CN105884614A - Preparation method and application of derivative containing magnolol and obtained by esterifying honokiol analogs and nonsteraidal anti-inflammatory drugs - Google Patents
Preparation method and application of derivative containing magnolol and obtained by esterifying honokiol analogs and nonsteraidal anti-inflammatory drugs Download PDFInfo
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Abstract
The invention discloses a magnolol, a series of derivatives obtained by esterifying honokiol analogs (magnolol, trans-magnolol, tetrahydromagnolol and honokiol) and nonsteraidal anti-inflammatory drugs and a preparation method of the derivatives. The chemical formulas of the derivatives are shown in the formula (I). The derivatives in the formula (I) are applied in the aspects of anti-inflammatory drugs, dermatological agents and functional cosmetics and the like.
Description
Technical field
The present invention relates to new drug compound technical, be specifically related to the preparation and application of magnolol and honokiol derivative and carboxylic acid non-steroidal anti-inflammatory agent esterification products.
Technical background
NSAIDs (nonsteraidal anti-inflammatory drugs, NSAIDs) be a class have antipyretic, analgesia, the medicine of anti-inflammatory curative effect, belong to Class B OTC, be now widely used in the treatment of heating, pain, inflammatory disease, rheumatic disease and soft tissue and injury gained in sports.But, the oral NSAIDs of long-term, high-dose can bring series of side effects to patient, such as hemorrhage of gastrointestinal tract, lesions of liver and kidney, Cardiovascular Damage etc..
Magnolol and honokiol are all that the main component of Chinese tradition Cortex Magnoliae Officinalis, magnolol and honokiol have multiple physiologically active and the pharmacological actions such as anti-inflammatory, anti-oxidant, antitumor, antibacterial, anti-aging, reducing blood lipid and blood sugar.But, further investigation revealed that magnolol and honokiol activity in vivo is on the low side, absorb not exclusively, bioavilability is low, significantly limit its application, the structural modification to magnolol and honokiol is concentrated mainly on following youngster aspect at present: CN 101223120A；CN 102884035A；CN 103113264A.
Summary of the invention
It is an object of the invention to provide the compound of magnolol and honokiol derivative and carboxylic acid non-steroidal anti-inflammatory agent esterification.
Further object is that the preparation method providing a kind of above-mentioned magnolol and honokiol derivative with carboxylic acid non-steroidal anti-inflammatory agent esterification.
Further object is that and provide a kind of above-mentioned magnolol and honokiol derivative and the derivative of carboxylic acid non-steroidal anti-inflammatory agent esterification in the oral or application of injection anti-inflammatory drug, dermatologic thing, functionalization cosmetic etc..
Above-mentioned purpose of the present invention is achieved by following scheme:
The present invention relates to the series compound of magnolol and honokiol derivative and carboxylic acid non-steroidal anti-inflammatory agent esterification, shown in its chemical constitution such as formula (I):
X and Y is at the same time or separately for structure shown in formula (1)-(13) formula.But wherein X and Y any one be OH.
The preparation method that the magnolol that the present invention relates to and honokiol derivative are esterified with carboxylic acid non-steroidal anti-inflammatory agent.The method comprises the steps:
The magnolol of 1-2mmol and the carboxylic acid non-steroidal anti-inflammatory agent of honokiol derivative and 2mmol are placed in round-bottomed flask, add 30mL dichloromethane and the DMAP (N of catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～3mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The eluant, eluent that column chromatography analysis purifies is ethyl acetate: hexamethylene=1: 10～1: 2, is spin-dried for solvent and obtains thick product, recrystallizes with acetone or alcohol, is vacuum dried to obtain target product.
The magnolol that the present invention relates to and honokiol derivative confirm through overtesting with carboxylic acid non-steroidal anti-inflammatory agent esterification gained derivative and antiinflammatory action thereof.
The magnolol of the present invention and honokiol derivative are esterified gained derivative with carboxylic acid non-steroidal anti-inflammatory agent, under the auxiliary combination that can receive with pharmaceutically and cosmetically specification, are prepared as emulsion, cream, aqua etc..
Compared with prior art, there is advantages that
1. the magnolol of the present invention and the derivative of honokiol carboxylic acid non-steroidal anti-inflammatory agent lactate synthesis, it is possible to resolve carboxylic acid non-steroidal anti-inflammatory agent is because of the part side effect brought and absorption problem.
2. magnolol and the honokiol carboxylic acid non-steroidal anti-inflammatory agent ester compounds of the present invention has good antiinflammatory action, can form the lead compound of the anti-inflammatory drug of a new generation.
Accompanying drawing explanation
In order to investigate single parent drug magnolol, corresponding carboxylic acid non-steroidal anti-inflammatory agent, the impact on mice auricle swelling inhibition of the compound of magnolol and corresponding carboxylic acid non-steroidal anti-inflammatory agent use in conjunction and correspondence, has smeared different medicines to mouse ear respectively according to above-mentioned animal model.The effect suppressed mice auricle swelling by the weight difference magnolol analog derivative of record Mice Auricle, using acetone as comparison.
