CN110638811A - New application of sesquiterpene compound in treating gout - Google Patents

New application of sesquiterpene compound in treating gout Download PDF

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CN110638811A
CN110638811A CN201810672310.6A CN201810672310A CN110638811A CN 110638811 A CN110638811 A CN 110638811A CN 201810672310 A CN201810672310 A CN 201810672310A CN 110638811 A CN110638811 A CN 110638811A
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uric acid
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sesquiterpene compound
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Abstract

The invention belongs to the field of medicines or health care products, and particularly relates to a new application of a sesquiterpene compound in reducing uric acid. The sesquiterpenoids have a structure shown in formula (I):
Figure DDA0001708686450000011
X、R1～R11such as bookThe definition of the invention specification is shown. The invention discovers that the sesquiterpene compound can promote the excretion of uric acid in vivo through a hyperuricemia animal model, has a remarkable uric acid reducing effect, and can be used as a potential medicament for reducing uric acid or treating gout.

Description

New application of sesquiterpene compound in treating gout
Technical Field
The invention belongs to the field of medicines or health-care products, and particularly relates to a new application of sesquiterpene compounds in treating gout.
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.
The feverfew has rich pharmacological activity, and polysaccharides, sesquiterpenes, flavonoids, phenolic acid compounds, various vitamins, metal elements and other chemical components are separated from the feverfew at present. Among them, sesquiterpenes (sesquiterpene lactones) are compounds of various structural types generated by further evolution of geranyl lactone (germacranolide) structure, and are one of bioactive components of medicinal plants. Sesquiterpene compounds are widely found in plants of Compositae, Umbelliferae, Magnoliaceae, Menispermaceae, Euphorbiaceae, Acanthaceae, Leguminosae, etc. Sesquiterpene lactones isolated from feverfew plants alone exceed 3000 compounds, and can be classified into Guaianolide (Guaianolide), pseudo-Guaianolide (pesudoaianolide), germanolide (germanolide), elemenolide (elemenolide), Eudesmanolide (Eudesmanolide), and eremophilane-type lactones (Eremophiladien) according to their structures. Researches show that the sesquiterpenoids have various pharmacological activities such as antitumor activity, cardiotonic activity, neurotoxicity, antimalarial activity and antibacterial activity.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to provide a new pharmacological application of the sesquiterpene compound in reducing uric acid and treating gout.
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 sesquiterpene compound shown in a formula (I) and a pharmaceutically acceptable salt, ester, a prodrug or a solvate thereof in preparing a medicine or health-care product with the effect of reducing uric acid,
Figure BDA0001708686440000031
wherein the content of the first and second substances,
Figure BDA0001708686440000032
is selected from
Figure BDA00017086864400000310
Or
Figure BDA00017086864400000311
，
Figure BDA00017086864400000312
To representIs selected from
Figure BDA00017086864400000313
Or without a bond, two adjacent
Figure BDA0001708686440000033
Is not simultaneously
Figure BDA00017086864400000314
；
X is selected from N or O; when X is O, attached to X
Figure BDA0001708686440000034
And
Figure BDA00017086864400000315
is not simultaneously
Figure BDA00017086864400000316
And
Figure BDA00017086864400000317
；；
R1、R2、R3、R4、R6independently of one another, from H, OH, unsubstituted or substituted C1-C4Alkyl, unsubstituted or substituted C1-C4Alkoxy, OAc or
Figure BDA0001708686440000035
R8、R9Independently of each other selected from H, OH, or R8、R9Forming an unsubstituted or substituted oxirane group;
Figure BDA0001708686440000036
form a
Figure BDA00017086864400000318
Or
Figure BDA00017086864400000319
，
Figure BDA0001708686440000037
Form a
Figure BDA00017086864400000320
Or
Figure BDA00017086864400000321
，
Figure BDA0001708686440000038
Form a
Figure BDA00017086864400000322
Or
Figure BDA00017086864400000323
，
Figure BDA0001708686440000039
Form a
Figure BDA00017086864400000324
Or
Figure BDA00017086864400000325
，
R5a、R7a、R10a、R11aIndependently of one another, from H, unsubstituted or from 1 to 3R10bSubstituted C1-C4Alkyl of R10bIs selected from C1-C4Alkoxy or OH.
