WO2023054759A1 - Dérivé de 2-aminoquinazoline et composition antivirale le comprenant - Google Patents
Dérivé de 2-aminoquinazoline et composition antivirale le comprenant Download PDFInfo
- Publication number
- WO2023054759A1 WO2023054759A1 PCT/KR2021/013418 KR2021013418W WO2023054759A1 WO 2023054759 A1 WO2023054759 A1 WO 2023054759A1 KR 2021013418 W KR2021013418 W KR 2021013418W WO 2023054759 A1 WO2023054759 A1 WO 2023054759A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- amino
- substituted
- formula
- alkyl group
- Prior art date
Links
- 230000000840 anti-viral effect Effects 0.000 title claims abstract description 11
- 239000000203 mixture Substances 0.000 title claims description 21
- CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical class C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 239000004480 active ingredient Substances 0.000 claims abstract description 13
- -1 tert-butanoyloxymethoxy group Chemical group 0.000 claims description 159
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical group 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000003277 amino group Chemical group 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 11
- 241000711573 Coronaviridae Species 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 230000009385 viral infection Effects 0.000 claims description 6
- 208000036142 Viral infection Diseases 0.000 claims description 5
- 241000700605 Viruses Species 0.000 claims description 5
- 239000003443 antiviral agent Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 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 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 235000013402 health food Nutrition 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 208000025721 COVID-19 Diseases 0.000 claims description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 229910052805 deuterium Inorganic materials 0.000 claims description 3
- 235000013305 food Nutrition 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 239000000126 substance Substances 0.000 abstract description 7
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 122
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 96
- 238000005160 1H NMR spectroscopy Methods 0.000 description 67
- 238000001308 synthesis method Methods 0.000 description 66
- 230000015572 biosynthetic process Effects 0.000 description 63
- 238000003786 synthesis reaction Methods 0.000 description 63
- 239000007787 solid Substances 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 45
- 238000005481 NMR spectroscopy Methods 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- 241001678559 COVID-19 virus Species 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 239000003480 eluent Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 208000015181 infectious disease Diseases 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- VUAXHMVRKOTJKP-UHFFFAOYSA-M 2,2-dimethylbutanoate Chemical compound CCC(C)(C)C([O-])=O VUAXHMVRKOTJKP-UHFFFAOYSA-M 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical class [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 102000053723 Angiotensin-converting enzyme 2 Human genes 0.000 description 5
- 108090000975 Angiotensin-converting enzyme 2 Proteins 0.000 description 5
- 208000001528 Coronaviridae Infections Diseases 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 5
- 150000008064 anhydrides Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 210000003501 vero cell Anatomy 0.000 description 5
- 238000010626 work up procedure Methods 0.000 description 5
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 4
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 4
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 4
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 4
- 241000315672 SARS coronavirus Species 0.000 description 4
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 101710198474 Spike protein Proteins 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229940096437 Protein S Drugs 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 3
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- JLEMKZDHFGCHLO-UHFFFAOYSA-N 1,3-dichloro-5-isothiocyanatobenzene Chemical compound ClC1=CC(Cl)=CC(N=C=S)=C1 JLEMKZDHFGCHLO-UHFFFAOYSA-N 0.000 description 2
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- DPUVJCSIXSYYGI-UHFFFAOYSA-N 2-amino-4-chloro-N-phenylmethoxybenzamide Chemical compound NC1=CC(Cl)=CC=C1C(=O)NOCC1=CC=CC=C1 DPUVJCSIXSYYGI-UHFFFAOYSA-N 0.000 description 2
- QISAUDWTBBNJIR-UHFFFAOYSA-N 2-phenylmethoxyacetyl chloride Chemical compound ClC(=O)COCC1=CC=CC=C1 QISAUDWTBBNJIR-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- BXDMGAZLMOSICU-UHFFFAOYSA-N 7-chloro-2-(3,5-difluoroanilino)-3H-quinazolin-4-one Chemical compound O=C1NC(NC2=CC(F)=CC(F)=C2)=NC2=CC(Cl)=CC=C12 BXDMGAZLMOSICU-UHFFFAOYSA-N 0.000 description 2
- 239000012103 Alexa Fluor 488 Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-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
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 2
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 2
- 208000019202 Orthocoronavirinae infectious disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 101000629318 Severe acute respiratory syndrome coronavirus 2 Spike glycoprotein Proteins 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 108010067390 Viral Proteins Proteins 0.000 description 2
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002543 antimycotic Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 2
- 229960003677 chloroquine Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- LNJAJHJFSKUCIR-UHFFFAOYSA-N ditert-butyl chloromethyl phosphate Chemical compound CC(C)(C)OP(=O)(OCCl)OC(C)(C)C LNJAJHJFSKUCIR-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229960004525 lopinavir Drugs 0.000 description 2
- 239000000314 lubricant 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
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- JYYLQSCZISREGY-UHFFFAOYSA-N 2-amino-4-chlorobenzoic acid Chemical compound NC1=CC(Cl)=CC=C1C(O)=O JYYLQSCZISREGY-UHFFFAOYSA-N 0.000 description 1
- RACLRJZSLQLCFA-UHFFFAOYSA-N 2-anilino-1h-quinazolin-4-one Chemical compound N1C2=CC=CC=C2C(=O)N=C1NC1=CC=CC=C1 RACLRJZSLQLCFA-UHFFFAOYSA-N 0.000 description 1
- SUHXTVABLHHRST-UHFFFAOYSA-N 2-azidoacetyl chloride Chemical compound ClC(=O)CN=[N+]=[N-] SUHXTVABLHHRST-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UEVKKBZJWXGNOE-UHFFFAOYSA-N 7-chloro-2-(3,5-dihydroxyanilino)-3H-quinazolin-4-one Chemical compound OC1=CC(O)=CC(NC(N2)=NC3=CC(Cl)=CC=C3C2=O)=C1 UEVKKBZJWXGNOE-UHFFFAOYSA-N 0.000 description 1
- DYEFRFDIJJPIIN-UHFFFAOYSA-N 7-chloro-2-(3-hydroxyanilino)-3H-quinazolin-4-one Chemical compound OC1=CC=CC(NC(N2)=NC3=CC(Cl)=CC=C3C2=O)=C1 DYEFRFDIJJPIIN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000494545 Cordyline virus 2 Species 0.000 description 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 101000929928 Homo sapiens Angiotensin-converting enzyme 2 Proteins 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 244000018633 Prunus armeniaca Species 0.000 description 1
- 235000009827 Prunus armeniaca Nutrition 0.000 description 1
- 208000037847 SARS-CoV-2-infection Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- JAWMENYCRQKKJY-UHFFFAOYSA-N [3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]methanone Chemical compound N1N=NC=2CN(CCC=21)CC1=NOC2(C1)CCN(CC2)C(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F JAWMENYCRQKKJY-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 102000048657 human ACE2 Human genes 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000001261 hydroxy acids Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- PELJISAVHGXLAL-UHFFFAOYSA-N iodomethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCI PELJISAVHGXLAL-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- SFMJNHNUOVADRW-UHFFFAOYSA-N n-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CC=C1N=C2 SFMJNHNUOVADRW-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000012744 reinforcing agent Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/11—Esters of phosphoric acids with hydroxyalkyl compounds without further substituents on alkyl
Definitions
- the present invention relates to a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof and an antiviral pharmaceutical composition containing the same as an active ingredient.
- Coronavirus Infectious Disease-19 is a respiratory syndrome caused by SARS-CoV-2 infection, starting in Wuhan City, Hubei Province, China in December 2019, and spreading rapidly worldwide, The rapid increase in the number of deaths is causing a great social problem.
- the SARS-CoV-2 pathogen is an RNA virus belonging to the Coronaviridae, which has been associated with SARS-CoV, the pathogen of Severe Acute Respiratory Syndrome (SARS) in 2002 and Middle East Respiratory Syndrome (MERS) in 2015. It is very closely related to the MERS coronavirus (MERS-CoV), the pathogen of SARS-CoV-2 and SARS-CoV bind to the ACE2 (Angiotensin Converting Enzyme2) receptor, and MERS-CoV utilizes DPP4 (Dipeptidyl Peptidase4; CD26) as a receptor.
- SARS Severe Acute Respiratory Syndrome
- MERS Middle East Respiratory Syndrome
- SARS-CoV-2 and SARS-CoV spike proteins have a very similar shape (Walls et al., 2020, Structure, Function and antigenicity of the SARS-CoV-2 spike SARS -It was found that CoV-2 also attaches strongly to the surface of host cells through the ACE2 receptor, and the molecular structure of the spike protein and ACE2 complex was recently revealed (Zhou et al., 2020 A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature.;Yan et al., 2020, Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2.Science, DOI: 10.1126/science.abb2762).
- SARS-CoV-2 transmits and spreads more rapidly than SARS-CoV, which is why SARS-CoV-2 binds more strongly to ACE2 in host cells and makes parts of the spike protein more easily cut by protein scissors. It is presumed that this is because it is deformed.
- the present inventors have completed the present invention by finding that 2-aminoquinazoline derivatives introduced with various substituents are compounds having an inhibitory effect on COVID-19.
- An object of the present invention is to provide a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
- an object of the present invention is to provide an antiviral pharmaceutical composition comprising a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
- an object of the present invention is to provide a health food composition for preventing and improving viral infection, which includes a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
- the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
- the present invention provides an antiviral pharmaceutical composition
- an antiviral pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention provides a pharmaceutical composition for COVID-19 coronavirus antivirus.
- composition of the present invention may further include one or more pharmaceutically acceptable carriers, and may further include one or more known antiviral agents.
- the present invention relates to a compound according to Formula 1; Or it provides a health food composition for preventing and improving viral infection comprising a food chemically acceptable salt thereof as an active ingredient.
- composition containing a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to the present invention has an excellent anti-proliferation activity against SARS-CoV-2 infected with Vero cell lines and It can be used as a virus treatment because of its low toxicity, and in particular, it can be used as a treatment for COVID-19 (Coronavirus Infectious Disease-19).
- the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
- alkyl or “alkyl group” refers to an aliphatic hydrocarbon radical and includes both straight-chain and branched-chain hydrocarbon radicals.
- C 1 ⁇ C 6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and the like are all included.
- alkene or “alkenyl group” refers to a group in which at least two carbon atoms contain at least one carbon-carbon double bond
- alkyne or “alkynyl group” refers to a group in which at least two carbon atoms contain at least one carbon-carbon double bond.
- heterocycle or “heterocyclic group” includes one or more heteroatoms, includes at least one of a single ring and multiple rings, and includes heteroaliphatic and heteroaromatic rings, unless otherwise specified. It may also be formed by combining adjacent functional groups.
- aryl or “aryl group” refers to one or more hydrocarbon rings having a covalent pi electron system, and includes, for example, phenyl, naphthyl, biphenyl, and the like.
- halogen refers to elements belonging to group 17 of the periodic table, and may be specifically fluorine, chlorine, bromine, and iodine.
- alkoxy or “alkoxy group” means a radical in which the hydrogen atom of a hydroxy group is substituted with an alkyl, unless otherwise defined, and for example, C 1 to C 6 alkoxy is methoxy, ethoxy, propoxy, n- Butoxy, n-pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, isopentyloxy and the like are all included.
- hydroxyl group means -OH.
- amino group means -NH 2 .
- benzyloxy group means a monovalent atomic group consisting of an oxy group and a benzyl group, that is, -O-CH 2 -C 6 H 5 .
- substitution means that one hydrogen atom is substituted, for example, when substituted with a hydroxyl group, -CH 3 is substituted with -CH 2 OH.
- the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
- R 4 may be absent
- R 1a is a substituted or unsubstituted C 1 ⁇ C 6 alkyl group; Or a substituted or unsubstituted C 2 ⁇ C 6 alkenyl group,
- alkenyl group of C 2 ⁇ C 6 when substituted, it is substituted with a hydroxyl group, an amino group, a halogen atom or an acetoxy group,
- R 1b is a C 1 ⁇ C 6 alkyl group; Or a substituted or unsubstituted C 6 ⁇ C 10 aryl group,
- R 1c is a hydroxyl group; C 1 ⁇ C 6 alkanoyloxy group; benzyloxy group; or NR a R b ;
- R 1d and R 1e are each independently hydrogen; sodium; Or a C 1 ⁇ C 6 alkyl group,
- n is an integer from 0 to 3;
- R 2 is hydrogen, a C 3 ⁇ C 6 cycloalkyl group; -(X) n -C 6 ⁇ C 10 An aryl group,
- R 1 and R 2 together may form a ring
- R 3a is a C 1 ⁇ C 6 alkanoyloxy group, o is 1 or 2;
- R 5 is hydrogen; halogen; cyano group; nitro group; hydroxy group; amino group; C 1 ⁇ C 6 Alkyl group; C 2 ⁇ C 6 Alkenyl group; A C 2 ⁇ C 6 alkynyl group; A C 1 ⁇ C 6 alkoxy group; C 1 ⁇ C 6 alkanoyloxy group; C 3 ⁇ C 6 Cycloalkyl group; C 6 ⁇ C 10 aryl group; A C 2 ⁇ C 10 heterocyclic group containing at least one heteroatom selected from O, N, and S; NR e R f ; And, when a is 1 or more, a plurality of R 5 are the same as or different from each other,
- a is an integer from 0 to 4.
- R a , R b , R c , R d , R e and R f are each independently hydrogen; Or a C 1 ⁇ C 3 alkyl group;
- the term 'ring' herein refers to a fused ring composed of an aliphatic ring having 3 to 20 carbon atoms, an aromatic ring having 6 to 20 carbon atoms, a heterocyclic ring having 2 to 20 carbon atoms, or a combination thereof, and includes a saturated or unsaturated ring.
- the present invention includes a compound in which Formula 1 is represented by Formula 2 below.
- R 1 , R 3 , R 4 , R 5 and a are the same as defined above,
- b is an integer from 0 to 5.
- the present invention includes a compound represented by any one of the following formulas 3 to 5 in the formula (1).
- R 1 , R 5 , R 6 , a and b are the same as defined above,
- R 7 is a C 1 ⁇ C 6 alkyl group; or a tert-butanoyloxymethoxy group.
- R 1a is a substituted or unsubstituted C 1 ⁇ C 6 alkyl group; or a substituted or unsubstituted C 2 ⁇ C 6 alkenyl group, where, when the C 1 ⁇ C 6 alkyl group is substituted, a C 1 ⁇ C 3 alkoxy group; substituted with a hydroxy group, an amino group, a halogen or an acetoxy group,
- alkenyl group of C 2 ⁇ C 6 when substituted, it is substituted with a hydroxyl group, an amino group, a halogen or an acetoxy group.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be any one of the following compounds.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be any one of the following compounds.
- the compound of Formula 1 or a pharmaceutically acceptable salt thereof may have a substituent containing an asymmetric atom, in which case the compound of Formula 1 or a salt thereof is (R), (S), or racemic (RS) may exist as optical isomers. Therefore, unless otherwise indicated, the compound of Formula 1 or a pharmaceutically acceptable salt thereof includes all optical isomers such as (R), (S), or racemic (RS) forms.
- the compound of Formula 1 of the present invention may be in the form of a pharmaceutically acceptable salt.
- Such salts include conventional acid addition salts, for example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid, and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, maleic acid, hydroxy acid.
- organic acids such as camphorsulfonic acid, capric acid, myristic acid, hypric acid or orotic acid.
- the salt is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, calcium carbonate, potassium t-butoxide, sodium ethoxide, triethylamine, ammonia, guanidine, ethylenediamine, ethanolamine, diethanol amines, triethanolamine, piperazine, morpholine, or salts derived from dicyclohexylamine.
- a pharmaceutically acceptable salt of the compound of Formula 1 can be prepared from the compound of Formula 1 by a conventional method.
- such salts can be prepared by reacting a compound of Formula 1 in free acid/base form with a stoichiometric amount or excess of the desired salt-forming inorganic acid, inorganic salt, organic acid or organic salt in a suitable solvent or various combinations of solvents.
- the present invention provides an antiviral pharmaceutical composition
- an antiviral pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- the pharmaceutical composition may include a pharmaceutically acceptable carrier such as a commonly used excipient, disintegrant, sweetener, lubricant, or flavoring agent, and may be formulated into tablets, capsules, powders, granules, and suspensions according to conventional methods. It may be formulated into oral preparations such as emulsions or syrups or preparations for parenteral administration such as injections. The formulation may be formulated in a variety of forms, for example single dose or multiple dose dosage forms.
- a pharmaceutically acceptable carrier such as a commonly used excipient, disintegrant, sweetener, lubricant, or flavoring agent
- composition of the present invention may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration.
- Compositions of the present invention are preferably administered orally.
- the composition of the present invention may be formulated in various forms such as tablets, capsules, aqueous solutions or suspensions.
- carriers such as lactose and corn starch and lubricants such as magnesium stearate may usually be added.
- lactose and/or dried corn starch may be used as diluents.
- the active ingredient may be combined with emulsifying and/or suspending agents.
- compositions according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4.
- a pharmaceutically acceptable carrier such as saline having a pH of 7.4. The solution can be introduced into the patient's intramuscular bloodstream by local bolus injection.
- a pharmaceutical composition according to the present invention can be administered in a therapeutically effective amount. Therefore, the compound of formula 1 contained in the pharmaceutical composition; Or a pharmaceutically acceptable salt thereof may be administered to the patient in an effective amount of about 10 mg/kg to about 500 mg/kg per day. Of course, the dose may be changed according to the patient's age, body weight, sensitivity, symptoms or efficacy of the compound.
- the present invention also provides a therapeutically effective amount of the compound of Formula 1; Or a method for preventing or treating a virus, preferably a coronavirus, more preferably COVID-19, comprising administering a pharmaceutically acceptable salt thereof to a mammal, including a human.
- a virus preferably a coronavirus, more preferably COVID-19
- composition of the present invention may further include one or more pharmaceutically acceptable carriers, and may further include one or more antiviral agents.
- the present invention also relates to a compound of Formula 1 for the preparation of a drug for preventing or treating a virus; or a pharmaceutically acceptable salt thereof.
- the present invention relates to a treatment for coronavirus, particularly COVID-19, comprising a 2-aminoquinazoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. it's about
- the 2-Aminoquinazoline derivative of Chemical Formula 1 effectively inhibits SARS-CoV-2 in a drug efficacy test using Vero cells infected with SARS-CoV-2 and is expected to have a therapeutic effect on coronavirus due to its low cytotoxicity. It was confirmed that it can be used, and in particular, it was confirmed that it can be used as a treatment for COVID-19.
- the therapeutic agent or pharmaceutical composition for COVID-19 containing the compound of Formula 1 according to the present invention as an active ingredient is added to the compound of Formula 1 with a conventional non-toxic pharmaceutically acceptable carrier, reinforcing agent or excipient, etc. in the pharmaceutical field.
- Oral administration preparations such as tablets, capsules, troches, solutions, suspensions, etc. can be formulated in conventional preparations.
- a pharmaceutical composition may be provided by using the compound of Formula 1 according to the present invention as an active ingredient and further including other antiviral agents.
- it can be provided as a conventional preparation in the pharmaceutical field by adding the compound of Formula 1, other antiviral agents and pharmaceutically acceptable carriers to a COVID-19 treatment or pharmaceutical composition.
- the dosage of the compound of Formula 1 may vary depending on the patient's age, weight, sex, dosage form, health condition and disease degree, and is generally 10 to 4,000 mg/day, and may be divided and administered once or several times a day at regular time intervals according to the judgment of a doctor or pharmacist.
- the present invention is a compound of Formula 1; Or it provides a health food composition for preventing and improving viral infection comprising a food chemically acceptable salt thereof as an active ingredient.
- the compound represented by Formula 1 according to the present invention may be prepared by reacting as shown in Reaction Scheme 1 below, but is not limited thereto.
- R 5 , R 6 , a and b have the same definition as above.
- Comp 1 (29.1 mmol, 1 eq) and urea (582.8 mmol, 20 eq) were placed in a 100 mL round bottom flask and heated at 150 °C for 2 hours. After the reaction was completed, the mixture was cooled at room temperature, 60 mL of water was added thereto, and the mixture was heated at 100° C. for 1 hour. Cooling the reactants precipitates a white solid. After filtering the white solid, it was washed with water and hexane and dried to obtain Comp 2 (yield: about 90%). Comp 2 was used in the next step without further purification.
- the compound represented by Formula 1 according to the present invention may be prepared by reacting as in Scheme 2-1 below, but is not limited thereto.
- the compound represented by Formula 1 according to the present invention may be prepared by reacting as in Scheme 2-3 below, but is not limited thereto.
- R 1a , R 5 , R 6 , a and b have the same definitions as above.
- Synthesis Examples 1, 2-1, 2-2, 2-3, and 2-4 are examples of the compound synthesis method according to the present invention, and include modification of some reagents, solvents, and chemical reaction sequences.
- Example 1-1 7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one
- Example 1-1 0.6 mmol, 200 mg
- potassium carbonate (0.72 mmol, 99.5 mg)
- dimethylacetamide (6 mL)
- iodomethyl pivalate 0.9 mmol, 140 ⁇ L
- work-up was performed with water and EA, and the organic layer was dried in MgSO 4 , filtered, and evaporated to obtain a crude product. .
- the crude product was purified with silica to obtain a product.
- Example 2-4 The reaction was carried out in the same manner as in Example 2-1, but using 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4( 3H )-one (Example 1-44). Thus, ((2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4-yl)oxy)methyl pivalate (Example 2-4) was obtained.
- Example 1-1 compound (7-chloro-2 - ((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (2.94 mmol, 1000 mg) was added to 100 mL RBF, sodium eye Sodium iodide (1.76 mmol, 264 mg) and cesium carbonate (8.82 mmol, 2874 mg) were added, sealed, and nitrogen substitution was performed. After adding DMAc (29.4 mL) and stirring, di-tert-butyl chloromethyl phosphate (7.35 mmol, 1.73 mL) was added and heated to 60 ° C.
- Example 1-1 (7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (10 mmol, 3 g) was added to 250 mL RBF. After adding acetic anhydride (100 mL) and stirring, TEA (30 mmoL, 4 mL) was slowly added dropwise. The reaction proceeded by heating the reactant to 85 ° C. After the reaction is completed, work-up is performed with brine and EA, and the organic layer is dried with MgSO 4 , filtered, and evaporated to obtain a crude product.
- Example 2-11 3-acetyl-7-chloro-2-((3,5-difluorophenyl)amino)quinazolin-4(3H)-one
- Example 1-1 7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one
- formic acid 100 ⁇ L
- acetic anhydride 500 ⁇ L
- work-up is performed using sodium bicarbonate and EA.
- the organic layer is dried over MgSO4, filtered, and evaporated to obtain a crude product.
- Example 1-1 (7-chloro-2 - ((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (200 mg, 0.587 mmol) was mixed with dichloromethane (3 mL) and triethylamine (164 mL. 1.174 mmL) and acetoxyacetyl chloride (195 mL, 1.761 mmol) was added. The reaction mixture was stirred at 40 ° C for 2.5 hours, and when the reaction was complete, it was diluted with dichloromethane (20 mL) and washed with water (20 mL).
- Example 1-1 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4( 3H )-one) was used to obtain 7-chloro-2-((3,5-dichlorophenyl)amino)-3-methylquinazolin-4(3H)-one (Example 2-27).
- Example 1-1 (7-chloro-2 - ((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (500 mg, 1.468 mmol) was mixed with dichloromethane (12 mL) and triethylamine (307 mL, 2.20 mmol) and dimethylaminopyridine (18 mg, 0.147 mmol) and methanesulfonyl chloride (136 mL, 1.762 mmol) were added at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours.
- 2-Amino-4-chloro-N-(2-(dimethylamino)ethyl)benzamide (0.2 g, 0.7 mmol) and 1,3-dichloro-5-isothiocyanatobenzene in DMF (6 mL) (0.143 g, 0.7 mmol) and a mixture of CuBr (0.05 g, 0.35 mmol) and triethylamine (0.05 mL, 0.36 mmol) was refluxed at 80 oC for 8 hours.
- Vero cells used in the present invention were purchased from the American Type Culture Collection (ATCC, CCL-81; Manassas, VA) and used, 10% heat inactivated fetal bovine serum and 1 ⁇ antibiotic-antimycotic , Gibco/Thermo Fisher Scientific, Waltham, MA) containing Dulbecco's modified Eagle's medium (DMEM; Welgene, Gyeongsan, Korea) and incubated at 37°C under 5% carbon dioxide.
- ATCC American Type Culture Collection
- CCL-81 Manassas, VA
- DMEM Dulbecco's modified Eagle's medium
- SARS-CoV-2 Korean isolate (MERS-CoV/KOR/KNIH/002_05_2015, Genbank accession no. KT029139.1 [Kim et al., 2015 doi:10.1128/genomeA.00787-15]) was obtained from the Korea Centers for Disease Control and Prevention, National Institutes of Health , and proliferated in Vero cells according to the method presented in Kim et al., 2016 doi: 10.1093/cid/ciw239. All experiments using MERS-CoV were performed at the Pasteur Institute in Korea, which followed the enhanced Biosafety Level 3 (BL-3) containment procedures of the National Institutes of Health approved by the Korea Centers for Disease Control and Prevention.
- BL-3 Biosafety Level 3
- Chloroquine diphosphate (CQ; C6628), lopinavir (LPV; GP6351), and Remdesivir were purchased from SelleckChem (Houston, TX) and Glentham Life Science (UK), respectively.
- the anti-SARS-CoV-2 spike antibody used as the primary antibody was manufactured by Sino Biological Inc. (Beijing, China).
- Alexa Fluor 488 goat anti-rabbit IgG as a secondary antibody and Hoechst 33342 as a nuclear chromosome were purchased from Molecular Probes/Thermo Fisher Scientific (Waltham, MA).
- PFA Paraformaldehyde
- aqueous solution and normal goat serum were obtained from Electron Microscopy Sciences (Hatfield, PA) and Vector Laboratories, Inc, respectively. (Burlingame, CA).
- cells infected with SARS-CoV-2 express viral proteins, it can be measured using antibodies that specifically bind to viral proteins.
- cells were stained using an antibody that binds to the spike protein of SARS-CoV-2, and infected cells were imaged through a microscope.
- the infection rate (number of cells expressing SARS-CoV-2 spike protein/total number of cells) was measured with an internally developed Image Mining 3.0 (IM 3.0) plug-in.
- infected cells treated with dimethyl sulfoxide (DMSO) were used as negative controls, and three compounds (CQ, LPV, Remdesivir) known to have antiviral activity against SARS-CoV-2 was used as a positive control to optimize the image-based assay.
- DMSO dimethyl sulfoxide
- Vero cells were plated at 1.2 ⁇ 10 4 cells per well in Opti-PROTM SFM containing 4 mM L-Glutamine and 1 ⁇ Antibiotic-Antimycotic in black, 384-well, microclear plates (Clear plates, Greiner bio-one, Kremsmunster, Austria). After 24 hours, small molecule compounds were added to each well using an automated liquid handling system (Apricot Designs, Covina, Calif.) prior to virus infection. The final concentration of the test compound was 2.5 to 28.2 ⁇ M, and the concentration of DMSO was maintained at 0.5%. The compound-treated group was transferred to a BL-3 containment room and infected with SARS-CoV-2 at an MOI of 0.0625.
- the fixed cells were stained using Alexa Fluor 488 goat anti-rabbit IgG and Hoechst 33342. After fixation and staining of infected cells, they were imaged on a fluorescence imaging system (Perkin Elmer Operetta, 20 ⁇ , Waltham, MA) at 20 ⁇ magnification.
- the infection rate for SARS-CoV-2 of the cells treated with the small molecule compound was converted into the negative control group (0% infection inhibition rate) and the positive control group (100% infection inhibition rate) on each plate, resulting in an inhibitory effect of 90% or more A low-molecular-weight compound was identified.
- the inhibitory effect of viral infection according to the concentration of the compound can be seen through a concentration-response curve experiment.
- the highest concentration of the test compound is 5 mM, diluted 2 times with DMSO, and serially diluted up to 10 steps. This is treated with cells prepared in the same way as in 1-5 above.
- the highest concentration of the final concentration of the test compound was 25 ⁇ M, and the concentration of DMSO was maintained at 0.5%.
- the compound-treated group was moved to a BL-3 containment room and infected with SARS-CoV-2 at an MOI of 0.0625. 24 hours after infection, the infection rate was imaged and converted in the same manner as in 1-5 above.
- Example 1-1 0.269 >25 92.9
- Example 1-2 0.403 >25 62.085
- Example 1-3 5.13 >25 4.87
- Example 1-4 2.064 >25 12.113
- Example 1-5 0.328 >25 76.3
- Example 1-6 0.272 >25 92
- Examples 1-7 0.254 >25 98.241
- Examples 1-8 >25 >25 One Examples 1-9 >25 >25 One Examples 1-10 4.877 12.9 2.64
- Example 1-11 >25 >25 One Examples 1-12 0.41 >25 60.94
- Examples 1-13 0.511 >25 48.93
- Examples 1-14 1.513 >25 16.52
- Examples 1-15 >25 >25 One Examples 1-16 >25 >25 >25 One Examples 1-17 >25 >25 One Examples 1-18 0.362 >25 71
- Examples 1-19 0.991 >25 25.22
- Examples 1-20 >25 >25 >25 68.67
- Examples 1-22 0.89 >25 28.1
- Examples 1-24 0.308 14.046 45.55
- the compound according to one aspect of the present invention has excellent antiviral inhibitory activity against SARS-CoV-2, it can be seen that it can be used as a treatment for COVID-19 (coronavirus infection-19). there is.
- the present invention is useful in the field of medicine and medicine through antiviral effects through a novel pharmaceutical composition of a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Biochemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne un dérivé de 2-aminoquinazoline ou un sel pharmaceutiquement acceptable de celui-ci et, plus spécifiquement, un composé représenté par la formule chimique 1 ou un sel pharmaceutiquement acceptable de celui-ci, et une composition pharmaceutique antivirale le comprenant en tant que principe actif. [formule chimique 1]
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/KR2021/013418 WO2023054759A1 (fr) | 2021-09-30 | 2021-09-30 | Dérivé de 2-aminoquinazoline et composition antivirale le comprenant |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/KR2021/013418 WO2023054759A1 (fr) | 2021-09-30 | 2021-09-30 | Dérivé de 2-aminoquinazoline et composition antivirale le comprenant |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023054759A1 true WO2023054759A1 (fr) | 2023-04-06 |
Family
ID=85782996
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2021/013418 WO2023054759A1 (fr) | 2021-09-30 | 2021-09-30 | Dérivé de 2-aminoquinazoline et composition antivirale le comprenant |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2023054759A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20070027487A (ko) * | 2003-09-16 | 2007-03-09 | 아스트라제네카 아베 | 퀴나졸린 유도체 |
WO2008009078A2 (fr) * | 2006-07-20 | 2008-01-24 | Gilead Sciences, Inc. | Dérivés de la quinazoline tri-substitués en 4,6-dl et en 2,4,6 utilisables pour traiter les infections virales |
US20140073642A1 (en) * | 2011-05-18 | 2014-03-13 | Janssen R&D Ireland | Quinazoline derivatives for the treatment of viral infections and further diseases |
KR20210143131A (ko) * | 2020-05-19 | 2021-11-26 | 한국화학연구원 | 2-아미노퀴나졸린 유도체 및 이를 포함하는 항바이러스용 조성물 |
-
2021
- 2021-09-30 WO PCT/KR2021/013418 patent/WO2023054759A1/fr unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20070027487A (ko) * | 2003-09-16 | 2007-03-09 | 아스트라제네카 아베 | 퀴나졸린 유도체 |
WO2008009078A2 (fr) * | 2006-07-20 | 2008-01-24 | Gilead Sciences, Inc. | Dérivés de la quinazoline tri-substitués en 4,6-dl et en 2,4,6 utilisables pour traiter les infections virales |
US20140073642A1 (en) * | 2011-05-18 | 2014-03-13 | Janssen R&D Ireland | Quinazoline derivatives for the treatment of viral infections and further diseases |
KR20210143131A (ko) * | 2020-05-19 | 2021-11-26 | 한국화학연구원 | 2-아미노퀴나졸린 유도체 및 이를 포함하는 항바이러스용 조성물 |
Non-Patent Citations (2)
Title |
---|
LEE JUN YOUNG, SHIN YOUNG SUP, JEON SANGEUN, LEE SE IN, NOH SOOJIN, CHO JUNG-EUN, JANG MIN SEONG, KIM SEUNGTAEK, SONG JONG HWAN, K: "Design, synthesis and biological evaluation of 2-aminoquinazolin-4(3H)-one derivatives as potential SARS-CoV-2 and MERS-CoV treatments", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 39, 1 May 2021 (2021-05-01), Amsterdam NL , pages 127885, XP055806252, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2021.127885 * |
SHUM, DAVID; SMITH, JESSICA L.; HIRSCH, ALEC J.; BHINDER, BHAVNEET; RADU, CONSTANTIN; STEIN, DAVID A.; NELSON, JAY A.; FRUEH, KLAU: "High-Content Assay to Identify Inhibitors of Dengue Virus Infection", ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES, MARY ANN LIEBERT, INC. PUBLISHERS, US, vol. 8, no. 5, 1 October 2010 (2010-10-01), US , pages 553 - 570, XP009154193, ISSN: 1540-658X, DOI: 10.1089/adt.2010.0321 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2017018805A1 (fr) | Composés dérivés de sulfamide du 1,3,4-oxadiazole utilisés comme inhibiteur de l'histone désacétylase 6, et composition pharmaceutique comprenant ceux-ci | |
WO2016080810A2 (fr) | Composé de biguanide et utilisation de celui-ci | |
AU2019310508B2 (en) | 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and pharmaceutical composition comprising the same | |
AU2019381113B2 (en) | Novel compound as protein kinase inhibitor, and pharmaceutical composition comprising thereof | |
EP3802495A1 (fr) | Dérivés hétérocycliques et leur utilisation | |
WO2014109530A1 (fr) | Dérivé 2-(phényléthynyl)thiéno[3,4-b]pyrazine, et composition pharmaceutique comprenant ce dérivé et destinée à la prévention ou au traitement du cancer | |
AU2021226297B2 (en) | 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same | |
AU2021225683B2 (en) | 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same | |
WO2023054759A1 (fr) | Dérivé de 2-aminoquinazoline et composition antivirale le comprenant | |
WO2018151562A9 (fr) | Nouveau dérivé de benzimidazole présentant une activité inhibitrice de la jnk et son utilisation | |
WO2022086110A1 (fr) | Dérivé de thiobenzimidazole ou sel pharmaceutiquement acceptable de celui-ci, et leur utilisation | |
AU2021255176B2 (en) | 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same | |
WO2013058613A2 (fr) | Dérivé de 2-hydroxyarylamide ou sel de qualité pharmaceutique de celui-ci, son procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer le contenant comme principe actif | |
WO2021137665A1 (fr) | Composé dérivé de 1,2,3-triazole utilisé en tant qu'inhibiteur de hsp90, et son utilisation | |
WO2017123038A1 (fr) | Dérivé de pyridinol ou sel pharmaceutiquement acceptable de celui-ci, et composition pharmaceutique contenant celui-ci utilisé comme principe actif | |
WO2022119090A1 (fr) | Dérivés de biphénylpyrrolidine et de biphényldihydroimidazole permettant d'inhiber l'activité du récepteur 5-ht7 de la sérotonine, et composition pharmaceutique le comprenant comme principe actif | |
WO2018044136A1 (fr) | Nouveau composé, son procédé de préparation et composition pharmaceutique le contenant en tant que principe actif pour la prévention ou le traitement de maladies associées à la poly (adp-ribose) polymérase -1 (parp -1) | |
WO2023191536A1 (fr) | Dérivé de thiobenzimidazole ou sel pharmaceutiquement acceptable de celui-ci et utilisation associée | |
WO2023113456A1 (fr) | Nouveau composé pour dégrader un polypeptide ou une protéine cible à l'aide d'une polyubiquitination | |
WO2024005526A1 (fr) | Nouveau composé utilisé en tant qu'inhibiteur de nadph oxydase 2 et composition pharmaceutique le contenant | |
WO2022164239A1 (fr) | Composé dérivé de pyrazole-carboxamide et utilisation associée | |
WO2022197069A1 (fr) | Nouveau composé inhibant l'activité de la transglutaminase-2 et son utilisation | |
WO2022203332A1 (fr) | Nouveaux inhibiteurs de l'indoléamine 2,3-dioxygénase, leurs procédés de préparation et compositions pharmaceutiques les comprenant | |
WO2023121022A1 (fr) | Nouveaux inhibiteurs du récepteur de leucotriène b4 et leur utilisation | |
WO2022145989A1 (fr) | Dérivé de pyrimidodiazépine servant d'inhibiteur sélectif de plk1 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21959530 Country of ref document: EP Kind code of ref document: A1 |