Fig. 1 is that different pharmaceutical affects figure to mice auricle swelling.As shown in Figure 1, individually parent drug, including Ketoprofen, naproxen, Diclofenac, Diflunisal and flufenamic acid all have inhibitory action in various degree to mice auricle swelling, also have reasonable inhibitory action to mice auricle swelling according to the parent drug honokiol of the mixed in molar ratio of corresponding proportion (1: 1 or 1: 2).Then auricle edema being had good inhibiting effect according to NSAIDs magnolol ester derivant of the present invention, wherein by comparing discovery, the inhibitory action of compound 3 is the most obvious.
In order to investigate the different pharmaceutical impact on mice auricle swelling inhibition, smear different medicines to mouse ear respectively according to above-mentioned swelling model.The effect suppressed mice auricle swelling by record Mice Auricle weight different pharmaceutical, to add acetone group as comparison.
Fig. 2 is the H&E colored graph that different pharmaceutical processes the auricle obtained.As in figure 2 it is shown, result shows, parent medicine Ketoprofen has a certain degree of inhibitory action to mice auricle swelling, also has reasonable inhibitory action to mice auricle swelling according to the parent drug honokiol of the mixed in molar ratio of corresponding proportion (1: 1).It is then the most obvious to auricle edema inhibitory action according to compound 3 of the present invention.
Detailed description of the invention
Below by way of specific embodiment, the present invention will be further described, but the present invention is not done any restriction by specific embodiment.
Embodiment 1: the synthesis of compound 1-2
The preparation process of the present embodiment, comprises the steps:
The brufen of the magnolol of 1.2mmol Yu 1.0mmol-2mmol is placed in round-bottomed flask, add 50mL dichloromethane and the DMAP (N of catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～3mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorates) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, is vacuum dried to obtain target product, i.e. compound 1 and compound 2.Productivity is respectively 91% and 70%.
Compound 1: white oil liquid.1H NMR (400MHz, CDCl3) δ 10.40 (s, 1H), 7.70 (dd, J=8.0, 1.6Hz, 1H), 7.45 (m, 1H), 7.28 (m, 2H), 7.21 (m, 1H), 7.15 (s, 1H), 7.12 (d, J=2.1Hz, 2H), 6.97 (m, 2H), 6.82 (m, 1H), 5.99 (m, 1H), 5.83 (m, 1H), 5.10 (d, J=1.3Hz, 2H), 5.00 (dd, J=13.5, 2.1Hz, 2H), 3.44 (d, J=6.7Hz, 2H), 3.33 (d, J=6.7Hz, 2H), 2.02 (s, 3H).
Compound 2: white oil liquid.1H NMR (400MHz, CDCl3) δ 7.11 (m, 2H), 7.01 (m, 10H), 6.89 (d, J=8.2Hz, 2H), 5.92 (dd, J=16.9,10.0Hz, 2H), 5.07 (m, 4H), 3.63 (q, J=7.1Hz, 2H), 3.33 (d, J=6.5Hz, 4H), 2.42 (d, J=7.2Hz, 4H), 1.83 (dp, J=13.5,6.7Hz, 2H), 1.28 (d, J=6.9Hz, 7H), 0.89 (d, J=6.6Hz, 12H).13C NMR (101MHz, CDCl3) δ 173.05,146.46,140.34,137.39,137.05,131.13,130.29,129.22,128.75,127.23,122.01,116.13,45.09,44.93,44.85,39.51,30.21,22.45.
Embodiment 2: the synthesis of compound 3 and 4
The Ketoprofen of the magnolol of 1.2mmol Yu 1.0mmol-2mmol is placed in round-bottomed flask, add the DMAP (N of 50mL dichloromethane and catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～3mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorates) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, is vacuum dried to obtain white oil liquid, i.e. compound 1 and compound 2.Productivity is respectively 88% and 73%.
Compound 3:1H NMR (400MHz, CDCl3null)δ7.81(m，2H)，7.69(s，1H)，7.61(m，2H)，7.49(t，J=7.6Hz，2H)，7.33(d，J=7.4Hz，2H)，7.22(dd，J=8.3，2.0Hz，1H)，7.15(d，J=1.9Hz，1H)，7.00(m，2H)，6.86(d，J=1.6Hz，1H)，6.76(d，J=8.3Hz，1H)，5.93(dddt，J=23.5，16.9，10.2，6.7Hz，2H)，5.39(s，1H)，5.05(m，4H)，3.80(d，J=7.2Hz，1H)，3.41(d，J=6.7Hz，2H)，3.26(d，J=6.6Hz，2H)，1.36(d，J=7.2Hz，3H).13C NMR (101MHz, CDCl3) δ 196.90,172.82,151.48,146.86,139.92,138.61,137.75,137.36,136.83,132.72,131.87,131.63,130.68,130.50,130.24,129.55,129.39,129.13,128.56,128.40,123.97,122.43,116.45,116.09,115.58,45.31,39.44,18.30.
Compound 4:1H NMR (400MHz, CDCl3) δ 7.79 (m, 4H), 7.65 (s, 3H), 7.58 (t, J=7.4Hz, 2H), 7.46 (t, J=7.1Hz, 4H), 7.32 (d, J=7.2Hz, 4H), 7.10 (d, J=7.7Hz, 2H), 7.01 (s, 2H), 6.88 (d, J=8.3Hz, 2H), 5.89 (m, 2H), 5.05 (m, 4H), 3.66 (s, 2H), 3.32 (d, J=6.3Hz, 4H), 1.33 (d, J=6.2Hz, 6H).13C NMR (101MHz, CDCl3) δ 196.28,172.32,146.27,140.07,137.69,137.50,136.87,132.49,131.64,131.12,130.18,130.07,129.31,128.96,128.51,128.32,121.91,116.24,45.06,39.45,18.29.
Embodiment 3: the synthesis of compound 5 and 6
The naproxen of the magnolol of 1mmol Yu 1.0mmol-2.0mmol is placed in round-bottomed flask, add 50mL dichloromethane and the DMAP (N of catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～3mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorates) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, is vacuum dried to obtain white oil liquid, i.e. compound 5 and compound 6.Productivity is respectively 97% and 70%.
Compound 5:1H NMR (400MHz, CDCl3) δ 7.58 (dd, J=13.6,8.8Hz, 2H), 7.49 (s, 1H), 7.18 (d, J=8.5Hz, 1H), 7.11 (m, 3H), 7.06 (d, J=2.0Hz, 1H), 6.97 (d, J=7.9Hz, 1H), 6.83 (m, 2H), 6.66 (d, J=8.2Hz, 1H), 5.85 (m, 2H), 5.01 (m, 4H), 3.83 (m, 4H), 3.33 (d, J=6.7Hz, 2H), 3.13 (d, J=6.6Hz, 2H), 1.40 (d, J=7.2Hz, 3H).13C NMR (101MHz, CDCl3) δ 173.65,157.76,151.37,147.01,138.59,137.82,136.88,134.67,133.85,131.84,130.54,129.50,129.03,127.28,126.13,123.92,122.66,118.93,116.40,115.58,105.69,55.35,45.28,39.42,29.81,20.84,18.41.
Compound 6:1H NMR (400MHz, CDCl3) δ 7.52 (m, 6H), 7.19 (d, J=8.5Hz, 2H), 7.07 (m, 4H), 6.89 (m, 4H), 6.71 (d, J=8.2Hz, 2H), 5.81 (m, 2H), 4.99 (m, 4H), 3.86 (s, 6H), 3.77 (d, J=7.1Hz, 2H), 3.16 (d, J=6.6Hz, 4H), 1.38 (d, J=7.0Hz, 6H).13C NMR (101MHz, CDCl3) δ 172.88,157.72,146.37,137.20,135.02,133.79,131.03,130.21,129.50,129.02,128.71,127.06,126.26,121.94,118.80,116.11,105.61,55.34,45.27,39.41,18.33.
Embodiment 4: the synthesis of compound 7 and 8
The salicylic acid of the magnolol of 1.2mmol Yu 1.0mmol-2.0mmol is placed in round-bottomed flask, add the DMAP (N of 50mL dichloromethane and catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～4mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorates) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, is vacuum dried, be i.e. compound 1 and compound 2.Productivity is respectively 92% and 51%.
Compound 7: light yellow solid, fusing point: 91.0-92.3 DEG C.1H NMR (400MHz, CDCl3null)δ10.14(s，1H)，7.71(dd，J=8.0，1.5Hz，1H)，7.37(s，1H)，7.23(d，J=2.0Hz，1H)，7.19(m， 2H)，6.91(m，2H)，6.86(d，J=8.4Hz，1H)，6.76(s，1H)，6.74(d，J=8.8Hz，1H)，5.92(ddt，J=16.8，10.0，6.8Hz，1H)，5.73(m，1H)，5.05(ddd，J=18.5，15.1，6.8Hz，2H)，4.96(s，1H)，4.85(m，2H)，3.38(d，J=6.7Hz，2H)，3.16(d，J=6.6Hz，2H).13C NMR (101MHz, CDCl3) δ 167.35,151.27,148.99,146.98,140.09,138.76,137.66,136.79,135.61,134.93,132.00,131.86,131.74,130.70,130.31,129.69,126.85,125.89,123.75,123.26,123.10,117.09,116.56,116.12,115.51,113.76,110.32,39.45,14.97.
Compound 8: white oil liquid.1H NMR (400MHz, CDCl3) δ 10.31 (d, J=6.2Hz, 2H), 7.92 (d, J=1.0Hz, 1H), 7.77 (dd, J=8.0,1.6Hz, 1H), 7.58 (m, 1H), 7.45 (m, 1H), 7.18 (m, 2H), 6.97 (dd, J=16.1,8.5Hz, 2H), 6.84 (ddd, J=8.0,7.4,1.4Hz, 3H), 5.82 (m, 2H), 4.98 (m, 4H), 3.34 (m, 4H).13C NMR (101MHz, CDCl3) δ 168.60,162.00,145.74,138.26,136.45,131.33,130.26,130.00,129.35,122.40,119.37,117.63,116.35,111.71,39.44,29.70.
Embodiment 5: the synthesis of compound 9 and 10
The mefenamic acid of the magnolol of 1.2mmol Yu 1.0mmol-2.0mmol is placed in round-bottomed flask, add the DMAP (N of 50mL dichloromethane and catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～4mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorates) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, is vacuum dried to obtain target product, i.e. compound 9 and compound 10.Productivity is respectively 92% and 71%.
Compound 9: light yellow solid, fusing point: 94.1-95.5 DEG C.1H NMR (400MHz, CDCl3null)δ8.92(s，1H)，7.90(dd，J=8.1，1.5Hz，1H)，7.29(d，J=1.7Hz，1H)，7.21(d，J=3.1Hz，2H)，7.07(m，2H)，6.99(m，3H)，6.83(d，J=8.2Hz，1H)，6.69(d，J=8.2Hz，1H)，6.60(s，1H)，5.99(d，J=6.9Hz，1H)，5.82(d，J=6.6Hz，1H)，5.20(s，1H)，5.12(m，2H)，4.95(m，2H)，3.45(d，J=6.8Hz，2H)，3.24(d，J=6.6Hz，2H)，2.29(s，3H)，2.07(s，3H).13C NMR (101MHz, CDCl3) δ 167.43,151.31,150.03,147.08,138.64,138.31,137.70,136.83,134.88,132.54,132.07-131.59,130.71,130.38,129.67,127.00,125.92,123.85,123.30,116.52,116.17,115.50,109.48,39.46,20.64,13.97.
Compound 10: light yellow solid, fusing point: 105.1-105.4 DEG C.1H NMR (400MHz, CDCl3null)δ9.04(s，2H)，7.94(d，J=8.0Hz，2H)，7.16(dt，J=8.2，7.3Hz，6H)，7.07(d，J=7.7Hz，2H)，7.01(d，J=7.8Hz，2H)，6.94(d，J=7.3Hz，2H)，6.69(d，J=8.6Hz，2H)，6.56(t，J=7.6Hz，2H)，5.81(ddd，J=16.6，8.5，5.1Hz，2H)，4.94(t，J=13.4Hz，4H)，3.30(d，J=6.6Hz，4H)，2.25(d，J=11.7Hz，8H)，2.06(d，J=5.2Hz，6H).13C NMR (101MHz, CDCl3) δ 167.16,149.96,146.52,138.53,138.20,137.53,136.95,134.65,132.42,132.02,131.40,130.75-130.51,129.09,126.86,125.91,123.10,122.80,117.65-115.02,113.58,109.92,39.58,29.76,20.64,13.99.
Embodiment 6: the synthesis of compound 11 and 12
The tolfenamic acid of the magnolol of 1.2mmol Yu 1.0mmol-2.0mmol is placed in round-bottomed flask, add the DMAP (N of 50mL dichloromethane and catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～4mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorates) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, is vacuum dried to obtain target product, i.e. compound 11 and compound 12.Productivity is respectively 93% and 79%.
Compound 11: yellow solid, fusing point: 101.3-101.7 DEG C.1H NMR (400MHz, CDCl3null)δ8.97(s，1H)，7.92(dd，J=8.1，1.5Hz，1H)，7.31(dd，J=8.2，2.1Hz，1H)，7.23(d，J=1.4Hz，1H)，7.18(dd，J=13.1，4.9Hz，2H)，7.08(t，J=7.9Hz，1H)，6.98(m，2H)，6.82(d，J=8.2Hz，1H)，6.75(d，J=8.4Hz，1H)，6.66(m，1H)，5.99(ddt，J=16.8，10.0，6.8Hz，1H)，5.81(ddt，J=16.9，10.3，6.6Hz，1H)，5.13(m，3H)，4.95(dd，J=12.4，6.0Hz，2H)，3.45(d，J=6.8Hz，2H)，3.24(d，J=6.6Hz，2H)，2.22(s，3H).13C NMR (101MHz, CDCl3) δ 169.17-168.85,161.91,151.13,146.35,139.18,137.55,136.49,131.91,130.75-129.35,123.29,122.98,119.39,117.59,116.62,116.02,115.55,111.64,39.59,39.19.
Compound 12: light yellow solid, fusing point: 88.1-89.0 DEG C.1H NMR (400MHz, CDCl3) δ 9.05 (s, 2H), 7.94 (dd, J=8.1,1.5Hz, 2H), 7.17 (m, 8H), 7.08 (s, 2H), 6.77 (d, J=8.4Hz, 2H), 6.66 (t, J=7.6Hz, 2H), 5.83 (d, J=6.8Hz, 2H), 4.99 (dd, J=20.8,5.5Hz, 4H), 3.34 (d, J=6.6Hz, 4H), 2.21 (s, 6H).13C NMR (101MHz, CDCl3) δ 167.01,148.93,146.37,140.18,137.65,136.85,135.57,134.71,132.02,131.63,131.38,130.51,129.12,126.81,125.76,122.94,122.69,117.02,116.15,113.76,110.64,39.53,29.73,14.95.
Embodiment 7: the synthesis of compound 13 and 14
The flufenamic acid of the magnolol of 1.2mmol Yu 1.0mmol-2.0mmol is placed in round-bottomed flask, add the DMAP (N of 50mL dichloromethane and catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～4mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorates) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, is vacuum dried to obtain target product, i.e. compound 13 and compound 14.Productivity is respectively 91% and 65%.
Compound 13: light green solid, fusing point: 99.3-100.1 DEG C.1H NMR (400MHz, CDCl3) δ 9.22 (s, 1H), 7.93 (dd, J=8.0, 1.4Hz, 1H), 7.41 (d, J=5.1Hz, 2H), 7.37 (m, 1H), 7.31 (m, 4H), 7.23 (t, J=5.8Hz, 2H), 6.98 (m, 2H), 6.78 (m, 2H), 5.99 (ddt, J=16.8.10.0, 6.8Hz, 1H), 5.82 (ddt, J=16.9, 10.3, 6.6Hz, 1H), 5.14 (m, 2H), 4.96 (dd, J=12.5, 5.9Hz, 2H), 3.45 (d, J=6.7Hz, 2H), 3.24 (d, J=6.6Hz, 2H).13C NMR (101MHz, CDCl3) δ 167.22,151.18,147.14,146.82,141.25,138.91,137.63,136.75,134.96,132.17,131.96,131.91,131.87,131.64,130.68,130.19,129.93,129.79,129.66,124.71,123.56,123.22,119.80,118.39,118.11,116.57,116.04,115.52,114.16,111.79,39.62,39.24.
Compound 14: light yellow solid, fusing point: 100.7-102.0 DEG C.1H NMR (400MHz, CDCl3) δ 9.30 (s, 2H), 7.95 (dd, J=8.0,1.2Hz, 2H), 7.39 (d, J=5.9Hz, 2H), 7.34 (dd, J=11.9,4.7Hz, 4H), 7.29 (d, J=12.2Hz, 3H), 7.22 (d, J=11.7Hz, 1H), 7.16 (s, 4H), 6.75 (t, J=7.6Hz, 2H), 5.82 (dd, J=16.9,10.1Hz, 2H), 5.06.4.91 (m, 4H), 3.33 (d, J=6.7Hz, 4H).13C NMR (101MHz, CDCl3) δ 166.90,147.12,146.33,141.40,137.88,136.83,134.82,132.25,131.98,131.66,131.42,130.43,129.90,129.23,128.04,125.33,124.53,122.66,119.68,118.40,118.04,116.21,114.20,112.13,39.54.
Embodiment 8: the synthesis of compound 15 and 16
The Diclofenac of the magnolol of 1.2mmol Yu 1.0mmol-2.0mmol is placed in round-bottomed flask, add the DMAP (N of 50mL dichloromethane and catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～4mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorates) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, is vacuum dried to obtain white oil liquid, i.e. compound 15 and compound 16.Productivity is respectively 92% and 77%.
Compound 15: white oil liquid.1H NMR (400MHz, CDCl3null)δ7.31(d，J=8.1Hz，2H)，7.23(m，1H)，7.19(d，J=1.9Hz，1H)，7.10(m，2H)，7.04(d，J=7.5Hz，2H)，6.96(t，J=8.1Hz，1H)，6.89(dd，J=9.0，5.2Hz，3H)，6.72(m，1H)，6.48(d，J=7.5Hz，2H)，5.91(dddt，J=33.6，16.8，10.1，6.8Hz，2H)，5.13(d，J=1.5Hz，2H)，5.08(m，1H)，5.48(m，4H)，3.78(s，2H)，3.40(m，2H)，3.21(d，J=6.7Hz，2H).13C NMR (101MHz, CDCl3) δ 171.06,151.10,146.81,142.67,138.90,137.80,136.73,131.89,130.90,130.41,130.16,129.79-129.41,128.81,128.12,124.15,123.56,122.80,122.19,118.36,116.57,116.31,115.58,39.45,37.86-37.06.
Compound 16: white oil liquid.1H NMR (400MHz, CDCl3) δ 7.81 (dd, J=7.9, 1.5Hz, 4H), 7.51 (td, J=8.0, 1.6Hz, 6H), 7.23 (m, 4H), 7.19 (m, 2H), 7.15 (m, 2H), 7.07 (d, J=8.1Hz, 2H), 7.00 (d, J=8.8Hz, 2H), 5.98 (ddt, J=16.9, 10.2, 6.7Hz, 2H), 5.84 (m, 1H), 5.08 (s, 2H), 5.01 (d, J=1.4Hz, 4H), 3.42 (d, J=6.7Hz, 1H), 3.34 (d, J=6.7Hz, 4H), 2.24 (s, 4H), 1.98 (s, 1H).13C NMR (101MHz, CDCl3) δ 170.93,146.20,142.69,137.96,136.88,131.10,130.08,129.91,129.61,128.89,127.94,124.00,122.15,118.25,116.24,39.46,37.98,29.73.
Embodiment 9: the synthesis of compound 17 and 18
The diflunisal of the magnolol of 1.2mmol Yu 1.0mmol-2.0mmol is placed in round-bottomed flask, add the DMAP (N of 50mL dichloromethane and catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～4mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorates) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, is vacuum dried to obtain target product, i.e. compound 17 and compound 18.Productivity is respectively 95% and 72%.
Compound 17: white oil liquid.1H NMR (400MHz, CDCl3) δ 10.29 (s, 1H), 7.90 (d, J=1.3Hz, 1H), 7.61 (m, 1H), 7.30 (m, 4H), 7.01 (d, J=8.7Hz, 1H), 6.98 (dd, J=4.3,2.2Hz, 2H), 6.92 (m, 2H), 6.81 (d, J=8.8Hz, 1H), 5.99 (d, J=6.8Hz, 1H), 5.76 (d, J=6.7Hz, 1H), 5.14 (m, 2H), 5.04 (s, 1H), 4.88 (m, 2H), 3.47 (d, J=6.7Hz, 2H), 3.21 (d, J=6.6Hz, 2H).13C NMR (101MHz, CDCl3) δ 168.51,161.41,151.10,146.24,139.24,137.47,136.85,136.62,132.01,131.87,131.06,130.62,130.42,130.01,129.87,129.64,126.32,123.28,122.82,117.88,116.67,115.96,115.52,111.77,111.56,104.69,104.44,104.18,39.60,39.15.
Compound 18: white oil liquid.1H NMR (400MHz, CDCl3) δ 10.31 (s, 2H), 7.92 (s, 2H), 7.59 (d, J=8.7Hz, 2H), 7.20 (m, 7H), 7.01 (d, J=8.7Hz, 2H), 6.84 (dt, J=19.4,8.5Hz, 4H), 5.81 (dd, J=17.2,9.7Hz, 2H), 4.98 (m, 5H), 3.34 (d, J=6.6Hz, 4H).13C NMR (101MHz, CDCl3) δ 168.29,161.45,145.69,138.47,136.64,131.34,130.87,130.34,130.03,129.44,126.25,123.81,122.13,117.91,116.40,111.71,111.48,104.61,104.36,104.10,39.41.
Embodiment 10: the synthesis of compound 19 and 20
The Etodolac of the magnolol of 1.2mmol Yu 1.0mmol-2.0mmol is placed in round-bottomed flask, add the DMAP (N of 50mL dichloromethane and catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～4mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorates) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, is vacuum dried to obtain target compound, i.e. compound 19 and compound 20.Productivity is respectively 90% and 78%.
Compound 19: white solid, fusing point: 95.8-96.9 DEG C.1H NMR (400MHz, CDCl3null)δ8.77(s，1H)，7.34(d，J=7.6Hz，1H)，7.27(d，J=2.0Hz，1H)，7.22(d，J=2.3Hz，1H)，7.05(dd，J=9.9，5.0Hz，2H)，7.00(dd，J=8.0，4.8Hz，2H)，6.94(d，J=2.0Hz，1H)，6.82(d，J=8.2Hz，1H)，5.93(ddd，J=35.0，16.9，10.1Hz，2H)，5.13(m，3H)，5.02(m，2H)，4.00(m，1H)，3.88(m，1H)，3.44(d，J=6.8Hz，2H)，3.27(d，J=6.7Hz， 2H)，3.04(d，J=16.6Hz，1H)，2.82(ddd，J=15.9，12.3，10.7Hz，4H)，2.70(m，1H)，1.69(m，4H)，1.30(t，J=7.6Hz，3H)，0.61(t，J=7.3Hz，3H).13C NMR (101MHz, CDCl3) δ 171.86,151.23,146.67,139.15,137.57,136.64,135.38,134.52,132.18,132.02,130.55,130.27,129.92,129.76,126.74,126.07,123.71,122.65,120.43,119.65,108.59,74.56,60.69,42.84,42.01,39.61,39.30,30.32,27.06,25.01,24.06,22.40,13.84,7.49.
Compound 20: white oil liquid.1H NMR (400MHz, CDCl3) δ 8.88 (s, 2H), 7.37 (d, J=7.7Hz, 2H), 7.22 (m, 4H), 7.07 (t, J=7.5Hz, 2H), 7.00 (dd, J=7.5,3.1Hz, 4H), 5.93 (d, J=8.2Hz, 2H), 5.09 (t, J=11.9Hz, 4H), 3.964 (m, 4H), 3.38 (s, 4H), 3.07 (d, J=16.9Hz, 3H), 2.80 (m, 10H), 1.87 (s, 3H), 1.30 (m, 7H), 0.65 (s, 6H).13C NMR (101MHz, CDCl3) δ 171.41,146.06,138.45,136.64,135.56,134.49,131.28,130.31,129.34126.60,126.12,122.26,120.36,119.63,108.58,74.45,60.64,42.80,39.52,30.30,24.00,22.40,13.72,7.42.
Embodiment 11: the synthesis of compound 21
The aspirin of the magnolol of 1.2mmol Yu 1.0mmol is placed in round-bottomed flask, add the DMAP (N of 50mL dichloromethane and catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 1～3mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, and vacuum drying obtains target product, i.e. compound 21.Productivity is respectively 73%.
Compound 21: colourless transparent liquid.1H NMR (400MHz, CDCl3) δ 10.40 (s, 1H), 7.70 (dd, J=8.0, 1.6Hz, 1H), 7.45 (m, 1H), 7.28 (m, 2H), 7.21 (m, 1H), 7.15 (s, 1H), 7.12 (d, J=2.1Hz, 2H), 6.97 (m, 2H), 6.82 (m, 1H), 5.99 (m, 1H), 5.83 (m, 1H), 5.10 (d, J=1.3Hz, 2H), 5.00 (dd, J=13.5, 2.1Hz, 2H), 3.44 (d, J=6.7Hz, 2H), 3.33 (d, J=6.7Hz, 2H), 2.02 (s, 3H).13C NMR (101MHz, CDCl3) δ 169.34,168.68,161.92,146.42,145.65,138.20,137.80,136.83,136.19,131.41,131.16,130.33,130.01,129.28,129.04,122.44,119.35,117.57,116.23,111.94,39.51,29.71,20.67.
Embodiment 12: the synthesis of compound 22
The acetic acid of the compound 21 of 1.2mmol with 1.0mmol is placed in round-bottomed flask, add the DMAP (N of 30mL dichloromethane and catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 1～3mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, and vacuum drying obtains target product, i.e. compound 22.Productivity is respectively 55%.
Compound 22: white oil liquid.1H NMR (400MHz, CDCl3) δ 7.81 (dd, J=7.9, 1.5Hz, 1H), 7.51 (td, J=8.0, 1.6Hz, 1H), 7.23 (m, 2H), 7.19 (m, 2H), 7.15 (m, 2H), 7.07 (d, J=8.1Hz, 1H), 7.00 (d, J=8.8Hz, 1H), 5.98 (ddt, J=16.9, 10.2, 6.7Hz, 1H), 5.84 (m, 1H), 5.08 (s, 2H), 5.01 (d, J=1.4Hz, 2H), 3.42 (d, J=6.7Hz, 2H), 3.34 (d, J=6.7Hz, 2H), 2.24 (s, 3H), 1.98 (s, 3H).13C NMR (101MHz, CDCl3) δ 169.61,162.66,151.19,146.23,137.84,136.94,134.30,132.01,131.29,130.22,129.11,126.03,123.87,122.77,122.42,116.26,39.56,20.83.
Embodiment 13: the synthesis of compound 23
The sasapyrin of the compound 7 of 1.2mmol with 1.0mmol is placed in round-bottomed flask, add the DMAP (N of 50mL dichloromethane and catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 1～3mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, and vacuum drying obtains target product, i.e. compound 23.Productivity is respectively 55%.
Compound 23: white oil liquid.1H NMR (400MHz, CDCl3null)δ10.28(t，J=13.6Hz，2H)，7.98(dd，J=8.0，1.4Hz，1H)，7.91(dd，J=7.9，1.4Hz，1H)，7.71-7.58(m，2H)， 7.52-7.40(m，2H)，7.39-7.31(m，1H)，7.25-7.15(m，4H)，7.11(dd，J=10.9，2.6Hz，2H)，7.04(d，J=8.2Hz，1H)，6.96(dd，J=12.4，8.4Hz，2H)，6.88(d，J=7.3Hz，1H)，6.78(t，J=7.6Hz，1H)，5.92-5.68(m，2H)，5.07-4.91(m，4H)，3.35(d，J=6.7Hz，2H)，3.28(d，J=6.6Hz，2H).13C NMR (101MHz, CDCl3null)δ168.61，168.57，162.29，161.98，161.91，150.29，146.09，145.69，138.20，137.93，136.76，136.63，136.32，136.15，134.34，131.94，131.35，131.10，130.71，130.38，130.11，129.97，129.37，129.13，126.49，123.82，122.62，122.40，122.38，119.46，119.31，117.63，116.24，116.20，111.89，111.75，39.43，39.41，29.70.
Embodiment 14: the synthesis of compound 24
The Indomethacin of the magnolol of 1.2mmol Yu 2.0mmol is placed in round-bottomed flask, add the DMAP (N of 50mL dichloromethane and catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～4mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorates) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The isolated and purified eluant, eluent of column chromatography is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent, and vacuum drying obtains target product, i.e. compound 24.Productivity is respectively 70%.
Compound 24: light green oil liquid.1H NMR (400MHz, CDCl3null)δ7.58(t，J=15.0Hz，4H)，7.44(d，J=8.5Hz，4H)，7.09(dd，J=8.3，2.0Hz，2H)，7.00(d，J=1.9Hz， 2H)，6.92(dd，J=8.6，3.6Hz，4H)，6.83(d，J=2.4Hz，2H)，6.66(dd，J=9.0，2.5Hz，2H)，5.85(ddt，J=17.1，10.4，6.7Hz，2H)，5.04(dd，J=12.0，6.0Hz，4H)，3.78(s，6H)，3.57(s，4H)，3.28(d，J=6.6Hz，4H)，2.05(s，6H).13C NMR (101MHz, CDCl3) δ 169.04,168.21,155.97,146.17,139.18,137.89,136.81,136.12,133.94,131.08,130.77,130.66,130.17,129.09,128.90,121.91,116.30,114.88,111.81,111.33,101.47,55.67,39.39,29.70,13.14.
Embodiment 17: the inhibitory action that macrophage RAW264.7 is grown by derivative
The implementation case selects macrophage RAW264.7, and the magnolol analog derivative preparing embodiment carries out suppressing the growth experiment of RAW264.7.
Mtt assay is used to carry out cell in vitro poison mensuration: to plant macrophage containing 0.2X 10 on 96 orifice plates5Cells/mL (0.2mL/ hole) hatches 24 hours.Each test sample effect RAW264.7 macrophage 72 hours of variable concentrations.Calculate compound concentration when Cell growth inhibition reaches 50% respectively, with IC50Represent, the results are shown in Table 1:
The table 1 magnolol analog derivative inhibitory action (IC to macrophage growth50/uM)
As can be seen from Table 1, after using method of the present invention that these carboxylic acids NSAIDs is carried out bark of official magnolia phenolic ester derivatization, the inhibitory activity to RAW264.7 has inhibitory action in various degree, wherein compound 12 can significantly inhibit the growth of macrophage RAW264.7, its IC50For 4.8uM.
Embodiment 18: the effect of Derivatives In Mice inflammatory model
5.1 experiment material
SPF level BALC/c mouse, female, body weight about 18～22g, Zhongshan University's Experimental Animal Center provide (quality certification number: SCXK/20130002).Card punch (diameter 6mm), buys voluntarily.
5.2 experimental technique
Take female BALC/c mouse 27, be randomly divided into blank group, TPA cause scorching group, positive control medicine curcumin group, derivative group, totally 9 groups, often organize 3.Ear smears administration, after 10min, the TPA 15 μ L cause inflammation of equivalent is all smeared on the positive and negative two sides of each group left and right two ears of mouse, after 6 hours, de-cervical vertebra puts to death mouse, the disk at the same position of left and right ear is swept away with diameter 6mm card punch, weighing on assay balance, left and right two ears of every mouse are inflammation swelling with blank group two auricle method of double differences values.Separately take female BALC/c mouse 27, be randomly divided into blank group, TPA cause scorching group, positive control medicine magnolol group, derivative group, totally 9 groups, often organize 3.Inhibiting rate calculates as follows: (negative group ear swell counterpoise-each experimental group ear swell counterpoise)/negative group ear swells counterpoise × 100%.
5.3 experimental result
5.3.1 TPA is caused the impact of mice auricle swelling
In order to investigate the impact on mice auricle swelling inhibition of the magnolol analog derivative concentration, smear different medicines to mouse ear respectively according to above-mentioned animal model.The effect suppressed mice auricle swelling by the weight difference magnolol analog derivative of record Mice Auricle, using acetone as comparison.
Table 2 derivative causes the impact of mice auricle swelling to TPA
Compare with negative control group, *: P ＜ 0.05；*: P ＜ 0.01.
As shown in table 2, the inhibiting rate of single parent drug magnolol is 54.7%, has the inhibiting rate of 21 compounds more than 54.7%.And in these compounds, 3,4,5,6,13,14, the 15 and 17 pairs of TPA inductions of magnolol compounds cause scorching mice auricle swelling and have obvious inhibitory action, and its inhibiting rate is both greater than 90%.
Proved by above-described embodiment, significant antiinflammation can be played according to the magnolol ester derivant of NSAIDs provided by the present invention.Above-described, only presently preferred embodiments of the present invention, it is not limited to the scope of the present invention, the above embodiment of the present invention can also make a variety of changes.Change simple, equivalent that the most every claims according to the present patent application and description are made and modification, fall within the claims of patent of the present invention.The most detailed description of the present invention be routine techniques content.
Claims (4)
1. the present invention relates to the series compound of magnolol and honokiol derivative and carboxylic acid non-steroidal anti-inflammatory agent esterification, shown in its chemical constitution such as formula (I):
X and Y is at the same time or separately for structure shown in formula (1)-(13).If X or Y forms monoesters with formula (1)-(13), then another is OH.
。
2. the compounds process for production thereof that the compound (I) described in a claim 1 is esterified with carboxylic acid non-steroidal anti-inflammatory agent.After the method comprises the steps: to react 2～24 hours at 55～80 DEG C with carboxylic acid non-steroidal anti-inflammatory agent in chloroacetic chloride or thionyl chloride solvent with magnolol and honokiol derivative, it is extracted with ethyl acetate 2～4 times, appropriate anhydrous sodium sulfate is dried 20～40 minutes, then with ethyl acetate: petroleum ether=1: 2 carry out column chromatography, obtain target compound.
Reaction equation is as follows:
3. the preparation method of the compound that the compound (I) described in a claim 1 is esterified with carboxylic acid non-steroidal anti-inflammatory agent.The method comprises the steps: to be placed in round-bottomed flask the carboxylic acid non-steroidal anti-inflammatory agent of the magnolia bark phenol derivative of 1mmol Yu 2mmol, add 30mL dichloromethane and the DMAP (N of catalytic amount, N-4-dimethyl aminopyridine) 0.01mmol, it is slowly added dropwise the dichloromethane solution containing 2～3mmolEDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorates) or DCC (dicyclohexylcarbodiimide) again under room temperature (25～30 DEG C), stirs reaction 1～4h, product is passed through column chromatographic isolation and purification.The eluant, eluent that column chromatography analysis purifies is ethyl acetate: petroleum ether=1: 10～1: 2, is spin-dried for solvent and obtains thick product, recrystallizes with acetone or alcohol, is vacuum dried to obtain target product.
Reaction equation is as follows:
4. as a new generation's nonsteroidal anti-inflammatory drug lead compound and it is in the application of the aspects such as anti-inflammatory drug and functionalization cosmetic for compound described in claim 1.
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| CN112587533A (en) * | 2019-09-17 | 2021-04-02 | 成都贝诺科成生物科技有限公司 | Application of honokiol derivative in preparation of medicine for preventing and/or treating bovine mastitis |
| WO2021052272A1 (en) * | 2019-09-20 | 2021-03-25 | 广东省禾基生物科技有限公司 | Magnolol derivative, preparation method therefor, and use thereof |
| CN111747921A (en) * | 2020-07-16 | 2020-10-09 | 中国药科大学 | Preparation method and medical application of daphnetin derivative |
| CN114014756A (en) * | 2021-12-24 | 2022-02-08 | 青岛科技大学 | Preparation method of 3-hydroxy-2-naphthoic acid phenyl ester |
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| CN114014756B (en) * | 2021-12-24 | 2023-09-19 | 青岛科技大学 | Preparation method of 3-hydroxy-2-phenyl naphthoate |
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