CN111714485A - Hyperuricemia pharmaceutical composition and application thereof - Google Patents
Hyperuricemia pharmaceutical composition and application thereof Download PDFInfo
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- CN111714485A CN111714485A CN201910213601.3A CN201910213601A CN111714485A CN 111714485 A CN111714485 A CN 111714485A CN 201910213601 A CN201910213601 A CN 201910213601A CN 111714485 A CN111714485 A CN 111714485A
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- Prior art keywords
- hyperuricemia
- pharmaceutical composition
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- drug
- gout
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- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- 229910021538 borax Inorganic materials 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
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- 235000005911 diet Nutrition 0.000 description 1
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- 239000003085 diluting agent Substances 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
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- 238000005516 engineering process Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- QWCNQXNAFCBLLV-YWALDVPYSA-N falcarindiol Chemical compound CCCCCCC\C=C/[C@H](O)C#CC#C[C@H](O)C=C QWCNQXNAFCBLLV-YWALDVPYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
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- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
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- DENOGTWTGDLIBH-SZMQGJMYSA-N lobetyolin Natural products CC=CC#CC#C[C@@H](O)[C@@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)C=CCCO DENOGTWTGDLIBH-SZMQGJMYSA-N 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
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- 235000019198 oils Nutrition 0.000 description 1
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229930000223 plant secondary metabolite Natural products 0.000 description 1
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- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
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- 235000005713 safflower oil Nutrition 0.000 description 1
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- 239000008159 sesame oil Substances 0.000 description 1
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- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
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- 238000007619 statistical method Methods 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
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- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/01—Hydrocarbons
- A61K31/015—Hydrocarbons carbocyclic
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention belongs to the field of chemical medicine, and particularly relates to a hyperuricemia pharmaceutical composition and application thereof, wherein the hyperuricemia pharmaceutical composition comprises a polyacetylene compound with a structure shown as a formula (I), and application of the polyacetylene compound, pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof in combination with a hyperuricemia drug in preparation of a combined drug for treating hyperuricemia, and the hyperuricemia pharmaceutical composition comprises the compound and one of benzbromarone or Racemado. The hyperuricemia drug composition can achieve the effect of reducing uric acid equivalent to or even better than that of hyperuricemia drugs in the prior art, can obviously reduce the toxic and side effects of the hyperuricemia drugs, improves the safety, and can be used for treating gout or gout complications caused by hyperuricemia and hyperuricemia.
Description
Technical Field
The invention relates to the field of chemical medicine, in particular to a hyperuricemia pharmaceutical composition and application thereof.
Background
In the field of chemical medicine, uric acid is the final metabolite of human purine compounds. Disorders of purine metabolism lead to hyperuricemia. Under normal purine diet, the level of uric acid in fasting blood twice a day is higher than 416 mu mol/L in male and higher than 360 mu mol/L in female, namely hyperuricemia (hyperuricemia). Generally, there is no subjective symptom when the patient is in a hyperuricemia symptom state, but if the patient is in the hyperuricemia symptom state for a long time, urate in blood is crystallized and deposited on joints, subcutaneous tissues, kidneys and other parts, and a series of clinical manifestations such as gout and gout complications occur. Recently published '2017 Chinese gout status report white paper', the number of hyperuricemia patients in China reaches 1.7 hundred million, wherein the number of gout patients exceeds 8000 ten thousand, and the annual growth rate is rapidly increased by 9.7% per year. In 2020, the number of gout people is estimated to reach 1 hundred million. Nowadays, gout becomes the second major metabolic disease of China, which is second only to diabetes, and seriously harms the life and health of people.
At present, when treating hyperuricemia, gout caused by hyperuricemia and gout complications, uric acid in blood needs to be controlled: for patients with uric acid dysexcretion (90% of the patients) are applicable to drugs for promoting uric acid excretion, such as: benzbromarone, rasidone, etc.; for patients with hyperuricemia, drugs (mainly xanthine oxidase inhibitors) for inhibiting uric acid production are suitable, such as: allopurinol and febuxostat. However, as the clinical application of these drugs increases, adverse reactions are gradually exposed.
Benzbromarone is a drug for promoting uric acid excretion, is marketed in France in 1976, brings a new way for treating chronic gout, has a remarkable curative effect on hyperuricemia, but can cause gastrointestinal discomfort, particularly diarrhea; the use of the medicine is limited by European market due to the possibility of causing serious liver function damage, and FDA refuses the application on the market due to adverse reaction, however, some countries including China still allow the use, but the effect of reducing uric acid is reduced by regulating the dosage of the medicine according to the intoxication clearance.
Leisinrad (Lesinurad) was originally developed by AstraZeneca (AstraZeneca), and was marketed in the united states at 12 months 2015 and in the european union at 2 months 2016, respectively, under the trade name Zurampic, and is the first uric acid transporter 1 inhibitor on the market, and is clinically used mainly in combination with xanthine oxidase inhibitors (such as allopurinol and febuxostat) for treating hyperuricemia associated with gout, and the common adverse reactions caused by Lesinurad include headache, influenza, increased serum creatinine, and gastroesophageal reflux disease, and the use of lesioned alone increases the risk of acute renal failure.
The drugs have large toxic and side effects under the conventional dosage, and the tolerance of the drugs is generally low, so that the clinical application of the drugs is limited to a certain extent.
Polyacetylenes or polyacetylenes are a special class of natural compounds, mostly having two or more conjugated triple bonds, and thus having considerable unsaturation and high reactivity. The polyacetylene compounds and the derivatives thereof are very important plant secondary metabolites and are widely distributed in the plant world, and more than 750 natural polyacetylenes and the derivatives thereof are reported only in compositae plants. Some plants (Compositae, Umbelliferae, etc.) containing polyacetylene components have long been used as medicines, but because such components are generally contained in small amounts and are not stable enough, the relationship between the effect of the medicines and the polyacetylene components is less studied. With the progress of chemical and pharmacological research methods, the compounds are reported to have physiological activities such as anti-inflammation, antifungal, sensitization, antitumor, antimicrobial, anticonvulsant and the like.
Disclosure of Invention
The first technical problem to be solved by the invention is to overcome the defect that the drug for treating hyperuricemia in the prior art has toxic and side effects, so that the application of the polyacetylene compound with the structure shown as the formula (I) and the pharmaceutically acceptable salt, ester, prodrug, solvate, polymorph, hydrate or derivative thereof in combination with the hyperuricemia drug in preparing the combined drug for treating hyperuricemia is provided.
The second technical problem to be solved by the invention is to overcome the defect that the drugs for treating hyperuricemia in the prior art have toxic and side effects, so that the invention provides the hyperuricemia drug composition which can reduce the toxic and side effects while maintaining the ideal effect of reducing the uric acid.
The third technical problem to be solved by the invention is to overcome the defect that the drugs for treating hyperuricemia in the prior art have toxic and side effects, so that the drug for treating hyperuricemia, which can reduce the toxic and side effects while maintaining the ideal effect of reducing uric acid, is provided.
The invention also provides application of the hyperuricemia pharmaceutical composition.
Therefore, the invention provides a polyacetylene compound with a structure shown as a formula (I) and application of pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof in preparing a combined drug for treating hyperuricemia. Further, the hyperuricemia drug is one of benzbromarone or resinide.
The invention provides a hyperuricemia pharmaceutical composition, which comprises the following components: an active ingredient having a synergistic effect with a hyperuricemia drug, and a hyperuricemia drug; wherein the hyperuricemia drug is a uric acid excretion promoting drug; the active ingredients are polyacetylene compounds with the structure shown in formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof:
wherein,
is selected from
Or
One of (1);
R1selected from H, OH,
Unsubstituted or substituted C1-C4Alkyl, unsubstituted or substituted C1-C4An alkenyl group of,
One of (1), RaSelected from H, OCOCH3One of (1);
R2selected from H, OH, OCOCH3Or R is1、R2To form unsubstituted or substituted phenyl;
R3selected from H, OH,
Unsubstituted or substituted C1-C10Alkyl, unsubstituted or substituted C1-C10Alkenyl of (a);
R4selected from H, OH, unsubstituted or substituted by 1 to 3R4aSubstituted C1-C12Alkyl or alkenyl of, R4aSelected from OH, OCOCH3From
Forming monosaccharide or disaccharide residues.
The hyperuricemia pharmaceutical composition comprises the following active ingredients:
the hyperuricemia drug is one of benzbromarone or Racinade.
The hyperuricemia drug composition comprises 14-91% of the active component and the hyperuricemia drug by mass.
The hyperuricemia pharmaceutical composition also comprises a pharmaceutically acceptable carrier.
The invention also provides a medicine for treating hyperuricemia, which comprises the hyperuricemia medicine composition, wherein the medicine is prepared by adding conventional auxiliary materials into the hyperuricemia medicine composition and preparing clinically acceptable tablets, capsules, pills, granules, paste, mixtures or suspensions according to a conventional process.
The invention also provides application of the hyperuricemia pharmaceutical composition in preparing hyperuricemia drugs or health care products.
The hyperuricemia pharmaceutical composition is used for preparing a hyperuricemia drug or a health-care product, and the hyperuricemia comprises gout or gout complications caused by the hyperuricemia.
The hyperuricemia pharmaceutical composition is used for preparing hyperuricemia drugs or health care products, wherein the gout comprises acute gout or chronic gout; the gout complications comprise gouty arthritis, gout attack, gouty nephropathy or uric acid renal calculus.
The technical scheme of the invention has the following advantages:
1. the invention provides a hyperuricemia drug composition, which can achieve the equivalent or even better effect of reducing uric acid compared with hyperuricemia drugs in the prior art, but can obviously reduce the toxic and side effects of the hyperuricemia drugs in the prior art, improve the safety, and can be used for treating hyperuricemia and gout or gout complications caused by the hyperuricemia.
2. The invention provides a drug for treating hyperuricemia, which can achieve the equivalent or even better effect of reducing uric acid compared with the hyperuricemia drug in the prior art, but can obviously reduce the toxic and side effects of the hyperuricemia drug in the prior art, improve the safety and be used for treating the hyperuricemia and gout or gout complications caused by the hyperuricemia.
Detailed Description
Example 1
This example provides methods for the extraction and characterization of compounds 4-7 from the active ingredient.
The ethanol, ethyl acetate, petroleum ether and methanol used in this example were all commercially available products.
Taking 100kg of Atractylodes lancea of Compositae (Compositae), pulverizing, soaking in 15 times volume of 70% ethanol water solution at 50-100 deg.C for 120min, and concentrating under reduced pressure to obtain concentrated solution A; separating the concentrated solution A with a low pressure D101 column (column diameter 28cm × height 162cm, column volume 100L), eluting with 30% and 95% ethanol-water solution for 4BV, and collecting 95% fraction; the concentrated part (solid content about 3kg) was separated by an LX-20SS column (column diameter 20 cm. times. height 78cm, column volume 25L), eluted with 70% by volume and 80% by volume of ethanol-water solution for 3BV, then eluted with 95% by volume and ethanol-water solution for 4BV, and the 95% part was collected to obtain a crude concentrated solution B (solid content about 1 kg).
Separating the concentrated solution B by silica gel column (column diameter is 11cm multiplied by 65cm high, column volume is 6L), and performing gradient elution by using petroleum ether-ethyl acetate as a mobile phase according to the following procedures: the volume ratio of petroleum ether to ethyl acetate is respectively 100:0, 50:1, 20:1, 10:1, 5:1 and 1:1, 3BV is eluted by the gradient, and finally, 3BV is eluted by an ethanol water solution with the volume concentration of 95 percent, the eluent of each mobile phase is respectively collected and concentrated under reduced pressure, and 7 eluates Fr.A-G are respectively obtained.
Wherein fr.c was separated by silica gel column (column diameter 11cm x height 65cm, column volume 6L) and gradient eluted with petroleum ether-ethyl acetate as mobile phase according to the following procedure: the volume ratio of petroleum ether to ethyl acetate is respectively 50:1, 30:1, 20:1, 10:1 and 1:1, 3BV is eluted by the gradients, finally, 3BV is eluted by ethanol water solution with the volume concentration of 95%, eluent of each mobile phase is respectively collected and concentrated under reduced pressure, and 6 eluates Fr.C1-6 are respectively obtained. C1, performing ODS preparative liquid chromatography, and separating with 75% methanol-water solution by volume concentration to obtain compound 7; and Fr.C5 is separated by ODS preparative liquid chromatography with a methanol-water solution of 65% by volume concentration to obtain compound 6.
Fr.D was separated by a silica gel column (column diameter 11 cm. times. height 65cm, column volume 6L) and gradient elution was carried out with petroleum ether-ethyl acetate as a mobile phase according to the following procedure: the volume ratio of petroleum ether to ethyl acetate is respectively 50:1, 30:1, 20:1, 15:1, 10:1, 5:1 and 1:1, 3BV is eluted by the gradients, finally, 3BV is eluted by ethanol water solution with the volume concentration of 95 percent, the eluent of each mobile phase is respectively collected and is decompressed and concentrated, and 8 eluates Fr.D1-8 are respectively obtained.
Performing ODS preparative liquid chromatography on Fr.D2, and separating with 70% methanol-water solution by volume concentration to obtain compound 4; and Fr.D4 is separated by ODS preparative liquid chromatography with a methanol-water solution with a volume concentration of 65% to obtain compound 5.
The isolated compounds 4-7 were identified by nmr spectroscopy and the structures of the compounds were determined by comparison with data from the prior art:
the references for the structure confirmation data of compound 4 are as follows: washino T, Yoshikura M, obata S.Polyacetylanic compounds of Arctium lappa L. [ J ]. Journal of the agricultural chemical Society of Japan,1986,60(5):377-383.
References to structure confirmation data for compounds 5-6 are shown below: lehner M S, Steigel A, BauerR. diacetoxy-pretreated polyacetylenes from aliphatic polyamides, lan [ J ]. Phytochemistry,1997,46(6): 1023-.
