CN111110687A - 一种抗脂代谢紊乱的合欢皮新木脂体化合物 - Google Patents
一种抗脂代谢紊乱的合欢皮新木脂体化合物 Download PDFInfo
- Publication number
- CN111110687A CN111110687A CN201910944109.3A CN201910944109A CN111110687A CN 111110687 A CN111110687 A CN 111110687A CN 201910944109 A CN201910944109 A CN 201910944109A CN 111110687 A CN111110687 A CN 111110687A
- Authority
- CN
- China
- Prior art keywords
- agent
- metabolism disorder
- compound
- lipid metabolism
- use according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000017170 Lipid metabolism disease Diseases 0.000 title claims abstract description 15
- 240000007185 Albizia julibrissin Species 0.000 title abstract description 9
- 235000011468 Albizia julibrissin Nutrition 0.000 title abstract description 9
- 229930013686 lignan Natural products 0.000 title abstract description 7
- 235000009408 lignans Nutrition 0.000 title abstract description 7
- -1 lignan compound Chemical class 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 5
- 206010019708 Hepatic steatosis Diseases 0.000 claims abstract description 4
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229930186217 Glycolipid Natural products 0.000 claims abstract description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 3
- 201000010099 disease Diseases 0.000 claims abstract description 3
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims description 9
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 3
- 102000007330 LDL Lipoproteins Human genes 0.000 claims description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 235000012000 cholesterol Nutrition 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 235000013305 food Nutrition 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 3
- 230000002745 absorbent Effects 0.000 claims 1
- 239000002250 absorbent Substances 0.000 claims 1
- 239000000853 adhesive Substances 0.000 claims 1
- 230000001070 adhesive effect Effects 0.000 claims 1
- 230000000181 anti-adherent effect Effects 0.000 claims 1
- 239000002518 antifoaming agent Substances 0.000 claims 1
- 239000011248 coating agent Substances 0.000 claims 1
- 238000000576 coating method Methods 0.000 claims 1
- 239000003086 colorant Substances 0.000 claims 1
- 239000006184 cosolvent Substances 0.000 claims 1
- 239000007884 disintegrant Substances 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 239000003995 emulsifying agent Substances 0.000 claims 1
- 238000005538 encapsulation Methods 0.000 claims 1
- 239000000945 filler Substances 0.000 claims 1
- 239000000796 flavoring agent Substances 0.000 claims 1
- 239000008394 flocculating agent Substances 0.000 claims 1
- 239000004088 foaming agent Substances 0.000 claims 1
- 235000013355 food flavoring agent Nutrition 0.000 claims 1
- 239000003205 fragrance Substances 0.000 claims 1
- 239000003906 humectant Substances 0.000 claims 1
- 230000010354 integration Effects 0.000 claims 1
- 239000000314 lubricant Substances 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 230000003204 osmotic effect Effects 0.000 claims 1
- 239000003961 penetration enhancing agent Substances 0.000 claims 1
- 239000004014 plasticizer Substances 0.000 claims 1
- 239000003755 preservative agent Substances 0.000 claims 1
- 230000002335 preservative effect Effects 0.000 claims 1
- 239000003380 propellant Substances 0.000 claims 1
- 239000003381 stabilizer Substances 0.000 claims 1
- 239000004094 surface-active agent Substances 0.000 claims 1
- 239000000375 suspending agent Substances 0.000 claims 1
- 239000002562 thickening agent Substances 0.000 claims 1
- 239000000080 wetting agent Substances 0.000 claims 1
- 235000021588 free fatty acids Nutrition 0.000 abstract description 10
- 208000015707 frontal fibrosing alopecia Diseases 0.000 abstract description 10
- 150000002632 lipids Chemical class 0.000 abstract description 8
- 230000007863 steatosis Effects 0.000 abstract description 7
- 231100000240 steatosis hepatitis Toxicity 0.000 abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
- 238000010828 elution Methods 0.000 description 22
- 239000012071 phase Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000000926 separation method Methods 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- 229910001868 water Inorganic materials 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241000026010 Dendrobium candidum Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 3
- 150000005692 lignans Chemical class 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 238000000825 ultraviolet detection Methods 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000000287 crude extract Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- BUBVKRMIMSPLND-UHFFFAOYSA-N (-)-syringaresinol 4-O-beta-D-apiofuranosyl-(1->2)-beta-D-glucopyranoside Natural products COC1=C(O)C(OC)=CC(C2C3C(C(OC3)C=3C=C(OC)C(OC4C(C(O)C(O)C(CO)O4)OC4C(C(O)(CO)CO4)O)=C(OC)C=3)CO2)=C1 BUBVKRMIMSPLND-UHFFFAOYSA-N 0.000 description 1
- ITOWTHYPYGRTRL-SYHAXYEDSA-N (2r,3s,4s,5r,6r)-2-(hydroxymethyl)-6-propoxyoxane-3,4,5-triol Chemical compound CCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O ITOWTHYPYGRTRL-SYHAXYEDSA-N 0.000 description 1
- YSCJAYPKBYRXEZ-HZPINHDXSA-N (2s,3s,4s,5r,6r)-6-[[(3s,4ar,6ar,6bs,8as,12as,14ar,14br)-4,4,6a,6b,11,11,14b-heptamethyl-8a-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxycarbonyl-1,2,3,4a,5,6,7,8,9,10,12,12a,14,14a-tetradecahydropicen-3-yl]oxy]-3-hydroxy-4-[(2s,3r,4s, Chemical compound O([C@H]1[C@H](O)[C@H](O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2C1(C)C)C)(C)CC[C@]1(CCC(C[C@H]14)(C)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)C(O)=O)[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O YSCJAYPKBYRXEZ-HZPINHDXSA-N 0.000 description 1
- 241000220433 Albizia Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000220485 Fabaceae Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002021 butanolic extract Substances 0.000 description 1
- 230000001914 calming effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000001044 red dye Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Botany (AREA)
- Microbiology (AREA)
- Food Science & Technology (AREA)
- Biotechnology (AREA)
- Alternative & Traditional Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Nutrition Science (AREA)
- Medical Informatics (AREA)
- Polymers & Plastics (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种抗脂代谢紊乱的合欢皮新木脂体化合物，属于生物医药技术领域。本发明制备的化合物在浓度为可有效治疗FFAs诱导的脂代谢紊乱及脂肪变性，在给药浓度为20μM，给药24h可以使脂滴面积减少约3倍，可用于制备脂代谢紊乱相关疾病包括糖尿病引起的糖脂代谢紊乱，或肝脂肪变性，或非酒精性脂肪肝疾病。
Description
技术领域
本发明涉及一种抗脂代谢紊乱的合欢皮新木脂体化合物，属于生物医药技术领域。
背景技术
合欢皮(Albiziae Cortex)是豆科植物合欢(Albzia julibrissin Durazz)的树皮，是一种较为常用的中药，性味甘、平，具有解郁、和血、宁心和消肿之功效。近年来，随着学者对合欢皮的深入研究，其化学成分和药理药效活性不断的被发现。
迄今为止,已从合欢属植物中分离出多种化合物,其中包括三萜、黄酮、木脂素类等。有文献表明，合欢皮中的木脂素类成分含量较低，对于综合评价合欢皮水溶性木脂素类成分的提取纯化工艺造成了一定的困难。同时，合欢皮常作为复方药物的一剂组分，极少单独应用，因而其含有的各类化学成分的药理活性尚不明确。
发明内容
本发明的第一个目的是提供结构式如式1所示化合物在制备预防和/或治疗脂代谢紊乱及其相关疾病的药物中的应用；
在一种实施方式中，所述脂代谢紊乱相关疾病包括糖尿病引起的糖脂代谢紊乱、肝脂肪变性或非酒精性脂肪肝疾病。
在一种实施方式中，所述药物含有式1所示化合物的药用盐或药用溶剂化物。
在一种实施方式中，所述组合物还含有药学上可接受的载体。
在一种实施方式中，所述药学上可接受的载体包括稀释剂、赋形剂或溶剂化物。
在一种实施方式中，所述药物组合物的剂型为片剂、胶囊、颗粒剂、散剂、糖浆剂、口服液或注射剂。
本发明还要求保护所述化合物在制备用于降低胆固醇、甘油三酯、低密度脂蛋白的食品、药品或保健品中的应用。
有益效果：本发明的化合物在浓度≥20μM的用量下可有效治疗FFAs诱导的脂代谢紊乱及脂肪变性，在给药浓度为20μM，给药24h可以使脂滴面积减少约3倍。
附图说明
图1为10:1洗脱段分析型高效液相色谱图。
图2为10:1组分Davisil C18反向柱42％CH3OH洗脱段半备型高效液相色谱图。
图3为化合物Aj4的1H-NMR色谱图。
图4为化合物Aj4的13C-NMR色谱图。
图5为albioside A的HR-ESI-MS色谱图。
图6A为化合物albioside A抑制FFAs诱导的脂滴生成(×400)；B为脂滴堆积面积值；其中，*P<0.05与对照组相比，#P<0.05与FFAs组相比，n＝3/组。
图7为8:1洗脱段分析型高效液相色谱图。
图8为8:1组分Davisil C18反向柱32％CH3OH洗脱段半备型高效液相色谱图。
图9为化合物Aj7的HR-ESI-MS色谱图。
图10为化合物Aj7的1H-NMR色谱图。
图11为化合物Aj7的13C-NMR色谱图。
具体实施方式
实施例1化合物的制备
(1)提取：取干燥合欢皮20kg,粉碎，用5倍75％乙醇(水)即每次100L，80℃回流提取2次，每次2小时。过滤除去合欢皮残渣，合并合欢皮75％乙醇提取液，冷冻干燥，得合欢皮乙醇粗提物1.6kg。将粗提物研碎，混悬于2L去离子水中，使其尽可能溶解。混悬后依次用乙酸乙酯及饱和正丁醇萃取，萃取采用每次添加乙酸乙酯和饱和正丁醇少量多次的原则，分别合并乙酸乙酯相及饱和正丁醇相的萃取液，得乙酸乙酯部位和正丁醇部位提取物。
(2)分离：取正丁醇部位254g，用去离子水溶解混悬，采用D101大孔吸附树脂进行分离纯化，分别用2～3倍柱体积的乙醇-水混合溶液为流动相进行梯度洗脱，富集30％乙醇洗脱段、50％乙醇洗脱段、70％乙醇洗脱段、95％乙醇洗脱段。大孔吸附树脂30％乙醇洗脱段经硅胶硅胶柱层析，以二氯甲烷-甲醇混合液为流动相，采用梯度溶剂二氯甲烷(CH2Cl2)：甲醇 (CH3OH)＝(40:1,20:1,16:1,10:1,8:1和6:1)进行梯度洗脱，分别以4倍柱体积左右的流动相进行洗脱，用250ml锥形瓶分别收集洗脱液，经TLC检测合并相同组分，得各洗脱段。
对硅胶10:1洗脱段进行分析型高效液相(HPLC)检测(色谱柱为X-Bridge C18,5μm，4.6×250mm，流速为1ml/min，柱温30℃),紫外检测波长为254nm，洗脱条件：
时间 CH3OH H2O
0min 5％ 95％
60min 100％ 0％
其结果如图1所示。根据图1液相检测条件下化合物的保留时间，确定硅胶10:1洗脱段中的化合物在C18反向柱上的洗脱条件所对应的保留时间为23min，30min，36min，60min，且各保留时间所对应的甲醇浓度为41％CH3OH，52％CH3OH，62％CH3OH，100％CH3OH。
将10:1洗脱段过反向硅胶柱(Davisil C18,50μm)，以甲醇和水为洗脱相进行洗脱。因为图1为分析型液相色谱图，色谱柱为X-Bridge C18(5μm,4.6×250mm),而DavisilC18反向柱填料为50μm，所以流动相甲醇浓度均减去10％。根据图1确定洗脱相组合为31％CH3OH, 42％CH3OH,52％CH3OH,100％CH3OH.对洗脱组分分别进行HPLC检测，根据分析型液相摸索42％CH3OH洗脱段的分离条件，确定最佳分离条件，如表1所示。最后对42％CH3OH洗脱段进行半制备液相分离(色谱柱为X-Bridge C18,5μm，10×250mm，流速为4ml/min，柱温 30℃)，其结果如图2所示，保留时间t＝26.50min处的化合物命名为albiosideA(Aj4)。
表1半制备液相色谱的不同分离条件
在表1所示的分离条件中，条件一、条件二及条件三无法有效分离Aj4，其保留时间附近具有杂峰干扰，分离条件四可较为有效分离化合物Aj4，本实验采用的分离条件在条件四的基础上进一步优化的最佳分离方法，其分离效果如图2所示。收集保留时间tR＝26.50min 处的化合物，75℃减压旋蒸，回收溶剂，真空干燥箱干燥得Aj4单体化合物。
(3)结构鉴定(图3～5所示)：Aj4为淡黄色粉末，通过UPLC-ESI-MS检测，ESI-MS m/z 633.1932[M+Cl-]，通过Monoisotopic Mass,Even Electron Ions确定其分子式为C28H38O14。
将样品Aj4用氘代甲醇溶解于核磁管中，采用全数字化核磁共振波谱仪测定1HNMR、13CNMR，其结果如下:
1H NMR(400MHz,CD3OD)δ6.76(2H,s,H-2’,6’),6.74(2H,s,H-2,6),6.56(1H,d,J＝16.0 Hz,H-7’),6.34(1H,dt,J＝15.8,5.5Hz,H-8’),4.81(1H,d,J＝7.2Hz,H-7),4.65(4H,s),4.29 (1H,dd,J＝9.0,4.8Hz,H-1”),4.24(2H,d,J＝5.4Hz,H-9’),3.96–3.88(2H,m),3.85(6H,s, 3,5-OMe),3.83(6H,s,3’,5’-OMe),3.77(1H,s),3.73–3.63(4H,m),3.60(1H,dd,J＝8.4,3.9Hz), 3.56–3.39(4H,m),3.22(s,1H).13C NMR(101MHz,CD3OD)δ153.08(C-3’,5’),152.39(C-3,5), 138.12(C-4’),134.99(C-4),134.13(C-1’),133.30(C-1),129.95(C-7’),128.51(C-8’),104.62(C-2,6), 104.26(C-1”),103.51(C-2’,6’),85.66(C-8),76.94(C-3”),76.37(C-5”),74.32(C-2”),72.64(C-7), 69.92(C-4”),62.16(C-9),61.17(C-9’),60.23(C-6”),55.61(3’,5’-OMe),55.28(3,5-OMe)。
根据质谱及1HNMR、13CNMR最终确定其结构如下，
化学名 2-[4-(3-Hydroxy-1-propenyl)-2,6-dimethoxy-phenoxy]-3-hydroxy-3-(4-hydroxy-3,5-dimethoxy-ph enyl)propyl-β-D-glucopyranoside.对其命名为合欢新木脂苷A(albiosideA，Aj4)。
实施例2改善脂代谢紊乱及脂肪变性
在含有25％葡萄糖、10％FBS(胎牛血清、Gibco)、100U/ml青霉素和100/ml链霉素的 DMEM中培养HepG2细胞(American Type Culture collection,USA)。在含有5％CO2的37℃恒温培养箱中培养。每1-2天更换培养基，将85-90％汇合的细胞以1：3汇合的比例传代。在所有实验中，细胞在第2代和第5代之间使用。取对数生长期的HepG2细胞，铺12孔板，每孔铺10万。待12h细胞贴壁生长后，弃去正常DMEM培养基，加入含有0.3mM FFAs(油酸:棕榈酸＝2:1,其中油酸用DMSO溶解，棕榈酸用超纯水75℃水浴溶解成40mM的溶解，在迅速与40％BSA的PBS溶解混匀，冷却过0.22μm无菌滤膜，用DMEM培养基稀释成0.3mM FFAs高脂培养基)的DMEM高脂培养基继续培养24h，即HepG2细胞被造模成为脂代谢紊乱模型后，每孔加入实施例1制备的化合物，给药浓度设置5个浓度梯度(其中以正常培养基培养的HepG2细胞为对照，对照组加相同体积的PBS作为空白对照组)，其余以5μM、 10μM、20μM、40μM、80μM的终浓度(albioside A用DMSO溶解成100mM，再分别用无菌PBS稀释，最后每孔加入20μL高浓度单体药物，使培养基终浓度为所设置浓度梯度)继续培养24h。
弃去12孔板的培养基，用PBS洗三遍，4％多聚甲醛固定30min，固定结束后以PBS充分洗涤，随后以60％异丙醇浸洗10～15秒，再以PBS洗三遍。以油红O染液(油红储存液：去离子水＝3：2)室温染色20～30min，显微镜下观察细胞着色情况，弃去油红染液，以60％异丙醇分化至间质清晰(分化约5～10秒即可，分化过度会导致油红O褪色)，最后以PBS 洗三遍，每孔加1ml PBS封片、拍照。
油红O染色结果如图6，与空白对照组脂滴面积100％相比，FFAs可显著诱导HepG2细胞脂滴累积及脂肪变性，此时脂滴面积与空白对照组相比平均为988.23％(*P<0.05，n＝3/ 组)，当给药24h后，给药浓度为10μM时，albioside A可有效减少脂滴的生成，当给药浓度为20μM时，与空白对照组相比脂滴平均面积为240.165％(与FFAs诱导组相比#P<0.05， n＝3/组)，说明albioside A可有效治疗FFAs诱导的脂代谢紊乱及脂肪变性。其中图6B，脂质堆积面积值使用Image-Pro Plus 6.0软件在相同参数下进行处理。
肝脂肪变性是2型糖尿病(T2DM)的显著特征，可能导致非酒精性脂肪肝疾病和心血管疾病。本实施例说明albioside A可有效治疗FFAs诱导的脂代谢紊乱及脂肪变性，可作为治疗非酒精性脂肪肝及相关肝细胞病变的潜在的天然药物，也可作为预防2型糖尿病及心血管疾病药物。
对比例1：
具体实施方式同实施例1，区别在于，对硅胶8:1洗脱段进行分析型高效液相(HPLC) 检测(色谱柱为X-Bridge C18,5μm，4.6×250mm，流速为1ml/min，柱温30℃),紫外检测波长为254nm，
洗脱条件：CH3OH H2O
0min 5％ 95％
60min 100％ 0％。
其检测结果如图7所示，根据图7的分析型高效液相色谱图中各组分的保留时间，确定对CH2Cl2:CH3OH＝8:1洗脱段进行过反向硅胶柱(Davisil C18,50μm)的洗脱条件为tR＝22min、 24min、26min，60min时所对应的CH3OH浓度39.8％、42.9％、46.2％、100％，因为图7为分析型液相色谱图，色谱柱为X-Bridge C18(5μm,4.6×250mm),而Davisil C18反向柱填料为 50μm，所以流动相甲醇浓度均减去10％，即29.8％、32.9％，36.2％，100％。以甲醇和水为洗脱相进行洗脱。根据图7确定洗脱相组合为29％CH3OH(H2O),32％CH3OH(H2O),36％CH3OH(H2O),100％CH3OH.对32％CH3OH洗脱组分进行分析型HPLC检测，摸索分离条件，以确定最佳分离方法。对32％CH3OH洗脱段进行半制备液相分离(色谱柱为X-Bridge C18,5μm，10×250mm，流速为4ml/min，柱温30℃)，如图8所示(UV检测波长290nm), 保留时间tR＝41.0min处的化合物为迭鞘石斛C(Picraquassioside C)(Aj7)，
Aj7为白色粉末，通过UPLC-ESI-MS检测，其质谱图如图9～11所示。HR-ESI-MS m/z633.1688[M+Cl]-，通过Monoisotopic Mass,Even Electron Ions确定其分子式为C28H38O14。将样品Aj7用氘代甲醇溶解于核磁管中，采用全数字化核磁共振波谱仪测定1H-NMR、13C-NMR，其结果如下:
1H-NMR(400MHz,CD3OD)δ6.76(2H,s,H-2,6),6.74(2H,s,H-2’,6’),6.57(1H,d, J＝15.8Hz,H-7’),6.33(1H,dt,J＝15.8,5.5Hz,H-8’),4.94(1H,d,J＝5.6Hz,H-7),4.81(1H,d,J ＝7.3Hz,H-1”),4.29(1H,dd,J＝9.0,4.8Hz,H-8),4.24(1H,d,J＝5.4Hz,H-9’),3.98–3.89 (2H,m),3.87(1H,s),3.85(6H,s,3,5-OMe),3.83(6H,s,3’,5’-OMe),3.77(1H,s),3.73–3.58(4H, m),3.52–3.41(4H,m),3.37(1H,s),3.22(s,2H).13C-NMR(101MHz,CD3OD)δ 153.09(C-3’,5’),152.40(C-3,5),138.12(C-1),135.02(C-4’),134.17(C-4),133.31(C-1’), 129.96(C-8’),128.53(C-7’),104.66(C-2,6),104.29(C-1”),103.55(C-2’,6’),85.68(C-8), 76.94(C-5”),76.39(C-3”),74.34(C-2”),72.67(C-7),69.95(C-4”),62.17(C-9’),61.20(C-6”), 60.25(C-9),55.63(3,5-OMe),55.31(3’,5’-OMe).
根据质谱及1HNMR、13CNMR最终确定其结构如下，中文名为迭鞘石斛C，英文名Picraquassioside C，与合欢新木脂苷A(albioside A)为互为同分异构体。
对比例2：
具体实施方式同实施例2，区别在于，若将albioside A替换成对比例1制备的迭鞘石斛C，虽然两者互为为同分异构体，结构类似，但迭鞘石斛C并不具有促进内皮血管新生、改善脂肪变性、抗氧化应激的药理活性。
虽然本发明已以较佳实施例公开如上，但其并非用以限定本发明，任何熟悉此技术的人，在不脱离本发明的精神和范围内，都可做各种的改动与修饰，因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (7)
1.结构式如式1所示的化合物在制备预防和/或治疗脂代谢紊乱及其相关疾病的药物中的应用；
2.根据权利要求1所述的应用，其特征在于，所述脂代谢紊乱相关疾病包括糖尿病引起的糖脂代谢紊乱，或肝脂肪变性，或非酒精性脂肪肝疾病。
3.根据权利要求1或2所述的应用，其特征在于，所述药物含有式1所示化合物的药用盐或药用溶剂化物。
4.根据权利要求1～3任一所述的应用，其特征在于，所述药物还含有药学上可接受的载体。
5.根据权利要求4所述的应用，其特征在于，所述药学上可接受的载体包括溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂或释放阻滞剂。
6.根据权利要求4或5所述的应用，其特征在于，剂型为片剂、胶囊、颗粒剂、散剂、糖浆剂、口服液或注射剂。
7.结构式如式1所示的化合物在制备用于降低胆固醇、甘油三酯、低密度脂蛋白的食品、药品或保健品中的应用；
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910944109.3A CN111110687A (zh) | 2019-09-30 | 2019-09-30 | 一种抗脂代谢紊乱的合欢皮新木脂体化合物 |
| PCT/CN2020/102544 WO2021063075A1 (zh) | 2019-09-30 | 2020-07-17 | 合欢皮木脂体化合物及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910944109.3A CN111110687A (zh) | 2019-09-30 | 2019-09-30 | 一种抗脂代谢紊乱的合欢皮新木脂体化合物 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111110687A true CN111110687A (zh) | 2020-05-08 |
Family
ID=70496042
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910944109.3A Pending CN111110687A (zh) | 2019-09-30 | 2019-09-30 | 一种抗脂代谢紊乱的合欢皮新木脂体化合物 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111110687A (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021063075A1 (zh) * | 2019-09-30 | 2021-04-08 | 江南大学 | 合欢皮木脂体化合物及应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590873B (zh) * | 2019-09-30 | 2020-12-01 | 江南大学 | 一种合欢皮新木脂体化合物 |
-
2019
- 2019-09-30 CN CN201910944109.3A patent/CN111110687A/zh active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590873B (zh) * | 2019-09-30 | 2020-12-01 | 江南大学 | 一种合欢皮新木脂体化合物 |
Non-Patent Citations (2)
| Title |
|---|
| KENSAKU TAKARA等: "New Phenolic Compounds from Kokuto , Non-centrifuged Cane Sugar.", 《BIOSCI. BIOTECHNOL. BIOCHEM.》 * |
| KOICHI MACHIDA等: "Structure elucidation and NMR spectral assignments of four neolignan glycosides with enantiometric aglycones from Osmanthus ilicifolius.", 《MAGN. RESON. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021063075A1 (zh) * | 2019-09-30 | 2021-04-08 | 江南大学 | 合欢皮木脂体化合物及应用 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110590873B (zh) | 一种合欢皮新木脂体化合物 | |
| CN110563781B (zh) | 一种合欢皮新木脂体单体化合物的制备方法 | |
| CN113105388B (zh) | 一种千金二萜烷化合物及其提取方法和应用 | |
| CN115716790B (zh) | 马齿苋中一种酰胺酯类生物碱的提取分离方法及其应用 | |
| CN107827726B (zh) | 马齿苋中化合物Oleracone E及其提取分离方法 | |
| CN111303154A (zh) | 马齿苋中一种具有抗炎活性生物碱及其提取分离方法与用途 | |
| CN108689851B (zh) | 一类惕各烷型二萜化合物及其制备方法和应用 | |
| CN110305084A (zh) | 马齿苋中一种含氮有机酸化合物及其提取分离方法与用途 | |
| CN111848565B (zh) | 单萜基双香豆素类化合物、药物组合物及其制备方法和用途 | |
| CN111110687A (zh) | 一种抗脂代谢紊乱的合欢皮新木脂体化合物 | |
| CN103494806B (zh) | 苯骈α-吡喃酮类化合物的应用及其制备方法 | |
| CN115521245B (zh) | 马齿苋中一种生物碱类化合物及其提取分离方法与应用 | |
| CN110638821A (zh) | 一种具有抗氧化活性的合欢皮新木脂体化合物及其应用 | |
| CN105837595A (zh) | 阿替洛尔的药物组合物及其在生物医药中的应用 | |
| CN110585221A (zh) | 一种改善脂肪变性的合欢皮新木脂体化合物及其应用 | |
| CN110559307A (zh) | 一种合欢皮新木脂体化合物及其新用途 | |
| CN110638822A (zh) | 一种促进内皮细胞增殖的合欢皮木脂素苷类化合物及应用 | |
| CN114989064A (zh) | 马齿苋中一种新型吡咯生物碱类化合物及其提取分离方法 | |
| CN110204589B (zh) | 青葙子有效成分、提取方法及其在制备神经保护药物方面的应用 | |
| CN114605422A (zh) | 一对对映体生物碱二聚体类化合物及其制备方法和应用 | |
| CN112851612A (zh) | 一种从牛蒡叶中提取的具有降低胆固醇活性化合物及其制备方法与应用 | |
| WO2021063075A1 (zh) | 合欢皮木脂体化合物及应用 | |
| TWI466674B (zh) | 臺灣梭羅木之生物活性組合物 | |
| WO2021063076A1 (zh) | 合欢皮木脂体化合物在改善脂肪变性方面的应用 | |
| CN109180632A (zh) | 一种从雷公藤中分离出的新化合物及其制备方法和医药用途 |
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 | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200508 |
|
| RJ01 | Rejection of invention patent application after publication |