CN1475488A - Fluoro isoflavone containing derivative, monufacturing method and its use - Google Patents
Fluoro isoflavone containing derivative, monufacturing method and its use Download PDFInfo
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- CN1475488A CN1475488A CNA031414877A CN03141487A CN1475488A CN 1475488 A CN1475488 A CN 1475488A CN A031414877 A CNA031414877 A CN A031414877A CN 03141487 A CN03141487 A CN 03141487A CN 1475488 A CN1475488 A CN 1475488A
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Abstract
A fluoric isoflavone derivative and its preparing process are disclosed. Said derivative can be used to prepare the medicines for treating cancer, hypertension, hyperglycemia, dysphoria and bacterial and viral diseases. Its advantages are high curative effect and low poison.
Description
Technical field
The present invention relates to fluorine isoflavone derivative, manufacture method and uses thereof, specifically, relate to the fluorine-containing osajin derivative that a class has anticancer, step-down, hypoglycemic, sedation and anti-anxiety, antibiotic, antivirus action.
Background technology
Isoflavonoid is distributed widely in vegitabilia, isoflavonoid have coronary artery dilator, anti-inflammatory, antibiotic, antitumor, hypotensive, prevent and treat trachitis and multiple physiologically active and pharmacological action such as protect the liver.But the biological activity of isoflavonoid a little less than, thereby limited its application at field of medicaments.In order to strengthen its effect, document (YanBing Shuan, etc.China's pharmaceutical chemistry magazine, 1995,5 (1): 44) report is introduced groups such as imidazoles, amino, alkyl in the isoflavonoid basic framework and synthetic a series of derivatives, though can improve the effect (as strengthening) of isoflavonoid to a certain extent, only can be used as lead compound and fail to be used for clinical to hematoblastic restraining effect.So the technology of above-mentioned bibliographical information fails to deal with problems effectively.
Summary of the invention
The technical issues that need to address of the present invention provide a kind of new fluorine-containing isoflavone derivative, to satisfy the needs of field of medicaments;
Two of the technical issues that need to address of the present invention provide the preparation method of above-mentioned fluorine-containing isoflavone derivative;
Another technical issues that need to address of the present invention provide the application of described fluorine-containing isoflavone derivative in the medicine of diseases such as preparation treatment cancer, hypertension, hyperglycemia, anxiety insomnia, mushroom or virus infection.
Technical conceive of the present invention is such: in order to strengthen the activity of isoflavonoid, the contriver introduces fluoro-containing group in the isoflavonoid, to obtain a kind of novel fluorine-containing isoflavone derivative, to improve the biological activity of isoflavonoid, to satisfy the needs of clinical application.
Fluorine-containing isoflavone 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 ', 5-two-hydroxyl-7-two fluoro methoxyl group isoflavones (code name 101)
5-hydroxyl-4 ', 7-two-two fluoro methoxyl group isoflavones (code name 102)
4 ', 5-two-methoxyl group-7-two fluoro methoxyl group isoflavones (code name 103)
4 ', 5-two-oxyethyl group-7-two fluoro methoxyl group isoflavones (code name 104)
4 ', 5-two-propoxy--7-two fluoro methoxyl group isoflavones (code name 105)
4 ', 5-two-benzyloxy-7-two fluoro methoxyl group isoflavones (code name 106)
4 ', 5-oxygen in two-heptan base-7-two fluoro methoxyl group isoflavones (code name 107)
4 ', 5-two-octyloxy-7-two fluoro methoxyl group isoflavones (code name 108)
4 ', 5-oxygen in two-last of the ten Heavenly stems base-7-two fluoro methoxyl group isoflavones (code name 109)
4 ', 5-two-two fluoro methoxyl group 7-methoxyl group isoflavones (code name 110)
4 ', 5-two-two fluoro oxygen in last of the ten Heavenly stems base 7-oxygen in last of the ten Heavenly stems base isoflavones (code name 111)
5-hydroxyl-4 '-methoxyl group-7-two fluoro methoxyl group isoflavones (code name 112)
5-hydroxyl-4 '-last of the ten Heavenly stems oxygen base-7-two fluoro methoxyl group isoflavones (code name 113).
