JP2012510523A - Ｈｃｖｎｓ５ａの阻害剤 - Google Patents
Ｈｃｖｎｓ５ａの阻害剤 Download PDFInfo
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- JP2012510523A JP2012510523A JP2011539662A JP2011539662A JP2012510523A JP 2012510523 A JP2012510523 A JP 2012510523A JP 2011539662 A JP2011539662 A JP 2011539662A JP 2011539662 A JP2011539662 A JP 2011539662A JP 2012510523 A JP2012510523 A JP 2012510523A
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- Prior art keywords
- compound
- group
- independently
- heteroaryl
- heterocycle
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000003112 inhibitor Substances 0.000 title description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 390
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 208000005176 Hepatitis C Diseases 0.000 claims abstract description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 219
- 125000001072 heteroaryl group Chemical group 0.000 claims description 205
- 125000003118 aryl group Chemical group 0.000 claims description 204
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 181
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 174
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 167
- 125000000217 alkyl group Chemical group 0.000 claims description 163
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 143
- 125000001589 carboacyl group Chemical group 0.000 claims description 142
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 138
- 239000001257 hydrogen Substances 0.000 claims description 125
- 229910052739 hydrogen Inorganic materials 0.000 claims description 125
- 150000002431 hydrogen Chemical group 0.000 claims description 112
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 111
- 125000003545 alkoxy group Chemical group 0.000 claims description 78
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 77
- 238000000034 method Methods 0.000 claims description 66
- 125000005842 heteroatom Chemical group 0.000 claims description 65
- -1 —OH Chemical group 0.000 claims description 60
- 229910052736 halogen Inorganic materials 0.000 claims description 58
- 150000002367 halogens Chemical class 0.000 claims description 58
- 150000003460 sulfonic acids Chemical class 0.000 claims description 57
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 50
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 46
- 229910052799 carbon Inorganic materials 0.000 claims description 42
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 39
- 229940124530 sulfonamide Drugs 0.000 claims description 39
- 150000003456 sulfonamides Chemical class 0.000 claims description 39
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 28
- 150000001413 amino acids Chemical class 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 229910052727 yttrium Inorganic materials 0.000 claims description 18
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000004122 cyclic group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000003367 polycyclic group Chemical group 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 19
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 9
- 150000003871 sulfonates Chemical class 0.000 claims 9
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- WTXXSZUATXIAJO-OWBHPGMISA-N (Z)-14-methylpentadec-2-enoic acid Chemical compound CC(CCCCCCCCCC\C=C/C(=O)O)C WTXXSZUATXIAJO-OWBHPGMISA-N 0.000 claims 1
- 125000004043 oxo group Chemical group O=* 0.000 claims 1
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- 238000002648 combination therapy Methods 0.000 abstract description 13
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 239000007787 solid Substances 0.000 description 56
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 54
- 238000010898 silica gel chromatography Methods 0.000 description 53
- 230000008569 process Effects 0.000 description 50
- 0 Cc1c[n]c(B*)n1 Chemical compound Cc1c[n]c(B*)n1 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 40
- 230000002829 reductive effect Effects 0.000 description 38
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000000543 intermediate Substances 0.000 description 21
- 238000002953 preparative HPLC Methods 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 19
- 150000003840 hydrochlorides Chemical class 0.000 description 19
- 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 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- 239000000460 chlorine Substances 0.000 description 17
- 239000012299 nitrogen atmosphere Substances 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 229940024606 amino acid Drugs 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000012267 brine Substances 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 14
- 238000001514 detection method Methods 0.000 description 13
- 230000014759 maintenance of location Effects 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
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- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 11
- 101800001014 Non-structural protein 5A Proteins 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- YDBPZCVWPFMBDH-QMMMGPOBSA-N tert-butyl (2s)-2-formylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C=O YDBPZCVWPFMBDH-QMMMGPOBSA-N 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
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- 238000004128 high performance liquid chromatography Methods 0.000 description 10
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 9
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- 108010050904 Interferons Proteins 0.000 description 9
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 9
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
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- 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 4
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- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 1
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11972308P | 2008-12-03 | 2008-12-03 | |
| US61/119,723 | 2008-12-03 | ||
| US17359009P | 2009-04-28 | 2009-04-28 | |
| US61/173,590 | 2009-04-28 | ||
| US18295209P | 2009-06-01 | 2009-06-01 | |
| US61/182,952 | 2009-06-01 | ||
| PCT/US2009/066451 WO2010065668A1 (en) | 2008-12-03 | 2009-12-02 | Inhibitors of hcv ns5a |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2012510523A true JP2012510523A (ja) | 2012-05-10 |
| JP2012510523A5 JP2012510523A5 (enExample) | 2013-01-31 |
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| JP2011539662A Pending JP2012510523A (ja) | 2008-12-03 | 2009-12-02 | Ｈｃｖｎｓ５ａの阻害剤 |
| JP2011539670A Pending JP2012510525A (ja) | 2008-12-03 | 2009-12-02 | Ｈｃｖｎｓ５ａの阻害剤 |
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| JP2012528195A (ja) * | 2009-05-29 | 2012-11-12 | メルク・シャープ・アンド・ドーム・コーポレーション | Ｃ型肝炎などの疾患を処置するための３つの結合アリール部分で構成された抗菌性化合物 |
| JP2013515746A (ja) * | 2009-12-24 | 2013-05-09 | ヴァーテックス ファーマシューティカルズ、 インコーポレイテッド | フラビウイルス感染症の治療又は予防のための類似体 |
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