CN102675378A - C-glucoside derivative containing cyclopropane structure and method and application of C- glucoside derivative - Google Patents
C-glucoside derivative containing cyclopropane structure and method and application of C- glucoside derivative Download PDFInfo
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- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
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Abstract
The invention relates to the field of medicines relevant to diabetes mellitus, in particular to a type 2 sodium galactose transporter [SGLT2 (sodium-dependent glucose transporter)] inhibitor of a C-glucoside type containing a cyclopropane structure, a preparation method of the type 2 sodium galactose transporter inhibitor, a medicinal composition containing the type 2 sodium galactose transporter inhibitor and application of the type 2 sodium galactose transporter inhibitor in terms of preparation of medicine for the diabetes mellitus. An R1 is one of H, F, Cl, Br, I, OR3, SR4, OCF3, CF3, CHF2, CH2F, alkyl of C1-C3 and a naphthenic base containing 3-5 carbon atoms, an R3 and an R4 are independently selected from alkyl of C1-C3, an R2 is selected from alkyl of C1-C3, cyclopropyl and OR5, and an R5 is one of alkyl of C1-C3 and cyclopropyl.
Description
Technical field
The present invention relates to the pharmaceutical field relevant with mellitus.Particularly, the present invention relates to the medicative C-glucose glycoside 2 type sodium glucose that contain the Trimetylene structure of mellitus cotransport son (SGLT2) suppressor factor and preparation method thereof and the pharmaceutical composition that contains them.
Background technology
Whole world diabetic subject is at present nearly about 1.7 hundred million, wherein about most II type (being non-insulin-depending type) diabetic subjects that are.Antidiabetic medicine in clinical use mainly contains N1,N1-Dimethylbiguanide class, sulfonylurea, insulin type, thiazolidinediones, alpha-glucosidase inhibitor class and dipeptidyl peptidase-iv inhibitor class medicine at present; These medicines have good therapeutic action; But there is safety issue in long-term treatment, as: problems such as liver toxicity, hypoglycemia, weight increase.
2 type sodium glucose (SGLT2) that cotransports is the novel targets of the treatment mellitus of discovered in recent years.SGLT2 mainly is distributed in the kidney proximal tubule, and its effect is the glucose that absorbs in the urine, and it is turned back in the blood, and that therefore suppresses SGLT2 just can reduce glucose concn in the blood, and this method has reduced glucose level from different in the past approach.When the SGLT2 function is obstructed, will secrete more glucose in the urine, this will help the diabetic subject to keep correct glucose level.Because the SGLT2 suppressor factor stays out of glucose metabolism, it can be used as the means of supplementing out economy of glycemic control main stream approach.
The compound that Chinese patent CN200610093189.9 discloses structure is as the SGLT2 suppressor factor:
Wherein, A is O, S, NH, (CH
2)
n, n=0-3.
The compound that Chinese patent CN200380110040.1 discloses structure is as the SGLT2 suppressor factor:
Wherein, A is a covalent linkage, O, S, NH, (CH
2)
n, n=1-3.
The compound that Chinese patent CN200480006761.2 discloses structure is as the SGLT2 suppressor factor:
Wherein, X is covalent linkage or low-grade alkylidene.
The compound that WO2005/012326 discloses structure is as the SGLT2 suppressor factor:
The invention discloses one type of C-glucoside analog derivative that contains the Trimetylene structure as novel SGLT2 suppressor factor, these suppressor factor can be used for the medicine of preparation treatment mellitus, particularly non insulin dependent diabetes.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of prior art, a kind of excellent activity that has is provided, have the compound of general formula I and pharmaceutically acceptable salt and prodrug ester.
Another object of the present invention provides preparation and has the compound of general formula I and the method for acceptable salt and prodrug ester pharmaceutically thereof.
A further object of the present invention provide the compound that contains general formula I and pharmaceutically acceptable salt and prodrug ester as effective constituent; And the medicinal compsns of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect the treatment mellitus.
Combine the object of the invention that content of the present invention is specifically described at present.
The compound that the present invention has general formula I has following structural formula:
Wherein,
R
1Be selected from H, F, Cl, Br, I, OR
3, SR
4, OCF
3, CF
3, CHF
2, CH
2F, C
1-C
3Alkyl, contain the naphthenic base of 3-5 carbon atom, wherein R
3And R
4Independently be selected from C
1-C
3Alkyl;
R
2Be selected from C
1-C
3Alkyl, cyclopropyl and OR
5, R wherein
5Be selected from C
1-C
3Alkyl and cyclopropyl.
Preferred following compound of Formula I,
Wherein,
R
1Be selected from H, F, Cl, OR
3, OCF
3, CF
3, Me, cyclopropyl, wherein R
3Definition as stated;
R
2Be selected from C
1-C
3Alkyl and OR
5, R wherein
5Be selected from C
1-C
3Alkyl.
The compound that has general formula I more preferably,
Compound of Formula I according to the invention can be synthetic through following steps:
Compound I I handles with trimethylsilyl reagent in the presence of alkali, obtains compound III, used alkali such as N-methylmorpholine, triethylamine, pyridine, 4-Dimethylamino pyridine etc., trimethylsilyl reagent such as trimethylchlorosilane etc.
Compound IV is used chloride reagent, like sulfur oxychloride or oxalyl chloride, is converted into corresponding acyl chlorides V.Compound V under aluminum chloride catalysis with Compound P hR
2The gram acylation reaction takes place to pay, and obtains compound VI.Compound VI is handled with methyl Grignard reagent MeMgX (X=Cl, Br, I), obtains compound VI I.Compound VI I, handles the generation dehydration reaction and obtains compound VIII like methylsulfonic acid, sulfuric acid, trifluoromethanesulfonic acid etc. with acid.Compound VIII is handled with methylene iodide in the presence of catalyst action, obtains compound I X, catalyzer such as Et
2Zn, Zn-Cu etc.Compound I X uses alkyl lithium reagents, like n-Butyl Lithium, handles, and obtains compounds X, and compounds X does not add to be separated in the reaction system and directly reacts with compound III, obtains compounds X I.Compounds X I is in acid, and like methylsulfonic acid, trifluoromethanesulfonic acid, tosic acid etc., catalysis is used methanol treatment down, obtains compounds X II.Compounds X II is at Lewis acid such as BF
3Et
2O, BF
3Existence such as MeCN or trifluoroacetic acid obtains compounds X III with reduction such as reductive agent such as triethyl silicane, tri isopropyl silanes down.Compounds X III is used in existence such as alkali such as sodium acetate, anhydrous, pyridine, 4-Dimethylamino pyridine and obtains XIV with reagent acetylizes such as acetic anhydride, Acetyl Chloride 98Min.s down.Compounds X IV handles with methods such as column chromatography or recrystallizations, obtains compounds X V.Compounds X V uses alkali, like processing such as sodium methylate, NaOH, KOH, takes off ethanoyl and obtains compound I.
The pharmaceutically acceptable prodrug ester of formula I compound according to the invention comprises the ester that any one or more hydroxyls and ethanoyl in the molecule, pivaloyl group, various phosphoryl, formamyl, alkoxyl formyl etc. form.
Formula I compound according to the invention can be processed pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be processed formulations such as solid orally ingestible, liquid oral medicine, injection.Said solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Compsn of the present invention can be accepted auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle on described pharmacy or the bromatology.
Compsn of the present invention can be accepted auxiliary material on described pharmacy or the bromatology.Weighting agent is one or more the compsn that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, lime carbonate, Microcrystalline Cellulose; Described tackiness agent comprises one or more compsn of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, TSK-Gel G 2000HXL, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more compsn of starch, crosslinked polyvidone, Sodium Croscarmellose, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
Compound of Formula I according to the invention has the restraining effect of SGLT2 enzyme, can be used as the medicine that effective constituent is used to prepare the mellitus aspect.The activity of compound of Formula I according to the invention is through hypoglycemic modelling verification in the body.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage of for example taking every day is divided into once or administration for several times in 1mg-1000mg/ people's scope.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by the doctor.These situation comprise: by curer's physical state, route of administration, age, body weight, to the individual reaction of medicine, the severity of symptom etc.
