EA015752B1 - Новые макроциклические ингибиторы репликации вируса гепатита с - Google Patents
Новые макроциклические ингибиторы репликации вируса гепатита с Download PDFInfo
- Publication number
- EA015752B1 EA015752B1 EA200800413A EA200800413A EA015752B1 EA 015752 B1 EA015752 B1 EA 015752B1 EA 200800413 A EA200800413 A EA 200800413A EA 200800413 A EA200800413 A EA 200800413A EA 015752 B1 EA015752 B1 EA 015752B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- alkyl
- substituted
- cycloalkyl
- hydroxy
- phenyl
- Prior art date
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- 241000711549 Hepacivirus C Species 0.000 title claims description 35
- 239000003112 inhibitor Substances 0.000 title description 2
- 230000029812 viral genome replication Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 300
- 238000000034 method Methods 0.000 claims abstract description 98
- 208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 35
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 445
- -1 chloropyridinyl Chemical group 0.000 claims description 382
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 378
- 125000001153 fluoro group Chemical group F* 0.000 claims description 338
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 330
- 229910052736 halogen Inorganic materials 0.000 claims description 286
- 150000002367 halogens Chemical class 0.000 claims description 242
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 230
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 214
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 198
- 229910052739 hydrogen Inorganic materials 0.000 claims description 195
- 125000003118 aryl group Chemical group 0.000 claims description 165
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 150
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 145
- 229910052799 carbon Inorganic materials 0.000 claims description 135
- 125000003545 alkoxy group Chemical group 0.000 claims description 128
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 127
- 125000004076 pyridyl group Chemical group 0.000 claims description 104
- 125000001072 heteroaryl group Chemical group 0.000 claims description 102
- 229910052757 nitrogen Inorganic materials 0.000 claims description 81
- 125000005842 heteroatom Chemical group 0.000 claims description 80
- 108091005804 Peptidases Proteins 0.000 claims description 70
- 239000004365 Protease Substances 0.000 claims description 70
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 69
- 239000001257 hydrogen Substances 0.000 claims description 68
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 64
- 150000003839 salts Chemical class 0.000 claims description 59
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 58
- 229910052717 sulfur Chemical group 0.000 claims description 58
- 239000011593 sulfur Chemical group 0.000 claims description 58
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 57
- 229910052760 oxygen Inorganic materials 0.000 claims description 57
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 56
- 239000001301 oxygen Substances 0.000 claims description 56
- 125000000623 heterocyclic group Chemical group 0.000 claims description 55
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims description 54
- 125000004429 atom Chemical group 0.000 claims description 54
- 125000005843 halogen group Chemical group 0.000 claims description 51
- 239000012634 fragment Substances 0.000 claims description 48
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 45
- 125000002950 monocyclic group Chemical group 0.000 claims description 45
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 42
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 40
- 150000003254 radicals Chemical class 0.000 claims description 40
- 125000002541 furyl group Chemical group 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 38
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 37
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 37
- 125000001624 naphthyl group Chemical group 0.000 claims description 37
- 125000002971 oxazolyl group Chemical group 0.000 claims description 37
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 36
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 35
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 34
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 34
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 31
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 30
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 30
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 29
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 29
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 28
- 125000004122 cyclic group Chemical group 0.000 claims description 28
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 28
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
- 125000003368 amide group Chemical group 0.000 claims description 27
- 229920006395 saturated elastomer Polymers 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 26
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 25
- 125000000335 thiazolyl group Chemical group 0.000 claims description 24
- 125000001544 thienyl group Chemical group 0.000 claims description 24
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 22
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 22
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 21
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 21
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 21
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 21
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 21
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 230000003993 interaction Effects 0.000 claims description 20
- 125000002757 morpholinyl group Chemical group 0.000 claims description 20
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 19
- 125000004193 piperazinyl group Chemical group 0.000 claims description 19
- 125000003386 piperidinyl group Chemical group 0.000 claims description 19
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 19
