CN1930141A

CN1930141A - Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof

Info

Publication number: CN1930141A
Application number: CNA2005800069449A
Authority: CN
Inventors: 弗兰克·希梅尔斯巴赫; 马赛厄斯·埃克哈特; 彼得·艾克尔曼; 爱德华·L·巴索米恩; 利奥·托马斯
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2004-03-16
Filing date: 2005-03-11
Publication date: 2007-03-14
Also published as: ZA200605511B; DE102004012676A1; UA89040C2

Abstract

The invention relates to glucopyranosyl-substitutedted benzol derivatives of general formula (I), wherein rests R<1> to R<6> and R<7a>, R<7b>, R<7c> are such as defined in the claim 1, including the tautomers, stereoisomers, mixtures and the salts thereof. The inventive compounds are useful for treating metabolic diseases.

Description

Phenyl derivatives, the medicine that contains this compound, its purposes and manufacture method thereof that glucopyranosyl replaces

The benzene derivative that the glucopyranosyl of the relevant general formula I of the present invention replaces

R wherein ¹To R ⁶With R ^7a, R ^7b, R ^7cBase be such as hereinafter definition, comprise its compounds tautomeric, stereoisomers, its mixture and its esters.The further relevant pharmaceutical composition that comprises formula I compound of the present invention of the present invention, and use the pharmaceutical composition of The compounds of this invention with preparation treatment metabolic disorder.In addition, the method for relevant preparation pharmaceutical composition of the present invention of the present invention and compound.

In the literature, propose to utilize for Na-dependent glucose-cotransporter SGLT2 tool inhibiting compounds for treating disease, particularly diabetes.

Aromatic series that glucopyranosyl replaces and preparation thereof with its as the SGLT2 inhibitor may be active by known in the following international application case, WO 98/31697, WO 01/27128, WO 02/083066, WO 03/099836, WO 2004/063209, WO 2004/080990, WO 2004/013118, WO 2004/052902, WO 2004/052903, and U.S. Patent application US 2003/0114390.

Goal of the invention

The objective of the invention is to find out the benzene derivative that new pyrans glycosyl replaces, particularly sodium is relied on glucose cotransporter SGLT, particularly SGLT2 has activity.Other purpose of the present invention is the benzene derivative that will illustrate that the pyrans glycosyl replaces, its in vivo with/or in vitro with the compound of known similar structures relatively, have enhanced for Na-dependent glucose cotransporter SGLT2 and suppress effect, and/or have preferable pharmacology or pharmacokinetic property.

Other purpose of the present invention is will provide new, be suitable for preventing and/or treating the particularly pharmaceutical composition of the metabolic disorder of diabetes.

Purpose of the present invention also provides the method for preparation according to The compounds of this invention.

Other purposes of the present invention directly can be clear by aforementioned and following explanation for being familiar with present technique person.

Goal of the invention

A first aspect of the present invention is the benzene derivative that the glucopyranosyl of relevant general formula I replaces

Wherein

R ¹Be selected from the definition of A base, and

If R ³Be when being selected from the definition of B base, R then ¹Also can additionally be selected from following meaning: hydrogen, fluorine, chlorine, bromine, iodine, C _1-4-alkyl, C _2-4-thiazolinyl-C _1-4-alkyl, C _2-4-alkynyl-C _1-4-alkyl, C _2-4-thiazolinyl-C _1-4-alkoxyl group, C _2-4-alkynyl-C _1-4-alkoxyl group, C _3-7-cycloalkyl-C _1-4-alkyl, C _5-7-cycloalkenyl group-C _1-4-alkyl, the methyl that replaces through 1-3 fluorine atom, through ethyl, the C of 1-5 fluorine atom replacement _1-4-alkoxyl group, the methoxyl group that replaces through 1-3-fluorine atom, through the oxyethyl group of 1-5 fluorine atom replacement, through hydroxyl or C _1-3The C that-alkoxyl group replaces _1-4-alkyl, through hydroxyl or C _1-3The C that-alkoxyl group replaces _2-4-alkoxyl group, C _3-6-cycloalkyl-C _1-3-alkoxyl group or hydroxyl,

Wherein, in above-mentioned cycloalkyl and cyclenes basic ring, 1 or 2 methylene radical ground warp O or CO replacement independently of one another, and

R ²Expression hydrogen, fluorine, chlorine, bromine, hydroxyl, C _1-4-alkyl, C _1-4-alkoxyl group, cyano group or nitro, wherein this alkyl or alkoxyl group can be through fluorine lists or polysubstituted, and

R ³Be the definition that is selected from the B base, and

If R ¹Be when being selected from the definition of A base, R then ³Also can be selected from following meaning in addition: hydrogen, fluorine, chlorine, bromine, iodine, C _1-6-alkyl, C _2-4-thiazolinyl-C _1-4-alkyl, C _2-4-alkynyl-C _1-4-alkyl, C _2-4-thiazolinyl-C _1-4-alkoxyl group, C _2-4-alkynyl-C _1-4-alkoxyl group, C _3-7-cycloalkyl, C _5-7-cycloalkenyl group, C _3-7-cycloalkyl-C _1-4-alkyl, C _5-7-cycloalkenyl group-C _1-4-alkyl, C _3-6-ring alkylidene group methyl, hydroxyl, C _1-6-alkoxyl group, C _3-6-cycloalkyl-C _1-3-alkoxyl group, aryl, aryl-C _1-3-alkyl, heteroaryl, heteroaryl-C _1-3-alkyl, aryloxy, aryl-C _1-3-alkyl-oxygen base, the methyl or methoxy that replaces through 1-3-fluorine atom, through the C of 1-5 fluorine atom replacement _2-4-alkyl or C _2-4-alkoxyl group, the C that replaces through cyano group _1-4-alkyl, through hydroxyl or C _1-3The C that-alkoxyl group replaces _1-4-alkyl, cyano group, carboxyl, C _1-3-carbalkoxy, aminocarbonyl, (C _1-3-alkylamino) carbonyl, two-(C _1-3-alkyl) aminocarbonyl, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, morpholine-4-base carbonyl, piperazine-1-base-carbonyl, 4-(C _1-3-alkyl)-piperazine-1-base-carbonyl, (C _1-4-alkyl) carbonyl amino, C _1-4-alkyl-sulfuryl amino, C _1-4-alkylthio, C _1-4-alkyl sulphinyl, C _1-4-alkane alkylsulfonyl, arylsulfonyl amino, aryl-C _1-3-alkane sulfo group amino or arylsulfonyl,

R ⁴, R ⁵Represent hydrogen, fluorine, chlorine, bromine, iodine, cyano group, nitro, C independently of one another _1-3-alkyl, C _1-3-alkoxyl group, the methyl or methoxy that replaces through 1-3-fluorine atom,

A represents C _2-6-alkynes-1-base, C _2-6-alkene-1-base, C _3-7-cycloalkyl, C _5-7-cycloalkenyl group, aryl, heteroaryl, C _1-4-alkyl carbonyl, aromatic carbonyl, assorted aromatic carbonyl, aminocarbonyl, C _1-4-alkane aminocarbonyl, two-(C _1-3-alkyl) aminocarbonyl, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, morpholine-4-base carbonyl, piperazine-1-base carbonyl, 4-(C _1-4-alkyl) piperazine-1-base carbonyl, fragrant aminocarbonyl, assorted fragrant aminocarbonyl, C _1-4-carbalkoxy, aryl-C _1-3-carbalkoxy, heteroaryl-C _1-3-carbalkoxy, amino, C _1-4-alkylamino, two-(C _1-3-alkyl) amino, tetramethyleneimine-1-base, pyrrolidin-2-one-1-base, piperidines-1-base, piperidines-2-ketone-1-base, morpholine-4-base, morpholine-3-ketone-4-base, piperazine-1-base, 4-(C _1-3-alkyl)-piperazine-1-base, C _1-4-alkane carbonyl amino, fragrant carbonyl amino, assorted fragrant carbonyl amino, C _3-7-cycloalkyloxy, C _5-7-cyclenes oxygen base, aryloxy, heteroaryloxy, C _1-4-alkyl sulfinyl, C _1-4-alkane alkylsulfonyl, C _3-7-cycloalkylthio, C _3-7-cycloalkanes sulfinyl, C _3-7-cycloalkanes alkylsulfonyl, C _5-7-cyclenes sulfenyl, C _5-7-cyclenes sulfinyl, C _5-7-cyclenes alkylsulfonyl, arylthio, fragrant sulfinyl, arylsulfonyl, heteroarylthio, assorted fragrant sulfinyl, assorted arylsulfonyl, cyano group or nitro,

Wherein, above-mentioned alkynyl and thiazolinyl can be through fluorine or chlorine lists or polysubstituted, and

Above-mentioned alkynyl and thiazolinyl can single or two replacements through identical or different L1 base, and

Above-mentioned cycloalkyl and cyclenes basic ring ground warp independently of one another are selected from fluorine and C _1-3The substituting group list of-alkyl or two replacement, and

In above-mentioned cycloalkyl and cyclenes basic ring, one or two methylene radical is ground warp O, S, CO, SO, SO independently of one another ₂Or NR ^NReplace,

B represents three-(C _1-4-alkyl) silylation-C _1-6-alkyl, C _2-6-alkynes-1-base, C _2-6-alkene-1-base, amino, C _1-3-alkylamino, two-(C _1-3-alkyl) amino, each alkane of pyrrole-1-base, pyrrolidin-2-one-1-base, piperidines-1-base, piperidines-2-ketone-1-base, morpholine-4-base, morpholine-3-ketone-4-base, piperazine-1-base, 4-(C _1-3-alkyl)-piperazine-1-base, fragrant carbonyl amino, assorted fragrant carbonyl amino, nitro, C _3-10-cycloalkyloxy, C _5-10-cyclenes oxygen base, C _3-10-cycloalkylthio, C _3-10-cycloalkanes sulfinyl, C _3-10-cycloalkanes alkylsulfonyl, C _5-10-cyclenes sulfenyl, C _5-10-cyclenes sulfinyl, C _5-10-cyclenes alkylsulfonyl, arylthio, fragrant sulfinyl, heteroarylthio or assorted fragrant sulfinyl,

Above-mentioned alkynyl and thiazolinyl can single or two replacements through identical or different L1 base,

Wherein, above-mentioned cycloalkyl and cyclenes basic ring independently of one another ground warp be selected from fluorine and C _1-3The substituting group list of-alkyl or two replacement, and

R ^NExpression H, C _1-4-alkyl, C _1-4-alkyl carbonyl or C _1-4-alkane alkylsulfonyl,

L1 is independently from each other hydroxyl, cyano group, nitro, C _3-7-cycloalkyl, aryl, heteroaryl, C _1-4-alkyl carbonyl, aromatic carbonyl, assorted aromatic carbonyl, aminocarbonyl, C _1-4-alkane aminocarbonyl, two-(C _1-3-alkyl)-aminocarbonyl, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, morpholine-4-base carbonyl, fragrant aminocarbonyl, assorted fragrant aminocarbonyl, C _1-4-carbalkoxy, aryl-C _1-3-carbalkoxy, heteroaryl-C _1-3-carbalkoxy, C _1-4-alkoxyl group, aryloxy, heteroaryloxy, C _1-4-alkylthio, arylthio, heteroarylthio, C _1-4-alkyl sulfinyl, fragrant sulfinyl, assorted fragrant sulfinyl, C _1-4-alkane alkylsulfonyl, arylsulfonyl and assorted arylsulfonyl, and

L2 is independently from each other fluorine, chlorine, bromine, iodine, C _1-3-alkyl, difluoromethyl, trifluoromethyl, C _1-3-alkoxyl group, difluoro-methoxy, trifluoromethoxy and cyano group, and

R ⁶、R ^7a、

R ^7b, R ^7cHave independently of one another and be selected from following meaning: hydrogen, (C _1-18-alkyl) carbonyl, (C _1-18-alkyl) oxygen base carbonyl, aromatic carbonyl and aryl-(C _1-3-alkyl)-carbonyl,

Wherein, the aryl of mentioning in the definition of above-mentioned base means phenyl or naphthyl, its identical or different single or two replacements of L2 base of ground warp independently of one another, and

The heteroaryl of mentioning in the definition of above-mentioned base means pyrryl, furyl, thienyl, pyridyl, indyl, benzofuryl, benzimidazole thiophanate phenyl, quinolyl, isoquinolyl or tetrazyl,

Or mean pyrryl, furyl, thienyl or pyridyl, wherein one or two methyne can replace through nitrogen-atoms,

Or mean indyl, benzofuryl, benzimidazole thiophanate phenyl, quinolyl or isoquinolyl, wherein one to three methyne can replace through nitrogen-atoms,

Wherein, the identical or different single or two replacements of L2 base of ground warp independently of one another of above-mentioned heteroaryl,

Wherein, except as otherwise noted, otherwise above-mentioned alkyl can be straight or branched,

Its compounds tautomeric, stereoisomers, its mixture and its esters.

Compound and physiologically acceptable salt thereof according to general formula I of the present invention have valuable pharmacological character, particularly have the inhibition effect for Na-dependent glucose cotransporter SGLT, particularly SGLT2.In addition, has the inhibition effect according to The compounds of this invention for Na-dependent glucose cotransporter SGLT1.When comparing with possible inhibition effect for SGLT1, The compounds of this invention preferably optionally suppresses SGLT2.

The present invention also is about according to The compounds of this invention and the inorganic or physiologically acceptable salt of organic acid.

The present invention also is relevant pharmaceutical composition, and is at least a according to compound of the present invention or according to physiologically acceptable salt of the present invention except comprising, and looks situation and also contains one or more inert supports and thinner.

The present invention also be relevant use at least a according to compound of the present invention or a kind of its physiologically acceptable salt with pharmaceutical compositions, this pharmaceutical composition is suitable for treatment or prevents affected disease or illness because of suppressing Na-dependent glucose cotransporter SGLT, particularly SGLT2.

The present invention also is the relevant at least a pharmaceutical composition that is suitable for treating metabolic disorder according to compound of the present invention or its a kind of physiologically acceptable salt with preparation that uses.

The present invention also is the relevant at least a medical compositions that is used to suppress Na-dependent glucose cotransporter SGLT, particularly SGLT2 according to compound of the present invention or its a kind of physiologically acceptable salt with preparation that uses.

The relevant preparation of the present invention is according to the method for medical compositions of the present invention in addition, it is characterized in that will adding one or more inert support and thinner according to compound of the present invention or its a kind of physiologically acceptable salt based on method non-chemically.

The present invention also is the method for relevant preparation according to compound of Formula I of the present invention, it is characterized in that a) in order to prepare as mentioned and defined compound of Formula I hereinafter,

General formula I I compound is being had in the presence of Lewis acid or the Bronsted acid and the reductive agent reaction, wherein the protecting group of any existence simultaneously or division successively fall;

Among the formula II

R ' expression H, C _1-4-alkyl, (C _1-18-alkyl) carbonyl, (C _1-18-alkyl) oxygen carbonyl, aromatic carbonyl and aryl-(C _1-3-alkyl)-and carbonyl, wherein this alkyl or aryl can be through halogen list or polysubstituted,

R ^8a、R ^8b、

R ^8c, R ^8dHave independently of one another and above or hereinafter give R ⁶, R ^7a, R ^7b, R ^7cThe meaning of one of base, expression benzyl or R ^aR ^bR ^cSi base or ketal or acetal radical, particularly alkylidene group or arylmethylene alkyl, ketal group or acetal radical; Yet, in each situation, two adjacent R ^8a, R ^8b, R ^8c, R ^8dBase can form cyclic ketal base or acetal radical, or 1,2-two (C _1-3-alkoxyl group)-1,2-two (C _1-3-alkyl)-and etheno, however two carbon atoms under above-mentioned etheno and two Sauerstoffatoms and the pyranose ring form monobasic two  alkane rings, particularly 2,3-dimethyl-2,3-two (C _1-3-alkoxyl group)-1,4-two  alkane rings, and wherein alkyl, aryl and/or benzyl can be by halogen or C _1-3-alkoxyl group list or polysubstituted, and benzyl also can be through two-(C _1-3-alkyl) the amino replacement, and

R ^a, R ^b, R ^cRepresent C independently of one another _1-4Alkyl, aryl or aryl-C _1-3-alkyl, wherein this aryl or alkyl can be through halogen lists or polysubstituted,

Yet the aryl of mentioning in the definition of above-mentioned base means phenyl or naphthyl, and is preferable with phenyl,

And, this R wherein ¹To R ⁵With R ⁶, R ^7a, R ^7b, R ^7cBase be as mentioned with the definien of institute hereinafter,

Or

B) in order to prepare wherein R ⁶, R ^7a, R ^7bWith R ^7cThe compound of Formula I of expression hydrogen is hydrolyzed compound of formula III

This R wherein ^8a, R ^8b, R ^8c, R ^8dWith R ¹To R ⁵Be as mentioned with the definien of institute hereinafter, but R ^8a, R ^8b, R ^8c, R ^8dIn the base at least one is not hydrogen, and

In case of necessity, with the wherein R that obtains thus ⁶The compound of Formula I of expression hydrogen atom changes into the acyl compounds of corresponding general formula I by acidylate, with/or

When needing, the protection basic capsule that any above-mentioned reaction is used goes, with/or

In case of necessity, the compound of Formula I that obtains thus is separated into its stereoisomers and

In case of necessity, the compound of Formula I that obtains is thus changed into its salt, particularly change into its physiologically acceptable salt for medicinal use.

The preparation method of the in addition relevant general formula I I compound of the present invention

Wherein

R ^8a、R ^8b、

R ^8c, R ^8dHas the R of giving independently of one another ⁶, R ^7a, R ^7b, R ^7cA kind of meaning of base, expression benzyl or R ^aR ^bR ^cSi base or ketal group or acetal radical; Yet, in each situation, two adjacent R ^8a, R ^8b, R ^8c, R ^8dBase can form cyclic ketal or acetal radical, or can form with two Sauerstoffatoms of pyranose ring replace 2,3-oxygen base two  alkane rings, particularly 2,3-dimethyl-2,3-two (C _1-3-alkoxyl group)-1,4-two  alkane rings, and wherein alkyl, aryl and/or benzyl can be by halogen or C _1-3-alkoxyl group list or polysubstituted; And benzyl also can be by two-(C _1-3-alkyl) the amino replacement, and

R ^a, R ^b, R ^cRepresent C independently of one another _1-4Alkyl, aryl or aryl-C _1-3-alkyl, wherein this alkyl or aryl can be by halogen list or polysubstituted,

And R ¹To R ⁵, R ⁶, R ^7a, R ^7b, R ^7cBe to define as mentioned with hereinafter,

Wherein, can obtain organometallic compound (V) by the carbon-halogen bond of halogen-metal exchange or the halogen-benzyl benzene compound by metal being inserted general formula I V

Wherein Hal represents Cl, Br and I, and R ¹To R ⁵Be to define as mentioned with hereinafter, and follow-up trans-metallation in case of necessity, be added on the glucose lactone of general formula I V

R wherein ^8a, R ^8b, R ^8c, R ^8dBe to define as mentioned with hereinafter, and

Then, the adducts that generated of order reacts (preferably situ reaction) with water or R '-OH alcohol under the condition that the acid or the ammonium chloride that for example have such as methanesulfonic, sulfuric acid, hydrochloric acid, acetate exist, in case of necessity the C that is substituted of R ' expression wherein _1-4-alkyl, and make the product that reacts obtained wherein R ' expression H with water according to circumstances, in subsequent reactions, change into wherein R ' expression (C with the acylating agent of an example such as corresponding sour muriate or acid anhydrides _1-18-alkyl) carbonyl, (C _1-18-alkyl) oxygen carbonyl, aromatic carbonyl or aryl-(C _1-3-alkyl)-and the product of the formula II of carbonyl, it can replace as above-mentioned.

