CN104910119B - One class cumarin substitution flavone derivative and its preparation method and application - Google Patents
One class cumarin substitution flavone derivative and its preparation method and application Download PDFInfo
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- CN104910119B CN104910119B CN201510216650.4A CN201510216650A CN104910119B CN 104910119 B CN104910119 B CN 104910119B CN 201510216650 A CN201510216650 A CN 201510216650A CN 104910119 B CN104910119 B CN 104910119B
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- 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 present invention relates to a kind of preparation of cumarin substitution flavone derivative and its application in diabetes medicament, the application synthesizes cumarin substituted flavonoids first, and α glucosidase inhibitory actives are evaluated first, as a result show cumarin substituted flavonoids IC50<30 μM, it is better than the inhibitory activity of acarbose, it was found that cumarin substitution flavone derivative can be good at suppressing α glucuroides, while derivative synthesis, purification process are simply, had broad prospects in the exploitation for the treatment of diabetes medicament with application aspect.
Description
Technical field
The invention belongs to noval chemical compound preparation method and medicinal usage field, especially class cumarin substitution flavonoids spreads out
Biology and its preparation method and application, is included in the application in antidiabetic medicine.
Background technology
Flavones and cumarin are two class compounds being widely present in natural plants, are present in all kinds of vegetables, fruit, medicine
Material etc., and be the main functional component as its health-care effect.Bicoumarin be got the Green Light code a class it is clinical
Anticoagulation medicine, and also have picture isoflavones in chromocor compound, the marketed drug such as Troxerutin.
Because flavonoids and coumarin kind compound have good bioactivity in itself, studied it also more next in recent years
More, the treatment diabetes medicament found by studying flavonoids and coumarin derivatives already turns into what is studied now
Focus.
The content of the invention
It is an object of the invention to provide class cumarin substitution flavone derivative and preparation method and application, this Shen
It please synthesize cumarin substituted flavonoids, this analog derivative has preferable alpha-glucosaccharase enzyme inhibition activity, synthesize
It is simple with purification process.Cumarin substituted flavonoids of the present invention have alpha-glucosaccharase enzyme inhibition activity, can be with
For treating diabetes, it can be applied to prepare the medicine for the treatment of diabetes.
What the purpose of the present invention was achieved through the following technical solutions：
One class cumarin replaces flavone derivative, and the general structure of derivative is as follows：
Wherein R1 is OH or H, R2 are OH or H, R3 are OH or H, R4 are OH or CH3O.
The R1 is one of OH or H.The R2 is one of OH or H.The R3 is one of OH, H.The R4 is OH, CH3O
One of.
The derivative can be following specific compound：
5', 7,7'- trihydroxy -2'- (4- hydroxy phenyls) -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 phenyls) -5', 7,7'- trihydroxies -2H, 4'H- [6,8'- dibenzopyrans] -2,4'- two
Ketone,
2'- (3,4- dihydroxy phenyls) -3', 5', 7,7'- tetrahydroxys -2H, 4'H- [6,8'- dibenzopyrans] -2,4'-
Diketone,
5', 7'- dihydroxy -2'- (4- hydroxy phenyls) -7- methoxyl groups -2H, 4'H- [6,8'- dibenzopyrans] -2,4'-
Diketone,
5', 7'- dihydroxy -2'- phenyl -7- methoxyl groups -2H, 4'H- [6,8'- dibenzopyrans] -2,4'- diketone,
5', 7'- dihydroxy -2'- (3,4- dihydroxy phenyls) -7- methoxyl groups -2H, 4'H- [6,8'- dibenzopyrans] -2,
4'- diketone,
2'- (3,4- dihydroxy phenyls) -3', 5', 7'- trihydroxy -7- methoxyl groups -2H, 4'H- [6,8'- dibenzo pyrroles
Mutter] -2,4'- diketone
One class cumarin replaces the preparation method of flavone derivative, and step is as follows：
Wherein, R1 is OH or H, R2 are OH or H, R3 are OH or H, R4 are OH or CH3O.
One class cumarin substitution flavone derivative suppresses the application of alpha-glucosidase activity.
One class cumarin replaces application of the flavone derivative in treatment diabetes medicament is prepared.
Advantages and positive effects of the present invention：
The application is designed using flavones as female ring, and its bioactivity is improved by the modification to 2,3 and 8, is drawn on 2
Enter different number of hydroxy phenyl to study alpha-glucosaccharase enzyme inhibition activity activity, hydroxyl is introduced on 3 to study 3 bases
The influence of group, introduces umbelliferone or ayapanin to study the influence of 8 cumarin groups at 8.This hair
Bright cumarin substituted flavonoids can be used with other treatment diabetes medicament active ingredient combinations.
