CN1159324A - 活性氧、自由基去除剂 - Google Patents
活性氧、自由基去除剂 Download PDFInfo
- Publication number
- CN1159324A CN1159324A CN96123286A CN96123286A CN1159324A CN 1159324 A CN1159324 A CN 1159324A CN 96123286 A CN96123286 A CN 96123286A CN 96123286 A CN96123286 A CN 96123286A CN 1159324 A CN1159324 A CN 1159324A
- Authority
- CN
- China
- Prior art keywords
- chemical compound
- hydantoin
- active oxygen
- free radical
- diseases
- 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.)
- Granted
Links
- 239000001301 oxygen Substances 0.000 title claims abstract description 46
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 46
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 229940123457 Free radical scavenger Drugs 0.000 title claims description 28
- 239000002516 radical scavenger Substances 0.000 title claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 15
- 150000001469 hydantoins Chemical class 0.000 claims abstract description 8
- 229940053195 antiepileptics hydantoin derivative Drugs 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 239000004615 ingredient Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 14
- 201000010099 disease Diseases 0.000 abstract description 13
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 3
- 208000002177 Cataract Diseases 0.000 abstract description 3
- 208000019693 Lung disease Diseases 0.000 abstract description 3
- 208000010125 myocardial infarction Diseases 0.000 abstract description 3
- 208000012659 Joint disease Diseases 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract 2
- 208000036487 Arthropathies Diseases 0.000 abstract 1
- 206010016654 Fibrosis Diseases 0.000 abstract 1
- 206010040070 Septic Shock Diseases 0.000 abstract 1
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 230000001627 detrimental effect Effects 0.000 abstract 1
- 230000004761 fibrosis Effects 0.000 abstract 1
- 208000027866 inflammatory disease Diseases 0.000 abstract 1
- 125000004043 oxo group Chemical group O=* 0.000 abstract 1
- 239000008177 pharmaceutical agent Substances 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 230000005855 radiation Effects 0.000 abstract 1
- 230000010410 reperfusion Effects 0.000 abstract 1
- 230000036303 septic shock Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 112
- -1 oxygen peroxide Chemical class 0.000 description 37
- 229940091173 hydantoin Drugs 0.000 description 34
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 18
- 150000003254 radicals Chemical class 0.000 description 12
- 208000027418 Wounds and injury Diseases 0.000 description 10
- 230000006378 damage Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- 239000012491 analyte Substances 0.000 description 8
- 208000014674 injury Diseases 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 210000003725 endotheliocyte Anatomy 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 102000019197 Superoxide Dismutase Human genes 0.000 description 5
- 108010012715 Superoxide dismutase Proteins 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- ZFLIKDUSUDBGCD-UHFFFAOYSA-N parabanic acid Chemical compound O=C1NC(=O)C(=O)N1 ZFLIKDUSUDBGCD-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 3
