WO2002081469A1 - Oxazolidinone-sulfoximines et sulfilimines en tant qu'antibiotiques - Google Patents

Oxazolidinone-sulfoximines et sulfilimines en tant qu'antibiotiques Download PDF

Info

Publication number
WO2002081469A1
WO2002081469A1 PCT/GB2002/001626 GB0201626W WO02081469A1 WO 2002081469 A1 WO2002081469 A1 WO 2002081469A1 GB 0201626 W GB0201626 W GB 0201626W WO 02081469 A1 WO02081469 A1 WO 02081469A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
ring
optionally substituted
phenyl
oxo
Prior art date
Application number
PCT/GB2002/001626
Other languages
English (en)
Inventor
Michael John Betts
Michael Lingard Swain
Neil James Hales
Hoan Khai Huynh
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2002081469A1 publication Critical patent/WO2002081469A1/fr

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • 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 faecium.
  • MRSA methicillin resistant staphylococcus
  • MRCNS methicillin resistant coagulase negative staphylococci
  • penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium.
  • the major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin.
  • Nancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing.
  • 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 (TB1) to (TB3) :-
  • 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,
  • 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 quatemised;
  • 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.
  • Z is a C5-C6 heteroaromatic ring joined to Y via a ring carbon atom, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quatemised) by (l-4C)alkyl.
  • 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 thio P hene.
  • halogen when present as an aromatic ring substituent is selected from any one of bromine, chlorine or fluorine, as an ali P hatic substituent from chlorine or fluorine.
  • 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 quatemised.
  • 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.
  • 4C)alkanesulfonamido include methanesulfonamido and ethanesulfonamido
  • examples of (l-4C)alkyIaminosulfonyl include methylaminosulfonyl and ethylaminosulfonyl
  • examples of di-(l-4C)alkylaminosuIfonyl include dimethylaminosulfonyl, diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl
  • examples of (1- 4C)alkanesulfonyloxy include methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy
  • examples of (l-4C)alkanoyloxy include acetoxy
  • examples of (l-4C)alkylaminocarbonyl include methylaminocarbonyl and ethylaminocarbonyl
  • 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.
  • 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.
  • 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-pyrrolo[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
  • 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,l-b]oxazole or imidazo[2,l-b]oxazole.
  • 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 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 CY are mono- or disubstitution by substituents independently selected from (l-4C)alkyl (including geminal disubstitution), hydroxy, (1- 4C)alkoxy, (l-4C)alkylthio, acetamido, (l-4C)alkanoyl, cyano, and trifluoromethyl.
  • 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.
  • certain salts of the sulfoximine NH residue are envisaged, by way of non - limiting example sulphonic acid derivatives, methane sulfonate, hydrochloride and hydrobromide salts.
  • 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).
  • 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 grou P ), followed by oxidation (if necessary) and de P rotection.
  • a suitably protected phosphorylating agent for example, containing a chloro or dialkylamino leaving grou P
  • Prodrugs 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 prodmg 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-( 1 -4C)alkyl .
  • 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
  • antibacterial activity for example by resolution of the racemic form by recrystallisation techniques, by chiral synthesis, by enzymatic resolution, by biotransformation or by chromatographic separation
