WO2007138381A2 - Oxazolidinones phosphonées et leurs utilisations pour la prévention et le traitement des infections des os et des articulations - Google Patents
Oxazolidinones phosphonées et leurs utilisations pour la prévention et le traitement des infections des os et des articulations Download PDFInfo
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- WO2007138381A2 WO2007138381A2 PCT/IB2006/004233 IB2006004233W WO2007138381A2 WO 2007138381 A2 WO2007138381 A2 WO 2007138381A2 IB 2006004233 W IB2006004233 W IB 2006004233W WO 2007138381 A2 WO2007138381 A2 WO 2007138381A2
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- Prior art keywords
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- phosphonated
- independently
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- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title claims description 128
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- 206010031252 Osteomyelitis Diseases 0.000 claims abstract description 11
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- 150000001875 compounds Chemical class 0.000 claims description 206
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- SIMWTRCFFSTNMG-AWEZNQCLSA-N n-[[(5s)-3-[3-fluoro-4-[4-(2-hydroxyacetyl)piperazin-1-yl]phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCN(C(=O)CO)CC1 SIMWTRCFFSTNMG-AWEZNQCLSA-N 0.000 claims description 74
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- XJHXLMVKYIVZTE-LOALFDMRSA-N chloroeremomycin Chemical compound O([C@@H]1C2=CC=C(C(=C2)Cl)OC=2C=C3C=C(C=2O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@@H]2O[C@@H](C)[C@H](O)[C@@](C)(N)C2)OC2=CC=C(C=C2Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]2C(=O)N[C@@H]1C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@@H](O)[C@H](C)O1 XJHXLMVKYIVZTE-LOALFDMRSA-N 0.000 claims description 6
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical class CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- ZZLLAUXCOUTIQE-UHFFFAOYSA-N methyl 4-[2,2-bis(dimethoxyphosphoryl)ethyl]benzoate Chemical compound COC(=O)C1=CC=C(CC(P(=O)(OC)OC)P(=O)(OC)OC)C=C1 ZZLLAUXCOUTIQE-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229940051866 mouthwash Drugs 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- OLBKOBIUGJNQJK-UHFFFAOYSA-N n-[4-(diethoxyphosphorylmethyl)phenyl]-2,2,2-trifluoroacetamide Chemical compound CCOP(=O)(OCC)CC1=CC=C(NC(=O)C(F)(F)F)C=C1 OLBKOBIUGJNQJK-UHFFFAOYSA-N 0.000 description 1
- UKQDRSOXSXSRTB-UHFFFAOYSA-N n-[4-[bromo(diethoxyphosphoryl)methyl]phenyl]-2,2,2-trifluoroacetamide Chemical compound CCOP(=O)(OCC)C(Br)C1=CC=C(NC(=O)C(F)(F)F)C=C1 UKQDRSOXSXSRTB-UHFFFAOYSA-N 0.000 description 1
- ZFVLGSLIBYLODS-SFHVURJKSA-N n-[[(5s)-3-[4-[4-[2,2-bis(dimethoxyphosphoryl)ethyl]piperazin-1-yl]-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound C1CN(CC(P(=O)(OC)OC)P(=O)(OC)OC)CCN1C1=CC=C(N2C(O[C@@H](CNC(C)=O)C2)=O)C=C1F ZFVLGSLIBYLODS-SFHVURJKSA-N 0.000 description 1
- HTKOJXMSIUCGHR-MHZLTWQESA-N n-[[(5s)-3-[4-[4-[4,4-bis[di(propan-2-yloxy)phosphoryl]butanoyl]piperazin-1-yl]-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound C1CN(C(=O)CCC(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C)CCN1C1=CC=C(N2C(O[C@@H](CNC(C)=O)C2)=O)C=C1F HTKOJXMSIUCGHR-MHZLTWQESA-N 0.000 description 1
- PEYIEDSBJZPBHF-NDEPHWFRSA-N n-[[(5s)-3-[4-[4-[5,5-bis[di(propan-2-yloxy)phosphoryl]pentanoyl]piperazin-1-yl]-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound C1CN(C(=O)CCCC(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C)CCN1C1=CC=C(N2C(O[C@@H](CNC(C)=O)C2)=O)C=C1F PEYIEDSBJZPBHF-NDEPHWFRSA-N 0.000 description 1
- UZJDBIDFEHBERK-QFIPXVFZSA-N n-acetyl-3,3-bis(diethoxyphosphoryl)-n-[[(5s)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]propanamide Chemical compound O=C1O[C@@H](CN(C(=O)CC(P(=O)(OCC)OCC)P(=O)(OCC)OCC)C(C)=O)CN1C(C=C1F)=CC=C1N1CCOCC1 UZJDBIDFEHBERK-QFIPXVFZSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- PUUSSSIBPPTKTP-UHFFFAOYSA-N neridronic acid Chemical compound NCCCCCC(O)(P(O)(O)=O)P(O)(O)=O PUUSSSIBPPTKTP-UHFFFAOYSA-N 0.000 description 1
- 229950010733 neridronic acid Drugs 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical class CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
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- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
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- 230000020477 pH reduction Effects 0.000 description 1
- WXHIJDCHNDBCNY-UHFFFAOYSA-N palladium dihydride Chemical compound [PdH2] WXHIJDCHNDBCNY-UHFFFAOYSA-N 0.000 description 1
- WYMSBXTXOHUIGT-UHFFFAOYSA-N paraoxon Chemical compound CCOP(=O)(OCC)OC1=CC=C([N+]([O-])=O)C=C1 WYMSBXTXOHUIGT-UHFFFAOYSA-N 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- UCUUFSAXZMGPGH-UHFFFAOYSA-N penta-1,4-dien-3-one Chemical class C=CC(=O)C=C UCUUFSAXZMGPGH-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical class CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 150000003007 phosphonic acid derivatives Chemical class 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 125000005496 phosphonium group Chemical group 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical class CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical class OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical group N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- BTVYFIMKUHNOBZ-QXMMDKDBSA-N rifamycin s Chemical class O=C1C(C(O)=C2C)=C3C(=O)C=C1NC(=O)\C(C)=C/C=C\C(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C(C)C(OC)\C=C/OC1(C)OC2=C3C1=O BTVYFIMKUHNOBZ-QXMMDKDBSA-N 0.000 description 1
- 229940081192 rifamycins Drugs 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical class OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229940041030 streptogramins Drugs 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical class OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003441 thioacyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N vinyl ethyl ether Natural products CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- GDJZZWYLFXAGFH-UHFFFAOYSA-M xylenesulfonate group Chemical group C1(C(C=CC=C1)C)(C)S(=O)(=O)[O-] GDJZZWYLFXAGFH-UHFFFAOYSA-M 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
Definitions
- the invention relates to phosphonated derivatives of oxazolidinones. These compounds are useful as antibiotics for prevention and/or the treatment of bone and joint infections, especially for the prophylaxis and/or treatment of osteomyelitis.
- Osteomyelitis is an inflammation of bone caused by a variety of microorganisms, mainly
- Staphylococcus aureus (Carek et al. , American Family Physician (2001 ), Vo1 12, 12:2413-2420). This painful and debilitating disease occurs more commonly in children. Within the adult population, diabetics and kidney dialysis patients are also vulnerable. The acute form of the disease is treatable with antibiotics, but requires a lengthy period of daily therapy. It can, however, revert to a recurrent or chronic form requiring repeated hospital stays and heavy treatment regimens.
- Oxazolidinones are a new class of synthetic antimicrobial agents which inhibit the initiation of protein synthesis at the ribosomal level (Renslo et al Bioorganic & Medicinal Chemistry (2006), 14, 4227-4240). Best known oxazolidinones are certainly linezolid (International PCT patent application WO 95/07271 ) and eperezolid (US patent No. 5,652,238). Both drugs were proven clinically and microbiologically to have potent activity against gram- positive organisms including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., and Streptococcus spp.
- Bisphosphonates are well-characterized bone-seeking agents. These compounds are known to have a high affinity to the bones due to their ability to bind the Ca 2+ ions found in the hydroxyapatite forming the bone tissues (Hirabayashi and Fujisaki, Clin. Pharmacokinet. (2003) 42(15): 1319-1330). Therefore, many different types of bisphosphonate-conjugated compounds have been made for targeting drugs selectively to the bone, including proteins (Uludag et a/., Biotechnol Prog.
- the present invention is directed to antimicrobial compounds which have an affinity for binding bones. More particularly, the invention is directed to phosphonated derivatives of oxazolidinones. These compounds are useful as antibiotics for the prevention or treatment of bone and joint infections, especially for the prevention and treatment of osteomyelitis.
- the compounds of the invention are represented by the general Formula (I) as illustrated below:
- A is an oxazolidinone antimicrobial molecule
- B is a phosphonated group having a high affinity to osseous tissues
- L is a bond or a linker for covalently coupling B to A
- n is an 1 ,2 or 3.
- B is a phosphonated group having a high affinity to osseous tissues.
- B is a bisphosphonate. More preferably, B is a bisphosphonate selected from the group consisting of:
- each R* is independently selected from the group consisting of H, lower alkyl, cycloalkyl, aryl and heteroaryl, with the proviso that at least two R* are H;
- X is H, OH 1 NH 2 , or a halo group;
- X 1 are both H, or each is independently selected from the group consisting of H, OH, NH 2 , and a halo group.
- L is a cleavable linker for covaltently and reversibly coupling B to A.
- L couples B to A through one or more hydroxyl groups on A, through one or more nitrogen atoms on A, or through one or more hydroxyl groups and one or more nitrogen atoms on A.
- L couples B to A through a hydroxyl group on A, preferably L is one of the following linkers:
- n is an integer ⁇ 10, preferably 1 , 2, 3 or 4, more preferably 1 or 2; each p is independently O or an integer ⁇ 10, preferably 0, 1 , 2, 3 or 4, more preferably 0 or 1 ; q is 2 or 3 r is 1 , 2, 3, 4 or 5
- W 1 and W 2 are integers ⁇ 0 such that their sum (W 1 + W 2 ) is 1 ,2 or 3 each R L is independently selected from the group consisting of H, ethyl and methyl, preferably H;
- B represents the phosphonated group
- a ' and the substructure ° of the linker represents the hydroxyl moiety of A.
- L couples B to A through a nitrogen atom on A
- L is one of the following linkers:
- n is an integer ⁇ 10, preferably 1 , 2, 3 or 4, more preferably 1 or 2; each p is independently 0 or an integer ⁇ 10, preferably 0, 1 , 2, 3 or 4, more preferably 0 or 1 ; q is 2 or 3; each R L is independently selected from the group consisting of H, ethyl and methyl, preferably H;
- R a is C x H y where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1 ;
- X is CH 2 , -CONR L -, -CO-O-CH 2 -, or— CO— O— ;
- B represents the phosphonated group; and
- a a represents the nitrogen atom on A.
- at least one of B — L — is coupled to a hydroxyl functionality on the oxazolidinone antimicrobial molecule A.
- B — L — is one of the following:
- each B represents a phosphonated group; each p is independently 0 or an integer ⁇ 10, preferably 0, 1 , 2, 3, or 4, more preferably 0 or 1 ; each R L is independently selected from the group consisting of H, ethyl and methyl, preferably H; q is 2 or 3; n is an integer ⁇ 10, preferably 1 , 2, 3, or 4, more preferably 1 or 2; r is 1 , 2, 3, 4 or 5; and
- W 1 and W 2 are each integers ⁇ 0 such that their sum (W 1 + W 2 ) is 1 , 2 or 3.
- at least one of B— L— is coupled to a nitrogen atom on the oxazolidinone antimicrobial molecule A.
- B — L — is one of the following:
- B represents said phosphonated group
- n is an integer s 10, preferably 1 , 2, 3, or 4, more preferably 1 or 2
- each p is independently 0 or an integer ⁇ 10, preferably 0, 1 , 2, 3, or 4, more preferably 0 or 1
- each R L is independently selected from the group consisting of H, ethyl and methyl, preferably H
- q is 2 or 3;
- n is an integer of 2 to 3
- at least one of B— L— is coupled to a hydroxyl functionality on the oxazolidinone antimicrobial molecule A
- at least one of B — L — is coupled to a nitrogen atom on the oxazolidinone antimicrobial molecule A.
- B — L — is one of the following:
- each B represents a phosphonated group; each p is independently 0 or an integer ⁇ 10, preferably 0, 1 , 2, 3, or 4, more preferably 0 or 1 ; each R L is independently selected from the group consisting of H, ethyl and methyl, preferably H; q is 2 or 3; n is an integer ⁇ 10, preferably 1 , 2, 3, or 4, more preferably 1 or 2; r is 1 , 2, 3, 4 or 5; and
- W 1 and W 2 are each integers ⁇ 0 such that their sum (W 1 + W 2 ) is 1 , 2 or 3.
- B— L— is one of the following:
- B represents said phosphonated group
- n is an integer ⁇ 10, preferably 1 , 2, 3, or 4, more preferably 1 or 2
- each p is independently 0 or an integer ⁇ 10, preferably 0, 1, 2, 3, or 4, more preferably 0 or 1
- each R L is independently selected from the group consisting of H, ethyl and methyl, preferably H
- q is 2 or 3;
- R 3 is C x Hy where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1. In a further preferred embodiment, n is 1 , 2 or 3.
