CN114057764A - 具有抗炎活性的乌药烷型二聚倍半萜及其制备方法和用途 - Google Patents
具有抗炎活性的乌药烷型二聚倍半萜及其制备方法和用途 Download PDFInfo
- Publication number
- CN114057764A CN114057764A CN202111486837.8A CN202111486837A CN114057764A CN 114057764 A CN114057764 A CN 114057764A CN 202111486837 A CN202111486837 A CN 202111486837A CN 114057764 A CN114057764 A CN 114057764A
- Authority
- CN
- China
- Prior art keywords
- column chromatography
- methanol
- organic solvent
- volume ratio
- sarcandra
- 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
- 229930003839 sesquiterpene dimer Natural products 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 230000003110 anti-inflammatory effect Effects 0.000 title abstract description 11
- JLYXXMFPNIAWKQ-GNIYUCBRSA-N gamma-hexachlorocyclohexane Chemical compound Cl[C@H]1[C@H](Cl)[C@@H](Cl)[C@@H](Cl)[C@H](Cl)[C@H]1Cl JLYXXMFPNIAWKQ-GNIYUCBRSA-N 0.000 title abstract description 7
- JLYXXMFPNIAWKQ-UHFFFAOYSA-N gamma-hexachlorocyclohexane Natural products ClC1C(Cl)C(Cl)C(Cl)C(Cl)C1Cl JLYXXMFPNIAWKQ-UHFFFAOYSA-N 0.000 title abstract description 7
- 229960002809 lindane Drugs 0.000 title abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 12
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 84
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 238000004440 column chromatography Methods 0.000 claims description 24
- 239000000499 gel Substances 0.000 claims description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- 239000000463 material Substances 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 19
- 239000003208 petroleum Substances 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000010898 silica gel chromatography Methods 0.000 claims description 13
- 241000196324 Embryophyta Species 0.000 claims description 12
- 241000736026 Sarcandra Species 0.000 claims description 12
- 238000010828 elution Methods 0.000 claims description 12
- 239000000284 extract Substances 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- 238000002953 preparative HPLC Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000003480 eluent Substances 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 240000004274 Sarcandra glabra Species 0.000 claims description 7
- 238000004587 chromatography analysis Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000010298 pulverizing process Methods 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 230000002441 reversible effect Effects 0.000 claims description 4
- 241000124001 Alcyonacea Species 0.000 claims description 3
- 235000010842 Sarcandra glabra Nutrition 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 238000013375 chromatographic separation Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 235000013399 edible fruits Nutrition 0.000 claims description 2
- 239000011347 resin Substances 0.000 claims description 2
- 229920005989 resin Polymers 0.000 claims description 2
- 238000011894 semi-preparative HPLC Methods 0.000 claims description 2
- 239000003981 vehicle Substances 0.000 claims description 2
- 244000039545 Salacia macrophylla Species 0.000 claims 1
- 238000007654 immersion Methods 0.000 claims 1
- 238000000638 solvent extraction Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 8
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 30
- 206010061218 Inflammation Diseases 0.000 description 12
- 230000004054 inflammatory process Effects 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 10
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 6
- -1 bacteriostats Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000028709 inflammatory response Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229930014626 natural product Natural products 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 description 4
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 3
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229930182947 sarcodictyin Natural products 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 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 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 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
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- NTNWOCRCBQPEKQ-YFKPBYRVSA-N N(omega)-methyl-L-arginine Chemical compound CN=C(N)NCCC[C@H](N)C(O)=O NTNWOCRCBQPEKQ-YFKPBYRVSA-N 0.000 description 2
- NTNWOCRCBQPEKQ-UHFFFAOYSA-N NG-mono-methyl-L-arginine Natural products CN=C(N)NCCCC(N)C(O)=O NTNWOCRCBQPEKQ-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 2
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 208000025747 Rheumatic disease Diseases 0.000 description 2
- 241001310044 Sarcandra hainanensis Species 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000004071 biological effect 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
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 208000037976 chronic inflammation Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000002158 endotoxin Substances 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
- 239000008187 granular material Substances 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 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
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000419 plant extract Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 201000006306 Cor pulmonale Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 206010014561 Emphysema Diseases 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
- 239000004471 Glycine Substances 0.000 description 1
- 206010019375 Helicobacter infections Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-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
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 108010082786 Interleukin-1alpha Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010036631 Presenile dementia Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 208000004186 Pulmonary Heart Disease Diseases 0.000 description 1
- 241000257190 Sarcophaga <genus> Species 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
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 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
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 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
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000004665 defense response Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 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
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 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
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 238000005040 ion trap Methods 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002235 sarcomere Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 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
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
- 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
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 238000002495 two-dimensional nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000002137 ultrasound extraction Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于植物化学和药物领域，涉及具有抗炎活性的乌药烷型二聚倍半萜sarcglabralides A–C及其制备方法和用途，还涉及含有作为活性药物成分的sarcglabralides A–C的药物组合物，以及sarcglabralides A–C的制药用途。本发明的乌药烷型二聚倍半萜sarcglabralides A–C具有较好的抗炎活性，可以用于治疗炎性疾病。
Description
技术领域
本发明属于植物化学和药物技术领域，具体而言，涉及三个具有抗炎活性的乌药烷型二聚倍半萜sarcglabralides A–C，含有其中任一种或两种或三种组合的药物组合物，还涉及化合物sarcglabralides A–C的制备方法，及其在制备用于抗炎药物中的应用。
背景技术
炎症是具有血管***的活体组织对内源性或外源性刺激所做出的一种主动防御反应。正常生理条件下，适度可控的炎症可帮助机体清除和修复损伤。在病理条件下，不可控和过度的炎症又会导致组织和器官的损伤。长期持续的慢性炎症对人体健康有许多危害，如：诱导癌症的发生—幽门螺旋杆菌感染性炎症、EB病毒感染性炎症、肝炎病毒炎症分别与胃癌、鼻咽癌和肝癌相关；危及心血管健康—血管中脂肪斑块引发的慢性炎症能形成血栓最终导致肺动脉高压、慢性阻塞性肺疾病、肺气肿和心脏病等；诱发阿尔茨海默氏症—随着年龄增大，炎症反应导致免疫***的调控机制发生紊乱，增加早老年痴呆的发生；此外，长期过度的炎症反应还能引起糖尿病及其并发症、帕金森氏病、黄斑变性和骨关节炎等。随着城镇化、老龄化进程的不断加快和生活方式的改变、炎性疾病已成为影响全球人群健康的重要威胁之一，正在全球范围蔓延并且已演变成严重危害人类健康和社会经济可持续发展的重要公共卫生问题。
炎症反应涉及到一系列生理病理变化：如受损组织毛细血管通透性增高，花生四烯酸代谢产物及血小板活化因子的释放，炎症因子(IL-1、 IL-6、TNF-α、组胺、5-羟色胺)的释放等，这些生理病理变化组成了炎症反应网络。NO(一氧化氮)在炎症反应中起到关键调节作用，尤其是在炎症反应的发生和信号传导方面。NO是一氧化氮合酶(NOS)催化L-精氨酸生成后，作用到自生细胞，或扩散到邻近细胞，结合到其目的受体(转录因子、蛋白激酶等)，从而发挥一系列调节作用。在免疫性炎症进程中，体内NO在高浓度状态下，能激活NF-κB，诱导促炎症细胞因子TNF-α、 IL-1β等的产生，IL-1和TNF-α的产生又能激活iNOS(诱导型一氧化氮合酶)，促进机体产生更多的NO，使细胞因子的分泌以及其NO自生表达得以持续，使炎症反应更持久，更剧烈。故在炎症反应中抑制NO的生成能使炎症症状得到改善。
目前，炎症的治疗主要为甾体类(糖皮质激素类：如***、强的松、氢化可的松等)和非甾体类(NSAIDS：如阿司匹林、布洛芬、吲哚美辛等)化学合成药，它们都具有多种副作用，如：胃肠道反应、心脏毒性、肝毒性、肾毒性和免疫功能障碍等。因此，继续寻找新的抗炎先导化合物，研究开发具有疗效好、副作用小的抗炎药物，是必要且迫切的。
天然产物在自然界中经过长期而漫长的进化过程，其化学结构的新颖性和生物活性的多样性是药物研发的重要资源之一，从天然产物中寻找具有抗炎活性的先导化合物有着巨大的潜力。
发明内容：
有鉴于此，本发明的目的在于三个新的乌药烷型二聚倍半萜天然产物，即化合物sarcglabralide A、sarcglabralide B和sarcglabralide C，以及该三个化合物作为活性成分在制备治疗抗炎药物中的应用，为炎性疾病的治疗提供疗效好、副作用小的天然产物。
本发明的目的可以通过以下技术方案来实现。
在第一方面，本发明提供了乌药烷型二聚倍半萜，即化合物 sarcglabralides A、B和C，其分别具有下述式I、Ⅱ和Ⅲ所示的结构式：
在第二方面，本发明提供了用于治疗炎性疾病的药物组合物，其包含作为活性药物成分的乌药烷型二聚倍半萜化合物sarcglabralides A、B 或C或其组合，或其药学上可接受的衍生物，以及药学上可接受的载体、佐剂和赋形剂。
在第三方面，本发明涉及乌药烷型二聚倍半萜化合物sarcglabralides A、B或C或其药学上可接受的衍生物在制备用于治疗炎性疾病的药物中的应用。
在第四方面，本发明提供了制备乌药烷型二聚倍半萜化合物 sarcglabralidesA、B或C的方法，包括以下步骤：
1)将草珊瑚属(Sarcandra)植物材料干燥、粉碎，采用有机溶剂提取后脱溶，得到草珊瑚属植物材料提取物；
2)对所述草珊瑚属植物材料提取物依次采用柱层析、中压分离凝胶及半制备高压液相色谱得到化合物sarcglabralides A–C。
在优选的实施方案中，有机溶剂包括石油醚、氯仿、二氯甲烷、乙酸乙酯、丙酮、乙醇、甲醇、正丁醇、乙腈和甲酸中的至少一种。
与现有技术相比，本发明具有明显的有益效果。具体而言，本发明的乌药烷型二聚倍半萜sarcglabralides A–C，具有显著的抗炎活性，可以用于治疗炎性疾病。
附图说明
图1为本发明乌药烷型二聚倍半萜化合物sarcglabralides A–C的化学结构式。
图2为本发明化合物乌药烷型二聚倍半萜sarcglabralides A–C确定绝对构型的ECD(电子圆二色谱)计算结果图。
具体实施方式
为了便于理解本发明，下面将对本发明进行更全面的描述，并给出了本发明的优选实施方案。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施方案。相反，提供这些实施方案的目的是使对本发明公开内容的理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与本发明所属技术领域的技术人员通常理解的含义相同。在本发明的说明书中所用的术语只是为了描述具体的实施方案的目的，并非旨在限制本发明的范围。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
根据第一方面，本发明提供了乌药烷型二聚倍半萜化合物 sarcglabralides A、B和C，其结构式分别如下式I、Ⅱ和Ⅲ所示：
根据本发明的第二方面，本发明提供了用于治疗炎性疾病的药物组合物，其包含作为活性药物成分的乌药烷型二聚倍半萜化合物 sarcglabralides A、B或C或其药学上可接受的衍生物，以及药学上可接受的载体、佐剂或赋形剂。
在本发明药物组合物的实施方案中，炎性疾病包括但不限于：皮肤炎症、风湿性疾病、心血管疾病及自身免疫病等。
在本发明药物组合物的实施方案中，作为活性成分的乌药烷型二聚倍半萜可以是化合物sarcglabralides A–C中的任一种、任意两种或三种。
本领域技术人员应当理解，本发明的化合物sarcglabralides A–C的药学上可接受的衍生物，例如化合物sarcglabralides A–C的盐、溶剂化物或水合物也可以用于本发明的药物组合物中。
药学上可接受的盐可以是例如药学上可接受的加碱成盐。
药学上可接受的加碱成盐包括衍生自诸如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝等无机碱的盐。衍生自药学上可接受的无毒有机碱的盐包括伯胺、仲胺和叔胺的盐，包括天然存在的取代胺、环胺和碱性离子交换树脂，例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺以及乙醇胺和三乙醇胺。
因此，在本发明药物组合物的实施方案中，活性药物成分可以是sarcglabralides A–C中的任一种化合物、任意两种或三种的混合物或其碱加成盐、溶剂化物、水合物等衍生物。
合适的药物赋形剂是本领域技术人员众所周知的。药用载体或赋形剂是一种或多种固体、半固体和液体稀释剂、填料以及药物制品辅剂，包括但不仅限于填充剂(稀释剂)、润滑剂(助流剂或抗粘着剂)、分散剂、湿润剂、粘合剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。粘合剂包括糖浆、***胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物(如微晶纤维素、羧甲基纤维素钠、乙基纤维素或羟丙甲基纤维素等)、明胶浆、糖浆、淀粉浆或聚乙烯吡咯烷酮等；填充剂包括乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐(如硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等)、山梨醇或甘氨酸等；润滑剂包括微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇等；崩解剂包含淀粉及其衍生物(如羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉等)、聚乙烯吡咯烷酮或微晶纤维素等；湿润剂包括十二烷基硫酸钠、水或醇等；抗氧剂包括亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、二丁基苯酸等；抑菌剂包括0.5％苯酚、0.3％甲酚、 0.5％三氯叔丁醇等；乳化剂包括聚山梨酯-80、没酸山梨坦、卵磷酯、豆磷脂等；增溶剂包括吐温-80、胆汁、甘油等。
本发明的乌药烷型二聚倍半萜用作药物时，可以直接施用，或者以药物组合物的形式施用。在本发明的药物组合物中，按药物组合物总重量计，药物组合物可以含有0.1–99％的sarcglabralides A、B或C，优选为 0.5–90％。
乌药烷型二聚倍半萜化合物Sarcglabralides A、B或C或其药学上可接受的衍生物例如碱加成盐的“有效量”是指，足以实现所需生物学效果的量。应当理解，有效剂量会取决于接受者的年龄、性别、健康状况和体重。通常，有效量由施用治疗的人例如治疗医师来决定。
本发明的药物组合物可以以单位体重服用量的形式施用。所有以乌药烷型二聚倍半萜sarcglabralides A–C或其药学上可接受的衍生物例如碱加成盐为有效成分的药物组合物采用制药和食品领域公认的方法制备成各种剂型，例如液体制剂(注射剂、混悬剂、乳剂、溶液剂、糖浆剂等)、固体制剂(片剂、胶囊剂、颗粒剂、冲剂等)、喷剂、气雾剂等。本发明的药物组合物可经注射(静脉注射、静脉滴注、肌肉注射、腹腔注射、皮下注射)和口服、舌下给药、粘膜透析等给药途径进行炎性疾病的治疗。
根据第三方面，本发明提供了本发明的乌药烷型二聚倍半萜化合物sarcglabralides A–C或其药学上可接受的衍生物在制备用于治疗炎性疾病的药物中的用途。
在本发明的实施方案中，炎性疾病包括但不限于：皮肤炎症、风湿性疾病、心血管疾病及自身免疫病等。
根据第四方面，本发明提供了制备乌药烷型二聚倍半萜化合物 sarcglabralidesA–C的方法，包括以下步骤：
1)将草珊瑚属(Sarcandra)植物材料干燥、粉碎，采用有机溶剂浸提后脱溶，得到草珊瑚属植物提取物；
2)对所述草珊瑚属植物提取物依次采用柱层析、中压色谱分离凝胶及半制备高效液相色谱，得到sarcglabralides A–C。
在具体实施方案中，草珊瑚属植物材料可以是草珊瑚属植物的各部位，例如根、茎、枝叶或果实，或全株植物。在本发明的实施方案中，草珊瑚属植物材料可以是草珊瑚(S.glabra)、海南草珊瑚(S.hainanensis) 植物的各部位(例如根、茎、枝叶或果实)或全株。在本发明优选的实施方案中，草珊瑚植物材料来自草珊瑚(S.glabra)。
在本发明的实施方案中，步骤1)提取所用有机溶剂包括石油醚、氯仿、二氯甲烷、乙酸乙酯、丙酮、乙醇、甲醇、正丁醇、乙腈、和甲酸中的至少一种，优选，有机溶剂为甲醇、乙酸乙酯或95％乙醇。
在本发明的实施方案中，提取方法可以是有机溶剂冷浸提取、加热回流提取或超声提取等。
在本发明的实施方案中，用有机溶剂对草珊瑚属植物材料进行提取次数为至少1次，例如2、3、4次，优选3次。
在本发明的实施方案中，有机溶剂与干燥的草珊瑚属植物材料的体积比为1:1到5:1，例如1:1、2:1、3:1、4:1、5:1，以及上述任意两个比例之间的比例，例如1.5:1、2.5:1、3.5:1、4.5:1等，优选为3:1。
在本发明的具体实施方案中，步骤2)具体包括：
在本发明的具体实施方案中，在步骤2)中，所述柱层析包括正相硅胶柱层析、反相硅胶柱层析(例如RP-18)、凝胶柱层析(例如Sephadex LH-20)、中压色谱分离凝胶(例如MCIGel CHP20P)和制备或半制备高效液相色谱(HPLC)。
在本发明的具体实施方案中，在步骤2)中，柱层析所用洗脱剂包括石油醚、氯仿、二氯甲烷、乙酸乙酯、丙酮、乙醇、甲醇、正丁醇、乙腈、水和甲酸中的一种或任意两种的组合；正相硅胶柱层析采用石油醚和乙酸乙酯按体积比从1:0到0:1梯度洗脱，例如1:0、50:1、25:1、10:1、 5:1、0:1；或正相硅胶柱层析采用氯仿和甲醇按体积比从100:1到1:1梯度洗脱，例如100:1、50:1、30:1、10:1、1:1；反相RP-18柱层析采用甲醇和水按体积比从2:8到1:0梯度洗脱；凝胶柱层析，例如Sephadex LH-20 凝胶柱层析，采用甲醇、氯仿-甲醇(v:v 1:1)洗脱；中压色谱分离凝胶(MCI Gel)采用甲醇和水按体积比从2:8到1:0梯度洗脱；制备或半制备HPLC 采用乙腈和水按体积比从2:8到6:4梯度洗脱。
下面结合实施例对本发明的优选实施方式进行详细说明。需要理解的是以下实施例的给出仅是为了起到说明的目的，并不是用来限制本发明的保护范围。本领域的技术人员在不背离本发明的宗旨和精神的情况下，可以对本发明进行各种修改和替换，所有这些修改和替换都落入了本发明权利要求书请求保护的范围内。
下述实施例中所用的实验方法如无特殊说明，均为常规方法。下述实施例中所用的材料、试剂等，如无特殊说明，均可通过商业途径获得。
Agilent UPLC/Q-Tof液质联用仪测定；紫外光谱(UV)在甲醇中用ShimazuUV-2401PC紫外光谱仪测定；HPLC分析和制备用Agilent 1260 型或1100型高效液相色谱仪，色谱柱为AgilentZORBAX-SB-C18层析在下述实施例中，1H,13C NMR和2D NMR谱在BrukerDRX-500核磁共振仪上测定；电喷雾电离质谱(ESI-MS)由Waters XevoTQ-S三重四极杆串联质谱联用仪或Bruker HTC/Esquire液相-离子阱色谱质谱联用仪测定；高分辨质谱(HR-ESI-MS)由柱(5μm；4.6×150mm)或Agilent ZORBAX-SB-C18层析柱(5μm；9.4×250mm)；柱层析用正相硅胶 (200–300目)及薄层层析板均为青岛海洋化工厂产品；薄层层析通过10％ FeCl3-乙醇溶液观察其斑点；Sephadex LH-20为GE Healthcare公司产品；反相材料Rp-8及Rp-18为Merck公司产品。MCI Gel CHP20P为日本三菱化学产品。
实施例1：化合物sarcglabralides A–C的制备方法一
草珊瑚(S.glabra)根(干燥)，粉碎后用乙酸乙酯在室温下按有机溶剂和植物材料的体积比为3:1，冷浸提取4次，2天/次，合并提取液后减压蒸馏得到膏状提取物。膏状提取物经硅胶柱层析，用石油醚-乙酸乙酯梯度洗脱(40:1→1:1,v/v)，得到6个组分(Fr.1–Fr.6)。将收集得到的Fr.4部分经过RP-18反相柱层析，用甲醇-水梯度洗脱(2:8→1:0，v/v)，得到6 个组分Fr.4.1–Fr.4.6。Fr.4.3采用凝胶柱层析(Sephadex LH-20)，以氯仿：甲醇(1:1，v/v)为洗脱剂，然后通过半制备高效液相色谱(HPLC)，以乙腈 -水为流动相，采用等度洗脱的方法(乙腈浓度45％，v/v)进行制备可得到 sarcglabralideA和sarcglabralideB。Fr.4.5采用正相硅胶柱层析，以氯仿 -甲醇(30:1，v/v)进行洗脱得到sarcglabralideC。
SarcglabralideA的物理常数和波谱数据：黄色胶状物；
UV(MeOH)λmax(logε)216(2.93)nm；CD(MeOH)λmax(Δε) 225(3.50)nm；IR(KBr)νmax 3440,2925,2853,1720,1632,1454,1384,1263, 1128cm-1；1H NMR(CDCl3,600MHz)δ2.06(1H,dt,J＝9.1,5.2Hz,H-1), 0.83(1H,m,H-2α),1.72(1H,m,H-2β),1.67(1H,o,H-3),4.26(1H,s,H-9), 1.34(3H,s,H3-13),1.06(3H,s,H3-14),1.58(1H,m,H-15α),2.64(1H,dd,J ＝14.6,3.7Hz,H-15β),1.67(1H,o,H-1′),0.64(1H,td,J＝8.9,5.5Hz, H-2′α),1.17(1H,m,H-2′β),1.70(1H,o,H-3′),1.82(1H,o,H-5′),1.91(1H, d,J＝12.8Hz,H-6′α),1.80(1H,d,J＝12.8Hz,H-6′β),2.83(1H,dd,J＝ 13.5,3.8Hz,H-9′),6.55(1H,s,H-13′a),5.70(1H,s,H-13′b),0.91(3H,s, H3-14′),4.07(1H,d,J＝11.0Hz,H-15′a),3.93(1H,d,J＝11.0Hz,H-15′b), 6.88(1H,q,J＝7.1Hz,H-3″),1.82(3H,d,J＝7.1Hz,H3-4″),1.85(3H,s, H3-5″),6.12(1H,s,H-1″′),3.47(3H,s,MeO-1″′),3.77(3H,s,MeO-12)；13CNMR(CDCl3,150MHz)δ31.9(C-1,d),9.5(C-2,t),27.2(C-3,d),92.6 (C-4,s),90.2(C-5,s),148.1(C-6,s),143.1(C-7,s),198.1(C-8,s),81.2(C-9, d),54.8(C-10,s),63.3(C-11,s),173.0(C-12,s),25.6(C-13,q),14.3(C-14, q),33.2(C-15,t),27.1(C-1′,d),10.8(C-2′,t),29.3(C-3′,d),78.7(C-4′,s), 53.1(C-5′,d),33.2(C-6′,t),57.7(C-7′,s),95.9(C-8′,s),50.0(C-9′,d),41.5 (C-10′,s),143.5(C-11′,s),167.6,(C-12′,s),126.6(C-13′,t),23.8(C-14′,q), 69.4(C-15′,t),168.0(C-1″,s),128.4(C-2″,s),138.2(C-3″,d),14.6(C-4″, q),12.3(C-5″,q),121.2(C-1″′,d),54.1(MeO-1″′,q),53.3(MeO-12,q)。 HRESIMS m/z 727.2537[M+Cl]-(calcd.for C38H44O12Cl,727.2527)。
Sarcglabralide B的物理常数和波谱数据：黄色胶状物；
UV(MeOH)λmax(logε)220(3.13)nm；CD(MeOH)λmax(Δε) 223(14.8),333(–1.04)nm；IR(KBr)νmax 3446,2928,2854,1714,1643, 1441,1381,1263,1132cm-1；1H NMR(CDCl3,500MHz)δ2.03(1H,dt,J＝ 8.6,5.0Hz,H-1),0.73(1H,m,H-2α),0.81(1H,m,H-2β),2.28(1H,ddd,J＝ 8.6,5.9,3.6Hz,H-3),4.23(1H,s,H-9),1.33(3H,s,H3-13),1.02(3H,s,H3-14),1.40(1H,t,J＝14.3Hz,H-15α),3.31(1H,dd,J＝14.6,3.1Hz, H-15β),1.58(1H,m,H-1′),0.61(1H,td,J＝8.9,5.5Hz,H-2′α),1.14(1H,m, H-2′β),1.69(1H,m,H-3′),1.76(1H,s,H-5′),1.92(1H,d,J＝11.5Hz, H-6′α),1.75(1H,d,J＝11.5Hz,H-6′β),2.42(1H,dd,J＝13.9,3.0Hz,H-9′), 6.56(1H,s,H-13′a),5.72(1H,s,H-13′b),0.86(3H,s,H3-14′),4.06(1H,d,J ＝11.0Hz,H-15′a),3.89(1H,d,J＝11.0Hz,H-15′b),6.87(1H,q,J＝7.1Hz, H-3″),1.81(3H,d,J＝7.1Hz,H3-4″),1.84(3H,s,H3-5″),2.23(1H,q, H-2″′),3.77(3H,s,MeO-12)；3.18(1H,s,5-OH),3.42(1H,d,J＝4.0Hz, 9-OH)；13C NMR(CDCl3,125MHz)δ29.9(C-1,d),7.7(C-2,t),27.1(C-3, d),89.4(C-4,s),78.6(C-5,s),150.3(C-6,s),141.3(C-7,s),198.1(C-8,s), 80.9(C-9,d),54.6(C-10,s),63.3(C-11,s),173.0(C-12,s),25.7(C-13,q), 13.7(C-14,q),31.7(C-15,t),27.1(C-1′,d),10.9(C-2′,t),29.3(C-3′,d),78.7 (C-4′,s),52.8(C-5′,d),32.9(C-6′,t),57.4(C-7′,s),96.7(C-8′,s),50.1(C-9′, d),41.3(C-10′,s),142.9(C-11′,s),167.6,(C-12′,s),127.1(C-13′,t),24.1(C-14′,q),69.4(C-15′,t),168.0(C-1″,s),128.4(C-2″,d),138.2(C-3″,d), 14.6(C-4″,q),12.3(C-5″,q),169.3(C-1″′,s),22.2(Me-2″′,q),53.3 (MeO-12,q)。HRESIMS m/z715.2723[M+Na]+(calcd.for C38H44O12Na, 715.2725)。
Sarcglabralide C的物理常数和波谱数据：黄色胶状物；
UV(MeOH)λmax(logε)214(3.24)nm；CD(MeOH)λmax(Δε) 260(5.93),212(–9.53),343(–1.58)nm；IR(KBr)νmax 3440,2955,2924, 1738,1636,1437,1382,1241,1126cm-1；1H NMR(CDCl3,600MHz)δ2.05 (1H,m,H-1),0.98(1H,m,H-2α),0.28(1H,m,H-2β),1.83(1H,o,H-3), 3.91(1H,s,H-6),3.93(1H,s,H-9),1.88(3H,s,H3-13),1.01(3H,s,H3-14), 2.59(1H,dt,J＝16.5,5.1Hz,H-15α),2.75(1H,d,J＝16.5Hz,H-15β),1.58 (1H,o,H-1′),0.72(1H,td,J＝8.7,6.0Hz,H-2′α),1.28(1H,m,H-2′β),1.43 (1H,td,J＝8.6,3.6Hz,H-3′),1.75(1H,dd,J＝13.8,5.8Hz,H-5′),2.41(1H, dd,J＝18.4,5.8Hz,H-6′α),2.72(1H,dd,J＝18.4,13.8Hz,H-6′β),1.83 (1H,o,H-9′),4.81(1H,s,H-13′a),4.81(1H,s,H-13′b),0.86(3H,s,H3-14′), 4.06(1H,d,J＝11.6Hz,H-15′a),3.75(1H,d,J＝11.6Hz,H-15′b),2.13 (3H,s,H3-2″),2.09(3H,s,H-2″′),3.78(3H,s,MeO-12)；13C NMR(CDCl3,150MHz)δ25.5(C-1,d),16.0(C-2,t),24.8(C-3,d),142.4(C-4,s),131.7 (C-5,s),40.9(C-6,d),131.4(C-7,s),200.5(C-8,s),80.4(C-9,d),51.3 (C-10,s),148.0(C-11,s),170.6(C-12,s),20.6(C-13,q),15.3(C-14,q),25.4 (C-15,t),25.8(C-1′,d),12.0(C-2′,t),28.2(C-3′,d),77.2(C-4′,s),60.7 (C-5′,d),23.0(C-6′,t),171.5(C-7′,s),93.3(C-8′,s),55.9(C-9′,d),44.8 (C-10′,s),123.7(C-11′,s),172.3,(C-12′,s),55.2(C-13′,t),26.5(C-14′,q), 71.6(C-15′,t),170.7(C-1″′,s),20.6(C-2″′,q),52.8(MeO-12,q)。HRESIMS m/z 659.2465[M+Na]+(calcd.for C35H40O11Na,659.2463)。
实施例2：化合物sarcglabralidesA–C的制备方法二
草珊瑚(S.glabra)全株(干燥)，粉碎后用95％乙醇按有机溶剂和植物材料的体积比为2:1加热回流提取3次，每次2小时，合并提取液后减压蒸馏回收至小体积(乙醇浓度约为25％-30％)，再过LS-700B大孔树脂柱，先用5个柱体积蒸馏水洗脱除去糖，再用75％乙醇洗脱，回收乙醇溶剂得到膏状提取物。膏状经MCI柱层析，用甲醇-水梯度洗脱(3:7、5:5、8:2， v/v)，每个梯度4～6个柱体积，得到3个组分(Fr.1–Fr.3)。将收集得到的 Fr.2部分采用正相硅胶柱层析(硅胶用量与样品的质量比为20:1)，以石油醚-乙酸乙酯为洗脱剂进行梯度洗脱(每个梯度3～5个柱体积)，得到六个部分即：Fr.2.1(石油醚：乙酸乙酯＝1:0，v/v)、Fr.2.2(石油醚：乙酸乙酯＝50:1，v/v)、Fr.2.3(石油醚：乙酸乙酯＝25:1，v/v)、Fr.2.4(石油醚：乙酸乙酯＝10:1，v/v)、Fr.2.5(石油醚：乙酸乙酯＝5:1，v/v)；Fr.2.6(石油醚：乙酸乙酯＝0:1，v/v)；Fr.2.5采用凝胶柱层析(Sephadex LH-20)，以氯仿：甲醇(1:1，v/v)为洗脱剂，然后通过半制备高效液相色谱(HPLC)，以乙腈-水为流动相，采用梯度洗脱的方法(乙腈浓度20％→60％，v/v)进行制备得到sarcglabralide A、sarcglabralide B和sarcglabralide C。
实施例3：化合物sarcglabralidesA–C的制备方法三
草珊瑚(S.glabra)枝叶(干燥)，粉碎后用甲醇在室温下按有机溶剂和植物材料的体积比为5:1，冷浸提取3次，2天/次，合并提取液后减压蒸馏得到膏状提取物。合并提取液后减压蒸馏回收溶剂得浸膏，浸膏过中压色谱分离凝胶(MCI Gel)柱层析，用甲醇-水梯度洗脱(2:8、5:5、8:2， 10:0，v/v)，每个梯度4～6个柱体积，得到3个组分(Fr.1–Fr.,4)。将收集得到的Fr.2部分采用正相硅胶柱层析(硅胶用量与样品的质量比为20:1)，以氯仿-甲醇为洗脱剂进行梯度洗脱(100:1→1:1,v/v)，得到五个部分得到 5个组分Fr.2.1–Fr.2.5。；Fr.2.4采用凝胶柱层析(Sephadex LH-20)，以氯仿：甲醇(1:1，v/v)为洗脱剂，然后通过半制备高效液相色谱(HPLC)，以乙腈-水为流动相，采用梯度洗脱的方法(乙腈浓度30％→55％，v/v)进行制备得到sarcglabralide A、sarcglabralide B和sarcglabralide C。
实施例4：化合物sarcglabralides A–C的制备方法四
海南草珊瑚(S.hainanensis)全株(干燥)，粉碎后用甲醇在室温下按有机溶剂和植物材料的体积比为4:1，超声波提取2次，合并提取液后减压蒸馏得到膏状提取物。膏状提取物经硅胶柱层析，用石油醚-乙酸乙酯梯度洗脱(1:0→0:1,v/v)，得到8个组分(Fr.1–Fr.8)。将收集得到的Fr.5部分经过中压色谱分离凝胶(MCI Gel)柱层析，用甲醇-水梯度洗脱(2:8→10:0， v/v)，得到5个组分Fr.5.1–Fr.5.5。将Fr.5.2采用凝胶柱层析(SephadexLH-20)，以甲醇为洗脱剂，然后通过半制备高效液相色谱(HPLC)，以乙腈-水为流动相，采用梯度洗脱的方法(乙腈浓度30％→45％，v/v)进行制备可得到sarcglabralide A–C。
实施例5：SarcglabralidesA–C的抗炎活性
一氧化氮(nitric oxide,NO)具有广泛而重要的生物学调控功能，在炎症、肿瘤及心血管***等均有重要作用。当免疫细胞遭受微生物内毒素、炎症介质等刺激时，会生成大量的诱导型一氧化氮合成酶(induced NO synthase，iNOS)，产生NO进行免疫应答，因此抑制NO生成是化合物抗炎活性的直接指标。
将RAW264.7细胞接种至96孔板，用1μg/ml LPS进行诱导刺激，同时加入待测化合物(终浓度50μg/ml)处理，设置不含药物组和L-NMMA阳性药物组做对照。细胞过夜培养后取培养基检测NO生成，在570nm处测定吸光值。在剩余培养基中加入MTS进行细胞存活率检测，排除化合物对细胞的毒性影响。
NO生成抑制率(％)＝(非药物处理组OD570nm–样品组OD570nm)/非药物处理组OD570nm×100％
IC50(半抑制浓度)按Reed&Muench法计算。
实验结果如表1和表2所示，sarcglabralidesA–C具有显著的抗NO 生成活性，它们的IC50值分别是16.60、13.43和17.19μM，是阳性对照药L-NMMA(41.33μM)的2.4–3.1倍。
表1.sarcglabralidesA–C对NO生成抑制率(％)
aL-NMMA为阳性对照药
表2.sarcglabralidesA–C抑制NO生成的IC50值
aL-NMMA为阳性对照药。
Claims (9)
1.乌药烷型二聚倍半萜(sarcglabralides)，其特征在于，具有以下结构式I、Ⅱ或Ⅲ：
2.一种用于治疗炎性疾病的药物组合物，其特征在于，包含作为活性药物成分的权利要求1所述的化合物sarcglabralidesA、B或C或其药学上可接受的衍生物，以及药学上可接受的载体、佐剂或赋形剂。
3.权利要求1所述的化合物乌药烷型二聚倍半萜或其药学上可接受的衍生物在制备用于治疗炎性疾病的药物中的应用。
4.制备权利要求1所述乌药烷型二聚倍半萜的方法，其特征在于，包括以下步骤：
1)将草珊瑚属(Sarcandra)植物材料干燥粉碎，采用有机溶剂提取后脱溶，得到草珊瑚属植物材料提取物；
2)对所述草珊瑚属植物材料提取物依次采用柱层析、半制备高效液相色谱，得到化合物sarcglabralides A–C。
5.根据权利要求4所述的方法，其特征在于，所述草珊瑚属植物材料是草珊瑚(S.glabra)或海南草珊瑚(S.hainanensis)的根、茎、枝叶、果实或全株。
6.根据权利要求4所述的方法，其特征在于，在步骤1)中，所述有机溶剂提取法包括有机溶剂室温冷浸法、有机溶剂加热回流法或超声法；所述有机溶剂和草珊瑚植物材料的体积比为1:1到5:1，优选3:1。
7.根据权利要求4所述的方法，其特征在于，在步骤1)，中所述有机溶剂包括石油醚、氯仿、二氯甲烷、乙酸乙酯、丙酮、乙醇、甲醇、正丁醇和乙腈中的至少一种。优选地，所述有机溶剂包括乙酸乙酯、甲醇或95％乙醇。
8.根据权利要求4所述的方法，其特征在于，在步骤2)中，所述柱层析包括正相硅胶柱层析、反相硅胶柱层析、树脂柱层析、凝胶柱层析、中压色谱分离凝胶(MCI Gel)和制备或半制备高效液相色谱(HPLC)。
9.根据权利要求4所述的方法，其特征在于，在步骤2)中，柱层析所用洗脱剂包括石油醚、氯仿、二氯甲烷、乙酸乙酯、丙酮、乙醇、甲醇、正丁醇、乙腈、水和甲酸中的一种或两种以上的组合；正相硅胶柱层析采用石油醚和乙酸乙酯按体积比从1:0到0:1梯度洗脱；或正相硅胶柱层析采用氯仿和甲醇按体积比从100:1到1:1梯度洗脱；反相RP-18柱层析采用乙腈和水按体积比从2:8到1:0梯度洗脱；凝胶柱层析采用甲醇、氯仿与甲醇(1:1，v/v)洗脱；中压色谱分离凝胶(MCI Gel)采用甲醇和水按体积比从2:8到1:0梯度洗脱；制备或半制备HPLC采用乙腈和水按体积比从2:8到6:4梯度洗脱。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111486837.8A CN114057764B (zh) | 2021-12-07 | 2021-12-07 | 具有抗炎活性的乌药烷型二聚倍半萜及其制备方法和用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111486837.8A CN114057764B (zh) | 2021-12-07 | 2021-12-07 | 具有抗炎活性的乌药烷型二聚倍半萜及其制备方法和用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114057764A true CN114057764A (zh) | 2022-02-18 |
| CN114057764B CN114057764B (zh) | 2023-09-08 |
Family
ID=80228851
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111486837.8A Active CN114057764B (zh) | 2021-12-07 | 2021-12-07 | 具有抗炎活性的乌药烷型二聚倍半萜及其制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114057764B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116730957A (zh) * | 2023-08-11 | 2023-09-12 | 山东省食品药品检验研究院 | 一种乌药烷型倍半萜二聚体及其制备方法与应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101712184B1 (ko) * | 2015-12-31 | 2017-03-06 | 한국과학기술연구원 | Nrf2 활성화 효능의 세스퀴터핀 화합물 및 이를 유효성분으로 포함하는 약학조성물 |
-
2021
- 2021-12-07 CN CN202111486837.8A patent/CN114057764B/zh active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101712184B1 (ko) * | 2015-12-31 | 2017-03-06 | 한국과학기술연구원 | Nrf2 활성화 효능의 세스퀴터핀 화합물 및 이를 유효성분으로 포함하는 약학조성물 |
Non-Patent Citations (5)
| Title |
|---|
| BAI BAI, ET AL.: "Chloraserrtone A, a Sesquiterpenoid Dimer from Chloranthus serratus", 《JOURNAL OF NATURAL PRODUCTS》, vol. 82, no. 2, pages 407 - 411 * |
| MI ZHANG, ET AL.: "Anti-inflammatory sesquiterpenes and sesquiterpene dimers from Chloranthus fortunei", 《JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH》, vol. 14, no. 7, pages 708 - 712 * |
| SHANSHAN WEI, ET AL.: "Anti-inflammatory lindenane sesquiterpeniods and dimers from Sarcandra glabra and its upregulating AKT/Nrf2/HO-1 signaling mechanism", 《INDUSTRIAL CROPS & PRODUCTS》, vol. 137, pages 367 - 376 * |
| XIU-FENG HE, ET AL.: "Sarcanolides A and B: Two sesquiterpenoid dimers with a nonacyclic scaffold from Sarcandra hainanensis", 《TETRAHEDRON》, vol. 67, no. 18, pages 3170 - 3174 * |
| 陈芳有: "草珊瑚化学成分及生物活性研究进展", 《中国中药杂志》, vol. 47, no. 4, pages 872 - 879 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116730957A (zh) * | 2023-08-11 | 2023-09-12 | 山东省食品药品检验研究院 | 一种乌药烷型倍半萜二聚体及其制备方法与应用 |
| CN116730957B (zh) * | 2023-08-11 | 2023-10-20 | 山东省食品药品检验研究院 | 一种乌药烷型倍半萜二聚体及其制备方法与应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114057764B (zh) | 2023-09-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1800685A1 (en) | Steroidal saponin pharmaceutical composition, its preparation method and use | |
| US20020040050A1 (en) | Immunosuppressive agents | |
| CN109293729B (zh) | 两种甾体类化合物和一种三萜类化合物及其提取方法与应用 | |
| CN112979727B (zh) | 达玛烷型四环三萜化合物及其提取方法和应用 | |
| WO2017220042A2 (zh) | 氨力农的药物组合物及其在高血压治疗中的应用 | |
| KR101449796B1 (ko) | 헤디치움 코로나리움 유래 랍단 디터펜 화합물 및 이의 용도 | |
| CN114057764B (zh) | 具有抗炎活性的乌药烷型二聚倍半萜及其制备方法和用途 | |
| CN103626824B (zh) | 一种雪胆葫芦烷型四环三萜化合物,含有该化合物的药物组合物及其应用 | |
| WO2017219510A1 (zh) | 一种具有抗肿瘤活性和抗炎活性的醌式查尔酮碳苷二聚体化合物及其制备方法 | |
| CN108689851B (zh) | 一类惕各烷型二萜化合物及其制备方法和应用 | |
| Peng et al. | Biologically active secoiridoids: A comprehensive update | |
| CN106220701A (zh) | 三萜化合物及其制备方法与应用 | |
| CN116606269B (zh) | 米团花二倍半萜化合物与提取物l01及其在制药中的应用 | |
| JP2006503102A (ja) | 糖尿病の予防および治療のための天然化合物、その調製方法、およびその薬物的使用。 | |
| CN109180632B (zh) | 一种从雷公藤中分离出的化合物的制备方法 | |
| CN111909228B (zh) | 一种生物碱类化合物及其制备方法和应用 | |
| KR101780939B1 (ko) | 인삼 유래 화합물 분리방법 및 이를 이용한 항염증 조성물 | |
| KR101745504B1 (ko) | 잠분으로부터 항암 활성을 갖는 보미폴리올 및 스티그마스테롤을 분리하는 방법 | |
| CN114213375A (zh) | 一种倍半萜内酯化合物及其制备方法与应用 | |
| CN107163009A (zh) | 灵芝杂萜化合物、其药用组合物及其应用 | |
| CN106822088B (zh) | 一种双烯环烯醚萜化合物在制备抗癌药物中的用途 | |
| CN105777839B (zh) | 一种抗肿瘤化合物、其提取方法及其应用 | |
| CN114533719B (zh) | 松香烷型二萜类化合物在制备抗炎药物中的应用 | |
| JPH1087692A (ja) | 三七人参由来の新規サポニン配糖体 | |
| WO2017220051A2 (zh) | 盐酸苄丝肼的药物组合物及其降血糖的医药用途 |
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 | ||
| OL01 | Intention to license declared |