JP2017530194A - 重合胆汁酸誘導体によるb型肝炎ウイルス及びd型肝炎ウイルスとntcp輸送の阻害 - Google Patents
重合胆汁酸誘導体によるb型肝炎ウイルス及びd型肝炎ウイルスとntcp輸送の阻害 Download PDFInfo
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- JP2017530194A JP2017530194A JP2017535955A JP2017535955A JP2017530194A JP 2017530194 A JP2017530194 A JP 2017530194A JP 2017535955 A JP2017535955 A JP 2017535955A JP 2017535955 A JP2017535955 A JP 2017535955A JP 2017530194 A JP2017530194 A JP 2017530194A
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- alkyl
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- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical class C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 title claims abstract description 35
- 208000037262 Hepatitis delta Diseases 0.000 title claims abstract description 35
- 230000005764 inhibitory process Effects 0.000 title claims description 10
- 108091006611 SLC10A1 Proteins 0.000 title description 26
- 102100021988 Sodium/bile acid cotransporter Human genes 0.000 title description 26
- 208000002672 hepatitis B Diseases 0.000 title 1
- 208000015181 infectious disease Diseases 0.000 claims abstract description 43
- 208000029570 hepatitis D virus infection Diseases 0.000 claims abstract description 34
- 239000003613 bile acid Substances 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 19
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 19
- 239000003833 bile salt Substances 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 13
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 7
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000011734 sodium Substances 0.000 claims abstract description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 5
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 5
- 229920001184 polypeptide Polymers 0.000 claims abstract description 4
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 claims abstract 2
- -1 3-oxe Tarnyloxy Chemical group 0.000 claims description 107
- 239000000203 mixture Substances 0.000 claims description 74
- 125000001424 substituent group Chemical group 0.000 claims description 49
- 125000004432 carbon atom Chemical group C* 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 125000003118 aryl group Chemical group 0.000 claims description 40
- 125000005842 heteroatom Chemical group 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 22
- 125000003342 alkenyl group Chemical group 0.000 claims description 21
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 239000000178 monomer Substances 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 150000003254 radicals Chemical class 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 9
- 125000005647 linker group Chemical group 0.000 claims description 9
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 8
- 229910019142 PO4 Inorganic materials 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
- 239000010452 phosphate Substances 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000000524 functional group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 229910052698 phosphorus Inorganic materials 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 6
- 150000004705 aldimines Chemical class 0.000 claims description 5
- 229910052710 silicon Inorganic materials 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 4
- 229910002651 NO3 Inorganic materials 0.000 claims description 4
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 claims description 4
- INBXHFRQITUXGJ-UHFFFAOYSA-N diazidoazaniumylideneazanide Chemical compound [N-]=[N+]=N[N+](=[N-])N=[N+]=[N-] INBXHFRQITUXGJ-UHFFFAOYSA-N 0.000 claims description 4
- DIXBSCZRIZDQGC-UHFFFAOYSA-N diaziridine Chemical compound C1NN1 DIXBSCZRIZDQGC-UHFFFAOYSA-N 0.000 claims description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 4
- QDGZDCVAUDNJFG-FXQIFTODSA-N entecavir (anhydrous) Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)C1=C QDGZDCVAUDNJFG-FXQIFTODSA-N 0.000 claims description 4
- 125000005067 haloformyl group Chemical group 0.000 claims description 4
- 150000007857 hydrazones Chemical class 0.000 claims description 4
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical group O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000003949 imides Chemical class 0.000 claims description 4
- 150000002466 imines Chemical class 0.000 claims description 4
- 239000012948 isocyanate Substances 0.000 claims description 4
- 150000002513 isocyanates Chemical class 0.000 claims description 4
- 150000002540 isothiocyanates Chemical class 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 150000002923 oximes Chemical class 0.000 claims description 4
- 150000002978 peroxides Chemical class 0.000 claims description 4
- 150000004714 phosphonium salts Chemical group 0.000 claims description 4
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 4
- 150000003457 sulfones Chemical class 0.000 claims description 4
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- 125000005555 sulfoximide group Chemical group 0.000 claims description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 4
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 3
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 3
- 150000001343 alkyl silanes Chemical class 0.000 claims description 3
- 150000003857 carboxamides Chemical class 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 claims description 3
- 229960000815 ezetimibe Drugs 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 3
- 150000004767 nitrides Chemical class 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 claims description 2
- 125000006526 (C1-C2) alkyl group Chemical class 0.000 claims description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 2
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 claims description 2
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 229960001997 adefovir Drugs 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- 229940002637 baraclude Drugs 0.000 claims description 2
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 claims description 2
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- GHAFORRTMVIXHS-UHFFFAOYSA-L bromosulfophthalein sodium Chemical compound [Na+].[Na+].C1=C(S([O-])(=O)=O)C(O)=CC=C1C1(C=2C=C(C(O)=CC=2)S([O-])(=O)=O)C(C(Br)=C(Br)C(Br)=C2Br)=C2C(=O)O1 GHAFORRTMVIXHS-UHFFFAOYSA-L 0.000 claims description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 2
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- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 claims description 2
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- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 2
- 238000011445 neoadjuvant hormone therapy Methods 0.000 claims description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 claims description 2
- 229960003147 reserpine Drugs 0.000 claims description 2
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 claims description 2
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 2
- 229960000672 rosuvastatin Drugs 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 claims description 2
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 claims description 2
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 229940063032 tyzeka Drugs 0.000 claims description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 claims 1
- MAHNFPMIPQKPPI-UHFFFAOYSA-N disulfur Chemical compound S=S MAHNFPMIPQKPPI-UHFFFAOYSA-N 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- MGAIVONYQMSAIX-UHFFFAOYSA-N nitro(nitroso)silane Chemical compound [N+](=O)([O-])[SiH2]N=O MGAIVONYQMSAIX-UHFFFAOYSA-N 0.000 claims 1
- 239000002367 phosphate rock Substances 0.000 claims 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 1
- BHTRKEVKTKCXOH-AYSJQVDDSA-N taurochenodeoxycholic acid Chemical group C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)C1C2C2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-AYSJQVDDSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 241000700721 Hepatitis B virus Species 0.000 description 53