The present invention also comprises the salt of the compound of being addressed, and said salt comprises sodium salt, sylvite or calcium salt, particular certain cancers.
The preparation method of compound of the present invention is as follows:
Wherein:
Preparation method with compound of general formula (1) comprises the steps: commercially available prod A and B are obtained having the compound of general formula C under catalyzer and solvent action.
Temperature of reaction is 5～65 ℃, 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 KOH, NaOH or Ca (OH)
2In a kind of or mixture, preferred NaOH.
Reference literature (Nirada Devi, et al.Indian J.Chem.1993,2B:874) disclosed method, the 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 DMF, pyridine or the triethylamine, preferred DMF;
Said catalyzer is ZnCl
2/ POCl
3Or DMF/MeSO
2Cl, preferred ZnCl
2/ POCl
3
Reaction expression is as follows:
Preparation method with compound of general formula (2) comprises the steps:
With the compound of said 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 1～36 hour;
Said catalyzer is a kind of or mixture among Zn, Pt or the Pd, preferred Zn;
Reaction expression is as follows:
Preparation method with compound of general formula (3) comprises the steps:
The compound of said general formula (1) is reacted with hydrazine hydrate under catalyst action, promptly obtain the compound of general formula (3), temperature of reaction is 0～120 ℃, and the reaction times is 1～36 hour;
Said catalyzer is KOH, NaOH or Ca (OH)
2In a kind of or mixture, preferred NaOH;
Reaction expression is as follows:
Preparation method with compound of general formula (4) comprises the steps:
With the compound of said general formula (2), under catalyst action,, obtain the compound of general formula (4) with the hydrazine hydrate reaction, temperature of reaction is 0～120 ℃, the reaction times is 1～36 hour;
Said catalyzer is KOH, NaOH or Ca (OH)
2In a kind of or mixture, preferred NaOH.
Reaction expression is as follows:
The preparation method of compound of the present invention also comprises following method:
4 ' 5,7-trihydroxy-isoflavones descend and HCF in 70～75 ℃ in solvent
2Cl reaction 6～12 hours obtains target product 4 ', 5-two-hydroxyl-7-two fluoro methoxyl group isoflavones and 5-hydroxyl-4 ', 7-two-two fluoro methoxyl group isoflavones.
Said solvent is dioxane, aqueous sodium hydroxide solution; Reaction formula is as follows:
To have general structure (1), (2), the compound of (3) or (4) 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.
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 (2), the compound of (3) or (4) has significant cytotoxicity, its IC
50Value is 0.06～25.0nM.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 92.3%.If abdominal injection 5-25mg/kg general formula (1), (2), the compound of (3) or (4), the S-180 that can suppress the ICR-Jc1 mouse hypodermic inoculation stays growth, and the half inhibiting rate is 0.1-10mg/kg.
The tranquilizing soporific aspect:
0.01-0.50mg/Kg general formula (1), (2), the compound of (3) or (4) has significant sedative-hypnotic effect.
Antibiosis: general formula (1), (2), and the compound of (3) or (4) has significant anti-microbial effect, and its MIC is 0.0016-23.10 μ g/ml.
Hypoglycemic aspect: oral 0.1-40mg/Kg general formula (1), (2), the compound of (3) or (4) detects blood sugar concentration and finds general formula (1) after 7 days, and (2), the compound of (3) or (4) can make blood sugar concentration reduce 50.1-90.1%.
Hypotensive aspect: oral 1.0-25mg/Kg general formula (1), (2), the compound of (3) or (4) detects blood pressure and finds general formula (1) after 14 days, and (2), the compound of (3) or (4) can make blood pressure reduce 40-60mmHg.
Anti-virus aspect: general formula (1), (2), the compound of (3) or (4) 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), (3) or the compound of (4), 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), (2), the toxicity of compound data of (3) or (4).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 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, compound of the present invention and salt thereof can be used for preparing anticancer, step-down, hypoglycemic, sedation and anti-anxiety, antibiotic, antiviral drug.
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, capsule, pill, granule, syrup, emulsion, suspension liquid and solution with method well known in the art, 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 1
4 ', 5-two-hydroxyl-7-two fluoro methoxyl group isoflavones (code name 101) and 5-hydroxyl-4 ', the preparation of 7-two-two fluoro methoxyl group isoflavones (code name 102):
With 0.01mol4 ', 5,7-trihydroxy-isoflavone 1 10ml concentration be in 40% dioxane and the aqueous sodium hydroxide solution in 72 ℃ down and 0.03molHCF
2Cl reaction 9 hours, with ethyl acetate extraction 3 times, anhydrous sodium sulfate drying, use ethyl acetate then: sherwood oil=1: 3 column chromatography, obtain target product 4 ', 5-two-hydroxyl-7-two fluoro methoxyl group isoflavones 2 yield 45.2% and 5-hydroxyl-4 ', 7-two-two fluoro methoxyl group isoflavones 3, yield 52.6%.
Related data is as follows: 4 ', and 5-two-hydroxyl-7-two fluoro methoxyl group isoflavones 2 (code name 101) MS (EI, 70ev) m/z:320; IR υ
Max(cm
-1, KBr): 1662 (C=O), 3319,3528 (OH);
1H NMR (300MHz, CDCl
3): 6.599 (1H, d, J=2.4), 6.820 (2H, d, J=12.0), 6.867 (1H, d, J=2.4), 7.371 (2H, d, J=12.0), 7.427 (1H, t, J=72.8), 8.244 (1H, s), 9.550 (1H, s), 12.994 (1H, s);
19FNMR (300MHz)-84.372 (d, J=72.8) .Anal.Calcd.for C
16H
10F
2O
5: C, 60.08, H, 3.15; Found C, 60.07, H, 2.94.
5-hydroxyl-4 ', 7-two-two fluoro methoxyl group isoflavones 3 (code name 102) MS (EI, 70ev) m/z:370; IR υ
Max(cm
-1, KBr): 1653 (C=O), 3074 (OH);
1H NMR (300MHz, CDCl
3): 6.561 (1H, t, J=73.8), 6.590 (1H, d, J=2.4), 6.638 (1H, t, J=72.3), 6.684 (1H, d, J=2.4), 7.229 (2H, d, J=9.0), 7.551 (2H, d, J=9.0), 7.975 (1H, s); 19F NMR (300MHz)-80.953 (d, J=73.8) ,-82.414 (d, J=72.3) .Anal.Calcd.for C
17H
10F
4O
5: C, 55.31, H, 2.74; Found C, 55.40, H, 2.53.
Embodiment 24 ', the preparation of 5-two-methoxyl group-7-two fluoro methoxyl group isoflavones (code name 103)
With 0.03mol methyl iodide and 0.01mol4 ', 5-two-hydroxyl-7-two fluoro methoxyl group isoflavones 2 are dissolved in the 25ml acetone, add 10 gram catalyzer K
2CO
3, got target product 4 ', 5-two-methoxyl group-7-two fluoro methoxyl group isoflavones in 4 hours 60 ℃ of reactions.
Related data is as follows: MS (EI, 70ev) m/z:348; IR υ
Max(cm
-1, KBr): 1637 (C=O);
1H NMR (300MHz, CDCl
3): 3.834 (3H, s), 3.970 (3H, s), 6.546 (1H, d, J=2.1), 6.642 (1H, t, J=72.4), 6.724 (1H, d, J=2.1), 6.940 (2H, d, J=8.7), 7.472 (2H, d, J=8.7), 7.811 (1H, s);
19F NMR (300MHz)-82.150 (d, J=72.4).
