JP2009155212A - Therapeutic agent for diabetes comprising c-phenyl 1-thioglucitol compound as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To carry out prophylaxis of diabetes by inhibiting the activity of SGLT1 (sodium-dependent glucose transporter 1) and suppressing absorption of glucose etc., or to provide a prophylactic or therapeutic agent for the diabetes suppressing postprandial hyperglycemia in the diabetes. <P>SOLUTION: The compound is represented by formula (I) [wherein, X is a hydrogen atom, or a 1-6C alkyl group; Y is a 1-6C alkylene group, or -O-(CH<SB>2</SB>)n- (wherein, n represents an integer of 1-5); Z represents -CONHR<SP>A</SP>or -NHCONHR<SP>B</SP>(wherein n is not 1 when Z represents -NHCONHR<SP>B</SP>), with the proviso that R<SP>A</SP>is a 1-6C alkyl group substituted with 1-3 groups selected from among the group consisting of a hydroxy group, and -CONH<SB>2</SB>; and R<SP>B</SP>represents a hydrogen atom or a 1-6C alkyl group substituted with 1-3 groups selected from among the group consisting of a hydroxy group, and -CONH<SB>2</SB>]. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to sodium-dependent glucose cotransporter 1 (SGLT1) activity inhibition related to absorption of glucose and the like in the small intestinal epithelium, or sodium-dependent glucose related to glucose reabsorption in the kidney in addition to its action. The present invention relates to a preventive or therapeutic agent for diabetes comprising a C-phenyl 1-thioglucitol compound having an inhibitory activity on co-transporter 2 (SGLT2) as an active ingredient.

  When suffering from diabetes, the fasting blood glucose level is 126 mg / dL or more. Moreover, even if the fasting blood glucose level is normal, if it shows a high blood glucose level of 140 to 200 mg / dL after meal, it is diagnosed as abnormal glucose tolerance (hereinafter referred to as IGT (impaired glucose tolerance)). The Delaying the onset of diabetes from IGT is thought to reduce the risk of cardiovascular disorders and several findings have been obtained. For example, in Da Qing IGT and Diabetes Study conducted in China in 1997, it was reported that the transition from IGT to type 2 diabetes was significantly suppressed by performing diet and exercise (see Non-Patent Document 1). . As an effective example of drug treatment, the transition from IGT to type 2 diabetes occurs when an α-glucosidase inhibitor acarbose that inhibits sugar hydrolase and delays the absorption of sugar from the small intestine is administered. In addition, it has been reported that the onset of hypertension is also significantly suppressed (see Non-Patent Document 2).

  From the above, in order to suppress the onset of diabetes, it is important to control IGT by diet therapy, exercise and drug therapy.

  Nevertheless, when diabetes develops, blood glucose control is required from time to time. The basis of diabetes treatment is diet therapy and exercise therapy, but if sufficient effects are not obtained even if these are performed, it is necessary to adopt drug therapy.

  Sodium-dependent glucose cotransporter 1 (SGLT1) is frequently expressed in the small intestinal epithelium of mammals. SGLT1 is known to depend on sodium in the small intestine and to control active transport of glucose or galactose. Thus, pyrazole derivatives that inhibit SGLT1 activity have been reported based on the concept of suppressing dietary glucose absorption and preventing or treating IGT (see Patent Documents 1 to 6).

  In addition, sodium-dependent glucose cotransporter 2 (SGLT2) is frequently expressed in the kidney, and glucose once filtered by glomeruli is reabsorbed via SGLT2 (Non-patent Document). 3). When an SGLT2 inhibitor is administered to diabetic rats, it promotes glucose excretion into urine and induces a hypoglycemic effect, and SGLT2-specific inhibitors are now considered as target molecules for new antidiabetic drugs ( Non-patent document 4). Against this background, SGLT2 inhibitors have been studied and various O-aryl glycoside derivatives have been provided (see Patent Documents 7 and 8).

  Therefore, if SGLT1 and SGLT2 activities can be simultaneously inhibited, it is considered that a new type of anti-diabetic drug having both postprandial hyperglycemic inhibitory action based on SGLT1 inhibition and occasional hypoglycemic action based on SGLT2 inhibition can be provided.

  So far, C-phenyl glucitol derivatives having selective inhibitory activity on SGLT2 have been reported (see Patent Document 9), but C-phenyl 1-thioglucitol derivatives that strongly inhibit both SGLT1 and SGLT2 are reported. There are no reports.

International Publication No. WO2002 / 098893 Pamphlet International Publication No. WO2004 / 014932 Pamphlet International Publication No. WO2004 / 018491 Pamphlet International Publication No. WO2004 / 019958 Pamphlet International Publication No. WO2005 / 121161 Pamphlet International Publication No. WO2004 / 050122 Pamphlet European Patent Application No. 0850948 International Publication No. WO2001 / 068660 Pamphlet International Publication No. WO2001 / 027128 Pamphlet Pan XR, et al. Diabets Care, 20, 534, 1997 J.-L. Chiasson, et al. Lancent, 359, 2072, 2002 E. M. Wright, Am. J. Physiol. Renal. Physiol., 280, F10, 2001 G. Toggenburger, et al. Biochem. Biophys. Acta., 688, 557, 1982

  The present invention relates to diabetes containing, as an active ingredient, a C-phenyl 1-thioglucitol compound that inhibits SGLT1 activity and suppresses absorption of glucose and the like to prevent diabetes or suppress postprandial hyperglycemia in diabetes It is an object of the present invention to provide a preventive or therapeutic agent. Furthermore, the present invention relates to C-phenyl 1-thioglucitol which is expected as a prophylactic agent for diabetes and a therapeutic agent for diabetes that inhibits the activities of both SGLT1 and SGLT2 and has both glucose absorption suppression and urinary glucose excretion action. It aims at providing the preventive or therapeutic agent of diabetes characterized by containing a compound as an active ingredient.

  As a result of intensive studies to solve the above problems, the present inventors have found that a C-phenyl 1-thioglucitol compound (hereinafter referred to as “the compound of the present invention”) in which a specific side chain is introduced at the end of an aglycone is excellent. The present inventors have found that it has an SGLT1 activity inhibitory action, or an SGLT2 activity inhibitory action in addition to that action, and has completed the present invention.

  That is, the present invention is characterized by containing a C-phenyl 1-thioglucitol compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. It is a preventive or therapeutic agent for diabetes.

In the formula, X is a hydrogen atom or a C _1-6 alkyl group,
Y is a C _1-6 alkylene group, or —O— (CH ₂ ) n — (n represents an integer of 1 to 5);
Z is —CONHR ^A or —NHCONHR ^B
(Where n is not 1 when Z represents —NHCONHR ^B ).
However,
R ^A is a C _1-6 alkyl group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group and —CONH ₂ ;
R ^B represents a hydrogen atom or a C _1-6 alkyl group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group and —CONH ₂ .

Another aspect of the present invention, Y is a C _1-6 alkylene group, wherein R ^B is a C _1-6 alkyl group substituted by a hydrogen atom, or a hydroxyl group C- phenyl 1- Chiogurushito - le compound Alternatively, it is a prophylactic or therapeutic agent for diabetes, comprising a pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

  According to the present invention, there is provided a prophylactic or therapeutic agent for diabetes characterized in that it contains a C-phenyl 1-thioglucitol compound having SGLT1 activity inhibition or SGLT2 activity inhibition in addition to its action as an active ingredient. It has become possible.

  The terms used in the present invention are defined below.

The “C _1-6 alkyl group” means a linear or branched alkyl group having 1-6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, and n-hexyl group can be mentioned.

The “C _1-6 alkylene group” means a divalent group obtained by removing one hydrogen from a carbon atom of a C _1-6 alkyl group. For example, a methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, propane-1,2-diyl group, butane-1,2-diyl group and the like can be mentioned.

“C _1-6 alkyl group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group and —CONH ₂ ” means that a hydrogen atom on a C _1-6 alkyl group has 1 to 3 hydroxyl groups. , and an alkyl group substituted by at least one -CONH _2. For example, hydroxymethyl group, hydroxyethyl group, 2-hydroxy-1,1-dimethylethyl group, 1,3-dihydroxy-2-methylpropan-2-yl group, 1,3-dihydroxy-2-hydroxymethylpropane- A 2-yl group, a carbamoylmethyl group, and a 2-carbamoylethyl group are exemplified.

  In addition, the “pharmaceutically acceptable salt” is a salt with an alkali metal, an alkaline earth metal, ammonium, alkylammonium, or the like, a salt with a mineral acid or an organic acid, such as a sodium salt, Potassium, calcium, ammonium, aluminum, triethylammonium, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate, citrate, stearate, Succinate, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluene Sulfonate, lauryl sulfate, malate, aspartate, glutamate, adipate, cystein Salt with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, Mention may be made of undecanoic acid salts, salts with acrylic acid polymers, salts with carboxyvinyl polymers.

  “Hydrate” is a pharmaceutically acceptable hydrate of the compound of the present invention or a salt thereof. The compound of the present invention or a salt thereof may be exposed to air or recrystallized to absorb moisture and form adsorbed water, or may become a hydrate. The hydrate in the present invention includes such a hydrate.

  Since some of the compounds and intermediates of the present invention have chiral centers, they may exist as diastereomers or enantiomers. In addition, some of the compounds of the present invention and intermediates may exist as, for example, keto-enol tautomers. In addition, some of the compounds of the present invention and intermediates may exist as geometric isomers (E, Z forms). Accordingly, the compounds and intermediates of the present invention include all the individual isomers mentioned above and mixtures thereof.

  Preferred embodiments of the compound of the present invention are listed below.

  A preferred embodiment of X is a hydrogen atom.

A preferred embodiment of Y is a C _1-6 alkylene group, more preferably a C _2-4 alkylene group.

When Z is —CONHR ^A , a preferred embodiment of R ^A is a C _1-4 alkyl group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group and —CONH ₂ . When Z is —NHCONHR ^B , a preferred embodiment of R ^B is a C _1-4 alkyl group substituted with 1 to 3 hydroxyl groups, more preferably a C _1-4 alkyl group substituted with hydroxyl groups. is there.

  Hereinafter, the production method of the compound (I) of the present invention will be described in detail by way of examples, but is not particularly limited to those exemplified.

Manufacturing method 1
In the compound (I) of the present invention, a compound in which X is a hydrogen atom or a C _1-6 alkyl group, Y is a C _2-6 alkylene group, and Z is —CONHR ^A is synthesized by the following method. Can do.

Y ¹ represents a single bond or a C _1-4 alkylene group, R ¹ and R ² are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group, A represents a chlorine atom or a bromine atom, Other symbols are as defined above.

(1) Step 1 (Heck reaction)
Compound (IV) can be synthesized by subjecting compound (II) and olefin carboxylic acid (III) to Heck reaction in the presence of a palladium catalyst, a phosphine ligand, and an appropriate base. Examples of the palladium catalyst used at this time include palladium acetate, tetrakis (triphenylphosphine) palladium, dibenzylideneacetone palladium, bis (triphenylphosphine) palladium dichloride, bis (tricyclohexylphosphine) palladium dichloride, and palladium activated carbon. Examples of the phosphine ligand include triphenylphosphine and tris (2-methylphenyl) phosphine. As the base, triethylamine, N-ethyl-N, N-diisopropylamine, potassium carbonate, calcium carbonate, cesium carbonate, potassium t-butoxide and the like are used. Examples of the solvent used for the reaction include acetonitrile, toluene, tetrahydrofuran and the like. The reaction temperature is from 0 ° C. to reflux temperature, but a microwave may be used.

(2) Step 2 (Conversion to amide group)
Compound (IV) is dehydrated and condensed with amine (R ^A NH ₂ ) to obtain compound (V). As a solvent used in this reaction, chloroform, dichloromethane, N, N-dimethylformamide and the like are preferable, and as a dehydrating condensing agent, N, N′-dicyclohexylcarbodiimide (DCC), N-ethyl-N′-3-dimethyl is used. Aminopropylcarbodiimide hydrochloride (WSC), 1,1′-carbonyldiimidazole (CDI), WSC / 1-hydroxybenzotriazole monohydrate and the like are preferable. The reaction temperature here is 0 ° C to 60 ° C.

(3) Step 3 (reduction, deprotection)
The compound (V) obtained above is subjected to catalytic hydrogenation under a hydrogen atmosphere using a catalyst such as palladium activated carbon, palladium hydroxide, or platinum-palladium activated carbon to simultaneously reduce and debenzylate the olefin. Inventive compound (I) can be obtained. Of these, palladium activated carbon and palladium hydroxide are preferred as the catalyst. Examples of the solvent used in this reaction include methanol, ethanol, isopropanol, ethyl acetate, acetic acid, and a mixed solvent thereof. The reaction temperature is from room temperature to reflux temperature, but room temperature is preferred.

In the debenzylation, acids such as BCl ₃ , BCl ₃ .Me ₂ S, BBr ₃ , AlCl ₃ , CF ₃ COOH, TfOH can be used. Examples of the solvent used in this reaction include chloroform, dichloromethane, acetonitrile, diethyl ether, tetrahydrofuran, dimethyl sulfide, anisole and the like. Among these, a method using CF ₃ COOH, TfOH, or ethanedithiol in dimethyl sulfide is preferable. The reaction temperature is preferably -78 ° C to 40 ° C.

Manufacturing method 2
In the compound (I) of the present invention, a compound in which X is a hydrogen atom or a C _1-6 alkyl group, Y is a C _2-6 alkylene group, and Z is —NHCONHR ^B can be synthesized by the following method.
However, the symbols in the formula are as defined above.

(4) Step 4 (Heck reaction)
Compound (II) and alkenyl urea derivative (VI) can be converted to compound (VII) by the Heck reaction described in Step 1.

(5) Step 5 (reduction, deprotection)
The compound (I) of the present invention can be obtained by subjecting the compound (VII) obtained above to dehydrogenation by catalytic hydrogenation or Lewis acid described in Step 3.

Production method 3
In the compound (I) of the present invention, a compound in which X is a hydrogen atom or a C _1-6 alkyl group, Y is —O— (CH ₂ ) n—, and Z is —CONHR ^A is obtained by the following method. Can be synthesized.
R ³ represents a C _1-6 alkyl group, and the other symbols are as defined above.

(6) Step 6 (coupling)
The aryl lithium reagent (IX) can be prepared using an organometallic reagent such as n-butyllithium, sec-butyllithium, tert-butyllithium or the like for the aryl halide. Compound (X) can be obtained by adding intermediate compound (VIII) to this. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is from -80 ° C to room temperature, preferably -78 ° C to -25 ° C. In addition, Grignard reagent (IX) can be produced using 1 equivalent of metallic magnesium. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, diglyme and the like.

(7) Step 7 (reduction, deprotection)
Compound (XI) can be produced by reacting compound (X) obtained above with Et ₃ SiH, i-Pr ₃ SiH, t-BuMe ₂ SiH or Ph ₂ SiHCl in the presence of a Lewis acid. . Examples of the Lewis acid used in this reaction include BF ₃ .Et ₂ O, CF ₃ COOH, InCl ₃ , and examples of the solvent include chloroform, dichloromethane, acetonitrile, or a mixed solvent thereof, and acetonitrile is preferable. -It is a mixed solvent with acetonitrile, such as chloroform and acetonitrile-dichloromethane. The reaction temperature here is −60 ° C. to 25 ° C., preferably −30 ° C. to 25 ° C.

(8) Step 8 (alkylation)
Compound (XIII) can be obtained by reacting compound (XI) with reagent (XII) under basic conditions. As the base used in this reaction, sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydride, pyridine, triethylamine and the like are preferable. Examples of the solvent include dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide and the like. The reaction temperature is preferably 20 to 100 ° C.

(9) Step 9 (hydrolysis, amidation)
Compound (XIII) can be converted to the corresponding carboxylic acid by hydrolysis of the ester under basic conditions. The base used in this reaction is preferably potassium carbonate, lithium hydroxide, sodium hydroxide, triethylamine or the like, and examples of the solvent include methanol, ethanol, ethyl acetate, or a mixed solvent of these with water. The reaction temperature is preferably 20 to 100 ° C.
The carboxylic acid obtained here and R ^A NH ₂ can be condensed by the method described in the above Step 2 to lead to the compound (XIV).

(10) Step 10 (deprotection)
Compound (XIV) can be converted to the title compound (I) by the method described in Step 3.

Manufacturing method 4
In the compound (I) of the present invention, a compound in which X is a hydrogen atom or a C _1-6 alkyl group, Y is —O— (CH ₂ ) n—, and Z is —NHCONHR ^B is obtained by the following method. Can be synthesized.
In the formula, Y ² represents a C _2-5 alkylene group, and other symbols are as defined above.

(11) Step 11 (coupling)
Compound (XVII) can be synthesized from compound (XV) (which can be produced according to International Publication No. WO06 / 073197) and (XVI) in the same manner as in Step 6.

(12) Step 12 (reduction, deprotection)
Compound (XI) can be synthesized by reducing the hydroxyl group of compound (XVII) and removing the protecting group in the same manner as in Step 7. Compound (XI) can also be synthesized in Step 7 above.

(13) Step 13 (substitution reaction)
Compound (XIX) can be obtained by reacting compound (XI) with reagent (XVIII) under basic conditions. As the base used in this reaction, sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydride, pyridine, triethylamine and the like are preferable. Examples of the solvent include dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide and the like. The reaction temperature is preferably 20 to 100 ° C.

(14) Step 14 (dephthalimide)
Amine (XX) can be obtained by reacting compound (XIX) with hydrazine hydrate or methyl hydrazine in a suitable solvent. As the solvent used here, methanol, ethanol, tetrahydrofuran, water, and a mixed solvent thereof are preferable. The reaction temperature is room temperature to 100 ° C, preferably room temperature to 60 ° C.

(15) Step 15 (ureaization)
Compound (XX) can be synthesized compound (XXI) with a carbonylating reagent and NH ₂ R ^B. Examples of the carbonylating reagent used here include 1,1′-carbonyldiimidazole, p-nitrophenyl chloroformate, triphosgene and the like. For this reaction, a base such as triethylamine, pyridine, N-methylmorpholine may be used. Examples of the solvent used here include chloroform, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, and the like, and a mixed solvent thereof may be used. Preferred mixed solvents are chloroform / N, N-dimethylformamide, chloroform / dimethylsulfoxide, tetrahydrofuran / N, N-dimethylformamide. The reaction temperature is room temperature to 80 ° C., and the temperature can be raised when the reaction proceeds slowly.

(16) Step 16 (deprotection)
The title compound (I) can be synthesized by deprotecting the compound (XXI) in the same manner as in Step 3.

Manufacturing method 5
Production method of intermediate (II) Production methods of intermediates (II) and (VIII) necessary for the production of the compound (I) of the present invention are shown below. However, D ¹ represents a Li or MgBr, and other symbols are as defined above.

(17) Step 17 (coupling)
An aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium for the intermediate compound (XXII). Compound (XXIII) can be obtained by adding thiolactone (XVI) thereto. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is from -80 ° C to room temperature, preferably -78 ° C to -25 ° C.

(18) Step 18 (acid hydrolysis)
Compound (VIII) can be produced by hydrolyzing the acetal group in compound (XXIII) with hydrochloric acid, p-toluenesulfonic acid monohydrate, or the like. As the solvent used at this time, tetrahydrofuran, ethanol, methanol, water, or a mixed solvent thereof is preferable. The reaction temperature is from 4 ° C to room temperature, preferably room temperature. Moreover, although reaction time changes with reaction temperature, it is 1 hour-24 hours.

(19) Step 19 (coupling)
The monolithium compound (XXIV) can be produced by using 1 equivalent of n-butyllithium, sec-butyllithium, tert-butyllithium, etc. with respect to the 4-halo-bromobenzene derivative. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is from -80 ° C to room temperature, preferably -78 ° C to -25 ° C. The reaction time is preferably 5 to 30 minutes. In addition, Grignard reagent (XXIV) can be produced using 1 equivalent of metallic magnesium. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, diglyme and the like. Next, compound (XXV) can be produced by adding intermediate compound (VIII) to compound (XXIV). The reaction temperature is from -80 ° C to room temperature, preferably -78 ° C to -25 ° C.

(20) Step 20 (Reduction of hydroxyl group)
The title compound (II) can be produced by reacting the compound (XXV) obtained above under the conditions of Step 7.

