CN109893521A - A kind of new application of poly- acetylene compound anti-trioxypurine - Google Patents
A kind of new application of poly- acetylene compound anti-trioxypurine Download PDFInfo
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Abstract
The invention belongs to drug or field of health care products, and in particular to a kind of new application of poly- acetylene compound anti-trioxypurine.The poly- acetylene compound has structure shown in formula (I):R1And R2As shown in the definition of description of the invention.The present invention has found that poly- acetylene compound of the invention has significant anti-trioxypurine effect in vivo by hyperuricemia animal model, can be used as potential anti-trioxypurine or treats the drug of gout.
Description
Technical field
The invention belongs to drug or field of health care products, and in particular to a kind of new application of poly- acetylene compound anti-trioxypurine.
Background technique
Uric acid is the final metabolite of mankind's purine compound, and purine metabolic disturbance then leads to hyperuricemia.Just
Under normal purine diet state, non-empty stomach serum uric acid level male is higher than 416 μm of ol/L twice on the same day, and women is higher than 360 μm of ol/
L, i.e. referred to as hyperuricemia (hyperuricemia).Gout is the crystal correlation caused by monosodium urate salt (MSU) deposition
Arthropathy, clinical manifestation directly related with hyperuricemia caused by purine metabolic disturbance and (or) underexcretion
For hyperuricemia, gouty acute arthritis recurrent exerbation, gouty chornic arthritis and tophus, gouty nephropathy and
Kidney calculus urate etc., severe one may occur in which joint deformity and renal insufficiency.In addition, gout often with Central obesity, hyperlipidemia,
The diseases such as hypertension, type II diabetes and cardiovascular disease.Gout has become the second largest metabolism class disease after diabetes, seriously
Endanger the life and health of the mankind.According to " the Chinese gout status report white paper in 2017 " announced recently, China's height urine
For acidaemia patient numbers up to 1.7 hundred million, wherein patient with gout is more than 80,000,000 people, and just rapid with 9.7% annual growth
Increase；The year two thousand twenty is expected, the gout number in China is up to 100,000,000.
Currently, treatment hyperuricemia, gout and gout complication, mainly by being controlled to the uric acid in blood
System, mechanism of action mainly includes following two: (1) by inhibiting xanthine oxidase (xanthine oxidase, XO) living
Property effectively inhibits the formation of uric acid, and representative drugs have allopurinol, Febustat etc.；(2) excretion for promoting uric acid, represents
Property drug has probenecid, Benzbromarone etc..However, said medicine it is equal toxic side effect it is usually larger, such as: allopurinol can draw
Send out the serious toxic side effects such as allergy (disease incidence 10-15%), super quick syndrome, bone marrow suppression；Probenecid, Benzbromarone
Then there is stimulating gastrointestinal road, cause the side effects such as renal colic, excitation gout acute attack；Febustat will increase cardiovascular system
The risk of disease, serious person may occur in which Stevens-Johnson syndrome；Moreover, the tolerance of said medicine is generally lower.It is comprehensive
On, these problems limit the clinical application of these drugs to a certain extent.Therefore, the drug of novel treatment gout is studied
It is of great significance.
Poly- acetylene compound (polyacetylenes) or polyacetylene compound are a kind of more special natural compounds
Object has two or more conjugated triple bonds mostly, thus has comparable unsaturation and very high activity.Carbene class chemical combination
Object and its derivative are a kind of very important Secondary metabolites, and the distribution in plant kingdom is relatively broad, only composite family
Plant just has more than 750 natural carbene classes and its derivative is reported.Plant (composite family, umbrella shape of some constituents containing carbene
Section etc.) as medicinal long-standing, but because the usual content of this constituents is less and be not sufficiently stable, for drug effect with
Relationship research existing for carbene constituents is less.With the progress of chemistry and pharmacological research method, chain carbene class and thiphene ring
The correlative study of carbene class makes some progress.Chain carbene class usually has following physiological activity: antimycotic, sensitization,
It is antitumor etc.；And the pharmacological action of thiphene ring carbene class is concentrated mainly on antimicrobial acivity at present.
In the prior art in spite of document report: certain poly- acetylene compounds of chain are in vitro to xanthine oxidase (XO)
With certain inhibiting effect, however lead to its suppression to xanthine oxidase (XO) in vivo since it is easy metabolism in vivo
Production use is weaker, therefore can not be as anti-trioxypurine or the potential drug for the treatment of gout.
Summary of the invention
For this purpose, the technical problem to be solved by the present invention is to existing poly- acetylene compounds in vitro to xanthine oxidase
(XO) weaker to the inhibiting effect of xanthine oxidase (XO) in vivo with certain inhibiting effect, to provide one kind
The new application of poly- acetylene compound anti-trioxypurine.
