Patent Application
20050032861
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 faecium.
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 lactams, quinolones and macrolides used for the treatment of upper respiratory tract infections, also caused by certain Gram negative strains including H.influenzae 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, (ii) the evolution of means to chemically deactivate a given pharmacophore and/or (iii) the development and/or up-regulation of efflux mechanisms. 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 MRSA and MRCNS and, in particular, against various strains exhibiting resistance to vancomycin and against E. faecium strains resistant to both aminoglycosides and clinically used β-lactams, but also to fastidious Gram negative strains such as H.influenzae, M.catarrbalis, 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,
wherein
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
For the avoidance of doubt, in the above definitions of TA1, TA2 and TB, ( )n1, ( )o1, ( )n1′, ( )o1′, ( )p1 and ( )p1 indicate (—CH2—)n1, (—CH2-)o1, (—CH2-)n1′, (—CH2-)o1′, (—CH2-)p1 and (—CH2-)p1′ respectively.
In this specification, HET as an N-linked 5-membered ring, as defined in definition (i) above, may be a fully or partially unsaturated heterocyclic ring, provided there is some degree of unsaturation in the ring.
Particular examples of N-linked 5-membered heteroaryl rings containing 2 to 4 heteroatoms independently selected from N, O and S (with no O—O, O—S or S—S bonds) are preferably rings containing 2 to 4 N atoms, in particular pyrazole, imidazole, 1,2,3-triazole (preferably 1,2,3-triazol-1-yl), 1,2,4-triazole (preferably 1,2,4-triazol-1-yl) and tetrazole (preferably tetrazol-2-yl).
Particular examples of N-linked 6-membered di-hydro-heteroaryl rings containing up to three nitrogen heteroatoms in total (including the linking heteroatom) include di-hydro versions of pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine and pyridine.
In this specification, where it is stated that a ring may be linked via an sp2 carbon atom, which ring is fully saturated other than (where appropriate) at a linking sp2 carbon atom, it is to be understood that the ring is linked via one of the carbon atoms in a C═C double bond.
In this specification the term ‘alkyl’ includes straight chained and branched structures. For example, (1-6C)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(1-4C)alkyl includes 1-bromoethyl and 2-bromoethyl.
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.
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 (1-4C)alkyl and (1-5C)alkyl include methyl, ethyl, propyl, isopropyl and t-butyl; examples of (1-6C)alkyl include methyl, ethyl, propyl, isopropyl, t-butyl, pentyl and hexyl; examples of (1-10C)alkyl include methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyl and nonyl; examples of (1-4C)alkanoylamino-(1-4C)alkyl include formamidomethyl, acetamidomethyl and acetamidoethyl; examples of hydroxy(1-4C)alkyl and hydroxy(1-6C)alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of (1-4C)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; examples of 2-((1-4C)alkoxycarbonyl)ethenyl include 2-(methoxycarbonyl)ethenyl and 2-(ethoxycarbonyl)ethenyl; examples of 2-cyano-2-((1-4C)alkyl)ethenyl include 2-cyano-2-methylethenyl and 2-cyano-2-ethylethenyl; examples of 2-nitro-2-((1-4C)alkyl)ethenyl include 2-nitro-2-methylethenyl and 2-nitro-2-ethylethenyl; examples of 2-((1-4C)alkylaminocarbonyl)ethenyl include 2-(methylaminocarbonyl)ethenyl and 2-(ethylaminocarbonyl)ethenyl; examples of (2-4C)alkenyl include allyl and vinyl; examples of (2-4C)alkynyl include ethynyl and 2-propynyl; examples of (1-4C)alkanoyl include formyl, acetyl and propionyl; examples of (1-4C)alkoxy include methoxy, ethoxy and propoxy; examples of (1-6C)alkoxy and (1-10C)alkoxy include methoxy, ethoxy, propoxy and pentoxy; examples of (1-4C)alkylthio include methylthio and ethylthio; examples of (1-4C)alkylamino include methylamino, ethylamino and propylamino; examples of di-((1-4C)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 (1-4C)alkylsulfonyl include methylsulfonyl and ethylsulfonyl; examples of (1-4C)alkoxy-(1-4C)alkoxy and (1-6C)alkoxy-(1-6C)alkoxy include methoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy and 3-methoxypropoxy; examples of (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy include 2-(methoxymethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy; 3-(2-methoxyethoxy)propoxy and 2-(2-ethoxyethoxy)ethoxy; examples of (1-4C)alkylS(O)2amino include methylsulfonylamino and ethylsulfonylamino; examples of (1-4C)alkanoylamino and (1-6C)alkanoylamino include formamido, acetamido and propionylamino; examples of (1-4C)alkoxycarbonylamino include methoxycarbonylamino and ethoxycarbonylamino; examples of N-(1-4C)alkyl-N-(1-6C)alkanoylamino include N-methylacetamido, N-ethylacetamido and N-methylpropionamido; examples of (1-4C)alkylS(O)pNH— wherein p is 1 or 2 include methylsulfinylamino, methylsulfonylamino, ethylsulfinylamino and ethylsulfonylamino; examples of (1-4C)alkylS(O)p((1-4C)alkyl)N— wherein p is 1 or 2 include methylsulfinylmethylamino, methylsulfonylmethylamino, 2-(ethylsulfinyl)ethylamino and 2-(ethylsulfonyl)ethylamino; examples of fluoro(1-4C)alkylS(O)pNH— wherein p is 1 or 2 include trifluoromethylsulfinylamino and trifluoromethylsulfonylamino; examples of fluoro(1-4C)alkylS(O)p((1-4C)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-(1-4C)alkoxyphosphoryl include di-methoxyphosphoryl, di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl; examples of (1-4C)alkylS(O)q— wherein q is 0, 1 or 2 include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; examples of phenylS(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 benzyloxy-(1-4C)alkyl include benzyloxymethyl and benzyloxyethyl; examples of a (3-4C)alkylene chain are trimethylene or tetramethylene; examples of (1-6C)alkoxy-(1-6C)alkyl include methoxymethyl, ethoxymethyl and 2-methoxyethyl; examples of hydroxy-(2-6C)alkoxy include 2-hydroxyethoxy and 3-hydroxypropoxy; examples of (1-4C)alkylamino-(2-6C)alkoxy include 2-methylaminoethoxy and 2-ethylaminoethoxy; examples of di-(1-4C)alkylamino-(2-6C)alkoxy include 2-dimethylaminoethoxy and 2-diethylaminoethoxy; examples of phenyl(1-4C)alkyl include benzyl and phenethyl; examples of (1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl; examples of di((1-4C)alkyl)carbamoyl include di(methyl)carbamoyl and di(ethyl)carbamoyl; examples of hydroxyimino(1-4C)alkyl include hydroxyiminomethyl, 2-(hydroxyimino)ethyl and 1-(hydroxyimino)ethyl; examples of (1-4C)alkoxyimino-(1-4C)alkyl include methoxyiminomethyl, ethoxyiminomethyl, 1-(methoxyimino)ethyl and 2-(methoxyimino)ethyl; examples of