JP2009502889A - C型肝炎ウイルスの大員環式阻害剤 - Google Patents
C型肝炎ウイルスの大員環式阻害剤 Download PDFInfo
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- JP2009502889A JP2009502889A JP2008523382A JP2008523382A JP2009502889A JP 2009502889 A JP2009502889 A JP 2009502889A JP 2008523382 A JP2008523382 A JP 2008523382A JP 2008523382 A JP2008523382 A JP 2008523382A JP 2009502889 A JP2009502889 A JP 2009502889A
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- 239000003112 inhibitor Substances 0.000 title abstract description 22
- 241000711549 Hepacivirus C Species 0.000 title description 99
- 150000001875 compounds Chemical class 0.000 claims abstract description 360
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 83
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 82
- 150000003839 salts Chemical class 0.000 claims abstract description 54
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 44
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims abstract description 38
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims abstract description 37
- 229960000311 ritonavir Drugs 0.000 claims abstract description 37
- 239000001257 hydrogen Substances 0.000 claims abstract description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 31
- 125000001424 substituent group Chemical group 0.000 claims abstract description 30
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 28
- 125000003118 aryl group Chemical group 0.000 claims abstract description 25
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 22
- 125000005843 halogen group Chemical group 0.000 claims abstract description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 14
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 229910052717 sulfur Chemical group 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims abstract description 3
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 239000001301 oxygen Chemical group 0.000 claims abstract description 3
- 239000011593 sulfur Chemical group 0.000 claims abstract description 3
- -1 cyano, carboxyl Chemical group 0.000 claims description 195
- 238000000034 method Methods 0.000 claims description 108
- 238000006243 chemical reaction Methods 0.000 claims description 91
- 239000002253 acid Substances 0.000 claims description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 229940079593 drug Drugs 0.000 claims description 22
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
- 125000002757 morpholinyl group Chemical group 0.000 claims description 17
- 125000003386 piperidinyl group Chemical group 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 150000002678 macrocyclic compounds Chemical class 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 13
- 125000004193 piperazinyl group Chemical group 0.000 claims description 12
- 241001465754 Metazoa Species 0.000 claims description 11
- 230000010076 replication Effects 0.000 claims description 10
- 238000007363 ring formation reaction Methods 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 238000006751 Mitsunobu reaction Methods 0.000 claims description 6
- 125000000524 functional group Chemical group 0.000 claims description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 150000001540 azides Chemical class 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 238000005865 alkene metathesis reaction Methods 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 6
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 2
- QECVIPBZOPUTRD-UHFFFAOYSA-N N=S(=O)=O Chemical compound N=S(=O)=O QECVIPBZOPUTRD-UHFFFAOYSA-N 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 28
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 157
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 151
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 117
- 239000000543 intermediate Substances 0.000 description 111
- 230000015572 biosynthetic process Effects 0.000 description 109
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 103
- 239000011541 reaction mixture Substances 0.000 description 100
- 238000003786 synthesis reaction Methods 0.000 description 100
- 239000000203 mixture Substances 0.000 description 95
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
- 238000002360 preparation method Methods 0.000 description 84