The terms in the claims and the specification of the present invention have the following meanings unless otherwise specified.
In the claims of the present invention, C represents a carbon atom,
Figure BDA0001708686440000042
Figure DA00017086864447643
Figure BDA0001708686440000047
or
Figure BDA0001708686440000048
C of less than 4 covalent bonds may be complemented by H for its covalent bond.
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.
Alkoxy means: the resulting group having an alkyl group bonded to an oxygen atom. For example: alkoxy groups include, but are not limited to, methoxy (-OCH)3) Ethoxy (-OCH)2CH3) And the like.
OAc represents an acetoxy group.
Preferably, the application of the sesquiterpenoids shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof in preparing the medicines or health care products with the effect of reducing uric acid,
R1、R2、R3、R4、R6independently of one another, from H, OH, OCH3、OCH2CH3、OAc、CH3Or
Figure BDA0001708686440000045
R8、R9Independently of each other selected from H, OH, or R8、R9Form a
R5a、R7a、R10a、R11aIndependently of one another from H,CH3、
Figure BDA0001708686440000051
Or
Figure BDA0001708686440000052
Further preferably, the sesquiterpene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof are applied to preparing medicines or health care products with the effect of reducing uric acid, and the sesquiterpene compound shown in the formula (I) is selected from the following structures:
Figure BDA0001708686440000053
Figure BDA0001708686440000061
further preferably, the sesquiterpene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof are applied to preparation of medicines or health care products with the effect of reducing uric acid, and the sesquiterpene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof are applied to preparation of medicines or health care products with the effect of promoting uric acid excretion.
Preferably, the sesquiterpene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof are applied to preparation of drugs or health care products with the effect of reducing uric acid, and the sesquiterpene 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, emplastrums, suppositories, aerosols, ointments or injections.
In a second aspect, the invention provides an application of a sesquiterpenoid shown in formula (I) and pharmaceutically acceptable salts, esters, prodrugs or solvates thereof in preparing medicines or health care products for treating gout,
Figure BDA0001708686440000071
wherein the content of the first and second substances,
Figure BDA0001708686440000072
is selected fromOr
Figure BDA00017086864400000715
，
Figure BDA00017086864400000716
Is selected from
Figure BDA00017086864400000717
Or without a bond, two adjacent
Figure BDA0001708686440000073
Is not simultaneously
Figure BDA00017086864400000718
；
X is selected from N or O; when X is O, attached to X
Figure BDA0001708686440000074
And
Figure BDA00017086864400000719
is not simultaneously
Figure BDA00017086864400000720
And
Figure BDA00017086864400000721
；
R1、R2、R3、R4、R6independently of one another, from H, OH, unsubstituted or substituted C1-C4Alkyl, unsubstitutedOr substituted C1-C4Alkoxy, OAc or
Figure BDA0001708686440000075
R8、R9Independently of each other selected from H, OH, or R8、R9Forming an unsubstituted or substituted oxirane group;
form aOr
Figure BDA00017086864400000722
，
Figure BDA0001708686440000078
Form a
Figure BDA0001708686440000079
Or
Figure BDA00017086864400000723
，
Figure BDA00017086864400000710
Form aOr
Figure BDA00017086864400000724
，Form a
Figure BDA00017086864400000713
Or
Figure BDA00017086864400000725
，
R5a、R7a、R10a、R11aIndependently of one another, from H, unsubstituted or from 1 to 3R10bSubstituted C1-C4Alkyl of R10bIs selected from C1-C4Alkoxy or OH.
