CN104586863A - 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, be specifically related to a kind of digallic acid ester derivant and the application of pharmaceutically acceptable salt in preparation treatment antihyperuricemic disease drug thereof, and a kind of pharmaceutical composition for the treatment of hyperuricemia and gout.
Background technology
In chemical medicine, uric acid is the end last metabolite of mankind's purine compound.Purine metabolic disturbance causes hyperuricemia.Under normal purine diet state, non-twice fasting blood uric acid level male is on the same day higher than 420 μm of ol/L, and women, higher than 360 μm of ol/L, is namely called hyperuricemia (hyperuricemia).Primary disease prevalence is subject to the impact of many factors, relevant with heredity, sex, age, life style, dietary habit, Drug therapy and economic development level etc.According to the report of various places prevalence of hyperuricemia in recent years, about there is hyperuricemia person 1.2 hundred million in current China, accounts for 10% of total population, and the age occurred frequently is middle-aging male and postmenopausal women, but has rejuvenation trend in recent years.Along with change and the growth in the living standard of people's dietary structure, the sickness rate of hyperuricemia improves year by year, it is reported about have the adult male of twenty percent to be in the state of hyperuricemia by title at present.Usually, the simple hyperuricemia state that is in does not have subjective symptoms, if but long-time this state laissez-faire, to crystallization be there is in the urate in blood, the urate of crystallization will be deposited on the positions such as joint, subcutaneous tissue, kidney, and then occur the series of clinical manifestations such as gout, arthritis, subcutaneous gout calculus, kidney stone or gouty nephropathy.Therefore, suitably the uric acid level controlled in blood is prevention, to improve with gout be hyperuricemia basic of representative.
At present, the control of uric acid in blood is mainly realized by following two kinds of approach: (1) suppresses the generation of uric acid.Uric acid is generated through the effect of xanthine oxidase by hypoxanthine and xanthine.Xanthine oxidase is the above-mentioned reaction of catalysis and then generates the necessary enzyme of uric acid, therefore, suppresses xanthine oxidase (xanthine oxidase, XO) activity effectively can suppress the formation of uric acid, and then plays the effect of the symptoms such as treatment gout.The medicine of suppression uricopoiesis conventional at present has allopurinol, Febuxostat etc.; (2) excretion of uric acid is promoted.The medicine of promotion urate excretion conventional at present has probenecid, benzbromarone etc.
Above-mentioned two kinds of modes all can play the effect reducing uric acid in blood, and then curative effect is produced to diseases such as gout, arthritis, subcutaneous gout calculus, kidney stone or gouty nephropathies that hyperuricemia causes, but said medicine toxic and side effects is usually larger, such as, allopurinol can cause the serious toxic and side effects such as allergy (sickness rate 10-15%), super quick syndrome, bone marrow depression; Probenecid, benzbromarone then have stimulating gastrointestinal road, cause renal colic, excite the side effect such as gout acute attack, limit the clinical practice of these medicines to a certain extent.
Gallic acid is a kind of compound extensively existed in plant, according to bibliographical information [chemistry world, 2009 (5), 273-276], gallic acid has certain xanthine oxidase inhibitory activity, but only report its vitro inhibition xanthine oxidase activity, there is no further animal experimental data.We are in follow-up research, the a series of gallate derivatives of unexpected discovery, they have identical in vitro or are significantly higher than the xanthine oxidase inhibitory activity of gallic acid, in vivo in zoopery, these derivants have the activity of the reduction animal blood uric acid apparently higher than gallic acid.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of digallic acid ester derivant and pharmaceutically acceptable salt thereof for the preparation of the purposes for the treatment of antihyperuricemic disease drug, and a kind of pharmaceutical composition for the treatment of hyperuricemia and gout.