  • the invention relates to all tautomeric forms of the compounds of the formula (I) that possess antibacterial activity.
  • E is preferably -CO- or -SO 2 - and R 2s 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
  • 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.
  • R 13 is hydrogen, (l-lOC)alkyl [optionally substituted by one or more hydroxy] or R 1 C(O)O(l-6C)alkyl.
  • Especially preferred compounds of the present invention are of the formula (IB):
  • 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 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 Rip as hereinafter defined sited ortho to the carbon atom on the adjacent sulfilimine/sulfoximine ring, (ii) when a 6-membered ring this may be
  • Y is -NR4- wherein R4 is hydrogen, or (l-6C)alkyl or -COOR5 wherein R5 is (1- 6C)alkyl optionally substituted by one or more chlorine atoms;
  • 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.
  • 5- or 6-membered heteroaryl ring systems are furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.
  • R2 F and R F 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); oroptionally 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, (
  • E is absent or is SO2-;
  • Y is NH
  • Z is isoxazol-3-yl.
  • the present invention provides a process for P re P aring a compound of formula (I) or a P harmaceutically-acce P table 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.
  • 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.
  • Resins may also be used as a protecting group.
  • 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 (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
  • heterocyclic compound Y-Z is appropriately derivatised for coupling with a compound of formula (II); or (c) by oxidation
  • LG is a replaceable substituent - such as chloride, bromide, iodide, or trifluoromethylsulfonyloxy; with a compound of the formula (NU), or an analogue thereof, which is suitable to give a T substituent as defined by (TAl), in which the link is via an sp 2 carbon atom, or (TA2), or a bi- or tri-cyclic ring analogue of (NH) which is suitable to give a T substituent as defined by (TB);
  • 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
  • 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.
  • R 2s group it is also possible to convert one R 2s group into another R 2s 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.
  • 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, NN-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
  • the compound of the formula (II) 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 from the hydroxy compound under standard conditions.
  • compounds of the formula (IU) may be prepared by procedures which are selected from standard chemical techniques, techniques which are analogous to the synthesis of known, stmcturally 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.
  • compounds may be prepared by procedures which are selected from standard chemical techniques, techniques which are analogous to the synthesis of known, stmcturally similar compounds, or techniques which are analogous to the procedures described in the Examples.
  • standard chemical techniques are as described in Houben Weyl, Methoden der Organische Chemie, E8a, Pt.I (1993), 45-225, B.J.Wakefield (for isoxazoles) and E8c, Pt.I (1994), 409-525, U.Kraatz (for 1,2,4- oxadiazoles).
  • 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.
  • 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-
  • 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 10 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 (for example to enhance stability) a suitable bactericide, antioxidant or reducing agent, or a suitable sequestering agent.
  • the pharmaceutically-acceptable compounds of the present invention are useful antibacterial agents having a good spectmm 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 spectram 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.
  • MSQS methicillin sensitive and quinolone sensitive
  • MRQR methicillin resistant and quinolone resistant
  • DMF is N,N-dimethylformamide
  • DMA is N,N-dimethylacetamide
  • TLC thin layer chromatography
  • HPLC high pressure liquid chromatography
  • MPLC medium pressure liquid chromatography
  • DMSO is dimethylsulfoxide
  • DMSO-d6 is deuterated DMSO
  • CDC1 3 is deuterated chloroform
  • MS mass spectroscopy
  • ESP electrospray
  • THF is tetrahydrofuran
  • TFA is trifluoroacetic acid
  • NMP is N- methylpyrrolidone
  • HOBT 1-hydroxy-benzotriazole
  • EtOAc is ethyl acetate
  • MeOH is methanol
  • phosphoryl is (HO) 2 -P(O)-O-
  • phosphiryl is (HO) 2 -P-O-
  • EDC is l-(3- dimethylaminopropyl)-3-ethylcarbodiimide
  • Example 1 cis and tr »s-(5R)- ⁇ 3-[3-Fluoro-4-(l-imino-l-oxo-tetrahvdrothiopyran-4-yl)- phenyl]-2-oxo-oxazolidin-5-ylmethyl
  • Example 2 Essentially the procedure of the relevant intermediate of Example 1 was used, but starting from (5R)- ⁇ 3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5- ylmethyl ⁇ -isoxazol-3-yl-carbamic acid tert-butyl ester (1.19 g, 2.5 mM). Crude product was chromatographed on a 20 g silica Mega Bond Elut® column, eluting with a gradient from 0 to 100% ethyl acetate in dichloromethane, then 0 to 10% methanol in dichloromethane. Relevant fractions were combined to give the desired product (500 mg). MS (ESP): 492 (M ⁇ + ) for C 23 ⁇ 26 FN 3 O 6 S
  • Example 3 cis and tr ⁇ ny-(5S)-f3-[3-Fluoro-4-(l-imino-l-oxo-tetrahvdrothiopyran-4-yl)- phenvn-5-(isoxazol-3-ylaminomethyl)-oxazolidin-2-one
  • Example 5 Acetic acid cis and tr »y-(5S)-(4- ⁇ 2-fluoro-4-r5-(isoxazol-3-ylaminomethyl)- 2-oxo-oxazolidin-3-vn-phenyl ⁇ -l-oxo-tetrahvdrothiopyran-l-ylidenecarbamoyl)-methyl ester
  • Example 6 Cis and tr ⁇ ns-(5S)-N-(4- ⁇ 2-fluoro-4-r5-(isoxazol-3-ylaminomethyl)-2-oxo- oxazolidin-3-vn-phenyl)-l-oxo-tetrahvdrothiopyran-l-ylidene)-2-hvdroxy-acetamide
  • 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°.
  • n-Butyllithium (1.6M in hexanes, 131 ml, 0.21 M) was mn in over 15 minutes, keeping the temperature below -65°, and the mixture then stirred a further 30 minutes at -70°.
  • Example 3 Using essentially the procedure of Example 3 , but starting from (5R)- ⁇ 3-[3,5-difluoro-4- (iR5-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl ⁇ - isoxazol-3-yl-carbamic acid tert-butyl ester (150 mg, 0.21 mM) gave the title product (119 mg) as its TFA salt after precipitation from dichloromethane / diethyl ether.
  • the free base may be prepared by distributing the salt between ethyl acetate and dilute aqueous ammonia, and evaporation of the organic layer.
  • Example 10 (5S)-(4- ⁇ 2,6-Difluoro-4-r5-(isoxazol-3-ylaminomethyl)-2-oxo-oxazolidin-3- yn-phenyl)-_?RS-l-oxo-3.6-dihvdrothiopyran-l-ylidene)-carbamic acid methyl ester
  • Example 3 Using essentially the procedure of Example 3 but starting from (5R)-[4-(4- ⁇ 5-[(tert- butoxycarbonyl-isoxazol-3-yl-amino)-methyl]-2-oxo-oxazolidin-3-yl ⁇ -2,6-difluoro-phenyl)- iRS-l-oxo-3,6-dihydrothiopyran-l-ylidene]-carbamic acid methyl ester (130 mg, 0.22 mM) gave the title compound (100 mg) after chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane and combining relevant fractions.
  • Example 13 (55)-Ethanesulfonic acid (4- ⁇ 2,6-difluoro-4-[5-(isoxazol-3-ylaminomethyl)- 2-oxo-oxazolidin-3-yl1-phenyl)-_?RS-l-oxo-3,6-dihydrothiopyran-l-ylidene)-amide
  • Example 3 Essentially the procedure of Example 3 was used, but starting from acetic acid (5R)-[4-(4- ⁇ 5- [(tert-butoxycarbonyl-isoxazol-3-yl-amino)-methyl]-2-oxo-oxazolidin-3-yl ⁇ -2,6-difluoro- phenyl)-iR5-l-oxo-3,6-dihydrothiopyran-l-ylidenecarbamoyl]-methyl ester (460 mg, 0.74 mM).
  • Acetic acid (5S)-(4- ⁇ 2,6-difluoro-4-[5-(isoxazol-3-ylaminomethyl)-2-oxo-oxazolidin-3-yl]- phenyl ⁇ -IRS- 1 -oxo-3 ,6-dihydrothiopyran- 1 -ylidenecarbamoyl)-methyl ester (310 mg, 0.59 mM) was dissolved in tetrahydrofuran (5 ml), treated with saturated ammonia in methanol (10 ml) and stirred at ambient temperature for 18 hours.
  • Example 2 ((5R)-3-[3-Fluoro-4-(/RS-l-imino-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5- (isoxazol-3-yl-aminomethyl-tert-butoxycarbonyl)-oxazolidin-2-one mesitylene sulfonate salt) (200mg, 0.28 mmol) was dissolved in dichloromethane (2ml) and pyridine (0.5ml). The mixture was cooled to " 20 °C and a solution of acetic anhydride (53 ⁇ L, 0.57mmol) in dichloromethane (2ml) was added dropwise.
