TW200529822A - Novel ketoamides with cyclic p4's as inhibitors of ns3 serine protease of hepatitis c virus - Google Patents

Info

Publication number

TW200529822A

TW200529822A TW094105517A TW94105517A TW200529822A TW 200529822 A TW200529822 A TW 200529822A TW 094105517 A TW094105517 A TW 094105517A TW 94105517 A TW94105517 A TW 94105517A TW 200529822 A TW200529822 A TW 200529822A

Authority

TW

Taiwan

Prior art keywords

compound

group

mmol

solution

alkyl

Prior art date

2004-02-27

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• 241000711549 Hepacivirus C Species 0.000 title claims description 56
• 239000003112 inhibitor Substances 0.000 title description 13
• 108010022999 Serine Proteases Proteins 0.000 title description 12
• 102000012479 Serine Proteases Human genes 0.000 title description 12
• 125000004122 cyclic group Chemical group 0.000 title description 6
• 150000004797 ketoamides Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 275
• 238000000034 method Methods 0.000 claims abstract description 114
• 108091005804 Peptidases Proteins 0.000 claims abstract description 27
• 239000004365 Protease Substances 0.000 claims abstract description 27
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract 8
• -1 compounds Salt Chemical class 0.000 claims description 83
• 239000000203 mixture Substances 0.000 claims description 72
• 125000000217 alkyl group Chemical group 0.000 claims description 54
• 125000003118 aryl group Chemical group 0.000 claims description 38
• 150000003839 salts Chemical class 0.000 claims description 28
• 125000000623 heterocyclic group Chemical group 0.000 claims description 27
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 23
• 239000000126 substance Substances 0.000 claims description 23
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
• 125000001072 heteroaryl group Chemical group 0.000 claims description 20
• 229940079322 interferon Drugs 0.000 claims description 18
• 125000000304 alkynyl group Chemical group 0.000 claims description 17
• 239000012453 solvate Substances 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 16
• 238000011282 treatment Methods 0.000 claims description 16
• 108010050904 Interferons Proteins 0.000 claims description 14
• 102000014150 Interferons Human genes 0.000 claims description 14
• 150000002148 esters Chemical class 0.000 claims description 13
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
• 102000004196 processed proteins & peptides Human genes 0.000 claims description 13
• 125000001424 substituent group Chemical group 0.000 claims description 13
• 239000004480 active ingredient Substances 0.000 claims description 12
• 125000003342 alkenyl group Chemical group 0.000 claims description 12
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
• 229910052739 hydrogen Inorganic materials 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 12
• 208000005176 Hepatitis C Diseases 0.000 claims description 11
• 230000036961 partial effect Effects 0.000 claims description 11
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• 229920001184 polypeptide Polymers 0.000 claims description 9
• 230000000694 effects Effects 0.000 claims description 8
• 201000010099 disease Diseases 0.000 claims description 7
• 238000004519 manufacturing process Methods 0.000 claims description 7
• 208000024891 symptom Diseases 0.000 claims description 7
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 6
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
• 125000005038 alkynylalkyl group Chemical group 0.000 claims description 5
• 239000003443 antiviral agent Substances 0.000 claims description 5
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
• 125000000565 sulfonamide group Chemical group 0.000 claims description 5
• 229910052727 yttrium Inorganic materials 0.000 claims description 5
• 102000006992 Interferon-alpha Human genes 0.000 claims description 4
• 108010047761 Interferon-alpha Proteins 0.000 claims description 4
• 125000005110 aryl thio group Chemical group 0.000 claims description 4
• 125000004104 aryloxy group Chemical group 0.000 claims description 4
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 4
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 4
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
• 238000000338 in vitro Methods 0.000 claims description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
• 230000002265 prevention Effects 0.000 claims description 3
• 125000001425 triazolyl group Chemical group 0.000 claims description 3
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
• 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 2
• 125000005281 alkyl ureido group Chemical group 0.000 claims description 2
• 125000003368 amide group Chemical group 0.000 claims description 2
• 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 2
• 125000002704 decyl 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])* 0.000 claims description 2
• 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 2
• 229910052720 vanadium Inorganic materials 0.000 claims description 2
• BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 claims 4
• 125000003277 amino group Chemical group 0.000 claims 3
• 239000003937 drug carrier Substances 0.000 claims 3
• GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 claims 2
• 125000004149 thio group Chemical group *S* 0.000 claims 2
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 1
• SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical group O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims 1
• 229930194542 Keto Natural products 0.000 claims 1
• XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims 1
• 125000005422 alkyl sulfonamido group Chemical group 0.000 claims 1
• 125000005128 aryl amino alkyl group Chemical group 0.000 claims 1
• 125000005421 aryl sulfonamido group Chemical group 0.000 claims 1
• 125000001475 halogen functional group Chemical group 0.000 claims 1
• 125000000468 ketone group Chemical group 0.000 claims 1
• 229910052710 silicon Inorganic materials 0.000 claims 1
• 239000010703 silicon Substances 0.000 claims 1
• 239000000243 solution Substances 0.000 description 167
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 130
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 90
• 238000002360 preparation method Methods 0.000 description 90
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 62
• 235000019439 ethyl acetate Nutrition 0.000 description 59
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
• 239000000047 product Substances 0.000 description 52
• 239000011541 reaction mixture Substances 0.000 description 49
• 239000012267 brine Substances 0.000 description 44
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 44
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
• 238000003756 stirring Methods 0.000 description 39
• 229910001868 water Inorganic materials 0.000 description 39
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
• 238000006243 chemical reaction Methods 0.000 description 36
• 239000000543 intermediate Substances 0.000 description 36
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 34
• 239000010410 layer Substances 0.000 description 32
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 28
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 28
• 239000012044 organic layer Substances 0.000 description 27
• 229920006395 saturated elastomer Polymers 0.000 description 26
• 150000001412 amines Chemical class 0.000 description 25
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 25
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
• 239000002253 acid Substances 0.000 description 24
• 239000002904 solvent Substances 0.000 description 24
• 239000007787 solid Substances 0.000 description 23
• 239000007864 aqueous solution Substances 0.000 description 20
• 238000003818 flash chromatography Methods 0.000 description 20
• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 20
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
• 125000004432 carbon atom Chemical group C* 0.000 description 18
• 102100038132 Endogenous retrovirus group K member 6 Pro protein Human genes 0.000 description 17
• 238000000746 purification Methods 0.000 description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
• 239000003921 oil Substances 0.000 description 16
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 15
• 230000002829 reductive effect Effects 0.000 description 14
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
• 229910052681 coesite Inorganic materials 0.000 description 13
• 229910052906 cristobalite Inorganic materials 0.000 description 13
• 229910052682 stishovite Inorganic materials 0.000 description 13
• 239000000725 suspension Substances 0.000 description 13
• 229910052905 tridymite Inorganic materials 0.000 description 13
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• 239000007788 liquid Substances 0.000 description 12
• 239000000377 silicon dioxide Substances 0.000 description 12
• 239000000758 substrate Substances 0.000 description 12
• 229910052717 sulfur Inorganic materials 0.000 description 12
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 11
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
• 239000012043 crude product Substances 0.000 description 11
• 238000001514 detection method Methods 0.000 description 11
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• 101710144111 Non-structural protein 3 Proteins 0.000 description 10
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• KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 10
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• 125000006413 ring segment Chemical group 0.000 description 10
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
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• 239000002585 base Substances 0.000 description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
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• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
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• 230000015572 biosynthetic process Effects 0.000 description 8
• NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 8
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• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
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• WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 7
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
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• 229910000147 aluminium phosphate Inorganic materials 0.000 description 7
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
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