CN114835691A - 一种苯并咪唑衍生物及其用途 - Google Patents
一种苯并咪唑衍生物及其用途 Download PDFInfo
- Publication number
- CN114835691A CN114835691A CN202110135739.3A CN202110135739A CN114835691A CN 114835691 A CN114835691 A CN 114835691A CN 202110135739 A CN202110135739 A CN 202110135739A CN 114835691 A CN114835691 A CN 114835691A
- Authority
- CN
- China
- Prior art keywords
- acid
- pharmaceutically acceptable
- benzimidazole derivative
- acceptable salt
- reaction
- 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.)
- Pending
Links
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 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
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000002207 metabolite Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 25
- 239000003814 drug Substances 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 11
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 208000005176 Hepatitis C Diseases 0.000 abstract description 5
- 101800001014 Non-structural protein 5A Proteins 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 51
- 239000000243 solution Substances 0.000 description 38
- 239000012074 organic phase Substances 0.000 description 25
- 239000000543 intermediate Substances 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 238000005406 washing Methods 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000005457 ice water Substances 0.000 description 15
- 239000012141 concentrate Substances 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 101710188663 Non-structural protein 5a Proteins 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 230000008034 disappearance Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 239000007821 HATU Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 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 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 101150003085 Pdcl gene Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 101710172711 Structural protein Proteins 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 230000003472 neutralizing effect Effects 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 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 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 238000011001 backwashing Methods 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 2
- 229940096397 interleukin-8 Drugs 0.000 description 2
- 231100000053 low toxicity Toxicity 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
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 150000004841 phenylimidazoles Chemical class 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- -1 plasters Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- VDZXAOBGHPKGCS-UHFFFAOYSA-M sodium;1,4-dioxane;hydroxide Chemical compound [OH-].[Na+].C1COCCO1 VDZXAOBGHPKGCS-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 229960004295 valine Drugs 0.000 description 2
- 230000029812 viral genome replication Effects 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- BSAYEGDCKUEPNE-YUMQZZPRSA-N (2s,5s)-5-methyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C[C@H]1CC[C@@H](C(O)=O)N1C(=O)OC(C)(C)C BSAYEGDCKUEPNE-YUMQZZPRSA-N 0.000 description 1
- KTZVZZJJVJQZHV-UHFFFAOYSA-N 1-chloro-4-ethenylbenzene Chemical compound ClC1=CC=C(C=C)C=C1 KTZVZZJJVJQZHV-UHFFFAOYSA-N 0.000 description 1
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- WIHHVKUARKTSBU-UHFFFAOYSA-N 4-bromobenzene-1,2-diamine Chemical compound NC1=CC=C(Br)C=C1N WIHHVKUARKTSBU-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 101100393871 Arabidopsis thaliana GT12 gene Proteins 0.000 description 1
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241000872931 Myoporum sandwicense Species 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010058874 Viraemia Diseases 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- LJHFUFVRZNYVMK-CYBMUJFWSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3R)-3-hydroxypyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@@H](CC1)O LJHFUFVRZNYVMK-CYBMUJFWSA-N 0.000 description 1
- LJHFUFVRZNYVMK-ZDUSSCGKSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3S)-3-hydroxypyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@H](CC1)O LJHFUFVRZNYVMK-ZDUSSCGKSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 229960000458 allantoin Drugs 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229940092738 beeswax Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 description 1
- 229910000020 calcium bicarbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- SHWNNYZBHZIQQV-UHFFFAOYSA-L calcium;disodium;2-[2-[bis(carboxylatomethyl)azaniumyl]ethyl-(carboxylatomethyl)azaniumyl]acetate Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-L 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ORPJQSFBLBHKPN-UHFFFAOYSA-N dichloromethane;methylsulfinylmethane Chemical compound ClCCl.CS(C)=O ORPJQSFBLBHKPN-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 102000010982 eIF-2 Kinase Human genes 0.000 description 1
- 108010037623 eIF-2 Kinase Proteins 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical class OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 235000006109 methionine Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 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
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003376 silicon Chemical class 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940045136 urea Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 230000004572 zinc-binding Effects 0.000 description 1
Images
Classifications
-
- 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
- C07D403/14—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 three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Landscapes
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种苯并咪唑衍生物及其用途，所述苯并咪唑衍生物具有NS5A抑制活性并且可用于丙肝药物或缓解性药物的化合物，具体来说，本发明提供一种如式I所示的苯并咪唑衍生物或其药学上可接受的盐：L1a‑M1a‑C(＝O)‑Q1a‑T1a‑Q1b‑C(＝O)‑M1b‑L1b(I)。
Description
技术领域
本发明属于药物化学领域，具体涉及一类苯基咪唑衍生物及其用途，特别是作为通过抑制非结构蛋白5A复制发挥抑制HCV病毒复制的用途，所涉及的生物标志物包括但不限于NS5A(非结构蛋白5A)。
背景技术
据世界卫生组织(WHO)公布，全球约有8000万(6400万～1.3亿)慢性丙型肝炎患者，其病毒血症发病率(HCV RNA阳性)约为1.1％。全球抗-HCV流行率(提示既往病毒血症感染)为1.6％，对应人口为1.5亿(9200万-1.49亿)。每年约有70万人死于丙型肝炎相关并发症，包括肝硬化和肝癌等。HCV的高发区包括非洲西部、欧洲东部和亚洲中部。
新的直接抗病毒小分子药物(DAAs)的问世预示着消灭丙型肝炎的时代即将到来。然而，不同基因型HCV的分布各不相同，直接影响了治疗的决策。如基因1型和2型主要分布在北美、日本和欧洲，基因3型主要分布在非洲东南部和印度。在中东和非洲南部地区，最常见的分别是基因4型和5型。中国的HCV基因型主要包括4种基因型、9个亚型，其中最为常见的是基因1型(69.6％)，汉族感染基因6型的人群主要分布在我国南部和西部。治疗方面，随着治疗手段和药物的进展和开发，自上世纪八十年代至今，HCV的持续病毒学应答(SVR)率在不断上升。
NS5A也属于乙肝病毒的非结构蛋白，而且是一种高度磷酸化的非结构蛋白，不具备酶催化活性，其磷酸化水平在HCV基因组的复制和翻译过程中也起着调节的作用。NS5A非结构蛋白含有447个氨基酸，有3个不同的结构域。结构域I(氨基酸序列:1-213)由一个高度保守的两性α-螺旋和一个疏水的侧链及带电的侧链组成，是NS5A与RNA结合的重要区域。其晶体结构(图2)显示它是一个二聚体，有一个包含四个半胱氨酸残基(Cys39、Cys57、Cys59、Cys80)的锌结合区域，此区域对蛋白的稳定性起着重要作用。结构域II(氨基酸序列:250-342)和结构域III(氨基酸序列：356-447)也对病毒的复制和组装有着重要作用。
NS5A可以诱导白细胞介素-8(IL-8)的表达，从而使HCV对α-干扰素的抗病毒作用产生抑制。同时，NS5A蛋白上的干扰素敏感性决定位点(interferon sensitivitydeterminingregion，ISDR)可以通过与依赖RNA的蛋白激酶(PKR)结合抑制细胞对α-干扰素的应答过程，而且NS5A的磷酸化水平在HCV基因组的复制和翻译过程中也起着调节的作用，NS5A功能的重要性和多样性使它成为抗HCV的重要靶点。
目前随着泛基因型抗HCV药物进入临床和上市，针对抗HCV的药物研发进入快车道，提供高效、低毒全新结构的药物化合物是必要的。
发明内容
本发明提供了一类具有NS5A抑制活性并且可用于丙肝药物或缓解性药物的化合物。
具体来说，本发明提供一种如式I所示的苯并咪唑衍生物或其药学上可接受的盐：
L1a-M1a-C(＝O)-Q1a-T1a-Q1b-C(＝O)-M1b-L1b
(I)
其中：T1a为
或在任意一个位置被一个或多个卤素、烷基、卤代烷基的基团取代；
X是-CH＝CH-；
其中，Q1a是：
Q1b是
M1a是：
M1b是：
L1a是-N(H)(烷氧基羰基)、-N(H)C(＝O)CH3；
L1b是-N(H)(烷氧基羰基)、-N(H)C(＝O)CH3；
优选的，本发明所述的苯并咪唑衍生物或其药学上可接受的盐，具有通式(II)的结构：
优选的，本发明所述苯并咪唑衍生物选自以下化合物：
其中，本发明所述的苯并咪唑衍生物药学上可接受的盐，为本发明苯并咪唑衍生物与下列酸形成的盐：盐酸、对甲苯磺酸、酒石酸、马来酸、乳酸、甲磺酸、硫酸、磷酸、柠檬酸、乙酸或三氟乙酸。
优选的，所述的酸为对甲苯磺酸、盐酸、酒石酸或三氟乙酸。
本发明所述的苯并咪唑衍生物药学上可接受的盐进一步包括它们的溶剂化物，代谢物前药等。
本发明提供的苯并咪唑衍生物对HCV抑制活性进行评价，结果表明这类化合物具有很好的抗HCV活性。
本发明提供的苯并咪唑衍生物具有很好的抗HCV活性，开拓了一类新型丙肝药物的研究方向。
本发明还提供一种含有本发明所述衍生物或其药学上可接受的盐的药物组合物。
本发明的药物组合物，优选的是单位剂量的药物制剂形式，在制成药物制剂时可以制成任何可药用的剂型，这些剂型选自：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、混悬剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、贴剂。优选的是口服制剂形式，最佳优选的是片剂，胶囊剂。
进一步的，本发明所述药物组合物还含有药学上可接受的载体。
可以采用制剂学常规技术制备该药物制剂，所述药学上可接受的的载体包括但不限于：甘露醇、山梨醇、山梨酸或钾盐、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素A、维生素C、维生素E、维生素D、氮酮、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、丙二醇、乙醇、土温60-80、司班-80、蜂蜡、羊毛脂、液体石蜡、十六醇、没食子酸酯类、琼脂、三乙醇胺、碱性氨基酸、尿素、尿囊素、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β－环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的药物组合物，在制成药剂时，单位剂量的药剂可含有本发明的药物活性物质0.1-1000mg，其余为药学上可接受的载体。药学上可接受的载体以重量计可以是制剂总重量的0.1-99.9％。
本发明的药物组合物在使用时根据病人的情况确定用法用量。
本发明还包括所述苯并咪唑衍生物、或其药学上可接受的盐在制备与NS5A相关的疾病的药物中的用途。所述与NS5A相关的疾病包括但不限于丙型肝炎。本发明所述的苯并咪唑衍生物，可以采用以下制备方法制备：
方案一：
方案一中，以左旋苯甘氨酸和L-缬氨酸为原料与3氯甲酸甲酯在碱性条件下反应，得到中间体1-1和1-2。
方案二：
方案二中，以1-3为起始原料，依次经过取代、还原、水解、环合，溴代、脱保护等反应得到关键这中间体1-10。
方案三：
方案三中，以(2S,5S)-N-Boc-5-甲基吡咯烷-2-甲酸为原料经过缩合、环合、Heck偶联、Suzuki偶联、氧化等反应，得到中间体1-16。
方案四：
方案四中，以1-19为原料经过缩合、Suzuki偶联等反应，得到目标化合物1、2、3、4。
有益效果：
本发明提供了结构新颖高效、低毒的新化合物。
本发明的新化合物的特点在于：(1)在细胞水平上的活性优异，其针对基因型1a和1b的IC50可以达到40pM以下；(2)所述化合物可以作为NS5A抑制剂用于丙肝药物。
附图说明：
图1.化合物1的1H-NMR谱图
图2.化合物2的1H-NMR谱图
图3化合物3的1H-NMR谱图
图4.化合物4的1H-NMR谱图
具体实施方式：
下面结合具体实施例对本发明作进一步的说明。
实施例1：中间体1-1和1-2的合成
中间体1-1的合成
将左旋苯甘氨酸5g(33mmol，1equiv)加入到圆底烧瓶中，然后加入30ml5％1,4-二氧六环氢氧化钠水溶液，再加入氯甲酸甲酯3.75g(39.7mmol，1.2equiv)。将反应液加热到60℃反应12h。反应在结束后将反应液倒入冰水中，滴加2M稀盐酸酸化至中性，乙酸乙酯萃取，静置后分取有机层，依次用水、饱和食盐水洗涤，无水硫酸钠干燥，然后浓缩；浓缩物用硅胶柱层析分离两次(PE，200-300目)，得到5.6g产品即1-1。MS(ESI):m/z＝210.12[M+1]+，1H NMR:400MHz DMSOδ12.85(s,1H),7.42(d,J＝8Hz,1H),7.41-7.28(m,5H),5.14-5.12(d,J＝8Hz,1H),3.55(s,3H).
中间体1-2的合成
将L-缬氨酸4g(34mmol，1equiv)加入到圆底烧瓶中，然后加入30ml 5％1,4-二氧六环氢氧化钠水溶液，再加入氯甲酸甲酯3.87g(40.9mmol，1.2equiv)。将反应液加热到60℃反应12h。反应在结束后将反应液倒入冰水中，滴加2M稀盐酸酸化至中性，乙酸乙酯萃取，静置后分取有机层，依次用水、饱和食盐水洗涤，无水硫酸钠干燥，然后浓缩；浓缩物用硅胶柱层析分离两次(PE，200-300目)，得到5.1g产品即1-1。MS(ESI):m/z＝176.222[M+1]+，1HNMR:400MHz CDCl3δ5.13-5.10(d,J＝12Hz,1H),4.27-4.24(m,1H),3.63(s,3H),2.19-2.12(m,1H),0.95-0.88(m,6H).
实施例2：中间体1-10的合成
化合物1-10的合成
将50g 1-3(182.9mmol，1equiv)加入到250ml圆底烧瓶中，然后加入100ml10％氢氧化锂水溶液，将反应液50℃反应6h，TLC检测反应完全后，将反应液倒入冰水混合物中，滴加2M稀盐酸至酸性，乙酸乙酯萃取，以饱和食盐水洗涤有机层，减压浓缩，浓缩物以硅胶柱层析分离(200-300，PE:EA＝5:1)，得到产品42g即为1-4。MS(ESI):m/z＝274.29[M+H]+.
将40g化合物1-4(154mmol，1equiv)加入到500ml三口瓶中，然后加入80ml无水四氢呋喃，冰浴下加入100ml 1.6mol/L而甲硫醚硼烷溶液，氩气保护下将反应液在80℃反应3h，将反应液在冰浴下淬灭，将混合物真空中减压浓缩，浓缩物以硅胶柱层析分离得到油状物29.6g即为化合物1-5。MS(ESI):m/z＝246.29[M+H]+.
将29g 1-5(118mmol，1equiv)加入到250ml圆底烧瓶中，然后加入21g TEA(142mmol，1.2equiv)，-70℃下加入15.7g草酰氯(124mmol，1.05equiv)，最后加入DMSO二氯甲烷溶液30ml(11.8mmol，0.1equiv)，将反应液-70℃下反应4h，TLC检测反应完全后，将反应液倒入冰水混合物中，饱和碳酸氢钠中和，乙酸乙酯萃取，以饱和食盐水洗涤有机层，减压浓缩，浓缩物以硅胶柱层析分离(200-300，PE:EA＝10:1)，得到油状物21g即为1-6。
将21g 1-6(86.3mmol，1equiv)加入到250ml圆底烧瓶中，然后加入40ml 7M NH3/MeOH溶液，冰浴下加入7.5g乙二醛(129mmol，1.5equiv)，将反应液0-25℃反应4h，TLC检测反应完全后，将反应液倒入冰水混合物中，乙酸乙酯萃取，以饱和食盐水洗涤有机层，减压浓缩，浓缩物以pre-HPLC分离，得到产品16g即为1-7。MS(ESI):m/z＝282.31[M+H]+.
将16g 1-7(56.9mmol，1equiv)加入到250ml圆底烧瓶中，然后加入80ml二氯甲烷，-15℃下加入11.1g NBS(62.6mmol，1.1equiv)，将反应液-15℃反应2h，TLC检测反应完全后，将反应液倒入冰水混合物中，二氯甲烷萃取，以饱和食盐水洗涤有机层，减压浓缩，浓缩物以pre-HPLC分离，得到产品10g即为1-8。MS(ESI):m/z＝439.05[M+H]+.
将16g 1-8(36.4mmol，1equiv)加入到100ml圆底烧瓶中，然后加入40ml Ethanol/H2O溶液(3:7)，然后加入6.89g亚硫酸钠(54.7mmol，1.5equiv)，将反应液80℃反应12h，TLC检测反应完全后，将反应液倒入冰水混合物中，乙酸乙酯萃取，以饱和食盐水洗涤有机层，减压浓缩，浓缩物以硅胶柱层析分离(200-300，PE:EA：DCM＝10:1:1)，得到油状物5.1g即为1-9。MS(ESI):m/z＝360.0[M+H]+.1H NMR:400MHz DMSO-d6 δ12.21-12.16(d,1H),7.12-7.09(d,1H),4.69-4.61(m,1H),3.64-3.56(m,1H),3.34-3.32(d,2H),3.23(s,3H),3.14-3.09(t,1H),2.46-2.40(m,2H),2.33-2.26(m,1H),1.28(s,9H).
将5g 1-9(13.9mmol，1equiv)加入到100ml圆底烧瓶中，然后加入30ml Ethanol/HCl溶液(1M)，将反应液60℃反应6h，TLC检测反应完全后，将反应液倒入冰水混合物中，乙酸乙酯萃取，以饱和食盐水洗涤有机层，减压浓缩，浓缩物以硅胶柱层析分离(200-300，PE:EA：DCM＝10:1:1)，得到油状物3.4g即为1-10。MS(ESI):m/z＝260.1[M+H]+.1H NMR:400MHzDMSO-d6 δ10.43(s,1H),9.37(s,1H),7.41-7.39(d,1H),4.74-4.70(m,1H),3.41-3.37(m,3H),3.27-3.26(d,3H),3.16(s,2H),3.06-3.01(m,1H),2.68-2.64(t,1H),2.47-2.42(m,1H),1.98-1.90(m,1H).
实施例3：中间体1-16的合成
将5g化合物1-11(21.8mmol，1equiv)、8.3g的HATU(21.8mmol，1equiv)、11.3gDIPEA(87.2mmol，4equiv)和10ml N,N-二甲基甲酰胺放入100ml圆底烧瓶中，然后再加入6.1g 4-溴邻苯二胺(32.7mmol，1.5equiv)，氩气保护下于室温下反应过夜，将反应液倒入冰水中，乙酸乙酯萃取，有机相减压浓缩，浓缩物以硅胶柱层析分离得到8g化合物1-12。直接进行下步反应。
将8g 1-12(20mmol，1equiv)加入100ml圆底烧瓶中，然后再加入40ml无水乙醇，氩气保护下于100℃下反应16h，将反应液倒入冰水中，乙酸乙酯萃取，有机相减压浓缩，浓缩物以硅胶柱层析分离得到5.2g化合物1-13。MS(ESI):m/z＝380.1[M+H]+，直接进行下步反应。
将5g 1-13(13.1mmol，1equiv)、0.24g的乙酸钯(1.05mmol，0.08equiv)、3.1gXPhos(6.6mmol，0.5equiv)、2.2g的4-氯苯乙烯(15.7mmol，1.2equiv)和15ml 1,4-二氧六环装入微波反应管中，氩气保护下于130℃下反应30min，将反应液倒入冰水中，乙酸乙酯萃取，有机相减压浓缩，浓缩物以硅胶柱层析分离得到3.6g 1-14，MS(ESI):m/z＝438.2[M+H]+。
将3.6g 1-14(8.2mmol，1equiv)、0.6g的Pd2(dba)3(0.65mmol，0.08equiv)、1.9gXPhos(4.1mmol，0.5equiv)、1.2g乙酸钾(12.3mmol，1.5equiv)、2.5g的联硼酸频那醇酯(9.9mmol，1.2equiv)和15ml 1,4-二氧六环装入微波反应管中，氩气保护下于130℃下反应30min，将反应液倒入冰水中，乙酸乙酯萃取，有机相减压浓缩，浓缩物以硅胶柱层析分离得到3.7g 1-15，MS(ESI):m/z＝530.4[M+H]+。
将3.7g 1-15(7mmol，1equiv)、3g的NaIO4(14mmol，2equiv)和30ml四氢呋喃水溶液加入100ml圆底烧瓶中，氩气保护下于室温下反应16h，将反应液倒入冰水中，乙酸乙酯萃取，有机相减压浓缩，浓缩物以硅胶柱层析分离得到2.4g 1-16，MS(ESI):m/z＝448.3[M+H]+，1H NMR:400MHz CD3OD δ7.73(s,1H),7.65-7.63(d,2H),7.59-7.56(d,4H),7.39-7.35(d,1H),7.22-7.18(d,1H),4.93(s,1H),4.13-4.06(m,1H),2.40-2.18(m,3H),1.76-1.72(m,1H),1.47(s,6H),1.20(s,6H).
实施例4：化合物1的合成
将0.2g中间体1-10溶于2ml N,N-二甲基甲酰胺中，然后加入0.1g DIPEA，再加入0.29g HATU，冰浴下加入0.19g中间体1-1，将反应液于室温下反应2h，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，萃取，加入约50ml乙酸乙酯，用水洗三次(水的总量约30ml)，有机相再用饱和NaCl溶液洗一次，有机相旋干，拌样，柱层析分离(二氯甲烷：甲醇＝60：1)，真空干燥30分钟，得到微黄色固体0.28g，即化合物1-18。MS(ESI):m/z＝451.14[M+H]+，1H NMR:400MHz CDCl3 δ7.40-7.37(m,5H),6.94(s,1H),6.00-5.96(d,1H),5.20-5.17(t,1H),3.66(s,3H),3.55-3.51(m,1H),3.43-3.39(m,1H),3.35-3.32(m,1H),3.25(s,3H),3.18-3.16(m,1H),2.61-2.58(m,1H),2.34-2.27(m,2H).
将0.6g中间体1-16加入到100ml圆底烧瓶中，然后加入15ml二氯甲烷，冰浴下滴加TFA的DCM溶液(7.5ml DCM和7.5ml TFA)，之后室温搅拌1h，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，将反应液倒入冰水中，NaHCO3中和至中性，乙酸乙酯萃取，然后有机相用饱和NaCl溶液反洗一次，有机相旋干，得到淡黄色固体450mg，即中间体1-19，直接下步反应。
将0.3g中间体1-19加入到50ml圆底烧瓶中，然后加入4ml N,N-二甲基甲酰胺，再加入0.11g DIPEA、0.33g HATU，冰浴下加入0.18g中间体1-2，将反应液于室温反应2小时，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，拌样，柱层析分离(二氯甲烷：甲醇＝40：1)，真空干燥30分钟，得到白色固体164mg，即1-21。MS(ESI):m/z＝505.19[M+H]+，1H NMR:400MHzDMSO δ8.08(s,2H),7.80-7.78(d,2H),7.58-7.53(m,3H),7.44-7.40(d,1H),7.24-7.20(d,2H),5.10-5.06(t,1H),4.73-4.70(t,1H),3.55(s,3H),2.33(m,2H),1.86(m,2H),1.44(m,2H),1.35(s,3H),1.28-1.23(m,3H),0.87-0.86(d,3H),0.74-0.73(d,2H).
将49mg 1-18、60mg 1-21、4mg PdCl2(dppf)、15mg KOAc和2ml 1,4-dioxane放入微波反应管中，氮气保护，135℃微波反应30min，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，拌样，柱层析分离(二氯甲烷：甲醇＝20：1)，得到褐色固体23mg，即化合物1。MS(ESI):m/z＝829.24[M-H]-，1H NMR:400MHz CDCl3 δ7.69-7.67(m,3H),7.55-7.39(m,9H),7.26-7.05(t,3H),5.97-5.93(d,1H),5.41-5.35(m,3H),4.68(s,1H),4.27-4.22(m,1H),3.81(s,1H),3.71-3.56(m,6H),3.42-3.37(m,1H),3.26-3.23(m,5H),2.43-1.99(m,8H),1.27-1.26(d,3H),1.18-1.16(d,1H),1.10-1.04(dd,2H),0.99-0.97(d,2H),0.82-0.80(d,2H).
实施例5：化合物2的合成
将0.2g中间体1-10溶于2ml N,N-二甲基甲酰胺中，然后加入0.1g DIPEA，再加入0.29g HATU，冰浴下加入0.16g中间体1-2，将反应液于室温下反应2h，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，用水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，拌样，柱层析分离(二氯甲烷：甲醇＝60：1)，真空干燥30分钟，得到微黄色固体0.26g，即化合物1-17。MS(ESI):m/z＝417.15[M+H]+，1H NMR:400MHz CDCl3 δ6.92(s,1H),4.39-4.35(m,1H),4.07-4.06(d,1H),3.75-3.68(m,1H),3.67(s,3H),3.56-3.52(m,1H),3.34(s,3H),3.29-3.24(m,1H),3.20-3.15(m,1H).
将0.6g中间体1-16加入到100ml圆底烧瓶中，然后加入15ml二氯甲烷，冰浴下滴加TFA的DCM溶液(7.5ml DCM和7.5ml TFA)，之后室温搅拌1h，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，将反应液倒入冰水中，NaHCO3中和至中性，乙酸乙酯萃取，然后有机相用饱和NaCl溶液反洗一次，有机相旋干，得到淡黄色固体450mg，即中间体1-19，直接下步反应。
将0.15g中间体1-19加入到25ml圆底烧瓶中，然后加入2ml N,N-二甲基甲酰胺，再加入56mg DIPEA、0.16g HATU，冰浴下加入0.1g中间体1-1，将反应液于室温反应2h，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，拌样，柱层析分离(二氯甲烷：甲醇＝40：1)，真空干燥30分钟，得到白色固体120mg，即1-20。MS(ESI):m/z＝539.30[M+H]+，1H NMR:400MHz DMSO δ12.26(s,1H),8.21(s,1H),8.04(s,2H),7.86-7.79(m,2H),7.58-7.44(m,3H),7.41-7.36(m,5H),7.23-7.19(d,1H),6.97-6.93(d,1H),5.58-5.54(t,1H),4.17-4.02(m,1H),3.62-3.57(m,1H),3.53(s,3H),3.15-3.12(m,1H),2.34-2.27(m,2H),1.82-1.74(m,1H),1.47-1.45(d,2H),1.27-1.24(t,3H).
将42mg 1-17、60mg 1-20、4mg PdCl2(dppf)、14mg KOAc和2ml 1,4-dioxane放入微波反应管中，氮气保护，135℃微波反应30min，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，柱层析分离(二氯甲烷：甲醇＝20：1)，得到深棕色固体20mg，即化合物2。MS(ESI):m/z＝829.51[M-H]-，1H NMR:400MHz CDCl3 δ7.64-7.61(m,2H),7.55-7.49(m,3H),7.44-7.39(m,6H),7.37-7.35(d,2H),7.25-7.21(d,1H),7.14-7.10(d,1H),5.92-5.90(d,1H),5.50-5.42(m,3H),4.11-4.07(m,2H),3.72(s,5H),3.27-3.22(m,1H),2.99(s,1H),2.48(s,1H),2.11-2.05(m,1H),1.84-1.43(m,9H),1.33-1.32(d,4H),1.25(s,4H).
实施例6：化合物3的合成
将38mg 1-18、50mg 1-20、3mg PdCl2(dppf)、12mg KOAc和2ml 1,4-dioxane放入微波反应管中，氮气保护，135℃微波反应30min，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，柱层析分离(二氯甲烷：甲醇＝20：1)，得到深褐色固体20mg，即化合物3。MS(ESI):m/z＝863.45[M-H]-，1H NMR:400MHz CDCl3 δ7.71-7.69(m,2H),7.56-7.52(m,2H),7.48-7.40(m,10H),7.25-7.05(m,2H),5.99-5.92(m,1H),5.52-5.39(m,3H),4.06(s,1H),3.70-3.63(m,5H),3.57-3.53(m,2H),3.38(m,1H),3.24(m,4H),3.02(s,1H),2.64-2.40(m,4H),1.83(s,2H),1.33-1.31(d,2H),1.28-1.22(m,5H),0.88-0.86(d,1H).
实施例7：化合物4的合成
将38mg 1-17、50mg 1-21、3mg PdCl2(dppf)、12mg KOAc和2ml 1,4-dioxane放入微波反应管中，氮气保护，135℃微波反应30min，TLC监测原料点消失(二氯甲烷：甲醇＝20：1)。反应结束后，乙酸乙酯萃取，水洗三次，有机相再用饱和NaCl溶液洗一次，有机相旋干，柱层析分离(二氯甲烷：甲醇＝20：1)，得到棕色固体16mg，即化合物4。(MS：GQQ-19-1212，1H-NMR：GQQ-19-2)。MS(ESI):m/z＝795.16[M-H]-，1H NMR:400MHz CDCl3 δ10.67(s,1H),7.70-7.30(m,6H),7.14-7.12(m,1H),7.02-6.97(m,1H),6.92(d,1H),6.85-6.83(d,1H),5.43-5.35(m,2H),5.17-5.13(t,1H),5.02-4.92(m,2H),4.39-4.35(m,1H),4.06-4.04(m,1H),3.69(s,3H),3.56-3.52(m,1H),3.41-3.36(m,6H),3.28-3.23(m,2H),2.78-2.70(m,1H),2.61-2.56(m,2H),2.43-2.37(m,2H),2.07-1.87(m,5H),1.43(s,6H),1.33(s,3H),0.78-0.76(d,3H).
实施例8：化合物对Huh-7细胞和HCV-1a及1b抑制实验
方法过程：
(1)实验方案
应用HCV GT1b和GT1a稳定转染复制子细胞检测化合物对HCV GT1b和GT1a的抑制活性。
(2)方法与操作
(1)对化合物进行3倍系列稀释8个浓度点，双复孔，加入96孔板中。
(2)设置DMSO为无加化合物对照。
(3)将HCV GT1b或GT1a细胞悬浮在含10％FBS的培养液中。
(4)将培养液种到含有化合物的96孔板中。
(5)细胞在5％CO2、37℃条件下培养3天。
(6)然后用CellTiter-Fluor(Promega)测定化合物对HCV GT1b复制子细胞毒性。
(7)用Bright-Glo(Promega)检测荧光素酶测定化合物抗HCV GT1b和GT1a复制子活性。
(8)采用GraphPad Prism软件分析数据并计算EC50和CC50值。
表1所选化合物对对复制子GT1a的抑制活性
表2所选化合物对对复制子GT12的抑制活性
Claims (10)
1.一种如式I所示的苯并咪唑衍生物或其药学上可接受的盐：
其中：T1a为
或在任意一个位置被一个或多个卤素、烷基、卤代烷基的基团取代；
X是-CH＝CH-；
其中，Q1a是：
Q1b是
M1a是：
M1b是：
L1a是-N(H)(烷氧基羰基)、-N(H)C(＝O)CH3；
L1b是-N(H)(烷氧基羰基)、-N(H)C(＝O)CH3。
2.根据权利要求1所述的苯并咪唑衍生物或其药学上可接受的盐，具有通式(II)的结构：
3.根据权利要求2所述的苯并咪唑衍生物或其药学上可接受的盐，选自以下化合物：
4.根据权利要求1所述的苯并咪唑衍生物或其药学上可接受的盐，其中，所述药学上可接受的盐，为苯并咪唑衍生物与下列酸形成的盐：盐酸、对甲苯磺酸、酒石酸、马来酸、乳酸、甲磺酸、硫酸、磷酸、柠檬酸、乙酸或三氟乙酸。
5.根据权利要求4所述的苯并咪唑衍生物或其药学上可接受的盐，其中，所述药学上可接受的盐，为苯并咪唑衍生物与下列酸形成的盐：对甲苯磺酸、盐酸、酒石酸或三氟乙酸。
6.根据权利要求1所述的苯并咪唑衍生物或其药学上可接受的盐，进一步包括它们的溶剂化物，代谢物前药等。
7.权利要求1所述的苯并咪唑衍生物或其药学上可接受的盐在制备抗HCV药物中的应用。
8.含有权利要求1所述的苯并咪唑衍生物或其药学上可接受的盐的药物组合物。
9.根据权利要求8所述的药物组合物，是单位剂量的药物制剂形式，在制成药物制剂时可以制成任何可药用的剂型。
10.根据权利要求9所述的药物组合物，所述剂型为片剂或胶囊剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110135739.3A CN114835691A (zh) | 2021-02-01 | 2021-02-01 | 一种苯并咪唑衍生物及其用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110135739.3A CN114835691A (zh) | 2021-02-01 | 2021-02-01 | 一种苯并咪唑衍生物及其用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114835691A true CN114835691A (zh) | 2022-08-02 |
Family
ID=82560865
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110135739.3A Pending CN114835691A (zh) | 2021-02-01 | 2021-02-01 | 一种苯并咪唑衍生物及其用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114835691A (zh) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011031904A1 (en) * | 2009-09-11 | 2011-03-17 | Enanta Pharmaceuticals, Inc | Hepatitis c virus inhibitors |
| WO2011081918A1 (en) * | 2009-12-14 | 2011-07-07 | Enanta Pharmaceuticals, Inc | Hepatitis c virus inhibitors |
| CN102427731A (zh) * | 2009-02-27 | 2012-04-25 | 英安塔制药有限公司 | 丙型肝炎病毒抑制剂 |
| CN102858157A (zh) * | 2010-03-04 | 2013-01-02 | 埃南塔制药公司 | 作为hcv复制的抑制剂的组合药物活性剂 |
| WO2013052369A1 (en) * | 2011-10-04 | 2013-04-11 | Enanta Pharmaceuticals, Inc. | Novel benzimidazole derivatives |
-
2021
- 2021-02-01 CN CN202110135739.3A patent/CN114835691A/zh active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102427731A (zh) * | 2009-02-27 | 2012-04-25 | 英安塔制药有限公司 | 丙型肝炎病毒抑制剂 |
| WO2011031904A1 (en) * | 2009-09-11 | 2011-03-17 | Enanta Pharmaceuticals, Inc | Hepatitis c virus inhibitors |
| WO2011081918A1 (en) * | 2009-12-14 | 2011-07-07 | Enanta Pharmaceuticals, Inc | Hepatitis c virus inhibitors |
| CN102858157A (zh) * | 2010-03-04 | 2013-01-02 | 埃南塔制药公司 | 作为hcv复制的抑制剂的组合药物活性剂 |
| WO2013052369A1 (en) * | 2011-10-04 | 2013-04-11 | Enanta Pharmaceuticals, Inc. | Novel benzimidazole derivatives |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108546277B (zh) | 新的核苷氨基磷酸酯化合物及其应用 | |
| CN107033087B (zh) | 1h-吲唑-4-胺类化合物及其作为ido抑制剂的用途 | |
| WO2008098368A1 (en) | Inhibitors of hepatitis c ns3 protease | |
| CN102838523A (zh) | 抗肠病毒71(ev71)戊内酰胺类化合物及其制备方法和用途 | |
| CN103145608A (zh) | 抗肠病毒71(ev71)己内酰胺类化合物及其制备方法和用途 | |
| CN103145617A (zh) | 菲啶类衍生物及其药物组合物和其制备方法与应用 | |
| WO2022107745A1 (ja) | Ｃｏｖｉｄ－１９の治療剤又は予防剤 | |
| CA2979555C (en) | Inhibitors of hepatitis c virus polymerase | |
| WO2020001089A1 (zh) | 一种结晶性氨基甲酸甲酯类化合物 | |
| AU2017239338B2 (en) | Uridine phosphoramide prodrug, preparation method therefor, and medicinal uses thereof | |
| CN114835691A (zh) | 一种苯并咪唑衍生物及其用途 | |
| WO2004096774A1 (en) | Acyl isoindoline derivatives and acyl isoquinoline derivatives as anti-viral agents | |
| CA2647163C (en) | Modified macrophage migration inhibitory factor inhibitors | |
| CN108129366B (zh) | 抗病毒化合物、制备方法及其用途 | |
| CN116693447A (zh) | 酮酰胺类衍生物及其制药用途 | |
| CN107074876B (zh) | 一类抑制丙肝病毒的大环状杂环化合物及其制备和用途 | |
| CN116648240A (zh) | 一种环肽类病毒蛋白酶抑制剂，其制备方法，及其在抗病毒药物中的应用 | |
| CN115160301A (zh) | 一种山荷叶素衍生物、其制备方法及用途 | |
| JP6958797B2 (ja) | Ｃ型肝炎ウイルス阻害剤およびその使用 | |
| WO2017173960A1 (zh) | 一类抑制丙肝病毒的大环状杂环化合物及其制备和用途 | |
| JP2007506788A (ja) | Ｈｃｖ感染阻害剤とその使用法 | |
| TW201718608A (zh) | 用於抗ｃ型肝炎病毒感染的含矽化合物 | |
| CN105272978A (zh) | 喹喔啉酮类化合物及其制备方法和抗丙型肝炎病毒之用途 | |
| WO2023230472A1 (en) | Inhibitors of molluscum contagiosum infection and methods using the same | |
| WO2010074764A1 (en) | Synthesis of oligomeric neolignans and their use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |