KR100441638B1 - 새로운 에이사이클릭 뉴클레오사이드 포스포네이트유도체, 그의 염 및 합성 방법 - Google Patents
새로운 에이사이클릭 뉴클레오사이드 포스포네이트유도체, 그의 염 및 합성 방법 Download PDFInfo
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- KR100441638B1 KR100441638B1 KR10-2002-0003051A KR20020003051A KR100441638B1 KR 100441638 B1 KR100441638 B1 KR 100441638B1 KR 20020003051 A KR20020003051 A KR 20020003051A KR 100441638 B1 KR100441638 B1 KR 100441638B1
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- Prior art keywords
- methyl
- compound
- amino
- oxy
- purin
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 150000003839 salts Chemical class 0.000 title claims abstract description 14
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical class NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title description 129
- 150000001875 compounds Chemical class 0.000 claims description 392
- -1 hydroxy, amino Chemical group 0.000 claims description 183
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 claims description 107
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 94
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 41
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 15
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- CKVPQQHQULRWSI-UHFFFAOYSA-N 4-butylphosphanylbutyl 2,2-dimethylpropanoate Chemical compound CCCCPCCCCOC(=O)C(C)(C)C CKVPQQHQULRWSI-UHFFFAOYSA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 10
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 9
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- KDNSSKPZBDNJDF-UHFFFAOYSA-N [1-[(2-aminopurin-9-yl)methyl]cyclopropyl]oxymethylphosphonic acid Chemical compound C12=NC(N)=NC=C2N=CN1CC1(OCP(O)(O)=O)CC1 KDNSSKPZBDNJDF-UHFFFAOYSA-N 0.000 claims description 7
- HHDJSHNMIYBEFV-UHFFFAOYSA-N [[1-[(2-amino-6-chloropurin-9-yl)methyl]cyclopropyl]oxymethyl-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate Chemical compound C1=NC2=C(Cl)N=C(N)N=C2N1CC1(OCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)CC1 HHDJSHNMIYBEFV-UHFFFAOYSA-N 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- IQFVBEFIAJGERK-UHFFFAOYSA-N [[1-[(2-amino-6-oxo-3h-purin-9-yl)methyl]cyclopropyl]oxymethyl-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate Chemical compound C1=NC(C(N=C(N)N2)=O)=C2N1CC1(OCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)CC1 IQFVBEFIAJGERK-UHFFFAOYSA-N 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- NNQNNHMEFBBMJY-UHFFFAOYSA-N 2-[1-[(2-amino-6-oxo-3h-purin-9-yl)methyl]cyclopropyl]ethylphosphonic acid Chemical compound C12=NC(N)=NC(O)=C2N=CN1CC1(CCP(O)(O)=O)CC1 NNQNNHMEFBBMJY-UHFFFAOYSA-N 0.000 claims description 5
- HJGDZNIKQVIHLM-UHFFFAOYSA-N 2-[1-[(2-aminopurin-9-yl)methyl]cyclopropyl]propylphosphonic acid Chemical compound C1=NC2=CN=C(N)N=C2N1CC1(C(CP(O)(O)=O)C)CC1 HJGDZNIKQVIHLM-UHFFFAOYSA-N 0.000 claims description 5
- SOZWOLUYZONMNT-UHFFFAOYSA-N 2-[1-[(6-aminopurin-9-yl)methyl]cyclopropyl]ethylphosphonic acid Chemical compound C1=NC=2C(N)=NC=NC=2N1CC1(CCP(O)(O)=O)CC1 SOZWOLUYZONMNT-UHFFFAOYSA-N 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- GFWRXBKJRHHOBQ-UHFFFAOYSA-N [[1-[(2-aminopurin-9-yl)methyl]cyclopropyl]oxymethyl-(2-methylpropanoyloxymethoxy)phosphoryl]oxymethyl 2-methylpropanoate Chemical compound C1=NC2=CN=C(N)N=C2N1CC1(OCP(=O)(OCOC(=O)C(C)C)OCOC(=O)C(C)C)CC1 GFWRXBKJRHHOBQ-UHFFFAOYSA-N 0.000 claims description 5
- YQQZFOTZFRQHRK-UHFFFAOYSA-N [[1-[(2-aminopurin-9-yl)methyl]cyclopropyl]oxymethyl-(piperidine-1-carbonyloxymethoxy)phosphoryl]oxymethyl piperidine-1-carboxylate Chemical compound C12=NC(N)=NC=C2N=CN1CC1(OCP(=O)(OCOC(=O)N2CCCCC2)OCOC(=O)N2CCCCC2)CC1 YQQZFOTZFRQHRK-UHFFFAOYSA-N 0.000 claims description 5
- LBMGUBIXYLAHIP-UHFFFAOYSA-N [[1-[(2-aminopurin-9-yl)methyl]cyclopropyl]oxymethyl-(pyrrolidine-1-carbonyloxymethoxy)phosphoryl]oxymethyl pyrrolidine-1-carboxylate Chemical compound C12=NC(N)=NC=C2N=CN1CC1(OCP(=O)(OCOC(=O)N2CCCC2)OCOC(=O)N2CCCC2)CC1 LBMGUBIXYLAHIP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910052760 oxygen Chemical group 0.000 claims description 5
- 239000001301 oxygen Chemical group 0.000 claims description 5
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
- VUDVGFWLOQIDAI-UHFFFAOYSA-N 2-[1-[(2-amino-6-oxo-3h-purin-9-yl)methyl]cyclopropyl]propylphosphonic acid Chemical compound C1=NC2=C(O)N=C(N)N=C2N1CC1(C(CP(O)(O)=O)C)CC1 VUDVGFWLOQIDAI-UHFFFAOYSA-N 0.000 claims description 4
- ARKBKBKWZNRBNM-UHFFFAOYSA-N 2-[1-[[2-amino-6-(4-methylphenyl)sulfanylpurin-9-yl]methyl]cyclopropyl]ethylphosphonic acid Chemical compound C1=CC(C)=CC=C1SC1=NC(N)=NC2=C1N=CN2CC1(CCP(O)(O)=O)CC1 ARKBKBKWZNRBNM-UHFFFAOYSA-N 0.000 claims description 4
- YMQMBIAIIHITON-UHFFFAOYSA-N [2-[1-[(6-aminopurin-9-yl)methyl]cyclopropyl]propyl-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate Chemical compound C1=NC2=C(N)N=CN=C2N1CC1(C(CP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C)CC1 YMQMBIAIIHITON-UHFFFAOYSA-N 0.000 claims description 4
- GEUIDDQMYDDZSI-UHFFFAOYSA-N [[1-[(2-amino-6-oxo-3h-purin-9-yl)methyl]-2,2-dimethylcyclopropyl]oxymethyl-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate Chemical compound C1=NC2=C(O)N=C(N)N=C2N1CC1(OCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)CC1(C)C GEUIDDQMYDDZSI-UHFFFAOYSA-N 0.000 claims description 4
- NKLGCQQNQKVRIZ-UHFFFAOYSA-N [[1-[(2-aminopurin-9-yl)methyl]-2-methylcyclopropyl]oxymethyl-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate Chemical compound CC1CC1(OCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)CN1C2=NC(N)=NC=C2N=C1 NKLGCQQNQKVRIZ-UHFFFAOYSA-N 0.000 claims description 4
- LIABTJQQLNRCSU-UHFFFAOYSA-N [[1-[(2-aminopurin-9-yl)methyl]-2-methylcyclopropyl]peroxy-methylphosphoryl]oxymethyl propan-2-yl carbonate Chemical compound CP(OCOC(=O)OC(C)C)(OOC1(C(C1)C)CN1C2=NC(=NC=C2N=C1)N)=O LIABTJQQLNRCSU-UHFFFAOYSA-N 0.000 claims description 4
- YEWJLUJHAMPZMH-UHFFFAOYSA-N [[1-[(6-aminopurin-9-yl)methyl]-2,2-dimethylcyclopropyl]peroxy-methylphosphoryl]oxymethyl propan-2-yl carbonate Chemical compound CP(OCOC(=O)OC(C)C)(OOC1(C(C1)(C)C)CN1C2=NC=NC(=C2N=C1)N)=O YEWJLUJHAMPZMH-UHFFFAOYSA-N 0.000 claims description 4
- VGWYPDOWKXCMHS-UHFFFAOYSA-N [[1-[(6-aminopurin-9-yl)methyl]-2-methylcyclopropyl]oxymethyl-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate Chemical compound CC1CC1(OCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)CN1C2=NC=NC(N)=C2N=C1 VGWYPDOWKXCMHS-UHFFFAOYSA-N 0.000 claims description 4
- LAJHSIZIGGIPEP-UHFFFAOYSA-N [[1-[(6-aminopurin-9-yl)methyl]cyclopropyl]oxymethyl-(cyclopentanecarbonyloxymethoxy)phosphoryl]oxymethyl cyclopentanecarboxylate Chemical compound C1=NC=2C(N)=NC=NC=2N1CC1(OCP(=O)(OCOC(=O)C2CCCC2)OCOC(=O)C2CCCC2)CC1 LAJHSIZIGGIPEP-UHFFFAOYSA-N 0.000 claims description 4
- PSNTZKJYCNHIOZ-UHFFFAOYSA-N [[1-[(6-aminopurin-9-yl)methyl]cyclopropyl]peroxy-methylphosphoryl]oxymethyl propan-2-yl carbonate Chemical compound CP(OCOC(=O)OC(C)C)(OOC1(CC1)CN1C2=NC=NC(=C2N=C1)N)=O PSNTZKJYCNHIOZ-UHFFFAOYSA-N 0.000 claims description 4
- OFGXUHRKEJNOBZ-UHFFFAOYSA-N [[1-[[2-amino-6-(4-methoxyphenyl)sulfanylpurin-9-yl]methyl]-2-methylcyclopropyl]oxymethyl-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate Chemical compound C1=CC(OC)=CC=C1SC1=NC(N)=NC2=C1N=CN2CC1(OCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C(C)C1 OFGXUHRKEJNOBZ-UHFFFAOYSA-N 0.000 claims description 4
- DPGMGOAMHIECPC-UHFFFAOYSA-N [[[1-[(2-aminopurin-9-yl)methyl]cyclopropyl]-ethylamino]methyl-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate Chemical compound C1=NC2=CN=C(N)N=C2N1CC1(N(CP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)CC)CC1 DPGMGOAMHIECPC-UHFFFAOYSA-N 0.000 claims description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 3
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 3
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 3
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 claims description 3
- OIIOPWHTJZYKIL-PMACEKPBSA-N (5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one Chemical compound C1(=C(N=C(C2=C(C(C3=CC=CC(=C3Cl)C3=NC(OC)=C(N=C3)CNC[C@H]3NC(=O)CC3)=CC=C2)Cl)C=N1)OC)CNC[C@H]1NC(=O)CC1 OIIOPWHTJZYKIL-PMACEKPBSA-N 0.000 claims description 3
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 claims description 3
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 claims description 3
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 3
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 claims description 3
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 claims description 3
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 claims description 3
- IJRKLHTZAIFUTB-UHFFFAOYSA-N 5-nitro-2-(2-phenylethylamino)benzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1NCCC1=CC=CC=C1 IJRKLHTZAIFUTB-UHFFFAOYSA-N 0.000 claims description 3
- 229940126657 Compound 17 Drugs 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 3
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 claims description 3
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 claims description 3
- CCADTCDFWSSIAM-UHFFFAOYSA-N [1-[(5-methyl-2,4-dioxopyrimidin-1-yl)methyl]cyclopropyl]oxymethylphosphonic acid Chemical compound O=C1NC(=O)C(C)=CN1CC1(OCP(O)(O)=O)CC1 CCADTCDFWSSIAM-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 229940125773 compound 10 Drugs 0.000 claims description 3
- 229940125758 compound 15 Drugs 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 3
- 229940125833 compound 23 Drugs 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- 229940125877 compound 31 Drugs 0.000 claims description 3
- 229940125807 compound 37 Drugs 0.000 claims description 3
- 229940127271 compound 49 Drugs 0.000 claims description 3
- 229940125898 compound 5 Drugs 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000005727 virus proliferation Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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Abstract
Description
화합물 번호 | EC50(μM) in HBV | CC50(μM) in HepG2.2.15 |
PMEA (대조약제) | 5.0 | >500 |
1 | >1.0 | >1000 |
2 | >0.1 | >1000 |
3 | >0.5 | >1000 |
5 | >0.1 | >1000 |
9 | >0.3 | >1000 |
10 | >0.08 | >1000 |
11 | >20 | >1000 |
13 | >1.0 | >1000 |
15 | >0.8 | >1000 |
17 | >0.5 | >1000 |
19 | >0.3 | >1000 |
23 | >0.1 | >1000 |
25 | >5.0 | >1000 |
31 | >50 | >1000 |
37 | >5.0 | >1000 |
41 | >1.0 | >1000 |
45 | >0.5 | >1000 |
46 | >1.0 | >1000 |
62 | >0.5 | >1000 |
66 | >0.1 | >1000 |
69 | >1.0 | >1000 |
95 | >0.5 | >1000 |
97 | >0.05 | >1000 |
98 | >1.0 | >1000 |
99 | >5.0 | >1000 |
100 | >0.05 | >1000 |
101 | >0.1 | >1000 |
화합물 번호 | 투여량(㎎/㎏/day) | 결과(약효군 마리수/ 투여군 마리수) | 투여방법 |
23 | 10 | 4/4 | 피하 |
66 | 10 | 4/4 | 피하 |
97 | 10 | 4/4 | 피하 |
95 | 10 | 3/4 | 피하 |
98 | 10 | 4/4 | 피하 |
PMEA 디피복실 | 2 | 1/3 | 경구 |
PMEA 디피복실 | 0.4 | 1/6 | 경구 |
10 | 2 | 4/4 | 경구 |
10 | 0.4 | 5/6 | 경구 |
Claims (8)
- 하기 화학식 1의 에이사이클릭 뉴클레오사이드 포스포네이트 유도체, 약제학적으로 허용되는 그의 염 및 입체화학적 이성체:[화학식 1]상기식에서는 단일결합 또는 이중결합을 나타내며,R1, R2, R3, R7및 R8은 각각 독립적으로 수소, 할로겐, 하이드록시, 아미노, C1-C7-알킬, C2-C6-알케닐, C1-C5-알킬아미노, C1-C5-아미노알킬, 또는 C1-C5-알콕시를 나타내고,R4및 R5는 각각 독립적으로 수소를 나타내거나, 할로겐(특히, 불소), C1-C4-알콕시, 페녹시, C7-C10-페닐알콕시, 또는 C2-C5-아실옥시에 의해 치환되거나 비치환된 C1-C4-알킬을 나타내거나, C1-C7-아실, C6-C12-아릴 또는 치환되거나 비치환된 카바모일을 나타내거나, -(CH2)m-OC(=O)-R6을 나타내며, 여기서 m은 1 내지 12의 정수이고, R6은 C1-C12-알킬, C2-C7-알케닐, C1-C5-알콕시, C1-C7-알킬아미노, 디(C1-C7-알킬)아미노, C3-C6-사이클로알킬 또는 질소 및 산소로 구성된 그룹중에서 선택된 1 또는 2개의 헤테로원자를 포함하는 3 내지 6원 헤테로사이클을 나타내며,Y 는 -O-, -S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N-, -SiH(Z)-, 또는 =Si(Z)- 를 나타내고, 여기서 Z는 수소, 하이드록시 또는 할로겐을 나타내거나, C1-C7-알킬, C1-C5-알콕시, 알릴, 하이드록시-C1-C7-알킬, C1-C7-아미노알킬 또는 페닐을 나타내고,Q 는 하기 구조식의 그룹을 나타내며:여기에서X1, X2, X3및 X4는 각각 독립적으로 수소, 아미노, 하이드록시 또는 할로겐을 나타내거나, 각각 니트로 또는 C1-C5-알콕시에 의해 치환되거나 비치환된 C1-C7-알킬, C1-C5-알콕시, 알릴, 하이드록시-C1-C7-알킬, 페닐, 또는 페녹시를 나타내거나, 니트로, 아미노, C1-C6-알킬 또는 C1-C4-알콕시에 의해 치환되거나 비치환된 C6-C10-아릴티오를 나타내거나, C6-C12-아릴아미노, C1-C7-알킬아미노, 디(C1-C7-알킬)아미노, C3-C6-사이클로알킬아미노 또는의 구조를 나타내고, 여기에서 n은 1 또는 2의 정수이며, Y1은 O, CH2또는 N-R (R은 C1-C7-알킬 또는 C6-C12-아릴이다)을 나타낸다.
- 제1항에 있어서, 약제학적으로 허용되는 염이 황산, 메탄설폰산 또는 할로겐화수소산의 부가염인 화합물.
- 제1항에 있어서,는 단일결합을 나타내며,R1, R2, R3, R7및 R8은 각각 독립적으로 수소, 불소, 하이드록시, C1-C7-알킬, C2-C6-알케닐, C1-C5-알킬아미노, C1-C5-아미노알킬, 또는 C1-C5-알콕시를 나타내고,R4및 R5는 각각 독립적으로 수소를 나타내거나, 불소, C1-C4-알콕시, 또는 페녹시에 의해 치환되거나 비치환된 C1-C4-알킬을 나타내거나, C1-C5-알킬에 의해 치환된 카바모일을 나타내거나, -(CH2)m-OC(=O)-R6을 나타내며, 여기서 m은 1 내지 12의 정수이고, R6은 C1-C12-알킬, C2-C7-알케닐, C1-C5-알콕시, C1-C7-알킬아미노, 디(C1-C7-알킬)아미노, C3-C6-사이클로알킬 또는 질소 및 산소로 구성된 그룹중에서 선택된 1 또는 2개의 헤테로원자를 포함하는 3 내지 6원 헤테로사이클을 나타내며,Y 는 -O-, -S-, 또는 -N(Z)- 를 나타내고, 여기서 Z는 수소, 하이드록시, C1-C7-알킬, 또는 하이드록시-C1-C7-알킬을 나타내고,Q 는 하기 구조식의 그룹을 나타내며:여기에서X1은 수소, 아미노, 하이드록시 또는 할로겐을 나타내거나, 각각 니트로 또는 C1-C5-알콕시에 의해 치환되거나 비치환된 C1-C7-알킬, C1-C5-알콕시, 하이드록시-C1-C7-알킬, 또는 페녹시를 나타내거나, 니트로, 아미노, C1-C6-알킬 또는 C1-C4-알콕시에 의해 치환되거나 비치환된 C6-C10-아릴티오를 나타내거나, C6-C12-아릴아미노, C1-C7-알킬아미노, 디(C1-C7-알킬)아미노, C3-C6-사이클로알킬아미노 또는의 구조를 나타내고, 여기에서 n은 1 또는 2의 정수이며, Y1은 O, CH2또는 N-R (R은 C1-C7-알킬이다)을 나타내고,X2, X3및 X4는 각각 독립적으로 수소, 아미노, 하이드록시, 할로겐, C1-C7-알킬, C1-C5-알콕시, 또는 C1-C7-알킬아미노을 나타내는 화합물.
- 제1항에 있어서,({1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스폰산(화합물 1);3-[({1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 2);({1-[(2-아미노-6-클로로-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스폰산(화합물 3);3-[({1-[(2-아미노-6-클로로-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 4);({1-[(2-아미노-6-하이드록시-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸 포스폰산(화합물 5);3-[({1-[(2-아미노-6-하이드록시-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 6);({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스폰산(화합물 9);3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 10);({1-[(2-아미노-6-사이클로프로필아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스폰산(화합물 11);[(1-{[2-아미노-6-(디메틸아미노)-9H-퓨린-9-일]메틸}사이클로프로필)옥시]메틸포스폰산(화합물 15);3-{[(1-{[2-아미노-6-(디메틸아미노)-9H-퓨린-9-일]메틸}사이클로프로필)옥시]메틸}-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 16);[(1-{[2-아미노-6-(이소프로필아미노)-9H-퓨린-9-일]메틸}사이클로프로필)옥시]메틸포스폰산(화합물 17);3-{[(1-{[2-아미노-6-(이소프로필아미노)-9H-퓨린-9-일]메틸}사이클로프로필)옥시]메틸}-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 18);({1-[(2,6-디아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스폰산(화합물 19);3-[({1-[(2,6-디아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 20);({1-[(2-아미노-6-메톡시-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스폰산(화합물 21);3-[({1-[(2-아미노-6-메톡시-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 22);({1-[(2-아미노-6-에톡시-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스폰산(화합물 23);3-[({1-[(2-아미노-6-에톡시-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 24);[(1-{[5-메틸-2,4-디옥소-3,4-디하이드로-1(2H)-피리미디닐]메틸}사이클로프로필)옥시]메틸포스폰산(화합물 31);8,8-디메틸-3-{[(1-{[5-메틸-2,4-디옥소-3,4-디하이드로-1(2H)-피리미디닐]메틸}사이클로프로필)옥시]메틸}-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 32);[(1-{[2-아미노-6-(4-모폴리닐)-9H-퓨린-9-일]메틸}사이클로프로필)옥시]메틸포스폰산(화합물 37);3-{[(1-{[2-아미노-6-(4-모폴리닐)-9H-퓨린-9-일]메틸}사이클로프로필)옥시] 메틸}-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 38);비스(2,2,2-트리플루오로에틸) ({1-[(2-아미노-6-하이드록시-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스포네이트(화합물 45);비스(2,2,2-트리플루오로에틸) ({1-[(2-아미노-6-클로로-9H-퓨린-9-일)메틸] 사이클로프로필}옥시)메틸포스포네이트(화합물 46);비스(2,2,2-트리플루오로에틸) ({1-[(2,6-디아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스포네이트(화합물 47);비스(2,2,2-트리플루오로에틸) ({1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스포네이트(화합물 48);비스(2,2,2-트리플루오로에틸) ({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스포네이트(화합물 49);비스(2,2,2-트리플루오로에틸) ({1-[(2-아미노-6-디메틸아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스포네이트(화합물 52);비스(2,2,2-트리플루오로에틸) ({1-[(2-아미노-6-이소프로필아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스포네이트(화합물 53);비스(2,2,2-트리플루오로에틸) ({1-[(2-아미노-6-메톡시-9H-퓨린-9-일)메틸] 사이클로프로필}옥시)메틸포스포네이트(화합물 54);비스(2,2,2-트리플루오로에틸) [(1-{[2-아미노-6-(4-모폴리닐)-9H-퓨린-9-일]메틸}사이클로프로필)옥시]메틸포스포네이트(화합물 58);비스(2,2,2-트리플루오로에틸) [(1-{[2-아미노-6-(페닐설파닐)-9H-퓨린-9-일]메틸}사이클로프로필)옥시]메틸포스포네이트(화합물 61);비스(2,2,2-트리플루오로에틸) {[1-({2-아미노-6-[(4-메틸페닐)설파닐]-9H- 퓨린-9-일}메틸)사이클로프로필]옥시}메틸포스포네이트(화합물 62);비스(2,2,2-트리플루오로에틸) {[1-({2-아미노-6-[(4-메톡시페닐)설파닐]- 9H-퓨린-9-일}메틸)사이클로프로필]옥시}메틸포스포네이트(화합물 63);비스(2,2,2-트리플루오로에틸) {[1-({2-아미노-6-[(4-니트로페닐)설파닐]- 9H-퓨린-9-일}메틸)사이클로프로필]옥시}메틸포스포네이트(화합물 64);[(1-{[2-아미노-6-(페닐설파닐)-9H-퓨린-9-일]메틸}사이클로프로필)옥시]메틸포스폰산(화합물 65);{[1-({2-아미노-6-[(4-메틸페닐)설파닐]-9H-퓨린-9-일}메틸)사이클로프로필] 옥시}메틸포스폰산(화합물 66);3-({[1-({2-아미노-6-[(4-메틸페닐)설파닐]-9H-퓨린-9-일}메틸)사이클로프로필]옥시}메틸)-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 68);비스{[(t-부톡시카보닐)옥시]메틸}({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스포네이트(화합물 69);비스{[(이소프로폭시카보닐)옥시]메틸}({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스포네이트 (화합물 70);비스{[(에톡시카보닐)옥시]메틸}({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스포네이트(화합물 71);비스{[(이소부톡시카보닐)옥시]메틸}({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스포네이트(화합물 72);3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-9-메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파덱-1-일 3-메틸부타노에이트(화합물 74);3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8-메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 2-메틸프로파노에이트(화합물 78);3-({[1-({2-아미노-6-[(4-메톡시페닐)설파닐]-9H-퓨린-9-일}메틸)사이클로프로필]옥시}메틸)-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 79);3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-3,7-디옥소-7-(1-피롤리디닐)-2,4,6-트리옥사-3λ5-포스파헵트-1-일 1-피롤리딘카르복실레이트(화합물 80);3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-3,7-디옥소-7-(1-피페리디닐)-2,4,6-트리옥사-3λ5-포스파헵트-1-일 1-피페리딘카르복실레이트(화합물 81);3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-7-(4-모폴리닐)-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파헵트-1-일 4-모폴린카르복실레이트(화합물 82);비스{[(t-부톡시카보닐)옥시]메틸}[(1-{[2-아미노-6-하이드록시-9H-퓨린-9-일]메틸}사이클로프로필)옥시]메틸포스포네이트(화합물 83);비스{[(이소프로폭시카보닐)옥시]메틸}[(1-{[2-아미노-6-하이드록시-9H-퓨린-9-일]메틸}사이클로프로필)옥시]메틸포스포네이트(화합물 84);비스{[(이소프로폭시카보닐)옥시]메틸}{[1-({2-아미노-[6-(4-메톡시페닐)설파닐]-9H-퓨린-9-일}메틸)사이클로프로필]옥시}메틸포스포네이트(화합물 85);3-[({1-[(2-아미노-6-하이드록시-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-7-사이클로펜틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파헵트-1-일 사이클로펜탄카르복실레이트(화합물 86);3-({[1-({2-아미노-[6-(4-니트로페닐)설파닐]-9H-퓨린-9-일}메틸)사이클로프로필]옥시}메틸)-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 87);비스{[(이소프로폭시카보닐)옥시]메틸}{[1-({2-아미노-[6-(4-니트로페닐)설파닐]-9H-퓨린-9-일}메틸)사이클로프로필]옥시}메틸포스포네이트(화합물 88);비스{[(이소프로폭시카보닐)옥시]메틸}({1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸포스포네이트(화합물 89);3-[({1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-9-메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파덱-1-일 3-메틸부타노에이트(화합물 90);3-[({1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-7-사이클로펜틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파헵트-1-일 사이클로펜탄카르복실레이트(화합물 91);비스{[(t-부톡시카보닐)옥시]메틸}{[1-({2-아미노-[6-(4-메톡시페닐)설파닐]-9H-퓨린-9-일}메틸)사이클로프로필]옥시}메틸포스포네이트(화합물 92);비스{[(t-부톡시카보닐)옥시]메틸}{[1-({2-아미노-[6-(4-니트로페닐)설파닐]-9H-퓨린-9-일}메틸)사이클로프로필]옥시}메틸포스포네이트(화합물 93);{[1-({2-아미노-[6-(4-니트로페닐)설파닐]-9H-퓨린-9-일}메틸)사이클로프로필]옥시}메틸포스폰산(화합물 95);{[1-({2-아미노-[6-(4-메톡시페닐)설파닐]-9H-퓨린-9-일}메틸)사이클로프로필]옥시}메틸포스폰산(화합물 96);({1-[(2-아미노-6-하이드록시-9H-퓨린-9-일)메틸]-2-메틸사이클로프로필}옥시)메틸포스폰산(화합물 97);({1-[(2-아미노-9H-퓨린-9-일)메틸]-2-메틸사이클로프로필}옥시)메틸포스폰산(화합물 98);{[1-({2-아미노-[6-(4-메톡시페닐)설파닐]-9H-퓨린-9-일}메틸)-2-메틸사이클로프로필]옥시}메틸포스폰산(화합물 99);{[1-({2-아미노-[6-(4-니트로페닐)설파닐]-9H-퓨린-9-일}메틸)-2-메틸사이클로프로필]옥시}메틸포스폰산(화합물 100);{[1-({2-아미노-[6-(4-메틸페닐)설파닐]-9H-퓨린-9-일}메틸)-2-메틸사이클로프로필]옥시}메틸포스폰산(화합물 101);({1-[(2,6-디아미노-9H-퓨린-9-일)메틸]-2-메틸사이클로프로필}옥시)메틸포스폰산(화합물 102);({1-[(6-아미노-9H-퓨린-9-일)메틸]-2-메틸사이클로프로필}옥시)메틸포스폰산(화합물 103);3-[({1-[(2-아미노-6-하이드록시-9H-퓨린-9-일)메틸]-2-메틸사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 105);3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]-2-메틸사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 106);3-[({1-[(6-아미노-9H-퓨린-9-일)메틸]-2-메틸사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 107);3-({[1-({2-아미노-6-[(4-메톡시페닐)설파닐]-9H-퓨린-9-일}메틸)-2-메틸사이클로프로필]옥시}메틸)-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 108);비스{[(이소프로폭시카보닐)옥시]메틸}[(1-{[2-아미노-6-하이드록시-9H-퓨린-9-일]메틸}-2-메틸사이클로프로필)옥시]메틸포스포네이트(화합물 109);비스{[(이소프로폭시카보닐)옥시]메틸}({1-[(2-아미노-9H-퓨린-9-일)메틸]-2-메틸사이클로프로필}옥시)메틸포스포네이트(화합물 110);비스{[(이소프로폭시카보닐)옥시]메틸}{[1-({2-아미노-[6-(4-메톡시페닐)설파닐]-9H-퓨린-9-일}메틸)-2-메틸사이클로프로필]옥시}메틸포스포네이트(화합물 112);비스{[(t-부톡시카보닐)옥시]메틸}{[1-({2-아미노-[6-(4-메톡시페닐)설파닐]-9H-퓨린-9-일}메틸)-2-메틸사이클로프로필]옥시}메틸포스포네이트(화합물 113);비스(2,2,2-트리플루오로에틸){[1-({2-아미노-6-[(4-메톡시페닐)설파닐]-9H-퓨린-9-일}메틸)-2-메틸사이클로프로필]옥시}메틸포스포네이트(화합물 114);비스(2,2,2-트리플루오로에틸) {[1-({2-아미노-6-[(4-니트로페닐)설파닐]-9H-퓨린-9-일}메틸)-2-메틸사이클로프로필]옥시}메틸포스포네이트(화합물 115);비스{[(t-부톡시카보닐)옥시]메틸}{[1-({2-아미노-[6-(4-니트로페닐)설파닐]-9H-퓨린-9-일}메틸)-2-메틸사이클로프로필]옥시}메틸포스포네이트(화합물 116);비스{[(이소프로폭시카보닐)옥시]메틸}{[1-({2-아미노-[6-(4-니트로페닐)설파닐]-9H-퓨린-9-일}메틸)-2-메틸사이클로프로필]옥시}메틸포스포네이트(화합물 117);3-({[1-({2-아미노-6-[(4-니트로페닐)설파닐]-9H-퓨린-9-일}메틸)-2-메틸사이클로프로필]옥시}메틸)-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 118);({1-[(2-아미노-6-하이드록시-9H-퓨린-9-일)메틸]사이클로프로필}아미노)메틸포스폰산(화합물 119);({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}아미노)메틸포스폰산(화합물 120);({1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필}아미노)메틸포스폰산(화합물 121);[{1-[(2-아미노-6-하이드록시-9H-퓨린-9-일)메틸]사이클로프로필}(메틸)아미노]메틸포스폰산(화합물 122);[{1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필}(에틸)아미노]메틸포스폰산(화합물 125);3-{[{(1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필)(메틸)아미노)메틸}-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 126);비스{[(이소프로폭시카보닐)옥시]메틸}[{1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필}(메틸)아미노]메틸포스포네이트(화합물 127);3-{[{1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}(에틸)아미노]메틸}-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 129);2-{1-[(2-아미노-6-하이드록시-9H-퓨린-9-일)메틸]사이클로프로필}에틸포스폰산(화합물 138);2-{1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}에틸포스폰산(화합물 