CN108285439A

CN108285439A - A kind of 2 inhibitor of carbon glycoside class sodium glucose transporter body

Info

Publication number: CN108285439A
Application number: CN201711416357.8A
Authority: CN
Inventors: 王国成; 汪国松
Original assignee: Jiangsu Tasly Diyi Pharmaceutical Co Ltd
Current assignee: Jiangsu Tasly Diyi Pharmaceutical Co Ltd
Priority date: 2017-01-09
Filing date: 2017-12-25
Publication date: 2018-07-17
Anticipated expiration: 2037-12-25
Also published as: WO2018127194A1; CN108285439B

Abstract

The present invention relates to a kind of 2 inhibitor of carbon glycoside class sodium glucose transporter body, preparation method and use, 2 inhibitor of carbon glycoside class sodium glucose transporter body of the invention, the structures with general formula (I)

Description

Carbon glycoside sodium glucose transporter 2 inhibitor

Technical Field

The invention relates to the field of diabetes-related chemicals, and particularly relates to a sodium-glucose transporter type 2 (SGLT-2) inhibitor with a carbon glycoside sodium glucose transporter body structure. The invention also discloses a preparation method and application thereof.

Background

Diabetes mellitus is a metabolic disorder syndrome characterized by hyperglycemia due to defective insulin secretion and/or insufficient insulin action, and is classified into type 1 (T1DM), which is caused by insufficient insulin production (absolute insulin deficiency) by islet β -cells and occurs in adolescents, and type 2 (T2DM), which is caused by insufficient insulin secretion or insulin resistance (relative insulin deficiency) and occurs in middle-aged and elderly people.

SGLT2 is low affinity, high capacity, and specialized transport of glucose located on the surface of renal epithelial cells, while SGLT1 is expressed not only in the kidney but also in the intestine and other tissues, filtered glucose is reabsorbed by SGLT2 in approximately 90% of the proximal tubule (S1 and S2 segments) and reabsorption by SGLT1 in the proximal tubule distal (S3 segment) the remainder is reabsorbed by SGLT1 in the absence of SGLT2, SGLT1 is able to absorb filtered approximately 70% of the glucose.

SGLT2 inhibitors are mainly classified into oxygen glycoside, carbon glycoside, nitrogen glycoside, and non-glycoside SGLT2 inhibitors. Because the oxygen glycoside is sensitive to glycosidase and easy to hydrolyze, and pharmacokinetic experiments are poor, and finally the development of the oxygen glycoside is stopped, people turn the research direction to the design and development of C-glycoside drugs, the C-glycoside drugs directly replace O in glycosidic bonds with C, the hydrolytic stability is greatly enhanced while the drug effect and the pharmacokinetic properties are not influenced, and the oxygen glycoside is a very promising drug. Is also a sodium glucose transporter 2 inhibitor which is currently on the market and is more researched. Several of the following compounds circumvent the problem of sensitivity to glycosidases by removing the anomeric glycosidic oxygen.

However, the existing compounds have some defects such as short half-life period of blood plasma, short time of hypoglycemic action, vomiting, diarrhea side effect and the like which need to be improved while increasing the drug effect and enhancing the stability.

Disclosure of Invention

Based on the prior art, related groups are modified, and the compound has stronger hypoglycemic effect, prolonged action time and reduced side effect.

The invention discloses a C-glycoside SGLT2 inhibitor compound with a general formula (I),

wherein,

n is 0, 1, 2 or 3;

x is selected from C3-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl or substituted phenyl shown in formula (II),

or substituted adamantyl as shown in formula (III),

wherein R is₁、R₂、R₃Independently selected from-H, -CH₃、-CH₂CH₃、-CH₂CH₂CH₃、-OCH₃、-OCH₂CH₃、-OH、-CH₂OH、-CH₂CH₂OH；

Wherein R is₄、R₅、R₆Independently selected from-H, -CH₃、-CH₂CH₃、-OCH₃、-OCH₂CH₃、-OH、-CH₂OH、-NH₂、-NHCOCH₃；