The application synthesizes cumarin substituted flavonoids, and this analog derivative can suppress alpha-glucosaccharase enzyme activity
Property, preferably as treatment diabetes medicament, open up the research direction of a class novel therapeutic diabetes medicament.
Brief description of the drawings
Fig. 1 is the nuclear-magnetism figure of the compound of embodiment 1；
Fig. 2 is the nuclear-magnetism figure of the compound of embodiment 2；
Fig. 3 is the nuclear-magnetism figure of the compound of embodiment 3；
Fig. 4 is the nuclear-magnetism figure of the compound of embodiment 4；
Fig. 5 is the nuclear-magnetism figure of the compound of embodiment 5；
Fig. 6 is the nuclear-magnetism figure of the compound of embodiment 6；
Fig. 7 is the nuclear-magnetism figure of the compound of embodiment 8.
Embodiment
In order to understand the present invention, with reference to embodiment, the invention will be further described；Following embodiments are illustrative
, it is not limited, it is impossible to limit protection scope of the present invention with following embodiments.
The present invention provides a kind of derivative as shown in formula (I), and the application is using flavones as female ring, by 2,3 and 8
Modify to improve its bioactivity, different number of hydroxy phenyl is introduced on 2 to study alpha-glucosaccharase enzyme inhibition activity
Activity, introduces hydroxyl to study the influence of 3 groups on 3, umbelliferone or ayapanin is introduced at 8
To study the influence of 8 cumarin groups.
The application synthesizes cumarin substituted flavonoids first, has good bioactivity based on flavones, this kind of
Derivative has preferable alpha-glucosaccharase enzyme inhibition activity, its majority of compounds alpha-glucosaccharase enzyme inhibition activity be better than Ah
Card ripple sugar, preferably as treatment diabetes medicament.The cumarin substituted flavonoids that the present invention is provided can be controlled with other
Diabetes medicament active ingredient combinations are treated to use.
Offer formula (I) compound of the present invention
Formula (I)
Wherein, R1 is OH or H, R2 are OH or H, R3 are OH or H, R4 are OH or CH3O.
The present invention particularly including compound：
(1) 5', 7,7'- trihydroxy -2'- (4- hydroxy phenyls) -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 phenyls) -5', 7,7'- trihydroxies -2H, 4'H- [6,8'- dibenzopyrans] -2,4'-
Diketone
(4) 2'- (3,4- dihydroxy phenyls) -3', 5', 7,7'- tetrahydroxys -2H, 4'H- [6,8'- dibenzopyrans] -2,
4'- diketone
(5) 5', 7'- dihydroxy -2'- (4- hydroxy phenyls) -7- methoxyl groups -2H, 4'H- [6,8'- dibenzopyrans] -2,
4'- diketone
(6) 5', 7'- dihydroxy -2'- phenyl -7- methoxyl groups -2H, 4'H- [6,8'- dibenzopyrans] -2,4'- diketone
(7) 5', 7'- dihydroxy -2'- (3,4- dihydroxy phenyls) -7- methoxyl groups -2H, 4'H- [6,8'- dibenzo pyrroles
Mutter] -2,4'- diketone
(8) 2'- (3,4- dihydroxy phenyls) -3', 5', 7'- trihydroxy -7- methoxyl groups -2H, 4'H- [6,8'- dibenzo pyrroles
Mutter] -2,4'- diketone
Offer formula (I) compound synthesis route of the present invention is as follows：
Specific synthetic example.
Embodiment 1
5', 7,7'- trihydroxy -2'- (4- hydroxy phenyls) -2H, 4'H- [6,8'- dibenzopyrans] -2,4'- diketone
(1) take 10g (79.29mmol) phloroglucin to be placed in 250mL round-bottomed flasks, addition 160mL 1,2- dichloroethanes,
Stirred under condition of ice bath and 21.14g (158.58mmol) aluminum trichloride (anhydrous)s are added after 5min and 10min is stirred, then use constant pressure
Dropping funel, which is added dropwise, to be warmed to room temperature after 7.57mL (95.15mmol) chloracetyl chloride, stirring 10min and makees tail gas suction with alkali lye
Receive, after reaction bulb be placed in 100 DEG C of oil baths be heated to reflux 8h, be cooled to after room temperature be poured into 300mL aqueous hydrochloric acid solutions (6mL,
12mol/L HCl) suction filtration, dry 2,4,6- trihydroxy benzenes-chloroethene ketone 9.95g, yield 62% after stirring 30min.
(2) take 13.84g (0.25mol) potassium hydroxide and be configured to after 40%KOH solution be poured into 100mL round-bottomed flasks, plus
Enter 10mL ethanol and 6.24g (51.11mmol) parahydroxyben-zaldehyde, be eventually adding 10.00g (51.11mmol) 2,4,6- tri-
Hydroxy benzenes-chloroethene ketone, which stirs to room temperature to be placed in 60 DEG C of oil baths, reacts 6h, and after TLC detection reactions completely, reaction solution is poured into
In hydrochloric acid ice-water bath, pH to 3-4, suction filtration, dry apiolin 11.07g, yield 83% are adjusted.
(3) take 10g (37mmol) apiolin to be placed in 100mL pressure bottles, and dissolved with 30mL DMF, in stirring bar
25.57g (0.185mol) Anhydrous potassium carbonates and 31.45g (0.185mol) 2- iodopropanes are added under part, is placed in 60 DEG C of oil baths anti-
Answer 24 hours, after TLC detection reactions completely, reaction solution is extracted with ethyl acetate, and by organic phase saturated common salt
Washing 3 times, merges organic phase, and anhydrous sodium sulfate is dried, and uses solvent petroleum ether:Ethyl acetate=40:1,200-300 mesh
Silica gel column chromatography is purified, and obtains 5,7- diisopropoxies -2- (4- isopropyl phenyls) -4H- benzopyran-4-one 10.70g, is produced
Rate 73%.
(4) 10g (25.22mmol) 5,7- diisopropoxies -2- (4- isopropyl phenyls) -4H- benzopyran-4-ones are taken
It is placed in 100mL round-bottomed flasks, and is dissolved with 30mLDMF, in after addition 6.81g (30.27mmol) NBS under stirring condition
It is placed in 70 DEG C of oil baths and reacts 10h, after TLC detection reactions completely, reaction solution is extracted with ethyl acetate, merged organic
Phase, and organic phase is washed 2 times with saturated common salt washing 1 time, saturated sodium thiosulfate solution, anhydrous sodium sulfate is dried, and uses
Solvent petroleum ether:Ethyl acetate=40:1,200-300 mesh silica gel column chromatography is purified, and obtains bromo- 5, the 7- diisopropoxies -2- of 8-
(4- isopropyl phenyls) -4H- benzopyran-4-one 6.98g, yield 53%.
(5) take 2.00g (6.62mmol) 7- methoxyl group -6- iodine cumarins to be placed in 100mL round-bottomed flasks, use 60mLDMSO
Dissolving, is separately added into 3.36g (13.24mmol) connection boric acid pinacol ester, 0.1761g (0.99mmol) under agitation
PdCl2(dppf), 1.36g (13.24mmol) potassium acetate, the stirring reaction 24h in 80 DEG C of oil baths, after TLC detection reactions completely,
Extracted with ethyl acetate, merge organic phase and washed 2 times with saturated common salt, through anhydrous sodium sulfate drying, use solvent stone
Oily ether:Ethyl acetate=10:1,200-300 mesh silica gel column chromatography purify, obtain 7- methoxyl groups -6- (4,4,5,5- tetramethyls -1,3,
2- dioxy boric acid -2- esters) -2H- chromen-2-one 1.56g, yield 78%.
(6) 400mg (0.77mmol) 8- bromo- 5,7- diisopropoxies -2- (4- isopropyl phenyls) -4H- benzo pyrroles are taken
Mutter -4- ketone, 277.62mg (0.92mmol) 7- methoxyl groups -6- (4,4,5,5- tetramethyl -1,3,2- dioxy boric acid -2- esters) -2H-
Chromen-2-one, 132.73mg (0.12mmol) tetra-triphenylphosphine palladium, 498.98mg (0.154mmol) cesium carbonate, are put into
In 50mL reaction bulbs, 10mL Isosorbide-5-Nitraes-dioxane is added, argon gas protection reacts 12h in 100 DEG C of oil baths.TLC detection reactions
After completely, it is extracted with ethyl acetate, merges organic phase, and organic phase is washed 3 times with saturated common salt, anhydrous sodium sulfate drying.
Re-crystallizing in ethyl acetate, obtains 5', 7'- diisopropoxies -2'- (4- isopropyl phenyls) -7- methoxyl groups -2H, 4'H- [6,8'-
Dibenzopyrans] -2,4'- diketone 183.53mg, yield 42%.
(7) 57mg (0.01mmol) 5', 7'- diisopropoxy -2'- (4- isopropyl phenyls) -7- methoxyl groups -2H, 4' are taken
H- [6,8'- dibenzopyrans] -2,4'- diketone is dissolved with 5mL dichloromethane in 25mL round-bottomed flasks, is placed at -78 DEG C and stirs
10min is mixed, 200mg (0.80mmol) Boron tribromide is added dropwise, reacting liquid temperature is slowly raised room temperature reaction 12h.Stirring
Under the conditions of, add excessive frozen water to reaction solution and be quenched and react, Rotary Evaporators remove dichloromethane solvent, and suspension is taken out
Filter, dry 5', 7,7'- trihydroxy -2'- (4- hydroxy phenyls) -2H, 4'H- [6,8'- dibenzopyrans] -2,4'- diketone
41.78mg, yield 100%.
1H NMR (400MHz, DMSO) δ 10.82 (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 explanation 1, yield 100%.
1HNMR (400MHz, DMSO) δ 11.01 (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 phenyls) -5', 7,7'- trihydroxies -2H, 4'H- [6,8'- dibenzopyrans] -2,4'- diketone
Method is with explanation 1, yield 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 phenyls) -3', 5', 7,7'- tetrahydroxys -2H, 4'H- [6,8'- dibenzopyrans] -2,4'-
Diketone
The compound is direct material by flavones Quercetin, and other method is with explanation 1, yield 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'- dihydroxy -2'- (4- hydroxy phenyls) -7- methoxyl groups -2H, 4'H- [6,8'- dibenzopyrans] -2,4'-
Diketone
57mg (0.1mmol) 5,7,4 '-triisopropyl -8- (ayapanin) apiolins are taken in 25mL round-bottomed flasks
In, dissolved with 5mL dichloromethane, be placed at 0 DEG C and stir 10min, 70mg (0.6mmol/1M inDCM) boron chloride adds dropwise
Enter, reacting liquid temperature is slowly raised 40 DEG C of back flow reaction 4h.Question response is cooled under room temperature, stirring condition, to reaction solution plus
Enter excessive frozen water quenching reaction, Rotary Evaporators remove dichloromethane solvent, and to suspension suction filtration, dry 5', 7'- bis-
Hydroxyl -2'- (4- hydroxy phenyls) -7- methoxyl groups -2H, 4'H- [6,8'- dibenzopyrans] -2,4'- diketone 43mg, yield
97%.
1HNMR (400MHz, DMSO) δ 10.93 (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'- dihydroxy -2'- phenyl -7- methoxyl groups -2H, 4'H- [6,8'- dibenzopyrans] -2,4'- diketone
Method is with explanation 5, reaction yield 98%.
1HNMR (400MHz, DMSO) δ 11.07 (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'- dihydroxy -2'- (3,4- dihydroxy phenyls) -7- methoxyl groups -2H, 4'H- [6,8'- dibenzopyrans] -2,
4'- diketone
Method is with explanation 5, yield 95%.
1HNMR(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 phenyls) -3', 5', 7'- trihydroxy -7- methoxyl groups -2H, 4'H- [6,8'- dibenzo pyrroles
Mutter] -2,4'- diketone
Method is with explanation 5, reaction yield 98%
1HNMR(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：Test to alpha-glucosaccharase enzyme inhibition activity
The alpha-glucosidase commodity (Sigma, G5003) extracted from brewer's yeast are target protein, with 4- nitros
Benzene-α-D glucopyranosides (pNGP, Sigma, N1377) are substrate.Compound and acarbose are dissolved in DMSO solution.
Enzyme and substrate are dissolved in during concentration is the kaliumphosphate buffer that 0.05mol/L pH value is 6.8.It is α-Portugal in enzymatic reaction system
The μ L (0.06U) of polyglycoside enzyme 20, substrate is 1mmol/L30 μ L, the μ L of testing compound 10,140 μ L phosphate buffers, in 37 DEG C of temperature
Apply 30 minutes.With ELIASA in wavelength be at 405nm detection enzymatic activity.Final result be by three it is independent repeat empirical averages and
.
The cumarin substituted flavonoids alpha-glucosaccharase enzyme inhibition activity of table 1
Claims (2)
1. a class cumarin replaces the preparation method of flavone derivative, it is characterised in that：The general structure of the derivative is such as
Under：
Wherein, R1For OH or H, R2For OH or H, R3For OH or H, R4For OH or CH3O；
Prepare reaction equation as follows：
Wherein R1For OH or H, R2For OH or H, R3For OH or H, R4For OH or CH3O。
2. cumarin substitution flavone derivative the answering in treatment diabetes medicament is prepared prepared by a class claim 1
With.
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| 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 |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| 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 |
Non-Patent Citations (2)
| Title |
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| Flavone-coumarin hybrids from Gnidia socotrana;Katrin Franke et al.;《Phytochemistry》;20021231;第61卷(第7期);873-878 * |
| Total synthesis of 8-(6"-umbelliferyl)-apigenin and its analogs as anti-diabetic reagents;Guojun Pan et al.;《European Journal of Medicinal Chemistry》;20160711;第122卷;674-683 * |
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