Embodiment 34 ', the preparation of 5-two-oxyethyl group-7-two fluoro methoxyl group isoflavones (code name 104)
Replace methyl iodide can obtain compound 4 ', 5-two-oxyethyl group-7-two fluoro methoxyl group isoflavones with the 0.03mol monobromethane according to the operation of embodiment 2.Related data is as follows: MS (EI, 70ev) m/z:376; IR υ
Max(cm
-1, KBr): 1613 (C=O);
1H NMR (300MHz, CDCl
3): 1.386-1.572 (6H, m), 4.023-4.181 (4H, m), 6.525 (1H, d, J=2.4), 6.628 (1H, t, J=72.6), 6.699 (1H, d, J=2.4), 6.931 (2H, d, J=8.4), 7.436 (2H, d, J=8.4), 7.780 (1H, s);
19F NMR (300MHz)-82.085 (d, J=72.6).
Embodiment 44 ', the preparation of 5-two-propoxy--7-two fluoro methoxyl group isoflavones (code name 105)
Replace methyl iodide can obtain compound 4 ', 5-two-propoxy--7-two fluoro methoxyl group isoflavones with the 0.03mol N-PROPYLE BROMIDE according to the operation of embodiment 2.Related data is as follows: MS (EI, 70ev) m/z:404; IR υ
Max(cm
-1, KBr): 1651 (C=O);
1H NMR (300MHz, CDCl
3): 0.972-1.120 (4H, m), 1.157 (3H, t, J=7.5), 1.223 (3H, t, J=7.5), 3.987-4.164 (4H, m), 6.643 (1H, d, J=2.4), 6.761 (1H, t, J=72.6), 6.807 (1H, d, J=2.4), 7.053 (2H, d, J=9.0), 7.547 (2H, d, J=9.0), 7.886 (1H, s);
19F NMR (300MHz)-82.142 (d, J=72.6).
Embodiment 54 ', the preparation of 5-two-benzyloxy-7-two fluoro methoxyl group isoflavones (code name 106)
Replace methyl iodide can obtain compound 4 ', 5-two-benzyloxy-7-two fluoro methoxyl group isoflavones with 0.03mol bromobenzyl alkane according to the operation of embodiment 2.Related data is as follows: MS (EI, 70ev) m/z:500; IR υ
Max(cm
-1, KBr): 1647 (C=O);
1H NMR (300MHz, CDCl
3): 4.636 (4H, s), 7.314-7.342 (18H, m);
19F NMR (300MHz)-82.161 (d, J=72.2).
Embodiment 64 ', the preparation of 5-oxygen in two-heptan base-7-two fluoro methoxyl group isoflavones (code name 107)
Replace methyl iodide can obtain compound 4 ', 5-oxygen in two-heptan base-7-two fluoro methoxyl group isoflavones with the 0.03mol heptyl bromide according to the operation of embodiment 2.Related data is as follows: MS (EI, 70ev) m/z:516; IR υ
Max(cm
-1, KBr): 1652 (C=O);
1H NMR (300MHz, CDCl
3): 0.906-2.016 (26H, m), 3.950 (2H, t, J=6.6), 4.047 (2H, t, J=6.6), 6.512 (1H, d, J=2.1), 6.648 (1H, d, J=2.1), 6.764 (1H, t, J=72.9), 6.893 (2H, d, J=9.0), 7.412 (2H, d, J=9.0), 7.759 (1H, s);
19F NMR (300MHz)-82.897 (d, J=72.9).
Embodiment 74 ', the preparation of 5-two-octyloxy-7-two fluoro methoxyl group isoflavones (code name 108)
Replace methyl iodide can obtain compound 4 ', 5-two-octyloxy-7-two fluoro methoxyl group isoflavones with the 0.03mol bromooctane according to the operation of embodiment 2.Related data is as follows: MS (EI, 70ev) m/z:544; IR υ
Max(cm
-1, KBr): 1651 (C=O);
1H NMR (300MHz, CDCl
3): 0.860-12.181 (30H, m), 3.985-4.064 (4H, m), 6.378 (1H, d, J=2.1), 6.423 (1H, d, J=2.1), 6.531 (1H, t, J=74.1), 7.155 (2H, d, J=8.7), 7.543 (2H, d, J=8.7), 7.748 (1H, s);
19F NMR (300MHz)-80.555 (d, J=74.1).
