AU2006265632B2 - HCV inhibitors - Google Patents
HCV inhibitors Download PDFInfo
- Publication number
- AU2006265632B2 AU2006265632B2 AU2006265632A AU2006265632A AU2006265632B2 AU 2006265632 B2 AU2006265632 B2 AU 2006265632B2 AU 2006265632 A AU2006265632 A AU 2006265632A AU 2006265632 A AU2006265632 A AU 2006265632A AU 2006265632 B2 AU2006265632 B2 AU 2006265632B2
- Authority
- AU
- Australia
- Prior art keywords
- alkyl
- amino
- compound
- hydrogen
- alkoxy
- 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.)
- Ceased
Links
- 239000003112 inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 219
- 238000000034 method Methods 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 208000005176 Hepatitis C Diseases 0.000 claims abstract description 8
- 208000010710 hepatitis C virus infection Diseases 0.000 claims abstract description 6
- -1 amino, monosubstituted amino Chemical group 0.000 claims description 269
- 125000000217 alkyl group Chemical group 0.000 claims description 180
- 229910052739 hydrogen Inorganic materials 0.000 claims description 124
- 239000001257 hydrogen Substances 0.000 claims description 123
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 101
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 88
- 125000003118 aryl group Chemical group 0.000 claims description 82
- 125000003545 alkoxy group Chemical group 0.000 claims description 79
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 72
- 125000005843 halogen group Chemical group 0.000 claims description 67
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 67
- 125000000623 heterocyclic group Chemical group 0.000 claims description 58
- 125000001072 heteroaryl group Chemical group 0.000 claims description 57
- 239000000203 mixture Substances 0.000 claims description 45
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 39
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 37
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 35
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 34
- 125000001188 haloalkyl group Chemical group 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 30
- 125000004414 alkyl thio group Chemical group 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000003282 alkyl amino group Chemical group 0.000 claims description 27
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 26
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 125000002723 alicyclic group Chemical group 0.000 claims description 21
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 18
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- 125000004442 acylamino group Chemical group 0.000 claims description 16
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 16
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 150000001408 amides Chemical class 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 12
- 125000004104 aryloxy group Chemical group 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 12
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 12
- 125000001931 aliphatic group Chemical group 0.000 claims description 11
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 11
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 11
- 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 claims description 11
- 125000002768 hydroxyalkyl 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 125000005110 aryl thio group Chemical group 0.000 claims description 10
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 10
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 10
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 10
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 125000006413 ring segment Chemical group 0.000 claims description 9
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 7
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 7
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 7
- 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 claims description 7
