EA030730B1 - Антибактериальные производные 1h-индазола и 1h-индола - Google Patents

Info

Publication number

EA030730B1

EA030730B1 EA201600475A EA201600475A EA030730B1 EA 030730 B1 EA030730 B1 EA 030730B1 EA 201600475 A EA201600475 A EA 201600475A EA 201600475 A EA201600475 A EA 201600475A EA 030730 B1 EA030730 B1 EA 030730B1

Authority

EA

Eurasian Patent Office

Prior art keywords

hydroxy

methyl

methylsulfonyl

butanamide

hydroxymethyl

Prior art date

2013-12-19

Links

• Espacenet
• Global Dossier
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• 230000000844 anti-bacterial effect Effects 0.000 title abstract description 18
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title description 3
• BNIFVTPIXGUZCU-UHFFFAOYSA-N 1h-indazole Chemical compound C1=CC=C2C=NNC2=C1.C1=CC=C2C=NNC2=C1 BNIFVTPIXGUZCU-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 459
• 150000003839 salts Chemical class 0.000 claims abstract description 68
• 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 28
• 208000035143 Bacterial infection Diseases 0.000 claims abstract description 27
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
• -1 2-hydroxyacetamido, 1-aminocyclopropyl Chemical group 0.000 claims description 426
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 61
• DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 48
• 229910052736 halogen Inorganic materials 0.000 claims description 43
• 150000002367 halogens Chemical class 0.000 claims description 43
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
• 125000000217 alkyl group Chemical group 0.000 claims description 34
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 31
• 125000003545 alkoxy group Chemical group 0.000 claims description 28
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 28
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 21
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 17
• 239000011737 fluorine Substances 0.000 claims description 17
• 229910052731 fluorine Inorganic materials 0.000 claims description 17
• 125000005309 thioalkoxy group Chemical group 0.000 claims description 17
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 14
• 125000005133 alkynyloxy group Chemical group 0.000 claims description 13
• 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 13
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
• YWRPAKATXRUAAF-UHFFFAOYSA-N 2-methyl-2-methylsulfonylbutanamide Chemical compound CCC(C)(C(N)=O)S(C)(=O)=O YWRPAKATXRUAAF-UHFFFAOYSA-N 0.000 claims description 8
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
• 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 5
• 230000002265 prevention Effects 0.000 claims description 4
• CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 208000027096 gram-negative bacterial infections Diseases 0.000 claims description 2
• LRZFEBJUJIQVDQ-UHFFFAOYSA-N methyl 2-(dimethylamino)acetate Chemical compound COC(=O)CN(C)C LRZFEBJUJIQVDQ-UHFFFAOYSA-N 0.000 claims description 2
• DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 2
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
• GMDRGYIMVBVLHY-QMMMGPOBSA-N (1s)-1-(4-ethynylphenyl)ethanol Chemical compound C[C@H](O)C1=CC=C(C#C)C=C1 GMDRGYIMVBVLHY-QMMMGPOBSA-N 0.000 claims 1
• 239000004480 active ingredient Substances 0.000 claims 1
• 229940124350 antibacterial drug Drugs 0.000 claims 1
• 239000003814 drug Substances 0.000 abstract description 19
• 238000002360 preparation method Methods 0.000 abstract description 7
• 238000000034 method Methods 0.000 description 264
• 238000005481 NMR spectroscopy Methods 0.000 description 121
• 230000000052 comparative effect Effects 0.000 description 120
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 109
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 86
• 239000000243 solution Substances 0.000 description 76
• 239000007787 solid Substances 0.000 description 75
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 73
• 238000000746 purification Methods 0.000 description 63
• 239000011541 reaction mixture Substances 0.000 description 63
• 239000000543 intermediate Substances 0.000 description 60
• 238000006243 chemical reaction Methods 0.000 description 58
• 238000002953 preparative HPLC Methods 0.000 description 56
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 55
• 239000000203 mixture Substances 0.000 description 55
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
• 239000003921 oil Substances 0.000 description 34
• 235000019198 oils Nutrition 0.000 description 34
• 229910052740 iodine Inorganic materials 0.000 description 30
• 239000012267 brine Substances 0.000 description 28
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
• 125000004432 carbon atom Chemical group C* 0.000 description 27
• 208000015181 infectious disease Diseases 0.000 description 26
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
• 239000002904 solvent Substances 0.000 description 24
• 241000894006 Bacteria Species 0.000 description 23
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
• 238000004296 chiral HPLC Methods 0.000 description 23
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
• 239000006260 foam Substances 0.000 description 19
• 230000002829 reductive effect Effects 0.000 description 19
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 14
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 14
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 13
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 13
• 239000002253 acid Substances 0.000 description 13
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 13
• 229910052794 bromium Inorganic materials 0.000 description 13
• 239000003480 eluent Substances 0.000 description 13
• 239000011630 iodine Substances 0.000 description 13
• 239000000047 product Substances 0.000 description 13
• 230000029936 alkylation Effects 0.000 description 12
• 238000005804 alkylation reaction Methods 0.000 description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
• 235000019341 magnesium sulphate Nutrition 0.000 description 12
• 239000000725 suspension Substances 0.000 description 12
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
• 241000588626 Acinetobacter baumannii Species 0.000 description 11
• VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 11
• 241000588747 Klebsiella pneumoniae Species 0.000 description 11
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 11
• KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 11
• 230000003115 biocidal effect Effects 0.000 description 11
• 230000015572 biosynthetic process Effects 0.000 description 11
• 229910000104 sodium hydride Inorganic materials 0.000 description 11
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 10
• 125000006239 protecting group Chemical group 0.000 description 10
• 239000011734 sodium Substances 0.000 description 10
• 239000000126 substance Substances 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• 229940079593 drug Drugs 0.000 description 9
• 150000002148 esters Chemical class 0.000 description 9
• 125000000623 heterocyclic group Chemical group 0.000 description 9
• 229910052739 hydrogen Inorganic materials 0.000 description 9
• 230000014759 maintenance of location Effects 0.000 description 9
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
• 241000589517 Pseudomonas aeruginosa Species 0.000 description 8
• MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 8
• 239000012230 colorless oil Substances 0.000 description 8
• 239000012043 crude product Substances 0.000 description 8
• 125000002768 hydroxyalkyl group Chemical group 0.000 description 8
• LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 8
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 7
• 244000166102 Eucalyptus leucoxylon Species 0.000 description 7
• 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 7
• 125000002837 carbocyclic group Chemical group 0.000 description 7
• 239000003054 catalyst Substances 0.000 description 7
• 238000010511 deprotection reaction Methods 0.000 description 7
• 238000002474 experimental method Methods 0.000 description 7
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 7
• 229910052763 palladium Inorganic materials 0.000 description 7
• 238000007127 saponification reaction Methods 0.000 description 7
• 238000003786 synthesis reaction Methods 0.000 description 7
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 7
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 6
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
• 125000003118 aryl group Chemical group 0.000 description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
• 125000001246 bromo group Chemical group Br* 0.000 description 6
• 239000007795 chemical reaction product Substances 0.000 description 6
• 238000001514 detection method Methods 0.000 description 6
• 239000001257 hydrogen Substances 0.000 description 6
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
• 238000004519 manufacturing process Methods 0.000 description 6
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
• 238000003756 stirring Methods 0.000 description 6
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 5
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
• 108090000204 Dipeptidase 1 Proteins 0.000 description 5
• 241000588724 Escherichia coli Species 0.000 description 5
• KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 5
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
• 206010048723 Multiple-drug resistance Diseases 0.000 description 5
• 101150003085 Pdcl gene Proteins 0.000 description 5
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
• 150000001345 alkine derivatives Chemical class 0.000 description 5
• 125000004103 aminoalkyl group Chemical group 0.000 description 5
• 239000003242 anti bacterial agent Substances 0.000 description 5
• 102000006635 beta-lactamase Human genes 0.000 description 5
• 238000003776 cleavage reaction Methods 0.000 description 5
• 238000010828 elution Methods 0.000 description 5
• 238000000105 evaporative light scattering detection Methods 0.000 description 5
• 239000000706 filtrate Substances 0.000 description 5
• 125000001072 heteroaryl group Chemical group 0.000 description 5
• 238000004128 high performance liquid chromatography Methods 0.000 description 5
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 5
• 125000004536 indazol-1-yl group Chemical group N1(N=CC2=CC=CC=C12)* 0.000 description 5
• 230000002401 inhibitory effect Effects 0.000 description 5
• FBTNXKPMTVSCRR-UHFFFAOYSA-N n-methylsulfonylbutanamide Chemical compound CCCC(=O)NS(C)(=O)=O FBTNXKPMTVSCRR-UHFFFAOYSA-N 0.000 description 5
• 229910052757 nitrogen Inorganic materials 0.000 description 5
• 230000007017 scission Effects 0.000 description 5
• 238000010561 standard procedure Methods 0.000 description 5
• 238000004809 thin layer chromatography Methods 0.000 description 5
• CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 5
• 238000000825 ultraviolet detection Methods 0.000 description 5
• 208000019206 urinary tract infection Diseases 0.000 description 5
• RHYTUJSZDNPFIW-UHFFFAOYSA-N (2-fluoro-4-methoxyphenoxy)boronic acid Chemical compound FC1=C(C=CC(=C1)OC)OB(O)O RHYTUJSZDNPFIW-UHFFFAOYSA-N 0.000 description 4
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
• GYUSTTSSRXDFKG-UHFFFAOYSA-N 2-(4-iodophenyl)ethanol Chemical compound OCCC1=CC=C(I)C=C1 GYUSTTSSRXDFKG-UHFFFAOYSA-N 0.000 description 4
• 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 4
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• 102000002260 Alkaline Phosphatase Human genes 0.000 description 4
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• ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 4
• 238000000926 separation method Methods 0.000 description 4
• 125000006526 (C1-C2) alkyl group Chemical group 0.000 description 3
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 3
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
• HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 3
• NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 3
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• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
• 108090000371 Esterases Proteins 0.000 description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
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• 229940088710 antibiotic agent Drugs 0.000 description 3
• 239000000010 aprotic solvent Substances 0.000 description 3
• 239000012298 atmosphere Substances 0.000 description 3
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• YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 3
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• 229960003405 ciprofloxacin Drugs 0.000 description 3
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
• 229910052805 deuterium Inorganic materials 0.000 description 3
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
• 125000004990 dihydroxyalkyl group Chemical group 0.000 description 3
• UBHZUDXTHNMNLD-UHFFFAOYSA-N dimethylsilane Chemical compound C[SiH2]C UBHZUDXTHNMNLD-UHFFFAOYSA-N 0.000 description 3
• 230000002255 enzymatic effect Effects 0.000 description 3
• 229940047650 haemophilus influenzae Drugs 0.000 description 3
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
• 150000007529 inorganic bases Chemical class 0.000 description 3
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
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