1-oxo-2-azacyclononane derivatives, process for their synthesis and use thereof

Abstract

The application discloses a series of 1-oxygen-2-azacyclononane derivatives, a synthesis method and application thereof, and belongs to the technical field of medicines. Test results of the applicant show that the target compounds have good inhibiting 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 1-oxo-2-azacyclononane derivatives, their synthesis methods, and applications, belonging to the field of pharmaceutical technology. Background Technology

[0002] The azircyclic nonane skeleton is a key core skeleton in natural products, materials, and drug molecules, and is an important physiologically active unit with significant applications in anti-inflammatory and antitumor activities. However, the unfavorable entropy and enthalpy of the azircyclic nine-membered ring skeleton, along with the sharp increase in ring strain with increasing ring size, has made its construction a persistent challenge in organic synthesis, significantly limiting the applications of these compounds. Current strategies for synthesizing this nine-membered heterocyclic skeleton include palladium-catalyzed tandem reactions (R. Shintani, K. Ikehata, T. Hayashi, J. Org. Chem. 2011, 76, 4776-4780) and multi-component tandem reactions (AF De la Torre, D G Rivera, O. Concepción, R. Echemendia, AG Correa, MW Paixao, J. Org. Chem. 2016, 81, 803-809). However, these methods suffer from poor functional group compatibility and cumbersome raw material preparation steps. Summary of the Invention

[0003] The technical problem to be solved by the present invention is to provide a series of 1-oxo-2-azacyclononane derivatives with novel structures and 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 1-oxo-2-azacyclononane derivatives described in this invention are compounds having the structure shown in formula (I) below, or pharmaceutically acceptable salts thereof:

[0006]

[0007] in:

[0008] R 1 Represents hydrogen atom, halogen atom, C 1～4 alkyl, C 1～4 alkoxy or C 1～4 The alkyl group is a perfluoroalkyl group, or an unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted phenyl group, or an unsubstituted furanyl group, or an unsubstituted thiophenyl group, or an unsubstituted naphthyl group; wherein the substituent is C 1～4 alkoxy, C 1～4 perfluoroalkyl, C 1～4Alkyl, cyano, or halogen atoms;

[0009] R 2 Indicate C 1～4 alkyl, C 1～4 alkoxy or C 1～4 The alkyl group is a perfluoroalkyl group, or an unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted phenyl group, or an unsubstituted furanyl group, or an unsubstituted thiophenyl group, or an unsubstituted naphthyl group; wherein the substituent is C 1～4 alkoxy, C 1～4 perfluoroalkyl, C 1～4 Alkyl, cyano, or halogen atoms;

[0010] R 3 Represents hydrogen atom, halogen atom, C 1～8 alkyl, C 1～6 alkoxy or C 1～4 The alkyl group is a perfluoroalkyl group, or an unsubstituted, monosubstituted, or disubstituted phenyl group; wherein the substituent is C. 1～4 alkoxy, C 1～4 perfluoroalkyl, C 1～6 alkyl or halogen atoms;

[0011] R 4 Represents hydrogen atom, halogen atom, C 1～8 alkyl, C 1～6 alkoxy or C 1～4 The alkyl group is a perfluoroalkyl group, or an unsubstituted, monosubstituted, or disubstituted phenyl group; wherein the substituent is C. 1～4 alkoxy, C 1～4 perfluoroalkyl, C 1～6 alkyl or halogen atoms;

[0012] R 5 Represents hydrogen atom, halogen atom, C 1～8 alkyl, C 1～6 alkoxy or C 1～4 The alkyl group is a perfluoroalkyl group, or an unsubstituted, monosubstituted, or disubstituted phenyl group; wherein the substituent is C. 1～4 alkoxy, C 1～4 perfluoroalkyl, C 1～6 alkyl or halogen atoms;

[0013] X represents a nitrogen methyl group, an oxygen atom, or a sulfur atom.

[0014] In the general formula structure of the above-mentioned 1-oxo-2-azacyclononane derivatives, the preferred substituents are as follows:

[0015] R 1 Represents hydrogen atom, halogen atom, or C 1～4 Alkoxy;

[0016] R 2 Indicate C 1～4 Alkyl, or unsubstituted or monosubstituted alkenyl, or unsubstituted, monosubstituted or disubstituted phenyl, or unsubstituted furanyl;

[0017] R 3 It represents a hydrogen atom, or an unsubstituted, monosubstituted, or disubstituted phenyl group;

[0018] R 4 Represents a hydrogen atom or C 1～5 Alkyl groups, or unsubstituted, monosubstituted, or disubstituted phenyl groups;

[0019] R 5 Represents a hydrogen atom, or an unsubstituted or monosubstituted carbon atom. 1～5 Alkyl groups, or unsubstituted, monosubstituted, or disubstituted phenyl groups;

[0020] R 4 R 5 When cyclic, it indicates 3- to 7-membered rings or spirorings with or without heteroatoms;

[0021] X represents a nitrogen methyl group, an oxygen atom, or a sulfur atom.

[0022] Furthermore, in the general formula of the above-mentioned 1-oxo-2-azacyclononane derivatives, the substituents are more preferably as follows:

[0023] R 1 Represents a hydrogen atom, 5-methoxy group, or 5-fluorine group;

[0024] R 2 This indicates unsubstituted phenyl, 4-trifluoromethylphenyl, 3-methoxyphenyl, styryl or 2-furanyl;

[0025] R 3 Indicates a hydrogen atom or a phenyl group;

[0026] R 4 Indicates a hydrogen atom, phenyl, methyl, or ethyl;

[0027] R 5 This indicates a hydrogen atom, phenyl, methyl, n-butyl, tert-butyl, or 3-chloropropyl.

[0028] R 4 R 5 When cyclic, it represents cycloheptyl, tetrahydropyranyl, or 1,4-dioxaspiro[4,5]decyl;

[0029] X represents a nitrogen methyl group or an oxygen atom.

[0030] Furthermore, the 1-oxo-2-azacyclononane derivative described in this invention can specifically be any one of the following compounds 3a to 3r:

[0031] 3a:R 1 =H,R 2 =Ph,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0032] 3b:R 1 =H,R 2 =Ph,R 3 =H,R 4 =Ph,R 5 =n-Bu,X=O;

[0033] 3c:R 1 =H,R 2 =Ph,R 3 =H,R 4 =H,R 5 =Ph,X=O;

[0034] 3d:R 1 =H,R 2 =Ph,R 3 =H,R 4 =H,R 5 =t-Bu,X=O;

[0035] 3e:R 1 =H,R 2 =Ph,R 3 =H,R 4 =H,R 5 =-(CH2)3Cl, X=O;

[0036] 3f:R 1 =H,R 2 =Ph,R 3 =H,R 4 =-(CH2)3-,R 5 =-CH2-,X=O;

[0037] 3g:R 1 =H,R 2 =Ph,R 3 =H,R 4 =-(CH2)4-,R 5 =-CH2-,X=O;

[0038] 3h:R 1 =H,R 2 =Ph,R 3=H,R 4 =-(CH2)2O-,R 5 =-CH2-,X=O;

[0039] 3i:R 1 =H,R 2 =Ph,R 3 =H,R 4 =2-(CH2)2-(1,3-dioxocyclopentane)-,R 5 =-CH2-,X=O;

[0040] 3j:R 1 =H,R 2 =4-CF3Ph,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0041] 3k:R 1 =H,R 2 =3-OMePh,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0042] 3l:R 1 =H,R 2 =2-Furanyl,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0043] 3m:R 1 =H,R 2 =styryl,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0044] 3n:R 1 =5-OMe,R 2 =Ph,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0045] 3o:R 1 =5-F,R 2 =Ph,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0046] 3p:R1 =H,R 2 =Ph,R 3 =H,R 4 =Me,R 5 =Me,X=N-Me;

[0047] 3q:R 1 =H,R 2 =Ph,R 3 =Ph,R 4 =Me,R 5 =Me,X=O;

[0048] 3r:R 1 =H,R 2 =Ph,R 3 =Ph,R 4 =Et,R 5 =H,X=O.

[0049] The method for synthesizing the 1-oxo-2-azacyclononane derivative 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, a photosensitizer and a catalyst, and reacting under the irradiation of a blue light source to obtain the crude product of the target compound;

[0050]

[0051] R 1 Represents hydrogen atom, halogen atom, C 1～4 alkyl, C 1～4 alkoxy or C 1～4 The alkyl group is a perfluoroalkyl group, or an unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted phenyl group, or an unsubstituted furanyl group, or an unsubstituted thiophenyl group, or an unsubstituted naphthyl group; wherein the substituent is C 1～4 alkoxy, C 1～4 perfluoroalkyl, C 1～4 Alkyl, cyano, or halogen atoms;

[0052] R 2 Indicate C 1～4 alkyl, C 1～4 alkoxy or C 1～4 The alkyl group is a perfluoroalkyl group, or an unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted phenyl group, or an unsubstituted furanyl group, or an unsubstituted thiophenyl group, or an unsubstituted naphthyl group; wherein the substituent is C 1～4 alkoxy, C 1～4 perfluoroalkyl, C 1～4 Alkyl, cyano, or halogen atoms;

[0053] R 3 Represents hydrogen atom, halogen atom, C 1～8 alkyl, C 1～6 alkoxy or C 1～4 The alkyl group is a perfluoroalkyl group, or an unsubstituted, monosubstituted, or disubstituted phenyl group; wherein the substituent is C. 1～4 alkoxy, C 1～4 perfluoroalkyl, C 1～6 alkyl or halogen atoms;

[0054] R 4 Represents hydrogen atom, halogen atom, C 1～8 alkyl, C 1～6 alkoxy or C 1～4 The alkyl group is a perfluoroalkyl group, or an unsubstituted, monosubstituted, or disubstituted phenyl group; wherein the substituent is C. 1～4 alkoxy, C 1～4 perfluoroalkyl, C 1～6 alkyl or halogen atoms;

[0055] R 5 Represents hydrogen atom, halogen atom, C 1～8 alkyl, C 1～6 alkoxy or C 1～4 The alkyl group is a perfluoroalkyl group, or an unsubstituted, monosubstituted, or disubstituted phenyl group; wherein the substituent is C. 1～4 alkoxy, C 1～4 perfluoroalkyl, C 1～6 alkyl or halogen atoms;

[0056] X represents a nitrogen methyl group, an oxygen atom, or a sulfur atom.

[0057] In the above synthesis method, the light source emitting blue light is preferably a blue LED lamp. There are no special requirements for the power of the blue LED lamp, but it is preferably 5 to 30W.

[0058] In the above synthesis method, the reaction is usually carried out under air conditions, with or without heating, preferably below 100°C, and more preferably at room temperature to 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 room temperature to 80°C, a reaction time of 1 to 4 days is suitable.

[0059] In the above synthesis method, the organic solvent is preferably selected from one or more combinations of 1,2-dichloroethane, benzene, toluene, cyclohexane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, diethyl ether, dichloromethane, acetone, chloroform, n-hexane, and dioxane. The amount of organic solvent used is preferably sufficient to dissolve the reactants; typically, based on 1 mmol of the compound represented by formula (II), all reactants are usually dissolved in 1–10 mL of organic solvent.

[0060] In the above synthesis method, the basic substance can be a conventional choice from existing technologies, preferably selected from one or more combinations of pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, triethylamine, and triethylenediamine. The amount of the basic substance used is usually 1 to 3 times the amount of the compound shown in formula (II).

[0061] In the above synthesis method, the photosensitizer is preferably selected from one or more of the following: ruthenium tripyridine chloride hexahydrate (Ru(bpy)3Cl2), tris(2-phenylpyridine)iridium (Ir(ppy)3), methylene blue, Bengal rose red, and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2”-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) (Ir[dF(CF3)ppy]2(dtbbpy)PF6); the amount used is usually 0.02 to 0.1 times the amount of the compound shown in formula (II).

