[go: up one dir, main page]

CN103570657A - Phenyl-glucoside derivative containing gem-dimethyl, preparation method and use thereof - Google Patents

Phenyl-glucoside derivative containing gem-dimethyl, preparation method and use thereof Download PDF

Info

Publication number
CN103570657A
CN103570657A CN201210398612.1A CN201210398612A CN103570657A CN 103570657 A CN103570657 A CN 103570657A CN 201210398612 A CN201210398612 A CN 201210398612A CN 103570657 A CN103570657 A CN 103570657A
Authority
CN
China
Prior art keywords
compound
preparation
stir
dissolved
injection
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
CN201210398612.1A
Other languages
Chinese (zh)
Inventor
赵桂龙
王玉丽
魏群超
吴疆
侯佳佳
魏巍
徐为人
邹美香
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 CN201210398612.1A priority Critical patent/CN103570657A/en
Publication of CN103570657A publication Critical patent/CN103570657A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to the medicine field related to the diabetes. Specifically, the invention relates to a sodium galactose transporter-2 (SGLT2) inhibitor of phenyl-glucoside structure containing gem-dimethyl, a preparation method of the SGLT2 inihibitor, pharmaceutical composition containing the same and application of the same in preparing medicine for treating the diabetes.

Description

One class is containing phenyl C-glucoside derivative, the Preparation Method And The Use of gem-dimethyl
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes.Particularly, the present invention relates to 2 type sodium glucose of the medicative phenyl C-glucoside structure that contains gem-dimethyl of diabetes cotransport son (SGLT2) inhibitor and preparation method thereof and the pharmaceutical composition that contains them.
Background technology
Whole world diabetic subject is nearly 1.7 hundred million left and right at present, and wherein approximately most is II type (being non-insulin-depending type) diabetic subject.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: liver toxicity, some drugs still has the problems such as body weight increase.
2 type sodium glucose (SGLT2) that cotransports is the novel targets of the treatment diabetes of discovered in recent years.SGLT2 is mainly distributed in kidney proximal tubule, and its effect is the glucose absorbing in urine, and returns it in blood, and that therefore suppresses SGLT2 just can reduce the concentration of glucose in blood, and this method has reduced glucose level from the past different approach.When SGLT2 function is obstructed, in urine, will secrete more glucose, this will contribute to diabetic subject to keep correct glucose level.Because 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 compound that Chinese patent CN200610093189.9 discloses time array structure is as SGLT2 inhibitor:
Figure BDA00002276072100011
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 SGLT2 inhibitor:
Figure BDA00002276072100021
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 SGLT2 inhibitor:
Figure BDA00002276072100022
Wherein, X is covalent linkage or low-grade alkylidene.
Chinese patent CN102134226A discloses following structure as SGLT2 inhibitor:
Figure BDA00002276072100023
Wherein, (1) R 5=R 6=F; (2) R 5=R 6=Me; (3) R 5=Me, R 6=OMe; (4) R 5=Me, R 6=H; (5) R 5=Me, R 6=F; (6) R 5=F, R 6=H; (7) R 5=OMe, R 6=H.
Chinese patent CN102408459A discloses following structure as SGLT2 inhibitor:
Figure BDA00002276072100024
Wherein, R 6and R 7independently be selected from H and C 1-C 5alkyl or cycloalkyl.
The invention discloses a class containing the phenyl C-glucoside analog derivative of gem-dimethyl as novel SGLT2 inhibitor, these inhibitor can be for the preparation of the medicine of the medicine, particularly non insulin dependent diabetes for the treatment of 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, there is the compound of general formula I structure and acceptable prodrug ester pharmaceutically thereof.
Another object of the present invention is to provide preparation and has the compound of general formula I structure and the method for acceptable prodrug ester pharmaceutically thereof.
A further object of the present invention be to provide the compound that contains general formula I structure and pharmaceutically acceptable prodrug ester as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect treatment diabetes.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I structure is comprised of following 8 compounds, I-1 to I-8.They have following structure:
Figure BDA00002276072100031
The pharmaceutically acceptable prodrug ester of formula I compound of the present invention, comprises the ester that any one or more hydroxyls in molecule and ethanoyl, pivaloyl group, various phosphoryl, formamyl, alkoxyl formyl etc. form.
Formula I compound of the present invention, can make pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made the formulations such as solid orally ingestible, liquid oral medicine, injection.Described 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.
Composition of the present invention, can accept auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle in described pharmacy or bromatology.
