EA018935B1 - Нуклеозидный ингибитор для вгс (hcv) - Google Patents

Info

Publication number

EA018935B1

EA018935B1 EA200970358A EA200970358A EA018935B1 EA 018935 B1 EA018935 B1 EA 018935B1 EA 200970358 A EA200970358 A EA 200970358A EA 200970358 A EA200970358 A EA 200970358A EA 018935 B1 EA018935 B1 EA 018935B1

Authority

EA

Eurasian Patent Office

Prior art keywords

compound

methyl

hcv

azido

deoxycytidine

Prior art date

2006-10-10

Links

• Espacenet
• Global Dossier
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• 239000002777 nucleoside Substances 0.000 title description 40
• 150000003833 nucleoside derivatives Chemical class 0.000 title description 26
• 239000003112 inhibitor Substances 0.000 title description 19
• 150000001875 compounds Chemical class 0.000 claims abstract description 113
• 201000010099 disease Diseases 0.000 claims abstract description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
• 230000001404 mediated effect Effects 0.000 claims abstract description 6
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 5
• 241000711549 Hepacivirus C Species 0.000 claims description 67
• -1 triphosphate ester Chemical class 0.000 claims description 62
• 150000003839 salts Chemical class 0.000 claims description 33
• 238000011282 treatment Methods 0.000 claims description 28
• 125000000217 alkyl group Chemical group 0.000 claims description 26
• 239000001226 triphosphate Substances 0.000 claims description 21
• 235000011178 triphosphate Nutrition 0.000 claims description 20
• 239000003814 drug Substances 0.000 claims description 19
• 229910052739 hydrogen Inorganic materials 0.000 claims description 18
• 229940079593 drug Drugs 0.000 claims description 15
• 239000008194 pharmaceutical composition Substances 0.000 claims description 14
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
• 238000002360 preparation method Methods 0.000 claims description 14
• 239000001257 hydrogen Substances 0.000 claims description 13
• 230000010076 replication Effects 0.000 claims description 12
• 239000003937 drug carrier Substances 0.000 claims description 11
• 239000003085 diluting agent Substances 0.000 claims description 10
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
• 239000003443 antiviral agent Substances 0.000 claims description 6
• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 239000001177 diphosphate Substances 0.000 claims description 5
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
• XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 4
• 235000011180 diphosphates Nutrition 0.000 claims description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
• 150000002431 hydrogen Chemical class 0.000 claims description 4
• 150000004712 monophosphates Chemical class 0.000 claims description 4
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
• 210000000987 immune system Anatomy 0.000 claims description 2
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
• 101100452676 Arabidopsis thaliana INVB gene Proteins 0.000 claims 2
• 239000000203 mixture Substances 0.000 abstract description 41
• 238000000034 method Methods 0.000 abstract description 18
• 208000005176 Hepatitis C Diseases 0.000 abstract description 4
• 229940123066 Polymerase inhibitor Drugs 0.000 abstract description 2
• 239000000543 intermediate Substances 0.000 abstract description 2
• DEUZIURSVQYVJZ-UUCPZDEKSA-N 4-amino-1-[(2r,3s,4s,5r)-5-azido-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidin-2-one Chemical compound C[C@H]1[C@H](O)[C@](CO)(N=[N+]=[N-])O[C@H]1N1C(=O)N=C(N)C=C1 DEUZIURSVQYVJZ-UUCPZDEKSA-N 0.000 abstract 2
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
• 239000000243 solution Substances 0.000 description 38
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
• 210000004027 cell Anatomy 0.000 description 34
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
• 239000011541 reaction mixture Substances 0.000 description 26
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
• 238000006243 chemical reaction Methods 0.000 description 24
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
• UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 18
• 108091032973 (ribonucleotides)n+m Proteins 0.000 description 17
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• 239000002904 solvent Substances 0.000 description 16
• 238000003786 synthesis reaction Methods 0.000 description 16
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
• 239000004480 active ingredient Substances 0.000 description 14
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• 239000000651 prodrug Substances 0.000 description 14
• 229940002612 prodrug Drugs 0.000 description 14
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
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• 238000005917 acylation reaction Methods 0.000 description 11
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• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
• ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 10
• 230000010933 acylation Effects 0.000 description 10
• 125000004432 carbon atom Chemical group C* 0.000 description 10
• 239000003153 chemical reaction reagent Substances 0.000 description 10
• 238000010898 silica gel chromatography Methods 0.000 description 10
• 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 description 9
• 238000004458 analytical method Methods 0.000 description 9
• 125000003118 aryl group Chemical group 0.000 description 9
• 239000012267 brine Substances 0.000 description 9
• 239000004615 ingredient Substances 0.000 description 9
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
• 238000002560 therapeutic procedure Methods 0.000 description 9
• WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 8
• 238000004587 chromatography analysis Methods 0.000 description 8
• 229940126208 compound 22 Drugs 0.000 description 8
• 125000003835 nucleoside group Chemical group 0.000 description 8
• 239000012074 organic phase Substances 0.000 description 8
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
• 230000002829 reductive effect Effects 0.000 description 8
• 229960000329 ribavirin Drugs 0.000 description 8
• 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 description 8
• 210000002966 serum Anatomy 0.000 description 8
• 239000011734 sodium Substances 0.000 description 8
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• 102000004190 Enzymes Human genes 0.000 description 7
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• 239000004367 Lipase Substances 0.000 description 7
• 102000004882 Lipase Human genes 0.000 description 7
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• 108091005804 Peptidases Proteins 0.000 description 7
• 239000004365 Protease Substances 0.000 description 7
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
• 239000002253 acid Substances 0.000 description 7
• 229940079322 interferon Drugs 0.000 description 7
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• 230000000840 anti-viral effect Effects 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 210000003494 hepatocyte Anatomy 0.000 description 6
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• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
• LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 6
• 239000010410 layer Substances 0.000 description 6
• 239000007788 liquid Substances 0.000 description 6
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
• 230000004048 modification Effects 0.000 description 6
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• RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 6
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