[0062] In the above synthesis method, the catalyst can specifically 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 0.5 times the amount of the compound shown in formula (II).

[0063] In the synthetic method described in this invention, the compound represented by formula (II) is an N-alkenyl-α,β-unsaturated ketoxime derivative, which can be synthesized with reference to existing literature (J. Zhao, B. Huang, B. Zhu, X. Ma, DL Mo, Adv. Synth. Catal. 2021, 363, 4575-4581.) or by designing a synthetic route of your choice, which will not be detailed here. The compound represented by formula (III) is an alkenylboronic acid, which can be directly purchased from the market (such as 2-butenylboronic acid, cyclohexenylboronic acid, cyclopentenylboronic acid, styrylboronic acid, etc.), or can be synthesized with reference to existing literature (ASPatil, D. Mo, H. Wang, D.S. Mueller, L.L. Anderson. Angew. Chem. Int. Ed. 2012, 51, 7799.).

[0064] In the synthesis method described in this invention, the proportions of each raw material are stoichiometric. In actual operation, the molar ratio of the compound shown in formula (II) to the compound shown in formula (III) is usually 1:1 to 5.

[0065] 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 50:1 to 5:1, or a mixed solvent of n-hexane and ethyl acetate in a volume ratio of 50:1 to 5:1.

[0066] The applicant discovered through experiments that the 1-oxo-2-azacyclononane derivative of the present invention has good anti-inflammatory activity. Based on this, the present invention also provides the use of the above-mentioned 1-oxo-2-azacyclononane derivative or its pharmaceutically acceptable salt in the preparation of a medicament for treating inflammation, and further, its use in the preparation of a medicament for treating inflammation caused by lipopolysaccharide.

[0067] Furthermore, the present invention also includes a pharmaceutical composition comprising a therapeutically effective dose of the above-described 1-oxo-2-azacyclononane derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and at least one pharmaceutically acceptable carrier.

[0068] Compared with existing technologies, this invention provides a series of novel 1-oxo-2-azacyclononane derivatives and their synthetic methods. 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 in lipopolysaccharide-induced mouse RAW 264.7 macrophages, and can be used to prepare drugs for treating inflammation. Detailed Implementation

[0069] 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.

[0070] The N-alkenyl-α,β-unsaturated ketoxime derivatives (i.e., compounds represented by formula (II)) involved in the following embodiments were synthesized according to the following synthetic route:

[0071]

[0072] The specific synthesis method is as follows:

[0073] 1) In a 100 mL reaction flask, add o-hydroxyacetophenone S1 (10 mmol), potassium carbonate (20 mmol, 2.0 equiv.), and DMF (30 mL). Then, stir the reaction mixture at 60 °C for 0.5 h. After cooling to room temperature, add allyl bromide (15 mmol, 1.5 equiv.) to the mixture and stir the reaction mixture until o-hydroxyacetophenone S1 is completely consumed (monitored by TLC). At this point, extract the organic layer with diethyl ether and remove the solvent under reduced pressure to provide S2.

[0074] 2) Next, S2, benzaldehyde (2.0 equiv.), and potassium hydroxide (2.0 equiv.) were mixed with methanol (30 mL) in a 100 mL reaction flask with a Teflon cap and reacted for 10 h at room temperature. After removing the methanol under reduced pressure, the crude product was purified by rapid column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 20, v / v) to provide compound S3.

[0075] 3) S3, hydroxylamine hydrochloride (2.0 equiv.), pyridine (3.0 equiv.), and methanol (5 mL) were added to a 25 mL reaction flask at room temperature and reacted for 10 h. After purification by rapid column chromatography, product 1 (i.e., the N-alkenyl-α,β-unsaturated ketoxime derivative of formula (II)) was obtained.

[0076] The alkenylboronic acid (i.e., the compound shown in formula (III)) involved in the following embodiments was synthesized according to the following synthetic route:

[0077]

[0078] The specific synthesis method is as follows: Pinaryl boronic acid ester (1 eq), NaIO4 (3 eq), and NH4OAc (3 eq) are added to a mixture of acetone and water (volume ratio of acetone to water is 1:1) to form a 0.04 mol / L solution of pinaryl boronic acid ester. The resulting solution is stirred vigorously for 2 days. The solution is then filtered, diluted with ethyl acetate or diethyl ether, and extracted with water. Afterward, the solution is washed with brine and the organic layer is dried with MgSO4. The solution is then concentrated under reduced pressure to obtain product 2 (i.e., the compound alkenylboronic acid shown in formula (III)).

[0079] Example 1

[0080] The 1-oxo-2-azacyclononane derivatives of this invention were synthesized according to the following synthetic route.

[0081]

[0082] 3a:R 1 =H,R 2 =Ph,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0083] 3b:R 1 =H,R 2 =Ph,R 3 =H,R 4 =Ph,R 5 =n-Bu,X=O;

[0084] 3c:R 1 =H,R 2 =Ph,R 3 =H,R 4 =H,R 5 =Ph,X=O;

[0085] 3d:R 1 =H,R 2 =Ph,R 3 =H,R 4 =H,R 5 =t-Bu,X=O;

[0086] 3e:R 1 =H,R 2 =Ph,R 3 =H,R 4 =H,R 5 =-(CH2)3Cl, X=O;

[0087] 3f:R 1 =H,R 2 =Ph,R 3 =H,R4 =-(CH2)3-,R 5 =-CH2-,X=O;

[0088] 3g:R 1 =H,R 2 =Ph,R 3 =H,R 4 =-(CH2)4-,R 5 =-CH2-,X=O;

[0089] 3h:R 1 =H,R 2 =Ph,R 3 =H,R 4 =-(CH2)2O-,R 5 =-CH2-,X=O;

[0090] 3i:R 1 =H,R 2 =Ph,R 3 =H,R 4 =2-(CH2)2-(1,3-dioxocyclopentane)-,R 5 =-CH2-,X=O;

[0091] 3j:R 1 =H,R 2 =4-CF3Ph,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0092] 3k:R 1 =H,R 2 =3-OMePh,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0093] 3l:R 1 =H,R 2 =2-Furanyl,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0094] 3m:R 1 =H,R 2 =styryl,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0095] 3n:R1 =5-OMe,R 2 =Ph,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0096] 3o:R 1 =5-F,R 2 =Ph,R 3 =H,R 4 =Me,R 5 =Me,X=O;

[0097] 3p:R 1 =H,R 2 =Ph,R 3 =H,R 4 =Me,R 5 =Me,X=N-Me;

[0098] 3q:R 1 =H,R 2 =Ph,R 3 =Ph,R 4 =Me,R 5 =Me,X=O;

[0099] 3r:R 1 =H,R 2 =Ph,R 3 =Ph,R 4 =Et,R 5 =H,X=O.

[0100] In a reaction flask, N-alkenyl-α,β-unsaturated ketoxime derivative 1 (0.3 mmol), alkenylboronic acid 2 (0.6 mmol, 2.0 equiv.), copper bromide (0.06 mmol, 0.2 equiv.), pyridine (0.9 mmol, 3.0 equiv.), tris(2,2'-bipyridine)ruthenium dichloride (0.015 mmol, 0.05 equiv.), and 1,2-dichloroethane (3 mL) were added to air. The reaction mixture was then stirred for 1–2 days at room temperature under a blue LED lamp (30 W), followed by heating to 80 °C and continuing the reaction under a blue LED lamp (30 W) for 1–4 days until N-alkenyl-α,β-unsaturated ketoxime derivative 1 was completely consumed (monitored by TLC). The solvent was removed from the resulting reaction mixture under reduced pressure, and the residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1, v / v) to obtain the target product 3. The different target products and their characterizations are as follows:

[0101] 3a: Pale yellow oil, 0.066g, 66% yield. 1H NMR (400MHz, CDCl3): δ7.71(d,J=8.0Hz,1H),7.39-7.36(m,4H),7.28-7.25(m,1H),7.14-7.11(m,1H),6.92-6.88(m,1H),6.85(d,J=8.0Hz,1H),6 .58(d,J=9.6Hz,1H),4.30-4.24(m,2H),4.18-4.06(m,2H),3.70(br,1H) ,3.01(d,J=10.4Hz,1H),2.78(s,1H),1.98(s,3H),1.46(d,J=6.0Hz,3H); 13 C NMR (100MHz, CDCl3): δ170.3,153.4,146.3,129.9,129.1,128.6,126.9,126.4,124.3 ,123.6,121.2,120.3,117.8,73.1,66.0,49.0,46.0,35.7,22.4,13.4; HRMS(ESI)m / z calcd for C 22 H 24 NO2(M+H) + 334.1802, found 334.1790. Its structural formula is as follows:

[0102]

[0103] 3b: Pale yellow oil, 0.072g, 55% yield. 1 H NMR (400MHz, CDCl3): δ7.74 (dd, J=1.6Hz, J=8.0Hz, 1H), 7.57-7.54 (m, 2H), 7.41-7.27 (m, 8H), 7.15-7.11 (m, 1H),6.93-6.89(m,1H),6.87(dd,J=1.2Hz,J=8.0Hz,1H),6.66(d,J=9.6Hz,1H),4.48(dd,J=4.4Hz,J=11.6Hz ,1H),4.29-4.23(m,2H),4.19(dd,J=2.4Hz,J=11.2Hz,1H),3.82(d,J=9.6Hz,1H),3.43(dd,J=5.2Hz,J=12.0 Hz,1H),3.06(d,J=10.8Hz,1H),2.58-2.48(m,1H),1.99-1.90(m,1H),1.32-1.15(m,4H),0.81-0.78(m,3H); 13C NMR (100MHz, CDCl3): δ170.8,153.5,146.2,137.1,129.6,129.2,128.6,128.5,127.1,126.9,126.7,1 25.8,123.6,121.2,120.4,117.9,73.9,65.8,54.1,47.9,36.3,30.6,29.6,22.9,14.0; HRMS(ESI)m / z calcd forC 30 H 32 NO2(M+H) + 438.2428, found 438.2436. Its structure is as follows:

[0104]

[0105] 3c: Pale yellow solid, 0.083g, 73% yield. Mp: 155-156℃; 1 H NMR (400MHz, CDCl3): δ7.69 (d, J = 8.0 Hz, 1H), 7.22-7.10 (m, 11H), 6.98 (d, J = 6. 4Hz,1H),6.94-6.90(m,1H),6.86(d,J=8.0Hz,1H),6.49(d,J=11.6Hz,1H),5.0 6-5.01(m,1H),4.59(d,J=4.0Hz,J=12.0Hz,1H),4.37-4.31(m,1H),4.23(d,J= 11.2Hz,1H),3.97(d,J=10.0Hz,1H),3.78-3.74(m,1H),3.55(d,J=11.6Hz,1H); 13 C NMR (100MHz, CDCl3): δ155.5,154.5,141.6,137.1,129.3,128.5,128.3,128.0,127.2,127 .0,126.8,126.0,123.5,121.4,121.1,117.9,73.3,66.6,57.8,50.5,37.4; HRMS(ESI)m / z calcd for C 26 H 24 NO2(M+H) + 382.1802, found 382.1795. Its structural formula is as follows:

[0106]

[0107] 3d: Pale yellow oily substance, 67% yield. 1H NMR (400MHz, CDCl3): δ7.57(d,J=7.6Hz,1H),7.35(d,J=7.6Hz,2H),7.30-7.27(m,2 H),7.23-7.19(m,1H),7.17-7.13(m,1H),6.96-6.92(m,1H),6.85(d,J=8.0Hz,1H), 6.56(d,J=16.0Hz,1H),6.22(d,J=15.6Hz,1H),4.36(dd,J=2.8Hz,J=11.2Hz,1H),4 .26(dd,J=3.2Hz,J=11.2Hz,1H),4.07-4.00(m,2H),2.23-2.20(m,3H),1.03(s,9H); 13 C NMR (100MHz, CDCl3): δ157.3,152.7,136.6,136.5,131.7,130.8,128.5,128.3,12 7.5,126.5,121.4,116.6,64.3,62.1,54.9,49.0,34.5,31.2,30.0; HRMS(ESI)m / z calcd for C 24 H 28 NO2(M+H) + 362.2115, found 362.2112. Its structure is as follows:

[0108]

[0109] 3e: Pale yellow oil, 0.024g, 21% yield. 1 H NMR (400MHz, CDCl3): δ7.59 (d, J = 8.0Hz, 1H), 7.40-7.36 (m, 4H), 7.29-7.26 (m, 1H), 7.12 -7.08(m,1H),6.91-6.82(m,3H),6.23(d,J=11.6Hz,1H),4.64-4.58(m,1H),4.46(dd,J= 4.0Hz, J=12.4Hz, 1H), 4.30-4.19 (m, 2H), 3.97 (dd, J=2.4Hz, J=11.2Hz, 1H), 3.50 (d, J=1 1.6Hz,1H),3.41-3.38(m,2H),2.71-2.69(m,1H),1.95-1.80(m,2H),1.70-1.64(m,2H); 13C NMR (100MHz, CDCl3): δ157.7,154.5,142.5,129.0,128.5,127.9,127.0,126.9,126.8,1 23.4,121.4,121.1,117.9,72.5,66.6,49.8,49.0,44.6,37.1,31.4,29.2; HRMS(ESI)m / z calcd for C 23 H 25 ClNO2(M+H) + 382.1568, found 382.1569. Its structure is as follows:

[0110]

[0111] 3f: Pale yellow oil, 0.050g, 46% yield. 1 H NMR (400MHz, CDCl3): δ7.74 (d, J = 7.6Hz, 1H), 7.34 (s, 4H), 7.25 (s, 1H), 7.16-7 .12(m,1H),6.96-6.92(m,1H),6.87(d,J=8.0Hz,1H),6.61(d,J=12.0Hz,1H),5. 51-5.46(m,1H),4.39-4.25(m,2H),4.17(d,J=11.2Hz,1H),3.96(d,J=9.6Hz,1 H),3.39-3.11(m,2H),2.19-2.11(m,2H),1.64-1.61(m,3H),1.37-1.20(m,3H); 13 C NMR (100MHz, CDCl3): δ168.1,154.4,141.7,129.7,128.6,128.4,128.0,126.3,123.3,121. 4,121.3,120.4,118.0,72.5,66.6,45.3,43.0,37.2,27.9,23.2,20.4,19.4; HRMS(ESI)m / z calcd for C 24 H 26 NO2(M+H) + 360.1958, found 360.1946. Its structure is as follows:

[0112]

[0113] 3g: Pale yellow oil, 0.054g, 48% yield. 1H NMR (400MHz, CDCl3): δ7.68 (d, J = 8.0Hz, 1H), 7.37-7.31 (m, 4H), 7.25-7.22 (m, 1H), 7.14-7.10 (m, 1H) ),6.93-6.89(m,1H),6.86(d,J=8.0Hz,1H),6.53(d,J=12.0Hz,1H),5.23(br,1H),4.34(d,J=8.4Hz,2 H),4.18(d,J=11.2Hz,1H),3.97(dd,J=1.5Hz,J=11.2Hz,1H),3.52(br,1H),3.41(d,J=7.2Hz,1H),2 .40-2.35(m,1H),2.10-2.05(m,1H),1.78(s,2H),1.68-1.61(m,1H),1.42-1.26(m,4H),1.09(s,1H); 13 C NMR (100MHz, CDCl3): δ172.0,154.2,129.2,128.5,126.4,123.3,122.3,121.2,117 .9,71.6,66.4,48.7,44.3,36.9,33.4,29.7,28.7,28.3,28.1; HRMS(ESI)m / zcalcd for C 25 H 28 NO2(M+H) + 374.2115, found 374.2116. Its structure is as follows:

[0114]

[0115] 3h: Pale yellow oil, 0.090g, 83% yield. 1H NMR (600MHz, CDCl3): δ7.76(m,1H),7.39-7.36(m,4H),7.27-7.25(m,1H),7.17-7.14(m,1H),6.97-6.94(m, 1H),6.88(d,J=7.8Hz,1H),6.66(d,J=12.0Hz,1H),5.42-5.39(m,1H),4.42(dd,J=4.8Hz,J=12.6Hz,1H),4.3 3-4.29(m,1H),4.20(d,J=12.0Hz,1H),3.98(dd,J=3.0Hz,J=11.4Hz,1H),3.88-3.85(m,1H),3.79-3.75(m, 1H),3.54-3.51(m,1H),3.47(d,J=6.0Hz,2H),3.38(d,J=12.0Hz,1H),2.52-2.47(m,1H),2.40-2.35(m,1H); 13 C NMR (100MHz, CDCl3): δ162.8,154.5,140.4,129.7,128.7,128.6,128.1,126.8,123.4,1 21.6,121.5,121.2,118.1,72.8,66.6,64.6,64.3,45.3,42.6,37.1,28.9; HRMS(ESI)m / z calcd for C 23 H 24 NO3(M+H) + 362.1751, found 362.1741. Its structure is as follows:

[0116]

[0117] 3i: Pale yellow oil, 0.114g, 91% yield. 1H NMR (400MHz, CDCl3): δ7.74(d,J=8.4Hz,1H),7.37-7.31(m,4H),7.25-7.21(m,1H),7.16-7.13(m,1H),6.96-6.93(m,1H),6 .87(d,J=8.0Hz,1H),6.61(d,J=12.0Hz,1H),5.59-5.56(m,1H),4.40(dd,J=4.4Hz,J=12.0Hz,1H),4.30-4.24(m,1H),4.16 (d,J=11.2Hz,1H),3.96(dd,J=2.8Hz,J=11.2Hz,1H),3.85-3.80(m,2H),3.70-3.65(m,2H),3.58-3.54(m,1H),3.37(d,J=1 1.6Hz,1H),2.33-2.22(m,2H),1.98-1.91(m,1H),1.82-1.78(m,1H),1.66-1.59(m,1H),1.38(dd,J=5.2Hz,J=14.0Hz,1H); 13 C NMR (100MHz, CDCl3): δ165.9,154.4,141.3,130.0,128.6,128.5,127.9,126.4,123.4,121.4,1 21.2,120.0,118.0,108.7,72.8,66.5,63.9,42.1,41.9,37.1,33.1,32.4,27.9; HRMS(ESI)m / z calcd for C 26 H 28 NO4(M+H) + 418.2013, found 418.2012. Its structure is as follows:

[0118]

[0119] 3j: Pale yellow oil, 0.064g, 53% yield. 1H NMR (400MHz, CDCl3): δ7.69(d,J=8.0Hz,1H),7.65(d,J=7.6Hz,2H),7.48(d,J=8.0Hz,2H),7.17-7.13(m,1H),6.93-6.89(m,1H),6.86-6.84(m,1H), 6.50(d,J=9.2Hz,1H),4.30-4.25(m,2H),4.18-4.08(m,2H),3.80(br,1H) ,3.01(d,J=10.0Hz,1H),2.78(br,1H),1.98(s,3H),1.46(d,J=4.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ169.8, 153.5, 130.7, 129.1 (d, J = 32.8Hz), 128.9, 128.8, 127.3, 126.0 (d, J = 2.9Hz), 125 .9,125.4,123.5,123.0,122.7,121.3,120.0(t,J=270.5Hz),117.9,73.1,65.9,48.9,45.9,36.8,22.3,13.4; 19 F NMR (376MHz, CDCl3): δ-62.4; HRMS (ESI) m / zcalcd for C 23 H 23 F3NO2(M+H) + 402.1675, found 402.1663. Its structure is as follows:

[0120]

[0121] 3k: Pale yellow oil, 0.075g, 69% yield. 1 H NMR (400MHz, CDCl3): δ7.70 (d, J = 7.6Hz, 1H), 7.31-7.27 (m, 1H), 7.14-7.10 ( m,1H),6.95(d,J=7.6Hz,1H),6.91-6.88(m,2H),6.84-6.79(m,2H),6.56(d, J=9.6Hz,1H),4.28-4.23(m,2H),4.17-4.06(m,2H),3.83(s,3H),3.68(br,1 H),3.00(d,J=10.0Hz,1H),2.77(br,1H),1.98(s,3H),1.45(d,J=5.6Hz,3H); 13C NMR (100MHz, CDCl3): δ170.3,160.0,153.4,147.9,130.0,129.9,128.6,124.1,123.5,121.1,1 20.3,119.2,117.8,113.3,111.1,73.1,65.9,55.2,49.0,46.0,35.6,22.3,13.4; HRMS(ESI)m / z calcd for C 23 H 26 NO3(M+H) + 364.1907, found 364.1890. Its structure is as follows:

[0122]

[0123] 3L: Pale yellow oil, 0.087g, 73% yield. 1 H NMR (400MHz, CDCl3): δ7.74(d,J=7.6Hz,1H),7.38(s,1H),7.17-7.13(m,1H),6.95-6.91(m,1H),6.86(d,J=8.0Hz,1H),6.51(d,J=9.2Hz,1H), 6.34(s,1H),6.19(d,J=2.8Hz,1H),4.27-4.21(m,2H),4.17-4.04(m,2H ),3.87(br,1H),2.95-2.90(m,2H),2.02(s,3H),1.32(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ169.8,157.5,153.5,141.4,131.0,128.9,123.6,121.2,120.7 ,120.1,117.8,110.2,104.9,72.9,65.9,46.6,39.4,35.7,22.0,12.9; HRMS(ESI)m / z calcd for C 20 H 22 NO3(M+H) + 324.1594, found 324.1599. Its structure is as follows:

[0124]

[0125] 3m: Pale yellow oil, 0.026g, 24% yield. 1H NMR (600MHz, CDCl3): δ7.72 (dd, J=1.8Hz, J=8.4Hz, 1H), 7.40 (dd, J=1.2Hz, J=7.8Hz, 2H), 7. 34-7.31(m,2H),7.25-7.22(m,1H),7.15-7.12(m,1H),6.93-6.90(m,1H),6.85(dd,J=0.6Hz ,J=7.8Hz,1H),6.47-6.41(m,2H),6.29(d,J=9.0Hz,1H),4.27-4.16(m,3H),4.07(t,J=12.0 Hz,1H),3.34(s,1H),2.90(d,J=7.2Hz,1H),2.70(s,1H),1.99(s,3H),1.36(d,J=7.2Hz,3H); 13 C NMR (125MHz, CDCl3): δ169.7,153.4,137.0,133.3,129.8,128.6,128.5,127.5,126.1,12 3.5,123.2,121.2,120.3,117.8,72.9,65.9,43.4,35.9,29.7,22.3,12.8; HRMS(ESI)m / z calcd forC 24 H 26 NO2(M+H) + 360.1958, found 360.1958. Its structure is as follows:

[0126]

