WO2003099824A1 - R-enantiomers of pyranoindole derivatives against hepatitis c - Google Patents
R-enantiomers of pyranoindole derivatives against hepatitis c Download PDFInfo
- Publication number
- WO2003099824A1 WO2003099824A1 PCT/US2003/015823 US0315823W WO03099824A1 WO 2003099824 A1 WO2003099824 A1 WO 2003099824A1 US 0315823 W US0315823 W US 0315823W WO 03099824 A1 WO03099824 A1 WO 03099824A1
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- WO
- WIPO (PCT)
- Prior art keywords
- carbon atoms
- cycloalkyl
- straight chain
- chain alkyl
- substituted
- Prior art date
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- ABPJREHLAYHTHW-UHFFFAOYSA-N pyrano[2,3-g]indole Chemical class O1C=CC=C2C3=NC=CC3=CC=C21 ABPJREHLAYHTHW-UHFFFAOYSA-N 0.000 title description 11
- 208000006454 hepatitis Diseases 0.000 title description 4
- 231100000283 hepatitis Toxicity 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 185
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 101
- 125000000217 alkyl group Chemical group 0.000 claims description 66
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 52
- 239000000203 mixture Substances 0.000 claims description 51
- 125000003118 aryl group Chemical group 0.000 claims description 43
- -1 furanylmethyl Chemical group 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- 229910001868 water Inorganic materials 0.000 claims description 36
- 239000007787 solid Substances 0.000 claims description 35
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 24
- 125000003342 alkenyl group Chemical group 0.000 claims description 23
- 125000000304 alkynyl group Chemical group 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000004429 atom Chemical group 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- ZNGSVRYVWHOWLX-KHFUBBAMSA-N (1r,2s)-2-(methylamino)-1-phenylpropan-1-ol;hydrate Chemical compound O.CN[C@@H](C)[C@H](O)C1=CC=CC=C1.CN[C@@H](C)[C@H](O)C1=CC=CC=C1 ZNGSVRYVWHOWLX-KHFUBBAMSA-N 0.000 claims description 2
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 4
- 238000001035 drying Methods 0.000 claims 3
- 238000005406 washing Methods 0.000 claims 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 2
- BLMMDSMMSYATKY-GOSISDBHSA-N 2-[(1r)-5-cyano-6-fluoro-8-methyl-1-propyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl]acetic acid Chemical compound N1C2=C(C)C=C(F)C(C#N)=C2C2=C1[C@@](CCC)(CC(O)=O)OCC2 BLMMDSMMSYATKY-GOSISDBHSA-N 0.000 claims 1
- XPRHNEYVMCFUIS-QGZVFWFLSA-N 2-[(1r)-5-cyano-8-fluoro-1-propyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl]acetic acid Chemical compound N1C2=C(F)C=CC(C#N)=C2C2=C1[C@@](CCC)(CC(O)=O)OCC2 XPRHNEYVMCFUIS-QGZVFWFLSA-N 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 55
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- 239000007832 Na2SO4 Substances 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 229940093499 ethyl acetate Drugs 0.000 description 14
- 241000711549 Hepacivirus C Species 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 12
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- 239000000377 silicon dioxide Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 229920001213 Polysorbate 20 Polymers 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 7
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 7
- 208000005176 Hepatitis C Diseases 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
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- 125000000623 heterocyclic group Chemical group 0.000 description 6
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- 239000011734 sodium Substances 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
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- 208000036142 Viral infection Diseases 0.000 description 4
- 125000004663 dialkyl amino group Chemical group 0.000 description 4
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- 125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 125000005058 dihydrotriazolyl group Chemical group N1(NNC=C1)* 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000003617 erythrocyte membrane Anatomy 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- KWYAZZFDXVBWOB-UHFFFAOYSA-N ethyl 2-(5-cyano-6-fluoro-8-methyl-1-propyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetate Chemical compound N1C2=C(C)C=C(F)C(C#N)=C2C2=C1C(CCC)(CC(=O)OCC)OCC2 KWYAZZFDXVBWOB-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 1
- 125000005367 heteroarylalkylthio group Chemical group 0.000 description 1
- 125000005326 heteroaryloxy alkyl group Chemical group 0.000 description 1
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012092 media component Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 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
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
- 239000008181 tonicity modifier Substances 0.000 description 1
- 229940034610 toothpaste Drugs 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- This invention is directed to pharmaceutical compositions containing stereoisomers of pyranoindole derivatives and processes for their preparation.
- Hepatitis C is a common viral infection that can lead to chronic Hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. Infection with the Hepatitis C virus (HCV) leads to chronic Hepatitis in at least 85% of cases, is the leading reason for liver transplantation, and is responsible for at least 10,000 deaths annually in the United States (Hepatology, 1997, 26 (Suppl. 1), 2S-10S).
- HCV Hepatitis C virus
- the Hepatitis C virus is a member of the Flaviviridae family, and the genome of HCV is a single-stranded linear RNA of positive sense (Hepatology, 1997, 26 (Suppl. 1), 11S-14S). HCV displays extensive genetic heterogeneity; at least 6 genotypes and more than 50 subtypes have been identified. [0004] There is no effective vaccine to prevent HCV infection. The only therapy currently available is treatment with interferon- ⁇ (INF- ⁇ ) or combination therapy of INF- ⁇ with the nucleoside analog ribavirin (Antiviral Chemistry and Chemotherapy, 1997, 8, 281-301). However, only about 40% of treated patients develop a sustained response, so there is a need for more effective anti-HCV therapeutic agents.
- INF- ⁇ interferon- ⁇
- ribavirin Antiviral Chemistry and Chemotherapy, 1997, 8, 281-301
- the HCV genome contains a number of non-structural proteins: NS2, NS3, NS4A, NS4B, NS5A, and NS5B (J. General Virology, 2000, 81, 1631-1648).
- NS5B is a RNA-dependent RNA polymerase which is essential for viral replication, and therefore, the inhibition of NS5B is a suitable target for the development of therapeutic agents.
- pyranoindole derivatives are disclosed and the compounds are stated to have antidepressant and antiulcer activity: 3,880,853 (4/29/75), 4,118,394 (10/3/78).
- US patent 4,179,503 (12/18/79) pyranoindoles are disclosed and stated to have diuretic activity.
- pyranoindole derivatives are disclosed and the compounds are stated to have antiinflammatory, analgesic, antibacterial, and antifungal activity: 3,843,681 (10/22/74), 3,939,178 (2/17/76), 3,974,179 (8/10/76), 4,070,371 (1/24/78), 4,076,831 (2/28/78).
- pyranoindole derivatives are disclosed and the compounds are stated to have antiinflammatory and analgesic activity: 4,670,462 (6/2/87), 4,686,213 (8/11/87), 4,785,015 (11/15/88), 4,810,699 (3/7/89), 4,822,781 (4/18/89), 4,960,902 (10/2/90).
- US patent 5,776,967 (7/7/98) and US patent 5,830,911 (1 1/3/98)
- pyranoindole derivatives are disclosed and the compounds are said to inhibit cyclooxegenase-2 and be useful for treating arthritic disorders, colorectal cancer, and Alzheimer's disease.
- This invention relates to a pharmaceutical composition comprising stereoisomers of pyranoindole derivatives, processes for their preparation, and pharmaceutical compositions containing them and to their use in the treatment of Hepatitis C viral infection.
- Ri is H, a straight chain alkyl of 1 to 8 carbon atoms, a branched alkyl of 3 to 12 carbon atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an alkynyl of 2 to 7 carbon atoms, or an arylalkyl or an alkylaryl of 7 to 12 carbon atoms;
- R 2 is H, a straight chain alkyl of 1 to 12 carbon atoms, a branched alkyl of 3 to 12 carbon atoms, a cycloalkyl of 3 to 12 carbon atoms, an alkenyl of 2 to 7 carbon atoms, an alkynyl of 2 to 7 carbon atoms, an alkoxyalkyl of 2 to 12 carbon atoms, an arylalkyl or alkylaryl of 7 to 12 carbon atoms, a cyanoalkyl of 1 to 8 carbon atoms, an alkylthioalkyl of 2 to 16 carbon atoms, a cycloalkyl-alkyl of 4 to 24 carbon atoms, a substituted or unsubstituted aryl, or a heteroaryl;
- R 3 - R 6 are independently H, a straight chain alkyl of 1 to 8 carbon atoms, a branched alkyl of 3 to 12 carbon atoms, a cyclo
- Ri i - R ⁇ 2 are independently H, straight chain alkyl of 1 to 8 carbon atoms, branched alkyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, a substituted or unsubstituted aryl or heteroaryl;
- Y is a bond, CH 2 , CH 2 CH , aryl, or R 2 and Y together with the ring carbon atom to which they are attached may additionally form a spirocyclic cycloalkyl ring of 3 to 8 carbon atoms; or
- the pharmaceutical compositions comprise: (R)-5-cyano-8-methyl-l-propyl-l,3,4,9-tetrahydropyrano[3,4-b]indol-l- yl]acetic acid; (R)-5-cyano-8-fluoro-l-propyl-l,3,4,9-tetrahydropyrano[3,4-b]indol- l-yl]acetic acid; (R)-5,8-dichloro-l-propyl-l,3,4,9-tetrahydropyrano[3,4-b]indol-l- yljacetic acid; or (R)-5-cyano-6-fluoro-8-methyl-l-propyl-l, 3,4,9- tetrahydropyrano[3,4-b]indol-l-l
- alkyl includes both straight and branched alkyl moieties, preferably of 1 to 8 carbon atoms.
- alkenyl refers to a radical aliphatic hydrocarbon containing one double bond and includes both straight and branched alkenyl moieties of 2 to 7 carbon atoms. Such alkenyl moieties may exist in the E or Z configurations; the compounds of this invention include both configurations.
- alkynyl includes both straight chain and branched moieties containing 2 to 7 carbon atoms having at least one triple bond.
- cycloalkyl refers to alicyclic hydrocarbon groups having 3 to 12 carbon atoms and includes but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, or adamantyl.
- aryl is defined as an aromatic hydrocarbon moiety and may be substituted or unsubstituted.
- An aryl may be selected from but not limited to, the group: phenyl, ⁇ -naphthyl, ⁇ -naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, or phenanthrenyl groups.
- the substituted aryl may be optionally mono-, di-, tri- or tetra-substituted with substituents selected from, but not limited to, the group consisting of alkyl, acyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, cyano, halogen, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, trifluoropropyl, amino, alkylamino, dialkylamino, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, -SO 3 H, -SO 2 NH 2 , -SO 2 NHalkyl, -SO 2 N(alkyl) 2 , -CO 2 H, CO 2 NH 2 , CO 2 NHalkyl, and -CO 2 N(alkyl) 2 .
- substituents selected from, but not limited to, the group consisting of alkyl, acyl
- heteroaryl is defined as an aromatic heterocyclic ring system (monocyclic or bicyclic) where the heteroaryl moieties are five or six membered rings containing 1 to 4 heteroatoms selected from the group consisting of S, N, and O, and include but is not limited to: (1) furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N- methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole
- aryloxy is defined as aryl-O-; the term “heteroaryloxy” is defined as heteroaryl-O-; wherein alkyl, aryl, and heteroaryl are as defined above.
- arylalkyl is defined as aryl-Cl- C6-alkyl-; arylalkyl moieties include benzyl, 1-phenylethyl, 2-phenylethyl, 3- phenylpropyl, 2-phenylpropyl and the like.
- alkylaryl is defined as C1-C6- alkyl-aryl-.
- alkylthio is defined as C1-C6- alkyl-S-.
- alkoxyalkyl For purposes of this invention "alkoxyalkyl,” “cycloalkyl-alkyl,”
- alkylthioalkyl denotes an alkyl group as defined above that is further substituted with an alkoxy, cycloalkyl, alkylthio, aryloxy, or heteroaryloxy group as defined above.
- alkoxy alkoxyalkoxy
- alkylthioalkoxy and “heteroarylalkoxy” denote an alkoxy group as defined above that is further substituted with an aryl, alkoxy, alkylthio, or heteroaryl group as defined above.
- arylthio and “heteroarylthio,” denote a thio group that is further substituted with an aryl or heteroaryl group as defined above.
- arylthioalkyl and heteroarylthioalkyl denote an alkyl group as defined above that is further substituted with an arylthio or heteroarylthio group as defined above.
- arylalkylthio is defined as aryl- Cl-C8-alkyl-S-; "heteroarylalkylthio” is defined as heteroaryl-Cl-C8-akyl-S-, where aryl and heteroaryl are as defined above.
- aryloxyalkylthio is defined as aryloxy-Cl-
- heteroaryloxyalkylthio is defined as heteroaryloxy-Cl-C8-alkyl-S-; where aryloxy, heteroaryloxy, and alkyl are defined above.
- phenylalkynyl is an alkynyl group further substituted with a phenyl group.
- a substituted methyl comprises a methyl substituent further substituted with for example a furanyl group.
- a furanyl substituent is further substituted with a methyl group.
- trifluoromethoxy includes but is not limited to CF 3 O-.
- trifluoromethylthio includes but is not limited to CF 3 S-.
- trifluoroethoxy is CF 3 CH 2 O-.
- trifluoroethylthio is CF 3 CH 2 S-.
- monoalkylamino and dialkylamino refer to moieties with one or two alkyl groups wherein the alkyl chain is 1 to 8 carbons and the groups may be the same or different.
- monoalkylaminoalkyl and dialkylaminoalkyl refer to monoalkylamino and dialkylamino moieties with one or two alkyl groups (the same or different) bonded to the nitrogen atom which is attached to an alkyl group of 1 to 8 carbon atoms.
- alkylsulfinyl is a R'SO- radical, where R' is an alkyl radical of 1-8 carbon atoms.
- Alkylsulfonyl is a R'S0 2 - radical, where R' is an alkyl radical of 1-8 carbon atoms.
- Alkylsulfonamido, alkenylsulfonamido, alkynylsulfonamido are R'SO 2 NH- radicals, where R' is an alkyl radical of 1-8 carbon atoms, an alkenyl radical of 2-8 carbon atoms, or an alkynyl radical of 2-8 carbon atoms, respectively.
- Saturated or partially saturated heteroaryl groups are defined in this invention as heterocyclic rings selected from but not limited to the moieties; azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl
- the compounds of this invention contain one or more asymmetric carbon atoms and may thus give rise to stereoisomers, such as enantiomers and diastereomers.
- the stereioisomers of the instant invention are named according to the Cahn-Ingold-Prelog System. While the C- carbon of formula (A) is specified the present invention includes all the other possible stereoisomers; as well as the racemic mixtures and other mixtures of R and S stereoisomers (scalemic mixtures which are mixtures of unequal amounts of enantiomers) and pharmaceutically acceptable salts thereof. It should be noted that stereoisomers of the invention having the same relative configuration at a chiral center may nevertheless have different R and S designations depending on the substitution at the indicated chiral center.
- these compounds of the invention may be present as non-racemic mixtures of two diastereomers owing to the existence of a predefined stereocenter.
- the predefined stereocenter is assigned based on the Cahn- Ingold-Prelog System and the undefined stereocenter is designated R* to denote a mixture of both R and S stereoisomers at this center.
- R* to denote a mixture of both R and S stereoisomers at this center.
- the compound of the invention is comprised of a ratio of Isomer A to Isomer B of greater than 1 :1. In the most preferred embodiment the compound is comprised of 100% Isomer A. In further embodiments the compound is comprised of a ratio of Isomer A to Isomer B of at least about 9:1. In another embodiment the compound is comprised of a ratio of Isomer A to Isomer B of at least about 8: 1. Additionally the compound is comprised of a ratio of Isomer A to Isomer B of at least about 7:1.
- salts of the compounds of formula (I) having acidic moieties at R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , or Rio may be formed from organic and inorganic bases.
- alkali metal salts sodium, lithium, or potassium and N- tetraalkylammonium salts such as N-tetrabutylammonium salts.
- salts can be formed from organic and inorganic acids.
- salts can be formed from acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.
- the compounds are preferably provided orally or subcutaneously.
- the compounds may be provided by intralesional, intraperitoneal, intramuscular or intravenous injection; infusion; liposome-mediated delivery; topical, nasal, anal, vaginal, sublingual, uretheral, transdermal, intrathecal, ocular or otic delivery.
- a compound of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention.
- the compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compounds may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
- the effective amount will be known to one of skill in the art; it will also be dependent upon the form of the compound.
- One of skill in the art could routinely perform empirical activity tests to determine the bioactivity of the compound in bioassays and thus determine what dosage to administer.
- the compounds of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent, a color additive, or a carrier.
- the carrier may be for example a diluent, an aerosol, a topical carrier, an aqueous solution, a nonaqueous solution or a solid carrier.
- the carrier may be a polymer or a toothpaste.
- a carrier in this invention encompasses any of the standard pharmaceutically accepted carriers, such as phosphate buffered saline solution, acetate buffered saline solution, water, emulsions such as an oil/water emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets and capsules.
- standard pharmaceutically accepted carriers such as phosphate buffered saline solution, acetate buffered saline solution, water, emulsions such as an oil/water emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets and capsules.
- such compounds When provided orally or topically, such compounds would be provided to a subject by delivery in different carriers.
- such carriers contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc, vegetable fats or oils, gums, or glycols.
- the specific carrier would need to be selected based upon the desired method of delivery, for example, phosphate buffered saline (PBS) could be used for intravenous or systemic delivery and vegetable fats, creams, salves, ointments or gels may be used for topical delivery.
- PBS phosphate buffered saline
- compositions are liquids or lyophilized or otherwise dried formulations and include diluents of various buffer content (for example, Tris-HCl, acetate, phosphate), pH and ionic strength, additives such as albumins or gelatin to prevent absorption to surfaces, detergents (for example, TWEEN 20, TWEEN 80, PLURONIC F68, bile acid salts), solubilizing agents (for example, glycerol, polyethylene glycerol), anti- oxidants (for example ascorbic acid, sodium metabisulfate), preservatives (for example, thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (for example, lactose, mannitol), co
- compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance of the compound or composition.
- the choice of compositions will depend on the physical and chemical properties of the compound capable of treating or preventing a Hepatitis C viral infection.
- the compound of the present invention may be delivered locally via a capsule that allows a sustained release of the compound over a period of time.
- Controlled or sustained release compositions include formulation in lipophilic depots (for example, fatty acids, waxes, oils).
- a chiral amine comprises a nitrogen atom in a three-membered ring connected to another atom bearing an unshared pair of electrons and may be, but is not limited to, ephedrine hemihydrate or cinchomine.
- R2 of formula (A) is a sec- butyl group.
- the chiral carbon of the sec-butyl group has an S to R configuration ratio of 1 : 1.
- the chiral carbon of the sec-butyl group has an S to R configuration ratio selected from the group consisting of at least 7:1, at least 8: 1, and at least 9: 1.
- the chiral carbon of the sec-butyl group has 100% S configuration.
- Optically active isomers may be prepared, for example, by resolving racemic derivatives or by asymmetric synthesis. The resolution can be carried out by methods known to those skilled in the art such as in the presence of a resolving agent, by chromatography, or combinations thereof.
- NS5B from the BK strain (lb subtype) is expressed in E. coli as a protein in which the 21 C-terminal amino acids are replaced with a short linker and a hexahistidine tag (GSHHHHHH).
- the purified protein is mixed with radioactive nucleotides and allowed to replicate a heteropolymeric RNA substrate, primed by an endogenous short hairpin, resulting in an approximately 760 nt product.
- the radioactive product is captured on a filter and quantitated after removal of the unincorporated nucleotides.
- CTP 10 mM cytidine 5'-triphosphate
- GTP guanine 5'-triphosphate
- BSA boveine Serum Albumin
- Millipore Multiscreen liner for use in microbeta 1450-106 casette (Wallac) Perkin
- DTT Dithiothreitol (solid) (SIGMA # D9779)
- RNA Spin down a tube of RNA (5 ⁇ g/tube stored in 75% ethanol and 0.3 M sodium acetate) in a microcentrifuge for 20 minutes, at 4°C.
