KR101913789B1 - Compound for the treatment of diseases caused by corona virus infection - Google Patents
Compound for the treatment of diseases caused by corona virus infection Download PDFInfo
- Publication number
- KR101913789B1 KR101913789B1 KR1020170035178A KR20170035178A KR101913789B1 KR 101913789 B1 KR101913789 B1 KR 101913789B1 KR 1020170035178 A KR1020170035178 A KR 1020170035178A KR 20170035178 A KR20170035178 A KR 20170035178A KR 101913789 B1 KR101913789 B1 KR 101913789B1
- Authority
- KR
- South Korea
- Prior art keywords
- halogen
- substituted
- branched
- straight
- linear
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 133
- 201000010099 disease Diseases 0.000 title claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 21
- 208000001528 Coronaviridae Infections Diseases 0.000 title claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 135
- 150000002367 halogens Chemical class 0.000 claims description 130
- 125000000217 alkyl group Chemical group 0.000 claims description 88
- -1 nitro, phenyl Chemical group 0.000 claims description 64
- 125000003545 alkoxy group Chemical group 0.000 claims description 43
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 43
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 150000001412 amines Chemical class 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 24
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 125000004414 alkyl thio group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 230000003287 optical effect Effects 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- ZPCZNIYGVQMCOV-UHFFFAOYSA-N 2-methyl-4-nitro-1-phenylmethoxybenzene Chemical compound CC1=CC([N+]([O-])=O)=CC=C1OCC1=CC=CC=C1 ZPCZNIYGVQMCOV-UHFFFAOYSA-N 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 8
- CXVOZOWHZKPHQK-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-methyl-5-nitro-2-phenylmethoxybenzene Chemical group C(C1=CC=CC=C1)OC1=C(C=C(C=C1C)[N+](=O)[O-])C1=CC=C(C=C1)Cl CXVOZOWHZKPHQK-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- GICFSJSZQVHSFD-UHFFFAOYSA-N 3-(4-chlorophenyl)-5-methyl-4-phenylmethoxyaniline Chemical compound C(C1=CC=CC=C1)OC1=C(C=C(C=C1C1=CC=C(C=C1)Cl)N)C GICFSJSZQVHSFD-UHFFFAOYSA-N 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 230000036541 health Effects 0.000 claims description 6
- RAFBMRZNEUIWDW-UHFFFAOYSA-N tert-butyl N-(3-methyl-4-phenylmethoxyphenyl)carbamate Chemical compound C(C1=CC=CC=C1)OC1=C(C=C(C=C1)NC(OC(C)(C)C)=O)C RAFBMRZNEUIWDW-UHFFFAOYSA-N 0.000 claims description 6
- MDYHSVFGRXRAKR-UHFFFAOYSA-N 1-[4-(2-aminophenoxy)-3-methoxyphenyl]-6-(3,4-dimethylphenyl)hexan-2-one Chemical compound NC1=C(OC2=C(C=C(C=C2)CC(CCCCC2=CC(=C(C=C2)C)C)=O)OC)C=CC=C1 MDYHSVFGRXRAKR-UHFFFAOYSA-N 0.000 claims description 5
- RHRNFMLVDBBCKJ-UHFFFAOYSA-N 1-bromo-3-methyl-5-nitro-2-phenylmethoxybenzene Chemical compound C(C1=CC=CC=C1)OC1=C(C=C(C=C1C)[N+](=O)[O-])Br RHRNFMLVDBBCKJ-UHFFFAOYSA-N 0.000 claims description 5
- ZLUBTTCNPOFRAX-UHFFFAOYSA-N 1-phenoxy-4-phenylmethoxybenzene Chemical compound C=1C=CC=CC=1COC(C=C1)=CC=C1OC1=CC=CC=C1 ZLUBTTCNPOFRAX-UHFFFAOYSA-N 0.000 claims description 5
- VGYTVZWIKWXFMR-UHFFFAOYSA-N 3-(3-bromo-5-methyl-4-phenylmethoxyanilino)butan-2-one Chemical compound C(C1=CC=CC=C1)OC1=C(C=C(C=C1C)NC(C(C)=O)C)Br VGYTVZWIKWXFMR-UHFFFAOYSA-N 0.000 claims description 5
- AMGLLLYBWLEKAC-UHFFFAOYSA-N 3-bromo-5-methyl-4-phenylmethoxyaniline Chemical compound C(C1=CC=CC=C1)OC1=C(C=C(C=C1C)N)Br AMGLLLYBWLEKAC-UHFFFAOYSA-N 0.000 claims description 5
- FEEJFQCBQNEYPA-UHFFFAOYSA-N 5-[4-[(4-chlorophenyl)methoxy]phenoxy]-2-nitrobenzoic acid Chemical compound ClC1=CC=C(COC2=CC=C(OC=3C=CC(=C(C(=O)O)C=3)[N+](=O)[O-])C=C2)C=C1 FEEJFQCBQNEYPA-UHFFFAOYSA-N 0.000 claims description 5
- VBDFALOOAXMMFW-UHFFFAOYSA-N methyl 4-[4-[(4-chlorophenyl)methoxy]phenoxy]-2-nitrobenzoate Chemical compound ClC1=CC=C(COC2=CC=C(OC3=CC(=C(C(=O)OC)C=C3)[N+](=O)[O-])C=C2)C=C1 VBDFALOOAXMMFW-UHFFFAOYSA-N 0.000 claims description 5
- CADLUJRSKCJOCP-UHFFFAOYSA-N 2-(3-chlorophenoxy)aniline Chemical compound NC1=CC=CC=C1OC1=CC=CC(Cl)=C1 CADLUJRSKCJOCP-UHFFFAOYSA-N 0.000 claims description 4
- QTVVUPRJWRMNEQ-UHFFFAOYSA-N 3-[3-(4-chlorophenyl)-5-methyl-4-phenylmethoxyanilino]butan-2-one Chemical compound C(C1=CC=CC=C1)OC1=C(C=C(C=C1C1=CC=C(C=C1)Cl)NC(C(C)=O)C)C QTVVUPRJWRMNEQ-UHFFFAOYSA-N 0.000 claims description 4
- SPQQOHIJKCFWJF-UHFFFAOYSA-N 3-methyl-4-phenylmethoxyaniline Chemical compound CC1=CC(N)=CC=C1OCC1=CC=CC=C1 SPQQOHIJKCFWJF-UHFFFAOYSA-N 0.000 claims description 4
- JDRKNEMJCQALHM-UHFFFAOYSA-N 4-fluoro-2-phenylaniline Chemical compound NC1=CC=C(F)C=C1C1=CC=CC=C1 JDRKNEMJCQALHM-UHFFFAOYSA-N 0.000 claims description 4
- SYVITUYDQOZHNA-UHFFFAOYSA-N 5-[4-[(2,4-dichlorophenyl)methoxy]phenoxy]-2-nitrobenzoic acid Chemical compound ClC1=C(COC2=CC=C(OC=3C=CC(=C(C(=O)O)C=3)[N+](=O)[O-])C=C2)C=CC(=C1)Cl SYVITUYDQOZHNA-UHFFFAOYSA-N 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 235000013376 functional food Nutrition 0.000 claims description 4
- IIPHGJRWGDMKKV-OVCLIPMQSA-N (5e)-5-[[2-[(4-fluorophenyl)methoxy]-5-nitrophenyl]methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one Chemical compound S/1C(=S)NC(=O)C\1=C/C1=CC([N+](=O)[O-])=CC=C1OCC1=CC=C(F)C=C1 IIPHGJRWGDMKKV-OVCLIPMQSA-N 0.000 claims description 3
- PITCIFCXPVRFQQ-UHFFFAOYSA-N 1-(3-chlorophenyl)naphthalene Chemical compound ClC1=CC=CC(C=2C3=CC=CC=C3C=CC=2)=C1 PITCIFCXPVRFQQ-UHFFFAOYSA-N 0.000 claims description 3
- OBCBJNFGAMHBTC-UHFFFAOYSA-N 1-chloro-4-phenylmethoxybenzene Chemical compound C1=CC(Cl)=CC=C1OCC1=CC=CC=C1 OBCBJNFGAMHBTC-UHFFFAOYSA-N 0.000 claims description 3
- CVFKAMADWGOMSI-UHFFFAOYSA-N 1-fluoro-4-phenoxy-2-(trifluoromethyl)benzene Chemical compound C1=C(C(F)(F)F)C(F)=CC=C1OC1=CC=CC=C1 CVFKAMADWGOMSI-UHFFFAOYSA-N 0.000 claims description 3
- WKHVAQKNKVBRON-UHFFFAOYSA-N 2,4-dimethoxy-1-(2-nitrophenyl)benzene Chemical group COC1=CC(OC)=CC=C1C1=CC=CC=C1[N+]([O-])=O WKHVAQKNKVBRON-UHFFFAOYSA-N 0.000 claims description 3
- OOICRSNZHKYTFO-UHFFFAOYSA-N 2-(3,5-dichlorophenyl)-4-fluoroaniline Chemical compound Nc1ccc(F)cc1-c1cc(Cl)cc(Cl)c1 OOICRSNZHKYTFO-UHFFFAOYSA-N 0.000 claims description 3
- KBWPRTRQAVBICU-VXLYETTFSA-N 2-[[5-bromo-2-methoxy-4-[(E)-(2-oxo-1H-indol-3-ylidene)methyl]phenoxy]methyl]benzonitrile Chemical compound BrC=1C(=CC(=C(OCC2=C(C#N)C=CC=C2)C=1)OC)/C=C\1/C(NC2=CC=CC=C/12)=O KBWPRTRQAVBICU-VXLYETTFSA-N 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- FOWOANYXCPUXGM-OVCLIPMQSA-N (5e)-5-[[2-[(2-fluorophenyl)methoxy]-5-nitrophenyl]methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one Chemical compound S/1C(=S)NC(=O)C\1=C/C1=CC([N+](=O)[O-])=CC=C1OCC1=CC=CC=C1F FOWOANYXCPUXGM-OVCLIPMQSA-N 0.000 claims description 2
- URCLAPRSZLWPGP-UHFFFAOYSA-N 1-phenyl-4-phenylmethoxybenzene Chemical compound C=1C=CC=CC=1COC(C=C1)=CC=C1C1=CC=CC=C1 URCLAPRSZLWPGP-UHFFFAOYSA-N 0.000 claims description 2
- JPVNZNPTXPQPDF-UHFFFAOYSA-N 4-oxo-4-(2-phenylanilino)butanoic acid Chemical compound OC(=O)CCC(=O)NC1=CC=CC=C1C1=CC=CC=C1 JPVNZNPTXPQPDF-UHFFFAOYSA-N 0.000 claims description 2
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 claims description 2
- CBPMBYMIZJNSJS-UHFFFAOYSA-N [4-(2-amino-5-fluorophenyl)phenyl]-phenylmethanone Chemical compound NC1=C(C=C(C=C1)F)C1=CC=C(C=C1)C(=O)C1=CC=CC=C1 CBPMBYMIZJNSJS-UHFFFAOYSA-N 0.000 claims description 2
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims 10
- 125000005843 halogen group Chemical group 0.000 claims 5
- 241000711573 Coronaviridae Species 0.000 abstract description 23
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 239000000839 emulsion Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 125000001072 heteroaryl group Chemical group 0.000 description 42
- 125000003118 aryl group Chemical group 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 18
- 241000700605 Viruses Species 0.000 description 18
- 206010057190 Respiratory tract infections Diseases 0.000 description 16
- 230000002829 reductive effect Effects 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 230000000840 anti-viral effect Effects 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 208000015181 infectious disease Diseases 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 9
- ZSBDGXGICLIJGD-UHFFFAOYSA-N 4-phenoxyphenol Chemical compound C1=CC(O)=CC=C1OC1=CC=CC=C1 ZSBDGXGICLIJGD-UHFFFAOYSA-N 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 125000005129 aryl carbonyl group Chemical group 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 230000000241 respiratory effect Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- 150000004820 halides Chemical class 0.000 description 6
- 241000008904 Betacoronavirus Species 0.000 description 5
- 241000315672 SARS coronavirus Species 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 208000011580 syndromic disease Diseases 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- 230000009385 viral infection Effects 0.000 description 5
- 0 *c(c(*)c1*)c(*)c(*)c1O Chemical compound *c(c(*)c1*)c(*)c(*)c1O 0.000 description 4
- HXBMIQJOSHZCFX-UHFFFAOYSA-N 1-(bromomethyl)-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1CBr HXBMIQJOSHZCFX-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 4
- 241000004176 Alphacoronavirus Species 0.000 description 4
- 208000036142 Viral infection Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241000271566 Aves Species 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 3
- 229940077388 benzenesulfonate Drugs 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 235000010290 biphenyl Nutrition 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
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- LSYJVNBLKIGSRE-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-methyl-2-phenylmethoxybenzene Chemical group C(C1=CC=CC=C1)OC1=C(C=CC=C1C1=CC=C(C=C1)Cl)C LSYJVNBLKIGSRE-UHFFFAOYSA-N 0.000 description 2
- KQNBRMUBPRGXSL-UHFFFAOYSA-N 1-(bromomethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1 KQNBRMUBPRGXSL-UHFFFAOYSA-N 0.000 description 2
- CLVZAOXIUCQNKS-UHFFFAOYSA-N 1-nitro-2-[(4-phenoxyphenoxy)methyl]benzene Chemical compound [N+](=O)([O-])C1=C(C=CC=C1)COC1=CC=C(C=C1)OC1=CC=CC=C1 CLVZAOXIUCQNKS-UHFFFAOYSA-N 0.000 description 2
- REZBJCUQELMZBL-UHFFFAOYSA-N 1-tert-butyl-4-phenoxybenzene Chemical compound C1=CC(C(C)(C)C)=CC=C1OC1=CC=CC=C1 REZBJCUQELMZBL-UHFFFAOYSA-N 0.000 description 2
- OIMRLHCSLQUXLL-UHFFFAOYSA-N 3-chlorobutan-2-one Chemical compound CC(Cl)C(C)=O OIMRLHCSLQUXLL-UHFFFAOYSA-N 0.000 description 2
- NGWCWGDJHVTKSP-UHFFFAOYSA-N 5-(4-hydroxyphenoxy)-2-nitrobenzoic acid Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(OC=2C=CC(O)=CC=2)=C1 NGWCWGDJHVTKSP-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 241000282836 Camelus dromedarius Species 0.000 description 2
- 241000288673 Chiroptera Species 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 241001461743 Deltacoronavirus Species 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 208000000059 Dyspnea Diseases 0.000 description 2
- 206010013975 Dyspnoeas Diseases 0.000 description 2
