CN105001302A - C型肝炎病毒复制的环肽抑制剂 - Google Patents
C型肝炎病毒复制的环肽抑制剂 Download PDFInfo
- Publication number
- CN105001302A CN105001302A CN201510341151.8A CN201510341151A CN105001302A CN 105001302 A CN105001302 A CN 105001302A CN 201510341151 A CN201510341151 A CN 201510341151A CN 105001302 A CN105001302 A CN 105001302A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- replaced
- cycloalkyl
- independently
- heteroaryl
- 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.)
- Pending
Links
- 241000711549 Hepacivirus C Species 0.000 title claims description 98
- 239000003112 inhibitor Substances 0.000 title description 127
- 230000029812 viral genome replication Effects 0.000 title description 6
- 108010069514 Cyclic Peptides Proteins 0.000 title description 2
- 102000001189 Cyclic Peptides Human genes 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 397
- 238000000034 method Methods 0.000 claims abstract description 205
- 238000011282 treatment Methods 0.000 claims abstract description 169
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 351
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 319
- 239000011737 fluorine Substances 0.000 claims description 319
- 229910052731 fluorine Inorganic materials 0.000 claims description 319
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 276
- 125000003118 aryl group Chemical group 0.000 claims description 261
- -1 multicyclic moeity Chemical group 0.000 claims description 202
- 229910052736 halogen Inorganic materials 0.000 claims description 188
- 150000002367 halogens Chemical class 0.000 claims description 188
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 175
- 229910052757 nitrogen Inorganic materials 0.000 claims description 149
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 144
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 130
- 239000003814 drug Substances 0.000 claims description 127
- 229910052739 hydrogen Inorganic materials 0.000 claims description 116
- 108010074328 Interferon-gamma Proteins 0.000 claims description 111
- 102100037850 Interferon gamma Human genes 0.000 claims description 105
- 108010047761 Interferon-alpha Proteins 0.000 claims description 102
- 102000006992 Interferon-alpha Human genes 0.000 claims description 102
- 238000007920 subcutaneous administration Methods 0.000 claims description 100
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 99
- 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 97
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 79
- 125000000623 heterocyclic group Chemical group 0.000 claims description 77
- 229910052799 carbon Inorganic materials 0.000 claims description 73
- 208000015181 infectious disease Diseases 0.000 claims description 67
- 125000002757 morpholinyl group Chemical group 0.000 claims description 62
- 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 61
- 239000001257 hydrogen Substances 0.000 claims description 61
- 108091005804 Peptidases Proteins 0.000 claims description 58
- 102000035195 Peptidases Human genes 0.000 claims description 52
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 49
- 125000004193 piperazinyl group Chemical group 0.000 claims description 49
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 48
- 125000004429 atom Chemical group 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 41
- 125000005842 heteroatom Chemical group 0.000 claims description 40
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 39
- 239000000651 prodrug Substances 0.000 claims description 39
- 229940002612 prodrug Drugs 0.000 claims description 39
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 38
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 34
- 125000005418 aryl aryl group Chemical group 0.000 claims description 33
- 108010010648 interferon alfacon-1 Proteins 0.000 claims description 33
- 239000002243 precursor Substances 0.000 claims description 33
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 30
- 206010019668 Hepatic fibrosis Diseases 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 239000000460 chlorine Substances 0.000 claims description 30
- 229910052801 chlorine Inorganic materials 0.000 claims description 30
- 230000003993 interaction Effects 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 230000000694 effects Effects 0.000 claims description 27
- 150000001413 amino acids Chemical class 0.000 claims description 26
- 229940090438 infergen Drugs 0.000 claims description 26
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 230000003908 liver function Effects 0.000 claims description 21
- 125000005936 piperidyl group Chemical group 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 230000009385 viral infection Effects 0.000 claims description 18
- 125000004076 pyridyl group Chemical group 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 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 13
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical group 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 13
- 229960000311 ritonavir Drugs 0.000 claims description 13
- 229910052720 vanadium Inorganic materials 0.000 claims description 13
- 239000002777 nucleoside Substances 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
- 239000005864 Sulphur Substances 0.000 claims description 10
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 10
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 10
- 229910052727 yttrium Inorganic materials 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 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 8
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 239000004365 Protease Substances 0.000 claims description 7
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 7
- 229960000329 ribavirin Drugs 0.000 claims description 7
- 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 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- 102000008070 Interferon-gamma Human genes 0.000 claims description 6