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000005089 alkenylaminocarbonyl group Chemical group 0.000 claims description 4
- 125000005225 alkynyloxycarbonyl group Chemical group 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 claims description 3
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 claims description 3
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 14
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 2
- 125000004889 1-methylethylamino group Chemical group CC(C)N* 0.000 claims 1
- 108091053735 lin-4 stem-loop Proteins 0.000 claims 1
- 108091032363 lin-4-1 stem-loop Proteins 0.000 claims 1
- 108091028008 lin-4-2 stem-loop Proteins 0.000 claims 1
- 150000008054 sulfonate salts Chemical class 0.000 claims 1
- 230000010076 replication Effects 0.000 abstract description 12
- 230000008569 process Effects 0.000 abstract description 7
- 239000003443 antiviral agent Substances 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 249
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 161
- 235000019439 ethyl acetate Nutrition 0.000 description 88
- 239000011541 reaction mixture Substances 0.000 description 75
- 229940093499 ethyl acetate Drugs 0.000 description 73
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 46
- 239000000243 solution Substances 0.000 description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 239000012267 brine Substances 0.000 description 45
- 239000010410 layer Substances 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 41
- 150000003254 radicals Chemical class 0.000 description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000007787 solid Substances 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 229920006395 saturated elastomer Polymers 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 30
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 28
- 241000711549 Hepacivirus C Species 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 21
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 20
- 239000011734 sodium Substances 0.000 description 20
- 239000002253 acid Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 17
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 239000004215 Carbon black (E152) Substances 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
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- 150000003840 hydrochlorides Chemical class 0.000 description 10
- 238000006460 hydrolysis reaction Methods 0.000 description 10
- 150000001204 N-oxides Chemical class 0.000 description 9
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 125000004185 ester group Chemical group 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
- 230000007170 pathology Effects 0.000 description 6
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 6
- ZQEBQGAAWMOMAI-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCC1C(O)=O ZQEBQGAAWMOMAI-UHFFFAOYSA-N 0.000 description 5
- 229910004298 SiO 2 Inorganic materials 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
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- 235000015165 citric acid Nutrition 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 4
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 4
- BJXRGRFVAKXJAF-UHFFFAOYSA-N 3-cyclopropyl-6-methoxyisoquinoline Chemical compound C=1C2=CC(OC)=CC=C2C=NC=1C1CC1 BJXRGRFVAKXJAF-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
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- 238000005903 acid hydrolysis reaction Methods 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- BENKAPCDIOILGV-MLWJPKLSSA-N (2s)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC(O)C[C@H]1C(O)=O BENKAPCDIOILGV-MLWJPKLSSA-N 0.000 description 3
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- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 3
- 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 3
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 3
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 1
