CN104910119A - Coumarin substituted flavonoid derivatives, and preparation method and application thereof - Google Patents
Coumarin substituted flavonoid derivatives, and preparation method and application thereof Download PDFInfo
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- CN104910119A CN104910119A CN201510216650.4A CN201510216650A CN104910119A CN 104910119 A CN104910119 A CN 104910119A CN 201510216650 A CN201510216650 A CN 201510216650A CN 104910119 A CN104910119 A CN 104910119A
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- Prior art keywords
- dibenzopyrans
- diketone
- phenyl
- application
- methoxyl group
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- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 235000001671 coumarin Nutrition 0.000 title abstract description 7
- 229960000956 coumarin Drugs 0.000 title abstract description 7
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 title abstract 6
- 150000002214 flavonoid derivatives Chemical class 0.000 title abstract 4
- 239000003814 drug Substances 0.000 claims abstract description 14
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 12
- 102100024295 Maltase-glucoamylase Human genes 0.000 claims abstract description 7
- 108010028144 alpha-Glucosidases Proteins 0.000 claims abstract description 7
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 230000000694 effects Effects 0.000 claims description 14
- 150000002212 flavone derivatives Chemical class 0.000 claims description 12
- 229930003935 flavonoid Natural products 0.000 abstract description 11
- 235000017173 flavonoids Nutrition 0.000 abstract description 11
- -1 flavonoid compounds Chemical class 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 7
- 238000000746 purification Methods 0.000 abstract description 5
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 abstract description 3
- 229960002632 acarbose Drugs 0.000 abstract description 3
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- 150000002215 flavonoids Chemical class 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 230000005311 nuclear magnetism Effects 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000013019 agitation Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229930003944 flavone Natural products 0.000 description 5
- 150000002213 flavones Chemical class 0.000 description 5
- 235000011949 flavones Nutrition 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- XADJWCRESPGUTB-UHFFFAOYSA-N apigenin Natural products C1=CC(O)=CC=C1C1=CC(=O)C2=CC(O)=C(O)C=C2O1 XADJWCRESPGUTB-UHFFFAOYSA-N 0.000 description 3
- 235000008714 apigenin Nutrition 0.000 description 3
- KZNIFHPLKGYRTM-UHFFFAOYSA-N apigenin Chemical compound C1=CC(O)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 KZNIFHPLKGYRTM-UHFFFAOYSA-N 0.000 description 3
- 229940117893 apigenin Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- LIIALPBMIOVAHH-UHFFFAOYSA-N herniarin Chemical compound C1=CC(=O)OC2=CC(OC)=CC=C21 LIIALPBMIOVAHH-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 description 1
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 1
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 150000004775 coumarins Chemical class 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- DOBMPNYZJYQDGZ-UHFFFAOYSA-N dicoumarol Chemical compound C1=CC=CC2=C1OC(=O)C(CC=1C(OC3=CC=CC=C3C=1O)=O)=C2O DOBMPNYZJYQDGZ-UHFFFAOYSA-N 0.000 description 1
- 239000013070 direct material Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 1
- 150000002515 isoflavone derivatives Chemical class 0.000 description 1
- 235000008696 isoflavones Nutrition 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 description 1
- 229960001553 phloroglucinol Drugs 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- IKGXIBQEEMLURG-NVPNHPEKSA-N rutin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-NVPNHPEKSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 229960003232 troxerutin Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
Abstract
The invention relates to preparation of coumarin substituted flavonoid derivatives and an application of the coumarin substituted flavonoid derivatives in diabetes drugs; the coumarin substituted flavonoid compounds are synthesized for the first time, the alpha-glucosidase inhibitory activity is evaluated for the first time, and results indicate that the IC50 of the coumarin substituted flavonoid compounds is less than 30 [mu]M and is better than the inhibitory activity of acarbose, and the coumarin substituted flavonoid derivatives are discovered to be capable of well inhibiting alpha-glucosidase; and at the same time, the derivatives are simple in synthesis and purification methods, and have broad prospects in development and application of the diabetes treating drugs.
Description
Technical field
The invention belongs to new compound preparation method and pharmaceutical use field, especially a class tonka bean camphor replaces flavone derivative and its preparation method and application, is included in the application in antidiabetic medicine.
