CN115504970B - Flavonoid derivative for treating myocardial ischemia and preparation method thereof - Google Patents

Abstract

The invention provides a flavonoid derivative for treating myocardial ischemia and a preparation method thereof. The compound is a derivative based on flavonoid compounds, has improved myocardial ischemia treatment effect, has obvious effects of preventing or relieving myocardial injury, improving ischemia and anoxia states, protecting myocardial cells, and can improve the oxygen free radical scavenging capacity of an organism and reduce the damage of lipid peroxides to the myocardium. Therefore, the compound has good myocardial ischemia treatment effect and is a potential feasible medicament.

Description

A flavonoid derivative for treating myocardial ischemia and its preparation method

technical field

The invention relates to the field of medicine, in particular, the invention relates to a flavonoid derivative for treating myocardial ischemia and a preparation method thereof.

Background technique

Myocardial ischemia is a pathological state in which myocardial metabolism is abnormal due to insufficient blood supply to the heart and decreased oxygen supply to the myocardium caused by various reasons, and the heart cannot work normally. Due to its high incidence, myocardial ischemia has become a common non-communicable disease in all countries in the world. It has the characteristics of difficult treatment and heavy treatment burden, and has become the number one killer threatening human health.

Myocardial ischemia can cause damage to the body through a variety of ways. Ischemia will cause insufficient oxygen supply to cardiomyocytes, which will affect the anti-apoptotic Bcl-2 and pro-apoptotic Bax in the Bcl-2 family of factors that control apoptosis, resulting in myocardial infarction. The apoptosis of cells causes tissue damage, which leads to myocardial dysfunction; due to the decline of myocardial function, the dynamic balance between oxygen free radicals and anti-oxidative self-defense system is out of balance, and oxidative stress occurs, which damages the functions of cells and organs. Activate the inflammatory factor NF-κB, increase the inflammatory factor tumor necrosis factor-α (TNF-α), interleukin-6, etc. to cause myocardial inflammation; when the ischemic myocardium is reperfused, the cells will quickly accumulate Ca ²⁺ , causing Ca ²⁺ overload damages the inner membrane of mitochondria, which not only causes cell damage, but also induces apoptosis and eventually causes myocardial infarction.

At present, the main methods for the treatment of myocardial ischemic diseases are surgical treatment and targeted use of western medicine to relieve symptoms, commonly used include nitrates, β-receptor blockers and myocardial metabolic drugs. However, Western medicine has the disadvantages of single therapeutic effect, large adverse reactions, and high price. However, natural medicines can treat myocardial ischemia diseases by affecting various physiological processes, and have the advantages of low price, various treatment methods, and small adverse reactions, so they have received widespread attention. In recent years, researchers have discovered that a variety of natural medicines have clear therapeutic effects on myocardial ischemia, mainly including: saponins, such as ginsenosides, notoginseng saponins, astragaloside IV, etc.; flavonoids, such as hypericum Glycosides, quercetin, etc., puerarin, baicalein; alkaloid compounds, such as ligustrazine, gluconate, total alkaloids of Corydalis, seabuckthorn seed alkaloids, etc.; phenolic acid compounds, such as salvianolic acid A Phenolic acid B, lychee phenolic acid extract, etc.; terpenoids, such as ginkgo diterpene lactones, styrax triterpenoids, cornel iridoids, etc. However, natural medicines have deficiencies in pharmacological activity, water solubility, bioavailability, etc., and structural improvements are often required to obtain better medicines.

Contents of the invention

The present invention provides a new drug for treating myocardial ischemia based on flavonoids, and the compound has good activity in treating myocardial ischemia.

The present invention provides a compound of formula (I) or its pharmaceutically acceptable salt, prodrug, stereoisomer:

Wherein, at least two of R ₁ -R ₉ are selected from hydroxyl, C1-C6 alkoxy, and the rest are selected from hydrogen;

L is selected from C1-C6 alkylene;

M is selected from -O-, -S-, -NR-, -OCO-, -NRCO-;

R is selected from hydrogen, C1-C4 alkyl;

R ₁₀ is independently selected from hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, amino, C1-6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

n is selected from 0, 1, 2 or 3;

R ₁₁ is selected from the following substituted or unsubstituted groups: C1-6 alkyl, C3-C12 cycloalkyl, 5-8 membered heterocycloalkyl, C6-C10 aryl.

In the present invention, the "substituted..." refers to one or more selected from deuterium, halogen, hydroxyl, cyano, nitro, ester, ketone, C1-C6 alkyl, C1-6 alkoxy , C1-C6 alkylamino group substitution.

In one embodiment, the compounds of formula (I) include the following compounds of formula (I-1) and formula (I-2):

In one embodiment, at least 2 of R ₁ -R ₄ are selected from hydroxyl or C1-C6 alkoxy, and the rest are selected from hydrogen.

Preferably, at least 2 of R ₁ -R ₄ are selected from hydroxyl groups, and the rest are selected from hydrogen.

More preferably, R ₁ and R ₃ are selected from hydroxyl, and R ₂ and R ₄ are selected from hydrogen.

In one embodiment, at least one of R ₅ -R ₉ is selected from hydroxyl or C1-C6 alkoxy, and the rest are selected from hydrogen.

Preferably, at least 2 of R ₆ -R ₈ are selected from hydroxyl or C1-C6 alkoxy, and the rest are selected from hydrogen; R ₅ and R ₉ are selected from hydrogen.

More preferably, R ₆ is selected from hydroxyl, R ₅ , R ₇ -R ₉ are selected from hydrogen; or, R ₆ , R ₇ are selected from hydroxyl, R ₅ , R ₈ -R ₉ are selected from hydrogen; or, R ₆ - R ₈ is selected from hydroxyl, and R ₅ and R ₉ are selected from hydrogen.

In one embodiment, L is selected from C2-C5 alkylene.

Preferably, L is selected from -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ ) ₂ CH ₂ -.

More preferably, L is selected from -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -.

In one embodiment, M is selected from -O-, -NH-, -OCO-, -NHCO-.

Preferably, M is selected from -O-, -OCO-.

More preferably, M is selected from -OCO-.

In one embodiment, R ₁₀ is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, trifluoromethyl, isopropyl, methoxy, ethoxy.

Preferably, R ₁₀ is selected from hydrogen.

In one embodiment, R _is selected from substituted or unsubstituted following groups: C1-4 alkyl, C3-C7 cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl; "Substituted..." means replaced by one or more selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, nitro, methyl, ethyl, isopropyl, n-propyl, trifluoromethyl , methoxy, ethoxy, dimethylamino, diethylamino, oxy groups are monosubstituted or multisubstituted.

Preferably, R ₁₁ is selected from the following groups substituted or unsubstituted by hydroxy: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl.

More preferably, R ₁₁ is selected from methyl, isopropyl, hydroxy-substituted isopropyl, cyclopropyl, cyclopentyl.

In a preferred embodiment, the compound of formula (I) is selected from:

Some specific chemical structures of the compounds of the formula (I) of the present invention have been enumerated above, but the present invention is not limited to these chemical structures listed. All are based on the compounds of the formula (I), and the substituents should be as defined above. included.

In the present invention, the term "pharmaceutically acceptable salt" refers to the salt prepared by reacting the compound of the present invention with an acid, and such acid addition salt includes the following salts: acetate, adipate, alginate, Partiate, Benzoate, Besylate, Bisulfate, Butyrate, Citrate, Camphorate, Cyclopentane Propionate, Lauryl Sulfate, Ethylate, Fumarate, Glucoheptonate, Hemisulfate, Caproate, Hydrochloride, Hydrobromide, Hydroiodide, Lactate, Maleate, Methanesulfonate, Nicotinate , oxalate, persulfate, picrate, pivalate, propionate, succinate, tartrate, tosylate and undecanoate, etc. A compound of the invention in free form may be converted into the corresponding compound in salt form; and vice versa. Compounds of the invention in free form or in salt and solvate forms can be converted into the corresponding compounds in free or salt form in unsolvated form; and vice versa.

In the present invention, the term "prodrug" or prodrug refers to certain derivatives which themselves may have little or no pharmacological activity, and when they are administered into the body or on the body, they are cleaved by, for example, hydrolysis and converted to compounds of the invention having the desired activity. Detailed information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol.14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Editor: E.B. Roche , American Pharmaceutical Association).

In the present invention, the term "stereoisomer" may mean enantiomers, diastereomers and the like. The compounds of the invention may, for example, contain asymmetric carbon atoms and thus exist in the form of enantiomers or diastereomers and mixtures thereof, for example in the form of racemates. The compounds of the present invention may exist in the (R)-, (S)- or (R,S)-configuration, preferably the (R)- or (S)-configuration at specific positions of the compound.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt, prodrug, stereoisomer, and a pharmaceutically acceptable carrier or excipient agent.

In the present invention, the term "pharmaceutically acceptable" refers to substances, such as carriers or excipients, which do not eliminate the biological activity or properties of the compounds described herein. Such a substance is administered to an individual without causing an undesired biological effect or interacting in a deleterious manner with any component of the composition in which it is contained. A wide variety of carriers and excipients can be used depending on the desired route of administration (eg, oral, parenteral). Thus, for liquid oral formulations, such as suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, etc.; for solid oral formulations , such as powders, capsules and tablets, suitable carriers and additives include starch, sugar, diluents, granulating agents, lubricants, binders, disintegrants and the like. Solid oral dosage forms may also be coated with substances such as sugars or enteric-coated to modify the major site of absorption. For parenteral administration, the carrier will usually consist of sterile water or other ingredients which may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers together with appropriate additives.

Preferably, these compositions are presented in unit dosage form such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosols or liquid sprays formulations for parenteral, intranasal, sublingual or rectal administration or for administration by inhalation or spray. Alternatively, the composition may be presented for weekly or monthly administration as appropriate; for example, an insoluble salt of the active compound, such as the caprate salt, may be adapted to provide a depot formulation for intramuscular injection.

The precise dosage and dosing regimen of the compounds of this invention and compositions thereof will depend on the biological activity of the compound itself, the age, weight and sex of the patient, the needs, degree of affliction or need of the individual receiving the drug administration, and the judgment of the practitioner. In general, parenteral administration requires lower dosages than other methods of administration that are more dependent on absorption. However, for humans the dosage is preferably 0.001-10 mg/kg body weight. In general, the dosage for enteral and parenteral administration will range from 0.1 to 1000 mg of total active ingredient per day.

The compounds of the present invention may be used alone or in combination with other therapeutic agents. Combination therapy may provide a synergistic effect, ie, the effect achieved when the active ingredients are used together is greater than the sum of the effects of the compounds when used separately. Therefore, the pharmaceutical composition of the present invention may also contain other drugs that are helpful for the treatment of myocardial ischemia.

In yet another aspect, the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt, prodrug, or stereoisomer thereof in the preparation of a medicament.

In one embodiment, the medicament is for the treatment of myocardial ischemic disease.

In one embodiment, the medicament is used for cardioprotection, treatment of myocardial ischemia, treatment of myocardial infarction.

Treatment according to the invention includes prophylactic purposes. As used herein, the term treatment and other similar synonyms include alleviating, alleviating or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing the underlying metabolic cause of the symptoms, inhibiting the disease or condition, e.g. arresting the development of the disease or condition, relieving disease or condition, ameliorating the disease or condition, alleviating the symptoms caused by the disease or condition, or halting the symptoms of the disease or condition, furthermore, the term encompasses the purpose of prophylaxis. The term also includes obtaining a therapeutic and/or prophylactic effect. The therapeutic effect refers to curing or improving the underlying disease being treated. Also, a cure or amelioration of one or more physical symptoms associated with the underlying disease is a therapeutic effect, eg, an improvement in a patient's condition is observed although the patient may still be affected by the underlying disease. For a prophylactic effect, the composition may be administered to a patient at risk for a particular disease, or to a patient presenting with one or more physiological symptoms of the disease even if the disease has not yet been diagnosed.

In yet another aspect, the present invention provides a method for preparing a compound of formula (I), comprising the following steps:

Wherein, at least two of R ₁ -R ₉ are selected from C1-C6 alkoxy, and the rest are selected from hydrogen;

L is selected from C1-C6 alkylene;

M is selected from -O-, -S-, -NR-, -OCO-, -NRCO-;

R is selected from hydrogen, C1-C4 alkyl;

R ₁₀ is independently selected from hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, amino, C1-6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy;

n is selected from 0, 1, 2 or 3;

R ₁₁ is selected from the following substituted or unsubstituted groups: C1-6 alkyl, C3-C12 cycloalkyl, 5-8 membered heterocycloalkyl, C6-C10 aryl;

Xa, Xb are independently selected from leaving groups, preferably chlorine or bromine.

In one embodiment, the method further comprises:

Convert C1-C6 alkoxy groups in R ₁ -R ₉ to hydroxyl groups.

Beneficial effect

The invention relates to a flavonoid derivative for treating myocardial ischemia and a preparation method thereof. The compound of the present invention is based on flavonoid compounds, especially flavonoid lead compounds such as quercetin and hyperoside, and undergoes structural modification to obtain a drug for treating myocardial ischemia disease with better effect. The compound of the present invention can reduce the deviation of the S-T segment of rats with myocardial ischemia and shorten the Q-T interval, can reduce the activity of serum CK and LDH, reduce the area of myocardial ischemia, can reduce the content of MDA in serum and improve the activity of SOD, and has the advantages of Significantly prevent or reduce myocardial injury, improve ischemia and hypoxia, and protect myocardial cells, improve the body's ability to scavenge oxygen free radicals, and reduce lipid peroxide damage to the myocardium. Therefore, the compound of the present invention has a good therapeutic effect on myocardial ischemia and is a potential feasible drug.

Detailed ways

Preferred examples of the invention will be described in detail below. The examples given are to better understand the content of the invention, and the content of the invention is not limited to the examples. Non-essential improvements and adjustments to the embodiment according to the content of the invention still belong to the scope of the invention.

The experimental methods in the following examples are conventional methods unless otherwise specified. If no specific technique or condition is indicated in the examples, it shall be carried out according to the technique or condition described in the literature in this field, or according to the product specification.

Embodiment 1: the preparation of compound 1

3.58g (10mmol) of compound a-1 was added to a reactor equipped with a magnetic stirring device, then 80ml of N,N-dimethylformamide was added to dissolve it, 3.26g (10mmol) of cesium carbonate and 3.0 g (20 mmol) of sodium iodide was heated to 85° C. and stirred for 1 h. Then 2.07 g (11 mmol) of compound b-1 in 1,2-dibromoethane was added dropwise, and the temperature was continued to reflux, and the reaction was stirred overnight. After the reaction, add 200ml of ice-water mixture to precipitate a precipitate, collect the precipitate, dry it, dissolve it with ethyl acetate, and wash it twice with 0.1N hydrochloric acid and water respectively, then dry it with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure , the residue was recrystallized from ethanol to obtain intermediate c-1, 4.14g, with a yield of 89%.

The above-mentioned 2.32g (5mmol) of intermediate c-1 and 0.96g (5mmol) of compound d-1 were added to a reactor equipped with a magnetic stirring device, and then 30ml of N,N-dimethylformamide was added to After it was dissolved, 2ml of triethylamine and 1.12g (7.5mmol) of sodium iodide were added, heated to 95°C and stirred for 3h. Cool to room temperature after the reaction is over, then add 60ml of distilled water, then extract with dichloromethane (80ml×3), combine the organic phases, wash with saturated sodium chloride solution and distilled water twice, dry over anhydrous magnesium sulfate, and reduce pressure The solvent was distilled off, and the residue was recrystallized from a mixed solvent of ethanol/cyclohexane=1:1 to obtain intermediate e-1, 2.42g, with a yield of 84%.

Take 5ml of hydrogen bromide solution (40%), join in the reactor that is equipped with magnetic stirring device, add 1.44g (2.5mmol) intermediate e wherein in batches, reflux and stir overnight after adding. After the reaction, cool to room temperature, add 30ml of distilled water to it, then extract with ethyl acetate (30ml×3), combine the organic phases, wash with water, dry over anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, and the residue is chromatographed on silica gel. Column separation, the elution phase was petroleum ether/ethyl acetate=5:1, and compound 1 was obtained as a white solid, 1.18g, HPLC purity≧99.0%, yield 91%.

HRESI-MS: 542.1439[M+Na] ⁺ (theoretical value 542.1427)

Elemental Analysis: C ₂₈ H ₂₅ NO ₉ ; Theoretical C,64.74; H,4.85; N,2.70; O,27.72; Found C,64.76; H,4.83; N,2.75; O,27.71

¹ H NMR (400MHz,DMSO-d ₆ )δ12.55(s,1H),10.98(s,1H),7.71–7.61(m,3H),7.55(s,1H),7.38(s,1H), 7.17(d,J=8.8Hz,1H),6.80(d,J=8.4Hz,1H),6.29(s,1H),6.21(s,1H),4.88(s,1H),4.50(m,4H ),3.39(dd,J＝6.5,3.7Hz,1H),3.33(dd,J＝6.5,3.7Hz,1H),2.96(s,3H),2.85–2.69(m,2H),1.92(m, 2H).

Embodiment 2: the preparation of compound 2

The same preparation method as in Example 1 was carried out, and compound d-1 was replaced by equimolar d-2 to obtain compound 2 (1.07 g), with HPLC purity≧99.1%.

HRESI-MS: 570.1728[M+Na] ⁺ (theoretical value 570.1740)

Elemental analysis: C ₃₀ H ₂₉ NO ₉ ; Theoretical C, 65.81; H, 5.34; N, 2.56; O, 26.30; Found C, 65.78;

Embodiment 3: the preparation of compound 3

The same preparation method as in Example 1 was carried out, compound b-1 was replaced by equimolar b-3, and compound d-1 was replaced by equimolar d-3 to obtain compound 3 (1.29g), HPLC purity≧99.2 %.

HRESI-MS: 600.1830[M+Na] ⁺ (theoretical value 600.1846)

Elemental analysis: C ₃₁ H ₃₁ NO ₁₀ ; Theoretical C, 64.47; H, 5.41; N, 2.43; O, 27.70; Found C, 64.43; H, 5.39; N, 2.47;

Embodiment 4: the preparation of compound 4

The same preparation method as in Example 1 was carried out, compound b-1 was replaced by equimolar b-3, and compound d-1 was replaced by equimolar d-4 to obtain compound 4 (1.47g), HPLC purity≧98.8 %.

HRESI-MS: 610.2073[M+Na] ⁺ (theoretical value 610.2053)

Elemental analysis: C ₃₃ H ₃₃ NO ₉ ; Theoretical C, 67.45; H, 5.66; N, 2.38; O, 24.50; Found C, 67.47;

Embodiment 5: the preparation of compound 5

The same preparation method as in Example 1 was implemented, compound a-1 was replaced by equimolar a-5, and compound b-1 was replaced by equimolar b-3 to obtain compound 5 (0.93g), HPLC purity≧99.0 %.

HRESI-MS: 524.1668[M+Na] ⁺ (theoretical value 524.1685)

Elemental analysis: C ₂₉ H ₂₇ NO ₇ ; Theoretical C, 69.45; H, 5.43; N, 2.79; O, 22.33; Found C, 69.41; H, 5.44; N, 2.82;

Embodiment 6: the preparation of compound 6

The same preparation method as in Example 1 was implemented, compound a-1 was replaced by equimolar a-6, and compound d-1 was replaced by equimolar d-2 to obtain compound 6 (0.97g), HPLC purity≧99.3 %.

HRESI-MS: 538.1856[M+Na] ⁺ (theoretical value 538.1842)

Elemental analysis: C ₃₀ H ₂₉ NO ₉ ; Theoretical C, 69.89; H, 5.67; N, 2.72; O, 21.72; Found C, 69.94;

Drug effect example: Anti-myocardial ischemia effect of compound in vivo (ISO induces myocardial ischemia in rats)

Animals: 100 clean-grade male SD rats, weighing about 200 g, were purchased from Shanghai Xipuer-Bikay Experimental Animal Co., Ltd.

Main reagents: creatine kinase (CK) test box, lactate dehydrogenase (LDH) test box, malondialdehyde (MDA) test box, superoxide dismutase (SOD) test box were purchased from Nanjing Jiancheng Bioengineering Institute . Isoproterenol (ISO) was purchased from Shanghai Hefeng Pharmaceutical Co., Ltd.

Drugs: Compounds 1-6 and positive control quercetin were formulated with 5% DMSO, 2% Tween80 and 93% normal saline to prepare a 20 mg/ml suspension liquid, and ultrasonically mixed before use; each rat was given 100 μl /100g administration volume, the administration dose is 20mg/kg·d.

表示，多组间比较采用方差分析，两组间比较采用t检验。结果如表1-3所示：The above-mentioned male SD rats were adaptively fed and modeled after one week. Anesthetized with 25% urethane intraperitoneally (1g/kg), fixed in the dorsal position, first recorded the normal electrocardiogram of the rats before the administration, discarded the rats with abnormal changes in the ST segment, T wave and arrhythmia, and screened out 90 rats. Rats were randomly and evenly divided into groups according to their body weight, among which the blank group, model group, positive control group, compound 1 group, compound 2 group, compound 3 group, compound 4 group, compound 5 group and compound 6 group were allocated 10 Only. Animals in each treatment group were administered intragastrically, once a day, for 7 consecutive days, half an hour after intragastric administration on the fifth day, multi-point injection of ISO (5 mg/kg) subcutaneously, and the injection sites included: extremities A total of 5 to 6 points on the root and back, the injection is completed within 10 seconds, and the injection is continued for 3 days. The blank group and the model group were intragastrically administered the same volume of solvent, the blank group was subcutaneously injected with the same volume of normal saline from the 5th day, and the model group was similarly subcutaneously injected with ISO (5 mg/kg) at multiple points from the 5th day. After the last injection of ISO, BL-420S biological function experiment system (Chengdu Taimeng Technology Co., Ltd.) was used to record the 10-minute lead II electrocardiogram of rats. Compared with the electrocardiogram before ischemia, the shift of the ST segment was observed using the line connecting the starting point of the QRS complex wave as the isoelectric line, and the ST segment shift value (△ST) and the change value of the QT interval ( △QT), with its mean as the observation index. At least one of the following conditions is the criterion for successful modeling: 1) The downward or upward shift of the J point ≥ 0.1mV; 2) The T wave is towering, exceeding 1/2 of the R wave in the same lead; 3) The T wave is towering with J point shift. Six hours after the last injection of ISO, blood was collected from the eyeballs of the rats in each group, centrifuged at 4°C for 15 minutes at low temperature (3500r/min), and the serum was collected, and the contents of CK, LDH, SOD and MDA were determined according to the instructions of the test box. After the blood was collected, the heart of the rat was dissected, the hemorrhage in the cardiac cavity was washed with normal saline, the atrial tissue and fat were removed, weighed, and the left ventricular myocardium was cut into 4 to 5 slices, and then immersed in N-BT phosphate buffer solution. Put it in a constant temperature water bath at 37°C, take it out after the staining is complete, stain the normal tissue, and not stain the ischemic tissue. The ischemic myocardium was excised and weighed, and the myocardial ischemic area (MIS) was calculated by the percentage of the ischemic myocardium and the wet weight of the left ventricle. The experimental data were processed with SPSS 10.0 statistical software, and the mean ± standard deviation

The analysis of variance was used for comparison between multiple groups, and the t test was used for comparison between two groups. The results are shown in Table 1-3:

Table 1: Effects of Compounds on △ST and △QT of Myocardial Ischemia Rats

Note: ^** P<0.01vs blank group; ^# P<0.05, ^## P<0.01vs model group; ^& P<0.05, ^&& P<0.01vs positive control group

The results in Table 1 show that the rat model group △ST>0.1mv, and the difference was statistically significant compared with the blank group (P<0.01), indicating that the experimental modeling was successful. Both the positive control group and the compound administration group of the present invention can reduce the deviation of the S-T segment and shorten the Q-T interval, suggesting that it has the effect of preventing or alleviating myocardial injury, improving ischemia and hypoxia, and protecting myocardial cells; and the compound of the present invention Better than the positive control.

Table 2: Effects of compounds on CK, LDH, MIS in rats with myocardial ischemia

Note: ^** P<0.01vs blank group; ^# P<0.05, ^## P<0.01vs model group; ^& P<0.05, ^&& P<0.01vs positive control group

When cardiomyocytes are damaged by ischemia, the permeability of the cell membrane increases, and the leakage of intracellular CK and LDH leads to the increase of LDH and CK in the blood. Therefore, the activities of LDH and CK in serum can indirectly reflect the changes in the degree of myocardial injury. The results in Table 2 showed that the activity of LDH and CK in the model group was significantly higher than that in the blank group (P<0.01), and the myocardial ischemia was also significantly higher than that in the blank group (P<0.01). Both the positive control group and the compound administration group of the present invention can significantly reduce the activity of rat serum CK and LDH, and greatly reduce the area of myocardial ischemia, suggesting that it has the effect of protecting myocardial cells and improving myocardial ischemia injury; and the compound of the present invention Better than the positive control.

Table 3: Effects of Compounds on MDA and SOD in Myocardial Ischemia Rats

Note: ^** P<0.01vs blank group; ^# P<0.05, ^## P<0.01vs model group; ^& P<0.05, ^&& P<0.01vs positive control group

A large number of oxygen free radicals are produced during myocardial ischemia, and the aggregation of oxygen free radicals can cause cell membrane damage or cell death. SOD is an enzyme protein containing metal ions in aerobic organisms. It is an important enzyme for the body to scavenge oxygen free radicals. Its activity indirectly reflects the body's ability to scavenge free radicals. When the myocardium is damaged, the activity of SOD decreases, and fatty acids containing double bonds are peroxidized to generate MDA, which can cause cross-linking and polymerization between membrane components. Therefore, the content of MDA can indirectly reflect the severity of cardiomyocytes attacked by oxygen free radicals. The results in Table 3 showed that the MDA content of rats in the model group was significantly higher than that of the blank group (P<0.01), and the SOD content was significantly lower than that of the blank group (P<0.01). Both the positive control group and the compound administration group of the present invention can significantly reduce the content of MDA in the serum and increase the activity of SOD, indicating that it can improve the ability of the body to scavenge oxygen free radicals, inhibit the lipid peroxidation process, and reduce the lipid peroxidation. damage to myocardium; and the effect of the compound of the present invention is better than that of the positive control.

The preferred embodiments of the present invention have been described above, but they are not intended to limit the present invention. Modifications and changes to the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.

Claims (7)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (I-1) and compounds of formula (I-2) below:

wherein R is ₁ 、R ₃ Selected from hydroxy, R ₂ 、R ₄ -R ₉ Selected from hydrogen; or R ₆ 、R ₇ Selected from hydroxy, R ₁ -R ₅ 、R ₈ 、R ₉ Selected from hydrogen; or R ₁ 、R ₃ 、R ₆ 、R ₇ Selected from hydroxy, R ₂ 、R ₄ 、R ₅ 、R ₈ 、R ₉ Selected from hydrogen;

l is selected from C1-C6 alkylene;

m is selected from-OCO-;

R ₁₀ independently selected from hydrogen;

n is selected from 0, 1,2 or 3;

R ₁₁ selected from the following substituted or unsubstituted groups: c1-4 alkyl, C3-C7 cycloalkyl; the "substituted …" refers to mono-substitution by a group selected from hydroxyl.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is selected from C2-C5 alkylene.

3. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R is ₁₁ Selected from methyl, isopropyl, hydroxyl substituted isopropyl, cyclopropyl, cyclopentyl.

4. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound of formula (I) is selected from:

5. a pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

6. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-4, in the manufacture of a medicament for use in the treatment of a myocardial ischaemic disorder.

7. The use according to claim 6, wherein the medicament is for cardioprotection, treatment of myocardial ischemia, treatment of myocardial infarction.