- the oxazolidinone antimicrobial molecule A has a structure represented by the following Formula A1 :
- Each of X is independently hydrogen or a halogen, preferably a hydrogen or fluorine;
- W 1 is hydroxy, halo, amino, azido, (1-4C)alkanesulfonyloxy, (1-4C)alkylthio, (1-4C)alkylaminocarbonyloxy, NHS(O) m (1-4C)alkyl, NHCOR c , NHCSR c ; isoxazol-3-oxy, isothiazol-3-oxy, (1 ,2,5-thiadiazol)-3-oxy, (1,2,5-oxadiazol)-3-oxy, isoxazol-3-amino, isothiazol-3- amino, (1 ,2,5-thiadiazol)-3- amino, (1 ,2,5-oxadiazol)-3-amino, tetrazol-2-yl, tetrazol-1-yl, (1,2,3-triazol)-1-yl, or (4-ethynyl-1,2,3-triazol)-1-yl wherein: m is 0, 1 , or 2 and R 0 is H
- W 2 is selected from the group consisting of formulae M9-M16
- D 1 is independently CH or N and D 2 , D 3 and D 4 , are each independently CH, CH 2 , N, S or O and each zzzzz represents either a single bond or a double bond;
- T 1 is O, S, SO, SO 2 , NH, NR a , NCOCH 2 OH, OrNCOR 3 , C(OH)CH 2 N(R a ) 2 , C(OH)CH 2 OR 3 , CH-(tetrazol-2-yl), or CH(tetrazol-1 -yl) wherein each R a is independently H, aryl, (1-4C)aIkyl, cycloalkyl, heteroaryl, amino, (1-
- T 2 is hydroxyl, amino, chloro, fluoro, bromo, -CO 2 H, cyano, Or-C(O)N(Ro) 2 , wherein each
- R d is defined as above. V is N or CH
- R 4 is H or (1-4C) alkyl, -(CH 2 ) x -(CH(OH))-(CH 2 ) y -Q, -(CH 2 ) x -(CH(NH 2 ))-(CH 2 ) y -Q or -
- R 5 is one of either -C 3 H b , -(CH 2 ) a -(CH(OH))-(CH 2 ) c -, -(CH 2 ) a -(CH(NH 2 ))-(CH 2 ) c -,
- the oxazolidinone antimicrobial molecule A is Linezolid, Eperezolid, N- ((3-(3-fluoro-4-(piperazin-1 -yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (eperezolid amine) or has a structure represented by one of the following formulas or an antimicrobial derivative thereof:
- the compounds of the invention are represented by Formula (II) or a pharmaceutically acceptable salt or prodrug thereof:
- Each of X is independently hydrogen or a halogen, preferably a hydrogen or fluorine;
- ' 3 is selected from the group consisting of formulae M4-M8
- Wi is hydroxy, halo, amino, azido, (1-4C)alkanesulfonyloxy, (1-4C)alkylthio, (1-4C)alkylaminocarbonyloxy, NHS(0) m (1-4C)alkyl, NHCOR 0 OrNHCSR c ; isoxazol-3-oxy, isothiazol-3-oxy, (1 ,2,5-thiadiazol)-3-oxy, (1 ,2,5-oxadiazol)-3-oxy, isoxazol-3-amino, isothiazol-3- amino, (1 ,2,5-thiadiazol)-3- amino, (1 ,2,5-oxadiazol)-3-amino, tetrazol-2-yl, tetrazol-1-yl, (1 ,2,3-triazol)-1-yl, (4-ethynyl-1 ,2,3-triazol)-1-yl, -OL 1 , Or -N(R 0 )L 2 where
- W 2 is selected from the group consisting of formulae M9-M16
- D 1 is independently CH or N and D 2 , D 3 and D 4 , are each independently CH, CH 2 , N, S or O and each zzzzz represents either a single bond or a double bond;
- T 1 is O, S, SO, SO 2 , NH, NR 3 , NCOCH 2 OH 1 NCOR 3 , C(OH)CH 2 N(R a ) 2 , C(OH)CH 2 OR 3 , CH-(tetrazol-2-yl), CH(tetrazol-1 -yl), NL 4 , CHOL 5 , C(OL 6 )CH 2 N(R a ) 2 , C(OH)CH 2 N(R 3 ) L 7 ,
- each R 3 Is independently H, aryl, (1-4C)alkyl, cycloalkyl, heteroaryl, amino, (1-
- T 2 is hydroxyl, amino, chloro, fluoro, bromo, -CO 2 H, cyano, -C(O)N(R d ) 2 , -OL 10 , -N(R d )L 11 , -N(L 12 ) 2 , -C(O)N(L 13 ) 2 or -C(O)N(R d )(L 14 ) wherein each R d is defined as above.
- V is N or CH
- R 4 is H or (1 -4C) alkyl, -(CH 2 ) x -(CH(OH))-(CH 2 ) y -Q, -(CH 2 ) x -(CH(NH 2 ))-(CH 2 )y-Q, , -(CH 2 J x -
- R 5 is one of either -CJH n , -(CH 2 ) m -(CH(OH))-(CH 2 ) b -, -(CH 2 ) m -(CH(NH 2 ))-(CH 2 ) b -, -
- Each L 1 , L 3 , L 5 , L 6 , L 8 , L 9 , L 10 , L 15 , L 20 , and L 23 is a linker independently selected from the group of
- B represents said phosphonated group; each p is independently 0 or an integer ⁇ 10; each R L is independently selected from the group consisting of H, ethyl and methyl; q is 2 or 3; n is an integer ⁇ 10; r is 1, 2, 3, 4 or 5; and W 1 and W 2 are each integers ⁇ 0 such that their sum (W 1 + W 2 ) is 1 , 2 or 3.
- Each L 2 , L 4 , L 7 , L 11 , L 12 , L 13 , L 14 , L 16 , L 17 , L 18 , L 19 , L 21 , L 22 , L 24 , and L 25 is a linker independently selected from the group of
- B represents said phosphonated group; n is an integer ⁇ 10; each p is independently 0 or an integer ⁇ 10; each R L is independently selected from the group consisting of H, ethyl and methyl; q is 2 or 3;
- R 3 is C x H y where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1.
- B is a phosphonated group selected from the group consisting of:
- each R* is independently selected from the group consisting of H, lower alkyl, cycloalkyl, aryl and heteroaryl, with the proviso that at least two R* are H;
- X is H, OH, NH 2 , or a halo group;
- each X 1 is independently selected from the group consisting of H, OH, NH 2 , and a halo group; with the proviso that at least one of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 , L 12 , L 13 , L 14 , L 15 , L 16 , L 17 , Lie, L 19 , L 20 , L 21 , L 22 , L 23 , L 24 and L 25 is present.
- the compounds of the invention have a structure selected among the structures illustrated below, as well as pharmaceutically acceptable salts and prodrugs thereof:
- compositions comprising one or more of the compounds as defined herein and a pharmaceutically acceptable carrier or excipient.
- the present invention also encompasses methods for treating a bacterial infection in a subject, comprising administering to a subject having a bacterial infection or otherwise in need of such treatment a pharmaceutically effective amount of one or more of the compounds as defined herein, or a pharmaceutical composition as defined herein.
- the subject may be an animal, preferably a mammal, more preferably a human.
- the present invention further encompasses methods for prophylaxis for a bacterial infection in a subject, comprising administering to a subject a prophylactically effective amount of one or more of the compounds as defined herein, or a pharmaceutical composition as defined herein.
- the prophylactically effective amount of the compounds or pharmaceutical composition may be administered to a subject prior to, during, or after an invasive medical treatment.
- the subject may be an animal, preferably a mammal, more preferably a human.
- the present invention also encompasses methods for treating a bacterial infection in a subject, comprising administering to a subject having a bacterial infection or otherwise in need of such treatment a pharmaceutically effective amount of one or more of the compounds as defined herein, or a pharmaceutical composition as defined herein, and concurrently administering a second therapeutic agent.
- a pharmaceutically effective amount of one or more of the compounds as defined herein, or a pharmaceutical composition as defined herein and concurrently administering a second therapeutic agent.
- the second therapeutic agent is an antibiotic.
- the second therapeutic agent is an antibiotic selected from the group consisting of tetracycline, a tetracycline derived antibacterial agent, glycylcycline, a glycylcycline derived antibacterial agent, minocycline, a minocycline derived antibacterial agent, an oxazolidinone antibacterial agent, an aminoglycoside antibacterial agent, a quinolone antibacterial agent, vancomycin, a vancomycin derived antibacterial agent, a teicoplanin, a teicoplanin derived antibacterial agent, eremomycin, an eremomycin derived antibacterial agent, chloroeremomycin, a chloroeremomycin derived antibacterial agent, daptomycin, a daptomycin derived antibacterial agent, Rifamycin, a Rifamycin derived antibacterial agent, Rifampin, a Rifampin derived antibacterial agent, Rifalazil, a Rifalazil derived antibacterial agent,
- the invention also provides a method for accumulating oxazolidinone antimicrobial molecule in a bone of a subject, comprising administering to a subject one or more of the compounds as defined herein, or a pharmaceutical composition as defined herein.
- Such method for accumulating oxazolidinone antimicrobial molecules in a bone of a subject may also be used to prolong the presence of oxazolidinone antimicrobial molecule in a bone of a subject.
- the subject may be an animal, preferably a mammal, more preferably a human.
- An advantage of the invention is that it provides antimicrobial compounds having an increased binding affinity for bone.
- the invention also provides methods for the unmet medical need of prevention and treatment of bone and joint infections. Additional objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of preferred embodiments with reference to the accompanying drawings which are exemplary and should not be interpreted as limiting the scope of the present invention.
- Figure 1 is a bar graph showing increased binding affinity to ossoues materials for phosphonated derivatives 60 and 62 of oxazolidinone according to the invention.
- Figure 2 is a bar graph showing readout of fluorescence (luciferase; RLU) for measuring the effect of phosphonated compounds 68, 69, 70, 71 , 72, 79 and 80 at 20 ⁇ M on in vitro coupled transcription-translation using E. coli S30 extracts with a luciferase readout.
- Figure 3 is a bar graph showing amounts of selected phosphonated compounds 68, 72, 74 and 80 found in the femur of mice 1 h and 24 h post injection (10 mg/kg IV , 3 mice per time point).
- Figure 4 is a bar graph showing the sum of drug and prodrug concentrations in plasma of rat treated with 1 mg/kg and 10mg/kg of compound 72 (IV bolus) after 1 h.
- Figures 5A and 5B are bar graphs showing combined drug and prodrug (Fig. 5A) and regenerated eperezolid (Fig. 5B) in rat tibia at 1h and 24h after an IV bolus dosage of compound 72 at 1 mg/kg and 10 mg/kg
- Figure 6 is a curve representing the concentration of bisphosphonated prodrug 72 and regenerated eperezolid found in rat tibia after an IV bolus dosage of compound 72 at 10 mg/kg
- the present invention discloses phosphonated derivatives of oxazolidinones of structural Formula I and Formula Il as defined above. These compounds are useful antimicrobial agents effective against a number of human and veterinary pathogens.
- the essence of the invention lies in the presence of a phosphonated group attached to an oxazolidinone antibiotic. Since phosphonic acid derivatives are known to have a high affinity to bone due to their ability to bind the Ca 2+ ions found in the hydroxyapatite forming bone tissues, the present inventors have hypothesized that it would be possible to increase the binding affinity, adso ⁇ tion and retention of oxazolidinone antibiotics by the bones by tethering a phosphonated group to such an antibiotic.
- the present inventors have synthesized such phosphonated derivatives of oxazolidinone and demonstrated that these derivatives have an increased affinity for bony materials.
- the present inventors have also shown that these phosphonated derivatives accumulate in bones of mammals in amounts greater than amounts of a non-phosphonated equivalent of oxazolidinone antimicrobials and that it is possible to prolong the presence of oxazolidinone antimicrobials in the bones by administering such phosphonated derivatives.
- the compounds of the invention are particularly useful for the prevention and/or the treatment of bone-related infections and bone-related diseases such as osteomyelitis.
- the present invention discloses phosphonated oxazolidinone antimicrobial molecules, in particular, those phosphonated compounds defined in Formula (I) and Formula (II) as defined above and hereinafter. These compounds are useful antimicrobial agents effective against a number of human and veterinary pathogens.
- a phosphonated group is reversibly coupled to an oxazolidinone antimicrobial molecule via a cleavable linker.
- Phosphonated oxazolidinone antimicrobial molecules have been synthesized demonstrated to have an increased affinity for osseous materials. In vivo, these phosphonated compounds accumulate in bones in amounts greater than amounts of non-phosphonated equivalents. The presence of oxazolidinone antimicrobial molecules in the bones can be prolonged by administering phosphonated derivatives of oxazolidinone antimicrobial molecules according to the invention. Accordingly, the compounds of the invention are particularly useful for the prophylaxis and/or treatment of bone and joint-related infections and bone-related diseases such as osteomyelitis.
- alkyl refers to saturated aliphatic groups including straight-chain, branched- chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms (preferably 1 to 6).
- alkyl groups include, but are not limited to groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, and adamantyl.
- Cyclic alkyl groups e.g.
- cycloalkyl or heterocycloalkyl can consist of one ring, including, but not limited to, groups such as cycloheptyl, or multiple fused rings, including, but not limited to, groups such as adamantyl or norbornyl.
- alkylaryl refers to an alkyl group having the number of carbon atoms designated, appended to one, two, or three aryl groups.
- N-alkylaminocarbonyl refers to the radical -C(O)NHR where R is an alkyl group.
- N.N-dialkylaminocarbonyl refers to the radical -C(O)NR 3 R b where R 3 and R b are each independently an alkyl group.
- alkylthio refers to the radical -SR where R is an alkyl group.
- alkoxy refers to an alkyl, alkenyl, or alkynyl linked to an oxygen atom and having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms (preferably 1 to 6).
- alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, tert-butoxy, and allyloxy.
- alkoxycarbonyl refers to the radical -C(O)OR where R is an alkyl.
- alkylsulfonyl refers to the radical -SO 2 R where R is an alkyl group.
- alkylene means a saturated divalent aliphatic group including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms (preferably 1 to 6), e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methyl-propylene, butylene, pentylene, cyclopentylmethylene, and the like.
- substituted alkyl means an alkyl group as defined above that is substituted with one or more substituents, preferably one to three substituents selected from the group consisting of halogen, alkyl, aryl, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
- the phenyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen , alkyl, aryl, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide.
- substituents selected from the group consisting of halogen , alkyl, aryl, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide.
- substituted alkyl groups include, but are not limited to — CF 3 , — CF 2 — CF 3 , hydroxymethyl, 1- or 2-hydroxyethyl, methoxymethyl, 1- or 2-ethoxyethyl, carboxymethyl, 1- or 2-carboxyethyl, methoxycarbonylmethyl, 1-or2-methoxycarbonyl ethyl, benzyl, pyrdinylmethyl, thiophenylmethyl, imidazolinylmethyl, dimethylaminoethyl and the like.
- substituted alkylene means an alkylene group as defined above that is substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of halogen, alkyl, aryl, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
- substituents preferably one to three substituents, selected from the group consisting of halogen, alkyl, aryl, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, car
- the phenyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen, alkyl, aryl, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide.
- substituted alkyl groups include, but are not limited to -CF 2 -, -CF 2 -CF 2 -, hydroxymethylene, 1- or 2-hydroxyethylene, methoxymethylene, 1- or 2-ethoxyethylene, carboxymethylene, 1- or 2-carboxyethylene, and the like.
- alkynyl refers to unsaturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms (preferably 1 to 6), which contain at least one triple bond (— C ⁇ C— ).
- alkynyl groups include, but are not limited to acetylene, 2-butynyl, and the like.
- alkynylene refers to unsaturated divalent aliphatic groups including straight- chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms (preferably 1 to 6), which contain at least one triple bond ( — C ⁇ C — ).
- alkynylene groups include, but are not limited to —C ⁇ C—, —C ⁇ C— CH 2 -, and the like.
- substituted alkenyl or “substituted alkynyl” refers to the alkenyl and alkynyl groups as defined above that are substituted with one or more substituents selected from the group consisting of halogen, alkyl, aryl, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
- substituted alkenylene or “substituted alkynylene” refers to the alkenylene and alkynylene groups as defined above that are substituted with one or more substituents selected from the group consisting of halogen, alkyl, aryl, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
- substituents selected from the group consisting of halogen, alkyl, aryl, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy
- aryl refers to an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (including but not limited to groups such as phenyl) or multiple condensed rings (including but not limited to groups such as naphthyl or anthryl), and includes both unsubstituted and substituted aryl groups.
- Substituted aryl is an aryl group that is substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, monoordialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, aryloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
- substituents preferably one to three substituents, selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, monoordialkylamino, hydroxyl, mercapto, carboxy, benzyl
- aryloxy refers to an aryl group linked to an oxygen atom at one of the ring carbons.
- alkoxy groups include, but are not limited to, groups such as phenoxy, 2-, 3-, or 4-methylphenoxy, and the like.
- arylthio group refers to the radical -SR 0 where R 0 is an aryl group.
- heteroarylthio group refers to the radical
- R d is a heteroaryl
- arylene refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1 ,2-phenylene, 1 ,3-phenylene, 1 ,4-phenylene, 1 ,2- naphthylene and the like.
- amino refers to the group — NH 2 .
- N-alkylamino ' and “N,N-dialkylamino” means a radical — NHR and — NRR 1 respectively where R and R 1 independently represent an alkyl group as defined herein.
- Representative examples include, but are not limited to N,N-dimethylamino, N-ethyl-N- methylamino, N,N-di(1-methylethyl)amino, N-cyclohexyl-N-methylamino, N-cyclohexyl-N- ethylamino, N-cyclohexyl-N-propylamino, N-cyclohexylmethyl-N-methylamino, N- cyclohexylmethyl-N-ethylamino, and the like.
- thioalkoxy means a radical — SR where R is an alkyl as defined above e.g., methylthio, ethylthio, propylthio, butylthio, and the like.
- acyl group means a radical -C(O)R, where R is hydrogen, halogen, alkyl, aryl, heteroaryl, alkoxy, aryloxy, N-alkylamino, N.N-dialkylamino, N-arylamino, thioalkoxy, thioaryloxy or substituted alkyl wherein alkyl, aryl, heteroaryl, and substituted alkyl are as defined herein.
- thioacyl group means a radical -C(S)R, where R is hydrogen, halogen, alkyl, aryl, heteroaryl, aikoxy, aryloxy, N-alkylamino, N,N-dialkylamino, N-arylamino, thioalkoxy, thioaryloxy or substituted alkyl wherein alkyl, aryl, heteroaryl, and substituted alkyl are as defined herein.
- sulfonyl group means a radical -SO 2 R, where R is hydrogen, halogen, alkyl, aryl, heteroaryl, alkoxy, aryloxy, N-alkylamino, N,N-dialkylamino, N-arylamino, thioalkoxy, thioaryloxy or substituted alkyl wherein alkyl, aryl, heteroaryl, and substituted alkyl are as defined herein.
- Representative examples include, but are not limited to formyloxy, acetyloxy, cylcohexylcarbonyloxy, cyclohexylmethylcarbonyloxy, benzoyloxy, benzylcarbonyloxy, and the like.
- heteroalkyl refers to alkyl, alkenyl, and alkynyl groups respectively as defined above, that contain the number of carbon atoms specified (or if no number is specified, having 1 to 12 carbon atoms, preferably 1 to 6) which contain one or more heteroatoms, preferably one to three heteroatoms, as part of the main, branched, or cyclic chains in the group.
- Heteroatoms are independently selected from the group consisting of — NR-, -NRR, -S-, -S(O) — , -S(O) 2 -, —0—, -SR, -S(O)R, -S(O) 2 R, —OR —PR—, -PRR, -P(O)R- and -P(O)RR; (where each R is hydrogen, alkyl or aryl) preferably -NR where R is hydrogen or alkyl and/or O.
- Heteroalkyl, heteroalkenyl, and heteroalkynyl groups may be attached to the remainder of the molecule either at a heteroatom (if a valence is available) or at a carbon atom.
- heteroalkyl groups include, but are not limited to, groups such as — O— CH 3 , -CH 2 -O-CH 3 , -CH 2 -CH 2 -O-CH 3 , -S-CH 2 -CH 2 -CH 3 , —CH 2 —CH(CH 3 )—S—CH 3 , -CH 2 -CH 2 -NH-CH 2 -CH 3 , 1-ethyl-6- propylpiperidino, 2-ethylthiophenyl, piperazino, pyrrolidino, piperidino, morpholino, and the like.
- heteroaryl or' ⁇ etAr refers to an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, or 18 -member ring atoms, including 1 , 2, 3, 4, or 5 heteroatoms, preferably one to three heteroatoms including, but _
- heteroatoms such as N, O 1 P, or S
- Representative examples include, but are not limited to single ring such as imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyridyl, thiophene, and the like, or multiple condensed rings such as indolyl, quinoline, quinazoline, benzimidazolyl, indolizinyl, benzothienyl, and the like.
- heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl groups can be unsubstituted or substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, benzyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, aryloxy, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxyand carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
- substituents preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, benzyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl,
- the heteroatom(s) as well as the carbon atoms of the group can be substituted.
- the heteroatom(s) can also be in oxidized form.
- heteroarylene refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6-pyridinylene, 2,4- pyridinylene, 1 ,2-quinolinylene, 1 ,8-quinolinylene, 1 ,4-benzofuranylene, 2,5-pyridinylene, 2,5- indolenylene, and the like.
- heteroalkylene refers to the diradical group derived from heteroalkyl, heteroalkenyl, and heteroalkynyl (including substituted heteroalkyl, heteroalkenyl, and heteroalkynyl) as defined above.
- Carboxaldehyde means — CHO.
- carbboxy refers to the radical -C(O)OH.
- carbamoyl refers to the radical -C(O)NH 2 .
- halogen or "halo" as used herein refer to Cl, Br, F or I substituents, preferably fluoro or chloro.
- hydroxy refers to a —OH radical.
- “Isomers” Compounds that have the same molecular formula (or elemental composition) but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers in which the connectivity between atoms is the same but which differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example which is bonded to four different groups, a pair of enantiomers is possible.
- An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn, lngold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
- a chiral compound can exist as either an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
- the compounds of this invention may possess one or more asymmetric centers. Such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.
- each of compounds 6 and 17 as described in the Exemplification section possesses a carbon (carbon 5 of the oxazolidinone ring) linked to a hydrogen atom, an oxygen atom, and two different methylene groups, and therefore these carbons are asymmetric centers.
- the compounds 6 and 17 can exist as stereoisomers.
- the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
- the description is also intended to include all possible diastereomers and mixtures thereof.
- the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992).
- optically pure As generally understood by those skilled in the art, an optically pure compound is one that is enantiomerically pure. As used herein, the term “optically pure” is intended to mean a compound which comprises at least a sufficient amount of a single enantiomer to yield a compound having the desired pharmacological activity. Preferably, “optically pure” is intended to mean a compound that comprises at least 90% of a single isomer (80% enantiomeric excess), preferably at least 95% (90% e.e.), more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.). Preferably, the compounds of the invention are optically pure.
- Protecting group refers to a chemical group that exhibits the following characteristics: 1 ) reacts selectively with the desired functionality in good yield to give a protected substrate that .
- Preferred amino protecting groups include, but are not limited to, benzyloxycarbonyl (CBz), t-butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBDMS), 9-fluorenylmethyl-oxycarbonyl (Fmoc), or suitable photolabile protecting groups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzil, 5-bromo-7-nitroindolinyl, and the like.
- CBz benzyloxycarbonyl
- Boc t-butyloxycarbonyl
- TDMS t-butyldimethylsilyl
- Fmoc 9-fluorenylmethyl-oxycarbonyl
- suitable photolabile protecting groups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxy
- Preferred hydroxyl protecting groups include acetyl (Ac), benzoyl (Bz), benzyl (Bn), Tetrahydropyranyl (THP), TBDMS, photolabile protecting groups (such as nitroveratryl oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem (methoxy ethoxy methyl ether).
- Particularly preferred protecting groups include NPEOC (4-nitrophenethyloxycarbonyl) and NPEOM (4-nitrophenethyloxy-methyloxycarbonyl).
- “Prodrug” Phosphonated oxazolidinone antimicrobial molecules of the present invention may be formulated as prodrugs.
- a prodrug is an inactive (or significantly less active) form of any of the phosphonated oxazolidinone antimicrobial molecule compounds of the present invention.
- prodrugs of the present invention Upon in vivo processing, release an active phosphonated oxazolidinone antimicrobial molecule.
- Prodrugs of phosphonated oxazolidinone antimicrobial molecules of the present invention may be prepared by modifying functional groups present on the phosphonated oxazolidinone antimicrobial molecules in such a way that the modifications may be cleaved in vivo to release the oxazolidinone antimicrobial molecules.
- Prodrugs include compounds of Formula (I) and/or Formula (II) wherein a hydroxy or amino group in the oxazolidinone antimicrobial molecule portion of the compound is bonded to any group that may be cleaved in vivo to regenerate the free carboxyl or amino group, respectively.
- Such prodrug groups are in addition to the phosphonated linker that may be coupled to a hydroxy and/or amino group of an oxazolidinone antimicrobial molecule.
- prodrug groups include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) on hydroxy functional groups of the oxazolidinone antimicrobial molecule portion of the phosphonated compounds of the present invention.
- the present invention also includes those prodrugs requiring two or more events in prodrug cleavage. According to that embodiment, more complex compounds would release, upon cleavage, a prodrug of phosphonated oxazolidinone antimicrobial molecule, the latter prodrug being activatable to release a desired phosphonated oxazolidinone antimicrobial molecule.
- prodrugs of phosphonated oxazolidinone antimicrobial molecules of the present invention may undergo two cleavage events, one of which cleaves the cleavable linker and thus releases the phosphonate group, the other of which results in the release of the prodrug group.
- a “pharmaceutically acceptable prodrug” is intended to mean prodrug of phosphonated oxazolidinone antimicrobial molecule, such as a prodrug of a compound of Formula (I) and/or Formula (II), in a formulation that may be administered to a subject, such as a mammal, preferably a human.
- the prodrug may be in a formulation comprising a pharmaceutically acceptable carrier or excipient.
- a “pharmaceutically acceptable active metabolite” is intended to mean a pharmacologically active product produced through metabolism in the body of a compound of Formula (I) or Formulae (II) as defined herein.
- a "pharmaceutically acceptable solvate” is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of compounds of Formula I and/or Formula II.
- pharmaceutically acceptable solvates include, but are not limited to water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
- a "pharmaceutically acceptable carrier or excipient” means any compound, solution, substance or material that can be used in a formulation of the compounds of the present invention that may be administered to a subject.
