CN113603743B - A kind of CDDO/Ligustrazinol hybrid compound with combined therapeutic effect and preparation method and use thereof - Google Patents

Abstract

本发明采用双前药策略，利用LAP响应片段亮氨酸酰基对CDDO类药物的CUK进行前药保护，并与川芎嗪醇活性片段进行偶联，形成CDDO/川芎嗪醇杂合物。本发明利用前药在LAP过表达的肝脏炎症组织中，选择性地裂解亮氨酸酰胺键片段，释放出CDDO类药物和川芎嗪醇，从而提高两种药物在肝损伤炎症组织的浓度，增加了炎症治疗作用，降低了药物剂量，改善了CDDO类药物的毒副作用，提高了药物安全性。The invention relates to the technical field of biomedicine, in particular to a class of CDDO/Ligustrazinol hybrid compounds with combined therapeutic action and a preparation method and application thereof, which have the structure shown in the general formula I:

The invention adopts the double prodrug strategy, utilizes the LAP response fragment leucine acyl to carry out prodrug protection on the CUK of CDDO drugs, and couples with the active fragment of ligustrazinol to form a CDDO/ligusinol hybrid compound. The present invention utilizes the prodrug to selectively cleave leucine amide bond fragments in the liver inflammatory tissue overexpressed by LAP to release CDDO drugs and ligustrazinol, thereby increasing the concentrations of the two drugs in the liver damaged inflammatory tissue, increasing the The inflammatory treatment effect is reduced, the drug dose is reduced, the toxic and side effects of CDDO drugs are improved, and the drug safety is improved.

Description

A kind of CDDO/Ligustrazinol hybrid compound with combined therapeutic effect and its preparation method and use

technical field

The invention relates to the technical field of biomedicine, in particular to a CDDO/ligusinol hybrid compound with combined therapeutic effect and a preparation method and application thereof.

Background technique

Hepatitis is a general term for inflammation of the liver, mainly caused by alcohol consumption, drugs and viral infections. If hepatitis cannot be treated reasonably in time, it will even evolve into liver fibrosis, liver cirrhosis, and even liver cancer. Therefore, it has become one of the research hotspots to find drugs that can effectively treat hepatitis.

Pentacyclic triterpenoids have a wide range of biological activities, especially in anti-tumor, anti-inflammatory and immune regulation. Studies have shown that oleanolic acid (OA) has a protective effect on the liver and has anti-inflammatory activity. Among a series of OA derivatives, methyl 2-nitrile-3,12-dioxooleanolic acid-1,9(11)-diene-28-carboxylate (CDDO-Me) received the most The same series of CDDO drugs have shown good anti-hepatitis activity, but the clinical results show that these drugs have serious cardiotoxicity, which is serious Limiting its clinical application, subsequent molecular mechanism studies found that α-cyano-α,β-unsaturated ketone (CUK) of CDDO drugs can activate Nrf2 signaling pathway to produce anti-inflammatory effects by combining with Keap. The activity of CUK is too high, and it can combine with nucleophilic macromolecules other than Keap, thus resulting in greater toxic and side effects. If the prodrug mode can be used, the active structure CUK can be protected, and CDDO-like drugs can be selectively released at the disease site to avoid its side effects on normal tissues, so as to reduce the toxicity of the drugs.

Ligustrazine (tetramethylpyrazine, TMP) is an alkaloid, also known as tetramethylpyrazine, widely exists in traditional Chinese medicine Chuanxiong. TMP has a wide range of pharmacological effects, such as anti-inflammatory, antioxidant, myocardial protection, liver protection, etc., and has good clinical application prospects. Mechanistic studies have shown that the anti-inflammatory and antioxidant functions of TMP are also related to its activation of the Nrf2 signaling pathway. 2-Hydroxymethyl-3,5,6-trimethylpyrazine (Ligustrazinol) is a metabolite of TMP in vivo, which has anti-inflammatory, antioxidant and other activities similar to TMP.

SUMMARY OF THE INVENTION

The purpose of the present invention is to solve the shortcomings existing in the prior art, and propose a class of CDDO/Ligustrazinol hybrid compound with combined therapeutic effect and its preparation method and application.

In order to achieve the above object, the present invention adopts the following technical solutions:

A class of CDDO/Ligustrazinol hybrids with combined therapeutic effect, having the structure shown in general formula I:

中的一种；n＝0或1。Wherein, R represents one of H, tert-butoxycarbonyl; R' represents OMe, NHMe,

One of; n=0 or 1.

Preferably, in the structure of the formula I, R, R' and n are selected from the following combinations:

R=H, R'=NHMe, n=0;

Or R=H, R'=OMe, n=1;

n＝1。or R = tert-butoxycarbonyl,

n=1.

The preferred structure is shown in Table 1:

Table 1. The compound code of formula I part and its corresponding structure

Wherein, I ₁ : (4aS, 6aR, 6bS, 8aS, 12aS, 14aR, 14bS)-10-(2-amino-4-methylpentanamide)-11-cyano-N,2,2,6a,6b ,9,9,12a-Octamethyl-14-oxo-12-((3,5,6-trimethylpyrazin-2-yl)methoxy)-1,2,3,4,4a ,5,6,6a,6b,7,8,8a,9,12,12a,14,14a,14b-octadecylhydropyran-4a-carbamate;

I ₂ : (4aS, 6aR, 6bS, 8aR, 12aS, 14aR, 14bS)-methyl-10-((4-(2-amino-4-methylpentanamide)benzyl)oxy)-11-cyano Base-2,2,6a,6b,9,9,12a-heptamethyl-14-oxo-12-((3,5,6-trimethylpyrazin-2-yl)methoxy)- 1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,14,14a,14b-octadecylhydropyran-4a-carboxylate;

I ₃ : tert-butyl(1-((4-(((((4aR, 6aS, 6bR, 8aS, 12aS, 12bR, 14bS)-2-cyano-8a-(1H-imidazole-1-carbonyl)-4 ,4,6a,6b,11,11,14b-heptamethyl-13-oxo-1-((3,5,6-trimethylpyrazin-2-yl)methoxy)-1,4 ,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydropyran-3-yl)oxo)methyl )phenyl)amino)-4-methyl-1-oxopentanoic acid-2-yl)carbamate.

The present invention also provides a kind of preparation method of CDDO/Ligustrazinol hybrid compound with combined therapeutic effect, comprising the following steps:

A. N-Boc protected L-leucine 2 in HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate) Condensed with p-aminobenzyl alcohol 1 in the presence of DIPEA (N,N-diisopropylethylamine) to generate amide compound 3, and compound 3 obtains bromide 5 under the action of phosphorus tribromide;

B. On the one hand, CDDO original drug 4 and ligustrazinol are treated with DMF/K ₂ CO ₃ to obtain enol intermediate 8, and then enol intermediate 8 and compound 5 are etherified to obtain CDDO-Me and ligustrazinol. The enol ether compound 6 or I _a ; On the other hand, the enol intermediate 8 and N-tert-butoxycarbonyl-L-leucine 2 are subjected to EDCI, DMAP condensation acylation to obtain compound I _a ;

C. Finally, deBoc of intermediate 6 via MeOH/HCl resulted in the formation of compound _Ib in high yield.

Both I _a and I _b belong to formula I.

The synthetic route is as follows:

中的一种；n＝0或1。Wherein, R represents one of H, tert-butoxycarbonyl; R' represents OMe, NHMe,

One of; n=0 or 1.

The present invention also provides the application of a class of CDDO/ligusinol hybrids with combined therapeutic effect for selective targeted therapy in inflammatory tissue of liver injury.

Among them, the selective release of CDDO original drug and ligustrazinol in liver injury inflammatory tissue in vivo can be achieved; the combined therapeutic effect of CDDO original drug and ligustrazinol in liver injury inflammatory tissue in vivo can be achieved.

Compared with the prior art, the present invention has the following beneficial effects:

1. The present invention adopts a double prodrug strategy, utilizes LAP-responsive fragment leucine acyl to protect the CUK of CDDO drugs, and couples with the active fragment of ligustrazinol to form a CDDO/ligusinol hybrid.

2. The present invention utilizes the prodrug to selectively cleave the leucine amide bond fragment in the liver inflammatory tissue overexpressed by LAP to release CDDO drugs and ligustrazinol, thereby increasing the concentration of the two drugs in the inflammatory tissue of liver injury , increased the inflammatory treatment effect, reduced the drug dosage, improved the toxic and side effects of CDDO drugs, and improved the safety of the drug.

Detailed ways

The technical solutions in the embodiments of the present invention will be described clearly and completely below, so that those skilled in the art can better understand the advantages and features of the present invention, and thus make a clearer definition of the protection scope of the present invention. The embodiments described in the present invention are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other implementations obtained by those of ordinary skill in the art without creative work For example, all belong to the protection scope of the present invention.