Preferably, the C-glycoside SGLT2 inhibitor compound of the invention has the general formula (I),

n is 0, 1 or 2;

x is selected from substituted phenyl shown in formula (II),

or substituted adamantyl as shown in formula (III),

wherein,

R₁、R₂、R₃independently selected from-H, -CH₃、-CH₂CH₃、-CH₂CH₂CH₃；

R₄、R₅、R₆Independently selected from-H, -CH₃、-CH₂CH₃；

More preferably, the C-glycoside SGLT2 inhibitor compounds of the present invention are the following specific compounds:

further preferably, the C-glycoside SGLT2 inhibitor compound of the present invention is a specific compound as follows:

most preferably, the C-glycoside SGLT2 inhibitor compounds of the present invention are the following specific compounds:

the present invention further provides a process for the preparation of the compounds of the invention, which may take the following route:

5-bromo-2-chlorobenzoic acid is used as an initial raw material, acylation, condensation and reduction reactions are carried out to obtain 5-bromo-2-chloro-4' -methoxy diphenylmethane 4, ether methyl is removed from a compound 4 through boron tribromide, phenolic hydroxyl is protected to obtain 6, and the compound 6 and gluconolactone (9) are subjected to condensation, anomeric hydroxyl etherification and demethoxylation reactions to obtain a key intermediate 1-chloro-4- (β -D-glucopyranosyl-1-yl) -2- (4-hydroxy-benzyl) -benzene 10.

The alcohols of alkane, alkene, cyclane, alkyne and arene respectively react with p-toluenesulfonyl chloride to obtain p-toluenesulfonyl ester 12 of the corresponding alcohol, and the compound 12 reacts with the intermediate 10 to obtain each target compound. The general synthetic route is as follows.

The compound of formula (I) of the present invention may form stable salts, esters, solvates and other derivatives as required,

pharmaceutically acceptable, non-toxic pharmaceutically acceptable salts are obtained, including salts with inorganic acids, such as hydrochloric acid, sulfuric acid, salts with organic acids, such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid, and salts with amino acids, such as alanine, aspartic acid, lysine or with sulfonic acids, such as methanesulfonic acid, p-toluenesulfonic acid.

Or if necessary, can form a pharmaceutical salt with a basic substance, such as an alkali metal salt, an alkaline earth metal salt, a silver salt, a barium salt, and the like.

The compounds of formula (I) of the present invention may also exist in the form of solvates (e.g. hydrates), and therefore, such solvates (e.g. hydrates) are also included in the compounds of the present invention.

The present invention also provides a hypoglycemic pharmaceutical composition containing a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, as an active ingredient. The weight ratio of the active component contained in the pharmaceutical composition in the composition is 0.1-99.9%, and the weight ratio of the pharmaceutically acceptable carrier in the composition is 0.1-99.9%. The pharmaceutical composition is in the form of a formulation suitable for pharmaceutical use. The pharmaceutically acceptable formulations are preferably such as: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, capsules, hard capsules, soft capsules, sustained-release capsules, powders.

The pharmaceutical composition of the present invention is in the form of a preparation, wherein each preparation contains 0.1-1000 mg of the compound of the present invention, and each preparation unit, such as each tablet of a tablet, each capsule, or each dose, such as 100mg per dose.

The pharmaceutical composition of the present invention may be prepared into solid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets, using a solid carrier. The solid carrier which may be used is preferably one or more substances selected from diluents, flavouring agents, solubilising agents, lubricants, suspending agents, binders, bulking agents and the like, or may be an encapsulating substance. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, cocoa butter, and the like. Because of their ease of administration, tablets, powders and capsules are the most suitable oral solid formulations.

The preferred dosage for a given situation can be determined by one skilled in the art in a routine manner. Generally, the amount of the active ingredient to be initially treated is lower than the optimum dose of the active ingredient, and then the dose to be administered is gradually increased until the optimum therapeutic effect is achieved. For convenience, the total daily dose may be divided into several portions and administered in fractions.

The invention further provides application of the SGLT2 inhibitor shown in the formula (I) in preparing a medicament for treating type 2 diabetes, and the SGLT2 inhibitor shown in the formula (I) and a pharmaceutical composition thereof can be used as auxiliary diet and exercise to improve blood sugar control in adults with type 2 diabetes.

The compound, particularly the compound 13h and the compounds 13i and 13j, have the characteristics of stronger hypoglycemic effect, prolonged action time and low side effect compared with the existing similar compounds.

Drawings

MS map of FIG. 113 c

Of FIG. 213 c¹HNMR atlas

FIG. 313 c¹³CNMR atlas

DEPT map of FIG. 413 c

MS map of FIG. 513 d

FIG. 613 d¹HNMR atlas

FIG. 713 d¹³CNMR atlas

DEPT map of FIG. 813 d

MS map of FIG. 913 e

Of fig. 1013 e¹HNMR atlas

FIG. 1113 e¹³CNMR atlas

DEPT map of FIG. 1213 e

FIG. 1313 f MS map

Of FIG. 1413 f¹HNMR atlas

Of FIG. 1513 f¹³CNMR atlas

DEPT map of FIG. 1613 f

FIG. 1713 g MS map

FIG. 1813 g¹HNMR atlas

Of FIG. 1913 g¹³CNMR atlas

FIG. 2013 g DEPT map

FIG. 2113 h MS map

Of FIG. 2213 h¹HNMR atlas

2313 h of the drawings¹³CNMR atlas

FIG. 2413 h DEPT map

FIG. 2513 i MS map

Of FIG. 2613 i¹HNMR atlas

See FIG. 2713 i¹³CNMR atlas

DEPT map of FIG. 2813 i

FIG. 2913 j MS map

FIG. 3013 j¹HNMR atlas

Of FIG. 3113 j¹³CNMR atlas

FIG. 3213 j DEPT map

FIG. 3313 c graph of hSGLT1 and hSGLT2 inhibitory activity

FIG. 3413 d graph of hSGLT1 and hSGLT2 inhibitory activity

FIG. 3513 e graphs of hSGLT1 and hSGLT2 inhibitory activity

FIG. 3613 f graphs of hSGLT1 and hSGLT2 inhibitory Activity

FIG. 3713 g graphs of hSGLT1 and hSGLT2 inhibitory activity

FIG. 3813 h graphs of hSGLT1 and hSGLT2 inhibitory Activity

FIG. 3913 i graphs of hSGLT1 and hSGLT2 inhibitory activity

FIG. 4013 j graph of hSGLT1 and hSGLT2 inhibitory activity

FIG. 41 graphs of hSGLT1 and hSGLT2 inhibitory activity of control dapagliflozin

Detailed Description

The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.

Example 1

Synthesis of 5-bromo-2-chlorobenzoyl chloride (2)

60.00g (0.26mol) of 5-bromo-2-chlorobenzoic acid (1) is added into 200mL of dry dichloromethane, 1.5mL (5.2mol) of DMF is dropwise added, 32mL (0.39mmol) of oxalyl chloride is slowly dropwise added into the reaction liquid for four times under the condition of ice salt bath, the temperature of the reaction liquid is required to be between 0 and 5 ℃, and after dropwise addition, the reaction liquid is slowly heated to room temperature for reaction for 12 hours. The reaction was monitored by thin layer chromatography TLC until the starting material was reacted, the solvent and oxalyl chloride were distilled off under reduced pressure and oxalyl chloride was distilled off three times with methylene chloride, and after cooling, 53.5g of a milky white solid (2) was obtained in 89.1% yield of MS-EI (M/z):255.1[ M + H ] +

Example 2

Synthesis of 5-bromo-2-chloro-4' -methoxybenzophenone (3)

Adding 34.10g (0.26mol) of anhydrous aluminum trichloride into dry 110mL of dichloromethane in three batches under an ice bath condition, stirring for 15min, slowly dropwise adding 23mL (0.22mol) of anisole into the reaction solution, controlling the dropwise adding speed to ensure that the temperature of the reaction solution is 0-5 ℃, slowly dropwise adding a dichloromethane (115mL) solution of the intermediate 2(66g) into the reaction solution after 30min, controlling the dropwise adding speed to ensure that the temperature of the reaction solution is kept at 0-5 ℃, and reacting for 4h in an ice bath after dropwise adding. The temperature is raised to room temperature for reaction for 6 h. After the reaction, the reaction mixture was slowly poured into 750mL of ice water, stirred for 45min, the organic layer was separated, washed successively with 1 mol. L-1 aqueous sodium hydroxide solution, 2 mol. L-1 hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 58.11g of white needle-like crystals (3), with a yield of 78.4%. The purity was 89.3% by HPLC. MS-EI (M/z):325.1[ M ] +

Example 3

Synthesis of 5-bromo-2-chloro-4' -methoxydiphenylmethane (4)

5mL (0.31mol) of triethylsilane and 5.5g (0.17mol) of 3 were added to 20mL of a 1:2 mixture of dichloromethane and acetonitrile with stirring, and 2.5mL of boron trifluoride ether solution was added slowly at 10 ℃ with the temperature being controlled so as not to exceed 20 ℃ as the reaction proceeded. The reaction was monitored by HPLC and if not complete, the reaction was stirred overnight, supplemented with 0.5mL of triethylsilane and 0.3mL of boron trifluoride etherate and then allowed to warm to 50 ℃ and stirred for 4 h. After cooling, the reaction was stopped with 5mL of 7N KOH solution, the aqueous phase was extracted with dichloromethane (2X), the organic phases were combined, washed sequentially with 2N KOH and saturated brine (2X), dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was recrystallized from ethanol to give 3.1g of a white solid with a yield of 65.0%. MS-EI (M/z):311.6[ M]⁺,312.4[M+H]^-

Example 4

Synthesis of 4- (5-bromo-2-chlorobenzyl) phenol (5)

Dissolving 20.0g (64mmol) of 4 in 80mL of dichloromethane under the stirring condition, slowly dropwise adding 6mL (70.4mmol) of boron tribromide solution, controlling the reaction temperature to be 0-4 ℃, after dropwise adding, slowly heating the mixed solution to room temperature, stirring for reaction for 3.5h, cooling the reaction solution to-78 ℃, stopping the reaction by using 100mL of methanol solution, pouring the mixed solution into 500mL of ice water, stirring for reaction for 30min, adjusting the pH to 7-8 by using 1N of sodium hydroxide solution, extracting by using dichloromethane, combining organic phases, drying by using anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and recrystallizing the residual ethanol to obtain 19.62g of the compound 5 as an off-white solid with the yield of 78.0%. MS-EI (M/z):298[ M ]]⁺,321.4[M+Na]^-

Example 5

Synthesis of (4- (5-bromo-2-chlorobenzyl) phenoxy) (tert-butyl) dimethylsilane (6)

60.00g (0.2mol) of 5 and 39mL (0.28mol) of triethylamine are dissolved in 125mL of dichloromethane, tert-butyldimethylchlorosilane is slowly added under ice bath conditions, after the addition is finished, the mixed solution is slowly raised to the room temperature, and the reaction is continuously stirred for 15 hours. TLC detection of thin layer chromatography till the reaction is complete, pouring the reaction solution into 200mL of ice water, continuing stirring for 20min, separating out a solid, filtering, extracting the filtrate with dichloromethane, evaporating the solvent by organic phase under reduced pressure, and passing the residue through a silica gel column (petroleum ether: ethyl acetate: 10:1) to obtain a milky viscous solid 6, 60, 12g with a yield of 97.7%. MS-EI (M/z):411[ M/z):411]⁺.

Example 6

Synthesis of 2,3,4, 6-tetra-O-trimethylsilyl- β -D-gluconolactone (9)

Stirring 14.00g (0.08mol) of 1, 5-gluconolactone and 80mL of N-methylmorpholine-5 ℃ in 120mL of tetrahydrofuran solution for reaction, slowly dripping 50mL (0.48mol) of trimethylchlorosilane into the mixed solution, controlling the dripping speed to ensure that the reaction temperature does not exceed 5 ℃, stirring for reaction for 1h, raising the temperature to 35 ℃ for continuous reaction for 15h, then cooling to room temperature and stirring overnight, diluting with 100mL of dichloromethane, pouring into ice water, controlling the temperature not to exceed 10 ℃, stirring for reaction for 25min, separating out an organic phase, sequentially washing with 10% hydrochloric acid solution, water and saturated salt water, drying and filtering with anhydrous sodium sulfate, evaporating the filtrate under reduced pressure to remove the solvent to obtain a colorless oily liquid, and recrystallizing the residue with anhydrous ethanol to obtain the compound 9, 140.3g and the yield of 92.4%. MS-EI (M/z):465[ M-H]⁺,466[M]⁺.

