EP1206449A1 - Inhibiteurs lactame de la protease ns3 du virus de l'hepatite c - Google Patents
Inhibiteurs lactame de la protease ns3 du virus de l'hepatite cInfo
- Publication number
- EP1206449A1 EP1206449A1 EP00950642A EP00950642A EP1206449A1 EP 1206449 A1 EP1206449 A1 EP 1206449A1 EP 00950642 A EP00950642 A EP 00950642A EP 00950642 A EP00950642 A EP 00950642A EP 1206449 A1 EP1206449 A1 EP 1206449A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- substituted
- group
- amino
- alkyl
- phenyl
- 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.)
- Withdrawn
Links
- 150000003951 lactams Chemical class 0.000 title claims abstract description 26
- 239000003112 inhibitor Substances 0.000 title abstract description 19
- 108700012707 hepatitis C virus NS3 Proteins 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 86
- 150000003839 salts Chemical group 0.000 claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- -1 cyclic boron ester Chemical class 0.000 claims description 288
- 150000001875 compounds Chemical class 0.000 claims description 91
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 67
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 63
- 125000004432 carbon atom Chemical group C* 0.000 claims description 55
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 47
- 125000005842 heteroatom Chemical group 0.000 claims description 47
- 229910052757 nitrogen Inorganic materials 0.000 claims description 45
- 229910052717 sulfur Inorganic materials 0.000 claims description 41
- 150000002148 esters Chemical class 0.000 claims description 39
- MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 claims description 34
- 229910052731 fluorine Inorganic materials 0.000 claims description 30
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 28
- 125000001624 naphthyl group Chemical group 0.000 claims description 28
- 229910052796 boron Inorganic materials 0.000 claims description 27
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 27
- 229910052794 bromium Inorganic materials 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 229910052740 iodine Inorganic materials 0.000 claims description 26
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 25
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 25
- 150000001413 amino acids Chemical class 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 19
- 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 14
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 14
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 12
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 11
- 125000005620 boronic acid group Chemical group 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- MOILFCKRQFQVFS-OORONAJNSA-N (1s,3r,4s,5s)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@H]2C(C)(C)[C@@H]1C[C@@H](O)[C@]2(O)C MOILFCKRQFQVFS-OORONAJNSA-N 0.000 claims description 10
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 10
- 125000003601 C2-C6 alkynyl 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
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 150000002009 diols Chemical group 0.000 claims description 9
- 208000015181 infectious disease Diseases 0.000 claims description 9
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 8
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 8
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 5
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 5
- 229940035437 1,3-propanediol Drugs 0.000 claims description 5
- OBGFNGZXMSFPAR-UHFFFAOYSA-N 2,5-dimethylhexane-3,3-diol Chemical compound CC(C)CC(O)(O)C(C)C OBGFNGZXMSFPAR-UHFFFAOYSA-N 0.000 claims description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 5
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 claims description 5
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- FUGIIBWTNARRSF-UHFFFAOYSA-N decane-5,6-diol Chemical compound CCCCC(O)C(O)CCCC FUGIIBWTNARRSF-UHFFFAOYSA-N 0.000 claims description 5
- ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 claims description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 5
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 5
- 235000013772 propylene glycol Nutrition 0.000 claims description 5
- 229960004063 propylene glycol Drugs 0.000 claims description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 4
- JHDMMNYIVVWNOF-UHFFFAOYSA-N 1,2-dicyclohexylethane-1,1-diol Chemical compound C1CCCCC1C(O)(O)CC1CCCCC1 JHDMMNYIVVWNOF-UHFFFAOYSA-N 0.000 claims description 4
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 4
- ZYUZLEUJKZZXNN-UHFFFAOYSA-N C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 Chemical group C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 ZYUZLEUJKZZXNN-UHFFFAOYSA-N 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 125000006126 n-butyl sulfonyl group Chemical group 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- JAQOMSTTXPGKTN-UHFFFAOYSA-N propylboronic acid Chemical compound CCCB(O)O JAQOMSTTXPGKTN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- JSZFXNCCDXABCT-NSHDSACASA-N (2r)-3-bromo-n-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide Chemical compound BrC[C@@](O)(C)C(=O)NC1=CC=C(C#N)C(C(F)(F)F)=C1 JSZFXNCCDXABCT-NSHDSACASA-N 0.000 claims 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 37
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 abstract description 21
- 238000003556 assay Methods 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 6
- 238000009007 Diagnostic Kit Methods 0.000 abstract 1
- 208000036142 Viral infection Diseases 0.000 abstract 1
- 230000009385 viral infection Effects 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 137
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 107
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 100
- 239000000243 solution Substances 0.000 description 100
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 239000000047 product Substances 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 235000019439 ethyl acetate Nutrition 0.000 description 36
- 239000002253 acid Substances 0.000 description 35
- 238000006243 chemical reaction Methods 0.000 description 35
- 239000000463 material Substances 0.000 description 35
- 241000711549 Hepacivirus C Species 0.000 description 34
- 239000011734 sodium Substances 0.000 description 30
- 229940024606 amino acid Drugs 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 29
- 235000001014 amino acid Nutrition 0.000 description 28
- 230000002829 reductive effect Effects 0.000 description 28
- 239000003921 oil Substances 0.000 description 26
- 238000010898 silica gel chromatography Methods 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- 239000002904 solvent Substances 0.000 description 21
- 238000003756 stirring Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 150000001412 amines Chemical class 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 108090000765 processed proteins & peptides Proteins 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 16
- 125000000623 heterocyclic group Chemical group 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 14
- 108091005804 Peptidases Proteins 0.000 description 14
- 102000035195 Peptidases Human genes 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 125000004429 atom Chemical group 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000004365 Protease Substances 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 12
- 102000004190 Enzymes Human genes 0.000 description 11
- 108090000790 Enzymes Proteins 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 235000019419 proteases Nutrition 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 239000000872 buffer Substances 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 10
- 125000004093 cyano group Chemical group *C#N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 150000004702 methyl esters Chemical class 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
- 125000002524 organometallic group Chemical group 0.000 description 7
- 239000013612 plasmid Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- 238000006219 Matteson homologation reaction Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 229940124530 sulfonamide Drugs 0.000 description 6
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- 239000011885 synergistic combination Substances 0.000 description 1
- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 230000036964 tight binding Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003104 tissue culture media Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 108010087967 type I signal peptidase Proteins 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229920002554 vinyl polymer Chemical group 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
- 150000003953 γ-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates generally to a novel class of lactams which are useful as serine protease inhibitors, and more particularly as Hepatitis C virus NS3 protease inhibitors .
- This invention also relates to pharmaceutical compositions comprising these compounds and methods of using the same.
- Hepatitis C virus is the major cause of transfusion and community-acquired non-A, non-B hepatitis worldwide. Approximately 2% of the world's population are infected with the virus. In the Unites States, hepatitis C represents approximately 20% of cases of acute hepatitis. Unfortunately, self-limited hepatitis is not the most common course of acute HCV infection. In the majority of patients, symptoms of acute hepatitis resolve, but alanine aminotransferase (a liver enzyme diagnostic for liver damage) levels often remain elevated and HCV RNA persists.
- HCV Hepatitis C virus
- a propensity to chroninicity is the most distinguishing characteristic of hepatitis C, occurring in at least 85% of patients with acute HCV infection.
- the factors that lead to chronicity in hepatitis C are not well defined.
- Chronic HCV infection is associated with increased incidence of liver cirrhosis and liver cancer.
- No vaccines are available for this virus, and current treatment is restricted to the use of alpha interferon, which is effective in only 15-20% of patients.
- Recent clinical studies have shown that combination therapy of alpha interferon and ribavirin leads to sustained efficacy in 40% of patients (Poynard, T. et al . Lancet 1998, 352, 1426- 1432.). However, a majority of patients still either fail to respond or relapse after completion of therapy. Thus, there is a clear need to develop more effective therapeutics for treatment of HCV-associated hepatitis.