In order to solve the above technical problems, the present invention is achieved through the following technical solutions:
In a first aspect, the present invention provides poly- acetylene compound and its pharmaceutically acceptable salt shown in formula (I), ester, preceding
The application of medicine or solvate in the drug or health care product that preparation has anti-trioxypurine effect,
Wherein, R1Selected from unsubstituted or 1 to 3 R1aSubstituted C1-C12Alkyl,
R2Selected from unsubstituted or 1 to 3 R2aSubstituted C1-C12Alkoxy, unsubstituted or 1 to 3 R2aSubstituted C1-C12
Alkyl, unsubstituted or 1 to 7 R2bSubstituted aryl, unsubstituted or 1 to 6 R2cSubstituted heteroaryl,
R1aSelected from-OCOCH3、C1-C6Alkenyl,
R2aSelected from-OH ,-OCH3、
R2bSelected from C1-C6Alkyl, hydroxyl replace C1-C6Alkyl, the C that replaces of 1 to 3 halogen1-C6Alkyl ,-
OH、C1-C6Alkoxy ,-CN, halogen ,-NH2, 1 to 2 C1-C6Alkyl-substituted amido；
R2cIt is selected from
R3Selected from unsubstituted or 1 to 3 R3aSubstituted C1-C12Alkyl, unsubstituted or 1 to 7 R3bSubstituted aryl, not
Substitution or 1 to 6 R3cSubstituted heteroaryl,
R3aIt is selected from
R3bSelected from-OH ,-OCH3；
R3cSelected from C1-C6Alkyl, hydroxyl replace C1-C6Alkyl, the C that replaces of 1 to 3 halogen1-C6Alkyl ,-
OH、C1-C6Alkoxy ,-CN, halogen ,-NH2, 1 to 2 C1-C6Alkyl-substituted amido；
R4Selected from-H ,-OH.
Unless otherwise specified, the term of claims of the present invention and specification has following meanings.
Alkyl refers to: fully saturated straight chain or branch alkyl.Such as: alkyl include but is not limited to methyl, ethyl,
N-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methyl
Hexyl, 2,2- dimethyl amyl group, 2,3- dimethyl amyl group, n-heptyl, n-octyl, n-nonyl, positive decyl etc..
Alkenyl refers to: the straight chain containing at least one ethylene linkage or branch alkyl.Such as: alkenyl includes but is not limited to second
Alkenyl, allyl etc..
Aryl refers to: the aromatics ring system of monocycle or fused bicyclic containing 6 to 10 ring carbon atoms.Such as: aryl can be with
It is phenyl, naphthalene.
For heteroaryl as above to the definition of aryl, wherein one or more ring members are hetero atoms.Such as C5-10Heteroaryl
At least there are 5 members as shown in its carbon atom, but these carbon atoms can be substituted by hetero atom.Therefore, C5-10Heteroaryl packet
Include pyridyl group, indyl, indazolyl, quinoxalinyl, quinolyl, benzofuranyl, benzopyranyl, benzothiopyran derivative base, benzo
[1,3] dioxole, imidazole radicals, benzimidazolyl, pyrimidine radicals, furyl, oxazolyl, isoxazolyl, triazolyl, tetrazolium
Base, pyrazolyl, thienyl etc..
Preferably, poly- acetylene compound and its pharmaceutically acceptable salt, ester, prodrug or solvent shown in above-mentioned formula (I)
Application of the object in the drug or health care product that preparation has anti-trioxypurine effect is closed,
R1Selected from unsubstituted or 1 to 3 R1aSubstituted C1-C3Alkyl,
R1aSelected from-OCOCH3、C1-C4Alkenyl,
R2Selected from-OCH3、-CH3、-CH2OH、-CHO、-COOH、
R3It is selected from-
CH3、-COOH。
It is further preferred that poly- acetylene compound and its pharmaceutically acceptable salt, ester, prodrug shown in above-mentioned formula (I)
Or solvate is preparing the application in the drug or health care product with anti-trioxypurine effect, poly- acetylene compound shown in formula (I)
It is selected from:
It is further preferred that poly- acetylene compound and its pharmaceutically acceptable salt, ester, prodrug shown in above-mentioned formula (I)
Or solvate is preparing the application in the drug or health care product with anti-trioxypurine effect, poly- acetylene compound shown in formula (I)
And its pharmaceutically acceptable salt, ester, prodrug or solvate are added customary adjuvant, are made and clinically may be used according to common process
Tablet, capsule, powder, mixture, pill, granule, syrup, emplastrum, suppository, aerosol, ointment or the note of receiving
Penetrate agent.
Second aspect, the present invention provide poly- acetylene compound and its pharmaceutically acceptable salt shown in formula (I), ester, preceding
The application of medicine or solvate in the drug or health care product of preparation treatment gout,
Wherein, R1Selected from unsubstituted or 1 to 3 R1aSubstituted C1-C12Alkyl,
R2Selected from unsubstituted or 1 to 3 R2aSubstituted C1-C12Alkoxy, unsubstituted or 1 to 3 R2aSubstituted C1-C12
Alkyl, unsubstituted or 1 to 7 R2bSubstituted aryl, unsubstituted or 1 to 6 R2cSubstituted heteroaryl,
R1aSelected from-OCOCH3、C1-C6Alkenyl,
R2aSelected from-OH ,-OCH3、
R2bSelected from C1-C6Alkyl, hydroxyl replace C1-C6Alkyl, the C that replaces of 1 to 3 halogen1-C6Alkyl ,-
OH、C1-C6Alkoxy ,-CN, halogen ,-NH2, 1 to 2 C1-C6Alkyl-substituted amido；
R2cIt is selected from
R3Selected from unsubstituted or 1 to 3 R3aSubstituted C1-C12Alkyl, unsubstituted or 1 to 7 R3bSubstituted aryl, not
Substitution or 1 to 6 R3cSubstituted heteroaryl,
R3aIt is selected from
R3bSelected from-OH ,-OCH3；
R3cSelected from C1-C6Alkyl, hydroxyl replace C1-C6Alkyl, the C that replaces of 1 to 3 halogen1-C6Alkyl ,-
OH、C1-C6Alkoxy ,-CN, halogen ,-NH2, 1 to 2 C1-C6Alkyl-substituted amido；
R4Selected from-H ,-OH.
Preferably, poly- acetylene compound and its pharmaceutically acceptable salt, ester, prodrug or solvent shown in above-mentioned formula (I)
Application of the object in the drug or health care product of preparation treatment gout is closed,
R1Selected from unsubstituted or 1 to 3 R1aSubstituted C1-C3Alkyl,
R1aSelected from-OCOCH3、C1-C4Alkenyl,
R2Selected from-OCH3、-CH3、-CH2OH、-CHO、-COOH、
R3It is selected from-
CH3、-COOH。
It is further preferred that poly- acetylene compound and its pharmaceutically acceptable salt, ester, prodrug shown in above-mentioned formula (I)
Or application of the solvate in the drug or health care product of preparation treatment gout, poly- acetylene compound shown in formula (I) are selected from:
It is further preferred that poly- acetylene compound and its pharmaceutically acceptable salt, ester, prodrug shown in above-mentioned formula (I)
Or solvate is preparing the application in the drug or health care product for the treatment of gout, poly- acetylene compound and its medicine shown in formula (I)
Acceptable salt, ester, prodrug or solvate on are added customary adjuvant, are made clinically acceptable according to common process
Tablet, capsule, powder, mixture, pill, granule, syrup, emplastrum, suppository, aerosol, ointment or injection.
The customary adjuvant are as follows: filler, disintegrating agent, lubricant, suspending agent, adhesive, sweetener, corrigent, anti-corrosion
Agent, matrix etc..Filler includes: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose etc.；It collapses
Solving agent includes: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low substitution hydroxyl
Third cellulose, cross-linked carboxymethyl cellulose are received；Lubricant includes: magnesium stearate, lauryl sodium sulfate, talcum powder, dioxy
SiClx etc.；Suspending agent includes: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methyl cellulose etc.；Bonding
Agent includes starch slurry, polyvinylpyrrolidone, hydroxypropyl methyl cellulose etc.；Sweetener includes: saccharin sodium, aspartame, sugarcane
Sugar, honey element, enoxolone etc.；Corrigent includes: sweetener and various essence；Preservative include: parabens, benzoic acid,
Sodium benzoate, sorbic acid and its esters, benzalkonium bromide, the fixed, eucalyptus oil of acetic acid chloroethene etc.；Matrix include: PEG6000,
PEG4000, insect wax etc..
Technical solution of the present invention has the advantages that
The present invention has found that poly- acetylene compound of the invention has significantly in vivo by hyperuricemia animal model
Anti-trioxypurine effect can be used as potential anti-trioxypurine or treat the drug of gout.
Specific embodiment
In following embodiment of the present invention and experimental example, poly- acetylene compound can be carried out according to the method for the embodiment of the present invention
It prepares, can also be prepared according to the method in existing technical literature.
Ethyl alcohol/methanol concentration is volumetric concentration.
Atisine chloride Atractydin and(compound 14) is commercially available product.
Xanthine, xanthine oxidase, allopurinol, dehydrated alcohol, chloroform, methanol, the ethyl acetate, steaming for analyzing pure grade
Distilled water, dimethyl sulfoxide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate are commercial product.
Instrument of the present invention includes that standby liquid phase, Ika blender, Buchi vacuum rotary evaporator, whirlpool are suppressed in Buchi
Revolve oscillator, water-bath, Biofuge Primo R Multipurpose table type supercentrifuge, Mettlerae240 electronic balance,
Beckman Coulter AU480 Biochemical Analyzer.
Embodiment 1The preparation of compound 1-6
Specific steps are as follows:
Rhizoma atractylodis pharmaceutical decocting piece 100kg is taken, is added 80 DEG C of ethanol water extractions 3 times that 10 volumes measure 70% again, mentions every time
1.5h is taken, filtration removes the dregs of a decoction, is concentrated under reduced pressure into 100L, wherein solid content about 15kg, obtains concentrate A.
It is water-soluble with ethyl alcohol by concentrate A through low pressure D101 post separation (column diameter 28cm × high 162cm, column volume 100L)
Liquid gradient elution (first elutes 4BV with 30% ethanol water, then elutes 4BV with 95% ethanol water), collects 95%
Ethanol water eluent and be concentrated into solid content about 3kg, obtain concentrate B.
By concentrate B through LX-20SS post separation (column diameter 20cm × high 78cm, column volume 25L), with ethanol water ladder
Degree elution (first elutes 3BV with 70% ethanol water, then with 80% ethanol water elution 3BV, then with 95% ethyl alcohol
Aqueous solution elutes 4BV), it collects the eluent of 95% ethanol water and is concentrated into solid content about 1kg, obtain concentrate C.
By concentrate C through silica gel post separation (column diameter 11cm × high 65cm, column volume 6L), with petrol ether/ethyl acetate
Gradient elution is carried out (first to elute 3BV with the petrol ether/ethyl acetate of 100:0, then eluted with the petrol ether/ethyl acetate of 50:1
3BV, then 3BV is eluted with the petrol ether/ethyl acetate of 20:1, then elute 3BV with the petrol ether/ethyl acetate of 10:1, then use 5:1
Petrol ether/ethyl acetate elution elution 3BV, then with the petrol ether/ethyl acetate of 1:1 elution 3BV, finally with 95% ethanol water
Solution elutes 3BV), the eluent of above each mobile phase collects 2L, and being tentatively divided into 7 elution positions, (number is respectively FrA-
G), 9 bottles (numbering such as Fr A1-9, Fr B1-9 by 1-9 respectively in each elution position) are respectively collected at each elution position.
FrA4 is separated through ODS preparation chromatography with 75% methanol aqueous solution to get compound 1.It is prepared into above-mentioned
To 0.6g compound pass through respectively1H-NMR、13C-NMR and HPLC-MS carry out structural confirmation, by with existing literature (A new
9-nor-atractylodin from Atractylodes lancea,and the antibacterial activity of
The atractylodin derivatives.Fitoterapia, 2012,83 (1), 199-203.) in1H-NMR、13C-
NMR and HPLC-MS are compared respectively, it is known that preparation-obtained compound is compound 1.
FrA6 is separated through ODS preparation chromatography with 75% methanol aqueous solution to get compound.It is prepared above-mentioned
Compound pass through respectively1H-NMR、13C-NMR and HPLC-MS carry out structural confirmation, by with existing literature (rhizoma atractylodis carbene class
Chemical constitution study new Chinese medicine and clinical pharmacology, 2015,4,525-528.) in1H-NMR、13C-NMR and HPLC-MS points
It is not compared, it is known that preparation-obtained compound is compound 2.
FrD9 is separated through ODS preparation chromatography with 70% methanol aqueous solution, and two compounds are respectively obtained.It will be above-mentioned
Two compounds being prepared pass through respectively1H-NMR、13C-NMR and HPLC-MS carry out structural confirmation, by with existing literature
(Further phenols and polyacetylenes from the rhizomes of Atractylodes lancea
And their anti-inflammatory activity.Planta Medica, 2001,67 (5), 437-442.) in1H-NMR、13C-NMR and HPLC-MS are compared respectively, it is known that preparation-obtained compound is compound 3,4.
FrG2 is separated through ODS preparation chromatography with 20% methanol aqueous solution, and two compounds are respectively obtained.It will be above-mentioned
Two compounds being prepared pass through respectively1H-NMR、13C-NMR and HPLC-MS carry out structural confirmation, by with existing literature
(document 1:Glycosides of Atractylodes ovata.Chemical&pharmaceutical bulletin,
2003,51 (9), 1106-1108. document 2:Glycosides of Atractylodes lancea.Chemical&
Pharmaceutical bulletin, 2003,51 (6), 673-678.) in1H-NMR、13C-NMR and HPLC-MS respectively into
Row compares, it is known that preparation-obtained compound is compound 5,6.
Embodiment 2The preparation of compound 7-12
Synthetic route is as follows:
Reaction condition is specific as follows:
A:SeO2, Isosorbide-5-Nitrae-dioxane, 90 DEG C；
B:(1) Ag2O,H2O/NaOH (40%), 0 DEG C；(2) HCl (36%), pH=5, r.t.；
C: benzoic acid, DCC, DMAP, CH2Cl2, r.t.；
D:4- methyl benzoic acid, DCC, DMAP, CH2Cl2, r.t.；
E:HCHO, AlCl3, HCl, CH2Cl2；
F:CH3COOCH3, HCl/AcOH (10%), r.t..
Specific steps are as follows:
10g Atisine chloride Atractydin is taken to be dissolved in 30mL Isosorbide-5-Nitrae-dioxane, 0.6g SeO is added in solution2, stirred at 90 DEG C anti-
It answers 8 hours, reaction solution is filtered by 45 μM of millipore filters then, is then with volume ratio by silica gel column chromatography
The petroleum ether-ethyl acetate of 20:1~5:1 be mobile phase isolated and purified, respectively obtain 0.6g compound (yield 6%) and
4g intermediate product M-atractylol (yield 42%).The above-mentioned 0.6g compound being prepared is passed through respectively1H-NMR、13C-
NMR and HPLC-MS carry out structural confirmation, by with existing literature (A new 9-nor-atractylodin from
Atractylodes lancea,and the antibacterial activity of the atractylodin
Derivatives.Fitoterapia, 2012,83 (1), 199-203.) in1H-NMR、13C-NMR and HPLC-MS respectively into
Row compares, it is known that preparation-obtained compound is compound 7.
It takes 0.3g silver oxide to be dissolved in 10% sodium hydrate aqueous solution of 30mL water and 20mL, is vigorously stirred suspension, and
200mg intermediate product M-atractylol is added portionwise in 30 minutes, keeps reacting liquid temperature to be lower than 30 DEG C during charging, adds
Continue to stir 1h after having expected.After reaction, collargol is filtered and is washed with water, filtrate is acidified with concentrated hydrochloric acid, collects precipitating
Object is simultaneously washed with water to get 0.2g compound (yield 90%).The above-mentioned compound being prepared is passed through respectively1H-NMR、13C-NMR and HPLC-MS carry out structural confirmation, by with existing literature (A new 9-nor-atractylodin from
Atractylodes lancea,and the antibacterial activity of the atractylodin
Derivatives.Fitoterapia, 2012,83 (1), 199-203.) in1H-NMR、13C-NMR and HPLC-MS respectively into
Row compares, it is known that preparation-obtained compound is compound 8.
1g benzoic acid is dissolved in 120mL anhydrous methylene chloride, and adds it to 15mg 4-dimethylaminopyridine DMAP
With 150mg dicyclohexylcarbodiimide DCC, in, be stirred at room temperature mixing 15 minutes after, be added 0.8g intermediate product M-it is grey
Art element alcohol is stirred to react 4 hours.Reaction solution is first passed through 45 μM of millipore filters to be filtered, then passes through silica gel column chromatography
It is isolated and purified using volume ratio for the petroleum ether-ethyl acetate of 10:1 as mobile phase to get 1g compound (yield 82%).It will
The above-mentioned compound being prepared passes through respectively1H-NMR、13C-NMR and HPLC-MS carry out structural confirmation, by with existing literature
(A new 9-nor-atractylodin from Atractylodes lancea,and the antibacterial
Activity of the atractylodin derivatives.Fitoterapia, 2012,83 (1), 199-203.) in
's1H-NMR、13C-NMR and HPLC-MS are compared respectively, it is known that preparation-obtained compound is compound 9.
1g 4- methyl benzoic acid is dissolved in 120mL anhydrous methylene chloride, and adds it to 15mg4- dimethylamino pyrrole
Pyridine DMAP and 150mg dicyclohexylcarbodiimide DCC) in, after mixing being stirred at room temperature 15 minutes, 0.8g intermediate product is added
M-atractylol is stirred to react 4 hours.Reaction solution is first passed through 45 μM of millipore filters to be filtered, then passes through silicagel column
Chromatography is isolated and purified using volume ratio for the petroleum ether-ethyl acetate of 10:1 as mobile phase to get 0.4g compound (yield
76%).The above-mentioned compound being prepared is passed through respectively1H-NMR、13C-NMR and HPLC-MS carry out structural confirmation, by with
Existing literature (A new 9-nor-atractylodin from Atractylodes lancea, and the
Antibacterial activity of the atractylodin derivatives.Fitoterapia, 2012,83
(1), 199-203.) in1H-NMR、13C-NMR and HPLC-MS are compared respectively, it is known that preparation-obtained compound is
Compound 10.
0.5g Atisine chloride Atractydin, 50mg formaldehyde, 30mL chloroform CHCl are added into three-neck flask3And 6.0mL concentrated hydrochloric acid
Reaction solution is heated 5h at 65 DEG C, is cooled to room temperature, reaction solution is poured into water after reaction then by mixed liquor, is used
Ethyl acetate extraction, obtains ethyl acetate organic layer extract liquor.Ethyl acetate organic layer extract liquor is successively used into water, saturation Na2CO3
Aqueous solution and salt water are washed, and are then dried, filtered and are concentrated in vacuo with magnesium sulfate, obtain concentrate.Concentrate is crossed into silica gel
Petroleum ether-ethyl acetate of the column chromatography using volume ratio for 20:1 is isolated and purified as mobile phase (to be produced to get 437mg compound
Rate 86%).The above-mentioned compound being prepared is passed through respectively1H-NMR、13C-NMR and HPLC-MS carries out structural confirmation, passes through
With existing literature (A new 9-nor-atractylodin from Atractylodes lancea, and the
Antibacterial activity of the atractylodin derivatives.Fitoterapia, 2012,83
(1), 199-203.) in1H-NMR、13C-NMR and HPLC-MS are compared respectively, it is known that preparation-obtained compound is
Compound 11.
0.5g Atisine chloride Atractydin is added into 12mL acetone, is stirred at room temperature, then in N2The lower addition 1.5mL hydrochloric acid of protection/
Reaction solution is stirred at room temperature reaction about 9 hours, filtered by acetum (HCl/AcOH, 10%, v/v), and filtrate decompression is dense
Contracting, obtains concentrate.Concentrate is crossed silica gel column chromatography to be divided for the petroleum ether-ethyl acetate of 20:1 as mobile phase using volume ratio
From purifying to get 210mg compound (yield 38%).The above-mentioned compound being prepared is passed through respectively1H-NMR、13C-NMR
With HPLC-MS carry out structural confirmation, by with existing literature (A new 9-nor-atractylodin from
Atractylodes lancea,and the antibacterial activity of the atractylodin
Derivatives.Fitoterapia, 2012,83 (1), 199-203.) in1H-NMR、13C-NMR and HPLC-MS respectively into
Row compares, it is known that preparation-obtained compound is compound 12.
