RU2298001C2 - Ингибиторы вируса гепатита с - Google Patents
Ингибиторы вируса гепатита с Download PDFInfo
- Publication number
- RU2298001C2 RU2298001C2 RU2004137480/04A RU2004137480A RU2298001C2 RU 2298001 C2 RU2298001 C2 RU 2298001C2 RU 2004137480/04 A RU2004137480/04 A RU 2004137480/04A RU 2004137480 A RU2004137480 A RU 2004137480A RU 2298001 C2 RU2298001 C2 RU 2298001C2
- Authority
- RU
- Russia
- Prior art keywords
- alkyl
- compound according
- alkoxy
- compound
- stage
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 6
- 241000711549 Hepacivirus C Species 0.000 title abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 473
- 150000001875 compounds Chemical class 0.000 claims abstract description 408
- 239000000203 mixture Substances 0.000 claims abstract description 168
- -1 (C7-C14)-alkylaryl Chemical group 0.000 claims abstract description 105
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 42
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims abstract description 33
- 125000005843 halogen group Chemical group 0.000 claims abstract description 26
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims abstract description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 20
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 17
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 claims abstract description 13
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 8
- 125000004001 thioalkyl group Chemical group 0.000 claims abstract description 7
- 208000015181 infectious disease Diseases 0.000 claims abstract description 5
- MKCBRYIXFFGIKN-UHFFFAOYSA-N bicyclo[1.1.1]pentane Chemical compound C1C2CC1C2 MKCBRYIXFFGIKN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 223
- 125000000217 alkyl group Chemical group 0.000 claims description 115
- 125000003545 alkoxy group Chemical group 0.000 claims description 55
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 42
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 40
- 229920002554 vinyl polymer Polymers 0.000 claims description 39
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 239000012453 solvate Substances 0.000 claims description 29
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- 150000001412 amines Chemical class 0.000 claims description 25
- 239000000651 prodrug Substances 0.000 claims description 25
- 229940002612 prodrug Drugs 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 18
- 150000002537 isoquinolines Chemical group 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
- 229910005965 SO 2 Inorganic materials 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 125000005907 alkyl ester group Chemical group 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000005248 alkyl aryloxy group Chemical group 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 108060004795 Methyltransferase Proteins 0.000 claims description 5
- 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 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 229960000329 ribavirin Drugs 0.000 claims description 4
- 108010006035 Metalloproteases Proteins 0.000 claims description 3
- 102000005741 Metalloproteases Human genes 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 239000002955 immunomodulating agent Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 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 3
- 229940122604 HCV protease inhibitor Drugs 0.000 claims description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 2
- 229960003805 amantadine Drugs 0.000 claims description 2
- 229940047124 interferons Drugs 0.000 claims description 2
- 208000010710 hepatitis C virus infection Diseases 0.000 claims 1
- 230000002519 immonomodulatory effect Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 46
- 230000015572 biosynthetic process Effects 0.000 abstract description 35
- 238000003786 synthesis reaction Methods 0.000 abstract description 25
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 9
- 230000004071 biological effect Effects 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 abstract 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 2
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 abstract 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 230000007721 medicinal effect Effects 0.000 abstract 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract 1
- 239000000047 product Substances 0.000 description 347
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 305
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 217
- 230000014759 maintenance of location Effects 0.000 description 203
- 239000000243 solution Substances 0.000 description 179
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 140
- 230000004048 modification Effects 0.000 description 136
- 238000012986 modification Methods 0.000 description 136
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 123
- 239000007787 solid Substances 0.000 description 114
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 93
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 73
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 71
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 69
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 66
- 239000007858 starting material Substances 0.000 description 62
- 239000011541 reaction mixture Substances 0.000 description 59
- 238000004811 liquid chromatography Methods 0.000 description 57
- 239000002904 solvent Substances 0.000 description 57
- 239000000543 intermediate Substances 0.000 description 56
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 52
- 235000019439 ethyl acetate Nutrition 0.000 description 52
- 238000006243 chemical reaction Methods 0.000 description 51
- 239000012267 brine Substances 0.000 description 45
- 239000000284 extract Substances 0.000 description 45
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- 239000000460 chlorine Substances 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 37
- 229960002429 proline Drugs 0.000 description 35
- 241000182988 Assa Species 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 239000002253 acid Substances 0.000 description 31
- 239000002585 base Substances 0.000 description 30
- 108090000765 processed proteins & peptides Proteins 0.000 description 30
- 239000006260 foam Substances 0.000 description 29
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 28
- 239000003921 oil Substances 0.000 description 28
- 235000019198 oils Nutrition 0.000 description 28
- 239000000725 suspension Substances 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- GPKDGVXBXQTHRY-UHFFFAOYSA-N 3-chloropropane-1-sulfonyl chloride Chemical compound ClCCCS(Cl)(=O)=O GPKDGVXBXQTHRY-UHFFFAOYSA-N 0.000 description 25
- 239000007821 HATU Substances 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 24
- 238000002953 preparative HPLC Methods 0.000 description 24
- 125000006239 protecting group Chemical group 0.000 description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 22
- 239000010410 layer Substances 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 20
- 238000005804 alkylation reaction Methods 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 239000012071 phase Substances 0.000 description 20
- 230000029936 alkylation Effects 0.000 description 19
- 239000012043 crude product Substances 0.000 description 19
- 238000000746 purification Methods 0.000 description 19
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 18
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000003776 cleavage reaction Methods 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 239000000843 powder Substances 0.000 description 18
- 230000002441 reversible effect Effects 0.000 description 18
- 230000007017 scission Effects 0.000 description 18
- BRGZEQXWZWBPJH-UHFFFAOYSA-N 1,3-dichloroisoquinoline Chemical compound C1=CC=C2C(Cl)=NC(Cl)=CC2=C1 BRGZEQXWZWBPJH-UHFFFAOYSA-N 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- 229910004298 SiO 2 Inorganic materials 0.000 description 15
- 229940024606 amino acid Drugs 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 238000009833 condensation Methods 0.000 description 15
- 230000005494 condensation Effects 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- 150000001413 amino acids Chemical class 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- UWSLQXIVJUYAIV-UHFFFAOYSA-N 3-bromo-1-chloroisoquinoline Chemical compound C1=CC=C2C(Cl)=NC(Br)=CC2=C1 UWSLQXIVJUYAIV-UHFFFAOYSA-N 0.000 description 13
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 229910052796 boron Inorganic materials 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- 239000005457 ice water Substances 0.000 description 13
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 13
- 229940124530 sulfonamide Drugs 0.000 description 13
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 12
- MSQCQINLJMEVNJ-UHFFFAOYSA-N 1-chloroisoquinoline Chemical class C1=CC=C2C(Cl)=NC=CC2=C1 MSQCQINLJMEVNJ-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 description 12
- 238000007429 general method Methods 0.000 description 12
- KUGLDBMQKZTXPW-JEDNCBNOSA-N methyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)C(C)C KUGLDBMQKZTXPW-JEDNCBNOSA-N 0.000 description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- 239000003039 volatile agent Substances 0.000 description 12
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 11
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- XOFZPIYYMJUNRG-UHFFFAOYSA-N (4-methylphenyl) carbonochloridate Chemical compound CC1=CC=C(OC(Cl)=O)C=C1 XOFZPIYYMJUNRG-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 125000003368 amide group Chemical group 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 239000012634 fragment Substances 0.000 description 10
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 9
- UCOVESIAFFGEOR-UHFFFAOYSA-N 1-chlorophthalazine Chemical compound C1=CC=C2C(Cl)=NN=CC2=C1 UCOVESIAFFGEOR-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 125000003277 amino group Chemical group 0.000 description 9
- 125000001589 carboacyl group Chemical group 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 9
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 9
- 239000008194 pharmaceutical composition Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 238000009835 boiling Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 8
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 8
- 239000012047 saturated solution Substances 0.000 description 8
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 7
- QZBWBBHQRLUOTM-UHFFFAOYSA-N 1-chloro-6-fluoroisoquinoline Chemical compound ClC1=NC=CC2=CC(F)=CC=C21 QZBWBBHQRLUOTM-UHFFFAOYSA-N 0.000 description 7
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 7
- PMMYEEVYMWASQN-BKLSDQPFSA-N 4-hydroxy-L-proline Chemical compound OC1C[NH2+][C@H](C([O-])=O)C1 PMMYEEVYMWASQN-BKLSDQPFSA-N 0.000 description 7
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
- 101710144111 Non-structural protein 3 Proteins 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 238000006482 condensation reaction Methods 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 125000004185 ester group Chemical group 0.000 description 7
- 125000004494 ethyl ester group Chemical group 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 150000003254 radicals Chemical class 0.000 description 7
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DMPRLQGGRJZPDN-LRDDRELGSA-N tert-butyl (1s,2s)-2-ethyl-1-(2-trimethylsilylethoxycarbonylamino)cyclopropane-1-carboxylate Chemical compound CC[C@H]1C[C@@]1(NC(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C DMPRLQGGRJZPDN-LRDDRELGSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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| US60/382,055 | 2002-05-20 |
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| RU2006134702/04A Division RU2315039C9 (ru) | 2002-05-20 | 2003-05-20 | Ингибиторы вируса гепатита с |
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| RU2006134703/04A RU2317303C1 (ru) | 2002-05-20 | 2003-05-20 | Ингибиторы вируса гепатита с |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2373952C1 (ru) * | 2008-07-30 | 2009-11-27 | Юрий Михайлович Амбалов | Способ лечебного питания больных хроническим гепатитом с, получающих комплексную противовирусную терапию |
| RU2515318C2 (ru) * | 2007-12-21 | 2014-05-10 | Авила Терапьютикс, Инк. | Ингибиторы протеазы вируса гепатита с и их применение |
| RU2523790C2 (ru) * | 2007-12-21 | 2014-07-27 | Авила Терапьютикс, Инк. | Ингибиторы протеазы вируса гепатита с и их применение |
| RU2554087C2 (ru) * | 2009-12-18 | 2015-06-27 | Айденикс Фармасьютикалз, Инк. | 5,5-конденсированные ариленовые или гетероариленовые ингибиторы вируса гепатита с |
Families Citing this family (278)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU93056617A (ru) * | 1992-12-16 | 1996-12-27 | Американ Цианамид Компани | Ингибиторы ретровирусной протеазы, способ их получения, промежуточные продукты, способ лечения и фармацевтическая композиция |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2515318C2 (ru) * | 2007-12-21 | 2014-05-10 | Авила Терапьютикс, Инк. | Ингибиторы протеазы вируса гепатита с и их применение |
| RU2523790C2 (ru) * | 2007-12-21 | 2014-07-27 | Авила Терапьютикс, Инк. | Ингибиторы протеазы вируса гепатита с и их применение |
| RU2373952C1 (ru) * | 2008-07-30 | 2009-11-27 | Юрий Михайлович Амбалов | Способ лечебного питания больных хроническим гепатитом с, получающих комплексную противовирусную терапию |
| RU2554087C2 (ru) * | 2009-12-18 | 2015-06-27 | Айденикс Фармасьютикалз, Инк. | 5,5-конденсированные ариленовые или гетероариленовые ингибиторы вируса гепатита с |
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