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- 239000000047 product Substances 0.000 description 64
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- WMSPXQIQBQAWLL-UHFFFAOYSA-N cyclopropanesulfonamide Chemical compound NS(=O)(=O)C1CC1 WMSPXQIQBQAWLL-UHFFFAOYSA-N 0.000 description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 52
- 235000019439 ethyl acetate Nutrition 0.000 description 43
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 41
- 239000002904 solvent Substances 0.000 description 40
- 239000007787 solid Substances 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 34
- 239000002585 base Substances 0.000 description 34
- 239000012267 brine Substances 0.000 description 34
- 239000012044 organic layer Substances 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 32
- 238000005859 coupling reaction Methods 0.000 description 32
- 125000006239 protecting group Chemical group 0.000 description 32
- 239000011734 sodium Substances 0.000 description 32
- 150000002148 esters Chemical class 0.000 description 31
- 238000011282 treatment Methods 0.000 description 29
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 26
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 25
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 25
- 101710144111 Non-structural protein 3 Proteins 0.000 description 24
- 150000001412 amines Chemical class 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 24
- 230000008878 coupling Effects 0.000 description 23
- 238000010168 coupling process Methods 0.000 description 23
- 238000000746 purification Methods 0.000 description 23
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 22
- 239000003208 petroleum Substances 0.000 description 22
- 239000000843 powder Substances 0.000 description 22
- 208000015181 infectious disease Diseases 0.000 description 21
- 238000007792 addition Methods 0.000 description 20
- 229910052799 carbon Inorganic materials 0.000 description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 20
- 238000010992 reflux Methods 0.000 description 20
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- 239000003795 chemical substances by application Substances 0.000 description 19
- 239000000725 suspension Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 125000003277 amino group Chemical class 0.000 description 17
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 17
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical class C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 15
- 230000007062 hydrolysis Effects 0.000 description 15
- 238000006460 hydrolysis reaction Methods 0.000 description 15
- 239000007858 starting material Substances 0.000 description 15
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 14
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 14
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
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- ATJVVVCODTXRAE-UHFFFAOYSA-N 1-methylcyclopropane-1-sulfonamide Chemical compound NS(=O)(=O)C1(C)CC1 ATJVVVCODTXRAE-UHFFFAOYSA-N 0.000 description 12
- LPPRPUJPNUYIKH-UHFFFAOYSA-N 7-methoxy-8-methyl-2-(4-propan-2-yl-1,3-thiazol-2-yl)-1h-quinolin-4-one Chemical compound N=1C2=C(C)C(OC)=CC=C2C(O)=CC=1C1=NC(C(C)C)=CS1 LPPRPUJPNUYIKH-UHFFFAOYSA-N 0.000 description 12
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- VIPQGIJWKLGMHM-UHFFFAOYSA-N 2-propylhexadec-5-enoic acid Chemical compound CCCCCCCCCCC=CCCC(C(O)=O)CCC VIPQGIJWKLGMHM-UHFFFAOYSA-N 0.000 description 9
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- 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 6
- UNJWJSFDEJPNML-UHFFFAOYSA-N 8-chloro-7-methoxy-2-(4-propan-2-yl-1,3-thiazol-2-yl)-1h-quinolin-4-one Chemical compound N=1C2=C(Cl)C(OC)=CC=C2C(O)=CC=1C1=NC(C(C)C)=CS1 UNJWJSFDEJPNML-UHFFFAOYSA-N 0.000 description 6
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 6
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940021993 prophylactic vaccine Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- BXNMTOQRYBFHNZ-UHFFFAOYSA-N resiquimod Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CC(C)(C)O)C3=C(N)N=C21 BXNMTOQRYBFHNZ-UHFFFAOYSA-N 0.000 description 1
- 229950010550 resiquimod Drugs 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 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
- 229960004231 thymalfasin Drugs 0.000 description 1
- 239000003970 toll like receptor agonist Substances 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229950002810 valopicitabine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
Classifications
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- 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
- C07D487/04—Ortho-condensed systems
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- 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
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
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- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
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- C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
【化1】
[式中、各破線は任意の二重結合を表し、XはN、CHであり、そしてXが二重結合を持つ場合、これはCであり、R1は−OR7、−NH−SO2R8であり、R2は水素であり、そしてXがCまたはCHの場合、R2はまたC1−6アルキルであってもよく、R3は水素、C1−6アルキル、C1−6アルコキシC1−6アルキル、C3−7シクロアルキルであり、R4はアリールまたはHetであり、nは3、4、5または6であり、R5はハロ、C1−6アルキル、ヒドロキシ、C1−6アルコキシ、フェニルまたはHetであり、R6はC1−6アルコキシまたはジメチルアミノであり、R7は水素;アリール;Het;場合によりC1−6アルキルで置換されていてもよいC3−7シクロアルキル;または場合によりC3−7シクロアルキル、アリールまたはHetで置換されていてもよいC1−6アルキルであり、R8はアリール;Het;場合によりC1−6アルキルで置換されていてもよいC3−7シクロアルキル;または場合によりC3−7シクロアルキル、アリールまたはHetで置換されていてもよいC1−6アルキルであり、アリールは場合により1、2または3個の置換基で置換されていてもよいフェニルであり、Hetは窒素、酸素および硫黄から選択されるヘテロ原子を1から4個含有する5員もしくは6員の飽和、部分不飽和もしくは完全不飽和複素環式環であり、そしてこれは場合により1、2または3個の置換基で置換されていてもよい]で表されるHCV複製阻害剤およびN−オキサイド、塩または立体異性体;化合物(I)を含有させた製薬学的組成物および化合物(I)の製造方法。また、式(I)で表されるHCV阻害剤とリトナビルの生物学的利用性組み合わせも提供する。
Description
リンと組み合わせて用いることが基になっている。このような組み合わせ治療によって、遺伝子型1のウイルスに感染した患者の中の40%以上および遺伝子型2および3に感染した患者の中の約80%が持続的なウイルス学的反応を示すようになっている。そのような組み合わせ治療は、1型HCVに対する効力が限られている以外に重大な副作用を有し、数多くの患者がそれに耐えられない。主要な副作用には、インフルエンザの如き症状、血液学的異常および神経精神症状が含まれる。従って、より有効で便利で許容性がより良好な治療が求められている。
各破線(−−−で表す)は、任意の二重結合を表し、
Xは、N、CHであり、そしてXが二重結合を持つ場合、これはCであり、
R1は、−OR7、−NH−SO2R8であり、
R2は、水素であり、そしてXがCまたはCHの場合、R2はまたC1−6アルキルであってもよく、
R3は、水素、C1−6アルキル、C1−6アルコキシC1−6アルキル、C3−7シクロアルキルであり、
R4は、アリールまたはHetであり、
nは、3、4、5または6であり、
R5は、ハロ、C1−6アルキル、ヒドロキシ、C1−6アルコキシ、ポリハロC1−6アルキル、フェニルまたはHetを表し、
R6は、C1−6アルコキシ、モノもしくはジC1−6アルキルアミノを表し、
R7は、水素;アリール;Het;場合によりC1−6アルキルで置換されていてもよいC3−7シクロアルキル;または場合によりC3−7シクロアルキル、アリールまたはHetで置換されていてもよいC1−6アルキルであり、
R8は、アリール;Het;場合によりC1−6アルキルで置換されていてもよいC3−7シクロアルキル;または場合によりC3−7シクロアルキル、アリールまたはHetで置換されていてもよいC1−6アルキルであり、
アリールは、基または基の一部として、場合によりハロ、ヒドロキシ、ニトロ、シアノ、カルボキシル、C1−6アルキル、C1−6アルコキシ、C1−6アルコキシC1−6アルキル、C1−6アルキルカルボニル、アミノ、モノもしくはジ−C1−6アルキルアミノ、アジド、メルカプト、ポリハロC1−6アルキル、ポリハロC1−6アルコキシ、C3−7シクロアルキル、ピロリジニル、ピペリジニル、ピペラジニル、4−C1−6アルキルピペラジニル、4−C1−6アルキルカルボニルピペラジニルおよびモルホリニルから選択される1、2または3個の置換基で置換されていてもよいフェニルであり、ここで、前記モルホリニルおよびピペリジニル基は場合により1または2個のC1−6アルキル基で置換されていてもよく、
Hetは、基または基の一部として、窒素、酸素および硫黄から各々独立して選択されるヘテロ原子を1から4個含有する5員もしくは6員の飽和、部分不飽和もしくは完全不飽和複素環式環であり、ここで、前記複素環式環は場合によりベンゼン環と縮合していてもよく、そしてHetは、全体として、場合によりハロ、ヒドロキシ、ニトロ、シアノ、カルボキシル、C1−6アルキル、C1−6アルコキシ、C1−6アルコキシC1−6アルキル、C1−6アルキルカルボニル、アミノ、モノ−もしくはジ−C1−6アルキルアミノ、アジド、メルカプト、ポリハロC1−6アルキル、ポリハロC1−6アルコキシ、C3−7シクロアルキル、ピロリジニル、ピペリジニル、ピペラジニル、4−C1−6アルキルピペラジニル、4−C1−6アルキルカルボニルピペラジニルおよびモルホリニルから成る群から各々独立して選択される1、2または3個の置換基で置換されていてもよく、ここで、前記モルホリニルおよびピペリジニル基は場合により1または2個のC1−6アルキル基で置換されていてもよい]
で表され得るHCV複製阻害剤およびこれらのN−オキサイド、塩および立体異性体に関する。
、2−プロピル、1−ブチル、2−ブチル、2−メチル−1−プロピルなどを定義するものであり、「C1−6アルキル」は、C1−4アルキル基および炭素原子数が5から6の高級同族体、例えば1−ペンチル、2−ペンチル、3−ペンチル、1−ヘキシル、2−ヘキシル、2−メチル−1−ブチル、2−メチル−1−ペンチル、2−エチル−1−ブチル、3−メチル−2−ペンチルなどを包含する。C1−6アルキルの中でC1−4アルキルに興味が持たれる。
して存在する。本明細書で用いる如き用語「立体化学異性体形態物」は、同じ結合配列で結合している同じ原子で構成されているが交換不能な異なる三次元構造[式(I)で表される化合物が持ち得る]を有する可能な化合物の全部を定義するものである。
炭素の同位体にはC−13およびC−14が含まれる。
便利には塩基形態物をそのような適切な酸で処理することで得ることができる。適切な酸には、例えば無機酸、例えばハロゲン化水素酸、例えば塩酸または臭化水素酸など、硫酸、硝酸、燐酸など、または有機酸、例えば酢酸、プロピオン酸、ヒドロキシ酢酸、乳酸、ピルビン酸、しゅう酸(即ちエタン二酸)、マロン酸、こはく酸(即ちブタン二酸)、マレイン酸、フマル酸、リンゴ酸(即ちヒドロキシブタン二酸)、酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸、シクラミン酸、サリチル酸、p−アミノサリチル酸、パモ酸などが含まれる。
いる。
で表される如きシクロプロピル基を含有する。
(a)R2が水素である;
(b)Xが窒素である;
(c)炭素原子7と8の間に二重結合が存在する。
(a)R2が水素である;
(b)XがCHである;
(c)炭素原子7と8の間に二重結合が存在する。
に定義する他のいずれかのサブグループの化合物にまた前記化合物のN−オキサイド、付加塩、第四級アミン、金属錯体および立体化学異性体形態物のいずれも包含させることを意味すると理解されるべきである。
(a)R1が−OR7[ここで、R7は特にC1−6アルキル、例えばメチル、エチルまたはt−ブチル(または第三ブチル)、より好適にはR7は水素である]であるか、
(b)R1が−NHS(=O)2R8[ここで、R8は特にC1−6アルキル、C3−C7シクロアルキルまたはアリールであり、例えばR8はメチル、シクロプロピルまたはフェニルである]であるか、或は
(c)R1が−NHS(=O)2R8[ここで、R8は特にC1−6アルキルで置換されているC3−C7シクロアルキルであり、好適にはR8はシクロプロピル、シクロブチル、シクロペンチルまたはシクロヘキシル(これらはいずれもC1−4アルキル、即ちメチル、エチル、プロピル、イソプロピル、ブチル、t−ブチルまたはイソブチルで置換されている]である、
式(I)で表される化合物または式(I)で表される化合物のサブグループのいずれかである。
(a)R2が水素であるか;
(b)R2がC1−6アルキル、好適にはメチルである、
式(I)で表される化合物または式(I)で表される化合物のサブグループのいずれかである。
(a)XがN、C(Xが二重結合で結合している)またはCH(Xが単結合で結合している)でありそしてR2が水素であるか;
(b)XがC(Xが二重結合で結合している)でありそしてR2がC1−6アルキル、好
適にはメチルである、
式(I)で表される化合物または式(I)で表される化合物のサブグループのいずれかである。
(a)R3が水素であるか;
(b)R3がC1−6アルキルであるか;
(c)R3がC1−6アルコキシC1−6アルキルまたはC3−7シクロアルキルである、
式(I)で表される化合物または式(I)で表される化合物のサブグループのいずれかである。
より具体的には、R4aは、水素、ハロ、C1−6アルキル、アミノ、またはモノ−もし
くはジ−C1−6アルキルアミノ、ピロリジニル、ピペリジニル、モルホリニル、ピペラジニル、4−C1−6アルキルピペラジニルであってもよく、ここで、前記モルホリニルおよびピペリジニル基は場合により1または2個のC1−6アルキル基で置換されていてもよく、
より具体的には、各R4aは、各々独立して、水素、ハロ、C1−6アルキル、アミノ、またはモノ−もしくはジ−C1−6アルキルアミノであり、そして
R4aが窒素原子上の置換基の場合、それは好適には炭素含有置換基であり、この置換基は炭素原子または炭素原子の中の1つを通して窒素と連結しており、そしてこの場合には、好適には、R4aはC1−6アルキルである]
から成る群から選択される式(I)で表される化合物または式(I)で表される化合物のサブグループのいずれかである。
るRhに興味が持たれる。この水添反応を好適には溶媒、例えばアルコール、例えばメタノール、エタノールなど、エーテル、例えばTHFなど、またはこれらの混合物中で実施する。また、前記溶媒もしくは溶媒混合物に水を添加することも可能である。
1)アシル基、例えばホルミル、トリフルオロアセチル、フタリルおよびp−トルエンスルホニルなど、
2)芳香カルバメート基、例えばベンジルオキシカルボニル(CbzまたはZ)および置換ベンジルオキシカルボニルおよび9−フルオレニルメチルオキシカルボニル(Fmoc)など、
3)脂肪カルバメート基、例えばt−ブチルオキシカルボニル(Boc)、エトキシカルボニル、ジイソプロピルメトキシ−カルボニルおよびアリルオキシカルボニルなど、
4)環式アルキルカルバメート基、例えばシクロペンチルオキシカルボニルおよびアダマンチルオキシカルボニルなど、
5)アルキル基、例えばトリフェニルメチル、ベンジルまたは置換ベンジル、例えば4−メトキシベンジルなど、
6)トリアルキルシリル、例えばトリメチルシリルまたはt−ブチルジメチルシリルなど、および
7)チオール含有基、例えばフェニルチオカルボニルおよびジチアスクシノイルなど。
興味の持たれる保護基はBocまたはFmocである。
ジルエーテル、例えば4−メトキシベンジルエーテルなど、ベンゾイルもしくは置換ベンゾイルエステル、例えば4−ニトロベンゾイルエステルなどとしてか、或はトリアルキルシリル基(例えばトリメチルシリルまたはt−ブチルジメチルシリル)を用いて受けさせておいてもよい。
てもよいか、或はPG1は強酸または接触水添で除去可能なベンジルエステルであってもよく、後者の2つのケースにおけるPG1は、例えば安息香酸エステル、例えば4−ニトロ安息香酸エステルなどである。
であり、そしてXがNの場合、L1はまた窒素保護基(この上で定義した如きPG)であってもよく、そしてXがCの場合、L1はまた基−COOPG2a(ここで、基PG2aは、PG2と同様なカルボキシル保護基であるが、PG2aはPG2に対して選択的に開裂し得る)であってもよい。1つの態様におけるPG2aはt−ブチルでありそしてPG2はメチルまたはエチルである。
それらにさらなる処理をこの上に示したようにして受けさせてもよい。
P1とP2構成ブロックの連結を前記手順に従うアミド形成反応を用いて実施する。P1構成ブロックにカルボキシル保護基PG2を持たせておいてもよい[(12b)に示したように]か、或はそれを既にP1’基と連結させておいてもよい[(12c)に示したように]。L2はN−保護基(PG)またはこの上に示した如き基(b)である。L3はヒドロキシ、−OPG1またはこの上に示した如き基−O−R9である。以下の反応スキームのいずれにおいてもL3がヒドロキシの場合、各反応段階を実施する前に、それに保護を基−OPG1として受けさせておいてもよく、そして必要ならば、その後、脱保護を実施することで遊離ヒドロキシ官能に戻してもよい。この上に記述した様式と同様にして、そのヒドロキシ官能を基−O−R9に変化させることができる。
ピロリジン部分を有するP2構成ブロックでは、(5a)と(5b)の連成に関して上述した手順に従い、カルバメート形成反応を用いてP3とP2またはP3とP2−P1構成ブロックを連成させる。ピロリジン部分を有するP2ブロックを連成させる一般的な手順を以下の反応スキームに示すが、ここで、L3はこの上に示した通りであり、そしてL4は基−OPG2、基
させることができる。
P2構成ブロックはピロリジン、シクロペンタンまたはシクロペンテン部分のいずれかを含有し、これは基−O−R4で置換されている。
および(17i)であり、これらはこの上に示した中間体(13a)または(16a)に相当する。
大員環を生じさせる前または後のいずれかに−R9基を付加させる方策である。後者の手順では、P2部分にヒドロキシ基を持たせるが、それにヒドロキシ保護基PG1による保護を受けさせておいてもよい。
P1フラグメントの調製で用いるシクロプロパンアミノ酸は商業的に入手可能であるか或は本技術分野で公知の手順を用いて調製可能である。
(12)を用いて、それに最初にN−保護基PGを導入しそして次に基PG2を除去することで実施可能である。
P3構成ブロックは商業的に入手可能であるか或は本分野の技術者に公知の方法に従って調製可能である。そのような方法の1つを以下のスキームに示し、このスキームではモノアシル化アミン、例えばトリフルオロアセトアミドまたはBoc保護アミンなどを用いる。
に感染した被験体または感染する危険性がある被験体における感染に対して予防的に働くか、感染を安定化させるか或は低下させるに充分な量である。さらなる面において、本発明は、本明細書に示す如き製薬学的組成物を製造する方法に関し、この方法は、製薬学的に受け入れられる担体を治療的に有効な量の本明細書に示す如き式(I)で表される化合物または本明細書に示す如き式(I)で表される化合物のサブグループのいずれかの化合物と密に混合することを含んで成る。
Virology 75:4614−4624に記述されたさらなる修飾を受けさせたシステムを用いて実施し、これを実施例章で更に例示する。このモデルは、HCVにとって完全な感染モデルではないが、現在利用可能な自律的HCV RNA複製の最も健全で効率の良いモデルであるとして幅広く受け入れられている。この細胞モデルで抗HCV活性を示す化合物は、哺乳動物のHCV感染治療におけるさらなる進展に適した候補品であると見なす。HCVの機能を特定的に妨害する化合物をHCVレプリコンモデルで細胞障害または細胞増殖抑制効果を及ぼす結果としてHCV RNAまたは連鎖レポーター酵素濃度を低下させる化合物と区別することが重要であることは理解されるであろう。細胞の細胞障害、例えば蛍光性酸化還元色素、例えばレザズリンなどを用いたミトコンドリア酵素の活性が基になったそれを評価するに適した検定は本技術分野で公知である。その上、連鎖レポーター遺伝子活性、例えば蛍ルシフェラーゼなどの非選択的阻害を評価するに適した細胞カウンタースクリーン(counter screens)も存在する。適切な細胞株に発現が構成的活性遺伝子プロモーターに依存するルシフェラーゼレポーター遺伝子による安定なトランスフェクションを受けさせることでそれを組み入れることができ、そしてそのような細胞をカウンタースクリーンとして用いて非選択的阻害剤を除去することができる。
物を抗ウイルス的に有効な量で投与することを含んで成る。
I)で表されるNS3/4aプロテアーゼ阻害剤またはこれのサブグループのいずれかとリトナビルまたはこれの製薬学的に受け入れられる塩もしくはエステルの1日当たりの投薬レベルは0.02から5.0グラムの桁であってもよい。
共投与する場合の1回分当たりの量を、式(I)で表される化合物が約50から約1500mgでリトナビルの量が約50から約1500mgになるようにする。更に別の態様では、日に1回もしくは2回共投与する場合の1回分当たりの量を、式(I)で表される化合物が約100から約1000mgでリトナビルの量が約100から約800mgになるようにする。更に別の態様では、日に1回もしくは2回共投与する場合の1回分当たりの量を、式(I)で表される化合物が約150から約800mgでリトナビルの量が約100から約600mgになるようにする。更に別の態様では、日に1回もしくは2回共投与する場合の1回分当たりの量を、式(I)で表される化合物が約200から約600mgでリトナビルの量が約100から約400mgになるようにする。更に別の態様では、日に1回もしくは2回共投与する場合の1回分当たりの量を、式(I)で表される化合物が約200から約600mgでリトナビルの量が約20から約300mgになるようにする。更に別の態様では、日に1回もしくは2回共投与する場合の1回分当たりの量を、式(I)で表される化合物が約100から約400mgでリトナビルの量が約40から約100mgになるようにする。
以下の実施例は本発明を例示することを意図したものであり、本発明を限定するものでない。
4−ヒドロキシ−7−メトキシ−8−メチル−2−(チアゾール−2−イル)キノリン(4)の合成
(ヘキソ−5−エニル)(メチル)アミン(21)の合成
N−メチルトリフルオロアセトアミド(25g)をDMF(140mL)に入れることで生じさせた0℃の溶液に水素化ナトリウム(1.05当量)をゆっくり加えた。その混合物を窒素下室温で1時間撹拌した。次に、ブロモヘキセン(32.1g)をDMF(25mL)に入れることで生じさせた溶液を滴下した後、その混合物を70℃に12時間加熱した。その反応混合物を水(200mL)の上に注ぎ、エーテル(4x50mL)で抽出し、乾燥(MgSO4)させ、濾過した後、蒸発させることで目標生成物20を黄色がかった油として35g得て、それをさらなる精製無しに次の段階で用いた。
20(35g)をメタノール(200mL)に入れることで生じさせた溶液に水酸化カリウム(187.7g)を水(130mL)に入れることで生じさせた溶液を滴下した。その混合物を室温で12時間撹拌した。次に、その混合物を水(100mL)の上に注ぎ、エーテル(4x50mL)で抽出し、乾燥(MgSO4)させ、濾過した後、そのエーテルを大気圧下で留出させた。その結果として得た油を真空下の蒸留(13mmHgの圧力、50℃)で精製することで表題の生成物21を無色の油として7.4g(34%)得た:
1H NMR(CDCl3):δ5.8(m,1H),5(ddd,J=17.2Hz,3.5Hz,1.8Hz,1H),4.95(m,1H),2.5(t,J=7.0Hz,2H),2.43(s,3H),2.08(q,J=7.0Hz,2H),1.4(m,4H),1.3(br s,1H)。
段階A
4−ヒドロキシ−2−(4−イソプロピルチアゾール−2−イル)−7−メトキシ−8−メチルキノリン(36)の合成
N−(t−ブチルオキシカルボニル)−3−メトキシ−2−メチルアニリン(32)の合成
3−メトキシ−2−メチルアニリン(33)の合成
(2−アミノ−4−メトキシ−3−メチルフェニル)(メチル)ケトン(34)の合成
2’−[[(4−イソプロピルチアゾール−2−イル)(オキソ)メチル]アミノ]−4’−メトキシ−3’−メチルアセトフェノン(35)の合成
N−メチルトリフルオロアセトアミド(25g)をDMF(140mL)に入れることで生じさせた0℃の溶液に水素化ナトリウム(1.05当量)をゆっくり加えた。その混合物を窒素下室温で1時間撹拌した。次に、ブロモヘキセン(32.1g)をDMF(25mL)に入れることで生じさせた溶液を滴下した後、その混合物を70℃に12時間加熱した。その反応混合物を水(200mL)の上に注ぎ、エーテル(4x50mL)で抽出し、乾燥(MgSO4)させ、濾過した後、蒸発させることで目標の生成物37を黄色がかった油として35g得て、それをさらなる精製無しに次の段階で用いた。
37(35g)をメタノール(200mL)に入れることで生じさせた溶液に水酸化カリウム(187.7g)を水(130mL)に入れることで生じさせた溶液を滴下した。その混合物を室温で12時間撹拌した。次に、その反応混合物を水(100mL)の上に注ぎ、エーテル(4x50mL)で抽出し、乾燥(MgSO4)させ、濾過した後、エーテルを大気圧下で留出させた。その結果として得た油を真空下の蒸留(13mmHgの圧力、50℃)で精製することで表題の生成物38を無色の油として7.4g(34%)得た: 1H NMR(CDCl3):δ5.8(m,1H),5(ddd,J=17.2Hz,3.5Hz,1.8Hz,1H),4.95(m,1H),2.5(t,J=7.0Hz,2H),2.43(s,3H),2.08(q,J=7.0Hz,2H),1.4(m,4H),1.3(br s,1H)。
H),7.48(s,1H),8.03(d,J=9Hz,1H)。
2’−[[(4−イソプロピルチアゾール−2−イル)(オキソ)メチル]アミノ]−3’−クロロ−4’−メトキシアセトフェノン(51)の合成
8−クロロ−4−ヒドロキシ−2−(4−イソプロピルチアゾール−2−イル)−7−メ
トキシ−キノリン(52)の合成
化合物53
化合物53の調製をアルコール43および8−クロロ−4−ヒドロキシ−2−(4−イソプロピルチアゾール−2−イル)−7−メトキシ−キノリン(52)を用いて44に記述した手順に従って実施したm/z=723(M+H)+。
化合物54の調製
化合物55の調製
ザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボニル](シクロプロピル)スルホンアミド(56)の調製
4−ヒドロキシ−7−メトキシ−8−メチルキノリン−3−カルボン酸エチル(58)の合成
の粉末として9.2g(57.5%)得た:m/z=262(M+H)+。
4−ヒドロキシ−7−メトキシ−8−メチルキノリン(59)の合成
4−クロロ−7−メトキシ−8−メチルキノリン(60)の合成
4−クロロ−7−メトキシ−8−メチルキノリンN−オキサイド(61)の合成
4−ベンジルオキシ−7−メトキシ−8−メチルキノリンN−オキサイド(62)の合成
4−ベンジルオキシ−2−クロロ−7−メトキシ−8−メチルキノリン(63)の合成
4−ヒドロキシ−2−(3−イソプロピルピラゾール−1−イル)−7−メトキシ−8−メチルキノリン(64)の合成
17−[2−(3−イソプロピルピラゾール−1−イル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸(65)の合成
チルキノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボニル](シクロプロピル)スルホンアミド(66)の調製
N−[2−(1−ヒドロキシエチル)−3−メトキシフェニル]ピバロイルアミド(66)の合成
N−[2−エチル−3−メトキシフェニル]ピバロイルアミド(67)の合成
2−エチル−m−アニシジン(68)の合成
た(体積の1/3)。その溶液を5℃に6時間維持した。出現した固体を濾過で取り出した後、ジイソプロピルエーテルで洗浄することで目標の生成物をHCl塩として22.35g得た。K2CO3を用いた処理で遊離塩基を生じさせることで目標の生成物68を20.85g(83%)得た:m/z=152(M+H)+。
8−エチル−4−ヒドロキシ−2−(4−イソプロピルチアゾール−2−イル)−7−メトキシキノリン(69)の合成
17−[8−エチル−2−(4−イソプロピルチアゾール−2−イル)−7−メトキシ−キノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸(70)の合成
8−フルオロ−4−ヒドロキシ−2−(4−イソプロピルチアゾール−2−イル)−7−メトキシキノリン(72)
)+。
17−[8−フルオロ−2−(4−イソプロピルチアゾール−2−イル)−7−メトキシ−キノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸(73)の合成
キソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸(73)およびシクロプロピルスルホンアミドを用いてN−[17−[8−クロロ−2−(4−イソプロピルチアゾール−2−イル)−7−メトキシキノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボニル](シクロプロピル)スルホンアミド(56)の調製で報告した手順に従って実施した:m/z=754(M+H)+。 1H NMR(CDCl3):0.75−1.52(m,15H),1.64−2.05(m,4H),2.77(m,1H),2.41(m,2H),2.59(m,2H),2.92(m,2H),3.04(s,3H),3.19(m,1H),3.40(m,2H),4.07(s,3H),4.60(m,1H),5.05(t,J=10.5Hz,1H),5.37(m,1H),5.66(m,1H),6.17(s,1H),7.07(s,1H),7.54(s,1H),7.86(m,1H),10.77(幅広 s,1H)。
N−(ヘプト−6−エニル)フタルイミド(75)の合成
6−ヘプテニルアミン(76)の合成
中間体(77)の合成
中間体78の合成
中間体79の合成
)シクロプロパンカルボン酸エチルエステル25を用いて中間体26の調製で報告した手順に従って実施した:m/z=407(M+H)+。
18−[2−(4−イソプロピルチアゾール−2−イル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]−2,15−ジオキソ−3,14−ジアザトリシクロ[14.3.0.04,6]ノナデコ−7−エン−4−カルボン酸(80)の合成
中間体82の合成
モル)と4−ヒドロキシ−2−(4−イソプロピルチアゾール−2−イル)−7−メトキシ−8−メチルキノリン(36、769mg、2.04ミリモル)と2−ジフェニルホスファニルピリジン(751mg、2.86ミリモル)を高真空下で1時間乾燥させた。次に、無水THFを窒素下で加えた後、その結果として得た反応混合物を−15℃に冷却した。次に、DIADを滴下した。−5℃で1時間後の溶液を室温に温めた。16時間後の反応混合物を氷冷水とAcOEtの間で分離させた。その有機層を逐次的に1MのHClそして食塩水で激しく洗浄し、乾燥(MgSO4)させ、濾過した後、蒸発させた。シリカゲル使用カラムクロマトグラフィー(AcOEt/CH2Cl2を0:10から5:95の勾配)による精製で所望生成物82を無色の油として940mg(85%)得た:m/z=542(M+H)+。
中間体83の合成
中間体84の合成
中間体85の合成
N−(ヘプト−6−エニル)−N−(4−メトキシベンジル)アミン86の合成
中間体87の合成
中間体88の合成
素下で80℃に4時間加熱した。次に、その反応混合物を濃縮した後、フラッシュクロマトグラフィー(AcOEt/CH2Cl2を0:1から2:8の勾配)で精製することで表題の生成物88を褐色がかった発泡体として900mg(65%)得た:m/z=796(M+H)+。
中間体89の合成
N−[[18−[2−[4−(イソプロピル)チアゾール−2−イル]−7−メトキシ−8−メチルキノリン−4−イルオキシ]−2,15−ジオキソ−14−(4−メトキシベンジル)−3,14,16−トリアザトリシクロ[14.3.0.04,6]ノナデコ−7−エン−4−イル]カルボニル](シクロプロピル)スルホンアミド(90)の合成
4,8−ジクロロ−2−(4−イソプロピルチアゾール−2−イル)−7−メトキシキノリン(92)の合成
中間体93の合成
N−[[18−[8−クロロ−2−[4−(イソプロピル)チアゾール−2−イル]−7−メトキシキノリン−4−イルオキシ]−2,15−ジオキソ−3,14,16−トリアザトリシクロ[14.3.0.04,6]ノナデコ−7−エン−4−イル]カルボニル](シクロプロピル)スルホンアミド(94)の合成
6−メチルピリジン−2−カルボン酸(6−アセチル−3−メトキシ−2−メチルフェニル)−アミド(96)の合成
4−ヒドロキシ−2−(6−メチル−2−ピリジル)−7−メトキシ−8−メチルキノリン(97)の合成
クロ波照射で150℃に30分間加熱した後、ピリジンの80−85%を減圧下で蒸発させた。その残留物を氷の上に注いだ後、酢酸で中性にした。沈澱物を濾過で取り出した後、乾燥させることで表題の化合物を得た(1.8g、95%):m/z=299(M+H)+。
2−(1−エトキシカルボニル−2−ビニルシクロプロピルカルバモイル)−4−[2−(6−メチル−2−ピリジル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]シクロペンタンカルボン酸t−ブチルエステル(98)の合成
2−(1−エトキシカルボニル−2−ビニルシクロプロピルカルバモイル)−4−[2−(6−メチル−2−ピリジル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]シクロペンタンカルボン酸(99)の合成
1−{2−(ヘキソ−5−エニルメチルカルバモイル)−4−[2−(6−メチル−2−ピリジル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]シクロペンタンカルボニル}アミノ−2−ビニルシクロプロパンカルボン酸エチルエステル(100)の合成
17−[2−(6−メチルピリジン−2−イル)−7−メトキシ−8−メチル−キノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザ−トリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸エチルエステル(101)の合成
17−[2−(6−メチル−2−ピリジル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸(102)の合成
シクロプロパンスルホン酸{17−[2−(6−メチル−2−ピリジル)−7−メトキシ
−8−メチル−キノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボニル}−アミド(103)の合成
2−イソプロピルピリジン−N−オキサイド(104)の合成
2−シアノ−6−イソプロピルピリジン(105)の合成
6−イソプロピルピリジン−2−カルボン酸(106)の合成
6−イソプロピルピリジン−2−カルボン酸(6−アセチル−3−メトキシ−2−メチルフェニル)アミド(107)の合成
4−ヒドロキシ−2−(6−イソプロピル−2−ピリジル)−7−メトキシ−8−メチルキノリン(108)の合成
0.62g(95%)得た(1.8g、95%):m/z=309(M+H)+。
2−(1−エトキシカルボニル−2−ビニルシクロプロピルカルバモイル)−4−[2−(6−イソプロピル−ピリジン−2−イル)−7−メトキシ−8−メチル−キノリン−4−イルオキシ]−シクロペンタンカルボン酸t−ブチルエステル(109)の合成
2−(1−エトキシカルボニル−2−ビニルシクロプロピルカルバモイル)−4−[2−(6−イソプロピル−2−ピリジル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]シクロペンタンカルボン酸(110)の合成
1−{2−(ヘキソ−5−エニルメチルカルバモイル)−4−[2−(6−イソプロピル−2−ピリジル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]シクロペンタンカルボニル}アミノ−2−ビニルシクロプロパンカルボン酸エチルエステル(111)の合成
17−[2−(6−イソプロピル−2−ピリジル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸エチルエステル(112)の合成
17−[2−(6−イソプロピル−2−ピリジル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸(113)の合成
シクロプロパンスルホン酸{17−[2−(6−イソプロピル−2−ピリジル)−7−メトキシ−8−メチル−キノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザ−トリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボニル}アミド(114)の合成
mg、0.31ミリモル)とDMAP(76.5mg、0.62ミリモル)とEDC(151mg、0.78ミリモル)をDMF(5mL)に入れることで生じさせた溶液を室温で一晩撹拌した(この酸の活性化をLC−MSで監視した)。次に、シクロプロピルスルホンアミド(191mg、1.56ミリモル)に続いてDBU(228μL、1.56ミリモル)を加えた。その結果として生じた溶液を室温で一晩撹拌した後、酢酸で中性にし、そして蒸発させた。その残留物をMeOHに再溶解させた後、調製用HPLCで精製することで表題の化合物114を90mg(39%)得た:m/z=744(M+H)+。
シクロヘキサンカルボチオ酸アミド(115)の合成
2−シクロヘキシルチアゾール−4−カルボン酸エチルエステル(116)の合成
2−シクロヘキシルチアゾール−4−カルボン酸(117)の合成
2−シクロヘキシルチアゾール−4−カルボン酸(6−アセチル−3−メトキシ−2−メチルフェニル)アミド(118)の合成
2−(2−シクロヘキシルチアゾール−4−イル)−4−ヒドロキシ−7−メトキシ−8−メチルキノリン(119)の合成
た。その混合物を数バッチに分割した後、各バッチを個別にマイクロ波照射で150℃に30分間加熱した。次に、いろいろなバッチを一緒にした後、ピリジンを蒸発させた。その残留物をクエン酸水溶液で処理することで懸濁液を得た後、それを少量のEtOHで希釈し、次に水とCH2Cl2の間で分離させた。有機層を乾燥(Na2SO4)させた後、蒸発させた。その残留物をカラムクロマトグラフィー(CH2Cl2:MeOHを1:0から93:7の勾配)で精製することで表題の化合物119を白色の粉末として1.8g(72.5%)得た:m/z=355(M+H)+。
1−{[4−[2−(2−シクロヘキシルチアゾール−4−イル)−7−メトキシ−8−メチル−キノリン−4−イルオキシ]−2−(ヘキソ−5−エニルメチルカルバモイル)シクロペンタンカルボニル]アミノ}−2−ビニルシクロプロパンカルボン酸エチルエステル(120)の合成
17−[2−(2−シクロヘキシルチアゾール−4−イル)−7−メトキシ−8−メチル−キノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸エチルエステル(121)の合成
17−[2−(2−シクロヘキシルチアゾール−4−イル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸(122)の合成
(6S)−シクロプロパンスルホン酸{17−[2−(2−シクロヘキシルチアゾール−4−イル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザ−トリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボニル}−アミド(123)および(6R)−シクロプロパンスルホン酸{17−[2−(2−シクロヘキシルチアゾール−4−イル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザ−トリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボニル}−アミド(124)の合成
4−ヒドロキシ−2−(3−t−ブチルピラゾール−1−イル)−7−メトキシ−8−メチルキノリン(126)の合成
17−[2−(3−t−ブチルピラゾール−1−イル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸(127)の合成
3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸(127)およびシクロプロピルスルホンアミドを用いてN−[17−[8−クロロ−2−(4−イソプロピルチアゾール−2−イル)−7−メトキシキノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボニル](シクロプロピル)スルホンアミド(56)の調製で報告した手順に従って実施した:m/z=747(M+H)+。 1H NMR(CDCl3):0.95−1.12(m,2H),1.13−1.30(m,2H),1.31−1.55(m,11H),1.63−2.05(m,4H),2.20−2.55(m,9H),2.80−2.98(m,1H),3.03(s,3H),3.36−3.47(m,2H),3.61−3.70(m,1H),3.97(s,3H),4.60(t,J=12.2Hz,1H),5.04(t,J=10.3Hz,1H),5.26−546(m,1H),5.61−5.69(m,1H),6.35(d,J=2.5Hz,1H),6.42(br s,1H),7.13(d,J=9.1Hz,1H),7.32(s,1H),7.95(d,J=9.1Hz,1H),8.67(d,J=2.5Hz,1H),10.9(br s,1H)。
4−ヒドロキシ−2−(3,5−ジメチルピラゾール−1−イル)−7−メトキシ−8−メチルキノリン(129)の合成
17−[2−(3,5−ジメチルピラゾール−1−イル)−7−メトキシ−8−メチルキノリン−4−イルオキシ]−13−メチル−2,14−ジオキソ−3,13−ジアザトリシクロ[13.3.0.04,6]オクタデコ−7−エン−4−カルボン酸(130)の合成
Boc保護プロリン(4g、17.3ミリモル)とHATU(6.9g、18.2ミリモル)とWO 03/099274に記述されているようにして調製した1−アミノ−2−ビニル−シクロプロパンカルボン酸エチルエステル(3.5g、18.3ミリモル)をDMF(60ml)に溶解させた後、氷浴上で0℃に冷却した。ジイソプロピルエチルアミン(DIPEA)(6ml)を加えた。前記氷浴を取り外して、その混合物を周囲温度に一晩放置した。次に、ジクロロメタン(〜80ml)を加え、その有機相を炭酸水素ナトリウム水溶液、クエン酸、水そして食塩水で洗浄した後、硫酸ナトリウムで乾燥させた。フラッシュクロマトグラフィー(エーテル→エーテル中7%のメタノール)による精製で高純度の表題化合物を得た(6.13g、96%)。
化合物132(6.13g、16.6ミリモル)と4−ニトロ安息香酸(4.17g、25ミリモル)とPPh3(6.55g、25ミリモル)をTHF(130ml)に溶解させた。その溶液を〜0℃に冷却した後、アジドカルボン酸ジイソプロピル(5.1g、25ミリモル)をゆっくり加えた。次に、冷却を取り外して、その混合物を周囲条件に一晩放置した。炭酸水素ナトリウム水溶液(60ml)を加えた後の混合物をジクロロメタンで抽出した。フラッシュクロマトグラフィー(ペンタン−エーテルを2:1→ペンタン−エーテルを1:2→エーテル中2%のメタノール)による精製で高純度の表題化合物を得た(6.2g、72%)。
トリフルオロメタンスルホン酸をジクロロメタンに33%入れることで生じさせた混合物を氷で冷却しながらこれに化合物133(6.2g、12ミリモル)を溶解させた。次に、氷浴を取り外して、その混合物を室温に〜1.5時間放置した。溶媒を蒸発させ、0.25Mの炭酸ナトリウムを加えた後、その混合物にジクロロメタンを用いた抽出を受けさせた。蒸発を実施することで表題の化合物(4.8g、95%)を黄色がかった粉末として得た。
化合物134(4.5g、10.8ミリモル)をTHF(160mL)に入れることで生じさせた溶液にNaHCO3(テーブルスプーン一杯)およびトルエン中のホスゲン(1.93M、11.5mL、22ミリモル)を加えた。その混合物を室温で1時間激しく撹拌した後、濾過し、そして蒸発させた。その残留物をCH2Cl2(160mL)に溶解させた後、NaHCO3(テーブルスプーン一杯)およびヘプト−5−エニル−(p−メトキシベンジル)−アミン(4.3g、18.5ミリモル)を加えた。撹拌を室温で一晩実施した後の反応混合物を濾過した後、蒸発乾固させた。シリカゲル使用フラッシュカラムクロマトグラフィー(EtOAc:トルエンを25:75→40:60)で表題の化合物(6.59g、90%)を明褐色のシロップとして得た。
化合物135(1g、1.48ミリモル)を1,2−ジクロロエタン(2 l)に溶解させた。その混合物にアルゴン流を用いた脱気を15分間受けさせた。Hoveyda−Grubbs触媒(II)(50mg、5モル%)を加えた後の混合物を4時間還流させた。溶媒を蒸発させ、その粗エステルをテトラヒドロフラン(100ml)とメタノール(50ml)と水(50ml)に溶解させた。その混合物を氷浴上で0℃に冷却した。水酸化リチウム水溶液(20ml、1M)を加えた後の混合物を0℃で4時間撹拌した。次に、水で体積を2倍にした後の混合物を酢酸で酸性にした。抽出(ジクロロメタン)に続くフラッシュクロマトグラフィー(エーテル中1→5%のメタノール)で高純度の表題化合物を得た(450mg、61%)。MS(M+H)+500。
アルコール136(230mg、0.460ミリモル)とキノリノール36(218mg、0.690ミリモル)とトリフェニルホスフィン(182mg、0.690ミリモル)を無水THFに溶解させた後、その混合物を0℃に冷却した。その溶液を0℃で撹拌しながらこれにDIAD(130μL、0.690ミリモル)を30分かけて滴下した後、その溶液を室温にして、次に一晩撹拌した。溶媒を蒸発させた後、その粗材料をフラッシュカラムクロマトグラフィー(トルエン/酢酸エチルを1:1)で精製することで表題の化合物を得た(366mg)(M+H)+計算値:796.4;測定値:796.7。
エチルエステル137(366mg、0.460ミリモル)を2:1:1のTHF/MeOH/H2O(30mL)に溶解させ、1MのLiOH(4.6mL、4.40ミリモル)を室温で5分間かけて滴下した後、その溶液を一晩撹拌した。その混合物のpHを固体状のクエン酸を添加することで酸性にして3−4にした後、有機溶媒を蒸発させた。その水相を食塩水(50mL)で希釈した後、DCMで3回抽出した。その有機相を一緒にして食塩水で2回洗浄した後、乾燥させ、濾過した後、濃縮した。次に、その粗生成物をフラッシュカラムクロマトグラフィー(酢酸エチル/メタノールを7:1)で精製することで表題の化合物を得た(212mg、60%)(M+H)+計算値:768.3;測定値:768.7。
酸138(212mg、0.276ミリモル)をジクロロメタン(7mL)に溶解させて、これにEDC(69mg、0.359ミリモル)を加えた後、その反応混合物を室温で撹拌した。7時間後にTLCおよびLC−MSは、出発材料が相当するオキサゾリジノンに完全に変化したことを示していた。その反応混合物をジクロロメタン(20mL)で希釈し、その有機相を水で2回洗浄した後、その有機相を乾燥させ、濾過した後、濃縮した。その残留物をジクロロメタン(5mL)に溶解させ、シクロプロピルメチルスルホンアミド(53mg、0.394ミリモル)およびDBU(78μL、0.525ミリモル
)を加えた後、その反応混合物を室温で20時間撹拌した。その混合物をジクロロメタン(30mL)で希釈した後、その有機相を10%のクエン酸で2回そして食塩水で1回洗浄した。その有機相を乾燥させ、濾過し、濃縮した後、その粗生成物をフラッシュカラムクロマトグラフィー(トルエン/酢酸エチルを1:1、1:2、酢酸エチル、酢酸エチル/メタノールを9:1)で精製することで表題の化合物を無色の固体として得た(108mg、44%)。LC−MSによる純度:>95%。(M+H)+計算値:885.4;測定値:885.7。
化合物139(106mg、0.120ミリモル)をジクロロメタン(18mL)に溶解させて、これにトリエチルシラン(38μL、0.240ミリモル)およびTFA(9mL)を加えた後、その反応混合物を室温で1時間撹拌した。溶媒を蒸発させた後、トルエンと一緒に3回蒸発させた。その残留物をジクロロメタンに溶解させた後、その有機相を飽和NaHCO3溶液で2回洗浄した。その有機相を乾燥させ、濾過し、濃縮した後、その粗生成物をフラッシュカラムクロマトグラフィー(トルエン/酢酸エチルを1:1)で精製することで表題の化合物を若干黄色の固体として得た(73mg、80%)。LC−MSによる純度:>95%。(M+H)+計算値:765.3;測定値:765.7。
4−アミノ−5−シアノ−2−ヒドロキシ−3−メチル安息香酸エチルエステル(141)の合成
5モル)をエタノール(1.3L)に添加することで新しく調製]に酢酸エチルプロピオニル(25g、0.17モル)を加えた後、その溶液を室温で1時間撹拌した。前記溶液にエトキシメチレンマロノンニトリル(21g、0.17モル)を室温で加えた後、その反応混合物を80℃で2時間還流させた。その反応混合物を冷却し、1.5NのHClを添加してpH=7に中和した後、真空下で濃縮した。その得た残留物を水(100mL)で希釈した後、濾過した。固体を水で洗浄した後、真空下50℃で乾燥させることで粗生成物を得た(27g)。その粗固体を石油エーテル中5%の酢酸エチルで洗浄することで高純度の表題化合物を得た(22.5g、59%)。TLC:3:7のEtOAc/石油エーテル、Rf=0.4。
4−アミノ−5−シアノ−2−ヒドロキシ−3−メチル安息香酸(142)の合成
2−アミノ−4−ヒドロキシ−3−メチルベンゾニトリル(143)の合成
2−アミノ−4−メトキシ−3−メチルベンゾニトリル(144)の合成
1−(2−アミノ−4−メトキシ−3−メチル−フェニル)−エタノン(34)の合成
レプリコン検定
前記式(I)で表される化合物にHCV RNA複製阻害活性に関する試験を細胞検定で受けさせた。この検定で、前記式(I)で表される化合物が細胞培養物の中で機能するHCVレプリコンに対して活性を示すことを立証した。この細胞検定は、Lohmann他(1999)Science、285巻、110−113頁に記述されている如き2シストロン性発現構築物が基になっており、複数の標的を選別する方策になるように、それにKrieger他(2001)Jouranl of Virology 75:4614−4624に記述されている修飾を受けさせた。この方法は本質的に下記の通りであった。この検定では、安定なトランスフェクションを受けさせておいた細胞株Huh−7 luc/neo(本明細書では以降Huh−Lucと呼ぶ)を用いた。その細胞株は2シストロン性発現構築物をコードするRNAを含有し、その構築物は、脳心筋炎ウイルス(EMCV)に由来する内部リボソーム侵入部位(IRES)から翻訳された1b型HCVの野生型NS3−NS5B領域を含有しそしてこれの前方にレポーター部分(FfL−ルシフェラーゼ)を含有しかつ選択可能マーカー部分(neoR、ネオマイシンホスホトランスフェラーゼ)を含有して成っていた。この構築物は1b型HCVの5’および3’NTR(非翻訳領域)に隣接して位置する。このレプリコン細胞の培養がG418(neoR)の存在下で持続するか否かはHCV RNAの複製に依存する。そのようにHCV RNA(自己複製しかつとりわけルシフェラーゼを高濃度でコードする)を発現するように安定なトランスフェクションを受けさせておいたレプリコン細胞を抗ウイルス性化合物の選別で用いる。
x(商標)ultraHTSミクロプレート画像形成装置を使用]。阻害剤を全く存在させていない対照培養物の中のレプリコン細胞はルシフェラーゼを高度に発現する。前記Huh−Luc細胞を用いて当該化合物がルシフェラーゼ活性に対して示す阻害活性を監視することで各試験化合物が示す用量反応曲線を作成した。次に、EC50値を計算したが、この値は、検出ルシフェラーゼ活性レベル、より具体的には、遺伝的に関連したHCVレプリコンRNAが複製する能力を50%低下させるに要する化合物量に相当する。
このインビトロ検定の目的は、本発明の化合物がHCV NS3/4Aプロテアーゼ複合体を阻害するか否かを測定することにあった。この検定を用いて、本発明の化合物がHCV NS3/4A蛋白分解活性の阻害でいかに有効であるかを示す。
化合物番号47がラットにおいて示す薬物動態に対してリトナビルがインビトロで示す効果
化合物番号47を50%PEG400/水に入れた製剤を用いてオスおよびメスのSprague−Dawleyラットに10mg/kgの用量で1回投与した後の経口薬物動態およびリトナビルを10mg/kgの量で用いて「増進」させた時の影響を調査した。
Claims (21)
- 式
各破線(−−−で表す)は、任意の二重結合を表し、
Xは、N、CHであり、そしてXが二重結合を持つ場合、これはCであり、
R1は、−OR7、−NH−SO2R8であり、
R2は、水素であり、そしてXがCまたはCHの場合、R2はまたC1−6アルキルであってもよく、
R3は、水素、C1−6アルキル、C1−6アルコキシC1−6アルキル、C3−7シクロアルキルであり、
R4は、アリールまたはHetであり、
nは、3、4、5または6であり、
R5は、ハロ、C1−6アルキル、ヒドロキシ、C1−6アルコキシ、ポリハロC1−6アルキル、フェニルまたはHetを表し、
R6は、C1−6アルコキシまたはジメチルアミノを表し、
R7は、水素;アリール;Het;場合によりC1−6アルキルで置換されていてもよいC3−7シクロアルキル;または場合によりC3−7シクロアルキル、アリールまたはHetで置換されていてもよいC1−6アルキルであり、
R8は、アリール;Het;場合によりC1−6アルキルで置換されていてもよいC3−7シクロアルキル;または場合によりC3−7シクロアルキル、アリールまたはHetで置換されていてもよいC1−6アルキルであり、
アリールは、基または基の一部として、場合によりハロ、ヒドロキシ、ニトロ、シアノ、カルボキシル、C1−6アルキル、C1−6アルコキシ、C1−6アルコキシC1−6アルキル、C1−6アルキルカルボニル、アミノ、モノもしくはジ−C1−6アルキルアミノ、アジド、メルカプト、ポリハロC1−6アルキル、ポリハロC1−6アルコキシ、C3−7シクロアルキル、ピロリジニル、ピペリジニル、ピペラジニル、4−C1−6アルキルピペラジニル、4−C1−6アルキルカルボニルピペラジニルおよびモルホリニルから選択される1、2または3個の置換基で置換されていてもよいフェニルであり、ここで、前記モルホリニルおよびピペリジニル基は場合により1または2個のC1−6アルキル基で置換されていてもよく、
Hetは、基または基の一部として、窒素、酸素および硫黄から各々独立して選択されるヘテロ原子を1から4個含有する5員もしくは6員の飽和、部分不飽和もしくは完全不飽和複素環式環であり、ここで、前記複素環式環は場合によりベンゼン環と縮合していても
よく、そしてここで、前記Hetは、全体として、場合によりハロ、ヒドロキシ、ニトロ、シアノ、カルボキシル、C1−6アルキル、C1−6アルコキシ、C1−6アルコキシC1−6アルキル、C1−6アルキルカルボニル、アミノ、モノ−もしくはジ−C1−6アルキルアミノ、アジド、メルカプト、ポリハロC1−6アルキル、ポリハロC1−6アルコキシ、C3−7シクロアルキル、ピロリジニル、ピペリジニル、ピペラジニル、4−C1−6アルキルピペラジニル、4−C1−6アルキルカルボニルピペラジニルおよびモルホリニルから成る群から各々独立して選択される1、2または3個の置換基で置換されていてもよく、ここで、前記モルホリニルおよびピペリジニル基は場合により1または2個のC1−6アルキル基で置換されていてもよい]
で表される化合物、これのN−オキサイド、塩または立体異性体。 - R5がメチル、エチル、イソプロピル、t−ブチル、フルオロ、クロロまたはブロモでありそしてR6がメトキシである請求項1−3のいずれか1項記載の化合物。
- (a)R1が−OR7[ここで、R7はC1−6アルキルまたは水素である]であるか、
(b)R1が−NHS(=O)2R8[ここで、R8はメチル、シクロプロピルまたはフェニルである]であるか、或はR1が−NHS(=O)2R8[ここで、R8はメチルで置換されているシクロプロピルである]である、
請求項1−4のいずれか1項記載の化合物。 - nが4または5である請求項1−5のいずれか1項記載の化合物。
- R3が水素またはC1−6アルキル、特にR3が水素またはメチルである請求項1−6のいずれか1項記載の化合物。
- R6がメトキシである請求項1−9のいずれか1項記載の化合物。
- N−オキサイドでも塩でもない請求項1−14のいずれか記載の化合物。
- (a)請求項1−15のいずれか1項記載の化合物またはこれの製薬学的に受け入れられる塩、および
(b)リトナビルまたはこれの製薬学的に受け入れられる塩、
を含有して成る組み合わせ。 - 担体および請求項1−15のいずれか1項記載の化合物または請求項16記載の組み合わせを抗ウイルス的に有効な量で有効成分として含有して成る製薬学的組成物。
- 薬剤として用いるための請求項1−15のいずれか記載の化合物または請求項16記載の組み合わせ。
- 請求項1−15のいずれか記載の化合物または請求項16記載の組み合わせの使用であって、HCV複製抑制用薬剤を製造するための使用。
- 温血動物におけるHCV複製を抑制する方法であって、請求項1−15のいずれか記載の化合物を有効量でか或は請求項16記載組み合わせの中の各成分を有効量で投与するこ
とを含んで成る方法。 - 請求項1−15のいずれか記載の化合物を製造する方法であって、
(a)以下の反応スキームに概略を示すようにして、C7とC8の間に二重結合を生じさせる、特にオレフィンメタセシス反応によって生じさせることに伴わせて環化を起こさせて大員環を生じさせることで、C7とC8の間の結合が二重結合である式(I)で表される化合物[これは式(I−i)で表される化合物である]を生じさせ:
(b)前記式(I−i)で表される化合物の中のC7−C8二重結合に還元を受けさせることで、式(I−i)で表される化合物を大員環の中のC7とC8の間の結合が単結合である式(I)で表される化合物、即ち式(I−j):
(c)以下のスキーム[ここで、Gは基:
(f)官能基変換反応によって式(I)で表される化合物を互いに変化させるか、或は
(g)遊離形態の式(I)で表される化合物を酸もしくは塩基と反応させることで塩形態物を生じさせる、
ことを含んで成る方法。
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JP2013227314A (ja) * | 2008-09-11 | 2013-11-07 | Abbott Lab | 大環状c型肝炎セリンプロテアーゼ阻害薬 |
JP2012519158A (ja) * | 2009-02-27 | 2012-08-23 | ジヤンセン・フアーマシユーチカルズ・インコーポレーテツド | Hcvの大環状阻害剤の無定形塩 |
JP2015143240A (ja) * | 2009-02-27 | 2015-08-06 | ジヤンセン・フアーマシユーチカルズ・インコーポレーテツドJanssen Pharmaceuticals,Inc. | Hcvの大環状阻害剤の無定形塩 |
JP2013501068A (ja) * | 2009-08-05 | 2013-01-10 | アイディニックス ファーマシューティカルズ インコーポレイテッド | 大環状セリンプロテアーゼ阻害剤 |
JP2013522273A (ja) * | 2010-03-16 | 2013-06-13 | ジヤンセン・フアーマシユーチカルズ・インコーポレーテツド | Hcvの大環状プロテアーゼ阻害剤の製造のための方法及び中間体 |
JP2015526504A (ja) * | 2012-08-31 | 2015-09-10 | ヤンセン ファーマシューティカルズ,インコーポレーテッド | Hcvの大環状プロテアーゼ阻害剤と、非ヌクレオシドhcv阻害剤と、リトナビルとの組み合わせ |
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