CN113603616A - Paeonol derivative, and preparation method, preparation and application thereof - Google Patents

Paeonol derivative, and preparation method, preparation and application thereof Download PDF

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CN113603616A
CN113603616A CN202110758936.0A CN202110758936A CN113603616A CN 113603616 A CN113603616 A CN 113603616A CN 202110758936 A CN202110758936 A CN 202110758936A CN 113603616 A CN113603616 A CN 113603616A
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paeonol
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CN113603616B (en
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刘新华
石静波
朱仁德
吴静
胡阳生
张昭燕
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Anhui Medical University
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Abstract

The invention discloses a paeonol derivative, a preparation method, a preparation and an application thereof, and relates to the technical field of development of anti-inflammatory drugs, the paeonol derivative belongs to novel compounds, the compounds are designed and successfully synthesized for the first time, and the structure of the compounds is characterized; the preparation method of the paeonol derivative is simple and convenient to operate, and the compounds can be quickly synthesized; researches show that the paeonol derivative has good anti-inflammatory activity and shows good application prospect in the treatment of various skin inflammations.

Description

Paeonol derivative, and preparation method, preparation and application thereof
The technical field is as follows:
the invention relates to the technical field of development of anti-inflammatory drugs, and particularly relates to a paeonol derivative, and a preparation method, a preparation and application thereof.
Background art:
peony, which has various medicinal values, is widely used in traditional oriental medicine for thousands of years. Paeonol is a main component separated from the root bark of peony, and the pharmacological action of peony is mainly attributed to paeonol. Paeonol injection has been successfully used in China for nearly 50 years for inflammation/pain related indications. At present, paeonol approved by the State Food and Drug Administration (FDA) includes tablets, injections and external preparations such as ointments and plasters. To date, the clinical use of paeonol has focused primarily on anti-inflammatory activity. The anti-inflammation is the basic pharmacological action of paeonol, and the paeonol blocks the inflammatory reaction stimulated by lipopolysaccharide in BV-2 and RAW264.7 inflammatory cell models. The external ointment preparation for treating skin inflammation is most widely applied in the aspect of anti-inflammation. However, the action of paeonol in anti-inflammatory is not outstanding, so that the development of the anti-inflammatory activity of paeonol is promising.
Figure BDA0003148433590000011
Paeonol has a plurality of structural modification sites, and most of the structural modification researches based on paeonol skeletons are focused on hydroxyl groups at present. The structure of urea is widely used in drug design, synthesis and optimization, which is inherent in many clinically approved drugs such as sorafenib, celiprolol and boceprevir. In order to obtain a lead compound with remarkable anti-inflammatory activity and explore SAR (structure-activity relationship), the invention introduces a urea joint into 5-position of paeonol to synthesize a series of paeonol derivatives, and researches the anti-inflammatory activity of the paeonol derivatives, so that the screening of anti-inflammatory drugs with application prospect is expected.
The invention content is as follows:
the technical problem to be solved by the invention is to provide a paeonol derivative and a preparation method thereof, wherein a compound with excellent anti-inflammatory activity is screened out from the paeonol derivative, and the paeonol derivative is used for developing high-efficiency anti-inflammatory drugs and is used as an active component of anti-inflammatory drug preparations.
The technical problem to be solved by the invention is realized by adopting the following technical scheme:
the first purpose of the invention is to provide a paeonol derivative, which comprises compounds with structures shown as a formula I and a formula II:
Figure BDA0003148433590000021
wherein R is1And R2Is selected from any one of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl, R3Selected from morpholinyl, pyrrolyl, thiazolyl, substituted piperazinyl.
Preferably, R1＝H，-CH3，-CH2CH3，-CH(CH3)2；R2＝-CH3，-CH2CH3，-CH(CH3)2，-C(CH3)3，-OCH3，-CH2CF3，
Figure BDA0003148433590000022
Figure BDA0003148433590000023
The second purpose of the invention is to provide a preparation method of the paeonol derivative, wherein the compound 1 is reacted under the conditions of nitric acid and acetic acid to obtain a compound 2, the compound 2 is reacted with hydrogen under the conditions of hydrochloric acid and Pd/C to obtain a compound 3, and the compound 3 and the amine derivative are reacted under the conditions of N, N-diisopropylethylamine and triphosgene to obtain the paeonol derivative.
The reaction equation is as follows:
Figure BDA0003148433590000031
the amine derivative is any one of methylamine, ethylamine, cyclopropylamine, piperazine, aniline, 3-fluoroaniline, 3-methylaniline, 3-methoxyaniline, 4-trifluoromethylaniline, 3-fluoromethylphenylethylamine, 4-fluorobenzylamine, 2-chlorobenzylamine, phenylethylamine, 4-fluorophenylethylamine and 4-methoxyphenylethylamine.
The paeonol derivative comprises a compound with the following structure:
Figure BDA0003148433590000032
Figure BDA0003148433590000041
Figure BDA0003148433590000051
the third purpose of the invention is to provide the application of the paeonol derivative in preparing anti-inflammatory drugs.
The fourth purpose of the invention is to provide a pharmaceutical preparation using the paeonol derivative as an active compound.
The dose of the active compound in the pharmaceutical preparation is 0.01-500 mg/kg.
Preferably, the dose of active compound in the pharmaceutical preparation is 250 mg/kg.
The pharmaceutical preparation is prepared by adding pharmaceutically acceptable adjuvants into active compounds, and making into tablet, capsule, lozenge, injection, suspension, suppository or ointment.
The auxiliary materials comprise an excipient and a carrier.
The excipient is one or more of calcium carbonate, calcium phosphate, saccharides, starch, cellulose derivatives, gelatin, vegetable oil and polyethylene glycol.
The carrier is one or more of diluent, disintegrant, adhesive and lubricant.
The invention has the beneficial effects that:
(1) the paeonol derivative belongs to novel compounds, and the compounds are designed and successfully synthesized for the first time, and the structure of the compounds is characterized.
(2) The preparation method of the paeonol derivative is simple and convenient to operate, and the compounds can be quickly synthesized.
(3) Researches show that the paeonol derivative has good anti-inflammatory activity and shows good application prospect in the treatment of various skin inflammations.
Description of the drawings:
FIG. 1 is a graph of the present invention applied to the changes in skin characterization in an imiquimod-induced dermatitis model;
FIG. 2 is a graph of the present invention applied to the changes in the pathological tissues of the skin in an imiquimod-induced dermatitis model;
figure 3 is a graph of the in vivo inflammatory factor changes in the present invention applied to an imiquimod-induced dermatitis model.
The specific implementation mode is as follows:
in order to make the technical means, the original characteristics, the achieved purposes and the effects of the invention easy to understand, the invention is further explained by combining the specific embodiments and the drawings.
Example 1
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3-methylurea:
Figure BDA0003148433590000061
preparation of intermediates 1-2:
paeonol (10g,0.06mmol) was dissolved in acetic acid (40ml), and nitric acid (16ml) was added dropwise to the reaction system under an ice-water bath environment, followed by stirring at room temperature for 3 hours. After the reaction is finished, pouring ice water into the reaction system, and performing suction filtration to obtain a yellow filter cake, namely the intermediate 1-2.
Preparation of intermediates 1-3:
the intermediate compound 2-1 was dissolved in methanol (40ml), 10% Pd-C (4% mmol) was added, and the pH was adjusted to 3-4 with 1N Cl. And introducing hydrogen into the reaction system, and reacting for 4 hours at normal pressure. After the reaction is finished, filtrate is obtained by suction filtration, and light yellow solid is obtained by vacuum concentration, and the intermediate 1-3 is obtained.
Preparation of Compound I-1:
compound 1-3(100mg,0.552mmol) and N, N-diisopropylethylamine (273. mu.l, 1.656mmol) were dissolved in dichloromethane (5ml) in an ice-water bath, triphosgene (67mg,0.226mmol) dissolved in dichloromethane (2ml) was added dropwise thereto, and after completion of stirring at room temperature for 1 hour, methylamine hydrochloride (44.7mg,0.662mmol) was added to the reaction system. After completion of the reaction, the reaction system was concentrated in vacuo and purified by column chromatography to give compound I-1. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.46(s,1H),8.52-8.47(m,1H),7.82(s,1H),6.62-6.53(m,2H),3.90(s,3H),2.64(d,J＝4.6Hz,3H),2.51(s,3H).13C NMR(101MHz,DMSO-d6)δ203.54,159.18,156.51,155.69,122.30,120.39,112.51,99.63,56.75,27.04,26.47.HRMS(ESI):m/z[M+Na]+calcd for C11H14N2O4:261.0846；found:261.0846.
example 2
Preparation of 3- (5-acetyl-4-hydroxy-2-methoxyphenyl) -1, 1-diethylurea (the structure is shown in formula I-2):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),7.98(s,1H),7.32(s,1H),6.56(s,1H),3.86(s,3H),3.30(q,J＝7.1Hz,4H),2.53(s,3H),1.10(t,J＝7.1Hz,6H).13C NMR(101MHz,DMSO-d6)δ203.45,161.01,159.12,155.20,126.45,121.45,112.63,99.78,56.82,41.09(2C),27.13,14.27(2C).HRMS(ESI):m/z[M+H]+calcd for C14H20N2O4:281.1496；found:281.1498.
example 3
Preparation of 3- (5-acetyl-4-hydroxy-2-methoxyphenyl) -1, 1-diisopropylurea (the structure is shown in formula I-3):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.21(s,1H),7.02(s,1H),6.58(s,1H),3.99-3.90(m,2H),3.89(s,3H),2.53(s,3H),1.23(d,J＝6.8Hz,12H).13C NMR(101MHz,DMSO-d6)δ203.54,160.19,157.36,154.53,123.47,121.90,112.62,99.75,57.04,45.23(2C),27.20,21.56(4C).HRMS(ESI):m/z[M+Na]+calcd for C16H24N2O4:331.1628；found:331.1631.
example 4
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3-methoxy urea (the structure is shown as formula I-4):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),9.67(s,1H),8.26(s,1H),7.99(s,1H),6.61(s,1H),3.90(s,3H),3.64(s,3H),2.53(s,3H).13C NMR(101MHz,DMSO-d6)δ203.37,160.67,157.36,157.24,123.24,119.97,112.68,99.99,64.31,56.97,27.17.HRMS(ESI):m/z[M+Na]+calcd for C11H14N2O5:277.0795；found:277.0797.
example 5
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (2,2, 2-trifluoroethyl) urea (the structure is shown in formula I-5):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.47(d,J＝4.7Hz,1H),8.12(s,1H),7.31(t,J＝6.4Hz,1H),6.58(s,1H),3.99-3.89(m,5H),2.51(s,3H).13C NMR(101MHz,DMSO-d6)δ203.50,159.60,155.81,155.40,129.54,125.57(d,J＝279.0Hz),120.77,112.55,99.79,56.83,40.46,27.09.HRMS(ESI):m/z[M+Na]+calcd for C12H13F3N2O4:329.0720；found:329.0718.
example 6
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3-ethylurea (structure shown in formula I-6):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.44(s,1H),8.51(s,1H),7.76(s,1H),6.69(t,J＝4.7Hz,1H),6.54(s,1H),3.89(s,3H),3.12-3.06(m,2H),2.50(s,3H),1.04(t,J＝7.2Hz,3H).13CNMR(151MHz,DMSO-d6)δ203.45,159.09,155.76,155.58,122.35,120.22,112.54,99.58,56.71,34.32,26.97,15.83.HRMS(ESI):m/z[M+Na]+calcd for C12H16N2O4:275.1002；found:275.1005.
example 7
Preparation of 3- (5-acetyl-4-hydroxy-2-methoxyphenyl) -1, 1-dimethylurea (structure shown in formula I-7):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.55(s,1H),7.96(s,1H),7.46(s,1H),6.56(s,1H),3.85(s,3H),2.90(s,6H),2.52(s,3H).13C NMR(151MHz,DMSO-d6)δ203.31,161.03,159.17,156.50,126.39,121.45,112.66,99.80,56.72,56.70,36.46,27.03.HRMS(ESI):m/z[M+H]+calcd for C12H16N2O4:253.1183；found:253.1185.
example 8
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (tert-butyl) urea (the structure is shown as formula I-8):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.45(s,1H),8.52(s,1H),7.72(s,1H),6.66(s,1H),6.53(s,1H),3.89(s,3H),2.52(s,3H),1.28(s,9H).13C NMR(151MHz,DMSO-d6)δ203.51,158.83,155.30,155.01,122.60,119.57,112.51,99.52,56.70,49.79,29.53(3C),27.09.HRMS(ESI):m/z[M+H]+calcd for C14H20N2O4:281.1496；found:281.1495.
example 9
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3-cyclopropyl urea (structure shown in formula I-9):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.45(s,1H),8.52(s,1H),7.69(s,1H),6.91(s,1H),6.55(s,1H),3.89(s,3H),2.51(m,4H),0.62(m,2H),0.37(m,2H).13C NMR(151MHz,DMSO-d6)δ203.46,159.18,156.51,155.55,122.11,120.21,112.54,99.63,56.78,27.00,22.74,6.71(2C).HRMS(ESI):m/z[M+H]+calcd for C13H16N2O4:265.1183；found:265.1183.
example 10
Preparation of N- (5-acetyl-4-hydroxy-2-methoxyphenyl) -4-methylpiperazine-1-carboxamide (the structure is shown in formula II-1):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.56(s,1H),7.87(s,1H),7.73(s,1H),6.55(s,1H),3.84(s,3H),3.38(d,J＝10.4Hz,4H),2.52(s,3H),2.29(s,4H),2.19(s,3H).13C NMR(151MHz,DMSO-d6)δ203.31,161.35,159.80,156.03,127.52,121.10,112.71,99.88,56.66,54.86(2C),46.18,44.01(2C),27.09.HRMS(ESI):m/z[M+H]+calcd for C15H21N3O4:308.1605；found:308.1606.
example 11
Preparation of N- (5-acetyl-4-hydroxy-2-methoxyphenyl) morpholine-4-carboxamide (the structure is shown as formula II-2):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.56(s,1H),7.89(s,1H),7.78(s,1H),6.56(s,1H),3.84(s,3H),3.60(s,4H),3.38(d,J＝4.1Hz,4H),2.53(s,3H).13C NMR(151MHz,DMSO-d6)δ203.29,161.42,159.84,156.25,127.64,120.93,112.73,99.92,66.39(2C),56.67,44.53(2C),27.10.HRMS(ESI):m/z[M+H]+calcd for C14H18N2O5:295.1288；found:295.1290.
example 12
Preparation of N- (5-acetyl-4-hydroxy-2-methoxyphenyl) pyrrolidine-1-carboxamide (the structure is shown as formula II-3):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.55(s,1H),8.07(s,1H),7.23(s,1H),6.57(s,1H),3.87(s,3H),3.34(t,J＝4.9Hz,4H),2.52(d,J＝2.8Hz,3H),1.85(t,J＝6.5Hz,4H).13CNMR(101MHz,DMSO-d6)δ203.44,160.86,158.75,154.60,125.80,121.31,112.61,99.79,56.77,45.91(2C),27.10(2C),25.53.HRMS(ESI):m/z[M+H]+calcd for C14H18N2O4:279.1339；found:279.1339.
example 13
Preparation of N- (5-acetyl-4-hydroxy-2-methoxyphenyl) -4-ethylpiperazine-1-carboxamide (the structure is shown in formula II-4):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.58(s,1H),7.88(s,1H),7.74(s,1H),6.56(s,1H),3.85(s,3H),3.43-3.39(m,4H),2.53(s,3H),2.34(dd,J＝12.3,5.5Hz,6H),1.02(t,J＝7.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ203.41,161.47,159.99,156.06,127.84,121.07,112.68,99.90,56.68,52.69,52.09,44.09,27.16,12.39.HRMS(ESI):m/z[M+Na]+calcd for C16H23N3O4:344.1581；found:344.1584.
example 14
Preparation of N- (5-acetyl-4-hydroxy-2-methoxyphenyl) thiazolidine-3-formamide (the structure is shown as formula II-5):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.58(s,1H),7.87(d,J＝4.6Hz,1H),7.84(s,1H),6.58(s,1H),4.50(s,2H),3.85(s,3H),3.68(t,J＝6.3Hz,2H),3.04(t,J＝6.3Hz,2H),2.53(s,3H).13C NMR(101MHz,DMSO-d6)δ203.38,161.75,160.14,154.96,128.30,120.51,112.72,100.01,56.71,49.10,48.82,30.77,27.17.HRMS(ESI):m/z[M+Na]+calcd for C13H16N2O4S:319.0723；found:319.0727.
example 15
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (furan-2-ylmethyl) urea (structure shown in formula I-10):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.52(s,1H),7.95(s,1H),7.60(d,J＝1.2Hz,1H),7.15(t,J＝5.6Hz,1H),6.57(s,1H),6.41(dd,J＝3.1,1.9Hz,1H),6.27(d,J＝3.1Hz,1H),4.29(d,J＝5.6Hz,2H),3.90(s,3H),2.52(s,3H).13C NMR(101MHz,DMSO-d6)δ203.55,159.27,155.60,155.58,153.45,142.61,122.10,120.25,112.51,110.92,107.01,99.67,56.78,36.50,27.08.HRMS(ESI):m/z[M+Na]+calcd for C15H16N2O5:327.0951；found:327.0955.
example 16
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3-phenylurea (the structure is shown in formula I-11):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.49(s,1H),9.19(s,1H),8.56(s,1H),8.14(s,1H),7.45(d,J＝7.7Hz,2H),7.27(t,J＝7.9Hz,2H),6.96(t,J＝7.3Hz,1H),6.61(s,1H),3.95(s,3H),2.55(s,3H).13C NMR(151MHz,DMSO-d6)δ203.44,159.60,155.87,153.11,140.20,129.23(2C),122.18,121.45,120.84,118.43(2C),112.67,99.84,56.89,27.12.HRMS(ESI):m/z[M+H]+calcd for C16H16N2O4:301.1183；found:301.1184.
example 17
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (m-tolyl) urea (structure shown in formula I-12):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.49(s,1H),9.12(s,1H),8.56(s,1H),8.12(s,1H),7.32(s,1H),7.20(d,J＝8.1Hz,1H),7.15(t,J＝7.7Hz,1H),6.78(d,J＝7.4Hz,1H),6.61(s,1H),3.95(s,3H),2.55(s,3H),2.28(s,3H).13C NMR(151MHz,DMSO-d6)δ203.46,159.56,155.82,153.07,140.14,138.42,129.07,122.93,121.50,120.72,118.91,115.61,112.65,99.82,56.88,27.12,21.67.HRMS(ESI):m/z[M+H]+calcd for C17H18N2O4:315.1339；found:315.1338.
example 18
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (o-tolyl) urea (structure shown in formula I-13):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.48(s,1H),8.56(s,1H),8.55(s,1H),8.41(s,1H),7.81(d,J＝8.0Hz,1H),7.16(d,J＝7.3Hz,1H),7.13(t,J＝7.6Hz,1H),6.94(t,J＝7.4Hz,1H),6.61(s,1H),3.96(s,3H),2.53(s,3H),2.25(s,3H).13C NMR(151MHz,DMSO-d6)δ203.45,159.53,156.00,153.45,137.82,130.59,128.27,126.47,123.17,122.05,121.62,121.11,112.65,99.82,56.87,27.07,18.50.HRMS(ESI):m/z[M+H]+calcd for C17H18N2O4:315.1339；found:315.1339.
example 19
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (p-tolyl) urea (structure shown in formula I-14):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.49(s,1H),9.09(s,1H),8.55(s,1H),8.09(s,1H),7.34(d,J＝8.3Hz,2H),7.08(d,J＝7.9Hz,2H),6.60(s,1H),3.94(s,3H),2.54(s,3H),2.24(s,3H).13C NMR(151MHz,DMSO-d6)δ203.46,159.53,155.81,153.14,137.63,130.98,129.62(2C),121.55,120.71,118.50(2C),112.65,99.80,56.88,27.09,20.76.HRMS(ESI):m/z[M+H]+calcd for C17H18N2O4:315.1339；found:315.1339.
example 20
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (3-fluorophenyl) urea (structure shown in formula I-15):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.49(s,1H),9.41(s,1H),8.53(s,1H),8.19(s,1H),7.51(d,J＝12.0Hz,1H),7.30(dd,J＝15.3,7.9Hz,1H),7.08(d,J＝7.7Hz,1H),6.77(td,J＝8.5,2.4Hz,1H),6.62(s,1H),3.95(s,3H),2.55(s,3H).13C NMR(151MHz,DMSO-d6)δ203.43,163.69,162.09,159.78,155.98,152.94,142.06(d,J＝11.4Hz),130.78(d,J＝9.9Hz),121.10,114.11,112.69,108.49(d,J＝21.1Hz),105.07(d,J＝26.5Hz),99.91,56.92,27.15.HRMS(ESI):m/z[M+H]+calcd for C16H15FN2O4:319.1089；found:319.3030.
