CN104586863B - Application of digallate derivative to preparation of medicine for treating hyperuricemia - Google Patents
Application of digallate derivative to preparation of medicine for treating hyperuricemia Download PDFInfo
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Abstract
The invention discloses application of a digallate derivative which has a formula (I) and a pharmaceutically acceptable salt thereof to preparation of a medicine for treating hyperuricemia. The digallate derivative has a strong effect of inhibiting xanthine oxidase in vitro, can be used for reducing the level of serum uric acid of a mouse with hyperuricemia significantly, is dose dependent and can be used for treating hyperuricemia and gout or gout complications caused by hyperuricemia as a potential xanthine oxidase inhibitor and a potential uric acid lowering medicine.
Description
Technical field
The invention belongs to chemical medicine, and in particular to a kind of digallic acid ester derivant and its pharmaceutically acceptable
Application of the salt in treatment antihyperuricemic disease drug is prepared, a kind of and medicine group for treating hyperuricemia and gout
Compound.
Background technology
In chemical medicine, uric acid is the end metabolite eventually of mankind's purine compound.Purine metabolic disturbance causes
Hyperuricemia.Under normal purine diet state, it is non-on the same day twice empty stomach serum uric acid level male be higher than 420 μm of ol/L, female
Property be higher than 360 μm of ol/L, i.e. referred to as hyperuricemia (hyperuricemia).Primary disease prevalence is affected by various factors,
It is relevant with heredity, sex, age, life style, dietary habit, Drug therapy and economic development level etc..According to various places in recent years
The report of prevalence of hyperuricemia, current China there are about hyperuricemia person 1.2 hundred million, account for the 10% of total population, year occurred frequently
Age is middle-aging male and postmenopausal women, but has rejuvenation trend in recent years.With the change and life of people's dietary structure
The raising of level, the sickness rate of hyperuricemia are improved year by year, it was reported that claimed, and there are about the adult male of twenty percent at present in high urine
The state of acidemia.Generally, it is simple not have a subjective symptomss in hyperuricemia state, but if long-time let alone should
State, the urate in blood will be deposited on there is crystallization, the urate of crystallization the positions such as joint, subcutaneous tissue, kidney, enter
And there are the series of clinical manifestations such as gout, arthritis, subcutaneous gout calculus, kidney stone or gouty nephropathy.Therefore, suitably
It is to prevent, improve the basic of hyperuricemia with gout as representative to control the uric acid level in blood.
At present, the control to uric acid in blood is mainly realized by following two approach：(1) suppress the life of uric acid
Into.Uric acid is generated by the effect of hypoxanthine and xanthine Jing xanthine oxidases.Xanthine oxidase is in catalysis
State reaction, and then generate uric acid necessary to enzyme, therefore, suppress xanthine oxidase (xanthine oxidase, XO) activity
The formation of uric acid can effectively be suppressed, and then play a part of to treat the symptoms such as gout.Suppression uricopoiesis conventional at present
Medicine has allopurinol, Febuxostat etc.；(2) promote the excretion of uric acid.The medicine of promotion urate excretion conventional at present has third
Sulphur relaxes, benzbromarone etc..
Above two mode can play a part of reduce uric acid in blood, and then to hyperuricemia cause gout,
The diseases such as arthritis, subcutaneous gout calculus, kidney stone or gouty nephropathy produce curative effect, but said medicine toxic and side effects are logical
Often larger, for example, allopurinol can cause allergy (sickness rate 10-15%), super quick syndrome, bone marrow depression etc. serious
Toxic and side effects；Probenecid, Benzbromarone then have stimulating gastrointestinal road, cause renal colic, excite the side effect such as gout acute attack,
The clinical practice of these medicines is limited to a certain extent.
Gallic acid is a kind of compound being widely present in plant, according to document report [chemistry world, 2009 (5),
273-276], gallic acid has certain xanthine oxidase inhibitory activity, but only reports its vitro inhibition xanthine oxidase
Change enzymatic activity, no further animal experimental data.We have been surprisingly found that a series of epicatechol gallate in follow-up research
Derivant, they have xanthine oxidase inhibitory activity that is identical or being significantly higher than gallic acid in vitro, move in vivo
In thing experiment, activity of these derivants with the reduction animal blood uric acid apparently higher than gallic acid.
