CN109893521B - Application of polyacetylene compounds in reducing uric acid - Google Patents
Application of polyacetylene compounds in reducing uric acid Download PDFInfo
- Publication number
- CN109893521B CN109893521B CN201711284363.2A CN201711284363A CN109893521B CN 109893521 B CN109893521 B CN 109893521B CN 201711284363 A CN201711284363 A CN 201711284363A CN 109893521 B CN109893521 B CN 109893521B
- Authority
- CN
- China
- Prior art keywords
- uric acid
- compound
- nmr
- formula
- polyacetylene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention belongs to the field of medicines, and particularly relates to application of a polyacetylene compound in reducing uric acid. The polyacetylene compound has a structure shown in a formula (I):
R1and R2As defined in the description of the invention. The invention discovers that the polyacetylene compound has a remarkable uric acid reducing effect in vivo through a hyperuricemia animal model, and can be used as a potential medicament for reducing uric acid or treating gout.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of a polyacetylene compound in reducing uric acid.
Background
Uric acid is the final metabolite of human purine compounds, and purine metabolic disorders 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). Gout is crystal-related arthropathy caused by deposition of monosodium urate (MSU), is directly related to hyperuricemia caused by purine metabolic disorder and/or reduction of uric acid excretion, and is clinically mainly manifested by hyperuricemia, repeated attack of gouty acute arthritis, gouty chronic arthritis, tophus, gouty nephropathy, renal urate calculi and the like, and serious patients can have joint disability and renal insufficiency. In addition, gout is often associated with abdominal obesity, hyperlipidemia, hypertension, type ii diabetes, and cardiovascular diseases. Gout has become the second largest metabolic disease after diabetes, seriously harming human life and health. According to the 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%; the number of gout people in China is estimated to reach 1 hundred million by 2020.
At present, hyperuricemia, gout and gout complications are treated mainly by controlling uric acid in blood, and the action mechanisms of the traditional Chinese medicine mainly comprise the following two mechanisms: (1) the formation of uric acid is effectively inhibited by inhibiting the activity of Xanthine Oxidase (XO), and representative drugs comprise allopurinol, febuxostat and the like; (2) promoting the excretion of uric acid, and typical drugs include probenecid, benzbromarone, and the like. However, the toxic side effects of all of the above drugs are generally large, such as: allopurinol can cause severe toxic and side effects such as allergic reaction (the morbidity is 10-15%), hypersensitivity syndrome, bone marrow suppression and the like; probenecid and benzbromarone have the side effects of stimulating gastrointestinal tracts, causing renal colic, exciting gout acute attack and the like; febuxostat can increase the risk of cardiovascular system diseases, and Stevens-Johnson syndrome can occur in severe cases; moreover, the tolerance of the above drugs is generally low. In conclusion, these problems limit the clinical application of these drugs to some extent. Therefore, the research on novel medicines for treating gout is of great significance.
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 related research on chain polyacetylenes and thiophene ring polyacetylenes has made a certain progress. Chain polyacetylenes generally have the following physiological activities: antifungal, sensitizing, antitumor, etc.; the pharmacological actions of the thiophene cyclopolyynes are currently mainly focused on antimicrobial activity.
In the prior art, although documents are reported: certain chain polyacetylene compounds have a certain inhibition effect on Xanthine Oxidase (XO) in vitro, but are easy to metabolize in vivo, so that the Xanthine Oxidase (XO) in vivo has a weak inhibition effect, and therefore, the chain polyacetylene compounds cannot be used as potential drugs for reducing uric acid or treating gout.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is that the existing polyacetylene compound has a certain inhibition effect on Xanthine Oxidase (XO) in vitro and has a weak inhibition effect on Xanthine Oxidase (XO) in vivo, so that the polyacetylene compound can be used for reducing uric acid.
In order to solve the technical problems, the invention is realized by the following technical scheme:
in a first aspect, the invention provides application of a polyacetylene compound shown as a formula (I) and pharmaceutically acceptable salts, esters, prodrugs or solvates thereof in preparing a medicament with a uric acid reducing effect,
wherein R is1Selected from unsubstituted or 1 to 3R1aSubstituted C1-C12Alkyl group of (A) or (B),
R2Selected from unsubstituted or 1 to 3R2aSubstituted C1-C12Alkoxy of (a), unsubstituted or 1 to 3R2aSubstituted C1-C12Unsubstituted or 1 to 7R2bSubstituted aryl, unsubstituted or 1 to 6R2cSubstituted heteroaryl, and their use as herbicides,
R1aIs selected from-OCOCH3、C1-C6An alkenyl group of,
R2aSelected from-OH and-OCH3、
R2bIs selected from C1-C6Alkyl, hydroxy-substituted C of1-C6Alkyl of (2), 1 to 3 halogen-substituted C1-C6Alkyl, -OH, C1-C6Alkoxy, -CN, halogen, -NH21 to 2C1-C6Alkyl-substituted amino groups of (a);
R2cis selected from
R3Selected from unsubstituted or 1 to 3R3aSubstituted C1-C12Unsubstituted or 1 to 7R3bSubstituted aryl, unsubstituted or 1 to 6R3cSubstituted heteroaryl, and their use as herbicides,
R3aIs selected from
R3bSelected from-OH and-OCH3；
R3cIs selected from C1-C6Alkyl, hydroxy-substituted C of1-C6Alkyl of (2), 1 to 3 halogen-substituted C1-C6Alkyl, -OH, C1-C6Alkoxy of (a)CN, halogen, -NH21 to 2C1-C6Alkyl-substituted amino groups of (a);
R4is selected from-H and-OH.
The terms in the claims and the specification of the present invention have the following meanings unless otherwise specified.
Alkyl refers to: fully saturated straight or branched chain hydrocarbon radicals. For example: alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
Alkenyl means: a linear or branched hydrocarbon group containing at least one ethylenic bond. For example: alkenyl groups include, but are not limited to, vinyl, allyl, and the like.
Aryl means: a monocyclic or fused bicyclic aromatic ring system containing 6 to 10 ring carbon atoms. For example: aryl can be phenyl, naphthyl.
Heteroaryl is as defined above for aryl, wherein one or more ring members are heteroatoms. E.g. C5-10Heteroaryl groups have a minimum of 5 members as indicated by their carbon atoms, but these carbon atoms may be replaced by heteroatoms. Thus, C5-10Heteroaryl groups include pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo [1,3 ]]Dioxoles, imidazolyl, benzimidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, and the like.
Preferably, the application of the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof in preparing the medicine with the effect of reducing uric acid,
R1selected from unsubstituted or 1 to 3R1aSubstituted C1-C3Alkyl group of (A) or (B),
R1aIs selected from-OCOCH3、C1-C4An alkenyl group of,
R2Is selected from-OCH3、-CH3、-CH2OH、-CHO、-COOH、
R3Is selected from
-CH3、
-COOH。
Further preferably, the application of the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof in preparing the medicine with the effect of reducing uric acid is that the polyacetylene compound shown in the formula (I) is selected from:
further preferably, the application of the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof in preparing the medicine with the effect of reducing uric acid is that the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof are added with conventional auxiliary materials according to the conventional process to prepare clinically acceptable tablets, capsules, powder, mixtures, pills, granules, syrups, emplastrum, suppositories, aerosols, ointments or injections.
In a second aspect, the invention provides application of a polyacetylene compound shown as a formula (I) and pharmaceutically acceptable salts, esters, prodrugs or solvates thereof in preparing a medicine for treating gout,
wherein R is1Selected from unsubstituted or 1 to 3R1aSubstituted C1-C12Alkyl group of (A) or (B),
R2Selected from unsubstituted or 1 to 3R2aSubstituted C1-C12Alkoxy of (a), unsubstituted or 1 to 3R2aSubstituted C1-C12Unsubstituted or 1 to 7R2bSubstituted aryl, unsubstituted or 1 to 6R2cSubstituted heteroaryl, and their use as herbicides,
R1aIs selected from-OCOCH3、C1-C6An alkenyl group of,
R2aSelected from-OH and-OCH3、
R2bIs selected from C1-C6Alkyl, hydroxy-substituted C of1-C6Alkyl of (2), 1 to 3 halogen-substituted C1-C6Alkyl, -OH, C1-C6Alkoxy, -CN, halogen, -NH21 to 2C1-C6Alkyl-substituted amino groups of (a);
R2cis selected from
R3Selected from unsubstituted or 1 to 3R3aSubstituted C1-C12Unsubstituted or 1 to 7R3bSubstituted aryl, unsubstituted or 1 to 6R3cSubstituted heteroaryl, and their use as herbicides,
R3aIs selected from
R3bSelected from-OH and-OCH3；
R3cIs selected from C1-C6Alkyl, hydroxy-substituted C of1-C6Alkyl of (2), 1 to 3 halogen-substituted C1-C6Alkyl, -OH, C1-C6Alkoxy, -CN, halogen, -NH21 to 2C1-C6Alkyl-substituted amino groups of (a);
R4is selected from-H and-OH.
Preferably, the application of the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof in preparing the medicines for treating gout,
R1selected from unsubstituted or 1 to 3R1aSubstituted C1-C3Alkyl group of (A) or (B),
R1aIs selected from-OCOCH3、C1-C4An alkenyl group of,
R2Is selected from-OCH3、-CH3、-CH2OH、-CHO、-COOH、
R3Is selected from
-CH3、
-COOH。
Further preferably, the application of the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof in preparing the medicine for treating gout is that the polyacetylene compound shown in the formula (I) is selected from:
further preferably, the application of the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof in preparing the medicines for treating gout is that the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof are added with conventional auxiliary materials according to the conventional process to prepare clinically acceptable tablets, capsules, powder, mixture, pills, granules, syrup, emplastrum, suppositories, aerosols, ointments or injections.
The conventional auxiliary materials are as follows: fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, bases, and the like. The filler comprises: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc.; the disintegrating agent comprises: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, cross-linked sodium carboxymethyl cellulose, etc.; the lubricant comprises: magnesium stearate, sodium lauryl sulfate, talc, silica, and the like; the suspending agent comprises: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, and the like; the adhesive comprises starch slurry, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.; the sweetener comprises: saccharin sodium, aspartame, sucrose, sodium cyclamate, glycyrrhetinic acid, and the like; the flavoring agent comprises: sweeteners and various essences; the preservative comprises: parabens, benzoic acid, sodium benzoate, sorbic acid and its salts, benzalkonium bromide, chloroacetidine acetate, eucalyptus oil, etc.; the matrix comprises: PEG6000, PEG4000, insect wax, etc.
The technical scheme of the invention has the following advantages:
the invention discovers that the polyacetylene compound has a remarkable uric acid reducing effect in vivo through a hyperuricemia animal model, and can be used as a potential medicament for reducing uric acid or treating gout.
Detailed Description
In the following examples and experimental examples of the present invention, the polyacetylene compounds can be prepared according to the methods of the examples of the present invention, and can also be prepared according to the methods of the prior art documents.
The concentration of ethanol/methanol is the volume concentration.
Atractylodin and
(Compound 14) is a commercially available product.
Xanthine, xanthine oxidase, allopurinol, analytically pure absolute ethanol, chloroform, methanol, ethyl acetate, distilled water, dimethyl sulfoxide, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate are all commercially available products.
The apparatus used in the invention comprises a Buchi medium pressure preparation liquid phase, an Ika stirrer, a Buchi vacuum rotary evaporator, a vortex oscillator, a water bath kettle, a Biofuge Primo R multipurpose table type high-speed centrifuge, a Mettlere 240 electronic balance and a Beckman Coulter AU480 biochemical analyzer.
Example 1Preparation of Compounds 1-6
The specific operation steps are as follows:
taking 100kg of rhizoma atractylodis medicinal decoction pieces, adding 70% ethanol water 10 times the volume of the rhizoma atractylodis medicinal decoction pieces, extracting at 80 ℃ for 3 times, extracting for 1.5h each time, filtering to remove residues, and concentrating under reduced pressure to 100L, wherein the solid content is about 15kg, thus obtaining concentrated solution A.
Separating the concentrated solution A with a low-pressure D101 column (the column diameter is 28cm, the column height is 162cm, and the column volume is 100L), performing gradient elution with ethanol water solution (firstly, eluting with 30% ethanol water solution for 4BV, and then eluting with 95% ethanol water solution for 4BV), collecting 95% ethanol water solution eluent, and concentrating to solid content of about 3kg to obtain concentrated solution B.
Separating the concentrated solution B by an LX-20SS column (the column diameter is 20cm, the height is 78cm, the column volume is 25L), performing gradient elution by using an ethanol water solution (firstly, 70% ethanol water solution is used for eluting 3BV, then 80% ethanol water solution is used for eluting 3BV, and then 95% ethanol water solution is used for eluting 4BV), collecting eluent of 95% ethanol water solution, and concentrating to obtain the concentrated solution C with the solid content of about 1 kg.
Separating the concentrated solution C with silica gel column (diameter of column 11cm × height 65cm, column volume 6L), gradient eluting with petroleum ether/ethyl acetate (petroleum ether/ethyl acetate 100: 0 for 3BV, petroleum ether/ethyl acetate 50:1 for 3BV, petroleum ether/ethyl acetate 20:1 for 3BV, petroleum ether/ethyl acetate 10:1 for 3BV, petroleum ether/ethyl acetate 5:1 for 3BV, petroleum ether/ethyl acetate 1:1 for 3BV, and 95% ethanol water solution for 3BV), collecting eluates of the above mobile phases for 2L, preliminarily dividing into 7 eluates (numbered FrA-G), collecting 9 bottles for each eluates (numbered for each elution position according to 1-9 such as Fr A1-9 Fr, respectively), Fr B1-9, etc.).
FrA4 by ODS preparative chromatography using 75% methanol aqueous solution to obtain Compound 1. 0.6g of the compound prepared above was separately prepared by1H-NMR、13Structural confirmation by C-NMR and HPLC-MS, by comparison with that in the existing literature (A new 9-nor-amyloidodes from amyloidodes lancea, and the antibiotic activity of the amyloidodes derivatives, Fitoteappaia, 2012, 83(1), 199-1H-NMR、13C-NMR and HPLC-MS are respectively compared, and the prepared compound is the compound 1.
FrA6 the compound is obtained by separating with 75% methanol aqueous solution by ODS preparative chromatography. Respectively passing the compounds prepared above through1H-NMR、13The structure is confirmed by C-NMR and HPLC-MS, and the structural confirmation is carried out by comparing the structure with that in the prior literature (research on chemical components of atractylodes rhizome polyacetylene, novel traditional Chinese medicine and clinical pharmacology, 2015, 4, 525 and 528.)1H-NMR、13C-NMR and HPLC-MS are respectively compared, and the prepared compound is a compound 2.
FrD9 it was separated by ODS preparative chromatography using 70% aqueous methanol to give two compounds. The two compounds prepared by the method are respectively passed through1H-NMR、13Structural confirmation by C-NMR and HPLC-MS, by comparison with that in the existing literature (fuse phenols and polyacetylenes from the microorganisms of the spectra and anti-inflammatory activity. plant medicine, 2001, 67(5), 437-442.)1H-NMR、13C-NMR and HPLC-MS are respectively compared, and the prepared compounds are the compounds 3 and 4.
FrG2 was separated by ODS preparative chromatography using 20% aqueous methanol to give two compounds. The two compounds prepared by the method are respectively passed through1H-NMR、13Structural confirmation by C-NMR and HPLC-MS was carried out by comparison with the existing literature (literature 1: Glycosides of Atractylodes ovata&pharmaceutical bulletin, 2003, 51(9), 1106 and 1108, document 2: glycosides of Atractylodes lancea chemical&pharmaceutMedical bulletin, 2003, 51(6), 673-1H-NMR、13C-NMR and HPLC-MS are compared respectively, and the prepared compounds are the compounds 5 and 6.
Example 2Preparation of Compounds 7-12
The synthetic route is as follows:
the reaction conditions are specifically as follows:
a：SeO21, 4-dioxane, 90 ℃;
b：(1)Ag2O,H2O/NaOH(40％)，0℃；(2)HCl(36％)，pH＝5，r.t.；
c: benzoic acid, DCC, DMAP, CH2Cl2，r.t.；
d: 4-methylbenzoic acid, DCC, DMAP, CH2Cl2，r.t.；
e：HCHO，AlCl3，HCl，CH2Cl2；
f：CH3COOCH3，HCl/AcOH(10％)，r.t..
The specific operation steps are as follows:
dissolving 10g of atractylodin in 30mL of 1, 4-dioxane, and adding 0.6g of SeO into the solution2The reaction solution is stirred and reacted for 8 hours at 90 ℃, then the reaction solution is filtered by a 45 mu M microporous filter, and then is separated and purified by silica gel column chromatography by using petroleum ether-ethyl acetate as a mobile phase with the volume ratio of 20: 1-5: 1, so as to respectively obtain 0.6g of a compound (yield: 6%) and 4g of an intermediate product M-xanthinol (yield: 42%).0.6g of the compound prepared above was separately prepared by1H-NMR、13Structural confirmation by C-NMR and HPLC-MS, by comparison with that in the existing literature (A new 9-nor-amyloidodes from amyloidodes lancea, and the antibiotic activity of the amyloidodes derivatives, Fitoteappaia, 2012, 83(1), 199-1H-NMR、13C-NMR and HPLC-MS are respectively compared, and the prepared compound is a compound 7.
0.3g of silver oxide was dissolved in 30mL of water and 20mL of 10% aqueous sodium hydroxide solution, the suspension was stirred vigorously and 200mg of the intermediate M-xanthinol were added in portions over 30 minutes, the temperature of the reaction mixture being kept below 30 ℃ during the addition and stirring continued for 1h after the addition. After the reaction was completed, the colloidal silver was filtered and washed with water, the filtrate was acidified with concentrated hydrochloric acid, and the precipitate was collected and washed with water to obtain 0.2g of a compound (yield 90%). Respectively passing the compounds prepared above through1H-NMR、13Structural confirmation by C-NMR and HPLC-MS, by comparison with that in the existing literature (A new 9-nor-amyloidodes from amyloidodes lancea, and the antibiotic activity of the amyloidodes derivatives, Fitoteappaia, 2012, 83(1), 199-1H-NMR、13C-NMR and HPLC-MS are respectively compared, and the prepared compound is a compound 8.
1g of benzoic acid is dissolved in 120mL of anhydrous dichloromethane, and the obtained solution is added into 15mg of 4-dimethylaminopyridine DMAP and 150mg of dicyclohexylcarbodiimide DCC, stirred and mixed for 15 minutes at room temperature, then 0.8g of intermediate product M-xanthinol is added, and stirred and reacted for 4 hours. The reaction solution was filtered through a 45 μ M microporous filter, and then separated and purified by silica gel column chromatography using petroleum ether-ethyl acetate as a mobile phase at a volume ratio of 10:1, to obtain 1g of the compound (yield 82%). Respectively passing the compounds prepared above through1H-NMR、13Structural confirmation by C-NMR and HPLC-MS, by comparison with that in the existing literature (Angle 9-nor-amyloidon from amyloidons lancea, and the antibiotic activity of the amyloidon derivatives, Fitoteappaia, 2012, 83(1), 199-1H-NMR、13C-NMRAnd comparing the compound with HPLC-MS respectively to obtain the compound 9.
Dissolving 1g of 4-methylbenzoic acid in 120mL of anhydrous dichloromethane, adding the obtained solution into 15mg of 4-dimethylaminopyridine DMAP and 150mg of dicyclohexylcarbodiimide DCC), stirring and uniformly mixing at room temperature for 15 minutes, adding 0.8g of intermediate product M-xanthinol, and stirring and reacting for 4 hours. The reaction solution was filtered through a 45 μ M microporous filter, and then separated and purified by silica gel column chromatography using petroleum ether-ethyl acetate as a mobile phase at a volume ratio of 10:1, to obtain 0.4g of the compound (yield 76%). Respectively passing the compounds prepared above through1H-NMR、13Structural confirmation by C-NMR and HPLC-MS, by comparison with that in the existing literature (A new 9-nor-amyloidodes from amyloidodes lancea, and the antibiotic activity of the amyloidodes derivatives, Fitoteappaia, 2012, 83(1), 199-1H-NMR、13C-NMR and HPLC-MS are respectively compared, and the prepared compound is the compound 10.
Into a three-necked flask, 0.5g of atractylodin, 50mg of formaldehyde and 30mL of chloroform CHCl were added3And 6.0mL of concentrated hydrochloric acid, heating the reaction solution at 65 ℃ for 5 hours, cooling to room temperature after the reaction is finished, pouring the reaction solution into water, and extracting with ethyl acetate to obtain an ethyl acetate organic layer extract. Sequentially extracting the ethyl acetate organic layer extract with water and saturated Na2CO3The aqueous solution and brine were washed, then dried over magnesium sulfate, filtered and concentrated in vacuo to give a concentrate. Separating and purifying the concentrated solution by silica gel column chromatography with petroleum ether-ethyl acetate as mobile phase at volume ratio of 20:1 to obtain 437mg (86% yield) of compound. Respectively passing the compounds prepared above through1H-NMR、13Structural confirmation by C-NMR and HPLC-MS, by comparison with that in the existing literature (A new 9-nor-amyloidodes from amyloidodes lancea, and the antibiotic activity of the amyloidodes derivatives, Fitoteappaia, 2012, 83(1), 199-1H-NMR、13C-NMR and HPLC-MS are compared respectively, and the prepared compound is the compound 11.
Adding 0.5g of atractylodin into 12mL of acetone, stirring at room temperature, and then stirring at N2Adding 1.5mL hydrochloric acid/acetic acid solution (HCl/AcOH, 10%, v/v) under protection, stirring the reaction solution at room temperature for about 9 hours, filtering, and concentrating the filtrate under reduced pressure to obtain concentrated solution. Separating and purifying the concentrated solution by silica gel column chromatography with petroleum ether-ethyl acetate as mobile phase at volume ratio of 20:1 to obtain 210mg (38% yield) of compound. Respectively passing the compounds prepared above through1H-NMR、13Structural confirmation by C-NMR and HPLC-MS, by comparison with that in the existing literature (A new 9-nor-amyloidodes from amyloidodes lancea, and the antibiotic activity of the amyloidodes derivatives, Fitoteappaia, 2012, 83(1), 199-1H-NMR、13C-NMR and HPLC-MS are respectively compared, and the prepared compound is the compound 12.
Example 3Preparation of Compound 13
The synthetic route is as follows:
the specific operation steps are as follows:
under the protection of nitrogen, the catalyst contains 2.0mol of 1-bromo-2-styrene and 0.02mol of PdCl2(PPh3)20.04mol of CuI and 1.5mol of Et3N in 0.2mol/L THF was stirred rapidly and a solution of 1.0mol 1, 4-bis (trimethylsilyl) -1, 3-diacetylene in 0.2mol/L THF was added at room temperature. After 1 hour of reaction, 100mL of saturated NH were used4The reaction was quenched with aqueous Cl and extracted with 3 × 50mL ethyl acetate to give an ethyl acetate organic layer extract. The ethyl acetate organic layer extract was washed with 50mL of saturated aqueous NaCl solution and then with Na2SO4Drying, and vacuum concentrating to obtain concentrated solution. Subjecting the concentrated solution to silica gel column chromatography with petroleum ether-acetic acidAnd (4) separating and purifying the ethyl ester serving as a mobile phase to obtain the ethyl ester.
Respectively passing the compounds prepared above through1H-NMR、13Structural confirmation by C-NMR and HPLC-MS, by comparison with that in the existing literature (A: direct corrected synthesis of systematic polydiendines by differentiation reactions of simple derivatives. journal of organic Chemistry, 1998, 566(1-2), 251-1H-NMR、13C-NMR and HPLC-MS are compared respectively, and the prepared compound is a compound 13.
Experimental example 1Research on uric acid reducing effect of compound of the invention
1. Experimental Material
200 healthy male KM mice, weighing 15-18g, were provided by Shanghai Ling Chang Biotech limited; after 5 cages of the strain were treated in separate cages, the strain was kept in a barrier system for 4 days.
2. Experimental methods
2.1 Experimental groups
180 mice with concentrated body weight are selected from 200 mice and are randomly and averagely divided into 180 groups according to the body weight, and each group comprises 10 mice, namely a blank control group, a model control group, a positive control group and an experimental group 1-15 groups.
2.2 methods of administration
After the adaptation period, the mice were administered by gavage for 7 days, with gavage being performed 1 time in the morning every day.
Experimental groups 1 to 14 were administered with 1 to 1330 mg/kg of the compound prepared in examples 1 to 3 and 1430 mg/kg of a commercially available compound, respectively, and experimental group 15 was administered with 30mg/kg of atractylodin, respectively, and suspended in a 0.5% sodium carboxymethylcellulose (CMC-Na) solution; febuxostat 1.0mg/kg is given to the positive control group, and the febuxostat is suspended by 0.5% sodium carboxymethylcellulose (CMC-Na) solution; both the blank control group and the model control group are subjected to intragastric perfusion by using 0.5% sodium carboxymethylcellulose (CMC-Na) solution; each group was administered by continuous gavage for 7 days.
After the administration by gavage for 0.5 hour on the 7 th morning, the mice of each group were subjected to abdominal injection for hyperuricemia modeling. Wherein the blank control group is administered with 0.5% sodium carboxymethylcellulose (CMC-Na) solution via intraperitoneal injection; 300mg/kg of Potassium Oxonate (OA) was injected into each of the model control group, the positive control group and the experimental groups 1 to 15, and dissolved in a CMC-Na solution.
3. Experimental data detection and processing
3.1 detection index
After 1.5 hours of hyperuricemia modeling, removing eyeballs from each group of mice to collect blood, wherein the blood collecting capacity is not lower than 0.5mL, placing the mice at room temperature for about 1 hour after blood collection, centrifuging the mice for 10 minutes at 3500rpm/4 ℃ after the blood is completely coagulated, taking serum to re-separate the mice for 5 minutes under the same condition, and then taking 0.2mL of serum to detect UA value through a biochemical analyzer.
3.2 statistical analysis
Statistical analysis of the data was performed using Excel and SPSS, mean and SD calculated, and differences between groups were compared after one-way anova.
4. Results of the experiment
The effect of each group on serum uric acid levels in hyperuricemic mice 7 days after administration is shown in table 1.
TABLE 1 Effect on the serum uric acid level in hyperuricemic mice
| Group of | Uric acid (mu mol/L) |
| Blank control group | 45.79 |
| Model control group | 155.31## |
| Positive control group | 11.60** |
| Experimental group 1 group | 61.73** |
| Experimental group 2 groups | 89.76** |
| Experimental group 3 groups | 68.91** |
| Experimental group 4 groups | 73.08** |
| Experimental group 5 groups | 81.25** |
| Experimental group 6 | 76.30** |
| Experimental group 7 groups | 63.61** |
| Experimental group 8 | 53.97** |
| Experimental group 9 | 72.44** |
| Experimental group 10 | 85.38** |
| Experimental group 11 groups | 105.23* |
| Experimental group 12Group of | 109.78* |
| Experimental group 13 groups | 87.33** |
| Experimental group 14 groups | 94.60** |
| Experimental group 15 | 129.75* |
Note:##indicates P in comparison with the blank control group<0.01；**Representation and comparison with model control group, P<0.01；
*Representation and comparison with model control group, P<0.05 (t-test)
As can be seen from Table 1: (1) compared with a blank control group, the serum of the mouse of the model control group has obviously increased uric acid (P <0.01), which indicates that the model building of the hyperuricemia model is successful;
(2) the reduction in serum uric acid levels in the mice of experimental groups 1-15 was significantly different (P <0.01 or P <0.05) compared to the model control group;
(3) the effect of reducing the serum uric acid level of the mice of the experimental groups 1 to 14 was superior to that of the mice of the experimental group 15.
5. Conclusion of the experiment
The polyacetylene compound has a remarkable uric acid reducing effect in vivo, and can be used as a potential uric acid reducing drug.
Experimental example 2Pharmacokinetic experiments
1. Purpose of experiment
The pharmacokinetic properties of the compounds of the invention were studied.
2. Experimental methods
2.1 Experimental animals and groups
180 healthy male SD rats with weight of 180-; after 5 cages of the strain are treated in different cages, the strain is adaptively raised in a barrier system of Kaixiang Biotechnology Co., Ltd, Suzhou for 5 days, 150 strains of the strain are selected from 180 strains, and the strain is randomly and averagely divided into 15 groups according to the weight, wherein each group comprises 10 strains, and the groups comprise a control group and an experimental group 1-14 groups respectively.
2.2 methods of administration
Experimental groups 1 to 14 groups were administered 1 to 1320 mg/kg of the compound prepared in examples 1 to 3 and 1420 mg/kg of the commercially available compound, respectively, and suspended in 0.5% sodium carboxymethylcellulose (CMC-Na) solution; the control group was administered with 20mg/kg of atractylodin by gavage, and suspended with 0.5% sodium carboxymethylcellulose (CMC-Na) solution.