The object of the invention is to be achieved through the following technical solutions:
One has the purposes in preparation treatment antihyperuricemic disease drug such as formula the digallic acid ester derivant of structure (I) Suo Shi and pharmaceutically acceptable salt thereof,
Wherein:
X
1, X
2, X3, X4 are independent of each other is selected from-H ,-OH ,-OR ,-F ,-Cl ,-Br ,-I ,-N (R)
2,-C (O) R ,-C (O) OR ,-CHO, one in-CN;
R is selected from-H, substituted or unsubstituted C
1to C
6alkane, one in cycloalkane or heterocycloalkane;
Y
1, Y
2the one be selected from C, P-OH, S or S=O independent of each other;
Z
1, Z
2the one be selected from CHRa, O, NH, NRa or S independent of each other; Ra is selected from the one in the alkane of-H or C1-C8, cycloalkane;
V is selected from separately or V and Ra is connected forms replacement or unsubstituted C
1to C
18alkane, branched paraffin, substituted or unsubstituted C
3to C
8cycloalkane ,-(CH
2)
mone in-Rc, benzyl, aromatic radical; Wherein Rc is substituted or unsubstituted C
3to C
8cycloalkane or heterocycloalkane, the value of m is 1-8.
Preferably, described digallic acid ester derivant has such as formula structure (II) Suo Shi:
Wherein:
R is selected from-H, substituted or unsubstituted C
1to C
6alkane, one in cycloalkane or heterocycloalkane;
Y
1, Y
2the one be selected from C, P-OH, S or S=O independent of each other;
Z
1, Z
2the one be selected from CHRa, O, NH, NRa or S independent of each other; Ra is selected from the one in the alkane of-H or C1-C8, cycloalkane;
V is selected from separately or V and Ra is connected forms replacement or unsubstituted C
1to C
18alkane, branched paraffin, substituted or unsubstituted C
3to C
8cycloalkane ,-(CH
2)
mone in-Rc, benzyl, aromatic radical; Wherein Rc is substituted or unsubstituted C
3to C
8cycloalkane or heterocycloalkane, the value of m is 1-8.
Further preferably, described digallic acid ester derivant has such as formula structure (III) Suo Shi:
Wherein:
Wherein:
Z
1, Z
2the one be selected from CHRa, O, NH, NRa or S independent of each other; Ra is selected from the one in the alkane of-H or C1-C8, cycloalkane;
V is selected from separately or V and Ra is connected forms replacement or unsubstituted C
1to C
18alkane, branched paraffin, substituted or unsubstituted C
3to C
8cycloalkane ,-(CH
2)
mone in-Rc, benzyl, aromatic radical; Wherein Rc is substituted or unsubstituted C
3to C
8cycloalkane or heterocycloalkane, the value of m is 1-8.
More preferably, described digallic acid ester derivant has structure as follows:
Described medicine also comprises pharmaceutically acceptable carrier.
Described medicine adds customary adjuvant and makes clinical acceptable tablet, capsule, oral solutions, powder, drop pill, granule or injection.
Described hyperuricemia comprises the gout and gout complication that hyperuricemia causes.
Described gout complication comprises gouty arthritis, gouty nephropathy, lithangiuria or cardiovascular disease.
The present invention also provides a kind of pharmaceutical composition being used for the treatment of hyperuricemia, containing digallic acid ester derivant of the present invention and pharmaceutically acceptable salt thereof in described pharmaceutical composition.
The invention has the advantages that:
Digallic acid ester derivant of the present invention not only demonstrates stronger In-vitro Inhibitory Effect to xanthine oxidase, also can obviously reduce the serum uric acid level suffering from hyperuricemia mice, and present dose dependent, and have no side effect, safety is high, therefore can be used as the treatment of gout that potential xanthine oxidase inhibitor and uric acid resisting medicine cause for hyperuricemia and hyperuricemia or gout complication.
Experimental example
The xanthine used in the present invention, xanthine oxidase, allopurinol, the dehydrated alcohol of analytical pure level, chloroform, methanol, ethyl acetate, distilled water, dimethyl sulfoxine, potassium dihydrogen phosphate, dipotassium hydrogen phosphate are commercially available prod.
Instrument of the present invention comprises compacting in Buchi standby liquid phase, Ika agitator, Buchi vacuum rotary evaporator, turbula shaker, water-bath, Biofuge Primo R Multipurpose table type high speed centrifuge, METTLERAE240 electronic balance, BECKMAN COULTER AU480 biochemistry analyzer.
Compound 1 is obtained for the present invention is separated from corresponding plant; Compound 2-8 is for obtain precursor compound through chemical conversion, and details are see embodiment 1-8.
Experimental example 1: digallic acid ester derivant is to the In-vitro Inhibitory Effect of xanthine oxidase
Solution preparation:
Phosphate buffered solution: the K taking 19.48g
2hPO
4.3H
2the KH of O and 1.99g
2pO
4be dissolved in 500mL distilled water, be made into the phosphate buffered solution (pH=7.5) that concentration is 0.2mmol/L;
Xanthine substrate solution: take xanthine 15.2mg, is dissolved in 250mL distilled water, is made into the xanthine substrate solution that concentration is 0.4mmol/L;
Xanthine oxidase solution: get xanthine oxidase 5U, is diluted to 160mL by above-mentioned phosphate buffered solution, is made into the xanthine oxidase solution that concentration is 80U/L, 4 DEG C of preservations;
Sample and positive control solution: precision takes sample (compound 1-8), gallic acid, allopurinol (as positive control), respectively with dimethyl sulfoxine dissolve, distilled water diluting, being made into concentration is that the solution of the variable concentrations of 0.01-2 μm of ol/L carries out testing (wherein the ultimate density of dimethyl sulfoxine is less than 1%).
Inhibitory action is tested:
Sample sets is tested: in 2mL centrifuge tube, add xanthine substrate solution 200 μ L, sample solution (compound 1-8) 100 μ L and xanthine oxidase solution 200 μ L successively, vortex shakes within 5 seconds, to be placed in 25 DEG C of water-baths and reacts 5 minutes, add 1.5mL dehydrated alcohol after completion of the reaction, vortex shakes 5 seconds cessation reactions.Reactant liquor centrifugal 5 minutes through 3500rpm, draw in 200 μ L to 1.5mL centrifuge tubes, detect the UA value of each sample by biochemistry analyzer respectively, each sample parallel operates three times and averages.
Blank group is tested: in 2mL centrifuge tube, add xanthine substrate solution 200 μ L, phosphate buffered solution 100 μ L and xanthine oxidase solution 200 μ L successively, and detect the UA value of blank group with method, operation repetitive is averaged for three times.
Positive controls is tested: in 2mL centrifuge tube, add xanthine substrate solution 200 μ L, positive control solution 100 μ L and xanthine oxidase solution 200 μ L successively, and detect the UA value of positive controls with method, operation repetitive is averaged for three times.
Test result:
According to xanthine oxidase suppression ratio=[(blank group UA value-sample sets UA value)/blank group UA value] * 100, calculate suppression ratio; Drug level C=C in enzymatic reaction
0* 0.1/3.1 (C
0for sample solution concentration); Drug level and suppression ratio are returned, obtains regression equation; C value when being 50% according to regression equation calculation suppression ratio, i.e. half-inhibition concentration IC
50, result is as shown in table 1.
Table 1 compound 1-8 is to the In-vitro Inhibitory Effect (IC of xanthine oxidase
50, μm ol/L)
| Test-compound | IC 50 |
| 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 demonstrates stronger In-vitro Inhibitory Effect to xanthine oxidase, can be used as the treatment of potential xanthine oxidase inhibitor for hyperuricemia.
Experimental example 2: digallic acid ester derivant is to the serum uric acid level reducing hyperuricemia mice
Experimental animal and grouping: healthy male KM mice 80, body weight is 15-18g, and by Shanghai, Ling Chang bio tech ltd provides;
After only carrying out point cage process by every cage 5,4 days are raised at the barrier system endoadaptation of Kai Xiang bio tech ltd, Suzhou, 70 mices choosing body weight concentrated from 80 mices are divided into 7 groups by body weight stochastic averagina, often organize 10, be respectively blank group, hyperuricemia model group, positive controls, gallic acid group, test-compound group (being respectively the compounds of this invention 2,5,8).
The modeling of hyperuricemia:
Immediately gastric infusion is carried out to mice after the laundering period, every morning gavage 1 time, wherein test-compound group and gallic acid group pure water carry out suspendible, carry out gavage according to 20mg/kg; Positive control Febustat pure water carries out suspendible, carries out gavage according to 2.5mg/kg; Blank group and hyperuricemia model group all contrast by pure water gavage, continuous gavage 7 days;
The 7th day morning gavage after 0.5 hour, lumbar injection modeling is carried out to mice, wherein blank group lumbar injection 0.5% sodium carboxymethyl cellulose (CMC-Na) solution; Hyperuricemia model group, positive controls and test-compound group injection Oteracil Potassium (OA), dissolve with CMC-Na solution, injection volume is 300mg/kg body weight;
Lumbar injection extracts mice eyeball after 1.5 hours is taken a blood sample, blood sampling capacity is not less than 0.5mL, place about 1 hour in room temperature after blood specimen collection, after blood solidifies completely under 3500rpm/4 DEG C of condition centrifugal 10 minutes, get serum under equal conditions multiple from 5 minutes, then get 0.2mL serum and use biochemistry analyzer to detect UA value;
With Excel and SPSS, statistical analysis is carried out to data, calculate average and SD, the group difference of more each experimental group after one factor analysis of variance, compared with blank group, the serum uric acid level of hyperuricemia model group, positive controls and test-compound group mice significantly improves, there is significant difference, show modeling success.
Table 2 compound 2,5,8 is on the impact (μm ol/L) of hyperuricemia mice serum uric acid level
Note: * * represents compared with hyperuricemia model group, P<0.01 (t-test inspection).
Digallic acid ester derivant of the present invention can obviously reduce the serum uric acid level suffering from hyperuricemia mice, has statistical significance compared with hyperuricemia model group, can be used as the treatment of potential uric acid resisting medicine for hyperuricemia.
Experimental example 3: digallic acid ester derivant reduces the quantitative dose-effect relationship of hyperuricemia mice serum uric acid level
Experimental animal and grouping:
Healthy male KM mice 100, body weight is 13-15g, and by Shanghai, Ling Chang bio tech ltd provides;
After only carrying out point cage process by every cage 5,4 days are raised at the barrier system endoadaptation of Kai Xiang bio tech ltd, Suzhou, 90 mices choosing body weight concentrated from 100 mices divide 9 groups by body weight stochastic averagina, often organize 10, be respectively blank group, hyperuricemia model group, positive controls Febustat, test-compound group (totally 6 groups, be respectively the compounds of this invention 2,4, and each compound divides 3 kinds of dosage).
The modeling of hyperuricemia:
Immediately gastric infusion is carried out to mice after the laundering period, every morning gavage 1 time, wherein test-compound group, compound pure water suspendible, carries out gavage according to 10mg/kg, 50mg/kg, 200mg/kg Three doses respectively; Positive controls, Febustat pure water suspendible, carries out gavage according to 2.5mg/kg; Blank group and hyperuricemia model group all contrast by pure water gavage, continuous gavage 7 days;
After gavage 0.5h, lumbar injection modeling was carried out to mice in the 7th day morning, wherein blank group lumbar injection 0.5%CMC-Na solution; Hyperuricemia model group, positive controls and test-compound group injection Oteracil Potassium (OA), dissolve with CMC-Na solution, injection volume is 300mg/kg;
The eyeball extracing mice after lumbar injection 1.5h is taken a blood sample, blood sampling capacity is not less than 0.5mL, about 1h is placed in room temperature after blood specimen collection, after blood solidifies completely under 3500rpm/4 DEG C of condition centrifugal 10min, get serum under equal conditions repeated centrifugation 5min, then get 0.2mL serum and use biochemistry analyzer to detect UA value;
With Excel and SPSS, statistical analysis is carried out to data, calculate average and SD, the group difference of more each experimental group after one factor analysis of variance, compared with blank group, the serum uric acid level of hyperuricemia model group, positive controls and test-compound group mice significantly improves, there is significant difference, show modeling success.
Table 3 various dose compound is on the impact of hyperuricemia mice serum uric acid level
Note: * represents compared with hyperuricemia model group, P<0.05; * represents compared with hyperuricemia model group, P<0.01 (t-test inspection).
Digallic acid ester derivant of the present invention can obviously reduce the serum uric acid level suffering from hyperuricemia mice, and present dose dependent, compared with hyperuricemia model group, there is statistical significance, can be used as the treatment of potential uric acid resisting medicine for hyperuricemia.
Detailed description of the invention
Embodiment 1: the extraction of the compounds of this invention 1 and sign
Get Fructus Phyllanthi medical material 5kg, pulverize, under the micro-state of boiling of maintenance, extract 40min with 5L water.By extracting solution vacuum concentration to 1L, concentrated solution Diaion HP-20 macroporous adsorbent resin carries out column chromatography for separation, is that eluent carries out eluting respectively with water, 30% ethanol, 60% ethanol, 95% ethanol.The eluent getting 20g water elution carries out column chromatography for separation with anti-phase C18 silica gel, is that eluent carries out eluting, can obtains the compounds of this invention 1 with the ethanol of 5%-10%; It is detected and characterization data as follows:
Compound 1:C
20h
20o
14, molecular weight 485 [M+H]
+
1H-NMR(MeOH-d
4,400MHz)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-d
4,100MHz)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。Its structure visible is correct.
Embodiment 2: the UV absorber of the compounds of this invention 2
The compounds of this invention 2-8 can adopt following synthetic route to prepare:
In the present embodiment, prepare compound 2 of the present invention according to following synthetic route:
Concrete operations are as follows:
The benzoic synthesis of (1) 3,4,5-tribenzyl
17.0g gallic acid is dissolved in the dimethyl formamide (being called for short DMF, lower same) of 800ml, and uses nitrogen protection, add 113g Anhydrous potassium carbonate at 25 DEG C in batches, after stirring 1h, be warmed up to 40 DEG C, then 143ml benzyl bromine is added drop-wise in reaction system in 30min; After dropwising, reaction mixture is stirred 12h at 40 DEG C; Utilize TLC point plate to show result and determine that reaction is carried out completely, stop heating, make reaction temperature be down to room temperature 25 DEG C; Be added in reaction system by the ethyl acetate of 400ml water and 1L, separatory extracts, and organic facies 500ml water washing three times, then uses anhydrous sodium sulfate drying, and vacuum concentration is to dry; Dry thing is dissolved in the mixed liquor of 5M (i.e. mol/L) sodium hydroxide solution of 500ml ethanol and 500ml, return stirring 10h, utilize TLC to show result to determine to be hydrolyzed completely, by mixed liquor cool to room temperature, add 500ml water wherein, use concentrated hydrochloric acid adjust ph to 2 again, collect the solid of separating out.By gained solid recrystallization in 1L methanol, obtain 37.5 grams of white solids (productive rate 85%), be 3,4,5-tribenzyl-benzene formic acid (compd A see in synthetic route);
The synthesis of (2) 3,4,5-tribenzyl-benzene formyl chlorides
Get 10g step 1) in prepare 3; 4; 5-tribenzyl-benzene formic acid, is dissolved in 20ml thionyl chloride, and uses nitrogen protection; 3.5h is stirred at 65 DEG C; then vacuum is revolved and is steamed the unnecessary unreacted thionyl chloride of removing, the grease 100ml normal hexane of gained and 100ml toluene is steamed twice respectively altogether thoroughly to remove unnecessary unreacted thionyl chloride, obtains 3 of solid; 4,5-tribenzyl-benzene formyl chloride (compd B see in synthetic route).
(3) synthesis of two (3,4,5-tribenzyl-benzene formic acid) glycol ester
Get the DMAP (being called for short DMAP, lower same) of 2g, 3g ethylene glycol and 10ml pyridine respectively, be dissolved in 150ml dichloromethane, and use nitrogen protection, at room temperature stir; Get step 2) in prepare 3 of solid, 4,5-tribenzyl-benzene formyl chloride, be dissolved in 100ml dichloromethane, and be added drop-wise in the reaction system of above-mentioned DMAP, ethylene glycol, pyridine, dichloromethane formation, return stirring 5h, then mixed liquor is concentrated, by residue by silicagel column purification (sil-gel), with petroleum ether-ethyl acetate system gradient elution, obtain two (3,4,5-tribenzyl-benzene formic acid) glycol esters (Compound C see in synthetic route) of 19g;
(4) synthesis of two (Gallic Acid) glycol ester
Get 10g step 3) in prepare two (3,4,5-tribenzyl-benzene formic acid) glycol ester is dissolved in 200ml methanol, again the 10%Pd-C catalyst of 500ml is joined in reaction system slowly, replacing hydrogen again, 4h is stirred under hydrogen environment, TLC is utilized to show after result determines to react completely, filter, filtrate is spin-dried for, and then uses silica column purification (silica gel), with petroleum ether-ethyl acetate system gradient elution, obtain 3.5g white solid, obtain compound 2.
Product is detected and characterization data as follows:
Compound 2:C
16h
14o
10, molecular weight 367 [M+H]
+
1H NMR(400MHz,CD
3OD)δ6.91(s,4H),4.30(t,4H)；
13C NMR(100MHz,CD
3OD)δ165.1(C×2),146.4(C×4),141.5(C×2),120.9(C×2),109.6(C×4),64.5(C×2)。Its structure visible is correct.
Embodiment 3: the UV absorber of the compounds of this invention 3
In the present embodiment, the compounds of this invention 3 adopts the synthetic route identical with compound 2 and synthetic method to prepare, and distinguishes and is only, by step 3) in ethylene glycol replace with piperazine, the compounds of this invention 3 can be obtained, product is detected and characterization data as follows:
Compound 3:C
18h
18o
8n
2, molecular weight 391 [M+H]
+
1h NMR (400MHz, CD
3oD) δ 6.91 (s, 4H), 3.45 (t, 4H);
13c NMR (100MHz, CD
3oD) δ 168.1 (C × 2), 146.4 (C × 4), 137.1 (C × 2), 130.4 (C × 2), 108.7 (C × 4), 48.9 (C × 4) as seen its structure are correct.
Embodiment 4: the UV absorber of the compounds of this invention 4
In the present embodiment, the compounds of this invention 4 adopts the synthetic route identical with compound 2 and synthetic method to prepare, and distinguishes and is only, by step 3) in ethylene glycol replace with catechol, the compounds of this invention 4 can be obtained, product is detected and characterization data as follows:
Compound 4:C
20h
14o
10, molecular weight 415 [M+H]
+
1H NMR(400MHz,CD
3OD)δ7.12(s,4H),7.45(d,2H),7.39(t,2H)；
13CNMR(100MHz,CD
3OD)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)。Its structure visible is correct.
Embodiment 5: the UV absorber of the compounds of this invention 5
In the present embodiment, the compounds of this invention 5 adopts the synthetic route identical with compound 2 and synthetic method to prepare, and distinguishes and is only, by step 3) in ethylene glycol replace with benzhydrol, the compounds of this invention 5 can be obtained, product is detected and characterization data as follows:
Compound 5:C
22h
18o
10, molecular weight 443 [M+H]
+,
1H NMR(400MHz,CD
3OD)δ6.95(s,4H),7.04(d,4H),5.18(s,4H)；
13CNMR(100MHz,CD
3OD)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)。Its structure visible is correct.
Embodiment 6: the UV absorber of the compounds of this invention 6
In the present embodiment, the compounds of this invention 6 adopts the synthetic route identical with compound 2 and synthetic method to prepare, and distinguishes and is only, by step 3) in ethylene glycol replace with two Polyethylene Glycol, the compounds of this invention 6 can be obtained, product is detected and characterization data as follows:
Compound 6:C
18h
18o
11, molecular weight 411 [M+H]
+
1H NMR(400MHz,CD
3OD)δ6.97(s,4H),4.35(t,4H),3.94(t,4H)；
13CNMR(100MHz,CD
3OD)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)。Its structure visible is correct.
Embodiment 7: the UV absorber of the compounds of this invention 7
In the present embodiment, the compounds of this invention 7 adopts the synthetic route identical with compound 2 and synthetic method to prepare, and difference is only, by step 3) in ethylene glycol replace with 1,3 butanediols, can obtain the compounds of this invention 7, product is detected and characterization data as follows:
Compound 7:C
18h
18o
10, molecular weight 395 [M+H]
+
1H NMR(400MHz,CD
3OD)δ6.96(s,4H),4.25(t,2H),4.13(m,1H),2.21(q,2H),1.37(d,3H)；
13C NMR(100MHz,CD
3OD)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。Its structure visible is correct.
Embodiment 8: the UV absorber of the compounds of this invention 8
In the present embodiment, the compounds of this invention 8 adopts the synthetic route identical with compound 2 and synthetic method to prepare, and distinguishes and is only, by step 3) in ethylene glycol replace with curcumin, the compounds of this invention 8 can be obtained, product is detected and characterization data as follows:
Compound 8:C
18h
18o
11, molecular weight 411 [M+H]
+
1H NMR(400MHz,CD
3OD)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,CD
3OD)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。Its structure visible is correct.
Embodiment 9: medicinal composition tablets of the present invention
[prescription]
Take the digallic acid ester derivant compound 2 of recipe quantity, starch and L-HPC, mixing, cross 60 mesh sieve three times, mix homogeneously; Add the starch slurry soft material processed in right amount of 10%, granulate, dry, after granulate, add micropowder silica gel, magnesium stearate mix homogeneously, tabletting, film coating, to obtain final product.
Embodiment 9: medicament composition capsule agent of the present invention
[prescription]
Take the digallic acid ester derivant compound 5 of recipe quantity and above-mentioned adjuvant, cross 60 mesh sieve three times, mix homogeneously, incapsulates and get final product.
Obviously, above-described embodiment is only for clearly example being described, and the restriction not to embodiment.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here exhaustive without the need to also giving all embodiments.And thus the apparent change of extending out or variation be still among the protection domain of the invention.
Claims (9)
1. there is the digallic acid ester derivant such as formula structure (I) Suo Shi and the purposes of pharmaceutically acceptable salt in preparation treatment antihyperuricemic disease drug thereof,
Wherein:
X
1, X
2, X3, X4 are independent of each other is selected from-H ,-OH ,-OR ,-F ,-Cl ,-Br ,-I ,-N (R)
2,-C (O) R ,-C (O) OR ,-CHO, one in-CN;
R is selected from-H, substituted or unsubstituted C
1to C
6alkane, one in cycloalkane or heterocycloalkane;
Y
1, Y
2the one be selected from C, P-OH, S or S=O independent of each other;
Z
1, Z
2the one be selected from CHRa, O, NH, NRa or S independent of each other; Ra is selected from-H or C
1-C
8alkane, one in cycloalkane;
V is selected from separately or V and Ra is connected forms replacement or unsubstituted C
1to C
18alkane, branched paraffin, substituted or unsubstituted C
3to C
8cycloalkane ,-(CH
2)
mone in-Rc, benzyl, aromatic radical; Wherein Rc is substituted or unsubstituted C
3to C
8cycloalkane or heterocycloalkane, the value of m is 1-8.
2. purposes according to claim 1, is characterized in that, described digallic acid ester derivant has such as formula structure (II) Suo Shi:
Wherein:
R is selected from-H, substituted or unsubstituted C
1to C
6alkane, one in cycloalkane or heterocycloalkane;
Y
1, Y
2the one be selected from C, P-OH, S or S=O independent of each other;
Z
1, Z
2the one be selected from CHRa, O, NH, NRa or S independent of each other; Ra is selected from the one in the alkane of-H or C1-C8, cycloalkane;
V is selected from separately or V and Ra is connected forms replacement or unsubstituted C
1to C
18alkane, branched paraffin, substituted or unsubstituted C
3to C
8cycloalkane ,-(CH
2)
mone in-Rc, benzyl, aromatic radical; Wherein Rc is substituted or unsubstituted C
3to C
8cycloalkane or heterocycloalkane, the value of m is 1-8.
3. purposes according to claim 2, described digallic acid ester derivant has such as formula structure (III) Suo Shi:
Wherein:
Z
1, Z
2the one be selected from CHRa, O, NH, NRa or S independent of each other; Ra is selected from the one in the alkane of-H or C1-C8, cycloalkane;
V is selected from separately or V and Ra is connected forms replacement or unsubstituted C
1to C
18alkane, branched paraffin, substituted or unsubstituted C
3to C
8cycloalkane ,-(CH
2)
mone in-Rc, benzyl, aromatic radical; Wherein Rc is substituted or unsubstituted C
3to C
8cycloalkane or heterocycloalkane, the value of m is 1-8.
4. purposes according to claim 3, is characterized in that, described digallic acid ester derivant has structure as follows:
5., according to the arbitrary described purposes of claim 1-4, it is characterized in that, described medicine also comprises pharmaceutically acceptable carrier.
6. according to the arbitrary described purposes of claim 1-5, it is characterized in that, described medicine adds customary adjuvant and makes clinical acceptable tablet, capsule, oral solutions, powder, drop pill, granule or injection.
7. according to the arbitrary described purposes of claim 1-6, it is characterized in that, described hyperuricemia comprises the gout and gout complication that hyperuricemia causes.
8. purposes according to claim 7, it is characterized in that, described gout complication comprises gouty arthritis, gouty nephropathy, lithangiuria or cardiovascular disease.
9. be used for the treatment of a pharmaceutical composition for hyperuricemia, it is characterized in that, containing, for example the arbitrary described digallic acid ester derivant of claim 1-4 and pharmaceutically acceptable salt thereof in described pharmaceutical composition.
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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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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104940216A (en) * | 2015-06-10 | 2015-09-30 | 苏州禾研生物技术有限公司 | Application of galloyl-glucoside derivative and pharmaceutical composition for treating hyperuricemia |
| CN109893521A (en) * | 2017-12-07 | 2019-06-18 | 苏州凯祥生物科技有限公司 | A kind of new application of poly- acetylene compound anti-trioxypurine |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104940216A (en) * | 2015-06-10 | 2015-09-30 | 苏州禾研生物技术有限公司 | Application of galloyl-glucoside derivative and pharmaceutical composition for treating hyperuricemia |
| CN104940216B (en) * | 2015-06-10 | 2018-06-26 | 苏州禾研生物技术有限公司 | The application of galloyl glucose glycoside derivative and the pharmaceutical composition for treating hyperuricemia |
| CN108451959A (en) * | 2015-06-10 | 2018-08-28 | 苏州禾研生物技术有限公司 | The application of galloyl glucose glycoside derivative and the pharmaceutical composition for treating hyperuricemia |
| CN109893521A (en) * | 2017-12-07 | 2019-06-18 | 苏州凯祥生物科技有限公司 | A kind of new application of poly- acetylene compound anti-trioxypurine |
| 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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| CN104586863B (en) | 2017-05-03 |
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