The content of the invention
The technical problem to be solved is to provide a kind of digallic acid ester derivant and its can pharmaceutically connect
The salt received is used for the purposes for preparing treatment antihyperuricemic disease drug, and a kind of medicine group for treating hyperuricemia and gout
Compound.
The purpose of the present invention is achieved through the following technical solutions：
It is prepared by a kind of digallic acid ester derivant and its pharmaceutically acceptable salt with the structure as shown in formula (I)
Purposes in treatment antihyperuricemic disease drug,
Wherein：
X1、X2, X3, X4 it is independent of each other selected from-H ,-OH ,-OR ,-F ,-Cl ,-Br ,-I ,-N (R)2、-C(O)R、-C(O)
One kind in OR ,-CHO ,-CN；
R is selected from-H, substituted or unsubstituted C1To C6Alkane, the one kind in cycloalkane or heterocycloalkane；
Y1、Y2One kind in C, P-OH, S or S=O independent of each other；
Z1、Z2One kind in CHRa, O, NH, NRa or S independent of each other；Ra selected from-H or C1-C8 alkane,
One kind in cycloalkane；
V is independently chosen from or V is connected with Ra to form replacement or unsubstituted C1To C18Alkane, branched paraffin, take
Generation or unsubstituted C3To C8Cycloalkane ,-(CH2)mOne kind in-Rc, benzyl, aromatic radical；Wherein Rc is substituted or unsubstituted
C3To C8Cycloalkane or heterocycloalkane, the value of m is 1-8.
Preferably, the digallic acid ester derivant is with the structure as shown in formula (II)：
Wherein：
R is selected from-H, substituted or unsubstituted C1To C6Alkane, the one kind in cycloalkane or heterocycloalkane；
Y1、Y2One kind in C, P-OH, S or S=O independent of each other；
Z1、Z2One kind in CHRa, O, NH, NRa or S independent of each other；Ra selected from-H or C1-C8 alkane,
One kind in cycloalkane；
V is independently chosen from or V is connected with Ra to form replacement or unsubstituted C1To C18Alkane, branched paraffin, take
Generation or unsubstituted C3To C8Cycloalkane ,-(CH2)mOne kind in-Rc, benzyl, aromatic radical；Wherein Rc is substituted or unsubstituted
C3To C8Cycloalkane or heterocycloalkane, the value of m is 1-8.
It is further preferred that the digallic acid ester derivant is with the structure as shown in formula (III)：
Wherein：
Wherein：
Z1、Z2One kind in CHRa, O, NH, NRa or S independent of each other；Ra selected from-H or C1-C8 alkane,
One kind in cycloalkane；
V is independently chosen from or V is connected with Ra to form replacement or unsubstituted C1To C18Alkane, branched paraffin, take
Generation or unsubstituted C3To C8Cycloalkane ,-(CH2)mOne kind in-Rc, benzyl, aromatic radical；Wherein Rc is substituted or unsubstituted
C3To C8Cycloalkane or heterocycloalkane, the value of m is 1-8.
It is highly preferred that the digallic acid ester derivant has structure as shown below：
The medicine also includes pharmaceutically acceptable carrier.
Medicine addition customary adjuvant make clinically-acceptable tablet, capsule, oral solutionses, powder, drop pill,
Granule or injection.
The hyperuricemia includes the gout and gout complication that hyperuricemia causes.
The gout complication includes gouty arthritises, gouty nephropathy, lithangiuria or cardiovascular disease.
The present invention also provides a kind of pharmaceutical composition for treating hyperuricemia, containing this in described pharmaceutical composition
The described digallic acid ester derivant of invention and its pharmaceutically acceptable salt.
