CN101696228A - N-pyrazolyl glycosides derivatives as well as preparation method and application thereof - Google Patents
N-pyrazolyl glycosides derivatives as well as preparation method and application thereof Download PDFInfo
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- CN101696228A CN101696228A CN200910071152A CN200910071152A CN101696228A CN 101696228 A CN101696228 A CN 101696228A CN 200910071152 A CN200910071152 A CN 200910071152A CN 200910071152 A CN200910071152 A CN 200910071152A CN 101696228 A CN101696228 A CN 101696228A
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- glucopyranose
- deoxidation
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Abstract
The invention relates to the field of medicaments related to diabetes, in particular to 2-type sodium galactosyl transporter (SGLT2) inhibitors with an N-pyrazolyl glycosides structure as well as a preparation method, a pharmaceutical composition containing the 2-type sodium galactosyl transporter (SGLT2) inhibitors and application thereof in preparing medicaments for treating diabetes, wherein the group definition is stated as an instruction.
Description
Technical field
The present invention relates to the pharmaceutical field relevant with diabetes.Particularly, the present invention relates to 2 type sodium glucose to the medicative N-of the containing pyrazolyl glycosides of diabetes structure cotransport son (SGLT2) inhibitor 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: liver toxicity, the part medicine still has problems such as weight increase.
2 type sodium glucose (SGLT2) that cotransports is the novel targets of the treatment diabetes 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 inhibitor stays out of glucose metabolism, it can be used as the means of supplementing out economy of glycemic control main stream approach.
The present invention has comprised N-pyrazolyl glycosides analog derivative as novel SGLT2 inhibitor, and these inhibitor lay the foundation for the medicine that further can be used for the treatment of diabetes, particularly non insulin dependent diabetes.
Summary of the invention
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.
Another object of the present invention provides the method that preparation has the compound 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:
Wherein,
N is selected from 1 and 2,
R
1And R
2Independently be selected from H, C
1-C
5Alkyl,
R
3Be selected from H, F, Cl, Br, I, OR
4, CN, NO
2, C
1-C
5Alkyl, five yuan and hexa-atomic aromatic ring and fragrant heterocycle are by F, Cl, Br, I, C
1-C
3Alkyl, NO
2, CN, MeS five yuan and hexa-atomic aromatic ring and fragrant heterocycle, wherein R replacing
4Be selected from C
1-C
5Alkyl.
Preferred following compound of Formula I,
Wherein,
N=1 and 2,
R
1And R
2Independently be selected from H, C
1-C
4Alkyl,
R
3Be selected from H, F, Cl, OR
4, CN, NO
2, C
1-C
3Alkyl, phenyl, thiophene, furans, pyrazoles, 1,3, the 4-thiadiazoles, 1,3, the 4-oxadiazole is by F, Cl, C
1-C
3Alkyl, NO
2, CN, methylthio group substituted-phenyl, thiophene, furans, pyrazoles, 1,3,4-thiadiazoles, 1,3,4-oxadiazole, wherein R
4Be selected from C
1-C
3Alkyl.