Embodiment 3The preparation of compound 13
Synthetic route is as follows:
Specific steps are as follows:
Under nitrogen protection, the bromo- 2- styrene of 2.0mol 1-, 0.02mol PdCl will be contained2(PPh3)2, 0.04mol
CuI and 1.5mol Et3The THF solution of the 0.2mol/L of N quickly stirs, and is added contains 1.0mol Isosorbide-5-Nitrae-bis- (front threes at room temperature
Base silicyl) -1,3- diacetylene 0.2mol/L THF solution.After reaction 1 hour, NH is saturated with 100mL4Cl aqueous solution
Then quenching reaction is extracted with 3*50mL ethyl acetate, obtains ethyl acetate organic layer extract liquor.Ethyl acetate organic layer is extracted
Liquid is saturated NaCl aqueous solution with 50mL and washs, and then uses Na2SO4Dry, vacuum concentration obtains concentrate.Concentrate is passed through into silicon
Rubber column gel column chromatography using petroleum ether-ethyl acetate as mobile phase isolated and purified to get.
The above-mentioned compound being prepared is passed through respectively1H-NMR、13C-NMR and HPLC-MS carries out structural confirmation, passes through
With existing literature (A straightforward synthesis of symmetrical polyendiynes by
dimerization reactions of silyl derivatives.Journal of Organometallic
Chemistry, 1998,566 (1-2), 251-257.) in1H-NMR、13C-NMR and HPLC-MS are compared respectively, it is known that
Preparation-obtained compound is compound 13.
Experimental example 1The research of the compounds of this invention anti-trioxypurine effect
1, experimental material
It healthy male KM mouse 200, weight 15-18g, is provided by Shanghai Ling Chang Biotechnology Co., Ltd；By every
After cage 5 only carries out point cage processing, adaptive feeding 4 days in barrier system.
2, experimental method
2.1 experimental group
180 mouse that weight is concentrated are chosen from 200 mouse is divided into 18 groups by weight stochastic averagina, every group 10,
Respectively blank control group, model control group, positive controls, experimental group 1-15 group.
2.2 medication
Laundering period carries out gastric infusion to mouse immediately later, and every morning stomach-filling 1 time, continuous gavage is administered 7 days.
Experimental group 1-14 group gives compound 1-13 30mg/kg of embodiment 1-3 preparation, commercially available compound 14 respectively
30mg/kg, 15 groups of experimental group are given Atisine chloride Atractydin 30mg/kg, are carried out respectively with 0.5% sodium carboxymethylcellulose (CMC-Na) solution
It is suspended；Positive controls give Febustat 1.0mg/kg, are mixed with 0.5% sodium carboxymethylcellulose (CMC-Na) solution
It is outstanding；Blank control group and model control group use 0.5% sodium carboxymethylcellulose (CMC-Na) solution stomach-filling；Each group continuously fills
Stomach is administered 7 days.
After morning gastric infusion 0.5 hour the 7th day, intraperitoneal injection progress hyperuricemia is carried out to each group mouse and is made
Mould.Wherein, 0.5% sodium carboxymethylcellulose (CMC-Na) solution is injected intraperitoneally in blank control group；Model control group, positive control
Group, experimental group 1-15 group inject 300mg/kg Oteracil Potassium (OA), are dissolved with CMC-Na solution.
3, experimental data detection and processing
3.1 Testing index
After hyperuricemia modeling 1.5 hours, each group mouse extracts eyeball, and blood was collected, and blood sampling capacity is not less than 0.5mL,
In being placed at room temperature for about 1 hour after blood specimen collection, it is centrifuged 10 minutes, takes under the conditions of 3500rpm/4 DEG C after blood solidifies completely
Serum is under equal conditions multiple from 5 minutes, and 0.2mL serum is then taken to detect UA value by Biochemical Analyzer.
3.2 statistical analysis
It is for statistical analysis to data with Excel and SPSS, average and SD are calculated, is compared after one-way analysis of variance
The group difference of each experimental group.
4, experimental result
After administration 7 days, influence of each group to the serum uric acid level of hyperuricemia mouse is as shown in table 1.
Influence of the table 1 to uric acid level in hyperuricemia mice serum
Note:##Expression is compared with blank control group, P < 0.01；**Expression is compared with model control group, P < 0.01；
*Expression is compared with model control group, P < 0.05 (t-test inspection)
As shown in Table 1: (1) with blank control group compared with, the uric acid in serum of model control group mouse significantly increase (P <
0.01), this shows hyperuricemia model modeling success；
(2) compared with model control group, the reduction of the uric acid in serum level of experimental group 1-15 group mouse has conspicuousness
Difference (P < 0.01 or P < 0.05)；
(3) reducing effect of the uric acid in serum level of experimental group 1-14 group mouse is better than the serum of 15 groups of mouse of experimental group
The reducing effect of middle uric acid level.
5, experiment conclusion
The poly- acetylene compound of the present invention has significant anti-trioxypurine effect in vivo, can be used as the medicine of potential anti-trioxypurine
Object.
Experimental example 2Pharmacokinetics experiment
1, experiment purpose
Study the pharmacokinetic profile of the compounds of this invention.