- HCV is a positive-stranded RNA virus. Based on comparison of deduced amino acid sequence and the extensive similarity in the 5' untranslated region, HCV has been classified as a separate genus in the Flaviviridae family, which also includes flaviviruses such as yellow fever virus and animal pestiviruses like bovine viral diarrhea virus and swine fever virus. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame .
- RNA genome is about 9.6 Kb in length, and encodes a single polypeptide of about 3000 amino acids.
- the 5' untranslated region contains an internal ribosome entry site (IRES) , which directs cellular ribosomes to the correct AUG for initiation of translation.
- IRS internal ribosome entry site
- the precursor protein is cotranslationally and posttranslationally processed into at least 10 viral structural and nonstructural (NS) proteins by the action of a host signal peptidase and by two distinct viral proteinase activities .
- the translated product contains the following proteins: core-El-E2-p7-NS2-NS3-NS4A-NS4B-NS5A- NS5B.
- NS3 functions as a proteolytic enzyme that is responsible for the cleavage of sites liberating the nonstructural proteins NS4A, NS4B, NS5A, and NS5B.
- NS3 has further been shown to be a serine protease. Although the functions of the NS proteins are not completely defined, it is known that NS4A is a protease cofactor and NS5B is an RNA polymerase involved in viral replication. Thus agents that inhibit NS3 proteolytic processing of the viral polyprotein are expected to have antiviral activity.
- W098/22496 discloses peptide inhibitors of the following general formula: R 9 -NH-CH (R 8 ) -CO-NH-CH (R 7 ) -CO- N(R 6 ) -CH(R 5 ) -CO-NH-CH (R 4 ) -CO-N (R 3 ) -CH (R 2 ) -CO-NH-CH (R 1 ) -E where E either an aldehyde or a boronic acid.
- R 1 represents lower alkyl (optionally substituted by halo, cyano, lower alkylthio, aryl-lower alkylthio, aryl or heteroaryl) , lower alkenyl or lower akynyl .
- Llinas-Brunet, Bailey et al WO99/07734 have described hexa- to tetra-peptide analogs containing a Pi electrophilic carbonyl group, a phosphonate ester, or an aza-aminoacid analog.
- Llinas-Brunet, Poupart et al . W099/07733 describe peptides terminating in a carboxylate. This latter group of compounds are similar to those described by Steinkuhler et al . Biochemistry 37, 8899-8905 (1998) and Ingallinella et al . Biochemistry 37, 8906-8914 (1998) .
- HCV protease Additional peptide inhibitors of HCV protease have been disclosed.
- Hart et al WO9846630 have described hepta- peptide analogs containing an ester linkage at the scissile bond.
- Zhang et al . O9743310 discloses high molecular weight peptide inhibitors. These compounds are also distinct from the present inventions .
- one object of the present invention is to provide novel HCV NS3 protease inhibitors .
- It is another object of the present invention to provide pharmaceutical compositions with HCV NS3 protease inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof. It is another object of the present invention to provide a method of inhibiting HCV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention. It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HCV NS3 protease, HCV growth, or both.
- n, R 1 , R 2 , R 3 , R 4 , R 5 , and X are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective HCV NS3 protease inhibitors.
- the lactam ring of Formula (I) is substituted with 0-2 R b ;
- Y 1 and Y 2 are independently selected from: a) -OH, b) -F, c) -NR 18 R 19 , d) Ci-C ⁇ alkoxy, or when taken together, Y 1 and Y 2 form: e) a cyclic boron ester comprising from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O; f) a cyclic boron amide comprising from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or 0; or g) a cyclic boron amide-ester comprising from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or 0;
- R 1 is selected from the group:
- R la is selected from the group:
- R a is selected at each occurrence from the group:
- R b is selected at each occurrence from the group:
- R 2 is H
- R 1 and R 2 combine to form a C 3 - 5 cycloalkyl group
- R 3 is selected from the group: C 1 - 6 alkyl substituted with 0-2 R a ;
- R 4 is selected from the group: H,
- R 5 is H or Q-R 5 ;
- Q is 0, 1, 2, or 3 amino acids;
- R 5 a -j_ s selected from the group: -S(0)R 6 , -S(0) 2 R 6 , -C(0)R 6 , -C(0)OR 8 , -C(0)NHR 6 , C ⁇ - 3 alkyl-R 6a , C 2 - 6 alkenyl-R 6a , and C 2 - 6 alkynyl-R 6a ;
- R 6 is selected from the group:
- R 6a is selected from the group: phenyl substituted with 0-3 R c ; naphthyl substituted with 0-3 R c ; benzyl substituted with 0-3 R c ; and
- heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N, substituted with 0-3 R c ;
- R c is selected at each occurrence from the group:
- R d is selected at each occurrence from the group: H and CH 3 ;
- R 7 is selected at each occurrence from the group: H and Ci- 6 alkyl
- R 8 is selected from the group: C 1 - 6 alkyl, benzyl, and C 3 - 6 cycloalkyl-methyl ;
- R 18 and R 19 at each occurrence are independently selected from H, C 1 -C 4 alkyl, aryl (C 1 -C 4 alkyl)-, and C 3 -C 7 cycloalkyl ;
- n is selected from the group: 1, 2, and 3;
- q is selected from the group: 0, 1, and 2.
- the lactam ring of Formula (I) is substituted with 0-2 R b ;
- Y 1 and Y 2 are independently selected from: a) -OH, b) -F, c) -NR 18 R 19 , d) Ci-Cs alkoxy, or when taken together, Y 1 and Y 2 form: e) a cyclic boron ester comprising from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or 0; f) a cyclic boron amide comprising from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or 0; or g) a cyclic boron amide-ester comprising from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or 0; R 1 is selected from the group:
- R la is selected from the group:
- heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and
- R b is selected at each occurrence from the group:
- R 2 is H
- R 1 and R 2 combine to form a C 3 - 5 cycloalkyl group
- R 3 is selected from the group: C ⁇ - 6 alkyl substituted with 0-2 R a ; C 2 - 6 alkenyl substituted with 0-2 R a ; C 2 - 6 alkynyl substituted with 0-2 R a ; -(CH 2 ) q -C 3 - 6 cycloalkyl substituted with 0-2 R a ;
- R 4 is selected from the group: H,
- R 5 is H or Q-R 5a ;
- Q is 0, 1, 2, or 3 amino acids
- R 5a is selected from the group: -S(0)R 6 , -S(0) 2 R 6 , -C(0)R 6 , -C(0)OR 8 , -C(0)NHR 6 , C ⁇ _ 3 alkyl-R 6a , C 2 - 6 alkenyl-R ⁇ 3 , and C 2 - 6 alkynyl-R 6a ;
- R 6 is selected from the group:
- R 6a is selected from the group: phenyl substituted with 0-3 R c ; naphthyl substituted with 0-3 R c ; benzyl substituted with 0-3 R c ; and
- heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N, substituted with 0-3 R c ;
- R c is selected at each occurrence from the group:
- R d is selected at each occurrence from the group: H and CH 3 ;
- R 7 is selected at each occurrence from the group: H and Ci- 6 alkyl
- R 8 is selected from the group: C ⁇ _ 6 alkyl, benzyl, and C 3 - 6 cycloalkyl-methyl ;
- R 18 and R 19 at each occurrence are independently selected from H, C 1 -C 4 alkyl, aryl (C 1 -C 4 alkyl)-, and C 3 -C 7 cycloalkyl;
- n is selected from the group: 1, 2, and 3;
- q is selected from the group: 0, 1, and 2.
