HK1112239B

HK1112239B - 1-thio-d-glucitol derivatives

Info

Publication number: HK1112239B
Application number: HK08107451.9A
Authority: HK
Inventors: 浩行柿沼; 优子桥本; 隆宏大井; 仁美高桥
Original assignee: 大正制药株式会社
Priority date: 2005-01-07
Filing date: 2006-01-10
Publication date: 2012-11-16

Abstract

It is intended to provide a 1-thio-D-glucitol compound represented by the following formula which shows an effect of inhibiting the activity of SGLT2, a pharmaceutically acceptable salt thereof or a hydrate thereof; and a drug containing such a compound as the active ingredient, in particular, a preventive or a remedy for diabetes, diabetes-associated diseases or diabetic complications. It is also intended to provide a method of producing the 1-thio-D-glucitol compound and an intermediate thereof.

Description

1-thio-D-glucitol derivatives

Technical Field

The present invention relates to a 1-thio-D-glucitol derivative that inhibits the activity of sodium-dependent glucose co-transporter 2(SGLT2) involved in the reabsorption of glucose in the kidney.

Background

It is generally considered that chronic hyperglycemia lowers insulin secretion and at the same time lowers insulin sensitivity, which further causes elevation of blood glucose and worsens diabetes. Hyperglycemia is considered to be a major risk factor for diabetic complications. Therefore, it is considered that maintaining a normal blood glucose level can improve insulin sensitivity and suppress the onset of diabetic complications. Heretofore, biguanide drugs, sulfonylurea drugs, glycosidase inhibitors, insulin resistance improvers, and the like have been used as diabetes therapeutic agents. However, biguanide drugs have been reported to have a side effect of lactic acidosis, sulfonylurea drugs have a side effect of hypoglycemia, and glycosidase inhibitors have side effects of diarrhea and severe liver dysfunction. Therefore, development of a novel therapeutic agent for diabetes, which has a different action mechanism from the conventional one, is expected.

Phlorizin, a glucose derivative isolated from natural substances, inhibits reabsorption of excess glucose in the kidney, promotes excretion of glucose, and has a hypoglycemic effect (non-patent documents 1 and 2). Then, it was clarified that glucose was reabsorbed by sodium-dependent glucose co-transporter 2(SGLT2) present in the renal proximal tubule S1 segment (non-patent document 3). It is known that administration of phlorizin, an SGLT 2-specific inhibitor for diabetic rats, promotes excretion of sugar into urine and exerts an action of lowering blood sugar, and therefore, it is considered that SGLT 2-specific inhibitors are target molecules of novel therapeutic drugs for diabetes.

Under these circumstances, many phlorizin-related compounds have been studied, and O-aryl glucosides have been disclosed (patent documents 1 to 11). However, when O-aryl glucoside is administered orally, the glycosidic bond is hydrolyzed by β -glucosidase present in the small intestine, and the absorption efficiency of the unchanged body is poor, so that a prodrug has been developed.

Further, a compound in which O-aryl glucoside is converted into chemically stable C-aryl glucoside has been reported (patent document 12). Also reported are compounds in which a glucose moiety is directly bonded to an aryl or heteroaryl group in the same manner as described above (patent documents 13 to 15). However, the compound C-aryl glucoside disclosed in the above-mentioned documents (patent documents 12 to 15) is generally amorphous, and therefore has a problem in terms of formulation (patent document 12). For this purpose, it is necessary to crystallize the compound together with an appropriate amino acid such as phenylalanine or proline (U.S. Pat. No. 4,6774112). Therefore, a compound which has excellent crystallinity, is easy to purify, store and formulate into a pharmaceutical preparation, and is easy to handle as a pharmaceutical is required.

Further, a method for producing an aryl 5-thio- β -D-glucopyranoside (O-aryl 5-thio- β -glucoside) or heteroaryl 5-thio- β -D-glucopyranoside (O-heteroaryl 5-thio- β -glucoside) derivative by bonding 5-thioglucose and an aryl or heteroaryl group by β -glycosidic bond has been reported (patent documents 16 to 17). SGLT inhibitory activity of the above compounds has also been reported (patent documents 18 to 19). However, it is known from the above report (patent document 16) that the reaction characteristics of glucosylation are completely different depending on the kind of sugar, and the reaction conditions under which glucosylation can be carried out with glucose cannot be applied to thioglucose.

Therefore, there is no method for producing a 1-thio-D-glucitol derivative in which 5-thioglucose and an aryl group or a heterocycle are directly bonded, and there is no report on a 1-thio-D-glucitol derivative. Several compounds disclosed in patent documents 1 to 15 have already been clinically tested and may become new therapeutic drugs for diabetes in the future, but development thereof may be difficult for any reason in human clinical tests, and therefore, there is still a need for a group of compounds having a novel skeleton which does not exist at present even though the mechanism of action is the same.

Non-patent document 1: rossetti, L., et al.J.Clin.invest., vol.80, 1037, 1987

Non-patent document 2: rossetti, L., et al.J.Clin.invest., volume 79, item 1510, 1987

Non-patent document 3: kanai, y., et al, j.clin.invest., volume 93, 397, 1994

Patent document 1: european patent application publication No. 0850948

Patent document 2: european patent application publication No. 0598359

Patent document 3: international publication No. WO01/068660

Patent document 4: international publication No. WO01/016147

Patent document 5: international publication No. WO01/074834

Patent document 6: international publication No. WO01/074835

Patent document 7: international publication No. WO02/053573

Patent document 8: international publication No. WO02/068439

Patent document 9: international publication No. WO02/068440

Patent document 10: international publication No. WO02/036602

Patent document 11: international publication No. WO02/088157

Patent document 12: international publication No. WO01/027128

Patent document 13: U.S. patent application publication No. 2001/0041674 specification

Patent document 14: international publication No. WO04/013118

Patent document 15: international publication No. WO04/080990

Patent document 16: international publication No. WO04/014930

Patent document 17: international publication No. WO04/089966

Patent document 18: international publication No. WO04/014931

Patent document 19: international publication No. WO04/089967

Disclosure of Invention

The purpose of the present invention is to provide a novel 1-thio-D-glucitol compound which is not present at present and which inhibits the activity of a sodium-dependent glucose co-transporter (SGLT2) involved in the reabsorption of glucose in the kidney, promotes the excretion of urine glucose, and has a hypoglycemic effect. It is also an object of the present invention to provide excellent selective inhibitors of SGLT2 activity. It is another object of the present invention to provide a compound which has excellent crystallinity, can be easily purified, stored and formulated into a pharmaceutical preparation, and can be easily handled as a pharmaceutical. Further, the present invention aims to provide a process for producing a 1-thio-D-glucitol compound and an intermediate thereof.

The present inventors have conducted extensive studies to solve the above problems, and as a result, have found a production method in which an aryl group or a heterocyclic ring is directly bonded to 5-thio-glucose, and have found that a 1-thio-D-glucitol derivative obtained by this method has an excellent SGLT2 inhibitory activity, thereby completing the present invention. Further, the 1-thio-D-glucitol derivative of the present invention is excellent in crystallinity, so that it does not require cocrystallization with an amino acid or the like, can be easily purified, stored, and formulated, and is suitable for handling as a pharmaceutical product.

The following describes a scheme of the 1-thio-D-glucitol derivative of the present invention (hereinafter referred to as "the compound of the present invention").

One of the schemes of the invention is

A1-thio-D-glucitol compound represented by the following formula I, a pharmaceutically acceptable salt thereof, or a hydrate of either.

[ in the formula, R¹、R²、R³And R⁴Are identical to each otherOr different, represents a hydrogen atom, C_1-6Alkyl, -CO₂R^a2、-COR^b1Or may be selected from halogen atoms, -NO₂And C substituted with 1 or more substituents of OMe_7-12Aralkyl group (in the formula, R^a2Is represented by C_1-6Alkyl radical, R^b1Is represented by C_1-6Alkyl radical, C_7-10Aralkyl or phenyl. ),

a represents- (CH)₂)n-、-CONH(CH₂)n-、-NHCO(CH₂) n-, -O-, -S-, -NH-or- (CH)₂) And nCH ═ CH- (wherein n represents an integer of 0 to 3. ),

Ar¹represents an arylene, heteroarylene or heterocycloalkylene group,

Ar²represents aryl, heteroaryl or heterocycloalkyl,

R⁵、R⁶、R⁷、R⁸、R⁹and R¹⁰Identical or different, represent

(i) A hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C which may be substituted with 1 or more substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-8An alkyl group, a carboxyl group,

(v)-(CH₂) m-Q { wherein m represents an integer of 0 to 4, Q represents-CHO or-NH₂、-NO₂、-CN、-CO₂H、-SO₃H、-OR^c1、-CO₂R^a3、-CONH₂、-CONHR^a4、-CONR^a5R^a5、-COR^d1、-OCOR^d2、-SR^e1、-SOR^e2、-SO₂R^e3、-NHC(＝O)H、-NHCOR^d3、-NHCO₂R^d4、-NHCONH₂、-NHSO₂R^e4、-NHR^a6or-NR^a7R^a7(in the formula, R^a3、R^a4、R^a5、R^a6And R^a7Is represented by C_1-6Alkyl radical, R^c1Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^d1、R^d2、R^d3And R^d4Is represented by C_1-6Alkyl radical, C_7-10Aralkyl, phenyl or C_3-7Cycloalkyl radical, R^e1、R^e2、R^e3And R^e4Is represented by C_1-6Alkyl, phenyl or tolyl. ). },

(vi)-O-(CH₂) m '-Q' { wherein m 'represents an integer of 1 to 4, and Q' represents a hydroxyl group or-CO₂H、-OR^c2、-CO₂R^a8、-CONH₂、-CONHR^a9、-CONR^a10R^a10、-NH₂、-NHR^a11、-NR^a12R^a12or-NHCO₂R^d5(in the formula, R^a8、R^a9、R^a10、R^a11And R^a12Is represented by C_1-6Alkyl radical, R^c2Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^d5Is represented by C_1-6Alkyl radical, C_7-10Aralkyl, phenyl or C_3-7A cycloalkyl group. ). },

(vii)-OR^f{ formula (II) wherein R^fRepresents a group which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a13(in the formula, R^a13Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_3-7Cycloalkyl radicals which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a14(in the formula, R^a14Is represented by C_1-6An alkyl group. ) The aryl group substituted with 1 or more substituents selected from the group consisting of a halogen atom, a hydroxyl group and C_1-6Alkyl and-OR^a15(in the formula, R^a15Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group,

or may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a16(in the formula, R^a16Is represented by C_1-6An alkyl group. ) And (3) heterocycloalkyl substituted with 1 or more substituents. },

(viii)-NHR^g{ formula (II) wherein R^gRepresents a group which may be selected from halogen atomsHydroxy, C_1-6Alkyl and-OR^a17(in the formula, R^a17Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group. },

(ix) may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a18(in the formula, R^a18Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_3-7A cycloalkyl group,

(x) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a19(in the formula, R^a19Is represented by C_1-6An alkyl group. ) Aryl substituted with 1 or more substituents in (1),

(xi) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a20(in the formula, R^a20Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group,

(xii) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a21(in the formula, R^a21Is represented by C_1-6An alkyl group. ) Heteroaryl substituted with 1 or more substituents in (1),

(xiii) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a22(in the formula, R^a22Is represented by C_1-6An alkyl group. ) A heterocycloalkyl group substituted with 1 or more substituents in (1),

(xiv)C_2-6alkenyl, or

(xv)C_2-6Alkynyl.]

Other scheme of the invention is

A1-thio-D-glucitol compound represented by the following formula I A, a pharmaceutically acceptable salt thereof, or a hydrate of either.

[ in the formula, R¹、R²、R³And R⁴The same or different represent a hydrogen atom, C_1-6Alkyl, -CO₂R^a2、-COR^b1Or may be selected from halogen atoms, -NO₂And C substituted with 1 or more substituents of OMe_7-12Aralkyl group (in the formula, R^a2Is represented by C_1-6Alkyl radical, R^b1Is represented by C_1-6Alkyl radical, C_7-10Aralkyl or phenyl. ),

a represents- (CH)₂)n-、-CONH(CH₂)n-、-NHCO(CH₂) n-, -O-, -S-, -NH-or- (CH)₂) nCH ═ CH- (wherein n represents an integer of 0 to 3),

Ar¹represents an arylene, heteroarylene or heterocycloalkylene group,

Ar²represents aryl, heteroaryl or heterocycloalkyl,

R⁵’、R⁶’、R⁷’、R⁸’、R⁹' and R¹⁰' same or different, mean

(v)-(CH₂) m-Q { wherein m represents an integer of 0 to 4, Q represents-CHO or-NH₂、-NO₂、-CN、-CO₂H、-SO₃H、-OR^c1、-CO₂R^a3、-CONH₂、-CONHR^a4、-CONR^a5R^a5、-COR^d1、-OCOR^d2、-SR^e1、-SOR^e2、-SO₂R^e3、-NHC(＝O)H、-NHCOR^d3、-NHCO₂R^d4、-NHCONH₂、-NHSO₂R^e4、-NHR^a6or-NR^a7R^a7(in the formula, wherein,R^a3、R^a4、R^a5、R^a6and R^a7Is represented by C_1-6Alkyl radical, R^c1Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^d1、R^d2、R^d3And R^d4Is represented by C_1-6Alkyl radical, C_7-10Aralkyl, phenyl or C_3-7Cycloalkyl radical, R^e1、R^e2、R^e3And R^e4Is represented by C_1-6Alkyl, phenyl or tolyl. ). },

(vi)-O-(CH₂) m '-Q' { wherein m 'represents an integer of 1 to 4, and Q' represents a hydroxyl group or-CO₂H、-OR^c2、-CO₂R^a8、-CONH₂、-CONHR^a9、-CONR^a10R^a10、-NH₂、 -NHR^a11、-NR^a12R^a12or-NHCO₂R^d5(in the formula, R^a8、R^a9、R^a10、R^a11And R^a12Is represented by C_1-6Alkyl radical, R^c2Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^d5Is represented by C_1-6Alkyl radical, C_7-10Aralkyl, phenyl or C_3-7A cycloalkyl group. ). },

(vii)-OR^f{ formula (II) wherein R^fRepresents a group which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a13(in the formula, R^a13Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_3-7Cycloalkyl radicals which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a14(in the formula, R^a14Is represented by C_1-6An alkyl group. ) Aryl substituted with 1 or more substituents selected from halogen atom, hydroxy group, C_1-6Alkyl and-OR^a15(in the formula, R^a15Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group. },

(viii)-NHR^g{ formula (II) wherein R^gRepresents a group which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl radicaland-OR^a17(in the formula, R^a17Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group. },

(xiii) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a22(in the formula, R^a22Is represented by C_1-6An alkyl group. ) And (3) heterocycloalkyl substituted with 1 or more substituents.]。

Embodiment 1 of the present invention is Ar in formula I or formula I A¹1-thio-D-glucitol compound which is an arylene group, or a pharmaceutically acceptable salt thereof, or a hydrate of either.

One of the above embodiments of the present invention is Ar in formula I or formula I A¹1-thio-D-glucitol compound which is phenylene or naphthylene, a pharmaceutically acceptable salt thereof, or a hydrate of either.

In another embodiment of the present invention, A is- (CH)₂)n-、-CONH(CH₂) n-, -O-or- (CH)₂) n CH ═ CH- (wherein, n is as defined in the specificationRepresents an integer of 0 to 3. ) The 1-thio-D-glucitol compound according to any one of the above, or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the salt.

In another embodiment of the present invention, A is-CH₂Any one of the above 1-thio-D-glucitol compounds or a pharmaceutically acceptable salt thereof or a hydrate of the compound.

Another embodiment of the present invention is Ar²Is phenyl, thienyl, benzo [ b ]]Thienyl, thieno [2, 3-b]Any one of the above 1-thio-D-glucitol compounds of thienyl, benzofuranyl, benzothiazolyl, indolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl or isoxazolyl, or a pharmaceutically acceptable salt thereof or a hydrate of the compound.

Embodiment 1 of the present invention particularly relates to

A1-thio-D-glucitol compound represented by the following formula II, a pharmaceutically acceptable salt thereof, or a hydrate of either (hereinafter referred to as "embodiment (1)").

R^A、R^B、R^Cand R^DAt least one of them represents a hydrogen atom, and others are the same or different and represent

(i) Hydrogen atom, (ii) halogenAtom, (iii) hydroxyl group, (iv) C which may be substituted with 1 or more substituents selected from halogen atom and hydroxyl group_1-8An alkyl group, a carboxyl group,

(v)-(CH₂)m-Q^A{ wherein m represents an integer of 0 to 4, and Q^Arepresents-NH₂、-CO₂H、-OR^c1、-CO₂R^a3、-CONH₂、-CONHR^a4、-CONR^a5R^a5、-COR^d1、-OCOR^d2、-SR^e1、-SOR^e2、-SO₂R^e3、-NHC(＝O)H、-NHCOR^d3、-NHCO₂R^d4、-NHCONH₂、-NHSO₂R^e4、-NHR^a6or-NR^a7R^a7(in the formula, R^a3、R^a4、R^a5、R^a6And R^a7Is represented by C_1-6Alkyl radical, R^c1Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^d1、R^d2、R^d3And R^d4Is represented by C_1-6Alkyl radical, C_7-10Aralkyl, phenyl or C_3-7Cycloalkyl radical, R^e1、R^e2、R^e3And R^e4Is represented by C_1-6Alkyl, phenyl or tolyl. ). },

(vii)-OR^f{ formula (II) wherein R^fRepresents a compound which may be selected from among halogen atomsSeed, hydroxy group, C_1-6Alkyl and-OR^a13(in the formula, R^a13Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_3-7Cycloalkyl radicals which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a14(in the formula, R^a14Is represented by C_1-6An alkyl group. ) Aryl substituted with 1 or more substituents in (1),

may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a15(in the formula, R^a15Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group. },

(viii)-NHR^g{ formula (II) wherein R^gRepresents a group which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a17(in the formula, R^a17Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group. },

(ix) may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a19(in the formula, R^a19Is represented by C_1-6An alkyl group. ) Aryl substituted with 1 or more substituents in (A), or

(x) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a22(in the formula, R^a22Is represented by C_1-6An alkyl group. ) A heterocycloalkyl group substituted with 1 or more substituents in (1),

R^E、R^Fand R^GIdentical or different, represent

(vii)-OR^f{ formula (II) wherein R^fRepresents a group which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a13(in the formula, R^a13Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_3-7Cycloalkyl radicals which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a14(in the formula, R^a14Is represented by C_1-6An alkyl group. ) Aryl substituted with 1 or more substituents in (1),

may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a15(in the formula, R^a15Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10Aralkyl, or may be selected from halogen atoms, hydroxy, C_1-6Alkyl and-OR^a16(in the formula, R^a16Is represented by C_1-6An alkyl group. ) And (3) heterocycloalkyl substituted with 1 or more substituents. },

(xiv)C_2-6alkenyl, or

(xv)C_2-6Alkynyl.]。

Another embodiment of the present invention is a 1-thio-D-glucitol compound represented by the formula II wherein,

R^Aand R^CRepresents a hydrogen atom, and is represented by,

R^Brepresents a hydrogen atom, a halogen atom, a hydroxyl group, C_1-8An alkyl group, a carboxyl group,

-O-(CH₂) m '-Q' { wherein m 'represents an integer of 1 to 4, and Q' represents a hydroxyl group or-CO₂H、-OR^c2、-CO₂R^a8、-CONH₂、-CONHR^a9、-CONR^a10R^a10、-NH₂、-NHR^a11、-NR^a12R^a12or-NHCO₂R^d5(in the formula, R^a8、R^a9、R^a10、R^a11And R^a12Is represented by C_1-6Alkyl radical, R^c2Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^d5Is represented by C_1-6Alkyl radical, C_7-10Aralkyl, phenyl or C_3-7A cycloalkyl group. ). Either alone or

-OR^f1{ formula (II) wherein R^f1Represents C which may be substituted by halogen atoms_1-6Alkyl, or may be selected from halogen atoms, hydroxy, C_1-6Alkyl and-OR^a15(in the formula, R^a15Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group. },

R^Drepresents a hydrogen atom, a halogen atom, a hydroxyl group, C_1-8Alkyl OR-OR^f2{ formula (II) wherein R^f2Represents C which may be substituted by halogen atoms_1-6Alkyl, or may be selected from halogen atoms, hydroxy, C_1-6Alkyl and-OR^a15(in the formula, R^a15Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group. },

R^Eand R^FThe same or different represent a hydrogen atom, a halogen atom, C_1-8Alkyl OR-OR^c3{ formula (II) wherein R^c3Represents C which may be substituted by halogen atoms_1-6An alkyl group. },

R^Grepresents (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, or (iv) C which may be substituted with 1 or more substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-8An alkyl group, a carboxyl group,

(vi)-O-(CH₂) m '-Q' { wherein m 'represents an integer of 1 to 4, and Q' represents a hydroxyl group or-CO₂H、-OR^c2、-CO₂R^a8、-CONH₂、-CONHR^a9、-CONR^a10R^a10、-NH₂、-NHR^a11、 -NR^a12R^a12or-NHCO₂R^d5(in the formula, R^a8、R^a9、R^a10、R^a11And R^a12Is represented by C_1-6Alkyl radical, R^c2Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^d5Is represented by C_1-6Alkyl radical, C_7-10Aralkyl, phenyl or C_3-7A cycloalkyl group. ). },

(vii)-OR^f{ formula (II) wherein R^fRepresents a group which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a13(in the formula, R^a13Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_3-7Cycloalkyl radicals which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a14(in the formula, R^a14Is represented by C_1-6An alkyl group. ) The aryl group substituted with 1 or more substituents selected from the group consisting of a halogen atom, a hydroxyl group and C_1-6Alkyl and-OR^a15(in the formula, R^a15Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10Aralkyl, or

May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a16(in the formula, R^a16Is represented by C_1-6An alkyl group. ) And (3) heterocycloalkyl substituted with 1 or more substituents. },

(x) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a19(in the formula, R^a19Is represented by C_1-6An alkyl group. )1 inAn aryl group substituted with the above substituent(s),

(xiii) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a22(in the formula, R^a22Is represented by C_1-6An alkyl group. ) And (3) heterocycloalkyl substituted with 1 or more substituents.

Still another embodiment of the present invention is the 1-thio-D-glucitol compound according to the embodiment (1) -1 or a pharmaceutically acceptable salt thereof or a hydrate thereof (hereinafter referred to as "embodiment (1) -2") wherein,

R^Brepresents a hydrogen atom, C_1-6Alkyl, -OR^f1{ formula (II) wherein R^f1Represents C which may be substituted by halogen atoms_1-6An alkyl group. ) Or a halogen atom,

R^Drepresents a hydrogen atom, a hydroxyl group, -OR^f1{ formula (II) wherein R^f1Represents C which may be substituted by halogen atoms_1-6Alkyl, or may be selected from halogen atoms, hydroxy, C_1-6Alkyl and-OR^a15(in the formula, R^a15Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group. }.

Still another embodiment of the present invention is a 1-thio-D-glucitol compound described in embodiment (1) -1 or embodiment (1) -2 of the present invention or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein,

R^Grepresents (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, and (iv) may be selectedC substituted by 1 or more substituents selected from halogen atoms and hydroxy groups_1-8An alkyl group, a carboxyl group,

(v)-CO₂H、(vi)-OR^c1、(vii)-CO₂R^a3、(viii)-CONH₂、(ix)-CONHR^a4、(x)-CONR^a5R^a5、(xi)-COR^d1、(xii)-OCOR^d2、(xiii)-SR^e1、(xiv)-SOR^e2、(xv)-SO₂R^e3、(xvi)-NHR^a6、(xvii)-NR^a7R^a7

(in the formula, R^a3、R^a4、R^a5、R^a6And R^a7Is represented by C_1-6Alkyl radical, R^c1Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^d1And R^d2Is represented by C_1-6Alkyl radical, C_7-10Aralkyl, phenyl or C_3-7Cycloalkyl radical, R^e1、R^e2And R^e3Is represented by C_1-6Alkyl, phenyl or tolyl. ),

(xviii)-O-(CH₂) m '-Q' { wherein m 'represents an integer of 1 to 4, and Q' represents a hydroxyl group or-CO₂H、-OR^c2、-CO₂R^a8、-CONH₂、-CONHR^a9、-CONR^a10R^a10、-NH₂、-NHR^a11or-NR^a12R^a12(in the formula, R^a8、R^a9、R^a10、R^a11And R^a12Is represented by C_1-6Alkyl radical, R^c2Represents C which may be substituted by halogen atoms_1-6An alkyl group. ). },

(xix)-OR^f{ formula (II) wherein R^fRepresents a group which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a13(in the formula, R^a13Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_3-7Cycloalkyl radicals which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a14(in the formula, R^a14Is represented by C_1-6An alkyl group. ) Aryl substituted by more than 1 substituent in (1)Radical, which may be chosen from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a15(in the formula, R^a15Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10Aralkyl, or may be selected from halogen atoms, hydroxy, C_1-6Alkyl and-OR^a16(in the formula, R^a16Is represented by C_1-6An alkyl group. ) And (3) heterocycloalkyl substituted with 1 or more substituents. },

(xx) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a19(in the formula, R^a19Is represented by C_1-6An alkyl group. ) Aryl substituted with 1 or more substituents in (1),

(xxi) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a20(in the formula, R^a20Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group,

(xxii) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a21(in the formula, R^a21Is represented by C_1-6An alkyl group. ) Heteroaryl substituted with 1 or more substituents in (1),

(xxiii) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a22(in the formula, R^a22Is represented by C_1-6An alkyl group. ) And (3) heterocycloalkyl substituted with 1 or more substituents.

(xix)-OR^f2{ formula (II) wherein R^f2Represents a group which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a13(in the formula, R^a13Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_3-7Cycloalkyl radicals, or

May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a16(in the formula, R^a16Is represented by C_1-6An alkyl group. ) And (3) heterocycloalkyl substituted with 1 or more substituents. Either alone or

(xx) May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a22(in the formula, R^a22Is represented by C_1-6An alkyl group. ) And (3) heterocycloalkyl substituted with 1 or more substituents.

Embodiment 1 of the present invention also particularly relates to

A1-thio-D-glucitol compound represented by the following formula III, a pharmaceutically acceptable salt thereof, or a hydrate of either (hereinafter referred to as "embodiment (2) of claim 1").

R^Hand R^IIdentical or different, represent

Hydrogen atom, halogen atom, hydroxyl group, C_1-8Alkyl, or

-OR^f1{ formula (II) wherein R^f1Represents C which may be substituted by halogen atoms_1-6Alkyl, or

Ar³is thienyl, benzo [ b]Thienyl, thieno [2, 3-b]Thienyl, benzofuranyl, benzothiazolyl, indolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl or isoxazolyl,

R^8aand R^9aThe same or different represent a hydrogen atom, a halogen atom, a hydroxyl group, C_1-8Alkyl OR-OR^c3(R^c3Represents C which may be substituted by halogen atoms_1-6An alkyl group),

R^10arepresents a hydrogen atom, may be selected from a halogen atom, a hydroxyl group, C_1-6Alkyl and-OR^a19(in the formula, R^a19Is represented by C_1-6An alkyl group. ) Aryl substituted with 1 or more substituents in (A), or

May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a21(in the formula, R^a21Is represented by C_1-6An alkyl group. ) Heteroaryl substituted with 1 or more substituents in (1).]。

Embodiment 2 of the present invention relates to Ar in formula I or formula I A¹1-thio-D-glucitol compound which is a heteroarylene group, or a pharmaceutically acceptable salt thereof, or a hydrate of either.

Embodiment 2 of the present invention also relates to the fact that A is- (CH)₂) n- (wherein n represents an integer of 0 to 3) or a pharmaceutically acceptable salt thereof, or a hydrate of the compound.

Embodiment 2 of the present invention relates to

A1-thio-D-glucitol compound represented by the following formula IV or a pharmaceutically acceptable salt thereof or a hydrate of either.

[ in the formula, R¹、R²、R³And R⁴The same or different represent a hydrogen atom, C_1-6Alkyl, -CO₂R^a2、-COR^b1Or may be selected from halogen atoms, -NO₂And 1 or more substituents in OMeSubstituted C_7-12Aralkyl group (in the formula, R^a2Is represented by C_1-6Alkyl radical, R^b1Is represented by C_1-6Alkyl radical, C_7-10Aralkyl or phenyl. ),

Ar⁴is thienylene, benzo [ b ]]A thienyl group or a pyridylene group, in which,

R^20aand R^21aThe same or different represent a hydrogen atom, a halogen atom, a hydroxyl group, C_1-8Alkyl OR-OR^c3(R^c3Represents C which may be substituted by halogen atoms_1-6An alkyl group),

R^Jand R^KThe same or different represent a hydrogen atom, a halogen atom, C_1-8Alkyl OR-OR^c3(R^c3Represents C which may be substituted by halogen atoms_1-6An alkyl group),

R^Lrepresents (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, or (iv) C which may be substituted with 1 or more substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-8Alkyl group, (v) -CO₂H、(vi)-OR^c1、(vii)-CO₂R^a3、(viii)-CONH₂、(ix)-CONHR^a4、(x)-CONR^a5R^a5、(xi)-COR^d1、(xii)-OCOR^d2、(xiii)-SR^e1、(xiv)-SOR^e2、(xv)-SO₂R^e3、(xvi)-NHR^a6、(xvii)-NR^a7R^a7

Another embodiment of the present invention relates to a 1-thio-D-glucitol compound represented by the formula IV wherein R is represented by the formula IV or a pharmaceutically acceptable salt thereof or a hydrate of the compound or the salt^LIs a hydrogen atom, a halogen atom, C_1-8Alkyl OR-OR^c3(R^c3Represents C which may be substituted by halogen atoms_1-6Alkyl groups).

The following is a pharmaceutical regimen of the compounds of the present invention.

One embodiment of the present invention is a pharmaceutical composition comprising any of the above 1-thio-D-glucitol compounds or pharmaceutically acceptable salts thereof or hydrates thereof.

Another embodiment of the present invention is an inhibitor of the activity of the sodium-dependent glucose co-transporter 2, which comprises any one of the above-mentioned 1-thio-D-glucitol compounds or pharmaceutically acceptable salts thereof or hydrates thereof.

Another embodiment of the present invention is an inhibitor of the activity of a sodium-dependent glucose co-transporter 2 which is a prophylactic or therapeutic agent for diabetes, a diabetes-related disease, or a diabetic complication, and which comprises any of the above-described 1-thio-D-glucitol compounds, pharmaceutically acceptable salts thereof, or hydrates thereof.

Another embodiment of the present invention is a pharmaceutical composition comprising any one of the 1-thio-D-glucitol compounds described above or a pharmaceutically acceptable salt thereof or a hydrate thereof and at least 1 drug selected from the group consisting of an insulin sensitizer, a glycosidase inhibitor, a biguanide drug, an insulin secretion stimulator, an insulin preparation, and a dipeptidyl peptidase IV inhibitor, wherein the insulin sensitizer is selected from the group consisting of a PPAR γ agonist, a PPAR α/γ agonist, a PPAR δ agonist, and a PPAR α/γ/δ agonist.

Another embodiment of the present invention is a pharmaceutical composition comprising any one of the 1-thio-D-glucitol compounds described above or a pharmaceutically acceptable salt thereof or a hydrate thereof and a compound selected from the group consisting of hydroxymethylglutaryl-coa reductase inhibitors, fibrates (fibrates) compounds, squalene synthase inhibitors, acetyl-coa: at least 1 of a cholesterol acyltransferase inhibitor, a low density lipoprotein receptor agonist, a microsomal triglyceride transfer protein inhibitor, and an appetite suppressant.

The following is a scheme of a preparation method of the compound of the present invention.

One embodiment of the present invention is a process for producing a 1-thio-D-glucitol compound represented by the following formula I or a pharmaceutically acceptable salt thereof or a hydrate of either,

the preparation method comprises the following steps: a step of adding more than 1 equivalent of Grignard reagent (Grignard reagent) represented by the formula IX to thiolactone (thiolactone) represented by the formula VIII to obtain a compound V according to the following scheme; a step of reducing the compound V; a step of deprotecting the obtained compound as required,

in the formula, R¹¹、R¹²、R¹³And R¹⁴Same or different, represent C_1-6Alkyl, -SiR^a1 ₃、-CH₂CH＝CH₂Or may be selected from halogen atoms, -NO₂And C substituted with more than one substituent of OMe_7-12Aralkyl group (in the formula, R^a1Is represented by C_1-6An alkyl group. ) X is a halogen atom, Ar¹、Ar²、R⁵、R⁶、R⁷、R⁸、R⁹And R¹⁰As defined above for formula I.

Another embodiment of the present invention is the above production method, wherein the step of adding the Grignard reagent represented by formula IX is a step of adding about 0.8 to about 1.2 equivalents of R to the thiolactone represented by formula VIII³⁰MgX(R³⁰Is represented by C_1-8Alkyl or C_3-7Cycloalkyl group, X represents a halogen atom), and then adding a Grignard reagent represented by the formula IX to obtain a compound V.

Another embodiment of the present invention is a process for producing a 1-thio-D-glucitol compound represented by the following formula I or a pharmaceutically acceptable salt thereof or a hydrate of either,

the preparation method comprises the following steps: a step (1) wherein a reagent represented by the formula XI is added to a compound represented by the formula X to obtain a compound XII; but when Y is a hydroxyl group, further reducing compound XII, and obtaining a compound wherein Y is hydrogen with beta-type stereoselectivity; and (3) deprotecting the compound obtained in (1) or (2) as required.

Wherein Y represents a hydrogen atom or a hydroxyl group (when Y is a hydrogen atom, the 1-position is in the S configuration),

R¹¹、R¹²、R¹³and R¹⁴Same or different, represent C_1-6Alkyl, -SiR^a1 ₃、-CH₂CH＝CH₂Or may be selected from halogen atoms, -NO₂And C substituted with more than one substituent of OMe_7-12Aralkyl group (in the formula, R^a1Is represented by C_1-6An alkyl group. ) Ar, Ar²、R⁸、R⁹And R¹⁰As defined above for formula I, R^A、R^B、R^CAnd R^DAs defined above for formula II.

Aa represents-CH (W) (CH)₂)n’-、-CONH(CH₂) n-or-CH ═ CH- (wherein W is a hydrogen atom or a hydroxyl group, n is an integer of 0 to 3, and n' represents an integer of 0 to 2. ),

ea is-CHO-, -CO₂H or-CH₂X，

Da represents- (CH)₂)n’Li、-(CH₂)n’MgX、-CH₂PPh₃ ⁺X^-、-CH₂PO(OR^a23)、-(CH₂)nNH₂or-SnBu₃(wherein X is a halogen atom, R^a23Is represented by C_1-6An alkyl group, n is an integer of 0 to 3, and n' represents an integer of 0 to 2. ).

However, when Ea is-CHO, Da is- (CH)₂)n’Li、-(CH₂)n’MgX、-CH₂PPh₃ ⁺X ^-or-CH₂PO(OR^a23) Reaction of reagent XI of (a) to give a reaction product in which Aa is-CH (W) (CH)₂) n' -or-CH ═ CH-of compounds XII,

ea is-CO₂H is, with Da, - (CH)₂)nNH₂Condensation of reagent XI of (a) to give (Aa is-CONH (CH)₂) A compound XII of the formula n-,

ea is-CH₂X is, with Da, is-SnBu₃By condensation of the reagent XI to give Aa is-CH₂Compound (XII) of (XII).

The following is a scheme of intermediates of the preparation process of the compounds of the present invention.

One embodiment of the present invention is a compound represented by the following formula XIII or a salt or hydrate thereof,

[ wherein Y represents a hydrogen atom or a hydroxyl group (when Y is a hydrogen atom, the 1-position is in the S configuration),

R²¹、R²²、R²³and R²⁴The same or different represent a hydrogen atom, C_1-6Alkyl, -SiR^a1 ₃、-CH₂CH＝CH₂、-CO₂R^a2、-COR^b1Or may be selected from halogen atoms, -NO₂And C substituted with more than one substituent of OMe_7-12Aralkyl group (in the formula, R^a1And R^a2Is represented by C_1-6Alkyl radical, R^b1Is represented by C_1-6Alkyl radical, C_7-10Aralkyl or phenyl. ). However, when Y is a hydrogen atom, R²¹、R²²、R²³And R²⁴Not simultaneously hydrogen atoms. Other symbols and the same as in formula I aboveThe meaning is the same.]. In the formula XIII, Y is a hydrogen atom or R²¹～R²⁴is-SiR^a1 ₃or-CH₂CH＝CH₂Compounds having other substituents are repeated as the above-mentioned compounds of the present invention because the compounds function not only as intermediates but also as final products and as active compounds or prodrugs thereof.

Another embodiment of the present invention is a compound represented by the following formula XIV or a salt thereof or a hydrate of either.

e represents-CHO, -CO₂H or-CO₂R^a24(in the formula, R^a24Is represented by C_1-6An alkyl group. ) -CH₂M^a(in the formula, M^aRepresents a hydroxyl group or a halogen atom. )1, 3-dioxolan-2-yl or 1, 3-dioxan-2-yl,

R²¹、R²²、R²³and R²⁴As defined in formula XIII above,

R^A、R^B、R^Cand R^DAs defined in formula II.]

Another embodiment of the present invention is a compound represented by the following formula XV or a salt thereof.

[ wherein Ar is⁵Is thienyl, benzo [ b]Thienyl, benzofuranyl, benzothiazolyl, pyridyl or phenyl,

G¹represents a halogen atom, and is a halogen atom,

G²represents a hydrogen atom or a hydroxyl group, G²' represents a hydrogen atom or with G²Together represent an oxo group,

G^3arepresents a hydrogen atom, a halogen atom, a hydroxyl group, C which may be substituted with 1 or more substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-8Alkyl, -SR^a25、-SOR^a25、-SO₂R^a25、-OR^h1(in the formula, R^a25Is represented by C_1-6Alkyl radical, R^h1Represents C which may be substituted by halogen atoms_1-6Alkyl or C_7-10An aralkyl group. ) May be selected from halogen atom, hydroxyl group, C_1-6Alkyl and-OR^a19(in the formula, R^a19Is represented by C_1-6An alkyl group. ) Aryl substituted with 1 or more substituents in (A), or

May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a21(in the formula, R^a21Is represented by C_1-6An alkyl group. ) Heteroaryl substituted with 1 or more substituents in (1),

G^3band G^3cThe same or different represent a hydrogen atom, a halogen atom, a hydroxyl group, C_1-8Alkyl OR-OR^c3(in the formula, R^c3Represents C which may be substituted by halogen atoms_1-6An alkyl group. ),

G⁴represents C which may be substituted by halogen atoms_1-6Alkyl or halogen atoms, R^h2Represents C which may be substituted by halogen atoms_1-6Alkyl or C_7-10An aralkyl group.]。

Detailed Description

The present invention will be described in detail below, but the present invention is not limited to the examples.

The definitions and examples of terms used in the present invention are intended to be illustrative of the present specification and claims, and are not intended to be limiting.

The "aryl group" includes monocyclic or fused-ring aromatic hydrocarbon groups having 6 to 15 carbon atoms, and examples thereof include phenyl groups, naphthyl groups (including 1-naphthyl group and 2-naphthyl group), pentalenyl groups, indenyl groups, indanyl groups, azulenyl groups, heptalenyl groups, and fluorenyl groups. Preferably phenyl, naphthyl, indenyl, indanyl (2, 3-indanyl) or azulenyl, more preferably naphthyl, phenyl.

The "heteroaryl" is a monocyclic or fused aromatic heterocyclic group containing 1 or more heteroatoms selected from O, S and N. When the aromatic heterocyclic group is a condensed ring, the condensed ring may have a monocyclic ring which is partially hydrogenated. Examples of the heteroaryl group include pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, (1, 2, 3-) and (1, 2, 4-) triazolyl, tetrazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzo [ b ] thienyl, thieno [2, 3-b ] thienyl, (1, 2) -and (1, 3) -benzoxazolyl (benzoxathiol) yl, benzopyranyl (chromenyl), 2-oxobenzopyranyl, benzothiadiazolyl, quinolizinyl, 2, 3-naphthyridinyl, 1, 5-naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl.

The "heterocycloalkyl group" refers to a heterocycloalkyl group having 3 to 12 atoms and containing 1 or more heteroatoms selected from O, S and N, and for example, refers to a cyclic amino group having 1 or more nitrogen atoms, and optionally 1 or more oxygen atoms and sulfur atoms in the ring. Examples of the heterocycloalkyl group include a morpholinyl group, a piperidinyl group, a piperazinyl group, a 1-pyrrolidinyl group and an aza groupBase (azepin)yl), thiomorpholinyl, oxolanyl (oxolanyl), oxocyclohexyl (oxolanyl), dioxolanyl, dioxacyclohexyl.

By "arylene" is meant a 2-valent aromatic ring group bonded on one side to the 5-thiosugar residue and on the other side to the-A-. Examples of the arylene group include a phenylene group, a naphthylene group (including a 1-naphthylene group and a 2-naphthylene group), a pentalenylene group, an indenyl group, an indanylene group, an azulenylene group, a heptalenylene group, and a fluorenyl group. Preferred is a phenylene group, a naphthylene group, an indenyl group, an indanylene group or an azulenylene group, and more preferred is a naphthylene group or a phenylene group.

The term "heteroarylene" refers to a 2-valent aromatic heterocyclic group having one side bonded to a 5-thiosugar residue and the other side bonded to-A-. Examples of the heteroarylene group include a pyrazolyl group, a thiazolyl group, an isothiazolylene group, a thiadiazolylene group, an imidazolyl group, a furanylene group, a thienyl group, an oxazolylene group, an isoxazolylene group, a pyrrolylene group, an imidazolyl group, a triazolylene group, (1, 2, 3-) and (1, 2, 4-) a triazolylene group, a tetrazolylene group, a pyranyl group, a pyridyl group, a pyrimidylene group, a pyrazinylene group, a pyridazinylene group, a quinolylene group, an isoquinolylene group, a benzofuranylene group, an isobenzofuranylene group, an indolyl group, an isoindolylene group, an indazolylene group, a benzimidazolylene group, a benzotriazolylene group, a benzoxazolyl group, a benzothiazolyl group, a benzo [ b ] thienyl group, a benzopyran 2-oxobenzopyran group, a benzothiadiazolylene group, a quinolizylene group, a 2, 3-naphthyrylene group, 1, 5-naphthyridinylene, quinoxalinylene, quinazolinylene, cinnolinylene, carbazolyl.

By "heterocycloalkylene" is meant a heterocycloalkyl group of valency 2, bonded on one side to the 5-thiosugar residue and on the other side to the group-A-. Examples of the aforementioned heterocycloalkylene group include a morpholinylene group, a piperidylene group, a piperazinyl group, a pyrrolidinylene group, and an azalene groupRadicals (azepinylene), thiomorpholino radicals, oxacyclopentylene radicals, oxylene radicalsHeterocyclohexyl, dioxolene, dioxacyclohexylene.

In addition, compounds of the invention according to Ar¹In different classes, 3 substituents R are present⁵、R⁶、R⁷And not both bonded to the group.

So-called "C_1-6The "alkyl" represents a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a n-pentyl group, a tert-pentyl group, a 3-methylbutyl group, a neopentyl group and a n-hexyl group.

So-called "C_2-6The alkenyl group "represents a linear or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms and a double bond, and examples thereof include a vinyl group, a propenyl group, and a butenyl group.

So-called "C_2-6The alkynyl group "represents a linear or branched aliphatic hydrocarbon group having a triple bond and having 2 to 6 carbon atoms, and examples thereof include an ethynyl group, a propynyl group, and a butynyl group.

Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

So-called "C_7-10Aralkyl "represents an arylalkyl group having 7 to 10 carbon atoms, and examples thereof include benzyl and phenethyl.

R¹～R⁴、R¹¹～R¹⁴And R²¹～R²⁴C in the definition "may be substituted_7-12"aralkyl" means a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms, C_7-12The substituents of the aralkyl radicals being selected from halogen atoms, -NO₂And 1 or more substituents in OMe. Preferred substituents are chlorine atoms, -NO₂or-OMe. As substituted C_7-12Examples of the aralkyl group include a 4-methoxybenzyl group, a3, 4-dimethoxybenzyl group, a 4-chlorobenzyl group and a 4-nitrobenzyl group.

By "C which may be substituted_1-8The "alkyl group" represents a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms. C_1-8The substituent of the alkyl group is 1 or more substituents selected from a halogen atom and a hydroxyl group. The number of substitution of the halogen atom is preferably 1 to 6, more preferably 1 to 4, and the preferred halogen atoms are chlorine atom and fluorine atom, more preferably fluorine atom. The number of generations of hydroxyl groups is preferably 1 to 6, more preferably 1 to 3. As substituted C_1-8Examples of the alkyl group include a trifluoromethyl group, a difluoromethyl group, a 1, 1, 1-trifluoroethyl group, a 1, 1, 1-trifluoropropyl group, a 1, 1, 1-trifluorobutyl group, a 1, 3-difluoropropan-2-yl group, a hydroxymethyl group, a hydroxyethyl group (e.g., a 1-hydroxyethyl group), a hydroxypropyl group, and a hydroxybutyl group. Trifluoromethyl, difluoromethyl, 1, 1, 1-trifluoroethyl, 1, 3-difluoropropan-2-yl, hydroxymethyl, and hydroxyethyl are preferred, and trifluoromethyl, difluoromethyl, 1, 1, 1-trifluoroethyl, hydroxymethyl, and hydroxyethyl are more preferred.

So-called "C_3-7Cycloalkyl "represents a cyclic alkyl group having 3 to 7 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more preferred is cyclopropyl, cyclobutyl.

By C "which may be substituted by halogen atoms_1-6The "alkyl group" represents a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms. The number of substitution of the halogen atom is 1 or more. The number of substitution of the halogen atom is preferably 1 to 6, more preferably 1 to 4, and the preferred halogen atoms are chlorine atom and fluorine atom, more preferably fluorine atom. As substituted C_1-6Examples of the alkyl group include a trifluoromethyl group, a difluoromethyl group and a 1, 1, 1-trifluoroethyl group.

By "C which may be substituted_3-7The cycloalkyl group means a substituted or unsubstituted cycloalkyl group having 3 to 7 carbon atoms. The substituents in the cycloalkyl group being selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a13(OR-OR)^a18)(R^a13And R^a18Is C_1-6Alkyl) 1 or more substituents.

The "aryl group which may be substituted" means a substituted or unsubstituted aryl group. The substituents in the aryl group being selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a14(OR-OR)^a19)(R^a14And R^a19Is C_1-6Alkyl) 1 or more substituents. Preferred substituents are halogen atoms, hydroxy groups, C_1-4Alkyl, methoxy and ethoxy. Examples of the substituted aryl group include a 4-chlorophenyl group, a 4-fluorophenyl group, a 4-hydroxyphenyl group and a 4-methoxyphenyl group.

By "C which may be substituted_7-10The "aralkyl group" means an aralkyl group having 7 to 10 carbon atoms which may be substituted or unsubstituted. The substituents in the aralkyl group being selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a15(OR-OR)^a17OR-OR^a20)(R^a15、R^a17And R^a20Is C_1-6Alkyl) 1 or more substituents. Preferred substituents are halogen atoms, hydroxy groups, C_1-4Alkyl, methoxy and ethoxy. As substituted C_7-10Examples of the aralkyl group include a 4-methoxybenzyl group, a3, 4-dimethoxybenzyl group, a 4-chlorobenzyl group and a 4-chlorophenethyl group.

By "heteroaryl which may be substituted" is meant substituted or unsubstituted heteroaryl. The substituents in the heteroaryl group being selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a21(R^a21Is C_1-6Alkyl) 1 or more substituents. Preferred substituents are halogen atoms, C_1-4Alkyl, methoxy and ethoxy groups, and methyl and ethyl groups are more preferred. Examples of the substituted heteroaryl group include a 4-methylthiazol-2-yl group, a 2-methylpyridin-5-yl group, a 1-methylpyrazol-4-yl group, a 1-ethylpyrazol-4-yl group, a 1-methylpyrrolyl group, a 2-methylimidazolyl group and a 4-methoxyindolyl group.

The term "heterocycloalkyl group which may be substituted" means a substituted or unsubstituted heterocycloalkyl group. The substituents in the heterocycloalkyl group being selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a16(OR-OR)^a22)(R^a16And R^a22Is C_1-6Alkyl) 1 or more substituents. Preferred substituents are halogen atoms and C_1-4The alkyl group is preferably a methyl group or an ethyl group. Examples of the substituted heterocycloalkyl group include a 4-methylpiperazin-1-yl group and a 4-ethylpiperazin-1-yl group.

The term "pharmaceutically acceptable salt" refers to a salt with an alkali metal, an alkaline earth metal, ammonium, alkylammonium or the like, or a salt with an inorganic or organic acid, and examples thereof include a sodium salt, a potassium salt, a calcium salt, an ammonium salt, an aluminum salt, a triethylammonium salt, an acetate, a propionate, a butyrate, a formate, a trifluoroacetate, a maleate, a tartrate, a citrate, a stearate, a succinate, an ethylsuccinate, a lactobionate, a gluconate, a glucoheptonate, a benzoate, a methanesulfonate, an ethanesulfonate, a 2-hydroxyethanesulfonate, a benzenesulfonate, a p-toluenesulfonate, a dodecylsulfate, a malate, an aspartate, a glutamate, an adipate, a salt with cysteine, a salt with N-acetylcysteine, a hydrochloride, a hydrobromide, a phosphate, a sulfate, a salt with an inorganic or organic acid, Hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, salts with acrylic polymers, salts with carboxyvinyl polymers.

The "salt" refers to a salt with an alkali metal, an alkaline earth metal, ammonium, alkylammonium or the like, a salt with an inorganic acid or an organic acid, and a salt other than a pharmaceutically acceptable salt is also included.

Since a part of the compounds and intermediates of the present invention has a chiral center, various diastereomers or enantiomers exist. Keto-enol tautomers also exist as part of the compounds and intermediates of the invention. In addition, geometric isomers (E configuration, Z configuration) also exist as part of the compounds and intermediates of the present invention. Thus, the compounds of the present invention and intermediates include all of the isomers described above and mixtures thereof.

As shown in the test examples below, the compound of the present invention can inhibit the activity of sodium-dependent glucose co-transporter (SGLT2) involved in the reabsorption of glucose in the kidney, and can provide a drug having an excellent prophylactic or therapeutic effect on diabetes, diabetes-related diseases, or diabetic complications.

As will be described in detail below, the compound of the present invention is excellent in crystallinity, easy to purify, store and formulate into a pharmaceutical preparation, and also excellent in handling as a pharmaceutical. Compounds of the invention which have particularly good crystallinity are those of the formulae I, IA, II, III and IV R¹～R⁴A compound which is hydrogen.

Most of conventional glucitol compounds are amorphous substances, and when they are formulated, it is necessary to co-crystallize the compounds with an appropriate amino acid such as phenylalanine or proline (U.S. Pat. No. 6774112). However, the compound of the present invention in which glucitol is changed to 1-thio-glucitol has good crystallinity, and therefore, it is not necessary to co-crystallize with an amino acid or the like.

For example, the glucitol compound Xa described in U.S. Pat. No. US6515117 is glassy and has poor crystallinity. However, the compound Xb of the present invention, which is 1-thio-glucitol, can be crystallized as a colorless powder having a melting point of 79.0 to 83.0 ℃.

The preferred embodiments of the present invention are as follows.

In formulae I and IA, A is preferably- (CH)₂) n- (wherein n is an integer of 0 to 3, preferably 1 or 2). ) -CONH (CH)₂) n- (wherein n is an integer of 0 to 3, preferably 0). ) Or- (CH)₂) And nCH ═ CH- (wherein n is an integer of 0 to 3, preferably n ═ 0 or 1. ) and-O-.

A is preferably-CH₂-。

In the case of the formulae I and IA,A-Ar²the preferred bonding position of (b) is the meta position relative to the thiosugar.

Preferred embodiments of the compounds of formula II of the present invention are shown below.

In the formula (II), R^AAnd R^CPreferably a hydrogen atom.

R^BPreferably a hydrogen atom, a halogen atom, a hydroxyl group, C_1-8Alkyl, or

-O-(CH₂) m ' -Q ' { wherein m ' represents an integer of 1 to 4, preferably 1. Q' represents hydroxy, -CO₂H、-OR^c2、-CO₂R^a8、-CONH₂、-CONHR^a9、-CONR^a10R^a10、-NH₂、-NHR^a11、-NR^a12R^a12or-NHCO₂R^d5(in the formula, R^a8、R^a9、R^a10、R^a11And R^a12Is represented by C_1-6Alkyl radical, R^c2Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^d5Is represented by C_1-6Alkyl radical, C_7-10Aralkyl, phenyl or C_3-7A cycloalkyl group. ). Either alone or

-OR^f1{ formula (II) wherein R^f1Represents C which may be substituted by halogen atoms_1-6Alkyl, or may be selected from halogen atoms, hydroxy, C_1-6Alkyl and-OR^a15(in the formula, R^a15Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group. }

Wherein R is^BPreferably a hydrogen atom, C_1-6Alkyl, halogen atom, C_1-6Alkoxy, -O-CH₂-Q '[ wherein Q' represents-CO₂H or-CO₂R^a8(R^a8The same as defined above), particularly preferably a methyl group, a chlorine atom or a methoxy group.

R^DPreferably a hydrogen atom, a halogen atom, a hydroxyl group, C_1-8Alkyl, -OR^f2{ formula (II)In, R^f2Represents C which may be substituted by halogen atoms_1-6Alkyl, or may be selected from halogen atoms, hydroxy, C_1-6Alkyl and-OR^a15(in the formula, R^a15Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_7-10An aralkyl group. }.

Wherein R is^DPreferably a hydrogen atom, a hydroxyl group, C_1-6Alkoxy, particularly preferably hydroxy or methoxy.

R^EAnd R^FThe same or different, preferably a hydrogen atom, a halogen atom, C_1-8Alkyl, -OR^c3(R^c3Represents C which may be substituted by halogen atoms_1-6An alkyl group. ).

Wherein R is^EAnd R^FPreferably a hydrogen atom or a fluorine atom.

R^GPreferably a hydrogen atom, a halogen atom, a hydroxyl group, C which may be substituted with 1 or more substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-8An alkyl group.

Among them, preferred is a halogen atom, a hydroxyl group, C which may be substituted with 1 or more substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-8An alkyl group. Particularly preferred are methyl, ethyl, isopropyl and hydroxymethyl.

R^GOther preferred group of (A) is-CO₂H、-OR^c1、-CO₂R^a3、-CONH₂、-CONHR^a4、-CONR^a5R^a5、-COR^d1、-OCOR^d2、-SR^e1、-SOR^e2、-SO₂R^e3、-NHR^a6or-NR^a7R^a7(in the formula, R^a3、R^a4、R^a5、R^a6And R^a7Is represented by C_1-6Alkyl radical, R^c1Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^d1And R^d2Is represented by C_1-6Alkyl radical, C_7-10Aralkyl, phenyl or C_3-7Cycloalkyl radical, R^e1、R^e2AndR^e3is represented by C_1-6Alkyl, phenyl or tolyl. ).

Among them, preferred is-CO₂H、-OR^c1、-CO₂R^a3、-SR^e1and-NR^a7R^a7(R^c1、R^a3、R^e1、R^a7As defined above. ) Particularly preferred are methoxy, ethoxy, isopropoxy, methylthio, -CO₂Me。

R^GOther preferred group of (a) is-O- (CH)₂) m ' -Q ' { wherein m ' represents an integer of 1 to 4, preferably 1 or 2. Q' represents hydroxy, -CO₂H、-OR^c2、-CO₂R^a8、-CONH₂、-CONHR^a9、-CONR^a10R^a10、-NH₂、-NHR^a11or-NR^a12R^a12(in the formula, R^a8、R^a9、R^a10、R^a11、R^a12Is represented by C_1-6Alkyl radical, R^c2Represents C which may be substituted by halogen atoms_1-6An alkyl group. ). }.

Among them, preferred is-O-CH₂CO₂Me、-O-CH₂CO₂H、-O-CH₂CONMe₂、-O-CH₂CH₂OH、-O-CH₂CH₂NMe₂。

R^GOther preferred groups of (A) are-OR^f2{ formula (II) wherein R^f2Represents a group which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a13(in the formula, R^a13Is represented by C_1-6An alkyl group. ) C substituted by more than 1 substituent in (1)_3-7Cycloalkyl radicals, or

May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl radical andand-OR^a22(in the formula, R^a22Is represented by C_1-6An alkyl group. ) And (3) heterocycloalkyl substituted with 1 or more substituents.

Among them, preferred is-O-C_3-7Cycloalkyl, -O-heterocycloalkyl, particularly preferably tetrahydropyranyloxy, cyclopentyloxy, morpholinyl.

Preferred embodiments of the compounds of formula III of the present invention are shown below.

In the formula (III), Ar³Preferably thienyl, benzo [ b]Thienyl, thieno [2, 3-b]Thienyl, benzofuranyl, benzothiazolyl, indolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, or isoxazolyl.

Ar above³Substituents R on radicals^8a、R^9aAnd R^10aThe same or different, preferably hydrogen atom, halogen atom, hydroxyl group, C_1-8Alkyl radical, C_1-6An alkoxy group.

Ar³When it is thienyl, R^8a、R^9aAnd R^10aAt least one of which may be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a19(in the formula, R^a19Is represented by C_1-6An alkyl group. ) Aryl substituted with 1 or more substituents selected from halogen atom, hydroxy group, C_1-6Alkyl and-OR^a21(in the formula, R^a21Is represented by C_1-6An alkyl group. ) The heteroaryl group substituted with 1 or more substituents in (1) is preferably a hydrogen atom, a halogen atom or C_1-8Alkyl radical, C_1-6An alkoxy group.

Preferred embodiments of the compounds of formula IV of the present invention are described below.

In the formula (IV), Ar⁴Preferably thienylene, benzo [ b ]]Thienyl or pyridylene. Substituents R on the above radicals^20a、R^21a、R^JAnd R^KPreferably a hydrogen atom, a halogen atom, a hydroxyl group, C_1-8Alkyl radical, C_1-6An alkoxy group. In addition, R^LPreference is given to R in the formula (II)^GThe preferred groups of (2) are those listed above.

Preferred compounds of the present invention are specifically shown below.

(1S) -1, 5-anhydro-1- [3- (4-ethylbenzyl) phenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-ethoxybenzyl) phenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- [ (1-benzothien-2-yl) methyl ] -4-methoxyphenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (4-ethoxybenzyl) phenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-ethoxybenzyl) -4-methoxyphenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- [ (1-benzothien-2-yl) methyl ] -4-chlorophenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- [ (1-benzothien-2-yl) methyl ] phenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-ethoxybenzyl) -6-methoxy-phenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- [ (1-benzothien-2-yl) methyl ] -6-methoxyphenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-ethoxybenzyl) -6-hydroxyphenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [4, 6-dimethoxy-3- (4-ethoxybenzyl) phenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-ethoxybenzyl) -4-fluorophenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-ethoxybenzyl) -4-hydroxyphenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (2, 5-difluoro-4-ethoxybenzyl) phenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (3-fluoro-4-ethoxybenzyl) phenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (3-chloro-4-ethoxybenzyl) phenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-ethoxybenzyl) -4-methylphenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (3, 4-dimethoxybenzyl) phenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (4-methoxybenzyl) phenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-ethoxybenzyl) -6-methoxy-4-methylphenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-tert-butylbenzyl) -4-chlorophenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (2-fluoro-4-ethoxybenzyl) phenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- [ (1-benzothien-2-yl) methyl ] -4, 6-dimethoxyphenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (4-methylbenzyl) phenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (4-methylthiobenzyl) phenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (4-hydroxybenzyl) phenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (4-ethylbenzyl) phenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (4-isopropylbenzyl) phenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (4-ethoxy-methylbenzyl) phenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-ethoxybenzyl) -6-hydroxy-4-methylphenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [3- [ (1-benzofuran-2-yl) methyl ] -4-chlorophenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (4-ethoxybenzyl) -6-methoxyphenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-ethoxybenzyl) -4, 6-dihydroxyphenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-ethylbenzyl) -6-methoxy-4-methylphenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (4-ethylbenzyl) -6-methoxyphenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [ 4-chloro-3- (4-isopropylbenzyl) -6-methoxyphenyl ] -1-thioxo-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-methylbenzyl) -6-methoxy-4-methylphenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-1- [3- (4-isopropylbenzyl) -6-methoxy-4-methylphenyl ] -1-thio-D-glucitol

The intermediates of formula XV of the present invention are characterized by having the substituent-OR^h2By having such a substituent, the intermediate has an advantage of being excellent in yield and selectivity in synthesis as compared with a compound having no such substituent.

Specifically, in the method for producing an intermediate represented by formula XV (for example, scheme 8 below), FriThe yield of the del-Crafts reaction is high. In addition, when the target is, for example, Ar⁵In the case of the compound represented by formula XV in which the phenyl group is para-substituted with respect to the linking bond, only a para-substituted compound is formed, and a positional isomer (ortho-substituted compound) as a by-product is hardly formed.

In the intermediates of the formula XV according to the invention, G²' and G²Compounds representing together oxo (corresponding to Compound II o of scheme 8) and G²' and G²Many of the compounds which are hydrogen atoms (corresponding to compound II a in scheme 8) have good crystallinity, and can be easily recrystallized into colorless powder.

Preferred embodiments of the intermediate of formula XV of the present invention are described below.

Ar⁵When it is phenyl, G^3aPreferably a hydroxyl group, C which may be substituted with 1 or more substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-8Alkyl, -SR^a25、-SOR^a25、-SO₂R^a25OR-OR^h1(in the formula, R^a25Is represented by C_1-6Alkyl radical, R^h1Represents C which may be substituted by halogen atoms_1-6Alkyl or C_7-10An aralkyl group. ) Among them, C which may be substituted by a halogen atom is more preferable_1-8Alkyl, -SMe, -SOMe, -SO₂Me, C which may be substituted by halogen atoms_1-6Alkoxy or benzyloxy. In addition, G^3aThe substitution position(s) is preferably in the para position relative to the linking bond. The other symbols are as defined for formula XV, G^3bAnd G^3cThe same or different, hydrogen atom or fluorine atom is more preferable.

Ar⁵Is benzo [ b]Thienyl, benzofuranyl, benzothiazolyl or pyridyl, G^3a、G^3bAnd G^3cThe same or different, preferably hydrogen atom, halogen atom, hydroxyl group, C_1-8Alkyl or C_1-6An alkoxy group.

Ar⁵When it is thienyl, G^3aMay be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a19(in the formula, R^a19Is represented by C_1-6An alkyl group. ) Aryl substituted with 1 or more substituents in (A), or

May be selected from halogen atoms, hydroxy groups, C_1-6Alkyl and-OR^a21(in the formula, R^a21Is represented by C_1-6An alkyl group. ) Heteroaryl substituted by more than 1 substituent in (1), G^3bAnd G^3cThe same or different, preferably a hydrogen atom, a halogen atom, C_1-8Alkyl or C_1-6An alkoxy group.

Ar⁵Preferably phenyl.

The following are specific descriptions of various methods for producing the compounds of the present invention, but the methods are not limited to the examples. At present, it has been reported that D-glucitol derivatives can be synthesized as follows: d-glucitol derivatives are synthesized via C-arylglucopyranosides obtained by adding 1 equivalent of aryl lithium or an aryl Grignard reagent to gluconolactone derivatives (patent document 12). However, the 1-thio-glucitol of the present invention cannot be produced by the same method as described above. The present inventors have conducted intensive studies and, as a result, have found that 1-thio-glucitol can be produced by a method satisfying the conditions described below.

(Process for producing Compound of the present invention 1)

According to the method shown in schemes 1-3, the compound shown in formula I can be prepared by obtaining the compound shown in formula V from the compound (aglycone) shown in formula II A and the compound (thiolactone) shown in formula VIII, reducing the compound shown in formula V as shown in scheme 4, and deprotecting as required. The synthetic method of the compound (aglycon) shown in the formula II A is shown in a scheme 5-8, and the synthetic method of the compound (thiolactone) shown in the formula VIII is shown in a scheme 9.

Scheme 1: the aglycone forms a reaction with the carbon-carbon bond of the 5-thiosugar 1.

Scheme 1

(wherein X represents a halogen atom, particularly bromine, iodine or chlorine. Ar)¹Represents aryl, heteroaryl or heterocycloalkyl, and the other symbols are as defined above. )

As shown in scheme 1, thiolactone (compound VIII) is added to a Grignard reagent prepared from an aryl, heteroaryl or heterocycloalkyl halide (compound II A) and magnesium to provide compound V. Here, the amount of the grignard reagent added to the thiolactone is at least about 2 equivalents or more, and preferably about 2 equivalents to about 2.2 equivalents, in order to obtain about 1 equivalent of the target compound V. The reaction temperature in this case is preferably-20 ℃ to 25 ℃. Examples of the solvent used for preparing the grignard reagent include diethyl ether, tetrahydrofuran, and diglyme, and a catalytic amount of iodine or 1, 2-dibromoethane can be used as an additive. The reaction temperature in this case is 25 to 150 ℃ and preferably 40 to 100 ℃.

Aryl lithium, heteroaryl lithium or heterocycloalkyl lithium synthesized by reacting compound II A with a lithium reagent selected from n-butyl lithium, t-butyl lithium, 2, 4, 6-trimethylphenyl (mesityl) lithium (2, 4, 6-trimethylphenyl lithium) and the like at-78 ℃ to-20 ℃ is not reacted with compound VIII. However, magnesium bromide (MgBr) is added to the above-mentioned aryl lithium, heteroaryl lithium or heterocycloalkyl lithium₂) To form a Grignard reagent capable of reacting with compound VIII. The solvent used in this reaction may be diethyl ether or tetrahydrofuran, and the reaction temperature is preferably from-20 ℃ to 25 ℃.

Scheme 2: carbon-carbon bond formation reaction of aglycone with 5-thiosugar 2

Scheme 2

(wherein Ar is¹Represents an aryl group, a heteroaryl group,Heterocycloalkyl group, the other symbols being as defined above. )

As shown in scheme 2, compound V can also be synthesized by adding a metal halide such as copper (I) iodide or cesium chloride to aryl lithium, heteroaryl lithium or heterocycloalkyl lithium prepared by the same method as described above, and reacting the resulting complex with compound VIII by transmetallation to form a complex (compound II'). The reaction temperature in the preparation of the lithium reagent is preferably from-78 ℃ to-20 ℃, and the solvent used in the reaction includes diethyl ether, tetrahydrofuran, and the like. Then, the prepared lithium reagent was dropped into a suspension of copper iodide or cesium chloride and diethyl ether to prepare a complex II'. The reaction temperature is-78 deg.C-0 deg.C, preferably-25 deg.C-0 deg.C. Then, sultone VIII was added under the same conditions as in scheme 1, or complex II' was added to sultone VIII, whereby compound V could be obtained.

Scheme 3: the carbon-carbon bond formation reaction of the aglycone with the 5-thiosugar 3.

Scheme 3

(wherein Ar is¹Represents aryl, heteroaryl, heterocycloalkyl, R³⁰Is represented by C_1-8Alkyl or C_3-7Cycloalkyl, the other symbols being as defined above. )

In the process shown in scheme 3, the equivalent of compound il a necessary for the reaction can be reduced relative to thiolactone VIII. Taking advantage of the fact that thiolactone VIII does not react with 1 equivalent of Grignard reagent, first, about 0.8 to about 1.2 equivalents, preferably about 0.9 to about 1.0 equivalents, of R are added relative to thiolactone VIII³⁰MgX. As C at this time_1-8As the alkyl magnesium halide, isopropyl magnesium chloride, isopropyl magnesium bromide and tert-butyl magnesium chloride can be used. In addition, as C_3-7Examples of the cycloalkyl magnesium halide include cyclohexyl magnesium chloride. As solvent for useExamples thereof include diethyl ether and tetrahydrofuran. The reaction temperature is preferably-20 ℃ to 25 ℃. Then, Grignard reagent IX prepared using compound II A is added, together with the R initially added³⁰MgX does not react, but selectively reacts with IX to obtain a national standard compound V. The amount of the Grignard reagent IX can be adjusted depending on the amount of the target compound V to be required, and about 1 equivalent of the Grignard reagent IX can be sufficiently reacted in order to obtain about 1 equivalent of the target compound. In this case, the preferred solvent is diethyl ether or tetrahydrofuran, and the reaction temperature is preferably from-20 ℃ to 25 ℃.

The method can reduce the equivalent of the high-price compound IIA and can efficiently synthesize the 1-thio-glucitol.

Scheme 4: reduction reaction and deprotection reaction.

Scheme 4

(wherein the symbols are as defined above.)

As shown in scheme 4, compound V is reduced to stereoselectively synthesize compound XIII of the present invention in the β configuration. Et can be used as a reducing agent suitable for the reaction₃SiH、i-Pr₃SiH or Ph₂SiHCl as Lewis acid, BF may be mentioned₃·Et₂O、CF₃COOH、InCl₃And the like. Examples of the solvent include chloroform, dichloromethane, acetonitrile, ethyl acetate, diethyl ether, 1, 4-dioxane, tetrahydrofuran, and a mixed solvent thereof. In the reduction reaction, a by-product α body is produced at a ratio of several% to 15%, but the ratio of the by-product can be reduced by combining a reagent and a reaction solvent. As the reducing agent, Et is preferred₃SiH、i-Pr₃SiH, preferably Et₃SiH. As Lewis acid, BF is preferred₃·Et₂O、CF₃COOH, more preferably BF₃·Et₂And O. The reaction temperature is-60 DEG C-25 ℃, preferably-40 ℃ to 0 ℃. Among these, the selection of the solvent is important, and a mixed solvent of acetonitrile, acetonitrile-chloroform, acetonitrile-dichloromethane, or the like and acetonitrile is preferable.

from-OR of the compounds X III of the invention, by methods adapted to the type of substituent²¹～-OR²⁴In which R is removed²¹～R²⁴When the hydroxyl group is changed, I a of the present invention can be obtained.

For example, R²¹、R²²、R²³、R²⁴In the case of a benzyl group or a 4-methoxybenzyl group, the benzyl group can be removed by catalytic hydrogenation in a hydrogen atmosphere using a catalyst such as palladium activated carbon, palladium hydroxide, or platinum-palladium activated carbon. Examples of the solvent used in the reaction include methanol, ethanol, isopropanol, ethyl acetate, and acetic acid. Alternatively, BCl may be used₃、BCl₃·Me₂S、BBr₃、AlCl₃、 CF₃COOH, TfOH and other Lewis acids. Examples of the solvent used in the reaction include chloroform, dichloromethane, acetonitrile, diethyl ether, tetrahydrofuran, anisole, etc., and the reaction temperature may be from-78 ℃ to 40 ℃.

R²¹、R²²、R²³、R²⁴Is allyl (-CH)₂CH＝CH₂) When the catalyst is used, it may be isomerized (-CH ═ CHCH) by reaction with potassium tert-butoxide in dimethyl sulfoxide₃) After that, hydrochloric acid or HgCl is used₂the/HgO removed it. Pd (PPh) may be used in the presence of an organic acid such as acetic acid, p-toluenesulfonic acid hydrate, N' -dimethylbarbituric acid and the like₃)₄、PdCl₂And palladium activated carbon, etc. The solvent used in the reaction may be acetonitrile, diethyl ether, tetrahydrofuran, or the like, and the reaction temperature may be 25 to 100 ℃.

Scheme 5: method for the synthesis of the aglycone part 1.

Scheme 5

(wherein A' represents- (CH)₂) n '- (n' is an integer of 0 to 2), -CH ═ CH-, or-C ≡ C, Ar¹Represents aryl, heteroaryl or heterocycloalkyl, and the other symbols are as defined above. ).

In the compound II A as an intermediate, A is- (CH)₂) When n- (n is an integer of 1 to 3), the synthesis can be carried out by referring to International patent publication No. WO 0127128. Alternatively intermediate il d was prepared according to scheme 5.

Compound II a was formulated as a Grignard reagent using 1 equivalent of magnesium according to the method described above. Or compound II a is formulated into monoaryllithium using 1 equivalent of n-butyllithium or tert-butyllithium. Then, compound II c can be synthesized by adding commercially available compound II b to the grignard reagent or monoaryl lithium. The solvent used in the reaction may be diethyl ether or tetrahydrofuran, and the reaction temperature is preferably-78 to 25 ℃.

Next, compound IIc is reduced, for example, with Et in the presence of a Lewis acid₃SiH、i-Pr₃SiH or Ph₂SiHCl reacts to synthesize a compound II d. Examples of the Lewis acid used in the reaction include BF₃·Et₂O、CF₃COOH、InCl₃Examples of the solvent include chloroform, dichloromethane, acetonitrile, and a mixed solvent thereof, and preferably a mixed solvent of acetonitrile and acetonitrile such as acetonitrile-chloroform, acetonitrile-dichloromethane, and the like. The reaction temperature at this time is-60 ℃ to 25 ℃, preferably-30 ℃ to 25 ℃.

Scheme 6: method for the synthesis of the aglycone part 2.

Scheme 6

(wherein M represents-O-or-NH-, Ar¹Represents aryl, heteroaryl or heterocycloalkyl, and the other symbols are as defined above. )

Aryl boronic acids, heteroaryl boronic acids or heterocycloalkyl boronic acid derivatives II f can be coupled with compounds II e in the presence of a base using a palladium or copper catalyst to give compounds IIA where A is-O-or-NH-. The palladium catalyst includes, for example, Pd₂(OAc)₂、Pd(dba)₂(dba: dibenzylidene acetone), palladium activated charcoal, Pd (PPh)₃)₄Etc., as the copper catalyst, Cu (OAc) is preferable₂And the like. Examples of the base to be used include potassium tert-butoxide and Na₂CO₃、K₂CO₃KOH, pyridine, triethylamine, and the like. Examples of the solvent used in the reaction include chloroform, dichloromethane, N-dimethylformamide, tetrahydrofuran, dioxane, and dimethoxyethane.

Scheme 7: synthesis of aglycone part method 3.

Scheme 7

(wherein Ar is¹Represents aryl, heteroaryl or heterocycloalkyl, and the other symbols are as defined above. )

Friedel-Crafts reaction can be carried out using compound II g with II h to give compound II i. Examples of the Lewis acid used in this reaction include AlCl₃、CF₃COOH、EtAlCl₂Examples of the solvent include chloroform, dichloromethane, and toluene. The reaction temperature here is-30 ℃ to 60 ℃, preferably-15 ℃ to 25 ℃. Then, the compound II j can be obtained by the same method as the reduction shown in scheme 5. Further using bromine,And (3) regioselectively brominating the compound II j by sodium bromide, potassium bromide, hydrogen bromide or N-bromosuccinimide (NBS) to prepare the compound II A. As the solvent in this case, chloroform, dichloromethane, CF are preferable₃COOH, acetic acid, and the like. More preferably NBS-CF₃COOH-H₂SO₄A mixture of (a).

Scheme 8: synthesis of aglycone part method 4.

Scheme 8

(wherein Ar is¹The aryl, heteroaryl and other symbols are as defined above. )

For example, substituents R of starting materials II k or II n⁵And R⁹When both are alkoxy groups, if the reaction is carried out according to scheme 7, the site selectivity of bromination may be lowered, and the target product may not be efficiently obtained. In this case, as shown in scheme 8, it is preferable to perform halogenation in the first step, and then perform Friedel-Crafts reaction and reduction in order, since the compound II A can be produced in high yield. The reaction conditions for each reaction at this time were the same as in scheme 7.

Scheme 9: and (4) synthesizing thiolactone.

Scheme 9

(wherein the symbols are as defined above.)

Compound VIII can be synthesized by reference to Yuasa, h., et al.j.chem.soc.perkin trans.1, item 2763, 1990. Alternatively, compound VIII is synthesized according to scheme 9, described below.

The hydroxyl group at position 1 of compound IIIa (see International publication WO04/106352 for preparation) is protected with a protecting group which is resistant to basic conditions and deprotects under neutral or acidic conditions. For example, compound IIIb is synthesized by protecting the hydroxyl group with tetrahydropyranyl group using 3, 4-dihydro-2H-pyran (3, 4-DHP), p-toluenesulfonic acid 1 hydrate, pyridinium-toluenesulfonic acid (PPTS). Examples of the solvent used in this reaction include N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, chloroform, dichloromethane, toluene, and the like.

Next, the acetyl group of compound IIIb is removed. The acetyl group can be removed using a base such as sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, or triethylamine, and methanol, ethanol, aqueous methanol, or the like can be used as a solvent. Then, R can be reacted with an appropriate base¹¹-R¹⁴X, for example benzyl bromide, benzyl chloride, allyl bromide, methyl iodide, etc., acts to give compound IIIc. Examples of the base include triethylamine, N-ethyl-N, N-diisopropylamine, pyridine, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, etc., and potassium carbonate, calcium carbonate, cesium carbonate, and sodium hydride are preferable. Examples of the solvent used in the reaction include N, N-methylformamide, tetrahydrofuran, dioxane, dimethoxyethane, etc., and the reaction temperature is-20 to 25 ℃.

Next, the protecting group at position 1 of compound IIIc is removed to give compound IIId. For example, the THP group can be removed by treating compound IIIc with PPTS in methanol or ethanol. Finally, compound IIId can be treated with an appropriate oxidizing agent to produce thiolactone VIII. As the oxidizing agent used in the reaction, dimethyl sulfoxide-acetic anhydride, Dess-Martin periodinane (Dess-Martin periodinane), IBX and the like are preferable, and the reaction temperature is 0 to 40 ℃.

(Process for producing Compound of the present invention 2)

A of Compound I of the present invention is- (CH)₂) n- (n is an integer of 1 to 3)) Alternatively, the synthesis can be carried out by the method shown in scheme 10. Other preparation methods for the synthetic intermediate VA of scheme 10 are shown in scheme 11.

Scheme 10: a method 2 for preparing a compound shown as a formula I.

Scheme 10

(wherein Ar is¹Y represents a bromine atom in a compound II r, MgBr or Li in a compound II s, and the other symbols are as defined above. )

Commercially available compound II p was heated under reflux with ethylene glycol and p-toluenesulfonic acid 1 hydrate in toluene or benzene to give compound II q. The reaction time in this case is 1 to 24 hours, and a dehydration operation may be performed by a Dean-Stark apparatus or the like during heating. Then, after the grignard reagent of the compound II q was prepared in the same manner as described in the above preparation example 1, thiolactone VIII was added to obtain the compound IV a.

Next, one of the routes for preparing the compound I of the present invention from the compound IV a will be described. First, the ethylene acetal (ethyeneacetal) of compound IV a can be removed with an acid to give compound IV b. Examples of the acid used in this reaction include hydrochloric acid, p-toluenesulfonic acid 1 hydrate, acetic acid, perchloric acid, and Ph₃CBF₄Examples of the solvent include methanol, ethanol, acetone, dichloromethane, water, and a mixture thereof. The reaction temperature is preferably from 25 ℃ to 100 ℃.

Next, compound IV c can be synthesized by adding compound IV b to a grignard reagent or organolithium II s prepared from a commercially available bromine derivative II r by the same method as described in scheme 4 of the above preparation example 1. The solvent used in the reaction may be diethyl ether, tetrahydrofuran, dimethoxyethane or the like, and the reaction temperature is-78 to 25 ℃.

The hydroxyl group in compound IV c is reduced in the same manner as described in scheme 4 of preparation Process 1, thereby preparing Compound I of the present invention.

In addition, compounds I of the present invention can also be synthesized from compounds IV a using other routes. First, compound VA can be obtained by removing the glycolacetal group after reducing the thiosugar hydroxyl group of compound IV a. The reaction conditions are the same as in the above method. Next, compound VA is added to the grignard reagent or the organolithium IIs compound to obtain compound Vx. The compound Vx can then be reacted with Et in the presence of a Lewis acid₃SiH、i-Pr₃SiH or Ph₂SiHCl reacts, hydroxyl is reduced, and the compound I is synthesized. Examples of the Lewis acid used in the reaction include BF₃·Et₂O、CF₃COOH、InCl₃Examples of the solvent include chloroform, dichloromethane, acetonitrile, and a mixed solvent thereof, and preferably a mixed solvent of acetonitrile and acetonitrile such as acetonitrile-chloroform, acetonitrile-dichloromethane, and the like. The reaction temperature here is from-60 ℃ to 100 ℃ and preferably from-10 ℃ to 60 ℃.

Scheme 11: a synthetic method of an intermediate V A.

Scheme 11

(wherein Ar is¹Represents aryl or heteroaryl, and the other symbols are as defined above. )

Intermediate V A can be synthesized as shown in scheme 11 by treating compound V a with N-butyllithium and then adding N, N-dimethylformamide. The solvent used in the reaction may be tetrahydrofuran or ether, and the reaction temperature is preferably-78 to 25 ℃.

(Process for producing Compound of the present invention 3)

A of the Compound I of the invention is-CH₂-, in particular R⁸is-COR^dor-CO₂R^aWhen isocynatic, compound I can be synthesized using Stille coupling via compound V b as shown in scheme 12, or via intermediate IV f as shown in scheme 13 (Espinet, p., et al, angelw. chem. int.ed. engl. volume 43, item 4704, 2004, Stille, j.k., angelw.chem. int.ed. engl. volume 25, item 508, 1986).

Scheme 12: a method 3 for preparing a compound shown as a formula I.

Scheme 12

(wherein Ar is¹Represents an aryl group or a heteroaryl group, Y' represents a chlorine atom or a bromine atom, and the other symbols are as defined above. )

The grignard reagent was prepared by the method described in scheme 5 of preparation method 1 using 1 equivalent of magnesium and a commercially available compound II a. Or using i-PrMgCl-LiCl (Kitagawa, K., et al. Angew. chem. Int. Ed. Engl. 39, 2481, 2000, Knochel, P., et al. Angew. chem. Int. Ed. Engl. 43, 3333, 2004) to prepare an acid-based complex (atecomplex). Compound VIII can be added to the prepared reagent to give compound IV d. Then, the hydroxyl group of compound IV d can be reduced in the same manner as described in scheme 4 of production method 1 to produce compound Va. Then, Bu can be used₆Sn₂And compound Va was treated with a palladium catalyst to synthesize compound V b. The palladium catalyst used in this reaction may be Pd₂(OAc)₂、Pd(dba)₂、Pd(PPh₃)₄The solvent is preferably toluene, etc., and the reaction temperature is 60 ℃ to 120 ℃.

Next, compound Vb and the compound can be treated with a palladium catalystCompound II t, compound I of the invention. The palladium catalyst used in this reaction may be Pd₂(OAc)₂、Pd(dba)₂、Pd(PPh₃)₄、PdCl₂(PPh₃)₂Examples of the solvent include toluene, tetrahydrofuran, and N, N-dimethylformamide, and the reaction temperature is 40 to 120 ℃.

Scheme 13

As shown in scheme 13, Compound I of the present invention can be obtained by Stille coupling of intermediate IV f and organotin compound II z.

Intermediate IV f may be prepared as follows.

First, the hydroxyl group of compound IV b is reduced under the same conditions as in scheme 4 to give compound IV e. Then, by brominating the hydroxymethyl group of compound IV e, intermediate IV f can be obtained. As the bromination method in this case, PPh may be used₃-CBr₄Or PPh₃-a combination of N-bromosuccinimide. Alternatively, methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonyl chloride is sulfonated in the presence of a base and then brominated with NaBr or LiBr. Examples of the solvent used at this time include chloroform, dichloromethane, acetonitrile, diethyl ether, tetrahydrofuran, dioxane, etc., and the base is preferably Na₂CO₃、K₂CO₃KOH, pyridine, triethylamine, and the like.

(Process for producing Compound of the present invention 4)

A of Compound I of the present invention is- (CH)₂) When n "- (n" is an integer of 0 to 2), -O-, or-NH-, the formula may be usedCompound I was synthesized via Suzuki coupling of compound V c shown in scheme 14 (Bellina, f., equivalent.synthesis, vol 15, item 2419, 2004, Miyaura, n., et al, chem.rev., vol 95, item 2457, 1995).

Scheme 14: a method 4 for preparing a compound shown as a formula I.

Scheme 14

(wherein Ar is¹Represents aryl, heteroaryl, A 'is-O-or-NH-, A' represents a bond, -CH₂-or-CH ═ CH-, R^1kIs represented by C_1-6An alkyl group. Other symbols are as defined above. )

After addition of n-butyllithium to tetrahydrofuran, compound V a was reacted with tris (C)_1-6Alkoxy) boranes, B (OR)^1k) And (4) acting. The reaction temperature at this time is-78 ℃ to 25 ℃. Then treated with hydrochloric acid or the like to synthesize a boronic acid derivative Vc.

Next, compound Vc and compound II u can be treated with a palladium catalyst in the presence of an appropriate base to give compound I of the present invention. Examples of the solvent used in the reaction include dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran, N-dimethylformamide, dimethoxyethane/water, ethanol/water, toluene/ethanol, etc., and the base is preferably t-BuOK, Na₂CO₃、K₂CO₃KOH, pyridine, triethylamine, and the like. Examples of the palladium catalyst include palladium activated carbon and Pd₂(OAc)₂、Pd(dba)₂、Pd(PPh₃)₄、PdCl₂(PPh₃)₂And the like. When compound II u in which a' "is-CH ═ CH-is reacted, the reaction product can be changed to a compound in which a is-C by catalytic hydrogenation as shown in scheme 4 in preparation process 1₂H₄-a compound of formula I.

In addition, compound I (A is-O-or-NH-) of the present invention can also be obtained from compound V c and compound II v by the method shown in scheme 6 in preparation Process 1.

(Process for producing Compound of the present invention 5)

A of Compound I of the present invention represents-CONH (CH)₂)n-、-NHCO(CH₂) The compound n- (n is an integer of 0 to 3) can be produced by the method via intermediate V d shown in scheme 15 or the method via intermediate V f shown in scheme 16.

Scheme 15: a method 5 for preparing a compound shown as a formula I.

Scheme 15

By using the acid radical type complex i-PrBu which can be prepared from n-butyllithium and i-PrMgCl or i-PrMgBr₂MgLi, a treatment compound II y, may produce an organometallic reagent II aa. By adding it to thiolactone VIII, compound IV g can be obtained. Then, the carboxylic acid derivative V d can be synthesized by reducing the hydroxyl group under the same conditions as in scheme 4 and then hydrolyzing the tert-butyl ester with acid. Examples of the solvent used in this reaction include dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran, N-dimethylformamide, dimethoxyethane/water, ethanol/water, toluene/ethanol, etc., and examples of the acid include formic acid, hydrochloric acid, CF₃COOH, etc. The carboxylic acid derivative Vd can also be synthesized by treating compound Va with n-butyllithium and then bubbling carbon dioxide gas. The solvent used in the reaction may be tetrahydrofuran, diethyl ether or the like, and the reaction temperature is preferably-78 to 25 ℃.

Next, compound V d and amine II w may be dehydrocondensed to give compound I b of the present invention. The solvent used in this reaction is preferably chloroform, dichloromethane, N-dimethylformamide, etc., and the dehydration condensation agent is preferably N, N-bicyclic carbodiimide (DCC), N-ethyl-N' -3-dimethylaminopropylcarbodiimide hydrochloride (WSC), N-Carbonyldiimidazole (CDI), WSC/1-hydroxybenzotriazole 1 hydrate, etc. The reaction temperature at this time is 0 ℃ to 60 ℃.

Scheme 16: process 5' for the preparation of compounds of formula I.

Scheme 16

In scheme 16, compound V d and SOCl are reacted in a solvent₂Or (COCl)₂In action, the acid chloride of compound Vd is prepared. Examples of the solvent used in the reaction include chloroform and dichloromethane. In n-Bu₄In the presence of NBr, an amide derivative of compound V d is obtained by reacting NBr with sodium azide, and compound Ve is obtained by refluxing the amide derivative with t-butanol under heating. As the solvent used in this reaction, chloroform, toluene, and the like are preferable. Removal of the tert-butoxycarbonyl (Boc) group of compound V e by treatment with an appropriate acid gave compound V f. As the acid used in the reaction, hydrochloric acid and CF are preferred₃COOH, etc.

Next, the compound Vf and the carboxylic acid II x were dehydrated and condensed to obtain the compound I c of the present invention. The solvent used in this reaction is preferably chloroform, dichloromethane, N-dimethylformamide or the like, and the dehydration condensation agent is preferably N, N-bicyclic carbodiimide (DCC), N-ethyl-N' -3-dimethylaminopropylcarbodiimide hydrochloride (WSC), N-Carbonyldiimidazole (CDI), WSC/1-hydroxybenzotriazole 1 hydrate or the like. The reaction temperature at this time is 0 ℃ to 60 ℃.

In addition, the substituents R on the aryl, heteroaryl or heterocycloalkyl ring of the compounds of the invention⁵、R⁶、R⁷、R⁸、R⁹Or R¹⁰In the case of a hydroxyl group or an amino group, the substituent may be changed by alkylation or acylation. For example, an example of the case of a hydroxyl group is shown in scheme 17. The hydroxyl group can be reacted with methyl bromoacetate in the presence of a base to provide compound I d. Examples of the solvent used in this reaction include dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran, and N, N-dimethylformamide, and the base is preferably Na₂CO₃、K₂CO₃KOH, pyridine, triethylamine, and the like.

Next, the methoxycarbonyl group is hydrolyzed by a method known to those skilled in the art to become a carboxylic acid. The dehydration condensation compound I d and the primary or secondary amine may become an amide derivative. Alternatively, the carbonyl group of compound I d can be reduced to become an alcohol.

Scheme 17

The compounds of the present invention can block sodium-dependent glucose co-transporter 2(SGLT2) (j. clin. invest., volume 93, 397, 1994) associated with glucose reabsorption in the kidney.

The compound of the present invention can treat diabetes by blocking SGLT2, inhibiting sugar reabsorption, and excreting excess sugar to the outside of the body, and therefore, can correct hyperglycemia and improve insulin resistance without increasing the burden on pancreatic β cells.

Accordingly, the present invention provides a medicament for preventing or treating diseases or conditions that can be improved by inhibiting the activity of SGLT2, such as diabetes, diabetes-related diseases, and diabetic complications.

Here, the term "diabetes" includes type I diabetes, type II diabetes, and other types of diabetes caused by specific causes.

Examples of the "diabetes-related diseases" include obesity, hyperinsulinemia, glucose metabolism disorder, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, hypertension, congestive heart failure, edema, hyperuricemia, and gout.

Here, "diabetic complications" can be classified into acute complications as well as chronic complications.

Examples of the "acute complications" include hyperglycemia (ketoacidosis, etc.), and infections (skin, soft tissue, biliary system, respiratory system, urinary tract infections, etc.).

Examples of the "chronic complications" include microangiopathy (nephropathy, retinopathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, arterial occlusion of lower limbs, etc.), neurological disorders (sensory nerve, motor nerve, autonomic nerve, etc.), gangrene of the foot, and the like.

The main complications are diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.

The compound of the present invention can be used in combination with a diabetes therapeutic agent, a diabetes complication therapeutic agent, a hyperlipemia therapeutic agent, a hypertension therapeutic agent, and the like having different mechanisms of action other than SGLT2 activity inhibitors. For the above diseases, by combining the compound of the present invention with other drugs, a synergistic effect can be obtained when used in combination, as compared with the effect obtained by the separate administration.

Examples of the "therapeutic agents for diabetes and diabetic complications" which can be used in combination include insulin sensitizers (PPAR γ agonists, PPAR α/γ agonists, PPAR δ agonists, PPAR α/γ/δ agonists and the like), glycosidase inhibitors, biguanide drugs, insulin secretion promoters, insulin preparations, glucagon receptor antagonists, insulin receptor kinase promoters, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glycogenesis inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, glucokinase activators, D-Chiroinositol (D-Chiroinositol), glycogen synthase kinase 3 inhibitors, glucagon-like peptide-1, Glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, amyrin analogs, amyrin agonists, glucocorticoid receptor antagonists, 11 beta-hydroxysteroid dehydrogenase inhibitors, aldose reductase inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF- κ B inhibitors, I KK β inhibitors, lipid peroxidase inhibitors, NAALADase (N-acetylated- α -linked acidic dipeptidase), N-acetylated- α -linked-acid-dipeptidase) inhibitors, insulin-like growth factor-I, platelet-derived growth factor (PDGF) analogs, epithelial proliferation factor (EGF), Nerve Growth Factor (NGF), insulin-like growth factor (TGF-beta-glucosidase, and insulin, Carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, VIMOCHROMOR, sulodexide, Y-128, TAK-428, etc.

The therapeutic agents for diabetes and the therapeutic agents for diabetic complications include the following drugs.

Examples of the "biguanide drugs" include metformin hydrochloride, phenformin, and the like.

Among the "insulin secretion enhancers", sulfonylureas include glibenclamide (glibenclamide), glipizide, gliclazide, chlorpropamide, and non-sulfonylureas include nateglinide, repaglinide, mitiglinide, and the like.

"insulin preparations" include genetically recombinant human insulin and animal insulin. In addition, according to the action time, the method can be divided into 3 types: namely quick-acting type (human insulin and human neutral insulin), intermediate-acting type (insulin-human low protamine insulin aqueous suspension, human neutral insulin-human low protamine insulin aqueous suspension, human insulin zinc aqueous suspension, insulin zinc aqueous suspension), long-acting type (human crystalline insulin zinc suspension), and the like.

Examples of the "glycosidase inhibitor" include acarbose, voglibose, miglitol, and the like.

Examples of the "insulin sensitizer" include troglitazone, pioglitazone, and rosiglitazone as PPAR γ agonists, MK-767(KRP-297), Tesaglitazar, LM4156, LY510929, DRF-4823, and TY-51501 as PPAR α/γ dual agonists, and GW-501516 as PPAR8 agonists.

Examples of the "tripeptidylpeptidase II inhibitor" include UCL-139 and the like.

Examples of the "dipeptidyl peptidase IV inhibitor" include NVP-DPP728A, LAF-237, P32/98, and TSL-225.

Examples of the "aldose reductase inhibitor" include ascorbyl gallate (pancarbyl gallate), tolrestat, epalrestat, fadesine, sorbinil, ponalrestat, risistat, and zenarestat.

Examples of the "gamma-aminobutyric acid receptor antagonist" include topiramate (topiramate).

Examples of the "sodium channel antagonist" include mexiletine hydrochloride.

Examples of the "transcription factor NF-. kappa.B inhibitor" include dexlipotam and the like.

Examples of the "lipid peroxidase inhibitor" include tirapazamide mesylate (tirapazadmesylate).

Examples of the "NAALADase inhibitor" include GPI-5693.

Examples of the "carnitine derivative" include carnitine and acetyl L-carnitine hydrochloride (levacenecarbonine hydrochloride).

Examples of the "hyperlipemia therapeutic agent and hypertension therapeutic agent" which can be used in combination include hydroxymethylglutaryl-CoA reductase inhibitor, fibrate compound and beta₃-adrenergic receptor agonists, AMPK activators, acetyl-coa: cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor promoters, nicotinic acid derivatives, bile acid adsorbents, Na +/bile acid transporter inhibitors, cholesterol ester transporter inhibitors, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilators, sympatholytic agents, central hypotensives, alpha-statins, alpha-glucosidase inhibitors, alpha-₂-adrenergic receptor agonists, antiplatelet agents, uric acid production inhibitors, uric acid excretion promoters, urine alkalinizing agents, appetite suppressants, AGE inhibitors, adiponectin receptor agonists, GPR40 agonists, GPR40 antagonists, and the like.

Examples of the hyperlipemia therapeutic agent and the hypertension therapeutic agent include the following agents.

Examples of the "hydroxymethylglutaryl-coenzyme a reductase inhibitor" include fluvastatin, lovastatin, pravastatin, cerivastatin, pitavastatin and the like.

Examples of the "fibrate compound" include bezafibrate, binifibrate, and the like.

Examples of the "squalene synthetase inhibitor" include TAK-475 and α -phosphonosulfonate (α -phosphono sulfonate) derivatives (USP 5712396).

As "acetyl-coa: examples of the cholesterol acyltransferase inhibitor include CI-1011, NTE-122, FCE-27677, RP-73163, MCC-147, and DPU-129.

Examples of the "low-density lipoprotein receptor-promoting agent" include MD-700 and LY-295427.

Examples of the "microsomal triglyceride transfer protein inhibitor (MTP inhibitor)" include compounds described in USP5739135, USP5712279, USP5760246 and the like.

Examples of the "appetite suppressant" include adrenergic and noradrenergic drugs (e.g., Mazindol and ephedrine), 5-hydroxytryptamine drugs (selective 5-hydroxytryptamine reuptake inhibitors such as fluvoxamine), adrenergic and 5-hydroxytryptamine drugs (e.g., sibutramine), melanocortin 4 receptor (MC4R) agonists, α -melanocyte stimulating hormone (α -MCH), leptin, and cocaine-amphetamine-regulated transcription factor (CART).

Examples of the "thyroid hormone receptor agonist" include sodium iodothyronine and levothyroxine sodium.

Examples of the "cholesterol absorption inhibitor" include ezetimibe and the like.

Examples of the "lipase inhibitor" include orlistat and the like.

Examples of the "carnitine palmitoyltransferase inhibitor" include etomoxider.

Examples of the "nicotinic acid derivative" include nicotinic acid, nicotinamide, nicormor, nicorandil and the like.

Examples of the "bile acid adsorbent" include cholestyramine, colesevelam, and colesevelam hydrochloride.

Examples of the "angiotensin converting enzyme inhibitor" include captopril, enalapril maleate, alacepril, cilazapril and the like.

Examples of the "angiotensin II receptor antagonist" include candesartan cilexetil, losartan potassium, eprosartan mesylate, and olmesartan medoxomil.

Examples of the "endothelin-converting enzyme inhibitor" include CGS-31447 and CGS-35066.

Examples of the "endothelin receptor antagonist" include L-749805, TBC-3214, BMS-182874 and the like.

For example, in the treatment of diabetes and the like, it is preferable to use the compound of the present invention in combination with at least 1 drug selected from the group consisting of insulin sensitizers (PPAR γ agonists, PPAR α/γ agonists, PPAR δ agonists, PPAR α/γ/δ agonists and the like), glycosidase inhibitors, biguanide drugs, insulin secretion promoters, insulin preparations and dipeptidyl peptidase IV inhibitors.

Alternatively, it is preferred to use the compounds of the invention in combination with a compound selected from the group consisting of hydroxymethylglutaryl-coenzyme a reductase inhibitors, fibrates, squalene synthetase inhibitors, acetyl-coenzyme a: at least 1 drug selected from the group consisting of cholesterol acyltransferase inhibitors, low density lipoprotein receptor agonists, microsomal triglyceride transfer protein inhibitors, and appetite suppressants.

The drug of the present invention can be administered systemically or locally by a non-oral route such as oral or rectal, subcutaneous, intramuscular, intravenous, or transdermal.

When the compound of the present invention is used as a pharmaceutical, it may be in any form of a solid composition, a liquid composition, and other compositions, and the optimum form may be selected as needed. The pharmaceutical composition of the present invention can be prepared by formulating a pharmaceutically acceptable carrier in the compound of the present invention. Specifically, a conventional excipient, an extender, a binder, a disintegrant, a coating agent, a sugar-coating agent, a pH adjuster, a dissolving agent, or an aqueous or non-aqueous solvent may be added to the composition to prepare a tablet, a pill, a capsule, a granule, a powder, a liquid, an emulsion, a suspension, an injection, etc. by a conventional preparation technique. Examples of the excipient and the extender include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cacao oil, ethylene glycol and the like, and other commonly used substances.

The compound of the present invention may be formulated as an inclusion compound with α, β, γ -cyclodextrin, methylated cyclodextrin, or the like.

The dose of the compound of the present invention varies depending on the disease, symptoms, body weight, age, sex, administration route, etc., and the dose is preferably 0.1 to 1000mg/kg body weight/day, more preferably 0.1 to 200mg/kg body weight/day for an adult, and may be administered 1 time or several times.

Examples

Preparation example

The following is an explanation of a preparation example of the aglycone part of the compound of the present invention.

Preparation example 1

Synthesis of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-gluconic acid-1, 5-lactone

To a solution of 2, 3, 4, 6-tetra-O-acetyl-5-thio-D-glucopyranose (2.0g, 5.49mmol) in chloroform (40mL) were added 3, 4-dihydro-2H-pyran (1.5mL, 16.5mmol) and p-toluenesulfonic acid 1 hydrate (104mg, 0.549mmol), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, washing of the organic layer with a saturated saline solution, and drying with anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) to give tetrahydro-2H-pyran-2-yl 2, 3, 4, 6-tetra-O-acetyl-5-thio-D-glucopyranose (2.56g) as a pale yellow amorphous form.

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

A mixture of tetrahydro-2H-pyran-2-yl 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucopyranose (3.30g, 5.15mmol), pyridinium p-toluenesulfonic acid (518mg, 2.06mmol) and ethanol (58mL) was stirred at 80 ℃ for 2 hours. The reaction solution was cooled to room temperature, and the solvent was concentrated. The resulting residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate: 3: 1) to obtain colorless crystals of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucopyranose (2.89g, quantitative value (quant)).

¹³C NMR(125MHz，CDCl₃)δ41.3，67.8，71.6，73.0，73.2，75.6，76.2，81.9，82.9，84.4，127.5，127.7，127.8，127.9，128.0，128.3，128.4，128.5，137.8，138.3，138.8.

A mixture of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucopyranose (2.82g, 5.07mmol), dimethyl sulfoxide (47mL), and acetic anhydride (39mL) was stirred at room temperature for 12 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate, washing of the organic phase with water, a saturated aqueous sodium bicarbonate solution and a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate ═ 6: 1) to give the title compound (2.3g, 82%) as a colorless oil.

¹H NMR(200MHz，CDCl₃)δppm 3.70(d，J＝4.8Hz，2H)3.86-4.02(m，2H)4.09-4.22(m，2H)4.40-4.68(m，7H)4.83(d，J＝11.4Hz，1H)7.12-7.41(m，20H).

Preparation example 2

Synthesis of 2, 3, 4, 6-tetra-O- (4-methoxybenzyl) -5-thio-D-gluconic acid-1, 5-lactone

The title compound was synthesized in the same manner as in preparation example 1 using 4-methoxybenzyl chloride instead of benzyl bromide.

¹H NMR(300MHz，CDCl₃)δppm 3.60-3.66(m，2H)3.77-3.81(m，12H)3.81-3.91(m，2H)4.01-4.15(m，2H)4.29-4.58(m，7H)4.74(d，J＝11.2Hz，1H)6.78-6.90(m，8H)7.03-7.10(m，2H)7.11-7.30(m，6H).

Preparation example 3

Synthesis of 1-bromo-3- (4-ethoxybenzyl) benzene

To a mixture of 4-bromobenzene diethyl ether (2.87g, 0.0143mol) and tetrahydrofuran (30mL) was added a 2.6M solution of n-butyllithium in hexane (5.8mL) at-78 ℃. After stirring for 0.5 hour, a solution of 3-bromobenzaldehyde (2.65g, 0.0143mol) in tetrahydrofuran (15mL) was added and the mixture was stirred for another 15 minutes, and the temperature of the reaction mixture was raised to room temperature. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate ═ 7: 1 to 5: 1) to give (3-bromophenyl) (4-ethoxyphenyl) methanol (3.94g, 90%) as a colorless oil.

Then, atTo a solution of (3-bromophenyl) (4-ethoxyphenyl) methanol (3.92g, 0.0128mol) in chloroform (22mL) at-60 ℃ was added Et sequentially₃SiH (4.09mL, 0.0256mol) and BF₃·Et₂O (1.47mL, 0.0116 mol). After stirring for 1 hour, the reaction mixture was warmed to room temperature. To the reaction mixture was added a saturated aqueous sodium carbonate solution, followed by extraction with chloroform, washing of the organic layer with a saturated saline solution, and drying with anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 50: 1) to give the title compound (2.84g, 76%) as a colorless oil.

¹H NMR(300MHz，CDCl₃)δppm 1.40(t，J＝7.0Hz，3H)3.88(s，2H)4.01(q，J＝7.0Hz，2H)6.83(d，J＝8.9Hz，2H)7.07(d，J＝8.9Hz，2H)7.09-7.18(m，2H)7.29-7.34(m，2H).

Preparation example 4

Synthesis of 2- (5-bromo-2-methoxybenzyl) -1-benzothiophene

To a mixture of benzo [ b ] thiophene (6.6g, 0.049mol) and tetrahydrofuran (66mL) was added a 1.6M solution of n-butyllithium in hexane (30.5mL) at-78 ℃. After stirring for 0.5 hour, a solution of 5-bromo-2-methoxybenzaldehyde (10.0g, 0.047mol) in tetrahydrofuran (50mL) was added thereto, and the mixture was stirred for another 5 minutes, and the reaction mixture was warmed to room temperature. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate ═ 6: 1) to give (1-benzothien-2-yl) (5-bromo-2-methoxyphenyl) methanol (11.3g, 69%) as pale yellow crystals.

Next, Et was added sequentially to a solution of (1-benzothien-2-yl) (5-bromo-2-methoxyphenyl) methanol (11.2g, 0.0321mol) in chloroform (110mL) at-15 deg.C₃SiH (10.3mL, 0.0642mol) and BF₃·Et₂O (4.10mL, 0.0321 mol). After stirring for 0.5 hour, saturated aqueous sodium bicarbonate solution was added. Extracting with chloroformThe mixture was washed with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate. The residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate: 30: 1) to give the title compound (9.84g, 92%) as yellow crystals.

¹H NMR(300MHz，CDCl₃)δppm 3.84(s，3H)4.17(s，2H)6.76(d，J＝8.7Hz，1H )7.01(s，1H)7.19-7.37(m，4H)7.65(d，J＝7.8Hz，1H)7.73(d，J＝7.8Hz，1H)

EI 332，334(M⁺，M+2)

Preparation example 5

Synthesis of 2- (5-bromo-2-chlorobenzyl) -1-benzothiophene

To a solution of 5-bromo-2-chlorobenzoic acid (10.0g, 0.0425mol) in chloroform (20mL) was added oxalyl chloride (3.78mL, 0.0441mmol) and N, N-dimethylformamide (0.06 mL). The reaction mixture was stirred at room temperature for 1 day and night, and the reaction solvent was distilled off under reduced pressure. The resulting yellow oil was dissolved in chloroform (20 mL). This solution was added dropwise to a mixture of N, O-dimethoxyhydroxylamine hydrochloride (4.56g, 0.0468mol), triethylamine (12.3mL, 0.0882mol) and chloroform (50mL) over 15 minutes while maintaining the reaction temperature at 5 ℃ to 10 ℃. After stirring for 15 minutes, the reaction mixture was warmed to room temperature. Water (20mL) was added to the reaction mixture, the organic layer was separated, washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to give 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (11.8g, 99.7%) as colorless crystals. This was used in the next reaction without purification.

LiAlH was slowly added to a solution of 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (10.8g, 0.0388mol) in tetrahydrofuran (108mL) at an internal temperature of not more than-10 ℃₄(1.47g, 0.0388 mol). The reaction mixture was stirred at-15 ℃ for 1 hour, saturated aqueous ammonium chloride solution was carefully added thereto, and the insoluble matter precipitated was filtered through celite. With acetic acidThe filtrate was extracted with ethyl ester, and the organic layer was washed with 1M hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated saline solution, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to give 5-bromo-2-chlorobenzaldehyde (8.1g, 95%) as pale yellow crystals. It was used in the next reaction without purification.

To a mixture of benzo [ b ] thiophene (5.8g, 0.043mol) and tetrahydrofuran (58mL) at-78 deg.C was added over 20 minutes a 1.6M n-butyllithium hexane solution (26.9 mL). After stirring for 0.5 hour, a solution of 5-bromo-2-chlorobenzaldehyde (9.0g, 0.041mol) in tetrahydrofuran (50mL) was added and stirred for an additional 5 minutes. The reaction was warmed to room temperature. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 10: 1) to give (1-benzothien-2-yl) (5-bromo-2-chlorophenyl) methanol (10.3g, 71%) as a pale yellow oil.

Next, Et was added sequentially to a solution of (1-benzothien-2-yl) (5-bromo-2-chlorophenyl) methanol (10.2g, 0.0288mol) in chloroform (110mL) at-15 deg.C₃SiH (9.2mL, 0.058mol) and BF₃·Et₂O (3.6mL, 0.029 mol). The reaction solution was warmed to room temperature, and stirred at that temperature for 10 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, and the organic phase was separated, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 60: 1) to give the title compound (5.5g, 56%) as a colorless oil.

¹H NMR(300MHz，CDCl₃)δppm 4.30(s，2H)6.98-7.06(m，1H)7.22-7.37(m，4H)7.43(d，J＝2.3Hz，1H)7.64-7.71(m，1H)7.72-7.80(m，1H).

EI 336(M⁺)，338(M+2)，340(M+4).

Preparation example 6

Synthesis of 1- (benzyloxy) -2-bromo-4- (4-ethoxybenzyl) benzene

To a mixture of 3-bromo-4-hydroxybenzaldehyde (5.0g, 0.025mol), tetrabutylammonium iodide (0.92g, 2.5mmol), potassium carbonate (6.9g, 0.050mol) and N, N-dimethylformamide (70mL) was added benzyl bromide (3.1mL, 0.026mol) at room temperature, and the mixture was stirred for 2.5 hours. A mixture of ice and water (100mL) was added to the reaction mixture, and the mixture was stirred for 1 hour. The precipitated precipitate was filtered and dried to give 4-benzyloxy-3-bromobenzaldehyde (7.1g, 98%) as a pale yellow powder.

Next, a 1.6M solution of n-butyllithium in hexane (22.9mL) was added to a mixture of 4-bromobenzene diethyl ether (7.3g, 0.037mol) and tetrahydrofuran (70mL) at-78 ℃. After stirring for 0.5 hour, a solution of 4-benzyloxy-3-bromobenzaldehyde (7.0g, 0.024mol) in tetrahydrofuran (70mL) was added and the mixture was stirred for a further 15 minutes, and the reaction mixture was warmed to room temperature. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give [4- (benzyloxy) -3-bromophenyl ] (4-ethoxyphenyl) methanol (8.7g, 86%) as a colorless oil.

Next, to [4- (benzyloxy) -3-bromophenyl group at-15 deg.C]Et was added sequentially to a solution of (4-ethoxyphenyl) methanol (8.7g, 0.021mol) in chloroform (90mL)₃SiH (6.7mL, 0.042mol) and BF₃·Et₂O (2.7mL, 0.021 mol). After stirring for 1 hour, the reaction mixture was warmed to room temperature. To the reaction mixture was added a saturated aqueous sodium carbonate solution, followed by extraction with chloroform, washing of the organic layer with a saturated saline solution, and drying with anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 10: 1) to give the title compound (8.8g, quantitative value) as a colorless oil.

¹H NMR(300MHz，CDCl₃)δppm 1.40(t，J＝7.0Hz，3H)3.82(s，2H)4.00(q，J＝7.0Hz，2H)5.12(s，2H)6.78-6.87(m，3H)6.98-7.10(m，3H)7.27-7.50(m，6H).

Preparation example 7

Synthesis of 1-bromo-3- (4-ethoxybenzyl) -4-methoxybenzene

The title compound was prepared in the same manner as in preparation example 3 using 5-bromo-2-methoxybenzaldehyde and 4-bromobenzene ethyl ether.

¹H NMR(300MHz，CDCl₃)δppm 1.40(t，J＝7.0Hz，3H)3.79(s，3H)3.85(s，2H)4.01(q，J＝7.0Hz，2H)6.72(d，J＝8.6Hz，1H)6.81(d，J＝8.7Hz，2H)7.09(d，J＝8.7Hz，1H)7.13(d，J＝2.5Hz，1H)7.27(dd，J＝8.6，2.5Hz，1H).

Preparation example 8

Synthesis of 1-bromo-3- (4-ethoxybenzyl) -6-methoxybenzene

The title compound was prepared in the same manner as in preparation example 3 using 3-bromo-4-methoxybenzaldehyde and 4-bromophenylether.

¹H NMR(300MHz，CDCl₃)δppm 1.40(t，J＝7.0Hz，3H)3.83(s，2H)3.86(s，3H)4.01(q，J＝7.0Hz，2H)6.78-6.85(m，3H)7.03-7.10(m，3H)7.35(d，J＝2.2Hz，1H).

EI 320，322(M⁺，M+2).

Preparation example 9

Synthesis of 2- (3-bromobenzyl) -1-benzothiophene

The title compound was prepared in the same manner as in preparation example 4 using 3-bromobenzaldehyde and benzo [ b ] thiophene.

¹H NMR(300MHz，CDCl₃)δppm 4.19(s，2H)7.02(s，1H)7.15-7.47(m，6H)7.65-7.70(m，1H)7.71-7.77(m，1H).

EI 302，304(M⁺，M+2).

Preparation example 10

Synthesis of 2- (3-bromo-4-methoxybenzyl) -1-benzothiophene

The title compound was prepared in the same manner as in preparation example 4 using 3-bromo-4-methoxybenzaldehyde and benzo [ b ] thiophene.

¹H NMR(300MHz，CDCl₃)δppm 3.89(s，3H)4.15(s，2H)6.86(d，J＝8.4Hz，1H)7.01(s，1H)7.16-7.35(m，3H)7.48(d，J＝1.9Hz，1H)7.64-7.70(m，1H)7.71-7.77(m，1H).

EI 332，334(M⁺，M+2).

Preparation example 11

Synthesis of 1-bromo-3- (4-ethoxybenzyl) -4, 6-dimethoxybenzene

The title compound was prepared in the same manner as in preparation example 3 using 5-bromo-2, 4-dimethoxybenzaldehyde and 4-bromophenetole.

¹H NMR(200MHz，CDCl₃)δppm 1.39(t，J＝7.0Hz，3H)3.80(s，2H)3.82(s，3H)3.88(s，3H)4.00(q，J＝7.0Hz，2H)6.47(s，1H)6.75-6.85(m，2H)7.02-7.12(m，2H)7.17(s，1H)

EI 350，352(M⁺，M+2).

Preparation example 12

Synthesis of 1-bromo-3- (4-ethoxybenzyl) -4-fluorobenzene

The title compound was prepared in the same manner as in preparation example 3 using 5-bromo-2-fluorobenzaldehyde and 4-bromobenzene ethyl ether.

¹H NMR(200MHz，CDCl₃)δppm 1.40(t，J＝7.0Hz，3H)3.88(s，2H)4.01(q，J＝7.0Hz，2H)6.79-6.96(m，3H)7.05-7.16(m，2H)7.19-7.32(m，2H).

EI 309，311(M⁺，M+2).

Preparation example 13

Synthesis of 1- (benzyloxy) -4-bromo-2- (4-ethoxybenzyl) benzene

The title compound was synthesized from 3-bromo-2-hydroxybenzaldehyde by the same method as in preparation example 6.

¹H NMR(200MHz，CDCl₃)δppm 1.40(t，J＝6.8Hz，3H)3.90(s，2H)4.01(q，J＝6.8Hz，2H)5.03(s，2H)6.72-6.85(m，3H)7.02-7.13(m，2H)7.15-7.43(m，7H).

Preparation example 14

Synthesis of 1-bromo-4-chloro-3- (4-ethoxy-2, 5-difluorobenzyl) benzene

To 5-bromo-2-chlorobenzoic acid (5.0g, 0.0212mol) in chloroform (10mL) was added oxalyl chloride (1.89mL, 0.0220mol) and N, N-dimethylformamide (0.03mL), and the mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure to obtain a yellow oil, which was dissolved in chloroform (10 mL). To this solution was added 2, 5-difluorophenetole (3.4g, 0.0214mol) at-10 ℃ followed by slow addition of aluminium chloride (2.9g, 0.0214mol) over 5 minutes. After stirring the reaction mixture at 5 ℃ for 2 hours, ice water was added. Extracted 3 times with chloroform. The combined organic layer was washed with 1M hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate ═ 10: 1) to give (5-bromo-2-chlorophenyl) (4-ethoxy-2, 5-difluorophenyl) methanone (5.59g, 70%) as colorless crystals.

Next, Et was added sequentially to a solution of (5-bromo-2-chlorophenyl) (4-ethoxy-2, 5-difluorophenyl) methanone (5.58g, 0.0149mol) in chloroform-acetonitrile (1: 1; 60mL) at 4 deg.C₃SiH (5.93mL, 0.0371mol) and BF₃·Et₂O (2.83mL, 0.0224 mol). The reaction mixture was warmed to room temperature, stirred for 12 hours, and further stirred at 45 ℃ for 3 hours. To the direction ofThe reaction mixture was added with saturated aqueous sodium carbonate solution, extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 10: 1) to give the title compound (3.8g, 71%) as a colorless oil.

¹H NMR(300MHz，CDCl₃)δppm 1.46(t，J＝7.0Hz，3H)3.98(s，2H)4.08(q，J＝7.0Hz，2H)6.71(dd，J＝11.3，7.1Hz，1H)6.82(dd，J＝11.3，7.1Hz，1H)7.18-7.38(m，3H).

EI 360(M⁺)，362(M+2)，364(M+4).

Preparation example 15

Synthesis of 1-bromo-4-chloro-3- (4-ethoxy-3-fluorobenzyl) benzene

The title compound was synthesized by the same procedure as in preparation 14 using 5-bromo-2-chlorobenzoic acid and 2-fluorophenethyl ether.

¹H NMR(300MHz，CDCl₃)δppm 1.44(t，J＝7.0Hz，3H)3.97(s，2H)4.09(q，J＝7.0Hz，2H)6.79-6.95(m，3H)7.18-7.35(m，3H)

EI 342(M⁺)，344(M+2)，346(M+4).

Preparation example 16

Synthesis of 1-bromo-4-chloro-3- (3-chloro-4-ethoxybenzyl) benzene

The title compound was synthesized in the same manner as in preparation example 14 using 5-bromo-2-chlorobenzoic acid and 2-chlorophenethyl ether.

¹H NMR(300MHz，CDCl₃)δppm 1.46(t，J＝7.0Hz，3H)3.96(s，2H)4.08(q，J＝7.0Hz，2H)6.85(d，J＝8.4Hz，1H)6.95-7.03(m，1H)7.18(d，J＝2.2Hz，1H)7.23-7.33(m，3H).

Preparation example 17

Synthesis of 1-bromo-3- (4-ethoxybenzyl) -4-methylbenzene

The title compound was synthesized in the same manner as in preparation example 14 using 5-bromo-2-methylbenzoic acid (see International patent publication WO0127128 for synthesis) and phenetole.

¹H NMR(200MHz，CDCl₃)δppm 1.40(t，J＝7.0Hz，3H)2.18(s，3H)3.86(s，2H)4.00(q，J＝7.0Hz，2H)6.76-6.87(m，2H)6.94-7.07(m，3H)7.17-7.30(m，2H).

EI 304(M⁺)，306(M+2).

Preparation example 18

Synthesis of 1-bromo-4-chloro-3- (2, 4-dimethoxybenzyl) benzene

The title compound was synthesized in the same manner as in preparation 14 using 5-bromo-2-chlorobenzoic acid and 1, 3-dimethoxybenzene.

¹H NMR(200MHz，CDCl₃)δppm 3.79(s，3H)3.80(s，3H)3.95(s，2H)6.36-6.53(m，2H)6.94(d，J＝8.4Hz，1H)7.13-7.28(m，3H).

Preparation example 19

Synthesis of 1-bromo-4-chloro-3- (4-methoxybenzyl) benzene

The title compound was synthesized by the same method as in preparation example 14 using 5-bromo-2-chlorobenzoic acid and anisole.

¹H NMR(300MHz，CDCl₃)δppm 3.80(s，3H)3.99(s，2H)6.82-6.89(m，2H)7.06-7.13(m，2H)7.197.30(m，3H).

Preparation example 20

Synthesis of 1-bromo-4-chloro-3- (4-tert-butylbenzyl) benzene

The title compound was synthesized in the same manner as in preparation example 14 using 5-bromo-2-chlorobenzoic acid and tert-butylbenzene.

¹H NMR(200MHz，CDCl₃)δppm 1.31(s，9H)4.03(s，2H)7.11(d，J＝7.9Hz，2H)7.22-7.37(m，5H).

Preparation example 21

Synthesis of 1-bromo-4-chloro-3- (4-methylbenzyl) benzene

The title compound was synthesized in the same manner as in preparation example 14 using 5-bromo-2-chlorobenzoic acid and toluene.

¹H NMR(200MHz，CDCl₃)δppm 2.33(s，3H)4.02(s，2H)7.03-7.16(m，4H)7.18-7.32(m，3H).

EI 294(M⁺)，296(M+2).

Preparation example 22

Synthesis of 1-bromo-4-chloro-3- (4-methylthiobenzyl) benzene

The title compound was synthesized by the same method as in preparation example 14 using 5-bromo-2-chlorobenzoic acid and thioanisole.

¹H NMR(300MHz，CDCl₃)δppm 2.47(5，3H)4.01(s，2H)7.06-7.14(m，2H)7.17-7.32(m，5H).

Preparation example 23

Synthesis of 1-bromo-4-chloro-3- (4-ethylbenzyl) benzene

The title compound was synthesized in the same manner as in preparation example 14 using 5-bromo-2-chlorobenzoic acid and ethylbenzene.

¹H NMR(200MHz，CDCl₃)δppm 1.23(t，J＝7.7Hz，3H)2.63(q，J＝7.7Hz，2H)4.02(s，2H)7.04-7.18(m，4H)7.18-7.32(m，3H)

EI 308(M⁺)，310(M+2).

Preparation example 24

Synthesis of 1-bromo-4-chloro-3- (4-isopropylbenzyl) benzene

The title compound was synthesized in the same manner as in preparation example 14 using 5-bromo-2-chlorobenzoic acid and cumene.

¹H NMR(200MHz，CDCl₃)δppm 1.22(s，3H)1.26(s，3H)2.79-2.97(m，1H)4.02(s，2H)7.05-7.32(m，7H).

EI 322(M⁺)，324(M+2).

Preparation example 25

Synthesis of 2- (5-bromo-2-chlorobenzyl) benzofuran

The title compound was synthesized by the same method as in preparation example 5 using benzofuran instead of benzothiophene.

¹H NMR(200MHz，CDCl₃)δppm 4.20(s，2H)6.40-6.46(m，1H)7.13-7.54(m，7H).

EI 319(M⁺)，321(M+2).

Preparation example 26

Synthesis of 1-bromo-3- (4-ethoxybenzyl) -6-methoxy-4-methylbenzene

To a mixture of 4-methoxy-2-methylbenzoic acid (10g, 0.060mol), Fe (0.20g, 3.61mmol) and chloroform (10mL) was added dropwise bromine (3.87mL, 0.076mol) at 5 ℃. After the temperature of the reaction mixture was changed to room temperature, the mixture was stirred overnight. Chloroform (600mL) was added to the reaction solution, and the suspension was washed with 10% sodium hydrogensulfate (200 mL. times.2) and a saturated saline solution, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, a pale yellow powder obtained by removing the solvent by distillation under the reduced pressure was recrystallized 2 times from methanol to give 5-bromo-4-methoxy-2-methylbenzoic acid (4.96g, 34%).

Or, 4 '-hydroxy-2' -methylacetophenone can be used as a starting material to synthesize 5-bromo-4-methoxy-2-methylbenzoic acid. To a solution of 4 '-hydroxy-2' -methylacetophenone (0.552g, 3.47mmol) in acetone (10mL) was added potassium carbonate (0.720mg, 5.21mmol) and methyl iodide (0.542g, 3.82mmol) at room temperature, and the mixture was stirred for 12 hours. Methyl iodide (0.24g, 1.73mmol) was added thereto, and the mixture was refluxed for 2 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. Chloroform was added to the residue, and after insoluble matter was filtered, the filtrate was concentrated to give 4 '-methoxy-2' -methylacetophenone (0.57 g). Next, to a solution of 4 '-methoxy-2' -methylacetophenone (0.21g, 1.27mmol) in acetone (4mL) -water (4mL) was added oxone (0.79g, 1.27mmol) and NaBr (0.13g, 1.27mmol) at room temperature, and the mixture was stirred for 1 hour. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated, washed with water, a saturated aqueous sodium carbonate solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to give a 4: 1 mixture (0.28g) of 5 '-bromo-4' -methoxy-2 '-methylacetophenone and 3' -bromo-4 '-methoxy-2' -methylacetophenone. Then, a 4: 1 mixture (0.26g) of 5 '-bromo-4' -methoxy-2 '-methylacetophenone and 3' -bromo-4 '-methoxy-2' -methylacetophenone was added with a 5% NaOCl solution (3mL) and potassium hydroxide (0.92g), and the mixture was refluxed for 2.5 hours. After cooling to room temperature, 2M HCl was added to make the reaction solution acidic. The mixture was extracted with ethyl acetate, and the organic phase was washed with 1M HCl and saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was washed with methanol to give 5-bromo-4-methoxy-2-methylbenzoic acid (112mg) as a colorless powder.

Next, the title compound (5.80g) was synthesized from 5-bromo-4-methoxy-2-methylbenzoic acid (4.93g, 0.0201mol) and phenetole by the same method as in preparation example 14.

¹H NMR(300MHz，CDCl₃)δppm 1.40(t，J＝7.0Hz，3H)2.19(s，3H)3.82(s，2H)3.87(s，3H)4.00(q，J＝7.0Hz，2H)6.71(s，1H)6.77-6.83(m，2H)6.95-7.04(m，2H)7.24(s，1H).

EI 335(M⁺)，337(M+2).

Preparation example 27

Synthesis of 1-bromo-4-chloro-3- (4-ethoxybenzyl) -6-methoxybenzene

2-bromo-5-chlorophenol (2.85g, 13.7 mmol; see International patent publication No. WO 0109122), potassium carbonate (1.89g, 13.7mmol), and n-Bu₄A suspension of NI (50mg, 0.137mmol), methyl iodide (1.28mL, 20.6mmol) and N, N-dimethylformamide (8.0mL) was stirred for 2 hours. Ice water was added, and the resulting mixture was extracted 2 times with ethyl acetate. The combined organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 95: 5) to give 2-bromo-5-chloroanisole (2.94g, 97%) as a colorless oil.

Next, oxalyl chloride (1.23mL, 15.1mmol) and N, N-dimethylformamide (2 drops) were added to 4-ethoxybenzoic acid (2.28g, 13.7mmol) in chloroform (8mL) and stirred for 5 hours. The solvent was distilled off under reduced pressure to obtain a yellow oil, which was dissolved in chloroform (5 mL). To this solution was added a chloroform solution (10mL) of 2-bromo-5-chloroanisole (2.94g, 13.3mmol) at-10 deg.C, followed by slow addition of aluminum chloride (2.07g, 15.5mmol) over 5 minutes. The reaction mixture was stirred at 5 ℃ for 1 hour, then warmed to room temperature, and stirred for 13 hours. The reaction mixture was poured into ice water, and extracted with chloroform 3 times. The combined organic layer was washed with 1M hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by NH-type silica gel column chromatography (hexane: ethyl acetate ═ 9: 1) to give (5-bromo-2-chloro-6-methoxyphenyl) (4-ethoxyphenyl) methanone (1.53g, 31%) as colorless crystals.

Next, Et was added sequentially to a solution of (5-bromo-2-chloro-6-methoxyphenyl) (4-ethoxyphenyl) methanone (1.50g, 4.06mmol) in chloroform-acetonitrile (1: 1; 16mL) at-5 deg.C₃SiH (1.62mL, 10.1mmol) and BF₃·Et₂O (0.772mL, 6.09 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. Adding saturated carbon to the reaction solutionThe sodium acid aqueous solution was extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 20: 1) to give the title compound (1.48g, 99%) as a colorless oil.

¹H NMR(200MHz，CDCl₃)δppm 1.40(t，J＝7.0Hz，3H)3.87(s，3H)3.93(s，2H)4.01(q，J＝7.0Hz，2H)6.77-6.87(m，2H)6.90(s，1H)7.03-7.12(m，2H)7.29(s，1H).

EI 354(M⁺)，356(M+2)，358(M+4).

Preparation example 28

Synthesis of 1-bromo-4-chloro-3- (4-ethylbenzyl) -6-methoxybenzene

The title compound was synthesized by the same procedure as in preparation 27, using 4-ethylbenzoic acid instead of 4-ethoxybenzoic acid.

¹H NMR(300MHz，CDCl₃)δppm 1.22(t，J＝7.6Hz，3H)2.62(q，J＝7.6Hz，2H)3.87(s，3H)3.97(s，2H)6.91(s，1H)7.04-7.18(m，4H)7.32(s，1H).

EI 338，340，342(M⁺，M+2，M+4).

Preparation example 29

Synthesis of 1-bromo-4-chloro-3- (4-isopropylbenzyl) -6-methoxybenzene

The title compound was synthesized in the same manner as in preparation example 27, using 4-isopropylbenzoic acid instead of 4-ethoxybenzoic acid.

¹H NMR(300MHz，CDCl₃)δppm 1.24(d，J＝7.0Hz，6H)2.82-2.94(m，1H)3.87(s，3H)3.97(s，2H)6.91(s，1H)7.05-7.20(m，4H)7.33(s，1H).

EI 352，354，356(M⁺，M+2，M+4).

Preparation example 30

Synthesis of 1-benzyloxy-2-bromo-4- (4-ethoxybenzyl) -5-methylbenzene

The title compound was synthesized in the same manner as in preparation example 3 using 4-benzyloxy-3-bromo-6-methylbenzaldehyde instead of 3-bromobenzaldehyde.

¹H NMR(300MHz，CDCl₃)δppm 1.40(t，J＝7.0Hz，3H)2.l7(s，3H)3.82(s，2H)4.00(q，J＝7.0Hz，2H)5.12(s，2H)6.76(s，1H)6.77-6.85(m，2H)6.96-7.05(m，2H )7.27(s，1H)7.30-7.44(m，3H)7.45-7.53(m，2H).EI410(M^-)，412(M+2).

Preparation example 31

Synthesis of 1-bromo-2, 4- (dibenzyloxy) -5- (4-ethoxybenzyl) benzene

Mixing 5-bromo-2, 4-dihydroxybenzoic acid (5.0g, 0.0215mol), potassium carbonate (9.8g, 0.0710mol), and n-Bu₄A suspension of NI (79mg, 0.215mmol), benzyl bromide (8.4mL, 0.0710mol), and N, N-dimethylformamide (40.0mL) was stirred for 60 hours. Ice water was added thereto, and the mixture obtained above was extracted 2 times with ethyl acetate. The combined organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was dissolved in tetrahydrofuran (150 mL). The solution was cooled to-15 ℃ and LiAlH was slowly added₄(1.22g, 0.0323 mol). After stirring the mixture at-5 ℃ for 1.5 hours, LiAIH was added₄(0.41g, 0.011 mol). The reaction mixture was stirred at 5 ℃ for 1 hour, saturated aqueous ammonium chloride solution was carefully added thereto, and insoluble matter precipitated was filtered with celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with 1M hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to give 5-bromo-2, 4- (dibenzyloxy) benzyl alcohol (12.1 g). This was used in the next reaction without purification.

Manganese dioxide (IV) (13.1g, 0.150mol) was added to a solution of 5-bromo-2, 4- (dibenzyloxy) benzyl alcohol (12.1g) in toluene (150 mL). The mixture was stirred at room temperature for 15 hours, at 80 ℃ for 4 hours and at 100 ℃ for 2 hours. Manganese dioxide (IV) (4.0g) was added thereto, and the mixture was stirred at 100 ℃ for 4 hours. Cooled to room temperature and the insoluble material was filtered through celite. The solid obtained by concentrating the filtrate was recrystallized from a mixed solvent of hexane and ethyl acetate to give 5-bromo-2, 4- (dibenzyloxy) benzaldehyde (3.6g, 43%) as a colorless powder.

Next, the title compound was synthesized in the same manner as in preparation example 3 using 5-bromo-2, 4- (dibenzyloxy) benzaldehyde instead of 3-bromobenzaldehyde.

¹H NMR(300MHz，CDCl₃)δppm 1.40(t，J＝7.0Hz，3H)3.84(s，2H)4.01(q，J＝7.0Hz，2H)4.96(s，2H)5.07(s，2H)6.53(s，1H)6.75-6.82(m，2H)7.02-7.10(m，2H)7.20-7.48(m，11H).

EI 525(M⁺)，527(M+2).

Preparation example 32

Synthesis of 1-bromo-2-methoxy-4-methyl-5- (4-methylbenzyl) benzene

To a solution of 4-methoxy-2-methylbenzoic acid (5.0g, 0.0300mol) in chloroform (60mL) was added oxalyl chloride (3.43mL, 0.0400mmol) and N, N-dimethylformamide (2 drops). The reaction solution was stirred at room temperature for 1 hour, and then the reaction solvent was distilled off under reduced pressure. The resulting yellow oil was dissolved in chloroform (60 mL). Toluene (3.52mL, 0.0330mol) and aluminum chloride (8.02g, 0.0601mol) were added to the solution under ice-cooling, and the reaction mixture was stirred under ice-cooling for 3.5 hours. 5% hydrochloric acid was added to the reaction mixture, followed by extraction with chloroform, and the organic phase was washed with 10% hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 15: 1) to give (4-methoxy-2-methylphenyl) (4-methylphenyl) methanone (4.26g, 58.9%) as a yellow oily substance.

¹H NMR(300MHz，CDCl₃)δppm 2.39(s，3H)2.42(s，3H)3.86(s，3H)6.74(dd，J＝8.5，2.56Hz，1H)6.81(d，J＝2.6Hz，1H)7.21-7.27(m，2H)7.31(d，J＝8.4Hz，1H)7.64-7.71(m，2H)

ESI m/z＝263(M+Na)

Et was added to a mixed solution of chloroform (8mL) and acetonitrile (32mL) containing (4-methoxy-2-methylphenyl) (4-methylphenyl) methanone₃SiH (8.5mL, 0.0531mol), BF was added dropwise under ice cooling₃·Et₂O (4.5mL, 0.0354 mol). The reaction mixture was warmed to room temperature and stirred at 50 ℃ for 1 hour. The reaction mixture was added with a saturated aqueous sodium bicarbonate solution under ice-cooling, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 15: 1) to give 4-methoxy-2-methyl-1- (4-methylbenzyl) benzene (3.89g, 97%) as a colorless oil.

¹H NMR(300MHz，CDCl₃)δppm 2.21(s，3H)2.31(s，3H)3.78(s，3H)3.88(s，2H)6.65-6.74(m，2H)6.97-7.03(m，3H)7.03-7.11(m，2H)

EI 226(M⁺)

Br was added dropwise to a solution of 4-methoxy-2-methyl-1- (4-methylbenzyl) benzene in acetic acid (35mL) under ice-cooling₂. The reaction mixture was stirred at 110 ℃ for 2 hours. Water was added to the reaction mixture under ice-cooling, extraction was performed with ethyl acetate, and the organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 15: 1) to obtain the title compound (4.21g, 80%) as a yellow oil.

¹H NMR(300MHz，CDCl₃)δppm 2.20(s，3H)2.31(s，3H)3.85(s，2H)3.87(s，3H)6.71(s，1H)6.94-7.11(m，4H)7.26(s，1H).

EI 304(M⁺)，306(M+2).

Preparation example 33

Synthesis of 1-bromo-2-methoxy-4-methyl-5- (4-ethylbenzyl) benzene

The title compound was synthesized by the same method as in preparation example 32 using ethylbenzene instead of toluene.

¹H NMR(300MHz，CDCl₃)δppm 1.22(t，J＝7.6Hz，3H)2.20(s，3H)2.61(q，J＝7.6Hz，2H)3.85(s，2H)3.87(s，3H)6.71(s，1H)6.97-7.14(m，4H)7.27(s，1H).

EI 318(M⁺).

Preparation example 34

Synthesis of 1-bromo-2-methoxy-4-methyl-5- (4-isopropylbenzyl) benzene

The title compound was synthesized in the same manner as in preparation example 32 using cumene instead of toluene.

¹H NMR(300MHz，CDCl₃)δppm 1.22(s，3H)1.24(s，3H)2.21(s，3H)2.81-2.92(m，1H)3.85(bs，2H)3.87(s，3H)6.71(s，1H)6.98-7.06(m，2H)7.10-7.16(m，2H)7.28(s，1H).

EI 322(M⁺)，334(M+2).

Preparation example 35

Synthesis of 2- (4-ethylbenzyl) phenol

To a suspension of magnesium (17.2g) and tetrahydrofuran (50mL) was added 1-bromo-4-ethylbenzene (6.69g, 0.036mol), and the mixture was refluxed. A solution of 1-bromo-4-ethylbenzene (97.9g, 0.529mol) in tetrahydrofuran (300mL) was then added over 2 hours at room temperature. After stirring at room temperature for 1.5 hours, the reaction mixture was cooled to 4 ℃ and a solution of 2-benzyloxybenzaldehyde (100g, 0.471mol) in tetrahydrofuran (100mL) was added over 1 hour. The reaction mixture was stirred for 2 hours and then poured into a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent 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 95: 5) to give (2-benzyloxyphenyl) (4-ethylphenyl) methanol (152g) as a colorless solid.

¹H-NMR(CDCl₃)δ1.23(t，J＝7.6Hz，3H)，2.64(q，J＝7.6Hz，2H)，2.90(d，J＝5.6Hz，1H)，5.03(s，2H)，6.03(d，1H，J＝5.6Hz)，6.90-7.37(m，12H).

Next, a mixture of (2-benzyloxyphenyl) (4-ethylphenyl) methanol (78.5g), 10% palladium-activated charcoal (5.2g), concentrated hydrochloric acid (10.4mL), and methanol (850mL) was stirred under hydrogen atmosphere at room temperature for 24 hours. After insoluble matter was filtered, the residue obtained by removing the solvent by distillation under the reduced pressure was distilled under the reduced pressure to give the title compound (56.8g) as a colorless oil.

¹H-NMR(CDCl₃)δppm 1.21(t，J＝7.7Hz，3H)，2.62(q，J＝7.7Hz，2H)，4.00(s，2H)，4.64(s，1H)，6.77-7.18(m，8H).

EI 213(M+H).

Preparation example 36

Synthesis of 3- (4-ethylphenoxy) -bromobenzene

At room temperature, 3-bromophenol (2.3g, 13.3mmol), 4-ethylphenylboronic acid (1.0g, 6.67mmol), molecular sieves 4A (14.7g), Cu (OAc)₂A suspension of (121g, 6.67mmol) and chloroform (25mL) was stirred for 3 minutes, and triethylamine (3.6mL) and pyridine (2.7mL) were added. After stirring for 15 hours, the insoluble matter was filtered through celite. After concentrating the filtrate, the residue was purified by silica gel column chromatography (hexane: ethyl acetate 95: 5) to give 1.89g of the title compound as a colorless oil.

EI 276(M⁺)、278(M+2).

Preparation example 37

Synthesis of 3-bromo-5- (4-ethoxybenzyl) pyridine

To a mixture of 1M solution of isopropyl magnesium chloride in tetrahydrofuran (21.1mL) and tetrahydrofuran (10mL) was added dropwise a solution of 3, 5-dibromopyridine (5g, 0.0211mol) in tetrahydrofuran (25mL) over 15 minutes at 4 ℃. After the reaction mixture was stirred at room temperature for 2.5 hours, 4-ethoxybenzaldehyde (2.93mL, 0.0211mol) was added and the mixture was further stirred for 15 hours. Water was added to the reaction mixture under ice-cooling, extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) to give (5-bromopyridin-3-yl) (4-ethoxyphenyl) methanol (5.0g, 77%) as a yellow oil.

Next, (5-bromopyridin-3-yl) (4-ethoxyphenyl) methanol (2.5g, 8.11mmol) and Et were added at 4 deg.C₃Trifluoroacetic acid (12.5mL, 0.162mol) was added dropwise to a chloroform solution of SiH (5.1mL, 40.6mmol), and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to obtain the title compound (1.83g, 77%) as colorless needles.

1H NMR(300MHz，CDCl₃)d ppm 1.41(t，J＝6.99Hz，3H)3.90(s，2H)4.02(q，J＝6.99Hz，2H)6.85(d，J＝8.70Hz，2H)7.07(d，J＝8.70Hz，2H)7.59(t，J＝2.02Hz，1H)8.40(s，1H)8.52(s，1H)

ESI m/z＝292(M+H)，294(M+2+H).

Preparation example 38

Synthesis of 1-bromo-3- [ (2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl ] benzene

To a mixture of (4-ethylbenzyl) triphenylphosphonium chloride (3.52g, 8.44mmol) and tetrahydrofuran (20mL) was added 2M lithium diisopropylamine (heptane/tetrahydrofuran/ethylbenzene solution, 4.2mL, 8.4mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solution was added dropwise to a tetrahydrofuran solution (10mL) of (3-bromophenyl) acetaldehyde (0.56g, 2.81mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with a saturated aqueous ammonium chloride solution under ice-cooling, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: chloroform ═ 20: 1) to give the title compound (0.41g, 50%, E/Z mixture) as a colorless oil.

1H NMR(300MHz，CDCl₃)δppm 1.17-1.30(m，J＝7.41，7.41，7.41Hz，3H)2.56-2.72(m，2H)3.47-3.68(m，2H)5.70-6.63(m，2H)7.04-7.46(m，8H).

EI 300，302(M⁺，M+2).

Preparation example 39

Synthesis of 3-bromo-7- (4-methylbenzyl) -1-benzothiophene

To a solution of 7- (4-methylbenzyl) -1-benzothiophene (1.24g, 5.20mmol) in acetonitrile (30mL) was added N-bromosuccinimide (1.01g, 5.72mmol), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and diluted with ethyl acetate. The organic phase was washed with a 20 wt% aqueous solution of sodium thiosulfate and a saturated common salt solution, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate: 100: 1 to 50: 1) to give the title compound (0.92g, 56%) as a colorless powder.

1H NMR(300MHz，CDCl₃)d ppm 2.31(s，3H)4.12-4.26(m，2H)7.07-7.23(m，5H)7.37-7.50(m，2H)7.72(d，J＝7.46Hz，1H).EI 316，318(M⁺，M+2).

Example 1

Synthesis of 2, 3, 4, 6-tetra-O-benzyl-1-C- [3- (4-ethylbenzyl) phenyl ] -5-thio-D-glucopyranose

A mixture of magnesium (55mg, 2.25mmol), 1-bromo-3- (4-ethylbenzyl) benzene (496mg, 1.80 mmol; see International patent publication No. WO0127128 for synthesis), and tetrahydrofuran (2.0mL) was heated at reflux for 1 hour. After stirring at room temperature for 1 hour, the reaction solution was cooled to 0 ℃. To the solution was added dropwise a solution of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone (500mg, 0.901mmol) in tetrahydrofuran (5.0mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to give the title compound (440mg, 65%) as a colorless oil.

¹H NMR(300MHz，CDCl₃)δppm 1.19(t，J＝7.6Hz，3H)2.59(q，J＝7.6Hz，2H)3.04(s，1H)3.48-3.57(m，1H)3.64(dd，J＝10.1，2.7Hz，1H)3.74(d，J＝10.1Hz，1H)3.88-4.17(m，6H)4.41(d，J＝10.1Hz，1H)4.52(s，2H)4.65(d，J＝10.7Hz，1H)4.81-4.95(m，3H)6.67-6.74(m，2H)7.03-7.21(m，10H)7.22-7.36(m，14H)7.47-7.57(m，2H).

ESI m/z＝773(M+Na).

Example 2

Synthesis of 2, 3, 4, 6-tetra-O-benzyl-1-C- [3- (4-ethylbenzyl) phenyl ] -5-thio-D-glucopyranose via acid radical type complex

A mixture of 1-bromo-3- (4-ethylbenzyl) benzene (1.0g, 3.63mmol) and diethyl ether (10mL) was cooled to-78 deg.C and a 2.6M n-butyllithium in hexane (1.4mL) was added under an argon stream. After stirring for 20 minutes, the reaction mixture was heated to-20 ℃ and stirred for 45 minutes. The solution was dropped into a suspension of CuI (347mg, 1.82mmol) in diethyl ether (10mL) with a cannula. During the dropping, the suspension turned black and was heated to-9 ℃. After dropwise addition, the mixture was stirred at-15 ℃ for 15 minutes, and a solution of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone (671mg, 1.21mmol) in diethyl ether (4.0mL) was added dropwise and stirred for 20 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give the title compound (1.0g) as a colorless oil. The NMR spectrum was in accordance with example 1.

Example 3

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- (4-ethylbenzyl) phenyl ] -1-thio-D-glucitol

To 2, 3, 4, 6-tetra-O-benzyl-1-C- [3- (4-ethylbenzyl) phenyl at-18 deg.C]Et was added to a solution of-5-thio-D-glucopyranose (410mg, 0.546mmol) in dichloromethane (20mL) in order₃SiH (0.523mL, 3.28mmol) and BF₃·Et₂O (0.276mL, 2.18mmol), stirred for 0.5 h. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 10: 1) to give the title compound (250mg, 62%) as a colorless powder.

¹H NMR(300MHz，CDCl₃)δppm 1.19(t，J＝7.6Hz，3H)2.59(q，J＝7.6Hz，2H)3.05-3.16(m，1H)3.53(t，J＝8.9Hz，1H)3.67-3.99(m，8H)4.47(d，J＝10.0Hz，1H)4.53(s，2H)4.60(d，J＝10.7Hz，1H)4.85-4.94(m，3H)6.62-6.69(m，2H)7.00-7.20(m，10H)7.22-7.36(m，16H).

ESI m/Z＝757(M+Na).mp 100.0-102.5℃.

Example 4

Synthesis of (1S) -1, 5-anhydro-1- [3- (4-ethylbenzyl) phenyl ] -1-thio-D-glucitol

To (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- (4-ethylbenzyl) phenyl at-78 deg.C]To a solution of (E) -1-thio-D-glucitol (200mg, 0.272mmol) in methylene chloride (20mL) was added dropwise 1M BBr₃Dichloromethane (4.08 mL). After stirring at this temperature for 2.5 hours, methanol (5.0mL) and pyridine (3.0mL) were added in this order. The mixture was heated to room temperature and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol: 10: 1) to give the title compound (23mg, 23%) as a colorless amorphous substance.

¹H NMR(300MHz，CD₃OD)δppm 1.19(t，J＝7.6Hz，3H)2.58(q，J＝7.6 Hz，2H)2.95-3.03(m，1H)3.20-3.28(m，1H)3.60(dd，J＝10.3，9.0Hz，1H)3.70-3.78(m，3H)3.88-3.98(m，3H)7.09(brs，5H)7.17-7.23(m，3H).

ESI m/z＝397(M+Na)，373(M-H).

Example 5

Synthesis of 2, 3, 4, 6-tetra-O-benzyl-1-C- [ 2-methoxy-4-methyl-5- (4-ethoxybenzyl) phenyl ] -5-thio-D-glucopyranose

To a mixture of magnesium (41mg, 1.67mmol), 1-bromo-3- (4-ethoxybenzyl) -6-methoxy-4-methylbenzene (0.51g, 1.51mmol) and tetrahydrofuran (2mL) was added dropwise 1, 2-dibromoethane (5 drops). After the mixture was heated under reflux for 1 hour, it was left to cool to room temperature to prepare a grignard reagent. A1.0M solution of isopropyl magnesium chloride in tetrahydrofuran (1.40mL) and the prepared Grignard reagent were added dropwise to a solution of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone (0.76g, 1.38mmol) in tetrahydrofuran (5mL) under ice-cooling, and the mixture was stirred for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give the title compound (0.76g, 68%) as a yellow oil.

¹H NMR(300MHz，CDCl₃)δppm 1.37(t，J＝6.92Hz，3H)2.21(s，3H)3.51-4.20(m，12H)3.85-3.89(m，3H)4.51(s，2H)4.65(d，J＝10.72Hz，1H)4.71(d，J＝5.75Hz，1H)4.78-4.99(m，3H)6.59-7.43(m，26H)

Example 6

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [ 2-methoxy-4-methyl-5- (4-ethoxybenzyl) phenyl ] -1-thio-D-glucitol

At-18 deg.C to 2, 3, 4, 6-tetra-O-benzyl-1-C- [ 2-methoxy-4-methyl-5- (4-ethoxybenzyl) phenyl]To a solution of-5-thio-D-glucopyranose (840mg, 1.04mmol) in acetonitrile (18mL) was added Et in sequence₃SiH (0.415mL, 2.60mmol) and BF₃·Et₂O (0.198mL, 1.56mmol) was stirred for 1 hour. Adding saturated aqueous sodium bicarbonate solution to the reaction solutionThe extract was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound (640mg, 77%).

¹H NMR(600MHz，CDCl₃)δppm 1.35(t，J＝6.88Hz，3H)2.21(s，3H)3.02-3.21(m，1H)3.55(t，J＝9.40Hz，1H)3.71(s，1H)3.74-3.97(m，10H)4.01(s，1H)4.45-4.56(m，3H)4.60(d，J＝10.55Hz，2H)4.86(s，2H)4.90(d，J＝10.55Hz，1H)6.58-6.76(m，5H)6.90(d，J＝7.34Hz，1H)7.09-7.19(m，5H)7.23-7.35(m，15H).

ESI m/z＝812(M+NH₄).

Example 7

Synthesis of (1S) -1, 5-anhydro-1- [3- (4-ethoxybenzyl) -6-methoxy-4-methylphenyl ] -1-thio-D-glucitol

A mixture of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [ 2-methoxy-4-methyl-5- (4-ethoxybenzyl) phenyl ] -1-thio-D-glucitol (630mg, 0.792mmol), 20% palladium hydroxide activated charcoal (650mg), and ethyl acetate (10mL) -ethanol (10mL) was stirred at room temperature for 66 hours under a hydrogen atmosphere. Insoluble matter in the reaction mixture was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol ═ 10: 1) to give the title compound (280mg, 81%) as a colorless powder as a 0.5 hydrate.

1H NMR(600MHz，CD₃OD)δppm 1.35(t，J＝6.9Hz，3H)2.17(s，3H)2.92-3.01(m，1H)3.24(t，J＝8.71Hz，1H)3.54-3.60(m，1H)3.72(dd，J＝11.5，6.4Hz，1H)3.81(s，3H)3.83(s，2H)3.94(dd，J＝11.5，3.7Hz，1H)3.97(q，J＝6.9Hz, 2H)4.33(s, 1H)6.77(d, J ═ 8.3Hz, 2H)6.76(s, 1H)6.99(d, J ═ 8.3Hz, 2H)7.10(s, 1H) ESI M/z ═ 452(M + NH4+), 493(M + CH3CO2-). mp 155.0-157.0 ℃. calcd for C₂₃H₃₀O₆S·0.5H₂O: c, 62.28; h, 7.06. found: c, 62.39; h, 7.10.

Example 8

Synthesis of 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (4-ethoxybenzyl) phenyl ] -5-thio-D-glucopyranose

To a mixture of magnesium (175mg, 7.20mmol), 1- (benzyloxy) -2-bromo-4- (4-ethoxybenzyl) benzene (2.29g, 5.76mmol) and tetrahydrofuran (6.0mL) was added 1, 2-dibromoethane (3 drops), and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, and 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone (1.6g, 2.9mmol) in tetrahydrofuran (5.0mL) was added dropwise to the mixture, followed by stirring at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 6: 1) to give the title compound (1.48g, 59%) as a pale yellow powder.

¹H NMR(300MHz，CDCl₃)δppm 1.38(t，J＝7.0Hz，3H)3.48-3.71(m，2H)3.77-4.10(m，9H)4.51(brs，2H)4.59-4.74(m，2H)4.77-4.94(m，3H)5.09(s，2H)6.64-7.40(m，32H).

ESI m/z＝895(M+Na).

Example 9

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-ethoxybenzyl) phenyl ] -1-thio-D-glucitol

To 2, 3, 4, 6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (4-ethoxybenzyl) phenyl at-20 deg.C]To a solution of-5-thio-D-glucopyranose (850mg, 0.974mmol) in chloroform (8.0mL) -acetonitrile (8.0mL) was added Et in sequence₃SiH (0.933mL, 5.84mmol) and BF₃·Et₂O (0.494mL, 3.90mmol), stir for 1 hour. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 8: 1) to give the title compound (810mg, 97%) as a colorless powder.

¹H NMR(300MHz，CDCl₃)δppm 1.36(t，J＝7.0Hz，3H)3.04-3.18(m，1H)3.54(t，J＝8.4Hz，1H)3.65-3.76(m，1H)3.77-4.06(m，8H)4.40-4.73(m，5H)4.83-5.12(m，5H)6.62-6.87(m，5H)6.92-7.46(m，27H).

ESIm/z＝879(M+Na)

Example 10

Synthesis of (1S) -1, 5-anhydro-1- [5- (4-ethylbenzyl) -2-hydroxyphenyl ] -1-thio-D-glucitol

A mixture of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-ethoxybenzyl) phenyl ] -1-thioxo-D-glucitol (810mg, 0.954mmol), 20% palladium hydroxide activated charcoal (800mg), and ethyl acetate (5.0mL) -ethanol (5.0mL) was stirred at room temperature for 46 hours under a hydrogen atmosphere. Insoluble matter in the reaction mixture was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol ═ 10: 1 to 5: 1) to give the title compound (202mg, 53%) as a colorless powder as a 0.7 hydrate.

¹H NMR(300MHz，CD₃OD) δ ppm 1.37(t, J ═ 7.0Hz, 3H)2.94-3.05(M, 1H)3.22-3.29(M, 1H)3.60(M, 1H)3.69-3.88(M, 4H)3.90-4.04(M, 3H)4.33(d, J ═ 10.6Hz, 1H)6.71(d, J ═ 8.2Hz, 1H)6.76-6.90(M, 3H)7.03-7.15(M, 3H) ESI M/z ═ 429(M + Na), 405 mp (M-H) 145.0-150.0 ℃. calcd₂₃H₂₈O₆S·0.7H₂O: c, 61.00; h, 6.86. found: c, 60.81; h, 6.89.

Example 11

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [ 4-chloro-3- (4-ethoxy-2-methylbenzyl) phenyl ] -1-thio-D-glucitol

To a mixture of magnesium (1.11g, 45.7mmol), 2- (5-bromo-2-chlorophenyl) -1, 3-dioxolane (9.64g, 36.5mmol) and tetrahydrofuran (20mL) was added 1, 2-dibromoethane (5 drops), and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, and 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone (10.14g, 36.5mmol) in tetrahydrofuran (15mL) was added dropwise to the mixture, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by distillation under the reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: 4: 1 to 3: 1) to obtain colorless amorphous 2, 3, 4, 6-tetra-O-benzyl-1-C- [ 4-chloro-3- (1, 3-dioxolan-2-yl) phenyl ] -5-thio-D-glucopyranose (11.81g, 87%).

¹H NMR(300MHz，CDCl₃)δppm 3.06(s，1H)3.47-3.58(m，1H)3.64(dd，J＝10.0，2.9Hz，1H)3.83-4.21(m，9H)4.48-4.56(m，3H)4.66(d，J＝10.6Hz，1H)4.82-4.97(m，3H )6.15(s，1H)6.77(dd，J＝7.9，1.5Hz，2H)7.08-7.21(m，5H)7.23-7.37(m，14H)7.55(dd，J＝8.4，2.5Hz，1H)7.92(d，J＝2.5Hz，1H).

Subsequently, 6M hydrochloric acid (120mL) was added to a tetrahydrofuran (50mL) solution of 2, 3, 4, 6-tetra-O-benzyl-1-C- [ 4-chloro-3- (1, 3-dioxolan-2-yl) phenyl ] -5-thio-D-glucopyranose (6.01g, 8.12mmol) under ice cooling, and the mixture was stirred at room temperature for 2 days. Ice water was added to the reaction mixture, which was extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane: ethyl acetate: 3: 1), and colorless amorphous 2, 3, 4, 6-tetra-O-benzyl-1-C- (4-chloro-3-formylphenyl) -5-thio-D-glucopyranose (4.53g, 80%) was obtained.

¹H NMR(300MHz，CDCl₃)δppm 3.14(s，1H)3.43-3.58(m，1H)3.63(dd，J＝10.0，2.6Hz，1H)3.87-4.16(m，5H)4.45-4.72(m，4H)4.80-5.05(m，3H)6.73(d，J＝7.8Hz，2H)7.02-7.43(m，19H)7.74(dd，J＝8.4，2.5Hz，1H)8.06(d，J＝2.5Hz，1H)10.39(s，1H).

Next, a 2.6M n-butyllithium in hexane (1.6mL) was added to a mixture of 1-bromo-4-ethoxy-2-methylbenzene (0.94g, 4.37mmol) and tetrahydrofuran (12mL) at-78 ℃. After stirring for 1 hour, a solution of 2, 3, 4, 6-tetra-O-benzyl-1-C- (4-chloro-3-formylphenyl) -5-thio-D-glucopyranose (1.52g, 2.18mmol) in tetrahydrofuran (10mL) was added, and the reaction mixture was allowed to warm to room temperature for an additional 20 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent 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 obtain a yellow amorphous diastereomer mixture of 2, 3, 4, 6-tetra-O-benzyl-1-C- [ 4-chloro-3- [ (4-ethoxy-2-methylphenyl) (hydroxy) methyl ] phenyl ] -5-thio-D-glucopyranose (1.72g, 95%).

Next, 2, 3, 4, 6-tetra-O-benzyl-1-C- [ 4-chloro-3- [ (4-ethoxy-2-methylphenyl) (hydroxy) methyl group was added under ice-cooling]Phenyl radical]To a solution of-5-thio-D-glucopyranose (1.72g, 2.06mmol) in acetonitrile (20mL) was added Et in sequence₃SiH (1.98mL, 12.4mmol) and BF₃·Et₂O (1.04mL, 8.27 mmol). After stirring for 1 hour, the reaction mixture was warmed to room temperature and stirred for 3 hours. To the reaction mixture was added a saturated aqueous sodium carbonate solution, followed by extraction with ethyl acetate, washing of the organic layer with a saturated saline solution, and drying over anhydrous magnesium sulfate. The drying agent was filtered off, and the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to give (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [ 4-chloro-3- (4-ethoxy-2-methylbenzyl) phenyl ] as a colorless powder]-1-thio-D-glucitol (1.01g, 61%).

¹H NMR (300MHz，CDCl₃)δppm 1.40(t，J＝7.0Hz，3H)2.14(s，3H)3.01-3.12(m，1H)3.48(t，J＝8.9Hz，1H)3.65-4.06(m，10H)4.46-4.61(m，4H)4.80-4.91(m，3H)6.58(dd，J＝8.2，2.5Hz，1H)6.68-6.76(m，2H)6.81(d，J＝8.4Hz，1H)6.98(d，J＝2.2Hz，1H)7.10-7.39(m，21H).

Example 12

Synthesis of (1S) -1, 5-anhydro-1- [ 4-chloro-3- (4-ethoxy-2-methylbenzyl) phenyl ] -1-thio-D-glucitol

To (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [ 4-chloro-3- (4-ethoxy-2-methylbenzyl) phenyl at room temperature]AlCl was added to a solution of (0.99g, 1.23mmol) of (E) -1-thio-D-glucitol in anisole (10mL)₃(0.83g, 6.19mmol), and stirred for 30 minutes. Ice water was added to the reaction mixture, which was extracted with ethyl acetate, and the organic phase was washed with 1M hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 10: 1) to give the title compound (55mg, 10%) as colorless amorphous.

¹H NMR(300MHz，CD₃OD)δppm 1.37(t，J＝6.9Hz，3H)2.17(s，3H)2.90-3.01(m，1H)3.14-3.24(m，1H)3.54(dd，J＝10.3，9.2Hz，1H)3.60-3.76(m，3H)3.86-4.06(m，5H)6.66(dd，J＝8.6，2.7Hz，1H)6.75(d，J＝3.0Hz，1H)6.85-6.95(m，2H)7.19(dd，J＝8.2，2.2Hz，1H)7.35(d，J＝8.2Hz，1H).

ESI m/z＝461(M+Na)，437(M-H).

Example 13

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [4- (4-tetrahydropyranyloxy) benzyl ] phenyl ] -1-thio-D-glucitol

To a mixture of 1-bromo-4- (4-tetrahydropyranyloxy) benzene (0.545g, 2.12mmol) and tetrahydrofuran (6mL) was added a 2.6M solution of n-butyllithium in hexane (0.8mL) at-78 ℃. After stirring for 1.5 hours, a solution of 2, 3, 4, 6-tetra-O-benzyl-1-C- (3-formylphenyl) -5-thio-D-glucopyranose (0.70g, 1.06mmol) in tetrahydrofuran (8mL) was added and the reaction was allowed to warm to room temperature for an additional 3 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate ═ 2: 1) to give 2, 3, 4, 6-tetra-O-benzyl-1-C- [3- [ [4- (4-tetrahydropyranyloxy) phenyl ] (hydroxy) methyl ] phenyl ] -5-thio-D-glucopyranose (0.67g, 76%).

Next, 2, 3, 4, 6-tetra-O-benzyl-1-C- [3- [ [4- (4-tetrahydropyranyloxy) phenyl ] was reacted at-15 deg.C](hydroxy) methyl group]Phenyl radical]To a solution of-5-thio-D-glucopyranose (0.67g, 0.802mmol) in acetonitrile (8mL) was added Et in sequence₃SiH (0.78mL, 4.90mmol) and BF₃·Et₂O (0.41mL, 3.27 mmol). After stirring for 1 hour, the reaction mixture was warmed to room temperature and stirred for 3 hours. To the reaction mixture was added a saturated aqueous sodium carbonate solution, followed by extraction with ethyl acetate, washing of the organic layer with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give the title compound (0.37g, 57%) as a colorless powder.

1H NMR(300MHz，CDCl₃)δppm 1.66-1.81(m，2H)1.88-2.02(m，2H)3.05-3.15(m，1H)3.47-3.59(m，3H)3.64-4.00(m，10H)4.33-4.42(m，1H)4.46(d，J＝9.95Hz，1H)4.52(s，2H)4.60(d，J＝10.41Hz，1H)4.84-4.93(m，3H)6.60-6.67(m，2H)6.72-6.79(m，2H)6.99-7.19(m，8H)7.20-7.35(m，16H).ESI m/Z＝824(M+NH4).

Example 14

Synthesis of (1S) -1, 5-anhydro-1- [3- [4- (4-tetrahydropyranyloxy) benzyl ] phenyl ] -1-thio-D-glucitol

Using the same procedure as in example 7, from (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [4- (4-tetrahydropyranyloxy) benzyl ] phenyl ] -1-thioxo-D-glucitol, amorphous title compound (18mg) was obtained.

Example 15

Synthesis of 2, 3, 4, 6-tetra-O-allyl-1-C- [ 4-chloro-5- (4-ethoxybenzyl) -2-methoxyphenyl ] -5-thio-D-glucopyranose

To a mixture of magnesium (171mg, 7.03mmol), 1-bromo-4-chloro-3- (4-ethoxybenzyl) -6-methoxybenzene (2.0g, 5.62mmol) and tetrahydrofuran (5mL) was added 1, 2-dibromoethane (3 drops), and the mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, and a solution of 2, 3, 4, 6-tetra-O-allyl-5-thio-D-glucono-1, 5-lactone (1.5g, 4.22mmol) in tetrahydrofuran (20mL) was added dropwise to the mixture, followed by stirring at room temperature for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by reduced pressure distillation was purified by silica gel column chromatography (hexane: ethyl acetate ═ 6: 1 → 5: 1) to give the title compound (1.41g, 53%) as a pale yellow oil.

¹H NMR(300MHz，CDCl₃)δppm 1.39(t，J＝7.0Hz，3H)3.36-3.47(m，1H )3.49-4.10(m，17H)4.10-4.44(m，4H)4.84-4.97(m，2H)5.08-5.35(m，5H)5.42-5.60(m，1H)5.75-6.07(m，3H)6.78(d，J＝8.6Hz，2H)6.92(s，1H)7.03(d，J＝8.6Hz，2H)7.32(brs，1H)

ESI m/z＝653(M+Na)，655(M+2+Na).

Example 16

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-allyl-1- [ 4-chloro-5- (4-ethoxybenzyl) -2-methoxyphenyl ] -1-thio-D-glucitol

To 2, 3, 4, 6-tetra-O-allyl-1-C- [ 4-chloro-5- (4-ethoxybenzyl) -2-methoxyphenyl at-15 DEG C]To a solution of-5-thio-D-glucopyranose (1.41g, 2.23mmol) in chloroform (20mL) -acetonitrile (20mL) was added Et in sequence₃SiH (2.16mL, 13.4mmol) and BF₃·Et₂O (1.13mL, 8.92mmol), and stirred for 1 hour. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 10: 1) to give the title compound (895mg, 65%) as a colorless powder.

¹H NMR(300MHz，CDCl₃)δppm 1.39(t，J＝7.0Hz，3H)2.95-3.04(m，1H)3.21-3.30(m，1H)3.41-3.79(m，5H)3.81(s，3H)3.84-4.20(m，8H)4.25-4.42(m，4H)4.81-4.91(m，2H)5.09-5.33(m，6H)5.34-5.52(m，1H)5.79-6.04(m，3H)6.78(d，J＝8.9Hz，2H)6.87(s，1H)7.03(d，J＝8.9Hz，2H)7.21(brs，1H)

ESI m/z＝637(M+Na)，639(M+2+Na).

Example 17

Synthesis of (1S) -1, 5-anhydro-1- [ 4-chloro-5- (4-ethoxybenzyl) -2-methoxyphenyl ] -1-thioxo-D-glucitol

A mixture of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-allyl-1- [ 4-chloro-5- (4-ethoxybenzyl) -2-methoxyphenyl ] -1-thio-D-glucitol (100mg, 0.163mmol), tetrakis (triphenylphosphine) palladium (38mg, 0.0325mmol), N' -dimethylbarbituric acid (203mg, 1.3mmol), and tetrahydrofuran (1.0mL) was stirred at 90 ℃ for 1.5 hours under an argon stream atmosphere. The reaction mixture was cooled to room temperature, added to a saturated aqueous sodium carbonate solution, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (chloroform: methanol ═ 10: 1 → 5: 1) to give the title compound (63mg, 85%) as a colorless powder.

1H NMR(600MHz，CD₃OD)δppm 1.35(t，J＝6.9Hz，3H)2.92-3.00(m，1H)3.22(t，J＝8.9Hz，1H)3.53-3.59(m，1H)3.72(dd，J＝11.7，6.7Hz，1H)3.82(s，3H)3.88-3.95(m，3H)3.99(q，J＝6.9Hz，2H)6.79(d，J＝8.7Hz，2H)6.98(s，1H)7.06(d，J＝8.71Hz，2H)7.20(s，1H).ESI m/z＝477(M+Na)，479(M+2+Na)，453(M-H)，455(M+2-H).mp 177.0-179.0℃.

Example 18

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [ 4-chloro-3- (tert-butoxycarbonyl) phenyl ] -1-thio-D-glucitol

To a mixture of 1.0M isopropyl magnesium bromide in tetrahydrofuran (2.23mL) and tetrahydrofuran (9mL) was added 2.6M n-butyllithium in hexane (1.72mL) at-5 ℃. After stirring for 0.5 h, the reaction mixture was cooled to-78 deg.C and a solution of tert-butyl 5-bromo-2-chlorobenzoate (542mg, 1.86mmol) in tetrahydrofuran (4.0ml) was added. After stirring the solution for 1 hour, a solution of 2, 3, 4, 6-tetra-O-benzyl-5-thio-D-glucono-1, 5-lactone (430mg, 0.798mmol) in tetrahydrofuran (3.0mL) was added and the mixture was stirred for an additional 15 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by distillation under the reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to give 2, 3, 4, 6-tetra-O-benzyl-1-C- [ 4-chloro-3- (tert-butoxycarbonyl) phenyl ] -5-thio-D-glucopyranose (60mg, 10%).

ESI m/z＝789(M+Na)，791(M+2+Na)

Next, 2, 3, 4, 6-tetra-O-benzyl-1-C- [ 4-chloro-3- (tert-butoxycarbonyl) phenyl was reacted at-40 deg.C]To a solution of-5-thio-D-glucopyranose (60mg, 0.0782mmol) in chloroform (1.0mL) -acetonitrile (1.0mL) was added Et in sequence₃SiH (0.031mL, 0.195mmol) and BF₃·Et₂O (0.015mL, 0.117 mmol). After stirring for 1.5 hours, a saturated aqueous sodium carbonate solution was added, and the organic solvent was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate; 5: 1) to give the title compound (26mg, 44%).

1H NMR(300MHz，CDCl₃)δppm 1.61(s，9H)3.06-3.21(m，1H)3.51-3.64(m，1H)3.66-3.77(m，1H)3.78-4.06(m，5H)4.48-4.67(m，4H)4.84-4.95(m，3H)6.75(dd，J＝7.54，1.79Hz，2H)7.08-7.20(m，5H)7.24-7.46(m，15H)7.77(d，J＝2.02Hz，1H).ESIm/z＝768(M+Na)，770(M+2+Na).

Example 19

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [ 4-chloro-3- [ [ (4-ethylphenyl) amino ] carbonyl ] phenyl ] -1-thio-D-glucitol

Concentrated hydrochloric acid (1.0mL) was added to a solution of (1S) -1, 5-anhydro-1- [ 4-chloro-5- (4-ethoxybenzyl) -2-methoxyphenyl ] -1-thio-D-glucitol (30mg, 0.040mmol) in tetrahydrofuran (2.0mL), and the reaction mixture was stirred at room temperature for 24 hours and at 40 ℃ for 2 hours, followed by addition of ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by distillation under the reduced pressure to give (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [ 4-chloro-3-carboxyphenyl ] -1-thio-D-glucitol.

Next, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13mg, 0.069mmol) and 1-hydroxybenzotriazole (9mg, 0.069mmol) were added to a solution of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [ 4-chloro-3-carboxyphenyl ] -1-thio-D-glucitol and 4-ethylaniline (13mg, 0.104mmol) in chloroform. The reaction mixture was stirred at room temperature for 21 hours, diluted with chloroform, and the organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution and dried over anhydrous magnesium sulfate. After the drying agent 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 above anilide compound (22 mg).

1H NMR(300MHz，CDCl₃) δ ppm 1.26(t, J ═ 7.15Hz, 3H)2.65(q, J ═ 7.67Hz, 1H)3.06-3.24(M, 1H)3.50-3.61(M, 1H)3.71(dd, J ═ 9.87, 3.03Hz, 1H)3.78-4.09(M, 6H)4.52(s, 2H)4.62(t, J ═ 10.34Hz, 2H)4.84-4.98(M, 3H)6.75-6.85(M, 2H)7.08-7.56(M, 25H)7.72(d, J ═ 2.02Hz, 1H) ESI M/Z ═ 9(M-H) light yellow powder

Example 20

Synthesis of (1S) -1, 5-anhydro-1- [ 4-chloro-3- [ [ (4-ethylphenyl) amino ] carbonyl ] phenyl ] -1-thio-D-glucitol

To a mixture of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [ 4-chloro-3- [ [ (4-ethylphenyl) amino ] carbonyl ] phenyl ] -1-thioxo-D-glucitol (20mg, 0.025mmol), trifluoroacetic acid (0.5mL), dimethylsulfide (0.3mL), m-cresol (0.08mL), ethanedithiol (0.02mL) was added trifluoromethanesulfonic acid (0.1mL) at-15 ℃. After stirring for 15 minutes, a saturated aqueous sodium bicarbonate solution was added, and extraction was performed with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (chloroform: methanol ═ 10: 1) to give the title compound (6mg, 54%) as a colorless powder.

1H NMR(600MHz，CD₃OD) δ ppm 1.23(t, J ═ 7.57Hz, 3H)2.64(q, J ═ 7.79Hz, 2H)3.00-3.07(M, 1H)3.27(t, J ═ 8.71Hz, 1H)3.59-3.64(M, 1H)3.73-3.82(M, 2H)3.89(d, J ═ 10.09Hz, 1H)3.95(dd, J ═ 11.69, 3.44Hz, 1H)7.20(d, J ═ 8.25Hz, 2H)7.47(s, 2H)7.53(s, 1H)7.56(d, J ═ 8.71Hz, 2H) ESI M/Z ═ 438(M + Na), 440(M +2+ Na) colorless powder

Example 21

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- (hydroxymethyl) phenyl ] -1-thio-D-glucitol

To a solution of 2, 3, 4, 6-tetra-O-benzyl-1-C- (3-formylphenyl) -5-thio-D-glucopyranose (4.0g, 6.05mmol) in chloroform (35mL) -acetonitrile (35mL) at-15 deg.C was added Et in sequence₃SiH (5.8mL, 36.3mmol) and BF₃·Et₂O (3.1mL, 24.2 mmol). After stirring for 1.5 hours, a saturated aqueous sodium bicarbonate solution was added, the mixture was extracted with chloroform, and the organic phase was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solid obtained by removing the solvent by distillation under reduced pressure was washed with hexane/ethyl acetate (10: 1) to give the title compound as a colorless powderProduct (3.2g, 77%).

1H NMR(300MH z，CDCl₃)δppm 3.07-3.18(m，1H)3.55(t，1H)3.72(dd，1H)3.78-4.01(m，5H)4.46-4.69(m，6H)4.87-4.96(m，3H)6.69(dd，J＝7.69，1.48Hz，2H)7.07-7.45(m，22H).

Example 22

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- (bromomethyl) phenyl ] -1-thio-D-glucitol

To a solution of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- (hydroxymethyl) phenyl ] -1-thio-D-glucitol (100mg, 0.155mmol) in tetrahydrofuran (1.5mL) at 4 deg.C was added methanesulfonyl chloride (0.018mL) and triethylamine (0.021 mL). The reaction mixture was stirred at room temperature for 3 hours and diluted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to give (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- (methylsulfonoxymethyl) phenyl ] -1-thio-D-glucitol (150 mg). Then, a mixture of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- (methylsulfonoxymethyl) phenyl ] -1-thioxo-D-glucitol (150mg), LiBr (40mg, 0.466mmol) and acetone (3mL) was stirred at room temperature for 2 hours. After the reaction solution was concentrated, ethyl acetate and water were added. The organic layer was separated, washed with saturated saline, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to give the title compound (70mg, 64%).

1H NMR(300MHz，CDCl₃)δppm 3.06-3.17(m，1H)3.55(t，J＝8.94Hz，1H)3.72(dd，1H)3.78-4.02(m，5H)4.41-4.65(m，6H)4.85-4.96(m，3H)6.66-6.72(m，J＝7.46，2.02Hz，2H)7.10-7.51(m，22H).

ESI m/z＝726(M+NH₄ ⁺).728(M+2+NH₄ ⁺)

Example 23

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [ (1-methyl-1H-pyrrolyl-2-yl) methyl ] phenyl ] -1-thio-D-glucitol

(1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- (bromomethyl) phenyl at 60 deg.C]-1-thio-D-glucitol (200mg, 0.282mmol), 1-methyl-2- (tributylstannyl) -1H-pyrrolyl (208mg, 0.564mmol), tris (dibenzylideneacetone) dipalladium (38mg, 0.0423mmol), 2- (dicyclohexylphosphino) biphenyl (36mg, 0.0987mmol), KF (67mg, 1.16mmol), CsCO₃A mixture of (257mg, 0.792mmol) and 1, 4-dioxane (5mL) was stirred for 8 hours. After insoluble matter was filtered, the residue obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to give the title compound (190mg, 95%).

1H NMR(300MHz，CDCl₃)δppm 3.04-3.16(m，1H)3.32(s，3H)3.53(t，J＝8.70Hz，1H)3.67-3.75(m，1H)3.75-4.00(m，7H)4.46-4.56(m，3H)4.60(d，J＝10.57Hz，1H)4.84-4.96(m，3H)5.89(dd，J＝3.73，1.55Hz，1H)6.04(t，J＝3.03Hz，1H)6.49-6.54(m，1H)6.70(dd，J＝7.62，1.71Hz，2H)7.05-7.18(m，7H)7.22-7.36(m，14H)7.39-7.46(m，1H).ESI m/Z＝710(M+H)，732(M+Na).

Example 24

Synthesis of (1S) -1, 5-anhydro-1- [3- [ (1-methyl-1H-pyrrol-2-yl) methyl ] phenyl ] -1-thioxo-D-glucitol

To a mixture of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [ (1-methyl-1H-pyrrol-2-yl) methyl ] phenyl ] -1-thioxo-D-glucitol (190mg), trifluoroacetic acid (1.0mL), dimethylsulfide (0.6mL), m-cresol (0.16mL), ethanedithiol (0.04mL) was added trifluoromethanesulfonic acid (0.2mL) at-15 ℃. After stirring for 15 minutes, a saturated aqueous sodium bicarbonate solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (chloroform: methanol ═ 10: 1) to give the title compound (16mg, 17%) as a colorless powder.

1H NMR(300MHz，CD₃OD)δppm 2.92-3.05(m，1H)3.19-3.29(m，1H)3.39(s，3H)3.59(t，J＝9.64Hz，1H)3.68-3.83(m，3H)3.86-4.02(m，3H)5.80-5.87(m，1H)5.94(t，J＝3.11Hz，1H)6.55(d，J＝1.87Hz，1H)7.03(dd，J＝6.99，1.71Hz，1H)7.12-7.28(m，3H).ESI m/Z＝372(M+Na).

Example 25

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [ (4-methoxy-1H-indol-1-yl) methyl ] phenyl ] -1-thio-D-glucitol

To a solution of 4-methoxyindole (83mg, 0.564mmol) in N, N-dimethylformamide (1.0mL) was added sodium hydride (22mg, 0.564 mmol; 60% oil) at room temperature, and the mixture was stirred for 20 minutes. To the solution was added a solution of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- (bromomethyl) phenyl ] -1-thio-D-glucitol (200mg, 0.282mmol) in N, N-dimethylformamide (2.0mL), and the mixture was stirred at room temperature for 3 hours and then water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound (290 mg).

1H NMR(300MHz，CDCl₃)δppm 3.05-3.14(m，1H)3.46-3.56(m，1H)3.66-3.74(m，1H)3.76-3.92(m，5H)3.95(s，3H)4.46(d，J＝10.10Hz，1H)4.52(s，2H)4.59(d，J＝10.57Hz，1H)4.84-4.93(m，3H)5.25(d，J＝2.49Hz，2H)6.46-7.39(m，29H).ESI m/z＝793(M+NH₄)

Example 26

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [ (4-hydroxyphenyl) methyl ] phenyl ] -1-thio-D-glucitol

The title compound (253mg) was obtained as a colorless oil from (4-bromophenoxy) tert-butyl-dimethylsilane (2.17g) and 2, 3, 4, 6-tetra-O-benzyl-1-C- (3-formylphenyl) -5-thio-D-glucopyranose (2.50g) by the same method as in example 11.

1H NMR(300MHz，CDCl₃)δppm 3.03-3.15(m，1H)3.52(t，J＝8.78Hz，1H)3.66-3.74(m，1H)3.75-3.97(m，6H)4.43-4.55(m，3H)4.56-4.74(m，3H)4.84-4.94(m，3H)6.62-6.70(m，4H)7.00(d，J＝8.70Hz，2H)7.06-7.20(m，6H)7.21-7.41(m，16H)

ESI m/z＝740(M+NH₄).

Example 27

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [4- (2-methoxy-2-oxoethoxy) benzyl ] phenyl ] -1-thio-D-glucitol

To a solution of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [ (4-hydroxyphenyl) methyl ] phenyl ] -1-thio-D-glucitol (364mg, 0.504mmol) in N, N-dimethylformamide (5mL) at 4 ℃ were added potassium carbonate (91mg, 0.660mmol) and methyl bromoacetate (0.058mL, 0.610mmol), and the mixture was stirred at room temperature for 5 hours. After water was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give the title compound (334mg, 83%) as a colorless oil.

1H NMR(300MHz，CDCl₃)δppm 3.05-3.15(m，1H)3.52(t，J＝8.94Hz，1H)3.66-3.75(m，1H)3.75-3.98(m，10H)4.41-4.64(m，6H)4.83-4.95(m，3H)6.60-6.79(m，4H)6.98-7.19(m，8H)7.22-7.36(m，16H).ESIm/Z＝817(M+Na).

Example 28

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [4- (carboxymethoxy) benzyl ] phenyl ] -1-thio-D-glucitol

Lithium hydroxide 1 hydrate (11mg, 0.27mmol) was added to a solution of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [ [4- (methoxycarbonylmethoxy) phenyl ] methyl ] phenyl ] -1-thio-D-glucitol (180mg, 0.226mmol) in water-methanol-tetrahydrofuran (1: 3, 1.4mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified by addition of 10% HCl, and the precipitated residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the drying agent was filtered off, and then the solvent was distilled off under reduced pressure to give the title compound (149mg, 84%) as a colorless powder.

1H NMR(300MHz，CDCl₃)δppm 3.04-3.15(m，1H)3.46-3.58(m，1H)3.66-3.96(m，7H)4.41-4.54(m，3H)4.55-4.63(m，3H)4.82-4.95(m，3H)6.65(dd，J＝8.00，1.48Hz，2H)6.76(d，J＝8.86Hz，2H)7.00-7.36(m，24H).ESI m/z＝798(M+NH4).779(M-H).

Example 29

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [4- [2- (dimethylamino) -2-oxoethoxy) benzyl ] phenyl ] -1-thio-D-glucitol

To a chloroform solution (2mL) of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [4- (carboxymethoxy) benzyl ] phenyl ] -1-thio-D-glucitol (149mg, 0.191mmol) was added a 2M dimethylamine solution in tetrahydrofuran (0.19mL, 0.382mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (44mg, 0.229mmol) and 1-hydroxybenzotriazole (31mg, 0.229 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, diluted with chloroform, and the organic phase was washed with water and saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 1: 2) to give the title compound (128mg, 83%).

1H NMR(300MHz，CDCl₃)δppm 2.96(s，3H)3.05(s，3H)3.06-3.14(m，1H)3.52(t，J＝8.86Hz，1H)3.68-3.74(m，1H)3.76-3.96(m，7H)4.44-4.54(m，3H)4.56-4.63(m，3H)4.85-4.93(m，3H)6.65(dd，J＝7.93，1.55Hz，2H)6.76-6.83(m，2H)7.01-7.18(m，8H)7.22-7.35(m，16H).ESI m/Z＝825(M+NH₄).

Example 30

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [ [ [4- (2-N, N-dimethylaminoethyl) oxy ] phenyl ] methyl ] phenyl ] -1-thio-D-glucitol

To a solution of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [4- [2- (dimethylamino) -2-oxoethoxy) benzyl ] phenyl ] -1-thio-D-glucitol (88mg, 0.109mmol) in tetrahydrofuran (2mL) at 4 deg.C was added 1.2M borane tetrahydrofuran complex (0.54mL) and stirred at room temperature for 2 hours. The reaction solution was cooled to 4 ℃ and concentrated by adding methanol. To the resulting residue were added 1, 4-dioxane (1.0mL) and 6M HCl (0.5mL), and the mixture was stirred at 40 ℃ for 2 minutes. To the solution was added a 2M aqueous sodium hydroxide solution, made alkaline, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by NH-type silica gel column chromatography (hexane: ethyl acetate ═ 1: 1) to give the title compound (43mg, 50%) as a colorless solid.

1H NMR(300MHz，CDCl₃)δppm 2.35(s，6H)2.68-2.81(m，2H)3.04-3.16(m，1H)3.52(t，J＝8.70Hz，1H)3.66-3.76(m，1H)3.76-4.10(m，9H)4.47(d，J＝10.10Hz，1H)4.52(s，2H)4.60(d，J＝10.72Hz，1H)4.84-4.94(m，3H)6.65(dd，J＝7.85，1.32Hz，2H)6.72-6.81(m，2H)7.00-7.18(m，8H)7.20-7.36(m，16H).ESI m/Z＝794(M+H).

Example 31

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [ [ [4- (2-hydroxyethyl) oxo ] phenyl ] methyl ] phenyl ] -1-thio-D-glucitol

To (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [4- (2-methoxy-2-oxoethoxy) benzyl at 4 deg.C]Phenyl radical]LiAlH was added to a solution of (1-thio-D-glucitol (102mg, 0.128mmol) in tetrahydrofuran (2.5mL)₄(12mg, 0.321mmol) and stirred for 2.5 h. After dropping water, 28% ammonia water was added to filter the insoluble matter. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to give the title compound (100mg) as colorless crystals.

1H NMR(300MHz，CDCl₃)δppm 3.06-3.14(m，1H)3.52(t，J＝8.86Hz，1H)3.67-3.74(m，1H)3.77-4.04(m，11H)4.47(d，J＝9.95Hz，1H)4.52(s，2H)4.60(d，J＝10.72Hz，1H)4.86-4.93(m，3H)6.62-6.68(m，2H)6.73-6.79(m，2H)7.02-7.18(m，8H)7.21-7.35(m，16H).ESI m/Z＝784(M+NH4).

Example 32

Synthesis of 2, 3, 4, 6-tetra-O-allyl-1-C- [5- (4-ethoxybenzyl) pyridin-3-yl ] -5-thio-D-glucopyranose

Grignard reagent was prepared from 3-bromo-5- (4-ethoxybenzyl) pyridine (1.83g, 6.26mmol) in the same manner as in example 15 to give the title compound (508mg, 29%) as a brown oil.

1H NMR(300MHz，CDCl₃)δppm 1.40(t，J＝6.99Hz，3H)2.98-3.18(m，1H)3.29-3.47(m，2H)3.56-4.05(m，12H)4.06-4.43(m，4H)4.77-4.91(m，2H)5.07-5.37(m，7H)5.79-6.04(m，3H)6.81(d，J＝8.86Hz，2H)7.04(d，J＝8.86Hz，2H)7.72(s，1H)8.41(d，J＝1.86Hz，1H)8.70(d，J＝2.18Hz，1H).ESI m/z＝568(M+H)，590(M+Na).

Example 33

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-allyl-1- [5- (4-ethoxybenzyl) pyridin-3-yl ] -1-thio-D-glucitol

The title compound (137mg, 28%) was obtained as a colorless oil from 2, 3, 4, 6-tetra-O-benzyl-1-C- [5- (4-ethoxybenzyl) pyridin-3-yl ] -5-thio-D-glucopyranose (508mg, 0.894mmol) by the same method as in example 16.

1H NMR(300MHz，CDCl₃)δppm 1.40(t，J＝6.99Hz，3H)2.93-3.06(m，1H)3.25(t，J＝8.94Hz，1H)3.30-3.44(m，1H)3.49-4.05(m，12H)4.15(dd，J＝12.05，5.98Hz，1H)4.24-4.42(m，3H)4.80-4.92(m，2H)5.08-5.42(m，7H)5.78-6.03(m，3H)6.81(d，J＝8.70Hz，2H)7.03(d，J＝8.70Hz，2H)7.48(s，1H)8.42(dd，J＝16.16，2.18Hz，2H).ESI m/Z＝552(M+H).

Example 34

Synthesis of (1S) -1, 5-anhydro-1- [5- (4-ethoxybenzyl) pyridin-3-yl ] -1-thioxo-D-glucitol

Using the same method as in example 17, from (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-allyl-1- [5- (4-ethoxybenzyl) pyridin-3-yl ] -1-thio-D-glucitol (137mg, 0.248mmol), the title compound (71mg, 73%) was obtained as a colorless powder.

1H NMR(600MHz，CD₃OD)δppm 1.36(t，J＝7.18Hz，3H)3.01-3.05(m，1H)3.23-3.27(m，1H)3.60(dd，J＝10.32，8.94Hz，1H)3.71-3.78(m，2H)3.84(d，J＝10.55Hz，1H)3.92-3.97(m，3H)3.99(q，J＝7.18Hz，2H)6.82-6.85(m，2H)7.10-7.13(m，2H)7.64(t，J＝2.06Hz，1H)8.28(d，J＝2.29Hz，1H)8.34(d，J＝2.29Hz，1H).ESI m/Z＝392(M+Na)，390(M-H).

Example 35

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-allyl-1- [5- (4-ethylbenzyl) thiophen-2-yl ] -1-thio-D-glucitol

The title compound (890mg, 94%) was obtained as a yellow oil from 2-bromo-5- (4-ethylbenzyl) thiophene (1.0g, 3.55mmol) by the same methods as in examples 15 and 16.

1H NMR(300MHz，CDCl₃)δppm 1.22(t，J＝7.62Hz，3H)2.62(q，J＝7.62Hz，2H)2.91-3.03(m，1H)3.20(t，J＝9.01Hz，1H)3.43-3.79(m，5H)3.90-4.07(m，6H)4.09-4.18(m，1H)4.24-4.41(m，3H)4.92-5.02(m，2H)5.09-5.32(m，6H)5.50-5.66(m，1H)5.79-6.05(m，3H)6.61(d，J＝3.57Hz，1H)6.85(d，J＝3.42Hz，1H)7.07-7.16(m，4H).ESI m/z＝563(M+Na).

Example 36

Synthesis of (1S) -1, 5-anhydro-1- [5- (4-ethylbenzyl) thiophen-2-yl ] -1-thioxo-D-glucitol

Using the same method as in example 17, from (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-allyl-1- [5- (4-ethylbenzyl) thiophen-2-yl ] -1-thio-D-glucitol (890mg, 1.64mmol), the title compound (570mg, 92%) was obtained as a colorless powder.

1H NMR(300MHz，CD₃OD)δppm 1.20(t，J＝7.62Hz，3H)2.60(q，J＝7.62Hz，2H)2.92-3.03(m，1H)3.19(t，J＝8.86Hz，1H)3.50-3.63(m，2H)3.72(dd，J＝11.58，6.45Hz，1H)3.93(dd，J＝11.50，3.73Hz，1H)4.03(t，J＝4.97Hz，3H)6.58-6.67(m，1H)6.83(d，J＝3.57Hz，1H)7.08-7.17(m，4H).ESI m/z＝403(M+Na)，379(M-H).

Example 37

Synthesis of 2, 3, 4, 6-tetra-O-benzyl-1-C- [3- [ (E or Z) -2- (4-ethylphenyl) vinyl ] phenyl ] -5-thio-D-glucopyranose

To a mixture of (4-ethylbenzyl) triphenylphosphonium chloride (1.64g, 3.93mmol) and tetrahydrofuran (20mL) was added 2M lithium diisopropylamine (heptane/tetrahydrofuran/ethylbenzene solution, 2.0mL, 4.0mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. This solution was added dropwise to a solution of 2, 3, 4, 6-tetra-O-benzyl-1-C- (3-formylphenyl) -5-thio-D-glucopyranose (0.52g, 786. mu. mol) in tetrahydrofuran (10mL), and stirred at room temperature for 1 hour. The reaction mixture was added with a saturated aqueous ammonium chloride solution under ice-cooling, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate: 6: 1 to 3: 1) to give the title compound (0.49g, 82%, E/Z mixture) as a colorless oil.

1H NMR(300MHz，CDCl₃)d ppm 1.10-1.32(m，3H)2.48-2.74(m，2H)2.90-3.10(m，J＝38.55Hz，1H)3.47-3.71(m，2H)3.78-4.21(m，5H)4.41-4.73(m，4H)4.80-4.99(m，3H)6.50-6.99(m，3H)7.03-7.61(m，27H).ESI m/z＝785(M+Na).

Example 38

Synthesis of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [ (E or Z) -2- (4-ethylphenyl) vinyl ] phenyl ] -1-thio-D-glucitol

To 2, 3, 4, 6-tetra-O-benzyl-1-C- [3- [ (E or Z) -2- (4-ethylphenyl) ethenyl at-10 deg.C]Phenyl radical]To a solution of-5-thio-D-glucopyranose (0.49g, 642. mu. mol) in acetonitrile (20mL) was added Et in sequence₃SiH (0.35mL, 1.92mmol) and BF₃·Et₂O (0.20mL, 1.28mmol), stirred at this temperature for 10 min. To the reaction mixture was added a saturated aqueous sodium carbonate solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 8: 1) to give the title compound (0.31g, 66%, E/Z mixture) as a colorless powder.

1H NMR(300MHz，CDCl₃)d ppm 1.13-1.31(m，3H)2.46-2.72(m，2H)3.04-3.18(m，1H)3.47-3.62(m，1H)3.68-4.02(m，6H)4.45-4.66(m，4H)4.85-4.96(m，3H)6.49-6.80(m，3H)6.92-7.62(m，27H).ESI m/z＝769(M+Na).

Example 39

Synthesis of (1S) -1, 5-anhydro-1- [3- [2- (4-ethylphenyl) ethyl ] phenyl ] -1-thio-D-glucitol

20 wt% palladium hydroxide-carbon powder (300mg) was added to a solution of (1S) -1, 5-anhydro-2, 3, 4, 6-tetra-O-benzyl-1- [3- [ (E or Z) -2- (4-ethylphenyl) vinyl ] phenyl ] -1-thio-D-glucitol (0.30g, 401. mu. mol) in ethanol (5mL), and the inside of the system was replaced with hydrogen gas. After stirring at room temperature for 3 days, insoluble matter in the system was filtered off with celite. The residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (chloroform: methanol 10: 1) to give the title compound (13mg, 8%) as a colorless powder.

1H NMR(300MHz，CD₃OD)d ppm 1.20(t，J＝7.62Hz，3H)2.59(q，J＝7.62Hz，2H)2.85(s，4H)2.95-3.07(m，1H)3.21-3.28(m，1H)3.54-3.68(m，1H)3.69-3.83(m，3H)3.95(dd，J＝11.42，3.65Hz，1H)7.00-7.11(m，5H)7.13-7.28(m，3H).ESI m/z＝411(M+Na)，387(M-H).

Example 40

Synthesis of 2, 3, 4, 6-tetra-O-allyl-1-C- [3- [ (2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl ] phenyl ] -5-thio-D-glucopyranose

To a mixture of magnesium (1.11g, 45.7mmol), 1-bromo-3- [ (2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl ] benzene (0.401g, 1.33mmol) and tetrahydrofuran (7mL) was added 1, 2-dibromoethane (5 drops), and the mixture was heated under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and 2, 3, 4, 6-tetra-O-allyl-5-thio-D-glucono-1, 5-lactone (0.38g, 1.06mmol) in tetrahydrofuran (5mL) was added dropwise to the mixture, followed by stirring at room temperature for 30 minutes. The reaction mixture was added with a saturated aqueous ammonium chloride solution under ice-cooling, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give the title compound (42mg, 7%) as a colorless oil.

1H NMR(300MHz，CDCl₃)d ppm 1.16-1.30(m，3H)2.55-2.72(m，2H)2.90-3.03(m，1H)3.31-4.44(m，16H)4.82-4.94(m，2H)5.09-5.49(m，6H)5.80-6.05(m，5H)6.29-6.45(m，1H)7.08-7.32(m，6H)7.42-7.52(m，2H).ESI m/z＝599(M+Na)，575(M-H).

EXAMPLE 41

Synthesis of (1S) -2, 3, 4, 6-tetra-O-allyl-1, 5-anhydro-1- [3- [ (2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl ] phenyl ] -1-thio-D-glucitol

To 2, 3, 4, 6-tetra-O-allyl-1-C- [3- [ (2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl at-10 ℃]Phenyl radical]-5-thio-D-glucopyranose (42mg, 72. mu. mol) in acetonitrile (3mL) was added Et in sequence₃SiH (35 μ L, 218 μmol) and BF₃·Et₂O (20. mu.L, 145. mu. mol), stirred at this temperature for 10 minutes. To the reaction mixture was added a saturated aqueous sodium carbonate solution, followed by extraction with ethyl acetate, washing of the organic layer with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate: 10: 1 to 8: 1) to give the title compound (28mg, 70%) as a colorless oil.

1H NMR(300MHz，CDCl₃)d ppm 1.17-1.30(m，J＝7.62，7.62，7.62Hz，3H)2.57-2.71(m，2H)2.95-3.05(m，1H)3.26(t，J＝8.86Hz，1H)3.50(d，J＝6.68Hz，2H)3.58-3.91(m，5H)3.94-4.21(m，3H)4.23-4.44(m，3H)4.84-4.95(m，2H)5.09-5.52(m，8H)5.71-6.46(m，6H)7.09-7.29(m，8H).ESI m/z＝583(M+Na).

Example 42

Synthesis of (1S) -1, 5-anhydro-1- [3- [ (2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl ] phenyl ] -1-thio-D-glucitol

Tetrakis (triphenylphosphine) palladium (0) (11mg, 9. mu. mol) and 1, 3-dimethylbarbituric acid (58mg, 370. mu. mol) were added to a solution of (1S) -2, 3, 4, 6-tetra-O-allyl-1, 5-anhydro-1- [3- [ (2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl ] phenyl ] -1-thio-D-glucitol (26mg, 46. mu. mol) in tetrahydrofuran (3mL), and the mixture was refluxed for 2.5 hours. The reaction mixture was added with a saturated aqueous sodium carbonate solution under ice-cooling, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol: 10: 1). Further purification by silica gel column chromatography (NH silica gel, chloroform: methanol 9: 1) gave the title compound (13mg, 72%).

1H NMR(300MHz，CD₃OD)d ppm 1.14-1.27(m，J＝7.98，7.98，7.98Hz，3H)2.54-2.68(m，2H)2.95-3.05(m，1H)3.22-3.30(m，1H)3.51(d，J＝6.37Hz，1H)3.56-3.68(m，2H)3.70-3.83(m，3H)3.95(dd，J＝11.35，3.57Hz，1H)5.72-6.59(m，2H)7.07-7.30(m，8H).ESI m/z＝423(M+Na)，399(M-H).

Example 43

Synthesis of (1S) -1, 5-anhydro-1- [3- [3- (4-ethylphenyl) propyl ] phenyl ] -1-thioxo-D-glucitol

To a solution of (1S) -1, 5-anhydro-1- [3- [ (2E or Z) -3- (4-ethylphenyl) prop-2-en-1-yl ] phenyl ] -1-thio-D-glucitol (13mg, 32. mu. mol) in ethanol (2mL) was added 20 wt% palladium hydroxide-carbon powder (20mg), and the inside of the system was replaced with hydrogen gas. After stirring at room temperature for 2 days, insoluble matter in the system was filtered through celite. The residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (chloroform: methanol 9: 1) to give the title compound (8mg, 62%) as a colorless powder.

1H NMR(600MHz，CD₃OD)d ppm 1.20(t，J＝7.57Hz，3H)1.87-1.94(m，2H)2.56-2.63(m，6H)2.98-3.03(m，1H)3.26(t，J＝8.25Hz，1H)3.59-3.64(m，J＝10.32，8.94Hz，1H)3.71-3.82(m，3H)3.95(dd，J＝11.46，3.67Hz，1H)7.05-7.12(m，5H)7.14-7.25(m，3H)..ESI m/z＝425(M+Na)，401(M-H).

Example 44

Synthesis of 2, 3, 4, 6-tetra-O-allyl-1-C- [7- (4-methylbenzyl) -1-benzothien-3-yl ] -5-thio-D-glucopyranose

To a mixture of magnesium (77mg, 3.19mmol), 3-bromo-7- (4-methylbenzyl) -1-benzothiophene (0.92g, 2.90mmol), and tetrahydrofuran (5mL) was added 1, 2-dibromoethane (5 drops), and the mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, and 2, 3, 4, 6-tetra-O-allyl-5-thio-D-glucono-1, 5-lactone (0.51g, 1.45mmol) in tetrahydrofuran (5mL) was added dropwise to the mixture under ice cooling, followed by stirring for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate, washing of the organic phase with a saturated saline solution, and drying over anhydrous magnesium sulfate. After the drying agent was filtered off, the residue obtained by removing the solvent by distillation under the reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give the title compound (0.76g, 89%) as a yellow oil.

1H NMR(300MHz，CDCl₃)d ppm 2.31(s，3H)3.21(dd，J＝11.81，6.06Hz，1H)3.29(s，1H)3.46-3.93(m，6H)3.96-4.02(m，J＝4.66Hz，2H)4.15-4.26(m，4H)4.30(d，J＝5.75Hz，2H)4.42(dd，J＝12.12，5.91Hz，1H)4.57-4.78(m，2H)5.10-5.40(m，7H)5.80-6.08(m，3H)7.05-7.17(m，5H)7.32(t，1H)7.63(s，1H)8.19(d，J＝7.46Hz，1H).ESI m/z＝615(M+Na)，591(M-H).

Example 45

Synthesis of (1S) -2, 3, 4, 6-tetra-O-allyl-1, 5-anhydro-1- [7- (4-methylbenzyl) -1-benzothien-3-yl ] -1-thio-D-glucitol

The title compound (86%) was synthesized from 2, 3, 4, 6-tetra-O-allyl-1-C- [7- (4-methylbenzyl) -1-benzothien-3-yl ] -5-thio-D-glucopyranose using the same method as in example 16.

1H NMR(300MHz，CDCl₃)d ppm 2.31(s，3H)2.99-3.10(m，1H)3.27-3.40(m，2H)3.66-3.87(m，5H)4.00(d，J＝5.75Hz，2H)4.15-4.26(m，4H)4.31(d，J＝6.84Hz，2H)4.40(dd，J＝12.05，5.83Hz，1H)4.63-4.82(m，2H)5.09-5.37(m，7H)5.80-6.07(m，3H)7.04-7.17(m，5H)7.32(t，1H)7.41(s，1H)7.89(d，J＝7.93Hz，1H).ESI m/z＝599(M+Na).

Example 46

Synthesis of (1S) -1, 5-anhydro-1- [7- (4-methylbenzyl) -1-benzothien-3-yl ] -1-thio-D-glucitol

The title compound (76%) was synthesized as a colorless powder from (1S) -2, 3, 4, 6-tetra-O-allyl-1, 5-anhydro-1- [7- (4-methylbenzyl) -1-benzothien-3-yl ] -1-thioxo-D-glucitol by the same method as in example 17.

1H NMR(300MHz，CD₃OD)d ppm 2.26(s，2H)3.03-3.14(m，1H)3.32-3.40(m，1H)3.62-3.72(m，1H)3.77(dd，J＝11.50，6.37Hz，1H)3.93-4.06(m，2H)4.14(s，2H)4.32(d，J＝10.26Hz，1H)7.01-7.17(m，5H)7.33(t，1H)7.48(s，1H)7.90(d，J＝7.31Hz，1H).ESI m/z＝439(M+Na)，415(M-H).

By carrying out the same operations as in the above examples using the corresponding starting materials and reactants, the compounds of the present invention shown in the following tables were obtained. The compounds of the present invention obtained in the above examples are shown together in table 1.

Test example 1

After pre-culturing a suspension (protein concentration: 4mg/mL) of rat kidney Brush Border Membrane Vesicle (BBMV) prepared according to the method described in the literature (Aaanal. biochem., Vol.201, item 301, 1984) at 37 ℃ for 2 minutes, 150. mu.L of a mixture of a test compound dissolved in DMSO (final DMSO concentration: 1%) and 100mM mannitol, 100mM NaSCN or KSCN, 10mM HEPS/Tris pH7.4, D-glucose (final concentration: 0.1mM), D- [6-³H]1 μ Ci of glucose (Amazonia). After 5 seconds of reaction at 37 ℃, 1mL of ice-cooled reaction-stopping solution (150mM NaCl, 10mM HEPES/trispH7.4, 0.3mM phloridzin) was added to the reaction mixture, and immediately after the reaction was stopped, the reaction mixture was subjected to rapid filtration through a membrane filter (HAWP02500, Millipore) having a pore size of 0.45. mu.mFiltering and separating BBMV. The membrane filter was washed 3 times with 4.5mL of ice-cooled reaction-stopping solution, sufficiently dried, and then measured for radioactivity by a liquid scintillation counter (Beckman) to quantify the amount of glucose taken up by BBMV on the membrane filter.

The concentration of the compound at which the glucose uptake was inhibited by 50% (IC) was calculated by taking the glucose uptake without the addition of the compound as 100%₅₀Value).

The results are shown in Table 2.

TABLE 2

Compound numbering	IC₅₀(μM)
		Compound 75	1.600
Compound 76	0.320
		Compound 79	0.220
Compound 127	0.350
		Compound 128	0.790

Test example 2

Cloning and introduction into expression vector of human SGLT1 and human SGLT2

Human SGLT1 sequence (NM-000343) was reverse-transcribed from human small intestine-derived mRNA, amplified, 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). The sequence of each clone was confirmed to be identical to the reported sequence.

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 (SGLT2) at a concentration of 500. mu.g/mL, and resistant strains were selected and obtained as an index of specific sugar uptake activity according to the following test.

Inhibition of sodium-dependent sugar uptake in cells

Cells stably expressing human SGLT1 or human SGLT2 were used in sodium-dependent glucose uptake activity inhibition assays.

1mL of a buffer for pretreatment (140mM choline chloride, 2mM KCl, 1mM CaCl)₂、1mM MgCl₂10mM HEPES/5mM Tris, pH7.4) for 20 minutes. After removing the buffer for pretreatment, 200. mu.L of a buffer for ingestion containing the test compound (comprising [ alpha ], [ solution ]¹⁴C]methyl-alpha-D-glucopyranoside of methyl-alpha-D-glucopyranoside (0.1 mM for SGLT1 inhibition and 1mM for SGLT2 inhibition), 140mM NaCl, 2mM KCl, 1mM CaCl₂、1mM MgCl₂10mM HEPES/5mM TrispH7.4) was carried out at 37 ℃ for 30 minutes (SGLT1) or 1 hour (SGLT2) of the uptake reaction. 1mL of a washing buffer (10mM methyl-. alpha. -D-glucopyranoside, 140mM choline chloride, 2mM KCl, sodium chloride, potassium,1mM CaCl₂、1mM MgCl₂10mM HEPES/5mM Tris, pH7.4) the cells after the reaction were washed 2 times and dissolved in 400. mu.L of a 0.2M NaOH solution. Aquazole2(Perkin Elmer) was added, mixed well and the radioactivity was measured by liquid scintillation counter (Beckman Coulter). The control group was prepared as a buffer for uptake without test compound. An uptake buffer containing choline chloride without NaCl was prepared as a base uptake buffer.

IC was calculated using the appropriate 6 concentrations of test compound₅₀Value, the concentration of test compound (IC) at which the sugar uptake was 50% inhibited was calculated relative to the sugar uptake (100%) of the control group₅₀Value). The results are shown in Table 3.

TABLE 3

Compound numbering	Human SGLT2(μ M)	SGLT1(μM)	SGLT1/SGLT2
				Compound 74	1.190	15.3	12.8
Compound 75	2.830	27.4	9.7
				Compound 76	0.080	1.2	14.6
Compound 77	0.690	8.0	11.6
				Compound 78	1.040	120.0	115.4
Compound 79	0.370	2.7	7.2
				Compound 80	0.190	2.9	15.2
Compound 81	0.600	6.5	10.9
				Compound 82	3.780	15.0	4.0
Compound 83	0.030	1.5	48.7
				Compound 84	0.170	2.1	12.5
Compound 85	1.270	6.1	4.8
				Compound 86	0.060	1.1	18.3
Compound 88	0.080	0.2	2.8
				Compound 89	0.065	6.3	97.5
Compound 91	0.110	1.7	15.5
				Compound (I)92	0.030	0.2	7.7
Compound 93	0.021	0.4	21.0
				Compound 94	0.250	0.3	1.3
Compound 95	0.028	0.6	22.3
				Compound 96	0.062	7.3	116.3
Compound 98	0.015	0.1	6.5
				Compound 99	0.032	5.6	178.6
Compound 100	1.520	4.4	2.9
				Compound 101	0.040	2.6	63.1
Compound 102	0.040	3.5	86.6
				Compound 103	0.069	23.9	347.9
Compound 104	0.034	1.0	29.8
				Compound 105	0.093	17.0	182.5
Compound 127	1.120	0.7	0.6
				Compound 128	0.140	0.6	4.4
Compound 129	3.000	12.8	4.3
				Compound 130	2.120	＞10	-
Compound 131	0.890	4.1	4.7
				Compound 132	0.497	4.4	8.9
Compound 134	2.910	-	-
				Compound 138	33.000	-	-
Compound 139	114.000	-	-

Industrial applicability

According to the present invention, a 1-thio-D-glucitol compound having a sodium-dependent glucose cotransporter (SGLT2) inhibitory activity, exhibiting a hypoglycemic action by promoting urinary glucose excretion, and an excellent therapeutic agent for diabetes, which is attributed to a novel skeleton that does not exist at present, can be provided. Further, the 1-thio-D-glucitol derivative of the present invention does not require cocrystallization with an amino acid or the like because of good crystal growth, and is easy to purify, store, and formulate, and thus is suitable for handling as a pharmaceutical.

Claims

1. A1-thio-D-glucitol compound represented by the following formula I, a pharmaceutically acceptable salt thereof, or a hydrate of either,

in the formula, R¹、R²、R³And R⁴Represents a hydrogen atom, and is represented by,

a represents- (CH)₂) n-wherein, n represents 1,

Ar¹represents phenylene, pyridylene or thienylene,

Ar²represents phenyl, thienyl, benzo [ b ]]A thienyl group or a benzofuranyl group,

R⁵、R⁶、R⁷、R⁸、R⁹and R¹⁰The same or different, represents (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, or (iv) C which may be substituted by 1 or more substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-8An alkyl group, a carboxyl group,

(v)-(CH₂) m-Q, wherein m represents 0 and Q represents-OR^c1or-SR^e1Wherein R is^c1Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^e1Is represented by C_1-6Alkyl, or

(x) A phenyl group.

2. The 1-thio-D-glucitol compound according to claim 1 or a pharmaceutically acceptable salt thereof or a hydrate of either thereof, wherein Ar is¹Is phenylene.

3. The 1-thio-D-glucitol compound according to claim 1, wherein the 1-thio-D-glucitol compound is a compound selected from the group consisting of,

4. the 1-thio-D-glucitol compound according to claim 1, wherein the 1-thio-D-glucitol compound is a compound selected from the group consisting of,

5. A1-thio-D-glucitol compound represented by the following formula II, a pharmaceutically acceptable salt thereof, or a hydrate of either,

R^A、R^B、R^Cand R^DAt least one of (a) represents a hydrogen atom, and the others, which are the same or different, represent (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, and (iv) C which may be substituted with 1 or more substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-8Alkyl, or

(v)-(CH₂)m-Q^AWherein m represents 0, Q^Arepresents-OR^c1or-SR^e1Wherein R is^c1Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^e1Is represented by C_1-6An alkyl group, a carboxyl group,

R^E、R^Fand R^GThe same or different, represents (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, or (iv) C which may be substituted by 1 or more substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-8Alkyl, or

(v)-(CH₂) m-Q, wherein m represents 0 and Q represents-OR^c1or-SR^e1Wherein R is^c1Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^e1Is represented by C_1-6An alkyl group.

6. The 1-thio-D-glucitol compound according to claim 5, wherein,

R^Aand R^CRepresents a hydrogen atom, and is represented by,

R^Brepresents a hydrogen atom, a halogen atom, a hydroxyl group, C_1-8Alkyl, or

-OR^f1Wherein R is^f1Represents C which may be substituted by halogen atoms_1-6An alkyl group, a carboxyl group,

R^Drepresents a hydrogen atom, a halogen atom, a hydroxyl group, C_1-8Alkyl OR-OR^f2Wherein R is^f2Represents C which may be substituted by halogen atoms_1-6An alkyl group, a carboxyl group,

R^Eand R^FThe same or different represent a hydrogen atom, a halogen atom, C_1-8Alkyl OR-OR^c3Wherein R is^c3Represents C which may be substituted by halogen atoms_1-6An alkyl group, a carboxyl group,

R^Grepresents (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, or (iv) C which may be substituted with 1 or more substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-8Alkyl, or

7. The 1-thio-D-glucitol compound according to claim 6, wherein,

R^Brepresents a hydrogen atom, C_1-6Alkyl, -OR^f1Or a halogen atom, wherein R^f1Represents C which may be substituted by halogen atoms_1-6An alkyl group, a carboxyl group,

R^Drepresents a hydrogen atom, a hydroxyl group, -OR^f1Wherein R is^f1Represents C which may be substituted by halogen atoms_1-6An alkyl group.

8. A1-thio-D-glucitol compound represented by the following formula III or a pharmaceutically acceptable salt thereof or a hydrate of either,

R^Hand R^IThe same or different represent a hydrogen atom, a halogen atom, a hydroxyl group, C_1-8Alkyl, or

Ar³is thienyl, benzo [ b]A thienyl group or a benzofuranyl group,

R^8aand R^9aThe same or different represent a hydrogen atom, a halogen atom, a hydroxyl group, C_1-8Alkyl OR-OR^c3，R^c3Represents C which may be substituted by halogen atoms_1-6An alkyl group, a carboxyl group,

R^10arepresents a hydrogen atom or a phenyl group.

9. A1-thio-D-glucitol compound represented by the following formula IV or a pharmaceutically acceptable salt thereof or a hydrate of either,

Ar⁴is a thienylene group or a pyridylene group,

R^20aand R^21aRepresents a hydrogen atom, and is represented by,

R^Jand R^KThe same or different represent a hydrogen atom, a halogen atom, C_1-8Alkyl OR-OR^c3Wherein R is^c3Represents C which may be substituted by halogen atoms_1-6An alkyl group, a carboxyl group,

R^Lrepresents (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, and (iv) 1 or more selected from the group consisting of a halogen atom and a hydroxyl groupC substituted by substituents_1-8Alkyl, (vi) -OR^c1Or (xiii) -SR^e1，

Wherein R is^c1Represents C which may be substituted by halogen atoms_1-6Alkyl radical, R^e1Is represented by C_1-6An alkyl group.

10. The 1-thio-D-glucitol compound according to claim 9, wherein R is a pharmaceutically acceptable salt thereof or a hydrate of the salt^LIs a hydrogen atom, a halogen atom, C_1-8Alkyl OR-OR^c3，R^c3Represents C which may be substituted by halogen atoms_1-6An alkyl group.

11. A pharmaceutical composition comprising the 1-thio-D-glucitol compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a hydrate of the compound or the salt.

12. The pharmaceutical composition of claim 11, which is an inhibitor of the activity of sodium-dependent glucose co-transporter 2.

13. The pharmaceutical composition according to claim 12, which is a prophylactic or therapeutic agent for diabetes, diabetes-related diseases, or diabetic complications.

14. A process for producing a 1-thio-D-glucitol compound represented by the formula I or a pharmaceutically acceptable salt thereof or a hydrate of either,

in the formula, Ar¹、Ar²A and R¹-R¹⁰As defined in claim 1, in the same way,

the method comprises the following steps: a step of adding more than 1 equivalent of a Grignard reagent represented by the formula IX to a thiolactone represented by the formula VIII in accordance with the following reaction scheme to obtain a compound V; a step of reducing the compound V; a step of deprotecting the obtained compound as required,

in the formula, R¹¹、R¹²、R¹³And R¹⁴Same or different and represents-CH₂CH＝CH₂Or may be selected from halogen atoms, -NO₂And C substituted with more than one substituent of OMe_7-12Aralkyl radical, X is a halogen atom, A, Ar¹、Ar²、R⁵、R⁶、R⁷、R⁸、R⁹And R¹⁰As defined in claim 1.

15. The method according to claim 14, wherein the step of adding the Grignard reagent represented by the formula IX is a step of adding 0.8 to 1.2 equivalents of R to the thiolactone represented by the formula VIII³⁰MgX, and adding a Grignard reagent represented by formula IX to obtain a compound V, wherein R³⁰Is represented by C_1-8Alkyl or C_3-7Cycloalkyl and X represents a halogen atom.

16. A process for producing a 1-thio-D-glucitol compound represented by the formula I or a pharmaceutically acceptable salt thereof or a hydrate of either,

the method comprises the following steps: a step (1) wherein a reagent represented by the formula XI is added to a compound represented by the formula X to obtain a compound XII; a step (2) for further reducing the compound XII in the case where Y is a hydroxyl group, to thereby obtain a compound wherein Y is hydrogen in a β -type stereoselectivity; and (2) deprotecting the compound obtained in the step (1) or (2) if necessary,

wherein Y represents a hydrogen atom or a hydroxyl group, and when Y is a hydrogen atom, the 1-position is in the S configuration,

R¹¹、R¹²、R¹³and R¹⁴Same or different and represents-CH₂CH＝CH₂Or may be selected from halogen atoms, -NO₂And C substituted with more than one substituent of OMe_7-12Aralkyl, Ar²、R⁸、R⁹And R¹⁰R is as defined in claim 1^A、R^B、R^CAnd R^DAs defined in claim 5, in the same way,

aa represents-CH (W) (CH)₂) n '-, wherein W is a hydrogen atom or a hydroxyl group, n' represents 0,

ea is-CHO or-CH₂X，

Da represents- (CH)₂)n’Li、-(CH₂) n' MgX or-SnBu₃Wherein X is a halogen atom, n' represents 0,

when Ea is-CHO, Da is- (CH)₂) n' Li or- (CH)₂) n' MgX to obtain a reaction product in which Aa is-CH (W) (CH)₂) The compound XII of n' is,

17. A compound represented by the following formula XIII, a salt thereof or a hydrate of the salt,

R²¹、R²²、R²³and R²⁴Same or different and represents-CH₂CH＝CH₂Or may be selected from halogen atoms, -NO₂And C substituted with more than one substituent of OMe_7-12Aralkyl, the other symbols are as defined in claim 1.

18. A compound represented by the formula XIV below or a salt or hydrate thereof,

e represents-CHO, -CO₂H、-CO₂R^a24、-CH₂M^aOr 1, 3-dioxolan-2-yl, wherein R^a24Is represented by C_1-6Alkyl radical, M^aRepresents a hydroxyl group or a halogen atom,

R²¹、R²²、R²³and R²⁴As defined in claim 17, in the same way,

R^A、R^B、R^Cand R^DAs defined in claim 5.