Composition of the present invention, can accept auxiliary material in described pharmacy or bromatology.Weighting agent is one or more the composition that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium 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 has the restraining effect of SGLT2 enzyme, can be used as effective constituent for the preparation of the medicine of diabetes aspect.The activity of compound of Formula I of the present invention is by hypoglycemic modelling verification in body.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage of for example taking every day, within the scope of 1mg-500mg/ people, is divided into once or administration for several times.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.These situations comprise: the person's of being treated physical state, route of administration, age, body weight, the individual reaction to medicine, the severity of symptom etc.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment is only for explanation, and 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-[1-of 1-{4-(4-ethynyl phenyl)-1-methylethyl] phenyl }-1-deoxidation-β-D-Glucopyranose (I-1)
Figure BDA00002276072100051
2.50g (10mmol) compound 1 and 1.08g (10mmol) methyl-phenoxide are dissolved in the methylene dichloride that 20mL is dry, under ice-water bath, stir, and slowly add the anhydrous AlCl of 1.47g (11mmol) 3.After adding, at this temperature, continue to stir 3 hours, be poured into water, with dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated on Rotary Evaporators, the resistates column chromatography purification obtaining, obtains the sterling of compound 2, ESI-MS, m/z=339,341,343 ([M+H] +).
Compound 2 is dissolved in the methylene dichloride that 20mL is dry, stirs at-30 ℃, slowly drips 1mLBCl 3after be slowly warmed up to room temperature, continue to stir 1 hour, be carefully poured in frozen water, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated on Rotary Evaporators, the resistates column chromatography purification obtaining, obtain the sterling of compound 3, ESI-MS, m/z=325,327,329 ([M+H] +).
1.63g (5mmol) compound 3 and 15mmol imidazoles are dissolved in 10mLDMF, stir, and add 5mmol TERT-BUTYL DIMETHYL CHLORO SILANE (TBDMSCl), continue to stir and spend the night under room temperature.Reaction mixture is poured in water, with dichloromethane extraction, and saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated on Rotary Evaporators, the resistates column chromatography purification obtaining, obtain the sterling of compound 4, ESI-MS, m/z=439,441,443 ([M+H] +).
4mmol compound 4 is dissolved in THF that 10mL is dry and the dry toluene of 5mL, stirs at-78 ℃, slowly adds the THF solution of 4mmol (2mL, 2M) n-BuLi with syringe.Then at this temperature, continue stirring 1 hour, more slowly add 4mmol 2,3,4 with syringe, 6-tetra--O-is trimethyl silicon based-D-Glucose acid lactone, after one hour, with syringe, slowly add 10mmol methylsulfonic acid to be dissolved in the solution that 5mL anhydrous methanol is made again.Under room temperature, stirring is poured in frozen water after spending the night, ethyl acetate extraction, and salt solution washing, anhydrous sodium sulfate drying, solvent evaporated on Rotary Evaporators, the resistates obtaining is the crude product of compound 5.This crude product is dissolved in acetonitrile that 5mL is dry and the dry methylene dichloride of 5mL, adds the triethyl silicane of 10mmol, stirs at-20 ℃, slowly drips the boron trifluoride diethyl etherate of 5mmol.Then slowly be warmed up under room temperature and stir.Reaction mixture is poured in water, and by dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated on Rotary Evaporators, the resistates obtaining is 6 sterling, ESI-MS, m/z=409,411 ([M+H] +).Compound 6 is dissolved in 5mL Glacial acetic acid, adds 5mL acetic anhydride and 0.5g sodium acetate, anhydrous, refluxes half an hour, be poured in frozen water, stir, with dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated on Rotary Evaporators, the resistates obtaining is 8, obtains the sterling of compound 8 after column chromatography purification, ESI-MS, m/z=619,621 ([M+H] +).
2.5mmol compound 8 is dissolved in 20mL ethanol, adds the NaOH solution of 2mL30%, and temperature rising reflux 1 hour, is cooled to after room temperature, is poured in frozen water, with hydrochloric acid, regulates pH=5-6.With dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated on Rotary Evaporators, the resistates obtaining is 9, obtains the sterling of compound 9 after column chromatography purification, ESI-MS, m/z=409,411 ([M+H] +).
1.8mmol compound 9 is dissolved in 10mL dry methylene chloride, stirs, and adds 5mmol triethylamine, and 1mmol DMAP, then adds 2.0mmol N, N-bis-(trifyl) aniline.Under compound of reaction room temperature, stir 5 hours, topple in rear frozen water, with dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, solvent evaporated on Rotary Evaporators, the resistates obtaining is 10, after column chromatography purification, obtain the sterling of compound 10, ESI-MS, m/z=541,543 ([M+H] +).
1mmol compound 10,1mmol trimethyl silicane ethyl-acetylene, 0.3mmol Pd (PPh 3) 2cl 2, 0.3mmolCuI and 5mmol triethylamine be dissolved in the DMF that 10mL is dry, in nitrogen atmosphere, under 100 degree, vigorous stirring is spent the night.Cooling, topple in rear frozen water, with dichloromethane extraction, washing, after being dried, evaporate to dryness methylene dichloride, the resistates obtaining is dissolved in 5mL anhydrous methanol, adds 0.5g salt of wormwood, stirs 3 hours under room temperature, is then poured in frozen water, with hydrochloric acid, regulates pH=5-6.With dichloromethane extraction, salt water washing, anhydrous sodium sulfate drying, solvent evaporated on Rotary Evaporators, the resistates obtaining is I-1, obtains the sterling of Compound I-1 after column chromatography purification, ESI-MS, m/z=417,419 ([M+H] +).
