JP7414981B2 - ウイルス性肝炎を治療又は予防するための薬物組成物及びその応用 - Google Patents
ウイルス性肝炎を治療又は予防するための薬物組成物及びその応用 Download PDFInfo
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- JP7414981B2 JP7414981B2 JP2022522823A JP2022522823A JP7414981B2 JP 7414981 B2 JP7414981 B2 JP 7414981B2 JP 2022522823 A JP2022522823 A JP 2022522823A JP 2022522823 A JP2022522823 A JP 2022522823A JP 7414981 B2 JP7414981 B2 JP 7414981B2
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- 206010019799 Hepatitis viral Diseases 0.000 title description 14
- 201000001862 viral hepatitis Diseases 0.000 title description 14
- 239000008194 pharmaceutical composition Substances 0.000 title description 8
- 241000700721 Hepatitis B virus Species 0.000 claims description 80
- 239000003814 drug Substances 0.000 claims description 80
- 229940079593 drug Drugs 0.000 claims description 75
- 150000001875 compounds Chemical class 0.000 claims description 71
- 208000002672 hepatitis B Diseases 0.000 claims description 34
- 101710142246 External core antigen Proteins 0.000 claims description 30
- 230000001225 therapeutic effect Effects 0.000 claims description 26
- 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 claims description 23
- 239000000203 mixture Substances 0.000 claims description 22
- 108010050904 Interferons Proteins 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 239000002777 nucleoside Chemical class 0.000 claims description 19
- 102000014150 Interferons Human genes 0.000 claims description 18
- 229960000980 entecavir Drugs 0.000 claims description 18
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 claims description 18
- -1 digluconate Chemical compound 0.000 claims description 17
- 229940079322 interferon Drugs 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 16
- 230000000069 prophylactic effect Effects 0.000 claims description 15
- 241000700605 Viruses Species 0.000 claims description 12
- 229960004946 tenofovir alafenamide Drugs 0.000 claims description 12
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 claims description 12
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 claims description 10
- 229940024606 amino acid Drugs 0.000 claims description 9
- 150000001413 amino acids Chemical class 0.000 claims description 9
- 208000006454 hepatitis Diseases 0.000 claims description 9
- 231100000283 hepatitis Toxicity 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000000539 amino acid group Chemical group 0.000 claims description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 7
- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 229960002480 nitazoxanide Drugs 0.000 claims description 6
- 229960004150 aciclovir Drugs 0.000 claims description 5
- 230000002685 pulmonary effect Effects 0.000 claims description 5
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 229960001997 adefovir Drugs 0.000 claims description 4
- 230000029812 viral genome replication Effects 0.000 claims description 4
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 claims description 3
- 229940080296 2-naphthalenesulfonate Drugs 0.000 claims description 3
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical class CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical class NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-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
- 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 3
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 claims description 3
- 229940072056 alginate Drugs 0.000 claims description 3
- 235000010443 alginic acid Nutrition 0.000 claims description 3
- 229920000615 alginic acid Polymers 0.000 claims description 3
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 3
- 229940009098 aspartate Drugs 0.000 claims description 3
- 229940077388 benzenesulfonate Drugs 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 3
- 229940050390 benzoate Drugs 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims description 3
- 229940043264 dodecyl sulfate Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 3
- 150000002169 ethanolamines Chemical class 0.000 claims description 3
- 229960004396 famciclovir Drugs 0.000 claims description 3
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 claims description 3
- 229960000848 foscarnet sodium Drugs 0.000 claims description 3
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 3
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 3
- 229960001627 lamivudine Drugs 0.000 claims description 3
- 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 3
- 229940049920 malate Drugs 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 claims description 3
- 235000001968 nicotinic acid Nutrition 0.000 claims description 3
- 239000011664 nicotinic acid Substances 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 229960001355 tenofovir disoproxil Drugs 0.000 claims description 3
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 claims description 3
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 claims description 3
- DFHAXXVZCFXGOQ-UHFFFAOYSA-K trisodium phosphonoformate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)P([O-])([O-])=O DFHAXXVZCFXGOQ-UHFFFAOYSA-K 0.000 claims description 3
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 claims description 3
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 238000007913 intrathecal administration Methods 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims description 2
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 claims 4
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 claims 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims 4
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 claims 4
- 229960001203 stavudine Drugs 0.000 claims 4
- SCBFBAWJWLXVHS-ZCFIWIBFSA-N 2-amino-9-[(2r)-4-hydroxy-2-(hydroxymethyl)butyl]-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(C[C@H](CO)CCO)C=N2 SCBFBAWJWLXVHS-ZCFIWIBFSA-N 0.000 claims 2
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 claims 2
- ILAYIAGXTHKHNT-UHFFFAOYSA-N 4-[4-(2,4,6-trimethyl-phenylamino)-pyrimidin-2-ylamino]-benzonitrile Chemical compound CC1=CC(C)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 ILAYIAGXTHKHNT-UHFFFAOYSA-N 0.000 claims 2
- JFIWEPHGRUDAJN-DYUFWOLASA-N 4-amino-1-[(2r,3r,4s,5r)-4-ethynyl-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@](O)(C#C)[C@@H](CO)O1 JFIWEPHGRUDAJN-DYUFWOLASA-N 0.000 claims 2
- GZSDAHQGNUAEBC-XLPZGREQSA-N 4-amino-1-[(2r,4s,5s)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidin-2-one Chemical compound O=C1N=C(N)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 GZSDAHQGNUAEBC-XLPZGREQSA-N 0.000 claims 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims 2
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 claims 2
- DCYBPMFXJCWXNB-JWIUVKOKSA-N CNDAC Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](C#N)[C@H](O)[C@@H](CO)O1 DCYBPMFXJCWXNB-JWIUVKOKSA-N 0.000 claims 2
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 claims 2
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 claims 2
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 claims 2
- 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 2
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 claims 2
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims 2
- IBHARWXWOCPXCR-WELGVCPWSA-N [(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl (2-decoxy-3-dodecylsulfanylpropyl) hydrogen phosphate Chemical compound C1[C@H](N=[N+]=[N-])[C@@H](COP(O)(=O)OCC(CSCCCCCCCCCCCC)OCCCCCCCCCC)O[C@H]1N1C(=O)NC(=O)C(C)=C1 IBHARWXWOCPXCR-WELGVCPWSA-N 0.000 claims 2
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- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 claims 2
- KZOWNALBTMILAP-JBMRGDGGSA-N ancitabine hydrochloride Chemical compound Cl.N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 KZOWNALBTMILAP-JBMRGDGGSA-N 0.000 claims 2
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- DARSMUGUKCGKHQ-UHFFFAOYSA-M chembl1256733 Chemical compound O.O.[Na+].[N-]1N=C([N+]([O-])=O)C(=O)N2N=C(SC)N=C21 DARSMUGUKCGKHQ-UHFFFAOYSA-M 0.000 claims 2
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- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 claims 2
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- OSYWBJSVKUFFSU-SKDRFNHKSA-N festinavir Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@](CO)(C#C)O1 OSYWBJSVKUFFSU-SKDRFNHKSA-N 0.000 claims 2
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- 229960002963 ganciclovir Drugs 0.000 claims 2
- 229960002687 ganciclovir sodium Drugs 0.000 claims 2
- VPABMVYNSQRPBD-AOJMVMDXSA-N methyl (2r)-2-[[(4-bromophenoxy)-[[(2s,5r)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy]phosphoryl]amino]propanoate Chemical compound N1([C@@H]2O[C@@H](C=C2)COP(=O)(N[C@H](C)C(=O)OC)OC=2C=CC(Br)=CC=2)C=C(C)C(=O)NC1=O VPABMVYNSQRPBD-AOJMVMDXSA-N 0.000 claims 2
- CNUMCGXPKWOQFJ-FBXIHYFWSA-N methyl (2s)-2-[[[(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate Chemical compound N1([C@@H]2O[C@@H]([C@H](C2)N=[N+]=[N-])COP(=O)(N[C@@H](C)C(=O)OC)OC=2C=CC=CC=2)C=C(C)C(=O)NC1=O CNUMCGXPKWOQFJ-FBXIHYFWSA-N 0.000 claims 2
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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Description
好ましくは、前記薬学的に許容される塩は、酢酸塩、アジピン酸塩、アルギン酸塩、アスパラギン酸塩、安息香酸塩、ベンゼンスルホン酸塩、重硫酸塩、ブタン酸塩、クエン酸塩、カンフル酸塩、カンファースルホン酸塩、シクロペンタンプロピオン酸塩、ジグルコン酸塩、ドデシル硫酸塩、エタンスルホン酸塩、フマル酸塩、グルコヘプト酸塩、グリセロリン酸塩、ヘミ硫酸塩、ヘプタン酸塩、ヘキサン酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、2-ヒドロキシエタンスルホン酸塩、乳酸塩、リンゴ酸塩、マレイン酸塩、メタンスルホン酸塩、2-ナフタレンスルホン酸塩、ニコチン酸塩、シュウ酸塩、チオシアン酸塩、トルエンスルホン酸塩、ウンデカン酸塩、ナトリウム塩、カルシウム塩、カリウム塩、アンモニウム塩、テトラエチルアンモニウム塩、メチルアンモニウム塩、ジメチルアンモニウム塩及びエタノールアミン塩から選ばれる少なくとも1種である。
(式中、化合物1-3において、「AA」とは、アミノ酸残基を意味し、即ち、20種類の天然アミノ酸からカルボキシル基を除去した後の残り部分を意味する)
から選択されるウイルス性肝炎を治療又は予防するための薬物組成物をさらに提供する。
(式中、化合物1-3において、「AA」とは、アミノ酸残基を意味し、即ち、20種類の天然アミノ酸からカルボキシル基を除去した後の残り部分を意味し、例えば、アラニン、グリシン等である)
から選択されるものを含む。
置換基の定義
本文で使用された「重水素化」とは、元の水素原子が水素元素の同位体である重水素原子によって置き換えられる置換方式を意味する。本文で使用された「ハロゲン」とは、フッ素、塩素、臭素及びヨウ素の中の少なくとも1種を意味する。本文で使用された「アミノ基が保護された」とは、-NH2基がアミド結合を形成することによって保護され、代謝過程中に、インビボにおける酵素による分解によって、活性アミノ基を形成して、機能してもよいことを意味する。例えば、アラニン等のアミノ酸のカルボキシル基とアミノ基とを脱水反応させて形成されたアミド結合である。「AA」とは、アミノ酸残基を意味し、即ち、20種類の天然アミノ酸からカルボキシル基を除去した後の残り部分を意味する。即ち、アミノ酸が活性-NH2基とアミド結合を形成することで、元の活性アミノ基を保護することを意味する。
ウイルス性肝炎の病因学的な分類は、現在A型、B型、C型、D型及びE型の5種類の肝炎ウイルスが公認されており、それぞれHAV、HBV、HCV、HDV、HEVと記載されており、B型肝炎ウイルスがDNAウイルスであることを除いて、その他はいずれもRNAウイルスである。
何らかの実施形態において、前記他の治療剤又は予防剤は、エンテカビル、フマル酸テノホビルジソプロキシル及びテノホビルアラフェナミドから選択される1種又は複数種であり、例えば、エンテカビル、フマル酸テノホビルジソプロキシル及びテノホビルアラフェナミドから選択される1種であり、或いは、エンテカビル、フマル酸テノホビルジソプロキシル及びテノホビルアラフェナミドから選択される少なくとも2種である。
米国特許US5206244には、エンテカビル及びそのB型肝炎ウイルス治療の用途が開示されている。WO9809964には、新たなエンテカビルの合成方法が開示されている。WO0164421には、低用量のエンテカビルの固形製剤が開示されている。