- 241000008920 Gammacoronavirus Species 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 241001109669 Human coronavirus HKU1 Species 0.000 description 2
- 241001428935 Human coronavirus OC43 Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 231100000676 disease causative agent Toxicity 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- HZPPFLLSXHUBMU-UHFFFAOYSA-N methyl 2-(2,4-diaminophenoxy)benzoate Chemical compound COC(=O)C1=CC=CC=C1OC1=CC=C(N)C=C1N HZPPFLLSXHUBMU-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 1
- MPTWJHQTHSKJER-UHFFFAOYSA-N 1,3-difluoro-5-phenylbenzene Chemical group FC1=CC(F)=CC(C=2C=CC=CC=2)=C1 MPTWJHQTHSKJER-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JAFLVWLZURLDHU-UHFFFAOYSA-N 1-(2-methylsulfanylphenyl)-2-nitrobenzene Chemical compound CSC1=CC=CC=C1C1=CC=CC=C1[N+]([O-])=O JAFLVWLZURLDHU-UHFFFAOYSA-N 0.000 description 1
- KXVHRVKZHQNSBL-UHFFFAOYSA-N 1-(3-chlorophenoxy)cyclohexa-3,5-diene-1,2-diamine Chemical compound ClC=1C=C(OC2(C(C=CC=C2)N)N)C=CC=1 KXVHRVKZHQNSBL-UHFFFAOYSA-N 0.000 description 1
- RGLQSFFFIREZFV-UHFFFAOYSA-N 1-(bromomethyl)-2,4-dichlorobenzene Chemical compound ClC1=CC=C(CBr)C(Cl)=C1 RGLQSFFFIREZFV-UHFFFAOYSA-N 0.000 description 1
- RSQUAQMIGSMNNE-UHFFFAOYSA-N 1-methyl-3h-indol-2-one Chemical compound C1=CC=C2N(C)C(=O)CC2=C1 RSQUAQMIGSMNNE-UHFFFAOYSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- OQSQUIZZPAFLIO-UHFFFAOYSA-N 2-[(4-phenoxyphenoxy)methyl]aniline Chemical compound O(C1=CC=CC=C1)C1=CC=C(OCC2=C(N)C=CC=C2)C=C1 OQSQUIZZPAFLIO-UHFFFAOYSA-N 0.000 description 1
- AJMYXGRHDGEXOJ-UHFFFAOYSA-N 2-bromo-6-methyl-4-nitrophenol Chemical compound CC1=CC([N+]([O-])=O)=CC(Br)=C1O AJMYXGRHDGEXOJ-UHFFFAOYSA-N 0.000 description 1
- MYTCPOIRLJGZEV-UHFFFAOYSA-N 2-iodo-6-methyl-4-nitrophenol Chemical compound CC1=CC([N+]([O-])=O)=CC(I)=C1O MYTCPOIRLJGZEV-UHFFFAOYSA-N 0.000 description 1
- KDQPMQNHVQVVMR-UHFFFAOYSA-N 2-methyl-4-nitrophenol Chemical compound CC1=CC([N+]([O-])=O)=CC=C1O KDQPMQNHVQVVMR-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 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
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 1
- PGRHWCVTZCINIQ-UHFFFAOYSA-N 5-chloro-2-(1-chloronaphthalen-2-yl)oxyaniline Chemical compound NC1=CC(Cl)=CC=C1OC1=CC=C(C=CC=C2)C2=C1Cl PGRHWCVTZCINIQ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 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
- 102000053723 Angiotensin-converting enzyme 2 Human genes 0.000 description 1
- 108090000975 Angiotensin-converting enzyme 2 Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WERNCCVZMCGANB-NSCUHMNNSA-N C/C=C(\C(N1)=O)/SC1=S Chemical compound C/C=C(\C(N1)=O)/SC1=S WERNCCVZMCGANB-NSCUHMNNSA-N 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 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
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 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
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- RVMOCRWUDDYZKM-OVCLIPMQSA-N FC1=C(COC2=C(\C=C\3/C(CC(N/3)=S)=O)C=C(C=C2)[N+](=O)[O-])C=CC=C1 Chemical compound FC1=C(COC2=C(\C=C\3/C(CC(N/3)=S)=O)C=C(C=C2)[N+](=O)[O-])C=CC=C1 RVMOCRWUDDYZKM-OVCLIPMQSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 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
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 1
- 241000711467 Human coronavirus 229E Species 0.000 description 1
- 241000482741 Human coronavirus NL63 Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- FMRDQSUDXAZJBP-UHFFFAOYSA-N N#CCNC(CNc(c(-c1ccccc1)cc(F)c1)c1F)=O Chemical compound N#CCNC(CNc(c(-c1ccccc1)cc(F)c1)c1F)=O FMRDQSUDXAZJBP-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- UXEUXXQAXURKNO-UHFFFAOYSA-N Nc1ccccc1Oc(cc1)cc(C(F)(F)F)c1F Chemical compound Nc1ccccc1Oc(cc1)cc(C(F)(F)F)c1F UXEUXXQAXURKNO-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 241001125039 Pipistrellus Species 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229940096437 Protein S Drugs 0.000 description 1
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 241000287219 Serinus canaria Species 0.000 description 1
- 101710198474 Spike protein Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 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
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-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
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- SHTAJBWYWDYIMT-OVCLIPMQSA-N [O-][N+](C(C=C1)=CC(/C=C(\C(C2)=O)/NC2=S)=C1OCC(C=C1)=CC=C1F)=O Chemical compound [O-][N+](C(C=C1)=CC(/C=C(\C(C2)=O)/NC2=S)=C1OCC(C=C1)=CC=C1F)=O SHTAJBWYWDYIMT-OVCLIPMQSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- YTIVTFGABIZHHX-UHFFFAOYSA-L acetylenedicarboxylate(2-) Chemical compound [O-]C(=O)C#CC([O-])=O YTIVTFGABIZHHX-UHFFFAOYSA-L 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000012387 aerosolization Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 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
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229940126675 alternative medicines Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 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
- 238000010241 blood sampling Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 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
- 230000002068 genetic effect Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 208000021760 high fever Diseases 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- MNFPMOTUZUWDFZ-UHFFFAOYSA-N methyl 4-(4-hydroxyphenoxy)-2-nitrobenzoate Chemical compound OC1=CC=C(OC2=CC(=C(C(=O)OC)C=C2)[N+](=O)[O-])C=C1 MNFPMOTUZUWDFZ-UHFFFAOYSA-N 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 238000013081 phylogenetic analysis Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- 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
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
- A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Mycology (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- Nutrition Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a compound for the treatment of diseases caused by coronavirus infection, and the compound according to the present invention exhibits an excellent inhibitory activity against coronavirus. Therefore, the present invention relates to a pharmaceutical composition for preventing or treating diseases such as mers, It is useful as an emulsion composition.
Description
The present invention relates to compounds for treating diseases caused by coronavirus infection.
The coronavirus is a single-stranded positive RNA virus in the envelope and the genome size is 25-32 kb, which is a relatively large virus among known RNA viruses. It is said that the virus name comes from the Latin Corona, which has a special shape of a flame or crown with spike protein, which is stick-shaped protuberance, on the outer skin.
The coronaviruses found in birds, animals, birds, cats, dogs, cows, pigs, and rats were first divided into four groups (Alpha-, Beta-, Gamma-, and Deltacoronavirus) Loses. The alpha and beta coronavirus groups are predominantly infected in mammals, while the gamma and delta coronavirus groups are found in birds. Coronavirus is known to cause a variety of diseases in animals such as gastrointestinal and respiratory diseases.
HCoV-229E and HCoV-OC43 found in the 1960s, HCoV-NL63 (2004) and HCoV-HKU1 (2005) found after the SARS pandemic, and these are generally associated with upper respiratory tract infections It is known, but it can lead to severe lung disease in immunodeficiency patients. It has been reported that the rate of coronavirus infection is increased mainly in winter and early spring, and coronavirus is the causative agent among adult cold patients. In 2003, SARS-CoV was first reported to cause Severe Acute Respiratory Syndrome (SARS). According to the World Health Organization (WHO) report, 8,273 patients worldwide There were 775 deaths (about 10% mortality), and by 2004, additional patient outbreaks and deaths were reported.
In September 2012, there was a serious respiratory disease patient with respiratory symptoms such as high fever, cough, and shortness of breath similar to SARS, and the causative agent was HCoV-EMC, which is different from the known virus.
The new coronavirus was classified as Middle East respiratory syndrome-coronavirus (MERS-CoV) in the coronavirus study group of the International Committee on Taxonomy of Viruses in May 2013. The virus is presumed to be the most potent source of bats, since genetic sequencing is similar to Pipistrellus Bat CoV-HKU5 and HKU4 found in bats. However, a recent study, published in The Lancet Infectious Diseases journals, found that all of the 50 blood samplings of Oman's dromedary camel were found, indicating that MERS-CoV antibody was found. In the Canary Islands, however, 15 out of 105 were positive for antibodies.
Although the virus itself was not found, the study showed that these camels were infected with mers or similar virus at some point and showed that the virus host is very likely to be a camel.
After the first case of infection in Saudi Arabia in September 2012, MERS-CoV coronavirus (MERS-CoV) infection was officially reported to WHO until June 2018, with 808 worldwide and 313 deaths (34.5%).
Early diagnosis of MERS-CoV coronavirus (MERS-CoV) The patient's clinical symptoms were significantly similar to SARS, and there was concern that SARS might have a significant association with SARS. However, It has been found that it is a new virus that is significantly different from the SARS virus.
First, the Middle East Respiratory Syndrome coronavirus (MERS-CoV) showed about 55% lower nucleotide homology with the SARS virus. In the phylogenetic analysis, the two viruses showed different evolutionary differences, The middle respiratory syndrome coronavirus (MERS-CoV) in the B group of beta-coronavirus belonged to the C group of beta-coronaviruses. Those belonging to the beta coronavirus group are known to be the SAR coronaviruses and human coronaviruses HCoV-HKU1 and HCoV-OC43.
In addition, the pathway for SARS and the respiratory syndrome coronavirus (MERS-CoV) is also different. The SARS virus is the ACE2 receptor distributed in human airway epithelium, the MERS-CoV DDP4 (also called CD26) in the parental cells is used. Both MERS-CoV and SARS viruses have high mortality rates, but they must be spread through large droplets after progressing to pneumonia. Therefore, influenza A Suggests that infectivity may be reduced by as much as compared to diseases that spread to aerosols, such as measles cases. However, in the case of SARS, the risk of infectious disease is still high because the spreading power can be considerably increased in the case of close exposure to SARS or aerosolization of respiratory droplets.
It is not yet clear what the initial source of the MERS-CoV coronavirus (MERS-CoV) was and how it spread to humans and caused the disease. However, two cases of confirmed new coronavirus cases were found to be on farm and animal contact. This shows the possibility of common infection of the new coronavirus.
Major clinical symptoms are fever (87%), cough (89%), dyspnea, and some patients have vomiting and diarrhea (35%). Renal failure also occurs in patients with impaired immune function, with a mortality rate of 34.5%. (Saudi Arabia, Qatar, etc.), and it is estimated that these areas are infected areas, but they can not accurately identify the exact route of infection. However, there has been no evidence of widespread infection among people, but it has been confirmed that close contact is made with family members or medical staff. The incubation period is estimated from 9 days to 12 days.
There is no developed drug or preventive vaccine for which the therapeutic effect of the MERS-CoV virus has been confirmed yet in the Middle East respiratory syndrome coronavirus (MERS-CoV). Until now, there has been no special treatment or prevention method except to avoid contact with suspected viral infection patients and thorough personal hygiene. Currently, antibiotics, ribavirin, interferon, and patient's serum have been used to treat infections of the Middle East Respiratory Syndrome Coronavirus (MERSCoV), but these therapeutic agents have not been shown to have a specific effect. However, recently, it has been known that radtunib has potential for treatment of respiratory viral diseases (Patent Document 1).
Therefore, it is very urgent to develop alternative medicines for the treatment and prevention of diseases of the respiratory syndrome coronavirus (MERS-CoV) in the Middle East.
It is an object of the present invention to provide a pharmaceutical composition for antiviral use.
Another object of the present invention is to provide a health functional food composition for preventing or ameliorating diseases caused by a virus infection.
Another object of the present invention is to provide a novel structure compound showing antiviral activity against the virus.
Another object of the present invention is to provide a process for producing the compound of the novel structure.
In order to achieve the above object,
The present invention provides an antiviral pharmaceutical composition comprising, as an active ingredient, a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]
(In the
-L- is a single bond, -O-, or -O- (CH 2) -, and;
R 1 is selected from the group consisting of -H, -OH, -NH 3+ , halogen, amine, nitro, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, C 6-10 aryl,
Wherein p and q are independently an integer from 0 to 3 and A 1 is -COOH or -NA 2 A 3 wherein A 2 and A 3 are independently -H, CN is a substituted C 1-5 straight chain or branched chain alkyl, or A 2 and A 3 are heterocycloalkyl of 5 to 10 ring members, which are linked together and contain at least one N and are unsubstituted or substituted by one -OH,
Wherein B 1 is heterocycloalkyl of unsubstituted or substituted 5 to 10-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, and said substituted 5- to 10-membered heterocyclo Alkyl is heterocycloalkyl of 5 to 10 ring members substituted with at least one substituent selected from the group consisting of = O and = S;
R 2 is -H, or halogen;
R 3 is -H, halogen, amine, nitro, phenyl, unsubstituted or substituted phenyloxy, -NE 1 E 2 , or
Here, the substituted phenyloxy is halogen, the group consisting of nitro, a -COOH, a linear or branched alkyl, straight-chain or branched alkoxycarbonyl straight or branched C 1-5 alkoxy and C 1-5 of the C 1-5 Is phenyloxy substituted with one or more substituents selected from < RTI ID = 0.0 >
Wherein E 1 and E 2 are independently -H, C 1-5 linear or branched alkoxycarbonyl, C 1-5 straight or branched chain alkylcarbonyl C 1-5 straight or branched chain alkyl,
Wherein B 2 is heteroaryl of unsubstituted or substituted 5 to 10-membered rings containing one or more N, heteroaryl of substituted 5 to 10-membered rings is heteroaryl of 5 to 10-membered rings substituted with one or more = Aryl;
R 4 is -H, or halogen;
R 5 is -H, halogen, C 1-10 straight or branched chain alkyl, or
Wherein B 3 is heteroaryl of unsubstituted or substituted 5- to 10-membered rings containing at least one N, and heteroaryl of said substituted 5 to 10-membered rings is substituted with at least one ═O and at least one C 1-3 straight chain Or heteroaryl of 5 to 10 heterocycle substituted with side chain alkyl;
R 6 is -H, halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, or C 1-10 straight or branched alkylsulfanyl;
R 7 is -H, halogen, or C 1-10 straight or branched chain alkyl unsubstituted or substituted with one or more halogens;
R 8 is selected from the group consisting of -H, halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, C 1-10 straight or branched alkoxycarbonyl, C 6-10 arylcarbonyl, Or a straight-chain alkylcarbonyl C 1-3 straight-chain alkyl of C 6-10 aryl C 1-5 substituted with one or more methyl groups, or is joined together with R 7 to form an unsubstituted C 6-10 aryl;
R 9 is -H, or halogen; And
R 10 is -H, -CN, halogen, amine, C 1-10 linear or branched alkoxycarbonyl, or R 9 is taken together to form an unsubstituted C 6-10 aryl.
The present invention also provides a health functional food composition for preventing or ameliorating a disease caused by a viral infection comprising a compound represented by the following general formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1]
(In the
-L- is a single bond, -O-, or -O- (CH 2) -, and;
R 1 is selected from the group consisting of -H, -OH, -NH 3+ , halogen, amine, nitro, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, C 6-10 aryl,
Wherein p and q are independently an integer from 0 to 3 and A 1 is -COOH or -NA 2 A 3 wherein A 2 and A 3 are independently -H, CN is a substituted C 1-5 straight chain or branched chain alkyl, or A 2 and A 3 are heterocycloalkyl of 5 to 10 ring members, which are linked together and contain at least one N and are unsubstituted or substituted by one -OH,
Wherein B 1 is heterocycloalkyl of unsubstituted or substituted 5 to 10-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, and said substituted 5- to 10-membered heterocyclo Alkyl is heterocycloalkyl of 5 to 10 ring members substituted with at least one substituent selected from the group consisting of = O and = S;
R 2 is -H, or halogen;
R 3 is -H, halogen, amine, nitro, phenyl, unsubstituted or substituted phenyloxy, -NE 1 E 2 , or
Here, the substituted phenyloxy is halogen, the group consisting of nitro, a -COOH, a linear or branched alkyl, straight-chain or branched alkoxycarbonyl straight or branched C 1-5 alkoxy and C 1-5 of the C 1-5 Is phenyloxy substituted with one or more substituents selected from < RTI ID = 0.0 >
Wherein E 1 and E 2 are independently -H, C 1-5 linear or branched alkoxycarbonyl, C 1-5 straight or branched chain alkylcarbonyl C 1-5 straight or branched chain alkyl,
Wherein B 2 is heteroaryl of unsubstituted or substituted 5 to 10-membered rings containing one or more N, heteroaryl of substituted 5 to 10-membered rings is heteroaryl of 5 to 10-membered rings substituted with one or more = Aryl;
R 4 is -H, or halogen;
R 5 is -H, halogen, C 1-10 straight or branched chain alkyl, or
Wherein B 3 is heteroaryl of unsubstituted or substituted 5- to 10-membered rings containing at least one N, and heteroaryl of said substituted 5 to 10-membered rings is substituted with at least one ═O and at least one C 1-3 straight chain Or heteroaryl of 5 to 10 heterocycle substituted with side chain alkyl;
R 6 is -H, halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, or C 1-10 straight or branched alkylsulfanyl;
R 7 is -H, halogen, or C 1-10 straight or branched chain alkyl unsubstituted or substituted with one or more halogens;
R 8 is selected from the group consisting of -H, halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, C 1-10 straight or branched alkoxycarbonyl, C 6-10 arylcarbonyl, Or a straight-chain alkylcarbonyl C 1-3 straight-chain alkyl of C 6-10 aryl C 1-5 substituted with one or more methyl groups, or is joined together with R 7 to form an unsubstituted C 6-10 aryl;
R 9 is -H, or halogen; And
R 10 is -H, -CN, halogen, amine, C 1-10 linear or branched alkoxycarbonyl, or R 9 is taken together to form an unsubstituted C 6-10 aryl.
Further, the present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]
(In the
-L- is a single bond, -O-, or -O- (CH 2) -, and;
R 1 is selected from the group consisting of -H, -OH, -NH 3+ , halogen, amine, nitro, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, C 6-10 aryl,
Wherein p and q are independently an integer from 0 to 3 and A 1 is -COOH or -NA 2 A 3 wherein A 2 and A 3 are independently -H, CN is a substituted C 1-5 straight chain or branched chain alkyl, or A 2 and A 3 are heterocycloalkyl of 5 to 10 ring members, which are linked together and contain at least one N and are unsubstituted or substituted by one -OH,
Wherein B 1 is heterocycloalkyl of unsubstituted or substituted 5 to 10-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, and said substituted 5- to 10-membered heterocyclo Alkyl is heterocycloalkyl of 5 to 10 ring members substituted with at least one substituent selected from the group consisting of = O and = S;
R 2 is -H, or halogen;
R 3 is -H, halogen, amine, nitro, phenyl, unsubstituted or substituted phenyloxy, -NE 1 E 2 , or
Here, the substituted phenyloxy is halogen, the group consisting of nitro, a -COOH, a linear or branched alkyl, straight-chain or branched alkoxycarbonyl straight or branched C 1-5 alkoxy and C 1-5 of the C 1-5 Is phenyloxy substituted with one or more substituents selected from < RTI ID = 0.0 >
Wherein E 1 and E 2 are independently -H, C 1-5 linear or branched alkoxycarbonyl, C 1-5 straight or branched chain alkylcarbonyl C 1-5 straight or branched chain alkyl,
Wherein B 2 is heteroaryl of unsubstituted or substituted 5 to 10-membered rings containing one or more N, heteroaryl of substituted 5 to 10-membered rings is heteroaryl of 5 to 10-membered rings substituted with one or more = Aryl;
R 4 is -H, or halogen;
R 5 is -H, halogen, C 1-10 straight or branched chain alkyl, or
Wherein B 3 is heteroaryl of unsubstituted or substituted 5- to 10-membered rings containing at least one N, and heteroaryl of said substituted 5 to 10-membered rings is substituted with at least one ═O and at least one C 1-3 straight chain Or heteroaryl of 5 to 10 heterocycle substituted with side chain alkyl;
R 6 is -H, halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, or C 1-10 straight or branched alkylsulfanyl;
R 7 is -H, halogen, or C 1-10 straight or branched chain alkyl unsubstituted or substituted with one or more halogens;
R 8 is selected from the group consisting of -H, halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, C 1-10 straight or branched alkoxycarbonyl, C 6-10 arylcarbonyl, Or a straight-chain alkylcarbonyl C 1-3 straight-chain alkyl of C 6-10 aryl C 1-5 substituted with one or more methyl groups, or is joined together with R 7 to form an unsubstituted C 6-10 aryl;
R 9 is -H, or halogen; And
R 10 is -H, -CN, halogen, amine, C 1-10 linear or branched alkoxycarbonyl, or R 9 is taken together to form an unsubstituted C 6-10 aryl.
The present invention also relates to a process for producing a compound represented by the formula (1)
Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (1a).
[Reaction Scheme 1]
(In the
X is halogen; L 1 is -O- (CH 2 ) -; L 2 is methylene;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently as defined in
The compound represented by the formula (1a) is a compound contained in the compound represented by the formula (1).
Further, the present invention relates to a process for the preparation of
There is provided a process for preparing a compound represented by the above formula (1), comprising the step of treating a compound represented by the formula (1b) with hydrochloric acid to prepare a compound represented by the formula (1c).
[Reaction Scheme 2]
(In the above Reaction Scheme 2,
L 1 is -O- (CH 2 ) -;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently as defined in
The compounds represented by formulas (1b) and (1c) are independently included in the compound represented by formula (1).
The compounds according to the present invention exhibit an excellent inhibitory activity against coronaviruses, and therefore are useful as pharmaceutical compositions for preventing or treating diseases caused by coronaviruses such as MERS, SARS, and the like.
Figure 1 shows immunoblot analysis of the antiviral activity effects of the example compounds in Murs coronavirus infected Huh-7 cells.
Hereinafter, the present invention will be described in detail.
The present invention provides an antiviral pharmaceutical composition comprising, as an active ingredient, a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]
(In the
-L- is a single bond, -O-, or -O- (CH 2) -, and;
R 1 is selected from the group consisting of -H, -OH, -NH 3+ , halogen, amine, nitro, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, C 6-10 aryl,
Wherein p and q are independently an integer from 0 to 3 and A 1 is -COOH or -NA 2 A 3 wherein A 2 and A 3 are independently -H, CN is a substituted C 1-5 straight chain or branched chain alkyl, or A 2 and A 3 are heterocycloalkyl of 5 to 10 ring members, which are linked together and contain at least one N and are unsubstituted or substituted by one -OH,
Wherein B 1 is heterocycloalkyl of unsubstituted or substituted 5 to 10-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, and said substituted 5- to 10-membered heterocyclo Alkyl is heterocycloalkyl of 5 to 10 ring members substituted with at least one substituent selected from the group consisting of = O and = S;
R 2 is -H, or halogen;
R 3 is -H, halogen, amine, nitro, phenyl, unsubstituted or substituted phenyloxy, -NE 1 E 2 , or
Here, the substituted phenyloxy is halogen, the group consisting of nitro, a -COOH, a linear or branched alkyl, straight-chain or branched alkoxycarbonyl straight or branched C 1-5 alkoxy and C 1-5 of the C 1-5 Is phenyloxy substituted with one or more substituents selected from < RTI ID = 0.0 >
Wherein E 1 and E 2 are independently -H, C 1-5 linear or branched alkoxycarbonyl, C 1-5 straight or branched chain alkylcarbonyl C 1-5 straight or branched chain alkyl,
Wherein B 2 is heteroaryl of unsubstituted or substituted 5 to 10-membered rings containing one or more N, heteroaryl of substituted 5 to 10-membered rings is heteroaryl of 5 to 10-membered rings substituted with one or more = Aryl;
R 4 is -H, or halogen;
R 5 is -H, halogen, C 1-10 straight or branched chain alkyl, or
Wherein B 3 is heteroaryl of unsubstituted or substituted 5- to 10-membered rings containing at least one N, and heteroaryl of said substituted 5 to 10-membered rings is substituted with at least one ═O and at least one C 1-3 straight chain Or heteroaryl of 5 to 10 heterocycle substituted with side chain alkyl;
R 6 is -H, halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, or C 1-10 straight or branched alkylsulfanyl;
R 7 is -H, halogen, or C 1-10 straight or branched chain alkyl unsubstituted or substituted with one or more halogens;
R 8 is selected from the group consisting of -H, halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, C 1-10 straight or branched alkoxycarbonyl, C 6-10 arylcarbonyl, Or a straight-chain alkylcarbonyl C 1-3 straight-chain alkyl of C 6-10 aryl C 1-5 substituted with one or more methyl groups, or is joined together with R 7 to form an unsubstituted C 6-10 aryl;
R 9 is -H, or halogen; And
R 10 is -H, -CN, halogen, amine, C 1-10 linear or branched alkoxycarbonyl, or R 9 is taken together to form an unsubstituted C 6-10 aryl.
Preferably,
-L- is a single bond, -O-, or -O- (CH 2) -, and;
R 1 is selected from the group consisting of -H, -OH, -NH 3+ , halogen, amine, nitro, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, C 6-10 aryl,
Wherein p and q are independently an integer from 0 to 3 and A 1 is -COOH or -NA 2 A 3 wherein A 2 and A 3 are independently -H, CN is a substituted C 1-3 straight or branched chain alkyl or A 2 and A 3 are heterocycloalkyl of a hexa-ring substituted with one or more of N and unsubstituted or substituted by one -OH,
Wherein B 1 is heterocycloalkyl of unsubstituted or substituted 5 to 10-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, and said substituted 5- to 10-membered heterocyclo Alkyl is heterocycloalkyl of 5 to 10 ring members substituted with at least one substituent selected from the group consisting of = O and = S;
R 2 is -H, or halogen;
R 3 is -H, halogen, amine, nitro, phenyl, unsubstituted or substituted phenyloxy, -NE 1 E 2 , or
Here, the substituted phenyloxy is halogen, the group consisting of nitro, a -COOH, a linear or branched alkyl, straight-chain or branched alkoxycarbonyl straight or branched C 1-3 alkoxy and C 1-3 of the C 1-3 Is phenyloxy substituted with one or more substituents selected from < RTI ID = 0.0 >
Wherein E 1 and E 2 are independently -H, C 1-3 linear or branched alkoxycarbonyl, C 1-3 linear or branched alkylcarbonyl C 1-3 linear or branched alkyl,
Wherein B 2 is heteroaryl of unsubstituted or substituted 5 to 10-membered rings containing one or more N, heteroaryl of substituted 5 to 10-membered rings is heteroaryl of 5 to 10-membered rings substituted with one or more = Aryl;
R 4 is -H, or halogen;
R 5 is -H, halogen, C 1-5 linear or branched alkyl, or
Wherein B 3 is heteroaryl of unsubstituted or substituted 5- to 10-membered rings containing at least one N, and heteroaryl of said substituted 5 to 10-membered rings is substituted with at least one ═O and at least one C 1-3 straight chain Or heteroaryl of 5 to 10 heterocycle substituted with side chain alkyl;
R 6 is -H, halogen, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, or C 1-5 straight or branched alkylsulfanyl;
R 7 is -H, halogen, or C 1-5 straight or branched chain alkyl unsubstituted or substituted with one or more halogens;
R 8 is selected from the group consisting of -H, halogen, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, C 1-5 straight or branched alkoxycarbonyl, C 6-10 arylcarbonyl, or straight chain alkyl of straight-chain alkyl-carbonyl C 1-2 aryl C 1-5 of a C 6-10 substituted with at least a methyl group is connected with the R 7 forms an aryl unsubstituted C 6;
R 9 is -H, or halogen; And
R 10 is -H, -CN, halogen, amine, C 1-5 linear or branched alkoxycarbonyl, or joined together with R 9 to form an unsubstituted C 6 aryl.
More preferably,
-L- is a single bond, -O-, or -O- (CH 2) -, and;
R 1 is -H, methyl, methoxy, amine, -NH 3+ , nitro,
R 2 is -H, or -F;
R 3 is -H, -Cl, amine, nitro, phenyl,
R 4 is -H, -F, -Cl, or -Br;
R < 5 > is -H, methyl, -Br or
R 6 is -H, -F, -Cl, methoxy, or methylsulfanyl;
R 7 is -H, -Cl, or -CF 3 ;
R 8 is -H, -F, -Cl, methoxy, tert-butyl, phenylcarbonyl,
R 9 is -H, or -Cl;
R 10 is -H, -Cl, -CN, amine, or
Most preferably,
The compound represented by the formula (1) is any one selected from the following group of compounds.
(1) 2 - ((4-phenoxyphenoxy) methyl) benzene amine;
(2) Methyl 4- (4- (4-chlorobenzyloxy) phenoxy) -2-nitrobenzoate;
(3) 5- (4- (4-chlorobenzyloxy) phenoxy) -2-nitrobenzoic acid;
(4) 5- (4- (2,4-dichlorobenzyloxy) phenoxy) -2-nitrobenzoic acid;
(5) 2 - ((Biphenyl-4-yloxy) methyl) benzene amine;
(6) 2 - ((4-chlorophenoxy) methyl) benzene amine;
(7) 4- (benzyloxy) -3-methylbenzenamine;
(8) 1- (Benzyloxy) -2-methyl-4-nitrobenzene;
(9) tert-Butyl 4- (benzyloxy) -3-methylphenylcarbamate;
(10) (E) -methyl 4 - ((2 - ((1-methyl-2-oxoindolin-3-ylidene) methyl) phenoxy) methyl) benzoate;
(11) (E) -2 - ((5-Bromo-2-methoxy-4 - ((2-oxoindolin-3-ylidene) methyl) phenoxy) methyl) benzonitrile;
(12) 4- (benzyloxy) -3-bromo-5-methylbenzenamine;
(13) 2- (benzyloxy) -1-bromo-3-methyl-5-nitrobenzene;
(14) 3- (4- (Benzyloxy) -3-bromo-5-methylphenylamino) butan-2-one;
(15) 6- (Benzyloxy) -4'-chloro-5-methylbiphenyl-3-amine;
(16) 2- (Benzyloxy) -4'-chloro-3-methyl-5-nitrobiphenyl;
(17) 3- (6- (Benzyloxy) -4'-chloro-5-methylbiphenyl-3-ylamino) butan-2-one;
(18) 2- (4-tert-butylphenoxy) benzene amine;
(19) 2- (4-Fluoro-3- (trifluoromethyl) phenoxy) benzene amine;
(20) 1- (4- (2-Aminophenoxy) -3-methoxyphenyl) -6- (3,4-dimethylphenyl) hexan-2-one;
(21) 2- (3-chlorophenoxy) benzenaminium;
(22) 5-Chloro-2- (1-chloronaphthalen-2-yloxy) benzeneamine;
(23) methyl 2- (2,4-diaminophenoxy) benzoate;
(24) (E) -5- (2- (2-fluorobenzyloxy) -5-nitrobenzylidene) -2-thioxothiazolidin-4-one;
(25) (E) -5- (2- (4-fluorobenzyloxy) -5-nitrobenzylidene) -2-thioxothiazolidin-4-one;
(26) 5-fluorobiphenyl-2-amine;
(27) 4- (Biphenyl-2-ylamino) -4-oxobutanoic acid;
(28) 3 ', 5'-Dichloro-5-fluorobiphenyl-2-amine;
(29) 2,4-dimethoxy-2'-nitrobiphenyl;
(30) N- (Biphenyl-2-yl) -3- (3-hydroxypiperidin-1-yl) propanamide;
(31) 4-Chloro-2- (naphthalen-1-yl) benzene amine;
(32) methyl (2'-nitrobiphenyl-2-yl) sulfanyl;
(33) N- (Cyanomethyl) -2- (3,5-difluorobiphenyl-2-ylamino) acetamide; And
(34) (2'-amino-5'-fluorobiphenyl-4-yl) (phenyl) methanone.
In the pharmaceutical composition according to the present invention, the compound represented by the formula (1), or a pharmaceutically acceptable salt thereof, can be administered in various forms of oral and parenteral administration at the time of clinical administration. Such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like.
Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain binders such as starch, agar, alginic acid or sodium salts thereof Release or boiling mixture and / or absorbent, colorant, flavor, and sweetening agent.
The pharmaceutical composition containing the compound represented by the formula (1) as an active ingredient may be administered parenterally, and the parenteral administration may be by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
In this case, in order to formulate the composition for parenteral administration, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, . The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.
Furthermore, the dose of the compound of the present invention represented by the formula (1) or a pharmaceutically acceptable salt thereof in the human body may vary depending on the patient's age, weight, sex, dosage form, health condition and disease severity, The dose is generally 0.1-1000 mg / day, preferably 1-500 mg / day, based on an adult patient of 70 kg, and may be administered once a day to a certain number of days It may be administered in divided doses.
The antiviral pharmaceutical composition preferably has antiviral activity against coronavirus, and the antiviral pharmaceutical composition can be used for the prevention or treatment of diseases caused by coronavirus infection.
At this time, the disease caused by the coronavirus infection is middle respiratory syndrome such as Mers or SARS.
The present invention also provides a health functional food composition for preventing or ameliorating a disease caused by a viral infection comprising a compound represented by the following general formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1]
(In the
-L- is a single bond, -O-, or -O- (CH 2) -, and;
R 1 is selected from the group consisting of -H, -OH, -NH 3+ , halogen, amine, nitro, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, C 6-10 aryl,
Wherein p and q are independently an integer from 0 to 3 and A 1 is -COOH or -NA 2 A 3 wherein A 2 and A 3 are independently -H, CN is a substituted C 1-5 straight chain or branched chain alkyl, or A 2 and A 3 are heterocycloalkyl of 5 to 10 ring members, which are linked together and contain at least one N and are unsubstituted or substituted by one -OH,
Wherein B 1 is heterocycloalkyl of unsubstituted or substituted 5 to 10-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, and said substituted 5- to 10-membered heterocyclo Alkyl is heterocycloalkyl of 5 to 10 ring members substituted with at least one substituent selected from the group consisting of = O and = S;
R 2 is -H, or halogen;
R 3 is -H, halogen, amine, nitro, phenyl, unsubstituted or substituted phenyloxy, -NE 1 E 2 , or
Here, the substituted phenyloxy is halogen, the group consisting of nitro, a -COOH, a linear or branched alkyl, straight-chain or branched alkoxycarbonyl straight or branched C 1-5 alkoxy and C 1-5 of the C 1-5 Is phenyloxy substituted with one or more substituents selected from < RTI ID = 0.0 >
Wherein E 1 and E 2 are independently -H, C 1-5 linear or branched alkoxycarbonyl, C 1-5 straight or branched chain alkylcarbonyl C 1-5 straight or branched chain alkyl,
Wherein B 2 is heteroaryl of unsubstituted or substituted 5 to 10-membered rings containing one or more N, heteroaryl of substituted 5 to 10-membered rings is heteroaryl of 5 to 10-membered rings substituted with one or more = Aryl;
R 4 is -H, or halogen;
R 5 is -H, halogen, C 1-10 straight or branched chain alkyl, or
Wherein B 3 is heteroaryl of unsubstituted or substituted 5- to 10-membered rings containing at least one N, and heteroaryl of said substituted 5 to 10-membered rings is substituted with at least one ═O and at least one C 1-3 straight chain Or heteroaryl of 5 to 10 heterocycle substituted with side chain alkyl;
R 6 is -H, halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, or C 1-10 straight or branched alkylsulfanyl;
R 7 is -H, halogen, or C 1-10 straight or branched chain alkyl unsubstituted or substituted with one or more halogens;
R 8 is selected from the group consisting of -H, halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, C 1-10 straight or branched alkoxycarbonyl, C 6-10 arylcarbonyl, Or a straight-chain alkylcarbonyl C 1-3 straight-chain alkyl of C 6-10 aryl C 1-5 substituted with one or more methyl groups, or is joined together with R 7 to form an unsubstituted C 6-10 aryl;
R 9 is -H, or halogen; And
R 10 is -H, -CN, halogen, amine, C 1-10 linear or branched alkoxycarbonyl, or R 9 is taken together to form an unsubstituted C 6-10 aryl.
Preferable ranges of the respective substituents of the compound represented by the formula (1) are the same as those described in the above-mentioned pharmaceutical composition, and thus the description thereof will be omitted. Preferably, the virus is coronavirus, and the disease caused by the viral infection is middle-respiratory syndrome such as Mers or SARS.
Further, the present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]
(In the
-L- is a single bond, -O-, or -O- (CH 2) -, and;
R 1 is selected from the group consisting of -H, -OH, -NH 3+ , halogen, amine, nitro, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, C 6-10 aryl,
Wherein p and q are independently an integer from 0 to 3 and A 1 is -COOH or -NA 2 A 3 wherein A 2 and A 3 are independently -H, CN is a substituted C 1-5 straight chain or branched chain alkyl, or A 2 and A 3 are heterocycloalkyl of 5 to 10 ring members, which are linked together and contain at least one N and are unsubstituted or substituted by one -OH,
Wherein B 1 is heterocycloalkyl of unsubstituted or substituted 5 to 10-membered rings containing at least one heteroatom selected from the group consisting of N, O and S, and said substituted 5- to 10-membered heterocyclo Alkyl is heterocycloalkyl of 5 to 10 ring members substituted with at least one substituent selected from the group consisting of = O and = S;
R 2 is -H, or halogen;
R 3 is -H, halogen, amine, nitro, phenyl, unsubstituted or substituted phenyloxy, -NE 1 E 2 , or
Here, the substituted phenyloxy is halogen, the group consisting of nitro, a -COOH, a linear or branched alkyl, straight-chain or branched alkoxycarbonyl straight or branched C 1-5 alkoxy and C 1-5 of the C 1-5 Is phenyloxy substituted with one or more substituents selected from < RTI ID = 0.0 >
Wherein E 1 and E 2 are independently -H, C 1-5 linear or branched alkoxycarbonyl, C 1-5 straight or branched chain alkylcarbonyl C 1-5 straight or branched chain alkyl,
Wherein B 2 is heteroaryl of unsubstituted or substituted 5 to 10-membered rings containing one or more N, heteroaryl of substituted 5 to 10-membered rings is heteroaryl of 5 to 10-membered rings substituted with one or more = Aryl;
R 4 is -H, or halogen;
R 5 is -H, halogen, C 1-10 straight or branched chain alkyl, or
Wherein B 3 is heteroaryl of unsubstituted or substituted 5- to 10-membered rings containing at least one N, and heteroaryl of said substituted 5 to 10-membered rings is substituted with at least one ═O and at least one C 1-3 straight chain Or heteroaryl of 5 to 10 heterocycle substituted with side chain alkyl;
R 6 is -H, halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, or C 1-10 straight or branched alkylsulfanyl;
R 7 is -H, halogen, or C 1-10 straight or branched chain alkyl unsubstituted or substituted with one or more halogens;
R 8 is selected from the group consisting of -H, halogen, C 1-10 linear or branched alkyl, C 1-10 straight or branched alkoxy, C 1-10 straight or branched alkoxycarbonyl, C 6-10 arylcarbonyl, Or a straight-chain alkylcarbonyl C 1-3 straight-chain alkyl of C 6-10 aryl C 1-5 substituted with one or more methyl groups, or is joined together with R 7 to form an unsubstituted C 6-10 aryl;
R 9 is -H, or halogen; And
R 10 is -H, -CN, halogen, amine, C 1-10 linear or branched alkoxycarbonyl, or R 9 is taken together to form an unsubstituted C 6-10 aryl.
The most preferred individual compounds of the compound represented by the formula (1) are any compounds selected from the following group of compounds.
(1) 2 - ((4-phenoxyphenoxy) methyl) benzene amine;
(2) Methyl 4- (4- (4-chlorobenzyloxy) phenoxy) -2-nitrobenzoate;
(3) 5- (4- (4-chlorobenzyloxy) phenoxy) -2-nitrobenzoic acid;
(4) 5- (4- (2,4-dichlorobenzyloxy) phenoxy) -2-nitrobenzoic acid;
(9) tert-Butyl 4- (benzyloxy) -3-methylphenylcarbamate;
(12) 4- (benzyloxy) -3-bromo-5-methylbenzenamine;
(13) 2- (benzyloxy) -1-bromo-3-methyl-5-nitrobenzene;
(14) 3- (4- (Benzyloxy) -3-bromo-5-methylphenylamino) butan-2-one;
(15) 6- (Benzyloxy) -4'-chloro-5-methylbiphenyl-3-amine;
(16) 2- (Benzyloxy) -4'-chloro-3-methyl-5-nitrobiphenyl;
(17) 3- (6- (Benzyloxy) -4'-chloro-5-methylbiphenyl-3-ylamino) butan-2-one;
(20) 1- (4- (2-Aminophenoxy) -3-methoxyphenyl) -6- (3,4-dimethylphenyl) hexan-2-one; And
(21) 2- (3-chlorophenoxy) benzenaminium.
The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chloro Such as benzenesulfonate, benzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.
The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of
In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).
Furthermore, the present invention includes all the solvates, stereoisomers, hydrates, and the like, which can be prepared therefrom, as well as the compound represented by
Further, the present invention relates to a process for preparing a compound represented by the following
Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (1a).
[Reaction Scheme 1]
(In the
X is halogen; L 1 is -O- (CH 2 ) -; L 2 is methylene;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently as defined in
The compound represented by the formula (1a) is a compound contained in the compound represented by the formula (1).
The present invention also relates to a process for producing a compound represented by the formula
There is provided a process for preparing a compound represented by the above formula (1), comprising the step of treating a compound represented by the formula (1b) with hydrochloric acid to prepare a compound represented by the formula (1c).
[Reaction Scheme 2]
(In the above Reaction Scheme 2,
L 1 is -O- (CH 2 ) -;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently as defined in
The compounds represented by formulas (1b) and (1c) are independently included in the compound represented by formula (1).
Samples used in the production method according to
For example, the reaction temperature may be from -30 ° C to 90 ° C, preferably from -10 ° C to 80 ° C, more preferably from 0 ° C to 70 ° C, even more preferably from 10 ° C to 50 ° C, Lt; RTI ID = 0.0 > 25 C < / RTI >
For example, the reaction time can be 0 to 12 hours, preferably 20 minutes to 6 hours, more preferably 30 minutes to 5 hours, even more preferably 1 Hour to 4 hours, and most preferably 2 hours.
The compounds according to the present invention exhibit an excellent inhibitory activity against coronaviruses, and therefore are useful as pharmaceutical compositions for preventing or treating diseases caused by coronaviruses such as MERS, SARS, and the like.
More specifically,
Experiments were carried out to evaluate the anticoronivirus activity of the compounds of the examples according to the present invention. As a result, it was confirmed that the compounds according to the present invention exhibited excellent anticoronavirus activity, and in particular, Examples 1, 5 and 6 , 12, 17, 21 and 34 were found to exhibit significantly superior anti-coronavirus activity compared to other example compounds (see Table 2 in Experimental Example 1).
Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.
However, the following examples and experimental examples illustrate the present invention in detail, but the present invention is not limited thereto.
< Example 1 > 2 - ((4- Phenoxyphenoxy ) methyl ) Benzene amine
The compound of Example 1 was prepared according to the following reaction scheme, and a detailed synthesis method will be described step by step.
step 1: 1 - Nitro-2 - ((4- Phenoxyphenoxy ) methyl ) Synthesis of benzene
2-Nitrobenzyl bromide (2.5 g, 11.57 mmol), 4-phenoxyphenol (2.17 g, 11.68 mmol) and potassium carbonate (3.19 g, 23.08 mmol) were mixed in dimethylformamide (30 mL) Lt; / RTI > The reaction mixture was added with ice water, extracted with ethyl acetate (60 mL), washed with distilled water (2 x 30 mL), and the water was removed (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was separated by flash column chromatography (ethyl acetate: hexane = 1:10) to give 1-nitro-2 - ((4-phenoxyphenoxy) methyl) benzene (3.05 g, yield 83%).
1 H NMR (300 MHz, DMSO ) δ 5.444 (s, 2H), 6.918-7.102 (m, 7H), 7.325-7.378 (t, J = 7.5 Hz, 2H), 7.606-7.663 (m, 1H), 7.809 -7.818 (m, 2H), 8.117-8.144 (d, J = 8.1 Hz, 1H).
step 2: 2 -((4- Phenoxyphenoxy ) methyl ) Synthesis of aniline
After dissolving 1-nitro-2 - ((4-phenoxyphenoxy) methyl) benzene (3.05 g, 9.49 mmol) prepared in the
1 H NMR (300 MHz, DMSO ) δ 4.953 (s, 2H), 5.041 (s, 2H), 6.534-6.583 (t, J = 7.2 Hz, 1H), 6.672-6.698 (d, J = 7.8 Hz, 1H J = 7.8 Hz, 2H), 6.979-7.090 (m, 6H), 7.166-7.191 (d, J = 7.5 Hz, 1H), 7.317-7.370 2H).
< Example 2> methyl 4- (4- (4- Chlorobenzyloxy ) Phenoxy )-2- Nitrobenzoate
In
Using 1- (bromomethyl) -4-chlorobenzene instead of 2-nitrobenzyl bromide; The objective compound was prepared using methyl 4- (4-hydroxyphenoxy) -2-nitrobenzoate instead of 4-phenoxyphenol.
< Example 3 > 5- (4- (4- Chlorobenzyloxy ) Phenoxy )-2- Nitroben Exceed
In
Using 1- (bromomethyl) -4-chlorobenzene instead of 2-nitrobenzyl bromide; The objective compound was prepared using 5- (4-hydroxyphenoxy) -2-nitrobenzoic acid instead of 4-phenoxyphenol.
< Example 4 > 5- (4- (2,4- Dichlorobenzyloxy ) Phenoxy )-2- Nitroben Exceed
In
Instead of using 2-nitrobenzyl bromide, 1- (bromomethyl) -2,4-dichlorobenzene was used; The objective compound was prepared using 5- (4-hydroxyphenoxy) -2-nitrobenzoic acid instead of 4-phenoxyphenol.
< Example 5 > 2 - (( Biphenyl -4- Sake ) methyl ) Benzene amine
Were obtained from Korea Compound Bank. (ChemBack ID: 223796)
< Example 6 > 2 - ((4- Chlorophenoxy ) methyl ) Benzene amine
Were obtained from Korea Compound Bank. (ChemBack ID: 27219)
< Example 7> 4- ( Benzyloxy ) -3- Methylbenzene amine
Were obtained from Korea Compound Bank. (ChemBack ID: 227394)
< Example 8 > 1- ( Benzyloxy )-2- methyl -4-nitrobenzene
Were obtained from Korea Compound Bank. (ChemBack ID: 227371)
< Example 9> tert -Butyl 4- ( Benzyloxy ) -3- Methylphenylcarbamate
The compound of Example 9 was prepared according to the following reaction scheme, and a detailed synthesis method will be described step by step.
step 1: 1 - ( Benzyloxy )-2- methyl -4-nitrobenzene (1) Synthesis of
Acetonitrile (100 mL) was added to 2-dimethyl-4-nitrophenol (1.5 g, 1 mmol), potassium carbonate (1.79 g, 1.3 mmol) and benzyl bromide (1.42 mL, 1.2 mmol) Lt; / RTI > When the reaction was completed, the reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / n-hexane = 1/20) to give the desired compound as a colorless liquid. (1.9 g, yield: 78.1%).
1 H NMR (300 MHz, CDCl 3) δ 7.49 - 7.20 (m, 5H), 6.73 (d, J = 8.6 Hz, 1H), 6.50 (s, 1H), 6.40 (d, J = 8.6 Hz, 1H) , 4.96 (s, 2 H), 2.22 (s, 3 H).
step 2: 4 - ( Benzyloxy ) -3- Of methylbenzene amine Synthesis (2)
Ethanol (500 mL), water (125 mL) and iron (59 g, 1.056 mol) were added to 1- (benzyloxy) -2-methyl-4-nitrobenzene (25.7 g, 0.105 mol) And reacted at 125 ° C for 4 hours. When the reaction is completed, the reaction mixture is cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/9 - > 1/1) to give the title compound as a brown liquid. (19.3 g, yield: 75.7%).
1 H NMR (300 MHz, CDCl 3 )? 7.35 (m, 5H), 6.71 (d, J = 8.4 Hz, 1H), 6.55 (s, 2H), 3.37 (brs, 2H), 2.21 (s, 3H).
Step 3: tert -Butyl 4- ( Benzyloxy ) -3- Methylphenylcarbamate Synthesis (3)
Di-tert-butyl-dicarbonate (2.25 g, 10. 3 mmol) was added to 4- (benzyloxy) -3-methylbenzenamine (2 g, 9.3 mmol) After completion of the reaction, the reaction is concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/9? 1/1) to obtain the target compound as a white solid. (3.02 g, yield: 100%).
1 H NMR (300 MHz, CDCl 3) δ 7.36 (m, 5H), 7.18 (s, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.29 (s, 1 H), 5.04 (s, 2 H), 2.26 (s, 3 H).
< Example 10> (E) - methyl 4 - ((2 - ((1- methyl -2- Oxoindoline -3- Iriden ) methyl ) Phenoxy ) Methyl) benzoate
Were obtained from Korea Compound Bank. (ChemBack ID: 394668)
< Example 11> (E) -2 - ((5- Bromo -2- Methoxy -4 - ((2- Oxoindoline -3- Iriden ) methyl ) Pe Lt; / RTI > methyl) benzonitrile
Were obtained from Korea Compound Bank. (ChemBack ID: 368038)
< Example 12 > 4- ( Benzyloxy ) -3- Bromo -5- Methylbenzene amine
The compound of Example 12 was prepared according to the following reaction scheme, and the detailed synthesis method will be described step by step.
step 1: 2 - ( Benzyloxy )-One- Bromo -3- methyl Synthesis of 5-nitrobenzene (9)
Acetonitrile (249 mL) was added to 2-bromo-6-methyl-4-nitrophenol (11.24 g, 0.0484 mol) and benzyl bromide (6.9 mL, 0.581 mol) and potassium carbonate (8.7 g, 0.0629 mol) The reaction is then carried out at 105 ° C for 2 hours. When the reaction is complete, the reaction mixture is cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/9 - > 1/4) to give the title compound as off-white solid. (16.7 g, yield: quantitative)
1 H NMR (300 MHz, CDCl 3) δ 8.34 (s, 1H), 8.04 (s, 1H), 7.49 (m, 2H), 7.38 (m, 3H), 5.04 (s, 2H), 2.34 (s, 3H).
step 2: 4 - ( Benzyloxy ) -3- Bromo -5- Of methylbenzene amine Synthesis (10)
Ethanol (240 mL), water (60 mL) and iron (25.5 g, 0.456 mol) were added to 2- (benzyloxy) -1-bromo-3-methyl-5-nitrobenzene (14.7 g, 0.0456 mol) Five drops of concentrated hydrochloric acid were added and reacted at 110 DEG C for 3 hours. When the reaction is completed, the reaction mixture is cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/9 -> 1/1) to give the title compound as a light yellow liquid. (11.3 g, yield: 80.0%).
1 H NMR (300 MHz, CDCl 3) δ 7.52 (d, J = 6.8 Hz, 2H), 7.47 - 7.33 (m, 3H), 6.75 (d, J = 2.6 Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 4.86 (s, 2H), 3.51 (brs, 2H), 2.21 (s, 3H).
< Example 13 > 2- ( Benzyloxy )-One- Bromo -3- methyl -5-nitrobenzene
Example 13 The compound is the compound corresponding to
1 H NMR (300 MHz, CDCl 3) δ 8.34 (s, 1H), 8.04 (s, 1H), 7.49 (m, 2H), 7.38 (m, 3H), 5.04 (s, 2H), 2.34 (s, 3H).
< Example 14 > 3- (4- ( Benzyloxy ) -3- Bromo -5- Methylphenylamino ) Butan-2-one
(100 mL), sodium bicarbonate (4.2 g, 0.0510 mol), lithium (100 mL), and the like were added to 4- (benzyloxy) -3-bromo-5-methylbenzenamine (9.33 g (4.16 g, 0.0479 mol) and 3-chlorobutan-2-one (4.8 mL, 0.0479 mol) were added and reacted overnight at 100 ° C. When the reaction is complete, it is cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/9 -> 1/2) to obtain the title compound as a brown liquid. (11.5 g, yield: 99.5%).
1 H NMR (300 MHz, CDCl 3) δ 7.52 (d, J = 7.0 Hz, 2H), 7.38 (dd, J = 15.8, 8.1 Hz, 3H), 6.61 (d, J = 2.5 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 4.85 (s, 2H), 4.32 (brs, 1H), 2.23 (s, 6H), 1.41 (d,
< Example 15> 6- ( Benzyloxy )-4'- Chloro -5- Methyl biphenyl -3- Amine
With reference to the step 2 reaction (NO 2 - > NH 2 ) of Example 9, the desired compound was prepared from the compound of Example 16 below.
< Example 16 > 2- ( Benzyloxy )-4'- Chloro -3- methyl -5- Nitrobiphenyl
The compound of Example 16 was prepared according to the following reaction scheme, and the detailed synthesis method will be described step by step.
step 1: 2 - Iodo -6- methyl Synthesis of 4-nitrophenol (4)
After dissolving 2-methyl-4-nitrophenol (10 g, 0.065 mol) in dimethylsulfoxide (326 mL) and adding iodine (16. 5 g, 0.13 mol) at 110 ° C. for 2 hours, The reaction mixture was diluted with ethyl acetate (500 mL), and the organic solvent layer was washed with Na 2 S 2 O 3 aqueous solution three times with brine once, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/7 - > 1/2) to obtain the title compound as a light yellow solid. (15.04 g, yield: 82.5%).
1 H NMR (300 MHz, CDCl 3 )? 8.43 (s, IH), 8.04 (s, IH), 2.39 (s, 3H).
step 2: 4 '- Chloro -3- methyl -5- Nitrobiphenyl -2- O Synthesis (5)
1,4-dioxane (215 mL) and water (258 mL) were added to 2-iodo-6-methyl-4-nitrophenol (15 g, 0.0537 mol) and 4-chlorophenylboronic acid (16.8 g, 0.107 mol), 10% palladium carbon (2.86 g, 0.00268 mol) and potassium carbonate (22.2 g, 0.161 mol) were added and reacted at 95 ° C for 2 hours. When the reaction was completed, the reaction mixture was cooled to room temperature, After concentration, the remaining water layer is diluted with brine and extracted with ethyl acetate. The organic solvent layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/7 -> 1/4) to give the desired compound as a off-white solid . (9.1 g, yield: 64.3%).
1 H NMR (300 MHz, CDCl 3) δ 8.08 (s, 1H), 8.00 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 5.73 (s, 1 H), 2.38 (s, 3 H).
step 3: 2 - ( Benzyloxy )-4'- Chloro -3- methyl -5- Nitrobiphenyl Synthesis (6)
To the solution was added acetonitrile (101 mL), benzyl bromide (4.32 g, 0.0364 mol) and potassium carbonate (5.45 g, 0.0364 mol) were added to 4'-chloro-3-methyl-5-nitrobiphenyl- 0.0394 mol) was added and reacted at 110 ° C for 1.5 hours. When the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/7 - > 1/4) to give the title compound as a light yellow solid. (11.3 g, yield: quantitative)
1 H NMR (300 MHz, CDCl 3) δ 8.08 (s, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.34 - 7.21 (m, 3H) , 7.09 (d, J = 4.2 Hz, 2H), 4.49 (s, 2H), 2.36 (s, 3H).
< Example 17 > 3- (6- ( Benzyloxy )-4'- Chloro -5- Methyl biphenyl -3- Amino ) Butan-2-one
The compound of Example 17 was prepared according to the following reaction scheme, and the detailed synthesis method will be described step by step.
step 1: 6 - ( Benzyloxy )-4'- Chloro -5- Methyl biphenyl -3- Amine Synthesis (7)
Ethanol (120 mL), water (30 mL) and iron (2 mL) were added to the 2- (benzyloxy) -4'-chloro-3-methyl-5-nitrobiphenyl 16.9 g, 0.303 mol) was added, and 5 drops of concentrated hydrochloric acid was added thereto, followed by reaction at 110 ° C for 3 hours. When the reaction is completed, the reaction mixture is cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/9 -> 1/2) to obtain the desired compound in the form of a yellow liquid. (8.08 g, yield: 82.3%).
1 H NMR (300 MHz, CDCl 3) δ 7.61 - 7.46 (m, 2H), 7.44 - 7.33 (m, 2H), 7.27 (td, J = 4.6, 0.9 Hz, 3H), 7.10 (dd, J = 6.5 (D, J = 11.8, 2.8 Hz, 2H), 4.33 (s, 2H), 3.53 (brs, 2H), 2.25 (s, 3H).
step 2: 3 - (6- ( Benzyloxy )-4'- Chloro -5- Methyl biphenyl -3- Amino ) Butan-2-one < / RTI > (8)
To the solution was added ethanol (80 mL), sodium bicarbonate (3.11 g, 0.0370 mol), lithium bromide (3.01 mol), and the like to 7.5 g (0.0232 mol) of 6- (benzyloxy) g, 0.0347 mol) and 3-chlorobutan-2-one (3.5 mL, 0.0347 mol) were added and reacted overnight at 100 ° C. When the reaction is complete, it is cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1/7 - > 1/2) to obtain the title compound as a yellow liquid. (8.8 g, yield: 96.4%).
1 H NMR (300 MHz, CDCl 3) δ 7.52 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 7.27 (dd, J = 4.3, 2.6 Hz, 3H), 7.16 3H), 2.23 (s, 3H), 1.43 (d, J = 6.9 Hz, 2H), 7.00 (m, 2H), 6.39 (dd, J = Hz, 3H).
< Example 18 > 2- (4- tert - Butylphenoxy ) Benzene amine
Were obtained from Korea Compound Bank. (ChemBack ID: 111862)
< Example 19> 2- (4- Fluoro -3- ( Trifluoromethyl ) Phenoxy ) Benzene amine
Were obtained from Korea Compound Bank. (ChemBack ID: 223640)
< Example 20 > 1- (4- (2- Aminophenoxy ) -3- Methoxyphenyl ) -6- (3,4- Dimethylphenyl ) Hexane -2-one
Were obtained from Korea Compound Bank. (ChemBack ID: 207453)
< Example 21> 2- (3- Chlorophenoxy ) Benzenediamine
Were obtained from Korea Compound Bank. (ChemBack ID: 111609)
< Example 22> 5- Chloro -2- (1-chloronaphthalene-2- Sake ) Benzene amine
Were obtained from Korea Compound Bank. (ChemBack ID: 345769)
< Example 23> methyl 2- (2,4- Diaminophenoxy ) Benzoate
Were obtained from Korea Compound Bank. (ChemBack ID: 362990)
< Example 24> (E) -5- (2- (2- Fluorobenzyloxy ) -5- Nitrobenzylidene )-2- Thioxo Azolidine-4-one
Were obtained from Korea Compound Bank. (ChemBack ID: 52267)
< Example (E) -5- (2- (4- Fluorobenzyloxy ) -5- Nitrobenzylidene )-2- Thioxo Azolidine-4-one
Were obtained from Korea Compound Bank. (ChemBack ID: 52267)
< Example 26> 5- Fluorobiphenyl -2- Amine
Were obtained from Korea Compound Bank. (ChemBack ID: 229168)
< Example 27> 4- ( Biphenyl -2- Amino )-4- Oxobutaneik Exceed
Were obtained from Korea Compound Bank. (ChemBack ID: 310182)
< Example 28 > 3 ', 5'- Dichloro -5- Fluorobiphenyl -2- Amine
Were obtained from Korea Compound Bank. (ChemBack ID: 229167)
< Example 29> 2,4- Dimethoxy -2'- Nitrobiphenyl
Were obtained from Korea Compound Bank. (ChemBack ID: 65406)
< Example 30 > N- ( Biphenyl Yl) -3- (3- Hydroxypiperidine -1 day) Propanamide
Were obtained from Korea Compound Bank. (ChemBack ID: 397534)
< Example 31> 4- Chloro -2- (naphthalen-1-yl) Benzene amine
Were obtained from Korea Compound Bank. (ChemBack ID: 399045)
< Example 32> Methyl (2'-nitrobiphenyl-2-yl) sulfane
Were obtained from Korea Compound Bank. (ChemBack ID: 67828)
< Example 33 > N- ( Cyanomethyl ) -2- (3,5- Difluorobiphenyl -2- Amino ) Acetamide
Were obtained from Korea Compound Bank. (ChemBack ID: 398436)
< Example 34> (2'-amino-5'- Fluorobiphenyl Yl) (phenyl) Methanone
Were obtained from Korea Compound Bank. (ChemBack ID: 229169)
The specific structures of the compounds prepared or prepared in Examples 1 to 34 are shown in Table 1 below.
< Experimental Example 1> Ant colony virus Activity evaluation
The following experiments were conducted to evaluate the anticoronivirus activity of the compounds of the examples according to the present invention.
<1-1> Culture of cell line
Huh7 (human hepatocellular carcinoma) was purchased from Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, purchased from the Japanese Collection of Research Biosources Cell Bank (JCRB Cell Bank) Lt; RTI ID = 0.0 > 37 C < / RTI > in a 5% CO2 incubator.
<1-2> Corona virus Potency Measure
Mors coronavirus was isolated from domestic patients and received from the CDC. The virus was proliferated in Vero (CCL-81) and the virus titer was measured using a plaque assay.
<1-3> Cell-based Ant colony virus Activity evaluation
For antiviral activity, Huh-7 cells were cultured on a 96-well plate and the cells prepared for the next day were infected with Mors coronavirus (MOI 0.1) for 1 hour.
After infection, the virus is removed and treated with the compounds of Examples 1 to 34 diluted in triplicate, or the control compound gemcitabine. Infected 48 hours later CellTiter 96 ® AQueous One Solution Cell Proliferation Assay (Promega, USA) cytotoxicity of the drug using a (50% cytotoxicity concentration, CC 50 ) and wherein by the virus effect cell viability (50% effective concentration, EC 50 ) Were measured. Statistical analysis of CC 50 and EC 50 was performed using GraphPad Prism 6 (GraphPad Software, USA). The results are summarized in Table 2 below.
(SI)
In Table 2,
The EC 50 is the cell viability due to the antiviral effect; the lower the value, the better the antiviral effect of the compound;
CC 50 is a cytotoxic indicator at the concentration; the higher the value, the lower the toxicity of the compound;
The SI value is the SI value calculated based on the EC 50 / CC 50 value. The higher the value, the better the effect of the compound and the lower the toxicity; And
n.d. means no effect.
As shown in Table 2,
It can be seen that the compounds of the examples according to the present invention exhibit excellent anti-coronavirus activity. In particular, the compounds of Examples 1, 5, 6, 12, 17, 21 and 34 exhibited significantly superior anti-coronavirus activity compared to the compounds of the other examples.
<1-4> Immunity Blot analysis
Huh-7 cells were cultured in 6-well plates and infected with Mors coronavirus (MOI 0.02) for 1 hour. After infection, treatment with 0.1 [mu] M, 1 [mu] M, 10 [mu] M candidate compounds (Examples 1, 5, 6) or the control drug gemcitabine was performed. Negative controls were treated with 0.02% DMSO. Twenty-four hours after infection, cells were transferred to PVDF (polyvinylidene difluoride membrane, Millipore, USA) by electrophoresis in 12% SDS-PAGE using 30 μg of cell lysate. Mers coronavirus NP protein is detected using a secondary antibody conjugated with an anti-mouse NP monoclonal antibody (Cat. 100211-RP02, Sino Biological Inc., China) and horseradish peroxidase (HRP). Anti-β-actin antibody was used to confirm the loading of the same concentration of protein. Proteins were developed using SuperSignal West Pico Chemiluminescence Substrate (Pierce, USA) and images were developed with a LAS-4000 Luminescent Image Analyzer (Fujifilm, Japan). The results are shown in Fig.
Figure 1 shows immunoblot analysis of the antiviral activity effects of the example compounds in Murs coronavirus infected Huh-7 cells.
As shown in FIG. 1, the compounds of Examples 1, 5, and 6 according to the present invention were found to exhibit antimers activity by decreasing mersin NP protein expression at a concentration of 1 μM or less.
Claims (14)
[Chemical Formula 1]
(In the formula 1,
-L- is a single bond, or -O- (CH 2) -, and;
R 1 is selected from the group consisting of -H, an amine, nitro, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, phenyl unsubstituted or substituted with one or more halogens,
Wherein p is an integer of 0 or 1 and q is an integer of 0 or 2 and A 1 is -COOH or -NA 2 A 3 wherein A 2 and A 3 are independently -H, unsubstituted or is substituted by a -CN or a linear or branched alkyl of 1-3 C a 2 and a 3 are connected with one containing the N and which is unsubstituted or is substituted with one -OH hexagonal ring heterocycloalkyl ego,
Wherein B 1 is heterocycloalkyl of an unsubstituted or substituted pentyl ring that comprises at least one heteroatom selected from the group consisting of N and S and wherein said heterocycloalkyl of said substituted pentyl is selected from the group consisting of = O and = ≪ RTI ID = 0.0 > S < / RTI >
R 2 is -H, or halogen;
R 3 is -H, halogen, nitro, phenyl, unsubstituted or substituted phenyloxy, -NE 1 E 2 , or
Wherein said substituted phenyloxy is phenyloxy substituted with one or more substituents selected from the group consisting of nitro, -COOH, and straight or branched C 1 -C 3 alkoxycarbonyl,
Wherein E 1 and E 2 are independently -H, C 1-5 linear or branched alkoxycarbonyl, C 1-3 straight or branched alkylcarbonyl C 1-3 straight or branched alkyl;
R 4 is -H, or halogen;
R 5 is -H, halogen, C 1-5 linear or branched alkyl, or
R 6 is -H, halogen, C 1-5 linear or branched alkoxy, or C 1-5 straight or branched chain alkylsulfanyl;
R 7 is -H, or halogen;
R 8 is -H, halogen, C 1-5 linear or branched alkoxy, C 1-5 straight or branched alkoxycarbonyl, or phenylcarbonyl;
R 9 is -H, or halogen; And
R 10 forms a -H, -CN, or halogen, or an amine are linked together with the phenyl ring with R 9 Beach).
-L- is a single bond, or -O- (CH 2) -, and;
R 1 is -H, methyl, methoxy, amine, nitro,
R 2 is -H, or -F;
R 3 is -H, -Cl, amine, nitro, phenyl,
R 4 is -H, -F, -Cl, or -Br;
R < 5 > is -H, methyl, -Br or
R 6 is -H, -F, -Cl, methoxy, or methylsulfanyl;
R 7 is -H, or -Cl;
R 8 is -H, -F, -Cl, methoxy, phenylcarbonyl, or
R 9 is -H, or -Cl;
R 10 is a pharmaceutical composition characterized by forming a -H, -Cl, -CN, or an amine, or is connected with the R 9 unsubstituted phenyl beach.
(1) 2 - ((4-phenoxyphenoxy) methyl) benzene amine;
(2) Methyl 4- (4- (4-chlorobenzyloxy) phenoxy) -2-nitrobenzoate;
(3) 5- (4- (4-chlorobenzyloxy) phenoxy) -2-nitrobenzoic acid;
(4) 5- (4- (2,4-dichlorobenzyloxy) phenoxy) -2-nitrobenzoic acid;
(5) 2 - ((Biphenyl-4-yloxy) methyl) benzene amine;
(6) 2 - ((4-chlorophenoxy) methyl) benzene amine;
(7) 4- (benzyloxy) -3-methylbenzenamine;
(8) 1- (Benzyloxy) -2-methyl-4-nitrobenzene;
(9) tert-Butyl 4- (benzyloxy) -3-methylphenylcarbamate;
(10) (E) -methyl 4 - ((2 - ((1-methyl-2-oxoindolin-3-ylidene) methyl) phenoxy) methyl) benzoate;
(11) (E) -2 - ((5-Bromo-2-methoxy-4 - ((2-oxoindolin-3-ylidene) methyl) phenoxy) methyl) benzonitrile;
(12) 4- (benzyloxy) -3-bromo-5-methylbenzenamine;
(13) 2- (benzyloxy) -1-bromo-3-methyl-5-nitrobenzene;
(14) 3- (4- (Benzyloxy) -3-bromo-5-methylphenylamino) butan-2-one;
(15) 6- (Benzyloxy) -4'-chloro-5-methylbiphenyl-3-amine;
(16) 2- (Benzyloxy) -4'-chloro-3-methyl-5-nitrobiphenyl;
(17) 3- (6- (Benzyloxy) -4'-chloro-5-methylbiphenyl-3-ylamino) butan-2-one;
(19) 2- (4-Fluoro-3- (trifluoromethyl) phenoxy) benzene amine;
(20) 1- (4- (2-Aminophenoxy) -3-methoxyphenyl) -6- (3,4-dimethylphenyl) hexan-2-one;
(21) 2- (3-chlorophenoxy) benzenaminium;
(24) (E) -5- (2- (2-fluorobenzyloxy) -5-nitrobenzylidene) -2-thioxothiazolidin-4-one;
(25) (E) -5- (2- (4-fluorobenzyloxy) -5-nitrobenzylidene) -2-thioxothiazolidin-4-one;
(26) 5-fluorobiphenyl-2-amine;
(27) 4- (Biphenyl-2-ylamino) -4-oxobutanoic acid;
(28) 3 ', 5'-Dichloro-5-fluorobiphenyl-2-amine;
(29) 2,4-dimethoxy-2'-nitrobiphenyl;
(30) N- (Biphenyl-2-yl) -3- (3-hydroxypiperidin-1-yl) propanamide;
(31) 4-Chloro-2- (naphthalen-1-yl) benzene amine;
(32) methyl (2'-nitrobiphenyl-2-yl) sulfanyl;
(33) N- (Cyanomethyl) -2- (3,5-difluorobiphenyl-2-ylamino) acetamide; And
(34) (2'-amino-5'-fluorobiphenyl-4-yl) (phenyl) methanone.
Wherein said pharmaceutical composition for anticoronavirus is used for prevention or treatment of a disease caused by coronavirus infection.
Wherein the disease caused by the coronavirus infection is mers or sars.
[Chemical Formula 1]
(In the formula 1,
-L- is a single bond, or -O- (CH 2) -, and;
R 1 is selected from the group consisting of -H, an amine, nitro, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, phenyl unsubstituted or substituted with one or more halogens,
Wherein p is an integer of 0 or 1 and q is an integer of 0 or 2 and A 1 is -COOH or -NA 2 A 3 wherein A 2 and A 3 are independently -H, unsubstituted or is substituted by a -CN or a linear or branched alkyl of 1-3 C a 2 and a 3 are connected with one containing the N and which is unsubstituted or is substituted with one -OH hexagonal ring heterocycloalkyl ego,
Wherein B 1 is heterocycloalkyl of an unsubstituted or substituted pentyl ring that comprises at least one heteroatom selected from the group consisting of N and S and wherein said heterocycloalkyl of said substituted pentyl is selected from the group consisting of = O and = ≪ RTI ID = 0.0 > S < / RTI >
R 2 is -H, or halogen;
R 3 is -H, halogen, nitro, phenyl, unsubstituted or substituted phenyloxy, -NE 1 E 2 , or
Wherein said substituted phenyloxy is phenyloxy substituted with one or more substituents selected from the group consisting of nitro, -COOH, and straight or branched C 1 -C 3 alkoxycarbonyl,
Wherein E 1 and E 2 are independently -H, C 1-5 linear or branched alkoxycarbonyl, C 1-3 straight or branched alkylcarbonyl C 1-3 straight or branched alkyl;
R 4 is -H, or halogen;
R 5 is -H, halogen, C 1-5 linear or branched alkyl, or
R 6 is -H, halogen, C 1-5 linear or branched alkoxy, or C 1-5 straight or branched chain alkylsulfanyl;
R 7 is -H, or halogen;
R 8 is -H, halogen, C 1-5 linear or branched alkoxy, C 1-5 straight or branched alkoxycarbonyl, or phenylcarbonyl;
R 9 is -H, or halogen; And
R 10 forms a -H, -CN, or halogen, or an amine are linked together with the phenyl ring with R 9 Beach).
Wherein the disease caused by the coronavirus infection is mers or sars.
[Chemical Formula 1]
(In the formula 1,
-L- is -O- (CH 2) -, and;
R 1 is selected from the group consisting of -H, an amine, nitro, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, phenyl unsubstituted or substituted with one or more halogens,
Wherein p is an integer of 0 or 1 and q is an integer of 0 or 2 and A 1 is -COOH or -NA 2 A 3 wherein A 2 and A 3 are independently -H, unsubstituted or is substituted by a -CN or a linear or branched alkyl of 1-3 C a 2 and a 3 are connected with one containing the N and which is unsubstituted or is substituted with one -OH hexagonal ring heterocycloalkyl ego,
Wherein B 1 is heterocycloalkyl of an unsubstituted or substituted pentyl ring that comprises at least one heteroatom selected from the group consisting of N and S and wherein said heterocycloalkyl of said substituted pentyl is selected from the group consisting of = O and = ≪ RTI ID = 0.0 > S < / RTI >
R 2 is -H, or halogen;
R 3 is -H, unsubstituted or substituted phenyloxy,
Wherein said substituted phenyloxy is phenyloxy substituted with one or more substituents selected from the group consisting of nitro, -COOH, and straight or branched C 1 -C 3 alkoxycarbonyl;
R 4 is -H, or halogen;
R 5 is -H, halogen, or C 1-5 linear or branched alkyl,
R 6 is -H, halogen, C 1-5 linear or branched alkoxy, or C 1-5 straight or branched chain alkylsulfanyl;
R 7 is -H, or halogen;
R 8 is -H, halogen, C 1-5 linear or branched alkoxy, C 1-5 straight or branched alkoxycarbonyl, or phenylcarbonyl;
R 9 is -H, or halogen; And
R 10 forms a -H, -CN, or halogen, or an amine are linked together with the phenyl ring with R 9 Beach).
(1) 2 - ((4-phenoxyphenoxy) methyl) benzene amine;
(2) Methyl 4- (4- (4-chlorobenzyloxy) phenoxy) -2-nitrobenzoate;
(3) 5- (4- (4-chlorobenzyloxy) phenoxy) -2-nitrobenzoic acid;
(4) 5- (4- (2,4-dichlorobenzyloxy) phenoxy) -2-nitrobenzoic acid;
(9) tert-Butyl 4- (benzyloxy) -3-methylphenylcarbamate;
(12) 4- (benzyloxy) -3-bromo-5-methylbenzenamine;
(13) 2- (benzyloxy) -1-bromo-3-methyl-5-nitrobenzene;
(14) 3- (4- (Benzyloxy) -3-bromo-5-methylphenylamino) butan-2-one;
(15) 6- (Benzyloxy) -4'-chloro-5-methylbiphenyl-3-amine;
(16) 2- (Benzyloxy) -4'-chloro-3-methyl-5-nitrobiphenyl;
(17) 3- (6- (Benzyloxy) -4'-chloro-5-methylbiphenyl-3-ylamino) butan-2-one;
(20) 1- (4- (2-Aminophenoxy) -3-methoxyphenyl) -6- (3,4-dimethylphenyl) hexan-2-one; And
(21) 2- (3-chlorophenoxy) benzenaminium.
Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (1a):
[Reaction Scheme 1]
(In the above Reaction Scheme 1,
X is halogen; L 1 is -O- (CH 2 ) -; L 2 is methylene;
R 1 is selected from the group consisting of -H, an amine, nitro, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, phenyl unsubstituted or substituted with one or more halogens,
Wherein p is an integer of 0 or 1 and q is an integer of 0 or 2 and A 1 is -COOH or -NA 2 A 3 wherein A 2 and A 3 are independently -H, unsubstituted or is substituted by a -CN or a linear or branched alkyl of 1-3 C a 2 and a 3 are connected with one containing the N and which is unsubstituted or is substituted with one -OH hexagonal ring heterocycloalkyl ego,
Wherein B 1 is heterocycloalkyl of an unsubstituted or substituted pentyl ring that comprises at least one heteroatom selected from the group consisting of N and S and wherein said heterocycloalkyl of said substituted pentyl is selected from the group consisting of = O and = ≪ RTI ID = 0.0 > S < / RTI >
R 2 is -H, or halogen;
R 3 is -H, halogen, nitro, phenyl, unsubstituted or substituted phenyloxy, -NE 1 E 2 , or
Wherein said substituted phenyloxy is phenyloxy substituted with one or more substituents selected from the group consisting of nitro, -COOH, and straight or branched C 1 -C 3 alkoxycarbonyl,
Wherein E 1 and E 2 are independently -H, C 1-5 linear or branched alkoxycarbonyl, C 1-3 straight or branched alkylcarbonyl C 1-3 straight or branched alkyl;
R 4 is -H, or halogen;
R 5 is -H, halogen, C 1-5 linear or branched alkyl, or
R 6 is -H, halogen, C 1-5 linear or branched alkoxy, or C 1-5 straight or branched chain alkylsulfanyl;
R 7 is -H, or halogen;
R 8 is -H, halogen, C 1-5 linear or branched alkoxy, C 1-5 straight or branched alkoxycarbonyl, or phenylcarbonyl;
R 9 is -H, or halogen; And
R 10 forms a -H, -CN, or halogen, or an amine are linked together with the phenyl ring with R 9 Beach).
A process for preparing a compound, comprising the step of treating a compound represented by the formula (1b) with hydrochloric acid to prepare a compound represented by the formula (1c)
[Reaction Scheme 2]
(In the above Reaction Scheme 2,
L 1 is -O- (CH 2 ) -;
R 1 is selected from the group consisting of -H, an amine, nitro, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, phenyl unsubstituted or substituted with one or more halogens,
Wherein p is an integer of 0 or 1 and q is an integer of 0 or 2 and A 1 is -COOH or -NA 2 A 3 wherein A 2 and A 3 are independently -H, unsubstituted or is substituted by a -CN or a linear or branched alkyl of 1-3 C a 2 and a 3 are connected with one containing the N and which is unsubstituted or is substituted with one -OH hexagonal ring heterocycloalkyl ego,
Wherein B 1 is heterocycloalkyl of an unsubstituted or substituted pentyl ring that comprises at least one heteroatom selected from the group consisting of N and S and wherein said heterocycloalkyl of said substituted pentyl is selected from the group consisting of = O and = ≪ RTI ID = 0.0 > S < / RTI >
R 2 is -H, or halogen;
R 4 is -H, or halogen;
R 5 is -H, halogen, C 1-5 linear or branched alkyl, or
R 6 is -H, halogen, C 1-5 linear or branched alkoxy, or C 1-5 straight or branched chain alkylsulfanyl;
R 7 is -H, or halogen;
R 8 is -H, halogen, C 1-5 linear or branched alkoxy, C 1-5 straight or branched alkoxycarbonyl, or phenylcarbonyl;
R 9 is -H, or halogen; And
R 10 forms a -H, -CN, or halogen, or an amine are linked together with the phenyl ring with R 9 Beach).
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170035178A KR101913789B1 (en) | 2017-03-21 | 2017-03-21 | Compound for the treatment of diseases caused by corona virus infection |
| PCT/KR2018/002762 WO2018174442A1 (en) | 2017-03-21 | 2018-03-08 | Compound for treating diseases caused by coronavirus infection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020170035178A KR101913789B1 (en) | 2017-03-21 | 2017-03-21 | Compound for the treatment of diseases caused by corona virus infection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20180106599A KR20180106599A (en) | 2018-10-01 |
| KR101913789B1 true KR101913789B1 (en) | 2018-10-31 |
Family
ID=63585564
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020170035178A KR101913789B1 (en) | 2017-03-21 | 2017-03-21 | Compound for the treatment of diseases caused by corona virus infection |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR101913789B1 (en) |
| WO (1) | WO2018174442A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021235616A1 (en) | 2020-05-20 | 2021-11-25 | 주식회사 신테카바이오 | Preventive or therapeutic composition for severe acute respiratory syndrome coronavirus type 2 infectious disease |
| US11213511B2 (en) | 2020-05-20 | 2022-01-04 | Syntekabio, Inc. | Composition for preventing or treating SARS coronavirus 2 infection disease |
| KR20220052292A (en) | 2020-10-20 | 2022-04-27 | 주식회사 엑소스템텍 | Vaccine or pharmaceutical composition for preventing or treating COVID-19 using exosomes |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021187670A1 (en) * | 2020-03-18 | 2021-09-23 | 재단법인 경기도경제과학진흥원 | Composition for alleviating coronavirus infection using raloxifene |
| KR102603956B1 (en) * | 2020-12-29 | 2023-11-21 | 한국화학연구원 | Novel quinolone derivatives, and an anticoronavirus composition containing the same as an active ingredient |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004339103A (en) * | 2003-05-14 | 2004-12-02 | Masashi Fujii | Skin external preparation and mouth wash for prevention of coronavirus infection |
| CN103435562A (en) | 2013-08-26 | 2013-12-11 | 华东理工大学 | 6-substituted benzodiazepine-2,4-diketone compound and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008157844A1 (en) * | 2007-06-21 | 2008-12-24 | Forest Laboratories Holdings Limited | Novel piperazine derivatives as inhibitors of stearoyl-coa desaturase |
| US8362127B2 (en) * | 2010-01-25 | 2013-01-29 | Chemtura Corporation | Flame retardant halogenated phenyl ethers |
| KR101284174B1 (en) * | 2011-01-05 | 2013-07-09 | 한국과학기술연구원 | Antibacterial agents containing diphenyl derivatives |
-
2017
- 2017-03-21 KR KR1020170035178A patent/KR101913789B1/en active IP Right Grant
-
2018
- 2018-03-08 WO PCT/KR2018/002762 patent/WO2018174442A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004339103A (en) * | 2003-05-14 | 2004-12-02 | Masashi Fujii | Skin external preparation and mouth wash for prevention of coronavirus infection |
| CN103435562A (en) | 2013-08-26 | 2013-12-11 | 华东理工大学 | 6-substituted benzodiazepine-2,4-diketone compound and application thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021235616A1 (en) | 2020-05-20 | 2021-11-25 | 주식회사 신테카바이오 | Preventive or therapeutic composition for severe acute respiratory syndrome coronavirus type 2 infectious disease |
| US11213511B2 (en) | 2020-05-20 | 2022-01-04 | Syntekabio, Inc. | Composition for preventing or treating SARS coronavirus 2 infection disease |
| JP2022528813A (en) * | 2020-05-20 | 2022-06-16 | シンテカバイオ インコーポレイティッド | Composition for the prevention or treatment of coronavirus infection of the second kind severe acute respiratory syndrome |
| JP7104449B2 (en) | 2020-05-20 | 2022-07-21 | シンテカバイオ インコーポレイティッド | Composition for prevention or treatment of coronavirus infection of type 2 severe acute respiratory syndrome |
| KR20220052292A (en) | 2020-10-20 | 2022-04-27 | 주식회사 엑소스템텍 | Vaccine or pharmaceutical composition for preventing or treating COVID-19 using exosomes |
| KR20240004152A (en) | 2020-10-20 | 2024-01-11 | 성균관대학교산학협력단 | Vaccine or pharmaceutical composition for preventing or treating COVID-19 using exosomes |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2018174442A1 (en) | 2018-09-27 |
| KR20180106599A (en) | 2018-10-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101913789B1 (en) | Compound for the treatment of diseases caused by corona virus infection | |
| JP6134338B2 (en) | Inhibitors of hepatitis B virus covalently closed circular DNA formation and methods for their use | |
| RU2612530C2 (en) | Benzimidazole derivatives effective in treating respiratory syncytial virus infection | |
| AU2017209925B2 (en) | Aryl substituted pyrimidines for use in influenza virus infection | |
| AU2016359907B2 (en) | Heterocyclic indoles for use in influenza virus infection | |
| AU2018216954B2 (en) | Piperazine derivatives for influenza virus inhibition | |
| JP7001601B2 (en) | Functionalized pentanic acid for use in influenza virus infection | |
| JP2023537402A (en) | Functionalized peptides as antiviral agents | |
| JPS60120871A (en) | Manufacture of 5-propylthio-2-benzimidazole carbamic acid metylester | |
| PL167076B1 (en) | Method of obtaining novel derivatives of bezacetamide | |
| JP5404607B2 (en) | Aniline derivative having anti-RNA virus action | |
| KR19990022363A (en) | Antiviral compounds | |
| WO2014190899A1 (en) | 2,3-butanediamide epoxide compound and preparation method and use thereof | |
| CN103497146A (en) | 2-(N-alkyl piperidinol-4-amino)-4-(substituent phenol) benzene ring derivative as well as preparation method and application thereof | |
| US20230133581A1 (en) | Novel 3,5-Diaminobenzoic Acid Compound, and PIN1 Inhibitor and Therapeutic Agent for Inflammatory Diseases Using Same | |
| US9890155B2 (en) | Aza-oxo-indoles for the treatment and prophylaxis of respiratory syncytial virus infection | |
| KR102187953B1 (en) | Novel quinolinone derivatives, preparation method thereof, and an antiviral composition containing the same as an active ingredient | |
| KR20200095934A (en) | Pharmaceutical composition for treating or preventing middle east respiratory syndrome | |
| CN110869350B (en) | Alkynyl compounds, their preparation and their therapeutic use | |
| KR102603956B1 (en) | Novel quinolone derivatives, and an anticoronavirus composition containing the same as an active ingredient | |
| RU2805064C2 (en) | Phenyl-n-quinoline derivatives for treatment of rna viral infection | |
| KR20210002386A (en) | Novel quinolinone derivatives, preparation method thereof, and an antiviral composition containing the same as an active ingredient | |
| JP2023520819A (en) | Antiviral 1,3-di-oxo-indene compounds | |
| KR20130107554A (en) | Novel n-phenylpyrimidin-4-amine derivatives or pharmaceutically acceptable salts thereof and pharmaceutical composition for prevention or treatment of diseases induced by influenza virus containing the same as an active ingredient | |
| KR20080020862A (en) | Urea derivatives, process for the preparation thereof, and antiviral composition containing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant |