CN1475487A - Fluoro flavon containing compound, manufacturing method and its use - Google Patents
Fluoro flavon containing compound, manufacturing method and its use Download PDFInfo
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- CN1475487A CN1475487A CNA031414869A CN03141486A CN1475487A CN 1475487 A CN1475487 A CN 1475487A CN A031414869 A CNA031414869 A CN A031414869A CN 03141486 A CN03141486 A CN 03141486A CN 1475487 A CN1475487 A CN 1475487A
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Abstract
A fluoric flavone compound and its preparing process are disclosed. Said compound can be used to prepare medicines for treating cancer, hypertension, hyperglycemia, dysphoria and bacterial and viral diseases. The compound is prepared by introducing fluorine-containing group into flavone-like compound. Its advantage is high curative effect and low poison.
Description
Technical field
The present invention relates to fluorine flavonoid compound, manufacture method and uses thereof, specifically, relate to the fluorine-containing flavonoid compound that a class has anticancer, step-down, hypoglycemic, sedation and anti-anxiety, effect such as antibiotic, antiviral.
Background technology
Flavonoid compound is distributed widely in vegitabilia, and about 20% herbal medicine contains flavonoid compound (Tu Shizhong.The pharmacy circular, 1979,14:37), at industrial natural dyestuff and the grease sanitas of being used as.Pharmaceutical research shows, flavonoid compound have coronary artery dilator, anti-inflammatory, antibiotic, antitumor, hypotensive, prevent and treat trachitis and multiple physiologically active and pharmacological action (Wang Lanming, Chinese Journal of Pharmaceuticals, 1990,21 (9): 423) such as protect the liver.But the biological activity of flavonoid compound weak (Liu Zhong then, herbal medicine, 1987,18 (4): 34), thereby limit its application.In order to strengthen its effect, YanBing Shuan etc. (Chinese pharmaceutical chemistry magazine, 1995,5 (1): 44) introduce groups such as imidazoles, amino, alkyl in the flavonoid compound basic framework and synthetic a series of derivatives by report.Though these compounds can improve the effect (as strengthening hematoblastic restraining effect) of flavonoid compound to a certain extent, but only can be used as lead compound and fail to be used for clinical, the more weak shortcoming of biological activity fails to solve effectively, can not satisfy the needs of field of medicaments.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of new fluorine-containing flavonoid compound, to overcome the more weak shortcoming of biological activity that prior art exists;
Another technical problem that the present invention need solve is the preparation method who discloses described compound;
Another technical issues that need to address of the present invention are to disclose the application of described compound in the medicine of diseases such as preparation treatment cancer, hypertension, hyperglycemia, anxiety insomnia, bacterium or virus infection, satisfy the needs of field of medicaments.
Technical conceive of the present invention is such:
The contriver introduces fluoro-containing group in the flavonoid compound, has obtained a kind of new higher bioactive flavonoid compound that has.
Fluorine-containing flavone derivative of the present invention is the compound with one of following general structure:
Wherein: R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10Can be identical or different, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10Represent hydrogen, oxygen, halogen, alkyl, alkoxyl group, acyl alkoxyl group, alkynyl, thiazolinyl; cycloalkyl, aralkyl, phenyl, cyano group alkyl, 4-nitro alkyl, carboxyl, alkylhalide group, list or polyhydroxy alkyl, alkyl-thio-alkyl, alkyl sulfonyl alkyl, acyloxy alkyl, acyl group alkyl, nitro, sulfonic group ,-RN;-SR ,-NR
2,-NRR ' or-RCF
2R '
Wherein, R represents in oxygen, sulphur, halogen, alkyl, thiazolinyl, alkynyl, benzene, aralkyl or the hydroxyl, and R ' represents in hydrogen, oxygen, sulphur, halogen, alkyl, thiazolinyl, alkynyl, benzene, aralkyl or the hydroxyl, R
1, R
2, R
3, R
4, R
6, R
7, R
8, R
9, R
10In at least one is-RCF
2R '.
Preferred R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10Comprise C
1-C
8Alkyl, C
1-C
16Alkoxyl group, C
2-C
6Alkynyl, thiazolinyl, C
3-C
9Cycloalkyl, C
1-C
10Perfluoroalkyl and two fluoro methoxyl groups.
The preferred compound of the present invention comprises:4 '-trifluoromethyl-5; 7-dihydroxyflavone (code name 101) 4 '-trifluoromethyl-7-flavonol (code name 102) 3 '-trifluoromethyl-5; 7-dihydroxyflavone (code name 103) 3 '-trifluoromethyl-7-flavonol (code name 104) 5; The 7-dimethoxy-4 ' '-trifluoromethyl flavones (code name 105) 5; 7-didecyl oxygen base-4 '-trifluoromethyl flavones (code name 106) 5; 7-dimethoxy-3 '-trifluoromethyl flavones (code name 107) 5; 7--3’- （108）7--4’- （109）7--4’- （110）7--3’- （111）7--3’- （112）5--7- （113）5--7- （114）7--5- （115）5，7-- （116）7--5- （117）6--（4’-）-3- （118）6--（4’-）-3- （119）6--（4’-）-3- （120）。
The present invention also comprises the salt of above-claimed cpd, and said salt comprises sodium salt, sylvite or calcium salt, particular certain cancers.
The preparation method of fluorine-containing flavonoid compound of the present invention comprises the steps:
Having the compound of general formula (1) synthetic is to be raw material with the aryl methyl ketone, forms through phenyl styryl ketone oxidation closed loop (phenyl styryl ketone route) or β-propanedione (acidifying closed loop) route.
Specifically, the compound by the synthetic general formula (1) of phenyl styryl ketone route is performed such: adopt commercially available prod phenyl methyl ketone with general formula A and the aromatic aldehyde with Formula B to obtain having the compound of general formula C under catalyzer and solvent action.
Temperature of reaction is-5～25 ℃, and the reaction times is 2～48 hours; Said solvent comprises ethanol, methyl alcohol or water, preferably water; Said catalyzer is KOH, NaOH or Ca (OH)
2In a kind of or mixture, preferred NaOH.
Reference literature (Meyer Dayan M, et al.Symp Pap-IUPAC Int Symp Chem NatProd, 11
Th, 1978, method 3:21), the compound of general formula C obtains the compound of general formula (1) under catalyzer and solvent action.
Temperature of reaction is 0～60 ℃, and the reaction times is 1～24 hour; Said solvent comprises ethanol, methyl alcohol or water, preferably water; Said catalyzer is Tl (NO
3)
3Perhaps Tl
2(CO
3)
3In a kind of or mixture, preferred Tl (NO
3)
3
Reaction expression is as follows:
Compound by the synthetic general formula (1) of β-propanedione route is performed such: reference literature (Baker W.J Chem Soc, method 1933:1381), the compound that adopts commercially available prod phenyl methyl ketone with general formula A and fragrant formyl chloride under catalyzer and solvent action, to obtain having general formula E with general formula D.
