Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture

SIGNATURE OF THE APPLICANT

SIGNATURE OF ATTORNEY

Dr. Maria Rosa Fabara Vera

Dr. Maria Rosa Fabara Vera

TECHNICAL MEMORY

Glucopyranosyl substituted benzonitrile derivatives, pharmaceutical compositions containing compounds of this type, their use and manufacturing process

The present invention relates to glucopyranosyl substituted benzonitrile derivatives of the general formula I

<img file="ECSP088774A_D0001.tif" />

where the group R³ is defined herein below, including its tautomers, its stereoisomers, its mixtures, and its salts. The invention also relates to pharmaceutical compositions containing a compound of formula I according to the invention, as well as the use of a compound according to the invention to prepare a pharmaceutical composition for the treatment of metabolic disorders. Furthermore, the invention relates to processes for preparing a pharmaceutical composition, as well as a compound according to the invention.

In the literature, compounds having an inhibitory effect on the sodium-dependent glucose cotransporter SGLT2 have been proposed for the treatment of diseases, in particular diabetes.

Glucopyranosyl-substituted aromatic groups and their preparation and their possible activity as SGLT2 inhibitors are known from the international application WO 2005/092877 and the publications cited therein.

Objective of the invention

The purpose of the present invention is to find new glucopyranosyl-substituted benzonitrile derivatives, particularly those that are active with respect to the sodium-dependent glucose cotransporter SGLT, particularly SGLT2. A further objective of the present invention is to discover glucopyranosyl-substituted benzonitrile derivatives that have an improved inhibitory effect on the sodium-dependent glucose cotransporter SGLT2 in vitro and/or in vivo compared to known and structurally similar compounds and/or that have better pharmacological or pharmacokinetic properties.

A further objective of the present invention is to provide new pharmaceutical compositions that are suitable for the prevention and/or treatment of metabolic disorders, in particular diabetes.

Other objects of the present invention will be apparent to those skilled in the art as a direct result of the above and following comments.

Object of the invention

In a first aspect, the present invention relates to glucopyranosyl substituted benzonitrile derivatives of formula I

<img file="ECSP088774A_D0002.tif" />

in which

R.³ means hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, iso-butyl, tert.-butyl, 3-methyl-but-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -hydroxycyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy¡ -2-methylprop-1 -yl, 3-hydroxy-3-methyl-but-1 -yl, 1 -hydroxy-1-methyl-ethyl, 2,2,2-trif fluoro-1 -hydroxy-1 -methyl-ethyl, 2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy , difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, or cyano, or a derivative thereof, wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C alkyl₁₁₈)carbonyl, (C alkyl₁₁₈)oxycarbonyl, phenylcarbonyl and phenyl-(alkylCi_₃)-carbonyl;

including its tautomers, stereoisomers, or mixtures thereof; and their physiologically acceptable salts.

The compounds 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 SGLT2. In addition, the compounds according to the invention can have an inhibitory effect on the sodium-dependent glucose cotransporter SGLT1. Compared to a possible inhibitory effect on SGLT1, the compounds according to the invention preferentially inhibit SGLT2 selectively.

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

This invention also relates to pharmaceutical compositions, containing at least one compound according to the invention or a physiologically acceptable salt according to the invention, optionally together with one or more inert carriers and/or diluents.

This invention also relates to the use of at least one compound according to the invention, or a physiologically acceptable salt thereof, for preparing a pharmaceutical composition that is suitable for the treatment or prevention of diseases or conditions that can be influenced by cotransporter inhibition. sodium-dependent glucose receptor SGLT, particularly SGLT2.

This invention also relates to the use of at least one compound according to the invention, or a physiologically acceptable salt thereof, for preparing a pharmaceutical composition that is suitable for the treatment of one or more metabolic disorders.

In a further aspect, the present invention relates to the use of at least one compound according to the invention, or one of the physiologically acceptable salts thereof, for preparing a pharmaceutical composition for preventing pancreatic beta cell degeneration and/or for improve and/or restore the functionality of pancreatic beta cells.

In a further aspect, the present invention relates to the use of at least one compound according to the invention, or one of the physiologically acceptable salts thereof, to prepare a pharmaceutical composition for preventing, slowing down, delaying or treating diseases or conditions attributed to an abnormal accumulation of fat in the liver in a patient who needs it.

This invention also relates to the use of at least one compound according to the invention, or a physiologically acceptable salt thereof, for preparing a pharmaceutical composition for inhibiting the sodium-dependent glucose cotransporter SGLT, in particular SGLT2.

The invention also refers to a process for preparing a pharmaceutical composition according to the invention, characterized in that a compound according to the invention, or one of its physiologically acceptable salts, is incorporated into one or more inert vehicles and/or diluents by means of a non-chemical method.

The present invention also relates to a process for preparing the compounds of general formula I according to the invention, characterized in that

a) in order to prepare compounds of general formula I that are defined as indicated above and hereinafter, a compound of general formula II

<img file="ECSP088774A_D0003.tif" />

in which

R' means H, Cm-alkyl, (C^isj-alkylcarbonyl, (Cvisjoxycarbonyl-alkyl, arylcarbonyl and aryl-CysJ-alkylcarbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted with halogen;

p8a p8b

R.^8c,R⁸⁰, independently of each other, signify hydrogen or an allyl group, a benzyl group, a (Ci.4-alkyl)carbonyl group, (C^alkyloxycarbonyl, arylcarbonyl, aryl-(Ci^alkylcarbonyl) and aryl(C13alkyl)oxycarbonyl , or signify a group R^toR.^bR.^cS, or a ketal or acetal group, particularly an alkylidene or arylalkylidene ketal or acetal group, while in each case two R groups^8a,R^8b,R^8c,R^8d adjacent can form a cyclic ketal or acetal group or a 1,2-di(Ci_3-alkoxy)-1,2-di(Ci-alkyl) bridge.₃)-ethylene, while the aforementioned ethylene bridge forms, together with two oxygen atoms and the two associated carbon atoms of the pyranose ring, can form a substituted dioxane ring, particularly a 2,3-dimethyl-2,3-ring -di(alkoxy C₁₃)-1,4-dioxane, and while the alkyl, allyl, aryl and/or benzyl groups may be mono- or polysubstituted with halogen or C^alkoxy, and while the benzyl groups may also be substituted with a group di-(alkyl Ci_₃-)Not me; and

R.^to,R^b,R^c, independently of each other, mean alkyl Ci_₄, aryl or aryl-(Ci_ alkyl₃), wherein the aryl or alkyl groups may be mono- or polysubstituted with halogen;

whereas by the aryl groups mentioned in the definition of the above groups is meant phenyl or naphthyl groups, preferably phenyl groups;

and where the group R³ is defined as before in this specification and as hereinafter;

reacted with a reducing agent in the presence of a Lewis or Bronsted acid, while any protecting groups present are cleaved simultaneously or subsequently; either

b) in order to prepare compounds of general formula I, a compound of general formula III

<img file="ECSP088774A_D0004.tif" />

where R^8a,R^8b,R^8c,R^8d and R³ are defined as herein before and as hereinafter, with the proviso that at least one selected substituent of R^8a,R^8b,R^8c,R^8d not be hydrogen;

protective groups R are cleaved^8a,R^8b,R^8c,R^8d that are not hydrogen; and if desired, a compound of general formula I, so obtained, is converted by acylation into a corresponding acyl compound of general formula I, and/or if necessary, any protecting groups used in the reactions described above are cleaved and/ or if desired, a compound of general formula I obtained in this way is separated into its stereoisomers and/or if desired, a compound of general formula I obtained in this way is converted into its salts, in particular, for pharmaceutical use, in their physiologically acceptable salts.

A further aspect of the present invention relates to novel intermediates as described in the reaction schemes in the experimental part appearing herein below.

Detailed description of the invention

Aspects according to the present invention, in particular the compounds, pharmaceutical compositions and uses thereof, relate to glucopyranosyl-substituted benzonitrile derivatives of general formula I as defined hereinabove and hereinafter, or derivatives thereof, including tautomers, stereoisomers or mixtures thereof, and their physiologically acceptable salts.

In the following, alternative preferred embodiments of the present invention are described:

According to a first embodiment of the present invention R³ means hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, iso-butyl, tert.-butyl, 3-methylbut-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy- 1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, or cyano.

According to a second embodiment of the present invention R³ means hydrogen, fluoro, chloro, bromo, iodo, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl or cyano.

According to a third embodiment of the present invention R³ means methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, iso-butyl, tert.-butyl, 3-methyl-but-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl or 2-ethoxy-ethyl.

According to a fourth embodiment of the present invention R³ means methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, iso-butyl, tert.-butyl, 3-methyl-but-1-yl, difluoromethyl, trifluoromethyl or pentafluoroethyl.

According to a fifth embodiment of the present invention R³ means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

According to a sixth embodiment of the present invention R³ means 1-hydroxycyclobutyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl or 1-hydroxy-cyclohexyl.

According to a seventh embodiment of the present invention R³ means 2-hydroxyethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl or 2-ethoxy-ethyl.

According to an eighth embodiment of the present invention R³ means 2-hydroxyethyl, hydroxymethyl, 3-hydroxy-propyl or 1-hydroxy-1-methyl-ethyl.

According to a ninth embodiment of the present invention R³ means hydroxy, difluoromethyloxy, trifluoromethyloxy or cyano.

According to a tenth embodiment of the present invention R³ means methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl or pentafluoroethyl.

Preferably, all hydroxyl groups of the β-D-glucopyranosyl group are unsubstituted or only the 0-6 hydroxyl group of the β-D-glucopyranosyl group is substituted as defined. Preferred substituents are selected from (C-alkyl_V8)carbonyl, (alkyl

Ci.₈)oxycarbonyl and phenylcarbonyl. Even more preferred substituents are selected from acetyl, methoxycarbonyl and ethoxycarbonyl, in particular acetyl and ethoxycarbonyl.

The nomenclature in the structural formulas used before and hereafter, in which a bond of a substituent of a cyclic group such as, for example, a phenyl ring, shows toward the center of the cyclic group, indicates, unless otherwise noted. specify otherwise, that this substituent may be attached to any free position of the cyclic group bearing an H atom.

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

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

Scheme 1: Addition of an Organometallic Compound to a Gluconolactone

<img file="ECSP088774A_D0005.tif" />

II

<img file="ECSP088774A_D0006.tif" />

The reaction according to Scheme 1 is preferably carried out starting from a halogenated benzylbenzene compound of general formula IV, where Hal means chloro, bromo or iodo. R.¹ in Scheme 1 means cyano or a group that can be subsequently converted to a cyano group such as chloro, bromo, carboxy, carboxylic ester, carboxamide or a derivative thereof, a boron or silyl group, a protected or masked aldehyde function such as , p. eg, acetal or thiazole, or a protected or masked amino functionality such as, e.g. eg, nitro. Benzylbenzene(V) lithium or Grignard reagent can be prepared from the corresponding chlorinated, brominated or iodinated benzylbenzene IV via the so-called metal-halogen exchange reaction or by inserting the metal into the carbon-halogen bond. Halogen-metal exchange to synthesize the corresponding lithium compound V can be carried out, for example, with an organolithium compound, such as e.g. eg, n-, sec- or tert.-butyllithium. The analogous magnesium compound can also be generated by metal-halogen exchange with a suitable Grignard reagent such as e.g. isopropyl- or sec.-butyl-magnesium bromide or chloride, or diisopropyl- or di-sec.-butyl magnesium without or with the presence of an additional salt such as, e.g. lithium chloride, which can speed up the metalation process; the specific transmetalating organomagnesium compound can also be generated in situ from suitable precursors (see, eg, Angew. Chem. 2004, 116, 3396- 3399 and Angew. Chem. 2006, 118, 165-169 and references cited therein). In addition, ate complexes of organomagnesium compounds resulting from combining, e.g. butyl magnesium chloride or bromide or isopropyl magnesium butyllithium chloride or bromide (see, eg, Angew. Chem. 2000, 112, 2594-2596 and Tetrahedron Lett. 2001, 42, 4841-4844 and cited references in them). Halogen-metal exchange reactions are preferably carried out between 40 °C and -100 °C, particularly preferably between 10 Ό and -80 °C, in an inert solvent or mixtures thereof, such as, for example , diethyl ether, dioxane, tetrahydrofuran, toluene, hexane, dimethyl sulfoxide, dichloromethane or mixtures thereof. The magnesium or lithium derivatized compounds thus obtained can optionally be transmetallated with metal salts, such as eg cerium trichloride, zinc chloride or bromide, indium chloride or bromide, to form alternative organometallic compounds (V) , suitable for addition. Alternatively, organometallic compound V can also be prepared by inserting a metal into the carbon-halogen bond of haloaromatic compound IV. Lithium or magnesium are suitable elemental metals for this transformation. Insertion can be achieved in solvents, such as e.g. g., diethyl ether, dioxane, tetrahydrofuran, toluene, hexane, dimethyl sulfoxide and their mixtures, at temperatures ranging from -80 to

100 °C, preferably at -70 to 40 °C. In cases where a spontaneous reaction does not take place, a prior activation of the metal might be necessary, such as e.g. eg, treatment with 1,2-dibromoethane, iodine, trimethylsilyl chloride, acetic acid, hydrochloric acid and/or ultrasonication. The addition of the organometallic compound V to gluconolactone or derivatives thereof (VI) is preferably carried out at temperatures between 40 °C and -100 °C_: particularly preferably at 0 to -80 °C, in an inert solvent or mixtures thereof, to obtain the compound of formula II. All of the foregoing reactions can be carried out in air, although execution under an inert gas atmosphere such as argon and nitrogen is preferred. The metallation and/or coupling reaction can also be carried out in microreactors and/or micromixers that allow high exchange rates; for example, analogously to the procedures described in WO 2004/076470. Suitable solvents for the addition of the metallated phenyl group V to the appropriately protected gluconolactone VI are, e.g. eg, diethyl ether, dimethoxyethane, benzene, toluene, methylene chloride, hexane, tetrahydrofuran, dioxane, /V-methylpyrrolidone and mixtures thereof. Addition reactions can be carried out without any additional adjuvants or, in the case of slow-reacting mating partners, in the presence of a promoter such as e.g. eg, BF₃OEt₂ or me₃S¡CI (see M. Schlosser, Organometallics in Synthesis, John Wiley &amp; Sons, Chichester/New

York/Brisbane/Toronto/Singapore, 1994). Preferred definitions of substituents R⁸ in Scheme 1 they are benzyl, benzyl, allyl, substituted trialkylsilyl, particularly preferably trimethylsilyl, triisopropylsilyl, allyl, 4-methoxybenzyl and benzyl. If two substituents R⁸ adjacent are bonded together, these two substituents are preferably part of a benzylideneacetal, 4-methoxybenzylideneacetal, isopropylketal or constitute a dioxane with 2,3-dimethoxybutylene, which is bonded through the 2- and 3-butane positions with the atoms of oxygen adjacent to the pyranose. The group R' preferably signifies hydrogen, C^ alkyl, C alkyl₁₄-carbonyl or C^-alkyloxycarbonyl, particularly preferably hydrogen, methyl or ethyl. The R' group is introduced after the addition of the organometallic compound V or a derivative thereof, to the gluconolactone VI. If R' is equal to hydrogen or C1-4alkyl, the reaction solution is treated with an alcohol such as e.g. eg methanol or ethanol or water in the presence of an acid such as e.g. g., acetic acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, trifluoroacetic acid or hydrochloric acid. R' can also be fixed after preparation of the hydrogenated compound II by reacting the anomeric hydroxyl group with a suitable electrophile such as e.g. eg methyl iodide, dimethyl sulphate, ethyl iodide, diethyl sulphate, acetyl chloride or acetic anhydride, in the presence of a base such as e.g. eg, triethylamine, ethyldiisopropylamine, sodium or potassium or cesium carbonate, sodium or potassium or cesium hydroxide. The hydroxyl group can also be deprotonated before the addition of the electrophile, eg. with sodium hydride. During the installation of R' the protecting groups R⁸ they can be cleaved if they are labile under the reaction conditions employed, resulting in the correspondingly protonated compound, ie compound II, where R⁸ is equal to h.

The synthesis of the haloaromatic compound of formula IV can be carried out using conventional transformations in organic chemistry, or at least by methods known in the specialized organic synthesis literature (see, among others, J. March, Advanced Organic Reactions, Reactions, Mechanisms, and Structure, 4-edition, John Wiley &amp; Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1992 and the bibliography cited in this publication). More specifically, the use of transition metals and organometallic compounds for the synthesis of aromatic compounds has been detailed in different monographs (see, for example, L. Brandsma, SF Vasilevsky, HD Verkruijsse, Application of Transition Metal Catalysts in Organic Synthesis , Springer-Verlag, Berlin/Heidelberg, 1998; M. Schlosser, Organometallics in Synthesis, John Wiley &amp; Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1994; PJ Stang, F. Diederich, Metal-Catalyzed CrossCoupling Reactions, Wiley-VCH, Weinheim, 1997 and references cited therein). The synthesis strategies described below provide a demonstration of this, by way of example. Furthermore, the aglycone part can also be assembled with the pyranose moiety already present, using the same synthesis approaches.

Scheme 2: Synthesis of the Diarylketone Fragment

<img file="ECSP088774A_D0007.tif" />

Scheme 2 shows the preparation of a precursor compound that can be used for the synthesis of the haloaromatic compound of formula IV, starting from a benzoyl chloride and a second aromatic group, applying Friedel-Crafts acylation conditions or its variations. R.¹ in Scheme 2 means cyano or a group that can be subsequently converted to a cyano group such as chloro, bromo, carboxy, carboxylic ester, carboxamide or a derivative thereof, a protected or masked aldehyde function such as e.g. eg thioacetal or thiazole, or a protected or masked amino functionality such as e.g. eg, nitro. This classical reaction has a wide range of substrates and is usually carried out in the presence of a catalyst that is used in catalytic or stoichiometric amounts such as, for example, AICI.₃, FeCI₃, iodine, iron, ZnCI₂, sulfuric acid, or trifluoromethanesulfonic acid. Instead of benzoyl chloride, the corresponding carboxylic acid, anhydride, ester or benzonitrile can also be used. The reactions are preferably carried out in chlorinated hydrocarbons such as, for example, dichloromethane and 1,2-dichloroethane at temperatures of -30⁹C to 120°C, preferably 30²C at 100Ό. However, solvent-free reactions or reactions in a microwave oven are also possible.

Scheme 3: Reduction of Diarylketones and Diarylmethanols to Diarylmethanes

<img file="ECSP088774A_D0008.tif" />

IV χ = leaving group, e.g.

Cl, Br, I, OSOjR, OOCR, OOCOR

<img file="ECSP088774A_D0009.tif" />

In Scheme 3 the substituent R means C-alkyl.₃or aryl and R¹ means cyano or a group that can be subsequently converted to a cyano group such as chloro, bromo, carboxy, carboxylic ester, carboxamide or a derivative thereof, a boron or silyl group, a protected or masked aldehyde function such as e.g. eg, acetal or thiazole, or a protected or masked amino function such as, e.g. eg, nitro. Starting from diarylketone or diarylmethanol, diarylmethane can be obtained in one or two reaction steps. The diarylketone can be reduced to diarylmethane in two steps via the corresponding diphenylmethanol, or in one step. In the two-stage variant, the ketone is reduced with a reducing agent such as, for example, a metal hydride, such as, for example, NaBH₄, L¡AIH₄ or Boo₂AIH to form the alcohol. The resulting alcohol can be converted in the presence of a Lewis acid such as, for example, BF₃OEt₂, lnCI₃ or AICI₃ or a Bronsted acid such as, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid or acetic acid with a reducing agent such as e.g. eg, et₃S¡H, NaBH₄ or Ph₂S¡CIH in the desired diphenylmethane. The one-step process starting from the ketone to obtain diphenylmethane can be carried out, for example, with a silane such as Et₃SiH, a borohydride such as, for example, NaBH₄, or an aluminum hydride such as LiAIH₄ in the presence of a Lewis or Brensted acid such as, for example, BF₃OEt₂, tris(pentafluorophenyl)borane, trifluoroacetic acid, hydrochloric acid, aluminum chloride or lnCI₃. The reactions are preferably carried out in solvents such as, for example, halogenated hydrocarbons, such as dichloromethane, toluene, or acetonitrile, or mixtures thereof, at temperatures of -30^yesC to 1500, preferably 20^B.C to 100°C. Hydrogen reductions in the presence of a transition metal catalyst such as, for example, Pd on charcoal, other synthesis methods being possible. Reductions according to Wolff-Kishner or its variants are also possible. The ketone is first converted with hydrazine or its derivative such as, for example, 1,2-bis(tert-butyldimethylsilyl)hydrazine, into the hydrazone which degrades under strongly basic reaction conditions and heating to form diphenylmethane and nitrogen. The reaction can be carried out in one reaction step, or after isolation of the hydrazone or its derivative in two separate reaction steps. Suitable bases include, e.g. KOH, NaOH or KOtBu in solvents such as e.g. eg, ethylene glycol, toluene, DMSO, 2-(2-butoxyethoxy)ethanol or tert.-butane 1; Solvent-free reactions are also possible. The reactions can be carried out at temperatures between 20^andC and 250°C, preferably between 80^QC and 200 O. An alternative to the basic conditions of the Wolff-Kishner reduction is the Clemmensen reduction, which is performed under acidic conditions, which can also be used herein. The alcohol function in diarylmethanol can also be converted to a better leaving group in the first place, such as e.g. eg, chloride, bromide, iodide, acetate, carbonate, phosphate or sulfate; the subsequent reduction step to form diarylmethane is widely described in the organic chemistry literature.

Scheme 4: Synthesis of the Diarylmethane Unit and its Possible Precursor Compounds

<img file="ECSP088774A_D0010.tif" />

Hal = Cl, Br, I, OSO₂CF_3> BEAR₂p-Tol stage 1 halogen-metal exchange

<img file="ECSP088774A_D0011.tif" />

<img file="ECSP088774A_D0012.tif" />

r³ T = COOH, COOAIk, CONRj,

CN, COCI____________ addition to carboxylic acid or a derivative thereof

M = metal such as, e.g.

Li, MgHal, B(OH)₂^etaP®⁴

<img file="ECSP088774A_D0013.tif" />

<img file="ECSP088774A_D0014.tif" />

<img file="ECSP088774A_D0015.tif" />

<img file="ECSP088774A_D0016.tif" />

Y = Cl, Br, I, OSO₂CF₃, BEAR₂p-Tol

<img file="ECSP088774A_D0017.tif" />

In Scheme 4 R¹ means cyano or a group that can be subsequently converted to a cyano group such as chloro, bromo, carboxy, carboxylic ester, carboxamide or a derivative thereof, a boron or silyl group, a protected or masked aldehyde function such as e.g. eg, acetal or thiazole, or a protected or masked amino function such as, e.g. eg, nitro. The term Alk means alkyl Ci_₄ and each R substituent is selected, independently from one another, from the group consisting of H, alkyl Ci-₃ and Ci-3 alkoxy. Scheme 4 outlines the synthesis of diarylmethanes and possible precursor compounds thereof, starting from a metallated phenyl group. Lithium- or magnesium-substituted aromatics can be synthesized from chlorinated, brominated, or iodinated aromatics by a metal-halogen exchange reaction with, for example, butyllithium, isopropylmagnesium halide, or diisopropylmagnesium, or by insertion of the elemental metal in the halogen-carbon bond. The corresponding boron-substituted compound, such as, for example, boric acid, boric acid ester, or dialkylarylborane, is accessible from these metallated phenyl groups by reaction with a boron electrophile, such as, for example, boron ester or its derivative. In addition, the borado aromatic compound can also be prepared from the corresponding halogenated or pseudohalogenated precursor and a diboron or borane compound via a transition metal, eg palladium-catalyzed reaction (see for example Tetrahedron Lett. 2003, pp. 4895-4898 and references cited in that document). Lithium or magnesium substituted phenyl compounds are added to benzaldehydes (step 3) and benzoic acids or their derivatives (step 4) such as benzoic acid esters, benzamides such as, for example, Weinreb type, benzonityls, or chlorides. of benzoyl. These reactions can be carried out, mainly, without another transition metal catalyst or the transmetalation of another metal such as, for example, oxide, indium or zinc; sometimes the use of one of the latter alternatives is advantageous. Arylboric acids can be added to benzaldehydes via a rhodium catalyst to form the respective diarylmethanol (see for example Adv. Synth. Catal. 2001, pp. 343-350 and references cited therein). Furthermore, arylboronic acids, their esters, dialkylboranes or aryltrifluoroborates can be coupled with benzoyl chlorides, via a transition metal such as, for example, palladium, a complex or a salt thereof, producing diarylketones. Metallated phenyl groups can be reacted with benzyl electrophiles such as benzyl chlorides, bromides or iodides to produce diarylmethanes. Phenyl compounds derivatized with lithium or magnesium are favorably, but not always necessarily, reacted in the presence of a transition metal such as, for example, copper, iron or palladium (see, for example, Org. Lett ., 2001, 3, 2871-2874 and the references cited in this publication). Transmetallation from lithium or magnesium to, for example, boron, tin, silicon or zinc produces, for example, the corresponding aromatic boric acids, stannanes, silanes or zinc compounds, respectively, which can be subjected to coupling with electrophiles of benzyl, for example benzyl halides, carbonates, phosphates, sulfonates or carboxylic esters. The reaction is carried out in the presence of a transition metal, e.g. eg palladium, nickel, rhodium, copper or iron (see, eg, Tetrahedron Lett. 2004, pp. 8225-8228 and Org. Lett. 2005, pp. 4875-4878 and references cited therein).