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 6
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 229960003130 interferon gamma Drugs 0.000 claims description 6
- 235000019419 proteases Nutrition 0.000 claims description 6
- QOJMQILDLLFGEE-UHFFFAOYSA-N 2-butyl-1,3-thiazole Chemical group CCCCC1=NC=CS1 QOJMQILDLLFGEE-UHFFFAOYSA-N 0.000 claims description 5
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 claims description 5
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 claims description 5
- 229960002656 didanosine Drugs 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 230000004044 response Effects 0.000 claims description 5
- 230000003612 virological effect Effects 0.000 claims description 5
- 229960002555 zidovudine Drugs 0.000 claims description 5
- 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 4
- 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 4
- 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 4
- 229960004748 abacavir Drugs 0.000 claims description 4
- 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 4
- 229960001997 adefovir Drugs 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 229960000724 cidofovir Drugs 0.000 claims description 4
- 229940014461 combivir Drugs 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 230000001419 dependent effect Effects 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 125000005647 linker group Chemical group 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 229960001203 stavudine Drugs 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 150000003527 tetrahydropyrans Chemical class 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- IHCHOVVAJBADAH-UHFFFAOYSA-N n-[2-hydroxy-4-(1h-pyrazol-4-yl)phenyl]-6-methoxy-3,4-dihydro-2h-chromene-3-carboxamide Chemical group C1C2=CC(OC)=CC=C2OCC1C(=O)NC(C(=C1)O)=CC=C1C=1C=NNC=1 IHCHOVVAJBADAH-UHFFFAOYSA-N 0.000 claims description 2
- 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 3
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 claims 3
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims 3
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical group O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 claims 3
- 229950003954 isatoribine Drugs 0.000 claims 3
- 150000004712 monophosphates Chemical class 0.000 claims 3
- 238000000338 in vitro Methods 0.000 claims 1
- 238000001727 in vivo Methods 0.000 claims 1
- 238000012797 qualification Methods 0.000 claims 1
- 230000001629 suppression Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 21
- 208000019425 cirrhosis of liver Diseases 0.000 abstract description 16
- 208000010710 hepatitis C virus infection Diseases 0.000 abstract 1
- 101710144111 Non-structural protein 3 Proteins 0.000 description 178
- 230000003203 everyday effect Effects 0.000 description 80
- 102000001617 Interferon Receptors Human genes 0.000 description 61
- 239000003443 antiviral agent Substances 0.000 description 51
- 229940079593 drug Drugs 0.000 description 42
- 108010054267 Interferon Receptors Proteins 0.000 description 40
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 description 39
- 239000000556 agonist Substances 0.000 description 39
- 210000002966 serum Anatomy 0.000 description 36
- 238000002648 combination therapy Methods 0.000 description 35
- 108010018844 interferon type III Proteins 0.000 description 29
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 26
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 26
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 25
- 230000003442 weekly effect Effects 0.000 description 25
- 235000001014 amino acid Nutrition 0.000 description 24
- 229940024606 amino acid Drugs 0.000 description 24
- 230000037396 body weight Effects 0.000 description 24
- 201000010099 disease Diseases 0.000 description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 24
- 229920000728 polyester Polymers 0.000 description 24
- 206010016654 Fibrosis Diseases 0.000 description 23
- 230000004761 fibrosis Effects 0.000 description 23
- 229910052717 sulfur Inorganic materials 0.000 description 21
- 229920001223 polyethylene glycol Polymers 0.000 description 20
- 239000002585 base Substances 0.000 description 18
- 210000003240 portal vein Anatomy 0.000 description 18
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 18
- 229960003073 pirfenidone Drugs 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- 201000006747 infectious mononucleosis Diseases 0.000 description 16
- 108090000765 processed proteins & peptides Proteins 0.000 description 16
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 description 15
- 230000008859 change Effects 0.000 description 14
- 101800001530 Thymosin alpha Proteins 0.000 description 13
- 241000700605 Viruses Species 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- 229940079322 interferon Drugs 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 102000014150 Interferons Human genes 0.000 description 11
- 108010050904 Interferons Proteins 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 241000283973 Oryctolagus cuniculus Species 0.000 description 10
- 210000004185 liver Anatomy 0.000 description 10
- 230000008901 benefit Effects 0.000 description 9
- 238000005336 cracking Methods 0.000 description 9
- MRKKUGDWODATMF-SECBINFHSA-N (2R)-2-[[5-methoxy-2-(methylamino)pyrimidin-4-yl]amino]hexan-1-ol Chemical compound CCCC[C@H](CO)Nc1nc(NC)ncc1OC MRKKUGDWODATMF-SECBINFHSA-N 0.000 description 8
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 8
- 108010082126 Alanine transaminase Proteins 0.000 description 8
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 8
- 229940124257 Interferon receptor agonist Drugs 0.000 description 8
- 125000000539 amino acid group Chemical group 0.000 description 8
- 230000001684 chronic effect Effects 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 101710159910 Movement protein Proteins 0.000 description 7