本開示の薬物又は薬物組成物は、治療を待っている病症に適するいずれの経路によって投与される。好適な経路は、経口、直腸、鼻、肺、局所(口腔及び舌下を含む)、腟及び非経口(皮下、筋肉内、静脈内、皮内、髄腔内及び硬膜外を含む)等を含む。
何らかの実施形態において、薬物組成物において、式1の化合物、化合物1-2乃至1-4又はその薬学的に許容される塩が使用される。本開示の薬物組成物は、通常の担体及び賦形剤を用いて(通常の慣行に従って選択する)製造してもよい。錠剤には、賦形剤、流動促進剤、充填剤、接着剤等が含まれる。水性製剤は、無菌形態で製造され、非経口投与によって送達に使用される場合、通常は等張性である。すべての製剤には、任意に賦形剤、例えば、「Handbook of Pharmaceutical Excipients」(1986)に記載された賦形剤を任意にを含む。賦形剤には、アスコルビン酸及びその他の抗酸化剤、EDTAのようなキレート剤、デキストラン、ヒドロキシアルキルセルロース、ヒドロキシアルキルメチルセルロース、ステアリン酸のような炭水化物を含む。製剤のpH範囲は、約3乃至約11であるが、通常は約7乃至10である。何らかの実施形態において、製剤のpH範囲は、約2乃至約5であるが、通常は約3乃至4である。
実施例1-HepG2-NTCP細胞を応用した式1の化合物のインビトロ抗HBV活性の評価
化合物の製造方法は、次の通りである。
対照化合物は、Shanghai Titan Scientific社から購入したETV(ロット番号:P1214012;99.0%の純度)を含む。陽性対照化合物RG7834(ロット番号:ET25747-14-P1;99.5%の純度)は、Shangha WuXi AppTec社から購入した。
サンプルの検出
1)qPCR法による細胞培養上清液中のHBV DNAの含有量の検出
QIAamp 96 DNA Blood Kitの説明書を参照して、細胞培養上清液の中からDNAを抽出した。HBV特異的プライマーqPCRによって、HBV DNAの含有量を検出した。PCR反応:95℃、10min;95℃、15sec、60℃、1min、40サイクル。
CellTiter-Gloキットの説明書を参照して、細胞活力を測定したが、この方法は、簡単に説明すると以下の通りである。細胞培養上清液を収集した後、各穴にCellTiter-Glo(培地と1対1で希釈する)を加え、室温で10分間インキュベートし、マイクロプレートリーダーで発光値を測定した。
HBV DNA抑制率(%)=(1-化合物群サンプルのHBVコピー数/DMSO群のHBVコピー数)×100%
Hbe/sAg抑制率(%)=(1-サンプルのHBe/sAg値/DMSO対照組HBe/sAg値)×100%
結果の分析
検出結果については、表4~6及び図1~7を参照した。
上記の試験結果は、空白対照群と比べて、式1の化合物がHBVウイルスの負荷を効果的に低減することができ、HBV DNAを73.01%に低減させる場合、同時にHBsAg及びHBeAgを46.12%及び78.13%に低減させることができることを示した。上記の細胞試験を並行して繰り返しすことにより(図6を参照)、式1の化合物は、HBV DNA、HBsAg及びHBeAgに対する抑制作用を示し、そして明らかな剤量依存性を示した。
実施例2-マウスのインビボ試験
実験方法:AAV-HBVマウスモデルでは、強制経口投与によって1日1回で、投与した。ここで、投与群(G10 HD042、即ち、セレコキシブ):セレコキシブの投与剤量は、60mpkであり、空白群(G1溶媒対照群):10% DMSO+40% PEG400+5% Tween 80+45% Saline(V/V)溶液を投与した。
本発明は、特定の実施形態を参照して説明してきたが、本発明の趣旨と範囲を逸脱せずに、前記実施方案に対して変更又は改良が可能であることは当業者にとって明らかであり、本発明の範囲が添付の特許請求の範囲によってのみ限定される。
Claims (18)
- 前記患者は、肝炎ウイルスに感染している、請求項1に記載の薬物。
- 前記肝炎ウイルスは、HBVである、請求項2に記載の薬物。
- 前記患者は、ウイルス複製が活発である患者である、請求項3に記載の薬物。
- 前記患者において、HBVの負荷を低減することができる、請求項4に記載の薬物。
- 前記患者において、HBVの負荷、HBsAgのレベル及び/又はHBeAgのレベルを低減することができる、請求項5に記載の薬物。
- 前記患者は、ウイルス複製が不活発である患者である、請求項3に記載の薬物。
- 前記患者において、HBsAgのレベル及び/又はHBeAgのレベルを低減することができる、請求項7に記載の薬物。
- 前記薬学的に許容される塩は、酢酸塩、アジピン酸塩、アルギン酸塩、アスパラギン酸塩、安息香酸塩、ベンゼンスルホン酸塩、重硫酸塩、ブタン酸塩、クエン酸塩、カンフル酸塩、カンファースルホン酸塩、シクロペンタンプロピオン酸塩、ジグルコン酸塩、ドデシル硫酸塩、エタンスルホン酸塩、フマル酸塩、グルコヘプト酸塩、グリセロリン酸塩、ヘミ硫酸塩、ヘプタン酸塩、ヘキサン酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、2-ヒドロキシエタンスルホン酸塩、乳酸塩、リンゴ酸塩、マレイン酸塩、メタンスルホン酸塩、2-ナフタレンスルホン酸塩、ニコチン酸塩、シュウ酸塩、チオシアン酸塩、トルエンスルホン酸塩、ウンデカン酸塩、ナトリウム塩、カルシウム塩、カリウム塩、アンモニウム塩、テトラエチルアンモニウム塩、メチルアンモニウム塩、ジメチルアンモニウム塩及びエタノールアミン塩から選ばれる少なくとも1種である、請求項1に記載の薬物。
- 前記薬物は、B型肝炎ウイルス(HBV)の負荷を低減することができる、請求項1に記載の薬物。
- 前記薬物は、HBsAgのレベルを効果的に低減することができる、請求項1に記載の薬物。
- 前記薬物は、1種又は複数種の他の治療剤又は予防剤をさらに含み、
前記他の治療剤又は予防剤は、インターフェロン、PEG化インターフェロン、又はニタゾキサニド、以下の式A:
前記ヌクレオシド類似体は、エンテカビル、フマル酸テノホビルジソプロキシル、テノホビルアラフェナミド、ラミブジン、ファムシクロビル、アシクロビル(acyclovir)、アデホビル、ホスカルネットナトリウム、ネビラピン、テノホビルジソプロキシル、ジドブジン、エファビレンツ、スタブジン、デラビルジン、エムトリシタビン、ジダノシン、ザルシタビン、ネララビン、アザシチジン(5-アザシチジン)、アシクロビル(aciclovir)、シクロシチジン塩酸塩、ペンシクロビル、ガンシクロビルナトリウム、ブロモデオキシウリジン(BrdU)、モルヌピラビル(EIDD-2801)、2’-デオキシシュードイソシチジン(2’-deoxypseudoisocytidine)、6-チオ-2’-デオキシグアノシン、アバカビル、AzddMeC、Azt-pmap、センサブジン(censavudine)、クレブジン、CNDAC、ダピビリン、エノシタビン(enocitabine)、エチニルシチジン、ホジブジンチドキシル(fozivudine tidoxil)、ガンシクロビル、オマシクロビル(omaciclovir)、レムデシビル、サパシタビン、スタンピジン(stampidine)、スタブジンナトリウム、テルビブジン、テザシタビン及びトリアザビリンから選択される、
請求項1に記載の薬物。 - 前記薬物は、経口、直腸、経鼻、経肺、局所、口腔及び舌下、腟、非経口、皮下、筋肉内、静脈内、皮内、髄腔内及び硬膜外から選択される経路により投与される、請求項1に記載の薬物。
- 前記式1の化合物、その誘導体又はその薬学的に許容される塩は、毎日1.67~13.33mg/kg体重の量で投与される、請求項1に記載の薬物。
- 前記式1の化合物、その誘導体又はその薬学的に許容される塩は、毎日100mg~800mgの量で投与される、請求項1に記載の薬物。
- 前記式1の化合物、その誘導体又はその薬学的に許容される塩は、毎日2回で投与される、請求項16に記載の薬物。
- 患者のHBVの負荷、HBsAgのレベル及びHBeAgのレベルから選択される1種又は複数種を低減するためのB型ウイルス性肝炎を治療又は予防するための薬物組成物であって、
治療有効量の式1:
前記他の治療剤又は予防剤は、インターフェロン、PEG化インターフェロン、ニタゾキサニド、式A:
前記誘導体は、以下の化合物1-2乃至化合物1-4:
から選択され、
前記ヌクレオシド類似体は、エンテカビル、フマル酸テノホビルジソプロキシル、テノホビルアラフェナミド、ラミブジン、ファムシクロビル、アシクロビル(acyclovir)、アデホビル、ホスカルネットナトリウム、ネビラピン、テノホビルジソプロキシル、ジドブジン、エファビレンツ、スタブジン、デラビルジン、エムトリシタビン、ジダノシン、ザルシタビン、ネララビン、アザシチジン(5-アザシチジン)、アシクロビル(aciclovir)、シクロシチジン塩酸塩、ペンシクロビル、ガンシクロビルナトリウム、ブロモデオキシウリジン(BrdU)、モルヌピラビル(EIDD-2801)、2’-デオキシシュードイソシチジン(2’-deoxypseudoisocytidine)、6-チオ-2’-デオキシグアノシン、アバカビル、AzddMeC、Azt-pmap、センサブジン(censavudine)、クレブジン、CNDAC、ダピビリン、エノシタビン(enocitabine)、エチニルシチジン、ホジブジンチドキシル(fozivudine tidoxil)、ガンシクロビル、オマシクロビル(omaciclovir)、レムデシビル、サパシタビン、スタンピジン(stampidine)、スタブジンナトリウム、テルビブジン、テザシタビン及びトリアザビリンから選択される、患者のHBVの負荷、HBsAgのレベル及びHBeAgのレベルから選択される1種又は複数種を低減するための薬物組成物。
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US20090298797A1 (en) | 2008-05-23 | 2009-12-03 | The University Of Hong Kong | Combination therapy for the treatment of influenza |
WO2016069854A1 (en) | 2014-10-30 | 2016-05-06 | Virginia Commonwealth University | Enhancing the anti-tumor, anti-viral, and anti-protozoan effects of 2-amino-n-[4-[5-phenanthren-2-yl-3-(trifluoromethyl)pyrazol-1-yl] phenyl]acetamide (osu-03012) and other pharmaceutical drugs |
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US20090298797A1 (en) | 2008-05-23 | 2009-12-03 | The University Of Hong Kong | Combination therapy for the treatment of influenza |
WO2016069854A1 (en) | 2014-10-30 | 2016-05-06 | Virginia Commonwealth University | Enhancing the anti-tumor, anti-viral, and anti-protozoan effects of 2-amino-n-[4-[5-phenanthren-2-yl-3-(trifluoromethyl)pyrazol-1-yl] phenyl]acetamide (osu-03012) and other pharmaceutical drugs |
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