Described intermediate product, particularly formula IV, formula II and formula III also are theme of the present invention.

Detailed Description Of The Invention

Except as otherwise noted, otherwise should base, residue and substituting group, particularly R ¹To R ⁵, A, B, L1, L2, R ^N, R ⁶, R ^7a, R ^7b, R ^7c, R ^8a, R ^8b, R ^8c, R ^8dBe to define as mentioned with hereinafter.

If when residue, substituting group or base had for several times in a compound, they may have identical or different meaning.

According to the present invention, the benzene derivative that replaces of the glucopyranosyl of general formula I preferably

Wherein

R ¹Be selected from the definition of A base, and

If R ³Be when being selected from the definition of B base, R then ¹Also can additionally be selected from following meaning: hydrogen, fluorine, chlorine, bromine, iodine, C _1-4-alkyl, C _2-4-thiazolinyl-C _1-4-alkyl, C _2-4-alkynyl-C _1-4-alkyl, C _3-7-cycloalkyl-C _1-4-alkyl, C _5-7-cycloalkenyl group-C _1-4-alkyl, the methyl that replaces through 1-3 fluorine atom, through ethyl, the C of 1-5 fluorine atom replacement _1-4-alkoxyl group, the methoxyl group that replaces through 1-3-fluorine atom, through the oxyethyl group of 1-5 fluorine atom replacement, through hydroxyl or-C _1-3The C that-alkoxyl group replaces _1-4-alkyl, through hydroxyl or C _1-3The C that-alkoxyl group replaces _2-4-alkoxyl group, C _3-6-cycloalkyl-C _1-3-alkoxyl group or hydroxyl,

Yet, in above-mentioned cycloalkyl and cyclenes basic ring, 1 or 2 methylene radical ground warp O or CO replacement independently of one another, and

R ³Be the definition that is selected from the B base, and

If R ¹Be when being selected from the definition of A base, R then ³Also can additionally be selected from following meaning: hydrogen, fluorine, chlorine, bromine, iodine, C _1-6-alkyl, C _2-4-thiazolinyl-C _1-4-alkyl, C _2-4Alkynyl-C _1-4-alkyl, C _3-7-cycloalkyl, C _5-7-cycloalkenyl group, C _3-7-cycloalkyl-C _1-4-alkyl, C _5-7-cycloalkenyl group-C _1-4-alkyl, C _3-6-ring alkylidene group methyl, hydroxyl, C _1-6-alkoxyl group, C _3-6-cycloalkyl-C _1-3-alkoxyl group, aryl, aryl-C _1-3-alkyl, heteroaryl, heteroaryl-C _1-3-alkyl, aryloxy, aryl-C _1-3-alkyl-oxygen base, the methyl or methoxy that replaces through 1-3-fluorine atom, through the C of 1-5 fluorine atom replacement _2-4-alkyl or C _2-4-alkoxyl group, the C that replaces through cyano group _1-4-alkyl, through hydroxyl or C _1-3The C that-alkoxyl group replaces _1-4-alkyl, cyano group, carboxyl, C _1-3-carbalkoxy, aminocarbonyl, (C _1-3-alkylamino) carbonyl, two-(C _1-3-alkyl) aminocarbonyl, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, morpholine-4-base carbonyl, piperazine-1-base-carbonyl, 4-(C _1-3-alkyl)-piperazine-1-base-carbonyl, (C _1-4-alkyl) carbonyl amino, C _1-4-alkyl-sulfuryl amino, C _1-4-alkylthio, C _1-4-alkyl sulfinyl, C _1-4-alkane alkylsulfonyl, arylsulfonyl amino, aryl-C _1-3-alkyl sulfo group amino or arylsulfonyl,

R ⁴, R ⁵Represent hydrogen, fluorine, chlorine, bromine, iodine, cyano group, nitro, C independently of one another _1-3-alkyl, C _1-3-alkoxyl group, the methyl or methoxy that replaces through 1 to 3 fluorine atom,

Wherein above-mentioned alkynyl and thiazolinyl can single or two replacements through identical or different L1 base, and

B represents three-(C _1-4-alkyl) silylation-C _1-6-alkyl, C _2-6-alkynes-1-base, C _2-6-alkene-1-base, amino, C _1-3-alkylamino, two-(C _1-3-alkyl) amino, tetramethyleneimine-1-base, pyrrolidin-2-one-1-base, piperidines-1-base, piperidines-2-ketone-1-base, morpholine-4-base, morpholine-3-ketone-4-base, piperazine-1-base, 4-(C _1-3-alkyl)-piperazine-1-base, fragrant carbonyl amino, assorted fragrant carbonyl amino, nitro, C _3-7-cycloalkyloxy, C _5-7-cyclenes oxygen base, C _3-7-cycloalkylthio, C _3-7-cycloalkanes sulfinyl, C _3-7-cycloalkanes alkylsulfonyl, C _5-7-cyclenes sulfenyl, C _5-7-cyclenes sulfinyl, C _5-7-cyclenes alkylsulfonyl, arylthio, fragrant sulfinyl, heteroarylthio or assorted fragrant sulfinyl,

Above-mentioned cycloalkyl and cycloalkenyl group ground warp independently of one another are selected from fluorine and C _1-3The substituting group list of-alkyl or two replacement, and

R ^NExpression H or C _1-4-alkyl,

L1 is independently from each other cyano group, nitro, aryl, heteroaryl, C _1-4-alkyl carbonyl, aromatic carbonyl, assorted aromatic carbonyl, aminocarbonyl, C _1-4-alkane aminocarbonyl, two-(C _1-3-alkyl)-aminocarbonyl, tetramethyleneimine--1 basic carbonyl, piperidines-1-base carbonyl, morpholine-4-base carbonyl, fragrant aminocarbonyl, assorted fragrant aminocarbonyl, C _1-4-carbalkoxy, aryl-C _1-3-carbalkoxy, heteroaryl-C _1-3-carbalkoxy, C _1-4-alkoxyl group, aryloxy, heteroaryloxy, C _1-4-alkylthio, arylthio, heteroarylthio, C _1-4-alkyl sulfinyl, fragrant sulfinyl, assorted fragrant sulfinyl, C _1-4-alkane alkylsulfonyl, arylsulfonyl and assorted arylsulfonyl, and

R ⁶、R ^7a、

R ^7b, R ^7cBe independently from each other and have following meaning: hydrogen, (C _1-18-alkyl) carbonyl, (C _1-18-alkyl) oxygen base carbonyl, aromatic carbonyl and aryl-(C _1-3-alkyl)-carbonyl,

The aryl of being mentioned in the definition of above-mentioned base means phenyl or naphthyl, and it is the single or two replacements of the identical or different L2 base of ground warp independently of one another, and

The heteroaryl of mentioning in the definition of above-mentioned base means pyrryl, furyl, thienyl, pyridyl, indyl, benzofuryl, benzimidazole thiophanate phenyl, quinolyl or isoquinolyl,

Or mean pyrryl, furyl, thienyl or pyridyl, wherein one or two methyne is to replace through nitrogen-atoms,

Or mean indyl, benzofuryl, benzimidazole thiophanate phenyl, quinolyl or isoquinolyl, wherein one to three methyne is to replace through nitrogen-atoms,

Yet, the identical or different single or two replacements of L2 base of ground warp independently of one another of above-mentioned heteroaryl,

Wherein, except as otherwise noted, otherwise above-mentioned alkyl can be straight or branched person,

Its compounds tautomeric, stereoisomers, its mixture and its esters.

Hereinafter will provide some preferred indivedual bases and substituent meaning according to The compounds of this invention.

R ³Base is preferably-CH ₂I.2, therefore between bridge or right position is preferred according to following formula I .1 and I.2 compound, particularly formula:

At L1, R ¹, R ³, the aryl that occurs in A and the B base term preferably represent phenyl.

At L1, R ¹, R ³, the heteroaryl that occurs in A and the B base term preferably represent pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazyl,  azoles base,  di azoly, thiazolyl or thiadiazolyl group.

The preferred expression of A base C _2-6-alkynes-1-base, C _2-6-alkene-1-base, C _3-7-cycloalkyl, C _5-7Cycloalkenyl group, C _1-4-alkyl carbonyl, aminocarbonyl, C _1-4-alkane aminocarbonyl, two-(C _1-3-alkyl) aminocarbonyl, pyridine alkane-1-base carbonyl, piperidines-1-base carbonyl, morpholine-4-base carbonyl, piperazine-1-base carbonyl, 4-(C _1-4-alkyl) piperazine-1-base carbonyl, C _1-4-carbalkoxy, amino, C _1-4-alkylamino, two-(C _1-3-alkyl) amino, tetramethyleneimine-1-base, pyrrolidin-2-one-1-base, piperidines-1-base, piperidines-2-ketone-1-base, morpholine-4-base, morpholine-3-ketone-4--base, piperazine-1-base, 4-(C _1-3-alkyl) piperazine-1-base, C _1-4-alkane carbonyl oxygen base, C _3-7-cycloalkyloxy, C _5-7-cyclenes oxygen base, C _1-4-alkyl sulfinyl, C _1-4-alkane alkylsulfonyl, C _3-7-cycloalkylthio, C _3-7-cycloalkanes sulfinyl, C _3-7-cycloalkanes alkylsulfonyl, C _5-7-cyclenes sulfenyl, C _5-7-cyclenes sulfinyl, C _5-7-cyclenes alkylsulfonyl, cyano group and nitro,

Wherein, above-mentioned alkynyl and thiazolinyl can be through fluorine or chlorine lists or polysubstituted, and be preferable with fluorine again, and

Above-mentioned alkynyl and thiazolinyl can be single or polysubstituted through identical or different L1 base, and

Above-mentioned cycloalkyl and cyclenes basic ring ground warp independently of one another are selected from fluorine and C _1-3The substituting group list of-alkyl replaces or two replacement, and

In above-mentioned cycloalkyl and cyclenes basic ring, one or two methylene radical is ground warp O, S, CO, SO, SO independently of one another ₂Or NR ^NReplace, preferred O or CO, special good person replaces through O.

Special good is that the A base is expression C _2-6-alkynes-1-base, C _2-6-alkene-1-base, C _3-7-cycloalkyl, C _5-7Cycloalkenyl group, C _3-7-cycloalkyloxy, C _5-7-cyclenes oxygen base, C _1-4-alkyl sulfinyl, C _1-4-alkane alkylsulfonyl, C _3-7-cycloalkylthio, C _3-7-cycloalkanes sulfinyl, C _3-7-cycloalkanes alkylsulfonyl, C _5-7-cyclenes sulfenyl, C _5-7-cyclenes sulfinyl, C _5-7-cyclenes alkylsulfonyl, cyano group and nitro,

Yet above-mentioned alkynyl and thiazolinyl can be through fluorine or chlorine lists or polysubstituted, and be preferable with fluorine, and

At above-mentioned C _5-6In-the cycloalkyl ring, methylene radical can replace through O.

Special good, the A base is expression C _2-6-alkynes-1-base, C _2-6-alkene-1-base, C _3-7-cycloalkyl, C _5-7Cycloalkyloxy, cyano group, yet, at C _5-7A methylene unit can be replaced by O in the-cycloalkyl.

The example of the definition of special good A base is ethynyl, third-1-alkynes-1-base, fourth-1-alkynes-1-base, cyano group, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy.

The B base is preferably represented three-(C _1-4-alkyl) silylation-C _1-6-alkyl, C _2-6-alkynes-1-base, C _2-6-alkene-1-base, amino, C _1-3-alkylamino, two-(C _1-3-alkyl) amino, tetramethyleneimine-1-base, pyrrolidin-2-one-1-base, piperidines-1-base, piperidines-2-ketone-1-base, morpholine-4-base, morpholine-3-ketone-4-base, piperazine-1-base, 4-(C _1-3-alkyl)-piperazine-1-base, nitro, C _3-7-cycloalkyloxy, C _5-7-cyclenes oxygen base, C _3-7-cycloalkylthio, C _3-7-cycloalkanes sulfinyl, C _3-7-cycloalkanes alkylsulfonyl, C _5-7-cyclenes sulfenyl, C _5-7-cyclenes sulfinyl, C _5-7-cyclenes alkylsulfonyl,

In above-mentioned cycloalkyl and cyclenes basic ring, one or two methylene radical is ground warp O, S, CO, SO, SO independently of one another ₂Or NR ^NReplace, with O, CO, S, SO ₂Or NR ^NPreferably, again to replace special good through O or CO.

Special good, the B base is expression three-(C _1-4-alkyl) silylation-C _1-6-alkyl, C _2-6-alkynes-1-base, C _2-6-alkene-1-base, nitro, C _3-7-cycloalkyloxy, C _5-7-cyclenes oxygen base, C _3-7-cycloalkylthio, C _3-7-cycloalkanes sulfinyl, C _3-7-cycloalkanes alkylsulfonyl, C _5-7-cyclenes sulfenyl, C _5-7-cyclenes sulfinyl, C _5-7-cyclenes alkylsulfonyl,

Yet above-mentioned alkynyl and thiazolinyl can be through fluorine or chlorine lists or polysubstituted, and

Special good, the B base is expression three-(C _1-4-alkyl) silylation-C _1-6-alkyl, C _2-6-alkynes-1-base, C _2-6-alkene-1-base, C _3-7-cycloalkyloxy, C _5-7-cyclenes oxygen base, C _3-7-cycloalkylthio, C _3-7-cyclenes sulfenyl, however above-mentioned alkynyl and thiazolinyl can be through fluorine lists or polysubstituted or replace through chlorine or L1 base is single; And in cycloalkyl and cycloalkenyl group, one or two methylene radical is ground warp O, S, CO, SO independently of one another ₂Or NR ^NReplace, preferred with O or CO.

The example of special good B base definition is the trimethyl silane ethyl, ethynyl, 1-propine-1-base, ethyl acetylene-1-base, tertiary butyl ethynyl, 2-hydroxyl third-2-ethyl-acetylene base, 2-methoxy propyl-2-ethyl-acetylene base, 3-hydroxyl-1-propine-1-base, 3-methoxyl group-1-propine-1-base, vinyl, the 1-propenyl, the 1-butylene base, tertiary butyl vinyl, the ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, the tetrahydrofuran oxygen base, tetrahydrochysene sulphur phenoxy group, 1,1-dioxo tetrahydrochysene sulphur phenoxy group, tetrahydro-pyran oxy, tetrahydrochysene sulphur pyran oxygen base, 1,1-dioxo tetrahydrochysene sulphur pyran oxygen base, tetrahydrofuran (THF) ketone group oxygen base, piperidyl oxygen base, piperidone base oxygen base, tetramethyleneimine-3-base oxygen base, pyrrolidone-3-base oxygen base, tetrahydrofuran base-sulfenyl, the cyclopropyl sulfenyl, the cyclobutyl sulfenyl, cyclopentyl sulfenyl and cyclohexyl sulfenyl are wherein at piperidyl, piperidone base, in pyrrolidyl or the pyrrolidone ring-the NH base can be through R ^N, C particularly _1-3-alkyl or ethanoyl replace.

Special good meaning is trimethyl silane ethyl, ethynyl, 2-hydroxyl third-2-ethynyl, 2-methoxy propyl-2-ethyl-acetylene base, 3-hydroxyl-1-propine-1-base, 3-methoxyl group-1-propine-1-base, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran (THF)-3-base oxygen base, tetrahydropyran-4-base oxygen base, piperidin-4-yl oxygen base, N-methyl piperidine-4-base oxygen base and N-ethanoyl piperidin-4-yl oxygen base.The example that deserves particular mention is ethynyl, trimethyl silane ethyl, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran (THF)-3-base oxygen base and tetrahydrofuran (THF)-4-base oxygen base.

If at residue or A, B, R ¹Or R ³In the base, existing wherein, two methylene radical are through O, S, NR ^NReplace or through S, NR ^N, CO, SO or SO ₂When cycloalkyl that replaces or cyclenes basic ring, then these methylene radical preferably directly are not connected to each other.Yet, if two first subunits are through O and CO or through NR ^NWhen replacing with CO, then these can directly be connected to each other, so as to form one-O-CO-or-NR ^N-CO base.

The preferred meaning of L1 base is to be selected from hydroxyl, cyano group, C _3-6-cycloalkyl, C _1-4-alkyl carbonyl, aminocarbonyl, C _1-4-alkane aminocarbonyl, two-(C _1-3-alkyl) aminocarbonyl, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, morpholine-4-base carbonyl, C _1-4-carbalkoxy, C _1-4-alkoxyl group, C _1-4-alkylthio, C _1-4-alkyl sulfinyl and C _1-4-alkane alkylsulfonyl.

The special good meaning of L1 base is to be selected from hydroxyl, C _1-4-alkoxyl group and C _1-4-alkylthio.

When if L1 represents hydroxyl, then this hydroxyl is not directly connected to two keys or triple-linked C atom.

Compound according to the first embodiment of the present invention can describe by general formula I, particularly formula I.1 with I.2, special good person be formula I.2, wherein

R ³One of definition of the B base that is selected from above to be given, and

Other bases are to define as mentioned with hereinafter with substituting group,

Comprise its compounds tautomeric, stereoisomers, its mixture and its esters.

According to this embodiment, R ¹The preferred meaning of base is hydrogen, fluorine, chlorine, bromine, iodine, C _1-4-alkyl, C _2-6-alkynyl, C _1-4-alkoxyl group, C _2-4-thiazolinyl-C _1-4-alkoxyl group, C _2-4-alkynyl-C _1-4-alkoxyl group, the methyl that replaces through 1-3 fluorine atom, the ethyl that replaces through 1-5 fluorine atom, through the methoxyl group of 1-3 fluorine atom replacement, through the oxyethyl group of 1-5-fluorine atom replacement, through hydroxyl or C _1-3The C that-alkoxyl group replaces _1-4-alkyl, through hydroxyl or C _1-3The C that-alkoxyl group replaces _2-4-alkoxyl group, C _2-6-thiazolinyl, C _3-6-cycloalkyl, C _3-6-cycloalkyl-C _1-3-alkyl, C _3-7-cycloalkyloxy, C _3-6-cycloalkyl-C _1-3-alkoxyl group, C _5-7-cyclenes oxygen base, hydroxyl, amino, nitro or cyano group, while are at C _5-6Methylene radical can replace through O in the-cycloalkyl.

