WO2020098635A1 - 单环内酰胺化合物及其应用 - Google Patents
单环内酰胺化合物及其应用 Download PDFInfo
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- WO2020098635A1 WO2020098635A1 PCT/CN2019/117472 CN2019117472W WO2020098635A1 WO 2020098635 A1 WO2020098635 A1 WO 2020098635A1 CN 2019117472 W CN2019117472 W CN 2019117472W WO 2020098635 A1 WO2020098635 A1 WO 2020098635A1
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- WO
- WIPO (PCT)
- Prior art keywords
- amino
- alkyl
- alkoxy
- hydroxy
- compound
- Prior art date
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- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical class 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 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 171
- 150000003839 salts Chemical class 0.000 claims abstract description 59
- 239000000651 prodrug Substances 0.000 claims abstract description 51
- 229940002612 prodrug Drugs 0.000 claims abstract description 51
- 239000012453 solvate Substances 0.000 claims abstract description 51
- 239000013078 crystal Substances 0.000 claims abstract description 38
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 20
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- -1 arylheterocyclyl Chemical group 0.000 claims description 169
- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 125000003545 alkoxy group Chemical group 0.000 claims description 63
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 47
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 125000000623 heterocyclic group Chemical group 0.000 claims description 34
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 15
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 15
- 125000004043 oxo group Chemical group O=* 0.000 claims description 15
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 12
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 8
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 8
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 7
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000002431 aminoalkoxy group Chemical group 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 4
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 4
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 241000617482 Kiwa Species 0.000 claims description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 22
- 125000002355 alkine group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 76
- 239000000203 mixture Substances 0.000 abstract description 16
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 11
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 108
- 238000006243 chemical reaction Methods 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 50
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 238000000034 method Methods 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- 208000015181 infectious disease Diseases 0.000 description 18
- 239000002994 raw material Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 241000894006 Bacteria Species 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 14
- 229940079593 drug Drugs 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 239000004576 sand Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 230000001580 bacterial effect Effects 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 241000588626 Acinetobacter baumannii Species 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 0 CNC([C@](CCCCN*)N)=O Chemical compound CNC([C@](CCCCN*)N)=O 0.000 description 9
- 206010035664 Pneumonia Diseases 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 125000002971 oxazolyl group Chemical group 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000006150 trypticase soy agar Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 8
- 239000003242 anti bacterial agent Substances 0.000 description 8
- 229940088710 antibiotic agent Drugs 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000012265 solid product Substances 0.000 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 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 235000008504 concentrate Nutrition 0.000 description 7
- 125000002541 furyl group Chemical group 0.000 description 7
- 125000002883 imidazolyl group Chemical group 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 125000001786 isothiazolyl group Chemical group 0.000 description 7
- 125000000842 isoxazolyl group Chemical group 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 125000001715 oxadiazolyl group Chemical group 0.000 description 7
- 125000003226 pyrazolyl group Chemical group 0.000 description 7
- 125000000168 pyrrolyl group Chemical group 0.000 description 7
- JAELLLITIZHOGQ-UHFFFAOYSA-N tert-butyl propanoate Chemical compound CCC(=O)OC(C)(C)C JAELLLITIZHOGQ-UHFFFAOYSA-N 0.000 description 7
- 125000000335 thiazolyl group Chemical group 0.000 description 7
- 125000001544 thienyl group Chemical group 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 6
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 125000001841 imino group Chemical group [H]N=* 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
- ALLGJVKOLKRAED-LLVKDONJSA-N tert-butyl (2R)-3-(4-bromophenoxy)-2-hydroxypropanoate Chemical compound BrC1=CC=C(OC[C@H](C(=O)OC(C)(C)C)O)C=C1 ALLGJVKOLKRAED-LLVKDONJSA-N 0.000 description 6
- 238000012546 transfer Methods 0.000 description 6
- 125000001425 triazolyl group Chemical group 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 241000588914 Enterobacter Species 0.000 description 5
- 241000588747 Klebsiella pneumoniae Species 0.000 description 5
- 241000607142 Salmonella Species 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 125000004609 dihydroquinazolinyl group Chemical group N1(CN=CC2=CC=CC=C12)* 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 5
- 229920002554 vinyl polymer Polymers 0.000 description 5
- 241000589291 Acinetobacter Species 0.000 description 4
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 4
- 241000588923 Citrobacter Species 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 208000008745 Healthcare-Associated Pneumonia Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
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- 239000007864 aqueous solution Substances 0.000 description 4
- 229960003644 aztreonam Drugs 0.000 description 4
- 102000006635 beta-lactamase Human genes 0.000 description 4
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- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 description 4
- 125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
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- 239000002054 inoculum Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 4
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 4
- 208000019206 urinary tract infection Diseases 0.000 description 4
- 239000002132 β-lactam antibiotic Substances 0.000 description 4
- 229940124586 β-lactam antibiotics Drugs 0.000 description 4
- XSRJWRWWEDIFOY-UHFFFAOYSA-N (2,2-dimethyl-4-oxoazetidin-1-yl) hydrogen sulfate Chemical compound CC1(C)CC(=O)N1OS(O)(=O)=O XSRJWRWWEDIFOY-UHFFFAOYSA-N 0.000 description 3
- FZGZDDRZAZBANV-QMMMGPOBSA-N (2S)-3-(4-bromophenoxy)propane-1,2-diol Chemical compound OC[C@H](O)COC1=CC=C(Br)C=C1 FZGZDDRZAZBANV-QMMMGPOBSA-N 0.000 description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
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- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 3
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 3
- XZLRJCSXDLXBSC-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonylamino]propyl 2-cyanoacetate Chemical group CC(C)(C)OC(=O)NCCCOC(=O)CC#N XZLRJCSXDLXBSC-UHFFFAOYSA-N 0.000 description 3
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
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- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 3
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- 229940126062 Compound A Drugs 0.000 description 3
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- 241000589516 Pseudomonas Species 0.000 description 3
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000005708 Sodium hypochlorite Substances 0.000 description 3
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- 239000002207 metabolite Substances 0.000 description 1
- 230000029052 metamorphosis Effects 0.000 description 1
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 1
- SANNKFASHWONFD-ZCFIWIBFSA-N methyl (2r)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C SANNKFASHWONFD-ZCFIWIBFSA-N 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229940076266 morganella morganii Drugs 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
- 229960000515 nafcillin Drugs 0.000 description 1
- GPXLMGHLHQJAGZ-JTDSTZFVSA-N nafcillin Chemical compound C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C(O)=O)=O)C(OCC)=CC=C21 GPXLMGHLHQJAGZ-JTDSTZFVSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229960001019 oxacillin Drugs 0.000 description 1
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229950009195 phenylpropanol Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
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- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical class [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- RFSWVJXWZXQOSW-ZDFSRXSCSA-M sodium;(5r,6z)-6-(6,8-dihydro-5h-imidazo[2,1-c][1,4]oxazin-2-ylmethylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound [Na+].C1COCC2=NC(/C=C3/C(=O)N4[C@@H]3SC=C4C(=O)[O-])=CN21 RFSWVJXWZXQOSW-ZDFSRXSCSA-M 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
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- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- PSMHFILWQMXZBO-LLVKDONJSA-N tert-butyl (2R)-2-hydroxy-3-(4-nitrophenoxy)propanoate Chemical compound [N+](=O)([O-])C1=CC=C(OC[C@H](C(=O)OC(C)(C)C)O)C=C1 PSMHFILWQMXZBO-LLVKDONJSA-N 0.000 description 1
- OTDUKGPTDGJHKD-HSZRJFAPSA-O tert-butyl (2R)-2-hydroxy-3-[4-[2-[3-[(2-methylpropan-2-yl)oxycarbonylamino]propoxy]-2,3-dihydro-1H-pyrazolo[1,2-a]pyrazol-4-ium-6-yl]phenoxy]propanoate Chemical compound C(C)(C)(C)OC([C@@H](COC1=CC=C(C=C1)C=1C=[N+]2N(C1)CC(C2)OCCCNC(=O)OC(C)(C)C)O)=O OTDUKGPTDGJHKD-HSZRJFAPSA-O 0.000 description 1
- PEJRBHSWGRTSEW-OAQYLSRUSA-N tert-butyl (2R)-2-hydroxy-3-[4-[2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]-3H-benzimidazol-5-yl]phenoxy]propanoate Chemical compound C(C)(C)(C)OC([C@@H](COC1=CC=C(C=C1)C1=CC2=C(NC(=N2)CNC(=O)OC(C)(C)C)C=C1)O)=O PEJRBHSWGRTSEW-OAQYLSRUSA-N 0.000 description 1
- APBDROVGLRLEDJ-UHFFFAOYSA-N tert-butyl 2-(1,3-dioxoisoindol-2-yl)oxypropanoate Chemical compound C1=CC=C2C(=O)N(OC(C)C(=O)OC(C)(C)C)C(=O)C2=C1 APBDROVGLRLEDJ-UHFFFAOYSA-N 0.000 description 1
- IXXMVXXFAJGOQO-UHFFFAOYSA-N tert-butyl 2-hydroxypropanoate Chemical compound CC(O)C(=O)OC(C)(C)C IXXMVXXFAJGOQO-UHFFFAOYSA-N 0.000 description 1
- YQBFDNKMCIIIGB-UHFFFAOYSA-N tert-butyl N-[3-(4-hydroxypyrazol-1-yl)propyl]carbamate Chemical compound C(C)(C)(C)OC(NCCCN1N=CC(=C1)O)=O YQBFDNKMCIIIGB-UHFFFAOYSA-N 0.000 description 1
- OSPRIEIOIUDYFI-UHFFFAOYSA-N tert-butyl N-[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCN1C=C(C=N1)B1OC(C)(C)C(C)(C)O1 OSPRIEIOIUDYFI-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960004659 ticarcillin Drugs 0.000 description 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229950003816 tomopenem Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- 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
- A61P31/04—Antibacterial agents
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- 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
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention belongs to the field of medicinal chemistry, and specifically relates to a class of monocyclic lactam compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs, methods for their preparation, and pharmaceutical compositions containing these compounds and The use of these compounds or compositions for the treatment of bacterial infections.
- Beta-lactam antibiotics are one of the most commonly used antibiotics, and their resistance has gradually emerged.
- the resistance of ⁇ -lactam antibiotics is mainly driven by ⁇ -lactamase, which can hydrolyze ⁇ -lactam and cause antibiotic inactivation.
- MBLs ⁇ -lactamases
- An object of the present invention is to provide a compound represented by the general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug,
- Another object of the present invention is to provide a method for preparing the compound of the general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug of the present invention.
- Still another object of the present invention is to provide a composition
- a composition comprising a compound of the general formula (I) of the present invention or its isomer, a pharmaceutically acceptable salt, a solvate, a crystal or prodrug, and a pharmaceutically acceptable carrier, as well as The compound of the general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug of the present invention and a combination of one or more drugs.
- Still another object of the present invention is to provide a compound of the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystalline or prodrug method for treating bacterial infections, and the general formula of the present invention Use of the compound of (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug in the preparation of a medicament for treating bacterial infection.
- the present invention provides a compound represented by general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug,
- Q 1 is selected from aryl, arylheterocyclyl, heteroarylheterocyclyl, And a 5-membered heteroaryl group, which is optionally substituted with one or more R 1 ;
- Q 2 is absent or selected from 4-6 membered heterocyclyl, arylheterocyclyl, heteroarylcycloalkyl, arylheteroaryl, heteroarylheterocyclyl, 5 membered heteroaryl Kiwa It is optionally substituted with one or more R 2 , R 3 is absent or R 2 , and R 4 is selected from aminoalkylacylamino and hydroxyaminoalkylacylamino;
- R 1 is selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino , Alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl and oxo groups;
- R 2 is selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, aminoalkoxy, nitro, carboxy, cyano, amino, Monoalkylamino, alkylacylamino, aminoalkylacylamino, hydroxyaminoalkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, cycloalkyl, Heterocyclyl, heterocyclylalkyl, aminoheterocyclyl, aminoalkylheterocyclyl, hydroxyalkylheterocyclyl, aryl, heteroaryl and oxo groups, which are optionally amino, aminoalkyl , Alkylamino, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy,
- L is absent or selected from -C (O) NH-, -NHC (O)-, -SO 2 NH-, -NHSO 2 ,-(CH 2 ) n- , and -C (O)-;
- n 1, 2, 3 or 4;
- n 1, 2, 3 or 4;
- Q 1 is aryl
- Q 2 is selected from arylheterocyclyl, heteroarylcycloalkyl, arylheteroaryl, and heteroarylheterocyclyl; or
- Q 1 is aryl
- Q 2 is Where R 3 is absent or R 2
- R 4 is selected from aminoalkylacylamino and hydroxyaminoalkylacylamino; or
- Q 1 is an aryl group
- Q 2 is a 5-membered heteroaryl group
- L is selected from -C (O) NH-, -NHC (O)-, -SO 2 NH-, -NHSO 2 -,-( CH 2 ) n -and -C (O)-; or
- Q 1 is an aryl group
- Q 2 is a 5-membered heteroaryl group
- L is absent
- m is 2, 3, or 4;
- Q 1 is selected from arylheterocyclyl and heteroarylheterocyclyl, then Q 2 is a 5-membered heteroaryl and L is absent; or
- Q 1 is a 5-membered heteroaryl group
- Q 2 is absent
- L is absent
- Q 1 is selected from 6-18 membered aryl, 9-20 membered arylheterocyclic, 9-20 membered heteroarylheterocyclic, And a 5-membered heteroaryl group, which is optionally substituted with one or more R 1 ;
- Q 1 is selected from 6-12 membered aryl, 9-12 membered arylheterocyclic, 9-12 membered heteroarylheterocyclic, And a 5-membered heteroaryl group, which is optionally substituted with one or more R 1 ;
- Q 1 is selected from phenyl, indolinyl, isoindolinyl, benzodihydrofuranyl, chroman, benzodihydrothienyl, benzoxazoline Ketone, benzodihydropyrazolyl, benzodihydroimidazolyl, benzodihydropyrazolyl, benzodihydrooxazolyl, benzodihydrothiazolyl, benzodihydroisoxazolyl, Benzodihydroisothiazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinazolinyl, dihydroquinazolinyl, dihydro Cinolinyl, tetrahydrocinolinyl, dihydroquinoxalinyl, tetrahydroquinox
- the compound of general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystalline or prodrug according to the invention wherein:
- Q 2 is absent or selected from 4-6 membered heterocyclyl, 9-20 membered arylcyclocycloalkyl, 9-20 membered arylcycloheterocyclyl, 9-20 membered heteroarylbicycloheterocyclyl, 5-membered heteroaryl and It is optionally substituted with one or more R 2 , R 3 is absent or R 2 , and R 4 is selected from amino C 1-12 alkylacylamino and hydroxyamino C 1-12 alkylacylamino;
- Q 2 is absent or selected from 4-6 membered heterocyclic groups, 9-12 membered arylcyclocycloalkyl groups, 9-12 membered arylcycloheterocyclic groups, and 9-12 membered heteroaryl groups.