Preferably, the application of the sesquiterpenoids shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof in preparing the medicines or health care products for treating gout,
R1、R2、R3、R4、R6independently of one another, from H, OH, OCH3、OCH2CH3、OAc、CH3Or
Figure BDA0001708686440000081
R8、R9Independently of each other selected from H, OH, or R8、R9Form a
Figure BDA0001708686440000082
R5a、R7a、R10a、R11aAre independently selected from H, CH3、
Figure BDA0001708686440000083
Or
Figure BDA0001708686440000084
Further preferably, the sesquiterpene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof are applied to preparing medicines or health care products for treating gout, and the sesquiterpene compound shown in the formula (I) is selected from the following structures:
Figure BDA0001708686440000091
preferably, the sesquiterpene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof are applied to preparation of medicines or health care products for treating gout, and the sesquiterpene 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.
In a third aspect, the invention provides a medicine or health care product with uric acid reducing effect or gout treatment, which comprises a therapeutically effective amount of the sesquiterpene compound shown in the formula (I) and pharmaceutically acceptable salts, esters, prodrugs or solvates thereof; preferably, the sesquiterpene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof with effective treatment amount are selected, and conventional auxiliary materials are added according to the conventional process to prepare clinically acceptable tablets, capsules, powder, mixture, pills, granules, syrup, emplastrum, suppositories, aerosol, ointment or injection.
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 sesquiterpenoids can have obvious uric acid reducing effect through a hyperuricemia animal model, and the uric acid reducing effect of the sesquiterpenoids is related to the promotion of uric acid excretion and reduction of uric acid reabsorption, so that the sesquiterpenoids can be used as potential uric acid reducing medicines or health care products for treating gout.
Detailed Description
In the following examples and experimental examples of the present invention, sesquiterpene 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 probenecid, the oteracil potassium, the analytically pure absolute ethyl alcohol, the chloroform, the methanol, the ethyl acetate, the acetone, the distilled water, the sodium carboxymethyl cellulose, the monopotassium phosphate and the dipotassium 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.
Figure BDA0001708686440000121
Example 1
Weighing 50kg of dried rhizome of bighead atractylodes rhizome, crushing the dried rhizome of bighead atractylodes rhizome, soaking and extracting for 3 times by using an ethanol solution with the volume fraction of 90% and the volume of 8 times of that of the dried rhizome of bighead atractylodes rhizome, and concentrating under reduced pressure to remove an organic solvent to obtain a concentrated solution A (the solid content in the concentrated solution A is 2.5 kg); passing the concentrated solution A through a 50L-D101 column (column diameter is 22cm multiplied by height is 150cm), washing 4 column volumes with 40% ethanol and 95% ethanol respectively, collecting eluate with 95% ethanol, concentrating under reduced pressure to remove organic solvent to obtain concentrated solution B (solid content in the concentrated solution B is 1kg), extracting the concentrated solution B with ethyl acetate for 3 times, and recovering the extraction solvent under reduced pressure to obtain 400g of ethyl acetate extract. The ethyl acetate extract was chromatographed on a 3.5L-silica gel column (column diameter 8 cm. times.height 70cm) using petroleum ether: gradient elution is carried out on the mixed solution of ethyl acetate and ethyl acetate in the volume ratio of 10:1, 5:1, 3:1 and 1:1, and the same parts are combined by TLC detection to obtain 5 eluates: Fr.A to E.
Wherein, Fr.A is separated again by silica gel column chromatography, petroleum ether: gradient elution is carried out on a mixed solution with ethyl acetate in a volume ratio (initial volume ratio is 15:1, final volume ratio is 5:1), TLC detection is carried out to combine the same parts, 5 fractions Fr.A1-A5 are obtained, wherein Fr.A2 is subjected to ODS preparative chromatography separation, gradient elution is carried out by taking 30%, 40% and 65% methanol aqueous solution as a mobile phase, compound 9, compound 10 and compound 11 are obtained, and Fr.A3 is subjected to ODS preparative chromatography separation, and elution is carried out by taking 65% methanol aqueous solution as a mobile phase, so as to obtain compound 22;
Fr.B is separated again by silica gel column chromatography, petroleum ether: gradient elution is carried out on the mixed solution with the volume ratio of ethyl acetate (the initial volume ratio is 10:1, and the final volume ratio is 5:1), and the same parts are combined by TLC detection to obtain a compound 12 and a compound 21;
fr.c silica gel column chromatography again, with petroleum ether: gradient elution is carried out on the mixed solution with the volume ratio of ethyl acetate (the initial volume ratio is 5:1, and the final volume ratio is 3:1), and the same parts are combined by TLC detection to obtain a compound 1, a compound 7 and a compound 8;
fr.d silica gel column chromatography again, with petroleum ether: gradient elution is carried out on the mixed solution with the volume ratio of ethyl acetate (initial volume ratio is 3:1, final volume ratio is 1:1), the same parts are combined by TLC detection, and then a compound 2, a compound 3 and a compound 6 are obtained;
and Fr.E is separated by ODS preparative chromatography, gradient elution is carried out by using 75% by volume and 85% by volume of methanol aqueous solution, and the same parts are combined by TLC detection, so that the compound 4 and the compound 5 are obtained.
Example 2
Weighing 50kg of elecampane medicinal material, crushing the elecampane medicinal material, soaking and extracting the elecampane medicinal material for 3 times by using an ethanol solution with the volume fraction of 90% and the volume of 8 times of that of the powder, and removing an organic solvent by vacuum concentration to obtain a concentrated solution A; passing the concentrated solution A through a 50L-D101 column (column diameter is 22cm multiplied by height is 150cm), washing 4 column volumes with 40% and 95% ethanol respectively, collecting eluate with 95% ethanol, concentrating under reduced pressure to remove organic solvent to obtain concentrated solution B (solid content in the concentrated solution B is 3.2kg), extracting the concentrated solution B with petroleum ether for 3 times, and recovering the extraction solvent under reduced pressure to obtain 2kg of petroleum ether extract. Separating the petroleum ether extract by silica gel column chromatography, sequentially treating with petroleum ether: gradient elution was performed on the mixed solution of ethyl acetate in volume ratio (initial volume ratio 100:1, final volume ratio 1:1), and the same fractions were combined by TLC detection to give 5 eluates: Fr.A to E.
Wherein, Fr.A is separated again by silica gel column chromatography, petroleum ether: gradient elution was performed on a mixed solution of ethyl acetate in a volume ratio (initial volume ratio 100:1, final volume ratio 20:1), and the same fractions were combined by TLC detection to give 4 eluates: Fr.A1 to Fr.A4; and Fr.A2 is subjected to ODS preparative chromatography, and gradient elution is carried out by using 30% by volume fraction, 40% by volume fraction and 65% by volume fraction of methanol aqueous solution as a mobile phase, so as to obtain a compound 13 and a compound 14.
Example 3
Weighing 60kg of the whole plant of the golden Tremella, cutting into pieces, soaking and extracting for 4 times by using ethanol solution with volume fraction of 85% 6 times of the volume, and concentrating under reduced pressure to remove organic solvent to obtain concentrated solution A; passing the concentrated solution A through a 50L-D101 column (column diameter is 22cm multiplied by height is 150cm), washing 4 column volumes with 40% and 95% ethanol respectively, collecting eluate with 95% ethanol, concentrating under reduced pressure to remove organic solvent to obtain concentrated solution B (solid content in the concentrated solution B is 1.1kg), extracting the concentrated solution B with acetone for 3 times, and recovering the extraction solvent under reduced pressure to obtain 750g of acetone extract. Separating acetone eluate by silica gel column chromatography, sequentially eluting with petroleum ether: gradient elution was performed on the mixed solution of ethyl acetate in volume ratio (initial 50:1, final 1:10), and the same fractions were combined by TLC detection to give 6 eluates: Fr.A to F.
Wherein, Fr.B is separated again by silica gel column chromatography, petroleum ether: gradient elution is carried out on a mixed solution with chloroform in a volume ratio (initial volume ratio is 50:1, and final volume ratio is 20:1), and TLC detection is carried out to combine the same parts, so that 5 parts are obtained: Fr.B1-B5, and Fr.B1 is separated by ODS preparative chromatography eluting with 55% methanol water solution by volume fraction to obtain compound 15; b3, eluting with 70% methanol water solution by ODS preparative chromatography to obtain compound 18;
fr.c silica gel column chromatography again, petroleum ether: gradient elution with chloroform in a mixed solution at a volume ratio (initial 50:1, final 20:1) and TLC detection of the same fractions combined to give 4 eluates: c1 to C4; and Fr, C1 is eluted by ODS preparative chromatography with 55% methanol water solution by volume fraction as a mobile phase to obtain a compound 16; and Fr.C3 is eluted by ODS preparative chromatography with a 65% by volume fraction aqueous methanol solution as a mobile phase to obtain compound 17.
Fr.E silica gel column chromatography again, gradient elution with chloroform-methanol mixture (initial 100:1, final 20:1) and TLC detection of the same fractions combined to give 4 eluates: Fr.E1-E4; and Fr.E2 is eluted by ODS preparative chromatography with 55 percent by volume of methanol aqueous solution as a mobile phase to obtain a compound 19; and Fr.E3 is eluted by ODS preparative chromatography with a 65% volume fraction aqueous methanol solution as a mobile phase to obtain compound 20.
Structure confirmation data of Compounds 1 to 41H NMR and13c NMR references are as follows: the separation and identification of atractylenolide IV, plant ecology news 1992(8):614-617.
Structure confirmation data of Compound 51H NMR and13c NMR references are as follows: new Sesquiteroils from the Rhizomes of Atractylodes macrocepha, Chinese pharmaceutical journal, 2005, 7(1):37-42.
Structure confirmation data of Compounds No. 6 to No. 81H NMR and13c NMR references are as follows: a sesquiterpene lactam from arylenes macrocytochemistry, 1997,45(4):765-767.
Structure confirmation data of Compound 91H NMR and13c NMR references are as follows: chemical components of volatile oil of rhizome of white atractylodes rhizome, 1980, (4) 93-94.
Structure confirmation data of Compounds 10 to 121H NMR and13c NMR references are as follows: comparison of chemical compositions of tissue culture Atractylodes macrocephala Koidz and native Atractylodes macrocephala Koidz. plant ecology bulletin, 1991(2): 164-.
Structure confirmation data of Compounds 13 to 141H NMR and13c NMR references are as follows: research on the chemical components of sesquiterpenes in elecampane inula root, Shizhen Chinese medicine 2007,18(11): 2738-.
Structure confirmation data of Compound 151H NMR and13c NMR references are as follows: the structures of helium Specifications.XI, the Structure of Pinnatifidin1,2 J.org.chem,1962,27(11):4041-4043.
Structure confirmation data of Compounds 16 to 171H NMR and13c NMR references are as follows: sesquiterpenoids from Carpesium divaricatum and of the cytoxic activity Fitoterapia 2012,83(8):1351-5.
Structure confirmation data of Compounds 18 to 201H NMR and13c NMR references are as follows: chemical composition study of dahua jingda, second military medical university, 2016.
Structure confirmation data of Compound 211H NMR and13c NMR references are as follows: a new double-sesquiterpene lactone in Chinese medicine Baizhu is reported by Zhongshan university, 1996(2) 75-76.
Structure confirmation data of Compound 221H NMR and13c NMR references are as follows: chang Y H, Kim C, Jung M, et al. inhibition of melanogenesis by selina-4(14),7(11) -dien-8-one isolated from Atractylis Rhizoma Alba [ J].Biological & Pharmaceutical Bulletin,2007,30(4):719-723.
Experimental example 1Research on uric acid reducing effect of compound of the invention
1. Experimental Material
280 healthy male KM mice with the weight of 15-18g are provided by Beijing Wintolite Hua 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
250 mice selected from 280 mice are randomly and averagely divided into 25 groups according to the weight, and each group comprises 10 mice, namely a blank control group, a model control group, a positive control group and an experimental group 1-22.
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.
Experiment groups 1-22 were administered compounds 1-2225 mg/kg, respectively, and compounds 1-22 were suspended in 0.5% sodium carboxymethylcellulose (CMC-Na) solution, respectively; probenecid is given to the positive control group at 80mg/kg, and 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 22, 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 serum uric acid levels in hyperuricemic mice (mean. mu. mol/L)
Group of Uric acid (mu mol/L) Group of Uric acid (mu mol/L)
Blank control group 52.33 Experimental group 11 groups 73.39**
Model control group 156.83 Experimental group 12 groups 84.89**
Positive control group 37.19** Experimental group 13 groups 60.23**
Experimental groupGroup 1 93.23* Experimental group 14 groups 60.77**
Experimental group 2 groups 94.93* Experimental group 15 66.02**
Experimental group 3 groups 92.05* Experimental group 16 groups 83.97**
Experimental group 4 groups 65.64** Experimental group 17 82.49**
Experimental group 5 groups 63.04** Experimental group 18 63.22**
Experimental group 6 56.27** Experimental group 19 61.67**
Experimental group 7 groups 87.73** Experimental group 20 92.35*
Experimental group 8 83.14** Experimental group 21 102.03*
Experimental group 9 62.37** Experimental group 22 groups 77.64**
Experimental group 10 78.27**
Note:**representing P compared to the hyperuricemia model group<0.01 (t-test);
*representing P compared to the hyperuricemia model group<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 of uric acid levels in serum of mice in experimental groups 1-22 was statistically significantly different (P <0.01 or P <0.05) compared to the model control group;
(3) the partial sesquiterpenoids (compounds 4, 5, 6, 9, 13, 14, 15, 18, 19 and 22) have excellent uric acid reducing effect.
5. Conclusion of the experiment
The sesquiterpene compound has a remarkable uric acid reducing effect in vivo, and can be used as a potential uric acid reducing medicine for treating hyperuricemia.
Experimental example 2Research on effect of promoting uric acid excretion of compound of the invention
1. Experimental Material
280 healthy male KM mice with the weight of 15-18g are provided by Beijing Wintolite Hua 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
250 mice with concentrated body weight are selected from 280 mice and are randomly and averagely divided into 25 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 1-22.
2.2 methods of administration
After the adaptation period, the mice were administered by gavage for 6 days, with gavage being performed 1 time in the morning and continuously.
Experiment groups 1-22 were administered compound 1-2225 mg/kg, respectively, suspended in 0.5% sodium carboxymethylcellulose (CMC-Na) solution; probenecid is given to the positive control group at 80mg/kg, and 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 6 days.
Mice were placed in metabolism cages after the 6 th day of dosing, and urine was collected from each group of mice for 0-24 h.
3. Experimental data detection and processing
3.1 detection index
Collecting urine of mice in a blank control group, a model control group, a positive control group and an experimental group 1-22, centrifuging, and detecting the uric acid value in the urine by using 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 the uric acid concentration in urine of hyperuricemic mice 6 days after administration is shown in table 2.
TABLE 2 Effect on uric acid levels in urine of hyperuricemia mice (mean. mu. mol/L)
Group of Uric acid (mu mol/L) Group of Uric acid (mu mol/L)
Blank control group 734.81 Experimental group 11 groups 908.73**
Model control group 751.09 Experimental group 12 groups 873.05*
Positive control group 1132.83** Experimental group 13 groups 913.82**
Experimental group 1 group 820.01 Experimental group 14 groups 886.19*
Experimental group 2 groups 857.72 Experimental group 15 927.44**
Experimental group 3 groups 833.56 Experimental group 16 groups 862.01
Experimental group 4 groups 921.24** Experimental group 17 903.56*
Experimental group 5 groups 884.15* Experimental group 18 892.88*
Experimental group 6 927.62** Experimental group 19 935.08**
Experimental group 7 groups 940.62** Experimental group 20 849.13
Experimental group 8 874.39 Experimental group 21 832.84
Experimental group 9 935.04** Experimental group 22 groups 910.44**
Experimental group 10 864.32
Note:**representing P compared to the hyperuricemia model group<0.01 (t-test);
*representing P compared to the hyperuricemia model group<0.05 (t-test)
As can be seen from Table 2: the urine uric acid levels of the mice in the experimental groups 1-22 were increased to different degrees compared to the model control group. The increase of uric acid level in urine of mice in experimental groups 4-7, 9, 11-15, 17-19 and 22 has significant difference (compared with hyperuricemia model group, P is less than 0.01 or P is less than 0.05), and the statistical significance is achieved.
5. Conclusion of the experiment
The action of the sesquiterpenoids for reducing uric acid is related to the promotion of the excretion of uric acid, has the effect similar to the action and the effect of the positive drug probenecid for promoting the excretion of uric acid, and can be used as a potential medicine for reducing uric acid for treating hyperuricemia.
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. The application of the sesquiterpenoids shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof in preparing the medicines or health products with the effect of reducing uric acid,
Figure FDA0001708686430000011
wherein the content of the first and second substances,
Figure FDA0001708686430000012
is selected from
Figure FDA0001708686430000013
Or- -, - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Figure FDA0001708686430000014
Is not simultaneously
Figure FDA0001708686430000015
X is selected from N or O; when X is O, attached to X
Figure FDA0001708686430000016
And is not simultaneously
Figure FDA0001708686430000017
And-;
R1、R2、R3、R4、R6independently of one another, from H, OH, unsubstituted or substituted C1-C4Alkyl, unsubstituted or substituted C1-C4Alkoxy, OAc or
Figure FDA0001708686430000018
R8、R9Independently of each other selected from H, OH, or R8、R9Forming an unsubstituted or substituted oxirane group;
Figure FDA0001708686430000019
form a
Figure FDA00017086864300000110
Or C-R5a，
Figure FDA00017086864300000111
Form a
Figure FDA00017086864300000112
Or C-R7a，Form a
Figure FDA0001708686430000022
Or C-R10a，
Figure FDA0001708686430000023
Form a
Figure FDA0001708686430000024
Or C-R11a，
R5a、R7a、R10a、R11aIndependently of one another, from H, unsubstituted or from 1 to 3R10bSubstituted C1-C4Alkyl of R10bIs selected from C1-C4Alkoxy or OH.
2. The application of the sesquiterpenoids shown in formula (I) and the pharmaceutically acceptable salts, esters, prodrugs or solvates thereof in preparing the medicines or health products with the effect of reducing uric acid according to claim 1,
R1、R2、R3、R4、R6independently of one another, from H, OH, OCH3、OCH2CH3、OAc、CH3Or
Figure FDA0001708686430000025
R8、R9Independently of each other selected from H, OH, or R8、R9Form a
Figure FDA0001708686430000026
R5a、R7a、R10a、R11aAre independently selected from H, CH3、
Figure FDA0001708686430000027
Figure FDA0001708686430000028
3. The use of the sesquiterpene compound of formula (i) and the pharmaceutically acceptable salts, esters, prodrugs or solvates thereof according to claim 1 or 2 for the preparation of a medicament or health product having uric acid lowering effect, wherein the sesquiterpene compound of formula (i) is selected from the following structures:
Figure FDA0001708686430000031
Figure FDA0001708686430000041
4. use of the sesquiterpene compound represented by the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof according to any one of claims 1 to 3 in preparation of medicines or health products with uric acid lowering effect, wherein the sesquiterpene compound represented by the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof are used in preparation of medicines or health products with uric acid excretion promoting effect.
5. The application of the sesquiterpene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof in preparing the medicine or health care product with the effect of reducing uric acid according to any one of claims 1 to 4, is characterized in that the sesquiterpene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof are added with conventional auxiliary materials according to a conventional process to prepare clinically acceptable tablets, capsules, powder, mixtures, pills, granules, syrups, emplastrum, suppositories, aerosols, ointments or injections.