Special good meaning is hydrogen, fluorine, chlorine, bromine, cyano group, methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, ethynyl, third-1-alkynes-1-base, fourth-1-alkynes-1-base, hydroxyl, methoxyl group, oxyethyl group, difluoro-methoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, particularly methyl and chlorine.

The compound of second embodiment according to the present invention can describe by general formula I, particularly formula I.1 with I.2, special good be formula I.2, wherein

R ¹Be the definition of the A base that is selected from above to be given, and

Comprise its compounds tautomeric, stereoisomers, its mixture and its esters.

According to this second embodiment, R ³The preferred meaning of base is hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano group, C _1-6-alkyl, TMS ethyl, C _2-6-thiazolinyl, C _2-6-alkynyl, difluoromethyl, trifluoromethyl, C _3-7-cycloalkyl, C _5-7-cycloalkenyl group, C _1-6-alkoxyl group, difluoro-methoxy, trifluoromethoxy, five fluorine oxyethyl groups, C _3-7-cycloalkyloxy, tetrahydrofuran oxygen base, tetrahydrofuran (THF) ketone oxygen base, C _1-6-alkylthio, ring propylidene methyl, aryl or heteroaryl.

According to this second embodiment, R ³The special good meaning of base is a hydrogen, fluorine, chlorine, methyl, ethyl, sec.-propyl, the tertiary butyl, ethynyl, the 1-proyl, the TMS ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxyl group, oxyethyl group, isopropoxy, cyclopentyloxy, difluoro-methoxy, trifluoromethoxy, five fluorine oxyethyl groups, tetrahydrofuran (THF)-3-base oxygen base, tetrahydrofuran (THF)-2-ketone-3-base oxygen base, the methyl sulfenyl, the ethyl sulfenyl, the sec.-propyl sulfenyl, ring propylidene methyl, phenyl, fluorophenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazyl,  azoles base, the  di azoly, thiazolyl or thiadiazolyl group.

According to this second embodiment, R ³The meaning of the best of base is hydrogen, fluorine, chlorine, methyl, ethyl, sec.-propyl, the tertiary butyl, ethynyl, 1-proyl, TMS ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxyl group, oxyethyl group, isopropoxy, cyclopentyloxy, difluoro-methoxy, trifluoromethoxy, five fluorine oxyethyl groups, tetrahydrofuran (THF)-3-base oxygen base, tetrahydrofuran (THF)-2-ketone-3-base oxygen base, methyl sulfenyl, ethyl sulfenyl, sec.-propyl sulfenyl, ring propylidene methyl.The example of the meaning that this class is special good is methyl, ethyl, methoxyl group, oxyethyl group, trimethyl silane ethyl, ethynyl, cyclopentyloxy, tetrahydrofuran (THF)-3-base oxygen base, tetrahydrofuran (THF)-2-ketone-3-base oxygen base, particularly trimethyl silane ethyl, oxyethyl group, cyclopentyloxy and tetrahydrofuran (THF)-3-base oxygen base.

Provide other bases and substituent meaning below, its according to general formula I, formula I.1 with I.2, also be preferred according to embodiment mentioned above:

R ²The preferred meaning of base is hydrogen, fluorine, chlorine, bromine, methyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethoxy, cyano group, nitro and methyl through 1-3 fluorine atom replacement.

R ²The preferred meaning of base is hydrogen, fluorine, hydroxyl, methoxyl group, oxyethyl group and methyl, particularly hydrogen and methyl.

R ⁴The preferred meaning of base is hydrogen and fluorine, particularly hydrogen.

R ⁵The preferred meaning of base is hydrogen and fluorine, particularly hydrogen.

R ^NBase is preferably represented H, methyl, ethyl or ethanoyl.

R ⁶Base is preferably hydrogen, (C according to the present invention _1-18-alkyl) oxygen carbonyl, C _1-8-alkyl carbonyl or benzyl acyl group, particularly hydrogen or (C _1-6-alkyl) oxygen carbonyl, C _1-6-alkyl carbonyl is hydrogen, methyl carbonyl, methoxycarbonyl or ethoxycarbonyl especially, and the most special good person is hydrogen or methoxycarbonyl.

Substituent R ^7a, R ^7b, R ^7cPreferably represent hydrogen, (C independently of one another _1-8-alkyl) oxygen carbonyl, (C _1-18-alkyl) carbonyl, benzyl acyl group, particularly hydrogen or (C _1-6-alkyl) oxygen carbonyl, (C _1-8-alkyl) carbonyl, special good is hydrogen, methoxycarbonyl, ethoxycarbonyl, methyl carbonyl or ethyl carbonyl.The most special good, R ^7a, R ^7b, R ^7cRepresent hydrogen.

R wherein ⁶, R ^7a, R ^7b, R ^7cHas for example C according to the present invention _1-8The formula I compound of the meaning beyond the hydrogen of-alkyl carbonyl is to be suitable for as synthetic wherein R ^7a, R ^7b, R ^7cThe intermediate product of the formula I compound of expression hydrogen.

I.2a extremely I.2d special good compound of Formula I is selected from formula, particularly I.2c:

Wherein, R ¹To R ⁶With R ^7a, R ^7b, R ^7cBase has one of aforesaid meaning, particularly preferably gives one of implication as having, and particularly

R ¹Expression hydrogen, fluorine, chlorine, bromine, iodine, C _1-4-alkyl, C _2-6-alkynyl, C _1-4-alkoxyl group, C _2-4-thiazolinyl-C _1-4-alkoxyl group, C _2-4-alkynyl-C _1-4-alkoxyl group, the methyl that replaces through 1-3 fluorine atom, the ethyl that replaces through 1-5 fluorine atom, through the methoxyl group of 1-3 fluorine atom replacement, through the oxyethyl group of 1-5-fluorine atom replacement, through hydroxyl or C _1-3The C that-alkoxyl group replaces _1-4-alkyl, through hydroxyl or C _1-3The C that-alkoxyl group replaces _2-4-alkoxyl group, C _2-6-thiazolinyl, C _3-6-cycloalkyl, C _3-6-cycloalkyl-C _1-3-alkyl, C _3-7-cycloalkyloxy, C _3-6-cycloalkyl-C _1-3-alkoxyl group, C _5-7-cyclenes oxygen base, hydroxyl, amino, nitro or cyano group, simultaneously are at C _5-6In-the cycloalkyl, methylene radical can replace through O; Special good is expression hydrogen, fluorine, chlorine, bromine, cyano group, methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, ethynyl, third-1-alkynes-1-base, fourth-1-alkynes-1-base, hydroxyl, methoxyl group, oxyethyl group, difluoro-methoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy or cyclohexyloxy, and

R ²Expression hydrogen, fluorine, hydroxyl, methoxyl group, oxyethyl group or methyl, particularly hydrogen or methyl, and

R ³Be to be selected from the B base, comprise the TMS ethyl, ethynyl, 1-propine-1-base, ethyl acetylene-1-base, tertiary butyl ethynyl, 2-hydroxyl third-2-ethyl-acetylene base, 2-methoxy propyl-2-ethyl-acetylene base, 3-hydroxyl-1-propine-1-base, 3-methoxyl group-1-propine-1-base, vinyl, the 1-propenyl, the 1-butylene base, tertiary butyl vinyl, the ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, the tetrahydrofuran oxygen base, tetrahydrochysene sulphur phenoxy group, 1,1-dioxo tetrahydrochysene sulphur phenoxy group, tetrahydro-pyran oxy, tetrahydrochysene sulphur pyran oxygen base, 1,1-dioxo tetrahydrochysene sulphur pyran oxygen base, tetrahydrofuran (THF) ketone group oxygen base, piperidyl oxygen base, piperidone base oxygen base, tetramethyleneimine-3-base oxygen base, pyrrolidone-3-base oxygen base, the tetrahydrofuran base sulfenyl, the cyclopropyl sulfenyl, the cyclobutyl sulfenyl, cyclopentyl sulfenyl and cyclohexyl sulfenyl; Wherein, in piperidyl, piperidone base, pyrrolidyl or pyrrolidone basic ring-the NH base can be through R ^N, C particularly _1-3-alkyl or ethanoyl replace; Special good is to be selected from TMS ethyl, ethynyl, 2-hydroxyl third-2-ethyl-acetylene base, 2-methoxy propyl-2-ethyl-acetylene base, 3-hydroxyl-1-propine-1-base, 3-methoxyl group-1-propine-1-base, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran (THF)-3-base oxygen base, tetrahydropyran-4-base oxygen base, piperidin-4-yl oxygen base, N-methyl piperidine-4-base oxygen base and N-ethanoyl piperidin-4-yl oxygen base, and

R ⁴Expression hydrogen or fluorine, particularly hydrogen, and

R ⁵Expression hydrogen or fluorine, particularly hydrogen, and

R ⁶Expression hydrogen, (C _1-6-alkyl) oxygen carbonyl, (C _1-6-alkyl) carbonyl or benzyl acyl group, particularly hydrogen, methyl carbonyl, methoxycarbonyl or ethoxycarbonyl, special good person is a hydrogen, and

R ^7a, R ^7b, R ^7cRepresent hydrogen, (C independently of one another _1-6-alkyl) oxygen carbonyl, (C _1-8-alkyl) carbonyl or benzyl acyl group, particularly hydrogen, methoxycarbonyl, ethoxycarbonyl, methyl carbonyl or ethyl carbonyl, special good is hydrogen,

Comprise its compounds tautomeric, stereoisomers, its mixture and its esters.

According to the variant of the embodiment that above gives, other also preferred compounds are wherein to have substituent R ³Phenyl have at least one other the substituent R different with hydrogen ⁴And/or R ⁵According to this variant, special good compound is to have the substituent R of representing fluorine ⁴.

Have substituent R ³Phenyl preferably be at most single fluorizated.

To provide the compound of general formula I at follow-up experimental section, and R wherein ⁶Have according to meaning of the present invention rather than hydrogen, particularly R wherein ⁶The derivative of the compound of Formula I of expression ethoxycarbonyl or methoxycarbonyl comprises that its compounds tautomeric, stereoisomers and its mixture are according to of the present invention preferred.

Special good compound of Formula I is to be selected from:

(1) 1-chloro-2-(4-encircles penta oxygen benzyl)-4-(β-D-Glucopyranose-1-yl)-benzene

(2) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-[4-((R)-tetrahydrofuran (THF)-3-base oxygen base)-benzyl]-benzene

(3) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-[4-((S)-tetrahydrofuran (THF)-3-base oxygen base)-benzyl]-benzene

(4) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-[4-(tetrahydrofuran (THF)-2-ketone-3-base oxygen base)-benzyl]-benzene

(5) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-(4-cyclobutoxy group-benzyl)-benzene

(6) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-(4-cyclohexyloxy-benzyl)-benzene

(7) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-[4-(tetrahydropyran-4-base oxygen)-benzyl]-benzene

(8) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-[4-(1-ethanoyl-piperidin-4-yl oxygen)-benzyl]-benzene

(10) 1-(β-D-Glucopyranose-1-yl)-4-methyl-3-[4-(tetrahydrofuran (THF)-3-base oxygen)-benzyl]-benzene

(11) 1-(β-D-Glucopyranose-1-yl)-4-methyl-3-[4-(2-TMS-ethyl)-benzyl]-benzene

(12) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-(4-ethynyl-benzyl)-benzene

(13) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-[4-(piperidin-4-yl oxygen)-benzyl]-benzene

(14) 1-fluoro-4-(β-D-Glucopyranose-1-yl)-2-(4-ethynyl-benzyl)-benzene

(15) 1-(β-D-Glucopyranose-1-yl)-3-(4-ethynyl-benzyl)-benzene

(16) 1-ethynyl-4-(β-D-Glucopyranose-1-yl)-2-(4-oxyethyl group-benzyl)-benzene

(17) 1-methoxyl group-4-(β-D-Glucopyranose-1-yl)-2-(4-ethynyl-benzyl)-benzene

And derivative, wherein R ⁶Having according to meaning of the present invention is not hydrogen, particularly R wherein ⁶Expression ethoxycarbonyl or methoxycarbonyl,

Comprise its compounds tautomeric, stereoisomers and its mixture.

In the method according to the invention, R ¹, R ², R ³, R ⁴With R ⁵Base preferably has the above meaning preferably to point out.And R ' preferably represents H, C _1-3-alkyl or benzyl, particularly H, ethyl or methyl.R ^8a, R ^8b, R ^8c, R ^8dPreferably represent H, C independently of one another _1-4Alkyl carbonyl or benzyl, particularly H, methyl carbonyl, ethyl carbonyl or benzyl.

In the present invention is synthetic, be general formula I V as intermediate product or raw material, the compound of general formula I V ' particularly

Wherein Hal represents chlorine, bromine or iodine, and R ¹, R ², R ⁴With R ⁵Be as hereinbefore defined and R ³Be to be selected from the B base, this also is a theme of the present invention.Special good is R ¹, R ², R ³, R ⁴With R ⁵Base has formula I.2a to the meaning that is I.2d given.The best is general formula I V ' compound, and wherein Hal represents chlorine, bromine or iodine, and R ¹, R ², R ⁴With R ⁵Base tool formula is I.2a to the meaning that is I.2d given, and R ³Basis representation ethynyl or C _3-6-1-alkynes-1-base, wherein, ethynyl can be through-SiR ₃Base replaces, yet the R base is to represent C independently of one another _1-4-alkyl, C _1-4-alkoxyl group or aryl, and this C _3-6-1-alkynes-1-base can be through hydroxyl or C _1-3-alkoxyl group replaces, particularly hydroxyl or methoxyl group.

The present invention is also relevant to synthesizing according to the intermediate product of The compounds of this invention or the general formula I I of parent material, the particularly compound of general formula I I '

Wherein R ', R ^8a, R ^8b, R ^8c, R ^8d, R ¹, R ², R ³, R ⁴With R ⁵Be as mentioned with the definien of institute hereinafter, particularly wherein R ' expression H, C _1-3-alkyl or benzyl, particularly H, ethyl or methyl; And R ^8a, R ^8b, R ^8c, R ^8dBe to represent H, C independently of one another _1-4-alkyl carbonyl or benzyl; Particularly H, methyl carbonyl, ethyl carbonyl or benzyl and R ¹, R ², R ³, R ⁴With R ⁵Base is person as hereinbefore defined, and R ³Base is to be selected from the B base.Special good, R ¹, R ², R ³, R ⁴With R ⁵Base has formula I.2a to the meaning that is I.2d given.

Below will for above-mentioned with hereinafter carry out more definite definition according to some term of The compounds of this invention in order to explanation.

The atom that comprises F, Cl, Br and I, particularly F, Cl and Br represented to be selected from the term of halogen.

C _1-nThe term of-alkyl, wherein n has 1 to 18 value, represents the alkyl with 1 to n C atom of saturated, side chain or straight chain.This type of basic example comprises methyl, ethyl, n-propyl, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, n-hexyl, isohexyl etc.

C _2-nThe term of-alkynyl, wherein n has 3 to 6 value, expression side chain or straight chain have 2 to n C atoms and a C ≡ C triple-linked alkyl.The example of this class base comprises ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base etc.Except as otherwise noted, otherwise alkynyl is the remainder that 1 C atom is connected in molecule through the position.Thereby, be to be equal to 1-propine-1-base, 2-propine-1-base, ethyl acetylene-1-base etc. such as the term of 1-proyl, 2-propynyl, ethyl acetylene base etc.This also is applied to C similarly _2-n-thiazolinyl.

C _1-nC represented in the term of-alkoxyl group _1-n-alkyl-O-base, wherein C _1-n-alkyl is as hereinbefore defined.The example of this class base comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, neopentyl oxygen, uncle's pentyloxy, positive hexyloxy, different hexyloxy etc.

C _1-nC represented in the term of-alkyl carbonyl _1-n-alkyl-C (=O) base, wherein C _1-n-alkyl as hereinbefore defined.The example of this class base comprises first carbonyl, B carbonyl, positive third carbonyl, isopropyl carbonyl, positive fourth carbonyl, isobutyl carbonyl, Zhong Ding carbonyl, uncle's fourth carbonyl, positive penta carbonyl, isoamyl carbonyl, new penta carbonyl, uncle's penta carbonyl, just own carbonyl, dissident's carbonyl etc.

C _3-nThe term of-cycloalkyl represent to have the saturated list of 3 to n C atoms-, two-, three-or spiral shell carbonyl cyclic group.The example of this class base comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, cyclo-dodecyl, dicyclo [3.2.1] octyl group, spiral shell [4.5] decyl, falls pinane base (norpinyl), norcamphyl (Norbony), falls isocyanides base (Norcaryl), adamantyl etc.Preferably, C _3-7Saturated monocycle base represented in the term of-cycloalkyl.

C _5-nThe C that defines as mentioned represented in the term of-cycloalkenyl group _5-n-cycloalkyl, and the two keys of other at least one undersaturated C=C of tool.

C _3-nWherein C represented in the term of-carbonyl naphthene _3-n-cycloalkyl is C as hereinbefore defined _3-n-cycloalkyl-C (=O) base.

Three-(C _1-4-alkyl) term of silylation comprises having and is equal to or the silylation of two or three different alkyl.

Two-(C _1-3-alkyl) An Ji term comprises having and is equal to or the amino of two different alkyl.

Above with hereinafter used form, wherein in phenyl substituent key table bright be when the phenyl ring center, unless other explanations are arranged in addition, otherwise this substituting group can be incorporated into the free position of the phenyl ring of any band H atom.

Can utilize according to compound of the present invention that known synthetic method obtains on the principle.Preferably, this compound is obtained by the following method that is described in more detail according to the present invention.

Glucose-derivative according to formula II of the present invention can synthesize (flow process 1) by the benzyl benzene compound that adds desired organometallic compound pattern by D-glucose lactone or derivatives thereof.

Flow process 1: organometallic compound is added to the glucose lactone

According to the reaction of flow process 1, preferably halogen-benzyl the benzene compound by general formula I V begins, and wherein Hal represents chlorine, bromine or iodine.IV begins by the halogen compound aromatic base, and the organometallic compound (V) of correspondence by so-called halogen-metal exchange, or is made by metal is inserted carbon-halogen bond.When carrying out this halogen-metal exchange with the aromatic base of bromine or iodine-replacement, can use-case such as just-, secondary-or the organolithium compound of tert-butyl lithium react, and produce corresponding lithiumation aromatic base thus.Similarly magnesium compound also can by with suitable Ge Lieya compound such as isopropyl-magnesium bromine compounds or di-isopropyl magnesium, carry out halogen-metal exchange and produce.This reaction preferably in the inert solvent or its mixture of its example such as ether, tetrahydrofuran (THF), toluene, hexane or methylene dichloride, is carried out at 0～-100 ℃, and Te Jia carries out under-10～-80 ℃.Therefore, the magnesium of gained or lithium compound can be looked situation by carrying out trans-metallation with the suitable organometallic compound (V) of adduction with metal-salt as cerous compounds.Perhaps, this organometallic compound (V) also can [carbon-halogen bond of V be made by metal being inserted the halogen compound aromatic base.Here Shi Yi metal such as lithium or magnesium.The glucose lactone or derivatives thereof of the formula that the is added to VI of organometallic compound V, preferably in inert solvent or its mixture, between 0～-100 ℃, Te Jia reacts between-30～-80 ℃, obtains formula II compound thus.For avoiding low temperature, this lithiation and/or coupled reaction also may be carried out in microreactor and/or micro mixer, for example are similar to WO 2004/076470 described method.

Appropriate solvent is for example ether, toluene, methylene dichloride, hexane, tetrahydrofuran (THF) or its mixture.This reaction can be without any need for other adjuvant, or can contain such as BF ₃* OEt ₂Or Me ₃Under the coupling companion's of reactionlessness situation, carry out under the Lewis acid of SiCl (with reference to M.Schlosser, Organometallics in Synthesis, John Wiley ﹠amp; Sons, Chichester/NewYork/Brisbane/Toronto/Singapore, 1994).R ^8a, R ^8b, R ^8c, R ^8dPreferable benzyl, the benzyl that is substituted, the trialkylsilanyl of being defined as of base, special good is TMS, tri isopropyl silane base, 4-methoxybenzyl and benzyl.If by R ^8a, R ^8b, R ^8c, R ^8dTwo adjacent bases constituting of base when interconnecting, these two bases part of benzylidene acetal, 4-methoxyl group benzylidene acetal, sec.-propyl ketal preferably then, or constitute 2, and 3-dimethoxy-butenyl, it is to be connected with the Sauerstoffatom of 3 positions with the pyranose ring of adjacency by 2 of butane.This R ' base is hydrogen or C preferably _1-4-alkyl, Te Jia are hydrogen, methyl or ethyl.This R ' base is to insert after organometallic compound V or derivatives thereof is added to glucose lactone VI.For this reason, make reaction soln have under the condition that exists such as the acid of methanesulfonic, toluenesulphonic acids, sulfuric acid or spirit of salt, handle with using such as methyl alcohol or alcoholic acid alcohols or water.

Synthesizing of the halogenated aromatic compound of formula IV, can utilize vitochemical standard handovers reaction, or be undertaken (with reference to J.March by the method for the known technical literature of organic synthesis at least, AdvancedOrganic Reactions, Reactions, Mechanisms, and Structure, 4 ^ThEdition, JohnWiley ﹠amp; Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1992, and the document of wherein being quoted).Synthesis strategy hereinafter described is a representative illustration.

Flow process 2: synthesis strategy 1

Synthesis strategy 1 (flow process 2) shows the preparation that is begun to carry out the halogenated aromatic compound of formula II by benzyl acyl chlorides and second aromatic base, and it changes into the diphenylketone derivative by the Friedel-CRafts acylation reaction.The reaction of these classics has very wide matrix range, and is using such as AlCl ₃, FeCl ₃, iodine, iron, ZnCl ₂, sulfuric acid or trifluoromethayl sulfonic acid catalytic amount or etc. carry out under the stoichiometric catalyzer condition.Except the carboxylic acid chloride, also can use carboxylic acid, acid anhydrides or its ester class or corresponding cyanobenzene.This reaction is at-30～120 ℃, preferably under 30～100 ℃ of temperature, preferably such as methylene dichloride and 1, carries out in the chlorinated hydrocarbon of 2-ethylene dichloride.Also can under solvent-free, react, or in microwave oven, react.In second reactions steps, diphenylketone is reduced into ditan.This reaction may be by correspondence two steps of diphenyl-carbinol carry out, or only carry out with a step.In the variant of two steps, utilize such as NaBH ₄, LiAlH ₄Or iBu ₂The metal hydride reducing agent of AiH carries out reductone and forms alcohol.Make the alcohol of generation, having such as BF ₃* OEt ₂, trifluoroacetic acid, InCl ₃Or AlCl ₃The condition that exists of Lewis acid under, use such as Et ₃SiH, NaBH ₄Or Ph ₂The reductive agent of SiClH transforms, and forms required ditan.Begin and the method that obtains the single stage method of ditan can be used such as Et by ketone ₃The silane of SiH, such as NaBH ₄Hydroborate or such as LiAlH ₄Alanate, having such as BF ₃* OEt ₂, three (pentafluorophenyl group)-borine, trifluoroacetic acid, aluminum chloride or InCl ₃The condition that exists of Lewis acid under carry out.Reaction preferably in the solvent such as halon, toluene or the acetonitrile of methylene dichloride, at-30～150 ℃, is preferably carried out in 20 to 100 ℃.Carry out reduction reaction with hydrogen in the presence of having such as the excessive metalcatalyzing agent of Pd/C, this is a kind of possible synthetic method equally.According to the reduction reaction of Wolff-Kishner, or its variant also is possible.At first with ketone and hydrazine or derivatives thereof, such as 1, two (tertiary butyl dimethylsilyl) hydrazines of 2-change into inferior hydrazine, and this Asia hydrazine can resolve into ditan and nitrogen under highly basic reaction conditions and heating.This reaction can a reactions steps be carried out, or adopts two reactions steps of separating and carry out after inferior hydrazine or derivatives thereof separates.Use suitable alkali to comprise KOH, NaOH, KOtBu, in solvent, carry out such as ethylene glycol, toluene, DMSO, 2-(2-fourth oxygen oxyethyl group) ethanol or the trimethyl carbinol; The reaction that does not have solvent also is possible.This reaction can preferably be carried out under 80～200 ℃ temperature at 20～250 ℃.The Clemmensen reduction reaction of the alternative method of the alkaline reduction condition of relevant Wolff-Kishner for carrying out under acidic conditions, the latter also may use in this article.

Flow process 3: synthesis strategy 2

Second synthesis strategy (flow process 3) shows the another kind of possibility that is used to make up halogen-aromatic base of formula II ', and it is the example of the ditan that replaces of trimethyl silane ethyl-acetylene.Be selected from iodine, bromine, chlorine or begin such as the aromatic base of the sulphonate of sulfonic acid trifluoro methyl esters by having two, be connected to the reactive end of dihalo aromatic substance through single coupling of transition metal catalytic, promptly the iodo-carbon bond adds alkynyl (step 1).The catalyzer that uses is for example element palladium or nickel or its esters or mixture.This reaction can be carried out with alkynes itself or the inferior acetyl of its metal (acetylidene).If when using this alkynes itself, coupling can have such as NEt ₃Alkali and a kind of co-catalyst of the mantoquita such as CuI carry out (Sonogashira coupling) under existing.This reaction is not limited to the trimethyl silane ethyl-acetylene, but can use the alkynes class of many terminals.This reaction describes in detail in the literature (with reference to P J.Stang with its all variants, F.Diederich, Metal-Catalysed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1997 and Angew.Chem.Iht.Ed.2003,42,1566-1568 and the document of wherein being quoted).Two steps that being used in addition prepares diphenylmethane derivatives comprise, the aryl rotating functionization that alkynes is replaced and obtain the aromatic base of metallization (Mg, Li), and this for example can illustrate by halogen-metal exchange (step 2) mentioned above.This can directly be used or, be added in the benzyl aldehyde derivatives further changeing the metallized aromatic substance that use the metallization back.Make and form the diphenyl-carbinol shown in the flow process.Another kind method also can be used such as benzyl acid esters, acid anhydrides, muriatic benzyl acid derivative or its acid itself or benzonitrile.What form is not pure but corresponding ketone, and it also can be obtained by above-mentioned Friedel-Crafts acylation reaction.Alcohol forms diphenylmethane derivatives and (step 3) is being described above with the further reaction of ketone.Yet the halogenated aromatic compound of this TMS ethinylation also can directly change into required product (step 4) after changeing metallization.For this reason, the lithium that should obtain after the halogen metal exchange or magnesium aromatic series can react with the electric base of benzyl parent such as bromotoluene or chlorine.This reaction can not have, and perhaps preferably carries out (reference example such as Org.Lett.2001,3,2871-2874, and the document of wherein quoting) under the condition that the transition-metal catalyst that has such as mantoquita or palladium mixture exists.Yet this aromatics lithium or magnesium also may for example turn to corresponding boric acid, boric acid ester, stannane, silane or zn cpds through changeing metal earlier.Then, it is connected to benzyl (with reference to LBrandsma by the transition metal such as palladium, nickel, rhodium, copper or iron, S.F.Vasilevsky, H.D.Verkruijsse, Application of Transition MetalsCatalysts in Organic Synthesis, Springer-Verlag, Berlin/Heidelberg, 1998).According to step 2 with 3 or step 4 aromatics that alkynes is replaced be converted into the intermediate product of formula II ', this paper is with R ³The example of expression ethynyl or trimethyl silane ethynyl describes, and also can use similar approach to carry out other R ³The aromatics of-replacement.

Flow process 4: synthesis strategy 3

Synthesis strategy 3 (flow process 4) shows the other pattern of synthesis strategy 2, and it also is to be illustrated according to the example with TMS acetylene aromatics II ', but should not be only limited to this.Should be synthetic be by the halogen atom that has such as chlorine, bromine or iodine, or such as the halogen of the pseudohalogen base of trifluoromethayl sulfonic acid ester; And such as B (OH) ₂, Si (OAlK) ₃Or SnBu ₃The aromatic base of metal center M initial.Selectively exchange each other of chemistry can be carried out in the center of these two what is called " activation ".Synthesis strategy 3 describes with an example, and wherein at first this halogen atom Hal exchanges with the alkynes substituting group in transition metal-catalyzed reaction, this so-called Sonogashira coupling.In second step, this metal center M carries out the exchange of activatory benzyl as benzyl halogenide in another transition metal-catalyzed coupled reaction with for example, and obtain required product (reference example such as Tetrahedron Lett.2003,44,9255-9258 and the document wherein quoted).These two steps are all using transition metal, such as carrying out under palladium, rhodium, nickel, copper or iron or its mixture.These two kinds of response styles all have detailed description in the literature.This method is not limited to described herein, but also may be with two reactions steps out of order.In this situation, at first this metal center M is connected to benzyl, make the exchange of halogen or pseudohalogen base Hal and alkynes then.

In order to prepare compound of Formula I, the method according to this invention a) in, general formula I I compound

Wherein R ', R ¹To R ⁵As hereinbefore defined and

R ^8a, R ^8b, R ^8c, R ^8dAs hereinbefore defined, and independently of one another typical example such as ethanoyl, pivaloyl, benzyl acyl group, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), trialkylsilanyl, benzyl or the benzyl that is substituted; Perhaps in indivedual situations, two adjacent R ^8a, R ^8b, R ^8c, R ^8dBase forms benzylidene acetal or isopropylidene ketal, or by butenyl 2 with 3 positions be connected with the Sauerstoffatom of pyranose ring 2,3-dimethoxy-butenyl, and form the two  alkane be substituted with them, it can as indicated abovely be obtained, and reacts under the condition that has Louis or Bronsted acid to exist with reductive agent.

The suitable reductive agent of this reaction comprises, such as triethyl-, tripropyl-, triisopropyl-or the silane of phenylbenzene-silane, sodium borohydride, SODIUM CYANO BOROHYDRIDE, boron zinc cyanide, borine, lithium aluminium hydride, diisobutyl alanate or means of samarium iodide.This reduction reaction is not or the Bronsted acid of suitable all example hydrochloric acids, methanesulfonic, trifluoroacetic acid or acetate arranged, or have such as boron trifluoride diethyl etherate, carry out under the condition that the Lewis acid of trifluoromethane sulfonic acid trimethyl silane ester, titanium tetrachloride, tin tetrachloride, trifluoromethane sulfonic acid scandium or zinc iodide exists.Decide on reductive agent and acid, this reaction can be carried out in the solvent such as methylene dichloride, chloroform, acetonitrile, toluene, hexane, ether, tetrahydrofuran (THF), two  alkane, ethanol, water or its mixture in temperature between-60 ℃～120 ℃.Have a kind of particularly suitable reagent composition to comprise for example triethyl silicane and boron trifluoride diethyl etherate, it is more convenient is to use in acetonitrile under-60 ℃～60 ℃ temperature or the methylene dichloride.In addition, can in the presence of the transition-metal catalyst that has such as Pd/C or Raney nickel, in solvent, use hydrogen, carry out described conversion such as tetrahydrofuran (THF), ethyl acetate, methyl alcohol, ethanol, water or acetate.

Alternately, for process in accordance with the present invention b) prepare according to compound of Formula I of the present invention, at the compound of general formula III

R wherein ¹To R ⁵Be as hereinbefore defined and

R ^8aTo R ^8dRepresent an above defined protecting group, such as acyl group, arylmethyl, acetal, ketal or silylation; And it can for example carry out reduction reaction by formula II compound as indicated above and obtain, and will protect basic capsule to go.

Used any acyl protecting group is to have under the condition that exists such as trifluoroacetic acid, hydrochloric acid or vitriolic acid; or at the alkali metal base that has such as lithium hydroxide, sodium hydroxide or potassium hydroxide; or for example having in the presence of the non-proton property of trimethyl silane iodine; in temperature between 0～120 ℃; preferably between 10～100 ℃ of temperature, for example in the aqueous solvent of water, isopropanol, acetic acid/water, tetrahydrofuran (THF)/water or two  alkane/water, be hydrolyzed and split.Trifluoroacetyl group is between 50～120 ℃ in temperature preferably, looks situation in the presence of the solvent that has such as acetate, uses the acid of all example hydrochloric acids to handle and split; Or be between 0～50 ℃ in temperature, look situation in the presence of having such as tetrahydrofuran (THF) or methanol solvent, handle and split with sodium hydroxide solution.

The acetal that uses or ketal protected be to have such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or under the sour existence condition of the non-proton property acid of for example iodine trimethyl silane; in temperature between 0 to 120 ℃; be preferably 10～100 ℃ temperature; in aqueous solvent for example, for example be hydrolyzed in water, isopropanol, acetic acid/water, tetrahydrofuran (THF)/water or the two  alkane/water and split.

TMS is for example at water, aequeous solvent mixture or in such as methyl alcohol or alcoholic acid low-carbon alcohol, splits under the condition that the alkali that has such as lithium hydroxide, sodium hydroxide, salt of wormwood or sodium methylate exists.In water-based or alcoholic solvent, the acid of all example hydrochloric acids, trifluoroacetic acid or acetate also is suitable.For splitting in the organic solvent such as ether, tetrahydrofuran (THF) or methylene dichloride, this also is fit to use the fluoride reagents such as the TBuA fluorochemical.

Benzyl, methoxybenzyl or carbobenzoxy-(Cbz) more advantageously split through hydrogenolysis, for example in appropriate solvent such as methyl alcohol, ethanol, ethyl acetate or Glacial acetic acid, utilize hydrogen in the presence of the catalyzer that has such as Pd/C, look the acid that situation is added all example hydrochloric acids, in temperature between 0～100 ℃, preferably 20～60 ℃ room temperature, and in hydrogen-pressure 1～7bar, but preferred and react with 3～5bar.Yet, 2, the 4-dimethoxy-benzyl preferably splits in trifluoroacetic acid having under the methyl-phenoxide existence condition.

The tertiary butyl or tertbutyloxycarbonyl be preferably by such as the acid treatment with trifluoroacetic acid or hydrochloric acid, or with the processing of iodine trimethyl silane and split; Look the solvent of situation use such as methylene dichloride, two  alkane, methyl alcohol or ether.

In reaction mentioned above, the reactive group of any existence all can during reaction be protected by habitual protecting group and be split once more after reaction such as ethynyl, hydroxyl, amino, alkylamino or imido grpup.

For example, the protecting group of ethynyl can be TMS or triisopropyl.Also can use the different third-2-base of 2-hydroxyl as protecting group equally.

For example, the protecting group of hydroxyl can be TMS, ethanoyl, trityl, benzyl or THP trtrahydropyranyl.

The protecting group of amino, alkylamino or imino-can be for example formyl radical, ethanoyl, trifluoroacetyl group, ethoxycarbonyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), benzyl, methoxybenzyl or 2,4-veratryl.

In addition, as indicated above, the compound of Formula I that obtains can be resolved becomes its enantiomer and diastereoisomer.Therefore, for example the cis/trans mixture can be resolved to its cis and trans-isomerism thing; And, the compound separation of an optical activity carbon atom of tool at least can be become its enantiomer.

Therefore for example, the mixture of the cis/trans of gained can resolve to its cis and trans-isomerism thing by stratography, the compound of Formula I that is the racemic mixture pattern of gained, can (compare Allinger N.L and Eliel E.L. by known method itself in " Topics in Stereochemistry ", Vol.6, Wiley Interscience, 1971) be divided into its optical antipode; And, can the known method of utilization itself, for example by stratography with or fractional crystallization, will have the compound of Formula I of at least two asymmetry carbon atoms, become its diastereoisomer according to the interpretation of the difference of its physicochemical property; And, when being the racemic mixture pattern, can follow-up they be resolved to enantiomer as above-mentioned as if these compounds.

The separation of enantiomer is preferably gone up mutually by the post separation in chirality and is undertaken, or react by the recrystallize in the optically-active solvent or by the optically active material, particularly acid that form with a kind of itself and this racemic compound salt or such as the derivative of ester or acid amides and activatory derivative thereof or alcohols; And,, separate the diastereoisomer mixture of this salt therefore obtained or derivative for example according to the difference of its solubleness; Wherein, the mapping object of free state can be by the appropriate formulations effect by disengaging in pure diastereoisomer salt or the derivative.Normally used optically active acid is the D-and the L-pattern of for example following acid: for example tartrate or dibenzyl acyl group tartaric acid, two-neighbour-tolyl tartrate, oxysuccinic acid, tussol, camphorsulfonic acid, L-glutamic acid, aspartic acid or quinic acid.The alcohol of optically active for example can be, (+) or (-) menthol and acyl group with the optically active of acid amides, for example (+)-or (-)- oxygen carbonyl.

Moreover, can use inorganic or organic acid that the formula I compound of gained is changed into its esters, particularly the physiologically acceptable salt that uses for medicine.Spendable for this reason acid comprises for example hydrochloric acid, Hydrogen bromide, sulfuric acid, methanesulfonic, phosphoric acid, fumaric acid, succsinic acid, lactic acid, citric acid, tartrate or toxilic acid.

Moreover, gained compound and amino acid are for example changed into mixture with 1: 1 or 1: 2, particularly with mixture such as the alpha amino acid of proline(Pro) or Phenylalanine, it has the special good character such as high crystalline.

According to The compounds of this invention, the more favourable method of following example of also can utilizing obtains, its also available professional is undertaken by known method in the document for this reason, for example particularly at WO 98/31697, WO 01/27128, WO 02/083066, WO 03/099836 and WO 2004/063209 described method.

Just as already mentioned, have valuable pharmacological character according to compound of Formula I of the present invention and physiologically acceptable salt thereof, particularly for suppressing Na-dependent glucose cotransporter SGLT, the preferably is the effect of SGLT2.