embodiment 2
The chloro-3-[1-of 1-{4-(4-((S)-tetrahydrofuran (THF)-3-oxygen) phenyl)-1-methylethyl] phenyl }-1-deoxidation-β-D-Glucopyranose (I-2)
Figure BDA00002276072100071
10mmol compound 9 (seeing embodiment 1) and 15mmol (R)-3-tolysulfonyl oxygen base tetrahydrofuran (THF) are dissolved in the DMF that 30mL is dry, add 30mmol cesium carbonate, and in nitrogen atmosphere, under 100 degree, vigorous stirring is spent the night.After reaction mixture is cooling, be poured in frozen water, be extracted with ethyl acetate, salt solution washing, anhydrous sodium sulfate drying, boils off solvent on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains product I-2.ESI-MS,m/z=479、481([M+H] +)。
embodiment 3
1-{4-methyl-3-[1-(4-((S)-tetrahydrofuran (THF)-3-oxygen) phenyl)-1-methylethyl] phenyl }-1-deoxidation-β-D-Glucopyranose (I-3)
Compound 18 is according to the method preparation of compound 9 in embodiment 1, ESI-MS, m/z=389 ([M+H] +).
Compound I-3 are prepared by compound 18 according to the method in embodiment 2, ESI-MS, m/z=459 ([M+H] +).
embodiment 4
(1S)-1,5-dehydration-1-{5-[1-(4-phenelyl)-1-methylethyl]-2-methoxyl group-4-aminomethyl phenyl }-1-sulfo--D-glucitol (I-4)
10mmol compound 19 and 12mmol phenyl ethyl ether are dissolved in the methylene dichloride that 50mL is dry, and the cooling lower stirring of ice-water bath, slowly adds the anhydrous AlCl of 12mmol 3, after adding, at this temperature, continue to stir 3 hours, be then poured in frozen water.Dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators, through column chromatography purification, obtains the sterling of compound 20, ESI-MS, m/z=363,365 ([M+H] +).
5mmol compound 20 is dissolved in dry THF, is cooled to after-78 ℃, with syringe, slowly adds 5mmol n-BuLi (the THF solution of 1.6M), continues to stir 1 hour at this temperature.Then with syringe, slowly add again 21 of 5mmol, after adding, at this temperature, continue to stir 1 hour, more slowly add 10mmol methylsulfonic acid to be dissolved into the solution of making in 15mL methyl alcohol with syringe.After adding, be slowly raised to room temperature, stirring is spent the night.Reaction mixture is poured in frozen water, stirs, and ethyl acetate extraction, anhydrous sodium sulfate drying, on Rotary Evaporators, evaporate to dryness obtains a resistates, is crude product 22.This crude product be dissolved in 10mL dry methylene chloride and 10mL acetonitrile in, stir at-20 ℃, add 20mmol triethyl silicane, then slowly drip 10mmol boron trifluoride diethyl etherate.After dropwising, be slowly warmed up to room temperature, continue to stir and spend the night.Reaction mixture is poured in frozen water, stirs, and dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators, through column chromatography purification, obtains the sterling of compound 23, ESI-MS, m/z=823 ([M+H] +).
2mmol compound 23 is dissolved in methyl alcohol, adds 0.4g10%Pd/C, and at 1MPa50 ℃, catalytic hydrogenation is 12 hours.Reaction mixture filters, and after filtrate evaporate to dryness, column chromatography purification obtains the sterling of I-4, ESI-MS, m/z=463 ([M+H] +).
embodiment 5
(1S, 3'R, 4'S, 5'S, 6'R)-6-[1-(4-ethylphenyl)-1-methylethyl]-3', 4', 5', 6'-tetrahydrochysene-6'-(methylol) spiral shell [isobenzofuran-1 (3H), 2'-[2H] pyrans]-3', 4', 5'-triol (I-5)
Figure BDA00002276072100101
10mmol compound 24 is dissolved in dry THF, and ice-water bath is cooling, with syringe, slowly drips 22mmol methylmagnesium-chloride, after dropwising, is warmed up to gradually room temperature, continues to stir 5 hours.Reaction mixture is poured in saturated ammonium chloride, stirs dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators is through column chromatography purification, obtain the sterling of compound 25, ESI-MS, m/z=323,325,327 ([M+H] +).
7mmol compound 25 and 10mmol ethylbenzene are dissolved in the methylene dichloride that 15mL is dry, stir, and slowly add 10mmol AlCl 3.Add rear continuation and stir one hour, then temperature rising reflux is 1 hour.Reaction mixture is cooling, reaction mixture is poured in saturated ammonium chloride, regulate pH=2-3, stir dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators, through column chromatography purification, obtains the sterling of compound 26, ESI-MS, m/z=367,369,371 ([M+H] +).
3mmol compound 26 and 5mmol chloro dme are dissolved in the THF that 5mL is dry, then add 2mL diisopropyl ethyl amine, under room temperature, stir and spend the night.Reaction mixture is poured in saturated ammonium chloride, regulate pH=2-3, stir, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators is through column chromatography purification, obtain the sterling of compound 27, ESI-MS, m/z=411,413,415 ([M+H] +).
1mmol compound 27 is dissolved in dry THF, is cooled to after-78 ℃, with syringe, slowly adds 1mmol n-BuLi (the THF solution of 1.6M), continues to stir 1 hour at this temperature.Then with syringe, slowly adding again 2,3,4 of 1mmol, 6-tetra--O-is trimethyl silicon based-D-Glucose acid lactone after adding, continues to stir 1 hour, more slowly adds 10mmol methylsulfonic acid to be dissolved into the solution of making in 5mL methyl alcohol with syringe at this temperature.After adding, be slowly raised to room temperature, stirring is spent the night.Reaction mixture is poured in frozen water, stirs, and ethyl acetate extraction, anhydrous sodium sulfate drying, on Rotary Evaporators, evaporate to dryness obtains a resistates, through column chromatography purification, obtains the sterling of Compound I-5, ESI-MS, m/z=449,451 ([M+H] +).
embodiment 6
The chloro-3-[1-of (1S, 2S, 3S, 4R, 5S)-5-{4-(4-phenelyl)-1-methylethyl] phenyl }-1-(methylol)-6,8-dioxa-bis-encircle [3.2.1] octane-2,3,4-triol (I-6)
10mmol compound 28 is dissolved in THF, is cooled to-78 ℃, under stirring, by syringe, slowly drips 10mmol n-BuLi, stirs 1 hour at this temperature, then by syringe, slowly drips 10mmol compound 29 again and is dissolved in the solution that THF makes.After dropwising, at this temperature, continue to stir 3 hours.Then be poured in frozen water, regulate pH=3.Stir, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators, through column chromatography purification, obtains the sterling of compound 31, ESI-MS, m/z=993,995 ([M+H] +).
5mmol compound 31 is dissolved in methyl-phenoxide, stirs, and then drips 15mmol trifluoroacetic acid, continues to stir 5 hours, is poured in frozen water, regulates pH=3.Stir, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators, through column chromatography purification, obtains the sterling of compound 32, ESI-MS, m/z=735,737 ([M+H] +).
2mmol compound 32 is dissolved in THF, adds 30mmol formic acid, stirs, and slowly adds 0.1g palladium black, continues to stir and spends the night.Suction filtration is removed solid, and liquid pouring is in frozen water.Stir, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators, through column chromatography purification, obtains the sterling of Compound I-6, ESI-MS, m/z=465,467 ([M+H] +).
embodiment 7
The chloro-3-[1-of (2S, 3R, 4R, 5S, 6S)-2-{4-(4-ethoxyl phenenyl)-1-methylethyl] phenyl }-6-methoxyl group-tetrahydropyrans-3,4,5-triol (I-7)
10mmol compound 28 is dissolved in THF, is cooled to-78 ℃, under stirring, by syringe, slowly drips 10mmol n-BuLi, stirs 1 hour at this temperature, then by syringe, slowly drips 10mmol compound 33 again and is dissolved in the solution that THF makes.After dropwising, at this temperature, continue to stir 3 hours.Then be poured in frozen water, regulate pH=3.Stir, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators, through column chromatography purification, obtains the sterling of compound 34, ESI-MS, m/z=577,579 ([M+H] +).
6mmol compound 34 is dissolved in 30mL Glacial acetic acid and 15mL water, is warming up to 100 ℃ and stirs 5 hours.After cooling, be poured in frozen water, stir, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators is dissolved in 50mL pyridine, the cooling lower stirring of ice-water bath, slowly drip 15mL acetic anhydride, then add 0.5g4-Dimethylamino pyridine, under room temperature, stir and spend the night.Reaction mixture is poured in frozen water, stirs dichloromethane extraction 1 hour, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators is through column chromatography purification, obtain the sterling of compound 35, ESI-MS, m/z=591,593 ([M+H] +).
4mmol compound 35 is dissolved in the HBr acetum that 20mL is saturated, and under room temperature, lucifuge stirs 5 hours.Reaction mixture is poured in frozen water, stir, dichloromethane extraction, organic phase is extremely neutral with saturated sodium carbonate solution washing, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators is through column chromatography purification, obtain the sterling of compound 36, ESI-MS, m/z=611,613,614 ([M+H] +).
1mmol compound 36 is dissolved in 50mL methyl alcohol, adds 1mmol ZnO, and backflow is spent the night.Suction filtration, filtrate evaporate to dryness, the resistates obtaining is dissolved in 20mL methyl alcohol, adds the NaOH solution of 2mL30%, temperature rising reflux 1 hour.After cooling, be poured in frozen water, regulate pH=5.Stir, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators, through column chromatography purification, obtains the sterling of Compound I-7, ESI-MS, m/z=437,439 ([M+H] +).
embodiment 8
(1S)-1,5-dehydration-1-{5-[1-(4-aminomethyl phenyl)-1-methylethyl]-2-hydroxy-4-methyl phenyl }-1-sulfo--D-glucitol (I-8)
Figure BDA00002276072100141
10mmol compound 37 and 12mmol toluene are dissolved in the methylene dichloride that 30mL is dry, and the cooling lower stirring of ice-water bath, slowly adds the anhydrous AlCl of 12mmol 3, after adding, at this temperature, continue to stir 3 hours, be then poured in frozen water.Dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators, through column chromatography purification, obtains the sterling of compound 38, ESI-MS, m/z=409,411 ([M+H] +).
5mmol compound 38 is dissolved in dry THF, is cooled to after-78 ℃, with syringe, slowly adds 5mmol n-BuLi (the THF solution of 1.6M), continues to stir 1 hour at this temperature.Then with syringe, slowly add again 21 of 5mmol, after adding, at this temperature, continue to stir 1 hour, more slowly add 10mmol methylsulfonic acid to be dissolved into the solution of making in 15mL methyl alcohol with syringe.After adding, be slowly raised to room temperature, stirring is spent the night.Reaction mixture is poured in frozen water, stirs, and ethyl acetate extraction, anhydrous sodium sulfate drying, on Rotary Evaporators, evaporate to dryness obtains a resistates, is crude product 39.This crude product be dissolved in 10mL dry methylene chloride and 10mL acetonitrile in, stir at-20 ℃, add 20mmol triethyl silicane, then slowly drip 10mmol boron trifluoride diethyl etherate.After dropwising, be slowly warmed up to room temperature, continue to stir and spend the night.Reaction mixture is poured in frozen water, stirs, and dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying, the resistates that evaporate to dryness obtains on Rotary Evaporators, through column chromatography purification, obtains the sterling of compound 40, ESI-MS, m/z=869 ([M+H] +).