Temperature of reaction is 0～60 ℃, and the reaction times is 1～24 hour; Said catalyzer is a kind of or mixture in pyridine, triethylamine or the ammoniacal liquor, preferred pyridine; Said solvent is a kind of or mixture in pyridine, ethanol or the acetone, preferred pyridine.
Compound with general formula E obtains having general formula under catalyzer and the solvent action compound of (1).
Temperature of reaction is 0～60 ℃, and the reaction times is 1～24 hour; Said catalyzer is pyridine, KOH or Ca (OH)
2In a kind of or mixture, preferred KOH.Said solvent is a kind of or mixture in pyridine, ethanol or the acetone, preferred pyridine.
Reaction expression is as follows:
Preparation method with compound of general formula (2) comprise the steps: compound with general formula (1) under catalyst action with hydrogen reaction, promptly obtain the compound of general formula (2).
Temperature of reaction is 25～120 ℃, and the reaction times is 1～24 hour; Said catalyzer is Zn, Pt, or a kind of or mixture among the Pd, preferred Zn.
Preparation method with compound of general formula (3) comprises the steps:
The phenyl methyl ketone that adopts the commercially available prod to have general formula A obtains having the compound of general formula F under catalyzer and solvent action.
Temperature of reaction is 0～25 ℃, and the reaction times is 1～10 hour;
Said catalyzer is pyridine, KOH or Ca (OH)
2In a kind of or mixture, preferred KOH.
Said solvent is a kind of or mixture in pyridine, ethanol or the acetone, preferred pyridine.
Compound with general formula F and the aromatic aldehyde with Formula B obtain the compound of general formula (3) under catalyzer and solvent action.
Reaction expression is as follows:
Or
The preparation method of fluorine-containing flavonoid compound of the present invention comprises the steps:
(1) being raw material with the Phloroglucinol, is catalyzer with the zinc chloride, with the hydrogen chloride gas precursor reactant, obtains compound 1 in solvent;
Temperature of reaction is-5～10 ℃, and the reaction times is 6～72 hours;
Said solvent is a kind of or mixture in ether, hexanaphthene or the tetrahydrofuran (THF), preferred ether;
Compound 1 with to the trifluoromethylated benzaldehyde reaction, obtain target product 5,7-dihydroxyl-4 '-trifluoromethyl flavones 2; Temperature of reaction is-5～10 ℃, and the reaction times is 2～72 hours;
Reaction formula is as follows:
(2) 5,7-dihydroxyflavones 3 descend and HCF in 70～75 ℃ in solvent
2Cl reaction 6～12 hours obtains target product 5-hydroxyl-7-two fluoro methoxyl group-flavones 4.
Said solvent is dioxane and aqueous sodium hydroxide solution;
Reaction formula is as follows:
(3) 5-hydroxyl-7-methoxyl group 5 descends and HCF in 70～75 ℃ in solvent
2Cl reaction 6～12 hours obtains target product 5-two fluoro methoxyl group-7-methoxy flavone 6; 5-two fluoro methoxyl group-7-methoxy flavone 6 is at solvent C H
2Cl
2In with BBr
3In room temperature reaction 0.5～2 hour, obtain target product 5-two fluoro methoxyl group-7-flavonol 7.
Reaction formula is as follows:
To have general structure (1), the compound of (2) or (3) and alkali react under 10～75 ℃ of conditions, promptly obtain the salt of the said compound of the present invention, and said alkali comprises sodium hydroxide, potassium hydroxide or calcium hydroxide, preferred sodium hydroxide.
Fluorine-containing flavonoid compound of the present invention has been carried out following pharmacological evaluation:
Anticancer aspect comprises in the body and experiment in vitro.Wherein general formula (1) detects with mtt assay and srb assay in experiment in vitro system, and the compound of (2) or (3) has significant cytotoxicity, its IC
50Value is 0.02～25.0nM.Experiment is performed such in the body: give the compound of lotus Lewis lung knurl mouse peritoneal injection general formula (I), and continuous 9 days, can significantly suppress the growth of Lewis lung knurl, inhibiting rate is 82.3%.If abdominal injection 5-25mg/kg general formula (1), the compound of (2) or (3) can suppress the S-180 knurl growth of ICR-Jc1 mouse hypodermic inoculation, and the half inhibiting rate is 0.2-16mg/kg.
The tranquilizing soporific aspect:
0.01-0.62mg/Kg general formula (1), the compound of (2) or (3) has significant sedative-hypnotic effect.
Antibiosis: general formula (1), the compound of (2) or (3) has significant anti-microbial effect, and its MIC is 0.0026-23.10 μ g/ml.
Hypoglycemic aspect: oral 0.2-40mg/Kg general formula (1), the compound of (2) or (3) detect blood sugar concentration and find general formula (1) after 7 days, and the compound of (2) or (3) can make blood sugar concentration reduce 59.1-92.1%.
Hypotensive aspect: oral 6.0-25mg/Kg general formula (1), the compound of (2) or (3) detect blood pressure and find general formula (1) after 14 days, and the compound of (2) or (3) can make blood pressure reduce 40-80mmHg.
Anti-virus aspect: general formula (1), the compound of (2) or (3) can significantly suppress the growth and breeding of HIV-1 virus.
Acute toxicity test: give mice lavage general formula (1) with 1 heavy dose, (2) or the compound of (3), observe index and toxic reaction degree such as small white mouse behavioral activity continuously, and when experiment finishes, put to death small white mouse and analyse, to obtain general formula (1), the toxicity of compound data of (2) or (3).Observed 14 days continuously, it is unusual that small white mouse does not have evident act, death also occurs, and maximum dose level 1000mg/kg and following dosage thereof that experiment is set all do not have overt toxicity to small white mouse.
Prove that by pharmacological evaluation fluorine-containing flavonoid compound of the present invention has in various degree anticancer, step-down, hypoglycemic, sedation and anti-anxiety, antibiotic, antivirus action.And toxicity is lower.
Therefore, fluorine-containing flavonoid compound of the present invention and salt thereof can be used for preparing anticancer, step-down, hypoglycemic, sedation and anti-anxiety, antibiotic, antiviral drug.
Fluorine-containing flavonoid compound of the present invention can composition form be applied to the patient who needs treatment, said composition comprises compound of the present invention and the salt and the pharmaceutically acceptable carrier for the treatment of significant quantity, said carrier comprises thinner (as water), weighting agent (as starch), wetting agent (as glycerine), tackiness agent (as derivatived cellulose) etc., and be prepared into tablet with method well known in the art, capsule, pill, granule, syrup, emulsion, suspension liquid and solution, administration routinely, preferential oral administration, dosage is 0.001～25mg/kg body weight.
By above-mentioned disclosed technical scheme as seen, compound of the present invention has good anticancer, step-down, hypoglycemic, sedation and anti-anxiety, antibiotic, antivirus action, and toxicity is less, and the preparation method is easy, be convenient to suitability for industrialized production, can satisfy the needs of field of medicaments.Compound of the present invention has curative effect height, low toxin.
Embodiment
Embodiment 14 '-trifluoromethyl-5, the preparation of 7-dihydroxyflavone (code name 101):
Add the 0.05mol Phloroglucinol in three-necked bottle, 0.1mol chloromethyl cyanide and 25ml anhydrous diethyl ether are bathed cooling with cryosel, stir to add the anhydrous ZnCl of 1.3 grams down
2, behind the feeding dry hydrogen chloride gas 2h reaction flask being placed the zero degree refrigerator one day, logical again hydrogenchloride 2h placed three days in the zero degree refrigerator.Inclining ether, uses the anhydrous diethyl ether washed twice, with about 250ml hot water crude product is transferred to round-bottomed flask, backflow 1h, and standing over night has the orange crystal to separate out, and suction filtration is used water crystallization, gets faint yellow needle 1, yield 68%.
In three-necked bottle, add 9.64mmol compound 1, make it to be dissolved in 95 ml methanol, add again, and then add 19.5 milliliters of potassium hydroxide solutions trifluoromethylated benzaldehyde 16.1mmol.Under room temperature, react half an hour.Add a normal hydrochloric acid soln, regulate pH value between 6～7, use ethyl acetate extraction.Use anhydrous sodium sulfate drying, filter, rotary distillation gets crude product.With sherwood oil and ethyl acetate is 3: 1 column chromatographies, obtains 4 '-trifluoromethyl-5,7-dihydroxyflavone, yield 92%.
Related data is as follows: MS (EI, 70ev) m/z:322; IR υ
Max(cm
-1, KBr): 1682 (C=O), 3096,3312 (OH);
1H NMR (300MHz, DMSO-d
6): 6.100 (1H, d, J=1.5), 6.230 (1H, d, J=1.5), 6.688 (1H, s), 7.801 (2H, d, J=8.1), 8.076 (2H, d, J=8.1), 11.006 (1H, s), 11.082 (1H, s).
19F NMR (300MHz)-70.95; Anal.Calcd.for C
16H
9F
3O
4: C, 59.64, H, 2.82; Found C, 59.44, H, 2.85.
The preparation of embodiment 24 '-trifluoromethyl-7-flavonol (code name 102):
Replace Phloroglucinol to prepare 4 '-trifluoromethyl-7-flavonol, yield 90% with the 0.05mol Resorcinol according to the method for embodiment 1.
Related data is as follows: MS (EI, 70ev) m/z:306; IR υ
Max(cm
-1, KBr): 1683 (C=O), 3072 (OH);
1H NMR (300MHz, CD
3COCD
3): 6.818 (1H, s), 6.857 (1H, dd, J=2.1,8.4), 6.899 (1H, d, J=2.1), 7.692 (1H, d, J=8.4), 7.774 (2H, d, J=6.8), 8.220 (2H, d, J=6.8), 10.138 (1H, s).
19F NMR (300MHz)-68.627.Anal.Calcd.for C
16H
9F
3O
3: C, 62.75, H, 2.96; Found C, 62.90, H, 3.44.
Embodiment 33 '-trifluoromethyl-5, the preparation of 7-dihydroxyflavone (code name 103):
Replace 4 '-trifluoromethylated benzaldehyde to prepare 3 '-trifluoromethyl-5,7-dihydroxyflavone, yield 91% with 0.05mol 3 '-trifluoromethylated benzaldehyde according to the method for embodiment 1.
Related data is as follows: MS (EI, 70ev) m/z:322; IR υ
Max(cm
-1, KBr): 1680 (C=O), 3092,3308 (OH);
1H NMR (300MHz, DMSO-d
6): 6.102 (1H, d, J=1.5), 6.222 (1H, d, J=1.5), 6.687 (1H, s), 7.806-7.963 (4H, m), 11.012 (1H, s), 11.102 (1H, s).
19FNMR (300MHz)-70.65; Anal.Calcd.for C
16H
9F
3O
4: C, 59.64, H, 2.82; FoundC, 59.74, H, 2.88.
The preparation of embodiment 43 '-trifluoromethyl-7-flavonol (code name 104):
Replace 4 '-trifluoromethylated benzaldehyde to prepare 3 '-trifluoromethyl-7-flavonol, yield 89% with 0.05mol 3 '-trifluoromethylated benzaldehyde according to the method for embodiment 2.
Related data is as follows: MS (EI, 70ev) m/z:306; IR υ
Max(cm
-1, KBr): 1680 (C=O), 3068 (OH);
1H NMR (300MHz, CD
3COCD
3): 6.810 (1H, s), 6.823 (1H, dd, J=2.1,8.4), 6.890 (1H, d, J=2.1), 7.691 (1H, d, J=8.4), 7.779-8.126 (4H, m), 10.136 (1H, s).
19F NMR (300MHz)-68.600.Anal.Calcd.for C
16H
9F
3O
3: C, 62.75, H, 2.96; Found C, 62.90, H, 3.26.
Embodiment 55, the 7-dimethoxy-4 ' '-preparation of trifluoromethyl flavones (code name 105):
With 0.03mol methyl iodide and 0.01mol 4 '-trifluoromethyl-5, the 7-dihydroxyflavone is dissolved in the acetone, adds 10 gram K
2CO
3,, get target product 5, the 7-dimethoxy-4 ' 50 ℃ of reactions 4 hours '-the trifluoromethyl flavones.
Related data is as follows: MS (EI, 70ev) m/z:350; IR υ
Max(cm
-1, KBr): 1705 (C=O);
1H NMR (300MHz, CDCl
3): 3.952 (3H, s), 3.972 (3H, s), 6.156 (1H, dJ=1.8), 6.412 (1H, d, J=1.8), 6.755 (1H, s), 7.671 (2H, d, J=8.4), 7.958 (2H, d, J=8.4).
19F NMR (300MHz)-62.686.Anal.Calcd.for C
18H
13F
3O
4: C, 61.75, H, 3.14; Found C, 61.90, H, 3.44.
