Application of terphenyl compound in preparation of anti-inflammatory drugs

Abstract

The invention discloses application of terphenyl compounds in preparation of anti-inflammatory drugs. The application refers to application of the compounds in preparation of drugs for preventing and / or treating related diseases caused by inflammation. The terphenyl derivative is found to be capable of obviously reducing the inflammatory reaction induced by lipopolysaccharide, and has good application prospect and commercial value.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a terphenyl compound, a composition and an application thereof, wherein the compound or composition has anti-inflammatory activity and can be used to treat related diseases caused by inflammation. Background Art

[0002] Inflammation is the body's natural biological response to infection and injury, aiming to eliminate harmful substances and restore the normal function of damaged tissues or organs (Medzhitov R. Cell. 2010, 140(6):771-776; Kishore N., et al. Eur. J. Med. Chem. 2019, 179:272-309.). The main signs of inflammation are fever (vasodilation), redness (vasodilation), swelling (increased vascular permeability), pain (physical and chemical stimulation of nociceptors), and loss of function (tissue structure destruction) (Scott A., et al. Br. J. Sports. Med. 2004, 38(3):248-249.). Inflammation is associated with the physiological and pathological processes of many diseases, such as obesity, atherosclerosis, rheumatoid arthritis (RA), gout, Alzheimer's disease (AD), depression, Parkinson's disease and cancer (Villarroya F., et al. J. Intern. Med. 2018, 284(5):492-504; Kasikara C., et al. J. Clin. Invest. 2018, 128(7):2713-2723; Chimenti MS, et al. Cell. Death. Dis. 2015, 6(9):e1887-e1896; So AK, et al. Nat. Rev. Rheumatol. 2017, 13(11):639-647; Heneka MT, et al. Nat. Immunol. 2015, 16(3):229-236; Koopman M., et al. al.Curr.Opin.Psychiatry.2017,30(5):369-377;JoshiN.,et al.J.Neurosci.Res.2018,96(3):379-390;RossiJ.F.Hematol.Transf.Cell.2021,43(S3):S9-S14). Glucocorticoids (steroidal anti-inflammatory drugs) and nonsteroidal anti-inflammatory drugs are two important anti-inflammatory drugs commonly used in clinical practice. The function of glucocorticoids in alleviating inflammatory diseases mainly depends on the interaction with glucocorticoid receptors through multiple pathways. However, long-term or high-dose treatment may lead to serious side effects, including osteoporosis, metabolic diseases and cardiovascular reactions (Rhen T.,et al.New.Engl.J.Med.2005,353(16):1711-1723). Nonsteroidal anti-inflammatory drugs are divided into two categories according to their mechanism of action: non-selective COX inhibitors and selective COX-2 inhibitors.Non-selective COX inhibitors (aspirin, naproxen, indomethacin, and ibuprofen, etc.) inhibit the expression of COX-1 in the gastrointestinal tract, causing it to lose its ability to resist gastric acid, thereby causing gastrointestinal mucosal damage and poor long-term medication safety. Subsequently, selective COX-2 inhibitors (celecoxib, rofecoxib, valdecoxib, parecoxib, etc.) were listed, and gastrointestinal adverse reactions were significantly reduced, but cardiovascular and cerebrovascular adverse reactions were significant (Schjerning AM, et al. Nat. Rev. Cardiol. 2020, 17(9): 574-584.)).

[0003] In recent years, biological agents and anti-cytokine treatments have been developed for the treatment of inflammation. Since anti-cytokine treatments only work outside cells rather than inside cells, organ toxicity and gastrointestinal diseases are rarely observed. However, these drugs can reduce the ability to defend against infection and may even induce cancer. These defects limit its further application (Dinarello CA Cell. 2010, 140 (6): 935-950.). Therefore, finding anti-inflammatory drugs with better efficacy, long-term safety and fewer side effects is an urgent clinical need. Due to its special ecological environment, the ocean has created its species richness and chemical diversity, and is an important source of lead compounds for anti-inflammatory drugs (Carroll AR, et al. Nat. Prod. Rep. 2019, 36 (1): 122-173.).

[0004] Terphenyls are mainly derived from fungi and actinomycetes and exist in nature mainly in the form of p-terphenyls. The structural characteristics of p-terphenyl are composed of a central benzene ring B and two phenyl groups (rings A and C) substituted at the para position of benzene ring B. To date, more than 230 p-terphenyls have been identified, and the number is still increasing. This compound shows a variety of biological activities, such as anti-inflammatory, antibacterial, antioxidant and α-glucosidase inhibition (Zhou G.Marine Life Science & Technology.2022,4:62–73). In recent years, a large number of p-terphenyls with biological activities have been reported. Tian et al. isolated the terphenyl compound 6′-hydroxy-4,2′,3′,4″-tetramethoxy-p-terphenyl from the halophilic actinomycete Nocardiopsis gilva YIM 90087, which showed antifungal activity against three pathogenic fungi, Fusarium avenaceum, F.graminearum, and F.culmorum, with MICs of 8, 16, and 128 μg / mL, respectively (Tian S. Z. Journal of Agricultural and Food Chemistry. 2013, 61(12):3006-3012.). Later, Wang et al. isolated the terphenyl compound nocarterphenyl A from the marine actinomycete Nocardiopsis species, which showed strong cytotoxic activity against HL60 and HCC1954 cancer cell lines, with an IC of 8. 50The values were 0.38 and 0.10 μM, respectively (Wang D. Journal of Natural Products. 2019, 82(12): 3504–3508). Chen et al. reported that candidusin A, a benzofuran terphenyl compound discovered from a marine compound library, is a potent AMPK activator and can be used as a new potential candidate therapeutic drug for the treatment of non-alcoholic steatohepatitis (NASH) (Chen J. Marine Life Science & Technology. 2023, 5: 196). In addition, terphenyl compounds also exhibit a wide range of biological activities such as antioxidant, anti-inflammatory and DNA topoisomerase inhibition, and have important research value (Li W. Journal of Asian Natural Products Research. 2018, 20(1): 1–13; Zhou G. Marine Life Science & Technology. 2022, 4: 62–73). In particular, the terphenyl derivative MK-8722 has been developed as a lead compound for hypoglycemic drugs. Therefore, the potential biological activities of this type of molecule deserve further exploration and research. Summary of the Invention

[0005] The following is a summary of some aspects of the present invention and is not intended to be limiting. These and other aspects are described in greater detail below. All references in this specification are incorporated herein by reference in their entirety. In the event of a discrepancy between the disclosure of this specification and a reference, the disclosure of this specification shall prevail.

[0006] The present invention provides a terphenyl compound for use in treating inflammation-related diseases, including but not limited to Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's disease, indeterminate colitis, mesothelioma, type 1 diabetes, type 2 diabetes, and atherosclerosis. The compound is easy to prepare, stable, and highly active, and therefore has promising clinical application prospects.

[0007] Specifically:

[0008] On the one hand, the present invention relates to a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, especially the use of an anti-inflammatory drug, characterized in that the compound has the following structure: In formula (I), wherein R is optionally wherein Z is optionally 1-5 substituents, wherein the substituents are H, D, F, Cl, Br, I, amino, N,N-dimethylamino, N-methylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C5H 11 , C6H 13 , vinyl, propenyl, allyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, ethynyl, propynyl, propargyl, butynyl, butyl ynyl, pentynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropionyl, 2-chloropropionyl, 2-bromopropionyl, valeryl, hexanoyl, methacryloyl, cyclopropane L is optionally substituted with a 3-amino-4-nitro-2-nitro-4-nitro-6-nitro-7-nitro-8-nitro-9-nitro-10-nitro-11-nitro-12-nitro-13-nitro-14-nitro-16-nitro-17-nitro-18-nitro-21-nitro-22-nitro-23-nitro-24-nitro-26-nitro-27-nitro-30-nitro-41-nitro-28-nitro-29-nitro-31-nitro-32-nitro-33-nitro-34-nitro-35-nitro-36-nitro-37-nitro-40-nitro-38-nitro-41-nitro-50-nitro-61-nitro-7-nitro-18-nitro-29-nitro-39-nitro-40-nitro-51-nitro-61-nitro-7-nitro-19-nitro-20-nitro-21-nitro-22-nitro-33-nitro-23-nitro-34-nitro-28-nitro-36-nitro-41-nitro-29-nitro-37-nitro-

[0009] In some embodiments, the compounds of the present invention have one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, the specific structure is as follows:

[0010]

[0011]

[0012] In another embodiment of the present invention, a terphenyl compound is provided as an anti-inflammatory drug, characterized in that it comprises a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] In addition, another embodiment of the present invention provides a similar terphenyl compound, characterized in that it contains compound au, and the specific structure is as follows:

[0014]

[0015] In another aspect, the present invention relates to a pharmaceutical composition comprising the compound disclosed in the present invention. The pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.

[0016] The term "pharmaceutically acceptable salt" in the present invention refers to non-toxic addition salts of inorganic or organic acids and / or bases; see "Salt selection for basic drugs", International Journal of Pharmaceutics. 1986, 33, 201-217.

[0017] Uses of the compounds and compositions of the present invention

[0018] The compounds or pharmaceutical compositions disclosed in the present invention are drugs that can treat and / or prevent related diseases, wherein the diseases include the diseases caused by inflammation, such as asthma, psoriasis, Parkinson's disease, prion disease, Alzheimer's disease, rheumatoid arthritis, gout, inflammatory bowel disease, cancer (solid tumors, gallbladder cancer), hepatitis, liver cancer, fatty liver disease, cirrhosis, acute or chronic hepatitis caused by viral infection, alcoholic hepatitis, drug or chemical poisoning, mononucleosis, amoebic dysentery, and other systemic infections caused by Epstein-Barr virus (EBV), cytomegalovirus (CMV) or bacteria, acute or chronic nephritis, interstitial nephritis, lupus nephritis, IgA nephropathy Buerg's disease, glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), autoimmune disorders associated with chronic kidney disease (CKD) and inflammation, Goodpasture's syndrome, Wegener's granulomatosis, pyelonephritis, exercise-induced nephritis, kidney stones, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behçet's disease and indeterminate colitis, mesothelioma, type 1 diabetes, type 2 diabetes, atherosclerosis, hypertension, obesity, cardiovascular disease lupus or rheumatism, lung damage, idiopathic pulmonary fibrosis, fungal skin diseases, heart disease, respiratory disease, stroke, scleroderma, scarring Pimples, myocardial fibrosis, diabetic nephropathy, myelodysplastic syndrome, sepsis, infections (such as viral, bacterial, or fungal infections), acne vulgaris, chronic obstructive pulmonary disease, autoimmune diseases, celiac disease, chronic (plaque) prostatitis, pelvic inflammatory disease, reperfusion injury, transplant rejection, interstitial cystitis, allergies (types 1, 2, and 3 hypersensitivity reactions, hay fever), inflammatory myopathies, systemic sclerosis, dermatomyositis, polymyositis, inclusion body myositis, Chediak-Higashi syndrome, chronic granulomatous disease, vitamin A deficiency, periodontitis, granulomatous inflammation (tuberculosis, leprosy, sarcoidosis) disease and syphilis), fibrinous inflammation, suppurative inflammation, serous inflammation, ulcerative inflammation and ischemic heart disease, atopic allergy, atopic dermatitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune polyendocrine syndrome, autoimmune urticaria, cold agglutinin disease, contact dermatitis, discoid lupus erythematosus, erythroblastosis fetalis, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's encephalopathy, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, autoimmune thrombocytopenic purpura, Meniere's disease, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyelitis optica, Devic's diseasedisease), neuromyotonia, oculoclavicular pemphigoid, opsoclonus-myoclonus syndrome, PANDAS (Streptococcal-associated pediatric autoimmune neuropsychiatric disorder), paraneoplastic cerebellar degeneration, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, rheumatic fever, sarcoidosis, subacute bacterial endocarditis (SBE), systemic lupus erythematosus, temporal arteritis (also known as "giant cell arteritis"), thrombocytopenia, undifferentiated connective tissue disease, urticarial vasculitis and vasculitis, and pancreatitis. DETAILED DESCRIPTION

[0019] The following specific examples are used to further illustrate the present invention, but the present invention is by no means limited to these examples.

[0020] Example 1: Compound 1

[0021]

[0022] 2',4"-bis(allyloxy)-3',6'-dimethoxy-[1,1':4',1"-terphenyl]-4-ol (hereinafter referred to as "Compound A") (30 mg, 0.071 mmol) was dissolved in dichloromethane (2 mL). In the presence of DMAP as a catalyst and EDC as a dehydrating agent, an acid reagent (2.5 eq) was added. The reaction was stirred in a 45°C water bath for 4 h. TLC was used to monitor the reaction. Upon completion of the reaction, the reaction was terminated and the mixture was extracted three times with dichloromethane. The organic phases were combined and concentrated under reduced pressure to afford a white solid in a 94% yield with an mp of 158.9–160.2°C. 1 H NMR (400MHz, CDCl3) δ8.26 (d, J=7.8Hz, 2H), 7.65 (t, J=7.6Hz, 1H), 7.57–7.49 (overlapped, 6H) ,7.30(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),6.72(s,1H),6.12(m,1H),5.81(m,1H),5.48(dq,J =17.2,1.6Hz,1H),5.34(dq,J=10.4,1.6Hz,1H),5.16(dq,J=17.2,1.6Hz,1H),5.09(dq,J=10.4 ,1.6Hz,1H),4.62(dt,J=5.6,1.6Hz,2H),4.32(dt,J=5.6,1.6Hz,2H),3.76(s,3H),3.64(s,3H). 13C NMR (100MHz, CDCl3) δ165.2,158.2,153.1,150.9,150.0,145.1,134.9,134.1,133.6,133.4,132.1,132.1,131.6,131.0,130.4,1 30.4,130.3,130.3,129.9,128.7,128.7,124.0,121.0,121.0,117.9,117.6,114.6,114.6,108.1,74.4,69.0,61.0,56.2.HRESIMS m / z 523.2120[M+H] + (calcd.For C 33 H 31 O6 + ,523.2115).

[0023] Example 2: Compound 2

[0024]

[0025] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 95% and mp 168.5–169.9°C. 1 H NMR (400MHz, CDCl3) δ8.13(d,J=8.4Hz,2H),7.54(d,J=8.8Hz,2H),7.49(d,J=8.4Hz,2H),7.34(d,J=8. 8Hz,2H),7.28(d,J=8.8Hz,2H),7.01(d,J=8.8Hz,2H),6.71(s,1H),6.11(m,1H),5.79(m,1H),5.47(dq, J=17.2,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),5.15(dq,J=17.2,1.6Hz,1H),5.08(dq,J=10.4,1.6H z,1H),4.61(dt,J=5.6,1.6Hz,2H),4.31(dt,J=5.6,1.6Hz,2H),3.75(s,3H),3.63(s,3H),2.47(s,3H). 13C NMR (100MHz, CDCl3) δ165.3,158.2,153.1,150.9,150.1,145.1,144.5,134.9,134.2,133.4,132.1,132.1,131.5,131.0,130.4,130. 4,130.4,130.4,129.4,129.4,127.1,124.0,121.0,121.0,117.9,117.6,114.6,114.6,108.2,74.4,69.0,61.0,56.2,21.9.HRESIMS m / z 537.2272[M+H] + (calcd.For C 34 H 33 O6 + ,537.2272).

[0026] Example 3: Compound 3

[0027]

[0028] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 96% and mp 167.9–169.3°C. 1 H NMR (400MHz, CDCl3) δ8.06(1H,s),8.05(1H,d,J=8.0Hz),7.55(2H,d,J=8.8Hz),7.50(2H,d,J=8.8Hz),7 .43(2H,m),7.29(2H,d,J=8.8Hz),7.01(2H,d,J=8.8Hz),6.71(1H,s),6.12(1H,m),5.80(1H,m),5.47(1 H,dq,J=17.2,1.6Hz),5.33(1H,dq,J=10.4,1.6Hz),5.15(1H,dq,J=17.2,1.6Hz),5.09(1H,dq,J=10.4, 1.6Hz), 4.61(2H,dt,J=5.6,1.5Hz), 4.31(2H,dt,J=5.6,1.5Hz), 3.76(3H,s), 3.63(3H,s), 2.47(3H,s); 13C NMR (100MHz, CDCl3) δ165.4,158.1,153.1,150.9,150.0,145.0,138.5,134.9,134.4,134.1,133.4,132.1,132.1,131.5,130.9,130. 8,130.4,130.4,129.8,128.6,127.5,124.0,121.0,121.0,117.9,117.6,114.6,114.6,108.1,74.4,69.0,61.0,56.2,21.5; HRESIMS m / z 537.2269[M+H] + (calcd.For C 34 H 33 O6 + ,537.2272).

[0029] Example 4: Compound 4

[0030]

[0031] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 97% and mp 173.1–174.8°C. 1 H NMR (400MHz, CDCl3) δ8.20 (1H, d, J = 7.6Hz), 7.55 (2H, d, J = 8.8Hz), 7.52–7.48 (3H, overlapped), 7.35 (2H ,t,J=7.6Hz),7.28(2H,d,J=8.8Hz),7.02(2H,d,J=8.8Hz),6.71(1H,s),6.12(1H,m),5.80(1H,m),5.47( 1H,dq,J=17.2,1.6Hz),5.33(1H,dq,J=10.4,1.6Hz),5.16(1H,dq,J=17.2,1.6Hz),5.09(1H,dq,J=10.4, 1.6Hz),4.61(2H,dt,J=5.6,1.5Hz),4.32(2H,dt,J=5.6,1.5Hz),3.75(3H,s),3.63(3H,s),2.72(3H,s); 13C NMR (100MHz, CDCl3) δ165.9,158.2,153.1,150.9,150.0,145.0,141.4,134.9,134.2,133.4,132.8,132.1,132.1,132.1,131.5,131. 3,131.0,130.4,130.4,128.9,126.1,124.0,121.1,121.1,117.9,117.5,114.6,114.6,108.1,74.4,69.0,61.0,56.2,22.1; HRESIMS m / z 537.2275[M+H] + (calcd.For C 34 H 33 O6 + ,537.2272).

[0032] Example 5: Compound 5

[0033]

[0034] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 95% and mp 166.9–168.5°C. 1 H NMR (400MHz, CDCl3) δ7.85(d,J=7.6Hz,1H),7.74(t,J=1.6Hz,1H),7.54(d,J=8.8Hz,2H),7.50(d,J=8.8Hz,2H),7.4 4(t,J=8.0Hz,1H),7.29(d,J=8.8Hz,2H),7.20(dd,J=8.0,2.8Hz,1H),7.01(d,J=8.8Hz,2H),6.71(s,1H),6.11(m,1 H),5.79(m,1H),5.47(dq,J=17.2,1.6Hz,1H),5.33(dq,J=10.6,1.4Hz,1H),5.15(dq,J=17.2,1.6Hz,1H),5.08(dq, J=10.6,1.4Hz,1H),4.61(dt,J=5.5,1.5Hz,2H),4.31(dt,J=5.5,1.5Hz,2H),3.90(s,3H),3.75(s,3H),3.63(s,3H). 13C NMR (100MHz, CDCl3) δ165.1,159.8,158.2,153.1,150.9,150.0,145.1,134.9,134.1,133.4,132.1,132.1,131.6,131.6,130.9,130. 4,130.4,129.7,124.0,122.7,121.0,121.0,120.3,117.9,117.6,114.6,114.6,114.6,108.1,74.4,69.0,61.0,56.2,55.7.HRESIMS m / z 553.2221[M+H] + (calcd.for C 34 H 33 O7 + ,553.2221).

[0035] Example 6: Compound 6

[0036]

[0037] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 91% and mp 125.3–126.9°C. 1 H NMR (400MHz, CDCl3) δ8.06 (dd, J=8.0, 1.6Hz, 1H), 7.58–7.53 (overlapped, 3H), 7.48 (d, J=8.4Hz, 2H), 7.3 0(d,J=8.4Hz,2H),7.07(d,J=8.0Hz,2H),7.02(d,J=8.4Hz,2H),6.70(s,1H),6.11(m,1H),5.79(m,1H),5. 47(dq,J=17.2,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),5.13(dq,J=17.2,1.6Hz,1H),5.07(dq,J=10.4,1 .6Hz,1H),4.61(dt,J=5.2,1.6Hz,2H),4.29(dt,J=5.2,1.6Hz,2H),3.97(s,3H),3.75(s,3H),3.63(s,3H). 13C NMR (100MHz, CDCl3) δ164.4,160.0,158.1,153.1,150.9,150.1,145.1,134.8,134.4,134.1,133.4,132.3,132.0,132.0,131.4,131. 0,130.3,130.3,124.1,121.1,121.1,120.3,119.4,117.9,117.6,114.6,114.6,112.3,108.2,74.4,69.0,61.0,56.2,56.2.HRESIMS m / z553.2221[M+H] + (calcd.for C 34 H 33 O7 + ,553.2221).

[0038] Example 7: Compound 7

[0039]

[0040] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 98% and mp 174.9–176.3°C. 1 H NMR (400MHz, CDCl3) δ8.19(d,J=8.8Hz,2H),7.54(d,J=8.8Hz,2H),7.48(d,J=8.8Hz,2H),7.27(d,J =8.8Hz,2H),7.02–6.99(overlapped,4H),6.70(s,1H),6.11(m,1H),5.79(m,1H),5.47(dq,J=17.2 ,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),5.13(dq,J=17.2,1.6Hz,1H),5.07(dq,J=10.4,1.6Hz,1 H),4.61(dt,J=5.2,1.5Hz,2H),4.30(dt,J=5.2,1.5Hz,2H),3.91(s,3H),3.75(s,3H),3.62(s,3H). 13C NMR (100MHz, CDCl3) δ165.0,164.0,158.2,153.1,150.9,150.1,145.1,134.8,134.2,133.4,132.4,132.4,132.1,132.1,131.4,131. 0,130.4,130.4,124.1,122.2,121.1,121.1,117.9,117.6,114.6,114.6,114.0,114.0,108.1,74.4,69.0,61.0,56.2,55.7.HRESIMS m / z553.2220[M+H] + (calcd.For C 34 H 33 O7 + ,553.2221).

[0041] Example 8: Compound 8

[0042]

[0043] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 92% and mp 147.7–148.9°C. 1 H NMR (400MHz, CDCl3) δ8.04 (dt, J=8.0, 1.6Hz, 1H), 7.92 (dt, J=8.0, 1.6Hz, 1H), 7.57–7.49 (overlapped, 5H) ),7.36(td,J=8.0,1.6Hz,1H),7.28(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),6.71(s,1H),6.12(m,1H),5.7 9(m,1H),5.47(dq,J=17.2,1.6Hz,1H),5.33(dq,J=10.5,1.4Hz,1H),5.15(dq,J=17.2,1.6Hz,1H),5.09(d q,J=10.5,1.4Hz,1H),4.61(dt,J=5.5,1.5Hz,2H),4.32(dt,J=5.5,1.5Hz,2H),3.76(s,3H),3.63(s,3H). 13 C NMR (100 MHz, CDCl3) δ 164.1 (d, 1 J C-F =245.1Hz),164.0,161.5,158.2,153.1,150.9,149.8,145.1,135.0,134.1,133.4,132.2,132.2,132.0(d, 3J C-F =7.4Hz),131.9,130.9,130.4,130.4,130.4(d, 3 J C-F =7.4Hz),126.0(d, 4 J C-F =2.9Hz),123.9,120.8,120.8,117.9,117.6,117.2(d, 2 J C-F =23.2Hz),114.6,114.6,108.1,74.4,69.0,61.0,56.2.HRESIMS m / z 541.2020[M+H] + (calcd.for C 33 H 30 O6F + ,541.2021).

[0044] Example 9: Compound 9

[0045]

[0046] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 95% and mp 145.9–147.2°C. 1 H NMR (400MHz, CDCl3) δ8.14(td,J=7.6,2.0Hz,1H),7.62(m,1H),7.55(d,J=8.8Hz,2H),7.50(d,J=8.8H z,2H),7.31(d,J=8.8Hz,2H),7.25(m,2H),7.01(d,J=8.8Hz,2H),6.71(s,1H),6.12(m,1H),5.79(m,1H ),5.47(dq,J=17.2,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),5.17(dq,J=17.2,1.6Hz,1H),5.08(dq,J =10.4,1.6Hz,1H),4.61(dt,J=5.4,1.6Hz,2H),4.31(dt,J=5.4,1.6Hz,2H),3.75(s,3H),3.63(s,3H). 13 C NMR(100MHz,CDCl3)δ163.7,162.8(d, 1 J C-F =245.1Hz),161.2,158.2,153.1,150.9,149.7,145.1,135.3(d, 3 J C-F=8.0Hz),134.9,134.1,133.4,132.6,132.1,132.1,131.8,130.9,130.3,130.3,124.3(d, 4 J C-F =4.0Hz),123.9,120.9,120.9,117.9,117.6,117.4(d, 2 J C-F =22.3Hz),114.6,114.6,108.1,74.4,69.0,61.0,56.2.HRESIMS m / z541.2021[M+H] + (calcd.For C 33 H 30 O6F + ,541.2021).

[0047] Example 10: Compound 10

[0048]

[0049] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 91% and mp 166.8–168.3°C. 1 H NMR (400MHz, CDCl3) δ8.28–8.23(2H, overlapped),7.54(2H,d,J=8.8Hz),7.49(2H,d,J=8.8Hz),7.27( 2H,d,J=8.8Hz),7.23–7.17(2H,overlapped),7.01(2H,d,J=8.8Hz),6.70(1H,s),6.11(1H,m),5.79(1H ,m),5.46(1H,dq,J=17.2,1.6Hz),5.33(1H,dq,J=10.4,1.6Hz),5.14(1H,dq,J=17.2,1.6Hz),5.08(1H, dq,J=10.4,1.6Hz),4.61(2H,dt,J=5.6,1.5Hz),4.31(2H,dt,J=5.6,1.5Hz),3.75(3H,s),3.62(3H,s); 13 C NMR (100MHz, CDCl3) δ167.5,165.0,164.3,158.2,153.1,150.9,149.9,145.1,135.0,134.1,133.4,132.9(d, 3 J C-F =7.9Hz),132.9(d, 3 JC-F =7.9Hz),132.2,132.2,131.8,131.0,130.4,130.4,126.1(d, 4 J C-F =3.2Hz),123.9,120.9,120.9,117.9,117.6,115.9(d, 2 J C-F =22.1Hz),114.6,114.6,108.2,74.4,69.0,61.0,56.2; HRESIMS m / z 541.2029[M+H] + (calcd.For C 33 H 30 O6F + ,541.2021).

[0050] Example 11: Compound 11

[0051]

[0052] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 96% and mp 168.3–169.7°C. 1 H NMR(400MHz, CDCl3)δ8.18(d,J=8.8Hz,2H),7.55(d,J=8.8Hz,2H),7.53–7.48(overlapped,4H) ,7.28(d,J=8.8Hz,2H),7.01(d,J=8.8Hz,2H),6.71(s,1H),6.11(m,1H),5.79(m,1H),5.47(dq,J =17.2,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),5.14(dq,J=17.2,1.6Hz,1H),5.08(dq,J=10.4 ,1.6Hz,1H),4.61(dt,J=5.6,1.5Hz,2H),4.31(dt,J=5.6,1.5Hz,2H),3.75(s,3H),3.63(s,3H). 13C NMR (100MHz, CDCl3) δ164.4,158.2,153.1,150.9,149.8,145.1,140.2,135.0,134.1,133.4,132.2,132.2,131.8,131.8,131.7,1 30.9,130.9,130.3,129.1,129.1,128.3,123.9,120.9,120.9,117.9,117.5,114.6,114.6,108.2,74.4,69.0,61.0,56.2.HRESIMS m / z 557.1724[M+H] + (calcd.for C 33 H 30 O6Cl + ,557.1725).

[0053] Example 12: Compound 12

[0054]

[0055] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 91% and mp 149.3–150.8°C. 1 H NMR (400MHz, CDCl3) δ8.22(t,J=1.6Hz,1H),8.12(dt,J=8.0,1.6Hz,1H),7.62(d,J=8.0Hz,1H),7.54(d,J=8. 8Hz,2H),7.51–7.46(overlapped,3H),7.27(d,J=8.8Hz,2H),7.01(d,J=8.8Hz,2H),6.70(s,1H),6.11(m,1H ),5.78(m,1H),5.47(dq,J=17.2,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),5.14(dq,J=17.2,1.6Hz,1H),5.0 8(dt,J=10.4,1.6Hz,1H),4.61(dt,J=5.6,1.6Hz,2H),4.30(dt,J=5.6,1.6Hz,2H),3.75(s,3H),3.62(s,3H). 13CNMR(100MHz, CDCl3)δ164.1,158.2,153.1,150.9,149.8,145.1,135.0,134.9,134.1,133.7,133.4,132.2,132.2,131.9,131.7,13 0.9,130.4,130.4,130.3,130.0,128.4,123.9,120.8,120.8,117.9,117.6,114.6,114.6,108.1,74.4,69.0,61.0,56.2.HRESIMSm / z 557.1722[M+H] + (calcd.For C 33 H 30 O6Cl + ,557.1725).

[0056] Example 13: Compound 13

[0057]

[0058] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 94% and mp 157.1–158.5°C. 1 H NMR (400MHz, CDCl3) δ8.08 (dd, J=8.0, 1.6Hz, 1H), 7.55 (d, J=8.8Hz, 2H), 7.54–7.49 (overlapped, 4H), 7 .41(td,J=8.0,1.6Hz,1H),7.32(d,J=8.8Hz,2H),7.01(d,J=8.8Hz,2H),6.71(s,1H),6.11(m,1H),5.79( m,1H),5.47(dq,J=17.2,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),5.15(dq,J=17.2,1.6Hz,1H),5.08(dq ,J=10.4,1.6Hz,1H),4.61(dt,J=5.6,1.6Hz,2H),4.31(dt,J=5.6,1.6Hz,2H),3.75(s,3H),3.63(s,3H). 13C NMR (100MHz, CDCl3) δ164.1,158.2,153.1,150.9,149.7,145.0,134.9,134.5,134.1,133.4,133.2,132.2,132.2,132.0,131.9,13 1.5,130.9,130.3,130.3,129.6,126.9,123.9,120.9,120.86,117.90,117.6,114.6,114.6,108.1,74.4,69.0,61.0,56.2.HRESIMS m / z557.1722[M+H] + (calcd.For C 33 H 30 O6Cl + ,557.1725).

[0059] Example 14: Compound 14

[0060]

[0061] A pale yellow solid was obtained by referring to the preparation method of Example 1 with a yield of 94% and mp 130–131.8°C. 1 H NMR (400MHz, CDCl3) δ7.90 (1H, d, J = 16.0Hz), 7.61 (2H, dd, J = 6.5, 3.0Hz), 7.54 (2H, d, J = 8.8Hz), 7.4 8–7.43(5H, overlapped),7.24(2H,d,J=8.0Hz),7.01(2H,d,J=8.8Hz),6.70(1H,s)6.67(1H,d,J=16 .0Hz),6.11(1H,m),5.78(1H,m),5.47(1H,d,J=17.2Hz),5.33(1H,d,J=10.4Hz),5.13(1H,d,J=17.2 Hz), 5.07 (1H, d, J = 10.4Hz), 4.61 (2H, d, J = 5.2Hz), 4.29 (2H, d, J = 5.2Hz), 3.75 (3H, s), 3.62 (3H, s). 13C NMR (100MHz, CDCl3) δ165.5,158.2,153.1,150.9,149.9,146.6,145.1,134.9,134.4,134.1,133.4,132.1,132.1,131.5,131.0,130.8,1 30.4,130.4,129.1,129.1,128.4,128.4,124.0,120.9,120.9,117.9,117.7,117.6,114.6,114.6,108.2,74.4,69.0,61.0,56.2; m / z 549.2274[M+H] + (calcd.For C 35 H 33 O6 + ,549.2272).

[0062] Example 15: Compound 15

[0063]

[0064] A pale yellow solid was obtained by referring to the preparation method of Example 1 with a yield of 96% and mp 156–157.7°C. 1 H NMR (400MHz, CDCl3) δ7.85(d,J=16.0Hz,1H),7.57(d,J=8.6Hz,2H),7.54(d,J=8.6Hz,2H),7.47(d,J=8.6Hz,2H) ,7.23(d,J=8.6Hz,2H),7.01(d,J=8.6Hz,2H),6.95(d,J=8.6Hz,2H),6.70(s,1H),6.54(d,J=16.0Hz,1H),6.11( m,1H),5.78(m,1H),5.47(dd,J=10.4,1.6Hz,1H),5.33(dd,J=10.4,1.6Hz,1H),5.13(dd,J=10.4,1.6Hz,1H),5. 07(dd,J=10.4,1.6Hz,1H),4.61(d,J=5.6Hz,2H),4.29(d,J=5.6Hz,2H),3.87(s,3H),3.75(s,3H),3.63(s,3H). 13C NMR (100MHz, CDCl3) δ165.8,161.8,158.1,153.1,150.9,150.0,146.2,145.0,134.8,134.1,133.4,132.0,132.0,131.3,131.0,130.4,130. 4,130.2,130.2,127.1,124.0,120.9,120.9,117.9,117.6,115.0,114.6,114.6,114.6,114.6,108.1,74.4,69.0,61.0,56.2,55.5.HRESIMS m / z 579.2380[M+H] + (calcd.for C 36 H 35 O7 + ,579.2377).

[0065] Example 16: Compound 16

[0066]

[0067] A pale yellow solid was obtained by referring to the preparation method of Example 1 with a yield of 92% and mp 160.1–161.6°C. 1 H NMR (400MHz, CDCl3) δ8.18(dd,J=8.0,1.6Hz,1H),7.55(d,J=8.8Hz,2H),7.49(d,J=8.8Hz,2H),7.47(td,J=7.2,2Hz, 1H),7.24(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),6.74(d,J=8.0Hz,1H),6.71(s,1H),6.68(d,J=8.0Hz,1H),6.12(m, 1H),5.80(m,1H),5.47(dq,J=17.2,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),5.15(dq,J=17.2,1.6Hz,1H),5.09(dq, J=10.4,1.6Hz,1H),4.61(dt,J=5.2,1.5Hz,2H),4.31(dt,J=5.2,1.5Hz,2H),3.75(s,3H),3.64(s,3H),2.95(s,3H). 13C NMR (100MHz, CDCl3) δ167.4,158.2,153.2,152.8,150.9,149.9,145.1,135.5,134.8,134.2,133.4,132.2,132.1,132.1,131.4,131. 0,130.4,130.4,124.1,121.2,121.2,117.9,117.5,114.6,114.6,114.6,111.0,109.1,108.2,74.4,69.0,61.0,56.2,29.7.HRESIMS m / z 552.2388[M+H] + (calcd.for C 34 H 34 O6N + ,552.2381).

[0068] Example 17: Compound 17

[0069]

[0070] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 91% and mp 158.3–159.8°C. 1 H NMR(400MHz, CDCl3) δ7.86(d,J=16.0Hz,1H),7.63–7.58(overlapped,2H),7.54(d,J=8.8Hz,2H),7.47(d,J=8.8H z,2H),7.23(d,J=8.8Hz,2H),7.13(t,J=8.8Hz,2H),7.01(d,J=8.8Hz,2H),6.70(s,1H),6.59(d,J=16.0Hz,1H),6 .11(m,1H),5.78(m,1H),5.47(dq,J=17.2,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),5.13(dq,J=17.2,1.6Hz,1H) ,5.07(dq,J=10.4,1.6Hz,1H),4.61(dt,J=5.4,1.5Hz,2H),4.29(dt,J=5.4,1.5Hz,2H),3.75(s,3H),3.62(s,3H). 13 C NMR (100 MHz, CDCl3) δ 165.5 (d, 1 J C-F=251.4Hz),163.0,158.2,153.1,150.9,149.8,145.2,145.1,134.9,134.1,133.4,132.1,132.1,131.5,131.0,130.7,130.6(d, 4 J C-F =7.8Hz),130.4,130.4(d, 3 J C-F =7.5Hz),130.3,124.0,120.8,120.8,117.9,117.6,117.4,116.3(d, 3 J C-F =22.1Hz),116.3(d, 3 J C-F =22.1Hz),114.6,114.6,108.1,74.4,69.0,61.0,56.2.HRESIMS m / z 567.2172[M+H] + (calcd.For C 35 H 32 O6F + ,567.2177).

[0071] Example 18: Compound 18

[0072]

[0073] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 92% and mp 151.2–152.8°C. 1 H NMR(400MHz, CDCl3) δ7.90(d,J=16.0Hz,1H),7.73–7.68(overlapped,4H),7.54(d,J=8.8Hz,2H),7.48(d,J =8.8Hz,2H),7.24(d,J=8.8Hz,2H),7.01(d,J=8.8Hz,2H),6.74(d,J=16.0Hz,1H),6.70(s,1H),6.11(m,1H), 5.78(m,1H),5.47(dq,J=17.2,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),5.13(dq,J=17.2,1.6Hz,1H),5.07 (dq,J=10.4,1.6Hz,1H),4.61(dt,J=5.2,1.6Hz,2H),4.30(dt,J=5.2,1.6Hz,2H),3.75(s,3H),3.62(s,3H). 13CNMR (100MHz, CDCl3) δ164.9,158.2,153.1,150.9,149.7,145.1,144.6,137.7,135.0 ,134.1,133.4,132.4,132.4,132.1,131.7,130.9,130.4,130.4,128.5,128.5,126.1( 1 J C-F =272.1Hz),126.1,123.9,122.6,120.8,120.8,120.3,117.9,117.6,114.6,114.6,108.1,74.4,69.0,61.0,56.2.HRESIMS m / z 617.2142[M+H] + (calcd.for C 36 H 32 O6F3 + ,617.2145).

[0074] Example 19: Compound 19

[0075]

[0076] A white solid was obtained by referring to the preparation method of Example 1 with a yield of 93% and mp 159.4–160.9°C. 1 H NMR (400MHz, CDCl3) δ7.84(d,J=16.0Hz,1H),7.54(d,J=8.0Hz,4H),7.47(d,J=8.8Hz,2H),7.41(d,J=8.8H z,2H),7.23(d,J=8.8Hz,2H),7.01(d,J=8.8Hz,2H),6.70(s,1H),6.64(d,J=16.0Hz,1H),6.11(m,1H),5.7 8(m,1H),5.47(dq,J=17.2,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),5.13(dq,J=17.2,1.6Hz,1H),5.07(d q,J=10.4,1.6Hz,1H),4.61(dt,J=5.4,1.5Hz,2H),4.30(dt,J=5.4,1.6Hz,2H),3.75(s,3H),3.62(s,3H). 13C NMR (100MHz, CDCl3) δ165.2,158.2,153.1,150.9,149.8,145.1,145.1,136.7,134.9,134.1,133.4,132.9,132.1,132.1,131.6,130.9,130 .4,130.4,129.6,129.6,129.4,129.4,123.9,120.8,120.8,118.2,117.9,117.5,114.6,114.6,108.1,74.4,69.0,61.0,56.2.HRESIMSm / z 583.1878[M+H] + (calcd.For C 35 H 32 O6Cl + ,583.1882).

[0077] Example 20: Compound 20

[0078]

[0079] A white solid was obtained by the preparation method of Example 1 with a yield of 89% and mp 95.3–96.8°C. 1 H NMR (400MHz, CDCl3) δ7.96(dd,J=8.0,2.0Hz,1H),7.54(d,J=8.8Hz,2H),7.48(d,J=8.8Hz,2H),7.44(td,J=8.4,1 .6Hz,1H),7.29(d,J=8.8Hz,2H),7.04–6.99(overlapped,3H),6.93(t,J=8.0Hz,1H),6.70(s,1H),6.11(m,1H),5 .79(m,1H),5.47(dq,J=17.2,1.6Hz,1H),5.33(dq,J=10.4,1.6Hz,1H),5.14(dq,J=17.2,1.6Hz,1H),5.07(dq,J= 10.4,1.6Hz,1H),4.61(dt,J=5.2,1.6Hz,2H),4.30(dt,J=5.2,1.6Hz,2H),3.75(s,3H),3.63(s,3H),2.97(s,6H). 13C NMR (100MHz, CDCl3) δ166.4,158.2,153.2,153.2,150.9,150.2,145.1,134.8,134.2,133.4,133.0,132.4,132.1,132.1,131.3,131.0, 130.4,130.4,124.1,121.0,121.0,119.9,118.7,117.9,117.6,117.0,114.6,114.6,108.2,74.4,69.0,61.0,56.2,44.0,44.0.HRESIMS m / z 566.2540[M+H] + (calcd.For C 35 H 36 O6N + ,566.2537).

[0080] Example 21: Compound 21

[0081]

[0082] A white solid was obtained by following the preparation method of Example 1 with a yield of 97% and an mp of 168.6–169.8°C. 1 H NMR (400MHz, CDCl3) δ7.89 (1H, d, J = 16.0Hz), 7.56–7.47 (6H, overlapped), 7.25 (4H, dd, J = 8.8, 2.0Hz ),7.02(2H,d,J=8.8Hz),6.71(1H,s),6.63(1H,d,J=16.0Hz),6.12(1H,m),5.79(1H,m),5.48(1H,dq, J=17.2,1.6Hz),5.34(1H,dq,J=10.4,1.6Hz),5.14(1H,dq,J=17.2,1.6Hz),5.08(1H,dq,J=10.4,1.6 Hz),4.62(2H,dt,J=5.2,1.5Hz),4.31(2H,dt,J=5.2,1.6Hz),3.76(3H,s),3.64(3H,s),2.42(3H,s); 13C NMR (100MHz, CDCl3) δ165.6,158.1,153.1,150.9,149.9,146.6,145.0,141.3,134.8,134.1,133.4,132.0,132.0,131.6,131.4,130.9,130. HRESIMS m / z 563.2430[M+H] + (calcd.for C 36 H 35 O6 + ,563.2428).

[0083] Example 22 Anti-inflammatory activity test

[0084] (1) Activity test cell model: LPS-induced RAW264.7 inflammation model.

[0085] (2) Activation and passage of RAW 264.7 macrophages: RAW 264.7 cells were removed and revived in a 37°C water bath. After transferring the cryopreservation solution, 5 times complete medium DMEM was added and placed in a centrifuge (800 rpm, 5 min). The cells were cultured in a 37°C, 5% CO2 incubator. The cell growth was observed. When the cells grew to cover 80–90% of the culture dish, they were passaged: the cells were digested with trypsin and cultured in a culture dish containing fresh culture medium. When the cells reached the logarithmic growth phase, the MTT assay was performed.

[0086] (3) MTT assay to detect the effect of compounds on RAW 264.7 cell activity: RAW 264.7 cells with good growth status were selected and cultured in DMEM medium containing 10% FBS, 100 μg / mL penicillin and 100 μg / mL streptomycin. 1×10 cells were cultured. 4 Cells were plated / well in a 96-well plate and incubated at 37°C in a 5% CO2 incubator for 12 hours. Test compounds were added at varying concentrations for 24 hours, with triplicate wells per group. After 24 hours of incubation, 120 μL of 5 mg / mL MTT was added to each well. After 4 hours of incubation, the supernatant was discarded and 200 μL of DMSO was added to each well. Dissolved by mixing, the OD values were measured at 570 nm using a microplate reader.

[0087] (3) Griess method was used to detect the effects of compounds on NO release in LPS-activated RAW 264.7 cells: the cell concentration was adjusted to 1.2×10 6 Cells / well were plated in a 6-well plate and cultured in an incubator for 24 hours. The culture medium was discarded, and 1 mL of serum-free DMEM was added to each well. Various concentrations of the compound of the present invention and LPS (1 μg / mL) were added and incubated for 24 hours. The supernatant was collected and the NO concentration in the culture supernatant was assayed according to the kit instructions. The OD value at 450 nm was measured using a microplate reader. Care was taken to protect the cells from light during the experiment, and triplicate wells were set for each sample.

[0088] Test results:

[0089] Table 1 Effects of the compounds of the present invention at 0.08 μM on NO release from LPS-activated RAW264.7 cells

[0090]

[0091]

[0092] Note: In the table, “++++” indicates an inhibition rate ≥ 70%; “+++” indicates an inhibition rate of 40-69%; “++” indicates an inhibition rate of 20-39%; “+” indicates an inhibition rate of 5-19%; and “-” indicates an inhibition rate of less than 5%.

[0093] Note: The present invention tested NG-Monomethyl-L-arginine, Monoacetate Salt (L-NMMA), Compound A in parallel. And compound au was used as a control.

[0094] Conclusion: After screening the effects of the compounds of the present invention on the release of NO from LPS-activated RAW264.7 cells, it was found that compared with compound A, compounds 1-21 of the present invention have stronger NO inhibition activity and have great application prospects in inflammatory diseases.

[0095] Example 23 ELISA assay for the effects of compounds on the release of TNF-α, IL-6, and IL-1β in LPS-activated RAW 264.7 cells

[0096] RAW 264.7 cells with good growth status were selected and cell suspension was prepared with DMEM culture medium. The cell concentration was adjusted to 1.2×10 6The concentration of cells / well was plated in a 6-well plate and cultured in an incubator for 24 hours. The culture medium was discarded, 1 mL of serum-free DMEM culture medium was added to each well, and different concentrations of the natural alkaloid compounds to be tested and LPS (1 μg / mL) were added and cultured for 24 hours. The supernatant was collected for detection. The kit and other required reagents were placed in a room temperature environment for 30 minutes in advance, the diluent and washing solution required for the experiment were diluted to 1×, and the standard was diluted according to the instructions. 50 μL of 1× diluent and sample were added to each well of the microplate, the wells were sealed with adhesive tape, and incubated at room temperature for 2 hours. Pour out the liquid in the wells, add 300 μL of 1× detergent to each well, repeat the wash three times, and fully remove the residual liquid. 100 μL of enzyme-labeled detection antibody was added to each well, the wells were sealed with adhesive tape, and incubated at room temperature for 2 hours. Discard the liquid in the wells and add 300 μL of 1x detergent to each well. Repeat the wash three times to thoroughly remove any residual liquid. Add 100 μL of chromogenic substrate to each well and incubate at room temperature in the dark for 30 minutes. Add 100 μL of stop solution to each well. Within 30 minutes, when the liquid in the wells turns from blue to yellow, measure the OD value at a wavelength of 450 nm using a microplate reader. Plot the curve according to the instructions and calculate the content.

[0097] Test results:

[0098] Table 2 Effects of some compounds of the present invention on the release of TNF-α, IL-6 and IL-1β in LPS-activated RAW 264.7 cells

[0099] Compound TNF-α inhibition rate (0.08μM) IL-6 inhibition rate (0.08μM) IL-1β inhibition rate (0.4μM) 6 ++++ ++++ ++ 9 ++++ ++++ + 15 - ns ns

[0100] Note: Compared with LPS group: "++++" in the table means **** p<0.0001; “+++” indicates *** p<0.001; “++” indicates ** p<0.01; “+” indicates * p<0.05; “-” indicates no activity; “ns” indicates not tested.

[0101] Conclusion: After screening the effects of some compounds of the present invention on the release of TNF-α, IL-6, and IL-1β from LPS-activated RAW264.7 cells, it was found that compounds 6 and 9 of the present invention had significant inhibitory effects on the release of TNF-α, IL-6, and IL-1β, further demonstrating the anti-inflammatory potential of the compounds and great application prospects in inflammatory diseases.

[0102] It should be noted that there are other ways to implement the present invention; accordingly, the embodiments of the present invention are described as examples, but are not limited to the contents described in the present invention, and may also be modifications made within the scope of the present invention or equivalent contents added in the claims; all publications or patents cited in the present invention will be used as references of the present invention.

Claims

1. A terphenyl compound, characterized in that: The compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, especially the use of an anti-inflammatory drug, characterized in that the compound has the following structure: In formula (I), wherein R is optionally wherein Z is optionally 1-5 substituents, wherein the substituents are H, D, F, Cl, Br, I, amino, N,N-dimethylamino, N-methylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C5H 11 , C6H 13 , vinyl, propenyl, allyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, ethynyl, propynyl, propargyl, butynyl, butyl ynyl, pentynyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropionyl, 2-chloropropionyl, 2-bromopropionyl, valeryl, hexanoyl, methacryloyl, cyclopropane L is optionally substituted with a 3-amino-4-nitro-2-nitro-4-nitro-6-nitro-7-nitro-8-nitro-9-nitro-10-nitro-11-nitro-12-nitro-13-nitro-14-nitro-16-nitro-17-nitro-18-nitro-21-nitro-22-nitro-23-nitro-24-nitro-26-nitro-27-nitro-30-nitro-41-nitro-28-nitro-29-nitro-31-nitro-32-nitro-33-nitro-34-nitro-35-nitro-36-nitro-37-nitro-40-nitro-38-nitro-41-nitro-50-nitro-61-nitro-7-nitro-18-nitro-29-nitro-39-nitro-40-nitro-51-nitro-61-nitro-7-nitro-19-nitro-20-nitro-21-nitro-22-nitro-33-nitro-23-nitro-34-nitro-28-nitro-36-nitro-41-nitro-29-nitro-37-nitro- 2. The compound according to claim 1, characterized in that Having one of the following structures or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, the specific structure is as follows:

3. A pharmaceutical composition, characterized in that Comprising the compound according to any one of claims 1-2.

4. The pharmaceutically acceptable salt of any one of claims 1 to 2 is selected from the group consisting of hydrochloride, sulfate, phosphate, oxalate, maleate, methanesulfonate, succinate, citrate, fumarate, glucuronate, formate, acetate, and succinate; and the solvate or solvate of the salt is selected from the group consisting of monohydrate, dihydrate, trihydrate, monomethanolate, dimethanolate, monoacetonitrile, diacetonitrile, monoacetoneate, diacetoneate, hemifumarate monohydrate, fumarate dihydrate, and fumarate monoethanolate.

5. A drug capable of treating and / or preventing diseases caused by inflammation, characterized in that The invention contains the compound according to claim 1 or 2, its stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof as an active ingredient.

6. Use of the drug according to claim 5 in treating and / or preventing related diseases, wherein the diseases include the diseases caused by inflammation such as asthma, psoriasis, Parkinson's disease, prion disease, Alzheimer's disease, rheumatoid arthritis, gout, inflammatory bowel disease, cancer (solid tumors, gallbladder cancer), hepatitis, liver cancer, fatty liver disease, cirrhosis, acute or chronic hepatitis caused by viral infection, alcoholic hepatitis, drug or chemical poisoning, mononucleosis, amoebic dysentery and other systemic infections caused by Epstein-Barr virus (EBV), cytomegalovirus (CMV) or bacteria, acute or chronic nephritis, interstitial nephritis, lupus nephritis, IgA nephropathy Buerg's disease, glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), autoimmune disorders associated with chronic kidney disease (CKD) and inflammation, Goodpasture's syndrome, Wegener's granulomatosis, pyelonephritis, exercise-induced nephritis, kidney stones, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behçet's disease and indeterminate colitis, mesothelioma, type 1 diabetes, type 2 diabetes, atherosclerosis, hypertension, obesity, cardiovascular disease lupus or rheumatism, lung damage, idiopathic pulmonary fibrosis, fungal skin diseases, heart disease, respiratory disease, stroke, scleroderma, scarring Pimples, myocardial fibrosis, diabetic nephropathy, myelodysplastic syndrome, sepsis, infections (such as viral, bacterial, or fungal infections), acne vulgaris, chronic obstructive pulmonary disease, autoimmune diseases, celiac disease, chronic (plaque) prostatitis, pelvic inflammatory disease, reperfusion injury, transplant rejection, interstitial cystitis, allergies (types 1, 2, and 3 hypersensitivity reactions, hay fever), inflammatory myopathies, systemic sclerosis, dermatomyositis, polymyositis, inclusion body myositis, Chediak-Higashi syndrome, chronic granulomatous disease, vitamin A deficiency, periodontitis, granulomatous inflammation (tuberculosis, leprosy, sarcoidosis) disease and syphilis), fibrinous inflammation, suppurative inflammation, serous inflammation, ulcerative inflammation and ischemic heart disease, atopic allergy, atopic dermatitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune polyendocrine syndrome, autoimmune urticaria, cold agglutinin disease, contact dermatitis, discoid lupus erythematosus, erythroblastosis fetalis, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's encephalopathy, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, autoimmune thrombocytopenic purpura, Meniere's disease, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyelitis optica, Devic's diseasedisease), neuromyotonia, oculoclavicular pemphigoid, opsoclonus-myoclonus syndrome, PANDAS (Streptococcal-associated pediatric autoimmune neuropsychiatric disorder), paraneoplastic cerebellar degeneration, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, rheumatic fever, sarcoidosis, subacute bacterial endocarditis (SBE), systemic lupus erythematosus, temporal arteritis (also known as "giant cell arteritis"), thrombocytopenia, undifferentiated connective tissue disease, urticarial vasculitis and vasculitis, and pancreatitis.

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