WO2010111935A1 - 一种新的丹酚酸化合物l、其制备方法和用途 - Google Patents
一种新的丹酚酸化合物l、其制备方法和用途 Download PDFInfo
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- WO2010111935A1 WO2010111935A1 PCT/CN2010/071388 CN2010071388W WO2010111935A1 WO 2010111935 A1 WO2010111935 A1 WO 2010111935A1 CN 2010071388 W CN2010071388 W CN 2010071388W WO 2010111935 A1 WO2010111935 A1 WO 2010111935A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
Definitions
- the invention relates to the field of traditional Chinese medicine, and in particular relates to a novel salvianolic acid compound.
- Salvia miltiorrhiza is the root of the genus Salvia, which is bitter and bitter, slightly cold, and is good for heart and liver. It has the effects of relieving pain, promoting blood circulation, clearing heart and removing trouble. Modern pharmacological studies have shown that Salvia miltiorrhiza has the functions of dilating coronary artery, improving microcirculation, and protecting the heart, inhibiting and relieving platelet aggregation, improving the body's ability to resist hypoxia, and anti-hepatitis, anti-tumor and anti-viral activities.
- the salvianolic acid L of the present invention is a new compound in Salvia miltiorrhiza found in a large number of screening research processes, and the compounds and pharmacological actions involving the structure have not been reported so far.
- a further object of the invention is to provide a pharmaceutical composition comprising salvianolic acid L.
- a further object of the present invention is to provide a process for the preparation of salvianolic acid L.
- a further object of the present invention is to provide the use of salvianolic acid L in the manufacture of a medicament for the treatment of cardiovascular diseases.
- novel compounds of the present invention are of the formula (I) and pharmaceutically acceptable salts, solvates thereof and hydrolyzable esters thereof.
- the phenolic acid novel compound of the present invention through physical and chemical properties of the compound, high resolution mass spectrometry (QFT-ESI), electrospray ionization mass spectrometry (ESI-MS), ⁇ -NMR, 13 C-NMR, DEPT, gCOSY, gHMBC, gHMQC map The identification confirmed its structure.
- Replacement page (Article 26)
- the compound of the present invention is a pale yellow powder.
- the thin layer chromatography FeCl 3 reagent of the present invention showed a positive color reaction, suggesting that it may be a phenolic compound.
- the molecular ion peak mfz 537 of the compound of the present invention easily removes the carboxyl group (-44) at the 8" position to form an ion of m/z 493 (the same structure as the ion peak of the salvianolic acid A molecule), and then according to Dan The cleavage of phenolic acid A produces ions of 313 and 295.
- the compound of the present invention has the same skeleton structure as salvianolic acid A.
- the information provided by the binding spectrum indicates that there are two 1,3,4-trisubstituted benzene rings and one 1 in the molecule. , 2,3,4-tetrasubstituted benzene ring, 1 trans double bond and 1 monosubstituted double bond; and these are consistent with the spectral characteristics of salvianolic acid compounds in Salvia miltiorrhiza.
- the compound of the present invention may be a phenolic acid compound which is structurally similar to the phenolic acid compound in the reported salvia miltiorrhiza.
- Salvianolic acid A compound of the invention
- the compound of the present invention is spectrally close to salvianolic acid A, with the difference that there are two pairs of trans double bond protons in the 'H-NMR of salvianolic acid A, and The compounds of the present invention have only one pair of trans double bonds and one monosubstituted double bond proton; in 13 C-NMR, the compound of the present invention has a carbonyl carbon signal more than salvianolic acid A, while C-7" and C-8" The chemical shifts were shifted to the low field by 8 pp m and 6 ppm, respectively, thus indicating that the difference between the compound of the present invention and salvianolic acid A was replaced by a carboxyl group at C-7" or C-8".
- the compound of the present invention is a novel salvianolic acid compound, which is named as salvianolic acid.
- the spectral data may vary due to possible conformational and conformational changes in the compounds of the present invention. However, various isomers resulting from changes in conformation and conformation are within the scope of the present invention.
- the salvianolic acid L of the present invention may also take the form of its pharmaceutically acceptable salt or solvate according to the ordinary skill in the art and the prior art.
- the pharmaceutically acceptable salts of salvianolic acid L of the present invention include conventional, pharmaceutically acceptable
- a salt formed by a base or an organic base which is prepared by a conventional salt formation method.
- suitable salts include salts of sodium, potassium, lithium, magnesium, aluminum, calcium, zinc, etc., or with hydrazine, ⁇ '-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B Diamine, guanidine-methylglucamine, procaine, berberine formed salts.
- the salvianolic acid L mentioned below includes salvianolic acid L represented by the formula (I), and pharmaceutically acceptable salts, solvates thereof and hydrolyzable esters thereof.
- the salvianolic acid L of the present invention is suitably administered in the form of a pharmaceutical composition.
- Such compositions may be combined in a conventional manner with one or more physiologically acceptable carriers or excipients.
- the salvianolic acid L of the present invention is therapeutically administered as a crude drug, and it is preferred that the active ingredient is directly used as a pharmaceutical preparation.
- the carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients and not deleterious to the subject.
- the present invention further provides pharmaceutical formulations of the salvianolic acid L of the present invention, comprising the salvianolic acid L of the present invention and one or more pharmaceutically acceptable carriers, with or without other therapeutic and/or prophylactic ingredient.
