NO331721B1 - Tiofenderivater som antivirale midler for flavivirusinfeksjon, farmasoytisk preparat, anvendelse av tiofenderivater for fremstilling av medikament og fremgangsmate for fremstilling av forbindelser. - Google Patents
Tiofenderivater som antivirale midler for flavivirusinfeksjon, farmasoytisk preparat, anvendelse av tiofenderivater for fremstilling av medikament og fremgangsmate for fremstilling av forbindelser. Download PDFInfo
- Publication number
- NO331721B1 NO331721B1 NO20035485A NO20035485A NO331721B1 NO 331721 B1 NO331721 B1 NO 331721B1 NO 20035485 A NO20035485 A NO 20035485A NO 20035485 A NO20035485 A NO 20035485A NO 331721 B1 NO331721 B1 NO 331721B1
- Authority
- NO
- Norway
- Prior art keywords
- carboxylic acid
- compound
- phenylthiophene
- amino
- thiophene
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 919
- 238000000034 method Methods 0.000 title claims description 29
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 22
- 238000002360 preparation method Methods 0.000 title claims description 20
- 239000003443 antiviral agent Substances 0.000 title claims description 13
- 239000003814 drug Substances 0.000 title claims description 6
- 206010054261 Flavivirus infection Diseases 0.000 title description 5
- 150000003577 thiophenes Chemical class 0.000 title 2
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 241000710781 Flaviviridae Species 0.000 claims abstract description 10
- 230000009385 viral infection Effects 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 74
- -1 benzoimidazolyl Chemical group 0.000 claims description 64
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 125000003118 aryl group Chemical group 0.000 claims description 46
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
- 125000000304 alkynyl group Chemical group 0.000 claims description 43
- 125000003342 alkenyl group Chemical group 0.000 claims description 42
- 230000003612 virological effect Effects 0.000 claims description 42
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 40
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 40
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 39
- 125000001544 thienyl group Chemical group 0.000 claims description 33
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 32
- 229910052799 carbon Inorganic materials 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- 108060004795 Methyltransferase Proteins 0.000 claims description 30
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 29
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 29
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 20
- 125000004076 pyridyl group Chemical group 0.000 claims description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 14
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 14
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 13
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 150000004678 hydrides Chemical class 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 11
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 11
- 125000001041 indolyl group Chemical group 0.000 claims description 11
- NUJXFKHOOMJUPO-UHFFFAOYSA-N methyl 3-[(2,4-dichlorobenzoyl)-propan-2-ylamino]-5-phenylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2C=CC=CC=2)=CC=1N(C(C)C)C(=O)C1=CC=C(Cl)C=C1Cl NUJXFKHOOMJUPO-UHFFFAOYSA-N 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 10
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 10
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 10
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 10
- 229960000329 ribavirin Drugs 0.000 claims description 10
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 9
- 125000004193 piperazinyl group Chemical group 0.000 claims description 9
- BUEBPSAMMWPXSE-UHFFFAOYSA-N 3-[(2,4-dichlorobenzoyl)-[4-(phenylmethoxycarbonylamino)cyclohexyl]amino]-5-phenylthiophene-2-carboxylic acid Chemical compound OC(=O)C=1SC(C=2C=CC=CC=2)=CC=1N(C(=O)C=1C(=CC(Cl)=CC=1)Cl)C(CC1)CCC1NC(=O)OCC1=CC=CC=C1 BUEBPSAMMWPXSE-UHFFFAOYSA-N 0.000 claims description 8
- CJBPLFJQSDNYFN-UHFFFAOYSA-N 3-[[1-[tert-butyl(dimethyl)silyl]oxy-1-phenylpropan-2-yl]-(2,4-dichlorobenzoyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C=1C=C(Cl)C=C(Cl)C=1C(=O)N(C1=C(SC(=C1)C=1C=CC=CC=1)C(O)=O)C(C)C(O[Si](C)(C)C(C)(C)C)C1=CC=CC=C1 CJBPLFJQSDNYFN-UHFFFAOYSA-N 0.000 claims description 8
- FNBZXUWCFRORLO-UHFFFAOYSA-N 3-[acetyl-[(4-chlorophenyl)methyl]amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1=C(C=2C=CC=CC=2)SC(C(O)=O)=C1N(C(=O)C)CC1=CC=C(Cl)C=C1 FNBZXUWCFRORLO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 7
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 7
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 7
- 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 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 208000010710 hepatitis C virus infection Diseases 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- WRAGVVOJOWAXNX-UHFFFAOYSA-N 3-[(2,4-dichlorobenzoyl)-(1-phenylethyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C=1C=CC=CC=1C(C)N(C1=C(SC(=C1)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=C(Cl)C=C1Cl WRAGVVOJOWAXNX-UHFFFAOYSA-N 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 125000003725 azepanyl group Chemical group 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000000532 dioxanyl group Chemical group 0.000 claims description 6
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 150000003536 tetrazoles Chemical class 0.000 claims description 6
- IUADGPRSRYATIY-UHFFFAOYSA-N 2-[[3-[(4-methylphenyl)sulfonylamino]-5-phenylthiophene-2-carbonyl]amino]acetic acid Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=C(C(=O)NCC(O)=O)SC(C=2C=CC=CC=2)=C1 IUADGPRSRYATIY-UHFFFAOYSA-N 0.000 claims description 5
- NYYKDALOYDQKPA-UHFFFAOYSA-N 3-(n-(2,4-dichlorobenzoyl)anilino)-5-phenylthiophene-2-carboxylic acid Chemical compound OC(=O)C=1SC(C=2C=CC=CC=2)=CC=1N(C=1C=CC=CC=1)C(=O)C1=CC=C(Cl)C=C1Cl NYYKDALOYDQKPA-UHFFFAOYSA-N 0.000 claims description 5
- UKNZREOUDLFUFF-UHFFFAOYSA-N 3-[(2,4-dichlorobenzoyl)(isopropyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1=C(C=2C=CC=CC=2)SC(C(O)=O)=C1N(C(C)C)C(=O)C1=CC=C(Cl)C=C1Cl UKNZREOUDLFUFF-UHFFFAOYSA-N 0.000 claims description 5
- WHIBBUNFHUZCSG-UHFFFAOYSA-N 3-[(2,4-dichlorophenyl)methylamino]-5-phenylthiophene-2-carboxylic acid Chemical compound OC(=O)C=1SC(C=2C=CC=CC=2)=CC=1NCC1=CC=C(Cl)C=C1Cl WHIBBUNFHUZCSG-UHFFFAOYSA-N 0.000 claims description 5
- CORJOVCCNWIHJE-UHFFFAOYSA-N 3-[(2-chlorophenyl)sulfonylamino]-5-phenylthiophene-2-carboxylic acid Chemical compound OC(=O)C=1SC(C=2C=CC=CC=2)=CC=1NS(=O)(=O)C1=CC=CC=C1Cl CORJOVCCNWIHJE-UHFFFAOYSA-N 0.000 claims description 5
- TVZQQBXPOAOCMB-UHFFFAOYSA-N 3-[[3-(1-benzofuran-2-yl)phenyl]methyl-(4-chloro-2,5-dimethylphenyl)sulfonylamino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1=C(Cl)C(C)=CC(S(=O)(=O)N(CC=2C=C(C=CC=2)C=2OC3=CC=CC=C3C=2)C2=C(SC(=C2)C=2C=CC=CC=2)C(O)=O)=C1C TVZQQBXPOAOCMB-UHFFFAOYSA-N 0.000 claims description 5
- IBUFNMKTIXHEFK-UHFFFAOYSA-N 3-[benzoyl(methyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1=C(C=2C=CC=CC=2)SC(C(O)=O)=C1N(C)C(=O)C1=CC=CC=C1 IBUFNMKTIXHEFK-UHFFFAOYSA-N 0.000 claims description 5
- VVWRGFRAROIXHC-UHFFFAOYSA-N 3-[cyclopropyl-(2,4-dichlorobenzoyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound OC(=O)C=1SC(C=2C=CC=CC=2)=CC=1N(C(=O)C=1C(=CC(Cl)=CC=1)Cl)C1CC1 VVWRGFRAROIXHC-UHFFFAOYSA-N 0.000 claims description 5
- FUJIGVKGWFWWHD-UHFFFAOYSA-N 5-bromo-3-[(2-methylphenyl)sulfonylamino]thiophene-2-carboxylic acid Chemical compound CC1=CC=CC=C1S(=O)(=O)NC1=C(C(O)=O)SC(Br)=C1 FUJIGVKGWFWWHD-UHFFFAOYSA-N 0.000 claims description 5
- 102000014150 Interferons Human genes 0.000 claims description 5
- 108010050904 Interferons Proteins 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 5
- 150000002084 enol ethers Chemical class 0.000 claims description 5
- 150000002118 epoxides Chemical class 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- 229940079322 interferon Drugs 0.000 claims description 5
- 229910052705 radium Inorganic materials 0.000 claims description 5
- 229910052701 rubidium Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- RILFEFGQFNKXNY-UHFFFAOYSA-N 2-[(2-methoxycarbonyl-5-phenylthiophen-3-yl)carbamoyl]benzoic acid Chemical compound COC(=O)C=1SC(C=2C=CC=CC=2)=CC=1NC(=O)C1=CC=CC=C1C(O)=O RILFEFGQFNKXNY-UHFFFAOYSA-N 0.000 claims description 4
- YOWQWFMSQCOSBA-UHFFFAOYSA-N 2-methoxypropene Chemical compound COC(C)=C YOWQWFMSQCOSBA-UHFFFAOYSA-N 0.000 claims description 4
- UKSOBLJLVYYLLC-UHFFFAOYSA-N 3-(3,4-dihydro-1h-isoquinoline-2-carbonylamino)-5-phenylthiophene-2-carboxylic acid Chemical compound C=1C(NC(=O)N2CC3=CC=CC=C3CC2)=C(C(=O)O)SC=1C1=CC=CC=C1 UKSOBLJLVYYLLC-UHFFFAOYSA-N 0.000 claims description 4
- XWKLBOBCZKPNBY-UHFFFAOYSA-N 3-[(2,4-dichlorobenzoyl)-(piperidin-4-ylmethyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound OC(=O)C=1SC(C=2C=CC=CC=2)=CC=1N(C(=O)C=1C(=CC(Cl)=CC=1)Cl)CC1CCNCC1 XWKLBOBCZKPNBY-UHFFFAOYSA-N 0.000 claims description 4
- NPJHZBXDMNKGMI-UHFFFAOYSA-N 3-[(2,4-dichlorobenzoyl)-[(1-phenylmethoxycarbonylpiperidin-4-yl)methyl]amino]-5-phenylthiophene-2-carboxylic acid Chemical compound OC(=O)C=1SC(C=2C=CC=CC=2)=CC=1N(C(=O)C=1C(=CC(Cl)=CC=1)Cl)CC(CC1)CCN1C(=O)OCC1=CC=CC=C1 NPJHZBXDMNKGMI-UHFFFAOYSA-N 0.000 claims description 4
- OEHCDMZEMTUBPJ-UHFFFAOYSA-N 3-[(2,4-dichlorobenzoyl)-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N(C1=C(SC(=C1)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=C(Cl)C=C1Cl OEHCDMZEMTUBPJ-UHFFFAOYSA-N 0.000 claims description 4
- BWMKEDQQGCKQPB-UHFFFAOYSA-N 3-[(2,4-dichlorobenzoyl)-[[2-(diethylamino)-1,3-thiazol-5-yl]methyl]amino]-5-phenylthiophene-2-carboxylic acid Chemical compound S1C(N(CC)CC)=NC=C1CN(C1=C(SC(=C1)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=C(Cl)C=C1Cl BWMKEDQQGCKQPB-UHFFFAOYSA-N 0.000 claims description 4
- VOAPMXGVYCQGFH-UHFFFAOYSA-N 3-[(2,4-dichlorobenzoyl)-propan-2-ylamino]-5-[4-(2h-tetrazol-5-yl)phenyl]thiophene-2-carboxylic acid Chemical compound C1=C(C=2C=CC(=CC=2)C=2NN=NN=2)SC(C(O)=O)=C1N(C(C)C)C(=O)C1=CC=C(Cl)C=C1Cl VOAPMXGVYCQGFH-UHFFFAOYSA-N 0.000 claims description 4
- CLVGSVVEEHMLBX-UHFFFAOYSA-N 3-[(2,4-dichlorobenzoyl)-propan-2-ylamino]-5-methylthiophene-2-carboxylic acid Chemical compound C1=C(C)SC(C(O)=O)=C1N(C(C)C)C(=O)C1=CC=C(Cl)C=C1Cl CLVGSVVEEHMLBX-UHFFFAOYSA-N 0.000 claims description 4
- LBRXWPRTCUVBRS-UHFFFAOYSA-N 3-[(2,4-dichlorophenyl)-propan-2-ylcarbamoyl]-5-phenylthiophene-2-carboxylic acid Chemical compound C=1C=C(Cl)C=C(Cl)C=1N(C(C)C)C(=O)C(=C(S1)C(O)=O)C=C1C1=CC=CC=C1 LBRXWPRTCUVBRS-UHFFFAOYSA-N 0.000 claims description 4
- OJJYFESFDVYTKN-UHFFFAOYSA-N 3-[(2,4-difluorophenyl)methyl-(2-methoxyacetyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1=C(C=2C=CC=CC=2)SC(C(O)=O)=C1N(C(=O)COC)CC1=CC=C(F)C=C1F OJJYFESFDVYTKN-UHFFFAOYSA-N 0.000 claims description 4
- YNMJDBBFKFXKRC-UHFFFAOYSA-N 3-[(2,4-dimethylphenyl)sulfonylamino]-5-phenylthiophene-2-carboxamide Chemical compound CC1=CC(C)=CC=C1S(=O)(=O)NC1=C(C(N)=O)SC(C=2C=CC=CC=2)=C1 YNMJDBBFKFXKRC-UHFFFAOYSA-N 0.000 claims description 4
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- GZNQIZXDGFRFOT-UHFFFAOYSA-N 3-[(2-chloro-4-cyanophenyl)sulfonylamino]-5-[4-(2-methylpropyl)phenyl]thiophene-2-carboxylic acid Chemical compound C1=CC(CC(C)C)=CC=C1C1=CC(NS(=O)(=O)C=2C(=CC(=CC=2)C#N)Cl)=C(C(O)=O)S1 GZNQIZXDGFRFOT-UHFFFAOYSA-N 0.000 claims description 4
- XDZHFMJXCOKCNO-UHFFFAOYSA-N 3-[(2-hydroxy-4-methylcyclohexanecarbonyl)-propan-2-ylamino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1=C(C=2C=CC=CC=2)SC(C(O)=O)=C1N(C(C)C)C(=O)C1CCC(C)CC1O XDZHFMJXCOKCNO-UHFFFAOYSA-N 0.000 claims description 4
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- BACMTCNFHNDMIM-UHFFFAOYSA-N 3-[(2-methylphenyl)sulfonylamino]-5-phenylthiophene-2-carboxylic acid Chemical compound CC1=CC=CC=C1S(=O)(=O)NC1=C(C(O)=O)SC(C=2C=CC=CC=2)=C1 BACMTCNFHNDMIM-UHFFFAOYSA-N 0.000 claims description 4
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- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229930007744 linalool Natural products 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- FDZZZRQASAIRJF-UHFFFAOYSA-M malachite green Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C(C=1C=CC=CC=1)=C1C=CC(=[N+](C)C)C=C1 FDZZZRQASAIRJF-UHFFFAOYSA-M 0.000 description 1
- 229940107698 malachite green Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- LQNWDZKGOWZSBI-UHFFFAOYSA-N methyl 3-(cyclohexylamino)-5-phenylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2C=CC=CC=2)=CC=1NC1CCCCC1 LQNWDZKGOWZSBI-UHFFFAOYSA-N 0.000 description 1
- XJNXHBMFZYDDGE-UHFFFAOYSA-N methyl 3-(tert-butylamino)-5-phenylthiophene-2-carboxylate Chemical compound CC(C)(C)NC1=C(C(=O)OC)SC(C=2C=CC=CC=2)=C1 XJNXHBMFZYDDGE-UHFFFAOYSA-N 0.000 description 1
- DRCQKJQLDPYZER-UHFFFAOYSA-N methyl 3-[(2,4-dichlorobenzoyl)-[[5-[3-(trifluoromethyl)phenyl]furan-2-yl]methyl]amino]-5-phenylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2C=CC=CC=2)=CC=1N(C(=O)C=1C(=CC(Cl)=CC=1)Cl)CC(O1)=CC=C1C1=CC=CC(C(F)(F)F)=C1 DRCQKJQLDPYZER-UHFFFAOYSA-N 0.000 description 1
- CLJPSYDWHVZAFT-UHFFFAOYSA-N methyl 3-[(4-chloro-2,5-dimethylphenyl)sulfonylamino]-5-phenylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2C=CC=CC=2)=CC=1NS(=O)(=O)C1=CC(C)=C(Cl)C=C1C CLJPSYDWHVZAFT-UHFFFAOYSA-N 0.000 description 1
- WHJBGOQJMFAKHY-UHFFFAOYSA-N methyl 3-amino-5-tert-butylthiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C(C)(C)C)=CC=1N WHJBGOQJMFAKHY-UHFFFAOYSA-N 0.000 description 1
- HSLZXALEQUIDCT-UHFFFAOYSA-N methyl 3-bromo-5-phenylthiophene-2-carboxylate Chemical compound BrC1=C(C(=O)OC)SC(C=2C=CC=CC=2)=C1 HSLZXALEQUIDCT-UHFFFAOYSA-N 0.000 description 1
- PBQQQIICHCMJIX-UHFFFAOYSA-N methyl 5-bromo-3-(propan-2-ylamino)thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(Br)=CC=1NC(C)C PBQQQIICHCMJIX-UHFFFAOYSA-N 0.000 description 1
- FKSYKJKBAIOVLP-UHFFFAOYSA-N methyl 5-bromo-3-[(4-methylcyclohexanecarbonyl)-propan-2-ylamino]thiophene-2-carboxylate Chemical compound S1C(Br)=CC(N(C(C)C)C(=O)C2CCC(C)CC2)=C1C(=O)OC FKSYKJKBAIOVLP-UHFFFAOYSA-N 0.000 description 1
- JPJVRWZASWWDQA-UHFFFAOYSA-N methyl 5-tert-butyl-3-[(2,4-dimethylphenyl)sulfonylamino]thiophene-2-carboxylate Chemical compound S1C(C(C)(C)C)=CC(NS(=O)(=O)C=2C(=CC(C)=CC=2)C)=C1C(=O)OC JPJVRWZASWWDQA-UHFFFAOYSA-N 0.000 description 1
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- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- VJYJOJXVMHQJIY-UHFFFAOYSA-N morpholine;thiophene Chemical compound C=1C=CSC=1.C1COCCN1 VJYJOJXVMHQJIY-UHFFFAOYSA-N 0.000 description 1
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- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
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- 108020004707 nucleic acids Proteins 0.000 description 1
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- 239000012053 oil suspension Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical compound C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 description 1
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- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 1
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- 125000003367 polycyclic group Chemical group 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
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- 230000002335 preservative effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
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- 230000020978 protein processing Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- OIMWEHOYHJJPJD-UHFFFAOYSA-N pyridine;pyrimidine Chemical compound C1=CC=NC=C1.C1=CN=CN=C1 OIMWEHOYHJJPJD-UHFFFAOYSA-N 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
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- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- BWYDBADHYPANCF-UHFFFAOYSA-M sodium;3-amino-5-phenylthiophene-2-carboxylate Chemical compound [Na+].S1C(C([O-])=O)=C(N)C=C1C1=CC=CC=C1 BWYDBADHYPANCF-UHFFFAOYSA-M 0.000 description 1
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- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- QYRACRBFAHKUPC-UHFFFAOYSA-N tert-butyl 4-[(2,4-dichlorobenzoyl)-(2-methoxycarbonyl-5-phenylthiophen-3-yl)amino]piperidine-1-carboxylate Chemical compound COC(=O)C=1SC(C=2C=CC=CC=2)=CC=1N(C(=O)C=1C(=CC(Cl)=CC=1)Cl)C1CCN(C(=O)OC(C)(C)C)CC1 QYRACRBFAHKUPC-UHFFFAOYSA-N 0.000 description 1
- LYIDOJMFDXEPEL-UHFFFAOYSA-N tert-butyl 4-[(2-methoxycarbonyl-5-phenylthiophen-3-yl)amino]piperidine-1-carboxylate Chemical compound COC(=O)C=1SC(C=2C=CC=CC=2)=CC=1NC1CCN(C(=O)OC(C)(C)C)CC1 LYIDOJMFDXEPEL-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- 230000008719 thickening Effects 0.000 description 1
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical class C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
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- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical compound COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D333/40—Thiophene-2-carboxylic acid
-
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Abstract
Den foreliggende oppfinnelse tilveiebringer nye forbindelser som har formel I eller farmasøytisk akseptable salter derav, som kan anvendes til behandling av virusinfeksjon med Flaviviridae.
Description
Oppfinnelsens område
Den foreliggende oppfinnelse vedrører nye forbindelser og en fremgangsmåte for behandling eller profylakse av Flavivirus-infeksjoner under anvendelse av nye forbindelser.
Oppfinnelsens bakgrunn
Hepatitt er en sykdom som opptrer over hele verden. Den er generelt av virustype, selv om andre årsaker er kjent. Viral hepatitt er den klart mest vanlige form av hepatitt. Nesten 750 000 amerikanere angripes av hepatitt hvert år, og av disse er mer enn 150 000 smittet med hepatitt C-viruset ("HCV").
HCV er et positiv-trådet RNA-virus som tilhører Flaviviridae- familien, og som har nærmest slektskap med pestivirusene som omfatter svinekoleravirus og bovint, viralt diarévirus (BVDV). HCV antas å replikere gjennom produksjonen av et komplementært negativ-tråd-RNA-templat. På grunn av mangelen på effektivt kultur-replikasjonssystem for viruset ble HCV-partikler isolert fra blandet humanplasma og påvist ved hjelp av elektronmikroskop å ha en diameter på ca. 50-60 nm. HCV-genomet er et enkelttrådet, positiv-sense-RNA med ca. 9 600 bp som koder for et polyprotein med 3 009-3 030 aminosyrer, som spaltes sam- og posttranslasjonelt ved hjelp av cellulære og to virale proteinaser til modne virus-proteiner (kjerne, El, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B). Det antas at de strukturelle proteinene El og E2, hovedglyko-proteinene, pakkes inn i en viruslipidkappe og danner stabile heterodimerer. Det antas også at det strukturelle kjerneprotein reagerer med virus-RNA-genomet slik at nukleokapsidet dannes. De ikke-strukturelle proteinene betegnet NS2 til NS5, omfatter proteiner med enzymatiske funksjoner som er involvert i virus-replikasjon og proteinprosessering, inkludert en polymerase, protease og helikase.
Hovedkilden til forurensning med HCV er blod. Størrelsen på HCV-infeksjonen som et helseproblem er illustrert ved utbred-elsen blant høyrisikogrupper. For eksempel er 60 til 90% av blødere og mer enn 80% av sprøytenarkomane i de vestlige landene kronisk smittet med HCV. For sprøytenarkomane varierer forekomsten fra ca. 28 til 70%, avhengig av populasjonen som skal studeres. Andelen av nye HCV-infeksjoner forbundet med posttransfusjon, er blitt merkbart redusert i den senere tid på grunn av fremskrittene innen diagnostiske redskaper som brukes til å skreene blodgivere.
Fra Chem. Pharm. Bull. Vol. 37, No. 8, 1989 er det kjent visse tienopyrimidinforbindelser og deres gastriske antisekre-toriske aktivitet. Videre beskriver J. Heterocycl. Chem., Vol. 33, No. 2, 1996 ulike forbindelser.
Den eneste behandling som for tiden er tilgjengelig for HCV-infeksjon, er interferon-a (IFN-a). Ifølge forskjellige kliniske studier normaliseres imidlertid alaninaminotransferase-nivåer (ALT-nivåer) i serumet hos bare 70% av behandlede pasienter, og etter opphør av IFN får 35 til 45% av disse tilbakefall. Generelt har bare 20 til 25% av pasientene langvarige responser på IFN. Kliniske studier har vist at kombinasjonsbehandling med IFN og ribavirin (RIBA) resulterer i en bedre klinisk respons enn IFN alene. Forskjellige genotyper av HCV gir forskjellig respons på IFN-terapi, genotype lb er mer resistent overfor IFN-terapi enn type 2 og 3.
Det er derfor et stort behov for utviklingen av antivirale midler.
studeres. Andelen av nye HCV-infeksjoner forbundet med posttransfusjon, er blitt merkbart redusert i den senere tid på grunn av fremskrittene innen diagnostiske redskaper som brukes til å skreene blodgivere.
Den eneste behandling som for tiden er tilgjengelig for HCV-infeksjon, er interferon-a (IFN-a). Ifølge forskjellige kliniske studier normaliseres imidlertid alaninaminotransferase-nivåer (ALT-nivåer) i serumet hos bare 70% av behandlede pasienter, og etter opphør av IFN får 35 til 45% av disse tilbakefall. Generelt har bare 20 til 25% av pasientene langvarige responser på IFN. Kliniske studier har vist at kombinasjonsbehandling med IFN og ribavirin (RIBA) resulterer i en bedre klinisk respons enn IFN alene. Forskjellige genotyper av HCV gir forskjellig respons på IFN-terapi, genotype lb er mer resistent overfor IFN-terapi enn type 2 og 3.
Det er derfor et stort behov for utviklingen av antivirale midler.
Oppsummering av oppfinnelsen
Ved ett aspekt tilveiebringer den foreliggende oppfinnelse nye forbindelser som har formel Ia:
eller et farmasøytisk akseptabelt salt derav,
hvor
X er:
R4er Ci-6-alkyl;
R8er H, Ci_i2-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3_i2-heteroaralkyl eller C6-i6_aralkyl; og Ris er H eller Ci_6-alkyl;
J er:
W er 0, S eller NR7;
R7er H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3-i2-heteroaralkyl eller C6-i6-aralkyl;
R6er H, Ci-12-alkyl, C6-i4_aryl eller C6-i6_aralkyl;
Y<1>er en binding, C2-6-alkenyl eller C2-6-alkynyl;
Y er COORie, COCOOR5, P(0)0Ra0Rb, S(0)0R5, S(0)2OR5, tetrazol, CON (R9) CH (R5) COOR5, CON (R9)-S02-R5 eller CONRgOH;
R9og R5er hver uavhengig av hverandre H, Ci_i2-alkyl, C2-i2-alkenyl, C2-i2~alkynyl, C3-i2_heteroring, C3_i8-heteroaralkyl eller C6-18-aralkyl;
Ra og Rber hver uavhengig av hverandre H, Ci_i2-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3_i8-heteroaralkyl eller Ce-ig-aralkyl;
eller Ra og Rbdanner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
Ri6er H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3-i8-heteroaralkyl eller C6-i8-aralkyl;
forutsatt at R16er forskjellig fra metyl og etyl;
Ri er C2-i2-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-12-heteroring, C3_i8-heteroaralkyl og C6-i8_aralkyl;
R2er C2-i2-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-i2-heteroring, C3_i8-heteroaralkyl eller C6-i8-aralkyl;
R3er H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-i2-heteroring, C3_i8-heteroaralkyl eller C6_i8-aralkyl; og
Z er H, halogen eller Ci-6-alkyl;
Forbindelsene ifølge foreliggende oppfinnelse er anvendbare innen terapi, særlig som antivirusmidler.
Ved et annet aspekt er det tilveiebrakt et farmasøytisk preparat som omfatter forbindelsen ifølge oppfinnelsen i kombinasjon med en farmasøytisk akseptabel bærer eller eksipiens.
Ved et annet aspekt er det tilveiebrakt et farmasøytisk preparat som videre omfatter etter eller flere ytterligere antivirale midler valgt fra interferon a og ribavirin.
Et annet aspekt ved oppfinnelsen er anvendelsen av en forbindelse i henhold til formel (Ia) til fremstilling av et medikament for behandling eller profylakse av virusinfeksjoner hos en vert og/eller for inhibering eller reduksjon av aktiviteten til viral polymerase hos en vert og/eller for inhibering eller reduksjon av aktiviteten til viral helikase hos en vert.
Nærmere beskrivelse av oppfinnelsen
Ved én utførelsesform omfatter forbindelser ifølge foreliggende oppfinnelse de hvor de følgende utførelsesformer er til stede, enten uavhengig av hverandre eller i kombinasjon.
Ved én utførelsesform tilveiebringer den foreliggende oppfinnelse forbindelser med formel (Ia):
eller et farmasøytisk akseptabelt salt derav;
hvor
X er:
hvor
R4er Ci-6-alkyl;
R8er H, Ci_i2-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-i2-heteroring, C3_i2-heteroaralkyl eller C6-i6-aralkyl; og Ri5er H eller Ci_6-alkyl;
W er 0, S eller NR7,
R7er H, Ci-i2-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3_i2-heteroaralkyl eller C6-i6-aralkyl;
R6er H, Ci-i2-alkyl, C6-i4_aryl eller C6-i6_aralkyl;
Y<1>er en binding, C2-6~alkenyl eller C2-6-alkynyl;
Y er COORie, C0C00R5, P(0)0Ra0Rb, S(0)0R5, S(0)2OR5, tetrazol, CON(R9)CH(R5)COOR5, CON (R9)-S02-R5 eller CONR9OH;
R9og R5er hver uavhengig av hverandre H, Ci-12-alkyl, C2-i2_alkenyl, C2-i2-alkynyl, C3-i2-heteroring, C3-i8-heteroaralkyl eller C6-i8-aralkyl;
Ra og Rber hver uavhengig av hverandre H, Ci-12-alkyl, C2-i2_alkenyl, C2-i2-alkynyl, C6-i4_aryl, C3_i2-heteroring, C3-i8-heteroaralkyl eller Ce-iB-aralkyl;
eller Ra og Rbdanner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
Ri6er H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-i2-heteroring, C3_i8-heteroaralkyl eller C6-i8-aralkyl;
forutsatt at Ri6er forskjellig fra metyl og etyl;
Ri er C2-i2-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-i2-heteroring, C3_i8-heteroaralkyl eller C6-i8_aralkyl;
R2er C2-i2-alkyl, C2-i2-alkenyl C2_i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3_i8-heteroaralkyl eller C6-i8-aralkyl;
R3er H, Ci_i2-alkyl, C2_i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3-i8-heteroaralkyl eller C6-i8-aralkyl;
Z er H, halogen eller Ci-6-alkyl;
hvor
i hvert tilfelle er alkyl rettkjedet, forgrenet eller syklisk, og er usubstituert eller substituert;
i hvert tilfelle er alkenyl usubstituert eller substituert;
i hvert tilfelle er alkynyl usubstituert eller substituert;
i hvert tilfelle er aryl fenyl eller naftyl, som er usubstituert eller substituert;
i hvert tilfelle er aralkyl en fenyl- eller naftylgruppe bundet til naboatomet ved hjelp av en Ci-6-alkyl-, C2-6-alkenyl-eller C2-6_alkynylgruppe, som er usubstituert eller substituert;
i hvert tilfelle er heteroring valgt blant epoksid, furanyl, benzofuranyl, isobenzofuranyl, oksatiolanyl, ditiolanyl, dioksolanyl, pyrrolyl, pyrrolidinyl, imidazol, pyridinyl, pyrimidinyl, indolyl, piperidinyl, morfolinyl, tiofenyl, tiomorfolinyl, tienyl, benzotiofenyl, piperazinyl, tiazolyl, isoksazolyl, tiadiazolyl, pyrazolyl, tetrazolyl, dioksanyl, azepanyl, kinolinyl, benzoimidazolyl, dihydropyridinyl, teterahydropyranyl, benzodioksolyl og triazaspirodekanyl, som er usubstituert eller substituert;
i hvert tilfelle er heteroaralkyl en heterosyklisk gruppe bundet til naboatomet ved hjelp av en Ci-6-alkyl-, C2-6_alkenyl-eller C2-6_alkynylgruppe, hvor den heterosykliske gruppen er valgt blant epoksid, furanyl, benzofuranyl, isobenzofuranyl, oksatiolanyl, ditiolanyl, dioksolanyl, pyrrolyl, pyrrolidinyl, imidazol, pyridinyl, pyrimidinyl, indolyl, piperidinyl, morfolinyl, tiofenyl, tiomorfolinyl, tienyl, benzotiofenyl, piperazinyl, tiazolyl, isoksazolyl, tiadiazolyl, pyrazolyl, tetrazolyl, dioksanyl, azepanyl, kinolinyl, benzoimidazolyl, dihydropyridinyl, tetrahydropyranyl, benzodioksolyl og triazaspirodekanyl, som i hvert tilfelle er usubstituert eller substituert;
med det forbehold at:
når X er benzamid, Ri er fenyl, Y<1>er en binding og Y er COOH, så er R3forskjellig fra hydrogen;
eller en forbindelse valgt blant:
Forbindelse 26 8-KLOR-3-(4-KLOR-2,5-DIMETYLBENZENSULFONYLAMINO)-4H-1,5-DITIASYKLOPENTA[A]NAFTALEN-2-KARB0KSYLSYRE;
Forbindelse 28 3-[3-(2,6-DIKLORPYRIDIN-4-YL)-UREIDO]-5-FENYLTI0FEN-2-KARB0KSYLSYRE;
Forbindelse 33 3-(4-KLORFENOKSYKARBONYLAMINO)-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 46 5-FENYL-3(5-[1,2,3]TIADIAZOL-4-YL-TIOFEN-2-SULFONYLAMINO)-TI0FEN-2-KARB0KSYLSYRE;
Forbindelse 51 3-(2-KARBOKSYBENZOYLAMINO)-5-FENYLTIOFEN-2-KARBOKSYLSYREMETYLESTER;
Forbindelse 79 3-(TOLUEN-2-SULFONYLAMINO)-5-TRIMETYL-SILANYLETYNYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 82 5-BENZOYL-3-(TOLUEN-2-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 90 5-(3-ACETYLAMINO-FENYL)-3-(TOLUEN-2-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 112 3-[(4-OKSO-l-FENYL-l,3,8-TRIAZA-SPIRO[4.5]DEKAN-8-KARBONYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 113 3-{[4-(2-OKSO-2,3-DIHYDRO-BENZOIMIDAZOL-l-YL)-PIPERIDIN-1-KARBONYL]-AMINO}-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 139 3-(2-ACETYLAMINO-4-METYL-TIAZOL-5-SULFONYLAMINO)-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 161 4,4'-BIS-(TOLUEN-2-SULFONYLAMINO)-[2,2']BITIOFENYL-5,5'-DIKARBOKSYLSYRE;
Forbindelse 163 5-(1-DIMETYLSULFAMOYL-1H-PYRAZOL-4-YL)-3-(TOLUEN-2-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 179 5-FENYL-3-[3-(3-FENYL-PROPYL)-UREIDO]-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 180 3-[(3,4-DIHYDRO-1H-ISOKINOLIN-2-KARBONYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 241 3-[ACETYL-(4-KLOR-BENZYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 287 3-[(2,4-DIKLOR-BENZOYL)-ISOPROPYL-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYREMETYLESTER;
Forbindelse 369 5(4-METANSULF0NYLAMIN0-FENYL)-3(TOLUEN-2-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 377 3-[(2-ACETOKSY-4-METYL-BENZOYL)-ISOPROPYL-AMINO] -5-FENYL-TIOFENE-2-KARBOKSYLSYRE;
Forbindelse 382 3-[(2,4-DIKLOR-BENZOYL)-ISOPROPYL-AMINO]-5-METYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 387 3-[ISOPROPYL-(5-METYL-3-OKSO-3H-ISOINDOL-1-YL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 426 3-[ACETYL-(2-METYL-BENZYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 430 3-[(2,4-DIKLOR-BENZOYL)-ISOPROPYL-AMINO]-5-[4-(1H-TETRAZOL-5-YL)-FENYL]-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 434 3-[ACETYL-(3-METYL-BENZYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 450 3-(ACETYL-BENZYL-AMINO)-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 452 3-[BENZYL-(2-METOKSY-ACETYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 455 3-[ACETYL-(4-KLOR-BENZYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 464 3-[ACETYL-(4-TRIFLUORMETYL-BENZYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 476 3-[ACETYL-(3-KLOR-BENZYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 478 3-[(3-KLOR-BENZYL)-(2-METOKSY-ACETYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE ;
Forbindelse 483 3-[ACETYL-(2,4-DIFLUOR-BENZYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 484 3-[(2,4-DIFLUOR-BENZYL)-(2-METOKSY-ACETYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 505 3-{[2-(HYDROKSYIMINO-METYL)-4-METYL-BENZOYL]-ISOPROPYL-AMINO}-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 512 3-[(4-BENZYLOKSYKARBONYLAMINO-SYKLOHEKSYL)-(2,4-DIKLOR-BENZOYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 515 3-[(4-BENZYLOKSYKARBONYLAMINO-SYKLOHEKSYL)-(2,4-DIKLOR-BENZOYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 545 3-[(2-TERT-BUTOKSYKARBONYLAMINO-l-METYL-ETYL)-(2,4-DIKLOR-BENZOYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 552 5-BROM-3-(TOLUEN-2-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 555 3-[[2-(TERT-BUTYL-DIMETYL-SILANYLOKSY)-1-METYL-2-FENYL-ETYL]-(2,4-DIKLOR-BENZOYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 556 3-[[2-(TERT-BUTYL-DIMETYL-SILANYLOKSY)-1-METYL-2-FENYL-ETYL]-(2,4-DIKLOR-BENZOYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 566 5-FENYL-3-(TOLUEN-4-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRETIAZOL-2-YLAMID;
Forbindelse 567 5-FENYL-3-(TOLUEN-4-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRESYKLOBUTYLAMID;
Forbindelse 568 3-(2,4-DIMETYL-BENZENSULFONYLAMINO)-5-FENYLTIOFEN-2-KARBOKSYLSYREAMID; og
Forbindelse 569 5-BROM-3-[(2,4-DIKLORBENZOYL)-ISOPROPYL-AMINO]-TIOFEN-2-KARBOKSYLSYRE.
Ved én utførelsesform er X:
Ved en ytterligere utførelsesform er X:
Ved én utførelsesform er Z valgt fra H, halogen og Ci_6-alkyl.
Ved ytterligere utførelsesformer er
Z H
Z halogen
Z fluorid
Z Ci-6-alkyl
Z valgt fra metyl, trifluormetyl, etyl, propyl, isopropyl, syklopropyl, butyl, isobutyl, syklobutyl, pentyl, neopentyl, syklopentyl, heksyl eller sykloheksyl.
Ved ytterligere utførelsesformer er:
Ri valgt fra C2-i2-alkyl, C2-i2-alkenyl, C2-i2_alkynyl, C6-i4-aryl, C3-12-heteroring, C3_i8-heteroaralkyl eller C6-i8_aralkyl.
Ri er valgt fra en C2_i2-alkyl-, C6-i4-aryl- og C3-i2_heteroring.
Ri er et C2-i2~alkyl.
Ri er et C6-i4~aryl.
Ri er en C3-i2-heteroring.
Ri er valgt fra t-butyl, isobutyl, allyl, etynyl, 2-fenyletenyl, isobutenyl, benzyl, fenyl, fenetyl, benzodioksolyl, tienyl, tiofenyl, pyridinyl, isoksazolyl, tiazolyl, pyrazolyl, tetrazolyl, benzofuranyl, indolyl, furanyl og benzotiofenyl som i hvert tilfelle er usubstituert eller substituert én eller flere ganger med halogen, nitro, nitroso, SO2R12, P03RcRd, CONR13R14, COOH, Ci_6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C6-i2-aralkyl, C6-i2_aryl, Ci-6-alkyloksy, C2-6_alkenyloksy, C2-6_alkynyloksy, C6-i2-aryloksy, C (0) Ci-e-alkyl, C (0) C2-6-alkenyl, C (0) C2-6-alkynyl, C (0) C6-i2-aryl, C (0) C6-i2-aralkyl, C3-i0-heteroring, hydroksyl, NR13R14, C(0)0Ri2, cyan, azido, amidino eller guanido;
og
R12, Rc, Rd, R13og Ri4er hver uavhengig av hverandre H, Ci-12-alkyl, C2-i2-alkenyl, C2_i2-alkynyl, C6-i4_aryl, C3_i2-heteroring, C3_i8-heteroaralkyl, C6-i8-aralkyl;
eller Rc og Rd danner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
eller R13og Ri4danner sammen med nitrogenatomet en heteroring med
3 til 10 medlemmer.
Ri er valgt fra tienyl, t-butyl, fenyl eller pyridinyl.
Ri er isoksazolyl substituert med minst ett metyl.
Ri er pyridinyl.
Ved én utf ørelsesf orm er Ri valgt fra en Ci-6-alkyl-, C6-12-aryl- og C3-i0-heteroring.
Ved én utførelsesform er Ri t-butyl, isobutyl, allyl, etynyl, 2-fenyletenyl, isobutenyl, benzyl, fenyl, fenetyl, benzodioksolyl, tienyl, tiofenyl, pyridinyl, isoksazolyl, tiazolyl, pyrazolyl, tetrazolyl, benzofuranyl, indolyl, furanyl eller benzotiofenyl, som i hvert tilfelle er usubstituert eller substituert én eller flere ganger med Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-10-heteroring, halogen, nitro, CONRi3Ri4, NR13R14, amidino, guanido, cyan, S02_Ci-6-alkyl, C(0)0Ri2, Ci-6-alkyloksy, C2-6~alkenyloksy, C2-6-alkynyloksy og C6-i2-aryloksy;
hvor Ri2f R13og R14er hver uavhengig av hverandre H, Ci-i2-alkyl, C2_i2-alkenyl, C2-i2-alkynyl, C6-i4~aryl, C3_i2-heteroring, C3-i8~heteroaralkyl og C6-i8-aralkyl;
eller R13og R14danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
Ved én utførelsesform er Ri valgt fra tienyl, t-butyl, fenyl, tiofenyl, pyridinyl og isoksazolyl, som i hvert tilfelle er usubstituert eller substituert én eller flere ganger med et halogenatom, Ci-6-alkyl, Ci-6-alkyloksy, C2_6-alkenyl, C2-6-alkynyl, nitro, cyan, SC>2-Ci-6-alkyl og NO-Ci-6-alkyl.
Ved ytterligere utførelsesformer er:
Ri fenyl,
Ri fenyl substituert med fluorid,
Ri fenyl substituert med minst ett fluorid,
Ri fenyl disubstituert med fluorid,
Ri fenyl substituert med klorid,
Ri fenyl substituert med minst ett klorid,
Ri fenyl disubstituert med klorid,
Ri fenyl substituert med fluorid og klorid,
Ri fenyl substituert med nitro,
Ri fenyl substituert med minst ett nitro,
Ri fenyl substituert med metoksy,
Ri fenyl substituert med OCF3,
Ri fenyl substituert med CF3,
Ri fenyl substituert med metyl,
Ri fenyl substituert med minst ett metyl,
Ri fenyl substituert med CN,
Ri fenyl substituert med SO2-CH3,
Ri fenyl substituert med NH(CO)-CH3.
Ved ytterligere utførelsesformer er:
Ri tiofenyl,
Ri tiofenyl substituert med minst ett halogenatom,
Ri tiofenyl substituert med minst ett klorid,
Ri tiofenyl substituert med minst ett metyl,
Ri tiofenyl substituert med minst ett metyl og ett klorid.
Ved ytterligere utførelsesformer er:
Ri tienyl,
Ri tienyl substituert med minst ett halogenatom,
Ri tienyl substituert med minst ett klorid,
Ri tienyl substituert med minst ett metyl,
Ri tienyl substituert med minst ett metyl og ett klorid, Ri isoksazol som er disubstituert med CH3,
Ri pyridin.
Ved én utførelsesform er M valgt fra:
Ved en ytterligere utførelsesform er M:
Ved en alternativ utførelsesform er M:
Ved én utførelsesform er J valgt fra:
hvor X er som definert ovenfor.
Ved en alternativ utførelsesform er J:
Ved en ytterligere utførelsesform er J:
Ved én utf ørelsesf orm er Y valgt fra COORi6, COCOOR5, P(0)ORaORb, S(0)OR5, tetrazol, CON (R9) CH (R5) COOR5 og CONR9OH.
Ved en ytterligere utførelsesform er hvilke som helst av R5, Ra, Rb, R9og R16uavhengig av hverandre valgt fra H og Ci_6_ alkyl, forutsatt at Ri6er forskjellig fra metyl og etyl.
Ved én utførelsesform er Y valgt fra COORi6og CON(R9)CH(R5)-COOR5.
Ved en ytterligere utførelsesform er hvilke som helst av R5, R9og Ri6uavhengig av hverandre valgt fra H og Ci-6-alkyl, forutsatt at Ri6er forskjellig fra metyl og etyl.
Ved en ytterligere utførelsesform er Y valgt fra COORi6 og CONR9CH2COOR5.
Ved en ytterligere utførelsesform er Y valgt fra COOR5, CONR5R5og CON(R5)CH(R5)COOR5.
Ved en ytterligere utførelsesform er Y COOH.
Ved en ytterligere utførelsesform er Y CONH2.
Ved en ytterligere utførelsesform er Y CONHCH2COOH.
Ved en ytterligere utførelsesform er Y COOCH3.
Ved en ytterligere utførelsesform er Y<1>valgt fra CH2, C=CH, CH-CH2og en binding.
Ved ytterligere utførelsesformer er:
R3valgt fra H, Ci-12-alkyl, C6-i8-aralkyl, C3_i2-heteroring og C3-18-heteroaralkyl,
R3valgt fra H, Ci-12-alkyl, C6-i8_aralkyl og C3_i2-heteroring.
R3Ci-iz-alkyl,
R3C6-i8-aralkyl,
R3C3-i2-heteroring,
R3valgt fra metyl, etyl, isopropyl, syklopropyl, sykloheksyl, allyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, aziridinyl, pyridinyl, piperidinylmetyl, dioksanyl, dioksolanyl, azepanyl og benzyl; som i hver tilfelle er usubstituert eller substituert én eller flere ganger med halogen, nitro, nitroso, S03Ri2, P03RcRd, CONR13R14, Ci-e-alkyl, C2-6-alkenyl, C2-6-alkynyl, C6-i2-aralkyl, C6-i2_aryl, Ci-6-alkyloksy, C2-6-alkenyloksy, C2-6-alkynyl-oksy, C6-i2-aryloksy, C (0) Ci-6-alkyl, C (0) C2-6-alkenyl, C(0)C2-6-alkynyl, C (0) C6-i2~aryl, C (0) C6-i2-aralkyl, C3_i0-heteroring, hydroksyl, NR13R14, C(0)0Ri2, cyan, azido, amidino og guanido;
hvor R12, Rc, Rd, R13og R14er hver uavhe ngig av hverandre H, Ci-i2— alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3-i8-heteroaralkyl eller C6-i8-aralkyl;
eller Rc og Rd danner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
eller Ri3og Ri4danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
R3er valgt fra H, metyl, isopropyl, piperidinyl, piperidinylmetyl, dioksolanyl og sykloheksyl.
Ved en ytterligere utførelsesform er R3H eller metyl. Ved en ytterligere utførelsesform er R3H.
Ved en ytterligere utførelsesform er R3metyl.
Ved en ytterligere utførelsesform er R3benzyl, tiofenyl-metyl eller furanylmetyl.
Ved tilleggsutførelsesformer er:
R2C2-i2~alkyl, C6-i4_aryl eller C3_i2-heteroring;
R2C3-6-heteroring;
R2valgt fra tienyl, furanyl, pyridinyl, oksazolyl, tiazolyl, pyrrolyl, benzofuranyl, indolyl, benzoksazolyl, benzotienyl, benzotiazolyl, piperazinyl, pyrrolidinyl og kinolinyl, som i hvert tilfelle er usubstituert eller substituert én eller flere ganger med halogen, nitro, nitroso, S03Ri2, P03RcRd, CONRi3Ri4, Ci-6-alkyl, C2-6-alkenyl, C2-6_alkynyl, C6-i2_aralkyl, C6-i2-aryl, Ci_6-alkyloksy, C2-6-alkenyloksy, C2-6~alkynyloksy, C6-i2-aryloksy, C (0) Ci-6-alkyl, C (0) C2-6-alkenyl, C (0) C2-6-alkynyl, C (0) C6-i2-aryl, C (0) C6-i2-aralkyl, C3_io-heteroring, hydroksyl, NRi3Ri4, C(0)0Ri2, cyan, azido, amidino og guanido;
hvor R12, Rc, Rd, Ri3og Ri4uavhengig av hverandre er valgt fra H, Ci-i2-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3-i8-heteroaralkyl og C6-i8_aralkyl;
eller Rc og Rd danner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
eller Ri3og Ri4danner sammen med nitrogenatomet en heteroring med
3 til 10 medlemmer.
R2er en heteroring valgt fra tienyl, furanyl, pyridinyl, pyrrolyl, indolyl, piperazinyl og benzotienyl.
R2er C2-i2-alkyl.
R2 er valgt fra syklopropyl, syklobutyl, syklopentyl, syklopentenyl, sykloheksyl, sykloheptyl, 2-(syklopentyl)etyl, metyl, etyl, vinyl, propyl, propenyl, isopropyl, butyl, butenyl, isobutyl, pentyl, neopentyl eller t-butyl, som i hvert tilfelle er usubstituert eller substituert én eller flere ganger med halogen, nitro, nitroso, S03Ri2, P03RcRd, CONRi3Ri4, Ci-6-alkyl, C2-6-alkenyl, C2-6"alkynyl, C6-i2-aralkyl, C6-i2_aryl, Ci-6-alkyloksy, C2-6_alkenyloksy, C2-6-alkynyloksy, C6-i2-aryloksy, C (0) Ci-6-alkyl, C (0) C2-6-alkenyl, C (0) C2-6-alkynyl, C (0) C6-i2-aryl, C (0) C6-i2-aralkyl, C3_i0-heteroring, hydroksyl, NRi3Ri4, C(0)0Ri2, cyan, azido, amidino og guanido;
hvor R12, Rc, Rd, R13og Ri4er hver uavhengig av hverandre H, C1-12-alkyl, C2-i2-alkenyl, C2_i2-alkynyl, C6-i«-aryl, C3_i2-heteroring, C3-i8-heteroaralkyl eller CVis-aralkyl;
eller Rc og Rd danner sammen med oksygenatomene en heteroring med eller Ri3og R14danner sammen med nitrogenatomet en heteroring med 3-10 medlemmer.
R2er C6-i2-aryl.
R2er et aryl valgt fra indenyl, naftyl og bifenyl.
R2er fenyl som er substituert med én eller flere substituenter valgt fra halogen, nitro, nitroso, SO3R12, POsRcRd, CONR13R14, C1-6-alkyl, C2-6-alkenyl, C2-6_alkynyl, C6-i2-aralkyl, C6-i2-aryl, Ci-6-alkyloksy, C2-6_alkenyloksy, C2-6-alkynyloksy, C6-i2_aryloksy, C(0)Ci-6-alkyl, C (0) C2-6-alkenyl, C (0) C2-6-alkynyl, C (0) C6-i2-aryl, C (0) C6-i2-aralkyl, C3-i0-heteroring, hydroksyl, NR13R14, C(0)0Ri2, cyan, azido, amidino og guanido;
hvor R12, Rc, Rd, R13og Ri4er hver uavhengig av hverandre H, C1-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-i2-heteroring, C3-i8-heteroaralkyl og C6-i8_aralkyl;
eller Rc og Rd danner sammen med oksygenatomene en heteroring med eller R13og R14danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
R2er fenyl substituert med én eller flere substituenter valgt fra halogen, nitro, nitroso, SO3R12, PC^RcRd, CONR13R14, Ci-6-alkyl, C2-6-alkenyl, C2-6_alkynyl, C6-i2_aralkyl, C6-i2_aryl, Ci-6-alkyloksy, C2.6-alkenyloksy, C2-6_alkynyloksy, C6-i2-aryloksy, C (0) Ci-6-alkyl, C (0) C2-6-alkenyl, C (0) C2-6-alkynyl, C (0) C6-i2-aryl, C (0) C6-i2-aralkyl, C3-io_heteroring, hydroksyl, NR13R14, C(0)0Ri2/cyan, azido, amidino og guanido;
hvor Ri2, Rc, Rd, R13og R14uavhengig av hverandre er valgt fra H, Ci-12-alkyl, C2-i2~alkenyl, C2-i2-alkynyl, C6-i4~aryl, C3_i2~heteroring, C3-i8_heteroaralkyl og C6-i8-aralkyl;
eller Rc og Rd danner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
eller Ri3og Ri4danner sammen med nitrogenatomet en heteroring med
3 til 10 medlemmer.
R2er fenyl som er substituert med én eller flere substituenter valgt fra halogen, nitro, CONR13R14, Ci-6-alkyl, C2-6_alkenyl, C1-6-alkyloksy, C (0) Ci-6-alkyl, C6-i2-aryl, C3-io-heteroring, hydroksyl, NR13Ri4, C(0)0Ri2, cyan og azido, hvor R12, R13og Ri4er hver uavhengig av hverandre H, Ci-12-alkyl, C2-i2_alkenyl, C2-i2_alkynyl, C6-i4_aryl, C3_i2-heteroring, C3-ia-heteroaralkyl og C6-i8-aralkyl; eller Ri3og R14danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
R2er fenyl som er substituert med én eller to substituenter valgt fra halogen, nitro, CONR13R14, Ci_6-alkyl, C2-6-alkenyl, Ci-6-alkyl-oksy, C (0) Ci-6-alkyl, C6-i2-aryl, C3-io~heteroring, hydroksyl, NR13R14, C(0)0Ri2, cyan og azido, hvor Ri2, R13og R14er hver uavhengig av hverandre H, Ci-12-alkyl, C2-i2-alkenyl, C2_i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3_i8-heteroaralkyl og C6-i8_aralkyl;
eller R13og R14danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
R2er fenyl som er substituert med én eller to substituenter valgt fra halogen, Ci-6-alkyl, NR13R14, nitro, CONR13R14, C (0) 0Ci-6-alkyl, COOH, Ci-6-alkyloksy-C (0) OR12, cyan og azido, hvor Ri2, R13og Ri4er hver uavhengig av hverandre H, Ci-12-alkyl, C2-i2_alkenyl, C2-12-alkynyl, C6-i4-aryl, C3-i2~heteroring, C3-is-heteroaralkyl og C6-i8-aralkyl;
eller Ri3og R14danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
Ved én utf ørelsesf orm er R2valgt fra C6-i4-aryl, C3-12-heteroring, C6-i2_aralkyl og C3_io-heteroaralkyl.
Ved en ytterligere utf ørelsesf orm er R2valgt fra en C6-i2-aryl-eller C3-io_heteroring.
Ved en ytterligere utførelsesform er R2en C6~aryl- eller en C3_6-heteroring.
Ved en ytterligere utførelsesform er R2valgt fra fenyl, pyridinyl, tiofenyl, benzofuran, tiazol, pyrazol, substituert med minst én substituent valgt fra et halogenatom, Ci-6-alkyl, C1-6-alkyloksy, CF3, COOH, C00Ci-6-alkyl, cyan, NH2, nitro, NH (Ci-6-alkyl) , N (Ci-6-alkyl) 2 og en C3-s-heteroring.
f*2 er valgt fra tienyl, furanyl, pyridyl, oksazolyl, tiazolyl, pyrrolyl, benzofuranyl, indolyl, benzoksazolyl, benzotienyl, benzotiazolyl og kinolinyl, som alle kan være substituert med minst én substituent valgt fra Ci-6-alkyl, amino, halogen, nitro, amido, CN, COOCi-e-alkyl og Ci_6-alkyloksy.
R2er metylfenyl.
R2er diklorfenyl.
Ved en ytterligere utførelsesform er R2valgt fra:
hvor:
Rw er H, 0 eller metyl;
Ry er H eller metyl;
Rw er H;
Rw er metyl;
Ry er H;
Ry er metyl;
og hvor Xa er S, N, 0 eller karbon.
Ved en ytterligere utførelsesform er hver av Ra, Rb, Rc, Rd, Re og Rf uavhengig av hverandre valgt fra H, Cl, Br, I, F, Ci_6_ alkyl, OCi-6-alkyl, CF3, COOH, COOCi-6-alkyl, CN, NH2, N02, NH(Ci-6-alkyl) og N (Ci_6-alkyl) 2.
Ved en ytterligere utførelsesform er hver av Ra, Rb, Rc, Rd, Re og Rf uavhengig av hverandre valgt fra H, Cl, Br, I, F, metyl, O-metyl, CF3, COOH, COOCH3, CN, NH2, N02, NH(CH3) og N(CH3)2.
Ved en ytterligere utførelsesform er hver av Ra, Rb, Rc, Rd, Re og Rf uavhengig av hverandre valgt fra H, Cl, Br, I, F, metyl, O-metyl, CF3, COOH, COOCH3, CN, NH2og N02.
Ved en ytterligere utførelsesform er hver av Ra, Rb, Rc, Rd, Re og Rf uavhengig av hverandre valgt fra H, Cl, metyl, 0-metyl, CF3, COOH, COOCH3, CN, NH2og N02.
Ved en ytterligere utførelsesform er hver av Ra, Rb, Rc, Rd, Re og Rf uavhengig av hverandre valgt fra H, Cl, F, metyl, CF3og O-metyl.
Ved en ytterligere utførelsesform er Rf H eller metyl. Ved en annen utførelsesform er Rf H.
Ved en annen utførelsesform er Rf metyl.
Ved en ytterligere utførelsesform er hver av Ra, Rb, Rc, Rd og Re uavhengig av hverandre valgt fra H og Cl.
Ved en ytterligere utførelsesform er hver av Ra, Rb, Rc, Rd og Re
H.
Ved én utførelsesform er:
Ra valgt fra Cl, F, metyl og O-metyl;
Rb H;
Rc valgt fra Cl, F, metyl og O-metyl;
Rd H;
Re valgt fra Cl, F, metyl og O-metyl.
Ved én utførelsesform er:
Ra metyl;
Rb H;
Rc Cl;
Rd H;
Re metyl.
Ved en ytterligere utførelsesform er hver av Rs, Rt og Ru uavhengig av hverandre valgt fra H, Cl, Br, I, F, Ci-6-alkyl, 0Ci_6~alkyl, CF3, COOH, COOCi-6-alkyl, CN, NH2, N02, NH (Ci-6-alkyl) og N(Ci-6-alkyl)2.
Ved en ytterligere utførelsesform er hver av Rs, Rt og Ru uavhengig av hverandre valgt fra H, Cl, Br, I, F, metyl, O-metyl, CF3, COOH, COOCH3, CN, NH2, N02, NH(CH3) og N(CH3)2.
Ved en ytterligere utførelsesform er hver av Rs, Rt og Ru uavhengig av hverandre valgt fra H, Cl, Br, I, F, metyl, O-metyl, CF3, COOH, COOCH3, CN, NH2og N02.
Ved en ytterligere utførelsesform er hver av Rs, Rt og Ru uavhengig av hverandre valgt fra H, Cl, Br, I, F, metyl, O-metyl, CF3, COOH, COOCH3, CN, NH2og N02.
Ved en ytterligere utførelsesform er hver av Rs, Rt og Ru uavhengig av hverandre valgt fra H, Cl, metyl, O-metyl, CF3, COOH, COOCH3, CN, NH2og N02.
Ved en ytterligere utførelsesform er hver av Rs, Rt og Ru uavhengig av hverandre valgt fra H, Cl, F, metyl, CF3og O-metyl.
Ved en ytterligere utførelsesform er hver av Rs, Rt og Ru uavhengig av hverandre valgt fra H og Cl.
Ved en ytterligere utførelsesform er hver av Rs, Rt og Ru
H.
Ved én utførelsesform er:
Rs og Ru Cl og Rt er H.
Rs Cl, Rt og Ru H.
Ved én utførelsesform er virusinfeksjonen valgt fra Fla vivirus- infeksjoner.
Ved én utførelsesform er Flavivirus-infeksjonen valgt fra hepatitt C-virus (HCV), bovint, viralt diaré-virus (BVDV), svinekoleravirus og gulfebervirus.
Ved en annen utførelsesform er Flavivirus-infeksjonen hepatitt C-virusinfeksjon.
Ved en ytterligere utførelsesform omfatter det farma-søytiske preparat videre ett eller flere tilleggsmidler valgt fra antivirusmiddel, immunmodulerende middel, antioksidantmiddel, antibakterielt middel og antisense-middel.
Ved én utførelsesform er antivirusmidlet valgt fra en viral serinproteaseinhibitor, viral polymeraseinhibitor og viral helikaseinhibitor.
Ved én utførelsesform er antivirusmidlet valgt fra interferon a og ribavirin.
Ved én utførelsesform er tilleggsmidlet valgt fra silybum marianum, interleukin-12, amantadin, ribozym, tymosin, N-acetylcystein og syklosporin.
Ved én utførelsesform tilveiebringer oppfinnelsen en fremgangsmåte for å inhibere eller redusere aktiviteten til viral helikase hos en vert, som omfatter å administrere en terapeutisk effektiv mengde av en forbindelse valgt fra: Forbind, nr. 14 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-(4-
klorfenyl)tiofen-2-karboksylsyre,
Forbind, nr. 19 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-(4-isobutylfenyl)tiofen-2-karboksylsyre,
Forbind, nr. 223 3-(4-brom-2-fluorbenzensulfonylamino)-5-(4-isobutylfenyl)tiofen-2-karboksylsyre,
Forbind, nr. 224 3-(4-brom-2-metylbenzensulfonylamino)-5-(4-isobutylfenyl)tiofen-2-karboksylsyre,
Forbind, nr. 225 5-(4-isobutylfenyl)-3-(3-metoksybenzensul-fonylamino)tiofen-2-karboksylsyre,
Forbind, nr. 581 5-(4-isobutylfenyl)-3-[5-(5-trifluormetyl-isoksazol-3-yl)tiofen-2-sulfonylamino]tiofen-2-karboksylsyre,
Forbind, nr. 227 3-[2,5-bis-(2,2,2-trifluoretoksy)benzensul-fonylamino]-5-(4-isobutylfenyl)tiofen-2-karboksylsyre,
Forbind, nr. 228 3-(2-klor-4-cyanbenzensulfonylamino)-5-(4-isobutylfenyl)tiofen-2-karboksylsyre,
Forbind, nr. 582 5-(4-isobutylfenyl)-3-(2,3,4-trifluorbenzen-sulfonylamino)tiofen-2-karboksylsyre,
eller farmasøytisk akseptable salter derav.
Ved ytterligere utførelsesformer er:
Den virale helikase Flaviviridae-helikase.
Den virale helikase HCV-helikase.
Ved ytterligere utførelsesformer tilveiebringer oppfinnelsen farmasøytisk preparat for inhibering eller redusering av aktiviteten til viral polymerase i en vert.
Ved ytterligere utførelsesformer er den virale polymerase Flaviviridae viral polymerase.
Den virale polymerase RNA-avhengig RNA-polymerase.
Den virale polymerase HCV-polymerase.
Ved én utførelsesform tilveiebringer oppfinnelsen farmasøytisk preparat for inhibering eller redusering av aktiviteten til viral helikase i en vert.
Ved én utførelsesform tilveiebringer oppfinnelsen anvendelse av en forbindelse valgt fra: Forbind, nr. 14 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-(4-
klorfenyl)tiofen-2-karboksylsyre,
Forbind, nr. 19 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-(4-isobutylfenyl)tiofen-2-karboksylsyre,
Forbind, nr. 223 3-(4-brom-2-fluorbenzensulfonylamino)-5-(4-isobutylfenyl)tiofen-2-karboksylsyre,
Forbind, nr. 224 3-(4-brom-2-metylbenzensulfonylamino)-5-(4-isobutylfenyl)tiofen-2-karboksylsyre,
Forbind, nr. 225 5-(4-isobutylfenyl)-3-(3-metoksybenzensul-fonylamino)tiofen-2-karboksylsyre,
Forbind, nr. 581 5-(4-isobutylfenyl)-3-[5-(5-trifluormetyl-isoksazol-3-yl)tiofen-2-sulfonylamino]tiofen-2-karboksylsyre,
Forbind, nr. 227 3-[2,5-bis-(2,2,2-trifluoretoksy)benzen-sulfonylamino]-5-(4-isobutylfenyl)tiofen-2-karboksylsyre,
Forbind, nr. 228 3-(2-klor-4-cyanbenzensulfonylamino)-5-(4-isobutylfenyl)tiofen-2-karboksylsyre, Forbind, nr. 582 5-(4-isobutylfenyl)-3-(2,3,4-trifluorbenzen-sulfonylamino)tiofen-2-karboksylsyre,
eller farmasøytisk akseptable salter derav, til inhibering eller reduksjon av aktiviteten til viral helikase hos en vert.
Ved ytterligere utførelsesformer er:
Den virale helikase Flaviviridae viral helikase.
Den virale helikase HCV-helikase.
Ved én utførelsesform tilveiebringer foreliggende oppfinnelse en kombinasjon som omfatter en forbindelse ifølge oppfinelsen og ett eller flere ytterligere midler valgt fra viral serinproteaseinhibitor, viral polymeraseinhibitor og viral helikaseinhibitor, immunmodulerende middel, antioksidantmiddel, antibakterielt middel eller antisense-middel.
Ved en ytterligere utførelsesform er tilleggsmidlet valgt fra silybum marianum, interleukin-12, amantadin, ribozym, tymosin, N-acetylcystein, syklosporin, interferon a og ribavirin.
Ved ytterligere utførelsesformer:
Ved enda en ytterligere utførelsesform tilveiebringer den foreliggende oppfinnelse en fremgangsmåte for fremstilling av en forbindelse med formel A:
hvor fremgangsmåten omfatter trinnene med å tilsette:
• en enoleter,
• et hydriddonerende middel, og
• en organisk karboksylsyre,
til en forbindelse med formel B:
hvor:
Y<1>er valgt fra en binding, Ci-6-alkyl, C2_6-alkenyl eller C2.6-alkynyl;
Y er valgt fra COORi6, COCOOR5, P(0)ORaORb, S(0)OR5, S(0)2OR5, tetrazol, CON (R9) CH (R5) COOR5, CONRi0Rn, CON (R9)-S02-R5, CONR9OHog halogen, hvor R9, R5, Ri0og Rn er uavhengig av hverandre valgt fra H, Ci_i2-alkyl, C2_i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3-i8-heteroaralkyl og C6-i8-aralkyl;
eller Rio og Rn danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer;
Ra og Rber uavhengig av hverandre valgt fra H, Ci-i2-alkyl, C2-i2-alkenyl, C2_i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3_i8-heteroaralkyl og C6-i8-aralkyl;
eller Ra og Rbdanner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
Ri6er valgt fra H, Ci_i2-alkyl, C2_i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-i2-heteroring, C3-i8-heteroaralkyl og C6-i8-aralkyl;
Ri er valgt fra Ci_i2-alkyl, C2_i2-alkenyl, C2_i2-alkynyl, C6-i4-aryl, C3-i2-heteroring, C3_i8-heteroaralkyl, C6-i8-aralkyl og halogen;
R2er valgt fra Ci_i2-alkyl, C2-i2-alkenyl, C2_i2-alkynyl, C3_i2-heteroring, C3-i8-heteroaralkyl og C6-i8-aralkyl;
R3er valgt fra H, Ci_i2-alkyl, C2_i2-alkenyl, C2_i2-alkynyl, C6_i4-aryl, C3.12-heteroring, C3_i8-heteroaralkyl og C6-i8_aralkyl;
Z er valgt fra H, halogen og Ci-6-alkyl.
Ved en ytterligere utførelsesform omfatter enoleteren a) et alkylert eller silylert enolat av et aldehyd, keton eller ester, eller b) 2-metoksypropen.
Ved en ytterligere utførelsesform er det hydriddonerende middel valgt fra gruppen bestående av borhydrid, natriumhydrid, aluminiumhydrid, natriumborhydrid (NaBH4) , natriumcyanborhydrid
(NaCNBH3) , natriumtriacetoksyborhydrid (NaBH(OAc)3) , boran-pyridin-kompleks (BH3-Py), harpiksbåret hydrid og polymerbåret hydrid.
Ved en ytterligere utførelsesform er den organiske karboksylsyren valgt fra gruppen bestående av alifatisk syre, aromatisk syre og dikarboksylsyre.
Ved en ytterligere utførelsesform er den alifatiske syre valgt fra gruppen bestående av eddiksyre, maursyre og trifluoreddiksyre.
Ved en ytterligere utførelsesform er karboksylsyren en aromatisk syre.
Ved en ytterligere utførelsesform omfatter den aromatiske syren benzosyre eller salisylsyre.
Ved en ytterligere utførelsesform er karboksylsyren dikarboksylsyre.
Ved en ytterligere utførelsesform omfatter dikarboksylsyren oksalsyre eller ftalsyre.
Det vil forstås av fagfolk innen teknikken at forbindelsene med formel (Ia) kan inneholde et kiralt senter på den generelle formel (I). Forbindelsene med formel (Ia) foreligger således i form av to forskjellige optiske isomerer (dvs. (+)- eller (-)-enantiomerer). Alle slike enantiomerer og blandinger derav, inkludert racemiske blandinger, er inkludert innenfor omfanget av oppfinnelsen. Den enkelte optiske isomer eller enantiomer kan fås ved hjelp av en metode som er godt kjent innenfor teknikken, slik som kiral HPLC, enzymatisk oppløsning og kiralt hjelpemiddel.
I overensstemmelse med den foreliggende oppfinnelse omfatter forbindelsene med formel (Ia): Forbind. 1 3-[(4-klor-2,5-dimetylbenzensulfonyl)-(3-jodbenzyl)-
amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 2 3-[(3-benzofuran-2-yl-benzyl)-(4-klor-2,5-dimetyl-benzensulf onyl ) amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 3 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-fenyl-tiof en-2 -karboksyl syre,
Forbind. 4 3-{ (2,4-diklorbenzyl)-[5-(3-trifluormetylfenyl)-furan-2-ylmetyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 5 3-[(4-klor-2,5-dimetylbenzensulfonyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 6 5-(4-fluorfenyl)-3-(toluen-4-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 7 3-(2,4-diklorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 8 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-(4-fluorfenyl)tiofen-2-karboksylsyre,
Forbind. 9 3-[(2,4-diklorbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 10 5-tert.-butyl-3-(4-klorbenzensulfonylamino)tiofen-2-karboksylsyre,
Forbind. 11 4-(toluen-4-sulfonylamino)-[2,3']bitiofenyl-5-karboksylsyre,
Forbind. 12 3-[(5-benzofuran-2-yl-tiofen-2-ylmetyl)-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 13 5-fenyl-3-(toluen-4-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 14 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-(4-klorfenyl)tiofen-2-karboksylsyre,
Forbind. 15 5-fenyl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 16 5-fenyl-3-(toluen-3-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 17 3-benzensulfonylamino-5-fenyltiofen-2-karboksylsyre, Forbind. 18 3-(4-klorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 19 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-(4-isobutylfenyl)tiofen-2-karboksylsyre,
Forbind. 20 5-tert.-butyl-3-(4-klor-2,5-dimetylbenzensulfonylamino) tiofen-2-karboksylsyre,
Forbind. 21 3-(2,5-dimetylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 22 3-(4-metoksy-2,3,6-trimetylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 23 5-fenyl-3-(tiofen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 24 4-(4-klor-2,5-dimetylbenzensulfonylamino)-[2,3']-bitiofenyl-5-karboksylsyre,
Forbind. 25 5-(3,5-bis-trifluormetylfenyl)-3-(4-klor-2,5-dimetylbenzensulfonylamino)tiofen-2-karboksylsyre, Forbind. 26 8-klor-3-(4-klor-2,5-dimetylbenzensulfonylamino)-4H-1,5-ditiasyklopenta[a]naftalen-2-karboksylsyre, Forbind. 27 3-(2,4-difluorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 28 3-[3-(2,6-diklorpyridin-4-yl)ureido]-5-fenyltiofen-2-karboksylsyre,
Forbind. 29 3-(2-klorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 30 3-(2-fluorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 31 5-fenyl-3-(2-trifluormetoksybenzensulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 32 3-(4-tert.-butylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 33 3-(4-klorfenoksykarbonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 34 3-(3,4-diklorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 35 5-fenyl-3-(2-trifluormetylbenzensulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 36 3-(5-brom-6-klorpyridin-3-sulfonylamino)-5-fenyl-tiof en-2 -karboksyl syre,
Forbind. 37 3- (5-klortiofen-2-sulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 38 3-(5-klor-3-metylbenzo[b]tiofen-2-sulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 39 3-(4-brombenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 40 3-(3-klorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 41 3-(5-klor-l,3-dimetyl-lH-pyrazol-4-sulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 42 3-(3-brombenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 43 3-(4-isopropylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 44 3-(2,6-diklorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 45 3-(2-nitrobenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 46 5-fenyl-3-(5-[1,2,3]tiadiazol-4-yl-tiofen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 47 5-fenyl-3-(pyridin-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 48 3-(2,4-diklorbenzylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 49 3-(3-fluorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 50 5-fenyl-3-(3-trifluormetylbenzensulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 51 3-(2-karboksybenzoylamino)-5-fenyltiofen-2-karboksylsyremetylester,
Forbind. 52 5-fenyl-3-(4-trifluormetylbenzensulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 53 3-(2,5-difluorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 54 3-(2-cyanbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 55 3-(2,5-diklortiofen-3-sulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 56 4-(toluen-2-sulfonylamino)-[2,2']bitiofenyl-5-karboksylsyre,
Forbind. 57 5'-klor-4-(toluen-2-sulfonylamino)-[2,2']bitiofenyl-5-karboksylsyre,
Forbind. 58 5-(2,4-diklorfenyl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 59 5-(4-nitrofenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 60 3-(toluen-2-sulfonylamino)-5-(4-trifluormetoksy-fenyl)tiofen-2-karboksylsyre,
Forbind. 61 5-kinolin-8-yl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 62 5-fenyl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 63 5- (3-nitrofenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 64 3-(toluen-2-sulfonylamino)-5-m-tolyltiofen-2-karboksylsyre,
Forbind. 65 5-(3-klorfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 66 5-(4-fluorfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 67 5-(3-fluorfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 68 5-(4-klorfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 69 5-(3,5-difluorfenyl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 70 5-(3,4-difluorfenyl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 71 3-(toluen-2-sulfonylamino)-5-vinyltiofen-2-karboksylsyre,
Forbind. 72 3-(4-klorbenzoylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 73 3-[(4-klorbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 74 5-fenyl-3-[(tiofen-2-karbonyl)amino]tiofen-2-karboksylsyre,
Forbind. 75 3-[metyl(tiofen-2-karbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 76 3-(2-brombenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 77 3-(2,4-difluorbenzoylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 78 3-[(2,4-difluorbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 79 3-(toluen-2-sulfonylamino)-5-trimetylsilanyletynyl-tiofen-2-karboksylsyre,
Forbind. 80 5-etynyl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 81 3-(toluen-2-sulfonylamino)5-(3-trifluormetoksy-fenyl)tiofen-2-karboksylsyre,
Forbind. 82 5-benzoyl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 83 5-(4-cyanfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 84 5-(3-klor-4-fluorfenyl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 85 5-(3,4-diklorfenyl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 86 5-pyridin-4-yl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 87 5-pyridin-3-yl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 88 3-(toluen-2-sulfonylamino)-5-(4-trifluormetylfenyl)-tiofen-2-karboksylsyre,
Forbind. 89 5-(4-metansulfonylfenyl)-3-(toluen-2-sulfonylamino) tiofen-2-karboksylsyre,
Forbind. 90 5-(3-acetylaminofenyl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 91 5-(3-klor-4-fluorfenyl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 92 3-(4-metylbenzoylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 93 3-[metyl-(4-metylbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 94 3-(3,5-dimetylisoksazol-4-sulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 95 3-[(2-klorbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 96 3-(2-metylbenzoylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 97 3-[metyl-(2-metylbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 98 5-fenyl-3-(5-trifluormetylpyridin-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 99 5-fenyletynyl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 100 3-(2,5-dimetylbenzensulfonylamino)-5-(4-nitrofenyl)-tiofen-2-karboksylsyre,
Forbind. 101 5-(2-fluorfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 102 5-(2-cyanfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 103 5-(2-etoksykarbonylfenyl)-3-(toluen-2-sulfonylamino) tiofen-2-karboksylsyre,
Forbind. 104 5-(2-metoksyfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 105 3<1->metyl-4-(toluen-2-sulfonylamino)-[2,2<1>]bitio-fenyl-5-karboksylsyre,
Forbind. 106 3-(toluen-2-sulfonylamino)-5-(2-trifluormetylfenyl)tiofen-2-karboksylsyre,
Forbind. 107 3-(2,5-dimetylbenzensulfonylamino)-5-(4-fluorfenyl)-tiofen-2-karboksylsyre,
Forbind. 108 5-styryl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 109 3-(2,4-difluorbenzensulfonylamino)-5-(4-nitro-fenyl) tiofen-2-karboksylsyre,
Forbind. 110 3-(2,4-difluorbenzensulfonylamino)-5-(4-fluor-fenyl)tiofen-2-karboksylsyre,
Forbind. 111 3-[[5-(3-klor-4-fluorfenyl)tiofen-2-ylmetyl]-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 112 3-[(4-okso-l-fenyl-1,3,8-triazaspiro[4,5]dekan-8-karbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 113 3-{[4-(2-okso-2,3-dihydrobenzoimidazol-l-yl)piperidin-l-karbonyl]amino}-5-fenyltiofen-2-karboksylsyre, Forbind. 114 3-{[4-(4-nitrofenyl)piperazin-l-karbonyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 115 5-(2-karboksyfenyl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 116 5-(4-klorfenyl)-3-(pyridin-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 117 5-(3-cyanfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 118 3-(2,5-dimetylbenzensulfonylamino)-5-p-tolyltiofen-2-karboksylsyre,
Forbind. 119 3-(2,4-difluorbenzensulfonylamino)-5-p-tolyltiofen-2-karboksylsyre,
Forbind. 120 5-fenetyl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 121 5-(3-etoksykarbonylfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 122 5-(4-metoksyfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 123 5-(3-metoksyfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 124 5-(4'-brombifenyl-4-yl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 125 5-(4-hydroksymetylfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 126 5-furan-3-yl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 127 5-benzofuran-2-yl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 128 5-pyridin-2-yl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 129 5-(4-nitrofenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 130 3-[(benzofuran-2-karbonyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 131 3-[(2,4-dimetylbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 132 3-[[5-(2-cyanfenyl)tiofen-2-ylmetyl]-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 133 5-(4-fluorfenyl)-3-(pyridin-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 134 5-[2-(4-klorfenyl)vinyl]-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 135 3-benzensulfonylamino-5-(4-fluorfenyl)tiofen-2-karboksylsyre,
Forbind. 136 3-(2,4-dimetylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 137 5-fenyl-3-(2-vinylbenzensulfonylamino)tiofen-2-karboksylsyre,
Forbind. 138 3-(4-brom-2,5-difluorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 139 3-(2-acetylamino-4-metyltiazol-5-sulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 140 3-(4-acetylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 141 3-(4-fluor-2-trifluormetylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 142 3-(2-metoksy-4-metylbenzensulfonylamino)-5-fenyl-tiof en-2 -karboksyl sy re,
Forbind. 143 3-(3,4-difluorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 144 4-(2-karboksy-5-fenyltiofen-3-ylsulfamoyl)-5-(4-klorfenyl)-2-metylfuran-3-karboksylsyreetylester, Forbind. 145 3-(4-fluor-3-trifluormetylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 146 3-(2-aminobenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 147 3-(3-nitrobenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 148 3-(4-nitrobenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 149 3-[ (2,4-diklorbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 150 5-(3-cyanbenzyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 151 5-fenyl-3-(2,4,6-trifluorbenzensulfonylamino)tiofen-2-karboksylsyre,
Forbind. 152 3-(4-metoksy-2-nitrobenzensulfonylamino)-5-fenyl-tiof en-2-karboksyl syre,
Forbind. 153 5-fenyl-3-(2,3,4-triklorbenzensulfonylamino)tiofen-2-karboksylsyre,
Forbind. 154 5-(2-karboksy-5-fenyltiofen-3-ylsulfamoyl)-2-metylfuran-3-karboksylsyrernetylester,
Forbind. 155 4-(2-karboksy-5-fenyltiofen-3-ylsulfamoyl)-2-metyl-1,5-difenyl-lH-pyrrol-3-karboksylsyreetylester, Forbind. 156 5-fenyl-3-{[4-(3-trifluormetylfenyl)piperazin-1-karbonyl]amin}tiofen-2-karboksylsyre,
Forbind. 157 3-{[4-(4-fluorfenyl)piperazin-l-karbonyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 158 3-{[4-(2,6-dimetylfenyl)piperazin-l-karbonyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 159 3-{[4-(2-klorfenyl)piperazin-l-karbonyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 160 3-{[4-(3-klorfenyl)piperazin-l-karbonyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 161 4,4<1->bis(toluen-2-sulfonylamino)-[2,2']bitiofenyl-5,5'-dikarboksylsyre,
Forbind. 162 3-[allyl-(4-metylbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 163 5-(1-dimetylsulfamoyl-lH-pyrazol-4-yl)-3- (toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 164 5-(3-aminofenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 165 5-(4-aminofenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 166 5-(4-acetylfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 167 4-(2-karboksy-5-fenyltiofen-3-ylsulfamoyl)-2,5-dimetyl-lH-pyrrol-3-karboksylsyreetylester,
Forbind. 168 4-(2-karboksy-5-fenyltiofen-3-ylsulfamoyl)-5-(4-klorfenyl)-3-metyl-l-fenyl-lH-pyrrol-2-karboksyl-syreetylester,
Forbind. 169 3-(3,5-diklor-4-hydroksybenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 170 5-(lH-pyrazol-4-yl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 171 5-(3-hydroksyfenyl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 172 3-[metyl-(3-metylbutyryl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 173 3-{[2-(4-fluorfenyl)acetyl]metylamino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 174 3-(4-pentylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 175 3-(metylfenylacetylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 176 3-[2,5-bis-(2,2,2-trifluoretoksy)benzensulfonyl-amino] -5-fenyltiofen-2-karboksylsyre,
Forbind. 177 3-(4-metyl-2-nitrobenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 178 5-tiazol-2-yl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 179 5-fenyl-3-[3-(3-fenylpropyl)ureido]tiofen-2-karboksylsyre,
Forbind. 180 3-[(3,4-dihydro-lH-isokinolin-2-karbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 181 3-{[4-(4-metoksyfenyl)piperazin-l-karbonyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 182 3-{[4-(6-metylpyridin-2-yl)piperazin-l-karbonyl]-amino}-5-fenyltiofen-2-karboksylsyrehydroklorid, Forbind. 183 3-{[4-(4-klorbenzyl)piperazin-l-karbonyl]amino}-5-fenyltiofen-2-karboksylsyrehydroklorid,
Forbind. 184 5-(5-metylpyridin-2-yl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 185 3-[etyl-(4-metylbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 186 3-[(3-klortiofen-2-karbonyl)metylamino]-5-fenyl-tiof en-2- karboksyl syre,
Forbind. 187 3-[(2-brombenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 188 3-[(4-butylbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 189 3-(2-klormetylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 190 5-(4-hydroksyfenyl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 191 5-(5-klorpyridin-2-yl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 192 5-(4-klorfenyl)-3-[metyl-(4-metylbenzoyl)amino]-tiofen-2-karboksylsyre,
Forbind. 193 5-(4-cyanfenyl)-3-[metyl-(4-metylbenzoyl)amino]-tiofen-2-karboksylsyre,
Forbind. 194 3-[metyl-(4-metylbenzoyl)amino]-5-(4-nitrofenyl)-tiofen-2-karboksylsyre,
Forbind. 195 5-(4-hydroksymetylfenyl)-3-[metyl-(4-metylbenzoyl)-amino]tiofen-2-karboksylsyre,
Forbind. 196 3-[metyl-(4-metylbenzoyl)amino]-5-(3-nitrofenyl)-tiofen-2-karboksylsyre,
Forbind. 197 5-(4-fluorfenyl)-3-[metyl-(4-metylbenzoyl)amino]-tiofen-2-karboksylsyre,
Forbind. 198 5-(4-metoksyfenyl)-3-[metyl-(4-metylbenzoyl)-amino]tiofen-2-karboksylsyre,
Forbind. 199 3-[metyl-(4-metylbenzoyl)amino]-5-p-tolyltiofen-2-karboksylsyre,
Forbind. 200 5-(4-aminofenyl)-3-[metyl-(4-metylbenzoyl)amino]-tiofen-2-karboksylsyre,
Forbind. 201 3-[syklopentyl-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 202 5-benzo[1,3]dioksol-5-yl-3-(toluen-2-sulfonylamino) tiofen-2-karboksylsyre,
Forbind. 203 3-[(2-hydroksyetyl)-(4-metylbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 204 3-[(2,4-diklorbenzoyl)isobutylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 205 3-[(2-metoksy-4-metylbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 206 5-(3-cyanfenyl)-3-[metyl-(4-metylbenzoyl)amino]-tiofen-2-karboksylsyre,
Forbind. 207 5-(2-klorfenyl)-3-[metyl-(4-metylbenzoyl)amino]-tiofen-2-karboksylsyre,
Forbind. 208 3-[(2,4-diklorbenzoyl)fenylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 209 3-[4-(trifluormetylbenzoyl)metylamin]-5-fenyltiofen-2-karboksylsyre,
Forbind. 210 3-[(4-klorbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 211 3-[isopropyl-(4-metylbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 212 5-(3,5-difluorfenyl)-3-[metyl-(4-metylbenzoyl)-amino]tiofen-2-karboksylsyre,
Forbind. 213 5-(3-fluorfenyl)-3-[metyl-(4-metylbenzoyl)amino]-tiofen-2-karboksylsyre,
Forbind. 214 5-(2,4-difluorfenyl)-3-[metyl-(4-metylbenzoyl)-amino]tiofen-2-karboksylsyre,
Forbind. 215 5-(4-hydroksyfenyl)-3-[metyl-(4-metylbenzoyl)-amino]tiofen-2-karboksylsyre,
Forbind. 216 3-[metyl-(4-metylbenzoyl)amino]-5-(4-trifluor-metoksyfenyl)tiofen-2-karboksylsyre,
Forbind. 217 5-(2-hydroksyfenyl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 218 3-[(2-klorbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 219 3-[(3,5-diklorbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 220 3-(4-brom-2-metylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 221 3-(5-karboksy-4-klor-2-fluorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 222 5-fenyl-3-(2,3,4-trifluorbenzensulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 223 3-(4-brom-2-fluorbenzensulfonylamino)-5-(4-iso-butylf enyl) tiofen-2-karboksylsyre,
Forbind. 224 3-(4-brom-2-metylbenzensulfonylamino)-5-(4-iso-butylf enyl )tiofen-2-karboksylsyre,
Forbind. 225 5-(4-isobutylfenyl)-3-(3-metoksybenzensulfonyl-amino) tiofen-2-karboksylsyre,
Forbind. 226 3-[(4-fluorbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 227 3-[2,5-bis-(2,2,2-trifluoretoksy)benzensulfonyl-amino] -5- (4-isobutylfenyl)tiofen-2-karboksylsyre, Forbind. 228 3-(2-klor-4-cyanbenzensulfonylamino)-5-(4-iso-butylf enyl) tiofen-2-karboksylsyre,
Forbind. 229 5<1->acetyl-4-(toluen-2-sulfonylamino)-[2,2<1>]bitio-fenyl-5-karboksylsyre,
Forbind. 230 5-benzo[b]tiofen-2-yl-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 231 5-(4-butylfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 232 5-(4-etylfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 233 3-[benzyl-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 234 3-[(4-klor-2-metylbenzoyl)isopropylamino]-5-fenyl-tiof en-2-karboksylsyre,
Forbind. 235 3-[(2,4-dimetylbenzensulfonyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 236 5-(4-acetylfenyl)-3-(2,4-dimetylbenzensulfonylamino) tiofen-2-karboksylsyre,
Forbind. 237 5- (4-acetylfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 238 5-(4-acetylfenyl)-3-(4-klorbenzensulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 239 5-(4-karboksyfenyl)-3-(toluen-2-sulfonylamino)tiofen-2 -karboksyl syr e-t ert .-butylester,
Forbind. 240 3-[(2,4-dimetylbenzensulfonyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 241 3-[acetyl-(4-klorbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 242 3-etansulfonylamino-5-fenyltiofen-2-karboksylsyre, Forbind. 243 3-[isopropyl-(4-trifluormetylbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 244 3-[(2,4-diklorbenzoyl)-(3-metyl-but-2-enyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 245 3-[(2,6-diklorpyridin-3-karbonyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 246 3-[(6-klorpyridin-3-karbonyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 247 3-[(4-tert.-butylbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 248 5-(4-karboksyfenyl)-3-(toluen-2-sulfonylamino)tiofen-2 -karboksyl syre,
Forbind. 249 5-(4-etoksyfenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 250 3-[(2,6-diklorpyridin-3-karbonyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 251 3-[(benzo[b]tiofen-2-karbonyl)metylamino]-5-fenyl-tiof en-2 -karboksyl sy re,
Forbind. 252 3-[metyl(naftalen-2-karbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 253 3-[(3,4-diklorbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 254 3-[(3,5-diklorbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 255 3-[(4-brom-3-metylbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 256 3-[(3-klorbenzo[b]tiofen-2-karbonyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 257 3-[metyl-(4-metyl-3-nitrobenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 258 5-(4-karbamoylfenyl)-3-(2,4-dimetylbenzensulfonylamino) tiofen-2-karboksylsyre,
Forbind. 259 5-(4-karbamoylfenyl)-3-(toluen-2-sulfonylamino)tiofen-2 -karboksyl syre,
Forbind. 260 5-(lH-indol-5-yl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 261 3-[sek.-butyl-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 262 3-[(2,4-dimetylbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 263 5-(4-azidofenyl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 264 3-[(2,4-diklorbenzoyl)-(1-fenyletyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 265 5-(4-karbamoylfenyl)-3-(4-klorbenzensulfonyl-amino) tiofen-2-karboksylsyre,
Forbind. 266 5-(2-fluorfenyl)-3-[metyl-(4-metylbenzoyl)amino]-tiofen-2-karboksylsyre,
Forbind. 267 3-[metyl-(4-metylbenzoyl)amino]-5-o-tolyltiofen-2-karboksylsyre,
Forbind. 268 3-[metyl-(4-metylbenzoyl)amino]-5-m-tolyltiofen-2-karboksylsyre,
Forbind. 269 5-(3-klorfenyl)-3-[metyl-(4-metylbenzoyl)amino]-tiofen-2-karboksylsyre,
Forbind. 270 5-(3,4-difluorfenyl)-3-[metyl-(4-metylbenzoyl)-amino]tiofen-2-karboksylsyre,
Forbind. 271 5-(3-aminofenyl)-3-[metyl-(4-metylbenzoyl)amino]-tiofen-2-karboksylsyre,
Forbind. 272 5-(3-acetylfenyl)-3-[metyl-(4-metylbenzoyl)amino]-tiofen-2-karboksylsyre,
Forbind. 273 5-(3-hydroksyfenyl)-3-[metyl-(4-metylbenzoyl)-amino]tiofen-2-karboksylsyre,
Forbind. 274 3-[metyl-(4-metylbenzoyl)amino]-5-(3-trifluormetylfenyl)tiofen-2-karboksylsyre,
Forbind. 275 3-[metyl-(4-metylbenzoyl)amino]-5-(4-trifluormetylfenyl)tiofen-2-karboksylsyre,
Forbind. 276 3-[(3,4-dimetoksybenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 277 3-[metyl-(2,4,6-trifluorbenzoyl)amino]-5-fenyl-tiof en-2-karboksylsyre,
Forbind. 278 3-[(2,3-difluor-4-trifluormetylbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 279 3-[(3-fluor-4-trifluormetylbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 280 3-[(2,3-difluor-4-metylbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 281 3-[(2-fluor-4-trifluormetylbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 282 5-(4-karbamoylfenyl)-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 283 5-(4-fluorfenyl)-3-[isopropyl-(4-metylbenzoyl)-amino]tiofen-2-karboksylsyre,
Forbind. 284 3-[(2-brom-4-klorbenzoyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 285 3-(2,6-dimetylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 286 3-[metyl-(4-metylsykloheksankarbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 287 3-[(2,4-diklorbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyrernetylester,
Forbind. 288 5-(4-cyanfenyl)-3-(2,4-dimetylbenzensulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 289 3-(4-klorbenzensulfonylamino)-5-(4-cyanfenyl)tiofen-2-karboksylsyre,
Forbind. 290 5-(4-cyanfenyl)-3-(toluen-4-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 291 5'-acetyl-4-(2,4-dimetylbenzensulfonylamino)-[2,2<1>]-bitiofenyl-5-karboksylsyre,
Forbind. 292 5<1->acetyl-4-(2,6-dimetylbenzensulfonylamino)-[2,2']-bitiofenyl-5-karboksylsyre,
Forbind. 293 3-[metyl-(4-metyltiofen-2-karbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 294 5-(3-klorfenyl)-3-[(2,4-diklorbenzoyl)isopropyl-amino] tiofen-2-karboksylsyre,
Forbind. 295 5'-cyan-4-(toluen-2-sulfonylamino)-[2,2']bitiofenyl-5-karboksylsyre,
Forbind. 296 3-[metyl-(4-metylbenzoyl)amino]-5-pyridin-2-yl-tiofen-2-karboksylsyre,
Forbind. 297 3-[(2,4-diklortiobenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 298 5-fenyl-3-(2,4,6-trimetylbenzensulfonylamino)tiofen-2-karboksylsyre,
Forbind. 299 3-[(1-karboksyetyl)-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 300 3-[(4-metylbenzoyl)-(3-metyl-but-2-enyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 301 3-[(2-hydroksy-4-metylbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 302 3-[metyl-(4-metylbenzoyl)amino]-5-pyridin-3-yl-tiofen-2-karboksylsyre,
Forbind. 303 5<1->acetyl-4-[metyl-(4-metylbenzoyl)amino]-[2,2']-bitiofenyl-5-karboksylsyre,
Forbind. 304 3-[isopropyl-(4-metylbenzoyl)amino]-5-(3-trifluormetylfenyl)tiofen-2-karboksylsyre,
Forbind. 305 3-[isopropyl-(4-metylbenzoyl)amino]-5-m-tolyltiofen-2-karboksylsyre,
Forbind. 306 3-[(2-brom-4-klorbenzoyl)isopropylamino]-5-fenyl-tiof en-2 -karboksyl sy re,
Forbind. 307 3-[(4-klor-2-fluorbenzoyl)isopropylamino]-5-fenyl-tiof en- 2 -karboksyl sy re,
Forbind. 308 3-(2,4-dimetylbenzensulfonylamino)-4-metyl-5-fenyl-tiof en-2 -karboksyl sy re,
Forbind. 309 3-[(2-brom-4-metylbenzoyl)isopropylamino]-5-fenyl-tiof en-2 -karboksyl sy re,
Forbind. 310 3-[(4-klor-2-jodbenzoyl)isopropylamino]-5-fenyl-tiof en-2-karboksylsyre,
Forbind. 311 3-[(4-cyanbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 312 3-[allyl-(4-metylbenzoyl)amino]-5-[4-(2-karboksy-vinyl)fenyl]tiofen-2-karboksylsyre,
Forbind. 313 3-[(4-klor-2-hydroksybenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 314 3-[(2,4-diklorbenzoyl)isopropylamino]-4-metyl-5-fenyltiofen-2-karboksylsyre,
Forbind. 315 5-tert.-butyl-3-(2,4-dimetylbenzensulfonylamino)-tiofen-2-karboksylsyre,
Forbind. 316 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 317 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 318 5-[4-(2-karboksyetyl)fenyl]-3-[(4-metylbenzoyl)pro-pylamino]tiofen-2-karboksylsyre,
Forbind. 319 5-benzofuran-2-yl-3-(2,4-dimetylbenzensulfonylamino) tiofen-2-karboksylsyre,
Forbind. 320 3-(2,4-dimetylbenzensulfonylamino)-5-(4-hydroksy-metylfenyl)tiofen-2-karboksylsyre,
Forbind. 321 3-(2,4-dimetylbenzensulfonylamino)-5-(4-metansul-fonylfenyl)tiofen-2-karboksylsyre,
Forbind. 322 5-[4-(2-karboksyvinyl)fenyl]-3-(2,4-dimetylbenzen-sulf onylamino) tiofen-2-karboksylsyre,
Forbind. 323 3-[allyl-(4-metylbenzoyl)amino]-5-[3-(2-karboksy-vinyl) fenyl]tiofen-2-karboksylsyre,
Forbind. 324 3-[isopropyl-(2,4,6-trimetylbenzoyl)amino]-5-fenyl-tiof en-2 -karboksyl sy re,
Forbind. 325 5-[3-(2-karboksyetyl)fenyl]-3-[(4-metylbenzoyl)pro-pylamino]tiofen-2-karboksylsyre,
Forbind. 326 3-[(2-fluor-4-trifluormetylbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 327 3-[tert.-butyl-(2,4-diklorbenzoyl)amino]-5-fenyl-tiof en-2 -karboksyl syre,
Forbind. 328 3-[(2-amino-4-klorbenzoyl)isopropylamino]-5-fenyl-tiof en-2-karboksylsyre,
Forbind. 329 3-[(4-klor-2-nitrobenzoyl)isopropylamino]-5-fenyl-tiof en-2 -karboksylsyre,
Forbind. 330 3-[(4-metylbenzoyl)-(3-trifluormetylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 331 3-[(3-fluor-4-metylbenzoyl)isopropylamino]-5-fenyl-tiof en-2 -karboksyl syre,
Forbind. 332 5-(4-karboksyfenyl)-3-(2,4-dimetylbenzensulfonylamino) tiofen-2-karboksylsyre,
Forbind. 333 3-[syklopropyl-(2,4-diklorbenzoyl)amino]-5-fenyl-tiof en- 2 -karboksyl sy re,
Forbind. 334 3-[(3-tert.-butylbenzyl)-(4-metylbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 335 3-[(3-klorbenzyl)-(4-metylbenzoyl)amino]-5-fenyl-tiof en- 2 -karboksyl sy re,
Forbind. 336 3-[(2,4-difluorbenzyl)-(4-metylbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 337 3-[(4-klor-2,5-difluorbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 338 3-[(2,4-diklorbenzoyl)isopropylamino]-5-(2-metyl-allyl)tiofen-2-karboksylsyre,
Forbind. 339 3-{allyl-[2-(4-klorfenyl)acetyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 340 3-[benzyl-(4-metylbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 341 3-[(4-klorbenzyl)-(4-metylbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 342 3-[(4-metylbenzoyl)-(4-nitrobenzyl)amino]-5-fenyl-tiof en-2 -karboksyl syre,
Forbind. 343 3-[(4-metylbenzoyl)-(2-metylbenzyl)amino]-5-fenyl-tiof en-2 -karboksylsyre,
Forbind. 344 3-[(3-metoksybenzyl)-(4-metylbenzoyl)amino]-5-fenyl-tiof en- 2 -karboksyl sy re,
Forbind. 345 3-[(2-klorbenzyl)-(4-metylbenzoyl)amino]-5-fenyl-tiof en-2 -karboksylsyre,
Forbind. 346 3-[(2,4-diklorbenzoyl)isopropylamino]-5-isobutyl-tiofen-2-karboksylsyre,
Forbind. 347 3-[allyl-(2-naftalen-2-yl-acetyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 348 3-{allyl-[2-(2,4-diklorfenyl)acetyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 349 3-{allyl-[2-(2-klor-4-fluorfenyl)acetyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 350 3-{allyl-[2-(3,4-diklorfenyl)acetyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 351 3-{allyl-[2-(2,4-difluorfenyl)acetyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 352 3-{allyl-[2-(4-trifluormetylfenyl)acetyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 353 3-{allyl-[2-(2,6-diklorfenyl)acetyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 354 3-[allyl-(2-m-tolylacetyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 355 5-(4-acetylfenyl)-3-[(2,4-diklorbenzoyl)isopropyl-amino] tiofen-2-karboksylsyre,
Forbind. 356 3-[(2,4-diklorbenzoyl)isopropylamino]-5-(4-fluor-fenyl)tiofen-2-karboksylsyre,
Forbind. 357 3-[(2,4-diklorbenzoyl)isopropylamino]-5-m-tolyltiofen-2-karboksylsyre,
Forbind. 358 5'-acetyl-4-[(2,4-diklorbenzoyl)isopropylamino]-[2,2']bitiofeny1-5-karboksylsyre,
Forbind. 359 3-[(2,4-diklorbenzoyl)isopropylamino]-5-(3-trifluormetylfenyl)tiofen-2-karboksylsyre,
Forbind. 360 4-[(2,4-diklorbenzoyl)isopropylamino]-5'-metyl-[2,2']bitiofenyl-5-karboksylsyre,
Forbind. 361 3-(2,4-dimetylbenzensulfonylamino)-5-(4-metoksy-fenyl)tiofen-2-karboksylsyre,
Forbind. 362 3-(sykloheksankarbonylisopropylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 363 3-{(2,4-diklorbenzoyl)-[1-(2,4-diklorbenzoyl)-piperidin-4-yl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 364 4-[(2-karboksy-5-fenyltiofen-3-yl)-(4-metylbenzoyl)-amino]piperidin-1-karboksylsyre-tert.-butylester, Forbind. 365 4-[ (2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklorbenzoyl) amino]piperidin-1-karboksylsyre-tert.-butylester,
Forbind. 366 3-[(4-metylbenzoyl)piperidin-4-yl-amino]-5-fenyl-tiof en-2 -karboksyl sy re,
Forbind. 367 5'-acetyl-4-(2,4-dimetylbenzensulfonylamino)-[2,3']bitiofenyl-5-karboksylsyre,
Forbind. 368 3-[(2,4-diklorbenzoyl)piperidin-4-yl-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 369 5-(4-metansulfonylaminofenyl)-3-(toluen-2-sulfonylamino) tiofen-2-karboksylsyre,
Forbind. 370 3-(4-fluor-2-metylbenzensulfonylamino)-5-fenyl-tiof en-2 -karboksyl sy re,
Forbind. 371 3-[(3-metylsykloheksankarbonyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 372 3-(4-klor-2-metylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 373 3-[(2,4-diklorbenzoyl)isopropylamino]-5-(4-metan-sulf onyl f enyl )tiofen-2-karboksylsyre,
Forbind. 374 3-[(2,4-diklorbenzoyl)isopropylamino]-5-(4-metan-sulf inyl f enyl )tiofen-2-karboksylsyre,
Forbind. 375 5-(4-karboksyfenyl)-3-[(2,4-diklorbenzoyl)iso-propylamino] tiofen-2-karboksylsyre,
Forbind. 376 5-benzofuran-2-yl-3-[(2,4-diklorbenzoyl)iso-propylamino] tiofen-2-karboksylsyre,
Forbind. 377 3-[(2-acetoksy-4-metylbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 378 3-[isopropyl-(2-metylsykloheksankarbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 379 3-[isopropyl-(2-metylsykloheksankarbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 380 3-(sykloheptankarbonylisopropylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 381 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-(3-trifluormetylfenyl)tiofen-2-karboksylsyre, Forbind. 382 3-[(2,4-diklorbenzoyl)isopropylamino]-5-metyltiofen-2-karboksylsyre,
Forbind. 383 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-(3-nitrofenyl)tiofen-2-karboksylsyre,
Forbind. 384 3-[ (3-syklopentylpropionyl)metylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 385 3-(butyrylmetylamino)-5-fenyltiofen-2-karboksylsyre, Forbind. 386 3-(metylpent-4-enoylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 387 3-[isopropyl-(5-metyl-3-okso-3H-isoindol-l-yl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 388 3-[metyl-(3-metylbutyryl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 389 3-(metylpentanoylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 390 3-[metyl-(4-metylpentanoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 391 3-(syklopentankarbonyletylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 392 3-[(3-syklopentylpropionyl)etylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 393 3-(syklobutankarbonyletylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 394 3-(but-2-enoyletylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 395 3-[isopropyl-(4-metyl-2-vinylbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 396 3-[isopropyl-(4-metylsykloheks-l-enkarbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 397 3-(allylheksanoylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 398 3-(allylsyklobutankarbonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 399 3-(allylpentanoylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 400 3-[allyl-(4-metylpentanoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 401 3-[allyl-(2-syklopentylacetyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 402 3-[(2-hydroksy-4-metylsykloheksankarbonyl)iso-propylamino] -5-fenyltiofen-2-karboksylsyre,
Forbind. 403 3-[(2,4-diklorbenzoyl)-(1-fenyletyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 404 3-[ (2,4-diklorbenzoyl)-(1-fenyletyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 405 3-[isopropyl-(3-metylsyklopent-3-enkarbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 406 3-[(2-benzyloksy-4-metylbenzoyl)isopropylamino]-5-(3-trifluormetylfenyl)tiofen-2-karboksylsyre, Forbind. 407 3-[(2,4-dimetylsykloheksankarbonyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 408 3-[isopropyl-(3-metylsyklopentankarbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 409 3-[(2-hydroksy-4-metylsykloheksankarbonyl)isopropyl-amino] -5-fenyltiofen-2-karboksylsyre,
Forbind. 410 5-fenyl-3-[propionyl-(4-trifluormetylbenzyl)-amino]tiofen-2-karboksylsyre,
Forbind. 411 3-[isobutyryl-(4-trifluormetylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 412 3-[(3-metylbutyryl)-(4-trifluormetylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 413 3-[syklopropankarbonyl-(4-trifluormetylbenzyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 414 3-[syklobutankarbonyl-(4-trifluormetylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 415 3-[butyryl-(4-trifluormetylbenzyl)amino]-5-fenyl-tiof en-2 -karboksyl sy re,
Forbind. 416 3-[ (2-syklopentylacetyl)-(4-trifluormetylbenzyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 417 3-[(4-tert.-butylbenzyl)propionylamino]-5-fenyl-tiof en-2 -karboksyl sy re,
Forbind. 418 3-[(4-nitrobenzyl)propionylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 419 3-[(3-metylbutyryl)-(4-nitrobenzyl)amino]-5-fenyl-tiof en-2 -karboksylsyre,
Forbind. 420 3-[syklopropankarbonyl-(4-nitrobenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 421 3-[(2-klorbenzyl)isobutyrylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 422 3-[(2-klorbenzyl)-(3-metylbutyryl)amino]-5-fenyl-tiof en-2 -karboksyl syre,
Forbind. 423 3-[ (2-klorbenzyl)syklopropankarbonylamino]-5-fenyl-tiof en-2-karboksyl syre,
Forbind. 424 3-[(adamantan-l-karbonyl)isopropylamino]-5-fenyl-tiof en-2-karboksylsyre,
Forbind. 425 3- [ (2-klorbenzyl) syklobutankarbonylairu.no]-5-f enyltiof en-2-karboksylsyre,
Forbind. 426 3-[acetyl-(2-metylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 427 3-[(2-metylbenzyl)propionylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 428 3-[(2-hydroksy-4-metylbenzoyl)isopropylamino]-5-(3-trifluormetylfenyl)tiofen-2-karboksylsyre, Forbind. 429 3-[ (l-acetylpiperidin-4-yl)-(2,4-diklorbenzoyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 430 3-[(2,4-diklorbenzoyl)isopropylamino]-5-[4-(1H-tetrazol-5-yl)fenyl]tiofen-2-karboksylsyre, Forbind. 431 3-[(2-cyan-4-metylbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 432 3-[syklobutankarbonyl-(2-metylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 433 3-[butyryl-(2-metylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 434 3-[acetyl-(3-metylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 435 3-[syklobutankarbonyl-(4-metylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 436 3-[sykloheksankarbonyl-(4-trifluormetylbenzyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 437 3-[(4-tert.-butylbenzyl)isobutyrylamino]-5-fenyl-tiof en-2 -karboksyl syre,
Forbind. 438 3-[(4-tert.-butylbenzyl)syklopropankarbonylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 439 3-[(4-tert.-butylbenzyl)syklobutankarbonylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 440 3-[(4-tert.-butylbenzyl)butyrylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 441 3-[(4-tert.-butylbenzyl)sykloheksankarbonylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 442 3-[(4-tert.-butylbenzyl)-(2-syklopentylacetyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 443 3-[(2-syklopentylacetyl)-(4-nitrobenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 444 3-[(2-klorbenzyl)sykloheksankarbonylamino]-5-fenyl-tiof en-2 -karboksyl syre,
Forbind. 445 3-[(2-syklopentylacetyl)-(3-metylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 446 3-[butyryl-(3-metylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 447 3-[butyryl-(2-klorbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 448 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-m-tolyltiofen-2-karboksylsyre,
Forbind. 449 3-[(2,4-diklorbenzoyl)isopropylamino]-5-tiazol-2-yl-tiofen-2-karboksylsyre,
Forbind. 450 3-(acetylbenzylamino)-5-fenyltiofen-2-karboksylsyre, Forbind. 451 3-(benzylpropionylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 452 3-[benzyl-(2-metoksyacetyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 453 3-[benzyl-(3-metylbutyryl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 454 3-(benzylsyklopropankarbonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 455 3-[acetyl-(4-klorbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 456 3-[ (4-klorbenzyl)propionylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 457 3-[ (4-klorbenzyl)isobutyrylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 458 3-[(4-klorbenzyl)-(3-metylbutyryl)amino]-5-fenyl-tiof en-2 -karboksyl sy re,
Forbind. 459 3-[(4-klorbenzyl)syklopropankarbonylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 460 5-(4-acetylfenyl)-3-[isopropyl-(4-metylsykloheksankarbonyl) amino]tiofen-2-karboksylsyre,
Forbind. 461 3-[(4-klorbenzyl)syklobutankarbonylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 462 3-[butyryl-(4-klorbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 463 3-[(4-klorbenzyl)-(2-syklopentylacetyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 464 3-[acetyl-(4-trifluormetylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 465 3-[isobutyryl-(3-metylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 466 3-[syklopropankarbonyl-(3-metylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 467 3-[(4-metylbenzyl)propionylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 468 3-[isobutyryl-(4-metylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 469 3-[syklopropankarbonyl-(4-metylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 470 3-[butyryl-(4-metylbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 471 3-[(3-metoksybenzyl)propionylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 472 3-[(3-metoksybenzyl)-(3-metylbutyryl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 473 3-[syklobutankarbonyl-(3-metoksybenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 474 3-[(2-karbamoyl-4-metylbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 475 3-[butyryl-(3-metoksybenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 476 3-[acetyl-(3-klorbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 477 3-[(3-klorbenzyl)propionylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 478 3-[(3-klorbenzyl)-(2-metoksyacetyl)amino]-5-fenyl-tiof en- 2 -karboksyl sy re,
Forbind. 479 3-[(3-klorbenzyl)-(3-metylbutyryl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 480 3-[(3-klorbenzyl)syklopropankarbonylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 481 3-[(3-klorbenzyl)syklobutankarbonylamino]-5-fenyl-tiof en-2 -karboksyl sy re,
Forbind. 482 3-[butyryl-(3-klorbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 483 3-[acetyl-(2,4-difluorbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 484 3-[ (2,4-difluorbenzyl)-(2-metoksyacetyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 485 3-[(2,4-difluorbenzyl)isobutyrylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 486 3-[(2,4-difluorbenzyl)-(3-metylbutyryl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 487 3-[benzyl-(2-syklopentylacetyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 488 3-[(2,4-diklorbenzoyl)isopropylamino]-5-(lH-indol-5-yl)tiofen-2-karboksylsyre,
Forbind. 489 3-(benzylsyklobutankarbonylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 490 3-[sykloheksankarbonyl-(2,4-difluorbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 491 3-{allyl-[2-(4-metoksyfenyl)acetyl]amino}-5-fenyltiofen-2-karboksylsyre,
Forbind. 492 3-(etylheksanoylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 493 3-(butyryletylamino)-5-fenyltiofen-2-karboksylsyre, Forbind. 494 3-[etyl-(4-metylpentanoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 495 3-[syklobutankarbonyl-(2,4-difluorbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 496 3-[butyryl-(2,4-difluorbenzyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 497 3-(syklopentankarbonylmetylamino)-5-fenyltiofen-2-karboksylsyre,
Forbind. 498 3-(sykloheksankarbonylmetylamino)-5-fenyltiofen-2-karboksylsyre, Forbind. 499 3-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklorbenzoyl )amino]-pyrrolidin-1-karboksylsyre-tert.-butylester,
Forbind. 500 3-[(1,4-dimetylsykloheksankarbonyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 501 5-(4-etylfenyl)-3-[(2-hydroksy-4-metylbenzoyl)iso-propylamino] tiofen-2-karboksylsyre,
Forbind. 502 3-[(2-hydroksy-4-metylbenzoyl)isopropylamino]-5-m-tolyltiofen-2-karboksylsyre,
Forbind. 503 3-[ (2,4-diklorbenzoyl)pyrrolidin-3-yl-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 504 4-{5-karboksy-4-[(2,4-diklorbenzoyl)isopropyl-amino] tiofen-2-yl}-3,6-dihydro-2H-pyridin-l-karboksylsyre-benzylester,
Forbind. 505 3-{[2-(hydroksyiminometyl)-4-metylbenzoyl]isopropyl-amino} -5-fenyltiofen-2-karboksylsyre,
Forbind. 506 3-[(l-karbamimidoylpiperidin-4-yl)-(2,4-diklorbenzoyl) amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 507 4-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklorbenzoyl) amino]-azepan-l-karboksylsyre-tert.-butylester,
Forbind. 508 4-{[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklorbenzoyl) amino]-metyl}piperidin-l-karboksylsyre-benzylester,
Forbind. 509 3-[azepan-4-yl-(2,4-diklorbenzoyl)amino]-5-fenyl-tiof en- 2 -karboksyl syre,
Forbind. 510 3-[(4-metylsykloheksankarbonyl)piperidin-4-ylamino]-5-fenyltiofen-2-karboksylsyre-litiumsalt,
Forbind. 511 3-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklorbenzoyl) amino]-piperidin-l-karboksylsyre-tert.-butylester,
Forbind. 512 3-[(4-benzyloksykarbonylaminosykloheksyl)-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 513 3-[isopropyl-(4-metyl-2-oksosykloheksankarbonyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 514 3-[(2,4-diklorbenzoyl)piperidin-3-yl-amino]-5-fenyltiofen-2-karboksylsyre; forbindelse med
generisk, uorganisk, nøytral bestanddel,
Forbind. 515 3-[(4-benzyloksykarbonylaminosykloheksyl)-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 516 3-[(2-benzyloksy-l-metyletyl)-(2,4-diklorbenzoyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 517 3-[(2,2-dimetyl-[1,3]dioksan-5-yl)-(4-metylsykloheksankarbonyl) amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 518 3-[(2,4-diklorbenzoyl)-(2-hydroksy-l-hydroksymetyl-etyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 519 3-[(2,4-diklorbenzoyl)piperidin-4-ylmetylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 520 3-[(2-klorbenzoyl)piperidin-4-ylmetylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 521 3-[(4,6-diklor-lH-indol-2-karbonyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 522 3-[(2,4-diklorbenzoyl)-(2-hydroksy-l-metyletyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 523 4-{1- [ (2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklorbenzoyl) amino]etyl}piperidin-l-karboksylsyre-benzylester,
Forbind. 524 4-{5-karboksy-4-[isopropyl-(4-metylsykloheksankarbonyl) amino] tiofen-2-yl}-3,6-dihydro-2H-pyridin-1-karboksylsyrebenzylester,
Forbind. 525 3-[(4-metylsykloheksankarbonyl)pyridin-4-yl-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 526 3-[(2,4-diklorbenzoyl)isopropylamino]-5-piperidin-4-yl-tiofen-2-karboksylsyre; forbindelse med
trifluoreddiksyre,
Forbind. 527 3-[isopropyl-(4-propylsykloheksankarbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 528 4-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklorbenzoyl) amino]-sykloheksylammonium; trifluoracetat, Forbind. 529 3-[(2,4-diklorbenzoyl)-(l-piperidin-4-yletyl)amino]-5-fenyltiofen-2-karboksylsyre; forbindelse med
trifluoreddiksyre,
Forbind. 530 3-[(sykloheks-3-enkarbonyl)isopropylamino]-5-fenyl-tiof en-2 -karboksyl syre,
Forbind. 531 3-[(4-etylsykloheksankarbonyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 532 3-[(4-klorsykloheksankarbonyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 533 4-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklorbenzoyl) amino]-3-metylpiperidin-l-karboksylsyre-benzylester,
Forbind. 534 3-[(2,4-diklorbenzoyl)-(2-metoksysykloheksyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 535 3-[(2,4-diklorbenzoyl)-(2,2-dimetyl-[1,3]dioksan-5-yl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 536 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-(l-metylpiperidin-4-yl)tiofen-2-karboksylsyre,
Forbind. 537 3-[(2,4-diklorbenzoyl)-(3-metylpiperidin-4-yl)-amino]-5-fenyltiofen-2-karboksylsyre; forbindelse
med trifluoreddiksyre,
Forbind. 538 3-[(2,4-diklorbenzoyl)-(2-hydroksysykloheksyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 539 4-{[(2-karboksy-5-fenyltiofen-3-yl)-(4-metylsykloheksankarbonyl ) amino]-metyl}piperidin-l-karboksylsyrebenzylester,
Forbind. 540 3-[((IR,2S,4R)-2-hydroksy-4-metylsykloheksankarbonyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 541 3-{isopropyl-[1-(4-metoksy-2,3,6-trimetylbenzen-sulfonyl)-5-metyl-l,2,3,6-tetrahydropyridin-2-karbonyl]amino}-5-fenyltiofen-2-karboksylsyre, Forbind. 542 3-[(2,4-diklorbenzoyl)isopropylamino]-4-fluor-5-fenyltiofen-2-karboksylsyre,
Forbind. 543 3-[(2,4-diklorbenzoyl)-(l-metylpiperidin-4-yl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 544 4-{[(2-karboksy-5-fenyltiofen-3-yl)-(4-metylsykloheksankarbonyl ) amino]metyl}piperidinium; trifluoracetat,
Forbind. 545 3-[ (2-tert.-butoksykarbonylamino-l-metyletyl)-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 546 2-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklorbenzoyl) amino]propylamintrifluoreddiksyresalt, Forbind. 547 3-[(3-karboksysyklopentyl)-(2,4-diklorbenzoyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 548 3-[(3-karboksysyklopentyl)-(2,4-diklorbenzoyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 549 2-[ (2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklorbenzoyl) amino]sykloheksylammoniumklorid,
Forbind. 550 3-(benzoylmetylamino)-5-fenyltiofen-2-karboksylsyre, Forbind. 551 {[5-fenyl-3-(toluen-4-sulfonylamino)tiofen-2-karbonyl]amino}eddiksyre,
Forbind. 552 5-brom-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre,
Forbind. 553 3-[sykloheksyl-(2,4-diklorbenzoyl)amino]-5-fenyl-tiof en-2-karboksylsyre,
Forbind. 554 3-[[1,3]dioksan-5-yl-(4-metylsykloheksankarbonyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 555 3-[[2-(tert.-butyldimetylsilanyloksy)-l-metyl-2-fenyletyl]-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 556 3-[[2-(tert.-butyldimetylsilanyloksy)-l-metyl-2-fenyletyl]-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 557 3-[(2,4-diklorbenzoyl)-(2-dietylaminotiazol-5-ylmetyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 558 (5-{ [ (2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklorbenzoyl)amino]-metyl}tiazol-2-yl)dietyl-ammonium; klorid,
Forbind. 559 5-(4-fluorfenyl)-3-[isopropyl-(4-metylsykloheksankarbonyl) amino]tiofen-2-karboksylsyre,
Forbind. 560 3-[((IS,2R,4S)-2-hydroksy-4-metylsykloheksankarbonyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre, Forbind. 561 3-[(2,4-diklorbenzoyl)-(2-metoksy-l-metyletyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 562 3-[(4S)-isopropyl-(4-metylsykloheks-l-enkarbonyl)-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 566 5-fenyl-3-(toluen-4-sulfonylamino)-tiofen-2-karboksylsyretiazol-2-ylamid,
Forbind. 567 5-fenyl-3-(toluen-4-sulfonylamino)tiofen-2-karboksylsyresyklobutylamid,
Forbind. 568 3-(2,4-dimetylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyreamid,
Forbind. 569 5-brom-3-[(2,4-diklorbenzoyl)isopropylamino]tiofen-2-karboksylsyre,
Forbind. 570 5-(4-klorfenyl)-3-[isopropyl-(4-metylsykloheksankarbonyl) amino]tiofen-2-karboksylsyre,
Forbind. 571 5-(4'-klorbifenyl-4-yl)-3-[isopropyl-(4-metylsykloheksankarbonyl) amino]tiofen-2-karboksylsyre,
Forbind. 572 3-[(4-metylsykloheksankarbonyl)-(tetrahydropyran-4-yl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 573 3-[(4-metylsykloheksankarbonyl)-(l-metylpiperidin-4-yl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 574 3-[(4-metylsykloheksankarbonyl)piperidin-4-yl-amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 575 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-(4-trifluormetylfenyl)tiofen-2-karboksylsyre, Forbind. 576 5-(4-cyanfenyl)-3-[isopropyl-(4-metylsykloheksankarbonyl )amino]tiofen-2-karboksylsyre, Forbind. 577 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-(4-metoksyfenyl)tiofen-2-karboksylsyre,
Forbind. 578 3-[(2-metoksy-l-metyletyl)-(4-metylsykloheksankarbonyl) amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 579 3-[sykloheksyl-(4-metylsykloheksankarbonyl)amino]-5-fenyltiofen-2-karboksylsyre,
Forbind. 581 5-(4-isobutylfenyl)-3-[5-(5-trifluormetylisoksazol-3-yl)tiofen-2-sulfonylamino]tiofen-2-karboksylsyre, Forbind. 582 5-(4-isobutylfenyl)-3-(2,3,4-trifluorbenzensul-fonylamino)tiofen-2-karboksylsyre,
Forbind. 583 3-[(2,4-diklorfenyl)isopropylkarbamoyl]-5-fenyl-tiof en-2 -karboksyl syre,
Forbind. 584 3-(metyl-p-tolylkarbamoyl)-5-fenyltiofen-2-karboksylsyre,
Forbind. 585 3-[(2,4-diklorfenyl)metylkarbamoyl]-5-fenyltiofen-2-karboksylsyre,
eller farmasøytisk akseptable salter derav.
Forbindelsene ifølge foreliggende oppfinnelse tilveie-bringes fortrinnsvis i form av en enkeltenantiomer som er minst 95%, mer foretrukket minst 97% og mest foretrukket minst 99% fri for den tilsvarende enantiomer.
Mer foretrukket er forbindelsen ifølge foreliggende oppfinnelse i form av (+)-enantiomeren som er minst 95% fri for den tilsvarende (-)-enantiomer.
Mer foretrukket er forbindelsen ifølge foreliggende oppfinnelse i form av (+)-enantiomeren som er minst 97% fri for den tilsvarende (-)-enantiomer.
Mer foretrukket er forbindelsen ifølge foreliggende oppfinnelse i form av (+)-enantiomeren som er minst 99% fri for den tilsvarende (-)-enantiomer.
Ved en mer foretrukket utførelsesform er forbindelsen ifølge foreliggende oppfinnelse i form av (-)-enantiomeren som er minst 95% fri for den tilsvarende (+)-enantiomer.
Mest foretrukket er forbindelsen ifølge foreliggende oppfinnelse i form av (-)-enantiomeren som er minst 97% fri for den tilsvarende (+)-enantiomer.
Mer foretrukket er forbindelsen ifølge foreliggende oppfinnelse i form av (-)-enantiomeren som er minst 99% fri for den tilsvarende (+)-enantiomer.
Det er også tilveiebrakt farmasøytisk akseptable salter av forbindelsene ifølge foreliggende oppfinnelse. Med uttrykket farmasøytisk akseptable salter av forbindelser med generell formel (I) eller (Ia) er det ment de som er avledet fra farmasøytisk akseptable uorganiske og organiske syrer og baser. Eksempler på egnede syrer omfatter saltsyre, hydrobromsyre, svovelsyre, salpetersyre, perklorsyre, fumarsyre, maleinsyre, fosforsyre, glykolsyre, melkesyre, salisylsyre, ravsyre, toluen-p-sulfonsyre, vinsyre, eddiksyre, trifluoreddiksyre, sitronsyre, metansulfonsyre, maursyre, benzosyre, malonsyre, naftalen-2-sulfonsyre og benzen-sulfonsyre. Andre syrer, slik som oksalsyre, kan selv om de ikke i seg selv er farmasøytisk akseptable, være anvendbare som mellomprodukter ved erholdelse av forbindelsene ifølge oppfinnelsen og deres farmasøytisk akseptable syreaddisjonssalter.
Salter avledet fra passende baser omfatter alkalimetall-(f.eks. natrium-), jordalkalimetall- (f.eks. magnesium-), ammonium-og NR4+- (hvor R er Ci-4-alkyl) salter.
Henvisninger nedenunder til en forbindelse ifølge oppfinnelsen omfatter forbindelser med den generelle formel (I) eller (Ia), og deres farmasøytisk akseptable salter.
Med mindre annet er definert, har alle tekniske og vitenskapelige uttrykk som er brukt her, den samme betydning som vanligvis forstås av fagfolk innen teknikken som denne oppfinnelsen tilhører. I tilfelle konflikt, vil den foreliggende beskrivelse, inkludert definisjonene, gjelde. I tillegg er materialene, frem-gangsmåtene og eksemplene bare illustrerende, og ikke ment å være begrensende.
Slik det er brukt i denne søknaden, er uttrykket "alkyl" en rettkjedet, forgrenet eller syklisk hydrokarbonrest som eventuelt kan være substituert med én eller flere av: halogen, nitro, nitroso, SO3R12, P03RcRd, CONR13Ri4, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C6-i2~aralkyl, C6-i2_aryl, Ci-6-alkyloksy, C2-6-alkenyl-oksy, C2-6_alkynyloksy, C6-i2-aryloksy, C (0) Ci-6-alkyl, C(0)C2-6_ alkenyl, C (0) C2-6-alkynyl, C (0) C6-i2-aryl, C (0) C6-i2-aralkyl, C3-i0-heteroring, hydroksyl, NRi3Ri4, C(0)0Ri2, cyan, azido, amidino eller guanido;
hvor R12, Rc, Rd, Ri3og Ri4uavhengig av hverandre er valgt fra H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-i2~heteroring, C3-ia-heteroaralkyl, C6-i8-aralkyl;
eller Rc og Rd danner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
eller Ri3og Ri4danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer. Anvendbare eksempler på alkylrester omfatter isopropyl, etyl, fluorheksyl og syklopropyl. Uttrykket alkyl er også ment å omfatte alkylrester hvor ett eller flere hydrogenatomer er erstattet med et oksygenatom, (f.eks. benzoyl) eller et halogenatom, mer foretrukket er halogenatomet fluor (f.eks. CF3- eller CF3CH2-) .
Uttrykkene "alkenyl" og "alkynyl" er en alkylrest som inneholder minst én umettet gruppe (f.eks. allyl, acetylen, etylen).
Uttrykket "aryl" er en karbosyklisk rest som inneholder minst én ring av benzentype som eventuelt kan være substituert med ett eller flere av halogen, nitro, nitroso, S03Ri2, P03RcRd, CONRi3Ri4, Ci_6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C6-i2-aralkyl, C6-i2-aryl, Ci-6-alkyloksy, C2-6-alkenyloksy, C2-6_alkynyloksy, C6-i2-aryl-oksy, C(0)Ci-6-alkyl, C (0) C2-6-alkenyl, C (0) C2-6-alkynyl, C(0)C6-i2- aryl, C (0) C6-i2-aralkyl, C3-i0-heteroring, hydroksyl, NRi3Ri4, C(0)0Ri2, cyan, azido, amidino og guanido;
hvor R12, Rc, Rd, Ri3og Ri4uavhengig av hverandre er valgt fra H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-i2-heteroring, C3_i8-heteroaralkyl og C6-i8_aralkyl;
eller Rc og Rd danner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
eller Ri3og Ri4danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer. Eksempler på aryl omfatter fenyl og naftyl.
Uttrykket "aralkyl" er en arylgruppe bundet til det tilgrensende atom med et Ci_6-alkyl, Ci_6-alkenyl eller Ci_6-alkynyl (f.eks. benzyl).
Uttrykket "heteroring" er en mettet eller umettet, syklisk rest hvor den sykliske rest er avbrutt av minst ett heteroatom (f.eks. oksygen, svovel eller nitrogen) som eventuelt kan være substituert med halogen, nitro, nitroso, S03Ri2, P03RcRd, CONRi3Ri4, Ci-e-alkyl, C2-6-alkenyl, C2-6-alkynyl, C6-i2-aralkyl, C6-i2-aryl, Ci-6-alkyloksy, C2-6-alkenyloksy, C2-6-alkynyloksy, C6-i2-aryloksy, C(0)Ci-6-alkyl, C (0) C2.6-alkenyl, C (0) C2-6-alkynyl, C (0) C6-i2-aryl, C (0) C6-i2-aralkyl, C3-i0-heteroring, hydroksyl, NRi3Ri4, C(0)0Ri2, cyan, azido, amidino og guanido;
hvor R12, Rc, Rd, Ri3og Ri4uavhengig av hverandre er valgt fra H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2_alkynyl, C6-i4-aryl, C3-i2-heteroring, C3-i8-heteroaralkyl og C6-i8-aralkyl;
eller Rc og Rd danner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
eller Ri3og Ri4danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer. Det skal forstås at uttrykket heterosyklisk ring er en mono- eller polysyklisk (f.eks. bisyklisk) ring. Eksempler på heterosykliske ringer omfatter, men er ikke begrenset til, epoksid; furan; benzofuran; isobenzofuran; oksatiolan; ditiolan; dioksolan; pyrrol; pyrrolidin; imidazol; pyridin; pyrimidin; indol; piperidin; morfolin; tiofen og tiomorfolin.
Uttrykket "heteroaralkyl" er en heteroringgruppe bundet til naboatomet med et Ci-6-alkyl, Ci-6-alkenyl eller Ci_6-alkynyl.
Når det er et svovelatom til stede, kan svovelatornet være på forskjellige oksidasjonsnivåer, dvs. S, SO eller SO2. Alle slike oksidasjonsnivåer er innenfor omfanget av den foreliggende oppfinnelse .
Uttrykket "uavhengig" betyr at en substituent kan ha den samme eller forskjellig definisjon i hvert tilfelle.
Slik det er brukt i denne søknaden, betyr uttrykket "hydriddonerende middel" en egnet ionisk eller kovalent, uorganisk forbindelse av hydrogen og et annet grunnstoff (f.eks. bor, natrium, litium eller aluminium) som lar prosessen inntre under reaksjonsbetingelsene uten å forårsake skadelig effekt på rea-gensene eller produktet. Anvendbare eksempler på hydriddonerende middel omfatter, men er ikke begrenset til, natriumborhydrid (NaBH4) , natriumcyanborhydrid (NaCNBH3) , natriumtriacetoksyborhydrid (Na(0Ac)3BH) og boran-pyridin-kompleks (BH3-Py). Alternativt kan det anvendes harpiks- eller polymerbåret hydriddonerende middel.
Uttrykket "organisk karboksylsyre" omfatter, men er ikke begrenset til, alifatisk syre (f.eks. eddiksyre, maursyre, trifluoreddiksyre), aromatisk syre (f.eks. benzosyre og salisylsyre), dikarboksylsyre (f.eks. oksalsyre og ftalsyre). Det vil forstås av fagfolk innen teknikken at harpiksbåret, organisk karboksylsyre også kan anvendes.
Uttrykket "enoleter" har slik det her er brukt, den samme betydning som vanligvis forstås av fagfolk innen teknikken som denne oppfinnelsen tilhører. Enoletere kan erholdes kommersielt eller fremstilles ved hjelp av velkjente metoder. Ikke-begrensende eksempler på fremstilling omfatter alkylering eller silylering av enolater erholdt fra karbonylforbindelser, slik som aldehyder, ketoner og estere.
Det vil forstås at mengden av en forbindelse ifølge oppfinnelsen som trengs for anvendelse ved behandling, vil variere ikke bare med den bestemte forbindelse som er valgt, men også med administreringsveien, typen av tilstanden som behandlingen kreves for, og alderen og tilstanden til pasienten, og vil til sist være opp til den behandlende lege eller veterinær. Generelt vil imidlertid en egnet dose være i området fra ca. 0,1 til ca.
750 mg/kg kroppsvekt pr. dag, fortrinnsvis i området fra 0,5 til 60 mg/kg/dag, mest foretrukket i området 1 til 20 mg/kg/dag.
Den ønskede dose kan passende presenteres i en endose eller som oppdelt dose administrert ved passende intervaller, f.eks. som to, tre, fire eller flere doser pr. dag.
Forbindelsen administreres passende i enhetsdoseringsform; f.eks. inneholdende 10 til 1 500 mg, passende 20 til 1 000 mg, mest passende 50 til 700 mg aktiv bestanddel pr. enhetsdoseringsform.
Ideelt sett bør den aktive bestanddel administreres for å oppnå topp-plasmakonsentrasjoner av den aktive forbindelse på fra ca. 1 til ca. 75 uM, fortrinnsvis ca. 2 til 50 uM, mest foretrukket ca. 3 til ca. 30 uM. Dette kan f.eks. oppnås ved hjelp av den intravenøse injeksjon av 0,1 til 5% oppløsning av den aktive bestanddel, eventuelt i saltoppløsning, eller administrert oralt som en bolus som inneholder ca. 1 til ca. 500 mg av den aktive bestanddel. Ønskelige blodnivåer kan opprettholdes ved hjelp av en kontinuerlig innsprøyting slik at det fås ca. 0,01 til ca. 5,0 mg/kg/time, eller ved avbrutte innsprøytinger som inneholder ca. 0,4 til ca. 15 mg/kg av den aktive bestanddel.
Selv om det for anvendelse ved behandling er mulig at en forbindelse ifølge oppfinnelsen kan administreres som råkjemi-kaliet, er det foretrukket å presentere den aktive bestanddel som en farmasøytisk formulering. Oppfinnelsen tilveiebringer således videre et farmasøytisk preparat som omfatter forbindelser med formel (I) eller (Ia), eller et farmasøytisk akseptabelt derivat derav sammen med én eller flere farmasøytisk akseptable bærere og eventuelt andre terapeutiske og/eller profylaktiske bestanddeler. Bæreren eller bærerne må være "akseptable" i betydningen av å være kompatible med de øvrige bestanddelene i preparatet, og ikke skadelige for mottakeren.
Farmasøytiske preparater omfatter de som er egnet for oral, rektal, nasal, topisk (inkludert bukkal og sublingual), transdermal, vaginal eller parenteral (inkludert intramuskulær, subkutan og intravenøs) administrering, eller i en form som er egnet for administrering ved inhalasjon eller insufflasjon. Preparatene kan, der hvor det er passende, presenteres i atskilte doseringsenheter, og kan fremstilles ved hjelp av hvilken som helst av metodene som er godt kjent innenfor farmasien. Alle metodene omfatter trinnet med å bringe den aktive forbindelse sammen med flytende bærere eller fint oppdelte faste bærere, eller begge deler, og så om nødvendig forme produktet til den ønskede formulering.
Farmasøytisk preparat egnet for oral administrering kan passende presenteres som atskilte enheter, slik som kapsler, oblatkapsler eller tabletter som hver inneholder en forutbestemt mengde av den aktive bestanddel; som et pulver eller granulater; som en oppløsning, en suspensjon eller som en emulsjon. Den aktive bestanddel kan også presenteres som en bolus, blandet med søtstoff eller som en pasta. Tabletter og kapsler for oral administrering kan inneholde vanlige eksipienser, slik som bindemidler, fyll-stoffer, smøremidler, desintegrasjonsmidler eller fuktemidler. Tablettene kan være belagt i henhold til metoder som er godt kjent innenfor teknikken. Orale væskepreparater kan være i form av f.eks. vann- eller oljesuspensjoner, oppløsninger, emulsjoner, siruper eller eliksirer, eller kan presenteres som et tørt produkt for kondisjonering med vann eller annen egnet bærer før bruk. Slike væskepreparater kan inneholde vanlige additiver, slik som oppslemningsmidler, emulgeringsmidler, ikke-vandige bærere (som kan omfatte spiselige oljer), eller konserveringsmidler.
Forbindelsene ifølge oppfinnelsen kan også være formulert for parenteral administrering (f.eks. ved injeksjon, f.eks. bolus-injeksjon eller kontinuerlig innsprøyting), og kan presenteres i enhetsdoseform i ampuller, på forhånd fylte sprøyter, småvolum-infusjon eller i multidosebeholdere med et tilsatt konserverings-middel. Preparatene kan ha slike former som suspensjoner, opp-løsninger eller emulsjoner i olje- eller vannbærere, og kan inneholde formuleringsmidler, slik som oppslemnings-, stabiliserings-og/eller dispergeringsmidler. Alternativt kan den aktive bestanddel være i pulverform, erholdt ved hjelp av aseptisk isolering av sterilt, fast stoff eller ved lyofilisering fra oppløsning, for kondisjonering med en egnet bærer, f.eks. sterilt, pyrogenfritt vann, før bruk.
For topisk administrering til epidermis kan forbindelsene ifølge oppfinnelsen formuleres som salver, kremer eller lotions, eller som et transdermalt plaster. Slike transdermale plaster kan inneholde penetrasjonsfremmere, slik som linalool, carvacrol, tymol, citral, mentol og t-anetol. Salver og kremer kan f.eks. formuleres med en vann- eller oljebase med tilsetning av egnede fortyknings- og/eller geldannelsesmidler. Lotions kan være formulert med en vann- eller oljebase og vil generelt også inneholde ett eller flere emulgeringsmidler, stabiliseringsmidler, dispergeringsmidler, oppslemningsmidler, fortykningsmidler eller fargemidler.
Preparater egnet for topisk administrering i munnen, omfatter sugetabletter som omfatter aktiv bestanddel i en smaks-tilsatt base, vanligvis sukrose og akasie eller tragant; pastiller som omfatter den aktive bestanddel i en inert base, slik som gelatin og glyserol eller sukrose og akasie; og munnvann som omfatter den aktive bestanddel i en egnet, flytende bærer.
Farmasøytiske preparater egnet for rektal administrering hvor bæreren er et fast stoff, presenteres mest foretrukket som enhetsdosesuppositorier. Egnede bærere omfatter kakaosmør og andre materialer som vanligvis anvendes innenfor teknikken, og supposi-toriene kan på passende måte formes ved blanding av den aktive forbindelse med den eller de myknede eller smeltede bærerne, etterfulgt av avkjøling og forming i støpeformer.
Formuleringer egnet for vaginal administrering, kan presenteres som pessarer, tamponger, kremer, geler, pastaer, skum eller sprayer som inneholder slike bærere som er kjent innenfor teknikken for å være passende, i tillegg til den aktive bestanddel.
For intranasal administrering kan forbindelsene ifølge oppfinnelsen anvendes som en flytende spray eller et dispergerbart pulver, eller i form av dråper. Dråper kan formuleres med en vann-eller ikke-vandig base som også omfatter ett eller flere dispergeringsmidler, oppløseliggjøringsmidler eller oppslemningsmidler. Flytende sprayer avleveres passende fra pakninger under trykk.
For administrering ved inhalasjon avleveres forbindelsene ifølge oppfinnelsen vanligvis fra en insufflator, forstøver eller en pakning under trykk eller annet passende middel for avlevering av en aerosolspray. Pakninger under trykk kan omfatte et egnet drivmiddel, slik som diklordifluormetan, triklorfluormetan, diklor-tetrafluoretan, karbondioksid eller annen egnet gass. I tilfellet med en aerosol under trykk kan doseringsenheten bestemmes ved å tilveiebringe en ventil for å avlevere en utmålt mengde.
Alternativt kan forbindelsene ifølge oppfinnelsen for administrering ved inhalasjon eller insufflasjon ha form av et tørt pulverpreparat, f.eks. en pulverblanding av forbindelsen og en egnet pulverbase, slik som laktose eller stivelse. Pulverpreparatet kan presenteres i enhetsdoseringsform, f.eks. i kapsler eller patroner, eller f.eks. gelatin- eller blisterpakninger, hvorfra pulveret kan administreres ved hjelp av en inhalator eller insufflator.
Når det er ønsket, kan de ovenfor beskrevne preparater tilpasset til å gi langvarig frigivelse av den aktive bestanddel, anvendes. Forbindelsene ifølge oppfinnelsen kan også anvendes i kombinasjon med andre antivirusmidler eller i kombinasjon med hvilke som helst tilleggsmidler som kan anvendes innen terapi, og kan administreres etter hverandre eller samtidig.
Ved ett aspekt av oppfinnelsen kan forbindelsene ifølge oppfinnelsen anvendes sammen med minst ett annet antivirusmiddel valgt fra proteaseinhibitorer, polymeraseinhibitorer og helikase-inhibitorer.
Ved et annet aspekt av oppfinnelsen kan forbindelsene ifølge oppfinnelsen anvendes sammen med minst ett annet antivirusmiddel valgt fra interferon-a og ribavirin.
Kombinasjonene som det er henvist til ovenfor, kan vanligvis presenteres for anvendelse i form av et farmasøytisk preparat, og farmasøytiske preparater som omfatter en kombinasjon som definert ovenfor, sammen med en farmasøytisk akseptabel bærer for denne, utgjør således et ytterligere aspekt av oppfinnelsen.
De enkelte komponentene i slike kombinasjoner kan administreres enten etter hverandre eller samtidig i separate eller kombinerte, farmasøytiske preparater.
Når forbindelsene med formel (Ia) eller et farmasøytisk akseptabelt salt derav anvendes i kombinasjon med et andre terapeutisk middel som er aktivt mot det samme virus, kan dosen av hver forbindelse være enten den samme som, eller forskjellig fra den når forbindelsen anvendes alene. Passende doser vil lett forstås av fagfolk innen teknikken.
De følgende generelle reaksjonsskjemaer og eksempler er gitt for å illustrere forskjellige utførelsesformer av den foreliggende oppfinnelse.
Eksempel 1
Fremstilling av 3-( 2- klorbenzensulfonylamino)- 5- fenyltiofen- 2-karboksylsyre, forbindelse nr. 29
TRINN I
3- amino- 5- fenyltiofen- 2- karboksylsyre
Til en suspensjon av 3-amino-5-fenyltiofen-2-karboksylsyremetylester (5 g, 21,459 mmol) i en blanding av THF:MeOH:H20 (3:2:1, 75 ml) ble 1 N vandig oppløsning av LiOH.H20 (64 ml, 64,378 mmol) tilsatt. Reaksjonsblandingen ble omrørt ved 85 °C (utvendig temperatur) i 4 timer. Oppløsningsmidler ble fjernet under redusert trykk og resten ble fordelt mellom vann og etylacetat. Vannlaget ble fraskilt og surgjort med 1 N HCl-oppløsning, og så ble etylacetat tilsatt til den. Den organiske fase ble fraskilt, tørket (Na2S04) og konsentrert, hvorved man fikk 3-amino-5-fenyltiofen-2- karboksylsyre (4,15 g, 88%) som et gulaktig, fast stoff.<1>H NMR (DMSO-de, 400 MHz): 7,59 (d, 2H) , 7,40 (m, 3H), 6,92 (s, 1H).
TRINN II
3-( 2- klorbenzensulfonylamino)- 5- fenyltiofen- 2- karboksylsyre
3-amino-5-fenyltiofen-2-karboksylsyre (100 mg, 0,457 mmol) ble tatt opp i en blanding av dioksan og vann (1:1, 25 ml), og så ble det tilsatt natriumkarbonat (242 mg, 2,285 mmol) og 1-klor-benzensulfonylklorid (289 mg, 1,369 mmol). Reaksjonsblandingen ble omrørt ved romtemperatur i 12 timer. Halvparten av oppløsnings-midlet ble fjernet under redusert trykk, og så ble det fortynnet med vann og eter i en skilletrakt. Eterlaget ble fraskilt, og vannlaget ble surgjort med 10% KHS04-oppløsning. Etylacetat ble tilsatt til vannfasen for å oppløse den hvite utfelling. Etyl-acetatlaget ble fraskilt, tørket (Na2S04) og konsentrert til 5 ml. Det hvite, faste stoff ble frafiltrert og så vasket med kaldt etylacetat, hvorved man fikk 3-(2-klorbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyre (125 mg, 69%). ^ NMR (DMSO-d6, 400 MHz): 10,51 (bs, 1H), 8,30 (d, 1H), 7,72-7,60 (m, 4H), 7,57 (m, 1H), 7,44 (m, 4H).
De følgende forbindelser ble fremstilt på en lignende måte som beskrevet i generelt reaksjonsskjema 1: forbindelse nr. 3, forbindelse nr. 5, forbindelse nr. 7, forbindelse nr. 13, forbindelse nr. 15, forbindelse nr. 16, forbindelse nr. 17, forbindelse nr. 18, forbindelse nr. 21, forbindelse nr. 22, forbindelse nr. 23, forbindelse nr. 29, forbindelse nr. 30, forbindelse nr. 34, forbindelse nr. 37, forbindelse nr. 38, forbindelse nr. 39, forbindelse nr. 40, forbindelse nr. 41, forbindelse nr. 42, forbindelse nr. 44, forbindelse nr. 45, forbindelse nr. 46, forbindelse nr. 49, forbindelse nr. 50, forbindelse nr. 52, forbindelse nr. 53, forbindelse nr. 54, forbindelse nr. 55, forbindelse nr. 76, forbindelse nr. 94. Eksempel 2 3-( toluen- 2- sulfonylamino)- 5- p- tolyltiofen- 2- karboksylsyre, forbindelse nr. 62
TRINN I
3-( bis-( toluen- 2- sulfonyl) amino) tiofen- 2- karboksylsyremetylester
Til en kald (0 °C) omrørt oppløsning av natriumhypokloritt (NaOCl, 10,8% kommersielt blekemiddel, 124 ml, 180,00 mmol) ble det tilsatt o-tiokresol (2,23 g, 2,12 ml, 18,0 mmol). Til denne kraftig omrørte oppløsning ble det dråpevis tilsatt konsentrert svovelsyre (forsiktig: ekstremt eksoterm, 92 g, 50 ml, 938 mmol). Den resulterende gule reaksjonsblanding ble omrørt i 2 timer ved den samme temperatur, fortynnet med vann (50 ml) og diklormetan (50 ml). Den organiske oppløsning ble fraskilt, og vannoppløsningen ble ekstrahert med CH2C12(2 x 50 ml). De kombinerte, organiske ekstrakter ble vasket med vann, saltoppløsning og tørket. Avdamping av oppløs- ningsmidlet under redusert trykk ga 2-metylsulfonylkloridet (3,13 g, 91,5% utbytte) som ble brukt i det neste trinn uten rensing.<1>H NMR (CDCI3, 300 MHz) 8,07 (td, J = 7,3, 1,5 Hz, 1H), 7,61 (tt, J = 7,5, 1,1 Hz, 1H), 7,44-7,40 (m, 2H), 2,80 (s, 3H).
Til en omrørt oppløsning av metyl-3-aminotiofen-2-karboksylsyren (1,0 g, 6,36 mmol) og DMAP (776 mg, 6,36 mmol) i CH2CI2ble det etter hverandre tilsatt trietylamin (1,61 g,
15,9 mmol, 2,5 ekv.) og o-toluensulfonylklorid (3,02 g, 15,9 mmol, 2,5 ekv.) og omrørt i 24 timer. Reaksjonsblandingen ble fortynnet med EtOAc (100 ml), vasket med 1,2 N HC1 (2 x 50 ml), 6 N HC1 (40 ml), mettet NaHCG-3-oppløsning, saltoppløsning og tørket. Avdamping av oppløsningsmidlet under redusert trykk ga 3-(bis-(toluen-2-sulfonyl)amino)tiofen-2-karboksylsyremetylester (2,78 g, 93,3%) som et fast stoff. Råproduktet ble brukt i det neste trinn uten rensing.<X>H NMR (CDC13, 300 MHz) 8,198 (dd, J = 8,0, 1,2 Hz, 2H) , 7,52 (d, J = 5,3 Hz, 1H), 7,5 (dt, J = 7,5 Hz, 1,1 Hz, 2H), 7,36 (t, J = 7,5 Hz, 3H), 7,28 (d, J = 7,6 Hz, 2H), 7,16 (d, J = 5,3 Hz, 1H), 3,44 (s, 3H), 2,43 (s, 3H) .
TRINN II
3-( toluen- 2- sulfonylamino) tiofen- 2- karboksylsyre
Til en omrørt blanding av 3-(bis-(toluen-2-sulfonyl)-amino)tiofen-2-karboksylsyremetylester (2,5 g, 5,35 mmol) i 1,4-dioksan/MeOH/vann (3:1:1; 62,5 ml) ble det tilsatt vandig 1 N NaOH-oppløsning (16,05 ml, 16,05 mmol, 3,0 ekv.) og varmet opp ved 85 °C i 3,5 timer, og det ble så avkjølt til romtemperatur. Til reaksjonsblandingen ble det tilsatt 1,2 N HC1 (16,0 ml), ekstrahert med CHCI3(3 x 30 ml), vasket med saltoppløsning og tørket. Avdamping av oppløsningsmidlet ga 3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre (1,5 g, 99%) som et hvitt, fast stoff.<X>H NMR (DMSO-d6, 300 MHz) 7,94 (dd, J = 7,9 Hz, 1,3 Hz, 1H) , 7,76 (d, J = 5,5 Hz, 1H), 7,55 (dt, J = 7,5 Hz, 1,3 Hz, 1H), 7,42-7,37 (m, 2H), 7,1 (d, J = 5,5 Hz, 1H), 2,57 (s, 3H).
TRINN III
3-( toluen- 2- sulfonylamino) tiofen- 2- karboksylsyre- tert.- butylester
Til en kald (-40 °C) blanding av 3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre (1,5 g, 5,05 mmol) i 1,4-dioksan/CHCl3(1:2, 12 ml) ble det boblet 2-metyl-2-propengass (15 ml) i et lukket rør. Til dette ble det tilsatt konsentrert H2S04(0,07 0 ml, 1,3 mmol) og sakte varmet opp til romtemperatur. Den resulterende reaksjonsblanding ble varmet opp ved 70 °C i 2,5 dager i et lukket rør, avkjølt til -40 °C, og korken ble fjernet. Reaksjonsblandingen ble sakte brakt opp til romtemperatur og omrørt inntil gassoverskuddet er frigjort. Blandingen ble ekstrahert med EtOAc, vasket med vandig NaHCC>3-oppløsning, saltoppløsning og tørket. Fordamping av oppløsningsmidlet og rensing av resten på silikagel under anvendelse av EtOAc/heksan (1:10) som elueringsmiddel ga 3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre-tert.-butylester (1,31 g, 73,5% basert på 90% omdannelse).<1>H NMR (CDC13, 300 MHz) 9,89 (s, 1H), 8,01 (d, J = 7,9 Hz, 1H), 7,43 (dt, J = 7,5 Hz, 1,5 Hz, 1H), 7,3-7,25 (m, 3H), 7,2 (d, J = 5,4 Hz, 1H), 2,69 (s, 3H), 1,56 (s, 9H).
TRINN IV
5- brom- 3-( toluen- 2- sulfonylamino) tiofen- 2- karboksylsyre- tert.-butylester
Til en kald (-30 °C) omrørt oppløsning av diisopropylamin (1,345 g, 1,86 ml, 13,3 mmol, 3,6 ekv.) i THF (74,0 ml) ble det dråpevis tilsatt n-BuLi (1,6 M i heksan, 7,63 ml, 12,21 mmol, 3,3 ekv.) og omrørt i 10 minutter. Til kald (-78 °C) LDA-oppløsning ble det dråpevis tilsatt en oppløsning av 3-(toluen-2-sulfonylamino-)tiofen-2-karboksylsyre-tert.-butylester (1,31 g, 3,7 mmol, 1,0 ekv.) i THF (20 ml), og oppløsningen ble omrørt i 2 timer ved den samme temperatur. Den resulterende rødfargede oppløsning ble så tilsatt 1,2-dibromtetrafluoretan (5,77 g, 2,65 ml, 22,2 mmol, 6,0 ekv., sendt gjennom K2CO3før bruk) i én porsjon og omrørt i 1 time før det ble tilsatt mettet NH4Cl-oppløsning (15,0 ml). Reaksjonsblandingen ble varmet opp til romtemperatur, ekstrahert med EtOAc, vasket med saltoppløsning og tørket. Fordamping av oppløsnings- midlet og rensing av resten over silikagelkolonne ga 5-brom-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre-tert.-butylester (1,2 g, 75% utbytte).<X>H NMR (CDCI3, 300 MHz) 9,72 (s, 1H) , 8,0 (dd, J = 7,8, 1,3 Hz, 1H) , 7,47 (dt, J = 7,5, 1,2 Hz, 1H), 7, 35-7, 30 (m, 2H), 7,24 (s, 1H), 2,68 (s, 3H), 1,53 (s, 9H).
TRINN V
3-( toluen- 2- sulfonylamino)- 5- p- tolyltiofen- 2- karboksylsyre- tert.-butylester
Til blandingen av 4-metylbenzenborsyre (38,0 mg,
0,279 mmol) og 5-brom-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre-tert.-butylester (40 mg, 0,0925 mmol) i en blanding i forholdet 5:1 av toluen/MeOH (2,0 ml) ble det tilsatt en oppløsning av Pd(PPh3)4(12,0 mg, 0,01 mmol, 10 mol%) i toluen (1,0 ml), etterfulgt av vandig 2 M Na2C03-oppløsning (0,1 ml, 0,2 mmol). Den resulterende reaksjonsblanding ble varmet opp ved 70 °C i 16 timer, avkjølt til romtemperatur, frafiltrert gjennom MgS04og vasket med EtOAc. Fordamping av oppløsningsmidlet og rensing av resten over preparativ TLC (1 mm, 60 Å) under anvendelse av etylacetat/heksan (1:10) som elueringsmiddel ga 3-(toluen-2-sulfonylamino)-5-p-tolyltiofen-2-karboksylsyre-tert.-butylester (36,0 mg, 81% utbytte).<X>H NMR (CDC13, 300 MHz) 9,94 (s, 1H) , 8,05 (d, J = 8,0 Hz, 1H), 7,44-7,25 (m, 6H), 7,18 (d, J = 8,1 Hz, 2H), 2,71 (s, 3H), 2,36 (s, 3H), 1,56 (s, 9H).
TRINN VI
3-( toluen- 2- sulfonylamino)- 5- p- tolyltiofen- 2- karboksylsyre
Til en omrørt oppløsning av 3-(toluen-2-sulfonylamino)-5-p-tolyltiofen-2-karboksylsyre-tert.-butylester (36,0 mg,
0,081 mmol) i CH2C12(1,0 ml) ble det tilsatt TFA (0,5 ml), omrørt i 1 time ved romtemperatur og fortynnet med heksan. Fordamping av oppløsningsmidlet under redusert trykk ga hovedsakelig det rene produkt som et fast stoff. Produktet ble renset ved triturering med heksan/CH2Cl2, og dette ga 3-(toluen-2-sulfonylamino)-5-p-tolyl-tiof en-2-karboksylsyre (28,0 mg, 89% utbytte).<X>H NMR (DMSO-d6, 300
MHz) 10,21 (br s, 1H), 8,06 (d, J = 7,9 Hz, 1H), 7,56-7,36 (m, 6H), 7,24 (d, J = 7,9 Hz, 2H), 2,59 (s, 3H), 2,48 (s, 3H).
De følgende forbindelser ble fremstilt på en lignende måte som beskrevet i generelt reaksjonsskjema 2: forbindelse nr. 6, forbindelse nr. 8, forbindelse nr. 11, forbindelse nr. 14, forbindelse nr. 24, forbindelse nr. 56, forbindelse nr. 57, forbindelse nr. 58, forbindelse nr. 59, forbindelse nr. 60, forbindelse nr. 62, forbindelse nr. 63, forbindelse nr. 64, forbindelse nr. 65, forbindelse nr. 66, forbindelse nr. 67, forbindelse nr. 68, forbindelse nr. 69, forbindelse nr. 70, forbindelse nr. 71, forbindelse nr. 552, forbindelse nr. 79, forbindelse nr. 80, forbindelse nr. 81, forbindelse nr. 83, forbindelse nr. 84, forbindelse nr. 85, forbindelse nr. 86, forbindelse nr. 87, forbindelse nr. 88, forbindelse nr. 89, forbindelse nr. 90 og forbindelse nr. 91.
Eksempel 3
3- ( 4- klorbenzoylamino)- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 72
TRINN I
3-( 4- klorbenzoylamino)- 5- fenyltiofen- 2- karboksylsyremetylester
Til en blanding av metyl-3-amino-5-fenyltiofen-2-kar-boksylat (100 mg, 0,428 mmol) i vannfritt pyridin (4,3 ml) ble det tilsatt p-klorbenzoylklorid (71 ul, 0,556 mmol). Blandingen ble omrørt i 3 timer ved romtemperatur og konsentrert. Rensekroma-tografi (silikagel, heksan til heksan: etylacetat; 95:5) ga 145 mg (91% utbytte) 3-(4-klorbenzoylamino)-5-fenyltiofen-2-karboksylsyremetylester.<1>H NMR (CDC13, 400 MHz) 8,54 (s, 1H) , 7, 99-7, 96 (m, 2H) , 7,73-7,71 (m, 2H), 7,52-7,50 (m, 2H), 7,46-7,39 (m, 3H), 3,95 (s, 3H) .
TRINN II
3-( 4- klorbenzoylamino)- 5- fenyltiofen- 2- karboksylsyre
Til en blanding av 3-(4-klorbenzoylamino)-5-fenyltiofen-2-karboksylsyremetylester (30 mg, 0,081 mmol) i 1 ml av en 3:2:1 oppløsning laget av henholdsvis tetrahydrofuran, metanol og vann, ble det tilsatt litiumhydroksidmonohydrat (20 mg, 0,484 mmol). Blandingen ble omrørt i 30 minutter ved 60 °C, avkjølt til romtemperatur, fortynnet med vann og vasket med eter (2x). Det oppsamlede vannlag ble så surgjort med KHS04, 2 0% til pH 3 og ekstrahert med etylacetat (3x). De kombinerte etylacetatlag ble vasket med saltoppløsning, tørket (Na2S04) og konsentrert. Det resulterende råprodukt ble tatt opp i etylacetat og på nytt ekstrahert med NaOH, 0,5 N (2x). De kombinerte vannlag ble så tilbakevasket med etylacetat og surgjort til pH 3 med KHS04, 20%, og tilbakeekstrahert med etylacetat (2x). De kombinerte, organiske lag ble vasket med saltoppløsning og tørket (Na2S04) .<1>H NMR (DMSO-d6, 400 MHz) 8,35 (s, 1H), 8,02-7,99 (m, 2H), 7,71-7,68 (m, 2H), 7,56-7,53 (m, 2H), 7,43-7,39 (m, 2H), 7,35-7,31 (m, 1H).
De følgende forbindelser ble fremstilt på en lignende måte som beskrevet i eksempel 3: forbindelse nr. 74, forbindelse nr. 77, forbindelse nr. 92 og forbindelse nr. 96.
Eksempel 4
3-( benzoylmetylamino)- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 550
TRINN I
3- metylamino- 5- fenyltiofen- 2- karboksylsyremetylester
Til en blanding av metyl-3-amino-5-fenyltiofen-2-kar-boksylat (200 mg, 0,855 mmol) i vannfritt N,N-dimetylformamid (4,6 ml) ble det tilsatt 4,2 ml (8,55 mmol) 2 M jodmetanoppløsning i t-butylmetyleter. Blandingen ble omrørt ved 60 °C i 18 timer, konsentrert og renset ved å anvende "Biotage"-teknikker (silikagel, heksan til heksan:etylacetat; 95:5, inneholdende noen få dråper trietylamin), hvorved man fikk 68 mg (32% utbytte) av 3-metylamino-5-fenyltiofen-2-karboksylsyremetylester. ^ NMR (CDC13, 400 MHz) 7,65-7,62 (m, 2H), 7,42-7,36 (m, 3H), 6,86 (bred s, 1H), 3,83 (s, 3H), 3,04 (d, 3H).
TRINN II
3-( benzoylmetylamino)- 5- fenyltiofen- 2- karboksylsyremetylester
Denne forbindelsen ble fremstilt på en lignende måte som for eksempel 3, trinn I; 3-(benzoylmetylamino)-5-fenyltiofen-2-karboksylsyremetylester.<X>H NMR (CDC13, 400 MHz) 7,60-7,49 (m, 2H), 7,47-7,35 (m, 5H), 7,28-7,20 (m, 3H), 7,11 (bred s, 1H), 3,83 (s, 3H), 3,44 (s, 3H).
TRINN III
3-( benzoylmetylamino)- 5- fenyltiofen- 2- karboksylsyre
Denne forbindelsen ble fremstilt på en lignende måte som i eksempel 3, trinn II; 3-(benzoylmetylamino)-5-fenyltiofen-2-karboksylsyre ble erholdt;<*>H NMR (CD3OD, 400 MHz) 7,64-7,62 (m, 2H), 7,47 (s, 1H), 7,44-7,36 (m, 5H), 7,29-7,20 (m, 3H), 3,42 (s, 3H) .
De følgende forbindelser ble fremstilt på en lignende måte som beskrevet i eksempel 4: forbindelse nr. 9, forbindelse nr. 73, forbindelse nr. 75, forbindelse nr. 75, forbindelse nr. 78, forbindelse nr. 93, forbindelse nr. 95. Eksempel 5 {[ 5- fenyl- 3-( toluen- 4- sulfonylamino) tiofen- 2- karbonyl] amino}-eddiksyre, forbindelse nr. 551
TRINN I
{[ 5- fenyl- 3-( toluen- 4- sulfonylamino) tiofen- 2- karbonyl] amino}-eddiksyremetylester
Til en blanding av 5-fenyl-3-(toluen-4-sulfonylamino)-tiofen-2-karboksylsyre (fremstilt ifølge eksempel 2) (50 mg, 0,134 mmol) i vannfritt dimetylformamid (1,4 ml) ble det tilsatt HATU (152 mg, 0,402 mmol), glysinmetylesterhydroklorid (20 mg, 0,161 mmol), etterfulgt av kollidin (124 ul, 0,938 mmol). Blandingen ble omrørt ved romtemperatur i 1 time, konsentrert og forabsorbert på SiC>2. Rensekromatograf i (heksan til heksan: etylacetat; 6:4 til diklormetan:metanol; 95:5) ga 47 mg av en blanding av {[5-fenyl-3-(toluen-4-sulfonylamino)tiofen-2-karbonyl]amino}eddiksyremetylester og kollidin.<X>H NMR (CDCI3, 400 MHz) 7,76-7,73 (m, 2H) , 7,61 (s, IH) , 7,57-7,54 (m, 2H), 7,42-7,36 (m, 3H), 7,24-7,22 (m, 2H), 6,19-6,17 (m, 1H), 4,14-4,12 (m, 2H), 3,79 (s, 3H), 2,35 (s, 3H).
TRINN II
{[ 5- fenyl- 3-( toluen- 4- sulfonylamino) tiofen- 2- karbonyl] amino}-eddiksyre
Ved å følge fremgangsmåten beskrevet i eksempel 3 (trinn II) , ble 28 mg (88% utbytte) {[5-fenyl-3-(toluen-4-sulfonylamino) tiof en-2-karbonyl] amino} eddiksyre isolert fra 33 mg (0,075 mmol) av {[5-fenyl-3-(toluen-4-sulfonylamino)tiofen-2-karbonyl]-amino}eddiksyremetylesteren.<1>H NMR (CD3OD, 400 MHz): 7,73-7,71 (m, 2H), 7,63-7,61 (m, 2H), 7,54 (s, 1H), 7,45-7,39 (m, 3H), 7,33-7,31 (m, 2H), 4,88 (s, 2H), 2,36 (s, 3H).
Eksempel 6
3-( 2, 4- diklorbenzylamino)- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 48
TRINN I
3-( 2, 4- diklorbenzylamino)- 5- fenyltiofen- 2- karboksylsyremetylester
Natriumhydrid (60% dispersjon i olje, 180 mg, 4,72 mmol) ble tilsatt til en iskald oppløsning av 3-amino-5-fenyltiofen-2-karboksylsyremetylester (1 000 mg, 4,29 mmol) i 25 ml dimetylformamid i en atmosfære av N2. Etter 5 minutter ble 2,4-diklor-l-klormetylbenzen (755 mg, 3,86 mmol) tilsatt til oppløsningen, og så ble reaksjonsblandingen omrørt i 30 minutter ved 0 °C og i 30 minutter ved romtemperatur. Blandingen ble fordelt mellom eter (20 ml) og vann (20 ml), og det organiske lag ble fraskilt. Vannfasen ble vasket to ganger med eter (2 x 20 ml), og det kombinerte eterlag ble tørket (MgS04) og konsentrert. Den erholdte rest ble så renset ved utfelling. Råproduktet ble tatt opp i 25 ml etylacetat, det kom ut en gul utfelling som ble filtrert, hvorved man fikk 3-(2,4-diklorbenzylamino)-5-fenyltiofen-2-karboksylsyrernetylester, 835 mg (55%).<X>H NMR (DMSO, 400 MHz): 7,67 ppm (m, 2H, Haro) , 7,44-7,35 ppm (m, 6H, Haro) , 7,26 ppm (s, 1H, Haro) , 4,63 ppm (d, 2H, N-CH2) , 3,75 ppm (s, 3H, 0-CH3) .
TRINN II
3-( 2, 4- diklorbenzylamino)- 5- fenyltiofen- 2- karboksylsyre
3-(2,4-diklorbenzylamino)-5-fenyltiofen-2-karboksylsyremetylester (70 mg, 0,18 mmol) ble oppløst i en blanding av THF-MeOH-H20 (3:2:1) (20 ml), og så ble 1 080 ul LiOH, 1 N tilsatt. Etter 16 timers omrøring ved temperatur på 100 °C ble oppløsnings-midler fjernet, og det ble så fordelt mellom 10 ml H20, 2 ml KHS04, 5%, og 10 ml EtOAc. Det organiske lag ble fraskilt, og vannfasen ble vasket to ganger med etylacetat (2 x 10 ml). Det kombinerte etylacetatlag ble tørket (MgS04) og konsentrert, hvorved man fikk 43 mg (63%) 3-(2,4-diklorbenzylamino)-5-fenyltiofen-2-karboksylsyre.<X>R NMR (DMSO, 400 MHz): 5 7,65 ppm (m, 3H, Haro) / 7,43-7,32 ppm (m, 5H, Haro) , 7,23 ppm (s, 1H, Haro) , 4,61 ppm (d, 2H, N-CHg) .
Eksempel 7
3-{( 2, 4- diklorbenzoyl)-[ 5-( 3- trifluormetylfenyl) furan- 2- ylmetyl]-amino}- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 4
TRINN I
5- fenyl- 3-{[ 5-( 3- trifluormetylfenyl) furan- 2- ylmetyl] amino} tiofen- 2-karboksylsyrernetylester
Til en omrørt oppløsning av 3-amino-5-fenyltiofen-2-karboksylsyremetylester (100 mg, 0,416 mmol) i diklormetan (15 ml) ble det tilsatt 5-(trifluormetylfenyl)furan-2-karbaldehyd (100 mg, 0,429 mmol) og molekylsikter. Reaksjonsblandingen ble omrørt ved romtemperatur over natten. Oppløsningen ble filtrert over celite, og filtratet ble inndampet under redusert trykk. Resten ble oppløst i vannfri metanol (15 ml), og det ble avkjølt til 0 °C i et isbad. Natriumborhydrid (18 mg, 1,1 ekv.) ble tilsatt. Reaksjonsblandingen ble omrørt ved denne temperatur i 2 timer. Mettet ammoniumklorid (10 ml) ble tilsatt, og omrøring ble fortsatt i ytterligere 15 minutter ved romtemperatur. Metanol ble fjernet, og den resulterende blanding ble ekstrahert med diklormetan (3 x 30 ml). Den organiske oppløsning ble vasket med vann, saltoppløsning og ble tørket over natriumsulfat. Oppløsningsmidlet ble avdampet, og råproduktet ble renset på silikagel under anvendelse av heksan:etylacetat 9:1 som elueringsmiddel, hvorved man fikk det ønskede produkt i 34% utbytte (65 mg).<X>H NMR (CDC13, 400 MHz) 7,80 (s, 1H), 7,73 (m, 1H), 7,55 (m, 2H), 7,41 (m, 2H), 7,33 (m, 3H), 6,93 (s, 1H), 6,48 (d, 1H), 6,24 (d, 1H), 4,43 (s, 2H), 3,76 (s, 3H) .
TRINN II
3-{( 2, 4- diklorben2oyl)-[ 5-( 3- trifluormetylfenyl) furan- 2- ylmetyl]-amino}- 5- fenyltiofen- 2- karboksylsyremetylester
Til en omrørt oppløsning av 5-fenyl-3-{[5-(3-trifluor-metylf enyl )furan-2-ylmetyl]amino}tiofen-2-karboksylsyremetylester (65 mg, 0,142 mmol) i diklormetan (3 ml) og mettet NaHC03~opp-løsning (3 ml) ble det tilsatt en oppløsning av 2,4-diklorbenzoylklorid (36 mg, 1,2 ekv.) i diklormetan (0,9 ml). Reaksjonsblandingen ble kraftig omrørt ved romtemperatur over natten. Den organiske fase ble samlet opp, og vannfasen ble ekstrahert to ganger med metylenklorid (2 x 15 ml). De organiske lagene ble slått sammen, vasket med vann, saltoppløsning og tørket over vannfritt Na2S04. Oppløsningsmiddel ble fjernet, og resten ble renset på silikagel under anvendelse av heksan:EtOAc =9:1 som elueringsmiddel, hvorved man fikk det ønskede produkt i 78% utbytte (70 mg). Proton-NMR indikerte tilstedeværelse av rotamerer.<1>H NMR (CDCI3, 400 MHz) 7,80 (s, 1H), 7,73 (m, 1H), 7,55 (m, 2H), 7,45 (m, 2H), 7,33 (m, 3H), 7,20 (m, 2H), 7,12 (m, 1H), 6,93 (s, 1H), 6,62 (d, 1H), 6,42 (d, 1H), 5,60 (bd, 1H), 4,70 (bd, 1H), 3,76 (s, 3H).
TRINN III
3-{( 2, 4- diklorbenzoyl)-[ 5-( 3- trifluormetylfenyl) furan- 2- ylmetyl]-amino}- 5- fenyltiofen- 2- karboksylsyre
3-{(2, 4-diklorbenzoyl)-[5-(3-trifluormetylfenyl)furan-2-ylmetyl]amino}-5-fenyltiofen-2-karboksylsyremetylester (62 mg, 0,098 mmol) ble oppløst i THF (5 ml) og vann (2 ml). En oppløsning av litiumhydroksid (13 mg, 3 ekv. i 2 ml vann) ble tilsatt dråpevis. Etter de første få dråpene kom det til syne en rosa farge som forsvant igjen. Blandingen ble omrørt i 5 timer og surgjort med 1 N HCl-oppløsning. Produktet ble ekstrahert over i etylacetat, det ble vasket med vann og tørket over magnesiumsulfat. Oppløsningsmidlet ble avdampet, og resten ble renset på silikagel (bundet eluat 2 g). Produktet ble eluert med en 20 ml gradient av heksan:EtOAc 9:1, 4:1, 7:3, 3:2, 1:1, 2:3 og EtOAc, hvorved man fikk det ønskede produkt i 76% utbytte (46 mg).<X>H NMR (CD3OD, 400 MHz): 7,90 (s, 1H), 7,83 (m, 1H), 7,55 (m, 2H), 7,40-7,20 (m, 8H), 7,10 (s, 1H),
6,82 (d, 1H), 6,42 (d, 1H), 5,60 (bd, 1H), 4,70 (bd, 1H), 3,86 (s, 3H) .
Eksempel 8
Fremstilling av 3-[( 4- klor- 2, 5- dimetylbenzensulfonyl)( 3- jod-benzyl) amino]- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 1, og 3-[( 3- benzofuran- 2- ylbenzyl)( 4- klor- 2, 5- dimetylbenzensulfonyl) amino]- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 2
TRINN I
Til en oppløsning av 3-(4-klor-2,5-dimetylbenzensulfonylamino) -5-f enyltiof en-2-karboksylsyremetylester (100 mg, 0,229 mmol) i vannfritt DMF (6 ml) ble 3-jodbenzylbromid (82 mg, 0,276 mmol) og cesiumkarbonat (88 mg, 0,276 mmol) tilsatt, og reaksjonsblandingen ble omrørt ved romtemperatur under N2-atmosfære i 12 timer. Reaksjonsblandingen ble fordelt mellom vann og eter. Eterlaget ble fraskilt, tørket (Na2S04) og konsentrert. Resten ble renset ved hjelp av silikagelkolonnekromatografi under anvendelse av etylacetat og heksan (1:3) som elueringsmiddel, hvorved man fikk 3-[(4-klor-2,5-dimetylbenzensulfonyl)(3-jodbenzyl)amino]-5-fenyltiofen-2-karboksylsyremetylester (130 mg, 87%) som en sirup.
TRINN II
3-[(4-klor-2,5-dimetylbenzensulfonyl)(3-jodbenzyl)amino]-5-fenyltiofen-2-karboksylsyremetylester (25 mg, 0,038 mmol) ble tatt opp i en blanding av THF:MeOH:H20 (3:2:1, 3 ml) og så tilsatt 1 N vandig oppløsning av LiOH.H20 (0,24 ml, 0,228 mmol). Reaksjonsblandingen ble omrørt ved romtemperatur i 12 timer. Oppløsnings-midler ble fjernet, og resten ble fordelt mellom vann og etylacetat. Vannlaget ble surgjort ved å anvende 10% KHS04-oppløsning. Det organiske laget ble fraskilt, tørket (Na2S04) og konsentrert. Resten ble renset ved hjelp av silikagelkolonnekromatografi under anvendelse av diklormetan og metanol (9:1), hvorved man fikk 3-[(4-klor-2,5-dimetylbenzensulfonyl)(3-jodbenzyl)amino]-5-fenyltiofen-2-karboksylsyre (22 mg, 88%) som et hvitt, fast stoff.<1>H NMR (CDC13, 400 MHz) 7,69 (m, 3H), 7,57 (m, 3H), 7,42 (m, 3H), 7,33 (d, 1H), 7,16 (s, 1H), 6,04 (dd, 1H), 4,90 (bs, 2H), 2,36 (s, 6H).
Forbindelse nr. 5 ble fremstilt på en lignende måte.
3-[(3-benzofuran-2-yl-benzyl)(4-klor-2,5-dimetylbenzen-sulf onyl ) amino] -5-f enyltiof en-2-karboksylsyre, forbindelse nr. 2.
TRINN I
Til en avgasset oppløsning av 3-[(4-klor-2,5-dimetyl-benzensulf onyl) (3-jodbenzyl)amino]-5-fenyltiofen-2-karboksylsyremetylester (110 mg, 0,169 mmol) og benzofuran-2-borsyre (55 mg, 0,185 mmol) i en blanding av DME (8 ml) og 2 M vandig Na2C03(4 ml) ble Pd(PPh3)4(9 mg) tilsatt, og reaksjonsblandingen ble omrørt ved refluksbetingelser i 2 timer under N2-atmosfære. Reaksjonsblandingen ble fortynnet med etylacetat og vann. Det organiske lag ble fraskilt, tørket (Na2S04) og konsentrert. 3-[ (3-benzofuran-2-ylbenzyl)(4-klor-2,5-dimetylbenzensulfonyl)amino]-5-fenyltiofen-2-karboksylsyremetylester (107 mg, 100%) ble isolert som en tykk sirup og brukt i den neste reaksjonen uten noen videre rensing.
TRINN II
3-[(3-benzofuran-2-yl-benzyl)(4-klor-2,5-dimetylbenzen-sulf onyl ) amino] -5-f enyltiof en-2-karboksylsyremetylester (20 mg, 0,031 mmol) ble tatt opp i en blanding av THF:MeOH:H20 (3:2:1,
3 ml) og så tilsatt 1 N vandig oppløsning av LiOH.H20 (0,20 ml, 0,186 mmol). Reaksjonsblandingen ble omrørt ved romtemperatur i 12 timer. Oppløsningsmidler ble fjernet, og resten ble fordelt mellom vann og etylacetat. Vannlaget ble surgjort ved å anvende 10% KHSO4-oppløsning. Det organiske lag ble fraskilt, tørket (NazSCU) og konsentrert. Resten ble renset ved hjelp av silikagelkolonnekromatografi under anvendelse av diklormetan og metanol (9:1), hvorved man fikk 3-[(3-benzofuran-2-yl-benzyl)(4-klor-2,5-dimetylbenzensulfonyl)amino]-5-fenyltiofen-2-karboksylsyre (14 mg, 70%) som et hvitt, fast stoff.<X>H NMR (DMSO, 400 MHz): 6 7,93 (s, 1H), 7,84 (s, 1H), 7,74 (bd, 1H), 7,65-7,22 (m, 14H), 4,95 (s, 2H), 2,33, 2,23 (2s, 6H). Eksempel 9 3-[( 4- klorbenzoyl) isopropylamino]- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 210
TRINN I
Metode A
En DMF-oppløsning (15 ml) av 3-amino-5-fenyltiofen-2-karboksylsyremetylester (500 mg, 21,5 mmol) ble avkjølt til 0 °C, og så ble isopropyljodid (2,57 ml) og NaH (60%, 775 mg, 32,3 mmol) tilsatt under N2-atmosfære. Isbadet ble fjernet, og reaksjonsblandingen ble omrørt ved romtemperatur i 1 time. Blandingen ble fordelt mellom eter og vann, eterlaget ble fraskilt, tørket (Na2S04) og konsentrert. Resten ble renset ved hjelp av silikagelkolonnekromatografi under anvendelse av etylacetat og heksan (5:95) som elueringsmiddel, hvorved man fikk 3-isopropylamino-5-fenyltiofen-2-karboksylsyremetylester (189 mg, 32%) som et fast stoff.<1>H NMR (CDCI3, 400 MHz): 7,62 (d, 2H) , 7,40 (m, 3H) , 6,91 (s, 1H) , 3,84
(s, 3H), 1,35 (d, 6H).
Til en omrørt oppløsning av 3-amino-5-fenyltiofen-2-karboksylsyremetylester (1,82 g, 7,8 mmol) i 1,2-dikloretan (40 ml) ble det sekvensvis tilsatt 2-metoksypropen (3,0 ml, 31,2 mmol), AcOH (1,8 ml, 31,2 mmol) og NaBH(OAc)3(3,31 g, 15,6 mmol) og omrørt i 2 timer. Det ble så fortynnet med EtOAc og H20. Vann-oppløsningen ble regulert til pH = 7 ved å tilsette NaHC03. Vannfasen ble ekstrahert med EtOAc, den kombinerte ekstrakt ble vasket med saltoppløsning og tørket på MgS04og filtrert. Rensing av bundet eluat med heksan til 5% EtOAc-heksan ga 3-amino-5-fenyltiofen-2-karboksylsyremetylester (2,07 g, 96% utbytte).
Mellomproduktforbindelsene 3-sykloheksylamino-5-fenyl-tiof en-2-karboksylsyremetylester, 3-(l-metylpiperidin-4-ylamino)-5-fenyltiofen-2-karboksylsyremetylester og 3-(l-metylpiperidin-4-ylamino)-5-fenyltiofen-2-karboksylsyremetylester ble fremstilt på en lignende måte som beskrevet, og brukt som mellomprodukter ved syntesen av forbindelse nr. 543, forbindelse nr. 553 og forbindelse nr. 573.
TRINN II
Til en suspensjon av 3-isopropylamino-5-fenyltiofen-2-karboksylsyremetylester (1,2 g, 4,364 mmol) i en blanding av H2O (22 ml) og dioksan (35 ml) ble 1 N vandig oppløsning av NaOH
(13 ml, 13,00 mmol) tilsatt. Reaksjonsblandingen ble omrørt ved 100 °C i 3 timer. Reaksjonsblandingen ble brukt i den neste reaksjonen uten noen ytterligere rensing.
Til denne reaksjonsblandingen av 3-amino-5-fenyltiofen-2-karboksylsyre-natriumsalt (23 ml, 1,41 mmol) ble 4-klorbenzoylklorid (0,269 ml, 2,11 mmol) tilsatt ved 0 °C. pH i oppløsningen ble holdt ved 9 ved å tilsette 1 N NaOH-oppløsning, og så ble det omrørt ved romtemperatur i 5 timer. Reaksjonsblandingen ble fortynnet med etylacetat og vann. Vannlaget ble surgjort ved å tilsette 1 N HCl-oppløsning. Det organiske lag ble fraskilt, tørket (Na2SC>4) og konsentrert. Råproduktet ble renset ved rekrystallisasjon fra etylacetat, hvorved man fikk den rene 3-[(4-klorbenzoyl)-isopropylamino]-5-fenyltiofen-2-karboksylsyre (45 mg) som et hvitt, fast stoff.<X>H NMR (DMSO-de, 400 MHz): 7,58 (d, 2H), 7,38-7,26 (m, 6H) , 7,13 (d, 1H), 4,77 (m, 1H), 1,25 (d, 3H), 1,02 (d, 3H) . ESI"
(M-H): 398.
På lignende måte ble de følgende forbindelser laget: forbindelse nr. 218, forbindelse nr. 219, forbindelse nr. 226, forbindelse nr. 234, forbindelse nr. 243, forbindelse nr. 246, forbindelse nr. 250, forbindelse nr. 262, forbindelse nr. 324, forbindelse nr. 326, forbindelse nr. 331.
Eksempel 10
3- [ ( 2, 4- diklorbenzoyl) isopropylamino]- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 149
TRINN I
3-( 2, 4- diklorbenzoylamino)- 5- fenyltiofen- 2- karboksylsyremetylester
Til en iskald oppløsning av 3-amino-5-fenyltiofen-2-karboksylsyremetylester 1 (5 g, 21,5 mmol) og trietylamin (4,56 g, 45,0 mmol) i diklormetan (100 ml) ble det tilsatt 2,4-diklorbenzoylklorid (3,90 g, 19,4 mmol). Reaksjonsblandingen ble omrørt i 30 minutter ved 0 °C og 16 timer ved romtemperatur. Så ble reaksjonsblandingen fordelt mellom 25 ml H20, 50 ml mettet NaHC03og 50 ml CH2CI2. Det organiske lag ble fraskilt, og vannfasen ble vasket to ganger med CH2CI2(2 x 50 ml). Det kombinerte diklor-metanlag ble tørket (MgS04) , konsentrert og resten ble renset ved rekrystallisasjon i CH2C12, hvorved man fikk 5,832 g (74%) som et hvitt, fast stoff av 3-(2,4-diklorbenzoylamino)-5-fenyltiofen-2-karboksylsyremetylester.<X>H NMR (CDCI3, 400 MHz): 8,30 ppm (s, 1H, Haro)/7, 74-7, 66 ppm (m, 3H, Haro) , 7,51 ppm (d, 1H, Haro) , 7,46-7,34 ppm (m, 4H, Haro), 3,91 ppm (s, 3H) .
TRINN II
3-[( 2, 4- diklorbenzoyl) isopropylamino]- 5- fenyltiofen- 2- karboksylsyremetylester
Natriumhydrid (60% dispersjon i olje, 190 mg, 5,2 mmol) ble tilsatt til en iskald oppløsning av 3-(2,4-diklorbenzoylamino)-5-fenyltiofen-2-karboksylsyremetylester (2) (1,5 g, 3,69 mmol) i 350 ml N,N-dimetylformamid i en N2-atmosfære. Etter 5 minutter ble 2- jodpropan (941 mg, 5,54 mmol) tilsatt til oppløsningen, og så ble reaksjonsblandingen omrørt i 30 minutter ved 0 °C og 64 timer ved romtemperatur. Blandingen ble fordelt mellom eter (200 ml) og vann (350 ml), og det organiske lag ble fraskilt. Vannfasen ble vasket to ganger med eter (2 x 70 ml), og det kombinerte eterlag ble tørket (MgS04) , konsentrert og resten ble renset ved hjelp av hurtigkromatografi (10% EtOAc/heksan), hvorved man fikk 908 mg (55%) 3-[(2,4-diklorbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyremetylester.<X>H NMR (CDC13, 400 MHz): Rotamerer 95/05: 7,54 ppm (dd, 2H, Haro) , 7, 49-7,35 ppm (m, 3H, Haro) , 7,29-7,25 ppm (m, 2H, Haro), 7,15 ppm (d, 1H, Haro) , 7,05 ppm (d, 1H, Haro) , 5,09 ppm (heks, 1H, N-CH(CH3), hovedrotamer), 3,99 ppm (heks, N-CH(CH3), birotamer), 3,89 ppm (s, 3H), 1,40 ppm (d, 3H, N-CH(CH3), hovedrotamer), 1,28 ppm (d, N-CH(CH3), birotamer), 1,09 ppm (d, 3H, N-CH(CH3), hovedrotamer), 1,01 ppm (d, N-CH(CH3), birotamer).
TRINN III
3- [( 2, 4- diklorbenzoyl) isopropylamino]- 5- fenyltiofen- 2- karboksylsyre
3-[(2,4-diklorbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyremetylester (3) (345 mg, 0,77 mmol) ble oppløst i en blanding av THF-MeOH-H20 (3:2:1) (30 ml), og 4,6 ml LiOH, IN, ble tilsatt til den. Etter 120 minutters omrøring ved romtemperatur ble oppløsningsmiddel fjernet, og så ble det fordelt mellom 25 ml H20, 4 ml KHSO4, 5%, og 25 ml EtOAc. Det organiske lag ble fraskilt, og vannfasen ble vasket to ganger med etylacetat (2 x 10 ml). Det kombinerte etylacetatlag ble tørket (MgS04) , konsentrert, og resten ble renset ved hjelp av preparativ kromatografi (10% MeOH/CH2Cl2) ,
hvorved man fikk 175 mg (53%) som et hvitt, fast stoff av 3-[(2,4-diklorbenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre.<1>H NMR (DMSO, 400 MHz): Rotamer 95/05, 7, 82 ppm (m, Haro, birotamer), 7,69 ppm (d, 2H, Haro) , 7,61 ppm (d, 1H, Haro) , 7,51-7,37 ppm (m, 4H, Haro)/ 7,35-7,28 ppm (m, 2H, Haro) , 4,89 ppm (heks, 1H, N-CH(CH3), hovedrotamer), 3,84 ppm (heks, N-CH(CH3), birotamer), 1,36 ppm (d, 3H, N-CH(CH3), hovedrotamer), 1,25 ppm (d, N-CH(CH3), birotamer),
1,03 ppm (d, 3H, N-CH(CH3), hovedrotamer), 0,93 ppm (d, N-CH(CH3), birotamer).
De følgende forbindelser ble fremstilt på en lignende måte: forbindelse nr. 201, forbindelse nr. 204, forbindelse nr. 233, forbindelse nr. 244, forbindelse nr. 261, forbindelse nr. 264, forbindelse nr. 299. Eksempel 11 3-[( 2, 4- diklorbenzoyl) fenylamino]- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 208
TRINN I
5- fenyl- 3- fenylaminotiofen- 2- karboksylsyrernetylester
Til en oppløsning av 3-amino-5-fenyltiofen-2-karboksylsyremetylester (1 g, 4,29 mmol) i diklormetan (50 ml) ble det tilsatt fenylborsyre (1,05 g, 8,6 mmol), pyridin (680 mg, 8,6 mmol) og kobber(II)acetat (1,18 g, 6,5 mmol). Reaksjonsblandingen ble omrørt i 16 timer ved romtemperatur. Så ble reaksjonsblandingen filtrert gjennom celite, konsentrert og resten ble renset ved hjelp av hurtigkromatografi (9:1 heksan/EtOAc), hvorved man fikk 435 mg (33%) 5-fenyl-3-fenylaminotiofen-2-karboksylsyremetylester.<1>H NMR (CDC13, 400 MHz): 7,38 ppm (dd, 2H, Haro) , 7,35-7,26 ppm (m, 5H, Haro), 7,19 ppm (s, 1H, Haro), 7,15 ppm (dd, 2H, Haro) , 7,02 ppm (ddt, 1H, Haro) , 3,82 ppm (s, 3H) .
TRINN II
3- [ ( 2, 4- diklorbenzoyl) fenylamino]- 5- fenyltiofen- 2- karboksylsyremetylester
Natriumhydrid (60% dispersjon i olje, 80 mg, 1,5 mmol) ble tilsatt til en iskald oppløsning av 5-fenyl-3-fenylaminotiofen-2-karboksylsyremetylester (2) (230 mg, 0,74 mmol) i 20 ml N,N-dimetylformamid i en N2-atmosfære. Etter 5 minutter ble 2,4-diklorbenzoylklorid (310 mg, 1,48 mmol) tilsatt til oppløsningen, og så ble reaksjonsblandingen omrørt i 30 minutter ved 0 °C og 16 timer ved romtemperatur. Blandingen ble fordelt mellom eter (20 ml) og vann (20 ml), og det organiske lag ble fraskilt. Vannfasen ble vasket to ganger med eter (2 x 10 ml), og det kombinerte eterlag ble tørket (MgSC^) , konsentrert og resten ble renset ved hjelp av preparativ kromatografi (30% EtOAc/heksan), hvorved man fikk 58 mg (16%) 3-[(2,4-diklorbenzoyl)fenylamino]-5-fenyltiofen-2-karboksylsyremetylester.<X>H NMR (CDC13, 400 MHz): 7,65-7,10 ppm (m, 14H, Haro), 3,77 ppm (s, 3H) .
TRINN III
3-[( 2, 4- diklorbenzoyl) fenylamino]- 5- fenyltiofen- 2- karboksylsyre
3-[(2,4-diklorbenzoyl)fenylamino]-5-fenyltiofen-2-karboksylsyremetylester (55 mg, 0,11 mmol) ble oppløst i en blanding av THF-MeOH-H20 (3:2:1) (15 ml), og så ble 0,66 ml LiOH, 1 N, tilsatt til den. Etter 60 minutters omrøring ved romtemperatur ble oppløsningsmidler fjernet, og så ble det fordelt mellom 15 ml H20, 4 ml KHS04, 5%, og 15 ml EtOAc. Det organiske lag ble fraskilt, og vannfasen ble vasket to ganger med etylacetat (2 x 10 ml). Det kombinerte etylacetatlag ble tørket (MgS04) , konsentrert og resten ble renset ved hjelp av preparativ kromatografi (10% MeOH/CH2Cl2) , hvorved man fikk 32 mg (60%) 3-[(2,4-diklorbenzoyl)fenylamino]-5-fenyltiofen-2-karboksylsyre.<*>H NMR (DMSO, 400 MHz): Rotamer: 7,75 ppm (d, 1H, Haro), 7,68 ppm (2H, Haro) , 7,53 ppm (d, Haro, birotamer), 7,51-7,23 ppm (m, 11H, Har0, birotamer), 7,17 ppm (Haro, birotamer).
Forbindelse nr. 525 ble fremstilt på en lignende måte.
Eksempel 12
3-[ tert.- butyl-( 2, 4- diklorbenzoyl) amino]- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 327
TRINN I
3- tert.- butylamino- 5- fenyltiofen- 2- karboksylsyremetylester
Konsentrert svovelsyre (10 dråper) ble tilsatt til en oppløsning av 3-amino-5-fenyltiofen-2-karboksylsyremetylester (500 mg, 2,15 mmol) i 20 ml dioksan/kloroform (2:3) i et lukket rør. Etter avkjøling av oppløsningen ved -78 °C ble det tilsatt 20 ml isobuten-gass. Røret ble lukket, og så ble reaksjonsblandingen omrørt i 6 dager ved 60 °C. Oppløsningsmidlet ble fjernet, og så ble det fordelt mellom 15 ml mettet Na2C03-oppløsning og 15 ml EtOAc. Det organiske lag ble fraskilt, vannfasen ble vasket to ganger med etylacetat, og det kombinerte etylacetatlag ble tørket (MgS04) , konsentrert og resten ble renset ved hjelp av hurtigkromatografi (5% EtOAc/heksan), hvorved man fikk 385 mg (62%) 3-tert.-butylamino-5-fenyltiofen-2-karboksylsyremetylester.<1>H NMR (CDC13, 400 MHz): 7,65 ppm (d, 2H, Haro) , 7, 44-7,38 ppm (m, 3H, Haro), 7,07 ppm (s, 1H, Haro) , 3,86 ppm (s, 3H) , 1,48 ppm (s, 9H) .
TRINN II
3-[ tert.- butyl-( 2, 4- diklorbenzoyl) amino]- 5- fenyltiofen- 2- karboksyl-syremetvlester
Til en oppløsning av 3-tert.-butylamino-5-fenyltiofen-2-karboksylsyremetylester (100 mg, 0,35 mmol) i dikloretan (10 ml) i en N2-atmosfære ble det tilsatt 2,4-diklorbenzoylklorid (79 mg, 0,38 mmol). Reaksjonsblandingen ble omrørt i 16 timer ved refluks. Så ble oppløsningsmidlene fjernet, og resten ble renset ved hjelp av hurtigkromatografi (9:1 heksan/EtOAc), hvorved man fikk 112 mg (69%) 3-[tert.-butyl-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyremetylester.<X>H NMR (CDC13, 400 MHz): 7,50 ppm (m, 2H, Haro), 7, 44-7, 34 ppm (m, 3H, Haro) , 7,27 ppm (s, 1H, Haro) , 7,18 ppm (dl, 1H, Haro), 7,14 ppm (d, 1H, Haro) , 7,00 ppm (dd, 1H, Haro) , 3,93 ppm (s, 3H), 1,56 ppm (s, 9H).
TRINN III
3-[ tert.- butyl-( 2, 4- diklorbenzoyl) amino]- 5- fenyltiofen- 2- karboksylsyre
3-[tert.-butyl-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyremetylester (112 mg, 0,24 mmol) ble oppløst i en blanding av THF-MeOH-H20 (3:2:1) (15 ml), og så ble 1,5 ml LiOH, 1 N, tilsatt til den. Etter 3 timers omrøring ved romtemperatur ble oppløsningsmiddel fjernet, og så ble det fordelt mellom 15 ml H20, 4 ml KHS04, 5%, og 15 ml EtOAc. Det organiske lag ble fraskilt, og vannfasen ble vasket to ganger med etylacetat (2 x 10 ml). Det kombinerte etylacetatlag ble tørket (MgS04) , konsentrert og resten ble renset ved hjelp av preparativ kromatografi (10% MeOH/CH2Cl2) , hvorved man fikk 32 mg (29%) 3-[tert.-butyl-(2,4-diklorbenzoyl)-amino]-5-fenyltiofen-2-karboksylsyre.<X>H NMR (DMSO, 400 MHz): 7,62 ppm (d, 2H, Haro), 7, 44-7, 34 ppm (m, 4H, Haro) , 7,32-7,12 ppm (m, 3H, Haro) , 2, 48 ppm (s, 9H) .
Eksempel 13
3-[ syklopropyl-( 2, 4- diklorbenzoyl) amino]- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 333
TRINN I
3- syklopropylamino- 5- fenyltiofen- 2- karboksylsyremetylester
Til en oppløsning av 3-brom-5-fenyltiofen-2-karboksylsyremetylester (250 mg, 0,89 mmol) i toluen (25 ml) ble det tilsatt syklopropylamin (57 mg, 1,0 mmol), cesiumkarbonat (382 mg, 1,2 mmol), BINAP (50 mg, 0,08 mmol) og tris-(dibenzylidenaceton)-dipalladium (0) (38 mg, 0,04 mmol). Reaksjonsblandingen ble omrørt i 16 timer ved 110 °C i et lukket rør. Blandingen ble fordelt mellom toluen (20 ml) og vann (20 ml), og det organiske lag ble fraskilt. Vannfasen ble vasket to ganger med toluen (2 x 10 ml), og det kombinerte toluenlag ble tørket (MgS04) , konsentrert og resten ble renset ved hjelp av preparativ kromatografi (10% EtOAc/heksan), hvorved man fikk 52 mg (22%) 3-syklopropylamino-5-fenyltiofen-2-karboksylsyremetylester.<X>H NMR (CDC13, 400 MHz): 7,67-7,62 ppm (m, 2H, Haro), 7, 43-7, 32 ppm (m, 3H, Haro) , 7,16 ppm (s, 1H, Haro) , 3,82 ppm (s, 3H), 2,65 ppm (m, 1H), 0,62 ppm (m, 2H), 0,35 ppm (m, 2H).
TRINN II
3-[ syklopropyl-( 2, 4- diklorbenzoyl) amino]- 5- fenyltiofen- 2- karboksylsyremetylester
Til en oppløsning av 3-syklopropylamino-5-fenyltiofen-2-karboksylsyremetylester (52 mg, 0,19 mmol) i dikloretan (10 ml) i en N2-atmosfære ble det tilsatt 2,4-diklorbenzoylklorid (45 mg, 0,21 mmol). Reaksjonsblandingen ble omrørt i 16 timer ved refluks. Så ble oppløsningsmidlet fjernet, og resten ble renset ved hjelp av hurtigkromatografi (8:2 heksan/EtOAc), hvorved man fikk 85 mg (99%) 3-[syklopropyl-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyremetylester.<X>H NMR (CDC13, 400 MHz): 7,64 ppm (d, 2H, Haro) , 7,47 ppm (m, 2H, Haro), 7, 44-7,33 ppm (m, 3H, Haro) , 7,21-7,12 ppm (m, 2H, Haro), 3,89 ppm (s, 3H) , 3,33 ppm (m, birotamer), 3,12 ppm (m, 1H,
hovedrotamer), 1,01-0,49 ppm (m, 4H).
TRINN III
3- [ syklopropyl-( 2, 4- diklorbenzoyl) amino]- 5- fenyltiofen- 2- karboksylsyre
3-[syklopropyl-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyremetylester (85 mg, 0,19 mmol) ble oppløst i en blanding av THF-MeOH-H20 (3:2:1) (10 ml), og så ble 1,2 ml LiOH, 1 N, tilsatt til den. Etter 60 minutters omrøring ved romtemperatur ble oppløsningsmiddel fjernet, og så ble det fordelt mellom 15 ml H20, 4 ml KHSO4, 5%, og 15 ml EtOAc. Det organiske lag ble fraskilt, og vannfasen ble vasket to ganger med etylacetat (2 x 10 ml). Det kombinerte etylacetatlag ble tørket (MgS04) , konsentrert og resten ble renset ved hjelp av preparativ kromatografi (10% Me0H/CH2Cl2) , hvorved man fikk 22 mg (27%) 3-[syklopropyl-(2,4-diklorbenzoyl)-amino]-5-fenyltiofen-2-karboksylsyre.<1>H NMR (DMSO, 400 MHz): rotamer: 7,75 ppm (m, 2H, Haro) / 7,68 ppm (m, Haro, birotamer), 7,62-7,55 ppm (m, 2H, Haro) t 7,52 ppm (m, Haro, birotamer), 7, 48-7, 27 ppm (m, 5H, Haro), 3,14 ppm (m, birotamer), 3,04 ppm (m, 1H, hovedrotamer), 0,87-0,42 ppm (m, 4H).
De følgende forbindelser ble fremstilt på en lignende måte:
forbindelse nr. 403, forbindelse nr. 404.
Eksempel 14
3-[( 2, 4- diklorbenzoyl) piperidin- 4- ylmetylamino]- 5- fenyltiofen- 2-karboksylsyre, forbindelse nr. 519
TRINN I
En suspensjon av 3-amino-5-fenyltiofen-2-karboksylsyremetylester (0,70 g, 3 mmol) og 4-formyl-N-Cbz-piperidin (0,74 g, 3 mmol) i THF (1,2 ml) ble behandlet med dibutyltinndiklorid (46 mg, 0,15 mol), etterfulgt av fenylsilan (0,41 ml, 3,3 mmol). Blandingen ble omrørt i 2 dager ved romtemperatur. Oppløsningsmidlet ble så avdampet, og resten ble renset ved hjelp av silikagelkolonnekromatografi under anvendelse av CH2CI2:heksaner:EtOAc som elueringsmiddel, hvorved man fikk 4-[(2-metoksykarbonyl-5-fenyltiofen-3-ylamino)metyl]piperidin-1-karboksylsyrebenzylester (0,6906 g, 50% utbytte).
TRINN II
4-[ (2-metoksykarbonyl-5-fenyltiofen-3-ylamino)metyl]-piperidin-l-karboksylsyrebenzylester (133 mg, 0,28 mmol) ble oppløst i 1,2-dikloretan (2,8 ml) og behandlet med 2,4-diklorbenzoylklorid (60 ul, 0,43 mmol). Oppløsningen ble varmet opp ved refluks i 1 dag. Oppløsningsmidlet ble så avdampet og resten renset ved hjelp av silikagelkolonnekromatografi under anvendelse av
heksaner:EtOAc som elueringsmiddel, hvorved man fikk 4-{[(2,4-diklorbenzoyl)(2-metoksykarbonyl-5-fenyltiofen-3-yl)amino]metyl}-piperidin-l-karboksylsyrebenzylester (0,156 g, 85% utbytte).
TRINN III
4-{[(2,4-diklorbenzoyl)(2-metoksykarbonyl-5-fenyltiofen-3-yl)amino]metyl}piperidin-l-karboksylsyrebenzylester (150 mg, 0,24 mmol) ble oppløst i en blanding av THF:MeOH:H20 (3:2:1, 2,4 ml) og behandlet med LiOH.H20 (29,6 mg, 0,7 mmol). Oppløsningen ble varmet opp ved 55 °C i 2 timer. Oppløsningsmidlene ble fjernet, og resten ble surgjort ved å anvende HC1. Produktet ble ekstrahert med EtOAc, og de organiske lagene ble vasket med saltoppløsning og tørket. Resten ble renset ved hjelp av silikagelkolonnekromatografi under anvendelse av EtOAc:MeOH:AcOH som elueringsmiddel, hvorved man fikk 4-{[(2-karboksy-5-fenyltiofen-3-yl)(2,4-diklorbenzoyl)amino]metyl}-piperidin-l-karboksylsyrebenzylester (124 mg, 85% utbytte).
TRINN IV
4-{[(2-karboksy-5-fenyltiofen-3-yl)(2,4-diklorbenzoyl)-amino]metyl}piperidin-l-karboksylsyrebenzylester (124 mg, 0,2 mmol) ble oppløst i MeOH (2 ml) og behandlet med 10% Pd/C (200 mg) under H2-glasskolbe. Reaksjonsblandingen ble omrørt ved romtemperatur i 18 timer, og blandingen ble filtrert på celite. Oppløsningen ble inndampet til en rest som ble renset ved hjelp av reversfase-HPLC, hvorved man fikk 3-[(2,4-diklorbenzoyl)piperidin-4-ylmetylamino]-5-fenyltiofen-2-karboksylsyre (17,3 mg, 18% utbytte).<X>H NMR (CD30D, 300 MHz): 7,55 (d, 1H), 7,50 (m, 2H), 7,27-7,39 (m, 4H), 7,25 (s, 1H), 7,18 (dd, 1H), 4,12 (m, 1H), 3,75 (m, 1H), 3,43 (m, 2H), 2,96 (q, 2H), 2,65 (d, 2H), 2,05 (m, 1H), 1,62 (m, 2H).
De følgende forbindelser ble fremstilt på en lignende måte: forbindelse nr. 503, forbindelse nr. 509, forbindelse nr. 519, forbindelse nr. 529, forbindelse nr. 537, forbindelse nr. 538, forbindelse nr. 516, forbindelse nr. 522, forbindelse nr. 535. Eksempel 15 3-[ isopropyl-( 3- metylsyklopent- 3- en- karbonyl) amino]- 5- fenyltiofen-2- karboksylsyre, forbindelse nr. 405
TRINN I
Til en kald (-78 °C) omrørt oppløsning av LDA (generert fra DIPA (1,42 ml, 10,14 mmol), BuLi (5,85 ml, 9,36 mmol) i THF ved -78 °C i 20 min) i THF (31 ml) ble det tilsatt en oppløsning av pent-4-en-syreetylester (1,0 g, 7,8 mmol, 1,2 ekv.) i THF (9,0 ml). Etter å være blitt omrørt i 1 time ble rent 3-brom-2-metylpropen (2,03 g, 15,0 mmol, 1,51 ml) tilsatt, og det ble sakte varmet opp til romtemperatur over natten. Reaksjonsblandingen ble så tilsatt mettet NH4Cl-oppløsning, ekstrahert med eter, vasket med salt-oppløsning og tørket. Avdamping av oppløsningsmidlet ga 2-allyl-4-metyl-pent-4-en-syreetylesteren (1,45 g, 100%) som en olje som ble brukt i det neste trinn uten rensing.<X>H NMR (400 MHz, CDC13) 5,78-5,71 (m, 1H), 5,05 (d, J = 18,6 Hz, 1H), 5,02 (d, J = 9,4 Hz, 1H), 4,76 (brs, 1H), 4,70 (s, 1H), 4,11 (dq, J = 7,2, 1,0 Hz, 2H) , 2,66-2,13 (m, 5H), 1,72 (s, 3H), 1,23 (dt, J = 7,2, 1,3 Hz, 3H).
TRINN II
Til en omrørt oppløsning av 2-allyl-4-metyl-pent-4-en-syreetylesteren (364 mg, 2,0 mmol) i CH2C12(100 ml, 0,02 M oppløsning) under koking med tilbakeløpskjøling ble det dråpevis tilsatt en oppløsning av trisykloheksylfosfin-(1,3-bis-(2,4,6- trimetylfenyl)-4,5-dihydroimidazol-2-yliden)(benzyliden)rutenium-(IV)dikloridet (85 mg, 0,1 mmol) i CH2C12(3,0 ml). Etter 50 minutter ble reaksjonsblandingen avkjølt til romtemperatur, konsentrert og renset på silikagel, og eluering under anvendelse av EtOAc/heksan (1:20) som elueringsmiddel ga 3-metylsyklopent-3-en-karboksylsyreetylesteren (286 mg, 93% utbytte) som en olje.<1>H NMR (CDC13, 400 MHz), 5,25 (brs, 1H) , 4,17 (q, J = 7,1 Hz, 2H) , 3,2-3,1 (m, 1H), 2, 65-2, 46 (m, 4H), 1,74 (s, 3H) , 1,28 (t, J = 7,1 Hz, 3H) .
TRINN III
En oppløsning av 3-metylsyklopent-3-en-karboksylsyreetyl-esteren (255 mg, 1,65 mmol) i MeOH (4,0 ml) og 10% vandig NaOH (3,3 ml, 8,25 mmol) ble varmet opp ved 50 °C i 16 timer, reaksjonsblandingen ble avkjølt til romtemperatur, oppløsningsmidlet ble avdampet, og det ble fortynnet med vann. Vannoppløsningen ble vasket med eter og surgjort med vandig 1 N HC1, og det ble ekstrahert med eter. Den eteriske oppløsning ble vasket med saltoppløs-ning og tørket. Avdamping av oppløsningsmidlet ga 3-metylsyklopent-3-en-karboksylsyren (200 mg, 97% utbytte) .<X>H NMR (CDCI3, 400 MHz) 5,27 (brs, 1H), 3,26-3,17 (m, 1H), 2,7-2,55 (m, 4H), 1,74 (s, 3H).
TRINN IV
Sammenkoblingen av 3-isopropylamino-5-fenyltiofen-2-karboksylsyremetylesteren (82 mg, 0,3 mmol) og 3-metylsyklopent-3-en-karboksylsyren (45 mg, 0,357 mmol) ved å anvende PPh3(95,4 mg, 0,363 mmol) og NCS (48,5 mg, 0,363 mmol) ga 3-[isopropyl-(3-metylsyklopent-3-en-karbonyl)amino]-5-fenyltiofen-2-karboksylsyre-metylesteren (70 mg, 61% utbytte).<X>H NMR (CDC13, 400 MHz 1:1 blanding av rotamerer), 7,68-7,64 (m, 4H), 7,5-7,4 (m, 6H), 7,1 (s, 1H), 7,09 (s, 1H), 5,2 (s, 1H), 5,1 (s, 1H), 5,06-4,98 (m, 2H), 3,88 (s, 3H), 3,87 (s, 3H), 3,08-3,0 (m, 2H), 2,85-2,76 (m, 2H), 2,5-2,42 (m, 2H), 2,3-2,1 (m, 4H), 1,69 (s, 3H) , 1,64 (s, 3H), 1,24 (d, J = 6,7 Hz, 3H), 1,23 (d, J = 6,7 Hz, 3H), 1,01 (d, J = 6,9 Hz, 3H), 1,007 (d, J 6,8 Hz, 3H).
Forsåpning av 3-[isopropyl-(3-metylsyklopent-3-en-karbonyl)amino]-5-fenyltiofen-2-karboksylsyremetylester (50 mg, 0,13 mmol) under anvendelse av LiOH.H20 (22 mg) som tidligere beskrevet, ga 3-[isopropyl-(3-metylsyklopent-3-en-karbonyl)amino]-5-fenyltiofen-2-karboksylsyren (30 mg, 62,5% utbytte) som et fast stoff.<*>H NMR (CD3OD, 400 MHz 1:1 blanding av rotamerer) 7,73-7,70 (m, 4H), 7,47-7,35 (m, 6H), 7,29 (s, 1H), 7,27 (s, 1H), 5,16 (s, 1H) , 5,08 (s, 1H), 4,9-4,8 (m, 2H), 3,15-3,05 (m, 2H), 2,76-2,65 (m, 2H), 2,42-2,12 (m, 6H), 1,65 (s, 3H), 1,61 (s, 3H), 1,25 (d, J = 6,6 Hz, 3H), 1,24 (d, J = 6,6 Hz, 3H) , 1,03 (d, J = 6,9 Hz, 6H) .
Eksempel 16
5- tert.- butyl- 3-( 2, 4- dimetylbenzensulfonylamino) tiofen- 2- karboksylsyre, forbindelse nr. 315
TRINN I
En blanding av 3-amino-5-tert.-butyltiofen-2-karboksylsyremetylester (106,5 mg, 0,5 mmol) og 2,4-dimetylsulfonylklorid (156 mg, 0,75 mmol) i pyridin (1,5 ml) ble varmet opp ved 72 °C i 16 timer. Reaksjonsblandingen ble fortynnet med EtOAc, vasket med vandig 1 N HC1, saltoppløsning og tørket. Avdamping av oppløsnings-midlet og rensing av resten på silikagelbundet eluering under anvendelse av EtOAc (1:20 til 1:10) som elueringsmiddel, ga 5-tert.-butyl-3-(2,4-dimetylbenzensulfonylamino)tiofen-2-karboksyl-syremetylestern (188 mg, 99% utbytte).<*>H NMR (CDCI3, 400 MHz) 9,73 (s, 1H), 7,89 (d, J = 8,6 Hz, 1H), 7,04-7,08 (m, 2H), 7,03 (s, 1H), 3,82 (s, 3H), 2,62 (s, 3H), 2,33 (s, 3H), 1,28 (s, 9H).
TRINN II
Hydrolyse av 5-tert.-butyl-3-(2,4-dimetylbenzensulfonylamino) tiofen-2-karboksylsyremetylesteren (55 mg, 0,14 mmol) under anvendelse LiOH.H20 (22 mg) som tidligere beskrevet, ga 5-tert.-butyl-3-(2,4-dimetylbenzensulfonylamino)tiofen-2-karboksylsyre (36 mg, 70% utbytte) som et fast stoff.<*>H NMR (CD3OD, 400 MHz) 7,85 (d, J = 8,6 Hz, 1H), 7,14-7,10 (m, 2H), 7,0 (s, 1H), 2,56 (s, 3H), 2,31 (s, 3H), 1,27 (s, 9H) .
Eksempel 17
5- benzo[ b] tiofen- 2- yl- 3-( toluen- 2- sulfonylamino) tiofen- 2- karboksylsyre, forbindelse nr. 230
TRINN I
Suzuki-sammenkobling av 5-brom-3-(toluen-2-sulfonylamino)-tiofen-2-karboksylsyre-tert.-butylester (43 mg, 0,1 mmol) og benzotiofen-2-borsyre (53,4 mg, 0,3 mmol) ble utført ved å anvende Pd(PPh3)4og Na2C03(som beskrevet i eksempel 2), hvilket resulterte i 5-benzo[b]tiofen-2-yl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre-tert.-butylester (27 mg, 55% utbytte).<X>H NMR (CDC13, 400 MHz) 9,92 (s, 1H), 8,07 (d, J=7,8 Hz, 1H), 7,79-7,71 (m, 2H), 7,45-7,24 (m, 7H), 2,7 (s, 3H), 1,56 (s, 9H).
TRINN II
5-benzo [b]tiofen-2-yl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre-tert.-butylester ble hydrolysert til syren under anvendelse av TFA som beskrevet for eksempel 2, hvorved man fikk 5-benzo[b]tiofen-2-yl-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre (24 mg, 99% utbytte).<X>H NMR (DMSO-d6, 400 MHz) 10,19 (s, 1H) , 8,0 (d, J = 7,7 Hz, 1H), 7, 79-7,74 (m, 1H), 7,86 (s, 1H),
7,84-7,81 (m, 1H), 7,54 (t, J = 7,7 Hz, 1H), 7,53-7,36 (m, 4H), 7,32 (s, 1H), 2,58 (s, 3H).
Eksempel 18
5-( lH- pyrazol- 3- yl)- 3-( toluen- 2- sulfonylamino) tiofen- 2- karboksylsyre, forbindelse nr. 170
TRINN I
Til en omrørt oppløsning av 5-brom-3-(toluen-2-sulfonylamino) tiof en-2-karboksylsyre-tert . -butylester (43 mg, 0,1 mmol) i toluen (3,0 ml) ble det sekvensvis tilsatt en oppløsning av Pd(PPh3)4(12 mg, 0,01 mmol) i toluen (1,0 ml) og 3-trimetylstann-anylpyrazol-l-sulfonsyredimetylamid (fremstilt i henhold til J. Med. Chem. (1998), 41, s. 2019) (75 mg, 0,2 mmol, 2,0 ekv.), og det resulterende ble varmet opp over natten ved 80 °C. Det ble så avkjølt ved romtemperatur, oppløsningsmidlet ble avdampet, og råproduktet ble renset på preparativ TLC under anvendelse av EtOAc/heksan (1:5). 5-(l-dimetylsulfamoyl-lH-pyrazol-3-yl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre-tert.-butylester (35 mg, 66,5% utbytte) ble isolert.<X>H NMR (CDC13, 400 MHz) 9,93 (s, 1H), 8,11 (d, J = 0,7 Hz, 1H), 8,02 (dd, J = 6,7, 1,32 Hz, 1H), 7,84 (d, J = 0,7 Hz, 1H), 7,45 (dt, J = 7,5, 1,3 Hz, 1H) , 7,31 (t, J = 8,2 Hz, 2H), 7,26 (d, J = 1,0 Hz, 1H), 2,98 (s, 6H) , 2,7 (s, 3H), 1,55 (s, 9H).
TRINN II
En reaksjonsblanding av 5-(1-dimetylsulfamoyl-lH-pyrazol-3-yl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre-tert.-butylester (10 mg, 0,019 mmol) og 4 N HC1 (0,3 ml) oppløsning i dioksan i MeOH (0,3 ml) ble omrørt ved romtemperatur i 26 time-r. Reaksjonsblandingen ble så fortynnet med vann og ekstrahert med EtOAc, konsentrert og renset på preparativ TLC under anvendelse av MeOH/CH2Cl2/AcOH (5:95:1) som ga 5-(lH-pyrazol-3-yl)-3-(toluen-2-sulfonylamino)tiofen-2-karboksylsyre (4,5 mg, 65,2% utbytte).<1>H NMR (CD3OD, 400 MHz) 7,99 (d, J = 7,9 Hz, 1H), 7,81 (s, 1H), 7,43 (t, J = 7,5, 1,3 Hz, 1H), 7,42-7,26 (m, 2H), 7,19 (s, 1H), 2,69 (s, 3H) .
Eksempel 19
3- isopropyl-[( 4- metylsykloheksankarbonyl) amino]- 5- m- tolyltiofen- 2-karboksylsyre, forbindelse nr. 448
TRINN I
Trans-4-metylsykloheksankarbonylklorid ble fremstilt ved oppvarming til refluks av trans-4-metylsykloheksankarboksylsyre (5 g, 0,035 mmol) i tionylklorid (5,0 ml) i 2 timer, etterfulgt av rensing av det tilsvarende acylklorid under redusert trykk i et Kugelrohr-apparat under oppsamling av fraksjonen som destillerte ved 95 °C, ga 5,1 g av det ønskede materiale som ble brukt i det neste trinn uten ytterligere rensing. Dette acylklorid (1,5 ml, ca. 10 mmol) ble oppløst sammen med 5-brom-3-isopropylaminotiofen-2-karboksylsyremetylester (2 g, 7,12 mmol) i vannfritt dikloretan (2 ml) og varmet opp ved 80 °C (lukket ampulle) i 12 timer. Opp-løsningsmidlene ble avdampet, det resulterende råmateriale ble oppløst i metanol og fikk stå i 30 minutter ved romtemperatur, ble konsentrert og renset via hurtigkromatografi på silikagel under anvendelse av en 5% EtOAc, 95% heksaner-blanding av eluerings-midler, og på denne måte ble 600 mg (21%) 5-brom-3-[isopropyl-(4-metylsykloheksankarbonyl)amino]tiofen-2-karboksylsyrernetylester isolert. 1H NMR (CDC13, 300 MHz): 6,78 (s, 1H), 4,93 (m, 1H) , 3,69 (s, 3H), 2,00-1,20 (m, 8H), 1,14 (d, 3H), 0,93 (d, 3H), 0,81 (d, 3H), 0,72-0,70 (m, 2H).
TRINN II
Til en avgasset oppløsning av 5-brom-3-[isopropyl-(4-metylsykloheksankarbonyl)amino]tiofen-2-karboksylsyrernetylester (100 mg, 0,249 mmol) og 3-metylborsyre (38 mg, 0,279 mmol) i en blanding av DME (6 ml) og 2 M vandig Na2C03(3 ml) ble Pd(PPh3)4(12 mg) tilsatt, og reaksjonsblandingen ble omrørt ved refluksbetingelser i 12 timer under N2~atmosfære. Reaksjonsblandingen ble fortynnet med etylacetat og vann. Det organiske lag ble fraskilt, tørket (Na2S04) og konsentrert. Resten ble renset ved hjelp av kolonnekromatografi under anvendelse av etylacetat og heksan (1:3) som elueringsmiddel. 35 mg (34%) 3-isopropyl-[(4-metylsykloheksankarbonyl) amino]-5-m-tolyltiofen-2-karboksylsyremetylester ble isolert.<1>H NMR (CDC13, 400 MHz): 7,45 (bs, 2H), 7,36 (t, 1H), 7,23 (m, 1H), 7,01 (s, 1H), 4,99 (m, 1H), 3,83 (s, 3H), 2,41 (s, 3H), 2,01-0,61 (m, 20H) .
TRINN III
3-isopropyl-[(4-metylsykloheksankarbonyl)amino]-5-m-tolyltiof en-2-karboksylsyremetylester (30 mg, 0,073 mmol) ble tatt opp i en blanding av THF:MeOH:H20 (3:2:1, 3 ml) og så tilsatt 1 N vandig oppløsning av LiOH.H20 (0,44 ml, 0,438 mmol). Reaksjonsblandingen ble omrørt ved romtemperatur i 12 timer. Oppløsnings-midler ble fjernet, og resten ble fordelt mellom vann og etyl-
acetat. Vannlaget ble surgjort ved å anvende 10% KHS04-oppløsning. Det organiske laget ble fraskilt, tørket (Na2S04) og konsentrert. Resten ble renset ved hjelp av preparativ TLC under anvendelse av kloroform:metanol:eddiksyre (9:1:0,1), hvorved man fikk 3-isopropyl-[(4-metylsykloheksankarbonyl)amino]-5-m-tolyltiofen-2-karboksylsyre (15 mg, 52%) som et hvitt, fast stoff.<X>H NMR (CDC13, 400 MHz): (s, 2H), 7,38 (t, 1H), 7,24 (m, 1H), 7,08 (s, 1H), 5,01 (s, 1H), 2,42 (s, 3H), 2,10-0,62 (m, 20H) . ESI" (M-H) : 398.
Eksempel 2 0
( IR, 2S, 4R)- 3-[ isopropyl-( 2- hydroksy- 4- metylsykloheksankarbonyl)-amino]- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 402
(IR,2S,4R)-2-hydroksy-4-metylsykloheksankarboksylsyre-metylester ble fremstilt som beskrevet i J. Org. Chem. (1993), 58, s. 6255-6265.<X>H NMR (CDC13, 400 MHz): 4,26 ppm (s, 1H) , 4,19-4,13 ppm (m, 2H), 3,16 ppm (s, 1H), 2, 35-2,29 ppm (m, 1H) , 1,92-1,74 ppm (m, 5H), 1,31-1,24 ppm (m, 3H), 1,08-1,01 ppm (m, 1H), 0,96-0,92 ppm (m, 1H), 0,88 ppm (d, 3H).
TRINN I
Til en oppløsning av (IR,2S,4R)-2-hydroksy-4-metylsyklo-heksankarboksylsyremetylester (450 mg, 2,42 mmol) i metanol (12 ml) ble det tilsatt en 2,5 M oppløsning av natriumhydroksid (9,7 ml, 24,2 mmol). Reaksjonsblandingen ble omrørt i 4 timer ved 50 °C. Så ble oppløsningsmidlene fjernet, og resten ble fordelt mellom 20 ml H20 surgjort til pH 4 og 20 ml EtOAc. Det organiske laget ble fraskilt, og vannfasen ble vasket med etylacetat (2 x 20 ml). De kombinerte etylacetatlag ble tørket (Na2S04) og konsentrert, hvorved man fikk 313 mg (82%) (IR,2S,4R)-2-hydroksy-4-metylsykloheksan-karboksylsyre. aH NMR (CDC13, 400 MHz): 4,34 ppm (s, 1H), 2,43-2,39 ppm (m, 1H), 1,96-1,76 ppm (m, 5H), 1,14-1,08 ppm (m, 1H), 1,02-0,93 ppm (m, 1H), 0,90 ppm (d, 3H).
TRINN II
Til en oppløsning av (IR,2S,4R)-2-hydroksy-4-metylsyklo-heksankarboksylsyre (162 mg, 1,02 mmol) i diklormetan (5 ml) ble det tilsatt pyridin (495 ul, 6,12 mmol), etterfulgt av eddik-syreanhydrid (385 ul, 4,08 mmol). Reaksjonsblandingen ble omrørt i 20 timer ved romtemperatur. Så ble oppløsningsmidlene fjernet, og 10 ml 3 N HCl-oppløsning ble tilsatt. Denne blandingen ble omrørt i 30 minutter, og så ble en mettet oppløsning av NaHC03sakte tilsatt inntil pH = 9-10. Denne oppløsningen ble så ekstrahert med etylacetat (2x5 ml). Vannfasen ble så surgjort med en 10% HCl-opp-løsning og ekstrahert med etylacetat (3x5 ml). De etterfølgende etylacetatlag ble slått sammen, tørket (Na2S04) og konsentrert, hvorved man fikk 109 mg (53%) (IR,2S,4R)-2-acetoksy-4-metylsyklo-heksankarboksylsyre.<X>H NMR (CDC13, 400 MHz): 5,45 ppm (s, 1H), 2,46-2,42 ppm (m, 1H), 2,02 ppm (s, 3H), 2,02-1,96 ppm (m, 1H), 1,91-1,76 ppm (m, 3H), 1,70-1,61 ppm (m, 1H), 1,16-1,08 ppm (m, 1H), 0,99-0,88 ppm (m, 1H), 0,87 ppm (d, 3H).
TRINN III
Til en oppløsning av (IR,2S,4R)-2-acetoksy-4-metylsyklo-heksankarboksylsyre (109 mg, 0,54 mmol) i diklormetan (2,7 ml) ble det tilsatt oksalylklorid (545 ul, 1,09 mmol), etterfulgt av 1 dråpe dimetylformamid. Reaksjonsblandingen ble omrørt i 4 timer ved romtemperatur. Oppløsningsmidlene ble så fjernet, hvorved man fikk 119 mg (99%) (IR,2S,4R)-2-acetoksy-4-metylsykloheksankarboksylsyre-klorid.
TRINN IV
Til en oppløsning av 3-isopropylamino-5-fenyltiofen-2-karboksylsyremetylester (136 mg, 0,50 mmol) i 1,2-dikloretan (1,0 ml) ble det tilsatt (IR,2S,4R)-2-acetoksy-4-metylsykloheksan-karboksylsyreklorid (119 mg, 0,54 mmol) oppløst i 1,2-dikloretan (0,6 ml), etterfulgt av PPh3(136 mg, 0,52 mmol). Den resulterende oppløsning ble omrørt i 20 timer ved 90 °C og så avkjølt til romtemperatur. Den ble så fortynnet med etylacetat (10 ml) og en oppløsning av mettet NaHC03(10 ml) . Vannfasen ble separert og vasket med etylacetat (2 x 10 ml), og de kombinerte, organiske lag ble tørket (Na2S04) , filtrert og konsentrert. Resten ble renset ved hjelp av hurtigkromatografi (0% til 25% EtOAc/heksan), hvorved man fikk 110 mg (45%) (IR,2S,4R)-3-[isopropyl-(2-acetoksy-4-metylsykloheksankarbonyl)amino]-5-fenyltiofen-2-karboksylsyremetylester.<1>H NMR (CDC13, 400 MHz) 1,5:1,0 blanding av rotamerer 7,73-7,70 ppm (m, 2H, Haro), 7, 69-7, 63 ppm (m, 1H, Haro) , 7,51-7,41 ppm (m, 4H, Haro), 7,13 ppm (s, 0,6H, Haro, hovedrotamer), 5,79 ppm (s, 0,4H, birotamer), 5,21 ppm (s, 0,6H, hovedrotamer), 4,95-4,88 ppm (m, 1H), 3,88 ppm (s, 1,8H, hovedrotamer), 3,87 ppm (s, 1,2H, birotamer), 2,40-2,36 ppm (m, 0,6H, hovedrotamer), 2,11 ppm (s, 3H), 1,78-0,77 ppm (m, 16H).
TRINN V
(lR,2S,4R)-3- [isopropyl-(2-acetoksy-4-metylsykloheksankarbonyl )amino]-5-fenyltiofen-2-karboksylsyremetylester (36 mg, 0,17 mmol) ble oppløst i en blanding av dioksan:H20 (4:1) (700 ul), og 470 ul LiOH, 1 N, ble tilsatt til den. Etter 3 timer ved 50 °C ble reaksjonsblandingen avkjølt til romtemperatur, og oppløsnings-midlene ble fjernet. Resten ble så fordelt mellom 10 ml H20 surgjort til pH 4 og 10 ml EtOAc. Det organiske lag ble fraskilt, og vannfasen ble vasket med etylacetat (2 x 10 ml). De kombinerte etylacetatlag ble tørket (Na2S04) , konsentrert og resten ble renset
ved hjelp av preparativ kromatografi, hvorved man fikk 9 mg (29%)
(IR,2S,4R)-3-[isopropyl-(2-hydroksy-4-metylsykloheksankarbonyl)-amino]-5-fenyltiofen-2-karboksylsyre.<1>R NMR (CDC13, 400 MHz) : 3:2 blanding av rotamerer 7,76-7,73 ppm (m, 2H, Haro) / 7,50-7,38 ppm (m, 3H, Haro), 7,36 ppm (s, 1H, Haro) , 4, 93-4, 87 ppm (m, 1H) , 4,25 ppm (s, 0,70H, hovedrotamer), 3,97 ppm (s, 0,3H, birotamer), 2,35-2,28 ppm (m, 1H), 1,99-1,53 ppm (m, 5H), 1,28 ppm (d, 0,6H, birotamer), 1,25 ppm (d, 1,4H, hovedrotamer), 1,06-1,03 ppm (m, 3H), 0,96-0,72 ppm (m, 1H), 0,79 ppm (d, 3H), 0,67-0,56 ppm (m, 1H).
Eksempel 21
3-[( 2, 4- diklorbenzoyl) piperidin- 4- yl- amino]- 5- fenyltiofen- 2-karboksylsyrehydrokloridsalt, forbindelse nr. 368
TRINN I
En suspensjon av 3-amino-5-fenyltiofen-2-karboksylsyremetylester (745 mg, 3,2 mmol) i tørt THF (1,3 ml), ved 21 °C, under nitrogen, ble behandlet med tert.-butyl-4-okso-l-piperidin-karboksylat (673 mg, 3,2 mmol), etterfulgt av dibutyltinn-diklorid (19 mg, 0,064 mmol, 0,02 ekv.). Etter 5 minutter ble reaksjonsblandingen behandlet med fenylsilan (435 ul, 380 mg, 3,52 mmol, 1,1 ekv.). Blandingen fikk stå med omrøring i 74 timer da det oppsto en klar oppløsning. Reaksjonsblandingen ble strippet for oppløsnings- middel, hvorved det ble tilbake en tykk blekgul gummi (1,59 g). Råmaterialet ble renset ved hjelp av kolonnekromatografi under anvendelse av (CH2Cl2:heksan:EtOAc = 15:5:1) som elueringsmiddel, hvorved man fikk 4-(2-metoksykarbonyl-5-fenyltiofen-3-ylamino)-piperidin-l-karboksylsyre-tert.-butylester som et gult skum (713 mg, 54%).<X>H NMR (CDC13, 400 MHz) 7,63-7,60 (m, 2H) , 7,74-7, 36 (m, 3H), 6, 90-6, 84 (bs, 1H) , 6,84 (s, 1H), 3,97-4,01 (m, 2H), 3,80 (s, 3H), 3,48 (bs, 1H), 3,06-2,99 (m, 2H), 2,03-1,99 (m, 2H), 1,51-1,48 (m, 2H), 1,47 (bs, 9H).
TRINN II
4-(2-metoksykarbonyl-5-fenyltiofen-3-ylamino)piperidin-l-karboksylsyre-tert . -butylester (200 mg, 0,48 mmol) ble behandlet med 2,4-diklorbenzoylklorid (202 ul, 302 mg, 1,44 mmol, 3 ekv.) under tidligere beskrevne betingelser (f.eks. eksempel 14), hvorved man etter kolonnekromatografi under anvendelse av
(CH2CI2:heksan:EtOAc = 15:5:1) som elueringsmiddel, fikk 4-[(2,4-diklorbenzoyl)(2-metoksykarbonyl-5-fenyltiofen-3-yl)amino]piperidin-l-karboksylsyre-tert .-butylester som et blekgult skum (165 mg, 58%).<*>H NMR (CDCI3, 400 MHz) 7,54-7,51 (m, 2H), 7,45-7,39 (m, 3H), 7,27-7,25 (m, 2H), 7,17 (d, J = 1,96 Hz, 1H), 7,06 (dd, J = 1,92 Hz, J = 8,34 Hz, 1H), 4,86-4,92 (m, 1H), 4,11-4,21 (m, 2H), 3,89 (s, 3H), 2,82-2,89 (m, 2H), 2,17-2,20 (m, 1H), 1,89-1,92 (m, 1H), 1,49-1,61 (m, 1H), 1,40 (bs, 9H), 1,19-1,25 (m, 1H).
TRINN III
En suspensjon av 4-[(2,4-diklorbenzoyl)(2-metoksykarbonyl-5-fenyltiofen-3-yl)amino]piperidin-l-karboksylsyre-tert.-butylester (160 mg, 0,27 mmol) ovenfor i dioksan:vann (4:1,3 ml) ble behandlet med litiumhydroksid (2 M vandig oppløsning, 41 ul, 341 mg, 0,814 mmol, 3 ekv.), og reaksjonsblandingen fikk stå til omrøring over natten i 18 timer. Reaksjonsblandingen ble strippet for opp-løsningsmiddel og resten fordelt mellom EtOAc:vann (4:1). Vannfasen ble fraskilt og ekstrahert flere ganger med EtOAc, etter surgjøring til pH 5,5 med 0,1 N HC1. Den kombinerte, organiske ekstrakt ble inndampet til et fast stoff. Det faste stoffet ble tatt opp i EtOAc, og den ovenfor nevnte syrevask gjentatt, hvorved man etter tørking og inndamping fikk 4-[(2-karboksy-5-fenyltiofen-3-yl)(2,4-diklorbenzoyl)amino]piperidin-l-karboksylsyre-tert.-butylester som et fargeløst, fast stoff (128 mg, 91%) . ^ NMR (aceton, 400 MHz) 7,75-7,70 (m, 1H), 7,64 (s, 1H), 7,52-7,40 (m, 3H), 7,52 (d, J= 1,98 Hz, 1H), 7,21 (dd, J = 1,96 Hz, J = 8,19 Hz, 1H), 4,80-4,71 (m, 1H), 4,26-4,01 (m, 2H), 2,71-2,30 (bs, 3H), 2,25-2,17 (m, 1H), 1,82-1,69 (m, 1H), 1,40 (bs, 9H), 1,33-1,24 (m, 1H).
TRINN IV
En oppløsning av 4-[(2-karboksy-5-fenyltiofen-3-yl)(2,4-diklorbenzoyl)amino]piperidin-l-karboksylsyre-tert.-butylester (240 mg, 0,42 mmol) i dioksan (4 ml) ved 21 °C under nitrogen ble behandlet med vannfri 4 M HC1 (3 ml, 12,6 mmol, 30 ekv.). Etter 4 timer ble reaksjonsblandingen strippet for oppløsningsmiddel og resten triturert med eter, hvorved man fikk 3-[(2,4-diklorbenzoyl) piperidin-4-yl-amino]-5-fenyltiofen-2-karboksylsyre som et blekgult pulver (214 mg, 100%).<X>H NMR (aceton, 400 MHz) 7,76-7,73 (m, 2H), 7,64 (s, 1H), 7,45-7,38 (m, 3H), 7,30 (bs, 1H), 7,28-7,24 (m, 1H), 4,93-4,84 (m, 1H), 3,56-3,49 (m, 2H), 3,25-3,14 (m, 2H), 3,05-2,55 (bs, 1H), 2,50-2,37 (m, 2H), 2,13-1,83 (m, 1H). Fremstilt på lignende måte ble forbindelse nr. 366, forbindelse nr. 553 og forbindelse nr. 543.
Eksempel 22
3-( benzylsyklopropankarbonylamino)- 5- fenyltiofen- 2- karboksylsyre, forbindelse nr. 454
TRINN I
En oppløsningsmiddelblanding av THF/MeOH/H20 (3:2:1) ble tilsatt til 3,04 g metyl-(3-amino-5-fenyl)tiofen-2-karboksylat (13 mmol) og 1,64 g litiumhydroksidmonohydrat (39 mmol). Blandingen ble kokt under tilbakeløpskjøling i 8 timer og konsentrert under vakuum. Råmaterialet ble tatt opp i 100 ml vann, det ble vasket med etylacetat (2 x 100 ml) og overført til en flerhalset kolbe. En 20% fosgenoppløsning i toluen (11 ml, 39 mmol) ble tilsatt dråpevis ved 0 °C. En utfelling ble så samlet opp ved filtrering og sekvensvis vasket ved triturering med en mettet oppløsning av bikarbonat, vann, aceton og dietyleter. 2,52 g (79%) 6-fenyl-lH-tieno[3,2-d][1,3]oksazin-2,4-dion ble isolert som et hvitt, fast stoff.<1>H NMR (DMSO-d6, 400 MHz): 7,79-7,76 ppm (m, 2H, Haro) , 7,52-7,47 ppm (m, 3H, Haro), 7,25 ppm (s, 1H, Hazoi) , 0,4 ppm (s, 1H, NH) .
TRINN II
En oppløsning av 6-fenyl-lH-tieno[3,2-d][1,3]oksazin-2,4-dion (lg, 4,1 mmol) og vannfritt natriumkarbonat (477 mg, 4,5 mmol) fortynnet i 15 ml vannfritt dimetylacetamid ble omrørt i 1 time under nitrogen før tilsetning av benzylbromid (785 mg, 4,5 mmol). Blandingen ble omrørt over natten ved romtemperatur. 912 mg (66,3%) l-benzyl-6-fenyl-lH-tieno[3,2-d][1,3]oksazin-2,4-dion ble erholdt som et blekgult, fast stoff etter filtrering og vasking av utfellingen med aceton og pentan.<1>H NMR (DMSO-d6, 400 MHz): 7,8-7,76 ppm (m, 3H, Haro) , 7,51-7,45 ppm (m, 3H, Haro) , 7,43-7,41 ppm (m, 2H, Haro) , 7,35-7,3 ppm (m, 2H, Haro) , 7, 28-7, 24 ppm (m, 1H, Haro) , 5,22 ppm (s, 1H, NCH2) .
TRINN III
Til en oppløsning av l-benzyl-6-fenyl-lH-tieno[3,2-d][1,3]oksazin-2,4-dion (880 mg, 2,62 mmol) ble det suksessivt tilsatt 32 ml dioksan og 7,87 ml NaOH, 1 N, vandig oppløsning. Blandingen ble kraftig omrørt i 2 timer, og så ble oppløsnings-midlene 'konsentrert under vakuum. Diklormetan ble tilsatt til råmaterialet, og natrium-3-benzylamino-5-fenyltiofen-2-karboksylat (1,07 g, 100%) feltes ut som et blekgult, fast stoff.<X>H NMR (DMSO-d6, 400 MHz): 7,76 ppm (t, 1H, J = 6,4 Hz, NH), 7,53-7,51 ppm (m, 2H, Haro), 7,33-7,26 ppm (m, 6H, Haro) , 7,23-7,16 ppm (m, 2H, Haro) , 7,07 ppm (s, 1H, Hazoi) , 4,36 ppm (d, 2H, J = 6, 4 Hz, NHCH2) .
TRINN IV
Til en oppløsning av natrium-3-benzylamino-5-fenyltiofen-2-karboksylat (41,1 mg, 0,1 mmol) ble det tilsatt 32 mg (0,3 mmol) syklopropankarbonylklorid, 1,5 ml dioksan og 0,5 ml vann. Blandingen ble omrørt over natten ved romtemperatur og konsentrert i vakuum. En 4 N hydrogenkloridoppløsning i dioksan (1 ml) ble tilsatt, og blandingen ble omrørt i 1 time ved romtemperatur. Blandingen ble på nytt konsentrert, og råmaterialet ble renset ved hjelp av reversfase-HPLC, hvorved man fikk 11,9 mg (31,5%) 3-(benzylsyklopropankarbonylamino)-5-fenyltiofen-2-karboksylsyre som et blekgult, fast stoff.<1>H NMR (DMSO-d6, 400 MHz): 7,56-7,54 ppm (m, 2H, Haro), 7,39-7,13 ppm (m, 10H, Haro, Hazoi og COOH), 5,27 ppm (d, 1H, J = 15,2 Hz), 4,48 ppm (d, 1H, J = 15,2 Hz), 1,49 ppm (m, 1H), 0,77 ppm (m, 2H), 0,61 ppm (m, 2H).
De følgende forbindelser ble fremstilt på en lignende måte: forbindelse nr. 172, forbindelse nr. 173, forbindelse nr. 175, forbindelse nr. 186, forbindelse nr. 187, forbindelse nr. 188, forbindelse nr. 241, forbindelse nr. 247, forbindelse nr. 251, forbindelse nr. 252, forbindelse nr. 253, forbindelse nr. 254, forbindelse nr. 255, forbindelse nr. 256, forbindelse nr. 257, forbindelse nr. 276, forbindelse nr. 277, forbindelse nr. 278, forbindelse nr. 279, forbindelse nr. 280, forbindelse nr. 281, forbindelse nr. 330, forbindelse nr. 334, forbindelse nr. 335, forbindelse nr. 336, forbindelse nr. 339, forbindelse nr. 340, forbindelse nr. 341, forbindelse nr. 342, forbindelse nr. 343, forbindelse nr. 344, forbindelse nr. 345, forbindelse nr. 347, forbindelse nr. 349, forbindelse nr. 350, forbindelse nr. 351, forbindelse nr. 352, forbindelse nr. 353 BCH-23932, forbindelse nr. 354, forbindelse nr. 384, forbindelse nr. 385, forbindelse nr. 386, forbindelse nr. 388, forbindelse nr. 389, forbindelse nr. 390, forbindelse nr. 391, forbindelse nr. 392, forbindelse nr. 393, forbindelse nr. 394, forbindelse nr. 397, forbindelse nr. 398, forbindelse nr. 399, forbindelse nr. 400, forbindelse nr. 401. Eksempel 23 3-[( 2, 4- diklorfenyl) isopropylkarbamoyl]- 5- fenyltiofen- 2- karboksylsyre
TRINN I
3- j od- 5- f enyltiof en- 2- karboksyl syrerne tyles ter
En suspensjon av 3-amino-5-fenyltiofen-2-karboksylsyremetylester (10 g, 43 mmol) i vannfri benzen (200 ml), ved 21 °C, under N2, ble behandlet med t-butylnitritt (21,8 g, 86 mmol), og den mørke blanding ble avkjølt til 0 °C og behandlet dråpevis i løpet av 15 minutter med jod (21,8 ml, 184 mmol). Etter 30 minutter ved 0 °C fikk oppløsningen varmes opp til omgivelsestemperatur og ble omrørt i 2 timer. Reaksjonsblandingen ble så helt over i vann (300 ml), og det ble kraftig omrørt i 15 minutter. Den organiske fase ble fraskilt og vasket flere ganger med 20% natriumtiosulfat (4 x 100 ml). Den resulterende emulsjon ble filtrert gjennom celite. Celiteputen ble vasket med EtOAc, og det kombinerte filtrat og vaskeoppløsningene ble vasket med mer natriumtiosulfat (100 ml), hvorved man fikk en orange oppløsning som ble vasket med saltopp- løsning og tørket. Avdamping av oppløsningsmidlet ga en olje (7,4
g). Den urensede olje ble renset ved hjelp av Biotage hurtigkromatografi under anvendelse av heksan/CH2Cl2/EtOAc (20/2/1) som
elueringsmiddel, hvorved man fikk 4,42 g (29%) 3-jod-5-fenyltiofen-2- karboksylsyremetylester som en blekgul olje.<1>H NMR (CDC13, 400 MHz): 7,62-7,57 (m, 2H), 7,58 (s, 1H), 7,50-7,36 (m, 3H), 3,91 (s, 3H) .
TRINN II
3- j od- 5- fenyltiofen- 2- karboksylsyre
En oppløsning av 3-jod-5-fenyltiofen-2-karboksylsyremetylester (4,4 g, 12,78 mmol) i dioksan/vann 4/1 (50 ml), ved 21 °C, under N2, ble behandlet med litiumhydroksid (2 N, 19,3 ml, 38 mmol), og oppløsningen fikk stå med omrøring i 21,5 timer. Reaksjonsblandingen ble inndampet til tørrhet og resten fordelt mellom EtOAc (75 ml) og vann (25 ml), og det ble surgjort med 2 N HC1 inntil pH 5,5. Vannfasen ble fraskilt og ekstrahert med EtOAc (3 x 50 ml). Den kombinerte, organiske ekstrakt ble vasket med saltoppløsning, tørket og inndampet, hvorved man fikk 4,12 g (97%) 3-jod-5-fenyltiofen-2-karboksylsyre som et blekgult, fast stoff.<1>H NMR (CD3OD, 400 MHz): 7,69-7,67 (m, 2H), 7,55 (s, 1H), 7,46-7,39
(m, 3H).
TRINN III
3- jod- 5- fenyltiofen- 2- karboksylsyre- tert.- butylester
En suspensjon av magnesiumsulfat (4,61 g, 38,32 mmol) i diklormetan (37 ml) ved 21 °C, under N2, ble behandlet med konsentrert H2S04(510 iil, 9,58 mmol). Etter 15 minutter ble fast 3-jod-5-fenyltiofen-2-karboksylsyre (3,7 g, 9,58 mmol) ble tilsatt, etterfulgt av t-butanol (4,55 ml, 47,9 mmol), og kolben ble lukket og fikk stå over natten i 19,5 timer. Reaksjonsblandingen ble behandlet med mettet, vandig bikarbonatoppløsning og filtrert. Det faste stoff ble vasket med CH2C12og filtratet tørket og konsentrert til en olje. Råmaterialet ble renset ved hjelp av hurtigkromatografi under anvendelse av heksan/CH2Cl2(3:1) som elueringsmiddel, hvorved man fikk 1,63 g (44%) 3-jod-5-fenyltiofen-2-karboksylsyre- tert.-butylester som et fargeløst, fast stoff.<1>H NMR (CDCI3, 400 MHz) 7,61-7,59 (m, 2H), 7,43-7,35 (m, 3H), 7,25 (s, 1H), 1,60 (bs, 9H) .
TRINN IV
3- formyl- 5- fenyltiofen- 2- karboksylsyre- tert.- butylester
En oppløsning av 3-jod-5-fenyltiofen-2-karboksylsyre-tert.-butylester (1,41 g, 3,65 mmol) i tørt THF (37 ml) ved -78 °C, under nitrogen, ble behandlet dråpevis i løpet av 5 minutter med n-butyllitium (4,8 ml, 7,66 mmol). Reaksjonsblandingen ble gradvis mørkere inntil en rødbrun farge. Etter 15 minutter ved -78 °C ble dimetylformamid (1,7 ml, 21,9 mmol) dråpevis tilsatt i løpet av 7 minutter. Den mørke oppløsning fikk omrøres i 2 timer og ble så tilsatt mettet NH4Cl-oppløsning (10 ml) og fikk nå 21 °C. Vannfasen ble fraskilt og ekstrahert med EtOAc (3 x 50 ml). De kombinerte, organiske ekstrakter ble inndampet og resten tatt opp i EtOAc og vasket med vann, saltoppløsning, tørket og konsentrert, hvorved man fikk 1,14 g av en brun olje. Det urene materiale ble renset ved hjelp av hurtigkromatografi under anvendelse av heksan/CH2Cl2(1/1) som elueringsmiddel, hvorved man fikk 303 mg (28%) 3-formyl-5-fenyltiofen-2-karboksylsyre-tert.-butylester som et fargeløst, fast stoff.<X>H NMR (CDCI3, 400 MHz): 10,62 (s, 1H), 7,78 (s, 1H), 7,64-7,62 (m, 2H), 7,48-7,38 (m, 3H), 1,62 (bs, 9H).
TRINN V
5- fenyltiofen- 2, 3- dikarboksylsyre- 2- tert.- butylester
En oppløsning av 3-formyl-5-fenyltiofen-2-karboksylsyre-tert.-butylester (300 mg, 1,04 mmol) i tørt THF (20 ml), ved 0 °C, under nitrogen, ble behandlet med metylsulfid (10 vekt% i THF, 3,8 ml, 5,2 mmol), etterfulgt av natriumdihydrogenfosfat (30% vandig oppløsning, 9,56 ml, 2,05 mmol). Etter 0,5 time ble oppløsningen behandlet med natriumkloritt (30 vekt% vandig oppløsning, 1,9 ml, 2,08 mmol) tilsatt i løpet av 1 minutt via en sprøyte. Den blekgule oppløsning ble omrørt i 1,5 time ved 0 °C, så fortynnet med vann (20 ml), og det ble ekstrahert med EtOAc (4 x 40 ml). Vannfasen ble fraskilt, det ble ekstrahert med mer EtOAc (40 ml), og de kombinerte ekstrakter ble vasket med saltoppløsning, tørket og konsentrert, hvorved man fikk 316 mg (100%) 5-fenyltiofen-2,3-dikarboksylsyre-2-tert.-butylester som et lysebrunt, fast stoff.<1>H NMR (CD3C0, 400MHz): 7,87 (s, 1H), 7,83-7,81 (m, 2H), 7,17-7,53
(m, 3H) , 1,65 (bs, 1H).
TRINN VI
3-[( 2, 4- diklorfenyl) isopropylkarbamoyl]- 5- fenyltiofen- 2- karboksylsyre- tert.- butylester
En oppløsning av 5-fenyltiofen-2,3-dikarboksylsyre-2-tert.-butylester (40 mg, 0,13 mmol) i CH2CI2(1,3 ml), under nitrogen, ved 0 °C, ble behandlet med diisopropyletylamin (27 ml, 0,16 mmol), etterfulgt av dimetylformamid (10 ml, 0,13 mmol) og oksalylklorid (170 1, 0,34 mmol). Det ble observert svak brusing. Reaksjonsblandingen ble holdt ved 0 °C i 30 minutter før den ble behandlet med (2,4-diklorfenyl)isopropylamin (beskrevet tidligere)
(79 mg, 0,39 mmol). Reaksjonsblandingen fikk nå 21 °C og ble så plassert i et bad ved 90 °C i 15 timer. Oppløsningsmiddel ble fjernet, hvorved man fikk en lysebrun gummi (144 mg). Det urensede materiale ble renset på Bond-Elute under anvendelse av heksan/CH2Cl2/EtOAc (12,5/2/1) som elueringsmiddel, hvorved man fikk 39 mg (62%) 3-[(2,4-diklorfenyl)isopropylkarbamoyl]-5-fenyltiofen-2- karboksylsyre-tert.-butylester som et lysebrunt, fast stoff.<1>H NMR (CDCI3, 400MHz) 7,50-7,48 (m, 2H), 7,38-7,25 (m, 6H), 7,10-7,03 (m, 1H), 5,05 (kvint., J = 6,88 Hz, 1H), 1,57 (bs, 9H), 1,40 (d, J = 6,88 Hz, 3H), 1,12 (d, J = 6,88 Hz, 3H).
TRINN VII
3- [( 2, 4- diklorfenyl) isopropylkarbamoyl]- 5- fenyltiofen- 2- karboksylsyre
En oppløsning av 3-[(2,4-diklorfenyl)isopropylkarbamoyl]-5-fenyltiofen-2-karboksylsyre-tert.-butylester (37 mg, 0,08 mmol) i CH2CI2(0,2 ml) ved romtemperatur under nitrogen ble behandlet med trifluoreddiksyre (0,8 ml). Etter 1 time ble reaksjonsblandingen konsentrert, og resten ble tatt opp i EtOAc og vasket sekvensvis med 2 N HC1 (2 x 15 ml), vann, saltoppløsning, tørket og inndampet til et skum (33 mg). Skummet ble på nytt oppløst i EtOAc, og den ovenfor sure vasking ble gjentatt, hvorved man fikk 27 mg (84%) 3-[(2,4-diklorfenyl)isopropylkarbamoyl]-5-fenyltiofen-2-karboksylsyre-forbindelse som lysebrunt skum.<*>H NMR (CD3OD, 400 MHz) 7,57-7,55 (m, 2H) , 7,49-7,36 (m, 6H), 7, 30-7, 27 (m, 1H), 4,89 (kvint., J = 6,73 Hz, 1H), 1,42 (d, J = 6,73 Hz, 3H), 1,12 (d, J = 6,73 Hz, 3H) .
Eksempel 24
Den følgende forbindelse ble erholdt fra Discovery Technology: 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-fenyltiofen-2-karboksylsyreamid, forbindelse nr. 580.
Eksempel 25
De følgende forbindelser ble erholdt fra Maybridge: 5-(4-klorfenyl)-3-(toluen-4-sulfonylamino)tiofen-2-karboksyl-syreamid, forbindelse nr. 563
5-(4-fluorfenyl)-3-(toluen-4-sulfonylamino)tiofen-2-karboksyl-syreamid, forbindelse nr. 564, GK 01137
5-(4-metoksyfenyl)-3-(toluen-4-sulfonylamino)tiofen-2-karboksyl-syreamid, forbindelse nr. 565, GK 01175
Eksempel 2 6
Evaluering av forbindelser i den HCV RNA-avhengige RNA-polymeraseanalyse.
Det vises til følgende litteraturhenvisninger:
1. Behrens, S., Tomei, L., De Francesco, R. (1996), EMBO 15, 12-22. 2. Harlow, E. og Lane, D. (1988), Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor,
NY.
3. Lohmann, V., Korner, F., Herian, U. og Bartenschlager, R.
(1997), J. Virol. 71, 8416-8428. 4. Tomei, L., Failla, C, Santolini, E., De Francesco, R. og La Monica, N. (1993), J. Virol. 67, 4017-4026. Forbindelser ble evaluert ved å anvende en in vitro-polymeraseanalyse inneholdende renset, rekombinant HCV RNA-avhengig RNA-polymerase (NS5B-protein). HCV NS5B ble uttrykt i insektsceller ved å anvende et rekombinant baculovirus som vektor. Forsøks-prosedyrene som ble brukt til kloningen, ekspresjonen og rensingen av HCV NS5B-proteinet, er beskrevet nedenunder. Det følgende er detaljer vedrørende de RNA-avhengige RNA-polymeraseanalysene brukt til å teste forbindelsene.
Ekspresjon av HCV NS5B- proteinet i insektsceller
cDNA-et som koder for hele NS5B-proteinet fra HCV-Bk-stamme, genotype lb, ble amplifisert ved hjelp av PCR under anvendelse av primerne NS5Nhe5' (5'- GCTAGCGCTAGCTCAATGTCCTACACATGG-3') og XhoNS53' (5'- CTCGAGCTCGAGCGTCCATCGGTTGGGGAG-3') og plasmidet pCD 3,8-9,4 som templat (Tomei et al., 1993). NS5Nhe5' og XhoNS53' inneholder to henholdsvis Miel- og Xhol-seter (sekvenser understreket) i sin 5'-ende. Det amplifiserte DNA-fragment ble klonet i bakterieekspresjonsplasmidet pET-21b (Novagen) mellom restriksjons-setene Nhel og Xhol, for å frembringe plasmidet pET/NS5B. Dette plasmidet ble senere brukt som templat for å PCR-amplifisere NS5B-kodingsregionen, under anvendelse av primerne
NS5B-H9 (5'-ATACATATGGCTAGCATGTCAATGTCCTACACATGG-3') og
NS5B-R4 (5'- GGATCCGGATCCCGTTCATCGGTTGGGGAG-3'). NS5B-H9 spenner over en region med 15 nukleotider i plasmidet pET-21b, etterfulgt av translasjonsinitieringskodonet (ATG) og 8 nukleotider som tilsvarer 5'-enden til NS5B-kodingsregionen (nt. 7590-7607 i HCV-sekvensen med deponeringsnummeret M58335). NS5B-R4 inneholder to SamHI-seter (understreket), etterfulgt av 18 nukleotider som tilsvarer regionen rundt stoppkodonet i HCV-genomet (nt. 9365-9347). Den amplifiserte sekvens på 1,8 kb ble fordøyd med Nhel og BamRI, og ligert til et forfordøyd pBlueBacII-plasmid (Invitrogen). Det resulterende rekombinante plasmid ble betegnet pBac/NS5B. Sf9-celler ble samtransfektert med 3 ug pBac/NS5B sammen med 1 ug linearisert baculovirus-DNA (Invitrogen), som beskrevet i produ-sentens protokoll. Etter to runder med plakkrensing ble det isolert et NS5B-rekombinant baculovirus, BacNS5B. Tilstedeværelsen av det rekombinante NS5B-protein ble bestemt ved hjelp av western blot-analyse (Harlow og Lane, 1988) av BacNS5B-infiserte Sf9-celler under anvendelse av et polyklonalt kanin-antiserum (anti-NS5B) frembrakt mot en His-merket versjon av NS5B-proteinet uttrykt i E. coli. Infeksjoner av Sf9-celler med dette plakkrensede virus ble utført i en-liters spinnerkolber ved en celletetthet på 1,2 x IO<6>celler/ml og en infeksjonsmultiplisitet på 5.
Fremstilling av et oppløselig rekombinant NS5B- protein
Sf9-celler ble infisert som beskrevet ovenfor. 60 timer etter infeksjon ble celler innhøstet og så vasket to ganger med fosfatbuffer-saltoppløsning (PBS). Alle proteiner ble oppløselig-gjort som beskrevet i Lohmann et al. (1997) med noen modifika-sjoner. I korte trekk ble proteiner ekstrahert i tre trinn, Sl, S2 og S3, ved å anvende lysebuffere (LB) I, LB II og LB III (Lohmann et al., 1997). Sammensetningen av LBII ble modifisert til å inneholde 0,1% triton X-100 og 150 mM NaCl for å redusere mengden av oppløseliggjort NS5B-protein på dette trinnet. I tillegg ble sonikering av celleekstrakter unngått gjennom fremgangsmåten for å bevare helheten til proteinstrukturen.
Rensing av rekombinant NS5B ved å anvende hurtig protein-vaeskekromatograf i ( FPLC)
Oppløselig NS5B-protein i S3-fraksjonen ble fortynnet for å senke NaCl-konsentrasjonen til 300 mM, så ble det inkubert satsvis med DEAE-sefarosekuler (Amersham-Pharmacia) i 2 timer ved 4 °C som beskrevet av Behrens et al. (1996). Ubundet materiale ble fjernet ved sentrifugering i 15 minutter ved 4 °C ved 25 000 rpm under anvendelse av en SW41-sentrifuge (Beckman). Supernatanten ble videre fortynnet for å senke NaCl-konsentrasjonen til 200 mM og deretter fylt, med en strømningshastighet på 1 ml/min, på en 5 ml HiTrap heparinkolonne (Amersham-Pharmacia) forbundet med et FPLC-system (Amersham-Pharmacia). Bundne proteiner ble eluert i 1 ml fraksjoner under anvendelse av en kontinuerlig NaCl-gradient på 0,2 til 1 M, over et volum på 25 ml. NS5B-holdige fraksjoner ble identifisert ved hjelp av natriumdodecylsulfat-polyakrylamidgel- elektroforese (SDS-PAGE), etterfulgt av western-blotting under anvendelse av anti-NS5B-antiserumet ved en fortynning på 1:2 000. Positive fraksjoner ble slått sammen, og elueringsbufferen ble byttet mot 50 mM NaP04pH 7,0, 20% glyserol, 0,5% triton X-100 og 10 mM DTT under anvendelse av en PD-10-kolonne (Amersham-Pharmacia). Prøven ble så fylt på en 1 ml HiTrap SP-kolonne (Amersham-Pharmacia), med en strømningshastighet på 0,1 ml/min. Bundne proteiner ble eluert ved å anvende en kontinuerlig 0 til 1 M NaCl-gradient over et volum på 15 ml. Eluerte fraksjoner ble analysert ved hjelp av SDS-PAGE og western-blotting. Alternativt ble proteiner visualisert etter SDS-PAGE ved sølvfarging under anvendelse av "Silver Stain Plus"-settet (BioRad) som beskrevet av produsenten. Positive fraksjoner ble testet med hensyn på RdRp-aktivitet (se nedenunder), og de mest aktive ble slått sammen og lagret som en 40% glyseroloppløsning ved -70 °C.
In vitro HCV RdRp Flashplate- scintillasjonsproksimitetsanalyse ( STREP- FLASH ASSAY) brukt for å evaluere analoger
Denne analysen består av å måle inkorporeringen av [<3>H]-radioaktivt merket UTP i en polyrA/biotinylert-oligo dT-templatprimer, oppfanget på overflaten av streptavidinbelagte scintillant-innpakkede mikrotiter-Flashplates (NEN Life Science Products Inc., MA, USA, SMP 103A). I korte trekk ble en 400 ng/ul polyrA-oppløsning (Amersham Pharmacia Biotech) blandet volum-til-volum med 5' biotin-oligo dTi5ved 20 pmol/ul. Templatet og primerne ble denaturert ved 95 °C i 5 minutter og så inkubert ved 37 °C i 10 minutter. Annealerte templatprimere ble deretter fortynnet i en Tris-HCl-holdig buffer og fikk bindes til streptavidinbelagte flashplater over natten. Ubundet materiale ble kassert, forbindelser ble tilsatt i en 10 ul oppløsning etterfulgt av en 10 ul oppløsning inneholdende 50 mM MgCl2, 100 mM Tris-HCl pH 7,5, 250 mM NaCl og 5 mM DTT. Den enzymatiske reaksjon ble initiert etter tilsetning av en 30 ul oppløsning inneholdende enzymet og substratet, hvorved man fikk de følgende konsentrasjoner: 25 uM UTP, 1 uCi [<3>H] UTP og 100 nM rekombinant HCV NS5B. RdRp-reaksjoner fikk forløpe i 2 timer ved romtemperatur, hvoretter brønner ble vasket tre ganger med 250 ul 0,15 M NaCl-oppløsning, lufttørket ved 37 °C og tellet ved å anvende en væskescintillasjonsteller (Wallac Microbeta Trilex, Perkin-Elmer, MA, USA). Resultatene er vist i tabell 1.
In vitro HCV RdRp-filtreringsanalyse brukt til å evaluere analoger: RdRp-analyser ble utført ved å anvende homopolymer templat/primer polyA/oligo dT. Alle RdRp-reaksjoner ble utført i et totalvolum på 50 ul, og i en basisk buffer bestående av 20 mM Tris-HC1 pH 7,5, 1 mM DTT, 50 mM NaCl, 5 mM MgCl2, 0,5 uCi[y32P]-UTP (3 000 Ci/mmol), 15 uM kald UTP og 20 U RNasin (Promega). Standard HCV RdRp-reaksjonsblandinger inneholdt 200 ng renset NS5B-protein. PolyA-RNA-er (Amersham-Pharmacia) ble på nytt oppslemmet ved 4 00 ng/ul. Primer-oligodTis(Canadian Life Technologies) ble fortynnet til en konsentrasjon på 20 pmol/ul (7,6 ng/ml). Templater og primere ble blandet volum-til-volum, denaturert ved 95 °C i 5 minutter og annealert ved 37 °C i 10 minutter. Etter en to-timers inkubasjon ved 22 °C ble reaksjonene stanset ved tilsetning av 100 ug sonikert laksesperma-DNA (Life Technologies) og 1 ml 10% trikloreddiksyre - 0,5% tetranatriumpyrofosfat (TCA-PPi). Nuklein-syrer ble utfelt ved 4 °C i 30 minutter, hvoretter prøver ble filtrert på GF/C glassmikrofiberfiltre (Millipore). Membraner ble deretter vasket med 25 ml av en 1% TCA - 0,1% PPi-oppløsning, og så lufttørket. Inkorporert radioaktivitet ble kvantifisert ved å anvende en væskescintillasjonsteller (1450-Microbeta, Wallac). Resultatene er vist i tabell 1.
Eksempel 27
Evaluering av analoger for måling av ATPase- aktivitet av HCV NS3-helikase
"Malachite Green"-analyse:
Målingen av ATPase-aktivitet ble utført ved å måle mengden av fritt, uorganisk fosfat frigjort under omdannelsen av ATP til ADP ved hjelp av HCV NS3-ATPase-aktiviteten. Analysen er som følger: I en 96-brønners mikrotiterplate ble forbindelser oppløst ved forskjellige konsentrasjoner i et sluttvolum på 25 ul ATPase- buffer inneholdende 400 uM ATP. Den enzymatiske reaksjon ble startet opp ved tilsetning av 25 ul ATPase-buffer inneholdende 6 nMHCV NS3-enzym uten ATP til brønnene, etterfulgt av en inkubasjon på 30 minutter ved 37 °C. I det alt vesentlige er sluttkonsentrasjonen av ATPase-bufferkomponentene som følger: 44 mM MOPS pH 7,0, 8,8 mM NaCl, 2,2 mM MgCl2, 125 ug/ml poly A, 1% DMSO, 200 uM ATP og 3 nM HCV-NS3-enzym. Reaksjonen ble stanset ved tilsetning av 100 ul Biomol Green-reagens (BIOMOL Research Laboratories Inc., Plymouth Meeting, PA). For å muliggjøre fremkallingen av den grønne farge ble platen inkubert i 15 minutter ved romtemperatur. Så ble platen avlest på en mikroplateavleser ved 620 nm. 50%-inhibitorkonsentrasjonen (IC5o) for anti-ATPase-aktivitet ble definert som den konsentrasjon av forbindelse som resulterte i en 50% reduksjon i signalet sammenlignet med det signal som ble observert i kontroll-prøve uten forbindelse. Det målte signal ble også korrigert fra bakgrunnssignalet erholdt med kontrollprøver med bare forbindelse. IC50ble bestemt ut fra doseresponskurver under anvendelse av 6 til 8 konsentrasjoner pr. forbindelse. Kurver ble tilpasset datapunkter ved å anvende en ikke-lineær regresjonsanalyse, og IC5o-verdier ble interpolert fra de resulterende kurver ved å anvende GraphPad Prism programvare, versjon 2.0 (GraphPad Software Inc., San Diego, CA).
HPLC-analyse:
Målingene av HCV NS3-ATPase-aktivitet ble utført ved å måle mengden av ADP fremstilt under omdannelsen av ATP til ADP ved hjelp av HCV NS3-enzymet under anvendelse av paret-ion HPLC på en reversfasekolonne. Analysen er som følger: Den samme fremgangsmåte som nevnt ovenfor, ble brukt, bortsett fra at sluttkonsentrasjonen av HCV NS3-enzym ble redusert til 1 nM i en 50 ul reaksjonsblanding, og at ATPase-reaksjonen ble stanset ved tilsetningen av 12,5 pl 0,5 M EDTA. Et modul-væskekromatografisystem (TSP Spectra-system, ThermoQuest Corporation, San Diego, USA) under anvendelse av ChromQuest programvare (ThermoQuest Corporation, San Diego, USA) kontrollerte den automatiske prøvetaking av 25 ul fra hver reaksjon. Mobilfasen var en isokratisk oppløsning av 0,15 M trietylamin, 6% metanol og fosforsyre til pH 5,5. ADP- og ATP- topper ble oppløst ved å anvende Aqua 5 u, C18, 125 Å, (150 x 4,6 mm)-reversfasekolonnen. Omfanget av ATP-omdannelse til ADP ble beregnet ved å måle arealet under den frembrakte ADP-topp som ble påvist ved 259 nm. Mengden av ADP ble korrigert for tilstedeværelsen av ADP-forurensning i den opprinnelige ATP-oppløsning. 50% inhibitorkonsentrasjonen (IC5o) for anti-ATPase-aktivitet ble definert som den konsentrasjon av forbindelse som resulterte i en 50% reduksjon av ADP-toppareal sammenlignet med ADP-topparealet observert i kontrollprøve uten forbindelse. IC5oble bestemt ut fra doseresponskurver under anvendelse av 6 til 8 konsentrasjoner pr. forbindelse. Kurver ble tilpasset til datapunkter ved å anvende en ikke-lineær regresjonsanalyse, og IC5o-verdier ble interpolert fra de resulterende kurver ved å anvende GraphPad Prism programvare, versjon 2.0 (GraphPad Software Inc., San Diego, CA).
