WO2011095050A1

WO2011095050A1 - C-glycoside derivatives containing saturated 6-member rings, preparation methods and uses thereof

Info

Publication number: WO2011095050A1
Application number: PCT/CN2011/000147
Authority: WO
Inventors: 赵桂龙; 邵华; 刘巍; 王玉丽; 汤立达; 徐为人; 龚珉; 谭初兵; 张士俊; 刘冰妮
Original assignee: 天津药物研究院
Priority date: 2010-02-05
Filing date: 2011-01-28
Publication date: 2011-08-11
Also published as: CN102146066A

Abstract

Disclosed are C-glycoside sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors containing saturated 6-member rings shown as following general formula I, preparation methods, compositions containing such compounds and uses thereof in the manufacture of diabetes drugs, in which X and Y are selected from: (1) X=Y=C atom; (2) X=Y=N atom; (3) X=N atom, Y=O atom; (4) X=N atom, Y=C atom, and the definitions of other groups are as those defined in the description.

Description

C-glucoside derivative containing saturated six-membered ring, preparation method and use thereof

The present invention relates to the field of medicines associated with diabetes. In particular, the present invention relates to a type 2 glucosinolate co-transporter (SGLT2) inhibitor containing a saturated six-membered ring C-glucoside structure which has a therapeutic effect on diabetes, a preparation method thereof, and a pharmaceutical composition containing the same. Background technique

There are currently about 170 million people with diabetes worldwide, and most of them are type II (ie, non-insulin dependent) diabetic patients. The antidiabetic drugs currently in clinical use are mainly metformin, sulfonylureas, insulins, thiazolidinediones, (X-glucosidase inhibitors and dipeptidyl peptidase-IV inhibitors, these The drug has a good therapeutic effect, but there are safety problems in long-term treatment, such as: liver toxicity, some drugs still have weight gain and many other problems.

Type 2 glucosamine co-transporter (SGLT2) is a new target for the treatment of diabetes found in recent years. SGLT2 is mainly distributed in the proximal tubules of the kidney. Its function is to absorb the glucose in the urine and return it to the blood. Therefore, inhibition of SGLT2 can reduce the blood glucose concentration. This method reduces blood sugar through different and previous ways. Level. When SGLT2 is blocked, more glucose will be secreted in the urine, which will help diabetics maintain the correct blood sugar levels. Since SGLT2 inhibitors are not involved in glucose metabolism, they can be used as a supplement to mainstream blood glucose control methods.

Chinese patent application CN 200610093189.9 discloses compounds of the following structure as SGLT2 inhibitors:

Where A is 0, S, NH, (CH ₂ ) _n and n = 0-3. Inhibitor:

Wherein A is a covalent bond, 0, S, NH, (CH ₂ ) _n , n = l-3. Inhibitor:, ^S ',

Wherein x is a covalent bond or a lower order fluorenylene group.

WO 2005/012326 GLT2 inhibitor:

Summary of invention

An object of the present invention is to overcome the shortcomings and deficiencies of the prior art and to provide a SGLT2 inhibitor having good activity, which is a saturated six-membered ring-containing C-glucoside having the structure of Formula I and a pharmaceutical thereof Acceptable salts and prodrug esters.

Another object of the present invention is to provide a process for the preparation of a saturated six-membered ring-containing C-glucoside having the structure of the formula I of the present invention.

A further object of the present invention is to provide a compound of formula I, and pharmaceutically acceptable salts and prodrugs thereof, as active ingredient, together with one or more pharmaceutically acceptable carriers, excipients and/or diluents Pharmaceutical composition, and its use in inhibiting type 2 glucosamine co-transporters, For example, in the treatment of diabetes.

The C-glucoside derivatives containing a saturated six-membered ring provided by the present invention are novel SGLT2 inhibitors, and these inhibitors lay the foundation for the preparation of a medicament which can be further used for the treatment of diabetes, particularly non-insulin dependent diabetes.

The present invention will now be described in detail with reference to the purpose of the invention.