- carriers and excipients of the present invention are those useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and that may present pharmacologically favorable profiles and that includes carriers and excipient that are acceptable for veterinary use as well as human pharmaceutical use.
- Suitable pharmaceutically acceptable carriers and excipients are well known in art and can be determined by those of skill in the art as the clinical situation warrants. The skilled artisan will understand that diluents are includes within the scope of the terms carriers and excipients.
- Suitable carriers and excipients include saline, buffered saline, dextrose, water, glycerol, ethanol, more particularly: (1) Dulbecco's phosphate buffered saline, pH about 7.4, containing about 1 mg/ml to 25 mg/ml human serum albumin, (2) 0.9% saline (0.9% w/v NaCI), (3) 5% (w/v) dextrose, and (4) water.
- a “pharmaceutically acceptable salt” is intended to mean a salt of phosphonated oxazolidinone antimicrobial molecule, such as a salt of a compound of Formula (I) and/or
- the salt may be in a formulation comprising a pharmaceutically acceptable carrier or excipient.
- Salt Phosphonated oxazolidinone derived antimicrobial molecules of the present invention may be in the form of a salt.
- Salts of phosphonated oxazolidinone antimicrobial molecules of the present invention means a salt that retains or improves the biological effectiveness and properties of the free acids and bases of the parent compound as defined herein or that takes advantage of an intrinsically charged functionality on the molecule and that is not biologically or otherwise undesirable.
- Such salts include the following:
- acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoicacid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesuIfonic acid, camphorsulfonic
- a charged functionality is present on the molecule and a suitable counterion is present, such as a tetraalkyl(aryl)ammonium functionality and an alkali metal ion, a tetraalkyl(aryl)phosphonium functionality and an alkali metal ion, an imidazolium functionality and an alkali metal ion, and the like.
- a suitable counterion such as a tetraalkyl(aryl)ammonium functionality and an alkali metal ion, a tetraalkyl(aryl)phosphonium functionality and an alkali metal ion, an imidazolium functionality and an alkali metal ion, and the like.
- the terms "bone”, “bone tissues” or “osseous tissues” refer to the dense, semi rigid, porous, calcified connective tissue forming the major portion of the skeleton of most vertebrates. It also encompasses teeth, osteo-articular tissues and calcifications that are frequently seen in
- bone As used herein, the terms “bone”, “bone tissues” or “osseous tissues” refer to the dense, semi rigid, porous, calcified connective tissue forming the major portion of the skeleton of most vertebrates. It also encompasses teeth, osteo-articular tissues and calcifications that are frequently seen in the walls of atherosclerotic vessels.
- oxazolidinone antimicrobial molecule and related terms have the same meaning and refer to antimicrobial agents which are part of the well known class of "oxazolidinones” as described in more detail herein.
- phosphonated group is intended to mean any compound non-toxic to humans having at least one phosphorus atom bonded to at least three oxygen atoms and having a measurable affinity to osseous tissues as described hereinafter.
- antibacterial includes those compounds that inhibit, halt or reverse growth of bacteria, those compounds that inhibit, halt, or reverse the activity of bacterial enzymes or biochemical pathways, those compounds that kill or injure bacteria, and those compounds that block or slow the development of a bacterial infection.
- treating and “treatment” are intended to mean at least the mitigation of a disease condition associated with a bacterial infection in a subject, including mammals such as a human, that is alleviated by a reduction of growth, replication, and/or propagation of any bacterium such as Gram-positive organisms, and includes curing, healing, inhibiting, relieving from, improving and/or alleviating, in whole or in part, the disease condition.
- prophylaxis is intended to mean at least a reduction in the likelihood that a disease condition associated with a bacterial infection will develop in a mammal, preferably a human.
- prevent and “prevention” are intended to mean blocking or stopping a disease condition associated with a bacterial infection from developing in a mammal, preferably a human.
- the terms are related to the treatment of a mammal to reduce the likelihood ("prophylaxis") or prevent the occurrence of a bacterial infection, such as bacterial infection that may occur during or following a surgery involving bone reparation or replacement.
- the terms also include reducing the likelihood ("prophylaxis") of or preventing a bacterial infection when the mammal is found to be predisposed to having a disease condition but not yet diagnosed as having it.
- reducing the likelihood or prevent a bacterial infection in a mammal by administering a compound of Formula (I) and/or Formula (II), or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof, before occurrence of such infection.
- subject is intended to mean an animal, such as a mammal, including humans and animals of veterinary importance, such as dogs, cats, horses, sheep, goats, and cattle.
- the compounds of the invention are represented by the general Formula (I): as well as pharmaceutically acceptable salts, esters and prodrugs thereof, where: A is an oxazolidinone antimicrobial molecule; B is a phosphonated group having a high affinity to osseous tissues; L is a bond or a linker for covalently coupling B to A; and n is an 1 ,2 or 3.
- the essence of the invention lies in the presence of a phosphonated group attached to an oxazolidinone antibiotic for increasing the affinity, binding, accumulation and/or retention time of the oxazolidinone antibiotic to or within the bones.
- All non-toxic phosphonated groups having a high affinity to the bones due to their ability to bind the Ca 2+ ions found in the hydroxyapatite forming the bone tissues are suitable according to the present invention.
- Suitable examples of phosphonated groups can be found in WO 04/026315 (Ilex Oncology Research), US 6,214,812 (MBC research), US 5,359,060 (Pfizer), US 5,854,227 and US 6,333,424 (Elizanor), US 6,548,042 (Arstad and Skattelbol) and WO 2004/089925 (Semaphore Pharmaceuticals).
- Examples of bisphosphonate and trisphosphonate groups suitable for the present invention include but are not limited to those having the formula:
- each R* is independently selected from the group consisting of H, lower alkyl, cycloalkyl, aryl and heteroaryl, with the proviso that at least two, preferably three, R* are H;
- R 4 is CH 2 , O, S, or NH;
- each R 5 is independently selected from the group consisting of H, R 6 , OR 8 , NR 6 , and SR 6 , wherein R 8 is H, lower alkyl, cycloalkyl, aryl, heteroaryl or NH 2 ;
- X is H, OH, NH 2 , or a halo group;
- X I are both H, or each is independently selected from the group consisting of H, OH, NH 2 , and a halo group.
- the bisphosphonate group is the bisphosphonate -CH(P(O)(OH) 2 ) 2 .
- oxazolidinone derivatives possessing such a bisphosphonate group have a strong binding affinity for hydroxyapatite powder.
- the phosphonated group may be an esterase-activated bisphosphonate radical (Vepsalainen J., Current Medicinal Chemistry, 9,
- Oxazolidinones are a well known class of synthetic Gram-positive antimicrobial agents
- Linezolid [(S)- ⁇ /-[[3-[3-fluoro-4-(4-mo ⁇ holinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]acetamide] and eperezolid [(S)- ⁇ /-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]- 2-oxo-5-oxazolidinyl]methyl] acetamide] are certainly the best known compounds in this class. Both drugs were proven clinically and microbiologically to have potent activity against Gram- positive organisms.
- the present invention is not restricted to a specific oxazolidinone, but encompasses all kinds of oxazolidinone molecules having a suitable antimicrobial activity including, but not limited to, those disclosed in the above-listed US patents and PCT patent applications (incorporated herein by reference) and other oxazolidinone derivatives and hybrids such as the oxazolidinone-quinolone hybrids disclosed by Morphochem Inc. (Gordeev et a/., Bioorg.Med.Chem.Lett. (2003), 13:4213-16) or by Vicuron Pharmaceuticals (Hubschewerlen et a/., Bioorg.Med.Chem.Lett. (2003) 13 :4229-33).
- oxazolidinone antimicrobial molecule includes all compounds having the Formula A 1 illustrated below: as pharmaceutically acceptable salts, esters and prodrugs thereof, where:
- Each of X is independently hydrogen or a halogen, preferably a hydrogen or fluorine;
- W 1 is hydroxy, halo, amino, azido, (1-4C)alkanesulfonyloxy, (1-4C)alkylthio, (1-4C)alkylaminocarbonyloxy, NHS(0) m (1-4C)alkyl, NHCOR c , NHCSR c ; isoxazol-3-oxy, isothiazol-3-oxy, (1,2,5-thiadiazol)-3-oxy, (1 ,2,5-oxadiazol)-3-oxy, isoxazol-3-amino, isothiazol-3- amino, (1 ,2,5-thiadiazol)-3- amino, (1 ,2,5-oxadiazol)-3-amino, tetrazol-2-yl, tetrazol-1-yi, (1,2,3-triazol)-1-yl, or (4-ethynyl-1,2,3-triazol)-1-yl wherein: m is 0, 1 , or2 and R 0 is H 1 (
- W 2 is selected from the group consisting of formulae M9-M16
- Di is independently CH or N and D 2 , D 3 and D 4 , are each independently CH, CH 2 , N, S or O and each ⁇ represents either a single bond or a double bond;
- T 1 is O, S, SO, SO 2 , NH, NR a , NCOCH 2 OH, or NCOR 3 , C(OH)CH 2 N(R a ) 2 , C(OH)CH 2 OR 3 ,
- R 3 Js independently H, aryl, (1-4C)alkyl, cycloalkyl, heteroaryl, amino, (1- 4C)alkylamino, or 0R b , wherein R b is (1-6C)alkyl T 2 is hydroxyl, amino, chloro, fluoro, bromo, -CO 2 H, cyano, Or-C(O)N(Ro) 2 , wherein each R d is defined as above.
- V is N or CH
- R 4 is H or (1-4C) alkyl, -(CH 2 ) x -(CH(OH))-(CH 2 ) y -Q, -(CH 2 ) x -(CH(NH 2 ))-(CH 2 ) y -Q or - (CH 2 ) x -C(O)-(CH 2 ) y -Q, wherein x and y are independently 0,1 or 2 and Q is N(R d ) 2 , imidazol-1-yl, 2-methyl-imidazol-1-yl, tetrazol-2-yl, or (1 ,2,3-triazol)-1-yl, with R d defined as above.
- R 5 is one of either -C a H b , -(CH 2 ) a -(CH(OH))-(CH 2 ) c -, -(CH 2 )a-(CH(NH 2 ))-(CH 2 )c-, (CH 2 ) a -(CH(OH))-(CH 2 ) c -C(O)-, or -(CH 2 ) a -(CH(NH 2 ))-(CH 2 ) c -C(O)-, wherein a is an integer >0 and ⁇ 10, b is an integer and >0 and ⁇ 2a and c is 0,1 or 2.
- the oxazolidinone antimicrobial molecule is a derivative of linezolid. According to another embodiment, the oxazolidinone antimicrobial molecule is a derivative of eperezolid. According to a third embodiment, the oxazolidinone antimicrobial molecule is a derivative of N-((3-(3-fluoro-4-(piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)acetamide (eperezolid amine), as defined below. The chemical structures of these three molecules are illustrated hereinafter. Arrows indicate preferred sites for attachment of the phosphonated group (direct attachment or via an optional linker):
- Eperezolid amine Specific examples of linezolid, eperezolid and eperezolid amine derivatives according to the invention are shown in the Exemplification section. Even though in the examples phosphonated groups have not been attached to all the preferred attachment sites shown by the arrows, the results presented in the Exemplification section confirm that it is possible to synthesize phosphonated biologically active linezolid and eperezolid derivatives having a highly increased affinity for bony materials. Similarly, although not tested, the invention encompasses phosphonated oxazolidinone derivatives having more than just one phosphonated group (one at each end of the eperezolid molecule for instance). As mentioned previously, the above identified sites of attachment are only preferred sites for tethering a phosphonated group and all other potential sites (on the aryl ring for instance) are covered by the present invention.
- a cleavable linker L covalently and reversibly couples the phosphonated group B to oxazolidinone antimicrobial molecules A.
- cleavable refers to a group that is chemically or biochemically unstable under physiological conditions. The chemical instability preferably results from spontaneous decomposition due to a reversible chemical process, an intramolecular chemical reaction or hydrolysis (i.e. splitting of the molecule or group into two or more new molecules or groups due to the net insertion of one or more water molecules) when it depends on an intermolecular chemical reaction. Cleavage of the linker may be very rapid or very slow.
- the half-life of the cleavable liker may be of about 1 minute, about 15 minutes, about 30 minutes, about 1 hour, about 5 hours, about 10 hours, about 15 hours, about 1 day or about 48 hours.
- the cleavable linker may be an enzyme-sensitive linker that is cleavable only by selected specific enzymes (e.g. amidase, esterase, metalloproteinase, etc) or may be susceptible to cleavage by other chemical means, such as but not limited to acid/base catalysis or self-cleavage.
- selected specific enzymes e.g. amidase, esterase, metalloproteinase, etc
- a cleavable linker which is not too easily cleavable in the plasma, thereby permitting a sufficient amount of the phosphonated oxazolidinone antimicrobial molecules to reach and accumulate within the osseous tissues before being cleaved to release the oxazolidinone antimicrobial molecules.
- the linker may be selected such that only 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, or 70% of the bone-bonded antibiotic is released through a time period extending to 1 minute, 15 minutes, 30 minutes, 1 hour, 5 hours, 10 hours, 15 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days 7 days, one week, two weeks, three weeks or more following administration of the compound of the invention.
- the linker is selected such that only about 1 % to about 25% of the bone-bonded oxazolidinone antimicrobial molecule is released per day.
- the choice of the linker may vary according to factors such as (i) the site of attachment of the phosphonated group to the oxazolidinone antimicrobial molecule, (ii) the type of phosphonated group used; (iii) the type of oxazolidinone antimicrobial molecule used, and (iv) the desired ease of cleavage of the linker and associated release of the oxazolidinone antimicrobial molecule.
- the linker L couples the phosphonated group B to an oxazolidinone antimicrobial molecule A through one or more hydroxyl groups on A, through one or more nitrogen atoms on A, through one or more sulhydryl groups on A, or a combination of one or more hydroxyl groups, one or more nitrogen atoms, and/or one or more sulhydryl groups, on A.
- Between 1 and 3 phosphonated groups may be coupled to A through any combination of linkers L.
- the linker is facultative because its presence is dependent upon (i) the site of attachment of the phosphonated group to the oxazolidinone molecule, (ii) the type of phosphonated group used; (iii) the type of oxazolidinone used, and (iv) the desired ease of cleavage of the linker and associated release of the oxazolidinone antibiotic. For instance, as is shown in the Exemplification section, it is possible to avoid the linker and tether a phosphonated group directly to the acetamide group of linezolid (compounds 54 and 56).
- L couples B to A through a hydroxyl group on A, preferably L is one of the following linkers:
- n is an integer ⁇ 10, preferably 1 , 2, 3 or 4, more preferably 1 or 2; each p is independently 0 or an integer ⁇ 10, preferably 0, 1 , 2, 3 or 4, more preferably 0 or 1 ; q is 2 or 3 r is 1 , 2, 3, 4 or 5
- W 1 and W 2 are integers ⁇ 0 such that their sum (W 1 + W 2 ) is 1 ,2 or 3 each R L is independently selected from the group consisting of H, ethyl and methyl, preferably H;
- B represents the phosphonated group
- L couples B to A through a nitrogen atom on A
- L is one of the following linkers:
- n is an integer ⁇ 10, preferably 1 , 2, 3 or 4, more preferably 1 or 2; each p is independently 0 or an integer ⁇ 10, preferably 0, 1 , 2, 3 or 4, more preferably 0 oM ; q is 2 or 3; each R L is independently selected from the group consisting of H, ethyl and methyl, preferably H;
- R 3 is C x H y where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1 ;
- X is CH 2 , -CONR L -, -CO-O-CH 2 -, or — CO— O— ;
- a 3 represents the nitrogen atom on A.
- the compounds of the invention are represented by Formula (II) or a pharmaceutically acceptable salt or prodrug thereof:
- Each of X is independently hydrogen or a halogen, preferably a hydrogen or fluorine; is either absent, in which case Il becomes
- W 1 is hydroxy, halo, amino, azido, (1-4C)alkanesulfonyloxy, (1-4C)alkylthio, (1-4C)alkylaminocarbonyloxy, NHS(O) m (1-4C)alkyl, NHCOR 0 OrNHCSR 0 ; isoxazol-3-oxy, isothiazol-3-oxy, (1 ,2,5-thiadiazol)-3-oxy, (1 ,2,5-oxadiazol)-3-oxy, isoxazol-3-amino, isothiazol-3- amino, (1 ,2,5-thiadiazol)-3- amino, (1 ,2,5-oxadiazol)-3-amino, tetrazol-2-yl, tetrazol-1-yl, (1 ,2,3-triazol)-1-yl, (4-ethynyl-1 ,2,3-triazol)-1-yl, -OL 1 , Or -N(R 0 )
- W 2 is selected from the group consisting of formulae M9-M16
- D 1 is independently CH or N and D 2 , D 3 and D 4 , are each independently CH, CH 2 , N, S or O and each ⁇ represents either a single bond or a double bond;
- T 1 is O, S, SO, SO 2 , NH, NR a , NCOCH 2 OH, NCOR 3 , C(OH)CH 2 N(R a ) 2 , C(OH)CH 2 OR 3 , CH-(tetrazol-2-yl), CH(tetrazol-1 -yl), NL 4 , CHOL 5 , C(OL 6 )CH 2 N(Ra) 2 , C(OH)CH 2 N(R 3 ) L 7 ,
- each R 3 is independently H, aryl, (1-4C)alkyl, cycloalkyl, heteroaryl, amino, (1-
- T 2 is hydroxyl, amino, chloro, fluoro, bromo, -CO 2 H, cyano, -C(O)N(R d ) 2 , -OL 10 , -N(R d )L 11 , -N(L 12 ) 2 , -C(O)N(L 13 J 2 or -C(O)N(R d )(L 14 ) wherein each R d is defined as above.
- V is N or CH
- R 4 is H or (1-4C) alkyl, -(CH 2 V(CH(OH)HCH 2 VQ, -(CH 2 ) x -(CH(NH 2 ))-(CH 2 ) y -Q 1 , -(CH 2 V
- R 5 is one of either -CJH n , -(CH 2 ) m -(CH(OH))-(CH 2 ) b -, -(CH 2 ) m -(CH(NH 2 ))-(CH 2 ) b -, -
- Each L 1 , L 3 , L 5 , L 6 , L 8 , L 9 , L 10 , L 15 , L 2 o, and L 23 is a linker independently selected from the group of
- B represents said phosphonated group; each p is independently 0 or an integer ⁇ 10; each R L is independently selected from the group consisting of H, ethyl and methyl; q is 2 or 3; n is an integer ⁇ 10; r is 1 , 2, 3, 4 or 5; and W 1 and W 2 are each integers ⁇ 0 such that their sum (W 1 + W 2 ) is 1 , 2 or 3.
- Each L 2 , L 4 , L 7 , L 11 , L 12 , L 13 , L 14 , L 16 , L 17 , L 18 , L 19 , L 21 , L 22 , L 24 , and L 25 is a linker independently selected from the group of
- B represents said phosphonated group; n is an integer ⁇ 10; each p is independently 0 or an integer ⁇ 10; each R L is independently selected from the group consisting of H, ethyl and methyl; q is 2 or 3;
- X is CH 2 , — CONR L -, -CO-O-CH 2 -, or — CO— O— ; and R a is C x H y where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1.
- B is a phosphonated group selected from the group consisting of:
- each R* is independently selected from the group consisting of H, lower alkyl, cycloalkyl, aryl and heteroaryl, with the proviso that at least two R* are H;
- X is H 1 OH, NH 2 , or a halo group;
- each X 1 is independently selected from the group consisting of H, OH, NH 2 , and a halo group; with the proviso that at least one of L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 , L 12 , L 13 , L 14 , L 15 , L 16 , L 17 , Lie, L 19 , L 20 , L 21 , L 22 , L 23 , L 24 and L 25 is present.
- the antibacterial molecules may be the same (e.g. two molecules of Eperezolid) or different (e.g. one molecule of the fluoroquinolone antibacterial ciprofloxacin (Cipro®; US 4,670,444) and one molecule of Eperezolid).
- the phosphonated group may also be tethered to similar groups (e.g. the hydroxyl groups) or to different groups (e.g. the carboxyl group of one fluoroquinolone molecule and the hydroxyl group of an oxazolidinone antimicrobial molecule).
- Examples of potentially useful, cleavable, multi-antibacterial linkers according to the invention include, but are not limited to, those having the structures:
- each R d is independently an alkyl or an aryl group
- p is O or an integer ⁇ 10, preferably 0, 1 , 2, 3 or 4, more preferably 0 or 1 ;
- the substructure of the linker represents the hydroxyl moiety of the oxazolidinone antimicrobial molecule A;
- a 3 represents an amine group of the oxazolidinone antimicrobial molecule A; O the substructure FQ ⁇ ° .- of the linker represents the carboxylic moiety of a fluoroquinolone antimicrobial.
- the phosphonated group B and the linker L are selected such that the linker is hydrolyzed or cleaved in vivo (preferably mostly in osseous tissues) thereby releasing: (i) the oxazolidinone antimicrobial molecule A and (ii) a chosen non-toxic phosphonated molecule having a proven bone therapeutic activity.
- Such compounds would thus have a double utility that is to: 1 ) provide locally to the bones for an extended period of time and/or at increased concentrations, an antibiotic useful in preventing and/or treating a bacterial bone infection, and 2) provide to the bones a drug stimulating bone regeneration or inhibiting bone resorption, thereby facilitating bone recovery from damages caused by an infection or other injury.
- Suitable phosphonated molecules with proven bone therapeutic activity useful according to the invention include but are not limited to pamidronate, alendronate and incadronate as well as others such as risedronate, olpadronate, etidronate, ibandronate, zolendronate or neridronate, these molecules being well known bisphosphonate bone resorption inhibitors commonly used for the treatment of osteoporosis.
- the pH-sensitive linker is a base-sensitive linker that is cleaved at a basic pH ranging from about 7 to about 9.
- the linker is an acid-sensitive linker that is cleaved at an acidic pH ranging from about 7.5 to about 4, preferably from about 6.5 and lower.
- a covalent bond or a non-cleavable linker may also covalently couple the phosphonated group B to the oxazolidinone A.
- Such bond or linker would be selected such that it would not be cleaved or would be cleaved mainly by the bacteria present at the actual site of infection. It is hypothesized that for such compounds the phosphonated group would remain tethered to the oxazolidinone antibiotic and the whole compound would gradually be released from the bone and absorbed by the bacteria, thereby exerting its antibacterial effect.
- linker may also contain an in vivo hydrolysable phosphonated group having an affinity to bones as disclosed by Ilex Oncology Research in WO 04/026315.
- the linker may also contain an active group (e.g. a releasable group stimulating bone formation or decreasing bone resorption).
- the present invention covers the compounds of Formula I and of Formula II, as well as pharmaceutically acceptable salts, esters and prodrugs thereof.
- pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4- dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methyl be nzoates, dinitrobenzoates, hydroxybenzo
- the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
- an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
- the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like.
- an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like.
- suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
- inventive compounds may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
- inventive compounds are used in optically pure form. It is conceivable that the compounds of the Formula I and/or of Formula Il be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the Formula I or of Formula II.
- prodrugs include in vivo hydrolysable esters of a compound of the Formula I and/or of Formula II.
- An in vivo hydrolysable ester of a compound of the Formula I and/or of Formula Il containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolyzed 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- dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; 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 and/or of Formula Il containing a hydroxy group includes inorganic esters such as phosphate esters and alpha- acyloxyalkyl ethers and related compounds which as a result of in vivo hydrolysis of the ester break down to give the parent hydroxy group.
- inorganic esters such as phosphate esters and alpha- acyloxyalkyl ethers and related compounds which as a result of in vivo hydrolysis of the ester break down to give the parent hydroxy group.
- alpha-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
- a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)- ⁇ /-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
- inventive compounds and their salts, solvates, crystal forms, active metabolites, and prodrugs, may be prepared by employing the techniques available in the art using starting materials that are readily available. Certain novel and exemplary methods of preparing the inventive compounds are described in the Exemplification section. Such methods are within the scope of this invention.
- a related aspect of the invention concerns the use of compounds of the invention as an active ingredient in a therapeutic or anti-bacterial composition for treatment or prevention purposes.
- the compounds of the present invention may be formulated as pharmaceutically acceptable compositions.
- the present invention provides for pharmaceutical compositions comprising a compound of the present invention (e.g., those compounds of Formula (I) and (II)) in combination with a pharmaceutically acceptable carrier or excipient.
- a pharmaceutically acceptable carrier or excipient e.g., those compounds of Formula (I) and (II)
- the compound of the present invention is a therapeutically effective amount of the compound.
- Such carriers include, but are not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.
- compositions according to the invention are known to those skilled in the art.
- pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for various routes of administration.
- the compounds and compositions of the invention are conceived to have a broad spectrum of activity, including antibiotic resistant strains, against both Gram-positive (e.g.
- Staphylococcus aureus Staphylococcus epidermis, Streptococcus pyogenes, Enterococcus faecalis
- Gram-negative bacteria e.g. E. coli, Chlamydia pneumoniae, Enterobactersp., H. influenza, K. pneumoniae, Legionella pneumoniae, P. aeruginosa.
- compositions and a second therapeutic agent are provided.
- a wide range of second therapeutic agents can be used in combination with the compounds, compositions and methods of the present invention.
- Antibiotics used as second therapeutic agents may act by interfering with cell wall synthesis, plasma membrane integrity, nucleic acid synthesis, ribosomal function, folate synthesis, etc.
- a non- limiting list of useful antibiotics with which the compounds and compositions might be combined includes: Rifamycins, sulfonamides, beta-lactams, tetracyclines, chloramphenicol, aminoglycosides, macrolides, glycopeptides, streptogramins, quinolones, fluoroquinolones, oxazolidinones and lipopeptides.
- tetracycline, tetracycline derived antibacterial agents, glycylcycline, glycylcycline derived antibacterial agents, minocycline, minocycline derived antibacterial agents, oxazolidinone antibacterial agents, aminoglycoside antibacterial agents, quinolone antibacterial agents, vancomycin, vancomycin derived antibacterial agents, teicoplanin, teicoplanin derived antibacterial agents, eremomycin, eremomycin derived antibacterial agents, chloroeremomycin, chloroeremomycin derived antibacterial agents, daptomycin, daptomycin derived antibacterial agents, rifamycin and rifamycin derived antibacterial agents are preferred.
- the present invention concerns methods of inhibiting bacterial growth, and more particularly growth of Gram-positive bacteria.
- the method comprises contacting the bacteria for the purpose of such inhibition with an effective amount of a phosphonated oxazolidinone compound or composition according to the invention (or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof).