It is as shown in the table that preferred the present invention has the compound of general formula I:
| Compound number | The compound title |
| ??I-1 | 1-(3-benzyl pyrazole-1-yl)-1-deoxidation-β-D-Glucopyranose |
| ??I-2 | The 1-{3-[(4-ethoxyl phenenyl) methyl]-4,5-dimethyl pyrazole-1-yl }-1-deoxidation-β-D-Glucopyranose |
| ??I-3 | The 1-{3-[(4-fluorophenyl) methyl]-4-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose |
| ??I-4 | The 1-{3-[(3-aminomethyl phenyl) methyl]-5-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose |
| ??I-5 | 1-{3-{[4-(1-methylpyrazole-3-yl) phenyl] methyl }-4-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose |
| ??I-6 | 1-(4-benzyl pyrazole-1-yl)-1-deoxidation-β-D-Glucopyranose |
| ??I-7 | The 1-{4-[(2-nitrophenyl) methyl]-3-1-yl }-1-deoxidation-β-D-Glucopyranose |
| Compound number | The compound title |
| ??I-8 | The 1-{4-[(4-cyano-phenyl) methyl]-3-1-yl }-1-deoxidation-β-D-Glucopyranose |
| ??I-9 | 1-{4-{[4-(3-chlorothiophene-2-yl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose |
| ??I-10 | 1-{4-{[4-(2-methylthio group-1,3,4-thiadiazoles-5-yl) phenyl] methyl }-3-1-yl }-1-deoxidation-β-D-Glucopyranose |
| ??I-11 | 1-{4-{[4-(2-methylthio group-1,3,4-oxadiazole-5-yl) phenyl] methyl }-3-sec.-propyl pyrazoles-1-yl }-1-deoxidation-β-D-Glucopyranose |
| ??I-12 | 1-{4-{[4-(2-nitrophenyl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose |
| ??I-13 | 1-{4-{[4-(4-cyano-phenyl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose |
| ??I-14 | 1-(5-benzyl-3-tertiary butyl pyrazol-1-yl)-1-deoxidation-β-D-Glucopyranose |
| ??I-15 | 1-{5-{[4-(5-methyl furan-2-yl) phenyl] methyl }-the 3-tertiary butyl-4-methylpyrazole-1-yl }-1-deoxidation-β-D-Glucopyranose |
| ??I-16 | 1-[3-(2-phenylethyl) pyrazol-1-yl]-1-deoxidation-β-D-Glucopyranose |
Compound of Formula I of the present invention is synthetic by following steps:
Compound I I and compound III reaction obtain compound IV, and compound IV obtains I under the sodium methylate effect.Wherein, Compound I I according to literature method preparation (Jia Yonglin, Li Bin, Bing Baichun, 2,3,4,6-four-O-ethanoyl-1-sulfydryl Glucopyranose synthetic, chemistry with bind 2007,29 (3): 189-192).
In the present invention, compound III is divided into following IIIa and two kinds of situations of IIIb again.
Wherein, for IIIa,, therefore there is the balance of IIIa and IIIa ' in practice because the unsubstituted pyrazoles of NH has tautomerism.
By the same token, also there is balance in IIIb with its tautomer IIIb '.
Compound III a is synthetic according to following method:
Wherein, compound V can buy or use ordinary method synthetic.
Compound III b is synthetic according to following method:
Wherein, compound VI can buy or use ordinary method synthetic.
Formula I compound of the present invention 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, 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 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.
Composition of the present invention can be accepted auxiliary material on described pharmacy or the 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, 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 has 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
1-(3-benzyl pyrazole-1-yl)-1-deoxidation-β-D-Glucopyranose (I-1)
Adding 4-phenyl-3-carbonyl butyraldehyde in the round-bottomed flask of a 100mL (3.24g, 20mmol), with dehydrated alcohol (15mL) dissolving, induction stirring under the room temperature, (1.8mL 25mmol), dropwises to stir under the room temperature of back and spends the night slowly to drip 70% hydrazine hydrate.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 3-benzyl pyrazole.This crude product then adds 2,3 with chloroform (20mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (5.3g, 50mmol), benzyl triethyl ammonium bromide (1.0g) and 3 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (200mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying; boil off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains pure product 1-(3-benzyl pyrazole-1-yl)-2; 3; 4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-(3-benzyl pyrazole-1-yl)-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.11g; in anhydrous methanol 2mmol) (15mL); stirred 3 hours under the room temperature, then add 1 gram exsiccant storng-acid cation exchange resin, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum, obtain final product 1-(3-benzyl pyrazole-1-yl)-1-deoxidation-β-D-Glucopyranose (white solid, 5.18g, overall yield 81%), ESI-MS, m/z=321 ([M+H]
+).
Embodiment 2
The 1-{3-[(4-ethoxyl phenenyl) methyl]-4,5-dimethyl pyrazole-1-yl }-1-deoxidation-β-D-Glucopyranose (I-2)
Add 1-(4-ethoxyl phenenyl)-3-methyl-2 in the round-bottomed flask of a 100mL, and the 4-diacetylmethane (4.68g, 20mmol), with dehydrated alcohol (15mL) dissolving, induction stirring under the room temperature slowly drips 70% hydrazine hydrate (1.8mL, 25mmol), dropwising the back stirs under the room temperature and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 4,5-dimethyl-3-[(4-ethoxyl phenenyl) methyl] pyrazoles.This crude product then adds 2,3 with chloroform (20mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (5.3g, 50mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (200mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying boils off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains; obtain pure product 1-{3-[(4-ethoxyl phenenyl) methyl]-4; 5-dimethyl pyrazole-1-yl }-2,3,4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-{3-[(4-ethoxyl phenenyl) methyl]-4; 5-dimethyl pyrazole-1-yl }-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.11g in anhydrous methanol 2mmol) (15mL), stirred under the room temperature 3 hours; then add 1 gram exsiccant storng-acid cation exchange resin, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum obtain final product 1-{3-[(4-ethoxyl phenenyl) methyl]-4,5-dimethyl pyrazole-1-yl }-1-deoxidation-β-D-Glucopyranose (white solid, 6.51g, overall yield 83%), ESI-MS, m/z=393 ([M+H]
+).
Embodiment 3
The 1-{3-[(4-fluorophenyl) methyl]-4-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (I-3)
(4.44g 20mmol), dissolves with dehydrated alcohol (15mL) to add 4-(4-fluorophenyl)-2-sec.-propyl-3-carbonyl butyraldehyde in the round-bottomed flask of a 100mL, induction stirring under the room temperature, (1.8mL 25mmol), dropwises to stir under the room temperature of back and spends the night slowly to drip 70% hydrazine hydrate.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 4-sec.-propyl-3-[(4-fluorophenyl) methyl] pyrazoles.This crude product then adds 2,3 with chloroform (20mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (5.3g, 50mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (200mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying; boil off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains pure product 1-{3-[(4-fluorophenyl) methyl]-4-sec.-propyl pyrazol-1-yl }-2; 3; 4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-{3-[(4-fluorophenyl) methyl]-4-sec.-propyl pyrazol-1-yl }-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.054g; in anhydrous methanol 1mmol) (20mL); stirred 3 hours under the room temperature, then add 1 gram exsiccant storng-acid cation exchange resin, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 50 ℃ of dryings of vacuum, obtain final product 1-{3-[(4-fluorophenyl) methyl]-4-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (white solid, 5.25g, overall yield 69%), ESI-MS, m/z=381 ([M+H]
+).
Embodiment 4
The 1-{3-[(3-aminomethyl phenyl) methyl]-5-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (I-4)
Add 1-(3-aminomethyl phenyl)-5-methyl-2 in the round-bottomed flask of a 100mL, and the 4-hexanedione (4.36g, 20mmol), with dehydrated alcohol (15mL) dissolving, induction stirring under the room temperature slowly drips 70% hydrazine hydrate (1.8mL, 25mmol), dropwising the back stirs under the room temperature and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 5-sec.-propyl-3-[(3-aminomethyl phenyl) methyl] pyrazoles.This crude product then adds 2,3 with chloroform (20mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (5.3g, 50mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (200mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying; boil off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains pure product 1-{3-[(3-aminomethyl phenyl) methyl]-5-sec.-propyl pyrazol-1-yl }-2; 3; 4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-{3-[(3-aminomethyl phenyl) methyl]-5-sec.-propyl pyrazol-1-yl }-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.054g; in anhydrous methanol 1mmol) (20mL); stirred 5 hours under the room temperature, then add 2 gram exsiccant storng-acid cation exchange resins, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 55 ℃ of dryings of vacuum, obtain final product 1-{3-[(3-aminomethyl phenyl) methyl]-5-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (white solid, 5.65g, overall yield 75%), ESI-MS, m/z=377 ([M+H]
+).
Embodiment 5
1-{3-{[4-(1-methylpyrazole-3-yl) phenyl] methyl }-4-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (I-5)
Add 4-{[4-(1-methylpyrazole-3-yl) phenyl in the round-bottomed flask of a 100mL] methyl }-2-sec.-propyl-3-carbonyl butyraldehyde (5.69g, 20mmol), dissolve with dehydrated alcohol (20mL), induction stirring under the room temperature, slowly drip 70% hydrazine hydrate (1.8mL, 25mmol), dropwising the back stirs under the room temperature and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 3-{[4-(1-methylpyrazole-3-yl) phenyl] methyl }-4-sec.-propyl pyrazoles.This crude product then adds 2,3 with chloroform (25mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (5.3g, 50mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (150mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying; boil off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains pure product 1-{3-{[4-(1-methylpyrazole-3-yl) phenyl] methyl }-4-sec.-propyl pyrazol-1-yl }-2; 3; 4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-{3-{[4-(1-methylpyrazole-3-yl) phenyl] methyl }-4-sec.-propyl pyrazol-1-yl }-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.054g; in anhydrous methanol 1mmol) (20mL); stirred 5 hours under the room temperature, then add 2 gram exsiccant storng-acid cation exchange resins, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum, obtain final product 1-{3-{[4-(1-methylpyrazole-3-yl) phenyl] methyl }-4-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (white solid, 6.28g, overall yield 71%), ESI-MS, m/z=443 ([M+H]
+).
Embodiment 6
1-(4-benzyl pyrazole-1-yl)-1-deoxidation-β-D-Glucopyranose (I-6)
Adding 2-benzyl mda in the round-bottomed flask of a 100mL (3.24g, 20mmol), with dehydrated alcohol (20mL) dissolving, induction stirring under the room temperature, (1.8mL 25mmol), dropwises to stir under the room temperature of back and spends the night slowly to drip 70% hydrazine hydrate.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 4-benzyl pyrazole.This crude product then adds 2,3 with chloroform (25mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (4.24g, 40mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (150mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying; boil off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains pure product 1-(4-benzyl pyrazole-1-yl)-2; 3; 4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-(4-benzyl pyrazole-1-yl)-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.054g; in anhydrous methanol 1mmol) (20mL); stirred 5 hours under the room temperature, then add 2 gram exsiccant storng-acid cation exchange resins, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum, obtain final product 1-(4-benzyl pyrazole-1-yl)-1-deoxidation-β-D-Glucopyranose (white solid, 4.74g, overall yield 74%), ESI-MS, m/z=321 ([M+H]
+).
Embodiment 7
The 1-{4-[(2-nitrophenyl) methyl]-3-1-yl }-1-deoxidation-β-D-Glucopyranose (I-7)
Add 3-(2-nitrophenyl)-2 in the round-bottomed flask of a 100mL, and the 4-diacetylmethane (4.70g, 20mmol), with dehydrated alcohol (20mL) dissolving, induction stirring under the room temperature slowly drips 70% hydrazine hydrate (1.8mL, 25mmol), dropwising the back stirs under the room temperature and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 4-[(2-nitrophenyl) methyl]-3.This crude product then adds 2,3 with chloroform (25mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (4.24g, 40mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (150mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying boils off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains; obtain pure product 1-{4-[(2-nitrophenyl) methyl]-3; 5-dimethyl pyrazole-1-yl }-2,3,4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-{4-[(2-nitrophenyl) methyl]-3; 5-dimethyl pyrazole-1-yl }-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.11g in anhydrous methanol 2mmol) (20mL), stirred under the room temperature 5 hours; then add 2 gram exsiccant storng-acid cation exchange resins, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum obtain final product 1-{4-[(2-nitrophenyl) methyl]-3-1-yl }-1-deoxidation-β-D-Glucopyranose (white solid, 6.29g, overall yield 80%), ESI-MS, m/z=394 ([M+H]
+).
Embodiment 8
The 1-{4-[(4-cyano-phenyl) methyl]-3-1-yl }-1-deoxidation-β-D-Glucopyranose (I-8)
Add 3-(4-cyano-phenyl)-2 in the round-bottomed flask of a 100mL, and the 4-diacetylmethane (4.30g, 20mmol), with dehydrated alcohol (20mL) dissolving, induction stirring under the room temperature slowly drips 70% hydrazine hydrate (1.8mL, 25mmol), dropwising the back stirs under the room temperature and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 4-[(4-cyano-phenyl) methyl]-3.This crude product then adds 2,3 with chloroform (25mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (4.24g, 40mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (150mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying boils off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains; obtain pure product 1-{4-[(4-cyano-phenyl) methyl]-3; 5-dimethyl pyrazole-1-yl }-2,3,4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-{4-[(4-cyano-phenyl) methyl]-3; 5-dimethyl pyrazole-1-yl }-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.11g in anhydrous methanol 2mmol) (20mL), stirred under the room temperature 5 hours; then add 2 gram exsiccant storng-acid cation exchange resins, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum obtain final product 1-{4-[(4-cyano-phenyl) methyl]-3-1-yl }-1-deoxidation-β-D-Glucopyranose (white solid, 6.35g, overall yield 85%), ESI-MS, m/z=374 ([M+H]
+).