Carried out detecting the physiological property of novel compound below:

This material suppresses the active ability of SGLT-2 and can show in the test of an arrangement, wherein with expression vector pZeoSV (Invitrogen, EMBL registration number L36849) (CHO-hSGLT2 or the HEK-hSGLT2) transfection stably of CHO-K1 clone (ATCC No.CCL 61) or alternate HEK293 clone (ATCC No.CRL-1573) with the cDNA of the sequence that comprises the human sodium glucose cotransporter 2 of coding (Genbank Acc.No.NM_003041).These clones will in the mode of Na-dependent ¹⁴The Alpha-Methyl of C-mark-glucose pyranyl glucosides ( ¹⁴C-AMG Amersham) is conveyed into cell interior.

The SGLT-2 analysis is carried out as follows:

The GHO-hSGLT2 cell is to cultivate in containing the Ham ' s F12 substratum of 10% foetal calf serum and 250 μ g/ml Zeocin (Invitrogen), and the HEK293-hSGLT2 cell is to cultivate in the DMEM substratum that contains 10% foetal calf serum and 250 μ g/ml Zeocin (Invitrogen).Wash twice with PBS, and then make cell by separating in the culture flask with trypsinase/EDTA processing.With cell centrifugation, resuspending calculates cell in substratum and with the Casy cell counter behind the interpolation cell culture medium.Then with 40,000 cell inoculations in every hole poly-in scribbling-culture plate in 96 holes of the white of D Methionin in, and in 37 ℃, 5%CO ₂Cultivation is spent the night.With cell with 300 μ l analysis buffer washed twice (HanksBalanced Salt Solution, 137mM NaCl, 5.4mM KCl, 2.8mM CaCl ₂, 1.2mMMgSO ₄With 10mM HEPES (pH 7.4), 50 μ g/ml gentamicins).In each hole, add the analysis buffer of 250 μ l and the tested compounds of 5 μ l then, and in incubator, cultivated again 15 minutes.With 10% the DMSO of 5 μ l as negative control group.By in each hole, adding 5 μ l's ¹⁴C-AMG (0.05 μ Ci) begins reaction.In 37 ℃, 5%CO ₂Cultivate after two hours, cell with 300 μ l PBS washings (20 ℃), dissolves (5min, 37 ℃) by the 0.1N NaOH that adds 25 μ l once more then.In each hole, add the MicroScint 20 (Packard) of 200 μ l, and continue to cultivate 20 minutes in 37 ℃.After having cultivated, use ¹⁴C scintillation counting program is measured in Topcount (Packard) ¹⁴The radioactivity that C-AMG absorbs.

For measuring selectivity for human SGLT1, carried out similar test, that wherein express in CHO-K1 or HEK293 cell is the cDNA of hSGLT1 (gene pool Acc.No.NM000343) rather than the cDNA of hSGLT2.

According to compound of Formula I of the present invention, can for example have the EC50-value that is lower than 1000nM, particularly be lower than 200nM, the best is for being lower than 50nM.

In view of it suppresses the active ability of SGLT, according to compound of Formula I of the present invention and corresponding medical acceptable salt thereof, be fit in principle treatment and preventative processing all because suppressing SGLT, particularly SGLT-2 activity and the affected state of an illness or disease.Thereby, particularly be suitable for prevention or treatment disease according to The compounds of this invention, metabolic disorder or particularly such as the illness of I type or type ii diabetes, the complication of diabetes is (such as retinopathy, renal lesions or DPN, diabetic foot, ulcer, macroangiopathy), metabolic acidosis or ketoacidosis, reactive hypoglycemia disease, hyperinsulinemia, the glucose metabolism illness, insulin resistance, metabolic syndrome, the hyperlipemia of Different Origin, arteriosclerosis and relative disease, obesity, hypertension, chronic heart failure exhausts, oedema and hyperuricemia.Therefore these materials also are fit to stop the β cell degradation, take off such as the cell of pancreatic beta cell and bite or downright bad.These materials also are fit to improve or recover the functional of pancreatic cell, also can increase the number and size of pancreas β cell.Also can be used as diuretic(s) and hypotensive agent use according to compound of the present invention, and be suitable for prevention and treatment acute renal failure.

Particularly, compound according to the present invention comprises its physiologically acceptable salt, is suitable for prevention or treatment diabetes, particularly I type and type ii diabetes, with/or diabetic complication.

Reach treatment or the required dosage of prevention respective action and look the kind and the seriousness of used compound, patient, disease or illness usually, and the method for using is decided with frequent degree; And, be by disposing doctor's decision.Aptly, during intravenously administrable, dosage can be 1～100mg, and is preferred with 1～30mg; During oral administration, be 1～1000mg, preferred with 1～100mg, each situation is used 1 to 4 time every day.For this purpose, formula I compound prepared in accordance with the present invention look situation can with other active substance combination, carrier and/or the thinner habitual with one or more inert, for example and W-Gum, lactose, raw sugar, Microcrystalline Cellulose, Magnesium Stearate, polyvinylpyrrolidone, citric acid, tartrate, water, water/ethanol, water/glycerine, water/sorbyl alcohol, water/polyoxyethylene glycol, propylene glycol, the cetearyl alcohol acid alcohol, carboxymethyl cellulose or such as the fatty substance of stearic fat, or its suitable mixture, and make habitual lid Lun Shi preparation, such as tablet, coated tablet, capsule, pulvis, liquor, suspension or suppository.

Also can use according to compound of the present invention, especially for treatment and prevent above-mentioned disease and illness with other active substance combination.Other active substances that are fit to this type of combination comprise that for example those can strengthen the result of treatment according to SGLT antagonism inhibitor of the present invention to described symptom, with/maybe can reduce dosage according to SGLT inhibitor of the present invention.The healing potion that is suitable for this type of combination comprises, antidiabetic drug for example is such as N1,N1-Dimethylbiguanide (metformin), sulfo group urea (Glyburide (glibenclamide) for example, tolbutamide peaceful (tolbutamide), glimepiride (glimepiride)), Nateglinide (nateglinide), repaglinide (repaglinide), thiazolidinedione (rosiglitazone (rosiglitazone) for example, pioglitazone (pioglitazone)), PPAR-γ-agonist (for example GI 262570) and antagonist, PPAR-γ/α adjusting control agent (for example KRP 297), alpha-glucosidase inhibitor (acarbose (acarbose) for example, voglibose (voglibose)), DPPIV inhibitor (LAF237 for example, MK-431), α 2-antagonist, Regular Insulin and insulin analog, GLP-1 and GLP-1 analogue (for example clothing ingot (exendin-4)) or white dextrin (amylin).Material--the protein tyrosine phosphatase inhibitors 1 that also comprises influence regulation and control glucose production in the liver that provides, such as G-6-Pase or fructose-1.6-diphosphatase, the inhibitor of the former Starch phosphorylase of candy etc., the glucagon receptor antagonist, with phosphoenolpyruvate carboxykinase, former synthase kinase of candy or the kinase whose inhibitor of pyruvic acid dehydrogenation, (for example suffering is cut down spit of fland (simvastatin), ground such as the HMG-CoA-reductase inhibitor, his spit of fland (atorvastatin) is cut down in holder), the special class (fibrates) of shellfish (bezafibrate (bezafibrate) for example, fenofibrate (fenofibrate)), the lipid depressant of niacin and derivative thereof, PPAR-α-agonist, the PPAR-delta agonists, ACAT inhibitor (for example A Faxin is than (avasimibe)) or such as the cholesterol absorption inhibitor of liking the venue of sports event close (ezetimibe), cholic acid binding substance such as Colestyramine (cholestyramine), the inhibitor that the ileum cholic acid transports, HDL rising compound such as CETP inhibitor or ABC1 adjusting control agent, or such as the active substance of western cloth naphthalene bright (sibutramine) treatment of obesity, or tetrahydrochysene lipid inhibitor (Tetrahydrolipstatin), Isomeride (dexfenfluramine), Ah institute's bank (axokine), cannabin(e) 1 receptor antagonist, the MCH-1 receptor antagonist, the MC4 receptor stimulant, NPY5 or NPY2 antagonist, or such as the β 3-agonist of SB-418790 or AD-9677, and 5HT2c receptor stimulant.

In addition, hypertensive with influence, chronic heart failure exhausts or the combination of the following medicine of arteriosclerosis such as A-II antagonist or ACE inhibitor, ECE inhibitor, diuretic(s), beta blocker, Ca-antagonist, the hypotensive agent of nervus centralis effect, α-2-adrenoceptor antagonists, neutral endopeptidase inhibitor, anticoagulant and other, or its combination all suits.The example of angiotensin II receptor antagonists is CARDESARTAN Xi Lesi Supreme Being (candesartan cilexetil), losartan sylvite (potassium losartan), Yi Pushatan methane sulfonate (eprosartan mesylate), valsartan (valsartan), telmisartan (telmisartan), irbesartan (irbesartan), EXP 3174, L-158809, EXP-3312, RNH 6270 (olmesartan), Mei Duosuomi (medoxomil), Tasosartan (tasosartan), KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701 etc.Angiotensin II receptor antagonists preferably is used for the treatment of or the complication of preventing hypertension and diabetes, usually with diuretic(s) combination such as hydrochlorothiazide plug (Hydrochlorothiazide).

Be suitable for treatment or prevention gout with the combination of uric acid synthetic inhibitor or excellent Li Kesu (uricosurics).

With GABA-receptor antagonist, Na-channel blocker, topiramate (topiramat), protein-kinase c inhibitor, further the combination of saccharification end product inhibitor or aldose reductase inhibitor can be used for treating or the complication of prevent diabetes.

The dosage of the combined partner capable of being mentioned above, suitable is normal recommended lowest dose level 1/5/ to 1/1 of normal recommended dosage.

Thereby, be to use relevant physiologically acceptable salt at another theme of the present invention, be suitable for treatment or prevent being suppressed affected disease or disease disease with preparation because of Na-dependent glucose cotransporter SGLT with at least a above-mentioned active substance combination as combined partner capable according to The compounds of this invention or this compounds.Metabolic trouble preferably, one of particularly above-mentioned disease or illness are in particular diabetes or diabetic complication most.

According to The compounds of this invention or its physiologically acceptable salt, with the use of the combination of other active substances can be simultaneously or staggered time, but particularly in the short timed interval.If they are when using simultaneously, give the patient together with two kinds of active substances; If during staggered the use, then giving these two kinds of active substances of patient is to be less than or equal within 12 hours, particularly is being less than or equal in 6 hours.

Therefore, another aspect of the present invention is relevant pharmaceutical composition, it comprises according to compound of the present invention, or the physiologically acceptable salt of this compounds, and at least a above-mentioned active substance as combined partner capable, look one or more inert supports of situation and thinner.

Therefore, pharmaceutical composition for example according to the present invention comprises according to the physiologically acceptable salt of formula I compound of the present invention or this compounds and the combination of at least a angiotensin II receptor antagonists, looks one or more inert supports of situation and thinner.

According to compound of the present invention or its physiologically acceptable salt, and the other active substance that will make up with it, for example be included in together in tablet or the capsular same preparation pattern, or be the two kinds of identical or different formulations that are divided in the so-called combination set for example.

Aforementioned with hereinafter, the H atom of hydroxyl is clear expression under each situation in structural formula.The following example is in explanation the present invention rather than is used for restriction:

The preparation of initial compounds:

Example I

(5-bromo-2-chloro-phenyl)-(4-methoxyl group-phenyl)-ketone

38.3ml oxalyl chloride and 0.8ml dimethyl formamide are joined the mixture of 5-bromo-2-chloro-benzyl acid in the 500ml methylene dichloride of 100g.Stirred this reaction mixture 14 hours, and filtered then and in the rotary evaporation ware, separate with all volatile component.Residue is dissolved in the 150ml methylene dichloride, solution is cooled to-5 ℃ and add the methyl-phenoxide of 46.5g.Then, the aluminum chloride of portion-wise addition 51.5g will make temperature be no more than 5 ℃.Make solution in 1～5 ℃ of restir 1 hour, be poured on ice then.Separate organic phase, and with methylene dichloride aqueous phase extracted three times again.The organic phase that merges is washed once with the 1M aqueous hydrochloric acid, washes twice and washes secondary with saturated nacl aqueous solution with the 1M sodium hydroxide solution.Dry then organic phase is removed solvent and is made residue recrystallize in ethanol.

Productive rate: 86.3g (theoretical value 64%).

Mass spectrum (ESI ⁺): m/z=325/327/329 (Br+Cl) [M+H] ⁺

Make following compounds with the method that is similar to example I:

(1) 5-bromo-2-iodo-phenyl)-(4-oxyethyl group-phenyl)-ketone

Mass spectrum (ESI ⁺): m/z=431/433 (Br) [M+H] ⁺

(2) 5-bromo-2-chloro-phenyl)-(4-iodo-phenyl)-ketone

Example II

4-bromo-1-chloro-2-(4-methoxyl group-benzyl)-benzene

Make (5-bromo-2-chloro-phenyl)-(4-methoxyl group-phenyl)-ketone and the solution of 101.5ml triethyl silicane in 75ml methylene dichloride and 150ml acetonitrile of 86.2g be cooled to 10 ℃.Then, stir the boron trifluoride diethyl etherate of adding 50.8ml down, make temperature be no more than 20 ℃.Make this solution stirring at room 14 hours, add other 9ml triethyl silicane and 4.4ml boron trifluoride diethyl etherate then.Make this solution in 45～50 ℃ of restir 3 hours, be cooled to room temperature then.Add the solution of 28g potassium hydroxide, and stirred the mixture 2 hours at 70ml water.Then, separate organic phase and with diisopropyl ether aqueous phase extracted 3 times again.The organic phase that merges is with 2M potassium hydroxide washed twice, and washes 1 time with sodium chloride aqueous solution, then through dried over sodium sulfate.After the separated from solvent, residue is developed in ethanol, separated once more and in 60 ℃ of dryings.

Productive rate: 50.0g (theoretical value 61%).

Mass spectrum (ESI ⁺): m/z=310/312/314 (Br+Cl) [M+H] ⁺

Make following compounds with the method that is similar to example II:

(1) 4-bromo-l-iodo-2-(4-oxyethyl group-benzyl)-benzene

Mass spectrum (ESI ⁺): m/z=434/436[M+NH ₄] ⁺

(2) 4-bromo-1-chloro-2-(4-iodo-benzyl)-benzene

EXAMPLE III

4-(5-bromo-2-chloro-benzyl)-phenol

4-bromo-1-chloro-2-(4-iodo-the benzyl)-solution of benzene in the 150ml methylene dichloride of 14.8g is cooled off in ice bath.Then, add the dichloromethane solution of the boron tribromide of 50nml 1M, and in this solution of stirring at room 2 hours.Then, this solution is cooled off in ice bath once more, and dropwise add the unsaturated carbonate potassium solution.Under the room temperature, regulate this mixture to pH 1, separate organic phase and with ethyl acetate aqueous phase extracted 3 times again with the 1M aqueous hydrochloric acid.The organic phase that merges is dewatered through sodium sulfate, and solvent is removed fully.

Productive rate: 13.9g (theoretical value 98%).

Mass spectrum (ESI ^-): m/z=295/297/299 (Br+Cl) [M-H] ^-

EXAMPLE IV

[4-(5-bromo-2-chloro-benzyl)-the phenoxy group]-tertiary butyl-dimethyl-silane

4-(5-bromo-2-chloro-the benzyl)-solution of phenol in the 140ml methylene dichloride of 13.9g is cooled off in ice bath.Then, add the muriatic 20ml dichloromethane solution of 7.54g tertiary butyl dimethylsilane, add 9.8ml triethylamine and 0.5g dimethyl aminopyridine thereupon.In this solution of stirring at room 16 hours, then with the dilution of 100ml methylene dichloride.Wash organic phase 2 times with the 1M hydrochloric acid solution, and wash 1 time, then through dried over sodium sulfate with sodium bicarbonate aqueous solution.Behind the removal of solvents, by filtered through silica gel residue (cyclohexane/ethyl acetate 100: 1).

Productive rate: 16.8g (theoretical value 87%).

Mass spectrum (ES): m/z=410/412/414 (Br+Cl) [M] ⁺

EXAMPLE V

1-bromo-4-tri isopropyl silane ethynyl-benzene

Under argon gas, with 11.6ml triisopropyl acetylene and 14.4ml triethylamine, then 0.2g cupric iodide and 0.73g two-(triphenyl phosphine)-palladium dichloride adds in the solution of anhydrous tetrahydro furan of 150ml of 1-bromo-4-iodo-benzene of the 15.0g that does not have oxygen.In this solution of stirring at room 16 hours, filter and evaporate to dryness by Celite then.Residue separates (hexanaphthene) through silica gel chromatography.

Productive rate: 17.4g (theoretical value 100%).

Mass spectrum (ESI ⁺): m/z=336/338 (Br) [M] ⁺

Method with similar embodiment V makes following compounds:

(1) 4-bromo-1-(tri isopropyl silane ethynyl)-2-(4-oxyethyl group-benzyl)-benzene

Be used as the parent material of above-mentioned coupled reaction with 4-bromo-1-iodo-2-(4-oxyethyl group-benzyl)-benzene.

Mass spectrum (ESI ⁺): m/z=471/473 (Br) [M+H] ⁺

(2) [4-(5-bromo-2-chloro-benzyl)-phenylacetylene base]-triisopropyl-silane

Be used as parent material with 4-bromo-1-chloro-2-(4-iodo-benzyl)-benzene.

This compound also can make according to the method for embodiment X.

Example VI

(5-bromo-2-fluoro-phenyl)-4-[(tri isopropyl silane base)-ethynyl]-phenyl }-methyl alcohol

Under argon gas, the hexane solution of the 1.6M n-Butyl Lithium of 33.8ml is dropwise added in the solution of 120ml anhydrous tetrahydro furan of 1-bromo-4-tri isopropyl silane ethynyl-benzene of the 17.4g that is cooled to-78 ℃.Stirred this solution 1 hour in-70 ℃.Then, dropwise to add the 30ml tetrahydrofuran solution of 10.8g 5-bromo-2-fluoro-benzyl aldehyde in 15 minutes.The solution that generates spends the night in cooling bath and rises again to room temperature.Add water then, and with the ethyl acetate extraction mixture.The organic phase that merges is through dried over sodium sulfate, and the removal solvent.Residue is through silica gel purification (cyclohexane/ethyl acetate 4: 1).

Productive rate: 14.3g (theoretical value 60%).

Mass spectrum (ESI ⁺): m/z=461/463 (Br) [M+H] ⁺

Method with similar embodiment VI makes following compounds:

(1) (3-bromo-phenyl)-4-[(tri isopropyl silane base)-ethynyl]-phenyl }-methyl alcohol

Mass spectrum (ESI ^-): m/z=487/489 (Br) [M+HCOO] ^-

(2) (5-bromo-2-methoxy-phenyl)-4-[(tri isopropyl silane base)-ethynyl]-phenyl }-methyl alcohol

Mass spectrum (ESI ⁺): m/z=473/475 (Br) [M+H]+

Example VII A

[4-(5-bromo-2-fluoro-benzyl)-phenylacetylene base]-triisopropyl-silane

With 5.6g (5-bromo-2-fluoro-phenyl)-4-[(tri isopropyl silane base)-ethynyl]-phenyl-dichloromethane solution of the 50ml of methyl alcohol and 4.1ml triethyl silicane cools off in ice bath.Then, slowly drip the trifluoroacetic acid of 4.7ml, in stirring at room solution 4 hours.Solution is diluted with methylene dichloride, and wash with sodium bicarbonate aqueous solution.Remove solvent after the sodium sulfate dehydration, residue is through silica gel purification (hexanaphthene).Productive rate: 2.6g (theoretical value 48%).

Mass spectrum (EI): m/z=445/447 (Br) [M] ⁺

Method with similar embodiment VII makes following compounds:

(1) [4-(3-bromo-benzyl)-phenylacetylene base]-triisopropyl-silane

Mass spectrum (ESI ⁺): m/z=427/429 (Br) [M+H] ⁺

(2) [4-(5-bromo-2-methoxyl group-benzyl)-phenylacetylene base]-triisopropyl-silane

Be different from aforesaid method, reaction soln stirred, in ice bath rather than at room temperature till reaction is finished.

Mass spectrum (ESI ⁺): m/z=457/459 (Br) [M+H] ⁺

Example VII A I

4-bromo-2-brooethyl-1-chloro-benzene

Make the N-bromo succinimide of 4.0g slowly add the 4-bromo-1-chloro-2-methylol-benzene of the 5.0g that is cooled to 5 ℃ and the 50ml tetrahydrofuran solution of 5.9g triphenyl phosphine.In stirring at room after 1 hour, the filtering throw out, and remove solvent in vacuum.Residue is through silica gel purification (cyclohexane/ethyl acetate 50: 1).

Productive rate: 4.9g (theoretical value 76%).

Mass spectrum (EI): m/z=282/284/286 (Br+Cl) [M] ⁺

Example I X

(4-iodo-phenylacetylene base)-triisopropyl-silane

Under argon gas, with 18.0g sodium iodide (anhydrous), 0.6g cupric iodide and 0.8g N, N '-dimethyl-hexanaphthene-1 is in the solution of (4-bromo-phenylacetylene base)-triisopropyl-silane of 2-diamines adding 20.0g, this solution reflux was stirred 24 hours down, be cooled to room temperature then.Add 1% ammonia solution (100ml), and use the ethyl acetate extraction mixture.After dried over sodium sulfate, remove solvent and make residue through silica gel purification (hexanaphthene).

Productive rate: 21.0g (theoretical value 92%).

Mass spectrum (EI): m/z=384[M] ⁺

Embodiment X

[4-(5-bromo-2-chloro-benzyl)-phenylacetylene base]-triisopropyl-silane

Under argon gas, the muriatic tetrahydrofuran solution of 2M isopropyl-magnesium of 0.66ml dropwise is added in the 2.2ml anhydrous tetrahydrofuran solution of 0.50g (the 4-iodo-phenylacetylene base)-triisopropyl-silane that is cooled to-25 ℃.Down stirred these solution 30 minutes in-25 ℃, then with tetrahydrofuran solution (preparing) merging of the CuCN*2LiCl of the 1M of 0.26ml by CuCN and the LiCl that dissolves 1: 2 ratio.Then, add 4-bromo-2-brooethyl-1-chloro benzene of 0.35g as early as possible, and make reaction mixture in cooling bath, be warming up to-5 ℃.In-5 ℃ stir 6 hours after, solution is heated to room temperature and stirs and spend the night.Then, add saturated ammonium chloride solution and 25% ammonia solution (9: 1), and the mixture that generates is added in the entry.Separate organic phase, and with the ethyl acetate extraction water, the organic phase of merging is through dried over sodium sulfate, and the removal solvent, residue is through silica gel purification (hexanaphthene).

Productive rate: 0.28g (theoretical value 50%).

Mass spectrum (EI): m/z=461/463/465 (Br+Cl) [M+H] ⁺

Embodiment XI

2,3,4,6-four-O-(TMS)-D-Glucopyranose ketone

With the D-glucose-1 of 20g, the 200ml tetrahydrofuran solution of 5-lactone and 98.5ml N-methylmorpholine is cooled to-5 ℃.Drip the TMS muriate of 85ml then, make temperature be no more than 5 ℃.Then, this solution was at room temperature stirred 1 hour, in 35 ℃ following 5 hours, and then at room temperature 14 hours.After adding 300ml toluene, solution is cooled off in ice bath, and add 500ml water, make temperature be no more than 10 ℃.Then, separate organic phase, and respectively with sodium dihydrogen phosphate, water and saturated sodium-chloride water solution washing once.Remove solvent, residue is dissolved in 250ml toluene, and removes solvent fully once more.

Productive rate: 52.5g (purity about 90%).

Mass spectrum (ESI ⁺): m/z=467[M+H] ⁺

Embodiment XII

1-fluoro-4-(1-methoxyl group-D-Glucopyranose-1-yl)-2-(4-tri isopropyl silane ethyl-acetylene base-benzyl)-benzene

The 30ml anhydrous ether solution of [4-(5-bromo-2-fluoro-benzyl)-phenylacetylene base]-tri isopropyl silane of 4.46g is cooled to-80 ℃ under argon gas.The pentane solution of the 1.7M tert-butyl lithium of 11.8ml slowly is added dropwise to this cooling solution, stirred these solution 45 minutes in-80 ℃ then.Then, by shift pin will be cooled to-80 ℃ 5.19g 2,3,4, the 50ml diethyl ether solution of 6-four-O-(TMS)-D-Glucopyranose ketone is added dropwise to this solution.In-78 ℃ stir the solution that generates 3 hours.Then, add the 50ml methanol solution of 1.7ml methanesulfonic, remove cooling bath, and in stirring at room solution 16 hours.Then, with the ethyl diisopropylamine neutralization solution and be evaporated to dried.Residue is through silica gel purification (methylene chloride 50: 1-＞4: 1).

Productive rate: 2.8g (theoretical value 50%).

Mass spectrum (ESI ⁺): m/z=576[M+NH ₄] ⁺

Make following compounds with the method that is similar to embodiment XII:

(1) 1-methoxyl group-4-(1-methoxyl group-D-Glucopyranose-1-yl)-2-(4-tri isopropyl silane ethyl-acetylene base-benzyl)-benzene

Advantageously, reaction mixture is only mixed with excessive a little methanesulfonic.

Mass spectrum (ESI ⁺): m/z=588[M+NH ₄] ⁺

(2) 1-chloro-4-(1-methoxyl group-D-Glucopyranose-1-yl)-2-(4-tri isopropyl silane ethyl-acetylene base-benzyl)-benzene

Mass spectrum (ESI ⁺): m/z=592/594 (Cl) [M+NH ₄] ⁺

Embodiment XIII

1-fluoro-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-2-(4-tri isopropyl silane ethyl-acetylene base-benzyl)-benzene

1-fluoro-4-(1-methoxyl group-D-Glucopyranose-1-yl)-2-(4-tri isopropyl silane ethyl-acetylene base-benzyl)-benzene of 0.8g and the 6ml methylene dichloride of 0.5ml triethyl silicane and the solution of 10ml acetonitrile are cooled to-10 ℃.The boron trifluoride diethyl etherate of 0.27ml is added dropwise to this cooling solution.Then, stirred this solution 3 hours down in ice bath.Add sodium bicarbonate aqueous solution and go into this solution, then with this mixture of ethyl acetate extraction.Make organic phase through dried over sodium sulfate, remove solvent, and residue is dissolved in the 6ml methylene dichloride.Then, add the 4-dimethylaminopyridine of 1.2ml pyridine, 1.3ml diacetyl oxide and 8mg.Stirred this solution under the room temperature 1 hour, then with hydration also.Through the dichloromethane extraction mixture, with 1M salt acid elution organic phase and through dried over sodium sulfate.After removing solvent, residue separates (cyclohexane/ethyl acetate 4: 1-＞1: 1) through silica gel chromatography.

Productive rate: 0.23g (theoretical value 23%).

Mass spectrum (ESI ⁺): m/z=714[M+NH ₄] ⁺

Make following compounds with the method that is similar to embodiment XIII:

(1) 1-methoxyl group-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-2-(4-tri isopropyl silane ethyl-acetylene base-benzyl)-benzene

Mass spectrum (ESI ⁺): m/z=726[M+NH ₄] ⁺

(2) 1-chloro-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-2-(4-tri isopropyl silane ethyl-acetylene base-benzyl)-benzene

Mass spectrum (ESI ⁺): m/z=730/732 (Cl) [M+NH ₄] ⁺

Embodiment XIV

1-(2,3,4,6-four-0-ethanoyl-1-methoxyl group-D-Glucopyranose-1-yl)-3-(4-tri isopropyl silane ethyl-acetylene base-benzyl)-benzene

Make the 20ml anhydrous ether solution of [4-(3-bromo-benzyl)-phenylacetylene base]-triisopropyl-silane of 2.6g under argon gas, be cooled to-80 ℃.The pentane solution of 7.9ml1.7M tert-butyl lithium slowly is added dropwise in this cooling solution; Then, stirred this solution 30 minutes down at-80 ℃.To be cooled to-80 ℃ 3.2g 2,3,4 then, the solution of the 30ml ether of 6-four-O-(TMS)-D-Glucopyranose ketone is added dropwise in this solution by shifting pin.Generate solution and stirred 2 hours in-78 ℃, then, drip another part and be cooled to-80 ℃ 1.0g 2,3,4, the 10ml diethyl ether solution of 6-four-O-(TMS)-D-Glucopyranose ketone.In-78 ℃ of restir after 1 hour, add the 20ml methanol solution of 2ml methanesulfonic, remove cooling bath and solution was at room temperature stirred 16 hours.Then, use the ethyl diisopropylamine neutralization solution, remove solvent fully and residue is dissolved in 50ml toluene.Add the 8.5ml ethyl diisopropylamine, and this solution is cooled off at ice bath.Add the 4-dimethylaminopyridine of 4.3ml diacetyl oxide and 0.15g then.Solution was at room temperature stirred 2 hours, mix with sodium bicarbonate aqueous solution then.Through ethyl acetate extraction, make organic phase through dried over sodium sulfate and remove solvent.Residue separates (cyclohexane/ethyl acetate 4: 1-＞1: 3) through silica gel chromatography.

Productive rate: 2.0g (theoretical value 46%).

Mass spectrum (ESI ⁺): m/z=726[M+NH ₄] ⁺

Make with the method that is similar to embodiment XIV:

(1) 1-(tri isopropyl silane ethynyl)-4-(2,3,4,6-four-O-ethanoyl-1-methoxyl group-D-Glucopyranose-1-yl)-2-(4-oxyethyl group-benzyl)-benzene

Mass spectrum (ESI ⁺): m/z=770[M+NH ₄] ⁺

Embodiment XV

1-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-3-(4-tri isopropyl silane ethyl-acetylene base-benzyl)-benzene

1.2ml triethyl silicane and 0.36ml boron trifluoride diethyl etherate are added dropwise to the 1-(2 of ice-cold 1.0g; 3; 4,6-four-O-ethanoyl-1-methoxyl group-D-Glucopyranose-1-yl)-the 10ml acetonitrile solution of 3-(4-tri isopropyl silane ethynyl-benzyl)-benzene and 25 μ l water.Then, in ice bath, stirred this solution 3 hours, and stirring at room 1 hour.Then, solution is cooled off at ice bath, add 1.2ml triethyl silicane and boron trifluoride diethyl etherate O.36ml again.Make this solution restir 0.5 hour and in stirring at room 2 hours in ice bath.Then, add sodium bicarbonate aqueous solution in this solution, and with the solution that generates through ethyl acetate extraction.Organic phase is through dried over sodium sulfate and remove solvent.

Productive rate: 0.78g (theoretical value 81%).

Mass spectrum (ESI ⁺): m/z=696[M+NH ₄] ⁺

Make following compounds with the method that is similar to embodiment XV:

(1) 1-(tri isopropyl silane ethynyl)-4-(2,3,4,6-four-O-ethanoyl-β-D-Glucopyranose-1-yl)-2-(4-oxyethyl group-benzyl)-benzene

Embodiment XVI

1-chloro-4-(β-D-Glucopyranose-1-yl)-2-(4-acrinyl)-benzene

The 42ml anhydrous ether solution of [4-(5-bromo-2-chloro-benzyl)-the phenoxy group]-tertiary butyl-dimethyl-silane of 4.0g is cooled to-80 ℃ under argon gas.The pentane solution of the 1.7M tert-butyl lithium of 11.6ml slowly is added dropwise in this cooling solution; Then, stirred this solution 30 minutes down at-80 ℃.Then, this solution is shifted pin by the dry ice refrigerative and be added dropwise to 2,3,4 of the 4.78g that is cooled to-80 ℃, the solution of the 38ml ether of 6-four-O-(TMS)-D-Glucopyranose ketone.The solution that generates stirred 3 hours at-78 ℃.Then, add the 35ml methanol solution of 1.1ml methanesulfonic, this solution was at room temperature stirred 16 hours.Then, with sodium bicarbonate solid this solution that neutralizes, add ethyl acetate and methyl alcohol and ether come along and remove.Sodium bicarbonate aqueous solution is added in the rest solution, and through ethyl acetate extraction four times.Organic phase is through dried over sodium sulfate and evaporate to dryness.Residue is dissolved in 30ml acetonitrile and the 30ml methylene dichloride, and solution is cooled to-10 ℃.After adding the 4.4ml triethyl silicane, drip the 2.6ml boron trifluoride diethyl etherate and make temperature be no more than-5 ℃ simultaneously.After add finishing,, add the sodium bicarbonate aqueous solution termination reaction then-5～-10 ℃ of following restir 5 hours.Separate organic phase, and through ethyl acetate extraction water four times.The organic phase that merges is removed solvent and is made residue through silica gel purification through dried over sodium sulfate.Then, products therefrom is about 6: 1 beta/alpha mixture, its can by with hydroxyl through the complete acidylate of the dichloromethane solution of diacetyl oxide and pyridine, and in ethanol recrystallize and change into pure β-end group isomer (anomer).By in methyl alcohol, reacting, products therefrom is changed into title compound with the 4M potassium hydroxide solution.

Productive rate: 1.6g (theoretical value 46%).

Mass spectrum (ESI ⁺): m/z=398/400[M+NH] ⁺

Embodiment XVII

1-chloro-4-(β-D-Glucopyranose-1-yl)-2-[4-(trifluoromethyl sulfonyloxy)-benzyl]-benzene

The 4-dimethylaminopyridine of 10mg is added to 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-(4-acrinyl)-benzene, 0.21ml triethylamine and the 0.39g N of 0.38g, N-is two-the 10ml anhydrous methylene chloride solution of (trifluoromethane sulfonyl group)-aniline in.At room temperature stirred this solution 4 hours, and mixed with sodium chloride aqueous solution then.Through ethyl acetate extraction, organic extract is through dried over sodium sulfate and remove solvent.Residue separates (methylene chloride 1: 0-＞4: 1) through silica gel chromatography.

Productive rate: 0.33g (theoretical value 64%).

Mass spectrum (ESI ⁺): m/z=530/532 (Cl) [M+NH ₄] ⁺

Embodiment XVIII

2,3,4,6-four-O-benzyl-D-Glucopyranose ketone

N-methylmorpholine-N-oxide compound of fresh activatory molecular sieve 4  of 4g and 3.3g is added 2,3,4 of 10.0g, in the 140ml dichloromethane solution of 6-four-O-benzyl-alpha-D-Glucopyranose ketone.At room temperature stir this solution 20 minutes, and added the ruthenic acid tetrapropyl ammonium excessively of 0.3g then.After 2 hours, this solution is filtered in stirring at room with the methylene dichloride dilution and through Celite.With sodium thiosulfate solution and this filtrate of washing, and through dried over sodium sulfate.After removing solvent, residue separates (cyclohexane/ethyl acetate 4: 1) through silica gel chromatography.

Productive rate: 8.2g (theoretical value 82%).

Mass spectrum (ESI ⁺): m/z=539[M+NH ₄] ⁺

Embodiment XIX

1-(2,3,4,6-four-O-benzyl-1-hydroxyl-D-Glucopyranose-1-yl)-3-[4-(tertiary butyl-dimethyl-silicon alkoxyl group)-benzyl]-4-methyl-benzene

Make the 3ml anhydrous tetrahydrofuran solution of [4-(5-bromo-2-methyl-benzyl)-the phenoxy group]-tertiary butyl-dimethyl-silane of 0.34g under argon gas, be cooled to-80 ℃.The hexane solution of the 1.6M n-Butyl Lithium of 0.54ml is added dropwise to this cooling solution, and this solution was stirred 1.5 hours down at-78 ℃.Be cooled to-80 ℃ 4.3g 2,3,4, the 2.5ml tetrahydrofuran solution of 6-four-O-benzyl-D-Glucopyranose ketone is added dropwise to this solution with the transfer pin.The solution of generation was stirred 5 hours at-78 ℃.Reaction is through the 1ml of 0.1ml acetate tetrahydrofuran solution termination reaction, and is heated to room temperature.Then, add sodium bicarbonate aqueous solution, and make mixture ethyl acetate extraction four times.Organic phase is through dried over sodium sulfate and evaporate to dryness.Residue separates (cyclohexane/ethyl acetate 15: 1-＞4: 1) through silica gel chromatography.

Productive rate: 0.48g (about 88% purity).

Mass spectrum (ESI ⁺): m/z=868[M+H] ⁺

Embodiment XX

1-(2,3,4,6-four-O-benzyl-β-D-Glucopyranose-1-yl)-3-(4-hydroxyl-benzyl)-4-methyl-benzene

Make 1-(2,3,4,6-four-O-benzyl-1-hydroxyl-D-glucopyranosyl)-3-[4-(tertiary butyl-dimethyl-silicon the alkoxyl group)-benzyl of 0.48g (about 88% purity)]-the 3.5ml anhydrous acetonitrile of 4-methyl-benzene is cooled to-40 ℃ under argon gas.Tri isopropyl silane and the 0.08ml boron trifluoride diethyl etherate of 0.13ml are added dropwise in this cooling solution.Stir this solution 3 hours down at-35 ℃, and then once add 0.02ml tri isopropyl silane and 0.01ml boron trifluoride diethyl etherate.In-40 ℃ place 2 hours again after, add wet chemical, and at room temperature stirred this solution 1 hour.Then, dilute with water and through ethyl acetate extraction four times.Organic phase through dried over sodium sulfate, concentrate and separate (cyclohexane/ethyl acetate 10: 1-＞4: 1) through silica gel chromatography.

Productive rate: 0.24g (theoretical value 68%).

Mass spectrum (ESI ⁺): m/z=738[M+NH ₄] ⁺

Embodiment XXI

1-(2,3,4,6-four-O-benzyl-β-D-Glucopyranose-1-yl)-3-[4-(first hydrogen furans-3-base oxygen base)-benzyl]-4-methyl-benzene

0.10g toluene-4-sulfonic acid-tetrahydrofuran (THF)-3-base ester is added the 1-(2 of 0.24g, 3,4,6-four-O-benzyl-β-D-glucopyranosyl-1-yl)-3-(4-hydroxyl-benzyl)-4-methyl-benzene and 0.13g carbon joins in the mixture of 2.5ml dimethyl formamide of caesium.Stir this mixture 4 hours down at 65 ℃, add water then.Through ethyl acetate extraction three times, make organic phase through dried over sodium sulfate and remove solvent.Make residue through silica gel purification (cyclohexane/ethyl acetate 10: 1-＞4: 1).

Productive rate: 0.23g (theoretical value 78%).

Mass spectrum (ESI ⁺): m/z=808[M+H] ⁺

Embodiment XXII

1-(2,3,4,6-four-O-benzyl-β-D-Glucopyranose-1-yl)-3-[4-(trifluoromethyl sulfonyloxy)-benzyl]-4-methyl-benzene

Make the 4.5ml anhydrous methylene chloride solution of 1-(2,3,4,6-four-O-benzyl-β-D-glucopyranosyl-1-yl)-3-(4-hydroxyl-benzyl)-4-methyl-benzene of 0.62g under argon gas, be cooled to-10 ℃.The 0.5ml dichloromethane solution of 0.14ml pyridine and 0.3g fluoroform alkyl sulphonic acid anhydride is added this cooling solution.This solution was stirred 0.5 hour down in-5～-10 ℃, add sodium bicarbonate aqueous solution then.Make dichloromethane extraction three times of this mixture, the organic phase of merging is washed with the 1M hydrochloric acid soln, and through dried over sodium sulfate.Behind removal of solvents, residue separates (cyclohexane/ethyl acetate 15: 1-＞7: 1) through silica gel chromatography.Productive rate: 0.62g (theoretical value 84%).

Mass spectrum (ESI ⁺): m/z=853[M+H] ⁺

Embodiment XXIII

1-(2,3,4,6-four-O-benzyl-β-D-Glucopyranose-1-yl)-3-[4-(trimethyl silane ethynyl)-benzyl]-4-methyl-benzene

Under argon gas with 27mg cupric iodide, 48mg two-(triphenylphosphine)-palladium difluoride, 0.30ml triethylamine and last 0.14ml trimethyl silane acetylene adds the 1-(2 of 0.60g, 3,4,6-four-O-benzyl-β-D-glucopyranosyl-1-yl)-3-[4-(trifluoromethyl sulfonyloxy)-benzyl]-the 3ml dimethyl formamide solution of 4-methyl-benzene.With the flask tight seal, and under 90 ℃, stirred 4 hours.Then, add two-(triphenylphosphine)-palladium dichloride and 0.6ml trimethyl silane acetylene of 20mg again, and stirred this solution 4 hours down at 90 ℃.Add sodium bicarbonate aqueous solution then.With this mixture of ethyl acetate extraction three times, the organic phase of merging is through dried over sodium sulfate.Behind removal of solvents, residue separates (cyclohexane/ethyl acetate 40: 1-＞10: 1) through silica gel chromatography.

Productive rate: 0.45g (theoretical value 80%).

Mass spectrum (ESI ⁺): m/z=818[M+NH ₄] ⁺

The preparation of whole compound

Embodiment 1

1-chloro-2-(4-encircles penta oxygen benzyl)-4-(β-D-Glucopyranose-1-yl)-benzene

0.16ml iodo pentamethylene is added in the mixture of 2.5ml dimethyl formamide of l-chloro-4-(β-D-Glucopyranose-1-yl)-2-(4-the acrinyl)-benzene of 0.25g and 0.4g cesium carbonate.Stir this mixture 4 hours down at 45 ℃, and then add 0.1g cesium carbonate and 0.05ml iodo pentamethylene., add sodium chloride aqueous solution, and use ethyl acetate extraction after 14 hours at 45 ℃ of following restir.Organic phase is removed solvent and is used the silica gel purification residue through dried over sodium sulfate.(methylene chloride 1: 0-＞5: 1).

Productive rate: 0.23g (theoretical value 78%).

Mass spectrum (ESI ⁺): m/z=466/468 (Cl) [M+NH ₄] ⁺

Make following compounds with the method that is similar to embodiment 1:

This reaction is to be that the coupling companion carries out with (S)-toluene-4-sulfonic acid-tetrahydrofuran (THF)-3-base ester.

Mass spectrum (ESI ⁺): m/z=451/453 (Cl) [M+H] ⁺

This reaction is to be that the coupling companion carries out with (R)-toluene-4-sulfonic acid-tetrahydrofuran (THF)-3-base ester.

Mass spectrum (ESI ⁺): m/z=451/453 (Cl) [M+H] ⁺

This reaction is to be that the coupling companion carries out with 3-bromo butyryl radicals lactone.

Mass spectrum (ESI ⁺): m/z=465/467 (Cl) [M+H] ⁺

(5) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-(4-cyclobutoxy group-benzyl)-benzene

Mass spectrum (ESI ⁺): m/z=452/454 (Cl) [M+NH ₄] ⁺

(6) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-(4-cyclohexyloxy-benzyl)-benzene

Mass spectrum (ESI ⁺): m/z=480/482 (Cl) [M+NH ₄] ⁺

(7) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-[4-(tetrahydrofuran (THF)-4-base oxygen base)-benzyl]-benzene

Mass spectrum (ESI ⁺): m/z=487/489 (Cl) [M+Na] ⁺

(8) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-[4-(1-ethanoyl-piperidin-4-yl oxygen base)-benzyl]-benzene

This reaction is to be electrophile carrying out with 1-ethanoyl-4-sulfonyloxy methyl oxygen base-piperidines.

Mass spectrum (ESI ⁺): m/z=506/508 (Cl) [M+H] ⁺

(9) 1-chloro-4-(β-D-Glucopyranose-1-yl)-2-[4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen base)-benzyl]-benzene

This reaction is to be electrophile carrying out with 1-tertbutyloxycarbonyl-4-sulfonyloxy methyl oxygen base-piperidines.

Mass spectrum (ESI ⁺): m/z=586/588 (Cl) [M+Na] ⁺

Example 10

1-(β-D-Glucopyranose-1-yl)-4-methyl-3-[4-(tetrahydrofuran (THF)-3-base oxygen base)-benzyl]-benzene

Make the 1-(2 of 0.21g, 3,4,6-four-O-benzyl-β-D-glucopyranosyl-1-yl)-3-[4-(tetrahydrofuran (THF)-3-base oxygen base)-benzyl]-mixture of the 3ml ethyl acetate of 10% palladium hydroxide/gac of 4-methyl-benzene and 0.1g, under 1atm hydrogen, at room temperature shook 24 hours.Then, add the catalyzer of same amount once more, and under hydrogen-pressure, shook this mixture again 24 hours.Remove by filter catalyzer then, evaporate to dryness filtrate also makes residue separate (methylene chloride 1: 0-＞5: 1) through silica gel chromatography.

Productive rate: 0.06g (theoretical value 49%).

Mass spectrum (ESI ⁺): m/z=448[M+NH ₄] ⁺

Example 11

1-(β-D-Glucopyranose-1-yl)-4-methyl-3-[4-(2-TMS-ethyl)-benzyl]-benzene

Make the 1-(2 of 0.29g, 3,4,6-four-O-benzyl-β-D-glucopyranosyl-1-yl)-4-methyl-3-[4-(trimethyl silane ethynyl)-benzyl]-mixture of the 3ml ethyl acetate of 10% palladium hydroxide/gac of benzene and 0.25g at room temperature shook under 1atm hydrogen 24 hours.Then, add the 0.2g catalyzer again, and under hydrogen-pressure, shook this mixture again 20 hours.Then, filtration catalizer, evaporate to dryness filtrate also makes residue separate (methylene chloride 1: 0-＞5: 1) through silica gel chromatography.

Productive rate: 0.08g (theoretical value 51%).

Mass spectrum (ESI ⁺): m/z=462[M+NH ₄] ⁺

Example 12

1-chloro-4-(β-D-Glucopyranose-1-yl)-2-(4-ethynyl-benzyl)-benzene

Under argon gas, with 25mg cupric iodide, 44mg two-the trimethyl silane acetylene of (triphenylphosphine)-palladium dichloride, 0.30ml triethylamine and last 0.14ml, under argon gas, add 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-[4-(trifluoromethyl sulfonyloxy)-benzyl of 0.32g]-stupid 3ml dimethyl formamide solution in.With the flask tight seal, and under 90 ℃, stirred 8 hours.Then, add two-(triphenylphosphine)-palladium dichloride and 0.1ml trimethyl silane acetylene of 25mg again, and this solution was stirred 10 hours down at 90 ℃ again.Then, add sodium hydrogen carbonate solution, with this mixture of ethyl acetate extraction three times, the organic phase of merging is through dried over sodium sulfate.After removing solvent, residue is dissolved in 5ml methyl alcohol and mixes with 0.12g salt of wormwood.Mixture was at room temperature stirred 1 hour, neutralize with 1M hydrochloric acid then.Evaporate to dryness methyl alcohol then, residue mixes with sodium chloride aqueous solution, and through ethyl acetate extraction.The organic extract collected through dried over sodium sulfate, and is removed solvent.Residue separates (methylene chloride 1: 0-＞5: 1) through silica gel chromatography.

Productive rate: 0.095g (theoretical value 40%).

Mass spectrum (ESI ⁺): m/z=406/408 (Cl) [M+NH ₄] ⁺

This compound also can make by the method for embodiment 14:

Embodiment 13

1-chloro-4-(β-D-Glucopyranose-1-yl)-2-[4-(piperidin-4-yl oxygen base)-benzyl]-benzene

1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-[4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen the base)-benzyl that the 2ml trifluoroacetic acid is added 0.19g]-the 4ml dichloromethane solution of benzene in.This solution was at room temperature stirred 1.5 hours, then with the ethyl acetate dilution, and with wet chemical furnishing alkalescence.Separate organic phase, and with the ethyl acetate extraction water.The organic phase that merges is through dried over sodium sulfate, and removes solvent fully.

Productive rate: 0.060g (theoretical value 38%).

Mass spectrum (ESI ⁺): m/z=464/466 (Cl) [M+H] ⁺

Embodiment 14

1-fluoro-4-(β-D-Glucopyranose-1-yl)-2-(4-ethynyl-benzyl)-benzene

The 1.5ml tetrahydrofuran solution that the tetrahydrofuran solution of the 1M TBuA fluorochemical of 0.33ml is added 1-fluoro-4-(2,3,4,6-four-O-ethanoyl-β-D-glucopyranosyl-1-yl)-2-(tri isopropyl silane ethynyl-benzyl)-benzene of 0.23g.This solution was at room temperature stirred 1 hour.Add the potassium hydroxide solution of the 4M of 1ml methyl alcohol and 1.5ml then, and make this solution room temperature restir one hour.Make this solution with the neutralization of 1M hydrochloric acid, boil off methyl alcohol then.Residue mixes with sodium chloride solution, and through ethyl acetate extraction.Collect organic extract, and, boil off solvent then through dried over sodium sulfate.Residue separates (methylene chloride 19: 1-＞2: 1) through silica gel chromatography.

Productive rate: 0.060g (theoretical value 49%).

Mass spectrum (ESI ⁺): m/z=390[M+H] ⁺

Make following compounds with the method that is similar to embodiment 14:

(15) 1-(β-D-Glucopyranose-1-yl)-3-(4-ethynyl-benzyl)-benzene

Mass spectrum (ESI ⁺): m/z=372[M+NH ₄] ⁺

(16) 1-ethynyl-4-(β-D-t Glucopyranose-1-yl)-2-(4-oxyethyl group-benzyl)-benzene

Mass spectrum (ESI ⁺): m/z=416[M+NH ₄] ⁺

(17) 1-methoxyl group-4-(β-D-Glucopyranose-1-yl)-2-(4-ethynyl-benzyl)-benzene

Mass spectrum (ESI ⁺): m/z=402[M+NH ₄] ⁺

Compound (1-chloro-4-(β-D-Glucopyranose-1-yl)-2-(4-ethynyl-benzyl)-benzene) according to embodiment (12) also can synthesize by the method that is similar to embodiment 14.Look situation ground, available TBuA fluorochemical goes to make intermediate stage 1-chloro-4-behind the silanization, and (2,3,4,6-four-O-ethanoyl-β-D-glucopyranosyl-1-yl)-2-(4-ethynyl-benzyl)-benzene can be by carrying out recrystallize and purifying in the ethanol.

Mass spectrum (ESI ⁺): m/z=406/408 (Cl) [M+NH ₄] ⁺

Employing is similar to the foregoing description and other make following compounds by known method in the document:

Now, we will illustrate some example of preparation type, and wherein the term of " active substance " represents that one or more according to compound of the present invention, comprise its esters.In mentioned above and situations one or more other active substance combination, term that should " active substance " also comprises other active substance.

Example A

The tablet that contains the 100mg active substance

Component:

Each tablet comprises:

Active substance 100.0mg

Lactose 80.0mg

W-Gum 34.0mg

Polyvinylpyrrolidone 4.0mg

Magnesium Stearate 2.0mg

220.0mg

The preparation method:

Mix this active substance, lactose and starch, and carry out wetting equably with the polyvinylpyrrolidone aqueous solution.After the moistening component of sieving (2.0mm mesh) and in the posture loft drier 50 ℃ down dry, and then sieve (1.5mm mesh) and add lubricant.The mixture of finishing is pressed into tablet.

Tablet weight: 220mg

Diameter: 10mm, biplane, all there is facet on the two sides, and one side has the matrix indentation.

Example B

The tablet that contains the 150mg active substance

Component:

Each tablet comprises:

Active substance 150.0mg

Powdery lactose 89.0mg

W-Gum 40.0mg

Gluey silicic acid 10.0mg

Polyvinylpyrrolidone 10.0mg

Magnesium Stearate 1.0mg

300.0mg

Preparation:

With lactose, W-Gum and silicic acid blended active substance through 20% pyrrolidone aqueous solution humidification, and the sieve by the 1.5mm mesh size.Make 45 ℃ of dry granules and pass through identical sieve once more, and mix the Magnesium Stearate of specified quantitative.Be pressed into tablet by mixture.

Tablet weight: 300mg

Metal pattern: 10mm is flat

Example C

The hard gelatin capsule that contains the 150mg active substance

Component:

Each capsule comprises:

Active substance 150.0mg

The about 180.0mg of W-Gum (drying)

The about 87.0mg of lactose (powder)

Magnesium Stearate 3.0mg

420.0mg

Preparation:

With active substance and mixed with excipients, make it pass through the sieve of 0.75mm mesh size.And in proper device with its uniform mixing.The mixture of finishing charged into No. 1 hard gelatin capsule.

Capsule filling: about 320mg

Capsule shell: No. 1 hard gelatin capsule.

Example D

The suppository that contains the 150mg active substance

Component:

Each suppository comprises:

Active substance 150.0mg

Polyethylene glycol 1500 550.0mg

Polyethylene glycol 6000 460.0mg

Stearinsaeure Sorbitan ethoxylate 840.0mg

2000.0mg

Preparation:

After the fusion of the material of suppository, with the active substance homogeneous distribution therein, and melts poured in the pre-cooled mould.

Example E

The ampoule that contains the 10mg active substance

Component:

Active substance 10.0mg

0.01N hydrochloric acid is an amount of

Add deionized water to 2.0ml

Preparation:

Active substance is dissolved among the 0.01N HCl of requirement, utilizes salt to make it become isotonic solution, sterile filtration is also filled the 2ml ampoule.

Example F

The ampoule that contains the 50mg active substance

Component:

Active substance 50.0mg

0.01N hydrochloric acid is an amount of

Add deionized water to 10.0ml

Preparation:

Active substance is dissolved in the 0.01N HCl of requirement, makes it become isotonic solution with salt, sterile filtration also charges into the 10ml ampoule.

Claims

1. the benzene derivative that replaces of the Glucopyranose of a tool general formula I

Wherein

R ¹Be selected from the definition of A base, and

If R ³Be when being selected from the definition of B base, R then ¹Also can be selected from following meaning in addition: hydrogen, fluorine, chlorine, bromine, iodine, C _1-4-alkyl, C _2-4-thiazolinyl-C _1-4-alkyl, C _2-4-alkynyl-C _1-4-alkyl, C _2-4-thiazolinyl-C _1-4-alkoxyl group, C _2-4-alkynyl-C _1-4-alkoxyl group, C _3-7-cycloalkyl-C _1-4-alkyl, C _5-7-cycloalkenyl group-C _1-4-alkyl, the methyl that replaces through 1-3 fluorine atom, through ethyl, the C of 1-5 fluorine atom replacement _1-4-alkoxyl group, the methoxyl group that replaces through 1-3-fluorine atom, through the oxyethyl group of 1-5 fluorine atom replacement, through hydroxyl or-C _1-3The C that-alkoxyl group replaces _1-4-alkyl, through hydroxyl or C _1-3The C that-alkoxyl group replaces _2-4-alkoxyl group, C _3-6-cycloalkyl-C _1-3-alkoxyl group or hydroxyl,

Simultaneously, in above-mentioned cycloalkyl and cyclenes basic ring, 1 or 2 methylene radical ground warp O or CO replacement independently of one another, and

R ³Be the definition that is selected from the B base, and

If R ¹Be when being selected from the definition of A base, R then ³Also can be selected from following meaning in addition: hydrogen, fluorine, chlorine, bromine, iodine, C _1-6-alkyl, C _2-4-thiazolinyl-C _1-4-alkyl, C _2-4-alkynyl-C _1-4-alkyl, C _2-4-thiazolinyl-C _1-4-alkoxyl group, C _2-4-alkynyl-C _1-4-alkoxyl group, C _3-7-cycloalkyl, C _5-7-cycloalkenyl group, C _3-7-cycloalkyl-C _1-4-alkyl, C _5-7-cycloalkenyl group-C _1-4-alkyl, C _3-6-ring alkylidene group methyl, hydroxyl, C _1-6-alkoxyl group, C _3-6-cycloalkyl-C _1-3-alkoxyl group, aryl, aryl-C _1-3-alkyl, heteroaryl, heteroaryl-C _1-3-alkyl, aryloxy, aryl-C _1-3-alkyl-oxygen base, the methyl or methoxy that replaces through 1-3-fluorine atom, through the C of 1-5 fluorine atom replacement _2-4-alkyl or C _2-4-alkoxyl group, the C that replaces through cyano group _1-4-alkyl, through hydroxyl or C _1-3The C that-alkoxyl group replaces _1-4-alkyl, cyano group, carboxyl, C _1-3-carbalkoxy, aminocarbonyl, (C _1-3-alkylamino) carbonyl, two-(C _1-3-alkyl) aminocarbonyl, tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, morpholine-4-base carbonyl, piperazine-1-base-carbonyl, 4-(C _1-3-alkyl)-piperazine-1-base-carbonyl, (C _1-4-alkyl) carbonyl amino, C _1-4-alkyl-sulfuryl amino, C _1-4-alkylthio, C _1-4-alkyl sulfinyl, C _1-4-alkane alkylsulfonyl, arylsulfonyl amino, aryl-C _1-3-alkane sulfuryl amino or arylsulfonyl,

B represents three-(C _1-4-alkyl) silylation-C _1-6-alkyl, C _2-6-alkynes-1-base, C _2-6-alkene-1-base, amino, C _1-3-alkylamino, two-(C _1-3-alkyl) amino, tetramethyleneimine-1-base, pyrrolidin-2-one-1-base, piperidines-1-base, piperidines-2-ketone-1-base, morpholine-4-base, morpholine-3-ketone-4-base, piperazine-1-base, 4-(C _1-3-alkyl)-piperazine-1-base, fragrant carbonyl amino, assorted fragrant carbonyl amino, nitro, C _3-10-cycloalkyloxy, C _5-10-cyclenes oxygen base, C _3-10-cycloalkylthio, C _3-10-cycloalkanes sulfinyl, C _3-10-cycloalkanes alkylsulfonyl, C _5-10-cyclenes sulfenyl, C _5-10-cyclenes sulfinyl, C _5-10-cyclenes alkylsulfonyl, arylthio, fragrant sulfinyl, heteroarylthio or assorted fragrant sulfinyl,

Yet above-mentioned cycloalkyl and cyclenes basic ring ground warp independently of one another are selected from fluorine and C _1-3The substituting group list of-alkyl or two replacement, and

L1 is independently from each other hydroxyl, cyano group, nitro, C _3-7-cycloalkyl, aryl, heteroaryl, C _1-4-alkyl carbonyl, aromatic carbonyl, assorted aromatic carbonyl, aminocarbonyl, C _1-4-alkane aminocarbonyl, two-(C _1-3-alkyl)-aminocarbonyl, tetramethyleneimine--1 basic carbonyl, piperidines-1-base carbonyl, morpholine-4-base carbonyl, fragrant aminocarbonyl, assorted fragrant aminocarbonyl, C _1-4-carbalkoxy, aryl-C _1-3-carbalkoxy, heteroaryl-C _1-3-carbalkoxy, C _1-4-alkoxyl group, aryloxy, heteroaryloxy, C _1-4-alkylthio, arylthio, heteroarylthio, C _1-4-alkyl sulfinyl, fragrant sulfinyl, assorted fragrant sulfinyl, C _1-4-alkane alkylsulfonyl, arylsulfonyl and assorted arylsulfonyl, and

R ⁶、R ^7a、

R ^7b, R ^7cHas following meaning independently of one another: hydrogen, (C _1-18-alkyl) carbonyl, (C _1-18-alkyl) oxygen base carbonyl, aromatic carbonyl and aryl-(C _1-3-alkyl)-carbonyl,

Yet the aryl of mentioning in the definition of above-mentioned base means phenyl or naphthyl, its identical or different single or two replacements of L2 base of ground warp independently of one another, and

Yet, the identical or different single replacement of L2 base or the two replacement of ground warp independently of one another of above-mentioned heteroaryl,

Yet except as otherwise noted, otherwise above-mentioned alkyl can be straight or branched,

Its compounds tautomeric, stereoisomers, its mixture and its esters.

2. the benzene derivative that replaces of the Glucopyranose of a tool general formula I .2

R wherein ¹To R ⁶With R ^7a, R ^7bAnd R ^7cThe base such as claim 1 definition.

3. the benzene derivative that replaces according to the Glucopyranose of claim 1 or 2 is characterized in that A basis representation C _2-6-alkynes-1-base, C _2-6-alkene-1-base, C _3-7-cycloalkyl, C _5-7Cycloalkenyl group, C _1-4-alkyl carbonyl, aminocarbonyl, C _1-4-alkane aminocarbonyl, two-(C _1-3-alkyl) aminocarbonyl, pyridine alkane-1-base carbonyl, piperidines-1-base carbonyl, morpholine-4-base carbonyl, piperazine-1-base carbonyl, 4-(C _1-4-alkyl) piperazine-1-base carbonyl, C _1-4-carbalkoxy, amino, C _1-4-alkylamino, two-(C _1-3-alkyl) amino, tetramethyleneimine-1-base, pyrrolidin-2-one-1-base, piperidines-1-base, piperidines-2-ketone-1-base, morpholine-4-base, morpholine-3-ketone-4-base, piperazine-1-base, 4-(C _1-3-alkyl) piperazine-1-base, C _1-4-alkane carbonyl oxygen base, C _3-7-cycloalkyloxy, C _5-7-cyclenes oxygen base, C _1-4-alkyl sulfinyl, C _1-4-alkane alkylsulfonyl, C _3-7-cycloalkylthio, C _3-7-cycloalkanes sulfinyl, C _3-7-cycloalkanes alkylsulfonyl, C _5-7-cyclenes sulfenyl, C _5-7-cyclenes sulfinyl, C _5-7-cyclenes alkylsulfonyl, cyano group or nitro,

In above-mentioned cycloalkyl and cyclenes basic ring, one or two methylene radical is ground warp O, S, CO, SO, SO independently of one another ₂Or NR ^NReplace, and

L1 and R ^NBe such as claim 1 the definien.

4. the benzene derivative that replaces according in the claim 1 to 3 or multinomial Glucopyranose is characterized in that B basis representation three-(C _1-4-alkyl) silylation-C _1-6-alkyl, C _2-6-alkynes-1-base, C _2-6-alkene-1-base, amino, C _1-3-alkylamino, two-(C _1-3-alkyl) amino, tetramethyleneimine-1-base, pyrrolidin-2-one-1-base, piperidines-1-base, piperidines-2-ketone-1-base, morpholine-4-base, morpholine-3-ketone-4-base, piperazine-1-base, 4-(C _1-3-alkyl)-piperazine-1-base, nitro, C _3-7-cycloalkyloxy, C _5-7-cyclenes oxygen base, C _3-7-cycloalkylthio, C _3-7-cycloalkanes sulfinyl, C _3-7-cycloalkanes alkylsulfonyl, C _5-7-cyclenes sulfenyl, C _5-7-cyclenes sulfinyl, C _5-7-cyclenes alkylsulfonyl,

L1 and R ^NBe such as claim 1 the definien.

5. the benzene derivative that replaces according in the claim 1 to 4 or multinomial Glucopyranose is characterized in that this R ³Base is the definition that is selected from according to the B base of claim 1 or 4.

6. the benzene derivative that replaces according in the claim 1 to 5 or multinomial Glucopyranose is characterized in that this R ¹Base is to be selected from hydrogen, fluorine, chlorine, bromine, iodine, C _1-4-alkyl, C _2-6-alkynyl, C _1-4-alkoxyl group, C _2-4-thiazolinyl-C _1-4-alkoxyl group, C _2-4-alkynyl-C _1-4-alkoxyl group, the methyl that replaces through 1-3 fluorine atom, the ethyl that replaces through 1-5 fluorine atom, through the methoxyl group of 1-3 fluorine atom replacement, through the oxyethyl group of 1-5-fluorine atom replacement, through hydroxyl or C _1-3The C that-alkoxyl group replaces _1-4-alkyl, through hydroxyl or C _1-3The C that-alkoxyl group replaces _2-4-alkoxyl group, C _2-6-thiazolinyl, C _3-6-cycloalkyl, C _3-6-cycloalkyl-C _1-3-alkyl, C _3-7-cycloalkyloxy, C _3-6-cycloalkyl-C _1-3-alkoxyl group, C _5-7-cyclenes oxygen base, hydroxyl, amino, nitro or cyano group, yet at C _3-6Methylene radical can replace through O in the-cycloalkyl.

7. the benzene derivative that replaces according in the claim 1 to 5 or multinomial Glucopyranose is characterized in that this R ¹Base is the definition that is selected from according to the A base in claim 1 or 3.

8. the benzene derivative that replaces according in claim 1 to 4 and 7 or multinomial Glucopyranose is characterized in that this R ³Base is to be selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano group, C _1-6-alkyl, TMS ethyl, C _2-6-thiazolinyl, C _2-6-alkynyl, difluoromethyl, trifluoromethyl, C _3-7-cycloalkyl, C _5-7-cycloalkenyl group, C _1-6-alkoxyl group, difluoro-methoxy, trifluoromethoxy, five fluorine oxyethyl groups, C _3-7-cycloalkyloxy, tetrahydrofuran oxygen base, tetrahydrofuran (THF) ketone oxygen base, C _1-6-alkylthio, ring propylidene methyl, aryl or heteroaryl.

9. the benzene derivative that replaces according in the claim 1 to 8 or multinomial Glucopyranose is characterized in that this R ²Basis representation hydrogen, fluorine, chlorine, bromine, methyl, hydroxyl, methoxyl group, oxyethyl group, trifluoromethyl, cyano group, nitro or the methyl that replaces through 1 to 3 fluorine atom.

10. the benzene derivative that replaces according in the claim 1 to 9 or multinomial Glucopyranose is characterized in that this R ⁴And/or R ⁵Base is to represent hydrogen or fluorine independently of one another.

11. the benzene derivative according in the claim 1 to 10 or multinomial Glucopyranose replace is characterized in that this R ⁶Basis representation hydrogen, (C _1-8-alkyl) oxygen carbonyl, C _1-8-alkyl carbonyl or benzyl acyl group are preferably hydrogen.

12. the benzene derivative according in the claim 1 to 11 or multinomial Glucopyranose replace is characterized in that this R ^7a, R ^7bWith R ^7cBase is represented hydrogen.

13. according at least one the compound and the physiologically acceptable salt of mineral acid or organic acid generation in the claim 1 to 12.

14. a pharmaceutical composition comprises according at least one compound in the claim 1 to 12, or according to the physiologically acceptable salt of claim 13, looks situation and contain one or more inert support and thinner.

15. one kind according to one in the claim 1 to 12 or multinomial compound or according to the purposes of the physiologically acceptable salt of claim 13, it is used to prepare and is suitable for treating or prevents because of the disease that suppressed by Na-dependent glucose cotransporter SGLT to be influenced or the pharmaceutical composition of illness.

16. one kind according at least one compound in the claim 1 to 12 or according to the purposes of the physiologically acceptable salt of claim 13, it is used to prepare the pharmaceutical composition that is suitable for treating or preventing metabolic disorder.

17. purposes according to claim 16, it is characterized in that this metabolic disorder is to be selected to comprise I type or type ii diabetes, hyperlipemia, arteriosclerosis and the relative disease of the complication of diabetes, metabolic acidosis or ketoacidosis, reactive hypoglycemia disease, hyperinsulinemia, glucose metabolism illness, insulin resistance, metabolism disease syndromes, Different Origin, obesity, hypertension, chronic heart failure exhaust, oedema and hyperuricemia.

18. one kind according at least one compound in the claim 1 to 12 or according to the purposes of the physiologically acceptable salt of claim 13, it is used to prepare the pharmaceutical composition that suppresses Na-dependent glucose cotransporter SGLT2.

19. one kind according at least one compound in the claim 1 to 12 or according to the purposes of the physiologically acceptable salt of claim 13, it is used to prepare and suppresses pancreas β cell degradation and improve and/or the pharmaceutical composition of recovery pancreas β cell function.

20. one kind according at least one compound in the claim 1 to 12 or according to the purposes of the physiologically acceptable salt of claim 13, it is used to prepare diuretic(s) and antihypertensive drug.

21. method for preparing according to the pharmaceutical composition of claim 14, it is characterized in that adding one or more inert supports with at least one compound in the claim 1 to 12 or according to the physiologically acceptable salt of claim 13 based on method non-chemically, with/or thinner in.

22. method for preparing according to the compound of Formula I in the claim 1 to 12; it is characterized in that general formula I I compound is reacted with reductive agent under the situation that has Louis or Bronsted acid to exist; wherein the protecting group of any existence then simultaneously or successively split

Wherein

R ^8a、R ^8b、

R ^8c, R ^8dHas R above a kind of or that hereinafter given independently of one another ⁶, R ^7a, R ^7b, R ^7cThe meaning of base, expression benzyl or R ^aR ^bR ^cSi base or ketal group or acetal radical; Yet, in each situation, two adjacent R ^8a, R ^8b, R ^8c, R ^8dBase can form cyclic ketal base or acetal radical, or 1,2-two (C _1-3-alkoxyl group)-1,2-two (C _1-3-alkyl)-etheno; Yet two carbon atoms under above-mentioned etheno and two Sauerstoffatoms and the pyranose ring form the two  alkane rings that replace, and alkyl, aryl and/or benzyl can pass through halogen or C _1-3-alkoxyl group list or polysubstituted,

Yet the aryl of mentioning in the definition of above-mentioned base means phenyl or naphthyl, is preferably phenyl,

And, this R ¹To R ⁵With R ⁶, R ^7a, R ^7b, R ^7cHave the meaning that claim 1 to 12 gives,

In case of necessity, make the wherein R that obtains thus ⁶The compound of Formula I of expression hydrogen atom changes into the acyl compounds of corresponding general formula I by acidylate, with/or

If when needing, the protection basic capsule that above-mentioned reaction is used goes, with/or

In case of necessity, the compound of Formula I that obtains is thus changed into its physiologically acceptable salt.

23., it is characterized in that this general formula I I compound is to make by claim 24 or 25 described methods according to the method for claim 22.

24. method for preparing general formula I I compound

Wherein

R ^8a、R ^8b、

R ^8c, R ^8dHas a kind of R that gives independently of one another ⁶, R ^7a, R ^7b, R ^7cThe meaning of base, expression benzyl or R ^aR ^bR ^cSi base or ketal group or acetal radical; Yet, in each situation, two adjacent R ^8a, R ^8b, R ^8c, R ^8dBase can form cyclic ketal or acetal radical, or 1,2-two (C _1-3-alkoxyl group)-1,2-two (C _1-3-alkyl)-etheno; Yet, two relevant carbon atoms of above-mentioned etheno and two Sauerstoffatoms and pyranose ring, the two  alkane rings that form to replace, and alkyl, aryl and/or benzyl can pass through halogen or C _1-3-alkoxyl group list or polysubstituted, and benzyl also can be through two-(C _1-3-alkyl) the amino replacement, and

And R ¹To R ⁵, R ⁶, R ^7a, R ^7b, R ^7cThe meaning that has in the claim 1 to 12 to be given,

Wherein Hal represents Cl, Br and I, and R ¹To R ⁵Being as hereinbefore defined, and looking the commentaries on classics metallization that situation is followed, is to add in the glucose lactone of general formula VI

R wherein ^8a, R ^8b, R ^8c, R ^8dBe person as hereinbefore defined, and

Then, the adducts that makes this generation under the situation that has acid to exist with water or wherein R ' expression look the C that situation is substituted _1-4The R ' of-alkyl-OH alcohol reacts, and looks situation and make the product that reacts the wherein R ' expression H that obtains with water, and changing into wherein with acylating agent in subsequent reactions, R ' represents (C _1-18-alkyl) carbonyl, (C _1-18-alkyl) oxygen carbonyl, aromatic carbonyl or aryl-(C _1-3-alkyl)-product of the formula II of carbonyl, itself and as described the person replace.

25., it is characterized in that this organometallic compound (V) is lithium or magnesium compound according to the method for claim 24.

26. one kind prepares wherein R ⁶, R ^7a, R ^7bWith R ^7cRepresent the method according to the compound of Formula I in the claim 1 to 12 of hydrogen, it is characterized in that compound of formula III is hydrolyzed

Wherein

R ^8a、R ^8b、

R ^8c, R ^8dHas a kind of R that gives independently of one another ⁶, R ^7a, R ^7b, R ^7cThe meaning of base, but R at least ^8a, R ^8b, R ^8c, R ^8dIn one of do not represent hydrogen, expression benzyl or R ^aR ^bR ^cSi base or ketal group or acetal radical; Yet, in each situation, two adjacent R ^8a, R ^8b, R ^8c, R ^8dBase can form cyclic ketal or acetal radical, or 1,2-two (C _1-3-alkoxyl group)-1,2-two (C _1-3-alkyl)-etheno; Yet two relevant carbon atoms of above-mentioned etheno and two Sauerstoffatoms and pyranose ring form the two  alkane rings that replace, and alkyl, aryl and/or benzyl can pass through halogen or C _1-3-alkoxyl group list or polysubstituted, and benzyl also can be through two-(C _1-3-alkyl) amido replaces, and

R ^a, R ^b, R ^cRepresent C independently of one another _1-4Alkyl, aryl or aryl-C _1-3-alkyl, wherein this alkyl or aryl can be through halogen list or polysubstituted,

Yet, mean phenyl or naphthyl according to the aryl of in the definition of above-mentioned base, mentioning, be preferably phenyl,

And, R ¹To R ⁵, R ⁶, R ^7a, R ^7b, R ^7cHave the meaning that is given according in the claim 1 to 12,

And

If when needing, the protection basic capsule that any above-mentioned reaction is used goes, with/or

In case of necessity, the compound of Formula I that obtains is thus changed into its salt, particularly medicinal use is changed into its physiologically acceptable salt.

27., it is characterized in that this compound of formula III is to make by means of the method according to claim 22 or 23 according to the method for claim 26.

28. general formula I V compound

Wherein Hal represents chlorine, bromine or iodine, and R ¹, R ², R ³, R ⁴With R ⁵Base is as one in the claim 1 and 3 to 10 or multinomial definition.

29. the general formula I V compound according to claim 28 is characterized in that formula

Wherein Hal represents chlorine, bromine or iodine, and R ¹, R ², R ⁴With R ⁵Base is as claim 1,3,6,7,9,10 one or multinomial definition; And R ³Base is the B base that is selected from according to claim 1 or 4.

30. general formula I I compound

Wherein

R ^8a、R ^8b、

R ^8c, R ^8dHas a kind of R of giving independently of one another ⁶, R ^7a, R ^7b, R ^7cThe meaning of base, or expression benzyl or R ^aR ^bR ^cSi base or ketal group or acetal radical; Yet, in each situation, two adjacent R ^8a, R ^8b, R ^8c, R ^8dBase can form cyclic ketal base or acetal radical, or 1,2-two (C _1-3-alkoxyl group)-1,2-two (C _1-3-alkyl)-etheno; Yet, two relevant carbon atoms of above-mentioned etheno and two Sauerstoffatoms and pyranose ring, the two  alkane rings that form to replace, and alkyl, aryl and/or benzyl can pass through halogen or C _1-3-alkoxyl group list or polysubstituted, and benzyl also can be through two-(C _1-3-alkyl) the amino replacement, and

R ^a, R ^b, R ^cRepresent C independently of one another _1-4Alkyl, aryl or aryl-C _1-3-alkyl, however this alkyl or aryl can be through halogen list or polysubstituted,

Yet, mean phenyl or naphthyl according to the aryl of in the definition of above-mentioned base, mentioning, preferable with phenyl,

And R ¹To R ⁵Base is as one in the claim 1 and 3 to 10 or multinomial definition.