Scheme 5: Introduction of the Cyano Remainder

<img file="ECSP088774A_D0018.tif" />

Hal'CN

<img file="ECSP088774A_D0019.tif" />

Hal = eg Cl, Br, I, OSO₂pTol, BEAR₂CF₃

R*

X n e.g. Me, COOH, COOAIk, YY γ = ci, Br, I, CH₂oh, ch₂OAIk, CH₂OAr_you |l &lt;

<img file="ECSP088774A_D0020.tif" />

OR^Ed

<img file="ECSP088774A_D0021.tif" />

UK

Scheme 5 indicates possible ways to attach the cyano moiety to the central phenyl group at various steps in the synthesis of target molecules. The cyano group can be introduced via a transition metal mediated coupling reaction of an appropriate cyano source such as e.g. g., sodium, potassium, zinc or copper cyanide with a halogenated or pseudo-halogenated phenyl group. Suitable catalysts can be derived from transition metals such as e.g. eg palladium, rhodium, nickel, iron or copper, which can be used in elemental form such as e.g. eg palladium on carbon, in the form of salts such as e.g. palladium chloride, bromide or acetate, or complexes with, e.g. eg phosphines such as e.g. eg triphenylphosphine, tri-tert-butylphosphine or dppf, or alkenes such as e.g. eg, dibenzylideneacetone. The active catalyst can be generated in situ or prior to addition to the reaction mixture. Additives such as e.g. eg, zinc as element or salt (see Tetrahedron Lett. 2005, 46, 1849-1853 and Tetrahedron Lett. 2005, 46, 1815-1818 and references cited therein). Another viable approach to installing the cyano functionality is to react the corresponding zinc, magnesium or lithium compound, accessible from the chlorinated, brominated or iodinated compound via a halogenated metal exchange reaction or by insertion of the respective metal into the halogen bond, with a cyano electrophile such as e.g. eg, p-tolylsulfonyl cyanide, cyanogen bromide or 2-pyridyl cyanate is another viable approach to installing cyano functionality (see, eg, Synth. Commun. 1996, 3709-3714 and references cited therein).

Scheme 6: Introduction of the cyano residue from the aldehyde or carboxylic acid derivative or

<img file="ECSP088774A_D0022.tif" />

<img file="ECSP088774A_D0023.tif" />

<img file="ECSP088774A_D0024.tif" />

X = eg Me, COOH, COOAlk,^R.XZXCH₂oh, ch₂OAIk, CH₂OAr, ||

<img file="ECSP088774A_D0025.tif" />

<img file="ECSP088774A_D0026.tif" />

An alternative introduction of the cyano group is the synthesis starting from an aldehyde or carboxamide (Scheme 6). The aldehyde function itself can be introduced as such, protected or masked. Popular protecting groups for the aldehyde function are ketals, but other protecting groups can also be used (see TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, John Wiley &amp; Sons, Inc., New York, 1999). Suitable masks for the aldehyde function are, for example, olefins and tlazoles. The aldehyde can be converted to the cyano function using e.g. eg hydroxylamine in combination with e.g. eg, formic acid, concentrated hydrochloric acid, polyphosphoric acid or pyridine-toluene. The intermediate oxime formed under these reaction conditions can be isolated prior to dehydration to provide the final product. Alternative hydroxylamine reagents such as e.g. e.g., bistrifluoroacetylhydroxylamine and NH₂BEAR₃ and the nitrile can be provided without additional reagents. Additional applicable reagents are e.g. eg, NH₄PO₄h₂ and nitropropane in acetic acid, trimethylsilyl azide or S,S-dimethylsulfur diimide.

Also carboxamides can be suitable nitrile precursors. The conversion can be carried out with dehydrating agents such as e.g. eg, trifluoroacetic acid, phosphorus pentoxide, POCI₃, CCI combination₄-phosphine, CI combination₃COCI-amine, Burgess's reagent, Vilsmeyer's reagent, SOCI₂ or cyanuric chloride. Starting from the corresponding monoalkylated carboxamide, carboxylic acid, carboxylic ester or chloride, the formation of the nitrile in one pot is also feasible without isolation of any intermediate products.

Scheme 7: Introduction of the cyano residue from the aniline precursor

<img file="ECSP088774A_D0027.tif" />

1.) d¡azot¡zation

2.) de-azionation with cyano (Sandmeyer reaction)

<img file="ECSP088774A_D0028.tif" />

X = e.g. Me, COOH, COOAIk,

CH₂oh, ch₂OAIk, CH₂OAr,

<img file="ECSP088774A_D0029.tif" />

<img file="ECSP088774A_D0030.tif" />

A well-established approach for introducing the nitrile function is the so-called Sandmeyer reaction with copper cyanide and the corresponding diazonium compound, accessible via diazotization of the respective aniline derivative. The synthesis of diazonium compounds and their subsequent de-diazotization to cyano have been widely documented in the organic chemistry literature.

Scheme 8: Alternative Synthesis of the Diarylmethane Unit

<img file="ECSP088774A_D0031.tif" />

<img file="ECSP088774A_D0032.tif" />

<img file="ECSP088774A_D0033.tif" />

COOAfk

<img file="ECSP088774A_D0034.tif" />

An alternative approach to the construction of the Diarylmethane Unit is shown in Scheme 8. It makes use of an ortho-fluoro-substituted benzonitrile, which is commercially available or obtainable by the aforementioned methods. The ortho fluoro-substituted benzonitrile is reacted with an R-substituted alkyl phenylacetate³ under basic conditions (see, eg, J. Org. Chem. 55, 1990, 4817-4821; J. Heterocycl. Chem, 32, 1995, 1461-1466) followed by ester cleavage and decarboxylation (see, p eg, J. Heterocycl. Chem, 32, 1995, 1461-1466; Org. Prep.

Proced. Int. 37, 2005, 550-555) or direct de-alkoxycarbonylation (see, eg, J. Med. Chem. 46, 2003, 5249-5257; Angew. Chem. Int. Ed. 47, 2004, 6493 -6496).

To prepare the compounds of general formula I, in process a) according to the invention, a compound of general formula II

<img file="ECSP088774A_D0035.tif" />

<img file="ECSP088774A_D0036.tif" />

where R' and R³ are as defined earlier in this specification and

R.^8a,R^8b,R^8c,R^8d are as defined herein above and represent, independently of each other, for example, acetyl, pivaloyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, allyl, trialkylsilyl, benzyl or substituted benzyl, or in each case, two adjacent R groups^8a,R^8b,R^8c,R^8d form a benzylideneacetal or isopropylidencetal or a 2,3-dimethoxy-butylene group which is bonded through the 2- and 3-positions of the butylene group to the oxygen atoms of the pyranose ring, and forms with them a substituted dioxane, which can be obtained as as described above, it is reacted with a reducing agent in the presence of a Lewis or Bronsted acid.

Suitable reducing agents for the reaction include for example silanes, such as triethyl, tripropyl-, triisopropyl- or diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, boranes, lithium aluminum hydride, diisobutylaluminum hydride or samarium iodide. Reductions are carried out without or in the presence of a suitable Bronsted acid such as, for example, hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid or acetic acid, or a Lewis acid such as, for example, boron trifluoride etherate, trimethylsilyl triflate. , titanium tetrachloride, tin tetrachloride, scandium triflate or zinc iodide. Depending on the reducing agent and acid, the reaction can be carried out in a solvent such as, for example, methylene chloride, chloroform, acetonitrile, toluene, hexane, diethyl ether, tetrahydrofuran, dioxane, ethanol, water, or mixtures thereof, to temperatures between -60°C and 120°C. A particularly suitable combination of reagents consists, for example, of triethylsilane and boron trifluoride etherate, which is conveniently used in acetonitrile or dichloromethane at temperatures between -60°C and 60°C. In addition, hydrogen in the presence of a transition metal catalyst such as, for example, palladium on charcoal or nickel-Raney, in solvents such as tetrahydrofuran, ethyl acetate, methanol, ethanol, water, or acetic acid, can be used for the transformation described.