Example 1 (4aS, 6aR, 6bS, 8aS, 12aS, 14aR, 14bS)-10-(2-amino-4-methylpentanamide)-11-cyano-N,2,2,6a,6b,9 ,9,12a-Octamethyl-14-oxo-12-((3,5,6-trimethylpyrazin-2-yl)methoxy)-1,2,3,4,4a,5 ,6,6a,6b,7,8,8a,9,12,12a,14,14a,14b-octadecylhydropyran-4a-carbamate (I ₁ )

Dissolve CDDO-NHMe (0.198mmol, 110mg) with anhydrous DMF (4ml), then add K ₂ CO ₃ (0.396mmol, 54.7mg), N ₂ protection, ice bath, after reaction for 12h, (3,5, 6-Trimethylpyrazin-2-yl)methanol (0.198 mmol, 30.1 mg) was dissolved in DMF (1 ml), then Boc-leucyl chloride (0.30 mmol, 74.7 mg) was added dropwise to the mixture with vigorous stirring , the reaction 2h. After the reaction was completed, the aqueous solution was extracted three times with CH ₂ Cl ₂ (60 mL), and the organic layer was dried over Na ₂ SO ₄ and concentrated, and column separation was performed to obtain intermediate 6a in 60% yield.

Intermediate 6a (0.980 mmol, 992 mg) was dissolved in methanol solution of hydrochloric acid and stirred at room temperature for 12 h. After the completion of the reaction, the mixture was concentrated and separated by column to obtain compound I ₁ in a yield of 60%.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.50 (s, 1H, NH), 7.23 (s, 1H, NH), 5.78 (s, 1H, CH=C), 5.45 (m, 2H, CH ₂ ), 4.97(d, J=8.0Hz, 1H, CH), 4.31(t, J=6.7Hz, 2H, CH ₂ ), 4.01(s, 1H, CH), 3.47(s, 3H, CH ₃ ), 3.30( s, 3H, OCH ₃ ), 3.07 (s, 3H, NCH ₃ ), 3.06 (m, 1H, CH), 2.92 (d, J=4.7Hz, 1H, CH), 1.99 (dd, J=10.0, 4.4 Hz, 1H, CH), 1.89 (dd, J=9.5, 4.3 Hz, 1H, CH), 1.79 (m, 4H, 2CH ₂ ), 1.26 (m, 12H, 4CH ₂ ), 1.13 (d, J=10.2 Hz, 6H, 2CH ₃ ), 1.03 (m, 8H, 4CH ₂ ), 0.97 (t, J=6.5Hz, 6H, 2CH ₃ ), 0.91 (s, 3H, CH ₃ ).

Example 2 (4aS, 6aR, 6bS, 8aR, 12aS, 14aR, 14bS)-methyl-10-((4-(2-amino-4-methylpentanamide)benzyl)oxy)-11-cyano Base-2,2,6a,6b,9,9,12a-heptamethyl-14-oxo-12-((3,5,6-trimethylpyrazin-2-yl)methoxy)- 1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,14,14a,14b-octadecylhydropyran-4a-carboxylate ( I ₂ )

4-Aminobenzyl alcohol (0.739 g, 6 mmol) was dissolved in anhydrous DMF (15 mL), protected by _N2 , then cooled to 0 °C, and DIPEA (1.55 g, 12 mmol), HATU (1.62 g, 12 mmol). Then after stirring for an additional 10 minutes, N-(tert-butoxycarbonyl)-L-leucine 2 (1.388 g, 6 mmol) was added. Then the reaction system was returned to room temperature for 2 h. After the completion of the reaction, the reaction solution was washed with saturated NaCl solution (3×200 mL), and extracted with ethyl acetate (3×150 mL), and the organic layer was dried over Na ₂ SO ₄ and concentrated, and purified by column chromatography to obtain compound 3 as the product. rate 85%. The intermediate product 3 (1.01 g, 3 mmol) was dissolved in CH ₂ Cl ₂ (30 mL), and after stirring in an ice bath for 10 min, phosphorus tribromide (0.81 g, 3 mmol) was slowly added dropwise and reacted for 1 h. After the reaction, the pH was adjusted to 7 with 2 mol/L sodium bicarbonate solution, then extracted with CH ₂ Cl ₂ , and the organic layer was dried and concentrated under reduced pressure to obtain compound 5 with a yield of 80%.

CDDO-Me (0.198 mmol, 100 mg) was dissolved in anhydrous DMF (4 ml), then K ₂ CO ₃ (0.396 mmol, 54.7 mg) was added, N ₂ protection, ice bath, after reaction for 12 h, (3,5, 6-Trimethylpyrazin-2-yl)methanol (0.198 mmol, 30.1 mg) was dissolved in DMF (1 ml), then Intermediate 5 (0.30 mmol, 119.4 mg) was added dropwise to the mixture with vigorous stirring, The reaction was carried out for 2h. After the reaction was completed, the aqueous solution was extracted three times with CH ₂ Cl ₂ (60 mL), and the organic layer was dried over Na ₂ SO ₄ and concentrated, and column separation was performed to obtain the target compound 6b in a yield of 60%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.63 (s, 1H, NH), 7.49 (d, J=8.2 Hz, 2H, 2ArH), 7.25 (d, J=8.0 Hz, 2H, 2ArH), 5.79 ( s, 1H, CH=C), 5.37 (m, 2H, CH ₂ ), 4.93 (d, J=9.9 Hz, 1H, CH), 4.53 (d, J=10.0 Hz, 1H, CH), 4.28 (s , 1H, CH), 4.22 (s, 1H, CH), 3.60 (s, 3H, CH ₃ ), 2.96 (dt, J=13.9, 4.1Hz, 1H, CH), 2.77 (d, J=4.7Hz, 1H, CH), 2.39(m, 9H, 3CH ₃ ), 2.02(d, J=18.5Hz, 2H, CH ₂ ), 1.72(m, 4H, 2CH ₂ ), 1.49(m, 10H, 5CH ₂ ), 1.22 (m, 6H, 2CH ₃ ), 1.08 (m, 12H, 4CH ₃ ), 0.96 (d, J=9.1 Hz, 6H, 2CH ₃ ), 0.85 (m, 15H, 5CH ₃ ).

Intermediate 6b (0.11 mmol, 100 mg) was dissolved in methanol solution of hydrochloric acid, and stirred at room temperature for 12 h. After the completion of the reaction, it was concentrated and separated by column to obtain compound I ₂ in a yield of 60%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.64 (s, 1H, NH), 7.65 (d, J=8.5 Hz, 2H, NH ₂ ), 7.37 (d, J=8.4 Hz, 2H, 2ArH), 5.87 (s, 1H, ArH)), 5.52(d, J＝11.1Hz, 1H, ArH), 5.42(d, J＝11.1Hz, 1H, CH＝C), 5.01(d, J＝9.9Hz, 1H, OCH), 4.60 (d, J=9.9Hz, 1H, CH), 4.39 (d, J=23.4Hz, 2H, OCH ₂ ), 3.67 (s, 3H, OCH ₃ ), 3.54 (dd, J=9.9, 3.7Hz, 1H, CH), 3.36(s, 1H, CH), 3.02(dd, J=13.7, 4.2Hz, 1H, CH), 2.85(d, J=4.7Hz, 1H, CH), 2.46(d , J=5.8Hz, 9H, 3CH ₃ ), 2.00 (dd, J=8.8, 5.7Hz, 4H, 2CH ₂ ), 1.81 (m, 8H, 4CH ₂ ), 1.49 (m, 6H, 3CH ₂ ), 1.26 (s, 3H, CH ₃ ), 1.20 (s, 3H, CH ₃ ), 1.16 (s, 3H, CH ₃ ), 1.11 (s, 3H, CH ₃ ), 1.04 (s, 3H, CH ₃ ), 1.01 (d, J=3.3Hz, 6H, 2CH ₃ ), 0.97 (d, J=3.4 Hz, 3H, CH ₃ ), 0.93 (s, 3H, CH ₃ ).

Example 3 tert-butyl(1-((4-((((4aR,6aS,6bR,8aS,12aS,12bR,14bS)-2-cyano-8a-(1H-imidazole-1-carbonyl)-4 ,4,6a,6b,11,11,14b-heptamethyl-13-oxo-1-((3,5,6-trimethylpyrazin-2-yl)methoxy)-1,4 ,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydropyran-3-yl)oxo)methyl )phenyl)amino)-4-methyl-1-oxopentanoic acid-2-yl)carbamate (I ₃ )

4-Aminobenzyl alcohol (0.739 g, 6 mmol) was dissolved in anhydrous DMF (15 mL), protected by _N2 , then cooled to 0 °C, and DIPEA (1.551 g, 12 mmol), HATU (1.62 g, 12 mmol). Then after stirring for an additional 10 minutes, N-(tert-butoxycarbonyl)-L-leucine (1.388 g, 6 mmol) was added. Then the reaction system was returned to room temperature for 2 h. After the completion of the reaction, the reaction solution was washed with saturated NaCl solution (3×200 mL), and extracted with ethyl acetate (3×150 mL), and the organic layer was dried over Na ₂ SO ₄ and concentrated, and purified by column chromatography to obtain compound 3 as the product. rate 85%. The intermediate product 3 (1.01 g, 3 mmol) was dissolved in CH ₂ Cl ₂ (30 mL), and after stirring in an ice bath for 10 min, phosphorus tribromide (0.812 g, 3 mmol) was slowly added dropwise and reacted for 1 h. After the reaction, the pH was adjusted to 7 with 2 mol/L sodium bicarbonate solution, then extracted with CH ₂ Cl ₂ , and the organic layer was dried and concentrated under reduced pressure to obtain compound 5 with a yield of 80%.

CDDO-Im (0.198 mmol, 107 mg) was dissolved in anhydrous DMF (4 ml), then K ₂ CO ₃ (0.396 mmol, 54.7 mg) was added, N ₂ protection, ice bath, after reaction for 12 h, (3,5, 6-Trimethylpyrazin-2-yl)methanol (0.198 mmol, 30.1 mg) was dissolved in DMF (1 ml), then Intermediate 5 (0.30 mmol, 119.4 mg) was added dropwise to the mixture with vigorous stirring, The reaction was carried out for 2h. After the reaction was completed, the aqueous solution was extracted three times with CH ₂ Cl ₂ (60 mL), and the organic layer was dried over Na ₂ SO ₄ and concentrated, and column separation was performed to obtain the target compound I ₃ in a yield of 62%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.63 (s, 1H, NH), 8.15 (m, 1H, ArH), 7.49 (d, J=8.2Hz, 2H, 2ArH), 7.46 (m, 1H, ArH) ), 7.26(m, 1H, ArH), 7.25(d, J=8.0Hz, 2H, 2ArH), 5.79(s, 1H, CH=C), 5.37(m, 2H, CH ₂ ), 4.93(d, J=9.9Hz, 1H, CH), 4.53 (d, J=10.0Hz, 1H, CH), 4.28 (s, 1H, CH), 4.22 (s, 1H, CH), 2.96 (dt, J=13.9, 4.1Hz, 1H, CH), 2.77 (d, J=4.7Hz, 1H, CH), 2.39 (m, 9H, 3CH ₃ ), 2.02 (d, J=18.5Hz, 2H, CH ₂ ), 1.72 (m , 4H, 2CH ₂ ), 1.49 (m, 10H, 5CH ₂ ), 1.22 (m, 6H, 2CH ₃ ), 1.08 (m, 12H, 4CH ₃ ), 0.96 (d, J=9.1Hz, 6H, 2CH _{3 )} ),0.85(m,15H,5CH ₃ ).

Example 4 Protection test of the compound of the present invention against inflammatory injury of hepatocytes

The protective effect of the compounds of the present invention on human hepatocyte LO2 cell line was evaluated by in vitro toxicity test using tetramethylazole blue colorimetry (MTT). First, take a bottle of LO2 cells in good exponential growth phase, add 0.25% trypsin to digest, make the adherent cells fall off, and prepare a suspension containing 2×10 ⁴ to 4×10 ⁴ cells per ml. The cell suspension was inoculated on a 96-well plate, 180 μL per well, and cultured in a constant temperature CO ₂ incubator for 24 h. The medium was changed, 0.1% carbon tetrachloride was added to injure hepatocytes for 24 hours, the compounds of the present invention were dissolved in DMSO and then diluted with PBS. MTT was added to a 96-well plate, 20 μL per well, and reacted in an incubator for 4 hours. Aspirate the supernatant, add 150 μL DMSO to each well, and shake on a plate shaker for 5 minutes. The absorbance of each well was measured at a wavelength of 570 nm with an enzyme-linked immunosorbent assay, and the cell viability was calculated. Cell viability = OD value of test substance group/OD value of negative control group×100%.

The experimental results found that the compounds of the present invention can effectively reverse the damage of hepatocytes and inhibit the death of hepatocytes at lower doses (10 and 40nM). the combined administration group. This shows that the compound of the present invention has a strong therapeutic effect on damaged hepatocytes.

Table 2 Cell activity of the compounds of the present invention against hepatocyte injury

Example 5 In vivo test of the compound of the present invention on liver injury in mice

Male ICR mice were fasted overnight, and the next day, CCl ₄ solution (CCl ₄ : olive oil=1:4 dilution, 2 mL/kg) was injected intraperitoneally, once every three days, for a total of two injections. On the seventh day, the liver function indexes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected in the blood. The liver-damaged mice were divided into four groups, namely model group, positive drug CDDO+Ligustrazinol group (34 μmol/kg), I ₂ (17 μmol/kg), and I ₂ (34 μmol/kg). A blank control group was also set (same frequency, same volume of PBS injection). The drug was given three times within 5 days, intraperitoneal injection, and the liver function indexes ALT and AST in the blood were measured on the second day after administration.

The experimental results found that the compound I ₂ of the present invention has a strong therapeutic effect on the mouse model of liver injury. By detecting the liver function indexes ALT and AST in the blood of the mice, it was found that the compound I ₂ (17 and 34 μmol/kg) groups of the present invention were both effective. It has a significant therapeutic effect on liver injury. The AST index of liver function is 6-7 times lower than that of the model group, and the ALT index is nearly 7 times lower than that of the model group. At the same time, it is significantly better than the combination of the positive drug CDDO-Me and ligustrazinol (34 μmol/kg) In the treatment group, the ALT and AST indexes were 2-3 times lower than those in the positive drug CDDO-Me and ligustrazinol combination treatment group, indicating that the compound of the present invention has better therapeutic effect, and the liver function indexes basically returned to normal levels. Therefore, the compounds of the present invention have a significant effect of treating liver injury and inflammation in vivo.

The description and practice disclosed in the present invention are easy to think and understand for those skilled in the art, and several improvements and modifications can be made without departing from the principles of the present invention. Therefore, modifications or improvements made without departing from the spirit of the present invention should also be regarded as the protection scope of the present invention.

Claims (6)

1. a class of CDDO/Ligustrazinol hybrid compound with combined therapeutic effect, is characterized in that, has the structure shown in general formula I:

Wherein, R represents one of H, tert-butoxycarbonyl; R' represents OMe, NHMe,

One of; n=0 or 1. 2. a class according to claim 1 has the CDDO/Ligustrazinol hybrid compound of combined therapeutic effect, it is characterized in that, in the structure of described formula I, R, R ' and n are selected from following combination: R=H, R'=NHMe, n=0; Or R=H, R'=OMe, n=1; or R = tert-butoxycarbonyl,

n=1. 3. a class according to claim 1 has the preparation method of the CDDO/Ligustrazinol hybrid compound of combined therapeutic effect, is characterized in that, comprises the steps: A. L-leucine 2 protected by N-Boc is condensed with p-aminobenzyl alcohol 1 in the presence of HATU and DIPEA to generate amide compound 3, and compound 3 obtains bromide 5 under the action of phosphorus tribromide; B. On the one hand, CDDO original drug 4 and ligustrazinol are treated with DMF/K ₂ CO ₃ to obtain enol intermediate 8, and then enol intermediate 8 and compound 5 are etherified to obtain CDDO-Me and ligustrazinol. The enol ether compound I _a ; On the other hand, the enol intermediate 8 and N-tert-butoxycarbonyl-L-leucine 2 are subjected to EDCI, DMAP condensation acylation to obtain compound I _a ; C. Finally, compound I _a is subjected to the action of MeOH/HCl to remove Boc resulting in the formation of compound I _b ; Both I _a and I _b belong to the general formula I; The synthetic route is as follows:

Wherein, R represents one of H, tert-butoxycarbonyl; R' represents OMe, NHMe,

One of; n=0 or 1. 4. The application of a class of CDDO/Ligustrazinol hybrids with combined therapeutic action according to claim 1 or 2 for preparing medicines for the treatment of inflammatory diseases of liver injury. 5. The application of a class of CDDO/Ligustrazinol hybrids with combined therapeutic action according to claim 1 or 2 for preparing a medicine for liver function protection of liver injury and inflammatory diseases. 6. a class of CDDO/Ligustrazinol hybrid compound with combined therapeutic effect according to claim 1 and 2 is used to prepare the medicine that realizes CDDO original drug and Ligustrazinol play combined therapeutic effect in liver injury inflammatory disease. application.