A type of tripterygium wilfordii-ligustrazine hybrid and its preparation method and use

Abstract

The present invention discloses a class of tripterine-ligustrazine hybrids, their preparation methods, and uses. The present invention relates to the field of pharmaceutical chemistry; the present invention also discloses a composition of the tripterine-ligustrazine hybrid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and their use in preparing PRDX1 inhibitors. The compounds of the present invention can be used to treat diseases such as tumors and silicosis. The present invention provides novel small molecule inhibitors that are highly efficient, low-toxic, and highly selective for targeting the PRDX1 protein. The compounds of the present invention can effectively inhibit the occurrence and development of tumors and other processes, while significantly improving silicosis inflammation and fibrosis.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of tripterine-ligustrazine hybrids, a preparation method thereof, and uses thereof in preparing PRDX1 inhibitors and in preparing drugs for treating diseases such as tumors and silicosis. Background Art

[0002] The peroxiredoxin (PRDX) family is an important class of antioxidant enzymes in cells. They maintain intracellular hydrogen peroxide balance and scavenge reactive oxygen species (ROS), playing a crucial role in regulating intracellular signal transduction and metabolism. Six PRDX isoforms, PRDX1 to PRDX6, are expressed in mammals. Among them, PRDX1 has the highest abundance and widest tissue distribution, making it one of the most sought-after antioxidants.

[0003] As an antioxidant, PRDX1 is closely associated with the cellular defense system against oxidative stress. PRDX1 can scavenge ROS in the body and inhibit oxidative stress-induced apoptosis through direct or indirect interactions with different types of kinases and enzymes. PRDX1 functions as a molecular chaperone and plays an important role in protecting cells from oxidative stress. PRDX1's chaperone function is independent of peroxidase activity and is related to the enzyme's oligomeric state. Furthermore, PRDX1 has immunomodulatory effects. Studies have found that PRDX1 can enhance the cytotoxicity of natural killer cells (NK) against tumor cells in vitro. In vivo, PRDX1 can specifically bind to macrophage migration inhibitory factor (MIF), thereby regulating the immune response. In summary, PRDX1 can be used as a drug target for the treatment of related diseases.

[0004] Celastrol (CSL), a natural corkane-type pentacyclic triterpenoid, is one of the active ingredients of Tripterygium wilfordii Hook.f., a plant of the Celastraceae family. It exhibits multiple pharmacological activities, including anti-inflammatory, antioxidant, and anti-tumor activities, making it a popular natural product of recent interest. However, its mechanism of action is complex, and reported target activity is weak, leading to an urgent need to identify more potent targets. While CSL exhibits promising pharmacological activity, it is inherently toxic and has a narrow therapeutic window. Structural modification to reduce toxicity and enhance efficacy is a current research hotspot. Tetramethylpyrazine (TMP), an alkaloid extracted from the rhizome of the traditional Chinese medicine Chuanxiong, is one of the main active ingredients in Chuanxiong and is clinically used to treat ischemic cardiovascular and cerebrovascular diseases. However, its low bioactivity and short half-life limit its clinical application. Therefore, structural modification and engineering of TMP are needed to address these shortcomings. Summary of the Invention

[0005] In order to solve the above problems, the present invention provides a class of tripterygium wilfordii-ligustrazine hybrids, and provides a specific preparation method of the compound and its pharmaceutical application as a PRDX1 protein inhibitor.

[0006] The technical solution of the present invention is: the present invention discloses a tripterygium wilfordii-ligustrazine hybrid or a pharmaceutically acceptable salt thereof as shown in the general formula (I):

[0007]

[0008] in:

[0009] X represents amino, oxygen or methylene;

[0010] R 1 Representative-OR 2 or -NR 2 R 3 , where R 2 and R 3 Each is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, three- to six-membered heterocycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, amide, or substituted with one or two or more substituents selected from hydroxy, hydroxy-substituted C1-C3 alkyl, amino, halogenated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, amide, carbamate, ether, thioether, carboxylic acid, C6-C10 aryl, halogen.

[0011] Furthermore, X preferably represents an amino group or an oxygen group.

[0012] Furthermore, R 1 Preferred Representative-OR 2 or -NR 2 R 3 , where R 2 and R 3 Each is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, three- to six-membered heterocycloalkyl, C2-C6 alkenyl, or amide.

[0013] Furthermore, the PRDX1 inhibitor of the present invention is selected from the following compounds:

[0014]

[0015]

[0016]

[0017]

[0018] Furthermore, the pharmaceutically acceptable salt is an acid addition salt of the compound of formula (I), wherein the acid used for salt formation is: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

[0019] The compounds of the general formula (I) of the present invention can be prepared by the following methods:

[0020]

[0021] Where X and R 1 The definition of is the same as above.

[0022] Further, where: X, Y, Z, R 1 、R 2 The definition of is the same as above.

[0023] Furthermore, the specific preparation steps of the method are as follows:

[0024] Step 1: The compound represented by Formula II is subjected to an amide or ester reaction to produce a compound represented by Formula III. The amide reaction can be carried out, for example, using 1-hydroxybenzotriazole (HOBT) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) as condensing agents, triethylamine as an acid-binding agent, and N,N-dimethylformamide as a solvent. The reaction time is, for example, 12 hours, and the reaction temperature is, for example, 25°C. The ester reaction can be carried out, for example, using sodium bicarbonate as a base and N,N-dimethylformamide as a solvent. The reaction time is, for example, 8 hours, and the reaction temperature is, for example, 25°C.

[0025] Step 2: The compound represented by Formula III is reacted with various substituted acid chlorides to form an ester to produce the compound represented by Formula I. The reaction can be carried out under conditions such as triethylamine as an acid-binding agent and dichloromethane as a solvent. The reaction time is, for example, 0.5 hours and the reaction temperature is, for example, 0°C.

[0026] The present invention also discloses a pharmaceutical composition comprising the compound of the above-mentioned general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; the compound can be added with a pharmaceutically acceptable carrier to prepare common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions, and injections, and can be added with common pharmaceutical excipients such as flavorings, sweeteners, liquid or solid fillers or diluents.

[0027] The use of the compound of general formula (I) and its hydrate, solvate or crystal in the preparation of PRDX1 inhibitor drugs is also within the protection scope of the present invention.

[0028] The present invention also provides the use of the tripterygium wilfordii-ligustrazine hybrid or a pharmaceutically acceptable salt thereof according to the present invention in preparing a PRDX1 inhibitor or in preparing a drug for treating diseases associated with PRDX1, especially tumors and silicosis.

[0029] The PRDX1-related diseases refer to diseases whose occurrence or progression is related to the PRDX1 signaling pathway, including inflammation, cancer, pneumoconiosis, obesity, and diabetes. Preferably, the tumors include lung cancer, liver cancer, and breast cancer, and the pneumoconiosis includes silicosis.

[0030] The beneficial effects of the present invention are: the present invention provides a new type of small molecule inhibitor targeting PRDX1 protein with high efficiency, low toxicity and good selectivity. The compounds involved in the present invention can effectively inhibit the occurrence and development of tumors, and at the same time, can significantly improve silicosis inflammation and fibrosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a diagram showing the HE staining results of lung tissue in an embodiment of the present invention. DETAILED DESCRIPTION

[0032] In order to more clearly illustrate the technical solution of the present invention, the technical solution of the present invention is further described in detail below with reference to the accompanying drawings:

[0033] Example 1:

[0034] Preparation of compound III-1:

[0035]

[0036] Place tripterygium wilfordii (II, 500 mg, 1.11 mmol), 2-bromoethyl-3,5,6-trimethylpyrazine (1.20 g, 5.55 mmol) and sodium bicarbonate (466 mg, 5.55 mmol) in a 50 mL eggplant-shaped flask and add 10 mL of DMF solution to dissolve them;

[0037] After the addition was complete, the reaction was stirred at 25°C for 16 hours. TLC analysis (dichloromethane:methanol = 40:1) showed that the reaction of tripterygium wilfordii was complete. The reaction solution was poured into 40 mL of water and stirred until it became turbid. It was then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was then separated by silica gel column chromatography (dichloromethane:methanol = 200:1 to 50:1) to obtain 470 mg of a yellow solid (yield 72.43%). 1 H NMR (600MHz, CDCl3) δ7.00(d,J=7.1Hz,1H),6.96(s,1H),6.47(s,1H),6.31(d,J=7.1Hz,1H),5.03(q,J=1 2.3Hz,2H),2.50(s,3H),2.47(s,3H),2.43(s,3H),2.38(t,J=11.0Hz,1H),2.19(s,4H),2.05-1.97(m,2H) ,1.85(td,J=14.1,6.1Hz,1H),1.70-1.58(m,5H),1.54(d,J=7.9Hz,2H),1.47(dd,J=14.7,4.9Hz,1H),1. 40(s,3H),1.39-1.33(m,1H),1.22(s,3H),1.19(s,3H),1.06(s,3H),0.95(d,J=14.0Hz,1H),0.50(s,3H). 13C NMR (151MHz, CDCl3) δ178.29,177.71,169.86,164.67,151.09,149.19,148 .92,145.99,144.94,134.06,127.36,119.51,118.11,116.98,65.23,45.01 ,44.23,42.86,40.59,39.48,38.12,36.33,34.75,33.52,32.73,31.56,30.72,30.49,29.90,29.61,28.61,21.57,21.49,21.40,20.42,18.51,10.24.

[0038] Example 2:

[0039] Preparation of compound III-2:

[0040]

[0041] Place tripterygium wilfordii (II, 373 mg, 0.83 mmol), 3,5,6-trimethylpyrazine-2-methylamine (150 mg, 0.99 mmol), HOBT (168 mg, 1.24 mmol), and EDCI (238 mg, 1.24 mmol) in a 50 mL eggplant-shaped flask, add 10 mL of DMF solution to dissolve, and then slowly add triethylamine (167.5 mg, 1.65 mmol) dropwise;

[0042] After the addition, the reaction was stirred at 25°C for 12 hours. TLC analysis (dichloromethane:methanol = 40:1) showed that the reaction of tripterygium wilfordii was complete. The reaction solution was poured into 40 mL of water and stirred to precipitate a large amount of reddish-brown solid. The solid was filtered, dried, and separated by silica gel column chromatography (dichloromethane:methanol = 200:1 to 50:1) to obtain 400 mg of a red solid (yield 82.77%). 1HNMR (600MHz, CDCl3) δ7.55(t,J=3.9Hz,1H),6.92(dd,J=7.1,1.5Hz,1H),6.42(d,J=1.5Hz,1H),6.25(d,J=7.1H z,1H),4.33-4.21(m,2H),2.61(q,J=7.3Hz,1H),2.50(d,J=15.9Hz,1H),2.47(s,3H),2.45(s,3H),2.37(s,3H), 2.14(s,3H),2.11(d,J=15.4Hz,1H),2.03(dq,J=15.7,4.0,3.4Hz,1H),1.86(dd,J=15.3,5.2Hz,2H),1.69-1.59 (m,5H),1.53-1.47(m,2H),1.39(s,3H),1.22(s,3H),1.19(s,3H),1.12(s,3H),1.09-1.04(m,3H),0.50(s,3H).

[0043] 13 C NMR (151MHz, CDCl3) δ178.26,177.81,170.13,164.60,149.47,147.80,147 .47,145.95,144.92,133.83,127.33,119.47,117.89,116.90,46.06,45.02 ,44.41,42.88,40.84,40.45,39.35,38.15,36.40,34.84,33.71,33.37,31.63,31.24,30.79,30.14,29.32,28.59,21.68,21.32,19.87,17.97,10.18.

[0044] Example 3:

[0045] Preparation of compound I-1:

[0046]

[0047] Compound III-2 (50 mg, 0.086 mmol) and triethylamine (17.4 mg, 0.172 mmol) were placed in a 25 mL eggplant-shaped flask, 5 mL of dichloromethane was added and stirred to dissolve, and acetyl chloride (10.1 mg, 0.128 mmol) was slowly added dropwise at 0°C;

[0048] After the addition was complete, the mixture was stirred at 0°C for 0.5 hours. TLC analysis (dichloromethane:methanol = 40:1) showed that compound III-2 had reacted completely. The reaction solution was dried and separated by silica gel column chromatography (dichloromethane:methanol = 200:1 to 50:1) to obtain 35 mg of a light yellow solid product (yield 65.35%). NMR(600MHz,Chloroform-d)δ7.62(s,1H),7.01(d,J=6.8Hz,1H),6.41(s,1H),6.28(d,J=7.1Hz,1H),4.34( q,J=17.3Hz,2H),3.12(d,J=6.3Hz,3H),2.53–2.52(m,2H),2.51(s,3H),2.46(s,3H),2.35(s,3H),2.13(s,3 H),2.06(dt,J=12.1,3.4Hz,1H),1.90(d,J=8.4Hz,1H),1.74(dd,J=15.8,8.0Hz,2H),1.64(dd,J=16.1,9.9H z,4H),1.56–1.52(m,2H),1.45(s,3H),1.42(s,3H),1.27(s,3H),1.23(s,3H),1.16(s,3H),0.56(s,3H).13C NMR(151MHz,Chloroform-d)δ177.90,177.44,172.03,168.69,162.99,142.95,1 35.27,133.91,133.48,126.28,124.46,122.95,119.50,119.09,117.63,45.83, 45.25,44.46,42.63,39.25,38.22,36.42,33.76,33.54,31.66,31.34,30.82,30.12,29.70,29.32,28.64,26.92,21.98,21.34,20.54,19.96,18.10,11.30,8.63.

[0049] Example 4:

[0050] Preparation of compound I-2:

[0051]

[0052] Compound III-2 (200 mg, 0.343 mmol) and triethylamine (69.63 mg, 0.686 mmol) were placed in a 25 mL eggplant-shaped flask, 5 mL of dichloromethane was added and stirred to dissolve, and propionyl chloride (47.54 mg, 0.514 mmol) was slowly added dropwise at 0°C;

[0053] After the addition was completed, the reaction was stirred at 0°C for 0.5 hours. TLC detection (dichloromethane:methanol = 40:1) showed that the reaction of compound III-2 was complete. The reaction solution was spin-dried and separated by silica gel column chromatography (dichloromethane:methanol = 200:1-50:1) to obtain 112 mg of yellow solid product (yield 51.13%). 1 H NMR(600MHz,Chloroform-d)δ7.62(s,1H),7.00(d,J=7.0Hz,1H),6.40(s,1H),6.28(d,J=7.1Hz,1H),4.38–4. 30(m,2H),3.12(d,J=2.6Hz,3H),2.68–2.64(m,2H),2.55-2.50(m,4H),2.50(s,3H),2.46(s,2H),2.24–2.15(m ,3H),2.12(s,3H),1.90(d,J=8.4Hz,1H),1.73(d,J=7.9Hz,1H),1.62(d,J=8.5Hz,2H),1.55(d,J=5.7Hz,1H), 1.42(s,3H),1.30(s,2H),1.28(s,2H),1.27(s,3H),1.23(s,3H),1.16(s,3H),1.14–1.06(m,3H),0.56(s,3H). 13 C NMR(151MHz,Chloroform-d)δ177.91,177.50,172.17,171.78,162.90,142.98,13 5.05,133.34,126.36,126.96,119.50,119.09,117.94,117.62,116.95,45.81,45. 23,44.46,42.59,40.44,39.23,38.21,36.42,34.84,33.77,33.52,31.66,31.33,30.82,30.11,29.70,29.32,28.64,27.22,21.99,21.34,18.10,11.24,9.18,8.63.

[0054] Example 5:

[0055] Preparation of Compound Ⅰ-3

[0056]

[0057] Compound III-2 (250 mg, 0.428 mmol) and triethylamine (173 mg, 1.712 mmol) were placed in a 25 mL eggplant-shaped flask, 5 mL of dichloromethane was added and stirred to dissolve, and n-butyryl chloride (136.9 mg, 1.285 mmol) was slowly added dropwise at 0°C;

[0058] After the addition was completed, the reaction was stirred at 0°C for 0.5 hours. TLC detection (dichloromethane:methanol = 40:1) showed that the reaction of compound III-2 was complete. The reaction solution was spin-dried and separated by silica gel column chromatography (dichloromethane:methanol = 200:1-50:1) to obtain 110 mg of a light yellow solid product (yield 39.31%). 1 H NMR(600MHz,Chloroform-d)δ7.63(s,1H),7.00(d,J=6.6Hz,1H),6.41(s,1H),6.28(d,J=6.9Hz,1H),4.35( q,J=16.7,15.4Hz,2H),2.61(t,J=7.2Hz,2H),2.53(s,3H),2.51(s,3H),2.47(s,3H),2.20(t,J=14.1Hz,2H ),2.12(s,3H),1.93–1.88(m,2H),1.83–1.79(m,2H),1.77–1.72(m,2H),1.63(d,J=9.0Hz,3H),1.57–1.52( m,2H),1.46(s,3H),1.30(s,2H),1.27(s,5H),1.24(s,3H),1.17(s,3H),1.06(t,J=7.3Hz,3H),0.56(s,3H). 13 C NMR(151MHz,Chloroform-d)δ177.90,177.50,171.72,171.33,162.86,143.00,134. 99,133.32,126.38,124.47,123.98,123.00,119.52,119.00,117.61,45.22,44.47,4 2.58,40.44,39.24,38.21,36.43,35.76,34.85,33.78,33.54,31.67,31.45,31.34,30.83,30.20,30.12,29.71,29.34,28.65,22.00,21.34,18.54,18.10,13.70,11.27.

[0059] Example 6:

[0060] Preparation of compound I-4:

[0061]

[0062] Compound III-2 (200 mg, 0.343 mmol) and triethylamine (139 mg, 1.372 mmol) were placed in a 25 mL eggplant-shaped flask, 5 mL of dichloromethane was added and stirred to dissolve, and cyclopropaneyl chloride (107 mg, 1.028 mmol) was slowly added dropwise at 0°C;

[0063] After the addition was complete, the reaction was stirred at 0°C for 0.5 hours. TLC analysis (dichloromethane:methanol = 40:1) showed that compound III-2 had reacted completely. The reaction solution was dried and separated by silica gel column chromatography (dichloromethane:methanol = 200:1 to 50:1) to obtain 85 mg of a light yellow solid product (yield 38.09%). HRMS (ESI): m / z [M+H] + .Calcd for C 41 H 54 N3O4:652.8920,Found:653.8933.

[0064] Example 7:

[0065] Preparation of compound I-5:

[0066]

[0067] Compound III-2 (100 mg, 0.171 mmol) and triethylamine (69.22 mg, 0.684 mmol) were placed in a 25 mL eggplant-shaped flask, 5 mL of dichloromethane was added and stirred to dissolve, and cinnamoyl chloride (85.61 mg, 0.514 mmol) was slowly added dropwise at 0°C;

[0068] After the addition was completed, the reaction was stirred at 0°C for 0.5 hours. TLC detection (dichloromethane:methanol = 40:1) showed that the reaction of compound III-2 was complete. The reaction solution was spin-dried and separated by silica gel column chromatography (dichloromethane:methanol = 200:1-50:1) to obtain 63 mg of a brown-yellow solid product (yield 51.52%). 1H NMR(600MHz,Chloroform-d)δ7.88(d,J=16.0Hz,1H),7.64(s,1H),7.59(dd,J=6.3,3.0Hz,2H),7.55(d,J=3.6Hz,1H),7.43–7.42(m,2H),7.04( d,J=7.0Hz,1H),6.70(d,J=16.0Hz,1H),6.47(s,1H),6.30(d,J=7.1Hz, 1H),4.36(q,J=17.5,15.9Hz,2H),2.53(s,3H),2.52(s,3H),2.47(s,3H) ,2.24(dd,J=14.1,3.6Hz,1H),2.21(s,1H),2.18(s,3H),2.09(d,J=12.7Hz,1H),1.91(dd,J=13.5,5.2Hz,2H),1.76(dd,J=15.9,8.1Hz,2H),1.6 5(dd,J=14.4,6.7Hz,3H),1.58(s,2H),1.48(s,3H),1.35(s,1H),1.30( s,1H),1.29(s,3H),1.28(s,1H),1.24(s,3H),1.17(s,3H),0.59(s,3H). 13 C NMR(151MHz,Chloroform-d)δ177.92,177.56,171.97,164.48,162.95,146.83,146.20,142.9 2,135.23,134.34,134.27,133.71,130.55,128.91,128.35,128.26,126.40,124.47,123.98, 123.06,117.67,116.82,45.27,44.49,42.66,40.45,39.28,38.24,36.44,34.87,33.78,33.58,31.68,31.36,30.83,30.13,29.70,29.37,28.66,26.93,22.01,21.34,19.96,18.12,11.42.

[0069] Example 8:

[0070] Preparation of compound I-6:

[0071]

[0072] Compound III-2 (100 mg, 0.171 mmol) and triethylamine (69.2 mg, 0.684 mmol) were placed in a 25 mL eggplant-shaped flask, 5 mL of dichloromethane was added and stirred to dissolve, and tetrahydropyran-4-carbonyl chloride (76.86 mg, 0.514 mmol) was slowly added dropwise at 0°C;

[0073] After the addition was completed, the reaction was stirred at 0°C for 0.5 hours. TLC detection (dichloromethane:methanol = 40:1) showed that the reaction of compound III-2 was complete. The reaction solution was spin-dried and separated by silica gel column chromatography (dichloromethane:methanol = 200:1-50:1) to obtain 48 mg of yellow solid product (yield 40.30%). 1 H NMR(600MHz,Chloroform-d)δ7.62(s,1H),7.01(d,J=7.1Hz,1H),6.40(s,1H),6.28(d,J=7.1Hz,1H),4.33( d,J=16.0Hz,2H),4.05(s,2H),3.52(s,2H),3.12(d,J=2.2Hz,2H),2.51(s,3H),2.43(s,2H),2.19(s,1H),2 .11(s,3H),2.03(s,1H),1.90(s,2H),1.74(s,2H),1.64(d,J=4.0Hz,2H),1.55(s,2H),1.45(s,3H),1.44(s ,3H),1.43(s,3H),1.42(s,3H),1.27(s,3H),1.23(s,3H),1.17(s,3H),0.88(d,J=7.0Hz,2H),0.54(s,3H). 13 C NMR(151MHz,Chloroform-d)δ178.31,177.89,177.24,174.33,172.21,171.78,164.68,163.01,160.04, 151.70,146.00,142.86,142.50,135.17,133.29,130.29,128.30,126.27,122.90,119.52,117.62,117. 00,116.24,67.11,66.94,45.81,45.26,44.46,42.63,40.45,40.15,39.77,39.25,38.22,36.42,34.84,33.75,33.52,31.66,31.33,30.91,30.20,29.31,28.62,26.92,21.99,21.35,19.94,18.10,11.18,8.63.

[0074] Example 9:

[0075] Preparation of compound I-7:

[0076]

[0077] Compound III-1 (50 mg, 0.085 mmol) and triethylamine (35 mg, 0.344 mmol) were placed in a 25 mL eggplant-shaped flask, 5 mL of dichloromethane was added and stirred to dissolve, and acetyl chloride (20.16 mg, 0.257 mmol) was slowly added dropwise at 0°C;

[0078] After the addition was completed, the reaction was stirred at 0°C for 0.5 hours. TLC detection (dichloromethane:methanol = 40:1) showed that the reaction of compound III-1 was complete. The reaction solution was spin-dried and separated by silica gel column chromatography (dichloromethane:methanol = 200:1-50:1) to obtain 28 mg of a light yellow solid product (yield 52.20%). 1 H NMR(600MHz,Chloroform-d)δ7.62(s,1H),7.01(d,J=7.0Hz,1H),6.41(q,J=1.7Hz,1H),6.28(dd,J=7.3,2.2Hz,1H),4.35(t,J =16.2Hz,2H),3.12(td,J=5.2,2.4Hz,3H),2.53(d,J=5.7Hz,3H),2.51(d,J=2.3Hz,3H),2.48–2.43(m,3H),2.36–2.34(m,3H), 1.90(dd,J=14.2,5.3Hz,2H),1.76–1.71(m,2H),1.64(dd,J=11.9,6.9Hz,3H),1.55(t,J=7.0Hz,2H),1.46–1.45(m,3H),1.44– 1.43(m,3H),1.35–1.34(m,1H),1.30(t,J=1.6Hz,1H),1.27(d,J=2.2Hz,3H),1.23(s,3H),1.16(s,3H),0.55(d,J=17.0Hz,3H). 13C NMR(151MHz,Chloroform-d)δ177.87,177.43,172.00,168.68,162.97,142.96,1 35.25,133.46,126.29,124.47,123.97,122.96,119.50,117.94,117.63,45.81, 45.25,44.47,42.63,40.44,39.25,38.22,36.42,34.87,33.76,33.54,31.66,31.34,30.82,30.12,29.33,28.64,26.92,21.99,21.35,20.54,18.10,11.30,8.63.

[0079] Example 10:

[0080] Preparation of compound I-8:

[0081]

[0082] Compound III-1 (50 mg, 0.085 mmol) and triethylamine (35 mg, 0.344 mmol) were placed in a 25 mL eggplant-shaped flask. 5 mL of dichloromethane was added and stirred to dissolve. Cinnamoyl chloride (42.8 mg, 0.257 mmol) was slowly added dropwise at 0°C. After addition, the mixture was stirred at 0°C for 0.5 hours. TLC analysis (dichloromethane:methanol = 40:1) showed that compound III-1 had reacted completely. The reaction solution was dried and separated by silica gel column chromatography (dichloromethane:methanol = 200:1 to 50:1) to obtain 32 mg of the product as a brownish-yellow solid (yield 52.30%). 1 H NMR(600MHz,Chloroform-d)δ7.90(d,J=15.9Hz,2H),7.60(s,2H),7.42(s,3H),7.10(d,J=6.3Hz ,1H),6.72(d,J=15.9Hz,2H),6.35(d,J=7.0Hz,1H),5.15–5.03(m,2H),2.55(s,3H),2.52(s,3H) ,2.48(s,3H),2.22(s,3H),2.10(s,2H),1.71–1.66(m,3H),1.60–1.57(m,2H),1.49(s,3H),1.35 (s,2H),1.30(s,3H),1.27(s,3H),1.24(s,3H),1.11(s,3H),1.00(d,J=14.7Hz,2H),0.59(s,3H). 13C NMR(151MHz,Chloroform-d)δ177.72,177.60,175.00,171.78,164.47,163.07,146.83,142.99, 135.51,134.35,133.83,130.56,129.03,128.92,128.35,128.26,126.41,124.47,123.98,123. 03,119.11,117.87,116.83,65.24,45.25,44.28,42.67,40.60,39.40,38.21,36.36,34.75,33.68,32.73,31.59,31.45,30.72,30.52,30.20,29.95,29.71,28.65,21.90,21.45,18.63,11.46.

[0083] Example 11: Pharmacological experiments and results of some compounds of this patent

[0084] 1. Testing of the inhibitory activity of PRDX1 protein in vitro

[0085] Experimental reagents:

[0086] Human peroxide redox enzyme-linked immunosorbent assay kit (PRDX1).

[0087] Experimental methods:

[0088] ①. Dilution of standard; ②. Sample addition: set up blank wells (blank control wells without adding sample and enzyme-labeled reagent, and the rest of the steps are the same), standard wells, and sample wells to be tested;

[0089] Accurately add 50 μL of the standard sample to the enzyme-labeled coated plate, first add 40 μL of the sample diluent to the sample well to be tested, and then add 10 μL of the sample to be tested (the final dilution of the sample is 5 times). Add the sample to the bottom of the ELISA plate well, trying not to touch the well wall, and gently shake to mix; ③, incubation: seal the plate with a sealing film and incubate at 37℃ for 30 minutes; ④, solution preparation: dilute the 30-fold concentrated washing solution with distilled water 30 times and set aside; ⑤, washing: carefully peel off the sealing film, discard the liquid, shake dry, fill each well with washing solution, let it stand for 30 seconds and then discard, repeat this 5 times, and pat dry; ⑥, enzyme addition: add 50μL of enzyme-labeled reagent to each well, except for the blank well; ⑦, incubation: operate as in 3; ⑧, washing: operate as in 5; ⑨, color development: first add 50μL of color developer A to each well, then add 50μL of color developer B, gently shake to mix, and develop at 37℃ in the dark for 15 minutes; ⑩, termination and measurement: add 50μL of stop solution to each well to terminate the reaction (the blue color immediately turns yellow); use the blank well as the zero condition, and measure the absorbance (OD value) of each well in sequence at a wavelength of 450nm.

[0090] calculate:

[0091] Draw a standard curve on coordinate paper with the concentration of the standard as the horizontal axis and the OD value as the vertical axis. Find the corresponding concentration from the standard curve based on the OD value of the sample; then multiply it by the dilution factor; or use the concentration and OD value of the standard to calculate the linear regression equation of the standard curve, substitute the OD value of the sample into the equation, calculate the sample concentration, and then multiply it by the dilution factor to get the actual concentration of the sample.

[0092] Test results:

[0093] Some compounds of the present invention were screened for their in vitro PRDX1 inhibitory activity. The results are shown in Table 1.

[0094] IC 50 :0-0.5μM (denoted as: A); IC 50 :0.5-1μM (denoted as: B); IC 50 :1-5μM (denoted as: C); IC 50 :>5μM (denoted as D).

[0095] Table 1. Inhibitory activity of some compounds against PRDX1

[0096]

[0097] The results in Table 1 show that most of the test compounds of the present invention have good inhibitory activity against PRDX1, among which compounds III-2, I-3 to I-5, and I-7 have inhibitory activities against PRDX1 within 500 nM, which are better than the positive control drugs CSL and Conoidin A.

[0098] 2. Test of tumor cell proliferation inhibitory activity

[0099] Test method:

[0100] The MTT method was used to select tumor cell lines such as A549, LTEP-a-2, H1975, MDA-MB-231, and SK-Hep-1. After digestion of cells in the logarithmic growth phase, they were blown into single-cell suspensions and inoculated into 96-well culture plates at a speed of 5×10 3Each well was incubated with 200 μL of culture medium at 37°C and 5% CO2 overnight in an incubator. After the cells adhered, the test compound and positive control drug at appropriate concentrations were added and incubated in an incubator for 3 days. Four hours before the end of the incubation, 20 μL of MTT solution (5 mg / ml) was added to each well. After the incubation was completed, the supernatant of each well was discarded, 150 μL of DMSO was added to each well, and the cells were shaken on a cell shaker for 10 minutes. After the crystals were fully dissolved, the OD value at a wavelength of 570 nm was measured using a microplate reader. The inhibition rate was calculated according to the following formula: Percentage of proliferation inhibitory activity (%) = (OD value of drug - OD value of background) / (OD value of control - OD value of background) × 100%, with drug concentration as the horizontal axis and the percentage of proliferation inhibitory activity corresponding to each concentration as the vertical axis. Nonlinear regression was performed using Graphpd Prism 5 to calculate the IC value of each compound. 50 value.

[0101] Test results:

[0102] Some compounds of the present invention were screened for their in vitro tumor cell proliferation inhibitory activity. The results are shown in Table 2.

[0103] IC 50 :0-3μM (denoted as: A); IC 50 :3-6μM (denoted as: B); IC 50 :6-10μM (denoted as: C); IC 50 :>10μM (denoted as: D); / : not determined.

[0104] Table 2. Inhibitory activity of some compounds on tumor cell proliferation

[0105]

[0106]

[0107] The results in Table 2 show that most of the tested compounds have strong inhibitory activity on the proliferation of the selected tumor cells, among which compounds I-3, I-5 and I-8 have the strongest activity.

[0108] 3. Test of therapeutic effect on silicosis mice:

[0109] Eight-week-old C57BL / 6J mice were randomly divided into four groups according to their body weight (20±2g), namely, blank control group, silica (CS) treatment group, CS combined with compound I-5 treatment group, and CS combined with tripterine (CSL) treatment group; CS was administered by nasal drops, and compound I-5 and CSL were administered by intraperitoneal injection; CS suspension (nm level, 50 mg / mL) was administered by nasal drops every 3 days, and I-5 (1 mg / kg) and CSL (1 mg / kg) were administered intraperitoneally once a day; after the end of the administration, fresh lung tissues were obtained by dissection and analyzed by HE staining.

[0110] The results showed that in the fresh lung tissue of mice, the lung volume of mice in the CS group was the largest and there were gravel protrusions on the surface, while the lung volume of mice given compound I-5 was the smallest and there was no obvious change; HE staining analysis found that compound I-5 could significantly inhibit the formation of silicosis nodules and the aggregation of inflammatory cells, and its activity was better than the positive control drug CSL.

[0111] The above are merely preferred embodiments of the present invention. The scope of protection of the present invention is not limited to the above embodiments. All technical solutions based on the principles of the present invention are within the scope of protection of the present invention. It should be noted that for those skilled in the art, various improvements and modifications that do not depart from the principles of the present invention should be considered within the scope of protection of the present invention.

Claims

1. A tripterygium wilfordii-ligustrazine hybrid or a pharmaceutically acceptable salt thereof, characterized in that: The heterocompound is selected from any one of the following compounds:

2. The tripterygium wilfordii-ligustrazine hybrid or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The pharmaceutically acceptable salt is an acid addition salt formed by the heterocomplex and the following acids: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

3. A pharmaceutical composition, characterized in that The invention comprises the heteroconjugate according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, characterized in that The preparation form is selected from tablets, capsules, syrups, suspensions and injections.

5. Use of the tripterine-ligustrazine hybrid or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a PRDX1 inhibitor drug.

6. The use according to claim 5, characterized in that The PRDX1 inhibitor drug is used to treat lung cancer, liver cancer or breast cancer.

7. Use of the following tripterygium wilfordii-ligustrazine hybrid or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a PRDX1 inhibitor drug for treating silicosis.

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