CN101817808A - Flavones derivative as well as preparation method and application thereof as alpha1 receptor antagonist - Google Patents
Flavones derivative as well as preparation method and application thereof as alpha1 receptor antagonist Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of new flavonoids compounds and application of the new flavonoids compounds as an alpha1 receptor antagonist, wherein R1 and R2 are defined as the specifications. A group with larger polarity is introduced in a flavones structure to enable the polarity of an integral molecule to be increased; meanwhile, the compounds have a certain alkalinity and can be formed into salts with common medicinal acids to ensure that the integral molecule has a certain water-solubility. Preliminary pharmacological tests indicate that the compounds have an alpha1 receptor antagonizing function.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to the preparation method and the α thereof of a class neoflavonoid (I)
1The purposes of receptor antagonist activity.
Background technology
Flavonoid compound is the common natural product of a class, extensively is distributed in higher plant and filiciform, stem, leaf, flower and the fruit, is the class secondary metabolite that plant produces in long-term natural selection process.Studies show that flavonoid compound has biologic activity clearly, as: the metabolism of sugar and fat, antitumor, anti-inflammatory and throe, anti-oxidant and delay senility, protect effects such as cardiovascular systems, radioprotective improved.Flavonol compounds molecular weight ratio is less, and bioavailability is higher, has become domestic and international many pharmacy workers' research focus in recent years, and has been found that and synthesized by structural modification the flavonoid compound of more biologically actives.(Progress?in?Drug?Research，2005，63：183；Journal?of?MedicinalChemistry，2006，49：7357；Journal?of?Medicinal?Chemistry，2007，50：350.)。
From first selectivity α in 1974
1Novel α after emerging, adrenoceptor antagonists is constantly arranged
1The receptor antagonist listing makes people to the pharmacological properties of this type of medicine more comprehensive understanding arranged, because α
1Receptor antagonist is safe and effective and useful to blood lipid metabolism, and is therefore more to the application of this class medicine, and some medicine has become a line medicine of treatment essential hypertension.Some α in recent years
1Receptor antagonist also is used for the treatment of male sex's benign prostatic hyperplasia.But, up to the present, the α of relevant flavonol compounds
1The research of receptor antagonist activity is fewer.
Summary of the invention
The present invention has designed and synthesized a series of flavonoid compounds, has studied its α
1Receptor antagonist activity.Simultaneously, flavonoid compound is exactly fat-soluble bigger in characteristics of application facet, among the present invention, in the structure of flavones, introduced the bigger group of polarity, the polarity of whole molecule is increased, and another characteristics of this compounds are to have certain alkalescence, can with general pharmaceutically useful sour salify, it is certain water-soluble that whole molecule is had.Preliminary pharmacological tests shows that The compounds of this invention has α
1Receptor antagonism.
Structural formula of compound of the present invention is as follows:
The present invention also comprises the enantiomer and the diastereomer of Compound I, also relates to the salt that they and pharmaceutically useful acid or alkali addition form, and these compounds are included in the scope of the present invention equally, have same drug effect.
R in the structural formula I compound
1Amino or halogen that on behalf of alkyl, hydroxyl, carboxyl, formyl radical, cyano group, methylol, the C1-C6 alkyl of hydrogen, C1-C6, the phenyl of representing phenyl or being replaced by 1～3 identical or different X group, X replace;
R
2The amino of representing the alkyl, hydroxyl, carboxyl, formyl radical, cyano group, methylol, C1-C6 alkyl of hydrogen, halogen, C1-C6 to replace;
n＝2～4。
R
1The preferred phenyl of representing the alkyl replacement of phenyl or C1-C6, more preferably phenyl, o-tolyl or p-methylphenyl.
R
2Preferably represent hydrogen or halogen, more preferably represent the chlorine atom of hydrogen atom and para-orientation.
Above-mentioned pharmacologically acceptable salts mainly refers to acid salt, these acid can add with compound of Formula I becomes salt, described acid can be acid pharmaceutically commonly used, example hydrochloric acid, Hydrogen bromide, phosphoric acid, acetate, sulfuric acid, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, methylsulfonic acid, dextrocamphoric acid etc.
