TW200948376A - Novel macrocyclic inhibitors of hepatitis C virus replication - Google Patents
Novel macrocyclic inhibitors of hepatitis C virus replication Download PDFInfo
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- TW200948376A TW200948376A TW098112554A TW98112554A TW200948376A TW 200948376 A TW200948376 A TW 200948376A TW 098112554 A TW098112554 A TW 098112554A TW 98112554 A TW98112554 A TW 98112554A TW 200948376 A TW200948376 A TW 200948376A
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- 239000003112 inhibitor Substances 0.000 title claims 2
- 241000711549 Hepacivirus C Species 0.000 title description 27
- 230000029812 viral genome replication Effects 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 322
- 239000000203 mixture Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 27
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 208000010710 hepatitis C virus infection Diseases 0.000 claims abstract description 7
- 208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 749
- 125000001424 substituent group Chemical group 0.000 claims description 475
- 125000001153 fluoro group Chemical group F* 0.000 claims description 414
- 125000003545 alkoxy group Chemical group 0.000 claims description 321
- 229910052739 hydrogen Inorganic materials 0.000 claims description 300
- 239000001257 hydrogen Substances 0.000 claims description 299
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 293
- 125000003118 aryl group Chemical group 0.000 claims description 278
- -1 nitro, hydroxy Chemical group 0.000 claims description 261
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 244
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 238
- 125000001072 heteroaryl group Chemical group 0.000 claims description 209
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 193
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 189
- 229910052757 nitrogen Inorganic materials 0.000 claims description 155
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 142
- 125000005843 halogen group Chemical group 0.000 claims description 131
- 239000002585 base Substances 0.000 claims description 121
- 125000000623 heterocyclic group Chemical group 0.000 claims description 103
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 103
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 102
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 102
- 125000003342 alkenyl group Chemical group 0.000 claims description 81
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 77
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 73
- 150000003839 salts Chemical class 0.000 claims description 72
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 claims description 69
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 63
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- 125000005842 heteroatom Chemical group 0.000 claims description 62
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 58
- 229910052799 carbon Inorganic materials 0.000 claims description 55
- 102000014150 Interferons Human genes 0.000 claims description 46
- 108010050904 Interferons Proteins 0.000 claims description 46
- 229940079322 interferon Drugs 0.000 claims description 45
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 41
- 125000005110 aryl thio group Chemical group 0.000 claims description 38
- 125000004104 aryloxy group Chemical group 0.000 claims description 38
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 38
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 36
- 125000004429 atom Chemical group 0.000 claims description 36
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 33
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- 125000002883 imidazolyl group Chemical group 0.000 claims description 28
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 27
- 125000004414 alkyl thio group Chemical group 0.000 claims description 27
- 210000004369 blood Anatomy 0.000 claims description 27
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- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 27
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- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 25
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 25
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- 125000002757 morpholinyl group Chemical group 0.000 claims description 24
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 23
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
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- YHQJZEZAGMDMMV-UHFFFAOYSA-N C(#N)N([N+](=O)[O-])OC#N Chemical compound C(#N)N([N+](=O)[O-])OC#N YHQJZEZAGMDMMV-UHFFFAOYSA-N 0.000 claims description 21
- 239000010949 copper Substances 0.000 claims description 21
- 125000004639 dihydroindenyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 21
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 21
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 229940079593 drug Drugs 0.000 claims description 19
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- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 17
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 16
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 claims description 16
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 15
