CN113214350B - 金钱松三萜内酯及其制法、药物组合物与用途 - Google Patents
金钱松三萜内酯及其制法、药物组合物与用途 Download PDFInfo
- Publication number
- CN113214350B CN113214350B CN202010080047.9A CN202010080047A CN113214350B CN 113214350 B CN113214350 B CN 113214350B CN 202010080047 A CN202010080047 A CN 202010080047A CN 113214350 B CN113214350 B CN 113214350B
- Authority
- CN
- China
- Prior art keywords
- inflammation
- pharmaceutical composition
- compound
- group
- compounds
- 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.)
- Active
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- -1 triterpenoid lactone Chemical class 0.000 title abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 239000003814 drug Substances 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 206010061218 Inflammation Diseases 0.000 claims description 67
- 230000004054 inflammatory process Effects 0.000 claims description 59
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 21
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 21
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 9
- 239000003826 tablet Substances 0.000 claims description 7
- 230000003412 degenerative effect Effects 0.000 claims description 6
- 239000006187 pill Substances 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 210000000056 organ Anatomy 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 208000011231 Crohn disease Diseases 0.000 claims description 4
- 241000221089 Jatropha Species 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 230000002008 hemorrhagic effect Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000011859 microparticle Substances 0.000 claims description 4
- 230000002956 necrotizing effect Effects 0.000 claims description 4
- 231100000572 poisoning Toxicity 0.000 claims description 4
- 230000000607 poisoning effect Effects 0.000 claims description 4
- 230000002062 proliferating effect Effects 0.000 claims description 4
- 208000006379 syphilis Diseases 0.000 claims description 4
- 201000008827 tuberculosis Diseases 0.000 claims description 4
- 239000000443 aerosol Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 239000007921 spray Substances 0.000 claims description 2
- 238000013268 sustained release Methods 0.000 claims description 2
- 239000012730 sustained-release form Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 2
- 238000013270 controlled release Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 12
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 10
- 241000218652 Larix Species 0.000 abstract description 7
- 235000005590 Larix decidua Nutrition 0.000 abstract description 7
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 241000218682 Pseudolarix amabilis Species 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 239000000843 powder Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 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 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000004262 preparative liquid chromatography Methods 0.000 description 5
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 5
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 206010014025 Ear swelling Diseases 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000049 pigment Substances 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 3
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- 240000001307 Myosotis scorpioides Species 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 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 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000112 colonic effect Effects 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 239000003405 delayed action preparation Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000002495 two-dimensional nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- 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 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- YMFNPBSZFWXMAD-UHFFFAOYSA-N JSH-23 Chemical compound NC1=CC(C)=CC=C1NCCCC1=CC=CC=C1 YMFNPBSZFWXMAD-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 206010062575 Muscle contracture Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 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
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 208000006111 contracture Diseases 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 235000012907 honey Nutrition 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 210000004876 tela submucosa Anatomy 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 229940035437 1,3-propanediol Drugs 0.000 description 1
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010063409 Acarodermatitis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010007247 Carbuncle Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 241000218631 Coniferophyta Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- 206010017553 Furuncle Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 102000018745 NF-KappaB Inhibitor alpha Human genes 0.000 description 1
- 108010052419 NF-KappaB Inhibitor alpha Proteins 0.000 description 1
- 201000009053 Neurodermatitis Diseases 0.000 description 1
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 1
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 241000199919 Phaeophyceae Species 0.000 description 1
- 241000218602 Pinus <genus> Species 0.000 description 1
- 240000007263 Pinus koraiensis Species 0.000 description 1
- 235000011615 Pinus koraiensis Nutrition 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000447727 Scabies Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000005747 Transcription Factor RelA Human genes 0.000 description 1
- 108010031154 Transcription Factor RelA Proteins 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 1
- 208000027503 bloody stool Diseases 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000005100 correlation spectroscopy Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000010864 dual luciferase reporter gene assay Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 208000035861 hematochezia Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003903 intestinal lesions Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 208000005687 scabies Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000011218 segmentation Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 210000001599 sigmoid colon Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical group C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了金钱松三萜内酯及其制法、药物组合物与用途，属于医药技术领域，具体涉及从金钱松(Pseudolarix amabilis(Nelson)Rehd)中分离得到的抗炎有效成分，包括两个新的三萜类化合物(1‑2)和四个已知三萜类化合物(3‑6)，其药效学上可接受的盐，及其制备方法，含有这类化合物的组合物，以及这类化合物在制备抗炎药物中的应用。
Description
技术领域
本发明属于医药技术领域，涉及金钱松三萜内酯类化合物(1-6)，其中包括新化合物(1-2)和已知化合物(3-6)，其药效学上可接受的盐，其制备方法，含有这类化合物的药物组合物，以及这类化合物在制备预防、缓解和/或治疗炎症药物中的用途。
背景技术
天然产物一直是抗炎药物的重要来源，从天然产物中寻找抗炎成分是新药开发的重要途径。市场上常用的非甾体抗炎药物阿司匹林就是来源于天然产物。金钱松为松科金钱松属特有种，也是我国特有种，在海拔100～1500米地带散生于针叶树、阔叶树林中。根皮和近根树皮为常见中药土槿皮，可祛风除湿，杀虫止痒，主治疥藓，湿疹，神经性皮炎。中国(Chen GF,Li ZL,Pan DJ.The isolation and structural elucidation of four noveltriterpene lactones,peudolarolides A,B,C,and D,from Pseudolarix kaempferi.JNat Prod,1993,56,1114-1122.)的研究者曾对该植物进行过化学成分的研究，并先后分离并鉴定了peudolarolides A-D的结构，但是其抗炎的活性从未被发现。
具有血管系统的活体组织对损伤因子的防御性反应称为炎症。炎症是十分常见而又重要的基本病理过程，体表的外伤感染和各器官的大部分常见病和多发病(如疖、痈、肺炎、肝炎、肾炎等)都属于炎症性疾病。特别的，溃疡性结肠炎是一种病因尚不十分明确的慢性非特异性炎性肠病。病变主要累及乙状结肠、直肠的黏膜和黏膜下层。临床表现主要为腹泻、黏液脓血便、腹痛等症状。对于中、重度溃疡性结肠炎患者常联合应用糖皮质激素控制症状，后以氨基酸水杨酸类维持缓解治疗。但长期使用后一旦停药或减量后，很快出现症状反复甚至加重。所以针对此种疾病的药物研发十分具有意义。
发明内容
本发明的要解决的技术问题是提供金钱松三萜内酯类化合物(1-6)，其中包括新化合物(1-2)和已知化合物(3-6)，其药效学上可接受的盐，其制备方法，含有这类化合物的药物组合物，以及这类化合物在制备预防、缓解和/或治疗炎症药物中的用途。
为解决本发明的技术问题，本发明提供如下技术方案
本发明技术方案的第一方面提供了式1所示的化合物1-2或其药学上可接受的盐，
本发明技术方案的第二方面是提供了一种药物组合物，其特征在于，含有有效剂量的第一方面所述的任一化合物或其药效学上可接受的盐，以及药效学上可接受的载体。所述的药物组合物选自颗粒剂、胶囊剂、片剂、口服液、丸剂、混悬剂、滴丸剂、微丸剂、口含片、口崩片、胶丸、软胶囊、分散片、溶液剂、气雾剂或喷雾剂。所述的药物组合物选自缓释制剂、控释制剂、微粒给药系统。该药物组合物可根据本领域公知的方法制备。用于此目的时，可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成可作为人药或兽药使用的适当的施用形式或剂量形式。通常本发明药物组合物含有0.1-95重量％的本发明化合物。在单元剂型中本发明化合物一般含量为0.05-1000mg，优选的单元剂型含有0.5-200mg。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、肌肉、皮下、静脉、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。
本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射、皮内注射和穴位注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型等。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明化合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
例如为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸钠等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
例如为了将给药单元制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等；粘合剂，如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊，将有效成分本发明化合物与上述的各种载体混合，并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂，混悬于水性介质中形成混悬剂，亦可装入硬胶囊中或制成注射剂应用。
例如，将本发明化合物制成注射用制剂，如溶液剂、混悬剂、乳剂、冻干粉针剂，这种制剂可以是含水或非水的，可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1，3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓释剂、pH调节剂等。这些辅料是本领域常用的。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量取决于许多因素，例如所要预防或治疗疾病的性质和严重程度，患者或动物的性别、年龄、体重、性格及个体反应，给药途径、给药次数、治疗目的，因此本发明的治疗剂量可以有大范围的变化。一般来讲，本发明中药学成分的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量，加以适当的调整，以达到其治疗有效量的要求，完成本发明的预防或治疗目的。本发明化合物的每天的合适剂量范围：本发明的化合物的用量为0.0001-100mg/kg体重，可一次服用或分多次服用。本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。
本发明技术方案的第三方面是第一方面所述化合物及其药效学上可接受的盐在制备预防、缓解和/或治疗炎症药物中的应用。所述的炎症包括变质性炎症、渗出性炎症、增生性炎症、特异性炎症以及炎性肠病。所述的变质性炎症包括实质器官的感染或中毒；所述的渗出性炎症包括浆液性炎、纤维素性炎、化脓性炎、出血性炎、坏死性炎、卡他性炎；所述的特异性炎症包括结核、梅毒、麻疯、淋巴肉芽肿；所述的炎性肠病包括溃疡性结肠炎和克罗恩病。
本发明技术方案的第四方面是提供了如式2所示化合物3-6及其药效学上可接受的盐在制备预防、缓解和/或治疗炎症药物中的应用：
所述的炎症包括变质性炎症、渗出性炎症、增生性炎症、特异性炎症以及炎性肠病。所述的变质性炎症包括实质器官的感染或中毒；所述的渗出性炎症包括浆液性炎、纤维素性炎、化脓性炎、出血性炎、坏死性炎、卡他性炎；所述的特异性炎症包括结核、梅毒、麻疯、淋巴肉芽肿；所述的炎性肠病包括溃疡性结肠炎和克罗恩病。
有意技术效果
本发明公开的金钱松三萜内酯类化合物具有显著的NF-κB抑制作用，对小鼠耳肿胀、溃疡性结肠炎具有较好的治疗作用。
附图说明
图1金钱松种子的提取分离流程图
具体实施方式
下面的实施例及药物活性实验用来进一步说明本发明，但这并不意味着对本发明的任何限制。
术语与简称
ESI-MS电喷雾质谱
COSY同核化学位移相关谱
DEPT无畸变极化转移增强谱
HMBC异核多键相关(一种测定分子中远程氢碳连接关系的二维核磁共振谱)
HPLC高效液相色谱
HRESI-MS高分辨电喷雾质谱
HSQC异核单量子相关(一种测定分子中氢碳直接相连关系的二维核磁共振谱)
IR红外光谱
NMR核磁共振
NOESY欧沃豪斯增益谱(一种测定分子中氢原子空间位置临近关系的二维核磁共振谱)
IC50半抑制浓度
实施例1：化合物1-6的分离及结构表征
金钱松种子100kg，粉碎，用95％乙醇冷浸提取3次，第一次12小时后两次每次2小时。提取液减压浓缩得到浸膏8.87kg，混悬在20L水中，依次用石油醚、二氯甲烷、乙酸乙酯和正丁醇萃取(各萃取3次)，合并萃取液并回收溶剂得二氯甲烷部位3.97kg。二氯甲烷部位经硅胶(160-200目)吸附色谱柱，依次以石油醚比乙酸乙酯30:1，20:1，10:1，5:1，1:1和乙酸乙酯洗脱，分别得到G1-G6六个流份。其中G3流份(480g)经硅胶(200-300目)吸附色谱柱，依次以石油醚比丙酮10:1，8:1，5:1，3:1，1:1洗脱，分别得到G3G1-G3G4四个流份。G3G1(4.55g)经LH-20凝胶色谱以二氯甲烷比甲醇1:1等度洗脱，得到G3G1L1-G3G1L3三个流分。流份G3G1L3(290mg)经制备型液相色谱(Shimadzu LC-6AD型色谱仪；YMC-pack ODS-A色谱柱，250×10mm，5μm；82％乙腈作为流动相；流速3.5ml/min)得到化合物1(19.8mg)、化合物3(6.9mg)、化合物4(80.6mg)和化合物5(33.7mg)。G3G3(147.6g)分多次经中压ODS色谱以30％、50％、70％、90％、100％甲醇和水洗脱，得到G3G3O1-G3G3O4四个流分。G3G3O2(44.0g)部分多次经LH-20凝胶色谱以二氯甲烷比甲醇1:1等度洗脱，得到G3G3O2L1-G3G3O2L2两个流分。G3G3O2L2(12.0g)经制备型液相色谱(Shimadzu LC-6AD型色谱仪；YMC-pack ODS-A色谱柱，250×20mm，5μm；90％甲醇作为流动相；流速5ml/min)分段得到G3G3O2L2-1至G3G3O2L2-4四段。G3G3O2L2-2经制备型液相色谱(Shimadzu LC-6AD型色谱仪；YMC-packODS-A色谱柱，250×10mm，5μm；60％乙腈作为流动相；流速3.5ml/min)得到化合物6(656.6mg)。G3G3O2L2-3经制备型液相色谱(Shimadzu LC-6AD型色谱仪；YMC-pack ODS-A色谱柱，250×10mm，5μm；60％乙腈作为流动相；流速3.5ml/min)分段得到G3G3O2L2-3-1至G3G3O2L2-3-4。G3G3O2L2-3-3经制备型液相色谱(Shimadzu LC-6AD型色谱仪；YMC-packODS-A C8色谱柱，250×10mm，5μm；70％甲醇作为流动相；流速3.5ml/min)得到化合物2(3.0mg)。
化合物1-6的结构式及鉴定方法
化合物1-6的波谱数据和理化性质
化合物1Pseudoamaolide A
白色粉末，HRESI-MS m/z 489.2992[M+Na]+；1H NMR and 13C NMR,(见表1)。
化合物2Pseudoamaolide B
白色粉末，HRESI-MS m/z 483.31009[M+H]+；1H NMR and 13C NMR,(见表1)。
化合物3Pseudolarnoid E
白色粉末，HRESI-MS m/z 491.315[M+Na]+；1H NMR and 13C NMR,(见表1)。
化合物4Pseudolarolide B
白色粉末，1H NMR and 13C NMR,(见表2)。
化合物5Pseudolarolide A
白色粉末，1H NMR and 13C NMR,(见表2)。
化合物6Pseudolarolide C acid
白色粉末，HRESI-MS m/z 501.32224[M-H]-；1H NMR and 13C NMR,(见表2)。
表1化合物1-3的1H和13C-NMR数据
表2化合物4-6的1H和13C-NMR数据
药理实验
实验例1分离得到全部三萜化合物(含活性最佳化合物1-6)抗炎活性测试
一、体外NF-κB通路抑制实验
(一)实验原理
NF-κB是一种核转录因子,通过调节炎性细胞因子的表达在免疫和炎症反应中发挥重要作用。静息状态下,NF-κB的亚基p50和p65通常以异二聚体的形式存在于细胞质中。当促炎刺激物(如TNF-α)作用于细胞时,会通过IκBα的降解和磷酸化来活化NF-κB,活化的NF-κB p65进入细胞核内与DNA结合,上调炎症基因COX-2、iNOS的转录。NF-κB被激活并启动促炎症基因的转录和表达,导致TNF-α、IL-6、IL-1β等多种促炎因子的过度分泌,从而加重炎症损伤。因此，对NF-κB的抑制作用与该化合物的抗炎作用密切相关。可通过测试化合物对NF-κB的抑制率反映抗炎作用。
(二)实验材料和方法：
1细胞毒性试验：用MTT法测定化合物对293T细胞的细胞毒性。
(1)293T细胞接种于96孔板(5×103/孔)培养过夜。
(2)用10μM的化合物与293T细胞共孵育24小时，将相同浓度的溶剂载体(DMSO，0.5％)作为对照。
(3)将20μl MTT(无菌PBS中的5mg/ml)加于每个孔中，继续培养4h。
(4)去除培养基，在每个孔中加入100μl二甲基亚砜，在490nm处检测吸光度。
2化合物对NF-κB转录激活效应的检测实验：双荧光素酶报告基因检测法。
1.将293T/NF-κB-luc细胞以每孔5×105的密度接种到96孔板中。培养24小时后，在LPS(500ng/ml)刺激前，用化合物预处理细胞30分钟。等浓度的溶剂媒剂(DMSO，0.5％)始终作为对照。
2.刺激6小时后，去除培养基，用荧光素酶分析系统中的溶解缓冲液溶解细胞。随后，将细胞溶解物与荧光素酶分析试剂混合，用酶标仪立即测定萤火虫荧光素酶的发光量。计算NF-κB通路的抑制率。JSH-23为阳性对照药。
测试结果：
表3.化合物1-6对NF-κB通路的抑制作用
注：JSH-23为阳性对照药
当该化合物有细胞毒作用时，抑制试验会有假阳性结果。杀伤率在20％以上的认为在本体系中有细胞毒作用。化合物1-6在10μM浓度下对细胞的杀伤率均在20％以下，可以认为在本体系中没有细胞毒作用，因而实验结果不存在假阳性。
表4.化合物1-6细胞毒活性
二、小鼠二甲苯耳肿胀实验(体内抗炎症模型)
实验原理：
二甲苯诱导小鼠耳肿胀炎症模型是化学接触性皮肤炎症的经典动物模型,表现为小鼠耳组织角质形成细胞增生,产生TNF-α、IL-6、IL-1β等炎性细胞因子,炎性细胞浸润增多,角质层明显增厚,耳组织增厚和耳质量增加等。本研究采用二甲苯诱导小鼠耳肿胀炎症小鼠模型,并以阿司匹林为阳性对照,来验证化合物的抗炎作用。
实验材料和方法：
1.小鼠：雌雄各半昆明种小鼠，18-22g，每组10只。
2.样品处理：样品临用前用生理盐水加吐温80配成母液，检测时用培养液稀释成一定浓度后使用。
3.阳性对照药：阿司匹林。
4.测试方法：称重后，按体重给药，空白组给相同体积生理盐水。药物处理一小时后在小鼠的右耳处均匀涂抹20μL的二甲苯。30min后处死老鼠，使用8mm打孔器均匀打孔。使用万分之一分析天平称重，肿胀度＝右耳质量-左耳质量。
测试结果：
表5.化合物4对二甲苯所致小鼠耳肿胀抑制率比较(X平均±SD)
*P<0.05；***P<0.001
三、化合物4对DSS诱导溃疡性结肠炎(UC)小鼠抗炎活性评价实验
实验原理：
溃疡性结肠炎(ulcerative colitis,UC)是以直肠、结肠黏膜及黏膜下层的炎症和溃疡形成为病理特点的非特异性炎性肠病,多呈反复发作的慢性病程.葡聚糖硫酸钠(dextran sulfate sodium,DSS)诱导的小鼠结肠炎模型的肠道病变与人类病理形态最为近似，所以常用来造模。
实验材料和方法：
1.实验动物
C57BL/6J小鼠，雄性(18-20g)；每组6只。购自北京华阜康生物科技股份有限公司；许可证号：SCXK(京)2014-0004。
2.实验分组
(1)正常对照组(Con组)：0.5％羧甲基纤维素钠灌胃。
(2)UC模型组(Mod组)：0.5％羧甲基纤维素钠灌胃。
(3)阳性药柳氮磺吡啶组(Pos组)：上海信谊药厂有限公司(批号:036151102)；500mg/kg，0.5％羧甲基纤维素钠灌胃。
(4)测试组JQS2(化合物4)：400mg/kg 0.5％羧甲基纤维素钠灌胃。
3实验方法
按实验室已建方法建模，并对UC关评价指标进行检测(见实验结果部分)。
测试结果：
1.测试组JQS2(化合物4)对DSS诱导UC模型小鼠体重的影响
表6.不同化合物组别对UC小鼠体重降低的改善作用
注：**p<0.01与对照组比较。
2.测试组JQS2(化合物4)对UC小鼠结肠挛缩的影响
表7.JQS2(化合物4)对UC小鼠结肠挛缩的影响
注：**p<0.01与对照组比较。
3.测试组JQS2(化合物4)对UC小鼠疾病综合指数DAI评分的影响
表8.JQS2(化合物4)对UC小鼠疾病综合指数DAI评分的影响
注：**p<0.01与对照组比较。##p<0.01与模型组比较。
Claims (10)
1.式1所示的化合物1-2或其药学上可接受的盐，
2.一种药物组合物，其特征在于，含有有效剂量的权利要求1的任一化合物或其药效学上可接受的盐，以及药效学上可接受的载体。
3.根据权利要求2的药物组合物，其特征在于，所述的药物组合物选自颗粒剂、胶囊剂、片剂、丸剂、混悬剂、溶液剂、气雾剂或喷雾剂。
4.根据权利要求2的药物组合物，其特征在于，所述的药物组合物选自缓释制剂、控释制剂、微粒给药系统。
5.权利要求1的任一化合物及其药效学上可接受的盐在制备预防、缓解和/或治疗炎症药物中的应用。
6.根据权利要求5的应用，其特征在于，所述的炎症选自变质性炎症、渗出性炎症、增生性炎症、特异性炎症以及炎性肠病。
7.根据权利要求6的应用，其特征在于，所述的变质性炎症选自实质器官的感染或中毒；所述的渗出性炎症选自浆液性炎、纤维素性炎、化脓性炎、出血性炎、坏死性炎、卡他性炎；所述的特异性炎症选自结核、梅毒、麻疯、淋巴肉芽肿；所述的炎性肠病选自溃疡性结肠炎和克罗恩病。
8.如式2所示化合物3-6及其药效学上可接受的盐在制备预防、缓解和/或治疗炎症药物中的应用：
9.根据权利要求8的应用，其特征在于，所述的炎症选自变质性炎症、渗出性炎症、增生性炎症、特异性炎症以及炎性肠病。
10.根据权利要求9的应用，其特征在于，所述的变质性炎症选自实质器官的感染或中毒；所述的渗出性炎症选自浆液性炎、纤维素性炎、化脓性炎、出血性炎、坏死性炎、卡他性炎；所述的特异性炎症选自结核、梅毒、麻疯、淋巴肉芽肿；所述的炎性肠病选自溃疡性结肠炎和克罗恩病。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010080047.9A CN113214350B (zh) | 2020-02-04 | 2020-02-04 | 金钱松三萜内酯及其制法、药物组合物与用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010080047.9A CN113214350B (zh) | 2020-02-04 | 2020-02-04 | 金钱松三萜内酯及其制法、药物组合物与用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113214350A CN113214350A (zh) | 2021-08-06 |
| CN113214350B true CN113214350B (zh) | 2024-01-12 |
Family
ID=77085663
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010080047.9A Active CN113214350B (zh) | 2020-02-04 | 2020-02-04 | 金钱松三萜内酯及其制法、药物组合物与用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113214350B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103421076A (zh) * | 2013-08-07 | 2013-12-04 | 南京标科生物科技有限公司 | 一种金钱松内酯b的制备方法 |
| CN104257666A (zh) * | 2014-09-15 | 2015-01-07 | 南京泽朗医药科技有限公司 | 金钱松内酯b在制备抗肿瘤药物中的应用 |
| CN108659092A (zh) * | 2018-06-25 | 2018-10-16 | 广东药科大学 | 一种抗炎三萜皂苷类化合物及其提取方法与应用 |
-
2020
- 2020-02-04 CN CN202010080047.9A patent/CN113214350B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103421076A (zh) * | 2013-08-07 | 2013-12-04 | 南京标科生物科技有限公司 | 一种金钱松内酯b的制备方法 |
| CN104257666A (zh) * | 2014-09-15 | 2015-01-07 | 南京泽朗医药科技有限公司 | 金钱松内酯b在制备抗肿瘤药物中的应用 |
| CN108659092A (zh) * | 2018-06-25 | 2018-10-16 | 广东药科大学 | 一种抗炎三萜皂苷类化合物及其提取方法与应用 |
Non-Patent Citations (4)
| Title |
|---|
| Cycloartane triterpenoids from Pseudolarix amabilis and their antiviral activity;Xiao-Tong Zhao等;《Phytochemistry》;第171卷;第112229/1-8页 * |
| -New triterpenoids and PTP1B inhibitory constituents of Pseudolarix amabilis;Chun Lei等;《Fitoterapia》;第139卷;第104414/1-7页 * |
| Oxidatively rearranged cycloartane triterpenoids from the seeds of Pseudolarix amabilis;Hui Guo等;《Natural Product Research》;第32卷(第15期);第1817-1823页 * |
| Pseudoamaolides A-O, anti-inflammatory triterpene spiroketal lactones from seeds of Pseudolarix amabilis;Yuxun Zhu等;《Bioorganic Chemistry》;第129卷;第1-10页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113214350A (zh) | 2021-08-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10624938B2 (en) | Total flavone extract of flower of abelmoschus manihot L. medic and preparation method thereof | |
| CN101279964B (zh) | 愈创木烷型倍半萜、其制备方法及其医药用途 | |
| WO2013060258A1 (zh) | 伸筋草碱a-c、其制法和其药物组合物与用途 | |
| CN100366264C (zh) | 山茱萸提取物及其用途 | |
| CN100443498C (zh) | 白薇总皂苷及其皂苷化合物在抗炎药物中的应用 | |
| CN108815218B (zh) | 药物组合物及其用途 | |
| US20050287230A1 (en) | Method of producing ginsenoside 20 (R)-Rh2 and composition of matter thereof | |
| JP7326561B1 (ja) | 炎症性疾患または腫瘍を治療する薬物の調製におけるクチナシグサの有効部位の抽出物の使用 | |
| CN113214350B (zh) | 金钱松三萜内酯及其制法、药物组合物与用途 | |
| JP6076361B2 (ja) | 胃潰瘍の治療用医薬の調製におけるＡｌｂｉｚｚｉａｃｈｉｎｅｎｓｉｓ抽出物の応用 | |
| CN103044377B (zh) | 具有抑制黄嘌呤氧化酶和降尿酸作用的化合物以及组合物 | |
| CN105030763A (zh) | 蟛蜞菊内酯在制备抗溃疡性结肠炎药物中的应用 | |
| CN108997468B (zh) | 蒲公英烷型三萜及其制备方法和用途 | |
| CN108148105B (zh) | 一种二聚环烯醚萜类化合物及其制备方法和应用 | |
| CN108785316A (zh) | 香加皮c21甾类在制备ido抑制剂中的用途 | |
| CN106188179B (zh) | 具有止泻作用的尖叶假龙胆提取物、化合物及药物组合物 | |
| KR100779026B1 (ko) | 염증성 질환 치료 및 예방에 유용한 구골 추출물 | |
| CN105884841B (zh) | 一种苯丙素类化合物的制备方法 | |
| CN112279811A (zh) | C20二萜生物碱、其制备及治疗疼痛相关疾病的用途 | |
| CN113214154B (zh) | 三聚苄基异喹啉生物碱、其制法和药物组合物与用途 | |
| CN111718360B (zh) | 一种混源萜类化合物及其制备方法及用途 | |
| CN110680819A (zh) | 一种三萜皂苷类化合物的应用 | |
| CN112168831B (zh) | 一个雷公藤内酯醇衍生物在防治炎症性肠病中的用途 | |
| CN114767810B (zh) | 一种治疗急性肺损伤的中药组合物及制备方法和应用 | |
| CN115124493B (zh) | 一种具有抗炎活性的化合物及其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |