CN105461625B - A kind of benzo pyridinone compounds and its preparation method and application - Google Patents
A kind of benzo pyridinone compounds and its preparation method and application Download PDFInfo
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- CN105461625B CN105461625B CN201510795499.4A CN201510795499A CN105461625B CN 105461625 B CN105461625 B CN 105461625B CN 201510795499 A CN201510795499 A CN 201510795499A CN 105461625 B CN105461625 B CN 105461625B
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 63
- 235000006386 Polygonum aviculare Nutrition 0.000 claims abstract description 19
- 241000028057 Cynanchum auriculatum Species 0.000 claims abstract description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 235000019441 ethanol Nutrition 0.000 claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 102000003425 Tyrosinase Human genes 0.000 claims abstract description 12
- 108060008724 Tyrosinase Proteins 0.000 claims abstract description 12
- 239000000284 extract Substances 0.000 claims abstract description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
- 238000002386 leaching Methods 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 238000000746 purification Methods 0.000 claims abstract description 6
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 241001377695 Polygonum arenastrum Species 0.000 claims abstract 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- 238000000926 separation method Methods 0.000 claims description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 238000010898 silica gel chromatography Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000003480 eluent Substances 0.000 claims description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- 241001289522 Fallopia Species 0.000 claims description 5
- 239000000287 crude extract Substances 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 8
- -1 formula (I) Chemical class 0.000 abstract description 8
- 239000002537 cosmetic Substances 0.000 abstract description 6
- 235000013402 health food Nutrition 0.000 abstract description 5
- 206010040829 Skin discolouration Diseases 0.000 abstract description 4
- 230000002087 whitening effect Effects 0.000 abstract description 4
- 238000011161 development Methods 0.000 abstract description 2
- 244000292697 Polygonum aviculare Species 0.000 description 15
- 238000010828 elution Methods 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 229960001866 silicon dioxide Drugs 0.000 description 9
- 238000000605 extraction Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 239000006187 pill Substances 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 235000008216 herbs Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000005299 pyridinones Chemical class 0.000 description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 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
- AKOGVJUSAFGQRH-UHFFFAOYSA-N 6,7-dimethoxy-2-methylisoquinoline-1,3,4-trione Chemical compound O=C1N(C)C(=O)C(=O)C2=C1C=C(OC)C(OC)=C2 AKOGVJUSAFGQRH-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 1
- 241000571089 Fezia pterocarpa Species 0.000 description 1
- 241000640209 Funastrum cynanchoides 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
- 206010028980 Neoplasm Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002034 butanolic fraction Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007941 film coated tablet Substances 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
- 235000013305 food Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000003929 heteronuclear multiple quantum coherence Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 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
- 235000009566 rice Nutrition 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
- C07D215/60—N-oxides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
-
- 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
-
- 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
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Birds (AREA)
- Dermatology (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of benzo pyridinone compounds and its preparation method and application.Shown in the structure of the benzo pyridinone compounds such as formula (I), preparation method includes：Cynanchum auriculatum Royle ex Wight knotweed herb after crushing is placed in organic solvent and is extracted, isolated leaching liquor, then leaching liquor is extracted, obtain extract after extract liquor is concentrated；Chromatography, purification process are carried out to extract, the benzo pyridinone compounds are made；Wherein, the organic solvent is one or more mixtures in methanol, ethyl alcohol, n-butanol and acetone.Present invention extracting and developing from cynanchum auriculatum Royle ex Wight knotweed herb obtains a kind of benzo pyridinone compounds with novel structure, the compound is preferable to tyrosinase inhibitory activity, inhibit drug, skin-lightening cosmetic or whitening health food available for preparing tyrosinase, there is good development prospect.
Description
Technical field
The present invention relates to active components of plants field more particularly to a kind of benzo pyridinone compounds and preparation method thereof and
Using.
Background technology
Cynanchum auriculatum Royle ex Wight knotweed (Classification system：Fallopia cynanchoides(Hemsl.)Harald.var.cynanchoide
s).Perennial herb.Stem is wound, 1-1.5 meter long, no vertical rib, close by brown pubescence and sparse to fall to grow bristle.The leaf width heart
Shape or wide halberd shape are heart-shaped, and 5-10 centimetres long, 3-8 centimetres wide, top is tapering, base portion innermost being shape, side life sliver round blunt or anxious point,
Edge full edge, have echinid, above the short strigose of sparsely grow, below it is close by the long pubescence of brown；Petiole is 3-5 centimetres long, close short by brown
Pubescence and sparse long bristle；Ochrea film quality, deflection, top point, dense bristle.Inflorescence is coniform, axillary or basidixed, long
10-15 centimetres, it is close by pubescence and it is sparse fall growth bristle；Bract is avette, and 1-1.5 millimeters long, top is tapering, by bristle,
Tool 2-4 flowers in per bud；5 drastic crack of perianth, light green, the wide ellipse of tapel are 1.5-2 millimeters long；Bennet is sturdy, long 2-2.5 millis
Rice, upper middle part have joint, dredge by pubescence；Stamen 8, shorter than perianth, filigree base portion is wider；Style 3, sturdy, base portion symphysis；Column
Head's shape, it is close by kick.Achene is avette, has 3 ribs, 2-2.5 millimeters long, black is glossy, is wrapped in persitent perianth.Florescence
The 8-9 months, the fruiting period 9-10 months【Hou Yuantong, Shandong Normal University's doctoral thesis 2006,290-295】.
Current study show that cynanchum auriculatum Royle ex Wight knotweed F.cynanchoides and adjacent kind of Fallopia xlipes (Hara)
It is mainly flavones ingredient in Holub and F.pterocarpa (Wall.ex Meisn.) Holub【Min-Ha Kim,Jin Hee
Park,Chong-Wook Park,Biochemical Systematics and Ecology 28(2000)433-441】.But
It is that pyridinone ingredient is not reported, for this purpose, the natural activity pyridone ingredient in research cynanchum auriculatum Royle ex Wight knotweed herb, can be ox
The disappear utilization of knotweed herb of skin provides new approaches.
Invention content
The present invention provides a kind of benzo pyridinone compounds, which obtains for extraction in the herb of cynanchum auriculatum Royle ex Wight knotweed
Natural active matter has antioxidant activity.
A kind of benzo pyridinone compounds, shown in structure such as formula (I)：
The benzo pyridinone compounds are the noval chemical compound that extracts and confirmed its structure from cynanchum auriculatum Royle ex Wight knotweed for the first time,
Result of study shows that the benzo pyridinone compounds have preferable inhibitory activity to tyrosinase, can effectively inhibit black
The synthesis of pigment, so as to the potentiality as skin-lightening cosmetic or whitening health food.
The present invention provides a kind of preparation methods of the benzo pyridinone compounds, include the following steps：
(1) using organic solvent to cynanchum auriculatum Royle ex Wight knotweed (the Fallopia cynanchoides (Hemsl.) after crushing
Harald.var.cynanchoides) herb is extracted to obtain leaching liquor；
The organic solvent is one or more mixtures in methanol, ethyl alcohol, n-butanol and acetone；
(2) leaching liquor obtained with extractant to step (1) extracts, and crude extract is obtained after extract liquor is concentrated；
(3) chromatography and purification process are carried out to the crude extract that step (2) obtains, obtains the benzo pyridine assimilation
Close object.
In step (1), the cynanchum auriculatum Royle ex Wight knotweed herb crushing is placed in organic solvent and is extracted, is more advantageous to benzene
And the leaching of pyridinone compounds.The cynanchum auriculatum Royle ex Wight knotweed herb and the weight ratio of organic solvent are preferably 1:1-1:8.Described
Extraction can be cold soaking or circumfluence distillation.
In step (2), the extractant is n-butanol.
Preferably, in step (2), the extracting solution is first concentrated, and is then added in diatomite and is mixed sample, adds institute
Extractant is stated to be extracted.
