 5H); 3.25 (q, 2H); 3.22 (m, IH); 3.10 (m, IH); 2.05 (s, 3H); 1.46 (t, 3H).
Example 22: N-r(5S)-{3-r3.5-Difluoro-4- R5-l-(acetylimino)-l-oxo-3.6- dihydrothiopyran-4-yl)-phenyIl-2-oxo-oxazolidin-5-ylmethyl}l-acetamide:
Figure imgf000071_0002
N-[(5S)-{3-[3,5-Difluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-ρhenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 2) as its mesitylene sulfonate salt (0.165 g, 0.275 mmol) was reacted with acetyl chloride (43 mg, 0.55 mmol) following the procedure outlined for Example 3 to give 0.11 g of the title compound. MS (ESP): 441.78 (MH+) for C19H2ιF2N3O5S
1H-NMR (DMSO-dfi) δ: 8.25 (dd, IH); 7.38 (m, 2H); 5.84 (m, IH); 4.80 (m, IH); 4.45 (m, IH); 4.30 (m, IH); 4.14 (dd, IH); 3.75 (m, 2H); 3.43 (m, 2H); 3.33 ( m, IH); 2.85 (m, 2H); 1.97 (s, 3H); 1.85 (s, 3H).
Example 23: N-r(5S)-{3-r3-Fluoro-4- RS-l-(((methylamino)carbonyl)imino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethvU1-acetamide:
Figure imgf000072_0001
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothioρyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.3 g, 0.52 mmol) was reacted with methyl isocyanate (58mg, 1.02 mmol) following the procedure outlined for Example 3 to give 0.196 g of the title compound. MS (ESP): 439.4(MH+) for C19H23FN4O5S
1H-NMR (DMSO-d, δ: 8.25 (dd, IH); 7.54 (dd, IH); 7.40 dd, IH); 7.32 (dd, IH); 6.77 (m, IH); 5.86 (m, IH); 4.76 (m, IH); 4.45 (m, IH); 4.14 (m, 2H); 3.76 (m, IH); 3.60 (m, 2H); 3.43 (m, 2H); 2.94 (m, 2H); 2.51 (d, 3H); 1.85(s, 3H).
Example 24: N-r(55)-{3-r3-Fluoro-4-qR5-l-(2-propylsulfonylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyll-2-oxo-oxazoIidin-5-ylmethvI|l-acetamide:
Figure imgf000072_0002
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.25 g, 0.43 mmol) was reacted with isopropylsulfonyl chloride (0.123 g, 0.86 mmol) following the procedure outlined for Example 3 to give 72 mg of the title compound. MS (ESP): 488.2(MH+) for C20H26FN3O«5S2 1H-NMR (CDCI δ: 7.51 (dd, IH); 7.26 (dd, IH); 7.20 (dd, IH); 6.00 (m, IH); 5.82 (m, IH); 4.82 (m, IH); 4.45 (m, IH); 4.10 (m, 2H); 3.55-3.85 (m, 5H); 3.33 (m, IH); 3.22 (m, IH); 3.10 (m, IH); 2.05 (s, 3H); 1.46 (d, 6H).
Example 25: N-r(55)-{3-r3.5-Difluoro-4- RS-l-(2-hvdroxyacetylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenvn-2-oxo-oxazolidin-5-ylmethyl}1-acetamide:
Figure imgf000073_0001
N- [(55)- { 3-[3 ,5-Difluoro-4-(7RS- 1 -imino- 1 -oxo-3 ,6-dihydrothioρyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 2) as its mesitylene sulfonate salt (0.225 g, 0.375 mmol) was reacted with acetyloxyacetyl chloride (0.103 g, 0.75mmol) following the procedure outlined for Example 3. This intermediate was dissolved in methanol (15 ml), catalytic amount of potassium carbonate was added and the mixture was stirred at room temperature for 3 hours. Ammonium chloride (leq.) was added, the solvent was evaporated and the residue was purified by flash chromatography with acetone to give 65 mg of the title compound as white solid. MS (ESP): 458.2(MH+) for C19H21F2N3O6S
1H-NMR (CDCI δ: 7.20 (d, 2H); 6.28 (dd, IH); 5.80 (d, IH); 4.82 (m, IH); 4.45 (m, IH); 4.18 (s, 2H); 4.10 (m, IH); 4.02 (dd, IH); 3.70-3.85 (m, 4H); 3.52 (m, IH); 3.03 (m, 2H); 2.05 (s, 3H). (The resonance for OH was not observed).
Example 26: N-r(55)-{3-r3-Fluoro-4-qRS-l-((2-methylprop-l-yl-oxycarbonyl)imino)-l- oxo-3,6-dihvdrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethyll1-acetamide:
Figure imgf000074_0001
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.3 g, 0.52 mmol) was reacted with isobutyl chloridocarbonate (0.107 g, 0.78 mmol) following the procedure outlined for Example 3 to give 0.213 g of the title compound. MS (ESP): 482.3(MH+) for C22H2sFN3O6S
1H-NMR (CDCI δ: 7.51 (dd, IH); 7.26 (dd, IH); 7.20 (dd, IH); 5.96 (m, IH); 5.82 (m, IH); 4.82 (m, IH); 4.45 ( , IH); 4.07 (m, 2H); 3.92 ( , 2H); 3.87 ( , IH); 3.60-3.80 ( , 3H); 3.55 (m, IH); 3.13 (m, 2H); 2.05 (s, 3H); 2.0 (m, IH); 0.98 (d, 6H).
Example 27: N-[(5S)-{3-r3-Fluoro-4- R5-l-(((2-methoxy)ethoxycarbonyl)imino)-l-oxo- 3,6-dihvdrothiopyran-4-yl)-phenvn-2-oxo-oxazolidin-5-ylmethyl>1-acetamide:
Figure imgf000074_0002
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) as its mesitylene sulfonate salt (0.3 g, 0.52 mmol) was reacted with 2-methylethylchloroformate (0.144 g, 1.04 mmol) following the procedure outlined for Example 3 to give 0.231 g of the title compound.