The references for the structure confirmation data of compound 7 are shown below: zhao jin, Deng jin Bao, Li Xiong, etc. research on the chemical components of the polyacetylene class of rhizoma atractylodis [ J ] research on new Chinese medicine and clinical pharmacology 2015(4) 525-.
Example 2
This example provides methods for the extraction and characterization of compounds 8-11 from the active ingredient.
The n-pentane, ethyl acetate, diethyl ether, ethanol and methanol used in this example were all commercially available products.
Cutting 20kg carrot into small pieces, cutting with a blender, sequentially extracting with 40L n-pentane and 30L ethyl acetate at room temperature for 3 times, respectively collecting n-pentane extractive solution and ethyl acetate extractive solution, and respectively concentrating under reduced pressure to remove organic solvent to obtain 20g n-pentane extract (component A) and 15g ethyl acetate extract (component B). Dissolving the component B in 35mL of mixed solution of n-hexane and ethyl acetate, wherein the volume ratio of the n-hexane to the ethyl acetate is 95: after dissolution, the mixture was separated and purified by a silica gel column (column diameter: 6 cm. times. height: 60cm, column volume: 1.7L), and gradient elution was carried out using a mixture of n-pentane and diethyl ether as a mobile phase according to the following procedure: the volume fractions of n-pentane are respectively 95%, 80%, 70% and 50%, and finally, the elution is carried out by using ethanol, the elution of each mobile phase is respectively carried out for 3BV, the elution liquid of each mobile phase is respectively collected and is concentrated under reduced pressure, and five elution substances Fr, B1-B5 are obtained.
Wherein, the Fr.B2 is separated by ODS preparative liquid chromatography, and eluted by using a methanol-water solution with the volume concentration of 80% as a mobile phase to obtain the compound 8.
And Fr and B4 are separated by ODS preparative liquid chromatography, and eluted by using a methanol-water solution with the volume concentration of 80% as a mobile phase to obtain the compounds 9 and 10.
And Fr.B5 is separated by ODS preparative liquid chromatography, and eluted by using a methanol-water solution with the volume concentration of 80% as a mobile phase to obtain the compound 11.
The isolated fractions were identified by nmr spectroscopy and the structure of the compounds was determined by comparison with data from the following prior art documents:
the structure confirmation data 1H NMR and 13C NMR of the compounds 8 to 9 are referred to the following documents: structural and Structural analysis of composition to the bit off-step of cargos (Daucus carota L.) and carrot pure. J.Agric Food Chem, 2003, 51(13), 3865-3873
The structure confirmation data 1H NMR and 13C NMR of the compounds 10 to 11 are referred to the following documents: structural determination of binary octylenes in Carrots (Daucus carota L.) and Enantioselective Synthesis of Falcarindiol, journal of Agricultural & food chemistry, 2009, 57 (22): 11030-11040
Example 3
This example provides methods for the extraction and characterization of compounds 12-14 from the active ingredient.
The ethanol, ethyl acetate, petroleum ether and methanol used in this example were all commercially available products.
Crushing 100kg of coreopsis tinctoria, soaking and extracting with 15 times volume of 70% ethanol aqueous solution at room temperature, and concentrating under reduced pressure to remove organic solvent to obtain concentrate. Extracting the concentrate with 1 volume of ethyl acetate for 3 times, mixing ethyl acetate layers, and concentrating under reduced pressure to remove organic solvent to obtain ethyl acetate extract. The ethyl acetate extract was subjected to ODS reverse phase silica gel column chromatography (column diameter: 6 cm. times. height: 60cm, column volume: 1.7L), and gradient elution was carried out using methanol-water solution as a mobile phase according to the following procedure: the volume fractions of methanol were 10%, 30%, 45%, 60%, 80%, 90%, and 100%, respectively, and the mobile phases were eluted at 1ml/min to give 6 fractions Fr.A-F.
Wherein, Fr.B is separated by silica gel column chromatography, gradient elution is carried out by using mixed solution of ethyl acetate and ethanol with the volume ratio of 30:1-7:3 to obtain 5 fractions (Fr.B1-5), Fr.B2 is subjected to gel column chromatography and elution is carried out by using methanol-water solution with the volume fraction of 20-80% to obtain the compound 12.
And Fr.D is subjected to silica gel column chromatography, and is eluted by 3BV respectively by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 100:0, 50:1, 20:1, 10:1, 5:1 and 1:1 and an ethanol aqueous solution with the volume fraction of 95 percent to obtain 7 fractions Fr.D 1-7. Wherein Fr D2 is separated by ODS preparative chromatography, and eluted with 70% methanol-water solution by volume fraction to obtain compound 13.