Embodiment
Below in conjunction with embodiment the present invention is further described.Need to prove that following embodiment is used for explanation, and is not to be used to limit 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
1-{4-chloro-3-[1-(4-ethoxyl phenenyl) Trimetylene-1-yl] phenyl }-1-deoxidation-β-D-Glucopyranose
A. (5-bromo-2-chloro-phenyl-) (4-ethoxyl phenenyl) ketone
Add oxalyl chloride and a DMF that 4.71g (20mmol) 5-bromo-2-chloro-benzoic acid, 20mL exsiccant methylene dichloride, 3.81g (30mmol) heavily steam in the dry round-bottomed flask of a 100mL; Gained white casse mixture is stirred overnight at room temperature, no longer includes gas up to system and emerges and become a clear soln.On Rotary Evaporators, steam excessive oxalyl chloride and solvent, the gained resistates adds 2.44g (20mmol) phenyl ethyl ether again with the dissolving of 15mL exsiccant methylene dichloride, and the ice-water bath cooling is stirred down, adds 4.00g (30mmol) aluminum trichloride (anhydrous) in batches.After adding, the gained mixture is stirred overnight at room temperature.
Reaction mixture carefully is poured in the 200mL frozen water, stirs, with the dichloromethane extraction of 50mL * 3.Merge extraction phase, use the saturated common salt water washing, anhydrous sodium sulfate drying.After suction filtration was removed siccative, filtrating boiled off solvent on Rotary Evaporators, obtain a resistates, and column chromatography purification obtains (5-bromo-2-chloro-phenyl-) pure article of (4-ethoxyl phenenyl) ketone.Clear crystal, fusing point 69-70 ℃, ESI-MS, m/z=339 ([M+H]
+), 341 ([M+H]
+).
B.1-(5-bromo-2-chloro-phenyl-)-1-(4-ethoxyl phenenyl) ethanol
(5-bromo-2-chloro-phenyl-) (4-ethoxyl phenenyl) ketone and the 60mL exsiccant THF that adds the above-mentioned preparation of 5.88g (17.3mmol) in the round-bottomed flask of an exsiccant 100mL is with sealing with the rubber cork behind the nitrogen purging.Flask places-10 ℃ cryosel to bathe cooling, and induction stirring dropwise adds the THF solution of the methylmagnesium-chloride of 8mL (24mmol) 3M in the flask with syringe.After dropwising, the gained mixture continues to stir half a hour under this temperature.
Reaction mixture carefully is poured in the 300mL frozen water, adds the 200mL methylene dichloride, stirs, and the gained two-phase mixture is through one deck zeyssatite suction filtration.From filtrating, tell organic phase, water is used the 50mL dichloromethane extraction once again.Merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.After suction filtration was removed siccative, filtrating boiled off solvent on Rotary Evaporators, obtain a resistates, and column chromatography purification obtains 1-(5-bromo-2-chloro-phenyl-)-pure article of 1-(4-ethoxyl phenenyl) alcoholic acid.Colorless oil,
1H NMR (DMSO-d
6, 400MHz), and δ 8.14 (d, 1H, J=2.4Hz), 7.47 (dd, 1H; J=2.4Hz and 8.4Hz), 7.23 (d, 1H, J=8.4Hz), 7.12 (d, 2H, J=8.8Hz); 6.80 (d, 2H, J=8.8Hz), 5.80 (s, 1H), 3.97 (q, 2H; J=6.9Hz), 1.88 (s, 3H), 1.29 (t, 3H, J=7.0Hz).
C.1-(5-bromo-2-chloro-phenyl-)-1-(4-ethoxyl phenenyl) ethene
Add 1-(5-bromo-2-chloro-phenyl-)-1-(4-ethoxyl phenenyl) ethanol and the 15mL methylene dichloride of the above-mentioned preparation of 5.33g (15mmol) in the round-bottomed flask of a 100mL, the gained mixture at room temperature stirs, and then adds 0.96g (10mmol) methylsulfonic acid.The gained mixture is stirred overnight at room temperature.