2mmol compound 40 is dissolved in methyl alcohol, adds 0.1g10%Pd/C, and at 1MPa50 ℃, catalytic hydrogenation is 12 hours.Reaction mixture filters, and after filtrate evaporate to dryness, column chromatography purification obtains the sterling of I-8, ESI-MS, m/z=419 ([M+H] +).
embodiment 9
Figure BDA00002276072100151
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix softwood processed, sieve, wet granular processed, in 50-60 ℃ dry, by carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in above-mentioned particle.
embodiment 10
Figure BDA00002276072100152
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix softwood processed, sieve, wet granular processed, in 50-60 ℃ dry, by carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in above-mentioned particle.
embodiment 11
Figure BDA00002276072100161
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix, softwood processed, sieves, and wet granular processed is dry in 50-60 ℃, Magnesium Stearate and talcum powder are sieved in advance, then join in above-mentioned particle, encapsulated, obtain.
embodiment 12
Figure BDA00002276072100162
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix, softwood processed, sieves, and wet granular processed is dry in 50-60 ℃, Magnesium Stearate and talcum powder are sieved in advance, then join in above-mentioned particle, encapsulated, obtain.
embodiment 13
Figure BDA00002276072100163
In distilled water, first add distilled water and citric acid, stirring and dissolving and after, add sample, low-grade fever makes to dissolve again, and adjust pH is 4.0-5.0, add 0.2 gram of activated carbon, under room temperature, stir 20 minutes, filter filtrate, strength of solution is determined in middle detection, by 5 milliliters of packing of every ampulla, high-temperature sterilization 30 minutes, obtains injection liquid.
embodiment 14
In distilled water, first add distilled water and citric acid, stirring and dissolving and after, add sample, low-grade fever makes to dissolve again, and adjust pH is 4.0-5.0, add 0.2 gram of activated carbon, under room temperature, stir 20 minutes, filter filtrate, strength of solution is determined in middle detection, by 5 milliliters of packing of every ampulla, high-temperature sterilization 30 minutes, obtains injection liquid.
embodiment 15
Figure BDA00002276072100173
Preparation technology: get water for injection 80mL, after adding main ingredient, N.F,USP MANNITOL, lactose, poloxamer and being stirred to dissolve, the Citric Acid that adds 1mol/L regulates PH to 7.0-9.0, mends and adds water to 100mL.Add 0.5g gac, stir 20 minutes at 30 ℃, de-charcoal, adopts filtering with microporous membrane degerming, filtrate is carried out packing by every 1ml, and pre-freeze is after 2 hours, freezing lower drying under reduced pressure 12 hours, to sample temperature after room temperature, dry 5 hours again, make white loose block, seal and get final product.
embodiment 16
Figure BDA00002276072100181
Preparation technology: main ingredient and auxiliary material are crossed respectively to 100 mesh sieves, fully mix, then take recipe quantity auxiliary material and fully mix with main ingredient.Add tackiness agent softwood processed, 14 mesh sieves are granulated again, and 55 ℃ dry, and the whole grain of 12 mesh sieves is measured heavily packing of bag.
embodiment 17
Sample is mixed with the suspension of 2mg/mL concentration with 1% Xylo-Mucine, administration capacity is 0.2mL/20g body weight, is equivalent to 20mg/kg dosage.
Healthy mice, male and female half and half, body weight 20-24g, meets primary standard.Animal fasting 16 hours, gavage awards testing compound (model group gives equal-volume 1% Xylo-Mucine), in the dextrose in saline solution of 2h pneumoretroperitoneum injection 2g/kg, then 0.5h, 1.0h, 1.5h, 2.5h and 3h regularly take kapillary and get blood from mouse ball rear vein beard, centrifugation serum, with each time point serum glucose level of determination of glucose oxidase.The hypoglycemic activity of testing compound is weighed by inhibiting rate (Inhibitory rate, %).Inhibiting rate=1-[AUC (testing compound)/AUC (model)] } * 100%, wherein, AUC is the area under curve (Area Under Carve) of " blood sugar concentration-time " curve.Compound hypoglycemic activity table with test results 1.
The test of table 1 compound hypoglycemic activity
Figure BDA00002276072100182
Figure BDA00002276072100191
Above result shows, Compound I-1 to the hypoglycemic ability of I-8 is all eager to excel than the compound that there is no gem-dimethyl of correspondence.
embodiment 18
Mouse, 18-20g, female, hero half and half, normally raised after 3 days, grouping, 10 every group, fasting, after 12 hours, gives respectively the compound of single dose, and dosage is 600mg/kg, observes behavior, death after administration.Situation is as shown in table 2.
Behavior observation situation after table 2 administration
Figure BDA00002276072100201
As can be seen from the above table, Compound I-1 is all large than the compound that there is no gem-dimethyl of correspondence to the mouse polarity toxicity of I-8.

