CN101508713A

CN101508713A - Glucoside containing 1,2,3-triazole structure, preparation method and application

Info

Publication number: CN101508713A
Application number: CNA2009100682885A
Authority: CN
Inventors: 赵桂龙; 徐为人; 王玉丽; 李祎亮; 邹美香; 王致峰; 刘巍; 谭初兵; 汤立达
Original assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Current assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date: 2009-03-30
Filing date: 2009-03-30
Publication date: 2009-08-19

Abstract

The invention relates to the diabetes-related drug field. More specifically, the invention relates to an sodium glucose transporter 2 (SGLT2) inhibitor containing a 1,2,3-triazolylglucoside structure, a preparation method and application thereof to preparation of antidiabetic drugs, wherein, radicals are defined as in the specification.

Description

Glucoside containing 1, 2, 3-triazole structure, preparation method and application thereof

Technical Field

The present invention relates to the field of diabetes related drugs. Specifically, the invention relates to a sodium glucose transporter type 2 (SGLT2) inhibitor containing a 1, 2, 3-triazolyl glucoside structure and having a treatment effect on diabetes, a preparation method thereof and a pharmaceutical composition containing the same.

Background

The diabetic patients around the world currently have about 1.7 hundred million, and the vast majority of the diabetic patients are type II (i.e. non-insulin-dependent) diabetic patients. At present, the traditional medicines for treating diabetes clinically used mainly comprise metformin, sulfonylurea and insulin drugs, and thiazolidinedione drugs, alpha-glucosidase inhibitors, dipeptidyl peptidase-IV inhibitors and the like which are on the market in recent years. These drugs have good therapeutic effects, but long-term treatment has problems such as hepatotoxicity and safety of weight gain.

The sodium glucose transporter type 2 (SGLT2) is a new target discovered in the recent years for the treatment of diabetes. The protein of SGLT2 is distributed mainly in the kidney and functions to absorb glucose in urine and return it to the blood, so that inhibition of the protein target of SGLT2 lowers the blood glucose level, unlike the conventional way of lowering blood glucose levels. Thus when SGLT2 is functionally impaired, more glucose in the urine will be excreted through the kidneys, which will help the diabetic to maintain the correct blood glucose level. Since SGLT2 inhibitors do not intervene in glucose metabolism, it can be used as a supplement to the mainstream approach to glycemic control.

The invention discloses novel SGLT2 inhibitors capable of effectively reducing plasma glucose levels, which lay the foundation for further preparing diabetes drugs, in particular to non-insulin dependent diabetes drugs.

Disclosure of Invention

It is an object of the present invention to overcome the disadvantages and drawbacks of the prior art and to provide a compound having a good activity with the general formula I and pharmaceutically acceptable esters thereof.

It is another object of the present invention to provide a process for the preparation of compounds having the general formula I and pharmaceutically acceptable esters thereof.

It is a further object of the present invention to provide pharmaceutical compositions containing a compound of formula I as an active ingredient, together with one or more pharmaceutically acceptable carriers, excipients or diluents, and their use in the treatment of diabetes.

The present disclosure will now be described in detail for the purpose of the invention.

The compounds of the present invention having the general formula I have the following structural formula:

wherein,

R₁selected from H, F, Cl, Br, I, C₁-C₅Alkyl, CN, NO₂、NR₃R₄And OR₅And disubstituted combinations of these groups, wherein R₃And R₄Independently selected from H and C₁-C₃Alkyl of R₅Is selected from C₁-C₅The alkyl group of (a) is,

R₂selection of H and C₁-C₅Alkyl group of (1).

Preferred are compounds of the following general formula I or pharmaceutically acceptable esters thereof,

wherein,

R₁selected from H, F, Cl, C₁-C₃Alkyl, CN, NO₂、NR₃R₄And OR₅And disubstituted combinations of these groups, wherein R₃And R₄Independently selected from H and C₁-C₃Alkyl of R₅Is selected from C₁-C₃The alkyl group of (a) is,

R₂selection of H and C₁-C₃Alkyl group of (1).

More preferred compounds of the invention having the general formula I and pharmaceutically acceptable esters thereof are shown in the following table:

compound numbering	Name of Compound
compound numbering	Name of Compound	I-1	4-benzyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside
I-2	4- [ (2-chlorophenyl) methyl group]-5-methyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside	I-1	4-benzyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside

I-3	4- [ (4-ethylphenyl) methyl group]-5-methyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside
I-3		I-4	4- [ (4-ethoxyphenyl) methyl group]-5-methyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside
I-5	5-Ethyl-4- [ (4-ethylphenyl) methyl group]-1, 2, 3-triazole-1-yl beta-D-glucopyranoside	I-4
I-5		I-6	4- [ (4-ethoxyphenyl) methyl group]-5-ethyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside
I-7	4- [ (4-ethylphenyl) methyl group]-5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside	I-6
I-7		I-8	4- [ (4-ethoxyphenyl) methyl group]-5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside
I-9	4- [ (4-Nitrophenyl) methyl group]-5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside	I-8
I-9		I-10	4- [ (3-cyanophenyl) methyl group]-5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside
I-11	4- [ (4-dimethylaminophenyl) methyl group]-5-isopropyl-1, 2, 3-triazole-1-yl beta-DGlucopyranoside	I-10
I-11		I-12	4- [ (2-chloro-4-ethylphenyl) methyl group]-5-ethyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside
I-13	4- [ (4-ethoxyphenyl) methyl group]-5-isopropyl-1, 2, 3-triazole-1-yl 6-O-methoxycarbonyl-beta-D-glucopyranoside	I-12
I-13		I-14	4- [ (4-ethylphenyl) methyl group]-5-isopropyl-1, 2, 3-triazole-1-yl 6-O-ethoxycarbonyl-beta-D-glucopyranoside

The compound of the general formula I is synthesized by the following steps:

and reacting the compound II with the compound III to generate a compound IV, and reacting the compound IV under the action of sodium methoxide to generate the compound I. Wherein, the compound II is prepared according to the literature method (synthesis and application in liquid chromatography of Dunhuang, Zhouyuyiwei, Liwenbin, 2, 3, 4, 6-tetraacetyl-beta-D-glucopyranosyl isothiocyanate, chemical reagent, 2007, 29(2), 99-10). R₁And R₂As defined above.

The pharmaceutically acceptable ester of the compound of the formula I comprises pharmaceutically acceptable ester formed by hydroxyl at 6-O position of glucose fragment in molecule and acetyl, propionyl, methoxycarbonyl, benzoyl and the like. Pharmaceutically acceptable esters of the compounds of formula I are prepared by the process shown in the following figure.

1 equivalent of R for the compound I₆COCl treatment and esterification at the 6-O position of the glucose fragment of compound I to obtain the corresponding ester V. It is composed ofIn, R₆And a pharmaceutically acceptable group selected from Me, Et, MeO, EtO, Ph and the like, preferably Me, MeO and EtO, more preferably MeO and EtO.

The compound of formula I or pharmaceutically acceptable ester thereof can be prepared into a pharmaceutical composition together with one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition can be made into solid oral preparation, liquid oral preparation, injection, etc. The solid and liquid oral formulations comprise: the injection preparation comprises injection water injection, injection freeze-dried powder injection, large infusion and small infusion.

The composition of the invention, the pharmaceutically or dietetically acceptable auxiliary materials are selected from: fillers, binders, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials, or other excipients.

The composition of the invention, and the pharmaceutically or dietetically acceptable auxiliary materials. The filler is one or a combination of more of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate and microcrystalline cellulose; the adhesive comprises one or a combination of more of sucrose, starch, polyvidone, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, medicinal ethanol and water; the disintegrating agent comprises one or more of starch, cross-linked polyvidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and effervescent disintegrating agent.

The compound of the general formula I or the ester thereof has the inhibiting effect of SGLT2 enzyme, and can be used as an effective component for preparing a medicament for treating diabetes. The activity of the compound of the general formula I is verified by an in vivo hypoglycemic model.

The compounds of formula I of the present invention are effective over a relatively wide dosage range. For example, the daily dosage may be in the range of about 1mg to about 1000mg per person, divided into one or more administrations. The actual dosage of the compounds of formula I to be administered according to the invention can be determined by the physician in the light of the relevant circumstances. These include: the physical state of the subject, the route of administration, the age, body weight, individual response to the drug, severity of the symptoms, and the like.

Detailed Description

The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of the teachings of the present invention may be made by those skilled in the art without departing from the scope of the claims of the present application.

Example 1

4-benzyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside (I-1)

A100 mL round-bottom flask was charged with 3.73g (10mmol) of Compound II, 1.16g (10mmol) of Compound III-1, and 30mL of anhydrous ethanol, and the reaction mixture was heated under electromagnetic stirring at reflux for 12 hours and cooled. The reaction mixture was evaporated in a rotary evaporator and the residue was purified by column chromatography to give pure compound IV-1. The obtained compound IV-1 was dissolved in 100mL of anhydrous methanol in which 0.10g (1.85mmol) of solid MeONa was dissolved in advance, and the mixture was stirred at room temperature for 1 hour, and then 5.0g of a dry 732 strongly acidic cation exchange resin was added and the mixture was stirred at room temperature for 3 hours. And (4) filtering to remove the resin, evaporating the filtrate to dryness to obtain a white solid, and drying to obtain the compound I-1. Colorless crystals, 2.73g, 85% yield. ESI-MS, M/z 322([ M + H)]⁺)。

Wherein compounds III-1 and IV-1 are each one of the compounds of the general formulae III and IV.

Example 2

4- [ (2-chlorophenyl) methyl ] -5-methyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside (I-2)

A100 mL round-bottom flask was charged with 3.73g (10mmol) of Compound II, 1.65g (10mmol) of Compound III-2, and 30mL of anhydrous ethanol, and the reaction mixture was heated under electromagnetic stirring at reflux for 12 hours and cooled. The reaction mixture was evaporated in a rotary evaporator and the residue was purified by column chromatography to give pure compound IV-2. The obtained compound IV-2 was dissolved in 100mL of anhydrous methanol in which 0.10g (1.85mmol) of solid MeONa was dissolved in advance, and the mixture was stirred at room temperature for 1 hour, and then 5.0g of a dry 732 strongly acidic cation exchange resin was added and the mixture was stirred at room temperature for 3 hours. And (4) filtering to remove the resin, evaporating the filtrate to dryness to obtain a white solid, and drying to obtain the compound I-2. Colorless crystals, 3.18g, yield 86%. ESI-MS, M/z 370([ M + H)]⁺)。

Wherein compounds III-2 and IV-2 are each one of the compounds of the general formulae III and IV.

Example 3

4- [ (4-ethylphenyl) methyl ] -5-methyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside (I-3)

A100 mL round-bottom flask was charged with 3.73g (10mmol) of Compound II, 1.58g (10mmol) of Compound III-3, and 30mL of anhydrous ethanol, and the reaction mixture was heated under electromagnetic stirring at reflux for 12 hours and cooled. The reaction mixture was evaporated in a rotary evaporator and the residue was purified by column chromatography to give pure compound IV-3. HandleThe obtained compound IV-3 was dissolved in 100mL of anhydrous methanol in which 0.10g (1.85mmol) of solid MeONa was dissolved in advance, and the mixture was stirred at room temperature for 1 hour, and then 5.0g of a dry 732 type strongly acidic cation exchange resin was added and stirred at room temperature for 3 hours. And (4) filtering to remove the resin, evaporating the filtrate to dryness to obtain a white solid, and drying to obtain the compound I-3. Colorless crystals, 2.94g, 81% yield. ESI-MS, M/z 364([ M + H)]⁺)。

Wherein compounds III-3 and IV-3 are each one of the compounds of the general formulae III and IV.