- 101710144117 Non-structural protein 4 Proteins 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 229940048921 humira Drugs 0.000 description 7
- 208000019423 liver disease Diseases 0.000 description 7
- 238000011125 single therapy Methods 0.000 description 7
- 239000000829 suppository Substances 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 206010028851 Necrosis Diseases 0.000 description 6
- 108010076039 Polyproteins Proteins 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000004888 barrier function Effects 0.000 description 6
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 6
- 229960003358 interferon alfacon-1 Drugs 0.000 description 6
- 238000012317 liver biopsy Methods 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 230000017074 necrotic cell death Effects 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 125000000335 thiazolyl group Chemical group 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 238000012377 drug delivery Methods 0.000 description 5
- 125000002541 furyl group Chemical group 0.000 description 5
- 230000000004 hemodynamic effect Effects 0.000 description 5
- 230000004060 metabolic process Effects 0.000 description 5
- 230000006320 pegylation Effects 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 125000003226 pyrazolyl group Chemical group 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 238000010254 subcutaneous injection Methods 0.000 description 5
- 239000007929 subcutaneous injection Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 4
- 102000009027 Albumins Human genes 0.000 description 4
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 4
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 4
- 108010017384 Blood Proteins Proteins 0.000 description 4
- 102000004506 Blood Proteins Human genes 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 206010019663 Hepatic failure Diseases 0.000 description 4
- 102100040018 Interferon alpha-2 Human genes 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 108010078233 Thymalfasin Proteins 0.000 description 4
- 108090000340 Transaminases Proteins 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000012062 aqueous buffer Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 230000001900 immune effect Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- 229940124531 pharmaceutical excipient Drugs 0.000 description 4
- 239000000902 placebo Substances 0.000 description 4
- 229940068196 placebo Drugs 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 4
- 229960004231 thymalfasin Drugs 0.000 description 4
- 102000014898 transaminase activity proteins Human genes 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 3
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 3
- 206010003445 Ascites Diseases 0.000 description 3
- 102000004328 Cytochrome P-450 CYP3A Human genes 0.000 description 3
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 101710107035 Gamma-glutamyltranspeptidase Proteins 0.000 description 3
- 101710173228 Glutathione hydrolase proenzyme Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 108010078049 Interferon alpha-2 Proteins 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 101800001020 Non-structural protein 4A Proteins 0.000 description 3
- 108700026244 Open Reading Frames Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108010094028 Prothrombin Proteins 0.000 description 3
- 102100027378 Prothrombin Human genes 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000012752 auxiliary agent Substances 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000003181 encephalopathic effect Effects 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 102000006640 gamma-Glutamyltransferase Human genes 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 208000007903 liver failure Diseases 0.000 description 3
- 231100000835 liver failure Toxicity 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 208000001297 phlebitis Diseases 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 229940039716 prothrombin Drugs 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 125000002769 thiazolinyl group Chemical group 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 239000004380 Cholic acid Substances 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 238000012752 Hepatectomy Methods 0.000 description 2
- 206010023126 Jaundice Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 108010050808 Procollagen Proteins 0.000 description 2
- 208000033240 Progressive symmetric erythrokeratodermia Diseases 0.000 description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical group CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 230000023852 carbohydrate metabolic process Effects 0.000 description 2
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 235000019416 cholic acid Nutrition 0.000 description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 2
- 229960002471 cholic acid Drugs 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 2
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 2
- 230000009266 disease activity Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000037356 lipid metabolism Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 108700023195 montirelin Proteins 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- DRYYOLGDWVJUCL-UHFFFAOYSA-N pyrimidin-2-ylcyanamide Chemical compound N#CNC1=NC=CC=N1 DRYYOLGDWVJUCL-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000007655 standard test method Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 125000005000 thioaryl group Chemical group 0.000 description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 description 1
- JXDNUMOTWHZSCB-XMTZKCFKSA-N (3s)-3-acetamido-4-[[(2s)-3-carboxy-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1r)-1-carboxy-2-sulfanylethyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(O)=O JXDNUMOTWHZSCB-XMTZKCFKSA-N 0.000 description 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 description 1
