JP6093456B2 - 抗ウイルス性化合物 - Google Patents
抗ウイルス性化合物 Download PDFInfo
- Publication number
- JP6093456B2 JP6093456B2 JP2015560639A JP2015560639A JP6093456B2 JP 6093456 B2 JP6093456 B2 JP 6093456B2 JP 2015560639 A JP2015560639 A JP 2015560639A JP 2015560639 A JP2015560639 A JP 2015560639A JP 6093456 B2 JP6093456 B2 JP 6093456B2
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- dichloro
- triazole
- diamine
- pyridin
- 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 - Fee Related
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- 150000001875 compounds Chemical class 0.000 title claims description 174
- 230000000840 anti-viral effect Effects 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims description 134
- 241000711549 Hepacivirus C Species 0.000 claims description 89
- -1 2,6-diaza-spiro [3.3] heptanyl Chemical group 0.000 claims description 66
- 125000000217 alkyl group Chemical group 0.000 claims description 66
- 239000003112 inhibitor Substances 0.000 claims description 27
- 208000015181 infectious disease Diseases 0.000 claims description 24
- 108010050904 Interferons Proteins 0.000 claims description 20
- 102000014150 Interferons Human genes 0.000 claims description 20
- 239000003443 antiviral agent Substances 0.000 claims description 19
- 210000000987 immune system Anatomy 0.000 claims description 18
- 229940079322 interferon Drugs 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000002950 monocyclic group Chemical group 0.000 claims description 13
- 230000010076 replication Effects 0.000 claims description 13
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- UGLWXDYLLILNED-UHFFFAOYSA-N 3-(3-chloro-4-pyridazin-3-ylphenyl)-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound ClC=1C=C(C=CC=1C=1N=NC=CC=1)C1(NNC(=N1)N)N UGLWXDYLLILNED-UHFFFAOYSA-N 0.000 claims description 9
- 101800001014 Non-structural protein 5A Proteins 0.000 claims description 9
- 150000004985 diamines Chemical class 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 7
- AYWOHARGWPLPMB-UHFFFAOYSA-N 1-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]-2-chlorophenyl]pyridin-2-one Chemical compound N1C(N)=NC(NC=2C=C(Cl)C(=CC=2)N2C(C=CC=C2)=O)=N1 AYWOHARGWPLPMB-UHFFFAOYSA-N 0.000 claims description 6
- VDLBMKDWBRBJPW-UHFFFAOYSA-N 3-[3-chloro-4-(1-methyltetrazol-5-yl)phenyl]-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound ClC=1C=C(C=CC=1C1=NN=NN1C)C1(NNC(=N1)N)N VDLBMKDWBRBJPW-UHFFFAOYSA-N 0.000 claims description 6
- UBGWGHQINPVZNF-UHFFFAOYSA-N 3-[4-(6-aminopyridin-3-yl)-3,5-dichlorophenyl]-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound N1NC(N)=NC1(N)C1=CC(Cl)=C(C=2C=NC(N)=CC=2)C(Cl)=C1 UBGWGHQINPVZNF-UHFFFAOYSA-N 0.000 claims description 6
- YNKDSOVOILOXEO-UHFFFAOYSA-N 4-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]-2,6-dichlorophenyl]-1h-pyridin-2-one Chemical compound N1C(N)=NC(NC=2C=C(Cl)C(=C(Cl)C=2)C2=CC(=O)NC=C2)=N1 YNKDSOVOILOXEO-UHFFFAOYSA-N 0.000 claims description 6
- FVYBHSULJHBHNY-UHFFFAOYSA-N 5-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]-2-chloro-6-(trifluoromethyl)phenyl]-n-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-2-sulfonamide Chemical compound C1=NC(S(=O)(=O)NC(C)(C)C(F)(F)F)=CC=C1C(C(=C1)C(F)(F)F)=C(Cl)C=C1NC1=NNC(N)=N1 FVYBHSULJHBHNY-UHFFFAOYSA-N 0.000 claims description 6
- 229940124683 HCV polymerase inhibitor Drugs 0.000 claims description 6
- KERUGSYEKGDVFN-UHFFFAOYSA-N n-[5-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]-2,6-dichlorophenyl]pyridin-2-yl]methanesulfonamide Chemical compound C1=NC(NS(=O)(=O)C)=CC=C1C(C(=C1)Cl)=C(Cl)C=C1NC1=NNC(N)=N1 KERUGSYEKGDVFN-UHFFFAOYSA-N 0.000 claims description 6
- QPQIHFGZTYMHQB-UHFFFAOYSA-N 1-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]-2,6-dichlorophenyl]pyridin-2-one Chemical compound N1C(N)=NC(NC=2C=C(Cl)C(=C(Cl)C=2)N2C(C=CC=C2)=O)=N1 QPQIHFGZTYMHQB-UHFFFAOYSA-N 0.000 claims description 5
- PIXSMUSWVHSXBD-UHFFFAOYSA-N 1-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]phenyl]pyridin-2-one Chemical compound N1C(N)=NC(NC=2C=CC(=CC=2)N2C(C=CC=C2)=O)=N1 PIXSMUSWVHSXBD-UHFFFAOYSA-N 0.000 claims description 5
- OQGVFXCKOKZYGU-UHFFFAOYSA-N 3-(3,5-dichloro-4-pyrazol-1-ylphenyl)-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound ClC=1C=C(C=C(C=1N1N=CC=C1)Cl)C1(NNC(=N1)N)N OQGVFXCKOKZYGU-UHFFFAOYSA-N 0.000 claims description 5
- UWDQIVBKAULEKH-UHFFFAOYSA-N 3-[3,5-dichloro-4-(6-methoxypyridin-3-yl)phenyl]-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound C1=NC(OC)=CC=C1C1=C(Cl)C=C(C2(N)N=C(N)NN2)C=C1Cl UWDQIVBKAULEKH-UHFFFAOYSA-N 0.000 claims description 5
- LBGBHROACFLVJB-UHFFFAOYSA-N 3-n-[3-fluoro-4-(6-fluoropyridin-3-yl)-5-(trifluoromethyl)phenyl]-1h-1,2,4-triazole-3,5-diamine Chemical compound N1C(N)=NC(NC=2C=C(C(C=3C=NC(F)=CC=3)=C(F)C=2)C(F)(F)F)=N1 LBGBHROACFLVJB-UHFFFAOYSA-N 0.000 claims description 5
- IEXBIMUFTKNJHA-UHFFFAOYSA-N 5-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]-2-chloro-6-(trifluoromethyl)phenyl]-n-tert-butylpyridine-2-sulfonamide Chemical compound C1=NC(S(=O)(=O)NC(C)(C)C)=CC=C1C(C(=C1)C(F)(F)F)=C(Cl)C=C1NC1=NNC(N)=N1 IEXBIMUFTKNJHA-UHFFFAOYSA-N 0.000 claims description 5
- 229940122604 HCV protease inhibitor Drugs 0.000 claims description 5
- 229940121759 Helicase inhibitor Drugs 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- QJBUDCLKYAPCFX-UHFFFAOYSA-N 3-[3,5-dichloro-4-(5-methylsulfonylpyridin-3-yl)phenyl]-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound ClC=1C=C(C=C(C=1C=1C=NC=C(C=1)S(=O)(=O)C)Cl)C1(NNC(=N1)N)N QJBUDCLKYAPCFX-UHFFFAOYSA-N 0.000 claims description 4
- ZGKLJLIROOEKRC-UHFFFAOYSA-N 3-[3-fluoro-4-pyridin-3-yl-5-(trifluoromethyl)phenyl]-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound FC=1C=C(C=C(C=1C=1C=NC=CC=1)C(F)(F)F)C1(N=C(NN1)N)N ZGKLJLIROOEKRC-UHFFFAOYSA-N 0.000 claims description 4
- FKVAICYUIZNMCQ-UHFFFAOYSA-N 3-[4-(2-aminopyrimidin-5-yl)-3,5-dichlorophenyl]-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound NC1=NC=C(C=N1)C1=C(C=C(C=C1Cl)C1(NNC(=N1)N)N)Cl FKVAICYUIZNMCQ-UHFFFAOYSA-N 0.000 claims description 4
- FVAIVWPCQSMRNO-UHFFFAOYSA-N 5-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]-2,6-dichlorophenyl]-1h-pyridin-2-one Chemical compound N1C(N)=NC(NC=2C=C(Cl)C(=C(Cl)C=2)C2=CNC(=O)C=C2)=N1 FVAIVWPCQSMRNO-UHFFFAOYSA-N 0.000 claims description 4
- SSQYGELCNBBBDQ-UHFFFAOYSA-N 5-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]-2-chloro-6-(trifluoromethyl)phenyl]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC=C1C(C(=C1)C(F)(F)F)=C(Cl)C=C1NC1=NNC(N)=N1 SSQYGELCNBBBDQ-UHFFFAOYSA-N 0.000 claims description 4
- FYFGLYYGDADPMI-UHFFFAOYSA-N COC1=CC=CC(=N1)C2=C(C=C(C=C2Cl)C3(NNC(=N3)N)N)Cl Chemical compound COC1=CC=CC(=N1)C2=C(C=C(C=C2Cl)C3(NNC(=N3)N)N)Cl FYFGLYYGDADPMI-UHFFFAOYSA-N 0.000 claims description 4
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- BSZYIFMNLPHVOI-UHFFFAOYSA-N 3-(3,5-dichloro-4-pyridin-4-ylphenyl)-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound ClC=1C=C(C=C(C=1C1=CC=NC=C1)Cl)C1(NNC(=N1)N)N BSZYIFMNLPHVOI-UHFFFAOYSA-N 0.000 claims description 3
- WWDSFKKRXDJIBL-UHFFFAOYSA-N 3-(3,5-dichloro-4-pyrimidin-5-ylphenyl)-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound ClC=1C=C(C=C(C=1C=1C=NC=NC=1)Cl)C1(NNC(=N1)N)N WWDSFKKRXDJIBL-UHFFFAOYSA-N 0.000 claims description 3
- YYDITELXOKPJEO-UHFFFAOYSA-N 3-[3,5-dichloro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound ClC=1C=C(C=C(C=1C=1CCNCC=1)Cl)C1(NNC(=N1)N)N YYDITELXOKPJEO-UHFFFAOYSA-N 0.000 claims description 3
- UHKGINBWNHZKOB-UHFFFAOYSA-N 3-[3,5-dichloro-4-(2-methoxypyridin-4-yl)phenyl]-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound ClC=1C=C(C=C(C=1C1=CC(=NC=C1)OC)Cl)C1(NNC(=N1)N)N UHKGINBWNHZKOB-UHFFFAOYSA-N 0.000 claims description 3
- AKTUWGRSJQEXAA-UHFFFAOYSA-N 3-[3,5-dichloro-4-(6-methylsulfonylpyridin-3-yl)phenyl]-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound ClC=1C=C(C=C(C=1C=1C=NC(=CC=1)S(=O)(=O)C)Cl)C1(NNC(=N1)N)N AKTUWGRSJQEXAA-UHFFFAOYSA-N 0.000 claims description 3
- AXXVQNZWKKSRHS-UHFFFAOYSA-N 3-[3-chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)phenyl]-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound ClC=1C=C(C=C(C=1C=1CCNCC=1)C(F)(F)F)C1(NNC(=N1)N)N AXXVQNZWKKSRHS-UHFFFAOYSA-N 0.000 claims description 3
- WPDJCDIHCVKPFQ-UHFFFAOYSA-N C1=C(C=C(C(=C1Cl)C2=CC(=CN=C2)Cl)Cl)C3(NNC(=N3)N)N Chemical compound C1=C(C=C(C(=C1Cl)C2=CC(=CN=C2)Cl)Cl)C3(NNC(=N3)N)N WPDJCDIHCVKPFQ-UHFFFAOYSA-N 0.000 claims description 3
- KKDCUOHKGUZVBE-UHFFFAOYSA-N C1=C(NN=C1)C2=C(C=C(C=C2Cl)C3(NNC(=N3)N)N)Cl Chemical compound C1=C(NN=C1)C2=C(C=C(C=C2Cl)C3(NNC(=N3)N)N)Cl KKDCUOHKGUZVBE-UHFFFAOYSA-N 0.000 claims description 3
- ABKMENNQWCRLMX-UHFFFAOYSA-N C1=C(SC(=C1)Cl)C2=C(C=C(C=C2Cl)C3(NNC(=N3)N)N)Cl Chemical compound C1=C(SC(=C1)Cl)C2=C(C=C(C=C2Cl)C3(NNC(=N3)N)N)Cl ABKMENNQWCRLMX-UHFFFAOYSA-N 0.000 claims description 3
- DTQDLRKZYBSYPY-UHFFFAOYSA-N C1=CC(=CN=C1)C2=C(C=C(C=C2Cl)C3(NNC(=N3)N)N)Cl Chemical compound C1=CC(=CN=C1)C2=C(C=C(C=C2Cl)C3(NNC(=N3)N)N)Cl DTQDLRKZYBSYPY-UHFFFAOYSA-N 0.000 claims description 3
- JFCCGKXLLGQDMK-UHFFFAOYSA-N C1=CC(=NC=C1C2=C(C=C(C=C2Cl)C3(NNC(=N3)N)N)Cl)C(F)(F)F Chemical compound C1=CC(=NC=C1C2=C(C=C(C=C2Cl)C3(NNC(=N3)N)N)Cl)C(F)(F)F JFCCGKXLLGQDMK-UHFFFAOYSA-N 0.000 claims description 3
- ZTUKDRQHJZSOCY-UHFFFAOYSA-N CN1N=C(C(F)(F)F)C(C(C(Cl)=CC(C2(N)N=C(N)NN2)=C2)=C2Cl)=C1 Chemical class CN1N=C(C(F)(F)F)C(C(C(Cl)=CC(C2(N)N=C(N)NN2)=C2)=C2Cl)=C1 ZTUKDRQHJZSOCY-UHFFFAOYSA-N 0.000 claims description 3
- OXVWVWFITOKMBT-UHFFFAOYSA-N COC1=NC=C(C=N1)C2=C(C=C(C=C2Cl)C3(NNC(=N3)N)N)Cl Chemical compound COC1=NC=C(C=N1)C2=C(C=C(C=C2Cl)C3(NNC(=N3)N)N)Cl OXVWVWFITOKMBT-UHFFFAOYSA-N 0.000 claims description 3
- HFRLJTFPQYNCPF-UHFFFAOYSA-N n-(1-adamantyl)-5-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]-2-chloro-6-(trifluoromethyl)phenyl]pyridine-2-sulfonamide Chemical compound N1C(N)=NC(NC=2C=C(C(C=3C=NC(=CC=3)S(=O)(=O)NC34CC5CC(CC(C5)C3)C4)=C(Cl)C=2)C(F)(F)F)=N1 HFRLJTFPQYNCPF-UHFFFAOYSA-N 0.000 claims description 3
- PZSRZZBPPOFCCC-UHFFFAOYSA-N tert-butyl 4-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]-2,6-dichlorophenyl]-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C=2C(=CC(NC=3N=C(N)NN=3)=CC=2Cl)Cl)=C1 PZSRZZBPPOFCCC-UHFFFAOYSA-N 0.000 claims description 3
- INTFTXDDTOPJPO-UHFFFAOYSA-N tert-butyl 4-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]-2-chloro-6-(trifluoromethyl)phenyl]-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C=2C(=CC(NC=3N=C(N)NN=3)=CC=2Cl)C(F)(F)F)=C1 INTFTXDDTOPJPO-UHFFFAOYSA-N 0.000 claims description 3
- OUSUVLYVAIJYNE-UHFFFAOYSA-N tert-butyl 6-[4-[(5-amino-1h-1,2,4-triazol-3-yl)amino]-2,6-dichlorophenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC21CN(C=1C(=CC(NC=3N=C(N)NN=3)=CC=1Cl)Cl)C2 OUSUVLYVAIJYNE-UHFFFAOYSA-N 0.000 claims description 3
- UJQOYZPXZQGEEA-UHFFFAOYSA-N 3-(3,5-dichloro-4-pyridazin-4-ylphenyl)-1,2-dihydro-1,2,4-triazole-3,5-diamine Chemical compound ClC=1C=C(C=C(C=1C1=CN=NC=C1)Cl)C1(NNC(=N1)N)N UJQOYZPXZQGEEA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 195
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 152
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- 238000006243 chemical reaction Methods 0.000 description 58
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- 238000000034 method Methods 0.000 description 50
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 38
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- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 34
- 239000000460 chlorine Substances 0.000 description 31
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- 239000012267 brine Substances 0.000 description 28
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
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- 239000000706 filtrate Substances 0.000 description 15
- 238000009472 formulation Methods 0.000 description 15
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 13
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
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- 238000002054 transplantation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- UDLLSOQWYYRFPP-UHFFFAOYSA-N tributyl(pyridazin-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=NN=C1 UDLLSOQWYYRFPP-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 108010077753 type II interferon receptor Proteins 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 108700001624 vesicular stomatitis virus G Proteins 0.000 description 1
- 230000007502 viral entry Effects 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 239000007966 viscous suspension Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/14—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
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- Oncology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description
Aは、不飽和もしくは部分不飽和の単環式もしくは二環式ヘテロアリールまたは単環式もしくはスピロ環式ヘテロシクロアルキルであり;
各R1は、独立してハロ、ハロ低級アルキル、または低級アルキルスルホニルであり;
mは、0、1または2であり;
各R2は、独立してハロ、低級アルコキシ、オキソ、アミノ、低級アルキル、C(=O)OR2’、S(=O)2R2’、S(=O)2NHR2’、ヒドロキシル低級アルキル、C(=O)NHR2’、またはC(=O)R2’であり;
nは、0、1または2であり;
R2’は、低級アルキル、ハロ低級アルキル、またはアダマンチルである]
またはその医薬的に許容できる塩を提供する。
本出願は、C型肝炎ウイルス(HCV)感染症を治療するための方法であって、その必要がある患者に療法有効量の式Iの化合物を投与することを含む方法を提供する。
本明細書中で用いる句“a”または“an”物は、1以上のその物を表わす;たとえば、化合物(a compound)は、1以上の化合物または少なくとも1つの化合物を表わす。したがって、用語“a”(または“an”)、“1以上(one or more)”、および“少なくとも1(at least one)”は本明細書中で互換性をもって使用できる。
)であるという意味をもつと解釈すべきである。すなわち、これらの用語は“少なくとも・・・をもつ(having at least)”または“少なくとも・・・を含む(including at least)”という句と同義に解釈すべきである。方法の文脈で用いる場合、用語“含む(comprising)”は、その方法が少なくとも列記した工程を含むけれども追加工程も含む可能性があることを意味する。化合物または組成物の文脈で用いる場合、用語“含む(comprising)”は、その化合物または組成物が少なくとも列記した特徴または成分を含むけれども追加の特徴または成分も含む可能性があることを意味する。
本明細書中で用いる用語“任意選択的な(optional)”または“任意選択的に(optionally)”は、その後に記載する事象または状況が起きてもよいがその必要はないこと、またその記載はその事象または状況が起きる場合と起きない場合を含むことを意味する。たとえば、“任意選択的に置換された”は、その任意選択的に置換された部分が水素原子または置換基を含む可能性があることを意味する。
用語“約(about)”は、本明細書中でおおよそ(approximately)、付近(in the region of)、おおまかに(roughly)、またはほぼ(around)を意味するために用いられる。用語“約(about)”を数値範囲と併せて用いる場合、それは境界をその明記した数値の上方および下方へ拡張することによりその範囲を改変する。一般に、用語“約(about)”は、本明細書中で、記載した数値の上方および下方へ20%の分散によって改変するために用いられる。
本明細書中で用いる用語“エステル”は、式−C(=O)ORの基を表わし、ここでRは本明細書中で定義する低級アルキルである。
本明細書中で用いる用語“スルホニル”は、−SO2−基を表わす。
本明細書中で用いる用語“アルキルスルホニル”および“アリールスルホニル”は、式−S(=O)2Rの基を表わし、ここでRはそれぞれアルキルまたはアリールであり、アルキルおよびアリールは本明細書中で定義したものである。本明細書中で用いる用語“ヘテロアルキルスルホニル”は、本明細書中で式−S(=O)2Rの基を表わし、ここでRは本明細書中で定義した“ヘテロアルキル”である。
本明細書中で用いる用語“トリフルオロメチルスルフィニル”は、式−S(=O)CF3の基を表わす。
本明細書中で用いる用語“ニトロ”は、式−N+(=O)O−の基を表わす。
本出願は、式Iの化合物:
Aは、不飽和もしくは部分不飽和の単環式もしくは二環式ヘテロアリールまたは単環式もしくはスピロ環式ヘテロシクロアルキルであり;
各R1は、独立してハロ、ハロ低級アルキル、または低級アルキルスルホニルであり;
mは、0、1または2であり;
各R2は、独立してハロ、低級アルコキシ、オキソ、アミノ、低級アルキル、C(=O)OR2’、S(=O)2R2’、S(=O)2NHR2’、ヒドロキシル低級アルキル、C(=O)NHR2’、またはC(=O)R2’であり;
nは、0、1または2であり;
R2’は、低級アルキル、ハロ低級アルキル、またはアダマンチルである]
またはその医薬的に許容できる塩を提供する。
本出願は、mが2である、式Iの化合物を提供する。
本出願は、一方のR1がハロであり、他方がハロ低級アルキルである、式Iの化合物を提供する。
本出願は、両方のR1がハロである、式Iの化合物を提供する。
本出願は、nが0である、前記の式Iのいずれかの化合物を提供する。
本出願は、あるいはnが1である、前記の式Iのいずれかの化合物を提供する。
本出願は、Aが、ピリジニル、ピリミジニル、ピリダジニル、トリアゾリル、テトラゾリル、ピペラジニル、2,6−ジアザ−スピロ[3.3]ヘプタニル、アゼチジニル、チオフェニル、またはピラゾリルである、前記の式Iのいずれかの化合物を提供する。
本出願は、下記のものからなる群から選択される化合物を提供する:
N3−[3,5−ジクロロ−4−(6−メトキシ−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(5−メタンスルホニル−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−1H−ピリジン−2−オン;
N3−[4−(6−アミノ−ピリジン−3−イル)−3,5−ジクロロ−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[4−(2−アミノ−ピリミジン−5−イル)−3,5−ジクロロ−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(2−メトキシ−ピリジン−4−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
4−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−1H−ピリジン−2−オン;
N−{5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−ピリジン−2−イル}−メタンスルホンアミド;
N5−[3−フルオロ−4−(6−フルオロ−ピリジン−3−イル)−5−トリフルオロメチル−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N5−(3−フルオロ−4−ピリジン−3−イル−5−トリフルオロメチル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(6−メタンスルホニル−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
6−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−2,6−ジアザ−スピロ[3.3]ヘプタン−2−カルボン酸 tert−ブチルエステル;
N3−(3−クロロ−4−ピリダジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3−クロロ−4−(1−メチル−1H−テトラゾール−5−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3−クロロ−4−(2−メチル−2H−[1,2,4]トリアゾール−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−(3,5−ジクロロ−4−ピラゾール−1−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
4−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−3,6−ジヒドロ−2H−ピリジン−1−カルボン酸 tert−ブチルエステル;
N3−[3,5−ジクロロ−4−(1,2,3,6−テトラヒドロ−ピリジン−4−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
4−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−3,6−ジヒドロ−2H−ピリジン−1−カルボン酸 tert−ブチルエステル;
N3−[3−クロロ−4−(1,2,3,6−テトラヒドロ−ピリジン−4−イル)−5−トリフルオロメチル−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N5−(3,5−ジクロロ−4−[1,2,4]トリアゾロ[4,3−a]ピリジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N−{3−クロロ−4−[6−(プロパン−2−スルホニル)−ピリジン−3−イル]−5−トリフルオロメチル−フェニル}−4H−[1,2,4]トリアゾール−3,5−ジアミン;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−ピリジン−2−スルホン酸 tert−ブチルアミド;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−ピリジン−2−スルホン酸 (2,2,2−トリフルオロ−1,1−ジメチル−エチル)−アミド;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−ピリジン−2−スルホン酸 アダマンタン−1−イルアミド;
N3−[2−クロロ−4’−(4−メチル−ピペラジン−1−イル)−6−トリフルオロメチル−ビフェニル−4−イル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−(3−クロロ−4−ピリダジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
1−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−フェニル]−1H−ピリジン−2−オン;
1−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−フェニル]−1H−ピリジン−2−オン;
1−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−1H−ピリジン−2−オン;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−ピリジン−2−カルボン酸 メチルアミド;
N3−(3,5−ジクロロ−4−ピリダジン−4−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
1−{3−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−チオフェン−2−イル}−エタノン;
N3−(3,5−ジクロロ−4−ピリジン−4−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(5−クロロ−チオフェン−2−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−(3,5−ジクロロ−4−ピリジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(1H−ピラゾール−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−(3,5−ジクロロ−4−ピリミジン−5−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(2−メトキシ−ピリミジン−5−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(6−トリフルオロメチル−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(1−メチル−3−トリフルオロメチル−1H−ピラゾール−4−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(5−クロロ−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;および
N3−[3,5−ジクロロ−4−(6−メトキシ−ピリジン−2−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン。
本出願は、さらに、その必要がある患者に療法有効量の免疫系抑制薬を投与することを含む、前記方法を提供する。
本出願は、さらに、HCVの複製を阻害する抗ウイルス薬の組合わせを投与することを含む、前記のいずれかの方法を提供する。
本出願は、さらに、免疫系調節薬がインターフェロンまたは化学的に誘導体化されたインターフェロンである、前記方法を提供する。
本出願は、HCVを予防するための医薬の調製における、式Iの化合物の使用を提供する。
本出願は、本明細書に記載するいずれかの化合物、組成物、方法または使用を提供する。
本発明に包含される本発明の範囲内の代表的化合物の例を次表に示す。これらの例および以下の製造は、当業者が本発明をより明確に理解し、実施することができるように提示される。それらは本発明の範囲を限定するものではなく本発明の例示および代表例にすぎないとみなすべきである。
一般スキーム
以下のスキームは式Iの化合物を得るための一般法を示す。
本発明の化合物は、多様な経口投与用の剤形およびキャリヤー中に配合できる。経口投与は錠剤、コーティング錠、糖衣錠、ハードおよびソフトゼラチンカプセル剤、液剤、乳剤、シロップ剤、または懸濁液剤の形態で行なうことができる。本発明の化合物は他の投与経路で投与した場合にも有効であり、それには他の投与経路のうち連続(静脈内点滴)、局所、非経口、筋肉内、静脈内、皮下、経皮(透過促進剤を含有してもよい)、口腔、経鼻、吸入および坐剤投与が含まれる。好ましい投与様式は一般に、罹患度および有効成分に対する患者の応答に従って調節できる好都合な各日投与計画を用いる経口法である。
適応症
本出願は、C型肝炎ウイルス(HCV)感染症を予防するための方法であって、その必要がある患者に療法有効量の式Iの化合物を投与することを含む方法を提供する。
本出願は、C型肝炎ウイルス(HCV)感染症を治療するための方法であって、その必要がある患者に療法有効量の式Iの化合物を投与することを含む方法を提供する。
本出願は、免疫系調節薬がインターフェロンまたは化学的に誘導体化されたインターフェロンである、前記方法を提供する。
本発明化合物およびそれらの異性体ならびにその医薬的に許容できる塩類は、単独で、あるいはHCVライフサイクルに関与するウイルス性または細胞性のエレメントまたは機能を標的とする他の化合物と併用した場合に、HCV感染症を治療および予防するのに有用である。本発明に有用な化合物のクラスには、限定ではなく、すべてのクラスのHCV抗ウイルス薬が含まれる。
本出願は、さらに、その必要がある患者に療法有効量の免疫系抑制薬を投与することを含む、前記方法を提供する。
本出願は、さらに、免疫系調節薬もしくはHCVの複製を阻害する抗ウイルス薬またはその組合わせを投与することを含む、前記のいずれかの方法を提供する。
本出願は、さらに、免疫系調節薬もしくはHCVの複製を阻害する抗ウイルス薬またはその組合わせを投与することを含み、その際、抗ウイルス薬が、HCVプロテアーゼ阻害薬、HCVポリメラーゼ阻害薬、HCVヘリカーゼ阻害薬、HCV NS5A阻害薬、またはそのいずれかの組合わせからなる群から選択される、前記のいずれかの方法を提供する。
一般に用いられる略号には下記のものが含まれる:アセチル(Ac)、アゾ−ビス−イソブチリルニトリル(AIBN)、大気(Atm)、9−ボラビシクロ[3.3.1]ノナン(9−BBNまたはBBN)、2,2’−ビス(ジフェニルホスフィノ)−1,1’−ビナフチル(BINAP)、tert−ブトキシカルボニル(Boc)、ピロ炭酸ジ−tert−ブチルまたはboc無水物(BOC2O)、ベンジル(Bn)、ブチル(Bu)、ケミカルアブストラクツ登録番号(Chemical Abstracts Registration Number)(CASRN)、ベンジルオキシカルボニル(CBZまたはZ)、カルボニルジイミダゾール(CDI)、1,4−ジアザビシクロ[2.2.2]オクタン(DABCO)、三フッ化ジエチルアミノ硫黄(DAST)、ジベンジリデンアセトン(dba)、1,5−ジアザビシクロ[4.3.0]ノナ−5−エン(DBN)、1,8−ジアザビシクロ[5.4.0]ウンデカ−7−エン(DBU)、N,N’−ジシクロヘキシルカルボジイミド(DCC)、1,2−ジクロロエタン(DCE)、ジクロロメタン(DCM)、2,3−ジクロロ−5,6−ジシアノ−1,4−ベンゾキノン(DDQ)、アゾジカルボン酸ジエチル(DEAD)、アゾジカルボン酸ジ−イソ−プロピル(DIAD)、水素化ジ−イソ−ブチルアルミニウム(DIBALまたはDIBAL−H)、ジ−イソ−プロピルエチルアミン(DIPEA)、N,N−ジメチルアセトアミド(DMA)、4−N,N−ジメチルアミノピリジン(DMAP)、N,N−ジメチルホルムアミド(DMF)、ジメチルスルホキシド(DMSO)、1,1’−ビス−(ジフェニルホスフィノ)エタン(dppe)、1,1’−ビス−(ジフェニルホスフィノ)フェロセン(dppf)、1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩(EDCI)、2−エトキシ−1−エトキシカルボニル−1,2−ジヒドロキノリン(EEDQ)、エチル(Et)、酢酸エチル(EtOAc)、エタノール(EtOH)、2−エトキシ−2H−キノリン−1−カルボン酸エチルエステル(EEDQ)、ジエチルエーテル(Et2O)、エチルイソプロピルエーテル(EtOiPr)、O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’N’−テトラメチルウロニウムヘキサフルオロホスフェート酢酸(HATU)、酢酸(HOAc)、1−N−ヒドロキシベンゾトリアゾール(HOBt)、高速液体クロマトグラフィー(HPLC)、イソ−プロパノール(IPA)、イソプロピルマグネシウムクロリド(iPrMgCl)、ヘキサメチルジシラザン(HMDS)、液体クロマトグラフィー−質量分析(LCMS)、リチウムヘキサメチルジシラザン(LiHMDS)、メタ−クロロペルオキシ安息香酸(m−CPBA)、メタノール(MeOH)、融点(mp)、MeSO2−(メシルまたはMs)、メチル(Me)、アセトニトリル(MeCN)、m−クロロ過安息香酸(MCPBA)、質量スペクトル(ms)、メチル t−ブチルエーテル(MTBE)、メチルテトラヒドロフラン(MeTHF)、N−ブロモスクシンイミド(NBS)、n−ブチルリチウム(nBuLi)、N−カルボキシアンハイドライド(NCA)、N−クロロスクシンイミド(NCS)、N−メチルモルホリン(NMM)、N−メチルピロリドン(NMP)、クロロクロム酸ピリジニウム(PCC)、ジクロロ−((ビス−ジフェニルホスフィノ)フェロセニル)パラジウム(II)(Pd(dppf)Cl2)、酢酸パラジウム(II)(Pd(OAc)2)、トリス(ジベンジリデンアセトン)二パラジウム(0)(Pd2(dba)3)、二クロム酸ピリジニウム(PDC)、フェニル(Ph)、プロピル(Pr)、イソ−プロピル(i−Pr)、ポンド/平方インチ(psi)、ピリジン(pyr)、1,2,3,4,5−ペンタフェニル−1’−(ジ−tert−ブチルホスフィノ)フェロセン(Q−Phos)、室温(周囲温度、rtまたはRT)、sec−ブチルリチウム(sBuLi)、tert−ブチルジメチルシリルまたはt−BuMe2Si(TBDMS)、フッ化テトラ−n−ブチルアンモニウム(TBAF)、トリエチルアミン(TEAまたはEt3N)、2,2,6,6−テトラメチルピペリジン 1−オキシル(TEMPO)、トリフレートまたはCF3SO2−(Tf)、トリフルオロ酢酸(TFA)、1,1’−ビス−2,2,6,6−テトラメチルヘプタン−2,6−ジオン(TMHD)、O−ベンゾトリアゾール−1−イル−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボレート(TBTU)、薄層クロマトグラフィー(TLC)、テトラヒドロフラン(THF)、トリメチルシリルまたはMe3Si(TMS)、p−トルエンスルホン酸一水和物(TsOHまたはpTsOH)、4−Me−C6H4SO2−またはトシル(Ts)、およびN−ウレタン−N−カルボキシアンハイドライド(UNCA)。接頭辞ノルマル(n)、イソ(i−)、第二級(sec−)、第三級(tert−)およびneoを含む一般的名称は、アルキル部分と共に用いられる場合、それらの一般的な意味をもつ(J. Rigaudy and D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.)。
本発明の化合物は、以下に実施例のセクションに記載する合成反応例に示す多様な方法により製造できる。
中間体1
方法1
N3−(4−ブロモ−3−クロロ−5−トリフルオロメチル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン(中間体1)
MS m/z 356 [M+H]。
方法1
N3−(4−ブロモ−3,5−ジクロロ−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン(中間体2)
1H NMR (300MHz, DMSO) □: 11.35 (s, 1H), 9.33 (s, 1H), 7.75 (s, 2H), 6.05 (s, 2H) ppm。
方法1
N5−(4−ブロモ−3−フルオロ−5−トリフルオロメチルフェニル)−1H−[1,2,4]−トリアゾール−3,5−ジアミン(中間体3)
1H NMR (300 MHz, DMSO-d6) □ ppm 7.84 (s, 1 H) 7.96 (dd, J=9.06, 2.27 Hz, 1 H)。
MS +m/z: 357.7 (M+1)。
1H NMR (300 MHz, DMSO-d6) □ ppm 2.78 (s, 3 H) 7.87 (s, 1 H) 7.97 (dd, J=1.00 Hz, 1 H) 10.38 (br. s, 1 H)。
MS +m/z: 339.9 (M+1)。
1H NMR (400 MHz, DMSO-d6) □ ppm 6.03 (s, 2 H) 7.81 (s, 1 H) 7.86 (d, J=12.13 Hz, 1 H) 9.52 (s, 1 H) 11.40 (s, 1 H)。
MS m/z 351 [M+H]。
MS m/z 399 [M+H]。
MS m/z 337 [M+H]。
MS m/z 336 [M+H]。
MS m/z 337 [M+H]。
MS m/z 352 [M+H]。
MS m/z 337 [M+H]。
MS m/z 414 [M+H]。
MS +m/z: 357.0 (M+1)。
MS +m/z: 339.0 (M+1)。
MS +m/z: 398.9/400.8 (M+1)。
MS -m/z: 386.9/389.0 (M-1)。
MS +m/z: 358/360 (M+1)。
MS +m/z: 457/459 (M+1)。
MS +m/z: 440.0/441.9 (M+1)。
MS -m/z: 356/358 (M-1)。
反応混合物を室温に冷却し、それを室温で一夜撹拌した。反応混合物を酢酸エチル(10mL)と水(10mL)の間で分配した。有機相を乾燥させ(Na2SO4)、濾過し、次いでシリカゲル上に濃縮した。シリカに担持された粗生成物を115gシリカゲルカラム(Analogix)に装填した。フラッシュクロマトグラフィー(70%酢酸エチル,ヘキサン類中)により、トリフェニルホスフィンオキシドを少量の不純物として含有する3−クロロ−4−ピリダジン−3−イル−フェニルアミン(700mg,90%)を得た。
セライトに担持された粗生成物を80g シリカゲルカラムに装填した。フラッシュクロマトグラフィー(15%−50%酢酸エチル−ヘキサン類)により、(Z)−4−(2−クロロ−4−(シアナミド−(メチルチオ)メチレンアミノ)−6−(トリフルオロメチル)フェニル)−5,6−ジヒドロピリジン−1(2H)−カルボン酸 tert−ブチル(0.776g,68%)を淡黄色の油として得た。
3−(2,6−ジクロロ−4−ニトロフェニル)−[1,2,4]トリアゾロ[4,3−a]ピリジン(105mg,0.34mmol)の、THF:飽和NH4Clの1:1混合物(4mL)中における溶液を、亜鉛末(67mg;1.0mmol)で処理し、反応混合物を2時間撹拌した。濾過に続いて揮発性成分を減圧下で除去すると、粗製反応生成物が得られた。シリカゲルクロマトグラフィー(EtOAc)により、4−([1,2,4]トリアゾロ[4,3−a]ピリジン−3−イル)−3,5−ジクロロアニリン(26mg,27%)を黄色の油として単離した。
ナトリウムハイドロジェンシアナミド(8.4mg,0.13mmol)を、3−(2,6−ジクロロ−4−イソチオシアナトフェニル)−[1,2,4]トリアゾロ[4,3−a]ピリジン(35mg,0.11mmol)の、1:1 CH3OH:CH3CN(2mL)中における溶液に添加した。反応混合物を3時間撹拌した後、TLCにより出発物質は検出されなかった。ヨードメタン(13.6μL;0.22mmol)を次いで添加し、反応混合物を一夜撹拌した。すべての揮発性成分を減圧下で除去するとろう状固体が得られ、それからシリカゲルクロマトグラフィー(AcOEt)により(Z)−メチル N−4−([1,2,4]トリアゾロ[4,3−a]ピリジン−3−イル)−3,5−ジクロロフェニル−N’−シアノカルバムイミドチオエート(29mg;71%)を精製した。
(Z)−メチル N−4−([1,2,4]トリアゾロ[4,3−a]ピリジン−3−イル)−3,5−ジクロロフェニル−N’−シアノカルバムイミドチオエート(26mg,0.069mmol)およびヒドラジン(10.8 L,0.34mmol)をエタノール中で3時間加熱した後、すべての揮発性成分を減圧下で除去した。粗生成物から、カラムクロマトグラフィーにより、N3−(3,5−ジクロロ−4−[1,2,4]トリアゾロ[4,3−a]ピリジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミンを白色固体(21mg,84%)として単離した。MH+ = 361.0。
1H NMR (300MHz, DMSO) δ: 11.55 (s, 1H), 9.99 (s, 1H), 7.74 (s, 2H), 6.14 (s, 2H) ppm。
MS- m/z: 438.0 (M-H)-。
MS+ m/z: 411.9 (M+H)+。
NMR (300 MHz, DMSO d6): 11.38 (1H, s); 9.45 (1H, s); 9.34 (1H, dd, J= 1, 6 Hz); 9.22 (1H, 幅広いs); 7.78 (2H, s); 7.74 (1H, dd, J= 3, 6 Hz); 6.06 (2H, s)。
N−3−(3,5−ジクロロ−4−(ピリジン−4−イル)フェニル)−1H−1,2,4−トリアゾール−3,5−ジアミン(化合物35)
N−3−[3,5−ジクロロ−4−(5−クロロ−チオフェン−2−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン(化合物36)
N−3−(3,5−ジクロロ−4−ピリジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン(化合物37)
N−3−[3,5−ジクロロ−4−(1H−ピラゾール−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン(化合物38)
N−3−(3,5−ジクロロ−4−ピリミジン−5−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン(化合物39)
N−3−[3,5−ジクロロ−4−(2−メトキシ−ピリミジン−5−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン(化合物40)
N−3−[3,5−ジクロロ−4−(6−トリフルオロメチル−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン(化合物41)
N−3−[3,5−ジクロロ−4−(1−メチル−3−トリフルオロメチル−1H−ピラゾール−4−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン(化合物42)
N−3−[3,5−ジクロロ−4−(5−クロロ−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン(化合物43)
N−3−[3,5−ジクロロ−4−(6−メトキシ−ピリジン−2−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン(化合物44)
生物学的実施例
偽型(pseudotyped)HCV粒子(HCVpp)レポーターアッセイを用いる、化合物のHCV GT1bおよびGT1a侵入阻害活性の判定
シュードタイプト ウイルス粒子の作製のための哺乳動物発現プラスミド:
GT1a H77株(Proc Natl Acad Sci USA 1997 94:8738-43)またはGT1b Con1株(Science 1999 285:110-3)のHCV E1およびE2エンベロープタンパク質を発現するプラスミドは、HCVコアタンパク質の最後の60個のアミノ酸ならびにHCV E1およびE2タンパク質全部をコードする核酸をpcDNA3.1(+)ベクターにクローニングすることにより構築された。水疱性口内炎ウイルス(vesicular stomatitis virus)のG糖タンパク質(VSV G)を発現するプラスミドpVSV−Gは、Clontech(カタログ# 631530)からのものである。ホタルルシフェラーゼレポーター遺伝子を発現するHIVパッケージング構築体は、エンベロープ欠損pNL.4.3.Luc−R−.E−ベクター(Virology 1995 206:935-44)を基礎として、HIVエンベロープタンパク質の一部をさらに欠如させることにより改変された。
偽型HCV GT1aおよびGT1b粒子(HCVpp)ならびに偽型VSV G粒子(VSVpp)を、一過性トランスフェクションしたHEK−293T細胞(ATCC カタログ# CRL−573)から作製した。HCVppを作製するために、トランスフェクション試薬としてポリエチレンイミン(Polysciences カタログ# 23966)を用いることにより、HEK−293T細胞に等量のHCVエンベロープタンパク質発現プラスミドおよびHIVパッケージングゲノム発現プラスミドをトランスフェクションした。VSVppを作製するために、ポリエチレンイミンを用いることにより、HEK−293T細胞に等量のVSV G発現プラスミドおよびHIVパッケージングゲノム発現プラスミドをトランスフェクションした。トランスフェクションの24時間後、トランスフェクション混合物を含有する細胞培養培地を、10%のウシ胎仔血清(Invitrogen カタログ# 10082−147)および2mMのL−グルタミン(Invitrogen カタログ# 25030−081)が補充された新鮮なダルベッコ改変イーグル培地(DMEM−Glutamax(商標)−I;Invitrogen カタログ# 10569−010)で交換した。トランスフェクションの48時間後に上清を採集し、滅菌0.45μmフィルターにより濾過した。上清のアリコートを凍結し、使用するまで−80℃で保存した。
Huh7−high CD81細胞をウェル当たり8000個の細胞密度で96ウェルプレート(Perkin Elmer,カタログ# 6005660)にプレーティングした。10%のウシ胎仔血清(Invitrogen カタログ# 10082−147)および1%のペニシリン/ストレプトマイシン(Invitrogen カタログ# 15070−063)を補充した100μlのダルベッコ改変イーグル培地(DMEM−Glutamax(商標)−I;Invitrogen カタログ# 10569−010)に細胞をプレーティングした。細胞を37℃および5% CO2で24時間平衡化させ、この時点で化合物および偽型ウイルスを添加した。アッセイ当日に、HCVppアリコートを37℃の水浴で融解し、使用するまで4℃に保持した。化合物(または対照としての培地)を3倍希釈系列で、2%のDMSOおよび2%のペニシリン/ストレプトマイシンを含むDMEM−Glutamax(商標)−I中に希釈した。各培養ウェル内の100μlのプレーティング培地を取り出し、続いて50μlの化合物希釈液および50μlの融解HCVppを添加した。化合物およびHCVppを添加した72時間後に、Steady−Gloルシフェラーゼアッセイシステム(Promega,カタログ# E2520)を用いて製造業者の指示に従ってホタルルシフェラーゼレポーター信号を読み取った。化合物の非存在下での対照試料と比較してホタルルシフェラーゼレポーターのレベルの50%低下がみられた化合物濃度としてEC50値を定義し、化合物用量応答データの非線形フィッティングにより判定した。
Huh7 hCD81細胞アッセイプレートおよび化合物希釈度を、HCVppアッセイと同じフォーマットに設定した。細胞プレーティングの24時間後に、融解VSVppを、10%ウシ胎仔血清を補充したDMEM−Glutamax(商標)−I中に800倍希釈した。培養ウェルから細胞プレーティング培地を取り出した後、50μlの化合物希釈液および50μlの希釈VSVppをウェルに添加した。化合物およびVSVppを添加した72時間後に、Steady−Gloルシフェラーゼアッセイシステム(Promega,カタログ# E2520)を用いてホタルルシフェラーゼレポーター信号を読み取った。化合物の非存在下での対照試料と比較してホタルルシフェラーゼレポーターのレベルの50%低下がみられた化合物濃度としてEC50値を定義し、化合物用量応答データの非線形フィッティングにより判定した。最大阻害率パーセントが90%未満、70%より大であれば、EC50値を概算した。
本明細書は以下の発明の開示を包含する:
[1]式Iの化合物:
Aは、不飽和もしくは部分不飽和の単環式もしくは二環式ヘテロアリールまたは単環式もしくはスピロ環式ヘテロシクロアルキルであり;
各R 1 は、独立してハロ、ハロ低級アルキル、または低級アルキルスルホニルであり;
mは、0、1または2であり;
各R 2 は、独立してハロ、低級アルコキシ、オキソ、アミノ、低級アルキル、C(=O)OR 2 ’、S(=O) 2 R 2 ’、S(=O) 2 NHR 2 ’、ヒドロキシル低級アルキル、C(=O)NHR 2 ’、またはC(=O)R 2 ’であり;
nは、0、1または2であり;
R 2 ’は、低級アルキル、ハロ低級アルキル、またはアダマンチルである]
またはその医薬的に許容できる塩。
[2]mが1である、[1]に記載の化合物。
[3]mが2である、[2]に記載の化合物。
[4]一方のR 1 がハロであり、他方がハロ低級アルキルである、[3]に記載の化合物。
[5]両方のR 1 がハロである、[3]に記載の化合物。
[6]nが0である、[1]〜[5]のいずれかに記載の化合物。
[7]nが1である、[1]〜[5]のいずれかに記載の化合物。
[8]nが2である、[1]〜[5]のいずれかに記載の化合物。
[9]Aが、ピリジニル、ピリミジニル、ピリダジニル、トリアゾリル、テトラゾリル、ピペラジニル、2,6−ジアザ−スピロ[3.3]ヘプタニル、アゼチジニル、チオフェニル、またはピラゾリルである、[1]〜[8]のいずれかに記載の化合物。
[10]R 2 が、ハロ、低級アルコキシ、オキソ、アミノ、低級アルキル、C(=O)OR 2 ’、S(=O) 2 R 2 ’、S(=O) 2 NHR 2 ’、ヒドロキシル低級アルキル、C(=O)NHR 2 ’、またはC(=O)R 2 ’である、[9]に記載の化合物。
[11]R 2 ’が、低級アルキルまたはハロ低級アルキルである、[10]に記載の化合物。
[12]下記のものからなる群から選択される化合物:
N 3 −[3,5−ジクロロ−4−(6−メトキシ−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −[3,5−ジクロロ−4−(5−メタンスルホニル−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−1H−ピリジン−2−オン;
N 3 −[4−(6−アミノ−ピリジン−3−イル)−3,5−ジクロロ−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −[4−(2−アミノ−ピリミジン−5−イル)−3,5−ジクロロ−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −[3,5−ジクロロ−4−(2−メトキシ−ピリジン−4−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
4−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−1H−ピリジン−2−オン;
N−{5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−ピリジン−2−イル}−メタンスルホンアミド;
N 5 −[3−フルオロ−4−(6−フルオロ−ピリジン−3−イル)−5−トリフルオロメチル−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 5 −(3−フルオロ−4−ピリジン−3−イル−5−トリフルオロメチル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −[3,5−ジクロロ−4−(6−メタンスルホニル−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
6−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−2,6−ジアザ−スピロ[3.3]ヘプタン−2−カルボン酸 tert−ブチルエステル;
N 3 −(3−クロロ−4−ピリダジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −[3−クロロ−4−(1−メチル−1H−テトラゾール−5−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −[3−クロロ−4−(2−メチル−2H−[1,2,4]トリアゾール−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −(3,5−ジクロロ−4−ピラゾール−1−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
4−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−3,6−ジヒドロ−2H−ピリジン−1−カルボン酸 tert−ブチルエステル;
N 3 −[3,5−ジクロロ−4−(1,2,3,6−テトラヒドロ−ピリジン−4−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
4−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−3,6−ジヒドロ−2H−ピリジン−1−カルボン酸 tert−ブチルエステル;
N 3 −[3−クロロ−4−(1,2,3,6−テトラヒドロ−ピリジン−4−イル)−5−トリフルオロメチル−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 5 −(3,5−ジクロロ−4−[1,2,4]トリアゾロ[4,3−a]ピリジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N−{3−クロロ−4−[6−(プロパン−2−スルホニル)−ピリジン−3−イル]−5−トリフルオロメチル−フェニル}−4H−[1,2,4]トリアゾール−3,5−ジアミン;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−ピリジン−2−スルホン酸 tert−ブチルアミド;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−ピリジン−2−スルホン酸 (2,2,2−トリフルオロ−1,1−ジメチル−エチル)−アミド;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−ピリジン−2−スルホン酸 アダマンタン−1−イルアミド;
N 3 −[2−クロロ−4’−(4−メチル−ピペラジン−1−イル)−6−トリフルオロメチル−ビフェニル−4−イル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −(3−クロロ−4−ピリダジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
1−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−フェニル]−1H−ピリジン−2−オン;
1−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−フェニル]−1H−ピリジン−2−オン;
1−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−1H−ピリジン−2−オン;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−ピリジン−2−カルボン酸 メチルアミド;
N 3 −(3,5−ジクロロ−4−ピリダジン−4−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
1−{3−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−チオフェン−2−イル}−エタノン;
N 3 −(3,5−ジクロロ−4−ピリジン−4−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −[3,5−ジクロロ−4−(5−クロロ−チオフェン−2−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −(3,5−ジクロロ−4−ピリジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −[3,5−ジクロロ−4−(1H−ピラゾール−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −(3,5−ジクロロ−4−ピリミジン−5−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −[3,5−ジクロロ−4−(2−メトキシ−ピリミジン−5−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −[3,5−ジクロロ−4−(6−トリフルオロメチル−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −[3,5−ジクロロ−4−(1−メチル−3−トリフルオロメチル−1H−ピラゾール−4−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N 3 −[3,5−ジクロロ−4−(5−クロロ−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;および
N 3 −[3,5−ジクロロ−4−(6−メトキシ−ピリジン−2−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン。
[13]C型肝炎ウイルス(HCV)感染症を予防するための方法であって、その必要がある患者に療法有効量の[1]〜[12]のいずれかに記載の化合物を投与することを含む方法。
[14]さらに、その必要がある患者に療法有効量の免疫系抑制薬を投与することを含む、[13]に記載の方法。
[15]C型肝炎ウイルス(HCV)感染症を治療するための方法であって、その必要がある患者に療法有効量の[1]〜[12]のいずれかに記載の化合物を投与することを含む方法。
[16]さらに、HCVの複製を阻害する抗ウイルス薬の組合わせを投与することを含む、[13]〜[15]のいずれかに記載の方法。
[17]さらに、免疫系調節薬もしくはHCVの複製を阻害する抗ウイルス薬またはその組合わせを投与することを含む、[13]〜[16]のいずれかに記載の方法。
[18]免疫系調節薬がインターフェロンまたは化学的に誘導体化されたインターフェロンである、[17]に記載の方法。
[19]抗ウイルス薬が、HCVプロテアーゼ阻害薬、HCVポリメラーゼ阻害薬、HCVヘリカーゼ阻害薬、HCV NS5A阻害薬、またはそのいずれかの組合わせからなる群から選択される、[17]に記載の方法。
[20][1]〜[12]のいずれかに記載の化合物および医薬的に許容できる賦形剤を含む組成物。
Claims (20)
- 式Iの化合物:
Aは、不飽和もしくは部分不飽和の単環式もしくは二環式ヘテロアリールまたは単環式もしくはスピロ環式ヘテロシクロアルキルであり;
各R1は、独立してハロ、ハロ低級アルキル、または低級アルキルスルホニルであり;
mは、1または2であり;
各R2は、独立してハロ、低級アルコキシ、オキソ、アミノ、低級アルキル、C(=O)OR2’、S(=O)2R2’、S(=O)2NHR2’、ヒドロキシル低級アルキル、C(=O)NHR2’、またはC(=O)R2’であり;
nは、0、1または2であり;
R2’は、低級アルキル、ハロ低級アルキル、またはアダマンチルである]
またはその医薬的に許容できる塩。 - mが1である、請求項1に記載の化合物。
- mが2である、請求項1に記載の化合物。
- 一方のR1がハロであり、他方がハロ低級アルキルである、請求項3に記載の化合物。
- 両方のR1がハロである、請求項3に記載の化合物。
- nが0である、請求項1〜5のいずれか1項に記載の化合物。
- nが1である、請求項1〜5のいずれか1項に記載の化合物。
- nが2である、請求項1〜5のいずれか1項に記載の化合物。
- Aが、ピリジニル、ピリミジニル、ピリダジニル、トリアゾリル、テトラゾリル、ピペラジニル、2,6−ジアザ−スピロ[3.3]ヘプタニル、アゼチジニル、チオフェニル、またはピラゾリルである、請求項1〜8のいずれか1項に記載の化合物。
- R2が、ハロ、低級アルコキシ、オキソ、アミノ、低級アルキル、C(=O)OR2’、S(=O)2R2’、S(=O)2NHR2’、ヒドロキシル低級アルキル、C(=O)NHR2’、またはC(=O)R2’である、請求項9に記載の化合物。
- R2’が、低級アルキルまたはハロ低級アルキルである、請求項10に記載の化合物。
- 下記のものからなる群から選択される化合物:
N3−[3,5−ジクロロ−4−(6−メトキシ−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(5−メタンスルホニル−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−1H−ピリジン−2−オン;
N3−[4−(6−アミノ−ピリジン−3−イル)−3,5−ジクロロ−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[4−(2−アミノ−ピリミジン−5−イル)−3,5−ジクロロ−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(2−メトキシ−ピリジン−4−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
4−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−1H−ピリジン−2−オン;
N−{5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−ピリジン−2−イル}−メタンスルホンアミド;
N5−[3−フルオロ−4−(6−フルオロ−ピリジン−3−イル)−5−トリフルオロメチル−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N5−(3−フルオロ−4−ピリジン−3−イル−5−トリフルオロメチル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(6−メタンスルホニル−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
6−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−2,6−ジアザ−スピロ[3.3]ヘプタン−2−カルボン酸 tert−ブチルエステル;
N3−(3−クロロ−4−ピリダジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3−クロロ−4−(1−メチル−1H−テトラゾール−5−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3−クロロ−4−(2−メチル−2H−[1,2,4]トリアゾール−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−(3,5−ジクロロ−4−ピラゾール−1−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
4−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−3,6−ジヒドロ−2H−ピリジン−1−カルボン酸 tert−ブチルエステル;
N3−[3,5−ジクロロ−4−(1,2,3,6−テトラヒドロ−ピリジン−4−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
4−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−3,6−ジヒドロ−2H−ピリジン−1−カルボン酸 tert−ブチルエステル;
N3−[3−クロロ−4−(1,2,3,6−テトラヒドロ−ピリジン−4−イル)−5−トリフルオロメチル−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N5−(3,5−ジクロロ−4−[1,2,4]トリアゾロ[4,3−a]ピリジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N−{3−クロロ−4−[6−(プロパン−2−スルホニル)−ピリジン−3−イル]−5−トリフルオロメチル−フェニル}−4H−[1,2,4]トリアゾール−3,5−ジアミン;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−ピリジン−2−スルホン酸 tert−ブチルアミド;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−ピリジン−2−スルホン酸 (2,2,2−トリフルオロ−1,1−ジメチル−エチル)−アミド;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−ピリジン−2−スルホン酸 アダマンタン−1−イルアミド;
N3−[2−クロロ−4’−(4−メチル−ピペラジン−1−イル)−6−トリフルオロメチル−ビフェニル−4−イル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−(3−クロロ−4−ピリダジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
1−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−フェニル]−1H−ピリジン−2−オン;
1−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−フェニル]−1H−ピリジン−2−オン;
1−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−1H−ピリジン−2−オン;
5−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2−クロロ−6−トリフルオロメチル−フェニル]−ピリジン−2−カルボン酸 メチルアミド;
N3−(3,5−ジクロロ−4−ピリダジン−4−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
1−{3−[4−(5−アミノ−1H−[1,2,4]トリアゾール−3−イルアミノ)−2,6−ジクロロ−フェニル]−チオフェン−2−イル}−エタノン;
N3−(3,5−ジクロロ−4−ピリジン−4−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(5−クロロ−チオフェン−2−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−(3,5−ジクロロ−4−ピリジン−3−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(1H−ピラゾール−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−(3,5−ジクロロ−4−ピリミジン−5−イル−フェニル)−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(2−メトキシ−ピリミジン−5−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(6−トリフルオロメチル−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(1−メチル−3−トリフルオロメチル−1H−ピラゾール−4−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;
N3−[3,5−ジクロロ−4−(5−クロロ−ピリジン−3−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン;および
N3−[3,5−ジクロロ−4−(6−メトキシ−ピリジン−2−イル)−フェニル]−1H−[1,2,4]トリアゾール−3,5−ジアミン。 - C型肝炎ウイルス(HCV)感染症を予防するための医薬組成物あって、請求項1〜12のいずれか1項に記載の化合物を含む医薬組成物。
- 免疫系抑制薬と組合わせて使用するための、請求項13に記載の医薬組成物。
- C型肝炎ウイルス(HCV)感染症を治療するための医薬組成物であって、請求項1〜12のいずれか1項に記載の化合物を含む医薬組成物。
- HCVの複製を阻害する抗ウイルス薬の組合わせと組合わせて使用するための、請求項13〜15のいずれか1項に記載の医薬組成物。
- さらに、免疫系調節薬もしくはHCVの複製を阻害する抗ウイルス薬またはその組合わせと組合わせて使用するための、請求項13〜16のいずれか1項に記載の医薬組成物。
- 免疫系調節薬がインターフェロンまたは化学的に誘導体化されたインターフェロンである、請求項17に記載の医薬組成物。
- 抗ウイルス薬が、HCVプロテアーゼ阻害薬、HCVポリメラーゼ阻害薬、HCVヘリカーゼ阻害薬、HCV NS5A阻害薬、またはそのいずれかの組合わせからなる群から選択される、請求項17に記載の医薬組成物。
- 請求項1〜12のいずれか1項に記載の化合物および医薬的に許容できる賦形剤を含む組成物。
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