- Heterocyclic group, 5-membered heteroaryl group and It is optionally substituted with one or more R 2 , R 3 is absent or R 2 , and R 4 is selected from amino C 1-6 alkylacylamino and hydroxyamino C 1-6 alkylacylamino;
- Q 2 is absent or selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, dihydrobenzofuranyl, dihydrobenzopyranyl, dihydro Benzothienyl, benzoxazolinone, dihydrobenzopyrazolyl, dihydrobenzimidazolyl, dihydrobenzopyrazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl , Dihydrobenzisoxazolyl, dihydrobenzisothiazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinazolinyl , Dihydroquinazolinyl, dihydrocinnolinyl, tetrahydrocinnolinyl, dihydroquinoxal
- the compound of general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystalline or prodrug according to the invention wherein:
- R 1 is selected from halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, Hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1 -6 alkylaminoacyl, bis C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, 6-12 membered Aryl, 5-12 membered heteroaryl and oxo groups;
- R 1 is selected from halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 Alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, amino Acyl, C 1-3 alkylamino acyl, bis C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl and oxo groups;
- R 1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tri Fluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, Hydroxymethoxy, hydroxyethoxy, hydroxypropoxy, nitro, carboxyl, cyano, amino, methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, methylacylamino, Ethylacylamino, vinylacylamino, methylacyl, ethylacyl, vinylacyl, aminoacyl, methylamino
- the compound of general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystalline or prodrug according to the invention wherein:
- R 2 is selected from halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, amino C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl Acylamino, amino C 1-12 alkyl acylamino, hydroxyamino C 1-12 alkyl acylamino, amino 3-6 membered heterocyclic group, C 1-6 alkyl acyl, amino acyl, C 1-6 alkyl Aminoamino acyl, bis C 1-6 alkylamino, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-6 alkyl, amino C 1-6 al
- R 2 is selected from halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, amino C 1-6 alkyl, C 1-3 alkoxy Group, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, amino C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkylacylamino, amino C 1-6 alkylacylamino, hydroxyamino C 1-6 alkylacylamino, C 1-3 alkylacyl, aminoacyl, C 1-3 alkylaminoacyl, bis C 1-3 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heterocyclic group C 1-3 alkyl Group, amino 3-6 membered heterocyclic group, amino C 1-3 alkyl
- R 2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tri Fluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, methoxy, ethoxy , Propoxy, isopropoxy, trifluoromethoxy, hydroxymethoxy, hydroxyethoxy, hydroxypropoxy, aminomethoxy, aminoethoxy, aminopropoxy, nitro, carboxyl , Cyano, amino, methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, methylacylamino, ethylacy
- R 2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, methoxy, Ethoxy, propoxy, isopropoxy, trifluoromethoxy, hydroxymethoxy, hydroxyethoxy, hydroxypropoxy, aminomethoxy, aminoethoxy, aminopropoxy, nitro Group, carboxyl, cyano, amino, methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, methylacylamino, ethylacyla
- R 2 is selected from methyl, ethyl, propyl, isopropyl, azetidinyl, azetidinylmethyl, azetidinylethyl, azetidinylpropyl , Aminomethyl, aminoethyl, aminopropyl, aminomethyloxy, aminoethyloxy, aminopropyloxy, aminomethylamide, aminoethylamide, aminopropylamide, amino Butylamide, aminopentylamide, hydroxymethylamide, hydroxyethylamide, hydroxypropylamide, aminoazacyclopropyl, aminoazacyclobutyl, aminoazacyclopentyl, It is optionally substituted by amino, amino C 1-3 alkyl, C 1-3 alkylamino, halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 al
- Q 1 is a 6-18 membered aryl group, which is optionally substituted with one or more R 1 ;
- Q 2 is selected from 9-20 membered arylheterocyclyl, 9-20 membered heteroarylcyclocycloalkyl, 9 -20 membered arylheteroaryl, 9-20 membered heteroarylheterocyclyl, which is optionally substituted with one or more R 2 ;
- Q 1 is a 6-12 membered aryl group, which is optionally substituted by one or more R 1 ;
- Q 2 is selected from a 9-12 membered arylheterocyclic group, a 9-12 membered heteroaryl fused ring Alkyl, 9-12 membered arylheteroaryl, 9-12 membered heteroarylheterocyclyl, which is optionally substituted with one or more R 2 ;
- Q 1 is phenyl, which is optionally substituted with one or more R 1 ;
- Q 2 is selected from dihydrobenzofuranyl, dihydrobenzopyranyl, dihydrobenzothiophenyl, benzene Oxazolinone, dihydrobenzopyrazolyl, dihydrobenzimidazolyl, dihydrobenzopyrazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenziso Oxazolyl, dihydrobenzisothiazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinazolinyl, dihydroquinazoline , Dihydrocinnolinyl, tetrahydrocinnolinyl, dihydroquinoxalinyl, tetrahydroquinoxalin,
- the compounds of the present invention are compounds of general formula (Ia) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals or prodrugs,
- R 3 does not exist or is R 2 , where R 2 has the definition described in the above general formula (I);
- R 4 is selected from aminoalkylacylamino and hydroxyaminoalkylacylamino.
- the compounds of general formula (I) or (Ia) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof according to the present invention wherein:
- R 4 is selected from amino C 1-12 alkylacylamino and hydroxyamino C 1-12 alkylacylamino
- R 4 is selected from amino C 1-6 alkylacylamino and hydroxyamino C 1-6 alkylacylamino;
- R 4 is selected from
- the compound of general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystalline or prodrug according to the invention wherein:
- Q 1 is a 6-18 membered aryl group, which is optionally substituted with one or more R 1 ;
- Q 2 is a 5 membered heteroaryl group, which is optionally substituted with one or more R 2 ;
- L is selected from -C (O ) NH-, -NHC (O)-, -SO 2 NH-, -NHSO 2 -,-(CH 2 ) n -and -C (O)-;
- Q 1 is a 6-12 membered aryl group, which is optionally substituted with one or more R 1 ;
- Q 2 is a 5 membered heteroaryl group, which is optionally substituted with one or more R 2 ;
- L is selected from -C (O) NH-, -NHC (O)-, -SO 2 NH-, -NHSO 2 -,-(CH 2 ) n -and -C (O)-;
- Q 1 is phenyl, which is optionally substituted with one or more R 1 ;
- Q 2 is selected from imidazolyl, pyrrolyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, Isoxazolyl, isothiazolyl, oxadiazolyl and triazolyl, which are optionally substituted with one or more R 2 ;
- L is selected from -C (O) NH-, -NHC (O)-, -SO 2 NH-, -NHSO 2 -,-(CH 2 ) n -and -C (O)-.
- the compounds of the present invention are compounds of general formula (Ib) or isomers thereof, pharmaceutically acceptable salts, solvates, crystals or prodrugs,
- L is selected from -C (O) NH-, -NHC (O)-, -SO 2 NH-, -NHSO 2 ,-(CH 2 ) n -and -C (O)-, R 5 , R 6
- the compound of general formula (Ib) or its isomer, pharmaceutically acceptable salt, solvate, crystalline or prodrug according to the present invention wherein R 5 is selected from methyl, ethyl Radical, propyl, cyclopropyl,
- the compound of general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystalline or prodrug according to the invention wherein:
- Q 1 is a 6-18 membered aryl group, which is optionally substituted with one or more R 1 ;
- Q 2 is a 5 membered heteroaryl group, which is optionally substituted with one or more R 2 ;
- L is absent, m is 2, 3 or 4;
- Q 1 is a 6-12 membered aryl group, which is optionally substituted with one or more R 1 ;
- Q 2 is a 5 membered heteroaryl group, which is optionally substituted with one or more R 2 ;
- L is not Exists, m is 2, 3 or 4;
- Q 1 is phenyl, which is optionally substituted with one or more R 1 ;
- Q 2 is selected from imidazolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, Isoxazolyl, isothiazolyl, oxadiazolyl and triazolyl, which are optionally substituted with one or more R 2 ;
- L is absent and m is 2, 3 or 4.
- the compound of general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug according to the present invention wherein:
- Q 1 is a 9-20 membered arylheterocyclic group, 9-20 membered heteroarylheterocyclic group, which is optionally substituted with one or more R 1 ;
- Q 2 is a 5 membered heteroaryl group, which is optionally Replaced by one or more R 2 ;
- L is absent;
- Q 1 is selected from 9-12 membered arylheterocyclic groups and 9-12 membered heteroarylheterocyclic groups, which are optionally substituted with one or more R 1 ;
- Q 2 is a 5 membered heteroaryl Group, which is optionally substituted with one or more R 2 ;
- L is absent;
- Q 1 is selected from indolinyl, isoindolinyl, benzodihydrofuranyl, chroman, benzodihydrothienyl, benzoxazolinone, Benzodihydropyrazolyl, benzodihydroimidazolyl, benzodihydropyrazolyl, benzodihydrooxazolyl, benzodihydrothiazolyl, benzodihydroisoxazolyl, benzodi Hydroisothiazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinazolinyl, dihydroquinazolinyl, dihydrocinnolinyl , Tetrahydrocinnoline, dihydroquinoxalinyl, tetrahydroquinoxalinyl,
- the compound of general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystalline or prodrug according to the invention wherein:
- Q 1 is It is optionally substituted with one or more R 1 ; L is absent, Q 2 is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl and piperazinyl, wherein the group is substituted by one or more R 2 is substituted; L is absent.
