CN115504970B - Flavonoid derivative for treating myocardial ischemia and preparation method thereof - Google Patents
Flavonoid derivative for treating myocardial ischemia and preparation method thereof Download PDFInfo
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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- A—HUMAN NECESSITIES
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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
Technical Field
The invention relates to the field of medicines, in particular to a flavonoid derivative for treating myocardial ischemia and a preparation method thereof.
Background
Myocardial ischemia (myocardial ischemia) refers to a pathological condition in which the heart fails to work normally due to abnormal myocardial metabolism caused by insufficient blood supply to the heart and decreased oxygen supply to the heart muscle due to various reasons. Myocardial ischemia has become a non-infectious disease ubiquitous in all countries in the world due to high incidence, has the characteristics of difficult treatment, heavy treatment burden and the like, and becomes a first killer threatening the health of human beings.
Myocardial ischemia can cause damage to an organism through various ways, the ischemia causes insufficient oxygen supply to myocardial cells, and anti-apoptotic Bcl-2 and apoptosis-promoting Bax in a factor Bcl-2 family which can influence the apoptosis of cells cause the apoptosis of the myocardial cells to cause tissue damage, thereby causing myocardial dysfunction; because the myocardial function is reduced, the dynamic balance between oxygen free radicals and an antioxidant self-defense system is disordered, oxidative stress reaction occurs, the functions of cells and organs are damaged, and meanwhile, an inflammatory factor NF-kB is also activated, so that inflammatory factors tumor necrosis factor-alpha (TNF-alpha), interleukin-6 and the like are increased to cause myocardial inflammatory reaction; when ischemia cardiac muscle is reperfused, cells can rapidly accumulate Ca 2+ Cause Ca 2+ Overload damages mitochondrial inner membrane, which not only causes cell damage, but also induces apoptosis, and finally causes myocardial infarction.
At present, the main means for treating myocardial ischemia diseases are surgical treatment and targeted use of western medicines for relieving symptoms, and the main means commonly comprise nitrates, beta-receptor blockers, myocardial metabolism medicines and the like. However, the western medicines have the defects of single treatment effect, large adverse reaction, high price and the like. The natural medicine can treat myocardial ischemia diseases by influencing various physiological processes, and has the advantages of low price, various treatment ways and small adverse reaction, thereby being widely concerned. In recent years, researchers have found that various natural drugs have a definite therapeutic effect on myocardial ischemia, and the therapeutic effect mainly includes: saponins such as ginsenoside, notoginsenoside, and astragaloside IV; flavonoids such as hyperoside, quercetin, puerarin, and baicalein; alkaloid compounds such as ligustrazine, lappaconitine, rhizoma corydalis total alkaloids, and semen Hippophae alkaloids; phenolic acid compounds such as salvianolic acid A, salvianolic acid B, and salvianolic acid extract; terpenoids such as ginkgolides, storax triterpenoids, dogwood iridoid, etc. However, natural drugs have disadvantages in pharmacological activity, water solubility, bioavailability, etc., and structural improvement is often required to obtain better drugs.
Disclosure of Invention
The invention provides a novel medicament for treating myocardial ischemia based on flavonoid compounds, and the flavonoid compounds have good activity in treating myocardial ischemia.
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, stereoisomer thereof:
wherein R is 1 -R 9 At least two of which are selected from hydroxy, C1-C6 alkoxy, the remainder being 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 independently selected from hydrogenDeuterium, halogen, cyano, nitro, hydroxy, amino, C1-6 alkyl, haloC 1-C6 alkyl, C1-C6 alkoxy;
n is selected from 0, 1,2 or 3;
R 11 selected from the group consisting of substituted or unsubstituted: c1-6 alkyl, C3-C12 cycloalkyl, 5-8 membered heterocycloalkyl, C6-C10 aryl.
In the present invention, the term "substituted …" means substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, nitro, ester, keto, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino.
In one embodiment, the compounds of formula (I) include compounds of the following formulas (I-1) and (I-2):
in one embodiment, R 1 -R 4 At least 2 of which are selected from hydroxy or C1-C6 alkoxy, the remainder being selected from hydrogen.
Preferably, R 1 -R 4 At least 2 of which are selected from hydroxyl groups, the remainder being selected from hydrogen.
More preferably, R 1 And R 3 Selected from hydroxy, R 2 And R 4 Selected from hydrogen.
In one embodiment, R 5 -R 9 At least 1 of which is selected from hydroxy or C1-C6 alkoxy, the remainder being selected from hydrogen.
Preferably, R 6 -R 8 At least 2 of which are selected from hydroxy or C1-C6 alkoxy, the remainder being selected from hydrogen; r is 5 And R 9 Selected from hydrogen.
More preferably, R 6 Selected from hydroxy, R 5 、R 7 -R 9 Selected from hydrogen; or, R 6 、R 7 Selected from hydroxy, R 5 、R 8 -R 9 Selected from hydrogen; or, R 6 -R 8 Selected from hydroxy, R 5 、R 9 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 of the process of the present invention, 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 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, trifluoromethyl, isopropyl, methoxy and ethoxy.
Preferably, R 10 Selected from hydrogen.
In one embodiment, R 11 Selected from the following substituted or unsubstituted groups: c1-4 alkyl, C3-C7 cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl; the term "substituted …" refers to mono-or polysubstituted with one or more groups selected from deuterium, fluoro, chloro, bromo, iodo, hydroxy, cyano, nitro, methyl, ethyl, isopropyl, n-propyl, trifluoromethyl, methoxy, ethoxy, dimethylamino, diethylamino, oxy.
Preferably, R 11 Selected from the group consisting of hydroxy-substituted or unsubstituted: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl.
More preferably, R 11 Selected from methyl, isopropyl, hydroxyl substituted isopropyl, cyclopropyl, cyclopentyl.
In a preferred embodiment, the compound of formula (I) is selected from:
while specific chemical structures of the compounds of formula (I) of the present invention have been illustrated above, the present invention is not limited to these specific structures, and all compounds of formula (I) are intended to be encompassed by the present invention, provided that the substituents are as defined above.
In the present invention, the term "pharmaceutically acceptable salt" refers to a salt prepared by reacting a compound of the present invention with an acid, and such acid addition salts include the following salts: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, hemisulfate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, nicotinate, oxalate, persulfate, picrate, pivalate, propionate, succinate, tartrate, tosylate, undecanoate, and the like. The compounds of the invention in free form may be converted to the corresponding compounds in salt form; and vice versa. The compounds of the invention in free form or in salt form and in solvate form may be converted into the corresponding compounds in non-solvate form, in free form or in salt form; and vice versa.
In the present invention, the term "prodrug", i.e. prodrug, refers to certain derivatives which may have little or no pharmacological activity by themselves and which, when administered in or on the body, are converted to the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. For details on the use of prodrugs see 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 (eds.: E.B.Roche, american Pharmaceutical Association).
In the present invention, the term "stereoisomer" may be an enantiomer, a diastereomer, or the like. The compounds of the invention may, for example, contain asymmetric carbon atoms and may therefore exist as enantiomers or diastereomers and mixtures thereof, for example as racemates. The compounds of the invention may exist in the (R) -, (S) -or (R, S) -configuration, preferably in the (R) -or (S) -configuration at a particular position 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 thereof, and a pharmaceutically acceptable carrier or excipient.
In the present invention, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or excipient, that does not abrogate the biological activity or properties of the compounds described herein. Such a substance is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. A wide variety of carriers and excipients can be used depending on the route of administration desired (e.g., oral, parenteral). Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral dosage forms may also be coated or enterically coated with a substance, such as sugar, to modify the primary site of absorption. For parenteral administration, the carrier will usually consist of sterile water or other ingredients to which solubility or storage enhancing properties may be added. Injectable suspensions or solutions may also be prepared using aqueous carriers along with appropriate additives.
Preferably, these compositions are presented in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; a dosage form for parenteral, intranasal, sublingual or rectal administration to the oral cavity or for administration by inhalation or spray. Alternatively, the composition may be presented in a suitable, once weekly or once monthly administration; for example, an insoluble salt of the active compound, such as a caprate, may be suitable to provide a depot formulation for intramuscular injection.
The precise dosage and dosing regimen of the compounds of the invention and compositions thereof will depend upon the biological activity of the compound itself, the age, weight and sex of the patient, the needs, suffering or extent of need of the individual receiving the drug administration, and the judgment of the practitioner. Generally, parenteral administration requires lower doses than other methods of administration that are more dependent on absorption. However, the dosage is preferably 0.001-10mg/kg body weight for humans. Generally, the dosage for enteral and parenteral administration will be in the range of 0.1 to 1000mg 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, i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by the separate use of the compounds. Therefore, other drugs useful for the treatment of myocardial ischemia may also be included in the pharmaceutical composition of the present invention.
In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, stereoisomer thereof, in the manufacture of a medicament.
In one embodiment, the medicament is for treating a myocardial ischemic disease.
In one embodiment, the medicament is for cardioprotection, treating myocardial ischemia, treating myocardial infarction.
The treatment according to the invention comprises a prophylactic purpose. As used herein, the term treating and other similar synonyms include alleviating, alleviating or ameliorating a symptom of a disease or disorder, preventing other symptoms, ameliorating or preventing the underlying metabolic cause of the symptom, inhibiting the disease or disorder, e.g., arresting the development of the disease or disorder, alleviating the disease or disorder, ameliorating the disease or disorder, alleviating a symptom caused by the disease or disorder, or discontinuing a symptom of the disease or disorder, and further, the term is intended to include prophylaxis. The term also includes obtaining a therapeutic effect and/or a prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. In addition, a cure or amelioration of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, e.g., an improvement in the condition of the patient is observed, although the patient may still be affected by the underlying disease. For prophylactic effect, the composition can be administered to a patient at risk of developing a particular disease, or to a patient presenting with one or more physiological symptoms of the disease, even if a diagnosis of the disease has not yet been made.
In yet another aspect, the present invention provides a process for the preparation of a compound of formula (I) comprising the steps of:
wherein R is 1 -R 9 At least two of which are selected from C1-C6 alkoxy groups, the remainder being 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 independently selected from hydrogen, deuterium, halogen, cyano, nitro, hydroxy, amino, C1-6 alkyl, haloC 1-C6 alkyl, C1-C6 alkoxy;
n is selected from 0, 1,2 or 3;
R 11 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 chloro or bromo.
In one embodiment, the method further comprises:
r is to be 1 -R 9 The C1-C6 alkoxy group in (A) is converted into a hydroxyl group.
Advantageous effects
The invention relates to a flavonoid derivative for treating myocardial ischemia and a preparation method thereof. The compound is based on flavonoid compounds, particularly flavonoid lead compounds such as quercetin, hyperin and the like, and is structurally modified, so that the medicament for treating the myocardial ischemia disease with better effect is obtained. The compound can reduce the deviation of S-T section of a rat with myocardial ischemia, shorten Q-T interval, reduce CK and LDH activity of serum of the rat, reduce myocardial ischemia area, reduce MDA content in the serum and improve SOD activity, has obvious effects of preventing or relieving myocardial injury, improving ischemia and anoxia states, protecting myocardial cells, improving oxygen radical scavenging capacity of an organism and reducing damage of lipid peroxide to the myocardium. Therefore, the compound has good myocardial ischemia treatment effect and is a potential feasible medicament.
Detailed Description
Hereinafter, preferred examples of the invention will be described in detail. The examples are given for the purpose of better understanding of the inventive content and are not intended to be limiting only. Insubstantial modifications and adaptations of the embodiments in accordance with the present disclosure remain within the scope of the invention.
The experimental procedures in the following examples are conventional unless otherwise specified. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications.
Example 1: preparation of Compound 1
3.58g (10 mmol) of Compound a-1 are introduced into a reactor equipped with a magnetic stirring apparatus, then 80ml of N, N-dimethylformamide are added to dissolve it, 3.26g (10 mmol) of cesium carbonate and 3.0g (20 mmol) of sodium iodide are added, and heating to 85 ℃ is carried out for 1h with stirring. Then 2.07g (11 mmol) of 1,2-dibromoethane of compound b-1 were added dropwise and the temperature was raised to reflux and the reaction was stirred overnight. After completion of the reaction, 200ml of an ice-water mixture was added to precipitate a precipitate, which was collected, dried, dissolved in ethyl acetate, washed with 0.1N hydrochloric acid and water 2 times, respectively, then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain intermediate c-1,4.14g, yield 89%.
2.32g (5 mmol) of the above intermediate c-1 and 0.96g (5 mmol) of the compound d-1 were charged into a reactor equipped with a magnetic stirring apparatus, and then dissolved by adding 30ml of N, N-dimethylformamide, 2ml of triethylamine and 1.12g (7.5 mmol) of sodium iodide were added, and the reaction was stirred at 95 ℃ for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, then 60ml of distilled water was added, followed by extraction with dichloromethane (80 ml × 3), the organic phases were combined, washed with a saturated sodium chloride solution and distilled water 2 times, respectively, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was extracted with ethanol/cyclohexane =1:1 to yield intermediate e-1,2.42g in 84% yield.
5ml of hydrogen bromide solution (40%) were introduced into a reactor equipped with a magnetic stirrer, and 1.44g (2.5 mmol) of intermediate e were added in portions and stirred under reflux overnight after the addition. After completion of the reaction, the reaction mixture was cooled to room temperature, 30ml of distilled water was added thereto, followed by extraction with ethyl acetate (30 ml × 3), the organic phases were combined and washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was separated by a silica gel column chromatography with the elution phases of petroleum ether/ethyl acetate =5:1, 1,1.18g of compound 1 as a white solid, an HPLC purity of 99.0% or more, and a yield of 91%.
HRESI-MS：542.1439[M+Na] + (theoretical value 542.1427)
Elemental analysis: c 28 H 25 NO 9 (ii) a Theoretical value 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)。
Example 2: preparation of Compound 2
The same preparation as in example 1 was carried out, except that the compound d-1 was replaced with d-2 in an equimolar amount, to give compound 2 (1.07 g) having an HPLC purity of ≧ 99.1%.
HRESI-MS：570.1728[M+Na] + (theoretical value 570.1740)
Elemental analysis: c 30 H 29 NO 9 (ii) a Theoretical value C,65.81; h,5.34; n,2.56; o,26.30; found C,65.78; h,5.32; n,2.59; o,26.31.
Example 3: preparation of Compound 3
The same preparation as in example 1 was carried out, except that the compound b-1 was replaced with an equal mole of b-3 and the compound d-1 was replaced with an equal mole of d-3, to give compound 3 (1.29 g), which had an HPLC purity of 99.2% or more.
HRESI-MS：600.1830[M+Na] + (theoretical value 600.1846)
Elemental analysis: c 31 H 31 NO 10 (ii) a Theoretical value C,64.47; h,5.41; n,2.43; o,27.70; found C,64.43; h,5.39; n,2.47; o,27.73.
Example 4: preparation of Compound 4
The same preparation as in example 1 was carried out, except that the compound b-1 was replaced with an equal mole of b-3 and the compound d-1 was replaced with an equal mole of d-4, to give compound 4 (1.47 g) with an HPLC purity of 98.8% or more.
HRESI-MS：610.2073[M+Na] + (theoretical value 610.2053)
Elemental analysis: c 33 H 33 NO 9 (ii) a Theoretical value C,67.45; h,5.66; n,2.38; o,24.50; found C,67.47; h,5.62; n,2.40; and O,24.48.
Example 5: preparation of Compound 5
The same preparation as in example 1 was carried out, except that the compound a-1 was replaced with an equal mole of a-5 and the compound b-1 was replaced with an equal mole of b-3, to give compound 5 (0.93 g) with an HPLC purity of 99.0% or more.
HRESI-MS：524.1668[M+Na] + (theoretical value 524.1685)
Elemental analysis: c 29 H 27 NO 7 (ii) a Theoretical value C,69.45; h,5.43; n,2.79; o,22.33; found C,69.41; h,5.44; n,2.82; o,22.29.
Example 6: preparation of Compound 6
The same preparation as in example 1 was carried out, except that the compound a-1 was replaced with an equal mole of a-6 and the compound d-1 was replaced with an equal mole of d-2, to give compound 6 (0.97 g), which had an HPLC purity of 99.3% or more.
HRESI-MS：538.1856[M+Na] + (theoretical value 538.1842)
Elemental analysis: c 30 H 29 NO 9 (ii) a Theoretical value C,69.89; h,5.67; n,2.72; o,21.72; found C,69.94; h,5.66; n,2.75; o,21.73.
The drug effect example: compound in vivo anti-myocardial ischemia effect (ISO induced rat myocardial ischemia)
Animals: 100 male clean grade SD rats weighing about 200g were purchased from Shanghai Sphere-BiKai laboratory animals Co.
The main reagents are as follows: creatine Kinase (CK) test kit, lactate Dehydrogenase (LDH) test kit, malondialdehyde (MDA) test kit and superoxide dismutase (SOD) test kit are all purchased from Nanjing to build the bioengineering institute. Isoproterenol (ISO) is available from shanghai proconk pharmaceuticals, inc.
Medicine preparation: preparing a suspension liquid medicine of 20mg/ml by using 5% DMSO, 2% Tween80 and 93% normal saline, and ultrasonically mixing the suspension liquid medicine and the compound 1-6 and positive control quercetin before use; each rat was given a dose of 20 mg/kg. Multidot.d in a dose volume of 100. Mu.l/100 g.
The male SD rats were acclimatized and modeled after one week. Carrying out intraperitoneal injection anesthesia (1 g/kg) by using 25% urethane, fixing the back, recording the normal electrocardiogram of rats before administration, discarding the rats with S-T sections and abnormal T wave changes and arrhythmia, screening 90 rats from the rats, and randomly and averagely grouping the rats according to the weight level, wherein 10 rats are respectively distributed in a blank group, a model group, a positive control group, a compound 1 group, a compound 2 group, a compound 3 group, a compound 4 group, a compound 5 group and a compound 6 group. The animals of each administration group are respectively administrated by intragastric administration for 1 time 1 day for 7 days continuously, after intragastric administration for half an hour on the 5 th day, ISO (5 mg/kg) is injected into subcutaneous multipoint, and the injection part comprises: the number of the four limbs is 5-6, and the injection is continuously performed for 3 days after the injection is finished within 10 s. The blank and model groups were gavaged with equal volumes of solvent, the blank group injected an equal volume of saline subcutaneously from day 5 and the model group injected ISO (5 mg/kg) subcutaneously in multiple points, also subcutaneously, from day 5. After the last ISO injection, a 10-minute long rat II-lead electrocardiogram was recorded using BL-420S Biofunction testing System (Chengdutai Union technologies Co., ltd.). Compared with the electrocardiogram before ischemia, the deviation of S-T section is observed by using the connecting line of the starting points of QRS complex as an isoelectric line, the deviation value (Delta ST) of the S-T section and the change value (Delta QT) of Q-T interval of 5 cardiac cycles are taken each time, and the average number of the deviation values is used as an observation index. At least one of the following conditions is adopted as a molding success standard: 1) The J point deviates downwards or upwards by more than or equal to 0.1mV; 2) The T wave is high and exceeds 1/2 of the R wave of the same lead; 3) T-wave towering with J-point shifting. After the last ISO injection for 6h, blood is taken from the eyeballs of the rats in each group, the rats are centrifuged at low temperature of 4 ℃ for 15min (3500 r/min), serum is taken, and the contents of CK, LDH, SOD and MDA are measured according to the specification of a test box. Collecting blood, dissecting rat heart, washing with normal saline, removing atrial tissue and fat, weighing, transversely cutting 4-5 pieces of left ventricular myocardium, soaking in N-BT phosphate buffer solution, placing in 37 deg.C constant temperature water bath, taking out after dyeing completely, and dyeing normal tissueColor, ischemic tissue did not stain. The excised ischemic myocardium was weighed and the area of Myocardial Ischemia (MIS) was calculated as the percentage of the wet weight of the ischemic myocardium to the left ventricle. The experimental data were processed with SPSS 10.0 statistical software as means. + -. Standard deviation
The expression, between groups comparison using variance analysis, two groups comparison using t test. The results are shown in tables 1-3:
table 1: effect of Compounds on DeltaST and DeltaQT in myocardial ischemia rats
Note: ** P<0.01vs blank; # P<0.05， ## P<0.01vs model set; & P<0.05， && P<0.01vs positive control group
The results in Table 1 show that the model group rat group Δ ST is greater than 0.1mv, and the difference compared with the blank group has statistical significance (P < 0.01), which indicates that the experiment modeling is successful. The positive control group and the compound administration group can reduce the deviation of an S-T section and shorten a Q-T interval, and the positive control group and the compound administration group have the effects of preventing or relieving myocardial damage, improving the ischemia and anoxia state and protecting myocardial cells; and compared with a positive control, the compound of the invention has better effect.
Table 2: effect of Compounds on CK, LDH, MIS in myocardial ischemia rats
Note: ** P<0.01vs blank; # P<0.05， ## P<0.01vs model set; & P<0.05， && P<0.01vs positive control group
When myocardial cells are subjected to ischemia injury, the permeability of cell membranes is increased, and cellular CK and LDH leak out to cause the increase of LDH and CK in blood, so that LDH and CK activities in blood serum can indirectly reflect the change of myocardial injury degree. The results in table 2 show that the model group rats had significantly higher LDH activity, CK activity than the blank group (P < 0.01), and myocardial ischemia than the blank group (P < 0.01). The positive control group and the compound administration group can obviously reduce the CK and LDH activity of rat serum, greatly reduce the area of myocardial ischemia and prompt that the compound administration group has the effects of protecting myocardial cells and improving myocardial ischemia injury; and compared with a positive control, the compound of the invention has better effect.
Table 3: effect of Compounds on MDA and SOD in rats with myocardial ischemia
Note: ** P<0.01vs blank; # P<0.05， ## P<0.01vs model set; & P<0.05， && P<0.01vs positive control group
Myocardial ischemia produces a large amount of oxygen radicals, and the accumulation of oxygen radicals causes damage to cell membranes or cell death. SOD is an enzyme protein containing metal ions in aerobic organisms, is an important enzyme for eliminating oxygen free radicals by organisms, and the activity indirectly reflects the ability of the organisms to eliminate the free radicals. When the myocardium is damaged, the SOD activity is reduced, fatty acid containing double bonds is oxidized to generate MDA, and the MDA can enable the membrane components to be crosslinked and polymerized. Therefore, the high and low MDA content can indirectly reflect the severity of attack of myocardial cells by oxygen free radicals. The results in table 3 show that the model rat has significantly higher MDA content than the blank (P < 0.01) and significantly lower SOD content than the blank (P < 0.01). The positive control group and the compound administration group can obviously reduce the MDA content in serum and improve the activity of SOD, which shows that the compound can improve the oxygen free radical scavenging capability of organisms, inhibit the lipid peroxidation process and reduce the damage of lipid peroxides to cardiac muscle; and compared with a positive control, the compound of the invention has better effect.
The above description is of the preferred embodiment of the present invention, but it is not intended to limit the present invention. Modifications and variations of 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.
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| WO2006045096A2 (en) * | 2004-10-20 | 2006-04-27 | Resverlogix Corp. | Flavanoids and isoflavanoids for the prevention and treatment of cardiovascular diseases |
| US8017649B2 (en) * | 2005-03-11 | 2011-09-13 | Howard Florey Institute Of Experimental Physiology And Medicine | Flavonoid compounds and uses thereof |
| WO2009064485A1 (en) * | 2007-11-16 | 2009-05-22 | Trustees Of Columbia University In The City Of New York | Antioxidant flavonoid derivatives |
| CN103987704A (en) * | 2011-08-05 | 2014-08-13 | 卡德尔治疗公司 | Flavonoid compounds |
| JP6122431B2 (en) * | 2011-08-11 | 2017-04-26 | アーマロン バイオ ピーティーワイ リミテッド | Flavonoid compounds and methods of use |
| SK50062012A3 (en) * | 2012-02-29 | 2013-09-03 | Ustav Experimentalnej Farmakologie A Toxikologie Sav | Quercetin derivatives, pharmaceutical compositions comprising them and their use |
| ES2730926T3 (en) * | 2012-10-11 | 2019-11-13 | Armaron Bio Pty Ltd | New flavonoid compounds and uses thereof |
| CN108774220B (en) * | 2018-05-27 | 2019-04-23 | 西安培华学院 | For treating compound and its application of myocardial ischemia |
| CN114349745B (en) * | 2022-01-14 | 2023-12-08 | 黑龙江中医药大学 | Medicine for treating myocardial ischemia and preparation method thereof |
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