- RHYBFKMFHLPQPH-UHFFFAOYSA-N N-methylhydantoin Chemical compound CN1CC(=O)NC1=O RHYBFKMFHLPQPH-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229960002163 hydrogen peroxide Drugs 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 229940090044 injection Drugs 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229960003330 pentetic acid Drugs 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 2
- MZQQHYDUINOMDG-UHFFFAOYSA-N 3-methylimidazolidine-2,4-dione Chemical compound CN1C(=O)CNC1=O MZQQHYDUINOMDG-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 206010008088 Cerebral artery embolism Diseases 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 201000003883 Cystic fibrosis Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010048768 Dermatosis Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 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 2
- 208000000185 Localized scleroderma Diseases 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 206010027982 Morphoea Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010034972 Photosensitivity reaction Diseases 0.000 description 2
- 206010037423 Pulmonary oedema Diseases 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 239000003005 anticarcinogenic agent Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- MMKRHZKQPFCLLS-UHFFFAOYSA-N ethyl myristate Chemical compound CCCCCCCCCCCCCC(=O)OCC MMKRHZKQPFCLLS-UHFFFAOYSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 201000010849 intracranial embolism Diseases 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000036211 photosensitivity Effects 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- QGVLYPPODPLXMB-UBTYZVCOSA-N (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b,9,9a-tetrahydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-1,1a,1b,4,4a,7a,7b,8,9,9a-decahydro-5H-cyclopropa[3,4]benzo[1,2-e]azulen-5-one Chemical compound C1=C(CO)C[C@]2(O)C(=O)C(C)=C[C@H]2[C@@]2(O)[C@H](C)[C@@H](O)[C@@]3(O)C(C)(C)[C@H]3[C@@H]21 QGVLYPPODPLXMB-UBTYZVCOSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- SKVNURXOPBKIGV-UHFFFAOYSA-N 1,3-dicyclohexylimidazolidine-2,4,5-trione Chemical compound O=C1C(=O)N(C2CCCCC2)C(=O)N1C1CCCCC1 SKVNURXOPBKIGV-UHFFFAOYSA-N 0.000 description 1
- NOHNSECEKFOVGT-UHFFFAOYSA-N 1-butylimidazolidine-2,4-dione Chemical compound CCCCN1CC(=O)NC1=O NOHNSECEKFOVGT-UHFFFAOYSA-N 0.000 description 1
- KKRHFSGBFULTCD-UHFFFAOYSA-N 1-cyclohexyl-3-methylimidazolidine-2,4-dione Chemical compound O=C1N(C)C(=O)CN1C1CCCCC1 KKRHFSGBFULTCD-UHFFFAOYSA-N 0.000 description 1
- GTRAYSWZNRCJMV-UHFFFAOYSA-N 1-cyclohexylimidazolidine-2,4,5-trione Chemical compound O=C1NC(=O)C(=O)N1C1CCCCC1 GTRAYSWZNRCJMV-UHFFFAOYSA-N 0.000 description 1
- QOYAISCZWRBCJK-UHFFFAOYSA-N 1-cyclohexylimidazolidine-2,4-dione Chemical compound O=C1NC(=O)CN1C1CCCCC1 QOYAISCZWRBCJK-UHFFFAOYSA-N 0.000 description 1
- NMMYTZNIRUQKQL-UHFFFAOYSA-N 1-decylimidazolidine-2,4,5-trione Chemical compound CCCCCCCCCCN1C(=O)NC(=O)C1=O NMMYTZNIRUQKQL-UHFFFAOYSA-N 0.000 description 1
- PQTADOSMPJLSLC-UHFFFAOYSA-N 1-hexylimidazolidine-2,4,5-trione Chemical compound CCCCCCN1C(=O)NC(=O)C1=O PQTADOSMPJLSLC-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- SGYPGSFWKGUDJS-UHFFFAOYSA-N C(C)(C)OCC(C(OOCCC(C)C)(OCCCCC)OC(C)(C)C)(C(OC(C)CC)(OCC(C)C)OCCCC)C Chemical compound C(C)(C)OCC(C(OOCCC(C)C)(OCCCCC)OC(C)(C)C)(C(OC(C)CC)(OCC(C)C)OCCCC)C SGYPGSFWKGUDJS-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 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 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 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
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 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 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- WARKVSXNYNTODC-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C12.C(C)(C)(C)N1C=NC=C1 Chemical compound N1=CC=CC2=CC=CC=C12.C(C)(C)(C)N1C=NC=C1 WARKVSXNYNTODC-UHFFFAOYSA-N 0.000 description 1
- BBICAZHLDPMROZ-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C12.C(CCC)N1C=NC=C1 Chemical compound N1=CC=CC2=CC=CC=C12.C(CCC)N1C=NC=C1 BBICAZHLDPMROZ-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- BKFBPPAQUICQLS-UHFFFAOYSA-N ON1C(=C(CC1)C)C Chemical compound ON1C(=C(CC1)C)C BKFBPPAQUICQLS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010053615 Thermal burn Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 229940126179 compound 72 Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000006184 cosolvent 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
- 125000002704 decyl 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])C([H])([H])C([H])([H])* 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001362 electron spin resonance spectrum Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003631 expected effect Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000001400 nonyl 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])C([H])([H])[H] 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- QGVLYPPODPLXMB-QXYKVGAMSA-N phorbol Natural products C[C@@H]1[C@@H](O)[C@]2(O)[C@H]([C@H]3C=C(CO)C[C@@]4(O)[C@H](C=C(C)C4=O)[C@@]13O)C2(C)C QGVLYPPODPLXMB-QXYKVGAMSA-N 0.000 description 1
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 1
- 239000002644 phorbol ester Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000012488 sample solution Substances 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
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- PXLIDIMHPNPGMH-UHFFFAOYSA-N sodium chromate Chemical compound [Na+].[Na+].[O-][Cr]([O-])(=O)=O PXLIDIMHPNPGMH-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000004079 stearyl 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])C([H])([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])C([H])([H])[H] 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
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
- A61K31/41—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
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明的目的在于提供制剂容易、副作用少且可口服的新型自由基、活性氧去除剂。本发明的活性氧、自由基去除剂是含有用通式(I)表示的乙内酰脲衍生物或其药学上可允许的盐作为有效成分的活性氧、自由基去除剂,(式中R1及R2分别相同或不相同地表示氢原子、烷基或环烷基,X、Y分别相同或不相同地表示氢原子、烷基、羟基或烷氧基或X及Y一起表示氧基)。上式乙内酰脲衍生物具有去除活性氧、自由基的作用,所以可以作为治疗与活性氧、自由基有关的疾病的药物、这些疾病包括如心肌梗塞、再灌流障碍、脑栓塞、自身免疫疾病、纤维症、肺疾病、皮肤疾病、关节炎、抗癌剂的副作用、放射性障碍、细菌性休克、炎症性疾病、白内障等多种疾病。
Description
本发明涉及含有乙内酰脲衍生物或其药学上可允许的盐为有效成分的新型活性氧、自由基去除剂。
近年来,对于由自由基和活性氧引起的生物分子、膜、组织的损伤以及由其引起的疾病给予了极大的关注。所称的自由基是具有不成对电子的化学基,其性质不稳定,具有很高的反应性。另外,作为活性氧有过氧化物、羟基自由基、过氧化氢、单态氧等,其中过氧化物和羟基自由基是自由基类型,特别是已公知的羟基自由基是具有极高反应性的自由基。作为受到自由基及活性氧伤害的生体内靶向分子,涉及到脂质、核酸、酶、蛋白质、糖质等,特别是存在于细胞膜的脂质中的高度不饱和脂肪酸极易受到攻击,氧化变性生成过氧化脂质。随之不仅细胞膜受到损伤、膜的结构被破坏,而且存在于该处并活动的蛋白质的酶及受体功能也受到很大的损害。另外还知道生成的过氧化脂质从局部流到血液中,会成为以血管病变为首的二次病变的原因。
与自由基及活性氧相关连的疾病已有很多的报告,因此,去除自由基、活性氧的药品的有效性非常引人注目。去除生物体内过氧化物的物质SOD(超氧化物歧化酶)是代表性的去除自由基、活性氧的物质,现正在开发成药剂。作为SOD可治疗的病症,可以举出心肌梗塞、再灌流障碍、脑栓塞、自身免疫疾病(胶原病、贝切特氏病、溃疡性大肠炎)、纤维症、肺疾病(肺浮肿、肺纤维症)、皮肤疾病(烫伤、外伤、硬斑病、日光过敏、皮肤炎)、关节疾病、抗癌剂的付作用、放射线伤害、细菌性休克、炎症性疾病、白内障等多种疾病。(参照如“自由基的病态生化学和临床、炎症和抗炎症”日本临床、第46卷、第10号、93-97页、1988年等)。
SOD是一种蛋白质制剂,存在血中半衰期短,难于进入细胞内等问题,所以目前正在研究各种的制剂技术。因而希望开发出制剂容易,而且副作用少的新的自由基、活性氧去除剂。
本发明的目的在于提供这样的新型自由基、活性氧去除剂。
本发明的活性氧、自由基去除剂的有效成分是用下述通式(I)表示的乙内酰脲衍生物。
(式中R1及R2分别相同或不相同地表示氢原子、烷基或环烷基,X、Y分别相同或不相同地表示氢原子、烷基、羟基或烷氧基或X及Y一起表示氧基)。
上述(I)中R1及R2分别相同或不相同地表示氢原子、烷基,优选的是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、叔戊基、己基、二甲基丁基、庚基、辛基、壬基、癸基、硬脂酰基等直链或支链的碳原子数1~20的烷基或环烷基,优选的是环丙基、环丁基、环戊基、环己基、环庚基、环辛基等碳原子数3~8的环烷基。
X、Y分别相同或不相同地表示氢原子、烷基,优选甲基、乙基、丙基、异丙基等直链或支链的碳原子数1~3的烷基、羟基或烷氧基,优选的是甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、异戊氧基、新戊氧基等直链或支链的碳原子数1~5的烷氧基或用X、Y表示氧基。
本发明中优选的化合物如下。
(化合物1)乙内酰脲
(化合物2)1-甲基乙内酰脲
(化合物3)3-甲基乙内酰脲
(化合物4)1-乙基乙内酰脲
(化合物5)1-丙基乙内酰脲
(化合物6)1-丁基乙内酰脲
(化合物7)1-叔丁基乙内酰脲
(化合物8)1-己基乙内酰脲
(化合物9)1-(1,3-二甲基丁基)乙内酰脲
(化合物10)1-癸基乙内酰脲
(化合物11)1-硬脂酰基乙内酰脲
(化合物12)1,3-二甲基乙内酰脲
(化合物13)1,5-二甲基乙内酰脲
(化合物14)3,5-二甲基乙内酰脲
(化合物15)1-环戊基乙内酰脲
(化合物16)1-环己基乙内酰脲
(化合物17)1-环己基-3-甲基乙内酰脲
(化合物18)3-环己基乙内酰脲
(化合物19)1,3-二环己基乙内酰脲
(化合物20)5-羟基乙内酰脲
(化合物21)5-羟基-1-甲基乙内酰脲
(化合物22)5-羟基-3-甲基乙内酰脲
(化合物23)5-羟基-1-乙基乙内酰脲
(化合物24)5-羟基-1-丙基乙内酰脲
(化合物25)5-羟基-1-丁基乙内酰脲
(化合物26)5-羟基-1-叔丁基乙内酰脲
(化合物27)5-羟基-1-己基乙内酰脲
(化合物28)5-羟基-1-(1,3-二甲基丁基)乙内酰脲
(化合物29)5-羟基-1-癸基乙内酰脲
(化合物30)5-羟基-1-硬脂酰基乙内酰脲
(化合物31)5-羟基-1-环戊基乙内酰脲
(化合物32)5-羟基-1-环己基乙内酰脲
(化合物33)5-羟基-1-环己基-3-甲基乙内酰脲
(化合物34)5-羟基-1,3-二甲基乙内酰脲
(化合物35)5-羟基-1,5-二甲基乙内酰脲
(化合物36)5-羟基-3,5-二甲基乙内酰脲
(化合物37)5-羟基-1,3-二环己基乙内酰脲
(化合物38)5-甲氧基乙内酰脲
(化合物39)5-甲氧基-1-甲基乙内酰脲
(化合物40)5-甲氧基-3-甲基乙内酰脲
(化合物41)5-甲氧基-1-乙基乙内酰脲
(化合物42)5-甲氧基-1-丙基乙内酰脲
(化合物43)5-甲氧基-1-丁基乙内酰脲
(化合物44)5-甲氧基-1-环己基乙内酰脲
(化合物45)5-甲氧基-1-环己基乙内酰脲
(化合物46)5-乙氧基乙内酰脲
(化合物47)5-乙氧基-1-甲基乙内酰脲
(化合物48)5-乙氧基-3-甲基乙内酰脲
(化合物49)5-乙氧基-1-乙基乙内酰脲
(化合物50)5-乙氧基-1-丙基乙内酰脲
(化合物51)5-乙氧基-1-丁基乙内酰脲
(化合物52)5-丙氧基乙内酰脲
(化合物53)5-丙氧基-1-甲基乙内酰脲
(化合物54)5-丙氧基-3-甲基乙内酰脲
(化合物55)5-丙氧基-1-乙基乙内酰脲
(化合物56)5-丙氧基-1-丙基乙内酰脲
(化合物57)5-丙氧基-1-丁基乙内酰脲
(化合物58)5-丁氧基乙内酰脲
(化合物59)5-丁氧基-1-甲基乙内酰脲
(化合物60)5-丁氧基-3-甲基乙内酰脲
(化合物61)5-叔丁氧基乙内酰脲
(化合物62)5-叔丁氧基-1-甲基乙内酰脲
(化合物63)5-叔丁氧基-3-丁基乙内酰脲
(化合物64)咪唑啉三酮
(化合物65)1-甲基咪唑啉三酮
(化合物66)1-乙基咪唑啉三酮
(化合物67)1-丁基咪唑啉三酮
(化合物68)1-异丁基咪唑啉三酮
(化合物69)1-叔丁基咪唑啉三酮
(化合物70)1-己基咪唑啉三酮
(化合物71)1-(1,3-二甲基丁基)咪唑啉三酮
(化合物72)1-癸基咪唑啉三酮
(化合物73)1-环戊基咪唑啉三酮
(化合物74)1-环戊基-3-乙基咪唑啉三酮
(化合物75)1-环己基咪唑啉三酮
(化合物76)1,3-二甲基咪唑啉三酮
(化合物77)1,3-二环己基咪唑啉三酮
本发明的乙内酰脲包括用上述通式(1)表示的盐,例如与盐酸、硫酸、硝酸、氢溴酸、磷酸、高氯酸、硫氰酸、硼酸、甲酸、醋酸、卤代酸、丙酸、羟基乙酸、拧檬酸、酒石酸、琥珀酸、葡糖酸、乳酸、丙二酸、富马酸、邻氨基苯甲酸、桂皮酸、对甲苯磺酸、萘磺酸、对氨基苯磺酸等的加成盐,或者与钠、钾等碱金属、钙、镁、钡等碱土类金属或铝、锌等金属形成的盐。
这些盐可以用公知的方法,由游离的本发明的乙内酰脲衍生物制造,或者也可以相互转换。
本发明的化合物中,在存在顺-反异构体、光学异构体、构象异构体等立体异构体的情况下,或者以水合物及络合物状态存在的情况下,本发明也都包括了上述的立体异构体、水合物、络合物。上述本发明的乙内酰脲衍生物及其制造方法,在特开昭61-122275号公报、特开昭62-14号公报中已经公开。
本发明的化合物与适当的医药用载体或稀释剂组合可以制成医药品,用通常的任何方法可以制成制剂,可以制成片剂、胶囊剂、粉剂、液剂等口服制剂,也可以制成皮下、静脉内、肌肉内、直肠内、鼻腔内给药的非口服制剂。
在配方时,可以将本发明化合物以其药学上可允许的盐的形式使用,也可以将本发明化合物单独或适宜地组合后使用,也可以与其他的医药活性成分作成配合剂使用。
制成口服制剂时,可以直接使用或者加入适当的添加剂,例如乳糖、甘露糖醇、玉米淀粉、马铃薯淀粉、柠檬酸钙等常用的赋形剂,同时加入结晶纤维素、羟丙基纤维素等纤维素衍生物、阿拉伯树胶、玉米淀粉、明胶等粘合剂、玉米淀粉、马铃薯淀粉、羟甲基纤维素钙等崩解剂、滑石、硬脂酸镁等润滑剂、其他增量剂、湿润剂、缓冲剂、保存剂、香料等进行适宜的组合,制成片剂、散剂、颗粒剂或胶囊剂。
作为注射剂,可以制成注射用蒸馏水、生隆盐水、葡萄糖注射液等的水溶性溶剂或者制成植物油、合成脂肪酸甘油酯、高级脂肪酸酯、丙二醇等的非水性溶剂的溶液、悬浮液或乳液,根据需要,也可以适宜添加通常使用的助溶剂、等渗剂、悬浮化剂、乳化剂、稳定剂、保存剂等添加剂。
进而,根据疾病的种类和患者的情况,除上述剂型之外,还可以使用适应于治疗的其他剂型,例如糖浆剂、栓剂、吸入剂、气雾剂、滴眼剂、外用剂(软膏剂、凝胶剂、贴剂)等制剂化形式。
本发明的理想给药量是根据给药对象、剂型、给药方向、给药期间等而变化,但为了得到期望的效果,一般对于成年人,口服给药有效成分量为-日1至1000mg,最好是5至600mg。非经口给药时(例如注射剂),用比经口给药量少的量也可以得到预期的效果,所以一般考虑使用经口给药量的1/3~1/10的用量。
以下表示含有本发明化合物作为有效成分的医药组合物的配方例,但并不限定本发明。
表1
以下举出含有用上述通式(1)表示的化合物作为有效成分的本发明活性氧、自由基去除剂的优选实施方案。
配方例1(片剂) | 成分 | 每1片 |
本发明化合物乳糖结晶纤维素羟丙基纤维素硬脂酸镁 | 100mg35mg5mg5mg5mg | |
共计150mg |
1.含有通式(1)的X及Y中的任何一方是氢原子的化合物作为有效成分的活性氧、自由基去除剂。
2.上述1项所述的化合物中X及Y的剩下一方是羟基的活性氧、自由基去除剂。
3.上述2项所述的化合物中R1及R2的任何一方是烷基,另一方是氢原子所活性氧、自由基去除剂。
4.上述3项所述的化合物中R1是烷基的活性氧、自由基去除剂。
5.上述4项所述的化合物中R1是碳原子数1~4的烷基的活性氧、自由基去除剂。
6.上述5项所述的化合物中R1是甲基的活性氧、自由基去除剂。
7.含有通式(1)的X及Y同是氢原子的化合物作为有效成分的活性氧、自由基去除剂。
8.上述7项所述的化合物中R1及R2的任何一方是烷基,另一方是氢原子的活性氧、自由基去除剂。
9.上述8项所述的化合物中R1是烷基的活性氧、自由基去除剂。
10.上述9项所述的化合物中R1是碳原子数1~4的烷基的活性氧、自由基去除剂。
11.上述10项所述的化合物中R1是甲基的活性氧、自由基去除剂。
12.上述1项所述的化合物中X及Y的剩下一方是烷氧基的活性氧、自由基去除剂。
13.上述12项所述的化合物中R1是烷基,R2是氢原子的活性氧、自由基去除剂。
14.上述13项所述的化合物中R1是甲基的活性氧、自由基去除剂。
15.上述1项所述的化合物中X及Y的剩下一方是烷基的活性氧、自由基去除剂。
16.上述15项所述的化合物中R1是烷基,R2是氢原子的活性氧、自由基去除剂。
17.上述16项所述的化合物中R1是甲基的活性氧、自由基去除剂。
18.含有通式(1)中的X及Y一起表示氧基的化合物作为有效成分的活性氧、自由基去除剂。
19.上述18项所述的化合物中R1是烷基,R2是氢原子的活性氧、自由基去除剂。
20.上述19项所述的化合物中R1是甲基的活性氧、自由基去除剂。
21.含有用通式(1)表示的化合物作为有效成分的活性氧、自由基去除剂。
22.含有上述1项~20项分别记载的化合物作为有效成分的活性氧、自由基去除剂。
实施例
(1)羟基自由基去除能力的测定
使用常用的ESR自旋吸收法来检测羟基自由基,测定被检物质去除羟基自由基的能力。羟基自由基的发生是通过用DTPA(二亚乙基三胺五乙酸)螯合的二价铁与过氧化氢反应后,利用发生羟基自由基的芬顿反应而进行的。DMPO(dimethyl-pyrroline-N-oxide)与产生的羟基自由基迅速地反应,其反应生成物显示出具有特征的1∶2∶2∶1的强度比的四条线ESR信号。在此反应系中,如果存在有可消去羟基自由基作用的被检物质时,由于可以抑制上述特征信号,所以可以以此为指标测定去除羟基自由基的能力。
亦即,将1mM的硫酸亚铁和DTPA的混合溶液〔在100mM的磷酸缓冲液(pH7.8)中溶解〕75ml加入试管中,再加入含有被检物质试样溶液50μl及1mM或2mM的DMPO20μl,最后加入1mM的过氧化氢溶液75μl,开始反应。过氧化氢溶液在各试验之前配制,反应在室温下进行。本反应系的ESR谱按常法进行测定。由DMPO-OH产生的信号强度可以求出,在被检物质存在下的情况与不存在的情况相比,能够抑制50%的信号强度的被检物质浓度(IC50)。
下例表示DMPO为1mM时的结果。示出了将过去公知的具有羟基自由基去除作用的二甲亚砜作为比较对照剂的结果。
表2
被检物质 | IC50(M) |
二甲基亚砜化合物21 | 1.6×10-41.0×10-3 |
(2)对于由活性化白细胞引起内皮细胞伤害的抑制作用。
用以下的试验可以测定本发明化合物对于由活性化白细胞引起的内皮细胞伤害抑制作用。
将从牛下行大动脉得到的酶处理后的血管内皮细胞,使用含有15%牛胎儿血清的MEM Earle培养基,在48孔板上培养。向到达汇集点的内皮细胞中添加51Cr(铬酸钠)3.7kBq,进行18小时培养,使51Cr进入内皮细胞中。洗去介质中的氯后,加入被检物质、人的白细胞及佛波醇酯(佛波醇肉豆蔻酸乙酯),进行6小时培养。使用γ计数器测定从受到活性化白细胞伤害的内皮细胞游离出的氯的放射活性,用下式求出内皮细胞的伤害比率。
将不存在被检物质情况下的上述伤害比率作为100%(对照)结果表示在图1中。
从上述试验结果可以看出本发明物质显示了去除羟基自由基的作用。在上述药理试验(1)中,改变添加的DMPO浓度,本发明化合物的IC50也随之按比例变化,暗示了本发明化合物的羟基自由基去除作用是与DMPO的竞争拮抗作用。
因此,具有活性氧、自由基去除作用的本发明乙内酰胺衍生物,对于与活性氧和自由基相关的疾病,例如作为SOD适应症的以下各种疾病是有效的,如心肌梗塞、曹灌流障碍、脑栓塞、自身免疫疾病(胶原病、贝切特氏病、溃疡性大肠炎)、纤维症、肺疾病(肺浮肿、肺纤维症)、皮肤疾病(烫伤、外伤、硬斑病、日光过敏、皮肤炎)、关节炎、抗癌剂的付作用、放射性伤害、细菌性休克、炎症性疾病、白内障等。
本发明化合物与对细胞有伤害作用的二甲基亚砜不同,具有极低毒性,安全性也高,而且可以经口给药,所以也适用于需要长期给药的慢性疾病,作为医药的实用性很高。
图1例示了本发明化合物对于抑制羟基自由基引起的细胞伤害作用的结果。
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP34983195 | 1995-12-20 | ||
JP349831/95 | 1995-12-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1159324A true CN1159324A (zh) | 1997-09-17 |
CN1093401C CN1093401C (zh) | 2002-10-30 |
Family
ID=18406411
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN96123286A Expired - Fee Related CN1093401C (zh) | 1995-12-20 | 1996-12-19 | 活性氧、自由基去除剂 |
Country Status (11)
Country | Link |
---|---|
US (1) | US6197806B1 (zh) |
EP (1) | EP0780125B1 (zh) |
KR (1) | KR100468109B1 (zh) |
CN (1) | CN1093401C (zh) |
AT (1) | ATE200622T1 (zh) |
AU (1) | AU705447B2 (zh) |
CA (1) | CA2193551C (zh) |
DE (1) | DE69612540T2 (zh) |
DK (1) | DK0780125T3 (zh) |
ES (1) | ES2158223T3 (zh) |
TW (1) | TW461814B (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103360320A (zh) * | 2013-07-30 | 2013-10-23 | 邱智东 | 1-甲基海因的制备方法 |
CN104159887A (zh) * | 2011-11-25 | 2014-11-19 | 圣卡塔琳娜州联邦大学 | 酰基-腙和噁二唑化合物、含有它们的药物组合物及其用途 |
US10265345B2 (en) | 2008-11-11 | 2019-04-23 | Vanworld Pharmaceutical (Rugao) Co., Ltd. | Use of extracts from rabbit skin inflamed by vaccinia virus for the manufacture of a medicament for the treatment of acute cerebrovascular disease |
CN110740729A (zh) * | 2017-06-13 | 2020-01-31 | 国立研究开发法人国立癌症研究中心 | 致癌抑制剂 |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000012175A2 (en) * | 1998-08-31 | 2000-03-09 | Sentron Medical, Inc. | Methimazole derivatives and tautomeric cyclic thiones to treat autoimmune diseases |
AU754989B2 (en) * | 1998-11-16 | 2002-11-28 | Nippon Zoki Pharmaceutical Co., Ltd. | A therapeutic agent for intractable vasculitis |
JP4711523B2 (ja) | 2001-02-13 | 2011-06-29 | 日本臓器製薬株式会社 | 低アルブミン血症改善剤 |
EP1384715A4 (en) | 2001-04-11 | 2005-06-01 | Senju Pharma Co | NOVEL IMIDAZOLIDINEDIONE DERIVATIVES AND THEIR USE AS A MEDICINAL PRODUCT |
ES2319626T3 (es) * | 2001-11-19 | 2009-05-11 | Medigene Ag | Farmaco para el tratamiento de enfermedades tumorales y de la piel virales. |
TWI353979B (en) * | 2002-04-10 | 2011-12-11 | Nippon Zoki Pharmaceutical Co | Novel crystal form of 5-hydroxy-1-methylhydantoin |
US20060241163A1 (en) * | 2005-04-20 | 2006-10-26 | Kaoru Okamoto | Optically active (S)-hydantoin derivative |
US20060241162A1 (en) * | 2005-04-20 | 2006-10-26 | Kaoru Okamoto | Optically active (R)-hydantoin derivative |
EP2801573A1 (en) * | 2013-05-09 | 2014-11-12 | Sanofi | Hydantoine derivatives as CD38 inhibitors |
Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4099007A (en) | 1969-04-02 | 1978-07-04 | Hoechst Aktiengesellschaft | N,n-substituted 2,4,5-triketoimidazolidines and a process for their preparation |
US3818031A (en) | 1971-03-26 | 1974-06-18 | Ciba Geigy Corp | Imidazolidinetrionecarboxylic acid derivatives |
IL39042A (en) | 1971-03-26 | 1976-04-30 | Ciba Geigy Ag | 2,4,5-trioxoimidazolidine-1-carboxylic acid derivatives,their preparation and their use for the control of plant metabolism |
CH563711A5 (en) | 1972-03-03 | 1975-07-15 | Ciba Geigy Ag | Agents for regulating plant metabolism - contg. imidazolidine-2,4,5-trione-3-carboxylic acid derivs. |
DE2612926A1 (de) | 1976-03-26 | 1977-10-06 | Boehringer Mannheim Gmbh | Neue acyl-derivate der 6-(alpha- amino-phenylacetamido)-penicillansaeure |
JPH0686436B2 (ja) | 1984-11-15 | 1994-11-02 | 日本臓器製薬株式会社 | 新規ヒダントイン誘導体及び該化合物を含有する医薬組成物 |
AU578068B2 (en) | 1984-03-08 | 1988-10-13 | Nippon Zoki Pharmaceutical Co., Ltd. | Hydantoin derivatives and pharmaceutical compositions containing them |
US4832682A (en) | 1984-08-08 | 1989-05-23 | Survival Technology, Inc. | Injection method and apparatus with electrical blood absorbing stimulation |
US4661469A (en) | 1984-08-08 | 1987-04-28 | Survival Technology, Inc. | t-PA composition capable of being absorbed into the blood stream and method of administration |
US4658830A (en) | 1984-08-08 | 1987-04-21 | Survival Technology, Inc. | Method and apparatus for initiating reperfusion treatment by an unattended individual undergoing heart attack symptoms |
ATE82505T1 (de) | 1984-08-08 | 1992-12-15 | Survival Technology | Absorptionsverbesserer. |
US4656034A (en) | 1985-05-20 | 1987-04-07 | Survival Technology, Inc. | Absorption enhancing agents |
US5078680A (en) | 1984-08-08 | 1992-01-07 | Survival Technology, Inc. | Automatic injector for emergency treatment |
US5340829A (en) * | 1984-11-20 | 1994-08-23 | Washington Research Foundation | Immunoregulatory agents |
JPH0764729B2 (ja) | 1985-02-06 | 1995-07-12 | 日本臓器製薬株式会社 | イミダゾリジントリオン誘導体を含有する医薬組成物 |
EP0194226B1 (en) | 1985-02-06 | 1990-02-07 | Nippon Zoki Pharmaceutical Co. Ltd. | A pharmaceutical composition containing an imidazolidinetrione derivative or pharmaceutically acceptable salt thereof |
JP2567593B2 (ja) | 1986-12-29 | 1996-12-25 | 日本臓器製薬株式会社 | イミダゾリジントリオン誘導体及び該化合物を有効成分として含有するアレルギ−性疾患治療剤 |
JPS6456614A (en) | 1987-08-27 | 1989-03-03 | Ono Pharmaceutical Co | Maillard reaction inhibitor |
JPH01156965A (ja) | 1987-09-29 | 1989-06-20 | Taiho Yakuhin Kogyo Kk | チオヒダントイン化合物 |
JP2544183B2 (ja) | 1988-07-29 | 1996-10-16 | 日本臓器製薬株式会社 | 新規パラバン酸誘導体及び該化合物を有効成分として含有する医薬組成物 |
JP2817219B2 (ja) | 1988-09-08 | 1998-10-30 | 武田薬品工業株式会社 | カルバジン酸誘導体、その製造法及び製剤 |
JPH02225485A (ja) | 1989-02-27 | 1990-09-07 | Taiho Yakuhin Kogyo Kk | チエノピリミジン―3―酢酸誘導体 |
CA2011899A1 (en) | 1989-03-13 | 1990-09-13 | Masaaki Toda | Benzopyran derivatives |
JP2678499B2 (ja) | 1989-08-09 | 1997-11-17 | 日本臓器製薬 株式会社 | 尿毒症毒素低下剤 |
JPH0667827A (ja) | 1992-08-18 | 1994-03-11 | Nec Software Ltd | データ表示制御装置 |
JP3267698B2 (ja) | 1992-10-27 | 2002-03-18 | 株式会社三和化学研究所 | ヒダントイン誘導体及びその塩並びにこれらを有効成分とするメイラード反応阻害剤 |
ES2168294T3 (es) | 1993-02-26 | 2002-06-16 | Otsuka Pharma Co Ltd | Derivados de tiazol o imidazol inhibidores de la reaccion de maillard. |
JPH06305964A (ja) | 1993-02-26 | 1994-11-01 | Otsuka Pharmaceut Co Ltd | メイラード反応阻害剤 |
DE69519921T2 (de) | 1994-07-29 | 2001-06-13 | Suntory Limited, Osaka | Imidazolidin-derivate und ihre verwendung |
JPH08157473A (ja) | 1994-10-06 | 1996-06-18 | Nissan Chem Ind Ltd | ピラゾール系チアゾリジン類 |
US5681843A (en) | 1994-12-20 | 1997-10-28 | Nippon Zoki Pharmaceutical Co., Ltd. | Parabanic acid derivatives |
US5912261A (en) | 1994-12-20 | 1999-06-15 | Nippon Zoki Pharmaceutical Co., Ltd. | Carboxyalkyl heterocyclic derivatives |
-
1996
- 1996-12-18 US US08/769,008 patent/US6197806B1/en not_active Expired - Fee Related
- 1996-12-19 CN CN96123286A patent/CN1093401C/zh not_active Expired - Fee Related
- 1996-12-20 CA CA002193551A patent/CA2193551C/en not_active Expired - Fee Related
- 1996-12-20 DE DE69612540T patent/DE69612540T2/de not_active Expired - Lifetime
- 1996-12-20 EP EP96120597A patent/EP0780125B1/en not_active Expired - Lifetime
- 1996-12-20 AT AT96120597T patent/ATE200622T1/de not_active IP Right Cessation
- 1996-12-20 DK DK96120597T patent/DK0780125T3/da active
- 1996-12-20 KR KR1019960069207A patent/KR100468109B1/ko not_active IP Right Cessation
- 1996-12-20 ES ES96120597T patent/ES2158223T3/es not_active Expired - Lifetime
- 1996-12-20 AU AU76414/96A patent/AU705447B2/en not_active Ceased
-
1997
- 1997-01-04 TW TW086100051A patent/TW461814B/zh not_active IP Right Cessation
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10265345B2 (en) | 2008-11-11 | 2019-04-23 | Vanworld Pharmaceutical (Rugao) Co., Ltd. | Use of extracts from rabbit skin inflamed by vaccinia virus for the manufacture of a medicament for the treatment of acute cerebrovascular disease |
CN104159887A (zh) * | 2011-11-25 | 2014-11-19 | 圣卡塔琳娜州联邦大学 | 酰基-腙和噁二唑化合物、含有它们的药物组合物及其用途 |
CN103360320A (zh) * | 2013-07-30 | 2013-10-23 | 邱智东 | 1-甲基海因的制备方法 |
CN103360320B (zh) * | 2013-07-30 | 2015-12-02 | 邱智东 | 1-甲基海因的制备方法 |
CN110740729A (zh) * | 2017-06-13 | 2020-01-31 | 国立研究开发法人国立癌症研究中心 | 致癌抑制剂 |
CN110740729B (zh) * | 2017-06-13 | 2023-05-16 | 国立研究开发法人国立癌症研究中心 | 致癌抑制剂 |
Also Published As
Publication number | Publication date |
---|---|
EP0780125B1 (en) | 2001-04-18 |
KR970032863A (ko) | 1997-07-22 |
KR100468109B1 (ko) | 2005-04-13 |
EP0780125A2 (en) | 1997-06-25 |
CN1093401C (zh) | 2002-10-30 |
US6197806B1 (en) | 2001-03-06 |
DE69612540D1 (de) | 2001-05-23 |
AU7641496A (en) | 1997-06-26 |
TW461814B (en) | 2001-11-01 |
EP0780125A3 (en) | 1997-11-05 |
CA2193551A1 (en) | 1997-06-21 |
AU705447B2 (en) | 1999-05-20 |
CA2193551C (en) | 2006-03-21 |
ATE200622T1 (de) | 2001-05-15 |
ES2158223T3 (es) | 2001-09-01 |
DE69612540T2 (de) | 2001-08-30 |
DK0780125T3 (da) | 2001-05-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1093401C (zh) | 活性氧、自由基去除剂 | |
CN1050514C (zh) | 眼用或鼻用抗过敏组合物 | |
CN100335049C (zh) | 泻药组合物 | |
CN1244323C (zh) | 用于治疗原发性和继发性再狭窄的新的脂肪酸类似物 | |
CN1289082C (zh) | 用于治疗糖尿病的药物组合物 | |
CN1160079C (zh) | 发泡性肠溶制剂 | |
CN1269719A (zh) | 调节性活力的芳酰基哌嗪 | |
CN1522147A (zh) | 含有15-酮基-前列腺素类化合物的用于治疗药物诱导的便秘的组合物 | |
CN1168794A (zh) | 减少与非心脏局部缺血有关的组织损伤的方法 | |
CN103687593A (zh) | 组织蛋白酶k抑制用于治疗和/或预防肺动脉高压和/或心力衰竭的用途 | |
EP3091972B1 (en) | Method of treating liver disorders | |
CN1753680A (zh) | 用于治疗腹部不适的前列腺素衍生物 | |
CN1871010A (zh) | 门静脉高压的预防和/或治疗 | |
EP0137832B1 (en) | Pharmaceutical compositions of anti-pancreatic inflammatory effect | |
WO2018079149A1 (ja) | 白内障の予防剤、治療剤、およびこれらを製造するためのhat阻害剤の使用 | |
CN1076727C (zh) | 作为阿朴脂蛋白-b合成抑制剂的新型三唑酮 | |
CN1092645C (zh) | 糖尿病并发症的预防/治疗药 | |
CN1197572C (zh) | 低白蛋白血症改善剂 | |
CN1610548A (zh) | 依贝沙坦在制备用来预防或治疗肺动脉高压的药物中的应用 | |
KR900006993B1 (ko) | 아테롬성 동맥경화증 치료제로서의 dl-5-[(2-벤질-3,4-디하이드로-2H-벤조피란-6-일)메틸]티아졸리딘-2,4-디온 | |
CN1533277A (zh) | 用于预防或治疗由eNOS表达而引起的疾病的药物 | |
JP3836203B2 (ja) | 活性酸素・フリーラジカル消去剤 | |
CN101068548A (zh) | 用于减少、稳定富含脂质的斑块和/或防止富含脂质的斑块破裂的方法 | |
WO2003007984A1 (de) | Verwendung von thrombin-inhibitoren zur behandlung von arthritis | |
EP3139911B1 (en) | Method of treating advanced non-alcoholic steatohepatitis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20021030 Termination date: 20111219 |