TWI639602B - 三環旋轉酶抑制劑 - Google Patents

Info

Publication number

TWI639602B

TWI639602B TW102132841A TW102132841A TWI639602B TW I639602 B TWI639602 B TW I639602B TW 102132841 A TW102132841 A TW 102132841A TW 102132841 A TW102132841 A TW 102132841A TW I639602 B TWI639602 B TW I639602B

Authority

TW

Taiwan

Prior art keywords

ring

group

compound

membered

heteroatoms

Prior art date

2012-09-12

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• 239000002271 gyrase inhibitor Substances 0.000 title abstract description 6
• 150000001875 compounds Chemical class 0.000 claims abstract description 459
• 239000000651 prodrug Substances 0.000 claims abstract description 100
• 229940002612 prodrug Drugs 0.000 claims abstract description 100
• 150000003839 salts Chemical class 0.000 claims abstract description 45
• 125000001424 substituent group Chemical group 0.000 claims description 348
• 239000000203 mixture Substances 0.000 claims description 254
• 229910052760 oxygen Inorganic materials 0.000 claims description 222
• 229910052717 sulfur Inorganic materials 0.000 claims description 207
• 230000002452 interceptive effect Effects 0.000 claims description 188
• 229910052757 nitrogen Inorganic materials 0.000 claims description 152
• -1 aminocyclopropyl Chemical group 0.000 claims description 148
• 125000001072 heteroaryl group Chemical group 0.000 claims description 136
• 125000005842 heteroatom Chemical group 0.000 claims description 128
• 125000003118 aryl group Chemical group 0.000 claims description 113
• 229910052801 chlorine Inorganic materials 0.000 claims description 74
• 229910052739 hydrogen Inorganic materials 0.000 claims description 70
• 125000001183 hydrocarbyl group Chemical group 0.000 claims description 69
• 229910052731 fluorine Inorganic materials 0.000 claims description 67
• 150000001412 amines Chemical class 0.000 claims description 63
• 125000004429 atom Chemical group 0.000 claims description 63
• 125000005647 linker group Chemical group 0.000 claims description 58
• 229910052794 bromium Inorganic materials 0.000 claims description 56
• 229910052799 carbon Inorganic materials 0.000 claims description 39
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 32
• 150000003512 tertiary amines Chemical class 0.000 claims description 32
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 27
• 239000001257 hydrogen Substances 0.000 claims description 27
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
• 238000011282 treatment Methods 0.000 claims description 26
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
• 125000004122 cyclic group Chemical group 0.000 claims description 24
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 23
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 21
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 21
• 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims description 19
• 229910005965 SO 2 Inorganic materials 0.000 claims description 18
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
• 238000006467 substitution reaction Methods 0.000 claims description 18
• 229910004013 NO 2 Inorganic materials 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 17
• 238000004519 manufacturing process Methods 0.000 claims description 16
• 125000000623 heterocyclic group Chemical group 0.000 claims description 14
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 14
• 125000004434 sulfur atom Chemical group 0.000 claims description 14
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 13
• 208000035143 Bacterial infection Diseases 0.000 claims description 12
• 125000000217 alkyl group Chemical group 0.000 claims description 12
• 208000022362 bacterial infectious disease Diseases 0.000 claims description 12
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 10
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 10
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 9
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
• 150000003973 alkyl amines Chemical class 0.000 claims description 7
• 125000003277 amino group Chemical group 0.000 claims description 7
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
• 239000004215 Carbon black (E152) Substances 0.000 claims description 5
• 229910052736 halogen Inorganic materials 0.000 claims description 5
• 229930195733 hydrocarbon Natural products 0.000 claims description 5
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 150000002367 halogens Chemical class 0.000 claims description 3
• 125000006657 (C1-C10) hydrocarbyl group Chemical group 0.000 claims description 2
• GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 2
• 101150065749 Churc1 gene Proteins 0.000 claims description 2
• 102100038239 Protein Churchill Human genes 0.000 claims description 2
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
• 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 4
• 125000006658 (C1-C15) hydrocarbyl group Chemical group 0.000 claims 3
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 1
• 125000003282 alkyl amino group Chemical group 0.000 claims 1
• 150000001924 cycloalkanes Chemical class 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 119
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 24
• 150000002148 esters Chemical class 0.000 abstract description 8
• 230000000844 anti-bacterial effect Effects 0.000 abstract description 7
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 256
• 239000000243 solution Substances 0.000 description 139
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 129
• 235000019439 ethyl acetate Nutrition 0.000 description 100
• 239000007787 solid Substances 0.000 description 99
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
• 238000002360 preparation method Methods 0.000 description 91
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 89
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 70
• 238000006243 chemical reaction Methods 0.000 description 68
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 63
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
• 239000000047 product Substances 0.000 description 54
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
• 239000000460 chlorine Substances 0.000 description 50
• 230000008569 process Effects 0.000 description 48
• 238000005481 NMR spectroscopy Methods 0.000 description 45
• 239000011541 reaction mixture Substances 0.000 description 44
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 43
• 239000012044 organic layer Substances 0.000 description 42
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 38
• 239000000543 intermediate Substances 0.000 description 37
• 150000003335 secondary amines Chemical class 0.000 description 37
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
• 125000006239 protecting group Chemical group 0.000 description 36
• QYBCFRNSVYOIBT-UHFFFAOYSA-N 6-fluoro-n-methyl-2,4-bis(methylsulfonyl)-9h-pyrimido[4,5-b]indol-8-amine Chemical compound N1C2=NC(S(C)(=O)=O)=NC(S(C)(=O)=O)=C2C2=C1C(NC)=CC(F)=C2 QYBCFRNSVYOIBT-UHFFFAOYSA-N 0.000 description 34
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
• 239000011734 sodium Substances 0.000 description 34
• 238000004440 column chromatography Methods 0.000 description 33
• 150000004702 methyl esters Chemical class 0.000 description 33
• 239000002904 solvent Substances 0.000 description 33
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 32
• 230000002829 reductive effect Effects 0.000 description 32
• 239000012043 crude product Substances 0.000 description 29
• 230000015572 biosynthetic process Effects 0.000 description 28
• 238000003756 stirring Methods 0.000 description 28
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
• 125000004744 butyloxycarbonyl group Chemical group 0.000 description 25
• 239000003921 oil Substances 0.000 description 25
• 235000019198 oils Nutrition 0.000 description 25
• 238000002390 rotary evaporation Methods 0.000 description 25
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
• 239000000706 filtrate Substances 0.000 description 24
• 239000012299 nitrogen atmosphere Substances 0.000 description 23
• 239000007858 starting material Substances 0.000 description 23
• 238000003786 synthesis reaction Methods 0.000 description 23
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
• 239000000725 suspension Substances 0.000 description 22
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 230000000694 effects Effects 0.000 description 21
• 238000004128 high performance liquid chromatography Methods 0.000 description 21
• 239000003208 petroleum Substances 0.000 description 21
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 21
• VGOOYBDFYRWUNC-NTQMXBNMSA-N tert-butyl (1R,4R,5R)-1-amino-2-[8-[chloromethoxycarbonyl(methyl)amino]-6-fluoro-2-(2-methylpyrimidin-5-yl)oxy-9H-pyrimido[4,5-b]indol-4-yl]-2-azabicyclo[2.2.1]heptane-5-carboxylate Chemical compound C(=O)(OC(C)(C)C)[C@H]1[C@@H]2CN([C@@](C1)(C2)N)C2=NC(=NC=1NC3=C(C=C(C=C3C12)F)N(C(OCCl)=O)C)OC=1C=NC(=NC1)C VGOOYBDFYRWUNC-NTQMXBNMSA-N 0.000 description 21
• 238000000746 purification Methods 0.000 description 20
• FDGQPXKJKYBMIK-IDHHARJASA-N tert-butyl n-[(1r,4r,5r)-2-[6-fluoro-8-(methylamino)-2-(2-methylpyrimidin-5-yl)oxy-9h-pyrimido[4,5-b]indol-4-yl]-2-azabicyclo[2.2.1]heptan-5-yl]carbamate Chemical compound CNC1=CC(F)=CC(C2=C(N3[C@@H]4C[C@@H]([C@@H](C4)NC(=O)OC(C)(C)C)C3)N=3)=C1NC2=NC=3OC1=CN=C(C)N=C1 FDGQPXKJKYBMIK-IDHHARJASA-N 0.000 description 20
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 19
• 229940126062 Compound A Drugs 0.000 description 19
• NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 19
• 239000012230 colorless oil Substances 0.000 description 19
• 229910000027 potassium carbonate Inorganic materials 0.000 description 19
• 150000003141 primary amines Chemical class 0.000 description 19
• 238000004366 reverse phase liquid chromatography Methods 0.000 description 19
• 239000005457 ice water Substances 0.000 description 18
• 229910004298 SiO 2 Inorganic materials 0.000 description 17
• 229960000583 acetic acid Drugs 0.000 description 17
• 239000013058 crude material Substances 0.000 description 16
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
• 229920006395 saturated elastomer Polymers 0.000 description 15
• DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 15
• 238000010898 silica gel chromatography Methods 0.000 description 15
• SEOZPKYDFRZJMV-UHFFFAOYSA-N 3-[(2-oxo-1,3-oxazolidin-3-yl)phosphanyl]-1,3-oxazolidin-2-one Chemical compound O=C1OCCN1PN1C(=O)OCC1 SEOZPKYDFRZJMV-UHFFFAOYSA-N 0.000 description 14
• 102000004190 Enzymes Human genes 0.000 description 14
• 108090000790 Enzymes Proteins 0.000 description 14
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 14
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 14
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
• 239000012267 brine Substances 0.000 description 14
• 230000003993 interaction Effects 0.000 description 14
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
• OHFVPBGSKPYIED-UHFFFAOYSA-N 2-methylpyrimidin-5-ol Chemical compound CC1=NC=C(O)C=N1 OHFVPBGSKPYIED-UHFFFAOYSA-N 0.000 description 13
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
• 230000008878 coupling Effects 0.000 description 13
• 238000010168 coupling process Methods 0.000 description 13
• 238000005859 coupling reaction Methods 0.000 description 13
• 229940079593 drug Drugs 0.000 description 13
• 239000003112 inhibitor Substances 0.000 description 13
• 238000009101 premedication Methods 0.000 description 13
• 235000018102 proteins Nutrition 0.000 description 13
• 108090000623 proteins and genes Proteins 0.000 description 13
• 102000004169 proteins and genes Human genes 0.000 description 13
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
• 239000002585 base Substances 0.000 description 12
• 239000000284 extract Substances 0.000 description 12
• 238000012545 processing Methods 0.000 description 12
• 239000000126 substance Substances 0.000 description 12
• 125000004432 carbon atom Chemical group C* 0.000 description 11
• 239000008241 heterogeneous mixture Substances 0.000 description 11
• 239000010410 layer Substances 0.000 description 11
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
• 239000012298 atmosphere Substances 0.000 description 10
• 238000001914 filtration Methods 0.000 description 10
• 238000009472 formulation Methods 0.000 description 10
• 208000015181 infectious disease Diseases 0.000 description 10
• 239000000546 pharmaceutical excipient Substances 0.000 description 10
• 239000002244 precipitate Substances 0.000 description 10
• CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 10
• OTAZDABHOSBZMD-KRWDZBQOSA-N 4-[(7R)-7-amino-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-N-methyl-2-[(2-methylpyrimidin-5-yl)methyl]-9H-pyrimido[4,5-b]indol-8-amine Chemical compound N[C@H]1CN(CC11CC1)C1=NC(=NC=2NC3=C(C=C(C=C3C=21)F)NC)CC=1C=NC(=NC=1)C OTAZDABHOSBZMD-KRWDZBQOSA-N 0.000 description 9
• 239000002253 acid Substances 0.000 description 9
• 239000003795 chemical substances by application Substances 0.000 description 9
• 239000003085 diluting agent Substances 0.000 description 9
• 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 9
• 239000007924 injection Substances 0.000 description 9
• 238000002347 injection Methods 0.000 description 9
• 150000002678 macrocyclic compounds Chemical class 0.000 description 9
• 238000010992 reflux Methods 0.000 description 9
• 241000588724 Escherichia coli Species 0.000 description 8
• 239000003242 anti bacterial agent Substances 0.000 description 8
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 239000002552 dosage form Substances 0.000 description 8
• 238000005516 engineering process Methods 0.000 description 8
• VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 8
• 238000003818 flash chromatography Methods 0.000 description 8
• 239000002808 molecular sieve Substances 0.000 description 8
• 239000012071 phase Substances 0.000 description 8
• URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 8
• 231100000419 toxicity Toxicity 0.000 description 8
• 230000001988 toxicity Effects 0.000 description 8
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
• 108010041052 DNA Topoisomerase IV Proteins 0.000 description 7
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
• 239000004480 active ingredient Substances 0.000 description 7
• 239000008280 blood Substances 0.000 description 7
• 210000004369 blood Anatomy 0.000 description 7
• 239000013078 crystal Substances 0.000 description 7
• 230000008570 general process Effects 0.000 description 7
• 238000010438 heat treatment Methods 0.000 description 7
• 229910052740 iodine Inorganic materials 0.000 description 7
• 239000000843 powder Substances 0.000 description 7
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
• 125000004076 pyridyl group Chemical group 0.000 description 7
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 7
• 235000009518 sodium iodide Nutrition 0.000 description 7
• JHLVEBNWCCKSGY-UHFFFAOYSA-N tert-butyl n-methylcarbamate Chemical compound CNC(=O)OC(C)(C)C JHLVEBNWCCKSGY-UHFFFAOYSA-N 0.000 description 7
• 238000005160 1H NMR spectroscopy Methods 0.000 description 6
• 108010054814 DNA Gyrase Proteins 0.000 description 6
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
• 229910019142 PO4 Inorganic materials 0.000 description 6
• 239000007864 aqueous solution Substances 0.000 description 6
• 239000000969 carrier Substances 0.000 description 6
• 238000004587 chromatography analysis Methods 0.000 description 6
• 239000006184 cosolvent Substances 0.000 description 6
• 125000000524 functional group Chemical group 0.000 description 6
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
• 238000000338 in vitro Methods 0.000 description 6
• 238000001727 in vivo Methods 0.000 description 6
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 6
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
• 235000019341 magnesium sulphate Nutrition 0.000 description 6
• 239000000463 material Substances 0.000 description 6
• 239000010452 phosphate Substances 0.000 description 6
• RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 6
• 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
• 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
• 239000012258 stirred mixture Substances 0.000 description 6
• HJKZGKMJUUPEGQ-UHFFFAOYSA-N 3,5-difluoro-n-methyl-2-nitroaniline Chemical compound CNC1=CC(F)=CC(F)=C1[N+]([O-])=O HJKZGKMJUUPEGQ-UHFFFAOYSA-N 0.000 description 5
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
• 108091006112 ATPases Proteins 0.000 description 5
• 102000057290 Adenosine Triphosphatases Human genes 0.000 description 5
• 241000894006 Bacteria Species 0.000 description 5
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
• 230000002378 acidificating effect Effects 0.000 description 5
• 238000004458 analytical method Methods 0.000 description 5
• NQYFSRNBBUXTIQ-UHFFFAOYSA-N benzylsulfonylurea Chemical compound NC(=O)NS(=O)(=O)CC1=CC=CC=C1 NQYFSRNBBUXTIQ-UHFFFAOYSA-N 0.000 description 5
• 239000002775 capsule Substances 0.000 description 5
• 230000003197 catalytic effect Effects 0.000 description 5
• 229960001760 dimethyl sulfoxide Drugs 0.000 description 5
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