CN108285439B

CN108285439B - Carbonoside sodium glucose transport protein body 2 inhibitor

Info

Publication number: CN108285439B
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: 2023-05-02
Anticipated expiration: 2037-12-25
Also published as: WO2018127194A1; CN108285439A

Abstract

The invention relates to a carbon glycoside sodium glucose transport protein body 2 inhibitor, a preparation method and application thereof, and the carbon glycoside sodium glucose transport protein body 2 inhibitor has a structure of a general formula (I)

Description

Carbonoside sodium glucose transport protein body 2 inhibitor

Technical Field

The invention relates to the field of chemical medicines related to diabetes, in particular to a sodium glucose transporter type 2 (SGLT-2) inhibitor of a carboglycoside sodium glucose transporter structure. The invention also discloses a preparation method and application thereof.

Background

Diabetes mellitus is a metabolic disorder syndrome characterized by hyperglycemia due to insulin secretion deficiency and/or insulin action deficiency, and is classified into two types, type 1 (T1 DM) and type 2 (T2 DM), the former due to insufficient insulin production by islet β -cells (absolute insulin deficiency), and the latter due to insulin secretion deficiency or insulin resistance (relative insulin deficiency), which are common in middle-aged and elderly people.

Sodium-dependent glucose transporters (SGLTs) rely on the electrochemical potential ion of sodium to actively transport extracellular glucose into the cytoplasm. SGLT2 is a low affinity, high capacity specialized transport of glucose located on the surface of kidney epithelial cells, whereas SGLT1 is expressed not only in the kidney, but also in the intestine and other tissues. About 90% of the filtered glucose is reabsorbed proximal to the proximal tubule (segments S1 and S2) by SGLT2, and the remainder is reabsorbed distal to the proximal tubule (segment S3) by SGLT 1. In the absence of SGLT2, SGLT1 is capable of absorbing and filtering about 70% of glucose. SGLT2 inhibitors reduce glucose reabsorption in the proximal renal tubular and achieve a negative balance of energy by increasing urinary glucose excretion. Since the inhibitors are independent of insulin action, they can be used in any stage of diabetes development, and can continuously and effectively reduce blood sugar even under the conditions of beta cell deterioration and insulin resistance, which makes SGLT2 inhibitors the only choice for diabetes treatment.

SGLT2 inhibitors are largely classified into oxyglycosides, carboglycosides, azoglycosides, and non-glycosidic SGLT2 inhibitors. Because the oxyglycosides are sensitive to glycosidase and are easy to hydrolyze, and the pharmacokinetic test is poor, and finally the development of the oxyglycosides is stopped, people shift the research direction to the design and development of C-glycoside drugs, and the C-glycoside drugs directly change O in glycosidic bonds into C, so that the hydrolytic stability is greatly enhanced while the drug effect and the drug generation property are not influenced, and the oxyglycosides are very promising drugs. Is also a sodium glucose transporter 2 inhibitor which is currently marketed and is more studied. The following compounds circumvent the problem of sensitivity to glycosidases by removing the isosorbide.

However, the existing compounds have the defects of short half-life of plasma, short blood sugar reducing effect time, vomiting, diarrhea side effects and the like when improving the drug effect and enhancing the stability.

Disclosure of Invention

The invention is based on the prior art, and related groups are modified, and the unexpected discovery that the compound of the invention has stronger hypoglycemic effect, longer action time and reduced side effect.