- a phosphonated oxazolidinone compound or composition according to the invention or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof.
- a phosphonated oxazolidinone compound or composition according to the invention or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof.
- the contacting may be carried out in vitro (in biochemical and/or cellular assays), in vivo in a non-human animal, in vivo in mammals, including humans and/or ex vivo (e.g. for sterilization purposes).
- the activity of the inventive compounds as inhibitors of ribosomal-dependent protein synthesis may be measured by any of the methods available to those skilled in the art, including in vivo and in vitro assays.
- suitable assays for measurement of ribosomal- dependent protein synthesis have been described by Pratt et al. (Journal of Biomolecular Screening 9(1 ), 2004), Murray et al.
- a related aspect of the invention concerns the use of a compound of the invention as an active ingredient in a pharmaceutical, therapeutic or anti-bacterial composition for treatment pu ⁇ oses.
- “treating” or “treatgment” means at least the mitigation of a disease condition associated with a bacterial infection in a subject, including mammals such as a human, that is alleviated by a reduction of growth, replication, and/or propagation of any bacterium, such as Gram-positive organisms, and includes curing, healing, inhibiting, relieving from, improving and/or alleviating, in whole or in part, the disease condition.
- compositions may be administered in any effective, convenient manner including, for instance, administration by topical, parenteral, oral, anal, intravaginal, intravenous, intraperitoneal, intramuscular, intraocular, subcutaneous, intranasal, intrabronchial, or intradermal routes among others.
- the compound(s) of the invention and/or pharmaceutically acceptable prodrugs, salts, active metabolites and solvates may be administered to an individual as an injectable composition, for example as a sterile aqueous dispersion, preferably isotonic.
- the composition may be formulated for topical application for example in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, mouthwash, impregnated dressings and sutures and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams.
- Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions. Such carriers may constitute from about 1 % to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
- Alternative means for systemic administration include transmucosal and transdermal administration using penetrants such as bile salts or fusidic acids or other detergents.
- penetrants such as bile salts or fusidic acids or other detergents.
- oral administration may also be possible. Administration of these compounds may also be topical and/or localized, in the form of salves, pastes, gels, and the like.
- the treatment can be administered in a systemic manner through the means described above, it may also be administered in a localized manner.
- the treatment may be administered directly to a bone, such as through an injection into a bone.
- the treatment may also be administered in other localized manners, such as application to a wound through a topical composition or directly into a subcutaneous or other form of wound.
- the active compound(s) and its pharmaceutically acceptable prodrugs, salts, metabolites and solvates may be also administered to an individual as part of a bone substitute or bone- repair compound such as bone cements or fillers (e.g. SkeliteTM, Millenium Biologies, Springfield, ON, Canada) and calcium or hydroxyapatite beads.
- a dose of the pharmaceutical composition contains at least a pharmaceutically- or therapeutically-effective amount of the active compound (i.e., a compound of Formula (I), of Formula (II) and/or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof), and is preferably made up of one or more pharmaceutical dosage units.
- the selected dose may be administered to a mammal, for example, a human patient, in need of treatment.
- a "therapeutically effective amount” is intended to mean that amount of a compound of Formula (I) and/or of Formula (II) (and/or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof) that confers a therapeutic effect on the subject treated.
- the therapeutic effect may be objective (i.e. measurable by some test or marker (e.g. lower bacterial count)) or subjective (i.e. the subject gives an indication of or feels an effect).
- the amount that will correspond to a "therapeutically effective amount” will vary depending upon factors such as the particular compound, the route of administration, excipient usage, the disease condition and the severity thereof, the identity of the mammal in need thereof, and the possibility of co-usage with other agents for treating a disease. Nevertheless the therapeutically effective amount can be readily determined by one of skill in the art.
- the daily dosage level of the active compound will be from 0.1 mg/kg to 200 mg/kg, typically around 1-5 mg/kg.
- the physician in any event will determine the actual dosage that will be most suitable for an individual and will vary with the age, weight and response of the particular individual.
- the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
- the invention provides a method of treating a subject in need of treatment wherein a phosphonated Oxazolidinone antimicrobial molecule having high affinity to osseous tissues is administered to the subject.
- a phosphonated Oxazolidinone antimicrobial molecule having high affinity to osseous tissues is administered to the subject.
- the phosphonated group is coupled to the Oxazolidinone antimicrobial molecule through a cleavable linker.
- the subject is a mammal, such as a human.
- the method of treatment may also be applied in a veterinary aspect, to animals such as farm animals including horses, cattle, sheep, and goats, and pets such as dogs, cats and birds.
- the invention is preferably directed to the prevention and/or treatment of bone- related infections
- the invention encompasses therapeutic and prophylactic methods against other diseases caused by or related to bacterial infection, including but not limited to otitis, conjunctivitis, pneumonia, bacteremia, sinusitis, pleural emphysema and endocarditis, low grade infections in the vicinity of calcifications of atherosclerotic vessels, and meningitis.
- an effective therapeutic or prophylactic amount of an antibacterial compound and/or composition as defined hereinbefore is administered to a mammal (preferably a human) in an amount sufficient to provide a therapeutic effect and thereby prevent or treat the infection of the mammal.
- Exact amounts can be routinely determined by one skilled in the art and will vary depending on several factors, such as the particular bacterial strain involved and the particular antibacterial compound used.
- an additional use that is particularly contemplated for the compounds invention is for prophylaxis and prevention purposes. Indeed, many orthopedic surgeons considerthat humans with prosthetic joints should be considered for antibiotic prophylaxis before a treatment that could produce a bacteremia. Deep infection is a serious complication sometimes leading to loss of the prosthetic joint and is accompanied by significant morbidity and mortality.
- the compounds and compositions of the invention may therefore be used as a replacement for prophylactic antibiotics in this situation.
- the compounds and/or compositions of the invention may be administered by injection to achieve a systemic and/or local effect against relevant bacteria shortly before an invasive medical treatment, such as surgery or insertion of an in- dwelling device (e.g. joint replacement (hip, knee, shoulder, etc.), bone grafting, fracture repair, dental operation or implant. Treatment may be continued after invasive medical treatment, such as post-operatively or during the in-body time of the device.
- the compound and/or composition may also be administered before the invasive medical treatment to permit the accumulation of the compound into the bone tissues prior to the treatment.
- the compound(s) of the invention could be administered once, twice, thrice or more, from 1 , 2, 3, 4, 5, 6, 7 days or more, to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 hour or less before surgery for permitting an advisable systemic or local presence of the compounds, and/or accumulation in the bones, preferably in the areas potentially exposed to bacterial contamination during the surgical procedure.
- the phosphonated compounds of the invention would be administered such that they can reach a local concentration of about 5, 10, 20, 30, 40, 50, 75, 100, 500 or even 1000 fold higher concentration than the concentration that would normally be achieved during the administration of the unmodified parent Oxazolidinone antimicrobial molecule, i.e. a non-phosphonated equivalent.
- the compound(s) may be administered after the invasive medical treatment for a period of time, such as 1 , 2, 3, 4, 5 or 6 days, 1 , 2, 3 or more weeks, or for the entire time in which the device is present in the body.
- the invention provides a method of inducing accumulation of an oxazolidinone antimicrobial molecule in bones of a mammal wherein a phosphonated Oxazolidinone antimicrobial molecule having high affinity to osseous tissues is administered to a mammal.
- the phosphonated Oxazolidinone antimicrobial molecule binds osseous tissues and accumulates in bones of the mammal in amounts greater than amounts of a non-phosphonated equivalent of the Oxazolidinone antimicrobial molecule.
- the phosphonated group is coupled to the Oxazolidinone antimicrobial molecule through a cleavable linker.
- the invention further provides a method for prolonging the presence of an oxazolidinone antimicrobial molecule in bones of a mammal wherein a phosphonated Oxazolidinone antimicrobial molecule having a high affinity to osseous tissues is administered to a mammal.
- the phosphonated group is coupled to the Oxazolidinone antimicrobial molecule through a cleavable linker.
- the phosphonated Oxazolidinone antimicrobial molecule binds osseous tissues and accumulates in bones of the mammal, and the linker is cleaved gradually within the bones thereby releasing the Oxazolidinone antimicrobial molecule and prolonging the presence of the Oxazolidinone antimicrobial molecule in the bones.
- in-dwelling device refers to surgical implants, orthopedic devices, prosthetic devices and catheters, i.e., devices that are introduced to the body of an individual and remain in position for an extended time.
- Such devices include, but are not limited to, artificial joints and implants, heart valves, pacemakers, vascular grafts, vascular catheters, cerebrospinal fluid shunts, urinary catheters, continuous ambulatory peritoneal dialysis (CAPD) catheters.
- the in-dwelling device is bathed in or sprayed with a concentration of about 1 mg/ml to about 10 mg/ml of the compound and/or the composition of the invention, before its insertion in the body.
- the in-dwelling device is made of, or pre-coated with, an osseous-like type of material (e.g. calcium phosphate, Ca-ion and hydroxyapatite (Yoshinari et al., Biomaterials (2001 ), 22(7): 709-715)).
- an osseous-like type of material e.g. calcium phosphate, Ca-ion and hydroxyapatite (Yoshinari et al., Biomaterials (2001 ), 22(7): 709-715).
- Such material is likely to advantageously improve binding of the compounds of the invention to the in-dwelling device, either during the coating of the device with the compounds of the invention and/or after their local or systemic administration.
- the in-dwelling devices may also be coated with an osseous material pre-loaded with or containing bound bone-targeting compound(s) according to the invention.
- hydroxyapatite would be preferred as the osseous material. More details on coating methods, uses and advantages of hydroxyapatite-coated prostheses are found in the review by Dumbleton and Manly (The Journal of Bone & Joint Surgery (2004) 86A:2526-40) which is incorporated herein by reference.
- inventive compounds and their salts, solvates, crystal forms, active metabolites, and prodrugs, may be prepared by employing the techniques available in the art using starting materials that are readily available. Certain novel and exemplary methods of preparing the inventive compounds are described in the Exemplification section below. Such methods are within the scope of this invention.
- Examples set forth herein below provide exemplary syntheses of certain representative compounds of the invention. Also provided are exemplary methods for assaying the compounds of the invention for their activity as inhibitors of protein synthesis, assays for determining the minimum inhibitory concentration (MIC) of the compounds of the invention against microorganisms, and methods for testing in vivo activity and cytotoxicity.
- MIC minimum inhibitory concentration
- Example 1 Synthesis of linezolid, eperezolid amine and eperezolid bisphosphonate conjugates
- benzyl substituted bisphosphonate building blocks of the general structures III and V can be obtained by alkylation of the anion of I with 4-substituted benzyl bromide Il or bromoacetate IV.
- Nitro compound Ilia can be converted to aniline IHb by reduction of the nitro group under hydrogenation conditions, using a catalyst such as PtO 2 .
- Esters like IUc and Va can be converted to the corresponding acids HId or Vb via ester cleavage.
- Diethyl (ethoxyphosphinyl)methylphosphonate Vl can be prepared using the procedure described in Synth. Comm. 2002, 32, 2951-2957 and patent US 5,952,478 (1999). It can be coupled with a 4-substituted bromobenzene (VII) to access acid VHIb, following cleavage of the ester intermediate Villa.
- VI 4-substituted bromobenzene
- Amine IX can be prepared from dibenzylamine, diethyl phosphite and triethyl orthoformate following a protocol described in Synth. Comm. 1996, 26, 2037-2043. Acylation of IX with succinic anhydride Xa or glutaric anhydride Xb can provide acids XIa and XIb respectively (J. Drug Targeting 1997, 5, 129-138). ?,P(OR) 2
- Olefin XII can be prepared from I following a protocol described in J. Org. Chem. 1986, 51, 3488-3490. It can also be converted to acid XV via malonate XIII using conditions described in Tetrahedron 2001 , 57, 1837-1847.
- o o (RO) 2 P VN ⁇ P(OR) 2 H 2 N ⁇ 'n XVIIIa: n 2
- alcohols of general structure XVII(a-f) and amines of general structure XVIII(a-c) can be prepared by alkylation of the anion of I by protected ⁇ -hydroxy bromides of various chain length XVI(a-c). After deprotection, alcohols can be converted to the corresponding amines via a sequence of mesylation, displacement with azide anion and reduction of the azide.
- Alcohols XVII(d-f) can also be converted to the corresponding iodides X ⁇ X(a-c) via treatment with in situ generated triphenylphosphine:iodine complex. These alcohols may additionally be converted to acids of general structure Vb, XV and XX by conventional methods of oxidation, such as treatment with pyridinium dichromate.
- Thiol XXI can be prepared by alkylation of the anion of I with a protected 3-iodopropane- 1-thiol following the protocol described in Bioorg. Med. Chem. 1999, 7, 901-919.
- Vinyl ketones such as XXIII(a-c) can be prepared through the condensation of the parent (hydroxyphenyl) vinyl ketone XXII with iodides X ⁇ X(a-c) in the presence of an appropriately chosen base.
- Diethyl (ethoxyphosphinyl)methylphosphonate XXIV can be prepared using the procedure described in Synth. Comm. (2002), 32: 2951-2957 and patent US 5,952,478 (1999). It can be coupled with a halogenated 1 ,3-dioxolone XXV to furnish bisphosphonate XXVI. This can be followed by a radical halogenation reaction to provide bisphosphonate XXVII.