Manufacturing method 6
Production Method of Thiolactone (XVI) Compound (XVI) can be synthesized by the method described in Yuasa, H., et al. J. Chem. Soc. Perkin Trans. 1, 2763, 1990. Or it can also manufacture according to the following schemes.

(21) Step 21 (protection of hydroxyl group)
The hydroxyl group at the 1-position of compound (XVIa) (which can be produced according to International Publication No. WO04 / 106352) is protected with a protecting group that is resistant to basic conditions and deprotectable under neutral or acidic conditions. For example, a compound (XVIb) protected with a tetrahydropyranyl group using 3,4-dihydro-2H-pyran (3,4-DHP), p-toluenesulfonic acid monohydrate and pyridinium-toluenesulfonic acid (PPTS). ). Examples of the solvent used in this reaction include N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, chloroform, dichloromethane, toluene and the like.

(22) Step 22 (deprotection, protection)
Next, the acetyl group is removed. The acetyl group can be removed using a base such as sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, triethylamine, etc., and methanol, ethanol, hydrous methanol, etc. can be used as the solvent. it can. Next, compound (XVIc) can be obtained by reacting benzyl bromide or benzyl chloride with an appropriate base. Examples of the base include triethylamine, N-ethyl-N, N-diisopropylamine, pyridine, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium methoxide, t-BuOK, etc. Potassium carbonate, calcium carbonate, cesium carbonate, sodium hydride. Examples of the solvent used in this reaction include N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane and the like, and the reaction temperature is -20 ° C to 25 ° C.

(23) Step 23 (deprotection)
Next, the protecting group at position 1 is deprotected to obtain compound (XVId). For example, the THP group can be removed by treating compound (XVIc) with p-toluenesulfonic acid monohydrate in methanol or ethanol, or PPTS.

(24) Step 24 (oxidation)
Finally, compound (XVId) can be treated with a suitable oxidizing agent to produce thiolactone (XVI). As the oxidizing agent used in this reaction, dimethyl sulfoxide-acetic anhydride, Dess-Martin periodinane, IBX and the like are preferable, and the reaction temperature is 0 ° C to 40 ° C.

  The compound of the present invention inhibits SGLT1 activity and suppresses glucose absorption from the digestive tract. Or the activity of both SGLT1 and SGLT2 can be inhibited, IGT can be improved by the urinary glucose excretion action in addition to glucose absorption suppression, and diabetes can be prevented or treated.

  Therefore, the compound of the present invention can be used as an active ingredient of a SGLT1 or SGLT2 inhibitor, or a preventive or therapeutic agent for diabetes, diabetes-related diseases and diabetic complications.

  Here, “diabetes” includes type 1 diabetes, type 2 diabetes, and other types of diabetes caused by a specific cause.

  Here, “diabetes-related disease” means obesity, hyperinsulinemia, glucose metabolism abnormality, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism abnormality, hypertension, congestive heart failure, edema, high Examples include uricemia and gout.

  Here, “diabetic complications” are classified into acute complications and chronic complications.

  “Acute complications” include hyperglycemia (such as ketoacidosis), infections (such as skin, soft tissue, biliary system, respiratory system, urinary tract infection) and the like.

“Chronic complications” include microangiopathy (nephropathy, retinopathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, lower limb arterial occlusion, etc.), neuropathy (sensory, motor, Autonomic nerves) and foot gangrene.
The main complications are diabetic retinopathy, diabetic nephropathy, diabetic neuropathy.

  The compound of the present invention is a therapeutic agent for diabetes having a different mechanism other than SGLT1 and SGLT2 activity inhibitor, for the purpose of enhancing the action of the compound or reducing the dose of the compound, It can be used in combination with drugs such as antihyperlipidemic agents, antihypertensive agents, antiobesity agents, diuretics, antithrombotic agents (hereinafter abbreviated as concomitant drugs). In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Furthermore, the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by mass of the concomitant drug may be used per 1 part by mass of the compound of the present invention.

  Examples of diabetes therapeutic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli or yeast; insulin zinc; protamine insulin zinc; Insulin fragment or derivative (eg, INS-1 etc.), oral insulin preparation), insulin resistance improving agent (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate) Riboglitazone (CS-011) (R-119702), Sipoglitazar (TAK-654), Metaglidasen (MBX-1 0 2), Naveglitazar LY-51981), MX-6054, Balaglitazone (NN-2344), T-1 31 (AMG131), PPA Rγ agonist, PPA Rγ antagonist, PPA Rγ / α dual agonist, α-glucosidase inhibitor ( Examples, voglibose, acarbose, miglitol, emiglitate), biguanides (eg, phenformin, metformin, buformin or their salts (eg, hydrochloride, fumarate, succinate)), insulin secretagogues (sulfonylurea ( E.g. tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybsol, etc.), repaglinide, senaglinide, nateglinide, mitiglinide or its Lucium salt hydrate), GPR40 agonist, GPR40 antagonist, GLP-1 receptor agonist (eg, GLP-1, GLP-1 MR agent, Liraglutide (NN-2211), Exenatide (AC-2993) (exendin-4 ), Exenatide LAR, BIM51077, A ib (8, 35) hGLP-1 (7, 37) NH2, CJC-1 13 1, AVE0010, GSK-716155), amylin agonist (eg, pramlintide), phosphotyrosine phosphatase Inhibitors (eg, sodium vanadate), dipeptidyl peptidase I V inhibitors (eg, compounds described in WO02 / 038541, NVP-DPP-278, PT-100, P32 / 98, vildagliptin (Vildagliptin) ) (LAF-237), P93 / 01, Sitagliptin (MK-431), Saxagliptin (BMS-477118), SYR-322, MP-513, T-6666, GRC-8200, etc.), β3 Agonists (eg, AJ-9777, AZ40140, etc.), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, fructose-1,6-bisphosphatase inhibitors), SGLT ( sodium-glucose transporter) inhibitor (eg, compound described in WO04 / 014931, WO04 / 0899967, WO06 / 073197, T-1095, Serglflozin (GSK-869682), GSK- 189075, KGT-1251, KGT-1681, KGA-2727, BMS-512148, AVE2268, SAR7226, etc.), 11 β-hydroxysteroid dehydrogenase inhibitors (eg, WO06 / 051662), BVT-3498, INCB13739) , GPR119 agonist (eg, PSN-632408, APD-668), adiponectin or agonist thereof, IKK inhibitor (eg, AS-2868), AMPK activator, leptin resistance improving agent, somatostatin receptor agonist, gluco Examples include kinase activators (eg, Ro-28-1675), pancreatic lipase inhibitors (eg, orlistat, ATL-962), and DGAT-1 inhibitors.

  Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112), neurotrophic factors and their increasing agents (eg, NGF). , NT-3, BDNF, neurotrophin production / secretion promoter), nerve regeneration promoter (eg, Y-128), PKC inhibitor (eg, ruboxistaurine mesylate (LY-333531)) AGE inhibitors (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-2 26, pyridoline, pyridoxamine), active oxygen scavengers (eg, Thioctic acid), brain Tube expansion agent (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., B I M 2 3 1 9 0), apoptosis signal regulating kinase--1 (ASK-1) inhibitors.

  Antihyperlipidemic agents include, for example, statin compounds (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, rosuvastatin, pitavastatin or their salts (eg, sodium salt, calcium salt)), squalene synthesis Enzyme inhibitors (eg, TAK-475), fibrate compounds (eg, bezafibrate, clofibrate, simfibrate, clinofibrate), ACAT inhibitors (eg, avasimibe, elucimibe), anion exchange resin (Eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, nicoritrol), ethyl icosapentate, plant sterols (eg, soto) Isosterol, gamma oryzanol), CETP inhibitor (eg, Torcetrapib, JTT-705, JTT-302, FM-VP4 etc.), cholesterol absorption inhibitor (eg, ezetimibe etc.) Is raised.

  Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril), angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, azilsartan (TAK-536) ), Calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel openers (eg, lebucromacarim, L-2 7 1 5 2, A L0 6 7 1, NIP-12 1), clonidine Is mentioned.

  Examples of anti-obesity agents include central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphetopramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonist (Eg, compounds described in WO06 / 035967, SB-568849; SNAP-7941, T-226296); neuropeptide Y antagonists (eg, CP-422935); cannabinoid receptor antagonists (eg, rimonabant ( SR-141716), SR-147778); Ghrelin antagonists; 1 1-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498, INCB13739)), pancreatic lipase inhibitors (eg, orlistat, ATL-9) 2), DGAT-1 inhibitor, β3 agonist (eg, AJ-9777, AZ40140), peptidic appetite suppressant (eg, leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonist (eg, lynchtripto) , FPL-15849), an antifeedant (eg, P-57).

  Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide. , Methiclotiazide), anti-aldosterone preparation (eg, spironolactone, triamterene), carbonic anhydrase inhibitor (eg, acetazolamide), chlorobenzenesulfonamide preparation (eg, chlorthalidone, mefluside, indapamide), azosemide, isosorbide, ethacrynic acid Piretanide, bumetanide, furosemide.

  Examples of the antithrombotic agent include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium, AVE-5026), warfarin (eg, warfarin potassium, etc.), antithrombin drug (eg, argatroban) , Ximelagatran, Dabigatran, Odiparcil, Lepirudin, bivalirudin, Desirudin, ART-123, Idraparinux, SR-12571, TCG-9737, TCG-9737, TCG-9737, TCG-9737 -30870, MPC-0920, Pegmusirudin, Org-426951, etc.), thrombolytic drugs ( Urokinase, tisokinase, alteplase, natepase, monteplase, pamiteplase, etc., platelet aggregation inhibitor (e.g., ticlopidine hydrochloride) ), Ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, etc.), anti-Xa inhibitors (eg, Fondaparinux, BAY-59-7939, DU-176b, YM-17, ap65, SRp65 , Razababan, L -571717, MLN-102, Octapine, Otamixavan, EMD-503982, TC-10, CS-3030, AVE-3247, GSK-813893, KFA-1982, etc., plasma carboxypeptidase B (or active thrombin-activatable) and inhibitors (also known as fibrinolysis inhibitor [TAFIa]) (eg, AZD-9684, EF-6265, MN-462).

  When the compound of the present invention is provided as a pharmaceutical, various forms of preparations such as solid preparations and liquid preparations can be appropriately adopted. In that case, it is also possible to mix | blend a pharmaceutically acceptable carrier. Examples of such carriers include common excipients, bulking agents, binders, disintegrants, coating agents, dragees, pH adjusters, solubilizers or aqueous or non-aqueous solvents. Tablets, pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections and the like can be prepared from the compound of the present invention and these carriers.

  In addition, the compound of the present invention can be included in α, β, γ-cyclodextrin, methylated cyclodextrin or the like to improve its solubility.

  The dose of the compound of the present invention varies depending on the disease, symptoms, body weight, age, sex, route of administration, etc., but is 0.1 to 1000 mg / kg body weight per day for an adult, 0.1 to 200 mg / kg. kg body weight is preferable, and 0.1 to 10 mg / kg body weight is more preferable. This can be administered once to several times a day.

  Hereinafter, the present invention will be described in more detail with reference examples, examples and test examples.

Reference example 1
Production of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (compound (XVI))

(1) Production of tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose 2,3,4,6-tetra-O-acetyl- To a solution of 5-thio-D-glucopyranose (2.0 g, 5.49 mmol) in chloroform (40 mL), 3,4-dihydro-2H-pyran (1.5 mL, 16.5 mmol) and p-toluenesulfonic acid 1 water A Japanese product (104 mg, 0.549 mmol) was added and stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the pale yellow amorphous title compound (2.56 g). Obtained.

(2) Preparation of tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-benzyl-5-thio-D-glucopyranose Next, tetrahydro-2H-pyran-2-yl 2, A solution of 3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (2.5 g) in methanol (40 mL) was added 25 wt% sodium methoxide in methanol (0.11 mL, 0.55 mmol). The mixture was further stirred for 3 hours. A small amount of dry ice was added to neutralize the reaction solution, and then the reaction solution was concentrated. The obtained residue was dissolved in N, N-dimethylformamide (20 mL). This solution was added dropwise to a suspension of sodium hydride (1.3 g, 32.9 mmol; 60% oil) and N, N-dimethylformamide (4 mL) under ice cooling. The reaction was stirred at room temperature for 20 minutes, then cooled to 4 ° C. and benzyl bromide (5.6 g, 32.9 mmol) was added. The reaction solution was stirred at room temperature for 12 hours, methanol (5 mL) was added, and the mixture was stirred for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give the title compound (3.36 g, 96%; 2 steps). )

(3) Production of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucopyranose Tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-benzyl- A mixture of 5-thio-D-glucopyranose (3.30 g, 5.15 mmol), pyridinium p-toluenesulfonic acid (518 mg, 2.06 mmol) and ethanol (58 mL) was stirred at 80 ° C. for 2 hours. The reaction was cooled to room temperature and the solvent was concentrated. The obtained residue was dissolved in ethyl acetate. This solution was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (2.89 g, quant.) As colorless crystals.
¹³ C NMR (125 MHz, CHLOROFORM-d) δ 41.3, 67.8, 71.6, 73.0, 73.2, 75.6, 76.2, 81.9, 82.9, 84.4, 127.5, 127.7, 127.8, 127.9, 128.0, 128.3, 128.4, 128.5, 137.8, 138.3, 138.8.

(4) Production of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone 2,3,4,6-tetra-O-benzyl-5-thio- A mixture of D-glucopyranose (2.82 g, 5.07 mmol), dimethyl sulfoxide (47 mL) and acetic anhydride (39 mL) was stirred at room temperature for 12 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give the title compound (2.3 g, 82%) as a colorless oil. )
¹ H NMR (200 MHz, CHLOROFORM-d) δ ppm 3.70 (d, J = 4.8 Hz, 2 H) 3.86-4.02 (m, 2 H) 4.09-4.22 (m, 2 H) 4.40-4.68 (m, 7 H) 4.83 (d, J = 11.4 Hz, 1 H) 7.12-7.41 (m, 20 H).

Reference example 2
Preparation of 2- [4- (benzyloxy) -5-bromo-2-methylphenyl] -1,3-dioxolane (Compound (XXII))

(1) Preparation of 1- [4- (benzyloxy) -2-methylphenyl] ethanone To a solution of 4′-hydroxy-2′-methylacetophenone (3.06 g, 20 mmol) in N, N-dimethylformamide (20 mL) Potassium carbonate (3.66 g, 26.4 mmol), benzyl bromide (2.7 mL, 22.4 mmol) and n-Bu ₄ NI (0.75 g, 2.03 mmol) were added and stirred at room temperature for 14 hours. Under ice cooling, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and then water and ethyl acetate were added to separate the organic layer. The extract was washed with an aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1 → 6: 1) to give the title compound ( 5.05 g, quant.).
¹ H NMR (300 MHz, CHLOROFORM-d) δppm 2.55 (s, 3 H) 2.57 (s, 3 H) 5.11 (s, 2 H) 6.78 − 6.86 (m, 2 H) 7.30 − 7.47 (m, 5 H ) 7.75 (dd, J = 7.93, 1.09 Hz, 1 H).

(2) Preparation of 4- (benzyloxy) -5-bromo-2-methylbenzoic acid 1- [4- (benzyloxy) -2-methylphenyl] ethanone (20.9 g, 87.1 mmol) in acetone ( 300 mL) solution was added NaBr (9.86 g, 95.9 mmol) in water (100 mL), water (200 mL) and Oxone (Oxone monopersulfate, Aldrich) (59.0 g, 95.9 mmol). And stirred at room temperature for 2.5 hours. Under ice cooling, an aqueous solution (50 mL) of sodium sulfite (20 g) was added to the reaction solution, and then water and ethyl acetate were added to separate the organic layer. The organic layer was 20 wt. The extract was washed with an aqueous sodium sulfite solution and saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give 1- [4- (benzyloxy) -5-bromo-2-methylphenyl] ethanone and 1- [4- (benzyloxy) -3-bromo. A mixture (27.2 g) of 2-methylphenyl] ethanone was obtained. To this was added a 5% sodium hypochlorite solution (300 mL, 255 mmol) and an aqueous solution (10 mL) of potassium hydroxide (4.80 g, 85.3 mmol), stirred at 120 ° C. for 1 hour, and then cooled to room temperature. The precipitated insoluble material was filtered off. 2N Hydrochloric acid was added to the insoluble material, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was washed with methanol to give the title compound (16.6 g, 59%, 2 steps) as a colorless powder.
¹ H NMR (300 MHz, DMSO-D6) δ ppm 2.45 − 2.57 (m, 3 H) 5.28 (s, 2 H) 7.18 (s, 1 H) 7.31 − 7.54 (m, 5 H) 8.03 (s, 1 H) 12.83 (brs, 1 H).

(3) Production of 2- [4- (benzyloxy) -5-bromo-2-methylphenyl] -1,3-dioxolane 4- (Benzyloxy) -5-bromo-2-methylbenzoic acid (16. To a suspension of 6 g, 51.7 mmol) in chloroform (80 mL), oxalyl chloride (5 mL, 56.9 mmol) and N, N-dimethylformamide (6 drops) were added and stirred at room temperature for 1 hour. Then, 4- (benzyloxy) -5-bromo-2-methylbenzoyl chloride was obtained. Next, a suspension of N, O-dimethylhydroxylamine hydrochloride (5.55 g, 56.9 mmol) and triethylamine (15 mL, 103 mmol) in chloroform (60 mL) was added to 4- (benzyloxy) -5- 5 under ice cooling. A solution of bromo-2-methylbenzoyl chloride in chloroform (60 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Under ice-cooling, water and chloroform were added to separate the organic layer, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain 4- (benzyloxy) -5-bromo-N-methoxy-N-dimethylbenzamide. Lithium aluminum hydride (1.96 g, 51.7 mmol) was added to the THF (150 mL) solution at −10 ° C., and the mixture was stirred at the same temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, ethyl acetate was added to separate the organic layer, and the organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain 4- (benzyloxy) -5-bromo-2-methylbenzaldehyde. Ethylene glycol (30 mL, 517 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.58 mmol) were added to this toluene (120 mL) solution, and heated under reflux for 1.5 hours using a Dean-Stark apparatus. did. Ethyl acetate was added to the reaction solution, and the organic layer was separated. The organic layer was washed with water, saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1). The product was further purified by NH silica gel column chromatography (chloroform) to obtain the title compound (12.8 g, 71%, 3 steps) as a colorless powder.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.34 (s, 3 H) 3.92 − 4.19 (m, 4 H) 5.15 (s, 2 H) 5.87 (s, 1 H) 6.74 (s, 1 H) 7.27 − 7.51 (m, 5 H) 7.72 (s, 1 H).
ESI m / z = 348, 350 (M + 2).

Reference example 3
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-bromobenzyl) -4-methylphenyl] -1 -Production of thio-D-glucitol

(1) 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (1,3-dioxolan-2-yl) -4-methylphenyl] -5 -Preparation of thio-D-glucopyranose To a solution of 2- [4- (benzyloxy) -5-bromo-2-methylphenyl] -1,3-dioxolane (12.9 g, 36.9 mmol) in THF (100 mL). Under a nitrogen atmosphere, a 2.67Mn-butyllithium hexane solution (14.5 mL, 36.9 mmol) was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (9.77 g, 17.6 mmol) in tetrahydrofuran (40 mL) was added dropwise to the same temperature. And stirred for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 2: 1) to give the title compound as a colorless and transparent amorphous substance. (10.6 g, 73%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.39 (s, 3 H) 3.46-3.72 (m, 2 H) 3.86-4.22 (m, 8 H) 4.43-5.00 (m, 8 H) 5.10 (s , 2 H) 5.92 (s, 1 H) 6.66-6.90 (m, 3 H) 7.00-7.38 (m, 23 H) 7.57 (brs, 1 H).
ESI m / z = 847 (M + Na).

(2) Production of 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-formyl-4-methylphenyl] -5-thio-D-glucopyranose 2 , 3,4,6-Tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (1,3-dioxolan-2-yl) -4-methylphenyl] -5-thio-D -To a solution of glucopyranose (11.1 g, 13.5 mmol) in tetrahydrofuran (100 mL) was added 6N hydrochloric acid (100 mL) under ice cooling, and the mixture was stirred at room temperature for 12 hours. Under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (10.1 g) as a pale yellow oily compound. , Quant.).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.64 (s, 3 H) 3.51-3.70 (m, 2 H) 3.84-4.29 (m, 4 H) 4.46-4.97 (m, 8 H) 5.04-5.24 (m, 2 H) 6.62-6.82 (m, 3 H) 6.99-7.38 (m, 23 H) 7.60 (brs, 1 H) 10.05 (s, 1 H).
ESI m / z = 803 (M + Na).

(3) (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-bromobenzyl) -4-methylphenyl Preparation of 1-thio-D-glucitol 2.67Mn-butyllithium hexane in a tetrahydrofuran (50 mL) solution of 1,4-dibromobenzene (6.08 g, 25.8 mmol) at −78 ° C. in a nitrogen atmosphere The solution (10.0 mL, 25.8 mmol) was added dropwise. Then 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-formyl-4-methylphenyl] -5-thio-D-glucopyranose (10.0 g, A solution of 13.0 mmol) in tetrahydrofuran (30 mL) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 2: 1) to give a yellow amorphous product as a crude compound (8 .89 g).
To a solution of this crude compound (8.89 g) in acetonitrile (60 mL) at −10 ° C. in a nitrogen atmosphere, Et ₃ SiH (4.6 mL, 28.4 mmol) and BF ₃ .Et ₂ O (2.88 mL, 22. 7 mmol) was added and stirred at the same temperature for 20 minutes. The reaction solution was warmed to room temperature, chloroform (30 mL) was added, and the mixture was stirred for 3 and a half hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1 → 10: 1) to give the title compound as a colorless and transparent amorphous substance. (2.34 g, 20%; 2 steps).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.14 (s, 3 H) 3.05-3.18 (m, 1 H) 3.55 (t, J = 8.63 Hz, 1 H) 3.64-4.10 (m, 7 H) 4.48-4.69 (m, 5 H) 4.81-5.13 (m, 5 H) 6.71-6.95 (m, 4 H) 7.03-7.52 (m, 27 H).
ESI m / z = 922 (M + NH4), 924 (M + 2 + NH4).

Reference example 4
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-chloro-2-methylbenzyl) -4-methyl Of phenyl] -1-thio-D-glucitol

A solution of 2-bromo-5-chlorotoluene (2.59 g, 12.6 mmol) in tetrahydrofuran (20 mL) under an argon atmosphere at −78 ° C. with a 2.64 Mn-butyllithium hexane solution (4.6 mL, 12.2 mmol). ) Was added dropwise. Then 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-formyl-4-methylphenyl] -5-thio-D-glucopyranose (3.19 g, A solution of 4.08 mmol) in tetrahydrofuran (20 mL) was added dropwise. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (chloroform) to obtain a yellow amorphous as a crude compound (3.44 g).
To a solution of this crude compound (3.44 g) in acetonitrile-chloroform (1: 1, 76 mL) at 0 ° C. under a nitrogen atmosphere, Et ₃ SiH (1.8 mL, 11.4 mmol) and BF ₃ .Et ₂ O (0 .53 mL, 4.16 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (1.39 g) as a colorless and transparent amorphous. 39%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H) 2.21 (s, 3 H) 3.06-3.18 (m, 1 H) 3.48-3.61 (m, 1 H) 3.62-3.92 (m , 6 H) 3.95-4.07 (m, 1 H) 4.45-4.64 (m, 5 H) 4.73-4.94 (m, 3 H) 5.00-5.14 (m, 2 H) 6.52-6.65 (m, 1 H) 6.75 -6.89 (m, 3 H) 6.95-7.50 (m, 26 H).

Reference Example 5
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4-((1E) -3-carboxyprop-1 -En-1-yl) benzyl] -4-methylphenyl} -1-thio-D-glucitol

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-bromobenzyl) -4-methylphenyl] -1 -A solution of thio-D-glucitol (1.0 g, 1.10 mmol) in acetonitrile (11 mL) in vinyl acetate (227 mg, 2.64 mmol), palladium (II) acetate (49 mg, 0.218 mmol), tri-O-tolyl Phosphine (135 mg, 0.218 mmol) and triethylamine (558 mg, 5.51 mmol) were added, and the reaction was performed at 120 ° C. for 20 minutes using a biotage microwave. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 1: 1 → 1: 2) to give the title compound (598 mg, 60%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H) 3.00-3.34 (m, 3 H) 3.35-4.18 (m, 8 H) 4.45-4.68 (m, 5 H) 4.82-4.95 (m, 3 H) 4.97-5.16 (m, 2 H) 6.00-6.26 (m, 1 H) 6.33-6.50 (m, 1 H) 6.68-7.51 (m, 31 H).
ESI m / z = 909 (MH).

Reference Example 6
Production of N-allyl-N ′-(2-hydroxy-1,1-dimethylethyl) urea

Triethylamine (4.9 mL, 35.5 mmol) was added to a solution of allylamine (1.5 g, 26.3 mmol) in chloroform (60 mL), and 4-nitrophenyl chloroformate (6.09 g, 30.2 mmol) was added at 4 ° C. And stirred for 1 hour. To this reaction solution, a solution of 2-amino-2-methylpropanol (2.58 g, 28.9 mmol) in chloroform (3 mL) was added at the same temperature, and the mixture was stirred at room temperature overnight. The reaction solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → chloroform: methanol = 10: 1) to give the title compound as a yellow oily compound. (1.09 g, 24%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (s, 6 H) 3.55 (s, 2 H) 3.71-3.80 (m, 2 H) 4.85-5.08 (m, 2 H) 5.08-5.24 (m , 2 H) 5.77-5.91 (m, 1 H).
ESI m / z = 195 (M + Na).

Example 1
(1S) -1,5-Anhydro-1- [2-hydroxy-5- (4- {4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobutyl} benzyl) -4- Preparation of methylphenyl] -1-thio-D-glucitol

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-{(1E) -4- [ Preparation of (2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} benzyl) -4-methylphenyl] -1-thio-D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4-((1E) -3-carboxyprop-1-ene- 1-yl) benzyl] -4-methylphenyl} -1-thio-D-glucitol (410 mg, 0.449 mmol) in chloroform (4.5 mL) was added 2-amino-2-methyl-1-propano- (100 mg, 1.12 mmol), 1-hydroxybe Zotoriazo - Le monohydrate (114 mg, 0.846 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (162 mg, 0.846 mmol) was added and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 1: 2) to give the title compound as an orange-yellow oily compound. (200 mg, 45%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (s, 6 H) 2.16 (s, 3 H) 3.05-3.16 (m, 3 H) 3.49-3.61 (m, 3 H) 3.64-3.98 (m , 6 H) 4.00-4.13 (m, 1 H) 4.49-4.65 (m, 5 H) 4.81-4.94 (m, 3 H) 4.99-5.11 (m, 2 H) 5.55-5.62 (m, 1 H) 6.04 -6.20 (m, 1 H) 6.39-6.49 (m, 1 H) 6.71-6.83 (m, 3 H) 6.92-7.46 (m, 28 H).
ESI m / z = 1005 (M + Na).

(2) (1S) -1,5-anhydro-1- [2-hydroxy-5- (4- {4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobutyl} benzyl) Preparation of -4-methylphenyl] -1-thio-D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy ) -5- (4-{(1E) -4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} benzyl) -4-methylphenyl] Palladium hydroxide (200 mg) was added to a solution of -1-thio-D-glucitol (190 mg, 0.193 mmol) in ethanol (6 mL), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to give the title compound (86 mg, 83%) as a colorless powder. Obtained. NMR data and MS data are shown in Table 1-1.

Example 2
(1S) -1,5-Anhydro-1- {2-hydroxy-5- [4- (4-{[2-hydroxy-1- (hydroxymethyl) -1-methylethyl] amino} -4-oxobutyl) Preparation of [benzyl] -4-methylphenyl} -1-thio-D-glucitol

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4-((1E) -4- { [2-Hydroxy-1- (hydroxymethyl) -1-methylethyl] amino} -4-oxobut-1-en-1-yl) benzyl] -4-methylphenyl} -1-thio-D-glucitol In the same manner as in Example 1 (1) except that 2-amino-2-methyl-1,3-propanediol was used instead of 2-amino-2-methyl-1-propanol, a pale yellow color was obtained. To give the title compound (310 mg) as an amorphous.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18 (s, 3 H) 2.17 (s, 3 H) 3.06-3.19 (m, 3 H) 3.48-4.12 (m, 12 H) 4.49-4.64 (m , 5 H) 4.81-5.11 (m, 5 H) 5.99-6.22 (m, 2 H) 6.42-6.52 (m, 1 H) 6.72-6.85 (m, 3 H) 6.93-7.03 (m, 2 H) 7.06 -7.44 (m, 26 H).
ESI m / z = 1021 (M + Na).

(2) (1S) -1,5-Anhydro-1- {2-hydroxy-5- [4- (4-{[2-hydroxy-1- (hydroxymethyl) -1-methylethyl] amino} -4 Preparation of (Oxobutyl) benzyl] -4-methylphenyl} -1-thio-D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [ 2- (benzyloxy) -5- (4-{(1E) -4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} benzyl)- (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) instead of 4-methylphenyl] -1-thio-D-glucitol ) -5- [4-((1E) -4-{[2-hydroxy-1- ( Example 1 (2) using hydroxymethyl) -1-methylethyl] amino} -4-oxobut-1-en-1-yl) benzyl] -4-methylphenyl} -1-thio-D-glucitol ) To give the title compound (62 mg, 36%) as a colorless powder. NMR data and MS data are shown in Table 1-1.

Example 3
(1S) -1,5-Anhydro-1- {2-hydroxy-5- [4- (4-{[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] amino} -4-oxobutyl) benzyl ] -4-Methylphenyl} -1-thio-D-glucitol

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4-((1E) -4- { Of [2-hydroxy-1,1-bis (hydroxymethyl) ethyl] amino} -4-oxobut-1-en-1-yl) benzyl] -4-methylphenyl} -1-thio-D-glucitol Preparation The title compound (290 mg, 70%) as a pale yellow powder in the same manner as in Example 1 (1) using tris (hydroxymethyl) aminomethane instead of 2-amino-2-methyl-1-propanol Got.
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.19 (s, 3 H) 3.06-3.23 (m, 3 H) 3.47-4.05 (m, 15 H) 4.45-4.69 (m, 5 H) 4.79-4.94 (m, 3 H) 4.97-5.11 (m, 2 H) 6.09-6.23 (m, 1 H) 6.48 (d, J = 17.88 Hz, 1 H) 6.64-6.84 (m, 4 H) 6.92-7.02 (m , 2 H) 7.09-7.44 (m, 25 H).
ESI m / z = 1036 (M + Na).

(2) (1S) -1,5-Anhydro-1- {2-hydroxy-5- [4- (4-{[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] amino} -4- Preparation of (oxobutyl) benzyl] -4-methylphenyl} -1-thio-D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2 -(Benzyloxy) -5- (4-{(1E) -4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} benzyl) -4 -Methylphenyl] -1-thio-D-glucitol instead of (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4-((1E) -4-{[2-hydroxy-1,1-bis (hydro Cymethyl) ethyl] amino} -4-oxobut-1-en-1-yl) benzyl] -4-methylphenyl} -1-thio-D-glucitol, the same method as in Example 1 (2) Gave the title compound (45 mg, 28%) as a colorless powder. NMR data and MS data are shown in Table 1-1.

Example 4
(1S) -1- [5- (4- {4-[(2-amino-1,1-dimethyl-2-oxoethyl) amino] -4-oxobutyl} benzyl) -2-hydroxy-4-methylphenyl] Production of -1,5-anhydro-1-thio-D-glucitol

(1) (1S) -1- [5- (4-{(1E) -4-[(2-amino-1,1-dimethyl-2-oxoethyl) amino] -4-oxobut-1-ene-1 -Il} benzyl) -2- (benzyloxy) -4-methylphenyl] -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-thio-D-glucitol The title compound (183 mg, 45%) was obtained as a colorless oily compound in the same manner as in Example 1 (1) using 2-amino-2-methylpropionamide instead of 2-amino-2-methyl-1-propanol. )
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.57 (s, 6 H) 2.15 (s, 3 H) 3.12 (d, J = 7.34 Hz, 3 H) 3.46-4.02 (m, 8 H) 4.06 ( d, J = 11.46 Hz, 1 H) 4.46-4.73 (m, 5 H) 4.78-4.96 (m, 3 H) 4.96-5.13 (m, 2 H) 6.04-6.26 (m, 2 H) 6.39-6.56 ( m, 2 H) 6.67-6.85 (m, 3 H) 6.90-7.03 (m, 2 H) 7.08-7.43 (m, 26 H).
ESI m / z = 1017 (M + Na).

(2) (1S) -1- [5- (4- {4-[(2-amino-1,1-dimethyl-2-oxoethyl) amino] -4-oxobutyl} benzyl) -2-hydroxy-4- Preparation of methylphenyl] -1,5-anhydro-1-thio-D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (Benzyloxy) -5- (4-{(1E) -4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} benzyl) -4- Instead of methylphenyl] -1-thio-D-glucitol, (1S) -1- [5- (4-{(1E) -4-[(2-amino-1,1-dimethyl-2-oxoethyl) ) Amino] -4-oxobut-1-en-1-yl} benzyl) -2- (benzyl) Oxy) -4-methylphenyl] -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-thio-D-glucitol is the same as in Example 1 (2). The title compound (59 mg, 59%) was obtained as a colorless powder by the method. NMR data and MS data are shown in Table 1-1.

Example 5
(1S) -1,5-Anhydro-1- [2-hydroxy-5- (4- {4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobutyl} -2-methylbenzyl ) -4-Methylphenyl] -1-thio-D-glucitol

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-{(1E) -4- [ (2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} -2-methylbenzyl) -4-methylphenyl] -1-thio-D-glucitol Preparation (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-chloro-2-methylbenzyl) -4- To a solution of methylphenyl] -1-thio-D-glucitol (661 mg, 0.755 mmol) in 1,4-dioxane (10 mL), vinyl acetate (0.15 mL, 1.81 mmol), bis (tricyclohexylphosphine) palladium dichloride ( 172 g, 0.233 mmol), cesium carbonate (836 mg, 2.57 mmol) was added, biotage Co. micro web - was stirred for 2 hours at 160 ° C. with a drive. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant and palladium catalyst were filtered through Celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain a crude compound (577 mg) as a pale yellow amorphous.
Furthermore, (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4-((1E) -3-carboxyprop -1-en-1-yl) benzyl] -4-methylphenyl} -1-thio-D-glucitol instead of crude compound (324 mg) obtained as in Example 1 (1). The title compound (43 mg, 10%) was obtained by the method.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (s, 6 H) 2.17 (s, 3 H) 2.25 (s, 3 H) 3.03-3.19 (m, 3 H) 3.46-3.65 (m, 3 H) 3.63-3.94 (m, 6 H) 3.97-4.10 (m, 1 H) 4.43-4.71 (m, 5 H) 4.74-4.95 (m, 3 H) 4.98-5.17 (m, 2 H) 5.64-5.73 (m, 1 H) 6.04-6.24 (m, 1 H) 6.43 (d, J = 14.77 Hz, 1 H) 6.55-7.54 (m, 30 H).

(2) (1S) -1,5-Anhydro-1- [2-hydroxy-5- (4- {4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobutyl} -2 Preparation of (methylbenzyl) -4-methylphenyl] -1-thio-D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2 -(Benzyloxy) -5- (4-{(1E) -4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} benzyl) -4 -(1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) instead of -methylphenyl] -1-thio-D-glucitol -5- (4-{(1E) -4-[(2-hydroxy-1,1-dimethyl) Example 1 (2) using ethyl) amino] -4-oxobut-1-en-1-yl} -2-methylbenzyl) -4-methylphenyl] -1-thio-D-glucitol (43 mg). ) To give the title compound (22 mg, 93%). NMR data and MS data are shown in Table 1-1.

Example 6
(1S) -1- {5- [4- (3-{[(2-hydroxy-1,1-dimethylethyl) aminocarbonyl] amino} propyl) benzyl] -2-hydroxy-4-methylphenyl} -1 Of 1,5-anhydro-1-thio-D-glucitol

(1) (1S) -1- {5- [4-((1E) -3-{[(2-hydroxy-1,1-dimethylethyl) aminocarbonyl] amino} prop-1-en-1-yl ) Benzyl] -2- (benzyloxy) -4-methylphenyl} -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-thio-D-glucitol (1S) ) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-bromobenzyl) -4-methylphenyl] -1-thio N-allyl-N ′-(2-hydroxy-1,1-dimethylethyl) urea (181 mg, 1.05 mmol), palladium acetate in a solution of D-glucitol (318 mg, 0.351 mmol) in acetonitrile (3.5 mL) (II) (20 mg, 0 0912mmol), tri -O- tolylphosphine (70mg, 0.231mmol), triethylamine (0.24 mL, 1.75 mmol) was added, biotage Co. micro web - was stirred for 20 minutes at 120 ° C. with a drive. The reaction solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 50: 1). Further purification by NH type silica gel column chromatography (chloroform → chloroform: methanol = 50: 1) gave the title compound (137 mg, 40%) as a pale yellow amorphous.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (s, 6 H) 2.14 (s, 3 H) 3.06-3.18 (m, 1 H) 3.45-3.62 (m, 2 H) 3.62-3.99 (m , 8 H) 4.01-4.13 (m, 1 H) 4.32-4.70 (m, 5 H) 4.79-5.17 (m, 6 H) 5.52-5.65 (m, 1 H) 5.96-6.12 (m, 1 H) 6.31 -6.43 (m, 1 H) 6.70-6.84 (m, 3 H) 6.89-7.46 (m, 28 H).
ESI m / z = 997 (M + H).

(2) (1S) -1- {5- [4- (3-{[(2-hydroxy-1,1-dimethylethyl) aminocarbonyl] amino} propyl) benzyl] -2-hydroxy-4-methylphenyl } -1,5-Anhydro-1-thio-D-glucitol preparation (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyl Oxy) -5- (4-{(1E) -4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} benzyl) -4-methylphenyl ] (1S) -1- {5- [4-((1E) -3-{[(2-hydroxy-1,1-dimethylethyl) aminocarbonyl]] instead of -1-thio-D-glucitol Amino} prop-1-en-1-yl) benzyl] -2- (ben Ruoxy) -4-methylphenyl} -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-thio-D-glucitol is the same as in Example 1 (2). The title compound (20 mg, 30%) was obtained as a colorless powder by the method. NMR data and MS data are shown in Table 1-1.

Example 7
(1S) -1- [5- (4- {3-[(Aminocarbonyl) amino] propyl} benzyl) -2-hydroxy-4-methylphenyl] -1,5-anhydro-1-thio-D-glucitol Manufacturing of

(1) (1S) -1- [5- (4- {3-[(Aminocarbonyl) amino] propyl} benzyl) -2- (benzyloxy) -4-methylphenyl] -1,5-anhydro-2 Preparation of 3,4,6-tetra-O-benzyl-1-thio-D-glucitol Implemented using allylurea instead of N-allyl-N ′-(2-hydroxy-1,1-dimethylethyl) urea The title compound (200 mg, 53%) was obtained as a yellow oily compound in the same manner as in Example 6 (1).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H) 3.06-3.18 (m, 1 H) 3.42-4.13 (m, 10 H) 4.32-4.75 (m, 5 H) 4.78-5.22 (m, 5 H) 5.94-6.12 (m, 1 H) 6.39 (d, J = 16.16 H, 1 H) 6.67-6.84 (m, 3 H) 6.86-7.46 (m, 28 H).
ESI m / z = 947 (M + Na).

(2) (1S) -1- [5- (4- {3-[(aminocarbonyl) amino] propyl} benzyl) -2-hydroxy-4-methylphenyl] -1,5-anhydro-1-thio- Production of D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-{(1E) -4 Instead of [[2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} benzyl) -4-methylphenyl] -1-thio-D-glucitol (1S) -1- [5- (4- {3-[(aminocarbonyl) amino] propyl} benzyl) -2- (benzyloxy) -4-methylphenyl] -1,5-anhydro-2,3, 4,6-tetra-O-benzyl-1-thio-D- The title compound (51 mg, 52%) was obtained as a colorless powder in the same manner as in Example 1 (2) using glucitol. NMR data and MS data are shown in Table 1-2.

Example 8
(1S) -1,5-Anhydro-1- [2-hydroxy-5- (4- {5-[(2-hydroxy-1,1-dimethylethyl) amino] -5-oxopentyl} benzyl) -4 -Methylphenyl] -1-thio-D-glucitol production

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4-((1E) -4-carboxy Preparation of but-1-en-1-yl) benzyl] -4-methylphenyl} -1-thio-D-glucitol In the same manner as in Reference Example 5 using 4-pentenoic acid instead of vinyl acetic acid The title compound (470 mg, 92%) was obtained as a brown oil.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.20 (s, 3 H) 2.33-2.55 (m, 4 H) 3.02-5.13 (m, 19 H) 5.45-5.93 (m, 2 H) 6.70-7.46 (m, 31 H).
ESI m / z = 923 (MH).

(2) (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-{(1E) -5- [ Preparation of (2-hydroxy-1,1-dimethylethyl) amino] -5-oxopent-1-en-1-yl} benzyl) -4-methylphenyl] -1-thio-D-glucitol (1S) -1 , 5-Anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4-((1E) -3-carboxyprop-1-ene-1- Yl) benzyl] -4-methylphenyl} -1-thio-D-glucitol instead of (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- { 2- (Benzyloxy) -5- [4-((1E) -4-carboxybut-1-ene- -Il) benzyl] -4-methylphenyl} -1-thio-D-glucitol was used to give the title compound (410 mg, 81%) as a light brown oil in the same manner as in Example 1 (1). .
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.28 (s, 6 H) 2.12-2.54 (m, 7 H) 2.85-5.15 (m, 21 H) 5.39-5.90 (m, 2 H) 6.71-7.47 (m, 31 H).
ESI m / z = 1018 (M + Na).

(3) (1S) -1,5-anhydro-1- [2-hydroxy-5- (4- {5-[(2-hydroxy-1,1-dimethylethyl) amino] -5-oxopentyl} benzyl ) Preparation of 4-methylphenyl] -1-thio-D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-{(1E) -4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} benzyl) -4-methylphenyl]- Instead of 1-thio-D-glucitol, (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4 -{(1E) -5-[(2-hydroxy-1,1-dimethylethyl) amino No] -5-oxopent-1-en-1-yl} benzyl) -4-methylphenyl] -1-thio-D-glucitol in the same manner as in Example 1 (2) as a colorless powder. The compound (92 mg, 41%) was obtained. NMR data and MS data are shown in Table 1-2.

Example 9
(1S) -1,5-Anhydro-1- [2-hydroxy-5- (4- {3-[(2-hydroxy-1,1-dimethylethyl) amino] -1-methyl-3-oxopropyl} (Benzyl) -4-methylphenyl] -1-thio-D-glucitol

(1) (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4-((E) -2-carboxy Preparation of -1-methylethenyl) benzyl] -4-methylphenyl}}-1-thio-D-glucitol A crude mixture containing the title compound in the same manner as in Reference Example 5 using crotonic acid instead of vinyl acetic acid ( 280 mg) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.17 (s, 3 H) 2.47-2.54 (m, 3 H) 3.06-4.11 (m, 11 H) 4.44-5.12 (m, 10 H) 6.05-6.09 (m, 1 H) 6.71-7.46 (m, 31 H).
ESI m / z = 933 (M + Na).

(2) (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-{(1E) -3- [ Production of (2-hydroxy-1,1-dimethylethyl) amino] -1-methyl-3-oxoprop-1-en-1-yl} benzyl) -4-methylphenyl] -1-thio-D-glucitol 1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4-((1E) -3-carboxyprop-1- En-1-yl) benzyl] -4-methylphenyl} -1-thio-D-glucitol instead of (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl -1- {2- (benzyloxy) -5- [4-((E) -2-carboxy-1- Methylethenyl) benzyl] -4-methylphenyl)}-1-thio-D-glucitol was used in the same manner as in Example 1 (1) to give the title compound (120 mg, 15% (2 steps)) as a colorless oil. Got.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 6 H) 2.19 (s, 3 H) 2.40-2.52 (m, 3 H) 3.07-3.17 (m, 1 H) 3.48-4.07 (m , 10 H) 4.44-4.63 (m, 5 H) 4.83-5.10 (m, 5 H) 5.48 (brs, 1 H) 5.81-5.86 (m, 1 H) 6.73-6.81 (m, 3 H) 6.97-7.46 (m, 28 H).
ESI m / z = 1004 (M + Na).

(3) (1S) -1,5-Anhydro-1- (2-hydroxy-5- (4- (3-((2-hydroxy-1,1-dimethylethyl) amino) -1-methyl-3- Preparation of (oxopropyl) benzyl) -4-methylphenyl) -1-thio-D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (Benzyloxy) -5- (4-{(1E) -4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} benzyl) -4- (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy)-in place of methylphenyl] -1-thio-D-glucitol 5- (4-{(1E) -3-[(2-hydroxy-1,1-dimethyl) Ruethyl) amino] -1-methyl-3-oxoprop-1-en-1-yl} benzyl) -4-methylphenyl] -1-thio-D-glucitol was used in the same manner as in Example 1 (2). The title compound (31 mg, 48%) was obtained as a colorless powder by the method. NMR data and MS data are shown in Table 1-2.

Example 10
(1S) -1,5-Anhydro-1- [2-hydroxy-5- (4- {3-[(2-hydroxy-1,1-dimethylethyl) amino] -3-oxopropyl} benzyl) -4 -Methylphenyl] -1-thio-D-glucitol production

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4-((E) -2-carboxy Ethenyl) benzyl] -4-methylphenyl} -1-thio-D-glucitol Production of the title compound as a pale yellow powder in the same manner as in Reference Example 5 using acrylic acid instead of vinyl acetic acid (365 mg, 74%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.16 (s, 3 H) 3.05-3.19 (m, 1 H) 3.47-4.12 (m, 7 H) 4.52 (s, 6 H) 4.80-5.12 (m , 5 H) 6.25-6.38 (m, 1 H) 6.73-6.82 (m, 3 H) 6.95-7.47 (m, 28 H) 7.60-7.73 (m, 1 H).

(2) (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-{(1E) -3- [ Production of (2-hydroxy-1,1-dimethylethyl) amino] -3-oxoprop-1-en-1-yl} benzyl) -4-methylphenyl] -1-thio-D-glucitol (1S) -1 , 5-Anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4-((1E) -3-carboxyprop-1-ene-1- Yl) benzyl] -4-methylphenyl} -1-thio-D-glucitol instead of (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- { 2- (Benzyloxy) -5- [4-((E) -2-carboxyethenyl) ben The title compound (342 mg, 88%) was obtained as a colorless powder in the same manner as in Example 1 (1) using [zyl] -4-methylphenyl} -1-thio-D-glucitol.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 6 H) 2.16 (s, 3 H) 3.05-3.19 (m, 1 H) 3.48-4.09 (m, 10 H) 4.34-5.12 (m , 10 H) 6.23 (d, J = 16.32 Hz, 1 H) 6.75 (s, 3 H) 6.95-7.59 (m, 29 H).

(3) (1S) -1,5-Anhydro-1- [2-hydroxy-5- (4- {3-[(2-hydroxy-1,1-dimethylethyl) amino] -3-oxopropyl} benzyl ) Preparation of 4-methylphenyl] -1-thio-D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-{(1E) -4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} benzyl) -4-methylphenyl]- Instead of 1-thio-D-glucitol, (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4 -{(1E) -3-[(2-hydroxy-1,1-dimethylethyl) Amino] -3-oxoprop-1-en-1-yl} benzyl) -4-methylphenyl] -1-thio-D-glucitol was obtained as a colorless powder in the same manner as in Example 1 (2). The compound (84 mg, 46%) was obtained. NMR data and MS data are shown in Table 1-2.

Example 11
(1S) -1,5-Anhydro-1- [2-hydroxy-5- (4- {2-[(2-hydroxy-1,1-dimethylethyl) amino] -2-oxoethoxy} benzyl) -4 -Methylphenyl] -1-thio-D-glucitol production

(1) 2,3,4,6-Tetra-O-benzyl-1-C- [2- (benzyloxy) -5- {hydroxy [4- (methoxymethoxy) phenyl] methyl} -4-methylphenyl] Preparation of -5-thio-α-D-glucopyranose A solution of 1-bromo-4- (methoxymethoxy) benzene (1.55 g, 7.13 mmol) in tetrahydrofuran (7.5 mL) at −60 ° C. under a nitrogen atmosphere. 2.67 Mn-butyllithium hexane solution (2.58 mL, 6.9 mmol) was added dropwise. Then 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-formyl-4-methylphenyl] -5-thio-D-glucopyranose (1.80 g, 2.30 mmol) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at −78 ° C. for 10 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 1: 1) to give the title compound (1 0.2 g, 57%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.19 (br. S., 3 H) 3.46 (s, 7 H) 3.89-4.03 (m, 2 H) 4.47-4.56 (m, 2 H) 4.64 ( d, J = 11.35 Hz, 1 H) 4.73-4.97 (m, 4 H) 4.99-5.22 (m, 5 H) 5.79-5.95 (m, 1 H) 6.66-7.39 (m, 31 H).
ESI m / z = 942 (M + Na).

(2) (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-hydroxybenzyl) -4-methylphenyl Preparation of 1, -1-thio-D-glucitol 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- {hydroxy [4- ( Methoxymethoxy) phenyl] methyl} -4-methylphenyl] -5-thio-α-D-glucopyranose (410 mg) in acetonitrile at −15 ° C. with Et ₃ SiH (0.214 mL, 1.34 mmol) and BF ₃ · Et ₂ O (0.062 mL, 0.491 mmol) was added, and the mixture was stirred at the same temperature for 10 minutes. Chloroform was added to the reaction solution, the temperature was raised to 0 ° C., BF ₃ .Et ₂ O (0.062 mL, 0.491 mmol) was added, and the mixture was stirred for 30 minutes. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (0.420 g, 40%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.17 (s, 3 H) 3.06-3.18 (m, 1 H) 3.75-3.98 (m, 4 H) 4.09-4.15 (m, 1 H) 4.43-4.66 (m, 5 H) 4.68-4.74 (m, 1 H) 4.80-4.95 (m, 3 H) 4.98-5.11 (m, 2 H) 6.52-7.47 (m, 31 H).

(3) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4- (2-methoxy-2-oxo) Preparation of (Ethoxy) benzyl] -4-methylphenyl} -1-thio-D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1 obtained above DMF of-[2- (benzyloxy) -5- (4-hydroxybenzyl) -4-methylphenyl] -1-thio-D-glucitol (256 mg, 0.304 mmol), potassium carbonate (147 mg, 1.06 mmol) (2.5 mL) To the suspension were added methyl bromoacetate (139 mg, 0.912 mmol) and tetrabutylammonium iodide (5 mg), and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (0.230 g, 83%).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.16 (s, 3 H) 3.06-3.17 (m, 1 H) 3.45-4.13 (m, 10 H) 4.34-4.72 (m, 7 H) 4.79-4.96 ( m, 3 H) 4.96-5.11 (m, 2 H) 5.19-5.24 (m, 1 H) 6.55-7.49 (m, 31 H).
ESI m / z = 933 (M + NH ₄ ).

(4) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4- {2-[(2-hydroxy Preparation of -1,1-dimethylethyl) amino] -2-oxoethoxy} benzyl) -4-methylphenyl] -1-thio-D-glucitol (1S) -1,5-anhydro-2, synthesized above 3,4,6-tetra-O-benzyl-1- {2- (benzyloxy) -5- [4- (2-methoxy-2-oxoethoxy) benzyl] -4-methylphenyl} -1-thio- 2M NaOH was added to a THF (1 mL) solution of D-glucitol (210 mg, 0.229 mmol), and the mixture was stirred at 50 ° C. for 3 hours. After cooling to 4 ° C., the reaction mixture was neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure to give a colorless liquid residue (230 mg).

(5) To a solution of the obtained residue in chloroform (2.0 mL), 2-amino-2-methyl-1-propanol (31 mg, 0.344 mmol), 1-hydroxybenzotriazole monohydrate ( 53 mg, 0.344 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (66 mg, 0.344 mmol) were sequentially added and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (150 mg, 67%) as a colorless oily compound. )
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31 (s, 6 H) 2.17 (s, 3 H) 3.07-3.16 (m, 1 H) 3.49-3.63 (m, 3 H) 3.64-4.09 (m , 7 H) 4.25-4.69 (m, 7 H) 4.84 (s, 2 H) 4.91 (d, J = 10.72 Hz, 1 H) 5.01-5.11 (m, 2 H) 6.51-6.82 (m, 5 H) 6.90-7.46 (m, 26 H).
ESI m / z = 945 (M + Na).

(6) (1S) -1,5-anhydro-1- [2-hydroxy-5- (4- {2-[(2-hydroxy-1,1-dimethylethyl) amino] -2-oxoethoxy} benzyl ) Preparation of 4-methylphenyl] -1-thio-D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-{(1E) -4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobut-1-en-1-yl} benzyl) -4-methylphenyl]- Instead of 1-thio-D-glucitol, (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4 -{2-[(2-hydroxy-1,1-dimethylethyl) amino] -2- Kisoetokishi} benzyl) -4-methylphenyl] -1-thio -D- glucitol, to give the title compound (40 mg, 50%) as a colorless powder in the same manner as in Example 1 (2). NMR data and MS data are shown in Table 1-2.

Formulation Example Production Method The drug (the compound of the present invention) is mixed with lactose monohydrate, crystalline cellulose, carboxymethyl cellulose calcium and hydroxypropyl cellulose, and this mixture is pulverized with a pulverizer. The pulverized mixture is mixed for 1 minute with a stirring granulator and then granulated with water for 4-8 minutes. The obtained granulated product is dried at 70 ° C. for 40 minutes. The granulated dry powder is sieved with a 500 μm sieve. The granulated dry powder after sieving and magnesium stearate are mixed for 3 minutes at 30 rpm using a V-type mixer. The granules for tableting obtained using a rotary tableting machine are compression-molded and tableted to obtain tablets having a tablet weight of 200 mg and a tablet diameter of 8 mm (round). The amount of each used is shown in Table 2.

Test example 1
(1) Cloning of human SGLT1 and human SGLT2 and introduction into expression vector Human SGLT1 sequence (NM_000343) was amplified from human small intestine-derived mRNA after reverse transcription and introduced into pCMV-tag5A (Stratagene). The human SGLT2 sequence (NM_003041) was prepared from human kidney-derived mRNA by the same method and introduced into pcDNA3.1 + hygro (Invitrogen). It was confirmed that the sequence of each clone matched the reported sequence.

(2) Preparation of CHO-k1 cells stably expressing human SGLT1 and human SGLT2 Human SGLT1 and human SGLT2 expression vectors were transfected into CHO-K1 cells using Lipofectamine 2000 (Invitrogen). SGLT-expressing cells were cultured in the presence of geneticin (SGLT1) or hygromycin B (SGLT2) at a concentration of 500 μg / mL, resistant strains were selected, and the sugar uptake specific activity was obtained using the system shown below as an index.

(3) Sodium-dependent sugar uptake inhibition test in cells Cells stably expressing human SGLT1 or human SGLT2 were used in sodium-dependent glucose uptake activity inhibition tests.

Add 200 μL of pretreatment buffer (140 mM choline chloride, 2 mM KCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ , 10 mM HEPES / 5 mM Tris, pH 7.4) to human SGLT1-expressing cells or 2 mL to human SGLT2-expressing cells for 20 minutes Incubated. The pretreatment buffer is removed and the uptake buffer containing the test compound ([ ¹⁴ C] methyl α-D-glucopyranoside containing methyl α-D-glucopyranoside (1 mM), 145 mM NaCl, 2 mM KCl, 1 mM CaCl ₂ , Add 75 μL (for SGLT1) or 200 μL (for SGLT2) and add 30 mM (for SGLT1) or 1 hour (for SGLT2) at 37 ° C. with 1 mM MgCl ₂ , 10 mM HEPES / 5 mM Tris, pH 7.4) Reaction was performed. After the reaction, the cells are washed with a washing buffer (10 mM methyl α-D-glucopyranoside, 140 mM choline chloride 2 mM KCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ , 10 mM HEPES / 5 mM Tris, pH 7.4) 200 μL (in the case of SGLT1) or 2 mL ( Washed twice with SGLT2) and dissolved in 75 μL 0.2M NaOH solution (for SGLT1) or 400 μL (for SGLT2). After adding a liquid scintillator (Perkin Elmer) and mixing well, the radioactivity was measured with a microBETA (for SGLT1) or a liquid scintillation counter (for SGLT2) (Beckman Coulter). As a control group, an uptake buffer containing no test compound was prepared. For basal uptake, an uptake buffer containing choline chloride instead of NaCl was prepared.

In determining the IC ₅₀ value, the test compound concentration (IC ₅₀ value) at which the sugar uptake amount was inhibited by 50% relative to the sugar uptake amount (100%) of the control group was calculated using appropriate 6 concentrations of the test compound. . The test results are shown in Table 3.

Test example 2
Test for confirming inhibitory effect on blood glucose level in streptozotocin diabetic model rats (1) Preparation of diabetic model rats Seven-week-old SD / IGS rats (Nippon Charles River Co., Ltd., male) were fasted for about 16 hours and then streptozotocin under ether anesthesia. (STZ) 50 mg / kg was administered into the tail vein to prepare diabetes model rats. Similarly, 1 mL / kg of 1.25 mmol / L citric acid physiological saline was administered into the tail vein under ether anesthesia to produce normal control rats. One week after administration of STZ or 1.25 mmol / L citrate physiological saline (8 weeks of age), it was subjected to an oral glucose tolerance test.

(2) Oral glucose tolerance test After fasting rats for about 16 hours, the drug-administered group received a drug (1 mg / kg) suspended in 0.5% carboxymethylcellulose (CMC) aqueous solution, and the control group received 0. Only 5% CMC aqueous solution was orally administered. Five minutes after drug administration, glucose solution (2 g / kg) was orally administered, and blood was collected at a total of 5 points before drug administration (0 time) and 0.25, 0.5, and 1, 2 hours after oral administration.

  Blood collection was performed under ether anesthesia using a heparin-coated blood collection tube from the rat orbital sinus, and after centrifugation, plasma was collected. The plasma glucose concentration was measured using Glucose CII Test Wako (Wako Pure Chemical Industries, Ltd.). The increase in blood glucose level is calculated by calculating the area under the blood glucose level-time curve (AUC) using the trapezoidal method from the blood glucose level from 0 to 1 hour in each drug administration group, and the area of increased blood glucose (ΔAUC) after subtracting basal ) And expressed as the rate of descent relative to that of the control group. The results are shown in Table 4.

According to the present invention, there is provided a C-phenyl 1-thioglucitol compound having an absorption suppressing action such as glucose by inhibiting the activity of SGLT1 (sodium-dependent glucose cotransporter 1) expressed in the small intestine epithelium. It is expected to provide a preventive or therapeutic agent for diabetes containing as an active ingredient. Furthermore, according to the present invention, in addition to the SGLT1 activity inhibition, the activity of SGLT2 (sodium-dependent glucose cotransporter 2) expressed in the kidney is inhibited. It is expected to provide a prophylactic or therapeutic agent for diabetes containing a C-phenyl 1-thioglucitol compound having an urinary glucose excretion action as an active ingredient.

Claims (2)

A prophylaxis or treatment for diabetes comprising a C-phenyl 1-thioglucitol compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient: Agent.

In the formula, X is a hydrogen atom or a C _1-6 alkyl group,
Y is a C _1-6 alkylene group, or —O— (CH ₂ ) n — (n represents an integer of 1 to 5);
Z is —CONHR ^A or —NHCONHR ^B
(Where n is not 1 when Z represents —NHCONHR ^B ).
However,
R ^A is a C _1-6 alkyl group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group and —CONH ₂ ;
R ^B represents a hydrogen atom or a C _1-6 alkyl group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group and —CONH ₂ . Y is a C _1-6 alkylene group, R ^B is a hydrogen atom, or a hydroxyl group is a substituted C _1-6 alkyl group of claim 1 C- phenyl 1- Chiogurushito - le compound or a pharmaceutically A prophylactic or therapeutic agent for diabetes comprising a pharmaceutically acceptable salt or a hydrate thereof as an active ingredient.