Example 7

Synthesis of (3R, 4S, 5S,6R) -2- (4-chloro-3- (4-hydroxybenzyl) phenyl) -6- (hydroxymethyl) -2-methyltetrahydro-2H-pyran-3, 4, 5-triol (7)

56.36g (0.13mol) of 6 is added into 300mL of tetrahydrofuran solution under the protection of nitrogen at-78 ℃, 2.3mL (0.18mol) of n-butylhexane solution is slowly added into the mixed solution dropwise, after stirring and reacting for 30min, the reaction solution is added into 3(80.10g,0.18mol) of toluene solution at pre-cooled-78 ℃ dropwise under the protection of nitrogen, after stirring and reacting for 1.5h, a methanol solution (250mL,0.6mol/L) of methanesulfonic acid is added, and the reaction solution is slowly heated to room temperature and reacts for 18 h. Adding 65mL of saturated sodium bicarbonate solution to quench the reaction, extracting with ethyl acetate solution, combining organic phases, drying with anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure to remove the solvent to obtain a crude product of 7, dissolving the crude product in hot toluene solution, and slowly adding the crude product into hexane solution to separate out yellow solid 7,47.8g and the yield of 84.8%. MS-EI (M/z) 412[ M + H]⁺,410[M]⁺

Example 8

Synthesis of 1-chloro-4- (β -D-glucopyranos-1-yl) -2- (4-hydroxy-benzyl) -benzene (10)

Dissolving 45.3g (0.11mol) of 7 in 300mL of dichloromethane acetonitrile (1:1) mixed solution, stirring for reaction, slowly adding 29mL (0.17mol) of triethylsilane into the mixed solution under the condition of cooling to-10 ℃, then slowly dropwise adding 16mL (0.13mol) of boron trifluoride ethyl ether solution, reacting for 5 hours under the ice bath condition, adding 150mL of saturated sodium bicarbonate solution for quenching reaction, stirring for reaction for 15 minutes, separating out an organic phase, evaporating the solvent under reduced pressure, stirring, reacting, standing and layering the residue with ethyl acetate and water, separating out the organic phase, extracting an aqueous phase with ethyl acetate (2 x), combining the organic phases, sequentially washing with water, saturated common salt water, drying the organic phase with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure from the filtrate, and recrystallizing the residue with anhydrous ethanol to obtain 10, 36.4g of the compound, wherein the yield is 87.1%. MS-EI (M/z):381[ M + H]⁺,380[M]⁺

Example 9

Synthesis of (3R,4R,5S,6R) -2- (3- (4-n-butoxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (13c)

1.7g (4.5mmol) of 10 and 2.1g (6.8mmol) of cesium carbonate were added to 9ml N, N-dimethylformamide under an oil bath at 55 ℃ and stirred for 13min, 1.35g (5.9mmol) of N-butyl p-toluenesulfonate was added to the oil bath at 60 ℃ and stirred for 15h, saturated saline was added thereto, extraction was performed with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtration was performed, the solvent was evaporated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane: methanol 20:1) to obtain 2.08g of colorless viscous solid 13c at a yield of 80.6%.

Example 10

Synthesis of (3R,4R,5S,6R) -2- (3- (4-n-hexyloxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (13d)

1.7g (4.5mmol) of 10 and 2.1g (6.8mmol) of cesium carbonate are added into 9mLN, N-dimethylformamide under the condition of an oil bath at 55 ℃ and stirred for reaction for 13min, 1.51g (5.9mmol) of N-hexyl p-toluenesulfonate is added under the condition of an oil bath at 60 ℃, stirred for reaction for 15h, saturated saline is added, ethyl acetate is extracted, an organic layer is dried by anhydrous sodium sulfate, filtered, the solvent is evaporated under reduced pressure, and the residue is chromatographed on a silica gel column (dichloromethane: methanol 20:1) to obtain 2.23g of colorless viscous solid 13d with the yield of 81.3%.

Example 11

Synthesis of (3R,4R,5S,6R) -2- (3- (4-propynyloxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (13e)

1.7g (4.5mmol) of 10 and 2.1g (6.8mmol) of cesium carbonate were added to 9ml N-dimethylformamide under an oil bath at 55 ℃ and stirred for reaction for 13min, 1.24g (5.9mmol) of propynyl p-toluenesulfonate was added to the oil bath at 60 ℃ and stirred for reaction for 15h, saturated saline was added thereto, extraction was performed with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol 20:1) to give 1.89g of colorless viscous solid 13e in a yield of 76.4%.

Example 12

Synthesis of (3R,4R,5S,6R) -2- (3- (4-phenoxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (13f)

1.7g (4.5mmol) of 10 and 2.1g (6.8mmol) of cesium carbonate were added to 9ml of N-dimethylformamide under an oil bath condition at 55 ℃ and stirred for reaction for 13min, 1.46g (5.9mmol) of phenyl p-toluenesulfonate was added to the oil bath condition at 60 ℃ and stirred for reaction for 15h, saturated saline was added thereto, extraction was performed with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtration was performed, the solvent was evaporated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane: methanol: 20:1) to obtain 1.91g of colorless viscous solid 13f at a yield of 70.7%.

Example 13

Synthesis of (3R,4R,5S,6R) -2- (3- (4-benzyloxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (13g)

Under the ice bath condition, 7.0G (37mmol) of p-toluenesulfonyl chloride and 5.0mL (37mmol) of triethylamine are added into 40mL of dichloromethane solution, after 10min, 2.5mL (23mmol) of benzyl alcohol is slowly added into the mixed solution, the temperature is controlled not to exceed 8 ℃, after 5h of reaction, TLC detection (petroleum ether: ethyl acetate ═ 25: 1) is carried out until the reaction is completed, 10mL of dichloromethane is added, the reaction solution is poured into ice water (10mL multiplied by 2), stirring is carried out for 15min, and then 10% hydrochloric acid solution, saturated sodium bicarbonate and saturated common salt water are sequentially used for washing, organic phase anhydrous sodium sulfate is dried, filtration is carried out, the filtrate is decompressed, the solvent is removed, and the residue passes through a silica gel column to obtain the compound benzyl 4-methylbenzenesulfonate (G13) for preparation of 13G.

1.7G (4.5mmol) of 10 and 2.1G (6.8mmol) of cesium carbonate were added to 9ml N-dimethylformamide under an oil bath at 55 ℃ and stirred for 13min, 1.55G (5.9mmol) of (G13) was added under an oil bath at 60 ℃ and stirred for 15h, saturated saline was added, extraction was performed with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtration was performed, the solvent was evaporated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane: methanol: 20:1) to give 13G of 2.16G of a colorless viscous solid at a yield of 77.9%.

Example 14

Synthesis of (3R,4R,5S,6R) -2- (3- (4-phenylethoxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (13H)

Under the ice bath condition, 7.0g (37mmol) of p-toluenesulfonyl chloride and 5.0mL (37mmol) of triethylamine are added into 40mL of dichloromethane solution, 2.35mL (23mmol) of phenethyl alcohol is slowly added into the mixed solution after 10min, the temperature is controlled not to exceed 8 ℃, after 5H of reaction, TLC detection (petroleum ether: ethyl acetate: 25: 1) is carried out until the reaction is completed, 10mL of dichloromethane is added, the reaction solution is poured into ice water (10mL multiplied by 2), stirring is carried out for 15min of reaction, 10% hydrochloric acid solution, saturated sodium bicarbonate and saturated common salt water are sequentially used for washing, organic phase anhydrous sodium sulfate is dried, filtration is carried out, the filtrate is decompressed, the solvent is removed, and the residue passes through a silica gel column to obtain the compound p-toluenesulfonate phenethyl ester (H13) which is used for preparation for 13H.

1.7g (4.5mmol) of 10 and 2.1g (6.8mmol) of cesium carbonate were added to 9ml N-dimethylformamide under an oil bath at 55 ℃ and stirred for 13min, 1.63g (5.9mmol) of (H13) was added under an oil bath at 60 ℃ and stirred for 15H, saturated saline was added, extraction was performed with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtration was performed, the solvent was evaporated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane: methanol: 20:1) to give 2.24g of a colorless viscous solid for 13H, with a yield of 78.4%.

Example 15

Synthesis of (3R,4R,5S,6R) -2- (3- (4-adamantyloxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (13i)

Under the ice bath condition, 7.0g (37mmol) of paratoluensulfonyl chloride and 5.0mL (37mmol) of triethylamine are added into 40mL of dichloromethane solution, after 10min, 3.50g (23mmol) of adamantanol is slowly added into the mixed solution, the temperature is controlled not to exceed 8 ℃, after 5h of reaction, TLC detection (petroleum ether: ethyl acetate ═ 25: 1) is carried out until the reaction is completed, 10mL of dichloromethane is added, the reaction solution is poured into ice water (10mL multiplied by 2), stirring is carried out for 15min, and the mixture is washed by 10% hydrochloric acid solution, saturated sodium bicarbonate and saturated common salt water in sequence, dried by organic phase anhydrous sodium sulfate, filtered, the filtrate is decompressed, the solvent is distilled off, and the residue passes through a silica gel column to obtain the compound of the adamantane tosylate (I13) for preparation of 13I.

1.7g (4.5mmol) of 10 and 2.1g (6.8mmol) of cesium carbonate were added to 9ml N-dimethylformamide under an oil bath at 55 ℃ and stirred for 13min, 1.81g (5.9mmol) of (I13) was added under an oil bath at 60 ℃ and stirred for 15h, saturated saline was added, extraction was performed with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtration was performed, the solvent was evaporated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane: methanol: 20:1) to give 2.20g of colorless viscous solid 13I with a yield of 72.5%.

Example 16

Synthesis of (3R,4R,5S,6R) -2- (3- (4-adamantylethoxy) benzyl) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (13j)

Under the ice bath condition, 7.0g (37mmol) of p-toluenesulfonyl chloride and 5.0mL (37mmol) of triethylamine are added into 40mL of dichloromethane solution, after 10min, 4.15g (23mmol) of adamantane ethanol is slowly added into the mixed solution, the temperature is controlled not to exceed 8 ℃, after 5h of reaction, TLC detection (petroleum ether: ethyl acetate ═ 25: 1) is carried out until the reaction is completed, 10mL of dichloromethane is added, the reaction solution is poured into ice water (10mL multiplied by 2), stirring is carried out for 15min of reaction, 10% hydrochloric acid solution, saturated sodium bicarbonate and saturated common salt water are sequentially used for washing, organic phase anhydrous sodium sulfate is dried, filtration is carried out, the filtrate is decompressed, the solvent is distilled off, and the residue passes through a silica gel column to obtain the compound of adamantane ethyl p-toluenesulfonate (J13) for preparation of 13J.

1.7g (4.5mmol) of 10 and 2.1g (6.8mmol) of cesium carbonate were added to 9ml N-dimethylformamide under an oil bath at 55 ℃ and stirred for 13min, 1.97g (5.9mmol) of (J13) was added under an oil bath at 60 ℃ and stirred for 15h, saturated saline was added, extraction was performed with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtration was performed, the solvent was evaporated under reduced pressure, and the residue was chromatographed on a silica gel column (dichloromethane: methanol: 20:1) to give 2.34g of colorless viscous solid 13J with a yield of 73.2%.

Example 17

The invention respectively carries out mass spectrum and nuclear magnetic resonance hydrogen spectrum (13 c-13 j) on 8 target compounds¹HNMR), carbon spectrum (¹³CNMR and¹³CDEPT 135).

The NMR data of the target compounds 13c-13j are shown in Table 1, the mass spectrum data are shown in Table 2, and the spectra are shown in figures 1-32.

TABLE 1 NMR data on target Compounds

TABLE 2 Mass Spectrometry (MS) data for the target Compounds

Example 19 in vitro SGLT inhibitory Activity screening

Experimental methods

Human SGLT2 and SGLT1 are stably expressed in Chinese hamster ovary Cells (CHO) and are therefore used in this activity assay, incubated in 96-well plates at 37 ℃ overnight, the activity of the target compounds to inhibit SGLT1 and SGLT2, respectively, the substrate for SGLT is assayed using the radiolabeled glucose analog α -methyl-D-glucopyranoside (AMG). assay of the ability of the inhibitor to inhibit the uptake of AMG is performed in buffer, which acts to mimic the conditions of glomerular filtered low protein, each compound will be assayed at 8 different concentrations in a glucose transport assay, response curves are fitted to a four parameter model to determine the concentration of inhibitor at half maximal response, denoted as half Inhibitory Concentration (IC)₅₀)。

Results of in vitro inhibitory Activity test

As can be seen from Table 3, the propargyl substituted derivative 13e, IC₅₀The values were 1.1nM each, with slightly higher inhibitory activity against SGLT2 than dapagliflozin control (IC)₅₀0.9nM), but the selectivity to SGLT1 is much higher than dapagliflozin. Of the three aromatic ring substituted derivatives (13f,13g,13h), the phenethyl substituted derivative 13h had the same inhibitory activity (IC) as SGLT2 compared to dapagliflozin (IC)₅₀Both 0.9nM), but more selective than dapagliflozin (540-fold and 373.4-fold, respectively). The inhibitory activity of the adamantane-substituted derivative (13i,13j) and the selectivity to SGLT1 were both inferior to dapagliflozin.

TABLE 3 in vitro hSGLT inhibition assay data

Note: a each IC₅₀Values represent the mean of two determinations b Selectivity values are by IC₅₀Value SGLT1/SGLT2, calculating, and taking the average value of two times

Conclusion

The structures of 8 target compounds are confirmed by MS and 1HNMR, 13C NMR and DEPT spectra, and the experimental result of the in vitro human SGLT1 inhibitory activity of the target compounds shows that the derivative (13h) substituted by phenethyl has better inhibitory activity than dapagliflozin, the selectivity to SGLT1 is higher than that of dapagliflozin, and the selectivity to SGLT2 of the compound (13d) substituted by n-hexyl is much higher than that of the dapagliflozin.

Claims

1. A carbon glycoside sodium glucose transporter 2 inhibitor which has the structure of a general formula (I)

Wherein,

n is 0, 1, 2 or 3;

or substituted adamantyl as shown in formula (III),

Wherein R is₄、R₅、R₆Independently selected from-H, -CH₃、-CH₂CH₃、-OCH₃、-OCH₂CH₃、-OH、-CH₂OH、-NH₂、-NHCOCH₃。

2. The inhibitor of the carbon glycoside sodium glucose transporter 2 of claim 1, wherein,

n is 0, 1 or 2;

x is selected from substituted phenyl shown in formula (II),

or substituted adamantyl as shown in formula (III),

wherein,

R₄、R₅、R₆Independently selected from-H, -CH₃、-CH₂CH₃。

3. The sodium carbon glycoside glucose transporter 2 inhibitor of claim 1, selected from the group consisting of:

4. the inhibitor of the carbon glycoside sodium glucose transporter 2 of claim 1, which can form stable salts, esters, solvates if desired.

5. The sodium carbon glycoside glucose transporter 2 inhibitor of claim 1, wherein the stable salt is a pharmaceutically acceptable non-toxic pharmaceutically acceptable salt, including salts with inorganic acids such as hydrochloric acid, sulfuric acid, salts with organic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid, and salts with amino acids such as alanine, aspartic acid, lysine or with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid; or if necessary, can form a medicinal salt with a basic substance, such as an alkali metal salt, an alkaline earth metal salt, a silver salt and a barium salt.

6. A pharmaceutical composition comprising the sodium carbon glycoside glucose transporter 2 inhibitor of claim 1.

7. The pharmaceutical composition according to claim 6, wherein the active ingredient, the sodium carbon glycoside glucose transporter 2 inhibitor, is contained in an amount of 0.1 to 99.9% by weight of the composition, and the pharmaceutically acceptable carrier is contained in an amount of 0.1 to 99.9% by weight of the composition.

8. The pharmaceutical composition according to claim 6, in a pharmaceutically suitable formulation selected from the group consisting of tablets, capsules, powders.

9. The method for preparing the inhibitor of the carbon glycoside sodium glucose transporter 2 of claim 1, which comprises the following steps:

using 5-bromo-2-chlorobenzoic acid as an initial raw material, carrying out acylation, condensation and reduction reactions to obtain 5-bromo-2-chloro-4' -methoxy diphenylmethane 4, removing ether methyl from the compound 4 by boron tribromide, protecting phenolic hydroxyl to obtain 6, carrying out condensation, anomeric hydroxyl etherification and demethoxy reaction on the compound 6 and gluconolactone (9) to obtain a key intermediate 1-chloro-4- (β -D-glucopyranosyl-1-yl) -2- (4-hydroxy-benzyl) -benzene 10;

respectively reacting the alcohols of alkane, alkene, cyclane, alkyne and arene with p-toluenesulfonyl chloride to obtain p-toluenesulfonyl ester 12 of the corresponding alcohol, and reacting the compound 12 with the intermediate 10 to obtain the target compound

10. The use of the inhibitor of the carbon glycoside sodium glucose transporter body 2 of claim 1 for the preparation of a medicament for the treatment of type 2 diabetes.