HK1188776B

HK1188776B - Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof

Info

Publication number: HK1188776B
Application number: HK14101768.2A
Authority: HK
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: 贝林格尔‧英格海姆国际有限公司
Priority date: 2004-03-16
Filing date: 2007-08-28
Publication date: 2016-04-08

Description

Glucopyranosyl-substituted phenyl derivatives, medicaments containing these compounds, their use and process for their preparation

The application is a divisional application of Chinese invention application (the name of the invention is glucopyranosyl-substituted phenyl derivative, a medicament containing the compound, the application and a manufacturing method thereof; the application date is 03 and 11 in 2005; and the application number is 200580006944.9).

The invention relates to glucopyranosyl-substituted benzene derivatives of the general formula I

Wherein R is¹To R⁶And R^7a、R^7b、R^7cThe groups are defined below, including tautomers, stereoisomers, mixtures thereof and salts thereof. The invention further relates to pharmaceutical compositions comprising the compounds of formula I according to the invention and to the use of the compounds according to the invention for the preparation of pharmaceutical compositions for the treatment of metabolic disorders. Furthermore, the invention relates to methods for preparing the pharmaceutical compositions and compounds of the invention.

In the literature, it is proposed to treat diseases, in particular diabetes, with compounds which have an inhibitory effect on the sodium-dependent glucose-cotransporter SGLT 2.

Glucopyranosyl-substituted aromatics and their preparation and their potential activity as SGLT2 inhibitors are known from the following international applications, WO98/31697, WO01/27128, WO02/083066, WO03/099836, WO2004/063209, WO2004/080990, WO2004/013118, WO2004/052902, WO2004/052903, and U.S. patent application US 2003/0114390.

Object of the Invention

The object of the present invention is to find novel pyranosyl-substituted benzene derivatives, which are active especially on the sodium-dependent glucose cotransporter SGLT, especially SGLT 2. It is a further object of the present invention to indicate pyranosyl-substituted benzene derivatives having an enhanced inhibitory effect on the sodium-dependent glucose cotransporter SGLT2 and/or having better pharmacological or pharmacokinetic properties in vivo and/or in vitro compared to known compounds of similar structure.

It is a further object of the present invention to provide novel pharmaceutical compositions suitable for the prevention and/or treatment of metabolic disorders, in particular diabetes.

The object of the present invention is also to provide a process for the preparation of the compounds according to the invention.

Other objects of the present invention will become apparent to those skilled in the art from the foregoing and following description.

Object of the Invention

The first aspect of the present invention relates to glucopyranosyl-substituted benzene derivatives of the general formula I

Wherein

R¹Is selected from the definitions of group A, and

if R is³Selected from the definitions of radicals B, then R¹It is also possible to choose the following meanings additionally: hydrogen, fluorine, chlorine, bromine, iodine, C_1-4Alkyl radical, C_2-4-alkenyl-C_1-4Alkyl radical, C_2-4-alkynyl-C_1-4Alkyl radical, C_2-4-alkenyl-C_1-4-alkoxy, C_2-4-alkynyl-C_1-4-alkoxy, C_3-7-cycloalkyl-C_1-4Alkyl radical, C_5-7-cycloalkenyl-C_1-4Alkyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, C_1-4Alkoxy, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms, hydroxy or C_1-3-alkoxy-substituted C_1-4Alkyl, via hydroxy or C_1-3-alkoxy-substituted C_2-4-alkoxy, C_3-6-cycloalkyl-C_1-3-an alkoxy group or a hydroxyl group,

wherein, in the cycloalkyl and cycloalkenyl rings mentioned above, 1 or 2 methylene groups may be replaced independently of one another by O or CO, and

R²represents hydrogen, fluorine, chlorine, bromine, hydroxyl, C_1-4Alkyl radical, C_1-4Alkoxy, cyano or nitro, wherein the alkyl or alkoxy radical may be mono-or polysubstituted by fluorine, and

R³selected from the definitions of radicals B, and

if R is¹Selected from the definitions of group A, then R³The following meanings may also be selected additionally: hydrogen, fluorine, chlorine, bromine, iodine, C_1-6Alkyl radical, C_2-4-alkenyl-C_1-4Alkyl radical, C_2-4-alkynyl-C_1-4Alkyl radical, C_2-4-alkenyl-C_1-4-alkoxy, C_2-4-alkynyl-C_1-4-alkoxy, C_3-7-cycloalkyl, C_5-7-cycloalkenyl radical, C_3-7-cycloalkyl-C_1-4Alkyl radical, C_5-7-cycloalkenyl-C_1-4Alkyl radical, C_3-6Cycloalkylidenemethyl, hydroxy, C_1-6-alkoxy, C_3-6-cycloalkyl-C_1-3Alkoxy, aryl-C_1-3Alkyl, heteroaryl-C_1-3Alkyl, aryloxy, aryl-C_1-3-alkyl-oxy, methyl or methoxy substituted by 1-3-fluorine atoms, C substituted by 1-5 fluorine atoms_2-4-alkyl or C_2-4Alkoxy, cyano-substituted C_1-4Alkyl, via hydroxy or C_1-3-alkoxy-substituted C_1-4Alkyl, cyano, carboxyl, C_1-3-alkoxycarbonyl, aminocarbonyl, (C)_1-3-alkylamino) carbonyl, di- (C)_1-3-alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-yl-carbonyl, 4- (C)_1-3-alkyl) -piperazin-1-yl-carbonyl, (C)_1-4-alkyl) carbonylamino, C_1-4-alkyl-sulfonylamino, C_1-4Alkylthio radical, C_1-4-alkylsulfinyl, C_1-4Alkanesulfonyl, arylsulfonylamino, aryl-C_1-3-an alkylsulfonamido or arylsulfonyl group,

R⁴、R⁵independently of one another, hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C_1-3Alkyl radical, C_1-3Alkoxy, methyl or methoxy substituted by 1 to 3 fluorine atoms,

a represents C_2-6-alkyn-1-yl, C_2-6-en-1-yl, C_3-7-cycloalkyl, C_5-7Cycloalkenyl, aryl, heteroaryl, C_1-4Alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, C_1-4Alkylaminocarbonyl, di- (C)_1-3-alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C)_1-4-alkyl) piperazin-1-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, C_1-4-alkoxycarbonyl, aryl-C_1-3-alkoxycarbonyl, heteroaryl-C_1-3-alkoxycarbonyl, amino, C_1-4Alkylamino, di- (C)_1-3-alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-3-one-4-yl, piperazin-1-yl, 4- (C)_1-3-alkyl) -piperazin-1-yl, C_1-4Alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C_3-7Cycloalkoxy, C_5-7Cycloalkenyloxy, aryloxy, heteroaryloxy, C_1-4-alkylsulfinyl, C_1-4-alkylsulfonyl, C_3-7Cycloalkylthio radical, C_3-7-cycloalkylsulfinyl radical, C_3-7-cycloalkanesulfonyl group, C_5-7-Cycloalkenylthio group, C_5-7-Cycloalkenylsulfinyl group, C_5-7-cycloalkenesulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, cyano or nitro,

wherein the alkynyl and alkenyl groups may be mono-or polysubstituted with fluorine or chlorine, and

the above-mentioned alkynyl and alkenyl groups may be mono-or disubstituted by the same or different radicals L1, and

the cycloalkyl and cycloalkenyl rings mentioned above may, independently of one another, be chosen from fluorine and C_1-3The substituents of alkyl being mono-or disubstituted, and

in the cycloalkyl and cycloalkenyl rings mentioned above, one or two methylene groups can be, independently of one another, O, S, CO, SO₂Or NR^NInstead of this, the user can,

b represents tri- (C)_1-4-alkyl) silyl-C_1-6Alkyl radical, C_2-6-alkyn-1-yl, C_2-6-en-1-yl, amino, C_1-3Alkylamino, di- (C)_1-3-alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-3-one-4-yl, piperazin-1-yl, 4- (C)_1-3-alkyl) -piperazin-1-yl, arylcarbonylamino, heteroarylcarbonylamino, nitro, C_3-10Cycloalkoxy, C_5-10-Cycloalkenyloxy, C_3-10Cycloalkylthio radical, C_3-10-cycloalkylsulfinyl radical, C_3-10-cycloalkanesulfonyl group, C_5-10-Cycloalkenylthio group, C_5-10-Cycloalkenylsulfinyl group, C_5-10-cycloalkenesulfonyl, arylthio, arylsulfinyl, heteroarylthio or heteroarylsulfinyl,

the alkynyl and alkenyl radicals mentioned above may be mono-or disubstituted by identical or different radicals L1,

wherein said cycloalkyl and cycloalkenyl rings may be independently selected from fluoro and C_1-3The substituents of alkyl being mono-or disubstituted, and

R^Nrepresentation H, C_1-4Alkyl radical, C_1-4-alkylcarbonyl or C_1-4-an alkanesulfonyl group,

l1 are each independently selected from the group consisting of hydroxy, cyano, nitro, C_3-7Cycloalkyl, aryl, heteroaryl, C_1-4Alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, C_1-4Alkylaminocarbonyl, di- (C)_1-3-alkyl) -aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, C_1-4-alkoxycarbonyl, aryl-C_1-3-alkoxycarbonyl, heteroaryl-C_1-3-alkoxycarbonyl, C_1-4Alkoxy, aryloxy, heteroaryloxy, C_1-4Alkylthio, arylthio, heteroarylthio, C_1-4-alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, C_1-4Alkanesulfonyl, arylsulfonyl and heteroarylsulfonyl radicals, and

l2 are each independently selected from fluorine, chlorine, bromine, iodine, C_1-3Alkyl, difluoromethyl, trifluoromethyl, C_1-3Alkoxy, difluoromethoxy, trifluoromethoxy and cyano, and

R⁶、R^7a、

R^7b、R^7cindependently of one another, have the following meanings: hydrogen, (C)_1-18-alkyl) carbonyl, (C)_1-18-alkyl) oxycarbonyl, arylcarbonyl and aryl- (C)_1-3-an alkyl group) -a carbonyl group,

wherein aryl in the above definitions of radicals denotes phenyl or naphthyl, which may be mono-or disubstituted independently of one another by identical or different radicals L2, and

heteroaryl as mentioned in the above definition of radicals means pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl or tetrazolyl,

or pyrrolyl, furyl, thienyl or pyridyl, in which one or two methines may be replaced by a nitrogen atom,

or indolyl, benzofuranyl, benzothienyl, quinolinyl or isoquinolinyl, in which one to three methine groups can be replaced by nitrogen atoms,

wherein the above-mentioned heteroaryl groups may be mono-or disubstituted independently of one another by identical or different radicals L2,

wherein, unless otherwise stated, the above alkyl groups may be straight or branched,

tautomers, stereoisomers, mixtures thereof and salts thereof.

The compounds of the general formula I according to the invention and their physiologically acceptable salts have valuable pharmacological properties, in particular an inhibitory effect on the sodium-dependent glucose cotransporter SGLT, in particular SGLT 2. In addition, the compounds according to the present invention have an inhibitory effect on the sodium-dependent glucose cotransporter SGLT 1. The compounds of the present invention preferably selectively inhibit SGLT2 when compared to the possible inhibitory effect on SGLT 1.

The invention also relates to physiologically acceptable salts of the compounds according to the invention with inorganic or organic acids.

The invention also relates to pharmaceutical compositions comprising, in addition to at least one compound according to the invention or a physiologically acceptable salt according to the invention, optionally one or more inert carriers and/or diluents.

The invention also relates to the use of at least one compound according to the invention or one of its physiologically acceptable salts for the preparation of a pharmaceutical composition suitable for the treatment or prevention of a disease or condition affected by the inhibition of the sodium-dependent glucose cotransporter SGLT, in particular SGLT 2.

The invention also relates to the use of at least one compound according to the invention or one of its physiologically acceptable salts for the preparation of a pharmaceutical composition suitable for the treatment of metabolic disorders.

The invention also relates to the use of at least one compound according to the invention or one of its physiologically acceptable salts for the preparation of a pharmaceutical composition for the inhibition of the sodium-dependent glucose cotransporter SGLT, in particular SGLT 2.

The invention furthermore relates to a process for the preparation of the pharmaceutical compositions according to the invention, characterized in that the compounds according to the invention or one of their physiologically acceptable salts are added to one or more inert carriers and/or diluents on a non-chemical basis.

The invention also relates to a method for producing the compounds of the general formula I according to the invention, characterised in that

a) For the preparation of the compounds of the general formula I as defined above and below,

reacting a compound of formula II with a reducing agent in the presence of a Lewis or Bronsted acid, wherein any protecting groups present are cleaved off simultaneously or sequentially;

in the formula II

R' represents H, C_1-4Alkyl radicals, (C)_1-18-alkyl) carbonyl, (C)_1-18-alkyl) oxycarbonyl, arylcarbonyl and aryl- (C)_1-3-alkyl) -carbonyl, wherein the alkyl or aryl group may be mono-or polysubstituted with halogens,

R^8a、R^8b、

R^8c、R^8dindependently of one another with R being administered above or below⁶、R^7a、R^7b、R^7cOne of the radicals having the meaning of benzyl or R^aR^bR^cSi groups or ketal or acetal groups, in particular alkylene or aralkylene ketal groups or acetal groups; however, in each case, two adjacent R' s^8a、R^8b、R^8c、R^8dThe radicals may form cyclic ketal or acetal groups, or 1, 2-bis (C)_1-3-alkoxy) -1, 2-bis (C)_1-3-alkyl) -ethylene bridge, the above-mentioned ethylene bridge and the two oxygen atoms and the two carbon atoms to which the pyranose ring belongs, however, forming a substituted di-alkylAlkyl rings, especially 2, 3-dimethyl-2, 3-di (C)_1-3-alkoxy) -1, 4-bisAlkyl rings, and in which the alkyl, aryl and/or benzyl groups may be substituted by halogen or C_1-3Alkoxy is mono-or polysubstituted, and benzyl may also be di-substituted-(C_1-3-alkyl) amino substituted, and

R^a、R^b、R^cindependently of one another represent C_1-4Alkyl, aryl or aryl-C_1-3Alkyl, where the aryl or alkyl radical may be mono-or polysubstituted by halogen,

the aryl radicals mentioned in the above radical definitions mean, however, phenyl or naphthyl, preferably phenyl,

and wherein R is¹To R⁵And R⁶、R^7a、R^7b、R^7cAre as defined above and below,

or

b) To prepare a compound in which R is⁶、R^7a、R^7bAnd R^7cCompounds of formula I representing Hydrogen Compounds of formula III are hydrolyzed

Wherein R is^8a、R^8b、R^8c、R^8dAnd R¹To R⁵As defined above and below, except that R^8a、R^8b、R^8c、R^8dAt least one of the radicals being other than hydrogen, and

if necessary, the compound of formula (I) wherein R is to be obtained⁶A compound of the formula I representing a hydrogen atom, an acyl compound which is converted into the corresponding formula I by acylation, and/or

If desired, cleaving the protecting group used in any of the above reactions, and/or

If desired, the compounds of the general formula I thus obtained are separated into their stereoisomers and/or

If desired, the compounds of the general formula I thus obtained are converted into their salts, in particular into their physiologically acceptable salts for pharmaceutical use.

The invention further relates to a process for the preparation of compounds of the general formula II

Wherein

R^8a、R^8b、

R^8c、R^8dindependently of each other with administration of R⁶、R^7a、R^7b、R^7cOne meaning of the radicals represents benzyl or R^aR^bR^cSi groups or ketal or acetal groups; however, in each case, two adjacent R' s^8a、R^8b、R^8c、R^8dThe radicals may form cyclic ketal or acetal groups or may form substituted 2, 3-oxydi radicals with two oxygen atoms of the pyranose ringAlkyl rings, especially 2, 3-dimethyl-2, 3-di (C)_1-3-alkoxy) -1, 4-bisAlkyl rings, in which the alkyl, aryl and/or benzyl groups may be substituted by halogen or C_1-3-alkoxy is mono-or polysubstituted; and benzyl may also be di- (C)_1-3-alkyl) amino, and

R^a、R^b、R^cindependently of one another represent C_1-4Alkyl, aryl or aryl-C_1-3Alkyl, where the alkyl or aryl radical may be mono-or polysubstituted by halogen,

and R¹To R⁵、R⁶、R^7a、R^7b、R^7cAs defined above and below,

wherein the organometallic compound (V) can be obtained by halogen-metal exchange or by insertion of a metal into the carbon-halogen bond of the halogen-benzylbenzene compound of the general formula IV

Wherein Hal represents Cl, Br and I, and R¹To R⁵As defined above and below, and, if desired, subsequent transmetallation, on the gluconolactone of the formula VI

Wherein R is^8a、R^8b、R^8c、R^8dAs defined above and below, and

the adduct formed is then reacted (preferably in situ) with water or an R '-OH alcohol in the presence of an acid such as methanesulphonic acid, sulphuric acid, hydrochloric acid, acetic acid or ammonium chloride, wherein R' represents optionally substituted C_1-4The product obtained by reaction of an alkyl group, optionally with water, in which R 'represents H, is converted in a subsequent reaction with an acylating agent, for example the corresponding acid chloride or anhydride, in which R' represents (C)_1-18-alkyl) carbonyl, (C)_1-18-alkyl) oxycarbonyl, arylcarbonyl or aryl- (C)_1-3-alkyl) -carbonyl of formula II, which may be substituted as described above.

The intermediates, in particular of the formulae IV, II and III, are also subject matter of the present invention.

Detailed Description

Unless otherwise indicated, the radicals, residues and substituents, in particular R¹To R⁵、A、B、L1、L2、R^N、R⁶、R^7a、R^7b、R^7c、R^8a、R^8b、R^8c、R^8dAs defined above and below.

If the residue, substituent or group is present several times in a compound, they may have the same or different meanings.

According to the invention, glucopyranosyl-substituted benzene derivatives of the general formula I are preferred

Wherein

R¹Selected from the definitions of the radicals A, and if R³Selected from the definitions of radicals B, then R¹It is also possible to choose the following meanings additionally: hydrogen, fluorine, chlorine, bromine, iodine, C_1-4Alkyl radical, C_2-4-alkenyl-C_1-4Alkyl radical, C_2-4-alkynyl-C_1-4Alkyl radical, C_3-7-cycloalkyl-C_1-4Alkyl radical, C_5-7-cycloalkenyl-C_1-4Alkyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, C_1-4Alkoxy, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms, hydroxy or-C_1-3-alkoxy-substituted C_1-4Alkyl, via hydroxy or C_1-3-alkoxy-substituted C_2-4-alkoxy, C_3-6-cycloalkyl-C_1-3-an alkoxy group or a hydroxyl group,

however, in the cycloalkyl and cycloalkenyl rings mentioned above, 1 or 2 methylene groups may be replaced independently of one another by O or CO, and

R²represents hydrogen, fluorine, chlorine, bromine, hydroxyl group,C_1-4Alkyl radical, C_1-4Alkoxy, cyano or nitro, wherein the alkyl or alkoxy radical may be mono-or polysubstituted by fluorine, and

R³selected from the definitions of radicals B, and if R¹Selected from the definitions of group A, then R³It is also possible to choose the following meanings additionally: hydrogen, fluorine, chlorine, bromine, iodine, C_1-6Alkyl radical, C_2-4-alkenyl-C_1-4Alkyl radical, C_2-4-alkynyl-C_1-4Alkyl radical, C_3-7-cycloalkyl, C_5-7-cycloalkenyl radical, C_3-7-cycloalkyl-C_1-4Alkyl radical, C_5-7-cycloalkenyl-C_1-4Alkyl radical, C_3-6Cycloalkylidenemethyl, hydroxy, C_1-6-alkoxy, C_3-6-cycloalkyl-C_1-3Alkoxy, aryl-C_1-3Alkyl, heteroaryl-C_1-3Alkyl, aryloxy, aryl-C_1-3-alkyl-oxy, methyl or methoxy substituted by 1-3-fluorine atoms, C substituted by 1-5 fluorine atoms_2-4-alkyl or C_2-4Alkoxy, cyano-substituted C_1-4Alkyl, via hydroxy or C_1-3-alkoxy-substituted C_1-4Alkyl, cyano, carboxyl, C_1-3-alkoxycarbonyl, aminocarbonyl, (C)_1-3-alkylamino) carbonyl, di- (C)_1-3-alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-yl-carbonyl, 4- (C)_1-3-alkyl) -piperazin-1-yl-carbonyl, (C)_1-4-alkyl) carbonylamino, C_1-4-alkyl-sulfonylamino, C_1-4Alkylthio radical, C_1-4-alkylsulfinyl, C_1-4Alkanesulfonyl, arylsulfonylamino, aryl-C_1-3-an alkylsulfonamido or arylsulfonyl group,

R⁴、R⁵independently of one another, hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C_1-3Alkyl radical, C_1-3-alkoxy, methyl or methoxy substituted by 1 to 3 fluorine atoms,

a represents C_2-6-alkyn-1-yl, C_2-6-en-1-yl,C_3-7-cycloalkyl, C_5-7Cycloalkenyl, aryl, heteroaryl, C_1-4Alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, C_1-4Alkylaminocarbonyl, di- (C)_1-3-alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C)_1-4-alkyl) piperazin-1-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, C_1-4-alkoxycarbonyl, aryl-C_1-3-alkoxycarbonyl, heteroaryl-C_1-3-alkoxycarbonyl, amino, C_1-4Alkylamino, di- (C)_1-3-alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-3-one-4-yl, piperazin-1-yl, 4- (C)_1-3-alkyl) -piperazin-1-yl, C_1-4Alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C_3-7Cycloalkoxy, C_5-7Cycloalkenyloxy, aryloxy, heteroaryloxy, C_1-4-alkylsulfinyl, C_1-4-alkylsulfonyl, C_3-7Cycloalkylthio radical, C_3-7-cycloalkylsulfinyl radical, C_3-7-cycloalkanesulfonyl group, C_5-7-Cycloalkenylthio group, C_5-7-Cycloalkenylsulfinyl group, C_5-7-cycloalkenesulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, cyano or nitro,

wherein the aforementioned alkynyl and alkenyl groups may be mono-or disubstituted by the same or different radicals L1, and

b represents tri- (C)_1-4-alkyl) silyl-C_1-6Alkyl radical, C_2-6-alkyn-1-yl, C_2-6-en-1-yl, amino, C_1-3Alkylamino, di- (C)_1-3-alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-3-one-4-yl, piperazin-1-yl, 4- (C)_1-3-alkyl) -piperazin-1-yl, arylcarbonylamino, heteroarylcarbonylamino, nitro, C_3-7Cycloalkoxy, C_5-7-Cycloalkenyloxy, C_3-7Cycloalkylthio radical, C_3-7-cycloalkylsulfinyl radical, C_3-7-cycloalkanesulfonyl group, C_5-7-Cycloalkenylthio group, C_5-7-Cycloalkenylsulfinyl group, C_5-7-cycloalkenesulfonyl, arylthio, arylsulfinyl, heteroarylthio or heteroarylsulfinyl,

the cycloalkyl and cycloalkenyl radicals mentioned above may, independently of one another, be chosen from fluorine and C_1-3The substituents of alkyl being mono-or disubstituted, and

R^Nrepresents H or C_1-4-an alkyl group,

l1 are each independently selected from cyano, nitro, aryl, heteroaryl, C_1-4Alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, C_1-4Alkylaminocarbonyl, di- (C)_1-3-alkyl) -aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, C_1-4-alkoxycarbonyl, aryl-C_1-3-alkoxycarbonyl, heteroaryl-C_1-3-alkoxycarbonyl, C_1-4Alkoxy, aryloxy, heteroaryloxy, C_1-4Alkylthio, arylthio, heteroarylthio, C_1-4-alkylsulfinyl, arylsulfinylHeteroaryl sulfinyl, C_1-4Alkanesulfonyl, arylsulfonyl and heteroarylsulfonyl radicals, and

R⁶、R^7a、

R^7b、R^7cindependently of one another, are selected from the following meanings: hydrogen, (C)_1-18-alkyl) carbonyl, (C)_1-18-alkyl) oxycarbonyl, arylcarbonyl and aryl- (C)_1-3-an alkyl group) -a carbonyl group,

aryl in the above definitions of radicals means phenyl or naphthyl which may be mono-or disubstituted independently of one another by identical or different radicals L2 and

heteroaryl as mentioned in the above definition of radicals means pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothienyl, quinolinyl or isoquinolinyl,

or pyrrolyl, furyl, thienyl or pyridyl in which one or two methines are replaced by a nitrogen atom,

or indolyl, benzofuranyl, benzothienyl, quinolinyl or isoquinolinyl, in which one to three methine groups are replaced by nitrogen atoms,

however, the above-mentioned heteroaryl radicals may, independently of one another, be mono-or disubstituted by identical or different radicals L2,

wherein, unless otherwise stated, the above alkyl groups may be straight-chain or branched,

tautomers, stereoisomers, mixtures thereof and salts thereof.

The meanings of certain preferred individual radicals and substituents of the compounds according to the invention are given below.

R³The radical is preferably-CH₂The position of the bridges or pairs, and therefore the compounds according to the formulae I.1 and I.2 below,

particularly preferred is formula i.2:

at L1, R¹、R³The term aryl present in the groups A and B preferably denotes phenyl.

At L1, R¹、R³The term heteroaryl as present in groups A and B preferably denotes pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,Azolyl group,Oxadiazolyl, thiazolyl or thiadiazolyl.

The radical A preferably represents C_2-6-alkyn-1-yl, C_2-6-en-1-yl, C_3-7-cycloalkyl, C_5-7Cycloalkenyl radical, C_1-4-alkylcarbonyl, aminocarbonyl, C_1-4Alkylaminocarbonyl, di- (C)_1-3-alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C)_1-4-alkyl) piperazin-1-ylcarbonyl, C_1-4-alkoxycarbonyl, amino, C_1-4Alkylamino, di- (C)_1-3-alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-3-one-4-yl, piperazin-1-yl, 4- (C)_1-3-alkyl) piperazin-1-yl, C_1-4Alkanoylamino, C_3-7Cycloalkoxy, C_5-7-Cycloalkenyloxy, C_1-4-alkylsulfinyl, C_1-4-alkylsulfonyl, C_3-7Cycloalkylthio radical, C_3-7-cycloalkylsulfinyl radical, C_3-7-cycloalkanesulfonyl group, C_5-7-Cycloalkenylthio group, C_5-7-Cycloalkenylsulfinyl group, C_5-7Cycloalkenesulfonyl, cyano and nitro,

wherein the alkynyl and alkenyl groups may be mono-or polysubstituted with fluorine or chlorine, fluorine being preferred, and

the cycloalkyl and cycloalkenyl rings mentioned above may, independently of one another, be chosen from fluorine and C_1-3-alkyl substituents are mono-or disubstituted, and

in the cycloalkyl and cycloalkenyl rings mentioned above, one or two methylene groups can be, independently of one another, O, S, CO, SO₂Or NR^NInstead, O or CO is preferred, with O being particularly preferred.

Particularly preferably, the radical A represents C_2-6-alkyn-1-yl, C_2-6-en-1-yl, C_3-7-cycloalkyl, C_5-7Cycloalkenyl radical, C_3-7Cycloalkoxy, C_5-7-Cycloalkenyloxy, C_1-4-alkylsulfinyl, C_1-4-alkylsulfonyl, C_3-7Cycloalkylthio radical, C_3-7-cycloalkylsulfinyl radical, C_3-7-cycloalkanesulfonyl group, C_5-7-Cycloalkenylthio group, C_5-7-Cycloalkenylsulfinyl group, C_5-7Cycloalkenesulfonyl, cyano and nitro,

however, the abovementioned alkynyl and alkenyl radicals may be mono-or polysubstituted by fluorine or chlorine, fluorine being preferred, and

in the above-mentioned C_5-6In the cycloalkyl ring, methylene may be replaced by O.

Preferably, the radical A represents C_2-6-alkyn-1-yl, C_2-6-en-1-yl, C_3-7-cycloalkyl, C_3-7Cycloalkoxy, cyano, however, in C_5-7-one methylene unit of the cycloalkyl group can be replaced by O.

Examples of the definition of preferred A radicals are ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, cyano, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.

The radical B preferably represents tri- (C)_1-4-alkyl) silyl-C_1-6Alkyl radical, C_2-6-alkyn-1-yl, C_2-6-en-1-yl, amino, C_1-3Alkylamino, di- (C)_1-3-alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-3-one-4-yl, piperazin-1-yl, 4- (C)_1-3-alkyl) -piperazin-1-yl, nitro, C_3-7Cycloalkoxy, C_5-7-Cycloalkenyloxy, C_3-7Cycloalkylthio radical, C_3-7-cycloalkylsulfinyl radical, C_3-7-cycloalkanesulfonyl group, C_5-7-Cycloalkenylthio group, C_5-7-Cycloalkenylsulfinyl group, C_5-7-a cycloalkenylsulfonyl group,

in the cycloalkyl and cycloalkenyl rings mentioned above, one or two methylene groups can be, independently of one another, O, S, CO, SO₂Or NR^NInstead, O, CO, S, SO are preferred₂Or NR^NIn particular, O or CO substitution is also preferred.

Preferably, the radical B represents tri- (C)_1-4-alkyl) silyl-C_1-6Alkyl radical, C_2-6-alkyn-1-yl, C_2-6-en-1-yl, nitro, C_3-7Cycloalkoxy, C_5-7-Cycloalkenyloxy, C_3-7Cycloalkylthio radical, C_3-7-cycloalkylsulfinyl radical, C_3-7-cycloalkanesulfonyl group, C_5-7-Cycloalkenylthio group, C_5-7-Cycloalkenylsulfinyl group, C_5-7-a cycloalkenylsulfonyl group,

Preferably, the radical B represents tri- (C)_1-4-alkyl) silyl-C_1-6Alkyl radical, C_2-6-alkyn-1-yl, C_2-6-en-1-yl, C_3-7Cycloalkoxy, C_5-7-Cycloalkenyloxy, C_3-7Cycloalkylthio radical, C_3-7Cycloalkenylthio, however, the abovementioned alkynyl and alkenyl radicals may be mono-or polysubstituted by fluorine or mono-substituted by chlorine or the radical L1; and in cycloalkyl and cycloalkenyl, one or two methylene groups can be, independently of one another, O, S, CO, SO₂Or NR^NInstead, O or CO is preferred.

Examples of preferred definitions of group B are trimethylsilylethyl, ethynyl, 1-propyn-1-yl, 1-butyn-1-yl, tert-butylethynyl, 2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl, 3-hydroxy-1-propyn-1-yl, 3-methoxyprop-2-ylethynyl1-propyn-1-yl, vinyl, 1-propenyl, 1-butenyl, tert-butylvinyl, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuryloxy, tetrahydrothiophenyloxy, 1-dioxotetrahydrothiophenyloxy, tetrahydropyranyloxy, tetrahydrothiopyrayloxy, 1-dioxotetrahydrothiopyrayloxy, tetrahydrofuronyloxy, piperidinyloxy, pyrrolidin-3-yloxy, tetrahydrofuranyl-thio, cyclopropylthio, cyclobutylthio, cyclopentylthio and cyclohexylthio, wherein the-NH group in the piperidinyl, piperidinonyl, pyrrolidinyl or pyrrolidinonyl ring may be interrupted by R^NIn particular C_1-3-alkyl or acetyl substitution.

Preferred meanings are trimethylsilylethyl, ethynyl, 2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl, 3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy and N-acetylpiperidin-4-yloxy. Examples which may be mentioned in particular are ethynyl, trimethylsilylethyl, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran-3-yloxy and tetrahydropyran-4-yloxy.

If at residue or A, B, R¹Or R³In which two methylene groups are present through O, S, NR^NSubstituted or via S, NR^NCO, SO or SO₂When an alternative cycloalkyl or cycloalkenyl ring is used, then these methylene groups are preferably not directly linked to one another. However, if the two methylene groups are via O and CO or via NR^NWhen replaced by CO, these may then be linked directly to one another to form an-O-CO-or-NR^N-a CO group.

Preferred meanings of the group L1 are selected from the group consisting of hydroxy, cyano, C_3-6-cycloalkyl, C_1-4-alkylcarbonyl, aminocarbonyl, C_1-4Alkylaminocarbonyl, di- (C)_1-3-alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonylBase, C_1-4-alkoxycarbonyl, C_1-4-alkoxy, C_1-4Alkylthio radical, C_1-4-alkylsulfinyl with C_1-4-an alkylsulfonyl group.

Preferred meanings of the group L1 are selected from the group consisting of hydroxy, C_1-4Alkoxy radical and C_1-4-alkylthio.

If L1 represents a hydroxyl group, the hydroxyl group is not directly connected to a double or triple bonded C atom.

The compounds according to the first embodiment of the invention can be illustrated by the general formula I, in particular the formulae I.1 and I.2, particularly preferably the formula I.2, where

R³Selected from one of the definitions of radicals B given above, and

the other groups and substituents are as defined above and below,

including tautomers, stereoisomers, mixtures thereof and salts thereof.

According to this embodiment, R¹Preferred meanings of radicals are hydrogen, fluorine, chlorine, bromine, iodine, C_1-4Alkyl radical, C_2-6-alkynyl, C_1-4-alkoxy, C_2-4-alkenyl-C_1-4-alkoxy, C_2-4-alkynyl-C_1-4Alkoxy, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms, hydroxy or C_1-3-alkoxy-substituted C_1-4Alkyl, via hydroxy or C_1-3-alkoxy-substituted C_2-4-alkoxy, C_2-6-alkenyl, C_3-6-cycloalkyl, C_3-6-cycloalkyl-C_1-3Alkyl radical, C_3-7Cycloalkoxy, C_3-6-cycloalkyl-C_1-3-alkoxy, C_5-7Cycloalkenyloxy, hydroxy, amino, nitro or cyano, also at C_5-6-the methylene group in the cycloalkyl group may be replaced by O.

Preferred meanings are hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, hydroxy, methoxy, ethoxy, difluoromethoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, in particular methyl and chlorine.

The compounds according to the second embodiment of the invention can be illustrated by the general formula I, in particular the formulae I.1 and I.2, particularly preferably the formula I.2, where

R¹Selected from the group defined for group A given above, and

the other groups and substituents are as defined above and below,

including tautomers, stereoisomers, mixtures thereof and salts thereof.

According to this second embodiment, R³Preferred meanings of radicals are hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, C_1-6Alkyl, trimethylsilylethyl, C_2-6-alkenyl, C_2-6-alkynyl, difluoromethyl, trifluoromethyl, C_3-7-cycloalkyl, C_5-7-cycloalkenyl radical, C_1-6Alkoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, C_3-7Cycloalkoxy, tetrahydrofuroxy, tetrahydrofurketoxyo, C_1-6Alkylthio, cyclopropylmethylene, aryl or heteroaryl.

According to this second embodiment, R³Particularly preferred meanings of radicals are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, ethynyl, 1-propynyl, trimethylsilylethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, cyclopentyloxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-on-3-yloxy, methylthio, ethylthio, isopropylthio, cyclopropylmethyl, phenyl, fluorophenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, trifluoromethyl, cyclopentyl, methoxy, ethoxy, isopropoxy, cyclopentyloxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, tetrahydrofuranyl-3-yloxy, tetrahydrofuranyl-2-on-3-yloxy, methylthio, isopropylthio, cyclopropylmethyl, phenyl, fluorophenyl, pyridyl,azolyl group,Oxadiazolyl, thiazolyl or thiadiazolyl.

According to this second embodiment, R³The most preferred meaning of radicals is hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, ethynyl, 1-propynyl, trimethylsilylethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, cyclopentyloxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-on-3-yloxy, methylthio, ethylthio, isopropylthio, cyclopropylmethyl. Examples of such preferred meanings are methyl, ethyl, methoxy, ethoxy, trimethylsilylethyl, ethynyl, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-on-3-yloxy, in particular trimethylsilylethyl, ethoxy, cyclopentyloxy and tetrahydrofuran-3-yloxy.

The meanings of the other radicals and substituents are given below, according to the general formula I, the formulae I.1 and I.2, and also according to the preferred embodiments described above:

R²preferred meanings of radicals are hydrogen, fluorine, chlorine, bromine, methyl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, cyano, nitro and methyl substituted by 1 to 3 fluorine atoms.

R²Preferred meanings of radicals are hydrogen, fluorine, hydroxyl, methoxy, ethoxy and methyl, in particular hydrogen and methyl.

R⁴Preferred meanings of radicals are hydrogen and fluorine, in particular hydrogen.

R⁵Preferred meanings of radicals are hydrogen and fluorine, in particular hydrogen.

R^NThe radical preferably represents H, methyl, ethyl or acetyl.

R⁶According to the invention, preferably hydrogen, (C)_1-8-alkyl) oxycarbonyl, C_1-8-alkylcarbonyl or benzoyl, especially hydrogen or (C)_1-6-alkyl) oxycarbonyl, C_1-6Alkylcarbonyl, in particular hydrogen, methylcarbonyl, methoxycarbonyl or ethoxycarbonyl, most preferably hydrogen or methoxycarbonyl.

Substituent R^7a、R^7b、R^7cPreferably represents hydrogen, (C) independently of one another_1-8-alkyl) oxycarbonyl, (C)_1-18-alkyl) carbonyl, benzoyl, especially hydrogen or (C)_1-6-alkyl) oxycarbonyl, (C)_1-8-alkyl) carbonyl, preferably hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl. Most preferably, R^7a、R^7b、R^7cRepresents hydrogen.

Wherein R is⁶、R^7a、R^7b、R^7cAccording to the invention having, for example, C_1-8Compounds of the formula I in a meaning other than hydrogen of the alkylcarbonyl group are suitable as syntheses in which R^7a、R^7b、R^7cIntermediates of compounds of formula I which represent hydrogen.

Preferred compounds of formula I are selected from formulae i.2a to i.2d, in particular i.2c:

wherein R is¹To R⁶And R^7a、R^7b、R^7cThe radicals have one of the meanings stated above, in particular as having one of the meanings preferably given, and in particular

R¹Represents hydrogen, fluorine, chlorine, bromine, iodine, C_1-4Alkyl radical, C_2-6-alkynyl, C_1-4-alkoxy, C_2-4-alkenyl-C_1-4-alkoxy, C_2-4-alkynyl-C_1-4Alkoxy, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms, hydroxy or C_1-3-alkoxy-substituted C_1-4Alkyl, via hydroxy or C_1-3-alkoxy-substituted C_2-4-alkoxy, C_2-6-alkenyl, C_3-6-cycloalkyl, C_3-6-cycloalkyl-C_1-3Alkyl radical, C_3-7Cycloalkoxy, C_3-6-cycloalkyl-C_1-3-alkoxy, C_5-7Cycloalkenyloxy, hydroxy, amino, nitro or cyano, and also, at C_5-6-in cycloalkyl, methylene may be replaced by O; particularly preferably represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, hydroxy, methoxy, ethoxy, difluoromethoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy or cyclohexyloxy, and

R²represents hydrogen, fluorine, hydroxyl, methoxy, ethoxy or methyl, in particular hydrogen or methyl, and

R³selected from the group B consisting of trimethylsilylethyl, ethynyl, 1-propyn-1-yl, 1-butyn-1-yl, tert-butylethynyl, 2-hydroxypropan-2-ylethynyl, 2-methoxyprop-2-ylethynyl, 3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, ethenyl, 1-propenyl, 1-butenyl, tert-butylethenyl, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuryloxy, tetrahydrothiophenyloxy, 1-dioxotetrakisHydrothienyloxy, tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1-dioxotetrahydrothiopyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pyrrolidin-3-yloxy, tetrahydrofuranylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio and cyclohexylthio; wherein-NH in the piperidinyl, piperidonyl, pyrrolidinyl or pyrrolidinonyl ring may be via R^NIn particular C_1-3-alkyl or acetyl; particularly preferably from the group consisting of trimethylsilylethyl, ethynyl, 2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl, 3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy and N-acetylpiperidin-4-yloxy, and

R⁴represents hydrogen or fluorine, in particular hydrogen, and

R⁵represents hydrogen or fluorine, in particular hydrogen, and

R⁶represents hydrogen, (C)_1-6-alkyl) oxycarbonyl, (C)_1-6-alkyl) carbonyl or benzoyl, especially hydrogen, methylcarbonyl, methoxycarbonyl or ethoxycarbonyl, particularly preferably hydrogen, and

R^7a、R^7b、R^7cindependently of one another, represents hydrogen, (C)_1-6-alkyl) oxycarbonyl, (C)_1-8-alkyl) carbonyl or benzoyl, especially hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl, particularly preferably hydrogen,

including tautomers, stereoisomers, mixtures thereof and salts thereof.

According to variants of the embodiments given above, further, also preferred compounds are those in which the substituent R is present³The phenyl radical of (A) having at least one other substituent R which is different from hydrogen⁴And/or R⁵. According to this variant, preferably the compound is a compound of formula (I)With substituents R representing fluorine⁴In (1).

With substituents R³The phenyl groups of (a) are preferably at most monofluorinated.

The compounds of the formula I, and in which R is⁶Having the meaning according to the invention other than hydrogen, in particular wherein R⁶Derivatives of the compounds of the general formula I which represent ethoxycarbonyl or methoxycarbonyl, including tautomers, stereoisomers and mixtures thereof, are preferred according to the invention.

Preferably the compound of formula I is selected from:

(1) 1-chloro-2- (4-cyclopentyloxybenzyl) -4- (. beta. -D-glucopyranos-1-yl) -benzene

(2) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- ((R) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene

(3) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene

(4) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- (tetrahydrofuran-2-one-3-yloxy) -benzyl ] -benzene

(5) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- (4-cyclobutoxy-benzyl) -benzene

(6) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- (4-cyclohexyloxy-benzyl) -benzene

(7) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- (tetrahydropyran-4-yloxy) -benzyl ] -benzene

(8) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- (1-acetyl-piperidin-4-yloxy) -benzyl ] -benzene

(10)1- (beta-D-glucopyranos-1-yl) -4-methyl-3- [4- (tetrahydrofuran-3-yloxy) -benzyl ] -benzene

(11)1- (. beta. -D-glucopyranos-1-yl) -4-methyl-3- [4- (2-trimethylsilyl-ethyl) -benzyl ] -benzene

(12) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) -benzene

(13) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- (piperidin-4-yloxy) -benzyl ] -benzene

(14) 1-fluoro-4- (beta-D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) -benzene

(15)1- (beta-D-glucopyranos-1-yl) -3- (4-ethynyl-benzyl) -benzene

(16) 1-ethynyl-4- (beta-D-glucopyranos-1-yl) -2- (4-ethoxy-benzyl) -benzene

(17) 1-methoxy-4- (beta-D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) -benzene

And derivatives thereof, wherein R⁶Having the meaning according to the invention other than hydrogen, in particular wherein R⁶Represents an ethoxycarbonyl group or a methoxycarbonyl group,

including tautomers, stereoisomers, and mixtures thereof.

In the process according to the invention, R¹、R²、R³、R⁴And R⁵The radicals preferably have the meanings indicated above as preferred. Moreover, R' preferably represents H, C_1-3-alkyl or benzyl, in particular H, ethyl or methyl. R^8a、R^8b、R^8c、R^8dPreferably H, C independently of one another_1-4Alkylcarbonyl or benzyl, in particular H, methylcarbonyl, ethylcarbonyl or benzyl.

Compounds of the formula IV, in particular of the formula IV', are used as intermediates or starting materials in the synthesis of the invention

Wherein Hal represents chlorine, bromine or iodine, and R¹、R²、R⁴And R⁵As defined above and R³Selected from B radicals, which are also the present inventionThe subject matter of the invention is described. Preferably, R is¹、R²、R³、R⁴And R⁵The groups have the meanings given in formulae I.2a to I.2d. Most preferred are compounds of the formula IV' in which Hal represents chlorine, bromine or iodine and R¹、R²、R⁴And R⁵Having the meaning given in formulae I.2a to I.2d, and R³The radicals being ethynyl or C_3-6-1-alkyn-1-yl, wherein ethynyl may be via-SiR₃Substituted by radicals, the radicals R however being, independently of one another, C_1-4Alkyl radical, C_1-4Alkoxy or aryl, and the C_3-6The-1-yn-1-yl radical may be via hydroxyl or C_1-3-alkoxy, in particular hydroxy or methoxy.

The invention also relates to compounds of the formula II, in particular of the formula II', as intermediates or starting materials for the synthesis of the compounds according to the invention

Wherein R' and R^8a、R^8b、R^8c、R^8d、R¹、R²、R³、R⁴And R⁵As defined hereinbefore and hereinafter, in particular wherein R' represents H, C_1-3-alkyl or benzyl, in particular H, ethyl or methyl; and R is^8a、R^8b、R^8c、R^8dAre represented H, C independently of each other_1-4-alkylcarbonyl or benzyl; in particular H, methylcarbonyl, ethylcarbonyl or benzyl and R¹、R²、R⁴And R⁵Is as defined above, and R³The radicals are selected from the B radicals. Preferably, R¹、R²、R³、R⁴And R⁵The groups have the meanings given in formulae I.2a to I.2d.

Certain terms used above and below to describe the compounds according to the invention are defined more precisely below.

The term halogen denotes an atom selected from the group consisting of F, Cl, Br and I, in particular F, Cl and Br.

C_1-nThe term alkyl, where n has a value of 1 to 18, denotes a saturated, branched or straight-chain hydrocarbon radical having 1 to n C atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl and the like.

C_2-n-alkynyl, wherein n has a value of 3 to 6, denotes a branched or straight chain hydrocarbon radical having 2 to n C atoms and one C ≡ C triple bond. Examples of such radicals include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. Unless otherwise indicated, alkynyl is attached to the rest of the molecule via the C atom in position 1. Thus, for example, the terms 1-propynyl, 2-propynyl, 1-butynyl, and the like are equivalent to 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, and the like. This also applies analogously to C_2-n-alkenyl.

C_1-nThe term alkoxy represents C_1-n-alkyl-O-group, wherein C_1-n-alkyl is as defined above. Examples of such radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy, isohexoxy and the like.

C_1-nThe term alkylcarbonyl denotes C_1-n-alkyl-C (= O) group, wherein C is_1-n-alkyl is as defined above. Examples of such radicals include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl and the like.

C_3-nThe term cycloalkyl denotes a group havingSaturated mono-, di-, tri-or spirocarbonyl cyclic groups having 3 to n C atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1 ] n]Octyl, spiro [4.5 ]]Decyl, norpinyl (norpinyl), norbornyl (Norbony), norisocyanyl (norcarnyl), adamantyl, and the like. Preferably, C_3-7The term cycloalkyl denotes a saturated monocyclic group.

C_5-nThe term cycloalkenyl denotes C as defined above_5-n-cycloalkyl, and additionally having at least one unsaturated C = C double bond.

C_3-nThe term cycloalkanecarbonyl represents wherein C_3-n-cycloalkyl is C as defined above_3-n-cycloalkyl-C (= O) group.

Tri- (C)_1-4The term alkyl) silyl includes silyl groups having identical or two or three different alkyl groups.

Di- (C)_1-3-alkyl) amino includes amino groups having identical or two different alkyl groups.

The forms used above and below, wherein the bond of a substituent in a phenyl group is indicated as being towards the centre of the phenyl ring, unless otherwise indicated, this substituent may be bound to any free position of the phenyl ring bearing an H atom.

The compounds according to the invention can be obtained by synthetic methods known in principle. Preferably, the compounds are obtained according to the following process which is described in more detail according to the invention.

The glucose derivatives of formula II according to the present invention can be synthesized from D-gluconolactone or its derivatives by adding the desired benzylbenzene compound in the form of an organometallic compound (scheme 1).

Scheme 1: addition of organometallic compounds to gluconolactones

The reaction according to scheme 1 preferably starts from a halogen-benzylbenzene compound of the general formula IV wherein Hal represents chlorine, bromine or iodine. Starting from the haloaromatic compound IV, the corresponding organometallic compounds (V) are prepared by so-called halogen-metal exchange or by insertion of a metal into a carbon-halogen bond. When this halogen-metal exchange is carried out with bromine-or iodine-substituted aromatic radicals, it is possible to react with organolithium compounds, for example n-, sec-or tert-butyllithium, and thus to produce the corresponding lithiated aromatic radical. Similar magnesium compounds can also be produced by halogen-metal exchange with appropriate Grignard compounds such as isopropylmagnesium bromide or diisopropylmagnesium. The reaction is preferably carried out in an inert solvent such as diethyl ether, tetrahydrofuran, toluene, hexane or dichloromethane or mixtures thereof at from 0 to-100 ℃ and particularly preferably at from-10 to-80 ℃. Thus, the resulting magnesium or lithium compound can optionally be transmetalated with a metal salt such as cerium trichloride to form an organometallic compound (V) suitable for addition. Alternatively, the organometallic compound (V) can be prepared by inserting a metal into the carbon-halogen bond of the haloaromatic compound IV. Suitable metals here are, for example, lithium or magnesium. Addition of the organometallic compound V to the gluconolactone or derivative thereof of the formula VI preferably in an inert solvent or a mixture thereof, is carried out at a temperature of between 0 and-100 ℃ and particularly preferably between-30 and-80 ℃ to give the compound of the formula II. To avoid low temperatures, the lithiation and/or coupling reactions may also be carried out in microreactors and/or micromixers, for example analogously to the process described in WO 2004/076470.

Suitable solvents are, for example, diethyl ether, toluene, dichloromethane, hexane, tetrahydrofuran or mixtures thereof. The reaction may be carried out without any additional adjuvant or may be carried out with, for example, BF₃*OEt₂Or Me₃In the presence of a coupling partner which is inert to the reaction, under the action of a Lewis acid in SiCl (cf. M.Schlosser, Organometallics in Synthesis, John Wiley&Sons,Chichester/New York/Brisbane/Toronto/Singapore,1994)。R^8a、R^8b、R^8c、R^8dMore preferred definitions of radicals are benzyl, substituted benzyl, trialkylsilyl, particularly preferably trimethylsilyl, triisopropylsilyl, 4-methoxybenzyl and benzyl. If from R^8a、R^8b、R^8c、R^8dWhen two adjacent radicals of (a) are linked to each other, then the two radicals are preferably part of benzylidene acetal, 4-methoxybenzylidene acetal, isopropyl ketal or form a 2, 3-dimethoxy-butenyl radical which is linked to the adjacent pyranose ring oxygen atom via the 2 and 3 positions of the butane. The radical R' is preferably hydrogen or C_1-4Alkyl, particularly preferably hydrogen, methyl or ethyl. The R' group is inserted after addition of the organometallic compound V or a derivative thereof to gluconolactone VI. For this purpose, the reaction solution is treated with an alcohol such as methanol or ethanol or water in the presence of an acid such as methanesulfonic acid, toluenesulfonic acid, sulfuric acid or hydrochloric acid.

The synthesis of the haloaryl compounds of formula IV can be carried out using standard transformations of Organic chemistry, or at least by methods of the specialist literature known for Organic synthesis (cf. J. March, Advanced Organic Reactions, Mechanisms, and Structure, 4. the present invention is not limited to the examples given in this application^thEdition,John Wiley&Sons, Chichester/New York/Brisbane/Toronto/Singapore,1992, and references cited therein). The synthetic strategies described below are representative examples.

Scheme 2: synthesis strategy 1

Synthetic strategy 1 (scheme 2) shows the preparation of a halogenated aryl compound of formula II starting from benzoyl chloride and a second aromatic group, which is converted to a diphenyl ketone derivative by Friedel-CRafts acylation. The classical reaction, with a wide substrate extension, is carried out using, for example, AlCl₃、FeCl₃Iodine, iron, ZnCl₂Sulfuric acid orThe reaction is carried out under the condition of catalytic amount or chemical amount of catalyst of the trifluoromethane sulfonic acid. In addition to carboxylic acid chlorides, it is also possible to use carboxylic acids, anhydrides or esters thereof or the corresponding benzonitrile. The reaction is carried out at a temperature of-30 to 120 ℃, preferably 30 to 100 ℃, preferably in a chlorinated hydrocarbon such as dichloromethane and 1, 2-dichloroethane. The reaction can also be carried out without solvent or in a microwave oven. In a second reaction step, the diphenyl ketone is reduced to diphenylmethane. The reaction may be carried out in two steps, or in only one step, with the corresponding benzhydrol. In a two-step variant, use is made, for example, of NaBH₄、LiAlH₄Or iBu₂The metal hydride reducing agent of AlH performs the reduction of the ketone to form the alcohol. Subjecting the resulting alcohol to reaction in the presence of, for example, BF₃*OEt₂Trifluoroacetic acid, InCl₃Or AlCl₃In the presence of a Lewis acid of (2), using, for example, Et₃SiH、NaBH₄Or Ph₂The reducing agent of SiClH is converted to form the desired diphenylmethane. One-step process for obtaining diphenylmethane starting from a ketone may use, for example, Et₃SiH silanes, e.g. NaBH₄Of boron hydrides or of LiAlH, for example₄In the presence of an aluminium hydride such as BF₃*OEt₂Tris (pentafluorophenyl) -borane, trifluoroacetic acid, aluminum chloride or InCl₃In the presence of a Lewis acid of (a). The reaction is preferably carried out in a solvent such as a halogenated hydrocarbon of methylene chloride, toluene or acetonitrile at-30 to 150 ℃, preferably 20 to 100 ℃. The reduction with hydrogen in the presence of a transition metal catalyst such as Pd/C is also a possible synthesis method. Reduction according to Wolff-Kishner, or variants thereof, are also possible. The ketone and hydrazine or a derivative thereof, such as 1, 2-bis (tert-butyldimethylsilyl) hydrazine, are first converted to hydrazonone which decomposes under strongly basic reaction conditions and with heating to diphenylmethane and nitrogen. The reaction may be carried out in one reaction step or after isolation of the hydrazono or its derivative, in two separate reaction steps. Using suitable bases including KOH, NaOH, KOtBu, in e.g. ethylene glycol, toluene, DMSO, 2- (2-butoxyethoxy) ethanol or tert-butanolIs carried out in a solvent; reactions without solvent are also possible. The reaction can be carried out at a temperature of 20 to 250 ℃, preferably 80 to 200 ℃. An alternative to alkaline reduction conditions for Wolff-Kishner is the Clemmensen reduction carried out under acidic conditions, the latter also being possible for use herein.

Scheme 3: synthesis strategy 2

The second synthetic strategy (scheme 3), showing another possibility for constructing the halo-aromatic group of formula II', is an example of trimethylsilylacetylene substituted diphenylmethane. Starting from an aromatic radical bearing two sulfonic acid esters selected from iodine, bromine, chlorine or, for example, trifluoromethyl sulfonate, the transition metal catalyzed mono-coupling is attached to the reactive end of the dihaloaromatic compound, i.e., the iodine-carbon bond plus the alkynyl group (step 1). The catalysts used are, for example, elemental palladium or nickel or salts or complexes thereof. The reaction may be carried out with the alkyne itself or its metal isoacetylene (acetylidene). If the alkyne itself is used, the coupling may be effected, for example, in the presence of NEt₃In the presence of a co-catalyst of a copper salt, such as CuI (Sonogashira coupling). The reaction is not limited to trimethylsilylacetylene, but a number of terminal alkynes may be used. The reaction is described in detail in the literature as all its variants (cf. P.J.Stang, F.Diederich, Metal-catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim,1997 and Angew. chem. int. Ed.2003,42, 1566-containing 1568 and the references cited therein). An additional two steps for the preparation of diphenylmethane derivatives include the transfunctionalization of alkyne-substituted aryl groups to obtain metalated (Mg, Li) aryl groups, as can be illustrated, for example, by the halogen-metal exchange described above (step 2). The metalated aromatic compound, which may be used as such or after further transmetallization, is added to the benzaldehyde derivative. The benzhydrol shown in the scheme is formed. Alternatively, it is also possible to use benzoic acid derivatives such as, for example, the esters, anhydrides, chlorides orThe acid itself or the benzonitrile. Instead of the alcohol, the corresponding ketone is formed, which can also be obtained by the Friedel-Crafts acylation described above. The further reaction of the alcohol with the ketone to form the diphenylmethane derivative has been described above (step 3). However, the trimethylsilylacetylated haloaromatic compound may also be converted directly to the desired product after transmetallization (step 4). For this purpose, the lithium or magnesium aromatics obtained after the halogen metal exchange are reacted with benzylic electrophiles, such as benzylic bromide or chloride. The reaction can be carried out in the absence, or preferably in the presence, of a transition metal catalyst such as a copper salt or palladium complex (see, for example, org. Lett.2001,3,2871-2874, and references cited therein). However, it is also possible for the aromatic lithium or magnesium to be first metallised to the corresponding boronic acid, boronic ester, stannane, silane or zinc compound, for example. It is then linked to the benzyl group by means of a Transition metal, for example palladium, nickel, rhodium, copper or iron (cf. L.Brandsma, S.F.Vasilevsky, H.D.Verkruijsse, Application of Transition Metals Catalysts in Organic Synthesis, Springer-Verlag, Berlin/Heidelberg, 1998). Conversion of the alkyne-substituted aromatic into an intermediate product of the formula II' according to Steps 2 and 3 or step 4, herein denoted by R³Examples of ethynyl or trimethylsilylethynyl are illustrated, and other R's can be made using similar methods³-substituted aromatic.

Scheme 4: synthesis strategy 3

Synthetic strategy 3 (scheme 4) shows an additional version of synthetic strategy 2, which is also illustrated by the example with trimethylsilylacetylene aromatic II', but should not be limited thereto. The synthesis is from a halo group bearing a halogen atom such as chlorine, bromine or iodine, or a pseudohalo group such as trifluoromethanesulfonate; and for example B (OH)₂、Si(OAlK)₃Or SnBu₃The aromatic group of the metal center M of (a). These two so-called "activated" centers, can be chemically selectedAre exchanged with each other. Synthetic strategy 3 is illustrated by an example, in which first the halogen atom Hal is exchanged with an alkyne substituent in a transition metal catalyzed reaction, the so-called Sonogashira coupling. In a second step, this metal centre M is exchanged for an activated benzyl group, for example as benzyl halide, in a further transition metal catalysed coupling reaction to give the desired product (cf. for example Tetrahedron Lett.2003,44,9255-9258 and the references cited therein). Both steps are carried out using a transition metal, such as palladium, rhodium, nickel, copper or iron or a complex thereof. Both of these reaction types are described in detail in the literature. The method is not limited to that described herein, but it is also possible to reverse the order of the two reaction steps. In this case, the metal center M is first linked to a benzyl group, and then the halogen or pseudohalogen Hal is exchanged with an alkyne.

For the preparation of the compounds of the formula I, in the process a) according to the invention, compounds of the formula II

Wherein R' and R¹To R⁵As defined above and

R^8a、R^8b、R^8c、R^8das defined above and independently of one another, for example acetyl, pivaloyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, trialkylsilyl, benzyl or substituted benzyl; or in individual cases two adjacent R^8a、R^8b、R^8c、R^8dThe radicals forming benzylidene acetals or isopropylidene ketals, or 2, 3-dimethoxy-butenyl radicals linked to the pyranose ring oxygen atom via the 2 and 3 positions of the butenyl radical, and forming substituted di-butenyl radicals therewithAn alkane, which is a mixture of at least one of,

it can be obtained as described above, by reaction with a reducing agent in the presence of a Lewis or Bronsted acid.

Suitable reducing agents for this reaction include, for example, silanes such as triethyl-, tripropyl-, triisopropyl-or diphenyl-silane, sodium borohydride, sodium cyanoborohydride, zinc borocyanide, borane, lithium aluminum hydride, diisobutylaluminum hydride or samarium iodide. The reduction is carried out in the absence or presence of a suitable Bronsted acid such as hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid or acetic acid, or a Lewis acid such as boron trifluoride etherate, trimethylsilyl trifluoromethanesulfonate, titanium tetrachloride, tin tetrachloride, scandium trifluoromethanesulfonate or zinc iodide. Depending on the reducing agent and the acid, the reaction can be carried out at a temperature of between-60 ℃ and 120 ℃ in, for example, dichloromethane, chloroform, acetonitrile, toluene, hexane, diethyl ether, tetrahydrofuran, dioxaneAlkane, ethanol, water or a mixture thereof. One particularly suitable reagent composition comprises, for example, triethylsilane and boron trifluoride etherate, which is conveniently used in acetonitrile or dichloromethane at temperatures of-60 ℃ to 60 ℃. Alternatively, the conversion may be carried out using hydrogen in a solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, water or acetic acid in the presence of a transition metal catalyst such as Pd/C or Raney nickel.

Alternatively, for the preparation of the compounds of the formula I according to the invention according to step b) of the invention, the compounds of the formula III

Wherein R is¹To R⁵As defined above and

R^8ato R^8dRepresents a protecting group as defined above, such as an acyl group, an arylmethyl group, an acetal, a ketal or a silyl group; also, it may be, for example, made up ofThe compound of formula II is obtained by reduction and the protecting group is cleaved off.

Any acyl-protecting group used is in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or in the aprotic presence of trimethylsilyliodide, at a temperature of between 0 and 120 deg.C, preferably at a temperature of between 10 and 100 deg.C, for example in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or bisCleaved by hydrolysis in an aqueous solvent of alkane/water. The trifluoroacetyl group is cleaved off preferably by treatment with an acid such as hydrochloric acid at a temperature of between 50 and 120 ℃, optionally in the presence of a solvent such as acetic acid; or cleaved off by treatment with sodium hydroxide solution at a temperature between 0 and 50 ℃, optionally in the presence of a solvent such as tetrahydrofuran or methanol.

The acetal or ketal protecting groups used are in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or an aprotic acid such as iodotrimethylsilane at a temperature of between 0 and 120 ℃, preferably 10 to 100 ℃, in an aqueous solvent such as water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or bis (methyl) ethyl acetateThe alkane/water is hydrolyzed and cracked.

The trimethylsilyl group is cleaved off, for example, in water, aqueous solvent mixtures or lower alcohols such as methanol or ethanol in the presence of bases such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methoxide. In aqueous or alcoholic solvents, acids such as hydrochloric acid, trifluoroacetic acid or acetic acid are also suitable. For cleavage in organic solvents such as diethyl ether, tetrahydrofuran or dichloromethane, it is also suitable to use fluoride reagents such as tetrabutylammonium fluoride.

The benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageously cleaved off by hydrogen, for example in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, with hydrogen in the presence of a catalyst such as Pd/C, optionally with addition of an acid such as hydrochloric acid, at a temperature of from 0 to 100 ℃, preferably at room temperature of from 20 to 60 ℃ and under a hydrogen pressure of from 1 to 7bar, but preferably from 3 to 5 bar. However, the 2, 4-dimethoxybenzyl group is preferably cleaved off in trifluoroacetic acid in the presence of anisole.

The tert-butyl or tert-butoxycarbonyl group is cleaved off preferably by acid treatment, for example with trifluoroacetic acid or hydrochloric acid, or by treatment with iodotrimethylsilane; optionally using, for example, dichloromethane, bisAlkane, methanol or ether.

In the reactions described above, any reactive groups present, for example ethynyl, hydroxyl, amino, alkylamino or imino, can be protected during the reaction by customary protecting groups and cleaved off again after the reaction.

For example, the protecting group for the ethynyl group may be trimethylsilyl or triisopropyl. 2-hydroxyisopropyl-2-yl can likewise be used as a protecting group.

For example, the protecting group for a hydroxyl group may be trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl.

The protecting group for amino, alkylamino or imino can be, for example, formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2, 4-dimethoxybenzyl.

Furthermore, as described above, the compound of formula I obtained may be resolved into its enantiomers and/or diastereomers. Thus, for example, a cis/trans mixture can be resolved into its cis and trans isomers; furthermore, compounds having at least one optically active carbon atom can be separated into their enantiomers.

Thus, for example, the resulting cis/trans mixture can be resolved by chromatography into its cis and trans isomers, and the resulting compounds of the formula I, in the form of racemic mixtures, can be separated into their optical enantiomers in a manner known per se (compare Allinger N.L. with Eliel E.L. in "Topics in stereospecificity", Vol.6, Wiley Interscience, 1971); furthermore, the compounds of the general formula I having at least two asymmetric carbon atoms can be resolved into their diastereomers on the basis of their differences in their physicochemical properties by methods known per se, for example by chromatography and/or fractional crystallization; furthermore, if these compounds are in the form of racemic mixtures, they can subsequently be resolved into enantiomers as described above.

The separation of the enantiomers is preferably carried out by column separation on a chiral phase, or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms a salt or a derivative, such as an ester or an amide, with the racemic compound, in particular an acid and its activated derivatives or alcohols; and, for example, separating the diastereoisomeric mixture of salts or derivatives thus obtained, for example according to the difference in solubility thereof; wherein the free enantiomer may be released from the pure diastereoisomeric salt or derivative by action of a suitable formulation. Optically active acids which are generally used are, for example, the D-and L-forms of the following acids: such as tartaric or dibenzyltartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. The optically active alcohol may be, for example, (+) or (-) menthol with an optically active acyl group as an amide, such as (+) -or (-) -oxycarbonyl.

Furthermore, the resulting compounds of formula I can be converted into their salts, in particular physiologically acceptable salts for pharmaceutical use, using inorganic or organic acids. Acids which can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Furthermore, the resulting compounds with amino acids are converted, for example, in a 1:1 or 1:2 mixture, in particular with alpha amino acids such as proline or phenylalanine, which have particularly preferred properties such as high crystallinity.

The compounds according to the invention can advantageously also be obtained by the methods described in the examples below, for which purpose they can also be carried out by the methods known to the expert from the literature, for example, in particular as described in WO98/31697, WO01/27128, WO02/083066, WO03/099836 and WO 2004/063209.

As already mentioned, the compounds of the general formula I according to the invention and their physiologically acceptable salts have valuable pharmacological properties, in particular the effect of SGLT2, more preferably for inhibiting the sodium-dependent glucose cotransporter SGLT.

The physiological properties of the novel compounds were examined as follows:

the ability of this substance to inhibit SGLT-2 activity can be demonstrated in a scheduled assay in which a CHO-K1 cell line (ATCC No. ccl61) or an alternative HEK293 cell line (ATCC No. crl-1573) was stably transfected with an expression vector pZeoSV (Invitrogen, EMBL accession No. L36849) (CHO-hSGLT2 or HEK-hSGLT2) comprising a cDNA encoding the sequence of human sodium glucose cotransporter 2(Genbank acc No. nm — 003041). These cell lines will be in a sodium-dependent manner¹⁴C-labelled alpha-methyl-glucopyranosyl glycoside (A)¹⁴C-AMG, Amersham) into the cell.

SGLT-2 analysis was performed as follows:

GHO-hSGLT2 cells were cultured in Ham's F12 medium containing 10% fetal bovine serum and 250. mu.g/ml Zeocin (Invitrogen), while HEK293-hSGLT2 cells were cultured in DMEM medium containing 10% fetal bovine serum and 250. mu.g/ml Zeocin (Invitrogen). The cells were washed twice with PBS and then detached from the culture flasks by treatment with trypsin/EDTA. After addition of cell culture medium, the cells were centrifuged, resuspended in culture medium and counted in a Casy cell counter. Then, 40,000 cells per well were seeded into poly-D lysine-coated white 96-wellsIn the culture dish of (1), and at 37 ℃ with 5% CO₂The incubation was carried out overnight. Cells were washed twice with 300. mu.l of assay buffer (Hanks Balanced Salt Solution,137mM NaCl, 5.4mM KCl, 2.8mM CaCl)₂、1.2mMMgSO₄With 10mM HEPES (pH7.4), 50. mu.g/ml gentamicin). Then 250. mu.l of assay buffer and 5. mu.l of test compound were added to each well and incubated for a further 15 minutes in the incubator. As a negative control, 5. mu.l of 10% DMSO was used. By adding 5. mu.l of each well¹⁴C-AMG (0.05. mu. Ci) started the reaction. At 37 ℃ with 5% CO₂After two hours of incubation, the cells were washed again with 300. mu.l PBS (20 ℃) and then lysed by adding 25. mu.l of 0.1N NaOH (5min,37 ℃). 200. mu.l of MicroScint20(Packard) were added to each well and incubation continued for 20 min at 37 ℃. After cultivation, use¹⁴C scintillation counting procedure measurement in Topcount (packard)¹⁴C-AMG absorbs radioactivity.

To determine selectivity for human SGLT1, a similar test was performed in which cDNA of hSGLT1 (genbank acc. No. nm000343) was expressed in CHO-K1 or HEK293 cells instead of cDNA of hSGLT 2.

The compounds of the formula I according to the invention may, for example, have an EC50 value of less than 1000nM, in particular less than 200nM, most preferably less than 50 nM.

In view of their ability to inhibit SGLT activity, the compounds of the general formula I according to the invention and their corresponding pharmaceutically acceptable salts are in principle suitable for the therapeutic and/or prophylactic treatment of all conditions or diseases which are affected by the inhibition of SGLT, in particular SGLT-2 activity. The compounds according to the invention are therefore suitable in particular for the prophylaxis or treatment of diseases, in particular metabolic disorders or disorders such as type I or type II diabetes, complications of diabetes (e.g. retinopathy, nephropathy or neuropathy, diabetic foot, ulcers, macroangiopathy), metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorders, insulin resistance, metabolic syndrome, dyslipidemia of different origin, atherosclerosis and related diseases, obesity, hypertension, chronic heart failure, edema and hyperuricemia. These substances are therefore also suitable for preventing the degeneration of beta cells, for example the apoptosis or necrosis of pancreatic beta cells. These substances are also suitable for improving or restoring the functionality of pancreatic cells, and may also increase the number and size of pancreatic beta cells. The compounds according to the invention can also be used as diuretics and antihypertensive agents and are suitable for the prevention and treatment of acute renal failure.

In particular, the compounds according to the invention, including their physiologically acceptable salts, are suitable for the prevention or treatment of diabetes, in particular type I and type II diabetes, and/or diabetic complications.

The dosage required to achieve a therapeutic or prophylactic response will generally depend on the compound employed, the patient, the nature and severity of the disease or disorder, and the method and frequency of administration; moreover, it is decided by the treating physician. Suitably, the dosage may be 1-100 mg, preferably 1-30 mg, for intravenous administration; the dosage is 1-1000 mg, preferably 1-100 mg, and is administered 1-4 times per day. For this purpose, the compounds of the formula I prepared according to the invention can optionally be combined with other active substances with one or more inert customary carriers and/or diluents, for example with corn starch, lactose, raw sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetostearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat, or suitable mixtures thereof, and be formulated into customary galenic preparations, for example tablets, coated tablets, capsules, powders, solutions, suspensions or suppositories.

The compounds according to the invention can also be used in combination with other active substances, in particular for the treatment and/or prophylaxis of the diseases and disorders mentioned above. Other active agents suitable for such combinations include, for example, those that may enhance the therapeutic effect of an SGLT antagonist inhibitor according to the invention on said condition and/or may reduce the dose of an SGLT inhibitor according to the invention. Therapeutic agents suitable for such combinations include, for example, antidiabetics such as metformin (metformin), sulfoureas such as glibenclamide (glibenclamide), tolbutamide (tolbutamide), glimepiride (glimepiride), nateglinide (nateglinide), repaglinide (repaglinide), thiazolidinediones such as rosiglitazone (rosiglitazone), pioglitazone (pioglitazone), PPAR-gamma-agonists such as GI262570 and antagonists, PPAR-gamma/alpha modulators such as KRP297, alpha-glucosidase inhibitors such as acarbose (acarbose), voglibose (voglibose), DPPIV inhibitors such as LAF237, MK-431, alpha 2-antagonists, insulin and insulin analogs, GLP-1 and GLP-1 analogs such as extended-4 or cyclodextrin (amylin). Also included are substances affecting the regulation of glucose production in the liver-protein tyrosine phosphatase inhibitors 1, such as glucose-6-phosphatase or fructose-1, 6-bisphosphatase, inhibitors of glycogenphosphorylase and the like, antagonists of the glucagon receptor, and inhibitors of phosphoenolpyruvate carboxykinase, glycogensynthase kinase or pyruvate dehydrokinase, such as HMG-CoA-reductase inhibitors (e.g. simvastatin (simvastatin), atorvastatin (atorvastatin)), fibrates (e.g. bezafibrate (bezafibrate), fenofibrate (fenofibrate)), lipid lowering agents of nicotinic acid and its derivatives, PPAR-alpha-agonists, PPAR-agonists, ACAT inhibitors (e.g. acrasinib)) or cholesterol absorption inhibitors such as ecoxidine (ezetimibe), such as cholic acid binding substances of cholestyramine (cholestyramine), inhibitors of ileal bile acid transport, HDL-raising compounds such as CETP inhibitors or ABC1 modulators, or active substances such as sibutramine (sibutramine) for the treatment of obesity, or tetrahydrolipid inhibitors (Tetrahydrolipstatin), dexfenfluramine (dexfenfluramine), acamprosate (axokine), cannabinoid 1 receptor antagonists, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, or β 3-agonists such as SB-418790 or AD-9677, and 5HT2c receptor agonists.

Furthermore, combinations with the following drugs which affect hypertension, chronic heart failure or atherosclerosis, for example: A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, Ca-antagonists, centrally acting antihypertensive agents, alpha-2-adrenoceptor antagonists, neutral endopeptidase inhibitors, platelet aggregation inhibitors and others, or combinations thereof are suitable. Examples of angiotensin II receptor antagonists are candesartan cilexetil, losartan potassium salt (potassium losartan), eprosartan mesylate (eprosartan mesylate), valsartan (valsartan), telmisartan (telmisartan), irbesartan (irbesartan), EXP3174, L-158809, EXP-1582, olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, and the like. Angiotensin II receptor antagonists are preferably used for the treatment or prevention of hypertension and complications of diabetes, usually in combination with diuretics such as hydrochlorothiazide (hydrochlorothiazide).

Combinations with uric acid synthesis inhibitors or ulicolysis (uricosuric) are suitable for the treatment or prevention of gout.

In combination with a GABA-receptor antagonist, a Na-channel blocker, topiramate (topiramat), a protein-kinase C inhibitor, a further glycation end-product inhibitor or an aldose reductase inhibitor, may be used for the treatment or prevention of complications of diabetes.

The dosage of the combination partners mentioned above is suitably 1/5 at the normally recommended lowest dose/1/1 at the normally recommended dose.

Thus, another subject of the present invention is the use of a compound according to the invention or a physiologically acceptable salt of such a compound in combination with at least one active substance as described above as a combination partner for the preparation of a medicament suitable for the treatment or prevention of a disease or condition which is affected by the inhibition of the sodium-dependent glucose cotransporter SGLT. Preferably a metabolic disease, in particular one of the diseases or conditions mentioned above, most particularly diabetes or diabetic complications.

The use of the compounds according to the invention or their physiologically acceptable salts in combination with other active substances can be simultaneous or staggered in time, but in particular at short intervals. If they are administered simultaneously, the two active substances are administered together to the patient; if used alternately, the two active substances are administered to the patient within less than or equal to 12 hours, in particular within less than or equal to 6 hours.

Thus, in a further aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the invention, or a physiologically acceptable salt of such a compound, and at least one of the active substances mentioned above as a combination partner, optionally together with one or more inert carriers and/or diluents.

Thus, for example, the pharmaceutical composition according to the invention comprises a compound of formula I according to the invention or a physiologically acceptable salt of such a compound in combination with at least one angiotensin II receptor antagonist, optionally together with one or more inert carriers and/or diluents.

The compounds according to the invention or their physiologically acceptable salts, and the further active substances to be combined therewith, are contained together in the same formulation form, for example in tablets or capsules, or are divided into two identical or different dosage forms, for example in so-called combination kits.

In the foregoing and in the following, the H atoms of the hydroxyl groups are not in each case explicitly indicated in the structural formulae. The following examples are illustrative of the invention and are not intended to be limiting:

preparation of the starting compound:

example I

(5-bromo-2-chloro-phenyl) - (4-methoxy-phenyl) -methanone

38.3ml of oxalyl chloride and 0.8ml of dimethylformamide are added to a mixture of 100g of 5-bromo-2-chloro-benzoic acid in 500ml of dichloromethane. The reaction mixture was stirred for 14 hours, then filtered and separated from all volatile constituents in a rotary evaporation dish. The residue was dissolved in 150ml of dichloromethane, the solution was cooled to-5 ℃ and 46.5g of anisole were added. Then, 51.5g of aluminum trichloride were added in portions so that the temperature did not exceed 5 ℃. The solution was stirred at 1-5 ℃ for an additional 1 hour and then poured onto ice. The organic phase was separated and the aqueous phase was extracted three more times with dichloromethane. The combined organic phases were washed once with 1M aqueous hydrochloric acid, twice with 1M sodium hydroxide solution and twice with saturated sodium chloride solution. The organic phase is then dried, the solvent is removed and the residue is recrystallized from ethanol.

Yield: 86.3g (theoretical 64%).

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

The following compounds were prepared in analogy to example I:

(1) (5-bromo-2-iodo-phenyl) - (4-ethoxy-phenyl) -methanone

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

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

Example II

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

A solution of 86.2g of (5-bromo-2-chloro-phenyl) - (4-methoxy-phenyl) -methanone with 101.5ml triethylsilane in 75ml dichloromethane and 150ml acetonitrile was cooled to 10 ℃. Then, 50.8ml of boron trifluoride diethyl etherate was added with stirring so that the temperature did not exceed 20 ℃. The solution was stirred at room temperature for 14 hours, then another 9ml triethylsilane and 4.4ml boron trifluoride etherate were added. The solution was stirred at 45-50 ℃ for another 3 hours and then cooled to room temperature. A solution of 28g of potassium hydroxide in 70ml of water was added and the mixture was stirred for 2 hours. The organic phase was then separated and the aqueous phase was re-extracted 3 times with diisopropyl ether. The combined organic phases were washed twice with 2M potassium hydroxide and 1 time with aqueous sodium chloride solution and then dried over sodium sulfate. After separation of the solvent, the residue is stirred in ethanol, separated again and dried at 60 ℃.

Yield: 50.0g (61% of theory).

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

The following compounds were prepared in analogy to example II:

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

Mass spectrometry (ESI)⁺)：m/z=434/436[M+NH₄]⁺

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

Example III

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

A solution of 14.8g of 4-bromo-1-chloro-2- (4-methoxy-benzyl) -benzene in 150ml of dichloromethane was cooled in an ice bath. Then, 50ml of a 1M solution of boron tribromide in methylene chloride was added, and the solution was stirred at room temperature for 2 hours. Then, the solution was cooled again in an ice bath, and a saturated potassium carbonate solution was added dropwise. The mixture was adjusted to pH1 with 1M aqueous hydrochloric acid at room temperature, the organic phase was separated and the aqueous phase was extracted 3 more times with ethyl acetate. The combined organic phases were dehydrated over sodium sulfate and the solvent was completely removed.

Yield: 13.9g (98% of theory).

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

Example IV

[4- (5-bromo-2-chloro-benzyl) -phenoxy ] -tert-butyl-dimethyl-silane

A solution of 13.9g of 4- (5-bromo-2-chloro-benzyl) -phenol in 140ml of dichloromethane was cooled in an ice bath. Then, a solution of 7.54g of t-butyldimethylsilyl chloride in 20ml of methylene chloride was added, followed by 9.8ml of triethylamine and 0.5g of dimethylaminopyridine. The solution was stirred at room temperature for 16 hours and then diluted with 100ml of dichloromethane. The organic phase was washed 2 times with 1M hydrochloric acid solution and 1 time with aqueous sodium bicarbonate solution and then dried over sodium sulfate. After removal of the solvent, the residue was filtered through silica gel (cyclohexane/ethyl acetate 100: 1).

Yield: 16.8g (87% of theory).

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

example V

1-bromo-4-triisopropylsilylethynyl-benzene

11.6ml of triisopropylacetylene with 14.4ml of triethylamine and then 0.2g of copper iodide and 0.73g of bis- (triphenylphosphine) -palladium dichloride are added under argon to a solution of 15.0g of 1-bromo-4-iodo-benzene in 150ml of anhydrous tetrahydrofuran in the absence of oxygen. The solution was stirred at room temperature for 16 hours, then filtered through Celite and evaporated to dryness. The residue was chromatographed on silica gel (cyclohexane).

Yield: 17.4g (theoretical value 100%).

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

The following compounds were prepared in analogy to example V:

(1) 4-bromo-1- (triisopropylsilylethynyl) -2- (4-ethoxy-benzyl) -benzene 4-bromo-1-iodo-2- (4-ethoxy-benzyl) -benzene was used as the starting material for the above coupling reaction.

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

(2) [4- (5-bromo-2-chloro-benzyl) -phenylethynyl ] -triisopropyl-silane 4-bromo-1-chloro-2- (4-iodo-benzyl) -benzene was used as starting material.

This compound can also be prepared according to the method of example X.

Example VI

(5-bromo-2-fluoro-phenyl) - {4- [ (triisopropylsilyl) -ethynyl ] -phenyl } -methanol

33.8ml of a 1.6M hexane solution of n-butyllithium are added dropwise to a solution of 17.4g of 1-bromo-4-triisopropylsilylethynyl-benzene in 120ml of anhydrous tetrahydrofuran, cooled to-78 ℃ under argon. The solution was stirred at-70 ℃ for 1 hour. Then, a solution of 10.8g 5-bromo-2-fluoro-benzaldehyde in 30ml tetrahydrofuran was added dropwise over 15 minutes. The resulting solution was allowed to warm to room temperature overnight in a cooling bath. Then water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed. The residue was purified over silica gel (cyclohexane/ethyl acetate 4: 1).

Yield: 14.3g (theoretical 60%).

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

The following compounds were prepared in analogy to example VI:

(1) (3-bromo-phenyl) - {4- [ (triisopropylsilyl) -ethynyl ] -phenyl } -methanol

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

(2) (5-bromo-2-methoxy-phenyl) - {4- [ (triisopropylsilyl) -ethynyl ] -phenyl } -methanol

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

Example VII

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

A solution of 5.6g (5-bromo-2-fluoro-phenyl) - {4- [ (triisopropylsilyl) -ethynyl ] -phenyl } -methanol and 4.1ml triethylsilane in 50ml of dichloromethane was cooled in an ice bath. Then, 4.7ml of trifluoroacetic acid was slowly added dropwise thereto, and the solution was stirred at room temperature for 4 hours. The solution was diluted with dichloromethane and washed with aqueous sodium bicarbonate. After dehydration over sodium sulfate the solvent was removed and the residue was purified over silica gel (cyclohexane). Yield: 2.6g (theoretical 48%).

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

The following compounds were prepared in analogy to example VII:

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

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

(2) [4- (5-bromo-2-methoxy-benzyl) -phenylethynyl ] -triisopropyl-silane

Unlike the above method, the reaction solution was stirred in an ice bath instead of at room temperature until the reaction was completed.

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

Example VIII

4-bromo-2-bromomethyl-1-chloro-benzene

4.0g of N-bromosuccinimide are slowly added to a solution of 5.0g of 4-bromo-1-chloro-2-hydroxymethyl-benzene and 5.9g of triphenylphosphine in 50ml of tetrahydrofuran, cooled to 5 ℃. After stirring at room temperature for 1 hour, the precipitate was filtered off and the solvent was removed in vacuo. The residue was purified over silica gel (cyclohexane/ethyl acetate 50: 1).

Yield: 4.9g (theoretical 76%).

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

Example IX

(4-iodo-phenylethynyl) -triisopropyl-silane

18.0g of sodium iodide (anhydrous), 0.6g of copper iodide and 0.8g of 0.8g N, N' -dimethyl-cyclohexane-1, 2-diamine were added to a solution of 20.0g of (4-bromo-phenylethynyl) -triisopropyl-silane under argon, and the solution was stirred under reflux with heating for 24 hours and then cooled to room temperature. A1% ammonia solution (100ml) was added, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the solvent was removed and the residue was purified over silica gel (cyclohexane).

Yield: 21.0g (92% of theory).

Mass spectrum (EI): m/z =384[ M ]]⁺

Example X

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

0.66ml of a 2M solution of isopropylmagnesium chloride in tetrahydrofuran are added dropwise under argon to a solution of 0.50g of (4-iodo-phenylethynyl) -triisopropyl-silane in 2.2ml of anhydrous tetrahydrofuran cooled to-25 ℃. The solution was stirred at-25 ℃ for 30 minutes and then combined with 0.26ml of a 1M solution of CuCN x 2LiCl in tetrahydrofuran (prepared by dissolving CuCN and LiCl in a 1:2 ratio). Then, 0.35g of 4-bromo-2-bromomethyl-1-chlorobenzene was added as quickly as possible and the reaction mixture was warmed to-5 ℃ in a cooling bath. After stirring at-5 ℃ for 6 hours, the solution was warmed to room temperature and stirred overnight. Then, a mixture of saturated ammonium chloride solution and 25% ammonia solution (9:1) was added and the resulting mixture was added to water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate and the solvent was removed and the residue was purified over silica gel (cyclohexane).

Yield: 0.28g (theoretical 50%).

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

Example XI

2,3,4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone

20g of D-glucono-1, 5-lactone are cooled to-5 ℃ with 98.5ml of N-methylmorpholine in 200ml of tetrahydrofuran. 85ml of trimethylsilyl chloride are then added dropwise so that the temperature does not exceed 5 ℃. The solution was then stirred at room temperature for 1 hour, at 35 ℃ for 5 hours, and then at room temperature for a further 14 hours. After addition of 300ml of toluene, the solution was cooled in an ice bath and 500ml of water were added so that the temperature did not exceed 10 ℃. Then, the organic phase was separated and washed once with sodium dihydrogenphosphate solution, water and saturated aqueous sodium chloride solution, respectively. The solvent was removed, the residue was dissolved in 250ml of toluene, and the solvent was again completely removed.

Yield: 52.5g (purity about 90%).

Mass spectrometry (ESI)⁺)：m/z=467[M+H]⁺

Example XII

1-fluoro-4- (1-methoxy-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethynyl-benzyl) -benzene

A solution of 4.46g of [4- (5-bromo-2-fluoro-benzyl) -phenylethynyl ] -triisopropylsilane in 30ml of dry ether is cooled to-80 ℃ under argon. 11.8ml of a 1.7 molar solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, which is then stirred at-80 ℃ for 45 minutes. Then, 5.19g of a solution of 2,3,4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone in 50ml of diethyl ether cooled to-80 ℃ was added dropwise to this solution through a transfer needle. The resulting solution was stirred at-78 ℃ for 3 hours. Then, 1.7ml of methanesulfonic acid in 50ml of methanol was added, the cooling bath was removed, and the solution was stirred at room temperature for 16 hours. The solution was then neutralized with ethyldiisopropylamine and evaporated to dryness. The residue was purified over silica gel (dichloromethane/methanol 50:1- >4: 1).

Yield: 2.8g (theoretical 50%).

Mass spectrometry (ESI)⁺)：m/z=576[M+NH₄]⁺

The following compounds were prepared in analogy to example XII:

(1) 1-methoxy-4- (1-methoxy-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethynyl-benzyl) -benzene

Advantageously, the reaction mixture is mixed with only a slight excess of methanesulfonic acid.

Mass spectrometry (ESI)⁺)：m/z=588[M+NH₄]⁺

(2) 1-chloro-4- (1-methoxy-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethynyl-benzyl) -benzene

Mass spectrometry (ESI)⁺)：m/z=592/594(Cl)[M+NH₄]⁺

Example XIII

1-fluoro-4- (2,3,4, 6-tetra-O-acetyl-beta-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethynyl-benzyl) -benzene

A solution of 0.8g of 1-fluoro-4- (1-methoxy-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethynyl-benzyl) -benzene and 0.5ml of triethylsilane in 6ml of dichloromethane and 10ml of acetonitrile was cooled to-10 ℃. 0.27ml of boron trifluoride diethyl etherate was added dropwise to the cooled solution. The solution was then stirred under an ice bath for 3 hours. Aqueous sodium bicarbonate was added to the solution, and the mixture was extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is removed and the residue is dissolved in 6ml of dichloromethane. Then, 1.2ml of pyridine, 1.3ml of acetic anhydride and 8mg of 4-dimethylaminopyridine were added. The solution was stirred at room temperature for 1 hour and then combined with water. The mixture was extracted with dichloromethane, the organic phase was washed with 1M hydrochloric acid and dried over sodium sulfate. After removal of the solvent, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1- >1: 1).

Yield: 0.23g (theoretical 23%).

Mass spectrometry (ESI)⁺)：m/z=714[M+NH₄]⁺

The following compounds were prepared in analogy to example XIII:

(1) 1-methoxy-4- (2,3,4, 6-tetra-O-acetyl-beta-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethynyl-benzyl) -benzene

Mass spectrometry (ESI)⁺)：m/z=726[M+NH₄]⁺

(2) 1-chloro-4- (2,3,4, 6-tetra-O-acetyl-beta-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethynyl-benzyl) -benzene

Mass spectrometry (ESI)⁺)：m/z=730/732(Cl)[M+NH₄]⁺

Example XIV

1- (2,3,4, 6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl) -3- (4-triisopropylsilylethynyl-benzyl) -benzene

A solution of 2.6g of [4- (3-bromo-benzyl) -phenylethynyl ] -triisopropyl-silane in 20ml of dry ether is cooled to-80 ℃ under argon. 7.9ml of a 1.7M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution; the solution was then stirred at-80 ℃ for 30 minutes. A solution of 3.2g2,3,4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone in 30ml diethyl ether cooled to-80 ℃ is then added dropwise to this solution via a transfer needle. The resulting solution was stirred at-78 ℃ for 2 hours, then another 10ml ether solution of 2,3,4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone cooled to-80 ℃ was added dropwise. After stirring at-78 ℃ for a further 1 hour, 2ml of methanesulfonic acid in 20ml of methanol were added, the cooling bath was removed and the solution was stirred at room temperature for 16 hours. Then, the solution was neutralized with ethyldiisopropylamine, the solvent was completely removed and the residue was dissolved in 50ml of toluene. 8.5ml of ethyldiisopropylamine was added, and the solution was cooled in an ice bath. 4.3ml of acetic anhydride and 0.15g of 4-dimethylaminopyridine are then added. The solution was stirred at room temperature for 2 hours and then mixed with an aqueous sodium bicarbonate solution. Extraction with ethyl acetate, drying of the organic phase over sodium sulfate and removal of the solvent. The residue was chromatographed on silica gel (cyclohexane/ethyl acetate 4:1- >1: 3).

Yield: 2.0g (theoretical 46%).

Mass spectrometry (ESI)⁺)：m/z=726[M+NH₄]⁺

Prepared in analogy to example XIV:

(1)1- (triisopropylsilylethynyl) -4- (2,3,4, 6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl) -2- (4-ethoxy-benzyl) -benzene

Mass spectrometry (ESI)⁺)：m/z=770[M+NH₄]⁺

Example XV

1- (2,3,4, 6-tetra-O-acetyl-beta-D-glucopyranos-1-yl) -3- (4-triisopropylsilylethynyl-benzyl) -benzene

1.2ml triethylsilane and 0.36ml boron trifluoride are added dropwise to an ice-cold 10ml acetonitrile solution of 1.0g 1- (2,3,4, 6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl) -3- (4-triisopropylsilylethynyl-benzyl) -benzene and 25. mu.l water. Then, the solution was stirred in an ice bath for 3 hours and at room temperature for 1 hour. Then, the solution was cooled in the ice bath again, and 1.2ml of triethylsilane and 0.36ml of boron trifluoride diethyl etherate were added again. The solution was stirred in the ice bath for a further 0.5 h and at room temperature for 2 h. Then, an aqueous sodium hydrogencarbonate solution was added to this solution, and the resultant solution was extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed.

Yield: 0.78g (theoretical 81%).

Mass spectrometry (ESI)⁺)：m/z=696[M+NH₄]⁺

The following compounds were prepared in analogy to example XV:

(1)1- (triisopropylsilylethynyl) -4- (2,3,4, 6-tetra-O-acetyl-beta-D-glucopyranos-1-yl) -2- (4-ethoxy-benzyl) -benzene

Example XVI

1-chloro-4- (beta-D-glucopyranos-1-yl) -2- (4-hydroxybenzyl) -benzene

A solution of 4.0g of [4- (5-bromo-2-chloro-benzyl) -phenoxy ] -tert-butyl-dimethyl-silane in 42ml of dry ether was cooled to-80 ℃ under argon. 11.6ml of a 1.7 molar solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution; the solution was then stirred at-80 ℃ for 30 minutes. This solution was then added dropwise through a dry ice cooled transfer pin to a solution of 4.78g of 2,3,4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone in 38ml of diethyl ether cooled to-80 ℃. The resulting solution was stirred at-78 ℃ for 3 hours. Then, 1.1ml of methanesulfonic acid in 35ml of methanol was added, and the solution was stirred at room temperature for 16 hours. The solution was then neutralized with sodium bicarbonate solid, ethyl acetate was added and methanol was removed with ether. Aqueous sodium bicarbonate solution was added to the remaining solution and extracted four times with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to dryness. The residue was dissolved in 30ml acetonitrile and 30ml dichloromethane and the solution was cooled to-10 ℃. After addition of 4.4ml of triethylsilane, 2.6ml of boron trifluoride diethyl ether were added dropwise while keeping the temperature at-5 ℃ or lower. After the addition, the mixture was stirred at-5 to-10 ℃ for 5 hours, and then an aqueous solution of sodium hydrogencarbonate was added to terminate the reaction. The organic phase was separated and the aqueous phase was extracted four times with ethyl acetate. The combined organic phases were dried over sodium sulfate, the solvent was removed and the residue was purified over silica gel. The resulting product is then an approximately 6:1 beta/alpha mixture which can be converted to the pure beta-anomer by complete acylation of the hydroxyl groups with acetic anhydride in pyridine in dichloromethane and recrystallization in ethanol. The resulting product was converted to the title compound by reaction with 4M potassium hydroxide solution in methanol.

Yield: 1.6g (theoretical 46%).

Mass spectrometry (ESI)⁺)：m/z=398/400(Cl)[M+H]⁺

Example XVII

1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- (trifluoromethylsulfonyloxy) -benzyl ] -benzene

10mg of 4-dimethylaminopyridine are added to a solution of 0.38g of 1-chloro-4- (. beta. -D-glucopyranos-1-yl) -2- (4-hydroxybenzyl) -benzene, 0.21ml of triethylamine and 0.39 of 0.39g N, N-bis- (trifluoromethanesulfonyl) -aniline in 10ml of dry dichloromethane. The solution was stirred at room temperature for 4 hours and then mixed with an aqueous sodium chloride solution. Extraction with ethyl acetate, drying of the organic extract over sodium sulfate and removal of the solvent. The residue was chromatographed on silica gel (dichloromethane/methanol 1:0- >4: 1).

Yield: 0.33g (theoretical 64%).

Mass spectrometry (ESI)⁺)：m/z=530/532(Cl)[M+NH₄]⁺

Example XVIII

2,3,4, 6-tetra-O-benzyl-D-glucopyranosone

4g of freshly activated molecular sieveWith 3.3g of N-methylmorpholine-N-oxide, was added to a solution of 10.0g of 2,3,4, 6-tetra-O-benzyl-alpha-D-glucopyranosone in 140ml of dichloromethane. The solution was stirred at room temperature for 20 minutes, and then 0.3g of tetrapropylammonium perruthenate was added. After stirring at room temperature for 2 hours, the solution was diluted with dichloromethane and filtered through Celite. The filtrate was washed with aqueous sodium thiosulfate and water and dried over sodium sulfate. After removal of the solvent, the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 4: 1).

Yield: 8.2g (theoretical 82%).

Mass spectrometry (ESI)⁺)：m/z=539[M+H]⁺

Example XIX

1- (2,3,4, 6-tetra-O-benzyl-1-hydroxy-D-glucopyranos-1-yl) -3- [4- (tert-butyl-dimethyl-silyloxy) -benzyl ] -4-methyl-benzene

A solution of 0.34g of [4- (5-bromo-2-methyl-benzyl) -phenoxy ] -tert-butyl-dimethyl-silane in 3ml of anhydrous tetrahydrofuran was cooled to-80 ℃ under argon. 0.54ml of a 1.6M hexane solution of n-butyllithium was added dropwise to the cooled solution, and the solution was stirred at-78 ℃ for 1.5 hours. A solution of 0.43g of 2,3,4, 6-tetra-O-benzyl-D-glucopyranosone in 2.5ml of tetrahydrofuran cooled to-80 ℃ is added dropwise to this solution with a transfer needle. The resulting solution was stirred at-78 ℃ for 5 hours. The reaction was quenched with 0.1ml acetic acid in 1ml tetrahydrofuran and warmed to room temperature. Then, an aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted four times with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (cyclohexane/ethyl acetate 15:1- >4: 1).

Yield: 0.48g (about 88% purity).

Mass spectrometry (ESI)⁺)：m/z=868[M+H]⁺

Example XX

1- (2,3,4, 6-tetra-O-benzyl-beta-D-glucopyranos-1-yl) -3- (4-hydroxy-benzyl) -4-methyl-benzene

A solution of 0.48g (about 88% purity) of 1- (2,3,4, 6-tetra-O-benzyl-1-hydroxy-D-glucopyranosyl) -3- [4- (tert-butyl-dimethyl-silanyloxy) -benzyl ] -4-methyl-benzene in 3.5ml dry acetonitrile is cooled to-40 ℃ under argon. 0.13ml of triisopropylsilane and 0.08ml of boron trifluoride diethyl etherate were added dropwise to the cooled solution. The solution was stirred at-35 ℃ for 3 hours, after which 0.02ml of triisopropylsilane and 0.01ml of boron trifluoride diethyl etherate were added once more. After standing at-40 ℃ for another 2 hours, an aqueous potassium carbonate solution was added, and the solution was stirred at room temperature for 1 hour. Then, it was diluted with water and extracted four times with ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and chromatographed on silica gel (cyclohexane/ethyl acetate 10:1- >4: 1).

Yield: 0.24g (theoretical 68%).

Mass spectrometry (ESI)⁺)：m/z=738[M+NH₄]⁺

Example XXI

1- (2,3,4, 6-tetra-O-benzyl-beta-D-glucopyranos-1-yl) -3- [4- (tetrahydrofuran-3-yloxy) -benzyl ] -4-methyl-benzene

0.10g of toluene-4-sulfonic acid-tetrahydrofuran-3-yl ester was added to a mixture of 0.24g of 1- (2,3,4, 6-tetra-O-benzyl- β -D-glucopyranos-1-yl) -3- (4-hydroxy-benzyl) -4-methyl-benzene and 0.13g of cesium carbonate in 2.5ml of dimethylformamide. The mixture was stirred at 65 ℃ for 4 hours, then water was added. Extraction was carried out three times with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was removed. The residue was purified over silica gel (cyclohexane/ethyl acetate 10:1- >4: 1).

Yield: 0.23g (theoretical 78%).

Mass spectrometry (ESI)⁺)：m/z=808[M+H]⁺

Example XXII

1- (2,3,4, 6-tetra-O-benzyl-beta-D-glucopyranos-1-yl) -3- [4- (trifluoromethylsulfonyloxy) -benzyl ] -4-methyl-benzene

A solution of 0.62g of 1- (2,3,4, 6-tetra-O-benzyl- β -D-glucopyranos-1-yl) -3- (4-hydroxy-benzyl) -4-methyl-benzene in 4.5ml of anhydrous dichloromethane was cooled to-10 ℃ under argon. 0.14ml of pyridine and 0.3g of trifluoromethanesulfonic anhydride in 0.5ml of dichloromethane are added to this cooled solution. The solution was stirred at-5 to-10 ℃ for 0.5 hour, and then an aqueous sodium bicarbonate solution was added. The mixture was extracted three times with dichloromethane and the combined organic phases were washed with 1M hydrochloric acid solution and dried over sodium sulfate. After removal of the solvent, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 15:1- >7: 1).

Yield: 0.62g (84% of theory).

Mass spectrometry (ESI)⁺)：m/z=853[M+H]⁺

Example XXIII

1- (2,3,4, 6-tetra-O-benzyl-beta-D-glucopyranos-1-yl) -3- [4- (trimethylsilylethynyl) -benzyl ] -4-methyl-benzene

27mg of copper iodide, 49mg of bis- (triphenylphosphine) -palladium difluoride, 0.30ml of triethylamine and finally 0.14ml of trimethylsilylacetylene are added under argon to a solution of 0.60g of 1- (2,3,4, 6-tetra-O-benzyl- β -D-glucopyranos-1-yl) -3- [4- (trifluoromethylsulfonyloxy) -benzyl ] -4-methyl-benzene in 3ml of dimethylformamide. The flask was tightly sealed and stirred at 90 ℃ for 4 hours. Then, 20mg of bis- (triphenylphosphine) -palladium dichloride and 0.6ml of trimethylsilylacetylene were added and the solution was stirred at 90 ℃ for 4 hours. Then, an aqueous sodium bicarbonate solution was added. The mixture was extracted three times with ethyl acetate and the combined organic phases were dried over sodium sulfate. After removal of the solvent, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 40:1- >10: 1).

Yield: 0.45g (theoretical 80%).

Mass spectrometry (ESI)⁺)：m/z=818[M+NH₄]⁺

Preparation of the Final Compounds

Example 1

1-chloro-2- (4-cyclopentyloxybenzyl) -4- (. beta. -D-glucopyranos-1-yl) -benzene

0.16ml of iodocyclopentane was added to a mixture of 0.25g of 1-chloro-4- (. beta. -D-glucopyranos-1-yl) -2- (4-hydroxybenzyl) -benzene and 0.4g of cesium carbonate in 2.5ml of dimethylformamide. The mixture was stirred at 45 ℃ for 4 hours, then 0.1g cesium carbonate and 0.05ml cyclopentane iodide were added. After stirring at 45 ℃ for a further 14 hours, aqueous sodium chloride solution was added and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is removed and the residue is purified on silica gel. (dichloromethane/methanol 1:0- >5: 1).

Yield: 0.23g (theoretical 78%).

Mass spectrometry (ESI)⁺)：m/z=466/468(Cl)[M+NH₄]⁺

The following compounds were prepared in analogy to example 1:

(2) 1-chloro-4- (β -D-glucopyranos-1-yl) -2- [4- ((R) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene the reaction is carried out with (S) -toluene-4-sulfonic acid-tetrahydrofuran-3-yl ester as coupling partner.

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

(3) 1-chloro-4- (β -D-glucopyranos-1-yl) -2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene the reaction is carried out with (R) -toluene-4-sulfonic acid-tetrahydrofuran-3-yl ester as coupling partner.

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

(4) 1-chloro-4- (β -D-glucopyranos-1-yl) -2- [4- (tetrahydrofuran-2-one-3-yloxy) -benzyl ] -benzene the reaction was carried out with 3-bromobutyryl lactone as a coupling partner.

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

(5) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- (4-cyclobutoxy-benzyl) -benzene

Mass spectrometry (ESI)⁺)：m/z=452/454(Cl)[M+NH₄]⁺

Mass spectrometry (ESI)⁺)：m/z=480/482(Cl)[M+NH₄]⁺

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

(8) 1-chloro-4- (. beta. -D-glucopyranos-1-yl) -2- [4- (1-acetyl-piperidin-4-yloxy) -benzyl ] -benzene the reaction is carried out with 1-acetyl-4-methylsulfonyloxy-piperidine as the electrophile.

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

(9) 1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) -benzyl ] -benzene

The reaction is carried out using 1-tert-butoxycarbonyl-4-methylsulfonyloxy-piperidine as an electrophile.

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

Example 10

1- (beta-D-glucopyranos-1-yl) -4-methyl-3- [4- (tetrahydrofuran-3-yloxy) -benzyl ] -benzene

A mixture of 0.21g of 1- (2,3,4, 6-tetra-O-benzyl- β -D-glucopyranos-1-yl) -3- [4- (tetrahydrofuran-3-yloxy) -benzyl ] -4-methyl-benzene and 0.1g of 10% palladium hydroxide on charcoal in 3ml of ethyl acetate was shaken under 1atm hydrogen at room temperature for 24 hours. Then, the same amount of catalyst was added again, and the mixture was shaken under hydrogen pressure for another 24 hours. The catalyst was then removed by filtration, the filtrate evaporated to dryness and the residue chromatographed on silica gel (dichloromethane/methanol 1:0- >5: 1).

Yield: 0.06g (theoretical 49%).

Mass spectrometry (ESI)⁺)：m/z=448[M+NH₄]⁺

Example 11

1- (. beta. -D-glucopyranos-1-yl) -4-methyl-3- [4- (2-trimethylsilyl-ethyl) -benzyl ] -benzene

A mixture of 0.29g of 1- (2,3,4, 6-tetra-O-benzyl- β -D-glucopyranos-1-yl) -4-methyl-3- [4- (trimethylsilylethynyl) -benzyl ] -benzene and 0.25g of 10% palladium hydroxide on charcoal in 3ml of ethyl acetate was shaken under 1atm of hydrogen at room temperature for 24 hours. Then, 0.2g of catalyst was added and the mixture was shaken under hydrogen pressure for another 20 hours. Then, the catalyst was filtered off, the filtrate was evaporated to dryness and the residue was chromatographed on silica gel (dichloromethane/methanol 1:0- >5: 1).

Yield: 0.08g (theoretical 51%).

Mass spectrometry (ESI)⁺)：m/z=462[M+NH₄]⁺

Example 12

1-chloro-4- (beta-D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) -benzene

25mg of copper iodide, 44mg of bis- (triphenylphosphine) -palladium dichloride, 0.30ml of triethylamine and finally 0.14ml of trimethylsilylacetylene are added under argon to a solution of 0.32g of 1-chloro-4- (. beta. -D-glucopyranos-1-yl) -2- [4- (trifluoromethylsulfonyloxy) -benzyl ] -benzene in 3ml of dimethylformamide under argon. The flask was tightly sealed and stirred at 90 ℃ for 8 hours. Then, 25mg of bis- (triphenylphosphine) -palladium dichloride and 0.1ml of trimethylsilylacetylene were added and the solution was stirred for 10 hours at 90 ℃. Then, sodium bicarbonate solution was added, the mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate. After removal of the solvent, the residue was dissolved in 5ml of methanol and mixed with 0.12g of potassium carbonate. The mixture was stirred at room temperature for 1 hour and then neutralized with 1M hydrochloric acid. The methanol was then evaporated to dryness and the residue was mixed with aqueous sodium chloride and extracted with ethyl acetate. The collected organic extracts were dried over sodium sulfate and the solvent was removed. The residue was chromatographed on silica gel (dichloromethane/methanol 1:0- >5: 1).

Yield: 0.095g (theoretical 40%).

Mass spectrometry (ESI)⁺)：m/z=406/408(Cl)[M+NH₄]⁺

This compound can also be prepared as in example 14:

example 13

1-chloro-4- (beta-D-glucopyranos-1-yl) -2- [4- (piperidin-4-yloxy) -benzyl ] -benzene

2ml of trifluoroacetic acid are added to a solution of 0.19g of 1-chloro-4- (. beta. -D-glucopyranos-1-yl) -2- [4- (1-tert-butoxycarbonylpiperidin-4-yloxy) -benzyl ] -benzene in 4ml of dichloromethane. The solution was stirred at room temperature for 1.5 hours, then diluted with ethyl acetate and made basic with aqueous potassium carbonate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was completely removed.

Yield: 0.060g (theoretical 38%).

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

Example 14

1-fluoro-4- (beta-D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) -benzene

0.33ml of a 1M tetrahydrofuran solution of tetrabutylammonium fluoride was added to 0.23g of a 1.5ml tetrahydrofuran solution of 1-fluoro-4- (2,3,4, 6-tetra-O-acetyl-. beta. -D-glucopyranos-1-yl) -2- (triisopropylsilylethynyl-benzyl) -benzene. The solution was allowed to stir at room temperature for 1 hour. Then 1ml of methanol and 1.5ml of 4M potassium hydroxide solution were added and the solution was stirred at room temperature for a further hour. The solution was neutralized with 1M hydrochloric acid, and then methanol was distilled off. The residue was mixed with sodium chloride solution and extracted with ethyl acetate. The organic extracts were collected and dried over sodium sulfate, then the solvent was evaporated. The residue was chromatographed on silica gel (dichloromethane/methanol 19:1- >2: 1).

Yield: 0.060g (theoretical 49%).

Mass spectrometry (ESI)⁺)：m/z=390[M+NH₄]⁺

The following compounds were prepared in analogy to example 14:

(15)1- (beta-D-glucopyranos-1-yl) -3- (4-ethynyl-benzyl) -benzene

Mass spectrometry (ESI)⁺)：m/z=372[M+NH₄]⁺

(16) 1-ethynyl-4- (beta-D-glucopyranos-1-yl) -2- (4-ethoxy-benzyl) -benzene

Mass spectrometry (ESI)⁺)：m/z=416[M+NH₄]⁺

(17) 1-methoxy-4- (beta-D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) -benzene

Mass spectrometry (ESI)⁺)：m/z=402[M+NH₄]⁺

The compound according to example (12) (1-chloro-4- (. beta. -D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) -benzene) can also be synthesized in analogy to example 14. Optionally, the intermediate stage 1-chloro-4- (2,3,4, 6-tetra-O-acetyl-. beta. -D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) -benzene, which can be obtained after desilylation with tetrabutylammonium fluoride, can be purified by recrystallization from ethanol.

Mass spectrometry (ESI)⁺)：m/z=406/408(Cl)[M+NH₄]⁺

The following compounds were prepared analogously to the examples described above and in other ways known from the literature:

we will now describe certain examples of dosage forms in which the term "active agent" refers to one or more compounds according to the invention, including salts thereof. In the case of combinations with one or more further active substances as described above, the term "active substance" also includes further active substances.

Example A

Tablets containing lioamg active substance

Composition (A):

each tablet comprises:

the preparation method comprises the following steps:

the active substance, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the wet fraction (2.0mm mesh) and drying in a shelf-dryer at 50 ℃ then sieving again (1.5mm mesh) and adding the lubricant. The finished mixture was compressed into tablets.

Tablet weight: 220mg of

Diameter: 10mm, biplane, with facets on both sides and a concave indentation on one side.

Example B

Tablet containing 150mg of active substance

Composition (A):

each tablet comprises:

preparation:

the active substance, which is a mixture of lactose, corn starch and silicic acid, is moistened with a 20% aqueous solution of polyvinylpyrrolidone and passed through a sieve with a mesh size of 1.5 mm. The granules dried at 45 ℃ were passed through the same sieve again, and a specific amount of magnesium stearate was mixed. Tablets were compressed from the mixture.

Tablet weight: 300mg

Metal mold: 10mm, flat

Example C

Hard gelatin capsules containing 150mg of active substance

Composition (A):

each capsule comprises:

preparation:

the active substance is mixed with excipients and passed through a sieve of 0.75mm mesh size. And mixed homogeneously in a suitable apparatus. The finished mixture was filled into hard gelatin capsules No. 1.

Filling materials of the capsule: about 320mg

Capsule shell: hard gelatin capsule # 1.

Example D

Suppository containing 150rug active substance

Composition (A):

each suppository comprises:

preparation:

after melting of the suppository material, the active substance is homogeneously distributed therein and the melt is poured into a pre-cooled mould.

Example E

Ampoules containing 10mg of active substance

Composition (A):

active substance 10.0mg

0.01N hydrochloric acid, appropriate amount

Double distilled water was added to 2.0ml

Preparation:

the active substance was dissolved in the required amount of 0.01N HCl, made isotonic with common salt, sterile filtered and filled in) 2ml ampoules.

Example F

Ampoules containing 50mg of active substance

Composition (A):

active substance 50.0mg

0.01N hydrochloric acid, appropriate amount

Double distilled water was added to 10.0ml

Preparation:

dissolve the active substance in the desired amount of 0.01N HCl, make it an isotonic solution with common salt, filter aseptically and fill) 10ml ampoules with ethyl acetate.

In summary, the present invention relates to the following technical solutions:

1. glucopyranosyl-substituted benzene derivative with general formula I

Wherein

R¹Selected from the definitions of the radicals A, and if R³Is selected from the definition of B radicals, then R¹The following meanings may also be selected additionally: hydrogen, fluorine, chlorine, bromine, iodine, C_1-4Alkyl radical, C_2-4-alkenyl-C_1-4Alkyl radical, C_2-4-alkynyl-C_1-4Alkyl radical, C_2-4-alkenyl-C_1-4-alkoxy, C_2-4-alkynyl-C_1-4-alkoxy, C_3-7-cycloalkyl-C_1-4Alkyl radical, C_5-7-cycloalkenyl-C_1-4Alkyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, C_1-4Alkoxy, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms, hydroxy or-C_1-3-alkoxy-substituted C_1-4Alkyl, via hydroxy or C_1-3-alkoxy-substituted C_2-4-alkoxy, C_3-6-cycloalkyl-C_1-3-an alkoxy group or a hydroxyl group,

also, in the above cycloalkyl and cycloalkenyl rings, 1 or 2 methylene groups may be replaced independently of one another by O or CO, and

R³is selected from the definition of B radicals, and

if R is¹Is selected from the definition of A, then R³The following meanings may also be selected additionally: hydrogen, fluorine, chlorine, bromine, iodine, C_1-6Alkyl radical, C_2-4-alkenyl-C_1-4Alkyl radical, C_2-4-alkynyl-C_1-4Alkyl radical, C_2-4-alkenyl-C_1-4-alkoxy, C_2-4-alkynyl-C_1-4-alkoxy, C_3-7-cycloalkyl, C_5-7-cycloalkenyl radical, C_3-7-cycloalkyl-C_1-4Alkyl radical, C_5-7-cycloalkenyl-C_1-4Alkyl radical, C_3-6Cycloalkylidenemethyl, hydroxy, C_1-6-alkoxy, C_3-6-cycloalkyl-C_1-3Alkoxy, aryl-C_1-3Alkyl, heteroaryl-C_1-3Alkyl, aryloxy, aryl-C_1-3-alkyl-oxy, methyl or methoxy substituted by 1-3-fluorine atoms, C substituted by 1-5 fluorine atoms_2-4-alkyl or C_2-4Alkoxy, cyano-substituted C_1-4Alkyl, via hydroxy or C_1-3-alkoxy-substituted C_1-4Alkyl, cyano, carboxyl, C_1-3-alkoxycarbonyl, aminocarbonyl, (C)_1-3-alkylamino) carbonyl, di- (C)_1-3-alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-yl-carbonyl, 4- (C)_1-3-alkyl) -piperazin-1-yl-carbonyl, (C)_1-4-alkyl) carbonylamino, C_1-4-alkyl-sulfonylamino, C_1-4Alkylthio radical, C_1-4-alkylsulfinyl, C_1-4Alkanesulfonyl, arylsulfonylamino, aryl-C_1-3-an alkylsulfonylamino or arylsulfonyl group,

however, the above-mentioned alkynyl and alkenyl groups may be mono-or polysubstituted with fluorine or chlorine, and

however, the cycloalkyl and cycloalkenyl rings mentioned above may be independently of one another selected from fluorine and C_1-3The substituents of alkyl being mono-or disubstituted, and

l1 is independently of one another selected from the group consisting of hydroxy, cyano, nitro, C_3-7Cycloalkyl, aryl, heteroaryl, C_1-4Alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, C_1-4Alkylaminocarbonyl, di- (C)_1-3-alkyl) -aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, C_1-4-alkoxycarbonyl, aryl-C_1-3-alkoxycarbonyl, heteroaryl-C_1-3-alkoxycarbonyl, C_1-4-alkoxy radicalRadical, aryloxy, heteroaryloxy, C_1-4Alkylthio, arylthio, heteroarylthio, C_1-4-alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, C_1-4Alkanesulfonyl, arylsulfonyl and heteroarylsulfonyl radicals, and

l2 is independently of one another selected from the group consisting of fluorine, chlorine, bromine, iodine, C_1-3Alkyl, difluoromethyl, trifluoromethyl, C_1-3Alkoxy, difluoromethoxy, trifluoromethoxy and cyano, and

R⁶、R^7a、

however, aryl mentioned in the above definitions of radicals means phenyl or naphthyl which may be mono-or disubstituted independently of one another by identical or different radicals L2, and

heteroaryl as mentioned in the above definition of radicals means pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl or tetrazolyl,

or indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl, in which one to three methine groups can be replaced by nitrogen atoms,

the abovementioned heteroaryl radicals may, however, independently of one another be monosubstituted or disubstituted by identical or different radicals L2,

unless otherwise indicated, however, the above alkyl groups may be straight or branched,

tautomers, stereoisomers, mixtures thereof and salts thereof.

2. Glucopyranosyl-substituted benzene derivative with general formula I.2

Wherein R is¹To R⁶And R^7a、R^7bAnd R^7cThe method is as defined in claim 1.

3. Glucopyranosyl-substituted benzene derivatives according to claim 1 or 2, characterized in that the group A represents C_2-6-alkyn-1-yl, C_2-6-en-1-yl, C_3-7-cycloalkyl, C_5-7Cycloalkenyl radical, C_1-4-alkylcarbonyl, aminocarbonyl, C_1-4Alkylaminocarbonyl, di- (C)_1-3-alkyl) aminocarbonyl, pyridylalkan-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C)_1-4-alkyl) piperazin-1-ylcarbonyl, C_1-4-alkoxycarbonyl, amino, C_1-4Alkylamino, di- (C)_1-3-alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-3-one-4-yl, piperazin-1-yl, 4- (C)_1-3-alkyl) piperazin-1-yl, C_1-4Alkanoylamino, C_3-7Cycloalkoxy, C_5-7-Cycloalkenyloxy, C_1-4-alkylsulfinyl, C_1-4-alkylsulfonyl, C_3-7Cycloalkylthio radical, C_3-7-cycloalkylsulfinyl radical, C_3-7-cycloalkanesulfonyl group, C_5-7-Cycloalkenylthio group, C_5-7-Cycloalkenylsulfinyl group, C_5-7-cycloalkenesulfonyl, cyano or nitro,

in the cycloalkyl and cycloalkenyl rings mentioned above, one or two methylene groups can be, independently of one another, O, S, CO, SO₂Or NR^NInstead of, and

l1 and R^NIs as defined in claim 1.

4. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 3, characterized in that the radical B represents tri- (C)_1-4-alkyl) silyl-C_1-6Alkyl radical, C_2-6-alkyn-1-yl, C_2-6-en-1-yl, amino, C_1-3Alkylamino, di- (C)_1-3-alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-3-one-4-yl, piperazin-1-yl, 4- (C)_1-3-alkyl) -piperazin-1-yl, nitro, C_3-7Cycloalkoxy, C_5-7-Cycloalkenyloxy, C_3-7Cycloalkylthio radical, C_3-7-cycloalkylsulfinyl radical, C_3-7-cycloalkanesulfonyl group, C_5-7-Cycloalkenylthio group, C_5-7-Cycloalkenylsulfinyl group, C_5-7-a cycloalkenylsulfonyl group,

l1 and R^NIs as defined in claim 1.

5. According to one or more of claims 1 to 4Glucopyranosyl-substituted benzene derivatives, characterized in that R³The radicals are defined as being selected from the radicals B according to claim 1 or 4.

6. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 5, characterized in that R¹The radical is selected from hydrogen, fluorine, chlorine, bromine, iodine, C_1-4Alkyl radical, C_2-6-alkynyl, C_1-4-alkoxy, C_2-4-alkenyl-C_1-4-alkoxy, C_2-4-alkynyl-C_1-4Alkoxy, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms, hydroxy or C_1-3-alkoxy-substituted C_1-4Alkyl, via hydroxy or C_1-3-alkoxy-substituted C_2-4-alkoxy, C_2-6-alkenyl, C_3-6-cycloalkyl, C_3-6-cycloalkyl-C_1-3Alkyl radical, C_3-7Cycloalkoxy, C_3-6-cycloalkyl-C_1-3-alkoxy, C_5-7Cycloalkenyloxy, hydroxy, amino, nitro or cyano, however at C_5-6-the methylene group in the cycloalkyl group may be replaced by O.

7. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 5, characterized in that R¹The radical is defined as being selected from the radicals A according to claim 1 or 3.

8. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 4 and 7, characterized in that R³The radical is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, C_1-6Alkyl, trimethylsilylethyl, C_2-6-alkenyl, C_2-6-alkynyl, difluoromethyl, trifluoromethyl, C_3-7-cycloalkyl, C_5-7-cycloalkenyl radical, C_1-6Alkoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, C_3-7Cycloalkoxy, tetrahydrofuroxy, tetrahydrofurketoxyo, C_1-6Alkylthio, cyclopropylmethylene, aryl or heteroaryl.

9. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 8, characterized in that R²And the radical represents hydrogen, fluorine, chlorine, bromine, methyl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, cyano, nitro or methyl substituted by 1 to 3 fluorine atoms.

10. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 9, characterized in that R⁴And/or R⁵The radicals are, independently of one another, hydrogen or fluorine.

11. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 10, characterized in that R⁶The radicals are hydrogen or (C)_1-8-alkyl) oxycarbonyl, C_1-8-alkylcarbonyl or benzoyl, preferably hydrogen.

12. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 11, characterized in that R^7a、R^7bAnd R^7cThe radical represents hydrogen.

13. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 12 with inorganic or organic acids.

14. A pharmaceutical composition comprising a compound according to at least one of claims 1 to 12, or a physiologically acceptable salt according to claim 13, optionally together with one or more inert carriers and/or diluents.

15. Use of a compound according to one or more of claims 1 to 12 or a physiologically acceptable salt according to claim 13 for the preparation of a pharmaceutical composition suitable for the treatment or prevention of a disease or condition affected by the inhibition of the sodium-dependent glucose cotransporter SGLT.

16. Use of a compound according to at least one of the claims 1 to 12 or a physiologically acceptable salt according to claim 13 for the preparation of a pharmaceutical composition suitable for the treatment or prevention of a metabolic disorder.

17. The use according to claim 16, characterized in that the metabolic disorder is selected from the group comprising type I or type II diabetes, complications of diabetes, metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorders, insulin resistance, metabolic syndrome, dyslipidemia of different origin, atherosclerosis and related diseases, obesity, hypertension, chronic heart failure, edema and hyperuricemia.

18. Use of a compound according to at least one of claims 1 to 12 or a physiologically acceptable salt according to claim 13 for the preparation of a pharmaceutical composition for the inhibition of the sodium-dependent glucose cotransporter SGLT 2.

19. Use of a compound according to at least one of claims 1 to 12 or a physiologically acceptable salt according to claim 13 for the preparation of a pharmaceutical composition for inhibiting pancreatic beta cell degeneration and/or for improving and/or restoring pancreatic beta cell functionality.

20. Use of a compound according to at least one of claims 1 to 12 or a physiologically acceptable salt according to claim 13 for the preparation of a diuretic and/or antihypertensive.

21. A process for the preparation of a pharmaceutical composition according to claim 14, characterized in that a compound according to at least one of claims 1 to 12 or a physiologically acceptable salt according to claim 13 is added to one or more inert carriers, and/or diluents, on a non-chemical basis.

22. A process for the preparation of compounds of the general formula I according to claims 1 to 12, characterized in that a compound of the general formula II is reacted with a reducing agent in the presence of a Lewis or Bronsted acid, wherein any protecting groups present are cleaved off simultaneously or successively,

wherein

R^8a、R^8b、

R^8c、R^8dindependently of one another, has an R which is given above or below⁶、R^7a、R^7b、R^7cThe meaning of the radicals denotes benzyl or R^aR^bR^cSi groups or ketal or acetal groups; however, in each case, two adjacent R' s^8a、R^8b、R^8c、R^8dThe radicals may form cyclic ketal or acetal groups, or 1, 2-bis (C)_1-3-alkoxy) -1, 2-bis (C)_1-3-alkyl) -ethylene bridges; however, the above-mentioned ethylene bridge and the two oxygen atoms and the two carbon atoms to which the pyranose ring belongs form a substituted di-groupAlkyl rings, and alkyl, aryl and/or benzyl groups may be substituted by halogen or C_1-3Alkoxy is mono-or polysubstituted, and benzyl may also be di- (C)_1-3-alkyl) amino substituted, and

and, the R¹To R⁵And R⁶、R^7a、R^7b、R^7cHaving the significance given in the technical solutions 1 to 12,

if necessary, reacting the thus-obtained compound of formula (I) wherein R⁶A compound of the formula I representing a hydrogen atom is converted by acylation into the corresponding acyl compound of the formula I, and/or

If desired, cleaving the protecting groups used in the above reaction, and/or

If desired, the compounds of the general formula I thus obtained are converted into their physiologically acceptable salts.

23. The process according to claim 22, wherein the compound of formula II is prepared according to the process of claim 24 or 25.

24. A process for the preparation of a compound of formula II

Wherein

R^8a、R^8b、

R^8c、R^8dindependently of one another, has an R administered⁶、R^7a、R^7b、R^7cThe meaning of the radicals denotes benzyl or R^aR^bR^cSi groups or ketal or acetal groups; however, in each case, two adjacent R' s^8a、R^8b、R^8c、R^8dThe radicals may form cyclic ketal or acetal radicals, or 1, 2-di (C)_1-3-alkoxy) -1, 2-bis (C)_1-3-alkyl) -ethylene bridges; however, the above-mentioned ethylene bridgeAnd two oxygen atoms and two associated carbon atoms of the pyranose ring to form a substituted bisAlkyl rings, and alkyl, aryl and/or benzyl groups may be substituted by halogen or C_1-3Alkoxy is mono-or polysubstituted, and benzyl may also be di- (C)_1-3-alkyl) amino substituted, and

and R¹To R⁵、R⁶、R^7a、R^7b、R^7cHaving the significance given in the technical schemes 1 to 12,

Wherein Hal represents Cl, Br and I, and R¹To R⁵Is as defined above, and optionally followed by transmetallation, is added to the gluconolactone of the formula VI

Wherein R is^8a、R^8b、R^8c、R^8dIs as defined above, and

then, make the generated additionThe compound is reacted with water in the presence of an acid or wherein R' represents optionally substituted C_1-4-alkyl R ' -OH alcohol and converting the product obtained by reaction with water, wherein R ' represents H, in a subsequent reaction with an acylating agent to a product wherein R ' represents (C) as described above_1-18-alkyl) carbonyl, (C)_1-18-alkyl) oxycarbonyl, arylcarbonyl or aryl- (C)_1-3-alkyl) -carbonyl, substituted as specified.

25. The process according to claim 24, wherein the organometallic compound (V) is a lithium or magnesium compound.

26. Preparation of a compound in which R is⁶、R^7a、R^7bAnd R^7cProcess for the preparation of compounds of the formula I according to claims 1 to 12, which represent hydrogen, characterized in that compounds of the formula III are subjected to hydrolysis

Wherein

R^8a、R^8b、

R^8c、R^8dIndependently of one another with an administered R⁶、R^7a、R^7b、R^7cRadical, but at least R^8a、R^8b、R^8c、R^8dIn which one does not represent hydrogen, or represents benzyl or R^aR^bR^cSi groups or ketal or acetal groups; however, in each case, two adjacent R' s^8a、R^8b、R^8c、R^8dThe radicals may form cyclic ketal or acetal radicals, or 1, 2-di (C)_1-3-alkoxy) -1, 2-bis (C)_1-3-alkyl) -ethylene bridges; however, the above-mentioned ethylene bridge forms a substituted di-group with two oxygen atoms and two carbon atoms involved in the pyranose ringAlkyl rings, and alkyl, aryl and/or benzyl groups may be substituted by halogen or C_1-3Alkoxy is mono-or polysubstituted, and benzyl may also be di- (C)_1-3-alkyl) amino substituted, and

R^a、R^b、R^cindependently of one another represent C_1-4Alkyl, aryl or aryl-C_1-3Alkyl, where the alkyl or aryl radical may be mono-or polysubstituted by halogens,

according to the definition of the radicals mentioned above, aryl is, however, intended to mean phenyl or naphthyl, preferably phenyl,

and, R¹To R⁵、R⁶、R^7a、R^7b、R^7cHaving the significance given in accordance with the technical aspects 1 to 12,

and also

27. A process according to claim 26, characterized in that the compound of formula III is prepared by means of a process according to claim 22 or 23.

28. A compound of formula IV

Wherein Hal represents chlorine, bromine or iodine, and R¹、R²、R³、R⁴And R⁵The radicals are as defined in one or more of claims 1 and 3 to 10.

29. The compound of formula IV according to claim 28, characterized by formula

Wherein Hal represents chlorine, bromine or iodine, and R¹、R²、R⁴And R⁵The radicals are as defined in one or more of claims 1,3, 6, 7, 9, 10; and R is³The radical is selected from the group B according to claim 1 or 4.

30. A compound of formula II

Wherein

R^8a、R^8b、

R^8c、R^8dindependently of one another with an administration of R⁶、R^7a、R^7b、R^7cThe meaning of radical, or represents benzyl or R^aR^bR^cSi groups or ketal or acetal groups; however, in each case, two adjacent R' s^8a、R^8b、R^8c、R^8dThe radicals may form cyclic ketal or acetal groups, or 1, 2-bis (C)_1-3-alkoxy) -1, 2-bis (C)_1-3-alkyl) -ethylene bridges; however, the above-mentioned ethylene bridgeAnd two oxygen atoms and two associated carbon atoms of the pyranose ring to form a substituted bisAlkyl rings, and alkyl, aryl and/or benzyl groups may be substituted by halogen or C_1-3Alkoxy is mono-or polysubstituted, and benzyl may also be di- (C)_1-3-alkyl) amino substituted, and

R^a、R^b、R^cindependently of one another represent C_1-4Alkyl, aryl or aryl-C_1-3Alkyl, which alkyl or aryl may however be mono-or polysubstituted by halogen,

and R¹To R⁵As defined in claim 1 and one or more of claims 3 to 10.

Claims

1. Glucopyranosyl-substituted benzene derivatives of the general formula I.2c

Wherein

R¹Selected from chlorine, and

R²is hydrogen, and

R³selected from tetrahydrofuran-3-yloxy;

R⁴、R⁵represents hydrogen, and is represented by the formula,

R⁶、R^7a、R^7band R^7cIs a hydrogen atom, and is,

or a physiologically acceptable salt thereof.

2. Process for the preparation of compounds of the general formula i.2c according to claim 1, characterized in that a compound of the general formula II below is reacted with a reducing agent in the presence of a lewis or bronsted acid, wherein any protecting groups present are cleaved off simultaneously or successively:

wherein

R' represents H, C_1-3-alkyl or benzyl;

R^8a、R^8b、R^8c、R^8dh, C are represented independently of each other_1-4-alkylcarbonyl or benzyl; and

R¹to R⁵Having the meaning given in claim 1,

wherein the substituents R on the phenyl ring¹Para to the glucopyranosyl group and a substituent R on the benzyl ring³in-CH₂-para to the bridging group,

the compounds of the general formula i.2c thus obtained are, if desired, resolved into their stereoisomers.