Embodiment 65, the preparation of 7-didecyl oxygen base-4 '-trifluoromethyl flavones (code name 106):
With 0.03mol bromo-decane and 0.01mol 4 '-trifluoromethyl-5, the 7-dihydroxyflavone is dissolved in the acetone, adds 10 gram K
2CO
3, got target product 5,7-didecyl oxygen base-4 '-trifluoromethyl flavones in 4 hours 75 ℃ of reactions.
Related data is as follows: MS (EI, 70ev) m/z:602; IR υ
Max(cm
-1, KBr): 1703 (C=O);
1H NMR (300MHz, CDCl
3): 0.884-0.920 (6H, m), 1.298-1.496 (28H, m), 1.822-1.938 (4H, m), 4.053-4.145 (4H, m), 6.146 (1H, d, J=1.2), 6.378 (1H, d, J=1.2), 6.717 (1H, s), 7.679 (2H, d, J=8.1), 7.967 (2H, d, J=8.1).
19F NMR (300MHz)-76.194.HRMS.Calcd.for C
36H
49F
3O
4602.35545; Found:602.35829.
Embodiment 75, the preparation of 7-dimethoxy-3 '-trifluoromethyl flavones (code name 107):
With 0.03mol methyl iodide and 0.01mol 3 '-trifluoromethyl-5, the 7-dihydroxyflavone is dissolved in the acetone, adds 10 gram K
2CO
3, 60 ℃ of reactions got target product 5,7-dimethoxy-3 '-trifluoromethyl flavones in 4 hours.
Related data is as follows: MS (EI, 70ev) m/z:350; IR υ
Max(cm
-1, KBr): 1712 (C=O);
1H NMR (300MHz, CDCl
3): 3.950 (3H, s), 3.976 (3H, s), 6.154 (1H, dJ=1.8), 6.412 (1H, d, J=1.8), 6.752 (1H, s), 7.679-7.358 (4H, m).
19F NMR (300MHz)-62.636.Anal.Calcd.for C
18H
13F
3O
4: C, 61.75, H, 3.14; Found C, 61.88, H, 3.24.
Embodiment 85, the preparation of 7-didecyl oxygen base-3 '-trifluoromethyl flavones (code name 108):
With 0.03mol bromo-decane and 0.01mol 3 '-trifluoromethyl-5, the 7-dihydroxyflavone is dissolved in the acetone, adds 10 gram K
2CO
3, 75 ℃ of reactions got target product 5,7-didecyl oxygen base-3 '-trifluoromethyl flavones in 12 hours.
Related data is as follows: MS (EI, 70ev) m/z:602; IR υ
Max(cm
-1, KBr): 1709 (C=O);
1H NMR (300MHz, CDCl
3): 0.888-0.920 (6H, m), 1.298-1.494 (28H, m), 1.822-1.938 (4H, m), 4.053-4.145 (4H, m), 6.142 (1H, d, J=1.2), 6.372 (1H, d, J=1.2), 6.717 (1H, s), 7.679-7.887 (4H, m).
19F NMR (300MHz)-76.121.HRMS.Calcd.for C
36H
49F
3O
4: 602.35545; Found:602.35229.
The preparation of embodiment 97-methoxyl group-4 '-trifluoromethyl flavones (code name 109):
0.03mol methyl iodide and 0.02mol 4 '-trifluoromethyl-7-flavonol are dissolved in the acetone, add 10 gram K
2CO
3, 50 ℃ of reactions got target product 7-methoxyl group-4 '-trifluoromethyl flavones in 4 hours.
Related data is as follows: MS (EI, 70ev) m/z:320; IR υ
Max(cm
-1, KBr): 1702 (C=O);
1H NMR (300MHz, CD
3Cl
3): 3.972 (3H, s), 6.806 (1H, dd, J=2.1,9.3), 6.821 (1H, s), 7.709 (2H, d, J=8.4), 7.726 (1H, d, J=2.1), 7.745 (1H, d, J=9.3), 8.009 (2H, d, J=8.4).
19F NMR (300MHz)-71.206.
The preparation of embodiment 107-octyloxy-4 '-trifluoromethyl flavones (code name 110):
0.03mol bromooctane and 0.02mol 4 '-trifluoromethyl-7-flavonol are dissolved in the acetone, add 10 gram K
2CO
3, 75 ℃ of reactions got target product 7-octyloxy-4 '-trifluoromethyl flavones in 4 hours.
Related data is as follows: MS (EI, 70ev) m/z:418; IR υ
Max(cm
-1, KBr): 1701 (C=O);
1H NMR (300MHz, CD
3Cl
3): 0.909 (3H, t, J=6.6), 1.313-1.880 (12H, m), 4.088 (2H, t, J=6.6), 6.764 (1H, dd, J=2.1,6.6), 6.779 (1H, d, J=2.1), 6.789 (1H, s), 7.688 (2H, d, J=6.8), 7.712 (1 H, d, J=6.6), 7.985 (2H, d, J=6.8) .19F NMR (300MHz)-68.437.Anal.Calcd.for C
24H
25F
3O
3: C, 68.89, H, 6.02; Found C, 69.10, H, 6.13.
The preparation of embodiment 117-methoxyl group-3 '-trifluoromethyl flavones (code name 111):
Adopt the condition identical with embodiment 10, methyl iodide and 3 '-trifluoromethyl-7-flavonol 50～75 ℃ react 4 hours must target product 7-methoxyl group-3 '-trifluoromethyl flavones.
Related data is as follows: MS (EI, 70ev) m/z:320; IR υ
Max(cm
-1, KBr): 1705 (C=O);
1H NMR (300MHz, CD
3Cl
3): 3.974 (3H, s), 6.801 (1H, dd, J=2.1,9.3), 6.827 (1H, s), 7.716 (1H, d, J=2.1), 7.785 (1H, d, J=9.3), 7.889-8.009 (4H, m).
19F NMR (300MHz)-71.206.
The preparation of embodiment 127-octyloxy-3 '-trifluoromethyl flavones (code name 112):
Adopt the processing condition identical with embodiment 10, bromooctane and 3 '-trifluoromethyl-7-dihydroxyflavone 65 ℃ react 4 hours must target product 7-octyloxy-3 '-trifluoromethyl flavones.
Related data is as follows: MS (EI, 70ev) m/z:418; IR υ
Max(cm
-1, KBr): 1701 (C=O);
1H NMR (300MHz, CD
3Cl
3): 0.908 (3H, t, J=6.6), 1.319-1.880 (12H, m), 4.089 (2H, t, J=6.6), (6.766 1H, dd, J=2.1,6.6), 6.776 (1H, d, J=2.1), 6.789 (1H, s), 7.712 (1H, d, J=6.6), 7.879-7.985 (4H, m).
19F NMR (300MHz)-68.433.Anal.Calcd.for C
24H
25F
3O
3: C, 68.89, H, 6.02; Found C, 69.20, H, 6.19.
The preparation of embodiment 135-hydroxyl-7-two fluoro methoxy flavones (code name 113):
In three-necked bottle, add 9.64mmol compound 1, make it to be dissolved in 95 ml methanol, add phenyl aldehyde 16.1mmol again, and then add 19.5 milliliters of potassium hydroxide solutions.Under room temperature, react half an hour.Add 1 normal hydrochloric acid soln, regulate pH value, use ethyl acetate extraction 6.5.Use anhydrous sodium sulfate drying, filter, rotary distillation gets crude product.With sherwood oil and ethyl acetate is 4: 1 column chromatographies, obtains 5,7-dihydroxyflavone, yield 94%.Make solvent with dioxane, aqueous sodium hydroxide solution, 5,7-dihydroxyflavone and difluorochloromethane reaction obtained compound 5-hydroxyl-7-two fluoro methoxy flavones in 8 hours.
Related data is as follows: 7MS (EI, 70ev) m/z:304; IR υ
Max(cm
-1, KBr): 1662 (C=O);
1H NMR (300MHz, CD
3Cl
3): 6.580 (1H, d, J=2.4), 6.652 (1H, t, J=73.2), 6.770 (1H, d, J=2.4), 6.794 (1H, s), 7.535-7.604 (3H, m), 7.897-7.931 (2H, m), 12.801 (1H, s).
19F NMR (300MHz)-82.235 (J=73.2) .Anal.Calcd.forC
16H
10F
2O
4: C, 63.16, H, 3.13; Found C, 63.18 H, 2.88.
The preparation of embodiment 145-allyloxy-7-two fluoro methoxy flavones (code name 114):
5-hydroxyl-7-two fluoro methoxy flavones are at K
2CO
3Effect is made solvent with acetone down, and the allyl bromide 98 reaction obtains target product 5-allyloxy-7-two fluoro methoxy flavones.
Related data is as follows: 6 MS (EI, 70ev) m/z:344; IR υ
Max(cm
-1, KBr): 1706 (C=O);
1H NMR (300MHz, CD
3Cl
3): 4.690-4.716 (2H, m), 5.363-5.716 (2H, m), 6.058-6.116 (1H, m), 6.408 (1H, t, J=72.9), 6.552 (1H, d, J=2.4), 6.685 (1H, s), 6.838 (1H, d, J=2.4), 7.495-7.535 (3H, m), 7.845-7.878 (2H, m).
19F NMR (300MHz)-82.070 (J=72.9) .Anal.Calcd.for C
19H
14F
2O
4: C, 66.28, H, 4.10; Found C, 66.32, H, 4.30.
The preparation of embodiment 157-hydroxyl-5-two fluoro methoxy flavones (code name 115):
5-hydroxyl-7-methoxyl group 5 descends and HCF in 75 ℃ in solvent
2Cl reaction 9 hours obtains target product 5-two fluoro methoxyl group-7-methoxy flavone; 5-two fluoro methoxyl group-7-methoxy flavone is at solvent C H
2Cl
2In with BBr
3In room temperature reaction 1.2 hours, obtain target product 5-two fluoro methoxyl group-7-flavonol.
Related data is as follows: MS (EI, 70ev) m/z:304; IR υ
Max(cm
-1, KBr): 1660 (C=O);
1H NMR (300MHz, CD
3Cl
3): 6.585 (1H, d, J=2.4), 6.661 (1H, t, J=73.2), 6.770 (1H, d, J=2.4), 6.794 (1H, s), 7.535-7.600 (3H, m), 7.890-7.931 (2H, m), 9.871 (1H, s).
19F NMR (300MHz)-82.265 (J=73.2) .Anal.Calcd.for C
16H
10F
2O
4: C, 63.16, H, 3.13; Found C, 63.36 H, 2.95.
Embodiment 165, the preparation of 7-two-two fluoro methoxy flavones (code name 116):
5, the 7-dihydroxyflavone descends and HCF in 75 ℃ in dioxane, aqueous sodium hydroxide solution
2Cl reaction 30 hours obtains target product 5,7-two-two fluoro methoxy flavones.Related data is as follows: MS (EI, 70ev) m/z:354; IR υ
Max(cm
-1, KBr): 1632 (C=O);
1HNMR (300MHz, CD
3Cl
3): 6.683 (1H, t, J=72.0), 6.746 (1H, s), 6.760 (1H, t, J=75.0), 6.985 (1H, d, J=1.8), 7.239 (1H, d, J=1.8), 7.538-7.579 (3H, m), 7.878-7.911 (2H, m).
19F NMR (300MHz)-82.765 (1H, t, J=75.0) ,-83.804 (1H, t, J=72.0) .Anal.Calcd.for C
17H
10F
4O
4: C, 57.64, H, 2.82; Found C, 57.57 H, 3.23.
The preparation of embodiment 177-allyloxy-5-two fluoro methoxy flavones (code name 117):
At K
2CO
3Effect is made solvent with acetone down, and 0.01mol7-hydroxyl-5-two fluoro methoxyl group-flavones and the reaction of 0.01mol allyl bromide 98 obtained target product 7-allyloxy-5-two fluoro methoxy flavones in 3 hours.
Related data is as follows: MS (EI, 70ev) m/z:346; IR υ
Max(cm
-1, KBr): 1653 (C=O);
1H NMR (300MHz, CD
3Cl
3): 1.138 (3H, t, J=7.5), 1.938-2.008 (2H, m), 4.053 (2H, t, J=6.3), 6.540 (1H, d, J=2.4), 6.658 (1H, t, J=72.6), 6.706 (1H, s), 6.817 (1H, d, J=2.4), 7.525-7.501 (3H, m), 7.887-7.856 (2H, m), 12.801 (1H, s).
19F NMR (300MHz)-81.991 (J=72.6) .Anal.Calcd.for C
19H
16F
2O
4: C, 65.91, H, 5.21; Found C, 65.62 H, 5.62.
Synthesizing of embodiment 186-hydroxyl-(4 '-trifluoromethyl Ben Yajiaji) cumarone-3-ketone (code name 118)
5.5 gram (0.05mol) Resorcinol, 7.5 gram (0.1mol) chloromethyl cyanide and 25ml anhydrous diethyl ethers are bathed cooling with cryosel, stir to add the anhydrous ZnCl of 1.3 grams down
2, feed dry hydrogen chloride gas, behind the 2h reaction flask placed in the zero degree refrigerator one day, logical again hydrogenchloride 2h placed three days in the zero degree refrigerator.Inclining ether, uses the anhydrous diethyl ether washed twice, with about 250ml hot water crude product is transferred to round-bottomed flask, backflow 1h, standing over night has the orange crystal to separate out, and suction filtration is used water crystallization, get i.e. 2 ', the 4 '-dihydroxyl-2-chloro-acetophenone of the faint yellow needle compound of 6.9 grams, yield 78%.
In three-necked bottle, add 1.97 gram sodium, stir,, add 2 ', 4 '-dihydroxyl-2-chloro-acetophenone 3.44 grams (18.6mmol), add 30.7 ml methanol again with slow Dropwise 5 5.3 ml methanol of dropping funnel.Be warming up to 63 degrees centigrade of reflux temperatures, refluxed two hours.Cool off, add one mole hydrochloric acid soln, regulate pH value and approximate 7.With ethyl acetate extraction three times, the extract washing, anhydrous sodium sulfate drying is used in the saturated common salt washing again, filters, and is spin-dried for.Get crude product 1.8 grams.With methylene dichloride and acetone is to carry out column chromatography at 19: 1,6-hydroxyl benzofuran-3-ketone 1.47 grams, yield 93.5%.
In three-necked bottle, add 6-hydroxyl benzofuran-3-ketone 1.45 grams (9.64mmol), make it to be dissolved in 95 ml methanol, add again trifluoromethylated benzaldehyde 2.8 grams (16.1mmol), and then add 19.5 milliliters of potassium hydroxide solutions (being dissolved in 22 ml waters by 10.9 gram potassium hydroxide is made into).Be heated to room temperature (about 25 degrees centigrade), react half an hour.Add a normal hydrochloric acid soln, regulate the pH value, use ethyl acetate extraction 6.5.Use anhydrous sodium sulfate drying, filter, rotary distillation gets crude product.With sherwood oil and ethyl acetate is 3: 1 column chromatographies, gets 6-hydroxyl-(4 '-trifluoromethyl Ben Yajiaji) cumarone-3-ketone 1.32 grams, yield 85%.Related data is as follows: MS (EI, 70ev) m/z:306; IR υ
Max(cm
-1, KBr): 1778 (C=O);
1HNMR (300MHz, CD
3COCD
3): 6.781 (1H, s), 6.822 (1H, dd, J=2.1,7.8), 6.864 (1H, d, J=2.1), 7.656 (2H, d, J=8.4), 7.821 (1H, d, J=7.8), 8.174 (2H, d, J=8.4), 10.118 (1H, s).
19F NMR (300MHz)-70.772.Anal.Calcd.for C
16H
9F
3O
3: C, 62.75, H, 2.96; Found C, 62.69, H, 2.97.
Synthesizing of embodiment 196-methoxyl group-(4 '-trifluoromethyl Ben Yajiaji) cumarone-3-ketone (code name 119)
In three-necked bottle, add (Z)-6-hydroxyl-(4 '-trifluoromethyl Ben Yajiaji) cumarone-3-ketone 10mmol, methyl iodide 12mmol, 30mmolK
2CO
3(anhydrous) makes solvent with acetone, and back flow reaction 6h reclaims acetone, and K is removed in washing
2CO
3, use acetone recrystallization, get compound 6-methoxyl group-(4 '-trifluoromethyl Ben Yajiaji) cumarone-3-ketone, yield 96%.
Related data is as follows: MS (EI, 70ev) m/z:320; IR υ
Max(cm
-1, KBr): 1702 (C=O);
1H NMR (300MHz, CD
3Cl
3): 3.974 (3H, s), 6.798 (1H, s), 6.818 (1H, dd, J=2.1,7.8), 7.710 (1H, d, J=2.1), 7.715 (2H, d, J=8.4), 7.747 (1H, d, J=7.8), 8.004 (2H, d, J=8.4).
19F NMR (300MHz)-70.493.
Synthesizing of embodiment 206-oxygen in heptan base-(4 '-trifluoromethyl Ben Yajiaji) cumarone-3-ketone (code name 120)
In three-necked bottle, add (Z)-6-hydroxyl-(4 '-trifluoromethyl Ben Yajiaji) cumarone-3-ketone 10mmol, heptyl bromide 12mmol, 30mmolK
2CO
3(anhydrous) makes solvent with acetone, and back flow reaction 15h reclaims acetone, and K is removed in washing
2CO
3, use acetone recrystallization, get compound 6-oxygen in heptan base-(4 '-trifluoromethyl Ben Yajiaji) cumarone-3-ketone, yield 92%.Related data is as follows: MS (EI, 70ev) m/z:404; IR υ
Max(cm
-1, KBr): 1699 (C=O);
1HNMR (300MHz, CD
3Cl
3): 0.887 (3H, t, J=6.9), 0.925-1.873 (10H, m), 4.079 (2H, t, J=6.9), 6.756 (1H, dd, J=2.1,9.0), 6.773 (1H, d, J=2.1), 6.777 (1H, s), 7.677 (2H, d, J=7.8), 7.696 (1H, d, J=9.0), 7.972 (2H, d, J=7.8).
19F NMR (300MHz)-67.871.Anal.Calcd.for C
23H
23F
3O
3: C, 68.31, H, 5.73; Found C, 68.92, H, 6.21.
Embodiment 21
With reference to the method (Mosman, T.J.Immunol Methods.1983,65,55) of Mosman, by the MTT colorimetric method for determining cytotoxicity of embodiment 1～8 compound, it the results are shown in Table 1.
Table 1
| Active compound | Anti-cancer of the stomach IC50nM | Anti-prostate cancer IC50nM | Anti-cervical cancer IC50nM | Anti-lung cancer IC50nM | Anti-breast cancer IC50nM |
| Embodiment 1 | ????8.06 | ????0.30 | ????0.24 | ????6.50 | ????0.45 |
| Embodiment 2 | ????0.23 | ????1.65 | ????7.86 | ????5.03 | ????22.32 |
| Embodiment 3 | ????9.56 | ????3.33 | ????3.42 | ????0.05 | ????2.87 |
| Embodiment 4 | ????12.58 | ????0.06 | ????1.03 | ????4.35 | ????2.21 |
| Embodiment 5 | ????7.89 | ????9.89 | ????23.67 | ????0.39 | ????10.26 |
| Embodiment 6 | ????6.25 | ????9.07 | ????5.24 | ????0.82 | ????2.28 |
| Embodiment 7 | ????0.02 | ????16.33 | ????4.13 | ????1.07 | ????8.62 |
| Embodiment 8 | ????5.46 | ????2.73 | ????6.03 | ????8.36 | ????0.02 |
| Embodiment 9 | ????4.25 | ????3.87 | ????8.47 | ????1.33 | ????6.83 |
Embodiment 22
Reference literature (Japanese plum is new, etc.Acta Pharmacologica Sinica, 1996,12:479) utilize rabbit ASS, research various dose general formula (1), (2), the influence that the compound of (3) is regained consciousness and slept rat.It the results are shown in Table 2.Table 2
| Active compound | Dosage mg/Kg | Clear-headed | Shallow sleep | ????SWS | ????REMS％ |
| Embodiment 1 | ????0.01 | ????39.04 | ????26.24 | ????25.17 | ????6.02 |
| Embodiment 2 | ????0.26 | ????28.54 | ????32.03 | ????27.06 | ????7.35 |
| Embodiment 3 | ????0.62 | ????57.38 | ????20.45 | ????19.23 | ????3.58 |
| Embodiment 4 | ????0.01 | ????20.06 | ????26.58 | ????20.48 | ????1.24 |
| Embodiment 5 | ????0.35 | ????16.70 | ????30.22 | ????31.09 | ????2.32 |
Embodiment 23
Reference literature (Zhang Juntian chief editor, modern pharmacology experimental technique.) research various dose general formula (1), (2), the compound of (3) is to the effect of bacterium, fungi.It the results are shown in Table 3.Table 3
| Active compound | Staphylococcus MIC μ g/ml | Streptococcus m IC μ g/ml | Intestinal bacteria MIC μ g/ml | Candida albicans MIC μ g/ml | Cryptococcus neoformans MIC μ g/ml |
| Embodiment 1 | ????0.023 | ????9.29 | ????9.85 | ?0.19 | ????9.72 |
| Embodiment 2 | ????0.92 | ????0.017 | ????7.22 | ?10.67 | ????2.54 |
| Embodiment 3 | ????10.21 | ????2.78 | ????0.0026 | ?0.0067 | ????0.18 |
| Embodiment 4 | ????8.54 | ????8.65 | ????0.094 | ?19.22 | ????19.68 |
| Embodiment 5 | ????23.10 | ????18.10 | ????1.46 | ?3.17 | ????0.025 |
| Embodiment 6 | ????6.32 | ????22.06 | ????6.25 | ?5.01 | ????0.0073 |
Embodiment 24
Reference literature (Joon-Su Shin, et al.Bioorg.Med.Chem.Lett.1999, method research various dose general formula (1) 9:869), (2), the hypoglycemic activity of the compound of (3).It the results are shown in Table 4.Table 4
| Active compound | Dosage mg/Kg | Blood sugar reduces (%) |
| Embodiment 1 | ????0.2 | ????82.3 |
| Embodiment 2 | ????0.4 | ????76.5 |
| Embodiment 3 | ????0.8 | ????92.1 |
| Embodiment 4 | ????2.0 | ????66.4 |
| Embodiment 5 | ????10 | ????69.3 |
| Embodiment 6 | ????20 | ????89.5 |
| Embodiment 7 | ????40 | ????59.1 |
Embodiment 25
The tablet that the compound of the general formula that is used for the treatment of (I) adopts can be by method preparation well known in the art.The compound 125mg Magnesium Stearate 4mg talcum powder 6mg lactose 55mg starch 30mg of general formula (I)
Embodiment 26
The compound 100mg dolomol 20mg talcum powder 20mg lactose 55mg starch 10mg polyvinylpyrrolidone 10mg of The capsule that the compound of the general formula that is used for the treatment of (I) adopts can be by method preparation well known in the art. general formula (I)
Claims (15)
1. a fluorine-containing flavonoid compound is characterized in that, has the compound of one of following general structure:
Wherein: R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10Can be identical or different, R
1, R
2, R
3, R
2, R
5, R
6, R
7, R
8, R
9, R
10Represent hydrogen, oxygen, halogen, alkyl, alkoxyl group, acyl alkoxyl group, alkynyl, thiazolinyl; cycloalkyl, aralkyl, phenyl, cyano group alkyl, 4-nitro alkyl, carboxyl, alkylhalide group, list or polyhydroxy alkyl, alkyl-thio-alkyl, alkyl sulfonyl alkyl, acyloxy alkyl, acyl group alkyl, nitro, sulfonic group ,-RN;-SR ,-NR
2,-NRR ' or-RCF
2R ';
Wherein, R represents in oxygen, sulphur, halogen, alkyl, thiazolinyl, alkynyl, benzene, aralkyl or the hydroxyl, and R ' represents in hydrogen, oxygen, sulphur, halogen, alkyl, thiazolinyl, alkynyl, benzene, aralkyl or the hydroxyl, R
1, R
2, R
3, R
4, R
6, R
7, R
8, R
9, R
10In at least one is-RCF
2R '.
2. compound according to claim 1 is characterized in that R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10Comprise C
1-C
8Alkyl, C
1-C
16Alkoxyl group, C
2-C
6Alkynyl, thiazolinyl, C
3-C
9Cycloalkyl, C
1-C
10In perfluoroalkyl and the two fluoro methoxyl groups one.
3. compound according to claim 1; It is characterized in that; Said compound comprises:4 '-trifluoromethyl-5; 7-dihydroxyflavone (code name 101) 4 '-trifluoromethyl-7-flavonol (code name 102) 3 '-trifluoromethyl-5; 7-dihydroxyflavone (code name 103) 3 '-trifluoromethyl-7-flavonol (code name 104) 5; The 7-dimethoxy-4 ' '-trifluoromethyl flavones (code name 105) 5; 7-didecyl oxygen base-4 '-trifluoromethyl flavones (code name 106) 5; 7-dimethoxy-3 '-trifluoromethyl flavones (code name 107) 5; 7--3’- （108）7--4’- （109）7--4’- （110）7--3’- （111）7--3’- （112）5--7- （113）5--7- （114）7--5- （115）5，7-- （116）7--5- （117）6--（4’-）-3- （118）6--（4’-）-3- （119）6--（4’-）-3- （120）。
4. the salt of claim 1,2 or 3 described compounds.
5. salt according to claim 4 is characterized in that said salt comprises sodium salt, sylvite or calcium salt.
6. according to the preparation method of claim 1,2 or 3 described compounds, it is characterized in that the compound of general formula (1) comprises the steps:
The phenyl methyl ketone that will have a general formula A and the aromatic aldehyde with Formula B obtain having the compound of general formula C under catalyzer and solvent action;
Temperature of reaction is-5～25 ℃, and the reaction times is 2～48 hours; Said solvent is a kind of or mixture in ethanol, methyl alcohol or the water; Said catalyzer is KOH, NaOH or Ca (OH)
2In a kind of or mixture;
Compound with general formula C obtains the compound of general formula (1) under catalyzer and solvent action;
Temperature of reaction is 0～60 ℃, and the reaction times is 1～24 hour; Said solvent is a kind of or mixture in ethanol, methyl alcohol or the water, preferably water; Said catalyzer is Tl (NO
3)
3Perhaps Tl
2(CO
3)
3In a kind of or mixture,
Reaction expression is as follows:
Or
The phenyl methyl ketone that will have a general formula A and the fragrant formyl chloride with general formula D obtain having general formula E under catalyzer and solvent action compound;
Temperature of reaction is 0～60 ℃, and the reaction times is 1～24 hour; Said catalyzer is a kind of or mixture in pyridine, triethylamine or the ammoniacal liquor, and said solvent is a kind of or mixture in pyridine, ethanol or the acetone;
Compound with general formula E obtains having general formula under catalyzer and the solvent action compound of (1);
Temperature of reaction is 0～60 ℃, and the reaction times is 1～24 hour; Said catalyzer is pyridine, KOH or Ca (OH)
2In a kind of or mixture, preferred KOH.Said solvent is a kind of or mixture in pyridine, ethanol or the acetone;
Reaction expression is as follows:
7. method according to claim 6 is characterized in that, also comprise the steps: compound with general formula (1) under catalyst action with hydrogen reaction, promptly obtain the compound of general formula (2);
Temperature of reaction is 25～120 ℃, and the reaction times is 1～24 hour; Said catalyzer is Zn, Pt, or a kind of or mixture among the Pd.
8. according to the preparation method of claim 1,2 or 3 described compounds, it is characterized in that the phenyl methyl ketone that will have general formula A obtains having the compound of general formula F under catalyzer and solvent action; Temperature of reaction is 0～25 ℃, and the reaction times is 1～10 hour; Said catalyzer is pyridine, KOH or Ca (OH)
2In a kind of or mixture; Said solvent is a kind of or mixture in pyridine, ethanol or the acetone; Compound with general formula F and the aromatic aldehyde with Formula B obtain the compound of general formula (3) under catalyzer and solvent action, reaction expression is as follows:
9. one kind 5, the preparation method of 7-dihydroxyl-4 '-trifluoromethyl flavones is characterized in that, comprises the steps:
With the Phloroglucinol is raw material, is catalyzer with the zinc chloride, with the hydrogen chloride gas precursor reactant, obtains compound 1 in solvent; Temperature of reaction is-5～10 ℃, and the reaction times is 6～72 hours;
Said solvent is a kind of or mixture in ether, hexanaphthene or the tetrahydrofuran (THF), preferred ether;
Compound 1 with to the trifluoromethylated benzaldehyde reaction, obtain target product 5,7-dihydroxyl-4 '-trifluoromethyl flavones; Temperature of reaction is-5～10 ℃, and the reaction times is 2～72 hours.
10. the preparation method of 5-hydroxyl-7-two fluoro methoxyl group-flavones is characterized in that, comprises the steps:
5,7-dihydroxyflavone 3 descends and HCF in 70～75 ℃ in solvent
2Cl reaction 6～12 hours obtains target product 5-hydroxyl-7-two fluoro methoxyl group-flavones; Said solvent is dioxane and aqueous sodium hydroxide solution.
11. the preparation method of 5-two fluoro methoxyl group-7-methoxy flavone is characterized in that, comprises the steps:
5-hydroxyl-7-methoxyl group descends and HCF in 70～75 ℃ in solvent
2Cl reaction 6～12 hours obtains target product 5-two fluoro methoxyl group-7-methoxy flavone.
12. the preparation method of 5-two fluoro methoxyl group-7-flavonol is characterized in that, comprises the steps: that 5-two fluoro methoxyl group-7-methoxy flavone is at solvent C H
2Cl
2In with BBr
3In room temperature reaction 0.5～2 hour, obtain target product 5-two fluoro methoxyl group-7-flavonol.
13. the preparation method of the salt of claim 1,2 or 3 described compounds is characterized in that comprising the steps:
Compound and the alkali addressed are reacted under 10～75 ℃ of conditions, promptly obtain the salt of the said compound of the present invention, said alkali comprises sodium hydroxide, potassium hydroxide or calcium hydroxide.
14. contain the composition of the claim 1 for the treatment of significant quantity, 2 or 3 described compounds and pharmaceutically acceptable carrier.
15. claim 1,2 or 3 described compounds are anticancer in the preparation treatment, the application in step-down, hypoglycemic, sedation and anti-anxiety, antibiotic, the antiviral drug.
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|---|---|---|---|
| CNA031414869A CN1475487A (en) | 2003-07-09 | 2003-07-09 | Fluoro flavon containing compound, manufacturing method and its use |
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|---|---|---|---|
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106138195A (en) * | 2015-04-04 | 2016-11-23 | 兰州迈德生医药科技有限责任公司 | Application in preparing antibacterial, antiviral drugs for the tangut dragonhead purification of flavone |
| WO2018194172A1 (en) * | 2017-04-21 | 2018-10-25 | 土田 裕三 | Compound or salt thereof, antiviral agent, and pharmaceutical composition |
| CN110003157A (en) * | 2019-04-12 | 2019-07-12 | 黑龙江中医药大学 | A kind of novel flavone compound and its application with angst resistance effect |
| CN115160278A (en) * | 2022-06-13 | 2022-10-11 | 南华大学 | B-ring aryl urea flavonoid compound, preparation method and application thereof |
| CN117462539A (en) * | 2023-12-26 | 2024-01-30 | 云南中医药大学 | Application and preparation method of flavanonol compound for resisting coronavirus |
-
2003
- 2003-07-09 CN CNA031414869A patent/CN1475487A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106138195A (en) * | 2015-04-04 | 2016-11-23 | 兰州迈德生医药科技有限责任公司 | Application in preparing antibacterial, antiviral drugs for the tangut dragonhead purification of flavone |
| WO2018194172A1 (en) * | 2017-04-21 | 2018-10-25 | 土田 裕三 | Compound or salt thereof, antiviral agent, and pharmaceutical composition |
| CN110003157A (en) * | 2019-04-12 | 2019-07-12 | 黑龙江中医药大学 | A kind of novel flavone compound and its application with angst resistance effect |
| CN115160278A (en) * | 2022-06-13 | 2022-10-11 | 南华大学 | B-ring aryl urea flavonoid compound, preparation method and application thereof |
| CN117462539A (en) * | 2023-12-26 | 2024-01-30 | 云南中医药大学 | Application and preparation method of flavanonol compound for resisting coronavirus |
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