The present invention provides a compound of the I structure:

among them,

R ^{1 is} selected from the group consisting of H, F, Br, I, OR ³ , SR ⁴ , OCF ₃ , CF ₃ , CHF ₂ , CH ₂ F, a decyl group of dC ₃ , a cyclodecyl group having 3 to 5 carbon atoms, wherein R ³ and R ^{4 are} independently selected from the indenyl group of C _r C ₃ , which is optionally substituted by one or more atoms selected from the group consisting of F and C 1 ;

R ^{2 is} selected from the group consisting of H and C _r C ₅ ;

The definitions of X and Y are selected from the following cases:

(1) X = Y = carbon atom;

(2) Χ = Υ = nitrogen atom;

(3) Χ = nitrogen atom, Υ = oxygen atom;

(4) Χ = nitrogen atom, Υ = carbon atom. Preferred compounds having the structure of formula I are:

among them,

R ^{1 is} selected from the group consisting of H, F, OMe, SMe, OCF ₃ , CF ₃ , CHF ₂ , CH ₂ F, CH ₃ , a cyclodecyl group having 3 to 5 carbon atoms, optionally having a fluorenyl group and a cyclodecyl group. The ground is replaced by one or more atoms selected from F and C1;

R ^{2 is} selected from the group consisting of H and (^-(3⁄4);

The definitions of X and Y are selected from the following cases:

(1) X = Y = carbon atom; (2) X = Y = nitrogen atom;

(3) Χ = nitrogen atom, Υ = oxygen atom;

(4) Χ = nitrogen atom, Υ = carbon atom. The most preferred compounds of formula I have the following structure:

The compounds of formula I according to the invention can be synthesized by the following steps:

Wherein, the base A may be selected from the group consisting of N-methylmorpholine, triethylamine, pyridine and 4-dimethylaminopyridine, and the base B may be selected from the group consisting of anhydrous sodium acetate, pyridine and 4-dimethylaminopyridine. The base C may be selected from the group consisting of sodium methoxide, NaOH and KOH.

In the above synthetic step, the trimethylsilylating agent may be trimethylsilyl silane; the fluorenyl lithium reagent may be n-butyllithium; the acid may be selected from methanesulfonic acid, trifluoromethyl Sulfonic acid and p-toluenesulfonic acid; the Lewis acid may be selected from the group consisting of BF ₃ .Et ₂ 0, BF ₃ .MeCN and trifluoroacetic acid; the reducing agent may be selected from the group consisting of triethylsilyl and triisopropylsilyl The acetylating agent may be selected from the group consisting of acetic anhydride and acetyl chloride.

Compound II is treated with a trimethylsilylating agent in the presence of a base A to obtain a compound III, and a base A such as N-methylmorpholine, triethylamine, pyridine, 4-dimethylaminopyridine or the like; A methylsilylation reagent such as trimethylsilyl silane or the like. Compound IV is treated with a mercaptolithium reagent such as n-butyllithium to give compound V. Compound V is directly reacted with compound III in the reaction system without isolation to give compound VI. Compound VI is treated with methanol under the catalysis of an acid such as methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid to obtain a compound.

VII. Compound VII is reduced with a reducing agent such as triethylsilyl, triisopropylsilyl or the like in the presence of a Lewis acid such as BF ₃ .Et ₂ 0, BF ₃ .MeCN or trifluoroacetic acid to give compound VIII. Compound VIII is acetylated with a reagent such as acetic anhydride or acetyl chloride in the presence of a base such as anhydrous sodium acetate, pyridine or 4-dimethylaminopyridine to give IX. Compound IX is treated by column chromatography or recrystallization to give compound X. Compound X is treated with a base such as sodium methoxide, NaOH, KOH, etc., and the acetyl group is removed to obtain a compound.

More specifically, the compound of the formula I of the present invention is synthesized by the following steps:

Compound IV can be prepared by the following method depending on the difference between X and Y.

(1) Χ = Υ = carbon atoms,

At this time, compound IV is IV-1:

IV-1 Compound IV-1 can be synthesized by the following route:

XV Compound XI is reacted with Mg to give compound XII wherein Hal is selected from the group consisting of Cl, Br and I. Compound XII is reacted with compound XIII to give compound XIV. Compound XIV is treated with a halogenating agent such as PBr ₃ , P0C1 ₃ or the like to give compound XV wherein Hal is selected from the group consisting of Cl, Br and I. Compound XV is reduced with a reducing agent A such as LiAlH ₄ or the like to give compound IV-1. Alternatively, the reducing agent for compound XIV

B, such as triethylsilylphosphonium, triisopropylsilyl, or the like, is reduced in the presence of an acid such as boron trifluoride diethyl ether or trifluoroacetic acid to obtain a compound IV-1.