  • acetic anhydride 53 ⁇ L, 0.57mmol
  • Example 17 (55)-3-r3-Fluoro-4- R5-l-(2S-methyl-2S-acetoxyacetylimino)-l-oxo-3.6- dihvdrothiopyran-4-yl)-phenyl1-5-(isoxazol-3-yl-aminomethyl)-oxazolidin-2-one
  • Example 16 Essentially the same procedure was used as Example 16, but starting from (5R)-3-[3-fluoro-4- (iRS-l-(2,2-dimethyl-2-acetoxyacetylimino)-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5-
  • Example 16 Essentially the same procedure was used as Example 16, but starting from (5R)-3-[3-Fluoro-4- (iRS-l-(2R-phenyl-2R-formyloxyacetylimino)-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5- (isoxazol-3-yl-aminomethyl-tert-butoxycarbonyl)-oxazolidin-2-one (287mg, 0.43mmol).
  • Cmde product was purified by flash chromatography using 1.5% methanol in dichloromethane as eluent. Relevant fractions were combined giving the title compound (163mg).
  • the mesitylene sulfonate salt (Example 2) (400mg, 0.57mmol) was acylated with (R)-(-)- formylmandeloyl chloride (176 ⁇ l, 1.13mmol).
  • the cmde product was purified by flash chromatography using 1% methanol in dichloromethane as eluent. The relevant fractions were pooled giving the title compound (437mg).
  • Example 16 Essentially the same procedure was used as Example 16, but starting from (5R)-3-[3-Fluoro-4- (2RS-l-(2-isoxazol-5-yl-acetylimino)-l-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5-(isoxazol- 3-yl-aminomethyl-tert-butoxycarbonyl)-oxazolidin-2-one (240mg, 0.48mmol). Cmde product was purified by recrystallization from hot methanol giving the title product (lOmg).
  • the mesitylene sulfonate salt of Example 2 (300mg, 0.42mmol) was acylated with isoxazole-5- carbonyl chloride (HOmg, 0.84mmol).
  • the cmde product was purified by flash chromatography using 1% methanol in dichloromethane as eluent. The relevant fractions were combined giving the title compound (240mg).
  • Example 24 (5S)-3-[3-Fluoro-4- R5-l-(2-(3.5-dimethylisoxazol-4-yl)-acetylimino)-l- oxo-3,6-dihvdrothiopyran-4-yl)-phenyl1-5-(isoxazol-3-yl-aminomethyl)-oxazolidin-2-one
  • Example 25 (5S)-3-r3-Fluoro-4-qRS-l-(2-(4-methyl-l,2,3-thiadiazol-5-yl)-acetylimino)- l-oxo-3,6-dihvdrothiopyran-4-yl)-phenyl]-5-(isoxazol-3-yl-aminomethyl)-oxazolidin-2- one
  • Example 16 Essentially the same procedure as Example 16 was used, but starting from (5R)-3-[3-Fluoro-4- (iRS-l-(2-(4-methyl-l,2,3-thiadiazol-5-yl)-acetylimino)-l-oxo-3,6-dihydrothiopyran-4-yl)- phenyl]-5-(isoxazol-3-yl-aminomethyl-tert-butoxycarbonyl)-oxazolidin-2-one (680mg,
  • Example 16 Essentially the same procedure as Example 16 was used, but starting from (5R)-3-[3-Fluoro-4-
  • the mesitylene sulfonate salt of Example 2 (l.Og, 1.41mmol) was acylated with 1,3- dimethylpyrazole-5-carbonyl chloride (449mg, 2.83mmol).
  • the cmde product was purified by flash chromatography using 0.5 then 2% methanol in dichloromethane as eluent. The relevant fractions were combined giving the title compound (796 mg).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de la formule (I) ou un sel pharmaceutiquement acceptable, ou un ester hydrolysable in vivo de ceux-ci, dans laquelle, par exemple, T est choisi dans le groupe de la formule (TA1), ou (TA2), dans laquelle, par exemple, X1m représente O= et X2m représente R2s-(E)ms-N-, E représentant un groupe de retrait d'électrons, par exemple, -SO2- ou CO-; et, par exemple, R2s représente hydrogène ou (1-6C)alkyle; et, par exemple, HET(AR) représente un noyau aromatique ou hétéroaromatique à 5 ou 6 chaînons; et, par exemple, Y représente NH et Z un noyau C5-C6 hétéroaromatique, par exemple isoxazolyl. Ces composés peuvent être utilisés comme agents pharmaceutiques. L'invention concerne en outre des procédés de fabrication de compositions pharmaceutiques les renfermant.
PCT/GB2002/001626 2001-04-07 2002-04-03 Oxazolidinone-sulfoximines et sulfilimines en tant qu'antibiotiques WO2002081469A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0108793.1 2001-04-07
GB0108793A GB0108793D0 (en) 2001-04-07 2001-04-07 Chemical compounds

Publications (1)

Publication Number Publication Date
WO2002081469A1 true WO2002081469A1 (fr) 2002-10-17

Family

ID=9912468

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2002/001626 WO2002081469A1 (fr) 2001-04-07 2002-04-03 Oxazolidinone-sulfoximines et sulfilimines en tant qu'antibiotiques

Country Status (2)

Country Link
GB (1) GB0108793D0 (fr)
WO (1) WO2002081469A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028473A1 (fr) * 2003-09-23 2005-03-31 Pharmacia & Upjohn Company Llc Bioprecurseurs acyloxymethylcarbamate des oxazolidinones
US6969726B2 (en) 2003-06-03 2005-11-29 Rib X Pharmaceuticals Inc Biaryl heterocyclic compounds and methods of making and using the same
US7022705B2 (en) 2001-10-25 2006-04-04 Astrazeneca Ab Isoxazoline derivatives useful as antimicrobials
US7091196B2 (en) 2002-09-26 2006-08-15 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
US7129259B2 (en) 2003-12-17 2006-10-31 Rib-X Pharmaceuticals, Inc. Halogenated biaryl heterocyclic compounds and methods of making and using the same
WO2007000644A1 (fr) 2005-06-29 2007-01-04 Pharmacia & Upjohn Company Llc Oxazolidinones d'homomorpholine en tant qu'agents antibacteriens
US7199143B2 (en) 2002-02-28 2007-04-03 Astrazeneca Ab Chemical compounds
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US7473699B2 (en) 2002-02-28 2009-01-06 Astrazeneca Ab 3-cyclyl-5-(nitrogen-containing 5-membered ring)methyl-oxazolidinone derivatives and their use as antibacterial agents
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same
US8324398B2 (en) 2003-06-03 2012-12-04 Rib-X Pharmaceuticals, Inc. Process for the synthesis of biaryl oxazolidinones
US8399660B2 (en) 2005-06-08 2013-03-19 Rib-X Pharmaceuticals, Inc. Process for the synthesis of triazoles
US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
US8906913B2 (en) 2009-06-26 2014-12-09 Panacea Biotec Limited Azabicyclohexanes

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007271A1 (fr) * 1993-09-09 1995-03-16 The Upjohn Company Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine
WO1996015130A1 (fr) * 1994-11-15 1996-05-23 Pharmacia + Upjohn Company Agents antibacteriens du type oxazolidinone avec un substituant oxazine ou thiazine bicyclique
WO1999064417A2 (fr) * 1998-06-05 1999-12-16 Astrazeneca Ab Composes chimiques
WO2000021960A1 (fr) * 1998-10-09 2000-04-20 Astrazeneca Ab Heterocyclyl amino methyloxa zolidinones comme agents antibacteriens
WO2000032599A1 (fr) * 1998-11-27 2000-06-08 Pharmacia & Upjohn Company Agents antibacteriens oxazolidinone a fonction thiocarbonyle
WO2001046185A1 (fr) * 1999-12-21 2001-06-28 Pharmacia & Upjohn Company Oxazolidinones presentant une fonctionnalite sulfoximine et leur utilisation comme agents antimicrobiens

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007271A1 (fr) * 1993-09-09 1995-03-16 The Upjohn Company Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine
WO1996015130A1 (fr) * 1994-11-15 1996-05-23 Pharmacia + Upjohn Company Agents antibacteriens du type oxazolidinone avec un substituant oxazine ou thiazine bicyclique
WO1999064417A2 (fr) * 1998-06-05 1999-12-16 Astrazeneca Ab Composes chimiques
WO2000021960A1 (fr) * 1998-10-09 2000-04-20 Astrazeneca Ab Heterocyclyl amino methyloxa zolidinones comme agents antibacteriens
WO2000032599A1 (fr) * 1998-11-27 2000-06-08 Pharmacia & Upjohn Company Agents antibacteriens oxazolidinone a fonction thiocarbonyle
WO2001046185A1 (fr) * 1999-12-21 2001-06-28 Pharmacia & Upjohn Company Oxazolidinones presentant une fonctionnalite sulfoximine et leur utilisation comme agents antimicrobiens
US20010046987A1 (en) * 1999-12-21 2001-11-29 Hester Jackson B. Oxazolidinones having a sulfoximine functionality

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US7022705B2 (en) 2001-10-25 2006-04-04 Astrazeneca Ab Isoxazoline derivatives useful as antimicrobials
US7199143B2 (en) 2002-02-28 2007-04-03 Astrazeneca Ab Chemical compounds
US7473699B2 (en) 2002-02-28 2009-01-06 Astrazeneca Ab 3-cyclyl-5-(nitrogen-containing 5-membered ring)methyl-oxazolidinone derivatives and their use as antibacterial agents
US7091196B2 (en) 2002-09-26 2006-08-15 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
US7148219B2 (en) 2003-06-03 2006-12-12 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US8895741B2 (en) 2003-06-03 2014-11-25 Melinta Therapeutics, Inc. Process for the synthesis of biaryl oxazolidinones
US9550783B2 (en) 2003-06-03 2017-01-24 Melinta Therapeutics, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US8324398B2 (en) 2003-06-03 2012-12-04 Rib-X Pharmaceuticals, Inc. Process for the synthesis of biaryl oxazolidinones
US7456206B2 (en) 2003-06-03 2008-11-25 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US6969726B2 (en) 2003-06-03 2005-11-29 Rib X Pharmaceuticals Inc Biaryl heterocyclic compounds and methods of making and using the same
US7705026B2 (en) 2003-06-03 2010-04-27 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
WO2005028473A1 (fr) * 2003-09-23 2005-03-31 Pharmacia & Upjohn Company Llc Bioprecurseurs acyloxymethylcarbamate des oxazolidinones
US7129259B2 (en) 2003-12-17 2006-10-31 Rib-X Pharmaceuticals, Inc. Halogenated biaryl heterocyclic compounds and methods of making and using the same
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same
US8841263B2 (en) 2004-02-27 2014-09-23 Melinta Therapeutics, Inc. Macrocyclic compounds and methods of making and using the same
US8399660B2 (en) 2005-06-08 2013-03-19 Rib-X Pharmaceuticals, Inc. Process for the synthesis of triazoles
US8796465B2 (en) 2005-06-08 2014-08-05 Melinta Therapeutics, Inc. Process for the syntheses of triazoles
US9376400B2 (en) 2005-06-08 2016-06-28 Melinta Therapeutics, Inc. Process for the synthesis of triazoles
WO2007000644A1 (fr) 2005-06-29 2007-01-04 Pharmacia & Upjohn Company Llc Oxazolidinones d'homomorpholine en tant qu'agents antibacteriens
US8841306B2 (en) 2008-11-20 2014-09-23 Panacea Biotec Ltd. Antimicrobials
US8906913B2 (en) 2009-06-26 2014-12-09 Panacea Biotec Limited Azabicyclohexanes

Also Published As

Publication number Publication date
GB0108793D0 (en) 2001-05-30

Similar Documents

Publication Publication Date Title
US7087629B2 (en) Heterocyclylaminomethyloxazolidinones as antibacterials
AU753865B2 (en) Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them
EP1286998B1 (fr) Derives d'oxazolidinone ayant une activite antibiotique
EP1242416B1 (fr) Isoxazolines substituees et leur utilisation comme agents antibacteriens
EP1385844B1 (fr) Oxazolidinones contenant un groupe sulfonimide en tant qu'antibiotique
EP1446403B1 (fr) Oxazolidinones substituees par un groupe aryle presentant une activite antibacterienne
US20060035895A1 (en) Isoxazoline derivatives useful as antimicrobials
WO2002081469A1 (fr) Oxazolidinone-sulfoximines et sulfilimines en tant qu'antibiotiques
WO2002080841A2 (fr) Composes chimiques
WO2002081468A1 (fr) Oxazolidinones et leur utilisation comme agents antibacteriens
US7157482B2 (en) Antibacterial 1,3-oxazolidin-2-one derivatives
US7186738B2 (en) Antibacterial oxalidinones
ZA200006694B (en) Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

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

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP