KR20160097861A

KR20160097861A - Novel isoindolines derivatives, method of preparing thereof, and pharmaceutical composition including therof

Info

Publication number: KR20160097861A
Application number: KR1020150020273A
Authority: KR
Inventors: 조의환; 신희종; 권호석; 이재웅; 주정호; 이근국; 김종민; 김현태; 김재언; 이정록; 장범현
Original assignee: 삼진제약주식회사
Priority date: 2015-02-10
Filing date: 2015-02-10
Publication date: 2016-08-18

Abstract

The present invention relates to a novel isoindoline derivative, a process for its preparation and its use and, more particularly, to a novel sodium isoindoline derivative which acts as a sodium dependent glucose transporter (SGLT) inhibitor in the kidney, But are useful for the treatment and prevention of diseases including insulin resistance diseases and obesity.

Description

TECHNICAL FIELD The present invention relates to a novel isoindoline derivative, a method for preparing the same, and a pharmaceutical composition containing the novel isoindolines derivatives.

The present invention relates to a novel isoindoline derivative, a pharmaceutical composition comprising the same, and a method for preparing the same. More particularly, the present invention relates to a novel isoindoline derivative which acts as an inhibitor of sodium dependent glucose transporters (SGLT) To a pharmaceutical composition comprising a novel isoindolene derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof useful for the treatment and prevention of diseases including obesity, and a method for producing the same.

According to the World Health Organization, worldwide diabetes patients are estimated at 285 million people in 2010 (6.4% of the world's adult population). This figure is expected to increase to 438 million people (7.8% of the adult population) by 2030. Diabetes is a chronic metabolic disease caused by deficiency in the body's ability to respond appropriately to insulin-producing insufficiency and / or circulating insulin in the body. Insulin secreted from the pancreas increases the ability of tissues to absorb blood sugar. Thus, impaired insulin function results in a high blood glucose level that is common in diabetic patients. Two types of diabetes are commonly known. Type 1 diabetes or insulin-dependent diabetes mellitus is characterized by an autoimmune disease associated with pancreatic? -Cells, while type 2 diabetes or insulin-independent diabetes is characterized by? -Cell dysfunction and insulin resistance . Type 2 diabetes accounts for about 90-95% of all diabetes. Diabetes is increasing in number of patients due to population aging, dietary changes, and decreased physical activity.

Diabetes causes cardiovascular disease, stroke, kidney disease, retinopathy, kidney failure, and lower back infection and gangrene. High glucose levels worsen insulin resistance, impair beta-cell function, and ultimately cause beta -cell apoptosis. Loss of β-cell function exacerbates hyperglycemia resulting in malignant circulation that causes the destruction of β-cells.

Type 2 diabetes can be cured by improving lifestyle habits that promote weight loss. Or an antidiabetic drug alone or in combination therapies may be used. This therapy involves targeting the liver to reduce glucose release, targeting the small intestine to reduce glucose uptake, targeting fat accumulation or muscle to increase glucose cell uptake or to promote glucose metabolism, Plasma proteases are targeted to prolong incretin action, and the pancreas is targeted to promote insulin release. In addition, current therapies have a limited duration and / or have side effects such as gastrointestinal intolerance, hypoglycemia, weight gain, lactic acidosis and edema. Thus, there is a need for safer and more tolerable agents that provide increased efficacy and prolonged duration.

Although the human body continuously filters glucose through the kidney glomerulus, in the case of diabetic patients, the filtered sugar is mostly reabsorbed through the proximal tubule by the sodium-dependent glucose transporter (SGLT) . SGLT1 is located in the bowel, kidney and heart, and regulates cardiac glucose transport. It is estimated that 90% of renal glucose reabsorption is promoted by SGLT2 and the remaining 10% is mediated by SGLT1 in the late proximal tubule. (Van den Heuvel, LP et al., Hum, Genet., 2020, 111, 544-547) Reference). Therefore, inhibiting the activity of sodium-dependent glucose transporter (SGLT2) responsible for reabsorption of more than 90% of the glucose in the kidneys inhibits glucose reabsorption in the body, and as a result, It has also been reported that the efficacy of a test drug can be evaluated by measuring the amount of urine sugar released through animal experiments ( J. Clin. Invest ., 1994, 93 , 397-404, Br. J. Pharmacol., 2001, 132, 578-86, Diabetes , 1999, 48, 1794-1800, J. Pharmacol. Exp. , 2007, 320, 323-30, Diabetes , 2008, 57 , 1723-29).

Phlorizin was evaluated as the first SGLT inhibitor extracted from the root bark of apple trees, but was not developed as a drug due to metabolic instability in the intestinal tract. Bristol-Myers Squibb developed a C-aryl glucoside, dapagliflozin, as a potent selective SGLT2 inhibitor for the treatment of type 2 diabetes (Meng, W. et al. J. Med. Chem. 2008, 51, 1145-1149). On the other hand, Johnson & Johnson and Mitsubishi Tanabe Pharma jointly developed another novel C-aryl glucoside-induced SGLT2 inhibitor, canagliprofine (WO2008 of Tanebe et al. / 013321).

WO2008 / 013321

Lee, J. et. al., Bioorg. Med. Chem. 2010, 18, 2178-2194 van den Heuvel, L. P. et. al. Hum. Genet. 2020, 111, 544-547 J. Clin. Invest., 1994, 93, 397-404 Br. J. Pharmacol., 2001, 132, 578-86 Diabetes, 1999, 48, 1794-1800 J. Pharmacol. Exp., 2007, 320, 323-30 Diabetes, 2008, 57, 1723-29 Meng, W. et. al., J. Med. Chem. 2008, 51, 1145-1149

It is an object of the present invention to provide a novel isodorine derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

Another object of the present invention is to provide a novel method for preparing a novel isodorine derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

Another object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of diabetes, insulin resistance disease or obesity, which comprises a novel isodrine derivative, an isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof .

The present invention provides an isoindoline derivative compound represented by the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[Chemical Formula 1]

In Formula 1,

Of the R _1, R _2, R ₃ or R ₄ are each independently -H, halogen, nitro, cyano, hydroxyl, C ₁ -C ₆ linear or branched alkyl, C ₁ -C ₆ of Straight or branched chain alkoxy or C ₂ -C ₄ linear or branched alkoxycarbonyl.

The compound represented by Formula 1, its isomer, pharmaceutically acceptable salt thereof, or hydrate or solvate thereof acts as an inhibitor of sodium-dependent glucose transport (SGLT), and in particular acts as an excellent inhibitor against SGLT2 . As a result, the compound represented by Formula 1, its isomer, pharmaceutically acceptable salt thereof, or hydrate or solvate thereof acts as an inhibitor against a sodium-dependent glucose carrier found in the intestines and kidneys of mammals Diabetes, insulin resistance diseases and obesity. In particular, the compound represented by Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof may be used for the treatment and / or prophylaxis of type 2 diabetes, hyperglycemia, hyperinsulinemia, obesity, Syndrome, diabetic complications, atherosclerotic sclerosis and diseases associated therewith.

In the present invention, the compound represented by Formula 1 may be a compound represented by Formula 2 below.

(2)

Of the R _1, R _2, R ₃ or R ₄ are each independently -H, halogen, nitro, cyano, hydroxyl, C ₁ -C ₆ linear or branched alkyl, C ₁ -C ₆ of Straight-chain or branched alkoxy group or C ₂ -C ₄ linear or branched alkoxycarbonyl.

In the present invention, R ₁ and R ₂ may be the same or different from each other in the general formula (1) or (2).

In the present invention, R < ₃ > and R < ₄ > may be the same or different from each other in the formula (1) or (2).

In the present invention, each of R ₁ , R ₂ , R ₃ and R ₄ independently represents -H, -F, -Cl, -Br, -CN, -CH ₃ , -CH _{2 CH 3, -OCH 3, -OCH} 2 CH 3, -C (= O) may be OCH _3, or _{-C (= O) OCH 2 CH} 3.

In the present invention, the compound represented by the above formula (1) or (2), or an isomer thereof, may be a compound enumerated below.

1) 2- [3- (l, 3-Dihydro-isoindol-2-ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro-

2) 2- [3- (1,3-Dihydro-isoindol-2-ylmethyl) -4-methyl- phenyl] -6- hydroxymethyl-tetrahydro-

3) 2- [4-Chloro-3- (l, 3-dihydro-isoindol-2-ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro-

4) 2- [5- (l, 3-Dihydro-isoindol-2-ylmethyl) -2-methyl-phenyl] -6- hydroxymethyl-tetrahydro-

5) 2- [3- (1,3-Dihydro-isoindol-2-ylmethyl) -4-fluoro-phenyl] -6- hydroxymethyl-tetrahydro- All

6) 2- [5- (1,3-Dihydro-isoindol-2-ylmethyl) -2-fluoro-phenyl] -6- hydroxymethyl-tetrahydro- All

7) 2- [3- (1,3-Dihydro-isoindol-2-ylmethyl) -4-methoxy-phenyl] -6- hydroxymethyl-tetrahydro- All

8) 2- [5- (1,3-Dihydro-isoindol-2-ylmethyl) -2,4-difluoro-phenyl] -6- hydroxymethyl-tetrahydro- 5-triol

9) 2- [4-Chloro-3- (5-methoxy-l, 3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol

10) 2- [4-Fluoro-3- (5-methoxy-l, 3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- 4,5-triol

11) 2- [4-Chloro-3- (4-methoxy-l, 3-dihydro-isoindol-2-ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol

12) 2- [3- (4-Bromo- l, 3-dihydro-isoindol-2-ylmethyl) -4-chloro-phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol

13) 2- [3- (4-Bromo-l, 3-dihydro-isoindol-2-ylmethyl) -4-fluoro-phenyl] -6- hydroxymethyl-tetrahydro- 4,5-triol

14) 2- [3- (4-Fluoro-l, 3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- All

15) 2- [4-Chloro-3- (4-fluoro-l, 3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol

16) 2- [4-Fluoro-3- (4-fluoro-l, 3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- 4,5-triol

17) 2- [3- (4-Fluoro-l, 3-dihydro-isoindol-2-ylmethyl) -4-methyl- phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol

18) 2- [3- (4-Fluoro-l, 3- dihydro-isoindol-2-ylmethyl) -4-methoxy- phenyl] -6- hydroxymethyl- tetrahydro- 4,5-triol

19) 2- [4-Chloro-3- (5-fluoro-l, 3- dihvdro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol

20) 2- [4-Fluoro-3- (5-fluoro-l, 3- dihvdro- isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahvdro- 4,5-triol

21) 2- [4-Chloro-3- (5-chloro-l, 3- dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- 5-triol

22) 2- [3- (5-Chloro-l, 3- dihvdro-isoindol-2-ylmethyl) -4-methyl- phenyl] -6- hydroxymethyl-tetrahydro- 5-triol

23) 2- [4-Chloro-3- (5-methyl-l, 3-dihydro-isoindol- 2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- 5-triol

24) 2- [4-Chloro-3- (4-cyano-1,3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol

25) 2- [4-Chloro-3- (5-methoxycarbonyl-l, 3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- , 4,5-triol.

Preferably, the above-listed compounds may be optical isomers of the? -D form. For example, the compounds represented by the above formula (1) or (2) may be the compounds listed below.

1 -) (2S, 3R, 4R, 5S, 6R) -2- [3- (1,3- Dihydro- isoindol- 2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- Pyran-3,4,5-triol

2-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (l, 3- dihydro- isoindol- 2- ylmethyl) -4-methyl- phenyl] -6- hydroxymethyl -Tetrahydro-pyran-3,4,5-triol < / RTI >

3-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (l, 3- dihydro- isoindol- 2- ylmethyl) -phenyl] -6- hydroxymethyl -Tetrahydro-pyran-3,4,5-triol < / RTI >

4-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [5- (l, 3- dihydro- isoindol- 2- ylmethyl) -2- methyl- phenyl] -6- hydroxymethyl -Tetrahydro-pyran-3,4,5-triol < / RTI >

5-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (l, 3- dihydro- isoindol- 2- ylmethyl) -4-fluoro-phenyl] -6- Methyl-tetrahydro-pyran-3,4,5-triol

6-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [5- (l, 3- dihydro- isoindol- 2- ylmethyl) -2-fluoro-phenyl] -6- Methyl-tetrahydro-pyran-3,4,5-triol

7-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (1,3- dihydro- isoindol- 2- ylmethyl) -4-methoxy- phenyl] -6- Methyl-tetrahydro-pyran-3,4,5-triol

8-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [5- (l, 3- dihydro- isoindol- 2- ylmethyl) -2,4-difluoro- - hydroxymethyl-tetrahydro-pyran-3,4,5-triol

9-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (5- methoxy- l, 3- dihydro- isoindol- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol

10-1) (2S, 3R, 4R, 5S, 6R) -2- [4-Fluoro-3- -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

11-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro-3- (4- methoxy- l, 3- dihvdro- isoindol- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol

12-1) (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Bromo- l, 3- dihydro- isoindol- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol

13-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Bromo- l, 3- dihvdro- isoindol- -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

14-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Fluoro-l, 3-dihydro- isoindol- 2- ylmethyl) -phenyl] -6- Methyl-tetrahydro-pyran-3,4,5-triol

15-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4-fluoro-l, 3- dihvdro- isoindol- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol

16-1) (2S, 3R, 4R, 5S, 6R) -2- [4-Fluoro-3- -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

17-1) (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Fluoro-l, 3-dihydro- isoindol- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol

18-1) (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Fluoro-l, 3- dihydro- isoindol- 2- ylmethyl) -4- methoxy- phenyl] -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

19-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (5-fluoro-l, 3- dihvdro- isoindol- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol

20-1) (2S, 3R, 4R, 5S, 6R) -2- [4-Fluoro-3- -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

21-1) (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro- - hydroxymethyl-tetrahydro-pyran-3,4,5-triol

22-1) (2S, 3R, 4R, 5S, 6R) -2- [3- (5-Chloro- l, 3- dihvdro- isoindol- - hydroxymethyl-tetrahydro-pyran-3,4,5-triol

23-1) (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro- - hydroxymethyl-tetrahydro-pyran-3,4,5-triol

24-1) (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro-3- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol

25-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro-3- (5-methoxycarbonyl-l, 3-dihydro- isoindol- ] -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

In the present invention, the isomers may be enantiomers and include not only the pure enantiomers but also their racemates.

In the present invention, the isomers may include all kinds of isomers, and preferably include stereoisomers such as diastereomers or enantiomers. Also, when the isomer is an enantiomer, it includes not only each enantiomer but also racemates in which the enantiomers are mixed.

In the present invention, the pharmaceutically acceptable salt is a salt commonly used in the pharmaceutical industry, and may be an inorganic acid salt, an organic acid salt, a sulfonic acid salt, an amino acid salt or an amine salt. For example, the salt may be an inorganic acid salt prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid or sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid But are not limited to, malic acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, Sulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid or naphthalenesulfonic acid, glycine, arginine Or an amino acid salt prepared by lysine or the like, or an amine salt prepared by using trimethylamine, triethylamine, ammonia, pyridine, picoline or the like. However, Quot; is not limited to a specific kind of salt.

Preferably, the salt may be a salt prepared using maleic acid.

In the present invention, the hydrate or solvate may comprise a stoichiometric or non-stoichiometric amount of water that is coupled with non-covalent intermolecular forces.

The hydrate may contain 1 equivalent or more, preferably 1 to 5 equivalents of water. Such a hydrate can be prepared by crystallizing the compound represented by the above formula (1) or (2) of the present invention, the above-mentioned compound, an isomer thereof or a pharmaceutically acceptable salt thereof from a solvent containing water or water.

The solvate may comprise a stoichiometric or non-stoichiometric amount of solvent coupled with non-covalent intermolecular forces. Preferred examples of the solvent include nonvolatile, non-toxic or solvents suitable for administration to humans, for example, ethanol, methanol, propanol, methylene chloride, and the like.

The present invention

Reacting a compound represented by the following formula (3) or an isomer thereof with a compound represented by the following formula (4) to prepare a compound represented by the following formula (5) or an isomer thereof; And

There is provided a process for preparing a compound represented by the following general formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof, which comprises deacetylating a compound represented by the general formula (5) or an isomer thereof .

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 1]

In the above formulas (1), (3), (4) and (5)

Of the R _1, R _2, R ₃ or R ₄ are each independently -H, halogen, nitro, cyano, hydroxyl, C ₁ -C ₆ linear or branched alkyl, C ₁ -C ₆ of A linear or branched alkoxy group or a C ₂ -C ₄ linear or branched alkoxycarbonyl;

Wherein X is -CH ₂ Br, -CH ₂ Cl or -C (= O) H, and;

Ac is an acetyl group.

In the present invention, the compound represented by the formula (3) may be a compound represented by the following formula (6), (7) or (8)

[Chemical Formula 6]

(7)

[Chemical Formula 8]

Wherein R ₁ or R ₂ are each independently selected from the group consisting of -H, a halogen, a nitro group, a cyano group, a hydroxyl group, a C ₁ -C ₆ linear or branched alkyl group, a C ₁ -C ₆ Straight or branched chain alkoxy group or C ₂ -C ₄ straight or branched chain alkoxycarbonyl;

Ac is an acetyl group.

In the present invention, R ₁ , R ₂ , R ₃ or R ₄ are each independently selected from the group consisting of -H, -F, -, _{Cl, -Br, -CN, -CH 3} , -CH 2 CH 3, -OCH 3, -OCH 2 CH 3, -C (= O) OCH 3, or _{-C (= O) OCH 2 CH} 3 may be have.

In the present invention, when the compound represented by Formula 3 is a compound represented by Formula 6 or 7, the compound represented by Formula 6 or Formula 7 or an isomer thereof is reacted with the compound represented by Formula 4 The compound represented by the general formula (5) or an isomer thereof can be produced.

The reaction of the compound represented by the above formula (6) or (7) or the isomer thereof with the compound represented by the above formula (4) can be carried out in the presence of a base. The base may be a metal hydride or metal carbonate, preferably sodium hydride, potassium carbonate, sodium carbonate or a mixture thereof, more preferably sodium hydride.

The reaction of the compound represented by the above formula (6) or (7) or the isomer thereof with the compound represented by the above formula (4) can be carried out in a solvent. The solvent may be dimethyl formamide, methyl acetate, ethyl acetate, diethyl ether, methyl-tert-butyl ether or a mixture thereof, preferably dimethyl formamide.

The reaction of the compound represented by the above formula (6) or (7) or the isomer thereof with the compound represented by the above formula (4) is carried out at -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C, .

For example, the compound represented by formula (5) of the present invention can be prepared by the reaction represented by the following reaction formula (1) or (2).

[Reaction Scheme 1]

[Reaction Scheme 2]

In the above Reaction Schemes 1 and 2,

R ₁ , R ₂ , R _3, R ₄ , or Ac are each independently as defined above in formulas 4, 5, 6 and 7.

In the present invention, when the compound represented by the general formula (3) is a compound represented by the general formula (8), the compound represented by the general formula (8) or an isomer thereof is reacted with a compound represented by the general formula (4) Isomers.

The reaction of the compound represented by the formula (8) or an isomer thereof and the compound represented by the formula (4) can be carried out in the presence of an acid and a reducing agent. The acid may be acetic acid, preferably acetic anhydride, and the reducing agent may be sodium triacetoxyborohydride or sodium borohydride (NaBH ₄ ).

The reaction of the compound represented by the formula (8) or an isomer thereof and the compound represented by the formula (4) can be carried out in a solvent. The solvent may be 1,2-dichloromethane, 1,2-dichloroethane or mixtures thereof, preferably 1,2-dichloroethane.

The reaction of the compound represented by the formula (8) or an isomer thereof and the compound represented by the formula (4) can be carried out at -10 ° C to 10 ° C, preferably -5 ° C to 5 ° C, more preferably 0 ° C.

For example, the compound represented by formula (5) of the present invention can be prepared by a reaction represented by the following reaction formula (3).

[Reaction Scheme 3]

In Scheme 3,

R ₁ , R ₂ , R _3, R ₄ , or Ac are each independently as defined above in formulas 4, 5 and 8.

In the present invention, the compound represented by the general formula (5) or an isomer thereof may be subjected to a deacetylation reaction to produce a compound represented by the following general formula (1) or an isomer thereof.

In the embodiments of the present invention, the deacetylation reaction may be carried out by reacting the compound represented by Chemical Formula 5 or an isomer thereof with a hydroxide of an alkali metal or oxalic acid in a solvent. The solvent may be tetrahydrofuran, water, 1,4-dioxane, methanol or a mixture thereof, preferably tetrahydrofuran / water, 1-2-dioxane / water, tetrahydrofuran / methanol or tetrahydrofuran / Methanol / water, more preferably tetrahydrofuran / methanol or tetrahydrofuran / methanol / water.

The hydroxide of the alkali metal may be lithium hydroxide, sodium hydroxide or potassium hydroxide.

For example, the deacetylation reaction can be carried out by reacting the compound represented by the formula (5) or an isomer thereof with sodium methoxide in a tetrahydrofuran / methanol solvent.

In other embodiments of the present invention, the deacetylation reaction may be carried out by reacting the compound represented by Formula 5 or an isomer thereof with a carbonate of ammonia or an alkali metal in a solvent. The solvent may be methanol, ethanol, isopropanol or butanol, preferably methanol. The ammonia may be an aqueous ammonia solution or an ammonia gas, and the carbonate of the alkali metal may be potassium carbonate or sodium carbonate.

For example, the compound represented by the formula (1) can be prepared from the compound represented by the formula (5) by the reaction represented by the following reaction formula (4).

[Reaction Scheme 4]

In Scheme 4,

R ₁ , R ₂ , R _3, R ₄ , or Ac are each independently as defined in the above formulas (1) and (5).

The present invention relates to a method for the treatment or prevention of diseases selected from the group consisting of diabetes, insulin resistance diseases and obesity, which comprises a compound represented by the following formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof A pharmaceutical composition is provided.

[Chemical Formula 1]

In Formula 1,

The pharmaceutical composition of the present invention acts as an inhibitor of the sodium-dependent glucose transporter (SGLT), and in particular acts as an inhibitor against SGLT2. As a result, the pharmaceutical composition of the present invention acts as an inhibitor against sodium-dependent glucose transporters found in the intestines and kidneys of mammals and is useful for the treatment and prevention of diseases such as diabetes, insulin resistance diseases and obesity. In particular, the pharmaceutical composition of the present invention is useful for the prevention and treatment of type 2 diabetes, hyperglycemia, hyperinsulinemia, obesity, neutropenia, syndrome X, diabetic complications, atherosclerotic sclerosis and related diseases.

In the pharmaceutical composition of the present invention, the compound represented by Formula 1 may be a compound represented by Formula 2 below.

(2)

In the pharmaceutical composition of the present invention, R ₁ and R ₂ in Formula 1 or 2 may be the same or different from each other.

In the pharmaceutical composition of the present invention, R ₃ and R ₄ in Formula 1 or Formula 2 may be the same or different from each other.

In the pharmaceutical composition of the present invention, R ₁ , R ₂ , R ₃ or R ₄ are each independently -H, -F, -Cl, -Br, -CN, -CH ₃ , it may be _{-CH 2 CH 3, -OCH 3,} -OCH 2 CH 3, -C (= O) OCH 3, or _{-C (= O) OCH 2 CH} 3.

The present invention provides a method for the treatment or prevention of one or more diseases selected from the group consisting of diabetes, insulin resistance diseases and obesity, including the compounds listed below, isomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof A pharmaceutical composition is provided:

Preferably, the pharmaceutical compositions of the present invention may comprise enantiomers of the? -D form of the compounds listed above.

For example, the invention encompasses one or more diseases selected from the group consisting of diabetes, insulin resistance diseases and obesity, including the compounds listed below, isomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, For the treatment or prevention of < RTI ID = 0.0 >

As described above, in the present invention, isomers may be enantiomers and include not only the pure enantiomers but also their racemates.

The pharmaceutical composition of the present invention may contain conventional pharmaceutically acceptable additives. The pharmacologically acceptable means pharmacologically acceptable and does not cause an allergic reaction such as gastrointestinal disorder, dizziness or the like when administered to humans, examples of which include carriers, excipients and diluents. . Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The pharmaceutical composition may further contain an antioxidant, a buffer, a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.

The pharmaceutical composition of the present invention may be formulated according to a conventional method and may be formulated into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions or parenteral administration such as intramuscular, intravenous or subcutaneous administration Can be prepared in a dosage form.

When the pharmaceutical composition of the present invention is prepared in the form of an oral dosage form, examples of the additives to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, Calcium, gelatin, talc, surfactants, suspending agents, emulsifying agents, diluents and the like.

When the pharmaceutical composition is formulated into a liquid preparation such as a suspension for oral administration, a liquid medicament, an emulsion or a syrup, a simple diluent such as water, liquid or paraffin, a humectant, a sweetener, a fragrance, a preservative, A coloring agent and the like may be added to formulate it. For example, the pharmaceutical composition may be formulated by further adding a sweetening agent such as peppermint oil, eucalyptus oil or saccharin.

When the pharmaceutical composition of the present invention is prepared in the form of an injection, the additive may include water, saline solution, glucose aqueous solution, pseudosugar solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, Rides, surfactants, suspending agents, and emulsifiers.

In the pharmaceutical composition of the present invention, the content of the additive is not particularly limited, and can be appropriately adjusted within the range of contents used in conventional formulation.

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intrathecally, or topically), and the dosage may vary depending on the patient's body weight, age, sex, The range may vary depending on the administration time, administration method, administration period or habit, excretion rate, sperm specificity, properties of the preparation, severity of the disease and the like.

The pharmaceutical composition of the present invention contains about 0.01 to 100 mg of the compound represented by Formula 1 or 2, the compound enumerated above, the isomer thereof, the pharmaceutically acceptable salt thereof, or the hydrate or solvate thereof as the active ingredient / kg / day, preferably 0.1 to 30 mg / kg / day, and may be administered once or several times a day as needed.

The pharmaceutical composition of the present invention may further comprise a therapeutic agent for one or more other types of antidiabetic agents or antidiabetic agents that can be administered orally or by injection.

The anti-diabetic agent may be an insulin secretagogue or an insulin sensitizer, and may preferably be one or more antidiabetic or antihyperglycemic agents, including other antidiabetic agents having a mechanism of action different from that of the SGLT2 inhibitor. Specific examples thereof include agonists, sulfonylureas, glucosidase inhibitors, peroxisome proliferator activated receptor (PPAR) agonists (e.g., thiazole, pyrimidinedione), dipeptidyl peptides Glucagon-like peptide-1 (GLP-1), protein tyrosine phosphatase 1B (PTP1B) inhibitor, glycogen phosphorylase inhibitor and glucose-6- Phosphatase inhibitors and the like.

Examples of therapeutic agents for diseases other than the antidiabetic agent include anti-obesity agents, antihypertensive agents, anti-platelet agents, anti-atherosclerotic agents, lipid lowering agents, and mixtures thereof.

The compounds of the present invention act as inhibitors of sodium dependent glucose transport (SGLT), and may in particular act as excellent inhibitors to SGLT2. Therefore, the compounds of the present invention are effective for the treatment and prevention of diseases such as diabetes, insulin resistance diseases and obesity.

Figures 1A-1D show the sodium-dependent glucose transport inhibitory effects of the compounds according to the invention.
FIGS. 2A to 2D are graphs showing blood glucose-lowering effects of the compounds according to the present invention. FIG.

Hereinafter, preferred embodiments and experimental examples are provided to facilitate understanding of the present invention. However, the following examples and experimental examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples and experimental examples.

In addition, the reagents and solvents mentioned below were purchased from Sigma-Aldrich unless otherwise noted, and ¹ H-NMR data were measured with a Bruker Advance 400 NMR spectrometer from Bruker.

Example 1: Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (l, 3- dihydro- isoindol- 2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- Preparation of Pyran-3,4,5-triol

Step 1) (2S, 3R, 4R, 5S, 6R) -6-Acetoxymethyl-2- [3- (l, 3- dihydro- isoindol- Preparation of 5-triacetoxy-tetrahydro-pyran

Method A)

228 milligrams (1.91 millimoles) of isoindoline were dissolved in 20 milliliters (mL) of dimethylformamide and 153 milligrams (3.52 millimoles) of 55% (v / v) sodium hydride at 0 ^° C And the mixture was stirred for about 40 minutes. Thereafter, 3 - ((2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-yl] benzyl bromide 800 100 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure. The residue was purified by column chromatography to obtain 420 mg of the compound (yield: 70.7%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ):? 7.39 (1H, s), 7.21-7.19 (5H, m), 7.01 (2H, m), 4.01-3.92 (6H, m), 3.82 (1H, m), 2.08 (6H, d), 2.02 (3H, s), 1.82 (3H, s)

Method B)

925 mg (2.12 mmol) of 3 - ((2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran- (2.45 mmol) of isoindoline, 254 mg (4.24 mmol) of acetic acid and 674 mg (3.18 mmol) of sodium triacetoxyborohydride were added to the reaction mixture and the mixture was stirred at about 20 ° C. for about 3 The reaction mixture was cooled to 0 ^° C, neutralized with saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic solution was dried over anhydrous magnesium sulfate, concentrated by filtration and then purified by column chromatography To obtain 850 mg of the above compound (yield: 74.6%).

Step 2) A solution of (2S, 3R, 4R, 5S, 6R) -2- [3- (l, 3- dihydro- isoindol- 2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- -3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -6-acetoxymethyl-2- [3- (1,3- dihydro- isoindol- 2- ylmethyl) -phenyl] -3 (28% (w / w)) dissolved in methanol was dissolved in 15 ml of tetrahydrofuran and 30 ml of methanol, followed by the addition of 1.21 (w / w) of sodium methoxide dissolved in methanol Milliliter (6.32 mmol) was added thereto, followed by stirring at room temperature for about 2 hours. After the reaction was concentrated, 100 milliliters of water was added to the filtrate, followed by extraction with ethyl acetate, drying over anhydrous magnesium sulfate, filtration and concentration. The residue was purified by column chromatography to obtain 450 mg of the compound (yield: 76.6%).

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.50 (1H, d), 7.43 (1H, d), 7.35 (1H, dd), 7.30 (1H, s), 7.20 (4H, s), 4.97 ( (2H, m), 4.80 (2H, m), 4.01 (1H, d), 3.95-3.84 (6H, m)

Example 2: Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (l, 3- dihydro- isoindol- 2- ylmethyl) -4-methyl- phenyl] -6- hydroxymethyl -Tetrahydro-pyran-3,4,5-triol < / RTI >

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2- (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran instead of benzyl bromide -2-yl) benzyl bromide, the title compound was synthesized in the same manner as in Example 1).

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.43 (1H, s), 7.17 (4H, m), 7.12 ~ 7.05 (2H, m), 4.12 (1H, s), 3.87 ~ 3.79 (6H, m ), 4.01 (1H, d), 3.64-3.52 (4H, m), 3.40-3.35 (2H, m), 2.28

Example 3 Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (l, 3- dihydro- isoindol- 2- ylmethyl) -phenyl] -6- hydroxymethyl -Tetrahydro-pyran-3,4,5-triol < / RTI >

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.62 (1H, s), 7.33 (1H, d), 7.19 (4H, s), 7.15 (1H, d), 4.07 (2H, m), 4.30 ~ M), 3.32 (2H, m), 3.64 (2H, s), 3.53-3.49 (5H, m)

Example 4 Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [5- (l, 3- dihydro- isoindol-2- ylmethyl) -2- methyl- phenyl] -6- hydroxymethyl -Tetrahydro-pyran-3,4,5-triol < / RTI >

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.38 (1H, s), 7.22 ~ 7.16 (4H, m), 7.11 ~ 7.04 (2H, m), 5.22 ~ 5.14 (2H, m), 4.07 (2H m), 4.71 (1H, d), 4.58 (1H, d), 4.11 (2H, m), 4.03 (1H, m), 3.81 m), 2.22 (3 H, s)

Example 5 Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (l, 3- dihydro- isoindol- 2- ylmethyl) -4-fluoro-phenyl] -6- Preparation of methyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2- (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydrobenzo [b] thiophene instead of benzyl bromide Pyran-2-yl) benzyl bromide, the title compound was synthesized in the same manner as in Example 1).

¹ H NMR (400 MHz, DMSO-d ₆ ):? 7.46 (1H, dd), 7.31-7.27 (1H, m), 7.24-7.11 ), 4.49 (1H, t), 4.03 (1H, d), 3.95-3.84 (6H, m), 3.72-3.68

Example 6 Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [5- (l, 3- dihydro- isoindol- 2- ylmethyl) -2-fluoro-phenyl] -6- Preparation of methyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2- (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydrobenzo [b] thiophene instead of 4- Pyran-2-yl) benzyl bromide, the title compound was synthesized in the same manner as in Example 1).

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.45 (1H, dd), 7.30 (1H, m), 7.25 ~ 7.15 (5H, m), 4.04 (1H, d), 3.95 ~ 3.87 (6H, m ), 3.70 (1H, m), 3.35-3.15 (5H, m)

Example 7 Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (l, 3- dihydro- isoindol- 2- ylmethyl) -4- methoxy- phenyl] -6- Preparation of methyl-tetrahydro-pyran-3,4,5-triol

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.52 (1H, s), 7.22 (1H, d), 7.17 ~ 7.11 (4H, m), 6.83 (1H, d), 4.97 (2H, d), (2H, m), 3.59-3.47 (7H, m), 3.24 (1H, d)

Example 8: Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [5- (l, 3- dihydro- isoindol- 2- ylmethyl) -2,4-difluoro- - hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2- (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl < / RTI > -Tetrahydropyran-2-yl) benzyl bromide, the title compound was synthesized in the same manner as in Example 1).

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.52 (1H, t), 7.23 ~ 7.13 (5H, m), 5.00 (2H, m), 4.95 (1H, d), 4.51 (1H, t), (2H, m), 4.01-3.88 (6H, m), 3.36-3.14 (6H, m)

Example 9 Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (5- methoxy- l, 3- dihydro- isoindol- Preparation of 6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2- (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran instead of benzyl bromide -2-yl) benzyl bromide, and using the same molar 5-methoxyisoindoline instead of isoindoline, the title compound was synthesized.

¹ H NMR (400 MHz, DMSO-d ₆ ):? 7.51 (IH, d), 7.38 (IH, d), 7.27 (1H, dd), 4.96 (2H, m), 4.85 (1H, d), 4.46 , 3.29-3.07 (5H, m)

Example 10) (2S, 3R, 4R, 5S, 6R) -2- [4-Fluoro-3- (5- methoxy- l, 3- dihydro- -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2- (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydrobenzo [b] thiophene instead of benzyl bromide Pyran-2-yl) benzyl bromide and using the same molar 5-methoxyisoindoline instead of isoindoline, the title compound was synthesized.

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.45 (1H, dd), 7.29 ~ 7.26 (1H, m), 7.11 (1H, t), 6.81 (1H, d), 6.73 (1H, dd), (2H, m), 4.81 (1H, d), 4.46 (1H, t), 4.02 (1H, d), 3.89-3.79 m), 3.28 ~ 3.08 (5H, m)

Example 11 Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4- methoxy- l, 3- dihydro- isoindol- Preparation of 6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2- (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran instead of benzyl bromide -2-yl) benzyl bromide, and using the same molar 4-methoxyisoindoline instead of isoindoline, the title compound was synthesized in the same manner as in Example 1).

¹ H NMR (400 MHz, DMSO-d ₆ ):? 7.32 (IH, d), 7.29 (IH, d), 7.25-7.15 (3H, m), 6.84 M), 3.19-3.02 (6H, m), 4.93 (1H, d), 4.93 m)

Example 12) (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Bromo- l, 3- dihvdro- isoindol- Preparation of 6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-one in method B) of step 1 of Example 1) (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran in place of benzaldehyde -2-yl) benzaldehyde, and using the same molar amount of 4-bromoisoindoline instead of isoindoline, the title compound was synthesized.

¹ H NMR (400 MHz, DMSO-d ₆ ):? 7.51 (IH, d), 7.39 (IH, d), 7.29 (2H, d), 4.87 (1H, dd), 4.50 (1H, t), 4.06-3.92 (7H, m), 3.70-3.68

Example 13) (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Bromo- l, 3- dihvdro- isoindol- 2- ylmethyl) -4- fluoro- -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-one in method B) of step 1 of Example 1) (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-yl) The title compound was synthesized in the same manner as in Example 1 except that benzaldehyde was used and 4-bromoisoindoline was used instead of isoindoline.

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.45 (1H, dd), 7.39 (1H, d), 7.29 (1H, m), 7.24 (1H, d), 7.17 ~ 7.11 (2H, m), (1H, m), 4.75 (2H, m), 4.82 (1H, d), 4.46 4H, m)

Example 14) (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Fluoro-l, 3-dihydro- isoindol- 2- ylmethyl) -phenyl] -6- Preparation of methyl-tetrahydro-pyran-3,4,5-triol

The title compound was synthesized in the same manner as in Example 1), except that the same molar amount of 4-fluoroisoindoline was used instead of isoindoline in the method B) of the step 1 of the above Example 1) Respectively.

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.49 (1H, d), 7.45 (1H, m), 7.33 ~ 7.25 (2H, m), 7.17 ~ 7.10 (2H, m), 7.02 (1H, t ), 4.02 (1H, d), 3.95-3.91 (6H, m), 3.46 (1H, m), 3.31-3.13 (5H,

Example 15) (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro-3- (4-fluoro-l, 3-dihydro- isoindol- Preparation of 6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-one in method B) of step 1 of Example 1) (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran in place of benzaldehyde -2-yl) benzaldehyde, and using the same molar 4-fluoroisopyridine instead of isoindoline, the title compound was synthesized.

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.52 (1H, d), 7.39 (1H, d), 7.29 ~ 7.23 (2H, m), 7.09 (1H, d), 7.02 (1H, t), (2H, m), 3.99-3.94 (6H, m), 3.44-3.15 (5H, m)

Fluoro-l, 3-dihydro-isoindol-2-ylmethyl) -phenyl] - (4- -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-one in method B) of step 1 of Example 1) (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydro-quinolin- Pyran-2-yl) benzaldehyde and using the same molar 4-fluoroisoindoline instead of isoindoline, the title compound was synthesized.

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.45 (1H, dd), 7.31 ~ 7.22 (2H, m), 7.15 ~ 7.07 (2H, m), 7.01 (1H, t), 4.95 (2H, dd ), 4.83 (1H, d), 4.46 (1H, t), 4.03 (1H, d), 3.94-3.91 (6H, m), 3.48-3.42

Example 17) (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Fluoro-l, 3-dihydro- isoindol- Preparation of 6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

¹ H NMR (400 MHz, DMSO-d ₆ ):? 7.43 (1 H, s), 7.19-7.13 (3H, m), 6.92 3.92 (4H, d), 3.77 (2H, s), 3.75-3.55 (5H, m), 3.40

Example 18) (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Fluoro-l, 3-dihydro- isoindol- 2- ylmethyl) -4- methoxy- phenyl] -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-one in method B) of step 1 of Example 1) (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydrobenzo [b] thiophene instead of 4- Pyran-2-yl) benzaldehyde and using the same molar 4-fluoroisoindoline instead of isoindoline, the title compound was synthesized.

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.46 (1H, s), 7.22 (1H, d), 7.11 (1H, m), 6.87 (1H, d), 6.83 ~ 6.81 (2H, m), (1H, d), 3.94 (1H, d), 3.94 (1H,

Example 19) (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro-3- Preparation of 6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-one in method B) of step 1 of Example 1) (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran in place of benzaldehyde -2-yl) benzaldehyde and using the same molar 5-fluoroisoindoline instead of isoindoline, the title compound was synthesized.

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.51 (1H, d), 7.39 (1H, d), 7.28 ~ 7.22 (2H, m), 7.08 (1H, dd), 7.00 (1H, m), (2H, m), 4.87 (2H, m), 4.84 (2H, m) 3.70 (1H, m), 3.43-3.14 (5H, m)

Example 20) (2S, 3R, 4R, 5S, 6R) -2- [4-Fluoro-3- -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-one in method B) of step 1 of Example 1) (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydro-quinolin- Pyran-2-yl) benzaldehyde and using the same molar 5-fluoroisoindoline instead of isoindoline, the title compound was synthesized.

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.44 (1H, m), 7.30 ~ 7.21 (3H, m), 7.14 ~ 7.06 (2H, m), 6.97 (1H, m), 4,95 (2H m), 4.82 (1H, d), 4.47 (1H, t), 4.02 (1H, d), 3.93-3.83 (6H, m), 3.72-3.65 )

Example 21) (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro-3- (5-chloro-1,3- dihydro- isoindol- - hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-one in method B) of step 1 of Example 1) (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran in place of benzaldehyde -2-yl) benzaldehyde and using the same molar 5-chloroisoindoline instead of isoindoline, the title compound was synthesized.

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.50 (1H, s), 7.39 ~ 7.24 (5H, m), 4,96 (2H, d), 4.86 (1H, d), 4.47 (1H, tm ), 4.03 (1H, d), 3.96-3.89 (6H, m), 3.69 (1H, m), 3.42-3.13

Example 22) (2S, 3R, 4R, 5S, 6R) -2- [3- (5-Chloro- l, 3- dihvdro- isoindol- - hydroxymethyl-tetrahydro-pyran-3,4,5-triol

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.43 (1H, s), 7.18 ~ 7.01 (5H, m), 4.10 (1H, s), 3.85 ~ 3.75 (6H, m), 3.61 ~ 3.47 (4H , < / RTI > m), 3.39-3.32 (2H, m), 2.27 (3H,

Example 23) (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro- - hydroxymethyl-tetrahydro-pyran-3,4,5-triol

① Method 1

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2- (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran instead of benzyl bromide -2-yl) benzyl bromide, and using the same molar 5-methylisoindoline instead of isoindoline, the title compound was synthesized.

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.57 (1H, s), 7.30 (1H, m), 7.14 (1H, d), 6.98 (2H, s), 6.92 (1H, s), 4.01 ( (1H, m), 3.86-3.79 (6H, m), 3.53-3.46 (5H, m), 3.21

② Method 2

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-one in method B) of step 1 of Example 1) (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran in place of benzaldehyde -2-yl) benzaldehyde, and using the same molar 5-methylisoindoline instead of isoindoline, the title compound was synthesized.

Example 24 (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro-3- Preparation of 6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-one in method B) of step 1 of Example 1) (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran in place of benzaldehyde -2-yl) benzaldehyde and using the same molar 4-cyanoisoindoline instead of isoindoline, the title compound was synthesized.

¹ H NMR (400 MHz, DMSO-d ₆ ):? 7.54 (IH, s), 7.45 (IH, d), 7.36 M), 3.46 (1H, t), 3.41 (1H, m)

Example 25 (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro-3- (5-methoxycarbonyl-l, 3-dihydro- ] -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

(2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-one in method B) of step 1 of Example 1) (2S, 3R, 4R, 5S, 6R) -3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran in place of benzaldehyde -2-yl) benzaldehyde and that the same molar amount of 5-methoxycarbonylisoindoline was used instead of isoindoline, the title compound was synthesized .

¹ H NMR (400 MHz, DMSO-d ₆ ):? 7.85 (1H, d), 7.75 (1H, s), 7.52 M), 3.23 (1H, m), 3.53 (2H, m)

Experimental Example 1: Evaluation of SGLT2 activity

Normal rats were used to measure the urinary and urinary levels after administration of the compounds according to the present invention, and the SGLT2 activity inhibitory effect of the compounds according to the present invention was evaluated.

Specifically, for the study of all animals, a male Sprague Dawley Rat weighing 200-250 g was purchased from Sam Taco, a manufacturer of experimental animals, and was adapted and used. A solution consisting of 5% (v / v) 1-methyl-2-pyrrolidone, 20% (v / v) PEG400 and 20 mM sodium diphosphate was used as the vehicle.

On the day of the experiment, the compound of the Example was dissolved in the vehicle at a concentration of 1 mg / ml, and the solution thus prepared was administered at a dose of 1 mg / kg, 5 mg / kg, 10 mg / kg, or 20 mg / Lt; RTI ID = 0.0 > 50% < / RTI > glucose solution. The same amount of vehicle (mL / kg) was used as the control group.

After the oral administration, water was freely taken from the metabolic cage during the experiment, and the urine was measured by the glucose oxidation method using Glucometer Breeze 2 (Bayer Co., Ltd.) for 24 hours. The results for compounds with excellent urinary sugar excretion are shown in Figs. 1a to 1d.

As shown in Figs. 1A to 1D, in an animal experiment using rats, the compounds according to the present invention inhibited the sodium-dependent glucose transporter (SGLT2) acting in the kidney and inhibited the glucose reabsorbed in the kidney, As shown in Fig. It was also found that urine volume increased with concentration.

Experimental Example 2: Measurement of blood glucose lowering effect

The compound of the present invention was orally administered to an alloxan-treated diabetic mouse, and then blood was collected to measure blood glucose, and the blood glucose lowering effect of the compound of the present invention was measured therefrom.

For all animal studies, male ICR Mice weighing 26-29 g were purchased from Sam Taco, a manufacturer of experimental animals, and adapted. To induce diabetic mice, single intravenous injection of aliskoic acid (Sigma) dissolved in cold physiological saline (4 ° C) at 45 mg / kg caused diabetes. After 5 days, the blood of the animals was collected through a tail vein, and diabetic mice having blood glucose levels ranging from 490 to 600 mg / dl were randomly selected and grouped into 10 mice (n = 10) per group. 5% Tween 80 (ICI Americas, Inc.) was used as a vehicle for oral administration of the compounds.

On the day of the experiment, the compound of Example was dissolved in a vehicle at a concentration of 1 mg / ml, and the solution was then administered at a dose of 1 mg / kg, 5 mg / kg, 10 mg / kg, or 20 mg / Lt; / RTI > in a single oral dose. As a control group, the same amount of vehicle (mL / kg) was used. As a comparative group, 20 mg / kg of 2- {3- [5- (4-fluorophenyl) thiophen- ] -4-methylphenyl} -6-hydroxymethyl-tetrahydropyran-3,4,5-triol (canagliprofine) was used. During the experiment, water was freely consumed. Blood was collected by time, and blood glucose by glucose oxidation method was measured using Glucometer Breeze 2 (Bayer).

The results are shown in Tables 1 to 4 and Figs. 2A to 2D, respectively.

Table 1 < tb > < tb > < tb > <

Table 2. Blood glucose level of mouse after administration of compound of Example 15 to alloxan-induced diabetic mice

Table 3. Blood glucose level of mouse after administration of compound of Example 22 to alloxan-induced diabetic mice

Table 4. Blood glucose level of mice after administration of compound of Example 23 to alloxan-induced diabetic mice

As shown in Tables 1 to 4 and FIGS. 2A to 2D, when the compound of the present invention was orally administered to the alloxan-treated diabetic mouse, blood was collected and blood glucose was measured. As a result, . From this, it was confirmed that the compound of the present invention inhibits reabsorption of glucose in the kidney and discharges it into the urine, thereby lowering blood glucose.

Claims

Claims 1. A compound represented by the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:
[Chemical Formula 1]

In Formula 1,
Of the R _1, R _2, R ₃ or R ₄ are each independently -H, halogen, nitro, cyano, hydroxyl, C ₁ -C ₆ linear or branched alkyl, C ₁ -C ₆ of Straight or branched chain alkoxy or C ₂ -C ₄ linear or branched alkoxycarbonyl.

The compound according to claim 1, wherein the compound represented by Formula 1 is a compound represented by Formula 2, an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:
(2)

The method according to claim 1 or 2, wherein R ₁ , R ₂ , R ₃ or R ₄ are each independently -H, -F, -Cl, -Br, -CN, -CH ₃ , -CH ₂ CH ₃ _{, -OCH 3, -OCH 2 CH 3} , -C (= O) OCH 3, -C (= O) OCH 2 CH 3 to a compound, isomer, pharmaceutically acceptable salt, or a thereof, Hydrate or solvate.

3. The method according to claim 1 or 2,
The compound represented by Formula 1 or Formula 2 or an isomer thereof is selected from the group consisting of the following compounds, isomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof:
1) 2- [3- (l, 3-Dihydro-isoindol-2-ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro-
2) 2- [3- (1,3-Dihydro-isoindol-2-ylmethyl) -4-methyl- phenyl] -6- hydroxymethyl-tetrahydro-
3) 2- [4-Chloro-3- (l, 3-dihydro-isoindol-2-ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro-
4) 2- [5- (l, 3-Dihydro-isoindol-2-ylmethyl) -2-methyl-phenyl] -6- hydroxymethyl-tetrahydro-
5) 2- [3- (1,3-Dihydro-isoindol-2-ylmethyl) -4-fluoro-phenyl] -6- hydroxymethyl-tetrahydro- All
6) 2- [5- (1,3-Dihydro-isoindol-2-ylmethyl) -2-fluoro-phenyl] -6- hydroxymethyl-tetrahydro- All
7) 2- [3- (1,3-Dihydro-isoindol-2-ylmethyl) -4-methoxy-phenyl] -6- hydroxymethyl-tetrahydro- All
8) 2- [5- (1,3-Dihydro-isoindol-2-ylmethyl) -2,4-difluoro-phenyl] -6- hydroxymethyl-tetrahydro- 5-triol
9) 2- [4-Chloro-3- (5-methoxy-l, 3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol
10) 2- [4-Fluoro-3- (5-methoxy-l, 3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- 4,5-triol
11) 2- [4-Chloro-3- (4-methoxy-l, 3-dihydro-isoindol-2-ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol
12) 2- [3- (4-Bromo- l, 3-dihydro-isoindol-2-ylmethyl) -4-chloro-phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol
13) 2- [3- (4-Bromo-l, 3-dihydro-isoindol-2-ylmethyl) -4-fluoro-phenyl] -6- hydroxymethyl-tetrahydro- 4,5-triol
14) 2- [3- (4-Fluoro-l, 3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- All
15) 2- [4-Chloro-3- (4-fluoro-l, 3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol
16) 2- [4-Fluoro-3- (4-fluoro-l, 3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- 4,5-triol
17) 2- [3- (4-Fluoro-l, 3-dihydro-isoindol-2-ylmethyl) -4-methyl- phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol
18) 2- [3- (4-Fluoro-l, 3- dihydro-isoindol-2-ylmethyl) -4-methoxy- phenyl] -6- hydroxymethyl- tetrahydro- 4,5-triol
19) 2- [4-Chloro-3- (5-fluoro-l, 3- dihvdro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol
20) 2- [4-Fluoro-3- (5-fluoro-l, 3- dihvdro- isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahvdro- 4,5-triol
21) 2- [4-Chloro-3- (5-chloro-l, 3- dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- 5-triol
22) 2- [3- (5-Chloro-l, 3- dihvdro-isoindol-2-ylmethyl) -4-methyl- phenyl] -6- hydroxymethyl-tetrahydro- 5-triol
23) 2- [4-Chloro-3- (5-methyl-l, 3-dihydro-isoindol- 2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- 5-triol
24) 2- [4-Chloro-3- (4-cyano-1,3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- , 5-triol
25) 2- [4-Chloro-3- (5-methoxycarbonyl-l, 3-dihydro-isoindol-2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- , 4,5-triol.

3. The method according to claim 1 or 2,
Wherein the compound represented by Formula 1 or Formula 2 is selected from the group consisting of the following compounds, an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:
1 -) (2S, 3R, 4R, 5S, 6R) -2- [3- (1,3- Dihydro- isoindol- 2- ylmethyl) -phenyl] -6- hydroxymethyl-tetrahydro- Pyran-3,4,5-triol
2-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (l, 3- dihydro- isoindol- 2- ylmethyl) -4-methyl- phenyl] -6- hydroxymethyl -Tetrahydro-pyran-3,4,5-triol < / RTI >
3-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (l, 3- dihydro- isoindol- 2- ylmethyl) -phenyl] -6- hydroxymethyl -Tetrahydro-pyran-3,4,5-triol < / RTI >
4-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [5- (l, 3- dihydro- isoindol- 2- ylmethyl) -2- methyl- phenyl] -6- hydroxymethyl -Tetrahydro-pyran-3,4,5-triol < / RTI >
5-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (l, 3- dihydro- isoindol- 2- ylmethyl) -4-fluoro-phenyl] -6- Methyl-tetrahydro-pyran-3,4,5-triol
6-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [5- (l, 3- dihydro- isoindol- 2- ylmethyl) -2-fluoro-phenyl] -6- Methyl-tetrahydro-pyran-3,4,5-triol
7-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (1,3- dihydro- isoindol- 2- ylmethyl) -4-methoxy- phenyl] -6- Methyl-tetrahydro-pyran-3,4,5-triol
8-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [5- (l, 3- dihydro- isoindol- 2- ylmethyl) -2,4-difluoro- - hydroxymethyl-tetrahydro-pyran-3,4,5-triol
9-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (5- methoxy- l, 3- dihydro- isoindol- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol
10-1) (2S, 3R, 4R, 5S, 6R) -2- [4-Fluoro-3- -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
11-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro-3- (4- methoxy- l, 3- dihvdro- isoindol- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol
12-1) (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Bromo- l, 3- dihydro- isoindol- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol
13-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Bromo- l, 3- dihvdro- isoindol- -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
14-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Fluoro-l, 3-dihydro- isoindol- 2- ylmethyl) -phenyl] -6- Methyl-tetrahydro-pyran-3,4,5-triol
15-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4-fluoro-l, 3- dihvdro- isoindol- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol
16-1) (2S, 3R, 4R, 5S, 6R) -2- [4-Fluoro-3- -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
17-1) (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Fluoro-l, 3-dihydro- isoindol- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol
18-1) (2S, 3R, 4R, 5S, 6R) -2- [3- (4-Fluoro-l, 3- dihydro- isoindol- 2- ylmethyl) -4- methoxy- phenyl] -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
19-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (5-fluoro-l, 3- dihvdro- isoindol- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol
20-1) (2S, 3R, 4R, 5S, 6R) -2- [4-Fluoro-3- -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
21-1) (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro- - hydroxymethyl-tetrahydro-pyran-3,4,5-triol
22-1) (2S, 3R, 4R, 5S, 6R) -2- [3- (5-Chloro- l, 3- dihvdro- isoindol- - hydroxymethyl-tetrahydro-pyran-3,4,5-triol
23-1) (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro- - hydroxymethyl-tetrahydro-pyran-3,4,5-triol
24-1) (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro-3- 6-Hydroxymethyl-tetrahydro-pyran-3,4,5-triol
25-1) Synthesis of (2S, 3R, 4R, 5S, 6R) -2- [4-Chloro-3- (5-methoxycarbonyl-l, 3-dihydro- isoindol- ] -6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol.

Reacting a compound represented by the following formula (3) or an isomer thereof with a compound represented by the following formula (4) to produce a compound represented by the following formula (5) or an isomer thereof; And
Deacetylation of the compound of formula 5
(1), an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which comprises:
(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 1]

In the above formulas (1), (4) and (5)
Of the R _1, R _2, R ₃ or R ₄ are each independently -H, halogen, nitro, cyano, hydroxyl, C ₁ -C ₆ linear or branched alkyl, C ₁ -C ₆ of A linear or branched alkoxy group or a C ₂ -C ₄ linear or branched alkoxycarbonyl;
Wherein X is -CH ₂ Br, -CH ₂ Cl or -C (= O) H, and;
Ac is an acetyl group.

The compound according to claim 6, wherein X of the compound represented by the general formula (3) is -CH ₂ Br or -CH ₂ Cl
Wherein the step of preparing the compound represented by the formula (5) is carried out under a base, a process for producing the compound represented by the formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof.

8. The method according to claim 7, wherein the base is a metal hydride, a compound represented by the formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

7. The compound according to claim 6, wherein X in the compound represented by Formula 3 is -C (= O) H,
Wherein the step of preparing the compound represented by the general formula (5) is carried out in the presence of an acid and a reducing agent, a method for producing the compound represented by the general formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof .

10. The method according to claim 9, wherein the acid is acetic acid, a compound of formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

10. The compound according to claim 9, wherein the reducing agent is sodium triacetoxyborohydride or sodium borohydride, an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof Gt;

Pharmaceuticals for the treatment or prophylaxis of diseases selected from the group consisting of diabetes mellitus, insulin resistance diseases and obesity including compounds represented by the following formula 1, isomers thereof, pharmaceutically acceptable salts thereof, or hydrates or solvates thereof Composition.
[Chemical Formula 1]

In Formula 1,
Of the R _1, R _2, R ₃ or R ₄ are each independently -H, halogen, nitro, cyano, hydroxyl, C ₁ -C ₆ linear or branched alkyl, C ₁ -C ₆ of Straight-chain or branched alkoxy group or C ₂ -C ₄ linear or branched alkoxycarbonyl.