JP2009120553A - Therapeutic agent for diabetes containing c-phenyl glucitol compound as effective ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preventive or therapeutic agent for diabetes including as an effective ingredient a novel C-phenylglucitol compound that inhibits both SGLT1 activity and SGLT2 activity thereby exhibiting an inhibiting action on glucose absorption through intestinal tracts and an excretion action of glucose in urine and therefore can be a preventive or therapeutic agent for diabetes. <P>SOLUTION: The preventive or therapeutic agent for diabetes includes as an effective ingredient a C-phenylglucitol compound represented by formula (I) [wherein Y is a 1-6C alkylene group or the like; and Z is -CONHR<SP>A</SP>(wherein R<SP>A</SP>is a hydroxy group or the like) or the like], or a salt or a hydrate thereof. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to C-phenyl glucito having an inhibitory activity on sodium-dependent glucose cotransporter 1 (SGLT1) and sodium-dependent glucose cotransporter 2 (SGLT2) involved in glucose reabsorption in the kidney. -The present invention relates to a preventive / therapeutic agent for diabetes characterized by containing a compound 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, although C-phenyl glucoside derivatives having selective inhibitory activity on SGLT2 have been reported (see Patent Document 9), reports on C-phenyl glucoside derivatives that strongly inhibit both SGLT1 and SGLT2 have been reported. Absent.

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 a C-phenyl glucitol compound that inhibits the activities of both SGLT1 and SGLT2, and is expected as a new type of therapeutic agent for diabetes that has both glucose absorption suppression from the digestive tract and urinary glucose excretion. It is an object to provide a preventive / therapeutic agent for diabetes as an active ingredient.

  As a result of intensive studies to solve the above problems, the present inventors have found that a C-phenyl glucitol compound into which a specific side chain is introduced at the end of an aglycon has an excellent SGLT1 and SGLT2 activity inhibitory action. The present invention has been completed.

  Such an embodiment of the present invention is characterized in that it contains a C-phenyl glycitol 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 formula (I),
R ¹ and R ² are the same or different and each represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom.

R ³ represents a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom.

Y represents a C _1-6 alkylene group, —O— (CH ₂ ) n — (n represents an integer of 1 to 4) or a C _2-6 alkenylene group. However, when Z shown below represents —NHC (═NH) NH ₂ or —NHCON (R ^B ) R ^C , n is not 1.

Z is —CONHR ^A , —NHC (═NH) NH ₂ , —NHCON (R ^B ) R ^C ,

Or

Indicates.

However,
R ^A represents a C _1-6 alkyl group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group, an amino group and a carbamoyl group.

R ^B is (a) a hydrogen atom, (b) a C _1-6 alkyl group which may be substituted with 1 to 3 groups selected from group A described later, (c) a hydroxyl group and a C _1-6 hydroxyalkyl group. A C _3-12 cycloalkyl group _optionally substituted with 1 to 3 groups selected from: (d) “O, N, S, SO ₂ , CO and NR ¹⁰ (wherein R ¹⁰ is a hydrogen atom) C _1-6 alkyl group, phenyl C _1-6 alkyl group or C _2-6 alkoxycarbonyl group.) C _3-12 heterocyclo containing 1 to 3 elements selected from the group consisting of 1 to 3 elements selected from the group consisting of an “alkyl group” or “O, N, S, SO ₂ , CO, and NR ¹⁰ (wherein R ¹⁰ is as defined above) are included in the ring. , A C _5-13 heteroaryl group which may be partially saturated ”, the C _3-12 heterocycloalkyl group and the C _5-13 heteroaryl The group may be substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group and a C _1-6 hydroxyalkyl group, or (e) a C _6-13 aryl group which may be partially saturated The aryl group is selected from the group consisting of a hydroxyl group and “a C _1-6 alkyl group, a phenyl C _1-6 alkyl group and a C _1-6 alkylsulfonyl group which may be substituted with a hydroxyl group”. Or it may be substituted with two groups.

However, group A means a halogen atom, a hydroxyl group, a “C _1-6 alkoxy group which may be substituted with a hydroxyl group”, a carboxyl group, a C _2-6 alkoxycarbonyl group, a carbamoyl group, an amino group, a C _1-6 alkyl. Amino group, di-C _1-6 alkylamino group, C _2-6 acylamino group, “C _1-6 alkylthio group optionally substituted with a hydroxyl group”, phenoxy group, 1 to 3 groups selected from group B described later in substituted and also a phenyl group (group B, a hydroxyl group, a halogen atom, C _1-6 alkoxy group "may be substituted with a hydroxyl C _1-6 alkyl group", C _1-6 alkylthio group, a thienyl group, a "hydroxyl group or a C _1-6 hydroxyalkyl may phenylthio group optionally substituted with a group", or "hydroxyl group or a C _1-6 hydroxyalkyl may piperidino group optionally substituted with a group".), "a hydroxyl group Fine C _1-6 1 to 3 amino which may be substituted with group C _3-12 cycloalkyl group selected from the group consisting of hydroxyalkyl group "," O, N, S , SO 2, CO and NR ¹⁰ ( In the formula, R ¹⁰ has the same meaning as described above.) A C _3-12 heterocycloalkyl group containing 1 to 3 elements selected from the group consisting of “in the ring”, or “O, N, S, SO _2. , CO and NR ¹⁰ (wherein, R ¹⁰ is as defined above.) a 1-3 elements selected from the group in the ring of which may be partially saturated C _5-13 heteroaryl An aryl group ”, and the C _3-12 heterocycloalkyl group and the C _5-13 heteroaryl group are substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group and a C _1-6 hydroxyalkyl group. also good, or, -CONR ^B1 R ^B2 (wherein, O together with R ^B1 and R ^B2 is a nitrogen atom, also comprise N or S There C _5-6 form a heterocycloalkyl group, said C _5-6 heterocycloalkyl group, may be substituted with a hydroxyl C _1-6 alkyl groups, C _2-6 alkoxycarbonyl group and a phenyl C _1- It may be substituted with 1 or 2 groups selected from the group consisting of ₆ alkyl groups.

R ^C may be substituted with one or two groups selected from the group consisting of a hydrogen atom, “hydroxyl group, di-C _1-6 alkylamino group, C _2-6 alkoxycarbonyl group and C _1-6 alkoxy group”. “A good C _1-6 alkyl group” or “C _3-12 cycloalkyl group _optionally substituted with a hydroxyl group” is shown. Or

R ^B and R ^C together with the adjacent nitrogen atom are C _3-12 hetero groups containing one or two elements selected from “O, N, NR ¹¹ , S, SO ₂ and CO in the ring. A cycloalkyl group, or together with an adjacent nitrogen atom, contains one or two elements selected from “O, N, NR ¹¹ , S, SO ₂ and CO in the ring and is partially saturated. _May form a C _5-13 heteroaryl group, and the C _3-12 heterocycloalkyl group and heteroaryl group may be a hydroxyl group, a C _2-6 alkoxycarbonyl group, a carbamoyl group, a C _2-6 acyl (C _{1 -6} alkyl) amino group, di-C _1-6 alkylaminocarbonyl group, pyrrolidinyl group, morpholino group, pyrrolidin-1-ylcarbonyl group, "hydroxyl group, pyrrolidin-1-yl group, phenyl group and C _2-6 alkoxycarbonyl" Consist of More 1-3 which may be substituted with a C _1-6 alkyl group "and" C _1-6 alkyl group selected, one to three selected from the group consisting of C _1-6 alkoxy group and a halogen atom It may be substituted with one or two groups selected from the group consisting of a phenyl group which may be substituted with a group.

R ¹¹ is a hydrogen atom, a C _2-6 acyl group, a “phenyl group optionally substituted with a hydroxyl group”, a pyridyl group, a furylcarbonyl group, an oxolanylcarbonyl group, a C _2-6 alkoxycarbonyl group, or "hydroxyl, phenyl, di-C _1-6 alkylamino group, one or two C _1-6 alkyl group optionally substituted with a group selected from the group consisting of a morpholino group and pyrrolidine-1-yl group ".

R ^D consists of a hydrogen atom, or a “hydroxyl group, a C _3-12 cycloalkyl group, a phenyl group optionally substituted with a hydroxyl group, a pyridyl group, a C _2-6 alkoxycarbonyl group, an imidazolyl group, and a 1-benzylimidazolyl group. A C _1-6 alkyl group which may be substituted with 1 or 2 groups selected from the group ";

R ^DA represents a hydrogen atom or a C _1-6 alkyl group.

  According to the present invention, it has become possible to provide a prophylactic / therapeutic agent for diabetes characterized by containing, as an active ingredient, a novel C-phenylglucitol compound that inhibits the activities of both SGLT1 and SGLT2.

  The terms used in the present invention are defined below.

“C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 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, tert-pentyl group, n-hexyl group, isohexyl Groups.

The “C _1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, and a C _1-4 alkoxy group is preferable. Examples of the C _1-4 alkoxy group include methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, and tert-butoxy group.

  The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

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, in a linear thing, a methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group is mentioned.

The “C _2-6 alkenylene group” means a divalent group obtained by removing one hydrogen from the carbon atom of the C _1-6 alkenyl group. For example, in a linear thing, a vinylene (ethenylene) group, a propenylene group, a butenylene group, a pentenylene group, a hexenylene group is mentioned.

“C _1-6 alkyl group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group, an amino group and a carbamoyl group” means 1 to 3 hydrogen atoms on the C _1-6 alkyl group. An alkyl group substituted with at least one of a hydroxyl group, an amino group and a carbamoyl group. 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.

The “C _3-12 cycloalkyl group” refers to a cyclic alkyl group having 3 to 12 carbon atoms, and also includes monocyclic, bicyclic and spiro hydrocarbons. For example, in the case of a monocyclic product, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group can be mentioned. Examples of the bicyclic product include an adamantyl group, a bicyclo [2.2.1] heptyl group, a bicyclo [2.2.2] heptyl group, and the like. Examples of the spiro hydrocarbon include a spiro [3.4] octyl group and a spiro [4.5] decanyl group.

“C _3-12 heterocycloalkyl group containing 1 to 3 elements selected from the group consisting of O, N, S, SO ₂ , CO, and NR ¹⁰ in the ring” means cycloalkyl as described above It means a saturated heterocycloalkyl group in which 1 to 3 methylene groups or methine groups of the group are substituted with O, N, NR ¹⁰ , S, SO ₂ or CO. For example, oxanyl group, 2-oxooxanyl group, 1,3-dioxanyl group, pyrrolidinyl group, piperidino group, 2-piperidyl group, 4-piperidyl group, piperazinyl group, morpholino group, thiomorpholino group, quinuclidinyl group, decahydroisoxin group Nolinyl group, decahydroquinolinyl group,

Is mentioned.

“C _5-13 heteroaryl group containing 1 to 3 elements selected from the group consisting of O, N, S, SO ₂ , CO, and NR ¹⁰ in the ring and may be partially saturated” Is a 5- to 13-membered unsaturated monocyclic, bicyclic or tricyclic heterocycle. For example, furyl group, imidazolyl group, thienyl group, pyridyl group, benzothienyl group, 2,3-dihydro-benzofuranyl group, 2,3-dihydro-1H-benzo [de] isoquinolinyl group, 2,3-dihydro-indolyl group 2,3-dihydro-isoindolyl group, 2,3,4,9-tetrahydro-1H-b-carbolinyl group and the like.

The “partially saturated C _6-13 aryl group” is a 6 to 13-membered unsaturated monocyclic, bicyclic or tricyclic hydrocarbon ring. Examples thereof include a phenyl group, a naphthyl group, a fluorenyl group, a 1,2,3,4-tetrahydronaphthyl group, an indanyl group, and the like.

Examples of “C _5-6 heterocycloalkyl group in which R ^B1 and R ^B2 may contain O, N, or S together with a nitrogen atom” include a piperidino group, a morpholino group, a thiomorpholino group, and the like.

“Phenyl C _1-6 alkyl group” means a group in which a hydrogen atom on an alkyl group is substituted with a phenyl group. Examples include a benzyl group and a phenylethyl group.

The “C _2-6 alkoxycarbonyl group” has a complex form of a linear or branched C _1-5 alkoxy group and a carbonyl group, preferably a C _2-5 alkoxycarbonyl group. Examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, and a t-butoxycarbonyl group.

The “C _1-6 alkylthio group” has a form in which a linear or branched alkyl group having 1 to 6 carbon atoms and one thio group (—S—) are combined. _1-4 alkylthio groups are preferred. Examples of the C _1-6 alkylthio group include a methylthio group, an ethylthio group, and a propylthio group.

The “C _1-6 alkylamino group” has a form in which a C _1-6 alkyl group and an amino group are combined. Examples thereof include a methylamino group and an ethylamino group.

The “di-C _1-6 alkylamino group” has a form in which two C _1-6 alkyl groups and an amino group are combined. For example, a dimethylamino group and a diethylamino group are mentioned.

The “C _2-6 acylamino group” has a form in which a C _2-6 acyl group and an amino group are combined, and an acetylamino group is preferable.

  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 absorb moisture or become adsorbed water or become a hydrate when exposed to the atmosphere or recrystallized. 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.

  In particular, in the compound of formula (I) of the present invention, the configuration of the 4-position-hydroxyl group (dashed line) means either R-form or S-form.

  Below, the manufacturing method of this invention compound (I) is demonstrated.

Manufacturing method 1
In the compound (I) of the present invention, a compound in which Y is a C _2-6 alkylene group or a C _2-6 alkenylene group and Z is —CONHR ^A can be synthesized by the following method.

In the formula, R ^11, R ¹² are the same or different, a hydrogen atom, a benzyloxy group, a methoxymethoxy group, (C _1-6 alkyl) ₃ SiO-, C _1-6 alkyl, C _1-6 An alkoxy group or a halogen atom, Y ¹ represents a single bond or a C _1-4 alkylene group, and other symbols are as defined above.

(1) Step 1 (Heck reaction)
Compound (IC) can be synthesized by subjecting compound (IA) and olefin acetic acid (IB) 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, tetrakistriphenylphosphine palladium, dibenzylideneacetone palladium, bistriphenylphosphine palladium chloride, 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 (IC) is subjected to dehydration condensation with amine (R ^A NH ₂ ) to obtain compound (ID). 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 (ID) 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, 2-propanol, 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, Lewis acids such as BF ₃ .Et ₂ O, BCl ₃ , BCl ₃ .Me ₂ S, BBr ₃ , AlCl ₃ , CF ₃ COOH, and TfOH can also 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.

  Furthermore, the compound in which Y is a single bond or a methylene group can be produced with reference to Step 2 and Step 3 of Production Method 1 using a compound having a carboxylic acid group described in Patent Document 9 as a raw material.

Manufacturing method 2
In the compound (I) of the present invention, Y is a C _2-6 alkylene group or a C _2-6 alkenylene group, and Z is —NHC (═NH) NH ₂ or —NHCON (R ^B ) R ^C. The compound can be synthesized by the following method. In the formula, Z ¹ represents a guanidino group protected with a benzyloxycarbonyl group, or —NHCON (R ^B ) R ^C. Other symbols are as defined above.

(4) Step 4 (Heck reaction)
Compound (IA) and allylamine (IE) can be led to compound (IF) by the Heck reaction described in Step 1 above.

(5) Step 5 (reduction, deprotection)
The present compound (I) in which Z is a guanidino group or a ureido group can be obtained by performing catalytic hydrogenation described in Step 3 or deprotection with a Lewis acid on the compound (IF) obtained above.

Production method 3
In the compound (I) of the present invention, a compound in which Y is a single bond or a C _1-6 alkylene group and Z is —NHCON (R ^B ) R ^C can also be synthesized by the following method.

In the formula, R ¹³ and R ¹⁴ are the same or different and are a hydrogen atom, benzyloxy group, C _1-6 alkyl group, C _1-6 alkoxy group or halogen atom, P ¹ is a methoxymethyl group, tetrahydropyrani Or a (C _1-6 alkyl) ₃ Si— group. Other symbols are as defined above. Intermediate (IIB) or intermediate (IIF) in which Y is a single bond or a C _1-6 alkylene group can also be produced using the following steps 34 to 36.

(6) Step 6
An intermediate compound (IIA) (which can be produced according to the pamphlet of International Publication No. WO06 / 073197) is prepared using an organometallic reagent such as n-butyllithium, sec-butyllithium, tert-butyllithium, etc. A rutile reagent can be prepared. This can be condensed with δ-lactone (X) to obtain compound (IIB). 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.

(7) Step 7 (Reduction of hydroxyl group)
The compound (IIB) can be reacted with Et ₃ SiH, i-Pr ₃ SiH, t-BuMe ₂ SiH or Ph ₂ SiHCl in the presence of a Lewis acid to reduce the hydroxyl group. Examples of the Lewis acid used in this reaction include BF ₃ .Et ₂ O, CF ₃ COOH, InCl ₃ , TiCl ₄ , TMSOTf, p-toluenesulfonic acid, methanesulfonic acid, and the like. Solvents include chloroform, dichloromethane , Toluene, tetrahydrofuran, acetonitrile or a mixed solvent thereof, and a mixed solvent with acetonitrile such as acetonitrile / chloroform, acetonitrile / dichloromethane, acetonitrile / tetrahydrofuran, acetonitrile / tetrahydrofuran / toluene and the like is preferable. The reaction temperature here is −60 ° C. to 25 ° C., preferably −30 ° C. to 25 ° C.

In the above reaction, depending on the reaction temperature, the protecting group P ¹ may be removed, so that a compound (IIC) from which P ¹ has been removed may be obtained.

(8) Step 8 (hydrolysis)
Subsequent to the step 7, the protecting group P ¹ is removed using hydrochloric acid, sulfuric acid, p-toluenesulfonic acid monohydrate, pyridinium p-toluenesulfonic acid, hydrogen fluoride pyridine, n-Bu ₄ NF, or the like. Can do. Examples of the solvent used in this reaction include methanol, ethanol, 2-propanol, chloroform, dichloromethane, toluene, tetrahydrofuran, acetonitrile, diisopropyl ether, water, or a mixed solvent thereof. A preferred acid when P ¹ is a methoxymethyl group is hydrochloric acid. The solvent is methanol, diisopropyl ether, toluene, or tetrahydrofuran, and more preferably a mixed solvent with methanol such as methanol / toluene, methanol / diisopropyl ether, or methanol / toluene / diisopropyl ether. The reaction temperature here varies depending on the solvent and the acid used, but is 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C.

(9) Step 9 (substitution reaction)
Compound (IIE) can be obtained by condensing compound (IIC) and reagent (IID) under Mitsunobu reaction conditions (Org. Reactions, Vol. 42, Item 335) using an azo reagent and phosphines.

  As the phosphines used in the Mitsunobu reaction, triphenylphosphine, tri-n-butylphosphine, tri-t-butylphosphine, tolylphosphine, diphenyl-2-pyridylphosphine, or the like can be used. Of these, triphenylphosphine and diphenyl-2-pyridylphosphine are preferable, and triphenylphosphine is more preferable. Diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1′-azobis (N, N-dimethylformamide) and 1,1 ′-(azodicarbonyl) as azo reagents Dipiperidine and the like can be used. Of these, diethyl azodicarboxylate and diisopropyl azodicarboxylate are preferable. The solvent is tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, acetonitrile, ethyl acetate, dimethyl sulfoxide, N, N-dimethylformamide or the like, preferably tetrahydrofuran or toluene. The reaction temperature is preferably from −20 ° C. to room temperature.

(10) Step 10 (Dephthalimide)
Amine (IIF) can be obtained by reacting compound (IIE) with hydrazine hydrate or methylhydrazine 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.

  The obtained amine (IIF) can also be purified by forming a salt with the mineral acid or organic acid described above. Preferred salts for purification here are hydrochloride, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, and p-toluenesulfonate, more preferably benzenesulfonate. It is.

(11) Step 11 (urea formation)
Compound (IIG) can be synthesized from compound (IIF) using a carbonylating reagent and NH (R ^B ) R ^C. 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.

(12) Step 12 (deprotection)
The present compound (I) in which Z is a ureido group can be obtained by subjecting the compound (IIG) obtained above to catalytic hydrogenation described in Step 3 or deprotection with a Lewis acid.

Manufacturing method 4
The compound (I) of the present invention in which Z is a ureido group can also be synthesized after converting a hydroxyl group of a sugar to an acyl protecting group such as an acetyl group.

(13) Step 13 (protection of amino group)
The amino group in compound (IIF) is protected with a protective group resistant to catalytic hydrogenation, such as tert-butyl carbonate (Boc), 9-fluorenylmethyl carbonate (Fmoc) and the like. Compound (IIJ) can be obtained by reacting compound (IIF) with (Boc) ₂ O or Fmoc-Cl in a solvent such as chloroform, dichloromethane, tetrahydrofuran or dioxane in the presence of a suitable base. As the base, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydroxide, sodium hydride, pyridine, triethylamine and the like are preferable.

(14) Step 14 (debenzylation)
Compound (IIK) can be obtained by performing deprotection by catalytic hydrogenation described in Step 3 on compound (IIJ) obtained above.

(15) Step 15 (acylation)
Compound (IIL) can be obtained by protecting the hydroxyl group in compound (IIK) with an acyl group such as an acetyl group. Compound (IIL) can be obtained by reacting compound (IIK) with acetic anhydride, pivaloyl chloride, benzoyl chloride or the like in a solvent in the presence of an appropriate base. Solvents used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like. As the base, triethylamine, collidine, pyridine and the like are preferable. 4-Dimethylaminopyridine can also be used as a catalyst. Moreover, preferable reaction temperature is 0 degreeC-room temperature.

(16) Step 16 (deprotection)
The compound (IIM) can be obtained by removing the amino-protecting group from the compound (IIL). In the case of the Boc group, the compound (IIL) is reacted with hydrochloric acid or trifluoroacetic acid in a solvent such as dichloromethane, chloroform, dioxane or the like without solvent. In the case of the Fmoc group, it is preferable to cause the compound (IIL) to react with piperidine or morpholine in N, N-dimethylformamide.

(17) Step 17 (urea formation)
(IIN) can be synthesized from compound (IIM) in the same manner as in step 11 above.

(18) Step 18 (deprotection)
Compound (I) can be obtained by removing the acyl group in compound (IIN) under basic conditions. As the base, a base such as sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, triethylamine or the like can be used. As the solvent, methanol, ethanol, hydrous methanol and the like are preferable.

Manufacturing method 5
In the compound (I) of the present invention, a compound in which Y is —O— (CH ₂ ) n— and Z is —NHCON (R ^B ) R ^C can be synthesized by the following method.
In the formula, Y ² represents a C _2-4 alkylene group, and other symbols are as defined above.

(19) Step 19
Compound (IIP) can be synthesized from compound (IIO) (which can be produced according to International Publication No. WO06 / 073197) and (X) in the same manner as in Production Method 3 and Step 6.

(20-21) Step 20 and Step 21
Compound (IIQ) can be synthesized by reducing the hydroxyl group of compound (IIP) and removing protecting group P1 in the same manner as in Production Method 3, Step 7 and Step 8.
(22) Step 22

  Compound (IIS) can be obtained by reacting compound (IIQ) with reagent (IIR) 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.

(23) Step 23
The compound (IIT) can be synthesized by removing the phthalimide group from the compound (IIS) in the same manner as in Production Method 3 and Step 10.

(24) Step 24
Compound (IIU) can be synthesized from compound (IIT) in the same manner as in Production Method 3 and Step 11.

(25) Step 25
The compound (I) of the present invention in which Y is —O— (CH ₂ ) n— can be synthesized from compound (IIU) by deprotection in the same manner as in Production Method 3 and Step 12.

Manufacturing method 6
In the compound (I) of the present invention, a compound in which Y is —O— (CH ₂ ) n— and Z is —CONHR ^A can be synthesized by the following method.
In the formula, Y ³ represents a C _1-4 alkylene group, L 1 represents a leaving group such as a halogen atom or MeSO ₂ O—, and the other symbols are as defined above.

(26) Step 26
Compound (IIW) can be obtained by reacting compound (IIQ) with (IIV) in the presence of a suitable base. As a suitable base, sodium hydride, potassium carbonate, cesium carbonate, sodium carbonate and n-butyllithium are preferable. As a solvent used in this reaction, THF, ether, N, N-dimethylformamide, acetone and DMSO are preferable. . Here, the temperature of this reaction is 0 ° C to 60 ° C.

(27) Step 27
Compound (I) of the present invention in which Y is —O— (CH ₂ ) n— and Z is —CONHR ^A is synthesized from compound (IIW) by the same method as in Production Method 3 and Step 12. be able to.

Manufacturing method 7
In the compound (I) of the present invention, Z is a heterocycloalkyl group such as a 2,4-dioxoimidazolidinyl group, for example, and can be produced by the following method.

In the formula, ^RN represents a hydroxyl group, a C _1-4 alkoxy group or a phenyl group, and other symbols are as defined above.

(28) Step 28
By condensing with compound (IIM) using, for example, 2-aminoacetophenone or an amine having a carbonyl group at the α-position such as amino acid as R ^A R ^B NH in the method described in Step 17 of Production Method 4. Compound (IIX) can be synthesized.

(29) Step 29 (deprotection under basic conditions)
Compound (IIX) is deprotected under basic conditions, and at the same time, the side chain in compound (IIX) is cyclized intramolecularly, and the present compound (1) wherein Z is the above heterocycloalkyl group ) Can be manufactured. The base used at this time is preferably sodium methoxide, and the solvent is preferably methanol or ethanol.

Manufacturing method 8
In the compound (I) of the present invention, a compound in which Y is a single bond, a methylene group or —O— (CH ₂ ) n— and Z is —NHC (═NH) NH ₂ can be synthesized by the following method.

(30) Step 30 (introduction of guanidino group)
The compound (IIA2) can be derived by reacting the reagent (IIA1) with the compound (IIF) or (IIT) synthesized in the step 38 or 23. Examples of the solvent used in this reaction include tetrahydrofuran, N, N-dimethylformamide, methanol, ethanol, isopropanol, ethyl acetate, toluene and the like. The reaction temperature is from room temperature to reflux temperature.

(31) Step 31
Deprotection from compound (IIA2) in the same manner as in production method 3 and step 12, Y is a single bond, methylene group or —O— (CH ₂ ) n—, and Z is —NHC (═NH) NH ₂ . The compound (I) of the present invention can be synthesized.

  The production method of the intermediate is shown below.

Production method of intermediate (IA) The production method of intermediate (IA) necessary for the production of compound (I) of the present invention is shown below. However, D ¹ denotes the Li or MgBr. Other symbols are as defined above.

(32) Step 32
An intermediate compound (IIIA) (which can be produced according to the pamphlet of International Publication No. WO06 / 073197) can be prepared using an organometallic reagent such as n-butyllithium, sec-butyllithium, tert-butyllithium, etc. A rutile reagent can be prepared. This can be condensed with δ-lactone (X) to obtain compound (IIIB). 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.

(33) Step 33 (acid hydrolysis)
Compound (IIIC) can be produced by hydrolyzing the acetal group in compound (IIIB) using 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.

(34) Step 34
Monolithium reagent compound (IIIE) can be produced using 1 equivalent of n-butyllithium, sec-butyllithium, tert-butyllithium, etc., relative to compound (IIID). 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 (IIIE) 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 (IIIF) can be produced by adding reagent (IIIE) to intermediate compound (IIIC). The reaction temperature is from -80 ° C to room temperature, preferably -78 ° C to -25 ° C.

(35) Step 35 (Reduction of hydroxyl group)
(IA) can be synthesized from compound (IIIF) in the same manner as in Step 7.

Production method of intermediate (IIB) or (IIF) Intermediate (IIB) or (IIF) described above can be synthesized by another route shown below.

(36) Step 36
Compound (IVC) or (IVD) can be synthesized from compound (IVA) or (IVB) in the same manner as in Step 21 above.

(37) Step 37 (Reduction of hydroxyl group)
Intermediate (IIB) can be synthesized from compound (IVC) in the same manner as in Step 7. In addition, intermediate (IVE) can be synthesized from compound (IVD).

(38) Step 38
By treating compound (IVE) with hydrochloric acid or trifluoroacetic acid in chloroform or dichloromethane, the protecting group trityl (Tr) of the amino group can be removed to synthesize intermediate (IIF). The reaction temperature at this time is preferably 0 ° C. to room temperature.

  The compound of the present invention inhibits the activities of both SGLT1 and SGLT2, improves IGT by inhibiting glucose absorption from the digestive tract and urinary glucose excretion, and can prevent or treat diabetes.

  Therefore, the compound of the present invention can be used as an active ingredient of an 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-102), Naveglitazar (Naveglitazar) Y-519818), MX-6054, Balaglitazone (NN-2344), T-131 (AMG131), PPARγ agonist, PPARγ antagonist, PPARγ / α dual agonist, α-glucosidase inhibitor (eg, voglibose, acarbose) , Miglitol, emiglitate), biguanide (eg, phenformin, metformin, buformin or salts thereof (eg, hydrochloride, fumarate, succinate)), insulin secretagogue (sulfonylsulfonyl (eg, tolbutamide, glibenclamide) , Gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybsol, etc.), repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt hydrate), PR40 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 Aib (8,35) hGLP-1 (7,37) NH2, CJC-1131, AVE0010, GSK-716155), amylin agonist (eg, pramlintide), phosphotyrosine phosphatase inhibitor (eg, sodium vanadate), Dipeptidyl peptidase IV inhibitors (eg, compounds described in WO02 / 038541; NVP-DPP-278, PT-100, P32 / 98, Vildagliptin (LAF-237), P93 / 1, Sitagliptin (MK-431), saxagliptin (BMS-477118), SYR-322, MP-513, T-6666, GRC-8200, etc.), β3 agonist (eg, AJ-9679, AZ40140) ), Gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, fructose-1,6-bisphosphatase inhibitor), SGLT (sodium-glucose transporter) inhibitor (eg , WO04 / 014931, WO04 / 089967, WO06 / 073197, T-1095, Serglflozin (GSK-869682), GSK-189075, KGT-1251, KGT-1681, KGA-2727, BMS-512148, AVE2268, SAR7226, etc.), 11β-hydroxysteroid dehydrogenase inhibitors (eg, compounds described in WO06051662, BVT-3498, INCB13739), GPR119 agonists (eg, PSN-632408, APD-668), adiponectin or agonist thereof, IKK inhibitor (eg, AS-2868), AMPK activator, leptin resistance ameliorating agent, somatostatin receptor agonist, glucokinase activator (eg, Ro-28) -1675), pancreatic lipase inhibitors (eg, orlistat, ATL-962), 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-226, pyridoline, pyridoxamine), active oxygen scavengers (eg, thioctic acid) ), Brain blood Vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), 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) Sterol (gamma-oryzanol), CETP inhibitor (eg, Torcetrapib, JTT-705, JTT-302, FM-VP4, etc.), cholesterol absorption inhibitor (eg, ezetimibe, etc.) Can be mentioned.

  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, lebucromakalim, L-27152, AL0671, NIP-121), clonidine.

  Examples of anti-obesity agents include central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphetopramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonist (Eg, compound described in WO06 / 035967, SB-568849; SNAP-7941, T-226296); neuropeptide Y antagonist (eg, CP-422935); cannabinoid receptor antagonist (eg, rimonabant ( SR-141716), SR-147778); ghrelin antagonist; 11β-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498, INCB13739)), pancreatic lipase inhibitor (eg, orlistat, ATL-962), DGAT-1 inhibition Drugs, β3 agonists (eg, AJ-9677, Z40140), peptidic appetite suppressants (eg, leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonists (eg, linchtripto, FPL-15849), antifeedants (eg, P-57) Can be mentioned.

  Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide. , Methiclotiazide), anti-aldosterone preparations (eg, spironolactone, triamterene), carbonic anhydrase inhibitors (eg, acetazolamide), chlorobenzenesulfonamide preparations (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-426751, etc.), thrombolytic drugs (examples) Urokinase, tisokinase, alteplase, natepase, monteplase, pamiteplase, etc., platelet aggregation inhibitor (eg, ticlopidine hydrochloride) , Ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, etc.), anti-Xa inhibitors (eg, Fondaparinux, BAY-59-7939, DU-176b, YM-150, SR-1257, SRp Razababan, LY-517717, M LN-102, Octaparine, Otamixaban, EMD-503982, TC-10, CS-3030, AVE-3247, GSK-881893, KFA-1982, etc., plasma carboxypeptidase B (or active thrombin-active fibrinolysis in vitroinhibitionis) Inhibitors (also known as TAFIa]) (eg, AZD-9684, EF-6265, MN-462) and the like.

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

(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 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 = 8: 1 to 6: 1) to give the title compound ( 5.05 g, quant.) Was obtained.
1H 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% aqueous 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 separated by furnace. 2M Hydrochloric acid was added to the insoluble material, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2M hydrochloric acid 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 washed with methanol to give the title compound (16.6 g, 59%, 2 steps) as a colorless powder.
1H 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).
ESI m / z = 319 (M−H), 321 (M + 2−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) were added oxalyl chloride (5 mL, 56.9 mmol) and N, N-dimethylformamide (6 drops), and the mixture was 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-methylbenzamide. To this tetrahydrofuran (150 mL) solution was added lithium aluminum hydride (1.96 g, 51.7 mmol) at −10 ° C., and the mixture was stirred at the same temperature for 1 hour. 1M Hydrochloric acid was added to the reaction mixture, ethyl acetate was added to separate the organic layer, and the organic layer was washed with 1M 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.
1H 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).

Reference Example 1-2
Preparation of 2- [4- (benzyloxy) -5-bromo-2-methylphenyl] -1,3-dioxolane 4- (Benzyloxy) -2-methylbenzaldehyde (0.50 g, 2.21 mmol) in methanol ( 3.75 mL) To the suspension was added pyridinium hydrobromide perbromide (1.06 g, 3.32 mmol) under ice cooling and stirred for 30 minutes. The reaction mixture was stirred at room temperature for 2.5 hours. A 20% Na ₂ SO ₃ solution, water, and ethyl acetate were added to the reaction solution. The mixture was extracted with ethyl acetate, 1M hydrochloric acid (20 mL) was added to the organic layer, and the mixture was stirred for 5 minutes. The organic layer was separated, 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 1.03 g of residue. Ethylene glycol (1.89 mL, 33.9 mmol) and pyridinium p-toluenesulfonic acid (43 mg, 0.170 mmol) were added to this toluene (7.0 mL) solution, and the mixture was heated to reflux for 14 hours using a Dean-Stark apparatus. . After cooling the reaction solution, the organic layer was washed with 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, and the resulting residue was recrystallized from hexane / ethyl acetate (10: 1) to obtain the title compound (748 mg, 63%).

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

(1) 2,3,4,6-Tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (1,3-dioxolan-2-yl) -4-methylphenyl] -D Synthesis of glucopyranose 2- [4- (benzyloxy) -5-bromo-2-methylphenyl] -1,3-dioxolane (5.82 g, 16.6 mmol) in tetrahydrofuran (36 mL) under nitrogen atmosphere 2.67 Mn-butyllithium hexane solution (6.40 mL, 16.6 mmol) was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. Next, a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (8.16 g, 15.1 mmol) in tetrahydrofuran (18 mL) was added dropwise and stirred at the same temperature for 20 minutes. did. 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 to 2: 1) to give the title compound (10 0.7 g, 87%).
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.40 (s, 3 H) 3.65 − 3.86 (m, 3 H) 3.89 − 4.21 (m, 8 H) 4.45 − 4.69 (m, 4 H) 4.78 − 5.03 ( m, 5 H) 5.91 (s, 1 H) 6.71 (s, 1 H) 6.97 (dd, J = 7.31, 2.18 Hz, 2 H) 7.10 − 7.37 (m, 23 H) 7.81 (s, 1 H).

(2) Production of 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-formyl-4-methylphenyl] -D-glucopyranose 4,6-Tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (1,3-dioxolan-2-yl) -4-methylphenyl] -D-glucopyranose (10. 6M Hydrochloric acid (80 mL) was added to a solution of 6 g, 13.0 mmol) in tetrahydrofuran (80 mL), and the mixture was stirred at room temperature for 14 hours. Ice 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 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 = 2: 1) to give the title compound (10.2 g, quant) as a yellow oily compound. .) Was obtained.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.66 (s, 3 H) 3.60 − 3.72 (m, 2 H) 3.74 − 3.82 (m, 1 H) 4.01 (t, J = 9.09 Hz, 1 H) 4.07 − 4.20 (m, 3 H) 4.40 − 4.61 (m, 5 H) 4.71 − 5.05 (m, 5 H) 6.70 (s, 1 H) 6.87 (d, J = 6.68 Hz, 2 H) 7.06 − 7.40 (m , 23 H) 8.07 (s, 1 H) 10.06 (s, 1 H).

(3) 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-[(4-bromophenyl) (hydroxy) methyl] -4-methylphenyl]- Production of D-glucopyranose A solution of 1,4-dibromobenzene (6.20 g, 26.1 mmol) in tetrahydrofuran (80 mL) at −78 ° C. with a 2.67 Mn-butyllithium hexane solution (10. 5 mL, 26.1 mmol) was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. Then 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-formyl-4-methylphenyl] -D-glucopyranose (10.0 g, 13.0 mmol) ) In tetrahydrofuran (20 mL) was added dropwise and stirred at the same temperature for 30 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 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 = 2: 1). The product was further purified by NH silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound as a yellow oil as a diastereomer mixture (5.50 g, 46%).
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.21 (s, 3 H) 3.54 − 3.82 (m, 3 H) 3.98 − 4.23 (m, 4 H) 4.36 − 4.64 (m, 4 H) 4.75 − 5.06 ( m, 5 H) 5.83− 5.86 (m, 1 H) 6.71 and 6.73 (each s, 1 H) 6.89 − 7.44 (m, 29 H) 7.67 and 7.71 (each s, 1 H).

(4) (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-bromobenzyl) -4-methylphenyl Preparation of -D-glucitol 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-[(4-bromophenyl) (hydroxy) methyl]- 4-methylphenyl] -D-glucopyranose (5.50 g, 5.96 mmol) in acetonitrile (60 mL), Et ₃ SiH (2.90 mL, 17.8 mmol) and BF at −10 ° C. under a nitrogen atmosphere. ₃ · Et ₂ O (1.90 mL, 14.9 mmol) was added, and the mixture was stirred at the same temperature for 15 minutes and at room temperature for 2.5 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 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 = 15: 1-10: 1) to give the title compound as a pale yellow oily compound. (2.70 g, 51%) was obtained.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.17 (s, 3 H) 3.53 − 3.63 (m, 1 H) 3.68 − 3.91 (m, 7 H) 4.00 (d, J = 11.04 Hz, 1 H) 4.39 − 4.95 (m, 8 H) 5.01 (s, 2 H) 6.75 (s, 1 H) 6.86 − 6.97 (m, 4 H) 7.10 − 7.35 (m, 24 H) 7.36 − 7.46 (m, 2 H).

Reference example 3
(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] -D-glucitol

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-bromobenzyl) -4-methylphenyl] -D -Glucitol (780 mg, 0.876 mmol) in acetonitrile (8.8 mL) in vinyl acetate (184 mg, 2.14 mmol), palladium (II) acetate (20 mg, 0.0890 mmol), tri-O-tolylphosphine ( 54 mg, 0.177 mmol) and triethylamine (0.64 mL, 4.38 mmol) were added, and the reaction was performed at 120 ° C. for 20 minutes using a biotage microwave. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1, chloroform: methanol = 40: 1) to give the title compound (681 mg) as an orange-yellow amorphous product. 87%).
1H NMR (600 MHz, CHLOROFORM-D) δ ppm 2.17 (s, 3 H) 3.25 (d, J = 5.50 Hz, 2 H) 3.53 − 3.84 (m, 6 H) 3.84 − 3.95 (m, 2 H) 4.00 (d, J = 10.55 Hz, 1 H) 4.43 (d, J = 10.55 Hz, 1 H) 4.50 (d, J = 11.92 Hz, 1 H) 4.57 − 4.65 (m, 2 H) 4.80 − 4.93 (m, 4 H) 4.99 (s, 2 H) 6.12 − 6.22 (m, 1 H) 6.42 (d, J = 15.59 Hz, 1 H) 6.74 (s, 1 H) 6.89 − 7.03 (m, 4 H) 7.11 − 7.47 (m, 26 H).
ESI m / z = 893 (M−H).

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

(1) 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- [hydroxy [4- [2- (tritylamino) ethyl] phenyl] methyl]- Synthesis of 4-methylphenyl] -D-glucopyranose To a solution of 2- (4-bromophenyl) -N-tritylethanamine (0.814 g, 1.84 mmol) in tetrahydrofuran (3 mL) at −78 ° C. under a nitrogen atmosphere. 2.66M n-butyllithium hexane solution (0.69 mL, 1.84 mmol) was added dropwise and stirred at the same temperature for 30 minutes. Then 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-formyl-4-methylphenyl] -D-glucopyranose (0.670 g, 0.876 mmol) ) In tetrahydrofuran (3 mL) was added dropwise and stirred at the same temperature for 30 minutes. Water 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 was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform) to obtain the title compound (0.634 g, 64%) as a yellow oily compound. .
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.12-2.22 (m, 3 H) 2.30-2.43 (m, 2 H) 2.65-2.76 (m, 2 H) 3.64-3.84 (m, 3 H) 3.99- 4.22 (m, 4 H) 4.42-4.65 (m, 5 H) 4.75-5.04 (m, 5 H) 5.83-5.91 (m, 1 H) 6.67-6.72 (m, 1 H) 6.88-7.43 (m, 44 H).

(2) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -4-methyl-5- [4- [2- ( Synthesis of tritylamino) ethyl] benzyl] phenyl] -D-glucitol 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- [hydroxy [4- [2 - Et ₃ SiH (tritylamino) ethyl] phenyl] methyl] -4-methylphenyl]-D-glucopyranose (0.638 g, 0.565 mmol) in acetonitrile (6 mL) solution under an atmosphere of nitrogen at 0 ℃ (0.27 mL, 1.695 mmol) and BF ₃ .Et ₂ O (1.58 mL, 1.24 mmol) were added, and the mixture was stirred at the same temperature 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 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 = 9: 1) to give the title compound (0.402 g) as a pale yellow oily compound. 59%).
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.16 (s, 3 H) 2.36 (t, J = 6.84 Hz, 2 H) 2.68 (t, J = 6.84 Hz, 2 H) 3.52-3.65 (m, 1 H) 3.67-3.92 (m, 7 H) 4.00 (d, J = 10.88 Hz, 1 H) 4.37-4.67 (m, 5 H) 4.78-5.06 (m, 5 H) 6.73 (s, 1 H) 6.83- 7.01 (m, 5 H) 7.05-7.45 (m, 40 H).

(3) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [5- [4- (2-aminoethyl) benzyl] -2- (benzyloxy) Of 4-methylphenyl] -D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- (2- (benzyloxy) -4-methyl- To a chloroform solution of 5- (4- [2- (tritylamino) ethyl] benzyl) phenyl) -D-glucitol (0.402 g, 0.336 mmol) was added trifluoroacetic acid (0.5 mL) at room temperature, and the same temperature. For 3 hours. After adding ethanol to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel chromatography (n-hexane: ethyl acetate = 4: 6 → chloroform: methanol = 20: 1) to give a colorless oil The title compound (0.296 g, quant.) Was obtained as a compound.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.20 (s, 3 H) 2.65 (t, J = 6.84 Hz, 2 H) 2.89 (t, J = 6.84 Hz, 2 H) 3.52-3.95 (m, 8 H) 4.00 (d, J = 10.72 Hz, 1 H) 4.38-4.67 (m, 5 H) 4.81-5.04 (m, 5 H) 6.74 (s, 1 H) 6.88-7.45 (m, 30 H).

Reference Example 5
Preparation of dibenzyl [(Z)-(allylamino) methylylidene] biscarbamate To a solution of allylamine (250 mg, 4.38 mmol) in tetrahydrofuran (4.3 mL), N, N′-bis-benzyloxycarbonyl-1-guanylpyrazole ( 1.98 g, 5.25 mmol) was added and stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (1.45 g, 90%) as a colorless powder.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 4.03 − 4.12 (m, 2 H) 5.11 − 5.28 (m, 6 H) 5.81 − 5.96 (m, 1 H) 7.23 − 7.43 (m, 10 H) 8.35 − 8.45 (m, 1 H) 11.76 (s, 1 H).
ESI m / z = 368 (M + H).

Reference Example 6
Preparation of N-allyl-4-methylpiperazine-1-carboxamide To a solution of allylamine (400 mg, 7.00 mmol) in chloroform (70 mL), triethylamine (1.31 mL, 9.45 mmol), 4-nitrophenyl chloroformate (1 0.62 g, 8.06 mmol) was added and stirred overnight at room temperature. 1-Methylpiperazine (771 mg, 7.70 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction solution was evaporated under reduced pressure, ethyl acetate was added to the resulting residue, and the precipitated insoluble material was filtered. The filtrate was concentrated, and the resulting residue was subjected to NH-type silica gel column chromatography (hexane: ethyl acetate = 5: 1 to ethyl acetate), silica gel column chromatography (ethyl acetate, chloroform: methanol = 20: 1 to 5). 1) to give the title compound (1.38 g, quant.) As a colorless powder.
1H NMR (300 MHz, DMSO-D ₆ ) δ ppm 2.16 (s, 3 H) 2.18 − 2.26 (m, 4 H) 3.23 − 3.31 (m, 4 H) 3.59 − 3.68 (m, 2 H) 4.95 − 5.12 (m, 2 H) 5.72 − 5.87 (m, 1 H) 6.63 (t, J = 5.44 Hz, 1 H).
ESI m / z = 206 (M + Na).

Reference Example 7
Preparation of tert-butyl [3- (but-3-enoylamino) propyl] carbamate N- (3-aminopropyl) carbamic acid tert-butyl ester in a solution of vinylacetic acid (500 mg, 5.81 mmol) in chloroform (58 mL) (2.02 g, 11.6 mmol), 1-hydroxybenzotriazole (0.86 g, 6.39 mmol) and WSC (1.56 g, 8.13 mmol) were added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with 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 = 1: 1 to ethyl acetate). The title compound (1.32 g, 94%) was obtained as a colorless powder.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.44 (s, 9 H) 1.52 − 1.71 (m, 2 H) 3.01 (d, J = 6.99 Hz, 2 H) 3.09 − 3.23 (m, 2 H) 3.30 (q, J = 6.37 Hz, 2 H) 4.89 (s, 1 H) 5.14 − 5.31 (m, 2 H) 5.83 − 6.06 (m, 1 H) 6.21 (s, 1 H).
ESI m / z = 265 (M + Na).

Reference Example 8
Preparation 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). In addition, 4-nitrophenyl chloroformate (6.09 g, 30.2 mmol) was added at 4 ° C., and the mixture was 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 evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (4.0 g, 88%) as a yellow oily compound.
1H 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).

Reference Example 9
Preparation of 1-benzyloxy-2-bromo-5-methyl-4- [4- [2- (methoxymethoxy) ethyl] benzyl] benzene

  2.6 Mn-butyllithium hexane solution of 1-bromo-4- [2- (methoxymethoxy) ethyl] benzene (50.2 g, 0.205 mol) in tetrahydrofuran (1 L) at −78 ° C. in a nitrogen atmosphere (78.8 mL, 0.205 mol) was added dropwise and stirred at the same temperature for 15 minutes. Then, a solution of 4-benzyloxy-5-bromo-2-methylbenzaldehyde (56.9 g, 0.195 mol) in tetrahydrofuran (150 mL) was added dropwise over 1 hour and stirred at the same temperature for 30 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 to obtain [4- (benzyloxy) -5-bromo-2-methylphenyl] [4- [2- (methoxymethoxy) ethyl] phenyl] methanol.

Next, [4- (benzyloxy) -5-bromo-2-methylphenyl] [4- [2- (methoxymethoxy) ethyl] phenyl] methanol (102 g) in chloroform (1 L) was added Et ₃ SiH (2 .90 mL, 17.8 mmol) and BF ₃ .Et ₂ O (1.90 mL, 14.9 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 15 minutes. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was warmed to room temperature. After extraction 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 NH-type silica gel column chromatography (hexane: ethyl acetate = 19: 1 to 9: 1) to give a pale yellow oily compound. The title compound (60 g, 68%) was obtained.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.16 (s, 3 H) 2.87 (t, J = 6.99 Hz, 2 H) 3.28 (s, 3 H) 3.75 (t, J = 6.99 Hz, 2 H) 3.85 (s, 2 H) 4.61 (s, 2 H) 5.12 (s, 2 H) 6.77 (s, 1 H) 7.03 (d, J = 8.08 Hz, 2 H) 7.15 (d, 2 H) 7.26 (d , J = 3.57 Hz, 1 H) 7.30-7.45 (m, 3 H) 7.47 (d, 2 H).

Reference Example 10
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- [4- (2-hydroxyethyl) benzyl] -4- Production of methylphenyl] -D-glucitol

  A solution of 1-benzyloxy-2-bromo-5-methyl-5- [4- [2- (methoxymethoxy) ethyl] benzyl] benzene (13.0 g, 28.5 mmol) in tetrahydrofuran (150 mL) under a nitrogen atmosphere, A 2.6 Mn-butyllithium hexane solution (11.0 mL, 28.5 mmol) was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 15 minutes. Then, a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (14.0 g, 26.0 mmol) in tetrahydrofuran (30 mL) was added dropwise and stirred at the same temperature for 15 minutes. did. 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 saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain 26 g of a residue.

This was dissolved in acetonitrile (70 mL) and tetrahydrofuran (70 mL), and Et ₃ SiH (2.90 mL, 17.8 mmol) and BF ₃ .Et ₂ O (1.90 mL, 14.9 mmol) were added under ice cooling. The mixture was stirred at the same temperature for 1 hour. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was warmed to room temperature. Water (70 mL) was added, and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After drying the desiccant, the solvent was distilled off under reduced pressure to obtain 27 g of a residue.

This was dissolved in isopropyl ether (140 mL). Next, 2-propanol (140 mL) and 6M hydrochloric acid (140 mL) were added, and the reaction mixture was stirred at 80 ° C. for 2 hours. After cooling to room temperature, water (70 mL) was added. This was extracted with toluene, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1-7: 3) to give the title compound (12 g, 54%) as a pale yellow oily compound. Obtained.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.20 (s, 3 H) 2.78 (t, J = 6.53 Hz, 2 H) 3.54-3.64 (m, 1 H) 3.68-3.88 (m, 8 H) 3.93 (br. s., 2 H) 4.00 (d, J = 10.72 Hz, 1 H) 4.42 (d, J = 10.72 Hz, 1 H) 4.50 (d, 1 H) 4.56-4.66 (m, 2 H) 4.81 -4.95 (m, 3 H) 5.00 (s, 2 H) 6.75 (s, 1 H) 6.92 (d, J = 7.77 Hz, 2 H) 7.02 (s, 4 H) 7.10-7.35 (m, 22 H) 7.36-7.44 (m, 2 H).
ESI m / z = 873 (M + NH ₄ ).

Reference Example 11
(1S) -1- [5- [4- [2- (Aminoethyl) benzyl] -2- (benzyloxy) -4-methylphenyl] -1,5-anhydro-2,3,4,6-tetra- Production of O-benzyl-D-glucitol benzenesulfonic acid

  (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- [4- (2-hydroxyethyl) benzyl-4-methyl Phenyl] -D-glucitol (12.0 g, 14.0 mmol), triphenylphosphine (5.51 g, 21.0 mmol) and phthalimide (2.27 g, 15.4 mmol) in tetrahydrofuran (140 mL) under a nitrogen stream, A toluene solution of 40% diisopropyl azodicarboxylate (11.1 mL, 21.0 mmol) was added at 0 ° C. over 3 minutes. After stirring the reaction solution at room temperature for 30 minutes, methanol (70 mL) was added. Then hydrazine monohydrate (6.79 mL, 140 mmol) was added and the reaction mixture was stirred at 60 ° C. for 3 hours. After cooling to room temperature, 2M aqueous sodium hydroxide solution (100 mL) was added and extracted with toluene. The organic layer was washed with 2M aqueous sodium hydroxide solution (100 mL) and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 22.7 g of residue.

This was dissolved in methanol (140 mL), a solution of benzenesulfonic acid monohydrate (2.51 g, 14.0 mmol) in methanol (50 mL) was added, and the mixture was stirred at room temperature for 15 min. To the amorphous obtained by evaporating the mixture under reduced pressure, 2-propanol (230 mL) and methanol (90 mL) were added and heated to reflux to dissolve the residue. The mixture was cooled to room temperature and left for 15 hours. The obtained crystals were filtered to give the colorless title compound (9.89 g, 70%).
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.12 (s, 3 H) 2.72-2.85 (m, 2 H) 2.89-3.05 (m, 2 H) 3.54-3.63 (m, 1 H) 3.68-3.89 ( m, 8 H) 3.99 (d, J = 10.57 Hz, 1 H) 4.39-4.53 (m, 2 H) 4.56-4.65 (m, 2 H) 4.82-4.94 (m, 3 H) 4.98 (s, 2 H ) 6.72 (s, 1 H) 6.79-6.85 (m, 2 H) 6.87-6.96 (m, 4 H) 7.06-7.44 (m, 25 H) 7.75-7.90 (m, 4 H).

Reference Example 12
(1S) -1- [5- [4- (2-Aminoethyl) benzyl] -2-acetoxy-4-methylphenyl] -1,5-anhydro-2,3,4,6-tetra-O-acetyl -Production of D-glucitol

(1) (1S) -1- [5- [4- (2-tert-Butoxycarbonylaminoethyl) benzyl] -2-acetoxy-4-methylphenyl] -1,5-anhydro-2,3,4 Preparation of 6-tetra-O-acetyl-D-glucitol (1S) -1- [5- [4- (2-aminoethyl) benzyl] -2- (benzyloxy) -4-methylphenyl] -1,5 -Anhydro-2,3,4,6-tetra-O-benzyl-D-glucitol To a solution of benzenesulfonic acid (10.7 g, 10.6 mmol) in chloroform (100 mL) under nitrogen atmosphere, triethylamine (2.22 mL, 15 0.9 mmol) and di-tert-butyl dicarbonate (2.78 g, 12.7 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was warmed to room temperature and extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After drying the desiccant, the solvent was distilled off under reduced pressure to obtain 11.8 g of a residue.

  This was dissolved in ethyl acetate (50 mL) and methanol (100 mL), and 20 wt. % Palladium hydroxide (2.50 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give a residue.

This was dissolved in pyridine (100 mL), acetic anhydride (6.01 mL, 63.6 mmol) and N, N-dimethylaminopyridine were added under nitrogen atmosphere, and the mixture was stirred overnight at room temperature. Thereafter, acetic anhydride (4.00 mL, 42.4 mmol) was further added, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 3M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After removing the desiccant from the oven, the solvent was distilled off under reduced pressure to obtain a residue. Ethyl acetate was added to the resulting residue to dissolve it, and hexane was added to obtain crystals, which were filtered to obtain the title compound (5.58 g, 74%) as a colorless powder.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.04 (s, 3 H) 2.07 (s, 3 H) 2.19 (s , 3 H) 2.35 (s, 3 H) 2.75 (t, J = 6.92 Hz, 2 H) 3.28-3.42 (m, 2 H) 3.75-3.83 (m, 1 H) 3.92 (s, 2 H) 4.08 ( dd, J = 12.43, 2.18 Hz, 1 H) 4.30 (dd, J = 12.36, 4.74 Hz, 1 H) 4.54 (t, 1 H) 5.14-5.23 (m, 1 H) 5.25-5.37 (m, 2 H ) 6.87 (s, 1 H) 7.02 (d, 2 H) 7.10 (d, 2 H) 7.16 (s, 1 H).
ESI m / z = 731 (M + NH ₄ ).

(2) (1S) -1- [5- [4- (2-Aminoethyl) benzyl] -2-acetoxy-4-methylphenyl] -1,5-anhydro-2,3,4,6-tetra- Preparation of O-acetyl-D-glucitol (1S) -1- [5- [4- (2-tert-butoxycarbonylaminoethyl) benzyl] -2-acetoxy-4-methylphenyl] -1,5-anhydro- Trifluoroacetic acid (23 mL) was added to a chloroform (80 mL) solution of 2,3,4,6-tetra-O-acetyl-D-glucitol, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate and filtering off the desiccant, the solvent was distilled off under reduced pressure to obtain the title compound (4.67 g, quant.) As a colorless powder.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.77 (s, 3 H) 2.00 (s, 3 H) 2.04 (s, 3 H) 2.07 (s, 3 H) 2.19 (s, 3 H) 2.35 (s , 3 H) 2.67 (t, 2 H) 2.85-3.07 (m, 2 H) 3.75-3.84 (m, 1 H) 3.92 (s, 2 H) 4.08 (dd, J = 12.36, 2.10 Hz, 1 H) 4.30 (dd, J = 12.36, 4.59 Hz, 1 H) 4.53 (t, 1 H) 5.13-5.23 (m, 1 H) 5.24-5.36 (m, 2 H) 6.86 (s, 1 H) 7.02 (d, 2 H) 7.11 (d, 2 H) 7.17 (s, 1 H).
ESI m / z = 614 (M + H).

Reference Example 13
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-hydroxy-2-methylbenzyl) -4-methyl Of phenyl] -D-glucitol

  A solution of 1-bromo-4-methoxymethoxy-2-methylbenzene (0.80 g, 3.46 mmol) in tetrahydrofuran (15 mL) in a 2.6 Mn-butyllithium hexane solution (1. 33 mL, 3.46 mmol) was added dropwise and stirred at the same temperature for 15 minutes. Then 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-formyl-4-methylphenyl] -D-glucopyranose (1.10 g, 1.44 mmol) ) In tetrahydrofuran (6 mL) was added dropwise and stirred at the same temperature for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was warmed to room temperature and 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 to obtain 1.7 g of an oily substance.

Next, this oily substance was dissolved in acetonitrile (10 mL) and chloroform (10 mL), and Et ₃ SiH (0.92 mL, 5.76 mmol) and BF ₃ · Et ₂ O (0.46 mL, 3. 60 mmol) was added. The reaction solution was stirred at the same temperature for 30 minutes and at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the low boiling point product was distilled off under reduced pressure, and the residue 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 = 3: 1) to give the title compound (420 mg, 35) as a pale yellow oily compound. %).
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.17 (s, 3 H) 2.22 (s, 3 H) 3.49-3.59 (m, 1 H) 3.63-3.84 (m, 6 H) 3.97 (d, J = 11.04 Hz, 1 H) 4.31-4.50 (m, 3 H) 4.52-4.68 (m, 3 H) 4.79-4.92 (m, 4 H) 5.02 (s, 2 H) 6.37 (dd, J = 8.32, 2.41 Hz , 1 H) 6.55 (d, J = 2.49 Hz, 1 H) 6.66 (d, J = 8.24 Hz, 1 H) 6.78 (s, 1 H) 6.88-6.97 (m, J = 5.21, 4.43 Hz, 2 H ) 7.01 (s, 1 H) 7.10-7.50 (m, 23 H).
ESI m / z = 858 (M + NH ₄ ), 839 (MH).

Reference Example 14
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- [4- [2- (1,3-dioxo-1) , 3-Dihydro-2H-isoindol-2-yl) ethoxy] -2-methylbenzyl] -4-methylphenyl] -D-glucitol

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-hydroxy-2-methylbenzyl) -4-methyl Phenyl] -D-glucitol (340 mg, 0.40 mmol) and N- (2-bromoethyl) phthalimide (1.02 g, 4.0 mmol) in N, N-dimethylformamide (5.0 mL) solution in potassium carbonate (553 mg, 4.0 mmol) and n-Bu ₄ NI (14 mg, 0.038 mmol) were added. The reaction mixture was stirred at 80 ° C. for 3.5 hours. After cooling to room temperature, water was added and 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 = 3: 1) to give the title compound (60 mg, 15) as a pale yellow oily compound. %).
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.17 (s, 3 H) 2.18 (s, 3 H) 3.49-3.60 (m, 1 H) 3.63-3.85 (m, 6 H) 3.89-4.19 (m, 5 H) 4.34-4.52 (m, 3 H) 4.53-4.65 (m, 3 H) 4.75-4.93 (m, 3 H) 5.01 (s, 2 H) 6.44 (dd, J = 8.55, 2.64 Hz, 1 H ) 6.60-6.71 (m, 2 H) 6.77 (s, 1 H) 6.88-6.97 (m, 2 H) 7.05 (s, 1 H) 7.13-7.45 (m, 23 H) 7.66-7.72 (m, 2 H ) 7.80-7.88 (m, 2 H).

Reference Example 15
(1S) -1- [5- [4- (2-Aminoethoxy) -2-methylbenzyl] -2- (benzyloxy) -4-methylphenyl] -1,5-anhydro-2,3,4 Preparation of 6-tetra-O-benzyl-D-glucitol

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- [4- [2- (1,3-dioxo-1) , 3-Dihydro-2H-isoindol-2-yl) ethoxy] -2-methylbenzyl] -4-methylphenyl] -D-glucitol (60 mg, 0.059 mmol) in tetrahydrofuran (0.8 mL) and methanol (0 .2 mL) solution was added hydrazine monohydrate (30 mg, 0.59 mmol) and the reaction mixture was stirred at 65 ° C. for 1 hour. After cooling to room temperature, 2M aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.21 (s, 3 H) 2.22 (s, 3 H) 3.03 (t, J = 4.74 Hz, 2 H) 3.50-3.62 (m, 1 H) 3.65-3.83 (m, 6 H) 3.88 (t, J = 4.74 Hz, 2 H) 3.98 (d, J = 10.88 Hz, 1 H) 4.34-4.51 (m, 3 H) 4.55-4.65 (m, 3 H) 4.77- 4.93 (m, 3 H) 5.02 (s, 2 H) 6.43-6.51 (m, 1 H) 6.66-6.72 (m, 2 H) 6.78 (s, 1 H) 6.91-6.98 (m, 2 H) 7.06 ( s, 1 H) 7.11-7.45 (m, 23 H)

Further, in the compound (I), 1-bromo-2-methoxy-4-methoxymethoxybenzene or 1-bromo-2-fluoro-4-methoxymethoxybenzene was used as a raw material in the same manner as in Reference Examples 13 to 15. , R ³ is a methoxy group or a fluorine atom.

Reference Example 16
Preparation of 4- (benzyloxy) -5-bromo-2-chlorobenzaldehyde

  To a chloroform (300 mL) solution of 2-chloro-4-hydroxybenzonitrile (14.0 g, 91.2 mmol), 0.95 M diisobutylaluminum hydride hexane solution (307 mL, 291 mmol) was added dropwise at −50 ° C. in a nitrogen atmosphere. And stirred at the same temperature for 1.5 hours. The temperature was raised to room temperature, and the mixture was further stirred for 3 hours. Subsequently, the reaction solution was ice-cooled and methanol was added dropwise. 3M Hydrochloric acid 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 the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain 7.25 g of a residue.

  This was dissolved in methanol (140 mL), pyridine hydrobromide perbromide (16.3 g, 50.9 mmol) was added under ice cooling under a nitrogen atmosphere, and the mixture was stirred for 4 hours. To the reaction solution was added 20% aqueous sodium sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 3M hydrochloric acid, 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 = 3: 1) to obtain 6.17 g of a colorless powder.

This was dissolved in acetone (260 mL), benzyl bromide (3.45 mL, 28.8 mmol) and potassium carbonate (4.70 g, 34.1 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at 50 ° C. for 4.5 hours. The reaction solution was cooled to room temperature and filtered through celite. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound (2.02 g, 6.9%) as a colorless powder. It was.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 5.23 (s, 2 H) 6.97 (s, 1 H) 7.32-7.50 (m, 5 H) 8.15 (s, 1 H) 10.27 (s, 1 H).
ESI m / z = 325 (M + H).

Reference Example 17
Preparation of [4- (benzyloxy) -5-bromo-2-chlorophenyl] [4- [2- (methoxymethoxy) ethyl] phenyl] methanol

2.6 Mn-butyllithium hexane solution of 1-bromo-4- [2- (methoxymethoxy) ethyl] benzene (1.52 g, 6.20 mmol) in tetrahydrofuran (6 mL) at −78 ° C. in a nitrogen atmosphere (2.38 mL, 6.20 mmol) was added dropwise and stirred at the same temperature for 10 minutes. Then, a solution of 4- (benzyloxy) -5-bromo-2-chlorobenzaldehyde (2.02 g, 6.20 mmol) in tetrahydrofuran (6 mL) was added dropwise over 10 minutes, and the mixture was stirred at the same temperature for 30 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 = 10: 1) to give the title compound (750 mg, 25% as a colorless oily compound). )
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.24 (d, J = 3.57 Hz, 1 H) 2.89 (t, J = 6.92 Hz, 2 H) 3.27 (s, 3 H) 3.75 (t, J = 6.84 Hz, 2 H) 4.60 (s, 2 H) 5.12 (s, 2 H) 6.09 (d, J = 3.57 Hz, 1 H) 6.91 (s, 1 H) 7.15-7.51 (m, 9 H) 7.80 (s , 1 H).
ESI m / z = 508 (M + NH ₄ ).

Reference Example 18
Preparation of 1- (benzyloxy) -2-bromo-5-chloro-4- [4- [2- (methoxymethoxy) ethyl] benzyl] benzene

To a solution of [4- (benzyloxy) -5-bromo-2-chlorophenyl] [4- [2- (methoxymethoxy) ethyl] phenyl] methanol (750 mg, 1.53 mmol) in chloroform (8 mL) was added Et ₃ SiH ( 367 μL, 2.30 mmol) and BF ₃ .Et ₂ O (232 μL, 1.83 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was warmed to room temperature. After extraction 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 = 4: 1) to give the title compound (290 mg, 40%) as a colorless oily compound. )
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.88 (t, J = 7.15 Hz, 2 H) 3.28 (s, 3 H) 3.75 (t, J = 6.99 Hz, 2 H) 3.97 (s, 2 H) 4.61 (s, 2 H) 5.12 (s, 2 H) 6.96 (s, 1 H) 7.10 (d, 2 H) 7.17 (d, 2 H) 7.28-7.50 (m, 6 H).
ESI m / z = 492 (M + NH ₄ ).

Reference Example 19
2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -4-chloro-5- [4- [2- (methoxymethoxy) ethyl] benzyl] phenyl] -D -Production of glucopyranose

A solution of 1- (benzyloxy) -2-bromo-5-chloro-4- [4- [2- (methoxymethoxy) ethyl] benzyl] benzene (290 mg, 0.609 mmol) in tetrahydrofuran (3 mL) under a nitrogen atmosphere, A 2.6 Mn-butyllithium hexane solution (234 μL, 0.609 mmol) was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 5 minutes. Then, a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (328 mg, 0.609 mmol) in tetrahydrofuran (3 mL) was added dropwise and stirred at the same temperature for 1 hour. 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) to give the title compound (124 mg, 22%) as a colorless oily compound. )
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.85 (t, J = 6.99 Hz, 2 H) 3.28 (s, 3 H) 3.60 (s, 5 H) 3.94-4.02 (m, 3 H) 4.04-4.15 (m, 3 H) 4.43-4.61 (m, 6 H) 4.71-4.97 (m, 5 H) 6.89 (s, 3 H) 7.37 (s, 27 H) 7.50 (s, 1 H).
ESI m / z = 952 (M + NH ₄ ).

Reference Example 20
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -4-chloro-5- [4- (2-hydroxyethyl) benzyl Production of phenyl] -D-glucitol

2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -4-chloro-5- [4- [2- (methoxymethoxy) ethyl] benzyl] phenyl] -D -To a solution of glucopyranose (124 mg, 0.133 mmol) in acetonitrile (0.5 mL) and tetrahydrofuran (0.5 mL), Et ₃ SiH (63.6 μL, 0.400 mmol) and BF ₃ .Et ₂ O (40.4 μL). 0.320 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours and at room temperature for 4.5 hours. Under ice-cooling, saturated aqueous sodium hydrogen carbonate 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 the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain 119 mg of residue.

This was dissolved in isopropyl ether (0.7 mL). Next, 2-propanol (0.7 mL) and 6M hydrochloric acid (0.7 mL) were added, and the reaction mixture was stirred at 80 ° C. for 3 hours. After cooling to room temperature, water was added and 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. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain the title compound (79.1 mg, 68%) as a colorless oily compound.
1H NMR (600 MHz, CHLOROFORM-D) δ ppm 2.77 (t, J = 6.42 Hz, 2 H) 3.52-3.60 (m, 1 H) 3.64-3.82 (m, 7 H) 3.92-3.99 (m, 3 H ) 4.03 (d, 1 H) 4.41-4.51 (m, 2 H) 4.54-4.64 (m, 2 H) 4.82-4.89 (m, 3 H) 4.91-4.97 (m, 2 H) 6.86 (d, J = 7.34 Hz, 2 H) 6.90 (s, 1 H) 7.02-7.06 (m, 2 H) 7.06-7.10 (m, 2 H) 7.13 (t, J = 7.34 Hz, 2 H) 7.15-7.20 (m, 3 H) 7.20-7.33 (m, 17 H) 7.36 (d, J = 7.79 Hz, 2 H).
ESI m / z = 892 (M + NH ₄ ).

Reference Example 21
(1S) -1- [5- [4- (2-Aminoethyl) benzyl] -2- (benzyloxy) -4-chlorophenyl] -1,5-anhydro-2,3,4,6-tetra-O -Preparation of benzyl-D-glucitol

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -4-chloro-5- [4- (2-hydroxyethyl) benzyl ] In a tetrahydrofuran (2.0 mL) solution of phenyl] -D-glucitol (79.0 mg, 0.090 mmol), triphenylphosphine (53.1 mg, 0.203 mmol) and phthalimide (23.9 mg, 0.162 mmol) in nitrogen. Under a stream of air, a toluene solution of 40% diisopropyl azodicarboxylate (386 μL, 0.203 mmol) was added with ice cooling. The reaction mixture was stirred at room temperature for 1.5 hours, and methanol (1 mL) was added. Then hydrazine monohydrate (43.7 μL, 0.90 mmol) was added and the reaction mixture was stirred at 60 ° C. for 3 hours. After cooling to room temperature, 2M aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain the title compound (39.2 mg, 50%) as a colorless oily compound.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.68 (t, 2 H) 2.83-2.96 (m, 2 H) 3.52-3.61 (m, 1 H) 3.62-3.86 (m, 5 H) 3.99 (t, J = 10.57 Hz, 3 H) 4.41-4.67 (m, 5 H) 4.81-4.92 (m, 3 H) 4.95 (s, 2 H) 6.88 (d, J = 5.60 Hz, 3 H) 6.97-7.43 (m , 28 H).
ESI m / z = 874 (M + H).

Reference Example 22
Production of 5-bromo-2-chlorobenzaldehyde

  N, N-dimethylformamide (0.5 mL) was added to a suspension of 5-bromo-2-chlorobenzoic acid (18.5 g, 78.5 mmol) in chloroform (157 mL), and oxalyl chloride (8.1 mL, 94.94). 2 mmol) was added dropwise at room temperature. After stirring for 30 minutes, the reaction solution was concentrated under reduced pressure. This residue was dissolved in chloroform (157 mL) and added dropwise at 0 ° C. to a chloroform suspension of N, O-dimethylhydroxylamine (9.19 g, 94.2 mmol) and triethylamine (26.3 mL, 188 mmol). After stirring at the same temperature for 30 minutes, the reaction solution was washed with water, a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain 24.0 g of a residue.

The obtained residue was dissolved in tetrahydrofuran (157 mL), and lithium aluminum hydride (1.19 g, 29.0 mmol) was gradually added at 0 ° C. The reaction mixture was cooled to 0 ° C., 2M hydrochloric acid was gradually added, and the mixture was stirred at room temperature for 30 min. The organic layer was washed successively 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. The obtained residue was recrystallized from an ethyl acetate-n-hexane mixed solution (1: 9) to give the title compound (11.3 g, 65%) as colorless crystals.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 7.35 (d, J = 8.47 Hz, 1 H) 7.65 (dd, J = 8.47, 2.56 Hz, 1 H) 8.04 (d, J = 2.56 Hz, 1 H) 10.41 (s, 1 H).

Reference Example 23
Preparation of (5-bromo-2-chlorophenyl) [4- [2- (methoxymethoxy) ethyl] phenyl] methanol

Using 5-bromo-2-chlorobenzaldehyde instead of 4- (benzyloxy) -5-bromo-2-chlorobenzaldehyde in the same manner as in Reference Example 17, the title compound (4.55 g, 63%).
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.89 (t, J = 6.99 Hz, 2 H) 3.26 (s, 3 H) 3.74 (t, J = 6.99 Hz, 2 H) 4.59 (s, 2 H) 6.11 (s, 1 H) 7.13-7.39 (m, 6 H) 7.82-7.84 (m, 1 H).

Reference Example 24
Preparation of 5-bromo-2-chloro-4- [4- [2- (methoxymethoxy) ethyl] benzyl] benzene

  Triethylamine (105 μL, 0.756 mmol) was added to a solution of (5-bromo-2-chlorophenyl) [4- [2- (methoxymethoxy) ethyl] phenyl] methanol (0.265 g, 0.687 mmol) in chloroform (1.4 mL). Methanesulfonyl chloride (58.5 μL, 0.756 mmol) was added dropwise at 0 ° C., and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice 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 to obtain a residue.

BF ₃ .Et ₂ O (104 μL, 0.824 mmol) was added to a chloroform (3.4 mL) solution of the obtained residue and Et ₃ SiH (165 μL, 1.03 mmol) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. . The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate solution (twice) and saturated brine, and 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 = 9: 1) to give a pale yellow crude product (41 mg). Obtained.
ESI m / z = 386 (M + NH ₄ ).

Reference Example 25
Preparation of 2,3,4,6-tetra-O-benzyl-1-C- [4-chloro-3- [4- [2- (methoxymethoxy) ethyl] benzyl] phenyl] -D-glucopyranose

5-Bromo-2-chloro-4- [4- [2 instead of 1- (benzyloxy) -2-bromo-5-chloro-4- [4- [2- (methoxymethoxy) ethyl] benzyl] benzene The crude title compound (1.07 g) was obtained as a colorless oil in the same manner as in Reference Example 19 using-(methoxymethoxy) ethyl] benzyl] benzene.
ESI m / z = 846 (M + NH ₄ ).

Reference Example 26
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [4-chloro-3- [4- (2-hydroxyethyl) benzyl] phenyl] -D-glucitol Manufacturing of

2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -4-chloro-5- [4- [2- (methoxymethoxy) ethyl] benzyl] phenyl] -D -2,3,4,6-tetra-O-benzyl-1-C- [4-chloro-3- [4- [2- (methoxymethoxy) ethyl] benzyl] phenyl] -D- instead of glucopyranose Using glucopyranose, the crude title compound (0.262 g) was obtained as a colorless oil in the same manner as in Reference Example 20.
ESI m / z = 786 (M + NH ₄ ).

Reference Example 27
Of (1S) -1- [3- [4- (2-aminoethyl) benzyl] -4-chlorophenyl] -1,5-anhydro-2,3,4,6-tetra-O-benzyl-D-glucitol Manufacturing

  (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -4-chloro-5- [4- (2-hydroxyethyl) benzyl ] Instead of [phenyl] -D-glucitol, (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [4-chloro-3- [4- (2-hydroxy) Ethyl) benzyl] phenyl] -D-glucitol was used to give the crude title compound (0.230 g) as a pale yellow oil in the same manner as in Reference Example 21.

Reference Example 28
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-bromobenzyl) -4-methylphenyl] -D -Production of galactitol

2,3,4,6-tetra-O-benzyl-D-galactono-1,5-lactone instead of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone And the title compound was synthesized in the same manner as in Reference Example 2.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.12 (s, 3 H) 3.32-3.81 (m, 4 H) 3.86 (s, 2 H) 4.07 (t, J = 10.72 Hz, 3 H) 4.32-4.47 (m, 2 H) 4.49-4.80 (m, 5 H) 4.93-5.07 (m, 3 H) 6.72 (s, 1 H) 6.80-7.01 (m, 4 H) 7.06-7.46 (m, 26 H). ESI m / z = 911 (M + Na). 913 (M + 2 + Na)

Reference Example 29
(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) -D-galactitol

  (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-bromobenzyl) -4-methylphenyl] -D -The title compound (377 mg, 41%) was obtained as a pale yellow amorphous product from galactitol (918 mg, 1.03 mmol) in the same manner as in Reference Example 3.

Example 1
(1S) -1,5-Anhydro-1- [2-hydroxy-5- [4- [4-[(2-hydroxy-1,1-dimethylethyl) amino] -4-oxobutyl] benzyl] -4- Of methylphenyl] -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] -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] -D-glucitol (200 mg, 0.223 mmol) in chloroform (2.2 mL) in 2-amino-2-methyl-1-propanol (40 mg, 0.446 mmol). 1-hydroxybenzotriazole (33 mg, 0.245 mmol) and WSC (60 mg, 0.312 mmol) were added, and the mixture was stirred overnight at room temperature. 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 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 to 1: 2) to give the title compound as an orange-yellow oily compound ( 120 mg, 56%).
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.26 (s, 6 H) 2.19 (s, 3 H) 3.11 (d, J = 7.46 Hz, 2 H) 3.54 − 3.63 (m, 3 H) 3.67 − 3.85 (m, 5 H) 3.89 − 4.05 (m, 3 H) 4.40 − 4.68 (m, 4 H) 4.81 − 4.95 (m, 3 H) 5.00 (s, 2 H) 5.60 (s, 1 H) 6.08 − 6.21 (m, 1 H) 6.45 (d, J = 15.54 Hz, 1 H) 6.75 (s, 1 H) 6.89 − 6.97 (m, 2 H) 7.03 (d, J = 7.93 Hz, 2 H) 7.11 − 7.45 ( m, 26 H).
ESI m / z = 988.5 (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] -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] -D-glucito To a solution of methanol (120 mg, 0.124 mmol) in methanol (1.2 mL) was added palladium-activated carbon (10%) (22 mg), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the residue obtained by evaporation under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 20: 1-5: 1) to give the title compound (58 mg, 90 mg) as a colorless powder. %). The NMR data and MS data are shown in Table 1.

Example 2
(1S) -1,5-Anhydro-1- [2-hydroxy-5- [4- [4-[[2-hydroxy-1- (hydroxymethyl) -1-methylethyl] amino] -4-oxobutyl] [Benzyl] -4-methylphenyl] -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- (hydroxymethyl) -1-methylethyl] amino] -4-oxobut-1-en-1-yl) benzyl] -4-methylphenyl] -D-glucitol 2- The title compound was obtained as a colorless oily compound in the same manner as in Example 1 (1) using 2-amino-2-methyl-1,3-propanediol instead of amino-2-methyl-1-propanol. The compound (91 mg, 44%) was obtained.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.19 (s, 3 H) 2.20 (s, 3 H) 3.15 (d, J = 6.06 Hz, 2 H) 3.49 − 3.83 (m, 10 H) 3.87 − 4.04 (m, 3 H) 4.37 − 4.67 (m, 4 H) 4.80 − 4.94 (m, 3 H) 5.00 (s, 2 H) 6.00 − 6.23 (m, 2 H) 6.40 − 6.52 (m, 1 H) 6.75 (s, 1 H) 6.93 (dd, J = 7.38, 1.94 Hz, 2 H) 7.03 (d, J = 8.24 Hz, 2 H) 7.11 − 7.35 (m, 24 H) 7.35 − 7.46 (m, 2 H) .
ESI m / z = 1004.5 (M + Na).

(2) (1S) -1,5-Anhydro-1- [2-hydroxy-5- [4- (4-[[2-hydroxy-1- (hydroxymethyl) -1-methylethyl] amino] -4 -Oxobutyl) benzyl] -4-methylphenyl] -D-glucitol
(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] -D-glucitol (91 mg, 0.0926 mmol) in methanol To the (1 mL) solution was added palladium-activated carbon (10%) (16 mg), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through celite, and the residue obtained by evaporation under reduced pressure was dissolved in methanol (1 mL). % Palladium hydroxide (91 mg) was added, and the mixture was stirred at room temperature for 2 days under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the residue obtained by evaporation under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to give the title compound (32 mg, 65%) as a colorless powder. The NMR data and MS data are shown in Table 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] -D-glucitol (compound 3)

(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-bis (hydroxymethyl) ethyl] amino] -4-oxobut-1-en-1-yl] benzyl] -4-methylphenyl] -D-glucitol 2-amino The title compound (151 mg, 55%) was obtained as a pale yellow powder in the same manner as in Example 1 (1) using tris (hydroxymethyl) aminomethane instead of -2-methyl-1-propanol.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.22 (s, 3 H) 3.18 (dd, J = 7.15, 1.09 Hz, 2 H) 3.43 − 3.81 (m, 12 H) 3.87 − 4.02 (m, 3 H ) 4.36 − 4.67 (m, 4 H) 4.80 − 4.93 (m, 3 H) 5.00 (s, 2 H) 6.10 − 6.22 (m, 1 H) 6.47 (d, J = 15.85 Hz, 1 H) 6.68 (s , 1 H) 6.75 (s, 1 H) 6.93 (d, J = 5.91 Hz, 2 H) 7.03 (d, J = 8.08 Hz, 2 H) 7.10 − 7.35 (m, 24 H) 7.36 − 7.44 (m, 2 H).
ESI m / z = 998.5 (M + H).

(2) (1S) -1,5-Anhydro-1- [2-hydroxy-5- [4- [4-[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] amino] -4- Production of Oxobutyl] benzyl] -4-methylphenyl] -D-glucitol In the same manner as in Example 2 (2), the title compound (60 mg, 76%) was obtained as a colorless powder. The NMR data and MS data are shown in Table 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-D-glucitol

(1) (1S) -1- [5- [4-[(1E) -4-[(2-amino-1,1-dimethyl-2-oxoethyl) amino] -4-oxobut-1-ene-1 Preparation of -yl] benzyl] -2- (benzyloxy) -4-methylphenyl] -1,5-anhydro-2,3,4,6-tetra-O-benzyl-D-glucitol 2-amino- The title compound (75 mg, 42%) was obtained as a pale yellow powder in the same manner as in Example 1 (1) using 2-amino-2-methylpropionamide instead of 2-methyl-1-propanol. .
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.55 (s, 3 H) 1.57 (s, 3 H) 2.19 (s, 3 H) 3.12 (dd, J = 7.38, 1.17 Hz, 2 H) 3.53 − 3.87 (m, 6 H) 3.89 − 4.05 (m, 3 H) 4.39 − 4.54 (m, 2 H) 4.57 − 4.66 (m, 2 H) 4.81 − 4.94 (m, 3 H) 5.00 (s, 2 H) 6.08 − 6.23 (m, 2 H) 6.46 (d, J = 16.01 Hz, 1 H) 6.75 (s, 1 H) 6.93 (dd, J = 7.07, 1.79 Hz, 2 H) 7.03 (d, J = 8.24 Hz, 2 H) 7.10 − 7.35 (m, 24 H) 7.36 − 7.45 (m, 2 H).
ESI m / z = 1001.5 (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-D-glucitol (1S) -1- [5- (4-[(1E) -4-[(2-amino-1,1-dimethyl-2-phenyl) Oxoethyl) amino] -4-oxobut-1-en-1-yl] benzyl) -2- (benzyloxy) -4-methylphenyl] -1,5-anhydro-2,3,4,6-tetra-O -Benzyl-D-glucitol (75 mg, 0.0765 mmol) in a methanol (1 mL) solution at 20 wt. % Palladium hydroxide (15 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the residue obtained by evaporation under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 5: 1, ethyl acetate: ethanol: water = 20: 2: 1) to give a colorless powder. To give the title compound (32 mg, 79%). The NMR data and MS data are shown in Table 1.

Example 5
(1S) -1- [5- [4- [3-[[Amino (imino) methyl] amino] propyl] benzyl] -2-hydroxy-4-methylphenyl] -1,5-anhydro-D-glucitol Manufacturing

(1) (1S) -1- [5- [4-[(1E) -3-[[Benzyloxycarbonylamino (benzyloxycarbonylimino) methyl] amino] prop-1-en-1-yl] benzyl] Preparation of 2- (benzyloxy) -4-methylphenyl] -1,5-anhydro-2,3,4,6-tetra-O-benzyl-D-glycitol
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-bromobenzyl) -4-methylphenyl] -D -Glucitol (271 mg, 0.305 mmol) in acetonitrile (3 mL) in dibenzyl [(Z)-(allylamino) methylylidene] biscarbamate (335 mg, 0.914 mmol), palladium (II) acetate (18 mg,. 0791 mmol), tri-O-tolylphosphine (61 mg, 0.201 mmol) and triethylamine (154 mg, 1.52 mmol) were added, and the reaction was performed at 120 ° C. for 20 minutes using a biotage microwave. The residue obtained by evaporating the reaction solution under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound (163 mg, 46%) as a pale yellow amorphous.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.18 (s, 3 H) 3.53 − 3.86 (m, 6 H) 3.91 (s, 1 H) 4.00 (d, J = 11.04 Hz, 1 H) 4.19 (t , J = 5.75 Hz, 2 H) 4.38 − 4.55 (m, 2 H) 4.57 − 4.67 (m, 2 H) 4.80 − 4.95 (m, 3 H) 5.00 (s, 2 H) 5.10 − 5.20 (m, 4 H) 6.03 − 6.16 (m, 1 H) 6.41 − 6.52 (m, 1 H) 6.75 (s, 1 H) 6.92 (dd, J = 7.31, 1.71 Hz, 2 H) 7.01 (d, J = 8.08 Hz, 2 H) 7.07 − 7.44 (m, 37 H) 8.38 − 8.45 (m, 1 H) 11.77 (s, 1 H)
ESI m / z = 1176 (M + H).

(2) (1S) -1- [5- [4- [3-[[Amino (imino) methyl] amino] propyl] benzyl] -2-hydroxy-4-methylphenyl] -1,5-anhydro-D -Production of Glucitol (1S) -1- [5- [4-[(1E) -3-[[Benzyloxycarbonylamino (benzyloxycarbonylimino) methyl] amino] prop-1-en-1-yl] benzyl ] -2- (benzyloxy) -4-methylphenyl] -1,5-anhydro-2,3,4,6-tetra-O-benzyl-D-glycitol (154 mg, 0.131 mmol) in methanol (2. 6 mL) -ethyl acetate (1.3 mL) mixed solution. % Palladium hydroxide (160 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the residue obtained by evaporation under reduced pressure was dissolved in methanol (1.5 mL). % Palladium hydroxide (63 mg) was added, and the mixture was stirred at room temperature for 2 days under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the residue obtained by evaporation under reduced pressure was subjected to silica gel column chromatography (ethyl acetate: ethanol: water = 10: 2: 1 to 5: 2: 1 to ethanol: water = 10: 1). To give the title compound (38 mg, 63%) as a colorless powder. The NMR data and MS data are shown in Table 1.

Example 6
(1S) -1,5-Anhydro-1- [2-hydroxy-4-methyl-5- [4- [3-[[(4-methylpiperazin-1-yl) carbonyl] amino] propyl] benzyl] phenyl Production of D-glucitol

(1) (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -4-methyl-5- [4-[(1E) Preparation of -3-[[(4-Methylpiperazin-1-yl) carbonyl] amino] prop-1-en-1-yl] benzyl] phenyl] -D-glycitol Dibenzyl [(Z)-(allylamino) methylylidene] The title compound (180 mg, 54%) was obtained as a pale yellow oily compound in the same manner as in Example 5 (1) using N-allyl-4-methylpiperazine-1-carboxamide instead of biscarbamate. .
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.18 (s, 3 H) 2.23-2.64 (m, 5 H) 3.31-3.86 (m, 11 H) 3.91 (s, 2 H) 3.95-4.07 (m, 2 H) 4.36-4.55 (m, 3 H) 4.55-4.66 (m, 2 H) 4.77-4.95 (m, 4 H) 5.00 (s, 2 H) 6.05-6.23 (m, 1 H) 6.38-6.50 ( m, 1 H) 6.74 (s, 1 H) 6.92 (dd, J = 8.24, 1.24 Hz, 2 H) 7.03 (t, J = 6.99 Hz, 2 H) 7.08-7.36 (m, 25 H) 7.37-7.46 (m, 2 H)
ESI m / z = 992 (M + H).

(2) (1S) -1,5-Anhydro-1- [2-hydroxy-4-methyl-5- [4- [3-[[(4-methylpiperazin-1-yl) carbonyl] amino] propyl] Production of [benzyl] phenyl] -D-glucitol The title compound (51 mg, 53%) was obtained as a colorless powder in the same manner as in Example 5 (2). The NMR data and MS data are shown in Table 1.

Example 7
(1S) -1- [5- [4- [4-[(3-Aminopropyl) amino] -4-oxobutyl] benzyl] -2-hydroxy-4-methylphenyl] -1,5-anhydro-D- Glucitol production

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- [4-[(1E) -4- [ Preparation of [3-[(tert-Butoxycarbonyl) amino] propyl] amino] -4-oxobut-1-en-1-yl] benzyl] -4-methylphenyl] -D-glycitol Dibenzyl [(Z)-( Allylamino) methylylidene] bis-carbamate is replaced with t-butyl [3- (but-3-enoylamino) propyl] carbamate in the same manner as in Example 5 (1) as the title compound (200 mg, 56 %).
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (s, 9 H) 1.49-1.67 (m, 2 H) 2.18 (s, 3 H) 3.05-3.20 (m, 4 H) 3.29 (q, J = 6.32 Hz, 2 H) 3.50-3.85 (m, 6 H) 3.91 (s, 2 H) 4.00 (d, J = 10.72 Hz, 1 H) 4.37-4.56 (m, 2 H) 4.56-4.67 (m, 2 H) 4.78-4.95 (m, 4 H) 5.00 (s, 2 H) 6.10-6.37 (m, 2 H) 6.46 (d, J = 15.70 Hz, 1 H) 6.74 (s, 1 H) 6.88-6.96 ( m, 2 H) 7.02 (d, J = 8.24 Hz, 2 H) 7.10-7.33 (m, 25 H) 7.37-7.44 (m, 2 H).
ESI m / z = 1073 (M + Na).

(2) (1S) -1- [5- [4-[(1E) -4-[(3-aminopropyl) amino] -4-oxobutyl-1-en-1-yl] benzyl] -2- ( Preparation of (benzyloxy) -4-methylphenyl] -1,5-anhydro-2,3,4,6-tetra-O-benzyl-D-glucitol (1S) -1,5-anhydro-2,3,4 , 6-Tetra-O-benzyl-1- [2- (benzyloxy) -5- [4-[(1E) -4-[[3-[(tert-butoxycarbonyl) amino] propyl] amino] -4 To a solution of -oxobut-1-en-1-yl] benzyl] -4-methylphenyl] -D-glycitol (200 mg, 0.190 mmol) in ethyl acetate (2 mL) was added 4M hydrochloric acid / ethyl acetate solution under ice-cooling. Stir at room temperature for 2 days. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, the organic layer was separated, washed with water 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 (chloroform: methanol = 5: 1 to ethyl acetate: ethanol: water = 5: 2: 1). The title compound (54 mg, 30%) was obtained as a pale yellow oily compound.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.83-1.98 (m, 2 H) 2.17 (s, 3 H) 2.87-3.03 (m, 2 H) 3.03-3.20 (m, 2 H) 3.26-3.40 ( m, 2 H) 3.51-3.83 (m, 6 H) 3.89 (s, 2 H) 4.00 (d, J = 10.57 Hz, 1 H) 4.38-4.54 (m, 2 H) 4.54-4.66 (m, 2 H ) 4.80-4.94 (m, 3 H) 4.99 (s, 2 H) 6.06-6.22 (m, 1 H) 6.37-6.62 (m, 2 H) 6.74 (s, 1 H) 6.91 (dd, J = 6.92, 1.63 Hz, 2 H) 7.01 (d, J = 8.08 Hz, 2 H) 7.07-7.35 (m, 25 H) 7.35-7.47 (m, 4 H).
ESI m / z = 951 (M + H).

(3) (1S) -1- [5- [4- [4-[(3-aminopropyl) amino] -4-oxobutyl] benzyl] -2-hydroxy-4-methylphenyl] -1,5-anhydro -Production of D-glucitol In the same manner as in Example 5 (2), the title compound (1 mg, 3.5%) was obtained as a colorless amorphous substance. The NMR data and MS data are shown in Table 1.

Example 8
(1S) -1,5-Anhydro-1- [5- [4- [3-[[(2-hydroxy-1,1-dimethylethyl) aminocarbonyl] amino] propyl] benzyl] -2-hydroxy-4 -Methylphenyl] -D-glucitol production

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [5- [4-[(1E) -3-[[(2-hydroxy-1 , 1-Dimethylethyl) aminocarbonyl] amino] prop-1-en-1-yl] benzyl] -2- (benzyloxy) -4-methylphenyl] -D-glucitol (1S) -1, 5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-bromobenzyl) -4-methylphenyl] -D-glucitol (0.48 g , 0.539 mmol) in acetonitrile (5.4 mL), N-allyl-N ′-(2-hydroxy-1,1-dimethylethyl) urea (223 mg, 1.29 mmol), palladium (II) acetate (24 mg, 0.108 mmol), Li -O- tolylphosphine (66mg, 0.216mmol), triethylamine (273 mg, 2.69 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 to chloroform: methanol = 50: 1) to obtain the title compound (210 mg, 40%) as a pale yellow amorphous. .
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.26 (s, 6 H) 2.19 (s, 3 H) 3.45-4.13 (m, 13 H) 4.31-4.69 (m, 6 H) 4.77-5.06 (m, 5 H) 5.98-6.18 (m, 1 H) 6.44 (d, J = 15.85 Hz, 1 H) 6.74 (s, 1 H) 6.86-7.48 (m, 31 H)
ESI m / z = 982 (M + H).

(2) (1S) -1- [2- (acetoxy) -5- [4- [3-[[[[2- (acetoxy) -1,1-dimethylethyl] amino] carbonyl] amino] propal] benzyl ] -4-Methylphenyl] -1,5-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol (1S) -1,5-anhydro-2,3,4 , 6-Tetra-O-benzyl-1- [5- [4-[(1E) -3-[[(2-hydroxy-1,1-dimethylethyl) aminocarbonyl] amino] prop-1-ene-1 -Yl) benzyl] -2- (benzyloxy) -4-methylphenyl] -D-glucitol (210 mg, 0.214 mmol) in ethanol (3 mL) at 20 wt. % Palladium hydroxide (210 mg) was added, and the mixture was stirred overnight at room temperature under 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 obtain a colorless powdery substance (83 mg). Acetic anhydride (0.25 mL) was added to this pyridine (1 mL) solution and stirred overnight at room temperature. 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 washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering 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: 3 to 1: 2) to give the title compound (70 mg) as a colorless amorphous product. Got.

(3) (1S) -1,5-Anhydro-1- [5- [4- [3-[[(2-hydroxy-1,1-dimethylethyl) aminocarbonyl] amino] propyl] benzyl] -2- Preparation of hydroxy-4-methylphenyl] -D-glucitol (1S) -1- [2- (acetoxy) -5- [4- [3-[[[[2- (acetoxy) -1,1- Dimethylethyl] amino] carbonyl] amino] propal] benzyl] -4-methylphenyl] -1,5-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol (70 mg) of methanol Sodium methoxide (1M methanol solution, 0.5 mL, 0.534 mmol) was added to the solution (1 mL), and the mixture was stirred at room temperature for 1 hour. Dry ice was added to the reaction solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain the title compound (35 mg, 31%, 3 steps) as a colorless oil. The NMR data and MS data are shown in Table 1.

Example 9
(1S) -1,5-Anhydro-1- [5- [4- [3-[[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] aminocarbonyl] amino] propyl] benzyl] -2 -Hydroxy-4-methylphenyl] -D-glucitol

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [5- [4-[(1E) -3-[[[2-hydroxy-1 , 1-Bis (hydroxymethyl) ethyl] aminocarbonyl] amino] prop-1-en-1-yl] benzyl] -2- (benzyloxy) -4-methylphenyl] -D-glucitol 2-amino- The title compound (322 mg) was obtained as a pale yellow amorphous product in the same manner as in Example 8 (1) using tris (hydroxymethyl) aminomethane instead of 2-methyl-1-propanol.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.19 (s, 3 H) 3.48-4.06 (m, 17 H) 4.34-5.08 (m, 11 H) 5.98-6.11 (m, 1 H) 6.44 (d, J = 16.32 Hz, 1 H) 6.74 (s, 1 H) 6.84-7.46 (m, 31 H)
ESI / APCl m / z = 1014 (M + H)

(2) (1S) -1,5-Anhydro-1- [5- [4- [2-[[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] aminocarbonyl] amino] propyl] benzyl ] Preparation of 2-hydroxy-4-methylphenyl] -D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [5- [4- [ (1E) -3-[[(2-Hydroxy-1,1-dimethylethyl) aminocarbonyl] amino] prop-1-en-1-yl] benzyl] -2- (benzyloxy) -4-methylphenyl] Instead of D-glucitol, (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [5- [4-[(1E) -3-[[ [2-hydroxy-1,1-bis (hydroxymethyl) ethyl] a Nocarbonyl] amino] prop-1-en-1-yl] benzyl] -2- (benzyloxy) -4-methylphenyl] -D-glucitol in the same manner as in Example 8 (2), and colorless powder To give the title compound (60 mg). The NMR data and MS data are shown in Table 1.

Example 10
(1S) -1,5-Anhydro-1- [5- [4- [2-[[(2-hydroxy-1,1-dimethylethyl) aminocarbonyl] amino] ethyl] benzyl] -2-hydroxy-4 -Methylphenyl] -D-glucitol production

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- [4- [2-[[[(2 Preparation of -hydroxy-1,1-dimethylethyl) amino] carbonyl] amino] ethyl] benzyl] -4-methylphenyl] -D-glucitol Toluene 4-nitrophenyl chloroformate (0.177 g, 0.879 mmol) (1S) -1- [5- [4- (2-Aminoethyl) benzyl] -2- (benzyloxy) -4 was added to a solution of pyridine (0.071 mL, 0.88 mmol) in chloroform (3 mL) under ice cooling. -Methylphenyl] -1,5-anhydro-2,3,4,6-tetra-O-benzyl-D-glucitol (0.250 g, 0.293 mmol) in chloroform (3 mL) was added dropwise at room temperature for 20 minutes. Stir for minutes. Thereafter, a solution of 2-amino-2-methyl-1-propanol (0.209 g, 2.344 mmol) in chloroform (3 mL) and dimethyl sulfoxide (3 mL) were added, and the mixture was stirred overnight at the same temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine (3 times), 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 NH-type silica gel column chromatography (chloroform) to give the title compound (0.184 g, 65%) as a pale yellow oily compound. Obtained.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.18 (s, 6 H) 2.21 (s, 3 H) 2.68 (t, J = 6.68 Hz, 2 H) 3.21-3.37 (m, 2 H) 3.45-3.94 (m, 10 H) 4.00 (d, J = 10.88 Hz, 1 H) 4.37-4.65 (m, 5 H) 4.81-5.03 (m, 5 H) 6.75 (s, 1 H) 6.87-7.05 (m, 7 H) 7.07-7.44 (m, 23 H).

(2) (1S) -1,5-Anhydro-1- [5- [4- [2-[[(2-hydroxy-1,1-dimethylethyl) aminocarbonyl] amino] ethyl] benzyl] -2- Preparation of hydroxy-4-methylphenyl] -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] carbonyl] amino] ethyl] benzyl] -4-methylphenyl] -D-glucitol (0.184 mg, 0.190 mmol ) In methanol (4 mL) was added palladium hydroxide (0.180 g), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the residue obtained by evaporation under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 17: 3) to give the title compound (57 mg, 58%) as a colorless powder. It was. The NMR data and MS data are shown in Table 1.

Example 11
(1S) -1,5-Anhydro-1- [5- [4- [2-[[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] aminocarbonyl] amino] ethyl] benzyl] -2 -Hydroxy-4-methylphenyl] -D-glucitol

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- [4- [2-[[[[[2 Preparation of -hydroxy-1,1-bis (hydroxymethyl) ethyl] amino] carbonyl] amino] ethyl] benzyl] -4-methylphenyl] -D-glucitol of 2-amino-2-methyl-1-propanol Instead, the title compound (251 mg) was obtained as a pale yellow amorphous in the same manner as in Example 10 (1) using tris (hydroxymethyl) aminomethane.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.22 (s, 3 H) 2.68 (t, J = 6.61 Hz, 2 H) 3.24-3.35 (m, 2 H) 3.41-3.99 (m, 14 H) 4.00 (d, J = 10.88 Hz, 1 H) 4.38-4.70 (m, 5 H) 4.79-5.03 (m, 5 H) 5.27 (s, 1 H) 6.76 (s, 1 H) 6.87-7.44 (m, 30 H).

(2) (1S) -1,5-Anhydro-1- [5- [4- [2-[[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] aminocarbonyl] amino] ethyl] benzyl ] -2-Hydroxy-4-methylphenyl] -D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) Instead of -5- [4- [2-[[[(2-hydroxy-1,1-dimethylethyl) amino] carbonyl] amino] ethyl] benzyl] -4-methylphenyl] -D-glucitol ( 1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- [4- [2-[[[[2-hydroxy-1 , 1-Bis (hydroxymethyl) ethyl] amino] carboni The title compound (85 mg) was obtained as a colorless powder in the same manner as in Example 10 (2) using [l] amino] ethyl] benzyl] -4-methylphenyl] -D-glucitol. The NMR data and MS data are shown in Table 1.

Example 12
(1S) -1,5-Anhydro-1- [5- [4- [2-[[[1- [1- (4-methylpiperazin-1-yl) carbonyl] -1- (methyl) ethyl] amino Preparation of carbonyl] amino] ethyl] benzyl] -2-hydroxy-4-methylphenyl] -D-glucitol

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- [4- [2-[[[[[1 Preparation of-[1- (4-methylpiperazin-1-yl) carbonyl] -1- (methyl) ethyl] amino] carbonyl] amino] ethyl] benzyl] -4-methylphenyl] -D-glucitol 2- The same method as in Example 10 (1) except that 2-methyl-1- (4-methylpiperazin-1-yl) -1-oxopropan-2-amine was used instead of amino-2-methyl-1-propanol Gave the title compound (326 mg) as a pale yellow amorphous.
1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.41 (s, 6 H) 2.20 (s, 3 H) 2.26 (s, 3 H) 2.31-2.37 (m, 4 H) 2.70 (t, J = 6.84 Hz , 2 H) 3.29-3.41 (m, 2 H) 3.50-3.94 (m, 12 H) 4.00 (d, J = 10.88 Hz, 1 H) 4.37-4.67 (m, 5 H) 4.81-5.02 (m, 5 H) 6.75 (s, 1 H) 6.88-7.44 (m, 30 H).

(2) (1S) -1,5-anhydro-1- [5- [4- [2-[[[1- [1- (4-methylpiperazin-1-yl) carbonyl] -1- (methyl) Preparation of [ethyl] aminocarbonyl] amino] ethyl] benzyl] -2-hydroxy-4-methylphenyl] -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] carbonyl] amino] ethyl] benzyl] -4-methylphenyl] (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- [4- [2] instead of -D-glucitol -[[[[1- [1- (4-methylpiperazin-1-yl) cal [Bonyl] -1- (methyl) ethyl] amino] carbonyl] amino] ethyl) benzyl] -4-methylphenyl] -D-glucitol was used as a colorless powder in the same manner as in Example A (2). Compound (35 mg) was obtained. The NMR data and MS data are shown in Table 1.

Example 13
(1S) -1,5-Anhydro-1- [5- [4- [2-[[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] aminocarbonyl] amino] ethoxy] -2-methyl Benzyl] -2-hydroxy-4-methylphenyl] -D-glucitol

  To a chloroform solution (0.5 mL) of 1,1′-carbonylimidazole (14 mg, 0.089 mmol) was added (1S) -1- [5- [4- (2-aminoethoxy) -2-methylbenzyl] -2. -(Benzyloxy) -4-methylphenyl] -1,5-anhydro-2,3,4,6-tetra-O-benzyl-D-glucitol (52 mg, 0.059 mmol) in chloroform (1.5 mL) And N-methylmorpholine (9 mg) were added, and the mixture was stirred at room temperature for 15 minutes. Next, tris (hydroxymethyl) aminomethane (21 mg, 0.177 mmol) and N, N-dimethylformamide (2 mL) were added to the reaction solution, and the reaction mixture was stirred at 60 ° C. for 1.5 hours. After cooling to room temperature, ethyl acetate was added, and this was washed with water, 1M hydrochloric acid 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 60 mg of a residue.

  The obtained residue was dissolved in methanol (1 mL), and 20 wt. % Palladium hydroxide (15 mg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the residue obtained by evaporation under reduced pressure was purified by silica gel column chromatography (ethyl acetate: ethanol: water = 10: 2: 1) to give the title compound (30 mg, 86%, colorless powder). ) The NMR data and MS data are shown in Table 1.

Example 14
(1S) -1,5-Anhydro-1- [4-chloro-5- [4- [2-[[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] aminocarbonyl] amino] ethyl] [Benzyl] -2-hydroxyphenyl] -D-glucitol

  To a chloroform solution (1 mL) of 1,1′-carbonylimidazole (10.8 mg, 0.0669 mmol) was added (1S) -1- [5- [4- (2-aminoethyl) benzyl] -2- (benzyloxy). ) -4-chlorophenyl] -1,5-anhydro-2,3,4,6-tetra-O-benzyl-D-glucitol (39.0 mg, 0.0446 mmol) in chloroform (1 mL) and N-methylmorpholine (7.36 μL) was added and stirred at room temperature for 10 minutes. Next, tris (hydroxymethyl) aminomethane (16.2 mg, 0.134 mmol) and N, N-dimethylformamide (1 mL) were added to the reaction solution, and the reaction mixture was stirred at 60 ° C. for 2 hours. After cooling to room temperature, ethyl acetate was added, and this was washed with water, 1M hydrochloric acid 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 41.2 mg of a residue.

The obtained residue (22.3 mg, 0.022 mmol) was dissolved in chloroform (250 μL) and ethanethiol (250 μL), BF ₃ .Et ₂ O (50 μL) was added with ice cooling, and the mixture was stirred at the same temperature for 2 hours. did. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol: water = 10: 2: 1 to methanol) to give the title compound (10.8 mg, 86%) as a colorless amorphous product. Got. The NMR data and MS data are shown in Table 1.

Example 15
(1S) -1,5-Anhydro-1- [5- [4- [2-[[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] aminocarbonyl] amino] ethyl] benzyl] -2 -Hydroxyphenyl] -D-glucitol production

  (1S) -1- [5- [4- (2-Aminoethoxy) -2-methylbenzyl] -2- (benzyloxy) -4-methylphenyl] -1,5-anhydro-2,3,4 Instead of 6-tetra-O-benzyl-D-glucitol, (1S) -1- [5- [4- (2-aminoethyl) benzyl] -2- (benzyloxy) -4-chlorophenyl] -1,5 The title compound (8.5 mg, 93%) was obtained as a colorless oily compound in the same manner as in Example 13 using -anhydro-2,3,4,6-tetra-O-benzyl-D-glucitol. The NMR data and MS data are shown in Table 1.

Example 16
(1S) -1,5-Anhydro-1- [3- [4- [2-[[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] aminocarbonyl] amino] ethyl] benzyl] phenyl] -Production of D-glucitol

  (1S) -1- [5- [4- (2-Aminoethoxy) -2-methylbenzyl] -2- (benzyloxy) -4-methylphenyl] -1,5-anhydro-2,3,4 Instead of 6-tetra-O-benzyl-D-glucitol, (1S) -1- [3- [4- (2-aminoethyl) benzyl] -4-chlorophenyl] -1,5-anhydro-2,3 The crude title compound was prepared using 4,6-tetra-O-benzyl-D-glucitol in the same manner as in Example 13, and then HPLC (0.025% acetic acid aqueous solution: acetonitrile = 3: 1, YMC- Purification using PACK ODS-AM 150 × 10 mm ID, 5.0 mL / min., Λ = 210 nM) gave the title compound (13 mg, 15%) as a colorless amorphous. The NMR data and MS data are shown in Table 1.

Example 17
(1S) -1,5-Anhydro-1- [4-chloro-3- [4- [2-[[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] aminocarbonyl] amino] ethyl] Preparation of [benzyl] phenyl] -D-glucitol

  (1S) -1- [5- [4- (2-Aminoethyl) benzyl] -2- (benzyloxy) -4-chlorophenyl] -1,5-anhydro-2,3,4,6-tetra-O -(1S) -1- [3- [4- (2-Aminoethyl) benzyl] -4-chlorophenyl] -1,5-anhydro-2,3,4,6-tetra instead of benzyl-D-glucitol The crude title compound was prepared using -O-benzyl-D-glucitol in the same manner as in Example 14, followed by HPLC (0.025% aqueous acetic acid: acetonitrile = 7: 3, Waters Sunfire PrepC, 150 × 19 mmI). D., 8.0 mL / min., Λ = 210 nM) to give the title compound (12 mg, 17%) as a colorless amorphous. The NMR data and MS data are shown in Table 1.

Example 18
(1S) -1,5-Anhydro-1- [2-hydroxy-5- [4- (4-[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] amino] -4-oxobutyl) benzyl ] -4-Methylphenyl] -D-galactitol

  In the same manner as in Example 3, (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) -D-galaxitol (199 mg, 0.222 mmol) gave the title compound (37 mg, 47%) as a colorless powder. Obtained. The NMR data and MS data are shown in Table 1.

  Compounds 19 to 36 were also synthesized from corresponding raw materials according to Reference Examples and Examples.

Example 11-1 (another production method of Example 11)
(1S) -1,5-Anhydro-1- [5- [4- [2-[[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] aminocarbonyl] amino] ethyl] benzyl] -2 -Hydroxy-4-methylphenyl] -D-glucitol

(1) (1S) -1,5-Anhydro-2,3,4,6-tetra-O-acetyl-1- [2-acetoxy-5- [4- [2-[[[[2-hydroxy- Preparation of 1,1-bis (hydroxymethyl) ethyl] amino] carbonyl] amino] ethyl] benzyl] -4-methylphenyl] -D-glucitol 1,1′-carbonylimidazole (7.30 mg, 0.045 mmol ) In chloroform solution (300 μL), (1S) -1- [5- [4- (2-aminoethyl) benzyl] -2-acetoxy-4-methylphenyl] -1,5-anhydro-2,3, A chloroform solution (150 μL) of 4,6-tetra-O-acetyl-D-glucitol (18.4 mg, 0.030 mmol) and N-methylmorpholine (4.95 μL, 0.045 mmol) were added. And the mixture was stirred for 30 minutes at room temperature. Next, tris (hydroxymethyl) aminomethane (10.9 mg, 0.09 mmol) and N, N-dimethylformamide (150 μL) were added to the reaction solution, and the reaction mixture was stirred at 60 ° C. overnight. After cooling to room temperature, ethyl acetate was added, and this was washed with water, 1M hydrochloric acid 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 (chloroform: methanol = 95: 5) to give the title compound (7.9 mg, 35 as a colorless amorphous). %).

(2) (1S) -1,5-Anhydro-1- [5- [4- [2-[[[2-hydroxy-1,1-bis (hydroxymethyl) ethyl] aminocarbonyl] amino] ethyl] benzyl ] -2-Hydroxy-4-methylphenyl] -D-glucitol (1S) -1,5-anhydro-2,3,4,6-tetra-O-acetyl-1- [2-acetoxy-5 [4- [2-[[[[2-Hydroxy-1,1-bis (hydroxymethyl) ethyl] amino] carbonyl] amino] ethyl] benzyl] -4-methylphenyl] -D-glucitol (7. 9 mg, 0.0104 mmol) in methanol (600 μL), 2.5 wt. % Sodium methoxide methanol solution (34 μL, 0.015 mmol) was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol) to obtain the title compound (3.0 mg, 52%) as a colorless amorphous.

  Compounds 37 to 188 were synthesized in the same manner as in Example 11-2 by using the corresponding amine.

Further, using ethylenediamine or N- methyl-1,3-propanediamine as a raw material in the same manner as in Example 11-2, in compound (III), R ^B is substituted with an amino group or an N- methylamino group A compound that is an alkyl group can be synthesized.

Example 189
(1S) -1,5-Anhydro-1- [5- [4- [2-[(4S) -4- (cyclohexylmethyl) -2,5-dioxoimidazolidin-1-yl] ethyl] benzyl] Of 2-hydroxy-4-methylphenyl] -D-glucitol

The title compound (5 mg, 29%) was obtained as a colorless oily compound in the same manner as in Example 11-2, using 3-cyclohexyl-L-alanine methyl ester hydrochloride instead of tris (hydroxymethyl) aminomethane. It was.
1H NMR (600 MHz, METHANOL-d ₃ ) δ ppm 0.81-1.00 (m, 2 H) 1.31 (br. S., 3 H) 1.38-1.47 (m, 1 H) 1.48-1.55 (m, 1 H) 1.56-1.78 (m, 4 H) 2.05 (s, 3 H) 2.83 (t, J = 7.34 Hz, 2 H) 3.28-3.33 (m, 2 H) 3.35-3.43 (m, 2 H) 3.46 (t, J = 8.71 Hz, 1 H) 3.54 (t, J = 9.17 Hz, 1 H) 3.57-3.71 (m, 3 H) 3.81-3.88 (m, 3 H) 3.96 (dd, J = 9.40, 4.36 Hz, 1 H) 4.50 (d, J = 10.09 Hz, 1 H) 6.60 (s, 1 H) 7.00 (d, 2 H) 7.04 (d, 2 H) 7.08 (d, J = 5.96 Hz, 1 H).
ESI m / z = 605 (M + Na). 581 (MH).

  Compounds 190 to 202 were synthesized in the same manner as in Example 189 by using the corresponding amino acid.

  Formulation examples

Manufacturing Method The drug 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 tableting granules obtained using a rotary tableting machine are compression-molded and tableted.

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 6.

  Table 7 shows the sugar uptake inhibition rate relative to the control group when the test compound concentration is 100 nM.

Test example 2
Test for confirming inhibitory effect on blood glucose level in streptozotocin diabetic model rats (1) Preparation of diabetic model rats 7-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 diabetic model rats. Similarly, under ether anesthesia, 1.25 mmol / L citrate physiological saline 1 mL / kg was administered into the tail vein to prepare 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 results are shown in Table 8.

  According to the present invention, SGLT1 (sodium-dependent glucose cotransporter 1) expressed in the small intestinal epithelium and SGLT2 (sodium-dependent glucose cotransporter 2) expressed in the kidney are inhibited, and glucose from the digestive tract is inhibited. It is possible to provide a prophylactic or therapeutic agent for diabetes containing a C-phenyl glucitol compound having both absorption inhibition and urinary glucose excretion as an active ingredient, and is expected to help diabetic medical promotion. The

Claims (16)

A prophylactic or therapeutic agent for diabetes comprising a C-phenyl glycitol compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

In formula (I),
R ¹ and R ² are the same or different and each represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom.
R ³ represents a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom.
Y represents a C _1-6 alkylene group, —O— (CH ₂ ) n — (n represents an integer of 1 to 4) or a C _2-6 alkenylene group. However, when Z shown below represents —NHC (═NH) NH ₂ or —NHCON (R ^B ) R ^C , n is not 1.
Z is —CONHR ^A , —NHC (═NH) NH ₂ , —NHCON (R ^B ) R ^C ,

Or

Indicates.
However,
R ^A represents a C _1-6 alkyl group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group, an amino group and a carbamoyl group.
R ^B is (a) a hydrogen atom, (b) a C _1-6 alkyl group which may be substituted with 1 to 3 groups selected from group A described later, (c) a hydroxyl group and a C _1-6 hydroxyalkyl group. A C _3-12 cycloalkyl group _optionally substituted with 1 to 3 groups selected from: (d) “O, N, S, SO ₂ , CO and NR ¹⁰ (wherein R ¹⁰ is a hydrogen atom) , C _1-6 alkyl group, phenyl C _1-6 alkyl group or C _2-6 alkoxycarbonyl group, the same shall apply hereinafter in this section.) 1 to 3 elements selected from the group consisting of 1 to 3 selected from the group consisting of “C _3-12 heterocycloalkyl group” or “O, N, S, SO ₂ , CO and NR ¹⁰ (wherein R ¹⁰ has the same meaning as described above). element to include in the ring, a may be partially saturated C _5-13 heteroaryl group ", said C _3-12 heterocycloalkyl And C _5-13 heteroaryl groups, with 1-3 substituents selected from the group consisting of hydroxyl and C _1-6 hydroxyalkyl groups may be substituted, or even saturated (e) partially A good C _6-13 aryl group, wherein the aryl group is a hydroxyl group and “a C _1-6 alkyl group, a phenyl C _1-6 alkyl group and a C _1-6 alkylsulfonyl group which may be substituted with a hydroxyl group”. It may be substituted with 1 or 2 groups selected from the group consisting of
However, group A means a halogen atom, a hydroxyl group, a “C _1-6 alkoxy group which may be substituted with a hydroxyl group”, a carboxyl group, a C _2-6 alkoxycarbonyl group, a carbamoyl group, an amino group, a C _1-6 alkyl. Amino group, di-C _1-6 alkylamino group, C _2-6 acylamino group, “C _1-6 alkylthio group optionally substituted with a hydroxyl group”, phenoxy group, 1 to 3 groups selected from group B described later in substituted and also a phenyl group (group B, a hydroxyl group, a halogen atom, C _1-6 alkoxy group "may be substituted with a hydroxyl C _1-6 alkyl group", C _1-6 alkylthio group, a thienyl group, a "hydroxyl group or a C _1-6 hydroxyalkyl may phenylthio group optionally substituted with a group", or "hydroxyl group or a C _1-6 hydroxyalkyl may piperidino group optionally substituted with a group".), "a hydroxyl group Fine C _1-6 1 to 3 amino which may be substituted with group C _3-12 cycloalkyl group selected from the group consisting of hydroxyalkyl group "," O, N, S , from SO _2, CO and NR ¹⁰ A C _3-12 heterocycloalkyl group containing 1 to 3 elements selected from the group consisting of “O, N, S, SO ₂ , CO and NR ¹⁰ , wherein R ¹⁰ is are synonymous.) includes within the ring 1-3 elements selected from the group consisting of a may be partially saturated C _5-13 heteroaryl group ", said C _3-12 heterocycloalkyl The group and the C _5-13 heteroaryl group may be substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group and a C _1-6 hydroxyalkyl group, or —CONR ^B1 R ^B2 (wherein R ^B1 and R ^B2 is O together with the nitrogen atom, it may also comprise N or S C _5-6 heterocycloalkyl group form And, said C _5-6 heterocycloalkyl group, may be substituted with a hydroxyl C _1-6 alkyl group, one or selected from the group consisting of C _2-6 alkoxycarbonyl group and a phenyl C _1-6 alkyl group It may be substituted with two groups.
R ^C may be substituted with one or two groups selected from the group consisting of a hydrogen atom, “hydroxyl group, di-C _1-6 alkylamino group, C _2-6 alkoxycarbonyl group and C _1-6 alkoxy group”. “A good C _1-6 alkyl group” or “C _3-12 cycloalkyl group _optionally substituted with a hydroxyl group” is shown. Or
R ^B and R ^C together with the adjacent nitrogen atom are C _3-12 hetero groups containing one or two elements selected from “O, N, NR ¹¹ , S, SO ₂ and CO in the ring. A cycloalkyl group, or together with an adjacent nitrogen atom, contains one or two elements selected from “O, N, NR ¹¹ , S, SO ₂ and CO in the ring and is partially saturated. _May form a C _5-13 heteroaryl group, and the C _3-12 heterocycloalkyl group and heteroaryl group may be a hydroxyl group, a C _2-6 alkoxycarbonyl group, a carbamoyl group, a C _2-6 acyl (C _{1 -6} alkyl) amino group, di-C _1-6 alkylaminocarbonyl group, pyrrolidinyl group, morpholino group, pyrrolidin-1-ylcarbonyl group, "hydroxyl group, pyrrolidin-1-yl group, phenyl group and C _2-6 alkoxycarbonyl" Consist of More 1-3 which may be substituted with a C _1-6 alkyl group "and" C _1-6 alkyl group selected, one to three selected from the group consisting of C _1-6 alkoxy group and a halogen atom It may be substituted with one or two groups selected from the group consisting of a phenyl group which may be substituted with a group.
R ¹¹ is a hydrogen atom, a C _2-6 acyl group, a “phenyl group optionally substituted with a hydroxyl group”, a pyridyl group, a furylcarbonyl group, an oxolanylcarbonyl group, a C _2-6 alkoxycarbonyl group, or "hydroxyl, phenyl, di-C _1-6 alkylamino group, one or two C _1-6 alkyl group optionally substituted with a group selected from the group consisting of a morpholino group and pyrrolidine-1-yl group ".
R ^D consists of a hydrogen atom, or a “hydroxyl group, a C _3-12 cycloalkyl group, a phenyl group optionally substituted with a hydroxyl group, a pyridyl group, a C _2-6 alkoxycarbonyl group, an imidazolyl group, and a 1-benzylimidazolyl group. A C _1-6 alkyl group which may be substituted with 1 or 2 groups selected from the group ";
R ^DA represents a hydrogen atom or a C _1-6 alkyl group. A prophylactic or therapeutic agent for diabetes comprising a C-phenyl glycitol compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

However, in formula (II), R ¹ , R ² , R ³ , Y and Z are as defined in claim 1. The C-phenyl glycitol according to claim 2, wherein R ¹ is a hydrogen atom, a hydroxyl group, a C _1-4 alkyl group or a C _1-6 alkoxy group, and R ² is a C _1-4 alkyl group or a halogen atom. A prophylactic or therapeutic agent for diabetes comprising a compound or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. Diabetes comprising the C-phenyl glycitol compound according to claim 2 or 3 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, wherein R ³ is a hydrogen atom. Preventive or therapeutic agent. Y is a C _1-6 alkylene group or —O— (CH ₂ ) n— (n represents an integer of 2 to 4), and Z is —NHCON (R ^B ) R ^C (wherein R ^B and R ^C is as defined in claim 1.) The C-phenyl glycitol compound of claim 3 or 4 or a pharmaceutically acceptable salt thereof or a hydrate thereof is an active ingredient. A preventive or therapeutic agent for diabetes, characterized by comprising Y is a C _1-6 alkylene group or —O— (CH ₂ ) n — (n represents an integer of 2 to 4), and Z is —NHCON (R ^B ) R ^C.
However,
R ^B is (a) a C _1-6 alkyl group which may be substituted with 1 to 3 groups selected from the group A described later; (b) 1 to 3 selected from a hydroxyl group and a C _1-6 hydroxyalkyl group; number of good C _3-12 cycloalkyl group optionally substituted with a group, (c) "O, N , S in and NR ¹⁰ (wherein, R ¹⁰ is a hydrogen atom, C _1-6 alkyl, phenyl C _{1 -6} alkyl group or C _2-6 alkoxycarbonyl group, the same shall apply hereinafter in this section)), or a C _3-12 heterocycloalkyl group containing 1 to 3 elements selected from the group consisting of "O, N, 1-3 elements selected from the group consisting of S and NR ¹⁰ wherein in the ring, partially may be saturated C _5-13 heteroaryl group, said C _3-12 The cycloalkyl group and the C _5-13 heteroaryl group are selected from the group consisting of a hydroxyl group and a C _1-6 hydroxyalkyl group. A C _6-13 aryl group which may be substituted with 1 to 3 groups, or (d) may be partially saturated, the aryl group may be substituted with a hydroxyl group as well as “hydroxyl group” It may be substituted with one or two groups selected from the group consisting of a C _1-6 alkyl group, a phenyl C _1-6 alkyl group, and a C _1-6 alkylsulfonyl group.
However, the group A means a halogen atom, a hydroxyl group, a “C _1-6 alkoxy group which may be substituted with a hydroxyl group”, a C _2-6 alkoxycarbonyl group, a carbamoyl group, a diC _1-6 alkylamino group, a “hydroxyl group”. C _1-6 alkylthio group which may be substituted with, phenoxy group, thienyl group, benzothienyl group, furyl group, “hydroxyl group, halogen atom, C _1-6 alkoxy group, C _{1- 6} alkyl group, C _1-6 alkylthio group, the group consisting of a hydroxyl group or a C _1-6 hydroxyalkyl may phenylthio group optionally substituted with a group, and a hydroxyl group or a C _1-6 hydroxyalkyl may piperidino group optionally substituted with a group may be substituted with 1-3 optionally substituted phenyl group with a group "," 1 to 3 groups selected from the group consisting of hydroxyl and C _1-6 hydroxyalkyl group more selected C _{3- 12} A cycloalkyl group "," O, N, a C _3-12 heterocycloalkyl group containing 1-3 elements selected from the group consisting of S and NR ¹⁰ in a ring, said heterocycloalkyl group, a hydroxyl group And 1 to 3 groups selected from the group consisting of C _1-6 hydroxyalkyl groups, or a 4-C _1-6 alkylpiperazin-1-ylcarbonyl group.
R ^C is a hydrogen atom. Or
R ^B and R ^C, substituted with adjacent with the nitrogen atom together "pyrrolidinyl group, or a di-C _1-6 alkylamino group or pyrrolidin-1 may be substituted with-yl group C _1-6 alkyl group C-phenyl glycitol compound or a pharmaceutically acceptable salt thereof or a hydration thereof according to claim 3 or 4, which forms a piperidine group ", a thiomorpholine group, or a decahydroisoquinoline group, which may be substituted. A preventive or therapeutic agent for diabetes, comprising a product as an active ingredient. Y is a C _1-6 alkylene group, and Z is —CONHR ^A (wherein 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 a carbamoyl group) The C-phenyl glycitol compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as an active ingredient. A prophylactic or therapeutic agent for diabetes. The C-phenyl glycitol compound or the pharmaceutically acceptable compound thereof according to any one of claims 2 to 4, wherein Y is a C _1-6 alkylene group, and Z is -NHC (= NH) NH _2. Or a hydrate thereof as an active ingredient. A preventive or therapeutic agent for diabetes. Y is a C _1-6 alkylene group,
Z is

Wherein R ^D is a C _1-6 alkyl group substituted with a C _3-12 cycloalkyl group or a phenyl group, and R ^DA is a hydrogen atom or a C _1-6 alkyl group. Diabetes prevention comprising the C-phenyl glycitol compound according to any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. Or a therapeutic agent. A preventive or therapeutic agent for diabetes comprising a compound represented by the following formula (III) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

In the formula (III), Y is a C _1-6 alkylene group, and Z is —CONHR ^A (wherein R ^A is substituted with 1 to 3 groups selected from the group consisting of “hydroxyl group and carbamoyl group”. C _1-6 alkyl group ”. A prophylactic or therapeutic agent for diabetes comprising a C-phenyl glucitol compound represented by the following formula (IV) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

In formula (IV),
Y is a C _1-6 alkylene group,
Z is —CONHR ^A1 , —NHC (═NH) NH ₂ , or —NHCOR ^B1 .
However,
R ^A1 is “a C _1-6 alkyl group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group, an amino group, and a carbamoyl group”;
R ^B1 is, "may be substituted with 1 to 3 hydroxyl groups or 4-C _1-6 alkyl-1-yl carbonyl group C _1-6 alkylamino group", or 4-C _1-6 alkyl piperazine It is a -1-yl group. Y is a C _1-6 alkylene group,
Z is —CONHR ^A1 , —NHC (═NH) NH ₂ , or

(Wherein R ^A1 is a C _1-6 alkyl group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group, an amino group, and a carbamoyl group). A prophylactic or therapeutic agent for diabetes comprising a phenyl glucitol compound or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. Y is a C _1-6 alkylene group, and Z is —CONHR ^A1 (wherein R ^A1 is a C _1-6 substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group, an amino group, and a carbamoyl group) It is an alkyl group.) The C-phenyl glycitol compound according to claim 11 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. Prophylactic or therapeutic agent. The C-phenyl glycitol compound or a pharmaceutically acceptable salt thereof or a water thereof according to claim 11, wherein Y is a C _1-6 alkylene group and Z is —NHC (═NH) NH _2. A prophylactic or therapeutic agent for diabetes, comprising a Japanese product as an active ingredient. Y is a C _1-6 alkylene group, and Z is —NHCOR ^B1 (wherein R ^B1 is a C group substituted with 1 to 3 hydroxyl groups or a 4-C _1-6 alkylpiperazin-1-ylcarbonyl group. . _1-6 alkylamino group, or a 4-C _1-6 alkyl-1-yl group), according to claim 11 wherein C- phenyl Gurishito - le compound or a pharmaceutically acceptable salt thereof Or the preventive or therapeutic agent of diabetes characterized by containing those hydrates as an active ingredient. Y is a C _1-6 alkylene group and Z is

A prophylactic or therapeutic agent for diabetes comprising the C-phenyl glycitol compound according to claim 11 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.