WO2010074219A1 - Benzothiophen compound - Google Patents

Abstract

Disclosed is a compound useful as an active ingredient of a pharmaceutical composition for treating diabetes. Extensive studies have been made on compounds having an SGLT-1/SGLT-2 dual inhibitory activity, and it is found that a benzothiophen compound of the invention has an SGLT-1/SGLT-2 dual inhibitory activity, exhibits an excellent hypoglycemic activity on a mild hyperglycemic condition as well as a severe hyperglycemic condition and therefore has an excellent hypoglycemic activity regardless of the severity of the hyperglycemic condition, and also has an excellent urinary glucose excretion activity on a condition having a normal blood glucose level.  It is also found that the benzothiophen compound has an extremely high hypoglycemic activity on a mild hyperglycemic condition compared to those of compounds that can inhibit SGLT-2 selectively.  The compound has an SGLT-1/SGLT-2 dual inhibitory activity, an excellent hypoglycemic activity regardless of the severity of the hyperglycemic condition and an excellent urinary glucose excretion activity on a condition having a normal blood glucose level, and therefore can be used as an active ingredient of a pharmaceutical composition for preventing and/or treating diabetes-related diseases including type-1 diabetes, type-2 diabetes, insulin resistance disease and obesity and fatty liver diseases including nonalcoholic steatohepatitis (NASH).

Description

Benzothiophene compounds

The present invention relates to a benzothiophene compound useful as an active ingredient of a pharmaceutical composition, particularly a pharmaceutical composition for treating diabetes.

Diabetes is due to a decrease in insulin secretion from pancreatic β-cells (insufficient amount of insulin) and a decrease in insulin sensitivity in peripheral tissues such as muscle and liver (insufficient qualities of insulin). It is one of the diseases with metabolic syndrome. Due to its pathophysiological characteristics, diabetes is basically divided into two categories, type 1 and type 2. Type 1 diabetes is mainly caused by a decrease in insulin secretion, and type 2 diabetes is considered to have both pathophysiologically important causes of both insulin secretion decrease and insulin sensitivity decrease. Regardless of the type of diabetes, when the hyperglycemic state deteriorates to such an extent that it causes urinary glucose excretion and polyuria, this hyperglycemic state causes a vicious cycle (sugar reduction such as impaired insulin secretion from β cells and worsening insulin resistance in peripheral tissues). (Diabetes Care 13, 610, 1990, Diabetes Care 15, 442, 1992). Thus, hyperglycemia, insulin secretion deficiency, and insulin resistance are all closely related to the onset and development of pathological conditions while interacting with each other. In addition, chronic hyperglycemia is defined as a risk factor for complications including cardiovascular disease, nephropathy, neuropathy and retinopathy, and complications including cardiovascular disease, nephropathy, neuropathy and retinopathy (Annu. Rev. Med. 46, 257, 1995, Diabetes Care 18, 258, 1995, Ann. Intern. Med. 122, 561, 1995, Diabetes 44) , 968, 1995, Diabetes 47, 1703, 1995). Therefore, the treatment policy for diabetes is based on diet therapy and exercise therapy to control the increase in blood sugar. Currently, several oral anti-diabetic drugs and insulin preparations have been developed (Joslin ’s Diabetes Mellitus. 13th ed., 508, 1994). Although each drug shows high effectiveness for a specific patient, it is difficult to control a good blood glucose state in many diabetic patients.

In recent years, as an anti-diabetic drug that quickly normalizes hyperglycemia and at the same time improves the energy balance in the body, it inhibits Na ⁺ -glucose cotransporter (SGLT) involved in sugar absorption in the intestine or sugar reabsorption in the kidney Drugs (Na ⁺ -glucose cotransporter inhibitors) are drawing attention. SGLT has at least three types of isoforms, SGLT-1, SGLT-2 and SGLT-3. It is known that glucose in the small intestine is absorbed into the blood via SGLT-1, and the increase in blood glucose level can be suppressed by inhibiting SGLT-1 and inhibiting sugar absorption in the small intestine. (International Publication No. 2004/014932, JP 2004-196788, Japanese Diabetes Society II-P239 and II-P240 (2004), and American Diabetes Society 0510-P (2007)). On the other hand, blood sugar is filtered by the glomeruli, and the filtered sugar is reabsorbed in the proximal tubule via SGLT-2 (Am. J. Physiol. Renal. Physiol., 280, F10, 2001). In addition, SGLT-1 is also expressed in the proximal tubule, so it may be involved in sugar reabsorption, but no clear knowledge about the contribution to sugar reabsorption has been obtained ( Am. J. Physiol. Renal. Physiol., 280, F10, 2001). From these findings, inhibition of SGLT-2 or SGLT-2 and SGLT-1 is expected to excrete excess glucose in the urine and normalize blood glucose levels. Furthermore, it is conceivable to improve obesity and fatty liver disease associated with excessive nutrition by excreting energy in the body as glucose in urine (WO 2008/116195 and WO 2006/009149). Pamphlet).

As described above, such Na ⁺ -glucose cotransporter inhibitors are not only diabetics such as type 1 diabetes and type 2 diabetes, but also various insulin-related diseases including insulin resistance diseases and obesity, and non-alcoholic fats. It is expected as an excellent therapeutic agent and preventive agent for fatty liver diseases including non-alcoholic steatohepatis (NASH).

Na ⁺ - As the glucose cotransporter inhibitors was known conventionally O- glycosides, in recent years, without using the oxygen of glucosidic linkages O- glycosides C- glycoside Na ⁺ - glucose cotransporter It has been developed as a transporter inhibitor.

For example, a C-glycoside derivative represented by the following formula or a salt thereof is known to exhibit a hypoglycemic action as a Na ⁺ -glucose cotransporter inhibitor (see Patent Document 1, the symbols in the formula) See the publication.)

In this document, there is a description of the compound of the general formula including the compound of the present invention, but there is no specific disclosure or suggestion of the compound of the present invention by Examples or the like.

In addition, there is a document reporting that the compound described in Patent Document 1 can exist as a co-crystal with L-proline (Patent Document 2), but there is no specific disclosure or suggestion of the compound of the present invention.

In addition, it is known that a compound represented by the following formula exhibits a blood glucose lowering action as a Na ⁺ -glucose cotransporter inhibitor (see Patent Document 3, for the symbols in the formula refer to the publication) thing.).

In this document, there is a description of the compound of the general formula including the compound of the present invention, but there is no specific disclosure or suggestion of the compound of the present invention by Examples or the like.

In addition, 1-phenyl 1-thio-D-glucitol derivatives, including the following compounds, inhibit both SGLT-1 and SGLT-2 activities, and have both glucose absorption suppression from the digestive tract and urinary glucose excretion promoting action. It has been reported that it can be an active ingredient of a therapeutic agent for diabetes (Patent Document 4). However, there is no specific disclosure or suggestion of the compound of the present invention in this document.

International Publication No. 2004/080990 Pamphlet International Publication No. 2007/114475 Pamphlet US Patent Application Publication No. 2005/0233988 International Publication No. 2008/072726 Pamphlet

Provided is a compound useful as an active ingredient of a pharmaceutical composition, particularly a pharmaceutical composition for treating diabetes.

As a result of intensive studies on compounds having a double inhibitory action of SGLT-1 and SGLT-2, the present inventors have found that the benzothiophene compound of the present invention has a double inhibitory action of SGLT-1 and SGLT-2. It has an excellent blood glucose lowering action not only for severe hyperglycemia but also for mild hyperglycemia, and has an excellent blood glucose lowering action regardless of the degree of hyperglycemia, and normal Knowing that it has an excellent urinary glucose excretion effect in a blood glucose state, the present invention has been completed. Further, the benzothiophene compound of the present invention has been found to have an extremely strong blood glucose lowering effect on mild hyperglycemia compared to a compound that selectively inhibits SGLT-2, and has completed the present invention.

That is, the present invention relates to a compound of formula (I) or a salt thereof (hereinafter sometimes referred to as the compound of the present invention), and a pharmaceutical composition containing a compound of formula (I) or a salt thereof, and an excipient. .

(In the formula (I), R ¹ is lower alkyl optionally substituted by —OH, lower alkyl optionally substituted by —O-, or cycloalkyl optionally substituted, and R ² is , -H, optionally substituted lower alkyl, -O-optionally substituted lower alkyl, or -OH, or R ¹ and R ² together form a lower alkylene. .)

Unless otherwise specified, when a symbol in a chemical formula in this specification is also used in another chemical formula, the same symbol has the same meaning.

The present invention also relates to a pharmaceutical composition for the treatment of diabetes, obesity or fatty liver disease comprising a compound of formula (I) or a salt thereof. This pharmaceutical composition includes a therapeutic agent for diabetes, obesity or fatty liver disease containing the compound of formula (I) or a salt thereof.

The present invention also relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of diabetes, obesity or fatty liver disease, and the effectiveness of a compound of formula (I) or a salt thereof. It relates to a method for treating diabetes, obesity or fatty liver disease comprising administering an amount to a patient.

The compound of formula (I) or a salt thereof is a double inhibitory action of SGLT-1 and SGLT-2, an excellent blood glucose lowering action regardless of the degree of hyperglycemia, and an excellent urinary glucose excretion action in normoglycemia And / or prevention and / or prevention of various diabetes-related diseases including type 1 diabetes, type 2 diabetes, insulin resistance disease and obesity, and nonalcoholic steatohepatitis (NASH) It can be used as an active ingredient of a therapeutic pharmaceutical composition.

The graph of a human small intestine glucuronic acid conjugation metabolism test result is shown. In the graph, the X axis is the elapsed time from the start of the reaction (reaction time), and the Y axis is the residual ratio of the test compound. Ex indicates an example number.

The present invention provides the following.
[1] A compound of the formula (I) or a salt thereof.

(In the formula (I), R ¹ is lower alkyl optionally substituted by —OH, lower alkyl optionally substituted by —O-, or cycloalkyl optionally substituted, and R ² is , -H, optionally substituted lower alkyl, -O-optionally substituted lower alkyl, or -OH, or R ¹ and R ² together form a lower alkylene. .)
[2] The compound of [1] or a salt thereof, wherein R ² is —H, methyl, methoxy, or —OH.
[3] The compound or a salt thereof according to [2], wherein R ² is —H, methyl, or —OH.
[4] The compound of [3] or a salt thereof, wherein R ² is —H.
[5] R ¹ is (a) lower alkyl optionally substituted with —OH, (b) —O-lower alkyl optionally substituted with 1 cyano or 1 to 3 fluoro, or (C) The compound or salt thereof according to any one of [1] to [4], which is cyclopropyl.
[6] The compound or a salt thereof according to [5], wherein R ¹ is (a) lower alkyl optionally substituted with —OH, or (b) methoxy.
[7] The compound of [1] or a salt thereof, wherein R ¹ and R ² are combined to form trimethylene or tetramethylene.
[8] (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-methoxyphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-methylphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-3,4-dimethylphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -4-ethyl-2-hydroxyphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-isopropylphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4- (hydroxymethyl) phenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [7- (1-benzothien-2-ylmethyl) -4-hydroxy-2,3-dihydro-1H-inden-5-yl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2,3-dihydroxy-4-methylphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -4- (cyanomethoxy) -2-hydroxyphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -4- (difluoromethoxy) -2-hydroxyphenyl] -D-glucitol, or (1S) -1,5 The compound or a salt thereof according to [1], which is -anhydro-1- [5- (1-benzothien-2-ylmethyl) -4-cyclopropyl-2-hydroxyphenyl] -D-glucitol.
[9] A pharmaceutical composition comprising the compound of [1] or a salt thereof, and a pharmaceutically acceptable excipient.
[10] A pharmaceutical composition for preventing or treating diabetes, obesity or fatty liver disease, comprising the compound of [1] or a salt thereof.
[11] Use of the compound of [1] or a salt thereof for the manufacture of a pharmaceutical composition for prevention or treatment of diabetes, obesity or fatty liver disease.
[12] The compound of [1] or a salt thereof for the manufacture of a pharmaceutical composition for prevention or treatment of diabetes, obesity or fatty liver disease.
[13] Use of the compound or a salt thereof according to [1] for the prevention or treatment of diabetes, obesity or fatty liver disease.
[14] A method for preventing or treating diabetes, obesity or fatty liver disease, comprising administering an effective amount of the compound or salt thereof according to [1] to a patient.
[15] A compound of formula 1a or a salt thereof in the first production method described later. In addition, this compound is a very important production intermediate for producing the compound of the formula (I) or a salt thereof.
[16] The compound or salt thereof before the protection with the protecting group P ¹ of the compound of formula 1a or a salt thereof in the first production method described later. That is, a compound or a salt thereof in which P ^{1 in} the structural formula of formula 1a is —H. In addition, this compound is a very important production intermediate for producing the compound of the formula (I) or a salt thereof.
[17] A process for producing the compound of [15] or a salt thereof, comprising a step of protecting the hydroxyl group of the compound of [16] or a salt thereof with P ¹ . In addition, this manufacturing method is a manufacturing method which should be employ | adopted as a very important intermediate manufacturing process in manufacturing the compound of Formula (I), or its salt.
[18] The method of [15] or [16] or a salt thereof, or a method for producing [17], wherein X is bromo, R ¹ is methyl, and R ² is —H.
[19] The compound of [18] or a salt thereof, or a production method, wherein P ¹ is methoxymethyl.

Hereinafter, the present invention will be described in detail.

In the present specification, “lower alkyl” means linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, hexyl, etc .; in another embodiment, straight-chain or branched alkyl having 1 to 4 carbon atoms; and in another embodiment, straight-chain or branched carbon having 1 to 4 carbon atoms In still another embodiment, it is alkyl having 1 to 2 carbon atoms.

“Lower alkylene” means linear or branched alkylene having 3 to 5 carbon atoms, such as trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene; in another embodiment, trimethylene or tetramethylene; Another embodiment is trimethylene.

“Cycloalkyl” is a saturated hydrocarbon ring group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc .; another embodiment is cyclopropyl.

In the present specification, “optionally substituted” means unsubstituted or having 1 to 5 substituents. In addition, when it has a some substituent, those substituents may be the same, or may mutually differ.

An embodiment of “lower alkyl optionally substituted with —OH” in R ¹ is lower alkyl; another embodiment is lower alkyl substituted with —OH.

As ^one aspect of “lower alkyl optionally substituted with —O-” in R ^1, there is —O— (lower alkyl optionally substituted with cyano or halogen); -(Lower alkyl optionally substituted with cyano or fluoro); in yet another embodiment is -O-lower alkyl; in yet another embodiment, -O- (lower substituted with cyano Yet another embodiment is -O- (lower alkyl substituted with 1 to 3 fluoro).

One embodiment of “optionally substituted cycloalkyl” for R ¹ is cycloalkyl.

One embodiment of “optionally substituted lower alkyl” for R ² is lower alkyl.

An embodiment of “lower alkyl optionally substituted with —O” in R ² is —O-lower alkyl.

Certain embodiments of the compound of formula (I) are shown below.
(1) A compound wherein R ¹ is lower alkyl optionally substituted with —OH. In another embodiment, the compound wherein R ¹ is methyl, ethyl, isopropyl, isobutyl, hydroxymethyl, or 2-hydroxypropan-2-yl.
(2) A compound in which R ¹ is optionally substituted -O-substituted lower alkyl. In another embodiment, the compound in which R ¹ is —O-lower alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of cyano and fluoro. In yet another embodiment, the compound wherein R ¹ is methoxy, ethoxy, isopropoxy, cyanomethoxy, difluoromethoxy, 2-fluoroethoxy, or trifluoromethoxy.
(3) A compound in which R ¹ is an optionally substituted cycloalkyl. In another embodiment, the compound wherein R ¹ is cyclopropyl.
(4) The compound wherein R ² is —H.
(5) The compound in which R ² is optionally substituted lower alkyl. In another embodiment, the compound wherein R ² is methyl.
(6) The compound wherein R ² is optionally substituted -O-lower alkyl. In another embodiment, the compound wherein R ² is methoxy.
(7) The compound wherein R ² is —OH.
(8) A compound in which R ¹ and R ² are combined to form a lower alkylene. In another embodiment, the compound in which R ¹ and R ² are combined and are trimethylene or tetramethylene.
(9) The compound according to any one of (1) to (3).
(10) The compound according to any one of (4) to (7).
(11) A compound which is a combination of (9) and (10).
(12) The compound according to any one of (8) to (11).

Examples of specific compounds included in the present invention include the following compounds.
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-methoxyphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-methylphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-3,4-dimethylphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -4-ethyl-2-hydroxyphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-isopropylphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4- (hydroxymethyl) phenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [7- (1-benzothien-2-ylmethyl) -4-hydroxy-2,3-dihydro-1H-inden-5-yl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2,3-dihydroxy-4-methylphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -4- (cyanomethoxy) -2-hydroxyphenyl] -D-glucitol,
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -4- (difluoromethoxy) -2-hydroxyphenyl] -D-glucitol,
(1S) -1,5-Anhydro-1- [5- (1-benzothien-2-ylmethyl) -4-cyclopropyl-2-hydroxyphenyl] -D-glucitol.

In the compound of the formula (I), tautomers and geometric isomers may exist depending on the type of substituent. In the present specification, the compound of the formula (I) may be described in only one form of an isomer, but the present invention also includes other isomers, separated isomers, or those And mixtures thereof.

In addition, the compound of the formula (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers based on this may exist. The present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.

Furthermore, the present invention includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985), and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.

The salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and may form an acid addition salt or a salt with a base depending on the type of substituent. is there. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts; inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine; salts and ammonium salts with various amino acids and amino acid derivatives such as acetylleucine Etc.

Furthermore, the present invention also includes various hydrates and solvates of the compound of formula (I) and salts thereof, and crystalline polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

(Production method)
The compound of the formula (I) and a salt thereof can be produced by applying various known synthesis methods utilizing characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protective group (a group that can be easily converted into the functional group) at the stage from the raw material to the intermediate. There is a case. Examples of such protecting groups include protecting groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PGM Wuts and TW Greene. These may be appropriately selected according to the reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.

In addition, the prodrug of the compound of formula (I) introduces a specific group at the stage from the raw material to the intermediate as in the case of the protective group, or further reacts with the obtained compound of formula (I). Can be manufactured. The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.

The compound of the formula (I) can be produced by the method described in Patent Document 1 described above, a method analogous thereto, or a method obvious to those skilled in the art.

Hereinafter, representative production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description. In addition, the manufacturing method of the compound of this invention is not limited to the example shown below.

(First manufacturing method)

(Wherein P ¹ represents a protecting group for a hydroxyl group that can be deprotected under acidic conditions, X represents chloro, bromo, or iodo, TMS represents trimethylsilyl, and R represents methyl or ethyl.)

In this production method, benzothiophene is added to halobenzaldehyde 1a substituted with an appropriate substituent to give 1c, the hydroxyl group is reduced to 1d, and glucose protected with a trimethylsilyl group is added, The trimethylsilyl group and the protecting group of the hydroxyl group that can be deprotected under the acidic condition shown by P ¹ are removed to give 1f, the hydroxyl group is protected, methoxy or ethoxy at the anomeric position is reduced and removed, and the deprotection reaction is further performed. It is the method of manufacturing this invention compound by attaching | subjecting.

In some embodiments, X is bromo, P ¹ is methoxymethyl, ethoxyethyl, 1-methoxy-1-methylethyl, methoxyethoxymethyl, or tetrahydropyran-2-yl, and R is methyl.

(Step 1-1)
This step is a step of adding compound 1b to compound 1a.
The addition reaction is carried out by reacting compound 1b with a base in a solvent inert to the reaction at −78 ° C. to room temperature, in one embodiment at −78 ° C. to −20 ° C., and then adding compound 1a. Stir for 5 hours. Examples of the base used include n-butyllithium, sec-butyllithium, tert-butyllithium, lithium hexamethyldisilazide, potassium hexamethyldisilazide and the like. Examples of the solvent used here are not particularly limited, but ethers such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dimethoxyethane and diglyme; saturated hydrocarbons such as hexane, pentane and heptane; Aromatic hydrocarbons such as benzene, toluene and xylene; and mixtures thereof.

(Step 1-2)
This step is a step of reducing compound 1c.
The reduction reaction is carried out by reacting compound 1c with a reducing agent in the presence of a Lewis acid in a solvent inert to the reaction at −78 ° C. to room temperature, and in one embodiment at −78 ° C. to −40 ° C. Stir for hours. Examples of the reducing agent used include triethylsilane, and examples of the Lewis acid include boron trifluoride / diethyl ether complex and trimethylsilyl triflate. Examples of the solvent used here are not particularly limited, but halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers; saturated hydrocarbons; aromatic hydrocarbons Acetonitrile; and mixtures thereof.

(Step 1-3)
This process adds the Compound 1e to Compound 1d, a step of removing the hydroxyl-protecting group capable deprotection under acidic conditions represented by a trimethylsilyl group and P ^1.
The addition reaction can be performed according to the first production method Step 1-1.

The reaction for removing the protecting group is carried out by allowing an acid to act on the product of the addition reaction in the previous step in methanol or ethanol under cooling to reflux, in one embodiment at 0 ° C. to room temperature, and usually stirring for 0.1 to 72 hours. Done. Examples of the acid used include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, camphorsulfonic acid, and methanesulfonic acid.

(Step 1-4)
In this step, in order to remove anomeric methoxy or ethoxy of compound 1f, the hydroxyl group is protected, the anomeric methoxy or ethoxy is reduced and removed, and the protecting group is further removed to obtain the compound of the present invention. It is.

The introduction of the protecting group is carried out by stirring in a solvent inert to the reaction under cooling to reflux, and in one embodiment, at 0 ° C. to room temperature, usually for 0.1 to 72 hours. The protecting group may be any group that cannot be removed by the following reduction reaction, and specifically includes an acetyl group. P. G. M. Wutsut and Green (T. W. Greene), `` Greene's Protective Groups in Organic Synthesis (4th edition, 2006) ”can be used.

The reduction reaction can be carried out according to the first production method Step 1-2. However, it may be preferable for the reaction to proceed by adding water.

The reaction for removing the protecting group is carried out by stirring in a solvent inert to the reaction under cooling to reflux, and in one embodiment, at 0 ° C. to room temperature, usually for 0.1 to 72 hours. Depending on the protecting group to be removed, select from the methods described in "Greene's Protective Groups Organic Synthesis Synthesis (4th edition, 2006)" by PG M. Wuts and Green (T. W. Greene). Can do. In the case of removing acetyl, alcohols; water; or a mixed solvent thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium methoxide, etc. It can also be carried out by allowing a base to act and stirring at 0 ° C. to room temperature for 0.1 to 72 hours.

The compound 1a or a salt thereof in this production method is a very useful production intermediate in the production of the compound of the formula (I) or a salt thereof. Can efficiently produce the compound of formula (I) or a salt thereof. In addition, compound 1a or a salt thereof can be produced by introducing a protecting group P ¹ into a compound in which P ^{1 in} the structural formula of compound 1a is —H, and the method is obvious to those skilled in the art. Or a similar method can be employed. For example, when P ¹ is methoxymethyl, compound 1a or a salt thereof can be produced by reacting in an appropriate solvent using a methoxymethylating agent such as methoxymethyl chloride and performing an appropriate treatment. .

(Second manufacturing method)

(In the formula, P ² represents a hydroxyl-protecting group, and Bn represents benzyl.)

In this production method, benzothiophene was added to halobenzaldehyde 2a substituted with an appropriate substituent to give 2b, the hydroxyl group was reduced to 2c, and glucose protected with a benzyl group was added to give 2e. And the anomeric hydroxyl group is reduced and removed, and further subjected to a deprotection reaction to produce the compound of the present invention.

In some embodiments, X is bromo and P ² is benzyl or lower alkyl.

(Step 2-1)
This step is a step of adding compound 1b to compound 2a.
The addition reaction can be performed according to the first production method Step 1-1.

(Step 2-2)
This step is a step of reducing compound 2b.
The reduction reaction can be performed according to the first production method Step 1-2.

(Step 2-3)
This step is a step of adding compound 2d to compound 2c.
The addition reaction can be performed according to the first production method Step 1-1.

(Step 2-4)
This step is a step of obtaining the compound of the present invention by reducing and removing the anomeric hydroxyl group of compound 2e and further removing the benzyl group and the hydroxyl protecting group represented by P ² .
The reduction reaction can be performed according to the first production method Step 1-2.

The reaction for removing the protecting group is carried out in a solvent inert to the reaction under cooling to reflux, and in one embodiment, at 0 ° C. to room temperature, usually for 0.1 to 72 hours with stirring. Depending on the protecting group to be removed, the method can be selected from the methods described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” by PG M. Wuts and T. W. Greene. When P ² is benzyl, a Lewis acid is allowed to act in a halogenated hydrocarbon solvent in the presence of pentamethylbenzene and stirred at -78 ° C to -20 ° C for 0.1 to 72 hours. You can also Examples of the Lewis acid used here include boron trichloride, boron tribromide, boron trifluoride / dimethyl sulfide complex, and the like.

(Raw material synthesis 1)

(In the formula, P ³ represents P ¹ in the first production method or P ² in the second production method, and Y represents chloro, bromo or iodo.)

The raw material 1a of the first production method and the raw material 2a of the second production method are prepared by converting the hydroxyl group of 3b obtained by bromination of 3a using, for example, tetrabutylammonium tribromide or pyridinium bromide perbromide to P ¹ or P ² It can be produced by lithiation of 3c protected with γ, reacting N, N-dimethylformamide to introduce a formyl group, and then brominating the resulting 3d with, for example, tetrabutylammonium tribromide.

(Raw material synthesis 2)

The raw material 1a of the first manufacturing method and the raw material 2a of the second manufacturing method were obtained by hydroxymethylating 3e obtained by bromination of 3a using, for example, tetrabutylammonium tribromide or pyridinium bromide perbromide using formaldehyde Thereafter, the obtained 3f hydroxyl group can be protected by P ¹ or P ² according to a conventional method, and the obtained 3 g can be oxidized with a normal oxidizing agent.

(Raw material synthesis 3)

The raw material 1a of the first production method and the raw material 2a of the second production method are prepared by converting the hydroxyl group of 4b obtained by bromination of 4a using, for example, tetrabutylammonium tribromide or pyridinium bromide perbromide into P ¹ or P ² It can manufacture by protecting with.

(Raw material synthesis 4)

3f, an intermediate of raw material synthesis 2, is produced, for example, by bromating 4c obtained by reacting 4a with a reducing agent such as sodium borohydride using tetrabutylammonium tribromide or pyridinium bromide perbromide. You can also.

The compound of formula (I) is isolated and purified as a free compound, its salt, hydrate, solvate, or crystalline polymorphic substance. The salt of the compound of the formula (I) can also be produced by subjecting it to a conventional salt formation reaction.

Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.

Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.

The pharmacological activity of the compound of formula (I) was confirmed by the following test.

Test Example 1 SGLT-1 and SGLT-2 Inhibitory Activity Measurement Test (1) Production of Human SGLT-1 and SGLT-2 Expression Vectors Using Superscript II (Gibco) and random hexamers, derived from human kidney Single-stranded cDNA was reverse transcribed from total RNA (Clontech). Using this as a template, DNA fragments encoding human SGLT-1 (GenBank M24847) and human SGLT-2 (GenBank M95549) were amplified by PCR using Pyrobest DNA polymerase (Takara) (this DNA fragment). The primer was used so that the Hind III site was introduced on the 5 'side and the EcoRI site was introduced on the 3' side).

The amplified fragment was cloned into pCR2.1-Topo vector using TopoTopTA Cloning kit (Invitrogen), introduced into competent cells of E. coli strain JM109, and ampicillin resistant clones were ampicillin (100 mg / Grown in LB medium containing L). A plasmid was purified from the grown Escherichia coli by the method of Hanahan (see Maniatis et al., Molecular Cloning), and this plasmid was digested with HindIII and EcoRI. A DNA fragment encoding human SGLT-2 was obtained by expression vector pcDNA3.1 ( Invitrogen) was ligated to the same site using T4 DNA ligase (Roche Diagonostics) and cloned. The ligated clone was introduced into a competent cell of E. coli JM109 strain in the same manner as described above, grown in LB medium containing ampicillin, and human SGLT-1 and SGLT-2 expression vectors were obtained by the method of Hanahan.

(2) Preparation of human SGLT-1 or SGLT-2 stable expression cells Human SGLT-1 or SGLT-2 expression vectors were introduced into CHO-K1 cells using Lipofectamine 2000 (Gibco). After gene transfer, cells contain penicillin (50 IU / mL Dainippon Pharmaceutical), streptomycin (50 μg / mL Dainippon Pharmaceutical), Geneticin (40 μg / mL Gibco) and 10% fetal bovine serum A geneticin-resistant clone was obtained by culturing in Ham's F12 medium (manufactured by Nissui Pharmaceutical) in the presence of 5% CO _{2 at} 37 ° C. for about 2 weeks. From these clones, cells stably expressing human SGLT-2 were selected using the specific activity of sugar uptake in the presence of sodium relative to the steady level as an index (see the following section for details of the method for measuring sugar uptake). .

(3) Measurement of methyl-α-D-glucopyranoside uptake inhibitory activity The medium of CHO cells stably expressing human SGLT-1 or SGLT-2 was removed, and a pretreatment buffer (choline chloride 140 mM, potassium chloride 2 mM) per well was removed. Buffer solution containing 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid, 5 mM tris (hydroxymethyl) aminomethane, pH 7.4) 100 μL was added and allowed to stand at 37 ° C. for 20 minutes.

Uptake buffer containing test compound (140 塩 化 ナ ト リ ウ ム mM sodium chloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 50 μM methyl-α-D-glucopyranoside, 2- [4- (2-hydroxyethyl) 1-piperazinyl] ethanesulfonic acid 10 mM, tris (hydroxymethyl) aminomethane 5 mM buffer pH 7.4) 1000 μL 11 μL methyl-α-D- (U-14C) glucopyranoside (Amersham Pharmacia Biotech) Product) and mixed to obtain a buffer for uptake. An uptake buffer containing no test compound was prepared in the control group. In addition, a basal uptake buffer solution containing 140 μM choline chloride instead of sodium chloride was prepared in the same manner for basal uptake measurement in the absence of the test compound and sodium.

The pretreatment buffer was removed, uptake buffer was added at 25 μL per well, and human SGLT-1 and SGLT-2 stably expressing cells were allowed to stand at 37 ° C. for 2 hours. The uptake buffer was removed and the wash buffer (choline chloride 140 mM, potassium chloride 2 mM, calcium chloride 1 mM, magnesium chloride 1 mM, methyl-α-D-glucopyranoside 10 mM, 2- [4- (2 -Hydroxyethyl) -1-piperazinyl] ethanesulfonic acid 10 mM and tris (hydroxymethyl) aminomethane 5 mM in buffer pH 7.4) were added at 200 μL per well and immediately removed. This washing operation was performed once more, and 0.5% sodium lauryl sulfate was added at 25 μL per well to solubilize the cells. 75 μL of micro scintillation 40 (manufactured by Packard) was added thereto, and radioactivity was measured with a micro scintillation countertop count (manufactured by Packard). The value obtained by subtracting the basal uptake from the uptake of the control group was taken as 100%, and the concentration at which 50% of the uptake was inhibited (IC ₅₀ value) was calculated from the concentration-inhibition curve by the least square method.

As a result, the compound of the present invention showed almost the same inhibitory activity against both SGLT-1 and SGLT-2. IC ₅₀ values of some compounds of the present invention and reference compounds are shown in Table 1. Ex indicates an example number. Reference compounds 1 and 2 are the compounds of Examples 159 and 127 described in WO 2004/080990, respectively, and are shown here as examples of compounds that selectively inhibit SGLT-2.

Test Example 2 Hypoglycemic Action Confirmation Test in Severe and Mild Hyperglycemia State KK-Ay mice (Claire Japan, male) in satiety and fasting (fasted for 16 hours) were used as experimental animals. KK-Ay mice (male) have a satiety blood glucose level of about 400 to 500 mg / dL, and KK-Ay mice (male) have a fasting blood glucose level of about 150 to 200 mg / dL.

The test compound was suspended in a 0.5% aqueous methylcellulose solution to a concentration of 1 mg / lOmL. The body weight of the mice was measured, the test compound suspension was forcibly administered orally at a dose of 10, 30 mg / kg (1, 3 mg / kg as the test compound), and the control group was administered only with a 0.5 wt% methylcellulose aqueous solution. . The number of mice per group was 5 or 6, and fasting and water-fasting conditions were applied after test compound administration. Blood was collected from the tail vein immediately before drug administration and 1, 2, 4, and 8 hours after drug administration, and the blood glucose level was measured using Glucose CII Test Wako (Wako Pure Chemical Industries). The strength of the hypoglycemic effect is calculated by calculating the blood glucose level-time curve area (AUC) using the trapezoidal method from the blood glucose level over time from 0 to 8 hours of each test compound administration group, and lowering the blood glucose level relative to that of the control group It was shown in rate (%).

As a result, some of the compounds of the present invention show that the test animals are satiety and fasting, that is, a severe hyperglycemia state with a blood glucose level of about 400 to 500 mg / dL and a blood glucose level of 150 to 200 mg / dL. In any mild hyperglycemic state, it was confirmed that the dose of 1 mg / kg has an excellent hypoglycemic effect. On the other hand, Reference Compounds 1 and 2 which are compounds that selectively inhibit SGLT-2 showed an excellent blood glucose lowering effect at a dose of 1 mg / kg at the time of satiety, that is, in a severe hyperglycemic state. In the fasting state, that is, in a mild hyperglycemic state, a dose of 3 mg / kg did not show sufficient effects. Table 2 shows the blood glucose lowering rate of some compounds of the present invention and reference compounds. Ex indicates an example number. Reference compounds 1 and 2 represent the same compounds as those described in Test Example 1 above. NT also indicates that the test has not been performed on the compound.

Test Example 3 Hypoglycemic Action Confirmation Test in Mild Hyperglycemia State KK-Ay mice (Japan Claire, female) at the time of satiation were used as experimental animals. The blood sugar level of KK-Ay mice (female) at the time of satiation is about 200 mg / dL, which is equivalent to the fasting blood sugar level of KK-Ay mice (male) in Test Example 2.

The test compound was suspended in a 0.5% aqueous methylcellulose solution to a concentration of 1 mg / lOmL. The body weight of the mice was measured, and the test compound suspension was forcibly orally administered at a dose of 10 mL / kg (1 mg / kg as the test compound), and only 0.5% methylcellulose aqueous solution was administered to the control group. The number of mice per group was 5 or 6, and fasting and water-fasting conditions were applied after test compound administration. Blood was collected from the tail vein immediately before drug administration and 1, 2, 4, and 8 hours after drug administration, and the blood glucose level was measured using Glucose CII Test Wako (Wako Pure Chemical Industries). The strength of hypoglycemic action is calculated by calculating the blood glucose level-time curve area (AUC) using the trapezoidal method from the blood glucose level over time from 0 to 8 hours of each test compound administration group It was shown in rate (%).

As a result, some of the compounds of the present invention have a blood glucose lowering action of 25% or more at a dose of 1 mg / kg when the test animal is satiety, that is, in a mild hyperglycemia state where the blood glucose level is about 200 mg / dL. As in the fasting of the KK-Ay mouse (male) of Test Example 2, there was a compound having an excellent effect.

The results of Test Examples 1 to 3 are summarized below.

From the SGLT-1 and SGLT-2 inhibitory activity measurement test, the compounds of the present invention showed almost the same inhibitory activity against both SGLT-1 and SGLT-2. It became clear that it has heavy inhibitory activity. In addition, some compounds of the present invention showed strong inhibitory activity of about 10 nM or less as IC ₅₀ values for both SGLT-1 and SGLT-2.

From the test for confirming the hypoglycemic effect in severe and mild hyperglycemic conditions, Reference Compounds 1 and 2 that selectively inhibit SGLT-2 have an excellent hypoglycemic effect on severe hyperglycemic conditions. It has been clarified that it does not have a sufficient hypoglycemic effect for mild hyperglycemia.

On the other hand, some compounds of the present invention exert a powerful hypoglycemic action at a dose as low as 1 mg / kg not only for severe hyperglycemia but also for mild hyperglycemia. It became clear that the said effect | action was excellent irrespective of the grade.

From the above, it was considered that not only SGLT-2 but also SGLT-1 must be inhibited in order to develop the hypoglycemic effect on mild hyperglycemia.

Therefore, the compound of the present invention having a dual inhibitory action of SGLT-1 and SGLT-2 even for mild hyperglycemia where a compound that selectively inhibits SGLT-2 cannot achieve a sufficient effect, Because it exhibits an excellent blood glucose lowering effect and exhibits a blood glucose lowering effect regardless of the level of hyperglycemia, it can be applied to more patient groups regardless of the severity of the disease in diabetes and various diabetes-related diseases It is clear that it is useful as an active ingredient of a therapeutic agent for the disease.

Test Example 4 SGLT-1 and SGLT-2 Inhibitory Activity Measurement Test The following comparative compounds were tested in the same manner as Test Example 1.

As a result, Comparative Compounds 1 and 2 showed almost the same inhibitory activity against SGLT-1 and SGLT-2 as the compounds of the present invention. On the other hand, Comparative Compounds 3 to 5 had almost the same inhibitory activity against SGLT-2 as that of the compound of the present invention, but the inhibitory activity against SGLT-1 was very weak compared with the compound of the present invention. Table 3 shows the IC ₅₀ values of Comparative Compounds 1 to 5.

Comparative compounds 1 to 5 are the compounds of Example 144, Table 37 (first row, third column), Examples 116, 142 and 143 described in International Publication No. 2004/080990, respectively. Is a compound in which R ^C in the following formula (II) is OH.

Test Example 5 Human Small Intestine Glucuronic Acid Conjugation Metabolism Test Reaction solution (50 mM Tris-HCl (pH 7.4), 50 μg / mg Alamethicin, 8 mM MgCl ₂ , 0.1 mg / mL Human intestinal Microsome) containing ₂ μM test compound Incubation was performed in a 37 ° C. water bath for 2 minutes, and 2 mM UDPGA was added to initiate the reaction. A part of the reaction solution was collected at 0, 10, 30, 60, 120 minutes after the start, and added to ice-cold acetonitrile to stop the reaction. The test compound in the solution where the reaction was stopped was analyzed by LC / MS / MS method, and the residual ratio of the test compound at each time point with respect to 0 minutes of reaction was calculated.

As a result, it was confirmed that some of the compounds of the present invention had a high residual rate of 60% or more even at 120 minutes after the start of the reaction, and were not easily subjected to human small intestinal glucuronide-metabolism. On the other hand, comparative compounds 1 and 2 have a rapid decrease in the residual rate after the start of the reaction, and the residual rate is extremely low at 10% or less at 120 minutes after the start of the reaction, and are very susceptible to human small intestinal glucuronidation metabolism. Was confirmed. A graph with the reaction time on the X axis and the residual rate on the Y axis is shown in FIG. 1, and the residual rate of the test compound at 120 minutes is shown in Table 4. Ex indicates an example number. Comparative compounds 1 and 2 represent the same compounds as those described in Test Example 4 above.

The results of Test Examples 4 and 5 are summarized below.

From the SGLT-1 and SGLT-2 inhibitory activity measurement test, Comparative Compounds 1 and 2 showed almost the same inhibitory activity against SGLT-1 and SGLT-2 as some compounds of the present invention. Compounds 3 to 5 have very weak inhibitory activity against SGLT-1 compared to some compounds of the present invention, and the IC ₅₀ values of Comparative Compounds 3 to 5 with respect to SGLT-1 are shown in Table 1. Some compounds were found to be about 15-170 times the IC ₅₀ values for SGLT-1 for some compounds.

As described above, it is considered necessary not only to inhibit SGLT-2 but also to inhibit SGLT-1 in order to exert a hypoglycemic effect in a mild hyperglycemic state.

Therefore, it is considered that the administration of a higher dose than the compound of the present invention is necessary for Comparative Compounds 3 to 5 to exhibit a blood glucose lowering effect equivalent to that of the compound of the present invention in a mild hyperglycemic state. There is also a concern of toxicity at such high doses.

In addition, as described below, it is important not only to inhibit SGLT-2 but also to inhibit SGLT-1 from the viewpoint of preventing the onset of diabetic complications and suppressing the progression. The purpose of glycemic control in diabetes is to prevent and prevent the development of macrovascular complications such as cardiovascular disease and correction of chronic hyperglycemia, and microvascular complications including nephropathy, neuropathy and retinopathy. is there. It has already been clarified that stricter glycemic control, that is, hemoglobin A1c (HbA1c), which is an indicator of long-term blood glucose level, is strongly reduced to increase the rate of suppression of complications (Annu Rev Med 46) 257, 1995, Diabetes Care 18, 258, 1995, Ann Intern Med 122,122561, 1995, Diabetes 44,44968, 1995, Diabetes 47, 1703 , 1995). About the relationship between blood glucose level and HbA1c, HbA1c (%) = average blood glucose level (mg / dL) from the average of 7 times daily blood glucose level measured in Diabetes Control and Complication Trial (DCCT) and HbA1c data /35.6+2.17 (Diabetes Care 25, 275, 2002). There is no consensus on whether HbA1c primarily reflects fasting blood glucose or postprandial blood glucose, but strict management of both is important to improve HbA1c improvement in diabetics It is clear (Diabetes Care 26, 881, 2003) that correcting not only postprandial hyperglycemia but also fasting (pre-meal) and inter-meal hyperglycemia is a diabetic complication. It is thought to be important for prevention of onset and progress suppression. For example, in a patient who is severely hyperglycemic after meals, such as the KK-Ay mouse (male) used in Test Example 2, but who is mildly hyperglycemic on an empty stomach, It is very important to correct fasting hyperglycemia as well as hyperglycemia.

Therefore, it is important to correct postprandial and fasting hyperglycemia from the viewpoint of preventing the development of diabetic complications and suppressing progression, and fasting hyperglycemia in patients who are mildly hyperglycemic during fasting. In order to correct this, it is necessary not only to inhibit SGLT-2 but also to inhibit SGLT-1.

From the human small intestine glucuronidation metabolism test, it was revealed that Comparative Compounds 1 and 2 are very susceptible to human small intestine glucuronidation metabolism. On the other hand, it was confirmed that some compounds of the present invention are not easily subjected to human small intestine glucuronidation metabolism. Since glucuronide conjugation metabolism is considered as one of the main metabolic pathways in vivo, some compounds of the present invention can exist stably and persistently as active substances in blood, It was suggested that it can be a long-lasting drug. It is well known that a long-lasting drug is useful as a medicine in that, for example, a single dose can be reduced or the number of administrations can be reduced.

Test Example 6 Confirmation of urinary glucose excretion in severe and mildly hyperglycemic conditions KK-Ay mice (CLEA Japan, male) in satiety and fasting (16-hour fast) were used as experimental animals. The test compound was suspended in a 0.5% aqueous methylcellulose solution to a concentration of 1 mg / 10 mL. After measuring the body weight of the mice, the test compound suspension was forcibly administered orally at a dose of 10 mL / kg (1 mg / kg as the test compound), and only 0.5% methylcellulose aqueous solution was administered to the control group. Moved to. The number of animals per group was 5 or 6. Thereafter, spontaneous urine up to 24 hours was collected and urine volume was measured. The urine sample is centrifuged (3,000 rpm, 10 minutes), and the urinary glucose concentration in the supernatant is measured using Glucose CII Test Wako (Wako Pure Chemical Industries). The amount was calculated.

As a result, some of the compounds of the present invention have a dose of 1 mg / kg at a dose of 1 mg / kg or more (about 600-800 mg in the control group) in severe hyperglycemia, and 1 mg in mild hyperglycemia. There was a compound having an excellent urinary glucose excretion at a dose of 100 mg / kg or more (the control group was 10 mg or less) and had such an effect.

Test Example 7 Test for confirming urinary glucose excretion in normoglycemic state ICR mice (Japan SLC, male) at the time of satiation were used as experimental animals. The test compound was suspended in a 0.5% aqueous methylcellulose solution to a concentration of 1 mg / 10 mL. After measuring the body weight of the mice, the test compound suspension was forcibly administered orally at a dose of 10 mL / kg (1 mg / kg as the test compound), and only 0.5% methylcellulose aqueous solution was administered to the control group. Moved. The number of animals per group was 5 or 6. Thereafter, spontaneous urine up to 24 hours was collected and urine volume was measured. The urine sample is centrifuged (3,000 rpm, 10 minutes), and the urinary glucose concentration in the supernatant is measured using Glucose CII Test Wako (Wako Pure Chemical Industries). The amount was calculated.

As a result, among the compounds of the present invention, in normoglycemic state, a compound having an excellent urinary glucose excretion action of 300 mg or more (the control group is 10 mg or less) at a dose of 1 mg / kg is shown. there were. On the other hand, (1S) -1,5-anhydro-1- [4-chloro-3- (4-ethoxybenzyl) phenyl] -D-glucitol, which is known as a compound that selectively inhibits SGLT-2, At a dose of 1 mg / kg, 137 mg of urinary glucose excretion was shown.

Test Example 8 Effect on non-alcoholic simple fatty liver model (KK-A ^y mouse) KK-A ^y mouse (female) was allowed to freely feed CMF (special breeding), and at 14 weeks of age, body weight and blood glucose Levels, plasma insulin levels, plasma triglyceride levels, and plasma alanine aminotransferase (ALT) are measured and grouped so that these items are uniform. The test compound suspension is administered by oral gavage at a dose of 0.01 to 10 mg / kg once a day for 2 weeks. Only 0.5% methylcellulose solution is administered to the control group. The number of animals per group is 6-8. The day after the final administration, the liver is collected under ether anesthesia, frozen in liquid nitrogen and stored at -80 ° C.

The triglyceride content of the liver can be measured by the following procedure.
1. Part of the liver (50-150 mg) that has been stored frozen at -80 ° C is dispensed into an assist tube.
2. Add 2 mL of methanol and crush with POLYTRON (KINEMATICA).
3. Add 4 mL of chloroform and stir vigorously at room temperature for 10 minutes.
4). Add 1 mL of milliQ water and stir vigorously.
5). Centrifugation was performed with a low-speed centrifuge (2,500 rpm, 5 min, room temperature).
6). Transfer a portion of the lower layer (total volume 4.5 mL) to an Eppendorf tube, and remove the solvent using a centrifugal evaporator.
7). Add 10 μL to the Eppendorf tube and redissolve in ethanol.
8). 1 mL of triglyceride E-Test Wako Reagent (Wako Pure Chemical Industries, Ltd.) is added thereto, and the triglyceride is quantified.

From the above, the triglyceride content per 1 g of liver is calculated. Data are shown as mean ± standard error.

Test Example 9 Effects on non-alcoholic steatohepatitis model (rats loaded with methionine / choline-deficient diet (MCD diet)) This study should be conducted with reference to the literature (J Hepatol., 2003, 39, 756-764) Can do. Wistar rats (male) are allowed to eat MCD diet (methionine / choline deficient diet) freely, and at 9 weeks of age, body weights are measured and divided into groups so as to be uniform (10 animals per group). ). The test compound suspension is administered by oral gavage at a dose of 0.01 to 10 mg / kg once a day for 16 weeks. The day after the final administration, the liver is collected under ether anesthesia, and a part of the liver is fixed with 10% neutral buffered formalin. Paraffin sections (3 μm) are prepared by a conventional method, and HE staining and van Gieson staining are performed. Inflamed lesions are assessed using HE-stained specimens, and fibrosis is assessed using Wangyson-stained specimens. The evaluation was based on the NASH activity score (NAS) for inflammatory lesions and the Brunt classification for fibrosis (edited by the Japan Liver Society, edited by NASH / NAFLD, 2006), 0, 1, 2, 3 respectively. 4 (see Table 5).

Test Example 10 Effect on non-alcoholic steatohepatitis model (choline-deficient amino acid substitution diet (CDAA diet) loaded rat) This study was based on literature (Biochem Biophys Res Commun., 2004, 315 (1), 187-195) A test can be performed. Wistar rats (male) are fed a CDAA diet (choline-deficient amino acid-substituted diet) freely, and at 9 weeks of age, body weights are measured and divided into groups so as to be uniform (10 animals in each group). ). The test compound suspension is administered by oral gavage at a dose of 0.01 to 10 mg / kg once a day for 5 weeks. Only 0.5% methylcellulose solution is administered to the control group. The liver is collected under ether anesthesia the day after the last dose. After fixing a part of the liver with 10% neutral buffered formalin, a paraffin section (3 μm) is prepared by a conventional method, and then stained with van Gieson. Fibrosis can be evaluated based on the Brunt classification (edited by the Japan Liver Society, edited by NASH / NAFLD, 2006) on a scale of 0, 1, 2, 3, 4 (see Table 5). .

Test Example 11 Effect on Obesity Model Male ICR mice (5 weeks old) are bred with a high-fat diet from 8 weeks of age, and equally divided into groups based on body weight at the age of 10 weeks. The test compound suspension is administered by repeated oral gavage once a day for 3 weeks at a dose of 0.01 to 10 mg / kg. Only 0.5% methylcellulose solution is administered to the control group. The number of animals per group is 6-8. At 13 weeks of age, the body weight and the amount of body weight fluctuation from the start of administration are measured, and the data are shown as mean ± standard error.

Hereinafter, the results of Test Examples 6 and 7 and Test Examples 8 to 11 will be summarized.

From the test for confirming urinary glucose excretion in severe and mildly hyperglycemic conditions, some compounds of the present invention can be administered at a dose of 1 mg / kg not only in severely hyperglycemic conditions but also in mildly hyperglycemic conditions. It was revealed that it exerts a sugar excretion action and exhibits an excellent action regardless of the degree of hyperglycemia.

From a test for confirming urinary glucose excretion in normoglycemic state, it was revealed that some compounds of the present invention exhibited excellent urinary glucose excretion at a dose of 1 mg / kg even in normoglycemic state.

Therefore, the compound of the present invention is based on the excretion of urinary glucose in severe and mild hyperglycemic conditions and in normoglycemic conditions. And non-alcoholic steatohepatis (NASH), and is expected to have an excellent ameliorating effect on fatty liver diseases including non-alcoholic steatohepatis (NASH). These improvement effects can be confirmed in Test Examples 8 to 11.

As described above, the compound of the present invention has a double inhibitory action of SGLT-1 and SGLT-2, an excellent hypoglycemic action regardless of the degree of hyperglycemia, and an excellent urinary glucose excretion action in normoglycemia. Prevention and / or treatment of various diabetes related diseases including type 1 diabetes, type 2 diabetes, insulin resistance disease, obesity, and fatty liver disease including non-alcoholic steatohepatis (NASH) It is clear that it is useful as an active ingredient of pharmaceutical compositions for medical use.

A pharmaceutical composition containing one or more of the compounds of formula (I) or a salt thereof as an active ingredient is an excipient usually used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier. Can be prepared by a commonly used method.

Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.

Tablets, powders, granules, etc. are used as solid compositions for oral administration. In such a solid composition, one or more active ingredients contain at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, or a solubilizing agent according to a conventional method. . If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.

The injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name). Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

Usually, in the case of oral administration, the daily dose is about 0.001 to 100 mg / kg, preferably 0.05 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 divided doses. When administered intravenously, the appropriate daily dose is about 0.0001 to 10 mg / kg per body weight, and is administered once to several times a day. As a transmucosal agent, about 0.001 to 100 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

The compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.

Hereinafter, based on an Example, the manufacturing method of the compound of Formula (I) is demonstrated in detail. In addition, this invention is not limited to the compound as described in the following Example. Moreover, the manufacturing method of a raw material compound is shown in a manufacture example, respectively. Further, the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below, and the compound of the formula (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.

Moreover, the following abbreviations may be used in Examples, Production Examples, and Tables below.
Rex: Production example number, Ex: Example number, Structure: Chemical structural formula, Data: Physicochemical data (FAB +: FAB-MS [M + H] ⁺ , FAB-: FAB-MS [MH] ⁻ , ESI +: ESI-MS [M + H] +, ESI-: ESI-MS [MH] -, EI: EI [M] +, NMR-DMSO-d 6: of the peaks in ¹ H-NMR in dimethylsulfoxide -d ₆ δ (ppm), NMR-CDCl ₃ : δ (ppm) of peak in ¹ H-NMR in deuterated chloroform, NMR-CD ₃ OD: δ (ppm) of peak in ¹ H-NMR in deuterated methanol, Me : Methyl, Et: ethyl, iPr: isopropyl, TBS: tert-butyldimethylsilyl, Bn: benzyl, Ac: acetyl, MOM: methoxymethyl. Rsyn and Syn: Production method (numbers indicate that the compound was produced using the corresponding raw material in the same manner as the compound having the number as a production example number or an example number).

Production Example 1
Pyridinium bromide perbromide (13.5 g) was added to a mixture of 4-hydroxy-2-methylbenzaldehyde (5 g), methanol (12.5 mL), and dichloromethane (12.5 mL), and the mixture was stirred at room temperature for 1.5 hours. Water was added, insoluble matter was collected by filtration, and heated and dried under reduced pressure to give 5-bromo-4-hydroxy-2-methylbenzaldehyde (3.65 g) as a white solid.

Production Example 2
Chloromethyl methyl ether (2.3 mL) was added dropwise to a mixture of 5-bromo-4-hydroxy-2-methylbenzaldehyde (5 g), potassium carbonate (4.5 g), and acetone (50 mL), and the mixture was stirred at room temperature for 3.5 hours. . Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure to obtain 5-bromo-4- (methoxymethoxy) -2-methylbenzaldehyde (6.07 g) as a white solid.

Production Example 3
To a mixture of benzothiophene (5.72 g) and tetrahydrofuran (60 mL) cooled to -15 ° C under a nitrogen stream, n-butyllithium (1.55 M n-hexane solution) (27.4 mL) was added dropwise at -15 ° C. Stir for 30 minutes. To the reaction mixture, a mixture of 5-bromo-4- (methoxymethoxy) -2-methylbenzaldehyde (10 g) and tetrahydrofuran (40 mL) was added and stirred for 1 hour while warming to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solvent was distilled off under reduced pressure to obtain an orange oil (16.4 g). Triethylsilane (2.44 mL) and boron trifluoride-ethyl ether complex (0.77 mL) were successively added dropwise to a mixture of orange oil (2.0 g) and toluene (20 mL) cooled to -45 ° C under a nitrogen stream. The mixture was stirred at -55 ° C for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the solvent was distilled off under reduced pressure. 2-propanol was added to the residue, heated and dissolved, and then allowed to cool to room temperature. The resulting solid was collected by filtration and dried by heating under reduced pressure to give 2- [5-bromo-4- (methoxymethoxy) -2-methylbenzyl] -1-benzothiophene (1.22 g) as a white solid.

Production Example 4
To a dichloromethane solution of 2- (4-methoxy-2,3-dimethylbenzyl) -1-benzothiophene (7.8 g) was added 1,2,3,4,5-pentamethylbenzene (10.2 g), and -40 ° C. Boron tribromide (1M in dichloromethane) (40 mL) was added dropwise. The mixture was stirred at the same temperature for 4 hours and then at room temperature for 15 hours. Ice-saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic layer was extracted. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the solvent was concentrated, and hexane was added to the residue and stirred. The solid was filtered, washed with hexane, and then dried under reduced pressure to obtain 4- (1-benzothien-2-ylmethyl) -2,3-dimethylphenol (7.2 g).

Production Example 5
A mixture of 4- (benzyloxy) -5-bromo-2-hydroxybenzaldehyde (16.48 g), t-butyldimethylchlorosilane (10.51 g), imidazole (4.75 g), N, N-dimethylformamide (165 mL) at room temperature For 3 days. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- (benzyloxy) -5-bromo-2-{[tert-butyl (dimethyl) silyl] oxy} benzaldehyde (13.95 g) was obtained as a white solid.

Production Example 6
Under a nitrogen stream, n-butyllithium (1.65 M n-hexane solution) (7.12 mL) was added dropwise to a mixture of benzothiophene (1.51 g) and tetrahydrofuran (30 mL) cooled to -73 ° C, and the mixture was -70 ° C. Stir for 30 minutes. A mixture of 4- (benzyloxy) -5-bromo-2-ethylbenzaldehyde (3 g) and tetrahydrofuran (30 mL) was added dropwise to the reaction mixture, and the mixture was stirred at -70 ° C. for 1 hour. The reaction mixture was warmed to 0 ° C., saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate), and 1-benzothien-2-yl [4- (benzyloxy) -5-bromo-2-ethylphenyl] methanol ( 4.26 g) was obtained as a light brown amorphous.

Production Example 7
To a mixture of 1-benzothien-2-yl [4- (benzyloxy) -5-bromo-2-ethylphenyl] methanol (4.26 g) and dichloromethane (64 mL) cooled to −60 ° C. under a nitrogen stream, triethyl was added. Silane (6.6 mL) and boron trifluoride-diethyl ether complex (1.77 mL) were successively added dropwise, and the mixture was stirred at −60 ° C. for 2 hours. The reaction mixture was warmed to 0 ° C., saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate), washed with hexane (100 mL) by adding hexane (100 mL), and the solid was collected by filtration. Under heat and drying, 2- [4- (benzyloxy) -5-bromo-2-ethylbenzyl] -1-benzothiophene (3.03 g) was obtained as a white solid.

Production Example 8
2- [4- (Benzyloxy) -5-bromo-2-ethylbenzyl] -1-benzothiophene (3.03 g), toluene (24 mL), tetrahydrofuran (6 mL) cooled to −60 ° C. under a nitrogen stream N-Butyllithium (1.65 M n-hexane solution) (5 mL) was added dropwise to the mixture, and the mixture was stirred at −60 ° C. for 20 minutes. A mixture of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (4.48 g), toluene (24 mL), tetrahydrofuran (6 mL) cooled to −60 ° C. And stirred at -60 ° C for 1 hour. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 1-C- [5- (1-benzothien-2-ylmethyl) -2- (benzyloxy) -4- Ethylphenyl] -2,3,4,6-tetra-O-benzyl-D-glucopyranose (5.9 g) was obtained as a white solid.

Production Example 9
1-C- [5- (1-benzothien-2-ylmethyl) -2- (benzyloxy) -4-ethylphenyl] -2,3,4,6-tetra-cooled to −60 ° C. under nitrogen flow To a mixture of O-benzyl-D-glucopyranose (5.9 g), dichloromethane (88.5 mL), and acetonitrile (88.5 mL), triethylsilane (3.2 mL) and boron trifluoride-diethyl ether complex (1.2 mL) were successively added dropwise. The mixture was stirred at -60 ° C for 30 minutes. The reaction mixture was warmed to 0 ° C., saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2 -(Benzyloxy) -4-ethylphenyl] -2,3,4,6-tetra-O-benzyl-D-glucitol (4.26 g) was obtained as a colorless oil.

Production Example 10
Under ice cooling, (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2- (benzyloxy) -4-{[tert-butyl (dimethyl) silyl] oxy} Phenyl] -2,3,4,6-tetra-O-benzyl-D-glucitol (14.8 g) and tetrahydrofuran (222 mL) were added dropwise with tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) (18.1 mL). And stirred at 0 ° C. for 45 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. Insolubles were filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (1S) -1,5-anhydro-1- [5- (1-benzothien -2-ylmethyl) -2- (benzyloxy) -4-hydroxyphenyl] -2,3,4,6-tetra-O-benzyl-D-glucitol (12.68 g) was obtained as a pale yellow amorphous.

Production Example 11
(1S) -1,5-Anhydro-1- [5- (1-benzothien-2-ylmethyl) -2- (benzyloxy) -4-hydroxyphenyl] -2,3,4,6-tetra-O- A mixture of benzyl-D-glucitol (800 mg), ethyl iodide (89 μL), potassium carbonate (153 mg) and N, N-dimethylformamide (10 mL) was stirred with heating at 60 ° C. for 5 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate). (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2 -(Benzyloxy) -4-ethoxyphenyl] -2,3,4,6-tetra-O-benzyl-D-glucitol (796 mg) was obtained as a pale yellow oil.

Production Example 12
(1S) -1,5-Anhydro-1- [5- (1-benzothien-2-ylmethyl) -2- (benzyloxy) -4-hydroxyphenyl] -2,3,4,6-tetra-O- To a mixture of benzyl-D-glucitol (500 mg) and toluene (7.5 mL), add 1,1 '-[(E) -diazene-1,2-diyldicarbonyl] dipiperidine (260 mg) and tri-n-butyl. Phosphine (0.26 mL) was added and stirred at room temperature for 10 minutes. Further, 2-fluoroethanol (0.051 mL) was added and stirred at room temperature. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, water was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate), and (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2 -(Benzyloxy) -4- (2-fluoroethoxy) phenyl] -2,3,4,6-tetra-O-benzyl-D-glucitol (376 mg) was obtained.

Production Example 13
(1S) -1,5-Anhydro-1- [5- (1-benzothien-2-ylmethyl) -2- (benzyloxy) -4-hydroxyphenyl] -2,3,4,6-tetra-O- A mixture of benzyl-D-glucitol (1 g), ethyl bromodifluoroacetate (0.35 mL), potassium carbonate (381 mg) and N, N-dimethylformamide (12.5 mL) was heated and stirred at 80 to 100 ° C. for 4 days. . The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) .The resulting mixture was added to ethanol (5 mL), tetrahydrofuran (5 mL), 1M aqueous sodium hydroxide solution (5 mL). ) Was added and stirred at 60 ° C. for 10 minutes. 1M Hydrochloric acid (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2 -(Benzyloxy) -4- (difluoromethoxy) phenyl] -2,3,4,6-tetra-O-benzyl-D-glucitol (246 mg) was obtained as a yellow oil.

Production Example 14
Under ice cooling, (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2- (benzyloxy) -4-hydroxyphenyl] -2,3,4,6- To a mixture of tetra-O-benzyl-D-glucitol (13.2 g), triethylamine (3.3 mL) and dichloromethane (150 mL) was added trifluoromethanesulfonic anhydride (2.97 mL), and the mixture was stirred at 0 ° C. for 10 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. Insolubles were filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (1S) -1,5-anhydro-1- [5- (1-benzothien -2-ylmethyl) -2- (benzyloxy) -4-{[(trifluoromethyl) sulfonyl] oxy} phenyl] -2,3,4,6-tetra-O-benzyl-D-glucitol (13.1 g) Was obtained as a pale yellow oil.

Production Example 15
(1S) -1,5-Anhydro-1- [5- (1-benzothien-2-ylmethyl) -2- (benzyloxy) -4- (methoxycarbonyl) phenyl] -2,3,4,6-tetra To a mixture of -O-benzyl-D-glucitol (402 mg), methanol (5 mL), tetrahydrofuran (3 mL) and water (1 mL), add 1 M aqueous sodium hydroxide solution (1.32 mL) at 60 ° C. The mixture was stirred for 13 hours. To the reaction mixture was added 1M hydrochloric acid (1.5 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Insolubles were filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (1S) -1,5-anhydro-1- [5- (1-benzothien -2-ylmethyl) -2- (benzyloxy) -4-carboxyphenyl] -2,3,4,6-tetra-O-benzyl-D-glucitol (373 mg) was obtained as a colorless amorphous solid.

Production Example 16
To a mixture of benzyl 7-bromo-2,3-dihydro-1H-inden-4-yl ether (7.6 g) and tetrahydrofuran (76 mL) cooled to -70 ° C under a nitrogen stream, n-butyllithium (1.61 M n-hexane solution) (18.7 mL) was added dropwise, and the mixture was stirred at -70 ° C for 30 minutes. N, N-dimethylformamide (3.9 mL) was added dropwise to the reaction mixture, and the mixture was stirred at -70 ° C for a while and then warmed to 0 ° C. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Washed with brine. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 7- (benzyloxy) indane-4-carbaldehyde (5.53 g) as a pale yellow oil.

Production Example 17
Under a carbon monoxide atmosphere, (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2- (benzyloxy) -4-{[(trifluoromethyl) sulfonyl] oxy } Phenyl] -2,3,4,6-tetra-O-benzyl-D-glucitol (100 mg), palladium acetate (2 mg), 1,3-bis (diphenylphosphino) propane (5.5 mg), triethylamine A mixture of (27.9 μL), N, N-dimethylformamide (1 mL), and methanol (2 mL) was stirred at 70 ° C. for 4.5 hours. Ethyl acetate and toluene were added to the reaction mixture, washed with water and saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (1S) -1,5-anhydro-1- [5- (1-benzothien -2-ylmethyl) -2- (benzyloxy) -4- (methoxycarbonyl) phenyl] -2,3,4,6-tetra-O-benzyl-D-glucitol (36.8 mg) was obtained as a colorless amorphous solid .

Production Example 18
A mixture of [4- (benzyloxy) -5-bromo-2- (trifluoromethoxy) phenyl] methanol (2.23 g), manganese dioxide (5.4 g), and chloroform (22 mL) was stirred with heating at 50 ° C. for 9 hours. . The insoluble material was filtered off through Celite filtration, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate), and 4- (benzyloxy) -5-bromo-2- (trifluoro) Methoxy) benzaldehyde (1.81 g) was obtained as a white solid.

Production Example 19
Under ice-cooling, sodium borohydride (405 mg) was added to a mixture of 4-hydroxy-2- (trifluoromethoxy) benzaldehyde (1.84 g) and ethanol (18 mL), and the mixture was stirred at 0 ° C. for 30 min. The solvent was evaporated under reduced pressure, a saturated aqueous ammonium chloride solution was added to the residue, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give 4- (hydroxymethyl) -3- (trifluoromethoxy) phenol (1.91 g) as a yellow oil.

Production Example 20
Mixture of 2-bromo-4- (hydroxymethyl) -5- (trifluoromethoxy) phenol (2.52 g), benzyl bromide (1.25 mL), potassium carbonate (1.45 g), N, N-dimethylformamide (25 mL) Was stirred with heating at 60 ° C. for 3 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate), and [4- (benzyloxy) -5-bromo-2- (trifluoromethoxy) phenyl] methanol (2.23 g) Was obtained as a pale yellow solid.

Production Example 21
To a mixture of 6-bromo-2,3-dimethoxyphenol (4.1 g), 8 M aqueous potassium hydroxide (2.42 mL), and water (15 mL), formaldehyde solution (37%) (4 mL), water (2 mL) ) Was added dropwise, and the mixture was heated and stirred at 50 ° C. for 6.5 hours. The reaction mixture was neutralized by adding 1 M hydrochloric acid dropwise, extracted with ether, and washed with saturated brine. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 6-bromo-4- (hydroxymethyl) -2,3-dimethoxyphenol (2.62 g) as a pale yellow solid. Obtained.

Production Example 22
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2- (benzyloxy) -4-{[(trifluoromethyl) sulfonyl] oxy} phenyl under nitrogen atmosphere ] -2,3,4,6-Tetra-O-benzyl-D-glucitol (1 g), cyclopropylboronic acid (669 mg), palladium acetate (67 mg), tricyclohexylphosphine (168 mg), phosphoric acid A mixture of tripotassium (2.23 g), toluene (20 mL) and water (1 mL) was heated to reflux for 9 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2 -(Benzyloxy) -4-cyclopropylphenyl] -2,3,4,6-tetra-O-benzyl-D-glucitol (0.7 g) was obtained as a pale yellow oil.

Production Example 23
2- [5-Bromo-4- (methoxymethoxy) -2-methylbenzyl] -1-benzothiophene (10 g), toluene (65 mL), diisopropyl ether (50 mL) cooled to −48 ° C. under a nitrogen stream N-butyllithium (1.55 M n-hexane solution) (17.9 mL) was added dropwise, and the mixture was stirred for 30 minutes while raising the temperature from -48 ° C to -25 ° C. The reaction mixture was cooled to −60 ° C. and a mixture of 2,3,4,5-tetrakis-O- (trimethylsilyl) -D-glucono-1,5-lactone (13.6 g), toluene (35 mL) was added, The mixture was stirred for 3 hours while raising the temperature from -60 ° C to -24 ° C. The reaction mixture was added to a mixture of ice-cooled hydrogen chloride (4 M ethyl acetate solution) (13.3 mL) and methanol (50 mL) under a nitrogen stream and stirred at room temperature for 2 hours. A 1M aqueous sodium hydroxide solution (110 mL) and water were added to the reaction mixture, and the mixture was washed with toluene. To the aqueous layer was added 1M hydrochloric acid (35 mL), extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solvent was distilled off under reduced pressure. Methyl 1-C- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-methylphenyl] -D-glucopyranoside (11.3 g) Was obtained as a pale yellow amorphous solid.

Production Example 24
Under a nitrogen stream, methyl 1-C- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-methylphenyl] -D-glucopyranoside (11.3 g), acetic anhydride (14.4 mL), pyridine (16.5 mL), 4-dimethylaminopyridine (310 mg), and ethyl acetate (110 mL) were stirred with heating at 45 ° C. for 12 hours. The reaction mixture was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the solvent was distilled off under reduced pressure, and methyl 1-C- [2-acetoxy-5- (1-benzothien-2-ylmethyl) -4-methylphenyl] -2,3,4,6 -Tetra-O-acetyl-D-glucopyranoside (14.2 g) was obtained as a brown amorphous solid.

Production Example 25
Methyl 1-C- [2-acetoxy-5- (1-benzothien-2-ylmethyl) -4-methylphenyl] -2,3,4,6-tetra-O- cooled to -30 ° C under nitrogen flow Trimethylsilyl trifluoromethanesulfonate (4.3 mL) was added dropwise to a mixture of acetyl-D-glucopyranoside (14.2 g), triethylsilane (6.9 mL), acetonitrile (140 mL), and water (0.38 mL) at -10 ° C for 3.5 hours. Stir. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, heated and dissolved, hexane was added and the mixture was allowed to cool to room temperature. The resulting solid was collected by filtration, dried by heating under reduced pressure, and (1S) -2,3,4,6-tetra-O-acetyl-1,5-anhydro-1- [5- (1-benzothien-2- (Ilmethyl) -2-hydroxy-4-methylphenyl] -D-glucitol (7.1 g) was obtained as an off-white solid.

Tables 6 and 7 show the chemical structures of the compounds produced in the above production examples. Further, in the same manner as in the above production examples, the production example compounds shown in Tables 8 to 11 were produced using the corresponding raw materials. In addition, production methods and instrumental analysis data of these production example compounds are shown in Tables 12 to 23.

Example 1
Under ice cooling, (1S) -2,3,4,6-tetra-O-acetyl-1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-methyl To a mixture of phenyl] -D-glucitol (7.05 g) and isopropyl alcohol (25 mL), 5M aqueous sodium hydroxide solution (13.5 mL) was added dropwise, and the reaction mixture was stirred for 2 hours while warming to room temperature. The reaction mixture was ice-cooled, and 5 M hydrochloric acid (13.5 mL) and water (95 mL) were successively added dropwise. The resulting solid was collected by filtration, dried by heating under reduced pressure, and (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-methylphenyl] -D -Glucitol (4.44 g) was obtained as a light brown solid.

Example 2
(1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2- (benzyloxy) -4-ethylphenyl] -2, cooled to −70 ° C. under a nitrogen stream Boron trichloride was added to a mixture of 3,4,6-tetra-O-benzyl-D-glucitol (4.26 g), 1,2,3,4,5-pentamethylbenzene (7.88 g) and dichloromethane (105 mL). (1.0 M n-heptane solution) (40 mL) was added dropwise, and the mixture was stirred at -70 ° C for 2 hours and 15 minutes. Methanol (40 mL) was added dropwise to the reaction mixture, the temperature was raised to room temperature, and the solvent was evaporated under reduced pressure. Hexane and methanol were added to the residue for liquid separation, and the solvent was distilled off from the methanol layer under reduced pressure. The pale yellow oil obtained by purifying the residue by silica gel column chromatography (chloroform-methanol) was triturated with 2-propanol-water, and the powder was collected by filtration, washed with water, and then dried by heating under reduced pressure. , (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -4-ethyl-2-hydroxyphenyl] -D-glucitol (0.805 g) was obtained as a white solid.

Example 3
Ice-cooled (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -4-carboxy-2-hydroxyphenyl] -D-glucitol (72 mg) in a nitrogen stream Borane-tetrahydrofuran complex (1 M tetrahydrofuran solution) (1.0 mL) was added dropwise to a tetrahydrofuran (1 mL) solution, and the mixture was warmed to room temperature and stirred for 3 hours. Tetrahydrofuran (5 mL) and borane-tetrahydrofuran complex (1 M tetrahydrofuran solution) (0.67 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added borane-tetrahydrofuran complex (1 M tetrahydrofuran solution) (1.67 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was ice-cooled, water and 1 M hydrochloric acid (0.5 mL) were added, and the solvent was evaporated under reduced pressure. The colorless amorphous solid obtained by purifying the residue by ODS column chromatography (water-acetonitrile) was pulverized with diethyl ether-hexane, and the powder was collected by filtration, dried by heating under reduced pressure, and (1S) -1,5 -Anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4- (hydroxymethyl) phenyl] -D-glucitol (28 mg) was obtained as a white solid.

Example 4
1,2 of (1S) -1,5-Anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-3-methoxy-4-methylphenyl] -D-glucitol (187 mg) Boron trifluoride-dimethyl sulfide complex (383 mg) was added to a solution of -dichloroethane (4 mL), and the mixture was stirred at room temperature for 4 hours. Methanol was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The brown amorphous solid obtained by purifying the residue by silica gel column chromatography (chloroform-methanol) and ODS column chromatography (water-acetonitrile) was pulverized with hexane, dried by heating under reduced pressure, and (1S) -1 , 5-Anhydro-1- [5- (1-benzothien-2-ylmethyl) -2,3-dihydroxy-4-methylphenyl] -D-glucitol (22.6 mg) was obtained as a light brown solid.

Example 5
(1S) -1,5-Anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-benzyloxy-4-carboxyphenyl] -2,3,4,6-tetra-O-benzyl- Trimethylsilyldiazomethane (2M diethyl ether solution) (0.47 mL) was added to a toluene (3 mL) solution of D-glucitol (280 mg), and the mixture was stirred at room temperature for 30 minutes. Acetic acid (38 μL) was added to the reaction mixture, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the resulting pale yellow amorphous solid (290 mg), 1,2,3,4,5-pentamethylbenzene (481 mg), toluene (10 mL) Boron trichloride (1 M n-heptane solution) (1.62 mL) was added dropwise at −70 ° C. under a nitrogen stream, and the reaction mixture was stirred for 1 hour while warming to room temperature. Hexane and methanol were added to the reaction mixture for liquid separation, and the solvent was distilled off from the methanol layer under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol). To a solution of the obtained pale yellow amorphous solid (129 mg) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (1 M tetrahydrofuran solution) (3.5 mL) under a nitrogen atmosphere. mL) was added and stirred at room temperature for 8 hours. Methyl magnesium bromide (1 M tetrahydrofuran solution) (7.0 mL) was added to the reaction mixture, and the mixture was heated with stirring at 60 ° C. for 5 days. To the reaction mixture, 1 M hydrochloric acid was added and the solvent was distilled off. The pale yellow amorphous solid obtained by purifying the residue by ODS column chromatography (water-acetonitrile) was pulverized with diethyl ether, dried by heating under reduced pressure, and (1S) -1,5-anhydro-1- [5 -(1-Benzothien-2-ylmethyl) -2-hydroxy-4- (1-hydroxy-1-methylethyl) phenyl] -D-glucitol (32 mg) was obtained as a pale orange solid.

Table 24 shows the chemical structures of the compounds produced in the above examples. Moreover, it carried out similarly to the method of the said Example, and manufactured the Example compound shown in Table 25 and Table 26, respectively using the corresponding raw material. In addition, Tables 27 to 30 show the production methods and instrumental analysis data of these Example compounds.

The compound of formula (I) or a salt thereof is a double inhibitory action of SGLT-1 and SGLT-2, an excellent blood glucose lowering action regardless of the degree of hyperglycemia, and an excellent urinary glucose excretion action in normoglycemia Various diabetes related diseases including type 1 diabetes, type 2 diabetes, insulin resistance disease and obesity, and fatty liver disease including nonalcoholic steatohepatitis (NASH) and / or It can be used as an active ingredient of a therapeutic pharmaceutical composition.

Claims (14)

1. A compound of formula (I) or a salt thereof.
   

   

   (Wherein R ¹ is lower alkyl optionally substituted with —OH, lower alkyl optionally substituted with —O, or optionally substituted cycloalkyl, and R ² represents —H Or lower alkyl optionally substituted, -O-lower alkyl optionally substituted, or -OH, or R ¹ and R ² together form a lower alkylene.)
2. The compound or a salt thereof according to claim 1, wherein R ² is -H, methyl, methoxy, or -OH.
3. The compound or a salt thereof according to claim 2, wherein R ² is -H, methyl, or -OH.
4. The compound or a salt thereof according to claim 3, wherein R ² is -H.
5. R ¹ is (a) lower alkyl optionally substituted with —OH, (b) —O-lower alkyl optionally substituted with 1 cyano or 1 to 3 fluoro, or (c) The compound or a salt thereof according to any one of claims 1 to 4, which is cyclopropyl.
6. The compound or a salt thereof according to claim 5, wherein R ¹ is (a) lower alkyl optionally substituted with -OH, or (b) methoxy.
7. The compound or a salt thereof according to claim 1, wherein R ¹ and R ² are combined to form trimethylene or tetramethylene.
8. (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-methoxyphenyl] -D-glucitol,
   (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-methylphenyl] -D-glucitol,
   (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-3,4-dimethylphenyl] -D-glucitol,
   (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -4-ethyl-2-hydroxyphenyl] -D-glucitol,
   (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4-isopropylphenyl] -D-glucitol,
   (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2-hydroxy-4- (hydroxymethyl) phenyl] -D-glucitol,
   (1S) -1,5-anhydro-1- [7- (1-benzothien-2-ylmethyl) -4-hydroxy-2,3-dihydro-1H-inden-5-yl] -D-glucitol,
   (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -2,3-dihydroxy-4-methylphenyl] -D-glucitol,
   (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -4- (cyanomethoxy) -2-hydroxyphenyl] -D-glucitol,
   (1S) -1,5-anhydro-1- [5- (1-benzothien-2-ylmethyl) -4- (difluoromethoxy) -2-hydroxyphenyl] -D-glucitol, or (1S) -1,5 The compound or a salt thereof according to claim 1, which is -anhydro-1- [5- (1-benzothien-2-ylmethyl) -4-cyclopropyl-2-hydroxyphenyl] -D-glucitol.
9. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof, and a pharmaceutically acceptable excipient.
10. A pharmaceutical composition for the prevention or treatment of diabetes, obesity or fatty liver disease, comprising the compound according to claim 1 or a salt thereof.
11. Use of the compound according to claim 1 or a salt thereof for the manufacture of a pharmaceutical composition for prevention or treatment of diabetes, obesity or fatty liver disease.
12. The compound or its salt of Claim 1 for manufacture of the pharmaceutical composition for prevention or treatment of diabetes, obesity, or fatty liver disease.
13. Use of the compound according to claim 1 or a salt thereof for the prevention or treatment of diabetes, obesity or fatty liver disease.
14. A method for preventing or treating diabetes, obesity, or fatty liver disease, comprising administering an effective amount of the compound or salt thereof according to claim 1 to a patient.

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