NO332329B1 - Forbindelser som NS3-serinproteaseinhibitorer for hepatitt C-virus, farmasoytiske preparater og anvendelse av forbindelsene til fremstilling av et medikament. - Google Patents

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Publication number

NO332329B1

NO332329B1 NO20030272A NO20030272A NO332329B1 NO 332329 B1 NO332329 B1 NO 332329B1 NO 20030272 A NO20030272 A NO 20030272A NO 20030272 A NO20030272 A NO 20030272A NO 332329 B1 NO332329 B1 NO 332329B1

Authority

NO

Norway

Prior art keywords

compound

mmol

compound according

solution

alkyl

Prior art date

2000-07-21

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 277
• 241000711549 Hepacivirus C Species 0.000 title claims description 48
• 238000004519 manufacturing process Methods 0.000 title claims description 30
• 239000000825 pharmaceutical preparation Substances 0.000 title claims description 26
• 239000003814 drug Substances 0.000 title claims description 14
• 229940079593 drug Drugs 0.000 title description 5
• 239000003001 serine protease inhibitor Substances 0.000 title description 3
• 238000000034 method Methods 0.000 claims abstract description 88
• 230000000694 effects Effects 0.000 claims abstract description 11
• 229940122604 HCV protease inhibitor Drugs 0.000 claims abstract description 3
• 239000000203 mixture Substances 0.000 claims description 100
• 238000002360 preparation method Methods 0.000 claims description 96
• -1 enantiomers Chemical class 0.000 claims description 81
• 239000000460 chlorine Substances 0.000 claims description 54
• 125000000217 alkyl group Chemical group 0.000 claims description 28
• 125000003118 aryl group Chemical group 0.000 claims description 22
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
• 125000004122 cyclic group Chemical group 0.000 claims description 18
• 125000001072 heteroaryl group Chemical group 0.000 claims description 18
• 238000011282 treatment Methods 0.000 claims description 18
• 108010050904 Interferons Proteins 0.000 claims description 17
• 102000014150 Interferons Human genes 0.000 claims description 17
• 229940079322 interferon Drugs 0.000 claims description 17
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
• 229910052739 hydrogen Inorganic materials 0.000 claims description 16
• 229910052757 nitrogen Inorganic materials 0.000 claims description 16
• 239000004480 active ingredient Substances 0.000 claims description 15
• 229910052760 oxygen Inorganic materials 0.000 claims description 15
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
• 229910052799 carbon Inorganic materials 0.000 claims description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
• 229910052717 sulfur Inorganic materials 0.000 claims description 12
• 125000003545 alkoxy group Chemical group 0.000 claims description 11
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 11
• 150000002148 esters Chemical class 0.000 claims description 11
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 10
• 125000004432 carbon atom Chemical group C* 0.000 claims description 10
• 208000035475 disorder Diseases 0.000 claims description 10
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 10
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
• 229910005965 SO 2 Inorganic materials 0.000 claims description 9
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
• 125000003342 alkenyl group Chemical group 0.000 claims description 8
• 125000004104 aryloxy group Chemical group 0.000 claims description 8
• 150000003839 salts Chemical class 0.000 claims description 8
• 108010047761 Interferon-alpha Proteins 0.000 claims description 7
• 102000006992 Interferon-alpha Human genes 0.000 claims description 7
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 229910052736 halogen Inorganic materials 0.000 claims description 7
• 150000002367 halogens Chemical class 0.000 claims description 7
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
• IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical group 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 6
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 6
• 125000004414 alkyl thio group Chemical group 0.000 claims description 6
• 125000000304 alkynyl group Chemical group 0.000 claims description 6
• 125000005110 aryl thio group Chemical group 0.000 claims description 6
• 238000002648 combination therapy Methods 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 125000000623 heterocyclic group Chemical group 0.000 claims description 6
• 229960000329 ribavirin Drugs 0.000 claims description 6
• 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 6
• 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 5
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
• 229910052731 fluorine Inorganic materials 0.000 claims description 5
• 150000002576 ketones Chemical class 0.000 claims description 5
• 239000012453 solvate Substances 0.000 claims description 5
• 238000006467 substitution reaction Methods 0.000 claims description 5
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 4
• 125000003282 alkyl amino group Chemical group 0.000 claims description 4
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
• 125000003368 amide group Chemical group 0.000 claims description 4
• 125000001769 aryl amino group Chemical group 0.000 claims description 4
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
• 239000004202 carbamide Substances 0.000 claims description 4
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 4
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
• 125000002619 bicyclic group Chemical group 0.000 claims description 3
• 229910052794 bromium Inorganic materials 0.000 claims description 3
• 229910052801 chlorine Inorganic materials 0.000 claims description 3
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
• 150000003254 radicals Chemical class 0.000 claims description 3
• 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 229910006074 SO2NH2 Inorganic materials 0.000 claims description 2
• 229940100389 Sulfonylurea Drugs 0.000 claims description 2
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
• DXHGFDJNJSZBJL-UHFFFAOYSA-N [N+](=O)([O-])S(=O)(=O)NS(=O)NS(=O)(=O)[N+](=O)[O-] Chemical compound [N+](=O)([O-])S(=O)(=O)NS(=O)NS(=O)(=O)[N+](=O)[O-] DXHGFDJNJSZBJL-UHFFFAOYSA-N 0.000 claims description 2
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
• 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 2
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
• 125000004947 alkyl aryl amino group Chemical group 0.000 claims description 2
• 125000005248 alkyl aryloxy group Chemical group 0.000 claims description 2
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
• 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 2
• 125000005281 alkyl ureido group Chemical group 0.000 claims description 2
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
• 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 2
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 2
• 125000005421 aryl sulfonamido group Chemical group 0.000 claims description 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
• 125000005518 carboxamido group Chemical group 0.000 claims description 2
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 2
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
• 125000005241 heteroarylamino group Chemical group 0.000 claims description 2
• 125000005222 heteroarylaminocarbonyl group Chemical group 0.000 claims description 2
• 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 2
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
• 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 claims description 2
• 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 2
• 125000005842 heteroatom Chemical group 0.000 claims description 2
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 239000001301 oxygen Substances 0.000 claims description 2
• 125000004437 phosphorous atom Chemical group 0.000 claims description 2
• 229910052698 phosphorus Inorganic materials 0.000 claims description 2
• 125000005936 piperidyl group Chemical group 0.000 claims description 2
• 125000004076 pyridyl group Chemical group 0.000 claims description 2
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
• 150000003457 sulfones Chemical class 0.000 claims description 2
• YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims description 2
• 239000011593 sulfur Substances 0.000 claims description 2
• 125000001544 thienyl group Chemical group 0.000 claims description 2
• 239000003443 antiviral agent Substances 0.000 claims 7
• 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims 1
• 108091005804 Peptidases Proteins 0.000 abstract description 22
• 239000004365 Protease Substances 0.000 abstract description 22
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 353
• 239000000243 solution Substances 0.000 description 277
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 234
• VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 166
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• 235000019439 ethyl acetate Nutrition 0.000 description 132
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 126
• 230000015572 biosynthetic process Effects 0.000 description 114
• 238000003786 synthesis reaction Methods 0.000 description 110
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 97
• 239000012044 organic layer Substances 0.000 description 94
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 91
• 239000000047 product Substances 0.000 description 88
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 84
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 82
• 239000011347 resin Substances 0.000 description 69
• 229920005989 resin Polymers 0.000 description 69
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 64
• 239000012267 brine Substances 0.000 description 63
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
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• 238000006243 chemical reaction Methods 0.000 description 52
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