(2) X = Y = nitrogen atom,

At this time, compound IV is IV-2:

Compound IV-2 can be synthesized by the following route:

XVI XVII IV-2 Compound XVI is reacted with compound XVII to give compound IV-2, wherein Hal is selected from Cl, Br

I

(3) X = nitrogen atom, Y = oxygen atom,

At this point compound IV is IV-3:

IV-3

Compound IV-3 can be synthesized using the following route:

XVI XVIII IV-3

Compound XVI is reacted with compound XVIII to give compound IV-3, wherein Hal is selected from Cl,

Br and I.

(4) X = nitrogen atom, Y = carbon atom,

At this time, compound IV is IV-4:

IV-3

Compound IV-4 can be synthesized by the following route

XVI XIX IV-4 Compound XVI is reacted with compound XIV to give compound IV-4, wherein Hal is selected from Cl, Br And I.

A pharmaceutically acceptable prodrug ester of a compound of formula I according to the invention, comprising any one or more of the hydroxyl groups in the molecule formed with an acetyl group, a pivaloyl group, various phosphoryl groups, carbamoyl groups, fluorenyl groups, and the like. Ester.

The compounds of formula I according to the invention may be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical composition. The pharmaceutical composition can be formulated into a solid oral preparation, a liquid oral preparation, an injection or the like. The solid and liquid oral preparations include: tablets, dispersible tablets, dragees, granules, dry powders, capsules, and solutions. The injection includes: a small needle, a large infusion, a lyophilized powder, and the like.

In the composition of the present invention, the pharmaceutically or foodly acceptable adjuvant is selected from the group consisting of: a filler, a disintegrant, a lubricant, a glidant, an effervescent agent, a flavoring agent, a preservative, a coating material, or Other excipients.

A composition of the invention, said pharmaceutically or foodly acceptable adjuvant. The filler is a filler comprising one or more of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, microcrystalline cellulose; The binder comprises sucrose, starch, povidone, sodium carboxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, polyethylene glycol, medicinal ethanol, water. Or a combination of several; the disintegrant comprises starch, cross-linked poly-microketone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethylcellulose, effervescent disintegration One or several compositions of the agents.

The compound of the formula I of the present invention has an inhibitory action on the SGLT2 enzyme and can be used as an active ingredient for the preparation of a therapeutic drug for diabetes. The activity of the compounds of formula I according to the invention is verified by an in vivo hypoglycemic model.

The compounds of formula I of the present invention are effective over a relatively wide dosage range. For example, the daily dose is about 1 mg-1000 mg/person, divided into one or several doses. The dosage of the compound of formula I of the present invention may be determined by the physician in light of the circumstances. These conditions include: the physical condition of the subject, the route of administration, age, weight, individual response to the drug, severity of symptoms, and the like.

The best way to implement the invention

The present invention will be further described below in conjunction with the embodiments. It should be noted that the following examples are for illustrative purposes only and are not intended to limit the invention. Those skilled in the art in accordance with the teachings of the present invention All changes made should be within the scope of protection required by the claims of the present application.

[3-(cyclohexylmethyl)-4- -1-deoxy-P-D-glucopyran;

A. 1-bromo-3-(cyclohexylmethyl)-4-fluorobenzene

2.03 g of 5-bromo-2-fluorobenzaldehyde and 10 mL of anhydrous tetrahydrofuran were added to a 100 mL round bottom flask. The solution was stirred and cooled with ice water, and 11 mL (1.0 mL) was added dropwise with a constant pressure dropping funnel. M) A solution of cyclohexylmagnesium bromide in THF. After the dropwise addition, the reaction mixture was stirred at room temperature for one hour, then poured into 200 mL of ice water and adjusted to pH 3-4 with concentrated hydrochloric acid. The obtained acidic system was extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine, dried over anhydrous sodium sulfate, and evaporated on a rotary evaporator to give a colorless oil (5- Bromo-2-fluorophenyl) (cyclohexyl)methanol. ESI-MS, m/z = 287.2 ([M ( ⁷⁹ Br) + 1]), 289.2 ([M ( ⁸¹ Br) + l]).