MS (ESP): 484.3(MH+) for C21H26FN3O7S
1H-NMR (CDC13) δ: 7.51 (dd, IH); 7.26 (dd, IH); 7.20 (dd, IH); 6.20 (m, IH); 5.82 ( , IH);
4.82 (m, IH); 4.50 (m, IH); 4.27 (m, 2H); 4.07 (m, 2H); 3.82 (m, IH); 3.6-3.75 (m, 5H);
3.55 (m, IH); 3.40 (s, 3H); 3.12 (m, 2H); 2.03 (s, 3H).
Example 28: N-r(5S)-{3-r3-Fluoro-4-qRS-l-((2S)-2-hvdroxy-3-(l-oxa- butoxy)propylimino)-l-oxo-3,6-dihvdrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5- ylmethvDI-acetamide:
Figure imgf000075_0001
A mixture of lithium perchlorate (0.106 g, 1 mmol) and (S)-(+)-glycidyl butyrate (0.144 g, 1 mmol) were dissolved in anhydrous acetonitrile (0.2 ml). Once the solution was formed, N- [(JS)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) (0.383 g, 1.0 mmol) was added followed by additional 0.8 ml of acetonitrile. The reaction mixture was stirred at 70°C for 24 hours, diluted with water, extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated to dryness. This residue was purified by flash chromatography with 5% methanol in dichloromethane to give 0.2 g of the title compound as a white solid. MS (ESP): 526.2(MH+) for C24H32FN3O7S 1H-NMR (CDC1 ) δ: 7.51 (dd, IH); 7.26 (dd, IH); 7.20 (dd, IH); 6.40 (m, IH); 5.80 (m, IH); 4.82 (m, IH); 4.20 (m, 2H); 4.07 (m, IH); 3.95 (m, 2H); 3.82 (m, 2H); 3.70 (m, 2H); 3.32 (m, 3H); 3.20 (m, IH); 3.05 (m, 3H); 2.32 (m, 2H); 2.03 (s, 3H); 1.68 (m, 2H); 0.97 (t, 3H).
Example 29: N-r(55)-{3-r3-Fluoro-4-qR5-l-((2R)-2-hvdroxy-3-(l-oxa- butoxy))propylimino)-l-oxo-3,6-dih.ydrothiopyran-4-yl)-phenyn-2-oxo-oxazoIidin-5- ylmethvUI-acetamide:
Figure imgf000075_0002
A mixture of lithium perchlorate (0.213 g, 2.0mmol) and (R)-(-)-glycidyl butyrate (0.288 g, 2.0mmol) were dissolved in anhydrous acetonitrile (0.4 ml). Once the solution was formed N- [(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide (Example 1) (0.383 g, 1.0 mmol) was added followed by additional 2.6 ml of acetonitrile. The reaction mixture was stirred at 70°C for 24 hours, then diluted with water, extracted with dichloromethane, the organic phase was dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was purified by flash chromatography with 5% methanol in dichloromethane to give 0.704 g of the title compound as a white solid.
MS (ESP): 526.2(MH+) for C24H32FN3O7S
1H-NMR (CDCh) δ: 7.51 (dd, IH); 7.26 (dd, IH); 7.20 (dd, IH); 6.40 (m, IH); 5.80 (m, IH); 4.82 (m, IH); 4.20 (m, 2H); 4.07 (m, IH); 3.95 (m, 2H); 3.82 (m, 2H); 3.70 (m, 2H); 3.32 (m, 3H); 3.20 (m, IH); 3.05 (m, 3H); 2.32 (m, 2H); 2.03 (s, 3H); 1.68 (m, 2H); 0.97 (t, 3H).
Example 30: N-r(5S)-{3-r3-Fluoro-4- RS-l-(((2R)-2,3-dihvdroxy)propylimino)-l-oxo- 3,6dihvdrothiopyran-4-yl)-phenyl1-2-oxo-oxazolidin-5-ylmethyl}1-acetamide:
Figure imgf000076_0001
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-((2R)-2-hydroxy-3-(l-oxa-butoxy))propylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide (Example 29) (0.43 g, 0.19mmol) was dissolved in 10 ml of methanol, catalytic amount of potassium carbonate was added and the mixture was stirred at room temperature for 3 hours. Ammonium chloride (leq.) was added, the solvent was evaporated and the residue was purified by flash chromatography with 10% methanol in dichloromethane to give 0.327 g of the title compound as a white solid.
MS (ESP): 422.4(MH+) for C2oH26FN3O6S
1H-NMR (DMSO-dfi) δ: 8.25 (dd, IH); 7.51 (dd, IH); 7.40 (dd, IH); 7.30 (dd, IH); 5.81 (m, IH); 5.78 (s, IH); 4.76 (m, IH); 4.45 (m, 2H); 4.10 (m, IH); 3.92 (m, IH); 3.89 (m, IH); 3.80 (m, lH); 3.48 (m, 4H); 2.80-3.10 (m, 4H); 1.85(s, 3H). Example 31: N-r(55)-13-r3-Fluoro-4- RS-l-(((25)-2.3-dihvdroxy)propylimino)-l-oxo- 3,6-dihydrothiopyran-4-yl)-phenvI1-2-oxo-oxazolidin-5-ylmethy l-acetamMe:
Figure imgf000077_0001
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-((2S)-2-hydroxy-3-(l-oxa-butoxy)propylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide (Example 28) (0.1 g, 0.82mmol) was dissolved in 15 ml of ethanol, catalytic amount of sodium carbonate was added and the mixture was stirred at room temperature for 3 hours. Ammonium chloride (leq.) was added, the solvent was evaporated and the residue was purified by flash chromatography with 10% methanol in dichloromethane to give 76 mg of the title compound as a white solid. MS (ESP): 422.4(MH+) for C2oH26FN3O6S
1H-NMR (DMSO-d6) δ: 8.25 (dd, IH); 7.51 (dd, IH); 7.40 (dd, IH); 7.30 (dd, IH); 5.81 (m, IH); 5.78 (s, IH); 4.76 (m, IH); 4.45 (m, 2H); 4.10 (m, IH); 3.92 (m, IH); 3.89 (m, IH); 3.80 (m, lH); 3.48 (m, 4H); 2.80-3.10 (m, 4H); 1.85(s, 3H).
