CN104109179A - C-aryl glucoside derivatives, preparation method and application thereof - Google Patents
C-aryl glucoside derivatives, preparation method and application thereof Download PDFInfo
- Publication number
- CN104109179A CN104109179A CN201310134087.7A CN201310134087A CN104109179A CN 104109179 A CN104109179 A CN 104109179A CN 201310134087 A CN201310134087 A CN 201310134087A CN 104109179 A CN104109179 A CN 104109179A
- Authority
- CN
- China
- Prior art keywords
- compound
- chloro
- glucopyranose
- preparation
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 **1C=CC(*2C34C=C([C@@]([C@]([C@@]5O)O)O[C@](CO)[C@]5O)C=C(*)C*(*)C=C[C@@]23C4)=C*(*)C=C1 Chemical compound **1C=CC(*2C34C=C([C@@]([C@]([C@@]5O)O)O[C@](CO)[C@]5O)C=C(*)C*(*)C=C[C@@]23C4)=C*(*)C=C1 0.000 description 5
- JVHXJTBJCFBINQ-ADAARDCZSA-N CCOc1ccc(Cc2cc([C@@H]([C@@H]([C@H]3O)O)O[C@H](CO)[C@H]3O)ccc2Cl)cc1 Chemical compound CCOc1ccc(Cc2cc([C@@H]([C@@H]([C@H]3O)O)O[C@H](CO)[C@H]3O)ccc2Cl)cc1 JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 2
- NQVCEPBRZMUJSC-YTJURQHKSA-N CC1(C([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)C=CC(C)=C(Cc2ccc(-c(cc3)ccc3F)[s]2)C1 Chemical compound CC1(C([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)C=CC(C)=C(Cc2ccc(-c(cc3)ccc3F)[s]2)C1 NQVCEPBRZMUJSC-YTJURQHKSA-N 0.000 description 1
- LQNOSVAGXIZRCS-ZQGJOIPISA-N CCOC(OC[C@H]([C@H]([C@@H]([C@H]1O)O)O)O[C@H]1c(cc1Cc(cc2)ccc2OCC)ccc1Cl)=O Chemical compound CCOC(OC[C@H]([C@H]([C@@H]([C@H]1O)O)O)O[C@H]1c(cc1Cc(cc2)ccc2OCC)ccc1Cl)=O LQNOSVAGXIZRCS-ZQGJOIPISA-N 0.000 description 1
- WAAWSAQTDFQCAI-BHFRNUBISA-N CCOc1ccc(C/C(/C)=C(/C=C\C([C@@H]([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)=C)\Cl)cc1 Chemical compound CCOc1ccc(C/C(/C)=C(/C=C\C([C@@H]([C@@H]([C@H]2O)O)O[C@H](CO)[C@H]2O)=C)\Cl)cc1 WAAWSAQTDFQCAI-BHFRNUBISA-N 0.000 description 1
- GMQJPBBQPCHWLS-MZRDYSPDSA-N CCOc1ccc(CC(CC([C@@H]([C@@H]([C@H]2O)O)O[C@H](COC(CCC(OC(C)=O)=O)=O)[C@H]2O)C=C2)=C2Cl)cc1 Chemical compound CCOc1ccc(CC(CC([C@@H]([C@@H]([C@H]2O)O)O[C@H](COC(CCC(OC(C)=O)=O)=O)[C@H]2O)C=C2)=C2Cl)cc1 GMQJPBBQPCHWLS-MZRDYSPDSA-N 0.000 description 1
- ZUNCHZBITMUSRD-UHFFFAOYSA-N CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1 Chemical compound CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1 ZUNCHZBITMUSRD-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Abstract
The invention provides C-aryl glucoside derivatives, a preparation method and an application thereof, relates to the field of medicines relative to diabetes and particularly relates to a sodium-dependent glucose transport protein type-2 (SGLT-2) inhibitor containing a C-aryl glucoside structure, the preparation method of the inhibitor and the application of the inhibitor in preparation of diabetes medicines. Definition of each substituent groups in general formula (I) is same as that in the description.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes.Particularly, the present invention relates to medicative 2 type sodium dependent glucose translocator (SGLT-2) inhibitor containing C-aryl glucoside structure of diabetes and preparation method thereof, the medical composition and its use that contains them.
Background technology
Diabetes have become one of serious public health problem in the whole world, data presentation, current global diabetic subject is 3.66 hundred million, expect the year two thousand thirty whole world and will reach 5.52 hundred million, be equivalent to increase for every 10 seconds a diabetic subject, or increase every year 1000 ten thousand patients, wherein most is II type (being non-insulin-dependent) diabetic subject.At present, existing medicine comprises biguanide compound, and sulfonyl urea compound, is listed as the DPPIV inhibitor etc. of how class, α-glucose glycosidase inhibitor and listing recently at agent for amelioration of insulin resistance.But these all antidiabetic medicines all exist the side effect of every aspect.For example, biguanide compound easily causes lactic acidosis, sulfonyl urea compound can cause significance hypoglycemia, agent for amelioration of insulin resistance easily causes oedema and cardiac failure, also have α-glucose glycosidase inhibitor can cause stomachache, abdominal distension, diarrhoea, DPPIV inhibitor needs and N1,N1-Dimethylbiguanide share and just can reach desirable hypoglycemic effect.In view of the foregoing, people urgently wish to develop a kind of novel, there is no these side effects and can effectively treat the medicine of diabetes.Wherein, become the emphasis of current research taking 2 type sodium dependent glucose translocators (SGLT-2) as the medicine of target spot.
SGLT-2 is made up of 672 amino acid.Plasma glucose is filtered in renal glomerulus, and is initiatively absorbed and turn back in blood again at proximal tubule.SGLT-2 is distributed in kidney, is the major protein of controlling this process, and its effect is the glucose absorbing in crude urine, and returns it in blood.Thereby the activity that therefore suppresses SGLT-2 just can increase the excretion of glucose in urine and reduce blood sugar concentration, and this method is from having reduced glucose level from the past different approach.Because SGLT-2 inhibitor stays out of glucose metabolism, it can be used as a kind of glycemic control method of novelty.Clinical study data show: even in bolus insulin and N1,N1-Dimethylbiguanide and (or) the failed situation of Thiazolidinediones combination therapy, add and still can effectively reduce blood sugar with SGLT-2 inhibitor, lose weight, in, effective treatment of patients with terminal brought new hope.
The C-aryl glucoside derivative SGLT-2 inhibitor that is used for the treatment of diabetes is disclosed below with reference to document:
The compound that WO2005012326 discloses time array structure is as SGLT-2 inhibitor:
The compound that Chinese patent CN200610093189.9 discloses time array structure is as SGLT-2 inhibitor:
Wherein: A is O, S, NH, (CH
2)
n, n=0-3.
The compound that Chinese patent CN200380110040.1 discloses time array structure is as SGLT-2 inhibitor:
Wherein A is covalent linkage, O, S, NH, (CH
2)
n, n=1-3.
The compound that Chinese patent CN200480006761.2 discloses time array structure is as SGLT-2 inhibitor:
Wherein, X is covalent linkage or low-grade alkylidene.
The invention provides a class C-aryl glucoside derivative as novel SGLT-2 inhibitor, these inhibitor lay the foundation for the medicine that further can be used for the treatment of diabetes, particularly non insulin dependent diabetes.
Summary of the invention
In order to overcome the easy moisture absorption of dapagliflozin raw material, the tablet of making is difficult for the deficiencies in the prior art parts such as storage, and spy of the present invention provides 2 type sodium dependent glucose translocator (SGLT-2) inhibitor, the preparation methods of the class shown in a kind of general formula (1) containing C-aryl glucoside structure, the medical composition and its use that contains them.
Wherein:
R is selected from following group:
Phenyl; C
1-C
7alkyl;-CH
2cH
2cOOH;
-OR
1; Wherein R
1for methyl, ethyl, sec.-propyl, the tertiary butyl, isobutyl-
-R
2oCH
3; Wherein R
2for C
1-C
4alkyl.
Preferred compound shown in general formula of the present invention (1) includes, but are not limited to:
General formula of the present invention (1) compound synthesizes by following steps:
Brief description of the drawings
Fig. 1 be compound gavage after 10 days to diabetic mice hypoglycemic activity figure;
Fig. 2 be compound gavage after 60 days to diabetic mice hypoglycemic activity figure.
Embodiment:
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment is only for explanation, but not for limiting the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
Embodiment 1
The chloro-3-[(4-ethoxyl phenenyl of 6-O-benzoyl-1-{4-) methyl] phenyl }-β-D-Glucopyranose
A. prepare 2,3,4,6-, tetra--O-TMS-D-Glucose acid lactone (III)
In the three-necked bottle of 2L, add 70g maltonic acid-1,5-lactone, 700ml THF (heavily steaming).Under stirring, add 360g N-methylmorpholine, be cooled to 5 DEG C, then add 296g trimethylchlorosilane, stir soup compound 15 minutes, be warming up to 35 DEG C, spend the night.
Reactant is cooled to below 5 DEG C, adds 1L toluene, then add the 1400ml shrend reaction of going out.Separatory, adds 26g NaH
2pO
4, the aqueous solution of 520g.Divide the phase of anhydrating, then wash with water, salt water washing, through anhydrous Na
2sO
4dry, concentrated, obtain 200g oily matter.
B. prepare the bromo-4 '-ethoxy diphenyl methylmethane of the chloro-5-of 2-
1. the chloro-5-bromo-benzoyl chloride of preparation 2-
In 3L three-necked bottle, add the chloro-5-bromo-benzoic acid of 224g2-, 2.2L methylene dichloride (using molecular sieve processing), 1ml DMF.Stir the lower 200ml oxalyl chloride that slowly drips, make internal temperature remain on 25 DEG C of left and right.React heat release slightly, have gas to emit.25 DEG C of left and right reaction 20h, obtain settled solution.By this solution for vacuum concentration, obtain the chloro-5-bromo-benzoyl chloride of colourless bright oily product 2-242g (0.95mol, yield 100%)
2. the bromo-4 '-ethoxy diphenyl ketone of the preparation chloro-5-of 2-
In 2L three-necked bottle, add 1L methylene dichloride, then add the anhydrous AlCl of 128g
3, reaction mixture is cooled to 0 DEG C, under stirring, slowly add 118g phenyl ethyl ether, interior temperature is remained on below 5 DEG C.After adding, mixture is cooled to 0 DEG C, stand-by.
In another three-necked bottle, add the chloro-5-bromo-benzoyl chloride of 242g2-and 400ml methylene dichloride.This solution is joined in the stand-by mixture of above-mentioned preparation, make interior temperature remain on 0-5 DEG C.Solution crimson.At 0-5 DEG C, stir, reaction 6h, TLC monitoring reacts completely.This mixture is joined in the mixture of 560ml2M hydrochloric acid under vigorous stirring and 280g ice to cancellation reaction.400ml2M salt acid elution for organic phase, the water of merging is used 200ml dichloromethane extraction once.Merge organic phase, use respectively saturated sodium bicarbonate solution and salt solution washed twice.Vacuum concentration organic phase, to dry, adds 600ml ethanol heating for dissolving resistates, slowly drips 300ml water, starts crystallization.Stir 2h, filter, filter cake washs 2-3 time with the water/ethanol (2: 1) of precooling.The dry faint yellow solid product 234g that obtains.
3. the bromo-4 '-ethoxy diphenyl methylmethane of the preparation chloro-5-of 2-
In the three-necked bottle of 3L, add 180g (0.53mol) compound 3 to be dissolved in 1.6L acetonitrile, solution is cooled to 10 DEG C.Add 170g triethyl silicane, then slowly drip 201g boron trifluoride diethyl etherate, interior temperature is remained on below 20 DEG C, after dripping, make temperature of reaction remain on 25 DEG C of left and right.After reaction 5h, HPLC monitoring shows that raw material reacts completely.In this reaction mixture, add 700ml methyl tertiary butyl ether (MTBE), stir 15min, use saturated sodium bicarbonate solution washed twice, water extracts with MTBE, merges organic phase, and uses salt solution washed twice, and vacuum concentration is to dry.Add 360ml ethanol heating for dissolving resistates, crystallisation by cooling, collecting precipitation, the washing with alcohol twice of a small amount of precooling for filter cake, vacuum-drying product, to constant weight, obtains 128g compound 4.
C. prepare methyl isophthalic acid-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-α-D-Glucopyranose
In the three-necked bottle (reactor one) of 1L, add the bromo-4 '-ethoxy diphenyl methylmethane of the chloro-5-of 60g2-, 600ml THF (heavily steaming), is cooled to-78 DEG C, then slowly drips 210g s-butyl lithium, keeps temperature of reaction to be no more than-68 DEG C.After dripping, react again 1.5h.
In the three-necked bottle of 2L, (reactor two) adds 87g2, and 3,4,6-, tetra--O-trimethyl silyl-D-Glucose acid lactone and 450ml heptane are cooled to-78 DEG C.Then the mixed solution in reactor one is transferred in reactor two, speed control temperature in reaction is no more than-68 DEG C.After transfer, then at-78 DEG C of reaction 3h.Mixture is warming up to-40 DEG C, slowly in mixture, drips 600ml water.Separatory, 150ml MTBE extraction for water, merges organic phase, with twice, 40 DEG C of vacuum concentration of saturated brine washing.Oily resistates is dissolved in to 250ml methyl alcohol, adds 8.8g methylsulfonic acid, 30 DEG C are stirred 12h, are then heated to 40 DEG C of reaction 3h.Add 10ml triethylamine, mixture is concentrated, then add 500ml ethyl acetate, wash with water twice, be concentrated into oily resistates, add 110ml toluene to be dissolved, be slowly added drop-wise in 1L heptane, have Precipitation, collecting precipitation, filters a small amount of heptane wash of filter cake.40 DEG C of vacuum-dryings are to constant weight.Obtain 75g target product.
D. prepare methyl-2,3,4,6-, tetra--O-ethanoyl-1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-α-D-Glucopyranose
200g methyl isophthalic acid-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-α-D-Glucopyranose is dissolved in to the THF of 1L, join in the three-necked bottle of 2L, add again 435g N, N '-diisopropylethylamine (DlEPA) and 2g4-Dimethylamino pyridine (DMAP).Mixture is cooled to 0-5 DEG C, slowly drips diacetyl oxide, interior temperature is remained on below 5 DEG C, drip and finish rear continuation at 0-5 DEG C of stirring 3h.Add the MTBE of 1L, then with frozen water washing, separatory, water layer extracts with MTBE, merges organic phase, 400ml10% phosphate aqueous solution washing for organic phase, then use saturated sodium bicarbonate solution washed twice, saturated brine washed twice.At 40 DEG C, vacuum concentration obtains 210g target compound 6.(productive rate 95%)
E. prepare 2,3,4,6-, tetra--O-ethanoyl-1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose
In the three-necked bottle of 500ml, add 52g2,3,4,6-, tetra--O-ethanoyl-1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose and 250ml acetonitrile.Mixture is cooled to 10 DEG C, adds 1.5ml pure water.Add 35g triethyl silicane, then slowly drip boron trifluoride diethyl etherate 30g, keep temperature in reaction to be no more than 15 DEG C.After adding, 25 DEG C of reaction 20h.Be cooled to 15 DEG C, add 250ml MTBE and 150ml sodium hydrogen carbonate solution, separatory, organic phase is washed with saturated sodium bicarbonate solution, and water extracts with MTBE, organic phase salt water washing, concentrated organic phase, adds 400ml ethanol, adds 5g gac, backflow 15min, filter, by the washing with alcohol of 50ml heat, be cooled to room temperature, be cooled to again 0 DEG C, stir 1h.Filter collecting precipitation, the cooled washing with alcohol of filter cake.40 DEG C of vacuum-drying products are to constant weight.Obtain 29.3g white solid, be compound 7.(productive rate 65%)
F. prepare 1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose
In the three-necked bottle of 500ml, add the 480ml THF/MeOH/H of 2,3,4,6-, tetra--O-ethanoyl-1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose (30g)
2o (2: 3: 1) solution, then add 2.5g LiOH.20 DEG C of stirrings are spent the night, and concentrate organic solvent.Resistates is dissolved in to 300ml ethyl acetate, then uses salt water washing, 10ml5%KHSO
4solution washing, finally uses salt water washing, through anhydrous Na
2sO
4dry.Concentrated, use a small amount of CH
2cl
2heavily evaporation, obtains 21g target product 8.
G. prepare the chloro-3-[(4-ethoxyl phenenyl of 6-O-benzoyl-1-{4-) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
In 250ml round-bottomed flask, add 5g1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose, 80ml2-methyltetrahydrofuran and 12g benzoyl oxide, 60-70 DEG C is stirred 24h.Through saturated sodium bicarbonate solution washed twice, washing twice, finally uses salt water washing, through anhydrous sodium sulfate drying, concentrated.By column chromatography for separation (ethyl acetate/normal hexane=1: 1) obtaining white foam shape solid is the chloro-3-[(4-ethoxyl phenenyl of 6-O-benzoyl-1-{4-) methyl] phenyl }-β-D-Glucopyranose.
1HNMR(400MHz，CDCl
3)：δ1.35(t，3H)，3.37-3.51(m，5H)，3.59-3.66(q，2H)，3.90-4.09(m，5H)，4.52-4.64(m，2H)，6.76(d，2H)，7.06(d，2H)，7.16(d，2H)，7.20(s，1H)，7.31(d，1H)，7.39(t，2H)，7.53(t，1H)，7.99(d，2H)
Embodiment 2
The chloro-3-[(4-ethoxyl phenenyl of 6-O-ethylene ester group-1-{4-) methyl] phenyl }-β-D-Glucopyranose
The chloro-3-[(4-ethoxyl phenenyl of preparation 6-O-ethylene ester group-1-{4-) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
In 250ml round-bottomed flask, add 5g1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose, 80ml2-methyltetrahydrofuran and 2g diethyl carbonate, 50 DEG C are stirred 24h.Through saturated sodium bicarbonate solution washed twice, washing twice, finally uses salt water washing, through anhydrous sodium sulfate drying, concentrated.By column chromatography for separation (ethyl acetate/normal hexane=1: 2) obtaining white foam shape solid is the chloro-3-[(4-ethoxyl phenenyl of 6-O-ethylene ester group-1-{4-) methyl] phenyl }-β-D-Glucopyranose.
1HNMR(400MHz，CDCl
3)：δ1.28(t，3H)，1.39(t，3H)，3.00(s，4H)，3.40-3.61(m，3H)，3.96-4.08(m，5H)，4.16(q，2H)，4.41(s，2H)，6.80(d，2H)，7.08(d，2H)，7.20(d，2H)，7.35(d，1H)
Embodiment 3
The chloro-3-[(4-ethoxyl phenenyl of 6-O-carbonic acid tert-butyl ester base-1-{4-) methyl] phenyl }-β-D-Glucopyranose
The chloro-3-[(4-ethoxyl phenenyl of preparation 6-O-carbonic acid tert-butyl ester base-1-{4-) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
In 250ml round-bottomed flask, add 5g1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose, 80ml2-methyltetrahydrofuran and the 2.5g chloroformic acid tert-butyl ester, 30 DEG C are stirred 24h.Through saturated sodium bicarbonate solution washed twice, washing twice, finally uses salt water washing, through anhydrous sodium sulfate drying, concentrated.By column chromatography for separation (ethyl acetate/normal hexane=1: 2) obtaining white foam shape solid is the chloro-3-[(4-ethoxyl phenenyl of 6-O-carbonic acid tert-butyl ester base-1-{4-) methyl] phenyl }-β-D-Glucopyranose.
1HNMR(400MHz，CDCl
3)：δ1.32(t，3H)，1.38(s，9H)，3.38-3.60(m，6H)，3.96(s，2H)，4.02-4.26(m，4H)，4.41(m，2H)，6.80(d，2H)，7.08(d，2H)，7.20(d，2H)，7.35(d，1H)
Embodiment 4
The chloro-3-[(4-ethoxyl phenenyl of 6-O-ethanoyl-1-{4-) methyl] phenyl }-β-D-Glucopyranose
The chloro-3-[(4-ethoxyl phenenyl of preparation 6-O-ethanoyl-1-{4-) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
In 250ml round-bottomed flask, add 5g1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose, 80ml2-methyltetrahydrofuran and 2g diacetyl oxide, 30 DEG C are stirred 24h.Through saturated sodium bicarbonate solution washed twice, washing twice, finally uses salt water washing, through anhydrous sodium sulfate drying, concentrated.By column chromatography for separation (ethyl acetate/normal hexane=1: 1) obtaining white foam shape solid is the chloro-3-[(4-ethoxyl phenenyl of 6-O-ethanoyl-1-{4-) methyl] phenyl }-β-D-Glucopyranose.
1HNMR(400MHz，CDCl
3)：δ1.37(t，3H)，2.04(s，3H)，3.37(q，2H)，3.46-3.55(m，2H)，3.71(s，3H)，3.93-4.07(m，5H)，4.31(s，2H)，6.09(d，2H)，7.08(d，2H)，7.17(d，2H)，7.35(d，1H)
Embodiment 5
The chloro-3-[(4-ethoxyl phenenyl of 6-O-isobutyl carbonate butyl ester base-1-{4-) methyl] phenyl }-β-D-Glucopyranose
The chloro-3-[(4-ethoxyl phenenyl of preparation 6-O-isobutyl carbonate butyl ester base-1-{4-) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
In 250ml round-bottomed flask, add 5g1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose, 80ml2-methyltetrahydrofuran and 2.5g isobutyl chlorocarbonate, 50 DEG C are stirred 24h.Through saturated sodium bicarbonate solution washed twice, washing twice, finally uses salt water washing, through anhydrous sodium sulfate drying, concentrated.By column chromatography for separation (ethyl acetate/normal hexane=1: 1) obtaining white foam shape solid is the chloro-3-[(4-ethoxyl phenenyl of 6-O-isobutyl carbonate butyl ester base-1-{4-) methyl] phenyl }-β-D-Glucopyranose.
1HNMR(400MHz，CDCl
3)：δ0.92(d，6H)，1.38(t，3H)，1.89-1.99(m，1H)，3.33-3.61(m，7H)，3.84-3.92(m，2H)，3.95-4.08(m，5H)，4.36-4.44(m，2H)，6.80(d，2H)，7.08(d，2H)，7.19(d，2H)，7.35(d，1H)
Embodiment 6
The chloro-3-[(4-ethoxyl phenenyl of 6-O-isobutyryl-1-{4-) methyl] phenyl }-β-D-Glucopyranose
The chloro-3-[(4-ethoxyl phenenyl of preparation 6-O-isobutyryl-1-{4-) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
In 250ml round-bottomed flask, add 5g1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose, 80ml2-methyltetrahydrofuran and 2.9g isobutyric anhydride, 50 DEG C are stirred 24h.Through saturated sodium bicarbonate solution washed twice, washing twice, finally uses salt water washing, through anhydrous sodium sulfate drying, concentrated.By column chromatography for separation (ethyl acetate/normal hexane=1: 1) obtaining white foam shape solid is the chloro-3-[(4-ethoxyl phenenyl of 6-O-isobutyryl-1-{4-) methyl] phenyl }-β-D-Glucopyranose.
1HNMR(400MHz，CDCl
3)：δ1.16(d，6H)，1.39(t，3H)，2.54-2.65(m，1H)，3.78(t，2H)，3.49-3.63(m，4H)，3.96-4.09(m，5H)，4.26-4.50(m，2H)，6.80(d，2H)，7.09(d，2H)，7.18(d，2H)，7.36(d，1H)
Embodiment 7
The chloro-3-[(4-ethoxyl phenenyl of 6-O-propionyl-1-{4-) methyl] phenyl }-β-D-Glucopyranose
The chloro-3-[(4-ethoxyl phenenyl of preparation 6-O-propionyl-1-{4-) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
In 250ml round-bottomed flask, add 4g1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose, 80ml2-methyltetrahydrofuran and 2.5g propionic anhydride, 40 DEG C are stirred 24h.Through saturated sodium bicarbonate solution washed twice, washing twice, finally uses salt water washing, through anhydrous sodium sulfate drying, concentrated.By column chromatography for separation (ethyl acetate/normal hexane=1: 1) obtaining white foam shape solid is the chloro-3-[(4-ethoxyl phenenyl of 6-O-propionyl-1-{4-) methyl] phenyl }-β-D-Glucopyranose.
1HNMR(400MHz，CDCl
3)：δ1.10(t，3H)，1.38(t，3H)，1.78-1.97(m，2H)，2.34(q，2H)，3.38(q，2H)，3.94-4.07(m，5H)，4.30-4.39(m，2H)，6.79(d，2H)，7.08(d，2H)，7.17(d，2H)，7.34(d，2H)
Embodiment 8
The chloro-3-[(4-ethoxyl phenenyl of 6-O-methoxy ethanoyl-1-{4-) methyl] phenyl }-β-D-Glucopyranose
The chloro-3-[(4-ethoxyl phenenyl of preparation 6-O-methoxy ethanoyl-1-{4-) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
In 250ml round-bottomed flask, add 4g1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose, 80ml2-methyltetrahydrofuran and 3g methoxyacetic anhydride, 50 DEG C are stirred 24h.Through saturated sodium bicarbonate solution washed twice, washing twice, finally uses salt water washing, through anhydrous sodium sulfate drying, concentrated.By column chromatography for separation (ethyl acetate/normal hexane=1: 1) obtaining white foam shape solid is the chloro-3-[(4-ethoxyl phenenyl of 6-O-methoxy ethanoyl-1-{4-) methyl] phenyl }-β-D-Glucopyranose.
1HNMR(400MHz，CDCl
3)：δ1.38(t，3H)，3.34(s，4H)，3.39-3.53(m，3H)，3.76(s，3H)，3.94-4.07(m，7H)，4.40(t，2H)，6.79(d，2H)，7.08(d，2H)，7.17(d，2H)，7.34(d，2H)
Embodiment 9
The chloro-3-[(4-ethoxyl phenenyl of the positive caproyl-1-{4-of 6-O-) methyl] phenyl }-β-D-Glucopyranose
The chloro-3-[(4-ethoxyl phenenyl of the preparation positive caproyl-1-{4-of 6-O-) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
In 250ml round-bottomed flask, add 4g1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose, 80ml2-methyltetrahydrofuran and 4g n-caproic anhydride, 60 DEG C are stirred 24h.Through saturated sodium bicarbonate solution washed twice, washing twice, finally uses salt water washing, through anhydrous sodium sulfate drying, concentrated.By column chromatography for separation (ethyl acetate/normal hexane=1: 1) obtaining white foam shape solid is the chloro-3-[(4-ethoxyl phenenyl of the positive caproyl-1-{4-of 6-O-) methyl] phenyl }-β-D-Glucopyranose.
1HNMR(400MHz，CDCl
3)：δ0.87(t，3H)，1.20-1.31(m，4H)，1.38(t，3H)，2.31(t，2H)，3.33-3.58(m，4H)，3.85(s，3H)，3.93-4.05(m，5H)，4.30-4.37(m，2H)，6.79(d，2H)，7.08(d，2H)，7.19(d，2H)，7.34(d，2H)
Embodiment 10
The chloro-3-[(4-ethoxyl phenenyl of 6-O-capryloyl-1-{4-) methyl] phenyl }-β-D-Glucopyranose
The chloro-3-[(4-ethoxyl phenenyl of preparation 6-O-capryloyl-1-{4-) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
In 250ml round-bottomed flask, add 4g1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose, 80ml2-methyltetrahydrofuran and 5g caprylic anhydride, 60 DEG C are stirred 24h.Through saturated sodium bicarbonate solution washed twice, washing twice, finally uses salt water washing, through anhydrous sodium sulfate drying, concentrated.By column chromatography for separation (ethyl acetate/normal hexane=1: 1) obtaining white foam shape solid is the chloro-3-[(4-ethoxyl phenenyl of 6-O-capryloyl-1-{4-) methyl] phenyl }-β-D-Glucopyranose.
1HNMR(400MHz，CDCl
3)：δ0.88(t，3H)，1.38(m，4H)，1.38(t，3H)，2.31(t，2H)，3.33-3.58(m，4H)，3.85(s，3H)，3.93-4.05(m，5H)，4.30-4.37(m，2H)，6.79(d，2H)，7.08(d，2H)，7.19(d，2H)，7.34(d，2H)
Embodiment 11
The chloro-3-[(4-ethoxyl phenenyl of 6-O-capryloyl-1-{4-) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
The chloro-3-[(4-ethoxyl phenenyl of preparation 6-O-capryloyl-1-{4-) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
In 250ml round-bottomed flask, add 4g1-C-(the chloro-4 '-ethoxy diphenyl of 2-methylmethane-3-yl)-β-D-Glucopyranose, 80ml2-methyltetrahydrofuran and 3g Succinic anhydried, 35 DEG C are stirred 24h.Through saturated sodium bicarbonate solution washed twice, washing twice, finally uses salt water washing, through anhydrous sodium sulfate drying, concentrated.By column chromatography for separation (ethyl acetate/normal hexane=5: 1) obtaining weak yellow foam shape solid is the chloro-3-[(4-ethoxyl phenenyl of 6-O-(4-carboxyl butyryl radicals)-1-{4-) methyl] phenyl }-β-D-Glucopyranose.
1HNMR(400MHz，CDCl
3)：δ1.33(t，3H)，2.75(t，2H)，2.80(t，2H)，3.38-3.64(m，5H)，3.79-3.96(m，3H)，4.15-4.27(m，4H)，4.33-4.41(m，2H)，6.81(d，2H)，7.08(d，2H)，7.20(d，2H)，7.36(d，2H)
Embodiment compound pharmacologically active preliminary assessment
Embodiment 1: the preliminary screening of embodiment compound to diabetic mice hypoglycemic activity
One test objective
Observe test-compound embodiment 1-11 and compound dapagliflozin, the impact of positive control N1,N1-Dimethylbiguanide on diabetic mice model blood sugar, blood sugar is measured also and analyzed after 10 days at continuous gastric infusion, its hypoglycemic activity in vivo of preliminary assessment.
Two animal subjects and diabetes modeling method
Kind, strain: ICR mouse
Source: Zhejiang Province's Experimental Animal Center, credit number: SCXK (Zhejiang) 2008-0033
Body weight: 25g
Sex: male
Number of animals: 150
Raising condition: clean level Animal House is raised, temperature: 22 ± 2 DEG C, humidity: 55-65%, illumination: 12 hours are dark, and 12 hours are bright.
Modeling method: mouse fasting be can't help after water 17h, abdominal injection 1%STZ, dosage is 0.15ml/10g (being 150mg/kg).Glucose level (before measuring, water 12h is can't help in fasting) is measured in modeling after 4 days.Be modeling success by fasting blood sugar higher than the level of 7.0mmol/L.
Three test methods
3.1 compound methods: appropriate sample and PVP K30 are by 1: 2-1: 5 are dissolved in dehydrated alcohol, volatilize ethanol, then water is mixed with suspension, dapagliflozin, embodiment 1-11 compound concentration are 14mg/kg.Positive drug Determination of metformin is 200mg/kg.
3.2 dosage settings: oral administration, is administered twice by 0.1ml/10g dosage respectively every day.
The mensuration of 3.3 blood glucose values:
Diabetic mice is carried out to randomized grouping, and start according to dosage to carry out administration, model control group gives water, measures glucose level respectively at 10days after administration.Before measuring, fasting be can't help adopting fresh blood mensuration after water 12h.Use SureStep
tMsteadily blood glucose meter is carried out measuring content of blood sugar (the results are shown in Table 1 and Fig. 1).
Table 1 compound gavage 10 days is to diabetic mice hypoglycemic activity
| Group | Blood glucose value (mmol/L) |
| Negative group | 19.03±6.66 |
| The positive group of N1,N1-Dimethylbiguanide | 13.87±6.54 ＊＊ |
| dapagliflozin | 12.71±3.23 ＊＊ |
| Embodiment 1 | 11.50±3.50 ＊ |
| Embodiment 2 | 14.01±4.38 ＊＊＊ |
| Embodiment 3 | 19.70±4.95 |
| Embodiment 4 | 16.67±3.90 |
| Embodiment 5 | 17.68±6.18 |
| Embodiment 6 | 15.82±3.22 ＊ |
| Embodiment 7 | 15.24±5.37 ＊＊ |
| Embodiment 8 | 14.90±4.11 ＊＊ |
| Embodiment 9 | 16.12±3.08 ＊ |
| Embodiment 10 | 15.76±3.11 ＊ |
| Embodiment 11 | 15.33±4.70 ＊ |
Note:
*p < 0.05,
*p < 0.01,
* *the negative group of P < 0.005vs.
Embodiment 1-11 compound is carried out to the preliminary screening of hypoglycemic activity, result shows that embodiment 1, embodiment 2 and embodiment 6-11 compound all can effectively reduce the blood-sugar content of diabetic mice in 10 days afterwards in gavage, and has statistical significance.
Embodiment 2: the preliminary assessment of embodiment compound to diabetic mice hypoglycemic activity
Observe test-compound dapagliflozin, embodiment 1, embodiment 2 and the impact of embodiment 6-11 on blood glucose in diabetic mice, blood sugar is measured also and analyzed after 60 days at successive administration, its hypoglycemic activity in vivo of preliminary assessment.Experimental animal and test method are with embodiment 1, and experimental animal quantity is 120, and compound concentration is respectively 10
-4mol/kg, dosage is 0.1ml/10g (the results are shown in Table 2 and Fig. 2).
Table 2 compound gavage 60 days is to diabetic mice hypoglycemic activity
| Group | Blood glucose value (mmol/L) |
| Negative group | 18.96±7.24 |
| dapagliflozin | 13.43±3.46 ＊＊ |
| Embodiment 1 | 12.88±3.02 ＊＊ |
| Embodiment 2 | 13.02±3.44 ＊ |
| Embodiment 6 | 15.10±3.21 ＊ |
| Embodiment 7 | 14.96±3.62 ＊＊ |
| Embodiment 8 | 15.37±4.04 ＊ |
| Embodiment 9 | 15.66±3.19 ＊＊ |
| Embodiment 10 | 14.83±4.30 ＊＊ |
| Embodiment 11 | 14.92±3.53 ＊ |
Note:
*p < 0.05,
*p < 0.01, the negative group of vs.
Embodiment 2 results show, can effectively reduce mouse's blood sugar content, and have statistical significance to embodiment 1,2 after the continuous gavage 60days of diabetic mice and embodiment 6-11 compound, and wherein embodiment 1,2 is all better than dapagliflozin.Further determine the blood sugar decreasing effect of above compound.
Claims (8)
1. there is the compound of general formula (I) structure and acceptable salt pharmaceutically thereof,
Wherein:
R is selected from following group:
Phenyl; C
1-C
7alkyl;-CH
2cH
2cOOH;
-OR
1; Wherein R
1for methyl, ethyl, sec.-propyl, the tertiary butyl, isobutyl-
-R
2oCH
3; Wherein R
2for C
1-C
4alkyl.
2. compound according to claim 1 or its pharmacy acceptable salt, wherein said compound is selected from:
3. a pharmaceutical composition, it is characterized in that, it contains pharmaceutically acceptable vehicle or carrier, and as the compound described in the claim 1-2 of activeconstituents or its each optical isomer, each crystal formation, pharmaceutically acceptable cocrystallization mixture, hydrate or solvate.
4. the purposes of the compound described in a claim 1-2 or its each optical isomer, each crystal formation, pharmaceutically acceptable cocrystallization mixture, hydrate or solvate, it is characterized in that, for the preparation of the composition of prevention or treatment hyperglycemia relative disease.
5. the purposes of the compound described in a claim 1-2 or its each optical isomer, each crystal formation, pharmaceutically acceptable cocrystallization mixture, hydrate or solvate, it is characterized in that, for the preparation of the inhibitor of the 2 type sodium dependent glucose translocators (SGLT-2) containing C-aryl glucoside structure.
6. pharmaceutical composition claimed in claim 4, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
7. solid and liquid oral medicine comprise according to claim 6: tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, oral solution, described injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion.
8. a method of preparing compound shown in general formula (I), is characterized in that, described method comprises the steps:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310134087.7A CN104109179A (en) | 2013-04-16 | 2013-04-16 | C-aryl glucoside derivatives, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310134087.7A CN104109179A (en) | 2013-04-16 | 2013-04-16 | C-aryl glucoside derivatives, preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104109179A true CN104109179A (en) | 2014-10-22 |
Family
ID=51706182
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310134087.7A Pending CN104109179A (en) | 2013-04-16 | 2013-04-16 | C-aryl glucoside derivatives, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104109179A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104327027A (en) * | 2014-10-14 | 2015-02-04 | 中国药科大学 | New C-aryl glycosidase SGLT2 (sodium glucose transporter type-2) inhibitor |
| CN105753827A (en) * | 2014-12-17 | 2016-07-13 | 中美华世通生物医药科技（武汉）有限公司 | Method for preparing compound |
| CN107108539A (en) * | 2014-09-15 | 2017-08-29 | 北京生命科学研究所 | Sodium glucose cotransporter 2 (SGLT 2) inhibitor |
| WO2018014866A1 (en) * | 2016-07-22 | 2018-01-25 | 江苏豪森药业集团有限公司 | Crystal form of dapagliflozin intermediate and preparation method therefor |
| WO2018155970A1 (en) * | 2017-02-24 | 2018-08-30 | 동아에스티 주식회사 | Novel glucose derivative as sglt-2 inhibitor |
| KR20180098173A (en) * | 2017-02-24 | 2018-09-03 | 동아에스티 주식회사 | Novel Glucose derivatives of SGLT-2 inhibitor |
| CN110698468A (en) * | 2019-09-24 | 2020-01-17 | 杭州华东医药集团新药研究院有限公司 | Preparation method of canagliflozin |
| WO2020040433A1 (en) * | 2018-08-22 | 2020-02-27 | 동아에스티 주식회사 | Method for preparation of sglt-2 inhibitor, dapagliflozin precursor |
| CN114163425A (en) * | 2021-12-20 | 2022-03-11 | 江西天戌药业有限公司 | Preparation method and application of empagliflozin impurity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100391963C (en) * | 2003-01-03 | 2008-06-04 | 布里斯托尔-迈尔斯斯奎布公司 | Methods of producing C-aryl glucoside SGLT2 inhibitors |
| WO2010127067A1 (en) * | 2009-04-30 | 2010-11-04 | Glaxosmithkline Llc | Chemical process |
-
2013
- 2013-04-16 CN CN201310134087.7A patent/CN104109179A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100391963C (en) * | 2003-01-03 | 2008-06-04 | 布里斯托尔-迈尔斯斯奎布公司 | Methods of producing C-aryl glucoside SGLT2 inhibitors |
| WO2010127067A1 (en) * | 2009-04-30 | 2010-11-04 | Glaxosmithkline Llc | Chemical process |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107108539A (en) * | 2014-09-15 | 2017-08-29 | 北京生命科学研究所 | Sodium glucose cotransporter 2 (SGLT 2) inhibitor |
| CN104327027A (en) * | 2014-10-14 | 2015-02-04 | 中国药科大学 | New C-aryl glycosidase SGLT2 (sodium glucose transporter type-2) inhibitor |
| CN104327027B (en) * | 2014-10-14 | 2017-04-05 | 中国药科大学 | One class novel C aryl glucoside SGLT2 inhibitor |
| CN105753827A (en) * | 2014-12-17 | 2016-07-13 | 中美华世通生物医药科技（武汉）有限公司 | Method for preparing compound |
| CN109219611A (en) * | 2016-07-22 | 2019-01-15 | 江苏豪森药业集团有限公司 | The crystal form and preparation method thereof of Dapagliflozin intermediate |
| JP2019521151A (en) * | 2016-07-22 | 2019-07-25 | 江▲蘇▼豪森▲薬▼▲業▼集▲団▼有限公司 | Crystal form of dapagliflozin intermediate and process for its preparation |
| US10836786B2 (en) | 2016-07-22 | 2020-11-17 | Jiangsu Hansoh Pharmaceutical Group Co., Ltd. | Crystal form of dapagliflozin intermediate and preparation method therefor |
| CN107641139A (en) * | 2016-07-22 | 2018-01-30 | 江苏豪森药业集团有限公司 | Crystal formation of Dapagliflozin intermediate and preparation method thereof |
| WO2018014866A1 (en) * | 2016-07-22 | 2018-01-25 | 江苏豪森药业集团有限公司 | Crystal form of dapagliflozin intermediate and preparation method therefor |
| CN110337442A (en) * | 2017-02-24 | 2019-10-15 | 东亚St株式会社 | Novel grape sugar derivatives as 2 type sodium dependent glucose transporter inhibitors |
| KR101954188B1 (en) * | 2017-02-24 | 2019-05-23 | 동아에스티주식회사 | Novel Glucose derivatives of SGLT-2 inhibitor |
| KR20180098173A (en) * | 2017-02-24 | 2018-09-03 | 동아에스티 주식회사 | Novel Glucose derivatives of SGLT-2 inhibitor |
| JP2020514327A (en) * | 2017-02-24 | 2020-05-21 | ドン−ア エスティ カンパニー リミテッド | Novel glucose derivative that is an SGLT-2 inhibitor |
| WO2018155970A1 (en) * | 2017-02-24 | 2018-08-30 | 동아에스티 주식회사 | Novel glucose derivative as sglt-2 inhibitor |
| JP7160821B2 (en) | 2017-02-24 | 2022-10-25 | ドン－ア エスティ カンパニー リミテッド | Novel glucose derivatives that are SGLT-2 inhibitors |
| CN110337442B (en) * | 2017-02-24 | 2023-05-12 | 东亚St株式会社 | Novel glucose derivatives as inhibitors of sodium-dependent glucose transporter type 2 |
| WO2020040433A1 (en) * | 2018-08-22 | 2020-02-27 | 동아에스티 주식회사 | Method for preparation of sglt-2 inhibitor, dapagliflozin precursor |
| CN110698468A (en) * | 2019-09-24 | 2020-01-17 | 杭州华东医药集团新药研究院有限公司 | Preparation method of canagliflozin |
| CN114163425A (en) * | 2021-12-20 | 2022-03-11 | 江西天戌药业有限公司 | Preparation method and application of empagliflozin impurity |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104109179A (en) | C-aryl glucoside derivatives, preparation method and application thereof | |
| CN102471248B (en) | Methods, compounds, and compositions for delivering 1,3-propan ed isulfonic acid | |
| CN104761522B (en) | Optically pure benzyl-4-chlorophenyl C-glucoside derivatives | |
| CN103748090B (en) | Glycosides derivatives and for treating the purposes of diabetes | |
| CN101486744A (en) | Polyethyleneglycol modified scutellarin compound and preparation thereof | |
| CN101787064B (en) | Cytarabine derivatives and purposes thereof in resisting cancers and tumors | |
| CN103619862A (en) | Glycoside derivatives and uses thereof | |
| CN104031098A (en) | Hypoglycemic medicine | |
| WO2023216533A1 (en) | Indole alkaloid, and preparation method therefor and use thereof | |
| CN104059042A (en) | C-triaryl glucoside SGLT-2 inhibitor | |
| CN102146066A (en) | C-glucoside derivatives containing saturated six-membered ring as well as preparation method and application thereof | |
| CN104151306A (en) | Canagliflozin new preparation method | |
| US20140155334A1 (en) | Polyphosphate and pyrophosphate derivative of saccharides | |
| CN104861002A (en) | 3,6-anhydroglucose structure-containing phenyl C-glucoside derivatives and their preparation method and use | |
| CN103270033B (en) | C-aryl glucoside derivative and its preparation method and application | |
| CN105131066A (en) | Pyrimidine derivatives, preparation method and applications thereof | |
| CN101497611A (en) | N-(3-carboxyl-9-benzyl carboline-1-yl) ethyl amino acid, as well as synthesizing method and use thereof | |
| CN103626722B (en) | Nitric oxide donator type Hypoglycemics, Preparation Method And The Use | |
| CN105237595A (en) | N2-glycosyl-substituted 1,2,3-triazole compound and synthesis method and application thereof | |
| CN102675378A (en) | C-glucoside derivative containing cyclopropane structure and method and application of C- glucoside derivative | |
| WO2020038279A1 (en) | Substituted pyrazole compound, and preparation method, pharmaceutical composition, and use thereof | |
| EP3470403B1 (en) | Taxoid compound and preparation method and use thereof | |
| CN104672227A (en) | Novel SGLT2 inhibitor compounds and pharmaceutical composition thereof | |
| CN104761523A (en) | Phenyl C-glucoside derivative containing 3-oxoglucose structure, preparation method and uses thereof | |
| CN110551088B (en) | Deuterium-modified benzyl-4-chlorophenyl C-glycoside derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20141022 |
|
| WD01 | Invention patent application deemed withdrawn after publication |