CN103304541A - 病毒聚合酶抑制剂 - Google Patents
病毒聚合酶抑制剂 Download PDFInfo
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- CN103304541A CN103304541A CN2013102311710A CN201310231171A CN103304541A CN 103304541 A CN103304541 A CN 103304541A CN 2013102311710 A CN2013102311710 A CN 2013102311710A CN 201310231171 A CN201310231171 A CN 201310231171A CN 103304541 A CN103304541 A CN 103304541A
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- Prior art keywords
- compound
- alkyl
- methyl
- pharmaceutically acceptable
- mmol
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title abstract description 71
- 230000003612 virological effect Effects 0.000 title abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 213
- 150000003839 salts Chemical class 0.000 claims abstract description 58
- 150000002148 esters Chemical class 0.000 claims abstract description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 131
- 238000000034 method Methods 0.000 claims description 122
- -1 Hydroxy, methyl Chemical group 0.000 claims description 95
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 64
- 125000001424 substituent group Chemical group 0.000 claims description 55
- 150000001412 amines Chemical class 0.000 claims description 49
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 44
- 229910052736 halogen Inorganic materials 0.000 claims description 43
- 229920006395 saturated elastomer Polymers 0.000 claims description 43
- 150000002367 halogens Chemical class 0.000 claims description 42
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 28
- 239000000460 chlorine Substances 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 25
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 25
- 125000005842 heteroatom Chemical group 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 21
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- 238000002360 preparation method Methods 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000004414 alkyl thio group Chemical group 0.000 claims description 14
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- 238000005859 coupling reaction Methods 0.000 claims description 11
- 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 11
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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 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
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- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 9
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 239000003937 drug carrier 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
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 4
- 150000001735 carboxylic acids Chemical class 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims 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 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- 108060004795 Methyltransferase Proteins 0.000 abstract description 18
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- 241000710781 Flaviviridae Species 0.000 abstract description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 2
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- 239000000243 solution Substances 0.000 description 111
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 43
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- 239000002904 solvent Substances 0.000 description 42
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 40
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D471/02—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 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
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- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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| US20050075279A1 (en) * | 2002-10-25 | 2005-04-07 | Boehringer Ingelheim International Gmbh | Macrocyclic peptides active against the hepatitis C virus |
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| US7098231B2 (en) | 2003-01-22 | 2006-08-29 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
| UY28500A1 (es) | 2003-09-05 | 2005-04-29 | Vertex Pharma | Inhibidores de proteasas de serina, en particular proteasa ns3-ns4a del vhc. |
| KR20120091276A (ko) * | 2004-02-20 | 2012-08-17 | 베링거 인겔하임 인터내셔날 게엠베하 | 바이러스 폴리머라제 억제제 |
| US7772271B2 (en) | 2004-07-14 | 2010-08-10 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| BRPI0511834A (pt) | 2004-07-14 | 2008-01-08 | Ptc Therapeutics Inc | métodos por tratar hepatite c |
| US7781478B2 (en) | 2004-07-14 | 2010-08-24 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
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| AR055395A1 (es) | 2005-08-26 | 2007-08-22 | Vertex Pharma | Compuestos inhibidores de la actividad de la serina proteasa ns3-ns4a del virus de la hepatitis c |
| US7816348B2 (en) | 2006-02-03 | 2010-10-19 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
| CN101489557B (zh) | 2006-02-27 | 2013-12-18 | 弗特克斯药品有限公司 | 包含vx-950的共晶体和包含所述共晶体的药物组合物 |
| NZ571280A (en) | 2006-03-16 | 2011-10-28 | Vertex Pharma | Deuterated hepatitis C protease inhibitors |
| GB0608928D0 (en) | 2006-05-08 | 2006-06-14 | Angeletti P Ist Richerche Bio | Therapeutic agents |
| BRPI0716060A2 (pt) | 2006-08-17 | 2013-09-17 | Boehringer Ingelheim Int | inibidores de polimerase viral. |
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2010
- 2010-05-10 JP JP2010108526A patent/JP5394978B2/ja not_active Expired - Fee Related
- 2010-09-27 US US12/891,112 patent/US8030309B2/en not_active Expired - Lifetime
- 2010-09-30 JP JP2010221765A patent/JP2010280740A/ja not_active Withdrawn
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2012
- 2012-04-15 IL IL219150A patent/IL219150A0/en unknown
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2013
- 2013-09-02 JP JP2013181619A patent/JP2013237708A/ja not_active Withdrawn
- 2013-10-25 AR ARP130103893A patent/AR093144A2/es unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2363274A1 (en) * | 1999-12-27 | 2001-07-05 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs for hepatitis c |
| CA2449180A1 (en) * | 2001-07-25 | 2003-02-06 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
| WO2003010140A2 (en) * | 2001-07-25 | 2003-02-06 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c virus polymerase inhibitors with heterobicyclic structure |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113620960A (zh) * | 2016-08-26 | 2021-11-09 | 吉利德科学公司 | 取代的吡咯嗪化合物及其用途 |
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