And blood is collected from the orbit before administration, 10min, 20 min, 30 min, 45 min, 60min and 2 h, 4h, 6 h, 8 h, 12 h and 24h after administration, 200uL of plasma is collected and added with 400uL of acetonitrile to precipitate protein, the mixture is mixed for 90s and 12000rpm, the centrifugation is carried out for 10min, and then 20uL of supernatant is taken to quantitatively detect the content of each component by using HPLC.
2.3HPLC chromatographic conditions
Agilent 1260 is provided with a DAD detector; c18 column (4.6X 250mm, 5 μm); the flow rate is 0.8 mL/min; the column temperature is 30 ℃; the sample volume is 10 mu L; the detection wavelength is 340 nm; mobile phase acetonitrile-water 76:24 (v/v).
Proved by methodology, the linearity of each compound blood sample processed by the method is good between 0.05 and 5.0mg/L, and the method can be used for quantitative analysis.
3. Results of the experiment
The data were statistically analyzed using DAS and SPSS processing software to calculate pharmacokinetic parameters for each compound, and the specific experimental results are shown in table 2.
TABLE 2 pharmacokinetic experiment results of the groups
| Group of | tmax(h) | Cmax(mg/L) | AUC0-∞(mg*h/L) | t1/2(h) |
| Control group | 0.65±0.3 | 1.87±0.8 | 17.5±6.8 | 1.89±1.1 |
| Experimental group 1 group | 1.34±0.4 | 2.38±0.7 | 27.8±9.3 | 5.52±0.7 |
| Experimental group 2 groups | 1.49±0.7 | 1.98±1.0 | 25.4±8.6 | 4.52±0.8 |
| Experimental group 3 groups | 2.17±0.9 | 1.56±0.6 | 19.6±7.9 | 4.01±0.6 |
| Experimental group 4 groups | 1.56±0.5 | 1.85±0.4 | 28.1±5.8 | 5.31±0.6 |
| Experimental group 5 groups | 1.21±0.2 | 3.01±0.9 | 36.9±7.1 | 6.56±0.4 |
| Experimental group 6 | 0.91±0.3 | 2.56±0.8 | 37.8±5.3 | 6.47±1.3 |
| Experimental group 7 groups | 1.56±0.2 | 2.28±0.6 | 28.6±4.5 | 4.35±0.7 |
| Experimental group 8 | 1.47±0.4 | 2.60±0.8 | 30.9±6.7 | 5.75±0.6 |
| Experimental group 9 | 1.18±0.6 | 1.79±0.7 | 24.8±3.9 | 4.01±1.5 |
| Experiment ofGroup 10 of | 1.16±0.8 | 1.83±0.7 | 25.9±8.3 | 4.32±0.7 |
| Experimental group 11 groups | 1.82±0.5 | 1.16±0.5 | 16.9±3.9 | 3.34±0.4 |
| Experimental group 12 groups | 1.75±0.4 | 1.23±0.8 | 18.1±5.4 | 3.88±0.5 |
| Experimental group 13 groups | 1.48±0.7 | 2.78±0.8 | 33.8±6.8 | 6.03±0.9 |
| Experimental group 14 groups | 1.35±0.9 | 2.64±0.9 | 31.7±7.2 | 5.91±0.9 |
As shown in Table 2, (1) Compounds 1-14 were all able to absorb into the blood after oral administration; (2) compared with atractylodin, the compounds 1-14 are slower in vivo elimination, smaller in blood concentration fluctuation and longer in vivo circulation time.
4. Conclusion of the experiment
The polyacetylene compounds 1-14 of the invention have slower elimination in vivo, smaller blood concentration fluctuation and longer in vivo circulation time, and are beneficial to the effect of reducing uric acid in vivo.
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 (4)
1. The application of the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt thereof in preparing the medicine with the effect of reducing uric acid is characterized in that the polyacetylene compound shown in the formula (I) is selected from:
2. the application of the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt thereof in preparing the medicines with the effect of reducing uric acid according to the claim 1 is characterized in that the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt thereof are added with conventional auxiliary materials according to a conventional process to prepare clinically acceptable tablets, capsules, powder, mixtures, pills, granules, syrups, emplastrums, suppositories, aerosols, ointments or injections.
