CN101508712A - Glucoside containing tetrazole structure, preparation method and application - Google Patents

Glucoside containing tetrazole structure, preparation method and application Download PDF

Info

Publication number
CN101508712A
CN101508712A CNA2009100682870A CN200910068287A CN101508712A CN 101508712 A CN101508712 A CN 101508712A CN A2009100682870 A CNA2009100682870 A CN A2009100682870A CN 200910068287 A CN200910068287 A CN 200910068287A CN 101508712 A CN101508712 A CN 101508712A
Authority
CN
China
Prior art keywords
compound
tetrazole
glucopyranoside
base
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
Application number
CNA2009100682870A
Other languages
Chinese (zh)
Inventor
赵桂龙
徐为人
王玉丽
刘巍
王致峰
张士俊
刘冰妮
谭初兵
汤立达
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tianjin Institute of Pharmaceutical Research Co Ltd
Original Assignee
Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Tianjin Institute of Pharmaceutical Research Co Ltd filed Critical Tianjin Institute of Pharmaceutical Research Co Ltd
Priority to CNA2009100682870A priority Critical patent/CN101508712A/en
Publication of CN101508712A publication Critical patent/CN101508712A/en
Pending legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

The invention relates to the diabetes-related drug field. More specifically, the invention relates to an sodium glucose transporter 2 (SGLT2) inhibitor containing a tetrazolylglucoside structure, a preparation method and application thereof to preparation of antidiabetic drugs, wherein, radicals are defined as the specification.

Description

The glucoside, the Preparation Method And The Use that contain tetrazole structure
Technical field
The present invention relates to the pharmaceutical field relevant with diabetes.Particularly, the present invention relates to medicative 2 type sodium glucose transporter (SGLT2) inhibitor that contain tetrazole base glucoside structure of diabetes 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, mostly approximately is II type (being non-insulin-depending type) diabetic subjects.At present, the conventional medicament of the treatment diabetes of clinical use mainly contains N1,N1-Dimethylbiguanide class, sulfonylurea and trypsin class medicine, and thiazolidinediones medicine, alpha-glucosidase inhibitor and the dipeptidyl peptidase-iv inhibitor etc. of listing in recent years.These medicines have good therapeutic action, but long-term treatment exists such as liver toxicity and weight increase safety issue.
2 type sodium glucose transporters (SGLT2) are the novel targets of the treatment diabetes found this year.The protein of SGLT2 mainly is distributed in kidney, its effect is the glucose that absorbs in the urine, and it is turned back in the blood, the protein target spot that therefore suppresses SGLT2 just can reduce glucose concn in the blood, and this method is different with the approach of the level of in the past lowering blood glucose.Therefore when the SGLT2 function is obstructed, the glucose in the urine will fall by renal secretion more, and this will help the diabetic subject to keep correct glucose level.Because the SGLT2 inhibitor stays out of glucose metabolism, it can be used as the means of supplementing out economy of glycemic control main stream approach.
The invention discloses the New type of S GLT2 inhibitor that can reduce plasma glucose levels effectively, these inhibitor lay the foundation for the medicine that further can be used to prepare diabetes medicament, 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 and the pharmaceutically acceptable ester thereof of general formula I.
Another object of the present invention provides the method that preparation has the compound and the pharmaceutically acceptable ester thereof of general formula I.
A further object of the present invention provide contain general formula I compound as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect the treatment diabetes.
Now content of the present invention is specifically described in conjunction with purpose of the present invention.
The compound that the present invention has general formula I has following structural formula:
Figure A200910068287D00061
Wherein,
R is selected from H, F, Cl, Br, I, C 1-C 5Alkyl, NO 2, NR 1R 2And OR 3, and two replacement combination, wherein R of these groups 1And R 2Independently be selected from H and C 1-C 3Alkyl, R 3Be selected from C 1-C 5Alkyl.
Preferred following compound of Formula I or its pharmaceutically acceptable ester,
Wherein,
R is selected from H, F, Cl, C 1-C 3Alkyl, NO 2, NR 1R 2And OR 3, and two replacement combination, wherein R of these groups 1And R 2Independently be selected from H and C 1-C 3Alkyl, R 3Be selected from C 1-C 3Alkyl.
It is as shown in the table that preferred the present invention has the compound and the pharmaceutically acceptable ester thereof of general formula I:
Compound number The compound title
I-1 5-benzyl tetrazole-2-base β-D-glucopyranoside
I-2 The 5-[(3-p-methoxy-phenyl) methyl] tetrazole-2-base β-D-glucopyranoside
I-3 The 5-[(4-ethoxyl phenenyl) methyl] tetrazole-2-base β-D-glucopyranoside
I-4 The 5-[(2-fluorophenyl) methyl] tetrazole-2-base β-D-glucopyranoside
I-5 The 5-[(4-chloro-phenyl-) methyl] tetrazole-2-base β-D-glucopyranoside
I-6 The 5-[(4-aminomethyl phenyl) methyl] tetrazole-2-base β-D-glucopyranoside
I-7 The 5-[(4-ethylphenyl) methyl] tetrazole-2-base β-D-glucopyranoside
I-8 The 5-[(4-nitrophenyl) methyl] tetrazole-2-base β-D-glucopyranoside
I-9 The 5-[(4-dimethylamino phenyl) methyl] tetrazole-2-base β-D-glucopyranoside
I-10 5-[(2-chloro-4-ethoxyl phenenyl) methyl] tetrazole-2-base β-D-glucopyranoside
I-11 5-[(3-fluoro-4-ethylphenyl) methyl] tetrazole-2-base β-D-glucopyranoside
I-12 The 5-[(4-ethoxyl phenenyl) methyl] tetrazole-2-base 6-O-methoxycarbonyl-β-D-glucopyranoside
Compound of Formula I of the present invention is synthetic by following steps:
Figure A200910068287D00071
Compound I I and compound III reaction generate compound IV, and compound IV is reacted under the sodium methylate effect and generated I.Wherein, Compound I I is according to literature method preparation (Jia Yonglin, Li Bin, Bing Baichun; 2,3,4,6-four-O-ethanoyl-1-sulfydryl Glucopyranose synthetic; chemistry and bonding, 2007,29 (3): 189-192); the preparation of compound III reference literature method (Wei Xianhong, He Baojuan, Chen Yongzhou; 1-bromo-5-phenyl-tetrazole synthetic, fine-chemical intermediate, 2005; 35 (3), 11-12,27).R's is described as defined above.
The pharmaceutically acceptable ester of formula I compound of the present invention comprises the pharmaceutically acceptable ester that the pulsating 6-O of glucose position hydroxyl and ethanoyl in the molecule, propionyl, methoxycarbonyl, benzoyl etc. form.The pharmaceutically acceptable ester of formula I compound prepares with method shown in figure below.
Figure A200910068287D00081
Compound I is with 1 normal R 4COCl handles, and esterification on the pulsating 6-O of Compound I glucose position makes its corresponding ester V.Wherein, R 4Be selected from pharmaceutically acceptable group such as Me, Et, MeO, EtO and Ph, preferred Me, MeO and EtO, more preferably MeO and EtO.
Formula I compound of the present invention or its pharmaceutically acceptable ester can be made pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: 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.
Composition of the present invention can be accepted auxiliary material and be selected from: weighting agent, tackiness agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle on described pharmacy or the bromatology.
Composition of the present invention can be accepted auxiliary material on described pharmacy or the bromatology.Described weighting agent is one or more the composition that 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 composition of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more composition of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
Compound of Formula I of the present invention or its ester have the restraining effect of SGLT2 enzyme, can be used as the medicine that effective constituent is used to prepare the diabetes aspect.The activity of compound of Formula I of the present invention is by hypoglycemic modelling verification in the body.
Compound of Formula I of the present invention is effective in quite wide dosage range.For example the dosage of 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 situations comprise: by curer's physical state, route of administration, age, body weight, to the individual reaction of medicine, the severity of symptom etc.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.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
5-benzyl tetrazole-2-base β-D-glucopyranoside (I-1)
Figure A200910068287D00091
Add 8.22g (20mmol) Compound I I in the round-bottomed flask of a 100mL, the 30mL chloroform, 30mL water, 0.50g (12.5mmol) solid NaOH and 1.60g (10mmol) compound III-1, stir under the mixture room temperature, then add benzyl triethyl ammonium bromide (PTC).Gained reaction mixture at room temperature vigorous stirring spends the night.Reaction mixture with the water washing of 50mL * 3, is used anhydrous Na with the dilution of 200mL chloroform 2SO 4Drying boils off solvent on Rotary Evaporators, the resistates that obtains obtains compound IV-1 through column chromatography purification.The compound IV that obtains-1 is dissolved in the 100mL anhydrous methanol that is dissolved with 0.10g (1.85mmol) solid MeONa in advance, stirred 1 hour under the room temperature, then add 5.0g exsiccant 732 type storng-acid cation exchange resins, stirred 3 hours under the room temperature.Suction filtration is removed resin, and the filtrate evaporate to dryness obtains a white solid, and drying obtains Compound I-1.Clear crystal, 2.61g, productive rate 81%.ESI-MS,m/z=323([M+H] +)。
Wherein, compound III-1 and IV-1 are respectively one that has in the compound of general formula III and IV.
Embodiment 2
The 5-[(3-p-methoxy-phenyl) methyl] tetrazole-2-base β-D-glucopyranoside (I-2)
Figure A200910068287D00101
Add 8.22g (20mmol) Compound I I in the round-bottomed flask of a 100mL, the 30mL chloroform, 30mL water, 0.50g (12.5mmol) solid NaOH and 1.90g (10mmol) compound III-2, stir under the mixture room temperature, then add benzyl triethyl ammonium bromide (PTC).Gained reaction mixture at room temperature vigorous stirring spends the night.Reaction mixture with the water washing of 50mL * 3, is used anhydrous Na with the dilution of 200mL chloroform 2SO 4Drying boils off solvent on Rotary Evaporators, the resistates that obtains obtains compound IV-2 through column chromatography purification.The compound IV that obtains-2 is dissolved in the 100mL anhydrous methanol that is dissolved with 0.10g (1.85mmol) solid MeONa in advance, stirred 1 hour under the room temperature, then add 5.0g exsiccant 732 type storng-acid cation exchange resins, stirred 3 hours under the room temperature.Suction filtration is removed resin, and the filtrate evaporate to dryness obtains a white solid, and drying obtains Compound I-2.Clear crystal, 2.96g, productive rate 84%.ESI-MS,m/z=353([M+H] +)。
Wherein, compound III-2 and IV-2 are respectively one that has in the compound of general formula III and IV.
Embodiment 3
The 5-[(4-ethoxyl phenenyl) methyl] tetrazole-2-base β-D-glucopyranoside (I-3)
Figure A200910068287D00102
Add 8.22g (20mmol) Compound I I in the round-bottomed flask of a 100mL, the 30mL chloroform, 30mL water, 0.50g (12.5mmol) solid NaOH and 2.04g (10mmol) compound III-3, stir under the mixture room temperature, then add benzyl triethyl ammonium bromide (PTC).Gained reaction mixture at room temperature vigorous stirring spends the night.Reaction mixture with the water washing of 50mL * 3, is used anhydrous Na with the dilution of 200mL chloroform 2SO 4Drying boils off solvent on Rotary Evaporators, the resistates that obtains obtains compound IV-3 through column chromatography purification.The compound IV that obtains-3 is dissolved in the 100mL anhydrous methanol that is dissolved with 0.10g (1.85mmol) solid MeONa in advance, stirred 1 hour under the room temperature, then add 5.0g exsiccant 732 type storng-acid cation exchange resins, stirred 3 hours under the room temperature.Suction filtration is removed resin, and the filtrate evaporate to dryness obtains a white solid, and drying obtains Compound I-3.Clear crystal, 3.11g, productive rate 85%.ESI-MS,m/z=367([M+H] +)。
Wherein, compound III-3 and IV-3 are respectively one that has in the compound of general formula III and IV.
Embodiment 4
The 5-[(2-fluorophenyl) methyl] tetrazole-2-base β-D-glucopyranoside (I-4)
Figure A200910068287D00111
Add 8.22g (20mmol) Compound I I in the round-bottomed flask of a 100mL, the 30mL chloroform, 30mL water, 0.50g (12.5mmol) solid NaOH and 1.78g (10mmol) compound III-4, stir under the mixture room temperature, then add benzyl triethyl ammonium bromide (PTC).Gained reaction mixture at room temperature vigorous stirring spends the night.Reaction mixture with the water washing of 50mL * 3, is used anhydrous Na with the dilution of 200mL chloroform 2SO 4Drying boils off solvent on Rotary Evaporators, the resistates that obtains obtains compound IV-4 through column chromatography purification.The compound IV that obtains-4 is dissolved in the 100mL anhydrous methanol that is dissolved with 0.10g (1.85mmol) solid MeONa in advance, stirred 1 hour under the room temperature, then add 5.0g exsiccant 732 type storng-acid cation exchange resins, stirred 3 hours under the room temperature.Suction filtration is removed resin, and the filtrate evaporate to dryness obtains a white solid, and drying obtains Compound I-4.Clear crystal, 2.75g, productive rate 81%.ESI-MS,m/z=341([M+H] +)。
Wherein, compound III-4 and IV-4 are respectively one that has in the compound of general formula III and IV.
Embodiment 5
The 5-[(4-chloro-phenyl-) methyl] tetrazole-2-base β-D-glucopyranoside (I-5)
Figure A200910068287D00121
Add 8.22g (20mmol) Compound I I in the round-bottomed flask of a 100mL, the 30mL chloroform, 30mL water, 0.50g (12.5mmol) solid NaOH and 1.94g (10mmol) compound III-5, stir under the mixture room temperature, then add benzyl triethyl ammonium bromide (PTC).Gained reaction mixture at room temperature vigorous stirring spends the night.Reaction mixture with the water washing of 50mL * 3, is used anhydrous Na with the dilution of 200mL chloroform 2SO 4Drying boils off solvent on Rotary Evaporators, the resistates that obtains obtains compound IV-5 through column chromatography purification.The compound IV that obtains-5 is dissolved in the 100mL anhydrous methanol that is dissolved with 0.10g (1.85mmol) solid MeONa in advance, stirred 1 hour under the room temperature, then add 5.0g exsiccant 732 type storng-acid cation exchange resins, stirred 3 hours under the room temperature.Suction filtration is removed resin, and the filtrate evaporate to dryness obtains a white solid, and drying obtains Compound I-5.Clear crystal, 3.14g, productive rate 88%.ESI-MS,m/z=357([M+H] +)。
Wherein, compound III-5 and IV-5 are respectively one that has in the compound of general formula III and IV.
Embodiment 6
The 5-[(4-aminomethyl phenyl) methyl] tetrazole-2-base β-D-glucopyranoside (I-6)
Figure A200910068287D00122
Add 8.22g (20mmol) Compound I I in the round-bottomed flask of a 100mL, the 30mL chloroform, 30mL water, 0.50g (12.5mmol) solid NaOH and 1.74g (10mmol) compound III-6, stir under the mixture room temperature, then add benzyl triethyl ammonium bromide (PTC).Gained reaction mixture at room temperature vigorous stirring spends the night.Reaction mixture with the water washing of 50mL * 3, is used anhydrous Na with the dilution of 200mL chloroform 2SO 4Drying boils off solvent on Rotary Evaporators, the resistates that obtains obtains compound IV-6 through column chromatography purification.The compound IV that obtains-6 is dissolved in the 100mL anhydrous methanol that is dissolved with 0.10g (1.85mmol) solid MeONa in advance, stirred 1 hour under the room temperature, then add 5.0g exsiccant 732 type storng-acid cation exchange resins, stirred 3 hours under the room temperature.Suction filtration is removed resin, and the filtrate evaporate to dryness obtains a white solid, and drying obtains Compound I-6.Clear crystal, 2.72g, productive rate 81%.ESI-MS,m/z=337([M+H] +)。
Wherein, compound III-6 and IV-6 are respectively one that has in the compound of general formula III and IV.
Embodiment 7
The 5-[(4-ethylphenyl) methyl] tetrazole-2-base β-D-glucopyranoside (I-7)
Figure A200910068287D00131
Add 8.22g (20mmol) Compound I I in the round-bottomed flask of a 100mL, the 30mL chloroform, 30mL water, 0.50g (12.5mmol) solid NaOH and 1.88g (10mmol) compound III-7, stir under the mixture room temperature, then add benzyl triethyl ammonium bromide (PTC).Gained reaction mixture at room temperature vigorous stirring spends the night.Reaction mixture with the water washing of 50mL * 3, is used anhydrous Na with the dilution of 200mL chloroform 2SO 4Drying boils off solvent on Rotary Evaporators, the resistates that obtains obtains compound IV-7 through column chromatography purification.The compound IV that obtains-7 is dissolved in the 100mL anhydrous methanol that is dissolved with 0.10g (1.85mmol) solid MeONa in advance, stirred 1 hour under the room temperature, then add 5.0g exsiccant 732 type storng-acid cation exchange resins, stirred 3 hours under the room temperature.Suction filtration is removed resin, and the filtrate evaporate to dryness obtains a white solid, and drying obtains Compound I-7.Clear crystal, 2.98g, productive rate 85%.ESI-MS,m/z=351([M+H] +)。
Wherein, compound III-7 and IV-7 are respectively one that has in the compound of general formula III and IV.
Embodiment 8
The 5-[(4-nitrophenyl) methyl] tetrazole-2-base β-D-glucopyranoside (I-8)
Figure A200910068287D00141
Add 8.22g (20mmol) Compound I I in the round-bottomed flask of a 100mL, the 30mL chloroform, 30mL water, 0.50g (12.5mmol) solid NaOH and 2.05g (10mmol) compound III-8, stir under the mixture room temperature, then add benzyl triethyl ammonium bromide (PTC).Gained reaction mixture at room temperature vigorous stirring spends the night.Reaction mixture with the water washing of 50mL * 3, is used anhydrous Na with the dilution of 200mL chloroform 2SO 4Drying boils off solvent on Rotary Evaporators, the resistates that obtains obtains compound IV-8 through column chromatography purification.The compound IV that obtains-8 is dissolved in the 100mL anhydrous methanol that is dissolved with 0.10g (1.85mmol) solid MeONa in advance, stirred 1 hour under the room temperature, then add 5.0g exsiccant 732 type storng-acid cation exchange resins, stirred 3 hours under the room temperature.Suction filtration is removed resin, and the filtrate evaporate to dryness obtains a white solid, and drying obtains Compound I-8.Clear crystal, 3.01g, productive rate 82%.ESI-MS,m/z=368([M+H] +)。
Wherein, compound III-8 and IV-8 are respectively one that has in the compound of general formula III and IV.
Embodiment 9
The 5-[(4-dimethylamino phenyl) methyl] tetrazole-2-base β-D-glucopyranoside (I-9)
Figure A200910068287D00151
Add 8.22g (20mmol) Compound I I in the round-bottomed flask of a 100mL, the 30mL chloroform, 30mL water, 0.50g (12.5mmol) solid NaOH and 2.03g (10mmol) compound III-9, stir under the mixture room temperature, then add benzyl triethyl ammonium bromide (PTC).Gained reaction mixture at room temperature vigorous stirring spends the night.Reaction mixture with the water washing of 50mL * 3, is used anhydrous Na with the dilution of 200mL chloroform 2SO 4Drying boils off solvent on Rotary Evaporators, the resistates that obtains obtains compound IV-9 through column chromatography purification.The compound IV that obtains-9 is dissolved in the 100mL anhydrous methanol that is dissolved with 0.10g (1.85mmol) solid MeONa in advance, stirred 1 hour under the room temperature, then add 5.0g exsiccant 732 type storng-acid cation exchange resins, stirred 3 hours under the room temperature.Suction filtration is removed resin, and the filtrate evaporate to dryness obtains a white solid, and drying obtains Compound I-9.Clear crystal, 3.10g, productive rate 85%.ESI-MS,m/z=366([M+H] +)。
Wherein, compound III-9 and IV-9 are respectively one that has in the compound of general formula III and IV.
Embodiment 10
5-[(2-chloro-4-ethoxyl phenenyl) methyl] tetrazole-2-base β-D-glucopyranoside (I-10)
Figure A200910068287D00152
Add 8.22g (20mmol) Compound I I in the round-bottomed flask of a 100mL, the 30mL chloroform, 30mL water, 0.50g (12.5mmol) solid NaOH and 2.38g (10mmol) compound III-10, stir under the mixture room temperature, then add benzyl triethyl ammonium bromide (PTC).Gained reaction mixture at room temperature vigorous stirring spends the night.Reaction mixture with the water washing of 50mL * 3, is used anhydrous Na with the dilution of 200mL chloroform 2SO 4Drying boils off solvent on Rotary Evaporators, the resistates that obtains obtains compound IV-10 through column chromatography purification.The compound IV that obtains-10 is dissolved in the 100mL anhydrous methanol that is dissolved with 0.10g (1.85mmol) solid MeONa in advance, stirred 1 hour under the room temperature, then add 5.0g exsiccant 732 type storng-acid cation exchange resins, stirred 3 hours under the room temperature.Suction filtration is removed resin, and the filtrate evaporate to dryness obtains a white solid, and drying obtains Compound I-10.Clear crystal, 3.49g, productive rate 87%.ESI-MS,m/z=401([M+H] +)。
Wherein, compound III-10 and IV-10 are respectively one that has in the compound of general formula III and IV.
Embodiment 11
5-[(3-fluoro-4-ethylphenyl) methyl] tetrazole-2-base β-D-glucopyranoside (I-11)
Figure A200910068287D00161
Add 8.22g (20mmol) Compound I I in the round-bottomed flask of a 100mL, the 30mL chloroform, 30mL water, 0.50g (12.5mmol) solid NaOH and 2.06g (10mmol) compound III-11, stir under the mixture room temperature, then add benzyl triethyl ammonium bromide (PTC).Gained reaction mixture at room temperature vigorous stirring spends the night.Reaction mixture with the water washing of 50mL * 3, is used anhydrous Na with the dilution of 200mL chloroform 2SO 4Drying boils off solvent on Rotary Evaporators, the resistates that obtains obtains compound IV-11 through column chromatography purification.The compound IV that obtains-11 is dissolved in the 100mL anhydrous methanol that is dissolved with 0.10g (1.85mmol) solid MeONa in advance, stirred 1 hour under the room temperature, then add 5.0g exsiccant 732 type storng-acid cation exchange resins, stirred 3 hours under the room temperature.Suction filtration is removed resin, and the filtrate evaporate to dryness obtains a white solid, and drying obtains Compound I-11.Clear crystal, 3.16g, productive rate 86%.ESI-MS,m/z=369([M+H] +)。
Wherein, compound III-11 and IV-11 are respectively one that has in the compound of general formula III and IV.
Embodiment 12
The 5-[(4-ethoxyl phenenyl) methyl] tetrazole-2-base 6-O-methoxycarbonyl-β-D-glucopyranoside (I-12)
Figure A200910068287D00171
Add 3.66g (10mmol) Compound I-3,1.01g (10mmol) triethylamine and 30mL exsiccant methylene dichloride in the round-bottomed flask of a 50mL, flask is cooled off and induction stirring with mixture of ice and water, slowly drip 0.95g (10mmol) methyl-chloroformate and be dissolved in the solution of making in the 2mL dry methylene chloride, after dropwising, reaction mixture at room temperature stirs and spends the night.Reaction system with the water washing of 100mL saturated common salt once, is used anhydrous sodium sulfate drying with the dilution of 150mL methylene dichloride, boils off solvent on Rotary Evaporators, and the resistates that obtains obtains the pure product of Compound I-12 through column chromatography purification.Clear crystal, 2.93g, productive rate 80%.ESI-MS,m/z=367([M+H] +)。
Embodiment 13
Consumption/sheet
Embodiment 1 sample (I-1) 100mg
Microcrystalline Cellulose 80mg
Pregelatinized Starch 70mg
Polyvinylpyrrolidone 6mg
Carboxymethyl starch sodium salt 5mg
Magnesium Stearate 2mg
Talcum powder 2mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, thorough mixing, add polyvinylpyrrolidonesolution solution, mix, the system softwood, sieve, the system wet granular is in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 14
Consumption/sheet
Embodiment 3 samples (I-3) 100mg
Microcrystalline Cellulose 80mg
Pregelatinized Starch 70mg
Polyvinylpyrrolidone 6mg
Carboxymethyl starch sodium salt 5mg
Magnesium Stearate 2mg
Talcum powder 2mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, thorough mixing, add polyvinylpyrrolidonesolution solution, mix, the system softwood, sieve, the system wet granular is in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 15
Consumption/grain
Embodiment 5 samples (I-5) 50mg
Microcrystalline Cellulose 30mg
Pregelatinized Starch 20mg
Polyvinylpyrrolidone 3mg
Magnesium Stearate 2mg
Talcum powder 1mg
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.
Embodiment 16
Consumption/grain
Embodiment 7 samples (I-7) 50mg
Microcrystalline Cellulose 30mg
Pregelatinized Starch 20mg
Polyvinylpyrrolidone 3mg
Magnesium Stearate 2mg
Talcum powder 1mg
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.
Embodiment 17
Consumption/50mL
Embodiment 8 samples (I-8) 50mg
Citric acid 100mg
NaOH an amount of (transferring pH4.0-5.0)
Distilled water 50mL
In distilled water, add earlier distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, 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 18
Consumption/50mL
Embodiment 10 samples (I-10) 50mg
Citric acid 100mg
NaOH an amount of (transferring pH4.0-5.0)
Distilled water 50mL
In distilled water, add earlier distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, 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
Embodiment 11 samples (I-11) 3.0g
Poloxamer 1.0g
Sodium hydroxide 0.2g
Citric Acid QS
N.F,USP MANNITOL 26.0g
Lactose 23.0g
Water for injection 100ml
Preparation technology: get water for injection 80ml, add main ingredient, N.F,USP MANNITOL, lactose, poloxamer 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 ℃, filtrate 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, dry 5 hours again, make the white loose block, seal promptly.
Embodiment 20
100 bags of granules
Embodiment 12 samples (I-12) 30.0g
Lactose 55.0g
N.F,USP MANNITOL 14.0g
The sweet 0.05g of A Siba
Essence 0.05g
2% hypromellose (pure water preparation) QS
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 21
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, and the administration capacity is the 0.4mL/20g body weight, is equivalent to 100mg/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 diamicron medicine), 0.5h, 1h, 2h, 3h and 4h regularly take kapillary and get blood from mouse ball rear vein beard after modeling, centrifugation serum is with each time point serum glucose level of determination of glucose oxidase.The results are shown in following table:
Figure A200910068287D00211
Above result shows that each administration all can significantly reduce the mouse blood sugar dosis tolerata that glucose causes.

Claims (10)

1. have the compound of general formula I structure and acceptable ester pharmaceutically thereof
Figure A200910068287C00021
Wherein,
R is selected from H, F, C1, Br, I, C 1-C 5Alkyl, NO 2, NR 1R 2And OR 3, and two replacement combination, wherein R of these groups 1And R 2Independently be selected from H and C 1-C 3Alkyl, R 3Be selected from C 1-C 5Alkyl.
Claim 1 defined have the compound of general formula I and pharmaceutically the acceptable ester wherein,
R is selected from H, F, Cl, C 1-C 3Alkyl, NO 2, NR 1R 2And OR 3, and two replacement combination, wherein R of these groups 1And R 2Independently be selected from H and C 1-C 3Alkyl, R 3Be selected from C 1-C 3Alkyl.
3. the defined compound of Formula I of claim 2 and pharmaceutically acceptable ester are selected from:
5-benzyl tetrazole-2-base β-D-glucopyranoside
The 5-[(3-p-methoxy-phenyl) methyl] tetrazole-2-base β-D-glucopyranoside
The 5-[(4-ethoxyl phenenyl) methyl] tetrazole-2-base β-D-glucopyranoside
The 5-[(2-fluorophenyl) methyl] tetrazole-2-base β-D-glucopyranoside
The 5-[(4-chloro-phenyl-) methyl] tetrazole-2-base β-D-glucopyranoside
The 5-[(4-aminomethyl phenyl) methyl] tetrazole-2-base β-D-glucopyranoside
The 5-[(4-ethylphenyl) methyl] tetrazole-2-base β-D-glucopyranoside
The 5-[(4-nitrophenyl) methyl] tetrazole-2-base β-D-glucopyranoside
The 5-[(4-dimethylamino phenyl) methyl] tetrazole-2-base β-D-glucopyranoside
5-[(2-chloro-4-ethoxyl phenenyl) methyl] tetrazole-2-base β-D-glucopyranoside
5-[(3-fluoro-4-ethylphenyl) methyl] tetrazole-2-base β-D-glucopyranoside
The 5-[(4-ethoxyl phenenyl) methyl] tetrazole-2-base 6-O-methoxycarbonyl-β-D-glucopyranoside.
4. synthesize the method for the defined compound of Formula I of claim 1-3, may further comprise the steps:
Figure A200910068287C00031
Compound I I and compound III reaction generate compound IV, and compound IV is reacted under the sodium methylate effect and generated I.Wherein, R's is described as defined above.
5. the synthetic defined compound of Formula I of claim 1-3 is the step of acceptable ester pharmaceutically,
Compound I is with 1 normal R 4COCl handles, and esterification on the pulsating 6-O of Compound I glucose position makes the pharmaceutically acceptable ester of the desired I of this claim 1-3.Wherein, R 4Be selected from pharmaceutically acceptable group such as Me, Et, MeO, EtO and Ph, preferred Me, MeO and EtO, more preferably MeO and EtO.
6. the defined compound of Formula I of claim 1-3 is as the application of 2 type sodium glucose transporter inhibitor.
7. the application of the defined compound of Formula I of claim 1-3 aspect preparation treatment diabetes medicament.
8. pharmaceutical composition contains compound of Formula I and appropriate carriers or the vehicle of one of claim 1-3.
9. the described pharmaceutical composition of claim 8, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
10. comprise according to described solid of claim 9 and liquid oral medicine: 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.
CNA2009100682870A 2009-03-30 2009-03-30 Glucoside containing tetrazole structure, preparation method and application Pending CN101508712A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CNA2009100682870A CN101508712A (en) 2009-03-30 2009-03-30 Glucoside containing tetrazole structure, preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CNA2009100682870A CN101508712A (en) 2009-03-30 2009-03-30 Glucoside containing tetrazole structure, preparation method and application

Publications (1)

Publication Number Publication Date
CN101508712A true CN101508712A (en) 2009-08-19

Family

ID=41001256

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA2009100682870A Pending CN101508712A (en) 2009-03-30 2009-03-30 Glucoside containing tetrazole structure, preparation method and application

Country Status (1)

Country Link
CN (1) CN101508712A (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104478819A (en) * 2015-01-13 2015-04-01 佛山市赛维斯医药科技有限公司 Diene tetrazole aniline compound and preparation method and usage thereof
CN104496923A (en) * 2015-01-13 2015-04-08 佛山市赛维斯医药科技有限公司 PAR-1 antagonist containing nitrobenzene diene tetrazolium, preparation method thereof and application thereof
CN104496925A (en) * 2015-01-13 2015-04-08 佛山市赛维斯医药科技有限公司 Diene tetrazole series compound and preparation method and applications thereof
CN104496927A (en) * 2015-01-13 2015-04-08 佛山市赛维斯医药科技有限公司 Diene tetrazole halobenzene series compound and preparation method and applications thereof
CN104744387A (en) * 2015-03-03 2015-07-01 佛山市赛维斯医药科技有限公司 PTP1B inhibitor containing tetrazole and halobenzene structures, preparation method of PTP1B inhibitor and use of PTP1B inhibitor
CN104744388A (en) * 2015-03-03 2015-07-01 佛山市赛维斯医药科技有限公司 PTP1B inhibitor containing tetrazole structure, preparation method of PTP1B inhibitor and use of PTP1B inhibitor
CN104987327A (en) * 2015-07-13 2015-10-21 朱绍清 Catalyzed synthesis method of tetrazole derivative
CN113336811A (en) * 2021-06-01 2021-09-03 浙江大学 Iridoid glycoside compounds, preparation and application thereof

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104478819A (en) * 2015-01-13 2015-04-01 佛山市赛维斯医药科技有限公司 Diene tetrazole aniline compound and preparation method and usage thereof
CN104496923A (en) * 2015-01-13 2015-04-08 佛山市赛维斯医药科技有限公司 PAR-1 antagonist containing nitrobenzene diene tetrazolium, preparation method thereof and application thereof
CN104496925A (en) * 2015-01-13 2015-04-08 佛山市赛维斯医药科技有限公司 Diene tetrazole series compound and preparation method and applications thereof
CN104496927A (en) * 2015-01-13 2015-04-08 佛山市赛维斯医药科技有限公司 Diene tetrazole halobenzene series compound and preparation method and applications thereof
CN104744387A (en) * 2015-03-03 2015-07-01 佛山市赛维斯医药科技有限公司 PTP1B inhibitor containing tetrazole and halobenzene structures, preparation method of PTP1B inhibitor and use of PTP1B inhibitor
CN104744388A (en) * 2015-03-03 2015-07-01 佛山市赛维斯医药科技有限公司 PTP1B inhibitor containing tetrazole structure, preparation method of PTP1B inhibitor and use of PTP1B inhibitor
CN104987327A (en) * 2015-07-13 2015-10-21 朱绍清 Catalyzed synthesis method of tetrazole derivative
CN113336811A (en) * 2021-06-01 2021-09-03 浙江大学 Iridoid glycoside compounds, preparation and application thereof

Similar Documents

Publication Publication Date Title
CN101508712A (en) Glucoside containing tetrazole structure, preparation method and application
CN102134226B (en) Phenyl C-glucoside derivatives, preparation method and use thereof
CN101445527A (en) Five-membered heteroaromatics tolylene glucoside and preparation method and use thereof
CN101445492B (en) Amide thiazole derivant, preparation method and use thereof
CN103864737A (en) Phenyl C-glucoside derivative containing deoxyglucose structure as well as preparation method and application thereof
CN101747305A (en) Five crystal forms of nicousamide compound and preparation method, pharmaceutical composition and usage thereof
CN101445528B (en) Sulpho-glucosan derivative and preparation method and application thereof
US7662364B2 (en) Drug for hyperphospheremia and its preparative method
CN101463055B (en) O-indican compounds, preparation and use thereof
CN103570657A (en) Phenyl-glucoside derivative containing gem-dimethyl, preparation method and use thereof
CN101508713A (en) Glucoside containing 1,2,3-triazole structure, preparation method and application
CN104861002A (en) 3,6-anhydroglucose structure-containing phenyl C-glucoside derivatives and their preparation method and use
CN101550112B (en) 4,5-disubstituted thiazole derivative, preparation method and use thereof
CN111072755B (en) Lipeptide complex, pharmaceutical composition thereof, preparation method and application thereof
CN102408459A (en) Anomeric alkyl-containing phenyl C-glucoside derivative, preparation thereof and application
CN101684103B (en) Compound with 1,2,4-triazole structure and preparation method and application thereof
CN101805336B (en) Compound containing tryptophane and isoxazole skeleton and preparation method and application thereof
CN101955502A (en) thiogalactosiTtderivatives, preparation method and application thereof
CN101805308B (en) Compound containing tyrosine and isoxazole skeleton and preparation method and application thereof
CN101684088B (en) Cyanomethyl pyrrole derivative and preparation method and application thereof
CN109288836A (en) A kind of dihydralazine sulfate,clonidine and hydrochlorothiazine preparation and its preparation method and application
CN101696228A (en) N-pyrazolyl glycosides derivatives as well as preparation method and application thereof
CN111195247B (en) Alpha-glucosidase inhibitor and application thereof in hypoglycemic drugs
CN101805337B (en) Compound containing proline and isoxazole skeleton and preparation method and application thereof
CN103664930B (en) One class is containing compound, the Preparation Method And The Use of thiazole structure

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Open date: 20090819