halo(1-4C)alkyl include, halomethyl, 1-haloethyl, 2-haloethyl, and 3-halopropyl; examples of nitro(1-4C)alkyl include nitromethyl, 1-nitroethyl, 2-nitroethyl and 3-nitropropyl; examples of amino(1-4C)alkyl include aminomethyl, 1-aminoethyl, 2-aminoethyl and 3-aminopropyl; examples of cyano(1-4C)alkyl include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; examples of (1-4C)alkanesulfonamido include methanesulfonamido and ethanesulfonamido; examples of (1-4C)alkylaminosulfonyl include methylaminosulfonyl and ethylaminosulfonyl; examples of di-(1-4C)alkylaminosulfonyl include dimethylaminosulfonyl, diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl; examples of (1-4C)alkanesulfonyloxy include methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy; examples of (1-4C)alkanoyloxy include acetoxy; examples of (1-4C)alkylaminocarbonyl include methylaminocarbonyl and ethylaminocarbonyl; examples of di((1-4C)alkyl)aminocarbonyl include dimethylaminocarbonyl and diethylaminocarbonyl; examples of (3-8C)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; examples of (4-7C)cycloalkyl include cyclobutyl, cyclopentyl and cyclohexyl; examples of di(N-(1-4C)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 1,2,5,6-tetrahydropyrid-4-yl). Particular examples of AR2b include, for example, tetrahydrofuran, pyrrolidine, morpholine (preferably morpholino), thiomorpholine (preferably thiomorpholino), piperazine (preferably piperazino), imidazoline and piperidine, 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl and 1,4-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[1,2-a]pyrrole, pyrrolo[2, 1-b]thiazole, 1H-imidazo[1,2-a]pyrrole, 1H-imidazo[1,2-a]imidazole, 1H,3H-pyrrolo[1,2-c]oxazole, 1H-imidazo[1,5-a]pyrrole, pyrrolo[1,2-b]isoxazole, imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine, pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrazine, pyrrolo[1,2-a]pyrimidine, pyrido[2,1-c]-s-triazole, s-triazole[1,5-a]pyridine, imidazo[1,2-c]pyrimidine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, imidazo[1,5-a]pyrazine, imidazo[1,5-a]pyrimidine, imidazo[1,2-b]-pyridazine, s-triazolo[4,3-a]pyrimidine, imidazo[5,1-b]oxazole and imidazo[2,1-b]oxazole. Other specific examples of such ring systems include, for example, [1H]-pyrrolo[2, 1-c]oxazine, [3H]-oxazolo[3,4-a]pyridine, [6H]-pyrrolo[2,1-c]oxazine and pyrido[2,1-c][1,4]oxazine. Other specific examples of 5/5-bicyclic ring systems are imidazooxazole or imidazothiazole, in particular imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, imidazo[5,1-b]oxazole or imidazo[2,1-b]oxazole.
Particular examples of AR3a and AR3b include, for example, indoline, 1,3,4,6,9,9a-hexahydropyrido[2,1c][1,4]oxazin-8-yl, 1,2,3,5,8,8a-hexahydroimidazo[1,5a]pyridin-7-yl, 1,5,8,8a-tetrahydrooxazolo[3,4a]pyridin-7-yl, 1,5,6,7,8,8a-hexahydrooxazolo[3,4a]pyridin-7-yl, (7aS)[3H,5H]-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl, (7aS)[5H]-1,2,3,7a-tetrabydropyrrolo[1,2c]imidazol-6-yl, (7aR)[3H,5H]-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl, [3H,5H]-pyrrolo[1,2-c]oxazol-6-yl, [5H]-2,3-dihydropyrrolo[1,2-c]imidazol-6-yl, [3H,5H]-pyrrolo[1,2-c]thiazol-6-yl, [3H,5H]-1,7a-dihydropyrrolo[1,2-c]thiazol-6-yl, [5H]-pyrrolo[1,2-c]imidazol-6-yl, [1H]-3,4,8,8a-tetrahydropyrrolo[2,1-c]oxazin-7-yl, [3H]-1,5,8,8a-tetrahydrooxazolo[3,4-a]pyrid-7-yl, [3H]-5,8-dihydroxazolo[3,4-a]pyrid-7-yl and 5,8-dihydroimidazo[1,5-a]pyrid-7-yl.
Particular values for AR4 include, for example, pyrrolo[a]quinoline, 2,3-pyrroloisoquinoline, pyrrolo[a]isoquinoline,1H-pyrrolo[1,2-a]benzimidazole, 9H-imidazo[1,2-a]indole, 5H-imidazo[2,1-a]isoindole,1H-imidazo[3,4-a]indole, imidazo[1,2-a]quinoline, imidazo[2,1-a]isoquinoline, imidazo[1,5-a]quinoline and imidazo[5,1-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 AR1, 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, (1-4C)alkyl S(O)q— (q is 0, 1 or 2) (this last substituent preferably on AR1 only), (1-4C)alkoxy, (1-4C)alkoxycarbonyl, cyano, nitro, (1-4C)alkanoylamino, —CONRvRw or —NRvRw}, trifluoromethyl, hydroxy, halo, nitro, cyano, thiol, (1-4C)alkoxy, (1-4C)alkanoyloxy, dimethylaminomethyleneaminocarbonyl, di(N-(1-4C)alkyl)aminomethylimino, carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkanoyl, (1-4C)alkylSO2amino, (2-4C)alkenyl {optionally substituted by carboxy or (1-4C)alkoxycarbonyl}, (2-4C)alkynyl, (1-4C)alkanoylamino, oxo (═O), thioxo (═S), (1-4C)alkanoylamino {the (1-4C)alkanoyl group being optionally substituted by hydroxy}, (1-4C)alkyl S(O)q— (q is 0, 1 or 2) {the (1-4C)alkyl group being optionally substituted by one or more groups independently selected from cyano, hydroxy and (1-4C)alkoxy}, —CONRvRw or —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl].
Further suitable substituents on AR1, 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, (1-4C)alkoxy or cyano}, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyimino(1-4C)alkyl, (1-4C)alkoxyimino(1-4C)alkyl, halo-(1-4C)alkyl, (1-4C)alkanesulfonamido, —SO2NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl].
Preferable optional substituents on Ar2b as 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl or 1,4-dioxan-2-yl are mono- or disubstitution by substituents independently selected from (1-4C)alkyl (including geminal disubstitution), (1-4C)alkoxy, (1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano, trifluoromethyl and phenyl].
Preferable optional substituents on CY are mono- or disubstitution by substituents independently selected from (1-4C)alkyl (including geminal disubstitution), hydroxy, (1-4C)alkoxy, (1-4C)alkylthio, acetamido, (1-4C)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) (1-4C)alkyl, (1-4C)alkanoyl {wherein the (1-4C)alkyl and (1-4C)alkanoyl groups are optionally substituted by (preferably one) substituents independently selected from cyano, hydroxy, nitro, trifluoromethyl, (1-4C)alkyl S(O)q— (q is 0, 1 or 2), (1-4C)alkoxy, (1-4C)alkoxycarbonyl, (1-4C)alkanoylamino, —CONRvRw or —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl]}, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxycarbonyl or oxo (to form an N-oxide).
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.
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 H.influenzae, 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 Q, 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 a pharmaceutically-acceptable salt or in-vivo hydrolysable ester thereof, as defined herein wherein Q is selected from Q1 to Q9. In another embodiment is provided a compound of formula (I) or a pharmaceutically-acceptable salt or in-vivo hydrolysable ester thereof, as defined herein wherein Q is Q10.
Preferably Q is selected from Q1, Q2, Q4, Q6 and Q9; especially Q1, Q2 and Q9; more particularly Q1 and Q2; and most preferably Q is Q1.