Embodiment 9
1-{4-{[4-(3-chlorothiophene-2-yl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (I-9)
Add 4-methyl-2-{[4-(3-chlorothiophene-2-yl) phenyl in the round-bottomed flask of a 100mL] methyl }-3-carbonyl valeral (6.42g, 20mmol), dissolve with dehydrated alcohol (20mL), induction stirring under the room temperature, slowly drip 70% hydrazine hydrate (1.8mL, 25mmol), dropwising the back stirs under the room temperature and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 4-{[4-(3-chlorothiophene-2-yl) phenyl] methyl }-3-sec.-propyl pyrazoles.This crude product then adds 2,3 with chloroform (25mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (4.24g, 40mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (150mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying; boil off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains pure product 1-{4-{[4-(3-chlorothiophene-2-yl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-2; 3; 4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-{4-{[4-(3-chlorothiophene-2-yl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.11g; in anhydrous methanol 2mmol) (20mL); stirred 5 hours under the room temperature, then add 2 gram exsiccant storng-acid cation exchange resins, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum, obtain final product 1-{4-{[4-(3-chlorothiophene-2-yl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (white solid, 7.66g, overall yield 80%), ESI-MS, m/z=479 ([M+H]
+).
Embodiment 10
1-{4-{[4-(2-methylthio group-1,3,4-thiadiazoles-5-yl) phenyl] methyl }-3-1-yl }-1-deoxidation-β-D-Glucopyranose (I-10)
Add 3-{[4-(2-methylthio group-1 in the round-bottomed flask of a 100mL, 3,4-thiadiazoles-5-yl) phenyl] methyl }-2, (6.41g 20mmol), dissolves with dehydrated alcohol (20mL) the 4-diacetylmethane, induction stirring under the room temperature, (1.8mL 25mmol), dropwises to stir under the room temperature of back and spends the night slowly to drip 70% hydrazine hydrate.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 4-{[4-(2-methylthio group-1,3,4-thiadiazoles-5-yl) phenyl] methyl }-3.This crude product then adds 2,3 with chloroform (25mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (4.24g, 40mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture is used the saturated common salt water washing, the organic phase anhydrous sodium sulfate drying with methylene dichloride (150mL) dilution; on Rotary Evaporators, boil off solvent; the resistates column chromatography purification that obtains obtains pure product 1-{4-{[4-(2-methylthio group-1,3; 4-thiadiazoles-5-yl) phenyl] methyl }-3; 5-dimethyl pyrazole-1-yl }-2,3,4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-{4-{[4-(2-methylthio group-1; 3; 4-thiadiazoles-5-yl) phenyl] methyl }-3-1-yl }-2,3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.11g in anhydrous methanol 2mmol) (20mL), stirred under the room temperature 5 hours; then add 2 gram exsiccant storng-acid cation exchange resins, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtains a white solid, 60 ℃ of dryings of vacuum, obtain final product 1-{4-{[4-(2-methylthio group-1,3,4-thiadiazoles-5-yl) phenyl] methyl }-3-1-yl }-1-deoxidation-β-D-Glucopyranose (white solid, 7.08g, overall yield 74%), ESI-MS, m/z=479 ([M+H]
+).
Embodiment 11
1-{4-{[4-(2-methylthio group-1,3,4-oxadiazole-5-yl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (I-11)
Add 2-{[4-(2-methylthio group-1 in the round-bottomed flask of a 100mL, 3,4-oxadiazole-5-yl) phenyl] methyl }-4-methyl-3-carbonyl valeral (6.37g, 20mmol), with dehydrated alcohol (20mL) dissolving, induction stirring under the room temperature slowly drips 70% hydrazine hydrate (1.8mL, 25mmol), dropwising the back stirs under the room temperature and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 4-{[4-(2-methylthio group-1,3,4-oxadiazole-5-yl) phenyl] methyl }-3-sec.-propyl pyrazoles.This crude product then adds 2,3 with chloroform (25mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (4.24g, 40mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (150mL); use the saturated common salt water washing, the organic phase anhydrous sodium sulfate drying boils off solvent on Rotary Evaporators; the resistates column chromatography purification that obtains; obtain pure product 1-{4-{[4-(2-methylthio group-1,3,4-oxadiazole-5-yl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-2; 3; 4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-{4-{[4-(2-methylthio group-1; 3; 4-oxadiazole-5-yl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-2; 3,4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.11g; in anhydrous methanol 2mmol) (20mL); stirred 5 hours under the room temperature, then add 2 gram exsiccant storng-acid cation exchange resins, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum obtain final product 1-{4-{[4-(2-methylthio group-1,3,4-oxadiazole-5-yl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (white solid, 6.77g, overall yield 71%), ESI-MS, m/z=477 ([M+H]
+).
Embodiment 12
1-{4-{[4-(2-nitrophenyl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (I-12)
Add 2-{[4-(2-nitrophenyl) phenyl in the round-bottomed flask of a 100mL] methyl }-4-methyl-3-carbonyl valeral (6.51g, 20mmol), dissolve with dehydrated alcohol (20mL), induction stirring under the room temperature, slowly drip 70% hydrazine hydrate (1.8mL, 25mmol), dropwising the back stirs under the room temperature and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 4-{[4-(2-nitrophenyl) phenyl] methyl }-3-sec.-propyl pyrazoles.This crude product then adds 2,3 with chloroform (25mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (4.24g, 40mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (150mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying; boil off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains pure product 1-{4-{[4-(2-nitrophenyl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-2; 3; 4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-{4-{[4-(2-nitrophenyl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.11g; in anhydrous methanol 2mmol) (20mL); stirred 5 hours under the room temperature, then add 1 gram exsiccant storng-acid cation exchange resin, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum, obtain final product 1-{4-{[4-(2-nitrophenyl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (white solid, 7.06g, overall yield 73%), ESI-MS, m/z=484 ([M+H]
+).
Embodiment 13
1-{4-{[4-(4-cyano-phenyl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (I-13)
Add 2-{[4-(4-cyano-phenyl) phenyl in the round-bottomed flask of a 100mL] methyl }-4-methyl-3-carbonyl valeral (6.11g, 20mmol), dissolve with dehydrated alcohol (20mL), induction stirring under the room temperature, slowly drip 70% hydrazine hydrate (1.8mL, 25mmol), dropwising the back stirs under the room temperature and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 4-{[4-(4-cyano-phenyl) phenyl] methyl }-3-sec.-propyl pyrazoles.This crude product then adds 2,3 with chloroform (25mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (4.24g, 40mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (150mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying; boil off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains pure product 1-{4-{[4-(4-cyano-phenyl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-2; 3; 4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-{4-{[4-(4-cyano-phenyl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.11g; in anhydrous methanol 2mmol) (20mL); stirred 5 hours under the room temperature, then add 1 gram exsiccant storng-acid cation exchange resin, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum, obtain final product 1-{4-{[4-(4-cyano-phenyl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose (white solid, 7.60g, overall yield 82%), ESI-MS, m/z=464 ([M+H]
+).
Embodiment 14
1-(5-benzyl-3-tertiary butyl pyrazol-1-yl)-1-deoxidation-β-D-Glucopyranose (I-14)
Add 1-phenyl-5,5-dimethyl-2,4-hexanedione (4.37g in the round-bottomed flask of a 100mL, 20mmol), with dehydrated alcohol (20mL) dissolving, induction stirring under the room temperature, (1.8mL 25mmol), dropwises to stir under the room temperature of back and spends the night slowly to drip 70% hydrazine hydrate.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 5-benzyl-3-tertiary butyl pyrazoles.This crude product then adds 2,3 with chloroform (25mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (4.24g, 40mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (150mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying; boil off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains pure product 1-(5-benzyl-3-tertiary butyl pyrazol-1-yl)-2; 3; 4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-(5-benzyl-3-tertiary butyl pyrazol-1-yl)-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.11g; in anhydrous methanol 2mmol) (20mL); stirred 5 hours under the room temperature, then add 1 gram exsiccant storng-acid cation exchange resin, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum, obtain final product 1-(5-benzyl-3-tertiary butyl pyrazol-1-yl)-1-deoxidation-β-D-Glucopyranose (white solid, 6.02g, overall yield 80%), ESI-MS, m/z=377 ([M+H]
+).
Embodiment 15
1-{5-{[4-(5-methyl furan-2-yl) phenyl] methyl }-the 3-tertiary butyl-4-methylpyrazole-1-yl }-1-deoxidation-β-D-Glucopyranose (I-15)
Add 1-[4-(5-methyl furan-2-yl) phenyl in the round-bottomed flask of a 100mL]-5,5-dimethyl-2,4-hexanedione (5.97g, 20mmol), with dehydrated alcohol (20mL) dissolving, induction stirring under the room temperature slowly drips 70% hydrazine hydrate (1.8mL, 25mmol), dropwising the back stirs under the room temperature and spends the night.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 5-{[4-(5-methyl furan-2-yl) phenyl] methyl }-the 3-tertiary butyl-4-methylpyrazole.This crude product then adds 2,3 with chloroform (25mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (4.24g, 40mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (150mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying; boil off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains pure product 1-{5-{[4-(5-methyl furan-2-yl) phenyl] methyl }-the 3-tertiary butyl-4-methylpyrazole-1-yl }-2; 3; 4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-{5-{[4-(5-methyl furan-2-yl) phenyl] methyl }-the 3-tertiary butyl-4-methylpyrazole-1-yl }-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.11g; in anhydrous methanol 2mmol) (20mL); stirred 5 hours under the room temperature, then add 1 gram exsiccant storng-acid cation exchange resin, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum, obtain final product 1-{5-{[4-(5-methyl furan-2-yl) phenyl] methyl }-the 3-tertiary butyl-4-methylpyrazole-1-yl }-1-deoxidation-β-D-Glucopyranose (white solid, 7.67g, overall yield 84%), ESI-MS, m/z=457 ([M+H]
+).
Embodiment 16
1-[3-(2-phenylethyl) pyrazol-1-yl]-1-deoxidation-β-D-Glucopyranose (I-16)
Adding 5-phenyl-3-carbonyl-valeral in the round-bottomed flask of a 100mL (3.52g, 20mmol), with dehydrated alcohol (20mL) dissolving, induction stirring under the room temperature, (1.8mL 25mmol), dropwises to stir under the room temperature of back and spends the night slowly to drip 70% hydrazine hydrate.Reaction mixture boils off solvent on Rotary Evaporators, resulting resistates is crude product 3-(2-phenylethyl) pyrazoles.This crude product then adds 2,3 with chloroform (25mL) dissolving; 4,6-four-O-ethanoyl-α-D-bromo glucose (II, 8.22g; 20mmol), (4.24g, 40mmol), benzyl triethyl ammonium bromide (1.0g) and 5 drips, gained mixture at room temperature vigorous stirring spends the night the yellow soda ash solid.Reaction mixture dilutes with methylene dichloride (150mL); use the saturated common salt water washing; the organic phase anhydrous sodium sulfate drying; boil off solvent on Rotary Evaporators, the resistates column chromatography purification that obtains obtains pure product 1-[3-(2-phenylethyl) pyrazol-1-yl]-2; 3; 4,6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose, white solid.Above-mentioned pure product 1-[3-(2-phenylethyl) pyrazol-1-yl]-2; 3; 4; 6-four-O-ethanoyl-1-deoxidation-β-D-Glucopyranose is dissolved into and contains sodium methylate (0.11g; in anhydrous methanol 2mmol) (20mL); stirred 5 hours under the room temperature, then add 1 gram exsiccant storng-acid cation exchange resin, stir under the room temperature and spend the night.Remove by filter ion exchange resin, filtrate is evaporate to dryness on Rotary Evaporators, obtain a white solid, 60 ℃ of dryings of vacuum, obtain final product 1-[3-(2-phenylethyl) pyrazol-1-yl]-1-deoxidation-β-D-Glucopyranose (white solid, 5.35g, overall yield 80%), ESI-MS, m/z=335 ([M+H]
+).
Embodiment 17
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 18
Consumption/sheet
Embodiment 2 samples (I-2) 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 19
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 20
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 21
Consumption/50mL
Embodiment 9 samples (I-9) 50mg
Citric acid 100mg
NaOH an amount of (transferring pH 4.0-5.0)
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 22
Consumption/50mL
Embodiment 11 samples (I-11) 50mg
Citric acid 100mg
NaOH an amount of (transferring pH 4.0-5.0)
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 23
Embodiment 14 samples (I-14) 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 24
100 bags of granules
Embodiment 16 samples (I-16) 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 25
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, and the administration capacity is the 0.2mL/20g body weight, is equivalent to 50mg/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, centrifugation serum is with each time point serum glucose level of determination of glucose oxidase.The results are shown in following table:
Above result shows that each administration all can significantly reduce the mouse blood sugar dosis tolerata that glucose causes.
Claims (8)
1. the compound that has the general formula I structure
Wherein,
N is selected from 1 and 2,
R
1And R
2Independently be selected from H, C
1-C
5Alkyl,
R
3Be selected from H, F, Cl, Br, I, OR
4, CN, NO
2, C
1-C
5Alkyl, five yuan and hexa-atomic aromatic ring and fragrant heterocycle are by F, Cl, Br, I, C
1-C
3Alkyl, NO
2, CN, MeS five yuan and hexa-atomic aromatic ring and fragrant heterocycle, wherein R replacing
4Be selected from C
1-C
5Alkyl.
2. the defined compound of claim 1 with general formula I,
Wherein,
N is selected from 1 and 2,
R
1And R
2Independently be selected from H, C
1-C
4Alkyl,
R
3Be selected from H, F, Cl, OR
4, CN, NO
2, C
1-C
3Alkyl, phenyl, thiophene, furans, pyrazoles, 1,3, the 4-thiadiazoles, 1,3, the 4-oxadiazole is by F, Cl, C
1-C
3Alkyl, NO
2, CN, methylthio group substituted-phenyl, thiophene, furans, pyrazoles, 1,3,4-thiadiazoles, 1,3,4-oxadiazole, wherein R
4Be selected from C
1-C
3Alkyl.
3. the defined compound of Formula I of claim 2 is selected from:
1-(3-benzyl pyrazole-1-yl)-1-deoxidation-β-D-Glucopyranose
The 1-{3-[(4-ethoxyl phenenyl) methyl]-4,5-dimethyl pyrazole-1-yl }-1-deoxidation-β-D-Glucopyranose
The 1-{3-[(4-fluorophenyl) methyl]-4-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose
The 1-{3-[(3-aminomethyl phenyl) methyl]-5-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose
1-{3-{[4-(1-methylpyrazole-3-yl) phenyl] methyl }-4-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose
1-(4-benzyl pyrazole-1-yl)-1-deoxidation-β-D-Glucopyranose
The 1-{4-[(2-nitrophenyl) methyl]-3-1-yl }-1-deoxidation-β-D-Glucopyranose
The 1-{4-[(4-cyano-phenyl) methyl]-3-1-yl }-1-deoxidation-β-D-Glucopyranose
1-{4-{[4-(3-chlorothiophene-2-yl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose
1-{4-{[4-(2-methylthio group-1,3,4-thiadiazoles-5-yl) phenyl] methyl }-3-1-yl }-1-deoxidation-β-D-Glucopyranose
1-{4-{[4-(2-methylthio group-1,3,4-oxadiazole-5-yl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose
1-{4-{[4-(2-nitrophenyl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose
1-{4-{[4-(4-cyano-phenyl) phenyl] methyl }-3-sec.-propyl pyrazol-1-yl }-1-deoxidation-β-D-Glucopyranose
1-(5-benzyl-3-tertiary butyl pyrazol-1-yl)-1-deoxidation-β-D-Glucopyranose
1-{5-{[4-(5-methyl furan-2-yl) phenyl] methyl }-the 3-tertiary butyl-4-methylpyrazole-1-yl }-1-deoxidation-β-D-Glucopyranose
1-[3-(2-phenylethyl) pyrazol-1-yl]-1-deoxidation-β-D-Glucopyranose.
4. the defined compound of Formula I of the claim 1-3 application of transporting sub-inhibitor as 2 type sodium semi-lactosis.
5. the application of the defined compound of Formula I of claim 4 aspect preparation treatment diabetes medicament.
6. pharmaceutical composition contains compound of Formula I or its pharmacy acceptable salt of one of claim 1-3 and appropriate carriers or vehicle.
7. the described pharmaceutical composition of claim 6, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
8. comprise according to described solid of claim 7 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.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US10577298B2 (en) | 2016-04-28 | 2020-03-03 | Givaudan S.A. | Aryl beta diketones and their use as odorants |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10577298B2 (en) | 2016-04-28 | 2020-03-03 | Givaudan S.A. | Aryl beta diketones and their use as odorants |
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