Methionine-substituted 2,3-dihydrofuran derivatives, processes for their preparation and uses thereof

Abstract

This invention belongs to the field of pharmaceutical technology and relates to 2,3-dihydrofuran derivatives of general formula I, their stereoisomers, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, wherein the substituents Ar1, R1, and R2 have the definitions given in the specification. This invention also relates to methods for preparing compounds of general formula I, and the related uses of the above compounds in the preparation, treatment, and prevention of inflammatory diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to methyl thioether-substituted 2,3-dihydrofuran derivatives, their preparation methods, and their application in the preparation of anti-inflammatory drugs. Background Technology

[0002] Inflammation is a fundamental pathological process in which the body responds to tissue damage caused by various inflammatory stimuli. It is also a common and frequently occurring disease. The inflammatory response is mediated by various inflammatory mediators, and in severe cases, it manifests as fever, accompanied by a significant increase in leukocytes and macrophages. It can lead to serious lesions in certain organs. For the treatment of inflammation, nonsteroidal anti-inflammatory drugs (NSAIDs) have developed into a diverse range of drugs with excellent anti-inflammatory, analgesic, and antirheumatic activities, holding a leading position in global pharmaceutical production. However, long-term use of NSAIDs can lead to adverse reactions such as gastrointestinal and cardiovascular toxicity. Therefore, the search for novel, highly effective, and low-toxicity anti-inflammatory drugs is one of the key focuses and hot topics for future research.

[0003] The 2,3-dihydrofuran skeleton is widely found in natural products and pharmaceuticals, serving as an important intermediate in pharmaceutical and fine chemical synthesis, and exhibiting certain anti-inflammatory activities. Therefore, constructing this skeleton is of great significance. In recent years, methods for preparing 2,3-dihydrofuran derivatives have mainly included Pd(II)-catalyzed organoboron-mediated Heck-type reactions, Pd-catalyzed sequential reactions of propadiene intermediates, and copper-catalyzed asymmetric [3+2] cycloaddition reactions of propyne esters and β-ketophosphonates. However, these reactions typically require various metal catalysts, excess oxidants, or multi-step synthesis, resulting in complex synthesis, expensive heavy metals, and high synthesis costs. Therefore, developing a mild, efficient, and green method for constructing 2,3-dihydrofuran derivatives is essential.

[0004] The inventors designed and synthesized a series of novel methyl sulfide-substituted 2,3-dihydrofuran derivatives via sulfination reaction using α-allyl-β-ketosulfone as a substrate. In vitro screening for their cyclooxygenase-2 (COX-2) inhibitor and cytotoxic activity demonstrated that these compounds possess high biological activity. Summary of the Invention

[0005] To address the problems existing in the prior art, this invention provides a novel class of 2,3-dihydrofuran derivatives and their uses; the 2,3-dihydrofuran derivatives have strong anti-inflammatory effects, and also relates to the use of such compounds and their pharmaceutically acceptable salts, hydrates, solvates or prodrugs in the preparation of drugs for treating inflammatory diseases, particularly in the preparation of drugs for treating and preventing inflammatory diseases.

[0006] To achieve the above objectives, the present invention provides 2,3-dihydrofuran compounds of general formula I and their pharmaceutically acceptable salts, hydrates, solvates, or prodrugs.

[0007] in:

[0008] Ar1 is hydrogen, or benzene selected from methyl, methoxy, halogen-substituted, or biphenyl or naphthyl groups;

[0009] R1 is hydrogen, or a methyl, methoxy, or halogen substituted at different positions;

[0010] R2 is hydrogen or methyl.

[0011] The halogen is fluorine, chlorine, or bromine.

[0012] This invention provides compounds represented by general formula I, their geometric isomers, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, selected from:

[0013]

[0014] Where R1 represents H, Me, OMe, t Bu, F, Cl or Br;

[0015] When R1 = H, it is named 2-((methylthio)methyl)-5-phenyl-4-benzenesulfonyl-2,3-dihydrofuran;

[0016] When R1 = 4-Me, it is named 2-((methylthio)methyl)-5-phenyl-4-p-methylbenzenesulfonyl-2,3-dihydrofuran;

[0017] When R1 = 4-OMe, it is named 4-(4-methoxyphenyl)sulfonyl-2-((methylthio)methyl)-5-phenyl-2,3-dihydrofuran;

[0018] R1 = 4- t When Bu was used, it was named 4-(4-tert-butylphenyl)sulfonyl-2-((methylthio)methyl)-5-phenyl-2,3-dihydrofuran;

[0019] When R1 = 4-F, it is named 4-(4-fluorophenyl)sulfonyl-2-((methylthio)methyl)-5-phenyl-2,3-dihydrofuran;

[0020] When R1 = 4-Cl, it is named 4-(4-chlorophenyl)sulfonyl-2-((methylthio)methyl)-5-phenyl-2,3-dihydrofuran;

[0021] When R1 = 4-Br, it is named 4-(4-bromophenyl)sulfonyl-2-((methylthio)methyl)-5-phenyl-2,3-dihydrofuran;

[0022] When R1 = 3-Me, it is named 2-((methylthio)methyl)-5-phenyl-4-(3-methylphenyl)sulfonyl-2,3-dihydrofuran;

[0023] When R1 = 2-Me, it is named 2-((methylthio)methyl)-5-phenyl-4-(2-methylphenyl)sulfonyl-2,3-dihydrofuran;

[0024] When R1 = 2-Cl, it is named 2-((methylthio)methyl)-5-phenyl-4-(2-chlorophenyl)sulfonyl-2,3-dihydrofuran;

[0025]

[0026] Wherein, Ar1 is 2-naphthalene, 4-biphenyl, or a benzene ring substituted at different positions, selected from Me, OMe, F, Cl or Br; when Ar1 = 2-naphthalene-, it is named 4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-5-(naphth-2-yl)-2,3-dihydrofuran; when Ar1 = 4-biphenyl-, it is named 5-([1,1'-diphenyl]-4-yl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran;

[0027] When Ar1 = 4-MeC6H5-, it is named 5-(4-methylphenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran;

[0028] When Ar1 = 4-OMeC6H5-, it is named 5-(4-methoxyphenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran;

[0029] When Ar1 = 4-ClC6H5-, it is named 5-(4-chlorophenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran;

[0030] When Ar1 = 4-BrC6H5-, it is named 5-(4-bromophenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran;

[0031] When Ar1 = 4-FC6H5-, it is named 5-(4-fluorophenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran;

[0032] When Ar1 = 3-FC6H5-, it is named 5-(3-fluorophenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran.

[0033] When Ar1 = 2-FC6H5-, it is named 5-(2-fluorophenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran;

[0034]

[0035] in,

[0036] R2 = H or Me, R3 = H, Br, Me or OMe;

[0037] When R2 = Me and R3 = H, it is named 2-methyl-2-((methylthio)methyl)-5-phenyl-4-(4-methylphenyl)sulfonyl-2,3-dihydrofuran;

[0038] When R2 = H and R3 = 4-Br, it is named 5-(4-bromophenyl)-2-((methylthio)methyl)-4-(4-methylphenyl)sulfonyl-2,3-dihydrofuran;

[0039] When R2 = H and R3 = 4-Me, it is named 5-(4-methylphenyl)-2-((methylthio)methyl)-4-(4-methylphenyl)sulfonyl-2,3-dihydrofuran;

[0040] When R2 = H and R3 = 4-OMe, it is named 5-(4-methoxyphenyl)-2-((methylthio)methyl)-4-(4-methylphenyl)sulfonyl-2,3-dihydrofuran;

[0041]

[0042] 5-(4-Chlorophenyl)-4-(4-Fluorophenyl)sulfonyl-2-((methylthio)methyl)-2,3-dihydrofuran;

[0043]

[0044] 5-(4-methoxyphenyl)-4-(4-bromophenyl)sulfonyl-2-((methylthio)methyl)-2,3-dihydrofuran;

[0045] The structural formulas of the above 25 compounds are as follows:

[0046]

[0047]

[0048] Furthermore, the present invention also includes prodrugs derived from the present invention. These prodrugs are derivatives of general formula I, which may themselves have weak or even no activity, but after administration, they can be metabolized and converted into their corresponding biologically active forms under physiological conditions.

[0049] This invention can contain derivatives of Formula I above, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare compositions, and formulated into clinically acceptable dosage forms. The aforementioned pharmaceutically acceptable excipients refer to any diluent, adjuvant, and / or carrier that can be used in the pharmaceutical field. The derivatives of this invention can be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions.

[0050] The pharmaceutical compositions of the present invention can be formulated into several dosage forms, containing some commonly used excipients in the pharmaceutical field. The dosage forms described above can be injections, tablets, capsules, aerosols, suppositories, films, pellets, topical liniments, ointments, and other dosage forms.

[0051] The carriers used in the pharmaceutical compositions of this invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, colorants, flavoring agents, preservatives, solvents, and matrices. The pharmaceutical formulations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or locally). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0052] In vitro anti-inflammatory activity assays showed that the methyl thioether-substituted 2,3-dihydrofuran derivatives of the present invention have anti-inflammatory activity and are cytotoxic to some tumor cells. Therefore, the compounds of the present invention can be used to prepare drugs for treating and / or preventing inflammatory diseases, as well as for the preparation of antitumor drugs.

[0053] The tumor cells mentioned are human liver cancer cells HepG-2, human colorectal cancer cells HCT116, human cervical cancer cells HeLa, or human lung adenocarcinoma cells A549.

[0054] The active compounds of the present invention, or their pharmaceutically acceptable salts and solvates thereof, can be used as anti-inflammatory drugs.

[0055] The examples and preparation methods provided below further illustrate and demonstrate the compounds of the present invention and their preparation methods. The scope of the examples and preparation methods described below does not limit the scope of the present invention in any way. All compounds of Formula I according to the present invention can be obtained by sulfonation of the corresponding starting material 1-1 (α-allyl-β-ketosulfonate compound) according to Route 1 to yield target compound 1-2.

[0056] Synthesis route:

[0057]

[0058] Synthetic route: The molar ratio of substrate, dibromoacetophenone, sodium persulfate and dipotassium hydrogen phosphate is 1:2:2:2, the solvent is DMF and DMSO (volume ratio v:v = 20:1), 80℃, N2 atmosphere, reaction time 48-66h.

[0059] Compared with the prior art, the 2,3-dihydrofuran-structured compound substituted with dimethyl sulfide described in this invention has the following advantages:

[0060] 1. This invention provides a novel and highly active methyl sulfide-substituted 2,3-dihydrofuran derivative prepared by a one-pot method.

[0061] 2. The reaction conditions of this invention are mild and the operation is simple and convenient; the reaction substrate has a wide range of applicability, and the yield and selectivity are both high. The yield of some reactions can reach more than 90%. The whole reaction is safe and environmentally friendly, with low cost and high economic benefits, and belongs to green chemical synthesis; the brominating reagent used is low-toxicity 2-bromoacetophenone, which is inexpensive, readily available, and easy to add. The auxiliary catalyst sodium persulfate is inexpensive, readily available, and pollution-free.

[0062] 3. The target product of this invention has good in vitro anti-inflammatory and cytotoxic activities. Detailed Implementation

[0063] The technical solution of the present invention will be further described below with reference to specific embodiments. However, the embodiments are intended to explain the present invention and should not be construed as limiting the present invention. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in the art or in accordance with the product instructions. Unless otherwise defined, the technical terms used in the following embodiments have the same meaning as commonly understood by those skilled in the art; the test reagents used, unless otherwise specified, are all conventional biochemical reagents; the experimental methods, unless otherwise specified, are all conventional methods. The proton NMR spectra of the compounds were determined using a Bruker ARX-500, and the mass spectrometry was determined using an Agilent 1100 LC / MS; all reagents used were analytical grade or chemically pure.

[0064] Example 1

[0065] Preparation of 2-((methylthio)methyl)-5-phenyl-4-p-methylbenzenesulfonyl-2,3-dihydrofuran (a-1)

[0066] In a reaction flask, 2-(4-methylphenyl)sulfonyl)-1-phenylpentyl-4-en-1-one substrate 1-1 (1 eq.), dibromoacetophenone (2 eq.), sodium persulfate (2 eq.), and dipotassium hydrogen phosphate (2 eq.) were weighed in. The solvent was DMF:DMSO (v:v = 20:1). The reaction was carried out under N2 atmosphere at 80 °C with stirring for 52 h. The reaction was monitored by TLC. After completion, the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and finally separated by silica gel column chromatography to give a pale yellow oily compound a-1 in 75% yield.

[0067] 1 H NMR (500MHz, CDCl3): δ H 7.66(dd,J=8.0,1.5Hz,2H),7.63(d,J=8.0Hz,2H),7.45(tt,J=8.0,6.0,1 .5Hz,1H),7.39(t,J=8.0Hz,2H),7.24(d,J=8.0Hz,2H),4.92-4.86(m,1H) ,3.27(dd,J=14.7,10.3Hz,1H),2.98(dd,J=14.7,7.5Hz,1H),2.83(dd,J= 13.7,6.3Hz,1H),2.70(dd,J=13.7,6.3Hz,1H),2.40(s,3H),2.13(s,3H); 13 C NMR (126MHz, CDCl3): δ c 163.0,143.7,138.9,130.9,129.6,129.5,128.4,127.8,127.0,110.4,80.7,38.8,37.2,21.5,16.3.

[0068] The preparation methods of the compounds in Examples a-2 to a-25 are the same as those in Example a-1, except that the starting material substrate is replaced only according to the different target products.

[0069] Example 2

[0070] Preparation of 2-((methylthio)methyl)-5-phenyl-4-benzenesulfonyl-2,3-dihydrofuran (a-2)

[0071] Yield 84%, pale yellow oily compound. 1 H NMR (500MHz, CDCl3): δ H7.74(dd,J=7.7Hz,2H),7.66(d,J=7.7Hz,2H),7.54(t,J=7.7Hz,1H),7.47-7.43(m,3H),7.39(t,J=7.7Hz,2H),4.94-4.88(m,1H),3 .29(dd,J=14.7,10.5Hz,1H),3.00(dd,J=14.7,7.3Hz,1H),2.83(dd,J=13.7,6.0Hz,1H),2.71(dd,J=13.7,6.0Hz,1H),2.13(s,3H); 13 C NMR (126MHz, CDCl3): δ c 163.5,141.8,132.8,131.0,129.5,128.9,128.3,127.8,126.9,110.1,80.8,38.8,37.1,16.4.

[0072] Example 3

[0073] Preparation of 4-(4-fluorophenyl)sulfonyl-2-((methylthio)methyl)-5-phenyl-2,3-dihydrofuran (a-3)

[0074] Yield 67%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.74-7.72(m,2H),7.64(d,J=7.7Hz,2H),7.47(t,J=7.7Hz,1H),7.39(t,J=7.7Hz,2H),7.12-7.08(m,2H),4.96-4.90(m,1H),3.2 9(dd,J=14.7,9.7Hz,1H),3.00(dd,J=14.7,6.5Hz,1H),2.83(dd,J=13.7,6.5Hz,1H),2.74(dd,J=13.7,6.5Hz,1H),2.14(s,3H); 13 C NMR (126MHz, CDCl3): δ c 171.1,165.2(d,J=255.5Hz),163.7,137.9(d,J=3.3Hz),131.1,129.7(d,J=9. 3Hz), 129.4, 128.2, 127.9, 116.1 (d, J = 22.6Hz), 110.2, 80.8, 38.9, 37.0, 16.4.

[0075] Example 4

[0076] Preparation of 4-(4-chlorophenyl)sulfonyl-2-((methylthio)methyl)-5-phenyl-2,3-dihydrofuran (a-4)

[0077] Yield 80%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.66-7.63(m,4H),7.47(t,J=7.3Hz,1H),7.41-7.38(m,4H),4.96-4.90(m,1H),3.28(dd,J=14.5,10.5Hz, 1H), 3.00 (dd, J=14.5, 7.5Hz, 1H), 2.83 (dd, J=13.7, 6.0Hz, 1H), 2.74 (dd, J=13.7, 6.0Hz, 1H), 2.13 (s, 3H); 13 C NMR (126MHz, CDCl3): δ c 164.0,140.3,139.4,131.1,129.4,129.2,128.4,128.2,127.9,109.9,80.9,38.8,36.9,16.4.

[0078] Example 5

[0079] Preparation of 4-(4-bromophenyl)sulfonyl-2-((methylthio)methyl)-5-phenyl-2,3-dihydrofuran (a-5)

[0080] Yield 73%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.64(dd,J=8.3,1.3Hz,2H),7.57(s,4H),7.49-7.45(m,1H),7.40(t,J=7.5Hz,2H),4.96-4.90(m,1H),3.28(dd,J=14. 5,10.5Hz,1H),3.00(dd,J=14.5,7.5Hz,1H),2.83(dd,J=13.5,6.0Hz,1H),2.74(dd,J=13.5,6.0Hz,1H),2.13(s,3H); 13 C NMR (126MHz, CDCl3): δ c 164.1,140.8,132.2,131.1,129.4,128.5,128.2,127.9,109.8,80.9,38.8,36.9,16.4.

[0081] Example 6

[0082] Preparation of 4-(4-methoxyphenyl)sulfonyl-2-((methylthio)methyl)-5-phenyl-2,3-dihydrofuran (a-6)

[0083] Yield 98%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.68-7.64(m,4H),7.45(t,J=7.3Hz,1H),7.39(t,J=7.3Hz,2H),6.90(d,J=8.5Hz,2H),4.94-4.86(m,1H),3.84(s,3H),3.26(d d,J=14.7,10.3Hz,1H),2.97(dd,J=14.7,7.0Hz,1H),2.83(dd,J=14.0,6.0Hz,1H),2.71(dd,J=14.0,6.0Hz,1H),2.13(s,3H); 13 C NMR (126MHz, CDCl3): δ c 163.1,162.6,133.5,130.8,129.4,129.2,128.5,127.8,114.1,110.8,80.7,55.6,38.8,37.2,16.3.

[0084] Example 7

[0085] Preparation of 4-(4-tert-butylphenyl)sulfonyl-2-((methylthio)methyl)-5-phenyl-2,3-dihydrofuran (a-7)

[0086] Yield 76%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.68-7.65(m,4H),7.46-7.43(m,3H),7.38(t,J=7.3Hz,2H),4.94-4.87(m,1H),3.28(dd,J=14.7,10.3Hz,1H),3. 00(dd,J=14.7,6.5Hz,1H),2.84(dd,J=13.7,6.5Hz,1H),2.71(dd,J=13.7,6.5Hz,1H),2.12(s,3H),1.32(s,9H); 13 C NMR (126MHz, CDCl3): δ c163.0,156.6,138.7,130.9,129.5,128.4,127.8,126.9,125.9,110.4,80.8,38.8,37.1,35.1,31.1,16.4.

[0087] Example 8

[0088] Preparation of 2-((methylthio)methyl)-5-phenyl-4-(3-methylphenyl)sulfonyl-2,3-dihydrofuran (a-8)

[0089] Yield 59%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.67-7.65(m,2H),7.54-7.52(m,2H),7.47-7.44(m,1H),7.41-7.38(m,2H),7.33-7.32(m,2H),4.94-4.88(m,1H),3.28(dd,J=14. 7,10.3Hz,1H),3.00(dd,J=14.7,7.5Hz,1H),2.83(dd,J=13.7,6.0Hz,1H),2.72(dd,J=13.7,6.0Hz,1H),2.35(s,3H),2.13(s,3H); 13 C NMR (126MHz, CDCl3): δ c 163.3,141.6,139.1,133.6,130.9,129.4,128.8,128.4,127.8,127.3,124.0,110.3,80.8,38.8,37.1,21.2,16.3.

[0090] Example 9

[0091] Preparation of 2-((methylthio)methyl)-5-phenyl-4-(2-chlorophenyl)sulfonyl-2,3-dihydrofuran (a-9)

[0092] Yield 91%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H7.95(d,J=8.0Hz,1H),7.55(d,J=7.0Hz,2H),7.36-7.32(m,3H),7.27-7.26(m,1H),7.26-7.20(m,2H),5.01-4.95(m,1H),3.41( dd,J=14.5,10.0Hz,1H),3.10(dd,J=14.5,7.5Hz,1H),2.91(dd,J=13.7,6.5Hz,1H),2.77(dd,J=13.7,6.5Hz,1H),2.16(s,3H). 13 C NMR (126MHz, CDCl3): δ c 164.2,138.2,133.7,132.5,131.5,131.3,130.9,129.2,128.1,127.7,126.5,109.2,81.3,38.8,37.1,16.3.

[0093] Example 10

[0094] Preparation of 2-((methylthio)methyl)-5-phenyl-4-(2-methylphenyl)sulfonyl-2,3-dihydrofuran (a-10)

[0095] Yield 73%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.92(d,J=8.0Hz,1H),7.63(d,J=7.5Hz,2H),7.41-7.36(m,2H),7.32(t,J =7.5Hz,2H),7.23(t,J=7.5Hz,1H),7.19(d,J=7.5Hz,1H),4.96-4.90(m,1H ),3.22(dd,J=14.7,10.7Hz,1H),2.93(dd,J=14.7,7.7Hz,1H),2.84(dd,J =13.7,6.0Hz,1H),2.73(dd,J=13.7,6.0Hz,1H),2.42(s,3H),2.13(s,3H); 13 CNMR (126MHz, CDCl3): δ c 163.1,138.7,137.6,132.9,132.3,130.9,129.5,129.4,128.1,127.7,125.9,109.6,80.8,38.9,37.1,19.8,16.4.

[0096] Example 11

[0097] Preparation of 4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-5-(naphth-2-yl)-2,3-dihydrofuran (a-11)

[0098] Yield 57%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 8.22(s,1H),7.90(d,J=8.3Hz,1H),7.84(t,J=8.3Hz,2H),7.71(dd,J=8.5,1.0 Hz,1H),7.68(d,J=8.5Hz,2H),7.56-7.51(m,2H),6.85(d,J=8.5Hz,2H),4.98-4 .92(m,1H),3.80(s,3H),3.33(dd,J=14.7,10.5Hz,1H),3.05(dd,J=14.7,7.3H z,1H),2.88(dd,J=14.0,6.0Hz,1H),2.75(dd,J=14.0,6.0Hz,1H),2.15(s,3H); 13 C NMR (126MHz, CDCl3): δ c 163.0,162.4,134.3,133.5,132.2,130.3,129.2,128.9,127.7,127.5,127.4,126.5,125.8,125.7,114.1,111.2,80.7,55.5,38.9,37.3,16.4.

[0099] Example 12

[0100] Preparation of 5-([1,1'-diphenyl]-4-yl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran (a-12)

[0101] Yield 70%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H7.78(d,J=8.7Hz,2H),7.72(d,J=8.7Hz,2H),7.62(d,J=8.7Hz,4H),7.46(t ,J=7.5Hz,2H),7.38(t,J=7.5Hz,1H),6.92(d,J=8.7Hz,2H),4.94-4.88(m, 1H),3.83(s,3H),3.28(dd,J=14.7,10.5Hz,1H),2.99(dd,J=14.7,7.3Hz,1 H),2.85(dd,J=13.7,6.0Hz,1H),2.72(dd,J=13.7,6.0Hz,1H),2.15(s,3H); 13 C NMR (126MHz, CDCl3): δ c 163.1,162.1,143.6,140.1,133.5,130.0,129.2,128.8,127.8,127.2,127.1,126.4,114.1,110.7,80.6,55.6,38.8,37.3,16.3.

[0102] Example 13

[0103] Preparation of 5-(4-methoxyphenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran (a-13)

[0104] Yield 34%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.69(d,J=8.5Hz,4H),6.92-6.89(m,4H),4.87-4.81(m,1H),3.84(s,6H),3.24(dd,J=14.5,10.5Hz,1H) ,2.94(dd,J=14.5,7.0Hz,1H),2.81(dd,J=14.0,6.0Hz,1H),2.67(dd,J=14.0,7.0Hz,1H),2.12(s,3H). 13 C NMR (126MHz, CDCl3): δ c 163.0,162.4,161.7,133.8,131.3,129.0,120.7,114.1,113.2,109.1,80.2,55.6,55.3,38.8,37.3,16.3.

[0105] Example 14

[0106] Preparation of 5-(4-methylphenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran (a-14)

[0107] Yield 43%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.68(d,J=8.7Hz,2H),7.58(d,J=7.7Hz,2H),7.19(d,J=7.7Hz,2H),6.90(d,J=8.7Hz,2H),4.89-4.83(m,1H),3.84(s,3H),3.24(dd,J= 14.5,10.3Hz,1H),2.95(dd,J=14.5,7.5Hz,1H),2.81(dd,J=13.7,6.0Hz,1H),2.68(dd,J=13.7,6.0Hz,1H),2.38(s,3H),2.12(s,3H). 13 C NMR (126MHz, CDCl3): δ c 163.0,162.7,141.2,133.7,129.4,129.1,128.5,125.6,114.1,110.0,80.5,55.6,38.8,37.2,21.5,16.3.

[0108] Example 15

[0109] Preparation of 5-(4-bromophenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran (a-15)

[0110] Yield 68%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.67(d,J=9.0Hz,2H),7.56(d,J=8.5Hz,2H),7.52(d,J=8.5Hz,2H),6.92(d,J=9.0Hz,2H),4.91-4.85(m,1H),3.85(s,3H),3.23 (dd,J=14.7,10.3Hz,1H),2.94(dd,J=14.7,7.5Hz,1H),2.81(dd,J=13.7,6.0Hz,1H),2.69(dd,J=13.7,6.0Hz,1H),2.12(s,3H); 13 C NMR (126MHz, CDCl3): δ c163.2,161.1,133.1,131.1,129.2,127.3,125.5,114.2,111.4,80.7,55.6,38.8,37.2,16.3.

[0111] Example 16

[0112] Preparation of 5-(4-chlorophenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran (a-16)

[0113] Yield 53%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.67(d,J=9.0Hz,2H),7.64(d,J=8.5Hz,2H),7.36(d,J=8.5Hz,2H),6.92(d,J=9.0Hz,2H),4.91-4.85(m,1H),3.85(s,3H),3.24 (dd,J=14.7,10.5Hz,1H),2.95(dd,J=14.7,7.3Hz,1H),2.81(dd,J=13.7,6.0Hz,1H),2.69(dd,J=13.7,6.0Hz,1H),2.12(s,3H); 13 C NMR (126MHz, CDCl3): δ c 163.2,161.1,137.0,133.3,130.9,129.2,128.1,126.9,114.2,111.4,80.7,55.6,38.8,37.2,16.3.

[0114] Example 17

[0115] Preparation of 5-(4-fluorophenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran (a-17)

[0116] Yield 75%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H7.72-7.69(m,2H),7.66(d,J=8.7Hz,2H),7.07(t,J=8.7Hz,2H),6.91(d,J=8.7Hz,2H),4.90-4.84(m,1H),3.84(s,3H),3.24(d d,J=14.5,10.0Hz,1H),2.95(dd,J=14.5,7.5Hz,1H),2.81(dd,J=13.7,6.0Hz,1H),2.69(dd,J=13.7,6.0Hz,1H),2.12(s,3H); 13 C NMR (126MHz, CDCl3): δ c 164.1(d,J=251.1Hz),163.2,161.3,133.3,131.8(d,J=8.7Hz),129.1,124.5( d, J=3.4Hz), 115.0 (d, J=21.9Hz), 114.2, 110.8, 80.6, 55.6, 38.8, 37.2, 16.3; 19 F NMR (470MHz, CDCl3): δ F -108.4(s)ppm.

[0117] Example 18

[0118] Preparation of 5-(3-fluorophenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran (a-18)

[0119] Yield 67%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.68(d,J=8.7Hz,2H),7.50(d,J=8.0Hz,1H),7.38-7.34(m,2H),7.16-7.13(m,1H),6.92(d,J=8.7Hz,2H),4.93-4.87(m,1H),3.85(s,3H ),3.26(dd,J=15.0,10.3Hz,1H),2.97(dd,J=15.0,7.5Hz,1H),2.82(dd,J=14.0,6.0Hz,1H),2.71(dd,J=14.0,6.0Hz,1H),2.13(s,3H). 13 C NMR (126MHz, CDCl3): δ c163.2,161.9(d,J=246.8Hz),160.7(d,J=2.4Hz),133.2,130.3(d,J=8.4Hz),129.4(d,J=8.2Hz),129.2,1 25.5(d,J=3.3Hz),117.8(d,J=21.2Hz),116.4(d,J=23.6Hz),114.2,111.9,80.8,55.6,38.8,37.2,16.3. 19 F NMR (470MHz, CDCl3): δ F -112.8(s)ppm.

[0120] Example 19

[0121] Preparation of 5-(2-fluorophenyl)-4-((4-methoxyphenyl)sulfonyl)-2-((methylthio)methyl)-2,3-dihydrofuran (a-19)

[0122] Yield 91%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.72(d,J=9.0Hz,2H),7.46-7.42(m,2H),7.20(td,J=7.5,1.0Hz,1H),7.10(t,J=9.0Hz,1H),6.94(d,J=9.0Hz,2H),4.97-4.91(m,1H),3.86( s,3H),3.21(dd,J=14.5,10.0Hz,1H),2.92(dd,J=14.5,7.5Hz,1H),2.84(dd,J=13.7,6.0Hz,1H),2.71(dd,J=13.7,6.0Hz,1H),2.13(s,3H); 13 CNMR (126MHz, CDCl3): δ c 163.2,160.9(d,J=251.6Hz),157.8,132.8,132.3(d,J=8.4Hz),131.4(d,J=2.3Hz),129.5,123.6( d,J=3.5Hz),117.3(d,J=15.1Hz),115.6(d,J=21.2Hz),114.2,113.7,81.8,55.6,38.7,36.0,16.3; 19 F NMR (470MHz, CDCl3): δ F -111.8(s)ppm.

[0123] Example 20

[0124] Preparation of 2-methyl-2-((methylthio)methyl)-5-phenyl-4-(4-methylphenyl)sulfonyl-2,3-dihydrofuran (a-20)

[0125] Yield 92%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.68-7.58(m,4.0H),7.44(t,J=7.3Hz,1.0H),7.40-7.36(m,2.0H),7.23-7.21(m ,2.0H),3.50(d,J=10.5Hz,0.3H),3.41(d,J=10.5Hz,0.3H),3.17(dd,J=14.7,2. 7Hz,1.0H),2.99(d,J=14.7Hz,0.3H),2.89(d,J=14.7Hz,0.7H),2.80-2.74(m,1. 4H),2.39(s,3.0H),2.10(s,2.1H),1.64(s,0.9H),1.58(s,0.9H),1.49(s,2.1H); 13 C NMR (126MHz, CDCl3): δ c 162.2,143.6,143.5,139.1,138.8,130.9,130.7,129.5,129.4,128.7,128.4,127.7,127.7,127.0,126.9,110.4,110.2,88.3,85.5,44.6,42.6,42.2,39.1,25.9,25.2,21.5,17.6.