Background technology
Flavones and tonka bean camphor are two compounds be extensively present in natural phant, are present in all kinds of vegetables, fruit, medicinal material etc., and are the main functional component as its health-care effect.Temparin is the clinical anticoagulation medicine of a class of code of having got the Green Light, and also has picture soybean isoflavones in chromocor compound, the marketed drug such as troxerutin.
Because flavonoid and coumarin kind compound itself have good biological activity, also got more and more in recent years to its research, the treatment diabetes medicament found by research flavonoid and coumarin derivatives becomes the focus of research now already.
Summary of the invention
A class tonka bean camphor is the object of the present invention is to provide to replace flavone derivative and preparation method thereof and application, the application synthesizes tonka bean camphor substituted flavonoids, this analog derivative has good alpha-glucosaccharase enzyme inhibition activity, synthesis and purification process simple.Tonka bean camphor substituted flavonoids of the present invention has alpha-glucosaccharase enzyme inhibition activity, may be used for treating diabetes, can be applicable to the medicine preparing treatment diabetes.
Object of the present invention is achieved through the following technical solutions:
One class tonka bean camphor replaces flavone derivative, and the general structure of derivative is as follows:
Wherein R1 is OH or H, R2 be OH or H, R3 be OH or H, R4 is OH or CH3O.
Described R1 is one of OH or H.Described R2 is one of OH or H.Described R3 is one of OH, H.Described R4 is OH, CH
3one of O.
Described derivative can be following concrete compound:
5', 7,7'-trihydroxy--2'-(4-hydroxy phenyl)-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
5', 7,7'-trihydroxy--2'-phenyl-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
2'-(3,4-dihydroxy phenyl)-5', 7,7'-trihydroxy--2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
2'-(3,4-dihydroxy phenyl)-3', 5', 7,7'-tetrahydroxy-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
5', 7'-dihydroxyl-2'-(4-hydroxy phenyl)-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
5', 7'-dihydroxyl-2'-phenyl-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
5', 7'-dihydroxyl-2'-(3,4-dihydroxy phenyl)-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
2'-(3,4-dihydroxy phenyl)-3', 5', 7'-trihydroxy--7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
One class tonka bean camphor replaces the preparation method of flavone derivative, and step is as follows:
Wherein, R1 is OH or H, R2 be OH or H, R3 be OH or H, R4 is OH or CH3O.
One class tonka bean camphor replaces the application of flavone derivative Inhibiting α-glucosidase activity.
One class tonka bean camphor replaces the application of flavone derivative in preparation treatment diabetes medicament.
Advantage of the present invention and positively effect:
The application's design is female ring with flavones, by to 2, the modification of 3 and 8 improves its biological activity, the hydroxy phenyl that 2 are introduced different number is active to study alpha-glucosaccharase enzyme inhibition activity, 3 are introduced hydroxyl study the impact of 3 groups, study the impact of 8 tonka bean camphor groups at 8 introducing umbelliferones or ayapanin.Tonka bean camphor substituted flavonoids of the present invention can be treated diabetes medicament active ingredient combinations with other and be used.
The application synthesizes tonka bean camphor substituted flavonoids, this analog derivative can Inhibiting α-glucosidase active, preferably as treatment diabetes medicament, opened up the research direction of a class novel therapeutic diabetes medicament.
Accompanying drawing explanation
Fig. 1 is the nuclear-magnetism figure of embodiment 1 compound;
Fig. 2 is the nuclear-magnetism figure of embodiment 2 compound;
Fig. 3 is the nuclear-magnetism figure of embodiment 3 compound;
Fig. 4 is the nuclear-magnetism figure of embodiment 4 compound;
Fig. 5 is the nuclear-magnetism figure of embodiment 5 compound;
Fig. 6 is the nuclear-magnetism figure of embodiment 6 compound;
Fig. 7 is the nuclear-magnetism figure of embodiment 8 compound.
Embodiment
In order to understand the present invention, below in conjunction with embodiment, the invention will be further described; Following embodiment is illustrative, is not determinate, can not limit protection scope of the present invention with following embodiment.
The invention provides a kind of such as formula the derivative shown in (I), the application take flavones as female ring, by to 2, the modification of 3 and 8 improves its biological activity, the hydroxy phenyl that 2 are introduced different number is active to study alpha-glucosaccharase enzyme inhibition activity, 3 are introduced hydroxyl study the impact of 3 groups, study the impact of 8 tonka bean camphor groups at 8 introducing umbelliferones or ayapanin.