- the compound of general formula (I) or its isomer, pharmaceutically acceptable salt, solvate, crystalline or prodrug according to the invention wherein:
- Q 1 is selected from imidazolyl, pyrrolyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and triazolyl, which is optionally Or multiple R 1 substitutions;
- the present invention provides compounds of general formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs of the present invention are inorganic salts of compounds of general formula (I) or Organic salts, preferably, the pharmaceutically acceptable salts are hydrochloride, hydrobromide, phosphate, sulfamate, nitrate, p-toluenesulfonate, benzenesulfonate, p-aminobenzene Sulfonate, methanesulfonate, sulfate, acetate, oxalate, phenylacetate, propionate, malonate, trifluoroacetate, succinate, glycolate, hard Fatty acid salt, ascorbate, pamoate, hydroxymaleate, glutamate, benzoate, salicylate, 2-acetoxybenzoate, fumarate , Ethane disulfonate, oxalate, isethionate, cit
- the present invention provides the following specific compounds or their isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs:
- the present invention provides a method for preparing a compound of the present invention, for example, a method for preparing a compound of formula (I) of the present invention includes but is not limited to the following steps:
- Q 1 , Q 3 , L, and m have the definitions described in the general formula (I), and the compounds of Formula 1, Formula 2, Formula 5, and Formula 7 are commercially available compounds or other techniques commonly used by those skilled in the art can be used Means to synthesize.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug, and also including but not limited to monocyclic lactam Antibiotics, such as monocyclic lactam antibiotics, are selected from the group consisting of ⁇ -lactam antibiotics and additional antibiotics and / or additional ⁇ -lactamase inhibitors, and any other compounds sensitive to serine ⁇ -lactamase.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal, or prodrug, in combination with one or more of the following : Penicillin, methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, temoxicillin, amoxicillin, ampicillin, amokra, azlocillin, carbenicillin, Ticarcillin, mezlocillin, piperacillin, cefalexin, ceftiophene, CXA-101, cefazolin, cefaclor, cefuroxime, cefantome, cefotetan, cefoxitin, ceftriaxone, Cefotaxime, cefpodoxime, cefixime, ceftazidime, cefpirome, cefepime, cefpirome, ceftaroline, imi
- the present invention provides a pharmaceutical composition comprising a compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug in combination with meropenem, aztreonam or ceftazidime .
- the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug and abamectan, tazobactam , Sulbactam and clavulanic acid combined.
- the present invention provides compounds of the present invention or isomers thereof, pharmaceutically acceptable salts, solvates, crystals or prodrugs and compounds containing the present invention or isomers thereof, pharmaceutically acceptable Pharmaceutical compositions of salts, solvates, crystals or prodrugs, which are used to treat bacterial infections.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the present invention or its isomer, a pharmaceutically acceptable salt, a solvate, a crystalline or prodrug, and a pharmaceutically acceptable carrier.
- the compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation, suitable for oral or Parenteral administration.
- Administration methods include, but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
- the formulation may be administered by any route, for example, by infusion or bolus injection, by the route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or local.
- preparations for oral administration include solid or liquid dosage forms, and specifically include tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, and the like.
- the formulations can be prepared by methods known in the art, and include carriers, diluents or excipients conventionally used in the field of pharmaceutical formulations.
- the present invention provides a compound represented by the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition containing the same for the treatment of bacteria Infection method and use in preparing medicine for treating bacterial infection.
- the bacterial infection of the present invention is an infection caused by Gram-negative bacteria, also known as "Gram-negative infection", wherein the Gram-negative bacteria may be selected from Genus: Citrobacter genus, Enterobacter genus, Escherichia genus, Klebsiella genus, Morganella genus, Morganella genus, Proteus genus, Salmonella genus ( Salmonella), Serratia, Pseudomonas, Acinetobacter, Bacteroides, Burkholderia, Campylobacter, Neisseria (Neisseria) and Oligomonas.
- Gram-negative bacteria also known as "Gram-negative infection”
- the Gram-negative bacteria may be selected from Genus: Citrobacter genus, Enterobacter genus, Escherichia genus, Klebsiella genus, Morganella genus, Morganella genus, Proteus genus, Salmonella genus ( Salmonella), Serratia, P
- specific bacterial species include Freund's Citrobacter, Citrobacter koseri, Enterobacter cloacae, Enterobacter faecalis, feces Enterobacter (faecium), Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Morganella morganii, Proteusmirabilis, Salmonella Genus species, Serratiamarcescens, Pseudomonas aeruginosa and Acinetobacter baumanii, as well as Bacteroides bivius, Bacteroides fragilis, Burke onion Burkholderia (cepacia), Campylobacter jejuni (Campylobacter jejuni), Neisseria gonorrhoeae (Neisseria gonorrhoeae) and Stenotrophomonas maltophilia (Stenotrophomonas maltophilia).
- the bacterial infection of the present invention is an infection caused by drug-resistant microorganisms (including multiple drug-resistant microorganisms). In other preferred embodiments, the bacterial infection of the present invention is an infection caused by multi-drug resistant microorganisms. In other preferred embodiments, the Gram-negative infections of the present invention are infections that are resistant to one or more antibiotics. In other preferred embodiments, the Gram-negative infections of the present invention are infections that are resistant to multiple drugs.
- the compounds of the present invention can be used to treat infections caused by the following bacteria: Enterobacteriaceae, including Salmonella, Escherichia coli, Klebsiella pneumoniae, Metamorphosis Proteus, Enterobacter, Serratia, Citrobacter, including pathogens, such as previous monocyclic lactam antibiotics such as aztreonam Sensitive KPC-producing Klebsiella pneumoniae and non-fermentative bacteria, including Pseudomonas aeruginosa, Acinetobacter, Burkholderia, Moraxella The genus Moraxella and the genus Oligomonas.
- Enterobacteriaceae including Salmonella, Escherichia coli, Klebsiella pneumoniae, Metamorphosis Proteus, Enterobacter, Serratia, Citrobacter, including pathogens, such as previous monocyclic lactam antibiotics such as aztreonam Sensitive KPC-producing Klebsiella pneumonia
- the present invention provides a compound represented by the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition containing the same Method for treating bacterial infection and use in preparing medicine for treating bacterial infection, wherein the bacterial infection includes but not limited to: gynecological infection, respiratory tract infection (RTI), urinary tract infection (UTI), complicated urinary tract Infections (including pyelonephritis), sexually transmitted diseases, acute attacks of chronic bronchitis (ACEB), acute otitis media, acute sinusitis, infections caused by drug-resistant bacteria, catheter-related septicemia, chancre, chlamydia, pneumonia , Prostatitis, community-acquired pneumonia (CAP), complicated skin and skin structure infections, uncomplicated skin and skin structure infections, skin and soft tissue infections, endocarditis, febrile neutropenia, gonococcus Meningitis, gonococcal
- the present invention provides a compound represented by the general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug, or a pharmaceutical composition containing the same Method for treating bacterial infection and use in preparing medicine for treating bacterial infection, wherein the bacterial infection includes but is not limited to: community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator-related Pneumonia (VAP), primary or secondary blood infection (septicemia), complicated urinary tract infection (including pyelonephritis), complicated intra-abdominal infection, postoperative related infections, etc.
- CAP community-acquired pneumonia
- HAP hospital-acquired pneumonia
- VAP ventilator-related Pneumonia
- septicemia primary or secondary blood infection
- complicated urinary tract infection including pyelonephritis
- complicated intra-abdominal infection postoperative related infections, etc.
- the present invention provides a method for treating one or more of the infections listed above, comprising administering to a subject suffering from a bacterial infection an effective amount of a compound of formula (I) or its combination with additional antibiotics or Pharmaceutically acceptable salts.
- the additional antibiotic is a ⁇ -lactam antibiotic.
- the additional antibiotic is a penicillin binding protein inhibitor.
- the "hydrogen”, "carbon” and “oxygen” in the compounds of the present invention include all isotopes thereof.
- Isotopes are understood to include those atoms having the same atomic number but different mass numbers.
- hydrogen isotopes include protium, tritium and deuterium
- carbon isotopes include 12 C, 13 C and 14 C
- oxygen isotopes include 16 O and 18 O.
- halogen in the present invention refers to fluorine, chlorine, bromine, and iodine.
- halogenated in the present invention means substituted with fluorine, chlorine, bromine or iodine.
- alkyl in the present invention refers to a linear or branched saturated aliphatic hydrocarbon group, preferably a linear or branched group containing 1 to 6 carbon atoms, and further preferably a linear or branched group containing 1 to 3 carbon atoms
- Chain groups non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc.
- the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
- carbonyl and “acyl” refer to -C (O)-.
- haloalkyl group refers to an alkyl group substituted with at least one halogen.
- hydroxyalkyl group refers to an alkyl group substituted with at least one hydroxy group.
- alkoxy in the present invention refers to -O-alkyl.
- alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, and the like.
- the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
- cycloalkyl in the present invention refers to a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
- heterocyclic group refers to a 3- to 20-membered non-aromatic group having 1 to 4 ring heteroatoms (where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon)
- the group of the ring system (“3-20 membered heterocyclic group”).
- the point of attachment can be a carbon or nitrogen atom, as long as valency permits.
- the heterocyclyl group may be saturated or may be partially unsaturated.
- Each example of a heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
- aryl group refers to an aromatic system which may contain a single ring or a fused polycyclic ring, preferably a single ring or a fused bicyclic aromatic system, which contains 6 to 18 carbon atoms, and preferably contains about 6 to about 12 carbon atoms.
- Suitable aryl groups include but are not limited to phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, fluorenyl, indanyl.
- the aryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.
- heteroaryl group refers to an aryl group having at least one carbon atom replaced by a heteroatom, consisting of 5-20 atoms (5-20 membered heteroaryl), and more preferably 5-12 atoms ( 5-12 membered heteroaryl), the heteroatoms are O, S, N.
- the "5-membered heteroaryl group” of the present invention refers to a monocyclic aromatic system composed of 5 atoms, including but not limited to imidazolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl , Isoxazolyl, isothiazolyl, oxadiazolyl and triazolyl.
- arylheteroaryl and “heteroarylheteroaryl” of the present invention include but are not limited to indolyl, isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, Benzopyranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, di Hydroquinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazolyl, pyrimidimidazolyl and the like.
- the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
- the "isomers" of the present invention are compounds that have the same molecular formula but differ in nature or in the bond sequence of their atoms or in the spatial arrangement of their atoms.
- Stereoisomers are isomers whose atoms are arranged differently in space.
- Stereoisomers that are not mirror images of each other are diastereomers and stereoisomers that are non-overlapping mirror images of each other are enantiomers.
- a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
- the enantiomer is characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the method of rotating the plane of polarized light by the molecule and designated as right-handed or left-handed ( That is, as (+) or (-)-isomers, respectively).
- Chiral compounds can exist as a single enantiomer or a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".
- the “pharmaceutically acceptable salts” of the present invention refer to salts of the compounds of the present invention. Such salts are safe and effective when used in mammals, and have proper biological activity.
- the "solvate” of the present invention refers to a complex formed by a combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water) in a conventional sense.
- a solute such as an active compound, a salt of an active compound
- a solvent such as water
- the solvent refers to a solvent known or easily determined by those skilled in the art. If it is water, the solvate is usually referred to as a hydrate, for example, hemihydrate, monohydrate, dihydrate, trihydrate, or their substitution amounts.
- the in vivo effects of the compound of formula (I) may be partially exerted by one or more metabolites formed in the human or animal body after administration of the compound of formula (I).
- the in vivo action of the compound of formula (I) can also be exerted via metabolism of the precursor compound ("prodrug").
- the "prodrug” of the present invention refers to a compound that is converted into a compound of formula (I) due to a reaction with an enzyme, stomach acid, etc. under physiological conditions in an organism, that is, into a formula by oxidation, reduction, hydrolysis, etc. of the enzyme
- Crystal in the present invention refers to a solid whose internal structure is formed by repeatedly repeating atoms (or groups thereof) in three dimensions, and is different from an amorphous solid that does not have such a regular internal structure.
- the "pharmaceutical composition” of the present invention refers to containing any one of the compounds of the present invention, including the corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and a Or a mixture of multiple pharmaceutically acceptable carriers and / or another or multiple drugs.
- the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
- the composition is generally used to prepare a medicament for treating and / or preventing a disease mediated by one or more kinases.
- the "pharmaceutically acceptable carrier” of the present invention refers to a carrier that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersants, surface active Agent isotonicity agent, thickener or emulsifier, preservative, solid binder, lubricant, etc. Unless any conventional carrier medium is incompatible with the compounds of the present invention.
- Some examples of pharmaceutically acceptable carriers include, but are not limited to sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, And cellulose and cellulose acetate; malt, gelatin, etc.
- excipient refers to an inert substance added to the pharmaceutical composition to further facilitate administration of the compound.
- Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oil, polyethylene glycol.
- the "infection" of the present invention can be caused by a variety of bacteria that may be treated with the claimed drugs in combination with penicillin binding protein inhibitors or by themselves.
- subject trapped in bacterial infection refers to an animal.
- the animal is a mammal.
- Individuals also refer to, for example, primates (eg humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
- the individual is a human.
- treatment refers to ameliorating the disease or disorder (ie, slowing or preventing or reducing the development of the disease or at least one of its clinical symptoms); in another embodiment , “Treatment” refers to reducing or improving at least one body parameter, including those body parameters that may not be discernable by the patient; in yet another embodiment, “treatment” refers to the body (eg, stabilizing discernable symptoms) , Physiologically (eg, stabilizing physical parameters), or both, regulate the disease or disorder. In yet another embodiment, “treatment” refers to preventing or delaying the onset or occurrence or progression of the disease or disorder.
- Example 1 (S) -3-((Z) -2-(((S) -2- (4-((1- (3-aminopropyl) -2- (azetidine-3 -Ylmethyl) -1H-pyrazol-2-ium-4-yl) carbamoyl) phenoxy) -1-carboxyethoxy) imino) -2- (2-aminothiazol-4-yl ) Acetamido) -2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- Step 1 Preparation of (R)-(1,3-dihydroxy-3-methylbutan-2-yl) carbamic acid tert-butyl ester
- Step 2 Preparation of (S) -2-((tert-butoxycarbonyl) amino) -3-hydroxy-3-methylbutyric acid
- Step 3 Preparation of (S)-(1-((benzyloxy) amino) -3-hydroxy-3-methyl-1-oxobutan-2-yl) carbamic acid tert-butyl ester
- Step 4 Preparation of (S)-(N-benzyloxy-4,4-dimethylazetidine-2-one-3-yl) carbamic acid tert-butyl ester
- Step 5 Preparation of (S)-(1-hydroxy-2,2-dimethyl-4-oxoazetidin-3-yl) carbamic acid tert-butyl ester
- Step 6 Preparation of (S) -3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate
- Step 7 Preparation of ethyl 2- (2-((tert-butoxycarbonyl) amino) thiazol-4-yl) -2-oxoacetate
- Step 8 Preparation of 2- (2-((tert-butoxycarbonyl) amino) thiazol-4-yl) -2-oxoacetic acid
- Step 9 Preparation of tert-butoxycarbonyl-3- (4-nitro-1H-pyrazol-1-yl) -1-propanamine
- Step 10 Preparation of tert-butoxycarbonyl-3- (4-amino-1H-pyrazol-1-yl) -1-propanamine
- Step 11 Preparation of tert-butoxycarbonyl-3-trifluoromethanesulfonyloxymethylazetidine
- Step 14 Preparation of (R) -3- (4-bromophenoxy) -2-hydroxypropionic acid tert-butyl ester
- Step 15 Preparation of (S) -3- (4-bromophenoxy) -2-((1,3-dioxoisoindolin-2-yl) oxy) propionic acid tert-butyl ester
- Step 16 (S) -4- (3- (tert-butoxy) -2-((1,3-dioxoisoindolin-2-yl) oxy) -3-oxopropoxy ) Preparation of Benzoic Acid
- place (S) -3- (4-bromophenoxy) -2-((1,3-dioxoisoindolin-2-yl) oxy) propionic acid tert-butyl ester (2.2g, 4.76mmol), palladium acetate (50mg, 0.22mmol), 4,5-bisdiphenylphosphine-9,9-dimethyl xanthene (0.27g, 0.47mmol), formic acid (0.36mL, 9.5mmol), triethylamine (1.3mL, 9.5mmol), acetic anhydride (0.88mL, 9.5mmol) and tert-butanol (0.88mL, 9.5mmol) were dissolved in toluene (30mL), argon replacement 3 times, heating The reaction was stirred overnight at 90 ° C.
- Step 17 (S) -3- (4-((1- (3-((tert-butoxycarbonyl) amino) propyl) -1H-pyrazol-4-yl) carbamoyl) phenoxy)- Preparation of 2-((1,3-dioxoisoindolin-2-yl) oxy) propionic acid tert-butyl ester
- Step 18 (S) -4- (4- (3- (tert-butoxy) -2-((1,3-dioxoisoindolin-2-yl) oxy) -3-oxo Propoxy) benzamide) -1- (3-((tert-butoxycarbonyl) amino) propyl) -2-((1- (tert-butoxycarbonyl) azetidin-3-yl) Preparation of methyl) -1H-pyrazol-2-ium trifluoromethanesulfonate
- Step 19 (S) -4- (4- (2- (Aminooxy) -3- (tert-butoxy) -3-oxopropoxy) benzamide) -1- (3- ( (Tert-butoxycarbonyl) amino) propyl) -2-((1- (tert-butoxycarbonyl) azetidin-3-yl) methyl) -1H-pyrazol-2-ium trifluoromethanesulfonate Preparation of acid salt
- Step 20 (S, Z) -4- (4- (3- (tert-butoxy) -2-((((2-((tert-butoxycarbonyl) amino) thiazol-4-yl) (carboxyl) Methylene) amino) oxy) -3-oxopropoxy) benzamide) -1- (3-((tert-butoxycarbonyl) amino) propyl) -2-((1- (tert Preparation of butoxycarbonyl) azetidin-3-yl) methyl) -1H-pyrazol-2-ium trifluoromethanesulfonate
- Step 21 (S) -3-((Z) -2-((((S) -1- (tert-butoxy) -3- (4-((1- (3-((tert-butoxycarbonyl ) Amino) propyl) -2-((1- (tert-butoxycarbonyl) azetidin-3-yl) methyl) -1H-pyrazol-2-ium-4-yl) carbamoyl) Phenoxy) -1-oxopropane-2-yl) oxy) imino) -2- (2-((tert-butoxycarbonyl) amino) thiazol-4-yl) acetamido) -2,2 Of dimethyl-4-oxoazetidin-1-yl sulfate
- Step 22 (S) -3-((Z) -2-(((S) -2- (4-((1- (3-Aminopropyl) -2- (azetidine-3- Methyl) -1H-pyrazol-2-ium-4-yl) carbamoyl) phenoxy) -1-carboxyethoxy) imino) -2- (2-aminothiazol-4-yl)
- Step 1 Preparation of (R) -3- (4-nitrophenoxy) -2-hydroxypropionic acid tert-butyl ester
- the preparation method is the same as the preparation method in steps 12-14 of Example 1, except that p-bromophenol is replaced with p-nitrophenol to prepare the title compound.
- Step 2 Preparation of (R) -3- (4-aminophenoxy) -2-hydroxypropionic acid tert-butyl ester
- Step 4 (S) -3- (4- (1- (3-((tert-butoxycarbonyl) amino) propyl) -1H-pyrazole-4-carboxamido) phenoxy) -2- ( Preparation of (1,3-dioxoisoindolin-2-yl) oxy) propionic acid tert-butyl ester
- Step 5 (S) -3-((Z) -2-(((S) -2- (4- (1- (3-Aminopropyl) -2- (azetidin-3-yl Methyl) -1H-pyrazol-2-ium-4-carboxamido) phenoxy) -1-carboxyethoxy) imino) -2- (2-aminothiazol-4-yl) acetamido ) -2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- the preparation method is the same as steps 18-22 in Example 1, except that the starting material (S) -3- (4-((1- (3-((tert-butoxycarbonyl) amino) propyl) -1H-pyrazole- 4-yl) carbamoyl) phenoxy) -2-((1,3-dioxoisoindolin-2-yl) oxy) propionic acid tert-butyl ester is replaced by (S) -3- ( 4- (1- (3-((tert-butoxycarbonyl) amino) propyl) -1H-pyrazole-4-carboxamido) phenoxy) -2-((1,3-dioxoisoind Indolin-2-yl) oxy) propionic acid tert-butyl ester to prepare the title compound.
- Step 1 Preparation of 6-bromo-2-hydroxy-2,3-dihydro-1H-pyrazolo [1,2-a] pyrazol-4-bromonium
- Step 3 6- (4-((R) -3- (tert-butoxy) -2-hydroxy-3-oxopropoxy) phenyl) -2- (3-((tert-butoxycarbonyl) Preparation of amino) propoxy) -2,3-dihydro-1H-pyrazolo [1,2-a] pyrazol-4-ium
- Step 4 6- (4-((S) -3- (tert-butoxy) -2-((1,3-dioxoisoindolin-2-yl) oxy) -3-oxo Propoxy) phenyl) -2- (3-((tert-butoxycarbonyl) amino) propoxy) -2,3-dihydro-1H-pyrazolo [1,2-a] pyrazole-4 -Preparation of onium
- the preparation method is the same as the preparation method of steps 19-22 in Example 1, except that the raw material (S) -4- (4- (3-tert-butoxy-2-((1,3-dioxoisoindole Olin-2-yl) oxy) -3-oxopropoxy) benzamide) -1- (3-((tert-butoxycarbonyl) amino) propyl) -2-((1- (tert Butoxycarbonyl) azetidin-3-yl) methyl) -1H-pyrazol-2-ium trifluoromethanesulfonate replaced by 6- (4-((S) -3- (tert-butoxy Yl) -2-((1,3-dioxoisoindolin-2-yl) oxy) -3-oxopropoxy) phenyl) -2- (3-((tert-butoxycarbonyl ) Amino) propoxy) -2,3-dihydro-1H-pyrazolo [
- Step 4 (S) -3- (4- (6-((S) -2,6-bis ((tert-butoxycarbonyl) amino) hexanamido) pyridin-3-yl) phenoxy) -2 -((1,3-Dioxyisoindolin-2-yl) oxy) propionic acid tert-butyl ester
- Step 5 2-((S) -2,6-bis ((tert-butoxycarbonyl) amino) hexanamido) -5- (4-((S) -3- (tert-butoxy) -2- Preparation of ((1,3-dioxoisoindolin-2-yl) oxy) -3-oxopropoxy) phenyl) -1-methylpyridine-1-iodo salt
- Step 6 5- (4-((S) -2- (aminooxy) -3- (tert-butoxy) -3-oxopropoxy) phenyl) -2-((S) -2, Preparation of 6-bis ((tert-butoxycarbonyl) amino) hexanamido) -1-methylpyridine-1-iodo salt
- Step 7 2-((S) -2,6-bis ((tert-butoxycarbonyl) amino) hexanamido) -5- (4-((S) -3- (tert-butoxy) -2- ((((Z)-(2-((tert-butoxycarbonyl) amino) thiazol-4-yl) (carboxy) methylene) amino) oxy) -3-oxopropoxy) phenyl) Preparation of -1-methylpyridine-1-iodo salt
- Step 8 2-((S) -2,6-bis ((tert-butoxycarbonyl) amino) hexanamido) -5- (4-((S) -3- (tert-butoxy) -2- ((((Z) -1- (2-((tert-butoxycarbonyl) amino) thiazol-4-yl) -2-(((S) -2,2-dimethyl-4-oxo- 1- (sulfonyloxy) azetidin-3-yl) amino) -2-oxoethylene) amino) oxy) -3-oxopropoxy) phenyl) -1-methyl
- pyridin-1-iodo salt 2-((S) -2,6-bis ((tert-butoxycarbonyl) amino) hexanamido) -5- (4-((S) -3- (tert-butoxy) -2- (((Z) -1- (2-((tert-butoxycarbonyl) amino)
- Step 9 (S) -3-((Z) -2- (2-aminothiazol-4-yl) -2-(((S) -1-carboxy-2- (4- (6-((S) -2,6-diaminohexanamido) -1-methylpyridin-1-ium-3-yl) phenoxy) ethoxy) imino) acetamido) -2,2-dimethyl-
- Example 5 The synthesis of Example 5 is similar to Example 4, except that step 5 is omitted, and the title compound is prepared.
- 1 H NMR 400MHz, DMSO-d 6 + D 2 O) ⁇ 8.59–8.50 (m, 1H), 8.18–8.01 (m, 2H), 7.64–7.53 (m, 2H), 7.06–6.91 (m, 2H), 6.87 (s, 1H), 4.89–4.79 (m, 1H), 4.73 (s, 1H), 4.47–4.34 (m, 1H), 4.32–4.23 (m, 1H), 4.11–4.03 (m, 1H), 2.91–2.72 (m, 2H), 1.92–1.74 (m, 2H), 1.69–1.53 (m, 2H), 1.46 (s, 3H ), 1.44–1.38 (m, 2H), 1.29–1.25 (m, 3H).
- the preparation method is similar to the preparation method of steps 13 and 14 of Example 1, except that the raw material (S) -3- (4-bromophenoxy) -1,2-propanediol is replaced with (R) -5- (4 -Bromophenoxy) pentane-1,2-diol to prepare the title compound.
- Step 9 (3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) Preparation of tert-butyl propyl) carbamate
- Step 10 (S) -3-((Z) -2-(((S) -4- (4- (1- (3-Aminopropyl) -2- (azetidine-3-ylmethyl Yl) -1H-pyrazol-2-ium-4-yl) phenoxy) -1-carboxybutoxy) imino) -2- (2-aminothiazol-4-yl) acetamido) -2 Of 2,2-dimethyl-4-oxoazetidin-1-yl sulfate
- the preparation method is similar to the preparation method of steps 3-9 of Example 4, except that (R) -3- (4-bromophenoxy) -2-hydroxypropionic acid tert-butyl ester is replaced with (R) -5- (4-Bromophenoxy) -2-hydroxyvaleric acid tert-butyl ester, di-tert-butyl (6-oxo-6-((5- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) pyridin-2-yl) amino) hexane-1,5-diyl) (S) -dicarbamate is replaced by (3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propyl) carbamic acid Tert-butyl ester, and replacing methyl iodide with 3-(((trifluoromethyl) sulfonyl)
- the preparation method is similar to Step 2 of Example 4, except that di (tert-butyl) (6-((5-bromopyridin-2-yl) amino) -6-oxohexane-1,5- Diyl) (S) -dicarbamate was replaced with (R) -3- (4-bromophenoxy) -2-hydroxypropionic acid tert-butyl ester to prepare the title compound.
- Step 5 (S) -3- (4- (2- (Aminomethyl) -1H-benzo [d] imidazol-5-yl) phenoxy) -2-((((Z) -1- ( 2-aminothiazol-4-yl) -2-(((S) -2,2-dimethyl-4-oxo-1- (sulfonyloxy) azetidin-3-yl) amino ) -2-oxoethylene) amino) oxy) propionic acid
- the preparation method is similar to the preparation method of steps 4 and 6-9 in Example 4, except that the raw material (R) -3- (4- (6-((S) -2,6-bis ((tert-butoxy Carbonyl) amino) hexanamido) pyridin-3-yl) phenoxy) -2-hydroxypropionic acid tert-butyl ester is replaced by (R) -3- (4- (2-(((tert-butoxycarbonyl) Amino) methyl) -1H-benzo [d] imidazol-5-yl) phenoxy) -2-hydroxypropionic acid tert-butyl ester to prepare the title compound.
- Example 12 3- (2-(((S) -2-((1- (3-aminopropyl) -2-methyl-1H-pyrazol-2-ium-4-yl) oxy)- 1-carboxyethoxy) imino) -2- (2-aminothiazol-4-yl) acetamido) -2,2-dimethyl-4-oxoazetidin-1-ylsulfuric acid salt
- Step 1 (3- (4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propane Preparation of tert-butyl carbamate
- Step 3 (2-(((S) -2-((1- (3-Aminopropyl) -2-methyl-1H-pyrazol-2-ium-4-yl) oxy) -1 -Carboxyethoxy) imino) -2- (2-aminothiazol-4-yl) acetamido) -2,2-dimethyl-4-oxoazetidin-1-yl sulfate Preparation
- the preparation method is similar to the preparation method of steps 4 and 6-9 in Example 4, except that the raw material (R) -3- (4- (6-((S) -2,6-bis ((tert-butoxy Carbonyl) amino) hexanamido) pyridin-3-yl) phenoxy) -2-hydroxypropionic acid tert-butyl ester is replaced by (3- (4-hydroxy-1H-pyrazol-1-yl) propyl) amino Tert-Butyl formate to prepare the title compound.
- ESI-MS m / z 605.3 [M + H] + .
- Example 1 of the present invention the compounds of Examples 13-20 were synthesized using different commercially available raw materials.
- the characterization parameters of these compounds are shown in Table 1:
- Compound A The compound represented by the following formula (Compound A) was prepared according to the method disclosed in Example 76 in WO2017 / 106064 (PCT / US2016 / 066064), and identified by hydrogen spectroscopy and mass spectrometry,
- Compound B The compound represented by the following formula (Compound B) was prepared according to the method disclosed in Example 22 in WO2015 / 148379 (PCT / US2015 / 022011), and identified by hydrogen spectroscopy and mass spectrometry,
- Compound C The compound represented by the following formula (Compound C) was prepared according to the method disclosed in Example 97 in WO2017 / 106064 (PCT / US2016 / 066064), and identified by hydrogen spectroscopy and mass spectrometry,
- Bacterial strains 6 strains of Acinetobacter baumannii (codenamed HDBAB-YK4, HDBAB-YK7, HDBAB-YK12, HDBAB-YK16, HDBAB_OXA_7, ATCC) 19606), 2 strains of Pseudomonas aeruginosa (codenamed HDBPA-YK9, HDBPA -YK15), one strain of E. coli (codenamed CLB30048) was provided by Huiyuan Biotechnology (Shanghai) Co., Ltd.
- Culture medium Trypticase soy agar (TSA) (BD BBL 211043), ion-corrected Mu-Hin Er broth (Cation-adjusted Mueller Hinton broth, CAMHB) (BD BBL212322)
- Bacteria used for the minimum inhibitory concentration (MIC) test are stored frozen at minus 80 ° C and need to be recovered 2 days in advance. Scrape a small amount of frozen bacteria with a sterile inoculation loop to inoculate on a TSA solid medium plate and place in a common incubator at 35 ⁇ 2 °C for 20-24 hours. Pick up 5-10 colonies with similar morphology from the above-mentioned petri dish with sterile inoculation loop, and inoculate it on the TSA solid medium plate again. Then put it into a common incubator and culture at 35 ⁇ 2 °C for 20-24 hours.
- MIC minimum inhibitory concentration
- the number of inoculated bacteria can be obtained by plate count (see section 2.4).
- One compound is arranged for each row of the 96-well test plate: the highest test concentration of each compound is 64 ⁇ g / mL, and a 2-fold dilution is performed.
- GC Growth control
- DMSO dimethyl sulfoxide
- Sterile control (Sterile control, SC): Contains 1.02X CAMHB and DMSO, no compound.
- test compounds were dissolved and diluted with DMSO. Transfer 50 ⁇ L of 3.2 mg / mL of each test compound to the initial well (A1-H1) of the dilution plate, and then transfer 25 ⁇ L of DMSO to other wells. Dilute the test compound twice in order from column 1 to column 11 (that is, draw 25 ⁇ L of test compound from column 1 to column 2 and mix well, then draw 25 ⁇ L of test compound from column 2 to column 3 and mix Mix well, then pipette 25 ⁇ L of test compound from column 3 to column 4 and mix, and then dilute to column 11).
- test plate After the system is added, the test plate is covered with a sterile cover, placed in a centrifuge at 800 rpm and centrifuged for 30 seconds, then shaken at 400 rpm on a shaker for 1 minute and mixed, then placed in an incubator and incubated at 35 ⁇ 2 ° C for 20 hours.
- the inoculated bacteria were diluted 10 times with liquid medium, from 10 -1 to 10 -3 . 100 ⁇ L of the above bacterial dilution was evenly spread in TSA dishes, with 2 replicates for each dilution. After the medium was absorbed by TSA for 10 minutes, the dish was inverted and cultured in an incubator at 35 ⁇ 2 ° C for 24 hours.
- test plate Place the test plate on the plate reading device, adjust the mirror to observe and record the growth of bacteria in each well. At the same time, each test board was photographed with the QCount system.
- MIC minimum inhibitory concentration
- the minimum inhibitory concentration (MIC) of some compounds of the present invention against Acinetobacter baumannii, Pseudomonas aeruginosa, and E. coli can be as low as 2 ⁇ g / mL or less, for example, Example 1, The compounds of Example 2, Example 3 and Example 9 showed excellent antibacterial activity.
- mice Male BALB / c mice, SPF grade, purchased from Changzhou Cavens Experimental Animal Co., Ltd .; 16-24g, license number: SCXK (Su) 2016-0010; an adaptation period of 2 to 3 days before the experiment.
- test compound Weigh 2 mg of the test compound, add it to physiological saline, vortex for 2 min, and ultrasound for 3 min to prepare a test solution with a concentration of 0.2 mg / mL for intravenous administration.
- the compound of Example 1 of the present invention has a blood concentration of 11.548 ⁇ g / mL (C0) at an intravenous dose of 2 mg / kg, which is much higher than the MIC of the compound, indicating that A dose of 2 mg / kg is sufficient to achieve excellent bacteriostatic effects.
- Bacterial strains clinically isolated Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and E. coli are all provided by Huiyuan Biotechnology (Shanghai) Co., Ltd.
- Culture medium Trypticase soy agar (TSA) (BDBBL 211043), ion-corrected Mu-Shin's broth (Cation-adjusted Mueller Hinton broth, CAMHB) (BD BBL212322).
- the experimental method is the same as the above Experimental Example 1.
- the experimental results are shown in Table 4.
- the compound of Example 1 exhibited excellent antibacterial activity against clinically isolated Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and E. coli, and in many strains The above effect is significantly better than compound C.
- the MIC value of the compound of Example 1 for A0244122, A0255830, A0273826, A0285299, A0285909, and Kp309 is only 1/4 of that of compound C.
- the compound of Example 1 had an MIC ⁇ 0.063 ⁇ g / mL for 11 strains (the lowest detection concentration), while compound C had a MIC ⁇ 0.063 ⁇ g / mL only for 2 strains, which was significantly better than compound C.
- the MIC 90 of the compound of Example 1 of the present invention to clinically isolated Acinetobacter baumannii was 4 ⁇ g / mL, and the MIC 90 of compound C to the clinically isolated Acinetobacter baumannii was 16 ⁇ g / mL.
- the MIC 90 of the compound of Example 1 is only a quarter of that of compound C, which is significantly better than compound C.
- the inventors of the present invention also tested the inhibitory activity of the compound of Example 1 and Compound C in combination with Relebactam on drug-resistant Acinetobacter baumannii (the experimental method is the same as Experimental Example 1).
- the experimental results show that for drug-resistant Acinetobacter baumannii HDBAB-YK12, HDBAB-YK16, HDBAB_OXA_7, combined with 4 ⁇ g / mL Relebactam, the MIC values of the compound of Example 1 were 2 ⁇ g / mL, 4 ⁇ g / mL, 2 ⁇ g / mL
- the MIC values of Compound C were 8 ⁇ g / mL, 16 ⁇ g / mL, and 16 ⁇ g / mL, respectively. It can be seen that the antibacterial activity of the compound of Example 1 is significantly better than that of Compound C.
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Abstract
Description
Claims (10)
- 一种通式(I)所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,其中,Q 2为不存在或选自4-6元杂环基、芳基并杂环基、杂芳基并环烷基、芳基并杂芳基、杂芳基并杂环基、5元杂芳基和 其任选被一个或多个R 2取代,R 3不存在或为R 2,R 4选自氨基烷基酰基氨基和羟基氨基烷基酰基氨基;R 1选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、环烷基、杂环基、芳基、杂芳基和氧代基团;R 2选自卤素、羟基、烷基、卤代烷基、羟基烷基、氨基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、氨基烷基酰基氨基、羟基氨基烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、环烷基、杂环基、杂环基烷基、氨基杂环基、氨基烷基杂环基、羟基烷基杂环基、芳基、杂芳基和氧代基团,其任选被氨基、氨基烷基、烷基氨基、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基烷氧基、硝基、羧基、氰基取代;L为不存在或选自-C(O)NH-、-NHC(O)-、-SO 2NH-、-NHSO 2、-(CH 2) n-和-C(O)-;m为1、2、3或4;n为1、2、3或4;且当Q 1为芳基时,则Q 2选自芳基并杂环基、杂芳基并环烷基、芳基并杂芳基和杂芳基并杂环基;或者当Q 1为芳基时,则Q 2为5元杂芳基,且L选自-C(O)NH-、-NHC(O)-、-SO 2NH-、-NHSO 2-、-(CH 2) n-和-C(O)-;或者当Q 1为芳基时,则Q 2为5元杂芳基,L为不存在,且m为2、3或4;或者当Q 1选自芳基并杂环基和杂芳基并杂环基时,则Q 2为5元杂芳基,且L为不存在;或者当Q 1为5元杂芳基时,则Q 2为不存在,且L为不存在。
- 根据权利要求1所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,其中Q 1选自6-18元芳基、9-20元芳基并杂环基、9-20元杂芳基并杂环基、 和5元杂芳基,其任选被一个或多个R 1取代;Q 2为不存在或选自4-6元杂环基、9-20芳基并杂环基、9-20杂芳基并环烷基、9-20芳基并杂芳基、9-20杂芳基并杂环基、5元杂芳基和 其任选被一个或多个R 2取代,R 3不存在或为R 2,R 4选自氨基C 1-12烷基酰基氨基和羟基氨基C 1-12烷基酰基氨基;R 1选自卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基、C 2-10烯基、C 2-10炔基、C 3-12环烷基、3-12元杂环基、6-12元芳基、5-12元杂芳基和氧代基团;和R 2选自卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、氨基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、氨基C 1-12烷基酰基氨基、羟基氨基C 1-12烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基、C 2-10烯基、C 2-10炔基、C 3-12环烷基、3-12元杂环基、3-12元杂环基C 1-6烷基、氨基3-12元杂环基、氨基C 1-6烷基3-12元杂环基、羟基C 1-6烷基3-12元杂环基、6-12元芳基、5-12元杂芳基和氧代基团,其任选被氨基、氨基C 1-6烷基、C 1-6烷基氨基、卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、氨基C 1-6烷氧基、硝基、羧基、氰基取代。
- 根据权利要求1或2所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,其中通式(I)具有以下通式(Ib)的结构,其中:L选自-C(O)NH-、-NHC(O)-、-SO 2NH-、-NHSO 2、-(CH 2) n-和-C(O)-;和R 5和R 6各自独立地选自卤素、羟基、烷基、卤代烷基、羟基烷基、氨基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、氨基烷基酰基氨基、羟基氨基烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、烯基、炔基、环烷基、杂环基、杂环基烷基、氨基杂环基、氨基烷基杂环基、羟基烷基杂环基、芳基、杂芳基和氧代基团,其任选被氨基、氨基烷基、烷基氨基、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、氨基烷氧基、硝基、羧基、氰基取代。
- 根据权利要求3所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药,其中:L选自-C(O)NH-和-NHC(O)-;和R 5和R 6各自独立地选自卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、氨基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、氨基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、氨基C 1-6烷基酰基氨基、羟基氨基C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环基、3-8元杂环基C 1-6烷基、氨基3-8元杂环基、氨基C 1-6烷基3-8元杂环基、羟基C 1-6烷基3-8元杂环基、芳基、3-8元杂芳基和氧代基团,其任选被氨基、氨基C 1-6烷基、C 1-6烷基氨基、卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、氨基C 1-6烷氧基、硝基、羧基、氰基取代。
- 一种药物组合物,其包含权利要求1至8之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药和可药用载体。
- 权利要求1-8之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药或权利要求9所述的药物组合物在制备用于治疗细菌感染的药物中的应用。
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