Hexa-peri-hexabenzofuran derivatives, methods of synthesis and applications thereof

Abstract

The application discloses a series of hexa-parallel hexa benzofuran derivatives, a synthesis method and application thereof, and belongs to the technical field of medicines. Test results of the applicant show that part of the target compounds have good inhibitory effect on the release of NO in lipopolysaccharide-induced mouse macrophage RAW 264.7, and can be used for preparing medicines for treating inflammation.

Description

Technical Field

[0001] This invention relates to hexabenzofuran derivatives, their synthesis methods, and applications, belonging to the field of pharmaceutical technology. Background Technology

[0002] Currently, there are few reports on the construction of hexa-hexabenzofuran skeletons; however, there is still much room for improvement in achieving efficient construction of hexa-hexabenzofuran skeletons. Based on this, this application provides a series of novel hexa-hexabenzofuran skeleton compounds, as well as a simple and efficient method for synthesizing hexa-hexabenzofuran skeletons. Summary of the Invention

[0003] The technical problem to be solved by the present invention is to provide a series of novel hexabenzofuran derivatives with good anti-inflammatory activity, as well as their synthesis methods and applications.

[0004] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0005] The hexabenzofuran derivatives described in this invention are compounds having the structure shown in formula (I) below, or pharmaceutically acceptable salts thereof:

[0006] (I);

[0007] in:

[0008] R 1 Indicates unsubstituted or monosubstituted styrene groups;

[0009] R 2 Indicates an unsubstituted or monosubstituted phenyl group;

[0010] R 3 R 4 These represent hydrogen atoms or unsubstituted or substituted carbon atoms, respectively. 1~4 Alkyl, or R 3 +R 4 It is cyclohexane;

[0011] R 5 Represents a hydrogen atom or C 1~4 Alkyl groups;

[0012] R 6 C represents 1~4 Alkyl groups;

[0013] R represents a hydrogen atom, a methyl atom, or a halogen atom.

[0014] In the general formula structure of the above-mentioned hexabenzofuran derivatives, the substituents are preferably as follows:

[0015] R 1Indicates unsubstituted or monosubstituted styrene groups;

[0016] R 2 Indicates an unsubstituted or monosubstituted phenyl group;

[0017] R 3 R 4 C atoms representing hydrogen atoms, methyl groups, or substituted atoms, respectively. 1~4 Alkyl, or R 3 +R 4 It is cyclohexane;

[0018] R 5 Indicates a hydrogen atom or a methyl group;

[0019] R 6 Indicates methyl;

[0020] R represents a hydrogen atom, a methyl atom, or a fluorine atom.

[0021] Furthermore, the hexabenzofuran derivatives described in this invention can specifically be any one of the following compounds 3a to 3h:

[0022] 3a: R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me, R=H;

[0023] 3b: R 1 =4-OMe-CH=CH-Ph, R 2 =4-OMe-Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me, R=H;

[0024] 3c:R 1 =4-CF3-CH=CH-Ph, R 2 =4-CF3-Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me, R=H;

[0025] 3d:R 1 =-CH=CH-Ph,R 2 =-Ph,R 3 +R 4 =cyclohexyl, R 5 =Me,R 6=Me, R=H;

[0026] 3e:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =H,R 4 =(CH2)3CO2Me, R 5 =Me,R 6 =Me, R=H;

[0027] 3f:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me, R=4-Me;

[0028] 3g:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me, R=4-F;

[0029] 3h:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me, R=H.

[0030] The method for synthesizing the hexabenzofuran derivatives of the present invention mainly includes the following steps: taking the compound shown in formula (II) and the compound shown in formula (III) into an organic solvent, adding an alkaline substance and a catalyst, and reacting under heating or non-heating conditions to obtain the crude product of the target compound;

[0031] (II) (III);

[0032] in:

[0033] R 1 Indicates unsubstituted or monosubstituted styrene groups;

[0034] R 2 Indicates an unsubstituted or monosubstituted phenyl group;

[0035] R 3 R 4These represent hydrogen atoms or unsubstituted or substituted carbon atoms, respectively. 1~4 Alkyl, or R 3 +R 4 It is cyclohexane;

[0036] R 5 Represents a hydrogen atom or C 1~4 Alkyl groups;

[0037] R 6 C represents 1~4 Alkyl groups;

[0038] R represents a hydrogen atom, a methyl atom, or a halogen atom;

[0039] X represents a bromine atom or a chlorine atom.