- the bisphosphonated hydrocinnamic acids XXXIII(a-b) can be obtained via a sequence of protections and deprotections from the bisphosphonated dihydrochromenone XXXIX, itself the product of a coupling between diethyl (ethoxyphosphinyl)methylphosphonate XXIV and halogenated dihydrochromenone XXVIII.
- the bisphosphonate building blocks described in this section are in the form of their phosphonic esters, R being Me, Et, /-Pr, AIIyI or Bn; or in the form of free bisphosphonic acids and/or free bisphosphonated salts.
- compound XXXVII can be obtained from the aldehyde XXXIV and aniline UIb and converted to amide XXXVIII.
- Compounds XL through XLV can be prepared by coupling the same amine XXXIXwith the appropriate acid using a coupling agent, such as BOPCI, under typical coupling conditions.
- a coupling agent such as BOPCI
- acids can be converted to the corresponding acid chlorides by treating the acid with SOCI 2 or oxalyl chloride.
- SOCI 2 or oxalyl chloride can as the acylating agent in the conversion of amine XXXIX, providing amides XL through XLV.
- Eperezolid (XLVII) and its amine precursor XLVI can be converted into bisphosphonate conjugates XLVIII through LIX by coupling with acids UId, Vb 1 XV, VIIIb 1 Xl(a-b) and XXXIII(a-b) following a protocol similar to the one for linezolid derivatives above.
- Acid chlorides derived from UId, Vb, XV, VIIIb, Xl(a-b) and XXXIII(a-b) can also be employed for this acylation to provide the same bisphosphonate conjugates.
- Amine functionalized oxazolidinones such as XXXIX and XLVI can be acylated with chloroalkyl chloroformates to furnish chloroalkyl carbamates such as LXIV and LXV.
- Chloroalkyl carbamate LXIV can react with carboxylic acids IMd, Vb, XV, XX, VIIIb, Xl(a- b) and XXXIII(a-b) in the presence of a non nucleophilic base, or with the corresponding carboxylate salts, to furnish bisphosphonates acyloxyalkyl carbamates LXVI to LXXI.
- Bisphosphonated amides such as XLI(a-b) and carbamates such as LXVI I (a-c) possessing a secondary nitrogen can be further acetylated to furnish bisphosphonated imides LXXVIII(a-b) and LXXIX(a-c)
- Antibacterial oxazolidinones possessing a secondary amine functionality such as XLVI can be treated with bisphosphonated enones XXIII(a-c) under mildly basic conditions to furnish bisphosphonated oxazolidinone ⁇ -aminoketones XC(a-b).
- R Me, Et or /-Pr
- the ester is treated with TMSBr in a solvent such as CH 2 CI 2 , with or without an amine or a heteroaromatic nitrogen containing base, and the resulting silylated intermediate is hydrolysed with water.
- R AIIyI
- the esters are hydrolyzed by treatment with a strong nucleophile in the presence of Pd(II) catalysts.
- Linezolid was prepared using a modified protocol derived from J. Med. Chem. 1996, 39, 673-679.
- the filtered solids were suspended in EtOAc (300 mL), filtered and washed with 3 x 100 mL EtOAc. The organic solutions were combined. The aqueous NH 4 CI solution and organic solution were combined, H 2 O was added (100 mL) and the layers were separated. The organic layer was washed with 2 x 200 mL H 2 O and saturated NaCI solution (100 mL), dried over Na 2 SO 4 , filtered and concentrated to yield 2 as an ochre solid (11.5 g, 70%).
- reaction mixture was washed with water (2 x 30 mL), and saturated sodium bicarbonate (2 x 30 mL), and dried over MgSO 4 . After chromatography (gradient elution 5-10% MeOH / CH 2 CI 2 ) the product was obtained as a white foam (709 mg, 91%).
- Cluster catalyst NaOf-Bu «3NaOC 6 H 4 -4-f-Bu
- NaOf-Bu (1.78 g, 18.5 mmol) portionwise to a stirred solution of 4-f-butyl phenol (2.09 g, 13.9 mmol) in dry THF (50 ml_). The solution was stirred for 30 min at room temperature, resulting in an almost clear solution of the catalyst.
- Tetrabenzyl 2-(4-carbomethoxyphenyl)ethane-1,1-diphosphonate (20).
- Sodium hydride (60% suspension in mineral oil, 225 mg, 5.63 mmol) was added portionwise to a solution of tetrabenzyl methylenediphosphonate (18c, 3.00 g, 5.59 mmol) in DMF (10 mL) at room temperature.
- the mixture was stirred at room temperature for 80 min and a solution of methyl (4-bromomethyl)benzoate (19a, 1.41 g, 6.15 mmol) in THF (2 mL) was then added.
- the mixture was stirred at room temperature for 40 min, and then quenched with saturated NH 4 CI (15 ml_).
- 20 using tetrabenzyl methylenediphosphonate (18c) and f-butyl 4-(bromomethyl)benzoate (19b).
- Tetramethyl 2-(4-nitrophenyl)ethane-1,1 -diphosphonate (23). As for 20, using tetramethyl methylenediphosphonate (18a) and 1-(bromomethyl)-4-nitrobenzene (19c). The reaction was quenched with saturated NH 4 CI (5 mL), and added to brine (100 mL) and EtOAc (50 mL). After separation the aqueous layer was extracted with EtOAc (2 x 50 mL), dried (MgSO 4 ), evaporated and chromatographed in EtOAc / MeOH mixtures, gradient elution. The product was obtained in 43% yield as a pale yellow solid.
- Tetraisopropyl 2-(4-carbomethoxyphenyl)ethane-1 ,1 -diphosphonate (24).
- Tetraisopropyl 2-(4-carbo-f-butoxyphenyl)ethane-1 ,1 -diphosphonate 25.
- the crude product was chromatographed using a gradient of 0-2% MeOH / EtOAc. The product was obtained in 61 % yield as a clear colorless oil.
- Tetramethyl 2-f-butoxycarbonylethylene-1 ,1 -bisphosphonate (27a).
- tetramethyl methylenebisphosphonate (18a, 5.1 g, 22.0 mmol) in dry DMF (44 mL) was added NaH (60% suspension in mineral oil, 916 mg, 22.0 mmol) portionwise.
- NaH 50% suspension in mineral oil, 916 mg, 22.0 mmol
- the resulting slurry was stirred for 1 h at room temperature, after which a solution of f-butyl bromoacetate (6.4 g, 33.0 mmol) in DMF (15 mL) was added dropwise.
- the reaction mixture was stirred for 30 min and quenched by adding 50 mL of a saturated solution of NH 4 CI.
- Tetraethyl 2-carboxyethylene-1,1-bisphosphonate (28d) Ester 27d (2.1 g, 5.2 mmol) was stirred in TFA (12 mL) for 2.5 min and concentrated under reduced pressure. Crude acid
- Tetraethyl 2-chlorocarbonylethylene-1 ,1 -bisphosphonate (29d): To acid 28d (1.02 g, 2.95 mmol) in CH 2 CI 2 (15 mL) was added freshly distilled SOCI 2 (0.84 mL, 11.6 mmol). The mixture was stirred at reflux for 3 h and concentrated to dryness to give crude 29d as a colourless oil (quantitative) which was immediately used for the next step without further purification.
- Tetraethyl 5-(2-Tetrahydro-2W-pyranyloxy)pentylene-1,1-bisphosphonate (40): To the suspension of sodium hydride (60 %, 840.5 mg, 21.01 mmol) in 40 mL of THF was carefully added tetraethyl methylenebisphosphonate (6.16 g, 20.95 mmol) and the resultant pale yellow clear solution was stirred at room temperature for 45 min. Then the bromide 39 (4.97 g, 20.96 mmol) was introduced plus 5 mL of THF rinse. The reaction was brought to reflux overnight and allowed to cool to room temperature before being quenched with saturated ammonium chloride aqueous solution.
- Tetraethyl 5-hydroxypentylene-1,1-bisphosphonate (41).
- the crude compound 40 was dissolved in 20 ml_ of methanol and 74.6 mg (0.3863 mmol) of p-toluenesulfonic acid monohydrate was added. After overnight stirring at room temperature, the mixture was concentrated and subjected to flash chromatography with gradient elution from 15:1 ethyl acetate/methanol to 8:1 then 6:1 to afford 41 as a colorless oil (3.1 g, 41 % over two steps).
- Tetraethyl 5-iodopentylene-1 ,1 -bisphosphonate (42).
- the alcohol 41 (1.419 g, 3.938 mmol), triphenylphosphine (1.25 g, 4.718 mmol) and imidazole (325.6 mg, 4.735 mmol) were dissolved in 15 mL of dry acetonitrile, and 1.196 g (4.703 mmol) of I 2 was added in several portions. After overnight stirring at room temperature, the solvent was removed in vacuo and the residue was taken up in ethyl acetate and saturated Na 2 S 2 O 3 aqueous solution. The mixture was stirred until the organic layer turned pale yellow and the two phases were separated.
- Tetraethyl 4-(2-Tetrahydro-2H-pyranyloxy)butylene-1,1-bisphosphonate 46.
- a suspension of NaH 60% suspension in mineral oil, 900 mg, 22.0 mmol
- dry THF 20 ml_
- tetraethyl methylenebisphosphonate 6.46 g, 22.4 mmol
- 2-(3-bromopropoxy)tetrahydro-2H- pyran 5.05 g, 22.6 mmol
- reaction mixture was heated to reflux for 6 h, diluted with CH 2 CI 2 (75 ml.) and washed with brine (2 x 50 ml_), dried (MgSO 4 ) and evaporated. It was used as such in the following step.
- Tetraethyl 4-hydroxybutylene-1,1-bisphosphonate (47).
- MeOH 40 mL
- Amberlite IR-120 0.6 g
- the reaction mixture was heated to 50 0 C for 4 h, filtered and evaporated.
- the crude product was purified by flash chromatography on silica gel with gradient elution from 5-10% methanol / ethyl acetate to give pure 47 (2.67 g, 34% from tetraethyl methylenebisphosphonate).
- Tetraethyl 3-carboxypropylene-1 ,1 -bisphosphonate 48.
- a solution of alcohol 47 (12.7 g, 36.7 mmol) in MeCN (200 mL) and phosphate buffer solution (200 mL, made from mixing equal volumes of 0.67M Na 2 HPO 4 solution and 0.67M NaH 2 PO 4 solution) at 35 0 C was added a catalytic amount of TEMPO (430 mg, 2.75 mmol).
- the other one was filled with a solution of household bleach (5.25%, 25 mL) in 250 mL H 2 O. About 1/5 of the NaCIO 2 solution was added, followed by about 1/5 of the bleach solution to initiate the reaction. The remainder of both solutions was added dropwise, simultaneously, with a rate adjusted so that both additions finished concurrently.
- the reaction mixture was stirred at 35 °C for 4 h, then at room temperature for 18 h.
- the reaction mixture was diluted with 300 mL H 2 O and the pH of the solution was adjusted to 8.0 by adding 1 M NaOH.
- the resulting solution was cooled to 0 0 C and a cold solution of Na 2 SO 3 (6.1 % wt, 185 mL) was added slowly.
- the mixture was stirred at 0 0 C during 30 min, after which a portion of Et 2 O was added. After stirring vigourously, the mixture was poured into an extraction funnel and the Et 2 O layer was separated and discarded. The aqueous layer was acidified to pH 3.4 with cone. HCI and extracted 3 x with CHCI 3 / /-PrOH mixture (4:1). The combined organic layers were dried over MgSO 4 , filtered and concentrated to dryness, yielding 48 as a pale yellow oil (12.9 g, 98%), which could be used without further purification.
- Tetraisopropyl 4-(2-Tetrahydro-2H-pyranyloxy)butylene-1,1-bisphosphonate 49.
- tetraisopropyl methylenebisphosphonate 10 mL, 31.4 mmol.
- 2-(3- bromopropoxy)tetrahydro-2H-pyran 7.00 g, 31.4 mmol was added dropwise.
- the reaction mixture was heated to reflux for 5 h and washed with saturated ammonium chloride solution.
- Tetraisopropyl 3-carboxypropylene-1,1-bisphosphonate (51).
- the product 51 (850 mg, 69 %) was isolated from a flash chromatography on silica gel with the elution of 20:1 (v/v) ethyl acetate/acetic acid as a pale yellow oil.
- N-(((S)-3-(3-fluoro-4-(piperazin-1-yl)phenyl)-2-oxo-oxazolidin-5-yl)methyl)acetamide bisphosphonic acid conjugate 64 A solution of compound 63 (100 mg, 0.11 mmol) in EtOH (25 mL) was placed in a Parr vessel and treated with 10% Pd / C (10 mg). The solution was shaken under 60 psi of H 2 for 30 min. The solution was filtered on Celite and concentrated under vacuum to give bisphosphonic acid 64 as a white solid (57 mg , 95%).
- Eperezolid tetramethylbisphosphonate 67 Acid 31 (60 mg, 0.21 mmol) was coupled with alcohol 17 (83 mg, 0.21 mmol) using the same protocol as for 61. The crude mixture was purified by flash chromatography using 15% MeOH / CH 2 CI 2 to afford ester 67 as a white solid (30 mg, 20%).
- Eperezolid bisphosphonic acid 68 Following the same protocol as for 60, bisphosphonate 67 (30 mg, 0.045 mmol) was deprotected to provide diphosphonic acid 68 as a pink solid (27 mg, quant.).
- 1 H NMR 400 MHz, D 2 O
- Eperezolid tetraisopropylbisphosphonate 69 Acid 26 (100 mg, 0.21 mmol) was coupled with alcohol 17 (83 mg, 0.21 mmol) using the same protocol as for 61. The crude mixture was purified by flash chromatography using 5% EtOH / EtOAc to afford ester 69 as a white solid (60 mg, 34%).
- Eperezolid bisphosphonic acid 70 Following the same protocol as for compound 60, bisphosphonate 69 (50 mg, 0.058 mmol) was deprotected to provide diphosphonic acid 70 as a white solid (37 mg, 92%).
- MS : 685.0 (M-H).
- Eperezolid tetraethylbisphosphonate 71 To a solution of acid 34 (1.27 g, 3.04 mmol), alcohol 17 (1.024 g, 2.60 mmol) and diisopropylethylamine (1.13 ml_, 6.5 mmol) in CH 2 CI 2 (60 ml.) were added bis(2-oxo-3-oxazolidinyl)phosphonic chloride (BOPCI, 0.793 g, 3.12 mmol) and a catalytic quantity of DMAP. The reaction mixture was stirred 26 h, and then evaporated onto SiO 2 (6 g).
- BOPCI bis(2-oxo-3-oxazolidinyl)phosphonic chloride
- Acid 35 (0.2063 g, 0.512 mmol) was coupled with alcohol 17 (0.2052 g, 0.520 mmol) using the same protocol as for 71.
- the crude mixture was purified twice by flash chromatography using a gradient of 10-20% MeOH / CH 2 CI 2 to afford 73 as a white solid (0.1637 g, 41% yield).
- Eperezolid bisphosphonic acid 74 Following the same protocol as for compound 72, bisphosphonate 73 (0.5011 g, 0.643 mmol) was deprotected to provide diphosphonic acid 74 as a white solid in quantitative yield. The crude material was purified by reverse phase chromatography to give 240 mg (49% recovery, assuming the product is the tetrasodium salt).
- Eperezolid tetraisopropylbisphosphonate 75.
- Acid 45 235 mg, 0.546 mmol
- eperezolid 215 mg, 0.545 mmol
- BOPCI 289 mg, 1.10 mmol
- DIPEA 0.20 ml_, 1.15 mmol
- DMAP a catalytic amount of DMAP in 3 mL of dichloromethane.
- the mixture was concentrated and subjected to flash chromatography eluting with 20:1 CH 2 CI 2 MeOH.
- the obtained impure product was then applied to a WATERS C18 sep-pakTM (12 cc) with gradient solvent of 18 mL water, 18 mL 2:1water:MeOH, 18 mL 1:2 waterMeOH and 18 mL methanol.
- the pure product 75 was obtained as a pale yellow oil (220 mg, 50 %).
- the product 84 (15 mg, 17 %) was isolated from a semi-preparative HPLC column (XTerra® Prep RP 1S , 10 ⁇ m, 10x300 mm) with gradient elution from water to methanol as a white powder.
- N-(((S)-3-(3-fluoro-4-(piperazin-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide bisphosphonate conjugate 87 To a solution of 15 (210 mg, 0.480 mmol) and 86 (199 mg, 0.504 mmol) in dry CH 2 CI 2 (5 ml_) were added diisopropylethylamine (125 ⁇ L, 0.720 mmol), DMAP (4 mg) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (BOPCI, 126 mg, 0.480 mmol).
- the solution was diluted with CH 2 CI 2 (10 mL) followed by washing with 5% aqueous HCI (5 mL), 5% aqueous sodium bicarbonate (10 mL), H 2 O (10 mL), saturated NaCI (10 mL) and drying over Na 2 SO 4 .
- the solvent was removed under reduced pressure resulting in the pale yellow coloured solid 93 (281 mg, 50%), which was used without purification.
- Example 2 Binding of bisphosphonated derivatives of oxazolidinones to hydroxyapatite powder
- Example 3 MIC determination of linezolid and eperezolid bisphosphonate conjugates
- Cytotoxicity assays Selected compounds were also tested for their ability to inhibit growth of mammalian cells so as to ascertain levels of cytotoxicity to the mammalian host. Two assays were used: ATP and MTS assays. Assays were performed in 96-well microtiter plates. In the ATP assay the production of ATP was used as the indicator of cell viability and in the MTS assay the production of reducing equivalents was used as the indicator of cell viability. Cryopreserved primary human hepatocytes (In vitro technologies) were used in the ATP assay and cultured HeIa cells (Promega) were v used in the MTS assay.
- ATP assay compounds at 100, 50, 25, and 12.5 ⁇ M were incubated with 1x10 4 primary human hepatocytes per well in Krebs-Henseleit Buffer (Sigma) for two hours at 37 0 C under 5% CO 2 . At the end of the incubation, the ATP content was determined by the addition of luciferin and luciferase and measurement of luminescence.
- MTS assay compounds at 100, 50, 25, and 12.5 ⁇ M were incubated with 2x10 4 HeIa cells per well in Dulbecco's Modified Eagle Medium (Invitrogen Corporation) containing 1% Bovine Growth Serum (HyClone) for 18 h at 37 0 C under 5% CO 2 .
- the amount of reducing equivalents was determined by the reduction of MTS reagent (3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium inner salt) to formazan product ((4,5-dimethylthiazol-2-yl)-3-(3- carboxymethoxyphenyl)-5-(4-sulfophenyl)-formazan) as revealed by absorbance at 490 nm.
- Example 4 Cleavage of linkers by esterase-like activity in serum To demonstrate directly that 67 and 69 were processed to release eperezolid by esterases present in serum (see previous Example), the fate of these two compounds in the presence of serum was evaluated by LC/MS. Briefly, MIC assays were set up in the presence of serum as described previously. Rat serum was purchased from Equitech-Bio Inc. and fresh human serum was obtained from four volunteers. To the well corresponding to the MIC for that compound, an equal volume of HPLC-grade methanol was added. After vortexing and centrifugation, the methanol-extracted material was subjected to evaluation by LC/MS. The results are reported in Table 2 as percentage of original compound detected after 24 h incubation in serum as compared to original amount loaded.
- rat and particularly mouse serum were very efficient in generating eperezolid from the prodrugs 67 and 69.
- human serum was only slightly effective in the conversion of prodrug to drug. This suggests, not unexpectedly, that esterases with specificity for these compounds are more abundant in rodents than in humans.
- Fresh human serum also appeared significantly more effective than commercially available pooled human serum.
- the deprotected bisphosphonic acids such as 68 and 70 MIC values are not affected by the presence of either mouse serum or human serum. _ .
- a kit for the E. coli S30 extract system for circular DNA from PromegaTM was used to assess the effect of the synthesized compounds on in vitro coupled transcription-translation, which is known to be inhibited by the oxazolidinone class of antibacterials.
- the procedure was as described by the manufacturer for reactions using 35 S-Methionine except that DMSO (2% final concentration) was included in each reaction.
- Compounds were added at 20 ⁇ M per reaction. After 90 min incubation at 30°C , the mixture was added to a Luciferase Assay Reagent (PromegaTM) and the luminescence generated was measured.
- mice were treated with eperezolid amine 15, eperezolid 17, and bisphosphonated eperezolid conjugates 68, 72, 74, and 80 and the drug content of the mouse femurs was analyzed at 1 h and at 24 h after injection. Each mouse was administered a single bolus intravenous (tail vein) dose of one of the compounds dissolved in 0.85% NaCI at 10 mg/kg of body weight. Groups of three mice were used for each experimental time point. Animals were humanely sacrificed at 1 and 24 h after i.v. dosing to evaluate the binding (if any) of the compounds to the bone. Femurs were recovered by dissection, cleaned from soft tissues and kept at -80 ° C before determination of the drug concentration of the bone. Extraction procedure
- the dried mouse femur was weighed, added to 400 ⁇ L 6M HCI and incubated at 50 0 C for 2 h. At the end of this period 200 ⁇ L 10M NaOH and 400 ⁇ L methanol were added to each sample. The samples were vortexed 15 min and centrifuged 10 min at 10,000 g. The supernatant was transferred into another vial and centrifuged again in the same conditions. 20 ⁇ L of the last supernatant was injected into the LC/MS. Unknown samples were evaluated against a calibration curve of eperezolid amine (10 to 1000 ng/mL) from standards prepared in spiked blank femur and treated in the same manner as the unknowns.
- the samples were injected on a ZorbaxTM SB-AQ (3.5 ⁇ , 2.1 x 30 mm) column with a flow rate of 0.3 mL/min using ammonium acetate 10mM pH 6.8 (aq) and acetonitrile (org) as eluents with the following program: 0-3 min: 12 ⁇ 20% org; 3-6 min: 20 ⁇ 50% org; 6-9 min: 50 - ⁇ 80% org; 9-10min: 80 ⁇ 12% org; 10-15min: 12% org.
- the APCI/ESI source was used on the MS trap (Agilent SL) in positive polarity with dry temperature set at 350 0 C, dry gas set at 10 L/min and nebulizer set at 45 psi.
- the acquisition spectrum was divided into 2 segments: the divert valve was selected in the first segment (0-2 min), followed by an SRM on MH + 337.1 (eperezolid amine) and 395.2 (eperezolid) for segment 2 (2-15min).
- Example 7 LC/MS analysis of samples from rat treated with compounds 72
- Rats were administered a single bolus intravenous (tail vein) dose of 72 dissolved in
- the dried rat tibia was powdered and two fractions of 100 mg were weighed.
- the rat plasma was also analysed as two identical fractions (100 ⁇ L each).
- the second fraction of plasma was incubated at 50 0 C for 2 h with 200 ⁇ L of 6M HCI. At the end of this period, water (600 ⁇ L) and internal standard were added, the mixture vortexed and centrifuged (10 min, 10,000 g). The supernatant was extracted on StrataTM (30 mg/1 mL) cartridge. The eluent (methanol) was evaporated to dryness, the dried residue reconstituted into 100 ⁇ l_ water and 20 ⁇ l_ injected into the LC/MS. The unknown samples were evaluated against a calibration curve (50 to 10,000 ng/mL) of eperezolid amine from standards prepared in spiked blank plasma and treated as the unknowns.
- the samples were injected on a ZorbaxTM SB-AQ (3.5 ⁇ , 2.1 x 30 mm) column with a flow rate of 0.3 mL/min using ammonium acetate 1OmM pH 6.8 (aq) and acetonitrile (org) as eluents with the following program: 0-3 min: 12 ⁇ 20% org; 3-6 min: 20 ⁇ 50% org; 6-9 min: 50 ⁇ 80% org; 9-10min: 80 ⁇ 12% org; 10-15min: 12% org.
- the APCI/ESI source was used on the MS trap (Agilent SL) in positive polarity with dry temperature set at 350 0 C, dry gas set at 10 L/min and nebulizer sets at 45 psi.
- the acquisition spectrum was divided into 3 segments: the divert valve was selected in the first segment (0-2min), followed by an SRM on MH + 337.1 (eperezolid amine) and 395.2 (eperezolid) for segment 2 (2-6.8min) and by SRM on MH + 338.2 (internal standard) for segment 3 (6.8-15min).
- eperezolid 17 eperezolid resulting from prodrug cleavage under physiological conditions
- 72 is sufficiently stable in rat blood that its degree of cleavage to 17 in one hour is negligible.
- This pharmacokinetic profile may be expected to be highly advantageous for treatment of chronic osteomyelitis, where the risk of relapse from current treatment regimens is very high, or in the prevention of osteomyelitis, where a small concentration of drug present at all times would prevent bacterial growth.
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Abstract
La présente invention concerne des dérivés phosphonés des oxazolidinones. Ces composés sont utilisables en tant qu'antibiotiques pour la prévention et/ou le traitement des infections des os et des articulations, en particulier pour la prophylaxie et/ou le traitement de l'ostéomyélite.
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US7572795B2 (en) | 2006-03-07 | 2009-08-11 | Bristol-Myers Squibb Company | Pyrrolotriazine aniline prodrug compounds useful as kinase inhibitors |
EP2097440A1 (fr) * | 2006-12-22 | 2009-09-09 | Targanta Therapeutics Inc. | Antibiotiques a base de glycopeptides et de lipoglycopeptides phosphones et leurs utilisations dans la prevention et le traitement d'infections osseuses et articulaires |
WO2009116090A2 (fr) * | 2008-03-18 | 2009-09-24 | Panacea Biotec Limited | Nouveaux antimicrobiens |
US7816379B2 (en) | 2003-12-18 | 2010-10-19 | Dong-A Pharm. Co., Ltd. | Oxazolidinone derivatives |
US8426389B2 (en) | 2009-02-03 | 2013-04-23 | Trius Therapeutics, Inc. | Crystalline form of R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate |
US8580767B2 (en) | 2009-05-28 | 2013-11-12 | Trius Therapeutics, Inc. | Oxazolidinone containing dimer compounds, compositions and methods to make and use |
US8604209B2 (en) | 2008-10-10 | 2013-12-10 | Trius Therapeutics, Inc. | Methods for preparing oxazolidinones and compositions containing them |
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WO2020005964A1 (fr) * | 2018-06-26 | 2020-01-02 | Frank Hallock Ebetino | Composés associés d'oxazolidinone antimicrobiens ciblés sur l'os, leurs formulations, et leurs utilisations |
CN112142795A (zh) * | 2020-10-19 | 2020-12-29 | 成都纽瑞特医疗科技股份有限公司 | 一种硒唑二膦酸化合物及其制备方法 |
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