2.58 g of the above-obtained (5-bromo-2-fluorophenyl)(cyclohexyl)methanol oil was dissolved in 3 mL of dry dichloromethane, and the mixture was stirred under ice cooling, followed by the addition of triethylsilyl ruthenium 2 mL. And 1 mL of boron trifluoride etherate. The resulting reaction system was stirred at room temperature overnight, carefully poured into 100 mL of ice water, adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine. Drying in anhydrous sodium sulfate, evaporation to dryness on a rotary evaporator to give a colorless oil, 1-bromo-3-(cyclohexylmethyl)-4-fluorobenzene, ESI-MS, m/z = 271.1 ([M( ⁷⁹ Br)+l]), 273.2 ([M( ⁸¹ Br)+l])„

B. 2,3,4,6-tetra-O-trimethylsilyl gluconolactone

A 250 mL round bottom flask was charged with 1.78 g of gluconolactone, 8.09 g of N-methylmorpholine and 20 mL of dry tetrahydrofuran. The system was stirred under ice cooling, and 6.52 g of the top three was slowly added dropwise. A solution obtained by dissolving chlorosilane in 10 mL of dry THF. After the completion of the dropwise addition, the system was stirred at room temperature overnight, diluted with 100 mL of toluene, and 10 mL of water was slowly added dropwise thereto while cooling with ice water, and then the resulting mixture was transferred to a separatory funnel, followed by 100 mL of saturated phosphoric acid. The sodium hydride solution and the saturated brine were washed, dried over anhydrous sodium sulfate, and evaporated to dryness on a rotary evaporator to obtain a colorless oil of 2,3,4,6-tetra-[-trimethylsilyl gluconic acid. Lactone, on a vacuum pump at room temperature Dry for two hours, spare.

C. 1-[3-(cyclohexylmethyl)-4-fluorophenyl]-1-deoxy-β-D-glucopyranose

A 100 mL round bottom flask was charged with 2.22 g of 1-bromo-3-(cyclohexylmethyl)-4-fluorobenzene prepared above, 10 mL of dry tetrahydrofuran and a magnet, and then sealed with a thin rubber stopper. It was cooled to -78 ° C in an acetone-dry ice system. Under stirring, slowly add 8 mL (1.0 M) of n-BuLi hexamethylene solution to the reaction vessel with a syringe. After the addition, the system was stirred at -78 ° C for an additional hour, and then transferred to the reaction vessel with a syringe. A solution of the above prepared 2,3,4,6-tetra-O-trimethylsilylgluconolactone dissolved in 10 mL of dry toluene was slowly added. After the addition, the system was further stirred for one hour, and then a solution of 1.92 g of methanesulfonic acid dissolved in 10 mL of anhydrous methanol was added by a syringe, and then the system was slowly warmed to room temperature and stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous solution of sodium chloride, and extracted twice with 100 mL of dichloromethane. The combined extracts were washed once with brine, dried over anhydrous sodium sulfate and evaporated to dryness , that is, 1-[3-(cyclohexylmethyl)-4-fluorophenyl]-a/pD-methylpyranoside, ESI-MS, m/z = 385.3 ([M+l]).

The above-obtained 1-[3-(cyclohexylmethyl)-4-fluorophenyl]-α/β-ϋ-methylpyranoside oil 2.08 g was dissolved in 3 mL of dry dichloromethane, ice The water was stirred under cooling, and then 2 mL of triethylsilane and 1 mL of boron trifluoride diethyl ether were successively added. The resulting reaction system was stirred at room temperature overnight, carefully poured into 100 mL of ice water, adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine. Drying in anhydrous sodium sulfate, evaporation to dryness on a rotary evaporator to give a colorless oil, 1-[3-(cyclohexylmethyl)-4-fluorophenyl]-a/pD-glucopyranose , ESI-MS, m/z = 355.1 ([M+l])„

1.78 g of the 1-[3-(cyclohexylmethyl)-4-fluorophenyl]-a/pD-glucopyranose colorless oil obtained above was dissolved in 20 mL of acetic anhydride, and 0.5 g of anhydrous sodium acetate was added. , Electromagnetic stirring was heated and refluxed for 1 hour. After cooling, the system was poured into 100 mL of water, stirred at room temperature overnight, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine, dried over anhydrous sodium sulfate, and evaporated on a rotary evaporator. An off-white solid was obtained, which was purified by silica gel column chromatography to afford crystals of crystals of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of of ]-1-deoxy-β-D-glucopyranose, ESI-MS, m/z = 523.2 ([M+l]) „

The above 2,3,4,6-tetra-O-acetyl-1-[3-(cyclohexylmethyl)-4-fluorophenyl]-1-deoxy-β-D-glucopyranose 1.98 g was dissolved in The mixture was stirred at room temperature for 5 hours in 7 mL of anhydrous methanol containing 0.11 g of sodium methoxide, and then lg dried strong acid cation exchange resin was added thereto, and stirred at room temperature overnight. Filter The resin was removed and the filtrate obtained was evaporated to dryness on a rotary evaporator to give a white solid: 1-[3-(cyclohexylmethyl)-4-fluorophenyl]-1-deoxy-β-D-glucopyranose , ESI-MS, m/z = 355.2 ([M+l]). Example 2-12

It will be appreciated that using the method and scheme of Example 1, the RR ² can be varied to provide the compounds listed in the table below.

Example 13

L-{3-[(4-ethylpiperazin-1-yl)-4-fluoro-phenyl}-1-deoxy-P-D-glucopyranose

A. ^bromo-2 - ^{[(4-ethyl-piperazin-1-yl)} methyl] Small-fluorophenyl

A 100 mL round bottom flask was charged with 2.84 g of 5-bromo-2-fluorobenzyl bromide, 1.14 g of 1-ethylpiperazine, 1.01 g of triethylamine and 20 mL of anhydrous tetrahydrofuran. After stirring overnight, the mixture was poured into 200 mL of water, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness Is 4-bromo-2-[(4-ethylpiperazin-1-yl)methyl]-1-fluorobenzene. ESI-MS, m/z = 301.2 ([M ( ⁷⁹ Br) + 1]), 303.1 ([M ( ⁸¹ Br) + l]).

B. l-{3-[(4-Ethylpiperazin-1-yl)methyl]-4-fluorophenyl}small deoxy-β-D-glucopyranose was added to a 100 mL round bottom flask 2.56 ₈ 4-bromo-2-[(4-ethylpiperazine) prepared above 1-yl)methyl]-1-fluorobenzene, 10 mL of dry tetrahydrofuran and a magnet, then sealed with a thin rubber stopper and placed in an acetone-dry ice system to cool to -78 °C. While stirring, 10 mL (1.0 M) of n-BuLi n-hexane solution was slowly added to the reaction vessel with a syringe. After the addition, the system was further stirred at -78 ° C for one hour, and then transferred to the reaction vessel with a syringe. A solution of 2,3,4,6-tetra-O-trimethylsilylgluconolactone prepared according to the method of Example 1 dissolved in 10 mL of dry toluene was slowly added thereto. After the addition was completed, the system was further stirred for one hour, and then a solution of 1.92 g of methanesulfonic acid dissolved in 10 mL of anhydrous methanol was added by a syringe, and then the system was slowly warmed to room temperature and stirred at room temperature overnight. The reaction mixture was poured into a saturated saline solution, adjusted to pH = 8 with a saturated sodium hydrogencarbonate solution, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine, dried over anhydrous sodium sulfate Evaporation on an evaporator to give a colorless oil that is 1-{3-[(4-ethylpiperazin-1-yl)methyl]-4-fluorophenyl}-α/β·0- Methylpyranoside, ESI-MS, m/z = 415.1 ([M+l]).

The 1-{3-[(4-ethylpiperazin-1-yl)methyl]-4-fluorophenyl}-a/pD-methylpyranoside oil obtained above was dissolved in 2. 5 g to 3 mL In the dry dichloromethane, the ice water was stirred under cooling, and then 2 mL of triethylsilane and 1 mL of boron trifluoride diethyl ether were successively added. The resulting reaction system was stirred at room temperature overnight, carefully poured into 100 mL of ice water, adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine. Drying in anhydrous sodium sulfate, evaporation to dryness on a rotary evaporator to give a colorless oil, 1-{3-[(4-ethylpiperazin-1-yl)methyl]-4-fluorobenzene }--/pD-glucopyranose, ESI-MS, m/z = 385.1 ([M+l]).

2-{3-[(4-Ethylpiperazin-1-yl)methyl]-4-fluorophenyl}-a/pD-glucopyranose obtained as a colorless oil 2.21 g dissolved in 20 mL of acetic acid To the anhydride, 0.5 g of anhydrous sodium acetate was added, and the mixture was heated under reflux with electromagnetic stirring for 1 hour. After cooling, the system was poured into 100 mL of water, stirred at room temperature overnight, adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted twice with 100 mL of dichloromethane, and the combined extracts were washed once with saturated brine. The aqueous solution was dried over sodium sulfate, and evaporated to dryness on a rotary evaporator to give an off-white solid, which was purified by silica gel column chromatography to give a colorless crystal, 2,3,4,6-tetra-O-acetyl-1-{3- [(4-Ethylpiperazin-1-yl)methyl]-4-fluorophenyl}small deoxy-β-D-glucopyranose,

ESI-MS, m/z = 553.1 ([M+l])„

The above 2,3,4,6-tetra-0-acetyl-1-{3-[(4-ethylpiperazin-1-yl)methyl]-4-fluorophenyl}small deoxy-β-D 2-2.3 g of glucopyranose was dissolved in 7 mL of anhydrous methanol containing 0.11 g of sodium methoxide, stirred at room temperature for 5 hours, and then lg dried strong acid cation exchange resin was added, and stirred at room temperature overnight. The resin was removed by filtration, and the obtained filtrate was evaporated to dryness on a rotary evaporator to give a white solid, which was 1-{3-[(4-ethylpiperazin-1-yl)methyl]-4-fluorophenyl} Deoxy-β-D-glucopyranose, ESI-MS, m/z = 384.3 ([M+l]).

Example 14-18

It will be appreciated that the compounds listed in the table below can be obtained by varying the R1, R2 and Y using the method and scheme of Example 13.

Dosage / film

10 mg :crystalline fiber: 80 mg

70 mg

Polyvinylpyrrolidone 6 mg

Carboxymethyl starch sodium salt 5 mg

Magnesium stearate 2 mg

Talc powder 2 mg

The active ingredient, the portion and the microcrystalline cellulose are sieved, thoroughly mixed, added to a solution of polyvinylpyrrolidone, mixed, made into a soft material, sieved, wet-dried, dried at 50-60 ° C, and carboxymethyl starch The sodium salt, stearic acid and talc are pre-screened and then added to the above granules for tableting. Example 20

Dosage / film

Example 4 Sample 10 mg

:crystalline fiber: 80 mg

70 mg

Polyvinylpyrrolidone 6 mg

Carboxymethyl starch sodium salt 5 mg

Magnesium stearate 2 mg

Talc powder 2 mg

The active ingredient, the portion and the microcrystalline cellulose are sieved, thoroughly mixed, added to a solution of polyvinylpyrrolidone, mixed, made into a soft material, sieved, wet-dried, dried at 50-60 ° C, and carboxymethyl starch The sodium salt, stearic acid and talc are pre-screened and then added to the above granules for tableting. Example 21

Dosage / grain

Example 5 Sample 10 mg

20 mg

Polyvinylpyrrolidone 3 mg

Magnesium stearate 2 mg

Talc powder 1 mg

The active ingredient, powder and microcrystalline cellulose are sieved, thoroughly mixed, and added to polyethylene Acetyl ketone solution, mixed, soft material, sifted, wet granules, dried at 50-60 ° C, pre-sintered the hard fat per magnesium and talc, and then added to the above granules, capsules, ie Got it. Example 22

Dosage / grain

Example 10 Sample 10 mg

: Crystal Fiber: 30 mg

20 mg

Polyethylene: Bile ketone 3 mg

Stearin i 2 mg

Talc powder 1 mg

The active ingredient, powder and microcrystalline cellulose are sieved, thoroughly mixed, added to a solution of polyvinylpyrrolidone, mixed, softened, sieved, wet granules, dried at 50-60 ° C, magnesium stearate Pre-screened with talcum powder, then added to the above granules, capsuled,

Example 23

Dosage /50mL

Example 11 Sample 10 mg

NaOH amount (adjust ρΗ 4·0-5·0)

Distilled water 50 mL

In distilled water, first add distilled water and citric acid, stir and dissolve, then add the sample, slightly heat to dissolve, adjust the pH value to 4.α.0, add 0.2 g of activated carbon, stir at room temperature for 20 minutes, filter , filtrate, medium control solution concentration of 5 liters per amp bottle, high temperature sterilization for 30 minutes, that is, the injection, Example 24

Dosage /50mL

Example 12 Sample 10 mg

Citric acid 100 mg

NaOH amount (pH 4.0-5.0)

Distilled water 50 mL In distilled water, first add distilled water and citric acid, stir and dissolve, then add the sample, slightly heat to dissolve, adjust the pH value to 4.0-5.0, add 0.2 g of activated carbon, stir at room temperature for 20 minutes, filter, filtrate, medium Control the concentration of the solution, add 5 liters per amp bottle, and sterilize for 30 minutes at high temperature to obtain the injection.

Example 25 Example 13 Sample 3.0g

Polosham l.Og

Sodium hydroxide 0.2g

Tannic acid QS

Mannitol 26.0g

Lactose 23.0g

Water for injection 100ml Preparation process: Take 80ml of water for injection, add the main drug, mannitol, lactose, poloxamer to stir. After dissolving, adjust the pH of lmol/L citrate to 7.0-9.0, add water to 100ml. 0.5 g of activated carbon was added, and the mixture was stirred at 30 ° C for 20 minutes, decarburized, and sterilized by filtration through a microporous membrane. The filtrate was dispensed in 1 ml each, and after pre-freezing for 2 hours, it was dried under reduced pressure for 12 hours under refrigeration. After the temperature of the sample reached room temperature, it was dried for another 5 hours to obtain a white loose mass, which was obtained by sealing.

Example 26 Granules 100 bags

Example 14 Sample 30.0g

Lactose 55.0g

Mannitol 14.0g

Aspartame 0.05g

Fragrance 0.05g

2% hypromellose (prepared in pure water) QS

Preparation process: The main drug and the auxiliary material are respectively passed through a 100 mesh sieve, thoroughly mixed, and then the prescription auxiliary material is sufficiently mixed with the main drug. Adding adhesive to soft material, 14 mesh sieve granules, drying at 55 ° C, 12 The sieve is sifted and the bag is repackaged.

Example 27 A sample prepared in the examples of the present invention was formulated into a suspension of 5 mg/mL in a concentration of 1% carboxymethylcellulose, and the dosage was 0.2 mL/20 g body weight, which was equivalent to a dose of 10 mg/kg. .

Healthy ICR mice, half male and half female, weighing 20-24 g, meet the first grade standard. The animals were fasted for 16 hours, and 2 g/kg of gluconate solution was injected intraperitoneally 2 hours after the drug (dpagliflozin drug 1.5 h after glucose injection). Capillary from the mouse ball was taken at 0.5 h, lh, 2 h, 3 h and 4 h after modeling. Blood was taken from the posterior venous plexus, serum was separated by centrifugation, and serum glucose content was measured by glucose oxidase method at each time point.

The results of the determination of some samples are shown in the following table:

The above results indicate that each administration can significantly reduce glucose tolerance in mice induced by glucose. It is demonstrated that the compound of the present invention having the structure of the general formula I can be used as an inhibitor of SGLT2 and can be further used for the treatment of diabetes, particularly non-insulin dependent diabetes.

Claims

EIC10310021P Patent Requirements

A compound having the structure of formula I or a pharmaceutically acceptable salt or prodrug ester thereof,

among them,

R ^{1 is} selected from the group consisting of H, F, Br, I, OR ³ , SR ⁴ , OCF ₃ , CF ₃ , CHF ₂ , CH ₂ F, dC ₃ and a cyclic fluorenyl group having 3 to 5 carbon atoms, wherein R ³ and R ⁴ independently independently selected a fluorenyl group of C _r C ₃ , which is optionally substituted by one or more atoms selected from F and C1;

R ^{2 is} selected from the group consisting of H and C _r C ₅ ;

The definitions of X and Y are selected from the following cases:

(1) X = Y = carbon atom;

(2) Χ = Υ = nitrogen atom;

(3) Χ = nitrogen atom, Υ = oxygen atom;

(4) X = nitrogen atom, Υ = carbon atom.

2. A compound of the formula I according to claim 1 or a pharmaceutically acceptable salt or prodrug thereof,

among them,

R ^{1 is} selected from the group consisting of H, F, OMe, SMe, OCF ₃ , CF ₃ , CHF ₂ , CH ₂ F, CH ₃ and a cyclic fluorenyl group having _{3 to} 5 carbon atoms, optionally having a fluorenyl group and a cyclodecyl group. The ground is replaced by one or more atoms selected from F and C1;

R ^{2 is} selected from the group consisting of H and C _r C ₃ ;

The definitions of X and Y are selected from the following cases:

= Y = carbon atom;

Oxygen atom;

(4) 氮 Nitrogen atom, Υ = carbon atom.

The compound of the formula I or the pharmaceutically acceptable salt or prodrug ester thereof according to claim 1 or 2, wherein the structure of the compound is selected from one of the following structures:

The compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof, according to any one of claims 1 to 3, wherein the pharmaceutically acceptable prodrug ester comprises any of the molecules An ester formed by a plurality of hydroxyl groups and one or more of an acetyl group, a pivaloyl group, a phosphoryl group, a carbamoyl group, and an alkoxycarbonyl group.

5. A process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof, according to any one of claims 1 to 4, which comprises the following synthetic steps:

Wherein the base A is selected from the group consisting of N-methylmorpholine, triethylamine, pyridine, and 4-dimethylaminopyridine, and the base B is selected from the group consisting of anhydrous sodium acetate, pyridine, and 4-dimethylaminopyridine. Base C is selected from the group consisting of sodium methoxide, NaOH and KOH.

The method according to claim 5, wherein the trimethylsilylating agent is trimethylsilylphosphonium; the mercaptolithium reagent is n-butyllithium; and the acid is selected from methanesulfonate. Acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid; the Lewis acid is selected from the group consisting of BF ₃ .Et ₂ 0, BF ₃ .MeCN and trifluoroacetic acid; the reducing agent is selected from the group consisting of triethylsilyl and triisopropyl Silicon oxime; the acetylating agent is selected from the group consisting of acetic anhydride and acetyl

The preparation method according to claim 5 or 6, wherein Said = ¥ = carbon atom, compound IV is IV-1:

IV-1 Compound IV-1 is synthesized using either of the following two routes:

The halogenating agent is PBr ₃ and/or P0C1 ₃ ; the reducing agent A is LiAlH ₄ ; the reducing agent B is triethylsilane and/or triisopropylsilyl; the acid is trifluoride Boron ether and / or trifluoroacetic acid; wherein, Hal is selected from the group consisting of Cl, Br and I;

(2) The X = Y = nitrogen atom and IV is IV-2:

Compound IV-2 was synthesized using the following route:

XVI XVII IV-2 wherein Hal is selected from the group consisting of Cl, Br and I;

(3) The X = nitrogen atom, Y = oxygen atom, and the compound IV is IV-3:

IV-3

Compound IV-3:

XVI XVIII IV-3

Wherein Hal is selected from the group consisting of Cl, Br and I;

(4) The X = nitrogen atom, Y = carbon atom, and the compound IV is IV-4:

IV-3

Compound IV-4 was synthesized using the following route:

XVI XIX IV-4 wherein Hal is selected from the group consisting of Cl, Br and I.

The preparation method according to any one of claims 5 to 7, which comprises the following synthesis steps:

9. Use of a compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, for inhibiting a type 2 glucosamine co-transporter.

10. Use of a compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, for the treatment of diabetes.

11. Use of a compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, for the preparation of a type 2 galactose transporter inhibitor.

12. Use of a compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a medicament for the treatment of diabetes.

13. A method of treating diabetes, the method comprising the right to administer an effective dose to a patient The compound of formula I according to any one of 1 to 4, or a pharmaceutically acceptable salt or prodrug ester thereof.

14. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier and / or excipients.

The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is a solid oral preparation, a liquid oral preparation or an injection preparation.

16. The pharmaceutical composition according to claim 15, wherein the solid oral preparation and the liquid oral preparation comprise: a dispersible tablet, an enteric coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a granule, and an oral solution, The preparation for injection includes a water injection needle, a lyophilized powder for injection, a large infusion, and a small infusion.