- the present invention provides novel compounds of Formula (I) , wherein;
- X is selected from the group: B(OH) 2 and BY ⁇ 2 ;
- Y 1 and Y 2 are independently selected from: a) -OH, b) Ci-C ⁇ alkoxy, or when taken together, Y 1 and Y 2 form: c) a cyclic boron ester comprising from 2 to 20 carbon atoms;
- R 1 is selected from the group:
- R a is selected at each occurrence from the group:
- heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N, and substituted with 0-3 R b ;
- R b is selected at each occurrence from the group:
- R 2 is H
- R 3 is selected from the group:
- R 4 is selected from the group: H, C 1 - 6 alkyl substituted with 0-3 R b ; phenyl substituted with 0-3 R b ; benzyl substituted with 0-3 R b ; and phenethyl substituted with 0-3 R b ;
- R 5 is H or Q-R 5a ;
- Q is 0, 1, 2, or 3 amino acids
- R 5a 3_ s selected from the group: -S(0)R 6 , -S(0) 2 R 6 , -C(0)R 6 , -C(0)OR 8 , -C(0)NHR 6 , C ⁇ _ 3 alkyl-R 6a , C 2 - 6 alkenyl-R 6a , and C 2 - 6 alkynyl-R 6a ;
- R 6 is selected from the group:
- heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N, substituted with 0-3 R c ;
- R 6a is selected from the group: phenyl substituted with 0-3 R c ; naphthyl substituted with 0-3 R c ; benzyl substituted with 0-3 R c ; and 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N, substituted with 0-3 R c ;
- R c is selected at each occurrence from the group:
- R d is selected at each occurrence from the group: H and CH 3 ;
- R 7 is selected at each occurrence from the group: H and Ci- 6 alkyl
- R 8 is selected from the group: C 1 - 6 alkyl, benzyl, and C 3 - 6 cycloalkyl-methyl ;
- n is selected from the group: 1, 2, and 3;
- q is selected from the group: 0, 1, and 2.
- the present invention provides novel compounds of Formula (II) , wherein;
- X is a boronic acid or a boron ester of formula BY 1 Y 2 ;
- Y 1 and Y 2 are independently selected from: a) C 1 -C 6 alkoxy, or when taken together, Y 1 and Y 2 form: b) a cyclic boron ester comprising from 2 to 16 carbon atoms;
- R 1 is selected from the group: ethyl, n-propyl, n-butyl, allyl, 2 , 2 , 2-trifluoroethyl, 2 , 2-difluoroethyl, 3,3,3- trifluoropropyl, 4 , 4, 4-trifluorobutyl , and 3-butenyl;
- R a is selected at each occurrence from the group:
- R b is selected at each occurrence from the group: C 1 - 6 alkyl, Cl, F, Br, I, OH, C ⁇ - 6 alkoxy, -CN, -N0 2 ,
- R 2 is H
- R 3 is selected from the group:
- R 4 is selected from the group: H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl; phenyl substituted with 0-3 R b ; benzyl substituted with 0-3 R b ; and phenethyl substituted with 0-3 R b ;
- R 5 is H or Q-R 5a ;
- Q is 0, 1, or 2 amino acids
- R 5a is selected from the group: -S(0)R 6 , -S(0) 2 R 6 , -C(0)R 6 , -C(0)OR 8 , -C(0)NHR 6 , C ⁇ _ 3 alkyl-R 6a , C 2 - 6 alkenyl-R 6a , and C 2 - 6 alkynyl-R 6a ;
- R 6 is selected from the group:
- R 6a is selected from the group: phenyl substituted with 0-3 R c ; naphthyl substituted with 0-3 R c ; benzyl substituted with 0-3 R c ; and
- heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from the group: 0, S, and N, substituted with 0-3 R c ;
- R c is selected at each occurrence from the group:
- R d is selected at each occurrence from the group: H and CH 3 ;
- R 7 is selected at each occurrence from the group: H and Ci- 6 alkyl
- R 8 is selected from the group: C ⁇ - 6 alkyl, benzyl, and C 3 - 6 cycloalkyl-methyl ;
- n 1 or 2;
- q is selected from the group: 0, 1, and 2.
- the present invention provides novel compounds of Formula (II) , wherein;
- X is a boronic acid or boron ester, wherein the ester is a diol selected from the group: pinanediol, pinacol, 1, 2-ethanediol, 1 , 3-propanediol, 1, 2-propanediol, 2,3- butanediol, 1, 2-diisopropylethanediol, 5, 6-decanediol , and 1 , 2-dicyclohexylethanediol;
- R 1 is selected from the group: ethyl, n-propyl, n-butyl, allyl, 2, 2, 2-trifluoroethyl, 2 , 2-difluoroethyl, 3,3,3- trifluoropropyl, 4 , 4, 4-trifluorobutyl, and 3-butenyl;
- R 2 is H
- R 3 is selected from the group: n-propyl, n-butyl, i-butyl, n-pentyl, neo-pentyl, cyclohexylmethyl, cyclopentylmethyl, phenyl, t-butoxymethyl, benzyloxymethyl, hydroxymethyl, methoxyme hyl , ethoxymethyl, propoxymethyl , and i-propoxymethyl ;
- R 4 is selected from the group: methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, sec-butyl, t-butyl, phenyl, benzyl, and phenethyl;
- R 5 is H or Q-R 5a ;
- Q is 0, 1, or 2 amino acids
- R 5a is selected from the group: -S(0) 2 R 6 , -C(0)R 6 , -C(0)OR 8 , -C(0)NHR 6 , and -CH 2 -R 6a ;
- R 6 is selected from the group: methyl substituted with 0-3 R c ; ethyl substituted with 0-3 R c ; propyl substituted with 0-3 R c ; butyl substituted with 0-3 R c ; phenyl substituted with 0-3 R c ; naphthyl substituted with 0-3 R c ; benzyl substituted with 0-3 R c ; and quinolinyl substituted with 0-3 R c ;
- R 6a is selected from the group: phenyl substituted with 0-3 R c ; naphthyl substituted with 0-3 R c ; benzyl substituted with 0-3 R c ; and quinolinyl substituted with 0-3 R c ;
- R c is selected at each occurrence from the group: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, propoxy, i-propoxy, CF 3 , OCF 3 , Cl, F, Br, I, OH, phenyl, C(0)OH, NH 2 , -CN, and N0 2 ;
- R 8 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, phenyl, and benzyl; and
- n 1 or 2.
- the present invention provides novel compounds of Formula (II) , wherein;
- X is a boronic acid or a boron ester of formula BY ⁇ 2 ;
- Y 1 and Y 2 are individually selected from Ci-C ⁇ alkoxy, or when taken together, Y 1 and Y 2 form a cyclic boron ester where said chain or ring contains from 2 to 14 carbon atoms;
- R 1 is selected from the group: ethyl, n-propyl, n-butyl, allyl, 2, 2, 2-trifluoroethyl, 2 , 2-difluoroethyl, 3,3,3- trifluoropropyl, 4 , 4, 4-trifluorobutyl, and 3-butenyl;
- R 2 is H
- R 3 is selected from the group: i-butyl, neo-pentyl, cyclohexylmethyl, t-butoxymethyl, benzyloxymethyl, hydroxymethyl, and phenyl;
- R 4 is selected from the group: ethyl, n-propyl, i-propyl, R-2-butyl, S-2-butyl, phenyl, benzyl, and phenethyl;
- R 5 is selected from the group: H, benzyl , m-methylphenylsulfonyl , -trifluoromethylphenylsulfonyl , p-i-propylpheny1sulfonyl , p-propylphenylsulfonyl, p-t-butylphenylsulfonyl , p-carboxylphenylsulfonyl ,
- N-phenylaminocarbonyl N- (p-n-butylphenyl ) aminocarbonyl , benzyloxycarbonyl , methoxycarbonyl , t-butyloxycarbonyl , benzoyl, methanesulfonyl , phenylsulfonyl , o-nitrophenylsulfonyl , m-nitrophenylsulfonyl, and m-aminophenylsulfonyl; and
- n 1 or 2
- the present invention provides novel compounds of Formula (II) , wherein;
- X is a boronic acid or boron ester, wherein the ester is a diol selected from the group: pinanediol, pinacol, 1, 2-ethanediol, 1, 3-propanediol, 1, 2-propanediol, 2,3- butanediol, 1, 2-diisopropylethanediol, 5, 6-decanediol, and 1, 2-dicyclohexylethanediol;
- R 1 is selected from the group: ethyl, n-propyl, n-butyl, allyl, 2, 2, 2-trifluoroethyl, 2 , 2-difluoroethyl, 3,3,3- trifluoropropyl, 4 , 4 , 4-trifluorobutyl, and 3-butenyl;
- R 2 is H
- R 3 is selected from the group: i-butyl, neo-pentyl, cyclohexylmethyl, t-butoxymethyl, benzyloxymethyl, hydroxymethyl, and phenyl;
- R 4 is selected from the group: ethyl, n-propyl, i-propyl, R-2-butyl, S-2-butyl, phenyl, benzyl, and phenethyl;
- R 5 is selected from the group: H, benzyl, m-methylphenylsulfonyl , m-trifluoromethylphenylsulfonyl, p-i-propylphenylsulfonyl , p-propylphenylsulfonyl , p-t-butylphenylsulfonyl, p-carboxylphenylsulfonyl ,
- N- (p-n-butylphenyl) aminocarbonyl benzyloxycarbonyl , methoxycarbonyl , t-butyloxycarbonyl , benzoyl, methanesulfonyl , phenylsulfonyl, o-nitrophenylsulfonyl , m-nitrophenylsulfonyl, and m-aminophenylsulfonyl;
- n i or 2.
- the compound of Formula (I) is selected from the group:
- the present invention provides a novel pharmaceutical composition
- a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula (I) or pharmaceutically acceptable salt form thereof.
- the present invention provides a novel method of treating HCV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I) or pharmaceutically acceptable salt form thereof.
- the present invention provides novel compounds of Formula (I) or pharmaceutically acceptable salt forms thereof for use in therapy.
- the present invention provides the use of novel compounds of Formula (I) or pharmaceutically acceptable salt forms thereof for the manufacture of a medicament for the treatment of HCV.
- the compounds herein described have asymmetric centers .
- Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials .
- Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms .
- substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
- 2 hydrogens on the atom are replaced.
- Keto substituents are not present on aromatic moieties.
- a ring system e.g., carbocyclic or heterocyclic
- the present invention is intended to include all isotopes of atoms occurring in the present compounds .
- Isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include tritium and deuterium.
- Isotopes of carbon include C-13 and C-14.
- alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
- C ⁇ - ⁇ o alkyl (or alkylene), is intended to include Ci, C 2 , C 3 , C 4 , C 5 , CQ , C ⁇ , CQ , Cg , and C 10 alkyl groups.
- alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
- haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl .
- Alkoxy represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
- C ⁇ - 10 alkoxy is intended to include Ci, C 2 , C 3 , C 4 , C 5 , CQ , C ⁇ , Cg, C 9 , and Cio alkoxy groups.
- alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
- Cycloalkyl is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
- C 3 _ 6 cycloalkyl is intended to include C 3 , C 4 , C 5 , and CQ cycloalkyl groups.
- Alkenyl or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl .
- C 2 - 10 alkenyl (or alkenylene) is intended to include C 2 , C 3 , C 4 , C 5 , CQ , C ⁇ , C ⁇ , C 9 , and Cio alkenyl groups.
- Alkynyl or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl .
- C 2 - 10 alkynyl (or alkynylene) is intended to include C 2 , C 3 , C 4 , C 5 , C ⁇ , , C 7 , C ⁇ , C 9 , and Cio alkynyl groups.
- Halo or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, and bromo.
- Countererion is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, or sulfate.
- heterocyclic group is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7 , 8, 9, or 10- membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- the nitrogen and sulfur heteroatoms may optionally be oxidized.
- the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
- heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
- a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1.
- aromatic heterocyclic group or “heteroaryl” is intended to mean a stable 5, 6, or 7- membered monocyclic or bicyclic or 7 , 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, 0 and S. It is to be noted that total number of S and 0 atoms in the aromatic heterocycle is not more than 1.
- heterocycles including heteroaryls, include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl , benzothiofuranyl, benzothiophenyl, benzoxazolyl , benzthiazolyl, benztriazolyl, benztetrazolyl , benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aif-carbazolyl , carbolinyl, chromanyl , chromenyl, cinnolinyl, decahydroquinolinyl , 2H, 6H-1 , 5, 2-dithiazinyl , dihydrofuro (2 , 3 -b) tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-in
- Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl , benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl , isothiazolopyridinyl , thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl , and pyrazolopyridinyl .
- Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
- Preferred 5 to 10 membered heteroaryls include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, indolyl, benzimidazolyl, li ⁇ -indazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, and benzisothiazolyl.
- Preferred 5 to 6 membered heteroaryls include, but are not limited to, pyridinyl, furanyl, thienyl, pyrazolyl, pyrazinyl, and imidazolyl . Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
- amino acid as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids (e.g., L-amino acids), modified and unusual amino acids (e.g., D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides , 5: 342-429, the teaching of which is hereby incorporated by reference.
- Natural protein occurring amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine.
- Natural non-protein amino acids include, but are not limited to arginosuccinic acid, citrulline, cysteine sulfinic acid, 3 , 4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine, 3-monoiodotyrosine, 3 , 5-diiodotryosine, 3 , 5, 5 ' -triiodothyronine, and 3 , 3 ' , 5 , 5 ' -tetraiodothyronine .
- Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, 2 , 4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine , phenylglycine, ⁇ -phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3 , 4-dehydroproline,
- boronic acid represents -B(OH) 2 .
- boronic acid ester or "boron ester” is intended to represent esterified versions of boronic acid, for example, -B0 R and -B(OR) 2 , wherein -B0 2 R represents a boronic acid esterified by a diol moiety R and -B(OR) 2 represents a boronic acid esterified by two separate OR moieties.
- Examples of useful diols for esterification with the boronic acids are pinanediol, pinacol, 1, 2-ethanediol, 1, 3 -propanediol, 1 , 2-propanediol, 2 , 3 -butanediol, 1,2- diisopropylethanediol, 5, 6-decanediol, and 1,2- dicyclohexylethanediol .
- phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
- examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids.
- the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
- inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
- organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
- such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
- Lists of suitable salts are found in Remington ' s Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
- prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc ... ) the compounds of the present invention may be delivered in prodrug form.
- the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same.
- Prodrugs are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject.
- Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
- Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
- Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
- Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent .
- “Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HCV infection or treat the symptoms of HCV infection in a host.
- the combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul . 1984, 22, 27-55, occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds . Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
- the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
- the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
- novel compounds of this invention may be prepared using the reactions and techniques described in this section.
- the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
- all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
- the compounds of this invention are intended to interact with the catalytic serine hydroxyl of Hepatitis C NS3 protease, and therefore incorporate an electrophilic moiety capable of such interaction.
- this moiety or its synthetic equivalent or precursor, is referred to as a "serine trap" and is defined by formula 9.
- a series of ⁇ -lactams of formula 12 are prepared by the method outlined in Scheme 1.
- Cbz protected, R 4 - substituted amino acid 1 is treated with paraformaldehyde and p-toluenesulfonic acid to give oxazolidinone 2.
- Subsequent alkylation with allyl bromide provides the racemic disubstituted oxazolidinone 3.
- Treatment with sodium methoxide in methanol affords amino acid methyl ester 4.
- the olefin in 4 is cleaved by ozonolysis to give aldehyde 5.
- Reductive amination of aldehyde 5 with amino acid methyl ester 6, followed by lactamization provides the lactam 7.
- Cbz protected amino acids 1 and amino acid methyl esters 6 are commercially available or may be prepared from commercial amino acid derivatives by simple protecting group manipulations. Others may be synthesized in racemic form using the Strecker synthesis or amidomalonate synthesis.
- Myers pseudoephedrine glycinamide alkylation method Myers, A. G.; Gleason, J. L.; Yoon, T; Kung, D. W.. J. Am . Chem . Soc . 1997, 119 , 656-673
- Evans electrophilic azidation Evans, D. A.; Britton, T. C . ; Ellman, J. A.; Dorow, R. L. J. Am .
- ⁇ , ⁇ -Disubstituted amino boronic esters 23 may be prepared as shown in Scheme 3.
- An isocyanide 21 (commercially available or synthesized by methods known to one skilled in the art. See for instance: Ugi, I.; et al . Angew. Chem . , Intl . Ed . Eng . 1965, 4 , 472.) is metallated with an alkyllithium or lithium dialkyl amide base (Hoppe, D. Angew. Chem . , Intl . Ed. Eng. 1974, 13 , 789-804 and reacted with a trialkyl borate ester.
- ⁇ -Ketoamides and other electrophilic ketone derivatives are generally introduced in the hydroxy form and oxidized to the active ketone form in the final synthetic step.
- Scheme 4 illustrates the synthesis of ⁇ - ketoamide ⁇ -lactam peptidomimetics .
- Other electrophilic ketone derivatives may be prepared analogously (Edwards, P. D.; Bernstein, P. R. Medicinal Res . Reviews 1994, 14 , 127- 194, and references cited therein).
- the amino alcohol is coupled to acid 8 to give 26.
- Saponification with LiOH affords acid 27, which is coupled to an amine Y-NH 2 , to give hydroxy amide 28.
- Hydrogenation of the Cbz group, followed by acylation, sulfonylation, reductive amination, etc. of the resulting amine 29 provides 30.
- a series of 6-lactam derivatives of formula 40 are prepared by the method outlined in Scheme 5. Allylated, R 4 substituted amino acid methyl ester 4, prepared as shown in Scheme 1, is hydroborated and oxidized to alcohol 32. Swern oxidation affords aldehyde 33, which is reductively aminated with R 3 substituted amino acid t-butyl ester 34 to afford amine 35. Saponification of the methyl ester in 35, followed by cyclization affords lactam 36. The t-butyl ester is removed with trifluoroacetic acid to give acid 37. Coupling acid 37 to serine trap 9 with PyAOP or via a mixed anhydride affords compounds of formula 38.
- Catalytic hydrogenation provides amine hydrochloride 39, which may be acylated, sulfonylated, reductively alkylated, etc. to provide ⁇ -lactams of formula 40.
- amine hydrochloride 39 which may be acylated, sulfonylated, reductively alkylated, etc. to provide ⁇ -lactams of formula 40.
- Numerous amino acid t- butyl esters 34 are commercially available or may be synthesized by methods known to one skilled in the art (Roeske, R. J. Org. Chem . 1963, 28, 1251-1253).
- a series of ⁇ -lactams of formula 49 may be synthesized by the method shown in Scheme 6.
- R 4 substituted oxazolidinone 3 is hydrolyzed to acid 41 with NaOH.
- the acid is coupled to R 3 substituted-N-allyl amino acid methyl ester 42 using activating reagents suitable for hindered peptide coupling reactions (Albericio, et al . J " . Org. Chem . 1998, 63 , 9678-9683. Wenschuh, H., et al . Tetrahedron Lett . 1996, 37, 5483-5486.) to afford dipeptide 43. Ring closing olefin metathesis with ruthenium catalyst 44 (Miller, S. J.
- R 3 substituted-N-allyl amino acid methyl esters 42 may be prepared from R 3 - substituted ⁇ -bromo esters ( (Gribble, G. W. ; Hirth, B. H. J. Heterocyclic Chem . 1996, 33 , 719-726.)
- Preparation of ⁇ -aminoboronic acids are well known in the art.
- Scheme 8 shows the synthesis of ⁇ -aminoboronic acids containing sidechains where R is ethyl, allyl, vinyl, and cyclopropyl .
- a Grignard reagent is added to a trialkyl boronate to give a substituted dialkyl boronate.
- Transesterification with a suitable diol protecting group gives the boronate ester 2. 2 is shown protected as the pinanediol ester.
- Pinanediol is the preferred protecting group, but other diol protecting groups are known to those skilled in the art, for example, a C2 symmetrical diol such as (R, R) 2 , 3-butandiol and (R, R) dicyclohexaneethanediol can also be used.
- the ⁇ -chloroalkyl intermediate 3_ is obtained by the addition of the anion of methylene chloride to the boronic acid ester.
- Li + CHC1 2 ⁇ is prepared in situ by the addition of LDA to a -78°C solution of the alkyl boronic acid ester in methylene chloride.
- CHCl 2 ⁇ Li + is prepared by reacting n-butyl lithium with methylene chloride at -100°C followed by the addition of the alkyl boronic acid 2.
- ZnCl 2 is added to more hindered alkyl boronic acid.
- 3. is treated with the lithium salt of hexamethyldisilazane to give the £>is-silane protected amine 4.
- Compound 4 is treated with either anhydrous HCI or trifluoroacetic acid to give the amine 5 as a hydrochloride salt or trifluoroacetate salt.
- Scheme 8a outlines a method of preparing ⁇ - aminoboronic acids suitable for incorporation in to a peptide and applied as enzyme inhibitors.
- Matteson (Matteson and Majumdar J “ . Organometallic Chem. 170 , 259- 264, 1979; Matteson and Arne Organometallics 1, 280-288, 1982) discloses the preparation of ⁇ -haloboronic acids.
- Compound 6 is prepared by the method described by Sadhu and Matteson Organometallics 4, 1687-1689, 1985. Compound 6 is allowed to react with thiophenol in presence of tertiary base to give the thiol ether 7.
- 7 can be prepared by reacting the lithium salt of thioanisole with a trialkyl boronate as described by Matteson and Arne Organometallics 1, 280-288 (1982) . 7 is treated with LDA followed by a hydrocarbon containing an electrophilic center. For this reaction l-bromo-2 , 2-difluoroethane was used to give a 2 , 2-difluoroethyl substituent 8,. The ⁇ - aminoboronic acid 9 , was obtained by treating 8. with methyl iodide or other suitable alkylating agent in the presence of iodide ion followed by lithium hexamethyldisilazane and HCI.
- the sidechain substituent is an electrophile. This provides a method of preparing 2-amino- 3 , 3-difluoropropyl boronic acid where conventional methods have failed.
- R -CH 2 CHF 2 or -alkyl or -haloalkyl
- Scheme 8b illustrates the preparation of ⁇ - aminoboronic acids with hydroxy substituted side chains, boroSerine and boroThreonine . Both are synthesized as their benzyl protected form and incorporated into peptides . The benzyl protecting groups are removed by catalytic hydrogenation to give the final product.
- the synthesis of 2-benzyloxy-l-chloroethane boronic acids esters has been described (Matteson et al . Organometallics 3 , 1284-1288, 1984).
- H-boroSer (OBzl) -C ⁇ 0 H ⁇ 6 the ⁇ -chloromethyl boronic acid is treated with the anion of benzyl alcohol to give the benzyl ether.
- H-boroSer(OBzl)-C 10 H 16 R H- or CH 3 -
- Scheme 8c describes the synthesis of boronic acid analogs of cysteine.
- Vinylmagnesium bromide is allowed to react with triethyl boronate to give vinylboronate diethyl ester.
- Transesterification with pinanediol gives the corresponding ester 16.
- the ⁇ -chloro group is readily converted to the amine using chemistry previously described (Scheme 8) .
- Final deprotection of the thiol is achieved after incorporation of the amine in peptides.
- One diasteriomer of a compound of Formula (I) may display superior activity compared with the others.
- the following stereochemistries are considered to be a part of the present invention.
- racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and
- a chiral compound of Formula (I) may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940) .
- a chiral catalyst or a chiral ligand e.g., Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940
- step (2e) Following a procedure analogous to that used in step (If), the material from step (2d) (0.127 g, 0.278 mmol) was hydrogenated to yield the the crude product as a colorless oil (79.5 mg, 88%), which was used without further purification .
- H-boroAlg pinanediol ester «hydrochloride .
