JP2016532661A - 窒素含有化合物およびその使用 - Google Patents
窒素含有化合物およびその使用 Download PDFInfo
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- JP2016532661A JP2016532661A JP2016521668A JP2016521668A JP2016532661A JP 2016532661 A JP2016532661 A JP 2016532661A JP 2016521668 A JP2016521668 A JP 2016521668A JP 2016521668 A JP2016521668 A JP 2016521668A JP 2016532661 A JP2016532661 A JP 2016532661A
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- Prior art keywords
- compound
- formula
- pharmaceutically acceptable
- subject
- antibacterial agent
- Prior art date
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 206
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 46
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 46
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims description 94
- 239000003242 anti bacterial agent Substances 0.000 claims description 70
- 239000008194 pharmaceutical composition Substances 0.000 claims description 47
- 239000000203 mixture Substances 0.000 claims description 45
- -1 cefurazine Chemical compound 0.000 claims description 32
- YXZKRYNZWYJBGG-NTSWFWBYSA-N [(2s,5r)-2-(aminomethyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl] hydrogen sulfate Chemical compound NC[C@@H]1CC[C@H]2N(OS(O)(=O)=O)C(=O)N1C2 YXZKRYNZWYJBGG-NTSWFWBYSA-N 0.000 claims description 31
- 241000894006 Bacteria Species 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 208000015181 infectious disease Diseases 0.000 claims description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 20
- 239000003781 beta lactamase inhibitor Substances 0.000 claims description 20
- 229940126813 beta-lactamase inhibitor Drugs 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 17
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 claims description 17
- 108090000204 Dipeptidase 1 Proteins 0.000 claims description 16
- 239000004599 antimicrobial Substances 0.000 claims description 16
- 102000006635 beta-lactamase Human genes 0.000 claims description 16
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 230000000844 anti-bacterial effect Effects 0.000 claims description 12
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 12
- 229960000484 ceftazidime Drugs 0.000 claims description 11
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 10
- 229960005256 sulbactam Drugs 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 8
- 239000011734 sodium Chemical group 0.000 claims description 8
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical group O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 claims description 6
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 6
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 6
