CN105669519A - Indole compounds and preparation method and application thereof as drug-resistant bacteria resistant drugs - Google Patents
Indole compounds and preparation method and application thereof as drug-resistant bacteria resistant drugs Download PDFInfo
- Publication number
- CN105669519A CN105669519A CN201610002989.9A CN201610002989A CN105669519A CN 105669519 A CN105669519 A CN 105669519A CN 201610002989 A CN201610002989 A CN 201610002989A CN 105669519 A CN105669519 A CN 105669519A
- Authority
- CN
- China
- Prior art keywords
- indole
- methoxycarbonyl
- methylene
- imidazol
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 57
- 239000003814 drug Substances 0.000 title claims abstract description 44
- 229940079593 drug Drugs 0.000 title claims abstract description 38
- 150000002475 indoles Chemical class 0.000 title claims abstract description 22
- 241000894006 Bacteria Species 0.000 title claims description 19
- -1 methylene, carbonyl Chemical group 0.000 claims abstract description 225
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 39
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000001257 hydrogen Chemical group 0.000 claims abstract description 16
- 229910052739 hydrogen Chemical group 0.000 claims abstract description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000645 desinfectant Substances 0.000 claims abstract description 9
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 9
- 150000007524 organic acids Chemical class 0.000 claims abstract description 9
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 6
- 239000000460 chlorine Chemical group 0.000 claims abstract description 6
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 6
- 239000011737 fluorine Substances 0.000 claims abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 94
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 58
- UBDZFAGVPPMTIT-UHFFFAOYSA-N 2-aminoguanidine;hydron;chloride Chemical compound [Cl-].NC(N)=N[NH3+] UBDZFAGVPPMTIT-UHFFFAOYSA-N 0.000 claims description 45
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 claims description 41
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 39
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 38
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 230000036961 partial effect Effects 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 3
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 19
- 241000191967 Staphylococcus aureus Species 0.000 abstract description 10
- 241000588626 Acinetobacter baumannii Species 0.000 abstract description 8
- 241000588747 Klebsiella pneumoniae Species 0.000 abstract description 8
- 238000002474 experimental method Methods 0.000 abstract description 8
- 230000003385 bacteriostatic effect Effects 0.000 abstract description 5
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 3
- 201000008225 Klebsiella pneumonia Diseases 0.000 abstract 1
- 206010035717 Pneumonia klebsiella Diseases 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000000543 intermediate Substances 0.000 description 26
- 239000000243 solution Substances 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- 239000002994 raw material Substances 0.000 description 21
- DNRYGKWSRGPPQO-UHFFFAOYSA-N 1-(benzenesulfonyl)-5-bromoindole-3-carbaldehyde Chemical compound C1=C(C=O)C2=CC(Br)=CC=C2N1S(=O)(=O)C1=CC=CC=C1 DNRYGKWSRGPPQO-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- PEENKJZANBYXNB-UHFFFAOYSA-N 5-bromo-1h-indole-3-carbaldehyde Chemical compound BrC1=CC=C2NC=C(C=O)C2=C1 PEENKJZANBYXNB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- UGLRSYDAOVKFIJ-UHFFFAOYSA-N methyl 3-formyl-1h-indole-5-carboxylate Chemical compound COC(=O)C1=CC=C2NC=C(C=O)C2=C1 UGLRSYDAOVKFIJ-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 7
- KRDRROJESQUFMJ-UHFFFAOYSA-N methyl 3-formyl-1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C(C=O)=CNC2=C1 KRDRROJESQUFMJ-UHFFFAOYSA-N 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 238000004659 sterilization and disinfection Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000004806 packaging method and process Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 230000001954 sterilising effect Effects 0.000 description 5
- 239000001974 tryptic soy broth Substances 0.000 description 5
- 108010050327 trypticase-soy broth Proteins 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- 206010035664 Pneumonia Diseases 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 108010059993 Vancomycin Proteins 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 229960003376 levofloxacin Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 4
- 229960003165 vancomycin Drugs 0.000 description 4
- 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 4
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) 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)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 4
- QXOGPTXQGKQSJT-UHFFFAOYSA-N 1-amino-4-[4-(3,4-dimethylphenyl)sulfanylanilino]-9,10-dioxoanthracene-2-sulfonic acid Chemical compound Cc1ccc(Sc2ccc(Nc3cc(c(N)c4C(=O)c5ccccc5C(=O)c34)S(O)(=O)=O)cc2)cc1C QXOGPTXQGKQSJT-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940126540 compound 41 Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- LNWXALCHPJANMJ-UHFFFAOYSA-N 1-(bromomethyl)-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(CBr)=C1 LNWXALCHPJANMJ-UHFFFAOYSA-N 0.000 description 2
- KQNBRMUBPRGXSL-UHFFFAOYSA-N 1-(bromomethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1 KQNBRMUBPRGXSL-UHFFFAOYSA-N 0.000 description 2
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 2
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 201000009906 Meningitis Diseases 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229920001971 elastomer Polymers 0.000 description 2
- 229940124307 fluoroquinolone Drugs 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 230000000642 iatrogenic effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- YUHSMQQNPRLEEJ-UHFFFAOYSA-N methyl 3-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=CC(CBr)=C1 YUHSMQQNPRLEEJ-UHFFFAOYSA-N 0.000 description 2
- NLWBJPPMPLPZIE-UHFFFAOYSA-N methyl 4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C=C1 NLWBJPPMPLPZIE-UHFFFAOYSA-N 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- PQCXFUXRTRESBD-UHFFFAOYSA-N (4-methoxycarbonylphenyl)boronic acid Chemical compound COC(=O)C1=CC=C(B(O)O)C=C1 PQCXFUXRTRESBD-UHFFFAOYSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 1
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 description 1
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- 208000031729 Bacteremia Diseases 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000031650 Surgical Wound Infection Diseases 0.000 description 1
- 208000009470 Ventilator-Associated Pneumonia Diseases 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 238000002802 antimicrobial activity assay Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical class BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006161 blood agar Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 229940126179 compound 72 Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- CRHWEIDCXNDTMO-UHFFFAOYSA-N ditert-butylphosphane Chemical compound CC(C)(C)PC(C)(C)C CRHWEIDCXNDTMO-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- DRYBMFJLYYEOBZ-UHFFFAOYSA-N methyl 1h-indole-5-carboxylate Chemical compound COC(=O)C1=CC=C2NC=CC2=C1 DRYBMFJLYYEOBZ-UHFFFAOYSA-N 0.000 description 1
- ZBELDPMWYXDLNY-UHFFFAOYSA-N methyl 9-(4-bromo-2-fluoroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Br)C=C1F ZBELDPMWYXDLNY-UHFFFAOYSA-N 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011265 semifinished product Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
- A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
- A01N47/44—Guanidine; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Agronomy & Crop Science (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses indole compounds represented by the general formula defined in the specification and salts and preparation method thereof, corresponding medical uses of the compounds and the salts thereof, and drugs and disinfectants containing the compounds and the salts thereof. A lot of experiments prove that the compounds and the salts thereof have good bacteriostatic and bactericidal activity on MRSA (drug-resistant staphylococcus aureus), MDR K.pneumonia (drug-resistant klebsiella pneumonia), and MDR A.baumanii (drug-resistant acinetobacter baumannii). In the formula, X is methylene, carbonyl or sulfonyl; R1 is fluorine, chlorine, bromine, methoxy acyl, nitro or hydrogen; R2 is methoxyl acyl, (p-methoxyl acyl)phenyl, (p-trifluoro oxy)phenyl, (p-trifluoro)phenyl, (m-methoxy acyl)phenyl, (m-trifluoro oxy)phenyl, (p-fluoro m-chloro)phenyl or hydrogen; and HA is inorganic acid or a part of organic acid with strong acidity, preferably hydrochloric acid or hydrobromic acid.
Description
Technical Field
The invention relates to the field of chemistry and medical application of compounds, in particular to an indole compound containing indole, aminoguanidine or hydrazinoketone, a salt thereof, a preparation method and medical application of the indole compound as a drug-resistant bacterium drug.
Background
In recent years, various antibiotics are continuously developed and applied to the market and clinic, and particularly, under the requirement of rapidly eliminating infected patients by some medical institutions and medical personnel and patients, large-dose and excessive abnormal use of the antibiotics is increasingly serious. These phenomena, make the development of resistant bacteria against antibacterial agents also rapid: the emergence of methicillin-resistant staphylococcus aureus (MRSA), methicillin-sensitive staphylococcus aureus (MSSA) and the like brings new troubles to clinical antibacterial and anti-infection treatment.
However, infection by pathogenic microorganisms such as bacteria is always one of the important diseases threatening human health. Due to the wide antibacterial spectrum, strong antibacterial activity and wide clinical application of fluoroquinolone medicaments, in recent years, the medicament resistance phenomenon of bacteria to fluoroquinolone medicaments is increasingly severe, and the propagation of medicament-resistant bacteria, the research of medical researchers and medical staff are forced to urgently develop and apply novel medicaments to overcome the problem of severe medicament resistance in the day. Among them, staphylococcus aureus is one of the most common bacteria causing iatrogenic and medical instrument infections: drug-resistant mutant strains such as newly emerging MRSA are extremely resistant to existing antibacterial drugs; klebsiella pneumoniae and Acinetobacter baumannii are typical iatrogenic or conditionally pathogenic bacteria, and Klebsiella pneumoniae can cause diseases such as pneumonia and meningitis; acinetobacter baumannii can cause bacteremia, urinary infection, secondary meningitis, surgical site infection, ventilator-associated pneumonia and the like.
Due to the emergence of the above-mentioned drug-resistant bacteria, conventional infectious diseases that have been controlled to some extent have become increasingly serious, and have attracted serious attention from clinical and microbiologists. The development of new drugs is slow at present, and the existing drugs can not treat drug-resistant bacteria, so that the problems are further aggravated. The development of drug molecules against drug-resistant bacteria with novel structures is a breakthrough to solve this problem.
Disclosure of Invention
The present invention is made to solve the above problems, and provides an indole compound and a salt thereof, a method for producing the indole compound and the salt thereof, a pharmaceutical use of the corresponding indole compound and the salt thereof, and a pharmaceutical and disinfectant containing the indole compound and the salt thereof. The inventor proves that the compound and the salt thereof have good bacteriostatic and bactericidal activity on MRSA (drug-resistant staphylococcus aureus), MDRK.
The invention provides an indole compound, which has a chemical structural general formula as follows:
wherein,
x is methylene, carbonyl or sulfonyl;
r1 is fluorine, chlorine, bromine, methoxyacyl, nitro or hydrogen;
r2 is methoxyacyl, (p-methoxyacyl) phenyl, (p-trifluoroxy) phenyl, (p-trifluoromethyl) phenyl, (m-methoxyacyl) phenyl, (m-trifluoroxy) phenyl, (p-fluoro-m-chloro) phenyl or hydrogen.
In order to obtain better bacteriostatic and bactericidal effects, the indole compound provided by the invention has R1Preferred are p-chloro, p-bromo, p-fluoro, p-methoxyacyl, p-nitrobenzyl, m-methoxyacyl, and m-nitro.
In order to obtain better bacteriostatic and bactericidal effects, the indole compound provided by the invention has R2Preferably 5-methoxyacyl, 6-methoxyacyl, 5- (p-methoxyacyl) phenyl, 5- (p-trifluoroxy) phenyl, 5- (p-trifluoro-yl) phenyl, 5- (m-methoxyacyl) phenyl, 5- (m-trifluoroxy) phenyl, 5- (p-fluoro-m-chloro) phenyl.
The indole compound provided by the invention and the corresponding X, R1、R2And compound numbers are shown in tables 1 and 2 below.
TABLE 1 Compounds of the general formula I
The indole compound of the general formula I is named as:
compound 1: 2- [ (1-p-chlorobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 2: 2- [ (1-p-fluorophenylmethyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 3: 2- [ (1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 4: 2- [ (1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 5: 2- [ (1-p-nitrobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 6: 2- [ (1-m-nitrobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 7: 2- [ (1-p-chlorobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 8: 2- [ (1-p-fluorophenylmethyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 9: 2- [ (1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 10: 2- [ (1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 11: 2- [ (1-p-nitrobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 12: 2- [ (1-m-nitrobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 13: 2- [ (1-benzoyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 14: 2- [ (1-benzoyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
compound 15: 2- [ (1-benzenesulfonyl-5- (4-methoxycarbonylphenyl) -3-indole) methylene ] aminoguanidine;
compound 16: 2- [ (1-benzenesulfonyl-5- (3-methoxycarbonylphenyl) -3-indole) methylene ] aminoguanidine;
compound 17: 2- [ (1-benzenesulfonyl-5- (4-trifluoromethoxyphenyl) -3-indole) methylene ] aminoguanidine;
compound 18: 2- [ (1-benzenesulfonyl-5- (3-trifluoromethoxyphenyl) -3-indole) methylene ] aminoguanidine;
compound 19: 2- [ (1-benzenesulfonyl-5- (4-trifluoromethylphenyl) -3-indole) methylene ] aminoguanidine;
compound 20: 2- [ (1-benzenesulfonyl-5- (4-fluoro-3-chlorophenyl) -3-indole) methylene ] aminoguanidine.
TABLE 2 Compounds of the general formula I
The indole compound of the general formula II is named as:
compound 21: 1-p-chlorobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 22: 1-p-fluorobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 23: 1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 24: 1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 25: 1-p-nitrobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 26: 1-m-nitrobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 27: 1-p-chlorobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 28: 1-p-fluorobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 29: 1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 30: 1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 31: 1-p-nitrobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 32: 1-m-nitrobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 33: 1-benzoyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone;
compound 34: 1-benzoyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone;
compound 35: 1-benzenesulfonyl-5- (4-methoxycarbonylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 36: 1-benzenesulfonyl-5- (3-methoxycarbonylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 37: 1-benzenesulfonyl-5- (4-trifluoromethoxyphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 38: 1-benzenesulfonyl-5- (3-trifluoromethoxyphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 39: 1-benzenesulfonyl-5- (4-trifluoromethylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
compound 40: 1-benzenesulfonyl-5- (4-fluoro-3-chlorophenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone.
The invention also provides a salt of an indole compound, which is characterized in that:
the salt is obtained by reacting the indole compound with an inorganic acid or an organic acid, and the structure of the salt is shown as follows:
wherein HA is inorganic acid or organic acid with strong partial acidity;
and X, R1,R2As defined above, namely:
x is methylene, carbonyl or sulfonyl;
r1 is fluorine, chlorine, bromine, methoxyacyl, nitro or hydrogen;
r2 is methoxyacyl, (p-methoxyacyl) phenyl, (p-trifluoroxy) phenyl, (p-trifluoromethyl) phenyl, (m-methoxyacyl) phenyl, (m-trifluoroxy) phenyl, (p-fluoro-m-chloro) phenyl or hydrogen.
Further in order to obtain better bacteriostasis and sterilization effect, R in the composition1Preferred are p-chloro, p-bromo, p-fluoro, p-methoxyacyl, p-nitrobenzyl, m-methoxyacyl, and m-nitro.
Further in order to obtain better bacteriostasis and sterilization effect, R in the composition2Preferably 5-methoxyacyl, 6-methoxyacyl, 5- (p-methoxyacyl) phenyl, 5- (p-trifluoroxy) phenyl, 5- (p-trifluoro-yl) phenyl, 5- (m-methoxyacyl) phenyl, 5- (m-trifluoroxy) phenyl, 5- (p-fluoro-m-chloro) phenyl.
Further, for the preparation process and the use effect, the inorganic acid is any one of sulfuric acid, phosphoric acid, hydrochloric acid and hydrobromic acid, and the organic acid is sulfonic acid.
Hair brushThe salts of the indole compounds provided are preferably hydrochloride or bromide, corresponding to X, R1、R2And compound numbers are shown in tables 3 and 4 below.
TABLE 3 Compounds of the general formula III
The salt name of the indole compound in the general formula III is:
compound 41: 2- [ (1-p-chlorobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 42: 2- [ (1-p-fluorophenylmethyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 43: 2- [ (1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 44: 2- [ (1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 45: 2- [ (1-p-nitrobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 46: 2- [ (1-m-nitrobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 47: 2- [ (1-p-chlorobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 48: 2- [ (1-p-fluorophenylmethyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 49: 2- [ (1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 50: 2- [ (1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 51: 2- [ (1-p-nitrobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 52: 2- [ (1-m-nitrobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 53: 2- [ (1-benzoyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 54: 2- [ (1-benzoyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
compound 55: 2- [ (1-benzenesulfonyl-5- (4-methoxycarbonylphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;
compound 56: 2- [ (1-benzenesulfonyl-5- (3-methoxycarbonylphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;
compound 57: 2- [ (1-benzenesulfonyl-5- (4-trifluoromethoxyphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;
compound 58: 2- [ (1-benzenesulfonyl-5- (3-trifluoromethoxyphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;
compound 59: 2- [ (1-benzenesulfonyl-5- (4-trifluoromethylphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;
compound 60: 2- [ (1-benzenesulfonyl-5- (4-fluoro-3-chlorophenyl) -3-indole) methylene ] aminoguanidine hydrochloride.
TABLE 4 Compounds of the general formula IV
The salt name of the indole compound of the general formula IV is as follows:
compound 61: 1-p-chlorobenzyl-5-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 62: 1-p-fluorobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 63: 1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 64: 1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 65: 1-p-nitrobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;
compound 66: 1-m-nitrobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;
compound 67: 1-p-chlorobenzyl-6-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 68: 1-p-fluorobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 69: 1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 70: 1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 71: 1-p-nitrobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;
compound 72: 1-m-nitrobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;
compound 73: 1-benzoyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 74: 1-benzoyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 75: 1-benzenesulfonyl-5- (4-methoxycarbonylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 76: 1-benzenesulfonyl-5- (3-methoxycarbonylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 77: 1-benzenesulfonyl-5- (4-trifluoromethoxyphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 78: 1-benzenesulfonyl-5- (3-trifluoromethoxyphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
compound 79: 1-benzenesulfonyl-5- (4-trifluoromethylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;
compound 80: 1-benzenesulfonyl-5- (4-fluoro-3-chlorophenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide.
The invention also provides a drug-resistant bacterium-resistant pharmaceutical composition, which is characterized in that:
the pharmaceutical composition contains the indole compounds of the general formulas I and II or the salts of the indole compounds of the general formulas III and IV and pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise excipients, diluents, stabilizers, flavoring agents and the like, and are mixed according to a conventional pharmaceutical method to prepare solid dosage forms such as tablets, capsules, granules, powder and the like and liquid dosage forms such as syrup, oral liquid and the like.
The amounts of compounds I, II and their salts III, IV administered vary with the age, sex, condition of the patient, etc. In general, the dose for adult humans may be 0.01 to 5000 mg/day, preferably 1 to 1000 mg/day, more preferably 5 to 500 mg/day.
The invention also provides a disinfectant for disinfecting and sterilizing medical instruments or hands, which is characterized in that:
wherein, the pharmaceutical composition contains the indole compounds of the general formulas I and II or the salts of the indole compounds of the general formulas III and IV and a proper solvent, such as water, ethanol or a mixed solvent thereof.
The concentration of the compounds I and II and the salts III and IV thereof in the disinfectant is related to the requirements of disinfection and sterilization, and the disinfection of the surgical instruments is generally carried out at the mass concentration of 0.05-2.0%, preferably 0.1-1.0%, and more preferably 0.5-1.0%.
The application of the indole compounds of the general formulas I and II or the salts of the indole compounds of the general formulas III and IV in the preparation of drugs for resisting drug-resistant bacteria.
The method for preparing the salts of the indole compounds of the formulas (III and IV) is characterized by comprising the steps of mixing and reacting compounds of a general formula (V) and a general formula (VI) in a dry and anhydrous polar solvent to obtain the salts of the indole compounds of the formulas (III and IV); the indole compounds of the formulas (I and II) can be obtained by alkalifying the salts of the indole compounds of the formulas (III and IV) with alkali
Wherein,
X,R1,R2HA HAs the same meaning as above;
i.e. when X in formula (V) is different,
when X is methylene, the intermediate 1- (3-or 4-substituted benzyl) -3-formyl-5 (or 6) -methoxycarbonylindole (3) is prepared by the following reaction scheme:
when X is carboxyl, the intermediate 1-benzoyl-3-formyl-5 (or 6) -methoxycarbonylindole (4) is prepared by the following reaction route:
when X is sulfonyl, the intermediate 1-benzenesulfonyl-3-formyl-5- (3-or 4-substituted phenyl) indole (8) is prepared by the following reaction scheme:
obtaining the above intermediates 3, 4, 8 (i.e. formula V) and reacting them with compounds of formula (VI) to obtain compounds of formula (III, I)
Alkalizing with NaOH solution to pH above 10;
the compounds in the general formulas (IV and II) can be obtained by the same method.
A method for preparing the indole compounds of the formulas (I and II) and the salts of the indole compounds of the formulas (III and IV), wherein the polar solvent is preferably any one of methanol, ethanol, acetonitrile and N, N-dimethylformamide or a mixed solvent thereof.
A process for preparing the indole compounds of the formulae (I, II) and salts of the indole compounds of the formulae (III, IV) mentioned above, wherein the temperature of the mixing reaction is preferably room temperature or reflux temperature.
Pharmacological experiments with the Compounds of the invention
(one) Experimental manipulations
The Minimum Inhibitory Concentration (MIC) is obtained by measuring the in vitro inhibitory activity by a 96-well microplate method, and the Minimum Bactericidal Concentration (MBC) is measured by a blood plate coating method.
(1) Experimental strains
The following 4 common human pathogenic strains were selected as test subjects in this experiment:
staphylococcus aureus, drug-resistant Klebsiella pneumoniae, drug-resistant Acinetobacter baumannii
(2) The experimental method comprises the following steps: in vitro antimicrobial Activity assay for Compounds
Culturing strains: a single colony growing on a Trypticase Soy Broth (TSB) plate is selected to be inoculated in liquid TSB at 37 ℃ and 200rpm for 18h, and a strain culture is obtained for subsequent determination of antibacterial activity.
The antibacterial activity determination method comprises performing antibacterial activity determination of compounds with sterile 96-well plate, performing primary screening of all strains with each compound at 100 μ g/ml concentration in parallel with 3-well plate to obtain primary antibacterial activity, selecting compounds with antibacterial activity at 100 μ g/ml concentration, further performing Minimum Inhibitory Concentration (MIC) determination, adding 2 times concentration culture medium (trypticase soy broth, TSB) diluted drug into each well, synthesizing each obtained positive compound to obtain primary solution with appropriate concentration, diluting with culture medium (2 ×) to obtain double concentration of each compound, adding 200 μ l of each positive compound, and adding 200 μ l of each positive compound into 96-well plateConcentrations of 100.0, 50.0, 25.0, 12.5, 6.3, 3.1, 1.6, 0.8, 0.4, 0.2, 0.1 and 0.05. mu.g/ml control levofloxacin 12 gradients were used to final concentrations of 64.0, 32.0, 16.0, 8.0, 4.0, 2.0, 1.0, 0.5, 0.25, 0.125, 0.063, 0.031 and 0.016. mu.g/ml respectively, followed by addition of a bacterium S.aureus (ATCC29213), MRSA, RK.pUMAUnie and MDRA.baumanii respectively to determine the MIC of each bacterium for each compound, 100. mu.l was inoculated per well and the amount per well was about 1.1 × 10-10 per well5cfu, final volume 200. mu.l per well. Each plate was provided with 2 growth positive control wells containing no antibacterial and two growth negative control wells using distilled water instead of the culture medium, the 96-well plate was capped and sealed with a transparent tape around, and placed in a wet box for static culture at 37 ℃. The absorbance at 600nm was measured at different time points for each well using a microplate reader, with the time points selected to be 0, 24h and 48h, respectively. Wells in which a clear difference between positive and negative growth control wells was observed after 48h were plated on blood agar plates with 1% DMSO as control. Thereby determining the bactericidal status of the drug and obtaining the Minimum Bactericidal Concentration (MBC).
(II) results of the experiment
Results of in vitro bacteriostatic experiments are shown in table 3.
In vitro inhibitory minimum concentration values (MIC in μ g/mL) of the compounds of interest in Table 5.
TABLE 5
Note: s.aureus: staphylococcus aureus bacteria; MRSA: drug-resistant staphylococcus aureus; pneumonia: drug-resistant klebsiella pneumoniae; baumann ii: drug-resistant acinetobacter baumannii; levofloxacin: levofloxacin; vancomycin: vancomycin; -: no experiment was conducted
Table 6 shows the comparison of the in vitro inhibitory and bactericidal minimum concentration values (MIC and MBC in. mu.g/mL) for some compounds.
TABLE 6
Note: MRSA: drug-resistant staphylococcus aureus; pneumonia: drug-resistant klebsiella pneumoniae; baumann ii: drug-resistant acinetobacter baumannii; vancomycin: vancomycin; and 6: greater than or equal to 100 mug/ml; -: no experiment was conducted
Action and Effect of the invention
As can be seen from tables 3 and 4, the salts (hydrochloride, hydrobromide) of the novel indole compounds of the present invention have very good activity against drug-resistant bacteria, wherein the in vitro antibacterial activity of the compounds 41, 47, 55, 56, 57, 58, 61, 68, 75, 77, 78, 79 against drug-resistant bacteria is far better than that of levofloxacin, and particularly, the compounds 41, 47, 61 also have excellent antibacterial activity against drug-resistant klebsiella pneumoniae and drug-resistant acinetobacter baumannii. Therefore, the compound and the salt thereof can be used for preparing medicines for resisting drug-resistant bacteria such as drug-resistant staphylococcus aureus and disinfectants for medical instruments.
Detailed Description
In order to make the technical means, creation features, achievement purposes and effects of the invention easy to understand, the following examples describe the preparation of the compound, compound salt, and the pharmaceutical use and dosage form of the invention in detail.
EXAMPLES preparation of Compounds of general formulae III, I
Preparation of intermediate 1- (3-or 4-substituted benzyl) -3-formyl-5 (or 6) -methoxycarbonylindole 3 in formula V
Preparation of 3-formyl-5 (or 6) -methoxycarbonylindole (2)
5 (or 6) -methoxycarbonylindole (1) and phosphorus oxychloride (POCl) respectively3) The Vilsmeier-Hack reaction is carried out under the condition of dry N, N-dimethyl sulfoxide to generate 3-formyl-5 (or 6) -methoxycarbonyl indole (2)
Preparation of 3-formyl-5 (or 6) -methoxycarbonylindole (2) operating example
Preparation of 3-formyl-5-methoxycarbonylindole
Indole-5-carboxylic acid methyl ester 5.00g (28.57mmol) was added to ultra dry DMF20mL under nitrogen and cooled to 0 ℃ before phosphorus oxychloride 3.62mL (38.86mol) was slowly added dropwise. After 10min at 0 ℃, the reaction was carried out at room temperature for 3 h. Cooling the reaction solution to 0 ℃, adding 60mL of water to quench the reaction, then adjusting the pH of the reaction solution to 10 by using 2M NaOH aqueous solution, continuing stirring for 5min, and heating to 70 ℃ for reaction for 30 min. Cooling the reaction solution to room temperature, carrying out vacuum filtration, and washing a filter cake with water and methanol respectively to obtain a light pink solid with the yield of 89 percent and m.p.231.4-233.0 ℃;1H-NMR(400MHz,DMSO):12.44(brs,1H,NH),9.98(s,1H,CHO),8.77(d,J=1.2,1H,Ar-H),8.44(s,1H,Ar-H),7.88(dd,J1=8.4,J2=1.6,1H,Ar-H),7.61(d,J=8.8,1H,Ar-H),3.87(s,3H,CH3);ES-MS204.1(M+H)+。
3-formyl-5 (or 6) -methoxycarbonylindole (2) and substituted benzyl bromide react in the presence of sodium hydride to generate (3)
Preparation of 1- (3-or 4-substituted benzyl) -3-formyl-5 (or 6) -methoxycarbonylindole (3) operating examples
Preparation of 1-p-chlorobenzyl-3-formyl-5-methoxycarbonylindole
Adding 0.50g (2.46mmol) of 3-formyl-5-methoxycarbonylindole into ultra-dry DMSO8mL under the protection of nitrogen, then adding 0.11g (2.71mmol) of sodium hydride, reacting at room temperature for 1h, adding 0.56g (2.71mmol) of p-chlorobenzyl bromide into the reaction liquid, reacting at room temperature for 10h, after the reaction is finished, adding 20mL of saturated ammonium chloride solution into the reaction liquid, extracting with dichloromethane (150mL × 3), washing the organic layer with saturated aqueous sodium chloride solution and water respectively, drying with anhydrous sodium sulfate, performing rotary evaporation and concentration to obtain a crude product, performing column chromatography, and eluting with dichloromethane to obtain 0.42g of a white solid, wherein the yield is 52%, and m.p.160.160.2-160.7 ℃;1H-NMR(400MHz,CDCl3):10.06(s,1H,CHO),9.03(s,1H,Ar-H),8.02(dd,J1=8.4,J2=1.6,1H,Ar-H),7.78(s,1H,Ar-H),7.35(d,J=8.4,2H,Ar-H),7.33(d,J=8.4,1H,Ar-H),7.10-7.12(d,J=8.4,2H,Ar-H),5.37(s,2H,CH2),3.95(s,3H,CH3);ES-MS328.1(M+H)+。
similarly, intermediates 3 with different R1, R2 substituents can be prepared:
the preparation method of the 1-p-fluorobenzyl-3-formyl-5-methoxycarbonylindole adopts 3-formyl-5-methoxycarbonylindole and p-fluorobenzyl bromide as raw materials. The yield is 96 percent, and m.p.153.3-153.9 ℃;1H-NMR(400MHz,CDCl3):10.05(s,1H,CHO),9.02(s,1H,Ar-H),8.03(dd,J1=8.8,J2=1.6,1H,Ar-H),7.77(s,1H,Ar-H),7.35(d,J=8.4,1H,Ar-H),7.17(dd,J1=8.8,J2=5.2,2H,Ar-H),7.06(t,J=8.8,2H,Ar-H),5.36(s,2H,CH2),3.94(s,3H,CH3);ES-MS312.1(M+H)+。
the preparation method of the 1-p-methoxycarbonylbenzyl-3-formyl-5-methoxycarbonylindole adopts the 3-formyl-5-methoxycarbonylindole and the p-methoxycarbonylbenzyl bromide as raw materials. The yield is 92 percent, and m.p.203.6-204.0 ℃;1H-NMR(400MHz,CDCl3):10.06(s,1H,CHO),9.03(d,J=1.2,1H,Ar-H),8.03(d,J=8.4,2H,Ar-H),8.00(dd,J1=8.8,J2=1.6,1H,Ar-H),7.81(s,1H,Ar-H),7.30(d,J=8.8,1H,Ar-H),7.21(d,J=8.4,2H,Ar-H),5.46(s,2H,CH2),3.94(s,3H,CH3),3.91(s,3H,CH3);ES-MS352.1(M+H)+。
the preparation method of the 1-m-methoxycarbonylbenzyl-3-formyl-5-methoxycarbonylindole adopts 3-formyl-5-methoxycarbonylindole and m-methoxycarbonylbenzyl bromide as raw materials. The yield is 91 percent, m.p.148.6-149.3 ℃;1H-NMR(400MHz,CDCl3):10.06(s,1H,CHO),9.03(d,J=1.2,1H,Ar-H),8.02(dd,J1=8.8,J2=1.2,2H,Ar-H),7.94(s,1H,Ar-H),7.80(s,1H,Ar-H),7.44(t,J=8.0,1H,Ar-H),7.34(d,J=8.8,1H,Ar-H),7.31(d,J=8.0,1H,Ar-H),5.44(s,2H,CH2),3.94(s,3H,CH3),3.91(s,3H,CH3);ES-MS352.1(M+H)+。
the preparation method of the 1-p-nitrobenzyl-3-formyl-5-methoxycarbonylindole adopts the 3-formyl-5-methoxycarbonylindole and the p-nitrobenzyl bromide as raw materials. The yield is 86 percent, m.p.219.2-219.6 ℃;1H-NMR(400MHz,DMSO):10.01(s,1H,CHO),8.80(d,J=1.2,1H,Ar-H),8.66(s,1H,Ar-H),8.21(d,J=8.8,2H,Ar-H),7.88(dd,J1=8.4,J2=1.6,1H,Ar-H),7.69(d,J=8.4,1H,Ar-H),7.51(d,J=8.8,2H,Ar-H),5.79(s,2H,CH2),3.87(s,3H,CH3);ES-MS339.1(M+H)+。
the preparation method of the 1-m-nitrobenzyl-3-formyl-5-methoxycarbonylindole adopts 3-formyl-5-methoxycarbonylindole and m-nitrobenzyl bromide as raw materials. The yield is 71 percent, m.p.190.9-193.9 ℃;1H-NMR(400MHz,CDCl3):10.09(s,1H,CHO),9.04(s,1H,Ar-H),8.21(d,J=8.4,1H,Ar-H),8.11(s,1H,Ar-H),8.03(dd,J1=8.8,J2=1.6,1H,Ar-H),7.85(s,1H,Ar-H),7.55(t,J=8.0,1H,Ar-H),7.41(d,J=8.0,1H,Ar-H),7.30(d,J=8.8Hz,1H,Ar-H),5.52(s,2H,CH2),3.95(s,3H,CH3);ES-MS339.1(M+H)+。
the preparation of 1-p-chlorobenzyl-3-formyl-6-methoxycarbonylindole adopts 3-formyl-6-methoxycarbonylindole and p-chlorobenzyl bromide asThe raw materials and the method are the same as above. The yield is 64 percent, and m.p.153.1-154.2 ℃;1H-NMR(400MHz,CDCl3):10.03(s,1H,CHO),8.36(d,J=8.0,1H,Ar-H),8.09(s,1H,Ar-H),8.02(dd,J1=8.4,J2=1.6,1H,Ar-H),7.82(s,1H,Ar-H),7.35(d,J=8.4,2H,Ar-H),7.12-7.14(d,J=8.4,2H,Ar-H),5.40(s,2H,CH2),3.94(s,3H,CH3);ES-MS328.1(M+H)+。
the preparation method of the 1-p-fluorobenzyl-3-formyl-6-methoxycarbonylindole adopts 3-formyl-6-methoxycarbonylindole and p-fluorobenzyl bromide as raw materials. The yield is 56 percent, and the m.p.155.6 to 155.7 ℃;1H-NMR(400MHz,CDCl3):10.03(s,1H,CHO),8.35(d,J=8.4,1H,Ar-H),8.11(s,1H,Ar-H),8.01(dd,J1=8.4,J2=1.6,1H,Ar-H),7.81(s,1H,Ar-H),7.20(dd,J1=8.8,J2=5.2,2H,Ar-H),7.07(t,J=8.4,2H,Ar-H),5.40(s,2H,CH2),3.94(s,3H,CH3);ES-MS312.1(M+H)+。
the preparation method of the 1-p-methoxycarbonylbenzyl-3-formyl-6-methoxycarbonylindole adopts the 3-formyl-6-methoxycarbonylindole and the p-methoxycarbonylbenzyl bromide as raw materials. The yield is 58 percent, and m.p.169.9-171.1 ℃;1H-NMR(400MHz,CDCl3):10.05(s,1H,CHO),8.37(d,J=8.0,1H,Ar-H),8.07(s,1H,Ar-H),8.03(d,J=8.4,2H,Ar-H),8.01-8.03(dd,J1=8.4,J2=1.2,1H,Ar-H),7.85(s,1H,Ar-H),7.23(d,J=8.4Hz,2H,Ar-H),5.50(s,2H,CH2),3.93(s,3H,CH3),3.91(s,3H,CH3);ES-MS352.1(M+H)+。
the preparation method of the 1-m-methoxycarbonylbenzyl-3-formyl-6-methoxycarbonylindole adopts 3-formyl-6-methoxycarbonylindole and m-methoxycarbonylbenzyl bromide as raw materials. The yield is 56 percent, m.p.141.2-141.7 ℃;1H-NMR(400MHz,CDCl3):10.03(s,1H,CHO),8.36(d,J=8.0,1H,Ar-H),8.10(s,1H,Ar-H),8.02(d,J=8.0,1H,Ar-H),8.01(dd,J1=8.0,J2=1.6,1H,Ar-H),7.94(s,1H,Ar-H),7.84(s,1H,Ar-H),7.45(t,J=7.6,1H,Ar-H),7.34(d,J=7.6,1H,Ar-H),5.47(s,2H,CH2),3.93(s,3H,CH3),3.91(s,3H,CH3);ES-MS352.1(M+H)+。
the preparation method of the 1-p-nitrobenzyl-3-formyl-6-methoxycarbonylindole adopts the 3-formyl-6-methoxycarbonylindole and the p-nitrobenzyl bromide as raw materials. The yield is 80 percent, m.p.184.5-184.9 ℃;1H-NMR(400MHz,CDCl3):10.08(s,1H,CHO),8.39(d,J=8.0,1H,Ar-H),8.22(d,J=8.8,2H,Ar-H),8.02-8.04(m,2H,Ar-H),7.89(s,1H,Ar-H),7.30(d,J=8.8,2H,Ar-H),5.56(s,2H,CH2),3.93(s,3H,CH3);ES-MS339.1(M+H)+。
the preparation method of the 1-m-nitrobenzyl-3-formyl-6-methoxycarbonylindole adopts 3-formyl-6-methoxycarbonylindole and m-nitrobenzyl bromide as raw materials. The yield is 70 percent, and m.p.153.8-155.3 ℃;1H-NMR(400MHz,CDCl3):10.07(s,1H,CHO),8.38(d,J=8.4,1H,Ar-H),8.21(dd,J1=8.4,J2=1.2,1H,Ar-H),8.10(s,1H,Ar-H),8.05(s,1H,Ar-H),8.03(dd,J1=8.4,J2=1.2,1H,Ar-H),7.89(s,1H,Ar-H),7.55(t,J=8.0,1H,Ar-H),7.42-7.44(d,J=8.0,1H,Ar-H),5.55(s,2H,CH2),3.93(s,3H,CH3);ES-MS339.1(M+H)+。
preparation of intermediate 1-benzoyl-3-formyl-5 (or 6) -methoxycarbonylindole of formula V, intermediate 4
3-formyl-5 (or 6) -methoxycarbonylindole (2) and benzoyl chloride react with DMF in the presence of sodium hydride to generate 1-benzoyl-3-formyl-5 (or 6) -methoxycarbonylindole (4)
Preparation of 1-benzoyl-3-formyl-5 (or 6) -methoxycarbonylindole (4) example
Preparation of 1-benzoyl-3-formyl-5-methoxycarbonylindole
Under the protection of argon, 0.10g (0.49mmol) of 3-formyl-5-methoxycarbonylindole was added to ultra-dry DMF2mL, and after cooling to 0 ℃, 0.02g (0.54mmol) of sodium hydride was added and the reaction was carried out at room temperature for 1 h. Then, the reaction mixture was cooled to 0 ℃ and 0.07mL (0.54mmol) of benzoyl chloride was added dropwise to the mixture, followed by reaction at room temperature overnight. After the reaction is finished, pouring the reaction liquid into 100mL of water for standing, performing vacuum filtration to obtain a crude product, and performing column chromatography to obtain an eluent, namely ethyl acetate: petroleum ether is 1: 8 (V: V), 0.11g of a white solid was obtained in a yield of 71%. m.p.172.7-173.3 ℃;1H-NMR(400MHz,CDCl3):10.10(s,1H,CHO),9.00(d,J=1.2,1H,Ar-H),8.35(d,J=8.8,1H,Ar-H),8.18(dd,J1=8.8,J2=1.6,1H,Ar-H),8.03(s,1H,Ar-H),7.81-7.79(m,2H,Ar-H),7.71(t,J=7.6,1H,Ar-H),7.61(t,J=7.6,2H,Ar-H),3.98(s,3H,CH3);ES-MS308.1(M+H)+。
similarly, intermediates 4 with different R1, R2 substituents can be prepared:
the preparation method of the 1-benzoyl-3-formyl-6-methoxycarbonylindole adopts the 3-formyl-6-methoxycarbonylindole as the raw material. The yield is 66 percent, m.p.176.1-176.4 ℃;1H-NMR(400MHz,CDCl3):10.09(s,1H,CHO),9.00(s,1H,Ar-H),8.38(d,J=8.0,1H,Ar-H),8.15(dd,J1=8.4,J2=1.2,1H,Ar-H),8.08(s,1H,Ar-H),7.81-7.79(m,2H,Ar-H),7.73(t,J=7.6,1H,Ar-H),7.62(t,J=7.6,2H,Ar-H),3.97(s,3H,CH3);ES-MS308.1(M+H)+。
preparation of intermediate 1-benzenesulfonyl-3-formyl-5- (3-or 4-substituted phenyl) indole of formula V intermediate (8)
Preparation of 3-formyl-5-bromoindole (6)
5-bromoindole (5) and phosphorus oxychloride (POCl)3) In the dry state of N, N-bisVilsmeier-Hack reaction is carried out under the condition of methyl sulfoxide to generate 3-formyl-5-bromoindole (6)
Preparation of 3-formyl-5-bromoindole (6) operating example
5.00g (25.5mmol) of 5-bromoindole was added to ultra-dry DMF (20ml) under nitrogen and cooled to 0 ℃ and then 3.22ml (34.68mol) of phosphorus oxychloride was slowly added dropwise. After reacting at 0 ℃ for 10min, the reaction was carried out at room temperature for 3 h. Cooling the reaction solution to 0 ℃, adding water (100ml) to quench the reaction, then adjusting the pH of the reaction solution to 8-9 by using 2M NaOH aqueous solution, continuing stirring for 5min, and heating to 70 ℃ for reaction for 30 min. The reaction solution was cooled to room temperature, filtered under reduced pressure to obtain a filter cake, which was dried to obtain 5.19g of a white solid with a yield of 99%. m.p.203.5-204.3 deg.C;1H-NMR(400MHz,DMSO):12.28(s,1H,NH),9.93(s,1H,CHO),8.35(s,1H,Ar-H),8.21(d,J=2.0,1H,Ar-H),7.49(d,J=8.4,1H,Ar-H),7.43(dd,J1=8.8,J2=2.0,1H,Ar-H);ES-MS225.1(M+H)+。
preparation of 1-benzenesulfonyl-3-formyl-5-bromoindole (7)
Reacting 3-formyl-5-bromoindole (6) with benzenesulfonyl chloride under the action of sodium hydride to generate 1-benzenesulfonyl-3-formyl-5-bromoindole (7)
Preparation of 1-benzenesulfonyl-3-formyl-5-bromoindole (7) operating example
Under the protection of nitrogen, adding 2.00g (8.8807mmol) of 3-formyl-5-methoxycarbonylindole into ultra-dry DMSO15ml, then adding 0.392g (9.7706mmol) of sodium hydride, reacting at room temperature for 1h, adding 1.883g (10.664mmol) of benzenesulfonyl chloride into the reaction solution, reacting at room temperature for 18h, after the reaction is finished, adding 100ml of saturated ammonium chloride solution into the reaction solution, extracting with dichloromethane (200ml of × 3), washing the organic layer with saturated sodium chloride solution and water respectively, drying with anhydrous sodium sulfate, concentrating by rotary evaporation to obtain a crude product, recrystallizing with acetone/n-hexane to obtain 2.675g of a white solid, wherein the yield is 83%, m.p.235.2-239.3 ℃;1H-NMR(400MHz,DMSO):10.06(s,1H,CHO),8.96(s,1H,Ar-H),8.22(d,J=2.0,1H,Ar-H),8.14-8.12(m,2H,Ar-H),7.95(d,J=8.8,1H,Ar-H),7.81-7.77(m,1H,Ar-H),7.69-7.65(m,2H,Ar-H),7.62(dd,J1=8.8,J2=2.0,1H,Ar-H);ES-MS365.2(M+H)+。
preparation of 1-benzenesulfonyl-3-formyl-5- (3-or 4-substituted phenyl) indole, intermediate (8)
1-benzenesulfonyl-3-formyl-5-bromoindole (7) and substituted phenylboronic acid in [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl2) Generates 1-benzenesulfonyl-3-formyl-5- (3-or 4-substituted phenyl) indole (8)
Preparation of 1-benzenesulfonyl-3-formyl-5- (3-or 4-substituted phenyl) indole (8) operating examples
Preparation of 1-benzenesulfonyl-3-formyl-5-p-methoxycarbonylphenylindole
Adding 0.5g (1.37mmol) of 1-benzenesulfonyl-3-formyl-5-bromoindole into 10ml of THF and 10ml of water, then sequentially adding 0.28g (2.055mmol) of potassium carbonate, 0.24g (1.64mmol) of p-methoxycarbonylphenylboronic acid and 8.9mg (0.0137mmol) of 1,1' -bis (di-tert-butylphosphine) ferrocene dichloropalladium, heating to 60 ℃, stirring for reaction for 8 hours, extracting with ethyl acetate (100ml × 3) after the reaction is finished, drying with anhydrous sodium sulfate, carrying out rotary evaporation and concentration to obtain a crude product, carrying out column chromatography, and eluting with ethyl acetate/petroleum ether to obtain 0.62g of a white solid, wherein the yield is 86%, m.p.166.5-166.8 ℃;1H-NMR(400MHz,CDCl3):10.13(s,1H,CHO),8.52(d,J=2.0,1H,Ar-H),8.27(s,1H,Ar-H),8.11(d,J=8.4,2H,Ar-H),8.04(d,J=8.8,1H,Ar-H),8.02-7.99(m,2H,Ar-H),7.70-7.63(m,4H,Ar-H),7.57-7.53(m,2H,Ar-H),3.94(s,3H,OCH3);ES-MS420.5(M+H)+。
similarly, intermediates 8 with different R1, R2 substituents can be prepared:
the 1-benzenesulfonyl-3-formyl-5-m-methoxycarbonylphenylindole is prepared by adopting 1-benzenesulfonyl-3-formyl-5-bromoindole as a raw material in the same way with the yield of 53 percent. m.p.186.8-187.1 ℃; 1HNMR (400MHz, CDCl)3):10.13(s,1H,CHO),8.50(d,J=1.6,1H,Ar-H),8.28-8.27(m,2H,Ar-H),8.05-7.99(m,4H,Ar-H),7.83-7.80(m,1H,Ar-H),7.69(dd,J1=8.8,J2=2.0,1H,Ar-H),7.66-7.63(m,1H,Ar-H),7.57-7.50(m,3H,Ar-H),3.95(s,3H,OCH3);ES-MS420.5(M+H)+。
The 1-benzenesulfonyl-3-formyl-5-p-trifluorooxyphenylindole is prepared by using 1-benzenesulfonyl-3-formyl-5-bromoindole as a raw material, wherein the yield is 89% by the same method. m.p.180.4-181.3 deg.C; 1H NMR (400MHz in DMSO):10.12(s,1H, CHO),8.98(s,1H, Ar-H),8.34(d, J ═ 1.6,1H, Ar-H),8.18-8.16(m,2H, Ar-H),8.07(d, J ═ 8.8,1H, Ar-H),7.80-7.75(m,2H, Ar-H),7.69-7.65(m,3H, Ar-H),7.61-7.57(m,2H, Ar-H),7.37(d, J ═ 8.4,1H, Ar-H); ES-MS446.4(M + H)+。
The 1-benzenesulfonyl-3-formyl-5-m-trifluorooxyphenylindole is prepared by using 1-benzenesulfonyl-3-formyl-5-bromoindole as a raw material, wherein the yield is 74 percent. m.p.150.4-151.0 deg.C; 1H-NMR (400MHz, DMSO):10.12(s,1H, CHO),8.98(s,1H, Ar-H),8.33(d, J ═ 1.6,1H, Ar-H),8.18-8.16(m,2H, Ar-H),8.07(d, J ═ 8.8,1H, Ar-H),7.78-7.74(m,4H, Ar-H),7.70-7.66(m,2H, Ar-H),7.45(d, J ═ 8.0,2H, Ar-H); ES-MS446.4(M + H)+。
The 1-benzenesulfonyl-3-formyl-5-p-trifluorophenylindole was prepared by using 1-benzenesulfonyl-3-formyl-5-bromoindole as a starting material in the same manner as above with a yield of 67%. m.p.216.5-216.8 ℃;1H-NMR(400MHz,CDCl3):10.13(s,1H,CHO),8.50(d,J=1.6,1H,Ar-H),8.28(s,1H,Ar-H),8.05(d,J=8.8,1H,Ar-H),8.03-8.00(m,2H,Ar-H),7.74-7.68(m,4H,Ar-H),7.68-7.63(m,2H,Ar-H),7.58-7.53(m,2H,Ar-H);ES-MS430.4(M+H)+。
the 1-benzenesulfonyl-3-formyl-5-p-fluoro m-chlorophenyl indole is prepared by using 1-benzenesulfonyl-3-formyl-5-bromoindole as a raw material in the same manner with the yield of 83 percent. m.p.171.1-171.6 deg.C; 1HNMR (400MHz, CDCl)3):10.12(s,1H,CHO),8.41(d,J=1.6,1H,Ar-H),8.27(s,1H,Ar-H),8.03-7.99(m,3H,Ar-H),7.67-7.62(m,2H,Ar-H),7.58-7.53(m,3H,Ar-H),7.46(ddd,J1=8.6,J2=4.4,J3=2.41H,Ar-H),7.21(t,J=8.6,1H,Ar-H);ES-MS414.9(M+H)+。
After the preparation of the intermediates 3, 4 and 8, the reaction can be carried out with salts of the general formula VI
Preparation of the target Compound III
The intermediate (3), the intermediate (4) or the intermediate (8) respectively reacts with aminoguanidine hydrochloride VI in dry methanol at room temperature to generate a target compound III
Preparation of 2- [ (1-p-chlorobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride (Compound 41 in Table 7) operating example
0.20g (0.61mmol) of 1-p-chlorobenzyl-3-formyl-5-methoxycarbonylindole was added to 5mL of anhydrous methanol, 0.07g (0.61mmol) of aminoguanidine hydrochloride was added thereto, and the reaction mixture was adjusted to pH 3 to 4 with concentrated hydrochloric acid at room temperature, followed by reaction at room temperature for 80 min. After the reaction is finished, adding ether into the reaction liquid, standing to separate out a solid, performing suction filtration under reduced pressure, and washing a filter cake with ether to obtain 0.22g of milky white solid with the yield of 87%. The experimental data for compound 41 and other compounds 42-60 are shown in Table 7.
The compounds 42-52 in Table 7 were prepared using intermediate (3) as the starting material in the same manner as above.
The compounds 53 and 54 in Table 7 were prepared using the intermediate (4) as starting material in the same manner as above.
The compounds 55-60 in Table 7 were prepared using intermediate (8) as the starting material in the same manner as above.
Preparation of the object Compound I
Dissolving or suspending 0.5-1.0g of the obtained target compound (III) powder in 5% -10% of ice-cold NaOH solution, adding 1 volume time of dichloromethane DCM solvent of the NaOH solution, vigorously stirring for 10-30 minutes until the pH value of the upper aqueous phase solution is more than 10 (granular NaOH solid can be properly added), standing for layering, extracting the organic phase by 0.5 volume time of DCM solvent, and concentrating under reduced pressure at the temperature of 30 ℃ until the target compound I is dried.
Table 7 shows the R1, R2 and X group collocation, yield and nuclear magnetic hydrogen spectrum data of the target compound III, which are shown in the attached table 7.
Similarly, by changing the aminoguanidine hydrochloride into sulfate, phosphate, hydrobromide or sulfonate, the corresponding sulfate, phosphate, hydrobromide or sulfonate of the target compound iii can be obtained by using ethanol, acetonitrile, N-dimethylformamide DMF or a mixed solvent thereof as the reaction solvent.
Advantageous effects and effects of the embodiment
The synthesis method of the target compounds i and iii provided by the embodiment has simple steps, is easy to purify by filtration and separation, has high yield and is easy to operate, and is suitable for future industrial production, and the reaction is carried out at normal temperature or under reflux.
EXAMPLES preparation of two-way compounds of formula IV, II
Preparation of the target Compound IV
Respectively carrying out reflux reaction on the intermediate (3), the intermediate (4) or the intermediate (8) and 4, 5-dihydroimidazole-2-hydrazine hydrogen bromide VI in dry methanol to obtain a target compound IV;
preparation of 1-p-chlorobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide (Compound 61 in Table 8)
0.05g (0.15mmol) of 1-p-chlorobenzyl-3-formyl-6-methoxycarbonylindole was added to 2mL of anhydrous methanol, and then 0.03g (0.15mmol) of 4, 5-dihydroimidazole-2-hydrazinebromide was added to the reaction mixture, and the mixture was heated to 75 ℃ for reaction. After the reaction is finished, cooling the reaction liquid to room temperature, adding ether, standing to separate out a solid, carrying out suction filtration under reduced pressure, and washing a filter cake with ether to obtain 0.07g of milky white solid with the yield of 87%. The experimental data for compound 61 and other compounds 62-80 are shown in Table 8.
The compounds 62-72 in Table 8 were prepared using intermediate (3) as the starting material in the same manner as above.
The preparation of compounds 73 and 74 in Table 8 was carried out in the same manner as above using intermediate (4) as starting material.
The compounds 75-80 of Table 8 were prepared using intermediate (8) as the starting material in the same manner as above.
Preparation of the target Compound II
Dissolving or suspending 0.5-1.0g of the obtained target compound IV powder in 5% -10% of ice-cold NaOH solution, adding 1 volume time of dichloromethane DCM solvent of the NaOH solution, vigorously stirring for 10-30 minutes until the pH value of the upper aqueous phase solution is more than 10 (granular NaOH solid can be properly added), standing for layering, extracting the organic phase by 0.5 volume time of DCM solvent, and concentrating under reduced pressure at the temperature of 30 ℃ until the target compound II is dried.
Table 8 shows the target compound IV R1, the group matching of R2 and X, the yield and nuclear magnetic hydrogen spectrum data, which are shown in the attached Table 8.
Similarly, the operation is carried out, only the aminoguanidine hydrochloride is changed into sulfate, phosphate, hydrobromide or sulfonate, and the corresponding sulfate, phosphate, hydrobromide or sulfonate of the target compound IV can be obtained by using ethanol, acetonitrile, N-dimethylformamide DMF or a mixed solvent thereof as a reaction solvent.
Advantageous effects and effects of the embodiment
The synthesis method of the target compounds II and IV provided by the embodiment has the advantages of simple steps, reaction at normal temperature or under reflux condition, high yield, easy extraction and purification of products, easy operation and suitability for future industrial production.
EXAMPLE III preparation of sterile injectable powder of the Compound of the invention
1. Prescription:
prescription 1:
250g (calculated by compound) of any one of compound III or IV
1000 pieces are prepared in total
Prescription 2:
500g (based on the compound) of any one of the compounds III or IV
1000 pieces are prepared in total
Prescription 3:
1000g (based on the compound) of any one of the compounds III or IV
1000 pieces are prepared in total
Prescription 4:
2000g (based on the compound) of any one of the compounds III or IV
1000 pieces are prepared in total
2. The preparation process comprises the following steps:
(1) performing aseptic treatment on antibiotic glass bottles, rubber plugs and the like used for preparation;
(2) weighing raw materials according to the prescription (charging after conversion), subpackaging the sterile powder in a subpackaging machine, and detecting the packaging amount at any time;
(3) and (4) plugging, capping, fully inspecting finished products, packaging and warehousing.
EXAMPLE four preparation of sterile lyophilized powder for injection of the Compound of the present invention
1. Prescription:
prescription 1:
2. the preparation process comprises the following steps:
(1) preparing a container, namely performing aseptic treatment on antibiotic vials, rubber plugs and the like used for preparation;
(2) preparing a solution, weighing raw materials according to a prescription (feeding after conversion), stirring and dissolving the raw materials in a container by using 500-800 ml of injection water, and simultaneously adjusting the solubility and the pH value by using 10% hydrochloric acid;
(3) filtering to obtain a semi-stoppered solution, filtering the solution, subpackaging, and semi-stoppered;
(4) freeze-drying, plugging, capping, inspecting the finished product, packaging and warehousing.
EXAMPLE five preparation of tablets of the Compound of the invention
1. Prescription:
prescription 1:
prescription 2:
2. the preparation process comprises the following steps:
(1) pulverizing the raw materials, sieving with 100 mesh sieve, and sieving the rest adjuvants with 100 mesh sieve respectively;
(2) weighing raw materials and auxiliary materials according to the prescription amount;
(3) dissolving hydroxypropyl methylcellulose in water to prepare a 2% aqueous solution for later use;
(4) uniformly mixing one of the compounds I, II, III or IV or B, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose, adding a proper amount of 2% HPMC aqueous solution, and uniformly stirring to prepare a proper soft material;
(5) sieving with 20 mesh sieve to obtain granule;
(6) drying the granules at 60 ℃;
(7) adding magnesium stearate, micropowder silica gel and carboxymethyl starch sodium into the dried granules, sieving with a 18-mesh sieve, grading, and mixing uniformly;
(8) sampling and testing a semi-finished product;
(9) tabletting the tablets according to the assay;
(10) and (6) fully inspecting the finished product, and packaging and warehousing.
EXAMPLE sixty preparation of the Compound disinfectant of the present invention
Dissolving the above compound I or II or III or IV with ethanol water mixed solvent to obtain 0.5% -1.0% solution, adding appropriate antiseptic, stabilizer (ethylene glycol, mannitol, etc.), and packaging.
Advantageous effects and effects of the embodiment
The disinfectants of the target compounds I, II, III and IV provided by the embodiment are easy to produce and manufacture, and can be widely used for disinfection and sterilization of hospital surgical instruments and the like.
Accessories
TABLE 7R 1, R2 and X group collocation, yield, melting point, nuclear magnetic hydrogen spectrum and mass spectrometry data for target compound III
TABLE 8 matching of R1, R2 and X groups, yield, melting point, nuclear magnetic hydrogen spectrum and mass spectrum data for the target compound IV
Claims (10)
1. An indole compound has a chemical structure general formula as follows:
wherein,
x is methylene, carbonyl or sulfonyl;
R1is fluorine, chlorine, bromine, methoxyacyl, nitro or hydrogen;
R2is methoxyacyl, (p-methoxyacyl) benzeneA group (p-trifluoroxy) phenyl, (m-methoxyacyl) phenyl, (m-trifluoroxy) phenyl, (p-fluoro-m-chloro) phenyl or hydrogen.
2. The indole compound of claim 1, wherein:
wherein R is1Is p-chloro, p-bromo, p-fluoro, p-methoxyacyl, p-nitro, m-methoxyacyl, m-nitro.
3. The indole compound of claim 1, wherein:
wherein R is25-methoxyacyl, 6-methoxyacyl, 5- (p-methoxyacyl) phenyl, 5- (p-trifluoroxy) phenyl, 5- (p-trifluoro-phenyl), 5- (m-methoxyacyl) phenyl, 5- (m-trifluoro-oxy) phenyl, 5- (p-fluoro-m-chloro) phenyl.
4. The indole compound of claim 1, wherein:
the compound is selected from:
2- [ (1-p-chlorobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-p-fluorophenylmethyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-p-nitrobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-m-nitrobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-p-chlorobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-p-fluorophenylmethyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-p-nitrobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-m-nitrobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-benzoyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-benzoyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine;
2- [ (1-benzenesulfonyl-5- (4-methoxycarbonylphenyl) -3-indole) methylene ] aminoguanidine;
2- [ (1-benzenesulfonyl-5- (3-methoxycarbonylphenyl) -3-indole) methylene ] aminoguanidine;
2- [ (1-benzenesulfonyl-5- (4-trifluoromethoxyphenyl) -3-indole) methylene ] aminoguanidine;
2- [ (1-benzenesulfonyl-5- (3-trifluoromethoxyphenyl) -3-indole) methylene ] aminoguanidine;
2- [ (1-benzenesulfonyl-5- (4-trifluoromethylphenyl) -3-indole) methylene ] aminoguanidine;
2- [ (1-benzenesulfonyl-5- (4-fluoro-3-chlorophenyl) -3-indole) methylene ] aminoguanidine;
1-p-chlorobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-p-fluorobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-p-nitrobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-m-nitrobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-p-chlorobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-p-fluorobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-p-nitrobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-m-nitrobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-benzoyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone;
1-benzoyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone;
1-benzenesulfonyl-5- (4-methoxycarbonylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-benzenesulfonyl-5- (3-methoxycarbonylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-benzenesulfonyl-5- (4-trifluoromethoxyphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-benzenesulfonyl-5- (3-trifluoromethoxyphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-benzenesulfonyl-5- (4-trifluoromethylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone;
1-benzenesulfonyl-5- (4-fluoro-3-chlorophenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinone.
5. A salt of an indole compound characterized by:
the salts are salts (III, IV) obtained by reacting the indole compound of any one of claims 1 to 4 with an inorganic or organic acid, and the structures of the salts are shown as follows:
wherein,
x is methylene, carbonyl or sulfonyl;
R1is fluorine, chlorine, bromine, methoxyacyl, nitro or hydrogen;
R2is methoxyacyl, (p-methoxyacyl) phenyl, (p-trifluoroxy) phenyl, (m-methoxyacyl) phenyl, (m-trifluoroxy) phenyl, (p-fluoro-m-chloro) phenyl or hydrogen;
HA is inorganic acid or organic acid with strong partial acidity.
6. The salt of an indole compound of claim 5, wherein:
wherein, the inorganic acid is any one of sulfuric acid, phosphoric acid, hydrochloric acid and hydrobromic acid, and the organic acid is sulfonic acid.
7. The salt of an indole compound of claim 5, wherein:
the salt of the indole compound is hydrochloride or bromide, and is selected from:
2- [ (1-p-chlorobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-p-fluorophenylmethyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-p-nitrobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-m-nitrobenzyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-p-chlorobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-p-fluorophenylmethyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-p-nitrobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-m-nitrobenzyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-benzoyl-5-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-benzoyl-6-methoxycarbonyl-3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-benzenesulfonyl-5- (4-methoxycarbonylphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-benzenesulfonyl-5- (3-methoxycarbonylphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-benzenesulfonyl-5- (4-trifluoromethoxyphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-benzenesulfonyl-5- (3-trifluoromethoxyphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-benzenesulfonyl-5- (4-trifluoromethylphenyl) -3-indole) methylene ] aminoguanidine hydrochloride;
2- [ (1-benzenesulfonyl-5- (4-fluoro-3-chlorophenyl) -3-indole) methylene ] aminoguanidine hydrochloride;
1-p-chlorobenzyl-5-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-p-fluorobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-p-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-m-methoxycarbonylbenzyl-5-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-p-nitrobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;
1-m-nitrobenzyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;
1-p-chlorobenzyl-6-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-p-fluorobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-p-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-m-methoxycarbonylbenzyl-6-methoxycarbonyl-3-indolylal, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-p-nitrobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;
1-m-nitrobenzyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;
1-benzoyl-5-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-benzoyl-6-methoxycarbonyl-3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-benzenesulfonyl-5- (4-methoxycarbonylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-benzenesulfonyl-5- (3-methoxycarbonylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-benzenesulfonyl-5- (4-trifluoromethoxyphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-benzenesulfonyl-5- (3-trifluoromethoxyphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazinoketone hydrogen bromide;
1-benzenesulfonyl-5- (4-trifluoromethylphenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide;
1-benzenesulfonyl-5- (4-fluoro-3-chlorophenyl) -3-indolecarboxaldehyde, (4, 5-dihydro-1H-imidazol-2-yl) hydrazonone hydrogen bromide.
8. A process for the preparation of a salt of an indole of the formula (iii, iv) as defined in any one of claims 5 to 7 and a salt of an indole of the formula (iii, iv) as defined in any one of claims 1 to 4, which comprises reacting a compound of the formula (v) with a compound of the formula (vi) in a dry, anhydrous polar solvent to obtain a salt of an indole of the formula (iii, iv); the indole compounds of the formulas (III and IV) can be obtained by alkalifying the salt of the indole compounds of the formulas (III and IV) with alkali
Wherein,
x is methylene, carbonyl or sulfonyl;
R1is fluorine, chlorine, bromine, methoxyacyl, nitro or hydrogen;
R2is methoxyacyl, (p-methoxyacyl) phenyl, (p-trifluoroxy) phenyl, (m-methoxyacyl) phenyl, (m-trifluoroxy) phenyl, (p-fluoro-m-chloro) phenyl or hydrogen;
HA is inorganic acid or organic acid with strong partial acidity,
the inorganic acid is preferably any one of sulfuric acid, phosphoric acid, hydrochloric acid and hydrobromic acid,
the organic acid is preferably a sulfonic acid.
9. The process according to claim 8 for the preparation of the salts of indoles of formula (iii, iv) as claimed in any one of claims 5 to 7 and of indoles of formula (iii, iv) as claimed in any one of claims 1 to 4, characterized in that:
wherein the polar solvent is any one or a mixed solvent of methanol, ethanol, acetonitrile and N, N-dimethylformamide,
the temperature of the mixing reaction is room temperature or reflux temperature.
10. An anti-drug-resistant bacteria pharmaceutical composition or disinfectant, characterized in that:
wherein the pharmaceutical composition or disinfectant comprises the indole compound according to any one of claims 1 to 4, or a salt of the indole compound according to any one of claims 5 to 7.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610002989.9A CN105669519B (en) | 2016-01-04 | 2016-01-04 | Benzazole compounds, preparation method and its application as drug-resistance bacteria medicine |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610002989.9A CN105669519B (en) | 2016-01-04 | 2016-01-04 | Benzazole compounds, preparation method and its application as drug-resistance bacteria medicine |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105669519A true CN105669519A (en) | 2016-06-15 |
CN105669519B CN105669519B (en) | 2018-01-05 |
Family
ID=56298818
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610002989.9A Expired - Fee Related CN105669519B (en) | 2016-01-04 | 2016-01-04 | Benzazole compounds, preparation method and its application as drug-resistance bacteria medicine |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105669519B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107522650A (en) * | 2017-09-19 | 2017-12-29 | 井冈山大学 | N Benzenesulfonylindole contracting amino guanidine antimicrobial compounds and preparation method thereof |
EP3388445A1 (en) * | 2017-04-10 | 2018-10-17 | F. Hoffmann-La Roche AG | Peptide macrocycles and use thereof in the treatment of bacterial infections |
CN114621214A (en) * | 2022-04-25 | 2022-06-14 | 宜春学院 | Antibacterial Schiff base N-acylate and preparation method and application thereof |
CN117185983A (en) * | 2023-06-05 | 2023-12-08 | 浙江工业大学 | Bisoxindole compound, preparation method thereof and application thereof in preparation of antibacterial agent |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1378542A (en) * | 1999-10-08 | 2002-11-06 | 史密丝克莱恩比彻姆公司 | FAB I inhibitors |
CN101652346A (en) * | 2007-02-01 | 2010-02-17 | 约瑟夫·傅立叶大学 | Novel indole derivative, its preparation method with and uses thereof, especially as the purposes of antiseptic-germicide |
CN102883602A (en) * | 2010-02-16 | 2013-01-16 | Uwm研究基金会有限公司 | Methods of reducing virulence in bacteria |
CN103958514A (en) * | 2011-04-15 | 2014-07-30 | 梅琳塔治疗公司 | Antimicrobial compounds and methods of making and using the same |
-
2016
- 2016-01-04 CN CN201610002989.9A patent/CN105669519B/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1378542A (en) * | 1999-10-08 | 2002-11-06 | 史密丝克莱恩比彻姆公司 | FAB I inhibitors |
CN101652346A (en) * | 2007-02-01 | 2010-02-17 | 约瑟夫·傅立叶大学 | Novel indole derivative, its preparation method with and uses thereof, especially as the purposes of antiseptic-germicide |
CN102883602A (en) * | 2010-02-16 | 2013-01-16 | Uwm研究基金会有限公司 | Methods of reducing virulence in bacteria |
CN103958514A (en) * | 2011-04-15 | 2014-07-30 | 梅琳塔治疗公司 | Antimicrobial compounds and methods of making and using the same |
Non-Patent Citations (1)
Title |
---|
叶英,等.: "吲哚-6-酰腙类化合物的微波合成及其抗菌活性研究", 《有机化学》 * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3388445A1 (en) * | 2017-04-10 | 2018-10-17 | F. Hoffmann-La Roche AG | Peptide macrocycles and use thereof in the treatment of bacterial infections |
WO2018189063A1 (en) * | 2017-04-10 | 2018-10-18 | F. Hoffmann-La Roche Ag | Peptide macrocycles and use thereof in the treatment of bacterial infections |
CN110494442A (en) * | 2017-04-10 | 2019-11-22 | 豪夫迈·罗氏有限公司 | The big ring of peptide and its purposes in treatment bacterium infection |
JP2020513039A (en) * | 2017-04-10 | 2020-04-30 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | Peptide macrocycles and their use in the treatment of bacterial infections |
US11091514B2 (en) | 2017-04-10 | 2021-08-17 | Hoffmann-La Roche Inc. | Peptide macrocycles and use thereof in the treatment of bacterial infections |
JP7155240B2 (en) | 2017-04-10 | 2022-10-18 | エフ.ホフマン-ラ ロシュ アーゲー | Peptide macrocycles and their use in treating bacterial infections |
CN110494442B (en) * | 2017-04-10 | 2023-07-25 | 豪夫迈·罗氏有限公司 | Peptide macrocycles and their use in the treatment of bacterial infections |
CN107522650A (en) * | 2017-09-19 | 2017-12-29 | 井冈山大学 | N Benzenesulfonylindole contracting amino guanidine antimicrobial compounds and preparation method thereof |
CN114621214A (en) * | 2022-04-25 | 2022-06-14 | 宜春学院 | Antibacterial Schiff base N-acylate and preparation method and application thereof |
CN114621214B (en) * | 2022-04-25 | 2024-04-26 | 宜春学院 | Antibacterial Schiff base N-acylate, and preparation method and application thereof |
CN117185983A (en) * | 2023-06-05 | 2023-12-08 | 浙江工业大学 | Bisoxindole compound, preparation method thereof and application thereof in preparation of antibacterial agent |
Also Published As
Publication number | Publication date |
---|---|
CN105669519B (en) | 2018-01-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105669519B (en) | Benzazole compounds, preparation method and its application as drug-resistance bacteria medicine | |
EP2428508B9 (en) | Diamino heterocyclic carboxamide compound | |
CN102316735A (en) | The micromolecular inhibitor of gangrenosum acne apoptosis | |
JP2017061578A (en) | Organic compound | |
CN109942546B (en) | Quinolone pyrimidine compound and preparation method and application thereof | |
EA020733B1 (en) | Actagardine derivatives | |
JPH0780842B2 (en) | Distamycin derivatives and methods for producing them | |
CN109574947A (en) | The Oxazolidinone derivative and preparation method thereof of the structure of hydrazone containing biaryl | |
CN105218427B (en) | Two amidine analog derivatives containing double amidino groups indoles benzene and its preparation method and application | |
CN106632133B (en) | Thiazole derivative and the preparation method and application thereof | |
CN110526910B (en) | Thiazole orange benzyl quaternary ammonium salt derivative and preparation method and application thereof | |
CN105367558B (en) | Andrographolidume derivative and its preparation method and application | |
CN105130960B (en) | 1,3,5- triazine derivatives and its application | |
CN113045494B (en) | Pyridone derivative and application thereof in preparation of drugs for preventing and/or treating tuberculosis caused by mycobacterium tuberculosis | |
CN102603738B (en) | Stable moxifloxacin hydrochloride compound | |
CN109851611B (en) | Sulfadiazine compound and preparation method and application thereof | |
WO2021244416A1 (en) | Pyridinyl morpholine compound, preparation method therefor, and application thereof | |
US9920039B2 (en) | 1,2,4-Oxadiazol compounds active against gram-positive pathogens | |
CN109111396B (en) | Quinoline aromatic vinyl derivative and preparation method and application thereof | |
Rajasekaran et al. | Synthesis, antitubercular, antibacterial and antioxidant activity of some 2-phenyl-3-substituted quinazolin-4 (3H)-ones | |
CN110437177A (en) | A kind of pleuromutilin derivative and its preparation method and application | |
CN103304556B (en) | Schiff bases compounds containing chromene, Preparation Method And The Use | |
CN103467448B (en) | 7-(3-amino-4-alcoxylimido-1-piperidyl)-1-[(1R, 2S)-2-fluoro-cyclopropyl] quinolone carboxylic acid compounds and preparation methods thereof | |
CN112209881B (en) | Emodin oxazole compound and preparation method and application thereof | |
CN112194631B (en) | Schiff base bridged sulfaimidazole compound and preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180105 Termination date: 20200104 |
|
CF01 | Termination of patent right due to non-payment of annual fee |