CN107629040B - N-aromatic heterocycle-containing flavanonol compound and preparation method and application thereof - Google Patents
N-aromatic heterocycle-containing flavanonol compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an N-aromatic heterocycle-containing flavanonol compound which has the following structure:
wherein the Ar substituent in the formula I is
Description
Technical Field
The invention relates to an N-aromatic heterocycle-containing flavanonol compound, a preparation method thereof and application thereof in preparing anti-inflammatory drugs.
Background
The inflammatory response is a defense response of the body to internal and external stimuli, and is usually manifested clinically by red and swollen, hot pain, dysfunction and other signs. In most cases, inflammation is beneficial, which is an automatic defense response of the human body. In the inflammation process, on one hand, the inflammatory factors can directly or indirectly damage human tissues and cells; on the other hand, the injury factors are diluted, killed and surrounded due to inflammatory hyperemia and exudative reaction; while the damaged tissue is regenerated and healed by parenchymal and mesenchymal cells. Inflammation can therefore be said to be a uniform process of injury and anti-injury. The anti-inflammatory drugs used clinically at present comprise non-steroidal anti-inflammatory drugs, immunosuppressive drugs and the like, which have good curative effects in the treatment of related inflammatory diseases, and meanwhile, the adverse reactions of the drugs are also very serious, such as serious gastrointestinal side reactions. Therefore, it is becoming important to find new, highly effective, low toxicity anti-inflammatory agents.
Flavanonol, english name: flavanonol, which is a derivative of flavonoid subjected to double bond hydrogenation at C-2 and 3 positions, wherein most of plant components have hydroxyl or methoxyl; when the C-3 position has a hydroxyl group, it is generally called flavanonols. The flavanone compounds are relatively limited in distribution in the natural world and few in related research reports as a class of trace flavonoid compounds, but recent molecular biology research results show that some compounds have remarkable anti-inflammatory activity.
Biomedical research has long been a desire for pharmaceuticals: i.e., reducing the number and duration of design cycles required to optimize lead compounds to high quality, safe and effective drug candidates; the cumin is also the target of medical chemists at home and abroad for continuous cumin pursuit. Efficient molecular element design is an important approach to achieve this goal. Among these, the substitution of the CH group on the aromatic ring with an N atom is an important concept. Such modifications can alter the physicochemical properties of many important effector molecules and improve the molecule-target interactions, which can improve drug efficacy. From this point of view, the "essential nitrogen atom" ("process nitrogen atom"; Penningto, L.D. et al.2017) has proven to be a common design element. The design idea can optimize multiple physical and chemical parameters of the candidate drug and improve key pharmacological parameters of the candidate drug in a multiplying way, thereby realizing providing guarantee for further application of the drug. Active ingredients in traditional Chinese medicines are used as lead compounds, and designing and synthesizing a medicine with stronger activity is always an important way for developing new medicines. Therefore, the screening of novel flavanonol compounds containing N-aromatic heterocyclic rings is very important for developing new flavanonol drugs.
Taxifolin is a typical flavanonol compound and is present in a variety of plant components. Taxifolin has a variety of biological activities, with anti-inflammatory activity being particularly pronounced (Kim, y.j.; Choi, s.e.; Lee, m.w.; Lee, c.s.j. pharm. pharmacol.,2010,11, 1465). The anti-inflammatory activity of the synthetic taxifolin obtained by the method is not different from that of the naturally extracted taxifolin, and the anti-inflammatory activity is greatly improved by taking the taxifolin as a lead compound and changing the B ring of the taxifolin, particularly introducing nitrogen-containing aromatic heterocyclic rings.
Disclosure of Invention
Based on the defects of the prior art, the technical problem solved by the invention is to design and synthesize a series of novel N-aromatic heterocyclic-containing flavanonol compounds, and on the basis of activity research, the novel N-aromatic heterocyclic-containing flavanonol compounds with excellent activity are found, and a preparation method of the compounds is provided.
The invention designs and synthesizes the novel flavanonol compound with the structure shown in the formula I by utilizing a computer simulation technology based on a receptor binding principle. Cell experiments show that the compounds have obvious inhibition effect on the release of inflammatory factors from RAW264.7 cells induced by LPS.
In order to solve the technical problems, the invention provides an N-aromatic heterocycle-containing flavanonol compound, which is characterized by having the following structure:
wherein the Ar substituent in the formula I is
And the substituted position of the indicated compound shall include all the positions on the N-aromatic heterocyclic ring which can be substituted.
A preparation method of N-aromatic heterocycle-containing flavanonol compounds is characterized by comprising the following steps:
preferably, the flavanonol compound containing N-aromatic heterocycle and the preparation method thereof provided by the present invention further include part or all of the following technical features:
as an improvement of the technical scheme, in the first step, anhydrous potassium carbonate and 2,4, 6-trihydroxyacetophenone are dissolved in acetone under the stirring condition, reflux stirring is carried out for 0.5-1 h, cooling is carried out slightly, chloromethyl ether is dropwise added under the ice bath condition, stirring reaction is carried out for 5-8 h, potassium carbonate is removed by filtration, and filtrate is dried by spinning to obtain 2, 4-dimethoxyxy-6-hydroxyacetophenone; wherein the mass ratio of the 2,4, 6-trihydroxyacetophenone (II), anhydrous potassium carbonate and chloromethyl ether is 1: 2-5: 1-3.
As an improvement of the technical scheme, in the second step, 2, 4-dimethoxymethoxy-6-hydroxyacetophenone, corresponding nitrogen-containing aromatic formaldehyde and NaOH are dissolved in methanol, stirred to react for 10-15 h, and subjected to suction filtration to obtain 2/,4/-dimethoxymethoxy-6/-hydroxy N-heteroaromatic chalcones; wherein the weight ratio of the 2, 4-dimethoxymethoxy-6-hydroxyacetophenone (III) to the corresponding N-containing aromatic formaldehyde (IV) to NaOH is 1: 1-2: 8-10.
As an improvement of the above technical scheme, the third step is 2/,4/-dimethoxymethoxy-6/Dissolving hydroxy N-heterocyclic chalcone in anhydrous tetrahydrofuran, dropwise adding 30% by mass of aqueous hydrogen peroxide and diethylamine under an ice bath condition, stirring to react for 5-8 h, adding ice water, and performing suction filtration to obtain 2, 4-dimethoxymethoxy N-heterocyclic dihydroflavonol; wherein said 2/,4/-dimethoxymethoxy-6/-hydroxy-N-heterocyclic chalcone (V), 30% by weight aqueous hydrogen peroxide and ethylenediamine, in a ratio of 1:2 to 5.
As an improvement of the technical scheme, in the fourth step, under the stirring condition, 5, 7-dimethoxymethoxy N-aromatic heterocyclic flavanonol is dissolved in methanol, concentrated hydrochloric acid is dropwise added, reflux reaction is carried out for 1-3 h, ice water is added, and suction filtration is carried out to obtain 5, 7-dihydroxy N-aromatic heterocyclic flavanonol; wherein the mass ratio of the 5, 7-dimethoxymethoxy N-heteroaromatic dihydroflavonol (VI) to the concentrated hydrochloric acid is 1: 3-5.
As an improvement of the technical scheme, the N-aromatic heterocycleBased on
And the substituted position of the indicated compound shall include all the positions on the N-aromatic heterocyclic ring which can be substituted.
The application of the flavanonol compound containing the N-aromatic heterocycle is characterized in that: the N-aromatic heterocycle-containing flavanonol compound is used for preparing anti-inflammatory drugs.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects:
the novel N-aromatic heterocyclic flavanonol compound has stronger anti-inflammatory activity, and the activities of some of the compounds are equivalent to or better than those of positive controls indomethacin and taxifolin. Therefore, can be used for preparing anti-inflammatory drugs.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical means of the present invention more clearly understood, the present invention may be implemented in accordance with the contents of the description, and in order to make the above and other objects, features, and advantages of the present invention more clearly understood, the following detailed description is given in conjunction with the preferred embodiments.
Detailed Description
Other aspects, features and advantages of the present invention will become apparent from the following detailed description, which, when taken in conjunction with the drawings, illustrate by way of example the principles of the invention.
Example 1: 2- (3/Total synthesis of (E) -3,5, 7-trihydroxychroman-4-one
(1) Preparation of 2, 4-dimethoxymethoxy-6-hydroxyacetophenone
Dissolving 1g of 2,4, 6-trihydroxyacetophenone in 30ml of acetone, adding 2.88g of anhydrous potassium carbonate, refluxing and stirring for 30min, cooling slightly, dropwise adding 1.13ml of chloromethyl ether, continuously refluxing, detecting by a TLC plate until the reaction is finished, adding water to quench the reaction, extracting by ethyl acetate, drying by anhydrous magnesium sulfate, filtering, and performing rotary evaporation to obtain 1.32g of 2, 4-dimethoxymethoxy-6-hydroxyacetophenone with the yield of 86.62%.
(2) 3-pyridyl-2/,4/-dimethoxymethoxy-6/Preparation of (E) -hydroxychalcone
0.72g of 3-pyridinecarboxaldehyde is dissolved in 25mL of anhydrous methanol, 5.20mL of 50% sodium hydroxide solution is added under ice-bath conditions, stirring is carried out, and then 1g of 2, 4-dimethoxymethoxy-6-hydroxyacetophenone is added. Reacting for 12h, adjusting the pH to be approximately equal to 6 by using concentrated hydrochloric acid after the reaction is finished, generating yellow solid, filtering, recrystallizing by using anhydrous methanol to obtain 3-pyridyl-2/,4/-dimethoxymethoxy-6/-hydroxychalcone 1.33g, yield 98.69%. Yellow solid, melting point: 114 to 115 ℃.
(3)2-(3/Preparation of (E) -pyridyl) -3-hydroxy-5, 7-dimethoxymethoxy chroman-4-one
1g of 3-pyridyl-2/,4/-dimethoxymethoxy-6/-hydroxy chalcone is dissolved in 20ml anhydrous tetrahydrofuran, 0.8ml 30% hydrogen peroxide aqueous solution and 0.8g diethylamine are dropped under the ice bath condition, the reaction is kept under the ice bath condition, TLC plate detection is carried out until the reaction is finished, 20ml cold water is added, the filtration and washing are carried out, and the recrystallization is carried out by using anhydrous methanol, thus obtaining 2- (3)/-pyridyl) -3-hydroxy-5, 7-dimethoxymethoxychroman-4-one 0.79 g.
(4)2-(3/Preparation of (E) -pyridyl) -3,5, 7-trihydroxychroman-4-one
0.5g of 2- (3)/Dissolving (E) -pyridyl) -3-hydroxy-5, 7-dimethoxymethoxy chroman-4-one in 15ml methanol, dropwise adding 0.20ml concentrated hydrochloric acid, heating and refluxing for reaction for 1.5h, adding 10ml cold water, extracting with ethyl acetate, combining organic layers, drying with anhydrous magnesium sulfate, evaporating to remove the solvent, and purifying by silica gel (100 meshes and 200 meshes) column chromatography to obtain 2- (3)/-pyridyl) -3,5, 7-trihydroxychroman-4-one 0.25g, white solid. Melting point: 127.9 to 130.2 ℃;1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),10.82(s,1H),8.80(s,1H),8.55(d,J＝5.2Hz,1H),7.95(d,J＝8.0Hz,1H),7.43(dd,J＝5.2,8.0Hz,1H),5.97(s,1H),5.91(s,1H),5.74(s,1H),5.02(d,J＝12.4Hz,1H),4.52(d,J＝12.4,1H).13C NMR(100MHz,DMSO-d6)δ197.48,167.28,164.27,163.25,148.72,146.79,132.84,131.42,122.93,101.24,96.72,96.07,81.21,72.69.
example 2: 2- (3/Study of anti-inflammatory Activity of (a) -pyridyl) -3,5, 7-trihydroxychroman-4-one
(1) Establishment of inflammation model
Collecting culture cells in logarithmic growth phase, digesting with trypsin, and preparing into 8 × 10 culture medium of H-DMEM containing 1% fetal calf serum4Each/ml single cell suspension was inoculated in a 96-well plate at 100. mu.l/well, and the plate was incubated at 37 ℃ with 5% CO2Culturing in an incubator, and discarding the old culture medium after 12 h. Complete culture medium containing LPS (1 mug/mL) is added, the culture is continued for 24h, and the modeling of the cell inflammation model is completed.
(2) ELISA method for detecting levels of inflammatory factors IL-1 beta, IL-6 and TNF-alpha in RAW264.7 cell culture medium induced by LPS
Collecting culture cells in logarithmic growth phase, digesting with trypsin, and preparing into 8 × 10 culture medium of H-DMEM containing 1% fetal calf serum4Each/ml single cell suspension was inoculated in a 96-well plate at 100. mu.l/well, and the plate was incubated at 37 ℃ with 5% CO2Culturing in an incubator, and discarding the old culture medium after 12 h. Molding according to the method of (1) inflammation model item, and after molding, grouping the drug concentration, wherein the drug concentration is the required concentrationThe medicine is prepared. After administration, the 96-well plate was placed at 37 ℃ and 5% CO2Culturing in an incubator, collecting cell supernatant after 24h, centrifuging, and detecting the amounts of inflammatory factors IL-1 beta, IL-6 and TNF-alpha according to a kit specification.
The results are shown in table 1:
TABLE 1 detection results of inflammatory factors IL-1 beta, IL-6, TNF-alpha
Vs LPS group:*P<0.05，**P<0.01，***P<0.001(
n＝3)
The results show that: 2- (3/The (a) pyridyl) -3,5, 7-trihydroxychroman-4-one has a remarkable inhibitory effect on inflammatory factors released by RAW264.7 cells induced by LPS, and the result of the (a) pyridyl) -3,5, 7-trihydroxychroman-4-one has better activity with positive drugs of indomethacin and taxifolin, and can be used as an anti-inflammatory drug.
Example 3: 2- (2/Total synthesis of (E) -furyl) -3,5, 7-trihydroxychroman-4-one
(1) Preparation of 2, 4-dimethoxymethoxy-6-hydroxyacetophenone
Dissolving 1g of 2,4, 6-trihydroxyacetophenone in 30ml of acetone, adding 2.88g of anhydrous potassium carbonate, refluxing and stirring for 30min, cooling slightly, dropwise adding 1.13ml of chloromethyl ether, continuously refluxing, detecting by a TLC plate until the reaction is finished, adding water to quench the reaction, extracting by ethyl acetate, drying by anhydrous magnesium sulfate, filtering, and performing rotary evaporation to obtain 1.32g of 2, 4-dimethoxymethoxy-6-hydroxyacetophenone with the yield of 86.62%.
(2) 2-furyl-2/,4/-dimethoxymethoxy-6/Preparation of (E) -hydroxychalcone
0.70g of 2-furaldehyde is dissolved in 25mL of anhydrous methanol, 5.20mL of 50% sodium hydroxide solution is added under ice-bath conditions, stirring is carried out, and then 1g of 2, 4-dimethoxymethoxy-6-hydroxyacetophenone is added. Reacting for 12h, adjusting the pH to be approximately equal to 6 by using concentrated hydrochloric acid after the reaction is finished, generating yellow solid, filtering, recrystallizing by using anhydrous methanol to obtain 2-furyl-2/,4/-dimethoxymethoxy-6/-hydroxychalcone 1.38g, yield 87.01%. A yellow solid, which is a solid,
melting point: 72-75 ℃,1H NMR(DMSO-d6,400MHz)δ5.91(s,2H),6.87-7.89(m,3H),7.97(d,1H,J＝15.2Hz),8.25(d,1H,J＝15.2Hz),10.49(s,1H),12.50(s,2H).
(3)2-(2/preparation of (E) -furyl) -3-hydroxy-5, 7-dimethoxymethoxy chroman-4-one
0.88g of 2-furyl-2/,4/-dimethoxymethoxy-6/-hydroxy chalcone is dissolved in 20ml anhydrous tetrahydrofuran, 0.8ml 30% hydrogen peroxide aqueous solution and 0.8g diethylamine are dropped under the ice bath condition, the reaction is kept under the ice bath condition, TLC plate detection is carried out until the reaction is finished, 20ml cold water is added, the filtration and washing are carried out, and the recrystallization is carried out by using anhydrous methanol, thus obtaining 2- (2)/-furyl) -3-hydroxy-5, 7-dimethoxychroman-4-one 0.88 g.
(4)2-(2/Preparation of (E) -furyl) -3,5, 7-trihydroxychroman-4-one
0.45g of 2- (2)/Dissolving (E) -furyl) -3-hydroxy-5, 7-dimethoxymethoxy chroman-4-one in 15ml methanol, dropwise adding 0.20ml concentrated hydrochloric acid, heating and refluxing for 1.5h, adding 10ml cold water, and reacting with ethyl acetateExtracting ester, combining organic layers, drying by anhydrous magnesium sulfate, evaporating solvent, and purifying by silica gel (100-200 mesh) column chromatography to obtain 2- (2)/-furyl) -3,5, 7-trihydroxychroman-4-one 0.22g, white solid. Melting point: 137-138 ℃;1H NMR(400MHz,DMSO-d6)δ11.94(s,1H),10.85(s,1H),7.46(s,1H),6.12～6.42(m,2H),6.00(s,1H),5.90(s,1H),5.72(d,J＝4.0Hz,1H),4.92(d,J＝12.0Hz,1H),4.52(dd,J＝12.0,4.0Hz,1H).13C NMR(100MHz,DMSO-d6)δ199.51,167.28,164.27,162.31,149.83,142.12,113.13,110.04,101.22,96.72,95.68,81.17,72.41.
example 4: 2- (2/Anti-inflammatory Activity of (b) furyl) -3,5, 7-Trihydroxychroman-4-one
(1) Establishment of inflammation model
Collecting culture cells in logarithmic growth phase, digesting with trypsin, and preparing into 8 × 10 culture medium of H-DMEM containing 1% fetal calf serum4Each/ml single cell suspension was inoculated in a 96-well plate at 100. mu.l/well, and the plate was incubated at 37 ℃ with 5% CO2Culturing in an incubator, and discarding the old culture medium after 12 h. Complete culture medium containing LPS (1 mug/mL) is added, the culture is continued for 24h, and the modeling of the cell inflammation model is completed.
(2) ELISA method for detecting levels of inflammatory factors IL-1 beta, IL-6 and TNF-alpha in RAW264.7 cell culture medium induced by LPS
Collecting culture cells in logarithmic growth phase, digesting with trypsin, and preparing into 8 × 10 culture medium of H-DMEM containing 1% fetal calf serum4Each/ml single cell suspension was inoculated in a 96-well plate at 100. mu.l/well, and the plate was incubated at 37 ℃ with 5% CO2Culturing in an incubator, and discarding the old culture medium after 12 h. Molding according to the method under the item of (1) inflammation model, and after molding is finished, grouping the drug concentrations, wherein the drug concentrations are the required concentrations for administration. After administration, the 96-well plate was placed at 37 ℃ and 5% CO2Culturing in an incubator, collecting cell supernatant after 24h, centrifuging, and detecting the amounts of inflammatory factors IL-1 beta, IL-6 and TNF-alpha according to a kit specification.
The results are shown in table 1:
TABLE 2 detection results of inflammatory factors IL-1 beta, IL-6, TNF-alpha
Vs LPS group:*P<0.05，**P<0.01，***P<0.001(
n＝3)
The results show that: compound 2- (2)/The (B) furyl) -3,5, 7-trihydroxychroman-4-one has weak inhibiting effect on inflammatory factors released by RAW264.7 cells induced by LPS, which indicates that the anti-inflammatory activity of the B ring is sharply reduced after the para position of the B ring is substituted by furan heterocycle, has no application value and cannot be used as an anti-inflammatory drug.
The above examples of the present invention show that all the synthesized novel N-containing aromatic heterocyclic flavanonol compounds have strong anti-inflammatory activity, and in previous toxicity studies, the compounds have no cytotoxicity at 20 μ M, so that they are further safe to be used as medicines. And the anti-inflammatory activity of other heterocyclic substituted flavanonol compounds is reduced or disappeared, so that the compounds cannot be used as anti-inflammatory drugs.
The raw materials listed in the invention, the upper and lower limits and interval values of the raw materials of the invention, and the upper and lower limits and interval values of the process parameters (such as temperature, time and the like) can all realize the invention, and the examples are not listed.
While the foregoing is directed to the preferred embodiment of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.
Claims (7)
1. An N-aromatic heterocycle-containing flavanonol compound is characterized by having the following structure:
wherein the Ar substituent in the formula I is
And the substituted position of the substituted compound contains all the positions capable of being substituted on the N aromatic heterocyclic ring.
2. The process for producing an N-heterocyclic aromatic dihydroflavonol compound as claimed in claim 1, which comprises the steps of:
step one, protecting two phenolic hydroxyl groups by chloromethyl ether
Step two, condensation reaction of carbonyl
Step three, hydrogen peroxide cyclization reaction
Step four, deprotection with hydrochloric acid
3. The process for producing an N-heterocyclic aromatic dihydroflavonol compound according to claim 2, wherein: dissolving anhydrous potassium carbonate and a compound II in an appropriate amount of acetone solution under the stirring condition, refluxing and stirring for 0.5-1 h, slightly cooling, dropwise adding chloromethyl ether under the ice bath condition, stirring and reacting for 5-8 h, filtering to remove potassium carbonate, and spin-drying the filtrate to obtain a compound III; wherein the mass ratio of the compound II, anhydrous potassium carbonate and chloromethyl ether is 1: 2-5: 1-3.
4. The process for producing an N-heterocyclic aromatic dihydroflavonol compound according to claim 2, wherein: dissolving the compound III, the corresponding nitrogen-containing aromatic formaldehyde and NaOH in methanol, stirring for reaction for 10-15 h, and performing suction filtration to obtain a compound V; wherein the amount ratio of the compound III to the corresponding nitrogen-containing aromatic formaldehyde IV to NaOH is 1: 1-2: 8-10.
5. The process for producing an N-heterocyclic aromatic dihydroflavonol compound according to claim 2, wherein: dissolving a compound V in anhydrous tetrahydrofuran, dropwise adding 30% by mass of aqueous hydrogen peroxide and diethylamine under an ice bath condition, stirring for reacting for 5-8 h, and performing suction filtration to obtain a compound VI; wherein the compound V, 30% by mass of aqueous hydrogen peroxide solution and diethylamine are in a ratio of 1: 2-5.
6. The process for producing an N-heterocyclic aromatic dihydroflavonol compound according to claim 2, wherein: dissolving the compound VI in methanol under the condition of stirring, dripping concentrated hydrochloric acid, performing reflux reaction for 1-3 h, and performing suction filtration to obtain a compound I; wherein the mass ratio of the compound VI to the concentrated hydrochloric acid is 1: 3-5.
7. Use of an N-aromatic heterocycle-containing flavanonol compound prepared by the method as claimed in any one of claims 2 to 6, characterized in that: the N-aromatic heterocycle-containing flavanonol compound is used for preparing anti-inflammatory drugs.
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| CN1990482A (en) * | 2005-12-26 | 2007-07-04 | 浙江海正天华新药研发有限公司 | Flavanonol compounds and their production method and use |
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| CN1990482A (en) * | 2005-12-26 | 2007-07-04 | 浙江海正天华新药研发有限公司 | Flavanonol compounds and their production method and use |
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| Title |
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| 类黄酮构效关系研究进展;方雅静 等;《华中农业大学学报》;20151130;第34卷(第6期);第146-154页 * |
| 黄酮类化合物的构效关系研究进展;赵雪巍 等;《中草药》;20151130;第46卷(第21期);第3264-3271页 * |
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