An imide compound, its preparation method and application

Abstract

This invention belongs to the field of anti-inflammatory drug technology, and discloses an imide compound, its preparation method, and its application. The imide compound provided by this invention is an N-benzoyl compound or an N-cinnamoyl compound. This invention involves reacting an amide compound, a substituted carboxylic acid, sodium hydride, and N,N'-carbonyldiimidazole in a solvent to obtain the imide compound. The imide compound obtained by the method of this invention, as well as its pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, exhibits highly effective and broad-spectrum anti-inflammatory properties and can be used in the preparation of pharmaceutical formulations for treating excessively inflammatory diseases.

Description

Technical Field

[0001] This invention relates to the field of anti-inflammatory drug technology, and in particular to an imide compound, its preparation method, and its application. Background Technology

[0002] Acute lung injury (ALI) is a life-threatening lung disease characterized by increased pulmonary epithelial permeability, alveolar damage, inflammatory cell infiltration, and pulmonary edema. ALI is caused by a variety of factors, including lipopolysaccharide, viruses, bacteria, and mycoplasma. The high mortality rate of ALI is due to multi-organ respiratory failure and decreased immune function resulting from local or systemic inflammatory responses, leading to secondary bacterial infections. Currently, the main treatments for severe pneumonia include antibiotics, glucocorticoids, and corticosteroids. It has been reported that a higher proportion of pneumonia patients are receiving unnecessary antibiotic treatment, which may lead to higher antibiotic resistance. A complex network of inflammatory factors and chemokines plays a crucial role in mediating, amplifying, and prolonging acute lung injury. Therefore, inhibiting the release of inflammatory factors has become an important approach to treating acute lung injury.

[0003] Dexamethasone is a glucocorticoid anti-inflammatory drug that inhibits various inflammatory factors. However, steroid anti-inflammatory drugs have serious side effects, and long-term use may lead to sequelae such as glaucoma, hypertension, and osteoporosis, as well as an increased risk of infection. Therefore, the development of low-toxicity, highly effective nonsteroidal anti-inflammatory drugs (NSAIDs) is of great significance for the clinical treatment of ALI. Summary of the Invention

[0004] The purpose of this invention is to provide an imide compound, its preparation method, and its application, in order to solve the problem that long-term use of existing steroid anti-inflammatory drugs leads to various sequelae and fails to meet the requirements of low toxicity and high-efficiency anti-inflammatory use.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] This invention provides an imide compound, wherein the imide compound is an N-benzoyl compound or an N-cinnamoyl compound;

[0007] The structural formulas of the N-benzoyl and N-cinnamyl compounds are shown in Formula I and Formula II:

[0008]

[0009] In N-benzoyl and N-cinnamyl compounds, A independently represents...

[0010] Preferably, the structural formula of the imide compound is:

[0011] The present invention also provides a method for preparing the aforementioned imide compounds, comprising the following steps:

[0012] An amide compound, a substituted carboxylic acid, sodium hydride, N,N'-carbonyldiimidazole, and a solvent are mixed and reacted to yield an imide compound.

[0013] Preferably, the amide compound is benzamide or cinnamamide; the substituted carboxylic acid is... The solvent is dichloromethane.

[0014] Preferably, the molar ratio of the amide compound, the substituted carboxylic acid, sodium hydride, and N,N'-carbonyldiimidazole is 1–1.3:0.8–1.1:1.3–1.8:1–1.3; and the molar volume ratio of the substituted carboxylic acid to the solvent is 0.8–1.1 mmol:4–6 mL.

[0015] Preferably, the reaction temperature is 20–30°C and the reaction time is 3–5 hours.

[0016] The present invention also provides the use of the amide compounds in the preparation of pharmaceutical formulations for treating hyperinflammatory diseases, such as acute lung injury, sepsis, arthritis, colitis, or hepatitis.

[0017] Preferably, the pharmaceutical preparation is an injection, tablet, capsule, aerosol, suppository, film, drop, or ointment; the excessive inflammatory disease is acute lung injury.

[0018] As can be seen from the above technical solution, compared with the prior art, the beneficial effects of the present invention are as follows:

[0019] The imidoid compounds of this invention can treat acute lung injury caused by inflammation. Biological experiments have verified that these compounds have anti-inflammatory activity and are very effective in treating acute lung injury caused by excessive expression and release of IL-6 or TNF-α. The synthesis method of this invention is simple, the process is short, and the product yield is 30-60%. Attached Figure Description

[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0021] Figure 1 The diagram shows the dose-response relationship of the imid compounds obtained in Example 14 inhibiting the release of IL-6 from LPS-stimulated RAW264.7 cells over 4 days. In this diagram, Con represents the blank group, Lps represents the lipopolysaccharide inflammatory stimulation group, 4d-10 represents the compound group with an administration concentration of 10 μM, 4d-5.0 represents the compound group with an administration concentration of 5.0 μM, 4d-2.5 represents the compound group with an administration concentration of 2.5 μM, 4d-1.25 represents the compound group with an administration concentration of 1.25 μM, IBP represents the positive control group with an administration concentration of 10 μM ibuprofen, NPX represents the positive control group with an administration concentration of 10 μM naproxen, and CUR represents the positive control group with an administration concentration of 10 μM curcumin.