Alternatively, to prepare the compounds of general formula I, according to process b) according to the invention, in a compound of general formula III

<img file="ECSP088774A_D0037.tif" />

where R³ is defined as before herein and

rhea_g p8d_yesg_noF_{can un0} d_and |_you protecting groups defined herein above such as, for example, an acyl, arylmethyl, allyl, acetal, ketal or silyl group, and obtainable, for example, by reduction of the compound of formula II as described herein above, the groups are cleaved protectors.

It is understood that one or more of the R groups^8a to R^8d they can be changed during the aforementioned synthesis procedures.

Any acyl protecting group used cleaves, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as acid 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 aprotically, for example in the presence of iodotrimethylsilane, at temperatures between 0^QC and 120°C, preferably at temperatures between 10^yesC and 100O. A trifluoroacetyl group is preferably cleaved by treatment with an acid, such as hydrochloric acid, optionally in the presence of a solvent, such as acetic acid, at temperatures between 50 and 120°C, or by treatment with a hydroxide solution. sodium, optionally in the presence of a solvent, such as tetrahydrofuran or methanol, at temperatures between 0²C and 50Ό.

Any acetal or ketal protecting group used cleaves, for example, hydrotrolytically in an aqueous solvent, for example in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or aprotically, for example in the presence of iodotrimethylsilane, at temperatures between 0⁹C and 120°C, preferably at temperatures between 10^andC and 100°C.

A trimethylsilyl group is cleaved, for example, in water, an aqueous solvent mixture, or a lower alcohol, such as methanol or ethanol, in the presence of a base, such as lithium hydroxide, sodium hydroxide, potassium carbonate, or sodium methoxide. .

In aqueous or alcoholic solvents, acids such as, for example, hydrochloric acid, trifluoroacetic acid or acetic acid are also suitable. For cleavage in organic solvents such as, for example, diethyl ether, tetrahydrofuran or dichloromethane, it is also suitable to use fluoride reagents, such as, for example, tetrabutylammonium fluoride.

A benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageously cleaved hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium/charcoal, in a suitable solvent such as methanol, ethanol, ethyl acetate or acetic acid. glacial, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0^QC and 100°C, but preferably at ambient temperatures between 20 and 60°C, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. However, a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A tert-butyl or tert-butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

In the reactions described above, any reactive groups present, such as ethynyl, hydroxy, amino, alkylamino or imino groups can be protected during the reaction by conventional protecting groups, which are cleaved off again after the reaction.

For example, a protecting group for an ethynyl group can be a trimethylsilyl or triisopropyl group. The 2-hydroxysoprop-2-yl group can also be used as a protecting group.

For example, a protecting group for a hydroxy group can be a trimethylsilyl, acetyl, trityl, benzyl, or tetrahydropyranyl group.

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

Furthermore, the obtained compounds of general formula I can be separated into their enantiomers and/or diastereoisomers as mentioned herein above. Thus, for example, cis/trans mixtures can be separated into their c/s and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.

Thus, for example, cis/trans mixtures can be separated by chromatography into their cis and trans isomers, the compounds of general formula I obtained that appear as racemates can be separated by methods known per se (see Allinger NL and Eliel EL in Topics in Stereochemistry , vol. 6, Wiley Interscience, 1971) into their optical antipodes, and compounds of general formula I with at least 2 asymmetric carbon atoms can be separated into their diastereoisomers based on their physicochemical differences using methods known per se, for example by chromatography and/or fractional crystallization and, if these compounds are obtained in racemic form, can be further separated into enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiral phases, or by recrystallization from an optically active solvent, or by reacting with an optically active substance which forms salts or derivatives such as, for example, esters or amides with the racemic compound, in particular acids and their alcohols and activated derivatives, and separating the diastereomeric mixture of the salts or derivatives thus obtained, for example based on their differences in solubility, while the free antipodes can be released from the salts or pure diastereoisomeric derivatives by the action of suitable agents. Commonly used optically active acids are e.g. eg, the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphosulfonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol can be, for example, (+)- or (-)-menthol, and an optically active acyl group in amides can be, for example, (+)- or (-)-menthyloxycarbonyl.

In addition, the compounds of formula I can be converted into their salts, in particular for pharmaceutical use, into the physiologically acceptable salts with inorganic or organic acids. Acids that 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 obtained compounds can be converted into mixtures, for example 1:1 or 1:2 mixtures, with amino acids, in particular with alpha-amino acids, such as proline or phenylalanine, which may have particularly favorable properties, such as high crystallinity.

The compounds according to the invention can advantageously also be obtained using the methods described in the examples below, which can also be combined for this purpose with methods known to the skilled person from the literature, for example the methods described in WO 98/31697, WO 01/27128, WO 02/083066, WO 03/099836, WO 2004/063209, WO 2005/092877 and WO 2006/120208.

The present invention also relates to novel intermediates as described in the reaction schemes hereinabove and as described in the experimental section appearing hereinafter.

In particular, the following intermediate compounds are a further aspect of the present invention:

<img file="ECSP088774A_D0038.tif" />

<img file="ECSP088774A_D0039.tif" />

LG

<img file="ECSP088774A_D0040.tif" />

<img file="ECSP088774A_D0041.tif" />

<img file="ECSP088774A_D0042.tif" />

R.

<img file="ECSP088774A_D0043.tif" />

¡.6 in which

R.^8a to R^8d are defined as herein above and preferably signify H or acetyl;

R' is defined as herein above and preferably signifies H, methyl or ethyl;

Alk means alkyl C₁₄, preferably methyl or ethyl;

R.¹ is defined as herein above and preferably means Br or CN, most preferably CN;

R.³ is defined as herein above, for example cyclopropyl or cyclobutyl, and is preferably selected from the group consisting of chloro, bromo, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, cyano;

LG means a leaving group such as Br, I, -O-(SO₂)-CF₃, preferably -O-(SO₂)-CF₃;

U stands for Cl, Br, I, -O-CO-C1-4alkyl, -OC(=O)-O-C1.4alkyl or -OPO(0-Ci-alkyl.₄)₂; preferably br

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 an inhibitory effect on the sodium-dependent glucose cotransporter SGLT, preferably SGLT2.

The biological properties of the new compounds can be investigated as follows:

The ability of the substances to inhibit SGLT-2 activity can be demonstrated in a test setup in which a CH0-K1 cell line (ATCC n⁹ CCL-61) or, alternatively, a HEK293 cell line (ATCC no.^yes CRL-1573), which is stably transfected with an expression vector pZeoSV (Invitrogen, EMBL accession number L36849), which contains the cDNA for the human sodium glucose cotransporter 2 coding sequence (Genbank no.^yes number NM_003041) (CH0-hSGLT2 or HEK-hSGLT2). These cell lines carry labeled alpha-methylglucopyranoside with¹⁴C(¹⁴C-AMG, Amersham) into the cell in a sodium-dependent manner.

The SGLT-2 assay is performed as follows:

CH0-hSGLT2 cells are grown in Ham's F12 medium (BioWhittaker) with 10% fetal calf serum and 250 pg/ml zeocin (Invitrogen), and HEK293-hSGLT2 cells are grown in DMEM medium with 10% fetal calf serum. and zeocin 250 pg/ml (Invitrogen). Cells are detached from the culture flasks by washing twice with PBS and subsequently treating with trypsin/EDTA. After addition of cell culture medium, cells are centrifuged, resuspended in culture medium, and counted in a Casy cell counter. 40,000 cells per well are then seeded into a poly-D-lysine-coated white 96-well plate and incubated overnight at 37°C, CO₂ at 5%. Cells are washed twice with 250 μΙ assay buffer (Hanks balanced salt solution, 137 mM NaCI, 5.4 mM KCI, CaCI₂ 2.8mM, MgSO₄ 1.2 mM and 10 mM HEPES (pH 7.4), 50 pg/mL gentamicin). 250 μΙ assay buffer and 5 μΙ test compound are then added to each well and the plate is incubated for a further 15 minutes in the incubator. 5 μΙ of 10% DMSO was used as a negative control. The reaction starts by adding 5 μΙ of¹⁴C-AMG (0.05 pCi) to each well. After 2 hours of incubation at 37 Ό, CO₂ at 5%, cells are washed again with 250 μΙ PBS (20 O) and then lysed by adding 25 μΙ 0.1 N NaOH (5 min at 37°C). 200 μΙ of MicroScint20 (Packard) are added to each well and incubation continues for an additional 20 min at 37Ό. After this incubation, the radioactivity of the¹⁴C-AMG absorbed into a Topcount (Packard) using a scintillation program of¹⁴c.

To determine selectivity to human SGLT1 an analogous assay is set up in which hSGLTI cDNA (Genbank accession no. NM_000343) is expressed instead of hSGLT2 cDNA in CHO-K1 or HEK293 cells.

Compounds according to the invention may, for example, have EC50 values ​​below 1000 nM, in particular below 200 nM, most preferably below 50 nM.

In view of their ability to inhibit SGLT activity, the compounds according to the invention and their corresponding pharmaceutically acceptable salts are suitable for the treatment and/or preventive treatment of all those conditions or diseases that can be affected by the inhibition of the SGLT activity, in particular SGLT-2 activity. Therefore, the compounds according to the invention are particularly suitable for the prevention or treatment of diseases, in particular metabolic disorders, or disorders such as type 1 and type 2 diabetes mellitus, complications of diabetes (such as, for example, retinopathy , nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathy), metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidemia of different origin, atherosclerosis and related diseases, obesity, arterial hypertension, chronic heart failure, edema and hyperuricemia. These substances are also suitable for preventing beta cell degeneration such as, for example, pancreatic beta cell apoptosis or necrosis. The substances are also suitable for improving or restoring the functionality of pancreatic cells, and also for increasing the number and size of pancreatic beta cells. The compounds according to the invention can also be used as diuretics or antihypertensives, and are suitable for the prevention and treatment of acute renal failure.

By administering a compound according to the invention an abnormal accumulation of fat in the liver can be reduced or inhibited. Therefore, according to another aspect of the present invention, a method is provided for preventing, slowing down, retarding or treating diseases or conditions attributed to an abnormal accumulation of fat in the liver in a patient in need thereof, characterized in that it is administered a compound or a pharmaceutical composition according to the present invention. Diseases or conditions which are attributed to abnormal accumulation of liver fat are particularly selected from the group consisting of general fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), hyperalimentation-induced fatty liver, fatty liver diabetic, alcohol-induced fatty liver, or toxic fatty liver.

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 1 and type 2 diabetes mellitus, and/or diabetic complications.

Furthermore, the compounds according to the invention are particularly suitable for the prevention or treatment of overweight, obesity (including class I, class II and/or class III obesity), visceral obesity and/or abdominal obesity.

The dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound to be administered, the patient, the nature and severity of the disease or condition, and the method and frequency of administration, and it is the physician of the patient. who should decide Conveniently, the dosage may be 1 to 100 mg, preferably 1 to 30 mg, intravenously, and 1 to 1000 mg, preferably 1 to 100 mg, orally, in each case administered 1 to 4 times daily. For this purpose, the compounds according to the invention can be formulated, optionally together with other active substances, together with one or more conventional inert carriers and/or diluents, for example with maize starch, lactose, glucose, microcrystalline cellulose, stearate of magnesium, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenical preparations, such as plain or coated tablets, capsules, powders, suspensions or suppositories.

The compounds according to the invention can also be used together with other active substances, in particular for the treatment and/or prevention of the aforementioned diseases and conditions. Other active substances that are suitable for these combinations include, for example, those that enhance the therapeutic effect of an SGLT antagonist according to the invention, with respect to one of the mentioned indications and/or that allow the dosage of an SGLT antagonist to be reduced. according to the invention. Therapeutic agents that are suitable for this combination include, for example, antidiabetic agents such as metformin, sulfonylureas (for example, glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (for example, rosiglitazone, pioglitazone), agonists (for example, , Gl 262570) and gamma-PPAR antagonists, gamma/alpha-PPAR modulators (eg, KRP 297), alpha-glucosidase inhibitors (eg, acarbose, voglibose), DPPIV inhibitors (eg LAF237, MK-431), alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (eg exendin-4), or amylin. The list also includes protein tyrosine phosphatase 1 inhibitors, substances that affect dysregulated glucose production in the liver such as, for example, glucose-6-phosphatase or fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase antagonists, glucagon receptor and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid-lowering agents such as, for example, HMG-CoA-reductase inhibitors (for example, simvastatin, atorvastatin), fibrates (for example, bezafibrate, fenofibrate), nicotinic acid and its derivatives, alpha-PPAR agonists, delta-PPAR agonists, ACAT inhibitors (for example, avasimibe) or inhibitors of cholesterol absorption such as, for example, ezetimibe, bile acid binding substances such as, for example, cholestyramine, inhibitors of iliac bile acid transport, HDL-increasing compounds, such as CETP inhibitors or ABC1 regulators, or active substances for treating obesity, such as sibutramine or tetrahydrolipostatin, dexfenfluramine, axokin, cannabinoid-1 receptor antagonists, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 antagonists or NPY2 or 83-agonists, such as SB-418790 or AD-9677, and 5HT2c receptor agonists.

Furthermore, combinations with drugs to influence arterial hypertension, chronic heart failure or atherosclerosis are suitable, such as for example A-ll antagonists or ACE inhibitors, ECE inhibitors, diuretics, 8-blockers, Ca antagonists , centrally acting antihypertensives, alpha-2-adrenergic receptor antagonists, neutral endopeptidase inhibitors, thrombocyte aggregation inhibitors and others, or their combinations. Examples of angiotensin II receptor antagonists are candesartan cilexetil, losartan potassium, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3671, GA- 0113, RU-64276, EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often in combination with a diuretic, such as hydrochlorothiazide.

A combination with inhibitors of uric or uricosuric acid synthesis is suitable for the treatment or prevention of gout.

A combination with GABA receptor antagonists, Na channel blockers, topiramate, protein kinase C inhibitors, advanced glycation end product inhibitors, or aldose reductase inhibitors may be used for treatment or prevention of complications. of diabetes.

Dosage for the aforementioned combination participants is typically 1/5 of the lowest typically recommended dose, up to 1/1 of the typically recommended dose.

Therefore, in another aspect, this invention relates to the use of a compound according to the invention, or a physiologically acceptable salt of this compound, combined with at least one of the active substances described above as a participant in the combination, to prepare a composition pharmaceutical that is suitable for the treatment or prevention of diseases or conditions that can be affected by the inhibition of the sodium-dependent glucose cotransporter SGLT. These are preferably metabolic diseases, in particular one of the diseases or conditions listed above, most in particular diabetes or diabetic complications.

The use of the compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance can take place simultaneously or in stages, but in particular within a short period of time. If administered simultaneously, the two active substances are administered to the patient together; while if they are used at staggered times, the two active substances are administered to the patient within a period of less than or equal to 12 hours, but in particular less than or equal to 6 hours.

Therefore, in another aspect, this invention relates to a pharmaceutical composition comprising a compound according to the invention, or a physiologically acceptable salt of this compound, and at least one of the active substances described above as participants in the combination, optionally together with one or more vehicles and/or inert diluents.

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

The compound according to the invention, or its physiologically acceptable salt, and the additional active substance to be combined with it can both be present together in one formulation, for example a tablet or capsule, or be separated in two identical or different formulations, for example in a so-called parts kit.

In the text above and below, the H atoms of the hydroxyl groups are not shown explicitly in each case in the structural formulas. The Examples which follow are intended to illustrate the present invention without restricting it. The expressions room temperature and ambient temperature are used interchangeably and mean temperatures of approximately 20°C. The following abbreviations are used: DMF dimethylformamide

NMP A/-methyl-2-pyrrolidine

THF tetrahydrofuran

Preparation of starting compounds:

Example I

br

ooh

4-bromo-3-hydroxymethyl-1-iodo-benzene

Oxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo-5-iodobenzoic acid in CH₂IC₂ (200mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h. Then the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 mL). The resulting solution is cooled in an ice bath and LiBH is added.₄ (3.4g) in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1 M hydrochloric acid. The organic layer is then separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na₂SW₄) and the solvent is evaporated under reduced pressure to give the crude product.

Yield: 47.0 g (99% of theory)

Example II

<img file="ECSP088774A_D0044.tif" />

4-bromo-3-chloromethyl-1-iodo-benzene

Thionyl chloride (13 mL) is added to a suspension of 4-bromo-3-hydroxymethyl-1-iodo-benzene (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at room temperature for 3h. Then the solvent and excess reagent are removed under reduced pressure. The residue is triturated with methanol and dried.

Yield: 41.0 g (82% of theory)

Example III

4-bromo-1-iodo-3-phenoxymethyl-benzene

Phenol (13 g) dissolved in 4 M KOH solution (60 mL) is added to 4-bromo-3-chloromethyl-1-iodobenzene (41.0 g), dissolved in acetone (50 mL). Nal (0.5 g) is added and the resulting mixture is stirred at 50 °C overnight. Then water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 19:1).