- 108091005804 Peptidases Proteins 0.000 claims description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
- 239000004365 Protease Substances 0.000 claims description 14
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 14
- 125000000524 functional group Chemical group 0.000 claims description 14
- 150000003852 triazoles Chemical group 0.000 claims description 14
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 13
- 125000003367 polycyclic group Chemical group 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 230000036961 partial effect Effects 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 11
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 125000004122 cyclic group Chemical group 0.000 claims description 11
- 101100079984 Caenorhabditis elegans nhr-9 gene Proteins 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 8
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
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- 230000004044 response Effects 0.000 claims description 7
- 230000003612 virological effect Effects 0.000 claims description 7
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical group NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 6
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- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 6
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Natural products C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 6
- 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 description 6
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- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 5
- 229910002651 NO3 Inorganic materials 0.000 claims description 5
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 5
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 claims description 5
- XBDYBAVJXHJMNQ-UHFFFAOYSA-N Tetrahydroanthracene Natural products C1=CC=C2C=C(CCCC3)C3=CC2=C1 XBDYBAVJXHJMNQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000005605 benzo group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000468 ketone group Chemical group 0.000 claims description 5
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 4
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- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
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- 229910052721 tungsten Inorganic materials 0.000 claims description 4
- PUNXVEAWLAVABA-UHFFFAOYSA-N 1,2,3,4-tetrahydroanthracene;1,2,5,6-tetrahydroanthracene Chemical group C1=CC=C2C=C(CCCC3)C3=CC2=C1.C1=CCCC2=C1C=C1CCC=CC1=C2 PUNXVEAWLAVABA-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
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- 206010019668 Hepatic fibrosis Diseases 0.000 claims description 3
- 208000005176 Hepatitis C Diseases 0.000 claims description 3
- 229910052805 deuterium Inorganic materials 0.000 claims description 3
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 3
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- MJUVRTYWUMPBTR-MRXNPFEDSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-[1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide Chemical compound FC=1C=C2N(C[C@@H](O)CO)C(C(C)(CO)C)=CC2=CC=1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 MJUVRTYWUMPBTR-MRXNPFEDSA-N 0.000 claims description 2
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- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical group NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- 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
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
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- 2009-04-14 SG SG2011080835A patent/SG175692A1/en unknown
- 2009-04-14 CN CN2009801189874A patent/CN102046622A/zh active Pending
- 2009-04-15 AR ARP090101327A patent/AR072779A1/es unknown
- 2009-04-15 TW TW098112554A patent/TW200948376A/zh unknown
-
2010
- 2010-10-06 IL IL208529A patent/IL208529A0/en unknown
- 2010-10-11 MA MA33242A patent/MA32225B1/fr unknown
- 2010-10-11 ZA ZA2010/07256A patent/ZA201007256B/en unknown
- 2010-10-15 NI NI201000174A patent/NI201000174A/es unknown
- 2010-10-15 CU CU20100203A patent/CU20100203A7/es unknown
- 2010-10-20 CO CO10130014A patent/CO6321290A2/es not_active Application Discontinuation
- 2010-11-15 EC EC2010010612A patent/ECSP10010612A/es unknown
- 2010-11-18 US US12/949,700 patent/US20110059047A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009142842A2 (en) | 2009-11-26 |
| EP2282762A2 (en) | 2011-02-16 |
| KR20110005869A (ko) | 2011-01-19 |
| AU2009249443A1 (en) | 2009-11-26 |
| CU20100203A7 (es) | 2012-06-21 |
| CO6321290A2 (es) | 2011-09-20 |
| US20090269305A1 (en) | 2009-10-29 |
| MX2010011306A (es) | 2010-11-09 |
| NI201000174A (es) | 2011-08-24 |
| AR072779A1 (es) | 2010-09-22 |
| BRPI0911260A2 (pt) | 2015-09-29 |
| SG175692A1 (en) | 2011-11-28 |
| CN102046622A (zh) | 2011-05-04 |
| WO2009142842A3 (en) | 2010-04-01 |
| US20110059047A1 (en) | 2011-03-10 |
| WO2009142842A9 (en) | 2010-11-25 |
| ECSP10010612A (es) | 2010-12-30 |
| MA32225B1 (fr) | 2011-04-01 |
| JP2011519364A (ja) | 2011-07-07 |
| IL208529A0 (en) | 2010-12-30 |
| AP2010005416A0 (en) | 2010-10-31 |
| ZA201007256B (en) | 2013-03-27 |
| CA2720729A1 (en) | 2009-11-26 |
| US8048862B2 (en) | 2011-11-01 |
| EA201071034A1 (ru) | 2011-06-30 |
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