- VNBFUGOVQMFIRN-UHFFFAOYSA-N 1-chlorobutan-2-ol Chemical compound CCC(O)CCl VNBFUGOVQMFIRN-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- ZUROCNHARMFRKA-UHFFFAOYSA-N 4,5-dibromo-1h-pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC(Br)=C(Br)N1 ZUROCNHARMFRKA-UHFFFAOYSA-N 0.000 description 1
- WREGKURFCTUGRC-UHFFFAOYSA-N 4-Amino-1-[5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1C1OC(CO)CC1 WREGKURFCTUGRC-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- 102100033312 Alpha-2-macroglobulin Human genes 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 102000018619 Apolipoproteins A Human genes 0.000 description 1
- 108010027004 Apolipoproteins A Proteins 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 206010057573 Chronic hepatic failure Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 101710118188 DNA-binding protein HU-alpha Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 208000010334 End Stage Liver Disease Diseases 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 241000710781 Flaviviridae Species 0.000 description 1
- 208000004576 Flaviviridae Infections Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 108050005077 Haptoglobin Proteins 0.000 description 1
- 102100025255 Haptoglobin Human genes 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000000857 Hepatic Insufficiency Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000599940 Homo sapiens Interferon gamma Proteins 0.000 description 1
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 1
- 101000896576 Homo sapiens Putative cytochrome P450 2D7 Proteins 0.000 description 1
- 101100431668 Homo sapiens YBX3 gene Proteins 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 108010079944 Interferon-alpha2b Proteins 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- ZKGNPQKYVKXMGJ-UHFFFAOYSA-N N,N-dimethylacetamide Chemical compound CN(C)C(C)=O.CN(C)C(C)=O ZKGNPQKYVKXMGJ-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 101710144128 Non-structural protein 2 Proteins 0.000 description 1
- 101800001019 Non-structural protein 4B Proteins 0.000 description 1
- 101800001014 Non-structural protein 5A Proteins 0.000 description 1
- 101710199667 Nuclear export protein Proteins 0.000 description 1
- 102000008021 Nucleoside-Triphosphatase Human genes 0.000 description 1
- 108010075285 Nucleoside-Triphosphatase Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 108010015078 Pregnancy-Associated alpha 2-Macroglobulins Proteins 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 102100021702 Putative cytochrome P450 2D7 Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 241000251555 Tunicata Species 0.000 description 1
- 208000032594 Vascular Remodeling Diseases 0.000 description 1
- 102100022221 Y-box-binding protein 3 Human genes 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000002300 anti-fibrosis Effects 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229940017687 beta-d-ribose Drugs 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 208000011444 chronic liver failure Diseases 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000002577 cryoprotective agent Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- UKPXULFIISGBHG-UHFFFAOYSA-N cyclopropene Chemical compound [CH]1C=C1 UKPXULFIISGBHG-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 208000013210 hematogenous Diseases 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 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 description 1
- 102000043557 human IFNG Human genes 0.000 description 1
- 229940014041 hyaluronate Drugs 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 1
- 229960004657 indocyanine green Drugs 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N iso-butene Natural products CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 238000007449 liver function test Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 108010026228 mRNA guanylyltransferase Proteins 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000005389 magnetism Effects 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- FGNGTWFJQFTFGN-UHFFFAOYSA-N n,n,n',n'-tetramethylethane-1,2-diamine Chemical compound CN(C)CCN(C)C.CN(C)CCN(C)C FGNGTWFJQFTFGN-UHFFFAOYSA-N 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000003041 necroinflammatory effect Effects 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
- 102000042567 non-coding RNA Human genes 0.000 description 1
- 229940127264 non-peptide agonist Drugs 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 108010092851 peginterferon alfa-2b Proteins 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 208000007232 portal hypertension Diseases 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 238000011158 quantitative evaluation Methods 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 1
- 229950006081 taribavirin Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003232 water-soluble binding agent Substances 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- 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
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- 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
-
- 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
- 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
-
- 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
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- 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
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Biotechnology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24646509P | 2009-09-28 | 2009-09-28 | |
| US61/246,465 | 2009-09-28 | ||
| US32425110P | 2010-04-14 | 2010-04-14 | |
| US61/324,251 | 2010-04-14 | ||
| US34573710P | 2010-05-18 | 2010-05-18 | |
| US61/345,737 | 2010-05-18 | ||