- 108010047761 Interferon-alpha Proteins 0.000 claims description 18
- 102000006992 Interferon-alpha Human genes 0.000 claims description 18
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 18
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 18
- 229930192474 thiophene Natural products 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 150000001408 amides Chemical class 0.000 claims description 17
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 17
- 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 16
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 15
- 125000004188 dichlorophenyl group Chemical group 0.000 claims description 15
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 15
- 230000003612 virological effect Effects 0.000 claims description 15
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 14
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 14
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 14
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 14
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 14
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 13
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 13
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 12
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 12
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 12
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 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
- 230000000694 effects Effects 0.000 claims description 11
- 239000011737 fluorine Substances 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 150000002431 hydrogen Chemical group 0.000 claims description 11
- 125000005647 linker group Chemical group 0.000 claims description 11
- 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 11
- 230000004044 response Effects 0.000 claims description 11
- DYDZWJOECBIVHD-UHFFFAOYSA-N 1-(3-methylpyridin-2-yl)-3-phenylpyrrolidine-2,5-dione Chemical compound CC1=CC=CN=C1N1C(=O)C(C=2C=CC=CC=2)CC1=O DYDZWJOECBIVHD-UHFFFAOYSA-N 0.000 claims description 10
- 108010074328 Interferon-gamma Proteins 0.000 claims description 10
- 102000014150 Interferons Human genes 0.000 claims description 10
- 108010050904 Interferons Proteins 0.000 claims description 10
- 229930194542 Keto Natural products 0.000 claims description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 10
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 10
- 125000000468 ketone group Chemical group 0.000 claims description 10
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 9
- JHRWWRDRBPCWTF-OLQVQODUSA-N captafol Chemical compound C1C=CC[C@H]2C(=O)N(SC(Cl)(Cl)C(Cl)Cl)C(=O)[C@H]21 JHRWWRDRBPCWTF-OLQVQODUSA-N 0.000 claims description 9
- 150000003857 carboxamides Chemical class 0.000 claims description 9
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 9
- 208000015181 infectious disease Diseases 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 239000013256 coordination polymer Substances 0.000 claims description 7
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims description 7
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 6
- WBUUCFGVXWJWQQ-UHFFFAOYSA-N 1,3-benzothiazole isoquinoline Chemical compound C1=CC=C2SC=NC2=C1.C1=NC=CC2=CC=CC=C21 WBUUCFGVXWJWQQ-UHFFFAOYSA-N 0.000 claims description 6
- 102100037850 Interferon gamma Human genes 0.000 claims description 6
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims description 6
- 101800001530 Thymosin alpha Proteins 0.000 claims description 6
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 108010010648 interferon alfacon-1 Proteins 0.000 claims description 6
- 229940127073 nucleoside analogue Drugs 0.000 claims description 6
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 6
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 claims description 6
- 150000003462 sulfoxides Chemical class 0.000 claims description 6
- 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 description 6
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical group 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 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 210000004185 liver Anatomy 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 229960000329 ribavirin Drugs 0.000 claims description 5
- 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 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
- 150000003457 sulfones Chemical class 0.000 claims description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- 125000005300 thiocarboxy group Chemical group C(=S)(O)* 0.000 claims description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 4
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 4
- 208000005176 Hepatitis C Diseases 0.000 claims description 4
- 102000008070 Interferon-gamma Human genes 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 230000003247 decreasing effect Effects 0.000 claims description 4
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 claims description 4
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 229940079322 interferon Drugs 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 3
- 125000006546 (C4-C10) cycloalkyl group Chemical group 0.000 claims description 3
- 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 description 3
- 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 3
- 125000000041 C6-C10 aryl group Chemical group 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 3
- 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
- 229940121759 Helicase inhibitor Drugs 0.000 claims description 3
- 229940121740 Inosine monophosphate dehydrogenase inhibitor Drugs 0.000 claims description 3
- 229940123066 Polymerase inhibitor Drugs 0.000 claims description 3
- 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 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 3
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims description 3
- 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 3
- 229960004748 abacavir Drugs 0.000 claims description 3
- 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 3
- 229960002964 adalimumab Drugs 0.000 claims description 3