It is an advantage of the current invention that：
Digallic acid ester derivant of the present invention not only shows to xanthine oxidase that stronger vitro inhibition is made
With, the serum uric acid level with hyperuricemia mice is also can obviously reduce, and dose dependent is presented, and nontoxic secondary work
With, it is safe, therefore hyperuricemia and height can be used for as potential xanthine oxidase inhibitor and uric acid resisting medicine
The treatment of gout or gout complication that hyperuricemia causes.
Experimental example
Xanthine, xanthine oxidase, allopurinol, the dehydrated alcohol for analyzing pure level used in the present invention, chloroform, first
Alcohol, ethyl acetate, distilled water, dimethyl sulfoxide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate are commercially available prod.
Instrument of the present invention includes compacting standby liquid phase, Ika agitators, Buchi vacuum rotary evaporators, whirlpool in Buchi
Rotation agitator, water-bath, Biofuge Primo R Multipurpose table type high speed centrifuges, METTLERAE240 electronic balances,
BECKMAN COULTER AU480 biochemistry analyzer.
Compound 1 is separated from corresponding plant for the present invention and is obtained；Compound 2-8 is through chemistry by precursor compound
Conversion is obtained, and details are referring to embodiment 1-8.
Experimental example 1：In-vitro Inhibitory Effect of the digallic acid ester derivant to xanthine oxidase
Solution is prepared：
Phosphate buffered solution：Weigh the K of 19.48g2HPO4.3H2The KH of O and 1.99g2PO4It is dissolved in 500mL distilled water,
It is made into the phosphate buffered solution (pH=7.5) that concentration is 0.2mmol/L；
Xanthine substrate solution：Xanthine 15.2mg is weighed, is dissolved in 250mL distilled water, being made into concentration is
The xanthine substrate solution of 0.4mmol/L；
Xanthine oxidase solution：Xanthine oxidase 5U is taken, and 160mL is diluted to above-mentioned phosphate buffered solution, is matched somebody with somebody
Into the xanthine oxidase solution that concentration is 80U/L, 4 DEG C of preservations；
Sample and positive control solution：Precision weighs sample (compound 1-8), gallic acid, and allopurinol is (as the positive
Control), respectively with dimethyl sulfoxide dissolving, distilled water diluting, the solution for being made into the variable concentrations that concentration is 0.01-2 μm of ol/L enters
Row test (wherein the ultimate density of dimethyl sulfoxide is less than 1%).
Inhibitory action is tested：
Sample sets are tested：200 μ L of xanthine substrate solution, sample solution (compound 1- are sequentially added in 2mL centrifuge tubes
8) 200 μ L of 100 μ L and xanthine oxidase solution, are vortexed to be placed in 25 DEG C of water-baths after shaking 5 seconds and react 5 minutes, reacted
1.5mL dehydrated alcohol is added after finishing, be vortexed 5 seconds terminating reactions of concussion.Reactant liquor Jing 3500rpm are centrifuged 5 minutes, draw 200 μ L
To in 1.5mL centrifuge tubes, the UA values of each sample are detected respectively with biochemistry analyzer, each sample operation repetitive is averaged for three times
Value.
Blank control group is tested：200 μ L of xanthine substrate solution, phosphate-buffered are sequentially added in 2mL centrifuge tubes molten
200 μ L of 100 μ L of liquid and xanthine oxidase solution, detect the UA values of blank control group with method, and operation repetitive is averaged for three times.
Positive controls are tested：200 μ L of xanthine substrate solution, positive control solution are sequentially added in 2mL centrifuge tubes
200 μ L of 100 μ L and xanthine oxidase solution, detect the UA values of positive controls with method, and operation repetitive is averaged for three times.
Test result：
According to xanthine oxidase suppression ratio=[(blank control group UA value-sample sets UA value)/blank control group UA
Value] * 100, calculate suppression ratio；Drug level C=C in enzymatic reaction0*0.1/3.1(C0For sample solution concentration)；By medicine
Concentration is returned with suppression ratio, obtains regression equation；The suppression of C values when being 50% according to regression equation calculation suppression ratio, i.e. half
Concentration IC processed50, as a result as shown in table 1.
In-vitro Inhibitory Effect (ICs of the 1 compound 1-8 of table to xanthine oxidase50, μm ol/L)
| Test-compound | IC50 |
| Compound 1 | 0.15 |
| Compound 2 | 0.13 |
| Compound 3 | 0.22 |
| Compound 4 | 0.25 |
| Compound 5 | 0.31 |
| Compound 6 | 0.19 |
| Compound 7 | 0.31 |
| Compound 8 | 0.72 |
| Gallic acid | 0.32 |
| Positive control | 0.07 |
Digallic acid ester derivant of the present invention shows stronger In-vitro Inhibitory Effect to xanthine oxidase, can
It is used for the treatment of hyperuricemia as potential xanthine oxidase inhibitor.
Experimental example 2：Serum uric acid level of the digallic acid ester derivant to reduction hyperuricemia mice
Experimental animal and packet：Healthy male KM mice 80, body weight is 15-18g, limited by the smooth biotechnology of Shanghai spirit
Company provides；
Only carry out after point cage process, in the barrier system endoadaptation of Suzhou Kai Xiang bio tech ltd by every cage 5
Raise 4 days, 70 mices that body weight concentration is chosen from 80 mices are divided into 7 groups by body weight stochastic averagina, 10 per group, respectively
For blank control group, hyperuricemia model group, positive controls, gallic acid group, test-compound group are (respectively of the invention
Compound 2,5,8).
The modeling of hyperuricemia：
Carry out gastric infusion after the laundering period immediately to mice, every morning gavage 1 time, wherein test-compound group and do not have
Gallate-based group is suspended with pure water, carries out gavage according to 20mg/kg；Positive control Febustat is suspended with pure water, is pressed
Gavage is carried out according to 2.5mg/kg；Blank control group and hyperuricemia model group are compareed with pure water gavage, continuous gavage 7
My god；
Lumbar injection modeling, wherein blank control group lumbar injection to mice are carried out after 0.5 hour in the 7th day morning gavage
0.5% sodium carboxymethyl cellulose (CMC-Na) solution；The injection of hyperuricemia model group, positive controls and test-compound group
Oteracil Potassium (OA), is dissolved with CMC-Na solution, and injection volume is 300mg/kg body weight；
Lumbar injection is extractd the eyeball of mice and is taken a blood sample after 1.5 hours, blood sampling capacity is not less than 0.5mL, blood specimen collection
Place about 1 hour after room temperature, treat that blood solidifies completely and be centrifuged 10 minutes under the conditions of 3500rpm/4 DEG C, serum is taken same
It is multiple from 5 minutes Deng under the conditions of, then take 0.2mL serum and use biochemistry analyzer to detect UA values；
With Excel and SPSS data are carried out with statistical analysiss, average and SD is calculated, is compared Jing after one factor analysis of variance
The group difference of each experimental group, compared with blank control group, hyperuricemia model group, positive controls and test-compound group
The serum uric acid level of mice is significantly improved, and has significant difference, shows modeling success.
The impact (μm ol/L) of 22,5,8 pairs of hyperuricemia mice serum uric acid levels of compound of table
Note：* represented compared with hyperuricemia model group, P<0.01 (t-test inspections).
Digallic acid ester derivant of the present invention can substantially reduce the serum uric acid with hyperuricemia mice
Level, with statistical significance compared with hyperuricemia model group, can be used for hyperuricemia as potential uric acid resisting medicine
Treatment.
Experimental example 3：Digallic acid ester derivant reduces the dose-effect relationship of hyperuricemia mice serum uric acid level and grinds
Study carefully
Experimental animal and packet：
Healthy male KM mice 100, body weight is 13-15g, is provided by Shanghai Ling Chang bio tech ltd；
Only carry out after point cage process, in the barrier system endoadaptation of Suzhou Kai Xiang bio tech ltd by every cage 5
Raise 4 days, 90 mices that body weight concentration is chosen from 100 mices divide 9 groups by body weight stochastic averagina, 10 per group, respectively
For blank control group, hyperuricemia model group, positive controls Febustat, test-compound group (totally 6 groups, respectively this
Invention compound 2,4,3 kinds of dosage of each compound point).
The modeling of hyperuricemia：
Carry out gastric infusion after the laundering period immediately to mice, every morning gavage 1 time, wherein test-compound group are changed
Compound is suspended with pure water, carries out gavage according to 10mg/kg, 50mg/kg, 200mg/kg Three doses respectively；Positive controls, it is non-
Bu Sita is suspended with pure water, carries out gavage according to 2.5mg/kg；Blank control group and hyperuricemia model group are filled with pure water
Stomach is compareed, continuous gavage 7 days；
Lumbar injection modeling, wherein blank control group lumbar injection to mice were carried out after morning gavage 0.5h at the 7th day
0.5%CMC-Na solution；Hyperuricemia model group, positive controls and test-compound group injection Oteracil Potassium (OA), use
CMC-Na solution is dissolved, and injection volume is 300mg/kg；
The eyeball that mice is extractd after lumbar injection 1.5h is taken a blood sample, and blood sampling capacity is not less than 0.5mL, blood specimen collection after
Room temperature places about 1h, treats that blood solidifies completely and 10min is centrifuged under the conditions of 3500rpm/4 DEG C, take serum under equal conditions
Repeated centrifugation 5min, then takes 0.2mL serum and uses biochemistry analyzer to detect UA values；
With Excel and SPSS data are carried out with statistical analysiss, average and SD is calculated, is compared Jing after one factor analysis of variance
The group difference of each experimental group, compared with blank control group, hyperuricemia model group, positive controls and test-compound group
The serum uric acid level of mice is significantly improved, and has significant difference, shows modeling success.
Impact of the 3 various dose compound of table to hyperuricemia mice serum uric acid level
Note：* represent compared with hyperuricemia model group, P<0.05；* represented compared with hyperuricemia model group, P<
0.01 (t-test inspections).
Digallic acid ester derivant of the present invention can substantially reduce the serum uric acid with hyperuricemia mice
Level, and dose dependent is presented, with statistical significance compared with hyperuricemia model group, can be used as potential uric acid resisting medicine
Thing is used for the treatment of hyperuricemia.
Specific embodiment
Embodiment 1：The extraction of the compounds of this invention 1 and sign
Fructus Phyllanthi medical material 5kg is taken, is crushed, extract 40min with 5L water in the state of micro-boiling is kept.Will be extracting solution vacuum dense
Be reduced to 1L, concentrated solution carries out column chromatography for separation with Diaion HP-20 macroporous adsorbent resins, respectively with water, 30% ethanol, 60%
Ethanol, 95% ethanol carry out eluting for eluent.The eluent for taking 20g water elutions carries out column chromatography for separation with anti-phase C18 silica gel,
It is that eluent carries out eluting with the ethanol of 5%-10%, you can obtain the compounds of this invention 1；Which is detected and characterize data
It is as follows：
Compound 1：C20H20O14, molecular weight 485 [M+H]+
1H-NMR(MeOH-d4,400MHz)δ:7.12(2H,s),7.06(2H,s),5.68(1H,d),4.54(1H,dd)
4.39(1H),4.01(1H,m),3.70(1H,m),3.53(1H,m),.3.24(1H,m)；13C-NMR(MeOH-d4,100MHz)
δ:168.0,166.6,146.1,146.1,140.1,139.5,139.5,120.9,120.9,120.2,120.2,110.2,
109.8,109.8,,95.6,77.6,76.1,73.7,70.8,64.1.It can be seen that its structure is correct.
Embodiment 2：The preparation of the compounds of this invention 2 and sign
The compounds of this invention 2-8 can be prepared using following synthetic route：
In the present embodiment, the compound 2 of the present invention is prepared according to following synthetic route：
Concrete operations are as follows:
(1) the benzoic synthesis of 3,4,5- tribenzyls
17.0g gallic acids are dissolved in the dimethylformamide (abbreviation DMF, similarly hereinafter) of 800ml, and are protected using nitrogen
Shield, is dividedly in some parts 113g Anhydrous potassium carbonates, after stirring 1h, is warmed up to 40 DEG C, then 143ml benzyls bromine is dripped in 30min at 25 DEG C
It is added in reaction system；After completion of dropping, reaction mixture is stirred into 12h at 40 DEG C；Show that result determines using TLC points plate
After reaction is carried out completely, stop heating, make reaction temperature be down to 25 DEG C of room temperature；The ethyl acetate of 400ml water and 1L is added to instead
In answering system, the extraction of point liquid, organic faciess 500ml water washings three times, then with anhydrous sodium sulfate drying, are concentrated in vacuo to dry；
In the mixed liquor of 5M (i.e. mol/L) sodium hydroxide solution that dried object is dissolved in 500ml ethanol and 500ml, 10h is refluxed,
Show that result is determined after hydrolysis completely using TLC, mixed liquor is cooled to into room temperature, 500ml water is added thereto to, then is used concentrated hydrochloric acid
PH value is adjusted to 2, the solid for separating out is collected.By gained solid in 1L methanol recrystallization, obtain 37.5 grams of white solid (yields
85%), as 3,4,5- tribenzyl-benzene formic acid (see the compound A in synthetic route)；
(2) synthesis of 3,4,5- tribenzyl-benzenes formyl chloride
Take 10g steps 1) in 3,4, the 5- tribenzyl-benzene formic acid that prepare, be dissolved in 20ml thionyl chlorides, and use nitrogen
Gas shielded, stirs 3.5h at 65 DEG C, and then vacuum revolving removes unnecessary unreacted thionyl chloride, and the grease of gained is used
100ml normal hexane and 100ml toluene steam twice respectively altogether thoroughly to remove unnecessary unreacted thionyl chloride, obtain final product the 3 of solid,
4,5- tribenzyl-benzene formyl chlorides (see the compound B in synthetic route).
(3) synthesis of double (3,4,5- tribenzyl-benzene formic acid) glycol esters
DMAP (abbreviation DMAP, similarly hereinafter), 3g ethylene glycol and the 10ml pyridines of 2g are taken respectively, are dissolved in 150ml
In dichloromethane, and protected using nitrogen, be stirred at room temperature；Take step 2) in the 3,4,5- tribenzyls of solid that prepare
Benzenecarbonyl chloride., is dissolved in 100ml dichloromethane, and is added drop-wise to the reaction that above-mentioned DMAP, ethylene glycol, pyridine, dichloromethane are constituted
In system, 5h is refluxed, then mixed liquor is concentrated, by residue by silicagel column purification (sil-gel), with petroleum ether-second
Acetoacetic ester system gradient elution, obtains final product double (3,4,5- tribenzyl-benzene formic acid) glycol esters of 19g (see the chemical combination in synthetic route
Thing C)；
(4) synthesis of double (3,4,5-trihydroxy benzoic acid) glycol esters
Take 10g steps 3) in double (3,4,5- tribenzyl-benzene formic acid) glycol esters for preparing be dissolved in 200ml methanol,
Again the 10%Pd-C catalyst of 500ml is added slowly in reaction system, then replacing hydrogen, stir under hydrogen environment
Using TLC, 4h, shows that result is determined after reaction completely, filter, filtrate is spin-dried for, then with silica column purification (silica gel),
With petroleum ether-ethyl acetate system gradient elution, 3.5g white solids are obtained, obtain final product compound 2.
Product is detected and characterize data is as follows:
Compound 2:C16H14O10, molecular weight 367 [M+H]+
1H NMR(400MHz,CD3OD)δ6.91(s,4H),4.30(t,4H)；13C NMR(100MHz,CD3OD)δ165.1
(C×2),146.4(C×4),141.5(C×2),120.9(C×2),109.6(C×4),64.5(C×2).It can be seen that its structure
Correctly.
Embodiment 3：The preparation of the compounds of this invention 3 and sign
In the present embodiment, the compounds of this invention 3 is adopted and is prepared with 2 identical synthetic route of compound and synthetic method,
Differ only in, by step 3) in ethylene glycol replace with piperazine, you can obtain the compounds of this invention 3, product detected
And characterize data is as follows：
Compound 3:C18H18O8N2, molecular weight 391 [M+H]+
1H NMR(400MHz,CD3OD)δ6.91(s,4H),3.45(t,4H)；13C NMR(100MHz,CD3OD)δ168.1
(C × 2), 146.4 (C × 4), 137.1 (C × 2), 130.4 (C × 2), 108.7 (C × 4), visible its structure in 48.9 (C × 4) is just
Really.
Embodiment 4：The preparation of the compounds of this invention 4 and sign
In the present embodiment, the compounds of this invention 4 is adopted and is prepared with 2 identical synthetic route of compound and synthetic method,
Differ only in, by step 3) in ethylene glycol replace with catechol, you can obtain the compounds of this invention 4, product carried out
Detection and characterize data are as follows：
Compound 4:C20H14O10, molecular weight 415 [M+H]+
1H NMR(400MHz,CD3OD)δ7.12(s,4H),7.45(d,2H),7.39(t,2H)；13CNMR(100MHz,
CD3OD)δ166.7(C×2),146.7(C×4),145.3(C×2),140.9(C×2),126.1(C×2),125.4(C×
2),120.1(C×2),109.7(C×4).It can be seen that its structure is correct.
Embodiment 5：The preparation of the compounds of this invention 5 and sign
In the present embodiment, the compounds of this invention 5 is adopted and is prepared with 2 identical synthetic route of compound and synthetic method,
Differ only in, by step 3) in ethylene glycol replace with to benzhydrol, you can obtain the compounds of this invention 5, product entered
Row detection and characterize data are as follows：
Compound 5:C22H18O10, molecular weight 443 [M+H]+,
1H NMR(400MHz,CD3OD)δ6.95(s,4H),7.04(d,4H),5.18(s,4H)；13CNMR(100MHz,
CD3OD)δ166.4(C×2),146.1(C×4),141.3(C×2),134.8(C×2),126.9(C×4),120.3(C×
2),109.7(C×4),65.6(C×2).It can be seen that its structure is correct.
Embodiment 6：The preparation of the compounds of this invention 6 and sign
In the present embodiment, the compounds of this invention 6 is adopted and is prepared with 2 identical synthetic route of compound and synthetic method,
Differ only in, by step 3) in ethylene glycol replace with two Polyethylene Glycol, you can obtain the compounds of this invention 6, product entered
Row detection and characterize data are as follows：
Compound 6:C18H18O11, molecular weight 411 [M+H]+
1H NMR(400MHz,CD3OD)δ6.97(s,4H),4.35(t,4H),3.94(t,4H)；13CNMR(100MHz,
CD3OD)δ166.3(C×2),146.9(C×4),140.5(C×2),121.7(C×2),110.3(C×4),69.0(C×
2),64.3(C×2).It can be seen that its structure is correct.
Embodiment 7：The preparation of the compounds of this invention 7 and sign
In the present embodiment, the compounds of this invention 7 is adopted and is prepared with 2 identical synthetic route of compound and synthetic method,
Differ only in, by step 3) in ethylene glycol replace with 1,3 butanediols, you can obtain the compounds of this invention 7, product carried out
Detection and characterize data are as follows：
Compound 7:C18H18O10, molecular weight 395 [M+H]+
1H NMR(400MHz,CD3OD)δ6.96(s,4H),4.25(t,2H),4.13(m,1H),2.21(q,2H),1.37
(d,3H)；13C NMR(100MHz,CD3OD)δ165.9(C×2),146.7(C×4),140.6(C×2),121.6(C×2),
109.6(C×4),67.6,59.5,35.5,19.9.It can be seen that its structure is correct.
Embodiment 8：The preparation of the compounds of this invention 8 and sign
In the present embodiment, the compounds of this invention 8 is adopted and is prepared with 2 identical synthetic route of compound and synthetic method,
Differ only in, by step 3) in ethylene glycol replace with curcumin, you can obtain the compounds of this invention 8, product examined
Survey and characterize data is as follows：
Compound 8:C18H18O11, molecular weight 411 [M+H]+
1H NMR(400MHz,CD3OD)δ7.60(d,2H),7.40(s,2H),7.36(d,2H),7.21(d,2H),7.12
(s,4H),6.91(d,2H),4.59(s,2H),3.83(s,6H)；13C NMR(100MHz,CD3OD)δ198.9(C×2),
165.2(C×2),151.5(C×2),146.1(C×4),142.8,(C×2),141.2(C×2),137.6(C×2),
131.8(C×2),130.4(C×2),125.6(C×2),124.4(C×2),121.9(C×2),110.9(C×2),110.0
(C×4),55.8(C×2),51.9.It can be seen that its structure is correct.
Embodiment 9：Medicinal composition tablets of the present invention
【Prescription】
The digallic acid ester derivant compound 2, starch and L-HPC of recipe quantity are weighed, are mixed, cross 60 mesh sieve three times,
Mix homogeneously；10% starch slurry soft material processed, granulation in right amount is added, is dried, after granulate, add micropowder silica gel, magnesium stearate to mix
Close uniform, tabletting, film coating are obtained final product.
Embodiment 9：Medicament composition capsule agent of the present invention
【Prescription】
The digallic acid ester derivant compound 5 and above-mentioned adjuvant of recipe quantity are weighed, 60 mesh sieve three times are crossed, mixing is equal
It is even, load capsule and obtain final product.
Obviously, above-described embodiment is only intended to clearly illustrate example, and the not restriction to embodiment.It is right
For those of ordinary skill in the art, can also make on the basis of the above description other multi-forms change or
Change.There is no need to be exhaustive to all of embodiment.And thus it is extended obvious change or
Among changing still in the protection domain of the invention.
Claims (6)
1. a kind of pharmaceutical composition for treating hyperuricemia, it is characterised in that containing as follows in described pharmaceutical composition
Shown digallic acid ester derivant and its pharmaceutically acceptable salt,
2. the digallic acid ester derivant with structure as shown below and its pharmaceutically acceptable salt are preparing the high urine for the treatment of
Purposes in acidemia disease drug,
3. purposes according to claim 2, it is characterised in that the medicine also includes pharmaceutically acceptable carrier.
4. purposes according to claim 3, it is characterised in that the medicine addition customary adjuvant is made clinically-acceptable
Tablet, capsule, oral solutionses, powder, drop pill, granule or injection.
5. the purposes according to any one of claim 2-4, it is characterised in that the hyperuricemia includes hyperuricemia
The gout for causing and gout complication.
6. purposes according to claim 5, it is characterised in that the gout complication includes gouty arthritises, gout
Property nephropathy or lithangiuria.
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| CN201410811123.3A CN104586863B (en) | 2014-12-23 | 2014-12-23 | Application of digallate derivative to preparation of medicine for treating hyperuricemia |
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| CN201410811123.3A CN104586863B (en) | 2014-12-23 | 2014-12-23 | Application of digallate derivative to preparation of medicine for treating hyperuricemia |
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| CN108451959B (en) * | 2015-06-10 | 2021-04-20 | 苏州禾研生物技术有限公司 | Application of galloylglucoside derivatives and pharmaceutical composition for treating hyperuricemia |
| CN109893521B (en) * | 2017-12-07 | 2022-01-11 | 苏州凯祥生物科技有限公司 | Application of polyacetylene compounds in reducing uric acid |
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| CN103919857A (en) * | 2014-03-31 | 2014-07-16 | 曹庸 | Folium eucalypti extractive with uric acid reduction effect as well as preparation method and application thereof |
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| CN103919857A (en) * | 2014-03-31 | 2014-07-16 | 曹庸 | Folium eucalypti extractive with uric acid reduction effect as well as preparation method and application thereof |
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