139);2-{1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필}에틸포스폰산(화합물 140);2-[1-({2-아미노-6-[(4-메틸페닐)설파닐]-9H-퓨린-9-일}메틸)사이클로프로필]에틸포스폰산(화합물 141);2-{1-[(2-아미노-6-하이드록시-9H-퓨린-9-일)메틸]사이클로프로필}프로필포스폰산(화합물 142);2-{1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필}프로필포스폰산(화합물 143);2-{1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}프로필포스폰산(화합물 144);3-(2-{1-[(6-아미노-9H-퓨린-9-일)메틸]사이클로프로필}프로필)-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 145);({1-[(2-아미노-6-하이드록시-9H-퓨린-9-일)메틸]-2,2-디메틸사이클로프로필}옥시)메틸포스폰산(화합물 146);({1-[(2-아미노-9H-퓨린-9-일)메틸]-2,2-디메틸사이클로프로필}옥시)메틸포스폰산(화합물 147);({1-[(6-아미노-9H-퓨린-9-일)메틸]-2,2-디메틸사이클로프로필}옥시)메틸포스폰산(화합물 148);3-[({1-[(2-아미노-6-하이드록시-9H-퓨린-9-일)메틸]-2,2-디메틸사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 149);3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]-2,2-디메틸사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 150);3-[({1-[(6-아미노-9H-퓨린-9-일)메틸]-2,2-디메틸사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일 피발레이트(화합물 151);비스{[(이소프로폭시카보닐)옥시]메틸}({1-[(6-아미노-9H-퓨린-9-일)메틸]-2,2-디메틸사이클로프로필}옥시)메틸포스포네이트(화합물 152); 및비스{[(이소프로폭시카보닐)옥시]메틸}[(1-{[2-아미노-6-하이드록시-9H-퓨린-9-일]메틸}-2,2-디메틸사이클로프로필)옥시]메틸포스포네이트(화합물 153) 중에서 선택된 화합물.
- 제1항에 있어서,는 단일결합을 나타내며, R1, R3, R7및 R8은 각각 독립적으로 수소를 나타내고, R2는 수소 또는 메틸을 나타내며, R4및 R5는 각각 독립적으로 t-부틸카보닐옥시메틸, 이소프로폭시카보닐옥시메틸 또는 2,2,2-트리플루오로에틸을 나타내고, Y는 -O- 를 나타내며, Q는 구조식을 나타내고, 여기에서 X1은 수소, 하이드록시, 에톡시, 4-메톡시페닐티오 또는 4-니트로페닐티오를 나타내며, X2는 아미노를 나타내는 화합물.
- (a) 하기 화학식 2의 화합물을 하기 화학식 3의 화합물과 반응시켜 화학식 1의 화합물을 수득하거나,(b) 하기 화학식 9의 화합물을 화학식 3의 화합물과 반응시켜 하기 화학식 10의 화합물을 형성시킨 후, 화학식 10의 화합물을 루이스산의 존재하에 가수분해시켜 하기 화학식 1a의 화합물을 수득하거나,(c) 화학식 1a의 화합물에 R4'및 R5'그룹을 도입시켜 하기 화학식 1b의 화합물을 수득하거나, 수득된 화합물에 대해 통상의 전환과정을 수행함을 특징으로하여 제1항에 정의된 화학식 1의 화합물을 제조하는 방법:[화학식 2][화학식 3]QH[화학식 9][화학식 10][화학식 1a][화학식 1b]상기식에서R1, R2, R3, R4, R5, R7, R8, Y 및 Q 는 제1항에서 정의한 바와 같고,L 은 이탈기를 나타내며,R9및 R10은 각각 독립적으로 치환되거나 비치환된 알킬을 나타내고,R4'및 R5'는 각각 독립적으로 수소를 제외한 R4및 R5를 나타낸다.
- 하기 화학식 2의 포스포네이트 화합물:[화학식 2]상기식에서R1, R2, R3, R4, R5, R7, R8및 Y는 제1항에서 정의한 바와 같고,L은 이탈기를 나타낸다.
- 유효 성분으로서 제1항에 정의된 화학식 1의 에이사이클릭 뉴클레오사이드 포스포네이트 유도체, 약제학적으로 허용되는 그의 염 또는 입체화학적 이성체를 약제학적으로 허용되는 담체와 함께 함유함을 특징으로 하는 B형 간염 치료제 조성물.
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NZ (1) | NZ526632A (ko) |
PL (1) | PL212730B1 (ko) |
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KR20180009195A (ko) | 2016-07-18 | 2018-01-26 | 일동제약(주) | 항바이러스성 약물의 오로트산염, 이의 제조 방법 및 상기 염을 포함하는 약제학적 조성물 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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KR100935904B1 (ko) | 2007-01-17 | 2010-01-07 | 주식회사 엘지생명과학 | 항바이러스성 약물의 말레산 단일염 및 이를 함유하는약제학적 조성물 |
KR20180009195A (ko) | 2016-07-18 | 2018-01-26 | 일동제약(주) | 항바이러스성 약물의 오로트산염, 이의 제조 방법 및 상기 염을 포함하는 약제학적 조성물 |
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