- 229950006081 taribavirin Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- AEMVKGWKKYVEFD-UHFFFAOYSA-N tert-butyl 2-[[1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]carbamoyl]-4-(6-methoxy-3-methylisoquinolin-1-yl)oxypyrrolidine-1-carboxylate Chemical compound C1C(OC=2C3=CC=C(OC)C=C3C=C(C)N=2)CN(C(=O)OC(C)(C)C)C1C(=O)NC(CCC)C(O)C(=O)NC1CC1 AEMVKGWKKYVEFD-UHFFFAOYSA-N 0.000 description 1
- 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229950002810 valopicitabine Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Pain & Pain Management (AREA)
- Oncology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69576705P | 2005-06-30 | 2005-06-30 | |
| US60/695,767 | 2005-06-30 | ||
| US11/478,337 US7608592B2 (en) | 2005-06-30 | 2006-06-28 | HCV inhibitors |
| US11/478,337 | 2006-06-28 | ||
| PCT/US2006/025996 WO2007005838A2 (en) | 2005-06-30 | 2006-06-29 | Hcv inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2006265632A1 AU2006265632A1 (en) | 2007-01-11 |
| AU2006265632B2 true AU2006265632B2 (en) | 2012-03-29 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2006265632A Ceased AU2006265632B2 (en) | 2005-06-30 | 2006-06-29 | HCV inhibitors |
Country Status (14)
| Country | Link |
|---|---|
| US (2) | US7608592B2 (enExample) |
| EP (2) | EP1906945B1 (enExample) |
| JP (2) | JP5368089B2 (enExample) |
| KR (1) | KR101369872B1 (enExample) |
| AU (1) | AU2006265632B2 (enExample) |
| BR (1) | BRPI0612104A8 (enExample) |
| CA (1) | CA2613112C (enExample) |
| EA (1) | EA015415B1 (enExample) |
| ES (1) | ES2552712T3 (enExample) |
| IL (1) | IL188207A (enExample) |
| MX (1) | MX2007016324A (enExample) |
| NO (1) | NO20080540L (enExample) |
| NZ (1) | NZ564257A (enExample) |
| WO (1) | WO2007005838A2 (enExample) |
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| JP2003007697A (ja) * | 2001-06-21 | 2003-01-10 | Hitachi Kokusai Electric Inc | 半導体装置の製造方法、基板処理方法および基板処理装置 |
| US7608592B2 (en) * | 2005-06-30 | 2009-10-27 | Virobay, Inc. | HCV inhibitors |
| NZ565059A (en) * | 2005-07-25 | 2011-08-26 | Intermune Inc | Novel macrocyclic inhibitors of hepatitus C virus replication |
| BRPI0617274A2 (pt) * | 2005-10-11 | 2011-07-19 | Intermune Inc | compostos e métodos para a inibição de replicação viral de hepatite c |
| EP2007789B1 (en) | 2006-04-11 | 2015-05-20 | Novartis AG | Spirocyclic HCV/HIV inhibitors and their uses |
| RU2008152171A (ru) * | 2006-07-05 | 2010-08-10 | Интермьюн, Инк. (Us) | Новые ингибиторы вирусной репликации гепатита с |
| PT2041156E (pt) | 2006-07-13 | 2014-02-21 | Achillion Pharmaceuticals Inc | Péptidos 4-amino-4-oxobutanoil como inibidores da replicação viral |
| US20080161254A1 (en) * | 2007-01-03 | 2008-07-03 | Virobay, Inc. | Hcv inhibitors |
| EP2125113A2 (en) | 2007-02-26 | 2009-12-02 | Achillion Pharmaceuticals, Inc. | Tertiary amine substituted peptides useful as inhibitors of hcv replication |
| AP2009005053A0 (en) * | 2007-05-03 | 2009-12-31 | Intermune Inc | Novel macrocyclic inhibitors of hepatitis c virus replication |
| AU2008251425A1 (en) | 2007-05-10 | 2008-11-20 | Array Biopharma, Inc. | Novel peptide inhibitors of hepatitis C virus replication |
| AU2008309589B2 (en) * | 2007-10-10 | 2012-07-05 | Novartis Ag | Spiropyrrolidines and their use against HCV and HIV infection |
| US8309685B2 (en) | 2007-12-21 | 2012-11-13 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
| TW201546079A (zh) | 2007-12-21 | 2015-12-16 | Celgene Avilomics Res Inc | Ｈｃｖ蛋白酶抑制劑及其用途（一） |
| US8293705B2 (en) | 2007-12-21 | 2012-10-23 | Avila Therapeutics, Inc. | HCV protease inhibitors and uses thereof |
| WO2009082697A1 (en) * | 2007-12-21 | 2009-07-02 | Avila Therapeutics, Inc. | Hcv protease inhibitors and uses thereof |
| EP2237793A4 (en) * | 2008-02-07 | 2013-07-31 | Virobay Inc | INHIBITORS OF CATHEPSIN B |
| WO2009114633A1 (en) * | 2008-03-12 | 2009-09-17 | Virobay, Inc. | Process for the preparation of (3s)-3-amino-n-cyclopropyl-2-hydroxyalkanamide derivatives |
| CA2720729A1 (en) * | 2008-04-15 | 2009-11-26 | Intermune, Inc. | Novel macrocyclic inhibitors of hepatitis c virus replication |
| US8188137B2 (en) | 2008-08-15 | 2012-05-29 | Avila Therapeutics, Inc. | HCV protease inhibitors and uses thereof |
| UY32099A (es) | 2008-09-11 | 2010-04-30 | Enanta Pharm Inc | Inhibidores macrocíclicos de serina proteasas de hepatitis c |
| KR101762842B1 (ko) | 2008-12-10 | 2017-08-04 | 아칠리온 파르마세우티칼스 인코포레이티드 | 바이러스 복제 억제제로서 유용한 신규한 4-아미노-4-옥소부타노일 펩티드 |
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| DE69709671T2 (de) * | 1996-10-18 | 2002-08-22 | Vertex Pharmaceuticals Inc., Cambridge | Inhibitoren von serinproteasen, insbesondere von ns3-protease des hepatitis-c-virus |
| BR9814018A (pt) * | 1997-11-11 | 2000-09-26 | Pfizer Prod Inc | Derivados de tienopirimidina e tienopiridina úteis como agentes anticâncer |
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| EP1730167B1 (en) | 2004-01-21 | 2011-01-12 | Boehringer Ingelheim International GmbH | Macrocyclic peptides active against the hepatitis c virus |
| AU2005219859A1 (en) * | 2004-02-27 | 2005-09-15 | Schering Corporation | Inhibitors of hepatitis C virus NS3 protease |
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| EP2029153A2 (en) * | 2006-01-27 | 2009-03-04 | Phenomix Corporation | Hepatitis c serine protease inhibitors and uses therefor |
-
2006
- 2006-06-28 US US11/478,337 patent/US7608592B2/en active Active
- 2006-06-29 EA EA200800178A patent/EA015415B1/ru not_active IP Right Cessation
- 2006-06-29 EP EP06774467.2A patent/EP1906945B1/en active Active
- 2006-06-29 NZ NZ564257A patent/NZ564257A/en not_active IP Right Cessation
- 2006-06-29 JP JP2008519691A patent/JP5368089B2/ja not_active Expired - Fee Related
- 2006-06-29 MX MX2007016324A patent/MX2007016324A/es active IP Right Grant
- 2006-06-29 WO PCT/US2006/025996 patent/WO2007005838A2/en not_active Ceased
- 2006-06-29 CA CA2613112A patent/CA2613112C/en not_active Expired - Fee Related
- 2006-06-29 ES ES06774467.2T patent/ES2552712T3/es active Active
- 2006-06-29 EP EP11190816.6A patent/EP2431379A3/en not_active Withdrawn
- 2006-06-29 KR KR1020077031049A patent/KR101369872B1/ko not_active Expired - Fee Related
- 2006-06-29 AU AU2006265632A patent/AU2006265632B2/en not_active Ceased
- 2006-06-29 BR BRPI0612104A patent/BRPI0612104A8/pt active Search and Examination
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2007
- 2007-12-18 IL IL188207A patent/IL188207A/en not_active IP Right Cessation
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2008
- 2008-01-29 NO NO20080540A patent/NO20080540L/no not_active Application Discontinuation
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2009
- 2009-10-23 US US12/605,271 patent/US8518874B2/en active Active
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2012
- 2012-05-15 JP JP2012111958A patent/JP2012176973A/ja active Pending
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| EP1136498A1 (en) * | 1996-10-18 | 2001-09-26 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis c virus NS3 protease |
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| IL188207A (en) | 2015-10-29 |
| MX2007016324A (es) | 2008-04-07 |
| US20100266537A1 (en) | 2010-10-21 |
| AU2006265632A1 (en) | 2007-01-11 |
| NO20080540L (no) | 2008-03-28 |
| JP2009500353A (ja) | 2009-01-08 |
| NZ564257A (en) | 2012-01-12 |
| EP1906945B1 (en) | 2015-08-05 |
| WO2007005838A3 (en) | 2008-01-17 |
| EP2431379A2 (en) | 2012-03-21 |
| JP2012176973A (ja) | 2012-09-13 |
| IL188207A0 (en) | 2008-03-20 |
| US20070054864A1 (en) | 2007-03-08 |
| CA2613112A1 (en) | 2007-01-11 |
| BRPI0612104A2 (pt) | 2012-09-04 |
| BRPI0612104A8 (pt) | 2017-12-26 |
| ES2552712T3 (es) | 2015-12-01 |
| US7608592B2 (en) | 2009-10-27 |
| EP1906945A4 (en) | 2009-07-15 |
| EP1906945A2 (en) | 2008-04-09 |
| KR20080027803A (ko) | 2008-03-28 |
| KR101369872B1 (ko) | 2014-03-06 |
| EA015415B1 (ru) | 2011-08-30 |
| EP2431379A3 (en) | 2013-05-15 |
| US8518874B2 (en) | 2013-08-27 |
| CA2613112C (en) | 2017-06-13 |
| JP5368089B2 (ja) | 2013-12-18 |
| EA200800178A1 (ru) | 2008-10-30 |
| WO2007005838A2 (en) | 2007-01-11 |
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