example 21
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (4-fluorophenyl) urea (structure shown in formula I-16):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.50(s,1H),9.23(s,1H),8.54(s,1H),8.12(s,1H),7.49-7.43(m,2H),7.15-7.08(m,2H),6.61(s,1H),3.94(s,3H),2.54(s,3H).13C NMR(101MHz,DMSO-d6)δ203.53,159.64,157.73(d,J＝237.9Hz),155.85,153.17,136.54(d,J＝2.4Hz),121.39,120.79,120.07(d,J＝7.7Hz,2C),115.80(d,J＝22.2Hz,2C),112.63,99.86,56.93,27.18.HRMS(ESI):m/z[M+Na]+calcd for C16H15FN2O3:341.0908；found:341.0904.
example 22
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (2-fluorophenyl) urea (structure shown in formula I-17):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.50(s,1H),9.13(d,J＝1.6Hz,1H),8.69(s,1H),8.55(s,1H),8.18(td,J＝8.3,1.4Hz,1H),7.22(ddd,J＝11.6,8.2,1.2Hz,1H),7.12(t,J＝7.7Hz,1H),7.03-6.96(m,1H),6.61(s,1H),3.94(s,3H),2.54(d,J＝5.0Hz,3H).13CNMR(101MHz,DMSO-d6)δ203.52,159.76,156.03,152.97,152.41(d,J＝242.4Hz),128.07(d,J＝10.4Hz),124.93(d,J＝3.7Hz),122.77(d,J＝7.8Hz),121.17(d,J＝17.3Hz),121.09(2C),115.43(d,J＝19.0Hz),112.61,99.88,56.90,27.19.HRMS(ESI):m/z[M+Na]+calcd for C16H15FN2O3:341.0908；found:341.0912.
example 23
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (3-methoxyphenyl) urea (the structure is shown as formula I-18):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.49(s,1H),9.21(s,1H),8.54(s,1H),8.12(s,1H),7.19-7.15(m,2H),6.94(dd,J＝8.1,0.7Hz,1H),6.60(s,1H),6.54(dd,J＝8.2,2.3Hz,1H),3.94(s,3H),3.73(s,3H),2.55(s,3H).13C NMR(151MHz,DMSO-d6)δ203.43,160.18,159.64,155.89,153.02,141.43,130.00,121.37,120.88,112.67,110.77,107.61,104.23,99.83,56.87,55.39,27.13.HRMS(ESI):m/z[M+Na]+calcd for C17H18N2O5:353.1108；found:353.1105.
example 24
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (2-methoxyphenyl) urea (the structure is shown as formula I-19):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.49(s,1H),8.79(d,J＝12.4Hz,2H),8.53(s,1H),8.11(dd,J＝8.0,1.6Hz,1H),7.00(dd,J＝8.1,1.3Hz,1H),6.94(td,J＝7.8,1.6Hz,1H),6.88(td,J＝7.8,1.3Hz,1H),6.59(s,1H),3.94(s,3H),3.86(s,3H),2.54(s,3H).HRMS(ESI):m/z[M+H]+calcd for C17H18N2O5:331.1288；found:331.1291.
example 25
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (4-methoxyphenyl) urea (the structure is shown as formula I-20):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.49(s,1H),9.02(s,1H),8.55(s,1H),8.05(s,1H),7.38-7.31(m,2H),6.90-6.82(m,2H),6.60(s,1H),3.94(s,3H),3.71(s,3H),2.54(s,3H).13CNMR(101MHz,DMSO-d6)δ203.55,159.49,155.74,154.83,153.27,133.26,121.66,120.52,120.13(2C),114.48(2C),112.60,99.80,56.89,55.61,27.16.HRMS(ESI):m/z[M+Na]+calcd for C17H18N2O4:353.1108；found:353.1108.
example 26
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (4- (trifluoromethyl) phenyl) urea (the structure is shown as formula I-21):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.50(s,1H),9.59(s,1H),8.54(s,1H),8.24(s,1H),7.66(d,J＝8.7Hz,2H),7.62(d,J＝8.8Hz,2H),6.62(s,1H),3.95(s,3H),2.55(s,3H).13CNMR(151MHz,DMSO-d6)δ203.39,159.88,156.00,152.82,143.90,126.51(d,J＝3.7Hz,2C),124.99(d,J＝270.8Hz),122.18(q,J＝31.8Hz),121.17,120.98,118.05(2C),112.68,99.90,56.93,27.11.HRMS(ESI):m/z[M+H]+calcd for C17H15F3N2O4:369.1057；found:369.1054.
example 27
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (3- (trifluoromethyl) phenyl) urea (the structure is shown as formula I-22):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.50(s,1H),9.54(s,1H),8.52(s,1H),8.19(s,1H),8.03(s,1H),7.54-7.48(m,2H),7.32-7.28(m,1H),6.62(s,1H),3.95(s,3H),2.56(s,3H).13CNMR(151MHz,DMSO-d6)δ203.43,159.89,156.05,152.98(d,J＝11.2Hz),141.05,130.38,130.06(d,J＝31.3Hz),124.64(d,J＝272.4Hz),121.93,121.12(d,J＝39.7Hz),118.42(d,J＝3.8Hz),114.22(d,J＝4.0Hz),112.70,99.91,79.59,56.91,27.18.HRMS(ESI):m/z[M+H]+calcd for C17H15F3N2O4:369.1057；found:369.1054.
example 28
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (4- (trifluoromethoxy) phenyl) urea (structure shown in formula I-23):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.49(s,1H),9.39(s,1H),8.54(s,1H),8.16(s,1H),7.57-7.53(m,2H),7.27(d,J＝8.6Hz,2H),6.61(s,1H),3.94(s,3H),2.54(s,3H).13C NMR(151MHz,DMSO-d6)δ203.39,159.75,155.92,153.01,143.00,139.46,122.11,121.20,120.99,120.64(q,J＝255.1Hz),119.56,119.46,112.66,99.85,79.59,56.87,27.07.HRMS(ESI):m/z[M+H]+calcd for C17H15F3N2O5:385.1006；found:385.1003.
example 29
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (2-chlorobenzyl) urea (the structure is shown as formula I-24):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.45(s,1H),8.52(s,1H),8.06(s,1H),7.45(dd,J＝7.8,1.2Hz,1H),7.41(dd,J＝7.6,1.5Hz,1H),7.35(td,J＝7.4,1.2Hz,1H),7.30(td,J＝7.7,1.7Hz,1H),7.25(t,J＝5.9Hz,1H),6.56(s,1H),4.37(d,J＝5.9Hz,2H),3.91(s,3H),2.50(s,3H).13C NMR(151MHz,DMSO-d6)δ203.44,159.28,155.78,137.67,132.56,129.56,129.47,129.06,127.67,122.12,120.36,112.55,99.68,79.60,56.76,41.18,27.02.HRMS(ESI):m/z[M+H]+calcd for C17H17ClN2O4:349.0950；found:349.0947.
example 30
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3-benzylurea (structure shown in formula I-25):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.48(s,1H),8.54(s,1H),7.97(s,1H),7.38-7.24(m,6H),6.57(s,1H),4.30(d,J＝5.8Hz,2H),3.91(s,3H),2.51(d,J＝2.6Hz,3H).13C NMR(101MHz,DMSO-d6)δ203.57,159.23,155.89,155.59,140.69,128.82(2C),127.60(2C),127.24,122.25,120.19,112.52,99.67,56.78,43.19,27.09.HRMS(ESI):m/z[M+Na]+calcd for C17H18N2O4:337.1159；found:337.1158.
example 31
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (4-methylbenzyl) urea (the structure is shown as formula I-26):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.54(s,1H),7.94(s,1H),7.21-7.12(m,5H),6.56(s,1H),4.25(d,J＝5.7Hz,2H),3.90(s,3H),2.51(s,3H),2.28(s,3H).13C NMR(101MHz,DMSO-d6)δ203.56,159.21,155.86,155.57,137.60,136.27,129.35(2C),127.60(2C),122.28,120.14,112.52,99.65,54.18,42.94,26.49,21.55.HRMS(ESI):m/z[M+Na]+calcd for C18H20N2O3:351.1315；found:351.1318.
example 32
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (4-fluorobenzyl) urea (the structure is shown as formula I-27):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.53(s,1H),7.96(s,1H),7.33(dd,J＝8.5,5.7Hz,2H),7.22(t,J＝5.9Hz,1H),7.20-7.13(m,2H),6.57(s,1H),4.28(d,J＝5.8Hz,2H),3.90(s,3H),2.51(s,3H).13C NMR(101MHz,DMSO-d6)δ203.54,161.61(d,J＝242.0Hz),159.27,155.88,155.63,136.95(d,J＝3.0Hz),129.53(d,J＝8.2Hz,2C),122.18,120.28,115.51(d,J＝21.3Hz,2C),112.53,99.67,56.77,42.45,27.08.HRMS(ESI):m/z[M+Na]+calcd for C17H17FN2O3:355.1065；found:355.1065.
example 33
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (4-methoxybenzyl) urea (structure shown in formula I-28):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.54(s,1H),7.92(s,1H),7.24-7.20(m,2H),7.13(t,J＝5.8Hz,1H),6.92-6.88(m,2H),6.56(s,1H),4.22(d,J＝5.7Hz,2H),3.90(s,3H),3.73(d,J＝2.8Hz,3H),2.52(s,3H).13C NMR(101MHz,DMSO-d6)δ203.57,159.18,158.67,155.82,155.56,132.54,128.97(2C),122.28,120.14,114.20(2C),112.52,99.65,56.78,55.52,42.66,27.09.HRMS(ESI):m/z[M+Na]+calcd for C18H20N2O5:367.1264；found:367.1260.
example 34
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (2-methoxybenzyl) urea (structure shown in formula I-29):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.53(s,1H),8.03(s,1H),7.24(td,J＝7.4,1.3Hz,2H),7.07(t,J＝5.8Hz,1H),7.00(d,J＝7.6Hz,1H),6.92(td,J＝7.4,0.9Hz,1H),6.56(s,1H),4.25(d,J＝5.8Hz,2H),3.90(s,3H),3.83(s,3H),2.51(s,3H).13CNMR(101MHz,DMSO-d6)δ203.57,159.15,157.25,155.85,155.58,128.63,128.51,128.02,122.33,120.63,120.14,112.50,110.92,99.64,56.76,55.78,38.51,27.07.HRMS(ESI):m/z[M+Na]+calcd for C18H20N2O5:367.1264；found:367.1261.
example 35
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3-phenethylurea (structure shown in formula I-30):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.48(s,1H),8.54(s,1H),7.90(s,1H),7.34-7.18(m,6H),6.79(t,J＝5.6Hz,1H),6.54(s,1H),3.89(s,3H),3.35(dd,J＝12.9,6.9Hz,2H),2.74(t,J＝7.1Hz,2H),2.52(s,3H).13C NMR(101MHz,DMSO-d6)δ203.57,159.13,155.84,155.56,140.05,129.17(2C),128.83(2C),126.54,122.34,120.14,112.51,99.63,56.75,41.04,36.37,27.08.HRMS(ESI):m/z[M+Na]+calcd for C18H20N2O4:351.1315；found:351.1318.
example 36
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (4-fluorophenethyl) urea (the structure is shown in formula I-31):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.46(s,1H),8.53(s,1H),7.87(s,1H),7.30-7.25(m,2H),7.17-7.10(m,2H),6.76(t,J＝5.6Hz,1H),6.55(s,1H),3.89(s,3H),3.32(dd,J＝12.9,6.9Hz,2H),2.73(t,J＝7.1Hz,2H),2.52(s,4H).13C NMR(101MHz,DMSO-d6)δ203.56,161.31(d,J＝241.5Hz),159.14,155.82,155.56,136.17(d,J＝3.1Hz),130.93(d,J＝7.8Hz,2C),122.30,120.14,115.47(d,J＝21.0Hz,2C),112.51,99.63,56.75,41.04,35.45,27.07.HRMS(ESI):m/z[M+Na]+calcd for C18H19FN2O4:369.1221；found:369.1225.
example 37
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (4-methoxyphenethyl) urea (the structure is shown as formula I-32):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.53(s,1H),7.88(s,1H),7.23-7.10(m,2H),6.93-6.81(m,2H),6.74(t,J＝5.6Hz,1H),6.55(s,1H),3.89(s,3H),3.72(d,J＝3.7Hz,3H),3.29(dd,J＝12.9,6.9Hz,2H),2.67(dd,J＝9.2,5.0Hz,2H),2.52(d,J＝1.8Hz,3H).13C NMR(101MHz,DMSO-d6)δ203.56,159.12,158.13,155.83,155.55,131.85,130.10(2C),122.36,120.10,114.23(2C),112.51,99.62,56.74,55.42,41.27,35.46,27.07.HRMS(ESI):m/z[M+Na]+calcd for C19H22N2O5:381.1421；found:384.1424.
example 38
Preparation of 1- (5-acetyl-4-hydroxy-2-methoxyphenyl) -3- (2-fluorophenethyl) urea (the structure is shown as formula I-33):
the same synthesis method as that of the compound I-1 is adopted. And (3) structural data characterization:1H NMR(600MHz,DMSO-d6)δ12.45(s,1H),8.51(s,1H),7.83(s,1H),7.34-7.25(m,2H),7.18-7.13(m,2H),6.80(t,J＝5.7Hz,1H),6.54(s,1H),3.89(s,3H),3.36-3.33(m,2H),2.78(t,J＝7.1Hz,2H),2.51(s,3H).13C NMR(151MHz,DMSO-d6)δ203.46,161.99,160.38,159.17,155.72(d,J＝29.4Hz),131.62(d,J＝5.0Hz),128.64(d,J＝8.1Hz),126.56(d,J＝15.9Hz),124.79(d,J＝3.4Hz),122.24,120.32,115.54(d,J＝22.0Hz),112.54,99.61,56.71,29.68,27.00,18.97.HRMS(ESI):m/z[M+Na]+calcd for C18H19FN2O4:369.1221；found:369.1221.
example 39
The paeonol derivative prepared in the above embodiments is used as an active compound, and the active compound is prepared into one or more dosage forms of tablets, capsules, troches, injections, suspending agents, suppositories and ointments according to a conventional preparation method of pharmaceutical preparations. Wherein, the preparation comprises the active compound and pharmaceutically acceptable auxiliary materials, and the auxiliary materials are carriers or excipients.
Wherein the dosage of the active compound in the pharmaceutical preparation is 0.01-500 mg/kg.
Wherein the excipient is calcium carbonate, calcium phosphate, saccharide, starch, cellulose derivative, gelatin, vegetable oil or polyethylene glycol; the carrier is diluent, disintegrant, binder or lubricant.
Anti-inflammatory activity verification experiment:
in order to verify that the paeonol derivative disclosed by the invention has anti-inflammatory activity, the paeonol derivative compound prepared in the embodiment is selected for carrying out an activity experiment:
1. the experimental principle is as follows: the test adopts an NO content determination method, nitrate is reduced into nitrite by nitrate reductase, and then the nitrite is detected by Griess Reagent, so that the total NO content is calculated.
2. The experimental procedure was as follows:
(1) collecting cells in logarithmic growth phase, and counting by using a cell counting plate; cell dilution with medium to a concentration of 1.4 x 105The cells are inoculated in a 24-well plate, the volume of each well is 500 mu L, and the cells are cultured overnight;
(2) the 24-well plate is divided into three groups: blank (cells only), model (cells + LPS), experimental (cells + LPS + compounds);
(3) changing the culture medium after overnight, directly changing 500 μ L fresh culture medium for blank group and model group, and adding compound solution 500 μ L containing different concentrations (40, 20, 10, 5, 2.5 μ M) into each well of experimental group;
(4) adding LPS after 1h for stimulation to make the final concentration of LPS be 1 μ g/mL (generally, high-concentration LPS can be diluted with a small amount of culture medium and then dripped);
(5) observing cell supernatant after 24h, detecting by using a nitric oxide detection kit produced in Biyun day, and calculating the concentration of NO in the cell supernatant;
(6) configuring a standard curve: diluting the standard substance with fresh culture medium to concentration of 1, 5, 10, 20, 40, 60, 100 μ M;
(7) adding the standard substance and the cell supernatant into a 96-well plate according to 50 mu L of each well;
(8) adding room temperature 50 mu LGriessreagent I and then adding 50 mu LGriessreagent II into each hole respectively;
(9) absorbance was measured at 540nm using a microplate reader, and the NO content was calculated by introducing a standard.
(10) The above experiments were repeated three times, and the results were analyzed and plotted using SPSS17.0 statistical analysis software.
3. The experimental results are as follows:
the results of the experiment are shown in table 1:
Figure BDA0003148433590000201
Figure BDA0003148433590000211
note: IC (integrated circuit)50The unit of value is: mu mol/L.
The relation between the balanced toxicity and the anti-inflammatory activity is taken as guidance to design and synthesize novel molecules with effective drug-like anti-inflammatory activity, and part of compounds show strong NO generation inhibition activity and have lower cytotoxicity to normal human liver cells.
As can be seen from table 1, the paeonol derivative provided in this example shows good anti-inflammatory activity in an LPS-induced RAW264.7 cell model, which indicates that it may have good application prospects in the treatment of various acute and chronic inflammations, and embodies good application potential in the treatment of chronic inflammations represented by skin inflammations.
Therefore, the compound with the best cell activity is evaluated by a classical skin inflammation model, namely an imiquimod-induced psoriasis-like skin inflammation model, the evaluation indexes are skin characterization, skin pathological changes and in-vivo cytokine changes, and the experimental results are shown in figures 1 to 3.
The compound significantly reduced the experimental symptoms during the treatment period as well as during the dexamethasone-treated group in a dose-dependent manner (FIG. 1). HE histopathological analysis was performed on skin tissue to assess the level of inflammation and tissue changes. A representative histological photograph of the tissue sections is shown in fig. 2. IMQ-induced mice develop pathological psoriatic lesions including loss of the stratum granulosum, epidermal hyperplasia, thickening of the acanthocyte layer, parakeratosis, and inflammatory cell infiltration. The level of the serum inflammatory factor IL-1 β is shown in FIG. 3, and the compounds significantly reduced the level of IL-1 β in serum in a dose-dependent manner.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (10)

1. A paeonol derivative is characterized in that: a compound comprising the structure shown in formula I and formula II:
Figure FDA0003148433580000011
wherein R is1And R2Is selected from any one of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, phenyl and substituted phenyl, R3Selected from morpholinyl, pyrrolyl, thiazolyl, substituted piperazinyl.
2. The method for producing a paeonol derivative according to claim 1, wherein: reacting the compound 1 under the conditions of nitric acid and acetic acid to obtain a compound 2, reacting the compound 2 with hydrogen under the conditions of hydrochloric acid and Pd/C to obtain a compound 3, and reacting the compound 3 with an amine derivative under the conditions of N, N-diisopropylethylamine and triphosgene to obtain a paeonol derivative;
the reaction equation is as follows:
Figure FDA0003148433580000012
3. the method for producing a paeonol derivative according to claim 2, wherein: the amine derivative is any one of methylamine, ethylamine, cyclopropylamine, piperazine, aniline, 3-fluoroaniline, 3-methylaniline, 3-methoxyaniline, 4-trifluoromethylaniline, 3-fluoromethylphenylethylamine, 4-fluorobenzylamine, 2-chlorobenzylamine, phenylethylamine, 4-fluorophenylethylamine and 4-methoxyphenylethylamine.
4. Use of the paeonol derivative of claim 1 for the preparation of an anti-inflammatory agent.
5. A pharmaceutical preparation comprising the paeonol derivative of claim 1 as an active ingredient.
6. The pharmaceutical formulation of claim 5, wherein: the dose of the active compound in the pharmaceutical preparation is 0.01-500 mg/kg.
7. The pharmaceutical formulation of claim 6, wherein: the dose of active compound in the pharmaceutical preparation is 250 mg/kg.
8. The pharmaceutical formulation of claim 5, wherein: the pharmaceutical preparation is prepared by adding pharmaceutically acceptable adjuvants into active compounds, and making into tablet, capsule, lozenge, injection, suspension, suppository or ointment.
9. The pharmaceutical formulation of claim 8, wherein: the auxiliary materials comprise an excipient and a carrier.
10. The pharmaceutical formulation of claim 9, wherein: the excipient is one or more of calcium carbonate, calcium phosphate, saccharides, starch, cellulose derivatives, gelatin, vegetable oil and polyethylene glycol, and the carrier is one or more of diluent, disintegrant, binder and lubricant.
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