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 229940124586 β-lactam antibiotics Drugs 0.000 claims description 6
- 229930186147 Cephalosporin Natural products 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229940124587 cephalosporin Drugs 0.000 claims description 5
- 150000001780 cephalosporins Chemical class 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 229930182555 Penicillin Natural products 0.000 claims description 4
- 239000004098 Tetracycline Substances 0.000 claims description 4
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims description 4
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 claims description 4
- 229960003644 aztreonam Drugs 0.000 claims description 4
- 150000001768 cations Chemical class 0.000 claims description 4
- 229960002100 cefepime Drugs 0.000 claims description 4
- HVFLCNVBZFFHBT-ZKDACBOMSA-N cefepime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229960002182 imipenem Drugs 0.000 claims description 4
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 claims description 4
- 229940049954 penicillin Drugs 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 150000003456 sulfonamides Chemical class 0.000 claims description 4
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 4
- 229960002180 tetracycline Drugs 0.000 claims description 4
- 229930101283 tetracycline Natural products 0.000 claims description 4
- 235000019364 tetracycline Nutrition 0.000 claims description 4
- 150000003522 tetracyclines Chemical class 0.000 claims description 4
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 3
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims description 3
- 229940126575 aminoglycoside Drugs 0.000 claims description 3
- 229960003791 cefmenoxime Drugs 0.000 claims description 3
- HJJDBAOLQAWBMH-YCRCPZNHSA-N cefmenoxime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NN=NN1C HJJDBAOLQAWBMH-YCRCPZNHSA-N 0.000 claims description 3
- 229960001668 cefuroxime Drugs 0.000 claims description 3
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 claims description 3
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 claims description 3
- 229960003324 clavulanic acid Drugs 0.000 claims description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 3
- 229920001184 polypeptide Polymers 0.000 claims description 3
- 229910052700 potassium Chemical group 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 3
- 239000000072 sodium resin Substances 0.000 claims description 3
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 claims description 3
- 229960003865 tazobactam Drugs 0.000 claims description 3