And Fr.E is subjected to silica gel column chromatography, and is eluted by 3BV respectively by using a mixed solution of petroleum ether and ethyl acetate in the volume ratio of 100:0, 20:1, 5:1 and 1:1 and an ethanol water solution with the volume fraction of 95 percent to obtain 5 fractions Fr.E1-5. Wherein Fr E3 is separated by ODS preparative chromatography, and eluted with 75% methanol-water solution by volume fraction to obtain compound 14.
The isolated fractions were identified by nmr spectroscopy and the structure of the compounds was determined by comparison with data from the following prior art documents:
the structure confirmation data 1H NMR and 13C NMR of compound 12 are referenced in the following documents: zhang Y, Shi S, ZhaoM, et al Coreosides A-D, C14-polyacetylene glycosides from the capitula of Coreosides activity against peptides COX-2 [ J ] Fitoterapia,2013,87(1):93-97.
The structure confirmation data 1H NMR and 13C NMR of the compounds 13 to 14 are referred to the following documents: bohlmann F, born owski h.
phenolisch substituierte natürliche Acetylenverbindungen[J].European Journal of Inorganic Chemistry,1966,99(4):1223-1225.
Example 4
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing benzbromarone and a compound 1 in a weight ratio of 3: 5. Compound 1 used in this example was atractylodin available from shanghai-derived leaf biotechnology limited, and the structural formula of compound 1 is as follows:
as an alternative to this example, compound 1 can be replaced by one of compounds 2-15 and benzbromarone can be replaced by resinide.
Example 5
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing benzbromarone and a compound 2 in a weight ratio of 4: 15. Compound 2 used in this example was cis-atractyloin available from sutchu gaken biotechnology, ltd, and the structural formula of compound 2 is as follows:
as an alternative mode of the embodiment, the compound 2 can be replaced by one of the compound 1 and the compounds 3 to 15, and the benzbromarone can be replaced by Racinadine.
Example 6
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing benzbromarone and a compound 3 in a weight ratio of 1: 5. Compound 3 used in this example was acetoatractylon available from seoul proconchonem biotechnology limited, and the structural formula of compound 3 is as follows:
as an alternative mode of the embodiment, the compound 3 can be replaced by one of the compounds 1-2 and the compounds 4-15, and the benzbromarone can be replaced by Racinidide.
Example 7
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing benzbromarone and a compound 5 in a weight ratio of 1: 10. Compound 5 used in this example was prepared according to example 1, the structural formula of compound 5 being as follows:
as an alternative mode of the embodiment, the compound 5 can be replaced by one of the compounds 1-4 and the compounds 6-15, and the benzbromarone can be replaced by Racinidide.
Example 8
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing 8:5 parts by weight of benzbromarone and 6. Compound 6 used in this example was prepared according to example 1, the structural formula of compound 6 being as follows:
as an alternative mode of the embodiment, the compound 6 can be replaced by one of the compounds 1-5 and the compounds 7-15, and the benzbromarone can be replaced by Racinidide.
Example 9
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing benzbromarone and a compound 7 in a weight ratio of 8: 15. Compound 7 used in this example was prepared according to example 1, the structural formula of compound 7 being as follows:
as an alternative mode of the embodiment, the compound 7 can be replaced by one of the compounds 1-6 and the compounds 8-15, and the benzbromarone can be replaced by Racinidide.
Example 10
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing 2:3 parts by weight of Racinonide and a compound 8. Compound 8 used in this example was prepared according to example 2, the structural formula of compound 8 being as follows:
as an alternative mode of the embodiment, the compound 8 can be replaced by one of the compounds 1-7 and the compounds 9-15, and the Raschiandride can be replaced by benzbromarone.
Example 11
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing 2:1 parts by weight of Racinonide and a compound 9. Compound 9 used in this example was prepared according to example 2, the structural formula of compound 9 being as follows:
as an alternative mode of the embodiment, the compound 9 can be replaced by one of the compounds 1-8 and the compounds 10-15, and the Raschiandride can be replaced by benzbromarone.
Example 12
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing Racinonide and a compound 12 in a weight ratio of 1: 3. Compound 12 used in this example was prepared according to example 3, the structural formula of compound 12 being as follows:
as an alternative mode of the embodiment, the compound 12 can be replaced by one of the compounds 1 to 11 and the compounds 13 to 15, and the Raschiandride can be replaced by benzbromarone.
Example 13
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing Racinonide and a compound 13 in a weight ratio of 6: 1. Compound 13 used in this example was prepared according to example 3, the structural formula of compound 13 being as follows:
as an alternative mode of the embodiment, the compound 13 can be replaced by one of the compounds 1-12 and the compounds 14-15, and the Raschiandride can be replaced by benzbromarone.
Example 14
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing 2:1 parts by weight of Racinonide and a compound 14. Compound 14 used in this example was prepared according to example 3, the structural formula of compound 14 being as follows:
as an alternative mode of the embodiment, the compound 14 can be replaced by one of the compounds 1-13 and the compound 15, and the Racemado can be replaced by benzbromarone.
Example 15
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing Racinonide and a compound 15 in a weight ratio of 1: 1. The compound 15 used in this example was an lobetyolin available from shanghai source, phyllo biotechnology limited, the structural formula of compound 15 being as follows:
as an alternative to this example, compound 15 can be replaced with one of compounds 1-14 and the rasidone can be replaced with benzbromarone.
Example 16
The present example provides a pharmaceutical tablet for treating hyperuricemia.
[ prescription ]
Weighing the hyperuricemia pharmaceutical composition, hydroxypropyl cellulose, starch, lactose and povidone according to the prescription amount, mixing, sieving with a 60-mesh sieve for three times, and uniformly mixing; adding appropriate amount of 10% starch slurry, making into soft material, sieving with 24 mesh sieve, granulating, drying, adding silica gel micropowder and magnesium stearate, mixing, granulating, tabletting, and coating.
Example 17
The embodiment provides a capsule of a medicine for treating hyperuricemia.
[ prescription ]
Weighing the hyperuricemia pharmaceutical composition, lactose, polyvidone, microcrystalline cellulose and sodium carboxymethyl starch according to the prescription amount, respectively sieving with a 100-mesh sieve, and uniformly mixing; adding appropriate amount of hypromellose solution, making into soft mass, sieving with 24 mesh sieve, granulating, drying in oven at 50-60 deg.C for 2-3 hr, adding silica gel micropowder and magnesium stearate, mixing, grading, and making into capsule.
The pharmaceutical compositions of the present invention may be administered by any means known in the art by those skilled in the art, including, but not limited to, oral, nasal, parenteral, topical, transdermal or rectal routes of administration. The pharmaceutical composition of the present invention is preferably suitable for oral or topical administration, for example, tablets, capsules (including hard capsules, soft capsules), pills, solutions, powders or granules, suspensions, patches and the like, and the drug of the present invention can be prepared into corresponding dosage forms using methods well known in the art.
As an alternative implementation manner of this embodiment, the pharmaceutical excipients such as microcrystalline cellulose can be replaced by other commonly used excipients, and the "conventional excipient" in the present invention refers to a pharmaceutically acceptable material, composition or vehicle, such as liquid or solid filler, diluent, excipient (such as cocoa butter and suppository wax), solvent or packaging material. The pharmaceutically acceptable carrier is compatible with the other ingredients of the composition, with the mode of administration, and is not injurious to the patient. The pharmaceutically acceptable carrier may be aqueous or non-aqueous. Conventional adjuvants include gums, such as gelatin; starches, such as corn starch, potato starch; sugars such as lactose, glucose and sucrose; cellulosic materials and mixtures thereof, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate. Materials that may be used as pharmaceutically acceptable carriers include, but are not limited to, powdered tragacanth, malt, talc, oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, and the like), alcohols (such as propylene glycol, ethanol, glycerol, sorbitol, mannitol, polyethylene glycol, and the like), esters (such as ethyl oleate, ethyl laurate, agar), buffers (such as magnesium hydroxide, aluminum hydroxide, boric acid and sodium borate, and phosphate buffers), alginic acid, pyrogen-free water, isotonic saline, ringer's solution.
Examples of the experiments
Benzbromarone, rexinader, analytically pure absolute ethyl alcohol, chloroform, methanol, ethyl acetate, distilled water, dimethyl sulfoxide, potassium dihydrogen phosphate and dipotassium hydrogen phosphate used in the experimental example are all commercial products; the apparatus used includes Buchi medium pressure preparation of liquid phase, Ika stirrer, Buchi vacuum rotary evaporator, vortex oscillator, water bath, Biofuge Primo R multipurpose desk top high speed centrifuge, Mettlere 240 electronic balance, Beckman Coulter AU480 biochemical analyzer.
Compounds 1 and 15 used in this example were obtained from Shanghai-derived leaf Biotech Co., Ltd; compounds 2, 3 were purchased from suzhou he bio-technology ltd; the remaining compounds were isolated from the corresponding plants according to examples 1-3 (HPLC > 98%).
Test animals and groups: taking healthy male KM mice with the weight of 15-18g, which is provided by Beijing Wittiulihua biotechnology limited; after 5 cages of the composition are treated in different cages, the composition is bred adaptively for 4 days in a barrier system of Kaixian Biotechnology Limited, Suzhou, and then the composition is randomly grouped according to the weight, wherein 10 animals in each group are respectively a blank control group (blank group for short), a hyperuricemia model group (model group for short), a positive control group (benzbromarone control group or Raxinard control group), a compound control group and a tested composition group (tested combination for short).
Modeling of hyperuricemia:
firstly, preparing a gastric lavage drug, and suspending benzbromarone or resinide by using 0.5% sodium carboxymethylcellulose (CMC-Na) solution in a positive control group; suspending compound 1-15 with 0.5% sodium carboxymethylcellulose (CMC-Na) solution; test composition groups a set dose of the pharmaceutical composition was suspended with 0.5% sodium carboxymethylcellulose (CMC-Na) solution, respectively. Immediately performing intragastric administration on the mice after the adaptation period of the mice, performing intragastric administration for 1 time in the morning every day, and continuously performing intragastric administration for 7 days, wherein a blank control group and a hyperuricemia model group are both subjected to intragastric administration by using 0.5% CMC-Na for control; performing intraperitoneal injection molding on the mice 0.5 hour after gavage in the morning on the 7 th day, wherein a blank control group is injected with 0.5% sodium carboxymethylcellulose (CMC-Na) solution in the abdominal cavity; hyperuricemia model group, positive control group, compound control group and test composition group were injected with oteracil potassium (OA) dissolved in CMC-Na solution, and the injection amount was 300mg/kg body weight.
Removing eyeballs of a mouse after 1.5 hours of intraperitoneal injection for blood sampling, wherein the blood sampling volume is not less than 0.5mL, placing the mouse at room temperature for 1 hour after the blood is collected, centrifuging the mouse at 3500rpm/4 ℃ for 10 minutes after the blood is completely coagulated, taking serum to re-separate for 5 minutes under the same condition, then taking 0.2mL serum, and detecting the levels of Uric Acid (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST) and Creatinine (CRE) in the serum by using a biochemical analyzer, wherein the alanine Aminotransferase (ALT), the aspartate Aminotransferase (AST) and the Creatinine (CRE) are used for representing toxic and side effects of the medicine, and the higher the content is, the larger the toxic and side effects are indicated.
And carrying out statistical analysis on the data by using Excel and SPSS, calculating the average number and SD, comparing the difference among the experimental groups after single-factor variance analysis, and obviously improving the serum uric acid level of mice in a hyperuricemia model group, a positive control group and a tested composition group compared with a blank control group, wherein the significant difference indicates that the molding is successful.
The dosages and test results of the used drugs and pharmaceutical compositions are shown in tables 1-30:
TABLE 1 Effect of Compound 1 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 2 Effect of Compound 1 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 3 Effect of Compound 2 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 4 Effect of Compound 2 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 5 Effect of Compound 3 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 6 Effect of Compound 3 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 7 Effect of Compound 4 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 8 Effect of Compound 4 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 9 Effect of Compound 5 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 10 Effect of Compound 5 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 11 Effect of Compound 6 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 12 Effect of Compound 6 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 13 Effect of Compound 7 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 14 Effect of Compound 7 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 15 Effect of Compound 8 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 16 Effect of Compound 8 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 17 Effect of Compound 9 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 18 Effect of Compound 9 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 19 Effect of Compound 10 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 20 Effect of Compound 10 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 21 Effect of Compound 11 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 22 Effect of Compound 11 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 23 Effect of Compound 12 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 24 Effect of Compound 12 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 25 Effect of Compound 13 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 26 Effect of Compound 13 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 27 Effect of Compound 14 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 28 Effect of Compound 14 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 29 Effect of Compound 15 and its combination with benzbromarone on the blood uric acid level (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
TABLE 30 Effect of Compound 15 and its combination with Racinadine on blood uric acid levels (UA), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Creatinine (CRE) in hyperuricemia mice
(a represents that P <0.05 compared with the blank group, b represents that P <0.01 compared with the blank group, c represents that P <0.05 compared with the hyperuricemia model group, d represents that P <0.01 compared with the hyperuricemia model group, e represents that P <0.05 compared with the corresponding dose compound control group, f represents that P <0.01 compared with the corresponding dose compound control group, # represents that P <0.05 compared with the positive control group 1, # represents that P <0.01 compared with the positive control group 1, # represents that P <0.05 compared with the positive control group 2, and # represents that P <0.01 compared with the positive control group 2).
From the above table results it follows:
1. the compound can obviously reduce the serum uric acid level of a hyperuricemia mouse, has statistical significance compared with a hyperuricemia model group, and can be used as a potential uric acid reduction medicine for treating hyperuricemia.
2. The low-dose benzbromarone/or rexinder is combined with the compound and then used, shows stronger effect of reducing uric acid under various dosage proportions, and has statistical significance compared with a hyperuricemia model group.
3. The compound disclosed by the invention is combined with low-dose benzbromarone or rexinder for use, shows stronger uric acid reducing effect than that of the compound used alone under a corresponding dose, and has statistical significance.
4. Compared with the corresponding positive control group 1, the effect of reducing uric acid after combined use of the test combination group 1 is better than that of the corresponding positive control group 1 (benzbromarone or rasidone), and the values of ALT, AST and CRE in each test combination group 1 are obviously lower than those of the corresponding positive control group 1, so that the test combination group 1 has statistical significance.
5. Compared with the corresponding positive control group 2, the effect of reducing uric acid after combined use of the tested combination group 2 is better than that of the corresponding positive control group 2 (benzbromarone or rasidone), and the values of ALT, AST and CRE in each tested combination group 2 are obviously lower than those of the corresponding positive control group 2, so that the statistical significance is achieved.
In conclusion, when the benzbromarone/or the rexinder is used in combination with the compound disclosed by the invention in a reduced dose, the same or better uric acid reduction effect of the benzbromarone/or the rexinder in a conventional dose can be obtained, but in terms of safety, when the benzbromarone/or the rexinder in a low dose is used in combination with the compound, the increase of CRE, ALT and AST caused by the benzbromarone/or the rexinder can be remarkably reduced, the toxic and side effects are further reduced, and the safety is higher than that of the benzbromarone/or the rexinder in a conventional dose when the benzbromarone/or the rexinder is used alone.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (10)
1. Application of a polyacetylene compound with a structure shown as a formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof in preparation of combined drugs for treating hyperuricemia.
2. A hyperuricemia pharmaceutical composition, comprising: an active ingredient having a synergistic effect with a hyperuricemia drug, and a hyperuricemia drug; wherein the hyperuricemia drug is a uric acid excretion promoting drug; the active ingredients are polyacetylene compounds with the structure shown in formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof:
wherein,
represents one selected from-, ═ or ≡ or;
R1selected from H, OH,
Unsubstituted or substituted C1-C4Alkyl, unsubstituted or substituted C1-C4An alkenyl group of,
One of (1), RaSelected from H, OCOCH3One of (1);
R2selected from H, OH, OCOCH3Or R is1、R2To form unsubstituted or substituted phenyl;
R3selected from H, OH,
Unsubstituted or substituted C1-C10Alkyl, unsubstituted or substituted C1-C10Alkenyl of (a);
R4selected from H, OH, unsubstituted or substituted by 1 to 3R4aSubstituted C1-C12Alkyl or alkenyl of, R4aSelected from OH, OCOCH3From
Forming monosaccharide or disaccharide residues.
3. The hyperuricemia pharmaceutical composition according to claim 2, wherein the active ingredient has a structure as shown below:
4. the hyperuricemia pharmaceutical composition of claim 2 or 3, wherein the hyperuricemia drug is one of benzbromarone or rexinader.
5. The hyperuricemia pharmaceutical composition according to any one of claims 2 to 4, wherein the mass of the active ingredient is 14% to 91% of the sum of the mass of the active ingredient and the hyperuricemia drug.
6. The hyperuricemia pharmaceutical composition according to any one of claims 2 to 5, further comprising a pharmaceutically acceptable carrier.
7. A medicine for treating hyperuricemia, which is characterized by comprising the hyperuricemia pharmaceutical composition as claimed in any one of claims 2 to 6, wherein the medicine is prepared by adding conventional auxiliary materials into the hyperuricemia pharmaceutical composition and preparing clinically acceptable tablets, capsules, pills, granules, paste, mixtures or suspensions according to a conventional process.
8. Use of the pharmaceutical composition for hyperuricemia according to any one of claims 2 to 6 in preparation of a drug or health product for hyperuricemia.
9. The use of the pharmaceutical composition for hyperuricemia according to claim 8, wherein the hyperuricemia comprises gout or gout complications caused by hyperuricemia.
10. Use of the hyperuricemia pharmaceutical composition according to claim 8 or 9, for preparing a hyperuricemia drug and a health product, wherein the gout comprises acute gout or chronic gout; the gout complications comprise gouty arthritis, gout attack, gouty nephropathy or uric acid renal calculus.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111714486A (en) * | 2019-03-20 | 2020-09-29 | 苏州凯祥生物科技有限公司 | New application of polyacetylene compound |
| WO2021204192A1 (en) * | 2020-04-08 | 2021-10-14 | 苏州凯祥生物科技有限公司 | Use of compound as sirt1 receptor agonist |
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| CN111714486B (en) * | 2019-03-20 | 2023-06-20 | 苏州凯祥生物科技有限公司 | Application of polyacetylene compound |
| WO2021204192A1 (en) * | 2020-04-08 | 2021-10-14 | 苏州凯祥生物科技有限公司 | Use of compound as sirt1 receptor agonist |
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