Example 32: N-r(55)-{3-r3-Fluoro-4-αRS-l-((2-hvdroxy-2-methyl)propylimino)-l-oxo- 3,6-dihvdrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidm-5-ylmethyl}1-acetamide
Figure imgf000077_0002
A mixture of lithium perchlorate (106mg, lmmol) and isobutylene oxide (79mg, l.lmmol) was dissolved in 0.2 ml anhydrous acetonitrile in a sealed tube. Once the solution was formed, N-[(5S)-{3-[3-Fluoro-4-(2RS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-ρhenyl]-2- oxo-oxazolidin-5-ylmethyl}]-acetamide (Example 1) (0.382 g, 1.0 mmol) was added followed by additional 0.8 ml of acetonitrile. The tube was then sealed and the reaction mixture was stirred at 50°C for 24 hours. It was diluted with water, extracted with dichloromethane and the organic phase was dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was purified by flash chromatography with 5% methanol in dichloromethane to give 71 mg of the title compound as a white solid. MS (ESP): 454.2(MH+) for C2iH28FN3O5S 1H-NMR (DMSO-dfi) δ: 8.25 (dd, IH); 7.51 (dd, IH); 7.36 (m, 2H); 5.81 (m, IH); 5.78 (s, IH); 4.76 (m, IH); 4.12 (m, IH); 4.03 (m, 2H); 3.92 (m, IH); 3.82 (m, IH); 3.43 (m, 2H); 3.21 (m, lH); 2.82-3.05 (m, 4H); 1.85(s, 3H); 1.09 (d, 6H).

Claims

1. A compound of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo- hydrolysable ester thereof,
Figure imgf000079_0001
(I) wherein:
T is selected from the groups in (TA) & (TB); (TA) T is selected from the following groups (TAl) and (TA2) :-
Figure imgf000079_0002
(TAl) (TA2) wherein : in (TAl), is 0 or 1 and represents a chain of carbon atoms (optionally substituted as defined for ARl) of length oj and M is a bond joining the adjacent carbon atoms, or M represents one or two carbon atoms, and defines a 4- to 7-membered monocyclic ring, which ring may optionally have one of
(i) one double bond between any two ring carbon atoms; or (ii) a C1-C3 bridge connecting any two appropriate, non-adjacent ring carbon atoms, which bridge may optionally contain one heteroatom selected from oxygen or >NRc; or (iii) a C2-C5 cyclic moiety including a ring carbon atom to define a spiro C2-C5 ring system, which ring may optionally contain one heteroatom selected from oxygen or >NRc; or (iv) a C1-C4 bridge connecting adjacent carbon atoms to define a fused ring, wherein a C2- C4 bridge may optionally contain one heteroatom selected from oxygen or >NRc; wherein Re is as defined hereinafter; wherein in (TA2), ()ni and ()θi are independently 0, 1 or 2 and represent chains of carbon atoms (optionally substituted as defined for ARl) of length ni and Oi respectively, and define a 4- to 8-membered monocyclic ring, which ring may optionally have one of (i) a C1-C3 bridge connecting any two appropriate, non-adjacent ring carbon atoms, which bridge contains one heteroatom selected from oxygen or >NRc; or
(ii) a C2-C5 cyclic moiety including a ring carbon atom to define a spiro C2-C5 ring system, which ring may optionally contain one heteroatom selected from oxygen or >NRc; or (iii) a C1-C4 bridge connecting adjacent carbon atoms to define a fused ring, wherein a C2-C4 bridge may optionally contain one heteroatom selected from oxygen or >NRc; wherein Re is as defined hereinafter; or (TB) T is selected from the following groups (TB 1) to (TB3) :-
Figure imgf000080_0001
(TBl) (TB2)
Figure imgf000080_0002
(TB3) wherein ()nι, Qoi, ()nr, ()or; ()p\ and ()pr represent chains of carbon atoms (optionally substituted as defined for ARl hereinafter) of length n^ olt n , o , i and p respectively, and are independently 0-2, with the proviso that in (TBl) and (TB2) the sum of n1; o^ n and O does not exceed 8 (giving a maximum ring size of 14 in (TBl) and 11 in (TB2)), and in (TB3) the sum of n^ o1; nr, O , pt and pr does not exceed 6 (giving a maximum ring size of 12);
Xlm and X2m taken together represent R2S-(E)ms-N=; or Xim is O= and X2m is R2s-(E)ms- -, and vice versa; wherein E is an electron withdrawing group selected from -SO2-, -CO-, -O-CO-, -CO-O-, - CS-, -CON(Rs)-, -SO2N(Rs)-, or E may represent a group of the formula R3s-C(=N-O-R3s)- C(=O)-, wherein R3s is H or as defined in R2S at (i) below; or, when E is -CON(Rs)- or -SO2N(Rs)-, R2s and Rs may link together to form a carbon chain which defines a 5- or 6-membered saturated, unsaturated or partially unsaturated ring linked via the N atom in E, which ring is optionally further substituted by an oxo substituent, and which ring may be optionally fused with a phenyl group to form a benzo-fused system, wherein the phenyl group is optionally substituted by up to three substituents independently selected from halo, cyano, (l-4C)alkyl and (l-4C)alkoxy; ms is O or 1; except, wherein in (TAl) (other than as defined in (i) - (iv) above), in (TA2) (other than as defined in (i) - (iii) above), or in (TBl) when TBl is TBlb:
Figure imgf000081_0001
TBlb and Xlm is O= and X2m is R2S-(E)ms-N-, or vice versa,
R2s-(E)ms- may not be hydrogen, (l-4C)alkyl (optionally substituted as defined for Rp below),
-C(=O)(l-4C)alkyl (optionally substituted as defined for Rp below), -C(=O)O(l-4C)alkyl (optionally substituted as defined for Rp below), -C(=O)NHRp, -C(=S)NHRP, or para-toluene sulphonyl,
wherein Rp is hydrogen, (l-4C)alkyl (optionally substituted with one or more halo, cyano, nitro, phenyl, (3-6C)cycloalkyl, ORp2> C(=O)Rp2, OC(=O)Rp2, C(=O)ORp2, S(=O)mpRp2, S(=O)mpNRp2Rp2, NRp2S02Rp2, NRp2NSO2Rp2Rp2, NRp2C(=O)Rp2, C(=O)NRp2Rp2, NRp2Rp2, oxo or oxime) or phenyl, wherein RP2 is hydrogen, (l-4C)alkyl or phenyl, wherein at each occurrence phenyl is optionally substituted with one or more halo, cyano, nitro, phenyl, (3-6C)cycloalkyl, ORp2, C(=O)Rp2, OC(=O)Rp2, C(=O)ORp2, S(=O)mρRp2, S(=O)mpNRp2Rp2, NRp2SO2Rp2, NRp2NSO2Rp2RP2, NRp2C(=O)Rp2, C(=O)NRp2Rp2, or