[0022] Figure 2 The diagram shows the dose-response relationship of the imid compounds obtained in Example 14 inhibiting the release of TNF-α from LPS-stimulated RAW264.7 cells over 4 days. In this diagram, Con represents the blank group, Lps represents the lipopolysaccharide inflammatory stimulation group, 4d-10 represents the compound group with an administration concentration of 10 μM, 4d-5.0 represents the compound group with an administration concentration of 5.0 μM, 4d-2.5 represents the compound group with an administration concentration of 2.5 μM, 4d-1.25 represents the compound group with an administration concentration of 1.25 μM, IBP represents the positive control group of ibuprofen with an administration concentration of 10 μM, NPX represents the positive control group of naproxen with an administration concentration of 10 μM, and CUR represents the positive control group of curcumin with an administration concentration of 10 μM.

[0023] Figure 3 The figure shows the physiological changes in IL-6 expression in bronchoalveolar lavage fluid during the 4-day relief of acute lung injury by the imid compounds obtained in Example 14. In the figure, Con is the blank group, Lps is the lipopolysaccharide inflammatory stimulation group, 4d is the 4d group treated with the compound, and DXM is the dexamethasone positive control group.

[0024] Figure 4 The figure shows the physiological changes in serum IL-6 expression in acute lung injury 4 days after the amide compounds obtained in Example 14 were administered. In the figure, Con is the blank group, Lps is the lipopolysaccharide inflammatory stimulation group, 4d is the compound administration group 4d, and DXM is the dexamethasone positive control group.

[0025] Figure 5The figure shows the physiological changes in TNF-α expression in bronchoalveolar lavage fluid during 4 days of acute lung injury relieving by the imid compounds obtained in Example 14. In this figure, Con is the blank group, Lps is the lipopolysaccharide inflammatory stimulation group, 4d is the 4d group of the administered compound, and DXM is the dexamethasone positive control group.

[0026] Figure 6 The figure shows the physiological changes in serum TNF-α expression in acute lung injury 4 days after the amide compounds obtained in Example 14 were administered. In the figure, Con is the blank group, Lps is the lipopolysaccharide inflammatory stimulation group, 4d is the compound administration group for 4 days, and DXM is the dexamethasone positive control group.

[0027] Figure 7 The figure shows the physiological changes in the number of neutrophils in bronchoalveolar lavage fluid during the 4-day relief of acute lung injury by the imid compounds obtained in Example 14. In the figure, Con is the blank group, Lps is the lipopolysaccharide inflammatory stimulation group, 4d is the group treated with the compound for 4 days, and DXM is the dexamethasone positive control group.

[0028] Figure 8 The graph shows the physiological changes in the ratio of wet weight to dry weight of lung tissue in the acute lung injury 4d after the amide compounds obtained in Example 14 were relieved. In the graph, Con is the blank group, Lps is the lipopolysaccharide inflammatory stimulation group, 4d is the group treated with the compound for 4d, and DXM is the dexamethasone positive control group.

[0029] Figure 9 The image shows the pathological changes in lung tissue after 4 days of relief of acute lung injury by the imid compounds obtained in Example 14. In the image, Shan-vehicle is the blank group, LPS-vehicle is the LPS lipopolysaccharide inflammatory stimulation group, LPS-4d is the LPS lipopolysaccharide inflammatory stimulation group after 4 days of preprotection with the administered compounds, and LPS-DXM is the LPS lipopolysaccharide inflammatory stimulation group after preprotection with dexamethasone. Detailed Implementation

[0030] This invention provides an imide compound, wherein the imide compound is an N-benzoyl compound or an N-cinnamoyl compound;

[0031] The structural formulas of the N-benzoyl and N-cinnamyl compounds are shown in Formula I and Formula II:

[0032]

[0033] In N-benzoyl and N-cinnamyl compounds, A independently represents...

[0034] In this invention, A is preferably found in Formula I. In formula II, A is preferably...

[0035] In this invention, the preferred structural formula of the imide compound is:

[0036] The present invention also provides a method for preparing the aforementioned imide compounds, comprising the following steps:

[0037] An amide compound, a substituted carboxylic acid, sodium hydride, N,N'-carbonyldiimidazole, and a solvent are mixed and reacted to yield an imide compound.

[0038] In this invention, the amide compound is preferably benzamide or cinnamamide; the substituted carboxylic acid is preferably... Furthermore, when the amide compound is benzamide, the substituted carboxylic acid is preferably...

[0039] When the amide compound is cinnamamide, the substituted carboxylic acid is preferred. The solvent is preferably dichloromethane.

[0040] In this invention, the molar ratio of the amide compound, the substituted carboxylic acid, sodium hydride, and N,N'-carbonyldiimidazole is preferably 1–1.3:0.8–1.1:1.3–1.8:1–1.3, more preferably 1.1–1.2:0.9–1:1.4–1.6:1.1–1.2, and even more preferably 1.1:1:1.5:1.1; the molar volume ratio of the substituted carboxylic acid to the solvent is preferably 0.8–1.1 mmol:4–6 mL, more preferably 0.9–1 mmol:4.5–5.5 mL.

