WO2011112429A1 - Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases - Google Patents
Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases Download PDFInfo
- Publication number
- WO2011112429A1 WO2011112429A1 PCT/US2011/027117 US2011027117W WO2011112429A1 WO 2011112429 A1 WO2011112429 A1 WO 2011112429A1 US 2011027117 W US2011027117 W US 2011027117W WO 2011112429 A1 WO2011112429 A1 WO 2011112429A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- membered
- alkyl
- independently
- occurrence
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 122
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 title abstract description 39
- 230000003612 virological effect Effects 0.000 title description 35
- 238000011282 treatment Methods 0.000 title description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 12
- 201000010099 disease Diseases 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 581
- -1 Silyl Compound Chemical class 0.000 claims abstract description 106
- 150000003839 salts Chemical class 0.000 claims abstract description 64
- 208000015181 infectious disease Diseases 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims description 103
- 125000000217 alkyl group Chemical group 0.000 claims description 78
- 229940124597 therapeutic agent Drugs 0.000 claims description 77
- 125000004432 carbon atom Chemical group C* 0.000 claims description 71
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 66
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 65
- 125000001072 heteroaryl group Chemical group 0.000 claims description 65
- 125000003118 aryl group Chemical group 0.000 claims description 64
- 125000005549 heteroarylene group Chemical group 0.000 claims description 57
- 229940079322 interferon Drugs 0.000 claims description 43
- 125000002950 monocyclic group Chemical group 0.000 claims description 41
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 38
- 239000003112 inhibitor Substances 0.000 claims description 38
- 238000002360 preparation method Methods 0.000 claims description 36
- 229910052799 carbon Inorganic materials 0.000 claims description 35
- 125000001188 haloalkyl group Chemical group 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 31
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 125000002619 bicyclic group Chemical group 0.000 claims description 26
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 25
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- 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 24
- 125000005843 halogen group Chemical group 0.000 claims description 24
- 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 22
- 229960000329 ribavirin Drugs 0.000 claims description 22
- 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 22
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 101800001014 Non-structural protein 5A Proteins 0.000 claims description 15
- 125000004122 cyclic group Chemical group 0.000 claims description 15
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000002947 alkylene group Chemical group 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 239000003443 antiviral agent Substances 0.000 claims description 13
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 229910052710 silicon Inorganic materials 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 10
- 125000005353 silylalkyl group Chemical group 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
- 239000004599 antimicrobial Substances 0.000 claims description 8
- 239000002955 immunomodulating agent Substances 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 229960005475 antiinfective agent Drugs 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims description 7
- 229940121354 immunomodulator Drugs 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910007161 Si(CH3)3 Inorganic materials 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 229940124772 HCV-NS5B polymerase inhibitor Drugs 0.000 claims description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 108091005804 Peptidases Proteins 0.000 claims description 3
- 239000004365 Protease Substances 0.000 claims description 3
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 3
- 239000010703 silicon Substances 0.000 claims description 2
- 108700008776 hepatitis C virus NS-5 Proteins 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 104
- 239000000243 solution Substances 0.000 description 182
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 178
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 175
- 239000000543 intermediate Substances 0.000 description 127
- 238000003756 stirring Methods 0.000 description 120
- 238000003786 synthesis reaction Methods 0.000 description 110
- 241000711549 Hepacivirus C Species 0.000 description 108
- 230000015572 biosynthetic process Effects 0.000 description 100
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 92
- 239000011541 reaction mixture Substances 0.000 description 89
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 86
- 238000006243 chemical reaction Methods 0.000 description 86
- 235000019439 ethyl acetate Nutrition 0.000 description 80
- 229910001868 water Inorganic materials 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 75
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
- 235000002639 sodium chloride Nutrition 0.000 description 65
- 239000007787 solid Substances 0.000 description 64
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 61
- 239000012044 organic layer Substances 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- 238000005481 NMR spectroscopy Methods 0.000 description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 108010050904 Interferons Proteins 0.000 description 38
- 102000014150 Interferons Human genes 0.000 description 38
- 0 C*c1ccc(C)[s]1 Chemical compound C*c1ccc(C)[s]1 0.000 description 34
- 239000003480 eluent Substances 0.000 description 34
- 238000000746 purification Methods 0.000 description 34
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 33
- 239000003795 chemical substances by application Substances 0.000 description 33
- 239000012267 brine Substances 0.000 description 32
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- 125000006413 ring segment Chemical group 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 23
- 239000010410 layer Substances 0.000 description 23
- 239000012043 crude product Substances 0.000 description 21
- 239000012453 solvate Substances 0.000 description 21
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 19
- 150000001721 carbon Chemical group 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- 235000019198 oils Nutrition 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 229960001866 silicon dioxide Drugs 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- 208000036142 Viral infection Diseases 0.000 description 17
- 230000009385 viral infection Effects 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 16
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 229940002612 prodrug Drugs 0.000 description 15
- 239000000651 prodrug Substances 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- 239000007821 HATU Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 125000000732 arylene group Chemical group 0.000 description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- 239000000377 silicon dioxide Substances 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- 125000000304 alkynyl group Chemical group 0.000 description 13
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 229960000583 acetic acid Drugs 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 239000002777 nucleoside Substances 0.000 description 11
- 229940124683 HCV polymerase inhibitor Drugs 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 238000002648 combination therapy Methods 0.000 description 10
- 150000003833 nucleoside derivatives Chemical class 0.000 description 10
- 230000010076 replication Effects 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 229940123627 Viral replication inhibitor Drugs 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 8
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- 229940122604 HCV protease inhibitor Drugs 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000006069 Suzuki reaction reaction Methods 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 239000000499 gel Substances 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 230000000875 corresponding effect Effects 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 6
- 239000005695 Ammonium acetate Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 229940123066 Polymerase inhibitor Drugs 0.000 description 6
- 101000767160 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Intracellular protein transport protein USO1 Proteins 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 235000019257 ammonium acetate Nutrition 0.000 description 6
- 229940043376 ammonium acetate Drugs 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000006260 foam Substances 0.000 description 6
- 208000010710 hepatitis C virus infection Diseases 0.000 description 6
- 230000002519 immonomodulatory effect Effects 0.000 description 6
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 5
- 229940126656 GS-4224 Drugs 0.000 description 5
- 208000005176 Hepatitis C Diseases 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 229940126545 compound 53 Drugs 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 238000010254 subcutaneous injection Methods 0.000 description 5
- 239000007929 subcutaneous injection Substances 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 229940021747 therapeutic vaccine Drugs 0.000 description 5
- 230000029812 viral genome replication Effects 0.000 description 5
- JXGVXCZADZNAMJ-NSHDSACASA-N (2s)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1=CC=CC=C1 JXGVXCZADZNAMJ-NSHDSACASA-N 0.000 description 4
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical group FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Cc1ccc(C)cc1 Chemical compound Cc1ccc(C)cc1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 4
- 241000282693 Cercopithecidae Species 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 102100040018 Interferon alpha-2 Human genes 0.000 description 4
- 108010079944 Interferon-alpha2b Proteins 0.000 description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 150000001204 N-oxides Chemical class 0.000 description 4
- 101800001020 Non-structural protein 4A Proteins 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000000692 anti-sense effect Effects 0.000 description 4
- 238000009175 antibody therapy Methods 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- VDQVEACBQKUUSU-UHFFFAOYSA-M disodium;sulfanide Chemical compound [Na+].[Na+].[SH-] VDQVEACBQKUUSU-UHFFFAOYSA-M 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 108010026228 mRNA guanylyltransferase Proteins 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 229960002429 proline Drugs 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000009097 single-agent therapy Methods 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910052979 sodium sulfide Inorganic materials 0.000 description 4
- 239000012258 stirred mixture Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 229940121759 Helicase inhibitor Drugs 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 108010078049 Interferon alpha-2 Proteins 0.000 description 3
- 108010047761 Interferon-alpha Proteins 0.000 description 3
- 102000006992 Interferon-alpha Human genes 0.000 description 3
- 241000764238 Isis Species 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 229910002666 PdCl2 Inorganic materials 0.000 description 3
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229940118555 Viral entry inhibitor Drugs 0.000 description 3
- MLESJYFEMSJZLZ-MAAOGQSESA-N [(2r,3r,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-4-fluoro-4-methyl-3-(2-methylpropanoyloxy)oxolan-2-yl]methyl 2-methylpropanoate Chemical compound C[C@@]1(F)[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 MLESJYFEMSJZLZ-MAAOGQSESA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 3
- 150000001642 boronic acid derivatives Chemical class 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- ZVTDLPBHTSMEJZ-JSZLBQEHSA-N danoprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCC[C@@H](C(N1C[C@@H](C[C@H]1C(=O)N2)OC(=O)N1CC2=C(F)C=CC=C2C1)=O)NC(=O)OC(C)(C)C)NS(=O)(=O)C1CC1 ZVTDLPBHTSMEJZ-JSZLBQEHSA-N 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 230000000155 isotopic effect Effects 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
- 208000019423 liver disease Diseases 0.000 description 3
- BRMYZIKAHFEUFJ-UHFFFAOYSA-L mercury diacetate Chemical compound CC(=O)O[Hg]OC(C)=O BRMYZIKAHFEUFJ-UHFFFAOYSA-L 0.000 description 3
- UJUXGWDHCCTDJD-UHFFFAOYSA-N n-[4-[6-tert-butyl-8-(2,4-dioxo-1,3-diazinan-1-yl)-5-methoxyquinolin-3-yl]phenyl]methanesulfonamide Chemical compound C12=NC=C(C=3C=CC(NS(C)(=O)=O)=CC=3)C=C2C(OC)=C(C(C)(C)C)C=C1N1CCC(=O)NC1=O UJUXGWDHCCTDJD-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000002553 single reaction monitoring Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 238000004885 tandem mass spectrometry Methods 0.000 description 3
- 229960002935 telaprevir Drugs 0.000 description 3
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 3
- 108010017101 telaprevir Proteins 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 210000002845 virion Anatomy 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 description 2
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 2
- WTMZYKCXBXPVPT-LURJTMIESA-N (2s)-4,4-difluoro-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(O)=O WTMZYKCXBXPVPT-LURJTMIESA-N 0.000 description 2
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 2
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 2
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical compound CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- RRRWAYWNXBSUFV-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonyl]-3-azabicyclo[2.2.2]octane-2-carboxylic acid Chemical compound C1CC2CCC1N(C(=O)OC(C)(C)C)C2C(O)=O RRRWAYWNXBSUFV-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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- WDWRIVZIPSHUOR-UHFFFAOYSA-N 4-azaniumyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(N)CC1C(O)=O WDWRIVZIPSHUOR-UHFFFAOYSA-N 0.000 description 2
- UPPWMBQIDFTBEQ-UHFFFAOYSA-N 6-(3,4-dimethoxyphenyl)-n-[4-(1,2,4-triazol-1-yl)phenyl]quinazolin-4-amine Chemical compound C1=C(OC)C(OC)=CC=C1C1=CC=C(N=CN=C2NC=3C=CC(=CC=3)N3N=CN=C3)C2=C1 UPPWMBQIDFTBEQ-UHFFFAOYSA-N 0.000 description 2
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- 241001227713 Chiron Species 0.000 description 2
- 208000006154 Chronic hepatitis C Diseases 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 241000710781 Flaviviridae Species 0.000 description 2
- 208000004576 Flaviviridae Infections Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 241000709721 Hepatovirus A Species 0.000 description 2
- 101000632319 Homo sapiens Septin-7 Proteins 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 2
- 241000720974 Protium Species 0.000 description 2
- 102100027981 Septin-7 Human genes 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 description 2
- 125000002015 acyclic group Chemical group 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 125000005206 alkoxycarbonyloxymethyl group Chemical group 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 150000001649 bromium compounds Chemical class 0.000 description 2
- JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000007819 coupling partner Substances 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 208000029570 hepatitis D virus infection Diseases 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 2
- UVNXNSUKKOLFBM-UHFFFAOYSA-N imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=CSC2=NC=CN21 UVNXNSUKKOLFBM-UHFFFAOYSA-N 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000012739 integrated shape imaging system Methods 0.000 description 2
- 229960003507 interferon alfa-2b Drugs 0.000 description 2
- 108010010648 interferon alfacon-1 Proteins 0.000 description 2
- 229940047124 interferons Drugs 0.000 description 2
- 150000004694 iodide salts Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 2
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 2
- 108010046177 locteron Proteins 0.000 description 2
- 239000000314 lubricant 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
- 238000004949 mass spectrometry Methods 0.000 description 2
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical compound COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- WJSGOXONRXFGRY-UHFFFAOYSA-N n-[[4-pentoxy-3-(trifluoromethyl)phenyl]carbamothioyl]pyridine-3-carboxamide Chemical compound C1=C(C(F)(F)F)C(OCCCCC)=CC=C1NC(=S)NC(=O)C1=CC=CN=C1 WJSGOXONRXFGRY-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229940078552 o-xylene Drugs 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000005550 pyrazinylene group Chemical group 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JTZZSQYMACOLNN-VDWJNHBNSA-N simeprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCN(C)C(=O)[C@H]1[C@H](C(N2)=O)C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(C)C)C)OC)NS(=O)(=O)C1CC1 JTZZSQYMACOLNN-VDWJNHBNSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- MIXCUJKCXRNYFM-UHFFFAOYSA-M sodium;diiodomethanesulfonate;n-propyl-n-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide Chemical compound [Na+].[O-]S(=O)(=O)C(I)I.C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl MIXCUJKCXRNYFM-UHFFFAOYSA-M 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 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 2
- 229950006081 taribavirin Drugs 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000005557 thiazolylene group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000002627 tracheal intubation Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical class CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- IFAMSTPTNRJBRG-YIZRAAEISA-N (1s,2s,4r)-3-[(2-methylpropan-2-yl)oxycarbonyl]-3-azabicyclo[2.2.1]heptane-2-carboxylic acid Chemical compound C1C[C@@H]2[C@@H](C(O)=O)N(C(=O)OC(C)(C)C)[C@H]1C2 IFAMSTPTNRJBRG-YIZRAAEISA-N 0.000 description 1
- RNEACARJKXYVND-KQGZCTBQSA-N (2r)-2-[[(5z)-5-[(5-ethylfuran-2-yl)methylidene]-4-oxo-1,3-thiazol-2-yl]amino]-2-(4-fluorophenyl)acetic acid Chemical compound O1C(CC)=CC=C1\C=C/1C(=O)N=C(N[C@@H](C(O)=O)C=2C=CC(F)=CC=2)S\1 RNEACARJKXYVND-KQGZCTBQSA-N 0.000 description 1
- HLQXYDHLDZTWDW-KAWPREARSA-N (2r,4s,5r)-1-(4-tert-butyl-3-methoxybenzoyl)-4-(methoxymethyl)-2-(pyrazol-1-ylmethyl)-5-(1,3-thiazol-2-yl)pyrrolidine-2-carboxylic acid Chemical compound C([C@]1(C[C@@H]([C@@H](N1C(=O)C=1C=C(OC)C(=CC=1)C(C)(C)C)C=1SC=CN=1)COC)C(O)=O)N1C=CC=N1 HLQXYDHLDZTWDW-KAWPREARSA-N 0.000 description 1
- PAORVUMOXXAMPL-SECBINFHSA-N (2s)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride Chemical compound CO[C@](C(Cl)=O)(C(F)(F)F)C1=CC=CC=C1 PAORVUMOXXAMPL-SECBINFHSA-N 0.000 description 1
- SZXBQTSZISFIAO-ZETCQYMHSA-N (2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 description 1
- ZPBIYZHGBPBZCK-VKHMYHEASA-N (2s)-4,4-difluoropyrrolidin-1-ium-2-carboxylate Chemical compound OC(=O)[C@@H]1CC(F)(F)CN1 ZPBIYZHGBPBZCK-VKHMYHEASA-N 0.000 description 1
- IRCDUOCGSIGEAI-XUXIUFHCSA-N (2s,5s)-1-[2-[(2s,5s)-2,5-dimethylphospholan-1-yl]ethyl]-2,5-dimethylphospholane Chemical compound C[C@H]1CC[C@H](C)P1CCP1[C@@H](C)CC[C@@H]1C IRCDUOCGSIGEAI-XUXIUFHCSA-N 0.000 description 1
- AQHMBDAHQGYLIU-XNFHFXFQSA-N (3s,6s,9s,12r,15s,18s,21s,24s,27r,30s,33s)-27-[2-(dimethylamino)ethylsulfanyl]-30-ethyl-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-24-(2-hydroxy-2-methylpropyl)-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18-tris(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10, Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)(C)O)N(C)C(=O)[C@@H](SCCN(C)C)N(C)C1=O AQHMBDAHQGYLIU-XNFHFXFQSA-N 0.000 description 1
- VYFGDLGHHBUDTQ-ZLGUVYLKSA-N (5r)-n-[(2s,3s)-2-(fluoromethyl)-2-hydroxy-5-oxooxolan-3-yl]-3-isoquinolin-1-yl-5-propan-2-yl-4h-1,2-oxazole-5-carboxamide Chemical compound O=C([C@]1(ON=C(C1)C=1C2=CC=CC=C2C=CN=1)C(C)C)N[C@H]1CC(=O)O[C@]1(O)CF VYFGDLGHHBUDTQ-ZLGUVYLKSA-N 0.000 description 1
- JBSNALXXNTWUEC-SFQUDFHCSA-N (e)-3-[4-[[1-[(3-cyclopentyl-1-methyl-2-pyridin-2-ylindole-6-carbonyl)amino]cyclobutanecarbonyl]amino]phenyl]prop-2-enoic acid Chemical compound C12=CC=C(C(=O)NC3(CCC3)C(=O)NC=3C=CC(\C=C\C(O)=O)=CC=3)C=C2N(C)C(C=2N=CC=CC=2)=C1C1CCCC1 JBSNALXXNTWUEC-SFQUDFHCSA-N 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 description 1
- QYMGRIFMUQCAJW-UHFFFAOYSA-N 1,2-dihydropyrazine Chemical compound C1NC=CN=C1 QYMGRIFMUQCAJW-UHFFFAOYSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- RNNZWFBZBNHQOO-UHFFFAOYSA-N 1-(5-bromo-1,3-thiazol-2-yl)ethanone Chemical compound CC(=O)C1=NC=C(Br)S1 RNNZWFBZBNHQOO-UHFFFAOYSA-N 0.000 description 1
- IGBZCOWXSCWSHO-UHFFFAOYSA-N 1-(5-bromothiophen-2-yl)ethanone Chemical compound CC(=O)C1=CC=C(Br)S1 IGBZCOWXSCWSHO-UHFFFAOYSA-N 0.000 description 1
- 125000005851 1-(N-(alkoxycarbonyl)amino)ethyl group Chemical group 0.000 description 1
- 125000005846 1-(alkanoyloxy)ethyl group Chemical group 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical class CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical class CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-UHFFFAOYSA-N 0.000 description 1
- 125000005847 1-methyl-1-(alkanoyloxy)-ethyl group Chemical group 0.000 description 1
- 125000005849 1-methyl-1-(alkoxycarbonyloxy)ethyl group Chemical group 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- ZJNLYGOUHDJHMG-UHFFFAOYSA-N 1-n,4-n-bis(5-methylhexan-2-yl)benzene-1,4-diamine Chemical compound CC(C)CCC(C)NC1=CC=C(NC(C)CCC(C)C)C=C1 ZJNLYGOUHDJHMG-UHFFFAOYSA-N 0.000 description 1
- YYKBFGMYHQMXIL-UHFFFAOYSA-N 1-phenyl-2,3,4-tri(propan-2-yl)benzene Chemical group CC(C)C1=C(C(C)C)C(C(C)C)=CC=C1C1=CC=CC=C1 YYKBFGMYHQMXIL-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YFXGICNMLCGLHJ-RSKRLRQZSA-N 2,2-dimethylpropyl (2s)-2-[[[(2r,3r,4r,5r)-5-(2-amino-6-methoxypurin-9-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy-naphthalen-1-yloxyphosphoryl]amino]propanoate Chemical compound C1=CC=C2C(OP(=O)(N[C@@H](C)C(=O)OCC(C)(C)C)OC[C@H]3O[C@H]([C@]([C@@H]3O)(C)O)N3C=4N=C(N)N=C(C=4N=C3)OC)=CC=CC2=C1 YFXGICNMLCGLHJ-RSKRLRQZSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- JXZYSNWHGBGZAI-GOSISDBHSA-N 2-[(1r)-5-cyano-8-methyl-1-propyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl]acetic acid Chemical compound N1C2=C(C)C=CC(C#N)=C2C2=C1[C@@](CCC)(CC(O)=O)OCC2 JXZYSNWHGBGZAI-GOSISDBHSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- FKJSFKCZZIXQIP-UHFFFAOYSA-N 2-bromo-1-(4-bromophenyl)ethanone Chemical compound BrCC(=O)C1=CC=C(Br)C=C1 FKJSFKCZZIXQIP-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical compound C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 description 1