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

wherein, the liquid crystal display device comprises a liquid crystal display device,

n=0, 1,2 or 3;

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

or a substituted adamantyl group represented by the formula (III),

wherein R is ₁ 、R ₂ 、R ₃ Independently selected from-H, -CH ₃ 、-CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₃ 、-OCH ₃ 、-OCH ₂ CH ₃ 、-OH、-CH ₂ OH、-CH ₂ CH ₂ OH；

Wherein R is ₄ 、R ₅ 、R ₆ Independently selected from-H, -CH ₃ 、-CH ₂ CH ₃ 、-OCH ₃ 、-OCH ₂ CH ₃ 、-OH、-CH ₂ OH、-NH ₂ 、-NHCOCH ₃ ；

Preferably, the C-glycoside SGLT2 inhibitor compounds of formula (I) according to the invention, wherein,

n=0, 1 or 2;

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

or a substituted adamantyl group represented by the formula (III),

R ₁ 、R ₂ 、R ₃ independently selected from-H, -CH ₃ 、-CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₃ ；

R ₄ 、R ₅ 、R ₆ Independently selected from-H, -CH ₃ 、-CH ₂ CH ₃ ；

More preferably, the C-glycoside SGLT2 inhibitor compound of the invention is the following specific compound:

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

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most preferably, the C-glycoside SGLT2 inhibitor compound of the invention is the following specific compound:

the 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 taken as a starting material, 5-bromo-2-chloro-4' -methoxyl diphenylmethane 4 is obtained through acylation, condensation and reduction reaction, after ether methyl is removed from the compound 4 under the action of boron tribromide, phenolic hydroxyl is protected to obtain 6, and the compound 6 and gluconolactone (9) are subjected to condensation, etherification of isocarboxy and demethoxy reaction to obtain a key intermediate 1-chloro-4- (beta-D-glucopyranose-1-yl) -2- (4-hydroxy-benzyl) -benzene 10.

The alcohols of alkane, alkene, cycloalkane, alkyne and arene are respectively reacted with p-toluenesulfonyl chloride to obtain p-toluenesulfonyl ester 12 of the corresponding alcohols, and the compound 12 is reacted with the intermediate 10 to obtain each target compound. The overall route of synthesis is as follows.

The compounds of formula (I) according to the invention may, if desired, also form stable salts, esters, solvates and the like derivatives,

pharmaceutically acceptable non-toxic pharmaceutically acceptable salts may be obtained, for example, 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 salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid.

Or, if desired, a pharmaceutically acceptable salt may be formed with an alkaline substance, such as an alkali metal salt, an alkaline earth metal salt, a silver salt, a barium salt, or 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 within the compounds of the present invention.

The present invention also provides a hypoglycemic pharmaceutical composition containing the compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, as an active ingredient. The weight ratio of the active ingredients contained in the pharmaceutical 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 a form suitable for pharmaceutical use. Preferred pharmaceutical formulations are as follows: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, capsules, hard capsules, soft capsules, sustained-release capsules and powder.

The pharmaceutical composition of the present invention, as a preparation form, contains an effective amount of the compound of the present invention of 0.1 to 1000mg per dose, which means each preparation unit such as each tablet, each capsule, and also means each administration dose such as 100mg per administration.

The pharmaceutical composition of the present invention may be used as a solid carrier in the preparation of solid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets. The solid carrier which can be used is preferably one or more substances selected from diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, expanding 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, methyl cellulose, sodium carboxymethyl cellulose, cocoa butter, and the like. Because of their ease of administration, tablets, powders and capsules are the most suitable oral solid formulations.

The person skilled in the art can determine the preferred dosage for a particular situation in a conventional manner. Generally, the amount to be treated is initially below the optimal dose of the active ingredient, and then the dosage is gradually increased until the optimal therapeutic effect is achieved. For convenience, the total daily dose may be divided into several portions and administered in several portions.

The invention further provides the use of the SGLT2 inhibitor shown in the formula (I) in the invention for treating type 2 diabetes, and for this purpose, the invention further provides the application of the SGLT2 inhibitor shown in the formula (I) and a pharmaceutical composition thereof in the preparation of medicines for treating type 2 diabetes, and the SGLT2 inhibitor can be used as an auxiliary diet and exercise for improving blood glucose control in adults with type 2 diabetes.

Compared with the existing similar compounds, the compound, particularly the compound 13h and the compounds 13i and 13j, have the characteristics of stronger blood sugar reducing effect, longer action time and low side effect.