As other preferred, in step (2), the extracting solution is first concentrated, and then plus water is suspended, then adds
Enter the extractant to be extracted.
Preferably, in step (3), the chromatography is normal-phase silica gel column chromatography separation, eluant, eluent for chloroform and
The mixed liquor of methanol.As a further preference, in normal-phase silica gel column chromatography separation：After loading, mixed with chloroform/methanol
Liquid is closed as eluant, eluent, by volume 9:1、5:1、3:1、1:1、1:3、1:9 carry out gradient elution, collect eluant, eluent volume ratio 3:
The fraction eluted when 1.
Preferably, in step (3), the purification process includes：Reversed-phase silica gel column chromatography separation, high performance liquid chromatography
One or more of separation and recrystallization.By purifying, the higher benzo pyridinone compounds of purity can be obtained.
The present invention also provides the benzo pyridinone compounds to prepare tyrosinase inhibition drug or anti-melanin
Application in tumor medicine.For the drug using the benzo pyridinone compounds of the present invention as main active, adding can in pharmacy
The auxiliary material of receiving is made, and preparation can be made according to the formulation preparation method recorded in pharmacy.The preparation can be injection
Liquid, drip solution, powder-injection, granule, tablet, electuary, powder, oral liquid, sugar coated tablet, film coated tablet, enteric coated tablet,
Mouth containing agent, granule, pill, paste, sublimed preparation, spray, pill, disintegrant, oral disintegrating tablet, pellet etc..
The present invention also provides application of the benzo pyridinone compounds in skin-lightening cosmetic.The cosmetics are with this
The benzo pyridinone compounds of invention are main active, add acceptable cosmetic and are made.
The present invention also provides application of the benzo pyridinone compounds in whitening health food is prepared.The health care
Food adds acceptable health food auxiliary material and is made using the benzo pyridinone compounds of the present invention as main active.
Present invention extracting and developing from cynanchum auriculatum Royle ex Wight knotweed herb obtains a kind of benzo pyridone chemical combination with novel structure
Object, this method is easy to operate, extraction yield is high, product purity is high, is suitble to large-scale production.
Inhibit to test by external tyrosinase activity, it is preferable to show that benzo pyridinone compounds provided by the invention have
Tyrosinase inhibitory action, IC50It is 19 μM to be worth, and inhibits drug, skin-lightening cosmetic or whitening available for preparing tyrosinase
Health food has good development prospect.
Description of the drawings
Fig. 1 is the HMBC correlation collection of illustrative plates of compound in embodiment 6.
Specific embodiment
The preparation of 1 benzo pyridinone compounds of embodiment
Take 5kg cynanchum auriculatum Royle ex Wights knotweed (Fallopia cynanchoides (Hemsl.) Harald.var.cynanchoides) complete
Grass dry, pulverize, and be impregnated 2 weeks with methanol (40L), and (100mL) is suspended with 1L distilled water after soak is concentrated, aqueous suspension
With 1L extracting n-butyl alcohols, butanol extraction liquid is concentrated to obtain medicinal extract；Sample is mixed with silica gel (100 mesh, 100g), carries out purification on normal-phase silica gel
Column chromatography for separation (200-300 mesh, 1kg；Silica gel column dimension L 500mm,), successively with volume ratio 9:1、5:1、3:
1、1:1、1:3、1:9 chloroform/methanol carries out gradient elution, each 5L；TLC detects fraction, collects elution ratio 3:1 fraction
Merge, again with methanol recrystallization.
The preparation of 2 benzo pyridinone compounds of embodiment
5kg cynanchum auriculatum Royle ex Wight knotweed herbs are taken, dry, pulverize, are extracted with 5L alcohol refluxs, extracting solution concentration (100mL), water is suspended
Liquid (1L) is extracted with 1L chloroforms, and chloroform layer discards.Water layer 1L extracting n-butyl alcohols；N-butanol fraction concentrate, with silica gel (100 mesh,
Sample 100g) is mixed, carries out normal-phase silica gel column chromatography separation (200-300 mesh, 1kg；Silica gel column dimension L 500mm,),
Successively with volume ratio 9:1、5:1、3:1、1:1、1:3、1:9 chloroform/methanol carries out gradient elution, each 5L；TLC detections evaporate
Point, collect elution ratio 3:1 fraction merges, again with methanol recrystallization.
The preparation of 3 benzo pyridinone compounds of embodiment
5kg cynanchum auriculatum Royle ex Wight knotweed herbs are taken, are crushed, are extracted with 5L methanol/ethanols mixed-liquor return, extract concentration (100mL),
Sample, 5L n-butanol thermal extractions are mixed with 100g diatomite；Carry out normal-phase silica gel column chromatography separation (200-300 mesh, 1kg；Silicagel column ruler
Very little L 500mm,), successively with volume ratio 9:1、5:1、3:1、1:1、1:3、1:9 chloroform/methanol mixed liquor into
Row gradient elution, each 5L；TLC detects fraction, collects elution ratio 3:1 fraction merges, then with acetone/n-hexane (volume
Than 1:1) it recrystallizes.
The preparation of 4 benzo pyridinone compounds of embodiment
5kg cynanchum auriculatum Royle ex Wight knotweed herbs are taken, are crushed, are extracted with 5L methanol/ethanols mixed-liquor return, extract concentration (100mL),
Sample, 5L n-butanol thermal extractions are mixed with 100g diatomite；Carry out normal-phase silica gel column chromatography separation (200-300 mesh, 1kg；Silicagel column ruler
Very little L 500mm,), successively with volume ratio 9:1、5:1、3:1、1:1、1:3、1:9 chloroform/methanol mixed liquor into
Row gradient elution, each 5L；TLC detects fraction, collects elution ratio 3:1 fraction merges；Fraction with reversed-phase silica gel column chromatography/
High performance liquid chromatography separation, eluant, eluent are methanol/water (9:1-1:9), the Detection wavelength of high performance liquid chromatography is 254nm；Use first
Alcohol recrystallizes.
The preparation of 5 benzo pyridinone compounds of embodiment
5kg cynanchum auriculatum Royle ex Wight knotweed herbs are taken, are crushed, with 5L methanol/ethanols/acetone mixture refluxing extraction, extract is concentrated into
Without alcohol taste, with 5L extracting n-butyl alcohols, extract liquor concentration, water upper macroreticular resin after being suspended (size L 500mm,)
Except sugar；Ethyl alcohol washes lower rear concentration, and 100g silica gel mixed samples carry out normal-phase silica gel column chromatography separation (200-300 mesh, 1kg；Silicagel column
Size L 500mm,), successively with volume ratio 9:1、5:1、3:1、1:1、1:3、1:9 chloroform/methanol mixed liquor
Carry out gradient elution, each 5L；TLC detects fraction, collects elution ratio 3:1 fraction merges；Fraction reverse phase silica gel column layer
Analysis/high performance liquid chromatography separation, eluant, eluent are methanol/water (9:1-1:9), the Detection wavelength of high performance liquid chromatography is 254nm；With
Recrystallizing methanol.
The Structural Identification of 6 benzo pyridinone compounds of embodiment
Purity carries out compound obtained using HPLC, sample of the purity more than 98% is total to mass spectrum and nuclear-magnetism
Technology of shaking carries out Structural Identification, and nuclear magnetic resonance is measured with Bruker AVANCE DRX-500NMR Sectrometer, in TMS works
Mark；High resolution mass spectrum FTICRMS is measured with Bruker ApexSpectrometer；Electrospray ionization mass spectrum ESI-MS Bruker
Esquire 3000plusSpectrometer is measured.
According to the one-dimensional NMR analysis result (being shown in Table 1) of compound and two-dimentional NMR analysis result (see Fig. 1), it is known that, the object
Matter be benzo pyridinone compounds, molecular formula C12H11NO5, structure is as follows：
The NMR data of 1 benzo pyridinone compounds of table
a Recorded on 125MHz.
b Multiplicities inferred from DEPT and HMQC experiments.
c Recorded on 500MHz.
7 benzo pyridinone compounds of embodiment analyze tyrosinase inhibitory activity
Benzo pyridinone compounds are dissolved to a concentration of 2.5% with methanol；Tyrosinase (28nM) and compound incubation 10
Minute；Add in LDOPA (0.5mM).Compound is as follows to the inhibitory activity calculation formula of tyrosinase：
Inhibiting rate (%)=[(B-S)/B] × 100%
Wherein, B is absorbed for blank, and S is absorbed for sample.
Known by experimental result, the IC of the compound50=19 μM, show that the compound is preferable to tyrosinase inhibitory activity.
The preparation of 8 dropping pill formulation of pyridinone compounds containing benzo of embodiment
0.5g benzos pyridinone compounds is taken to be uniformly mixed with 10.5g polyethylene glycol-6000, heating melts, and is moved after material
Into dripping pill trickle irrigation, liquid is dropped in 6~8 DEG C of atoleines, oil removing, and dripping pill 300 is made.
The preparation of 9 freeze drying powder injection of pyridinone compounds containing benzo of embodiment
Take benzo pyridinone compounds 0.5g, glucose 4.5g, sodium thiosulfate 0.9g and distilled water 1000ml, above-mentioned group
Point after mixing, freeze-drying, packing 400 to get.
Claims (9)
1. a kind of benzo pyridinone compounds, which is characterized in that shown in structure such as formula (I)：
2. a kind of preparation method of benzo pyridinone compounds as described in claim 1, which is characterized in that including following step
Suddenly：
(1) using organic solvent to cynanchum auriculatum Royle ex Wight knotweed (the Fallopia cynanchoides (Hemsl.) after crushing
Harald.var.cynanchoides) herb is extracted to obtain leaching liquor；
The organic solvent is one or more mixtures in methanol, ethyl alcohol, n-butanol and acetone；
(2) leaching liquor obtained with extractant to step (1) extracts, and crude extract is obtained after extract liquor is concentrated, described
Extractant is n-butanol；
(3) chromatography and purification process are carried out to the crude extract that step (2) obtains, obtains the benzo pyridone chemical combination
Object.
3. the preparation method of benzo pyridinone compounds according to claim 2, which is characterized in that the cynanchum auriculatum Royle ex Wight knotweed
The weight ratio of herb and organic solvent is preferably 1:1-1:8.
4. preparation method according to claim 2, which is characterized in that in step (2), the extracting solution first carries out dense
Then contracting adds in diatomite and mixes sample, adds the extractant and extracted.
5. preparation method according to claim 2, which is characterized in that in step (2), the extracting solution first carries out dense
Contracting, then plus water is suspended, and adds the extractant and is extracted.
6. preparation method according to claim 2, which is characterized in that in step (3), the chromatography is positive silicon
Plastic column chromatography detaches, and eluant, eluent is chloroform and the mixed liquor of methanol.
7. preparation method according to claim 2, which is characterized in that in step (3), the purification process includes：Instead
One or more of the separation of phase silica gel column chromatography, high performance liquid chromatography separation and recrystallization.
8. preparation method according to claim 7, which is characterized in that the eluant, eluent of reversed-phase silica gel column chromatography separation is
The mixed liquor of first alcohol and water.
9. a kind of application of benzo pyridinone compounds as described in claim 1 in preparing tyrosinase and inhibiting drug.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104224625A (en) * | 2014-09-12 | 2014-12-24 | 苏州禾研生物技术有限公司 | Application of polygonum capitatum extract in whitening product, and whitening product |
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| CN104224625A (en) * | 2014-09-12 | 2014-12-24 | 苏州禾研生物技术有限公司 | Application of polygonum capitatum extract in whitening product, and whitening product |
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