- NDYYWMXJZWHRLZ-UHFFFAOYSA-N 2-methoxyethyl carbonochloridate Chemical compound COCCOC(Cl)=O NDYYWMXJZWHRLZ-UHFFFAOYSA-N 0.000 description 1
- XSBINRYSUHFKST-UHFFFAOYSA-N 2-naphthalen-1-yl-1h-imidazole Chemical class C1=CNC(C=2C3=CC=CC=C3C=CC=2)=N1 XSBINRYSUHFKST-UHFFFAOYSA-N 0.000 description 1
- WLRYENIHLPMXMO-UHFFFAOYSA-N 2-nitroquinolin-3-amine Chemical compound C1=CC=C2N=C([N+]([O-])=O)C(N)=CC2=C1 WLRYENIHLPMXMO-UHFFFAOYSA-N 0.000 description 1
- TYEYBOSBBBHJIV-UHFFFAOYSA-M 2-oxobutanoate Chemical compound CCC(=O)C([O-])=O TYEYBOSBBBHJIV-UHFFFAOYSA-M 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical class BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- RZXQBIKGWSLVEK-UHFFFAOYSA-N 3-[(4-methylcyclohexanecarbonyl)-propan-2-ylamino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1=C(C=2C=CC=CC=2)SC(C(O)=O)=C1N(C(C)C)C(=O)C1CCC(C)CC1 RZXQBIKGWSLVEK-UHFFFAOYSA-N 0.000 description 1
- VFDUHNACOKTCSP-UHFFFAOYSA-N 3-hydroxy-3-(1-methylcyclopropyl)pyrrolidine-2,5-dione Chemical compound C1C(=O)NC(=O)C1(O)C1(C)CC1 VFDUHNACOKTCSP-UHFFFAOYSA-N 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- NYPIRLYMDJMKGW-VPCXQMTMSA-N 4-amino-1-[(2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidin-2-one Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C=C1 NYPIRLYMDJMKGW-VPCXQMTMSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- WPMJNLCLKAKMLA-UHFFFAOYSA-N 5-(3,3-dimethylbut-1-ynyl)-3-[(4-hydroxycyclohexyl)-[(4-methylcyclohexyl)-oxomethyl]amino]-2-thiophenecarboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C#CC(C)(C)C)C(O)=O)C1CCC(O)CC1 WPMJNLCLKAKMLA-UHFFFAOYSA-N 0.000 description 1
- COWZPSUDTMGBAT-UHFFFAOYSA-N 5-bromothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)S1 COWZPSUDTMGBAT-UHFFFAOYSA-N 0.000 description 1
- GWQYGDMKYIUOTM-UHFFFAOYSA-N 5-chlorocyclopenta-1,3-diene zirconium(2+) Chemical compound [Zr++].Cl[c-]1cccc1.Cl[c-]1cccc1 GWQYGDMKYIUOTM-UHFFFAOYSA-N 0.000 description 1
- WTDWVLJJJOTABN-UHFFFAOYSA-N 5-cyclopropyl-2-(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-n-methyl-1-benzofuran-3-carboxamide Chemical compound C1=C2C(C(=O)NC)=C(C=3C=CC(F)=CC=3)OC2=CC(N(CCO)S(C)(=O)=O)=C1C1CC1 WTDWVLJJJOTABN-UHFFFAOYSA-N 0.000 description 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 1
- NPMCAVBMOTZUPD-UHFFFAOYSA-N 6-bromonaphthalene-2-carboxylic acid Chemical compound C1=C(Br)C=CC2=CC(C(=O)O)=CC=C21 NPMCAVBMOTZUPD-UHFFFAOYSA-N 0.000 description 1
- TYBYHEXFKFLRFT-UHFFFAOYSA-N 6-nitroquinolin-5-amine Chemical compound C1=CC=C2C(N)=C([N+]([O-])=O)C=CC2=N1 TYBYHEXFKFLRFT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- PVRFQJIRERYGTQ-DSQUMVBZSA-N 9-[(2s,4ar,6r,7r,7ar)-7-fluoro-7-methyl-2-oxo-2-propan-2-yloxy-4,4a,6,7a-tetrahydrofuro[3,2-d][1,3,2]dioxaphosphinin-6-yl]-6-ethoxypurin-2-amine Chemical compound C([C@H]1O2)O[P@@](=O)(OC(C)C)O[C@H]1[C@](F)(C)[C@@H]2N1C(N=C(N)N=C2OCC)=C2N=C1 PVRFQJIRERYGTQ-DSQUMVBZSA-N 0.000 description 1
- 208000032484 Accidental exposure to product Diseases 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010065051 Acute hepatitis C Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- OLROWHGDTNFZBH-XEMWPYQTSA-N Alisporivir Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(CC)C(=O)[C@@H](C)N(C)C1=O OLROWHGDTNFZBH-XEMWPYQTSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108091093088 Amplicon Proteins 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- IQTFEGRDZZJBRS-ZNIKRAEXSA-N CC(C)(C)OC(N(C1CCC2CC1)[C@@H]2c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)=O Chemical compound CC(C)(C)OC(N(C1CCC2CC1)[C@@H]2c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)=O IQTFEGRDZZJBRS-ZNIKRAEXSA-N 0.000 description 1
- BUWDIZVWNAWPTB-UHFFFAOYSA-N CC(C)(C)OC(N(CCC1)S1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)=O Chemical compound CC(C)(C)OC(N(CCC1)S1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)=O BUWDIZVWNAWPTB-UHFFFAOYSA-N 0.000 description 1
- BZKAECFCVYNTAF-INIZCTEOSA-N CC(C)(C)OC(N(CCCC1)[C@@H]1c1ncc(-c(cc2)ccc2Br)[nH]1)=O Chemical compound CC(C)(C)OC(N(CCCC1)[C@@H]1c1ncc(-c(cc2)ccc2Br)[nH]1)=O BZKAECFCVYNTAF-INIZCTEOSA-N 0.000 description 1
- CEFVHPDFGLDQKU-YFKPBYRVSA-N CC(C)[C@@H](C(O)=O)NC(OC)=O Chemical compound CC(C)[C@@H](C(O)=O)NC(OC)=O CEFVHPDFGLDQKU-YFKPBYRVSA-N 0.000 description 1
- JRKIBOHHSBMZNB-NSHDSACASA-N CC([C@@H](C(C)=O)c1ccccc1)=N Chemical compound CC([C@@H](C(C)=O)c1ccccc1)=N JRKIBOHHSBMZNB-NSHDSACASA-N 0.000 description 1
- QIAFSDBHXBOXAX-UHFFFAOYSA-N CCC(C(CC(C(O[IH][N]#C)=O)=C)C(C)C)=O Chemical compound CCC(C(CC(C(O[IH][N]#C)=O)=C)C(C)C)=O QIAFSDBHXBOXAX-UHFFFAOYSA-N 0.000 description 1
- QFOLZTMLJYURTN-OVZPNWPYSA-N CCCC[C@@H](C(C(NC1CC1)=O)=O)NC([C@H]([C@H]1C(C)(C)CC1C1)N1C([C@H](C1(C)CCCCC1)NC(NC1(CS(C(C)(C)C)(=O)=O)CCCCC1)=O)=O)=O Chemical compound CCCC[C@@H](C(C(NC1CC1)=O)=O)NC([C@H]([C@H]1C(C)(C)CC1C1)N1C([C@H](C1(C)CCCCC1)NC(NC1(CS(C(C)(C)C)(=O)=O)CCCCC1)=O)=O)=O QFOLZTMLJYURTN-OVZPNWPYSA-N 0.000 description 1
- YQXIBTRTKSWFKH-MRXNPFEDSA-N C[C@@]1(c2nc(ccc3c4ccc(Br)c3)c4[nH]2)NCCC1 Chemical compound C[C@@]1(c2nc(ccc3c4ccc(Br)c3)c4[nH]2)NCCC1 YQXIBTRTKSWFKH-MRXNPFEDSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- GABZMWUBFGPQPX-UHFFFAOYSA-N Cc1cc(cc(C)cc2)c2[o]1 Chemical compound Cc1cc(cc(C)cc2)c2[o]1 GABZMWUBFGPQPX-UHFFFAOYSA-N 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 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 1
- 208000001490 Dengue Diseases 0.000 description 1
- 206010012310 Dengue fever Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 206010014596 Encephalitis Japanese B Diseases 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- CATMPQFFVNKDEY-YPMHNXCESA-N Golotimod Chemical compound C1=CC=C2C(C[C@H](NC(=O)CC[C@@H](N)C(O)=O)C(O)=O)=CNC2=C1 CATMPQFFVNKDEY-YPMHNXCESA-N 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 229940122750 HCV entry inhibitor Drugs 0.000 description 1
- 229940124771 HCV-NS3 protease inhibitor Drugs 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 208000005331 Hepatitis D Diseases 0.000 description 1
- 101001033233 Homo sapiens Interleukin-10 Proteins 0.000 description 1
- 238000009015 Human TaqMan MicroRNA Assay kit Methods 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 206010069803 Injury associated with device Diseases 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 201000005807 Japanese encephalitis Diseases 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- 125000002061 L-isoleucyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](C([H])([H])[H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 description 1
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 description 1
- 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 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 201000005805 Murray valley encephalitis Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N N,N′-Dicyclohexylcarbodiimide Substances C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 125000005850 N-(alkoxycarbonyl)aminomethyl group Chemical group 0.000 description 1
- GNMSLDIYJOSUSW-LURJTMIESA-N N-acetyl-L-proline Chemical compound CC(=O)N1CCC[C@H]1C(O)=O GNMSLDIYJOSUSW-LURJTMIESA-N 0.000 description 1
- 229940125977 NS4B inhibitor Drugs 0.000 description 1
- 241001481166 Nautilus Species 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 101710144128 Non-structural protein 2 Proteins 0.000 description 1
- 101710199667 Nuclear export protein Proteins 0.000 description 1
- YEPBUHWNLNKZBW-UEMKMYPFSA-N O=C([C@]12NC(=O)[C@H]3N(C(N(C)CCCC\C=C/[C@@H]1C2)=O)CC[C@@H](C3)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(F)(F)F)C)OC)NS(=O)(=O)C1(C)CC1 Chemical compound O=C([C@]12NC(=O)[C@H]3N(C(N(C)CCCC\C=C/[C@@H]1C2)=O)CC[C@@H](C3)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(F)(F)F)C)OC)NS(=O)(=O)C1(C)CC1 YEPBUHWNLNKZBW-UEMKMYPFSA-N 0.000 description 1
- PCQFIGWRWNCSPN-UHFFFAOYSA-N OBO.C1=CNC=N1 Chemical compound OBO.C1=CNC=N1 PCQFIGWRWNCSPN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 241001596784 Pegasus Species 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 108010089430 Phosphoproteins Proteins 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 241000219492 Quercus Species 0.000 description 1
- 108090000944 RNA Helicases Proteins 0.000 description 1
- 102000004409 RNA Helicases Human genes 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- 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 description 1
- 108010090287 SCY-635 Proteins 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- MHFMTUBUVQZIRE-WINRQGAFSA-N Sovaprevir Chemical compound C([C@H](C(=O)N1[C@@H](C[C@H](C1)OC=1C2=CC=C(C=C2N=C(C=1)C=1C=CC=CC=1)OC)C(=O)N[C@]1([C@@H](C1)C=C)C(=O)NS(=O)(=O)C1CC1)C(C)(C)C)C(=O)N1CCCCC1 MHFMTUBUVQZIRE-WINRQGAFSA-N 0.000 description 1
- 206010041896 St. Louis Encephalitis Diseases 0.000 description 1
- 108091027544 Subgenomic mRNA Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- BHTRKEVKTKCXOH-UHFFFAOYSA-N Taurochenodesoxycholsaeure Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)CC2 BHTRKEVKTKCXOH-UHFFFAOYSA-N 0.000 description 1
- 108010078233 Thymalfasin Proteins 0.000 description 1
- 208000004006 Tick-borne encephalitis Diseases 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 206010058874 Viraemia Diseases 0.000 description 1
- 201000006449 West Nile encephalitis Diseases 0.000 description 1
- 208000003152 Yellow Fever Diseases 0.000 description 1
- 241000710772 Yellow fever virus Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 229910007928 ZrCl2 Inorganic materials 0.000 description 1
- TVRCRTJYMVTEFS-ICGCPXGVSA-N [(2r,3r,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-4-hydroxy-2-(hydroxymethyl)-4-methyloxolan-3-yl] (2s)-2-amino-3-methylbutanoate Chemical compound C[C@@]1(O)[C@H](OC(=O)[C@@H](N)C(C)C)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C=C1 TVRCRTJYMVTEFS-ICGCPXGVSA-N 0.000 description 1
- HOOMGTNENMZAFP-NYNCVSEMSA-N [(2r,3r,5s)-2-(5-amino-2-oxo-[1,3]thiazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)oxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1C[C@@H](CO)O[C@H]1N1C(=O)SC2=CN=C(N)N=C21 HOOMGTNENMZAFP-NYNCVSEMSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- MOQOOKGPCBQMCY-UHFFFAOYSA-N acetic acid;hexane Chemical class CC(O)=O.CCCCCC MOQOOKGPCBQMCY-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 208000037621 acute hepatitis C virus infection Diseases 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 229940054685 alinia Drugs 0.000 description 1
- 108010058359 alisporivir Proteins 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000005275 alkylenearyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940124425 anti-infective immunomodulator Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000005251 aryl acyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- 229960002118 asunaprevir Drugs 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 1
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 1
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000005513 benzoazaindolyl group Chemical group 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 150000005347 biaryls Chemical class 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000003858 bile acid conjugate Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- TVRFAOJPBXYIRM-UHFFFAOYSA-N bis(chloromethyl)-dimethylsilane Chemical compound ClC[Si](C)(C)CCl TVRFAOJPBXYIRM-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 231100000319 bleeding Toxicity 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 229960000517 boceprevir Drugs 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 235000010338 boric acid Nutrition 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical group C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000008004 cell lysis buffer Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- WPMJNLCLKAKMLA-VVPTUSLJSA-N chembl3039503 Chemical compound C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C#CC(C)(C)C)C(O)=O)[C@@H]1CC[C@@H](O)CC1 WPMJNLCLKAKMLA-VVPTUSLJSA-N 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic 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)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 1
- SZZZMXFBEKWPBU-UHFFFAOYSA-N chloromethyl-ethenyl-dimethylsilane Chemical compound ClC[Si](C)(C)C=C SZZZMXFBEKWPBU-UHFFFAOYSA-N 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229940055354 copegus Drugs 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- KFGVRWGDTLZAAO-UHFFFAOYSA-N cyclopenta-1,3-diene dicyclohexyl(cyclopenta-1,3-dien-1-yl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.C1CCC(CC1)P(C1CCCCC1)c1ccc[cH-]1 KFGVRWGDTLZAAO-UHFFFAOYSA-N 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
- FKRSSPOQAMALKA-CUPIEXAXSA-N daclatasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C=2C=CC(=CC=2)C=2N=C(NC=2)[C@H]2N(CCC2)C(=O)[C@@H](NC(=O)OC)C(C)C)=CN1 FKRSSPOQAMALKA-CUPIEXAXSA-N 0.000 description 1
- 229960005449 daclatasvir Drugs 0.000 description 1
- 229950002891 danoprevir Drugs 0.000 description 1
- 229960001418 dasabuvir Drugs 0.000 description 1
- NBRBXGKOEOGLOI-UHFFFAOYSA-N dasabuvir Chemical compound C1=C(C(C)(C)C)C(OC)=C(C=2C=C3C=CC(NS(C)(=O)=O)=CC3=CC=2)C=C1N1C=CC(=O)NC1=O NBRBXGKOEOGLOI-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- UDMJANYPQWEDFT-ZAWFUYGJSA-N deldeprevir Chemical compound C([C@@H]1C(=O)N2[C@H](C(N[C@@]3(C[C@H]3\C=C/CCCCC1)C(=O)NS(=O)(=O)C1CC1)=O)C[C@H](C2)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(C)C)C)OC)C(=O)N1CCCC(F)(F)C1 UDMJANYPQWEDFT-ZAWFUYGJSA-N 0.000 description 1
- BMAIGAHXAJEULY-UKTHLTGXSA-N deleobuvir Chemical compound C12=CC=C(C(=O)NC3(CCC3)C=3N(C4=CC(\C=C\C(O)=O)=CC=C4N=3)C)C=C2N(C)C(C=2N=CC(Br)=CN=2)=C1C1CCCC1 BMAIGAHXAJEULY-UKTHLTGXSA-N 0.000 description 1
- 125000000422 delta-lactone group Chemical group 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N delta-valerolactam Natural products O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 208000025729 dengue disease Diseases 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 1
- 125000000950 dibromo group Chemical group Br* 0.000 description 1
- LMEDOLJKVASKTP-UHFFFAOYSA-N dibutyl sulfate Chemical class CCCCOS(=O)(=O)OCCCC LMEDOLJKVASKTP-UHFFFAOYSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 1
- 125000005049 dihydrooxadiazolyl group Chemical group O1N(NC=C1)* 0.000 description 1
- 125000005050 dihydrooxazolyl group Chemical group O1C(NC=C1)* 0.000 description 1
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 125000005072 dihydrothiopyranyl group Chemical group S1C(CCC=C1)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ZODWTWYKYYGSFS-UHFFFAOYSA-N diphenyl-bis(prop-2-enyl)silane Chemical compound C=1C=CC=CC=1[Si](CC=C)(CC=C)C1=CC=CC=C1 ZODWTWYKYYGSFS-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000009088 enzymatic function Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- LLGDPTDZOVKFDU-XUHJSTDZSA-N faldaprevir Chemical compound N([C@H](C(=O)N1[C@@H](C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1N=C(NC(=O)C(C)C)SC=1)Br)OC)C(=O)N[C@]1([C@@H](C1)C=C)C(O)=O)C(C)(C)C)C(=O)OC1CCCC1 LLGDPTDZOVKFDU-XUHJSTDZSA-N 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- SLVAPEZTBDBAPI-GDLZYMKVSA-N filibuvir Chemical compound CCC1=NC(CC)=CC(CC[C@]2(OC(=O)C(CC3=NN4C(C)=CC(C)=NC4=N3)=C(O)C2)C2CCCC2)=C1 SLVAPEZTBDBAPI-GDLZYMKVSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 125000005643 gamma-butyrolacton-4-yl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 108010049353 golotimod Proteins 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002373 hemiacetals Chemical group 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 102000052620 human IL10 Human genes 0.000 description 1
- 102000011749 human hepatitis C immune globulin Human genes 0.000 description 1
- 108010062138 human hepatitis C immune globulin Proteins 0.000 description 1
- 244000052637 human pathogen Species 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000005945 imidazopyridyl group Chemical group 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 229960003521 interferon alfa-2a Drugs 0.000 description 1
- 108010055511 interferon alfa-2c Proteins 0.000 description 1
- 229960003358 interferon alfacon-1 Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000003903 lactic acid esters Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007942 layered tablet Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000007403 mPCR Methods 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- HYLGKOGJOVGRNN-UHFFFAOYSA-N methyl 2-(bromomethyl)-3-methoxybenzoate Chemical compound COC(=O)C1=CC=CC(OC)=C1CBr HYLGKOGJOVGRNN-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 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
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- IMVIXDCJEMBUAY-UHFFFAOYSA-N n-(2-bromonaphthalen-1-yl)acetamide Chemical compound C1=CC=C2C(NC(=O)C)=C(Br)C=CC2=C1 IMVIXDCJEMBUAY-UHFFFAOYSA-N 0.000 description 1
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 1
- XMZSTQYSBYEENY-RMKNXTFCSA-N n-[4-[(e)-2-[3-tert-butyl-5-(2,4-dioxopyrimidin-1-yl)-2-methoxyphenyl]ethenyl]phenyl]methanesulfonamide Chemical compound C1=C(N2C(NC(=O)C=C2)=O)C=C(C(C)(C)C)C(OC)=C1\C=C\C1=CC=C(NS(C)(=O)=O)C=C1 XMZSTQYSBYEENY-RMKNXTFCSA-N 0.000 description 1
- UUROSJLZNDSXRF-UHFFFAOYSA-N n-[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-2-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]-2-oxoacetamide Chemical compound C1=C(C(C)(C)C)C=C(NS(C)(=O)=O)C(OC)=C1NC(=O)C(=O)C(C1=CC=CC=C11)=CC=C1OCCN1CCOCC1 UUROSJLZNDSXRF-UHFFFAOYSA-N 0.000 description 1
- 125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- NTNWKDHZTDQSST-UHFFFAOYSA-N naphthalene-1,2-diamine Chemical compound C1=CC=CC2=C(N)C(N)=CC=C21 NTNWKDHZTDQSST-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004957 naphthylene group Chemical group 0.000 description 1
- 125000005244 neohexyl group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960002480 nitazoxanide Drugs 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229940042443 other antivirals in atc Drugs 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000005565 oxadiazolylene group Chemical group 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000005564 oxazolylene group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- UAUIUKWPKRJZJV-MDJGTQRPSA-N paritaprevir Chemical compound C1=NC(C)=CN=C1C(=O)N[C@@H]1C(=O)N2C[C@H](OC=3C4=CC=CC=C4C4=CC=CC=C4N=3)C[C@H]2C(=O)N[C@]2(C(=O)NS(=O)(=O)C3CC3)C[C@@H]2\C=C/CCCCC1 UAUIUKWPKRJZJV-MDJGTQRPSA-N 0.000 description 1
- 229960002754 paritaprevir Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 108010092851 peginterferon alfa-2b Proteins 0.000 description 1
- 229940106366 pegintron Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical class OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- RYXIBQLRUHDYEE-UHFFFAOYSA-M potassium;5-(cyclohexen-1-yl)-3-[(4-methoxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound [K+].C1CC(OC)CCC1N(C1=C(SC(=C1)C=1CCCCC=1)C([O-])=O)C(=O)C1CCC(C)CC1 RYXIBQLRUHDYEE-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- TTZHDVOVKQGIBA-IAAJYNJHSA-N propan-2-yl (2s)-2-[[[(2r,3r,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)COP(=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IAAJYNJHSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005494 pyridonyl group Chemical class 0.000 description 1
- 125000005551 pyridylene group Chemical group 0.000 description 1
- 125000005576 pyrimidinylene group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- MAROONSWSSXHPU-UHFFFAOYSA-N quinoline-2,3-diamine Chemical compound C1=CC=C2N=C(N)C(N)=CC2=C1 MAROONSWSSXHPU-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229940053146 rebetol Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 238000011894 semi-preparative HPLC Methods 0.000 description 1
- DEKOYVOWOVJMPM-RLHIPHHXSA-N setrobuvir Chemical compound N1([C@H]2[C@@H]3CC[C@@H](C3)[C@H]2C(O)=C(C1=O)C=1NC2=CC=C(C=C2S(=O)(=O)N=1)NS(=O)(=O)C)CC1=CC=C(F)C=C1 DEKOYVOWOVJMPM-RLHIPHHXSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229960002091 simeprevir Drugs 0.000 description 1
- 244000309458 single stranded enveloped RNA virus Species 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- SSERCMQZZYTNBY-UHFFFAOYSA-M sodium;3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-phenylthiophene-2-carboxylate Chemical compound [Na+].C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC=CC=1)C([O-])=O)C1CCC(O)CC1 SSERCMQZZYTNBY-UHFFFAOYSA-M 0.000 description 1
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 1
- 229960002063 sofosbuvir Drugs 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003900 succinic acid esters Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 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
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- BHTRKEVKTKCXOH-LBSADWJPSA-N tauroursodeoxycholic 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)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-LBSADWJPSA-N 0.000 description 1
- BFFLLBPMZCIGRM-QMMMGPOBSA-N tert-butyl (2s)-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1CO BFFLLBPMZCIGRM-QMMMGPOBSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000005556 thienylene group Chemical group 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000005730 thiophenylene group Chemical group 0.000 description 1
- 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 1
- 229960004231 thymalfasin Drugs 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000005559 triazolylene group Chemical group 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical class OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic 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)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- 125000005853 β-dimethylaminoethyl group Chemical group 0.000 description 1
- 150000003954 δ-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom
-
- 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
- A61K31/695—Silicon compounds
-
- 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
Definitions
- the present invention relates to novel Fused Tricyclic Silyl Compounds
- compositions comprising at least one Fused Tricyclic Silyl Compound, and methods of using the Fused Tricyclic Silyl Compounds for treating or preventing HCV infection in a patient.