- These preparations are suitable for oral, parenteral (including subcutaneous injection or drug tablet; intradermal; intrathecal; intramuscular (eg, drug store; intravenous), rectal and topical (eg sublingual), but most suitable
- the route of administration will depend on the condition of the patient.
- the preparation may be a unit preparation and may be prepared by any method well known in the pharmaceutical art. All methods include the step of bringing the salvianolic acid L of the present invention into combination with a carrier which constitutes one or more accessory ingredients.
- the preparation process of the preparation is as follows: uniformly and tightly combine the salvianolic acid L of the present invention with a liquid carrier, or a finely pulverized solid carrier, or both, and then, if necessary, shape the product It is a necessary preparation.
- compositions of the present invention can be prepared by the use of standard pharmaceutical techniques, i.e., the salvianolic acid L of the present invention and a pharmaceutically acceptable carrier, including mixing, granulating, and compressing.
- a pharmaceutically acceptable carrier including mixing, granulating, and compressing.
- the pharmaceutically acceptable carrier used is various organic or inorganic carriers which can be administered in combination with the composition, for example: excipients, lubricants, binders, disintegrators and coating agents for solid preparations Pharmaceutical additives such as coloring agents and sweeteners can also be used.
- the pharmaceutically acceptable carrier is selected from the group consisting of: sugar alcohols such as mannitol and sorbitol, sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, disodium EDTA, calcium EDTA Sodium, monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose , dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginate, gelatin, polyvinylpyrrolidone, glycerol, Tween 80, agar, calcium carbonate, carbonic acid Hydrogen calcium, sur
- the pharmaceutical preparation form may be any pharmaceutically acceptable dosage form, and these dosage forms include: tablets, such as sugar-coated tablets, film-coated tablets, enteric coated tablets; capsules, such as hard capsules, soft capsules; oral liquids Oral granules; granules; granules; pills; powders; ointments; granules; suspensions; powders; solutions; injections; suppositories; ointments, such as ointments, salves; creams; Patch.
- tablets such as sugar-coated tablets, film-coated tablets, enteric coated tablets
- capsules such as hard capsules, soft capsules
- the preparation of the present invention is preferably an oral dosage form such as a capsule, a tablet, an oral solution, a granule, a pill, a powder, a remedy, a plaster, etc.; and an injection such as a powder injection, an injection, an infusion or the like.
- the preparation of the present invention is most preferably a tablet.
- the preparation for oral administration may contain common excipients, binders, fillers, diluents, compressed tablets, lubricants, disintegrating agents, coloring agents, flavoring agents and humectants, if necessary, tablets may be used. Carry out the coating.
- Preferred exemplary excipients include: lactose, D-mannitol, D-sorbitol, starches such as a-starch, dextrin, crystalline cellulose, low substituted hydroxypropylcellulose, sodium carboxymethylcellulose, arab Glue, amylopectin, light anhydrous silicic acid, synthetic aluminum silicate, aluminum magnesium silicate, and the like.
- Preferred exemplary lubricants include: magnesium stearate, calcium stearate, talc, silica gel, and the like.
- Preferred exemplary binders include: (X-starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sugar, D-mannitol, seaweed Sugar, dextrin, amylopectin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pyrrolidone, and the like.
- Preferred exemplary disintegrants include: lactose, sugar, starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium alkylammonium, sodium carboxymethyl starch, light anhydrous silicic acid, low substituted hydroxypropyl Cellulose and the like.
- Preferred exemplary coating agents include: hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, carboxymethylcellulose, polyvinyl alcohol, and the like.
- Preferred exemplary colorants include: water soluble edible yellow dyes (food dyes such as Edible Red No. 2 and No. 3, Edible Yellow No. 4 and No. 5, Edible Blue No. 1 and No. 2); Insoluble coloring dyes (such as the aluminum salts of the above water-soluble edible yellow dyes); natural dyes (such as carotene, chlorophyll, and iron oxide).
- water soluble edible yellow dyes food dyes such as Edible Red No. 2 and No. 3, Edible Yellow No. 4 and No. 5, Edible Blue No. 1 and No. 2
- Insoluble coloring dyes such as the aluminum salts of the above water-soluble edible yellow dyes
- natural dyes such as carotene, chlorophyll, and iron oxide
- Preferred exemplary sweeteners include: sodium saccharin, glycyrrhetinic acid, aspartame, stevia, and the like.
- Tablets are generally prepared by compressing or molding the salvianolic acid L of the present invention with one or more pharmaceutically acceptable excipients.
- the salvianolic acid L of the present invention can also be formulated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups and the like.
- the salvianolic acid L of the present invention may also be a dry product which is mixed with water or other suitable carrier before use.
- Such liquid preparations may contain conventional additives, and may include suspending agents such as sorbitol syrup, methylcellulose, glucose/syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or Hydrogenated edible fat; emulsifier, such as lecithin, sorbitan monooleate or gum arabic; non-aqueous carrier (which may include edible oils), such as almond oil, fractionated coconut oil, oily ester, propylene glycol or ethanol; Such as methyl or propyl paraben, sorbic acid.
- suspending agents such as sorbitol syrup, methylcellulose, glucose/syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or Hydrogenated edible fat
- emulsifier such as lecithin, sorbitan monooleate or gum arabic
- non-aqueous carrier which may include edible oils
- almond oil fractionated coconut oil, oily ester, propylene
- Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostats, isotonic agents, and the like; and aqueous and nonaqueous sterile suspensions, which may Includes suspending agents and thickeners.
- the formulations may be stored in single or multiple metering containers, such as sealed ampoules and vials, and may be stored under lyophilization (freeze-drying) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, prior to use.
- the preparation for rectal administration may be a suppository containing a conventional suppository base such as cocoa butter, a hard fatty acid or other glyceryl ester, or ethylene glycol.
- a conventional suppository base such as cocoa butter, a hard fatty acid or other glyceryl ester, or ethylene glycol.
- Formulations for topical administration include lozenges wherein the active ingredient is included in the flavored base, such as sucrose and acacia, and soft lozenges containing the active ingredient in the base
- the substrate can be gelatin and glycerin, or sucrose and gum arabic.
- the salvianolic acid L of the present invention can also be formulated into a drug depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- the salvianolic acid L of the present invention can be formulated with a suitable polymer or hydrophobic material (e.g., an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative, such as a sparingly soluble salt.
- Therapies contemplated by the present invention include prophylaxis and treatment of a given disease or condition, according to ordinary skill in the art and prior art.
- the amount of the salvianolic acid L of the present invention required for treatment will vary depending on the nature of the condition being treated and the condition of the patient, or as directed by the physician.
- the dosage for adult treatment will generally range from 0.02 to 5000 mg/day, preferably from 1 to 1500 mg/day.
- the desired dose may be a single dose or multiple doses administered at appropriate intervals, for example, two, three, four or more times per day.
- the preparation according to the invention may contain from 0.1 to 99% by weight of active ingredient, preferably from 30 to 95% by weight of active ingredient for tablets and capsules, and preferably from 3 to 50% by weight of active ingredient for liquid preparations.
- the extract obtained in the step (2) is passed through a silica gel column, dry-loaded, and the eluent is chloroform-methanol-formic acid, and the eluent is isocratically eluted; the thin layer chromatography is used for monitoring. During the elution process, the same eluate was combined to obtain the salvianolic acid 1 ⁇ .
- the mixture of Salvia miltiorrhiza or Dan is involved in other herbs, and may be cut into pieces, pulverized into granules or powder, preferably into a piece;
- the Salvia miltiorrhiza is preferably root of Salvia miltiorrhiza;
- It may be a Chinese medicinal material known to those skilled in the art and compatible with Salvia miltiorrhiza, preferably Panax notoginseng, Astragalus and/or Shouwu.
- the water extraction step is to add 4-8 times the volume of the medicinal material, preferably 4 times; decocting 1.5-3.5 h, preferably 2 h; filtering; the dregs continue to use 3-6 Decoction for l-3h, preferably 3 times the amount of water for 1h; filtered, the filtrate is combined, concentrated to a relative density of 1.11-1.28 (80 ° C) extract, preferably relative density of 1.2 (80 ° C ) The extract.
- the water extraction step is preferably carried out using an aqueous solution of a base, preferably sodium hydrogencarbonate, sodium carbonate, sodium hydroxide, potassium hydrogencarbonate, potassium carbonate and hydrogen.
- At least one of the group consisting of potassium oxide is further preferably sodium hydrogencarbonate or sodium hydroxide; and the aqueous solution of the base is 0.30% to 0.68% of sodium hydrogencarbonate or 0.0025%. -0.004%.
- Sodium hydroxide preferably 0.45% sodium bicarbonate.
- the alcohol precipitation step is carried out by adding 95% ethanol to the extract to carry out alcohol precipitation to 65%-70% (25 ° C), preferably 70%, and letting stand for 12-36 hours, preferably resting. 24h; Ethanol is recovered under reduced pressure and concentrated to an extract having a relative density of 1.30 to 1.38 (60 ° C), preferably an extract having a relative density of 1.37 (60 ° C).
- the alcohol extraction step is to add 5-8 times the volume of the medicine, 50%-95% ethanol, and decoct 2 times, each time l-2h, After filtration, the alcohol extract is discarded, and the dregs are continuously extracted according to the water extraction step described above.
- the macroporous adsorption resin column may be a non-polar active weakly polar resin, for example, AB-8 type, HPD450, HPD700, D101, D4020 or X5 type macroporous adsorption resin, preferably AB -8 type; the weight ratio of the original medicinal material to the macroporous adsorption resin is 5:1-1:1, preferably 4:1; rinsing with 8-15 times the volume of the bed volume, preferably using 12 times the volume of the bed Rinse with water.
- AB-8 type HPD450, HPD700, D101, D4020 or X5 type macroporous adsorption resin, preferably AB -8 type
- the weight ratio of the original medicinal material to the macroporous adsorption resin is 5:1-1:1, preferably 4:1
- rinsing with 8-15 times the volume of the bed volume preferably using 12 times the volume of the bed Rinse with water.
- the aqueous eluate is adjusted with hydrochloric acid to a pH of 2.2-3.5, preferably 3.0.
- the acidic aqueous eluate is again passed through the macroporous adsorption resin, and the weight ratio of the original drug to the macroporous adsorption resin is 5:1 to 1:1, preferably 4:1; and the hydrochloric acid is washed with a pH of 2.2-3.5, preferably 3.0. Nearly colorless.
- the extract is concentrated in the step (2) to dissolve the extract in an organic solvent, preferably dissolved in methanol; and the sample is added to the chromatographic silica gel, preferably by adding 200-300 mesh chromatography silica gel with a weight of the extract or the like.
- the sample is placed on a packed silica gel column, preferably 200-300 mesh silica gel; eluted with chloroform-methanol-formic acid (90:10:3-40:10:0.5), preferably chloroform-methanol-formic acid (85:15:3), the elution process may be isocratic elution (ie, the eluent ratio is unchanged), or may be a gradient elution (ie, eluent ratio change), the gradient
- the elution can be adjusted according to the common knowledge in the art according to the polarity of the substance to be collected, for example, the polarity of the eluate is gradually increased from small to small; in order to accurately follow the elution progress, chloroform-methanol-formic acid (50) is preferred. :10:2) Monitored by thin layer chromatography for the developing agent.
- the results of the drug efficacy test showed that the free radical scavenging power of salvianolic acid L was significantly greater than that of vitamin C (Table 3 and Figure 9); and the reducing power of salvianolic acid L was significantly stronger than that of vitamin C (Fig. 10). .
- the salvianolic acid L of the present invention also has an activity of inhibiting oxidation and scavenging free radicals. Therefore, the salvianolic acid L of the present invention can also be used for the preparation of a medicament having a scavenging activity or a prophylactic antioxidant function.
- the invention further relates to the use of salvianolic acid L in the manufacture of a medicament for the treatment of cardiovascular diseases.
- the cardiovascular disease includes at least one selected from the group consisting of vasodilation dysfunction caused by hypoxia; extracellular nerve cell damage caused by hypoxia, hypoglycemia and peroxidation, and acute myocardial ischemia.
- the salvianolic acid L of the invention has a wide range of pharmacological effects in the cardiovascular system, can reduce vascular endothelial damage caused by ischemia and hypoxia, promote vascular endothelial proliferation, and can improve myocardial cell damage caused by ischemia and hypoxia, and resist arterial Atherosclerosis, inhibition of platelet aggregation and antithrombotic effects.
- Salvianolic acid L also has a dilated coronary artery that increases coronary flow; and protects against cerebral ischemic injury.
- the salvianolic acid L of the invention has a significant improvement effect on the damage of the nerve cells in vitro caused by hypoxia, hypoglycemia and hydrogen peroxide damage, can improve the cell survival rate, and has the functions of protecting hypoxia, lack of sugar and The function of nerve cells in an oxidized state (Table 12-15).
- the results of the pharmacodynamic test of the present invention also show that the salvianolic acid L of the present invention has an anti-acute myocardial ischemia effect (Table 16-17).
- Figure 4 is a 13 C-NMR chart of salvianolic acid L, 125 MHz, CD 3 OD.
- FIG. 13 Electrocardiogram (ECG) after administration of vasopressin in the pituitary.
- ECG Electrocardiogram after administration of vasopressin in the pituitary.
- A the normal electrocardiogram of the model control group
- B the electrocardiogram of the model control group 15 seconds after administration of the vasopressin
- C the electrocardiogram of the model control group 30 seconds after the administration of the vasopressin.
- the obtained extract was dissolved in water, passed through an AB-8 macroporous adsorption resin, and rinsed with 12 volumes of bed volume of water, and the aqueous eluate was adjusted to pH 3.0 with hydrochloric acid.
- the acidic aqueous eluate was again passed through the AB-8 macroporous adsorption resin, rinsed to an almost colorless state with an acidic aqueous solution of pH 3.0, and eluted with 4 times the amount of 95% ethanol, and the eluate was concentrated to a concentrated extract.
- the eluate is concentrated to an alcohol-free taste to obtain an extract.
- the obtained extract was dissolved in methanol, and a considerable weight of 200-300 mesh chromatography silica gel was added, and the sample was placed on a packed silica gel column with chloroform-methanol-formic acid (85:15:3). Elution, detection by thin layer chromatography, and the same type of eluate is combined to obtain salvianolic acid L.
- the DEPT spectrum shows the presence of lxCH 2 , 12xCH, 14> ⁇ C in the molecule.
- the obtained extract was dissolved in water, passed through an AB-8 macroporous adsorption resin, rinsed with 12 volumes of bed volume of water, and the aqueous eluate was adjusted to pH 2.5 with hydrochloric acid.
- the acidic aqueous eluate was again passed through the AB-8 macroporous adsorption resin, rinsed to an almost colorless state with an acidic aqueous solution of pH 3.0, and eluted with 5 times the amount of 95% ethanol, and the eluate was concentrated to a concentrated extract.
- the eluate is concentrated to an alcohol-free taste to obtain an extract.
- the DEPT spectrum shows the presence of l xCH 2 , 12xCH, 14xC in the molecule.
- the dregs were added with 4 times the volume of water (containing 0.45% sodium bicarbonate), boiled for 2 h, and filtered; the dregs were further boiled for 3 h with water, filtered, and the filtrate was concentrated to a relative density of 1.2 (80 °C) extract; add 95% ethanol to the extract to 70% (25 °C), let stand for more than 12h, recover ethanol under reduced pressure, and concentrate to a relative density of 1.37 (60 ° C) The extract.
- the obtained extract was dissolved in water, passed through an AB-8 macroporous adsorption resin, and rinsed with 12 volumes of bed volume of water, and the aqueous eluate was adjusted to pH 3.0 with hydrochloric acid.
- the acidic aqueous eluate was again passed through the AB-8 macroporous adsorption resin, rinsed to an almost colorless state with an acidic aqueous solution of pH 3.0, and eluted with 4 times the amount of 95% ethanol, and the eluate was concentrated to a concentrated extract.
- the eluate is concentrated to an alcohol-free taste to obtain an extract.
- the obtained extract was dissolved in methanol, and a considerable weight of 200-300 mesh chromatography silica gel was added, and the sample was placed on a packed silica gel column with chloroform-methanol-formic acid (85:15:3). Elution, detection by thin layer chromatography, and the same type of eluate is combined to obtain salvianolic acid L.
- the salvianolic acid L and other excipients in the prescription are respectively passed through a 100 mesh sieve, and the prescription amount of salvianolic acid L and the microcrystalline cellulose, starch and sodium carboxymethyl starch are uniformly mixed by the equal amount, and an appropriate amount of 5% PVP is used.
- Salvianolic acid L and other excipients in the prescription are passed through a 100 mesh sieve, and the prescription amount of salvianolic acid L is mixed with starch and sodium carboxymethyl starch by equal amount addition method, and softened with an appropriate amount of 5% PVP anhydrous ethanol solution.
- the material was sieved by 14 mesh, dried at 50-60 ° C for 1 h, and the prescribed amount of magnesium stearate was added to the sieve with a 14 mesh sieve.
- Free radicals are a class of highly active substances that can be continuously produced during cellular metabolism. They can exert strong oxidation directly or indirectly, and participate extensively in the physiological and pathological processes of the body. Excessive free radicals in the body can attack life macromolecules such as nucleic acids, proteins, sugars and lipids through oxidation, causing them to undergo peroxidative degeneration, cross-linking and cleavage, thereby causing damage to cell structure and function. , resulting in tissue destruction and degenerative changes in the body. Numerous studies have shown that free radicals are involved in the pathological processes of many diseases, thereby inducing diseases such as cardiovascular disease, certain cancers, senile cataracts and macular degeneration, certain inflammations, and various neuronal diseases.
- the salvianolic acid compound is a donor of phenolic hydroxyl groups and has a structural basis of antioxidant activity.
- the present invention uses 1,1 -diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging reaction model to observe the scavenging efficiency of salvianolic acid L on free radicals.
- DPPH 1,1 -diphenyl-2-picryl-hydrazyl
- Salvianolic acid L having a purity of 95% or more, was supplied by Tianjin Tianshili Group Research Institute and prepared according to the method of Example 1. Both Vitamin C and DPPH were purchased from SIGMA.
- UV spectrophotometer UV-1800 purchased from Beijing Ruili Analytical Instrument Co., Ltd.
- the total volume of the reaction was 2 ml. 1 ml of different concentrations of sample 80% methanol solution was added to ⁇ ⁇ DPPH methanol solution, mixed and reacted in the dark for 25 min for 20 min, and the absorbance of the reaction solution at 517 nm was measured. Vitamin C was used as a positive comparison in the experiment.
- the free radical scavenging rate is calculated using the following formula:
- a sample is the absorbance value of the test sample
- A. . Ntral is the absorbance value of the untested sample.
- Table 3 and Figure 9 show the clearance of DPPH free radicals by different concentrations of salvianolic acid L and vitamin C.
- the free radical scavenging power of salvianolic acid L is significantly greater than the free radical scavenging power of vitamin C.
- the magnitude of the drug's reducing power reflects the strength of its preventive antioxidant function to some extent.
- the present invention conducts an experimental study on the reducing power of salvianolic acid L.
- Salvianolic acid L purity 95% or more, was supplied by Tianjin Tianshili Group Research Institute and prepared according to the method of Example 1. Potassium ferricyanide, analytically pure, purchased from Tianjin Chemical Reagent No. 1 Plant.
- Ferric chloride analytically pure, purchased from Tianjin Sailboat Chemical Reagent Technology Co., Ltd.
- Vitamin C was purchased from Sigma.
- UV spectrophotometer UV-1800 was purchased from Beijing Rayleigh Analytical Instruments Co., Ltd.
- Refrigerated centrifuge Z323K, purchased from HEMMLE, Germany.
- Figure 10 shows that both absorbance increases with increasing concentration.
- the reducing power of salvianolic acid L is significantly stronger than that of vitamin C.
- the materials used were all from the Institute of Traditional Chinese Medicine of Tianjin Tianshili Group Research Institute.
- the content of the extract 1 is: 6.825 g of crude drug / g ; the content of the extract 2 is: 4.162 g of crude drug / g.
- Salvianolic acid L The method of Example 1 of the present invention.
- Salvianolic acid L 0 Pharmacological effect 3 The effect of salvianolic acid L lyophilized powder on isolated thoracic aorta in rats
- Test substance and reagent Salvianolic acid L freeze-dried powder, from Tianjin Tianshili Group Research Institute of Traditional Chinese Medicine; norepinephrine (NA); acetylcholine (ACH): sigma company, batch number: 1377511 44908131; K-liquid preparation materials: potassium chloride, sodium chloride, potassium dihydrogen phosphate, sodium hydrogencarbonate, magnesium sulfate, glucose, calcium chloride.
- MedLab isolated tissue bath and Medlab-U / 8C acquisition system Nanjing Meiyi Technology Company; Zhang force transducer; CNC super constant temperature tank SC-15; analytical balance; pure water meter; oxygen cylinder.
- mice SD rats, suitable for both body weight and male and female, were provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., certificate: SCXK (Beijing) 2007-0001. It is kept in the animal word room, room temperature 20-25 °C, lighting time 12h, special feed for food rats (produced by Beijing Keao Xieli Feed Co., Ltd.), drinking tap water.