According to the present invention, The compounds of this invention can prepare according to following reaction scheme:
R
1, R
2, n described as defined above.
More detailed preferred the comprising the steps: of this method
(1) 7-flavonol and glycol dibromide obtain 7-(2-bromine oxethyl) flavones under the effect of salt of wormwood.
(2) phenylpiperazine and (1) resulting product stirring and refluxing 48 hours in toluene obtains target product I.
Product I and applicable sour salify pharmaceutically promptly get the pharmacy acceptable salt of compound of Formula I.
If be prepared into the pharmacy acceptable salt of the flavone derivative of general formula I, then prepare with laxative remedy:
R
1, R
2, n described as defined above.
Initial compounds among the present invention is commercially available, or those skilled in the art can be easy to obtain by conventional chemical reaction or the described chemical reaction of document.
Compound of the present invention and contain that their pharmaceutical composition is verified to have a α suitable with positive drug
1Receptor antagonist activity.
The pharmaceutical research of The compounds of this invention is in fact verified: they are nontoxic, to α
1Acceptor has the activity suitable with the positive control drug Prazosin.Thereby can determine: product of the present invention can be used for treating Stress, major depression, cardiovascular pathological changes such as hypertension etc. also can be used for treating Parkinson, diseases such as presenile dementia, product of the present invention also can be used for treating diseases such as male sex's benign prostatic hyperplasia in active another field.
These compounds will be preferable over the treatment male sex, hyperplasia of prostate, more preferably in the treatment benign prostatic hyperplasia.
The invention still further relates to pharmaceutical composition, its comprise salt that at least a formula (I) compound itself or itself and pharmaceutically useful acid or alkali form and with the combination of one or more pharmaceutically acceptable excipient.
The dosage of The compounds of this invention is different with age, the attribute that is suitable for approach, treatment indication or any relevant treatment according to patient's sex, body weight, and per 24 hours 0.01mg to 1g are suitable one or more times.
Be the pharmacology test and the data of part of compounds of the present invention below.
α
1The drug screening of receptor antagonist
1, reagent and material
1.1, reagent and sample
(Phenylephrine hydrochloride Phe) is Shanghai Hefeng Pharmaceutical Co., Ltd.'s product to Phenylephrine Hydrochloride, and (prazosin Pra) is the Sigma product to Prazosin.Krebs nutrient composition (mmol/L): NaCl 118.4, and KCl 4.7, CaCl
22.52, MgSO
41.2, KH
2PO
41.2, NaHCO
325, Glucose 11.1.
1.2, instrument
HW-400E type constant temperature unstriated muscle groove (Chengdu, Science and Technology Ltd. of safe alliance), the biological tension pick-up of FT-100 (Chengdu, Science and Technology Ltd. of safe alliance), BL-420S biological function experimental system (Chengdu, Science and Technology Ltd. of safe alliance), adjustable pipette (Finland, 5～40 μ l, 40～200 μ l, 200～1000 μ l)
Two, test method
Get male Sprague-Dawley rat, body weight 300～350g, the carotid artery bloodletting causes death, and opens the abdominal cavity along the lower abdomen center, exposes pubic symphysis, cut off pubic symphysis from the center and firmly make it and separate, find the anus musculus caudalis at the rectum end place, separate and remove anus musculus caudalis reticular tissue on every side, (sample is about 6～8mm) respectively at two ends threading ligation, cut sample then, insert in the Krebs nutritive medium that passes to 95%O2,5%CO2.Sample is fixed in the isolated organ perfusion system, and the bath volume is 20ml, passes to the mixing oxygen of 95%O2,5%CO2,37 ℃ of bath temperature, and nutritive medium pH is about 7.4.Tranquillization preload 1g, sample balance 1 hour before the test, during change in the groove liquid 6～8 times.After the baseline stability, begin test.
Begin earlier to compare curve, whenever add a neophryn dosage, treat to occur, add next dosage again to the maximum reaction according to the dosing of neophryn 20ml bath semi-invariant validity response curve method.After adding all dosage, after contraction reached maximum reaction, the flushing sample every 5～10min once, made the sample diastole to baseline.Then, in kind make the second control curve again.The second control curve is washed to baseline, (final concentration is 10nmol/L can to add Prazosin when adding above-mentioned pre-treatment medicine, 30nmol/L, 0.1 μ mol/L) or the respective concentration of test-compound (determining) by trial test, do from lower concentration, and a sample only uses a compound, behind the 20min, repeat to do the dose-effect response curve of neophryn, observe changing conditions with control curve.α
1The potency pA of receptor antagonist
2(be parameter for antagonist, it is meant that dosage is than the negative logarithm that is 2 o'clock competitive antagonism concentrations) expression, the high more α that shows of its value
1Receptor antagonist activity is than higher.PA generally speaking
2＞6 think to have certain α
1Receptor antagonist activity, pA
2＞6 explanation α
1Receptor antagonist activity is than higher.
Three, test-results
Pra10,30,100nmol/L make Phe accumulation amount effect curve are parallel and move to right, and maximum reaction does not have and obviously forces down each test-compound pA
2Value see Table 1 (routine number average is 3 examples)
The pA of table 1 part of compounds of the present invention
2Value
By the result of pharmacological screening as can be seen, flavone derivative of the present invention all has α
1Receptor antagonist activity, wherein Compound I-1, I-4, I-10, I-13 and the I-15 activity suitable with the positive drug Prazosin.
Embodiment
Embodiment 1
[(4 benzoic acid base)-2-hydroxy benzoyl]-benzoyl methane (II)
2,4-resacetophenone 6.4g and 24g salt of wormwood are dissolved in 150ml acetone, after being stirred to solution under 80 ℃ and becoming glassy yellow, slowly drip the 4.63ml Benzoyl chloride, add the back and refluxed 12 hours, stopped reaction is cooled to room temperature, suction filtration, filter cake fully stirs decomposition with 10% glacial acetic acid solution 200ml, the after-filtration that finishes, drying, obtain yellow powder 10.4g, yield 70.8%.
Embodiment 2
7-flavonol (III)
Above-mentioned 10.4g II and sodium acetate, anhydrous 16g, acetic acid 80ml are placed the 250ml three-necked bottle, and back flow reaction 12 hours is cooled to room temperature, it is an amount of to add frozen water, and suction filtration is used hot water, 5% sodium bicarbonate aqueous solution and hot wash successively, drying obtains white powder 5.2g, yield 74.9%.
Embodiment 3
7-bromo oxyethyl group flavones (IV)
With 7-flavonol 10mmol, Anhydrous potassium carbonate 50mmol and 400ml acetone add in the 500ml round-bottomed flask, and heated and stirred adds the glycol dibromide of 80mmol again to refluxing, and continue to reflux 72 hours, and TLC controls reaction process.Stopped reaction, evaporate to dryness acetone, the acetone that add to reclaim again continue decompression and steam excessive glycol dibromide, obtain the field gray milk, add water after, use dichloromethane extraction, the evaporate to dryness methylene dichloride is cooled to room temperature, obtains brown solid.Adopt the sudden strain of a muscle post to separate, obtain yellow solid 2.6g, yield 75.5%.
Embodiment 4
7-[2-(4-phenyl)-piperazine] oxyethyl group flavones (I-1)
3.4mmol phenylpiperazine and 1.7mmol IV are dissolved in 20ml toluene, reflux 24 hours.Stopped reaction filters, and filtrate decompression boils off solvent, adopts the sudden strain of a muscle post to separate, and obtains white solid 0.15g, and yield is 21.2%.mp?137-140℃，MS(ESI，m/z)：[M+H]
+427；
1H-NMR(300MHz，CDCl
3，δppm)：8.15(d，1H)，7.91(m，2H)，7.53(m，2H)，7.28(m，3H)，7.02(m，2H)，6.94(d，2H)，6.86(s，1H)，6.78(s，1H)，4.32(m，2H)，3.29(m，4H)，3.00(m，2H)，2.84(m，4H)。
Embodiment 5
7-[2-(4-phenyl)-piperazine] propoxy-flavones (I-2)
The same I-1 of preparation process replaces 7-bromo oxyethyl group flavones with 7-bromo propoxy-flavones and gets product I-2, and white solid, yield are 23.1%.mp156-158℃，MS(ESI，m/z)：[M+H]
+441；
1H-NMR(300MHz，CDCl
3，δppm)：8.14(d，1H，J＝9.6Hz)，7.91(m，2H)，7.51(m，3H)，7.30(m，1H)，7.27(s，1H)，7.00(m，1H)，6.93(m，4H)，6.78(s，1H)，4.21(t，2H，J＝6.3Hz)，3.34(m，4H)，2.79(m，6H)，2.20(m，2H)。
Embodiment 6
7-[2-(4-phenyl)-piperazine] butoxy flavones (I-3)
The same I-1 of preparation process replaces 7-bromo oxyethyl group flavones with 7-bromo butoxy flavones and gets product I-3, and white solid, yield are 22.7%.mp106-109℃，MS(ESI，m/z)：[M+H]
+455；
1H-NMR(300MHz，CDCl
3，δppm)：8.14(d，1H)，7.91(m，2H)，7.54(m，2H)，7.28(m，3H)，7.17(d，1H)，6.99-6.88(m，5H)，6.80(s，1H)，4.14(m，2H)，3.38(m，4H)，2.88(m，3H)，2.72(m，2H)，2.36(m，2H)，1.94(m，3H)。
Embodiment 7
7-[2-(4-p-methylphenyl)-piperazine] oxyethyl group flavones (I-4)
The same I-1 of preparation process gets product I-4 with p-methylphenyl piperazine substituted phenylpiperazine, and white solid, yield are 18.4%.mp139-142℃，MS(ESI，m/z)：[M+H]
+441；
1H-NMR(300MHz，CDCl
3，δppm)：8.16(d，1H，J＝9.3Hz)，7.92(m，2H)，7.53(m，2H)，7.09(d，2H，J＝8.1Hz)，7.03(m，2H)，6.87(d，2H)，6.78(s，1H)，5.30(s，2H)，4.28(t，2H)，3.21(m，3H)，2.96(m，2H)，2.80(m，3H)，2.27(s，3H)。
Embodiment 8
7-[2-(4-p-methylphenyl)-piperazine] propoxy-flavones (I-5)
The same I-4 of preparation process replaces 7-bromo oxyethyl group flavones with 7-bromo propoxy-flavones and gets product I-5, and white solid, yield are 23.7%.mp169-172℃，MS(ESI，m/z)：[M+H]
+455；
1H-NMR(300MHz，CDCl
3，δppm)：8.14(d，1H，J＝9.6Hz)，7.92(m，2H)，7.51(m，3H)，7.07(d，2H，J＝8.4Hz)，6.99(m，2H)，6.86(d，2H，J＝8.4Hz)，6.77(s，1H)，4.19(t，2H，J＝6.0Hz)，3.21(m，4H)，2.66(m，6H)，2.28(s，3H)，2.12(m，2H)。
Embodiment 9
7-[2-(4-p-methylphenyl)-piperazine] butoxy flavones (I-6)
The same I-4 of preparation process replaces 7-bromo oxyethyl group flavones with 7-bromo butoxy flavones and gets product I-5, and white solid, yield are 25.5%.mp105-107℃，MS(ESI，m/z)：[M+H]
+469；
1H-NMR(300MHz，CDCl
3，δppm)：8.14(d，1H，J＝8.4Hz)，7.92(m，2H)，7.52(m，3H)，7.07(d，2H，J＝8.4Hz)，6.99(m，2H)，6.86(d，2H，J＝8.4Hz)，6.77(s，1H)，4.19(t，2H，J＝6.0Hz)，3.17(m，4H)，2.66(m，4H)，2.51(m，2H)，2.27(s，3H)，1.92(m，2H)，1.79(m，2H).
Embodiment 10
7-[2-(4-o-tolyl)-piperazine] oxyethyl group flavones (I-7)
The same I-4 of preparation process replaces the p-methylphenyl piperazine with the o-tolyl piperazine and gets product I-7, and white solid, yield are 24.1%.mp127-131℃，MS(ESI，m/z)：[M+H]
+441；
1H-NMR(300MHz，CDCl
3，δppm)：8.15(d，1H，J＝8.7Hz)，7.92(m，2H)，7.54(m，3H)，7.17(m，2H)，7.02(m，4H)，6.79(s，1H)，5.30(br?s，2H)，4.72(m，3H)，3.40～2.58(m，7H)，2.32(s，3H)。
Embodiment 11
7-[2-(4-o-tolyl)-piperazine] propoxy-flavones (I-8)
The same I-7 of preparation process replaces 7-bromo oxyethyl group flavones with 7-bromo propoxy-flavones and gets product I-8, and white solid, yield are 24.6%.mp135-138℃，MS(ESI，m/z)：[M+H]
+455；
1H-NMR(300MHz，CDCl
3，δppm)：8.15(d，1H，J＝9.3Hz)，7.92(m，2H)，7.53(m，3H)，7.18(m，2H)，7.02(m，4H)，6.78(s，1H)，4.21(t，2H，J＝6.0Hz)，3.07(m，4H)，2.80(m，6H)，2.31(s，3H)，2.22(m，2H)。
Embodiment 12
7-[2-(4-o-tolyl)-piperazine] butoxy flavones (I-9)
The same I-7 of preparation process replaces 7-bromo oxyethyl group flavones with 7-bromo butoxy flavones and gets product I-9, and white solid, yield are 23.6%.mp167-171℃，MS(ESI，m/z)：[M+H]
+469；
1H-NMR(300MHz，CDCl
3，δppm)：8.14(d，1H，J＝8.4Hz)，7.92(m，2H)，7.53(m，3H)，7.17(m，2H)，7.00(m，4H)，6.77(s，1H)，5.301(brs，2H)，4.14(t，2H，J＝6.3Hz)，2.98(m，3H)，2.68(s，5H)，2.31(s，3H)，1.95(m，2H)，1.79(m，2H)。
Embodiment 13
7-[2-(4-phenyl)-piperazine] oxyethyl group-4 '-chlorine flavones (I-10)
The same I-1 of preparation process, with 7-bromo oxyethyl group-4 '-the chlorine flavones replaces 7-bromo oxyethyl group flavones and gets product I-10, white solid, yield are 19.7%.mp171-175℃，MS(ESI，m/z)：[M+H]
+461；
1H-NMR(300MHz，CDCl
3，δppm)：8.15(d，1H，J＝9.3Hz)，7.97(d，2H，J＝8.4Hz)，7.50(d，2H，J＝8.4Hz)，7.29(m，2H)，7.03(m，2H)，6.90(m，3H)，6.74(s，1H)，4.37(m，2H)，3.33(m，4H)，3.09～2.95(m，6H)。
Embodiment 14
7-[2-(4-phenyl)-piperazine] propoxy--4 '-chlorine flavones (I-11)
The same I-10 of preparation process, with 7-bromo propoxy--4 '-the chlorine flavones replace 7-bromo oxyethyl group-4 '-the chlorine flavones gets product I-11, white solid, yield are 23.4%.mp176-179℃，MS(ESI，m/z)：[M+H]
+475；
1H-NMR(300MHz，CDCl
3，δppm)：8.13(d，1H，J＝9.3Hz)，7.84(d，2H，J＝8.4Hz)，7.50(d，2H，J＝8.4Hz)，7.28(m，2H)，7.01～6.89(m，5H)，6.74(s，1H)，3.29(br?s，4H)，2.76(br?s，6H)，2.16(br?s，2H)。
Embodiment 15
7-[2-(4-phenyl)-piperazine] butoxy-4 '-chlorine flavones (I-12)
The same I-10 of preparation process, with 7-bromo butoxy-4 '-the chlorine flavones replace 7-bromo oxyethyl group-4 '-the chlorine flavones gets product I-12, white solid, yield are 20.9%.mp161-163℃，MS(ESI，m/z)：[M+H]
+489；
1H-NMR(300MHz，CDCl
3，δppm)：8.13(d，1H，J＝9.3Hz)，7.83(d，2H，J＝6.9Hz)，7.49(d，2H，J＝6.9Hz)，7.28(m，2H)，7.00～6.85(m，5H)，6.77(s，1H)，4.13(t，2H，J＝6.0Hz)，3.27(br?s，4H)，2.72～2.56(m，6H)，1.83(br?s，4H)。
Embodiment 16
7-[2-(4-p-methylphenyl)-piperazine] oxyethyl group-4 '-chlorine flavones (I-13)
The same I-10 of preparation process gets product I-13 with p-methylphenyl piperazine substituted phenylpiperazine, and white solid, yield are 19.4%.mp190-194℃，MS(ESI，m/z)：[M+H]
+475；
1H-NMR(300MHz，CDCl
3，δppm)：8.14(d，1H，J＝9.3Hz)，7.85(d，2H，J＝8.7Hz)，7.50(d，2H，J＝8.7Hz)，7.09(d，2H，J＝8.4Hz)，7.02(m，2H)，6.86(d，2H，J＝8.7Hz)，6.74(s，1H)，4.34(m，2H)，3.25(m，4H)，3.02(m，2H)，2.87(m，4H)，2.28(s，3H)。
Embodiment 17
7-[2-(4-p-methylphenyl)-piperazine] propoxy--4 '-chlorine flavones (I-14)
The same I-13 of preparation process, with 7-bromo propoxy--4 '-the chlorine flavones replace 7-bromo oxyethyl group-4 '-the chlorine flavones gets product I-14, white solid, yield are 23.5%.mp188-191℃，MS(ESI，m/z)：[M+H]
+489；
1H-NMR(300MHz，CDCl
3，δppm)：8.13(d，1H，J＝9.6Hz)，7.84(d，2H，J＝8.7Hz)，7.47(d，2H，J＝8.7Hz)，7.08(d，2H，J＝8.1Hz)，7.00(m，2H)，6.86(d，2H，J＝8.1Hz)，6.73(s，1H)，4.19(t，2H，J＝6.3Hz)，3.20(m，4H)，2.64(m，6H)，2.28(s，3H)，2.10(m，2H)。
Embodiment 18
7-[2-(4-p-methylphenyl)-piperazine] butoxy-4 '-chlorine flavones (I-15)
The same I-13 of preparation process, with 7-bromo butoxy-4 '-the chlorine flavones replace 7-bromo oxyethyl group-4 '-the chlorine flavones gets product I-15, white solid, yield are 20.6%.mp145-149℃，MS(ESI，m/z)：[M+H]
+503；
1H-NMR(300MHz，CDCl
3，δppm)：8.13(d，1H，J＝8.7Hz)，7.85(d，2H，J＝8.7Hz)，7.48(d，2H，J＝8.7Hz)，7.08(d，2H，J＝8.1Hz)，7.00(d，1H，J＝2.1Hz)，6.96(m，1H)，6.85(d，2H，J＝8.1Hz)，6.73(s，1H)，4.13(t，2H，J＝6.3Hz)，3.19(m，4H)，2.67(m，6H)，2.52(t，2H)，2.27(s，3H)，1.92(m，2H)，1.78(m，2H)。
Embodiment 19
7-[2-(4-o-tolyl)-piperazine] oxyethyl group-4 '-chlorine flavones (I-16)
The same I-13 of preparation process replaces the p-methylphenyl piperazine with the o-tolyl piperazine and gets product I-16, and white solid, yield are 20.1%.mp152-154℃，MS(ESI，m/z)：[M+H]
+475；
1H-NMR(300MHz，CDCl
3，δppm)：8.15(d，1H，J＝9.0Hz)，7.85(d，2H，J＝8.7Hz)，7.51(d，2H，J＝8.7Hz)，7.22(m，2H)，7.08～7.00(m，4H)，6.75(s，1H)，4.53(m，2H)，3.14(br?s，8H)，2.32(m，2H)，1.57(s，3H)。
Embodiment 20
7-[2-(4-o-tolyl)-piperazine] propoxy--4 '-chlorine flavones (I-17)
The same I-16 of preparation process, with 7-bromo propoxy--4 '-the chlorine flavones replace 7-bromo oxyethyl group-4 '-the chlorine flavones gets product I-17, white solid, yield are 22.7%.mp152-158℃，MS(ESI，m/z)：[M+H]
+489；
1H-NMR(300MHz，CDCl
3，δppm)：8.13(d，1H，J＝9.6Hz)，7.85(d，2H，J＝8.7Hz)，7.47(d，2H，J＝8.7Hz)，7.17(m，2H)，7.05～6.97(m，4H)，6.71(s，1H)，4.20(t，2H，J＝6.3Hz)，3.00(m，4H)，2.68(m，6H)，2.31(s，3H)，2.12(m，2H)。
Embodiment 21
7-[2-(4-o-tolyl)-piperazine] propoxy--4 '-chlorine flavones (I-18)
The same I-16 of preparation process, with 7-bromo butoxy-4 '-the chlorine flavones replace 7-bromo oxyethyl group-4 '-the chlorine flavones gets product I-18, white solid, yield are 24.7%.mp125-128℃，MS(ESI，m/z)：[M+H]
+503；
1H-NMR(300MHz，CDCl
3，δppm)：8.14(d，1H，J＝9.0Hz)，7.86(d，2H，J＝8.7Hz)，7.50(d，2H，J＝8.7Hz)，7.17(m，2H)，7.05～6.95(m，4H)，6.74(s，1H)，4.14(t，2H，J＝6.0Hz)，3.00(m，4H)，2.75～2.61(m，6H)，2.31(s，3H)，1.91(m，2H)。
Claims (10)
1. the flavone derivative of general formula I or its pharmacy acceptable salt:
Wherein: R
1Amino or halogen that on behalf of alkyl, hydroxyl, carboxyl, formyl radical, cyano group, methylol, the C1-C6 alkyl of hydrogen, C1-C6, the phenyl of representing phenyl or being replaced by 1～3 identical or different X group, X replace;
R
2Represent the amino of alkyl, hydroxyl, carboxyl, formyl radical, cyano group, methylol or the replacement of C1-C6 alkyl of hydrogen, halogen, C1-C6;
n＝2～4。
2. the flavone derivative of claim 1 or its pharmacy acceptable salt, wherein R
1Represent the phenyl of the alkyl replacement of phenyl or C1-C6.
3. the flavone derivative of claim 2 or its pharmacy acceptable salt, wherein R
1Represent phenyl, o-tolyl or p-methylphenyl.
4. the flavone derivative of claim 1 or its pharmacy acceptable salt, wherein R
2Represent hydrogen or halogen.
5. the flavone derivative of claim 4 or its pharmacy acceptable salt, wherein R
2Represent the chlorine atom of hydrogen atom or para-orientation.
6. the preparation method of the flavone derivative of claim 1 comprises:
R wherein
1, R
2, n definition with claim 1.
7. the flavone derivative of claim 1 or its pharmacy acceptable salt, wherein pharmacy acceptable salt is the salt that compound of Formula I and following acid form: hydrochloric acid, Hydrogen bromide, phosphoric acid, acetate, sulfuric acid, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, methylsulfonic acid or dextrocamphoric acid.
8. pharmaceutical composition contains compound of Formula I or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
9. the flavone derivative of claim 1 or its pharmacy acceptable salt are used for preparation treatment and α
1The purposes of the medicine of receptor antagonism relative disease.
10. the purposes of claim 9 is wherein with α
1The disease that receptor antagonism is relevant is hyperplasia of prostate or cardiovascular system diseases.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109400571A (en) * | 2018-12-26 | 2019-03-01 | 中国药科大学 | With α1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its pharmaceutical salt, preparation method and the usage |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3810896A (en) * | 1971-05-14 | 1974-05-14 | Boehringer Mannheim Gmbh | Flavonyloxyalkyl-piperazine compounds |
-
2010
- 2010-04-29 CN CN 201010159682 patent/CN101817808A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3810896A (en) * | 1971-05-14 | 1974-05-14 | Boehringer Mannheim Gmbh | Flavonyloxyalkyl-piperazine compounds |
Non-Patent Citations (1)
| Title |
|---|
| 《Bioorganic & Medicinal Chemistry》 20041231 Laura Betti等 Design, synthesis, and adrenoceptor binding properties of new arylpiperazine derivatives bearing a flavone nucleus as the terminal heterocyclic molecular portion 1527-1535，特别是1529页表1，右栏第一、5段，1530页figure2，1532页实施例化合物1，2 1-10 第12卷, 2 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109400571A (en) * | 2018-12-26 | 2019-03-01 | 中国药科大学 | With α1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its pharmaceutical salt, preparation method and the usage |
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