Terphenyl compound and effect of terphenyl compound as anti-inflammatory drug

Abstract

The invention relates to an application of a terphenyl compound as an anti-inflammatory drug, belongs to the field of medicinal chemistry, and particularly relates to a terphenyl compound which comprises a stereoisomer, a geometric isomer, a tautomer, nitrogen oxide, hydrate, solvate, metabolite and ester of the terphenyl compound. The pharmaceutically acceptable salt or the prodrug thereof and the pharmaceutical composition containing the compound are used as medicines, especially used for treating and / or preventing related diseases caused by inflammation.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals, and particularly relates to a terphenyl compound, a composition and an application. The compound or composition has anti-inflammatory activity and can be used for treating related diseases caused by inflammation. Background Art

[0002] Inflammation is a natural biological response of the body 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 (destruction of tissue structure) (Scott A., et al. Br. J. Sports. Med. 2004, 38(3): 248-249.). Inflammation is associated with the physiological and pathological processes of various diseases, such as obesity, atherosclerosis, rheumatoid arthritis (RA), gout, Alzheimer's disease (AD), depression, Parkinson's disease, and cancer, etc. (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 M.S., et al. Cell Death Dis. 2015, 6(9): e1887-e1896; So A.K., et al. Nat. Rev. Rheumatol. 2017, 13(11): 639-647; Heneka M.T., et al. Nat. Immunol. 2015, 16(3): 229-236; Koopman M., et al. Curr. Opin. Psychiatry. 2017, 30(5): 369-377; Joshi N., et al. J. Neurosci. Res. 2018, 96(3): 379-390; Rossi J.F. Hematol. Transf. Cell. 2021, 43(S3): S9-S14). Glucocorticoids (steroidal anti-inflammatory drugs) and non-steroidal 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 their 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). Therefore, finding anti-inflammatory drugs with better efficacy, safe for long-term use, and fewer side effects is an urgent clinical need.Due to its special ecological environment, the ocean has rich species and chemical diversity, making it an important source of anti-inflammatory drug lead compounds (Carroll A.R., et al. Nat. Prod. Rep. 2019, 36(1):122-173.).

[0003] Terphenyls are mainly derived from fungi and actinomycetes and mainly exist in the form of p-terphenyls in nature. The structure of p-terphenyl is composed of a central benzene ring B and two phenyl groups (ring A and C) substituted at the para position of benzene ring B. So far, more than 230 p-terphenyls have been identified, and the number is still increasing. This compound exhibits various biological activities such as anti-inflammatory, antibacterial, antioxidant, and α-glucosidase inhibitory effects (Zhou G. Marine Life Science & Technology. 2022, 4:62–73). Therefore, the potential biological activities of this class of molecules are worthy of further exploration and research. Summary of the Invention

[0004] The following only generally describes some aspects of the present invention and is not limited thereto. These aspects and other parts are more fully described later. All references in this specification are incorporated herein by reference in their entirety. When there are differences between the disclosure of this specification and the cited literature, the disclosure of this specification shall prevail.

[0005] The present invention provides a terphenyl compound for treating diseases caused by inflammation, including but not limited to Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's disease, indeterminate colitis, inflammatory bowel disease, etc. The compounds of the present invention are easy to prepare, have stable properties and strong activities, and thus have good clinical application prospects.

[0006] Specifically:

[0007] On the one hand, the present invention relates to a terphenyl compound, characterized in that it is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, especially for use as an anti-inflammatory drug, characterized in that the compound has the following structure:

[0008] In formula (I), wherein R1 and R2 are each independently optionally H, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 alkylamino, C 1-8 alkylacyl, C1-8 Halogenated alkoxy, C 1-8 Halogenated alkanamino, C 1-8 Halogenated alkanoyl, C 1-8 Aminoalkoxy, C 3-8 Cycloalkyl, 3- to 6-membered heterocyclic group, aryl, 5- to 6-membered heteroaryl, aryloxy, heteroaryloxy, heteroaroyl, heteroarylamino, heteroarylalkoxy, heteroarylalkamino, heterocyclic group alkanoyl, heterocycloalkyl, heterocyclic group oxy, heterocyclic group amino, heterocyclic group acyl, heterocyclic group alkoxy, heterocyclic group alkamino, heterocyclic group alkanoyl, azidoalkoxy, fused bicyclic group, fused heterobicyclic group, fused heteroaryl, fused bicyclic group aliphatic substituent, biaryl, triaryl, fused biaryl, fused triaryl,

[0009] R3 is optionally wherein Z is independently selected from C 3-8 Cycloalkyl, substituted or unsubstituted C 3-6 membered heterocyclic group, substituted or unsubstituted C 5-6 membered heteroaryl, heterocycloalkyl, heterocyclic group oxy, heterocyclic group amino, heterocyclic group alkoxy, heterocyclic group alkamino, azidoalkoxy, fused bicyclic group, fused heterobicyclic group, fused heteroaryl, fused bicyclic group aliphatic substituent, biaryl, triaryl, fused biaryl, fused triaryl, wherein C 3-6 heterocyclic group, C 5-6 heteroaryl may each independently optionally be substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C3-6 cycloalkyl, 3- to 6-membered heterocyclic group, aryl or 5- to 6-membered heteroaryl;

[0010] L is optionally a bond, C 1-6 alkylene, vinyl, propenyl, allyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, ethynyl, propynyl, propargyl, butynyl, butynyl, pentynyl.

[0011] In some embodiments, the compounds of the present invention have one of the following structures or their stereoisomers, geometric isomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs, and the specific structures are as follows:

[0012]

[0013] Another embodiment of the present invention provides the use of a polyhalogenated quinazolinone alkaloid as an anti-Staphylococcus aureus antibacterial agent, which is characterized in that it comprises a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

[0014] In addition, another embodiment of the present invention provides terphenyl compounds of the same kind, which are characterized by containing compound a-r, specifically:

[0015]

[0016] On the other hand, the present invention relates to a pharmaceutical composition, which contains the compounds disclosed in the present invention. The pharmaceutical composition according to the present invention further contains pharmaceutically acceptable excipients, carriers, adjuvants, solvents or combinations thereof.

[0017] 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.

[0018] Uses of the compounds and compositions of the present invention

[0019] The compounds or pharmaceutical compositions disclosed by the present invention can be used as drugs for treating and / or preventing related diseases, and the diseases include those caused by inflammation such as Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's disease and undetermined colitis, inflammatory bowel disease, cancer (solid tumor, gallbladder cancer), hepatitis, liver cancer, fatty liver disease, cirrhosis, asthma, psoriasis, Parkinson's disease, prion disease, Alzheimer's disease, rheumatoid arthritis, gout, acute or chronic hepatitis caused by viral infection, alcoholic hepatitis, drug or chemical poisoning, mononucleosis, amebic 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 (Berger's disease), glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), autoimmune disorders related to chronic kidney disease (CKD) and inflammation, Goodpasture syndrome, Wegener's granulomatosis, pyelonephritis, exercise-induced nephritis, kidney stones, mesothelioma, type I diabetes, type II diabetes, atherosclerosis, hypertension, obesity, cardiovascular disease, lupus or rheumatism, lung injury, idiopathic pulmonary fibrosis, dermatomycosis, heart disease, respiratory disease, stroke, scleroderma, keloid, myocardial fibrosis, diabetic nephropathy, myelodysplastic syndrome, sepsis, infection (such as viral, bacterial or fungal infection), acne vulgaris, chronic obstructive pulmonary disease, autoimmune disease, celiac disease, chronic (plaque) prostatitis, pelvic inflammatory disease, reperfusion injury, transplant rejection, interstitial cystitis, allergies (type 1, 2 and 3 hypersensitivity, hay fever), inflammatory myopathy, systemic sclerosis, dermatomyositis, polymyositis, inclusion body myositis, Chediak-Higashi syndrome, chronic granulomatous disease, vitamin A deficiency, periodontitis, granulomatous inflammation (tuberculosis, leprosy, sarcoidosis 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, subacute bacterial endocarditis (SBE), systemic lupus erythematosus, temporal arteritis (also known as "giant cell arteritis"), thrombocytopenia, undifferentiated connective tissue disease, urticarial vasculitis and vasculitis, pancreatitis, Meniere's disease, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyelitis optica, Devic'sdisease), neuromyotonia, cicatricial pemphigoid, opsoclonus myoclonus syndrome, PANDAS (streptococcal-related pediatric autoimmune neuropsychiatric disorders), paraneoplastic cerebellar degeneration, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, rheumatic fever, sarcoidosis.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0021] The present invention discovers that a terphenyl compound can significantly reduce the inflammatory response induced by lipopolysaccharide, and has good application prospects and commercial value. Detailed implementation manners

[0022] The following specific examples are used to further illustrate the present invention, but the present invention is by no means limited to these examples.

[0023] Example 1: Compound 1

[0024]

[0025] Dissolve 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) in dichloromethane (2 mL). Under the conditions of catalyst DMAP and dehydrating agent EDC, add an acid reagent (2.5 eq), and stir and react at 45 °C in a water bath for 4 h. Monitor by TLC plate. When Compound A has reacted completely, terminate the reaction. Extract with dichloromethane three times, combine the organic phases, and concentrate under reduced pressure to obtain a white solid with a yield of 92% and mp 121.5–122.7 °C. 1 H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.74 (d, J = 2.8 Hz, 1H), 8.18 (dt, J = 8.0, 2.8 Hz, 1H), 7.56–7.50 (overlapped, 4H), 7.29 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 6.11 (m, 1H), 5.79 (m, 1H), 5.47 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J = 10.4, 1.6 Hz, 1H), 5.13 (dq, J = 17.2, 1.6 Hz, 1H), 5.07 (dq, J = 10.4, 1.6 Hz, 1H), 4.61 (dt, J = 5.4, 1.5 Hz, 2H), 4.32 (dt, J = 5.4, 1.5 Hz, 2H), 3.76 (s, 3H), 3.63 (s, 3H). 1313C NMR (100 MHz, CDCl3) δ 162.8 (d, 1 J C-F = 258.5 Hz), 160.5, 158.2, 153.0, 150.8, 149.4, 147.2 (d, 3 J C-F = 4.3 Hz), 145.0, 142.8 (d, 2 J C-F = 23.2 Hz), 135.1, 134.1, 133.4, 132.3, 132.3, 132.3, 130.9, 130.3, 130.3, 127.3 (d, 3 J C-F = 3.6 Hz), 124.2 (d, 2 J C-F = 19.6 Hz), 123.7, 120.6, 120.6, 117.9, 117.5, 114.6, 114.6, 108.1, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 542.1985 [M+H] + (calcd. for C 32 H 29 O6NF + , 542.1973).

[0026] Example 2: Compound 2

[0027]

[0028] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 97%, mp 152.1–153.6 °C. 11H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 15.6 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 5.2 Hz, 1H), 7.34 (d, J = 4.0 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.10 (dd, J = 3.6, 5.2 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 6.47 (d, J = 15.6 Hz, 1H), 6.11 (m, 1H), 5.78 (m, 1H), 5.47 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J = 10.4, 1.6 Hz, 1H), 5.13 (dq, J = 17.2, 1.6 Hz, 1H), 5.07 (dq, J = 10.4, 1.6 Hz, 1H), 4.61 (dt, J = 5.4, 1.6 Hz, 2H), 4.29 (dt, J = 5.4, 1.6 Hz, 2H), 3.75 (s, 3H), 3.63 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 165.3, 158.1, 153.1, 150.9, 149.9, 145.0, 139.5, 138.9, 134.8, 134.1, 133.4, 132.0, 132.0, 131.7, 131.5, 130.9, 130.3, 130.3, 129.2, 128.4, 124.0, 120.8, 120.8, 117.9, 117.6, 116.3, 114.6, 114.6, 108.1, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 555.1831 [M+H] + (calcd. for C 33 H 31 O6S + , 555.1836).

[0029] Example 3: Compound 3

[0030]

[0031] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 94%, mp 137.4–138.8 °C. 11H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 1.8, 0.9 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.41 (dd, J = 3.6, 0.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 6.61 (dd, J = 3.6, 1.8 Hz, 1H), 6.11 (m, 1H), 5.77 (m, 1H), 5.47 (dq, J = 17.2, 1.6 Hz, 1H), 5.33 (dq, J = 10.4, 1.6 Hz, 1H), 5.13 (dq, J = 17.2, 1.6 Hz, 1H), 5.07 (dq, J = 10.4, 1.6 Hz, 1H), 4.61 (dt, J = 5.2, 1.6 Hz, 2H), 4.29 (dt, J = 5.2, 1.6 Hz, 2H), 3.75 (s, 3H), 3.62 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 158.1, 157.0, 153.1, 150.9, 149.3, 147.2, 145.0, 144.3, 134.9, 134.1, 133.4, 132.1, 132.1, 131.8, 130.9, 130.3, 130.3, 123.9, 120.8, 120.8, 119.4, 117.9, 117.6, 114.6, 114.6, 112.3, 108.1, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 513.1905 [M+H] + (calcd. for C 31 H 29 O7 + , 513.1908).

[0032] Example 4: Compound 4

[0033]

[0034] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 92%, mp 126.2–127.5 °C. 11H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.71 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 6.11 (m, 1H), 5.47 (dd, J = 17.2 Hz, 1H), 5.33 (dd, J = 17.2 Hz, 1H), 5.33 (dq, J = 10.4, 1.6 Hz, 1H), 5.13 (dd, J = 17.2 Hz, 1H), 5.07 (dq, J = 10.4, 1.6 Hz, 1H), 4.61 (dt, J = 5.4, 1.5 Hz, 2H), 4.30 (dt, J = 5.4, 1.5 Hz, 2H), 3.75 (s, 3H), 3.62 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 159.7, 159.0, 158.2, 153.0, 150.9, 150.1, 149.2, 145.0, 135.0, 134.1, 133.4, 132.3, 132.3, 132.2, 130.9, 130.3, 130.3, 129.4, 123.7, 120.7, 120.7, 117.9, 117.59, 114.6, 114.6, 108.1, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 530.1633 [M+H] + (calcd. for C 30 H 28 O6NS + , 530.1632).

[0035] Example 5: Compound 5

[0036]

[0037] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 95% and mp 151.7–152.9 °C. 11H NMR (400 MHz, CDCl3) δ 8.95 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.70 (s, 1H), 6.11 (m, 1H), 5.75 (m, 1H), 5.46 (dq, J = 17.2, 1.6 Hz, 1H), 5.32 (dq, J = 10.4, 1.6 Hz, 1H), 5.11 (dt, J = 17.2, 1.6 Hz, 1H), 5.06 (dt, J = 10.4, 1.6 Hz, 1H), 4.60 (dt, J = 5.2, 1.5 Hz, 2H), 4.28 (dt, J = 5.2, 1.5 Hz, 2H), 3.75 (s, 3H), 3.62 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 159.6, 158.1, 153.9, 153.1, 150.9, 149.6, 147.6, 145.0, 134.9, 134.0, 133.4, 132.2, 132.2, 131.9, 130.9, 130.3, 130.3, 128.8, 123.9, 120.9, 120.9, 117.9, 117.6, 114.6, 114.6, 108.1, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 530.1638 [M+H] + (calcd. for C 30 H 28 O6NS + , 530.1632).

[0038] Example 6: Compound 6

[0039]

[0040] A pale yellow solid was obtained by referring to the preparation method of Example 1, with a yield of 96% and mp 82.5–83.8 °C. 11H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 2.0 Hz, 1H), 7.56–7.50 (overlapped, 4H), 7.33 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 2.0 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.71 (s, 1H), 6.11 (m, 1H), 5.79 (m, 1H), 5.47 (dq, J = 17.2, 1.76 Hz, 1H), 5.33 (dq, J = 10.4, 1.6 Hz, 1H), 5.15 (dq, J = 17.2, 1.6 Hz, 1H), 5.09 (dq, J = 10.4, 1.6 Hz, 1H), 4.61 (dt, J = 5.2, 1.6 Hz, 2H), 4.32 (dt, J = 5.2, 1.6 Hz, 2H), 3.77 (s, 3H), 3.63 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 158.2, 153.1, 150.9, 149.4, 145.1, 135.0, 134.1, 133.4, 132.3, 132.3, 132.0, 130.9, 130.4, 130.4, 130.4, 123.9, 121.0, 121.0, 117.9, 117.6, 114.6, 114.6, 114.6, 109.5, 108.8, 108.2, 74.5, 69.0, 61.0, 56.2. HRESIMS m / z 513.2019 [M+H] + (calcd. for C 30 H 29 O6N2 + , 513.2020).

[0041] Example 7: Compound 7

[0042]

[0043] A white solid was obtained by referring to the preparation method of Example 1, with a yield of 96% and mp 94.2–95.7 °C. 11H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.69 (s, 1H), 6.11 (m, 1H), 5.75 (m, 1H), 5.46 (dq, J = 17.2, 1.6 Hz, 1H), 5.32 (dq, J = 10.4, 1.6 Hz, 1H), 5.11 (dq, J = 17.2, 1.6 Hz, 1H), 5.05 (dq, J = 10.4, 1.6 Hz, 1H), 4.60 (dt, J = 5.2, 1.6 Hz, 2H), 4.28 (dt, J = 5.2, 1.6 Hz, 2H), 4.14 (m, 2H), 3.99 (m, 1H), 3.91 (m, 1H), 3.73 (s, 3H), 3.61 (s, 3H), 3.38 (1H, m), 2.39 (1H, m), 2.28 (1H, m). 13 13C NMR (100 MHz, CDCl3) δ 172.4, 158.2, 153.1, 150.9, 149.6, 145.0, 134.9, 134.1, 133.4, 132.1, 132.1, 131.7, 130.9, 130.3, 130.3, 123.8, 120.6, 120.6, 117.9, 117.5, 114.6, 114.6, 108.1, 74.4, 70.5, 69.0, 68.50, 61.0, 56.2, 44.1, 29.8. HRESIMS m / z 517.2221 [M + H] + (calcd. for C 31 H 33 O7 + , 517.2221).

[0044] Example 8: Compound 8

[0045]

[0046] A pale yellow solid was obtained by referring to the preparation method of Example 1, with a yield of 93% and mp 165.1–166.4 °C. 11H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.51–7.48 (overlapped, 3H), 7.36 (d, J = 4.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.70 (s, 1H), 6.11 (m, 1H), 5.76 (m, 1H), 5.46 (dq, J = 17.3, 1.6 Hz, 1H), 5.32 (dq, J = 10.5, 1.6 Hz, 1H), 5.12 (dq, J = 17.3, 1.6 Hz, 1H), 5.05 (dq, J = 10.5, 1.6 Hz, 1H), 4.61 (dt, J = 5.4, 1.5 Hz, 2H), 4.30 (dt, J = 5.4, 1.5 Hz, 2H), 3.75 (s, 3H), 3.62 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 179.3, 158.2, 156.4, 154.5, 153.1, 150.9, 149.0, 147.3, 145.1, 135.1, 134.1, 133.4, 132.4, 132.3, 132.3, 130.9, 130.4, 130.4, 123.7, 120.6, 120.6, 120.0, 118.9, 117.9, 117.6, 114.6, 114.6, 108.2, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 541.1856 [M+H] + (calcd. for C 32 H 29 O8 + , 541.1857).

[0047] Example 9: Compound 9

[0048]

[0049] A pale yellow solid was obtained according to the preparation method of Reference Example 1, with a yield of 98% and mp 173.4–174.8 °C. 11H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.56–7.49 (overlapped, 5H), 7.38–7.32 (overlapped, 3H), 7.02 (d, J = 8.4 Hz, 2H), 6.71 (s, 1H), 6.11 (m, 1H), 5.78 (m, 1H), 5.47 (dq, J = 17.3, 1.6 Hz, 1H), 5.33 (dq, J = 10.5, 1.6 Hz, 1H), 5.14 (dq, J = 17.2, 1.6 Hz, 1H), 5.08 (dq, J = 10.4, 1.6 Hz, 1H), 4.61 (dt, J = 5.3, 1.6 Hz, 2H), 4.31 (dt, J = 5.3, 1.6 Hz, 2H), 3.76 (s, 3H), 3.63 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 158.2, 158.0, 156.2, 153.1, 150.9, 149.3, 145.1, 145.1, 135.0, 134.1, 133.4, 132.2, 132.2, 132.0, 130.9, 130.4, 130.4, 128.2, 127.1, 124.1, 123.8, 123.2, 120.8, 120.8, 117.9, 117.6, 115.5, 114.6, 114.6, 112.6, 108.2, 74.4, 69.0, 61.0, 56.2. HRESIMS m / z 563.2064 [M + H] + (calcd. for C 35 H 31 O7 + , 563.2064).

[0050] Example 10: Compound 10

[0051]

[0052] Dissolve 4”-(allyloxy)-3',6'-dimethoxy-[1,1':4',1”-terphenyl]-2',4-diol (hereinafter referred to as "Compound B") (30 mg, 0.079 mmol) in dichloromethane (2 mL). Under the conditions of catalyst DMAP and dehydrating agent EDC, add an acid reagent (2.5 eq). Under the condition of a 45 °C water bath, stir and react for 4 h. Monitor by TLC plate. After Compound A has reacted completely, terminate the reaction. Extract with dichloromethane three times. Combine the organic phases and concentrate under reduced pressure to obtain a white solid with a yield of 93% and mp 164.2–165.9 °C. 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, 0.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.40 (dd, J = 3.6, 0.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.61 (dd, J = 3.6, 1.6 Hz, 1H), 6.48 (s, 1H), 6.11 (m, 1H), 6.04 (s, 1H), 5.47 (dq, J = 17.3, 1.6 Hz, 1H), 5.33 (dq, J = 10.5, 1.6 Hz, 1H), 4.61 (dt, J = 5.4, 1.5 Hz, 2H), 3.75 (s, 3H), 3.45 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.3, 157.0, 153.5, 149.3, 147.4, 147.2, 144.2, 138.9, 133.3, 132.8, 132.1, 132.1, 131.2, 130.5, 129.9, 129.9, 121.0, 121.0, 119.5, 117.9, 115.7, 114.8, 114.8, 112.3, 103.9, 69.0, 60.9, 56.0. HRESIMS m / z 473.1595 [M+H] + (calcd. for C 28 H 25 O7 + , 473.1595).

[0053] Example 11: Compound 11

[0054]

[0055] A white solid was obtained by referring to the preparation method of Example 10, with a yield of 94% and mp 184.4–185.7 °C. 11H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.61–7.59 (overlapped, 3H), 7.44 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 3.2 Hz, 1H), 7.22–7.19 (overlapped, 3H), 7.00 (d, J = 8.8 Hz, 2H), 6.87 (s, 1H), 6.58 (dd, J = 3.5, 1.6 Hz, 1H), 6.50 (dd, J = 3.5, 1.6 Hz, 1H), 6.10 (m, 1H), 5.46 (dq, J = 17.3, 1.6 Hz, 1H), 5.32 (dq, J = 10.5, 1.6 Hz, 1H), 4.60 (dt, J = 5.4, 1.6 Hz, 2H), 3.78 (s, 3H), 3.40 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 158.4, 156.9, 156.8, 153.2, 149.6, 147.3, 147.2, 144.2, 143.7, 143.6, 142.3, 134.7, 133.3, 131.5, 131.5, 130.6, 130.3, 130.2, 130.2, 123.5, 121.1, 121.1, 119.6, 119.5, 117.9, 114.8, 114.8, 112.3, 112.2, 110.8, 69.0, 60.9, 56.3. HRESIMS m / z 567.1657 [M+H] + (calcd. for C 33 H 27 O9 + , 567.1650).

[0056] Example 12 Anti-inflammatory Activity Test

[0057] (1) Active test cell model: LPS-induced RAW264.7 inflammation model.

[0058] (2) Activation and passage of RAW 264.7 macrophages: Take out RAW 264.7 cells, resuscitate them in a 37 °C water bath. After transferring the cryopreservation solution, add 5-fold complete medium DMEM, put it into a centrifuge (800 rpm, 5 min), and culture it in an incubator at 37 °C and 5% CO2. Observe the cell growth situation. When the cells grow to cover 80–90% of the culture dish, passage: Digest the cells with trypsin, culture the cells in a culture dish containing fresh culture medium and continue to culture. When the cells grow to the logarithmic growth phase, perform the MTT experiment.

[0059] (3)MTT assay for detecting the effect of the compound on the activity of RAW 264.7 cells: Select RAW 264.7 cells in good growth state, add DMEM culture medium, 10% FBS, 100 U / mL penicillin and 100 μg / mL streptomycin, and seed the cells at 1×10 4 cells / well in a 96-well plate and culture them in an incubator at 37 °C and 5% CO2 for 12 h. Add the test compound at different concentrations and incubate for 24 h, with three replicates in each group. After culturing for 24 h, add 20 μL of MTT at a concentration of 5 mg / mL to each well. Incubate for 4 h, discard the supernatant, add 200 μL of DMSO to each well, mix well to dissolve, and measure the OD value at a wavelength of 570 nm using an enzyme-linked immunosorbent assay (ELISA) reader.

[0060] (3) Griess assay for detecting the effect of the compound on the NO release content in LPS-activated RAW 264.7 cells: Adjust the cell concentration to 1.2×10 6 cells / well and seed them in a 6-well plate, then culture them in an incubator for 24 h. Discard the culture medium, add 1 mL of serum-free DMEM culture medium to each well, add the compound of the present invention at different concentrations and LPS (1 μg / mL), and incubate for 24 h. Collect the supernatant, and according to the operation manual of the kit, detect the NO concentration in the culture supernatant and measure the OD value at 450 nm using an ELISA reader. During the experiment, avoid light, and set three replicates for each sample.

[0061] Test results:

[0062] Table 1 Effect of the compound of the present invention on the release of NO from LPS-activated RAW 264.7 cells at 0.08 μM

[0063] Compound Inhibition rate (%) Compound Inhibition rate (%) 1 +++ f 2 ++ g - 3 ++++ h - 4 +++ i - 5 +++ j - 6 +++ k - 7 ++ l - 8 ++++ m - 9 ++ n - 10 +++ o - 11 +++ p - L-NMMA ++++ q - a - r - b - A - c - B - e -

[0064] 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%; "-" indicates an inhibition rate < 5%.

[0065] Note: The present invention parallelly tested NG-Monomethyl-L-arginine, Monoacetate Salt (L-NMMA), Compound A Compound B and Compound a-r as controls.

[0066] Conclusion: By screening the effect of the compound of the present invention on the release of NO from LPS-activated RAW 264.7 cells, it was found that compared with Compound A, Compounds 1 - 11 of the present invention have stronger NO inhibitory activity and have great application prospects in inflammatory diseases.

[0067] Example 23 Detection of the effects of compounds on the release of TNF-α, IL-6, and IL-1β in LPS-activated RAW 264.7 cells by ELISA

[0068] RAW 264.7 cells in good growth state were selected, and a cell suspension was prepared with DMEM culture medium. The cell concentration was adjusted to 1.2×10 6 cells / well and seeded in a 6-well plate, and cultured in an incubator for 24 h. 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-like compounds to be tested and LPS (μg

[0069] / mL) were added and cultured for 24 h. The supernatant was collected for detection. The kit and other required reagents were pre-incubated at room temperature for 30 min. The diluent and washing solution required for the experiment were diluted to 1×, and the standard product was diluted according to the instructions. 50 μL of 1× diluent and samples were added to each well of the microplate, sealed with adhesive tape, and incubated at room temperature for 2 h. The liquid in the wells was poured out, 300 μL of 1× detergent was added to each well, and the washing was repeated three times to completely remove the residual liquid. 100 μL of enzyme-labeled detection antibody was added to each well, sealed with adhesive tape, and incubated at room temperature for 2 h. The liquid in the wells was poured out, 300 μL of 1× detergent was added to each well, and the washing was repeated three times to completely remove the residual liquid. 100 μL of chromogenic substrate was added to each well, and incubated at room temperature in the dark for 30 min. 100 μL of stop solution was added to each well. When the liquid in the wells changed from blue to yellow within 30 min, the OD value at a wavelength of 450 nm was measured with an enzyme-labeled instrument. The standard curve was plotted according to the instructions, and the content was calculated.

[0070] Test results:

[0071] Table 2 Effects of Compound 3 of the present invention on the release of TNF-α, IL-6, and IL-1β in LPS-activated RAW 264.7 cells

[0072] Compound TNF-α inhibition rate (0.08 μM) IL-6 inhibition rate (0.08 μM) IL-1β inhibition rate (0.08 μM) 3 ++++ ++++ ++++

[0073] Note: Compared with the LPS group: in the table, “++++” indicates **** p < 0.0001; “+++” indicates *** p < 0.001; “++” indicates ** p < 0.01; “+” indicates * p < 0.05; “-” indicates inactivity; “ns” indicates not tested.

[0074] Conclusion: Further studies were conducted to screen the effects of Compound 3 on the release of TNF-α, IL-6, and IL-1β from LPS-activated RAW264.7 cells. The results showed that at 0.08 μM, Compound 3 of the present invention had a significant inhibitory effect on the release of TNF-α, IL-6, and IL-1β, further indicating the anti-inflammatory potential of this compound and its great application prospects in inflammatory diseases.

[0075] It should be noted that there are other ways to implement the present invention; accordingly, the embodiments of the present invention are illustrative, but not limited to the content described in the present invention, and may also be modifications made within the scope of the present invention or equivalent content added in the claims; all publications or patents cited in the present invention will be used as references for the present invention.

Claims

1. A terphenyl compound, characterized in that, Use of a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof, especially as an anti-inflammatory drug, characterized in that the compound has the following structure: In formula (I), wherein R1 and R2 are each independently optionally H, propenyl, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 alkylamino, C 1-8 alkylacyl, C 1-8 haloalkoxy, C 1-8 haloalkylamino, C 1-8 haloalkylacyl, C 1-8 aminoalkoxy, C 3-8 cycloalkyl, 3- to 6-membered heterocyclic group, aryl, 5- to 6-membered heteroaryl, aryloxy, heteroaryloxy, heteroaroyl, heteroarylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclicalkylacyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, heterocycloacyl, heterocycloalkylalkoxy, heterocycloalkylalkylamino, heterocycloalkylalkylacyl, azidoalkoxy, fused bicyclic group, fused heterobicyclic group, fused heteroaryl, fused bicyclic aliphatic substituent, biaryl, triaryl, fused biaryl, fused triaryl, R3 is optionally wherein Z is independently selected from C 3-8 cycloalkyl, substituted or unsubstituted C 3-6 heterocycloalkyl, substituted or unsubstituted C 5-6 heteroaryl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, heterocycloalkylalkoxy, heterocycloalkylalkylamino, azidoalkoxy, fused bicyclic group, fused heterobicyclic group, fused heteroaryl, fused bicyclic aliphatic substituent, biaryl, terphenyl, fused biaryl, fused terphenyl, wherein C 3-6 heterocycloalkyl, C 5-6 heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, aryl or 5-6 membered heteroaryl; L is optionally a key, C 1-6 Alkylene, vinyl, propenyl, allyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, ethynyl, propynyl, propargyl, butynyl, ethynylbutyl, pentynyl.

2. The compound according to claim 1, wherein Having one of the following structures or its stereoisomer, geometric isomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and the specific structures are as follows:

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

4. The pharmaceutically acceptable salts according to any one of claims 1-2 are selected from: hydrochloride, sulfate, phosphate, oxalate, maleate, methanesulfonate, succinate, citrate, fumarate, glucuronate, formate, acetate, succinate; the solvates or solvates of salts are selected from: monohydrate, dihydrate, trihydrate, monomethanolate, dimethanolate, monoacetonitrile complex, diacetonitrile complex, monoacetone complex, diacetone complex, hemifumarate monohydrate, fumarate dihydrate, fumarate monoethanolate.

5. A drug capable of treating and / or preventing diseases caused by inflammation, characterized in that It contains the compound according to claims 1-2, its stereoisomer, geometric isomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof as an active ingredient.

6. Use of the drug described in claim 5 in a medicament for treating and / or preventing related diseases, wherein the diseases include the diseases caused by inflammation such as Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's disease and indeterminate colitis, inflammatory bowel disease, cancer (solid tumor, gallbladder cancer), hepatitis, liver cancer, fatty liver disease, cirrhosis, asthma, psoriasis, Parkinson's disease, prion disease, Alzheimer's disease, rheumatoid arthritis, gout, acute or chronic hepatitis caused by viral infection, alcoholic hepatitis, drug or chemical poisoning, mononucleosis, amebic 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 (Berger's disease), glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), autoimmune disorders related to chronic kidney disease (CKD) and inflammation, Goodpasture syndrome, Wegener's granulomatosis, pyelonephritis, exercise-induced nephritis, kidney stones, mesothelioma, type I diabetes, type II diabetes, atherosclerosis, hypertension, obesity, cardiovascular disease, lupus or rheumatism, lung injury, idiopathic pulmonary fibrosis, dermatomycosis, heart disease, respiratory disease, stroke, scleroderma, keloid, myocardial fibrosis, diabetic nephropathy, myelodysplastic syndrome, sepsis, infection (such as viral, bacterial or fungal infection), acne vulgaris, chronic obstructive pulmonary disease, autoimmune disease, celiac disease, chronic (plaque) prostatitis, pelvic inflammatory disease, reperfusion injury, transplant rejection, interstitial cystitis, allergy (type 1, 2 and 3 hypersensitivity, hay fever), inflammatory myopathy, systemic sclerosis, dermatomyositis, polymyositis, inclusion body myositis, Chediak-Higashi syndrome, chronic granulomatous disease, vitamin A deficiency, periodontitis, granulomatous inflammation (tuberculosis, leprosy, sarcoidosis 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, subacute bacterial endocarditis (SBE), systemic lupus erythematosus, temporal arteritis (also known as "giant cell arteritis"), thrombocytopenia, undifferentiated connective tissue disease, urticarial vasculitis and vasculitis, pancreatitis, Meniere's disease, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyelitis optica, Devic's disease, neuromyotonia,Ocular cicatricial pemphigoid, opsoclonus myoclonus syndrome, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus), paraneoplastic cerebellar degeneration, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, rheumatic fever, sarcoidosis.

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