Yield: 38.0 g (79% of theory)

Example IV

Br (5-bromo-2-chloro-phenyl)-(4-methoxyphenyl)methanone

38.3 mL of oxalyl chloride and 0.8 mL of dimethylformamide are added to a mixture of 100 g of 5-bromo-2-chlorobenzoic acid in 500 mL of dichloromethane. The reaction mixture is stirred for 14 h, then filtered and stripped of all volatile constituents on a rotary evaporator. The residue is dissolved in 150 mL of dichloromethane, the resulting solution is cooled to -5°C, and 46.5 g of anisole are added. Then 51.5 g of aluminum trichloride are added discontinuously so that the temperature does not exceed 5°C. The solution is stirred for 1 h at 5°C and then poured into crushed ice. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with 1 M hydrochloric acid, twice with 1 M sodium hydroxide solution and with brine. The organic phase is then dried over sodium sulfate, the solvent is removed and the residue is recrystallized from ethanol.

Yield: 86.3 g (64% of theory)

mass spectrum (ESI⁺): m/z = 325/327/329 (Br+CI) [M+Hf

Example V

<img file="ECSP088774A_D0045.tif" />

1-bromo-4-chloro-3-(4-methoxy-benz¡l)-benzene

A solution of 86.2 g of (5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone and 101.5 mL of triethylsilane in 75 mL of dichloromethane and 150 mL of acetonitrile is cooled up to 10Ϊ. Then, with stirring, 50.8 mL of boron trifluoride etherate are added so that the temperature does not exceed 20°C. The solution is stirred for 14 h at room temperature, before adding another 9 mL of triethylsilane and 4.4 mL of boron trifluoride etherate. The solution is stirred for a further 3h period at 45-50°C and then cooled to room temperature. A solution of 28 g of potassium hydroxide in 70 mL of water is added, and the resulting mixture is stirred for 2 h. The organic phase is separated and the aqueous phase is extracted three more times with diisopropyl ether. The combined organic phases are washed twice with 2 M potassium hydroxide solution and once with brine, and then dried over sodium sulfate. After evaporating the solvent, the residue is washed with ethanol and dried at 60 °C.

Yield: 50.0 g (61% of theory)

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

Example VI

<img file="ECSP088774A_D0046.tif" />

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

A solution of 14.8 g of 1-bromo-4-chloro-3-(4-methoxy-benzyl)-benzene in 150 mL of dichloromethane is cooled in an ice bath. 50 mL of a 1 M solution of boron bromide in dichloromethane are added, and the resulting solution is stirred for 2 h at room temperature. The solution is then cooled in an ice bath again, and saturated aqueous potassium carbonate solution is added dropwise. At room temperature, the mixture is adjusted to pH 1 with 1 M aqueous hydrochloric acid, the organic phase is separated and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is completely removed. Yield: 13.9 g (98% of theory)

Mass spectrum (ESI'): m/z = 295/297/299 (Br+CI) [MH]'

vile example

<img file="ECSP088774A_D0047.tif" />

[4-(5-bromo-2-chloro-benz¡IMenox¡l-tert-butyl-d¡ls¡lane

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

Yield: 16.8 g (87% of theory)

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

Example VIII

<img file="ECSP088774A_D0048.tif" />

1-bromo-4-(1-methox¡-D-qlucopyranos-1-¡l)-2-(phenox¡methyl)-benzene

A 2 M solution of ¡PrMgCI in THF (11 mL) is added to dry LiCI (0.47 g) suspended in THF (11 mL). The mixture is stirred at room temperature until all the LiCl has dissolved. This solution is added dropwise to a solution of 4-bromo-1-iodo-3-phenoxymethyl-benzene (8.0 g) in tetrahydrofuran (40 mL), cooled to -60 °C under argon atmosphere. The solution is warmed to 40 °C and then 2,3,4,6-tetrakis-0-(trimethylsilyl)-D-glucopyranone (10.7 g, 90% purity) in tetrahydrofuran (5 mL) is added. The resulting solution is warmed to -5 °C in the cooling bath and stirred for another 30 min at this temperature. Aqueous NH solution is added₄CI and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is dissolved in methanol (80 mL) and treated with methanesulfonic acid (0.6 mL). After stirring the reaction solution at 35-40 °C overnight, the solution is neutralized with NaHCO₃ solid and the methanol is removed under reduced pressure. The remainder is diluted with aqueous NaHCO solution.₃ and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and the solvent is evaporated to give the crude product which is reduced without further purification.

Yield: 7.8 g (93% of theory)

Example IX

<img file="ECSP088774A_D0049.tif" />

Boron trifluride etherate (4.9 mL) is added to a solution of 1-bromo-4-(1-methoxy-D-glucopyranos-1 -yl)-2-(phenoxymethyl)-benzene (8.7 g) and triethylsilane (9.1 mL) in dichloromethane (35 mL) and acetonitrile (50 mL) cooled to -20 Ό at a rate such that the temperature is maintained below -10 °C. The resulting solution is warmed to 0 °C over a period of 1.5 h and then treated with aqueous sodium bicarbonate solution. The resulting mixture is stirred for 0.5h, the organic solvent is removed and the residue is extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate, and the solvent is removed. The residue is taken up in dichloromethane (50 mL) and pyridine (9.4 mL), acetic anhydride (9.3 mL) and 4-dimethylaminopyridine (0.5 g) are successively added to the solution. The solution is stirred for 1.5 h at room temperature and then diluted with dichloromethane. This solution is washed twice with 1 M hydrochloric acid and dried over sodium sulfate. After removing the solvent, the residue is recrystallized from ethanol to give the product as a colorless solid.

Yield: 6.78 g (60% of theory)

mass spectrum (ESI⁺): m/z = 610/612 (Br) [M+NH₄] ⁺

Example X

<img file="ECSP088774A_D0050.tif" />

2-(phenoxymethyl)-4-(2,3,4,6-tetra-0-acet¡lD-qlucop¡ranos-1-¡l)-benzonitr¡le

One flask charged with zinc cyanide (1.0 g), zinc (30 mg), Pd₂(dibenzyldenacetone)₃*CHCI₃ (141 mg) and tri-tert.-butylphosphonium tetrafluoroborate (111 mg) is flushed with argon. A solution of 1 -bromo-4-(2,3,4,6-tetra-0-acetyl-D-glucopyranos-1 -yl)-2-(phenoxymethyl)-benzene (5.4 g) is then added in Degassed NMP (12 mL) and the resulting mixture was stirred at room temperature for 18 h. After dilution with ethyl acetate, the mixture is filtered and the filtrate is washed with aqueous sodium bicarbonate solution. The organic phase is dried (sodium sulfate), and the solvent is removed. The residue is recrystallized from ethanol.

Yield: 4.10 g (84% of theory) Mass Spectrum (ESI⁺): m/z = 557 [M+NH₄] ⁺

The compound described above is also obtained according to the following process:

A flask charged with a stir bar, 1-bromo-4-(2,3,4,6-tetra-0-acetyl-D-glucoparanos-1¡l)-2-(phenoxymethyl)-benzene (14 0.7 g), copper cyanide (4.1 g) and NMP (100 mL) is heated at reflux temperature for 8 h. After dilution with water (600 mL), the precipitate is separated, washed a few times with water, and subsequently dissolved in ethyl acetate (200 mL). The resulting solution is filtered through a plug of silica gel using ethyl acetate (300 mL) as eluent. The filtrate is concentrated under reduced pressure and the residue is dissolved in dichloromethane (100 mL) to reacetylate the deprotected oxygen groups during cyanation. Accordingly, pyridine (4 mL), 4-dimethylaminopyridine (0.3 g) and acetic anhydride (4.4 mL) are successively added. The resulting solution is stirred at room temperature for 1 h. Then, the reaction mixture is diluted with dichloromethane (50 mL) and washed three times with 1 M aqueous hydrochloric acid, once with aqueous sodium bicarbonate solution, and once with water. The organic phase is dried (sodium sulfate) and the solvent is removed. The residue is recrystallized from ethanol.

Yield: 10.0 g (75% of theory).