- the dose of salvianolic acid L lyophilized powder is based on the efficacy test of other salvianolic acid.
- the dose of this experiment is designed to be O. lmg/mL K's solution (mol/L): NaCl (120), NaHC0 3 (25), KH 2 P0 4 ( 1.2 ), MgS0 4 ( 1.2 ), KC1 (4.5 ), CaCl 2 ( 1.25 ), C 6 H 12 0 6 (glucose 11.1 )
- KC1 3mol/L KC1 solution is added to ⁇ ⁇ (final concentration 60mmol/L)
- Rats were given a free diet and were randomly assigned to a group based on the drug formulation of the day. Eight animals per group were guaranteed, and each animal had data for four vascular rings. It was divided into normal group, hypoxia model group and salvianolic acid L hypoxia group.
- SD rats were given a free diet and were randomly assigned to a group of 8 according to the drug formulation of the day.
- the animal was sacrificed by cervical vertebrae, the thoracic cavity was quickly opened, and the thoracic aorta was removed.
- the connective tissue was removed at 0 °C in oxygen, and the thoracic aorta was modified into a ring of about 2 mm.
- the basis of the tension is 2g, the vascular ring is balanced for 45 minutes, and the K-solution is replaced every 15 minutes.
- hypoxia model group 0.01 ⁇ 0.05 0.23 ⁇ 0.41 1.12 ⁇ 0.31 1.37 ⁇ 0.31 salvianolic acid Hypoxia group 0.1 -0.02 ⁇ 0.06 0.30 ⁇ 0.33 0.84 ⁇ 0.38 1.05 ⁇ 0.48
- the lyophilized powder of salvianolic acid L can cause a certain right shift in the vasoconstriction curve of norepinephrine, but there is no significant difference.
- Hypoxia 20min gradient relaxation can lead to vascular significantly decreased (P ⁇ 0.01) on carbachol-induced model group, there diastolic dysfunction; Sal L lyophilized gradient hypoxic vascular rings (10-5 in three ACH, 10- 4, 10- 3 mol / L ) of vasodilation were significantly enhanced (P ⁇ 0.05). It is indicated that salvianolic acid L has a significant improvement effect on vasodilation dysfunction caused by hypoxia.
- Ultra-clean workbench (Antai Purification Equipment Co., Ltd.), constant temperature C0 2 incubator (Heraeus, Germany) Enzyme-linked immunosorbent assay (US BIO-RAD), plate shaker (Jiangsu Guangming Experimental Instrument Factory), Inverted biological microscope (Japan OLYMPUS).
- DMEM high glucose medium DMEM high glucose medium
- DMEM sugar-free medium GIBCO
- trypsin SIGMA
- fetal bovine serum PAA
- MTT Sigma
- DMSO Sigma
- LDH test kit Najing Institute of Bioengineering
- Cell viability % (OD value of the administration group / OD value of the negative control group; ) ⁇ 100%
- ODu is the absorbance value of the sample to be tested
- OD c is the sample control absorbance value
- OD B is the blank tube absorbance value
- 00 3 is the pair The absorbance of the liquid
- C s is the standard concentration (2mmol / L)
- N is the dilution factor before the test.
- Solvent control group Forced 0.1% DMSO.
- Model group 3 ⁇ 40 2 concentrations were 0.25 mM, 0.5 mM, and lmM, respectively, for 1 h.
- Positive control group Edaravone (2 g/ml) was used as a positive control. After the addition, the cells were pretreated for 6 h, added with 0.5 mM 3 ⁇ 40 2 for 1 h, and then replaced with fresh DMEM + 10% FBS medium, 200 ⁇ l/well.
- Experimental grouping and treatment The experiment was divided into 3 groups, which were blank control group (normoxia+0.1% DMSO), model group (OGD+0.1% DMSO, hypoxia and hypoglycemia), positive control group (Idarafen). ).
- Model group The cells of the culture plate were changed to sugar-free DMEM medium, placed in an anoxic chamber, and timed from 0 2 % ⁇ 2.6 for 0.5 h, and then transferred to a normal incubator.
- Positive control group Edaravone (2 ⁇ ⁇ / ⁇ 1 ) was used as a positive control. After the drug was added, after pretreatment for 6 hours, the sugar-free DMEM medium was changed to 180 ⁇ l/well, re-dosed, placed in an anoxic chamber, and counted for 0.5 h from 0 2 % ⁇ 2.6, and then transferred to a normal incubator. Cultivate for a while and then measure
- the hypoxic and hypoglycemic model of the experiment was as follows: The cells were replaced with sugar-free DMEM medium, placed in an anoxic chamber, and timed from 0 2 % ⁇ 2.6 for 0.5 h, transferred to a normal incubator, and cultured for a period of time before measurement.
- Model group 3 ⁇ 40 2 concentration 0.5 mM, acting for 1 h.
- Positive control group Edaravone (2 ⁇ ⁇ / ⁇ 1) was used as a positive control. After adding cells for 6 h, the cells were added with 0.5 mM 3 ⁇ 40 2 for 1 h, and then replaced with fresh DMEM + 10% FBS medium.
- Drug treatment group After adding cells to the culture plate, first add different concentrations of different test drugs, 20 ⁇ 1/well, pre-treatment for 6h, 0.5mM H 2 O 2 damage for 1h, and then switch to fresh DMEM + 10% FBS medium. .
