EA026235B1 - Макроциклические ингибиторы вирусов flaviviridae - Google Patents

Info

Publication number

EA026235B1

EA026235B1 EA201492209A EA201492209A EA026235B1 EA 026235 B1 EA026235 B1 EA 026235B1 EA 201492209 A EA201492209 A EA 201492209A EA 201492209 A EA201492209 A EA 201492209A EA 026235 B1 EA026235 B1 EA 026235B1

Authority

EA

Eurasian Patent Office

Prior art keywords

mmol

mixture

alkyl

added

reaction mixture

Prior art date

2012-06-08

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• 239000003112 inhibitor Substances 0.000 title claims description 37
• 241000710781 Flaviviridae Species 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 299
• 239000000203 mixture Substances 0.000 claims abstract description 285
• 238000000034 method Methods 0.000 claims abstract description 54
• 150000003839 salts Chemical class 0.000 claims abstract description 51
• 230000009385 viral infection Effects 0.000 claims abstract description 17
• 208000005176 Hepatitis C Diseases 0.000 claims abstract description 6
• -1 (cyclopropylmethyl) - Chemical class 0.000 claims description 208
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• 125000000217 alkyl group Chemical group 0.000 claims description 42
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
• 125000004432 carbon atom Chemical group C* 0.000 claims description 29
• 229910052799 carbon Inorganic materials 0.000 claims description 25
• 201000010099 disease Diseases 0.000 claims description 21
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
• 125000000732 arylene group Chemical group 0.000 claims description 17
• 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 13
• 239000003814 drug Substances 0.000 claims description 13
• 125000005549 heteroarylene group Chemical group 0.000 claims description 12
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
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• 208000036142 Viral infection Diseases 0.000 claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 claims description 10
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
• 229910052731 fluorine Inorganic materials 0.000 claims description 9
• 239000011737 fluorine Substances 0.000 claims description 9
• 229960000329 ribavirin Drugs 0.000 claims description 9
• 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 9
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
• 108010050904 Interferons Proteins 0.000 claims description 8
• 102000014150 Interferons Human genes 0.000 claims description 8
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 239000013256 coordination polymer Substances 0.000 claims description 7
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
• 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 claims description 6
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
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• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
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• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
• 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 claims description 4
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• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 3
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
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• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
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• 108010017101 telaprevir Proteins 0.000 claims description 3
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
• 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 2
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
• GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 2
• 101150065749 Churc1 gene Proteins 0.000 claims description 2
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• 206010061218 Inflammation Diseases 0.000 claims description 2
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• 241000315672 SARS coronavirus Species 0.000 claims description 2
• 208000004006 Tick-borne encephalitis Diseases 0.000 claims description 2
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• 239000000556 agonist Substances 0.000 claims description 2
• 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
• 230000007882 cirrhosis Effects 0.000 claims description 2
• 208000019425 cirrhosis of liver Diseases 0.000 claims description 2
• 230000002519 immonomodulatory effect Effects 0.000 claims description 2
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• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
• UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical group COCl UCFFGYASXIPWPD-UHFFFAOYSA-N 0.000 claims description 2
• PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims description 2
• 235000020824 obesity Nutrition 0.000 claims description 2
• 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 claims description 2
• 229960002063 sofosbuvir Drugs 0.000 claims description 2
• 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 claims description 2
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
• WDPVNDRNBJNETA-JBLDHEPKSA-N (2s)-2-amino-6-[[(2s)-1-[[(1r)-1-carboxy-2-methylpropyl]amino]-1-oxo-4-sulfanylbutan-2-yl]amino]-6-oxohexanoic acid Chemical compound CC(C)[C@H](C(O)=O)NC(=O)[C@H](CCS)NC(=O)CCC[C@H](N)C(O)=O WDPVNDRNBJNETA-JBLDHEPKSA-N 0.000 claims 1
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