6. Application of sesquiterpene compound shown in formula (I) and pharmaceutically acceptable salt, ester, prodrug or solvate thereof in preparation of medicines or health care products for treating gout,
Figure FDA0001708686430000042
wherein the content of the first and second substances,is selected from
Figure FDA0001708686430000044
Or- -, - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Figure FDA0001708686430000051
Is not simultaneously
Figure FDA0001708686430000052
X is selected from N or O; when X is O, attached to X
Figure FDA0001708686430000053
And is not simultaneously
Figure FDA0001708686430000054
And-;
R1、R2、R3、R4、R6independently of one another, from H, OH, unsubstituted or substituted C1-C4Alkyl, unsubstituted or substituted C1-C4Alkoxy, OAc or
Figure FDA0001708686430000055
R8、R9Independently of each other selected from H, OH, or R8、R9Forming an unsubstituted or substituted oxirane group;
Figure FDA0001708686430000056
form aOr C-R5a，
Figure FDA0001708686430000058
Form a
Figure FDA0001708686430000059
Or C-R7a，
Figure FDA00017086864300000510
Form a
Figure FDA00017086864300000511
Or C-R10a，
Figure FDA00017086864300000512
Form a
Figure FDA00017086864300000513
Or C-R11a，
R5a、R7a、R10a、R11aIndependently of one another, from H, unsubstituted or from 1 to 3R10bSubstituted C1-C4Alkyl of (2)，R10bIs selected from C1-C4Alkoxy or OH.
7. The use of the sesquiterpene compound of formula (I) and the pharmaceutically acceptable salts, esters, prodrugs or solvates thereof according to claim 6 for the preparation of a pharmaceutical or nutraceutical product for the treatment of gout,
R1、R2、R3、R4、R6independently of one another, from H, OH, OCH3、OCH2CH3、OAc、CH3Or
Figure FDA00017086864300000514
R8、R9Independently of each other selected from H, OH, or R8、R9Form a
Figure FDA0001708686430000061
R5a、R7a、R10a、R11aAre independently selected from H, CH3、
Figure FDA0001708686430000062
Figure FDA0001708686430000063
8. Use of the sesquiterpene compound of formula (i) according to claim 6 or 7 or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof in the preparation of a medicament or health product for treating gout, wherein the sesquiterpene compound of formula (i) is selected from the following structures:
Figure FDA0001708686430000064
Figure FDA0001708686430000071
9. the use of the sesquiterpene compound represented by the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof according to any one of claims 6 to 8 in the preparation of drugs or health products for treating gout, wherein the sesquiterpene compound represented by the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof are prepared into clinically acceptable tablets, capsules, powders, mixtures, pills, granules, syrups, emplastrums, suppositories, aerosols, ointments or injections by adding conventional auxiliary materials according to a conventional process.
10. A drug or health product having uric acid lowering effect or gout treatment, comprising a therapeutically effective amount of the sesquiterpene compound represented by the formula (i) according to any one of claims 1 to 9 and a pharmaceutically acceptable salt, ester, prodrug or solvate thereof; preferably, the sesquiterpene compound shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug or solvate thereof with effective treatment amount are selected, and conventional auxiliary materials are added according to the conventional process to prepare clinically acceptable tablets, capsules, powder, mixture, pills, granules, syrup, emplastrum, suppositories, aerosol, ointment or injection.
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CN111714487A (en) * 2019-03-20 2020-09-29 苏州凯祥生物科技有限公司 Hyperuricemia pharmaceutical composition
CN111714491A (en) * 2019-03-20 2020-09-29 苏州凯祥生物科技有限公司 New application of sesquiterpene lactone compound
CN111714487B (en) * 2019-03-20 2023-05-12 苏州凯祥生物科技有限公司 Hyperuricemia pharmaceutical composition
CN111714491B (en) * 2019-03-20 2023-06-20 苏州凯祥生物科技有限公司 Application of sesquiterpene lactone compound
CN111840276A (en) * 2020-08-26 2020-10-30 河南中医药大学 Medical application of atractylenolide compound
CN111892563A (en) * 2020-08-26 2020-11-06 河南中医药大学 Compound 3 beta-acetoxyl-atractylenolide I, preparation method and application
CN111892563B (en) * 2020-08-26 2022-12-09 河南中医药大学 Compound 3 beta-acetoxyl-atractylenolide I, preparation method and application

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