Eksempel 27
Liste over forbindelser og tilhørende polymeraseaktivitet<*>
Claims (79)
1. Forbindelse,
karakterisert vedat den har formel Ia:
eller et farmasøytisk akseptabelt salt derav, hvor
X er:
M er:
R4er Ci-6-alkyl;
R8er H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-12-heteroring, C3_i2-heteroaralkyl eller C6-i6-aralkyl; og R15er H eller Ci-6-alkyl;
J er:
W er 0, S eller NR-?;
R7er H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-12-heteroring, C3_i2-heteroaralkyl eller C6-i6-aralkyl;
R6er H, Ci_i2-alkyl, C6-i4-aryl eller C6-i6-aralkyl;
Y1 er en binding, C2-6-alkenyl eller C2-6-alkynyl;
Y er COORie, COCOOR5, P(0)0Ra0Rb, S(0)0R5, S(0)2OR5, tetrazol, CON(R9)CH(R5)COOR5, CON (R9)-SO2-R5 eller C0NR90H;
R9og R5er hver uavhengig av hverandre H, C:-i2-alkyl, C2_i2-alkenyl, C2-i2-alkynyl, C3_i2-heteroring, C3_i8-heteroaralkyl eller C6-i8-aralkyl;
Ra og Rber hver uavhengig av hverandre H, Ci_i2-alkyl, C2-12-alkenyl, C2-i2~alkynyl, C6-i4~aryl, C3_i2-heteroring, C3-i8-heteroaralkyl eller C6-i8-aralkyl;
eller Ra og Rbdanner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
Rie er H, Ci-i2-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3_i8-heteroaralkyl eller C6-i8-aralkyl;
forutsatt at Ri6er forskjellig fra metyl og etyl;
Ri er C2-i2-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6_i4-aryl, C3-12-heteroring, C3_i8-heteroaralkyl og C6-i8-aralkyl;
R2er C2-i2-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-12-heteroring, C3_i8-heteroaralkyl eller C6-is-aralkyl;
R3er H, Ci_i2-alkyl, C2-i2-alkenyl, C2_i2-alkynyl, C6-i4-aryl, C3-12-heteroring, C3-i8-heteroaralkyl eller C6-i8-aralkyl; og Z er H, halogen eller Ci-6-alkyl;
hvor
i hvert tilfelle er alkyl rettkjedet, forgrenet eller syklisk, og er usubstituert eller substituert;
i hvert tilfelle er alkenyl usubstituert eller substituert;
i hvert tilfelle er alkynyl usubstituert eller substituert;
i hvert tilfelle er aryl fenyl eller naftyl, som er usubstituert eller substituert;
i hvert tilfelle er aralkyl en fenyl- eller naftylgruppe bundet til naboatomet ved hjelp av en Ci_6-alkyl-, C2-6-alkenyl- eller C2-6-alkynylgruppe, som er usubstituert eller substituert;
i hvert tilfelle er heteroring valgt blant epoksid, furanyl, benzofuranyl, isobenzofuranyl, oksatiolanyl, ditiolanyl, dioksolanyl, pyrrolyl, pyrrolidinyl, imidazol, pyridinyl, pyrimidinyl, indolyl, piperidinyl, morfolinyl, tiofenyl, tiomorfolinyl, tienyl, benzotiofenyl, piperazinyl, tiazolyl, isoksazolyl, tiadiazolyl, pyrazolyl, tetrazolyl, dioksanyl, azepanyl, kinolinyl, benzoimidazolyl, dihydropyridinyl, teterahydropyranyl, benzodioksolyl og triazaspirodekanyl, som er usubstituert eller substituert;
i hvert tilfelle er heteroaralkyl en heterosyklisk gruppe bundet til naboatomet ved hjelp av en Ci-6-alkyl-, C2-6-alkenyl- eller C2-6-alkynylgruppe, hvor den heterosykliske gruppen er valgt blant epoksid, furanyl, benzofuranyl, isobenzofuranyl, oksatiolanyl, ditiolanyl, dioksolanyl, pyrrolyl, pyrrolidinyl, imidazol, pyridinyl, pyrimidinyl, indolyl, piperidinyl, morfolinyl, tiofenyl, tiomorfolinyl, tienyl, benzotiofenyl, piperazinyl, tiazolyl, isoksazolyl, tiadiazolyl, pyrazolyl, tetrazolyl, dioksanyl, azepanyl, kinolinyl, benzoimidazolyl, dihydropyridinyl, tetrahydropyranyl, benzodioksolyl og triazaspirodekanyl, som i hvert tilfelle er usubstituert eller substituert;
med det forbehold at: når X er benzamid og Ri er fenyl, Y<1>er en binding og Y er COOH, så er R3forskjellig fra hydrogen; eller en forbindelse valgt blant:
Forbindelse 26 8-KLOR-3-(4-KLOR-2,5-DIMETYLBENZENSULFONYLAMINO) -4H-1,5-DITIASYKLOPENTA[A]NAFTALEN-2-KARBOKSYLSYRE;
Forbindelse 28 3-[3-(2,6-DIKLORPYRIDIN-4-YL)-UREIDO]-5-FENYLTI0FEN-2-KARB0KSYLSYRE;
Forbindelse 33 3-(4-KL0RFEN0KSYKARB0NYLAMIN0)-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 46 5-FENYL-3(5-[1,2,3]TIADIAZOL-4-YL-TIOFEN-2-SULFONYLAMINO)-TI0FEN-2-KARB0KSYLSYRE;
Forbindelse 51 3-(2-KARBOKSYBENZOYLAMINO)-5-FENYLTIOFEN-2-KARBOKSYLSYREMETYLESTER;
Forbindelse 79 3-(TOLUEN-2-SULFONYLAMINO)-5-TRIMETYL-SILANYLETYNYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 82 5-BENZOYL-3-(TOLUEN-2-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 90 5-(3-ACETYLAMINO-FENYL)-3-(TOLUEN-2-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 112 3-[(4-OKSO-l-FENYL-l,3,8-TRIAZA-SPIRO[4.5]DEKAN-8-KARBONYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 113 3-{[4-(2-OKSO-2,3-DIHYDRO-BENZOIMIDAZOL-l-YL)-PIPERIDIN-1-KARBONYL]-AMINO}-5-FENYL-TIOFEN-2-KARBOKSYLSYRE; Forbindelse 139 3-(2-ACETYLAMINO-4-METYL-TIAZOL-5-SULFONYLAMINO)-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 161 4,4'-BIS-(TOLUEN-2-SULFONYLAMINO)-[2,2']BITIOFENYL-5,5'-DIKARBOKSYLSYRE;
Forbindelse 163 5-(1-DIMETYLSULFAMOYL-1H-PYRAZOL-4-YL)-3-(TOLUEN-2-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 179 5-FENYL-3-[3-(3-FENYL-PROPYL)-UREIDO]-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 180 3-[(3,4-DIHYDRO-1H-ISOKINOLIN-2-KARBONYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 241 3-[ACETYL-(4-KLOR-BENZYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 287 3-[(2, 4-DIKLOR-BENZOYL)-ISOPROPYL-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYREMETYLESTER;
Forbindelse 369 5(4-METANSULFONYLAMINO-FENYL)-3(TOLUEN-2-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 377 3-[(2-ACETOKSY-4-METYL-BENZOYL)-ISOPROPYL-AMINO] -5-FENYL-TIOFENE-2-KARBOKSYLSYRE;
Forbindelse 382 3-[(2, 4-DIKLOR-BENZOYL)-ISOPROPYL-AMINO]-5-METYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 387 3-[ISOPROPYL-(5-METYL-3-OKSO-3H-ISOINDOL-1-YL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 426 3-[ACETYL-(2-METYL-BENZYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 430 3-[(2,4-DIKLOR-BENZOYL)-ISOPROPYL-AMINO]-5-[4-(1H-TETRAZOL-5-YL)-FENYL]-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 434 3-[ACETYL-(3-METYL-BENZYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 450 3-(ACETYL-BENZYL-AMINO)-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 452 3-[BENZYL-(2-METOKSY-ACETYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 455 3-[ACETYL-(4-KLOR-BENZYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 464 3-[ACETYL-(4-TRIFLUORMETYL-BENZYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 476 3-[ACETYL-(3-KLOR-BENZYL)-AMINO]-5-FENYLTIOFEN-2-KARBOKSYLSYRE;
Forbindelse 478 3-[(3-KLOR-BENZYL)-(2-METOKSY-ACETYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 483 3-[ACETYL-(2,4-DIFLUOR-BENZYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 484 3-[(2, 4-DIFLUOR-BENZYL)-(2-METOKSY-ACETYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 505 3-{[2-(HYDROKSYIMINO-METYL)-4-METYL-BENZOYL]-ISOPROPYL-AMINO}-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 512 3-[(4-BENZYLOKSYKARBONYLAMINO-SYKLOHEKSYL)-(2,4-DIKLOR-BENZOYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE; Forbindelse 515 3-[(4-BENZYLOKSYKARBONYLAMINO-SYKLOHEKSYL)-(2,4-DIKLOR-BENZOYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE; Forbindelse 545 3-[(2-TERT-BUTOKSYKARBONYLAMINO-l-METYL-ETYL)-(2,4-DIKLOR-BENZOYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE; Forbindelse 552 5-BROM-3-(TOLUEN-2-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 555 3-[[2-(TERT-BUTYL-DIMETYL-SILANYLOKSY)-1-METYL-2-FENYL-ETYL]-(2,4-DIKLOR-BENZOYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 556 3-[[2-(TERT-BUTYL-DIMETYL-SILANYLOKSY)-1-METYL-2-FENYL-ETYL]-(2,4-DIKLOR-BENZOYL)-AMINO]-5-FENYL-TIOFEN-2-KARBOKSYLSYRE;
Forbindelse 566 5-FENYL-3-(TOLUEN-4-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRETIAZOL-2-YLAMID;
Forbindelse 567 5-FENYL-3-(TOLUEN-4-SULFONYLAMINO)-TIOFEN-2-KARBOKSYLSYRESYKLOBUTYLAMID;
Forbindelse 568 3-(2, 4-DIMETYL-BENZENSULFONYLAMINO)-5-FENYLTIOFEN-2-KARBOKSYLSYREAMID; og
Forbindelse 569 5-BROM-3-[(2,4-DIKLORBENZOYL)-ISOPROPYL-AMINO] -TIOFEN-2-KARBOKSYLSYRE.
2. Forbindelse ifølge krav 1,
karakterisert vedat X er:
3. Forbindelse ifølge krav 1,karakterisert vedat X er:
4. Forbindelse ifølge krav 2,karakterisert vedatMer:
5. Forbindelse ifølge krav 2,karakterisert vedat M er
6. Forbindelse ifølge krav 3,karakterisert vedatJer
7. Forbindelse ifølge krav 6,karakterisert vedat W er 0.
8. Forbindelse ifølge krav 3,karakterisert vedatJer:
9. Forbindelse ifølge hvilket som helst av kravene 1 til 8,
karakterisert vedatZerH.
10. Forbindelse ifølge hvilket som helst av kravene 1 til 9,
karakterisert vedat Ri er C2-i2-alkyl.
11. Forbindelse ifølge hvilket som helst av kravene 1 til 9,
karakterisert vedat Ri er C6-i4-aryl.
12. Forbindelse ifølge hvilket som helst av kravene 1 til 9,
karakterisert vedat Ri er en C3_i2-heteroring.
13. Forbindelse ifølge hvilket som helst av kravene 1 til 9,
karakterisert vedat Ri er t-butyl, isobutyl, allyl, etynyl, 2-fenyletenyl, isobutenyl, benzyl, fenyl, fenetyl, benzodioksolyl, tienyl, tiofenyl, pyridinyl, isoksazolyl, tiazolyl, pyrazolyl, tetrazolyl, benzofuranyl, indolyl, furanyl eller benzotiofenyl, som i hvert tilfelle er usubstituert eller substituert én eller flere ganger med halogen, nitro, nitroso, SO3R12, P03RcRd, CONR13R14, COOH, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C6-i2-aralkyl, C6-i2-aryl, Ci-6-alkyloksy, C2-6-alkenyloksy, C2-6-alkynyloksy, C6-i2-aryloksy, C (0) Ci_6-alkyl, C (0) C2-6-alkenyl, C (0) C2-6-alkynyl, C (0) C6-i2~aryl, C (0) C6-i2-aralkyl, C3-i0-heteroring, hydroksyl, NR13R14, C(0)0Ri2, cyan, azido, amidino eller guanido; og
Ri2/Rc, Rd, R13og R14er hver uavhe ngig av hverandre H, C1-12— alkyl, C2_i2-alkenyl, C2_i2-alkynyl, C6-i4-aryl, C3-i2-heteroring, C3_i8-heteroaralkyl eller C6-i8-aralkyl;
eller Rc og Rd danner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
eller Ri3og R14danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
14. Forbindelse ifølge krav 13,
karakterisert vedat Ri er etynyl som er substituert eller usubstituert.
15. Forbindelse ifølge krav 13,
karakterisert vedat Ri er furanyl som er substituert eller usubstituert.
16. Forbindelse ifølge krav 13,
karakterisert vedat Ri er pyridinyl som er substituert eller usubstituert.
17. Forbindelse ifølge krav 13,
karakterisert vedat Ri er fenyl.
18. Forbindelse ifølge krav 13,karakterisert vedat Ri er fenyl substituert med minst ett fluorid.
19. Forbindelse ifølge krav 13,karakterisert vedat Ri er fenyl substituert med minst ett klorid.
20. Forbindelse ifølge krav 13,karakterisert vedat Ri er fenyl substituert med minst én metyl.
21. Forbindelse ifølge krav 13,karakterisert vedat Ri er fenyl substituert med minst én metoksy.
22. Forbindelse ifølge krav 13,karakterisert vedat Ri er tienyl.
23. Forbindelse ifølge krav 13,karakterisert vedat Ri er tienyl substituert med minst ett halogenatom.
24. Forbindelse ifølge krav 13,karakterisert vedat Ri er tienyl substituert med minst én metyl.
25. Forbindelse ifølge krav 13,karakterisert vedat Ri er pyridinyl.
26. Forbindelse ifølge hvilket som helst av kravene 1 - 25,karakterisert vedat Y<1>er en binding.
27. Forbindelse ifølge hvilket som helst av kravene 1 til 26,
karakterisert vedat Y er COOH.
28. Forbindelse ifølge hvilket som helst av kravene 1 til 27,
karakterisert vedat R3er Ci-12-alkyl, C2-12-alkenyl, C2-i2_alkynyl, C6-i4-aryl, C3_i2-heteroring, C3-i8-heteroaralkyl eller C6-i8_aralkyl.
29. Forbindelse ifølge hvilket som helst av kravene 1 til 27,
karakterisert vedat R3er H.
30. Forbindelse ifølge krav 28,
karakteris e» r t ved at R3er Ci-12-alkyl, C6-18-aralkyl, C3_i2-heteroring eller C3_i8-heteroaralkyl.
31. Forbindelse ifølge krav 28,karakterisert vedat R3er Ci_i2-alkyl.
32. Forbindelse ifølge' krav 28,karakterisert vedat R3er C6-i8-aralkyl.
33. Forbindelse ifølge krav 28,karakterisert vedat R3er C3_i2-heteroring.
34. Forbindelse ifølge krav 28,karakterisert vedat R3er metyl, etyl, isopropyl, syklopropyl, sykloheksyl, allyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, aziridinyl, pyridinyl, piperidinylmetyl, dioksanyl, azepanyl eller benzyl; som i hvert tilfelle er usubstituert eller substituert én eller flere ganger med halogen, nitro, nitroso, SO3R12, P03RcRd, CONR13R14, Ci_6-alkyl, C2-6-alkenyl, C2-6~alkynyl, C6-i2-aralkyl, C6-i2-aryl, Ci-6-alkyloksy, C2-6-alkenyloksy, C2-6_alkynyloksy, C6-i2-aryloksy, C (0) Ci-6-alkyl, C (0) C2-6-alkenyl, C (0) C2-6-alkynyl, C (0) C6-i2-aryl, C(0)C6-i2-aralkyl, C3_i0-heteroring, hydroksyl, NRi3Ri4, C(0)0Ri2, cyan, azido, amidino eller guanido;
hvor Ri2/Rc, Rd, R13og R14er hver uavhengig av hverandre H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3-i8-heteroaralkyl eller C6-i8_aralkyl; eller Rc og Rd danner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer; eller
R13og R14danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
35. Forbindelse ifølge krav 34,
karakterisert vedat R3er metyl, isopropyl, piperidinyl, piperidinylmetyl eller sykloheksyl.
36. Forbindelse ifølge krav 28,
karakterisert vedat R3er benzyl, tiofenyl-metyl eller furanylmetyl.
37. Forbindelse ifølge krav 28,
karakterisert vedat R3er isopropyl.
38. Forbindelse ifølge hvilket som helst av kravene 1 til 37,
karakterisert vedat R2er C2-i2-alkyl, C6-i4~aryl eller C3-i2-heteroring.
39. Forbindelse ifølge krav 38,
karakterisert vedat R2er tienyl, furanyl, pyridinyl, oksazolyl, tiazolyl, pyrrolyl, benzofuranyl, indolyl, benzoksazolyl, benzotienyl, benzotiazolyl, piperazinyl, pyrrolidinyl eller kinolinyl, som i hvert tilfelle er usubstituert eller substituert én eller flere ganger med halogen, nitro, nitroso, SO3R12, P03RcRd, CONR13R14, Ci_6-alkyl, C2-6-alkenyl, C2-e-alkynyl, C6-i2_aralkyl, C6-i2-aryl, Ci-6-alkyloksy, C2-6-alkenyloksy, C2-6-alkynyloksy, C6-i2-aryloksy, C (0) Ci-6-alkyl, C (0) C2-6~alkenyl, C (0) C2-e-alkynyl, C (0) C6-i2-aryl, C (0) C6-i2-aralkyl, C3-i0-heteroring, hydroksyl, NR13R14, C(0)0Ri2, cyan, azido, amidino eller guanido; hvor R12, Rc, Rd, R13og Ri4er hver uavhengig av hverandre H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-i2-heteroring, C3_i8-heteroaralkyl eller C6-i8_aralkyl; eller Rc og Rd danner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer; og
Ri3og R14danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
40. Forbindelse ifølge krav 38,
karakterisert vedat R2er C2-i2-alkyl.
41. Forbindelse ifølge krav 38,
karakterisert vedat R2er syklopropyl, syklobutyl, syklopentyl, syklopentenyl, sykloheksyl, sykloheptyl, 2-(syklopentyl)etyl, etyl, vinyl, propyl, propenyl, isopropyl, butyl, butenyl, isobutyl, pentyl, neopentyl eller t-butyl, som i hvert tilfelle er usubstituert eller substituert én eller flere ganger med halogen, nitro, nitroso, SO3R12, P03RcRd, CONR13R14, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C6-i2-aralkyl, C6-i2-aryl, Ci-6-alkyloksy, C2-6_alkenyloksy, C2-6_alkynyloksy, C6-i2-aryloksy, C(0)Ci-6-alkyl, C (0) C2-6-alkenyl, C (0) C2-6-alkynyl, C (0) C6-i2-aryl, C (0) C6-i2-aralkyl, C3_i0-heteroring, hydroksyl, NRi3Ri4, C(0)0Ri2, cyan, azido, amidino eller guanido;
hvor R12, Rc, Rd, R13og Ri4er hver uavhengig av hverandre H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3-i2-heteroring, C3_i8-heteroaralkyl eller C6-i8-aralkyl; eller Rc og Rd danner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer; eller
R13og R14danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
42. Forbindelse ifølge krav 38,
karakterisert vedat R2er C6-i4-aryl.
43. Forbindelse ifølge kravene 42,karakterisert vedat R2er fenyl substituert med én eller flere substituenter valgt fra halogen, nitro, nitroso, SO3R12, P03RcRd, CONR13R14, Ci-6-alkyl, C2-6-alkenyl, C2-e-alkynyl, C6-i2-aralkyl, C6-i2-aryl, Ci-6-alkyloksy, C2-6-alkenyloksy, C2-6-alkynyloksy, C6-i2_aryloksy, C (0) Ci_6-alkyl, C (0) C2-6_alkenyl, C (0) C2-6-alkynyl, C (0) C6-i2-aryl, C (0) C6-i2-aralkyl, C3-i0-heteroring, hydroksyl, NR13R14, C(0)0Ri2, cyan, azido, amidino og guanido;
hvor R12, Rc, Rd, Ri3og Ri4er hver uavhengig av hverandre H, Ci-12-alkyl, C2-i2-alkenyl, C2-i2-alkynyl, C6-i4_aryl, C3-i2-heteroring, C3-i8-heteroaralkyl eller C6-i8-aralkyl; eller Rc og Rd danner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer; eller
R13og R14danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
44. Forbindelse ifølge krav 42,
karakterisert vedatR2er fenyl substituert med én eller flere substituenter valgt fra halogen, nitro, CONRi3Ri4, Ci-e-alkyl, C2-6-alkenyl, Ci-6-alkyloksy, C (0) Ci-6-alkyl, C6-i2-aryl, C3_io-heteroring, hydroksyl, NRi3Ri4, C(0)0Ri2, cyan og azido, hvor Ri2, Ri3og Ri4er hver uavhengig av hverandre H, C1-12-alkyl, C2-i2_alkenyl, C2-i2-alkynyl, C6-i4-aryl, C3_i2-heteroring, C3_i8-heteroaralkyl eller C6-i8-aralkyl; eller
R13og R14danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
45. Forbindelse ifølge krav 42,karakterisert vedat R2er fenyl substituert med én eller to substituenter valgt fra halogen, Ci-6-alkyl, NR13R14, nitro, CONR13R14, C (0) OCi-e-alkyl, COOH eller Ci-6-alkyloksy-C (0) OR12, cyan og azido, hvor Ri2, R13og R14er hver uavhengig av hverandre H, Ci-12-alkyl, C2-i2~alkenyl, C2-i2~alkynyl, C6-i4-aryl, C3_i2-heteroring, C3_i8-heteroaralkyl eller C6-i8-aralkyl; eller
R13og R14danner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer.
46. Forbindelse ifølge krav 45,karakterisert vedat R2er metylfenyl.
47. Forbindelse ifølge krav 45,karakterisert vedat R2er diklorfenyl.
48. Forbindelse ifølge krav 45,karakterisert vedat R2er klorfenyl.
49. Forbindelse ifølge krav 1,
karakterisert vedat den er valgt blant: Forbind. 1 3-[(4-klor-2,5-dimetylbenzensulfonyl)-(3-jod-
benzyl) amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 2 3-[ (3-benzofuran-2-yl-benzyl)-(4-klor-2,5-
dimetylbenzensulfonyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 3 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-
fenyltiofen-2-karboksylsyre, Forbind. 4 3-{(2,4-diklorbenzyl)-[5-(3-trifluormetylfenyl)-
furan-2-ylmetyl]amino}-5-fenyltiofen-2-karboksylsyre, Forbind. 5 3-[(4-klor-2,5-dimetylbenzensulfonyl)metylamino]-
5-fenyltiofen-2-karboksylsyre, Forbind. 6 5-(4-fluorfenyl)-3-(toluen-4-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 7 3-(2,4-diklorbenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 8 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-(4-
fluorfenyl)tiofen-2-karboksylsyre, Forbind. 9 3-[(2,4-diklorbenzoyl)metylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 10 5-tert.-butyl-3-(4-klorbenzensulfonylamino)tiofen-
2-karboksylsyre, Forbind. 11 4-(toluen-4-sulfonylamino)-[2,3']bitiofenyl-5-
karboksylsyre, Forbind. 12 3-[(5-benzofuran-2-yl-tiofen-2-ylmetyl)-(2,4-
diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 13 5-fenyl-3-(toluen-4-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 14 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-(4-
klorfenyl)tiofen-2-karboksylsyre, Forbind. 15 5-fenyl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 16 5-fenyl-3-(toluen-3-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 17 3-benzensulfonylamino-5-fenyltiofen-2-karboksyl
syre, Forbind. 18 3-(4-klorbenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 19 3-(4-klor-2,5-dimetylbenzensulfonylamino)-5-(4-
isobutylfenyl)tiofen-2-karboksylsyre, Forbind. 20 5-tert.-butyl-3-(4-klor-2,5-dimetylbenzensulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 21 3-(2,5-dimetylbenzensulfonylamino)-5-fenyltiofen-
2-karboksylsyre, Forbind. 22 3-(4-metoksy-2,3,6-trimetylbenzensulfonylamino)-5-
fenyltiofen-2-karboksylsyre, Forbind. 23 5-fenyl-3-(tiofen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 24 4-(4-klor-2,5-dimetylbenzensulfonylamino)-[2,3']-
bitiofeny1-5-karboksylsyre, Forbind. 25 5-(3,5-bis-trifluormetylfenyl)-3-(4-klor-2, 5-
dimetylbenzensulfonylamino)tiofen-2-karboksylsyre, Forbind. 26 8-klor-3-(4-klor-2,5-dimetylbenzensulfonylamino)-
4H-1, 5-ditiasyklopenta[a]naftalen-2-karboksylsyre, Forbind. 27 3- (2, 4-difluorbenzensulfonylamino)-5-fenyltiofen-
2-karboksylsyre, Forbind. 28 3-[3-(2,6-diklorpyridin-4-yl)ureido]-5-fenyltio
fen-2-karboksylsyre, Forbind. 29 3-(2-klorbenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 30 3-(2-fluorbenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 31 5-fenyl-3-(2-trifluormetoksybenzensulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 32 3-(4-tert.-butylbenzensulfonylamino)-5-fenyltio
fen-2-karboksylsyre, Forbind. 33 3-(4-klorfenoksykarbonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 34 3-(3,4-diklorbenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 35 5-fenyl-3-(2-trifluormetylbenzensulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 36 3-(5-brom-6-klorpyridin-3-sulfonylamino)-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 37 3-(5-klortiofen-2-sulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 38 3-(5-klor-3-metylbenzo[b]tiofen-2-sulfonylamino)-
5-fenyltiofen-2-karboksylsyre, Forbind. 39 3-(4-brombenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 40 3-(3-klorbenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 41 3-(5-klor-l,3-dimetyl-lH-pyrazol-4-sulfonylamino)-
5-fenyltiofen-2-karboksylsyre, Forbind. 42 3-(3-brombenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 43 3-(4-isopropylbenzensulfonylamino)-5-fenyltiofen-
2-karboksylsyre, Forbind. 44 3-(2,6-diklorbenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 45 3-(2-nitrobenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 46 5-fenyl-3-(5-[1,2,3]tiadiazol-4-yl-tiofen-2-
sulfonylamino)tiofen-2-karboksylsyre, Forbind. 47 5-fenyl-3-(pyridin-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 48 3-(2,4-diklorbenzylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 49 3-(3-fluorbenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 50 5-fenyl-3-(3-trifluormetylbenzensulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 51 3-(2-karboksybenzoylamino)-5-fenyltiofen-2-
karboksylsyremetylester, Forbind. 52 5-fenyl-3-(4-trifluormetylbenzensulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 53 3-(2,5-difluorbenzensulfonylamino)-5-fenyltiofen-
2-karboksylsyre, Forbind. 54 3-(2-cyanbenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 55 3-(2,5-diklortiofen-3-sulfonylamino)-5-fenyltio
fen-2-karboksylsyre, Forbind. 56 4-(toluen-2-sulfonylamino)-[2,2']bitiofenyl-5-
karboksylsyre, Forbind. 57 5'-klor-4-(toluen-2-sulfonylamino)-[2,2<1>]bitio-
fenyl-5-karboksylsyre, Forbind. 58 5-(2,4-diklorfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 59 5-(4-nitrofenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 60 3-(toluen-2-sulfonylamino)-5-(4-trifluormetoksy-
fenyl)tiofen-2-karboksylsyre, Forbind. 61 5-kinolin-8-yl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 62 5-fenyl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 63 5-(3-nitrofenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 64 3-(toluen-2-sulfonylamino)-5-m-tolyltiofen-2-
karboksylsyre, Forbind. 65 5-(3-klorfenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 66 5-(4-fluorfenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 67 5-(3-fluorfenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 68 5-(4-klorfenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 69 5-(3,5-difluorfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 70 5-(3,4-difluorfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 71 3-(toluen-2-sulfonylamino)-5-vinyltiofen-2-
karboksylsyre, Forbind. 72 3-(4-klorbenzoylamino)-5-fenyltiofen-2-karboksyl
syre, Forbind. 73 3-[(4-klorbenzoyl)metylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 7 4 5-fenyl-3-[(tiofen-2-karbonyl)amino]tiofen-2-
karboksylsyre, Forbind. 75 3-[metyl(tiofen-2-karbonyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 76 3-(2-brombenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 77 3-(2,4-difluorbenzoylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 78 3-[(2,4-difluorbenzoyl)metylamino]-5-fenyltiofen-
2-karboksylsyre, Forbind. 79 3-(toluen-2-sulfonylamino)-5-trimetylsilanyl-
etynyltiofen-2-karboksylsyre, Forbind. 80 5-etynyl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 81 3-(toluen-2-sulfonylamino)5-(3-trifluormetoksy-
fenyl)tiofen-2-karboksylsyre, Forbind. 82 5-benzoyl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 83 5-(4-cyanfenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 84 5-(3-klor-4-fluorfenyl)-3-(toluen-2-sulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 85 5-(3,4-diklorfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 86 5-pyridin-4-yl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 87 5-pyridin-3-yl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 88 3-(toluen-2-sulfonylamino)-5-(4-trifluormetyl
fenyl)tiofen-2-karboksylsyre, Forbind. 89 5-(4-metansulfonylfenyl)-3-(toluen-2-sulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 90 5-(3-acetylaminofenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 91 5-(3-klor-4-fluorfenyl)-3-(toluen-2-sulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 92 3-(4-metylbenzoylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 93 3-[metyl-(4-metylbenzoyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 94 3-(3,5-dimetylisoksazol-4-sulfonylamino)-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 95 3-[(2-klorbenzoyl)metylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 96 3-(2-metylbenzoylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 97 3-[metyl-(2-metylbenzoyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 98 5-fenyl-3-(5-trifluormetylpyridin-2-sulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 99 5-fenyletynyl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 100 3-(2,5-dimetylbenzensulfonylamino)-5-(4-nitrofen-
yl)tiofen-2-karboksylsyre, Forbind. 101 5-(2-fluorfenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 102 5-(2-cyanfenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 103 5-(2-etoksykarbonylfenyl)-3-(toluen-2-sulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 104 5-(2-metoksyfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 105 3<1->metyl-4-(toluen-2-sulfonylamino)-[2,2']bitio-
fenyl-5-karboksylsyre, Forbind. 106 3-(toluen-2-sulfonylamino)-5-(2-trifluormetyl
fenyl)tiofen-2-karboksylsyre, Forbind. 107 3-(2,5-dimetylbenzensulfonylamino)-5-(4-fluor-
fenyl) tiofen-2-karboksylsyre, Forbind. 108 5-styryl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 109 3-(2,4-difluorbenzensulfonylamino)-5-(4-nitro-
fenyl)tiofen-2-karboksylsyre, Forbind. 110 3-(2,4-difluorbenzensulfonylamino)-5-(4-fluor-
fenyl) tiofen-2-karboksylsyre, Forbind. 111 3-[[5-(3-klor-4-fluorfenyl)tiofen-2-ylmetyl]-(2,4-
diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 112 3-[(4-okso-l-fenyl-1,3,8-triazaspiro[4,5]dekan-8-
karbonyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 113 3-{[4-(2-okso-2,3-dihydrobenzoimidazol-l-yl)-
piperidin-l-karbonyl]amino}-5-fenyltiofen-2-karboksylsyre, Forbind. 114 3-{[4-(4-nitrofenyl)piperazin-l-karbonyl]amino}-5-
fenyltiofen-2-karboksylsyre, Forbind. 115 5-(2-karboksyfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 116 5-(4-klorfenyl)-3-(pyridin-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 117 5-(3-cyanfenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 118 3-(2,5-dimetylbenzensulfonylamino)-5-p-tolyltio
fen-2-karboksylsyre, Forbind. 119 3-(2,4-difluorbenzensulfonylamino)-5-p-tolyltio
fen-2-karboksylsyre, Forbind. 120 5-fenetyl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 121 5-(3-etoksykarbonylfenyl)-3-(toluen-2-sulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 122 5-(4-metoksyfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 123 5-(3-metoksyfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 124 5-(4<1->brombifenyl-4-yl)-3-(toluen-2-sulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 125 5-(4-hydroksymetylfenyl)-3-(toluen-2-sulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 126 5-furan-3-yl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 127 5-benzofuran-2-yl-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 128 5-pyridin-2-yl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 129 5-(4-nitrofenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 130 3-[(benzofuran-2-karbonyl)metylamino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 131 3-[(2,4-dimetylbenzoyl)metylamino]-5-fenyltiofen-
2-karboksylsyre, Forbind. 132 3-[[5-(2-cyanfenyl)tiofen-2-ylmetyl]-(2,4-diklor
benzoyl) amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 133 5-(4-fluorfenyl)-3-(pyridin-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 134 5-[2-(4-klorfenyl)vinyl]-3-(toluen-2-sulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 135 3-benzensulfonylamino-5-(4-fluorfenyl)tiofen-2-
karboksylsyre, Forbind. 136 3-(2,4-dimetylbenzensulfonylamino)-5-fenyltiofen-
2-karboksylsyre, Forbind. 137 5-fenyl-3-(2-vinylbenzensulfonylamino)tiofen-2-
karboksylsyre, Forbind. 138 3-(4-brom-2,5-difluorbenzensulfonylamino)-5-
fenyltiofen-2-karboksylsyre, Forbind. 139 3-(2-acetylamino-4-metyltiazol-5-sulfonylamino)-5-
fenyltiofen-2-karboksylsyre, Forbind. 140 3-(4-acetylbenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 141 3-(4-fluor-2-trifluormetylbenzensulfonylamino)-5-
fenyltiofen-2-karboksylsyre, Forbind. 142 3-(2-metoksy-4-metylbenzensulfonylamino)-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 143 3-(3,4-difluorbenzensulfonylamino)-5-fenyltiofen-
2-karboksylsyre, Forbind. 144 4-(2-karboksy-5-fenyltiofen-3-ylsulfamoyl)-5-(4-
klorfenyl)-2-metylfuran-3-karboksylsyreetylester, Forbind. 145 3-(4-fluor-3-trifluormetylbenzensulfonylamino)-5-
fenyltiofen-2-karboksylsyre, Forbind. 146 3-(2-aminobenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 147 3-(3-nitrobenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 148 3-(4-nitrobenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 149 3-[(2,4-diklorbenzoyl)isopropylamino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 150 5-(3-cyanbenzyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 151 5-fenyl-3-(2,4,6-trifluorbenzensulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 152 3-(4-metoksy-2-nitrobenzensulfonylamino)-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 153 5-fenyl-3-(2,3,4-triklorbenzensulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 154 5-(2-karboksy-5-fenyltiofen-3-ylsulfamoyl)-2-
metylfuran-3-karboksylsyremetylester, Forbind. 155 4-(2-karboksy-5-fenyltiofen-3-ylsulfamoyl)-2-
metyl-1,5-difenyl-lH-pyrrol-3-karboksylsyre-etylester, Forbind. 156 5-fenyl-3-{[4-(3-trifluormetylfenyl)piperazin-l-
karbonyl] amino}tiofen-2-karboksylsyre, Forbind. 157 3-{[4-(4-fluorfenyl)piperazin-l-karbonyl]amino}-5-
fenyltiofen-2-karboksylsyre, Forbind. 158 3-{[4-(2,6-dimetylfenyl)piperazin-l-karbonyl]-
amino}-5-fenyltiofen-2-karboksylsyre, Forbind. 159 3-{[4-(2-klorfenyl)piperazin-l-karbonyl]amino}-5-
fenyltiofen-2-karboksylsyre, Forbind. 160 3-{[4-(3-klorfenyl)piperazin-l-karbonyl]amino}-5-
fenyltiofen-2-karboksylsyre, Forbind. 161 4,4'-bis(toluen-2-sulfonylamino)-[2,2<1>]bitiofenyl-
5,5'-dikarboksylsyre, Forbind. 162 3-[allyl-(4-metylbenzoyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 163 5-(1-dimetylsulfamoyl-lH-pyrazol-4-yl)-3-(toluen-
2-sulfonylamino)tiofen-2-karboksylsyre, Forbind. 164 5-(3-aminofenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 165 5-(4-aminofenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 166 5-(4-acetylfenyl)-3-(toluen-2-sulfonylamino)tio
fen-2 -karboksylsyre, Forbind. 167 4-(2-karboksy-5-fenyltiofen-3-ylsulfamoyl)-2,5-
dimetyl-lH-pyrrol-3-karboksylsyreetylester, Forbind. 168 4-(2-karboksy-5-fenyltiofen-3-ylsulfamoyl)-5-(4-
klorfenyl)-3-metyl-l-fenyl-lH-pyrrol-2-karboksyl-syreetylester, Forbind. 169 3-(3,5-diklor-4-hydroksybenzensulfonylamino)-5-
fenyltiofen-2-karboksylsyre, Forbind. 170 5-(lH-pyrazol-4-yl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 171 5- (3-hydroksyfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 172 3-[metyl-(3-metylbutyryl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 173 3-{[2-(4-fluorfenyl)acetyl]metylamino}-5-fenyl-
tiof en-2 -karboksyl sy re, Forbind. 174 3-(4-pentylbenzensulfonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 175 3-(metylfenylacetylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 176 3-[2,5-bis-(2,2,2-trifluoretoksy)benzensulfonyl-
amino] -5-fenyltiofen-2-karboksylsyre, Forbind. 177 3-(4-metyl-2-nitrobenzensulfonylamino)-5-fenyltio
fen-2-karboksylsyre, Forbind. 178 5-tiazol-2-yl-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 179 5-fenyl-3-[3-(3-fenylpropyl)ureido]tiofen-2-
karboksylsyre, Forbind. 180 3-[(3,4-dihydro-lH-isokinolin-2-karbonyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 181 3-{[4-(4-metoksyfenyl)piperazin-l-karbonyl]amino}-
5-fenyltiofen-2-karboksylsyre, Forbind. 182 3-{[4-(6-metylpyridin-2-yl)piperazin-l-karbonyl]-
amino}-5-fenyltiofen-2-karboksylsyrehydroklorid, Forbind. 183 3-{[4-(4-klorbenzyl)piperazin-l-karbonyl]amino}-5-
fenyltiofen-2-karboksylsyrehydroklorid, Forbind. 184 5-(5-metylpyridin-2-yl)-3-(toluen-2-sulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 185 3-[etyl-(4-metylbenzoyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 186 3-[(3-klortiofen-2-karbonyl)metylamino]-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 187 3-[ (2-brombenzoyl)metylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 188 3-[ (4-butylbenzoyl)metylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 189 3-(2-klormetylbenzensulfonylamino)-5-fenyltiofen-
2-karboksylsyre, Forbind. 190 5-(4-hydroksyfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 191 5-(5-klorpyridin-2-yl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 192 5-(4-klorfenyl)-3-[metyl-(4-metylbenzoyl)amino]-
tiofen-2-karboksylsyre, Forbind. 193 5-(4-cyanfenyl)-3-[metyl-(4-metylbenzoyl)amino]-
tiofen-2-karboksylsyre, Forbind. 194 3-[metyl-(4-metylbenzoyl)amino]-5-(4-nitrofenyl)-
tiofen-2-karboksylsyre, Forbind. 195 5-(4-hydroksymetylfenyl)-3-[metyl-(4-metylbenzo-
yl) amino]tiofen-2-karboksylsyre, Forbind. 196 3-[metyl-(4-metylbenzoyl)amino]-5-(3-nitrofenyl)-
tiofen-2-karboksylsyre, Forbind. 197 5-(4-fluorfenyl)-3-[metyl-(4-metylbenzoyl)amino]-
tiofen-2-karboksylsyre, Forbind. 198 5-(4-metoksyfenyl)-3-[metyl-(4-metylbenzoyl)-
amino]tiofen-2-karboksylsyre, Forbind. 199 3-[metyl-(4-metylbenzoyl)amino]-5-p-tolyltiofen-2-
karboksylsyre, Forbind. 200 5-(4-aminofenyl)-3-[metyl-(4-metylbenzoyl)amino]-
tiofen-2-karboksylsyre, Forbind. 201 3-[syklopentyl-(2,4-diklorbenzoyl)amino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 202 5-benzo[1,3]dioksol-5-yl-3-(toluen-2-sulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 203 3-[(2-hydroksyetyl)-(4-metylbenzoyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 204 3-[(2,4-diklorbenzoyl)isobutylamino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 205 3-[(2-metoksy-4-metylbenzoyl)metylamino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 206 5-(3-cyanfenyl)-3-[metyl-(4-metylbenzoyl)amino]-
tiofen-2-karboksylsyre, Forbind. 207 5-(2-klorfenyl)-3-[metyl-(4-metylbenzoyl)amino]-
tiofen-2-karboksylsyre, Forbind. 208 3-[(2,4-diklorbenzoyl)fenylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 209 3-[4-(trifluormetylbenzoyl)metylamin]-5-fenyltio
fen-2-karboksylsyre, Forbind. 210 3-[(4-klorbenzoyl)isopropylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 211 3-[isopropyl-(4-metylbenzoyl)amino]-5-fenyltiofen-
2-karboksylsyre, Forbind. 212 5-(3,5-difluorfenyl)-3-[metyl-(4-metylbenzoyl)-
amino]tiofen-2-karboksylsyre, Forbind. 213 5-(3-fluorfenyl)-3-[metyl-(4-metylbenzoyl)amino]-
tiofen-2-karboksylsyre, Forbind. 214 5-(2,4-difluorfenyl)-3-[metyl-(4-metylbenzoyl)-
amino]tiofen-2-karboksylsyre, Forbind. 215 5-(4-hydroksyfenyl)-3-[metyl-(4-metylbenzoyl)-
amino]tiofen-2-karboksylsyre, Forbind. 216 3-[metyl-(4-metylbenzoyl)amino]-5-(4-trifluor-
metoksyfenyl)tiofen-2-karboksylsyre, Forbind. 217 5-(2-hydroksyfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 218 3-[(2-klorbenzoyl)isopropylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 219 3-[(3,5-diklorbenzoyl)isopropylamino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 220 3-(4-brom-2-metylbenzensulfonylamino)-5-fenyltio
fen-2-karboksylsyre, Forbind. 221 3-(5-karboksy-4-klor-2-fluorbenzensulfonylamino)-
5-fenyltiofen-2-karboksylsyre, Forbind. 222 5-fenyl-3-(2,3,4-trifluorbenzensulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 223 3-(4-brom-2-fluorbenzensulfonylamino)-5-(4-iso-
butylf enyl) tiofen-2-karboksylsyre, Forbind. 224 3-(4-brom-2-metylbenzensulfonylamino)-5-(4-iso-
butylf enyl)tiofen-2-karboksylsyre, Forbind. 225 5-(4-isobutylfenyl)-3-(3-metoksybenzensulfonyl-
amino) tiofen-2-karboksylsyre, Forbind. 226 3-[ (4-fluorbenzoyl)isopropylamino]-5-fenyltiofen-
2-karboksylsyre, Forbind. 227 3-[2,5-bis-(2,2,2-trifluoretoksy)benzensulfonyl-
amino] -5-(4-isobutylfenyl)tiofen-2-karboksylsyre, Forbind. 228 3-(2-klor-4-cyanbenzensulfonylamino)-5-(4-iso-
butylf enyl) tiofen-2-karboksylsyre, Forbind. 229 5'-acetyl-4-(toluen-2-sulfonylamino)-[2,2']bitio-
fenyl-5-karboksylsyre, Forbind. 230 5-benzo[b]tiofen-2-yl-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 231 5-(4-butylfenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 232 5-(4-etylfenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 233 3-[benzyl-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-
2-karboksylsyre, Forbind. 234 3-[(4-klor-2-metylbenzoyl)isopropylamino]-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 235 3-[(2,4-dimetylbenzensulfonyl)metylamino]-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 236 5-(4-acetylfenyl)-3-(2,4-dimetylbenzensulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 237 5-(4-acetylfenyl)-3-(toluen-2-sulfonylamino)tio
fen-2 -karboksylsyre, Forbind. 238 5-(4-acetylfenyl)-3-(4-klorbenzensulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 239 5-(4-karboksyfenyl)-3-(toluen-2-sulfonylamino)tio
fen-2-karboksylsyre-tert.-butylester, Forbind. 240 3-[(2,4-dimetylbenzensulfonyl)isopropylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 241 3-[acetyl-(4-klorbenzyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 242 3-etansulfonylamino-5-fenyltiofen-2-karboksylsyre, Forbind. 243 3-[isopropyl-(4-trifluormetylbenzoyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 244 3-[(2,4-diklorbenzoyl)-(3-metyl-but-2-enyl)amino]-
5-fenyltiofen-2-karboksylsyre, Forbind. 245 3-[(2,6-diklorpyridin-3-karbonyl)metylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 246 3-[(6-klorpyridin-3-karbonyl)isopropylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 247 3-[(4-tert.-butylbenzoyl)metylamino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 248 5-(4-karboksyfenyl)-3-(toluen-2-sulfonylamino)tio
fen-2- karboksyl syre, Forbind. 249 5-(4-etoksyfenyl)-3-(toluen-2-sulfonylamino)tio
fen-2- karboksyl sy re, Forbind. 250 3-[ (2,6-diklorpyridin-3-karbonyl)isopropylamino]-
5-fenyltiofen-2-karboksylsyre, Forbind. 251 3-[(benzo[b]tiofen-2-karbonyl)metylamino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 252 3-[metyl(naftalen-2-karbonyl)amino]-5-fenyltiofen-
2-karboksylsyre, Forbind. 253 3-[(3,4-diklorbenzoyl)metylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 254 3-[(3,5-diklorbenzoyl)metylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 255 3-[(4-brom-3-metylbenzoyl)metylamino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 256 3-[(3-klorbenzo[b]tiofen-2-karbonyl)metylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 257 3-[metyl-(4-metyl-3-nitrobenzoyl)amino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 258 5-(4-karbamoylfenyl)-3-(2,4-dimetylbenzensulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 259 5-(4-karbamoylfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 260 5-(lH-indol-5-yl)-3-(toluen-2-sulfonylamino)tio
fen-2 -karboksylsyre, Forbind. 261 3-[sek.-butyl-(2,4-diklorbenzoyl)amino]-5-fenyl-
tiof en-2 -karboksyl sy re, Forbind. 262 3-[(2,4-dimetylbenzoyl)isopropylamino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 263 5-(4-azidofenyl)-3-(toluen-2-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 264 3-[(2,4-diklorbenzoyl)-(1-fenyletyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 265 5-(4-karbamoylfenyl)-3-(4-klorbenzensulfonyl-
amino) tiofen-2-karboksylsyre, Forbind. 266 5-(2-fluorfenyl)-3-[metyl-(4-metylbenzoyl)amino]-
tiofen-2-karboksylsyre, Forbind. 267 3-[metyl-(4-metylbenzoyl)amino]-5-o-tolyltiofen-2-
karboksylsyre, Forbind. 268 3-[metyl-(4-metylbenzoyl)amino]-5-m-tolyltiofen-2-
karboksylsyre, Forbind. 269 5-(3-klorfenyl)-3-[metyl-(4-metylbenzoyl)amino]-
tiofen-2-karboksylsyre, Forbind. 270 5-(3,4-difluorfenyl)-3-[metyl-(4-metylbenzoyl)-
amino]tiofen-2-karboksylsyre, Forbind. 271 5-(3-aminofenyl)-3-[metyl-(4-metylbenzoyl)amino]-
tiofen-2-karboksylsyre, Forbind. 272 5-(3-acetylfenyl)-3-[metyl-(4-metylbenzoyl)amino]-
tiofen-2-karboksylsyre, Forbind. 273 5-(3-hydroksyfenyl)-3-[metyl-(4-metylbenzoyl)-
amino]tiofen-2-karboksylsyre, Forbind. 274 3-[metyl-(4-metylbenzoyl)amino]-5-(3-trifluor-
metylf enyl) tiofen-2-karboksylsyre, Forbind. 275 3-[metyl-(4-metylbenzoyl)amino]-5-(4-trifluor-
metylf enyl) tiofen-2-karboksylsyre, Forbind. 276 3-[(3,4-dimetoksybenzoyl)metylamino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 277 3-[metyl-(2,4,6-trifluorbenzoyl)amino]-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 278 3-[(2,3-difluor-4-trifluormetylbenzoyl)metyl
amino] -5-fenyltiofen-2-karboksylsyre, Forbind. 279 3-[(3-fluor-4-trifluormetylbenzoyl)metylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 280 3-[(2,3-difluor-4-metylbenzoyl)metylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 281 3-[(2-fluor-4-trifluormetylbenzoyl)metylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 282 5-(4-karbamoylfenyl)-3-(toluen-2-sulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 283 5-(4-fluorfenyl)-3-[isopropyl-(4-metylbenzoyl)-
amino]tiofen-2-karboksylsyre, Forbind. 284 3-[(2-brom-4-klorbenzoyl)metylamino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 285 3-(2,6-dimetylbenzensulfonylamino)-5-fenyltiofen-
2-karboksylsyre, Forbind. 286 3-[metyl-(4-metylsykloheksankarbonyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 287 3-[(2,4-diklorbenzoyl)isopropylamino]-5-fenyltio
fen-2-karboksylsyremetylester, Forbind. 288 5-(4-cyanfenyl)-3-(2,4-dimetylbenzensulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 289 3-(4-klorbenzensulfonylamino)-5-(4-cyanfenyl)-
tiofen-2-karboksylsyre, Forbind. 290 5-(4-cyanfenyl)-3-(toluen-4-sulfonylamino)tiofen-
2-karboksylsyre, Forbind. 291 5'-acetyl-4-(2,4-dimetylbenzensulfonylamino)-
[2,2']bitiofenyl-5-karboksylsyre, Forbind. 292 5<1->acetyl-4-(2,6-dimetylbenzensulfonylamino)-
[2,2']bitiofenyl-5-karboksylsyre, Forbind. 293 3-[metyl-(4-metyltiofen-2-karbonyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 294 5-(3-klorfenyl)-3-[(2,4-diklorbenzoyl)isopropyl-
amino] tiofen-2-karboksylsyre, Forbind. 295 5'-cyan-4-(toluen-2-sulfonylamino)-[2,2<1>]bitio-
fenyl-5-karboksylsyre, Forbind. 296 3-[metyl-(4-metylbenzoyl)amino]-5-pyridin-2-yl-
tiofen-2-karboksylsyre, Forbind. 297 3-[(2,4-diklortiobenzoyl)isopropylamino]-5-fenyl-
tiof en-2 -karboksyl syre, Forbind. 298 5-fenyl-3-(2,4,6-trimetylbenzensulfonylamino)tio
fen-2 -karboksylsyre, Forbind. 299 3-[(1-karboksyetyl)-(2,4-diklorbenzoyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 300 3-[(4-metylbenzoyl)-(3-metyl-but-2-enyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 301 3-[(2-hydroksy-4-metylbenzoyl)isopropylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 302 3-[metyl-(4-metylbenzoyl)amino]-5-pyridin-3-yl-
tiofen-2-karboksylsyre, Forbind. 303 5<1->acetyl-4-[metyl-(4-metylbenzoyl)amino]-[2,2']-
bitiofenyl-5-karboksylsyre, Forbind. 304 3-[isopropyl-(4-metylbenzoyl)amino]-5-(3-tri
fluormetylfenyl)tiofen-2-karboksylsyre, Forbind. 305 3-[isopropyl-(4-metylbenzoyl)amino]-5-m-tolyltio
fen-2-karboksylsyre, Forbind. 306 3-[(2-brom-4-klorbenzoyl)isopropylamino]-5-fenyl-
tiof en- 2 -karboksyl syre, Forbind. 307 3-[(4-klor-2-fluorbenzoyl)isopropylamino]-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 308 3-(2,4-dimetylbenzensulfonylamino)-4-metyl-5-
fenyltiofen-2-karboksylsyre, Forbind. 309 3-[(2-brom-4-metylbenzoyl)isopropylamino]-5-fenyl-
tiof en-2 -karboksyl sy re, Forbind. 310 3-[(4-klor-2-jodbenzoyl)isopropylamino]-5-fenyl-
tiof en-2 -karboksyl syre, Forbind. 311 3-[(4-cyanbenzoyl)isopropylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 312 3-[allyl-(4-metylbenzoyl)amino]-5-[4-(2-karboksy-
vinyl)fenyl]tiofen-2-karboksylsyre, Forbind. 313 3-[(4-klor-2-hydroksybenzoyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre, Forbind. 314 3-[(2,4-diklorbenzoyl)isopropylamino]-4-metyl-5-
fenyltiofen-2-karboksylsyre, Forbind. 315 5-tert.-butyl-3-(2,4-dimetylbenzensulfonylamino)-
tiofen-2-karboksylsyre, Forbind. 316 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 317 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 318 5-[4-(2-karboksyetyl)fenyl]-3-[(4-metylbenzoyl)-
propylamino]tiofen-2-karboksylsyre, Forbind. 319 5-benzofuran-2-yl-3-(2,4-dimetylbenzensulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 320 3-(2,4-dimetylbenzensulfonylamino)-5-(4-hydroksy-
metylfenyl)tiofen-2-karboksylsyre, Forbind. 321 3-(2,4-dimetylbenzensulfonylamino)-5-(4-metansul-
fonylfenyl)tiofen-2-karboksylsyre, Forbind. 322 5-[4-(2-karboksyvinyl)fenyl]-3-(2,4-dimetylbenzen-
sulf onylamino) tiofen-2-karboksylsyre, Forbind. 323 3-[allyl-(4-metylbenzoyl)amino]-5-[3-(2-karboksy-
vinyl) fenyl]tiofen-2-karboksylsyre, Forbind. 324 3-[isopropyl-(2,4,6-trimetylbenzoyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 325 5-[3-(2-karboksyetyl)fenyl]-3-[(4-metylbenzoyl)-
propylamino]tiofen-2-karboksylsyre, Forbind. 326 3-[(2-fluor-4-trifluormetylbenzoyl)isopropyl-
amino] -5-fenyltiofen-2-karboksylsyre, Forbind. 327 3-[tert.-butyl-(2,4-diklorbenzoyl)amino]-5-fenyl-
tiof en-2 -karboksyl syre, Forbind. 328 3-[(2-amino-4-klorbenzoyl)isopropylamino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 329 3-[(4-klor-2-nitrobenzoyl)isopropylamino]-5-fenyl-
tiof en-2 -karboksyl sy re, Forbind. 330 3-[(4-metylbenzoyl)-(3-trifluormetylbenzyl)amino]-
5-fenyltiofen-2-karboksylsyre, Forbind. 331 3-[(3-fluor-4-metylbenzoyl)isopropylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 332 5-(4-karboksyfenyl)-3-(2,4-dimetylbenzensulfonyl
amino) tiofen-2-karboksylsyre, Forbind. 333 3-[syklopropyl-(2,4-diklorbenzoyl)amino]-5-fenyl-
tiof en-2 -karboksyl sy re, Forbind. 334 3-[(3-tert.-butylbenzyl)-(4-metylbenzoyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 335 3-[(3-klorbenzyl)-(4-metylbenzoyl)amino]-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 336 3-[(2,4-difluorbenzyl)-(4-metylbenzoyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 337 3-[(4-klor-2,5-difluorbenzoyl)isopropylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 338 3-[(2,4-diklorbenzoyl)isopropylamino]-5-(2-metyl-
allyl)tiofen-2-karboksylsyre, Forbind. 339 3-{allyl-[2-(4-klorfenyl)acetyl]amino}-5-fenyltio
fen-2-karboksylsyre, Forbind. 340 3-[benzyl-(4-metylbenzoyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 341 3-[(4-klorbenzyl)-(4-metylbenzoyl)amino]-5-fenyl-
tiof en-2 -karboksyl syre, Forbind. 342 3-[(4-metylbenzoyl)-(4-nitrobenzyl)amino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 343 3-[(4-metylbenzoyl)-(2-metylbenzyl)amino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 344 3-[(3-metoksybenzyl)-(4-metylbenzoyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 345 3-[(2-klorbenzyl)-(4-metylbenzoyl)amino]-5-fenyl-
tiof en-2 -karboksyl sy re, Forbind. 346 3-[(2, 4-diklorbenzoyl)isopropylamino]-5-isobutyl-
tiofen-2-karboksylsyre, Forbind. 347 3-[allyl-(2-naftalen-2-yl-acetyl)amino]-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 348 3-{allyl-[2-(2,4-diklorfenyl)acetyl]amino}-5-
fenyltiofen-2-karboksylsyre, Forbind. 349 3-{allyl-[2-(2-klor-4-fluorfenyl)acetyl]amino}-5-
fenyltiofen-2-karboksylsyre, Forbind. 350 3-{allyl-[2-(3,4-diklorfenyl)acetyl]amino}-5-
fenyltiofen-2-karboksylsyre, Forbind. 351 3-{allyl-[2-(2,4-difluorfenyl)acetyl]amino}-5-
fenyltiofen-2-karboksylsyre, Forbind. 352 3-{allyl-[2-(4-trifluormetylfenyl)acetyl]amino}-5-
fenyltiofen-2-karboksylsyre, Forbind. 353 3-{allyl-[2-(2,6-diklorfenyl)acetyl]amino}-5-
fenyltiofen-2-karboksylsyre, Forbind. 354 3-[allyl-(2-m-tolylacetyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 355 5-(4-acetylfenyl)-3-[(2,4-diklorbenzoyl)isopropyl-
amino] tiofen-2-karboksylsyre, Forbind. 356 3-[(2,4-diklorbenzoyl)isopropylamino]-5-(4-fluor-
fenyl) tiofen-2-karboksylsyre, Forbind. 357 3-[(2,4-diklorbenzoyl)isopropylamino]-5-m-tolyl-
tiof en-2 -karboksyl syre, Forbind. 358 5'-acetyl-4-[(2,4-diklorbenzoyl)isopropylamino]-
[2,2']bitiofenyl-5-karboksylsyre, Forbind. 359 3-[(2,4-diklorbenzoyl)isopropylamino]-5-(3-tri
fluormetylfenyl)tiofen-2-karboksylsyre, Forbind. 360 4-[(2,4-diklorbenzoyl)isopropylamino]-5'-metyl-
[2,2']bitiofenyl-5-karboksylsyre, Forbind. 361 3-(2,4-dimetylbenzensulfonylamino)-5-(4-metoksy-
fenyl)tiofen-2-karboksylsyre, Forbind. 362 3-(sykloheksankarbonylisopropylamino)-5-fenyltio
fen-2-karboksylsyre, Forbind. 363 3-{(2,4-diklorbenzoyl)-[1-(2,4-diklorbenzoyl)-
piperidin-4-yl]amino}-5-fenyltiofen-2-karboksylsyre, Forbind. 364 4-[(2-karboksy-5-fenyltiofen-3-yl)-(4-metylbenzo-
yl) amino]piperidin-l-karboksylsyre-tert.-butylester, Forbind. 365 4-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklor
benzoyl) amino]piperidin-l-karboksylsyre-tert.-butylester, Forbind. 366 3-[(4-metylbenzoyl)piperidin-4-yl-amino]-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 367 5'-acetyl-4-(2,4-dimetylbenzensulfonylamino)-
[2,3']bitiofenyl-5-karboksylsyre, Forbind. 368 3-[(2,4-diklorbenzoyl)piperidin-4-yl-amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 369 5-(4-metansulfonylaminofenyl)-3-(toluen-2-sulfon
ylamino) tiofen-2-karboksylsyre, Forbind. 370 3-(4-fluor-2-metylbenzensulfonylamino)-5-fenyl-
tiof en-2 -karboksyl sy re, Forbind. 371 3-[(3-metylsykloheksankarbonyl)isopropylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 372 3-(4-klor-2-metylbenzensulfonylamino)-5-fenyltio
fen-2-karboksylsyre, Forbind. 373 3-[(2,4-diklorbenzoyl)isopropylamino]-5-(4-metan-
sulf onylf enyl) tiofen-2-karboksylsyre, Forbind. 374 3-[(2,4-diklorbenzoyl)isopropylamino]-5-(4-metan-
sulf inylf enyl) tiofen-2-karboksylsyre, Forbind. 375 5-(4-karboksyfenyl)-3-[(2,4-diklorbenzoyl)iso-
propylamino] tiofen-2-karboksylsyre, Forbind. 376 5-benzofuran-2-yl-3-[(2,4-diklorbenzoyl)iso-
propylamino] tiofen-2-karboksylsyre, Forbind. 377 3-[(2-acetoksy-4-metylbenzoyl)isopropylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 378 3-[isopropyl-(2-metylsykloheksankarbonyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 379 3-[isopropyl-(2-metylsykloheksankarbonyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 380 3- (sykloheptankarbonylisopropylairri.no) -5-fenyltio
fen-2-karboksylsyre, Forbind. 381 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-
(3-trifluormetylfenyl)tiofen-2-karboksylsyre, Forbind. 382 3-[(2, 4-diklorbenzoyl)isopropylamino]-5-metyltio-
fen-2-karboksylsyre, Forbind. 383 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-
(3-nitrofenyl)tiofen-2-karboksylsyre, Forbind. 384 3-[(3-syklopentylpropionyl)metylamino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 385 3-(butyrylmetylamino)-5-fenyltiofen-2-karboksyl
syre, Forbind. 386 3-(metylpent-4-enoylamino)-5-fenyltiofen-2-kar
boksylsyre, Forbind. 387 3-[isopropyl-(5-metyl-3-okso-3H-isoindol-l-yl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 388 3-[metyl-(3-metylbutyryl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 389 3- (metylpentanoylairri.no)-5-fenyltiofen-2-karboksyl
syre, Forbind. 390 3-[metyl-(4-metylpentanoyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 391 3-(syklopentankarbonyletylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 392 3-[(3-syklopentylpropionyl)etylamino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 393 3-(syklobutankarbonyletylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 394 3-(but-2-enoyletylamino)-5-fenyltiofen-2-karboks
ylsyre, Forbind. 395 3-[isopropyl-(4-metyl-2-vinylbenzoyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 396 3-[isopropyl-(4-metylsykloheks-l-enkarbonyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 397 3-(allylheksanoylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 398 3-(allylsyklobutankarbonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 399 3-(allylpentanoylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 400 3-[allyl-(4-metylpentanoyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 401 3-[allyl-(2-syklopentylacetyl)amino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 402 3-[(2-hydroksy-4-metylsykloheksankarbonyl)iso-
propylamino] -5-fenyltiofen-2-karboksylsyre, Forbind. 403 3-[(2,4-diklorbenzoyl)-(1-fenyletyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 404 3-[(2,4-diklorbenzoyl)-(1-fenyletyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 405 3-[isopropyl-(3-metylsyklopent-3-enkarbonyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 406 3-[(2-benzyloksy-4-metylbenzoyl)isopropylamino]-5-
(3-trifluormetylfenyl)tiofen-2-karboksylsyre, Forbind. 407 3-[(2,4-dimetylsykloheksankarbonyl)isopropyl-
amino] -5-fenyltiofen-2-karboksylsyre, Forbind. 408 3-[isopropyl-(3-metylsyklopentankarbonyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 409 3-[(2-hydroksy-4-metylsykloheksankarbonyl)isopro-
pylamino] -5-fenyltiofen-2-karboksylsyre, Forbind. 410 5-fenyl-3-[propionyl-(4-trifluormetylbenzyl)-
amino]tiofen-2-karboksylsyre, Forbind. 411 3-[isobutyryl-(4-trifluormetylbenzyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 412 3-[(3-metylbutyryl)-(4-trifluormetylbenzyl)amino]-
5-fenyltiofen-2-karboksylsyre, Forbind. 413 3-[syklopropankarbonyl-(4-trifluormetylbenzyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 414 3-[syklobutankarbonyl-(4-trifluormetylbenzyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 415 3-[butyryl-(4-trifluormetylbenzyl)amino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 416 3-[(2-syklopentylacetyl)-(4-trifluormetylbenzyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 417 3-[(4-tert.-butylbenzyl)propionylamino]-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 418 3-[(4-nitrobenzyl)propionylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 419 3-[(3-metylbutyryl)-(4-nitrobenzyl)amino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 420 3-[syklopropankarbonyl-(4-nitrobenzyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 421 3-[(2-klorbenzyl)isobutyrylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 422 3-[(2-klorbenzyl)-(3-metylbutyryl)amino]-5-fenyl-
tiof en- 2 -karboksyl sy re, Forbind. 423 3-[(2-klorbenzyl)syklopropankarbonylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 424 3-[(adamantan-l-karbonyl)isopropylamino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 425 3-[(2-klorbenzyl)syklobutankarbonylamino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 426 3-[acetyl-(2-metylbenzyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 427 3-[(2-metylbenzyl)propionylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 428 3-[(2-hydroksy-4-metylbenzoyl)isopropylamino]-5-
(3-trifluormetylfenyl)tiofen-2-karboksylsyre, Forbind. 429 3-[(l-acetylpiperidin-4-yl)-(2,4-diklorbenzoyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 430 3-[(2,4-diklorbenzoyl)isopropylamino]-5-[4-(1H-
tetrazol-5-yl)fenyl]tiofen-2-karboksylsyre, Forbind. 431 3- [ (2-cyan-4-metylbenzoyl)isopropylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 432 3-[syklobutankarbonyl-(2-metylbenzyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 433 3-[butyryl-(2-metylbenzyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 434 3-[acetyl-(3-metylbenzyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 435 3-[syklobutankarbonyl-(4-metylbenzyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 436 3-[sykloheksankarbonyl-(4-trifluormetylbenzyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 437 3-[(4-tert.-butylbenzyl)isobutyrylamino]-5-fenyl-
tiof en-2 -karboksyl sy re, Forbind. 438 3-[(4-tert. -butylbenzyl) syklopropankarbonylairri.no] -
5-fenyltiofen-2-karboksylsyre, Forbind. 439 3-[(4-tert.-butylbenzyl)syklobutankarbonylamino]-
5-fenyltiofen-2-karboksylsyre, Forbind. 440 3-[(4-tert.-butylbenzyl)butyrylamino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 441 3-[(4-tert.-butylbenzyl)sykloheksankarbonylamino]-
5-fenyltiofen-2-karboksylsyre, Forbind. 442 3-[(4-tert.-butylbenzyl)-(2-syklopentylacetyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 443 3-[(2-syklopentylacetyl)-(4-nitrobenzyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 444 3-[(2-klorbenzyl)sykloheksankarbonylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 445 3-[(2-syklopentylacetyl)-(3-metylbenzyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 446 3-[butyryl-(3-metylbenzyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 447 3-[butyryl-(2-klorbenzyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 448 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5- m-tolyltiofen-2-karboksylsyre, Forbind. 449 3-[ (2,4-diklorbenzoyl)isopropylamino]-5-tiazol-2-
yl-tiofen-2-karboksylsyre, Forbind. 450 3-(acetylbenzylamino)-5-fenyltiofen-2-karboksyl
syre, Forbind. 451 3-(benzylpropionylamino)-5-fenyltiofen-2-karboks
ylsyre, Forbind. 452 3-[benzyl-(2-metoksyacetyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 453 3-[benzyl-(3-metylbutyryl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 454 3-(benzylsyklopropankarbonylamino)-5-fenyltiofen-
2-karboksylsyre, Forbind. 455 3-[acetyl-(4-klorbenzyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 456 3-[(4-klorbenzyl)propionylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 457 3-[(4-klorbenzyl)isobutyrylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 458 3-[(4-klorbenzyl)-(3-metylbutyryl)amino]-5-fenyl-
tiof en-2 -karboksyl sy re, Forbind. 459 3-[(4-klorbenzyl)syklopropankarbonylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 460 5-(4-acetylfenyl)-3-[isopropyl-(4-metylsyklo
heksankarbonyl )amino]tiofen-2-karboksylsyre, Forbind. 461 3-[(4-klorbenzyl)syklobutankarbonylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 462 3-[butyryl-(4-klorbenzyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 463 3-[(4-klorbenzyl)-(2-syklopentylacetyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 464 3-[acetyl-(4-trifluormetylbenzyl)amino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 465 3-[isobutyryl-(3-metylbenzyl)amino]-5-fenyltiofen-
2-karboksylsyre, Forbind. 466 3-[syklopropankarbonyl-(3-metylbenzyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 467 3-[(4-metylbenzyl)propionylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 468 3-[isobutyryl-(4-metylbenzyl)amino]-5-fenyltiofen-
2-karboksylsyre, Forbind. 469 3-[syklopropankarbonyl-(4-metylbenzyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 470 3-[butyryl-(4-metylbenzyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 471 3-[(3-metoksybenzyl)propionylamino]-5-fenyltiofen-
2-karboksylsyre, Forbind. 472 3-[(3-metoksybenzyl)-(3-metylbutyryl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 473 3-[syklobutankarbonyl-(3-metoksybenzyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 474 3-[(2-karbamoyl-4-metylbenzoyl)isopropylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 475 3-[butyryl-(3-metoksybenzyl)amino]-5-fenyltiofen-
2-karboksylsyre, Forbind. 476 3-[acetyl-(3-klorbenzyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 477 3-[(3-klorbenzyl)propionylamino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 478 3-[(3-klorbenzyl)-(2-metoksyacetyl)amino]-5-fenyl-
tiof en- 2 -karboksyl sy re, Forbind. 479 3-[(3-klorbenzyl)-(3-metylbutyryl)amino]-5-fenyl-
tiof en-2 -karboksyl syre, Forbind. 480 3-[(3-klorbenzyl)syklopropankarbonylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 481 3-[(3-klorbenzyl)syklobutankarbonylamino]-5-fenyl-
tiof en-2-karboksylsyre, Forbind. 482 3-[butyryl-(3-klorbenzyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 483 3-[acetyl-(2,4-difluorbenzyl)amino]-5-fenyltiofen-
2-karboksylsyre, Forbind. 484 3-[(2,4-difluorbenzyl)-(2-metoksyacetyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 485 3-[(2,4-difluorbenzyl)isobutyrylamino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 486 3-[(2,4-difluorbenzyl)-(3-metylbutyryl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 487 3-[benzyl-(2-syklopentylacetyl)amino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 488 3-[(2,4-diklorbenzoyl)isopropylamino]-5-(lH-indol-
5-yl)tiofen-2-karboksylsyre, Forbind. 489 3-(benzylsyklobutankarbonylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 490 3-[sykloheksankarbonyl-(2,4-difluorbenzyl)amino]-
5-fenyltiofen-2-karboksylsyre, Forbind. 491 3-{allyl-[2-(4-metoksyfenyl)acetyl]amino}-5-
fenyltiofen-2-karboksylsyre, Forbind. 492 3-(etylheksanoylamino)-5-fenyltiofen-2-karboksyl
syre, Forbind. 493 3-(butyryletylamino)-5-fenyltiofen-2-karboksyl
syre, Forbind. 494 3-[etyl-(4-metylpentanoyl)amino]-5-fenyltiofen-2-
karboksylsyre, Forbind. 495 3-[syklobutankarbonyl-(2,4-difluorbenzyl)amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 496 3-[butyryl-(2,4-difluorbenzyl)amino]-5-fenyltio
fen-2-karboksylsyre, Forbind. 497 3-(syklopentankarbonylmetylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 498 3-(sykloheksankarbonylmetylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 499 3-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklor
benzoyl) amino]-pyrrolidin-l-karboksylsyre-tert.-butylester, Forbind. 500 3-[(1,4-dimetylsykloheksankarbonyl)isopropyl-
amino] -5-fenyltiofen-2-karboksylsyre, Forbind. 501 5-(4-etylfenyl)-3-[(2-hydroksy-4-metylbenzoyl)iso-
propylamino] tiofen-2-karboksylsyre, Forbind. 502 3-[(2-hydroksy-4-metylbenzoyl)isopropylamino]-5-m-
tolyltiof en-2-karboksylsyre, Forbind. 503 3-[(2,4-diklorbenzoyl)pyrrolidin-3-yl-amino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 504 4-{5-karboksy-4-[(2,4-diklorbenzoyl)isopropyl-
amino] tiof en-2-yl }-3,6-dihydro-2H-pyridin-l-karboksylsyre-benzylester, Forbind. 505 3-{[2-(hydroksyiminometyl)-4-metylbenzoyl]isopro-
pylamino} -5-f enyltiof en-2 -karboksylsyre, Forbind. 506 3-[(l-karbamimidoylpiperidin-4-yl)-(2,4-diklor
benzoyl) amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 507 4-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklor
benzoyl) amino]-azepan-l-karboksylsyre-tert.-butylester, Forbind. 508 4-{[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklor
benzoyl) amino]-metyl}piperidin-l-karboksylsyre-benzylester, Forbind. 509 3-[azepan-4-yl-(2,4-diklorbenzoyl)amino]-5-fenyl-
tiof en-2 -karboksyl sy re, Forbind. 510 3-[(4-metylsykloheksankarbonyl)piperidin-4-yl-
amino]-5-fenyltiofen-2-karboksylsyre-litiumsalt, Forbind. 511 3-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklor
benzoyl) amino]-piperidin-l-karboksylsyre-tert.-butylester, Forbind. 512 3-[(4-benzyloksykarbonylaminosykloheksyl)-(2,4-
diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 513 3-[isopropyl-(4-metyl-2-oksosykloheksankarbonyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 514 3-[(2,4-diklorbenzoyl)piperidin-3-yl-amino]-5-
fenyltiofen-2-karboksylsyre; forbindelse med generisk, uorganisk, nøytral bestanddel, Forbind. 515 3-[(4-benzyloksykarbonylaminosykloheksyl)-(2,4-
diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 516 3-[(2-benzyloksy-l-metyletyl)-(2,4-diklorbenzoyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 517 3-[(2,2-dimetyl-[1,3]dioksan-5-yl)-(4-metylsyklo
heksankarbonyl) amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 518 3-[(2,4-diklorbenzoyl)-(2-hydroksy-l-hydroksy-
metyletyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 519 3-[(2,4-diklorbenzoyl)piperidin-4-ylmetylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 520 3-[(2-klorbenzoyl)piperidin-4-ylmetylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 521 3-[(4,6-diklor-lH-indol-2-karbonyl)isopropyl-
amino] -5-fenyltiofen-2-karboksylsyre, Forbind. 522 3-[(2,4-diklorbenzoyl)-(2-hydroksy-l-metyletyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 523 4-{l-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklor
benzoyl) amino]etyl}piperidin-l-karboksylsyre-benzylester, Forbind. 524 4-{5-karboksy-4-[isopropyl-(4-metylsykloheksan
karbonyl) amino]tiofen-2-yl}-3,6-dihydro-2H-pyridin-1-karboksylsyrebenzylester, Forbind. 525 3-[(4-metylsykloheksankarbonyl)pyridin-4-yl-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 526 3-[(2,4-diklorbenzoyl)isopropylamino]-5-piperidin-4- yl-tiofen-2-karboksylsyre; forbindelse med trifluoreddiksyre, Forbind. 527 3-[isopropyl-(4-propylsykloheksankarbonyl)amino]-5- fenyltiofen-2-karboksylsyre, Forbind. 528 4-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklor
benzoyl) amino]-sykloheksylammonium; trifluoracetat, Forbind. 529 3-[(2,4-diklorbenzoyl)-(l-piperidin-4-yletyl)-
amino]-5-fenyltiofen-2-karboksylsyre; Forbind. 530 3-[(sykloheks-3-enkarbonyl)isopropylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 531 3-[(4-etylsykloheksankarbonyl)isopropylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 532 3-[(4-klorsykloheksankarbonyl)isopropylamino]-5-
fenyltiofen-2-karboksylsyre, Forbind. 533 4-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklor
benzoyl) amino]-3-metylpiperidin-l-karboksylsyre-benzylester, Forbind. 534 3-[(2,4-diklorbenzoyl)-(2-metoksysykloheksyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 535 3-[(2,4-diklorbenzoyl)-(2,2-dimetyl-[1,3]dioksan-
5-yl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 536 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-
(l-metylpiperidin-4-yl)tiofen-2-karboksylsyre, Forbind. 537 3-[(2,4-diklorbenzoyl)-(3-metylpiperidin-4-yl)-
amino]-5-fenyltiofen-2-karboksylsyre; Forbind. 538 3-[(2,4-diklorbenzoyl)-(2-hydroksysykloheksyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 539 4-{[(2-karboksy-5-fenyltiofen-3-yl)-(4-metylsyklo
heksankarbonyl )amino]metyl}piperidin-1-karboksy1-syrebenzylester, Forbind. 540 3-[((IR,2S,4R)-2-hydroksy-4-metylsykloheksan
karbonyl)isopropylamino]-5-fenyltiofen-2-karboksylsyre, Forbind. 541 3-{isopropyl-[1-(4-metoksy-2,3,6-trimetylbenzen-
sulfonyl)-5-metyl-l,2,3,6-tetrahydropyridin-2-karbonyl]amino}-5-fenyltiofen-2-karboksylsyre, Forbind. 542 3-[(2,4-diklorbenzoyl)isopropylamino]-4-fluor-5-
fenyltiofen-2-karboksylsyre, Forbind. 543 3-[(2,4-diklorbenzoyl)-(l-metylpiperidin-4-yl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 544 4-{[(2-karboksy-5-fenyltiofen-3-yl)-(4-metylsyklo
heksankarbonyl) amino]metyl}piperidinium; trifluoracetat, Forbind. 545 3-[(2-tert.-butoksykarbonylamino-l-metyletyl)-
(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 546 2-[(2-karboksy-5-fenyltiofen-3-yl)-(2, 4-diklor
benzoyl) amino]propylamintrifluoreddiksyresalt, Forbind. 547 3-[(3-karboksysyklopentyl)-(2,4-diklorbenzoyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 548 3-[(3-karboksysyklopentyl)-(2,4-diklorbenzoyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 549 2-[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-diklor
benzoyl) amino]sykloheksylammoniumklorid, Forbind. 550 3-(benzoylmetylamino)-5-fenyltiofen-2-
karboksylsyre, Forbind. 551 {[5-fenyl-3-(toluen-4-sulfonylamino)tiofen-2-
karbonyl]amino}eddiksyre, Forbind. 552 5-brom-3-(toluen-2-sulfonylamino)tiofen-2-
karboksylsyre, Forbind. 553 3-[sykloheksyl-(2,4-diklorbenzoyl)amino]-5-fenyl-
tiof en-2 -karboksylsyre, Forbind. 554 3-[[1,3]dioksan-5-yl-(4-metylsykloheksankarbonyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 555 3-[[2-(tert.-butyldimetylsilanyloksy)-l-metyl-2-
fenyletyl]-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 556 3-[[2-(tert.-butyldimetylsilanyloksy)-l-metyl-2-
fenyletyl]-(2,4-diklorbenzoyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 557 3-[(2,4-diklorbenzoyl)-(2-dietylaminotiazol-5-
ylmetyl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 558 (5-{[(2-karboksy-5-fenyltiofen-3-yl)-(2,4-
diklorbenzoyl)amino]metyl}tiazol-2-yl)dietyl-ammonium; klorid, Forbind. 559 5-(4-fluorfenyl)-3-[isopropyl-(4-metylsykloheksan
karbonyl) amino]tiofen-2-karboksylsyre, Forbind. 560 3-[((1S,2R,4S)-2-hydroksy-4-metylsykloheksankar
bonyl )isopropylamino]-5-fenyltiofen-2-karboksylsyre, Forbind. 561 3-[(2,4-diklorbenzoyl)-(2-metoksy-l-metyletyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 562 3-[(4S)-isopropyl-(4-metylsykloheks-l-enkarbonyl)-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 566 5-fenyl-3-(toluen-4-sulfonylamino)tiofen-2-
karboksylsyretiazol-2-ylamid, Forbind. 567 5-fenyl-3-(toluen-4-sulfonylamino)tiofen-2-
karboksylsyresyklobutylamid, Forbind. 568 3-(2,4-dimetylbenzensulfonylamino)-5-fenyltiofen-
2-karboksylsyreamid, Forbind. 569 5-brom-3-[(2,4-diklorbenzoyl)isopropylamino]tio
fen-2 -karboksylsyre, Forbind. 570 5-(4-klorfenyl)-3-[isopropyl-(4-metylsykloheksan
karbonyl) amino]tiofen-2-karboksylsyre, Forbind. 571 5-(4'-klorbifenyl-4-yl)-3-[isopropyl-(4-metyl
sykloheksankarbonyl) amino]tiofen-2-karboksylsyre, Forbind. 572 3-[(4-metylsykloheksankarbonyl)-(tetrahydropyran-
4-yl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 573 3-[(4-metylsykloheksankarbonyl)-(1-metylpiperidin-4- yl)amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 574 3-[(4-metylsykloheksankarbonyl)piperidin-4-yl-
amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 575 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-
(4-trifluormetylfenyl)tiofen-2-karboksylsyre, Forbind. 576 5-(4-cyanfenyl)-3-[isopropyl-(4-metylsyklo
heksankarbonyl) amino]tiofen-2-karboksylsyre, Forbind. 577 3-[isopropyl-(4-metylsykloheksankarbonyl)amino]-5-
(4-metoksyfenyl)tiofen-2-karboksylsyre, Forbind. 578 3-[(2-metoksy-l-metyletyl)-(4-metylsykloheksan
karbonyl) amino]-5-fenyltiofen-2-karboksylsyre, Forbind. 579 3-[sykloheksyl-(4-metylsykloheksankarbonyl)amino]-5- fenyltiofen-2-karboksylsyre, Forbind. 581 5-(4-isobutylfenyl)-3-[5-(5-trifluormetylisoksa-
zol-3-yl)tiofen-2-sulfonylamino]tiofen-2-karboksylsyre, Forbind. 582 5-(4-isobutylfenyl)-3-(2,3,4-trifluorbenzensul-
fonylamino)tiofen-2-karboksylsyre, Forbind. 583 3-[(2,4-diklorfenyl)isopropylkarbamoyl]-5-fenyl-
tiof en-2 -karboksyl sy re, Forbind. 584 3-(metyl-p-tolylkarbamoyl)-5-fenyltiofen-2-
karboksylsyre, og Forbind. 585 3-[(2,4-diklorfenyl)metylkarbamoyl]-5-fenyltiofen-
2-karboksylsyre, og farmasøytisk akseptable salter derav.
50. Farmasøytisk preparat,
karakterisert vedat det omfatter minst én forbindelse ifølge hvilket som helst av kravene 1 til 49 og minst én farmasøytisk akseptabel bærer eller eksipiens.
51. Farmasøytisk preparat ifølge krav 50,karakterisert vedat det videre omfatter ett eller flere ytterligere antivirale midler valgt fra interferon a og ribavirin.
52. Farmasøytisk preparat ifølge hvilket som helst av kravene 50 til 51,
karakterisert vedat preparatet er for inhibering eller redusering av aktiviteten til viral polymerase i en vert.
53. Farmasøytisk preparat ifølge krav 52,karakterisert vedat den virale polymerase er en viral Flaviviridae-polymerase.
54. Farmasøytisk preparat ifølge krav 52,karakterisert vedat den virale polymerase er en RNA-avhengig RNA-polymerase.
55. Farmasøytisk preparat ifølge krav 52,karakterisert vedat den virale polymerase er HCV-polymerase.
56. Farmasøytisk preparat ifølge hvilket som helst av kravene 50 til 51,
karakterisert vedat preparatet er for inhibering eller redusering av aktiviteten til viral helikase i en vert.
57. Farmasøytisk preparat ifølge krav 56,karakterisert vedat den virale helikase er en Flaviviridae-helikase.
58. Farmasøytisk preparat ifølge krav 56,karakterisert vedat den virale helikase er HCV-helikase.
59. Anvendelse av minst én forbindelse ifølge hvilket som helst av kravene 1 til 49 til fremstilling av et medikament for behandling eller profylakse av viral Fla viviridae- infeksjon hos en vert og/eller for inhibering eller reduksjon av aktiviteten til viral polymerase hos en vert og/eller for inhibering eller reduksjon av aktiviteten til viral helikase hos en vert.
60. Anvendelse ifølge krav 59, hvor Flaviviridae-virusinfeksjonen er hepatitt C-virusinfeksjon (HCV).
61. Anvendelse ifølge krav 59, som videre omfatter ett eller flere ytterligere antivirale midler valgt fra interferon a og ribavirin.
62. Anvendelse ifølge krav 59, hvor den virale polymerase er viral Flaviviridae-polymerase.
63. Anvendelse ifølge hvilket som helst av kravene 59 og 62, hvor den virale polymerase er RNA-avhengig RNA-polymerase.
64. Anvendelse ifølge hvilket som helst av kravene 59, 62 og 63, hvor den virale polymerase er HCV-polymerase.
65. Anvendelse ifølge krav 59, hvor den virale helikase er viral Flaviviridae-helikase.
66. Anvendelse ifølge hvilket som helst av kravene 59 og 65, hvor den virale helikase er HCV-helikase.
67. Fremgangsmåte for fremstilling av en forbindelse med formel A:
karakterisert vedat det tilsettes: en enoleter, et hydriddonerende middel og en organisk karboksylsyre,
til en forbindelse med formel B:
hvor:
Y<1>er valgt blant en binding, Ci-C6-alkyl, C2-C6~alkenyl og C2-C6~alkynyl,
Y er valgt blant COORi6, COCOOR5, P(0)ORaORb, S(0)OR5, S(0)2OR5, tetrazol, CON (R9) CH (R5) COOR5, CONRi0Rn, CON (R9)-S02-R5, CONRgOH og halogen, hvor R9, R5, Rio og Rner uavhengig av hverandre valgt blant H, Ci-Ci2-alkyl, C2-Ci2-alkenyl, C2-Ci2-alkynyl, C6-Ci4-aryl, C3~Ci2-heteroring, Ca-Cie-heteroaralkyl og C6-CiB-aralkyl, eller Rio og Rndanner sammen med nitrogenatomet en heteroring med 3 til 10 medlemmer;
Ra og Rber uavhengig av hverandre valgt blant H, Ci-Ci2-alkyl, C2_Ci2-alkenyl, C2-Ci2-alkynyl, C6-Ci4-aryl, C3-Ci2-heteroring, C3-Cj.8-heteroaralkyl og C6-Cis-aralkyl;
Ra og Rbdanner sammen med oksygenatomene en heteroring med 5 til 10 medlemmer;
Ri6er valgt blant H, Ci-Ci2-alkyl, C2-Ci2-alkenyl, C2-Ci2-alkynyl, C6-Ci4-aryl, C3-Ci2-heteroring, C3-Cis-heteroaralkyl og C6-C18-aralkyl;
Ri er valgt blant Ci-Ci2-alkyl, C2-Ci2-alkenyl, C2-Ci2-alkynyl, C6~Ci4~aryl, C3-Ci2~heteroring, C3-Ci8-heteroaralkyl, C6-Ci8-aralkyl og halogen;
R2er valgt blant Ci-Ci2-alkyl, C2-Ci2~alkenyl, C2~Ci2-alkynyl, C3-Ci2_heteroring, C3-Ci8-heteroaralkyl og C6-Cis-aralkyl;
R3er valgt blant H, Ci-Ci2~alkyl, C2-Ci2~alkenyl, C2-Ci2-alkynyl, C6-Ci4-aryl, C3-Ci2-heteroring, C3-Cie-heteroaralkyl og C6-C18-aralkyl; og
Z er valgt blant H, halogen og Ci-C6-alkyl.
68. Fremgangsmåte ifølge krav 67,karakterisert vedat enoleteren omfatter a) et alkylert eller silylert enolat av et aldehyd, keton eller ester, eller b) 2-metoksypropen.
69. Fremgangsmåte ifølge krav 68,karakterisert vedat enoleteren er 2-metoksypropen.
70. Fremgangsmåte ifølge krav 67,karakterisert vedat det hydriddonerende middel er valgt fra gruppen bestående av borhydrid, natriumhydrid, aluminiumhydrid, natriumborhydrid (NaBH4) , natriumcyanborhydrid (NaCNBH3) , natriumtriacetoksyborhydrid (NaBH(OAc)3) , boran-pyridin-kompleks (BH3-Py), harpiksbåret hydrid og polymerbåret hydrid.
71. Fremgangsmåte ifølge krav 70,karakterisert vedat det hydriddonerende middel er NaBH(OAc)3.
72. Fremgangsmåte ifølge krav 67,karakterisert vedat den organiske karboksylsyren er valgt fra gruppen bestående av alifatisk syre, aromatisk syre og dikarboksylsyre.
73. Fremgangsmåte ifølge krav 72,karakterisert vedat den organiske karboksylsyre er en alifatisk syre.
74. Fremgangsmåte ifølge krav 73,karakterisert vedat den alifatiske syre er valgt fra gruppen bestående av eddiksyre, maursyre og trifluoreddiksyre.
75. Fremgangsmåte ifølge krav 74,karakterisert vedat den alifatiske syren er eddiksyre.
76. Fremgangsmåte ifølge krav 72,karakterisert vedat karboksylsyren er en aromatisk syre.
77. Fremgangsmåte ifølge krav 76,karakterisert vedat den aromatiske syren omfatter benzosyre eller salisylsyre.
78. Fremgangsmåte ifølge krav 72,karakterisert vedat karboksylsyren er dikarboksylsyre.
79. Fremgangsmåte ifølge krav 78,karakterisert vedat dikarboksylsyren omfatter oksalsyre eller ftalsyre.
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JP2005531608A (ja) * | 2002-06-06 | 2005-10-20 | スミスクライン・ビーチャム・コーポレイション | NF−κB阻害剤 |
US7179836B2 (en) * | 2002-09-20 | 2007-02-20 | Smithkline Beecham Corporation | Chemical compounds |
TW200418863A (en) * | 2002-10-17 | 2004-10-01 | Upjohn Co | Novel anthelmintic and insecticidal compositions |
US20050075279A1 (en) | 2002-10-25 | 2005-04-07 | Boehringer Ingelheim International Gmbh | Macrocyclic peptides active against the hepatitis C virus |
KR101058696B1 (ko) * | 2002-12-10 | 2011-08-22 | 바이로켐 파마 인코포레이티드 | 후라비바이러스 감염의 치료 또는 예방을 위한 화합물과방법 |
CA2508990C (en) * | 2002-12-10 | 2013-05-28 | Virochem Pharma Inc. | Compounds and methods for the treatment or prevention of flavivirus infections |
WO2004052879A1 (en) * | 2002-12-10 | 2004-06-24 | Virochem Pharma Inc. | Thiophenederivatives for the treatment of flavivirus infections |
WO2004056746A1 (en) | 2002-12-23 | 2004-07-08 | 4Sc Ag | Cycloalkene dicarboxylic acid compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
US7365094B2 (en) | 2002-12-23 | 2008-04-29 | 4Sc Ag | Compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
MXPA05006890A (es) * | 2002-12-23 | 2006-04-07 | 4Sc Ag | Compuestos como agentes anti-inflamatorios, inmunomoduladores y anti-proliferativos. |
US7247736B2 (en) | 2002-12-23 | 2007-07-24 | 4Sc Ag | Method of identifying inhibitors of DHODH |
SE0300091D0 (sv) * | 2003-01-15 | 2003-01-15 | Astrazeneca Ab | Novel compounds |
SE0300092D0 (sv) * | 2003-01-15 | 2003-01-15 | Astrazeneca Ab | Novel compounds |
US7223785B2 (en) | 2003-01-22 | 2007-05-29 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
ES2320771T3 (es) | 2003-04-16 | 2009-05-28 | Bristol-Myers Squibb Company | Inhibidores peptidicos de isoquinolina macrociclicos del virus de la hepatitis c. |
US7112601B2 (en) | 2003-09-11 | 2006-09-26 | Bristol-Myers Squibb Company | Cycloalkyl heterocycles for treating hepatitis C virus |
TWI375679B (en) | 2003-10-14 | 2012-11-01 | Hoffmann La Roche | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
SI1677827T1 (sl) * | 2003-10-27 | 2009-06-30 | Vertex Pharma | Zdravilni sestavek proti virusu hepatitisa c (hcv) |
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