NZ565059A - Novel macrocyclic inhibitors of hepatitus C virus replication - Google Patents
Novel macrocyclic inhibitors of hepatitus C virus replicationInfo
- Publication number
- NZ565059A NZ565059A NZ565059A NZ56505906A NZ565059A NZ 565059 A NZ565059 A NZ 565059A NZ 565059 A NZ565059 A NZ 565059A NZ 56505906 A NZ56505906 A NZ 56505906A NZ 565059 A NZ565059 A NZ 565059A
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- cycloalkyl
- substituted
- compound
- phenyl
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title description 197
- 230000029812 viral genome replication Effects 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 403
- 208000010710 hepatitis C virus infection Diseases 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 622
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 280
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 255
- -1 thioazolo Chemical group 0.000 claims description 220
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 209
- 125000003545 alkoxy group Chemical group 0.000 claims description 185
- 238000000034 method Methods 0.000 claims description 179
- 125000001153 fluoro group Chemical group F* 0.000 claims description 158
- 125000003118 aryl group Chemical group 0.000 claims description 150
- 239000003814 drug Substances 0.000 claims description 142
- 229910052739 hydrogen Inorganic materials 0.000 claims description 129
- 125000005843 halogen group Chemical group 0.000 claims description 124
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 97
- 239000005557 antagonist Substances 0.000 claims description 92
- 125000004076 pyridyl group Chemical group 0.000 claims description 78
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 68
- 108010010648 interferon alfacon-1 Proteins 0.000 claims description 67
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 65
- 229910052799 carbon Inorganic materials 0.000 claims description 64
- 150000003839 salts Chemical class 0.000 claims description 60
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 59
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 claims description 57
- 239000001257 hydrogen Substances 0.000 claims description 57
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 56
- 229940090438 infergen Drugs 0.000 claims description 50
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 48
- 229910052760 oxygen Inorganic materials 0.000 claims description 48
- 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 claims description 45
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 44
- 229960000329 ribavirin Drugs 0.000 claims description 43
- 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 claims description 43
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 39
- 125000001072 heteroaryl group Chemical group 0.000 claims description 38
- 125000002541 furyl group Chemical group 0.000 claims description 37
- 125000000623 heterocyclic group Chemical group 0.000 claims description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- 125000003342 alkenyl group Chemical group 0.000 claims description 33
- 229910052717 sulfur Inorganic materials 0.000 claims description 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
- 125000001624 naphthyl group Chemical group 0.000 claims description 28
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 28
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 201000010099 disease Diseases 0.000 claims description 26
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 24
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 24
- 125000002971 oxazolyl group Chemical group 0.000 claims description 24
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 23
- 125000000335 thiazolyl group Chemical group 0.000 claims description 22
- 125000001544 thienyl group Chemical group 0.000 claims description 22
- 125000002757 morpholinyl group Chemical group 0.000 claims description 21
- 125000001559 cyclopropyl group Chemical class [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 20
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 20
- 125000004193 piperazinyl group Chemical group 0.000 claims description 20
- 125000003386 piperidinyl group Chemical group 0.000 claims description 20
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 20
- 125000001995 cyclobutyl group Chemical class [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
- 102000014150 Interferons Human genes 0.000 claims description 18
- 108010050904 Interferons Proteins 0.000 claims description 18
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 18
- 229960003073 pirfenidone Drugs 0.000 claims description 18
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 17
- 108010074328 Interferon-gamma Proteins 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 16
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 230000003612 virological effect Effects 0.000 claims description 15
- 108010008165 Etanercept Proteins 0.000 claims description 14
- 108091005804 Peptidases Proteins 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
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 14
- 150000001408 amides Chemical class 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 12
- 101100516554 Caenorhabditis elegans nhr-5 gene Proteins 0.000 claims description 11
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 11
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 11
- 101100134925 Gallus gallus COR6 gene Proteins 0.000 claims description 10
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 10
- 125000003368 amide group Chemical group 0.000 claims description 10
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims description 10
- 125000004188 dichlorophenyl group Chemical group 0.000 claims description 10
- 229940079322 interferon Drugs 0.000 claims description 10
- 230000004044 response Effects 0.000 claims description 10
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims description 10
- 229960000311 ritonavir Drugs 0.000 claims description 10
- 101100079984 Caenorhabditis elegans nhr-9 gene Proteins 0.000 claims description 9
- 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 9
- 235000019000 fluorine Nutrition 0.000 claims description 9
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 229960002964 adalimumab Drugs 0.000 claims description 7
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 7
- 229960000403 etanercept Drugs 0.000 claims description 7
- 229960000598 infliximab Drugs 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 230000002459 sustained effect Effects 0.000 claims description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 229910052721 tungsten Inorganic materials 0.000 claims description 6
- IWUCXVSUMQZMFG-RGDLXGNYSA-N 1-[(2s,3s,4r,5s)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxamide Chemical compound N1=C(C(=O)N)N=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 IWUCXVSUMQZMFG-RGDLXGNYSA-N 0.000 claims description 5
- 101100294106 Caenorhabditis elegans nhr-3 gene Chemical group 0.000 claims description 5
- 101100448208 Human herpesvirus 6B (strain Z29) U69 gene Proteins 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 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 claims description 5
- 229950006081 taribavirin Drugs 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229930194542 Keto Natural products 0.000 claims description 4
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000000468 ketone group Chemical group 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000002777 nucleoside Substances 0.000 claims description 4
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 3
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 3
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 claims description 2
- 208000005176 Hepatitis C Diseases 0.000 claims description 2
- GLWHPRRGGYLLRV-XLPZGREQSA-N [[(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](N=[N+]=[N-])C1 GLWHPRRGGYLLRV-XLPZGREQSA-N 0.000 claims description 2
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 claims description 2
- 229960004748 abacavir Drugs 0.000 claims description 2
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- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims description 2
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- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 2
- 238000000338 in vitro Methods 0.000 claims description 2
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- 108010047761 Interferon-alpha Proteins 0.000 claims 6
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- 150000003557 thiazoles Chemical class 0.000 claims 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims 4
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- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 claims 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims 2
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- VGUNCVGRXFWLAS-UHFFFAOYSA-N thiophen-2-yl N-[carbamoyl(phenoxy)amino]sulfamate Chemical compound O(C1=CC=CC=C1)N(C(=O)N)NS(=O)(=O)OC=1SC=CC1 VGUNCVGRXFWLAS-UHFFFAOYSA-N 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- UJQBOUAGWGVOTI-XSSZXYGBSA-N 1-[(2r,4s,5r)-4-azido-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@](O)(N=[N+]=[N-])C1 UJQBOUAGWGVOTI-XSSZXYGBSA-N 0.000 claims 1
- TZYVRXZQAWPIAB-FCLHUMLKSA-N 5-amino-3-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4h-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound O=C1SC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O TZYVRXZQAWPIAB-FCLHUMLKSA-N 0.000 claims 1
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Classifications
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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| JP2003007697A (ja) * | 2001-06-21 | 2003-01-10 | Hitachi Kokusai Electric Inc | 半導体装置の製造方法、基板処理方法および基板処理装置 |
| MY140680A (en) | 2002-05-20 | 2010-01-15 | Bristol Myers Squibb Co | Hepatitis c virus inhibitors |
| US7491794B2 (en) * | 2003-10-14 | 2009-02-17 | Intermune, Inc. | Macrocyclic compounds as inhibitors of viral replication |
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| US20110312996A1 (en) | 2010-05-17 | 2011-12-22 | Intermune, Inc. | Novel inhibitors of hepatitis c virus replication |
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