Example 4

4- [ (4-ethoxyphenyl) methyl ] -5-methyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside (I-4)

A100 mL round-bottom flask was charged with 3.73g (10mmol) of Compound II, 1.74g (10mmol) of Compound III-4, and 30mL of anhydrous ethanol, and the reaction mixture was heated under electromagnetic stirring at reflux for 12 hours and cooled. The reaction mixture was evaporated in a rotary evaporator and the residue was purified by column chromatography to give pure compound IV-4. The obtained compound IV-4 was dissolved in 100mL of anhydrous methanol in which 0.10g (1.85mmol) of solid MeONa was dissolved in advance, and the mixture was stirred at room temperature for 1 hour, and then 5.0g of a dry 732 strongly acidic cation exchange resin was added and the mixture was stirred at room temperature for 3 hours. And (4) carrying out suction filtration to remove the resin, evaporating the filtrate to dryness to obtain a white solid, and drying to obtain the compound I-4. Colorless crystals, 3.03g, yield 80%. ESI-MS, M/z 380([ M + H)]⁺)。

Wherein compounds III-4 and IV-4 are each one of the compounds of the general formulae III and IV.

Example 5

5-ethyl-4- [ (4-ethylphenyl) methyl ] -1, 2, 3-triazole-1-yl beta-D-glucopyranoside (I-5)

A100 mL round-bottom flask was charged with 3.73g (10mmol) of Compound II, 1.72g (10mmol) of Compound III-5, and 30mL of anhydrous ethanol, and the reaction mixture was heated under electromagnetic stirring at reflux for 12 hours and cooled. The reaction mixture was evaporated in a rotary evaporator and the residue was purified by column chromatography to give pure compound IV-5. The obtained compound IV-5 was dissolved in 100mL of anhydrous methanol in which 0.10g (1.85mmol) of solid MeONa was dissolved in advance, and the mixture was stirred at room temperature for 1 hour, and then 5.0g of a dry 732 strongly acidic cation exchange resin was added and the mixture was stirred at room temperature for 3 hours. And (4) filtering to remove the resin, evaporating the filtrate to dryness to obtain a white solid, and drying to obtain the compound I-5. Colorless crystals, 3.20g, 85% yield. ESI-MS, M/z 378([ M + H)]⁺)。

Wherein compounds III-5 and IV-5 are each one of the compounds of the general formulae III and IV.

Example 6

4- [ (4-ethoxyphenyl) methyl ] -5-ethyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside (I-6)

A100 mL round-bottom flask was charged with 3.73g (10mmol) of Compound II, 1.88g (10mmol) of Compound III-6, and 30mL of anhydrous ethanol, and the reaction mixture was heated under electromagnetic stirring at reflux for 12 hours and cooled. The reaction mixture was evaporated in a rotary evaporator and the residue was purified by column chromatography to give pure compound IV-6. The obtained compound IV-6 was dissolved in 100mL of anhydrous methanol in which 0.10g (1.85mmol) of solid MeONa was dissolved in advance, and the mixture was stirred at room temperature for 1 hour, then 5.0g of a dry 732 strongly acidic cation exchange resin was added, and the mixture was stirred at room temperature for 3 hours. Filtering to remove resin, filteringThe solution was evaporated to dryness to give a white solid, which was dried to give compound I-6. Colorless crystals, 3.42g, yield 87%. ESI-MS, M/z 394([ M + H ]]⁺)。

Wherein compounds III-6 and IV-6 are each one of the compounds of the general formulae III and IV.

Example 7

4- [ (4-ethylphenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside (I-7)

A100 mL round-bottom flask was charged with 3.73g (10mmol) of Compound II, 1.86g (10mmol) of Compound III-7, and 30mL of anhydrous ethanol, and the reaction mixture was heated under electromagnetic stirring at reflux for 12 hours and cooled. The reaction mixture was evaporated in a rotary evaporator and the residue was purified by column chromatography to give pure compound IV-7. The obtained compound IV-7 was dissolved in 100mL of anhydrous methanol in which 0.10g (1.85mmol) of solid MeONa was dissolved in advance, and the mixture was stirred at room temperature for 1 hour, and then 5.0g of a dry 732 strongly acidic cation exchange resin was added and the mixture was stirred at room temperature for 3 hours. And (4) filtering to remove the resin, evaporating the filtrate to dryness to obtain a white solid, and drying to obtain the compound I-7. Colorless crystals, 3.32g, 85% yield. ESI-MS, M/z 392([ M + H)]⁺)。

Wherein compounds III-7 and IV-7 are each one of the compounds of the general formulae III and IV.

Example 8

4- [ (4-ethoxyphenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside (I-8)

One isA100 mL round-bottom flask was charged with 3.73g (10mmol) of Compound II, 2.02g (10mmol) of Compound III-8, and 30mL of anhydrous ethanol, and the reaction mixture was heated under electromagnetic stirring at elevated temperature under reflux for 12 hours and cooled. The reaction mixture was evaporated in a rotary evaporator and the residue was purified by column chromatography to give pure compound IV-8. The obtained compound IV-8 was dissolved in 100mL of anhydrous methanol in which 0.10g (1.85mmol) of solid MeONa was dissolved in advance, and the mixture was stirred at room temperature for 1 hour, and then 5.0g of a dry 732 strongly acidic cation exchange resin was added and the mixture was stirred at room temperature for 3 hours. And (4) filtering to remove the resin, evaporating the filtrate to dryness to obtain a white solid, and drying to obtain the compound I-8. Colorless crystals, 3.62g, 89% yield. ESI-MS, M/z 408([ M + H)]⁺)。

Wherein compounds III-8 and IV-8 are each one of the compounds of the general formulae III and IV.

Example 9

4- [ (4-nitrophenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside (I-9)

A100 mL round-bottom flask was charged with 3.73g (10mmol) of Compound II, 2.03g (10mmol) of Compound III-9, and 30mL of anhydrous ethanol, and the reaction mixture was heated under electromagnetic stirring at reflux for 12 hours and cooled. The reaction mixture was evaporated in a rotary evaporator and the residue was purified by column chromatography to give pure compound IV-9. The obtained compound IV-9 was dissolved in 100mL of anhydrous methanol in which 0.10g (1.85mmol) of solid MeONa was dissolved in advance, and the mixture was stirred at room temperature for 1 hour, and then 5.0g of a dry 732 strongly acidic cation exchange resin was added and the mixture was stirred at room temperature for 3 hours. And (4) filtering to remove the resin, evaporating the filtrate to dryness to obtain a white solid, and drying to obtain the compound I-9. Colorless crystals, 3.71g, 91% yield. ESI-MS, M/z 409([ M + H)]⁺)。

Wherein compounds III-9 and IV-9 are each one of the compounds of the general formulae III and IV.

Example 10

4- [ (3-cyanophenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside (I-10)

A100 mL round-bottom flask was charged with 3.73g (10mmol) of Compound II, 1.83g (10mmol) of Compound III-10, and 30mL of anhydrous ethanol, and the reaction mixture was heated under electromagnetic stirring at reflux for 12 hours and cooled. The reaction mixture was evaporated in a rotary evaporator and the residue was purified by column chromatography to give pure compound IV-10. The obtained compound IV-10 was dissolved in 100mL of anhydrous methanol in which 0.10g (1.85mmol) of solid MeONa was dissolved in advance, and the mixture was stirred at room temperature for 1 hour, and then 5.0g of a dry 732 strongly acidic cation exchange resin was added and the mixture was stirred at room temperature for 3 hours. And (4) filtering to remove the resin, evaporating the filtrate to dryness to obtain a white solid, and drying to obtain the compound I-10. Colorless crystals, 3.49g, yield 90%. ESI-MS, M/z 389([ M + H)]⁺)。

Wherein compounds III-10 and IV-10 are each one of the compounds of the general formulae III and IV.

Example 11

4- [ (4-dimethylaminophenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside (I-11)

A100 mL round-bottom flask was charged with 3.73g (10mmol) of Compound II, 2.01g (10mmol) of Compound III-11, and 30mL of anhydrous ethanol, and the reaction mixture was heated under electromagnetic stirring at reflux for 12 hours and cooled. The reaction mixture was evaporated on a rotary evaporator to remove the solvent and residuePurifying the residue by column chromatography to obtain the pure product of the compound IV-11. The obtained compound IV-11 was dissolved in 100mL of anhydrous methanol in which 0.10g (1.85mmol) of solid MeONa was dissolved in advance, and the mixture was stirred at room temperature for 1 hour, and then 5.0g of a dry 732 strongly acidic cation exchange resin was added and the mixture was stirred at room temperature for 3 hours. And (4) filtering to remove the resin, evaporating the filtrate to dryness to obtain a white solid, and drying to obtain the compound I-11. Colorless crystals, 3.65g, yield 90%. ESI-MS, M/z 407([ M + H)]⁺)。

Wherein compounds III-11 and IV-11 are each one of the compounds of the general formulae III and IV.

Example 12

4- [ (2-chloro-4-ethylphenyl) methyl ] -5-ethyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside (I-12)

A100 mL round-bottom flask was charged with 3.73g (10mmol) of Compound II, 2.21g (10mmol) of Compound III-12, and 30mL of anhydrous ethanol, and the reaction mixture was heated under electromagnetic stirring at reflux for 12 hours and cooled. The reaction mixture was evaporated in a rotary evaporator and the residue was purified by column chromatography to give pure compound IV-12. The obtained compound IV-12 was dissolved in 100mL of anhydrous methanol in which 0.10g (1.85mmol) of solid MeONa was dissolved in advance, and the mixture was stirred at room temperature for 1 hour, then 5.0g of a dry 732 strongly acidic cation exchange resin was added, and the mixture was stirred at room temperature for 3 hours. And (4) filtering to remove the resin, evaporating the filtrate to dryness to obtain a white solid, and drying to obtain the compound I-12. Colorless crystals, 4.05g, 95% yield. ESI-MS, M/z 426([ M + H)]⁺)。

Wherein compounds III-12 and IV-12 are each one of the compounds of the general formulae III and IV.

Example 13

4- [ (4-ethoxyphenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl 6-O-methoxycarbonyl-beta-D-glucopyranoside (I-13)

A50 mL round-bottomed flask was charged with 4.07g (10mmol) of Compound I-8, 1.01g (10mmol) of triethylamine and 30mL of dry dichloromethane, the flask was cooled with an ice-water mixture and stirred magnetically, a solution of 0.95g (10mmol) of methyl chloroformate in 2mL of dry dichloromethane was slowly added dropwise, and after the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction system was diluted with 150mL of dichloromethane, washed once with 100mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated on a rotary evaporator, and the resulting residue was purified by column chromatography to give a pure compound I-13. Colorless crystals, 4.28g, 92% yield. ESI-MS, M/z 466([ M + H)]⁺)。

Example 14

4- [ (4-ethylphenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl 6-O-ethoxycarbonyl-beta-D-glucopyranoside (I-14)

A50 mL round-bottom flask was charged with 3.91g (10mmol) of Compound I-7, 1.01g (10mmol) of triethylamine and 30mL of dry dichloromethane, the flask was cooled with an ice-water mixture and stirred magnetically, a solution of 1.09g (10mmol) of ethyl chloroformate in 2mL of dry dichloromethane was added dropwise slowly, and after the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction system was diluted with 150mL of dichloromethane, washed once with 100mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated on a rotary evaporator, and the resulting residue was purified by column chromatography to give a pure compound I-14. Colorless crystals, 4.17g, yield 90%. ESI-MS, M/z 464([ M + H)]⁺)。

Example 15

Dosage/tablet

Example 1 sample (I-1) 100mg

Microcrystalline cellulose 80mg

Pregelatinized starch 70mg

Polyvinylpyrrolidone 6mg

Carboxymethyl starch sodium salt 5mg

Magnesium stearate 2mg

Talcum powder 2mg

Sieving active ingredients, pregelatinized starch and microcrystalline cellulose, mixing, adding polyvinylpyrrolidone solution, mixing, making soft mass, sieving, making wet granule, drying at 50-60 deg.C, sieving carboxymethyl starch sodium salt, magnesium stearate and pulvis Talci, adding into the above granule, and tabletting.

Example 16

Dosage/tablet

Example 3 sample (I-3) 100mg

Microcrystalline cellulose 80mg

Pregelatinized starch 70mg

Polyvinylpyrrolidone 6mg

Carboxymethyl starch sodium salt 5mg

Magnesium stearate 2mg

Talcum powder 2mg

Example 17

Dosage/granule

EXAMPLE 4 sample (I-4) 50mg

Microcrystalline cellulose 30mg

Pregelatinized starch 20mg

Polyvinylpyrrolidone 3mg

Magnesium stearate 2mg

Talcum powder 1mg

Sieving active ingredients, pregelatinized starch and microcrystalline cellulose, mixing, adding polyvinylpyrrolidone solution, mixing, making soft material, sieving, making wet granule, drying at 50-60 deg.C, sieving magnesium stearate and pulvis Talci, adding into the above granule, and making into capsule.

Example 18

Dosage/granule

Example 6 sample (I-6) 50mg

Microcrystalline cellulose 30mg

Pregelatinized starch 20mg

Polyvinylpyrrolidone 3mg

Magnesium stearate 2mg

Talcum powder 1mg

Example 19

Dosage per 50mL

Example 7 sample (I-7) 50mg

Citric acid 100mg

Appropriate amount of NaOH (adjusting pH4.0-5.0)

50mL of distilled water

Adding distilled water and citric acid into distilled water, stirring for dissolving, adding sample, slightly heating for dissolving, adjusting pH to 4.0-5.0, adding 0.2g of activated carbon, stirring at room temperature for 20 min, filtering, measuring solution concentration by central control, packaging at 5 ml per ampoule, and sterilizing at high temperature for 30 min to obtain injection.

Example 20

Dosage per 50mL

Example 8 sample (I-8) 50mg

Citric acid 100mg

Appropriate amount of NaOH (adjusting pH4.0-5.0)

50mL of distilled water

Example 21

Example 12 sample (I-12) 3.0g

Poloxamer 1.0g

0.2g of sodium hydroxide

QS (citric acid)

Mannitol 26.0g

Lactose 23.0g

100ml of water for injection

The preparation process comprises the following steps: taking 80ml of water for injection, adding the main drug, mannitol, lactose and poloxamer, stirring to dissolve, adding 1mol/L citric acid to adjust the pH value to 7.0-9.0, and adding water to 100 ml. Adding 0.5g of activated carbon, stirring at 30 ℃ for 20 minutes, decarburizing, filtering with a microporous filter membrane for sterilization, subpackaging the filtrate with 1ml per piece, pre-freezing for 2 hours, freezing, drying under reduced pressure for 12 hours until the temperature of the sample reaches room temperature, drying for 5 hours again to obtain white loose blocks, and sealing to obtain the product.

Example 22

Granule 100 bags

Example 13 sample (I-13) 30.0g

Lactose 55.0g

Mannitol 14.0g

Aspartame 0.05g

Essence 0.05g

2% hydroxypropyl methylcellulose (made with pure water) QS

The preparation process comprises the following steps: the main drug and the auxiliary materials are respectively sieved by a 100-mesh sieve, fully mixed, and then the auxiliary materials with the prescription amount are weighed and fully mixed with the main drug. Adding adhesive to make soft material, granulating with 14 mesh sieve, drying at 55 deg.C, grading with 12 mesh sieve, measuring bag weight, and packaging.

Example 23

Samples were prepared as 5mg/mL suspensions in 1% sodium carboxymethylcellulose in a 0.4mL/20g body weight dose equivalent to a 100mg/kg dose.

Healthy ICR mice, each half male and female, weigh 20-24g, and meet the first-class standard. Animals are fasted for 16 hours, 2 hours after the injection, 2g/kg of glucose saline solution is injected into the abdominal cavity (1.5 hours after the injection of the gliclazide), 0.5 hour, 1 hour, 2 hours, 3 hours and 4 hours after the model building, capillaries are taken at regular time, blood is taken from the venous plexus after the mouse ball, serum is centrifugally separated, and the glucose content of the serum at each time point is measured by a glucose oxidase method. The results are shown in the following table:

the results show that each administration can significantly reduce the glucose tolerance of mice caused by glucose.

Claims

1. A compound having a structure of formula I and pharmaceutically acceptable esters thereof

Wherein,

R₂selection of H and C₁-C₅Alkyl group of (1).

2. A compound of formula I as defined in claim 1 and pharmaceutically acceptable esters thereof

Wherein,

R₂selection of H and C₁-C₃Alkyl group of (1).

3. A compound of formula I as defined in claim 2 and pharmaceutically acceptable esters thereof, selected from:

4-benzyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside

4- [ (2-chlorophenyl) methyl ] -5-methyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside

4- [ (4-ethylphenyl) methyl ] -5-methyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside

4- [ (4-ethoxyphenyl) methyl ] -5-methyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside

5-ethyl-4- [ (4-ethylphenyl) methyl ] -1, 2, 3-triazole-1-yl beta-D-glucopyranoside

4- [ (4-ethoxyphenyl) methyl ] -5-ethyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside

4- [ (4-ethylphenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside

4- [ (4-ethoxyphenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside

4- [ (4-nitrophenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside

4- [ (3-cyanophenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside

4- [ (4-dimethylaminophenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside

4- [ (2-chloro-4-ethylphenyl) methyl ] -5-ethyl-1, 2, 3-triazole-1-yl beta-D-glucopyranoside

4- [ (4-ethoxyphenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl 6-O-methoxycarbonyl-beta-D-glucopyranoside

4- [ (4-ethylphenyl) methyl ] -5-isopropyl-1, 2, 3-triazole-1-yl 6-O-ethoxycarbonyl-beta-D-glucopyranoside.

4. A process for the synthesis of a compound of general formula I as defined in claims 1 to 3, comprising the steps of:

and reacting the compound II with the compound III to generate a compound IV, and reacting the compound IV under the action of sodium methoxide to generate the compound I. R₁And R₂As defined above.

5. A step of synthesizing a pharmaceutically acceptable ester of a compound of general formula I as defined in claims 1 to 3,

1 equivalent of R for the compound I₆COCl treatment to esterify the glucose moiety of compound I at the 6-O position to produce a pharmaceutically acceptable ester of I as claimed in claims 1-3. Wherein R is₆And a pharmaceutically acceptable group selected from Me, Et, MeO, EtO, Ph and the like, preferably Me, MeO and EtO, more preferably MeO and EtO.

6. Use of a compound of general formula I as defined in claims 1-3 as sodium glucose transporter type 2 inhibitor.

7. Use of a compound of general formula I as defined in claims 1 to 3 for the preparation of a medicament for the treatment of diabetes.

8. A pharmaceutical composition comprising a compound of general formula I according to any one of claims 1 to 3 together with a suitable carrier or excipient.

9. The pharmaceutical composition of claim 8, wherein the composition is a solid oral preparation, a liquid oral preparation or an injection.

10. The solid and liquid oral formulation of claim 9 comprising: the injection preparation comprises injection water injection, injection freeze-dried powder injection, large infusion and small infusion.