[0127] 3n: Pale yellow oil, 0.088g, 81% yield. 1 H NMR (400MHz, CDCl3): δ7.38-7.35(m,4H),7.27-7.23(m,1H),7.19(s,1H),6.79-6.72(m,2H),6.52(d,J=9.6Hz,1H),4.27-4.22( m,2H),4.12-4.06(m,2H),3.76(s,3H),3.71(br,1H),2.98(d,J=10.0Hz,1H),2.77(br,1H),1.97(s,3H),1.45(d,J=4.8Hz,3H); 13CNMR (100MHz, CDCl3): δ170.3,153.9,147.8,146.2,129.9,129.0,126.8,126.6,124.6,1 20.8,118.4,114.9,108.1,73.1,66.0,55.8,49.0,46.0,35.6,22.3,13.4; HRMS(ESI)m / z calcd for C 23 H 26 NO3(M+H) + 364.1907, found 364.1910. Its structure is as follows:

[0128]

[0129] 3o: Pale yellow solid, 0.063g, 60% yield. MPa: 176-177℃; 1 H NMR (400MHz, CDCl3): δ7.40-7.34(m,5H),7.29-7.25(m,1H),6.86-6.77(m,2H),6.51(d,J=9.6Hz,1H),4.27-4.23( m,2H),4.13-4.03(m,2H),3.70(br,1H),3.00(d,J=10.0Hz,1H),2.78(br,1H),1.98(s,3H),1.45(d,J=5.6Hz,3H); 13 C NMR (100MHz, CDCl3): δ170.3, 158.7 (d, J = 236.3Hz), 149.5, 145.9, 129.4, 129.4 (d, J = 2.2Hz), 129.1, 128.4, 126.8 (d, J = 7.3Hz) ,126.7,125.6,121.4,121.3,118.9,118.8,115.7,115.5,109.3(d,J=24.1Hz),109.0,72.9,66.0,49.1,46.1,35.4,22.3,13.4; 19 F NMR (376MHz, CDCl3): δ-122.6; HRMS (ESI) m / z calcd forC 22 H 23 FNO2(M+H) + 352.1707, found 352.1712. Its structure is as follows:

[0130]

[0131] 3p: Pale yellow oil, 0.014g, 11% yield. 1 H NMR (400MHz, CDCl3): δ7.69(d,J=8.0Hz,1H),7.36(d,J=4.4Hz,4H),7.25-7.23(m,1H),7.14-7.11(m,1H),6.71-6.64(m,2H),6.46(d,J=9.6H z,1H),4.17-4.04(m,2H),3.72(br,1H),3.40-3.36(m,1H),3.09-3.02(m,2H),2.88(s,3H),2.78(br,1H),1.99(s,3H),1.46(d,J=6.4Hz,3H); 13 C NMR (100MHz, CDCl3): δ170.4,146.8,145.4,133.0,128.9,128.5,126.9,126.4,123.8,1 22.9,120.0,117.3,112.5,74.6,51.6,49.1,45.9,39.7,35.4,22.5,13.4; HRMS(ESI)m / z calcd for C 29 H 31 N₂O(M+H) + 347.2118, found 347.2114. Its structure is as follows:

[0132]

[0133] 3q: Pale yellow oil, 0.034g, 28% yield. 1 H NMR (400MHz, CDCl3): δ7.74(d,J=8.0Hz,1H),7.51(d,J=7.2Hz,2H),7.43-7.34(m, 7H),7.27-7.24(m,1H),7.17-7.13(m,1H),6.97-6.93(m,1H),6.90(d,J=8.0Hz,1H) ,6.60(d,J=12.0Hz,1H),5.52-5.47(m,1H),5.17(d,J=10.8Hz,1H),3.82-3.74(m, 2H),3.68-3.61(m,1H),3.40(d,J=10.8Hz,1H),1.76(s,3H),0.86(d,J=7.6Hz,3H); 13C NMR (100MHz, CDCl3): δ166.4,154.6,141.9,139.1,130.0,128.6,128.5,128.4,128.3,127.4,12 6.4,123.5,121.3,121.2,121.1,118.0,82.8,66.8,44.1,42.3,41.2,19.2,14.1; HRMS(ESI)m / z calcd for C 28 H 28 NO2(M+H) + 410.2115, found410.2116. Its structure is as follows:

[0134]

[0135] 3r: Pale yellow oil, 0.061g, 50% yield. 1 H NMR (400MHz, CDCl3): δ7.65(d,J=7.6Hz,1H),7.50(d,J=7.6Hz,2H),7.43-7.37( m,6H),7.32-7.29(m,1H),7.26-7.23(m,1H),7.13-7.09(m,1H),6.92-6.88(m,2 H),6.30(d,J=11.2Hz,1H),5.24-5.17(m,1H),5.14(d,J=10.8Hz,1H),3.77(s,2 H),3.40-3.34(m,2H),2.42-2.36(m,1H),2.14-2.05(m,2H),1.04-1.01(m,3H); 13 C NMR (100MHz, CDCl3): δ165.4,154.6,144.2,139.5,128.7,128.5,128.4,128.0,127.1,126.9,12 6.6,124.7,123.3,121.2,120.9,117.9,83.4,66.6,42.5,40.6,39.5,29.4,10.9; HRMS(ESI)m / z calcd for C 28 H 28 NO2(M+H) + 410.2115, found 410.2110. Its structure is as follows:

[0136]

[0137] Example 2: Preparation of compounds 3a, 3b, 3c, 3e, 3g, and 3h

[0138] Compound 3a: Example 1 was repeated, except that acetonitrile was used instead of 1,2-dichloroethane, copper trifluoromethanesulfonate instead of copper bromide, 4-dimethylaminopyridine instead of pyr, and methylene blue instead of Ru(bpy)3Cl2. The entire reaction was carried out under 20W blue LED light irradiation at 80°C until the N-alkenyl-α,β-unsaturated ketoxime derivative 1 was completely consumed (approximately 3 days). A pale yellow oil was finally obtained with a yield of 64%. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3a.

[0139] Compound 3b: Example 1 was repeated, except that ethyl acetate was used instead of 1,2-dichloroethane, cuprous chloride instead of copper bromide, 1,8-diazabicycloundec-7-ene instead of pyr, and Bengal rose red instead of Ru(bpy)3Cl2. The reaction was first carried out at room temperature under a 5W blue LED lamp with stirring for 2 days, then the temperature was increased to 60°C and the reaction continued under a 5W blue LED lamp until the N-alkenyl-α,β-unsaturated ketoxime derivative 1 was completely consumed (approximately 3 days). A pale yellow oil was finally obtained, with a yield of 54%. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3b.

[0140] Compound 3c: Example 1 was repeated, except that acetone was used instead of 1,2-dichloroethane, ytterbium trifluoromethanesulfonate was used instead of copper bromide, and Ir[dF(CF3)ppy]2(dtbbpy)PF6 was used instead of Ru(bpy)3Cl2. A pale yellow solid was finally obtained in 69% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3c.

[0141] Compound 3e: Example 1 was repeated, except that tetrahydrofuran was used instead of 1,2-dichloroethane, copper acetate instead of copper bromide, triethylenediamine instead of pyr, and Ir(ppy)3 instead of Ru(bpy)3Cl2. During the reaction, the mixture was first stirred at room temperature under a 10W blue LED light for 2 days, then heated to 40°C and continued to react under a 10W blue LED light until the N-alkenyl-α,β-unsaturated ketoxime derivative 1 was completely consumed (approximately 3 days). A pale yellow oil was finally obtained in 15% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3e.

[0142] Compound 3g: Example 1 was repeated, except that n-hexane was used instead of 1,2-dichloroethane, copper iodide instead of copper bromide, triethylamine instead of pyr, and methylene blue instead of Ru(bpy)3Cl2. The reaction was carried out to completion at room temperature. A pale yellow oil was finally obtained in 43% yield. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3g.

[0143] Compound 3r: Example 1 was repeated, except that the reaction was carried out entirely at room temperature until the N-alkenyl-α,β-unsaturated ketoxime derivative 1 was completely consumed (approximately 4 days). A pale yellow oil was obtained, with a yield of 39%. Characterization by 1H NMR, 1C NMR, and high-resolution mass spectrometry confirmed it to be compound 3r.

[0144] Experimental Example 1: In vitro anti-inflammatory activity experiment of the 1-oxo-2-azacyclononane derivative described in this invention

[0145] I. Determination of the viability of the compound and the positive control indomethacin at a concentration of 100 μM on RAW 264.7 cells (mouse mononuclear macrophage leukemia cells) using the MTT assay.

[0146] 1. Cell Plating: Culture test cells at RAW 264.7 to the logarithmic growth phase, discard the old culture medium, wash twice with PBS buffer, add culture medium containing 10% fetal bovine serum, and disperse into a single-cell suspension using a sterile plastic pipette. Seed into 96-well plates, adding 180 μL to each well. Add 200 μL of PBS buffer around the perimeter of the 96-well plate to reduce culture medium evaporation.

[0147] 2. Drug addition: When the cells in the wells have grown to 60% of the well area, add 20 μL of drug to each well, with a final drug concentration of 100 μM. Gently tap the plate and 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 the incubator and observe the cell survival under a microscope.

[0148] 3. Plate preparation: After adding the drug and continuing incubation for 24 hours, add 10 μL of MTT to each well for staining. Gently tap the plate and continue incubation for 4–6 hours. Then discard the culture medium in the wells, add 100 μL of DMSO to each well, and shake on a micro-shaker for 10 minutes to fully dissolve the generated formazan. Transfer the absorbance of each well to an ELISA reader and process the data using PASW software. The experimental results are shown in Table 1.

[0149] Table 1. Effects of compounds on RAW264.7 cell viability as determined by MTT assay

[0150]

[0151] At a concentration of 100 μM, the relative survival rates of compounds 3c, 3e, 3g, and 3r were comparable to those of the positive control, indicating low toxicity. Therefore, these compounds were selected for NO testing.

[0152] II. Determination of the inhibitory effect of low-toxicity compounds on NO release from lipopolysaccharide (LPS)-induced mouse macrophage RAW 264.7 cells using the Griess method

[0153] Compounds 3c, 3e, 3g, and 3r showed low toxicity to mouse macrophage RAW 264.7 cells. Therefore, the applicant further tested the effect of these compounds on inhibiting LPS-induced NO release from mouse macrophage RAW 264.7 cells.

[0154] Experimental methods and results:

[0155] 1. Cell seeding and pretreatment: RAW 264.7 cells that have grown to the logarithmic growth phase were seeded into 24-well culture plates at a density of 400 μL per well. There were control group, LPS stress model group (1 μg / mL LPS), and drug experimental group. The control group and LPS stress model group were supplemented with 100 μL of fresh culture medium. The experimental group was pretreated with 100 μL of different drug solutions (final concentration of 25 μM) for 1 h and then treated with 1 μg / mL LPS for 24 h. The cell supernatant was collected.

[0156] 2. Griess method for determining NO release: Diluted standard reagents of varying concentrations and cell culture supernatant (50 μL per well) were added to a 96-well plate. The procedure was performed according to the kit instructions. Specific steps are as follows:

[0157] (1) Add 50 μL of Griess Regent I reagent at room temperature to each well and let stand for 10 min.

[0158] (2) Add 50 μL of Griess Regent II reagent at room temperature to each well and let stand for 10 min.

[0159] (3) Measure the absorbance at 540 nm, obtain the standard curve, and calculate the NO concentration in the sample to be tested.

[0160] The Griess method was used to detect the ability of compounds 3c, 3e, 3g, and 3r to inhibit LPS-induced NO release from mouse macrophages at a concentration of 25 μM. The test results are shown in Table 2.

[0161] Table 2. Effects of different compounds on NO release in RAW264.7 cells at the same concentration (25 μM).

[0162]

[0163] As shown in Table 2, compounds 3c and 3e, compared with indomethacin, both exhibited good inhibitory effects on NO release from RAW264.7 cells, demonstrating potential for good anti-inflammatory activity.

Claims

1. The use of the following compounds 3c, 3e, 3g, or 3r in the preparation of medicaments for treating inflammation; 。

Images