[0041] In this invention, the reaction temperature is preferably 20-30°C, more preferably 22-28°C, and even more preferably 25°C; the reaction time is preferably 3-5 hours, and even more preferably 4 hours.

[0042] In this invention, before obtaining the imide compounds, the reaction product is post-processed; the post-processing steps are as follows: the obtained product is sequentially extracted, washed, dried, subjected to reduced pressure and column chromatography.

[0043] In this invention, the reagent used for extraction is preferably ethyl acetate; the reagent used for washing is preferably a saturated sodium chloride solution; the number of washings is preferably 2 to 4 times, more preferably 3 times; the reagent used for drying is preferably anhydrous magnesium sulfate; the temperature for depressurization is preferably 40 to 50°C, more preferably 45°C; the time for depressurization is preferably 5 to 30 minutes, more preferably 10 minutes; the solvent used for column chromatography is petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate is 1 to 2: 0.8 to 1.

[0044] The purpose of heating described in this invention is to remove dichloroethane; the purpose of depressurization described in this invention is to remove ethyl acetate.

[0045] The present invention also provides the use of the amide compounds in the preparation of pharmaceutical formulations for treating excessive inflammatory diseases, wherein the excessive inflammatory diseases are preferably acute lung injury, sepsis, arthritis, colitis or hepatitis, and more preferably acute lung injury.

[0046] In this invention, the pharmaceutical preparation is preferably an injection, tablet, capsule, aerosol, suppository, film, drop pill, or ointment, and more preferably an injection, tablet, capsule, aerosol, suppository, film, or ointment.

[0047] In this invention, when the imide compounds are used in the preparation of pharmaceutical formulations for treating excessive inflammatory diseases, the imide compounds preferably include one or more of imide compounds and their pharmaceutically acceptable salts, hydrates, solvates and prodrugs.

[0048] In this invention, the carrier of the pharmaceutical composition includes a binder, lubricant, disintegrant, solubilizer, diluent, stabilizer, suspending agent, colorant, flavoring agent, preservative, solvent, and matrix.

[0049] In this invention, the pharmaceutical preparation can be administered orally or via parenteral route (e.g., intravenously, subcutaneously, intraperitoneally, or locally). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0050] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0051] Example 1

[0052] Preparation of N-benzobenzylamide:

[0053] Add 5 mL of dichloromethane to a 50 mL round-bottom flask, followed by 1.1 mmol of [amount missing] mol / L. 1 mmol benzamide, 1.5 mmol sodium hydride, and 1.1 mmol N,N'-carbonyldiimidazole (CDI) were reacted at room temperature for 4 h. After the reaction, the product was extracted with ethyl acetate, and the resulting organic layer was washed three times with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated to dryness under reduced pressure at 45 °C for 10 min. Finally, N-benzobenzylamide was obtained by column chromatography in a mixed solvent of petroleum ether and ethyl acetate at a volume ratio of 1:0.8, and designated as 3a.

[0054] In this embodiment, the yield of N-benzobenzamide was 68%, and its structural formula was [insert structural formula here].

[0055] 1 H NMR (400MHz, DMSO-d6) δ11.35(s,1H),7.93(d,J=7.2Hz,4H),7.66(t,J=7.4Hz,2H),7.54(t,J=7.7Hz,4H). 13 C NMR(100MHz,DMSO-d6)δ168.21,134.29,133.10,129.11,128.88.LC-MS m / z:226.2(M+H) + .

[0056] Example 2

[0057] Preparation of N-benzoylnicotinamide:

[0058] The difference from Example 1 is that the substituted carboxylic acid is... The rest is the same as in Example 1. N-benzoylnicotinamide was obtained, denoted as 3b.

[0059] In this embodiment, the yield of N-benzoylnicotinamide was 38%, and its structural formula was [insert structural formula here].

[0060] 1 H NMR (400MHz, CDCl3) δ9.15–9.02(m,2H),8.86–8.80(m,1H),8.19(d,J=7.9Hz,1H),7.93(d ,J=7.4Hz,2H),7.67(t,J=7.4Hz,1H),7.56(t,J=7.7Hz,2H),7.48(dd,J=7.9,4.8Hz,1H). 13C NMR (100MHz, DMSO-d6) δ168.02,167.34,153.30,149.92,136.87,134.05,133.38,130.49,129.31,129.14,123.98.LC-MS m / z:227.1(M+H) + .

[0061] Example 3

[0062] Preparation of N-benzoylfuran-2-carboxamide:

[0063] The difference from Example 1 is that the substituted carboxylic acid is... The rest is the same as in Example 1. N-benzoylfuran-2-carboxamide was obtained, denoted as 3c.

[0064] In this embodiment, the yield of N-benzoylfuran-2-carboxamide was 35%, and its structural formula was [structural formula missing].

[0065]

[0066] 1 H NMR (400MHz, CDCl3) δ9.35 (s, 1H), 7.96–7.90 (m, 2H), 7.66 (t, J = 7.4Hz, 1H), 7.61 (d, J =0.9Hz,1H),7.56(t,J=7.6Hz,2H),7.43(d,J=3.6Hz,1H),6.66(dd,J=3.6,1.7Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ167.82,157.32,148.00,146.89,134.41,133.14,129.09,128.93,118.26,112.85.LC-MS m / z:216.1(M+H) + .

[0067] Example 4

[0068] Preparation of N-benzoylthiophene-2-carboxamide:

[0069] The difference from Example 1 is that the substituted carboxylic acid is... The rest is the same as in Example 1. N-benzoylthiophene-2-carboxamide was obtained and denoted as 3d.

[0070] In this embodiment, the yield of N-benzoylthiophene-2-carboxamide was 50%, and its structural formula was as follows:

[0071]

[0072] 1 H NMR (400MHz, CDCl3) δ10.24(s,1H),7.91–7.86(m,2H),7.66(t,J=7.4Hz,1H ),7.56(t,J=7.6Hz,2H),3.88–3.80(m,4H),3.41(s,2H),2.75–2.66(m,4H). 13 C NMR(100MHz,DMSO-d6)δ168.14,161.35,138.86,134.89,134.57,133.06,132.69,129.15,128.88,128.83.LC-MS m / z:230.1(M+H) - .

[0073] Example 5

[0074] Preparation of N-benzoyl-1H-indole-2-carboxamide:

[0075] The difference from Example 1 is that the substituted carboxylic acid is... The rest is the same as in Example 1. N-benzoyl-1H-indole-2-carboxamide was obtained, denoted as 3e.

[0076] In this embodiment, the yield of N-benzoyl-1H-indole-2-carboxamide was 45%, and its structural formula was [structural formula missing].

[0077]

[0078] 1 H NMR(400MHz,DMSO-d6)δ11.90(s,1H),11.24(s,1H),7.95–7.88(m,2H),7.72–7.64(m,2H),7.61(d,J =1.5Hz,1H),7.56(t,J=7.6Hz,2H),7.49(d,J=8.3Hz,1H),7.34–7.24(m,1H),7.11(t,J=7.2Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ167.96,160.86,138.09,134.68,133.02,130.61,129.15,128.88,127.23,125.39,122.84,120.76,113.06,107.89.LC-MS m / z:265.1(M+H) + .

[0079] Example 6

[0080] Preparation of N-benzoylquinoline-2-carboxamide:

[0081] The difference from Example 1 is that the substituted carboxylic acid is... The rest is the same as in Example 1. N-benzoylquinoline-2-carboxamide was obtained, denoted as 3f.

[0082] In this embodiment, the yield of N-benzoylquinoline-2-carboxamide was 30%, and its structural formula was [structural formula missing].

[0083]

[0084] 1 H NMR (400MHz, CDCl3) δ11.79(s,1H),8.45(s,2H),8.24(d,J=8.5Hz,1H),8.11(d,J=7.5Hz,2 H),7.98(d,J=8.2Hz,1H),7.88(t,J=7.5Hz,1H),7.77–7.67(m,2H),7.62(t,J=7.5Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ165.31,163.15,148.99,146.07,139.25,133.68,131.46,130.12,129.91,129.52,128.63,128.42,119.06.LC-MS m / z:277.2(M+H) + .

[0085] Example 7

[0086] Preparation of N-(2-(4-isobutylphenyl)propionyl)benzamide:

[0087] The difference from Example 1 is that the substituted carboxylic acid is... The rest is the same as in Example 1. N-(2-(4-isobutylphenyl)propionyl)benzamide was obtained, denoted as 3g.

[0088] In this embodiment, the yield of N-(2-(4-isobutylphenyl)propionyl)benzamide was 58%, and its structural formula was [insert structural formula here].

[0089] 1H NMR (400MHz, CDCl3) δ8.48(s,1H),7.73–7.67(m,2H),7.58(t,J=7.4Hz,1H),7.46(t,J=7.7Hz,2H),7.34(d,J=8.1Hz,2H),7.17 (d,J=8.0Hz,2H),4.68(d,J=7.0Hz,1H),2.49(d,J=7.2Hz,2H),1.94–1.84(m,1H),1.60(d,J=7.1Hz,3H),0.93(d,J=6.6Hz,7H). 13 C NMR(100MHz,DMSO-d6)δ175.26,166.93,140.23,138.72,134.02,133.15,129.54,128.94,128.78,127.83,45.62,44.72,30.11,22.68,19.04.LC-MS m / z:310.2(M+H) + .

[0090] Example 8

[0091] Preparation of N-(2-(6-methoxynaphth-2-yl)propionyl)benzamide:

[0092] The difference from Example 1 is that the substituted carboxylic acid is... The rest is the same as in Example 1. N-(2-(6-methoxynaphthyl-2-yl)propionyl)benzamide was obtained, denoted as 3h.

[0093] In this embodiment, the yield of N-(2-(6-methoxynaphthalene-2-yl)propionyl)benzamide was 55%, and its structural formula was [insert structural formula here].

[0094] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),7.81(dd,J=13.8,6.2Hz,5H),7.61(t,J=7.4Hz,1H),7.50(t,J=7.1Hz,3H ),7.30(d,J=2.2Hz,1H),7.17(dd,J=9.0,2.4Hz,1H),4.51(q,J=6.9Hz,1H),3.88(s,3H),1.51(d,J=7.0Hz,3H). 13C NMR(100MHz,DMSO-d6)δ175.32,165.84,157.70,144.22,136.41,134.77,133.85,131.00,129.71,1 29.55,128.89,128.64,127.46,126.99,126.36,121.20,119.26,106.20,55.68,46.13,19.03.LC-MS m / z:360.2(M+H) + .

[0095] Example 9

[0096] Preparation of tert-butyl 3-(benzoylcarbamoyl)pyrrolidine-1-carboxylate:

[0097] The difference from Example 1 is that the substituted carboxylic acid is... Other procedures are the same as in Example 1. 3-(benzoylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester was obtained, denoted as 3i.

[0098] In this example, the yield of tert-butyl 3-(benzoylcarbamoyl)pyrrolidine-1-carboxylate was 33%, and its structural formula was [insert structural formula here].

[0099] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),7.92(d,J=7.3Hz,2H),7.65(t,J=7.4Hz,1H),7.54(t,J=7.6Hz, 2H),3.65(s,1H),3.59–3.41(m,2H),3.39–3.34(m,1H),3.31(s,1H),2.21–2.00(m,2H),1.42(s,10H). 13 C NMR(100MHz,DMSO-d6)δ174.72,166.97,153.91,133.79,133.29,128.98,12 8.91,78.93,48.38,45.70,45.56,45.05,44.17,29.03,28.67,28.32.LC-MS m / z:317.2(MH) - .

[0100] Example 10

[0101] Preparation of N-benzoylpyrrolidine-3-carboxamide:

[0102] The difference from Example 1 is that the substituted carboxylic acid is... The rest is the same as in Example 1. N-benzoylpyrrolidine-3-carboxamide was obtained, denoted as 3j.

[0103] In this embodiment, the yield of N-benzoylpyrrolidine-3-carboxamide was 41%, and its structural formula was [structural formula missing].

[0104]

[0105] 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),7.94(d,J=7.6Hz,2H),7.67(t,J=7.4Hz,1H),7.55(t,J=7.7Hz,2H),3.86–3.77(m,1 H),3.53(s,1H),3.46(d,J=7.1Hz,2H),3.29–3.20(m,2H),2.30(dq,J=15.5,7.7Hz,1H),2.14(td,J=13.5,6.8Hz,1H).13C NMR(100MHz,DMSO-d6)δ173.94,166.97,133.49,128.98,46.89,45.27,43.99,28.64.LC-MS m / z:219.1(M+H) + .

[0106] Example 11

[0107] Preparation of N-cinnamoylcinnamamide:

[0108] The difference from Example 1 is that the substituted carboxylic acid is... The amide compound was cinnamamide; other aspects were the same as in Example 1. N-cinnamylcinnamamide was obtained, denoted as 4a.

[0109] In this embodiment, the yield of N-cinnamylcinnamamide was 31%, and its structural formula was [structural formula missing].

[0110]

[0111] 1 H NMR (400MHz, DMSO-d6) δ7.74(d,J=15.9Hz,1H),7.67(dd,J=6.7,2.4Hz,2H),7.48(dd,J=5.1,1.6Hz,3H),7.25(d,J=15.8Hz,1H). 13C NMR(100MHz,DMSO-d6)δ169.83,166.18,145.64,144.18,134.85,134.50,131.56,131.06,129.63,129.31,128.70,121.76,121.42.LC-MS m / z:278.1(M+H) + .

[0112] Example 12

[0113] Preparation of N-cinnamylbenzamide:

[0114] The difference from Example 1 is that the amide compound is cinnamamide; otherwise, it is the same as in Example 1. N-cinnamylbenzamide was obtained, denoted as 4b.

[0115] In this embodiment, the yield of N-cinnamylbenzamide was 35%, and its structural formula was [structural formula would be inserted here].

[0116]

[0117] 1 H NMR (400MHz, CDCl3) δ8.76 (s, 1H), 8.01–7.92 (m, 3H), 7.88 (d, J = 15.8Hz, 1H), 7.71–7.64 (m, 3H), 7.56 (t, J = 7.6Hz, 2H), 7.47–7.43 (m, 3H). 13 C NMR(100MHz,DMSO-d6)δ167.21,166.43,143.87,134.97,133.94,133.31,130.97,129.61,129.04,128.99,128.92,128.68,121.80.LC-MS m / z:252.1(M+H) + .

[0118] Example 13

[0119] Preparation of N-cinnamylfuran-2-carboxamide:

[0120] The difference from Example 1 is that the substituted carboxylic acid is... The amide compound was cinnamamide; other aspects were the same as in Example 1. N-cinnamylfuran-2-carboxamide was obtained, denoted as 4c.

[0121] In this embodiment, the yield of N-cinnamylfuran-2-carboxamide was 47%, and its structural formula was [structural formula missing].

[0122]

[0123] 1 H NMR (400MHz, CDCl3) δ8.94 (s, 1H), 7.92 (q, J = 15.7Hz, 2H), 7.81 (d, J = 3.1Hz, 1H),7.72(d,J=4.6Hz,1H),7.68(s,2H),7.45(s,3H),7.21(t,J=4.0Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ166.12,156.88,148.12,146.65,144.02,134.93,130.98,129.58,128.70,121.65,118.05,112.96.

[0124] Example 14

[0125] Preparation of N-cinnamylthiophene-2-carboxamide:

[0126] The difference from Example 1 is that the substituted carboxylic acid is... The amide compound was cinnamamide; other aspects were the same as in Example 1. N-cinnamylthiophene-2-carboxamide was obtained, denoted as 4d.

[0127] In this embodiment, the yield of N-cinnamylthiophene-2-carboxamide was 44%, and its structural formula was [structural formula would be inserted here].

[0128]

[0129] 1 H NMR (400MHz, CDCl3) δ8.94 (s, 1H), 7.92 (q, J = 15.7Hz, 2H), 7.81 (d, J = 3.1Hz, 1H), 7.73–7.66 (m, 3H), 7.45 (s, 3H), 7.21 (t, J = 4.0Hz, 1H). 13 C NMR(100MHz,DMSO-d6)δ166.46,161.14,144.08,138.91,135.09,134.94,132.21,131.00,129.59,129.00,128.72,128.34,121.59.LC-MS m / z:258.1(M+H) + .HRMS(ESI,positive)m / z calcd for C 14 H 12 NO2S(M+H) +:258.0589; found 258.0586; HPLC analysis: retention time=2.0min; peak area, >95% (254nm).

[0130] Example 15

[0131] Preparation of N-cinnamyl-1H-indole-2-carboxamide:

[0132] The difference from Example 1 is that the substituted carboxylic acid is... The amide compound was cinnamamide; other aspects were the same as in Example 1. N-cinnamyl-1H-indole-2-carboxamide was obtained, denoted as 4e.

[0133] In this embodiment, the yield of N-cinnamyl-1H-indole-2-carboxamide was 57%, and its structural formula was [structural formula missing].

[0134]

[0135] 1 H NMR (400MHz, DMSO-d6) δ11.90(s,1H),11.11(s,1H),7.72(s,4H),7.61(s,1H),7.49(s,5H),7.30(s,1H),7.12(s,1H). 13 C NMR(100MHz,DMSO-d6)δ166.21,160.65,143.86,138.14,135.02,130.96,130.48 ,129.61,128.67,127.26,125.41,122.86,121.85,120.80,113.08,107.37.LC-MS m / z:291.2(M+H) + .

[0136] Example 16

[0137] Preparation of N-cinnamylquinoline-2-carboxamide:

[0138] The difference from Example 1 is that the substituted carboxylic acid is... The amide compound was cinnamamide; other aspects were the same as in Example 1. N-cinnamylquinoline-2-carboxamide was obtained, denoted as 4f.

[0139] In this embodiment, the yield of N-cinnamylquinoline-2-carboxamide was 41%, and its structural formula was [structural formula missing].

[0140]

[0141] 1H NMR (400MHz, CDCl3) δ10.87 (s, 1H), 8.41 (q, J = 8.4Hz, 2H), 8.23 ​​(d, J = 8.5Hz, 1H), 8. 06–7.94(m,3H),7.87(t,J=7.6Hz,1H),7.73(t,J=7.0Hz,3H),7.46(d,J=3.5Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ165.33,163.74,148.98,146.21,144.88,139.12,134.86,131.48,131 .13,129.96,129.86,129.57,128.86,128.68,128.46,121.23,119.28.LC-MSm / z:303.1(M+H) + .

[0142] Example 17

[0143] Preparation of N-(2-(4-isobutylphenyl)propionyl)cinnamamide:

[0144] The difference from Example 1 is that the substituted carboxylic acid is... The amide compound was cinnamamide; other aspects were the same as in Example 1. N-(2-(4-isobutylphenyl)propionyl)cinnamamide was obtained, denoted as 4g.

[0145] In this embodiment, the yield of N-(2-(4-isobutylphenyl)propionyl)cinnamonamide was 50%, and its structural formula was [insert structural formula here].

[0146] 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),7.70–7.61(m,3H),7.50–7.42(m,3H),7.26(d,J=8.1Hz,2H),7.20–7.11(m,3H),4 .18(d,J=7.0Hz,1H),2.42(d,J=7.1Hz,2H),1.82(dt,J=13.5,6.8Hz,1H),1.39(d,J=7.0Hz,3H),0.87(d,J=6.6Hz,6H). 13C NMR (100MHz, DMSO-d6) δ175.33,165.85,144.24,140.33,138.52,134.75,131. 02,129.57,128.65,127.80,121.17,45.76,44.72,30.11,22.70,18.99.LC-MS m / z:336.3(M+H) + .

[0147] Example 18

[0148] Preparation of N-(2-(6-methoxynaphth-2-yl)propionyl)cinnamamide:

[0149] The difference from Example 1 is that the substituted carboxylic acid is... The amide compound was cinnamamide; other aspects were the same as in Example 1. N-(2-(6-methoxynaphthyl-2-yl)propionyl)cinnamamide was obtained, denoted as 4h.

[0150] In this embodiment, the yield of N-(2-(6-methoxynaphthalene-2-yl)propionyl)cinnamamide was 38%, and its structural formula was [insert structural formula here].

[0151] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.81(dd,J=16.5,7.3Hz,3H),7.65(d,J=23.0Hz,3H),7.46(d,J=17 .3Hz,4H),7.30(s,1H),7.17(d,J=12.5Hz,2H),4.36(d,J=6.2Hz,1H),3.87(s,3H),1.49(d,J=6.2Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ175.32,165.84,157.70,144.22,136.41,134.77,133.85,131.00,129.71,1 29.55,128.89,128.64,127.46,126.99,126.36,121.20,119.26,106.20,55.68,46.13,19.03.LC-MS m / z:360.2(M+H) + .

[0152] Example 19

[0153] Preparation of tert-butyl 3-(cinnamylcarbamoyl)pyrrolidine-1-carboxylate:

[0154] The difference from Example 1 is that the substituted carboxylic acid is... The amide compound was cinnamamide; other aspects were the same as in Example 1. 3-(cinnamylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester was obtained, denoted as 4i.

[0155] In this example, the yield of tert-butyl 3-(cinnamylcarbamoyl)pyrrolidine-1-carboxylate was 44%, and its structural formula was [insert structural formula here].

[0156] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),7.71(d,J=15.8Hz,1H),7.65(dd,J=6.5,2.9Hz,2H),7.47(dd,J=5.0,1.7Hz,3H),7. 13(d,J=15.8Hz,1H),3.58–3.48(m,2H),3.47–3.40(m,1H),3.33–3.24(m,2H),2.08(dd,J=40.4,5.6Hz,2H),1.42(s,10H). 13 C NMR (100MHz, DMSO-d6) δ165.63,144.21,134.73,131.06,129.60,128.66,121.22,78.94,48.21,28.67.LC-MS m / z:343.2(MH) - .

[0157] Example 20

[0158] Preparation of N-cinnamylpyrrolidine-3-carboxamide:

[0159] The difference from Example 1 is that the substituted carboxylic acid is... The amide compound was cinnamamide; other aspects were the same as in Example 1. N-cinnamylpyrrolidine-3-carboxamide was obtained, denoted as 4j.

[0160] In this embodiment, the yield of N-cinnamylpyrrolidine-3-carboxamide was 34%, and its structural formula was [structural formula missing].

[0161]

[0162] 1H NMR (400MHz, DMSO-d6) δ7.71(t,J=6.5Hz,2H),7.57(d,J=6.3Hz,1H),7.49(d,J=15.5Hz,1H),7.41(d,J=6.8Hz,2H),7.00(dd,J=15.6,9. 6Hz,2H),3.87(d,J=8.1Hz,1H),3.64(dd,J=8.4,4.2Hz,2H),3.60-3.53(m,1H),3.48–3.36(m,1H),3.10–2.90(m,1H),2.17–1.89(m,2H). 13 C NMR (100MHz, DMSO-d6) δ163.97,140.88,135.52,130.04,129.27,128.48,120.31,48.95,45.89,44.03,29.85.LC-MS m / z:245.2(M+H) + .

[0163] Application Example 1

[0164] The dose-response relationship of N-cinnamylthiophene-2-carboxamide obtained in Example 14 in inhibiting the release of inflammatory factors from lipopolysaccharide (LPS)-stimulated macrophages was tested using the following method:

[0165] 1.2×10 6RAW264.7 cells were cultured in 200 μL DMEM medium at 37°C. After 24 h, the culture medium was replaced, and the culture medium was divided into 9 equal portions, designated as samples 1–9. Sample 1 was untreated and served as the blank group. Sample 2 was treated with LPS (at a concentration of 0.5 μg / mL) and served as the lipopolysaccharide inflammatory stimulation group. Samples 3–6 were pretreated with N-cinnamylthiophene-2-carboxamide (at concentrations of 10 μM, 5.0 μM, 2.5 μM, and 1.25 μM, respectively). After 30 min, the cells were treated with LPS (at a concentration of 0.5 μg / mL) for another 24 h, and were designated as the compound group with a concentration of 10 μM, 5.0 μM, 2.5 μM, and 1.25 μM, respectively. The compound group was 1.25 μM. Ibuprofen was added to sample 7 (maintaining a concentration of 10 μM), designated as the 10 μM ibuprofen positive control group. Naproxen was added to sample 8 (maintaining a concentration of 10 μM), designated as the 10 μM naproxen positive control group. Curcumin was added to sample 9 (maintaining a concentration of 10 μM), designated as the 10 μM curcumin positive control group. Culture media from each group were collected, and the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were detected by ELISA. Total protein concentration was measured in RAW264.7 cells. ELISA results were compared by dividing the corresponding total protein concentration. The IL-6 content in the lipopolysaccharide-induced inflammation group was calibrated to 100, and the average value and error were calculated. The results are as follows: Figure 1 and Figure 2 As shown.

[0166] Depend on Figure 1 and 2 It can be seen that the obtained N-cinnamylthiophene-2-carboxamide can significantly inhibit the high expression of inflammatory factors IL-6 and TNF-α released by LPS-stimulated macrophages.

[0167] Application Example 2

[0168] The physiological changes in rats with acute lung injury alleviated by N-cinnamylthiophene-2-carboxamide obtained in Example 14 were tested using the following method:

[0169] N-cinnamylthiophene-2-carboxymethyl cellulose sodium (0.5% by mass) was used as a solvent to prepare a suspension of N-cinnamylthiophene-2-carboxamide at a dosage of 20 mg / kg for intraperitoneal administration. The experiment was divided into a blank group, a lipopolysaccharide (LPS) inflammatory stimulation group, a compound-administered group for 4 days, and a dexamethasone positive control group, with 8 mice in each group. Mice in each group were anesthetized with ether and their trachea exposed. Except for the blank group, 50 μL of 5 mg / kg LPS was slowly instilled into the trachea of ​​the other groups to induce acute lung injury. The control group received an equal volume of physiological saline in the same manner. The wounds of all mice were then sutured to establish an acute lung injury model. 24 hours later, mice were anesthetized with an intraperitoneal injection of 10% chloral hydrate at a dose of 5 mL / kg. The left lung was ligated after thoracotomy, and the right lung was lavaged with 1 mL of physiological saline. The lavage fluid was collected, and this procedure was repeated three times. Blood was collected in the form of 0.5-0.8 mL via ocular sampling. The blood was centrifuged at 4°C and 1000 r / min for 10 min. The supernatant serum was collected, and the expression levels of inflammatory factors IL-6 and TNF-α in the serum were measured.

[0170] After collecting bronchoalveolar lavage fluid (BAL), the fluid was centrifuged at 4℃ and 1000 rpm for 5 min. The supernatant was collected, and the protein concentration and expression levels of inflammatory factors IL-6 and TNF-α were measured. After centrifugation, the precipitate was resuspended in 50 μL of physiological saline, mixed thoroughly, and 20 μL was collected for total cell count using a Standard cell counter. Additionally, the upper lobe of the right lung was harvested, and after blotting with filter paper, the wet weight was measured. The tissue was then baked at 60℃ for at least 48 hours until its weight no longer changed, and the dry weight was measured. The wet weight / dry weight ratio (W / D) of the lung tissue was calculated to assess the degree of pulmonary edema. The results are as follows: Figures 3-8 As shown.

[0171] Depend on Figures 3-8 It can be seen that the obtained N-cinnamylthiophene-2-carboxamide can effectively alleviate acute lung injury in mice physiologically.

[0172] Application Example 3

[0173] The pathological changes in lung tissue during acute lung injury were assessed using N-cinnamylthiophene-2-carboxamide obtained in Example 14. The test method is as follows:

[0174] In Application Example 2, the right lung tissue of anesthetized mice was fixed with 2 mL of 4% paraformaldehyde, embedded, and then cut into 5 μm thick sections. The sections were stained using a H&E kit and scanned using a standard optical microscope to assess the degree of lung injury. The results are as follows: Figure 9 As shown.

[0175] Depend on Figure 9It was found that the alveolar cavities of normal mice were clear, structurally intact, and had smooth walls. After tracheal instillation of LPS to induce an acute lung injury model, the alveolar walls showed significant edema and thickening, and increased inflammatory cell infiltration. After treatment with N-cinnamylthiophene-2-carboxamide, cell edema and thickening were significantly reduced, and inflammatory cell infiltration was significantly decreased, with little difference from the normal group. This indicates that N-cinnamylthiophene-2-carboxamide can effectively alleviate lung tissue damage in acute lung injury.

[0176] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. An imide compound, characterized in that, The imide compounds are N-cinnamonyl compounds; The structural formula of the N-cinnamyl compounds is as follows: 。 2. The method for preparing the imide compound according to claim 1, characterized in that, Includes the following steps: Add 5 mL of dichloromethane to a 50 mL round-bottom flask, followed by 1.1 mmol of [amount missing] mol / L. 1 mmol cinnamamide, 1.5 mmol sodium hydride, and 1.1 mmol N,N'-carbonyldiimidazole were reacted at room temperature for 4 h. After the reaction, the product was extracted with ethyl acetate, and the resulting organic layer was washed three times with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated to dryness under reduced pressure at 45 °C for 10 min. Finally, N-cinnamylthiophene-2-carboxamide was obtained by column chromatography in a mixed solvent of petroleum ether and ethyl acetate at a volume ratio of 1:0.

8. .

3. The use of the imide compound of claim 1 in the preparation of a pharmaceutical formulation for treating excessive inflammatory diseases, characterized in that, The aforementioned excessive inflammatory disease is acute lung injury.

4. The use of the imidoid compound according to claim 3 in the preparation of pharmaceutical formulations for treating excessively inflammatory diseases, characterized in that, The pharmaceutical preparation is an injection, tablet, capsule, aerosol, suppository, film, drop pill, or ointment.

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