- the bis- trimethylsilane protected amine (Scheme 8) was prepared by dissolving hexamethyldisilizane (64.4 mmol) in dry THF (30 mL) and cooling to -78°C.
- n-Butyl lithium in hexane (1.6 N, 70.8 mmol) was added and the solution was allowed to warm to room temperature. It was recooled to -78°C and 1- chloro-3-butene boronate pinanediol (17.2 g, 64.4 mmol) was added in 30 L THF. The mixture was allowed to slowly warm to room temperature and to stir overnight.
- H-boroAbu pinanediol ester «hydrochloride.
- the amino boronic acid was prepared on a 0.09 mole scale and was purified by a procedure similar to the one described for Example 1 to yield 23 g of crude product. A proportion of this material (13 g) was purified by chromatography on an LH-20 column to give 7.47 g (54.9 %)of the desired product as a brown foam.
- Cyclopropylboronate pinacol ester The pinacol cyclopropyl bornate ester was prepared by the addition of cyclopropyl magnesium bromide was added to isopropylboronate pinacol ester. The latter compound was prepared by a previously described procedure (Andersen, M. . ; Hildebrandt, B.; Koster, G.; Hoffmann, R. W. Chem . Ber . 122, 1989, 1777-1782) .
- the Grignard reagent was prepared by adding cyclopropylbromide (3.0 mL, 37 mmol) to magnesium turnings (11 g, 0.46 mole) in THF (300 mL) at room temperature under nitrogen.
- the cyclopropyl Grignard reagent was added dropwise over a period of 3 h.
- the solution was allowed to warm to room temperature and stirred overnight.
- the solution was cooled to 0°C and 1 N HCI prepared in saturated aqueous NaCl (500 mL) was added dropwise over a period of 1 h.
- the solution was allowed to stir for an additional 4 h and the layers were separated.
- the aqueous layer was extracted with hexanes (3 x 300 mL) , dried over MgS0 4 , and concentrated using a rotary evaporator.
- Iodomethyl boronate pinacol THF (800 mL) was placed in a 3 L, 3 -necked flask equipped with two addition funnels. Triisopropyl boronate (Aldrich) (128 mL, 0.55 mol) and chloro-iodomethane (Aldrich) (100 g, 0.56 mol) were added. The mixture was cooled to -78°C and n butyl lithium (330 mL, 0.53 mol, 1.6 M in hexanes) was added dropwise. The solution was stirred for 2h and slowly allowed to warm to -10°C.
- Phenylthiomethane boronate pinacol ester Phenylthiomethane boronate pinacol ester. Thiophenol (11.6 mL, 113 mmol) was dissolved in DMF (40 L) and diisopropylethylamine (19.8 mL, 113 mmol) and chloromethyl boronate pinacol ester (20 g, 113 mmol) were added sequentially. (Iodomethyl boronate pinacol can be readily substituted for the chloro compound.) After stirring for 12 hours, solvent was removed by rotary evaporation and ether (70 mL) was added.
- H-boroThreonine (OBzl) -pinanediol Formula H 2 NCH (CH (Obenzyl ) CH 3 ) BO 2 C ⁇ 0 H ⁇ 6 *HCl Pinacol ( 1-chloroethyl) boronate .
- a 250 mL round bottom flask is charged with THF (60 mL) and CH 2 CI (2.63 mL, 41.0 mmol). The solution was cooled to - 100°C with a liquid nitrogen/methanol/H 2 ⁇ bath.
- n-BuLi 1.6 N in hexanes, 25.7 mL
- Pinanediol (2-benzyloxy-l-chloropropyl) boronate, dissolved (3.85 g, 10.6 mmol)) in THF (60 mL) was added to a solution of LiHMDS (10.6 mmol) in THF at -78°C. The solution was stirred for 1 h at -78°C and allowed to warm to room temperature . Solvent was evaporated and the residue redissolved in hexanes (120 mL) .
- H-boroSer (OBzl) -pinanediol HCI was prepared by adding Pinanediol l-chloro-2-benzyloxy-boronate (5.0g, 14.3 mmol) in THF (60 mL) to a solution of LiHMDS (15 mmol) in THF (60 mL) at -78°C. The solution was allowed to stir while warming to room temperature over a period of 3 h. The THF was evaporated, the residue redissolved in anhydrous hexanes (200 mL) , cooled to -78°C, and a solution of HCI in dioxane (4 N, 11.3 mL) was added.
- Pinanediol l-chloro-2-thio (phenyl) ethylboronate Phenylsulfenyl chloride (2.0 g, 13.8 mmol) was added to a solution of pinanediol vinyl boronate (2.85 g, 13.8 mmol) in CH 2 CI 2 (30 mL) . The solution was stirred for 30 min and then the solution was evaporated to yield 3.9 g (81%) of a pale yellow oil.
- Pinanediol l-chloro-2-thio (phenyl) ethylboronate (2.0 g, 5.7 mmol) dissolved in THF (40 mL) was added to a solution LiHMDS (6.0 mmol) in THF (60 mL) at -78°C. The solution was allowed to warm to room temperature and solvent was evaporated. The residue was redissolved in hexanes, filtered and recooled to -78°C. A solution of HCI in dioxane (4 N, 5 mL) was added and the mixture was allowed to stir overnight while warming to room temperature. The solvent was removed to yield 1.2 g (57%) of the desired product as a yellow foam.
- Phenylthiosulfenyl chloride was prepared by reacting benzene thiol with sulfur dichloride at -78°C using a published procedure (Can. J. Chem., 51, 3403-3412, 1973).
- phenyl ethyl boronate pinanediol was obtained by adding phenylthiosulfenyl chloride (3.2 g, 18.2 mmol) dissolved in dichloromethane (30 mL) dropwise over a period of 10 min to a solution of pinanediol vinylboronate (3.7 g, 18.2 mmol) in CH 2 CI 2 (50 mL) in the presence of CaC0 3 (30 mg) . The resulting solution was stirred for an additional 1 h at room temperature.
- Phenylthiomethane boronate pinacol ester was prepared by the procedure in H-borodifluoroethylglycine pinanediol. Diisopropylamine (4.7 ml, 33.6 mmol) was dissolved in THF (10 mL) and stirred at 0 °C in a 100 mL round bottom flask. Butyllithium (12.8 mL, 32.0 mmol, 2.5M in hexanes) was added dropwise to the solution.
- the compounds of Formula (I) are expected to inhibit the activity of Hepatitis C Virus NS3 protease.
- the NS3 protease inhibition is demonstrated using assays for NS3 protease activity, for example, using the assay described below for assaying inhibitors of NS3 protease.
- the compounds of Formula (I) are expected to show activity against NS3 protease in cells, as demonstrated by the cellular assay described below. Thus, the compounds of Formula (I) are potentially useful in the cure and prevention of HCV infections.
- NS3 Protease The plasmid cflSODp ⁇ OO, containing the complete coding region of HCV NS3 protease, genotype la, was obtained from ATCC (database accession: DNA Seq. Ace. M62321, originally deposited by Chiron Corporation) .
- PCR primers were designed that allow amplification of the DNA fragment encoding the NS3 protease catalytic domain (amino acids 1 to 192) as well as its two N-terminal fusions, a 5 amino acid leader sequence MGAQH (serving as a expression tag) and a 15 amino acid His tag MRGSHHHHHHMGAQH .
- the NS3 protease constructs were cloned in the bacterial expression vector under the control of the T7 promoter and transformed in E. coli BL 21 (DE3) cells. Expression of the NS3 protease was obtained by addition of 1 mM IPTG and cells were growing for additional 3 h at 25°C. The NS3 protease constructs have several fold difference in expression level, but exhibit the same level of solubility and enzyme specific activity. A typical 10 L fermentation yielded approximately 200 g of wet cell paste. The cell paste was stored at -80°C. The NS3 protease was purified based on published procedures (Steinkuhler C. et al. Journal of Virology 70, 6694-6700, 1996 and Steinkuhler C.
- lysis buffer (10 mL/g) containing PBS buffer (20 mM sodium phosphate, pH 7.4, 140 mM NaCl), 50% glycerol, 10 mM DTT, 2% CHAPS and ImM PMSF .
- Cell lysis was performed with use of microfluidizer . After homogenizing, DNase was added to a final concentration 70 U/mL and cell lysate was incubated at 4°C for 20 min.
- SP Sepharose column (Pharmacia) , previously equilibrated at a flow rate 3 mL/min in buffer A (PBS buffer, 10% glycerol, 3 mM DTT) .
- the column was extensively washed with buffer A and the protease was eluted by applying 25 column volumes of a linear 0.14 - 1.0 M NaCl gradient.
- NS3 containing fractions were pooled and concentrated on an Amicon stirred ultrafiltration cell using a YM-10 membrane. The enzyme was further purified on 26/60 Superdex 75 column (Pharmacia) , equilibrated in buffer A.
- the sample was loaded at a flow rate 1 mL/min, the column was then washed with a buffer A at a flow rate 2 mL/min. Finally, the NS3 protease containing fractions were applied on Mono S 10/10 column (Pharmacia) equilibrated in 50 mM Tris.HCl buffer, pH 7.5, 10% glycerol and 1 mM DTT and operating at flow rate 2 mL/min. Enzyme was eluted by applying 20 column volumes of a linear 0.1 - 0.5 M NaCl gradient. Based on SDS-PAGE analysis as well as HPLC analysis and active site titration, the purity of the HCV NS3 la protease was greater than 95%. The enzyme was stored at -70°C and diluted just prior to use.
- Concentrations of protease were determined in the absence of NS4a by using the peptide ester substrate Ac- DED (Edans ) EEAbu ⁇ (COO) ASK (Dabcy1) -NH 2 (Taliani et al . Anal. Biochem. 240, 60-67, 1996.) and the inhibitor, H-Asp-Glu- Val-Val-Pro-boroAlg-OH, and by using tight binding reaction conditions (Bieth, Methods Enzymol . 248, 59-85, 1995). Best data was obtained for an enzyme level of 50 nM.
- protease (63 ⁇ g/mL) was allowed to react with 3 ⁇ M NS4a, 0.10 mM Ac-Glu-Glu-Ala-Cys-pNA, and varying level of H-Asp-Glu-Val-Val-Pro-boroAlg-OH (0-6 ⁇ M) .
- Concentrations of protease were determined from linear plots of Activity vs. cone. Of H-Asp-Glu-Val-Val-Pro- boroAlg-OH. Molar concentrations of proteases were determined from the x-intercept.
- K m values were determined measuring the rate of hydrolysis of the ester substrate over a range of concentrations from 5.0 to 100 ⁇ M in the presence of 3 ⁇ M KKNS4a (KKGSWIVGRIVLSGKPAIIPKK) .
- Assay were run at 25°C, by incubating ⁇ 1 nM enzyme with NS4a for 5 min in 148 ⁇ l of buffer (50 mM Tri buffer, pH 7.0, 50% glycerol, 2% Chaps, and 5.0 mM DTT.
- Substrate (2.0 ⁇ l) in buffer was added and the reaction was allowed to proceed for 15 min. Reactions were quenched by adding 3.0 ⁇ L of 10% TFA, and the levels of hydrolysis were determined by HPLC.
- Enzyme activity was also measured by measuring the increase in fluorescence with time by exciting at 355 nm and measuring emission at 495 nm using a Perkin Elmer LS 50 spectrometer. A substrate level of 5.0 ⁇ M was used for all fluorogenic assays run on the spectrometer.
- Vi / v 0 is equal to the ratio of the Michaelis equations for velocities measured in the presence (vi) and absence (v Q ) of inhibitor. Values of vi / v 0 were measured over a range of inhibitor concentrations with the aid of an ExcelTM Spreadsheet. Reported Kj . values are the average of 3-5 separate determinations. Under the conditions of this assay, the IC 50 and K S are comparable measures of inhibitor effectiveness .
- the following method was devised to assess inhibitory action of test compounds on the HCV NS3 protease in cultured cells. Because it is not possible to efficiently infect cells with hepatitis C virus, an assay was developed based on co-expression in transfected cell lines of two plasmids, one is able to direct synthesis of the NS3 protease and the other to provide a polypeptide analogous to a part of the HCV non-structural protein containing a single known peptide sequence highly susceptible to cleavage by the protease. When installed in cultured cells by one of a variety of standard methods, the substrate plasmid produces a stable polypeptide of approximately
- the DNA plasmids are introduced into cultured cells using electroporation, liposomes or other means. Synthesis of the protease and the substrate begin shortly after introduction and may be detected within a few hours by immunological means. Therefore, test compounds are added at desired concentrations to the cells within a few minutes after introducing the plasmids. The cells are then placed in a standard CO 2 incubator at 37°C, in tissue culture medium eg Dulbecco-modified MEM containing 10% bovine serum.
- tissue culture medium eg Dulbecco-modified MEM containing 10% bovine serum.
- the cells are collected by physically scraping them from plastic dishes in which they have been growing, centrifuging them and then lysing about 10 6 of the concentrated cells in a minimal volume of buffered detergent, eg 20 ⁇ l of 1% sodium dodecyl sulfate in 0.10 M Tris-HCl, pH 6.5, containing 1% mercaptaethanol and 7% glycerol.
- buffered detergent eg 20 ⁇ l of 1% sodium dodecyl sulfate in 0.10 M Tris-HCl, pH 6.5, containing 1% mercaptaethanol and 7% glycerol.
- the samples are then loaded onto a standard SDS polyacrylamide gel, the polypeptides separated by electrophoresis, and the gel contents then electroblotted onto nitrocellulose or other suitable paper support, and the substrate and products detected by decoration with specific antibodies.
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Abstract
L'invention concerne des lactames de la formule (I), des formes stéréoisomères, des mélanges stéréoisomères ou leurs formes de sels pharmaceutiquement acceptables, qui sont utiles en tant qu'inhibiteurs de la protéase NS3 du VHC, ainsi que des compositions pharmaceutiques et des trousses de diagnostic les renfermant. Elle concerne enfin leurs procédés d'utilisation pour traiter des infections virales ou comme solution étalon ou réactif pour le dosage.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14563199P | 1999-07-26 | 1999-07-26 | |
US145631P | 1999-07-26 | ||
PCT/US2000/020189 WO2001007407A1 (fr) | 1999-07-26 | 2000-07-26 | Inhibiteurs lactame de la protease ns3 du virus de l'hepatite c |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1206449A1 true EP1206449A1 (fr) | 2002-05-22 |
Family
ID=22513923
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00950642A Withdrawn EP1206449A1 (fr) | 1999-07-26 | 2000-07-26 | Inhibiteurs lactame de la protease ns3 du virus de l'hepatite c |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1206449A1 (fr) |
AU (1) | AU6371900A (fr) |
CA (1) | CA2376961A1 (fr) |
WO (1) | WO2001007407A1 (fr) |
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US7122627B2 (en) | 1999-07-26 | 2006-10-17 | Bristol-Myers Squibb Company | Lactam inhibitors of Hepatitis C virus NS3 protease |
AU2002230763A1 (en) * | 2000-12-13 | 2008-01-03 | Bristol-Myers Squibb Pharma Company | Inhibitors of hepatitis c virus ns3 protease |
US6653295B2 (en) | 2000-12-13 | 2003-11-25 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus NS3 protease |
AU2002243508A1 (en) * | 2001-01-10 | 2002-07-24 | Bristol-Myers Squibb Company Patent Department | Alpha-aminoboronic acids prepared by novel synthetic methods |
GB0127568D0 (en) | 2001-11-16 | 2002-01-09 | Glaxo Group Ltd | Chemical compounds |
US7119072B2 (en) | 2002-01-30 | 2006-10-10 | Boehringer Ingelheim (Canada) Ltd. | Macrocyclic peptides active against the hepatitis C virus |
US7091184B2 (en) | 2002-02-01 | 2006-08-15 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor tri-peptides |
US6642204B2 (en) | 2002-02-01 | 2003-11-04 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor tri-peptides |
NZ561851A (en) | 2002-04-11 | 2009-05-31 | Vertex Pharma | Inhibitors of serine proteases, particularly hepatitis C virus NS3 - NS4 protease |
US7557137B2 (en) | 2002-08-05 | 2009-07-07 | Bristol-Myers Squibb Company | Gamma-lactams as beta-secretase inhibitors |
US20050075279A1 (en) | 2002-10-25 | 2005-04-07 | Boehringer Ingelheim International Gmbh | Macrocyclic peptides active against the hepatitis C virus |
TW200418791A (en) * | 2003-01-23 | 2004-10-01 | Bristol Myers Squibb Co | Pharmaceutical compositions for inhibiting proteasome |
DK1654261T3 (da) | 2003-05-21 | 2008-01-14 | Boehringer Ingelheim Int | Hepatitis C-inhibitorforbindelser |
AR045596A1 (es) | 2003-09-05 | 2005-11-02 | Vertex Pharma | Inhibidores de proteasas de serina en particular proteasa ns3-ns4a del vhc |
WO2005028501A1 (fr) | 2003-09-22 | 2005-03-31 | Boehringer Ingelheim International Gmbh | Peptides macrocycliques actifs contre le virus de l'hepatite c |
KR20060130027A (ko) | 2003-10-10 | 2006-12-18 | 버텍스 파마슈티칼스 인코포레이티드 | 세린 프로테아제, 특히 hcv ns3-ns4a 프로테아제의억제제 |
EP1944042A1 (fr) | 2003-10-27 | 2008-07-16 | Vertex Pharmceuticals Incorporated | Combinaisons pour le traitement HCV |
WO2005043118A2 (fr) | 2003-10-27 | 2005-05-12 | Vertex Pharmaceuticals Incorporated | Methode de decouverte de medicament |
WO2005070955A1 (fr) | 2004-01-21 | 2005-08-04 | Boehringer Ingelheim International Gmbh | Peptides macrocycliques actifs contre le virus de l'hepatite c |
US7683033B2 (en) | 2004-02-04 | 2010-03-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
US20070049593A1 (en) | 2004-02-24 | 2007-03-01 | Japan Tobacco Inc. | Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor |
SI1719773T1 (sl) | 2004-02-24 | 2009-08-31 | Japan Tobacco Inc | Kondenzirane heterotetraciklične spojine in njihova uporaba kot inhibitorji polimeraze HCV |
UY29016A1 (es) | 2004-07-20 | 2006-02-24 | Boehringer Ingelheim Int | Analogos de dipeptidos inhibidores de la hepatitis c |
ATE512971T1 (de) | 2004-07-20 | 2011-07-15 | Boehringer Ingelheim Int | Peptidanaloga als hepatitis c-hemmer |
US7388007B2 (en) | 2004-08-26 | 2008-06-17 | Bristol-Myers Squibb Company | Gamma-lactams as beta-secretase inhibitors |
US7659263B2 (en) | 2004-11-12 | 2010-02-09 | Japan Tobacco Inc. | Thienopyrrole compound and use thereof as HCV polymerase inhibitor |
US20090042858A1 (en) * | 2005-06-16 | 2009-02-12 | Paul Barsanti | Lactam containing hcv inhibitors |
US20070105781A1 (en) | 2005-08-02 | 2007-05-10 | Steve Lyons | Inhibitors of serine proteases |
SI2194043T1 (sl) | 2005-08-19 | 2014-04-30 | Vertex Pharmaceuticals Incorporated | Postopki |
AR055395A1 (es) | 2005-08-26 | 2007-08-22 | Vertex Pharma | Compuestos inhibidores de la actividad de la serina proteasa ns3-ns4a del virus de la hepatitis c |
US7705138B2 (en) | 2005-11-11 | 2010-04-27 | Vertex Pharmaceuticals Incorporated | Hepatitis C virus variants |
EP2392590A3 (fr) | 2005-11-11 | 2012-03-14 | Vertex Pharmaceuticals Incorporated | Variantes du virus de l'hépatite C |
US8017612B2 (en) | 2006-04-18 | 2011-09-13 | Japan Tobacco Inc. | Piperazine compound and use thereof as a HCV polymerase inhibitor |
EP1886685A1 (fr) | 2006-08-11 | 2008-02-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Méthodes, utilisations et compositions pour la modulation de la réplication du HCV par activation ou inhibition du récepteur farnesoid X |
US20100216161A1 (en) * | 2009-02-26 | 2010-08-26 | Vertex Pharmaceuticals Incorporated | Method for identifying protease inhibitors |
CN101815533A (zh) | 2007-05-04 | 2010-08-25 | 弗特克斯药品有限公司 | 用于治疗hcv感染的组合治疗 |
WO2012107589A1 (fr) | 2011-02-11 | 2012-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Méthodes et compositions pharmaceutiques pour le traitement et la prévention des infections à vhc |
JP7268049B2 (ja) | 2018-03-08 | 2023-05-02 | インサイト・コーポレイション | PI3K-γ阻害剤としてのアミノピラジンジオール化合物 |
WO2020010003A1 (fr) | 2018-07-02 | 2020-01-09 | Incyte Corporation | DÉRIVÉS D'AMINOPYRAZINE UTILISÉS EN TANT QU'INHIBITEURS DE PI3K-γ |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0636143B1 (fr) * | 1992-04-16 | 1997-09-24 | Zeneca Limited | Peptides d'acide alpha-aminoboronique et leur utilisation comme inhibiteurs d'elastase |
EP0636144A1 (fr) * | 1992-04-16 | 1995-02-01 | Zeneca Limited | Peptides d'acide alpha-aminoboronique et leur utilisation comme inhibiteurs d'elastase |
IL111175A0 (en) * | 1993-10-07 | 1994-12-29 | Du Pont Merck Pharma | Electrophilic peptide analogs as inhibitors of trypsin-like serine proteases and pharmaceutical compositions containing them |
US5618792A (en) * | 1994-11-21 | 1997-04-08 | Cortech, Inc. | Substituted heterocyclic compounds useful as inhibitors of (serine proteases) human neutrophil elastase |
ES2169880T3 (es) * | 1996-10-18 | 2002-07-16 | Vertex Pharma | Inhibidores de proteasas de serina, particularmente de la proteasa ns3 del virus de la hepatitis c. |
GB9623908D0 (en) * | 1996-11-18 | 1997-01-08 | Hoffmann La Roche | Amino acid derivatives |
RU2217436C2 (ru) * | 1996-12-06 | 2003-11-27 | Кортеч, Инк. | Производные оксадиазола, тиадиазола или триазола, являющиеся ингибиторами сериновых протеаз, и содержащие их фармацевтические композиции |
FR2758329B1 (fr) * | 1997-01-16 | 1999-02-12 | Synthelabo | Derives d'imidazole-4-butane boronique, leur preparation et leur utilisation en therapeutique |
NZ503262A (en) * | 1997-08-11 | 2002-10-25 | Boehringer Ingelheim Ca Ltd | Hepatitis C NS3 protease inhibitor peptides and peptide analogues |
ES2234144T3 (es) * | 1997-08-11 | 2005-06-16 | Boehringer Ingelheim (Canada) Ltd. | Analogos de peptidos inhibidores de la hepatitis c. |
-
2000
- 2000-07-26 AU AU63719/00A patent/AU6371900A/en not_active Abandoned
- 2000-07-26 EP EP00950642A patent/EP1206449A1/fr not_active Withdrawn
- 2000-07-26 WO PCT/US2000/020189 patent/WO2001007407A1/fr not_active Application Discontinuation
- 2000-07-26 CA CA002376961A patent/CA2376961A1/fr not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO0107407A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU6371900A (en) | 2001-02-13 |
WO2001007407A1 (fr) | 2001-02-01 |
CA2376961A1 (fr) | 2001-02-01 |
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