CN110551088B

CN110551088B - Deuterium-modified benzyl-4-chlorophenyl C-glycoside derivatives

Info

Publication number: CN110551088B
Application number: CN201910460511.4A
Authority: CN
Inventors: 陈博
Original assignee: Jilin Huisheng Biopharmaceutical Co ltd; Beijing Huizhiheng Biological Technology Co Ltd
Current assignee: Jilin Huisheng Biopharmaceutical Co ltd; Beijing Huizhiheng Biological Technology Co Ltd
Priority date: 2018-06-01
Filing date: 2019-05-30
Publication date: 2022-10-21
Anticipated expiration: 2039-05-30
Also published as: CN110551088A

Abstract

The invention belongs to the technical field of medicines, and particularly relates to deuterium-modified benzyl-4-chlorophenyl C-glycoside derivatives or pharmaceutically acceptable salts thereof, a method for preparing the compounds, a pharmaceutical preparation and a pharmaceutical composition containing the compounds, and application of the deuterium-modified benzyl-4-chlorophenyl C-glycoside derivatives or pharmaceutically acceptable salts thereof as a sodium-glucose cotransporter (SGLT) inhibitor in preparation of medicines for treating and/or preventing various diabetes (including insulin-dependent diabetes and non-insulin-dependent diabetes) or various diabetes-related diseases (including insulin resistance diseases and obesity).

Description

Deuterium-modified benzyl-4-chlorophenyl C-glycoside derivatives

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to deuterium-modified benzyl-4-chlorophenyl C-glycoside derivatives or pharmaceutically acceptable salts thereof, a method for preparing the compounds, a pharmaceutical preparation and a pharmaceutical composition containing the compounds, and application of the deuterium-modified benzyl-4-chlorophenyl C-glycoside derivatives or pharmaceutically acceptable salts thereof serving as a sodium-glucose cotransporter (SGLT) inhibitor in preparation of medicines for treating and/or preventing various diabetes (including insulin-dependent diabetes and non-insulin-dependent diabetes) or various diabetes-related diseases (including insulin resistance diseases and obesity).

Background

Approximately 1 million people worldwide suffer from type II diabetes, which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance. Hyperglycemia is considered to be a major risk factor for developing diabetic complications and may be directly associated with impaired insulin secretion in late stage type II diabetes. Normalization of insulin can therefore be expected to improve blood glucose in type II diabetic patients. Most of the existing diabetes drugs are insulinotropic drugs or insulin sensitizers, such as sulfonylureas, glinides, thiazolidinediones, metformin and the like, and have potential side effects, such as easy weight gain, hypoglycemia, lactic acidosis and the like, so that the development of antidiabetic drugs with novel, safe and effective action mechanisms is urgently needed.

In the kidney, glucose can freely filter from the glomerulus (about 180 g/day), but is almost actively transported in the proximal convoluted tubule and reabsorbed. Two sodium-glucose transporters play an important role in reabsorption of glucose, namely SGLT-1 and SGLT-2, and the SGLT-2 plays an especially prominent role. SGLT-2 is a transmembrane protein specifically expressed only in the S1 segment of the proximal tubule, and one of its most important physiological effects is the absorption of sugars in the blood flowing through the renal tubules, accounting for 90% of the absorption, SGLT-2 is expressed as sodium-glucose 1:1, and the SGLT-2 inhibitor inhibits the absorption of blood glucose into the renal tubules and causes a large amount of sugar to be excreted from the urine. SGLT-1 is mainly expressed in the distal convoluted tubule and accounts for 10 percent of the weight of the absorption effect, and SGLT-1 is expressed by sodium-glucose 2: a ratio of 1. SGLT-1 is also found in the intestinal tract and other tissues. These transporters function via the Na +/ATPase pump and are transported back into the blood by glucose transporter 2 (GLUT 2). This suggests that the SGLT-2 transporter, which is most likely to develop as a target for drug action, is on the one hand its absolute reabsorption of glucose and on the other hand it is only expressed in the kidney. The feasibility of the pathway is also proved in the research of the urine glucose of the familial nephropathy. Familial nephropathy urinary glucose is predominantly expressed as variable amounts of urinary sugar (about 10-120 g/day), but patients are generally in good condition and no long term adverse health effects are found. This benign urinary glucose is mainly due to mutations in the SGLT-2 transporter gene, suggesting that selective pharmacological inhibition of SGLT-2 has no adverse consequences other than the induction of diabetes. Evidence has shown that an important clinical advantage of SGLT-2 inhibitors is that they are less likely to cause hypoglycemia. However, the SGLT-1 inhibitor causes sugar-galactose malabsorption syndrome which can cause dehydration, and evidence shows that the SGLT-1 inhibitor can delay the absorption of carbohydrate and can cause gastrointestinal symptoms which are difficult to be tolerated by an individual, and the selection of the SGLT-2 inhibitor with high content can not block the action of SGLT-1 in the intestinal tract for transporting and absorbing glucose, so the gastrointestinal symptoms are difficult to cause. SGLT-1 is also highly expressed in human myocardial tissues, and its blockade may cause new or organic lesions in cardiac function. Therefore, the development of a compound having high selectivity for SGLT-2 is of great significance for the research of drugs for treating diabetes.

Although a number of SGLT-2 inhibitors are known in the art, it remains challenging to develop SGLT-2 inhibitors with good properties and small side effects, and thus there remains a need in the art to develop compounds with high selectivity for SGLT-2 and with better pharmacodynamics or pharmacokinetics.

Disclosure of Invention

The technical scheme of the invention is as follows:

the technical scheme 1: a compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein,

R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ 、R ¹⁹ 、R ²⁰ 、R ²¹ 、R ²² 、R ²³ 、R ²⁴ 、R ²⁵ 、R ²⁶ 、R ²⁷ 、R ²⁸ 、R ²⁹ each independently selected from hydrogen or deuterium, and R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ 、R ¹⁹ 、R ²⁰ 、R ²¹ 、R ²² 、R ²³ 、R ²⁴ 、R ²⁵ 、R ²⁶ 、R ²⁷ 、R ²⁸ 、R ²⁹ At least one is a deuterium atom.

The technical scheme 2 is as follows: a compound according to claim 1, or a pharmaceutically acceptable salt thereof:

wherein,

R ⁵ 、R ⁶ 、R ⁷ 、R ²³ 、R ²⁴ 、R ²⁵ 、R ²⁶ 、R ²⁷ 、R ²⁸ 、R ²⁹ each independently selected from hydrogen;

R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ 、R ¹⁹ 、R ²⁰ 、R ²¹ 、R ²² each independently selected from hydrogen or deuterium, and R ¹ 、R ² 、R ³ 、R ⁴ At least one is a deuterium atom.

Technical scheme 3: a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, having the structure shown in formula (II):

technical scheme 4: a compound according to claim 3 or a pharmaceutically acceptable salt thereof,

wherein,

R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ 、R ¹⁹ 、R ²⁰ 、R ²¹ 、R ²² each independently selected from hydrogen;

R ¹ 、R ² 、R ³ 、R ⁴ each independently selected from hydrogen or deuterium, and R ¹ 、R ² 、R ³ 、R ⁴ At least one is a deuterium atom.

The technical scheme 5 is as follows: a compound according to claim 4 or a pharmaceutically acceptable salt thereof,

wherein,

R ¹ 、R ² 、R ³ 、R ⁴ each independently selected from hydrogen or deuterium, and R ¹ 、R ² 、R ³ 、R ⁴ At least two are deuterium atoms.

Technical scheme 5-1: a compound according to claim 5 or a pharmaceutically acceptable salt thereof,

wherein,

R ¹ 、R ² 、R ³ 、R ⁴ each independently selected from hydrogen or deuterium, and R ¹ 、R ² 、R ³ 、R ⁴ At least three are deuterium atoms.

The technical scheme 6 is as follows: the compound according to claim 5 or 5-1 or a pharmaceutically acceptable salt thereof,

wherein,

R ¹ 、R ² 、R ³ 、R ⁴ each independently selected from deuterium;

R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ 、R ¹⁹ 、R ²⁰ 、R ²¹ 、R ²² each independently selected from hydrogen.

The technical scheme 7 is as follows: the method for preparing the compound according to claim 6, comprising the steps of:

reacting a compound represented by the formula (II-1) with

Reacting to obtain a compound of formula (II-2), reacting the compound of formula (II-2) under the protection of nitrogen to generate the compound of formula (II), wherein X is selected from fluorine, chlorine, bromine or iodine, G represents a hydroxyl protecting group selected from trimethylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl or trimethylsilylethyl, preferably G is selected from trimethylsilyl,

the technical scheme 8 is as follows: an intermediate compound selected from the group consisting of,

the technical scheme 9: an intermediate compound selected from the group consisting of,

wherein X is selected from fluorine, chlorine, bromine or iodine.

Technical scheme 10: the compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein,

R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ 、R ¹⁹ 、R ²⁰ 、R ²¹ 、R ²² each independently selected from hydrogen;

R ¹² 、R ¹³ each independently selected from hydrogen or deuterium, and R ¹² 、R ¹³ At least one is a deuterium atom.

The technical scheme 11 is as follows: the compound of claim 10 or a pharmaceutically acceptable salt thereof,

wherein,

R ¹² 、R ¹³ each independently selected from deuterium atoms.

Technical scheme 12: a compound according to claim 3 or a pharmaceutically acceptable salt thereof,

wherein,

R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ each independently selected from hydrogen;

R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ 、R ¹⁹ 、R ²⁰ 、R ²¹ 、R ²² selected from hydrogen or deuterium, and R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ 、R ¹⁹ 、R ²⁰ 、R ²¹ 、R ²² At least one is a deuterium atom.

Technical scheme 13: the compound of claim 12, selected from the following compounds:

numbering

R ¹⁴

R ¹⁵

R ¹⁶

R ¹⁷

R ¹⁸

R ¹⁹

R ²⁰

R ²¹

R ²²

4-1

H

D

H

D

H

4-2

D

H

D

H

D

H

4-3

D

H

D

H

4-4

D

H

4-5

D

4-6

D

H

D

H

4-7

H

D

H

D

H

4-8

H

D

H

D

H

4-9

H

D

4-10

H

D

H

D

H

4-11

H

D

H

D

H

D

H

4-12

H

D

H

D

H

D

Technical solution 14: a compound according to claim 3 or a pharmaceutically acceptable salt thereof,

wherein,

R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ each independently selected from hydrogen;

R ¹² 、R ¹³ 、R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ 、R ¹⁹ 、R ²⁰ 、R ²¹ 、R ²² each independently selected from hydrogen or deuterium, and R ¹² 、R ¹³ 、R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ 、R ¹⁹ 、R ²⁰ 、R ²¹ 、R ²² At least one is a deuterium atom.

Technical solution 15: the compound of claim 14, selected from the following compounds:

numbering

R ¹²

R ¹³

R ¹⁴

R ¹⁵

R ¹⁶

R ¹⁷

R ¹⁸

R ¹⁹

R ²⁰

R ²¹

R ²²

5-1

D

H

D

H

D

H

5-2

D

H

D

5-3

D

H

D

H

5-4

D

H

D

H

D

H

5-5

D

H

D

H

D

H

Technical scheme 16: a compound selected from the group consisting of,

in the present invention, the first and second liquid crystal display panels,

the "pharmaceutically acceptable salt" includes alkali metal salts such as sodium salt, potassium salt, lithium salt and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts such as ammonium salts; organic base salts such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylamine salt, tris (hydroxymethyl) aminomethane salt, and the like; hydrohalic acid salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide and the like; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate and the like; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate and the like; aryl sulfonates such as benzenesulfonate, p-benzenesulfonate and the like; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.; amino acid salts such as glycinate, trimethylglycinate, arginate, ornithine, glutamate, aspartate and the like.

The invention also claims a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof and one or more pharmaceutical carriers and/or diluents, and the pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. Administered to a patient in need thereof by oral, parenteral, rectal or pulmonary administration, and the like. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository etc. For pulmonary administration, it can be made into inhalant or spray. Each unit preparation contains 0.005g to 10g of the compound represented by the formula (I), which may be 0.005g, 0.01g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 10g, etc., in a physiologically effective amount.

The invention further claims a pharmaceutical composition of the compound or the pharmaceutically acceptable salt thereof and other pharmaceutical active ingredients, wherein the other pharmaceutical active ingredients can be one or more hypoglycemic drugs, and the hypoglycemic drugs are selected from hypoglycemic drugs selected from sitagliptin phosphate, vildagliptin, saxagliptin, alogliptin benzoate, linagliptin, tigliptin, gimagliptin, metformin, phenformin, exenatide or liraglutide.

The invention also claims the application of the compound or the pharmaceutically acceptable salt thereof in preparing medicines for treating and/or preventing various diabetes or diabetes-related diseases. The diabetes includes insulin-dependent diabetes (type I diabetes) and non-insulin-dependent diabetes (type II diabetes), and the diabetes-related diseases include insulin-resistant diseases, obesity, and the like.

The present invention further claims a method for the treatment and/or prophylaxis of various diabetes mellitus (including insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus) or various diabetes-related diseases (including insulin-resistant diseases and obesity), which comprises administering an effective dose of the compound of the present invention or a pharmaceutically acceptable salt thereof to a mammal including a human in need thereof.

The compound of the invention has the following characteristics:

(1) The compounds of the present invention have high selectivity for SGLT-2, and can be safely used for the treatment and/or prevention of diabetes mellitus in various mammals (including human beings) and various diseases caused by diabetes mellitus.

(2) The compound has high-efficiency inhibition effect on SGLT-2, obvious blood sugar reducing effect, quick response, small toxic and side effect and high safety.

(3) The compounds of the invention have good pharmacokinetic properties.

(4) The compound of the invention has good physicochemical properties, high purity, good stability and easily controlled quality, and is suitable for large-scale industrial production.

Detailed Description

Example 1 (2S, 3R,4R,5S, 6R) -2- (3- (4- (((1R, 3s, 5S) -bicyclo [ 3.1.0)]Hexane-3-yl) oxy) benzyl-2, 3,5,6-d ₄ ) Preparation of (E) -4-chlorophenyl) -6- (hydroxymethyl) -tetrahydro-2H-pyran-3, 4, 5-triol (Compound 1-1)

(1) 2,3,4,5,6-d anisole ₅ Preparation of

Reacting phenol-d ₆ (5.0 g, 0.05mmol) was added to 60mL of tetrahydrofuran, cooled to 0 deg.C, and NaH (60%, 2.4g, 0) was added06 mol), heating to 25 ℃, stirring for 1.0 hour, cooling to 0 ℃, adding methyl iodide, heating to 25 ℃, reacting for 4.0 hours, cooling to 0 ℃, adding 1mL of water, quenching, reacting, concentrating, adding 150mL of saturated sodium bicarbonate water solution and 150mL of ethyl acetate respectively, layering to obtain an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to obtain 5.2g of a product, and obtaining a yield of 91.9%.

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

5-bromo-2-chlorobenzoic acid (10.3 g,43.7 mmol) was added to DCM (100 mL), cooled to 0 deg.C, DMF (0.2 mL) was added and oxalyl chloride (16.6 g,0.13 mol) was slowly added dropwise, after completion of the addition, the temperature was raised to 25 deg.C for reaction for 3.0 hours, and the reaction solution was clarified and transferred to a constant pressure dropping funnel for the next reaction.

(3) (5-bromo-2-chlorophenyl) (4-methoxyphenyl-2, 3,5,6-d ₄ ) Preparation of ketones

Adding aluminum trichloride (6.12g, 45.9mmol) into 100mL dichloromethane, cooling to-5 ℃, adding anisole-2, 3,4,5,6-D ₅ (5.2 g,45.9 mmol), stirring for 0.5 hour, dropwise adding the dichloromethane solution in the previous step into the reaction solution, reacting at-5 ℃ for 3.0 hours, pouring 2mol/L hydrochloric acid (30 mL) after the reaction is finished, separating to obtain a dichloromethane phase, washing an organic phase by a saturated sodium bicarbonate aqueous solution, washing by a sodium chloride aqueous solution, drying by anhydrous sodium sulfate, filtering, concentrating the filtrate, and performing silica gel column chromatography (PE/EA = 50) to obtain 8.6g of a product, wherein the yield of the two steps is 59.7%.

(4) 1- (5-bromo-2-chlorobenzyl) -4-methoxybenzene-2, 3,5,6-d ₄ Preparation of

Reacting (5-bromo-2-chlorophenyl) (4-methoxyphenyl-2, 3,5, 6-d) ₄ ) Methanone (8.6g, 26.1mmol) was added to a mixed solvent of 50mL of dichloromethane and 100mL of acetonitrile, and triethylsilane (6.07g, 52.2mmol) was added thereto. The temperature is reduced to 0 ℃ under the protection of nitrogen, boron trifluoride ethyl ether (7.41g, 52.2mmol) is added dropwise, and the temperature is increased to 25 ℃ after the dropwise addition, so that the reaction lasts for 2.0 hours. After the reaction is finished, dichloromethane (200 mL) and saturated aqueous sodium bicarbonate (100 mL) are added, stirring is carried out for 0.5 hour, an organic phase is obtained by layering, the organic phase is washed twice by the saturated aqueous sodium bicarbonate, washed once by the saturated aqueous sodium chloride, dried by anhydrous sodium sulfate, filtered, concentrated by the filtrate, added with ethanol (100 mL), stirred at 25 ℃ for 0.5 hour, then stirred at ice bath to 0 ℃ for 0.5 hour, a large amount of solid is separated out, filtered, and dried by a filter cake to obtain 8.0g of a product with the yield of 97.1 percent.

(5) 4- (5-bromo-2-chlorobenzyl) benzene-2, 3,5,6-d ₄ Preparation of alcohols

1- (5-bromo-2-chlorobenzyl) -4-methoxybenzene-2, 3,5,6-d ₄ (8.0 g,25.3 mmol) is dissolved in 100mL of dichloromethane, the temperature is reduced to-78 ℃, 1M of boron tribromide dichloromethane solution (50.6 mL,50.6 mmol) is slowly dripped, the temperature is raised to 25 ℃ after the dripping is finished, the reaction is carried out for 2.0 hours, after the reaction is finished, 2mL of water is slowly dripped in an ice water bath to quench the reaction, 30mL of water is added again, an organic phase is obtained by layering, the organic phase is washed once by saturated sodium chloride aqueous solution, anhydrous sodium sulfate is dried and filtered, and the filtrate is concentrated to obtain 7.1g of a product, wherein the yield is 93.0%.

(6) (1R, 3s, 5S) -3- (4- (5-bromo-2-chlorobenzyl) phenoxy-2, 3,5,6-d ₄ ) Bicyclo [3.1.0]Preparation of hexane

4- (5-bromo-2-chlorobenzyl) benzene-2, 3,5,6-d ₄ Alcohol (7.1g, 23.5mmol) and (1R, 3r, 5S) -bicyclo [3.1.0]Hex-3-ylmethanesulfonate (8.3g, 47.1mmol) was added to 100mL of NMP, and cesium carbonate (15.3g, 47.0mmol) andbenzyl triethyl ammonium chloride (182mg, 0.80mmol), heating to 50 ℃ for reaction for 18 hours, adding water (200 mL), cooling to 0 ℃, filtering, washing filter cake with water, and drying to obtain 8.1g of product, yield: 90.3 percent.

(7) (3R, 4S,5S, 6R) -2- (3- (4- (((1R, 3s, 5S) -bicyclo [ 3.1.0)]Hexane-3-yl) oxy) benzyl-2, 3,5,6-d ₄ ) Preparation of (E) -4-chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol

Under the protection of nitrogen, (1R, 3s, 5S) -3- (4- (5-bromo-2-chlorobenzyl) phenoxy-2, 3,5,6-d ₄ ) Bicyclo [3.1.0]Hexane (3.8g, 10.0mmol) was added to a mixed solvent of toluene (60 mL) and tetrahydrofuran (60 mL), the temperature was reduced to-78 ℃, n-butyllithium (2.4M, 5.4mL, 13.0mmol) was added dropwise, after completion of the addition, reaction was carried out at-78 ℃ for 2.0 hours, which was extracted into toluene (60 mL) of (3R, 4S,5R, 6R) -3,4, 5-tris ((trimethylsilyl) oxy) -6- (((trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-one (6.06g, 13.0mmol), reacted at-78 ℃ for 1.0 hour, added to a solution of methanesulfonic acid (5.76g, 60.0mmol) in methanol (90 mL), reacted at-78 ℃ for 1.0 hour, heated to 25 ℃ for 24 hours, added to a saturated aqueous solution of sodium bicarbonate (50 mL) and quenched, dichloromethane (100 mL) was extracted, the organic phase was washed with a saturated aqueous sodium sulfate solution, washed without water, filtered, dried, and the yield was 4.4 g, dried: 82.8 percent.

(8) (2S, 3R,4R,5S, 6R) -2- (3- (4- (((1R, 3s, 5S) -bicyclo [ 3.1.0)]Hexane-3-yl) oxy) benzyl-2, 3,5,6-d ₄ ) Preparation of (E) -4-chlorophenyl) -6- (hydroxymethyl) -tetrahydro-2H-pyran-3, 4, 5-triol

Under the protection of nitrogen, (3R, 4S,5S, 6R) -2- (3- (4- (((1R, 3s, 5S) -bicyclo [ 3.1.0)]Hexane-3-yl) oxy) benzyl-2, 3,5,6-d ₄ ) -4-chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3, 4, 5-triol (2.3g, 4.65mmol) dissolved in bis (hydroxymethyl) phosphonium chlorideMethyl chloride (50 mL), cooled to-78 ℃, triethylsilane (2.05g, 17.63mmol) and boron trifluoride diethyl etherate (2.04g, 14.4 mmol) were added dropwise, and after completion of the addition, the temperature was slowly raised to 20 ℃ to react for 1.0 hour, after the completion of the reaction, a saturated aqueous sodium bicarbonate solution (100 mL) was added dropwise, followed by extraction with dichloromethane (100 mL), and the layers were separated to obtain an organic phase, followed by saturated sodium chloride water washing, anhydrous sodium sulfate drying, silica gel column chromatography (PE: EA =1 after DCM/MeOH = 15). The molecular formula is as follows: c ₂₅ H ₂₅ ClD ₄ O ₆ Molecular weight: 465.0

¹ H-NMR(400MHz,MeOD)δ:7.34-7.27-(m,3H),4.46-4.42(m,1H),4.11-4.07(m,1H),4.03-4.01(m,2H),3.90-3.87(m,1H),3.72-3.68(m,1H),3.46-3.39(m,3H),3.30-3.27(m,1H),2.35-2.30(m,2H),1.88-1.82(m,2H),1.38-1.31(m,2H),0.45-0.43(m,1H),0.12-0.09(m,1H)。

With the preparation method of reference example 1-1, using appropriate starting materials and intermediates, the following compounds were prepared.

Experimental example 1 in vitro pharmacological Activity of the Compound of the present invention

In vitro evaluation experiment

The in vitro evaluation method of the invention is to transfect the human SGLT1 or SGLT2 sequence onto Chinese hamster ovary cells for stable expression, and to inhibit the cell pair [ ¹⁴ C-sodium-dependent absorption of the marker-R-methyl-D-glucopyranoside (AMG), determination of the semi-inhibitory concentration IC ₅₀ 。

And (3) testing the sample: the compound of the invention is prepared by self, and the chemical name and the structural formula are as described in the specification.

Cell: CHO cell reagents derived from highly expressed Human-SGLT1 protein (hSGLT 1, gene bank: NM-000343):

NaCl(Fluka,Cat#71383)

CaCl ₂ (Sigma,Cat#5080)

KCl(Sigma,Cat#P9333)

MgCl ₂ (Sigma,Cat#M1028)

NaOH(Aldrich,Cat#221465)

Hepes(Invitrogen,Cat#15630130)

ultima Gold Cocktail scintillation fluid (Perkin Elmer, cat # 6013329)

[ ¹⁴ C]-Methylα-D-glucopyranoside(PerkinElmer,Cat#NEC659250UC)

Instruments and consumables:

96 well cell culture plate (Greiner, cat # 655098)

Scintillation tube (Perkin Elmer, cat # 6000192)

Liquid scintillation counter (PerkinElmer, tricarb)

Method and procedure for the Human-SGLT1 transport assay:

Human-SGLT1 cells at 8X 10 ⁴ Perwell addition to Cytostar-T96 well cell plates, 37 ℃,5% CO ₂ The culture was carried out overnight. The next day, samples were diluted with DMSO, all starting at 10mM (final 100 μ M) and 10 points diluted in 5-fold serial gradients. Using assay buffer (10mM hepes,1.2mM MgCl) ₂ ,4.7mM KCl,2.2mM CaCl ₂ 120mM NaCl [ will ] ¹⁴ C]Methyl α -D-glucopyranoside was diluted to 3 μ M. The cell plate was removed from the incubator and the cells were rinsed once with assay buffer. According to the layout of a 96-well plate, 49 mu L of experiment buffer solution is added into each well, and 1 mu L of compound solution with different concentrations is added; mu.L DMSO was added to the High signal control well (High control) and 1. Mu.L Dapaglifozin was added to the Low signal control well (Low control) to a final concentration of 100. Mu.M. Adding 50 μ L of 3 μ M [ mu ] M ] ¹⁴ C]Isotope to 96-well plate. Incubate at 37 ℃ for 2 hours. After the incubation was completed, detection was carried out by Microbeta Trilux using scintillation counting method [14C]Radioactivity of AMG, calculation of the semi-inhibitory concentration IC ₅₀ . Methods and steps for the Human-SGLT2 transport assay: human-SGLT2 cells at 6X 10 ⁴ Perwell addition to 96 well cell plates, 37 ℃,5% CO ₂ The culture was carried out overnight. The next day samples were diluted with DMSO, referenceThe initial concentration of the sample Dapaglifozin is 100 mu M (the final concentration is 1 mu M), and 10 points are diluted by 5 times of continuous gradient; compound 1-1 was initially at 2mM (20. Mu.M final concentration) and diluted in 10 spots in a 5-fold serial gradient. Using assay buffer (10mM hepes,1.2mM MgCl) ₂ ,4.7mM KCl,2.2mM CaCl ₂ 120mM NaCl [ will ] ¹⁴ C]Methyl α -glucopyranoside was diluted to 6 μ M. The cell plate was removed from the incubator and the cells were rinsed once with assay buffer. According to the layout of a 96-well plate, 49 mu L of experiment buffer solution is added into each well, and 1 mu L of compound solution with different concentrations is added; mu.L of DMSO was added to the High signal control well (High control) and 1. Mu.L of Dapaglifofozin was added to the Low signal control well (Low control) at a final concentration of 1. Mu.M. Adding 50 μ L of 6 μ M [ mu ] M ] ¹⁴ C]Isotope to 96-well plate. Incubate at 37 ℃ for 1 hour. After incubation, the wells were aspirated and washed with pre-chilled stop buffer (10mM hepes,1.2mM MgCl. RTM ₂ ,4.7mM KCl,2.2mM CaCl ₂ 120mM NaCl, 1. Mu.M Dapaglifozin) washed the cells 3 times. Cells were lysed with 10% NaOH solution. The cell lysate was pipetted into a scintillation vial, 2mL of scintillation fluid was added and read with Tricarb.

Experimental results and conclusions:

table 1 evaluation results of the inhibitory effect of the compounds of the present invention are as follows:

therefore, the compound has better inhibition effect and selectivity on SGLT 2.

Experimental example 2 Normal mouse urine glucose test of the Compound of the present invention

The test method comprises the following steps:

24 male SPF grade Sprague-Dawley rats, 6-8 weeks old, were randomly grouped by body weight, 8 per group, and 3mg/kg of compound 1-1 was orally administered, respectively, to a blank control group, which was orally administered with an equal volume of vehicle (0.1% SDS +0.5% MC), placed in a rat metabolic cage after administration, urine was collected 0-5h and 5-24h after administration, respectively, urine volume was recorded and urine glucose concentration was measured, and urine glucose content was calculated as follows.

The calculation method comprises the following steps:

urine sugar content UGE (mg/piece) = urine sugar concentration (mmol/L) × urine volume (L) × 180

The data are expressed by mean value plus or minus standard error, statistical analysis is carried out on the data by Student-t test, and the statistical difference is that p is less than 0.05.

And (3) test results:

TABLE 2 Effect of Compounds 1-1 on urine glucose concentration in SD rats after a single administration

Note: * p <0.05, p <0.001 compared to the blank control group.

TABLE 3 Effect of a Single administration of Compound 1-1 on urine volume in Normal SD rats

Note: * p <0.05, compared to the blank control group.

TABLE 4 Effect of Compound 1-1 on urine glucose levels in SD rats at various time periods after a single administration

Note: * p <0.05, p <0.001, compared to the blank control group.

And (4) test conclusion:

the compound of the invention shows better hypoglycemic effect. Has better pharmacokinetic property and better hypoglycemic effect, can reduce side effect, increase the stability of the medicine, enhance the curative effect and prolong the half-life period.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, selected from:

。

2. a process for the preparation of a compound according to claim 1, comprising the steps of:

reacting a compound represented by the formula (II-1) with

Reacting to obtain a compound of formula (II-2), and reacting the compound of formula (II-2) under the protection of nitrogen to obtain the compound of claim 1,

x is selected from fluorine, chlorine, bromine or iodine,

g represents a hydroxyl protecting group selected from trimethylsilyl, triethylsilyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl or trimethylsilylethyl,

。

3. the method of claim 2, wherein G is selected from the group consisting of trimethylsilyl.

4. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, optionally further comprising one or more pharmaceutically acceptable carriers.

5. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof as a sodium-glucose cotransporter inhibitor for the manufacture of a medicament for the treatment and/or prevention of diabetes or diabetes-related diseases;

the diabetes is selected from insulin-dependent diabetes and non-insulin-dependent diabetes, and the diabetes-related disease is selected from insulin-resistant disease and obesity.