- the three concentrations of the drug were prepared in 0.1%, 0.01%, and 0.001% DMSO, respectively, compared to the corresponding concentration of the solvent control group.
- the drug treatment group was compared with the model group (0.5 mM H 2 0 2 + EtOAc ).
- the model group (H 2 0 2 + EtOAc) was compared to the solvent control (EtOAc).
- the drug treated group was compared to the model group (0.5 mM H 2 0 2 + EtOAc) and the model group (H 2 0 2 + EtOAc) group was compared to the solvent control (EtOAc).
- Experimental grouping and treatment The experiment was divided into 4 groups, which were blank control group (normoxia+0.1% DMSO), model group (OGD+DMSO, hypoxia and hypoglycemia), positive control group (edaravone), Drug treatment group.
- Model group The cells in the culture plate were replaced with sugar-free DMEM medium, placed in an anoxic chamber, and timed from 0 2 % ⁇ 2.6 for 0.5 h, transferred to a normal incubator, and cultured overnight.
- Positive control group Edaravone (2 g/ml) was used as a positive control. After the drug was added, after 6 hours of pretreatment, it was replaced with sugar-free DMEM medium, 180 ⁇ l/well, re-dosed, placed in an anoxic chamber, and timed from 0 2 % ⁇ 2.6 for 0.5 h, transferred to a normal incubator, overnight. to cultivate.
- Drug treatment group After adding different concentrations of drugs, after pretreatment for 6h, change to sugar-free DMEM medium, 180 ⁇ 1/well, re-dosing, placed in anoxic chamber, timed from 0 2 % ⁇ 2.6 for 0.5h, transfer Into the normal incubator, overnight culture.
- the dose of salvianolic acid L was 0.02, 0.2 ⁇ ⁇ / ⁇ 1 ⁇ , and the survival rates were 48% (P ⁇ 0.01) and 37% (P ⁇ 0.05), respectively.
- the survival rate was 40% (P ⁇ 0.01)> 42% (P ⁇ 0.01); salvianolic acid L extract 2 was 0.02, 0.2, 2 g.
- the survival rates were 47% (P ⁇ 0.01), 47% (P ⁇ 0.01), and 41% (P ⁇ 0.05), respectively.
- the dosage of dry powder of salvianolic acid L was 2 g/ml ⁇ , and the activity of LDH was 40 (P ⁇ 0.05); the dose of salvianolic acid L extract 1 was 2 g/ml ⁇ , and the activity of LDH was 31 (P ⁇ 0.01); Salvianolic acid L extract 2 dose was 0.2 g / ml ⁇ , LDH activity was 31 (P ⁇ 0.05).
- the lyophilized powder of salvianolic acid L can significantly improve the damage of nerve cells in vitro caused by hypoxia and hypoglycemia and hydrogen peroxide damage, can improve cell survival rate, and protect nerve cells under hypoxia, hypoglycemia and peroxidation.
- Test substance and reagent Pit injection, produced by Nanjing Xinbai Pharmaceutical Co., Ltd., batch number: 070302; normal saline, produced by Tianjin Tianan Pharmaceutical Co., Ltd., specification 500ml/bottle, batch number: 200605241.
- mice SD rats, suitable for both body weight and male and female, were provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., certificate: SCXK (Beijing) 2007-0001. It is kept in the animal feeding room, room temperature 20-25 °C, lighting time 12h, special feed for rats (produced by Beijing Keao Xieli Feed Co., Ltd.), drinking tap water.
- the content of the extract 1 is: 6.825 g of crude drug / g.
- the content of the extract 2 is: 4.162 g of crude drug / g.
- both the extract 1 and the extract 2 were set in the high and low dose groups, respectively, and the doses were 1.086 g crude drug/kg and 0.543 g crude drug/kg, respectively.
- the high-dose salvianolic acid L lyophilized powder is administered at a dose of 4.67 mg/kg
- the low-dose salvianolic acid L lyophilized powder is administered at a dose of 2.33 mg/kg.
- Extract 2 does not contain salvianolic acid L.
- Salvianolic acid L lyophilized powder dosage 10.0mg/kg, 5.0mg/kgo
- the pituitary vasopressin (Ph) (1U/kg) was injected into the tail vein of the rats before the formal experiment.
- the electrocardiogram was normal and 5 min after the injection.
- the J-point elevation and T-wave abnormalities were observed and appeared before the injection.
- the selected rats were randomly divided into 7 groups, which were 1 model control group; 2 Danshen extract 1 low dose group (group A); 3 salvia miltiorrhiza extract 1 high dose group (group B); 4 salvia miltiorrhiza extract 2 low dose group (Group C); 5 Danshen extract 2 high dose group (D group); 6 salvianolic acid L lyophilized powder low dose group (E group); 7 salvianolic acid L lyophilized powder high dose group (F group);
- Rats in the model control group were intragastrically administered with an equal volume of physiological saline per day, and the administration group was administered an aqueous suspension of different samples daily, and all animals were continuously administered for 7 days. 40 min after the last dose, the rats were anesthetized, connected to the instrument, and the normal lead electrocardiogram of the II lead was traced. Pituitary vasopressin was injected at a constant rate from the tail vein of rats according to lU/kg body weight
- J-point definition J-point is the junction of the end of the QRS complex and the intersection of the ST segment.
- the pituitary vasopressin can contract coronary vessels, causing acute myocardial ischemia in rats, and the J-point and T-wave of ECG in rats are significantly increased. If a certain test substance is given, the J-point displacement of the drug-administered group is obviously restored, and the T wave also shows a downward trend, which gradually becomes normal, indicating that the drug has an acute myocardial deficiency caused by antagonizing the contraction of the vasopressin of the pituitary. Blood effect.
- phase I abnormality an abnormality caused by pituitrin in 0-45s
- phase II abnormality a abnormality caused by pituitrin in 45s-15min
- the pituitrin should use the same batch number, in order to avoid differences in drug potency and affect the results. Repeated injection of pituitrin should be separated by more than 2 hours to avoid tolerance. It is best to use the selected animals the next day.
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RU2011139614/04A RU2529491C2 (ru) | 2009-03-30 | 2010-03-29 | Соединение сальвианоловой кислоты л, способ его приготовления и применения |
SG2011069150A SG174548A1 (en) | 2009-03-30 | 2010-03-29 | New salvianolic acid compound l, preparation method and use thereof |
CA2756823A CA2756823C (en) | 2009-03-30 | 2010-03-29 | New compound of salvianolic acid l, preparation method and use thereof |
AU2010230770A AU2010230770B2 (en) | 2009-03-30 | 2010-03-29 | New salvianolic acid compound L, preparation method and use thereof |
MYPI2011004442A MY183588A (en) | 2009-03-30 | 2010-03-29 | New salvianolic acid compound l, preparation method and use thereof |
EP10758037.5A EP2415749B1 (en) | 2009-03-30 | 2010-03-29 | New salvianolic acid compound l, preparation method and use thereof |
US13/259,244 US20120041062A1 (en) | 2009-03-30 | 2010-03-29 | Compound of salvianolic acid l, preparation method and use thereof |
JP2012502437A JP5755633B2 (ja) | 2009-03-30 | 2010-03-29 | 新規サルビアノール酸化合物l、その調製方法及び使用 |
HK12107774.3A HK1168584A1 (zh) | 2009-03-30 | 2012-08-08 | 種新的丹酚酸化合物 、其製備方法和用途 |
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AU (1) | AU2010230770B2 (zh) |
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USRE49050E1 (en) | 2013-07-11 | 2022-04-26 | Tasly Pharmaceutical Group Co., Ltd. | Traditional Chinese medicine composition, and preparation and application thereof |
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US20160200661A1 (en) * | 2013-08-29 | 2016-07-14 | Tasly Pharmaceutical Group Co., Ltd. | New salvianolic acid compound t, preparation method therefor, and use thereof |
CN104418744B (zh) * | 2013-08-29 | 2017-03-01 | 天士力制药集团股份有限公司 | 一种新的丹酚酸化合物t、其制备方法和用途 |
RU2668955C2 (ru) * | 2013-08-29 | 2018-10-05 | Тасли Фармасьютикал Груп Ко., Лтд. | Новое соединение сальвианоловой кислоты т, способ его получения и его применение |
WO2015027891A1 (zh) * | 2013-08-29 | 2015-03-05 | 天士力制药集团股份有限公司 | 一种新的丹酚酸化合物t、其制备方法和用途 |
US10626077B2 (en) * | 2013-08-29 | 2020-04-21 | Tasly Pharmaceutical Group Co., Ltd. | Salvianolic acid compound T, preparation method therefor, and use thereof |
CN104434899A (zh) * | 2013-09-24 | 2015-03-25 | 天士力制药集团股份有限公司 | 丹酚酸l在制备治疗或预防肝纤维化和肾纤维化的药物中的应用 |
CN109748793A (zh) * | 2018-12-29 | 2019-05-14 | 正大青春宝药业有限公司 | 一种去除丹酚酸a钠中异丹酚酸a1和异丹酚酸a2的方法 |
CN109748793B (zh) * | 2018-12-29 | 2021-07-09 | 正大青春宝药业有限公司 | 一种去除丹酚酸a钠中异丹酚酸a1和异丹酚酸a2的方法 |
CN114075158A (zh) * | 2020-08-19 | 2022-02-22 | 西安碑林药业股份有限公司 | 丹参素和丹酚酸b含量的提取和检测方法 |
CN114075158B (zh) * | 2020-08-19 | 2023-12-15 | 西安碑林药业股份有限公司 | 丹参素和丹酚酸b含量的提取和检测方法 |
CN113214157A (zh) * | 2021-04-25 | 2021-08-06 | 广西壮族自治区花红药业集团股份公司 | 吡咯烷酮类化合物在制备治疗炎症性疾病的药物中的用途 |
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JP5755633B2 (ja) | 2015-07-29 |
US20120041062A1 (en) | 2012-02-16 |
EP2415749A1 (en) | 2012-02-08 |
HK1168584A1 (zh) | 2013-01-04 |
RU2529491C2 (ru) | 2014-09-27 |
AU2010230770B2 (en) | 2014-07-03 |
EP2415749B1 (en) | 2016-05-04 |
CA2756823C (en) | 2017-01-17 |
EP2415749A4 (en) | 2012-12-12 |
RU2011139614A (ru) | 2013-05-10 |
KR20120006029A (ko) | 2012-01-17 |
MY183588A (en) | 2021-02-27 |
CA2756823A1 (en) | 2010-10-07 |
AU2010230770A1 (en) | 2011-10-13 |
SG174548A1 (en) | 2011-10-28 |
JP2012522022A (ja) | 2012-09-20 |
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