Claims (13)

1. there is the compound of lower array structure and acceptable prodrug ester pharmaceutically thereof, be selected from:
Figure FDA00002276072000011
2. the preparation method of Compound I-1 in claim 1,
Figure FDA00002276072000021
3. the preparation method of Compound I-2 in claim 1,
Figure FDA00002276072000022
4. the preparation method of Compound I-3 in claim 1,
Figure FDA00002276072000031
5. the preparation method of Compound I-4 in claim 1,
Figure FDA00002276072000032
6. the preparation method of Compound I-5 in claim 1,
7. the preparation method of Compound I-6 in claim 1,
Figure FDA00002276072000042
8. the preparation method of Compound I-7 in claim 1,
Figure FDA00002276072000051
9. the preparation method of Compound I-8 in claim 1,
Figure FDA00002276072000052
10. compound that claim 1 defines and the pharmaceutically application of acceptable prodrug ester aspect preparation treatment diabetes medicament thereof.
11. 1 kinds of pharmaceutical compositions, contain pharmaceutically acceptable prodrug ester of the defined compound of claim 1 or its, and suitable carrier or vehicle.
12. pharmaceutical compositions as claimed in claim 11, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
13. pharmaceutical compositions as claimed in claim 12, wherein, described solid orally ingestible comprises: dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule; Described liquid oral medicine comprises: oral solution; Described injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion.
CN201210398612.1A 2012-07-19 2012-10-19 Phenyl-glucoside derivative containing gem-dimethyl, preparation method and use thereof Pending CN103570657A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201210398612.1A CN103570657A (en) 2012-07-19 2012-10-19 Phenyl-glucoside derivative containing gem-dimethyl, preparation method and use thereof

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN201210250149 2012-07-19
CN201210250149.6 2012-07-19
CN201210398612.1A CN103570657A (en) 2012-07-19 2012-10-19 Phenyl-glucoside derivative containing gem-dimethyl, preparation method and use thereof

Publications (1)

Publication Number Publication Date
CN103570657A true CN103570657A (en) 2014-02-12

Family

ID=50043443

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201210398612.1A Pending CN103570657A (en) 2012-07-19 2012-10-19 Phenyl-glucoside derivative containing gem-dimethyl, preparation method and use thereof

Country Status (1)

Country Link
CN (1) CN103570657A (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014187365A1 (en) * 2013-05-24 2014-11-27 四川海思科制药有限公司 Oxabicyclo derivatives, preparation method and use thereof
US9340553B2 (en) 2014-05-19 2016-05-17 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
US9394329B2 (en) 2013-09-27 2016-07-19 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivatives and their uses in medicine
CN113214263A (en) * 2020-02-06 2021-08-06 北京桦冠医药科技有限公司 Synthetic method of Rudesiwei key intermediate

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050187168A1 (en) * 2003-12-22 2005-08-25 Boehringer Ingelheim International Gmbh Glucopyranosyloxy-substituted aromatic compounds, medicaments containing such compounds, their use and process for their manufacture
CN1896088A (en) * 1999-10-12 2007-01-17 布里斯托尔-迈尔斯斯奎布公司 C-aryl glucoside sglt2 inhibitors
CN102149717A (en) * 2008-08-28 2011-08-10 辉瑞大药厂 Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
WO2011159067A2 (en) * 2010-06-18 2011-12-22 Green Cross Corporation Thiazole derivatives as sglt2 inhibitors and pharmaceutical composition comprising same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1896088A (en) * 1999-10-12 2007-01-17 布里斯托尔-迈尔斯斯奎布公司 C-aryl glucoside sglt2 inhibitors
US20050187168A1 (en) * 2003-12-22 2005-08-25 Boehringer Ingelheim International Gmbh Glucopyranosyloxy-substituted aromatic compounds, medicaments containing such compounds, their use and process for their manufacture
CN102149717A (en) * 2008-08-28 2011-08-10 辉瑞大药厂 Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
WO2011159067A2 (en) * 2010-06-18 2011-12-22 Green Cross Corporation Thiazole derivatives as sglt2 inhibitors and pharmaceutical composition comprising same

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BAIHUA XU ET AL.: "O-spiro C-aryl glucosides as novel sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors", 《BIOORG. MED. CHEM.》, vol. 19, 12 August 2009 (2009-08-12), pages 5632 - 5635 *
NICOLE C. GOODWIN ET AL.: "Novel L-Xylose Derivatives as Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitors for the Treatment of Type 2 Diabetes", 《J. MED. CHEM.》, vol. 52, 28 September 2009 (2009-09-28) *
SHI YONGHENG ET AL.: "gem-Dimethyl-bearing C-Glucosides as Sodium-glucose Co-transportor 2 (SGLT2) Inhibitors", 《CHIN. J. CHEM.》, vol. 29, 27 June 2011 (2011-06-27), pages 1192 - 1198 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014187365A1 (en) * 2013-05-24 2014-11-27 四川海思科制药有限公司 Oxabicyclo derivatives, preparation method and use thereof
US9394329B2 (en) 2013-09-27 2016-07-19 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivatives and their uses in medicine
US9340553B2 (en) 2014-05-19 2016-05-17 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
US9617293B2 (en) 2014-05-19 2017-04-11 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
US10039778B2 (en) 2014-05-19 2018-08-07 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
US10376531B2 (en) 2014-05-19 2019-08-13 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
US10813942B2 (en) 2014-05-19 2020-10-27 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
CN113214263A (en) * 2020-02-06 2021-08-06 北京桦冠医药科技有限公司 Synthetic method of Rudesiwei key intermediate
CN113214263B (en) * 2020-02-06 2022-09-30 北京桦冠医药科技有限公司 Synthetic method of Rudesiwei key intermediate

Similar Documents

Publication Publication Date Title
CN102134226B (en) Phenyl C-glucoside derivatives, preparation method and use thereof
JP2010538621A (en) Cycloastragenol monoglucoside, process for its production and use as a pharmaceutical composition
CN104017031A (en) Hypoglycemic drug and composition
CN1320926C (en) Ginkgo leaf extract composition and its prepn
CN100566714C (en) Huperzine serrata composition containing composite components of huperzine A and B and preparation method thereof
CN104031098A (en) Hypoglycemic medicine
CN103570657A (en) Phenyl-glucoside derivative containing gem-dimethyl, preparation method and use thereof
CN103893258A (en) Oral solid preparation containing desmodium styracifolium general flavone and application thereof
CN101508712A (en) Glucoside containing tetrazole structure, preparation method and application
CN110279866A (en) Combination product comprising limonoid and Thiazolidinediones
CN102146066A (en) C-glucoside derivatives containing saturated six-membered ring as well as preparation method and application thereof
CN100537560C (en) A polymethoxyflavone derivative with anticancer activity, pharmaceutical composition, preparation method and application thereof
CN101011452A (en) Plant extract with hypotensive effect and its preparing process and use
CN102481287B (en) Pharmaceutical composition of temozolomide comprising vitamin c or vitamin c derivative and preparation method thereof
CN111195247B (en) Alpha-glucosidase inhibitor and application thereof in hypoglycemic drugs
CN109988104A (en) Kaempferol and isonicotinamide co-crystal and preparation method and pharmaceutical composition and use thereof
CN104861002A (en) 3,6-anhydroglucose structure-containing phenyl C-glucoside derivatives and their preparation method and use
CN102838651B (en) Oleanolic acid derivatives, and preparation method and application thereof
CN102675378A (en) C-glucoside derivative containing cyclopropane structure and method and application of C- glucoside derivative
CN115124420B (en) Rhein and matrine eutectic hydrate, preparation method, composition and application thereof
CN1923241B (en) Pharmaceutical composition comprising epimedium extract, uncaria extract, gastrodin and its preparation method and application
CN102408459B (en) Anomeric alkyl-containing phenyl C-glucoside derivative, preparation thereof and application
CN101463055B (en) O-indican compounds, preparation and use thereof
CN1899410A (en) Medicine for treating cardiovascular disease and its preparing method and quality control method
CN100525759C (en) Ready-made medicine of traditional chinese medicine for treating ischemic cranial vascular disease

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for 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

Application publication date: 20140212