In another embodiment of the invention are provided compounds of formula (I), or a pharmaceutically-acceptable salt or in-vivo hydrolysable ester thereof, in which Q, T and other substituents mentioned above have the values disclosed hereinbefore, HET is selected from structures Za to Zf as hereinbefore defined (ie HET is as defined in definition (ii) for HET, as hereinbefore defined) and RT is selected from the group RTb.
In one embodiment RT has values (RTa) to (RTc1-3).
Preferable RT groups are those of (RTa) and (RTb). Even more preferable RT group is (RTb).
In (RTb), in one aspect, the (1-4C)alkyl group is preferably substituted, and more preferably is a substituted methyl group. In another aspect the (1-4C) alkyl group is prefeably unsubstituted, and more preferably is a methyl group.
In (RTb), when the (1-4C)alkyl group is substituted by a N-linked 5-membered heteroaryl ring it will be appreciated that the ring is aromatic and that when the ring is optionally substituted on an available carbon atom by oxo or thioxo then, when HET contains 1 to 3 further nitrogen heteroatoms, one of the further nitrogen heteroatoms is present as NH or as N-(1-4C)alkyl. Similarly, when the ring is optionally substituted on an available nitrogen atom by (1-4C)alkyl then the ring is substituted on an available carbon atom by oxo or thioxo. Preferred values for the N-linked 5-membered heteroaryl ring as a substituent in (RTb) are the following rings (HET-P1 to HET-P5):
In (RTc1) to (RTc3), particular rings are morpholino, tetrahydropyridyl and dihydropyrrolyl.
Preferable (RT) groups provided by optional F and/or Cl and/or one cyano further substituents in (RTa) and (RTb) are, for example, RT as trifluoromethyl, —CHF2, —CH2F, —CH2CN, —CF2NH(1-4C)alkyl, —CF2CH2OH, —CH2OCF3, —CH2OCHF2, —CH2OCH2F, —NHCF2CH3.
In one embodiment is provided a compound of formula (I) or a pharmaceutically-acceptable salt or in-vivo hydrolysable ester thereof, as defined herein wherein T is selected from (TA2) and (TB). In another embodiment is provided a compound of formula (I) as defined herein wherein T is (TA1).
In (TA1), when the ring has an optional double bond between any two ring carbon atoms, the ring is preferably linked via an sp2 carbon atom of the double bond.
Preferably (TA1) is (TA1a) or (TA1b), and preferably (TA2) is (TA2a):
wherein X1m and X2m are as defined above, and hereinafter.
In (TB1) to (TB3), preferably n1=o1 & n1′=o1′ (most preferably all are 1); p1=p1′ (most preferably both are 0); and further preferred values for the groups defined in (TB) are defined by formulae (TB1a, b), (TB2a) and (TB3a):
wherein X1m and X2m are as defined above, and hereinafter.
Preferably X1m is O═ and X2m is R2s—(E)ms—N—, and vice versa.
When ms is 0, R2s is preferably selected from:
When ms is 0, R2s is most preferably selected from
When ms is 1, E is preferably —CO— or —SO2— and R2s is preferably selected from:
When ms is 1, E is preferably —CO— or —SO2— and R2s is most preferably selected from:
In (TB) and (TA2), where ( )n1, ( )o1, ( )n1′, ( )o1′, ( )p1 and ( )p1′ represent chains of carbon atoms optionally substituted as defined for AR1 herein, preferable optional substituents are selected from (preferably one of) hydroxy, trifluoromethyl, (1-4C)alkyl S(O)q— (q is 0, 1 or 2), (1-4C)alkoxy, (1-4C)alkoxycarbonyl, cyano, nitro, (1-4C)alkanoylamino, —CONRvRw or —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl]. Most preferably, ( )n1, ( )o1, ( )n1′, ( )o1′, ( )p1 and ( )p1′ represent unsubstituted chains of carbon atoms.
The above preferred values of (TAa) to (TAc) and (TB) are particularly preferred when present in Q1 or Q2, especially Q1.
Preferably T is selected from (TA1a & b), (TA2a) and (TB1a & b). Especially preferred is each of these values of T when present in Q1 and Q2, particularly in Q1.
Preferable values for other substituents (which may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore or hereinafter) are:
For compounds of formula (I) preferred values for Rc are those in group (Rc2) when present in any of the definitions herein containing Rc.
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 (IA):
wherein HET is 1,2,3-triazole (especially 1,2,3-triazol-1-yl), 1,2,4-triazole (especially 1,2,4-triazol-1-yl) and tetrazole (preferably tetrazol-2-yl) or HET is a di-hydro version of pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine and pyridine; R2 and R3 are independently hydrogen or fluoro; and
Further especially preferred compounds of the present invention are of the formula (1A) defined above, wherein HET is selected from structures Za to Zf (as hereinbefore defined) and is 1,2,3-triazole (especially 1,2,3-triazol-1-yl), 1,2,4-triazole (especially 1,2,4-triazol-1-yl) and tetrazole (preferably tetrazol-2-yl); RT is selected from (RTa) or (RTb); R2 and R3 are independently hydrogen or fluoro; and T is selected from (TA1), (TA2) and (TB1) to (TB3); or in-vivo hydrolysable esters or pharmaceutically-acceptable salts thereof.
Further particularly preferred compounds of the present invention are of the formula (1A) defined above wherein RT is a methyl group from (RTb), substituted with any of those substituents defined herein in (RTb) other than an N-linked 5-membered heteroaryl ring; or in-vivo hydrolysable esters or pharmaceutically-acceptable salts thereof.
Further especially preferred compounds of the invention are of the formula (IA) wherein HET is 1,2,3-triazole (especially 1,2,3-triazol-1-yl), 1,2,4-triazole (especially 1,2,4-triazol-1-yl) or tetrazole (preferably tetrazol-2-yl;
In the above aspects and preferred compounds of formula (IA), in (TA1), (TA2) and (TB1) to (TB3); and especially in (TA1a & b), (TA2a) and (TB1a & b); preferably X1m is O═ and X2m is R2s—(E)ms—N—, and vice versa; and when ms is 0, R2s is preferably selected from (i) hydrogen, a (1-6C)alkyl group {optionally monosubstituted by (1-4C)alkanoyl group, cyano, cyano-imino, (1-4C)alkoxy, trifluoromethyl, (1-4C)alkoxycarbonyl, phenyl (optionally substituted as for AR1 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, (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), 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 (1-4C)alkyl], (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino, N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (1-4C)alkylS(O)pNH— or (1-4C)alkylS(O)p-((1-4C)alkyl)N— (p is 1 or 2)}; or
In a further aspect of the present invention is provided a compound of the formula (IB), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof,
wherein:
For compounds of the formula (IB), 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 AR1 to AR4a and CY inclusive) include halo, (1-4C)alkyl , hydroxy, nitro, carbamoyl, (1-4C)alkylcarbamoyl, di-((1-4C)alkyl)carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-4C)alkyl S(O)q— (q is 0, 1 or 2), carboxy, (1-4C)alkoxycarbonyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkanoyl, (1-4C)alkoxy, (1-4C)alkylS(O)2amino, (1-4C)alkanoylamino, benzoylamino, benzoyl, phenyl (optionally substituted by up to three substituents selected from halo, (1-4C)alkoxy or cyano), furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyimino(1-4C)alkyl, (1-4C)alkoxyimino(1-4C)alkyl, hydroxy-(1-4C)alkyl, halo-(1-4C)alkyl, nitro(1-4C)alkyl, amino(1-4C)alkyl, cyano(1-4C)alkyl, (1-4C)alkanesulfonamido, aminosulfonyl, (1-4C)alkylaminosulfonyl and di-((1-4C)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 quatermised.
For compounds of the formula (IB), 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.
AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a and CY are understood to be as hereinbefore defined for formula I.
Particular values for X1 and X2 are as follows:
More particular values are as follows:
In all of the above aspects and preferred compounds of formula (IA) and (IB), 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 (IC) as described hereinafter; i.e. 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).
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 prodrug. 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:
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 (1-6C)alkoxymethyl esters for example methoxymethyl, (1-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-onylmethyl esters for example 5-methyl-1,3-dioxolan-2-ylmethyl; and (1-6C)alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
An in-vivo hydrolysable ester of a compound 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 α-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 (1-10C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, (1-10C)alkoxycarbonyl (to give alkyl carbonate esters), di-(1-4C)alkylcarbamoyl and N-(di-(1-4C)alkylaminoethyl)-N-(1-4C)alkylcarbamoyl (to give carbamates), di-(1-4C)alkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl and phenylacetyl include chloromethyl or aminomethyl, (1-4C)alkylaminomethyl and di-((1-4C)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.
In addition a sulphoximine residue may be derivatised by a convenient biologically labile group to give a derivative suitable for use as a solubilising pro-drug.
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):
Particularly interesting are such cyclised pro-drugs when the 1,2-diol is on a (1-4C)alkyl chain linked to a carbonyl group in a substituent of formula Rc 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 (1-4C)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:
For the avoidance of doubt, phosphono is —P(O)(OH)2; (1-4C)alkoxy(hydroxy)-phosphoryl is a mono-(1-4C)alkoxy derivative of —O—P(O)(OH)2; and di-(1-4C)alkoxyphosphoryl is a di-(1-4C)alkoxy derivative of —O—P(O)(OH)2.
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 (1-4C)alkyl (such compounds also being interesting compounds in their own right), phenyl or phenyl-(1-4C)alkyl (such phenyl groups being optionally substituted by 1 or 2 groups independently selected from (1-4C)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. Prodrugs containing a group such as (PS1) may be obtained by analagous 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 Rc is defined by, for example, R14C(O)O(1-6C)alkyl-CO— (wherein R14 is for example, benzyloxy-(1-4C)alkyl, or phenyl). Suitable substituents on a phenyl group in such esters include, for example, 4-(1-4C)piperazino-(1-4C)alkyl, piperazino-(1-4C)alkyl and morpholino-(1-4C)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 (IC):
The present invention includes the pure enantiomer depicted above or mixtures of the 5R and 5S enantiomers, for example a racemic mixture. If a mixture of enantiomers is used, a larger amount (depending upon the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer. For example, the enantiomer depicted above is the 5(R) isomer when HET is 1,2,3- or 1,2,4-triazole or tetrazole.
Furthermore, some 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.
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 (in which, for example, 3,5-difluorophenyl, 3-fluorophenyl and (des-fluoro)phenyl containing intermediates may all be prepared by analogous procedures.
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:
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:
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 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.
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 (h) as follows (wherein a variable sulfoximine/sulfimine substituent is designated by R and the other variables are as defined above unless otherwise stated)
When LG is chloro, the compound of the formula (II) may be formed by reacting a compound of the formula (II) wherein LG 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 LG is chloro or iodo may also be prepared from a compound of the formula (II) wherein LG 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 LG is (1-4C)alkanesulfonyloxy or tosylate the compound (II) may be prepared by reacting the hydroxy compound with (1-4C)alkanesulfonyl chloride or tosyl chloride in the presence of a mild base such as triethylamine or pyridine.
When LG is a phosphoryl ester (such as PhO2—P(O)—O—) or Ph2—P(O)—O— the compound (II) may be prepared from the hydroxy compound under standard conditions.
If not commercially available, compounds of the formula (III) 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.
Furthermore, a similar reaction to reaction (c) may be performed in which Q—LG1 wherein LG1 is an amine group is reacted with the epoxide (V) (optionally in the presence of an organic base), and the product is reacted with, for example, phosgene to form the oxazolidinone ring.
Alternatively, a precursor of the group HET may be incorporated in place of the group HET in the epoxide of formula (V).
Such reactions and the preparation of starting materials in within the skill of the ordinary chemist with reference to the above-cited documents disclosing analogous reactions and preparations.
Compounds of the formula (II) wherein LG is hydroxy may be obtained as described in the references cited herein, for example, by reacting a compound T—Q—LG1 (IV) where LG1 is an amine, an isocyanate, or a urethane, especially a compound of the formula (IV, LG1=NHCO2R21) with a compound of formula (XIII):
wherein R21 is (1-6C)alkyl or benzyl and R22 is (1-4C)alkyl or —S(O)n(1-4C)alkyl where n is 0, 1 or 2. Preferably R22 is (1-4C)alkyl. Compounds of the formula (II), (IV), and (XIII) may be prepared by the skilled man, for example as described in International Patent Application Publication Nos. cited herein, the contents of which are hereby incorporated by reference, and by analogous processes.
Compounds of the formula T—Q—LG1 wherein LG1 is a urethane may be prepared by the skilled chemist, for example by analogous processes to those described in International Patent Application Publication Nos. WO 97/30995 and WO 97/37980. Compounds of the formula Q—LG1 wherein LG1 is an isocyanate may be prepared by the skilled chemist, for example by analogous processes to those described in 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. The general method is illustrated in Scheme 3.
Compounds of the formula T—Q—LG1 wherein LG1 is an amine may be prepared by arylating an amine of formula (XIV), ( )x and ( )x′ are chains of length x and x′, which is suitable to give a T substituent as defined by (TA2), or a bi-, or tricyclic ring analogue of (XII) which is suitable to give a T substituent as defined by (TB); with a nitroarylhalide, such as 3,4-difluoronitrobenzene, and reducing the nitro-compound so produced to the corresponding amine. The thioether may be oxidized to a sulfimine or sulfoximine at any convenient stage of the synthesis. Examples of the way that such reactions can be employed in the overall synthesis in different orders according to convenience are shown in Scheme 3A.
Suitable amine thioethers of the type shown in formula (XIV) may be synthesized by combination of the methods well-known in the art for the separate synthesis of cyclic amines and cyclic thioethers. Cyclic thioethers are readily available by reaction of sulfide anion with bifunctional alkylating agents, such as dibromides or bis-mesylates derived from diols. Certain cyclic thioethers are also available by cycloadditions, such as 1,3-dipolarcycloadditions of thiocarbonyl-ylids to olefins to give tetrahydrothiophenes and 1,4-cycloaddition of thiocarbonyl compounds to 1,3-dienes to give dihydrothiopyrans. Cyclic amines are available by similar reactions of analogous nitrogen compounds. In addition, cyclic amines are available by reduction of a wide range of imides and lactams. It will be apparent to the skilled chemist that the similar functional groups used to prepare the cyclic thioether and cyclic amine functionality may need to be selectively protected by methods known in the art.
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. Sufoximines 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 thioethers or sulfoxides and for oxidizing sulfimines is illustrated in Scheme 4. Convenient methods for the preparation of functionalised sulfilimines and sulfoximines include those in which a sulfilimine or sulfoximine is (i) alkylated, for instance by reductive amination using aldehydes, (ii) acylated for instance using acid chlorides in pyridine, or (iii) arylated, for instance by palladium coupling with (hetero)aryl halides or by cyclisation and heteroaromatisation of an acyclic substituent on the sulfoximine N. The general method for refunctionalizing sulfimines or sulfoximines in the final step is also illustrated in Scheme 4.
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).
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.
Convenient methods for the preparation of compounds of the formula (IB) include those in which as a last step;
Such methods are shown by way of non-limiting illustration below wherein LG6 represents a convenient leaving group:
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.
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 R2F group into another R2F group as a final step in the preparation of a compound of the formula (IB).
One compound of formula (IB) may be converted into another compound of formula (IB) by reacting a compound of formula (IB) 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.
If not commercially available, compounds 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, 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). Also, for example, 3-hydroxyisoxazole may be prepared by cyclisation of CH≡C—CO—NHOH (prepared from CH≡C—CO—O-(1-4C)alkyl) as described in Chem.Pharm.Bull.Japan, 14, 92, (1966).
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.
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 1 mg and 1 g of a compound of this invention, preferably between 100 mg and 1 g of a compound. Especially preferred is a tablet or capsule which contains between 50 mg and 800 mg of a compound of this invention, particularly in the range 100 mg to 500 mg.
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 1 mg/ml and 500 mg/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 of 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 5×104 CFU/spot. Typically, compounds are active in the range 0.01 to 256 μg/ml.
Staphylococci were tested in broth using an inoculum of 5×104 CFU/spot and an incubation temperature of 37° C. for 16-24 hours.
Streptococci were tested in Mueller-Hinton broth supplemented with 2.5% clarified lake horse blood with an innoculum of 104 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 24 h at 37° C., and with an innoculum of 5×104 CFU/well.
Certain intermediates and/or Reference Examples described hereinafter within the scope of the invention may also possess useful activity, and are provided as a further feature of the invention.
The invention is now illustrated but not limited by the following Examples in which unless otherwise stated:
(5R)-3-[3-Fluoro-4-(1RS-1-imino-1-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-2-oxazolidinone
(5R)-3-[3-Fluoro-4-(1RS-1-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-2-oxazolidinone (0.951 g, 2.5 mmol) was dissolved/suspended in dichloromethane (10 ml) at ambient temperature. O-mesitylenesulfonylhydroxylamine (0.68 g, 3.2 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 methanol (5 ml). The resulting precipitate was collected by filtration and subjected to chromatography on silica gel. with a gradient of 2-20% methanol in dichloromethane to give the desired product (220 mg) as free base.
MS (APCI): 392 (MH+) for C17H18FN5O3S
1H-NMR (DMSO-d6) δ: 2.89 (m, 2H); 3.20 (m, 2H); 3.83 (brs, 3H); 3.92 (dd, 1H); 4.26 (dd, 1H); 4.86 (m, 2H); 5.17 (m, 1H); 5.81 (m, 1H); 7.28 (dd, 1H); 7.38 (dd, 1H); 7.45 (dd, 1H); 7.79 (s, 1H); 8.19 (s, 1H).
The intermediates for this compound were prepared as follows:
(5R)-3-[3-Fluoro-4-(1RS-1-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-2-oxazolidinone
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-2-oxazolidinone (1.25 g, 3.5 mmol) was stirred in a mixture of methanol and ethyl acetate (1:1, 50 ml) at ambient temperature. Sodium periodate (0.93 g, 4.3 mmol) in water (10 ml) was added dropwise, and it was stirred for 18 hours. Precipitated salts were removed by filtration and solvents were removed under vacuum. 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 (1.152 g).
MS (ESP): 377 (MH+) for C17H17FN4O3S
1H-NMR (DMSO-d6) δ: 2.57 (m, 1H); 2.91 (m, 1H); 2.97 (m, 1H); 3.13 (m, 1H); 3.39 (m, 1H); 3.67 (m, 1H); 3.92 (dd, 1H); 4.27 (dd, 1H); 4.86 (m, 2H); 5.17 (m, 1H); 5.84 (m, 1H); 7.28 (dd, 1H); 7.39 (dd, 1H); 7.45 (dd, 1H); 7.79 (d, 1H); 8.20 (d, 1H).
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-2-oxazolidinone
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-azidomethyl-2-oxazolidinone (2 g, 5.7 mmol) was dissolved in dioxane (10 ml). Bicyclo[2.2.1]hepta-2,5-diene (3.1 ml, 28.7 mmol) was added and it was refluxed under nitrogen for 18 hours. The solvent was evaporated in vacuo and the residue subjected to chromatography on silica gel eluting with 25% ethylacetate in dichloromethane to give the title compound (1.51 g).
MS (ESP): 361 (MH+) for C17H17FN4O2S
1H-NMR (DMSO-d6) δ: 2.56 (m, 2H); 2.83 (dd, 2H); 3.31 (m, 2H); 3.91 (dd, 1H); 4.26 (dd, 1H); 4.86 (m, 2H); 5.17 (m, 1H); 6.06(m, 1H); 7.25 (dd, 1H); 7.33 (dd, 1H); 7.42 (dd, 1H); 7.78 (d, 1H); 8.19 (d, 1H).
(5R)-3-[4-(36-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-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 (pH 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-d6) δ: 2.56 (m, 2H); 2.83 (dd, 2H); 3.31 (m, 2H); 3.71 (dd, 1H); 3.80 (dd, 1H); 3.81 (dd, 1H); 4.17 (dd, 1H); 4.92 (m, 1H); 6.06(m, 1H); 7.34 (m, 2H); 7.50 (m, 1H). (No MS)
Methanesulfonic acid (5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl ester
(SR)-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 (pH 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-d6) δ: 2.56 (m, 2H); 2.83 (dd, 2H); 3.28 (s, 3H); 3.32 (m, 2H); 3.85 (dd, 1H); 4.21 (dd, 1H); 4.48 (dd, 1H); 4.53 (dd, 1H); 5.04 (m, 1H); 6.07 (m, 1H); 7.33 (dd, 1H); 7.36 (dd, 1H); 7.50 (dd, 1H). (No MS)
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-hydroxymethyl-2-oxazolidinone
4-(2-Fluoro-4-benzyloxycarbonylaminophenyl)-3,6-dihydro-2H-thiopyran (15.3 g, 44.6 mM) was dissolved on dry tetrahydrofuran (175 ml) and stirred under nitrogen at −70. n-Butyllithium (1.6M in hexanes, 30 ml, 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 (29 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.
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 isohexane to precipitate the desired product (11.3 g).
MS (ESP): 310 (MH+) for C15H16FNO3S
NMR (DMSO-d6) δ: 2.52 (m overlapped by DMSO, ˜2H); 2.78 (t, 2H); 3.27 (m, 2H); 3.52 (m, 1H); 3.65 (m, 1H); 3.80 (dd, 1H); 4.06 (dd, 1H); 4.65 (m, 1H); 5.19 (t, 1H); 6.01 (s, 1H); 7.28 (m, 2H); 7.47 (dd, 1H).
4-(2-Fluoro-4-benzyloxycarbonylaminophenyl)-3,6-dihydro-2H-thiopyran
4-(2-Fluoro-4-aminophenyl)-3,6-dihydro-2H-thiopyran (9.8 g, 46.8 mM) was dissolved in dry dichloromethane (196 ml), pyridine (6.23 g, 79.1 mM) added, and the mixture stirred under nitrogen at −20°. A solution of benzyl chloroformate (9.54 g, 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 1 M 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 (15.5 g).
MS (Negative ESP): 342 (M−H−) for C19H18FNO2S
NMR (DMSO-d6) δ: 2.50 (s, 2H); 2.79 (t, 2H); 3.26 (m, 2H); 5.15 (s, 2H); 5.99 (s, 1H); 7.18 (m, 2H); 7.38 (m, 6H); 10.01 (s, 1H).
4-(2-Fluoro-4-aminophenyl)-3,6-dihydro-2H-thiopyran
4-Hydroxy4-(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 (CDCl3) δ: 2.59 (m, 2H); 2.72 (t, 2H); 3.30 (m, 2H); 3.80 (br, 2H); 5.93 (m, 1H); 6.35 (dd, 1H); 6.39 (dd, 1H); 6.97 (t, 1H).
(5R)-3-[3,5-Difluoro-4-(1RS-1-imino-1-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-2-oxazolidinone
(5R)-3-[3,5-Difluoro-4-(1RS-1-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-2-oxazolidinone (0.54 g, 1.4 mmol) was dissolved/suspended in dichloromethane (20 ml) at ambient temperature. O-Mesitylenesulfonylhydroxylamine (0.3 g, 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 solvent was removed under vacuum and the product was precipitated from methanol by the addition of ethylacetate to give the title compound (0.72 g) as its mesitylene sulfonate salt.
MS (ESP): 410 (MH+) for C17H17F2N5O3S
NMR (DMSO-d6) δ: 2.19 (s, 2×3H ); 2.55 (s, 2×6H ); 2.92 (br, 2×2H ); 3.80-4.06 (m, 2×3H); 4.27 (m, 2×1H); 4.43 (brs, 2×1H); 4.51 (brs, 2×1H); 4.86 (m, 2×1H); 5.03 (m, 2×1H); 5.21 (m, 2×1H); 5.86 (m, 2×1H); 6.76 (s, 2×2H); 7.33 (d, 2H); 7.39 (d, 2H); 7.79 (s, 1H); 8.20 (s, 1H); 8.50 (brs, 1H); 8.71 (s, 1H); 8.89 (s, 1H). 3 exchangeables not detected, complex spectrum resulting from diasteromeric mixture.
The intermediates for this compound were prepared as follows:
(5R)-3-[3,5-Difluoro-4-(1RS-1-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-2-oxazolidinone
(R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-2-oxazolidinone (0.86 g, 2.3 mmol) was stirred in a mixture of methanol and ethyl acetate (1:1, 20 ml) at ambient temperature. Sodium periodate (0.50 g, 2.4 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 (0.69 g).
MS (ESP): 395 (MH+) for C17H16F2N4O3S
1H-NMR (DMSO-d6) δ: 2.41 (brs, 1H); 2.80 (m, 1H); 2.97 (brs, 1H); 3.15 (m, 1H); 3.39 (m, 1H); 3.67 (brs, 1H); 3.94 (m, 1H); 4.25 (dd, 1H); 4.85 (brs, 2H); 5.19 (m, 1H); 5.75 (brs, 1H); 7.33 (d, 2H); 7.79 (brs, 1H); 8.20 (brs, 1H ).
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-2-oxazolidinone
Methanesulfonic acid (5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-oxazolidin-5-ylmethyl ester (1.1 g, 5.7 mmol) was dissolved in dry N,N-dimethylformamide (5 ml) and sodium azide (0.35 g, 5.43 mmol) was added. It was heated at 60° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethylacetate, washed with water and dried over magnesium sulfate. Solvent was removed under vacuum to give an oil. The crude intermediate azide was not characterized. It was taken up in 1,4-dioxane (20 ml), bicyclo[2.2.1]hepta-2,5-diene (1.0 g, 10.9 mmol) was added and it was refluxed for 12 hours. Solvent was removed under vacuum and the residue chromatographed on silica gel with 5% methanol in dichloromethane to give the title compound (0.62 g).
MS (ESP): 379 (MH+) for C17H16F2N4O2S
NMR(DMSO-d6) δ: 2.43 (brs, 2H); 2.83 (dd, 2H); 3.31 (brs, 2H); 3.92 (m, 1H); 4.25 (dd, 1H); 4.84 (d, 2H); 5.18 (m, 1H); 5.98 (brs, 1H); 7.28 (d, 2H); 7.79 (brs, 1H); 8.19 (brs, 1H).
Methanesulfonic acid (5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-oxazolidin-5-ylmethyl ester
(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-d6) δ: 2.44 (m, 2H); 2.84 (dd, 2H); 3.28 (s, 3H); 3.31 (m, 2H); 3.86 (dd, 1H); 4.20 (dd, 1H); 4.50 (m, 2H); 5.10 (m, 1H); 5.99 (m, 1H); 7.36 (d, 2H). (No MS)
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-hydroxymethyl-2-oxazolidinone
4-(2,6-Difluoro-4-benzyloxycarbonylaminophenyl)-3,6-dihydro-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°. n-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 isohexane, then recrystallised from isopropanol to give the desired product (16.2 g).
MS (ESP): 328 (MH+) for C15H15F2NO3S
NMR (DMSO-d6) δ: 2.40 (m, 2H); 2.81 (t, 2H); 3.28 (m, 2H); 3.53 (m, 1H); 3.67 (m, 1H); 3.82 (dd, 1H); 4.08 (t, 1H); 4.70 (m, 1H); 5.21 (t, 1H); 5.95 (s, 1H); 7.33 (d, 2H).
4-(2,6-Difluoro-4-benzyloxycarbonylaminophenyl)-3,6-dihydro-2H-thiopyran
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 1 M 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−H−) for C19H17F2NO2S
NMR (DMSO-d6) δ: 2.37 (br, 2H); 2.78 (t, 2H); 3.24 (m, 2H); 5.16 (s, 2H); 5.89 (m, 1H); 7.17 (d, 2H); 7.38 (m, 5H); 10.18 (s, 1H).
4-(2,6-Difluoro-4-aminophenyl)-3,6-dihydro-2H-thiopyran
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 C11H11F2NS
NMR (CDCl3) δ: 2.48 (m, 2H); 2.83 (t, 2H); 3.30 (m, 2H); 3.80 (br, 2H); 5.87 (m, 1H); 6.16 (d, 2H).
4-Hydroxy-4-(2,6-difluoro-4-aminophenyl)tetrahydrothiopyran
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 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 sec-butyllithium (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 1 M 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 isohexane (300 ml). The desired product was precipitated from dichloromethane by isohexane to give a white solid (17.4 g).
MS (Negative ESP): 244 (M−H−) for C11H13F2NOS
NMR (CDCl3) δ: 2.26 (d, 2H); 2.39 (t, 4H); 2.65 (t, 1H); 3.27 (t, 2H); 3.82 (br, 2H); 6.17 (d, 2H).
(5R)-3-[3-Fluoro-4-(1-imino-1-oxido-4-thiazin-4-yl)phenyl]-5-(1-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one
(5R)-3-(3-Fluoro-4-(1-oxidothiomorpholin-4-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (0.5 g, 1.3 mmol) and sodium azide (0.19 g, 2.9 mmol) were added at ambient temperature under nitrogen to stirred polyphosphoric acid (10 g). The mixture was warmed at 60° C. for 12 h, cooled slowly to 0° C. and treated dropwise with water (40 ml) and then with enough 50% (w/w) sodium hydroxide to raise the pH to 11.0. This mixture was diluted with water (200 ml) then extracted with a mixture of chloroform and methanol (95:5). The organic extract was dried (Na2SO4) and concentrated under reduced pressure to give a residue that was purified by chromatography over silica-gel (elution with 10% methanol in ethyl acetate) to give the desired product (0.34 g) as a free base.
MS (APCI): 395 (M+H)+ for C16H19FN6O3S
1H-NMR (DMSO-d6) δ: 3.14 (m, 4H); 3.37 (m, 2H); 3.45 (m, 2H); 3.79 (s, 1H); 3.88 (dd, 1H); 4.23 (t, 1H); 4.84 (d, 2H); 5.14 (m, 1H); 7.14 (dd, 1H);, 7.19 (t, 1H); 7.43 (dd, 1H); 7.78 (d, 1H); 8.18 (d, 1H).
The intermediates for this example were prepared as follows:
(5R)-3-(3-Fluoro-4-thiomorpholin-4-ylphenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one
A mixture of (5R)-5-(azidomethyl)-3-(3-fluoro-4-thiomorpholin-4-ylphenyl)-1,3-oxazolidin-2-one (20 g, 59 mmol) [Ref: J. Med. Chem. 1996, 39, 680-685] and bicyclo[2.2.1]hepta-2,5-diene (20 ml) in dioxane (200 ml) was heated at reflux under nitrogen for 24 hours. The solvent was evaporated under reduced pressure and the involatile residue was purified by chromatography on silica-gel (elution with 10% methanol in dichloromethane) to give the title compound (18 g).
MS (APCI): 364 (M+H)+ for C16H18FN5O2S
1H-NMR (DMSO-d6) δ: 2.75 (t, 4H); 3.21 (t, 4H); 3.87 (dd, 1H); 4.21 (t, 1H); 4.84 (d, 2H); 5.13 (m, 1H); 7.12 (m, 2H); 7.40 (dd, 1H); 7.78 (d, 1H); 8.18 (d, 1H).
(5R)-3-[3-Fluoro-4-(1-oxidothiomorpholin-4-yl)phenyl ]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one
A solution of (5R)-3-(3-fluoro-4-thiomorpholin-4-ylphenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (16.0 g, 44.1 mmol) in a mixture of methanol and chloroform (2:1; 300 ml) was treated dropwise with a solution of sodium periodate (11.3 g, 52.9 mmol) in water (200 ml). The mixture was stirred at room temperature for 18 hours and then filtered. The filtrate was concentrated under reduced pressure and the involatile residue was diluted with water (150 ml) and then extracted with chloroform (6×250 ml). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a foamy solid. The foamy residue was purified by flash chromatography over silica-gel (elution with chloroform, and then with 5% methanol in chloroform) to give the title product (15.7 g).
MS (APCI): 380 (M+H)+ for C16H18FN5O3S
1H-NMR (DMSO-d6) δ: 2.86 (m, 2H); 3.04 (m, 2H); 3.19 (dd, 2H); 3.53 (t, 2H); 3.88 (dd, 1H); 4.22 (t, 1H); 4.84 (d, 2H); 5.15 (m, 1H); 7.15 (dd, 1H); 7.21 (t, 1H); 7.43 (dd, 1H); 7.78 (d, 1H); 8.19 (d, 1H).
(5R)-3-(3-Fluoro-4-[1-(methylimino)-1-oxido-4-thiazin-4-yl]phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one
Trifluoroacetic acid (170 μl, 2.3 mmol) was added to a mixture of (5R)-3-[3-fluoro-4-(1-imino-1-oxido-4-thiazin-4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 3) (0.3 g, 0.76 mmol), paraformaldehyde (0.1 g), and triethylsilane (364 μl, 2.3 mmol) in acetonitrile (8 ml) at room temperature. The mixture was stirred for 8 hours at room temperature under nitrogen, then diluted with water (50 ml), neutralized to pH 11, and extracted with 5% methanol in dichloromethane (4×50 ml). The combined organic extracts were dried over Na2SO4 and concentrated to give an involatile residue that was purified by flash chromatography over silica-gel (elution with 5% methanol in dichloromethane) to give the title compound (0.34 g).
MS (APCI): 409 (M+H)+ for C17H21FN6O3S
1H-NMR (DMSO-d6) δ: 2.69 (s, 3H); 3.20 (m, 2H); 3.27 (m, 2H); 3.37 (m, 2H); 3.43 (m, 2H); 3.88 (dd, 1H); 4.22 (t, 1H); 4.84 (d, 2H); 5.15 (m, 1H); 7.14 (dd, 1H); 7.19 (t, 1H); 7.43 (dd, 1H); 7.78 (d, 1H); 8.18 (d, 1H).
(5R)-3-(3-Fluoro-4-(1-((1H-imidazol-2-ylmethyl)imino)-1-oxido-4-thiazinan-4-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one
Trifluoroacetic acid (235 μl, 3.04 mmol) was added to a mixture of (5R)-3-[3-fluoro-4-(1-imino-1-oxido-4-thiazin-4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 3) (0.3 g, 0.76 mmol), imidazole-2-carboxaldehyde (0.29 g, 3.04 mmol), and triethylsilane (485 μl, 3.04 mmol) in acetonitrile (8 ml) at room temperature. The reaction mixture was stirred under nitrogen for 24 hours at 50° C., allowed to cool to room temperature, diluted with water (50 ml), neutralized to pH 11, and extracted with 5% methanol in dichloromethane (4×50 ml). The combined extracts were dried over Na2SO4 and concentrated under reduced pressure to give an involatile residue that was purified by flash chromatography over silica-gel (elution with 8% methanol in ethyl acetate) to give the title compound (0.18 g).
MS (APCI): 475 (M+H)+ for C20H23FN8O3S
1H-NMR (DMSO-d6) δ: 3.23-3.42 (m, 8H); 3.87 (dd, 1H); 4.20 (s, 2H); 4.21 (t, 1H); 4.84 (d, 2H); 5.15 (m, 1H); 6.79 (s, 1H); 7.01 (s, 1H); 7.13-7.19 (m, 3H); 7.42 (dd, 1H); 7.78 (d, 1H); 8.18 (d, 1H).
(5R)-3-(3-Fluoro-4-(1-((1-methylthio-1-(N-cyanoimino)methyl)imino)-1-oxido-4-thiazinan-4-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one
A mixture of (5R)-3-(3-fluoro-4-(1-imino-1-oxido-4-thiazinan-4-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 3) (1.0 g, 2.53 mmol) and dimethyl N-cyanodithioiminocarbonate was heated in a microwave oven at 140° C. for 1.5 hours. The involatile residue was purified by flash chromatography over silica-gel (elution with 7% methanol in ethyl acetate) to give the title compound (0.7 g).
MS (APCI): 493 (M+H)+ for C19H21FN8O3S2
1H-NMR (DMSO-d6) δ: 2.58 (s, 3H); 3.47 (m, 2H); 3.65 (m, 2H); 3.81 (m, 2H); 3.88 (dd, 1H); 3.97 (m, 2H); 4.23 (t, 1H); 4.84 (d, 2H); 5.15 (m, 1H); 7.16 (dd, 1H); 7.23 (t, 1H); 7.44 (dd, 1H); 7.78 (dd, 1H); 7.78 (d, 1H); 8.18 (d, 1H).
(5R)-3-(3-Fluoro-4-(1-((1-dimethylamino-1-(N-cyanoimino)methyl)imino)-1-oxido-4-thiazinan-4-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one
A mixture of (5R)-3-(3-fluoro-4-(1-((1-methylthio-1-(N-cyanoimino)methyl)imino)-1-oxido-1λ6-4-thiazinan-4-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 6) (0.24 g, 0.49 mmol) and dimethylamine (5 ml of a 2M solution in tetrahydrofuran) was heated at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the involatile residue was purified by flash chromatography over silica-gel (elution with 12% methanol in ethyl acetate) to give the title compound (0.18 g).
MS (APCI): 490 (M+H)+ for C20H24FN9O3S
1H-NMR (DMSO-d6) δ: 3.12 (s, 6H); 3.54 (m, 4H); 3.67 (m, 2H); 3.76 (m, 2H); 3.88 (dd, 1H); 4.23 (t, 1H); 4.85 (d, 2H); 5.15 (m, 1H); 7.16 (dd, 1H); 7.23 (t, 1H); 7.44 (dd, 1H); 7.78 (d, 1H); 8.18 (d, 1H).
(5R)-3-(3-Fluoro-4-(1-((4-amino-5-methoxycarbonylthiazol-2-yl)imino)-1-oxido-4-thiazinan-4-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one
A mixture of (5R)-3-(3-fluoro-4-(1-((1-methylthio-1-(N-cyanoimino)methyl)imino)-1-oxido-4-thiazinan-4-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 6) (0.4 g, 0.81 mmol) and methylthioglycolate (160 μl, 1.78 mmol) in dry ethanol (25 ml) was treated with triethylamine (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 24 hours then warmed up to 60° C. for 15 h. The mixture was concentrated under reduced pressure and the involatile residue was purified by chromatography on silica-gel (elution with 5% methanol in ethyl acetate) to give the title compound (180 mg).
MS (APCI): 551 (M+H)+ for C21H23FN8O5S2
1H-NMR (DMSO-d6) δ: 3.43 (m, 2H); 3.63 (m, 2H); 3.66 (s, 3H); 3.74 (m, 2H); 3.88 (dd, 1H); 3.94 (m, 2H); 4.22 (t, 1H); 4.84 (d, 2H); 5.15 (m, 1H); 6.86 (s, 2H); 7.15 (dd, 1H); 7.24 (t, 1H); 7.44 (dd, 1H); 7.78 (s, 1H); 8.18 (s, 1H).
(5R)-3-[3-Fluoro-4-(1RS-1-(acetylimino)-1-oxo-2,3-dihydro-thiopyran-4-yl)-phenyl]-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one
(5R)-3-[3-Fluoro-4-(1RS-1-imino-1-oxo-3,6-dihydro-thiopyran-4-yl)-phenyl]-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one (Example 1) as its free base (0.18 g, 0.46 mmol) was dissolved in pyridine (0.3 ml), dichloromethane (2 ml) was added and it was cooled to −20° C. 20 Acetylchloride (66 μl, 0.93 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 ethylacetate, washed with brine and dried over sodium sulfate. Chromatography on silicagel with acetone/hexane 2:1 gave 0.161 g of the title compound.
MS (ESP): 433.83 (MH+) for C19H20FN5O4S
1H-NMR (DMSO-d6) δ: 8.19 (d, 1H); 7.78 (brs, 1H); 7.47 (dd, 1H); 7.40 (dd, 1H); 7.29 (dd, 1H); 5.87 (m, 1H); 5.18 (m, 1H); 4.86 (d, 2H); 4.40 (m, 1H); 4.26 (dd, 1H); 4.23 (m, 1H); 3.92 (dd, 1H); 3.71 (m, 2H); 2.96 (m, 2H); 1.99 (s, 3H).
(5R)-3-[3,5-Difluoro-4-(1RS-1-(acetylimino)-1-oxo-2,3-dihydrothiopyran-4-yl)-phenyl]-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one
(5R)-3-[3,5-Difluoro-4-(1RS-1-imino-1-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one (Example 2) as its mesitylene sulfonate salt (0.1 g, 0.164 mmol) was dissolved in pyridine (0.3 ml), dichloromethane (2 ml) was added and it was cooled to −20° C. Acetylchloride (26 mg, 0.33 mmol) dissolved in dichloromethane (2 ml) was added dropwise and it was stirred for 30 min. It was quenched with methanol, extracted with ethylacetate, washed with saturated sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. Chromatography on silica gel with 5% methanol in dichloromethane gave 50 mg of the title compound.
MS (ESP): 451.75 (MH+) for C19H19F2N5O4S
1H-NMR (CDCl3) δ: 7.81 (d, 1H); 7.79 (d, 1H); 7.10 (d, 2H); 5.78 (m, 1H); 5.12 (m, 1H); 4.82 (d, 2H); 4.51 (m, 1H); 4.18 (dd, 1H); 4.10 (m, 2H); 3.72 (m, 1H); 3.45 (m, 1H); 3.0 (m, 2H); 2.18 (s, 3H).
(5R)-3-[3,5-Difluoro-4-(1RS-1-(2-hydroxyl-acetylimino)-1-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one
(5R)-3-[3,5-Difluoro-4-(1RS-1-imino-1-oxo-3,6-dihydrothiopyran-4-yl)-phenyl]-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one (Example 2) as its mesitylene sulfonate salt (0.2 g, 0.33 mmol) was reacted with acetyloxyacetyl chloride (90 mg, 0.66 mmol) following the procedure described under example 9. Chromatography on silica gel with 5% methanol in dichloromethane gave 100 mg of pure product. This intermediate was dissolved in 15 ml of methanol, catalytic amount of potassium carbonate was added and the mixture was stirred at room temperature for 3 hours. Ammonium chloride (1 eq.) was added and the solvent was evaporated. The residue was purified by flash chromatography with acetone to give 50 mg of the title compound as white solid.
MS (ESP): 467.75 (MH+) for C19H19F2N5O5S
1H-NMR (DMSO-d6) δ: 8.19 (d, 1H); 7.78 (d, 1H); 7.40 (d, 2H); 5.83 (m, 1H); 5.18 (m, 1H); 4.86 (d, 2H); 4.82 (dd, 1H); 4.45(m, 1H); 4.30 (m, 1H); 4.23 (dd, 1H); 3.92 (m, 3H); 3.71 (m, 2H); 2.90 (m, 2H).
| Number | Date | Country | Kind |
|---|---|---|---|
| 0108765.9 | Apr 2001 | GB | national |
| 60330588 | Oct 2001 | US | national |
This application is a national stage filing under 35 U.S.C. 371 of International Application No. PCT/GB02/01644, filed Apr. 3, 2002, which claims priority from United Kingdom Patent Application No. 0108765.9, filed Apr. 7, 2001, and U.S. Provisional Application No. 60/330,588, filed Oct. 25, 2001, the specifications of which are incorporated by reference herein. International Application No. PCT/GB02/01644 was published under PCT Article 21(2) in English.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/GB02/01644 | 4/3/2002 | WO |