Reaction mixture is poured in the 200mL saturated aqueous common salt, with the dichloromethane extraction of 50mL * 3.Merge extraction phase, saturated common salt water washing, anhydrous sodium sulfate drying.After suction filtration was removed siccative, filtrating boiled off solvent on Rotary Evaporators, obtain a resistates, and column chromatography purification obtains the pure article of 1-(5-bromo-2-chloro-phenyl-)-1-(4-ethoxyl phenenyl) ethene.ESI-MS，m/z＝337([M+H]
+)，339([M+H]
+).
D.1-(5-bromo-2-chloro-phenyl-)-1-(4-ethoxyl phenenyl) Trimetylene
Add exsiccant magneton, 10mL exsiccant THF and 5mL exsiccant DME in the exsiccant round-bottomed flask of a 250mL, behind nitrogen purging, seal the back with the rubber cork and in-20 ℃ cryostat, cool off, start induction stirring.With the past Et that wherein adds 24mL (24mmol) 1.0M of syringe
2The hexane solution of Zn then dropwise adds 12.86g (48mmol) methylene iodide with syringe in the flask and is dissolved in the solution that 10mL exsiccant THF processes.After dropwising, continue to stir 2 hours, 1-(5-bromo-2-chloro-phenyl-)-1-(4-ethoxyl phenenyl) ethene that then slowly drips the above-mentioned preparation of 4.05g (12mmol) through syringe is dissolved in the solution that 5mL exsiccant THF processes.Dropwise back gained mixture stirred overnight at room temperature, then again nitrogen atmosphere refluxed 1 hour.
After the reaction mixture cooling, carefully be poured in the 300mL frozen water, add the 200mL methylene dichloride, stir, the gained two-phase mixture is through one deck zeyssatite suction filtration.From filtrating, tell organic phase, water is used the 50mL dichloromethane extraction once again.Merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.After suction filtration was removed siccative, filtrating boiled off solvent on Rotary Evaporators, obtain a resistates, and column chromatography purification obtains the pure article of 1-(5-bromo-2-chloro-phenyl-)-1-(4-ethoxyl phenenyl) Trimetylene.ESI-MS，m/z＝351([M+H]
+)，353([M+H]
+).
E.2,3,4, the trimethyl silicon based Gluconolactone of 6-four-O-
Add 1.78g (10mmol) Gluconolactone, 8.09g (80mmol) N-methylmorpholine and dry tetrahydrofuran 20mL in the round-bottomed flask of a 250mL; System is induction stirring under the ice-water bath cooling, and the trimethylchlorosilane that slowly drips 6.52g (60mmol) is dissolved into the solution that obtains in the 10mL dry THF.After dropwising, system is stirred overnight at room temperature, uses the 100mL dilution with toluene, and the frozen water cooling is down toward wherein slowly dripping 10mL water; Then transfer to the gained mixture in the separating funnel, use saturated sodium dihydrogen phosphate of 100mL and saturated common salt water washing successively, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators; Obtaining a colorless oil, is 2,3,4; The trimethyl silicon based Gluconolactone of 6-four-O-, drying is two hours under room temperature on the vacuum oil pump, and is subsequent use.Colorless oil, 4.68g.
F.1-{4-chloro-3-[1-(4-ethoxyl phenenyl) Trimetylene-1-yl] phenyl }-1-deoxidation-β-D-Glucopyranose
2.99g (8.5mmol) 1-(5-bromo-2-chloro-phenyl-)-1-(4-ethoxyl phenenyl) Trimetylene that adds above-mentioned preparation in the round-bottomed flask of a 100mL; 10mL exsiccant THF and a magneton; Then seal, place acetone-dry ice system to be cooled to-78 ℃ with the TR thin rubber plug.Stir down, in this reaction vessel, slowly add 5.6mL (9mmol with syringe; 1.6M) hexane solution of n-BuLi; Add the back system-78 ℃ of following restir one hour, then in this reaction vessel, slowly add 2,3 of above-mentioned preparation again with syringe; 4, the trimethyl silicon based Gluconolactone of 6-four-O-is dissolved into the solution that forms in the 10mL dry toluene.After adding, system restir one hour then is dissolved into the solution that forms in the 10mL anhydrous methanol with the methylsulfonic acid that syringe adds 1.92g (20mmol), and then system slowly is warmed up to room temperature, stirred overnight under the room temperature.Reaction mixture is poured in the saturated aqueous common salt, extracts at twice with the 100mL methylene dichloride, and the water washing of combining extraction liquid body and function saturated common salt once; Anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators obtains a colorless oil; Be 1-{4-chloro-3-[1-(4-ethoxyl phenenyl) Trimetylene-1-yl] phenyl }-α/β-D-methyl glucopyranoside; Oily matter, ESI-MS, m/z=465 ([M+H]
+).
The above-mentioned 1-{4-chloro-3-that obtains [1-(4-ethoxyl phenenyl) Trimetylene-1-yl] phenyl }-α/β-D-methyl glucopyranoside oily matter is dissolved in the 3mL dry methylene chloride; The ice-water bath cooling is stirred down, successively adds triethyl silicane 2mL and BFEE 1mL.The gained reaction system is stirred overnight at room temperature, carefully is poured in the 100mL frozen water, is adjusted to pH=8 with saturated sodium bicarbonate solution; Extract at twice with the 100mL methylene dichloride, the water washing of combining extraction liquid body and function saturated common salt once, anhydrous sodium sulfate drying; Evaporate to dryness on Rotary Evaporators obtains a colorless oil, is 1-{4-chloro-3-[1-(4-ethoxyl phenenyl) Trimetylene-1-yl] phenyl }-1-deoxidation-α/β-D-Glucopyranose; Oily matter, ESI-MS, m/z=435 ([M+H]
+).
The above-mentioned 1-{4-chloro-3-that obtains [1-(4-ethoxyl phenenyl) Trimetylene-1-yl] phenyl }-1-deoxidation-α/β-D-Glucopyranose colorless oil is dissolved in the 20mL acetic anhydride, adds the 0.5g sodium acetate, anhydrous, induction stirring temperature rising reflux 1 hour.After the cooling, system is poured in the 100mL water, and stirred overnight under the room temperature extracts with the 100mL methylene dichloride at twice; The water washing of combining extraction liquid body and function saturated common salt once, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators obtains the off-white color solid; Obtain a clear crystal, 2,3,4 through purification by silica gel column chromatography; 6-four-O-ethanoyl-1-1-{4-chloro-3-[1-(4-ethoxyl phenenyl) Trimetylene-1-yl] phenyl }-1-deoxidation-β-D-Glucopyranose, ESI-MS, m/z=603 ([M+H]
+).
Above-mentioned 2; 3; 4,6-four-O-ethanoyl-1-1-{4-chloro-3-[1-(4-ethoxyl phenenyl) Trimetylene-1-yl] phenyl }-1-deoxidation-β-D-Glucopyranose is dissolved in the 10mL anhydrous methanol that contains 0.11g (2mmol) sodium methylate, stirred 5 hours under the room temperature; Then add 1g exsiccant strongly acidic cationic exchange resin, stirred overnight under the room temperature.Remove by filter resin, gained filtrating evaporate to dryness on Rotary Evaporators obtains a white solid, is 1-{4-chloro-3-[1-(4-ethoxyl phenenyl) Trimetylene-1-yl] phenyl }-1-deoxidation-β-D-Glucopyranose, white solid, ESI-MS, m/z=435 ([M+H]
+).
Embodiment 2-13
It is understandable that, use method and the flow process of embodiment 1, change R
1, R
2Can obtain the listed compound of following table.
Embodiment 14
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution; Mix, the system softwood sieves; The system wet granular is in 50-60 ℃ of drying, with the CMS sodium salt; Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 15
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution; Mix, the system softwood sieves; The system wet granular is in 50-60 ℃ of drying, with the CMS sodium salt; Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 16
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes; The system softwood sieves, and the system wet granular is in 50-60 ℃ of drying; Magnesium Stearate and talcum powder are sieved in advance, join then in the above-mentioned particle, encapsulated, promptly get.
Embodiment 17
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes; The system softwood sieves, and the system wet granular is in 50-60 ℃ of drying; Magnesium Stearate and talcum powder are sieved in advance, join then in the above-mentioned particle, encapsulated, promptly get.
Embodiment 18
In zero(ppm) water, add earlier zero(ppm) water and Hydrocerol A, stirring and dissolving and after, add sample again; Low-grade fever makes dissolving, and adjust pH is 4.0-5.0, adds 0.2 gram activated carbon, stirs 20 minutes under the room temperature; Filter, filtrating, strength of solution is decided in middle detection; By 5 milliliters of packing of every peace bottle, high-temperature sterilization 30 minutes promptly gets injection liquid.
Embodiment 19
In zero(ppm) water, add earlier zero(ppm) water and Hydrocerol A, stirring and dissolving and after, add sample again; Low-grade fever makes dissolving, and adjust pH is 4.0-5.0, adds 0.2 gram activated carbon, stirs 20 minutes under the room temperature; Filter, filtrating, strength of solution is decided in middle detection; By 5 milliliters of packing of every peace bottle, high-temperature sterilization 30 minutes promptly gets injection liquid.
Embodiment 20
Preparation technology: get water for injection 80mL, add main ingredient, N.F,USP MANNITOL, lactose, Prist stir make dissolving after, the Citric Acid that adds 1mol/L is regulated PH to 7.0-9.0, mends and adds water to 100mL.Add the 0.5g gac, stirred 20 minutes down, take off charcoal, adopt the filtering with microporous membrane degerming at 30 ℃; Filtrating is carried out packing by every 1mL, and pre-freeze is after 2 hours, freezing drying under reduced pressure down 12 hours, to sample temperature after room temperature; Drying is 5 hours again, makes the white loose block, seals promptly to get.
Embodiment 21
Preparation technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing takes by weighing recipe quantity auxiliary material and main ingredient thorough mixing then.Add tackiness agent system softwood again, 14 mesh sieves are granulated, 55 ℃ of dryings, and the whole grain of 12 mesh sieves is measured heavily packing of bag.
Embodiment 22
Sample is mixed with the suspension of 10mg/mL concentration with 1% Xylo-Mucine, and the administration capacity is the 0.2mL/20g body weight, is equivalent to 20mg/kg dosage.
Healthy ICR mouse, male and female half and half, body weight 20-24g meets primary standard.Animal fasting 16 hours; The dextrose in saline solution of 2h abdominal injection 2g/kg behind the medicine (1.5h injectable dextrose monohydrate behind the Dapagliflozin medicine); 0.5h, 1h, 2h, 3h and 4h regularly take kapillary and get blood from mouse ball rear vein beard after modeling; Spinning serum is with each time point serum glucose level of determination of glucose oxidase.With time is that X-coordinate is that ordinate zou is drawn area under the calculated curve (AUC) with the blood glucose value.The hypoglycemic activity of each compound calculates with the blood sugar inhibiting rate, inhibiting rate (%)=[AUC (model)-AUC (compound I or dapagliflozin)]/[AUC (model)-AUC (blank)] * 100%.The result is the form of face as follows:
Above result shows that each compound all can significantly reduce the mouse blood sugar dosis tolerata that glucose causes.
Claims (7)
1. have the compound of general formula I structure and pharmaceutically acceptable salt and prodrug ester:
Wherein,
R
1Be selected from H, F, Cl, Br, I, OR
3, SR
4, OCF
3, CF
3, CHF
2, CH
2F, C
1-C
3Alkyl, contain the naphthenic base of 3-5 carbon atom, wherein R
3And R
4Independently be selected from C
1-C
3Alkyl;
R
2Be selected from C
1-C
3Alkyl, cyclopropyl and OR
5, R wherein
5Be selected from C
1-C
3Alkyl and cyclopropyl.
2. claim 1 is defined has the compound of general formula I and pharmaceutically acceptable salt and a prodrug ester:
Wherein,
R
1Be selected from H, F, Cl, OR
3, OCF
3, CF
3, Me, cyclopropyl, wherein R
3Definition as stated;
R
2Be selected from C
1-C
3Alkyl and OR
5, R wherein
5Be selected from C
1-C
3Alkyl.
3. the defined compound of Formula I of claim 2 is selected from following compounds:
4. the defined compound of Formula I of claim 1-3 and pharmaceutically acceptable salt and the application of prodrug ester aspect preparation treatment diabetes medicament.
5. pharmaceutical composition contains the compound of Formula I of one of claim 1-3 and pharmaceutically acceptable salt and prodrug ester, and appropriate carriers or vehicle.
6. the described pharmaceutical composition of claim 5, wherein, described compsn is solid orally ingestible, liquid oral medicine or injection.
7. comprise according to said solid of claim 6 and liquid oral medicine: tablet, capsule, granule, oral solution, said injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100564388A CN102675378A (en) | 2011-03-09 | 2011-03-09 | C-glucoside derivative containing cyclopropane structure and method and application of C- glucoside derivative |
| PCT/CN2012/072053 WO2012119550A1 (en) | 2011-03-09 | 2012-03-07 | C-glucosidase derivative having cyclopropane structure, preparing method therefor, pharmaceutical composition, and use thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011100564388A CN102675378A (en) | 2011-03-09 | 2011-03-09 | C-glucoside derivative containing cyclopropane structure and method and application of C- glucoside derivative |
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| CN102675378A true CN102675378A (en) | 2012-09-19 |
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| CN2011100564388A Pending CN102675378A (en) | 2011-03-09 | 2011-03-09 | C-glucoside derivative containing cyclopropane structure and method and application of C- glucoside derivative |
Country Status (2)
| Country | Link |
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| CN (1) | CN102675378A (en) |
| WO (1) | WO2012119550A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827122A (en) * | 2011-06-17 | 2012-12-19 | 山东亨利医药科技有限责任公司 | Glucoside derivate |
| CN110054657A (en) * | 2018-01-18 | 2019-07-26 | 亚宝药业集团股份有限公司 | Sugar-substituted pyrazole compound of glucopyra and preparation method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104513283B (en) | 2013-09-27 | 2018-01-16 | 广东东阳光药业有限公司 | Glucopyranosyl derivatives and its application in medicine |
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| CN1407990A (en) * | 1999-10-12 | 2003-04-02 | 布里斯托尔-迈尔斯斯奎布公司 | C-aryl glucoside sgltz inhibitors |
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| KR101107425B1 (en) * | 2007-08-23 | 2012-01-19 | 테라코스, 인코포레이티드 | Benzylbenzene derivatives and methods of use |
| CN102134226B (en) * | 2010-01-26 | 2013-06-12 | 天津药物研究院 | Phenyl C-glucoside derivatives, preparation method and use thereof |
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- 2011-03-09 CN CN2011100564388A patent/CN102675378A/en active Pending
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2012
- 2012-03-07 WO PCT/CN2012/072053 patent/WO2012119550A1/en active Application Filing
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| CN1407990A (en) * | 1999-10-12 | 2003-04-02 | 布里斯托尔-迈尔斯斯奎布公司 | C-aryl glucoside sgltz inhibitors |
| CN1756759A (en) * | 2003-01-03 | 2006-04-05 | 布里斯托尔-迈尔斯斯奎布公司 | Methods of producing C-aryl glucoside SGLT2 inhibitors |
| CN101652377A (en) * | 2007-04-02 | 2010-02-17 | 泰拉科斯有限公司 | Benzylic glycoside derivatives and methods of use |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827122A (en) * | 2011-06-17 | 2012-12-19 | 山东亨利医药科技有限责任公司 | Glucoside derivate |
| CN102827122B (en) * | 2011-06-17 | 2015-01-14 | 山东轩竹医药科技有限公司 | Glucoside derivate |
| CN110054657A (en) * | 2018-01-18 | 2019-07-26 | 亚宝药业集团股份有限公司 | Sugar-substituted pyrazole compound of glucopyra and preparation method thereof |
| CN110054657B (en) * | 2018-01-18 | 2021-06-29 | 亚宝药业集团股份有限公司 | Glucopyranosyl substituted pyrazole compound and preparation method thereof |
| US11377465B2 (en) | 2018-01-18 | 2022-07-05 | Yabao Pharmaceutical Group Co., Ltd. | Pyranoglucose-substituted pyrazole compound, preparation method thereof and application thereof |
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| Publication number | Publication date |
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| WO2012119550A1 (en) | 2012-09-13 |
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