[0040] In the above synthesis method, the reaction is preferably carried out under the protection of an inert gas (such as nitrogen, argon, or helium). The reaction temperature is typically less than or equal to 100°C, and more preferably 50–80°C. The reaction is monitored by TLC until it is complete. Based on the applicant's experience, when the reaction is carried out at 80°C, a reaction time of 24–48 hours is suitable.

[0041] In the above synthesis method, the organic solvent can be selected from one or more combinations of benzene, toluene, cyclohexane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, dichloromethane, acetone, chloroform, n-hexane, and dioxane; preferably acetonitrile, toluene, or tetrahydrofuran. The amount of organic solvent can be determined as needed, usually to the extent that it can fully dissolve the reactants. Specifically, based on 0.1 mmol of the compound shown in formula (II), the total amount of organic solvent used for all reactants is usually 1-5 mL.

[0042] In the above synthesis method, the alkaline substance acts as an activator of compound (III) in the reaction. This alkaline substance can be a conventional choice from existing technologies, preferably selected from one or more combinations of tripotassium phosphate, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, pyridine, triethylamine, and N,N-diisopropylethylamine; more preferably, potassium carbonate or cesium carbonate. The amount of the alkaline substance is preferably 0.1 to 2.0 times the amount of the compound shown in formula (II).

[0043] In the above synthesis method, the catalyst can be one or a combination of two or more selected from copper salts, ytterbium salts, and scandium salts. Preferably, the copper salt is selected from one or a combination of two or more selected from copper bromide, copper iodide, copper chloride, copper sulfate, acetone, copper trifluoromethanesulfonate, cuprous bromide, cuprous iodide, and cuprous chloride; the ytterbium salt is preferably ytterbium trifluoromethanesulfonate; and the scandium salt is preferably scandium trifluoromethanesulfonate. The amount of catalyst used is preferably 0.1 to 0.2 times the amount of the compound shown in formula (II).

[0044] In the synthetic method described in this invention, the compound represented by formula (II) is an N-alkenyl α,β-unsaturated nitrone derivative, which can be referred to in existing literature (Xiao-Pan Ma, Liang-Gui Li, Hong-Ping Zhao, Min Du, Cui Liang, and Dong-Liang Mo). Synthesized according to Org. Lett. 2018, 20, 4571-4574, or by designing a custom synthetic route, details of which will not be elaborated here. The reactant shown in formula (III) is an α-haloamide reagent, which can be found in existing literature (IM Taily, D. Saha, and P. Banerjee). The synthesis can be carried out by means of the synthetic route (J. Org. Chem. 2022, 87, 2155–2166.), or you can design your own synthetic route, which will not be described in detail here.

[0045] In the synthesis method described in this invention, the proportions of each raw material are stoichiometric.

[0046] The method described above yields a crude product of compound (I), and the process also includes a purification step. Specifically, conventional purification methods can be used to improve the purity of compound (I), such as silica gel thin-layer chromatography or silica gel column chromatography, or recrystallization. The eluent used in chromatography is the same as the solvent used in recrystallization, which can be a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 1:1, or a mixed solvent of n-hexane and ethyl acetate in a volume ratio of 20:1 to 1:1.

[0047] The applicant discovered through experiments that the hexabenzofuran derivatives of the present invention have good anti-inflammatory activity. Based on this, the present invention also provides the use of the above-mentioned hexabenzofuran derivatives or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating inflammation, and further in the preparation of medicaments for treating inflammation caused by lipopolysaccharides.

[0048] Furthermore, the present invention also includes a pharmaceutical composition comprising a therapeutically effective dose of the above-mentioned hexabenzofuran derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and at least one pharmaceutically acceptable carrier.

[0049] Compared with existing technologies, this invention provides a series of novel hexabenzofuran derivatives and their synthetic methods. The synthetic methods provided by this invention are simple and easy to control, have a short cycle time, and achieve high yields, making them easier to industrialize. Furthermore, the applicant's experimental results show that some of the target compounds of this invention have a good inhibitory effect on the release of NO from lipopolysaccharide-induced mouse RAW 264.7 macrophages, and can be used to prepare drugs for treating inflammation. Detailed Implementation

[0050] To better explain the technical solution of the present invention, the present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited thereto.

[0051] The N-alkenyl α,β-unsaturated nitrone derivatives (i.e., compounds represented by formula (II)) involved in the following embodiments were synthesized according to the following synthetic route:

[0052]

[0053] Among them, R 1 Indicates unsubstituted or monosubstituted styrene group; R 2 Indicates unsubstituted or monosubstituted phenyl; R 3 R 4 These represent hydrogen atoms or unsubstituted or substituted carbon atoms, respectively. 1~4 Alkyl, or R 3 +R 4 It is cyclohexane.

[0054] The specific synthesis method is as follows: Cu(OAc)2 (0.3 mmol, 54 mg), α,β-unsaturated oxime substrate S1 (0.3 mmol) and alkenylboronic acid S2 (0.9 mmol) were placed in a reaction tube, 3 mL of 1,2-dichloroethane was added, and then pyridine (3 mmol, 0.24 mL) was added; the mixture was stirred at 25 °C for 12-24 h, water (10 mL) was added to the resulting reaction mixture, and the mixture was extracted with dichloromethane (2 × 10 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1~1:1, volume ratio) to obtain product 1 (i.e., the N-alkenyl α,β-unsaturated nitrone shown in formula (II)).

[0055] The α-haloamide reagents (i.e., the compounds shown in formula (III)) involved in the following examples were synthesized according to the following synthetic route:

[0056]

[0057] Among them, R 5 Represents a hydrogen atom or C 1~4 Alkyl group; R 6 C represents 1~4 Alkyl group; R represents a hydrogen atom, methyl group, or halogen atom; X represents a bromine atom. Specific α-haloamide reagents are as follows:

[0058] 2a: R 5 =Me,R 6 =Me, X=Br, R=H;

[0059] 2b: R 5 =Me,R 6 =Me, X=Br, R=H;

[0060] 2c: R 5 =Me,R 6 =Me, X=Br, R=H;

[0061] 2d:R 5 =Me,R 6 =Me, X=Br, R=H;

[0062] 2e:R 5 =Me,R 6 =Me, X=Br, R=H;

[0063] 2f:R 5 =Me,R 6 =Me, X=Br, R=H;

[0064] 2g:R 5 =Me,R 6 =Me, X=Br, R=H;

[0065] 2h: R 5 =H,R 6 =Me, X=Br, R=H.

[0066] The specific synthesis method is as follows: phenoxyhydroxylamine hydrochloride S4 (2.0 g, 12.5 mmol, 1.0 eq), dichloromethane (50 mL), and triethylamine (1.75 mL, 12.5 mmol, 1.0 eq) were added to a 100 mL round-bottom flask, and the reaction mixture was then cooled to 0 °C in an ice-water bath. Next, α-haloacyl bromide S3 (12.5 mmol, 1.0 eq) was added dropwise to the reaction mixture, and stirring was continued at 0 °C for 4 hours. The mixture was then transferred to room temperature and stirred for 5 min; the reaction was then quenched with water. The resulting mixture was extracted three times with dichloromethane, then once with saturated sodium chloride, filtered, and concentrated under vacuum. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1 to 1:1, v / v) to give product 2 (i.e., the α-haloamide reagent shown in formula (III)).

[0067] Example 1

[0068] The hexabenzofuran derivatives of this invention were synthesized according to the following synthetic route.

[0069]

[0070] 3a: R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me, R=H;

[0071] 3b: R 1 =4-OMe-CH=CH-Ph, R 2 =4-OMe-Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me, R=H;

[0072] 3c:R 1 =4-CF3-CH=CH-Ph, R 2 =4-CF3-Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me, R=H;

[0073] 3d:R 1 =-CH=CH-Ph,R 2 =-Ph,R 3 +R 4 =cyclohexyl, R5 =Me,R 6 =Me, R=H;

[0074] 3e:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =H,R 4 =(CH2)3CO2Me, R 5 =Me,R 6 =Me, R=H;

[0075] 3f:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me, R=4-Me;

[0076] 3g:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me, R=4-F;

[0077] 3h:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me, R=H.

[0078] At room temperature, N-alkenyl α,β-unsaturated nitroketone substrate 1 (0.2 mmol), α-haloamide 2 (0.4 mmol), copper trifluoromethanesulfonate (0.04 mmol), and potassium carbonate (0.4 mmol) were placed in a reaction tube, and acetonitrile (2 mL) was added. The mixture was heated to 80 °C and stirred for 24–48 h (TLC monitoring until complete). The solvent was removed from the resulting reactants under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1–6:1, volume ratio) to obtain target product 3 (i.e., the hexabenzofuran derivative of formula (I)). Different target products and their characterization are as follows:

[0079] 3a: Solid, 51 mg, 53% yield. Mp: 142–143 ℃; 1H NMR (400 MHz, CDCl3): δ7.40−7.36 (m, 2H), 7.34−7.30 (m, 1H), 7.25−7.20 (m, 4H), 7.16−7.15 (m, 4H),7.02 (d, J = 8.0 Hz, 1H), 6.67−6.63 (m, 1H), 6.55 (d, J = 16.4 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H), 6.18 (d, J = 7.2 Hz, 1H), 5.46 (s, 1H), 3.46 (d, J =10.4 Hz, 1H), 2.65−2.59 (m, 1H), 2.18−2.13 (m, 1H), 1.67 (s, 3H), 1.54 (s,3H), 1.53 (s, 3H), 0.76 (d, J = 6.0 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ172.9, 157.0, 140.6, 136.4, 135.5, 128.9, 128.8, 128.7, 128.4, 127.4, 127.3,126.4, 125.8, 125.0, 120.6, 110.0, 96.6, 79.9, 78.0, 55.7, 49.7, 40.4, 24.1,23.7, 19.5, 13.6; IR (thin film) 3463, 2934, 1638, 1266, 965, 694 cm HRMS(ESI) m / z calcd for C 31 H 33 N2O3 (M+H) + 481.2486, found 481.2474. Its structure is as follows:

[0080]

[0081] 3b: Solid, 43 mg, 40% yield. Mp: 165–166 °C; 1H NMR (400 MHz, CDCl3): δ7.20−7.18 (m, 2H), 7.16−7.12 (m, 1H), 7.07−7.05 (m, 2H), 7.01−6.99 (m, 1H),6.92−6.90 (m, 2H), 6.77−6.75 (m, 2H), 6.67−6.63 (m, 1H), 6.41 (d, J = 16.0Hz, 1H), 6.34 (d, J = 16.0 Hz, 1H), 6.22 (d, J = 7.2 Hz, 1H), 5.46 (s, 1H), 3.84 (s, 3H), 3.75 (s, 3H), 3.41 (d, J = 10.8 Hz, 1H), 2.58−2.52 (m, 1H), 2.13−2.04 (m, 1H), 1.65 (s, 3H), 1.53 (s, 6H), 0.75 (d, J = 6.4 Hz, 3H); 13 CNMR (125 MHz, CDCl3): δ 172.8, 159.1, 158.8, 157.0, 133.5, 132.5, 129.8,129.2, 129.0, 128.7, 127.6, 125.3, 125.1, 120.5, 114.2, 113.8, 110.0, 96.8,79.9, 78.0, 56.0, 55.3, 48.8, 40.5, 24.1, 23.7, 19.5, 13.6; IR (thin film)3419, 2968, 1684, 1252, 980, 695cm HRMS (ESI) m / z calcd for C 33 H 37 N2O5 (M+H) + 541.2697, found 541.2690. Its structure is as follows:

[0082]

[0083] 3c: Solid, 62 mg, 50% yield. Mp: 150–151 °C; 1H NMR (400 MHz, CDCl3): δ7.68−7.66 (m, 2H), 7.48−7.46 (m, 2H), 7.35−7.30 (m, 4H), 7.21−7.17 (m, 1H),7.05 (d, J = 8.0 Hz, 1H), 6.72−6.70 (m, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H), 6.17 (d, J = 7.2 Hz, 1H), 5.46 (s, 1H), 3.40 (d, J =10.8 Hz, 1H), 2.77−2.71 (m, 1H), 2.23−2.17 (m, 1H), 1.69 (s, 3H), 1.55 (s,3H), 1.54 (s, 3H), 0.76 (d, J = 6.8 Hz, 3H); 13 C NMR (125 MHz, CDCl3): δ173.1, 156.9, 144.7, 139.8, 137.5, 130.1 (q, J = 251.3 Hz), 129.8, 129.7,129.5, 129.4, 129.3, 126.6, 126.0, 125.9, 125.5 (q, J = 10.9 Hz), 124.8,124.5, 121.0, 113.4, 110.3, 96.2, 80.1, 77.9, 55.1, 49.8, 40.2, 24.1, 23.8,19.4, 13.6; IR (thin film) 3462, 2971, 1691, 1242, 957, 678 cm HRMS (ESI) m / z calcd for C 33 H 31 F6N2O3 (M+H) + 617.2233, found 617.2225. Its structure is as follows:

[0084]

[0085] 3d: Solid, 51 mg, 50% yield. Mp: 167–168 °C; 1H NMR (400 MHz, CDCl3): δ7.39−7.30 (m, 4H), 7.26−7.19 (m, 4H), 7.16−7.12 (m, 3H), 7.03−7.01 (m, 1H),6.62−6.58 (m, 1H), 6.54 (d, J = 16.0 Hz, 1H), 6.42 (d, J = 16.0 Hz, 1H), 5.99(d, J = 7.6 Hz, 1H), 5.57 (s, 1H), 3.33 (d, J = 10.8 Hz, 1H), 3.06−3.00 (m,1H), 2.40−2.36 (m, 1H), 2.20−2.10 (m, 2H), 1.78−1.74 (m, 2H), 1.68−1.60 (m,2H), 1.52 (s, 3H), 1.51 (s, 3H), 1.29−1.26 (m, 2H); 13 C NMR (125 MHz, CDCl3): δ 173.0, 157.1, 139.7, 136.3, 135.7, 129.0, 128.9, 128.7, 128.4, 127.5,127.4, 126.6, 126.4, 125.3, 120.4, 110.1, 96.7, 79.7, 55.6, 44.9, 40.3, 31.5,24.1, 23.8, 23.7, 22.1, 18.4; IR (thin film) 3714, 2909, 1649, 1270, 965, 694cm HRMS (ESI) m / z calcd for C 33 H 35 N2O3 (M+H) + 507.2642, found 507.2635. Its structure is as follows:

[0086]

[0087] 3e: Solid, 47 mg, 42% yield. Mp: 189−190 ℃; 1H NMR (400 MHz, CDCl3): δ7.39−7.36 (m, 2H), 7.34−7.30 (m, 1H), 7.26−7.21 (m, 4H), 7.19−7.13 (m, 4H),7.00 (d, J = 16.0 Hz, 1H), 6.69−6.65 (m, 1H), 6.49 (d, J = 16.0 Hz, 1H), 6.42(d, J = 16.0 Hz, 1H), 6.05 (d, J = 5.2 Hz, 1H), 4.83 (dd, J = 5.2 Hz, J =10.0 Hz, 1H), 3.60 (s, 3H), 3.45 (d, J = 9.2 Hz, 1H), 2.77−2.72 (m, 1H), 2.20−2.16 (m, 1H), 2.13−2.08 (m, 2H), 1.66 (s, 1H), 1.59 (s, 3H), 1.51 (s, 3H),1.41−1.28 (m, 2H); 13 C NMR (125 MHz, CDCl3): δ 174.0, 173.1, 157.3, 140.4,136.4, 133.5, 128.9, 128.8, 128.3, 127.4 127.3, 126.5, 126.0, 125.1, 120.6,109.8, 97.2, 81.5, 74.6, 56.2, 51.7, 48.8, 40.1, 33.4, 27.6, 24.3, 24.1,19.8, ; IR (thin film) 3300, 2982, 1676, 1178, 954, 694cm HRMS (ESI) m / zcalcd for C 34 H 37 N2O5 (M+H) + 553.2697, found 553.2682. Its structure is as follows:

[0088]

[0089] 3f: Solid, 55 mg, 56% yield. Mp: 134−135 ℃; 1H NMR (400 MHz, CDCl3): δ7.40−7.36 (m, 2H), 7.34−7.30 (m, 1H), 7.27−7.20 (m, 4H), 7.16−7.13 (m, 3H), 6.94−6.88 (m, 2H), 6.55 (d, J = 16.0 Hz, 1H), 6.40 (d, J = 16.4 Hz, 1H), 5.96(s, 1H), 5.46 (s, 1H), 3.41 (d, J = 10.4 Hz, 1H), 2.64−2.58 (m, 1H), 2.17−2.12 (m, 1H), 2.06 (s, 3H), 1.66 (s, 3H), 1.53 (s, 3H), 1.52 (s, 3H), 0.76(d, J = 6.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 172.8, 154.8, 140.7, 136.4,135.6, 129.8, 129.1, 128.9, 128.7, 128.6, 128.3, 127.4, 127.3, 126.4, 125.6,125.5, 109.5, 96.6, 79.9, 78.0, 55.7, 49.7, 40.4, 24.1, 23.7, 20.7, 19.4,13.6; IR (thin film) 3456, 2972, 1689, 1242, 969, 694cm HRMS (ESI) m / zcalcd for C 32 H 35 N2O3 (M+H) + 495.2642, found 495.2663. Its structure is as follows:

[0090]

[0091] 3g: Solid, 65 mg, 65% yield. MP: 190–191 °C; 1H NMR (400 MHz, CDCl3): δ7.41−7.37 (m, 2H), 7.35−7.31 (m, 1H), 7.27−7.21 (m, 4H), 7.18−7.14 (m, 3H),6.94−6.91 (m, 1H), 6.86−6.81 (m, 1H), 6.53 (d, J = 16.4 Hz, 1H), 6.40 (d, J =16.4 Hz, 1H), 5.89 (dd, J = 2.0 Hz, J = 8.0 Hz, 1H), 5.47 (s, 1H), 3.42 (d, J= 10.8 Hz, 1H), 2.64−2.58 (m, 1H), 2.19−2.13 (m, 1H), 1.68 (s, 3H), 1.53 (s,3H), 1.52 (s, 3H), 0.77 (d, J = 6.8 Hz, 3H); 13 C NMR (125 MHz, CDCl3): δ172.9, 158.3 (d, J = 237.0 Hz), 153.0, 140.0, 136.2, 135.1, 130.1 (d, J =102.8 Hz), 129.0, 128.8, 128.4, 127.7, 127.5, 126.4, 126.1, 115.2 (d, J =24.1 Hz), 112.5 (d, J = 35.0 Hz), 110.3 (d, J = 8.0 Hz), 97.1, 79.9, 78.1,56.0, 53.4, 49.4, 40.3, 24.1, 23.6, 19.5, 13.5; IR (thin film) 3485, 2989,1659, 1241, 955, 694 cm HRMS (ESI) m / z calcd for C 31 H 32 FN2O3 (M+H) + 499.2391, found 499.2378. Its structure is as follows:

[0092]

[0093] 3h: Solid, 54 mg, 58% yield. Mp: 136−137 ℃; 1H NMR (400 MHz, CDCl3): δ7.40−7.37 (m, 2H), 7.33−7.30 (m, 1H), 7.28−7.21 (m, 4H), 7.17−7.14 (m, 4H),7.00 (d, J = 7.6 Hz, 1H), 6.69−6.65 (m, 1H), 6.54 (d, J = 16.0 Hz, 1H), 6.42(d, J = 16.0 Hz, 1H), 6.24 (d, J = 7.2 Hz, 1H), 5.33 (s, 1H), 4.50 (q, J =6.8 Hz, 1H), 3.49 (d, J = 10.0 Hz, 1H), 2.25−2.17 (m, 1H), 1.64 (s, 3H), 1.56(d, J = 7.2 Hz, 3H), 0.77 (d, J = 6.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ170.0, 156.9, 140.8, 136.4, 135.2, 128.9, 128.8, 128.7, 128.4, 127.4, 126.5,126.1, 125.0, 120.7, 110.0, 96.5, 77.5, 76.1, 55.4, 50.2, 40.3, 19.3, 17.1,13.7; IR (thin film) 3496, 2965, 1663, 1263, 978, 698 cm HRMS (ESI) m / zcalcd for C 30 H 31 N2O3 (M+H) + 467.2329, found 467.2321. Its structure is as follows:

[0094]

[0095] Example 2: Preparation of compounds 3a-3h

[0096] Compound 3a: Example 1 was repeated, except that ethyl acetate was used instead of acetonitrile, copper bromide instead of copper trifluoromethanesulfonate, and pyridine instead of potassium carbonate. The reaction was carried out at 60°C until complete. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 20:1~10:1, volume ratio) to give a pale yellow solid in 63% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3a.

[0097] Compound 3b: Example 1 was repeated, except that acetone was used instead of acetonitrile and ytterbium trifluoromethanesulfonate was used instead of copper trifluoromethanesulfonate. A white solid was obtained in 60% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3b.

[0098] Compound 3c: Example 1 was repeated, except that tetrahydrofuran was used instead of acetonitrile and triethylamine was used instead of potassium carbonate. A white solid was obtained in 50% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3c.

[0099] Compound 3d: Example 1 was repeated, except that tetrahydrofuran was used instead of acetonitrile and cesium carbonate was used instead of potassium carbonate. A white solid was obtained in 50% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3d.

[0100] Compound 3e: Example 1 was repeated, except that tetrahydrofuran was used instead of acetonitrile and triethylamine was used instead of potassium carbonate. The reaction was carried out at 35°C until complete. A white solid was obtained in 42% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3e.

[0101] Compound 3f: Example 1 was repeated, except that tetrahydrofuran was used instead of acetonitrile and triethylamine was used instead of potassium carbonate. A white solid was obtained in 66% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3f.

[0102] Compound 3g: Example 1 was repeated, except that tetrahydrofuran was used instead of acetonitrile. A white solid was obtained in 65% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3g.

[0103] Compound 3h: Example 1 was repeated, except that triethylamine was used instead of potassium carbonate. A white solid was obtained in 58% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3h.

[0104] Experimental Example 1: In vitro anti-inflammatory activity experiment of the hexabenzofuran derivative described in this invention

[0105] I. Determination of the viability of the compound and the control drug indomethacin at a concentration of 100 μM on RAW264.7 cells (mouse mononuclear macrophage leukemia cells) using the MTT assay.

[0106] 1. Digestion and seeding of test cells: RAW 264.7 test cells were cultured to the logarithmic growth phase, digested with 0.25% trypsin, and culture medium containing 10% fetal bovine serum was added. The cells were then mixed with sterile plastic pipettes to form a single-cell suspension and seeded into 96-well plates. 180 μL of the suspension was added to each well, and 200 μL of PBS buffer was added around the perimeter of the 96-well plate to reduce culture medium evaporation.

[0107] 2. Adding drugs to the cell lines: When the cells in the wells have grown to cover about 70% of the total well area, add 20 μL of drug to each well to dilute the drug to 100 μM. Gently tap the well with your hand. Set up 5 replicates (parallel experiments). Set up blank wells (without drug) and zeroing wells (culture medium containing 10% fetal bovine serum) in each 96-well plate. Continue to place the plate in an incubator and observe the cell survival under a microscope.

[0108] 3. Plate preparation: After adding the drug and continuing incubation for 48 h, add 10 μL of MTT to each well for staining, gently tap the plate, and continue incubation for 4–6 h. Then discard the culture medium in the wells, add 100 μL of DMSO to each well, and shake on a micro-shaker for 10 min to fully dissolve the generated formazan. Transfer the plate to an ELISA reader to detect the absorbance of each well, and then process the data using PASW software. The experimental results are shown in Table 1.

[0109] Table 1. Effects of compounds on RAW264.7 cell viability as determined by MTT assay

[0110]

[0111] This experiment primarily investigated the bioactivity of compounds 3a and 3e, evaluating their anti-neuritis activity using LPS-stimulated RAW 264.7 cells as an inflammation model. First, the cytotoxicity of compounds 3a and 3e on RAW 264.7 cells was evaluated using the MTT assay; their effects on RAW 264.7 cells were comparable to those of the anti-inflammatory drug indomethacin. Therefore, the Griess assay was further used to detect their inhibitory effect on NO release from lipopolysaccharide-stimulated RAW 264.7 cells.

[0112] II. Griess method determination of the inhibitory effect of some low-toxicity compounds on the release of NO induced by lipopolysaccharides (LPS) from mouse macrophages RAW 264.7.

[0113] Compounds 3a and 3e showed low toxicity to mouse macrophage RAW 264.7 cells, so the applicant further tested the effect of these compounds on inhibiting LPS-induced NO release from mouse macrophage RAW 264.7 cells.

[0114] Experimental methods and results:

[0115] 1. Cell seeding and pretreatment: RAW 264.7 cells (mouse mononuclear macrophage leukemia cells) that had reached the logarithmic growth phase were seeded into 24-well culture plates at 400 μL per well. There were control group, LPS stress model group (1 μg / mL LPS), and experimental groups with different drug concentrations (6.25, 12.5, 25, 50 μg / mL). The control group and LPS stress model group were supplemented with medium with a final concentration of 0.1% DMSO. The experimental groups were pretreated with different concentrations of drug solution for 1 h and then treated with 1 μg / mL LPS for 24 h. The cell supernatant was collected.

[0116] 2. Griess method for determining NO release: Diluted standard reagents of varying concentrations and cell culture supernatant were added to 0.05 mL of each well in a 96-well plate. The procedure was performed according to the kit instructions. Specific steps are as follows:

[0117] (1) Add 0.05 mL of Griess Regent 1 reagent at room temperature to each well and let stand for 10 min.

[0118] (2) Add 0.05 mL of Griess Regent 2 reagent at room temperature to each well and let stand for 10 min.

[0119] (3) Measure the absorbance at 540 nm to obtain a standard curve and determine the NO concentration in the sample to be tested.

[0120] The ability of compounds 3a and 3e to inhibit LPS-induced NO release from mouse macrophages at a concentration of 6.25 μM was detected using the Griess method. The results are shown in Table 2.

[0121] Table 2. Effects of different compounds on NO release in RAW264.7 cells at the same concentration (6.25 μM).

[0122]

[0123] The experimental results in Table 2 show that compound 3e has low toxicity to RAW 264.7 cells and significantly inhibits the release of NO from RAW 264.7 cells stimulated by LPS, further indicating that the hexabenzofuran compounds and their derivatives described in this invention have potential anti-inflammatory activity.

Claims

1. A hexabenzofuran derivative or a pharmaceutically acceptable salt thereof with the structure shown in formula (I) below: (I)； The hexabenzofuran derivatives with the structure shown in formula (I) are specifically any one of the following 3a to 3h: 3a:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me,R=H; 3b:R 1 = ,R 2 =4-OMe-Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me,R=H; 3c:R 1 = ,R 2 =4-CF3-Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me,R=H; 3d:R 1 =-CH=CH-Ph,R 2 =-Ph,R 3 +R 4 =cyclohexyl, R 5 =Me,R 6 =Me, R=H; 3e:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =H,R 4 =(CH2)3CO2Me,R 5 =Me,R 6 =Me,R=H; 3f:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me,R=4-Me; 3g:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =Me,R 6 =Me,R=4-F; 3h:R 1 =-CH=CH-Ph,R 2 =Ph,R 3 =Me,R 4 =Me,R 5 =H,R 6 =Me,R=H。 2. The method for synthesizing the hexabenzofuran derivatives according to claim 1, characterized in that, Take the compound shown in formula (II) and the compound shown in formula (III) and place them in an organic solvent, add an alkaline substance and a catalyst, and react under heating or no heating conditions to obtain the crude product of the target compound; (II)、 (III): In equations (II) and (III), R 1 R 2 R 3 R 4 R 5 R 6 The choice of R corresponds to claim 1, where X represents a bromine atom or a chlorine atom.

3. The synthesis method according to claim 2, characterized in that, The reaction is carried out under the protection of an inert gas.

4. The synthesis method according to claim 2 or 3, characterized in that, The reaction was carried out at temperatures below 100°C.

5. The synthesis method according to claim 2 or 3, characterized in that, The organic solvent is selected from one or more of benzene, toluene, cyclohexane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, dichloromethane, acetone, chloroform, n-hexane, and dioxane; The alkaline substance is selected from one or more of the following: tripotassium phosphate, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, pyridine, triethylamine, and N,N-diisopropylethylamine. The catalyst is selected from one or more of copper salts, ytterbium salts, and scandium salts.

6. The synthesis method according to claim 2 or 3, characterized in that, It also includes a step of purifying the crude target compound obtained.

7. The use of the hexabenzofuran derivative of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating inflammation.

8. A pharmaceutical composition comprising a therapeutically effective dose of the hexabenzofuran derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.

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