NRp2Rp2, and mp is 0, 1 or 2;
R2s and Rs are independently selected from : (i) hydrogen (except where E is -SO2-or -O-CO-), or
(l-6C)alkyl {optionally substituted by one or more (l-4C)alkanoyl groups (including geminal disubstitution) and/or optionally monosubstituted by cyano, cyano-imino, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as defined for ARl hereinafter), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) hereinafter, (l-4C)alkylS(O)q- (q is 0, 1 or 2); and/or (with the proviso that where R2S is -SO2 or -O-CO- not on the first carbon atom of the (1-6C) alkyl chain) optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally further substituted, by no more than one of each of, oxo, - NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (1- 6C)alkanoylamino, (l-4C)alkoxycarbonylamino, N-(l-4C)alkyl-N-(l-6C)alkanoylamino, (1- 4C)alkylS(O)pNH- or (l-4C)alkylS(O)p.((l-4C)alkyl)N- (p is 1 or 2)}; or (ii) an optionally substituted aryl or optionally substituted heteroaryl group of the formula ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) hereinafter; or (where ms is 0 only);
(iii) cyano, -CO-NRvRw, -CO-NRv Rw', -SO2-NRvRw, -SO2-NRv Rw' [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl; Rw' is phenyl (optionally substituted as defined for ARl hereinafter), or a heteroaryl group selected from AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a (optionally substituted as defined hereinafter)], (l-4C)alkoxycarbonyl, trifluoromethyl, ethenyl, 2-(l-4C)alkylethenyl, 2-cyanoethenyl, 2- cyano-2-((l-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((l-4C)alkyl)ethenyl, 2-((l- 4C)alkylaminocarbonyl)ethenyl, 2-((l-4C)alkoxycarbonyl)ethenyl, 2-(ARl)ethenyl, 2- (AR2)ethenyl, or 2-(AR2a)ethenyl;
wherein Re is selected from groups (Rcl) to (Rc5) :-
(Rcl) optionally substituted (l-6C)alkyl;
(Rc2) R13CO- , R13SO2- or R13CS- wherein R13 is selected from (Rc2a) to (Rc2e) :-
(Rc2a) ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a and CY; (Rc2b) hydrogen, (l-4C)alkoxycarbonyl, trifluoromethyl, -NRvRw [wherein Rv is cyanoethenyl, 2-cyano-2-((l-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((l-4C)alkyl)ethenyl,
2-((l-4C)alkylaminocarbonyl)ethenyl, 2-((l-4C)alkoxycarbonyl)ethenyl, 2-(ARl)ethenyl, 2-(AR2)ethenyl, 2-(AR2a)ethenyl; (Rc2c) optionally substituted (l-lOC)alkyl;
(Rc2d) R14C(O)O(l-6C)alkyl wherein R1 is ARl, AR2, (l-4C)alkylamino (the (1-
4C)alkyl group being optionally substituted by (l-4C)alkoxycarbonyl or by carboxy), benzyloxy-(l-4C)alkyl or (l-lOC)alkyl {optionally substituted as defined for (Rc2c)};
(Rc2e) R15O- wherein R15 is benzyl, (l-6C)alkyl {optionally substituted as defined for
(Rc2c)}, CY, or AR2b;
(Rc3) hydrogen, cyano, 2-cyanoethenyl, 2-cyano-2-((l-4C)alkyl)ethenyl, 2-((l- 4C)alkylaminocarbonyl)ethenyl, 2-((l-4C)alkoxycarbonyl)ethenyl, 2-nitroethenyl, 2-nitro-2- (Q-4C)alkyl)ethenyl, 2-(ARl)ethenyl, 2-(AR2)ethenyl, or of the formula (Rc3a)
Figure imgf000083_0001
R16
(Rc3a) wherein X00 is -OR17, -SR17, -NHR17and -N(R17)2 ; wherein R17 is hydrogen (when X00 is -NHR17and -N(R17)2), and R17 is (l-4C)alkyl, phenyl or AR2 (when X00 is -OR17, -SR17 and -NHR17); and R16 is cyano, nitro, (l-4C)alkylsulfonyl, (4-
7C)cycloalkylsulfonyl, phenylsulfonyl, (l-4C)alkanoyl and (l-4C)alkoxycarbonyl;
(Rc4) trityl, ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b;
(Rc5) RdOC(Re)=CH(C=O)-, RfC(=O)C(=O)-, RgN=C(Rh)C(=O)- or
RiNHC(Rj)=CHC(=O)- wherein Rd is (l-6C)alkyl; Re is hydrogen or (l-6C)alkyl, or Rd and Re together form a (3-4C)alkylene chain; Rf is hydrogen, (l-6C)alkyl, hydroxy(l-6C)alkyl, (1-
6C)alkoxy(l-6C)alkyl, -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or
(l-4C)alkyl], (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-
4C)alkylamino(2-6C)alkoxy, di-(l-4C)alkylamino(2-6C)alkoxy; Rg is (l-6C)alkyl, hydroxy or
(l-6C)alkoxy; Rh is hydrogen or (l-6C)alkyl; Ri is hydrogen, (l-6C)alkyl, ARl, AR2, AR2a, AR2b and Rj is hydrogen or (l-6C)alkyl; wherein
CY is an optionally substituted cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl ring;
For the avoidance of doubt in the definition of (TAl) & (TA2) and (TB), it is to be understood that when R2S and Rs are independently selected from
(ii) (l-6C)alkyl {optionally substituted, for example, by no more than one of each of oxo and -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], to avoid duplication with the substituent -CO-NRvRw provided in section (iii) of the definition for R2s and Rs , then oxo and -NRvRw are not to be both selected together when (l-6C)alkyl is methyl; (HET)AR is a 5-6 membered aromatic or heteroaromatic ring, (i) when a 5-membered ring this may be a thiophene ring, comprising a single sulphur atom sited ortho to the nitrogen atom on the adjacent oxazolidinone ring, such a ring may have a single optional substituent Rl as hereinafter defined sited ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring, (ii) when a 6-membered ring this may be a phenyl ring or comprise a single nitrogen atom sited ortho to the nitrogen atom on the adjacent oxazolidinone ring, such ring may be optionally substituted at one or both positions ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring by Rl, where each
Rl is independently selected from hydrogen, halogen, methyl and methoxy, ethyl and ethoxy; Y is -NH-;
Z is hydrogen, -COR5 or -CSR5, wherein R5 is selected from: H, (l-6C)alkyl (optionally substituted with 1-4 halogen atoms), cyclopropyl, -O-(l-6C)alkyl, NH2 or NH-(1- 6C)alkyl or N-di((l-6C)alkyl).
2. A compound as claimed in claim 1, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof, wherein Z is hydrogen.
3. A compound as claimed in claim 1, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof, wherein Xlm and X2m taken together represent R2S-(E)ms-N= .
4. A compound as claimed in claim 1, or a pharmaceutically-acceptable salt, or an in-vivo- hydrolysable ester thereof, wherein in (TAl), ()°ι is 0 or 1 and represents a chain of carbon atoms (optionally substituted as defined for ARl) of length Oi and M is a bond joining the adjacent carbon atoms, or M represents one or two carbon atoms, and defines a 4- to 7-membered monocyclic ring, which ring contains one of (i) one double bond between any two ring carbon atoms; or
(ii) a C1-C3 bridge connecting any two appropriate, non-adjacent ring carbon atoms, which bridge may optionally contain one heteroatom selected from oxygen or >NRc; or (iii) a C2-C5 cyclic moiety including a ring carbon atom to define a spiro C2-C5 ring system, which ring may optionally contain one heteroatom selected from oxygen or >NRc; or (iv) a C1-C4 bridge connecting adjacent carbon atoms to define a fused ring, wherein a C2- C4 bridge may optionally contain one heteroatom selected from oxygen or >NRc; wherein Re is as defined hereinafter; wherein in (TA2), ()m and ()o\ are independently 0, 1 or 2 and represent chains of carbon atoms (optionally substituted as defined for ARl) of length ni and oi respectively, and define a 4- to 8-membered monocyclic ring, which ring contains one of (i) a C1-C3 bridge connecting any two appropriate, non-adjacent ring carbon atoms, which bridge contains one heteroatom selected from oxygen or >NRc; or (ii) a C2-C5 cyclic moiety including a ring carbon atom to define a spiro C2-C5 ring system, which ring may optionally contain one heteroatom selected from oxygen or >NRc; or (iii) a C1-C4 bridge connecting adjacent carbon atoms to define a fused ring, wherein a C2-C4 bridge may optionally contain one heteroatom selected from oxygen or >NRc.
5. A compound of the formula (I) or pharmaceutically acceptable salt, or in-vivo hydrolysable ester thereof, wherein:
T is (TAl);
Figure imgf000085_0001
TAl Xlm and X2m taken together represent R2s-(E)ms-N=, wherein E is an electron withdrawing group selected from SO2-, CO-, O-CO-, CO-O-, CS-, CON(Rs)-, SO2N(Rs)-, or E may represent a group of the formula R3s-C(=N-O-R3s)-C(=O)-, wherein R3s is H or as defined in R2S(i) below; or
Xlm is O= and X2m is R2s-(E)ms-N-, and vice versa; and R2s and Rs may be linked as a 5- or 6-membered unsaturated or partially unsaturated ring; ms is O or 1; R2s and Rs are independently selected from: (i) hydrogen (except where E is SO2 or O-CO-), a (1-6C) alkyl group {optionally substituted by one or more (l-4C)alkanoyl groups (including geminal disubstitution) and/or optionally monosubstituted by cyano, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for AR defined herein after, heteroaryl(optionally substituted and defined as below),(l-4C)alkylS(O)q- (q is 0, 1 or 2); or (with the proviso that where R2S is SO2 or O-CO- not on the first carbon atom of the (1-6C) alkyl chain) optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally monosubstituted by oxo, -NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (l-6C)alkanoylamino, (1-
4C)alkoxycarbonylamino, N-(l-4C)alkyl-N-(l-6C)alkanoylamino, (l-4C)alkylS(O)pNH- or
(l-4C)alkylS(O)p-((l-4C)alkyl)N- (p is 1 or 2)}; or
(ii) an optionally substituted aryl or heteroaryl group of the formula ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, or C Y all as hereinafter defined, or where m=0 only,
(iii) cyano (l-4C)alkoxycarbonyl, trifluoromethyl, ethenyl, 2-(l-4C)alkylethenyl, 2- cyanoethenyl, 2-cyano-2-((l-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((l-4C)alkyl)ethenyl,
2-((l-4C)alkylaminocarbonyl)ethenyl, 2-((l-4C)alkoxycarbonyl)ethenyl, 2-(ARl)ethenyl, 2-(AR2)ethenyl, or 2-(AR2a)ethenyl;
M is a bond joining the adjacent carbon atoms or represents one or two carbon atoms (each -CH2- or -CH-), the heterocyclic ring comprising M therefore has 5-7 ring atoms and may optionally have one or more of (i) one double bond between ring carbon atoms, (ii) a Cl- C3 bridge connecting two ring carbon atoms and optionally containing a heteroatom selected from oxygen or nitrogen, and (iii) a C2-C5 cyclic moiety around a ring carbon atom; ol = l; except that, (other than when the heterocyclic ring comprising M is optionally substituted as defined in (i) - (iii) above) when Xιm is O= and X2 is R2S-CE)πιs-N-, or vice versa, R2S-(E)ms- may not be hydrogen, (l-4C)alkyl (optionally substituted as defined for Rp below), -C(=O)(l-4C)alkyl (optionally substituted as defined for Rp below), -C(=O)O(l- 4C)alkyl (optionally substituted as defined for Rp below), -C(=O)NHRp, or -C(=S)NHRP, wherein Rp is hydrogen, (l-4C)alkyl (optionally substituted with one or more halo, cyano, nitro, phenyl, (3-6C)cycloalkyl, ORp2, C(=O)Rp2, OC(=O)Rp2, C(=O)ORp2, S(=O)mpRp2,
Figure imgf000087_0001
NRp2Rp2, oxo or oxime) or phenyl, wherein RP2 is hydrogen, (l-4C)alkyl or phenyl, wherein at each occurrence phenyl is optionally substituted with one or more halo, cyano, nitro, phenyl, (3-6C)cycloalkyl, ORp2, C(=O)Rp2, OC(=O)Rp2, C(=O)ORp2, S(=O)mpRp2,
Figure imgf000087_0002
or NRp2Rp2, mp is 0, 1 or 2;
(HET)AR is a 5-6 membered aromatic or heteroaromatic ring, (i) when a 5-membered ring this may be a thiophene ring, comprising a single sulphur atom sited ortho to the nitrogen atom on the adjacent oxazolidinone ring, such a ring may have a single optional substituent Rl as hereinafter defined sited ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring, (ii) when a 6-membered ring this may be a phenyl ring or comprise a single nitrogen atom sited ortho to the nitrogen atom on the adjacent oxazolidinone ring, such ring may be optionally substituted at one or both positions ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring by Rl, where each
Rl is independently selected from hydrogen, halogen, methyl and methoxy, ethyl and ethoxy;
Y is NH;
Z is hydrogen, -COR5 or-CSR5, wherein R5 is selected from: H, (l-6C)alkyl (optionally substituted with 1-4 halogen atoms), cyclopropyl, -O-(l-6C)alkyl, NH2 or NH-(1- 6C)alkyl or N-di((l-6C)alkyl); ARl is an optionally substituted phenyl or optionally substituted naphthyl;
AR2 is an optionally substituted 5- or 6-membered, fully unsaturated (i.e with the maximum degree of unsaturation) monocyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O-O, O-S or S-S bonds), and linked via a ring carbon atom, or a ring nitrogen atom if the ring is not thereby quaternised; AR2a is a partially hydrogenated version of AR2 (i.e. AR2 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom if the ring is not thereby quaternised; AR2b is a fully hydrogenated version of AR2 (i.e. AR2 systems having no unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom; AR3 is an optionally substituted 8-, 9- or 10-membered, fully unsaturated (i.e with the maximum degree of unsaturation) bicyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O-O, O-S or S-S bonds), and linked via a ring carbon atom in either of the rings comprising the bicyclic system; AR3a is a partially hydrogenated version of AR3 (i.e. AR3 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not thereby quaternised, in either of the rings comprising the bicyclic system;
AR3b is a fully hydrogenated version of AR3 (i.e. AR3 systems having no unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom, in either of the rings comprising the bicyclic system; AR4 is an optionally substituted 13- or 14-membered, fully unsaturated (i.e with the maximum degree of unsaturation) tricyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O-O, O-S or S-S bonds), and linked via a ring carbon atom in any of the rings comprising the tricyclic system; AR4a is a partially hydrogenated version of AR4 (i.e. AR4 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not thereby quaternised, in any of the rings comprising the tricyclic system; CY is an optionally substituted cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl ring.
6. A compound as claimed in claim 5, or pharmaceutically acceptable salt, or in-vivo hydrolysable ester thereof, wherein Z is hydrogen.
7. A compound as claimed in claim 5, or pharmaceutically acceptable salt, or in-vivo hydrolysable ester thereof, wherein:
Xιm and X2m taken together represent R2s-(E)ms-N= .
8. A compound as claimed in claim 5, or pahrmaceutically acceptable salt or in-vivo hydrolysable ester thereof, wherein: M is a bond joining the adjacent carbon atoms or represents one or two carbon atoms (each -CH2- or -CH-), the heterocyclic ring comprising M therefore has 5-7 ring atoms and also has one or more of (i) one double bond between ring carbon atoms, (ii) a C1-C3 bridge connecting two ring carbon atoms and optionally containing a heteroatom selected from oxygen or nitrogen, and (iii) a C2-C5 cyclic moiety around a ring carbon atom;
9. A compound of the formula (I) as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt, or in-vivo hydrolysable ester thereof, wherein: when ms is 0, R2S is selected from : (i) hydrogen, a (l-6C)alkyl group {optionally monosubstituted by (l-4C)alkanoyl group, cyano, cyano-imino, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for ARl defined herein), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein, (l-4C)alkylS(O)q- (q is 0, 1 or 2); or optionally substituted by one or more fluoro groups (including geminal disubstitution); or optionally substituted by one or more hydroxy groups (excluding geminal disubstitution), and/or optionally further substituted, by no more than one of each of, oxo, -NRvRw [wherein Rv is hydrogen or (1- 4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamino, N-(l-4C)alkyl-N-(l-6C)alkanoylamino, (l-4C)alkylS(O)pNH- or (l-4C)alkylS(O)p.((l- 4C)alkyl)N- (p is 1 or 2)}; or
(ii) an optionally substituted aryl or optionally substituted heteroaryl group of the formula
ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein; or
(iii) cyano, -CO-NRvRw, -CO-NRv Rw', -SO2-NRvRw, -SO2-NRv Rw' [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl; Rw' is phenyl (optionally substituted as for ARl defined herein), or a heteroaryl group selected from AR2, AR2a, AR2b, AR3,
AR3a, AR3b, AR4, AR4a (optionally substituted as defined herein)],
(l-4C)alkoxycarbonyl, trifluoromethyl; and wherein when ms is 1, E is -CO- or -SO2- and R2s is selected from : (i) (l-6C)alkyl {optionally monosubstituted by cyano, cyano-imino, (l-4C)alkoxy, trifluoromethyl, (l-4C)alkoxycarbonyl, phenyl (optionally substituted as for ARl defined herein), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein, (l-4C)alkylS(O)q- (q is 0, 1 or 2); and/or (with the proviso that where R2s is -S02- or -O-CO- not on the first carbon atom of the (1-6C) alkyl chain) optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally monosubstituted by -NRvRw [wherein Rv is hydrogen or (1-
4C)alkyl; Rw is hydrogen or (l-4C)alkyl], (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamino, N-(l-4C)aIkyl-N-(l-6C)aIkanoyIamino, (l-4C)aIkylS(O)pNH- or (l-4C)alkyIS(O)p.((l-
4C)alkyl)N- (p is 1 or 2)}; or
(ii) an optionally substituted aryl or heteroaryl group of the formula ARl, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY all as defined (and optionally substituted as defined) herein.
10. A compound of the formula (I) as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt, or in-vivo hydrolysable ester thereof, wherein: when ms is 0, R2s is selected from :
(i) hydrogen, (l-6C)alkyl {optionally monosubstituted by (l-4C)alkoxy, trifluoromethyl,
(l-4C)alkylS(O)q- (q is 0, 1 or 2); or optionally substituted by one or more fluoro-groups
(including geminal disubstitution); or optionally substituted by one or more hydroxy groups
(excluding geminal disubstitution)}; or (iii) -CO-NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl],
-CO-NRv Rw' [wherein Rv is hydrogen or (l-4C)alkyl; Rw' is phenyl (optionally substituted as for ARl defined herein)], (l-4C)alkoxycarbonyl; and wherein when ms is 1, E is -CO- or -SO2- and R2S is selected from :
(l-6C)alkyl {optionally monosubstituted by (l-4C)alkoxy, trifluoromethyl, (l-4C)alkylS(O)q- (q is 0, 1 or 2); or optionally substituted by one or more fluoro groups (including geminal disubstitution); or optionally substituted by one or more hydroxy groups (excluding geminal disubstitution)}, (l-6C)alkanoylamino, (l-4C)alkoxycarbonylamino.
11. A compound of the formula (I) as claimed in any one of claims 1 to 10, or a pharmaceutically acceptable salt, or in-vivo hydrolysable ester thereof, wherein:
Re is R13CO- and R13 is selected from (l-4C)alkoxycarbonyl, hydroxy(l-4C)alkyl, (l-4C)alkyl (optionally substituted by one or two hydroxy groups, or by an (l-4C)alkanoyl group), (l-4C)alkylamino, dimethylamino(l-4C)alkyl, (l-4C)alkoxymethyl, (l-4C)alkanoylmethyl, (l-4C)alkanoyloxy(l-4C)alkyl, (l-5C)alkoxy and 2-cyanoethyl.
12. A compound of the formula (I) as claimed in any one of claims 1 to 11, or a 5 pharmaceutically acceptable salt, or in-vivo hydrolysable ester thereof, wherein: R13 is 1,2-dihydroxyethyl, l,3-dihydroxyprop-2-yl, 1,2,3-trihydroxyprop-l-yl, methoxycarbonyl, hydroxymethyl, methyl, methylamino, dimethylaminomethyl, methoxymethyl, acetoxymethyl, methoxy, methylthio, naphthyl, tert-butoxy or 2-cyanoethyl.
10 13. A compound as claimed in any preceding claim or pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof wherein HET(AR) is phenyl and at each occurrence Rl is independently hydrogen or fluorine.
14. A compound as claimed in any preceding claim, or pharmaceutically acceptable salt or 15 in-vivo hydrolysable ester thereof wherein T is TAlb:
Figure imgf000091_0001
(TAlb) and wherein Xi and X2m are as defined in any one of the preceding claims.
20 15. A compound as claimed in any preceding claim, wherein said compound is selected from:
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)-{3-[3,5-Difluoro-4-(iRS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo- 25 oxazolidin-5-ylmethyl }]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(acetylimino)-l-oxo-3,6-dihydrothiopyran-4-yl)-ρhenyl]-2- oxo-oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(2-hydroxyacetylimino)-l-oxo-3,6-dihydrothiopyran-4-yl)- phenyl] -2-oxo-oxazolidin-5 -ylmethyl }] -acetamide; 30 N-[(5S)-{3-[3-Fluoro-4-(7RS-l-(2-hydroxy-2-methylpropionylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide; N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(2-acetoxy-2-methylpropionylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-((2S)-2-hydroxy-propionylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide; N-[(5S)-{3-[3-Fluoro-4-(iRS-l-((2S)-2-acetoxy-propionylimino)-l-oxo-3,6-dihydrothiopyran-
4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-( RS-l-((.^R)-?-foιτnyloxy-benzeneacetimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl] -2-oxo-oxazolidin-5-ylmethyl } ] -acetamide;
N- [(5S)- { 3- [3 ,5-Difluoro-4-(iRS- 1 -(methylsulfonylimino)- 1 -oxo-3 ,6-dihydrothiopyran-4-yl)- phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)-{3-[3,5-Difluoro-4-(iRS-l-(5-isoxazolecarboximino)-l-oxo-3,6-dihydrothiopyran-4- yl)-phenyl] -2-oxo-oxazolidin-5-ylmethyl } ] -acetamide;
N-[(5S)-{3-[3-Fluoro-4-(lRS-l-((ethoxycarbonyl)imino)-l-oxo-3,6-dihydrothiopyran-4-yl)- phenyl] -2-oxo-oxazolidin-5 -ylmethyl } ] -acetamide ; N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(4-(3,5-dimethylisoxazole)-sulfonylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(((ethylarnino)carbonyl)irnino)-l-oxo-3,6-dihydrothiopyran-4- yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(ethenesulfonylimino)-l-oxo-3,6-dihydrothiopyran-4-yl)- phenyl]-2-oxo-oxazolidin-5-ylmethyl }]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-((2-amino)-ethanesulfonylimino)-l-oxo-3,6-dihydrothiopyran-
4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-((prop-2-ene-l-oxycarbonyl)imino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide; N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(2-propenylimino)-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-
2-oxo-oxazolidin-5-ylmethyl } ] -acetamide ;
N- [(5S)- { 3 - [3 -Fluoro-4-(2RS- 1 -(((2-propylamino)carbonyl)imino)- 1 -oxo-3 ,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(7RS-l-(methylsulfonylimino)-l-oxo-3,6-dihydrothioρyran-4-yl)- phenyl]-2-oxo-oxazolidin-5-ylmethyl }]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(ethylsulfonylimino)-l-oxo-3,6-dihydrothiopyran-4-yl)- phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide; N- [(5S)- { 3-[3 ,5-Difluoro-4-(7RS- 1 -(acetylimino)- 1 -oxo-3 ,6-dihydrothiopyran-4-yl)-phenyl]-
2-oxo-oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)- { 3- [3-Fluoro-4-(i RS- 1 -(((methylamino)carbonyl)imino)- 1 -oxo- 1 ,2,3 ,6- tetrahydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide; 5 N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(2-propylsulfonylimino)-l-oxo-3,6-dihydrothiopyran-4-yl)- phenyl] -2-oxo-oxazolidin-5-ylmethyl } ] -acetamide;
N- [(5S)- { 3- [3 ,5-Difιuoro-4-(7RS- 1 -(2-hydroxyacetylimino)- 1 -oxo-3 ,6-dihydrothiopyran-4-yl)- phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)- { 3-[3-Fluoro-4-(iRS- 1 -((2-methylprop- 1 -yl-oxycarbonyl)imino)- 1 -oxo-3 ,6- 10 dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(((2-methoxy)ethoxycarbonyl)imino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazohdin-5-ylmethyl}]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-((2S)-2-hydroxy-3-(l-oxa-butoxy)propylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide; 15 N-[(5S)-{3-[3-Fluoro-4-(7RS-l-((2R)-2-hydroxy-3-(l-oxa-butoxy))propylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(((2R)-2,3-dihydroxy)propylimino)-l-oxo-
3 ,6dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl } ]-acetamide;
N-[(5S)-{3-[3-Fluoro-4-(iRS-l-(((2S)-2,3-dihydroxy)propylimino)-l-oxo-3,6- 20 dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide; and
N-[(5S)-{3-[3-Fluoro-4-(7RS-l-((2-hydroxy-2-methyl)propylimino)-l-oxo-3,6- dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide; and pharmaceutically-acceptable salts and in-vivo hydrolysable esters thereof.
25 16. A compound of the formula (I) as claimed in any preceding claim, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof, for use as a medicament.
17. The use of a compound of the formula (I) as claimed in any preceding claim, or a 30 pharmaceutically-acceptable salt, 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.
18. A pharmaceutical composition which comprises a compound of the formula (I) as claimed in any preceding claim, or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, and a pharmaceutically-acceptable diluent or carrier.
19. A method of manufacture of a compound as claimed in any preceding claim and pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof, according to a process (a) to (f) as follows (wherein the variables are as defined above unless otherwise stated) :
(a) by modifying a substituent in or introducing a substituent into another compound of formula (I); or
(b) by reaction of a compound of formula (II) :
Figure imgf000094_0001
(H) wherein LG is a displaceable group with a compound of the formula (III):
Y-Z
(m) wherein heterocyclic compound Y-Z is appropriately derivatised for coupling with a compound of formula (II); or (c) by oxidation
(i) with an aminating agent of a lower valent sulfur compound (IV), or an analogue thereof, which is suitable to give a T substituent as defined by (TA2), or a bi-, or tri-cyclic ring analogue of (IV) which is suitable to give a T substituent as defined by (TB); or (ii) with an oxygenating agent of a lower valent sulfur compound (V), or an analogue thereof, which is suitable to give a T substituent as defined by (TA2), or a bi-, or tri-cyclic ring analogue of (V) which is suitable to give a T substituent as defined by (TB);
Figure imgf000095_0001
(IV) (V) where n = 0 or 1 and ()x and ()x' are chains of length x and x' ; or (d)(i) by coupling of a compound of formula (VI) :
Figure imgf000095_0002
(VI) wherein Y-Z is as hereinbefore defined, LG is a replaceable substituent; with a compound of the formula (VII), or an analogue thereof, which is suitable to give a T substituent as defined by (TAl), in which the link is via an sp2 carbon atom, or (TA2), or a bi- or tri-cyclic ring analogue of (VII) which is suitable to give a T substituent as defined by (TB);
Figure imgf000095_0003
(VU) where n = 0 or 1 and ()x and ()x' are chains of length x and x'; D is NH or CH=C-Lg where Lg is a leaving group; or
(d) (ii) by coupling, of a compound of formula (VITI):
Figure imgf000095_0004
(VTU) wherein Y-Z is as hereinbefore defined, with a compound [Aryl]-LG, where LG is a replaceable substituent; or (e) by reduction of a compound formed by process (d) in which the T substituent (as defined by (TAl)) is linked via an sp2 carbon atom, to form the saturated analogue; or
(f) by reaction of a compound of the formula (IX) :
T-Q-Z(f) (IX) wherein Z(f) is an isocyanate, amine or urethane group with an epoxide of the formula (X):
C H
(X)
wherein Z is a (thio)acyl group as hereinabove defined; or with a related compound of formula (XI) where the hydroxy group at the internal C-atom is optionally conventionally protected and where the leaving group LG(f) at the terminal C-atom is a conventional leaving group.
Figure imgf000096_0001
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WO2005028473A1 (en) * 2003-09-23 2005-03-31 Pharmacia & Upjohn Company Llc Acyloxymethylcarbamate prodrugs of oxazolidinones
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WO2020021468A1 (en) 2018-07-25 2020-01-30 Cadila Healthcare Limited Substituted oxazolidinones for the treatment of mammalian infections
WO2020234636A1 (en) 2019-05-17 2020-11-26 Cadila Healthcare Limited Novel compounds for the treatment of mammalian infections
WO2021184339A1 (en) * 2020-03-20 2021-09-23 Merck Sharp & Dohme Corp. Oxazolidinone compound and methods of use thereof as an antibacterial agent

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