ES2358904T3 - Heterociclos de cicloalquilo para tratar el virus de la hepatitis c. - Google Patents
Heterociclos de cicloalquilo para tratar el virus de la hepatitis c. Download PDFInfo
- Publication number
- ES2358904T3 ES2358904T3 ES04782095T ES04782095T ES2358904T3 ES 2358904 T3 ES2358904 T3 ES 2358904T3 ES 04782095 T ES04782095 T ES 04782095T ES 04782095 T ES04782095 T ES 04782095T ES 2358904 T3 ES2358904 T3 ES 2358904T3
- Authority
- ES
- Spain
- Prior art keywords
- phenyl
- cyclohexyl
- methoxy
- methyl
- pyrazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 241000711549 Hepacivirus C Species 0.000 title description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 208000005176 Hepatitis C Diseases 0.000 claims abstract description 11
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 claims abstract description 11
- -1 5- {4 - [(4'-chloro-4-methoxy-1,1'-biphenyl-2-yl) methoxy] phenyl} -1-cyclohexyl-1H-pyrazole- 3-yl Chemical group 0.000 claims description 48
- 239000002253 acid Substances 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 23
- 239000003112 inhibitor Substances 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- VYELRUUMVSXCEN-QZQOTICOSA-N (e)-3-[1-cyclohexyl-4-phenyl-5-(4-phenylmethoxyphenyl)pyrazol-3-yl]prop-2-enoic acid Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1C1=C(C=2C=CC=CC=2)C(/C=C/C(=O)O)=NN1C1CCCCC1 VYELRUUMVSXCEN-QZQOTICOSA-N 0.000 claims description 5
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- UGQYGIUKZVOTBA-KNTRCKAVSA-N (e)-3-[5-cyclohexyl-1-(4-phenylmethoxyphenyl)pyrazol-3-yl]-2-methylprop-2-enoic acid Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1N1N=C(\C=C(/C)C(O)=O)C=C1C1CCCCC1 UGQYGIUKZVOTBA-KNTRCKAVSA-N 0.000 claims description 4
- VMPKFJSFWNDYKE-LFIBNONCSA-N (e)-3-[5-cyclohexyl-1-(4-phenylmethoxyphenyl)pyrazol-3-yl]prop-2-enoic acid Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1N1N=C(/C=C/C(=O)O)C=C1C1CCCCC1 VMPKFJSFWNDYKE-LFIBNONCSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 101800001014 Non-structural protein 5A Proteins 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 108010026228 mRNA guanylyltransferase Proteins 0.000 claims description 4
- 239000003475 metalloproteinase inhibitor Substances 0.000 claims description 4
- ZGRGSPCJXBTQLN-KNTRCKAVSA-N (e)-3-[1-cyclohexyl-2-(4-phenylmethoxyphenyl)imidazol-4-yl]-2-methylprop-2-enoic acid Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1C1=NC(\C=C(/C)C(O)=O)=CN1C1CCCCC1 ZGRGSPCJXBTQLN-KNTRCKAVSA-N 0.000 claims description 3
- JEOGSJAQYXAALE-KNTRCKAVSA-N (e)-3-[1-cyclohexyl-5-(4-phenylmethoxyphenyl)pyrazol-3-yl]-2-methylprop-2-enoic acid Chemical compound C1CCCCC1N1N=C(\C=C(/C)C(O)=O)C=C1C(C=C1)=CC=C1OCC1=CC=CC=C1 JEOGSJAQYXAALE-KNTRCKAVSA-N 0.000 claims description 3
- SNBHBCJDAOEYBM-DTQAZKPQSA-N (e)-3-[1-cyclohexyl-5-(4-phenylmethoxyphenyl)pyrazol-3-yl]prop-2-enoic acid Chemical compound C1CCCCC1N1N=C(/C=C/C(=O)O)C=C1C(C=C1)=CC=C1OCC1=CC=CC=C1 SNBHBCJDAOEYBM-DTQAZKPQSA-N 0.000 claims description 3
- YVDPRKZKNZXRHZ-FOCLMDBBSA-N (e)-3-[4-bromo-1-cyclohexyl-5-(4-phenylmethoxyphenyl)pyrazol-3-yl]prop-2-enoic acid Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1C1=C(Br)C(/C=C/C(=O)O)=NN1C1CCCCC1 YVDPRKZKNZXRHZ-FOCLMDBBSA-N 0.000 claims description 3
- WEDHMROCJDBYRG-UHFFFAOYSA-N 3-[1-[4-[[2-(4-chlorophenyl)-5-methoxyphenyl]methoxy]phenyl]-5-cyclohexylpyrazol-3-yl]propanoic acid Chemical compound C=1C(OC)=CC=C(C=2C=CC(Cl)=CC=2)C=1COC(C=C1)=CC=C1N1N=C(CCC(O)=O)C=C1C1CCCCC1 WEDHMROCJDBYRG-UHFFFAOYSA-N 0.000 claims description 3
- SCIBCPJGJALENC-UHFFFAOYSA-N 3-[1-cyclohexyl-5-(4-phenylmethoxyphenyl)pyrazol-3-yl]prop-2-ynoic acid Chemical compound C1CCCCC1N1N=C(C#CC(=O)O)C=C1C(C=C1)=CC=C1OCC1=CC=CC=C1 SCIBCPJGJALENC-UHFFFAOYSA-N 0.000 claims description 3
- QLAJJSCJSYZMGK-UHFFFAOYSA-N 3-[1-cyclohexyl-5-(4-phenylmethoxyphenyl)pyrazol-3-yl]propanoic acid Chemical compound C1CCCCC1N1N=C(CCC(=O)O)C=C1C(C=C1)=CC=C1OCC1=CC=CC=C1 QLAJJSCJSYZMGK-UHFFFAOYSA-N 0.000 claims description 3
- KXVASMASOFKFDU-UHFFFAOYSA-N 3-[5-[4-[[2-(4-chlorophenyl)-5-methoxyphenyl]methoxy]phenyl]-1-cyclohexylpyrazol-3-yl]propanoic acid Chemical compound C=1C(OC)=CC=C(C=2C=CC(Cl)=CC=2)C=1COC(C=C1)=CC=C1C1=CC(CCC(O)=O)=NN1C1CCCCC1 KXVASMASOFKFDU-UHFFFAOYSA-N 0.000 claims description 3
- VMPKFJSFWNDYKE-UHFFFAOYSA-N 3-[5-cyclohexyl-1-(4-phenylmethoxyphenyl)pyrazol-3-yl]prop-2-enoic acid Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1N1N=C(C=CC(=O)O)C=C1C1CCCCC1 VMPKFJSFWNDYKE-UHFFFAOYSA-N 0.000 claims description 3
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 3
- LPAPGWRWHPNLTF-DYTRJAOYSA-N ethyl (e)-3-[1-cyclohexyl-2-(4-phenylmethoxyphenyl)imidazol-4-yl]-2-methylprop-2-enoate Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1C1=NC(/C=C(\C)C(=O)OCC)=CN1C1CCCCC1 LPAPGWRWHPNLTF-DYTRJAOYSA-N 0.000 claims description 3
- DHFRYNPRXUSOGE-DYTRJAOYSA-N ethyl (e)-3-[1-cyclohexyl-5-(4-phenylmethoxyphenyl)pyrazol-3-yl]-2-methylprop-2-enoate Chemical compound C1CCCCC1N1N=C(/C=C(\C)C(=O)OCC)C=C1C(C=C1)=CC=C1OCC1=CC=CC=C1 DHFRYNPRXUSOGE-DYTRJAOYSA-N 0.000 claims description 3
- OHEJQHCIFZOLNC-UHFFFAOYSA-N ethyl 1-cyclohexyl-5-(4-phenylmethoxyphenyl)pyrazole-3-carboxylate Chemical compound C1CCCCC1N1N=C(C(=O)OCC)C=C1C(C=C1)=CC=C1OCC1=CC=CC=C1 OHEJQHCIFZOLNC-UHFFFAOYSA-N 0.000 claims description 3
- YVGLYSNGJNIBBC-UHFFFAOYSA-N ethyl 4-bromo-1-cyclohexyl-5-(4-phenylmethoxyphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1C1=C(Br)C(C(=O)OCC)=NN1C1CCCCC1 YVGLYSNGJNIBBC-UHFFFAOYSA-N 0.000 claims description 3
- YFSDKCIVIHGYBP-UHFFFAOYSA-N ethyl 5-cyclohexyl-1-(4-phenylmethoxyphenyl)pyrazole-3-carboxylate Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1N1N=C(C(=O)OCC)C=C1C1CCCCC1 YFSDKCIVIHGYBP-UHFFFAOYSA-N 0.000 claims description 3
- CJCBWFZZURZKMA-SAPNQHFASA-N methyl (e)-3-[1-cyclohexyl-2-(4-phenylmethoxyphenyl)imidazol-4-yl]prop-2-enoate Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1C1=NC(/C=C/C(=O)OC)=CN1C1CCCCC1 CJCBWFZZURZKMA-SAPNQHFASA-N 0.000 claims description 3
- PMVKQVWGPFPJRV-KNTRCKAVSA-N tert-butyl (e)-3-[1-cyclohexyl-2-(4-phenylmethoxyphenyl)imidazol-4-yl]prop-2-enoate Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1C1=NC(/C=C/C(=O)OC(C)(C)C)=CN1C1CCCCC1 PMVKQVWGPFPJRV-KNTRCKAVSA-N 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- ZGRUNGCYQBQKHG-DTQAZKPQSA-N (e)-3-[1-cyclohexyl-2-(4-phenylmethoxyphenyl)imidazol-4-yl]prop-2-enoic acid Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1C1=NC(/C=C/C(=O)O)=CN1C1CCCCC1 ZGRUNGCYQBQKHG-DTQAZKPQSA-N 0.000 claims description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- 208000036142 Viral infection Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- OROVCZDGCBQFMB-DYTRJAOYSA-N ethyl (e)-3-[5-cyclohexyl-1-(4-phenylmethoxyphenyl)pyrazol-3-yl]-2-methylprop-2-enoate Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1N1N=C(/C=C(\C)C(=O)OCC)C=C1C1CCCCC1 OROVCZDGCBQFMB-DYTRJAOYSA-N 0.000 claims description 2
- PDBQXNFRBSSDQC-SAPNQHFASA-N methyl (e)-3-[1-cyclohexyl-5-(4-phenylmethoxyphenyl)pyrazol-3-yl]prop-2-enoate Chemical compound C1CCCCC1N1N=C(/C=C/C(=O)OC)C=C1C(C=C1)=CC=C1OCC1=CC=CC=C1 PDBQXNFRBSSDQC-SAPNQHFASA-N 0.000 claims description 2
- BHWQNFQVKUJJSS-WUKNDPDISA-N methyl (e)-3-[4-bromo-1-cyclohexyl-5-(4-phenylmethoxyphenyl)pyrazol-3-yl]prop-2-enoate Chemical class C=1C=C(OCC=2C=CC=CC=2)C=CC=1C1=C(Br)C(/C=C/C(=O)OC)=NN1C1CCCCC1 BHWQNFQVKUJJSS-WUKNDPDISA-N 0.000 claims description 2
- PTTHVDNBOAMMHN-UHFFFAOYSA-N methyl 3-[1-cyclohexyl-5-(4-phenylmethoxyphenyl)pyrazol-3-yl]propanoate Chemical compound C1CCCCC1N1N=C(CCC(=O)OC)C=C1C(C=C1)=CC=C1OCC1=CC=CC=C1 PTTHVDNBOAMMHN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 claims description 2
- 229940121759 Helicase inhibitor Drugs 0.000 claims 3
- 229940123066 Polymerase inhibitor Drugs 0.000 claims 3
- 101000998548 Yersinia ruckeri Alkaline proteinase inhibitor Proteins 0.000 claims 3
- 238000011260 co-administration Methods 0.000 claims 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 54
- 239000000203 mixture Substances 0.000 abstract description 49
- 108060004795 Methyltransferase Proteins 0.000 abstract description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 115
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 66
- 235000019439 ethyl acetate Nutrition 0.000 description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 48
- 238000002360 preparation method Methods 0.000 description 48
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 36
- 150000002148 esters Chemical class 0.000 description 30
- 239000000543 intermediate Substances 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- 239000012267 brine Substances 0.000 description 28
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
- 239000007832 Na2SO4 Substances 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- 229910052938 sodium sulfate Inorganic materials 0.000 description 27
- 235000011152 sodium sulphate Nutrition 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 229910052681 coesite Inorganic materials 0.000 description 23
- 229910052906 cristobalite Inorganic materials 0.000 description 23
- 239000000377 silicon dioxide Substances 0.000 description 23
- 235000012239 silicon dioxide Nutrition 0.000 description 23
- 229910052682 stishovite Inorganic materials 0.000 description 23
- 229910052905 tridymite Inorganic materials 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 150000001299 aldehydes Chemical class 0.000 description 20
- 239000003153 chemical reaction reagent Substances 0.000 description 20
- 238000004587 chromatography analysis Methods 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 238000007127 saponification reaction Methods 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 238000003556 assay Methods 0.000 description 12
- 150000007942 carboxylates Chemical class 0.000 description 12
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 150000002989 phenols Chemical class 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 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 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 229940088598 enzyme Drugs 0.000 description 8
- 108700008776 hepatitis C virus NS-5 Proteins 0.000 description 8
- 150000004702 methyl esters Chemical class 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 229960000329 ribavirin Drugs 0.000 description 8
- 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 8
- 229910015844 BCl3 Inorganic materials 0.000 description 7
- 230000029936 alkylation Effects 0.000 description 7
- 238000005804 alkylation reaction Methods 0.000 description 7
- 239000006286 aqueous extract Substances 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 229940102396 methyl bromide Drugs 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 7
- 108010050904 Interferons Proteins 0.000 description 6
- 102000014150 Interferons Human genes 0.000 description 6
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 1
- 229950006081 taribavirin Drugs 0.000 description 1
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- AEMRXKADFDEFKE-JQIJEIRASA-N tert-butyl (E)-3-[1-cyclohexyl-2-(4-hydroxyphenyl)imidazol-4-yl]-2-methylprop-2-enoate Chemical compound C=1C=C(O)C=CC=1C1=NC(\C=C(/C)C(=O)OC(C)(C)C)=CN1C1CCCCC1 AEMRXKADFDEFKE-JQIJEIRASA-N 0.000 description 1
- JNIURKLEIMZPNI-UHFFFAOYSA-N tert-butyl 4-(4-chlorophenyl)-3-methylbenzoate Chemical compound CC1=CC(C(=O)OC(C)(C)C)=CC=C1C1=CC=C(Cl)C=C1 JNIURKLEIMZPNI-UHFFFAOYSA-N 0.000 description 1
- RIHBTHGKWXRWQX-UHFFFAOYSA-N tert-butyl 4-bromo-3-methylbenzoate Chemical compound CC1=CC(C(=O)OC(C)(C)C)=CC=C1Br RIHBTHGKWXRWQX-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 238000004809 thin layer chromatography Methods 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US50206703P | 2003-09-11 | 2003-09-11 | |
| US502067P | 2003-09-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2358904T3 true ES2358904T3 (es) | 2011-05-16 |
Family
ID=34434839
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES04782095T Expired - Lifetime ES2358904T3 (es) | 2003-09-11 | 2004-08-24 | Heterociclos de cicloalquilo para tratar el virus de la hepatitis c. |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US7112601B2 (https=) |
| EP (1) | EP1663105B1 (https=) |
| JP (1) | JP4897484B2 (https=) |
| AT (1) | ATE498398T1 (https=) |
| DE (1) | DE602004031435D1 (https=) |
| ES (1) | ES2358904T3 (https=) |
| WO (1) | WO2005034850A2 (https=) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT502258B1 (de) * | 2005-07-22 | 2007-09-15 | Univ Wien | Cox-i-inhibitorverbindungen |
| WO2007019397A2 (en) * | 2005-08-05 | 2007-02-15 | Genelabs Technologies, Inc. | 6-membered aryl and heteroaryl derivatives for the treatment of hepatitis c virus |
| RU2009109355A (ru) * | 2006-08-17 | 2010-09-27 | БЕРИНГЕР ИНГЕЛЬХАЙМ ИНТЕРНАЦИОНАЛЬ ГмбХ (DE) | Ингибиторы вырусной полимеразы |
| PT2144604E (pt) * | 2007-02-28 | 2011-10-19 | Conatus Pharmaceuticals Inc | Métodos para o tratamento da hepatite c viral crónica utilizando ro-113-0830 |
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| ES2381410T3 (es) | 2007-05-04 | 2012-05-28 | Vertex Pharmceuticals Incorporated | Terapia de combinación paa el tratamiento de infecciones por VHC |
| WO2009028418A1 (ja) | 2007-08-24 | 2009-03-05 | Sapporo Medical University | シクロスポリンａ結合タンパク質 |
| EP2234977A4 (en) | 2007-12-19 | 2011-04-13 | Boehringer Ingelheim Int | VIRAL POLYMERASE INHIBITORS |
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| KR20140003521A (ko) | 2010-12-30 | 2014-01-09 | 이난타 파마슈티칼스, 인코포레이티드 | 페난트리딘 매크로사이클릭 ｃ형 간염 세린 프로테아제 억제제 |
| EP2658859A4 (en) | 2010-12-30 | 2014-07-30 | Enanta Pharm Inc | MACROCYCLIC HEPATITIS C SERIN PROTEASE INHIBITORS |
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| EP3089757A1 (en) | 2014-01-03 | 2016-11-09 | AbbVie Inc. | Solid antiviral dosage forms |
| WO2019169193A1 (en) | 2018-03-01 | 2019-09-06 | Annapurna Bio Inc. | Compounds and compositions for treating conditions associated with apj receptor activity |
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| KR19990064310A (ko) * | 1995-10-17 | 1999-07-26 | 윌리암스 로저 에이 | 시클로옥시게나제-2의 검출방법 |
| AU756627B2 (en) | 1998-07-27 | 2003-01-16 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Diketoacid-derivatives as inhibitors of polymerases |
| ID27787A (id) | 1998-08-21 | 2001-04-26 | Viro Pharma Inc | Senyawa, komposisi dan metode untuk pengobatan atau pencegahan infeksi yang disebabkan oleh virus dan penyakit-penyakit yang berkaitan |
| BR9913406A (pt) | 1998-09-04 | 2002-01-29 | Viropharma Inc | Processo de tratamento de infecção causada por pelo menos um vìrus da famìlia flaviviridae e de doença associada com a citada infecção em um hospedeiro vivo possuindo a citada infecção |
| KR20010079907A (ko) | 1998-09-25 | 2001-08-22 | 비로파마 인코포레이티드 | 바이러스 감염 및 관련 질병의 치료 및 예방 방법 |
| AU1324300A (en) * | 1998-10-26 | 2000-05-15 | Vertex Pharmaceuticals Incorporated | Pentacyclic compounds useful as inhibitors of hepatitis c virus ns3 helicase |
| US6566365B1 (en) | 1999-11-04 | 2003-05-20 | Biochem Pharma Inc. | Method for the treatment of Flaviviridea viral infection using nucleoside analogues |
| US6770666B2 (en) | 1999-12-27 | 2004-08-03 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
| EP1162196A4 (en) | 1999-12-27 | 2003-04-16 | Japan Tobacco Inc | COMPOUNDS WITH JOINED CYCLES AND THEIR USE AS MEDICAMENTS |
| US6448281B1 (en) | 2000-07-06 | 2002-09-10 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
| EP1256628A3 (en) | 2001-05-10 | 2003-03-19 | Agouron Pharmaceuticals, Inc. | Hepatitis c virus (hcv) ns5b rna polymerase and mutants thereof |
| CN101624391A (zh) | 2001-06-11 | 2010-01-13 | 病毒化学医药公司 | 用作黄病毒感染抗病毒剂的噻吩衍生物 |
| AR035543A1 (es) * | 2001-06-26 | 2004-06-16 | Japan Tobacco Inc | Agente terapeutico para la hepatitis c que comprende un compuesto de anillo condensado, compuesto de anillo condensado, composicion farmaceutica que lo comprende, compuestos de benzimidazol, tiazol y bifenilo utiles como intermediarios para producir dichos compuestos, uso del compuesto de anillo con |
| CA2448737C (en) | 2001-07-20 | 2010-06-01 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
| EP2335700A1 (en) | 2001-07-25 | 2011-06-22 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C virus polymerase inhibitors with a heterobicylic structure |
| WO2003026587A2 (en) | 2001-09-26 | 2003-04-03 | Bristol-Myers Squibb Company | Compounds useful for treating hepatitus c virus |
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2004
- 2004-08-19 US US10/922,096 patent/US7112601B2/en not_active Expired - Lifetime
- 2004-08-24 ES ES04782095T patent/ES2358904T3/es not_active Expired - Lifetime
- 2004-08-24 DE DE602004031435T patent/DE602004031435D1/de not_active Expired - Lifetime
- 2004-08-24 JP JP2006526121A patent/JP4897484B2/ja not_active Expired - Fee Related
- 2004-08-24 WO PCT/US2004/027533 patent/WO2005034850A2/en not_active Ceased
- 2004-08-24 EP EP04782095A patent/EP1663105B1/en not_active Expired - Lifetime
- 2004-08-24 AT AT04782095T patent/ATE498398T1/de not_active IP Right Cessation
Also Published As
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|---|---|
| JP4897484B2 (ja) | 2012-03-14 |
| WO2005034850A2 (en) | 2005-04-21 |
| WO2005034850A3 (en) | 2006-03-16 |
| EP1663105A4 (en) | 2009-04-15 |
| EP1663105A2 (en) | 2006-06-07 |
| US20050075376A1 (en) | 2005-04-07 |
| US7112601B2 (en) | 2006-09-26 |
| EP1663105B1 (en) | 2011-02-16 |
| ATE498398T1 (de) | 2011-03-15 |
| DE602004031435D1 (de) | 2011-03-31 |
| JP2007505114A (ja) | 2007-03-08 |
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