The application synthesizes tonka bean camphor substituted flavonoids first, good biological activity is had based on flavones, this analog derivative has good alpha-glucosaccharase enzyme inhibition activity, and its majority of compounds alpha-glucosaccharase enzyme inhibition activity is better than acarbose, preferably as treatment diabetes medicament.Tonka bean camphor substituted flavonoids provided by the invention can be treated diabetes medicament active ingredient combinations with other and be used.
The invention provides formula I compound
Formula I
Wherein, R1 is OH or H, R2 be OH or H, R3 be OH or H, R4 is OH or CH3O.
The present invention is particularly including compound:
(1) 5', 7,7'-trihydroxy--2'-(4-hydroxy phenyl)-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
(2) 5', 7,7'-trihydroxy--2'-phenyl-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
(3) 2'-(3,4-dihydroxy phenyl)-5', 7,7'-trihydroxy--2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
(4) 2'-(3,4-dihydroxy phenyl)-3', 5', 7,7'-tetrahydroxy-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
(5) 5', 7'-dihydroxyl-2'-(4-hydroxy phenyl)-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
(6) 5', 7'-dihydroxyl-2'-phenyl-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
(7) 5', 7'-dihydroxyl-2'-(3,4-dihydroxy phenyl)-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
(8) 2'-(3,4-dihydroxy phenyl)-3', 5', 7'-trihydroxy--7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
The invention provides formula I compou nd synthesis route as follows:
Concrete synthetic example.
Embodiment 1
5', 7,7'-trihydroxy--2'-(4-hydroxy phenyl)-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
(1) get 10g (79.29mmol) Phloroglucinol and be placed in 250mL round-bottomed flask, add 160mL 1, 2-ethylene dichloride, add 21.14g (158.58mmol) aluminum trichloride (anhydrous) after stirring 5min under condition of ice bath and stir 10min, then 7.57mL (95.15mmol) chloroacetyl chloride is dropwise added with constant pressure funnel, rise to room temperature after stirring 10min and make tail gas absorption with alkali lye, after reaction flask is placed in 100 DEG C of oil bath reflux 8h, be cooled to impouring 300mL aqueous hydrochloric acid (6mL after room temperature, 12mol/L HCl) stir suction filtration after 30min, dry 2, 4, 6-trihydroxybenzene-chloroethene ketone 9.95g, productive rate 62%.
(2) get 13.84g (0.25mol) potassium hydroxide and impouring 100mL round-bottomed flask after being mixed with 40%KOH solution, add 10mL ethanol and 6.24g (51.11mmol) p-Hydroxybenzaldehyde, finally add 10.00g (51.11mmol) 2,4,6-trihydroxybenzene-chloroethene ketone is stirred to room temperature and is placed in 60 DEG C of oil baths and reacts 6h, after TLC detection reaction is complete, by in the water-bath of reaction solution impouring hydrochloric acid ice, regulate pH to 3-4, suction filtration, dry apigenin 11.07g, productive rate 83%.
(3) get 10g (37mmol) apigenin and be placed in 100mL pressure bottle, and dissolved with 30mL DMF, 25.57g (0.185mol) Anhydrous potassium carbonate and 31.45g (0.185mol) 2-iodopropane is added under agitation condition, be placed in 60 DEG C of oil bath reactions 24 hours, after TLC detection reaction is complete, reaction soln ethyl acetate is extracted, and organic phase saturated common salt is washed 3 times, merge organic phase, anhydrous sodium sulphate carries out drying, use developping agent sherwood oil: ethyl acetate=40:1, 200-300 order purification by silica gel column chromatography, obtain 5, 7-diisopropoxy-2-(4-isopropyl phenyl)-4H-benzopyran-4-one 10.70g, productive rate 73%.
(4) get 10g (25.22mmol) 5, 7-diisopropoxy-2-(4-isopropyl phenyl)-4H-benzopyran-4-one is placed in 100mL round-bottomed flask, and dissolved with 30mLDMF, under agitation condition, add 6.81g (30.27mmol) NBS be placed in 70 DEG C of oil baths and react 10h, after TLC detection reaction is complete, reaction soln ethyl acetate is extracted, merge organic phase, and organic phase saturated common salt is washed 1 time, saturated sodium thiosulfate solution washes 2 times, anhydrous sodium sulphate carries out drying, use developping agent sherwood oil: ethyl acetate=40:1, 200-300 order purification by silica gel column chromatography, obtain 8-bromo-5, 7-diisopropoxy-2-(4-isopropyl phenyl)-4H-benzopyran-4-one 6.98g, productive rate 53%.
(5) get 2.00g (6.62mmol) 7-methoxyl group-6-iodine tonka bean camphor and be placed in 100mL round-bottomed flask, dissolve with 60mL DMSO, add 3.36g (13.24mmol) under agitation respectively and join boric acid pinacol ester, 0.1761g (0.99mmol) PdCl
2(dppf), 1.36g (13.24mmol) potassium acetate, in 80 DEG C of oil baths stirring reaction 24h, TLC detection reaction completely after, extract by ethyl acetate, merge organic phase and wash 2 times, through anhydrous sodium sulfate drying with saturated common salt, use developping agent sherwood oil: ethyl acetate=10:1,200-300 order purification by silica gel column chromatography, obtains 7-methoxyl group-6-(4,4,5,5-tetramethyl--1,3,2-dioxy boric acid-2-ester)-2H-chromen-2-one 1.56g, productive rate 78%.
(6) get 400mg (0.77mmol) 8-bromo-5; 7-diisopropoxy-2-(4-isopropyl phenyl)-4H-benzopyran-4-one, 277.62mg (0.92mmol) 7-methoxyl group-6-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxy boric acid-2-ester)-2H-chromen-2-one, 132.73mg (0.12mmol) tetra-triphenylphosphine palladium, 498.98mg (0.154mmol) cesium carbonate; put into 50mL reaction flask; add 10mL 1; 4-dioxane, argon shield, reacts 12h in 100 DEG C of oil baths.After TLC detection reaction is complete, be extracted with ethyl acetate, merge organic phase, and organic phase saturated common salt is washed 3 times, anhydrous sodium sulfate drying.Re-crystallizing in ethyl acetate, obtains 5', 7'-diisopropoxy-2'-(4-isopropyl phenyl)-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone 183.53mg, productive rate 42%.
(7) get 57mg (0.01mmol) 5', 7'-diisopropoxy-2'-(4-isopropyl phenyl)-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone, in 25mL round-bottomed flask, dissolves with 5mL methylene dichloride, stirs 10min at being placed in-78 DEG C, 200mg (0.80mmol) boron tribromide dropwise adds, and reacting liquid temperature is slowly elevated to room temperature reaction 12h.Under agitation condition, excessive frozen water quencher reaction is added to reaction solution, Rotary Evaporators removing dichloromethane solvent, and to suspended substance suction filtration, dry 5', 7,7'-trihydroxy--2'-(4-hydroxy phenyl)-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone 41.78mg, productive rate 100%.
1H NMR(400MHz,DMSO)δ10.82(s,3H),9.90(s,1H),8.02(d,J＝9.3Hz,1H),7.65(s,1H),7.56(d,J＝8.0Hz,2H),6.90(s,1H),6.68(d,J＝7.9Hz,2H),6.52(s,1H),6.26(d,1H),6.23(s,1H).
Embodiment 2
5', 7,7'-trihydroxy--2'-phenyl-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
Method is with illustrating 1, productive rate 100%.
1HNMR(400MHz,DMSO)δ11.01(s,1H),10.89(s,1H),10.58(s,1H),8.01(d,J＝9.5Hz,1H),7.70(dd,J＝6.4,3.0Hz,2H),7.63(s,1H),7.33–7.26(m,3H),6.93(s,1H),6.59(s,1H),6.29(s,1H),6.26(d,J＝9.4Hz,1H).
Embodiment 3
2'-(3,4-dihydroxy phenyl)-5', 7,7'-trihydroxy--2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
Method is with illustrating 1, productive rate 100%.
1H NMR(400MHz,DMSO)δ10.83(s,1H),10.72(s,2H),9.58(s,1H),8.79(s,1H),8.01(d,J＝9.5Hz,1H),7.62(s,1H),7.08(d,J＝8.6Hz,H),7.06(s,1H),6.90(s,1H),6.64(d,J＝8.0Hz,1H),6.42(s,1H),6.34–6.16(m,2H)。
Embodiment 4
2'-(3,4-dihydroxy phenyl)-3', 5', 7,7'-tetrahydroxy-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
This compound is direct material by flavones Quercetin, and additive method is with illustrating 1, productive rate 100%.
1H NMR(400MHz,DMSO)δ12.63(s,1H),11.45(s,2H),9.26(s,2H),9.04(s,1H),7.94(d,J＝9.4Hz,1H),7.65(s,1H),7.52(s,1H),7.16(d,J＝8.5Hz,1H),6.82(s,1H),6.69(d,J＝8.5Hz,1H),6.26(s,1H),6.19(d,J＝9.3Hz,1H).
Embodiment 5
5', 7'-dihydroxyl-2'-(4-hydroxy phenyl)-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
Get 57mg (0.1mmol) 5,7,4 '-triisopropyl-8-(ayapanin) apigenin is in 25mL round-bottomed flask, dissolve with 5mL methylene dichloride, 10min is stirred at being placed in 0 DEG C, 70mg (0.6mmol/1M in DCM) boron trichloride dropwise adds, and reacting liquid temperature is slowly elevated to 40 DEG C of back flow reaction 4h.Question response is cooled to room temperature, under agitation condition, excessive frozen water quencher reaction is added, Rotary Evaporators removing dichloromethane solvent to reaction solution, and to suspended substance suction filtration, dry 5', 7'-dihydroxyl-2'-(4-hydroxy phenyl)-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone 43mg, productive rate 97%.
1H NMR(400MHz,DMSO)δ10.93(s,1H),10.82(s,1H),9.93(s,1H),8.08(d,J＝9.5Hz,1H),7.70(s,1H),7.52(d,J＝8.6Hz,2H),7.24(s,1H),6.69(d,J＝8.6Hz,2H),6.53(s,1H),6.36(d,J＝9.5Hz,1H),6.28(s,1H),3.83(s,3H).
Embodiment 6
5', 7'-dihydroxyl-2'-phenyl-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone method is with illustrating 5, reaction yield 98%.
1H NMR(400MHz,DMSO)δ11.07(s,1H),10.95(s,1H),8.07(d,J＝9.4Hz,1H),7.69(m,3H),7.32(m,3H),7.24(s,1H),6.60(s,1H),6.36(d,J＝9.4Hz,1H),6.31(s,1H),3.84(s,3H).
Embodiment 7
5', 7'-dihydroxyl-2'-(3,4-dihydroxy phenyl)-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
Method is with illustrating 5, productive rate 95%.
1H NMR(400MHz,DMSO)δ10.91(s,1H),10.80(s,1H),9.61(s,1H),8.82(s,1H),8.07(d,J＝9.5Hz,1H),7.68(s,1H),7.20(s,1H),7.07(s,1H),7.03(d,J＝8.3Hz,1H),6.67(d,J＝8.0Hz,1H),6.43(s,1H),6.35(d,J＝9.4Hz,1H),6.28(s,1H),3.84(s,3H).
Embodiment 8
2'-(3,4-dihydroxy phenyl)-3', 5', 7'-trihydroxy--7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone
Method is with illustrating 5, reaction yield 98%
1H NMR(400MHz,DMSO)δ12.61(s,1H),10.76(s,1H),9.62(s,1H),9.42(s,1H),9.06(s,1H),8.04(d,J＝9.5Hz,1H),7.64(s,1H),7.39(d,J＝2.1Hz,1H),7.23(s,1H),7.02(dd,J＝8.5,2.1Hz,1H),6.70(d,J＝8.5Hz,1H),6.39(s,1H),6.35(d,J＝9.5Hz,1H),3.77(s,3H).
Activity test: to the test of alpha-glucosaccharase enzyme inhibition activity
The alpha-glucosidase commodity (Sigma, G5003) extracted from cereuisiae fermentum are target protein, with 4-oil of mirbane-α-D glucopyranoside (pNGP, Sigma, N1377) for substrate.Compound and acarbose are dissolved in DMSO solution.It is 0.05mol/L pH value is in the potassium phosphate buffer of 6.8 that enzyme and substrate are dissolved in concentration.Be alpha-glucosidase 20 μ L (0.06U) in enzymatic reaction system, substrate is 1mmol/L30 μ L, testing compound 10 μ L, 140 μ L phosphoric acid buffers, applies 30 minutes 37 DEG C of temperature.With microplate reader in wavelength be 405nm place detect enzymic activity.Net result is obtained by three independent repetition empirical averages.
Table 1 tonka bean camphor substituted flavonoids alpha-glucosaccharase enzyme inhibition activity
Claims (5)
1. a class tonka bean camphor replaces flavone derivative, it is characterized in that: the general structure of described derivative is as follows:
Wherein, R
1for OH or H, R
2for OH or H, R
3for OH or H, R
4for OH or CH
3o.
2. tonka bean camphor according to claim 1 replaces flavone derivative, it is characterized in that: described derivative is
5', 7,7'-trihydroxy--2'-(4-hydroxy phenyl)-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
5', 7,7'-trihydroxy--2'-phenyl-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
2'-(3,4-dihydroxy phenyl)-5', 7,7'-trihydroxy--2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
2'-(3,4-dihydroxy phenyl)-3', 5', 7,7'-tetrahydroxy-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
5', 7'-dihydroxyl-2'-(4-hydroxy phenyl)-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
5', 7'-dihydroxyl-2'-phenyl-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
5', 7'-dihydroxyl-2'-(3,4-dihydroxy phenyl)-7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone,
Or 2'-(3,4-dihydroxy phenyl)-3', 5', 7'-trihydroxy--7-methoxyl group-2H, 4'H-[6,8'-dibenzopyrans]-2,4'-diketone.
3. tonka bean camphor as claimed in claim 1 replaces the preparation method of flavone derivative, it is characterized in that: reaction formula is as follows:
Wherein R
1for OH or H, R
2for OH or H, R
3for OH or H, R
4for OH or CH
3o.
4. class tonka bean camphor as claimed in claim 1 replaces the application of flavone derivative Inhibiting α-glucosidase activity.
5. class tonka bean camphor as claimed in claim 1 replaces the application of flavone derivative in preparation treatment diabetes medicament.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105601624B (en) * | 2016-02-17 | 2018-05-22 | 南京双科医药开发有限公司 | A kind of 1,2,4- triazines-coumarin type compound and its preparation method and purposes |
| CN110498739A (en) * | 2019-09-12 | 2019-11-26 | 南华大学 | A method of synthesis 6- hydroxyl -2,3,4- trimethoxy-alpha-chloro acetophenone |
| CN112645922A (en) * | 2020-12-24 | 2021-04-13 | 中国人民解放军空军军医大学 | Coumarin compound, preparation method and application |
| CN114621173A (en) * | 2020-12-10 | 2022-06-14 | 上海医药工业研究院 | Preparation method and intermediate of isoamylene heterocyclic compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101940614A (en) * | 2010-08-25 | 2011-01-12 | 吉林天药药物研发有限公司 | Application of juglans mandshurica maxim. ethyl acetate part in preparing alpha-glucosidase inhibitor medicament |
| WO2013022846A2 (en) * | 2011-08-05 | 2013-02-14 | Cardero Therapeutics, Inc. | Flavonoid compounds |
-
2015
- 2015-04-30 CN CN201510216650.4A patent/CN104910119B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101940614A (en) * | 2010-08-25 | 2011-01-12 | 吉林天药药物研发有限公司 | Application of juglans mandshurica maxim. ethyl acetate part in preparing alpha-glucosidase inhibitor medicament |
| WO2013022846A2 (en) * | 2011-08-05 | 2013-02-14 | Cardero Therapeutics, Inc. | Flavonoid compounds |
Non-Patent Citations (2)
| Title |
|---|
| GUOJUN PAN ET AL.: "Total synthesis of 8-(6"-umbelliferyl)-apigenin and its analogs as anti-diabetic reagents", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| KATRIN FRANKE ET AL.: "Flavone-coumarin hybrids from Gnidia socotrana", 《PHYTOCHEMISTRY》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105601624B (en) * | 2016-02-17 | 2018-05-22 | 南京双科医药开发有限公司 | A kind of 1,2,4- triazines-coumarin type compound and its preparation method and purposes |
| CN110498739A (en) * | 2019-09-12 | 2019-11-26 | 南华大学 | A method of synthesis 6- hydroxyl -2,3,4- trimethoxy-alpha-chloro acetophenone |
| CN114621173A (en) * | 2020-12-10 | 2022-06-14 | 上海医药工业研究院 | Preparation method and intermediate of isoamylene heterocyclic compound |
| CN112645922A (en) * | 2020-12-24 | 2021-04-13 | 中国人民解放军空军军医大学 | Coumarin compound, preparation method and application |
| CN112645922B (en) * | 2020-12-24 | 2022-01-07 | 中国人民解放军空军军医大学 | Coumarin compound, preparation method and application |
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