Tianmingjing lactone derivatives

Abstract

The present invention relates to styraxol derivatives having the structures of Formula (I), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof. These compounds have excellent anti-inflammatory activity and significantly inhibit the release of nitric oxide (NO), an inflammatory molecule, from mouse macrophages RAW264.7. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a derivative of the natural product tianmingjing lactone alcohol, and a preparation method and application thereof. Background Art

[0002] C. chinensis, also known as the northern crane louse, is a plant found in the genus Carpesium, Compostae, with 21 species worldwide. These include C. abrotanoides L., C. divaricatum Sieb. et Zucc., C. macrocephalum Franch. et Sav., C. triste Maxim., C. lipskyi Winkl., C. nepalense Less., C. faberi Winkl., and C. cernuum L., most of which are found in central and eastern Asia. In my country, there are 18 species and three varieties, primarily found in the mountainous areas of southwest my country, making the C. chinensis plant resource a significant resource. Many plants in this genus, such as C. chinensis, C. divaricatum Sieb. et Zucc., C. macrocephalum Franch. et Sav., C. triste Maxim., C. lipskyi Winkl., C. nepalense Less., C. faberi Winkl., and C. cernuum L., are used medicinally. Among them, Tianmingjing was first recorded in "Shennong Bencao Jing" and was listed as a top-grade medicine. It has the longest history of medicinal use and is widely used in clinical practice. It has been recorded in herbal books of all dynasties.

[0003] Studies have shown that the genus Asteraceae contains a variety of chemical components, including hundreds of compounds such as flavonoids, phenols, terpenes, steroids, and fatty acids. Among them, sesquiterpenes are the main components and the main active ingredients of Asteraceae plants. Literature records that extracts from Asteraceae plants have anti-inflammatory, anti-tumor, platelet aggregation inhibition, antibacterial, and immunomodulatory effects. A large number of sesquiterpenoid lactone compounds were isolated from the whole plant of Asteraceae. Asteraceae lactone is a calaburane-type sesquiterpenoid compound extracted and isolated from Asteraceae. It has anti-inflammatory, antibacterial, anti-tumor, and platelet aggregation inhibition effects. It is of great significance to use this compound as a lead compound and optimize its structure.

[0004] Carabrol is a calaburane-type sesquiterpenoid compound, a colorless oily solid with a molecular formula of C 15 H 22 O3, molecular weight 250.1569. It is an important chemical component in the big flower gold ear pick.

[0005] The structural formula of Tianmingjing lactone alcohol:

[0006]

[0007] Inflammation is the defensive response of living tissues with a vascular system to damaging factors. Inflammation plays a key role in many pathophysiological conditions, although it is an adaptive host defense mechanism against infection or injury. Macrophages are important players in the inflammatory process, providing immediate defense against foreign substances. Upon activation, macrophages produce cytokines such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), as well as other inflammatory mediators such as nitric oxide (NO) and prostaglandins (PGs). Excessive production of these cytokines and proinflammatory mediators is associated with many inflammatory diseases, such as atherosclerosis, rheumatoid arthritis, asthma, pulmonary fibrosis, and septic shock.

[0008] In the inflammatory response, the activation of macrophages leads to host damage by excessively releasing various proinflammatory cytokines, such as IL-1β, IL-6 and TNF-α. Many studies have shown that overexpression of IL-1β, IL-6 and TNF-α is responsible for regulating a series of cytokines, adhesion and pro-angiogenic activity in many chronic inflammatory diseases. In the case of inflammatory bowel disease, studies have suggested that the production of IL-1β, IL-6 and TNF-α is the result of inflammatory cells infiltrating into the inflamed tissue. It has been previously reported (HwaJin Lee et al., Biochem.Bioph.Res.Co., 2010; 391(3), 1400-1404) that tadalafil inhibits the expression of proinflammatory cytokines in LPS-stimulated RAW 264.7 macrophages. In activated RAW 264.7 macrophages, tadalafil reduced the levels of IL-1β, IL-6 and TNF-α and mRNA; tadalafil also inhibited the production of proinflammatory mediators NO and PGE2. Excessive production of NO and PGE2 are hallmarks of inflammation and have been used as targets for inflammatory diseases.

[0009] This study uses Tianmingjing lactone as the lead compound and modifies the 4-hydroxyl group, 11-13 double bonds and lactone ring in its structure in order to obtain a small molecule compound with strong anti-inflammatory activity and better drugability. Summary of the Invention

[0010] The purpose of the present invention is to provide a tannin lactone derivative or a pharmaceutically acceptable salt thereof, and to design a series of chemical derivatives using tannin lactone having anti-inflammatory biological activity as a lead compound.

[0011] Another object of the present invention is to provide a method for preparing the tianmingjing lactone alcohol derivative or a pharmaceutically acceptable salt thereof.

[0012] Another object of the present invention is to provide the use of the tianmingjing lactone derivative or a pharmaceutically acceptable salt thereof.

[0013] The present invention is achieved through the following technical solutions:

[0014] A tianmingjing lactone derivative having the structure of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof:

[0015]

[0016] Wherein, in formula (I),

[0017] R is tert-butylamino, aniline, morpholine, p-methoxyaniline, ethylamino, hexylamino, or pyrrolyl.

[0018] In formula (II),

[0019] R is ethylamino or morpholine.

[0020] In formula (III),

[0021] R is a methylamino group.

[0022] In formula (I), R is tert-butylamino, aniline, morpholine, p-methoxyaniline, ethylamino, hexylamino, or pyrrolyl, which are marked as compound 1-7 in the present invention.

[0023]

[0024] In formula (II), R is ethylamino or morpholine, which is marked as compound 9-10 in the present invention.

[0025]

[0026] In formula (III), R is a methylamino group, which is marked as compound 11 in the present invention.

[0027]

[0028] The preparation method of the above-mentioned tianmingjing lactone alcohol derivative or a pharmaceutically acceptable salt thereof comprises the following steps:

[0029] The reaction of t-butylamine and t-butylamine gives 13-t-butylaminot-butylamine (compound 1).

[0030] The reaction of tannin lactone and aniline gave 13-anilino tannin lactone (compound 2).

[0031] The reaction of 13-morpholino-13-olactone and morpholine gave 13-morpholino-13-olactone (compound 3).

[0032] The reaction of 13-p-methoxyanilino-13-olactone and p-methoxyaniline gave 13-p-methoxyanilino-13-olactone (compound 4).

[0033] The reaction of styraxol and ethylamine hydrochloride gives 13-ethylaminostyraxol (Compound 5).

[0034] The reaction of tannin lactone and hexylamine gave 13-hexylaminotannin lactone (compound 6).

[0035] The reaction of pyrrole with 13-pyrrolyl pyrrole (compound 7) was carried out.

[0036] Alternatively, the preparation method of the above-mentioned tianmingjing lactone derivative or a pharmaceutically acceptable salt thereof comprises the following steps:

[0037] The reaction of tianmingjing lactone alcohol and Dess-Martin reagent gave tianmingjing lactone ketone (compound 8).

[0038] The reaction of styraxone (Compound 8) and ethylamine hydrochloride gives 13-ethylstyraxone (Compound 9).

[0039] The reaction of morpholinone (compound 8) and morpholine gave 13-morpholinyl morpholinone (compound 10).

[0040] Alternatively, the preparation method of the above-mentioned tianmingjing lactone derivative or a pharmaceutically acceptable salt thereof comprises the following steps:

[0041] The reaction of tianmingjing lactone alcohol with KOH gave the tianmingjing lactone alcohol lactone ring opening product, and the tianmingjing lactone alcohol lactone ring opening product reacted with methylamine hydrochloride to give the 12-methylamino tianmingjing lactone alcohol ring opening product (Compound 11)

[0042] The use of the above-mentioned niacin lactone derivative or a pharmaceutically acceptable salt thereof in the preparation of anti-inflammatory drugs for diseases mediated by the pro-inflammatory cytokine nitric oxide (NO).

[0043] The beneficial effects of the present invention are:

[0044] The present invention chemically modifies the natural product tianmingjing lactone to obtain a series of tianmingjing lactone structural analogs. Pharmacological experiments show that they have a significant inhibitory effect on the release of the inflammatory molecule nitric oxide (NO) by mouse macrophages RAW264.7, and some compounds are superior to the parent compound. DETAILED DESCRIPTION

[0045] The present invention will be further described below with reference to specific embodiments so that those skilled in the art can better understand the present invention, but the present invention is not limited thereby.

[0046] (1) The reaction of 13-tert-butylamino ...

[0047] Wherein, when R in formula (I) is a tert-butylamino group, it is compound 1:

[0048]

[0049] (2) The reaction of tannin lactone and aniline gave 13-anilinotannin lactone (compound 2).

[0050] Wherein, when R in formula (I) is an aniline group, it is compound 2:

[0051]

[0052] (3) 13-morpholino-13-naphtholactone (Compound 3) is obtained by reacting 13-morpholino-13-naphtholactone with morpholine.

[0053] Wherein, when R in formula (I) is a morpholinyl group, it is compound 3:

[0054]

[0055] (4) The reaction of 13-p-methoxyanilino-13-nitro ...

[0056] Wherein, when R in formula (I) is p-methoxyanilino, it is compound 4:

[0057]

[0058] (5) The reaction of 13-ethylamino ...

[0059] Wherein, when R in formula (I) is an ethylamino group, it is compound 5:

[0060]

[0061] (6) The reaction of 13-hexylamino ...

[0062] Wherein, when R in formula (I) is hexylamino, it is compound 6:

[0063]

[0064] (7) The reaction of pyrrole with 13-pyrrolyl pyrrole (compound 7) was carried out.

[0065] Wherein, when R in formula (I) is pyrrolyl, it is compound 7:

[0066]

[0067] (8) The reaction of tianmingjing lactone alcohol and Dess-Martin reagent gave tianmingjing lactone ketone (Compound 8).

[0068]

[0069] (9) The reaction of styraxol with Dess-Martin reagent gave styraxone, which in turn reacted with ethylamine hydrochloride to give 13-ethylstyraxone (Compound 9).

[0070] Wherein, when R in formula (II) is ethyl, it is compound 9:

[0071]

[0072] (10) The reaction of taurine lactone with Dess-Martin reagent gave taurine lactone ketone, which then reacted with morpholine to give 13-morpholinyltaurine lactone (Compound 10).

[0073] Wherein, when R in formula (II) is a morpholinoamine group, it is compound 10:

[0074]

[0075] (11) The reaction of tianmingjing lactone with KOH gives the tianmingjing lactone lactone ring-opening product, and the tianmingjing lactone lactone ring-opening product reacts with methylamine hydrochloride to give the 12-methylaminotianmingjing lactone ring-opening product (Compound 11).

[0076]

[0077] Example 1:

[0078] Preparation of 13-tert-butylamino tert-butyl lactone (Compound 1):

[0079] Tianmingjing lactone (100 mg, 3.9 × 10 -1 mmol) was dissolved in methanol (5 mL), and then tert-butylamine (493 μL, 4.68 mmol) was added to the reaction system, and the reaction was stirred at room temperature for 7 h. The product was detected by TLC (dichloromethane-methanol, 100: 6). After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane-methanol (100: 3) to obtain the product with a yield of 70.3%. LC / MS (ESI-MS) showed [M+Na] + =346.2564, indicating that the molecular weight of the compound is 323.2460 and the molecular composition is C 19 H 33 NO3; 1H-NMR (C5D5N, 800MHz) δ: 4.68-4.66 (m, 1H, H-8), 4.02 (q, J=6.0Hz, 1H, H-OH), 3.27 (s, 1H, H-NH), 2.91 (d, J=13.3Hz, 1H, H-13), 2.06 (dd, J=13.5, 5.1Hz, 1H, H -13), 1.61 (s, 1H, H-9), 1.58 (d, J = 3.9Hz, 1H, H-9), 1.54 (d, J = 4.1Hz, 1H, H-3), 1.47 (s, 9H, H-2′, 3′, 4′), 1.35 (d, J=6.0Hz, 2H, H-6), 1.29-1.22 (m, 3H, H-15); 13 C NMR (C5D5N, 201MHz) δ: 178.37(C-12), 77.40(C-8), 66.24(C-4), 45.01(C-13), 41.75(C-1′), 40.26(C-9), 37.06(C-3), 36.74(C-11), 35.66(C -7), 30.91(C-2′), 29.80(C-3′), 27.99(C-15), 26.07(C-6), 25.94(C-1 ), 24.36(C-15), 22.96(C-2), 19.03(C-10), 17.99(C-5), 17.52(C-18).

[0080] Example 2:

[0081] Preparation of 13-anilino-1,3-diolactone (Compound 2):

[0082] Tianmingjing lactone (100 mg, 3.9 × 10 -1 mmol) was dissolved in methanol (5 mL), and then aniline (0.5 mL, 5.4 mmol) was added to the reaction system, and the reaction was stirred at 80 ° C for 5 h in a microwave reactor. The product was detected by TLC (dichloromethane-methanol, 100: 3). After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane-methanol (100: 1) to obtain the product with a yield of 68.3%. LC / MS (ESI-MS) showed [M+Na] + =366.2024, indicating that the molecular weight of the compound is 343.2147 and the molecular composition is C 21 H 29 NO3; 1H-NMR (CDCl3, 800MHz,) δ: 7.22 (t, J=7.7Hz, 1H, C-NH), 6.76 (d, J=7.8Hz, 1H, H-14′), 4.78-4.70 (m, 1H, H-OH), 3.80 (p, J=6.2 Hz, 1H, H-8), 3.36 (s, 1H, H-13), 1.56-1.50 (m, 1H, H-6), 1.25 (s, 3H, H-15), 1.19 (d, J=6.2Hz, 4H, H-5, 2), 1.05 (s, 3H, H-14); 13 C-NMR (CDCl3, 201MHz) δ: 178.09 (C-12), 177.60 (C-1′), 129.51 (C-3′, 5′) , 122.54(C-4′), 114.40(C-2′, 6′), 71.92(C-8), 67.96(C-4), 59.20(C-9), 47.47(C-7), 39.32(C-11), 37.42(C-13), 37.35(C-3), 36.95(C-1), 30.46( C-15), 29.70(C-6), 25.39(C-14), 23.65(C-2), 18.41(C-10), 18.26(C-5).

[0083] Example 3:

[0084] Preparation of 13-morpholinolactone (Compound 3):

[0085] Tianmingjing lactone (100 mg, 3.9 × 10 -1 mmol) was dissolved in methanol (5 mL), and then morpholine (300 μL, 3.6 mmol) and triethylamine (0.3 mL) were added to the reaction system to adjust the pH of the reaction system to 8-9. The reaction was stirred at room temperature for 6 h. The product was detected by TLC (dichloromethane-methanol, 100: 5). After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane-methanol (100: 3) to obtain the product in a yield of 64.3%. LC / MS (ESI-MS) showed [M+H] + =338.2536, indicating that the molecular weight of the compound is 337.2253 and the molecular composition is C 19 H 31 NO4; 1H-NMR (C5D5N, 800MHz,) δ: 4.81 (dd, J=10.9, 5.4Hz, 1H, H-OH), 4.09-4.06 (m, 1H, H-8), 3.73 (dd, J=21.5, 7.3Hz, 4H, H-C2′, 3′), 2 .78 (dd, J=11.9, 4.8Hz, 1H, H-13), 2.66-2.61 (m, 2H, H-C1′, 4′), 2.57-2.54 (m, 1H, H-13), 2.50 (d, J=8.2Hz, 2H, H-C3′), 2.39 (d, J=7.9Hz, 2H, H-13), 2.34 (dt, J=13.9, 7.2Hz, 1H, H-7), 2.22 (dt, J=9.1, 4.5Hz, 1H, H-11), 1.82 (dd, J=12.7, 6.7Hz, 1H, H-9), 1.7 1-1.68 (m, 1H, H-9), 1.58-1.55 (m, 3H, H-2), 1.39 (t, J=5.1Hz, 4H, H-3, 6, 9), 1.02 (d, J=6.6Hz, 3H, H-14), 0.91-0.84 (m, 1H, H-1); 13 C-NMR (C5D5N, 201MHZ) δ: 179 - 32(C-12), 129.66(C-2′), 115.10(C-3′), 76.89(C-8), 67.08(C-4), 66.84(C-9), 60.11(C-13), 54.19(C-11), 44.63(C-1′), 40.76 (C-4′), 38.55(C-3), 37.60(C-15), 35.58(C-7), 31.17(C-6), 26.03(C-2), 24.42(C-1), 23.56(C-14), 18.30(C-5), 17.36(C-10).

[0086] Example 4:

[0087] Preparation of 13-p-methoxyaniline benzoyl lactone (Compound 4):

[0088] Tianmingjing lactone (100 mg, 3.9 × 10 -1mmol) was dissolved in methanol (5 mL), and then p-anisidine (192.2 mg, 1.56 mmol) and triethylamine (0.3 mL) were added to the reaction system to adjust the pH of the reaction system to 8-9. The reaction was stirred at room temperature for 10 h. The product was detected by TLC (dichloromethane-methanol, 100:7). After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane-methanol (100:3) to obtain the product with a yield of 62.5%. LC / MS (ESI-MS) showed [M+Na] + =396.2143, indicating that the molecular weight of the compound is 373.2253 and the molecular composition is C 22 H 31 NO4; 1 H-NMR (CD3OD, 800MHz) δ: 6.78-6.76 (m, 2H, H-2′, 6′), 6.69-6.67 (m, 2H, H-3′, 5′), 5.34 (td, J=4.5, 2.2Hz, 3H, H-7′), 4.59 (s, 1H, OH-), 4.33 (ddd, J=11.7, 9.7, 3.4Hz, 1H, O=CO-, H-8), 3.71 (s, 3H, H-7′), 3.40-3.36 (m, 1H, H-13), 2.58 (ddd, J=11.7, 6.0, 4.6Hz, 1H, H-7), 1.85 (dtd, J=10.2, 8.7, 4.8Hz, 1H, H-9), 1.78-1.67 (m, 2H, H-9), 1.41 (s, 1H, H-5), 0.93 (d, J=6.6Hz, 2H, H-1), 0.90 (td, J=7.2, 1.4Hz, 8H), 0.87 (s, 3H, H-14); 13 C-NMR (CD3OD, 201MHz) δ: 178.66 (C-12), 177.95 (C-17), 153.31 (C-1′), 142.41 (C-5 ′), 129.93(C-3′), 114.65(C-2′), 114.46(C-6′), 82.61(C-8), 82.51(C-4), 54.76(C -7′), 44.48(C-9), 44.19(C-7), 44.00(C-11), 39.63(C-13), 35.14(C-3), 31.67(C-6 ), 29.42(C-2), 28.92(C-15), 26.70(C-14), 25.53(C-10), 22.34(C-5), 13.05(C-1).

[0089] Example 5:

[0090] Preparation of 13-ethylamino-1,3-di ...

[0091] Tianmingjing lactone (100 mg, 3.9 × 10 -1 mmol) was dissolved in methanol (5 mL), and then ethylamine hydrochloride (127.2 mg, 1.56 mmol) and triethylamine (0.3 ml) were added to the reaction system to adjust the pH of the reaction to 8-9. The reaction was stirred at room temperature for 12 h. The product was detected by TLC (dichloromethane-methanol, 100: 3). After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane-methanol (100: 1) to obtain the product in a yield of 62.3%. LC / MS (ESI-MS) showed [M+H] + =296.2243, indicating that the molecular weight of the compound is 295.2147 and the molecular composition is C 17 H 29 NO3; 1 H-NMR (600MHz, CD3OD) δ: 4.66-4.52 (m, 1H, H-OH), 3.82-3.79 (m, 1H, H-4), 3.39 (s, 1H, H-8), 3.21 (d, J=1.8Hz, 1H, H-13), 3.20 (d, J=1.8Hz, 1H, H-13), 2.75 (dt, J=8.6, 7.1Hz, 1H, H-7), 2.55-2.49 (m, 2H, H-1′), 2.28 (dd, J=13.3, 5.6Hz, 1H, H-11), 1.46 (s, 1H, H-9) , 1.45 (m, 1H, H-6), 1.42 (m, 2H, H-9, 3), 1.35 (t, J=7.3Hz, 3H, H-15), 1.22 (m, 3H, H-2′); 13 C-NMR (CDCl3, 151MHz) δ: 178.17(C-12), 78.99(C-8), 68.36(C-4), 44.85(C-9), 44.29(C-11), 40.25(C-7), 38.24(C-13), 37.72( C-1′), 36.67(C-3), 31.30(C-6), 26.42(C-2), 24.03(C-15), 23.54(C-14), 18.63(C-5), 18.38(C-10), 12.86(C-1), 11.27(C-2′).

[0092] Example 6:

[0093] Preparation of 13-hexylamino-1,3-diolactone (Compound 6):

[0094] Tianmingjing lactone (100 mg, 3.9 × 10 -1 mmol) was dissolved in methanol (5 mL), and then n-hexylamine (206 μL, 1.56 mmol) was added to the reaction system, and the reaction was stirred at room temperature for 10 h. The product was detected by TLC (dichloromethane-methanol, 100: 5). After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane-methanol (100: 3) to obtain the product with a yield of 67.5%. LC / MS (ESI-MS) showed [M+Na] + =374.2712, indicating that the molecular weight of the compound is 351.2773 and the molecular composition is C 21 H 37 NO3; 1 H-NMR (800MHz, CD3OD) δ: 4.50 (ddd, J=11.7, 9.7, 3.3Hz, 1H, H-OH), 3.73 (t, J=9.2Hz, 1H, H-4), 3.26 (dd, J=13.0, 9.7Hz, 1H, H-11), 3.21 (q, J=7.3Hz, 3H, H-13, 8), 3.09-3.01 (m, 1H, H-7), 1.72 (ddd, J=19.1, 10.8, 5.5, 2.5HZ, 1H, H-NH), 1.62 (td, J=10.5, 8.3Hz, 1H, H-9), 1.37 (tt, J=10.1, 9.0, 3.0Hz, 2H, H-9), 1.32 (t, J=7.3Hz, 4H, H-2′, 3′), 0.98-0.93 (m, 2H, H-6), 0.90 (s, 1H, H-5); 13 C-NMR (CD3OD, 200MHz) δ: 178.18 (C-12), 84.56 (C-8), 83.80 (C-4), 49.74 (C-9) , 48.37(C-1′), 47.86(C-7), 46.95(C-13), 46.11(C-11), 45.84(C-3), 45.26(C -4′), 39.85(C-2′), 32.39(C-6), 31.11(C-3′), 27.24(C-2), 26.92(C-15), 26. 39(C-5′), 23.47(C-14), 20.87(C-5), 17.82(C-10), 14.28(C-1), 9.22(C-6′).

[0095] Example 7:

[0096] Preparation of 13-pyrrolidone (Compound 7):

[0097] Tianmingjing lactone (100 mg, 3.9 × 10 -1 mmol) was dissolved in methanol (5 mL), and then pyrrole (0.1 mL, 1.56 mmol) and triethylamine (0.3 mL) were added to the reaction system to adjust the pH of the reaction system to 8-9. The reaction was stirred at 80°C in a microwave reactor for 6 h. The product was detected by TLC (dichloromethane-methanol, 100:7). After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane-methanol (100:3) to obtain the product with a yield of 71.3%. LC / MS (ESI-MS) showed [M+H] + =318.2112, indicating that the molecular weight of the compound is 317.1991 and the molecular composition is C 19 H 27 NO3; 1 H-NMR (CD3OD, 600MHz) δ: 6.07 (d, J=3.5Hz, 1H, 3′), 5.51 (d, J=3.2Hz, 1H, 1′), 4.3 5-4.30 (s, 1H, -OH), 3.80 (t, J=9.2HZ, 1H, H-13), 2.90 (ddt, J=12.4, 9.2, 6.2, 3.4H z, 1H, H-7), 2.32-2.30 (m, 1H, H-11), 1.91-1.84 (m, 1H, H-9), 1.16-1.13 (m, 1H, H-9 ), 0.97 (d, J=6.6Hz, 2H, H-1), 0.95-0.93 (m, 1H, H-5), 0.88 (d, J=5.0Hz, 3H, H-14); 13 C-NMR (151MHz, CD3OD) δ: 172.37 (C-12), 141.26 (C-1′, 4′), 119.70 (2′, 3′), 84.42 (C-8), 83.75 (C-4), 46.24 (C-13), 45.66 (C- 11), 45.50(C-9), 44.44(C-7), 39.30(C-3), 31.53(C-6), 28.93(C-2), 26.56(C-15), 20.90(C-14), 17.87(C-10), 13.28(C-1).

[0098] Example 8:

[0099] Preparation of Tianmingjing lactone (Compound 8):

[0100] Tianmingjing lactone (100 mg, 3.9 × 10 -1 mmol) was dissolved in dichloromethane (3 mL), and then Dess-Martin reagent (248.1219 mg, 5.85 × 10 -1mmol) was added to the reaction system three times (each time with an interval of 30 minutes), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was extracted with EtOAc (5 mL) and water (5 mL), and the organic phases were combined, dried over anhydrous Na2SO4, and dried under reduced pressure. The product was detected by TLC (dichloromethane-methanol, 100:2). The residue was purified by silica gel column chromatography using dichloromethane-methanol (100:0.5) to obtain the product with a yield of 68.7%. LC / MS (ESI-MS) showed [M+H] + =249.1484, indicating that the molecular weight of the compound is 248.1412 and the molecular composition is C 15 H 20 O3; 1 H-NMR (CDCl3, 800MHz) δ: 6.22 (d, J=2.8Hz, 1H, H-13), 5.53 (d, J=2.5Hz, 1H, H-13), 4.76 (ddd, J=11.5, 8.8, 6.1Hz, 1H, H-8), 3.14 (ddd, J=12.3, 9.2 , 6.0, 3.4Hz, 1H, H-7), 2.51 (t, J=7.5Hz, 2H, H-3), 2.14 (s, 3H, H-15), 1.6 0 (dq, J=14.3, 7.2HZ, 1H, H-9), 1.55-1.49 (m, 1H, H-6), 1.06 (s, 3H, H-14); 13 C-NMR (CDCl3, 201MHz) δ: 208.81 (C-4), 170.59 (C-12), 139.09 (C-11), 122.68 (C-13), 75.71 (C-8), 43.68 (C-3), 37.8 3(C-7), 37.39(C-9), 34.33(C-1), 30.84(C-6), 30.20(C-15), 23.45(C-2), 23.01(C-5), 18.33(C-14), 17.32(C-10).

[0101] Example 9:

[0102] Preparation of 13-ethyl benzoyl lactone (Compound 9):

[0103] Compound 8 (100 mg, 3.9 × 10 -1mmol) was dissolved in dichloromethane (5 mL), and then ethylamine hydrochloride (127.2 mg, 1.56 mmol) and triethylamine (0.3 mL) were added to the reaction system to adjust the pH of the reaction system to 8-9. The reaction was stirred at room temperature for 11 hours. The product was detected by TLC (dichloromethane-methanol, 100: 4). After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane-methanol (100: 2) to obtain the product with a yield of 71.2%. LC / MS (ESI-MS) showed [M+H] + =294.2112, indicating that the molecular weight of the compound is 293.1991 and the molecular composition is C 17 H 27 NO3; 1 H-NMR (CDCl3, 600MHz) δ: 3.82-3.79 (m, 1H, H-4), 3.39 (s, 1H, H-8), 3.21 (d, J=1. 8HZ, 1H, H-13), 3.20 (d, J=1.8Hz, 1H, H-13), 2.75 (dt, J=8.6, 7.1Hz, 1H, H-7), 2.5 5-2.49 (m, 2H, H-1′), 2.28 (dd, J=13.3, 5.6Hz, 1H, H-11), 1.46 (s, 1H, H-9), 1.45 (m, 1H, H-6), 1.42 (m, 2H, H-9, 3), 1.35 (t, J=7.3Hz, 3H, H-15), 1.22 (m, 3H, H-2′); 13 CNMR (151MHz, CDCl3) δ: 209.86 (C-4), 172.77 (C-12), 67.65 (C-8), 46.23 (C-9), 44.31 (C-7), 43.77 (C-13), 40.32 (C-11), 35.47 ( C-1′), 34.83(C-3), 29.77(C-15), 24.50(C-6), 21.52(C-1), 17.98(C-2), 14.50(C-14), 12.95(C-10), 11.42(C-5), 8.82(C-2′).

[0104] Example 10:

[0105] Preparation of 13-morpholino-1,3-dimethylamino-1,3-diolactone (Compound 10):

[0106] Compound 8 (100 mg, 3.9 × 10 -1mmol) was dissolved in dichloromethane (5 mL), and then morpholine (0.1 mL, 1.21 mmol) and triethylamine (0.3 mL) were added to the reaction system to make the pH of the reaction system = 8-9. The reaction was stirred at 80 ° C for 2 h in a microwave reactor. The product was detected by TLC (dichloromethane-methanol, 100: 5). After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane-methanol (100: 3) to obtain the product with a yield of 65.9%. LC / MS (ESI-MS) showed [M+Na] + =358.1982, indicating that the molecular weight of the compound is 335.2097 and the molecular composition is C 19 H 29 NO4; 1 H-NMR (C5D5N, 800MHz) δ: 4.37-4.33 (m, 1H, H-4), 3.70 (ddd, J=14.2, 11.2, 5.6, 3.0Hz, 3H, H-2′, 3′), 2.86 (dt, J=12.7, 4.0Hz, 1H, H-13), 2.82 -2.78 (m, 1H, H-1′), 2.72 (ddd, J=11.4, 8.2, 4.5Hz, 1H, H-4′), 2.65 (ddd, J=11.0, 8.0, 3.0Hz, 1H, H-7), 2.50 (dq, J=14.1, 4.5Hz, 2H, H-13), 2. 29-2.26 (m, 1H, H-5), 2.03 (ddd, J=19.5, 11.7, 8.9, 2.7Hz, 1H-11), 1.75 (ddt, J=13.6, 9.7, 4.5Hz, 2H, H-2), 1.67 (dtt, J=16.4, 6.8, 4.3Hz, 1H , H-9), 1.52 (ddd, J=14.7, 11.6, 3.1Hz, 1H, H-9), 1.36 (tt, J=11.4, 2.7Hz, 1H, H-6), 1.27 (q, J=12.0Hz, 1H, H-6), 0.99 (d, J=2.9Hz, 3H, H-14); 13C-NMR (C5D5N, 201MHz) δ: 207.77 (C-4), 177.26 (C-12), 80.76 (C-8), 66. 85(C-2′), 66.72(C-3′), 59.84(C-1′), 58.57(C-4′), 54.12(C-13), 50.0 3(C-9), 47.72(C-7), 46.13(C-11), 45.85(C-3), 44.37(C-1), 36.61(C- 15), 35.05(C-6), 29.27(C-2), 23.90(C-14), 21.75(C-5), 19.71(C-10).

[0107] Example 11:

[0108] Preparation of 12-methylamino-1,2-di ...

[0109] Tianmingjing lactone (100 mg, 3.9 × 10 -1 mmol) was dissolved in methanol (3 mL), and then a KOH aqueous solution (0.5 mL, 0.1 mol / L) was slowly added dropwise to the reaction system, stirred at room temperature for 30 min, and then methylamine hydrochloride (105.3 mg, 1.56 mmol) was added. After the reaction was completed, the reaction system was rotary evaporated to dryness, and then the mixture was extracted with EtOAc (5 mL) and water (5 mL). The organic phases were combined and dried over anhydrous Na2SO4. The product was detected by TLC (dichloromethane-methanol, 100:3). After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane-methanol (100:1) to obtain the product with a yield of 61.8%. LC / MS (ESI-MS) showed [M+Na] + =304.1898, the molecular weight of the compound is 281.1991, and the molecular composition is C 19 H 27 NO3; 1 H-NMR (CDCl3, 800MHz) δ: 7.22 (t, J=7.7Hz, 1H, -NH), 4.76-4.70 (m, 1H, -OH), 3.82-3.80 (m, 1H, H-8), 3.36 (s, 1H, H-4), 2.49 (qd, J=1 2.2, 11.1, 5.0Hz, 1H, H-7), 1.53 (dtt, J=23.8, 9.8, 5.3Hz, 3H, H-15), 1.25 (s, 4H, H-6, 9), 1.20 (s, 2H, H-2, 5), 1.05 (s, 4H, H-1, 14); 13C-NMR (CDCl3, 201MHz) δ: 179.64 (C-12), 177.60 (C-11), 129.51 (C-13), 71.92 (C-8), 67.95 (C-4), 59.19 (C-9), 47.47 (C-3) , 39.32(C-7), 30.45(C-1′), 29.70(C-15), 25.43(C-6), 23.63(C-2), 23.47(C-5), 18.41(C-10), 18.25(C-14), 10.52(C-1).

[0110] Using hydrocortisone as a positive control, the Griess method was used to conduct preliminary in vitro anti-inflammatory activity tests on tianmingjing lactone and the synthesized compounds. The studies demonstrated that the synthesized compounds significantly inhibited the release of the inflammatory molecule nitric oxide (NO) from mouse macrophage RAW264.7 cells, with some compounds exhibiting superior activity compared to the parent compound. The compound structures and in vitro experimental results are shown in Table 1.

[0111]

[0112] Table 1 In vitro anti-inflammatory activity of target compounds on mouse macrophage RAW264.7

[0113]

[0114]

[0115] Note: a is IC 50 It represents the half-maximal inhibitory concentration.

Claims

1. A tannin lactone derivative having a structure of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof: in, In formula (I), R is tert-butylamino, aniline, morpholine, p-methoxyaniline, ethylamino, hexylamino, or pyrrolyl, In formula (II), R is ethylamino or morpholine, In formula (III), R is a methylamino group.

2. The niacin lactone derivative of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R is tert-butylamino, aniline, morpholine, p-methoxyaniline, ethylamino, hexylamino, pyrrolidinyl, corresponding to compounds 1-7.

3. The niacin lactone derivative of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R is ethylamino or morpholine, corresponding to compound 9-compound 10.

4. The niacin lactone derivative of formula (III) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R is a methylamino group, corresponding to compound 11 5. The method for preparing the tianmingjing lactone derivative or a pharmaceutically acceptable salt thereof according to claim 2, comprising the following steps: (1) reacting tantalum lactone with tert-butylamine to obtain 13-tert-butylamino tantalum lactone compound 1; (2) the reaction of tannin lactone and aniline to obtain 13-anilino tannin lactone compound 2; (3) 13-morpholino-13-olactone compound 3 is obtained by reacting 13-morpholino-13-olactone with morpholine; (4) reacting tannin lactone with p-methoxyaniline to obtain 13-p-methoxyanilino tannin lactone compound 4; (5) reacting tannin lactone with ethylamine hydrochloride to obtain 13-ethylaminotannin lactone compound 5; (6) reacting tannin lactone with hexylamine to obtain 13-hexyl tannin lactone compound 6; (7) The reaction of pyrrole with 13-pyrrolyl pyrrole compound 7 was obtained.

6. The method for preparing the tianmingjing lactone derivative or a pharmaceutically acceptable salt thereof according to claim 3, comprising the following steps: (1) The reaction of tianmingjing lactone alcohol and Dess-Martin reagent gave tianmingjing lactone ketone compound 8; (2) the tannin lactone compound 8 reacts with ethylamine hydrochloride to obtain the 13-ethylaminotannin lactone alcohol compound 9; (3) The 13-morpholino 13-morpholino lactone compound 10 is obtained by reacting the 13-morpholino 13-morpholino lactone compound 8 with morpholine.

7. The method for preparing the tianmingjing lactone derivative or a pharmaceutically acceptable salt thereof according to claim 4, comprising the following steps: The reaction of tianmingjing lactone alcohol with KOH obtains the tianmingjing lactone alcohol lactone ring opening product, and the tianmingjing lactone alcohol lactone ring opening product reacts with methylamine hydrochloride to obtain the 12-methylamino tianmingjing lactone alcohol ring opening product compound 11.

8. Use of the niacinol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the preparation of an anti-inflammatory drug for treating diseases mediated by the pro-inflammatory cytokine nitric oxide (NO).

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