- RNA 5 ⁇ g/tube stored in 75% ethanol and 0.3 M sodium acetate
- One tube is enough for 1 - 1.5 plates. Remove as much ethanol from the tube as possible by inverting the tube. Be gentle, pellet RNA may not adhere to the tube. Vacuum dry the RNA. Resuspend the RNA by adding 1 ml of DEPC water, close the cap of the tube tightly. To dissolve RNA, incubate RNA solution on ice for -60 minutes and gently vortex. Spin briefly to ensure all RNA solution is down to the bottom of the tube before opening cap. Gently transfer RNA solution into a 5 ml or larger tube. Add another 3 ml of DEPC water (total 4 ml of volume).
- Prewet filters of Millipore multiscreen assay plate by adding 200 ⁇ l of 0.5 M sodium phosphate buffer, pH 7.0 into each well. Let stand at room temperature for 2 -3 minutes. (7) Place the multiscreen filter plate onto a Millipore Manifold and turn on vacuum to allow buffer to flow through. Turn off vacuum. Transfer 80 ⁇ l of the reaction product into each well of the filter plate. Let stand for 2 - 3 minutes. Turn on vacuum to filter reaction product.
- step (8) three more times.
- Percent inhibition is calculated after background subtraction as a percent reduction of activity relative to the positive control (average value of the plate excluding the negative controls). For the primary screen hits were chosen as showing >75 % inhibition.
- Clone A cells (licensed from Apath, LLC) are derived from Huh-7 cells (human hepatoma cell line) and constitutively express of the HCV replication proteins with concomitant amplification the HCV replicon (lb) genome. Cells are maintained and passaged in DMEM/10% FCS/1 mg/ml G418 (Geneticin from
- DMEM Dulbecco's Modified Eagle Media
- FCS Fetal Calf Serum
- IX pen/strep Gabco #15140-122
- NEAA non-essential amino acids
- Gibco #11 140-050 no G418 Glutaraldehyde (Fisher #02957-4) TWEEN-20, 10% (Roche #1332465) TRITON X-100 (Sigma #T-8787) Superblock in PBS (Pierce #37515) NS5a monoclonal antibody (Virostat #1873) Goat antimouse-HRP monoclonal antibody (BioRad #172-1011) 3,3',5,5' tetramethylbenzidine (TMB) substrate (Sigma #T-0440)
- [(R)-5-cyano-8-methyl-l-propyl- 1,3,4,9- tetrahydropyrano[3,4-b]indol-l-yl]acetic acid can be obtained by resolution with cinchonine according to the following procedure.
- ( ⁇ )-5-Cyano-8-methyl-l-propyl- l,3,4,9-tetrahydropyrano[3,4-b]indole-l-acetic acid (6.4 g, 20.5 mmol) and cinchonine (5.9 g, 20.0 mmol) were dissolved in a mixture of 2-butanone (125 mL) and water (5 mL) with heating.
- the two crops (total 4.7 g) were combined and treated with 50 mL of IN HC1 and 100 mL of ethyl acetate.
- the ethyl acetate layer was washed with IN HC1 (30 mL) and water (50 mL).
- the aqueous layers were combined and extracted with ethyl acetate (50 mL).
- This ethyl acetate layer was washed with water (50 mL).
- the combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 2.25 g.
- Iron powder (9.3g, 0.166mM) and ammonium chloride (1.7g, 0.032mM) were stirred in water (42ml) at 100°C for 30 minutes.
- Commercially available 2- nitro 4-bromo fluorobenzene (9.2g, 0.42mM) was added drop wise to the above solution over a period of 45 minutes. The reaction was stirred at 100°C for an additional five hours. Water was removed in vacuo. The resultant crude solution was stirred in ethyl acetate (lOOmL) for 20 minutes and the organic solution was decanted off. This wash was repeated two more times.
- Tin (II) chloride dihydrate (4.5g, 0.02mM) in concentrated HCl(aq) (3.5ml) was added drop wise to the above solution over a period of 30 minutes. After the addition, the solution was allowed to stir at 0°C for one hour.
- the reaction solution was basified (pH>7) by slowly adding a solution of 50%) aqueous NaOH to the reaction mixture.
- BF 3 -etherate (0.74ml, 0.0059mM) was added to a solution of 4-bromo-7- fluorotryptophol (1.0g, 0.0039mM) and ethyl butyrylacetate (0.93ml, 0.0059mM) in dry dichloromethane (15ml). This reaction was stirred for three hours at room temperature. Saturated NaHCO 3 (aq) (15ml) was added to quench the reaction. The solution was washed with DCM (2X). The organic layers were combined, dried (MgSO 4 ), passed through a plug of SiO 2 , and concentrated to afford 1.02g (66% yield) of the desired product as an off-white solid.
- Example 3 The procedure described for Example 3 was followed starting from 1-(R)- 5-cyano-8-fluoro-l-propyl-l,3,4,9-tetrahydropyrano[3,4-b]indole-l-acetic acid.
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Abstract
Description
Claims
Priority Applications (6)
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AU2003229336A AU2003229336A1 (en) | 2002-05-21 | 2003-05-21 | R-enantiomers of pyranoindole derivatives against hepatitis c |
EP03726928A EP1506201A1 (en) | 2002-05-21 | 2003-05-21 | R-enantiomers of pyranoindole derivatives for treatment of hepatitis c |
CA002486056A CA2486056A1 (en) | 2002-05-21 | 2003-05-21 | R-enantiomers of pyranoindole derivatives against hepatitis c |
MXPA04011063A MXPA04011063A (en) | 2002-05-21 | 2003-05-21 | R-enantiomers of pyranoindole derivatives against hepatitis c. |
BR0311222-5A BR0311222A (en) | 2002-05-21 | 2003-05-21 | R-enantiomers of pyranoindole derivatives against hepatitis c, their method of obtaining and pharmaceutical composition comprising them |
JP2004507481A JP2005533031A (en) | 2002-05-21 | 2003-05-21 | R-enantiomers of pyranoindole derivatives for hepatitis C |
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US38214802P | 2002-05-21 | 2002-05-21 | |
US60/382,148 | 2002-05-21 |
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WO2003099824A1 true WO2003099824A1 (en) | 2003-12-04 |
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PCT/US2003/015823 WO2003099824A1 (en) | 2002-05-21 | 2003-05-21 | R-enantiomers of pyranoindole derivatives against hepatitis c |
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US (1) | US6964979B2 (en) |
EP (1) | EP1506201A1 (en) |
JP (1) | JP2005533031A (en) |
CN (1) | CN1653069A (en) |
AR (1) | AR040088A1 (en) |
AU (1) | AU2003229336A1 (en) |
BR (1) | BR0311222A (en) |
CA (1) | CA2486056A1 (en) |
MX (1) | MXPA04011063A (en) |
TW (1) | TW200400963A (en) |
WO (1) | WO2003099824A1 (en) |
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US8232390B2 (en) | 2006-05-08 | 2012-07-31 | Istituto Di Richerche Di Biologia Molecolare P. Angeletti Spa | Pentacyclic indole derivatives as antiviral agents |
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ITMI20031471A1 (en) * | 2003-07-18 | 2005-01-19 | Chemi Spa | PROCESS FOR THE RACEMIZATION OF ETHODOLIC ACID |
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KR20230172524A (en) * | 2021-04-22 | 2023-12-22 | 엑스에프 테크놀로지스 인크. | Methods for synthesizing advantageous N-heterocyclic carbene catalysts |
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Also Published As
Publication number | Publication date |
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AR040088A1 (en) | 2005-03-16 |
AU2003229336A2 (en) | 2003-12-12 |
US6964979B2 (en) | 2005-11-15 |
US20040029947A1 (en) | 2004-02-12 |
CN1653069A (en) | 2005-08-10 |
BR0311222A (en) | 2005-03-01 |
EP1506201A1 (en) | 2005-02-16 |
JP2005533031A (en) | 2005-11-04 |
MXPA04011063A (en) | 2005-02-14 |
CA2486056A1 (en) | 2003-12-04 |
AU2003229336A1 (en) | 2003-12-12 |
TW200400963A (en) | 2004-01-16 |
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