- 229960001997 adefovir Drugs 0.000 claims description 3
- 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 3
- 239000005557 antagonist Substances 0.000 claims description 3
- 229960000724 cidofovir Drugs 0.000 claims description 3
- 229940014461 combivir Drugs 0.000 claims description 3
- 229960000598 infliximab Drugs 0.000 claims description 3
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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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- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
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- 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
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- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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- 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
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- 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
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- C07D487/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- 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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- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| US70219505P | 2005-07-25 | 2005-07-25 | |
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| US78980006P | 2006-04-06 | 2006-04-06 | |
| PCT/US2006/027738 WO2007015824A2 (en) | 2005-07-25 | 2006-07-17 | Novel macrocyclic inhibitors of hepatitis c virus replication |
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| EA200800413A EA015752B1 (ru) | 2005-07-25 | 2006-07-17 | Новые макроциклические ингибиторы репликации вируса гепатита с |
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| EA201170969A EA019888B1 (ru) | 2005-07-25 | 2006-07-17 | Промежуточное соединение для получения макроциклических ингибиторов репликации вируса гепатита с и способ его синтеза |
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| EP1356816B1 (en) | 2001-01-29 | 2009-12-23 | Shionogi & Co., Ltd. | Medicinal preparation containing 5-methyl-1-phenyl-2-(1h)-pyridone as active ingredient |
| 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 |
| GEP20105124B (en) * | 2005-07-25 | 2010-11-25 | Array Biopharma Inc | Novel macrocyclic inhibitors of hepatitis c virus replication |
| NZ591443A (en) * | 2005-09-22 | 2013-04-26 | Intermune Inc | Granule formation of pirfenidone and pharmaceutically acceptable excipients |
| BRPI0617274A2 (pt) | 2005-10-11 | 2011-07-19 | Intermune Inc | compostos e métodos para a inibição de replicação viral de hepatite c |
| US7741281B2 (en) * | 2005-11-03 | 2010-06-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| RU2008152171A (ru) * | 2006-07-05 | 2010-08-10 | Интермьюн, Инк. (Us) | Новые ингибиторы вирусной репликации гепатита с |
| MX2009000236A (es) * | 2006-07-07 | 2009-01-23 | Gilead Sciences Inc | Compuestos de fosfinato antivirales. |
| WO2008008776A2 (en) | 2006-07-11 | 2008-01-17 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| EP2041156B1 (en) | 2006-07-13 | 2013-11-20 | Achillion Pharmaceuticals, Inc. | 4-amino-4-oxobutanoyl peptides as inhibitors of viral replication |
| US7605126B2 (en) * | 2006-08-11 | 2009-10-20 | Enanta Pharmaceuticals, Inc. | Acylaminoheteroaryl hepatitis C virus protease inhibitors |
| US8343477B2 (en) | 2006-11-01 | 2013-01-01 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
| US7772180B2 (en) | 2006-11-09 | 2010-08-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7763584B2 (en) | 2006-11-16 | 2010-07-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8003604B2 (en) * | 2006-11-16 | 2011-08-23 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7888464B2 (en) | 2006-11-16 | 2011-02-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| WO2008070358A2 (en) * | 2006-11-16 | 2008-06-12 | Phenomix Corporation | N-cyclopropyl-hydroxyproline-based tripeptidic hepatitis c serine protease inhibitors containing an isoindole, pyrrolopyridine, pyrrolopyrimidine or pyrrolopyrazine heterocycle in the side chain |
| WO2008067981A2 (en) * | 2006-12-04 | 2008-06-12 | Dsm Ip Assets B.V. | Whole-cell catalytic system comprising a hydantoinase, a racemase and a carbamoylase |
| PL3053580T3 (pl) * | 2006-12-18 | 2021-12-20 | Intermune, Inc. | Sposób dostarczania pacjentowi terapii pirfenidonem |
| CA2679563A1 (en) * | 2007-01-08 | 2008-07-17 | Phenomix Corporation | Macrocyclic hepatitis c protease inhibitors |
| US7964580B2 (en) | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
| WO2008137779A2 (en) * | 2007-05-03 | 2008-11-13 | Intermune, Inc. | Novel macrocyclic inhibitors of hepatitis c virus replication |
| MX2009012093A (es) * | 2007-05-10 | 2010-01-25 | Intermune Inc | Nuevos peptidos inhibidores de la replicacion del virus de la hepatitis c. |
| MX2009013830A (es) | 2007-06-29 | 2010-03-01 | Gilead Sciences Inc | Compuestos antivirales. |
| AR067180A1 (es) * | 2007-06-29 | 2009-09-30 | Gilead Sciences Inc | Compuestos antivirales |
| KR101596524B1 (ko) * | 2007-06-29 | 2016-02-22 | 길리애드 사이언시즈, 인코포레이티드 | 항바이러스 화합물 |
| MX2007009796A (es) | 2007-08-14 | 2009-02-25 | Cell Therapy And Technology S | Gel conteniendo pirfenidona. |
| US8419332B2 (en) * | 2007-10-19 | 2013-04-16 | Atlas Bolt & Screw Company Llc | Non-dimpling fastener |
| WO2009053828A2 (en) * | 2007-10-22 | 2009-04-30 | Enanta Pharmaceuticals, Inc. | P3 hydroxyamino macrocyclic hepatitis c serine protease inhibitors |
| US8383583B2 (en) | 2007-10-26 | 2013-02-26 | Enanta Pharmaceuticals, Inc. | Macrocyclic, pyridazinone-containing hepatitis C serine protease inhibitors |
| CL2008003384A1 (es) * | 2007-11-14 | 2009-12-11 | Enanta Pharm Inc | Compuestos derivados de quinoxalina macrocíclica, inhibidores de serina proteasa; composicion farmaceutica que los comprende; y su uso en el tratamiento de la hepatitis c. |
| CA2708150A1 (en) | 2007-12-05 | 2009-06-18 | Enanta Pharmaceuticals, Inc. | Fluorinated tripeptide hcv serine protease inhibitors |
| CN101932242A (zh) | 2007-12-05 | 2010-12-29 | 益安药业 | 喹喔啉基衍生物 |
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