Embodiment 84 ', the preparation of 5-oxygen in two-last of the ten Heavenly stems base-7-two fluoro methoxyl group isoflavones (code name 109)
Replace methyl iodide can obtain compound 4 ', 5-oxygen in two-last of the ten Heavenly stems base-7-two fluoro methoxyl group isoflavones with bromo-decane according to the operation of embodiment 2.Related data is as follows: MS (EI, 70ev) m/z:600; IR υ
Max(cm
-1, KBr): 1658 (C=O);
1H NMR (300MHz, CDCl
3): 0.848-1.783 (38H, m), 3.966 (2H, t, J=6.6), 4.040 (2H, t, J=6.6), 6.513 (1H, d, J=2.1), 6.627 (1H, t, J=72.3), 6.674 (1H, d, J=2.1), 6.925 (2H, d, J=8.4), 7.423 (2H, d, J=8.4), 7.753 (1H, s);
19F NMR (300MHz)-82.052 (d, J=72.3).
Embodiment 94 ', the preparation (code name 110) of 5-two-two fluoro methoxyl group 7-methoxyl group isoflavones
Use 0.01mol4 ', 5-dihydroxyl-7-methoxyl group isoflavones replaces 4 ', 5,7 dihydroxy isoflavones to obtain compound 4 ', 5-two-two fluoro methoxyl group 7-methoxyl group isoflavones according to the operation of embodiment 1.Related data is as follows: MS (EI, 70ev) m/z:384; IR υ
Max(cm
-1, KBr): 1653 (C=O);
1H NMR (300MHz, CDCl
3): 3.917 (3H, s), 6.535 (1H, t, J=73.8), 6.684 (1H, t, J=75.6), 6.793 (1H, d, J=2.4), 6.802 (1H, d, J=2.40), 7.167 (2H, d, J=8.7), 7.516 (2H, d, J=8.7), 7.867 (1H, s);
19F NMR (300MHz)-80.775 (d, J=73.8) ,-83.750 (d, J=75.6) .Anal.Calcd.for C
18H
12F
4O
5: C, 56.26, H, 3.15; Found C, 56.28, H, 3.23.
Embodiment 104 ', the preparation (code name 111) of 5-two-two fluoro oxygen in last of the ten Heavenly stems base 7-oxygen in last of the ten Heavenly stems base isoflavones
Use 0.01mol4 ', 5-dihydroxyl-7-oxygen in last of the ten Heavenly stems base isoflavones replaces 4 ', 5,7 dihydroxy isoflavones to obtain compound 4 ', 5-two-two fluoro methoxyl group 7-oxygen in last of the ten Heavenly stems base isoflavones according to the operation of embodiment 8.Related data is as follows: MS (EI, 70ev) m/z:510; IR υ
Max(cm
-1, KBr): 1650 (C=O);
1H NMR (300MHz, CDCl
3): 0.848-1.783 (19H, m), 3.968 (2H, t, J=6.6), 6.516 (1H, d, J=2.1), 6.620 (1H, t, J=73.8), 6.684 (1H, t, J=75.6), 6.670 (1H, d, J=2.1), 6.927 (2H, d, J=8.4), 7.426 (2H, d, J=8.4), 7.758 (1H, s);
19F NMR (300MHz)-80.775 (d, J=73.8) ,-83.750 (d, J=75.6) .Anal.Calcd.for C
27H
30F
4O
5: C, 63.52, H, 5.88; Found C, 63.28, H, 6.23.
The preparation of embodiment 115-hydroxyl-4 '-methoxyl group-7-two fluoro methoxyl group isoflavones (code name 112)
With 0.02mol methyl iodide and 0.01mol4 ', 5-two-hydroxyl-7-two fluoro methoxyl group isoflavones 2 are dissolved in the 25ml acetone, add 10 gram catalyzer K
2CO
3, got target product 5-hydroxyl-4 '-methoxyl group-7-two fluoro methoxyl group isoflavones in 24 hours 0 ℃ of reaction.Related data is as follows: MS (EI, 70ev) m/z:334; IR υ
Max(cm
-1, KBr): 1630 (C=O), 3326 (OH);
1H NMR (300MHz, CDCl
3): 3.868 (3H, s), 6.542 (1H, d, J=2.1), 6.630 (1H, t, J=72.4), 6.724 (1H, d, J=2.1), 6.955 (2H, d, J=8.7), 7.422 (2H, d, J=8.7), 7.811 (1H, s), 12.995 (1H, s);
19F NMR (300MHz)-82.154 (d, J=72.4).
The preparation of embodiment 125-hydroxyl-4 '-last of the ten Heavenly stems oxygen base-7-two fluoro methoxyl group isoflavones (code name 113)
With 0.03mol bromo-decane alkane and 0.01mol4 ', 5-two-hydroxyl-7-two fluoro methoxyl group isoflavones 2 are dissolved in the 25ml acetone, add? gram catalyzer K
2CO
325 ℃ of reactions 24 hours target product 5-hydroxyl-4 '-last of the ten Heavenly stems oxygen base-7-two fluoro methoxyl group isoflavones.Related data is as follows: MS (EI, 70ev) m/z:460; IR υ
Max(cm
-1, KBr): 1655 (C=O), 3324 (OH);
1H NMR (300MHz, CDCl
3): 0.848-1.783 (19H, m), 3.954 (2H, t, J=6.6), 6.513 (1H, d, J=2.1), 6.622 (1H, t, J=72.3), 6.654 (1H, d, J=2.1), 6.965 (2H, d, J=8.4), 7.425 (2H, d, J=8.4), 7.753 (1H, s), 12.995 (1H, s);
19F NMR (300MHz)-82.050 (d, J=72.3).
Embodiment 13
With reference to the method (Mosman, T.J.Immunol Methods.1983,65,55) of Mosman, by the MTT colorimetric method for determining cytotoxicity of The compounds of this invention, the results are shown in Table 1.
Table 1
| The active compound code name | The anti-cancer of the stomach of IC50nM | The anti-prostate cancer of IC50nM | The IC50nM anti-cervical cancer | The anti-lung cancer of IC50nM | The IC50nM anti-breast cancer |
| ????101 | ????0.06 | ????0.36 | ????0.24 | ????6.55 | ????0.45 |
| ????102 | ????0.23 | ????1.65 | ????8.86 | ????5.03 | ????22.32 |
| ????103 | ????5.56 | ????3.33 | ????3.42 | ????1.05 | ????2.87 |
| ????104 | ????2.58 | ????0.06 | ????1.03 | ????4.35 | ????2.21 |
| ????105 | ????7.89 | ????20.89 | ????23.67 | ????0.39 | ????10.26 |
| ????106 | ????11.25 | ????9.07 | ????10.24 | ????0.82 | ????2.28 |
| ????107 | ????0.06 | ????16.33 | ????20.13 | ????1.07 | ????8.62 |
| ????108 | ????5.46 | ????9.73 | ????10.03 | ????8.36 | ????0.02 |
| ????109 | ????4.25 | ????3.87 | ????11.47 | ????1.33 | ????1.83 |
| ????110 | ????0.69 | ????6.23 | ????16.26 | ????4.65 | ????5.38 |
| ????111 | ????7.13 | ????1.26 | ????6.56 | ????8.41 | ????0.25 |
| ????112 | ????20.34 | ????3.27 | ????5.42 | ????7.61 | ????1.05 |
| ????113 | ????10.23 | ????1.19 | ????6.12 | ????5.85 | ????2.90 |
| ????114 | ????3.16 | ????1.65 | ????7.76 | ????8.35 | ????1.78 |
Embodiment 14
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 | ????32.04 | ????27.20 | ????26.47 | ????5.04 |
| Embodiment 2 | ????0.26 | ????28.04 | ????30.09 | ????27.36 | ????4.34 |
| Embodiment 3 | ????0.50 | ????27.31 | ????22.42 | ????18.23 | ????2.51 |
| Embodiment 4 | ????0.01 | ????20.06 | ????22.52 | ????22.42 | ????1.22 |
| Embodiment 5 | ????0.35 | ????16.22 | ????30.23 | ????29.02 | ????2.36 |
Embodiment 15
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 | ????2.29 | ????2.85 | ?0.19 | ????9.72 |
| Embodiment 2 | ????0.12 | ????0.011 | ????7.22 | ?10.33 | ????2.54 |
| Embodiment 3 | ????5.21 | ????2.78 | ????0.0026 | ?0.0030 | ????0.18 |
| Embodiment 4 | ????8.54 | ????2.65 | ????0.094 | ?19.22 | ????9.69 |
| Embodiment 5 | ????0.10 | ????8.10 | ????1.46 | ?3.17 | ????0.029 |
| Embodiment 6 | ????1.32 | ????12.02 | ????2.25 | ?5.01 | ????0.0074 |
Embodiment 16
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 | ????80.2 |
| Embodiment 2 | ????0.4 | ????66.5 |
| Embodiment 3 | ????0.8 | ????82.1 |
| Embodiment 4 | ????2.0 | ????76.4 |
| Embodiment 5 | ????10 | ????69.3 |
| Embodiment 6 | ????20 | ????79.5 |
| Embodiment 7 | ????40 | ????99.1 |
Embodiment 17
The tablet that contains the compound of general formula (I) can be by method preparation well known in the art.The compound 125mg Magnesium Stearate 4mg talcum powder 6mg lactose 45mg starch 50mg of general formula (I)
Embodiment 18
The capsule that contains the compound of general formula (I) can be by method preparation well known in the art.The compound 120mg Magnesium Stearate 20mg talcum powder 20mg lactose 45mg starch 20mg polyvinylpyrrolidone 10mg of general formula (I)
Claims (13)
1. a fluorine-containing isoflavone derivative is characterized in that, for having 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
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 and R ' can be the same or different, and R and R ' represent 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. fluorine-containing isoflavone derivative 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 or the two fluoro methoxyl groups one.
3. fluorine-containing isoflavone derivative according to claim 1 is characterized in that, described fluorine-containing isoflavone derivative comprises:
4 ', 5-two-hydroxyl-7-two fluoro methoxyl group isoflavones (code name 101);
5-hydroxyl-4 ', 7-two-fluoro methoxyl group isoflavones (code name 102);
4 ', 5-two-methoxyl group-7-two fluoro methoxyl group isoflavones (code name 103);
4 ', 5-two-oxyethyl group-7-two fluoro methoxyl group isoflavones (code name 104);
4 ', 5-two-propoxy--7-two fluoro methoxyl group isoflavones (code name 105);
4 ', 5-two-benzyloxy-7-two fluoro methoxyl group isoflavones (code name 106);
4 ', 5-oxygen in two-heptan base-7-two or two fluoro methoxyl group isoflavones (code name 107);
4 ', 5-two-octyloxy-7-two fluoro methoxyl group isoflavones (code name 108);
4 ', 5-oxygen in two-last of the ten Heavenly stems base-7-two fluoro methoxyl group isoflavones (code name 109);
4 ', 5-two-two fluoro methoxyl group 7-methoxyl group isoflavones (code name 110);
4 ', 5-two-two fluoro oxygen in last of the ten Heavenly stems base 7-oxygen in last of the ten Heavenly stems base isoflavones (code name 111);
5-hydroxyl-4 '-methoxyl group-7-two fluoro methoxyl group isoflavones (code name 112);
5-hydroxyl-4 '-last of the ten Heavenly stems oxygen base-7-two fluoro methoxyl group isoflavones (code name 113).
4. according to the salt of claim 1,2 or 3 described fluorine-containing isoflavone derivatives.
5. the salt of fluorine-containing isoflavone derivative according to claim 4 is characterized in that, described salt is sodium salt, sylvite or calcium salt.
6. the preparation method of fluorine-containing isoflavone derivative according to claim 1 is characterized in that, the compound with general formula (1) comprises the steps:
A and B are obtained Compound C under catalyzer and solvent action, temperature of reaction is 5～65 ℃, and the reaction times is 1～24 hour; Said solvent comprises ethanol, methyl alcohol or water; Said catalyzer comprises KOH, NaOH or Ca (OH)
2
Compound 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 DMF, pyridine or triethylamine;
Said catalyzer comprises ZnCl
2/ POCl
3Or DMF/MeSO
2Cl, reaction expression is as follows:
7. the preparation method of fluorine-containing isoflavone derivative according to claim 4 is characterized in that, also comprises the steps:
With the compound of said 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 1～36 hour; Said catalyzer comprises Zn, Pt or Pd.
8. the preparation method of fluorine-containing isoflavone derivative according to claim 4 is characterized in that, also comprises the steps:
The compound of said general formula (1) is reacted with hydrazine hydrate under catalyst action, promptly obtain the compound of general formula (3), temperature of reaction is 0～120 ℃, and the reaction times is 1～36 hour; Said catalyzer comprises KOH, NaOH or Ca (OH)
2
9. the preparation method of fluorine-containing isoflavone derivative according to claim 5 is characterized in that, also comprises the steps:
With the compound of said general formula (2), under catalyst action,, obtain the compound of general formula (4) with the hydrazine hydrate reaction, temperature of reaction is 0～120 ℃, the reaction times is 1～36 hour; Said catalyzer comprises KOH, NaOH or Ca (OH)
2
10. the preparation method of a fluorine-containing isoflavone derivative is characterized in that, comprises the steps:
4 ', 5, the 7-trihydroxy-isoflavone descends and HCF in 70～75 ℃ in solvent
2Cl reaction 6～12 hours obtains target product 4 ', 5-two-hydroxyl-7-two fluoro methoxyl group isoflavones and 5-hydroxyl-4 ', and 7-two-two fluoro methoxyl group isoflavones, said solvent is dioxane and aqueous sodium hydroxide solution, reaction expression is as follows:
11. the preparation method of the salt of fluorine-containing isoflavone derivative according to claim 4, it is characterized in that, said fluorine-containing isoflavone derivative and alkali are reacted under 10～75 ℃ of conditions, promptly obtain the salt of said compound, said alkali comprises sodium hydroxide, potassium hydroxide or calcium hydroxide.
12. contain the composition of each described fluorine-containing isoflavone derivative of claim 1～3 for the treatment of significant quantity and salt thereof and pharmaceutically acceptable carrier.
13. the application in, step-down anticancer in the preparation treatment, hypoglycemic, sedation and anti-anxiety, antibiotic, the antiviral drug according to each described fluorine-containing isoflavone derivative of claim 1～3 and salt thereof.
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| US7618998B2 (en) | 2008-02-26 | 2009-11-17 | Kaosiung Medical University | Isoflavone derivatives and pharmaceutical compositions comprising the same |
| CN101331913B (en) * | 2008-07-22 | 2011-03-16 | 广东新南都饲料科技有限公司 | Use of isoflavone with substituent at intermedium ring 2 position as animal feed additives |
| CN101225081B (en) * | 2007-01-17 | 2011-04-06 | 湖南师范大学 | Isoflavone compound, preparation method and use thereof |
| CN102351827A (en) * | 2011-08-16 | 2012-02-15 | 云南烟草科学研究院 | Isoflavone compound in tobacco rhizome and preparation method and application thereof |
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| CN101225081B (en) * | 2007-01-17 | 2011-04-06 | 湖南师范大学 | Isoflavone compound, preparation method and use thereof |
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| CN102351827A (en) * | 2011-08-16 | 2012-02-15 | 云南烟草科学研究院 | Isoflavone compound in tobacco rhizome and preparation method and application thereof |
| CN103073531A (en) * | 2012-12-22 | 2013-05-01 | 湖南师范大学 | 7-Difluoromethoxyl-5,4'-Dioctyl alkoxyl isoflavone synthesis method |
| 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 |
| CN116789628A (en) * | 2023-08-24 | 2023-09-22 | 成都中医药大学 | Fluorinated isoflavonoids, medicaments thereof and use thereof for selectively inhibiting PI3K |
| CN116789628B (en) * | 2023-08-24 | 2023-11-24 | 成都中医药大学 | Fluorinated isoflavonoids, medicaments thereof and use thereof for selectively inhibiting PI3K |
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