3. The application of the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt thereof in preparing medicines for treating gout is characterized in that the polyacetylene compound shown in the formula (I) is selected from:
4. the application of the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt thereof in preparing the medicines for treating gout according to the claim 3 is characterized in that the polyacetylene compound shown in the formula (I) and the pharmaceutically acceptable salt thereof are prepared into clinically acceptable tablets, capsules, powder, mixtures, pills, granules, syrups, emplastrum, suppositories, aerosols, ointments or injections by adding conventional auxiliary materials according to a conventional process.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711284363.2A CN109893521B (en) | 2017-12-07 | 2017-12-07 | Application of polyacetylene compounds in reducing uric acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711284363.2A CN109893521B (en) | 2017-12-07 | 2017-12-07 | Application of polyacetylene compounds in reducing uric acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109893521A CN109893521A (en) | 2019-06-18 |
| CN109893521B true CN109893521B (en) | 2022-01-11 |
Family
ID=66939052
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711284363.2A Active CN109893521B (en) | 2017-12-07 | 2017-12-07 | Application of polyacetylene compounds in reducing uric acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109893521B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111714485B (en) * | 2019-03-20 | 2021-11-23 | 苏州凯祥生物科技有限公司 | Hyperuricemia pharmaceutical composition and application thereof |
| CN111714486B (en) * | 2019-03-20 | 2023-06-20 | 苏州凯祥生物科技有限公司 | Application of polyacetylene compound |
| CN113491689A (en) * | 2020-04-08 | 2021-10-12 | 苏州凯祥生物科技有限公司 | Use of compounds as Sirt1 receptor agonists |
| CN113493374B (en) * | 2020-04-08 | 2022-11-22 | 苏州凯祥生物科技有限公司 | SIRT1 receptor agonist and medicine containing same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104586863A (en) * | 2014-12-23 | 2015-05-06 | 苏州凯祥生物科技有限公司 | Application of digallate derivative to preparation of medicine for treating hyperuricemia |
-
2017
- 2017-12-07 CN CN201711284363.2A patent/CN109893521B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104586863A (en) * | 2014-12-23 | 2015-05-06 | 苏州凯祥生物科技有限公司 | Application of digallate derivative to preparation of medicine for treating hyperuricemia |
Non-Patent Citations (3)
| Title |
|---|
| A new 9-nor-atractylodin from Atractylodes lancea and the antibacterial activity of the atractylodin derivatives;Yanjun Chen等;《Fitoterapia》;20111028;第83卷(第1期);第199-203页 * |
| A straightforward synthesis of symmetrical polyendiynes by dimerization reactions of silyl derivatives;Francesco Babudri等;《Journal of Organometallic Chemistry》;19981231;第566卷;第251-257页 * |
| Enzyme inhibitory activities of acetylene and sesquiterpene compounds in Atractylodes rhizome;Sakurai, Tetsuro;《Biological & Pharmaceutical Bulletin 》;19931231;第16卷(第2期);第142-145页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109893521A (en) | 2019-06-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109893521B (en) | Application of polyacetylene compounds in reducing uric acid | |
| JP6947644B2 (en) | Deuterated chenodeoxycholic acid derivative and drug composition containing this compound | |
| CN110638811B (en) | New application of sesquiterpene compound in treating gout | |
| EP2407474B1 (en) | Triacetyl-3-hydroxyphenyladenosine and its use for regulating blood fat | |
| CN109893538B (en) | Novel application of polyacetylenes in reducing uric acid | |
| CN109893517B (en) | Application of polyacetylene compound in treating gout | |
| CN109893533B (en) | New application of polyacetylene compounds in reducing uric acid | |
| JP6302102B2 (en) | A compound isolated from MONASCUS PURPUREUS, its preparation and use | |
| CN108451959B (en) | Application of galloylglucoside derivatives and pharmaceutical composition for treating hyperuricemia | |
| CN110638812B (en) | New application of sesquiterpenoids in reducing uric acid | |
| CN104586830A (en) | Application of gallate derivative to preparation of medicine for treating hyperuricemia | |
| CN111714485B (en) | Hyperuricemia pharmaceutical composition and application thereof | |
| CN113493374B (en) | SIRT1 receptor agonist and medicine containing same | |
| CN110638813A (en) | New application of phthalide compounds in reducing uric acid | |
| CN108785316B (en) | Use of cortex Periplocae Radicis C21 steroids in preparation of IDO inhibitor | |
| CN104586863B (en) | Application of digallate derivative to preparation of medicine for treating hyperuricemia | |
| CN111714491A (en) | New application of sesquiterpene lactone compound | |
| WO2021204192A1 (en) | Use of compound as sirt1 receptor agonist | |
| US9266852B2 (en) | Daidzein derivative, pharmaceutically acceptable salt and preparation method thereof, and pharmaceutical composition containing same | |
| CN108785317B (en) | Use of cortex Periplocae Radicis C21 steroid compound in preparation of IDO inhibitor | |
| CN111617071B (en) | Hyperuricemia medicine composition and medicine for treating hyperuricemia | |
| CN111714487B (en) | Hyperuricemia pharmaceutical composition | |
| CN108926571B (en) | Application of sulfated mannoglucuronic acid oligosaccharide in preparation of anti-cancer drugs or anti-cancer health products | |
| CN111617072A (en) | Hyperuricemia pharmaceutical composition and drug for treating hyperuricemia | |
| CN108191756B (en) | Quinoline derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |