CN101190937A - Compound with liver-protecting activity - Google Patents
Compound with liver-protecting activity Download PDFInfo
- Publication number
- CN101190937A CN101190937A CNA2006100706104A CN200610070610A CN101190937A CN 101190937 A CN101190937 A CN 101190937A CN A2006100706104 A CNA2006100706104 A CN A2006100706104A CN 200610070610 A CN200610070610 A CN 200610070610A CN 101190937 A CN101190937 A CN 101190937A
- Authority
- CN
- China
- Prior art keywords
- salt
- base
- compound
- group
- injection
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 97
- 230000000694 effects Effects 0.000 title description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 24
- 208000019423 liver disease Diseases 0.000 claims abstract description 8
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims description 72
- -1 sec.-propyl Chemical group 0.000 claims description 52
- 238000002347 injection Methods 0.000 claims description 43
- 239000007924 injection Substances 0.000 claims description 43
- 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 claims description 19
- 239000000460 chlorine Substances 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 239000008103 glucose Substances 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 230000002378 acidificating effect Effects 0.000 claims description 12
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000006017 1-propenyl group Chemical group 0.000 claims description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 7
- 229920002554 vinyl polymer Polymers 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- YVECGMZCTULTIS-PBXRRBTRSA-N glucal Chemical compound OC[C@H]1OC=C[C@@H](O)[C@@H]1O YVECGMZCTULTIS-PBXRRBTRSA-N 0.000 claims description 6
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 6
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 5
- 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 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 125000006039 1-hexenyl group Chemical group 0.000 claims description 3
- 125000006023 1-pentenyl group Chemical group 0.000 claims description 3
- 125000006040 2-hexenyl group Chemical group 0.000 claims description 3
- 125000006041 3-hexenyl group Chemical group 0.000 claims description 3
- 125000006042 4-hexenyl group Chemical group 0.000 claims description 3
- 125000006043 5-hexenyl group Chemical group 0.000 claims description 3
- 159000000013 aluminium salts Chemical class 0.000 claims description 3
- 229910000329 aluminium sulfate Inorganic materials 0.000 claims description 3
- 150000001621 bismuth Chemical class 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 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 claims description 3
- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 150000003751 zinc Chemical class 0.000 claims description 3
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical class NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 claims description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical class NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002519 galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 claims description 2
- 125000000487 histidyl group Chemical class [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000000311 mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 2
- JVJQPDTXIALXOG-UHFFFAOYSA-N nitryl fluoride Chemical compound [O-][N+](F)=O JVJQPDTXIALXOG-UHFFFAOYSA-N 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000000969 xylosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)CO1)* 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 9
- 239000000203 mixture Substances 0.000 abstract description 5
- 231100000012 chronic liver injury Toxicity 0.000 abstract description 4
- 230000002155 anti-virotic effect Effects 0.000 abstract description 3
- 230000006870 function Effects 0.000 abstract description 3
- 230000001154 acute effect Effects 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- 230000002443 hepatoprotective effect Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 41
- 239000008215 water for injection Substances 0.000 description 41
- 239000007788 liquid Substances 0.000 description 33
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 30
- 238000003756 stirring Methods 0.000 description 30
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 28
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 28
- 229940068968 polysorbate 80 Drugs 0.000 description 28
- 229920000053 polysorbate 80 Polymers 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- 241000700159 Rattus Species 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- 210000002966 serum Anatomy 0.000 description 21
- 239000002775 capsule Substances 0.000 description 17
- 239000000463 material Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 15
- 229920003081 Povidone K 30 Polymers 0.000 description 15
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 15
- 235000019359 magnesium stearate Nutrition 0.000 description 15
- 239000002994 raw material Substances 0.000 description 15
- 239000008354 sodium chloride injection Substances 0.000 description 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 13
- 229920000881 Modified starch Polymers 0.000 description 13
- 229940016286 microcrystalline cellulose Drugs 0.000 description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 13
- 239000008108 microcrystalline cellulose Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229960004756 ethanol Drugs 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 229920002307 Dextran Polymers 0.000 description 10
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 9
- 241000272525 Anas platyrhynchos Species 0.000 description 9
- 102000008186 Collagen Human genes 0.000 description 9
- 108010035532 Collagen Proteins 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 206010019668 Hepatic fibrosis Diseases 0.000 description 9
- 102000019197 Superoxide Dismutase Human genes 0.000 description 9
- 108010012715 Superoxide dismutase Proteins 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 208000019425 cirrhosis of liver Diseases 0.000 description 9
- 229920001436 collagen Polymers 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 229920002674 hyaluronan Polymers 0.000 description 9
- 229960003160 hyaluronic acid Drugs 0.000 description 9
- 238000012856 packing Methods 0.000 description 9
- 229940032362 superoxide dismutase Drugs 0.000 description 9
- 230000008961 swelling Effects 0.000 description 9
- 210000003371 toe Anatomy 0.000 description 9
- 241000700721 Hepatitis B virus Species 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 230000006837 decompression Effects 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000008187 granular material Substances 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000002504 physiological saline solution Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 235000014347 soups Nutrition 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 7
- 206010067125 Liver injury Diseases 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 235000010418 carrageenan Nutrition 0.000 description 7
- 229920001525 carrageenan Polymers 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 208000002672 hepatitis B Diseases 0.000 description 7
- 238000007689 inspection Methods 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000003187 abdominal effect Effects 0.000 description 6
- 230000003203 everyday effect Effects 0.000 description 6
- 238000001802 infusion Methods 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 230000000452 restraining effect Effects 0.000 description 6
- 230000000630 rising effect Effects 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 241000725618 Duck hepatitis B virus Species 0.000 description 5
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 230000002440 hepatic effect Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000007928 intraperitoneal injection Substances 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 210000005229 liver cell Anatomy 0.000 description 5
- 229940023488 pill Drugs 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 206010013786 Dry skin Diseases 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000003708 ampul Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000000679 carrageenan Substances 0.000 description 4
- 229940113118 carrageenan Drugs 0.000 description 4
- 239000003610 charcoal Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000011082 depyrogenation Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 231100000753 hepatic injury Toxicity 0.000 description 4
- 206010020718 hyperplasia Diseases 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 230000003859 lipid peroxidation Effects 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- YWVYZMVYXAVAKS-UHFFFAOYSA-N pyridin-1-ium;trifluoromethanesulfonate Chemical class C1=CC=[NH+]C=C1.[O-]S(=O)(=O)C(F)(F)F YWVYZMVYXAVAKS-UHFFFAOYSA-N 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000011265 semifinished product Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 229960003328 benzoyl peroxide Drugs 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 230000003908 liver function Effects 0.000 description 3
- 210000005228 liver tissue Anatomy 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 239000011122 softwood Substances 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 208000037816 tissue injury Diseases 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 235000020985 whole grains Nutrition 0.000 description 3
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 2
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 2
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 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
- 206010014025 Ear swelling Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 240000001307 Myosotis scorpioides Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000003035 anti-peroxidant effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000002469 basement membrane Anatomy 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 230000003750 conditioning effect Effects 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 229940089256 fungistat Drugs 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 229940100688 oral solution Drugs 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000003617 peroxidasic effect Effects 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 231100000572 poisoning Toxicity 0.000 description 2
- 230000000607 poisoning effect Effects 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- 240000006409 Acacia auriculiformis Species 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000272522 Anas Species 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- FITPCXSHEGAMCJ-JJKGCWMISA-N ClC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.[Na] Chemical compound ClC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.[Na] FITPCXSHEGAMCJ-JJKGCWMISA-N 0.000 description 1
- 229910020366 ClO 4 Inorganic materials 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 206010019837 Hepatocellular injury Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- 206010062049 Lymphocytic infiltration Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 150000001216 Samarium Chemical class 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229930006000 Sucrose Natural products 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
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 231100000439 acute liver injury Toxicity 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004500 asepsis Methods 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
- 239000011230 binding agent Substances 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N butyl alcohol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 150000001868 cobalt Chemical class 0.000 description 1
- 239000002131 composite material Chemical class 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 150000001896 cresols Chemical class 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000254 damaging effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 210000004024 hepatic stellate cell Anatomy 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 231100000437 hepatocellular injury Toxicity 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 230000003118 histopathologic effect Effects 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 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 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 150000002603 lanthanum Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 150000002696 manganese Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
Abstract
The invention pertains to the technical field of medicine, relating to new compounds which have hepatoprotective activity or stereoisomer and salt thereof, the preparation methods of the compounds or the stereoisomer thereof, medical compositions which comprise the compounds or the stereoisomer and salt thereof as necessary active ingredients, and the application of the compounds or the stereoisomer and salt thereof in the preparation of medicine to cure and/or prevent hepatopathy and inflammatorydisease. The compounds or the stereoisomer and salt thereof of the invention have prominent functions of resisting acute and chronic hepatic injury and good function of antivirus at the same time, as well as prominent anti-inflammatory activity.
Description
1, technical field
The present invention relates to have new compound or its steric isomer and the salt thereof of liver-protecting activity, the preparation method of these compounds or its steric isomer, contain these compounds or its steric isomer and salt thereof pharmaceutical composition as essential activeconstituents, and these compounds or its steric isomer and salt thereof treats and/or prevents application in the medicine of hepatic diseases and inflammatory diseases in preparation, belongs to medical technical field.
2, background technology
According to World Health Organization's statistics, it is chronic hepatitis patient or hepatitis B virus (HBV) carrier that the whole world in 2000 has 3.5 hundred million people approximately, has every year more than 100 ten thousand people to die from and hepatitis, liver cirrhosis, liver cancer diseases associated.China is the district occurred frequently of viral hepatitis, and the HBV carrier has 1.2 hundred million people, accounts for 1/3 of world HBV number of the infected, and wherein chronic hepatitis B patients is about 3,000 ten thousand, and about 10%～20% can develop into liver cirrhosis, and 1%～5% can develop into liver cancer.
Alpha-interferon and lamivudine are the internationally recognized curative effect medicine of hepatitis B virus resisting preferably at present, but there is patient more than half after treating, not heal for a long time, immunoregulation druge also is difficult to remove virus, cause virus in liver cell, to duplicate activity for a long time, hepatic tissue continues infringement, liver function persistent anomaly.Therefore protect liver cell, improving liver function is the important requisite aspect of treatment chronic hepatitis B (CHB), and any ideal treatment chronic hepatitis B scheme must have protection liver cell medicine.
3, summary of the invention
Chronic hepatitis B (CHB) has become a kind of common disease frequently-occurring disease of serious harm China people's health; in order to improve CHB patient's life quality; protect liver cell, improve liver function; our pharmaceuticals researcher has carried out many explorations, seeks the new compound that is used to prepare the medicine for the treatment of hepatic diseases.
We study and have synthesized a large amount of new compounds, find that by the pharmacological experiment study screening new compound of the present invention has significant liver-protecting activity, has good antivirus action simultaneously, also has significant anti-inflammatory activity.
Technical scheme of the present invention is as follows:
The invention provides suc as formula the compound shown in (I) or its steric isomer and salt thereof:
Wherein,
R
1Be F, Cl, Br or I;
R
2Be H, perhaps 1～3 molecule glucose base, glucal acidic group, arabopyranose base, arbinofuranose base, rhamanopyranosyl, ribosyl, deoxyribosyl, lactose base, galactosyl, galacturonic acidic group, malt-base, mannose group, xylosyl;
R
3, R
4, R
5Independently hydroxyl, perhaps replacement or unsubstituted C respectively do for oneself
1-6Alkyl, thiazolinyl or the alkane hydroxyl of straight or branched, be selected from methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, vinyl, 1-propenyl, 2-propenyl, different propenyl, 1-butylene base, crotyl, 3-butenyl, isobutenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, methylol, hydroxyethyl, hydroxypropyl, hydroxyl butyl; Wherein, described substituting group can be hydroxyl, amino, nitro, fluorine, chlorine, bromine, iodine, C
1-6The alkyl or alkenyl of straight or branched, be selected from methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, vinyl, 1-propenyl, 2-propenyl, different propenyl, 1-butylene base, crotyl, 3-butenyl, isobutenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, C
6-10Aryl, be selected from phenyl, Alpha-Naphthyl or betanaphthyl, C
1-4The alkyl amido of straight or branched is selected from formamido group, kharophen, propionamido, butyrylamino, C
1-4The alkoxy carbonyl of straight or branched is selected from methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl.
Preferred compound is:
R
1Be F, Cl or Br;
R
2Be H, perhaps 1～3 molecule glucose base, glucal acidic group, arabopyranose base, arbinofuranose base, rhamanopyranosyl;
R
3, R
4, R
5Independently hydroxyl, perhaps replacement or unsubstituted C respectively do for oneself
1-4Alkyl, thiazolinyl or the alkane hydroxyl of straight or branched, be selected from methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, vinyl, 1-propenyl, 2-propenyl, different propenyl, 1-butylene base, crotyl, 3-butenyl, isobutenyl, methylol, hydroxyethyl, hydroxypropyl, hydroxyl butyl; Described substituting group is same as above.
Further preferred compound is:
R
1Be F or Cl;
R
2Be H, perhaps 1～3 molecule glucose base, glucal acidic group, arabopyranose base, arbinofuranose base;
R
3, R
4, R
5Independently hydroxyl, perhaps replacement or unsubstituted C respectively do for oneself
1-3Alkyl, thiazolinyl or the alkane hydroxyl of straight or branched, be selected from methyl, ethyl, propyl group, sec.-propyl, vinyl, 1-propenyl, 2-propenyl, different propenyl, methylol, hydroxyethyl, hydroxypropyl; Described substituting group is same as above.
Further preferred compound is:
R
1Be F or Cl;
R
2Be H ,-β-D-glucosyl group ,-the alpha-D-glucose base or-β-D-glucal acidic group-alpha-D-glucose aldehydic acid base;
R
3Be methyl or methylol;
R
4Be methyl or methylol;
R
5Be methyl, hydroxyl or methylol.
Most preferred is:
3 beta-hydroxies-9-fluoro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid (hereinafter to be referred as compd A), structural formula is as follows:
3 beta-hydroxies-9-chloro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid (hereinafter to be referred as compd B), structural formula is as follows:
3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-fluoro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid (hereinafter to be referred as Compound C), structural formula is as follows:
3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-chloro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid (hereinafter to be referred as Compound D), structural formula is as follows:
3 beta-hydroxies-9-fluoro-18 β, 20 β-volatile oil-12-olefin(e) acid (hereinafter to be referred as compd E), structural formula is as follows:
3 beta-hydroxies-9-chloro-18 β, 20 β-volatile oil-12-olefin(e) acid (hereinafter to be referred as compound F 17-hydroxy-corticosterone), structural formula is as follows:
3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-fluoro-18 β, 20 β-volatile oil-12-olefin(e) acid (hereinafter to be referred as compound G), structural formula is as follows:
3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-chloro-18 β, 20 β-volatile oil-12-olefin(e) acid (hereinafter to be referred as compound H), structural formula is as follows:
Contain a plurality of chiral carbon in the structure of above-claimed cpd, the group on the chiral carbon can be α or beta comfiguration, so multiple steric isomer can be arranged, especially its α-H of 18 can become beta comfiguration, shown in (II), and wherein X, R
1, R
2, R
3, R
4, R
5Implication same as above.
Contain carboxyl in the structure of above-claimed cpd or its steric isomer, can salify in order to improve its water-soluble or stability etc., comprise: metal-salt, for example sodium salt, sylvite, lithium salts, magnesium salts, calcium salt, zinc salt, bismuth salt, aluminium salt, silver salt, mantoquita, molysite, manganese salt, cobalt salt, lanthanum salt, samarium salt etc., especially sodium salt, sylvite, magnesium salts, calcium salt, zinc salt, bismuth salt, aluminium salt; Ammonium salt; Organic amine salt, for example meglumine salt, arginic acid salt, lysine salt, Histidine salt, ornithine salt etc.; According to the difference of compound, can be single salt, disalt, three salt or composite salt.
The compounds of this invention can be by following prepared, but is not limited only to following technology:
Step 1---preparation midbody compound: in the exsiccant reaction flask, add diacetyl oxide and pyridine, stir the back and add compound shown in the structural formula (III) or its isomer (wherein X, R
2, R
3, R
4, R
5Implication same as above), be stirred to the reaction finish.Under vigorous stirring, reaction solution is poured in the frozen water, separate out solid, join in the reaction flask after 60 ℃ of dryings again, add the dehydrated alcohol and the vitriol oil, heated and stirred refluxes, reaction finishes, reclaim solvent, residuum is used ethyl acetate extraction after adding an amount of frozen water, merges organic layer and dry, reclaim solvent, get midbody compound.
Step 2---fluorine replaces: in the dry reaction bottle, under the nitrogen atmosphere, add step 1 gained midbody compound, N-fluorinated pyridine trifluoromethyl sulfonic acid, DMSO, after being warming up to 80 ℃ of stirring reactions, add N-fluorinated pyridine trifluoromethyl sulfonic acid again, continue stirring reaction, after reaction finished, DMSO was removed in decompression; After reducing to room temperature, add entry, use ethyl acetate extraction then, merge organic phase, dry and filtration, filtrate decompression concentrates, residuum is dissolved in the ethanol, adds sodium hydroxide, refluxes and stirs, in 50 ℃ of following decompression and solvent recoveries, residuum adds entry, regulates the pH value with dilute hydrochloric acid, separate out solid, filter, washing, 50 ℃ of drying under reduced pressure get The compounds of this invention or its isomer.
Perhaps: step 2---chlorine replaces: in the dry reaction bottle, under the nitrogen atmosphere, add step 1 gained midbody compound, tetracol phenixin, SO
2Cl
2/ tetracol phenixin, be warming up to 60 ℃ of stirring reactions after, remove solvent under reduced pressure; After reducing to room temperature, add entry, use ethyl acetate extraction then, merge organic phase and wash dry and filtration, concentrating under reduced pressure with saturated sodium bicarbonate solution, residuum is dissolved in 95% ethanol, adds sodium hydroxide, refluxes and stirs, in 50 ℃ of following decompression and solvent recoveries, residuum adds entry, regulates the pH value with dilute hydrochloric acid, separate out solid, filter, washing, 50 ℃ of drying under reduced pressure get The compounds of this invention or its isomer.
The further claimed above-claimed cpd of the present invention or its steric isomer and salt thereof treat and/or prevent purposes in the medicine of hepatic diseases in preparation.The compounds of this invention or its steric isomer and salt thereof have significant liver-protecting activity, have good antiviral activity simultaneously.Pharmacological evaluation shows, The compounds of this invention can significantly reduce tetracol phenixin and cause ALT and the AST level in the mice serum behind the acute liver damage, and alleviates liver tissue injury, to CCl
4The poisoning mice liver injury has remarkable provide protection; The compounds of this invention can significantly reduce the concentration of hyaluronic acid (HA) in the immunological liver fibrosis rat blood serum, ln (LN), mda (MDA), the concentration of remarkable rising superoxide-dismutase (SOD), reduce the hepatic disease degree, significant anti peroxidation of lipid damage and fibrosis effect are arranged; The compounds of this invention has remarkable restraining effect to duck DHBV virus, and no tangible rebound phenomenon after the drug withdrawal.Experimental result shows that The compounds of this invention has the effect that significantly resists acute and chronic hepatic injury, and (HBV) also has restraining effect to hepatitis B virus.
The further claimed above-claimed cpd of the present invention or its steric isomer and salt thereof treat and/or prevent purposes in the medicine of inflammatory diseases in preparation.The compounds of this invention or its steric isomer and salt thereof have significant anti-inflammatory activity.Pharmacological evaluation shows that rat toes swelling of The compounds of this invention on Carrageenan inductive and Oleum Tiglii inductive mice ear all have significant inhibitory effect, has the anti-inflammatory action that significantly continues.
The present invention also further the claimed above-claimed cpd or its steric isomer and salt thereof of comprising as the essential activeconstituents and the pharmaceutical composition of pharmaceutically acceptable carrier, for clinically or pharmaceutically acceptable arbitrary formulation; Can parenteral, mode such as oral, percutaneous dosing is applied to the patient who needs this treatment, is preferably oral preparations or injection.Containing of the present invention compound or its steric isomer and salt (in The compounds of this invention or its steric isomer) 2mg～2g thereof of physiology significant quantity in the aforementioned pharmaceutical compositions, for example can be 2mg, 2.5mg, 4mg, 5mg, 6mg, 10mg, 12mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 2g etc.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
The compounds of this invention or its steric isomer and salt thereof compared with prior art have the following advantages:
(1) provides first to have and significantly protected the liver antiviral and new compound anti-inflammatory activity, especially 3 beta-hydroxies-9-fluoro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid, 3 beta-hydroxies-9-chloro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid, 3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-fluoro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid, 3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-chloro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid have enriched the clinical application kind.
(2) pharmacological evaluation shows, The compounds of this invention has the effect of significant inhibition tetracol phenixin induced mice acute liver damage and Chinese People's Anti-Japanese Military and Political College's mouse hepatic fibrosis, duck DHBV virus had no tangible rebound phenomenon after remarkable restraining effect and the drug withdrawal, existing significant anti-acute and chronic hepatic injury effect also has good antivirus action.
(3) toes swelling of The compounds of this invention on Carrageenan inductive rat and Oleum Tiglii inductive mice ear all have significant inhibitory effect, have the anti-inflammatory action that significantly continues.
(4) The compounds of this invention has significant liver-protecting activity, good antiviral activity and significant anti-inflammatory action, has the good clinical using value.
Below routine by experiment beneficial effect of further setting forth The compounds of this invention.The compounds of this invention has following beneficial effect, but this should be interpreted as that The compounds of this invention only has following beneficial effect.
Replace 3 beta-hydroxies-9-fluoro-11-oxo-18 β with compd A in the following experimental example, 20 β-volatile oil-12-olefin(e) acid, compd B replaces 3 beta-hydroxies-9-chloro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid, Compound C replaces 3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-fluoro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid, Compound D replaces 3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-chloro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid.
Experimental example 1 The compounds of this invention causes the provide protection of chmice acute liver injury to tetracol phenixin
Animal subject: healthy mice, 60, body weight 20～25g, the male and female dual-purpose is divided into 6 groups at random, 10 every group.
Trial-product: sodium chloride injection: 250ml: 2.25g, Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.;
Compd A injection liquid: 10ml: 30mg;
Compd B injection liquid: 10ml: 30mg;
Compound C injection liquid: 10ml: 50mg;
Compound D injection liquid: 10ml: 50mg.
Dosage: see Table 1, normal control group and model group give sodium chloride injection.
Experimental technique: mouse is divided into normal control group, model group and each administration group, 10 every group at random by body weight.Normal control group and model group abdominal injection sodium chloride injection 20ml/kg, each administration group is diluted to desired concn intraperitoneal injection 20ml/kg by dosage shown in the table 1 with sodium chloride injection, every day 1 time, continuous 7 days.Behind the last administration 2h, normal control group abdominal injection sweet oil 10ml/kg, all the other respectively organize equal abdominal injection 0.1% tetracol phenixin (CCl
4) olive oil solution 10ml/kg.The sacrificed by decapitation animal is got serum behind the 20h, measures serum glutamic pyruvic transminase (ALT) and glutamic-oxal(o)acetic transaminase (AST) level.After broken end was got blood, hepatic tissue was done the routine pathology histological examination.
Experimental result: see Table 1.Compare with the normal control group, model group mice serum ALT and AST level sharply raise (p＜0.01), and histopathologic examination finds that hepatic tissue is obviously impaired, and necrosis occurs, and the modeling success is described.Compare with model group, compd A, compd B, Compound C, each administration group mice serum ALT of Compound D and AST water mean pole significantly reduce (p＜0.01), and liver tissue injury significantly alleviates.
Table 1 The compounds of this invention is to CCl
4The effect of liver injury mouse (X ± S, n=10)
Compare with the normal control group:
##P＜0.01; Compare with model group:
*P＜0.01.
Conclusion: peroxidatic reaction of lipid mainly takes place after entering body in tetracol phenixin in hepatomicrosome, cause the infringement of liver plasma membrane 26S Proteasome Structure and Function, and cell interior ALT, AST are overflowed, and causes the active rising of ALT in the blood, AST.The hepatic injury zone is big more, and ALT, AST activity are high more.We discover that The compounds of this invention can significantly reduce ALT and the AST level in the mice serum, and alleviates liver tissue injury, to CCl
4The poisoning mice liver injury has remarkable provide protection, aspect the anti-acute liver damage significant curative effect is being arranged.
The effect of experimental example 2 The compounds of this invention Chinese People's Anti-Japanese Military and Political College mouse hepatic fibrosis
Animal subject: healthy rat, 60, body weight 200～220g, the male and female dual-purpose is divided into 6 groups at random, 10 every group.
Trial-product: physiological saline: commercial;
Compd A capsule: 90mg;
Compd B capsule: 90mg;
Compound C capsule: 150mg
Compound D capsule: 150mg.
Dosage: see Table 2, normal control group and model group give physiological saline.
Experimental technique: rat is divided into normal control group, Liver Fibrosis Model group and each administration group, 10 every group at random by body weight.Liver Fibrosis Model group and each administration group rats by intraperitoneal injection calf serum, 0.5ml/ time/only, 2 times weekly, in totally 12 weeks, duplicate the rat immunity Liver Fibrosis Model.Each administration group is diluted to desired concn gastric infusion 20ml/kg by dosage shown in the table 2 with physiological saline in modeling, every day 1 time, continuous 12 weeks.The normal control group is irritated stomach and give equivalent physiological saline every day, abdominal injection sodium chloride injection simultaneously, 0.5ml/ time/, 2 times weekly, totally 12 weeks.12 weekends of administration, all animal fasting, can't help water, behind the 24h with Chloral Hydrate 1ml intraperitoneal injection of anesthesia, expose abdominal cavity and thoracic cavity from anterior median line, earlier with asepsis injector from every blood sampling of heart 4ml, the centrifugal serum of collecting is measured the level of hyaluronic acid (HA), ln (LN), mda (MDA) and superoxide-dismutase (SOD).Take out rat liver simultaneously, do HE dyeing and Masson collagen staining respectively.
Experimental result: (1) is to the influence of serum hepatic fibrosis index: see Table 2.Compare with the normal control group, the HA in the model group rat blood serum, LN concentration is extremely significantly rising (p＜0.01) all.Compare with model group, the HA in compd A, compd B, Compound C, each administration group rat blood serum of Compound D, LN concentration all extremely significantly reduce (p＜0.01).
(2) to the influence of lipid oxidation: see Table 2.Compare with the normal control group, the MDA concentration in the model group rat blood serum extremely significantly raises (p＜0.01), SOD concentration extremely significantly descend (p＜0.01).Compare with model group, the MDA concentration in compd A, compd B, Compound C, each administration group rat blood serum of Compound D all significantly reduces (p＜0.05), and SOD concentration is significantly rising (p＜0.05) all.
The Fibrotic effect of table 2 The compounds of this invention Chinese People's Anti-Japanese Military and Political College mouse immunological liver (X ± S, n=10)
Compare with the normal control group:
##P＜0.01; Compare with model group:
*P＜0.05,
*P＜0.01.
(3) influence that hepatic pathology is changed: rats in normal control group hepatic tissue structure is normal, portal area, sinus hepaticus clear in structure; The Masson collagen staining is not seen the fibrillar connective tissue hyperplasia.Liver Fibrosis Model group rat normal hepatocytes leaflet structure destroys, the extensive microvesicle sample of hepatic tissue steatosis, and a few cell generation acidophilia becomes and spotty necrosis; The visible fibrillar connective tissue hyperplasia of Masson collagen staining, obvious with the portal area, the part rat has significantly pseudolobuli formation, hepatocellular degeneration in the pseudolobuli, liver cell arrangement disorder, sinus hepaticus pressurized, the central vein off normal or lack as, visible kitchen range shape lymphocytic infiltration between outgrowth fiber.The also visible a small amount of cell infiltration of compd A, compd B, Compound C, Compound D treatment group, but the liver lobule structure deteriorate significantly alleviates, and hepatic cell fattydegeneration is lighter than model group; The slight hyperplasia of the most of rarely seen reticular tissue in rat portal area of Masson collagen staining.
Conclusion: hepatic fibrosis is that all kinds of liver parenchyma infringements turn to liver cirrhosis common pathology link, and is closely related with the prognosis of hepatopathy.Modern medicine thinks by the generation that reduces collegen filament and strengthens its degraded that the reverse of hepatic fibrosis is possible.
HA is a kind of sugared ammonia albumen, has tissue-specific extracellular matrix with formations such as collagen, fiber adhesion albumen and lns.LN is distinctive a kind of non-collagen sugar albumen in the basement membrane, is the main component of basement membrane, plays an important role in cytoadherence, differentiation and genetic expression.Studies show that HA, lN judge the important indicator that has or not the reactivity hepatic fibrosis, its rising degree and degree of hepatic fibrosis are proportionate.We discover that The compounds of this invention treatment group rat blood serum HA, LN concentration all significantly reduce than the liver cirrhosis pathology model group.Compare with model group liver organization pathological change, The compounds of this invention treatment group rats'liver leaflet structure destroys and obviously alleviates, the slight hyperplasia of the most of rarely seen reticular tissue in rat portal area of Masson collagen staining.
MDA is the product of lipid peroxidation, and its content can react the lipid peroxidation injury degree.SOD is a free-radical scavengers, can suppress peroxidatic reaction of lipid.In recent years studies show that superoxide anion, MDA etc. can stimulate inoblast or the expression of depot fat cell collagen mRNA and the generation of collagen, oxidative stress and lipid peroxidation are to cause hepatocellular injury and hepatic stellate cell activatory important mechanisms.Discover that pathological model group serum MDA concentration significantly increases, SOD concentration significantly descends, and shows the vital role of lipid peroxidation injury in the hepatic fibrosis forming process.Compare with the pathological model group, The compounds of this invention treatment group serum MDA concentration reduces, SOD concentration raises, and has significant anti peroxidation of lipid damaging action.
Result of study shows that The compounds of this invention has significant anti hepatic fibrosis, and chronic hepatic injury is had remarkable therapeutic action.
The effect of the anti-duck hepatitis B virus of experimental example 3 The compounds of this invention (DHBV)
Animal subject: 1 age in days Beijing duck, male and female dual-purpose.
Trial-product: sodium chloride injection: 250ml: 2.25g, Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.;
Compd A injection liquid: 10ml: 30mg;
Compd B injection liquid: 10ml: 30mg;
Compound C injection liquid: 10ml: 50mg;
Compound D injection liquid: 10ml: 50mg.
Dosage: see Table 3, model group gives sodium chloride injection.
Experimental technique: 1 age in days Beijing duck foot intravenous injection DHBV-DNA positive serum, every 0.2ml infects and got blood in back 7 days, separation of serum ,-20 ℃ of preservations are to be checked.Filter out 50 of the positive ducks that infect successfully, be divided into 5 groups at random, 10 every group, be respectively model group and each administration group.Infect back beginning in the 13rd day, model group abdominal injection sodium chloride injection 20ml/kg, each administration group group is diluted to desired concn intraperitoneal injection 20ml/kg by dosage shown in the table 3 with sodium chloride injection, every day 1 time, totally 2 weeks.Respectively at before the administration, after administration the 7th day, administration the 14th day and the drug withdrawal the 3rd day, from duck leg shin vein haemospasia, separation of serum ,-20 ℃ of preservations are to be checked.Detect above-mentioned duck serum with DHBV-DNA Dot Blot method, be worth as sample DHBV-DNA level value with hybridization spot absorbancy (OD).
Experimental result: see Table 3.Compare with model group, during the administration, compd A, compd B, Compound C, Compound D all have significant inhibitory effect (p＜0.05) to duck DHBV virus, and the DHBV-DNA level does not have obvious rising after the drug withdrawal.
Table 3 The compounds of this invention to the restraining effect of duck DHBV-DNA (X ± S, n=10)
Compare with model group:
*P＜0.05.
Conclusion: experimental result shows that The compounds of this invention has remarkable restraining effect to duck DHBV virus, and no tangible rebound phenomenon after the drug withdrawal, shows that the The compounds of this invention hepatitis B virus has good inhibitory effect.
Experimental example 4 The compounds of this invention on Carrageenan cause the influence of rat toes swelling
Animal subject: healthy rat, 50, body weight 200～220g, the male and female dual-purpose is divided into 5 groups at random, 10 every group.
Trial-product: sodium chloride injection: 250ml: 2.25g, Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.;
Compd A injection liquid: 10ml: 30mg;
Compd B injection liquid: 10ml: 30mg;
Compound C injection liquid: 10ml: 50mg;
Compound D injection liquid: 10ml: 50mg.
Dosage: see Table 4, model group gives sodium chloride injection.
Experimental technique: rat is divided into model group and each administration group, 10 every group at random by body weight.Model group abdominal injection sodium chloride injection 20ml/kg, each administration group is diluted to desired concn intraperitoneal injection 20ml/kg by dosage shown in the table 4 with sodium chloride injection, every day 1 time, for three days on end.After the last administration, every rat causes inflammation at right back toes subcutaneous injection 1% carrageenin suspension 0.1ml respectively, respectively survey toes swelling volume 1 time with injection back 0.5h, 1h, 2h, 4h with volumetric method before the injection carrageenin suspension, calculate the difference of injection front and back toes swelling.
Experimental result and conclusion: experimental result sees Table 4.After carrageenin caused inflammation, the right back toes swelling of model group rat was remarkable.Compare with model group, the rat toes swelling due to compd A, compd B, Compound C, the Compound D on Carrageenan all has remarkable restraining effect (p＜0.05, p＜0.01), and lasting anti-inflammatory, and effect is remarkable.Show that The compounds of this invention has significant anti-inflammatory action.
Table 4 The compounds of this invention to egg white cause the swelling of rat toes effect (X ± S, n=10)
Compare with model group:
*P＜0.05,
*P＜0.01.
Experimental example 5 The compounds of this invention bring out the influence of mouse ear swelling to Oleum Tiglii
Animal subject: healthy mice, 50, body weight 20～25g, the male and female dual-purpose is divided into 5 groups at random, 10 every group.
Trial-product: physiological saline: commercial;
Compd A capsule: 90mg;
Compd B capsule: 90mg;
Compound C capsule: 150mg;
Compound D capsule: 150mg.
Dosage: see Table 5, model group gives physiological saline.
Experimental technique: mouse is divided into model group and each administration group, 10 every group at random by body weight.Model group is irritated stomach and is given physiological saline 20ml/kg, and each administration group is diluted to desired concn abdomen gastric infusion 20ml/kg, every day 1 time, continuous 2 days by dosage shown in the table 5 with physiological saline.1h after the last administration, every mouse is dripped auris dextra with Oleum Tiglii mixture 0.1ml and causes inflammation, gets left and right sides ear with punch tool behind the 4h and weighs respectively, calculates the difference of left and right sides ear weight.
Table 5 The compounds of this invention to Oleum Tiglii bring out mouse ear swelling influence (X ± S, n=10)
Compare with model group:
*P＜0.01.
Experimental result and conclusion: after Oleum Tiglii caused inflammation, the swelling of model group mouse right ear was remarkable.Compare with model group, compd A, compd B, Compound C, Compound D all have utmost point significant inhibitory effect (p＜0.01) to the mice ear due to the Oleum Tiglii.Show that The compounds of this invention has significant anti-acute inflammation effect.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Replace 3 beta-hydroxies-9-fluoro-11-oxo-18 β with compd A in following examples, 20 β-volatile oil-12-olefin(e) acid, compd B replaces 3 beta-hydroxies-9-chloro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid, Compound C replaces 3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-fluoro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid, Compound D replaces 3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-chloro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid.
Embodiment 13 beta-hydroxies-9-fluoro-11-oxo-18 β, the preparation of 20 β-volatile oil-12-olefin(e) acid
Step 1: in the exsiccant reaction flask, add diacetyl oxide and each 30ml of pyridine, stir the back and add 4.7g (10mmol) 3 beta-hydroxies-11-oxidation-18 β, 20 β-volatile oil-12-olefin(e) acid, in 60 ℃ of stirring reaction 10h, reaction finishes, under vigorous stirring, reaction solution is poured in the frozen water, separated out yellow solid, join in the reaction flask again after 60 ℃ of dryings, add dehydrated alcohol 50ml and vitriol oil 1ml, heated and stirred backflow 5h, reaction finishes, and reclaims solvent, residuum extracts with ethyl acetate 50ml * 2 after adding an amount of frozen water, merge organic layer and dry, reclaim solvent, get 3 β-acetoxyl group-11-oxidation-18 β, 20 β-volatile oil-12-olefin(e) acid ethyl ester 4.1g, yield: 75.9%.
Step 2: in the dry reaction bottle, under the nitrogen atmosphere, add 3 β-acetoxyl group-11-oxidation-18 β, 20 β-volatile oil-12-olefin(e) acid ethyl ester 4.0g (7.4mmol), N-fluorinated pyridine trifluoromethyl sulfonic acid 1.7g (7.4mmol), DMSO50ml are warming up to 80 ℃ of stirring reaction 12h.Afterwards, add N-fluorinated pyridine trifluoromethyl sulfonic acid 1.7g (7.4mmol) again, stirring reaction 12h, reaction finishes, and DMSO is removed in decompression; After reducing to room temperature, add 50ml water, use 30ml * 3 ethyl acetate extractions then, merge organic phase, dry and filtration, filtrate decompression concentrates, residuum is dissolved in the 100ml95% ethanol, adds sodium hydroxide 0.9g, behind the stirring 1h that refluxes, in 50 ℃ of following decompression and solvent recoveries, residuum adds 50ml water, regulates pH5～6 with dilute hydrochloric acid, separates out faint yellow solid, filter, washing, 50 ℃ of drying under reduced pressure get 3 beta-hydroxies-9-fluoro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid 2.5g, yield: 69.4%.
Ultimate analysis (C
30H
45FO
4): C:73.54%, H:9.42%, F:3.77% (theory: C:73.73%, H:9.28%, F:3.89%).
Embodiment 23 beta-hydroxies-9-chloro-11-oxo-18 β, the preparation of 20 β-volatile oil-12-olefin(e) acid
Step 1: with step 1 among the embodiment 1.
Step 2: in the dry reaction bottle, under the nitrogen atmosphere, add 3 β-acetoxyl group-11-oxidation-18 β, 20 β-volatile oil-12-olefin(e) acid ethyl ester 4.0g (7.4mmol), tetracol phenixin 50ml, 10mlSO
2Cl
2/ tetracol phenixin 50ml is warming up to 60 ℃ of stirring reaction 3h, removes solvent under reduced pressure; After reducing to room temperature, add 50ml water, use 30ml * 3 ethyl acetate extractions then, merge organic phase and wash dry and filtration with saturated sodium bicarbonate solution, concentrating under reduced pressure, residuum is dissolved in 95% ethanol, adds sodium hydroxide 0.9g, behind the stirring 1h that refluxes, in 50 ℃ of following decompression and solvent recoveries, residuum adds 50ml water, regulates pH4～6 with dilute hydrochloric acid, separates out faint yellow solid, filter, washing, 50 ℃ of drying under reduced pressure get 3 beta-hydroxies-9-fluoro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid 3.2g, yield: 86.5%.
Ultimate analysis (C
30H
45ClO
4): C:71.11%, H:9.10%, Cl:6.92% (theory: C:71.33%, H:8.98%, Cl:7.02%).
Embodiment 3 3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-fluoro-11-oxo
-18 β, the preparation of 20 β-volatile oil-12-olefin(e) acid
With reference to preparation method among the embodiment 1, with 3 beta-hydroxies-11-oxidation-18 β, 20 β-volatile oil-12-olefin(e) acid is changed to 3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid, get 3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-fluoro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid 2.8g, yield: 55.1%.
Ultimate analysis (C
42H
61FO
16): C:59.85%, H:7.42%, F:2.15% (theory: C:59.99%, H:7.31%, F:2.26%)
Embodiment 4 3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-chloro-11-oxo
-18 β, the preparation of 20 β-volatile oil-12-olefin(e) acid
With reference to preparation method among the embodiment 1, with 3 beta-hydroxies-11-oxidation-18 β, 20 β-volatile oil-12-olefin(e) acid is changed to 3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid, get 3-(β base-2-O-β-D-glucopyranoside aldehydic acid base-α-D-glucopyranoside aldehydic acid)-9-chloro-11-oxo-18 β, 20 β-volatile oil-12-olefin(e) acid 3.0g, yield: 71.2%.
Ultimate analysis (C
42H
61ClO
16): C:58.71%, H:7.28%, Cl:4.05% (theory: C:58.84%, H:7.17%, Cl:4.14%)
The preparation of embodiment 5 The compounds of this invention liquid drugs injections
1, prescription:
Prescription 1:
Compd A or B 2.5g
Polysorbate 80 10g
Water for injection 2000ml
Prepare 1000 altogether
Prescription 2:
Compd A or B 6g
Polysorbate 80 10g
Water for injection 2000ml
Prepare 1000 altogether
Prescription 3:
Compd A or B 12g
Polysorbate 80 10g
Water for injection 5000ml
Prepare 1000 altogether
Prescription 4:
Compd A or B 30g
Polysorbate 80 20g
Water for injection 10000ml
Prepare 1000 altogether
Prescription 5:
Compound C or D 4g
Polysorbate 80 10g
Water for injection 2000ml
Prepare 1000 altogether
Prescription 6:
Compound C or D 10g
Polysorbate 80 10g
Water for injection 2000ml
Prepare 1000 altogether
Prescription 7:
Compound C or D 20g
Polysorbate 80 10g
Water for injection 5000ml
Prepare 1000 altogether
Prescription 8:
Compound C or D 50g
Polysorbate 80 20g
Water for injection 10000ml
Prepare 1000 altogether
2, preparation technology:
To produce with the ampoule dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation; Take by weighing raw material and auxiliary material by prescription, get the water for injection that Polysorbate 80 adds dosing amount 80%, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal, adds raw material in solution, and stirring and dissolving is measured the also pH value of regulator solution, and benefit adds to the full amount of water for injection, constant volume; Soup is checked clarity, the inspection of semifinished product through the smart filter of the millipore filtration of 0.22 μ m; Soup is loaded in the ampoule 100 ℃ of flowing steam sterilization 30min, leak detection, lamp inspection; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 The compounds of this invention powder pins
1, prescription:
Prescription 1:
Compd A or B 2.5g
Dextran 10 0g
Water for injection 3000ml
Prepare 1000 altogether
Prescription 2:
Compd A or B 6g
Dextran 10 0g
Water for injection 3000ml
Prepare 1000 altogether
Prescription 3:
Compd A or B 12g
Dextran 10 0g
Water for injection 3000ml
Prepare 1000 altogether
Prescription 4:
Compd A or B 30g
Dextran 20 0g
Water for injection 10000ml
Prepare 1000 altogether
Prescription 5:
Compound C or D 4g
Dextran 10 0g
Water for injection 3000ml
Prepare 1000 altogether
Prescription 6:
Compound C or D 10g
Dextran 10 0g
Water for injection 3000ml
Prepare 1000 altogether
Prescription 7:
Compound C or D 20g
Dextran 10 0g
Water for injection 3000ml
Prepare 1000 altogether
Prescription 8:
Compound C or D 50g
Dextran 20 0g
Water for injection 3000ml
Prepare 1000 altogether
2, preparation technology:
To produce used cillin bottle, plug and dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation; Take by weighing raw material and auxiliary material by prescription, dextran is added dosing amount 80% water for injection, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% then stirs 15min, filters, and takes off charcoal, adds raw material in solution, and stirring and dissolving is measured the also pH value of regulator solution, and benefit adds to the full amount of water for injection, constant volume; Soup is checked clarity, the inspection of semifinished product through the smart filter of the millipore filtration of 0.22 μ m; 2ml is in cillin bottle in the soup packing, half tamponade, freeze-drying, tamponade, Zha Gai; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 7 The compounds of this invention sodium chloride injections
1, prescription:
Prescription 1:
Compd A or B 25g
Polysorbate 80 20g
Sodium-chlor 900g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 2:
Compd A or B 50g
Polysorbate 80 30g
Sodium-chlor 900g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 3:
Compd A or B 70g
Polysorbate 80 30g
Sodium-chlor 900g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 4:
Compd A or B 90g
Polysorbate 80 40g
Sodium-chlor 900g
Water for injection 10000ml
Prepare 1000 bottles altogether
Prescription 5:
Compound C or D 40g
Polysorbate 80 20g
Sodium-chlor 900g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 6:
Compound C or D 80g
Polysorbate 80 30g
Sodium-chlor 900g
Water for injection 2000ml
Prepare 1000 bottles altogether
Prescription 7:
Compound C or D 120g
Polysorbate 80 60g
Sodium-chlor 900g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 8:
Compound C or D 150g
Polysorbate 80 80g
Sodium-chlor 900g
Water for injection 100000ml
Prepare 1000 bottles altogether
2, preparation technology:
With dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation; Take by weighing raw material and auxiliary material by prescription, get the water for injection that Polysorbate 80 adds dosing amount 80%, stirring and dissolving adds sodium-chlor, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal, adds raw material in solution, and stirring and dissolving is measured the also pH value of regulator solution, and benefit adds to the full amount of water for injection, constant volume; Soup is checked clarity, the inspection of semifinished product through the smart filter of the millipore filtration of 0.22 μ m; Soup is loaded in the infusion bottle 115 ℃ of pressure sterilizing 30min, leak detection, lamp inspection; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 The compounds of this invention glucose injections
1, prescription:
Prescription 1:
Compd A or B 30g
Polysorbate 80 20g
Glucose 5000g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 2:
Compd A or B 50g
Polysorbate 80 30g
Glucose 5000g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 3:
Compd A or B 70g
Polysorbate 80 30g
Glucose 10000g
Water for injection 200000ml
Prepare 1000 bottles altogether
Prescription 4:
Compd A or B 90g
Polysorbate 80 40g
Glucose 12500g
Water for injection 250000ml
Prepare 1000 bottles altogether
Prescription 5:
Compound C or D 50g
Polysorbate 80 20g
Glucose 5000g
Water for injection 100000ml
Prepare 1000 bottles altogether
Prescription 6:
Compound C or D 80g
Polysorbate 80 30g
Glucose 10000g
Water for injection 200000ml
Prepare 1000 bottles altogether
Prescription 7:
Compound C or D 120g
Polysorbate 80 60g
Glucose 10000g
Water for injection 200000ml
Prepare 1000 bottles altogether
Prescription 8:
Compound C or D 150g
Polysorbate 80 80g
Glucose 12500g
Water for injection 250000ml
Prepare 1000 bottles altogether
2, preparation technology:
With dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation; Take by weighing raw material and auxiliary material by prescription, get the water for injection that Polysorbate 80 adds dosing amount 80%, stirring and dissolving adds glucose, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal, adds raw material in solution, and stirring and dissolving is measured the also pH value of regulator solution, and benefit adds to the full amount of water for injection, constant volume; Soup is checked clarity, the inspection of semifinished product through the smart filter of the millipore filtration of 0.22 μ m; Soup is loaded in the infusion bottle 115 ℃ of pressure sterilizing 30min, leak detection, lamp inspection; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 9 The compounds of this invention sheets
1, prescription:
Prescription 1:
Compd A or B 30g
Microcrystalline Cellulose 50g
Pregelatinized Starch 100g
10%PVP K30 alcohol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 2:
Compd A or B 45g
Microcrystalline Cellulose 50g
Pregelatinized Starch 100g
10%PVP K30 ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 3:
Compd A or B 90g
Microcrystalline Cellulose 80g
Pregelatinized Starch 150g
10%PVP K30 alcohol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 4:
Compound C or D 50g
Microcrystalline Cellulose 50g
Pregelatinized Starch 100g
10%PVP K30 ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 5:
Compound C or D 80g
Microcrystalline Cellulose 60g
Pregelatinized Starch 120g
10%PVP K30 alcohol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 6:
Compound C or D 150g
Microcrystalline Cellulose 80g
Pregelatinized Starch 150g
10%PVP K30 ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
2, preparation technology:
It is standby that raw material and auxiliary material separated pulverizing are crossed 80 mesh sieves; Granulation solution preparation: getting PVP K30, to add concentration be that 30～95% medicinal alcohols are made 5～10% solution; Get raw material and auxiliary materials and mixing, add granulation solution and make softwood in right amount, 20 orders are granulated, and after 50～70 ℃ of dryings, the whole grain of 18 orders adds the Magnesium Stearate mixing; Measure granule content, compressing tablet, detection lug is heavy at random; Finished product is examined entirely, the packing warehouse-in.
The capsular preparation of embodiment 10 The compounds of this invention
1, prescription:
Prescription 1:
Compd A or B 30g
Microcrystalline Cellulose 50g
Pregelatinized Starch 100g
10%PVP K30 ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 2:
Compd A or B 45g
Microcrystalline Cellulose 50g
Pregelatinized Starch 100g
10%PVP K30 ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 3:
Compd A or B 90g
Microcrystalline Cellulose 80g
Pregelatinized Starch 150g
10%PVP K30 ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 4:
Compound C or D 50g
Microcrystalline Cellulose 50g
Pregelatinized Starch 100g
10%PVP K30 alcohol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 5:
Compound C or D 80g
Microcrystalline Cellulose 60g
Pregelatinized Starch 120g
10%PVP K30 alcohol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
Prescription 6:
Compound C or D 150g
Microcrystalline Cellulose 80g
Pregelatinized Starch 150g
10%PVP K30 ethanol liquid is an amount of
Magnesium Stearate 3g
Prepare 1000 altogether
2, preparation technology:
It is standby that raw material and auxiliary material separated pulverizing are crossed 80 mesh sieves; Granulation solution preparation: getting PVP K30, to add concentration be that 30～95% medicinal alcohols are made 5～10% solution; Get raw material and auxiliary materials and mixing, add granulation solution and make softwood in right amount, 20 orders are granulated, and after 50～70 ℃ of dryings, the whole grain of 18 orders adds the Magnesium Stearate mixing; Measure granule content, capsule is filled, with the machine testing loading amount; Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 11 The compounds of this invention particulate
1, prescription:
Prescription 1:
Compd A or B 30g
Icing Sugar 1000g
The 2%HPMC50% ethanolic soln is an amount of
Prepare 1000 bags altogether
Prescription 2:
Compd A or B 45g
Icing Sugar 1000g
The 2%HPMC50% ethanolic soln is an amount of
Prepare 1000 bags altogether
Prescription 3:
Compd A or B 90g
Icing Sugar 1000g
The 2%HPMC50% ethanolic soln is an amount of
Prepare 1000 bags altogether
Prescription 4:
Compd A or B 240g
Icing Sugar 1800g
The 2%HPMC50% ethanolic soln is an amount of
Prepare 1000 bags altogether
Prescription 5:
Compound C or D 50g
Icing Sugar 1000g
The 2%HPMC50% ethanolic soln is an amount of
Prepare 1000 bags altogether
Prescription 6:
Compound C or D 80g
Icing Sugar 1000g
The 2%HPMC50% ethanolic soln is an amount of
Prepare 1000 bags altogether
Prescription 7:
Compound C or D 150g
Icing Sugar 1000g
The 2%HPMC50% ethanolic soln is an amount of
Prepare 1000 bags altogether
Prescription 8:
Compound C or D 400g
Icing Sugar 1600g
The 2%HPMC50% ethanolic soln is an amount of
Prepare 1000 bags altogether
2, concrete steps:
Raw material and auxiliary material were pulverized 100 mesh sieves, standby; Take by weighing raw material and auxiliary material according to recipe quantity, the method that raw material and Icing Sugar are progressively increased with equivalent mixes, and it is an amount of to add the 2%HPMC50% ethanolic soln, stirs, and makes suitable softwood, crosses 20 mesh sieves and granulates, and the whole grain of 18 mesh sieves is crossed in 60 ℃ of oven dry; Sampling, the content of main ingredient is determined loading amount, packing in the work in-process chemical examination particle; Finished product is examined entirely, the packing warehouse-in.
Claims (10)
1. the compound that is shown below or its steric isomer and salt thereof:
Wherein,
X is
R
1Be F, Cl, Br or I;
R
2Be H, perhaps 1～3 molecule glucose base, glucal acidic group, arabopyranose base, arbinofuranose base, rhamanopyranosyl, ribosyl, deoxyribosyl, lactose base, galactosyl, galacturonic acidic group, malt-base, mannose group, xylosyl;
R
3, R
4, R
5Independently hydroxyl, perhaps replacement or unsubstituted C respectively do for oneself
1-6Alkyl, thiazolinyl or the alkane hydroxyl of straight or branched, be selected from methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, vinyl, 1-propenyl, 2-propenyl, different propenyl, 1-butylene base, crotyl, 3-butenyl, isobutenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, methylol, hydroxyethyl, hydroxypropyl, hydroxyl butyl; Wherein, described substituting group is selected from hydroxyl, amino, nitro, fluorine, chlorine, bromine, iodine, C
1-6The alkyl or alkenyl of straight or branched, C
6-10Aryl, C
1-4The alkyl amido of straight or branched, C
1-4The alkoxy carbonyl of straight or branched.
2. compound as claimed in claim 1 or its steric isomer and salt thereof, wherein,
X is
R
1Be F, Cl or Br;
R
2Be H, perhaps 1～3 molecule glucose base, glucal acidic group, arabopyranose base, arbinofuranose base, rhamanopyranosyl;
R
3, R
4, R
5Independently hydroxyl, perhaps replacement or unsubstituted C respectively do for oneself
1-4Alkyl, thiazolinyl or the alkane hydroxyl of straight or branched, be selected from methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, vinyl, 1-propenyl, 2-propenyl, different propenyl, 1-butylene base, crotyl, 3-butenyl, isobutenyl, methylol, hydroxyethyl, hydroxypropyl, hydroxyl butyl.
3. compound as claimed in claim 2 or its steric isomer and salt thereof, wherein,
X is
R
1Be F or Cl;
R
2Be H, perhaps 1～3 molecule glucose base, glucal acidic group, arabopyranose base, arbinofuranose base;
R
3, R
4, R
5Independently hydroxyl, perhaps replacement or unsubstituted C respectively do for oneself
1-3Alkyl, thiazolinyl or the alkane hydroxyl of straight or branched, be selected from methyl, ethyl, propyl group, sec.-propyl, vinyl, 1-propenyl, 2-propenyl, different propenyl, methylol, hydroxyethyl, hydroxypropyl.
4. compound as claimed in claim 3 or its steric isomer and salt thereof, wherein,
X is
R
1Be F or Cl;
R
2Be H ,-β-D-glucosyl group ,-the alpha-D-glucose base or-β-D-glucal acidic group-alpha-D-glucose aldehydic acid base;
R
3Be methyl or methylol;
R
4Be methyl or methylol;
R
5Be methyl, hydroxyl or methylol.
5. compound as claimed in claim 4 or its steric isomer and salt thereof, wherein,
X is
R
1Be F or Cl;
R
2For H or-β-D-glucal acidic group-alpha-D-glucose aldehydic acid base;
R
3Be methyl;
R
4Be methyl;
R
5Be methyl.
6. as the described arbitrary compound of claim 1～5 or its steric isomer and salt thereof, it is characterized in that described salt is metal-salt, be selected from sodium salt, sylvite, magnesium salts, calcium salt, zinc salt, bismuth salt, the aluminium salt one or more; Or ammonium salt; Or organic amine salt, be selected from meglumine salt, arginic acid salt, lysine salt, Histidine salt, ornithine salt.
7. treat and/or prevent application in the medicine of hepatic diseases as the described arbitrary compound of claim 1～5 or its steric isomer and salt thereof in preparation.
8. treat and/or prevent application in the medicine of inflammatory diseases as the described arbitrary compound of claim 1～5 or its steric isomer and salt thereof in preparation.
As the described arbitrary compound of claim 1～5 or its steric isomer and salt thereof as the essential activeconstituents and the pharmaceutical composition of pharmaceutically acceptable carrier.
10. pharmaceutical composition as claimed in claim 9 is oral preparations or injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100706104A CN101190937B (en) | 2006-12-01 | 2006-12-01 | Compound with liver-protecting activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100706104A CN101190937B (en) | 2006-12-01 | 2006-12-01 | Compound with liver-protecting activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101190937A true CN101190937A (en) | 2008-06-04 |
| CN101190937B CN101190937B (en) | 2012-05-30 |
Family
ID=39486152
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006100706104A Active CN101190937B (en) | 2006-12-01 | 2006-12-01 | Compound with liver-protecting activity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101190937B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070699A (en) * | 2011-02-28 | 2011-05-25 | 贵州省中国科学院天然产物化学重点实验室 | Trihydroxy-substituted pentacyclic triterpene compounds and preparation method and application thereof |
| CN108129542A (en) * | 2018-01-04 | 2018-06-08 | 中国科学院昆明植物研究所 | C-3,28,29- tri- replaces oleanane triterpene saponin and its pharmaceutical composition |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1593472A (en) * | 2003-09-10 | 2005-03-16 | 深圳市清华源兴生物医药科技有限公司 | Pharmaceutical composition for treating liver diseases and its application |
-
2006
- 2006-12-01 CN CN2006100706104A patent/CN101190937B/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070699A (en) * | 2011-02-28 | 2011-05-25 | 贵州省中国科学院天然产物化学重点实验室 | Trihydroxy-substituted pentacyclic triterpene compounds and preparation method and application thereof |
| CN108129542A (en) * | 2018-01-04 | 2018-06-08 | 中国科学院昆明植物研究所 | C-3,28,29- tri- replaces oleanane triterpene saponin and its pharmaceutical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101190937B (en) | 2012-05-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5294509B2 (en) | Cycloastragenol monoglucoside, process for its production and use as a pharmaceutical composition | |
| EP1364643A1 (en) | Composition improved in solubility or oral absorbability | |
| CN103893258B (en) | Oral solid formulation and its application containing Desmodium styracifolium general flavone | |
| CN1143908A (en) | Treatment of diabetic nephropathy with valsartan | |
| CN101108872B (en) | Plants natural base extract and formulated product and use thereof | |
| CN101190937B (en) | Compound with liver-protecting activity | |
| CN102481288A (en) | Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof | |
| CN102188417A (en) | Dronedarone medicinal composition | |
| CN101195582A (en) | Cinnamic amide derivant | |
| CN101108224B (en) | Plants natural base extractive and formulated product and use thereof | |
| CN109988104B (en) | Kaempferol and isonicotinamide eutectic crystal, preparation method, pharmaceutical composition and application thereof | |
| CN115124420B (en) | Rhein and matrine eutectic hydrate, preparation method, composition and application thereof | |
| CN101190935B (en) | Compound used for viral infect | |
| CN100563647C (en) | The Pharmaceutical composition of Herba Erigerontis and sodium tanshinon IIA silate injection | |
| CN100382799C (en) | Power for intravenous injection with liver-protecting action, and its preparation and quality control method | |
| CN105582546A (en) | Compound enteric-coated tablets of entecavir phospholipid complex and diammonium glycyrrhizinate | |
| CN101190936A (en) | Compound with antiviral activity | |
| CN105311044A (en) | Application of pharmaceutical composition to prepare medicines treating cutaneous vasculitis | |
| CN105311024A (en) | Application of oxymatrine and derivatives to prepare medicines treating skin vasculitis | |
| CN101190938A (en) | Compound used for liver disease | |
| CN111000807B (en) | A dripping pill containing ginkgolide as effective component and its preparation method | |
| CN101121696B (en) | Metal salt of pyritinol and hydrate of the same | |
| CN1899276B (en) | Composition of rheinic acid or rheinic acid compounds use in preparing medicine for preventing intestinal adhesion | |
| CN1985987B (en) | Medicine composition of glycyrrhizic acid or its salt and reduced glutathione | |
| JP3186365B2 (en) | Liver disease drug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20080530 Address after: Tianchen Avenue in Ji'nan high tech Development Zone in Shandong City, No. 2518, block A Applicant after: Shandong Xuanzhu Medical Technology Co., Ltd. Address before: Tianchen Avenue in Ji'nan high tech Development Zone in Shandong City, No. 2518, block A Applicant before: Huang Zhenhua |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170815 Address after: Tianchen Avenue in Ji'nan high tech Development Zone of Shandong province 250101 City No. 2518 block A Co-patentee after: Langfang high Bojing State Pharmaceutical Co. Ltd. Patentee after: Shandong Xuanzhu Medical Technology Co., Ltd. Address before: Tianchen Avenue in Ji'nan high tech Development Zone of Shandong province 250101 City No. 2518 block A Patentee before: Shandong Xuanzhu Medical Technology Co., Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190613 Address after: 101113 Room 301, Building 3, East of Qishanzhuang Village, Zhangjiawan Town, Tongzhou District, Beijing (in Beijing Sihuan Pharmaceutical Co., Ltd.) Co-patentee after: Langfang high Bojing State Pharmaceutical Co. Ltd. Patentee after: Beijing Aohe Pharmaceutical Research Institute Co., Ltd. Address before: 250101 Block A, 2518 Tianchen Street, Jinan High-tech Development Zone, Shandong Province Co-patentee before: Langfang high Bojing State Pharmaceutical Co. Ltd. Patentee before: Shandong Xuanzhu Medical Technology Co., Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210816 Address after: 134000 No. 4655 Jianguo Road, Meihekou City, Tonghua City, Jilin Province Patentee after: HONGHE PHARMACEUTICAL Co.,Ltd. Address before: 101113 Room 301, Building 3, East of Qishanzhuang Village, Zhangjiawan Town, Tongzhou District, Beijing (in Beijing Sihuan Pharmaceutical Co., Ltd.) Patentee before: Beijing Aohe Pharmaceutical Research Institute Co.,Ltd. Patentee before: Langfang high Bojing State Pharmaceutical Co.,Ltd. |
|
| TR01 | Transfer of patent right |