- INAHHIFQCVEWPW-RXMQYKEDSA-N (5r)-1-azabicyclo[3.2.0]heptan-7-one Chemical compound C1CCN2C(=O)C[C@H]21 INAHHIFQCVEWPW-RXMQYKEDSA-N 0.000 claims description 2
- QYQDKDWGWDOFFU-IUODEOHRSA-N Cefotiam Chemical compound CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 QYQDKDWGWDOFFU-IUODEOHRSA-N 0.000 claims description 2
- JWCSIUVGFCSJCK-CAVRMKNVSA-N Disodium Moxalactam Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C1=CC=C(O)C=C1 JWCSIUVGFCSJCK-CAVRMKNVSA-N 0.000 claims description 2
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 claims description 2
- 108010028921 Lipopeptides Proteins 0.000 claims description 2
- JSVCEVCSANKFDY-SFYZADRCSA-N carbacephem Chemical compound C1CC(C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)C)[C@H]21 JSVCEVCSANKFDY-SFYZADRCSA-N 0.000 claims description 2
- 238000004517 catalytic hydrocracking Methods 0.000 claims description 2
- 229960003012 cefamandole Drugs 0.000 claims description 2
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 claims description 2
- 229960001817 cefbuperazone Drugs 0.000 claims description 2
- SMSRCGPDNDCXFR-CYWZMYCQSA-N cefbuperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H]([C@H](C)O)C(=O)N[C@]1(OC)C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 SMSRCGPDNDCXFR-CYWZMYCQSA-N 0.000 claims description 2
- 229960003719 cefdinir Drugs 0.000 claims description 2
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 claims description 2
- 229960004682 cefoperazone Drugs 0.000 claims description 2
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 claims description 2
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- QDUIJCOKQCCXQY-WHJQOFBOSA-N cefozopran Chemical compound N([C@@H]1C(N2C(=C(CN3C4=CC=CN=[N+]4C=C3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=NSC(N)=N1 QDUIJCOKQCCXQY-WHJQOFBOSA-N 0.000 claims description 2
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- LNZMRLHZGOBKAN-KAWPREARSA-N cefpimizole Chemical compound N1=CNC(C(=O)N[C@@H](C(=O)N[C@@H]2C(N3C(=C(C[N+]=4C=CC(CCS(O)(=O)=O)=CC=4)CS[C@@H]32)C([O-])=O)=O)C=2C=CC=CC=2)=C1C(=O)O LNZMRLHZGOBKAN-KAWPREARSA-N 0.000 claims description 2
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- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 claims description 2
- UNJFKXSSGBWRBZ-BJCIPQKHSA-N ceftibuten Chemical compound S1C(N)=NC(C(=C\CC(O)=O)\C(=O)N[C@@H]2C(N3C(=CCS[C@@H]32)C(O)=O)=O)=C1 UNJFKXSSGBWRBZ-BJCIPQKHSA-N 0.000 claims description 2
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- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 claims description 2
- UCKZMPLVLCKKMO-LHLIQPBNSA-N cephamycin Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](C)[C@]21OC UCKZMPLVLCKKMO-LHLIQPBNSA-N 0.000 claims description 2
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 claims description 2
- 229960000895 doripenem Drugs 0.000 claims description 2
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229960000433 latamoxef Drugs 0.000 claims description 2
- 229960002260 meropenem Drugs 0.000 claims description 2
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 claims description 2
- IAIWVQXQOWNYOU-FPYGCLRLSA-N nitrofural Chemical compound NC(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 IAIWVQXQOWNYOU-FPYGCLRLSA-N 0.000 claims description 2
- 229960001907 nitrofurazone Drugs 0.000 claims description 2
- 229960002292 piperacillin Drugs 0.000 claims description 2
- 229940072132 quinolone antibacterials Drugs 0.000 claims description 2
- ATEBXHFBFRCZMA-VXTBVIBXSA-N rifabutin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC(=C2N3)C(=O)C=4C(O)=C5C)C)OC)C5=C1C=4C2=NC13CCN(CC(C)C)CC1 ATEBXHFBFRCZMA-VXTBVIBXSA-N 0.000 claims description 2
- 229960000885 rifabutin Drugs 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims 2
- YLPCXVWMHNNQGI-UHFFFAOYSA-N 1,2-diazabicyclo[3.2.1]octane Chemical compound C1C2CCN1NCC2 YLPCXVWMHNNQGI-UHFFFAOYSA-N 0.000 claims 1
- WVPAABNYMHNFJG-QDVBXLKVSA-N 2,2-dimethylpropanoyloxymethyl (6r,7r)-7-[[(z)-2-(2-amino-1,3-thiazol-4-yl)pent-2-enoyl]amino]-3-(carbamoyloxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OCOC(=O)C(C)(C)C)=O)C(=O)\C(=C/CC)C1=CSC(N)=N1 WVPAABNYMHNFJG-QDVBXLKVSA-N 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 230000003115 biocidal effect Effects 0.000 claims 1
- RRYMAQUWDLIUPV-BXKDBHETSA-N cefacetrile Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC#N)[C@@H]12 RRYMAQUWDLIUPV-BXKDBHETSA-N 0.000 claims 1
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- DKOQGJHPHLTOJR-WHRDSVKCSA-N cefpirome Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DKOQGJHPHLTOJR-WHRDSVKCSA-N 0.000 claims 1
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- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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Abstract
Description
本出願は、2013年10月11日に出願されたインド特許出願第3216/MUM/2013号の権利を主張する。同出願の開示全体が本明細書に再び完全に記載されたかのように参照によって本明細書に組み込まれる。
本発明は、窒素含有化合物と、その調製と、感染症の予防または処置におけるその使用と、に関する。
(a)式(II)
(b)式(III)の化合物を塩基の存在下でp−ニトロフェニルスルホニルクロリドと反応させて式(IV)
(c)式(IV)の化合物をアジ化ナトリウムと反応させて式(V)
(d)式(V)の化合物を式(VI)
(e)式(VI)の化合物を水素化分解して式(VII)
(f)式(VII)の化合物をスルホン化剤と反応させ、次に硫酸水素テトラブチルアンモニウムと反応させて式(VIII)
(g)式(VIII)の化合物を式(IX)
(h)式(IX)の化合物を適当な溶媒中でトリフルオロ酢酸と反応させ式(X)
(i)式(X)の化合物を式(XI)の化合物へ変換するステップと
を含むプロセスが提供される。
(a)式(II)
(b)式(III)の化合物をトリエチルアミンの存在下でp−ニトロフェニルスルホニルクロリドと反応させて式(IV)
(c)式(IV)の化合物をアジ化ナトリウムと反応させて式(V)
(d)式(V)の化合物をトリフェニルホスフィンと反応させ、次にジ−tert−ブチルジカルボナートで処理して式(VI)
(e)式(VI)の化合物を炭素担持パラジウム触媒および水素ガスの存在下で水素化分解して式(VII)
(f)式(VII)の化合物を三酸化硫黄−ピリジン錯体と反応させ、次に硫酸水素テトラブチルアンモニウムと反応させて式(VIII)
(g)式(VIII)の化合物の溶液を、ナトリウム樹脂を充填したカラムに流して式(IX)
(h)式(IX)の化合物を適当な溶媒中でトリフルオロ酢酸と反応させて式(X)
(i)式(X)の化合物を水イソプロピル混合物で処理することによって式(XI)の化合物へ変換するステップと
を含むプロセスが提供される。
ステップ1:(2S,5R)−6−(ベンジルオキシ)−2−(ヒドロキシメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(III)の調製:
(2S,5R)−6−ベンジルオキシ−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン−2−カルボン酸(II)のナトリウム塩(50g、0.16モル、インド特許出願第699/MUM/2013号に記載されている手順に従って調製した)をテトラヒドロフラン(500ml)に懸濁させた。撹拌しながら懸濁液にN−メチルモルホリン(18.4ml、0.16モル)を加えた。反応混合物を約−10℃に冷却し、滴下ロートによってクロロぎ酸エチルを加え、約−10℃で1時間撹拌した。撹拌しながら反応混合物にNaBH4(9.56g、0.25モル)を何回かに分けて加えた。薄層クロマトグラフィー(TLC)を用いて反応を監視した。反応の完了後、反応物に水(500ml)、次いで酢酸エチル(500ml)を加えた。反応混合物を30分間撹拌し、層分離させた。有機層を塩水(200ml)で洗浄した。真空下で溶媒を蒸発乾固して(2S,5R)−6−(ベンジルオキシ)−2−(ヒドロキシメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(III)43gを淡黄色の油として得た(99%収率)。
分析:
質量:263.2[M+1];分子式:C14H18N2O3;および分子量:262.3に対応。
1H NMR(CDCl3):δ 7.28〜7.49(m、5H)、4.96(dd、2H)、4.10〜4.16(m、1H)、3.60〜3.74(m、3H)、3.55〜3.59(m、2H)、1.92〜2.02(m、2H)、1.54〜1.58(m、2H)、1.36〜1.41(m、1H)。
ジクロロメタン(240ml)中の(2S,5R)−6−(ベンジルオキシ)−2−(ヒドロキシメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(24g、0.091モル)の溶液を約10℃に冷却した。上記溶液にトリエチルアミン(38.2ml、0.274モル)、次いでp−ニトロフェニルスルホニルクロリドを加えた。この反応混合物を同じ温度で2時間撹拌してから水(200ml)で反応停止させた。反応混合物を15分間撹拌し、層分離させた。有機層を塩水(200ml)で洗浄した。真空下で溶媒を蒸発させて(2S,5R)−2−(4−ニトロフェニルスルホニルオキシ−メチル)−6−(ベンジルオキシ)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(IV)35.3gを淡黄色の固体として得た(85%収率)。
分析:
質量:448.2[M+1];分子式:C20H21N3O7Sおよび分子量:447.5に対応。
1H NMR(CDCl3):δ 8.39(d、2H)、8.11(d、2H)、7.35〜7.40(m、5H)、5.00(dd、2H)、3.73〜4.21(m、2H)、3.33(m、1H)、2.98〜3.16(m、3H)、1.70〜2.00(m、2H)、1.51〜1.61(m、2H)。
N,N−ジメチルホルムアミド(150ml)中の(2S,5R)−6−(ベンジルオキシ)−2−(4−ニトロフェニルスルホニルオキシ−メチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(30g、0.067モル)の溶液に、NaN3(8.7g、0.134モル)を加え、反応混合物を約65℃で4時間加熱した。TLCで見て反応が完結した後、反応混合物を約25℃から30℃に冷却し、水(750ml)、次いで酢酸エチル(300ml)を加えた。反応物を15分間撹拌した。有機層を分離し、水(200ml)、次いで塩水(200ml)で洗浄した。真空下で溶媒を蒸発させて(2S,5R)−2−(アジドメチル)−6−(ベンジルオキシ)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(V)14gを固体として得た(72%収率)。
分析:
質量:288.1[M+1];分子式:C14H17N5O2;および分子量:287.3に対応。
1H NMR(CDCl3):δ 7.28〜7.42(m、5H)、4.94(dd、2H)、3.48〜3.57(m、2H)、3.29〜3.33(m、2H)、2.92(d、2H)、1.93〜2.02(m、2H)、1.41〜1.59(m、2H)。
テトラヒドロフラン(130ml)中の(2S,5R)−6−(ベンジルオキシ)−2−(アジドメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(13g、0.045モル)の溶液に、トリフェニルホスフィン(23.7g、0.19モル)を加え、反応混合物を約25〜30℃で12時間撹拌した。反応混合物に水(1ml)を加え、25〜30℃で約2時間撹拌した。2時間後、トリエチルアミン(19ml、0.135モル)、次いでピロ炭酸ジ−tert−ブチル(20.5ml、0.95モル)を加え、混合物を約25〜30℃で4時間撹拌した。TLCで見て反応が完結した後水(130ml)、次いで酢酸エチル(130ml)を加え、反応物を15分間撹拌した。有機層を分離し、塩水(200ml)で洗浄した。真空下で溶媒を蒸発させ、酢酸エチル:ヘキサン(2:8)の混合物を用いるシリカゲル(60〜120メッシュ)カラムクロマトグラフィーによって残留物を精製して(2S,5R)−6−ベンジルオキシ(benzylozy)−2−(tert−ブトキシカルボニルアミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(VI)8gを固体として得た(49%収率。
分析:
質量:362.1[M+1];分子式:C19H27N3O4および分子量:361.4に対応。
1H NMR(CDCl3):δ 7.28〜7.45(m、5H)、5.03(d、1H)、4.97(bs、1H)、4.89(d、1H)、3.43〜3.46(m、1H)、3.26〜3.36(m、3H)、2.84〜2.96(m、2H)、1.94〜2.04(m、3H)、1.57〜1.61(m、1H)、1.42(s、9H)。
メタノール(60ml)中の(2S,5R)−6−ベンジルオキシ(benzylozy)−2−(tert−ブトキシカルボニルアミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(8g、0.022モル)の溶液にチャコールに担持した10%パラジウムを加え、60psi圧力の水素ガス下この混合物を約25〜30℃で3時間水素化した。セライト床フィルターを通して反応混合物を濾過して触媒を除去し、真空下で濾液を濃縮して(2S,5R)−6−ヒドロキシ−2−(tert−ブトキシカルボニルアミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(VII)6gを白色の固体として得た(100%収率)。
分析:
質量:272.1[M+1];分子式:C12H21N3O4;および分子量:271.3に対応。
1H NMR(CDCl3):δ 4.92(bs、1H)、3.29〜3.73(m、3H)、2.75〜2.98(m、2H)、2.35〜2.65(m、3H)、1.96〜2.02(m、2H)、1.67〜1.73(m、1H)、1.47(s、9H)。
アルゴン雰囲気下約30℃において撹拌しながらジクロロメタン(60ml)中の(2S,5R)−6−ヒドロキシ−2−(tert−ブトキシカルボニルアミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(6g、0.022モル)の溶液にトリエチルアミン(9.2ml、0.066モル)、次いで三酸化硫黄−ピリジン錯体(7g、0.044モル)を加えた。反応混合物を2時間撹拌してから0.5Nリン酸二水素カリウム緩衝液(120ml)中に投入した。有機層を分離して捨てた。水層に固体の硫酸水素テトラブチルアンモニウム(6.75g、0.0.19モル)を加え、約30℃で2時間撹拌した。ジクロロメタン(60ml×2)で反応混合物を抽出した。層分離させた。有機層を一緒にし、真空下40℃より低温で蒸発させて(2S,5R)−6−スルホオキシ−2−(tert−ブトキシカルボニルアミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(VIII)のテトラブチルアンモニウム塩10gを白色の固体として得た(87%収率)。
分析:
質量:(M−1):350.1遊離スルホン酸として;分子式:C12H21N3O7S.N(C4H9)4;および分子量:592.9に対応。
1H NMR(CDCl3):δ 4.94(bs、1H)、3.28〜3.37(m、11H)、2.72〜2.95(m、3H)、2.32〜2.64(m、3H)、1.62〜1.78(m、11H)、1.40〜1.49(m、16H)、0.98〜1.02(m、12H)。
(2S,5R)−6−スルホオキシ−2−(tert−ブトキシカルボニルアミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタンのテトラブチルアンモニウム塩(9g)を10%テトラヒドロフラン:水に溶解し、ダウエックス50WX8 200 Na+樹脂を充填したカラム(長さ45cmおよび直径2.0cm)を通してこの溶液を流した。10%テトラヒドロフラン:水混合物(250ml)でカラムを溶離した。化合物を有する画分を一緒にし、真空下(4mmHg)で蒸発させて(2S,5R)−6−スルホオキシ−2−(tert−ブトキシカルボニルアミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(IX)のナトリウム塩2.9gを白色固体として得た(72%収率)。この中間体を次の反応のために用いた。
分析:
質量:(M−1):373.1遊離スルホン酸として;分子式:C12H20N3O7SNa;および分子量:374.74に対応。
(2S,5R)−6−スルホオキシ−2−(tert−ブトキシカルボニルアミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタンのナトリウム塩(2.4g、0.006モル)をジクロロメタン(6ml)に懸濁させ、この反応混合物に約0〜5℃でトリフルオロ酢酸(6ml)をゆっくり加えた。反応混合物を約0〜5℃の間でさらに2時間撹拌した。真空下40℃より低温で溶媒および過剰のトリフルオロ酢酸を元の体積の大体1/3まで蒸発させて淡黄色の油状残留物を得た。この油状残留物をジエチルエーテルでほぐし、エーテルをデカンテーションした(40ml×2)。粗製の固体を再びジクロロメタン(40ml×2)でほぐし、溶媒をデカンテーションした。真空下40℃より低温で最終的な固体を乾燥して(2S,5R)−6−スルホオキシ−2−(アミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(X)のナトリウムおよびトリフルオロ酢酸塩2.2gを得た(90%収率)。
分析:
質量:(M−1):250.1遊離スルホン酸として;分子式:C7H13N3O5SNaCF3COO;および分子量:387.26に対応。
1H NMR(DMSO−d6):δ 7.82(br.s、3H)、4.00(d、1H)、3.35〜3.40(m、3H)、2.28〜2.91(m、2H)、1.74〜1.79(m、3H)、1.44〜1.47(m、1H);および
HPLCで定量した純度:97.64%。
(2S,5R)−6−スルホオキシ−2−(アミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタンのナトリウムおよびトリフルオロ酢酸塩(2g、0.005モル)を蒸留水(2ml)に溶解し、約25℃においてこの透明な溶液にイソプロピルアルコール(14ml)をゆっくり加えた。反応混合物を12時間撹拌した。沈殿物を吸引濾過して固体を分離し、真空下40℃より低温で乾燥して(2S,5R)−6−スルホオキシ−2−(アミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(XI)1.2gを得た(92%収率)。
分析:
質量:252(M+1)、250(M−1);分子式:C7H14N3O5S;および分子量:251.3に対応。
1H NMR(DMSO−d6):δ 7.78(br.s、3H)、4.24(s、1H)、3.62〜3.65(m、1H)、3.20〜3.42(m、4H)、2.00〜2.18(m、2H)、1.81〜1.98(m、1H)、1.60〜1.65(m、1H);
13C NMR(D2O):18、20、40、43、56、60、171;および
HPLCで定量した純度:99.77%。
本発明による代表的な化合物のさまざまな細菌株に対する生物活性を検討した。典型的な検討において、一夜成長させた細菌培養物を適切に希釈し、試験化合物の2倍希釈物を含有する寒天培地に接種した。環境空気中35±2℃における16〜20時間のインキュベーション後に成長したかまたは成長しなかったかの観察を行った。手順全体を、クリニカル・アンド・ラボラトリー・スタンダーズ・インスティチュート(Clinical and Laboratory Standards Institute)(CLSI)勧告(クリニカル・アンド・ラボラトリー・スタンダーズ・インスティチュート(CLSI)、抗菌物質感染性試験のための性能基準、補遺情報第20(Perfomance Standards for Antimicrobial Susceptibility Testing, 20th Information Supplement)M 100−S20、30巻、1号、2010年)に従って行った。これらの検討の結果を表1および2にまとめる。これらの表においては抗菌活性を最小発育阻止濃度(MIC)として表す。表1は、(2S,5R)−6−スルホオキシ−2−(アミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン(化合物XI)の抗菌活性プロファイルを公知の抗菌剤と比べて示す。化合物(X)の遊離双性イオン形である化合物(XI)の抗菌活性プロファイルも調べた。化合物(XI)は、肺炎桿菌(K.pneumoniae)、大腸菌および緑膿菌(P.aeruginosa)といった抵抗性ESBL菌株に対して良好な抗菌活性を示す。化合物(XI)の活性プロファイルは、試験されたすべての細菌株に対してセフタジジムおよびセフェピムより良好であることを見いだした。化合物(XI)は、抵抗性ESBL菌株である肺炎桿菌および緑膿菌に対してイミペネムより良好な活性を示した。
Claims (29)
- Mは、水素、ナトリウムまたはカリウムである、請求項1に記載の化合物。
- (2S,5R)−6−スルホオキシ−2−(アミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタンまたはその立体異性体もしくは薬学的に許容される誘導体である、請求項1に記載の化合物。
- 請求項1から3のいずれか1項に記載の化合物を含む医薬品組成物。
- 対象における細菌感染症を予防または処置するための方法であって、請求項1から3のいずれか1項に記載の化合物の薬学的に有効な量を前記対象に投与するステップを含む方法。
- 対象における細菌感染症を予防または処置するための方法であって、前記感染症は、1種以上のベータ−ラクタマーゼ酵素を産生する細菌によって引き起こされ、前記方法は、請求項1から3のいずれか1項に記載の化合物の薬学的に有効な量を前記対象に投与するステップを含む方法。
- 少なくとも1種のベータ−ラクタマーゼ阻害剤または薬学的に許容されるその誘導体をさらに含む、請求項4に記載の医薬品組成物。
- 少なくとも1種の抗菌剤または薬学的に許容されるその誘導体をさらに含む、請求項4または7に記載の医薬品組成物。
- 対象における細菌感染症を予防または処置するための方法であって、請求項4、7または8に記載の医薬品組成物の薬学的に有効な量を前記対象に投与するステップを含む方法。
- 対象における細菌感染症を予防または処置するための方法であって、前記感染症は、1種以上のベータ−ラクタマーゼ酵素を産生する細菌によって引き起こされ、前記方法は、請求項4、7または8に記載の医薬品組成物の薬学的に有効な量を前記対象に投与するステップを含む方法。
- 対象における細菌感染症を予防または処置するための方法であって、(a)請求項1に記載の式(I)の化合物またはその立体異性体もしくは薬学的に許容される誘導体と、(b)少なくとも1種のベータ−ラクタマーゼ阻害剤または薬学的に許容されるその誘導体と、の薬学的に有効な量を前記対象に投与するステップを含む方法。
- 対象における細菌感染症を予防または処置するための方法であって、(a)請求項1に記載の式(I)の化合物またはその立体異性体もしくは薬学的に許容される誘導体と、(b)少なくとも1種の抗菌剤または薬学的に許容されるその誘導体と、の薬学的に有効な量を前記対象に投与するステップを含む方法。
- 対象における細菌感染症を予防または処置するための方法であって、(a)請求項1に記載の式(I)の化合物またはその立体異性体もしくは薬学的に許容される誘導体と、(b)少なくとも1種のベータ−ラクタマーゼ阻害剤または薬学的に許容されるその誘導体と、(c)少なくとも1種の抗菌剤または薬学的に許容されるその誘導体と、の薬学的に有効な量を前記対象に投与するステップを含む方法。
- 前記ベータ−ラクタマーゼ阻害剤は、スルバクタム、タゾバクタム、クラブラン酸、または薬学的に許容されるそれらの誘導体からなる群から選ばれる、請求項7または8に記載の医薬品組成物あるいは請求項11または13に記載の方法。
