WO2013044608A1

WO2013044608A1 - Anomeric alkyl-containing phenyl c-glucoside derivative, preparation method therefor and use thereof

Info

Publication number: WO2013044608A1
Application number: PCT/CN2012/071451
Authority: WO
Inventors: 赵桂龙; 吴疆; 邵华; 徐为人; 汤立达; 邹美香; 王玉丽; 龚珉; 付刚; 谭初兵; 周植星
Original assignee: 天津药物研究院
Priority date: 2011-09-29
Filing date: 2012-02-22
Publication date: 2013-04-04
Also published as: CN102408459B; CN102408459A

Abstract

The present invention relates to the field of drugs associated with diabetes. Specifically, the present invention relates an inhibitor of sodium-dependent glucose transporter-2 having an anomeric alkyl-containing phenyl C-glucoside structure represented by Formula I, and a preparation method for same, a pharmaceutical composition containing same and a use of same in the preparation of drugs for treating diabetes. In Formula I, R¹ is selected from C₁-C₅ alkyl groups; R² and R³ are each independently selected from H, OH, C₁-C₅ alkyl groups, F, Cl, Br, I, CN, NO₂, CF₃, CHF₂, CH₂F, OR⁸, SMe and cycloalkyl groups containing 3 to 5 carbon atoms, wherein R⁸ is selected from C₁-C₅ alkyl groups; R⁴ and R⁵ are each independently selected from H, C₁-C₅ alkyl groups and OR⁸, wherein R⁸ is selected from C₁-C₅ alkyl groups or cycloalkyl groups containing 3 to 5 carbon atoms; and R⁶ and R⁷ are each independently selected from H and C₁-C₅ alkyl groups, or R⁶ and R⁷, together with a carbon atom connected thereto, form a cycloalkyl group containing 3 to 5 carbon atoms.

Description

Phenyl C-glucoside derivative containing anomeric alkyl group, preparation method and use thereof

Technical field

The present invention relates to the field of medicines associated with diabetes. In particular, the present invention relates to a type 2 sodium glucose co-transporter (SGLT2) inhibitor having an alkyl group-containing phenyl C-glucoside structure in an anomeric position, and a method for preparing the same, and a method for preparing the same Pharmaceutical composition. Background technique

There are currently about 170 million people with diabetes worldwide, the vast majority of whom are type II (ie, non-insulin dependent) diabetics. Currently, the antidiabetic drugs currently used in clinical practice mainly include diterpenoids, sulfonylureas, insulins, thiazolidinediones, α-glucosidase inhibitors and dipeptidyl peptidase-IV inhibitors. These drugs have good therapeutic effects, 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 sodium glucose 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 concentration of glucose in the blood. This method reduces blood sugar levels by different ways from the past. . When SGLT2 is blocked, more glucose is secreted in the urine, which will help diabetics maintain the correct blood sugar levels. Since the SGLT2 inhibitor does not interfere with glucose metabolism, it can be used as a supplement to mainstream blood glucose control methods.

Chinese Patent CN200610093189.9 discloses a compound of the following structure as an SGLT2 inhibitor:

Where Α is 0, S, NH, (CH ₂ ) _n , n = 0-3.

Chinese patent CN200380110040.1 discloses compounds of the following structure as SGLT2 inhibitors:

Wherein A is a covalent bond, O, S, NH, (CH ₂ ) _n , n = l-3.

Chinese Patent CN200480006761.2 discloses compounds of the following structure as SGLT2 inhibitors:

among them

Summary of invention

It is an object of the present invention to overcome the shortcomings and deficiencies of the prior art and to provide a SGLT2 inhibitor having good activity, the SGLT2 inhibitor being a compound of formula I or a pharmaceutically acceptable salt or prodrug ester thereof.

Another object of the invention is to provide a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt or prodrug ester thereof.

A further object of the present invention is to provide a compound containing Formula I, or a pharmaceutically acceptable salt or prodrug ester thereof, as an active ingredient, together with one or more pharmaceutically acceptable carriers, excipients and/or Or a pharmaceutical composition of a diluent, and its use in the treatment of diabetes.

The anomeric alkyl-containing phenyl C-glucoside derivatives provided by the present invention are novel SGLT2 inhibitors, and these inhibitors lay the foundation for the preparation of drugs which can be further used for the treatment of diabetes, especially non-insulin dependent diabetes. . invention

The present invention provides a compound represented by (I)

among them,

R ^{1 is} selected from the group consisting of alkyl of dC ₅ , which is optionally substituted with one or more groups selected from F, Cl, Br, I and OH;

R ² and R ^{3 are} independently selected |] H, OH, dC ₅ alkyl, F, Cl, Br, I, CN, N0 ₂ , CF ₃ , CHF ₂ , CH ₂ F, OR ⁸ , SMe and 3- a cycloalkyl group of 5 carbon atoms, wherein R ^{8 is} selected from an alkyl group of dC ₅ , which is optionally substituted by one or more atoms selected from the group consisting of F and C 1 ;

R ⁴ and R ^{5 are} independently selected from H, C _r C ₅ alkyl group containing 3-5 carbon atoms and a cycloalkyl group OR ^8, wherein R ⁸ is selected from C _r C ₅ alkyl group or an 3-5 a cycloalkyl group of a carbon atom, the alkyl group or a cycloalkyl group being optionally substituted by one or more atoms selected from the group consisting of F and C1;

R ⁶ and R ^{7 are} independently selected from the alkyl group of H and C _r C ₅ , or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a cycloalkyl group having 3 to 5 carbon atoms.

Preferably, among the compounds represented by the formula (I),

R ^{1 is} selected from alkyl of dC ₃ , which is optionally substituted with one or more groups selected from the group consisting of F and OH;

R ² and R ^{3 are} independently selected from H, OH, dC ₃ alkyl, F, Cl, CN, N0 2, CF 3, OR 8, SMe and cyclopropyl, wherein R ⁸ is selected from a C _r C ₃ alkyl The alkyl or cyclopropyl group is optionally substituted with one or more F atoms;

R ⁴ and R ^{5 are} independently selected from H, dC ₃ alkyl, cyclopropyl and OR ⁸ , wherein R ⁸ is dC ₃ alkyl or cyclopropyl, said alkyl or cyclopropyl optionally being one or Multiple F atoms substituted; R ⁶ and R ^{7 are} independently selected from the group consisting of 11 and i-C ₃ alkyl groups, or R ⁶ and R ⁷ and the carbon atom to which they are attached form a cyclopropyl group.

More preferably, the compound represented by (I) is selected from

Above route

TTig reagent) III reacts with TBDPSCl and finally converts to IV; compound IV is converted to V by Wacker oxidation; compound V reacts with aryllithium compound VI to give compound VII; tert-butyldimercaptosilane group in compound VII (TBDPS) protecting group is removed by treatment with tetrabutylammonium fluoride (TBAF) to obtain compound VIII; compound VIII is subjected to acid-catalyzed cyclization to obtain compound IX, preferably the acid is trifluoroacetic acid, sulfonic acid, trifluoroanthracene Acid, sulfuric acid, HCl, etc.; Compound IX is deprotected with p-methoxybenzyl (PMB) protecting group with dichlorodicyanidine p-benzoquinone (DDQ) to obtain the target compound I; wherein -R ⁷ is as defined above R ⁹ and R ^{1G are} independently selected from the group consisting of H and C _r C ₄ alkyl groups.

n-Bu ₃ SnH/

AIBN/

R ⁹ R ^1G CH = R ¹ in the above route; Compound V is treated with a strong base and then reacted with Tf ₂ 0 to obtain Compound X, preferably the strong base is lithium diisopropylamide (LDA); Compound X XI with an aryl boronic acid under the Pd catalyzed coupling to give compound XII, preferably the Pd catalyst is Pd (PPh ₃₎ _4; compound XII 1 ₂ processing occurs cyclized compound XIII; compound XIII with «-Bu ₃ SnH and azobisisobutyronitrile (AIBN) treatment to remove iodine to obtain compound XIV; compound XIV is treated with DDQ to remove the PMB protecting group to obtain compound I; wherein -R ^{7 is} as defined above, R ⁹ and R ^{1G is} independently selected from the group consisting of H and C _r C ₄ alkyl groups.

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, aminodecanoyl groups, alkanoyl groups, and the like Ester.

The compounds of formula I of the present invention may be formulated into pharmaceutical compositions by mixing with one or more pharmaceutically acceptable carriers, excipients and/or diluents. The pharmaceutical composition can be formulated into a solid oral preparation, a liquid oral preparation, and an injection. The solid and liquid oral preparations include: Tablets, dispersible tablets, chewable tablets, coated tablets, granules, dry powders, capsules and solutions. The injection includes: a small needle, a large infusion, and a lyophilized powder needle.

The pharmaceutical composition according to the present invention comprises a pharmaceutically acceptable excipient selected from the group consisting of: a filler, a binder, a disintegrant, a lubricant, a glidant, an effervescent, and a flavor. Agents, preservatives, coating materials, surfactants, pH adjusters and stabilizers.

Preferably, the filler comprises one of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, dibasic calcium phosphate, sulfuric acid 4 bow, carbonic acid 4 bow and microcrystalline cellulose or Several kinds of binders include sugar, starch, povidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, mercapto cellulose, polyethylene glycol, medicinal ethanol and One or more of the water; the disintegrant comprises starch, cross-linked poly-microketone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, effervescent One or more of the decomposers; the lubricant comprises magnesium stearate; the glidant comprises talc; the flavoring agent comprises a flavor and aspartame; the surfactant comprises a polka Sham, sodium lauryl sulfate, Tween 80; the pH adjusting agent includes citric acid and sodium hydroxide, and the stabilizer includes citric acid or the like.

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 times. The dosage of the compound of formula I of the present invention may be determined by the physician in accordance with 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. Various changes made by those skilled in the art in light of the teachings of the present invention are intended to be included within the scope of the appended claims. Example 1

(2S,3R, ,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-hydroxydecyl-2-mercapto-2,3,5, 6-tetrahydro-2H-pyran-3,4,5-triol (1-1)

Synthesis Method A:

The compounds 1 to 1 and ΙΠ-1 to: IX-1 in the above synthetic route are each one of the compounds represented by the corresponding I and III to IX.

1. Synthesis of compound IV-1

6.61 g of compound II was added to a 100 mL dry round bottom flask and dried in 20 mL.

The THF was dissolved, and the flask was purged with nitrogen and then quickly sealed with a rubber stopper. The flask was cooled in an ice bath at -10 °C, and 25 mL of a 1.0 M compound ΠΙ-1 in THF was slowly added dropwise with a syringe. After the completion of the dropwise addition, the resulting reaction mixture was stirred at room temperature overnight. The flask was again cooled in an ice water bath, and a solution prepared by dissolving 2.75 g of TBDPSC1 (tert-butyldiphenylchlorosilane) in 2 mL of dry THF was slowly added dropwise by a syringe, and the resulting solution was stirred at room temperature for 2 hours.

The reaction mixture was carefully poured into 300 mL of a saturated NH ₄ C1 solution containing ice, stirred, and extracted with 50 mL of X 3 dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by column chromatography, to give pure Compound IV- 1, a colorless oil, ESI-MS, m / z = 897 ([M + H] +).

2. Synthesis of compound V-1

A 100 mL round bottom flask was charged with the compound IV-1 (7.27 g) prepared above to 50 Dissolve mL N,N-dimercaptoamide (DMF), stir at room temperature, then add 5 mL water, 0.10 g CuCl ₂ and 0.15 g PdCl ₂ , and the resulting mixture was stirred under a 0 ₂ atmosphere (balloon) for 24 hours. At this time, the thin layer color term (TLC) showed that the reaction was completed.

The reaction mixture was suction filtered, and the filtrate was poured into 300 mL brine, and then extracted with 50 The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by column chromatography, to give pure Compound V-1, a colorless oil, ESI-MS, m / z = 913 ([M + H] +).

3. Synthesis of Compound IX-1

Add a 3. 6 g (2-chloro-5-bromophenyl)(4-ethoxyphenyl)decane to a 100 mL dry round bottom flask, dissolve in 20 mL of dry tetrahydrofuran (THF), purge with nitrogen. After sealing with a rubber stopper. The flask was cooled with liquid nitrogen-ethanol at -78 °C, and electromagnetic stirring was started, and then 10 mL of 1.0 M "-BuLi n-hexane solution was slowly added dropwise by a syringe. After the completion of the dropwise addition, the reaction mixture was stirred at -78 ° C for 1 hour, and then heated to -20 ° C, and then slowly added dropwise with a syringe to the above-prepared V-1 (6.95 g) dissolved in 5 mL of dry THF. After the dropwise addition, the resulting mixture was stirred at room temperature for 1 hour.

10 mL of a 1.0 M solution of TBAF in THF was slowly added to the above reaction mixture with a syringe at room temperature, and the mixture was stirred at room temperature for 5 hours. Then, 9.6 g of MsOH (anthracenesulfonic acid) was slowly added to the flask with a syringe under cooling with ice water. The resulting mixture was stirred at room temperature overnight.

The reaction mixture was poured into 300 mL of brine and then extracted with 50 mL of EtOAc. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by column chromatography to give compound IX-1 pure product, a white solid, ESI-MS, m / z = 903 ([M + H] +).

4. Synthesis of Compound 1-1

The compound IX-1 (3.85 g) prepared above was added to a 100 mL round bottom flask, dissolved in 40 mL of dichloromethane, stirred at room temperature, and then 9.00 g of DDQ and 4 mL of water were added in sequence, and the mixture was obtained. After stirring at room temperature overnight, the temperature was refluxed for 3 hours. At this point TLC showed the reaction was complete.

The reaction mixture was diluted with 200 mL of dichloromethane, and then washed with a saturated aqueous solution of 100 mL of sodium hydrogencarbonate, and then washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Synthesis Method B:

Compounds X-1 to XIV-1 in the above synthetic route are each one of the compounds represented by the corresponding X and XIV.

1. Synthesis of compound X-1

A 100 mL dry round bottom flask was charged with 1.01 g of dry-Pr ₂ NH and 10 mL of dry THF. The flask was purged with nitrogen and quickly sealed with a rubber stopper, and then cooled in liquid nitrogen-ethanol at -78 °C to start electromagnetic stirring. To the flask, 6.2 mL of a 1.6 M solution of w-BuLi in n-hexane was slowly added dropwise with a syringe, and the resulting solution was stirred at the temperature for 1 hour. Then, a solution of 9.13 g of dry V-1 dissolved in 10 mL of dry THF was added dropwise with a syringe. After the completion of the dropwise addition, the resulting reaction mixture was further stirred at -78 ° C for 1 hour, and then a solution prepared by dissolving 2.82 g of Tf ₂ 0 in 2 mL of dry THF was slowly added dropwise with a syringe. After completion of the dropwise addition, the resulting reaction mixture was slowly warmed to room temperature and stirring was continued for 1 hour.

The reaction mixture was poured into cooled 300 mL of brine and extracted with 50 mL of dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue obtained was purified by column chromatography to yield purified crystals of Compound 1-1, ESI-MS, m/z = 1045 ([M+H] ⁺ )

2. Synthesis of compound XII-1

A 100 mL round bottom flask was charged with the compound X-1 (9.09 g) prepared in the previous step, 2.81 g of 4-chloro-3-(4-chlorobenzyl)phenylboronic acid, 2.12 g of sodium carbonate, and 0.23 g of Pd. (PPh ₃ ) ₄ , 40 mL of benzene, 20 The mixture was refluxed under nitrogen overnight at rt.

After the reaction mixture was cooled, it was poured into 300 mL of saturated brine and extracted with 100 mL of 3 dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

3. Synthesis of the compound ΧΠΙ-1

A 100 mL dry round bottom flask was charged with XII-1 (7.25 g) prepared in the previous step, dissolved in 30 mL of dry dichloromethane, stirred at room temperature, then 2.00 gl ₂ and stirred at room temperature overnight.

The reaction mixture was poured into 300 mL of brine and extracted with 50 mL of EtOAc. The extracts were combined, washed successively with 10% Na ₂ S ₂ ₃ and brine, dried over anhydrous sodium sulfate, and evaporated. The residue obtained was purified by EtOAc EtOAc (EtOAc)

4. Synthesis of compound XIV-1

A 100 mL dry round bottom flask was charged with the compound XIII-1 (3.86 g) prepared in the previous step, 3.0 g «-Bu ₃ SnH, 0.10 g AIBN (azobisisobutyronitrile) and 50 mL of dry benzene. The resulting mixture was refluxed for 3 hours under a nitrogen atmosphere, then 0.10 g of AIBN was added, and reflux 3 was continued. At this point TLC showed the reaction was complete.

After the reaction mixture was cooled, it was diluted with 200 mL of dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated. The resulting residue was purified by column chromatography to give compound XI V- pure 1, as a white solid, ESI-MS, m / z = 903 ([M + H] +).

5. Synthesis of Compound 1-1

The 1-1 was synthesized in accordance with the operation of the fourth step in the method A. White foamy solid, ESI-MS, m/z = 423 ([M+H] ⁺ ). Example 2-18

It will be appreciated that the use of methods A and B in Example 1, changing -R ^7, the compounds in the table below can be obtained. - -

IS UO/ZlOZ lD/lDd 809W0/£I0Z OAV - -

IS UO/ZlOZ lD/lDd 809 /£I0Z OAV Example 19 Ordinary tablet

Dosage / film

Example 1 Sample 10 mg

Microcrystalline cellulose 80 mg

Pregelatinized starch 70 mg

Povidone 6 mg

Carboxymethyl starch sodium 5 mg

Magnesium stearate 2 mg

Talc powder 2 mg

Example 1 was passed through an 80 mesh sieve.

The product, pregelatinized starch and microcrystalline cellulose are well mixed, mixed with a 10% (w/v) aqueous solution of povidone, softened, sieved, wet granules, and dried at 55 °C. Sodium carboxymethyl starch, magnesium stearate and talc are added to the above granules to determine the intermediate content, tableting, and packaging. Example 20 Recording

Dosage / film

Example 2 Sample 10 mg

Lactose 80 mg

Pregelatinized starch 70 mg

Hydroxypropyl cellulose 6 mg

Cross-linked povidone 5 mg

Magnesium stearate 4 mg

Example 2 was passed through an 80 mesh sieve.

The product, pregelatinized starch and lactose are well mixed, mixed with a 1% (w/v) aqueous solution of hydroxypropionate, made into a soft material, sieved, and wetted, and dried at 55 °C. The crospovidone and magnesium stearate are added to the above granules, and the intermediate content is determined, tableted, and packaged. Example 21 Chewable Tablets

Dosage / film

Example 4 Sample 10 mg

Mannitol 100 mg

Microcrystalline cellulose 30 mg Lactose 50 mg

聚维嗣 6m g

Aspartame 5 mg

Fragrance 2mg

Magnesium stearate 1 mg

The sample of Example 4 was passed through an 80 mesh sieve and the auxiliary material was passed through a 60 mesh sieve. The sample of Example 4 was weighed according to the prescription, the povidone, aspartame and the essence were firstly mixed uniformly, and then mixed with mannitol, microcrystalline cellulose and lactose in order, and then uniformly mixed with magnesium stearate. Intermediate content, tableting, packaging. Example 22 Capsule

Dosage / grain

Example 5 Sample 10 mg

Lactose 80 mg

Calcium hydrogen phosphate 20 mg

Hydroxypropyl cellulose 3 mg

Crosslinked like cellulose sodium 6mg

Magnesium stearate 2mg

Talc powder 1 mg

The sample of Example 5 was passed through an 80 mesh sieve, and the other auxiliary materials were passed through a 60 mesh sieve. The sample of Example 5, the calcium hydrogen phosphate, the croscarmellose sodium and the lactose were weighed uniformly according to the prescription amount, and mixed with a 2% (w/v) aqueous solution of hydroxypropylcellulose to prepare a soft material and sieved. The wet granules were dried at 55 °C. Magnesium stearate and talc powder were externally added to the above granules, and the content of the intermediate was measured, and the No. 3 capsule was placed and packaged. Example 23 Injection

Dosage /50mL

Example 8 Sample 10 mg

Citrate 100 mg

NaOH amount (pH 4.0-6.0)

Activated carbon

50 ml of water for injection Add citric acid to 40 ml of water for injection, stir and dissolve, then add the sample of Example 8, dissolve it by heat, adjust the pH to 4.0-6.0, add 1% activated carbon based on the weight of the whole injection, at room temperature. Stir for 20 minutes and measure the pH. Filter, decarbonize, add water for injection to the full amount. Packed in 5 ml per ampere, nitrogen filled, sealed. The mixture was sterilized at 121 ° C for 30 minutes to obtain an injection. Example 24 Injection

Dosage /50mL

Example 9 10 mg

Citrate 100 mg

Sodium dihydrogen phosphate 30mg

Water for injection 50 mL

Add citric acid to 40 ml of water for injection, stir and dissolve, then add the sample of Example 8 and sodium dihydrogen phosphate, dissolve it by heat, adjust the pH to 3.0-5.0, and add 1% based on the weight of the whole injection. The activated carbon was stirred at room temperature for 20 minutes, and the pH was measured. Filter, decarbonize, add water to the full amount. Packed in 2 ml per ampere, nitrogen filled, sealed. Sterilize at 121 °C for 30 minutes to obtain an injection. Example 25 Lyophilized formulation

Dosage /lOOmL

Example 10 3-0g

Polosham l.Og

Sodium hydroxide 0.2g

枸橼 acid amount (QS)

Mannitol 26.0g

Lactose 23.0g

Water for injection lOOmL

Preparation process: Take 80 mL of water for injection, add the sample of Example 10, mannitol, lactose and poloxamer to dissolve according to the prescription amount, and then adjust the pH to 6.0 - 8.0 by adding citric acid or sodium hydroxide, and add water for injection to 100mL. Add 0.5g of activated carbon, stir at 30 ° C for 20 minutes, decarbonize, filter and sterilize by microfiltration membrane, the filtrate is divided into 1 mL each, after pre-freezing for 2 hours, freeze under vacuum for 12 hours, until 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

Dosage / 100 bags

Example 11 Sample 30.0g

Lactose 55.0g

Mannitol 14.0g

Aspartame 0.05g

Fragrance 0.05g

2% hydroxypropyl cellulose

(prepared in pure water) ^QS

Preparation process: The sample of Example 11 was passed through an 80 mesh sieve, and the auxiliary material was passed through a 60 mesh sieve. Weigh the prescribed amount of lactose, mannitol, aspartame, essence and sample mixed well with Example 11, add 2% (w/v) hydroxypropionate aqueous solution to soft material, 16 mesh sieve, 55° C dry, 14 mesh sieve granules, determination of intermediate content and moisture, packaging, a total of 100 bags of granules were prepared. Example 27

The samples of Examples 1-2, 4-5, 8-12, 14 and 16-18 listed in Table 1 below were formulated at a concentration of 5 mg/mL with 1% (w/v) sodium carboxymethyl cellulose. The suspension was administered at a dose of 0.2 mL/20 g body weight, equivalent to a 10 mg/kg dose.

Healthy ICR mice, half male and half female, weigh 20-24 g, in line with the first grade standard. The animals were fasted for 16 h, 2 g/kg of dextrose solution was injected intraperitoneally 2 h after administration (glucose was injected 1.5 h after Dapagliflozin administration), and capillary was used at 0.5 h, 1.0 h, 1.5 h, 2.5 h and 3 h after modeling. The blood was taken from the posterior venous plexus of the mouse, and the serum was separated by centrifugation. The serum glucose content at each time point was measured by the glucose oxidase method (the results are shown in Table 1).

Table 1 Determination of serum glucose content at various time points by glucose oxidase method

3h blood glucose dose 0.5h blood glucose value 1.5h blood glucose value 2h blood glucose value 2.5h blood glucose value

(mg/kg) (mg/dl) (mg/dl) (mg/dl) (mg/dl) Value Model - 441.1±51.5 291.1±42.6 189.2±24.3 130.6±12.6

Dapagliflozin 10 243.2±32.1 132.4±25.5 96.3±26.2 81.4±22.3 Example 1 Sample 10 241.2±42.5 143.3±14.3 94.2±21.6 76.2±12.8 Example 2 Sample 10 290.2±43.5 171.2±37.2 107.2±21.6 72.2±24.2 Example 4 Sample 10 297.2 ± 31.4 167.2 ± 22.5 112.3 ± 15.2 82.2 ± 12.3 73.5 ± 12.1 Example 5 Sample 10 159.2 ± 41.0 130.2 ± 14.2 103.1 ± 10.1 70.1 ± 11.1 65.1 ± 11.4 Example 8 Sample 10 292.3 ± 34.2 201.4 ± 23.0 140.2±21.1 103.1±12.4 80.1±12.3 Example 9 Sample 10 220.2±32.4 165.1±22.1 113.4±15.5 91.1±14.5 70.2±21.0 Example 10 Sample 10 201.1±33.2 155.2±24.1 138.4±21.3 91.0±11.8 70.1±14.1 Example 11 Sample 10 210.3 ± 31.3 181.1 ± 34.5 120.1 ± 22.7 96.0 ± 12.7 67.0 ± 15.2 Example 12 Sample 10 295.1 ± 29.2 190.1 ± 24.1 107.3 ± 21.3 79.8 ± 21.8 65.1 ± 12.7 Example 14 Sample 10 152.2 ± 22.5 147.2 ± 28.2 92.2±11.3 69.1±20.7 65.1±12.3 Example 16 Sample 10 199.3±23.2 160.1±11.5 133.4±12.7 73.4±22.2 63.1±13.4 Example 17 Sample 10 248.4±43.4 181.1±21.7 140.1±22.3 103.1±11.7 77.1±12.1 Example 18 Sample 10 252.1 ± 34.5 151.3 ± 24.6 125.2 ± 33.3 121.1 ± 11.3 71.2 ± 11.5 The above results indicate that each administration can significantly reduce glucose-induced glucose tolerance in mice.

Claims

Rights request

among them,

R ⁴ and R ^{5 are} independently selected from H, C _r C ₅ alkyl group containing 3-5 carbon atoms and a cycloalkyl group OR ^8, wherein R ⁸ is selected from ₅ or dC alkyl having 3-5 carbon atoms a cycloalkyl group, optionally substituted by one or more atoms selected from the group consisting of F and C1;

R ⁶ and R ^{7 are} independently selected from the alkyl group of H and dC ₅ , or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a cycloalkyl group having 3 to 5 carbon atoms.

The compound according to claim 1 or a pharmaceutically acceptable salt or prodrug ester thereof, wherein

R ^{1 is} selected from C _r C decyl, and the alkyl group is optionally substituted with one or more groups selected from the group consisting of F and OH;

R ⁴ and R ^{5 are} independently selected from H, C _r C ₃ alkyl, cyclopropyl and OR ^8, wherein R ⁸ is selected from C _r C ₃ alkyl or cyclopropyl, and any of said alkyl or cyclopropyl The ground is replaced by one or more F atoms;

R ⁶ and R ^{7 are} independently selected from the alkyl group of H and dC ₃ , or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a cyclopropyl group.

3. A compound according to claim 2, or a pharmaceutically acceptable or prodrug ester thereof, Wherein the compound is selected from the group consisting of:

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

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable compound thereof A method of salt or prodrug ester, the method comprising the steps of:

RSR ^CH in the above route: !^; Compound II reacts with R ⁹ R ^{1 ()} C = PPh ₃ (Wittig reagent) III and then reacts with TBDPSCl to be finally converted to IV; Compound IV is converted to V by Wacker oxidation; Compound V is reacted with aryllithium compound VI to give compound VII; the TBDPS protecting group in compound VII is removed by treatment with TBAF (tetrabutylammonium fluoride) to give compound VIII; compound VIII is subjected to acid-catalyzed cyclization to give compound IX, preferably The acid is trifluoroacetic acid, trace acid, trifluoroantimonic acid, sulfuric acid or HCl; Compound IX is removed from the PMB (p-methoxybenzyl) protecting group with DDQ to obtain the target compound I; wherein -R ⁷ Definitions As defined in any one of claims 1 to 3, R ⁹ and R ^{1 G are} independently selected from the group consisting of H and C _r C ₄ alkyl.

6. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable compound thereof A method of salt or prodrug ester, the method comprising the steps of:

R ⁹ R ^1G CH = R ¹ in the above route; compound V is treated with a strong base and then reacted with Tf _{20 to} obtain compound X, preferably the strong base is LDA; compound X and aryl boronic acid XI in Pd catalyst catalyzed coupling to give the compound XII, preferably the Pd catalyst is Pd (PPh ₃₎ _4; compound XII 1 ₂ processing occurs cyclized compound XIII; compound XIII with "-Bu ₃ SnH and AIBN iodine off process, Compound XIV is obtained; compound XIV is treated with DDQ to remove the PMB protecting group to give compound I; wherein -R ⁷ is as defined in any one of claims 1-3, and R ⁹ and R ^{1G are} independently selected from H and C _r C ₄ alkyl groups.

The use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof, for the preparation of a medicament for treating diabetes; preferably, the diabetes is non-insulin dependent diabetes.

A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug ester thereof.

The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, excipients and/or diluents.

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

The pharmaceutical composition according to claim 10, wherein the solid and liquid oral preparations comprise: a dispersible tablet, an enteric coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a granule, and an oral solution, Injections include water for injection, lyophilized powder for injection, large infusion and small infusion.

12. A method of treating diabetes, the method comprising administering to a patient a therapeutically effective amount of a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or prodrug thereof; The therapeutic dose of the compound or a pharmaceutically acceptable salt or prodrug ester thereof ranges from 1 mg to 1000 mg per person per day.