| US34623810P | 2010-05-19 | 2010-05-19 | |
| US61/346,238 | 2010-05-19 | ||
| CN201080053601.9A CN102741270B (zh) | 2009-09-28 | 2010-09-24 | C型肝炎病毒复制的环肽抑制剂 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201080053601.9A Division CN102741270B (zh) | 2009-09-28 | 2010-09-24 | C型肝炎病毒复制的环肽抑制剂 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105001302A true CN105001302A (zh) | 2015-10-28 |
Family
ID=43796242
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510341151.8A Pending CN105001302A (zh) | 2009-09-28 | 2010-09-24 | C型肝炎病毒复制的环肽抑制剂 |
| CN201080053601.9A Expired - Fee Related CN102741270B (zh) | 2009-09-28 | 2010-09-24 | C型肝炎病毒复制的环肽抑制剂 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201080053601.9A Expired - Fee Related CN102741270B (zh) | 2009-09-28 | 2010-09-24 | C型肝炎病毒复制的环肽抑制剂 |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US20110081315A1 (enExample) |
| EP (1) | EP2483290A4 (enExample) |
| JP (1) | JP2013505952A (enExample) |
| KR (1) | KR20130026410A (enExample) |
| CN (2) | CN105001302A (enExample) |
| AR (1) | AR078462A1 (enExample) |
| AU (1) | AU2010298028A1 (enExample) |
| CA (1) | CA2775697A1 (enExample) |
| CO (1) | CO6531497A2 (enExample) |
| EA (1) | EA201290128A1 (enExample) |
| EC (1) | ECSP12011845A (enExample) |
| IL (1) | IL218766A0 (enExample) |
| IN (1) | IN2012DN02693A (enExample) |
| MA (1) | MA33720B1 (enExample) |
| MX (1) | MX2012003500A (enExample) |
| PH (1) | PH12012500602A1 (enExample) |
| TN (1) | TN2012000135A1 (enExample) |
| TW (1) | TW201124137A (enExample) |
| WO (1) | WO2011038293A1 (enExample) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GEP20105124B (en) | 2005-07-25 | 2010-11-25 | Array Biopharma Inc | Novel macrocyclic inhibitors of hepatitis c virus replication |
| BRPI0617274A2 (pt) * | 2005-10-11 | 2011-07-19 | Intermune Inc | compostos e métodos para a inibição de replicação viral de hepatite c |
| CN102046622A (zh) * | 2008-04-15 | 2011-05-04 | 因特蒙公司 | 丙型肝炎病毒复制的新颖大环抑制剂 |
| CA2740728A1 (en) * | 2008-10-15 | 2010-04-22 | Intermune, Inc. | Therapeutic antiviral peptides |
| TW201116540A (en) * | 2009-10-01 | 2011-05-16 | Intermune Inc | Therapeutic antiviral peptides |
| WO2011107530A2 (en) * | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Novel inhibitors |
| TW201211046A (en) * | 2010-06-07 | 2012-03-16 | Enanta Pharm Inc | Macrocyclic hepatitis C serine protease inhibitors |
| JP5641663B2 (ja) * | 2010-09-10 | 2014-12-17 | 塩野義製薬株式会社 | Ampk活性化作用を有するヘテロ環縮合イミダゾール誘導体 |
| WO2012054874A1 (en) * | 2010-10-22 | 2012-04-26 | Intermune, Inc. | Novel macrocyclic inhibitors of hepatitis c virus replication |
| US8957203B2 (en) | 2011-05-05 | 2015-02-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8691757B2 (en) | 2011-06-15 | 2014-04-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| AR087993A1 (es) * | 2011-09-22 | 2014-04-30 | Janssen Pharmaceuticals Inc | Procesos e intermediarios para la preparacion de un inhibidor macrociclico de la proteasa del hcv |
| MX2014015265A (es) | 2012-06-14 | 2015-08-12 | Basf Se | Metodos plaguicidas que utilizan compuestos de 3-piridiltiazol sustituido y derivados para combatir plagas de animales. |
| UA119315C2 (uk) | 2012-07-03 | 2019-06-10 | Гіліад Фармассет Елелсі | Інгібітори вірусу гепатиту с |
| WO2014062196A1 (en) | 2012-10-19 | 2014-04-24 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| US9643999B2 (en) | 2012-11-02 | 2017-05-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| EP2914613B1 (en) | 2012-11-02 | 2017-11-22 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| WO2014071007A1 (en) | 2012-11-02 | 2014-05-08 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| WO2014070974A1 (en) | 2012-11-05 | 2014-05-08 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| EP2964664B1 (en) | 2013-03-07 | 2017-01-11 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| US9512120B2 (en) | 2013-03-15 | 2016-12-06 | Syngenta Participations Ag | Microbicidally active imidazopyridine derivatives |
| EA029088B1 (ru) | 2013-03-15 | 2018-02-28 | Джилид Сайэнс, Инк. | Макроциклические и бициклические ингибиторы вируса гепатита c |
| CN105884779B (zh) * | 2015-02-13 | 2018-06-12 | 广东东阳光药业有限公司 | 作为丙型肝炎抑制剂的化合物及其在药物中的应用 |
| CN108314648A (zh) * | 2018-04-12 | 2018-07-24 | 苏州康润医药有限公司 | 4-溴-7-氟异喹啉的合成方法 |
| CN110305018B (zh) * | 2019-06-06 | 2022-07-15 | 浙江普洛家园药业有限公司 | 一种3-溴-2-氟硝基苯的制备方法 |
| CN112358447B (zh) * | 2020-11-16 | 2022-04-12 | 苏州康润医药有限公司 | 7-氟异喹啉-1-羧酸的合成方法 |
| CN114105800B (zh) * | 2021-11-25 | 2023-09-01 | 杭州国瑞生物科技有限公司 | 一种2,3-二氨基苯甲酸甲酯的制备方法 |
| WO2025257072A1 (en) * | 2024-06-14 | 2025-12-18 | Syngenta Crop Protection Ag | Pesticidally active 2-oxobenzimidazole compounds |
| CN119143611A (zh) * | 2024-11-15 | 2024-12-17 | 浙江大学衢州研究院 | 一种n-异丙基对氟苯胺的连续制备方法 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005037214A2 (en) * | 2003-10-14 | 2005-04-28 | Intermune, Inc. | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
| US20090005387A1 (en) * | 2007-06-26 | 2009-01-01 | Deqiang Niu | Quinoxalinyl macrocyclic hepatitis c virus serine protease inhibitors |
| WO2009067225A2 (en) * | 2007-11-20 | 2009-05-28 | Concert Pharmaceuticals, Inc. | Boceprevir derivatives for the treatment of hcv infections |
| WO2009080542A1 (en) * | 2007-12-21 | 2009-07-02 | F. Hoffmann-La Roche Ag | Process for the preparation of a macrocycle |
Family Cites Families (116)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3547119A (en) | 1967-12-08 | 1970-12-15 | Baxter Laboratories Inc | Catheter assembly |
| US3798209A (en) * | 1971-06-01 | 1974-03-19 | Icn Pharmaceuticals | 1,2,4-triazole nucleosides |
| US4211771A (en) | 1971-06-01 | 1980-07-08 | Robins Ronald K | Treatment of human viral diseases with 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide |
| US4311137A (en) | 1980-04-30 | 1982-01-19 | Sherwood Medical Industries Inc. | Infusion device |
| US4531937A (en) | 1983-01-24 | 1985-07-30 | Pacesetter Systems, Inc. | Introducer catheter apparatus and method of use |