- HCV Hepatitis C virus
- BB -NANBH blood-associated NANBH
- NANBH is to be distinguished from other types of viral-induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), delta hepatitis vims (HDV),
- HAV hepatitis A virus
- HBV hepatitis B virus
- HDV delta hepatitis vims
- CMV cytomegalovirus
- EBV Epstein-Barr virus
- HCV replication inhibition is a viable strategy for the prevention of hepatocellular carcinoma.
- Current therapies for HCV infection include a-interferon monotherapy and combination therapy comprising a-interferon and ribavirin. These therapies have been shown to be effective in some patients with chronic HCV infection, but suffer from poor efficacy and unfavorable side- effects and there are currently efforts directed to the discovery of HCV replication inhibitors that are useful for the treatment and prevention of HCV related disorders.
- chenodeoxycholic acid and conjugated bile acids (such as tauroursodeoxycholic acid).
- Phosphonoformic acid esters have also been proposed as potentially useful for the treatment of various viral infections, including HCV. Vaccine development, however, has been T/US2011/027117
- HCV NS5A is a 447 amino acid phosphoprotein which lacks a defined enzymatic function. It runs as 56kd and 58kd bands on gels depending on phosphorylation state (Tanji, et al J. Virol. 69:3980-3986 (1995)). HCV NS5A resides in replication complex and may be responsible for the switch from replication of RNA to production of infectious virus (Huang, Y, et al, Virology 364:1-9 (2007)).
- Multicyclic HCV NS5A inhibitors have been reported. See U.S. Patent Publication Nos. US20080311075, US20080044379, US20080050336, US20080044380, US20090202483 and US2009020478.
- HCV NS5A inhibitors having fused tricyclic moieties are disclosed in International Patent Publication Nos. WO 10/065681, WO 10/065668, and WO 10/065674.
- HCV NS5 A inhibitors and their use for reducing viral load in HCV infected humans have been described in U.S. Patent Publication No. US20060276511.
- the present invention provides Compounds of Formula (I)
- A is -alkylene-N(R 7 )(R n ), ⁇ alkylene-N(R 16 )(R 1 ! ), 4 to 7- membered monocyclic heterocycloalkyl, 4 to 7-membered monocyclic heterocycloalkenyl, 7 to 1 1- membered bicyclic heterocycloalkyl or R 15 , wherein said 4 to 7- membered monocyclic T U 2011/027117
- heterocycloalkyl group, said 4 to 7-membered monocyclic heterocycloalkenyl group, said 7 to 11 - membered bicyclic heterocycloalkyl group or said R ! 5 group can be optionally fused to a 3 to 7-membered cycloalkyl group, a 4 to 7-membered heterocycloalkyl group or an aryl group; and wherein said 4 to 7- membered monocyclic heterocycloalkyl group, said 4 to 7-membered monocyclic heterocycloalkenyl group, said 7 to 11- membered bicyclic heterocycloalkyl group or R 15 group can be optionally and independently substituted on one or more ring nitrogen atoms with R 4 , and on one or more ring carbon atoms with R i2 , such that two R J2 groups on the same ring carbon atom, together with the carbon atom to which they are attached, can join to form a spirocyclic 3 to 7-membered
- B is 5-membered monocyclic heteroarylene group or a 9-membered bicyclic heteroarylene group containing at least one nitrogen atom, wherein said 5-membered monocyclic heteroarylene group and said 9-membered bicyclic heteroarylene group can be optionally fused to a benzene, pyridine or pyrimidine ring, and wherein said 5-membered monocyclic heteroarylene group or its fused counterpart and said 9-membered bicyclic heteroarylene group or it's fused counterpart, can be optionally and independently substituted on one or more ring nitrogen atoms with R 6 and on one or more ring carbon atoms with R ;
- D is -alkylene-N(R 7 )(R u ), -alkylene-N(R i6 )(R u ), 4 to 7- membered monocyclic heterocycloalkyl, 4 to 7-membered monocyclic heterocycloalkenyl, 7 to 11- membered bicyclic heterocycloalkyl or R 15 , wherein said 4 to 7- membered monocyclic
- heterocycloalkyl group, said 4 to 7-membered monocyclic heterocycloalkenyl group, said 7 to 1 1 - membered bicyclic heterocycloalkyl group or said R 15 group can be optionally fused to a 3 to 7-membered cycloalkyl group, a 4 to 7-membered heterocycloalkyl group or an aryl group; and wherein said 4 to 7- membered monocyclic heterocycloalkyl group, said 4 to 7-membered monocyclic heterocycloalkenyl group, said 7 to 11- membered bicyclic heterocycloalkyl group or R 15 group can be optionally and independently substituted on one or more ring nitrogen atoms with R 4 , and on one or more ring carbon atoms with R 12 , such that two R 12 groups on the same ring carbon atom, together with the carbon atom to which P T/US2011/027117
- -N C(R 2 )-, -C(R ) 2 -0- ? -0-C(R 7 ) 2 -, -C(R 7 ) 2 -N(R 6 )- or -N(R 6 )-C(R 7 ) 2 - 3 such that two vicinal R groups of M , together with the carbon atoms to which they are attached, can optionally join to form a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group;
- X 1 is -C(R S )- or -N-;
- X 2 is -C(R 5 )- or -N-;
- each occurrence of R 1 is independently Ci-C 6 alkyl, ⁇ alkylene-0-(Ci-C6 alkyl), Cj-Ce haloalkyl, 3- to 7-membered cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl or heteroaryl, wherein said 3- to 7-membered cycloalkyl group, said 4- to 7-membered heterocycloalkyl group, said aryl group or said heteroaryl group can be optionally substituted with up to three groups, which can be the same or different, and are selected from Ci-C ⁇ j alkyl, 3- to 7-membered cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl, heteroaryl, halo, C,-C 6 haloalkyl, -Si(R t3 ) 3 , -CN, -OR 3 , -N(R 3 ) 2 , -C(0)R 10 ,
- each occurrence of R 3 is independently H, C C 6 alkyl, Ci-C 6 haloalkyl, -CrC 6 alkylene-OC(0)(Ci-C 6 alkyl), Q-Cehydroxyalkyl, 3 to 7-membered cycloalkyl, 4 to 7- membered heterocycloalkyl, aryl or heteroaryl wherein said 3- to 7-membered cycloalkyl group, said 4- to 7-membered heterocycloalkyl group, said aryl group or said heteroaryl group can be optionally and independently substituted with up to three groups
- each occurrence of R 4 is independently H, -Ci-C 6 alkyl, d-Ce haloalkyl, - [C(R 7 ) 2 ] q N(R 6 ) 2i -C(0)R 1 , -C ⁇ 0)-[C(R 7 ) 2 ] q N(R 6 ) 2 , -C(0)-[C(R 7 ) 2 ] q -R i ,-C(0)- -C(0)-[C(R 7 ) 2 ] q N(R 6 )C(0)0-R', - C(0)-[C(R 7 ) 2 ] q C(0)0-R 5 or -alkylene-N(R 6 )-[C(R 7 ) 2 ] q -N(R 6 )-C(0)0-R 1 ; U 2011/027117
- R 5 each occurrence of R 5 is independently H, Ci ⁇ C 6 alkyl, -Si(R !3 ) 3 , 3- to 7-mernbered cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl or heteroaryl;
- each occurrence of R 6 is independently H, Cs-C 6 alkyl, 3- to 7-membered cycloalkyl, 4 to 7-membered heterocycloalkyl, aryl or heteroaryl, wherein said 3- to 7-membered cycloalkyl group, said 4- to 7-membered heterocycloalkyl group, said aryl group or said heteroaryl group can be optionally and independently substituted with up to two R 8 groups, and wherein two R 6 groups that are attached to a common nitrogen atom, together with the nitrogen atom to which they are attached, can optionally join to form a 4- to 7-membered heterocycloalkyl group;
- each occurrence of R 7 is independently H, C]-Cg alkyl, Cj-C 6 haloalkyl,
- each occurrence of R 8 is independently H, Ci-C 6 alkyl, halo, -C] -C 6 haloalkyl, Ci-C 6 hydroxyalkyl, -OH, -C(0)NH-(C C 6 alkyl), -C(0)N(Ci -C 6 alkyl) 2 , -0-(C C 6 alkyl), -NH 2 , -NH(C,-C 6 alkyl), -N(C r C 6 alkyl) 2 and -NHC(0)-(C C 6 alkyl) or ⁇ Si(R B ) 3 ;
- each occurrence of R 10 is independently CrC 6 alkyl, Ci-C 6 haloalkyl, 3 to 7- membered cycloalkyl, 4 to 7-membered heterocycloalkyl, aryl, or heteroaryl;
- each occurrence of R ! 1 is independently H, -C-e alkyl, C]-C 6 haloalkyl, - [C(R ) 2 ] q N(R 6 ) 2 , -C(0)R l , -C(0)-[C(R 7 ) 2 ] q N(R 6 ) 2 ,
- each occurrence of R 12 is H, Cj-Ce alkyl, C C 6 haloalkyl, 3 to 7-membered cycloalkyl, 4 to 7-membered heterocycloalkyl, aryl, heteroaryl, halo, -CN, -OR 3 ,
- each occurrence of R 13 is independently selected from Ci-C 6 alkyl, 3- to 7- membered cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl, heteroaryl, Cj-C 6 haloalkyl, -CN and -OR 3 , wherein two R B groups, together with the silicon atom to which they are attached, can optionally join to form a 4- to 7-membered silicon-containing
- each occurrence of R is independently a monocyclic 5- to 7-membered
- one optional and additional heteroatom ring member elected from the group consisting of nitrogen, oxygen and sulfur, and wherein an R 15 group can be optionally and independently substituted on one or two ring carbon atoms with R ;
- R !6 is independently:
- heteroaryl has one or two ring nitrogen atoms and no other ring heteroatoms
- R 16 when R 16 is said 3 to 7-membered cycloalkyl group, said 4- to 7-membered heterocycloalkyl group, said phenyl group or said heteroaryl group, then R 16 can be optionally substituted with up to three groups, which can be the same or different, and are selected from C 3 -C 6 alkyl, halo, -C r C 6 haloalkyl, Ci-C 6 hydroxyalkyl, -OH, -C(0)NH-(C r C 6 alkyl), -C(0)N(Ci-C 6 alkyl) 2 , -0-(C C 6 alkyl), -NH 2> -NH(Ci-C 6 alkyl), -N(d-C 6 alkyl)2 and -NHC(0)-(C C 6 alkyl);
- each occurrence of R 17 is independently: (i) a 5- to 7-membered silylcycloalkyl ring having one -Si(R ] 3 ) 2 - ring member; or
- a 5- to 7-membered silylheterocycloalkyl ring having one -Si(R I3 ) 2 - ring member, and one to two heteroatom ring members, which can be the same or different, and are selected from the group consisting of nitrogen, oxygen, and sulfur, such that the -Si(R I3 ) 2 - group must be bonded only to ring carbon atoms; or
- R 17 group can be optionally and independently substituted on one or two ring carbon atoms with up to two R 12 groups;
- each occurrence of q is independently an integer ranging from 1 to 4; and each occurrence of r is independently an integer ranging from 0 to 6,
- a and D is R !S or ⁇ alkylene-N ⁇ R 16 )(R ! 1 ).
- the Compounds of Formula (I) (also referred to herein as the "Fused Tricyclic Silyl Compounds") and pharmaceutically acceptable salts thereof can be useful, for example, for inhibiting HCV viral replication or replicon activity, and for treating or preventing HCV infection in a patient. Without being bound by any specific theory, it is believed that the Fused Tricyclic Silyl Compounds inhibit HCV viral replication by inhibiting HCV NS5A.
- the present invention provides methods for treating or preventing HCV infection in a patient, comprising administering to the patient an effective amount of at least one Fused Tricyclic Silyl Compound.
- the present invention relates to novel Fused Tricyclic Silyl Compounds
- compositions comprising at least one Fused Tricyclic Silyl Compound, and methods of using the Fused Tricyclic Silyl Compounds for treating or preventing HCV infection in a patient.
- a "patient” is a human or non-human mammal. In one embodiment, a patient is a human. In another embodiment, a patient is a chimpanzee.
- an effective amount refers to an amount of Fused Tricyclic Silyl Compound and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from a viral infection or virus-related disorder.
- an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
- alkyl refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond.
- An alkyl group may be straight or branched and contain from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (C Gs alkyl) or from about 1 to about 4 carbon atoms (Cj-C 4 alkyl).
- alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n- hexyl, isohexyl and neohexyl.
- An alkyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O- alkyl,
- an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted,
- alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond.
- An alkenyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms.
- alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyt
- An alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O- alkyl, alkylthio, -N3 ⁇ 4, -NH(alkyl), -N(alkyl) 2 , -NH(cycloalkyl), -0-C(0)-alkyl, -O-C(O)- aryl, -0-C(0)-cycloalkyl, -C(0)OH and -C(0)0-alkyl.
- alkynyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and having one of its hydrogen atoms replaced with a bond.
- An alkynyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from 2011/027117
- an alkynyl group contains from about 2 to about 6 carbon atoms.
- alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
- An alkynyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -N3 ⁇ 4, - NH(alkyl), -N(alkyl) 2 , -NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and -C(0)0alkyl,
- C 2 -Q alkynyl refers to an alkynyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkynyl group is unsubstituted.
- alkylene refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond.
- alkylene groups include -CH 2 -, -03 ⁇ 403 ⁇ 4-, -CH 2 CH 2 CH 2 -, - CH2CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 ⁇ , -CH(CH 3 )- and -CH 2 CH(CH 3 )CH 2 -.
- an alkylene group has from 1 to about 6 carbon atoms.
- an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is -CH 2 -.
- the term "Ci-C 6 alkylene” refers to an alkylene group having from 1 to 6 carbon atoms.
- aryl refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains from about 6 to about 10 carbon atoms. An aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, an aryl group can be optionally fused to a cycloalkyl or cycloalkanoyl group. Non-limiting examples of aryl groups include phenyl and naphthyl. In one embodiment, an aryl group is phenyl. Unless otherwise indicated, an aryl group is unsubstituted.
- arylene refers to a bivalent group derived from an aryl group, as defined above, by removal of a hydrogen atom from a ring carbon of an aryl group.
- An arylene group can be derived from a monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an arylene group contains from about 6 to about 10 carbon atoms. In another embodiment, an arylene group is a naphthylene group. In another embodiment, an arylene group is a phenylene group.
- An arylene group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below.
- An arylene group is T/US2011/027117
- an arylene group can be optionally fused to a cycloalkyl or cycloalkanoyl group.
- arylene groups include phenylene and naphthalene.
- an arylene group is unsubstituted.
- an ar ene group is:
- cycloalkyl refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms. In one embodiment, a cycloalkyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkyl contains from about 3 to about 7 ring atoms. In another embodiment, a cycloalkyl contains from about 5 to about 6 ring atoms.
- cycloalkyl also encompasses a cycloalkyl group, as defined above, which is fused to an aryl (e.g., benzene) or heteroaryl ring.
- Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- Non-limiting examples of multicyclic cycloalkyls include 1-decalinyl, norbornyl and adamantyl.
- a cycloalkyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, a cycloalkyl group is unsubstituted.
- 3 to 7-membered cycloalkyl refers to a cycloalkyl group having from 3 to 7 ring carbon atoms. Unless otherwise indicated, a cycloalkyl group is unsubstituted. A ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group, An illustrative example of such a cycloalkyl group (also referred to herein as a "cycloalkanoyl” group) includes, but is not limited to, cyclobutanoyl:
- cycloaikenyl refers to a non-aromatic mono- or multicyclic ring system comprising from about 4 to about 10 ring carbon atoms and containing at least one endocyclic double bond. In one embodiment, a cycloaikenyl contains from about 4 to about 7 ring carbon atoms. In another embodiment, a cycloaikenyl contains 5 or 6 ring atoms.
- monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-l,3-dienyl, and the like.
- a cycloaikenyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below.
- a ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group.
- a cycloaikenyl group is cyclopentenyl.
- a cycloaikenyl group is cyclohexenyl.
- the term "4 to 7-membered cycloaikenyl” refers to a cycloaikenyl group having from 4 to 7 ring carbon atoms. Unless otherwise indicated, a cycloaikenyl group is unsubstituted.
- halo means -F, -CI, -Br or -I.
- haloalkyl refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 6 carbon atoms. In another
- a haloalkyl group is substituted with from 1 to 3 F atoms.
- haloalkyl groups include -CH 2 F, -CHF 2) -CF 3 , -CH 2 C1 and -CC1 3 .
- the term "Ci-C 6 haloalkyl” refers to a haloalkyl group having from 1 to 6 carbon atoms.
- hydroxyalkyl refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with an ⁇ OH group.
- a hydroxyalkyl group has from 1 to 6 carbon atoms.
- Non- limiting examples of hydroxyalkyl groups include -CH 2 OH, -CH2CH 2 OH, - CH 2 CH 2 CH 2 OH and -CH 2 CH(OH)CH 3 .
- C C 6 hydroxyalkyl refers to a hydroxyalkyl group having from 1 to 6 carbon atoms.
- heteroaryl refers to an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of 1 027117
- ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms.
- a heteroaryl group has 5 to 10 ring atoms.
- a heteroaryl group is monocyclic and has 5 or 6 ring atoms.
- a heteroaryl group is bicyclic.
- a heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
- a heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
- heteroaryl also encompasses a heteroaryl group, as defined above, which is fused to a benzene ring.
- heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,
- heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
- a heteroaryl group is a 5-membered heteroaryl
- a heteroaryl group is a 6-membered heteroaryl.
- a heteroaryl group comprises a 5- to 6-membered heteroaryl group fused to a benzene ring. Unless otherwise indicated, a heteroaryl group is unsubstituted.
- heteroarylene refers to a bivalent group derived from an heteroaryl group, as defined above, by removal of a hydrogen atom from a ring carbon or ring heteroatom of a heteroaryl group.
- a heteroarylene group can be derived from a monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms are each independently O, N or S and the remaining ring atoms are carbon atoms.
- a heteroarylene group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
- heteroarylene group is joined via a ring carbon atom or by a nitrogen atom with an open valence, and any nitrogen atom of a heteroarylene can be optionally oxidized to the corresponding N-oxide.
- heteroarylene also encompasses a heteroarylene group, as defined above, which is fused to a benzene ring.
- Non-limiting examples of heteroaryl enes include pyridylene, pyrazinylene, furanylene, thienylene, pyrimidinyl ene, 2011/027117
- pyridonylene (including those derived from N-substituted pyridonyls), isoxazolylene, isothiazolylene, oxazolylene, oxadiazolylene, thiazolylene, pyrazolylene, thiophenylene, furazanylene, pyrrolylene, triazolylene, 1,2,4-thiadiazolylene, pyrazinylene, pyridazinylene, quinoxalinylene, phthalazinylene, oxindolylene, imidazotl ⁇ -ajpyridinylene, imidazo[2,l- b] thiazolylene, benzofurazanylene, indolylene, azaindolylene, benzimidazolylene, benzothienylene, quinolinylene, imidazolylene, benzimidazolylene, thienopyridylene, quinazolinylene, thienopyrimidylene
- heteroarylene also refers to partially saturated heteroarylene moieties such as, for example, tetrahydroisoquinolylene,
- a heteroarylene group is divalent and either available bond on a heteroarylene ring can connect to either group flanking the heteroarylene group.
- a heteroarylene group is divalent and either available bond on a heteroarylene ring can connect to either group flanking the heteroarylene group.
- a heteroarylene group is a monocyclic heteroarylene group or a bicyclic heteroarylene group. In another embodiment, a heteroarylene group is a monocyclic heteroarylene group. In another embodiment, a heteroarylene group is a bicyclic heteroarylene group. In still another embodiment, a heteroarylene group has from about 5 to about 10 ring atoms. In another embodiment, a heteroarylene group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroarylene group is bicyclic and has 9 or 10 ring atoms. In another embodiment, a heteroarylene group is a 5-membered monocyclic heteroarylene.
- a heteroarylene group is a 6-membered monocyclic heteroarylene.
- a bicyclic heteroarylene group comprises a 5 or 6-membered monocyclic heteroarylene group fused to a benzene ring. Unless otherwise indicated, a heteroarylene group is unsubstituted.
- heterocycloalkyl refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 11 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S, N or Si, and the remainder of the ring atoms 2011/027117
- a heterocycloalkyl group can be joined via a ring carbon, ring silicon atom or ring nitrogen atom.
- a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms.
- a heterocycloalkyl group is monocyclic has from about 4 to about 7 ring atoms.
- a heterocycloalkyl group is bicyclic and has from about 7 to about 11 ring atoms.
- a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms.
- a heterocycloalkyl group is monocyclic.
- a heterocycloalkyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Any -NH group in a heterocycloalkyl ring may exist protected such as, for example, as an -N(BOC), -N(Cbz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention.
- the term "heterocycloalkyl” also encompasses a heterocycloalkyl group, as defined above, which is fused to an aryl (e.g., benzene) or heteroaryl ring.
- a heterocycloalkyl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
- the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
- monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,
- a ring carbon atom of a heterocycloalkyl group may be functional ized as a carbonyl group.
- An illustrative example of such a heterocycloalkyl group is; H
- a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered monocyclic heterocycloalkyl.
- the term "3 to 7-membered monocyclic cycloalkyl” refers to a monocyclic heterocycloalkyl group having from 3 to 7 ring atoms.
- the term "4 to 7- membered monocyclic cycloalkyl” refers to a monocyclic heterocycloalkyl group having from 4 to 7 ring atoms.
- 7 to 11-membered bicyclic heterocycloalkyl refers to a bicyclic heterocycloalkyl group having from 7 to 11 ring atoms. Unless otherwise indicated, an heterocycloalkyl group is unsubstituted.
- heterocycloalkenyl refers to a heterocycloalkyl group, as defined above, wherein the heterocycloalkyl group contains from 4 to 10 ring atoms, and at least one endocyclic carbon-carbon or carbon-nitrogen double bond.
- a heterocycloalkenyl group can be joined via a ring carbon or ring nitrogen atom.
- a heterocycloalkenyl group has from 4 to 7 ring atoms.
- heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heterocycloalkenyl group is bicyclic. A heterocycloalkenyl group can optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
- heterocycloalkenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2-dihydropyridinyl, 1 ,4- dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1 ,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyI, dihydrofuranyl, fluoro- substituted dihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl,
- a ring carbon atom of a heterocycloalkenyl group may be functionalized as a carbonyl group.
- a heterocycloalkenyl group is a 5-membered heterocycloalkenyl.
- a heterocycloalkenyl group is a 6-membered heterocycloalkenyl. The term "4 to 7-membered
- heterocycloalkenyl refers to a heterocycloalkenyl group having from 4 to 7 ring atoms. Unless otherwise indicated, a heterocycloalkenyl group is unsubstituted.
- ring system substituent refers to a substituent group attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system.
- Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene- heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, - alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C(0)-aryl, halo, -N0 2 , -CN, -SF 5 , - C(0)OH, -C(0)0-alkyl, -C(0)0-aryl, -C(0)0-alkylene-aryl, -S(0) 2 -alkyl, -alkyl, -alky
- Y s and Y 2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl.
- Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylenedioxy, ethylenedioxy, -C(CH 3 ) 2 - ample:
- silylalkyl refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a -Si(R*) 3 group, wherein each occurrence of R x is independently CrC 6 alkyl, phenyl or a 3- to 6- membered cycloalkyl group.
- a silylalkyl group has from 1 to 6 carbon atoms.
- a silyl alkyl group contains a -Si(CH 3 ) 3 moiety.
- Non- limiting examples of silylalkyl groups include
- substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group., provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
- stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
- substantially purified form refers to the physical state of a compound after the compound is isolated from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof.
- substantially purified form also refers to the physical state of a compound after the compound is obtained from a purification process or processes described herein or well-known to the skilled artisan ⁇ e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well-known to the skilled artisan.
- protecting groups When a functional group in a compound is termed "protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
- any substituent or variable e.g., alkyl, R 6 , R a , etc.
- its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- Prodrugs and solvates of the compounds of the invention are also contemplated herein.
- a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical T/US2011/027117
- prodrug means a compound ⁇ e.g., a drug precursor) that is transformed in vivo to provide a Fused Tricyclic Silyl Compound or a pharmaceutically acceptable salt or solvate of the compound.
- the transformation may occur by various mechanisms ⁇ e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
- a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Cj-Cg)alkyl, ⁇ -C ⁇ alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- 1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N)alkyl, ⁇ -C ⁇ alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1
- a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ct-Cejalkanoyloxymethyl, l-((Ci-C 6 )alkanoyloxy)ethyl, 1- methyl-1 -((Ci-Cg)alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N-(Cj- C6)alkoxycarbonylaminomethyl, succinoyl, (CrC 6 )alkanoyl, a-amino(Ci-C )alkyl, a- amino(Ci-C4)alkylene-aryl, arylacyl and a-aminoacyl, or ⁇ -aminoacyl-a-aminoacyl, where each ⁇ -aminoacyl group is independently selected from the
- a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl-, ROcarbonyl-, NRR'-carbonyl- wherein R and R' are each independently (Ci-Cio)alkyl, (C3-C7) cycloalkyl, benzyl, a natural a-aminoacyl,— C(OH)C(0)OY !
- Y 1 is H, (Ci-C 6 )alkyl or benzyl, — C(OY 2 )Y 3 wherein Y 2 is (C;-C 4 ) alkyl and Y 3 is (C C 6 )alkyl; carboxy (C C 6 )alkyl; amiiio(C C 4 )alkyl or mono-N- or di-N,N-(Ci-C 6 )alkylaminoalkyl; -C(Y )Y 5 wherein Y 4 is H or methyl and Y 5 is mono-N- or di-N ⁇ -id-Ceialkylami o morpholino; piperidin-l-yl or pyrrolidin-l-yl, and the like.
- esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy group of a hydroxyl compound, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (e.g., methyl, ethyl, n- propyl, isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (e.g., phenyl optionally substituted with, for example, halogen, Ci -4 alkyl, -0-(Ci- alkyl) or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfon
- the phosphate esters may be further esterified by, for example, a Ci. 2 o alcohol or reactive derivative thereof, or by a 2,3-di (C 6 . 2 )acyl glycerol.
- One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
- “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like. A “hydrate” is a solvate wherein the solvent molecule is water.
- One or more compounds of the invention may optionally be converted to a solvate.
- Preparation of solvates is generally known.
- the Fused Tricyclic Silyl Compounds can form salts which are also within the scope of this invention.
- Reference to a Fused Tricyclic Silyl Compound herein is understood to include reference to salts thereof, unless otherwise indicated.
- the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
- zwitterions may be formed and are included within the term "salt(s)" as used herein.
- the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt.
- the salt is other than a pharmaceutically acceptable salt.
- Salts of the Compounds of Formula (I) may be formed, for example, by reacting a Fused Tricyclic Silyl Compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
- Exemplary acid addition salts include acetates, ascorbates, benzoates,
- benzenesulfonates bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,
- methanesulfonates (“mesylates"), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like.
- a compound of formula (I) is present as its dihydrochloride salt.
- a compound of formula (I) is present as its dimesylate salt.
- acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G.
- Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like.
- alkali metal salts such as sodium, lithium, and potassium salts
- alkaline earth metal salts such as calcium and magnesium salts
- salts with organic bases for example, organic amines
- organic bases for example, organic amines
- amino acids such as arginine, lysine and the like.
- Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides ⁇ e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
- agents such as lower alkyl halides ⁇ e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl
- Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well-known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
- Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
- an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
- Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques. Also, some of the Fused Tricyclic Silyl
- Atropisomers e.g., substituted biaryls
- Enantiomers can also be directly separated using chiral chromatographic techniques.
- Fused Tricyclic Silyl Compounds may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.
- all keto-enol and imine-enamine forms of the compounds are included in the invention.
- All stereoisomers for example, geometric isomers, optical isomers and the like
- of the present compounds including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs, such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, 27117
- Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
- the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
- the use of the terms "salt”, “solvate 11 , “ester”, “prodrug” and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
- the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
- the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
- different isotopic forms of hydrogen (H) include protium and deuterium ( 2 H).
- Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
- Isotopically-enriched Compounds of Formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the ait or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
- a Compound of Formula (I) has one or more of its hydrogen atoms replaced with deuterium.
- DMF is NN-dimethylformamide
- dppf is diphenylphosphinoferrocene
- DMSO is dimethylsulfoxide
- EtOAc is ethyl acetate
- Et 2 0 is diethyl ether
- Et 3 N is triethylamine
- HATU is 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafiuorophosphate
- Hg(OAc) 2 is mercuric acetate
- HPLC high performance liquid chromatography
- HRMS is high resolution mass spectrometry
- KOAc is potassium acetate
- Lawesson's Reagent is 2,4- Bis(4-methoxyphenyl)-l,3-dithiadiphosphetane-2 J 4-disulfide
- LCMS is liquid
- LCMS low resolution mass spectrometry
- mCPBA m-chloroperbenzoic acid
- MeOH is methanol
- MTBE is feri-butylmethyl ether
- NBS is N-bromosuccinimide
- NH 4 OAc is ammonium acetate
- Pd(PPh 3 ) 4 is
- PdCi 2 (dppf)2 is [1.1 '-
- PdC ⁇ Cdppf CHbCb is [l,V- Bis(diphenylphosphino)ferrocene] dichloro palladium(II) complex with dichioromethane; pinacol 2 B 2 is bis(pinacolato)diboron; PPTS is pyridinium p-toluene sulfonate; RPLC is reverse-phase liquid chromatography; SEM-C1 is 2-(trimethylsilyl)ethoxymethyl chloride; TBAF is tetrabutylammonium fluoride; TBAI is tetrabutylammonium iodide; TBDMSCl is fert-butyldimethylsilyl chloride; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TLC is thin-layer chromatography; XPhos is 2-
- the pres nt invention provides Fused Tricyclic Silyl Compounds of Formula (I):
- A is selected from:
- A is selected from:
- B is a 5-membered monocyclic heteroarylene.
- B is:
- C is a monocyclic heteroarylene.
- C is a 6-membered monocyclic heteroarylene.
- C is a 5-membered monocyclic heteroarylene.
- C is a bicyclic heteroarylene.
- C is:
- R is an optional ring substituent selected from F, -OCH 3 , pyridyl, -OCH 2 CH 2 OH, ⁇ OCH 2 CH 2 OC(0)CH 3 , cyclopropyl and thiophenyl.
- D is selected from:
- a and D are each independently
- a and D are each selected from:
- R 4 is T/US2011/027117
- B is a 5-membered monocyclic heteroarylene
- R is an optional ring substituent selected from F, -OCH3, pyridyl,
- the Compounds of Formula (I) have the formula (la):
- A is -alkylene-N(R 7 )(R n ), -allcylene-N(R 16 )(R n ), 4 to 7- membered monocyclic heterocycloalkyl, 7 to 11- membered bicyclic heterocycloalkyl or R 15 , wherein said 4 to 7- membered monocyclic heterocycloalkyl group, said 7 to 11- membered bicyclic heterocycloalkyl group or said R 15 group can be optionally fused to a 3 to 7-membered cycloalkyl group, a 4 to 7-membered heterocycloalkyl group or an aryl group; and wherein said 4 to 7- membered monocyclic heterocycloalkyl group, said 7 to 11- membered bicyclic heterocycloalkyl group or R 15 group can be optionally and independently substituted on one or more ring nitrogen atoms with R 4 , and on one or more ring carbon atoms with R 12 , such that two
- D is -alkylene-N(R 7 )(R n ), ⁇ alkylene-N(R !6 )(R u ), 4 to 7- membered monocyclic heterocycloalkyl, 7 to 11- membered bicyclic heterocycloalkyl or R 15 , wherein said 4 to 7- membered monocyclic heterocycloalkyl group, said 7 to 11- membered bicyclic heterocycloalkyl group or said R 15 group can be optionally fused to a 3 to 7-membered cycloalkyl group, a 4 to 7-membered heterocycloalkyl group or an aryl group; and wherein said 4 to 7- membered monocyclic heterocycloalkyl group, said 7 to 1 1 - membered bicyclic heterocycloalkyl group or R 15 group can be optionally and independently substituted on one or more ring nitrogen atoms with R 4 , and on one or more ring carbon atoms with R 12 ,
- A is selected from:
- A is selected from: T/US2011/027117
- B is a 5 -membered monocyclic heteroarylene group containing at least one nitrogen atom, wherein said 5- membered monocyclic heteroarylene group can be optionally fused to a benzene, pyridine or pyrimidine ring, and wherein said 5-membered monocyclic heteroarylene group or its fused counterpart, can be optionally and independently substituted on one or more ring nitrogen atoms with K 6 and on one or more ring carbon atoms with R 1 .
- B is a 5-membered monocyclic heteroarylene.
- B is:
- C is a monocyclic heteroarylene.
- C is a 6-membered monocyclic heteroarylene.
- C is a 5-membered monocyclic heteroarylene.
- C is a bicyclic heteroarylene.
- C is 11 027117
- R is an optional ring substituent selected from halo, 3- to 7-membered cycioalkyl, 5- or 6-membered heteroaryl, 0-(Ci-C 6 alkyl), -0-(C]-C 6 hydroxyalkyl) and -0-(C r C 6 alkylene)-OC(0)-(C C 6 alkyl).
- C is:
- K i2 is an optional ring substituent selected from F, -OCH 3 , pyridyl,
- D is selected from:
- D is selected from:
- a and D are each independently selected from:
- a and D are each independently selected from:
- a and D are each independently a 4 to 7- membered monocyclic heterocycloalkyl, 7 to 1 1- membered bicyclic heterocycloalkyl or R 15 , wherein said 4 to 7- membered monocyclic heterocycloalkyl group or said R 15 group can be optionally fused to a 3 to 7-membered cycloalkyl group, a 4 to 7- membered heterocycloalkyl group or an aryl group; and wherein said 4 to 7- membered monocyclic heterocycloalkyl group can be optionally and independently substituted on one or more ring nitrogen atoms with R 4 , and on one or more ring carbon atoms with R 12 , such that two R 12 groups on the same ring carbon atom, together with the carbon atom to which they are attached, can join to form a spirocyclic 3 to 7-membered cycloalkyl group, or a spirocyclic 4
- a and D are each independently selected from:
- B is a 5-membered monocyclic heteroarylene
- R 12 is an optional ring substituent selected from F, -OCH 3; pyridyl,
- a and D are each independently selected from:
- R is an optional ring substituent selected from F, -OCH 3 , pyridyl,
- A, C, D, M 1 , X ! and X 2 are defined above for the Compounds of Formula (la) and B is 5-membered monocyclic heteroaryiene group containing at least one nitrogen atom, wherein said 5-membered monocyclic heteroaryiene group can be optionally fused to 11 027117
- a benzene, pyridine or pyrimidine ring and wherein said 5-membered monocyclic heteroarylene group or its fused counterpart, can be optionally and independently substituted on one or more ring nitrogen atoms with R 6 and on one or more ring carbon atoms with R 12 .
- A is ⁇ -alkylene-N(R 7 )(R n ). In another embodiment, for the Compounds of Formula (lb), A is -alkylene- N(R ,6 )(R n ).
- A is a 4 to 7-membered heterocycloalkyl.
- A is R ! 5 .
- A is selected from:
- A is selected from:
- A is selected from:
- A is selected from:
- A is , wherein each occurrence of R is independently H
- A is selected from:
- R is H, alkyl, haloalkyl, 3 to 7- membered cycloalkyl, 4 to 7- membered heterocycloalkyl, aryl or heteroaryl and R a is alkyl, haloalkyl, silylalkyl, 3 to 7- membered cycloalkyl or 4 to 7- membered heterocycloalkyl, aryl or heteroaryl.
- A is selected from:
- R 4 is: , wherein R a is H, methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, -CH 2 CH 2 Si(CH3)3, -C3 ⁇ 4CH 2 CF 3 , pyranyl, benzyl or phenyl, and R ! is methyl, ethyl or isopropyl.
- A is selected from:
- A is:
- A is -alkylene- N(alkyl)-C(0)-CH(alkyl)-NHC(0)0-alkyl, -alkylene-N(cycloa!kyl)-C(0)-CH(alkyl)- NHC(0)0-alkyl, -alkylene-N(cycloalkyl)-C(0)-CH(cycloalkyl)-NHC(0)0-alkyl J - alkyiene-N(cycloalkyl)-C(0)-CH(aryl)-NHC(0)0-alkyl or -alkylene-N(cycloalkyl)-C(0)- CH(heteroary!)-NHC(0)0-alkyl.
- B is a 5-membered monocyclic heteroarylene.
- B is:
- C is a monocyclic heteroarylene.
- C is a 6-membered monocyclic heteroarylene.
- C is a 5-membered monocyclic heteroarylene.
- C is abicyclic heteroarylene.
- R is an optional ring substituent selected from halo, 3- to 7-membered cycloalkyl, 5- or 6-membered heteroaryl, - 0-(C r C 6 alkyl), -0-(Ci-C 6 hydroxyalkyi) and -0-(C r C 6 alkylene)-OC(0)-(Ci-C 6 alkyl).
- R is an optional ring substituent selected from F, -OCH 3 , pyridyl,
- D isTMalkylene-N(R 7 )(R H ). In another embodiment, for the Compounds of Formula (lb), D is -alkylene- N(R 16 )(R n ).
- D is a 4 to 7-membered heterocycloalkyl.
- D is R 15 .
- D is selected from:
- D is selected from:
- D is selected from:
- D is selected from ;
- D is , wherein each occurrence of R 12 is independently H or F.
- D is selected from:
- R 4 is , wherein R 1 is H, alkyl, haloalkyl, 3 to 7- membered cycloalkyl, 4 to 7- membered heterocycloalkyi, aryl or heteroaryl and R a is alkyl, haloalkyl, silyialkyl, 3 to 7- membered cycloalkyl or 4 to 7- membered heterocycloalkyi, aryl or heteroaryl.
- D is selected from:
- R a is H, methyl, ethyl, propyl, isopropyl, -butyl, cyclopropyl, -CH 2 CH 2 Si(CH 3 )3, -CH 2 CH 2 CF 3 , pyranyl, benzyl or phenyl, and R 1 is methyl, ethyl or isopropyl.
- D is selected from:
- D is:
- R is independently H or F; and R 4 is
- D is:
- D is -alkylene- N(alkyl)-C(0)-CH(alkyl)-NHC(0)0-alkyl ; -alkylene-N(cycloalkyl)-C(0)-CH(alkyl)- NHC(0)Oalkyl, -alkylene-N(cycloalkyl)-C(0)-CH(cycloalkyl)-NHC(0)0-alkyl, - alkylene-N(cycloalkyl)-C(0)-CH(aryl)-NHC(0)0-alkyl or-alkylene-N(cycloa!kyl)-C(0)- CH(heteroaryl)-NHC(0)0-alkyl.
- M 1 is a bond.
- M 1 is -S(0) 2-
- M ! is -0-.
- M 1 is -C(R 7 ) 2 -.
- M 1 is -CH 2 -.
- M 1 is -N(R 6 )-.
- M 5 is a bond.
- M 1 is -CH-CH-.
- M s is -CH-N-.
- M 1 is -C(R 7 ) 2 -0-.
- M is -0-C(R ) 2 -.
- M 1 is -C(R 7 ) 2 -
- M 1 is -N(R 6 )-C(R 7 ) 2 -
- X C(R )-.
- X 1 N-.
- X 1 is -CH-.
- X 2 is -CH-.
- X 1 and X 2 are each -CH-.
- each of A and D is R i 5 .
- a and D are each independently
- a and D are each independently selected from:
- one of A and D is 1 5 and the other is selected from:
- one of A and D is and the other is selected from:
- one of A and D is selected from:
- one of A and D is R and the other is selected from: and each occurrence of R 4 is
- one of A and D is:
- each occurrence of R is independently H or F; the other of A and D is selected from:
- M is a bond
- M 1 is -S(0) 2- In another embodiment, for the Compounds of Formula (lb), M 1 is -0-.
- M is -C(R ) -.
- M 1 is -C3 ⁇ 4-.
- M 1 is ⁇ N(R 6 )-
- M 1 is a bond.
- M 1 is -C(R 7 ) 2 -0-, In another embodiment, for the Compounds of Formula (lb), M 1 is -0-C(R 7 ) 2 -, In yet another embodiment, for the Compounds of Formula (lb), M 1 is -C(R 7 ) 2 -
- M is -N(R )-C(R ) 2
- X ! (R 5 )-.
- X 1 is -N-.
- X 1 is -CH-.
- X is ⁇ (R )-.
- X 2 N-.
- X 2 is -CH-.
- X and X are each -CH
- C is phenylene, 5- or 6- membered monocyclic heteroarylene or 9-membered bicyclic heteroarylene, wherein said phenylene group, said 5- or 6-membered monocyclic heteroarylene group or said 9-membered bicyclic heteroarylene group can be optionally and independently substituted with up to two groups, which can be the same or different, and are selected from halo, 3- to 7-membered cycloalkyl, 5- or 6-membered heteroaryl, -0(CrC 6 alkyl), -0-(Ci-C 6 hydroxyalkyl), or -0-(C,-C 6 alkyl ene)-OC(0)-(Ci-Q alkyl);
- each occurrence of Z is independently -Si(R x ) 2 -, -C(R y ) 2 - or - ⁇ S(0) 2 -, such that at least one occurrence of Z is -Si(R ) 2 -; each occurrence of R x is independently Ci-C 6 alkyl or two R groups that are attached to the same Si atom, combine to form a ⁇ 3 ⁇ 4) 4 - or ⁇ (CH 2 )s- group; and
- each occurrence of R y is independently H or F;
- each occurrence of R 1 is independently Cj-C 6 alkyl
- each occurrence of R 4 is independently -C(0)CH(R 7 )NHC(0)OR 1 ;
- each occurrence of R 7 is independently Cj-C 6 alkyl, Cj-Ce silylalkyl or 4 to 7- membered heterocycloalkyl;
- C is:
- R is a single ring substituent selected from halo, 3- to 7-membered cycloalkyl, 5- or 6-membered heteroaryl, -0-(C ⁇ ⁇ Ce alkyl), -0-(CrC 6 hydroxyalkyl) and - 0-(C r C 6 alkylene)-OC(0)-(Ci-C 6 alkyl).
- R is an optional ring substituent selected from F, -OCH 3 , pyridyl,
- each occurrence of t is independently 1 or 2.
- each occurrence of t is 1.
- one occurrence of Z is -Si(R x ) 2 - and the other is ⁇ C(R y ) 2 -.
- each occun-ence of Z is -Si(R x ) 2 -
- each occurrence of Z is -C(R y ) 2 -.
- one occurrence of Z is -Si(C3 ⁇ 4) 2 - and the other is -C(R y ) 2 ⁇ .
- each occurrence of Z is independently -Si(R ) 2 - or -C(R y ) 2 -;
- each occurrence of R x is independently Ci-C 6 alkyl or two R x groups that are attached to the same Si atom, combine to form a ⁇ CH 2 )4- or -(CH 2 )s- group;
- each occurrence of R y is independently H or F
- one occurrence of Z is ⁇ Si(R x ) 2 - and the other is -C(R y ) 2 -.
- each occurrence of Z is -Si(R x ) 2 -.
- one occurrence of is -CF 2 -.
- one occurrence of Z -Si(CH 3 ) 2 - and the other is -CF 2 -.
- Z a is -Si(R x ) 2 -;
- Z b is ⁇ C(RV;
- each occurrence of R x is independently Ci-C 6 aikyl or two R x groups that are attached to the same Si atom, combine to form a -(CH 2 )4- or ⁇ (CH 2 ) 5 - group;
- each occurrence of R y is independently H or F.
- each occurrence of R x is methyl, of Z is -CF 2 -.
- each occurrence of R y is F.
- variables A, B, C, D, M 1 , X 1 and X 2 in the Compounds of Formula (I) are selected independently from each other.
- a Compound of Formula (I) is in substantially purified form.
- Other embodiments of the present invention include the following:
- composition comprising an effective amount of a Compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a
- HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
- a pharmaceutical combination that is (i) a Compound of Formula ( ⁇ ) and (ii) a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti -infective agents; wherein the Compound of Formula (I) and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HCV replication, or for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
- HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
- HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors. 1 027117
- (j) A method of inhibiting HCV replication in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).
- (k) A method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).
- the present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) inhibiting HCV replication or (b) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
- the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HCV antiviral agents, anti-infective agents, and immunomodulators.
- Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(k) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.
- compositions and methods provided as (a) through (k) above are understood to include all embodiments of the compounds, including such embodiments as result from combinations of embodiments.
- Non-limiting examples of the Compounds of Formula (I) include compounds 1-106, as set forth below.
- Compounds 1, 2, 15, 16, 20, 42, 44-51, 53-58, 60, 61, 65-67, 70-74, 76- 81, 83-97 and 99-106 were made using the methods described in the Schemes and Examples herein.
- Compounds 3-14, 17-19, 21-41, 43, 52, 59, 62-64, 68, 75, 82 and 98 can be made using the methods described in the Schemes and Examples herein.
- the Compounds of Formula (I) may be prepared from known or readily prepared starting materials, following methods known to one skilled in the ait of organic synthesis. Methods useful for making the Compounds of Formula (I) are set forth in the Examples below and generalized in Schemes 1-8 below. Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis. All stereoisomers and tautomeric forms of the compounds are contemplated.
- Scheme 1 shows a method useful for making the naphthyl imidazole compounds of formula A7 and A8, which are useful intermediates for making the Compounds of Formula
- Nitration of bromonaphthyl acetamide Al provides nitro analog A2 (J. Am. Chem. Soc, 73:4297 (1997)).
- the removal of acetyl group under acidic conditions followed by reduction of the nitro group should afford diaminonaphthalene A4.
- Coupling of the aniline to a cyclic or acyclic TV-protected a-amino acid A5 gives an amide of formula A6, which upon heating in acetic acid will cyclize to provide tricyclic bormonaphthylimidazole A7.
- the bromide could be converted to a boronate A8 with a palladium catalyst.
- Scheme 2 shows a method useful for making the quinolineimidazole compounds of formula B6, which are useful intermediates for making the Compounds of Formula (I).
- aminonitroquinoline Bl can be reduced to diaminoquinoline B2, which is then coupled to a cyclic or acyclic N-protected a-amino acid AS to providean amide B3. It can then be cyclized to quinolineimidazole B4 under acidic conditions. N- oxide B5 can then be obtained with w-chloroperbenzoic acid. Upon treatment with phosphorous oxychloride, B5 should give the desired chloroquinoline B6, which can used in Suzuki coupling reactions.
- Scheme 3 shows a method useful for making the boronic acid compounds of formula C4, which are useful intermediates for making the Compounds of Formula (I), where in “C” is a monocyclic 5 to 6-membered heteroaryl (examples: thiophene or pyridine).
- the Suzuki coupling partner C3 or C4 can be prepared from commercially available heteroaryl bromoacetyl compound of formula CI (Scheme 3).
- an N-protected amino acid PG-AA-OH
- DIPEA an amine base
- a ketoester C2 is formed. If heated together with ammonium acetate, the ketoester is converted to the desired imidazole derivative C3.
- the bromide can then be converted to a boronate C4 with a palladium catalyzed reaction.
- Scheme 4 shows methods useful for making the compounds of formula CI and C3, which are useful intermediates for making the Compounds of Formula (I), wherein variable C is other than a bond and B is an imidazole ring.
- heteroaryl bromoacetyl CI When heteroaryl bromoacetyl CI is not commercially available, it can be prepared by performing Friedel-Crafts acylation on a heteroaryl bromide of formula Dl using well- known methods, (e.g., those described in ricka et al, J. Chem. Soc. Per n Trans I 859- 863 (1973), and Kricka et al, Chem. Rew., 74, 101-123, (1974)) to provide the acylated products of formula D2.
- a compound of formula D2 can then be brominated using bromine, for example, to provide the compounds of formula CI.
- bromo-iodo substituted heteroaromatic rings D3 can undergo a
- Stilie coupling with (a-ethoxyvinyl) tributylstannane in the presence of a palladium catalyst using the methods including, but not limited to those described in Choshi et al., J. Org. Chem., 62:2535-2543 (1997), and Scott et al , J. Am. Chem. Soc, 106:4630 (1984)), to provide the ethyl-vinyl ether intermediate D4.
- Treating D4 with N-bromosuccimide gives the desired bromoacetyl intermediate CI, which can then be elaborated to advanced intermediates C3 or C4 for Suzuki coupling.
- a heteroaromatic dibromide of formula D5 can be lithiated using n- butyl lithium and then quenched with N-Boc- glycine Weinreb amide to provide a Boc- protected ⁇ -keto amino compound of formula D6.
- Removal of the Boc group using TFA for example, provides an amine compound of formula D7, which can then be coupled with an N -protected amino acid using typical amide bond forming reagents such as HATU to provide a ketoamide compound of formula D8.
- compound D8 Upon heated in the presence of ammonium acetate, compound D8 can be cyclized to the imidazole analog of formula C3.
- Scheme 5 shows a method useful for making the boronic acid compounds of formula E4, which are useful intermediates for making the Compounds of Formula (I).
- a heteroaromatic diamine El could be converted to a bicyclic imidazole E3 using the two step coupling-cyclization procedure described, for example, in Scheme 3.
- the corresponding boronate E4 can then easily be obtained from bromide E3 via well-known 1 027117
- Scheme 6 shows methods useful for making the Compounds of Formula (I) via a Suzuki Coupling process.
- a Suzuki coupling between protected imidazole boronate C4 (or boronic acid, not shown) and the fused bi-aryl tricyclic bromide A6 using, for example, the methods described in Angew Chem. Int. Ed. Engl. , 40 ? 4544 (2001) provide the compounds of formula Gl.
- Compounds of formula Gl can then be used to provide compounds of formula G2 by removal of the nitrogen protecting groups of Gl.
- An appropriate cap of group R can be added to the deprotected amino groups of G2 using reactions including, but not limited to acylation (with an acyl chloride or amino acid coupling reagent such as HATU or HOBt/EDCI), sulfonylation (with a sulfonyl chloride) or alkylation (with alkyl halide or reductive amination) to provide the desired Compounds of Formula (I).
- acylation with an acyl chloride or amino acid coupling reagent such as HATU or HOBt/EDCI
- sulfonylation with a sulfonyl chloride
- alkylation with alkyl halide or reductive amination
- Scheme 7 shows alternative methods useful for making the Compounds of Formula (I) via a Suzuki Coupling process.
- a bicyclic bromide of formula E3 and fused tricyclic boronate of formula A7 can be joined using the methods described in Scheme 6 above, to provide coupled intermediates of formula HI.
- the compounds of formula HI can then be further elaborated using, for example, the methods described in Scheme 6 above, to provide the Compounds of Formula (I), wherein C is a bond and B is a bicyclic heteroarylene group.
- ⁇ N ⁇ y N / ⁇ - ⁇ - ⁇ ⁇ . t N--7 ⁇ - ⁇ ⁇ .
- a boronate of formula C4 and chloroquinolineimidazole of formula B6 can be coupled under Suzuki coupling conditions similar to the methods described above to provideproducts of formula II, which can be transformed to the final targets of formula 13, using methods well-known to those skilled in the art of organic synthesis, including those described in Scheme 6 above.
- the amino acids such as, but not limited to proline, 4,4-difluoroproline, (S)-2-piperidine carboxylic acid, valine, alanine, norvaline, etc.
- the amino acids are incorporated as part of structures.
- amide bonds include but are not limited to, the use of a reactive carboxy derivative (e.g., an acid halide, or ester at elevated temperatures) or the use of an acid with a coupling reagent (e.g. , HOBt, EDCI, DCC, HATU, PyBrop) with an amine.
- a reactive carboxy derivative e.g., an acid halide, or ester at elevated temperatures
- a coupling reagent e.g. , HOBt, EDCI, DCC, HATU, PyBrop
- Such materials can be characterized using conventional means, including physical constants and spectral data.
- the Fused Tricyclic Silyl Compounds are useful in human and veterinary medicine for treating or preventing a viral infection in a patient.
- the Fused Tricyclic Silyl Compounds can be inhibitors of viral replication.
- the Fused Tricyclic Silyl Compounds can be inhibitors of HCV replication. Accordingly, the Fused Tricyclic Silyl Compounds are useful for treating viral infections, such as HCV.
- the Fused Tricyclic Silyl Compounds can be administered to a patient in need of treatment or prevention of a viral infection.
- the invention provides methods for treating a viral infection in a patient comprising administering to the patient an effective amount of at least one Fused Tricyclic Silyl Compound or a pharmaceutically acceptable salt thereof.
- the Fused Tricyclic Silyl Compounds can be useful for treating or preventing a viral infection caused by the Flaviviridae family of viruses.
- Flaviviridae infections that can be treated or prevented using the present methods include but are not limited to, dengue fever, Japanese encephalitis, yasanur Forest disease, Murray Valley encephalitis, St. Louis encephalitis, Tick-borne encephalitis, West Nile encephalitis, yellow fever and Hepatitis C Virus (HCV) infection.
- dengue fever Japanese encephalitis
- yasanur Forest disease Murray Valley encephalitis
- St. Louis encephalitis St. Louis encephalitis
- Tick-borne encephalitis West Nile encephalitis
- West Nile encephalitis yellow fever
- HCV Hepatitis C Virus
- the Flaviviridae infection being treated is hepatitis C virus infection.
- the Fused Tricyclic Silyl Compounds are useful in the inhibition of HCV (e.g., HCV NS5 A), the treatment of HCV infection and/or reduction of the likelihood or severity of symptoms of HCV infection and the inhibition of HCV viral replication and/or HCV viral production in a cell-based system.
- HCV e.g., HCV NS5 A
- the Fused Tricyclic Silyl Compounds are useful in treating infection by HCV after suspected past exposure to HCV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery or other medical procedures.
- the hepatitis C infection is acute hepatitis C. In another embodiment, the hepatitis C infection is chronic hepatitis C.
- the invention provides methods for treating HCV infection in a patient, the methods comprising administering to the patient an effective amount of at least one Fused Tricyclic Silyl Compound or a pharmaceutically acceptable salt thereof.
- the amount administered is effective to treat or prevent infection by HCV in the patient.
- the amount administered is effective to inhibit HCV viral replication and/or viral production in the patient.
- the Fused Tricyclic Silyl Compounds are also useful in the preparation and execution of screening assays for antiviral compounds.
- the Fused Tricyclic Silyl Compounds are useful for identifying resistant HCV replicon cell lines harboring mutations within NS5A, which are excellent screening tools for more powerful antiviral compounds.
- the Fused Tricyclic Silyl Compounds are useful in establishing or determining the binding site of other antivirals to the HCV replicase.
- compositions and combinations of the present invention can be useful for treating a patient suffering from infection related to any HCV genotype.
- HCV types and subtypes may differ in their antigenicity, level of viremia, severity of disease produced, and response to interferon therapy as described in Holland et al. , Pathology, 30(2): 192- 195 (1998).
- the nomenclature set forth in Simmonds et al., JGen Virol, 74(Ptl l :2391-2399 (1993) is widely used and classifies isolates into six major genotypes, 1 through 6, with two or more related subtypes, e.g., la and lb.
- genotypes 7-10 and 1 1 have been proposed, however the phylogenetic basis on which this classification is based has been questioned, and thus types 7, 8, 9 and 11 isolates have been reassigned as type 6, and type 10 isolates as type 3 (see Lamballerie et al., J Gen Virol, 78(Ptl):45-51 (1997)).
- the major genotypes have been defined as having sequence similarities of between 55 and 72% (mean 64.5%), and subtypes within types as having 75%-86% similarity (mean 80%) when sequenced in the NS-5 region (see Simmonds et al. , J Gen Virol, 75(Pt 5): 1053-1061 (1994)).
- the present methods for treating or preventing HCV infection can further comprise the administration of one or more additional therapeutic agents which are not Fused Tricyclic Silyl Compounds.
- the additional therapeutic agent is an antiviral agent.
- the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressive agent.
- the present invention provides methods for treating a viral infection in a patient, the method comprising administering to the patient: (i) at least one Fused Tricyclic Silyl Compound, or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than a Fused Tricyclic Silyl Compound, wherein the amounts administered are together effective to treat or prevent a viral infection.
- therapeutic agents in the combination may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
- the amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
- a Fused Tricyclic Silyl Compound and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g. , a capsule, a tablet and the like).
- the at least one Fused Tricyclic Silyl Compound is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
- the at least one Fused Tricyclic Silyl Compound and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a viral infection.
- the at least one Fused Tricyclic Silyl Compound and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a viral infection.
- the at least one Fused Tricyclic Silyl Compound and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a viral infection.
- the at least one Fused Tricyclic Silyl Compound and the additional therapeutic agent(s) are present in the same composition.
- this composition is suitable for oral administration.
- this composition is suitable for intravenous administration.
- this composition is suitable for subcutaneous administration.
- this composition is suitable for parenteral administration.
- Viral infections and virus-related disorders that can be treated or prevented using the combination therapy methods of the present invention include, but are not limited to, those listed above.
- the viral infection is HCV infection.
- the at least one Fused Tricyclic Silyl Compound and the additional therapeutic agent(s) can act additively or synergistically, A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy.
- Compound and the additional therapeutic agent(s) may inhibit the resistance of a viral infection to these agents.
- Non-limiting examples of additional therapeutic agents useful in the present compositions and methods include an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating an RNA-dependent polymerase-related disorder.
- the additional therapeutic agent is a viral protease inhibitor. In another embodiment, the additional therapeutic agent is a viral replication inhibitor,
- the additional therapeutic agent is an HCV NS3 protease inhibitor.
- the additional therapeutic agent is an HCV NS5B polymerase inhibitor.
- the additional therapeutic agent is a nucleoside inhibitor.
- the additional therapeutic agent is an interferon.
- the additional therapeutic agent is an HCV replicase inhibitor.
- the additional therapeutic agent is an antisense agent.
- the additional therapeutic agent is a therapeutic vaccine. In a further embodiment, the additional therapeutic agent is a virion production inhibitor.
- the additional therapeutic agent is an antibody therapy. In another embodiment, the additional therapeutic agent is an HCV NS2 inhibitor. In still another embodiment, the additional therapeutic agent is an HCV NS4A inhibitor.
- the additional therapeutic agent is an HCV NS4B inhibitor. In another embodiment, the additional therapeutic agent is an HCV NS5A inhibitor In yet another embodiment, the additional therapeutic agent is an HCV NS3 helicase inhibitor.
- the additional therapeutic agent is an HCV IRES inhibitor. In another embodiment, the additional therapeutic agent is an HCV p7 inhibitor. In a further embodiment, the additional therapeutic agent is an HCV entry inhibitor. In another embodiment, the additional therapeutic agent is an HCV assembly inhibitor.
- the additional therapeutic agents comprise a viral protease inhibitor and a viral polymerase inhibitor.
- the additional therapeutic agents comprise a viral protease inhibitor and an immunomodulatory agent.
- the additional therapeutic agents comprise a polymerase inhibitor and an immunomodulatory agent.
- the additional therapeutic agents comprise a viral protease inhibitor and a nucleoside.
- the additional therapeutic agents comprise an
- the additional therapeutic agents comprise an HCV protease inhibitor and an HCV polymerase inhibitor.
- the additional therapeutic agents comprise a nucleoside and an HCV NS5A inhibitor.
- the additional therapeutic agents comprise a viral protease inhibitor, an immunomodulatory agent and a nucleoside.
- the additional therapeutic agents comprise a viral protease inhibitor, a viral polymerase inhibitor and an immunomodulatory agent.
- the additional therapeutic agent is ribavirin.
- HCV polymerase inhibitors useful in the present compositions and methods include, but are not limited to, VP-19744 (Wyeth/ViroPharma), PSI-7851 (Pharmasset), RG7128 (Roche/Pharmasset), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), PSI-879 (Pharmasset), PSI-661 (Pharmasset), PF-868554/filib vir (Pfizer), VCH-759/VX-759 (ViroChem
- HCV-371 (Wyeth/VirroPharma), HCV-796 (Wyeth/ViroPharma), IDX- 184 (Idenix), IDX-375 (Idenix), NM-283 (Idenix/Novartis), GL-60667 (Genelabs), JTK- 109 (Japan Tobacco), PSI-6130 (Pharmasset), R1479 (Roche), R-1626 (Roche), R-7128 (Roche), MK-0608 (Isis/Merck), INX-8014 (Inhibitex), IMX-8018 (Inhibitex), INX-189 (Inhibitex), GS 9190 (Gilead), A-848837 (Abbott), ABT-333 (Abbott), ABT-072 (Abbott), A-837093 (Abbott), BI-207127 (Boehringer-Ingelheim), BILB-1941 (Boehringer- Ingelheim), M -3281 (Merc
- HC V polymerase inhibitors useful in the present compositions and methods include, but are not limited to, those disclosed in International Publication Nos. WO 08/082484, WO 08/082488, WO 08/083351, WO 08/136815, WO 09/032116, WO
- Interferons useful in the present compositions and methods include, but are not limited to, interferon alfa-2a, interferon alfa-2b, interferon alfacon-1 and PEG-interferon alpha conjugates.
- PEG-interferon alpha conjugates are interferon alpha molecules covalently attached to a PEG molecule.
- Illustrative PEG-interferon alpha conjugates include interferon alpha-2a (RoferonTM, Hoffman La-Roche, Nutley, New Jersey) in the form of pegylated interferon alpha-2a ⁇ e.g., as sold under the trade name PegasysTM), interferon alpha-2b (IntronTM, from Schering-Plough Corporation) in the form of pegylated interferon alpha-2b ⁇ e.g.
- interferon alpha-2b-XL ⁇ e.g., as sold under the trade name PEG-IntronTM
- interferon alpha-2c Boehringer Ingelheim, Ingelheim, Germany
- PEG- interferon lambda Boehringer Ingelheim, Ingelheim, Germany
- PEG- interferon lambda Boehringer Ingelheim, Ingelheim, Germany
- PEG- interferon lambda Boehringer Ingelheim, Ingelheim, Germany
- PEG- interferon lambda Boehringer Ingelheim, Ingelheim, Germany
- PEG- interferon lambda Boehringer Ingelheim, Ingelheim, Germany
- PEG- interferon lambda Boehringer Ingelheim, Ingelheim, Germany
- PEG- interferon lambda Boehringer Ingelheim, Ingelheim, Germany
- PEG- interferon lambda Boehringer Ingelheim, Ingelheim, Germany
- PEG- interferon lambda Boehringer Ingelheim, Ingel
- Antibody therapy agents useful in the present compositions and methods include, but are not limited to, antibodies specific to IL-10 (such as those disclosed in US Patent Publication No. US2005/0101770, humanized 12G8, a humanized monoclonal antibody against human IL-10, plasmids containing the nucleic acids encoding the humanized 12G8 light and heavy chains were deposited with the American Type Culture Collection (ATCC) as deposit numbers PTA-5923 and PTA-5922, respectively), and the like).
- ATCC American Type Culture Collection
- viral protease inhbitors useful in the present compositions and methods include, but are not limited to, an HCV protease inhibitor.
- HCV protease inhibitors useful in the present compositions and methods include, but are not limited to, those disclosed in U.S. Patent Nos. 7,494,988, 7,485,625, 7,449,447, 7,442,695, 7,425,576, 7,342,041, 7,253,160, 7,244,721, 7,205,330, 7,192,957, 7,186,747, 7,173,057, 7,169,760, 7,012,066, 6,914,122, 6,91 1,428, 6,894,072, 6,846,802, 6,838,475, 6,800,434, 6,767,991, 5,017,380, 4,933,443, 4,812,561 and 4,634,697; U.S. Patent Nos. 7,494,988, 7,485,625, 7,449,447, 7,442,695, 7,425,576, 7,342,041, 7,253,160, 7,244,721, 7,205,330, 7,192,957, 7,186,747, 7,173,057, 7,169,760, 7,012,066, 6,91
- HCV protease inhibitors useful in the present compositions and methods include, but are not limited to, VX-950 (Telaprevir, Vertex), VX-500 (Vertex), VX-813 (Vertex), VBY-376 (Virobay), BI-201335 (Boehringer Ingelheim), TMC-435
- HCV protease inhbitors useful in the present compositions and methods include, but are not limited to, those disclosed in Landro et al, Biochemistry,
- HCV protease inhibitors useful in the present compositions and methods include, but are not limited to, the following compounds:
- Viral replication inhibitors useful in the present compositions and methods include, but are not limited to, HCV replicase inhibitors, IRES inhibitors, NS4A inhibitors, NS3 helicase inhibitors, NS5A inhibitors, NS5B inhibitors, ribavirin, AZD-2836 (Astra Zeneca), viramidine, A-831 (Arrow Therapeutics), EDP-239 (Enanta), ACH-2928 (Achillion), GS- 5885 (Gilead); an antisense agent or a therapeutic vaccine.
- Viral entry inhibitors useful as second additional therapeutic agents in the present compositions and methods include, but are not limited to, PRO-206 (Progenies), REP-9C (REPICor), SP-30 (Samaritan Pharmaceuticals) and ITX-5061 (iTherx).
- HCV NS4A inhibitors useful in the useful in the present compositions and methods include, but are not limited to, those disclosed in U.S. Patent Nos. 7,476,686 and 7,273,885; U.S. Patent Publication No. US20090022688; and International Publication Nos. WO 2006/019831 and WO 2006/019832.
- Additional HCV NS4A inhibitors useful as second additional therapeutic agents in the present compositions and methods include, but are not limited to, AZD2836 (Astra Zeneca), ACH-1095 (Achillion) and ACH-806 (Achillion).
- HCV NS5A inhibitors useful in the present compositions and methods include, but are not limited to, A-832 (Arrow Therpeutics), PPI-461 (Presidio), PPI-1301 (Presidio) and BMS-790052 (Bristol-Myers Squibb).
- HCV replicase inhibitors useful in the present compositions and methods include, but are not limited to, those disclosed in U.S. Patent Publication No. US20090081636.
- Therapeutic vaccines useful in the present compositions and methods include, but are not limited to, IC41 (Intercell Novartis), CSL123 (Chiron/CSL), GI 5005
- compositions and methods examples include, but are not limited to, Ritonavir (Abbott), TT033 (Benitec/Tacere Bio/Pfizer), Sirna-034 (Sirna Therapeutics), GNI 04 (GENimmune), GI-5005
- HepaCide-I (NanoVirocides), MX3235 (Migenix), SCY-635 (Scynexis); PE02003002 ( emin Pharma), Lenocta (VioQuest Pharmaceuticals), IET - Interferon Enhancing Therapy (Transition Therapeutics), Zadaxin (SciClone Pharma), VP 50406TM (Viropharma, Incorporated, Exton, Pennsylvania); Taribavirin (Valeant Pharmaceuticals); Nitazoxanide (Romark); Debio 025 (Debiopharm); GS-9450 (Gilead); PF-4878691 (Pfizer); ANA773 (Anadys); SCV-07 (SciClone Pharmaceuticals); NIM-881 (Novartis); ISIS 14803TM (ISIS Pharmaceuticals, Carlsbad, California); HeptazymeTM (Ribozyme Pharmaceuticals, Boulder, Colorado); ThymosinTM (SciClone Pharmaceuticals, San
- the doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of HCV infection can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder.
- the Fused Tricyclic Silyl Compound(s) and the other agent(s) can be administered simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially.
- kits comprising the separate dosage forms is therefore advantageous.
- a total daily dosage of the at least one Fused Tricyclic Silyl Compound(s) alone, or when administered as combination therapy can range from about 1 to about 2500 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of administration.
- the dosage is from about 10 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses, in another embodiment, the dosage is from about 1 to about 500 mg day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 1 to about 100 mg day, administered in a single dose or in 2-4 divided doses, in yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses.
- the dosage is from about 500 to about 1500 mg day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 500 to about 1000 mg day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 100 to about 500 mg day, administered in a single dose or in 2-4 divided doses.
- the additional therapeutic agent is INT ON-A interferon alpha 2b (commercially available from Schering-Plough Corp.)
- this agent is administered by subcutaneous injection at 3MIU(12 mcg)/0.5mL/TIW for 24 weeks or 48 weeks for first time treatment.
- the additional therapeutic agent is PEG-INTRON interferon alpha 2b pegylated (commercially available from Schering-Plough Corp.)
- this agent is administered by subcutaneous injection at 1.5 mcg kg/week, within a range of 40 to 150 meg/week, for at least 24 weeks.
- the additional therapeutic agent is ROFERON A interferon alpha 2a (commercially available from Hoffmann-La Roche)
- this agent is administered by subcutaneous or intramuscular injection at 3MIU(11.1 mcg/mL)/TIW for at least 48 to 52 weeks, or alternatively 6MIU/TIW for 12 weeks followed by 3MIU/TIW for 36 weeks.
- the additional therapeutic agent when the additional therapeutic agent is PEGASUS interferon alpha 2a pegylated (commercially available from Hoffmann-La Roche), this agent is administered by subcutaneous injection at 180 mcg/lmL or 180 mcg/0.5mL, once a week for at least 24 weeks.
- the additional therapeutic agent when the additional therapeutic agent is INFERGEN interferon alphacon-1 (commercially available from Amgen), this agent is administered by subcutaneous injection at 9 mcg/TiW is 24 weeks for first time treatment and up to 15 mcg TIW for 24 weeks for non-responsive or relapse treatment.
- this agent is administered at a daily dosage of from about 600 to about 1400 mg/day for at least 24 weeks.
- one or more compounds of the present invention are
- an interferon an immunomod lator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a viral polymerase inhibitor a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating an RNA-dependent polymerase-related disorder.
- additional therapeutic agents selected from: an interferon, an immunomod lator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a viral polymerase inhibitor a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating an RNA-dependent polymerase-related disorder.
- one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV replication inhibitor, a nucleoside, an interferon, a pegylated interferon and ribavirin.
- the combination therapies can include any combination of these additional therapeutic agents.
- one or more compounds of the present invention are administered with one additional therapeutic agent selected from an HCV protease inhibitor, an interferon, a pegylated interferon and ribavirin.
- one or more compounds of the present invention are administered with two additional therapeutic agents selected from an HCV protease inhibitor, an HCV replication inhibitor, a nucleoside, an interferon, a pegylated interferon and ribavirin.
- one or more compounds of the present invention are administered with an HCV protease inhibitor and ribavirin.
- an HCV protease inhibitor and ribavirin.
- one or more compounds of the present invention are administered with a pegylated interferon and ribavirin.
- one or more compounds of the present invention are administered with three additional therapeutic agents selected from an HCV protease inhibitor, an HCV replication inhibitor, a nucleoside, an interferon, a pegylated interferon and ribavirin.
- one or more compounds of the present invention are
- one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from an HCV polymerase inhibitor, a viral protease inhibitor, an interferon, and a viral replication inhibitor.
- one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from an HCV polymerase inhibitor, a viral protease inhibitor, an interferon, and a viral replication inhibitor.
- one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from an HCV polymerase inhibitor, a viral protease inhibitor, an interferon, and ribavirin.
- one or more compounds of the present invention are
- one or more compounds of the present invention are administered with ribavirin.
- one or more compounds of the present invention are
- HCV polymerase inhibitor a viral protease inhibitor, an interferon, and a viral replication inhibitor.
- one or more compounds of the present invention are administered with ribavirin, interferon and another therapeutic agent.
- one or more compounds of the present invention are administered with ribavirin, interferon and another therapeutic agent, wherein the additional therapeutic agent is selected from an HCV polymerase inhibitor, a viral protease inhibitor, and a viral replication inhibitor.
- one or more compounds of the present invention are administered with ribavirin, interferon and a viral protease inhibitor.
- one or more compounds of the present invention are administered with ribavirin, interferon and an HCV protease inhibitor.
- one or more compounds of the present invention are administered with ribavirin, interferon and boceprevir or telaprevir.
- one or more compounds of the present invention are administered with ribavirin, interferon and an HCV polymerase inhibitor.
- one or more compounds of the present invention are administered with pegylated-interferon alpha and ribavirin.
- the Fused Tricyclic Silyl Compounds are useful in veterinary and human medicine. As described above, the Fused Tricyclic Silyl Compounds are useful for treating or preventing HCV infection in a patient in need thereof.
- the Fused Tricyclic Silyl Compounds can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle.
- the present invention provides pharmaceutical compositions comprising an effective amount of at least one Fused Tricyclic Silyl Compound and a pharmaceutically acceptable carrier.
- the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
- the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
- Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may be comprised of from about 0.5 to about 95 percent inventive composition. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
- suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes.
- lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
- Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.
- Liquid form preparations include solutions, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral injection.
- Liquid form preparations may also include solutions for intranasal administration.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
- liquid forms include solutions, suspensions and emulsions.
- a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed
- compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e., antiviral activity and the like.
- Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
- the one or more Fused Tricyclic Silyl Compounds are administered orally.
- the one or more Fused Tricyclic Silyl Compounds are administered intravenously.
- a pharmaceutical preparation comprising at least one Fused Tricyclic Silyl Compound is in unit dosage form.
- the preparation is subdivided into unit doses containing effective amounts of the active components.
- compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1% to about 99% of the Fused Tricyclic Silyl Compound(s) by weight or volume. In various embodiments, the present compositions can contain, in one embodiment, from about 1% to about 70% or from about 5% to about 60% of the Fused Tricyclic Silyl Compound(s) by weight or volume.
- the quantity of Fused Tricyclic Silyl Compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 2500 mg. In various embodiment, the quantity is from about 10 mg to about 1000 mg, 1 mg to about 500 mg, 1 mg to about 100 mg, and 1 mg to about 100 mg.
- the total daily dosage may be divided and administered in portions during the day if desired. In one embodiment, the daily dosage is administered in one portion. In another embodiment, the total daily dosage is administered in two divided doses over a 24 hour period. In another embodiment, the total daily dosage is administered in three divided doses over a 24 hour period. In still another embodiment, the total daily dosage is administered in four divided doses over a 24 hour period.
- a total daily dosage of the Fused Tricyclic Silyl Compounds range from about 0.1 to about 2000 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of administration.
- the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses.
- the dosage is from about 10 to about 2000 mg day, administered in a single dose or in 2-4 divided doses.
- the dosage is from about 100 to about 2000 mg day, administered in a single dose or in 2-4 divided doses.
- the dosage is from about 500 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses.
- compositions of the invention can further comprise one or more additional therapeutic agents, selected from those listed above herein. Accordingly, in one
- the present invention provides compositions comprising: (i) at least one Fused Tricyclic Silyl Compound or a pharmaceutically acceptable salt thereof; (ii) one or more additional therapeutic agents that are not a Fused Tricyclic Silyl Compound; and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the composition are together effective to treat HCV infection.
- the present invention provides compositions comprising a Compound of Formula (I) and a pharmaceutically acceptable carrier.
- compositions comprising a
- compositions comprising a Compound of Formula (I), a pharmaceutically acceptable carrier, and wto additional therapeutic agents, each of which are independently selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
- the present invention provides a kit comprising a therapeutically effective amount of at least one Fused Tricyclic Silyl Compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
- the present invention provides a kit comprising an amount of at least one Fused Tricyclic Silyl Compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more active ingredients result in a desired therapeutic effect.
- the one or more Fused Tricyclic Silyl Compounds and the one or more additional therapeutic agents are provided in the same container.
- the one or more Fused Tricyclic Silyl Compounds and the one or more additional therapeutic agents are provided in separate containers.
- N-Bromo succinimide (838.4 mg, 4.71 mmol) was added in portions over 15 minutes to a cooled (ice/water) CH 2 C1 2 (20 mL) solution of Int-7c (1.06 g, 4.50 mmol). The reaction mixture was allowed to stir for 75 minutes and concentrated in vacuo to an oil. The crude product was purified using silica-gel RPLC (Acetonitrile/ water/ 0.1% TFA) to separate the mono bromide from its dibromo analog (over bromination) and the starting material. The RPLC elute was neutralized with excess H3/MeOH, and the volatile IN2010.7118
- Int-9f was prepared from N-BOC-trans-fluoro-L-proline, (available from Alfa) using the method described above.
- Int-9g was prepared from N-Boc-4,4-difluoro-L-proline, (Aldrich) using the method described above.
- IN2010.7118 was prepared from N-Boc-4,4-difluoro-L-proline, (Aldrich) using the method described above.
- Int-9h was prepared from BOC-HYP-OH, (available from Aldrich) using the method described above.
- Int-9i was prepared from commercially available BOC-4-amino-pyrrolidine-2- carboxylic acid using the method described above.
- Int-9j was prepared from commercially available BOC-4-amino-pyrrolidine-2- carboxylic acid using the method described above, with appropriate fiinctionahzation with methyl chloroformate as in example 1.
- Int-9k was prepared from 2S-carboxy piperidine (prepared according to method described in Gudasheva et al., J. Med. Chem Ther. 1996, 31, 151). IN2010.7118
- lnt-91 was prepared from 2S-carboxy-4,4-F piperidine (prepared according to the method described in Chinese Patent No. CN 101462999).
- Int-9m was prepared from 2S-carboxy morpholine, using the method described above.
- Int-9q was prepared from commercially available Int-9o using the method described above
- the resulting crude Int-9r was purified using silica gel chromatography (80 g RediSep® SiC3 ⁇ 4 cartridge; 1-9% MeOH / EtOAc gradient) to provide Compound Int-9r (458 mg, 60% yield) as a yellow solid.
- Int-9s was prepared from (lR,3S,4S)-N-BOC-2-azabicyclo[2.2.1]-heptane-3- carboxylic acid using the method described above for the synthesis of compound Int-9r.
- Int-9t was prepared from 15 g of 2(S)-azabicyclo[2.2.2]-octane-2,3-dicarboxylic acid 2-tert-butyl ester (commercially available from Wuxi Apptech Co) using the method described above for the synthesis of compound Int-9r, to provide 10.1 g of Int-9t.
- reaction mixture was then diluted with water (150 mL) and diethyl ether (150 mL) and separated. The organic phase was washed with brine (200 mL), dried over MgSC>4, filtered and concentrated in vacuo. The resulting residue was purified using flash chromatography on an ISCO 330 g Redi-Sep column (0-20% EtOAc hexanes as eluent) to provide Compound Int-llb (7.47 g, 65 %).
- Int-9g Int-16c
- Compound Int-9g (5.7 g, 13.31 mmol), bis(pinacolaton)diboron (6.8 g, 26.78 mmol), Pd(PPh 3 ) 4 (0.76 g, 0,66 mmol), potassium acetate (2.0 g, 20.37 mmol) and 1,4- dioxane were added to a 500 mL flask .
- the resulting suspension was degassed and allowed to stir at 80 °C for about 15 hours.
- the reaction mixture was then cooled to room temperature and filtered.
- Int-16d, Int-16e, Int-16f and Int-16g were prepared from Int-9h, Int-9f, Int-9s and Int-9t, respectively, using the method described above.
- Compound Int-17g was prepared from N-BOC-trans-fluoro-L-proline, using the method described above.
- Compound Int-17h was prepared from N-Boc-4,4-difluoro-L-proline, using the method described above.
- Compound Int-17i was prepared from BOC-HYP-OH, using the method described above. IN2010.7118
- Int-17i Compound Int-17j was prepared from L-pipecolic acid, using the method described above.
- Compound Int-17k was prepared from 2S-carboxy mo ⁇ holine, using the method described above.
- Compound Int-171 was prepared from (1R, 3S, 4S)-N-BOC-2-azabicyclo[2.2.1]- heptane-3-carboxylic acid, using the method described above.
- Compound Int-17m was prepared from 2(S)-azabicyclo[2.2.2]-octane-2,3- dicarboxylic acid 2-tert-butyl ester, using the method described above. IN2010.71 18
- reaction mixture was filtered through Celite, and the Celite was rinsed with CH2CI2 (100 mL) and the combined filtrate and washing was concentrated in vacuo.
- the resulting residue was purified using flash chromatography on an ISCO 330 g Redi-Sep column using a gradient of 0-70% EtOAc/hexanes as eluent to provide Compound Int-18 as a yellow solid (19 g, 82%).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2012557114A JP2013522202A (en) | 2010-03-09 | 2011-03-04 | Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases |
MA35291A MA34147B1 (en) | 2010-03-09 | 2011-03-04 | SILYL FUSIONED TRICYCLIC COMPOUNDS AND METHODS OF USE IN THE TREATMENT OF VIRAL DISEASES |
MX2012010392A MX2012010392A (en) | 2010-03-09 | 2011-03-04 | Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases. |
CN2011800233538A CN102918049A (en) | 2010-03-09 | 2011-03-04 | Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases |
EA201290882A EA201290882A1 (en) | 2010-03-09 | 2011-03-04 | Condensed tricyclic silane compounds and methods of their use for the treatment of viral diseases |
SG2012063780A SG183526A1 (en) | 2010-03-09 | 2011-03-04 | Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases |
KR1020127026331A KR20130008040A (en) | 2010-03-09 | 2011-03-04 | Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases |
EP11707763.6A EP2545060B1 (en) | 2010-03-09 | 2011-03-04 | Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases |
CA2792121A CA2792121A1 (en) | 2010-03-09 | 2011-03-04 | Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases |
BR112012022125A BR112012022125A2 (en) | 2010-03-09 | 2011-03-04 | compound, dihydrochloride salt, pharmaceutical composition, use of the compound, and method for treating a patient |
AU2011224698A AU2011224698A1 (en) | 2010-03-09 | 2011-03-04 | Fused Tricyclic Silyl Compounds and methods of use thereof for the treatment of viral diseases |
ES11707763.6T ES2558554T3 (en) | 2010-03-09 | 2011-03-04 | Condensed tricyclic silyl compounds and methods of their use for the treatment of viral diseases |
TNP2012000416A TN2012000416A1 (en) | 2010-03-09 | 2012-08-15 | Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases |
ZA2012/06716A ZA201206716B (en) | 2010-03-09 | 2012-09-07 | Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US31201610P | 2010-03-09 | 2010-03-09 | |
US61/312,016 | 2010-03-09 | ||
US37193510P | 2010-08-09 | 2010-08-09 | |
US61/371,935 | 2010-08-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2011112429A1 true WO2011112429A1 (en) | 2011-09-15 |
Family
ID=43939669
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2011/027117 WO2011112429A1 (en) | 2010-03-09 | 2011-03-04 | Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases |
Country Status (25)
Country | Link |
---|---|
US (1) | US8609635B2 (en) |
EP (1) | EP2545060B1 (en) |
JP (1) | JP2013522202A (en) |
KR (1) | KR20130008040A (en) |
CN (1) | CN102918049A (en) |
AR (1) | AR080676A1 (en) |
AU (1) | AU2011224698A1 (en) |
BR (1) | BR112012022125A2 (en) |
CA (1) | CA2792121A1 (en) |
CL (1) | CL2012002489A1 (en) |
CO (1) | CO6592102A2 (en) |
CR (1) | CR20120460A (en) |
DO (1) | DOP2012000243A (en) |
EA (1) | EA201290882A1 (en) |
EC (1) | ECSP12012147A (en) |
ES (1) | ES2558554T3 (en) |
MA (1) | MA34147B1 (en) |
MX (1) | MX2012010392A (en) |
NI (1) | NI201200139A (en) |
PE (1) | PE20130062A1 (en) |
SG (1) | SG183526A1 (en) |
TN (1) | TN2012000416A1 (en) |
TW (1) | TW201136943A (en) |
WO (1) | WO2011112429A1 (en) |
ZA (1) | ZA201206716B (en) |
Cited By (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012068234A3 (en) * | 2010-11-17 | 2013-01-17 | 12Gilead Sciences, Inc. | Antiviral compounds |
US8541424B2 (en) | 2008-12-23 | 2013-09-24 | Abbott Laboratories | Anti-viral compounds |
US8546405B2 (en) | 2008-12-23 | 2013-10-01 | Abbott Laboratories | Anti-viral compounds |
US8552047B2 (en) | 2011-02-07 | 2013-10-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8575135B2 (en) | 2011-11-16 | 2013-11-05 | Gilead Sciences, Inc. | Antiviral compounds |
JP2014500861A (en) * | 2010-10-26 | 2014-01-16 | プレシディオ ファーマシューティカルズ インコーポレイテッド | Hepatitis C virus inhibitor |
US8669234B2 (en) | 2009-05-13 | 2014-03-11 | Gilead Sciences, Inc. | Antiviral compounds |
US8686026B2 (en) | 2010-06-10 | 2014-04-01 | Abbvie Inc. | Solid compositions |
US8691938B2 (en) | 2009-06-11 | 2014-04-08 | Abbvie Inc. | Anti-viral compounds |
US8716454B2 (en) | 2009-06-11 | 2014-05-06 | Abbvie Inc. | Solid compositions |
US8765731B2 (en) | 2009-07-16 | 2014-07-01 | Vertex Pharmaceuticals Incorporated | Benzimidazole analogues for the treatment or prevention of flavivirus infections |
US8779156B2 (en) | 2010-03-24 | 2014-07-15 | Vertex Pharmaceuticals Incorporated | Analogues for the treatment or prevention of flavivirus infections |
US8859595B2 (en) | 2010-08-26 | 2014-10-14 | Rfs Pharma, Llc | Potent and selective inhibitors of hepatitis C virus |
US8937150B2 (en) | 2009-06-11 | 2015-01-20 | Abbvie Inc. | Anti-viral compounds |
US20150057246A1 (en) * | 2011-09-14 | 2015-02-26 | Michael P. Dwyer | Silyl-containing heterocyclic compounds and methods of use thereof for the treatment of viral diseases |
US9034832B2 (en) | 2011-12-29 | 2015-05-19 | Abbvie Inc. | Solid compositions |
US9278922B2 (en) | 2009-04-15 | 2016-03-08 | Abbvie Inc. | Anti-viral compounds |
US9326973B2 (en) | 2012-01-13 | 2016-05-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9333204B2 (en) | 2014-01-03 | 2016-05-10 | Abbvie Inc. | Solid antiviral dosage forms |
US9393256B2 (en) | 2011-09-16 | 2016-07-19 | Gilead Pharmasset Llc | Methods for treating HCV |
US9394279B2 (en) | 2009-06-11 | 2016-07-19 | Abbvie Inc. | Anti-viral compounds |
US9546160B2 (en) | 2011-05-12 | 2017-01-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9717712B2 (en) | 2013-07-02 | 2017-08-01 | Bristol-Myers Squibb Company | Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus |
US9770439B2 (en) | 2013-07-02 | 2017-09-26 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9775831B2 (en) | 2013-07-17 | 2017-10-03 | Bristol-Myers Squibb Company | Combinations comprising biphenyl derivatives for use in the treatment of HCV |
US10039779B2 (en) | 2013-01-31 | 2018-08-07 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US10086011B2 (en) | 2013-08-27 | 2018-10-02 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
US10617675B2 (en) | 2015-08-06 | 2020-04-14 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US10800789B2 (en) | 2012-05-16 | 2020-10-13 | Gilead Pharmasset Llc | Antiviral compounds |
US11203599B2 (en) | 2014-06-11 | 2021-12-21 | Gilead Pharmasset Llc | Solid forms of an antiviral compound |
US11484534B2 (en) | 2013-03-14 | 2022-11-01 | Abbvie Inc. | Methods for treating HCV |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20190127365A1 (en) | 2017-11-01 | 2019-05-02 | Merck Sharp & Dohme Corp. | Inhibitors of hepatitis c virus replication |
EA020898B1 (en) | 2009-03-27 | 2015-02-27 | Мерк Шарп Энд Домэ Корп. | Inhibitors of hepatitis c virus replication |
EP2430015B1 (en) | 2009-05-12 | 2015-06-17 | Merck Sharp & Dohme Corp. | Fused tricyclic compounds useful for the treatment of viral diseases |
JP2012528194A (en) | 2009-05-29 | 2012-11-12 | メルク・シャープ・アンド・ドーム・コーポレーション | Antibacterial compounds composed of three aligned aryl moieties for treating diseases such as hepatitis C |
WO2010138791A1 (en) | 2009-05-29 | 2010-12-02 | Schering Corporation | Antiviral compounds composed of three linked aryl moieties to treat diseases such as hepatitis c |
US20130156731A1 (en) | 2009-12-22 | 2013-06-20 | Kevin X. Chen | Fused tricyclic compounds and methods of use thereof for the treatment of viral diseas |
MA34147B1 (en) | 2010-03-09 | 2013-04-03 | Merck Sharp & Dohme | SILYL FUSIONED TRICYCLIC COMPOUNDS AND METHODS OF USE IN THE TREATMENT OF VIRAL DISEASES |
EP2621501A4 (en) * | 2010-09-29 | 2014-04-09 | Merck Sharp & Dohme | Polycyclic heterocycle derivatives and methods of use thereof for the treatment of viral diseases |
US9254292B2 (en) | 2010-09-29 | 2016-02-09 | Merck Sharp & Dohme Corp. | Fused tetracycle derivatives and methods of use thereof for the treatment of viral diseases |
WO2012122716A1 (en) | 2011-03-17 | 2012-09-20 | Merck Sharp & Dohme Corp. | Tetracyclic xanthene derivatives and methods of use thereof for treatment of viral diseases |
WO2013030750A1 (en) | 2011-09-01 | 2013-03-07 | Lupin Limited | Antiviral compounds |
EP2812326A1 (en) | 2012-02-10 | 2014-12-17 | Lupin Limited | Antiviral compounds with a dibenzooxaheterocycle moiety |
CN104302636B (en) | 2012-04-25 | 2017-03-29 | 施万生物制药研发Ip有限责任公司 | Hepatitis C virus inhibitor |
SI2850075T1 (en) | 2012-04-25 | 2017-06-30 | Theravance Biopharma R&D Ip, Llc | Piperazine-piperidine compounds as hepatitis c virus inhibitors |
WO2014110687A1 (en) | 2013-01-16 | 2014-07-24 | Merck Sharp & Dohme Corp. | Thiazolyl-substitued tetracyclic compounds and methods of use thereof for treatment of viral diseases |
WO2017197055A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Heterocyclic degronimers for target protein degradation |
EP3455218A4 (en) | 2016-05-10 | 2019-12-18 | C4 Therapeutics, Inc. | C3-carbon linked glutarimide degronimers for target protein degradation |
WO2017197036A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
CN110382487B (en) * | 2017-03-22 | 2021-04-02 | 正大天晴药业集团股份有限公司 | Silicon-containing compounds for use against hepatitis c virus infection |
CN112679365A (en) * | 2021-03-15 | 2021-04-20 | 南京桦冠生物技术有限公司 | Industrial preparation method of 6-bromonaphthalene-1, 2-diamine |
Citations (66)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4634697A (en) | 1983-10-04 | 1987-01-06 | Shionogi & Co., Ltd. | Carboxyalkenamidocephalosporins |
US4812561A (en) | 1986-07-02 | 1989-03-14 | Shionogi & Co., Ltd. | Crystalline hydrate of oral cephalosporin and its composition |
WO1989004669A1 (en) | 1987-11-18 | 1989-06-01 | Chiron Corporation | Nanbv diagnostics and vaccines |
EP0381216A1 (en) | 1989-02-01 | 1990-08-08 | Asahi Glass Company Ltd. | Hydrochlorofluorocarbon azeotropic or azeotropic-like mixture |
US5017380A (en) | 1986-07-02 | 1991-05-21 | Shionogi & Co., Ltd. | Gelatin hard capsule containing crystalline hydrate of oral cephalosporin |
WO1998014181A1 (en) | 1996-09-30 | 1998-04-09 | Regents Of The University Of California | Treatment and prevention of hepatic disorders |
WO1998017679A1 (en) | 1996-10-18 | 1998-04-30 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease |
WO1998022496A2 (en) | 1996-11-18 | 1998-05-28 | F. Hoffmann-La Roche Ag | Antiviral peptide derivatives |
WO1999007734A2 (en) | 1997-08-11 | 1999-02-18 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor peptide analogues |
US20020068702A1 (en) | 2000-07-21 | 2002-06-06 | Marguerita Lim-Wilby | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
US20020160962A1 (en) | 2000-07-21 | 2002-10-31 | Saksena Anil K. | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
WO2003006490A1 (en) | 2001-07-11 | 2003-01-23 | Vertex Pharmaceuticals Incorporated | Bridged bicyclic serine protease inhibitors |
WO2003087092A2 (en) | 2002-04-11 | 2003-10-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis c virus ns3 - ns4 protease |
WO2004039859A1 (en) | 2002-10-30 | 2004-05-13 | Sumitomo Chemical Company, Limited | High-molecular compounds and polymerer light emitting devices made by using the same |
US6767991B1 (en) | 1997-08-11 | 2004-07-27 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C inhibitor peptides |
US6800434B2 (en) | 2000-07-21 | 2004-10-05 | Schering Corporation | Peptides as NS3-serine protease inhibitors of hepatitis C virus |
WO2004092161A1 (en) | 2003-04-11 | 2004-10-28 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
US6838475B2 (en) | 2000-07-21 | 2005-01-04 | Schering Corporation | Imidazolidinones as NS3-serine protease inhibitors of hepatitis C virus |
US6846802B2 (en) | 2000-04-05 | 2005-01-25 | Schering Corporation | Macrocyclic NS3-serine protease inhibitors of hepatitis C virus comprising N-cyclic P2 moieties |
US20050038037A1 (en) | 2001-06-06 | 2005-02-17 | Schering Aktiengesellschaft | Platelet adenosine diphosphate receptor antagonists |
US20050101770A1 (en) | 2003-11-10 | 2005-05-12 | Presta Leonard G. | Interleukin-10 antibodies |
US6894072B2 (en) | 2002-01-23 | 2005-05-17 | Schering Corporation | Compounds as NS3-serine protease inhibitors of hepatitis C virus |
US20050119168A1 (en) | 2003-09-26 | 2005-06-02 | Schering Corporation | Macrocyclic inhibitors of hepatitis C virus NS3-serine protease |
US6911428B2 (en) | 2000-12-12 | 2005-06-28 | Schering Corporation | Diaryl peptides as NS3-serine protease inhibitors of hepatitis C virus |
US6914122B2 (en) | 2000-04-19 | 2005-07-05 | Schering Corporation | Macrocyclic NS-3 serine protease inhibitors of hepatitis C virus comprising alkyl and aryl alanine P2 moieties |
US20050209164A1 (en) | 2004-02-27 | 2005-09-22 | Schering Corporation | Cyclobutenedione-containing compounds as inhibitors of hepatitis C virus NS3 serine protease |
WO2005087731A1 (en) | 2004-02-27 | 2005-09-22 | Schering Corporation | Sulfur compounds as inhibitors of hepatitis c virus ns3 serine protease |
US20050249702A1 (en) | 2004-05-06 | 2005-11-10 | Schering Corporation | (1R,2S,5S)-N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide as inhibitor of hepatitis C virus NS3/NS4a serine protease |
WO2006019832A1 (en) | 2004-07-22 | 2006-02-23 | Ptc Therapeutics, Inc. | Thienopyridines for treating hepatitis c |
WO2006019831A1 (en) | 2004-07-14 | 2006-02-23 | Ptc Therapeutics, Inc. | Methods for treating hepatitis c |
US7012066B2 (en) | 2000-07-21 | 2006-03-14 | Schering Corporation | Peptides as NS3-serine protease inhibitors of hepatitis C virus |
US20060276511A1 (en) | 2005-06-06 | 2006-12-07 | Michael Serrano-Wu | Inhibitors of HCV replication |
US7173057B2 (en) | 2004-02-27 | 2007-02-06 | Schering Corporation | Ketoamides with cyclic P4'S as inhibitors of NS3 protease of hepatitis C virus |
US7186747B2 (en) | 2004-02-27 | 2007-03-06 | Schering Corporation | Compounds as inhibitors of hepatitis C virus NS3 serine protease |
US7192957B2 (en) | 2004-02-27 | 2007-03-20 | Schering Corporation | Compounds as inhibitors of hepatitis C virus NS3 serine protease |
US7205330B2 (en) | 2004-02-27 | 2007-04-17 | Schering Corporation | Inhibitors of hepatitis C virus NS3 protease |
US7244721B2 (en) | 2000-07-21 | 2007-07-17 | Schering Corporation | Peptides as NS3-serine protease inhibitors of hepatitis C virus |
US7253160B2 (en) | 2003-11-20 | 2007-08-07 | Schering Corporation | Depeptidized inhibitors of hepatitis C virus NS3 protease |
US20070274951A1 (en) | 2006-02-09 | 2007-11-29 | Xiao Tong | Combinations comprising HCV protease inhibitor(s) and HCV polymerase inhibitor(s), and methods of treatment related thereto |
US20080044380A1 (en) | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US20080044379A1 (en) | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US20080050336A1 (en) | 2006-08-11 | 2008-02-28 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US7342041B2 (en) | 2004-02-27 | 2008-03-11 | Schering Corporation | 3,4-(cyclopentyl)-fused proline compounds as inhibitors of hepatitis C virus NS3 serine protease |
WO2008082488A1 (en) | 2006-12-22 | 2008-07-10 | Schering Corporation | 4, 5-ring annulated indole derivatives for treating or preventing of hcv and related viral infections |
WO2008082484A1 (en) | 2006-12-22 | 2008-07-10 | Schering Corporation | 4,5-ring annulated indole derivatives for treating or preventing of hcv and related viral infections |
WO2008083351A2 (en) | 2006-12-29 | 2008-07-10 | Genifuel Corporation | Controlled growth environments for algae cultivation |
WO2008124148A2 (en) | 2007-04-10 | 2008-10-16 | Schering Corporation | Sulfur compounds as inhiibitors of hepatitis c virus ns3 serine protease |
US7449447B2 (en) | 2003-08-26 | 2008-11-11 | Schering Corporation | Peptidomimetic NS3-serine protease inhibitors of hepatitis C virus |
WO2008136815A2 (en) | 2006-12-22 | 2008-11-13 | Schering Corporation | 5, 6-ring annulated indole derivatives and use thereof |
US20080311075A1 (en) | 2007-05-17 | 2008-12-18 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US7476686B2 (en) | 2002-11-19 | 2009-01-13 | Achillion Pharmaceuticals, Inc. | Substituted aryl thioureas and related compounds; inhibitors of viral replication |
US20090022688A1 (en) | 2003-04-11 | 2009-01-22 | Farmer Luc J | Inhibitors of serine protease, particularly hcv ns3-ns4a protease |
US20090020478A1 (en) | 2007-07-19 | 2009-01-22 | Bayer Material Science Ag | Processes for the regeneration of an anion exchanger loaded with hexachlorostannate |
US7485625B2 (en) | 2003-12-11 | 2009-02-03 | Schering Corporation | Inhibitors of hepatitis C virus NS3/NS4a serine protease |
US7494988B2 (en) | 2000-04-03 | 2009-02-24 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease |
WO2009032124A1 (en) | 2007-08-29 | 2009-03-12 | Schering Corporation | Substituted indole derivatives and methods of use thereof |
WO2009032125A1 (en) | 2007-08-29 | 2009-03-12 | Schering Corporation | 2,3-substituted azaindole derivatives for treating viral infections |
US20090068140A1 (en) | 2006-08-11 | 2009-03-12 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
WO2009032116A1 (en) | 2007-08-29 | 2009-03-12 | Schering Corporation | 2, 3-substituted indole derivatives for treating viral infections |
WO2009032123A2 (en) | 2007-08-29 | 2009-03-12 | Schering Corporation | Tetracyclic indole derivatives and their use for treating or preventing viral infections |
US20090081636A1 (en) | 2005-04-11 | 2009-03-26 | Mingjun Huang | Pharmaceutical compositions for and methods of inhibiting HCV replication |
CN101462999A (en) | 2007-12-21 | 2009-06-24 | 上海药明康德新药开发有限公司 | Fluoro or difluoro-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivatives, and preparation thereof |
US20090202483A1 (en) | 2008-02-13 | 2009-08-13 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
WO2009102633A1 (en) * | 2008-02-13 | 2009-08-20 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
WO2010065681A1 (en) | 2008-12-03 | 2010-06-10 | Presidio Pharmaceuticals, Inc. | Inhibitors of hcv ns5a |
WO2010065674A1 (en) | 2008-12-03 | 2010-06-10 | Presidio Pharmaceuticals, Inc. | Inhibitors of hcv ns5a |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5935982A (en) * | 1997-02-28 | 1999-08-10 | The University Of North Carolina At Chapel Hill | Methods of treating retroviral infection and compounds useful therefor |
US6183121B1 (en) * | 1997-08-14 | 2001-02-06 | Vertex Pharmaceuticals Inc. | Hepatitis C virus helicase crystals and coordinates that define helicase binding pockets |
AU1099000A (en) | 1998-10-05 | 2000-04-26 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions for treating hepatitis c infections |
TR200103147T1 (en) * | 1999-12-27 | 2002-06-21 | Japan Tobacco Inc. | Fused ring compounds and their use as drugs. |
US7547702B2 (en) * | 2000-09-20 | 2009-06-16 | Ortho-Mcneil Pharmaceutical, Inc. | 4-amino-quinazolines |
JP2007504152A (en) * | 2003-08-27 | 2007-03-01 | ビオタ, インコーポレイテッド | Novel tricyclic nucleosides or nucleotides as therapeutic agents |
US20070049593A1 (en) * | 2004-02-24 | 2007-03-01 | Japan Tobacco Inc. | Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor |
US7153848B2 (en) * | 2004-08-09 | 2006-12-26 | Bristol-Myers Squibb Company | Inhibitors of HCV replication |
US7994360B2 (en) * | 2005-05-16 | 2011-08-09 | Xtl Biopharmaceuticals Ltd. | Benzofuran compounds |
US7473784B2 (en) * | 2005-08-01 | 2009-01-06 | Bristol-Myers Squibb Company | Benzothiazole and azabenzothiazole compounds useful as kinase inhibitors |
TW200831084A (en) * | 2006-11-21 | 2008-08-01 | Genelabs Tech Inc | Anti-viral compounds |
WO2008098368A1 (en) * | 2007-02-16 | 2008-08-21 | Boehringer Ingelheim International Gmbh | Inhibitors of hepatitis c ns3 protease |
US7906655B2 (en) * | 2008-08-07 | 2011-03-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8420686B2 (en) * | 2009-02-17 | 2013-04-16 | Enanta Pharmaceuticals, Inc. | Linked diimidazole antivirals |
CA2753313A1 (en) | 2009-02-23 | 2010-08-26 | Presidio Pharmaceuticals, Inc. | Inhibitors of hcv ns5a |
US8101643B2 (en) * | 2009-02-27 | 2012-01-24 | Enanta Pharmaceuticals, Inc. | Benzimidazole derivatives |
US8426458B2 (en) * | 2009-02-27 | 2013-04-23 | Enanta Pharmaceuticals, Inc. | Hepatitis C Virus inhibitors |
EA020898B1 (en) * | 2009-03-27 | 2015-02-27 | Мерк Шарп Энд Домэ Корп. | Inhibitors of hepatitis c virus replication |
EP2430015B1 (en) * | 2009-05-12 | 2015-06-17 | Merck Sharp & Dohme Corp. | Fused tricyclic compounds useful for the treatment of viral diseases |
WO2010138791A1 (en) * | 2009-05-29 | 2010-12-02 | Schering Corporation | Antiviral compounds composed of three linked aryl moieties to treat diseases such as hepatitis c |
JP2012528194A (en) | 2009-05-29 | 2012-11-12 | メルク・シャープ・アンド・ドーム・コーポレーション | Antibacterial compounds composed of three aligned aryl moieties for treating diseases such as hepatitis C |
US8221737B2 (en) * | 2009-06-16 | 2012-07-17 | Enanta Pharmaceuticals, Inc. | Hepatitis C virus inhibitors |
JP2013512246A (en) * | 2009-11-25 | 2013-04-11 | メルク・シャープ・アンド・ドーム・コーポレーション | Condensed tricyclic compounds and derivatives useful for the treatment of viral diseases |
US8377980B2 (en) | 2009-12-16 | 2013-02-19 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US20130156731A1 (en) * | 2009-12-22 | 2013-06-20 | Kevin X. Chen | Fused tricyclic compounds and methods of use thereof for the treatment of viral diseas |
MA34147B1 (en) | 2010-03-09 | 2013-04-03 | Merck Sharp & Dohme | SILYL FUSIONED TRICYCLIC COMPOUNDS AND METHODS OF USE IN THE TREATMENT OF VIRAL DISEASES |
-
2011
- 2011-03-04 MA MA35291A patent/MA34147B1/en unknown
- 2011-03-04 SG SG2012063780A patent/SG183526A1/en unknown
- 2011-03-04 JP JP2012557114A patent/JP2013522202A/en not_active Withdrawn
- 2011-03-04 CN CN2011800233538A patent/CN102918049A/en active Pending
- 2011-03-04 US US13/041,082 patent/US8609635B2/en active Active
- 2011-03-04 EP EP11707763.6A patent/EP2545060B1/en active Active
- 2011-03-04 WO PCT/US2011/027117 patent/WO2011112429A1/en active Application Filing
- 2011-03-04 AU AU2011224698A patent/AU2011224698A1/en not_active Abandoned
- 2011-03-04 AR ARP110100696A patent/AR080676A1/en unknown
- 2011-03-04 BR BR112012022125A patent/BR112012022125A2/en not_active IP Right Cessation
- 2011-03-04 CA CA2792121A patent/CA2792121A1/en not_active Abandoned
- 2011-03-04 EA EA201290882A patent/EA201290882A1/en unknown
- 2011-03-04 MX MX2012010392A patent/MX2012010392A/en active IP Right Grant
- 2011-03-04 PE PE2012001466A patent/PE20130062A1/en not_active Application Discontinuation
- 2011-03-04 KR KR1020127026331A patent/KR20130008040A/en not_active Application Discontinuation
- 2011-03-04 ES ES11707763.6T patent/ES2558554T3/en active Active
- 2011-03-08 TW TW100107798A patent/TW201136943A/en unknown
-
2012
- 2012-08-15 TN TNP2012000416A patent/TN2012000416A1/en unknown
- 2012-09-07 DO DO2012000243A patent/DOP2012000243A/en unknown
- 2012-09-07 NI NI201200139A patent/NI201200139A/en unknown
- 2012-09-07 CL CL2012002489A patent/CL2012002489A1/en unknown
- 2012-09-07 ZA ZA2012/06716A patent/ZA201206716B/en unknown
- 2012-09-10 EC ECSP12012147 patent/ECSP12012147A/en unknown
- 2012-09-10 CR CR20120460A patent/CR20120460A/en unknown
- 2012-09-10 CO CO12155041A patent/CO6592102A2/en not_active Application Discontinuation
Patent Citations (74)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4634697A (en) | 1983-10-04 | 1987-01-06 | Shionogi & Co., Ltd. | Carboxyalkenamidocephalosporins |
US4812561A (en) | 1986-07-02 | 1989-03-14 | Shionogi & Co., Ltd. | Crystalline hydrate of oral cephalosporin and its composition |
US4933443A (en) | 1986-07-02 | 1990-06-12 | Shionogi & Co., Ltd. | Method for preparing crystalline hydrate of oral celphalosporin and its composition |
US5017380A (en) | 1986-07-02 | 1991-05-21 | Shionogi & Co., Ltd. | Gelatin hard capsule containing crystalline hydrate of oral cephalosporin |
WO1989004669A1 (en) | 1987-11-18 | 1989-06-01 | Chiron Corporation | Nanbv diagnostics and vaccines |
EP0381216A1 (en) | 1989-02-01 | 1990-08-08 | Asahi Glass Company Ltd. | Hydrochlorofluorocarbon azeotropic or azeotropic-like mixture |
WO1998014181A1 (en) | 1996-09-30 | 1998-04-09 | Regents Of The University Of California | Treatment and prevention of hepatic disorders |
WO1998017679A1 (en) | 1996-10-18 | 1998-04-30 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease |
WO1998022496A2 (en) | 1996-11-18 | 1998-05-28 | F. Hoffmann-La Roche Ag | Antiviral peptide derivatives |
WO1999007734A2 (en) | 1997-08-11 | 1999-02-18 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor peptide analogues |
US6767991B1 (en) | 1997-08-11 | 2004-07-27 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C inhibitor peptides |
US7494988B2 (en) | 2000-04-03 | 2009-02-24 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease |
US6846802B2 (en) | 2000-04-05 | 2005-01-25 | Schering Corporation | Macrocyclic NS3-serine protease inhibitors of hepatitis C virus comprising N-cyclic P2 moieties |
US6914122B2 (en) | 2000-04-19 | 2005-07-05 | Schering Corporation | Macrocyclic NS-3 serine protease inhibitors of hepatitis C virus comprising alkyl and aryl alanine P2 moieties |
US6800434B2 (en) | 2000-07-21 | 2004-10-05 | Schering Corporation | Peptides as NS3-serine protease inhibitors of hepatitis C virus |
US7244721B2 (en) | 2000-07-21 | 2007-07-17 | Schering Corporation | Peptides as NS3-serine protease inhibitors of hepatitis C virus |
US7169760B2 (en) | 2000-07-21 | 2007-01-30 | Schering Corporation | Peptides as NS3-serine protease inhibitors of hepatitis C virus |
US6838475B2 (en) | 2000-07-21 | 2005-01-04 | Schering Corporation | Imidazolidinones as NS3-serine protease inhibitors of hepatitis C virus |
US7012066B2 (en) | 2000-07-21 | 2006-03-14 | Schering Corporation | Peptides as NS3-serine protease inhibitors of hepatitis C virus |
US20020068702A1 (en) | 2000-07-21 | 2002-06-06 | Marguerita Lim-Wilby | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
US20020160962A1 (en) | 2000-07-21 | 2002-10-31 | Saksena Anil K. | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
US20050176648A1 (en) | 2000-07-21 | 2005-08-11 | Schering-Plough Corporation | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
US6911428B2 (en) | 2000-12-12 | 2005-06-28 | Schering Corporation | Diaryl peptides as NS3-serine protease inhibitors of hepatitis C virus |
US20050038037A1 (en) | 2001-06-06 | 2005-02-17 | Schering Aktiengesellschaft | Platelet adenosine diphosphate receptor antagonists |
WO2003006490A1 (en) | 2001-07-11 | 2003-01-23 | Vertex Pharmaceuticals Incorporated | Bridged bicyclic serine protease inhibitors |
US6894072B2 (en) | 2002-01-23 | 2005-05-17 | Schering Corporation | Compounds as NS3-serine protease inhibitors of hepatitis C virus |
WO2003087092A2 (en) | 2002-04-11 | 2003-10-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis c virus ns3 - ns4 protease |
US7273885B2 (en) | 2002-04-11 | 2007-09-25 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
WO2004039859A1 (en) | 2002-10-30 | 2004-05-13 | Sumitomo Chemical Company, Limited | High-molecular compounds and polymerer light emitting devices made by using the same |
US7476686B2 (en) | 2002-11-19 | 2009-01-13 | Achillion Pharmaceuticals, Inc. | Substituted aryl thioureas and related compounds; inhibitors of viral replication |
US20090022688A1 (en) | 2003-04-11 | 2009-01-22 | Farmer Luc J | Inhibitors of serine protease, particularly hcv ns3-ns4a protease |
WO2004092161A1 (en) | 2003-04-11 | 2004-10-28 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
US7449447B2 (en) | 2003-08-26 | 2008-11-11 | Schering Corporation | Peptidomimetic NS3-serine protease inhibitors of hepatitis C virus |
US20050119168A1 (en) | 2003-09-26 | 2005-06-02 | Schering Corporation | Macrocyclic inhibitors of hepatitis C virus NS3-serine protease |
US20050101770A1 (en) | 2003-11-10 | 2005-05-12 | Presta Leonard G. | Interleukin-10 antibodies |
US7442695B2 (en) | 2003-11-20 | 2008-10-28 | Schering Corporation | Depeptidized inhibitors of hepatitis C virus NS3 protease |
US7253160B2 (en) | 2003-11-20 | 2007-08-07 | Schering Corporation | Depeptidized inhibitors of hepatitis C virus NS3 protease |
US7485625B2 (en) | 2003-12-11 | 2009-02-03 | Schering Corporation | Inhibitors of hepatitis C virus NS3/NS4a serine protease |
US7173057B2 (en) | 2004-02-27 | 2007-02-06 | Schering Corporation | Ketoamides with cyclic P4'S as inhibitors of NS3 protease of hepatitis C virus |
US7186747B2 (en) | 2004-02-27 | 2007-03-06 | Schering Corporation | Compounds as inhibitors of hepatitis C virus NS3 serine protease |
US7425576B2 (en) | 2004-02-27 | 2008-09-16 | Schering Corporation | Compounds as inhibitors of hepatitis C virus NS3 serine protease |
US7192957B2 (en) | 2004-02-27 | 2007-03-20 | Schering Corporation | Compounds as inhibitors of hepatitis C virus NS3 serine protease |
WO2005087731A1 (en) | 2004-02-27 | 2005-09-22 | Schering Corporation | Sulfur compounds as inhibitors of hepatitis c virus ns3 serine protease |
US7205330B2 (en) | 2004-02-27 | 2007-04-17 | Schering Corporation | Inhibitors of hepatitis C virus NS3 protease |
US7342041B2 (en) | 2004-02-27 | 2008-03-11 | Schering Corporation | 3,4-(cyclopentyl)-fused proline compounds as inhibitors of hepatitis C virus NS3 serine protease |
US20070042968A1 (en) | 2004-02-27 | 2007-02-22 | Schering Corporation | Sulfur compounds as inhibitors of Hepatitis C virus NS3 serine protease |
US20050209164A1 (en) | 2004-02-27 | 2005-09-22 | Schering Corporation | Cyclobutenedione-containing compounds as inhibitors of hepatitis C virus NS3 serine protease |
US20050249702A1 (en) | 2004-05-06 | 2005-11-10 | Schering Corporation | (1R,2S,5S)-N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide as inhibitor of hepatitis C virus NS3/NS4a serine protease |
WO2006019831A1 (en) | 2004-07-14 | 2006-02-23 | Ptc Therapeutics, Inc. | Methods for treating hepatitis c |
WO2006019832A1 (en) | 2004-07-22 | 2006-02-23 | Ptc Therapeutics, Inc. | Thienopyridines for treating hepatitis c |
US20090081636A1 (en) | 2005-04-11 | 2009-03-26 | Mingjun Huang | Pharmaceutical compositions for and methods of inhibiting HCV replication |
US20060276511A1 (en) | 2005-06-06 | 2006-12-07 | Michael Serrano-Wu | Inhibitors of HCV replication |
US20070274951A1 (en) | 2006-02-09 | 2007-11-29 | Xiao Tong | Combinations comprising HCV protease inhibitor(s) and HCV polymerase inhibitor(s), and methods of treatment related thereto |
US20080044379A1 (en) | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US20090068140A1 (en) | 2006-08-11 | 2009-03-12 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
US20080050336A1 (en) | 2006-08-11 | 2008-02-28 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US20080044380A1 (en) | 2006-08-11 | 2008-02-21 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
WO2008136815A2 (en) | 2006-12-22 | 2008-11-13 | Schering Corporation | 5, 6-ring annulated indole derivatives and use thereof |
WO2008082484A1 (en) | 2006-12-22 | 2008-07-10 | Schering Corporation | 4,5-ring annulated indole derivatives for treating or preventing of hcv and related viral infections |
WO2008082488A1 (en) | 2006-12-22 | 2008-07-10 | Schering Corporation | 4, 5-ring annulated indole derivatives for treating or preventing of hcv and related viral infections |
WO2008083351A2 (en) | 2006-12-29 | 2008-07-10 | Genifuel Corporation | Controlled growth environments for algae cultivation |
WO2008124148A2 (en) | 2007-04-10 | 2008-10-16 | Schering Corporation | Sulfur compounds as inhiibitors of hepatitis c virus ns3 serine protease |
US20080311075A1 (en) | 2007-05-17 | 2008-12-18 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
US20090020478A1 (en) | 2007-07-19 | 2009-01-22 | Bayer Material Science Ag | Processes for the regeneration of an anion exchanger loaded with hexachlorostannate |
WO2009032125A1 (en) | 2007-08-29 | 2009-03-12 | Schering Corporation | 2,3-substituted azaindole derivatives for treating viral infections |
WO2009032116A1 (en) | 2007-08-29 | 2009-03-12 | Schering Corporation | 2, 3-substituted indole derivatives for treating viral infections |
WO2009032123A2 (en) | 2007-08-29 | 2009-03-12 | Schering Corporation | Tetracyclic indole derivatives and their use for treating or preventing viral infections |
WO2009032124A1 (en) | 2007-08-29 | 2009-03-12 | Schering Corporation | Substituted indole derivatives and methods of use thereof |
CN101462999A (en) | 2007-12-21 | 2009-06-24 | 上海药明康德新药开发有限公司 | Fluoro or difluoro-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivatives, and preparation thereof |
US20090202483A1 (en) | 2008-02-13 | 2009-08-13 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
WO2009102633A1 (en) * | 2008-02-13 | 2009-08-20 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
WO2010065681A1 (en) | 2008-12-03 | 2010-06-10 | Presidio Pharmaceuticals, Inc. | Inhibitors of hcv ns5a |
WO2010065668A1 (en) | 2008-12-03 | 2010-06-10 | Presidio Pharmaceuticals, Inc. | Inhibitors of hcv ns5a |
WO2010065674A1 (en) | 2008-12-03 | 2010-06-10 | Presidio Pharmaceuticals, Inc. | Inhibitors of hcv ns5a |
Non-Patent Citations (53)
Title |
---|
"Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS |
"Comprehensive Heterocyclic Chemistry", ELSEVIER |
"Comprehensive Organic Chemistry", ELSEVIER |
"Comprehensive Organic Functional Group Transformations" |
"Comprehensive Organic Transformation", WILY-CVH |
"Handbook of Pharmaceutical Salts. Properties, Selection and Use", 2002, WILEY-VCH |
"The Orange Book", FOOD & DRUG ADMINISTRATION |
A. L. BINGHAM ET AL., CHEM. COMMUN., 2001, pages 603 - 604 |
ANDERSON ET AL.: "The Practice of Medicinal Chemistry", 1996, ACADEMIC PRESS |
ANGEW CHEM. INT. ED. ENGL., vol. 40, 2001, pages 4544 |
BEAULIEU ET AL., CURRENT OPINION IN INVESTIGATIONAL DRUGS, vol. 5, 2004, pages 838 |
BIO WORLD TODAY, vol. 9, no. 217, 10 November 1998 (1998-11-10), pages 4 |
CHOSHI ET AL., J ORG. CHEM., vol. 62, 1997, pages 2535 - 2543 |
DIMASI ET AL., J VIROL, vol. 71, no. 10, 1997, pages 7461 - 7469 |
E. C. VAN TONDER ET AL., AAPS PHARMSCITECHOURS., vol. 5, no. 1, 2004 |
ELZOUKI ET AL., J HEPAT, vol. 271, 1997, pages 42 - 48 |
FANTA ET AL., SYNTH., 1974, pages 9 - 21 |
GREENE ET AL.: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE |
GUDASHEVA ET AL., J. MED. CHEM THER., vol. 31, 1996, pages 151 |
HAMADA ET AL., ORGANIC LETTERS, vol. 20, 2009, pages 4664 - 4667 |
HOLLAND ET AL., PATHOLOGY, vol. 30, no. 2, 1998, pages 192 - 195 |
HUANG, Y ET AL., VIROLOGY, vol. 364, 2007, pages 1 - 9 |
INGALLINELLA ET AL., BIOCHEMISTRY, vol. 37, no. 25, 1998, pages 8906 - 8914 |
J. AM. CHEM. SOC, vol. 73, 1997, pages 4297 |
JAN M. VROLIJK ET AL.: "A replicons-based bioassay for the measurement of interferons inpatients with chronic hepatitis C", J. VIROLOGICAL METHODS, vol. 110, 2003, pages 201 |
K. DEL CARMEN ET AL., ANNALS OF HEPATOLOGY, vol. 3, 2004, pages 54 |
KATO ET AL., GASTROENTEROLOGY., vol. 125, no. 6, 2003, pages 1808 - 17 |
KRICKA ET AL., CHEM. REW., vol. 74, 1974, pages 101 - 123 |
KRICKA ET AL., J. CHEM. SOC. PERKIN TRANS I, 1973, pages 859 - 863 |
KRICKA ET AL., J. CHEM. SOC. PERKIN TRANS L, 1973, pages 859 - 863 |
KURFUERST ET AL., COLL. CZECH. CHEM. COMM., vol. 54, 1989, pages 1705 - 1715 |
LAMBALLERIE ET AL., J GEN VIROL, vol. 78, no. 1, 1997, pages 45 - 51 |
LANDRO, BIOCHEMISTRY, vol. 36, no. 31, 1997, pages 9340 - 9348 |
LLINÀS-BRUNET ET AL., BIOORG MED CHEM LETT, vol. 8, no. 13, 1998, pages 1713 - 1718 |
LOHMANN ET AL., SCIENCE, vol. 285, no. 5424, 1999, pages 110 - 3 |
M. CAIRA ET AL., J. PHARMACEUTICAL SCI., vol. 93, no. 3, 2004, pages 601 - 611 |
MALCOLM ET AL., ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 50, 2006, pages 1013 - 1020 |
MARTIN ET AL., BIOCHEMISTRY, vol. 37, no. 33, 1998, pages 11459 - 11468 |
MARTIN ET AL., PROTEIN ENG, vol. 10, no. 5, 1997, pages 607 - 614 |
NI ET AL., CURRENT OPINION IN DRUG DISCOVERY AND DEVELOPMENT, vol. 7, no. 4, 2004, pages 446 |
P. GOULD, INTERNATIONAL J. OF PHARMACEUTICS, vol. 33, 1986, pages 201 - 217 |
PIETSCHMANN, T.; BARTENSCHLAGER, R., CURRENT OPINION IN DRUG DISCOVERY RESEARCH, vol. 4, 2001, pages 657 - 664 |
S. BERGE ET AL., JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 66, no. 1, 1977, pages 1 - 19 |
SAROJA ET AL., J. ORG. CHEM., vol. 69, 2004, pages 987 - 990 |
SCOTT ET AL., J. AM. CHEM. SOC., vol. 106, 1984, pages 4630 |
SIMMONDS ET AL., J GEN VIROL, vol. 74, no. 11, 1993, pages 2391 - 2399 |
SIMMONDS ET AL., J GEN VIROL, vol. 75, no. 5, 1994, pages 1053 - 1061 |
STEVEN S. CARROLL ET AL.: "lnhibition of Hepatitis C Virus RNA Replication by 2'-Modified Nucleoside Analogs", J. BIOLOGICAL CHEMISTRY, vol. 278, no. 14, 2003, pages 11979, XP002316770, DOI: doi:10.1074/jbc.M210914200 |
T. HIGUCHI; V. STELLA, PRO-DRUGS AS NOVEL DELIVERY SYSTEMS, vol. 14, 1987 |
T. W. GREENE ET AL.: "Protective Groups in Organic Synthesis", 1991, WILEY |
TAN ET AL., NATURE REVIEWS, vol. 1, 2002, pages 867 |
TANJI ET AL., J. VIROL., vol. 69, 1995, pages 3980 - 3986 |
YI ET AL., J VIRAL., vol. 78, no. 15, 2004, pages 7904 - 15 |
Cited By (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8541424B2 (en) | 2008-12-23 | 2013-09-24 | Abbott Laboratories | Anti-viral compounds |
US8546405B2 (en) | 2008-12-23 | 2013-10-01 | Abbott Laboratories | Anti-viral compounds |
US9249138B2 (en) | 2008-12-23 | 2016-02-02 | Abbvie Inc. | Anti-viral compounds |
US9163017B2 (en) | 2008-12-23 | 2015-10-20 | Abbvie Inc. | Anti-viral compounds |
US9278922B2 (en) | 2009-04-15 | 2016-03-08 | Abbvie Inc. | Anti-viral compounds |
US8822430B2 (en) | 2009-05-13 | 2014-09-02 | Gilead Pharmasset Llc | Antiviral compounds |
US9981955B2 (en) | 2009-05-13 | 2018-05-29 | Gilead Pharmasset Llc | Antiviral compounds |
US8669234B2 (en) | 2009-05-13 | 2014-03-11 | Gilead Sciences, Inc. | Antiviral compounds |
US9511056B2 (en) | 2009-05-13 | 2016-12-06 | Gilead Pharmasset Llc | Antiviral compounds |
US8841278B2 (en) | 2009-05-13 | 2014-09-23 | Gilead Pharmasset Llc | Antiviral compounds |
US8921514B2 (en) | 2009-06-11 | 2014-12-30 | Abbvie Inc. | Anti-viral compounds |
US8716454B2 (en) | 2009-06-11 | 2014-05-06 | Abbvie Inc. | Solid compositions |
US9586978B2 (en) | 2009-06-11 | 2017-03-07 | Abbvie Inc. | Anti-viral compounds |
US8691938B2 (en) | 2009-06-11 | 2014-04-08 | Abbvie Inc. | Anti-viral compounds |
US8937150B2 (en) | 2009-06-11 | 2015-01-20 | Abbvie Inc. | Anti-viral compounds |
US9394279B2 (en) | 2009-06-11 | 2016-07-19 | Abbvie Inc. | Anti-viral compounds |
US10028937B2 (en) | 2009-06-11 | 2018-07-24 | Abbvie Inc. | Anti-viral compounds |
US10039754B2 (en) | 2009-06-11 | 2018-08-07 | Abbvie Inc. | Anti-viral compounds |
US8765731B2 (en) | 2009-07-16 | 2014-07-01 | Vertex Pharmaceuticals Incorporated | Benzimidazole analogues for the treatment or prevention of flavivirus infections |
US8779156B2 (en) | 2010-03-24 | 2014-07-15 | Vertex Pharmaceuticals Incorporated | Analogues for the treatment or prevention of flavivirus infections |
US8686026B2 (en) | 2010-06-10 | 2014-04-01 | Abbvie Inc. | Solid compositions |
US9932326B2 (en) | 2010-08-26 | 2018-04-03 | Cocrystal Pharma, LLC | Potent and selective inhibitors of hepatitis C virus |
US9181227B2 (en) | 2010-08-26 | 2015-11-10 | Cocrystal Pharma, Inc. | Potent and selective inhibitors of hepatitis C virus |
US8859595B2 (en) | 2010-08-26 | 2014-10-14 | Rfs Pharma, Llc | Potent and selective inhibitors of hepatitis C virus |
US9309260B2 (en) | 2010-10-26 | 2016-04-12 | Presidio Pharmaceuticals, Inc. | Inhibitors of hepatitis C virus |
JP2014500861A (en) * | 2010-10-26 | 2014-01-16 | プレシディオ ファーマシューティカルズ インコーポレイテッド | Hepatitis C virus inhibitor |
US9085587B2 (en) | 2010-10-26 | 2015-07-21 | Presidio Pharmaceuticals, Inc. | Inhibitors of hepatitis C virus |
US9156823B2 (en) | 2010-11-17 | 2015-10-13 | Gilead Pharmasset Llc | Antiviral compounds |
US10344019B2 (en) | 2010-11-17 | 2019-07-09 | Gilead Pharmasset Llc | Antiviral compounds |
WO2012068234A3 (en) * | 2010-11-17 | 2013-01-17 | 12Gilead Sciences, Inc. | Antiviral compounds |
US9340520B2 (en) | 2011-02-07 | 2016-05-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8552047B2 (en) | 2011-02-07 | 2013-10-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9546160B2 (en) | 2011-05-12 | 2017-01-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
US10201541B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
US20150057246A1 (en) * | 2011-09-14 | 2015-02-26 | Michael P. Dwyer | Silyl-containing heterocyclic compounds and methods of use thereof for the treatment of viral diseases |
EP2755982A4 (en) * | 2011-09-14 | 2015-03-25 | Merck Sharp & Dohme | Silyl-containing heterocyclic compounds and methods of use thereof for the treatment of viral diseases |
US10456414B2 (en) | 2011-09-16 | 2019-10-29 | Gilead Pharmasset Llc | Methods for treating HCV |
US9393256B2 (en) | 2011-09-16 | 2016-07-19 | Gilead Pharmasset Llc | Methods for treating HCV |
US9221833B2 (en) | 2011-11-16 | 2015-12-29 | Gilead Pharmasset Llc | Antiviral compounds |
US8921341B2 (en) | 2011-11-16 | 2014-12-30 | Gilead Pharmasset Llc | Antiviral compounds |
US9051340B2 (en) | 2011-11-16 | 2015-06-09 | Gilead Pharmasset Llc | Antiviral compounds |
US9809600B2 (en) | 2011-11-16 | 2017-11-07 | Gilead Pharmasset Llc | Antiviral compounds |
US9868745B2 (en) | 2011-11-16 | 2018-01-16 | Gilead Pharmasset Llc | Antiviral compounds |
US8940718B2 (en) | 2011-11-16 | 2015-01-27 | Gilead Pharmasset Llc | Antiviral compounds |
US10807990B2 (en) | 2011-11-16 | 2020-10-20 | Gilead Pharmasset Llc | Antiviral compounds |
US8575135B2 (en) | 2011-11-16 | 2013-11-05 | Gilead Sciences, Inc. | Antiviral compounds |
US9034832B2 (en) | 2011-12-29 | 2015-05-19 | Abbvie Inc. | Solid compositions |
US9326973B2 (en) | 2012-01-13 | 2016-05-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US10800789B2 (en) | 2012-05-16 | 2020-10-13 | Gilead Pharmasset Llc | Antiviral compounds |
US10039779B2 (en) | 2013-01-31 | 2018-08-07 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US11484534B2 (en) | 2013-03-14 | 2022-11-01 | Abbvie Inc. | Methods for treating HCV |
US9717712B2 (en) | 2013-07-02 | 2017-08-01 | Bristol-Myers Squibb Company | Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus |
US9770439B2 (en) | 2013-07-02 | 2017-09-26 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9775831B2 (en) | 2013-07-17 | 2017-10-03 | Bristol-Myers Squibb Company | Combinations comprising biphenyl derivatives for use in the treatment of HCV |
US10086011B2 (en) | 2013-08-27 | 2018-10-02 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US11116783B2 (en) | 2013-08-27 | 2021-09-14 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US11707479B2 (en) | 2013-08-27 | 2023-07-25 | Gilead Sciences, Inc. | Combination formulation of two antiviral compounds |
US10105365B2 (en) | 2014-01-03 | 2018-10-23 | Abbvie Inc. | Solid antiviral dosage forms |
US9744170B2 (en) | 2014-01-03 | 2017-08-29 | Abbvie Inc. | Solid antiviral dosage forms |
US9333204B2 (en) | 2014-01-03 | 2016-05-10 | Abbvie Inc. | Solid antiviral dosage forms |
US11203599B2 (en) | 2014-06-11 | 2021-12-21 | Gilead Pharmasset Llc | Solid forms of an antiviral compound |
US10617675B2 (en) | 2015-08-06 | 2020-04-14 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
Also Published As
Publication number | Publication date |
---|---|
AR080676A1 (en) | 2012-05-02 |
EP2545060B1 (en) | 2015-11-25 |
EP2545060A1 (en) | 2013-01-16 |
SG183526A1 (en) | 2012-09-27 |
CN102918049A (en) | 2013-02-06 |
CL2012002489A1 (en) | 2012-11-30 |
ZA201206716B (en) | 2013-05-29 |
CR20120460A (en) | 2012-11-01 |
ECSP12012147A (en) | 2012-10-30 |
ES2558554T3 (en) | 2016-02-05 |
US8609635B2 (en) | 2013-12-17 |
DOP2012000243A (en) | 2012-12-31 |
MA34147B1 (en) | 2013-04-03 |
MX2012010392A (en) | 2012-10-03 |
US20110223134A1 (en) | 2011-09-15 |
BR112012022125A2 (en) | 2016-11-01 |
AU2011224698A1 (en) | 2012-11-01 |
NI201200139A (en) | 2013-01-24 |
JP2013522202A (en) | 2013-06-13 |
CO6592102A2 (en) | 2013-01-02 |
EA201290882A1 (en) | 2013-04-30 |
TN2012000416A1 (en) | 2014-01-30 |
KR20130008040A (en) | 2013-01-21 |
PE20130062A1 (en) | 2013-02-28 |
CA2792121A1 (en) | 2011-09-15 |
TW201136943A (en) | 2011-11-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2545060B1 (en) | Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases | |
EP2621279B1 (en) | Fused tetracycle derivatives and methods of use thereof for the treatment of viral diseases | |
EP2685984B1 (en) | Tetracyclic xanthene derivatives and methods of use thereof for the treatment of viral diseases | |
EP2621932A1 (en) | Tetracyclic heterocycle compounds for treating hepatitis c viral infection | |
EP2516430A1 (en) | Fused tricyclic compounds and methods of use thereof for the treatment of viral diseases | |
WO2012040923A1 (en) | Tetracyclic indole derivatives and methods of use thereof for the treatment of viral diseases | |
EP2435424A1 (en) | Antiviral compounds composed of three linked aryl moieties to treat diseases such as hepatitis c | |
WO2012018534A2 (en) | Substituted biphenylene compounds and methods of use thereof for the treatment of viral diseases | |
WO2012040924A1 (en) | Fused tetracyclic heterocycle compounds and methods of use thereof for treatment of viral diseases | |
MX2013003631A (en) | Tetracyclic indole derivatives for treating hepatitis c virus infection. | |
WO2012003642A1 (en) | Fused tricyclic compounds and use thereof for treating viral diseases | |
WO2014110687A1 (en) | Thiazolyl-substitued tetracyclic compounds and methods of use thereof for treatment of viral diseases | |
EP2755982A1 (en) | Silyl-containing heterocyclic compounds and methods of use thereof for the treatment of viral diseases | |
EP2755981A1 (en) | Silyl-containing heterocyclic compounds and methods of use thereof for the treatment of viral diseases | |
WO2014110688A1 (en) | Thiophene- sub stitued tetracyclic compounds and methods of use thereof for the treatment of viral diseases | |
EP3393585A1 (en) | Silane-containing heterocyclic compounds and methods of use thereof for the treatment of viral diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201180023353.8 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11707763 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 221485 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 7255/CHENP/2012 Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: 2792121 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12012501748 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012557114 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 001466-2012 Country of ref document: PE Ref document number: MX/A/2012/010392 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12155041 Country of ref document: CO Ref document number: CR2012-000460 Country of ref document: CR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1201004599 Country of ref document: TH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011707763 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 20127026331 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201290882 Country of ref document: EA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12867 Country of ref document: GE |
|
ENP | Entry into the national phase |
Ref document number: 2011224698 Country of ref document: AU Date of ref document: 20110304 Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112012022125 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112012022125 Country of ref document: BR Kind code of ref document: A2 Effective date: 20120831 |