2, experimental method
2.1 experimental animals and grouping
It healthy male SD rat 180, weight 180-220g, is provided by Shanghai Ling Chang Biotechnology Co., Ltd；By every
After cage 5 only carries out point cage processing, adaptive feeding 5 days in the barrier system of Suzhou Kai Xiang Biotechnology Co., Ltd, from 180
150 are selected in only, is divided into 15 groups by weight stochastic averagina, every group 10, respectively control group, experimental group 1-14 group.
2.2 medication
Experimental group 1-14 group gives compound 1-13 20mg/kg of embodiment 1-3 preparation, commercially available compound 14 respectively
20mg/kg is suspended with 0.5% sodium carboxymethylcellulose (CMC-Na) solution respectively；Atisine chloride Atractydin is given in control group stomach-filling
20mg/kg is suspended with 0.5% sodium carboxymethylcellulose (CMC-Na) solution.
And before administration, 10 after administration, 20,30,45,60min and 2,4,6,8,12, for 24 hours when eye socket take blood, collect blood plasma
200uL adds 400uL acetonitrile precipitation albumen, mixes 90s, 12000rpm, is centrifuged 10min, then takes supernatant 20uL fixed using HPLC
Amount detects the content of each ingredient.
2.3 HPLC chromatogram conditions
Agilent 1260 matches DAD detector；C18 chromatographic column (4.6 × 250mm, 5 μm)；Flow velocity 0.8mL/min；Column temperature
30℃；10 μ L of sample volume；Detection wavelength 340nm；Mobile phase: acetonitrile-water=76:24 (v/v).
It is linear good between 0.05-5.0mg/L after each compound blood sample treatments under this method by methodology validation,
It can be used for quantitative analysis.
3, experimental result
It is for statistical analysis to data with DAS and SPSS processing software, the pharmacokinetic parameters of each compound are calculated, it is specific real
Test that the results are shown in Table 2.
The pharmacokinetics experiment result of 2 each group of table
It as shown in Table 2, being capable of absorbed into serum after (1) compound 1-14 is oral；(2) compared with Atisine chloride Atractydin, compound 1-
Elimination is slower in 14 bodies, blood concentration fluctuation is smaller, circulation time in vivo is longer.
4, experiment conclusion
Eliminated in poly- acetylene compound 1-14 body of the invention slower, blood concentration fluctuation is smaller, circulation time in vivo more
It is long, be conducive to it and play anti-trioxypurine effect in vivo.
Obviously, the above embodiments are merely examples for clarifying the description, and does not limit the embodiments.It is right
For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of variation or
It changes.There is no necessity and possibility to exhaust all the enbodiments.And it is extended from this it is obvious variation or
It changes still within the protection scope of the invention.
Claims (8)
1. poly- acetylene compound shown in formula (I) and its pharmaceutically acceptable salt, ester, prodrug or solvate have in preparation
Application in the drug or health care product of anti-trioxypurine effect,
Wherein, R1Selected from unsubstituted or 1 to 3 R1aSubstituted C1-C12Alkyl,
R2Selected from unsubstituted or 1 to 3 R2aSubstituted C1-C12Alkoxy, unsubstituted or 1 to 3 R2aSubstituted C1-C12Alkane
Base, unsubstituted or 1 to 7 R2bSubstituted aryl, unsubstituted or 1 to 6 R2cSubstituted heteroaryl,
R1aSelected from-OCOCH3、C1-C6Alkenyl,
R2aSelected from-OH ,-OCH3、
R2bSelected from C1-C6Alkyl, hydroxyl replace C1-C6Alkyl, the C that replaces of 1 to 3 halogen1-C6Alkyl ,-OH, C1-
C6Alkoxy ,-CN, halogen ,-NH2, 1 to 2 C1-C6Alkyl-substituted amido；
R2cIt is selected from
R3Selected from unsubstituted or 1 to 3 R3aSubstituted C1-C12Alkyl, unsubstituted or 1 to 7 R3bIt is substituted aryl, unsubstituted
Or 1 to 6 R3cSubstituted heteroaryl,
R3aIt is selected from
R3bSelected from-OH ,-OCH3；
R3cSelected from C1-C6Alkyl, hydroxyl replace C1-C6Alkyl, the C that replaces of 1 to 3 halogen1-C6Alkyl ,-OH, C1-
C6Alkoxy ,-CN, halogen ,-NH2, 1 to 2 C1-C6Alkyl-substituted amido；
R4Selected from-H ,-OH.
2. poly- acetylene compound and its pharmaceutically acceptable salt, ester, prodrug shown in formula (I) according to claim 1
Or application of the solvate in the drug or health care product that preparation has anti-trioxypurine effect, which is characterized in that
R1Selected from unsubstituted or 1 to 3 R1aSubstituted C1-C3Alkyl,
R1aSelected from-OCOCH3、C1-C4Alkenyl,
R2Selected from-OCH3、-CH3、-CH2OH、-CHO、-COOH、
R3It is selected from-CH3、-COOH。
3. poly- acetylene compound shown in formula (I) according to claim 1 or 2 and its pharmaceutically acceptable salt, ester, preceding
The application of medicine or solvate in the drug or health care product that preparation has anti-trioxypurine effect, which is characterized in that shown in formula (I)
Poly- acetylene compound is selected from:
4. poly- acetylene compound shown in formula (I) according to claim 1-3 and its pharmaceutically acceptable salt,
The application of ester, prodrug or solvate in the drug or health care product that preparation has anti-trioxypurine effect, which is characterized in that formula (I)
Shown in poly- acetylene compound and its pharmaceutically acceptable salt, ester, prodrug or solvate be added normal according to common process
Auxiliary material is advised, clinically acceptable tablet, capsule, powder, mixture, pill, granule, syrup, emplastrum, bolt is made
Agent, aerosol, ointment or injection.
5. poly- acetylene compound shown in formula (I) and its pharmaceutically acceptable salt, ester, prodrug or solvate are treated in preparation
The drug of gout or the application in health care product,
Wherein, R1Selected from unsubstituted or 1 to 3 R1aSubstituted C1-C12Alkyl,
R2Selected from unsubstituted or 1 to 3 R2aSubstituted C1-C12Alkoxy, unsubstituted or 1 to 3 R2aSubstituted C1-C12Alkane
Base, unsubstituted or 1 to 7 R2bSubstituted aryl, unsubstituted or 1 to 6 R2cSubstituted heteroaryl,
R1aSelected from-OCOCH3、C1-C6Alkenyl,
R2aSelected from-OH ,-OCH3、
R2bSelected from C1-C6Alkyl, hydroxyl replace C1-C6Alkyl, the C that replaces of 1 to 3 halogen1-C6Alkyl ,-OH, C1-
C6Alkoxy ,-CN, halogen ,-NH2, 1 to 2 C1-C6Alkyl-substituted amido；
R2cIt is selected from
R3Selected from unsubstituted or 1 to 3 R3aSubstituted C1-C12Alkyl, unsubstituted or 1 to 7 R3bIt is substituted aryl, unsubstituted
Or 1 to 6 R3cSubstituted heteroaryl,
R3aIt is selected from
R3bSelected from-OH ,-OCH3；
R3cSelected from C1-C6Alkyl, hydroxyl replace C1-C6Alkyl, the C that replaces of 1 to 3 halogen1-C6Alkyl ,-OH, C1-
C6Alkoxy ,-CN, halogen ,-NH2, 1 to 2 C1-C6Alkyl-substituted amido；
R4Selected from-H ,-OH.
6. poly- acetylene compound and its pharmaceutically acceptable salt, ester, prodrug shown in formula (I) according to claim 5
Or application of the solvate in the drug or health care product of preparation treatment gout, which is characterized in that
R1Selected from unsubstituted or 1 to 3 R1aSubstituted C1-C3Alkyl,
R1aSelected from-OCOCH3、C1-C4Alkenyl,
R2Selected from-OCH3、-CH3、-CH2OH、-CHO、-COOH、
R3It is selected from-CH3、-COOH。
7. poly- acetylene compound shown in formula (I) according to claim 5 or 6 and its pharmaceutically acceptable salt, ester, preceding
The application of medicine or solvate in the drug or health care product of preparation treatment gout, which is characterized in that carbene class shown in formula (I)
Compound is selected from:
8. according to poly- acetylene compound shown in the described in any item formulas of claim 5-7 (I) and its pharmaceutically acceptable salt,
The application of ester, prodrug or solvate in the drug or health care product of preparation treatment gout, which is characterized in that shown in formula (I)
Customary adjuvant is added according to common process in poly- acetylene compound and its pharmaceutically acceptable salt, ester, prodrug or solvate,
Clinically acceptable tablet, capsule, powder, mixture, pill, granule, syrup, emplastrum, suppository, aerosol is made
Agent, ointment or injection.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN111714485A (en) * | 2019-03-20 | 2020-09-29 | 苏州凯祥生物科技有限公司 | Hyperuricemia pharmaceutical composition and application thereof |
| 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 |
| CN113493374A (en) * | 2020-04-08 | 2021-10-12 | 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 (4)
| Title |
|---|
| FRANCESCO BABUDRI等: "A straightforward synthesis of symmetrical polyendiynes by dimerization reactions of silyl derivatives", 《JOURNAL OF ORGANOMETALLIC CHEMISTRY》 * |
| SAKURAI, TETSURO: "Enzyme inhibitory activities of acetylene and sesquiterpene compounds in Atractylodes rhizome", 《BIOLOGICAL & PHARMACEUTICAL BULLETIN 》 * |
| YANJUN CHEN等: "A new 9-nor-atractylodin from Atractylodes lancea and the antibacterial activity of the atractylodin derivatives", 《FITOTERAPIA》 * |
| 陈红风: "《中医外科学》", 31 August 2016, 中国中医药出版社 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN111714485A (en) * | 2019-03-20 | 2020-09-29 | 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 |
| CN113493374A (en) * | 2020-04-08 | 2021-10-12 | 苏州凯祥生物科技有限公司 | SIRT1 receptor agonist and medicine containing same |
| 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 |
| WO2021204193A1 (en) * | 2020-04-08 | 2021-10-14 | 苏州凯祥生物科技有限公司 | Sirt1 receptor agonist and medicament comprising same |
| 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 |
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