CN101351206A - Therapeutic agent for liver disease and hepatic function- - Google Patents
Therapeutic agent for liver disease and hepatic function- Download PDFInfo
- Publication number
- CN101351206A CN101351206A CNA2006800502853A CN200680050285A CN101351206A CN 101351206 A CN101351206 A CN 101351206A CN A2006800502853 A CNA2006800502853 A CN A2006800502853A CN 200680050285 A CN200680050285 A CN 200680050285A CN 101351206 A CN101351206 A CN 101351206A
- Authority
- CN
- China
- Prior art keywords
- rifamycin
- group
- remedies
- hepatitis
- liver
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000019423 liver disease Diseases 0.000 title claims abstract description 64
- 239000003814 drug Substances 0.000 title abstract description 14
- 229940124597 therapeutic agent Drugs 0.000 title abstract 4
- 230000002440 hepatic effect Effects 0.000 title description 2
- 230000003908 liver function Effects 0.000 claims abstract description 45
- SQTCRTQCPJICLD-KTQDUKAHSA-N rifamycin B Chemical compound OC1=C(C(O)=C2C)C3=C(OCC(O)=O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O SQTCRTQCPJICLD-KTQDUKAHSA-N 0.000 claims abstract description 29
- SQTCRTQCPJICLD-OQQFTUDCSA-N rifomycin-B Natural products COC1C=COC2(C)Oc3c(C)c(O)c4c(O)c(NC(=O)C(=C/C=C/C(C)C(O)C(C)C(O)C(C)C(OC(=O)C)C1C)C)cc(OCC(=O)O)c4c3C2=O SQTCRTQCPJICLD-OQQFTUDCSA-N 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- -1 piperazinyl imino group Chemical group 0.000 claims description 46
- 239000003242 anti bacterial agent Substances 0.000 claims description 40
- 229940088710 antibiotic agent Drugs 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 29
- 229960001225 rifampicin Drugs 0.000 claims description 28
- 230000000246 remedial effect Effects 0.000 claims description 23
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- 208000006454 hepatitis Diseases 0.000 claims description 20
- 206010019799 Hepatitis viral Diseases 0.000 claims description 17
- 241001597008 Nomeidae Species 0.000 claims description 17
- 201000001862 viral hepatitis Diseases 0.000 claims description 17
- 231100000283 hepatitis Toxicity 0.000 claims description 15
- 239000004615 ingredient Substances 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 claims description 10
- 229960000885 rifabutin Drugs 0.000 claims description 10
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 9
- 229960002599 rifapentine Drugs 0.000 claims description 9
- WDZCUPBHRAEYDL-GZAUEHORSA-N rifapentine Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N(CC1)CCN1C1CCCC1 WDZCUPBHRAEYDL-GZAUEHORSA-N 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 5
- BBNQHOMJRFAQBN-UPZFVJMDSA-N 3-formylrifamycin sv Chemical compound OC1=C(C(O)=C2C)C3=C(O)C(C=O)=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O BBNQHOMJRFAQBN-UPZFVJMDSA-N 0.000 claims description 3
- 208000022309 Alcoholic Liver disease Diseases 0.000 claims description 3
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims description 3
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 3
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 3
- 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 3
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 3
- HJYYPODYNSCCOU-ZDHWWVNNSA-N Rifamycin SV Natural products COC1C=COC2(C)Oc3c(C)c(O)c4c(O)c(NC(=O)C(=C/C=C/C(C)C(O)C(C)C(O)C(C)C(OC(=O)C)C1C)C)cc(O)c4c3C2=O HJYYPODYNSCCOU-ZDHWWVNNSA-N 0.000 claims description 3
- 201000000742 primary sclerosing cholangitis Diseases 0.000 claims description 3
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 claims description 3
- 229940109171 rifamycin sv Drugs 0.000 claims description 3
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 26
- 230000002411 adverse Effects 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 30
- 239000002585 base Substances 0.000 description 26
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 19
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 19
- 208000005176 Hepatitis C Diseases 0.000 description 17
- 208000006154 Chronic hepatitis C Diseases 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 12
- 208000010710 hepatitis C virus infection Diseases 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 11
- 108010062580 Concanavalin A Proteins 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 102000014150 Interferons Human genes 0.000 description 9
- 108010050904 Interferons Proteins 0.000 description 9
- 229940079322 interferon Drugs 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- YVOFSHPIJOYKSH-NLYBMVFSSA-M sodium rifomycin sv Chemical compound [Na+].OC1=C(C(O)=C2C)C3=C([O-])C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O YVOFSHPIJOYKSH-NLYBMVFSSA-M 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 210000004185 liver Anatomy 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 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 6
- 229960001661 ursodiol Drugs 0.000 description 6
- 241000711549 Hepacivirus C Species 0.000 description 5
- 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 description 5
- 241000700605 Viruses Species 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 229960000329 ribavirin Drugs 0.000 description 5
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 239000000654 additive Substances 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 4
- 229960004949 glycyrrhizic acid Drugs 0.000 description 4
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 4
- 235000019410 glycyrrhizin Nutrition 0.000 description 4
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 4
- 230000002443 hepatoprotective effect Effects 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000008520 organization Effects 0.000 description 4
- 229940062280 rifamycin sodium Drugs 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 3
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 3
- 108010082126 Alanine transaminase Proteins 0.000 description 3
- 206010008909 Chronic Hepatitis Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004378 Glycyrrhizin Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229930189077 Rifamycin Natural products 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 241001655322 Streptomycetales Species 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 3
- 231100000753 hepatic injury Toxicity 0.000 description 3
- 208000002672 hepatitis B Diseases 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 229960003292 rifamycin Drugs 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 201000008827 tuberculosis Diseases 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- WWUVJRULCWHUSA-UHFFFAOYSA-N 2-methyl-1-pentene Chemical compound CCCC(C)=C WWUVJRULCWHUSA-UHFFFAOYSA-N 0.000 description 2
- WSSSPWUEQFSQQG-UHFFFAOYSA-N 4-methyl-1-pentene Chemical compound CC(C)CC=C WSSSPWUEQFSQQG-UHFFFAOYSA-N 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- 241001468213 Amycolatopsis mediterranei Species 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 102100028717 Cytosolic 5'-nucleotidase 3A Human genes 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 101710088194 Dehydrogenase Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000005331 Hepatitis D Diseases 0.000 description 2
- 102100040018 Interferon alpha-2 Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010079944 Interferon-alpha2b Proteins 0.000 description 2
- 102000003996 Interferon-beta Human genes 0.000 description 2
- 108090000467 Interferon-beta Proteins 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 241000219745 Lupinus Species 0.000 description 2
- 102000013460 Malate Dehydrogenase Human genes 0.000 description 2
- 108010026217 Malate Dehydrogenase Proteins 0.000 description 2
- YPIQVCUJEKAZCP-UHFFFAOYSA-N Malotilate Chemical compound CC(C)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1 YPIQVCUJEKAZCP-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920002675 Polyoxyl Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 235000003969 glutathione Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 208000005252 hepatitis A Diseases 0.000 description 2
- 201000010284 hepatitis E Diseases 0.000 description 2
- 229960001388 interferon-beta Drugs 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- 229960001627 lamivudine Drugs 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 230000002101 lytic effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229950000470 malotilate Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- XEABSBMNTNXEJM-UHFFFAOYSA-N propagermanium Chemical compound OC(=O)CC[Ge](=O)O[Ge](=O)CCC(O)=O XEABSBMNTNXEJM-UHFFFAOYSA-N 0.000 description 2
- 229950002828 propagermanium Drugs 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- IDQMDQWHGOWMKX-KBBWGOFYSA-N (2s,3r,4s,5r,6r)-6-[(2s,3r,4s,5s,6s)-2-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-6-carboxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-c Chemical compound NCC(O)=O.SC[C@H](N)C(O)=O.CSCC[C@H](N)C(O)=O.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O IDQMDQWHGOWMKX-KBBWGOFYSA-N 0.000 description 1
- 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 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical compound CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- LDTAOIUHUHHCMU-UHFFFAOYSA-N 3-methylpent-1-ene Chemical compound CCC(C)C=C LDTAOIUHUHHCMU-UHFFFAOYSA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- GDBUZIKSJGRBJP-UHFFFAOYSA-N 4-acetoxy benzoic acid Chemical compound CC(=O)OC1=CC=C(C(O)=O)C=C1 GDBUZIKSJGRBJP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OSQXTNJTHMENJZ-UHFFFAOYSA-N CC(=C)CC.[O] Chemical compound CC(=C)CC.[O] OSQXTNJTHMENJZ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000008964 Chemical and Drug Induced Liver Injury Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108010001202 Cytochrome P-450 CYP2E1 Proteins 0.000 description 1
- 102100024889 Cytochrome P450 2E1 Human genes 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010072268 Drug-induced liver injury Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 206010019837 Hepatocellular injury Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 1
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- XABHYBRQDPURMX-UHFFFAOYSA-N [O].CC(=C)CCC Chemical compound [O].CC(=C)CCC XABHYBRQDPURMX-UHFFFAOYSA-N 0.000 description 1
- LXXJPIQUZVHIQZ-UHFFFAOYSA-N [O].CC(C=C)CC Chemical compound [O].CC(C=C)CC LXXJPIQUZVHIQZ-UHFFFAOYSA-N 0.000 description 1
- BKHVEBSRLDAELY-UHFFFAOYSA-N [O].CC(CC=C)C Chemical compound [O].CC(CC=C)C BKHVEBSRLDAELY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 231100000439 acute liver injury Toxicity 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 229940046011 buccal tablet Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 201000008865 drug-induced hepatitis Diseases 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940116364 hard fat Drugs 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 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
- 239000011976 maleic acid Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229940063639 rifadin Drugs 0.000 description 1
- 229940049560 rimactane Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 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
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Disclosed is a therapeutic agent for a liver disease, which produces little adverse side effects, can be administered through oral route, has a high versatility, and is inexpensive. The therapeutic agent comprises rifamycin B or a derivative thereof or a pharmaceutically acceptable salt of rifamycin B or the derivative as an active ingredient. When administered to a patient suffering from a liver disease, the therapeutic agent can ameliorate the hepatic function and reduce the ALT or AST level which is an indicator of the hepatic function.
Description
Technical field
The present invention relates to for example remedies for liver diseases and hepatic function remedial agent.
Background technology
Liver has Detoxication, and have synthetic, decompose, store various functions such as nutrient and secretion of bile, be the homeostatic important organ of keeping organism, but suffer acute or chronic liver function injury because of a variety of causes such as hepatitis virus, medicine, ethanol sometimes.Thus, can bring out hepatopathys such as viral hepatitis, drug induced hepatic injury, alcoholic liver injury.
As the viral hepatitis of representative hepatopathy, be the hepatitis of bringing out owing to viral infection.As the typical example of viral hepatitis, can enumerate hepatitis C or hepatitis B, if the severity of symptoms of known these hepatitis then can cause the morbidity of liver cirrhosis or hepatocarcinoma.
(Hepatitis C Virus, HCV) the carrier number is 1,500,000 people (with reference to non-patent literatures 1) at hepatitis C virus in Japan by inference.In the hepatitis C virus carrier, there is 70～80% carrier can be transformed into chronic hepatitis C, become the chronic hepatitis C patient.Have 30% can become the third type liver cirrhosis patient among the chronic hepatitis C patient approximately in 10～30 years, about 80% of this third type liver cirrhosis patient can be suffered from hepatocarcinoma in 5～10 years.Like this, because chronic hepatitis C patient's hepatocarcinoma incidence rate is high, so that the treatment of chronic hepatitis C seems is very important.
As the composition that is used for the treatment of viral hepatitis, representative was interferon (Interferon) and ribavirin (Ribavirin) in the past.Specifically, separately with interferon to patient's administration, perhaps interferon and ribavirin are united and use and to patient's administration.Thus hepatitis virus is removed in body, therefore can treat viral hepatitis (with reference to patent documentation 1) sometimes.
Patent documentation 1: Japanese patent laid-open 6-234657 communique
Non-patent literature 1: the treatment of chronic hepatitis is instructed, and Japanese hepatology can be compiled, Wen Guangtang, the 21st～23rd page
Summary of the invention
Yet therefore the Therapeutic Method that is disclosed in the above-mentioned patent documentation 1 can cause very big burden to patient's body with serious adverse such as heating, thrombocytopenia, leukopenia, alopecia, headache, tinnitus, depressions.And interferon is a protein, therefore can't oral administration, so must rely on drug administration by injection, existing problems aspect convenience and safety.And medical expense is high, and there is difficulty economically sometimes in treatment.
And according to the medicine-feeding period that composition is used in the genotype (genotype) or the treatment of hepatitis virus, the situation that can not get curative effect is also a lot.Specifically, even by under the situation with interferon and ribavirin administering drug combinations, the maximum ratio that hepatitis virus can be removed in the body is about 50%.
According to above-mentioned these problems, when the Therapeutic Method that is disclosed at above-mentioned patent documentation 1 becomes and is not suitable for,, adopt rami hepatici to hold therapy (liver supporting therapy) sometimes in order to suppress development to liver cirrhosis or hepatocarcinoma.Hold in the therapy at this rami hepatici, compound glycyrrhizin (Stronger Neo-Minophagen C) or ursodesoxycholic acid (Ursodeoxycholicacid) are used as hepatic function remedial agent.Can improve liver function thus, can confirm also that above-mentioned rami hepatici is held therapy can be with aspartate aminotransferase (aspartate aminotransferase, AST), (alanineaminotransferase ALT) waits liver function index material value to remain in low value to alanine aminotransferase.
Yet compound glycyrrhizin is with the injection system administration, therefore existing problems aspect convenience and safety.And, if the long term administration meeting is hardened the injection site, therefore continue administration and also can become difficult sometimes.
In addition, though ursodesoxycholic acid can be taken orally, be not all effective to all patients, invalid to a part of chronic hepatitis C patient sometimes.
And then, for other hepatopathys, also exist and the same problem of the problems referred to above seen in the viral hepatitis.
Therefore, the object of the present invention is to provide a kind of few side effects, can be taken orally, versatility is high and cheap remedies for liver diseases.
Present inventors find: rifamycin (Rifamycin) class antibiotic can improve hepatopath's such as viral hepatitis liver function, with and the result can suppress hepatitis and develop to liver cirrhosis, and the generation of prevention hepatocarcinoma, thus finally finished the present invention.
Additional disclosure, rifamycinoid antibiotics are that the antibiotic that Mediterranean streptomycete (Streptomyces mediterranei) produces is rifamycin and derivant thereof, the one-tenth that the is used as the tuberculosis curative all the year round use that grades.
Yet, the discovered in recent years rifamycinoid antibiotics has the effect of angiogenesis inhibiting (angiogenesis), and disclosed according to this discovery, utilize rifamycinoid antibiotics can suppress the development (opening the 2004-75665 communique) of hepatocarcinoma with reference to the Japan Patent spy.Yet the administration purpose of rifamycinoid antibiotics is not the generation that prevents the cancerous cell in the liver organization that hepatopathy thus brings out by the treatment hepatopathy.Therefore, become the patient of rifamycinoid antibiotics administration object, only limit to produce in the liver organization the higher patient of probability of cancerous cell.
And rifamycinoid antibiotics only limited to as antibacterial to be not used in the patient who does not suffer from these diseases to tuberculosis patient and leper's administration in the past.
In addition, when rifamycinoid antibiotics was used for tuberculotherapy, its hepatotoxicity was worrying.Particularly report, unite use, occur serious side effects sometimes with other antitubercular agents.Therefore, rifamycinoid antibiotics is not to use as remedies for liver diseases or hepatic function remedial agent in the past.Only there is a report to claim: by carbon tetrachloride (CCl as a kind of noxious substance
4) in the caused animal pharmaceuticals hepatitis model, the rifampicin administration alleviates hepatocellular damage and makes liver function index material value reduce (Huang, R., Okuno, H., Takasu, M., Shiozaki, Y., and Inoue, K.Protective effect of rifampicin against acute liver injury induced by carbon tetrachloride inmice.Jpn J Pharmacol, 69:325-334,1995.; Takeda, K., Watanabe, J., Inoue, K., andKanamura, S.Rifampicin suppresses hepatic CYP2E1 expression and minimizes DNA injurycaused by carbon tetrachloride in perivenular hepatocytes of mice.Alcohol Clin Exp Res, 24:87S-92S, 2000.).But, by the drug induced hepatitis that carbon tetrachloride causes, be that toxicity pair cell owing to chemical substance damages and causes, these are different fully with the pathogeny that is considered to the hepatitis C that immunoreation participates in.The present invention has epoch making significance in the following areas: for be considered to a kind of have immunoreation participate in very dark human hepatitis C, and mice since ConA (concanavalin A, Con A) or rat because the treatment of the hepatitis that galactosamine (galactosamine) causes etc., rifampicin demonstration effectiveness.
Specifically, the invention provides following remedies for liver diseases and hepatic function remedial agent.
(1) a kind of remedies for liver diseases, its derivant or last permissible salt of its pharmacology with rifamycin B or rifamycin B is effective ingredient.
Wherein, so-called " derivant of rifamycin B ", be meant directly synthetic or through a plurality of intermediate and synthetic chemical compound specifically can be enumerated: Rifamycin Sodium, rifampicin, rifabutin (rifabutin), rifapentine (rifapentine) etc. by rifamycin B.
And so-called " the last permissible salt of pharmacology " is meant the salt that does not lose the liver disease effect, specifically can enumerate: base addition salts such as acid-addition salts such as hydrochlorate, sodium salt.
So-called " hepatopathy " is meant in the liver organization because the general name of inherent or external former thereby the chronic or acute illness that causes; As inherent or external reason, there are obesity, viral infection, absorption ethanol, immune unusual, relevant unusually bile in liver, to be detained etc. specifically with bile duct.
So-called " effective ingredient " is meant the composition that shows the liver disease effect.And remedies for liver diseases only otherwise lose the liver disease effect then can contain the composition beyond the effective ingredient.
(2) as (1) described remedies for liver diseases, the derivant of above-mentioned rifamycin B or rifamycin B is to go up permissible salt with general formula (I) represented rifamycinoid antibiotics or its pharmacology.
[Chemical formula 1]
[R in the formula
1Expression hydrogen or C
1-3Alkyl-carbonyl, R
2Expression hydrogen, C
1-3Alkyl-carbonyl, hydroxycarbonyl group methylene maybe can have substituent amino carbonyl methylene, R
3Expression hydrogen, formoxyl, C
1-10Alkoximino maybe can have substituent piperazinyl imino group, 2,4-dinitro benzene amido imino group]
Wherein, so-called " C
1-3Alkyl-carbonyl ", be meant that carbon number is the group that the carbonyl carbon bond of 1～3 catenate alkyl of straight chain shape or branch and carbonyl forms.
So-called " hydroxycarbonyl group methylene ", the group that is meant the carbonyl carbon bond of hydroxyl and carbonyl is that hydroxycarbonyl group has replaced 1 group that hydrogen atom forms on the methyl.
So-called " can have substituent amino carbonyl methylene " is meant with the represented group of general formula (III).Wherein, R
6, R
7Represent that respectively hydrogen, carbon number are 1～3 the catenate alkyl of straight chain shape or branch.
[Chemical formula 2]
So-called " C
1-10Alkoximino ", be meant that carbon number is the group that oxygen atom bond that 1～10 catenate alkyl and the oximido of straight chain shape or branch had forms.
So-called " can have substituent piperazinyl imino group " is meant with the represented group of general formula (IV).Wherein, R
8～R
15Represent that respectively hydrogen, carbon number are 1～3 the catenate alkyl of straight chain shape or branch, R
16Expression hydrogen, carbon number are 1～6 the catenate alkyl of straight chain shape or branch, cyclic aliphatic alkyl, the benzyl that carbon number is 3～8.
[chemical formula 3]
" 2,4-dinitro benzene amido imino group " are meant the hydrogen atom with the nitrogen-atoms bond of imino group, and by from 2, the group of removing 1 hydrogen atom in the amino of 4-dinitroaniline replaces the group that forms.
(3) remedies for liver diseases as claimed in claim 1, the derivant of wherein above-mentioned rifamycin B or rifamycin B are to go up permissible salt with general formula (II) represented rifamycinoid antibiotics or its pharmacology.
[chemical formula 4]
[R in the formula
4Expression hydrogen or C
1-3Alkyl-carbonyl, R
5Expression hydrogen, C
1-6Alkyl]
Wherein, so-called " C
1-6Alkyl ", be meant that carbon number is 1～6 the catenate alkyl of straight chain shape or branch.
(4) as (2) described remedies for liver diseases, wherein above-mentioned rifamycinoid antibiotics is to be selected from the group that is made up of rifampicin, rifamycin-SV, 3-formyl rifamycin (Formyl Rifamycin), rifapentine, rifamycin B.
(5) as (3) described remedies for liver diseases, described rifamycinoid antibiotics is a rifabutin.
(6) as each described remedies for liver diseases in (1) to (5), it is to be used for the treatment of the hepatopathy that is selected from the group that is made up of fat hepatitis, viral hepatitis, liver cirrhosis, primary biliary cirrhosis, alcoholic liver disease, autoimmune hepatitis, primary sclerosing cholangitis.
If utilize (6) described remedies for liver diseases, liver function is improved, therefore can treat hepatopathy.Therefore, can prevent the result who develops as hepatopathy and the generation of cancerous cell in the liver organization that causes, thereby also can prevent the morbidity of hepatocarcinoma.
At this, so-called " viral hepatitis " is meant by the caused hepatitis of hepatitis virus, for example can enumerate: hepatitis A, hepatitis B, hepatitis C, hepatitis D and hepatitis E.
(7) a kind of hepatic function remedial agent, it is that to go up permissible salt with the derivant of rifamycin B or rifamycin B or its pharmacology be effective ingredient.
Wherein, so-called " the last permissible salt of pharmacology " is meant the salt that does not lose liver function improvement effect, specifically can enumerate: base addition salts such as acid-addition salts such as hydrochlorate, sodium salt.
So-called " effective ingredient " is meant to show that liver function improves the composition of effect.And hepatic function remedial agent only otherwise losing liver function improves effect then can contain the composition beyond the effective ingredient.
[effect of invention]
According to remedies for liver diseases of the present invention, can obtain following effect.
Because with rifamycinoid antibiotics as effective ingredient, so can treat hepatopathy.Thus, also can prevent the result who develops as hepatopathy and the hepatocarcinoma that may fall ill.
Rifamycinoid antibiotics is compared with the dosage as antibacterial in the past, just can treat hepatopathy with less dose, therefore can reduce the probability that side effect takes place.
According to hepatic function remedial agent of the present invention, can obtain following effect.
Because with rifamycinoid antibiotics as effective ingredient, so can improve liver function.Thus, for example, can treat hepatopathy, also can prevent the result who develops as hepatopathy and the hepatocarcinoma that may fall ill.
Rifamycinoid antibiotics is compared with the dosage as antibacterial in the past, just can improve liver function with less dose, therefore can reduce to take place the probability of side effect.
And then, according to remedies for liver diseases of the present invention or hepatic function remedial agent, can obtain following effect.
Rifamycinoid antibiotics is absorbed and is not vulnerable to the influence of digestive enzyme easily rapidly from digestive tract, therefore can be taken orally.
Rifamycinoid antibiotics for example, also can be treated viral hepatitis for the patient who uses interferon or ursodesoxycholic acid not to obtain therapeutic effect sometimes, and versatility is higher.
And, because the rifamycinoid antibiotics price is low,, therefore can alleviate the financial burden that brings the patient so also can provide remedies for liver diseases or hepatic function remedial agent at an easy rate.
Description of drawings
Fig. 1 is the figure that patient's liver function undergoes senescence with time changes behind the drug administration of expression embodiments of the invention.
The specific embodiment
Below, embodiments of the present invention are described.
The present invention relates to the last permissible derivant of a kind of pharmacology with rifamycinoid antibiotics and/or rifamycinoid antibiotics is the remedies for liver diseases and the hepatic function remedial agent of effective ingredient.
(composition)
Remedies for liver diseases of the present invention and hepatic function remedial agent are to be effective ingredient with rifamycinoid antibiotics etc.
[effective ingredient]
(rifamycinoid antibiotics)
Rifamycinoid antibiotics so long as can be used as remedies for liver diseases or hepatic function remedial agent and the chemical compound that uses, then is not particularly limited.That is, rifamycinoid antibiotics is with general formula (I) or the represented chemical compound of general formula (II).Wherein, in the general formula (I), R
1Expression hydrogen, C
1-3Alkyl-carbonyl, R
2Expression hydrogen, C
1-3Alkyl-carbonyl, hydroxycarbonyl group methylene, can have substituent amino carbonyl methylene, R
3Expression hydrogen, formoxyl, C
1-10Alkoximino, can have substituent piperazinyl imino group.In the general formula (II), R
4Expression hydrogen, C
1-3Alkyl-carbonyl, R
5Expression hydrogen, C
1-6Alkyl.
R
2In " can have substituent amino carbonyl methylene " be with the represented group of general formula (III).Wherein, R
6, R
7Represent hydrogen, C respectively
1-3Alkyl.
R
3In " can have substituent piperazinyl imino group " be with the represented group of general formula (IV).Wherein, R
8～R
15Represent hydrogen, C respectively
1-3Alkyl, R
16Expression hydrogen, C
1-6Alkyl, C
3-8Cycloalkyl, benzyl, 2, the 4-dinitrophenyl.
Wherein, so-called " C
1-6Alkyl " be meant that carbon number is 1～6 the catenate alkyl of straight chain shape or branch; specifically can enumerate: methyl; ethyl; the 1-propyl group; the 2-propyl group; 2-methyl isophthalic acid-propyl group, 2-methyl-2-propyl group, the 1-butyl, the 2-butyl, the 1-amyl group, the 2-amyl group, the 3-amyl group, the 2-methyl-1-butene base, 3-methyl isophthalic acid-butyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl group, the 1-hexyl, the 2-hexyl, the 3-hexyl, 2-methyl-1-pentene base, 3-methyl-1-pentene base, 4-methyl-1-pentene base, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 2-methyl-3-amyl group, 3-methyl-3-amyl group, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2,2-dimethyl-1-butyl, 2-ethyl-1-butyl, 3,3-dimethyl-2-butyl, 2,3-dimethyl-2-butyl etc.
" C
1-3Alkyl " be meant above-mentioned C
1-6Carbon number is 1～3 alkyl in the alkyl.
So-called " C
1-10Alkoximino ", be meant C
1-10The group that the oxygen atom bond that alkyl and oximido had forms, this C
1-10Alkyl is meant that carbon number is 1～10 the catenate alkyl of straight chain shape or branch, specifically can enumerate: methoxyimino, ethoxy imino, 1-propoxyl group imino group, 2-propoxyl group imino group, 2-methyl isophthalic acid-propoxyl group imino group, 2-methyl-2-propoxyl group imino group, 1-butoxy imino group, 2-butoxy imino group, 1-amoxy imino group, 2-amoxy imino group, 3-amoxy imino group, 2-methyl-1-butene oxygen base imino group, 3-methyl isophthalic acid-butoxy imino group, 2-methyl-2-butoxy imino group, 3-methyl-2-butoxy imino group, 2,2-dimethyl-1-propoxyl group imino group, 1-hexyloxy imino group, 2-hexyloxy imino group, 3-hexyloxy imino group, 1-octyloxy imino group, 2-octyloxy imino group, 3-octyloxy imino group, 1-oxygen in ninth of the ten Heavenly Stems base imino group, 2-oxygen in ninth of the ten Heavenly Stems base imino group, 3-oxygen in ninth of the ten Heavenly Stems base, 1-oxygen in last of the ten Heavenly stems base, 2-oxygen in last of the ten Heavenly stems base, 3-oxygen in last of the ten Heavenly stems base, 2-methyl-1-pentene oxygen base imino group, 3-methyl-1-pentene oxygen base imino group, 4-methyl-1-pentene oxygen base imino group, 2-methyl-2-amoxy imino group, 3-methyl-2-amoxy imino group, 4-methyl-2-amoxy imino group, 2-methyl-3-amoxy imino group, 3-methyl-3-amoxy imino group, 2,3-dimethyl-1-butoxy imino group, 3,3-dimethyl-1-butoxy imino group, 2,2-dimethyl-1-butoxy imino group, 2-ethyl-1-butoxy imino group, 3,3-dimethyl-2-butoxy imino group, 2,3-dimethyl-2-butoxy imino group etc.
So-called " C
3-8Cycloalkyl " be meant that carbon number is 3～8 cyclic aliphatic alkyl, for example can enumerate: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group.
So-called " C
1-3Alkyl-carbonyl " be meant C
1-3The group that the carbonyl carbon bond of alkyl and carbonyl forms for example can be enumerated: methyl carbonyl, ethyl carbonyl, 1-propyl group carbonyl, 2-propyl group carbonyl.
In the represented rifamycinoid antibiotics of general formula (I), R
1Preferred hydrogen, methyl carbonyl, more preferably methyl carbonyl; R
2Preferred hydrogen, hydroxycarbonyl group methylene; R
3Preferred hydrogen, formoxyl, octyloxy imino group, 4-methyl piperazine base imino group, 4-cyclopentyl-based piperazine base imino group, 4-benzyl diethylenediamine base imino group, 2; 6-dimethyl-4-benzyl diethylenediamine base imino group, 2; 4-dinitro benzene amido imino group, more preferably hydrogen, formoxyl, 4-methyl piperazine base imino group, 4-cyclopentyl-based piperazine base imino group.
And, in the represented rifamycinoid antibiotics of general formula (II), R
4Preferred hydrogen, methyl carbonyl, more preferably methyl carbonyl, R
5Preferred 2-methyl-propyl.
And, in the represented rifamycinoid antibiotics of general formula (I), more preferably rifampicin (R
1=methyl carbonyl, R
2=hydrogen, R
3=4-methyl piperazine base imino group), rifamycin-SV (R
1=methyl carbonyl, R
2=hydrogen, R
3=hydrogen), 3-formyl rifamycin (R
1=methyl carbonyl, R
2=hydrogen, R
3=formoxyl), rifapentine (R
1=methyl carbonyl, R
2=hydrogen, R
3=4-cyclopentyl-based piperazine base imino group), rifamycin B (R
1=methyl carbonyl, R
2=hydroxycarbonyl group methylene, R
3=hydrogen), as with the represented rifamycinoid antibiotics of formula (II), more preferably rifabutin (R
4=methyl carbonyl, R
5=2-methyl-propyl).
(pharmacology of rifamycinoid antibiotics goes up permissible derivant)
The pharmacology of rifamycinoid antibiotics goes up permissible derivant, and is better in the following areas: can increase to solvent () dissolubility for example, water, thus can improve the absorption efficiency of health.Going up permissible derivant as the pharmacology, be not particularly limited, can be the salt of general use in the preparationization of medicine or the hydrate of these salt.Wherein, go up permissible salt, can enumerate: acid-addition salts or base addition salts etc. as the pharmacology.
As acid-addition salts, be not particularly limited, for example can enumerate: hydrochlorate, acetate, sulfate, nitrate, oxalates, maleic acid, tartrate, citrate, carbonate, succinate, benzoic acid, acetate, hydrobromate, iodate hydrogen salt, phosphate, fumarate, gluconate, tosilate, mesylate, esilate.
As base addition salts, be not particularly limited, can enumerate: alkali metal salts such as sodium salt, potassium salt, alkali salts such as calcium salt, magnesium salt, organic amine salts such as ethanolamine salt, triethylamine salt, methyl amine salt, ammonium salt etc.
[additive]
Remedies for liver diseases of the present invention or hepatic function remedial agent can be individually dosed, but preferably come administration with the medical composition form that further contains permissible additive on pharmacology and the galenic pharmacy.Upward reach permissible additive on the galenic pharmacy as the pharmacology, for example can enumerate: excipient, disintegrating agent, disintegrate adjuvant, emulsifying agent, suspending agent, dispersant, binding agent, lubricant, coating materials, pigment, diluent, substrate, lytic agent, cosolvent, isotonization agent, pH value regulator, stabilizing agent, propellant, sticker.
As excipient, can enumerate: glucose, lactose, D-mannitol, starch, crystalline cellulose etc.; As disintegrating agent and disintegrate adjuvant, can enumerate: carboxymethyl cellulose, starch, carboxymethyl cellulose potassium etc.; As emulsifying agent, suspending agent and dispersant, can enumerate: polyoxyl stearate (polyoxyl stearate), sucrose fatty acid ester, sodium laurylsulfate etc.; As binding agent, can enumerate: hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, gelatin etc.; As lubricant, can enumerate: magnesium stearate, aluminium silicate, Talcum etc.; As coating materials, can enumerate: hydroxypropyl emthylcellulose, white sugar, Polyethylene Glycol, titanium oxide etc.; As substrate, can enumerate: vaseline, Liquid Paraffin, Polyethylene Glycol, gelatin, Kaolin, glycerol, Purified Water, hard fat etc.
And the employed additive in the preparation for injection or drop is not particularly limited, as lytic agent or cosolvent, can enumerate: distilled water for injection, normal saline solution, propylene glycol etc., as the pH value regulator, can enumerate: mineral acid, organic acid, inorganic base, organic base etc.
(manufacture method)
(manufacture method of rifamycinoid antibiotics)
Rifamycin B as an example of rifamycinoid antibiotics of the present invention, be a kind of in the antibiotic that produces of Mediterranean streptomycete (Streptomyces mediterranei), can utilize well-known method from the culture fluid of Mediterranean streptomycete, to be separated (with reference to the special public clear 37-1697 communique of Japan Patent, right section the 32nd row of the right section of page 2 eighth row～page 4).
Rifampicin, rifapentine, rifabutin, Rifamycin Sodium and their derivant can utilize well-known method to be synthesized (with reference to section the 30th row～right side, the special public clear 62-41671 communique page 2 left side of Japan Patent section the 27th row by this rifamycin B; Section the 34th row～right side, the special public clear 62-41672 communique page 2 left side of Japan Patent section the 31st row; Section the 32nd row～right side, the special public clear 62-41673 communique page 2 left side of Japan Patent section the 29th row;～7 pages upper right section the 7th row of Japanese patent laid-open 1-149790 communique page 3 bottom right section the 12nd row ,～10 pages of lower-left sections of the 8th page of lower-left section the 4th row the 14th row;～the 21 section the 20th row of the 9th section the 9th row of Japanese patent laid-open 2-304090 communique; Japanese patent laid-open 2-56487 communique ,～18 pages upper left section the 9th row of the 13rd page upper left section the 18th row ,～28 pages upper left section the 13rd row of the 19th page upper right section the 15th row; Japanese patent laid-open 3-169884 communique ,～22 pages of lower-left sections of the 17th page of bottom right section the 18th row the 3rd row ,～33 pages of lower-left sections of the 23rd page of bottom right section the 10th row the 20th row; Japanese patent laid-open 4-159283 communique, paragraph 0038～0070,0081～0107; Japanese patent laid-open 4-230688 communique, paragraph 0065～0103,0118～0147; Japanese patent laid-open 4-247088 communique, paragraph 0076～0120,0136～0139; United States Patent (USP) the 4th, 002, No. 752 communiques).In addition, as rifamycinoid antibiotics, market " Rifampicin " as rifampicin on sale (Alexis corporate system), as " Rifafuchinn sheet (trade name) " (the Sanofi-Aventis corporate system) of rifapentine, as " Rifabutin " (U.S.P.Reference Standards corporate system) of rifabutin, as Rifamycin Sodium " Rifamycin SV sodium salt (Rifamycin Sodium sodium salt) " (MP Biomedicals corporate system) etc., also can use these goods.
(becoming the disease of administration object)
Remedies for liver diseases of the present invention or hepatic function remedial agent, can be used for fat hepatitis (for example, non-alcoholic stellato-hepatitis), viral hepatitis, liver cirrhosis, primary biliary cirrhosis, alcoholic liver disease, autoimmune hepatitis, primary sclerosing cholangitis, hepatocarcinoma etc.Wherein, as viral hepatitis, for example can enumerate: hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E.
The present invention also provides a kind of Therapeutic Method and liver function improvement method of hepatopathy as described below.
A kind of Therapeutic Method of hepatopathy, it comprises following steps: will be the remedies for liver diseases of effective ingredient with the derivant or the last permissible salt of its pharmacology of rifamycin B or rifamycin B, to the object of suffering from hepatopathy (for example, people, non-human animal) administration.
A kind of liver function improvement method, it comprises following steps: will be the remedies for liver diseases of effective ingredient with the derivant or the last permissible salt of its pharmacology of rifamycin B or rifamycin B, to object (for example, people, non-human animal) administration.
[instructions of taking, take form]
In remedies for liver diseases of the present invention or the hepatic function remedial agent, rifampicin, rifapentine and rifabutin have been used for the many patients of numbers of poles such as tuberculosis patient, so its usage and side effect are well known.Therefore, for remedies for liver diseases of the present invention or hepatic function remedial agent, can rule of thumb select to suppress medication, the form of medication of side effect.
Remedies for liver diseases of the present invention can be united use with the existing various compositions that are used for the treatment of hepatopathy.Specifically, can unite use with at least a above composition that is selected from by in the group of Remed for hepatopathy such as compound glycyrrhizin, ursodesoxycholic acid, propagermanium (Propagermanium), glutathion (Glutathione), Malotilate (Malotilate), glycyrrhizic acid.And, can be selected from that ((more than one compositions in the group that forms of Interferon-α-2b), interferon beta various interferon such as (Interferon-β) are united use for Interferon-α-2a), Interferon Alpha-2b by interferon-ALPHA (Interferon-α), Intederon Alpha-2a.And then, can unite use with at least a above composition that is selected from the group that forms by lamivudine (Lamivudine), ribavirin antiviral agents such as (Ribavilin).
Remedies for liver diseases of the present invention or hepatic function remedial agent can come administration by any form in oral administration or the non-oral administration (for example, intravenous injection, intramuscular injection, subcutaneous injection).Can suitably select form of medication according to the patient's who accepts administration the state of an illness, but consider the preferred oral administration from convenience and safety aspect.
Under case of oral administration, rifamycinoid antibiotics can come administration by the form of solid or liquid preparation, particularly, can carry out administration by forms such as tablet, granule, capsule, powder, buccal tablet, solution, suspension, emulsions.
Under non-case of oral administration, rifamycinoid antibiotics can carry out administration by the form that is dissolved in the appropriate solvent.
[dose]
The dose of remedies for liver diseases of the present invention or hepatic function remedial agent can wait suitably according to the disease that becomes object or medication and set.When oral rifampicin, dose is about 10～900mg/ day, is preferably about 50～450mg/ day.And when oral rifabutin, dose is about 10～600mg/ day, is preferably about 20～300mg/ day.And when oral rifapentine, dose is about 50～1800mg/ week, is preferably about 50～1200mg/ week.
[medicine-feeding period]
The medicine-feeding period of remedies for liver diseases of the present invention or hepatic function remedial agent depends on administration patient's symptom, and preferably continuously more than administration every day at least one month, more preferably administration is more than 1 year.
[embodiment]
The therapeutic effect of (embodiment 1) rifampicin a small amount of administration improvement chronic hepatitis C patient's liver function
Give 6 chronic hepatitis C (example of hepatopathy) patient's oral administration every day 150mg (1 capsules) Rimactane " Rifadin (registered trade mark) " (first drugmaker's system), and regularly gather each patient's blood.Alanine aminotransferase in the collection blood (ALT) value and aspartate aminotransferase (AST) value are measured.
At this, selected conduct is put to the test the patient of body for following state in the present embodiment.
The first, infer have 5 patients to be equivalent to the third type liver cirrhosis patient of F3～F4 for hepatic fibrosis among 6 patients according to biopsy (biopsy) and platelet count.
The second, all patients are has the chronic hepatitis C patient who is difficult to use the Ib type hepatitis C virus that interference usually treats.4 patients are carried out interferon therapy, and wherein 1 patient does not see therapeutic effect.And, all produce stronger side effect among 4 patients, therefore ended treatment.
The 3rd, for all these patients, carry out the ursodesoxycholic acid drug treatment, but there is no therapeutic effect.
Fig. 1 is 6 chronic hepatitis C patients' of expression the ALT value and the time dependent figure of meansigma methods of AST value.Because ALT value and AST value representation effusive transaminase's from the liver cell of damaged concentration, these values are higher to mean that then that more liver cell is arranged is impaired, and liver function descends.
Carry out the mensuration of ALT value as follows.
At first, from the blood of being gathered, isolate serum, use this serum and utilization according to JSCC (Japan Societyof Clinical Chemistry, Japan's clinical chemistry meeting) lactic acid dehydrogenase (lactate dehydrogenase) conjugation UV (ultraviolet) method (" Hitachi's automatic analysing apparatus 7350 ", Hitachi Hi-Technology corporate system), regularly measure, and calculate the ALT value.
And, carry out the mensuration of AST value as follows.
At first, from the blood of being gathered, isolate serum, use this serum and utilization malic dehydrogenase (malate dehydrogenase) conjugation UV (ultraviolet) method (" Hitachi's automatic analysing apparatus 7350 " according to JSCC, the HitachiHi-Technology corporate system) regularly measures, and calculate the AST value.
As shown in Figure 1, ALT value and AST value are compared after the beginning administration with before the drug administration, reduce significantly about about one month, all keep low value afterwards till six months.In addition, ALT value and AST value, its normal value is 11～40IU/L, and shows the high value that surpasses the normal value upper limit mostly in viral chronic hepatitis patient.For chronic hepatitis,, judge generally that then hepatitis symptom improves if ALT value and AST value reduce.Therefore, according to this result as can be known, can improve liver function, thereby improve the symptom of viral hepatitis by administration.
And, even this medicine also can substantially improve the symptom of viral hepatitis by oral administration as can be known.Even for the chronic hepatitis C patient of the hepatitis C virus with Ib type, rifampicin also can effectively improve the symptom of hepatitis.
The side effect of known rifampicin administration has hepatic injury, gastrointestinal disorder, hematologic disease, erythra, heating etc.Yet, in the present embodiment, in carrying out 6 patients of rifampicin administration, do not find these side effect.And, even after finishing evaluation period of present embodiment through time several years, though these patients have been carried out the rifampicin administration, side effect does not take place, ALT value and AST value long term maintenance are not found the morbidity of hepatocarcinoma than the state of hanging down yet.
According to above result as can be known, rifampicin has the effect of hepatic function remedial agent for chronic hepatitis C.
And, even know as the dose of the rifampicin of remedies for liver diseases and hepatic function remedial agent with compare significantly minimizing as the dose (for example, about 450mg, 1 time on the 1st) of tuberculotherapy agent, also can obtain liver disease effect and liver function and improve effect.
The hepatoprotective effect (1) of (embodiment 2) rifampicin administration
Utilization is estimated the hepatoprotective effect of rifampicin by the caused mice viral hepatitis of con A (ConA) model.That is,, give continuous 4 days oral administration Rimactanes " GK-001 " (Lupin Limited system) of 8 mices of each group with 50mg/kgday, 100mg/kgday, and the dosage of 200mg/kgday.Behind 1 hour of administration in the 4th day, the ConA that will be dissolved in the 0.2mg in the phosphoric acid normal saline (PBS (Phosphate Buffer Solution, phosphate buffer)) carries out administration by mouse tail vein.GK-001 with 200mg/kg has only been carried out single administration group mice and do not give mice in the group of GK-001, all implement same operation.After giving 24 hours of ConA, mice is implemented anesthesia, gather arterial blood.Measure ALT value, AST value in the blood, reach that lactic acid dehydrogenase (LDH) is worth in the blood.
From the blood of being gathered, isolate serum, use this serum and utilization, measure and calculate the LDH value according to para-nitro-pheneye phosphate (p-nitrophenyl phosphate) the substrate method (" automatic analysing apparatus 7170 ", Hitachi's corporate system) of JSCC.
More than the results are shown in table 1.
[table 1]
| GK-001 dosage (mg/kgday) | The administration natural law | The ConA administration | ALT (IU/L) | AST (IU/L) | LDH (IU/L) |
| 0 | - | - | 15±0 | 32±0 | 126±11 |
| 0 | - | + | 5963±1225 | 8655±1819 | 22390±4447 |
| 50 | 4 | + | 3565±991 | 4378±1568 | 12938±4683 |
| 100 | 4 | + | 1950±654 | 2178±862 * | 7120±2750 |
| 200 | 4 | + | 870±203 ** | 605±136 ** | 1963±403 |
| 200 | 1 | + | 1940±1003 * | 2710±1585 ** | 8090±4327 |
Meansigma methods ± standard deviation (population parameter 8)
*p＜0.05、
**p＜0.01
(with respect to GK-001 dosage 0mg/kgday, ConA administration (+))
According to table 1 as can be known, in rifampicin administration group, along with the increase of dosage, ALT value, AST value, and significantly reduction of LDH value.According to this result, the expression rifampicin has suppressed the decline by the caused liver function of ConA.
The hepatoprotective effect (2) of (embodiment 3) rifampicin administration
Utilization is estimated the hepatoprotective effect of rifampicin by the caused rat viral hepatitis of galactosamine (Gal) model.That is,, give continuous 4 days oral Rimactanes " GK-001 " (Lupin Limited system) of 8 rat of each group with 50mg/kgday, 100mg/kgday, and the dosage of 200mg/kgday.Behind 1 hour of administration in the 4th day, the Gal that is dissolved in the 350mg/kg in the normal saline is administered to the intraperitoneal of rat.GK-001 with 200mg/kg has only been carried out the rat of group of single administration and the rat that does not give the group of GK-001, all carried out same operation.After giving 24 hours of Gal, rat is implemented anesthesia, gather arterial blood.Measure ALT value, AST value in the blood, reach the LDH value.The results are shown in table 2.
[table 2]
| GK-001 administration (mg/kgday) | The administration natural law | The Gal administration | ALT (IU/L) | AST (IU/L) | LDH (IU/L) |
| 0 | - | - | 21±1 | 64±1 | 125±9 |
| 0 | - | + | 2218±434 | 3330±761 | 13815±4850 |
| 50 | 4 | + | 738±180 * | 1915±518 | 5658±2084 |
| 100 | 4 | + | 953±114 | 1910±216 | 4985±897 |
| 200 | 4 | + | 315±102 ** | 800±356 ** | 1493±896 ** |
| 200 | 1 | + | 435±133 * | 633±160 ** | 1135±536 ** |
Meansigma methods ± standard deviation (population parameter 8)
*p＜0.05，
**p＜0.01
(with respect to GK-001 dosage 0mg/kgday, Gal administration (+))
According to table 2 as can be known, in rifampicin administration group, along with the increase of dosage, ALT value, AST value, and significantly reduction of LDH value.According to this result, the expression rifampicin has suppressed to be descended by the caused liver function of Gal.
Claims (7)
1. a remedies for liver diseases is characterized in that: derivant or its pharmacology of rifamycin B or rifamycin B are gone up permissible salt as effective ingredient.
2. remedies for liver diseases as claimed in claim 1 is characterized in that: the derivant of described rifamycin B or rifamycin B is to go up permissible salt with general formula (I) represented rifamycinoid antibiotics or its pharmacology,
[Chemical formula 1]
R in the formula
1Expression hydrogen or C
1-3Alkyl-carbonyl, R
2Expression hydrogen, C
1-3Alkyl-carbonyl, hydroxycarbonyl group methylene maybe can have substituent amino carbonyl methylene, R
3Expression hydrogen, formoxyl, C
1-10Alkoximino maybe can have substituent piperazinyl imino group, 2,4-dinitro benzene amido imino group.
3. remedies for liver diseases as claimed in claim 1 is characterized in that: the derivant of described rifamycin B or rifamycin B is to go up permissible salt with general formula (II) represented rifamycinoid antibiotics or its pharmacology,
[Chemical formula 2]
R in the formula
4Expression hydrogen or C
1-3Alkyl-carbonyl, R
5Expression hydrogen, C
1-6Alkyl.
4. remedies for liver diseases as claimed in claim 2 is characterized in that: described rifamycinoid antibiotics is to be selected from the group that is made up of rifampicin, rifamycin-SV, 3-formyl rifamycin, rifapentine, rifamycin B.
5. remedies for liver diseases as claimed in claim 3 is characterized in that: described rifamycinoid antibiotics is a rifabutin.
6. as each described remedies for liver diseases in the claim 1 to 5, it is characterized in that: be used for the treatment of the hepatopathy that is selected from the group that forms by fat hepatitis, viral hepatitis, liver cirrhosis, primary biliary cirrhosis, alcoholic liver disease, autoimmune hepatitis, primary sclerosing cholangitis.
7. hepatic function remedial agent is characterized in that: going up permissible salt with the derivant of rifamycin B or rifamycin B or its pharmacology is effective ingredient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP000096/2006 | 2006-01-04 | ||
| JP2006000096 | 2006-01-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101351206A true CN101351206A (en) | 2009-01-21 |
Family
ID=38228247
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800502853A Pending CN101351206A (en) | 2006-01-04 | 2006-12-27 | Therapeutic agent for liver disease and hepatic function- |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP5061352B2 (en) |
| KR (2) | KR20080081351A (en) |
| CN (1) | CN101351206A (en) |
| WO (1) | WO2007077893A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111328279A (en) * | 2017-11-10 | 2020-06-23 | 科斯莫科技有限公司 | Oral rifamycin SV compositions |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5829353B2 (en) * | 2013-02-12 | 2015-12-09 | 公益財団法人がん研究会 | Method for examining cancer and / or carcinogenic risk, and method for screening medicine |
| US20230147364A1 (en) * | 2020-04-30 | 2023-05-11 | Kyoto University | Prophylactic or therapeutic agent for rna virus-related diseases |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003535912A (en) * | 2000-06-21 | 2003-12-02 | グラクソ グループ リミテッド | Nuclear orphan receptor |
| JP4393098B2 (en) * | 2002-06-21 | 2010-01-06 | 独立行政法人科学技術振興機構 | New uses of ansamycin antibiotics and screening methods for new angiogenesis inhibitors |
-
2006
- 2006-12-27 WO PCT/JP2006/326134 patent/WO2007077893A1/en active Application Filing
- 2006-12-27 KR KR1020087018356A patent/KR20080081351A/en active Search and Examination
- 2006-12-27 KR KR1020117012671A patent/KR20110074945A/en not_active Application Discontinuation
- 2006-12-27 CN CNA2006800502853A patent/CN101351206A/en active Pending
- 2006-12-27 JP JP2007552970A patent/JP5061352B2/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111328279A (en) * | 2017-11-10 | 2020-06-23 | 科斯莫科技有限公司 | Oral rifamycin SV compositions |
| US11564883B2 (en) | 2017-11-10 | 2023-01-31 | Cosmo Technologies Ltd. | Oral rifamycin SV compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007077893A1 (en) | 2007-07-12 |
| JP5061352B2 (en) | 2012-10-31 |
| JPWO2007077893A1 (en) | 2009-06-11 |
| KR20110074945A (en) | 2011-07-04 |
| KR20080081351A (en) | 2008-09-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2694087B1 (en) | Treatment for infection with hepatitis b virus alone or in combination with hepatitis delta virus and associated liver diseases | |
| CA2813093A1 (en) | Combination therapy for treating hcv infection | |
| CA2664935A1 (en) | Compositions for the treatment of hepatitis c and methods for using compositions for the treatment of hepatitis c | |
| JP5058156B2 (en) | Inflammatory bowel disease treatment | |
| US8912141B2 (en) | Treatment of hepatitis C virus | |
| TW201138773A (en) | Dosage regimens for HCV combination therapy | |
| CN109364074B (en) | Application of 6-aminonicotinamide as effective component in preparing medicament for treating hepatitis B | |
| WO2012011847A1 (en) | Substituted indoles, antiviral active component, method for producing and using same | |
| CN101351206A (en) | Therapeutic agent for liver disease and hepatic function- | |
| JP2006527185A5 (en) | ||
| KR20220018552A (en) | Use of Amlexanox for the manufacture of anti-hepatitis virus drugs | |
| US20190290673A1 (en) | Compositions and methods for the treatment of hbv infection | |
| WO2022095950A1 (en) | Pharmaceutical combination containing capsid protein inhibitor and nucleoside analog | |
| EP2305234A1 (en) | Pharmaceutical composition for treatment or prevention of hbv infection | |
| WO2021016543A1 (en) | Antiviral combinations of thiazolide compounds | |
| EP2519243B1 (en) | Compositions and methods for treating hepatitis b virus infection | |
| WO2023219360A1 (en) | Pharmaceutical composition for preventing or treating hepatitis b | |
| RU2407738C1 (en) | Antiviral active component, pharmaceutical composition, medicinal agent, method of treating viral diseases | |
| ES2968931T3 (en) | Synergistic effect of eyp001 and pegylated ifn-alpha for the treatment of hbv infection | |
| US20220047606A1 (en) | Treatment method with iap inhibitor | |
| KR100379155B1 (en) | New analgesic composition | |
| WO2021170741A1 (en) | Treatment of hbv | |
| JP4829411B2 (en) | Treatment for chronic hepatitis C | |
| RU2020143252A (en) | METHODS FOR THE TREATMENT OF CONDITIONS ASSOCIATED WITH THE S1P1 RECEPTOR | |
| EA046230B1 (en) | SYNERGIC ACTION OF EYP001 AND IFN IN THE TREATMENT OF HBV INFECTION |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1126143 Country of ref document: HK |
|
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20090121 |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1126143 Country of ref document: HK |