- 210000004027 cell Anatomy 0.000 description 49
- 150000001875 compounds Chemical class 0.000 description 47
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- HNBDRPTVWVGKBR-UHFFFAOYSA-N methyl pentanoate Chemical compound CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 25
- 230000000694 effects Effects 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- BHTRKEVKTKCXOH-UHFFFAOYSA-N Taurochenodesoxycholsaeure Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)CC2 BHTRKEVKTKCXOH-UHFFFAOYSA-N 0.000 description 16
- BHTRKEVKTKCXOH-LBSADWJPSA-N tauroursodeoxycholic acid Chemical group C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-LBSADWJPSA-N 0.000 description 16
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 15
- 238000005259 measurement Methods 0.000 description 15
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000000126 substance Substances 0.000 description 13
- WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 description 13
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 13
- 229960001661 ursodiol Drugs 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 12
- 150000001721 carbon Chemical group 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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Abstract
Description
OH、OAc(Ac=COCH3、アセテート)、OBz(Bz=COPh、ベンゾイル)、OBn(Bn=ベンジル)、OTs(Ts=トシル、p-トルエンスルホニル)、OMs(Ms=メタンスルホニル)、OSiR3、OTf(Tf=トリフルオロメタンスルホニル)、OTHP(THP、テトラヒドロピラン)、OCOR、OR、NH2、NHBoc(Boc=tert-ブチルオキシカルボニル)、NHAc(Ac=COCH3、アセテート)、NHBz(Bz=COPh、ベンゾイル)、NHTs (Ts=トシル、p-トルエンスルホニル)、NHTf(Tf=トリフルオロメタンスルホニル)、NHMs(Ms=メタンスルホニル)、NHSiR3、NHR;NBn2(Bn=ベンジル)、NTf2(Tf=トリフルオロメタンスルホニル)、NHCOR及びNR1R2、-N2、-N3;リン酸(-OP(O)(OH)2)、硫酸(-OSO 2 OH)又はカルボン酸 (-OCOH)、カルボン酸エステル(-OCOR);フォスフォライト(-OP(O)mO-)又はフォスフェート(-OP(OR)mO-)、スルホン酸エステル、硫酸エステル(-OS(O)mO-)、亜硫酸エステル(-OS(OR)mO-)、二亜硫酸エステル又はピロ硫酸エステル、中で、mは0、1及び2に等しく、R、R1及びR2のそれぞれは独立してH、最大15個の炭素原子を有する分岐鎖又は非分岐鎖のアルキル、アリール、アルケニル、アルキニル、カルボニル、又はエーテル遊離基、非置換の又はハロゲン、(C1-C4)-アルキル又は(C1-C4)-アルコキシル又は(C1-C6)-アルキルアミン、エチレンオキシドでモノ、ビス又はトリ置換された3〜15個の炭素原子を有するシクロ-(アルキル、アリール、アルケニル、アルキニル、カルボニル、又はエーテル)遊離基又はフェニル又はベンジル遊離基;
本出願は、慢性的なHBV及びHDV感染を治療することを含み、垂直伝播及び事故的被曝による新HBV感染を防ぎ、肝細胞が有毒な胆汁酸又は他のNTCP輸送物を取り込まないように肝臓移植後のHBVの再発及び指定されたNTCP阻害の病状を予防する。
特定の実施形態と実施例の説明は例として提供されるものであり、限定することを目的とするものではない。本質的に類似の結果がもたらされるように、重要でない様々なパラメータは変更又は修正されてもよいと当業者は容易に理解できる。
「ヘテロアリール」という用語は、N、O、及びSより選択される0〜6個のヘテロ原子を含むアリール基(又は環)を指し、前記窒素原子及び硫黄原子は任意に酸化され、かつ前記窒素ヘテロ原子は任意に四級化される。ヘテロアリール基は、ヘテロ原子を介して、分子の残りの部分に結合することができる。ヘテロアリール基の非限定的な例には、1-ピロリル、2-ピロリル、3-ピロリル、3-ピラゾリル、2-イミダゾリル、4-イミダゾリル、ピラジニル、2-オキサゾリル、4-オキサゾリル、2-フェニル-4-オキサゾリル、5-オキサゾリル、3-イソオキサゾリル、4-イソオキサゾリル、5-イソオキサゾリル、2-チアゾリル、4-チアゾリル、5-チアゾリル、2-フリル、3-フリル、2-チエニル、3-チエニル、2-ピリジル、3-ピリジル、4-ピリジル、2-ピリミジル、4-ピリミジル、5-ベンゾチアゾリル、プリニル、2-ベンゾイミダゾリル、5-インドリル、1-イソキノリル、5-イソキノリル、2-キノキサリニル、5-キノキサリニル、3-キノリル及び6-キノリルが含まれる。
上記用語(例えば、「アルキル」、「ヘテロアルキル」、「アリール」及び「ヘテロアリール」)はそれぞれ、指定された遊離基の置換及び非置換の形式の両方を含むことを意味する。それぞれの遊離基の好ましい置換基は下記のとおり。
HBV及びHDV感染測定。感染前にHepG2NTCP 細胞をPMMにて12〜24時間培養し、その後、200マルチゲノム当量(mge)のHBV、又は500mgeのHDVで接種し、5%のPEG8000のPMMの存在下で、37℃で約24時間培養する。具体的な測定法で指定されているように、前記細胞に試験される化学品を加える。感染後、接種物にPMMを再度補充する。感染後5日目(dpi)に、感染が検出された。
10mLの一口丸底フラスコの中で、(4R)-4-((3R,7S,9S,10S,13R,14S,17R)-3-アミノ-7-ヒドロキシ-10,13-ジメチルヘキサデカヒドロ-1H-シクロペンタ[α]フェナントレン-17-イル)ペンタン酸メチルエステル(120.0mg、0.3mmol、1.0当量)を室温で、DMF(2.0mL)に溶解する。 それから2-グルタル酸(39.6mg、0.3mmol、1.0当量)、DIEA(116.0mg、0.9mmol、3.0当量)、 DMAP(36mg、0.3mmol、1.0当量)及びEDC(173mg、0.9mmol、3.0当量)を添加する。添加完了後、混合物を室温で24 時間撹拌する。混合物をUPLCで確認し、濃縮し、カラムクロマトグラフィー(DCM:MeOH=20:1)で純化し、目標物(52mg)を得る。
100mLの一口丸底フラスコの中で、(4R)-4-((3R,7S,9S,10S,13R,14S,17R)-3,7-ジヒドロキシ-10,13-ジメチルヘキサデカヒドロ-1H-シクロペンタ[α]フェナントレン-17-イル) ペンタン酸(10.0g、25.5mmol、1.0当量)を室温で、MeOH(100mL)に溶解する。それからPTSA(触媒)を添加する。添加完了後、混合物を80℃で14時間撹拌する。混合物を濃縮し、濃いNaHCO3でpH>8まで塩基化し、それからEAで抽出し、減圧下で濃縮し、目標物(9.3g)を得る。これはNMRで確認される。
25mLの一口丸底フラスコの中で、(4R)-4-((3S,7S,9S,10S,13R,14S,17R)-7-ヒドロキシ-10,13-ジメチル-3-((メチルスルホニル)オキシ)ヘキサデカヒドロ-1H-シクロペンタ[α]フェナントレン-17-イル)ペンタン酸メチルエステル(1.2g、2.5mmol、1.0当量)を室温で、DMF(10mL)に溶解する。それからNaN3(325mg、5.0mmol、2.0当量)を添加する。添加完了後、混合物を80℃で1.5時間撹拌する。混合物を水で洗浄し、EAで抽出し、濃縮し、カラムクロマトグラフィー(PE:EA=5:1)で純化し、黄色固体としての目標物(700mg)を得る。これはNMRで確認される。
前記粗生成物を室温で、DMF(1.5mL)に溶解する。それから2-アミノエタンスルホン酸(17.8mg、0.142mmol、6.0当量)、DIEA(24.7mg、0.192mmol、8.0当量)、DMAP(3mg、0.024mmol、1.0当量)及びEDC(13.6mg、0.71mmol、3.0当量)を添加する。添加完了後、混合物を室温で14時間撹拌する。混合物を濃縮し、pre-HPLCで純化し、白色固体としての目標物(4.4mg)を得る。これはNMRで確認される。
表 Pの実例は表 Oに類推して得られる。
表 T の実例は表 Sに類推して得られる。
Claims (16)
- 重合胆汁酸又はその塩を必要とする人に投与することを含む、HBV又はHDV感染を治療する、又はヒトナトリウムタウロコール酸共輸送ポリペプチド(hNTCP)を阻害する方法。
- 前記重合胆汁酸は2、3又は4個の共有結合された単量体を含み、個々の単量体は式 Iの構造を独立して有する請求項1に記載の方法。
炭化水素又はヘテロ炭化水素基又はヘテロ原子を含有する官能基、又は
任意に置換されたアルキル又はヘテロアルキル、アルケニル又はヘテロアルケニル、アルキニル又はヘテロアルキニル、アルコキシル、又はヘテロアルコキシル、それぞれの環状及び置換の形式を含み、アリール及びヘテロアリール、中で、ヘテロ形式がN、O、P及びSのような1〜4個のヘテロ原子を含む、又は
ヒドロキシル、ハロホルミル、カルボニル、アルデヒド、カルボキシル、エステル、アセタール、 カルボキサミド、ヒドロペルオキシル、エポキシド、過酸化物、オキシム、アミン、イミン、イミド、アミド、第四級アンモニウム塩、アミンオキシド、アジ化物、アゾ、ジアゾ、アジド、アジリジン、ジアジリジン、ヒドラジン、ヒドラゾン、アルジミン、イソシアニド、イソシアネート、イソチオシアネート、シアネート、硝酸エステル、ニトリル、亜硝酸エステル、ニトリド、ニトロ、ニトロソ、シラン、アルキルシラン、シロキサン、ハロシラン、ホスフィン、フォスフォライト、フォスフェート、チオホスホン酸エステル、 第四ホスホニウム塩、ホスホノ、リン化物、硫化物、亜硫酸エステル、スルホン酸エステル、チオシアネート、チオ硫酸エステル、スルホキシド、スルフィミド、スルホン、スルホキシイミン、スルホニウム、及びスルフヒドリルより選択される官能基、又は
置換もしくは非置換の(C1-C4)アルキル、(C2-C4)アルケニル、(C6-C8)アルケニル、(C2-C4)アルキニル、(C6-C8)アルキニル、(C1-C4)アルコキシル、(C6-C8)アルコキシル、3-オキセタルニルオキシ、3-テトラヒドロフラニルオキシ、Cl、F、フッ素置換された(C1-C2)アルキル、(C1-C4)アルキル-SO2-、(C3-C6)シクロアルキル、又はN、O、P、Si又はSからそれぞれ独立して選択された1又は2個のヘテロ原子を有する(C5-C6)ヘテロ環。 - 置換基のぞれぞれは独立して、
OH、OAc(Ac=COCH3、アセテート)、OBz(Bz=COPh、ベンゾイル)、OBn(Bn=ベンジル)、OTs(Ts=トシル、p-トルエンスルホニル)、OMs(Ms=メタンスルホニル)、OSiR3、OTf(Tf=トリフルオロメタンスルホニル)、OTHP(O-テトラヒドロピラン)、OCOR、OR、NH2、NHBoc (Boc=tert-ブチルオキシカルボニル)、NHAc(Ac=COCH3、アセテート)、NHBz(Bz=COPh、ベンゾイル)、NHTs(Ts=トシル、p-トルエンスルホニル)、NHTf (Tf=トリフルオロメタンスルホニル)、NHMs(Ms=メタンスルホニル)、NHSiR3、NHR; NBn2 (Bn=ベンジル)、NTf2 (Tf=トリフルオロメタンスルホニル)、NHCOR及びNR1R2)、-N2、-N3;リン酸(-OP(O)(OH)2)、硫酸(-OSO2OH)又はカルボン酸(-OCOH)、カルボン酸エステル(-OCOR);フォスフォライト(-OP(O)mO-)又はフォスフェート(-OP(OR)mO-)、スルホン酸エステル、硫酸エステル(-OS(O)mO-)、亜硫酸エステル (-OS(OR)mO-)、二亜硫酸エステル又はピロ硫酸エステル、中で、mは0、1及び2に等しく、R、R1及びR2のそれぞれは独立してH、最大15個の炭素原子を有する分岐鎖又は非分岐鎖のアルキル、アリール、アルケニル、アルキニル、カルボニル、又はエーテル遊離基、非置換の又はハロゲン、(C1-C4)-アルキル又は(C1-C4)-アルコキシル又は(C1-C6)-アルキルアミンでモノ、ビス又はトリ置換された3〜15個の炭素原子を有するシクロ-(アルキル、アリール、アルケニル、アルキニル、カルボニル、又はエーテル)遊離基又はフェニル又はベンジル遊離基、
又は最大15個の炭素原子を有する分岐鎖又は非分岐鎖のアルキル、アリール、アルケニル、アルキニル、カルボニル、又はエーテル遊離基、非置換の又はハロゲン、(C1-C4)-アルキル、(C1-C4)-アルコキシル又は(C1-C6)-アルキルアミン、又はヘテロ原子でモノ、ビス、トリ置換された3〜15個の炭素原子を有するシクロ-(アルキル、アリール、アルケニル、アルキニル、カルボニル、又はエーテル)遊離基、フェニル又はベンジル遊離基
である請求項 2に記載の方法。 - C3、C6、C7及びC24はそれぞれ独立して、以下の基で置換されている請求項 2に記載の方法、
請求項 2の置換基、又は
請求項 3の置換基、又は
-NR1R2、-OR又は-COR、中で、R、R1及びR2はそれぞれ独立してH又は請求項2の置換基である。 - C24は以下の基で置換されている請求項 2に記載の方法、
-CH2OH、-COOM、中で、Mはアルカリ金属、アルカリ土類金属又は第四級アンモニウムイオン、又は
-CONHCH2CH2SO3H、-CONHRSO3H又は
-COOH、-COOR、-CONH2、-CH2NH2、-CONH又はNRR、
中で、Rはそれぞれ独立してH、最大15個の炭素原子を有する分岐鎖又は非分岐鎖のアルキル、アリール、アルケニル又はアルキニル遊離基、非置換の又はハロゲン(例えばF、Cl、Br)、(C1-C4)-アルキル又は(C1-C4)-アルコキシル又は(C1-C6)-アルキルアミンでモノ、ビス又はトリ置換された3〜15個の炭素原子を有するシクロアルキル遊離基又はフェニル又はベンジル遊離基。 - C3、C6及びC7はそれぞれ独立して、以下の基で置換されている請求項2に記載の方法、
中で、R、R1及びR2はそれぞれ独立して、最大15個の炭素原子を有する分岐鎖又は非分岐鎖のアルキル、アリール、アルケニル又はアルキニル遊離基、非置換の又はハロゲン(例えばF、Cl、Br)、(C1-C4)-アルキル又は(C1-C4)-アルコキシル又は(C1-C6)-アルキルアミンでモノ、ビス又はトリ置換された3〜15個の炭素原子を有するシクロアルキル遊離基又はフェニル又はベンジル遊離基。 - 前記単量体は1又は2又は3個のそれぞれ独立 してLであるリンカーで連続されており、Lは
(a)任意に置換され且つ任意にヘテロ原子を含有する最大15個の炭素原子を有する分岐鎖又は非分岐鎖のアルキル、アリール、アルケニル又はアルキニル遊離基、
(b)非置換の又はハロゲン(例えばF、Cl、Br)、(C1-C4)-アルキル、(C1-C4)-アルコキシル又は(C1-C6)-アルキルアミンでモノ、ビス、トリ置換された3〜15個の炭素原子を有するシクロアルキル遊離基、又はフェニル又は ベンジル遊離基、又は
(c)2〜200個の原子の間、且つMWが20〜2K Dの間の連続鎖を有する、又は
(d)アミド又はエステル結合で結合されたアルキル、アリール基及びヘテロ原子、アミノ酸又は他のアミノアルキルスルホン酸
である請求項2に記載の方法。 - 前記重合胆汁酸はTUDCA部分を含む請求項 1に記載の方法。
- 前記重合胆汁酸は本明細書の表に開示される請求項 1に記載の方法。
- 前記重合胆汁酸は所定の単位投薬量の有効量で採取される請求項 1に記載の方法。
- 異なる第二種のHBV又はHDV薬を前記人に投与することを更に含む請求項 1に記載の方法。
- 発生したhNTCP又はHBV又はHDV感染に対するの阻害を検出することを更に含む請求項 1に記載の方法。
- 異なる第二種のHBV又はHDV 薬と同時に処方された又は同時に包装された又は同時に投与された重合胆汁酸又はその塩を含む組成物。
- 前記薬はラミブジン(Epivir)、アデホビル(Hepsera)、テノホビル(Viread)、テルビブジン(Tyzeka)、エンテカビル(Baraclude)、ボセンタン、オキシステロール、エゼチミブ、レセルピン、ロスバスタチン、又はブロムスルファレインである請求項 13に記載の組成物。
- 前記重合胆汁酸は2、3又は4個の共有結合された単量体を含み、個々の単量体は式 I (上記参照)の構造を独立して有する請求項 13に記載の組成物。
- 請求項13〜16の何れかに記載の組成物の製薬における使用。
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