TWI577672B - Ｃ型肝炎病毒抑制劑 - Google Patents

Info

Publication number

TWI577672B

TWI577672B TW101140863A TW101140863A TWI577672B TW I577672 B TWI577672 B TW I577672B TW 101140863 A TW101140863 A TW 101140863A TW 101140863 A TW101140863 A TW 101140863A TW I577672 B TWI577672 B TW I577672B

Authority

TW

Taiwan

Prior art keywords

alkyl

group

methyl

etoac

mmol

Prior art date

2011-11-03

Links

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• 241000711549 Hepacivirus C Species 0.000 title claims description 51
• 239000003112 inhibitor Substances 0.000 title claims description 31
• 125000000217 alkyl group Chemical group 0.000 claims description 233
• 150000001875 compounds Chemical class 0.000 claims description 205
• 239000000543 intermediate Substances 0.000 claims description 103
• 239000001257 hydrogen Substances 0.000 claims description 94
• 229910052739 hydrogen Inorganic materials 0.000 claims description 94
• 238000000034 method Methods 0.000 claims description 86
• -1 -C(O)NR a R b Chemical group 0.000 claims description 80
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 72
• 125000000623 heterocyclic group Chemical group 0.000 claims description 66
• 229910052757 nitrogen Inorganic materials 0.000 claims description 53
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 52
• 125000005843 halogen group Chemical group 0.000 claims description 42
• 150000003839 salts Chemical class 0.000 claims description 40
• 239000008194 pharmaceutical composition Substances 0.000 claims description 38
• 125000001072 heteroaryl group Chemical group 0.000 claims description 34
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
• 241000124008 Mammalia Species 0.000 claims description 29
• 239000002777 nucleoside Substances 0.000 claims description 29
• 125000003545 alkoxy group Chemical group 0.000 claims description 28
• 108010050904 Interferons Proteins 0.000 claims description 26
• 102000014150 Interferons Human genes 0.000 claims description 26
• 239000003814 drug Substances 0.000 claims description 24
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 23
• 150000002431 hydrogen Chemical class 0.000 claims description 23
• 229910052799 carbon Inorganic materials 0.000 claims description 22
• 150000003833 nucleoside derivatives Chemical class 0.000 claims description 22
• UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 22
• 239000000460 chlorine Substances 0.000 claims description 21
• 101800001014 Non-structural protein 5A Proteins 0.000 claims description 20
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
• 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 18
• 229940124597 therapeutic agent Drugs 0.000 claims description 18
• 239000003795 chemical substances by application Substances 0.000 claims description 17
• 208000010710 hepatitis C virus infection Diseases 0.000 claims description 17
• 125000001424 substituent group Chemical group 0.000 claims description 17
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 17
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
• 229940124771 HCV-NS3 protease inhibitor Drugs 0.000 claims description 15
• 125000006239 protecting group Chemical group 0.000 claims description 15
• 230000010076 replication Effects 0.000 claims description 15
• 108700008776 hepatitis C virus NS-5 Proteins 0.000 claims description 14
• 229940047124 interferons Drugs 0.000 claims description 14
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
• 229960000329 ribavirin Drugs 0.000 claims description 14
• 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 14
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 13
• 125000006413 ring segment Chemical group 0.000 claims description 13
• 230000002401 inhibitory effect Effects 0.000 claims description 12
• 125000003277 amino group Chemical group 0.000 claims description 11
• 125000002883 imidazolyl group Chemical group 0.000 claims description 11
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
• 229910052801 chlorine Inorganic materials 0.000 claims description 10
• 229910052731 fluorine Inorganic materials 0.000 claims description 10
• 239000011737 fluorine Substances 0.000 claims description 10
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 9
• 150000001412 amines Chemical class 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 7
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 7
• 125000003835 nucleoside group Chemical group 0.000 claims description 7
• 238000006467 substitution reaction Methods 0.000 claims description 7
• 230000005764 inhibitory process Effects 0.000 claims description 6
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 125000003118 aryl group Chemical group 0.000 claims description 4
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 229910052760 oxygen Inorganic materials 0.000 claims description 4
• 239000001301 oxygen Substances 0.000 claims description 4
• 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 3
• 125000006242 amine protecting group Chemical group 0.000 claims description 3
• 239000000134 cyclophilin inhibitor Substances 0.000 claims description 3
• 125000002015 acyclic group Chemical group 0.000 claims description 2
• 238000002560 therapeutic procedure Methods 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 4
• 102000001493 Cyclophilins Human genes 0.000 claims 3
• 108010068682 Cyclophilins Proteins 0.000 claims 3
• 229940079593 drug Drugs 0.000 claims 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
• 229910052736 halogen Inorganic materials 0.000 claims 1
• 150000002367 halogens Chemical class 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 810
• 235000019439 ethyl acetate Nutrition 0.000 description 401
• 239000011541 reaction mixture Substances 0.000 description 167
• 239000000203 mixture Substances 0.000 description 123
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 110
• 238000002360 preparation method Methods 0.000 description 104
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 94
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 93
• 239000000243 solution Substances 0.000 description 91
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
• 239000000047 product Substances 0.000 description 72
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 67
• 239000012044 organic layer Substances 0.000 description 65
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 61
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 40
• 239000007787 solid Substances 0.000 description 32
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 30
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 30
• 239000002253 acid Substances 0.000 description 28
• 239000007821 HATU Substances 0.000 description 27
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
• 210000004027 cell Anatomy 0.000 description 25
• 150000002148 esters Chemical group 0.000 description 25
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
• 101100441092 Danio rerio crlf3 gene Proteins 0.000 description 24
• 239000012267 brine Substances 0.000 description 24
• 239000011734 sodium Substances 0.000 description 24
• 238000005481 NMR spectroscopy Methods 0.000 description 23
• 238000006243 chemical reaction Methods 0.000 description 23
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
• 230000008569 process Effects 0.000 description 20
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
• ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 18
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
• 238000004458 analytical method Methods 0.000 description 17
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 16
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 229910000027 potassium carbonate Inorganic materials 0.000 description 15
• 238000012360 testing method Methods 0.000 description 15
• 239000010410 layer Substances 0.000 description 14
• 239000003921 oil Substances 0.000 description 14
• 238000000746 purification Methods 0.000 description 14
• 239000013543 active substance Substances 0.000 description 13
• 235000019198 oils Nutrition 0.000 description 13
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
• 239000012043 crude product Substances 0.000 description 12
• 230000000694 effects Effects 0.000 description 12
• 229940079322 interferon Drugs 0.000 description 12
• 238000003756 stirring Methods 0.000 description 12
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 11
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 11
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
• 239000002609 medium Substances 0.000 description 11
• 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 10
• 239000003153 chemical reaction reagent Substances 0.000 description 10
• 239000013078 crystal Substances 0.000 description 10
• SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 10
• 239000000706 filtrate Substances 0.000 description 10
• 239000011570 nicotinamide Substances 0.000 description 10
• 229960003966 nicotinamide Drugs 0.000 description 10
• 230000002829 reductive effect Effects 0.000 description 10
• HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 9
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 9
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
• 238000004440 column chromatography Methods 0.000 description 9
• 201000010099 disease Diseases 0.000 description 9
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
• BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Natural products O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 9
• 239000003208 petroleum Substances 0.000 description 9
• 239000000546 pharmaceutical excipient Substances 0.000 description 9
• 108091032973 (ribonucleotides)n+m Proteins 0.000 description 8
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 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
• 238000006069 Suzuki reaction reaction Methods 0.000 description 8
• 238000003556 assay Methods 0.000 description 8
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
• 229910052794 bromium Inorganic materials 0.000 description 8
• 238000004128 high performance liquid chromatography Methods 0.000 description 8
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
• 235000011056 potassium acetate Nutrition 0.000 description 8
• 229910052938 sodium sulfate Inorganic materials 0.000 description 8
• 235000011152 sodium sulphate Nutrition 0.000 description 8
• PCRRPOJDJXDSHT-ZETCQYMHSA-N (2s)-2-(methoxycarbonylamino)-2-(oxan-4-yl)acetic acid Chemical compound COC(=O)N[C@H](C(O)=O)C1CCOCC1 PCRRPOJDJXDSHT-ZETCQYMHSA-N 0.000 description 7
• FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 7
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 7
• 239000005695 Ammonium acetate Substances 0.000 description 7
• 235000019257 ammonium acetate Nutrition 0.000 description 7
• 229940043376 ammonium acetate Drugs 0.000 description 7
• 239000002585 base Substances 0.000 description 7
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 7
• 239000000843 powder Substances 0.000 description 7
• 229920006395 saturated elastomer Polymers 0.000 description 7
• XTDXZSGSIMLARD-UHFFFAOYSA-N tert-butyl 2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC=CC=C1 XTDXZSGSIMLARD-UHFFFAOYSA-N 0.000 description 7
• CEFVHPDFGLDQKU-YFKPBYRVSA-N (2s)-2-(methoxycarbonylamino)-3-methylbutanoic acid Chemical compound COC(=O)N[C@@H](C(C)C)C(O)=O CEFVHPDFGLDQKU-YFKPBYRVSA-N 0.000 description 6
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
• YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 6
• 239000002775 capsule Substances 0.000 description 6
• DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 6
• 238000009472 formulation Methods 0.000 description 6
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• 208000015181 infectious disease Diseases 0.000 description 6
• IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 6
• 230000035772 mutation Effects 0.000 description 6
• 229960002715 nicotine Drugs 0.000 description 6
• 238000002390 rotary evaporation Methods 0.000 description 6
• 239000000741 silica gel Substances 0.000 description 6
• 229910002027 silica gel Inorganic materials 0.000 description 6
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
• 229910000029 sodium carbonate Inorganic materials 0.000 description 6
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
• BFNMOMYTTGHNGJ-SCSAIBSYSA-N (1s)-2,2-dimethylcyclopropane-1-carboxylic acid Chemical compound CC1(C)C[C@@H]1C(O)=O BFNMOMYTTGHNGJ-SCSAIBSYSA-N 0.000 description 5
• PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 5
• 102100040018 Interferon alpha-2 Human genes 0.000 description 5
• 108010079944 Interferon-alpha2b Proteins 0.000 description 5
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
• 108091005804 Peptidases Proteins 0.000 description 5
• 239000002202 Polyethylene glycol Substances 0.000 description 5
• 239000004365 Protease Substances 0.000 description 5
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 5
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
• 239000003963 antioxidant agent Substances 0.000 description 5
• 235000006708 antioxidants Nutrition 0.000 description 5
• 125000004432 carbon atom Chemical group C* 0.000 description 5
• 238000002648 combination therapy Methods 0.000 description 5
• 125000001153 fluoro group Chemical group F* 0.000 description 5
• 230000007246 mechanism Effects 0.000 description 5
• 239000012299 nitrogen atmosphere Substances 0.000 description 5
• 229910052763 palladium Inorganic materials 0.000 description 5
• 239000006187 pill Substances 0.000 description 5
• 229920001223 polyethylene glycol Polymers 0.000 description 5
• 238000010992 reflux Methods 0.000 description 5
• 238000004007 reversed phase HPLC Methods 0.000 description 5
• 235000017557 sodium bicarbonate Nutrition 0.000 description 5
• 239000002904 solvent Substances 0.000 description 5
• 239000000725 suspension Substances 0.000 description 5
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