- 対象における抗菌剤の抗菌有効性を増加させるための方法であって、前記抗菌剤または薬学的に許容されるその誘導体を、請求項1に記載の式(I)の化合物またはその立体異性体もしくは薬学的に許容される誘導体の薬学的に有効な量とともに同時投与するステップを含む方法。
- 前記抗菌剤は、アミノグリコシド系抗菌剤、アンサマイシン系抗菌剤、カルバセフェム系抗菌剤、セファロスポリン系抗菌剤、セファマイシン系抗菌剤、リンコサミド系抗菌剤、リポペプチド系抗菌剤、マクロライド系抗菌剤、モノバクタム系抗菌剤、ニトロフラン系抗菌剤、ペニシリン系抗菌剤、ポリペプチド系抗菌剤、キノロン系抗菌剤、スルホンアミド系抗菌剤、テトラサイクリン系抗菌剤またはオキサゾリジノン系抗菌剤からなる群から選ばれる、請求項8に記載の医薬品組成物あるいは請求項9、10、12、13、14または15のいずれか一項に記載の方法。
- 前記抗菌剤は、ベータラクタム系抗菌剤である、請求項8に記載の医薬品組成物あるいは請求項9、10、12、13、14または15のいずれか一項に記載の方法。
- 前記抗菌剤は、ペニシリン、ペネム、カルバペナム、セファロスポリンおよびモノバクタムからなる群から選ばれる、請求項8に記載の医薬品組成物あるいは請求項9、10、12、13、14または15のいずれか一項に記載の方法。
- 前記抗菌剤は、セファロチン、セファロリジン、セファクロル、セファドロキシル、セファマンドール、セファゾリン、セファレキシン、セフラジン、セフチゾキシム、セフォキシチン、セファセトリル、セフォチアム、セフォタキシム、セフスロジン、セフォペラゾン、セフメノキシム、セフメタゾール、セプファログリシン、セホニシド、セフォジジム、セフピロム、セフタジジム、セフトリアキソン、セフピラミド、セフブペラゾン、セフォゾプラン、セフェピム、セフォセリス、セフルプレナム、セフゾナム、セフピミゾール、セフクリジン、セフィキシム、セフチブテン、セフジニル、セフポドキシムアウキセチル、セフポドキシムプロキセチル、セフテラムピボキシル、セフェタメトピボキシル、セフカペンピボキシル、セフジトレンピボキセル、セフロキシム、セフロキシムアウキセチル、ロラカルバセフ、セフタロリン、セフトロザンおよびラタモキセフからなる群から選ばれる、セファロスポリン系抗生物質である、請求項8に記載の医薬品組成物あるいは請求項9、10、12、13、14または15のいずれか一項に記載の方法。
- 前記抗菌剤は、セタジジム、セフェピム、セフピロム、ピペラシリン、エルタペネム、ドリペネム、メロペネム、イミペネム、セフトラロリンおよびセフトロザンからなる群から選ばれる、請求項8に記載の医薬品組成物あるいは請求項9、10、12、13、14または15のいずれか一項に記載の方法。
- (a)(2S,5R)−6−スルホオキシ−2−(アミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタンまたはその立体異性体もしくは薬学的に許容される誘導体と、(b)スルバクタムまたは薬学的に許容されるその誘導体と、を含む請求項7に記載の医薬品組成物。
- 対象における細菌感染症を予防または処置するための請求項11に記載の方法であって、(a)(2S,5R)−6−スルホオキシ−2−(アミノメチル)−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタンまたはその立体異性体もしくは薬学的に許容される誘導体と、(b)スルバクタムまたは薬学的に許容されるその誘導体と、の薬学的に有効な量を前記対象に投与するステップを含む方法。
- 式(XI)
(a)式(II)
(b)式(III)の化合物を塩基の存在下でp−ニトロフェニルスルホニルクロリドと反応させて式(IV)
(c)式(IV)の化合物をアジ化ナトリウムと反応させて式(V)
(d)式(V)の化合物を式(VI)
(e)式(VI)の化合物を水素化分解して式(VII)
(f)式(VII)の化合物をスルホン化剤と反応させ、次に硫酸水素テトラブチルアンモニウムと反応させて式(VIII)
(g)式(VIII)の化合物を式(IX)
(h)式(IX)の化合物を適当な溶媒中でトリフルオロ酢酸と反応させて式(X)
(i)式(X)の化合物を式(XI)の化合物へ変換するステップと
を含むプロセス。 - 式(II)の化合物を塩基の存在下でクロロギ酸エチルと反応させ、次に還元剤で処理することによって式(III)の化合物が得られる、請求項23に記載のプロセス。
- 前記塩基は、N−メチルモルホリンであり、還元剤は、水素化ホウ素ナトリウムである、請求項24に記載のプロセス。
- ステップ(g)における式(IX)の化合物は、ナトリウム樹脂を充填したカラムを通して式(VIII)の化合物の溶液を流すことによって得られる、請求項23に記載のプロセス。
- 式(XI)
(a)式(II)
(b)式(III)の化合物をトリエチルアミンの存在下でp−ニトロフェニルスルホニルクロリドと反応させて式(IV)
(c)式(IV)の化合物をアジ化ナトリウムと反応させて式(V)
(d)式(V)の化合物をトリフェニルホスフィンと反応させ、次に炭酸ジ−tert−ブチルで処理して式(VI)
(e)式(VI)の化合物を炭素担持パラジウムおよび水素ガスの存在下で水素化分解して式(VII)
(f)式(VII)の化合物を三酸化硫黄−ピリジン錯体と反応させ、次に硫酸水素テトラブチルアンモニウムと反応させて式(VIII)
(g)式(VIII)の化合物の溶液を、ナトリウム樹脂を充填したカラムに流して式(IX)
(h)式(IX)の化合物を適当な溶媒中でトリフルオロ酢酸と反応させて式(X)
(i)式(X)の化合物を水イソプロピル混合物で処理することによって式(XI)の化合物に変換するステップと
を含むプロセス。 - HPLCによって定量して99%を超える純度を有する式(XI)の化合物。
- 請求項28に記載の式(XI)の化合物を含む医薬品組成物。
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