Drawings

MS spectrum of FIG. 1 13c

Fig. 2 13c ¹ HNMR profile

13c of FIG. 3 ¹³ CNMR profile

DEPT profile of FIG. 4 13c

FIG. 5 13d MS spectrum

Fig. 6 13d ¹ HNMR profile

Fig. 7 13d ¹³ CNMR profile

DEPT profile of FIG. 8 13d

FIG. 9 13e MS spectrum

Fig. 10 13e ¹ HNMR profile

Fig. 11 13e ¹³ CNMR profile

DEPT profile of FIG. 12 13e

FIG. 13f MS spectrum

Fig. 14 13f ¹ HNMR profile

Fig. 15 13f ¹³ CNMR profile

FIG. 16 13f DEPT profile

FIG. 17 MS spectrum of 13g

13g of FIG. 18 ¹ HNMR profile

FIG. 19 13g ¹³ CNMR profile

FIG. 20 13g DEPT spectrum

FIG. 21 MS spectrum 13h

Fig. 22 13h ¹ HNMR profile

FIG. 23 13h ¹³ CNMR profile

FIG. 24 DEPT spectra for 13h

FIG. 25 MS spectrum of 13i

FIG. 26 13i ¹ HNMR profile

FIG. 27 13i ¹³ CNMR profile

FIG. 28 DEPT of 13i

FIG. 29 MS spectrum of 13j

FIG. 30 13j ¹ HNMR profile

FIG. 31 13j ¹³ CNMR profile

DEPT profile of FIG. 32 13j

FIG. 33 13c graphs of hSGLT1 and hSGLT2 inhibitory activity

FIG. 34 hSGLT1 and hSGLT2 inhibition activity profile of 13d

FIG. 35 13e graphs of hSGLT1 and hSGLT2 inhibitory activity

FIG. 36 hSGLT1 and hSGLT2 inhibition activity profile of 13f

FIG. 37 13g hSGLT1 and hSGLT2 inhibitory Activity profile

FIG. 38 hSGLT1 and hSGLT2 inhibition activity profile of 13h

FIG. 39 13i is a graph showing hSGLT1 and hSGLT2 inhibitory activities

FIG. 40 hSGLT1 and hSGLT2 inhibition activity profile of 13j

FIG. 41 graphs of hSGLT1 and hSGLT2 inhibition activity of the control dapagliflozin

Detailed Description

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

Example 1

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

60.00g (0.26 mol) of 5-bromo-2-chlorobenzoic acid (1) was added to 200mL of dried dichloromethane, 1.5mL (5.2 mol) of DMF was added dropwise, 32mL (0.39 mmol) of oxalyl chloride was slowly added dropwise to the reaction solution in four times under the ice salt bath condition, the temperature of the reaction solution was required to be between 0 and 5 ℃, and after the addition, the reaction solution was slowly warmed to room temperature to react for 12 hours. TLC monitoring the reaction until the starting material was reacted, evaporating the solvent and oxalyl chloride under reduced pressure, and evaporating the oxalyl chloride with methylene chloride three times, cooling to give a milky solid (2) 53.5g, yield 89.1% MS-EI (m/z): 255.1[ M+H ] +

Example 2

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

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

Example 3

Synthesis of 5-bromo-2-chloro-4' -methoxydiphenyl methane (4)

5mL (0.31 mol) of triethylsilane and 5.5g (0.17 mol) of 3 were added to 20mL of a 1:2 mixture of dichloromethane and acetonitrile under stirring to react, the temperature was controlled at 10℃and 2.5mL of boron trifluoride etherate solution was slowly added, and the reaction temperature was controlled not to exceed 20℃as the reaction proceeded. The reaction was monitored by HPLC, and if not completed, the reaction was stirred overnight, 0.5mL of triethylsilane and 0.3mL of boron trifluoride etherate were added, and then the reaction temperature was raised to 50℃and stirred for 4 hours. After cooling, the reaction was stopped with 5mL of 7N KOH solution, the aqueous phase was extracted with dichloromethane (2×), the organic phases were combined, washed with 2N KOH, saturated brine (2×), 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 in 65.0% yield. MS-EI (m/z): 311.6[ M)] ⁺ ,312.4[M+H] ^-

Example 4

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

20.0g (64 mmol) of 4 is dissolved in 80mL of dichloromethane under stirring, 6mL (70.4 mmol) of boron tribromide solution is slowly added dropwise, the reaction temperature is controlled to be 0-4 ℃, after the dropwise addition, the mixed solution is slowly heated to room temperature, the reaction is stirred for 3.5h, the reaction solution is cooled to-78 ℃, 100mL of methanol solution is used for stopping the reaction, the mixed solution is poured into 500mL of ice water for stirring and reacting for 30min, and 1N of sodium hydroxide solution is used for regulating the PH to 7 DEG D8, dichloromethane extraction, combining organic phases, drying over anhydrous sodium sulfate, filtering, decompressing, evaporating the solvent, and recrystallizing the residue with ethanol to obtain 19.62g of compound 5 as off-white solid with a 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 (0.2 mol) of 5 and 39mL (0.28 mol) of triethylamine are dissolved in 125mL of dichloromethane, tertiary butyl dimethyl chlorosilane is slowly added under the ice bath condition, the mixture is slowly warmed to room temperature after the addition, and the reaction is continued to be stirred for 15h. The reaction was detected by thin layer chromatography TLC, the reaction solution was poured into 200mL ice water, the reaction was continued with stirring for 20min, solids were precipitated, filtered, the filtrate was extracted with dichloromethane, the solvent was distilled off under reduced pressure from the organic phase, and the residue was passed through a silica gel column (petroleum ether: ethyl acetate=10:1) to give a milky viscous solid 6, 60..12g, 97.7% yield, MS-EI (m/z): 411[ m] ⁺ .

Example 6

Synthesis of 2,3,4, 6-tetra-O-trimethylsilane-beta-D-gluconolactone (9)

14.00g (0.08 mol) of 1, 5-glucolactone and 80mL of N-methylmorpholine-5 ℃ are stirred and reacted in 120mL of tetrahydrofuran solution, 50mL (0.48 mol) of trimethylchlorosilane is slowly added into the mixed solution dropwise, the dropping speed is controlled, the reaction temperature is not more than 5 ℃, the temperature is raised to 35 ℃ for continuous reaction for 15h after stirring and reacting for 1h, then the mixture is cooled to room temperature and stirred overnight, 100mL of dichloromethane is used for dilution and then poured into ice water, the temperature is not more than 10 ℃, the stirring and reacting for 25min are controlled, an organic phase is separated, the mixture is dried and filtered by using 10% hydrochloric acid solution, water, saturated saline water, anhydrous sodium sulfate, the filtrate is decompressed and distilled to remove the solvent, and the residue anhydrous ethanol is recrystallized to obtain the compound 9, 140.3g and the yield is 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 (0.13 mol) of 6 is added into 300mL of tetrahydrofuran solution under the protection of nitrogen at the temperature of minus 78 ℃, 2.3mL (0.18 mol) of n-butyl hexane solution is slowly added into the mixed solution in a dropwise manner, the mixture is stirred and reacted for 30min, the reaction solution is dropwise added into 3 (80.10 g,0.18 mol) of toluene solution at the temperature of minus 78 ℃ under the protection of nitrogen, the mixture is stirred and reacted for 1.5h, and then methane sulfonic acid methanol solution (250 mL,0.6 mol/L) is added, and the mixture is slowly heated to room temperature and reacted for 18h. The reaction was quenched by adding 65mL of saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was distilled off under reduced pressure to give crude 7, which was dissolved in hot toluene solution, slowly added to hexane solution, and yellow solid 7,47.8g was isolated in 84.8% yield. MS-EI (m/z): 412[ M+H ]] ⁺ ,410[M] ⁺

Example 8

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

45.3g (0.11 mol) of 7 is dissolved in 300mL of dichloromethane acetonitrile (1:1) mixed solution, stirred and reacted, 29mL (0.17 mol) of triethylsilane is slowly added to the mixed solution under the condition of cooling to minus 10 ℃, 16mL (0.13 mol) of boron trifluoride diethyl ether solution is slowly added dropwise, the mixture is reacted for 5 hours under the ice bath condition, 150mL of saturated sodium bicarbonate solution is added for quenching reaction, stirred and reacted for 15 minutes, an organic phase is separated, the solvent is distilled off under reduced pressure, the residue is reacted and kept stand for layering by stirring with ethyl acetate and water, the organic phase is separated, the aqueous phase is extracted with ethyl acetate (2X), the organic phases are combined, water is sequentially used, saturated brine washing is carried out, the organic phase is dried by anhydrous sodium sulfate, the mixture is filtered, the solvent is distilled off under reduced pressure, and the residue is recrystallized by anhydrous ethanol, thus obtaining 10, 36.4g of the compound with the yield of 87.1 percent. 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 (13 c)

1.7g (4.5 mmol) of 10 and 2.1g (6.8 mmol) of cesium carbonate were added to 9mLN, N-dimethylformamide at 55℃under stirring for 13min, 1.35g (5.9 mmol) of n-butyl p-toluenesulfonate was added at 60℃under stirring for 15h, saturated brine was added, ethyl acetate was used for extraction, 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 2.08g of colorless viscous solid 13c in 80.6% yield.

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 (13 d)

1.7g (4.5 mmol) of 10 and 2.1g (6.8 mmol) of cesium carbonate were added to 9mLN, N-dimethylformamide at 55℃under stirring for 13min, 1.51g (5.9 mmol) of n-hexyl p-toluenesulfonate was added at 60℃under stirring for 15h, saturated brine was added, ethyl acetate was used for extraction, 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 2.23g of colorless viscous solid 13d in a 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 (13 e)

1.7g (4.5 mmol) of 10 and 2.1g (6.8 mmol) of cesium carbonate were added to 9mLN, N-dimethylformamide at 55℃under stirring for 13min, 1.24g (5.9 mmol) of propiolate tosylate was added at 60℃under stirring for 15h, saturated saline solution was added, extraction with ethyl acetate was performed, the organic layer was dried over anhydrous sodium sulfate, filtration and 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 76.4% yield.

Example 12

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

1.7g (4.5 mmol) of 10 and 2.1g (6.8 mmol) of cesium carbonate were added to 9mLN, N-dimethylformamide at 55℃under stirring for 13min, 1.46g (5.9 mmol) of phenyl p-toluenesulfonate was added at 60℃under stirring for 15h, saturated brine was added, ethyl acetate was extracted, 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 1.91g of colorless viscous solid 13f in 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 (13 g)

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

1.7G (4.5 mmol) of 10 and 2.1G (6.8 mmol) of cesium carbonate were added to 9mLN, N-dimethylformamide at 55deg.C under stirring for 13min, 1.55G (5.9 mmol) of (G13) was added at 60deg.C under stirring for 15h, saturated brine was added, ethyl acetate was extracted, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol=20:1) to give 2.16G of a colorless viscous solid 13G in 77.9% yield.

Example 14

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

Under ice bath condition, 7.0g (37 mmol) of p-toluenesulfonyl chloride and 5.0mL (37 mmol) of triethylamine are added into 40mL of dichloromethane solution, 2.35mL (23 mmol) of phenethyl alcohol is slowly added into the mixed solution after 10min, the temperature is controlled to be not higher than 8 ℃, TLC detection (petroleum ether: ethyl acetate=25:1) is carried out after 5H of reaction till the reaction is completed, 10mL of dichloromethane is added, the reaction solution is poured into ice water (10 mL multiplied by 2), stirring reaction is carried out for 15min, 10% hydrochloric acid solution, saturated sodium bicarbonate and saturated saline water are sequentially used, the organic phase anhydrous sodium sulfate is dried, filtration is carried out, the solvent is distilled off from the filtrate under reduced pressure, and the residue is subjected to a silica gel column to obtain the compound p-toluenesulfonic acid phenethyl ester (H13) used for 13H preparation.

1.7g (4.5 mmol) of 10 and 2.1g (6.8 mmol) of cesium carbonate were added to 9mLN, N-dimethylformamide at 55deg.C under stirring for 13min, 1.63g (5.9 mmol) of (H13) was added at 60deg.C under stirring for 15H, saturated brine was added, ethyl acetate was extracted, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol=20:1) to give 2.24g of colorless viscous solid 13H in 78.4% yield.

Example 15

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

Under ice bath condition, 7.0g (37 mmol) of p-toluenesulfonyl chloride and 5.0mL (37 mmol) of triethylamine are added into 40mL of dichloromethane solution, 3.50g (23 mmol) of adamantanol is slowly added into the mixed solution after 10min, the temperature is controlled to be not higher than 8 ℃, TLC detection (petroleum ether: ethyl acetate=25:1) is carried out after 5h of reaction till the reaction is completed, 10mL of dichloromethane is added, the reaction solution is poured into ice water (10 mL multiplied by 2), stirring reaction is carried out for 15min, 10% hydrochloric acid solution, saturated sodium bicarbonate and saturated saline water are sequentially used, the organic phase anhydrous sodium sulfate is dried, filtration is carried out, the solvent is evaporated under reduced pressure, and the residue is subjected to a silica gel column to obtain the compound, namely, adamantyl p-toluenesulfonate (I13) which is used for preparing 13I.

1.7g (4.5 mmol) of 10 and 2.1g (6.8 mmol) of cesium carbonate were added to 9mLN, N-dimethylformamide at 55deg.C under stirring for 13min, 1.81g (5.9 mmol) of (I13) was added at 60deg.C under stirring for 15h, saturated brine was added, ethyl acetate was extracted, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol=20:1) to give 2.20g of colorless viscous solid 13I in 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 (13 j)

Under ice bath condition, 7.0g (37 mmol) of p-toluenesulfonyl chloride and 5.0mL (37 mmol) of triethylamine are added into 40mL of dichloromethane solution, 4.15g (23 mmol) of adamantaneethanol is slowly added into the mixed solution after 10min, the temperature is controlled to be not higher than 8 ℃, TLC detection (petroleum ether: ethyl acetate=25:1) is carried out after 5h of reaction until the reaction is completed, 10mL of dichloromethane is added, the reaction solution is poured into ice water (10 mL multiplied by 2), stirring reaction is carried out for 15min, 10% hydrochloric acid solution, saturated sodium bicarbonate and saturated saline water are sequentially used, the organic phase anhydrous sodium sulfate is dried, filtration is carried out, the solvent is evaporated from the filtrate under reduced pressure, and the residue is subjected to a silica gel column to obtain the compound, namely, adamantane ethyl p-toluenesulfonate (J13) which is used for preparing 13J.

1.7g (4.5 mmol) of 10 and 2.1g (6.8 mmol) of cesium carbonate were added to 9mLN, N-dimethylformamide at 55deg.C under stirring for 13min, 1.97g (5.9 mmol) of (J13) was added at 60deg.C under stirring for 15h, saturated brine was added, ethyl acetate was extracted, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol=20:1) to give 2.34g of colorless viscous solid 13J in 73.2% yield.

Example 17

The invention respectively carries out mass spectrum and nuclear magnetic resonance hydrogen spectrum on 8 target compounds 13c-13j ¹ HNMR, carbon Spectrum @ ¹³ CNMR (CNMR) and preparation method thereof ¹³ CDEPT 135) validation.

The nuclear magnetic resonance hydrogen spectrum data of the 13c-13j target compound are shown in table 1, the mass spectrum data are shown in table 2, and the spectrograms are shown in the attached figures 1-32.

TABLE 1 Nuclear magnetic resonance Hydrogen Spectroscopy data for target Compounds

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TABLE 2 Mass Spectrometry (MS) data for target Compounds

Example 19 in vitro SGLT inhibitory Activity screening

Experimental method

Human SGLT2 and SGLT1 were stably expressed in chinese hamster ovary Cells (CHO) and therefore used in this activity assay, incubated in 96-well plates at 37 ℃ overnight. The activity assays of the target compounds in inhibiting SGLT1 and SGLT2 were examined, respectively. The substrate of SGLT is radiolabeled glucose analog alpha-methyl-D-glucopyranoside (AMG). The ability of the inhibitor to inhibit uptake of AMG was measured in a buffer which acts as a low protein condition simulating glomerular filtration. Each compound will be assayed for glucose transport at 8 different concentrations and a response curve fitted to a four parameter model to determine the concentration of inhibitor at half maximum response, recorded as half inhibitory concentration (IC ₅₀ )。

In vitro inhibitory Activity test results

As can be seen from Table 3, the propargyl-substituted derivative 13e, IC ₅₀ The values were 1.1nM each, slightly higher inhibitory activity on SGLT2 than dapagliflozin control (IC ₅₀ =0.9 nM), but the selectivity to SGLT1 is much higher than dapagliflozin. The phenethyl-substituted derivative 13h of the three aromatic ring-substituted derivatives (13 f,13g,13 h) had the same SGLT2 inhibitory activity (IC) ₅₀ 0.9 nM) but better than dapagliflozin (540-fold and 373.4-fold, respectively). The inhibitory activity of adamantane-substituted derivatives (13 i,13 j) was not as good as that of dapagliflozin for SGLT 1.

TABLE 3 in vitro hSGLT inhibition experimental data

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Note that: a each IC ₅₀ The value represents the mean value b selectivity value of the two determinations by IC ₅₀ The value SGLT1/SGLT2 is calculated, and the average value is taken twice

Conclusion(s)

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

Claims

1. A sodium carboglycoside glucose transporter 2 inhibitor, selected from the group consisting of:

2. the inhibitor of the sodium glucosidic glucose transporter 2 of claim 1, which may also form stable salts, esters, solvates, if desired.

3. The inhibitor of the sodium glucosidic glucose transporter 2 of claim 2, the stable salt being a pharmaceutically acceptable non-toxic pharmaceutically acceptable salt, including salts formed with hydrochloric acid, sulfuric acid, salts formed with 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 formed with alanine, aspartic acid, lysine or salts formed with methanesulfonic acid, p-toluenesulfonic acid; or forms alkali metal salts, alkaline earth metal salts, silver salts, barium salts with alkaline substances.

4. A pharmaceutical composition comprising the inhibitor of the sodium glucosidic glucose transporter 2 of claim 1.

5. The pharmaceutical composition according to claim 4, wherein the active ingredient, the inhibitor of the sodium glucosyl group glucose transporter 2, is present in an amount of 0.1 to 99.9% by weight of the composition and the pharmaceutically acceptable carrier is present in an amount of 0.1 to 99.9% by weight of the composition.

6. The pharmaceutical composition according to claim 4, in a pharmaceutically acceptable formulation selected from the group consisting of tablets, capsules, powders.

7. The method for preparing the inhibitor of the glucose transporter 2 of the sodium carboglycoside according to claim 1, comprising the following steps:

5-bromo-2-chlorobenzoic acid is taken as a starting material, and is subjected to acylation, condensation and reduction reaction to obtain a compound 4, wherein after the ether methyl is removed from the compound 4 under the action of boron tribromide, the phenolic hydroxyl group is protected to obtain a compound 6, and the compound 6 and the compound 9 are subjected to condensation, etherification of the isocephalic hydroxyl group and demethoxy reaction to obtain a compound 10;

reaction of adamantane ethanol with p-toluenesulfonyl chloride to obtain compound 12 of corresponding alcohol, and reaction of compound 12 with compound 10 to obtain target compound

8. Use of the inhibitor of the carbon glycoside sodium glucose transporter 2 as defined in claim 1 for the preparation of a medicament for the treatment of type 2 diabetes.