Application of a coumarin compound in the preparation of a drug for treating hepatitis

Abstract

The invention discloses an application of a coumarin compound in a drug for treating hepatitis, specifically 6,7,8-trihydroxycoumarin and fraxin, which have good activity in treating hepatitis. By reducing the level of proinflammatory factors in the body, acute liver damage induced by CCL4 is significantly alleviated, and can be used to treat liver cirrhosis. The activity of this type of coumarin compound is better than that of fraxinus cortex extract and fraxinin, and it has good safety, less side effects, high bioavailability, simple source and easy preparation, which provides a direction for the search and development of drugs for treating hepatitis and protecting the liver.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to application of a coumarin compound in preparing a drug for treating hepatitis. Background Art

[0002] Hepatitis is a general term for liver inflammation, usually caused by a variety of pathogenic factors such as viruses, bacteria, parasites, chemical poisons, drugs, alcohol, autoimmune factors, etc., which damage liver cells, damage liver function, and even develop into liver failure, which seriously endangers human health. At present, there are many kinds of Chinese and Western medicines with liver protection and enzyme reduction activities, such as anti-inflammatory and liver protection glycyrrhizic acid preparations, biofilm stabilizer silybin capsules, detoxification and liver protection drugs glutathione, enzyme reduction drugs bifendate dripping pills, etc. Its main mechanism of action is to inhibit inflammatory reactions in liver tissue and reduce serum transaminase activity. However, the Western medicines currently used in clinical treatment of hepatitis are expensive, and some drugs have more adverse reactions, and there will be problems such as repeated recurrence of the disease after stopping the drug, and strong drug resistance.

[0003] At present, the medical community has been committed to finding a new Chinese medicine with obvious activity in treating hepatitis and protecting the liver, which is simple in source and easy to prepare. It has been reported in the literature that the extract of Fraxinus cortex can effectively reduce liver damage induced by carbon tetrachloride and has a good liver protection effect. For example, by using the biotransformation method, fraxinus cortex or / and fraxinin are used as the starting materials, and 6,7,8-trihydroxycoumarin is generated by intestinal flora metabolism.

[0004] It has been reported in the literature that quercetin has a good liver protection effect, but quercetin is a glycoside drug, the drug absorption is poor, and the process of metabolism in the body to exert pharmacological effects is slow, and the bioavailability is low. The use of metabolites to make drugs can significantly improve this shortcoming. After the drug is metabolized in the body, its structure will undergo a series of changes, such as activation, detoxification, etc., the structural groups will be modified, and the fat solubility will increase. Therefore, the use of metabolites to make drugs can significantly improve the bioavailability and pharmacological activity of the drug. Summary of the invention

[0005] The present invention aims to provide an application of a coumarin compound in the preparation of a drug for treating hepatitis, so as to solve the problems existing in the current medical field in treating hepatitis.

[0006] The technical solution of the present invention is:

[0007] A use of a coumarin compound in the preparation of a drug for treating hepatitis, wherein the general structural formula of the coumarin compound is shown in Formula I below:

[0008]

[0009] When R 1 , R2 or R 3 When any one of the R groups is a hydroxyl group, the other two R groups are independently selected from any one of a hydroxyl group and a C1-C6 alkoxy group.

[0010] Furthermore, the structural formula of the coumarin compound is:

[0011]

[0012] Furthermore, the structural formula of the coumarin compound is:

[0013]

[0014] Furthermore, the hepatitis is acute hepatitis, chronic hepatitis, liver damage, or cirrhosis.

[0015] Furthermore, the dosage form of the drug for treating hepatitis is tablets, granules, capsules, pills, oral liquid or injection.

[0016] The present invention provides an application of a coumarin compound in the preparation of a drug for treating hepatitis, the main advantages of which are: quercetin and 6,7,8-trihydroxycoumarin belong to coumarin compounds, and 6,7,8-trihydroxycoumarin can be produced by intestinal flora metabolism using quercetin or quercetin as raw materials. Both quercetin and 6,7,8-trihydroxycoumarin can effectively treat acute hepatitis, chronic hepatitis, liver damage, cirrhosis and other diseases, and have a good protective effect on the liver, solving the problems of many adverse reactions and strong drug resistance of current clinical drugs; the above compounds have the advantages of high bioavailability, rich sources, simple preparation, low price, etc., providing a direction for the search and development of drugs for treating hepatitis and protecting the liver. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is the experimental result of 6,7,8-trihydroxycoumarin on CCL4-induced liver injury in mice;

[0018] Figure 2 This is the experimental result of quercetin on mice with CCL4-induced liver injury;

[0019] Figure 3 This is the experimental result of 6,7,8-trihydroxycoumarin, quercetin and quercetin on mice with CCL4-induced liver damage. DETAILED DESCRIPTION

[0020] In order to make the above-mentioned objects, features and advantages of the present invention more clearly understood, the technical solutions of the present invention are further described below in conjunction with embodiments. However, the present invention is not limited to the embodiments listed, and should also include any other known changes within the scope of the rights claimed by the present invention.

[0021] First, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0022] Example 1

[0023] Carbon tetrachloride-induced acute liver injury model in mice:

[0024] Balb / c male mice (6-8 weeks, weighing about 20 g)

[0025] The skeleton of coumarin compounds is benzo-α-pyrone mother nucleus, in which R 1 =OH, R 2 =OH, R 3 =OH, the structure is shown in formula (1). According to the compound naming rules, the compound is 6,7,8-trihydroxycoumarin.

[0026]

[0027] Establishment of CCL4-induced liver injury model:

[0028] The present invention selects CCL4 as an inducer of liver injury, bifendate dripping pills as a positive control (dosage of 150 mg / kg), two coumarin compounds are administered at a dose of (20 mg / kg), the administration time is 7 days, 2 hours after the last administration, 0.25% CCL4 is administered to induce, an acute liver injury model is prepared, and the mice are killed 24 hours later. Before the mice are killed, they are weighed, blood is collected from the eye sockets, and after natural coagulation, the upper serum is centrifuged to measure ALT, AST, and TBIL; the mice are killed by spinal dislocation, the livers are taken and weighed, and the liver tissue homogenates are centrifuged to measure the indicators such as MDA, SOD, GSH-Px, IL-6, and IL-1β; the livers are taken for HE staining, and the results are as follows: Figure 1 , 2 , 3. Please refer to Figures 1 to 3 , Figure 1 This is the experimental result of 6,7,8-trihydroxycoumarin on CCL4-induced liver injury in mice; Figure 2 This is the experimental result of quercetin on mice with CCL4-induced liver injury; Figure 3 This is the experimental result of 6,7,8-trihydroxycoumarin, quercetin and quercetin on mice with CCL4-induced liver damage.

[0029] like Figure 1As shown in Figure 2, 6,7,8-trihydroxycoumarin has a significant effect in treating hepatitis. Liver index can reflect the pathological changes of the liver and the nutritional status of the body. MDA can reflect the degree of liver damage. IL-6 and IL-1β are important inflammatory factors in the body. Figure 1 It can be seen that the liver index, TBIL, MDA, IL-6 and IL-1β were significantly lower than those in the model group, and the liver index, TBIL and MDA were better than those in the positive control bifendate. This result can fully illustrate that 6,7,8-trihydroxycoumarin can significantly reduce CCL4-induced acute liver injury and treat cirrhosis, and the mechanism may be to reduce the level of pro-inflammatory factors in the body. This conclusion can also be drawn from the HE staining results. The HE staining results show that the model group has a large area of ​​hepatocyte death and severe inflammatory cell infiltration. Compared with the model group, the liver injury symptoms in the THC group were greatly improved, and the degree of recovery was close to the normal level.

[0030] Example 2

[0031] The skeleton of coumarin compounds is benzo-α-pyrone mother nucleus, in which R 1 =CH3O, R 2 =OH, R 3 =OH, the structure is shown in formula (2), and the compound is quercetin.

[0032]

[0033] The establishment and implementation scheme of the model are the same as those in Example 1.

[0034] like Figure 2 As shown in the results, fraxinusin has good activity in reducing enzymes and protecting the liver. Figure 2 It can be seen that the ALT and AST indexes of the quercetin administration group were significantly lower than those of the model group, and the MDA was also significantly lower than that of the model group. In addition, from the results of liver tissue HE staining, it can be seen that the degree of damage in the quercetin administration group was significantly improved compared with the model group, with less inflammatory cell infiltration and less liver cell death. Its mechanism may be to increase the activity of enzymes that scavenge free radicals, inhibit oxidative stress, and reduce a series of lipid peroxidation caused by oxygen free radicals in the body, thereby achieving the effect of protecting the liver. Compared with the model group, the MDA content in the liver tissue of the quercetin administration group was lower, and the SOD and GSH-Px contents were increased. This can clearly reflect that quercetin can significantly increase the activity of enzymes that scavenge free radicals in the body, reduce a series of lipid peroxidation reactions caused by oxygen free radicals in the body, thereby reducing the degree of liver damage caused by CCL4 and achieving the purpose of protecting the liver.

[0035] In addition, the comparison of quercetin, quercetin and 6,7,8-trihydroxycoumarin showed that Figure 3As shown in the figure, compared with the quercetin group, the MDA and TBIL of the 6,7,8-trihydroxycoumarin group were significantly reduced, while the SOD and GSH-PX were significantly increased, indicating that compared with quercetin, 6,7,8-trihydroxycoumarin can significantly alleviate CCL4-induced liver damage and reduce inflammation. Its mechanism may be to increase the activity of enzymes that scavenge free radicals, inhibit oxidative stress, and reduce a series of lipid peroxidation caused by oxygen free radicals in the body, thereby achieving the effect of treating hepatitis and protecting the liver. The liver index can reflect the nutritional status and pathological conditions of the body. Compared with quercetin, 6,7,8-trihydroxycoumarin was significantly reduced, indicating that compared with quercetin, 6,7,8-trihydroxycoumarin can reduce CCL4-induced hepatomegaly and cirrhosis. 6,7,8-trihydroxycoumarin is a metabolite of quercetin in the body, and compared with quercetin, 6,7,8-trihydroxycoumarin has a better effect on the treatment of hepatitis and a higher bioavailability, which can better play the activity of treating hepatitis.

[0036] Compared with the prior art, the beneficial effects of the present invention are as follows: the application of a coumarin compound described in the present invention in a drug for treating hepatitis, specifically 6,7,8-trihydroxycoumarin and quercetin, has good activity in treating hepatitis. By reducing the level of pro-inflammatory factors in the body, acute liver damage induced by CCL4 is significantly alleviated, and it can be used to treat liver cirrhosis. This type of coumarin compound has good safety, fewer side effects, high bioavailability, simple source and easy preparation, which provides a direction for the search and development of drugs for treating hepatitis and protecting the liver.

[0037] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. Use of a coumarin compound in the preparation of a drug for treating acute liver injury, characterized in that: The structural formula of the coumarin compound is: or .

2. The use of a coumarin compound according to claim 1 in the preparation of a drug for treating acute liver injury, characterized in that: The dosage form of the drug for treating acute liver injury is tablets, granules, capsules, pills, oral liquid or injection.

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