[0126] Example 21

[0127] Preparation of 5-(4-bromophenyl)-2-((methylthio)methyl)-4-(4-methylphenyl)sulfonyl-2,3-dihydrofuran (a-21)

[0128] Yield 68%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H7.63(d,J=8.0Hz,2H),7.57(d,J=8.7Hz,2H),7.53(d,J=8.7Hz,2H),7.26(d,J=8.0Hz,2H),4.91-4.85(m,1H),3.24(dd,J=14.7, 9.7Hz,1H),2.95(dd,J=14.7,7.5Hz,1H),2.81(dd,J=13.7,6.0Hz,1H),2.69(dd,J=13.7,6.0Hz,1H),2.41(s,3H),2.12(s,3H); 13 C NMR (126MHz, CDCl3): δ c 161.6,143.9,138.6,131.1,131.1,129.7,127.2,127.0,125.6,111.0,80.8,38.8,37.2,21.6,16.3.

[0129] Example 22

[0130] Preparation of 5-(4-methylphenyl)-2-((methylthio)methyl)-4-(4-methylphenyl)sulfonyl-2,3-dihydrofuran (a-22)

[0131] Yield 72%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.64(d,J=8.3Hz,2H),7.58(d,J=8.3Hz,2H),7.25(d,J=8.3Hz,2H),7.20(d,J=8.3Hz,2H),4.89-4.83(m,1H),3.24(dd,J=14.7,10.3Hz ,1H),2.95(dd,J=14.7,7.0Hz,1H),2.82(dd,J=13.7,6.0Hz,1H),2.68(dd,J=13.7,6.0Hz,1H),2.40(s,3H),2.39(s,3H),2.12(s,3H); 13 C NMR (126MHz, CDCl3): δ c 163.2,143.6,141.3,139.0,129.5,129.4,128.5,127.0,125.5,109.5,80.6,38.7,37.2,21.5,21.5,16.3.

[0132] Example 23

[0133] Preparation of 5-(4-methoxyphenyl)-2-((methylthio)methyl)-4-(4-methylphenyl)sulfonyl-2,3-dihydrofuran (a-23)

[0134] Yield 61%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.70-7.68(m,2H),7.64(d,J=8.5Hz,2H),7.24(d,J=8.5Hz,2H),6.91-6.89(m,2H),4.88-4.82(m,1H),3.85(s,3H),3.24(dd,J=14. 5,10.0Hz,1H),2.95(dd,J=14.5,7.5Hz,1H),2.81(dd,J=14.0,6.5Hz,1H),2.67(dd,J=14.0,6.5Hz,1H),2.40(s,3H),2.12(s,3H). 13 C NMR (126MHz, CDCl3): δ c 162.8,161.7,143.6,139.1,131.3,129.6,126.9,120.6,113.2,108.6,80.3,55.3,38.8,37.3,21.5,16.3.

[0135] Example 24

[0136] Preparation of 5-(4-chlorophenyl)-4-(4-fluorophenyl)sulfonyl-2-((methylthio)methyl)-2,3-dihydrofuran (a-24)

[0137] Yield 73%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.74(dd,J=8.5,5.0Hz,2H),7.63(d,J=8.5Hz,2H),7.38(d,J=8.5Hz,2H),7.13(t,J=8.5Hz,2H),4.95-4.89(m,1H),3.25(dd ,J=14.7,10.3Hz,1H),2.96(dd,J=14.7,7.3Hz,1H),2.81(dd,J=13.7,6.0Hz,1H),2.72(dd,J=13.7,6.0Hz,1H),2.12(s,3H); 13 C NMR (126MHz, CDCl3): δ c165.1(d,J=256.0Hz),162.3,137.6(d,J=3.2Hz),137.3,130.9,129.7(d,J =9.6Hz),128.2,126.6,116.3(d,J=22.7Hz),110.5,80.8,38.8,37.0,16.4; 19 F NMR (470MHz, CDCl3): δ F -104.5(s)ppm.

[0138] Example 25

[0139] Preparation of 5-(4-methoxyphenyl)-4-(4-bromophenyl)sulfonyl-2-((methylthio)methyl)-2,3-dihydrofuran (a-25)

[0140] Yield 55%, pale yellow oily substance. 1 H NMR (500MHz, CDCl3): δ H 7.67(d,J=8.0Hz,2H),7.60(d,J=9.0Hz,2H),7.57(d,J=8.0Hz,2H),6.91(d,J=9.0Hz ,2H),4.91-4.86(m,1H),3.85(s,3H),3.26(dd,J=14.7,10.3Hz,1H),2.97(dd,J=14.7 7.0Hz, 1H), 2.81 (dd, J=14.0, 6.0Hz, 1H), 2.71 (dd, J=14.0, 6.0Hz, 1H), 2.13 (s, 3H). 13 C NMR (126MHz, CDCl3): δ c 163.9,161.9,141.1,132.2,131.3,128.4,127.8,120.3,113.3,108.0,80.5,55.3,38.8,37.1,16.4.

[0141] Pharmacological studies of some products of this invention

[0142] In vitro anti-inflammatory activity test

[0143] The anti-inflammatory activity of the target compound was tested. IC 50 The value was defined as the concentration at which the compound inhibited COX-2 by 50%. Celecoxib was selected as the positive control drug in the experiment; COX-2 solution and the test compound were added sequentially to a 96-well plate. Fluorescence was measured after incubation at 37°C in the dark for 5 minutes. The in vitro anti-inflammatory activity of the compounds prepared in the above examples is shown in Table 1.

[0144] Table 1. Anti-inflammatory activity test of COX-2

[0145]

[0146] The above experimental results show that the compound of general formula I to be protected by this invention has good in vitro COX-2 inhibition ability, and thus exhibits certain anti-inflammatory activity.

[0147] Cytotoxic activity assay

[0148] The cytotoxic activities of the target compounds against human hepatocellular carcinoma cells HepG-2, human colorectal carcinoma cells HCT116, human cervical carcinoma cells HeLa, and human lung adenocarcinoma cells A549 were tested. Cisplatin was selected as a positive control. Cells and culture media of different sample concentrations were added sequentially to 96-well plates, and cell growth was observed under incubation conditions at 37°C. The in vitro cytotoxic activity tests of the compounds prepared in the above examples are shown in Table 2.

[0149] Table 2. Cytotoxic Activity Assay

[0150]

[0151] The experimental results above demonstrate that the compound of general formula I protected by this invention exhibits good cytotoxic activity against tumor cells. Therefore, the compound of this invention has promising prospects for industrial application.

[0152] In this invention, compounds of general formula I can be administered alone, but are usually given in mixture with a pharmaceutical carrier. The choice of the pharmaceutical carrier depends on the desired route of administration and standard pharmaceutical practices. The following describes the new applications of this type of compound in the pharmaceutical field using various pharmaceutical dosage forms, such as tablets, capsules, injections, aerosols, suppositories, films, drops, liniments, and ointments.

[0153] Example 2: Tablets

[0154] 10g of a compound containing the compound of claim 1 (taking the compound of Example a-1 as an example) was mixed with 20g of excipients according to the general pharmaceutical tableting method and then compressed into 100 tablets, each weighing 300mg.

[0155] Example 3: Capsules

[0156] 10g of a compound containing the compound of claim 1 (taking the compound of Example a-1 as an example) and 20g of excipients were mixed in accordance with the requirements for pharmaceutical capsules and then filled into empty capsules, each capsule weighing 300mg.

[0157] Example 4: Injectable

[0158] 10g of a compound containing the compound of claim 1 (taking the compound of Example a-1 as an example) was adsorbed onto activated carbon according to conventional pharmaceutical methods, filtered through a 0.65μm microporous membrane, and then filled into a nitrogen cylinder to prepare an aqueous injection preparation, each containing 2mL, for a total of 100 bottles.

[0159] Example 5: Aerosol

[0160] 10g of a compound containing the compound of claim 1 (taking the compound of Example a-1 as an example) is dissolved in an appropriate amount of propylene glycol, and then distilled water and other additives are added to prepare a 500mL clear solution.

[0161] Example 6: Suppositories

[0162] 10g of a compound containing the compound of claim 1 (taking the compound of Example a-1 as an example) was finely ground, and an appropriate amount of glycerin was added. After grinding evenly, melted glycerin gelatin was added, and the mixture was ground evenly. The mixture was then poured into a mold coated with lubricant to prepare 50 suppositories.

[0163] Example 7: Film Formulation

[0164] Using 10g of a compound containing the compound of claim 1 (taking the compound of Example a-1 as an example), polyvinyl alcohol, pharmaceutical glycerin, water, etc. are stirred and expanded, then heated and dissolved. The mixture is filtered through an 80-mesh sieve, and then the compound of Example 18 is added to the filtrate and stirred and dissolved. 100 films are made by coating the film.

[0165] Example 8: Droplets

[0166] 10g of a compound containing the compound of claim 1 (taking the compound of Example a-1 as an example) was heated and melted with 50g of a matrix such as gelatin and mixed evenly. The mixture was then dropped into low-temperature liquid paraffin to prepare 1000 pellets.

[0167] Example 9: Topical lotion

[0168] The compound containing the compound of claim 1 (taking the compound of Example a-1 as an example) is mixed and ground with 2.5g of excipients such as emulsifiers according to conventional pharmaceutical methods, and then distilled water is added to 200mL to obtain the product.

[0169] Example 10: Ointment

[0170] The compound containing the compound of claim 1 (taking the compound of Example a-1 as an example) was ground into a fine powder and then mixed with 500g of an oily matrix such as petrolatum.

[0171] Although the invention has been described with reference to specific embodiments, modifications and equivalent variations will be apparent to those skilled in the art, and they are all included within the scope of the invention.

Claims

1. A compound as shown in general formula (Ⅰ): in, Ar1 is 2-naphthalene, 4-biphenyl, or a benzene ring substituted at different positions, selected from Me, OMe, F, Cl, or Br; R1 is hydrogen, or a methyl, methoxy, or halogen substituted at different positions. R2 is hydrogen or methyl; The halogen is fluorine, chlorine, or bromine.

2. The compound according to claim 1, characterized in that: The compound mentioned is selected from: Where R1 represents H, Me, OMe, t Bu, F, Cl or Br R2 = H or Me, R3 = H, Br, Me or OMe; 3. The compound according to claim 2, characterized in that: The compound is selected from 4. A pharmaceutical composition comprising a compound of any one of claims 1-2 as an active ingredient and a pharmaceutically acceptable excipient.

5. Use of the compound of any one of claims 1-2 in the preparation of medicaments for the treatment and prevention of anti-inflammatory diseases.

6. Use of the compound of any one of claims 1-2 in the preparation of an antitumor drug.

7. The use of the compound according to claim 6 in the preparation of an antitumor drug, characterized in that, The tumor cells mentioned are human liver cancer cells HepG-2, human colorectal cancer cells HCT116, human cervical cancer cells HeLa, or human lung adenocarcinoma cells A549.

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