| CS263951B1 (en) * | 1985-04-25 | 1989-05-12 | Antonin Holy | 9-(phosponylmethoxyalkyl)adenines and method of their preparation |
| US4755173A (en) | 1986-02-25 | 1988-07-05 | Pacesetter Infusion, Ltd. | Soft cannula subcutaneous injection set |
| US5539122A (en) | 1989-05-23 | 1996-07-23 | Abbott Laboratories | Retroviral protease inhibiting compounds |
| US5354866A (en) | 1989-05-23 | 1994-10-11 | Abbott Laboratories | Retroviral protease inhibiting compounds |
| GB8918806D0 (en) * | 1989-08-17 | 1989-09-27 | Shell Int Research | Chiral compounds,their preparation and use |
| US5518729A (en) | 1989-11-22 | 1996-05-21 | Margolin; Solomon B. | Compositions and methods for reparation and prevention of fibrotic lesions |
| US5716632A (en) | 1989-11-22 | 1998-02-10 | Margolin; Solomon B. | Compositions and methods for reparation and prevention of fibrotic lesions |
| US5310562A (en) | 1989-11-22 | 1994-05-10 | Margolin Solomon B | Composition and method for reparation and prevention of fibrotic lesions |
| DE674513T1 (de) | 1992-12-29 | 1996-01-18 | Abbott Lab | Inhibitoren der retroviralen protease. |
| US5545143A (en) | 1993-01-21 | 1996-08-13 | T. S. I. Medical | Device for subcutaneous medication delivery |
| US5624949A (en) * | 1993-12-07 | 1997-04-29 | Eli Lilly And Company | Protein kinase C inhibitors |
| US6693072B2 (en) * | 1994-06-02 | 2004-02-17 | Aventis Pharmaceuticals Inc. | Elastase inhibitors |
| US5756466A (en) * | 1994-06-17 | 1998-05-26 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1β converting enzyme |
| US6090822A (en) | 1995-03-03 | 2000-07-18 | Margolin; Solomon B. | Treatment of cytokine growth factor caused disorders |
| US6232333B1 (en) | 1996-11-21 | 2001-05-15 | Abbott Laboratories | Pharmaceutical composition |
| US6323180B1 (en) * | 1998-08-10 | 2001-11-27 | Boehringer Ingelheim (Canada) Ltd | Hepatitis C inhibitor tri-peptides |
| US6277830B1 (en) | 1998-10-16 | 2001-08-21 | Schering Corporation | 5′-amino acid esters of ribavirin and the use of same to treat hepatitis C with interferon |
| US6608027B1 (en) * | 1999-04-06 | 2003-08-19 | Boehringer Ingelheim (Canada) Ltd | Macrocyclic peptides active against the hepatitis C virus |
| US7256005B2 (en) | 1999-08-10 | 2007-08-14 | The Chancellor, Masters And Scholars Of The University Of Oxford | Methods for identifying iminosugar derivatives that inhibit HCV p7 ion channel activity |
| HK1047947A1 (zh) * | 2000-04-05 | 2003-03-14 | Schering Corporation | 包含n-环状p2部分的丙型肝炎病毒的大环ns3-丝氨酸蛋白酶抑制剂 |
| PE20011288A1 (es) * | 2000-04-19 | 2001-12-12 | Schering Corp | Compuestos macrociclicos como inhibidores de la serina proteasa ns3/ns4 del virus de la hepatitis c (vhc) |
| US7244721B2 (en) * | 2000-07-21 | 2007-07-17 | Schering Corporation | Peptides as NS3-serine protease inhibitors of hepatitis C virus |
| SI1385870T1 (sl) * | 2000-07-21 | 2010-08-31 | Schering Corp | Peptidi kot NS3-serin proteazni inhibitorji virusa hepatitisa C |
| WO2002060926A2 (en) * | 2000-11-20 | 2002-08-08 | Bristol-Myers Squibb Company | Hepatitis c tripeptide inhibitors |
| CA2446380A1 (en) * | 2001-05-08 | 2002-11-14 | Yale University | Proteomimetic compounds and methods |
| US6867185B2 (en) * | 2001-12-20 | 2005-03-15 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
| PL373399A1 (en) * | 2002-04-11 | 2005-08-22 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
| DE60324552D1 (en) * | 2002-05-20 | 2008-12-18 | Bristol Myers Squibb Co | Substituierte cycloalkyl p1' hepatitis c virus inhibitoren |
| AU2003299519A1 (en) * | 2002-05-20 | 2004-05-04 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| MY140680A (en) * | 2002-05-20 | 2010-01-15 | Bristol Myers Squibb Co | Hepatitis c virus inhibitors |
| DE60334205D1 (en) * | 2002-05-20 | 2010-10-28 | Bristol Myers Squibb Co | Heterocyclische sulfonamid-hepatitis-c-virus-hemmer |
| PL199412B1 (pl) * | 2002-10-15 | 2008-09-30 | Boehringer Ingelheim Int | Nowe kompleksy rutenu jako (pre)katalizatory reakcji metatezy, pochodne 2-alkoksy-5-nitrostyrenu jako związki pośrednie i sposób ich wytwarzania |
| US7148347B2 (en) * | 2003-04-10 | 2006-12-12 | Boehringer Ingelheim International Gmbh | Process for preparing macrocyclic compounds |
| EP2033654B1 (en) * | 2003-04-16 | 2012-05-16 | Bristol-Myers Squibb Company | Process for resolving a mixture of alkyl ester enantiomers using an enzyme |
| EP2143727B1 (en) * | 2003-04-18 | 2015-01-21 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl macrocyclic hepatitis C serine protease inhibitors |
| US7125845B2 (en) * | 2003-07-03 | 2006-10-24 | Enanta Pharmaceuticals, Inc. | Aza-peptide macrocyclic hepatitis C serine protease inhibitors |
| KR20060130027A (ko) * | 2003-10-10 | 2006-12-18 | 버텍스 파마슈티칼스 인코포레이티드 | 세린 프로테아제, 특히 hcv ns3-ns4a 프로테아제의억제제 |
| US7365092B2 (en) * | 2003-10-10 | 2008-04-29 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
| US7491794B2 (en) * | 2003-10-14 | 2009-02-17 | Intermune, Inc. | Macrocyclic compounds as inhibitors of viral replication |
| US7939538B2 (en) * | 2004-06-28 | 2011-05-10 | Amgen Inc. | Compounds, compositions and methods for prevention and treatment of inflammatory and immunoregulatory disorders and diseases |
| DE102004033312A1 (de) * | 2004-07-08 | 2006-01-26 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Kontinuierliches Metatheseverfahren mit Ruthenium-Katalysatoren |
| CA2573346C (en) * | 2004-07-20 | 2011-09-20 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor peptide analogs |
| CN101068828A (zh) * | 2004-08-27 | 2007-11-07 | 先灵公司 | 用作丙型肝炎病毒ns3丝氨酸蛋白酶抑制剂的酰基磺酰胺化合物 |
| JP2008513452A (ja) * | 2004-09-17 | 2008-05-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 超臨界流体中の閉環複分解方法 |
| EP1879607B1 (en) * | 2005-05-02 | 2014-11-12 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
| US7608592B2 (en) * | 2005-06-30 | 2009-10-27 | Virobay, Inc. | HCV inhibitors |
| US7601686B2 (en) * | 2005-07-11 | 2009-10-13 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| TWI389908B (zh) * | 2005-07-14 | 2013-03-21 | Gilead Sciences Inc | 抗病毒化合物類 |
| AR057456A1 (es) * | 2005-07-20 | 2007-12-05 | Merck & Co Inc | Inhibidores de la proteasa ns3 del vhc |
| GEP20105124B (en) * | 2005-07-25 | 2010-11-25 | Array Biopharma Inc | Novel macrocyclic inhibitors of hepatitis c virus replication |
| PE20070211A1 (es) * | 2005-07-29 | 2007-05-12 | Medivir Ab | Compuestos macrociclicos como inhibidores del virus de hepatitis c |
| RS52058B (sr) * | 2005-07-29 | 2012-04-30 | Tibotec Pharmaceuticals | Makrociklički inhibitori virusa hepatitisa c |
| EP2402331A1 (en) * | 2005-08-02 | 2012-01-04 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
| BRPI0617274A2 (pt) * | 2005-10-11 | 2011-07-19 | Intermune Inc | compostos e métodos para a inibição de replicação viral de hepatite c |
| US7772183B2 (en) * | 2005-10-12 | 2010-08-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| KR101020440B1 (ko) * | 2005-11-16 | 2011-03-08 | 에프. 호프만-라 로슈 아게 | 응고 인자 Xa의 억제제로서의 피롤리딘 유도체 |
| US7728148B2 (en) * | 2006-06-06 | 2010-06-01 | Enanta Pharmaceuticals, Inc. | Acyclic oximyl hepatitis C protease inhibitors |
| RU2008152171A (ru) * | 2006-07-05 | 2010-08-10 | Интермьюн, Инк. (Us) | Новые ингибиторы вирусной репликации гепатита с |
| 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 |
| CA2656816A1 (en) * | 2006-08-04 | 2008-02-14 | Enanta Pharmaceuticals, Inc. | Tetrazolyl macrocyclic hepatitis c serine protease inhibitors |
| US20090035267A1 (en) * | 2007-07-31 | 2009-02-05 | Moore Joel D | Acyclic, pyridazinone-derived hepatitis c serine protease inhibitors |
| US7635683B2 (en) * | 2006-08-04 | 2009-12-22 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl tripeptide hepatitis C virus inhibitors |
| US7718612B2 (en) * | 2007-08-02 | 2010-05-18 | Enanta Pharmaceuticals, Inc. | Pyridazinonyl macrocyclic hepatitis C serine protease inhibitors |
| US7662779B2 (en) * | 2006-08-11 | 2010-02-16 | Enanta Pharmaceuticals, Inc. | Triazolyl macrocyclic hepatitis C serine protease inhibitors |
| US7582605B2 (en) * | 2006-08-11 | 2009-09-01 | Enanta Pharmaceuticals, Inc. | Phosphorus-containing hepatitis C serine protease inhibitors |
| US20090098085A1 (en) * | 2006-08-11 | 2009-04-16 | Ying Sun | Tetrazolyl acyclic hepatitis c serine protease inhibitors |
| US20080038225A1 (en) * | 2006-08-11 | 2008-02-14 | Ying Sun | Triazolyl acyclic hepatitis c serine protease inhibitors |
| US7605126B2 (en) * | 2006-08-11 | 2009-10-20 | Enanta Pharmaceuticals, Inc. | Acylaminoheteroaryl hepatitis C virus protease inhibitors |
| US20090035268A1 (en) * | 2007-08-01 | 2009-02-05 | Ying Sun | Tetrazolyl acyclic hepatitis c serine protease inhibitors |
| US7687459B2 (en) * | 2006-08-11 | 2010-03-30 | Enanta Pharmaceuticals, Inc. | Arylalkoxyl hepatitis C virus protease inhibitors |
| US8343477B2 (en) * | 2006-11-01 | 2013-01-01 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
| US20080107625A1 (en) * | 2006-11-01 | 2008-05-08 | 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 |
| ES2470568T3 (es) * | 2006-11-17 | 2014-06-24 | Janssen R&D Ireland | Inhibidores macroc�clicos del virus de la hepatitis C |
| JP2010518128A (ja) * | 2007-02-16 | 2010-05-27 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | C型肝炎ns3プロテアーゼのインヒビター |
| WO2009008913A2 (en) * | 2007-03-23 | 2009-01-15 | Schering Corporation | P1-nonepimerizable ketoamide inhibitors of hcv ns3 protease |
| US20090123423A1 (en) * | 2007-04-26 | 2009-05-14 | Yonghua Gai | Hydroxyamic analogs as hepatitis c virus serine protease inhibitor |
| WO2008137779A2 (en) | 2007-05-03 | 2008-11-13 | Intermune, Inc. | Novel macrocyclic inhibitors of hepatitis c virus replication |
| WO2008137436A1 (en) * | 2007-05-04 | 2008-11-13 | Bristol-Myers Squibb Company | [6,5]-bicyclic gpr119 g protein-coupled receptor agonists |
| 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. |
| WO2009014730A1 (en) * | 2007-07-26 | 2009-01-29 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors |
| US20090053175A1 (en) * | 2007-08-24 | 2009-02-26 | Yat Sun Or | Substitute pyrrolidine derivatives |
| US20090060874A1 (en) * | 2007-09-05 | 2009-03-05 | Yao-Ling Qiu | Bicyclic pyrrolidine derivatives |
| WO2009042668A2 (en) * | 2007-09-24 | 2009-04-02 | Achillion Pharmaceuticals, Inc. | Urea-containing peptides as inhibitors of viral replication |
| US20090082366A1 (en) * | 2007-09-26 | 2009-03-26 | Protia, Llc | Deuterium-enriched telaprevir |
| JP5095824B2 (ja) * | 2007-10-10 | 2012-12-12 | ノバルティス アーゲー | スピロピロリジン類およびhcvおよびhiv感染に対するその使用 |
| WO2009055335A2 (en) * | 2007-10-25 | 2009-04-30 | Taigen Biotechnology Co., Ltd. | Hcv protease inhibitors |
| US8383583B2 (en) * | 2007-10-26 | 2013-02-26 | Enanta Pharmaceuticals, Inc. | Macrocyclic, pyridazinone-containing hepatitis C serine protease inhibitors |
| CN102046622A (zh) * | 2008-04-15 | 2011-05-04 | 因特蒙公司 | 丙型肝炎病毒复制的新颖大环抑制剂 |
| WO2010014134A1 (en) * | 2008-07-02 | 2010-02-04 | Idenix Pharamaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
| BRPI0916609A2 (pt) * | 2008-08-07 | 2015-08-04 | Hoffmann La Roche | Processo para a preparação de um macrociclo |
| US7906655B2 (en) * | 2008-08-07 | 2011-03-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| UY32099A (es) * | 2008-09-11 | 2010-04-30 | Enanta Pharm Inc | Inhibidores macrocíclicos de serina proteasas de hepatitis c |
| CN102159245B (zh) * | 2008-09-17 | 2013-07-24 | 贝林格尔.英格海姆国际有限公司 | Hcv ns3蛋白酶抑制剂与干扰素和利巴韦林的组合 |
| US8603737B2 (en) * | 2008-09-19 | 2013-12-10 | Celgene Avilomics Research, Inc. | Methods for identifying HCV protease inhibitors |
| US8563505B2 (en) * | 2008-09-29 | 2013-10-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8044087B2 (en) * | 2008-09-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US20100080770A1 (en) * | 2008-09-29 | 2010-04-01 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
| CA2740728A1 (en) * | 2008-10-15 | 2010-04-22 | Intermune, Inc. | Therapeutic antiviral peptides |
| AU2009316472B2 (en) * | 2008-11-20 | 2015-07-09 | Achillion Pharmaceuticals, Inc. | Cyclic carboxamide compounds and analogues thereof as of Hepatitis C virus |
| US20110064694A1 (en) * | 2009-09-09 | 2011-03-17 | Yale University | Anti-hepatitis c activity of meso-tetrakis-porphyrin analogues |
| US8703938B2 (en) * | 2009-09-11 | 2014-04-22 | Enanta Pharmaceuticals, Inc. | Hepatitis C virus inhibitors |
| US8815928B2 (en) * | 2009-09-11 | 2014-08-26 | Enanta Pharmaceuticals, Inc. | Hepatitis C virus inhibitors |
| US8927709B2 (en) * | 2009-09-11 | 2015-01-06 | Enanta Pharmaceuticals, Inc. | Hepatitis C virus inhibitors |
| EP2475256A4 (en) * | 2009-09-11 | 2013-06-05 | Enanta Pharm Inc | HEPATITIS C-VIRUS HEMMER |
| US8822700B2 (en) * | 2009-09-11 | 2014-09-02 | Enanta Pharmaceuticals, Inc. | Hepatitis C virus inhibitors |
| US8759332B2 (en) * | 2009-09-11 | 2014-06-24 | Enanta Pharmaceuticals, Inc. | Hepatitis C virus inhibitors |
| EP2477980B1 (en) * | 2009-09-15 | 2016-06-08 | Taigen Biotechnology Co., Ltd. | Hcv protease inhibitors |
| TW201116540A (en) * | 2009-10-01 | 2011-05-16 | Intermune Inc | Therapeutic antiviral peptides |
-
2010
- 2010-09-24 CN CN201510341151.8A patent/CN105001302A/zh active Pending
- 2010-09-24 MX MX2012003500A patent/MX2012003500A/es not_active Application Discontinuation
- 2010-09-24 CA CA2775697A patent/CA2775697A1/en not_active Abandoned
- 2010-09-24 US US12/890,475 patent/US20110081315A1/en not_active Abandoned
- 2010-09-24 IN IN2693DEN2012 patent/IN2012DN02693A/en unknown
- 2010-09-24 PH PH1/2012/500602A patent/PH12012500602A1/en unknown
- 2010-09-24 EA EA201290128A patent/EA201290128A1/ru unknown
- 2010-09-24 CN CN201080053601.9A patent/CN102741270B/zh not_active Expired - Fee Related
- 2010-09-24 EP EP10819571.0A patent/EP2483290A4/en not_active Withdrawn
- 2010-09-24 AU AU2010298028A patent/AU2010298028A1/en not_active Abandoned
- 2010-09-24 WO PCT/US2010/050298 patent/WO2011038293A1/en not_active Ceased
- 2010-09-24 JP JP2012531086A patent/JP2013505952A/ja not_active Withdrawn
- 2010-09-24 KR KR1020127010337A patent/KR20130026410A/ko not_active Withdrawn
- 2010-09-28 TW TW099132976A patent/TW201124137A/zh unknown
- 2010-09-28 AR ARP100103512A patent/AR078462A1/es unknown
-
2012
- 2012-03-21 IL IL218766A patent/IL218766A0/en unknown
- 2012-03-27 TN TNP2012000135A patent/TN2012000135A1/en unknown
- 2012-04-26 MA MA34813A patent/MA33720B1/fr unknown
- 2012-04-27 CO CO12069712A patent/CO6531497A2/es not_active Application Discontinuation
- 2012-04-27 EC ECSP12011845 patent/ECSP12011845A/es unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005037214A2 (en) * | 2003-10-14 | 2005-04-28 | Intermune, Inc. | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
| US20090005387A1 (en) * | 2007-06-26 | 2009-01-01 | Deqiang Niu | Quinoxalinyl macrocyclic hepatitis c virus serine protease inhibitors |
| WO2009067225A2 (en) * | 2007-11-20 | 2009-05-28 | Concert Pharmaceuticals, Inc. | Boceprevir derivatives for the treatment of hcv infections |
| WO2009080542A1 (en) * | 2007-12-21 | 2009-07-02 | F. Hoffmann-La Roche Ag | Process for the preparation of a macrocycle |
Non-Patent Citations (2)
| Title |
|---|
| DJ KEMPF等: "4 Pharmacokinetic boosting of VX-950, an inhibitor of HCV protease, by co-dosing with ritonavir", 《JOURNAL OF HEPATOLOGY》 * |
| THIBEAULT D等: "Use of the fused NS4A Peptide -NS3 protease domain to study the importance of the helicase domain for protease inhibitor binding to hepatitis C virus N3-NS4A", 《BIOCHEMISTRY》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2010298028A2 (en) | 2012-10-04 |
| US20110081315A1 (en) | 2011-04-07 |
| PH12012500602A1 (en) | 2017-08-23 |
| WO2011038293A1 (en) | 2011-03-31 |
| ECSP12011845A (es) | 2012-06-29 |
| EA201290128A1 (ru) | 2013-01-30 |
| EP2483290A4 (en) | 2013-05-01 |
| AR078462A1 (es) | 2011-11-09 |
| CN102741270A (zh) | 2012-10-17 |
| MA33720B1 (fr) | 2012-11-01 |
| IN2012DN02693A (enExample) | 2015-09-04 |
| JP2013505952A (ja) | 2013-02-21 |
| CO6531497A2 (es) | 2012-09-28 |
| TN2012000135A1 (en) | 2013-09-19 |
| EP2483290A1 (en) | 2012-08-08 |
| AU2010298028A1 (en) | 2012-04-19 |
| KR20130026410A (en) | 2013-03-13 |
| CA2775697A1 (en) | 2011-03-31 |
| IL218766A0 (en) | 2012-06-28 |
| TW201124137A (en) | 2011-07-16 |
| CN102741270B (zh) | 2015-07-22 |
| MX2012003500A (es) | 2012-08-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105001302A (zh) | C型肝炎病毒复制的环肽抑制剂 | |
| CA2557495C (en) | Sulfur compounds as inhibitors of hepatitis c virus ns3 serine protease | |
| US8299021B2 (en) | Macrocyclic inhibitors of hepatitis C virus replication | |
| CN101024671B (zh) | 丙型肝炎病毒抑制剂 | |
| CN102216321A (zh) | 治疗性抗病毒肽 | |
| US20090155209A1 (en) | Novel macrocyclic inhibitors of hepatitis c virus replication | |
| CN101679277A (zh) | 丙型肝炎病毒复制的新颖肽抑制剂 | |
| CN102046622A (zh) | 丙型肝炎病毒复制的新颖大环抑制剂 | |
| CN101304976A (zh) | 病毒复制抑制剂 | |
| CN101541784A (zh) | 丙型肝炎病毒抑制剂 | |
| CN104662033A (zh) | 黄病毒科病毒的大环抑制剂 | |
| AU2006252623A1 (en) | Controlled-release formulation useful for treating disorders associated with hepatitis C virus | |
| EP1773868A1 (en) | Substituted prolines as inhibitors of hepatitis c virus ns3 serine protease | |
| CN102617705B (zh) | 抑制丙肝病毒复制的大环类化合物 | |
| WO2012047764A1 (en) | Therapeutic antiviral peptides | |
| US20250059231A1 (en) | Protease inhibitors | |
| CN105530933B (zh) | 用于治疗hcv的包含联苯衍生物的组合产品 | |
| HK1176953A (en) | Cyclic peptide inhibitors of hepatitis c virus replication | |
| WO2024200819A1 (en) | Protease inhibitors for coronaviral infections | |
| HK1179247A (en) | Novel macrocyclic inhibitors of hepatitis c virus replication | |
| HK1144683A (en) | Novel macrocyclic inhibitors of hepatitis c virus replication |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20151028 |