Example XI

<img file="ECSP088774A_D0051.tif" />

2-bromomethyl-4-(2,3,4,6-tetra-0-acet¡lD-glucop¡ranos-1-¡l)-benzon¡trilo

A 33% solution of hydrobromic acid in acetic acid (15 mL) is added to a solution of 2-phenyloxymethyl-4-(2,3,4,6-tetra-0-acet¡lD-glucopyranos-1-yl)-benzonitrile (0.71 g) and acetic anhydride (0.12 mL) in acetic acid (10 mL). The resulting solution is stirred at 55^SC for 6 h and then rapidly cool in an ice bath. The reaction mixture is neutralized with cooled aqueous potassium carbonate solution and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate/cyclohexane (1:5) and the precipitate is filtered off and dried at 50°C to give the pure product. Yield: 0.52 g (75% of theory)

mass spectrum (ESI⁺): m/z = 543/545 (Br) [M+NHJ⁺

Example XII

<img file="ECSP088774A_D0052.tif" />

1-chloro-4-(8-D-qlucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene

A solution of 4.0 g of [4-(5-bromo-2-chloro-benzyl)-phenoxyj-ferc.-butyl-dimethyl-silane in 42 mL of dry diethyl ether is cooled to -80 °C under argon . 11.6 mL of a rapidly chilled solution (approx. -50^andC) 1.7 M tert-butyllithium in pentane is slowly added to the cooled solution, and then the solution is stirred for 30 min at -80 °C. This solution is then added dropwise via a transfer needle, which is cooled with dry ice, to a solution of 4.78 g of 2,3,4,6-tetraqu¡sO-(tñmethyls¡l¡l)- D-glucopyranone in 38 mL of quenched diethyl ether to -80°C. The resulting solution is stirred for 3h at -78°C. A solution of 1.1 mL of methanesulfonic acid in 35 mL of methanol is then added and the resulting reaction is stirred for another 16 h at room temperature. After the solution is neutralized with solid sodium hydrogen carbonate, ethyl acetate is added and the resulting solution is concentrated under reduced pressure. To the remaining solution, an aqueous sodium hydrogen carbonate solution is added, which is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is evaporated off. The residue is dissolved in 30 mL of acetonitrile and 30 mL of dichloromethane, and the resulting solution is cooled to -10 °C. After the addition of 4.4 mL of triethylsilane, 2.6 mL of boron tfluoride etherate are added dropwise, so that the temperature does not exceed -5°C. After the addition is complete, the reaction solution is stirred for a further 5 h at -5⁵C to -10°C and then quenched by adding aqueous sodium bicarbonate solution. The organic phase is separated and the aqueous phase is extracted four more times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol). The product obtained afterwards is a mixture of isomers that can be separated by global acetylation of the hydroxyl groups with acetic anhydride, pyridine and 4-dimethylaminopyridine in dichloromethane and recrystallization of the resulting acetylated product from ethanol. The pure β-acetylated product (precipitates from solution in ethanol), thus obtained, is converted to the title compound by removal of the acetyl groups in methanol with 4 M potassium hydroxide solution.

Yield: 1.6 g (46% of theory)

mass spectrum (ESI⁺): m/z = 398/400 (Cl) [M+NH₄] ⁺

Example XIII

<img file="ECSP088774A_D0053.tif" />

<img file="ECSP088774A_D0054.tif" />

1-chloro-2-(4-c¡clopent¡loxibenc¡l)-4-(8-D-qlucop¡ranos-1-¡l)-benzene

0.16 mL of iodocyclopentane is added to a mixture of 0.25 g of 1-chloro-4-(BD-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.4 g of cesium carbonate in 2.5 ml_ of dimethylformamide. The mixture is stirred for 4 h at 45°C, before adding another 0.1 g of cesium carbonate and 0.05 ml of iodocyclopentane. After another 14 h of stirring at 45 Ό, aqueous sodium chloride solution is added and the resulting mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is removed and the residue is purified using silica gel (dichloromethane/methanol 1:0>5:1).

Yield: 0.23 g (78% of theory) Mass Spectrum (ESI⁺): m/z = 466/468 (Cl) [M+NH₄]⁺

The following compound is obtained analogously to Example XIII:

(1) 1 -chloro-4-(3-D-glucopyranos-1-yl)-2-[4-((7=?J-tetrahydrofuran-3-yloxy)-benzyl]-benzene

The reaction is carried out with tetrahydrofuran-3-yl (S)-toluene-4-sulfonate as coupling partner.

<img file="ECSP088774A_D0055.tif" />

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

Example XIV

<img file="ECSP088774A_D0056.tif" />

1-chloro-4-(8-D-qlucopyranos-1-¡l)-2-[4-(tr¡fluoromet¡lsulfon¡lox¡)-benc¡ll-benzene

10 mg of 4-dimethylaminopyridine are added to a solution of 0.38 g of 1 -chloro-4-(R-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21 ml of triethylamine and 0.39 g of N,N-bis(trifluoromethanesulfonyl)-aniline in 10 ml of dry dichloromethane. The solution is stirred for 4 h at room temperature and then combined with brine. The resulting mixture is extracted with ethyl acetate, the organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->4:1).

Yield: 0.33 g (64% of theory)

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

The following compound is obtained analogously to Example XIV:

(1) 1 -cyano-4-(8-D-glucopyranos-1 -yl)-2-[4-(trifluoromethylsulfonyloxy)-benzyl]-benzene

<img file="ECSP088774A_D0057.tif" />

mass spectrum (ESI⁺): m/z = 504 [M+H]⁺

Example XV

<img file="ECSP088774A_D0058.tif" />

1-chloro-4-(2,3.4,6-tetra-0-acet¡l-8-D-alucoD¡ranos-1-¡l)-2-í4-(tñfluorom¡lsulfon¡lox¡)-ben¡ l1-benzene

To a solution of 5.6 g of 1 -chloro-4-(8-D-glucopyranos-1 -yl)-2-[4-(trifluoromethylsulfonyloxy)-benz¡l]benzene in 75 mL of dichloromethane are added consecutively 7 mL of pyridine, 7.8 mL of acetic anhydride and 0.12 g of 4-dimethylaminopyridine. The solution is stirred at room temperature for 1 h. After the addition of 50 ml of water, the resulting mixture is stirred for a further 5 min. The organic phase is separated and washed with 1M aqueous hydrochloric acid and aqueous sodium bicarbonate solution. After drying over magnesium sulfate and evaporation of the organic solvent, the product is produced as a white solid.

Yield: 7.0 g (94% of theory)

mass spectrum (ESI⁺): m/z = 698/700 (Cl) [M+NHJ⁺

The following compound is obtained analogously to Example XV:

(1) 1 -cyano-4-(2,3,4,6-tetra-O-acetyl-8-D-glucopyranos-1 -yl)-2-[4-(trifluoromethylsulfonyloxy)-benzyl]-benzene

<img file="ECSP088774A_D0059.tif" />

Example XVI

<img file="ECSP088774A_D0060.tif" />

1-chloro-2-(4-ethyn¡l-benz¡l)-4-(8-D-qlucop¡ranos-1-¡l)-benzene

25 mg of copper iodide, 44 mg of bis-(triphenylphosphine)-palladium dichloride, 0.30 ml of triethylamine and finally 0.14 ml of trimethylsilylacetylene are added under argon to a solution of 0.32 g of 1 -chloro-4(β-D-glucopyranos-l-yl)-2-[4-(t¡fluoromethyl-sulfon¡lox¡)-benz¡l]benzene in 3 ml of dimethylformamide. The flask is hermetically sealed and the mixture is stirred for 8 h at 90°C. Then another 25 mg of bis-(triphenylphosphine)-palladium dichloride and 0.1 ml of trimethylsilylacetylene are added, and the solution is stirred for a further 10 h at 90 O. After aqueous sodium hydrogen carbonate solution is added, the mixture The resultant is extracted three times with ethyl acetate and the combined organic phases are dried over sodium sulfate. After evaporating the solvent, the residue is dissolved in 5 ml of methanol and 0.12 g of potassium carbonate are added. The mixture is stirred for 1 h at room temperature and then neutralized with 1 M hydrochloric acid. After the methanol is evaporated, the residue is combined with brine and extracted with ethyl acetate. The collected organic extracts were dried over sodium sulfate and the solvent was removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0>5:1).

Yield: 0.095 g (40% of theory) Mass Spectrum (ESI⁺): m/z = 406/408 (Cl) [M+NH₄]⁺

Example XVII or

<img file="ECSP088774A_D0061.tif" />

-chloro-2-(4-ethyl-benzyl)-4-( β-D-allucopyrans-l -yl)-benzene

2.87 g of 1-chloro-2-(4-ethynyl-benzyl)-4-(BD-glucopyranos-1-yl)-benzene are dissolved in 10 ml of ethyl acetate and 5 ml of ethanol. 0.3 g of 10% palladium on carbon are added and the resulting mixture is stirred under an atmosphere of hydrogen (1 atm) overnight. The reaction mixture is filtered over Celite and the filtrate is concentrated. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->5:1).

Yield: 1.0 g (34% of theory)

mass spectrum (ESI⁺): m/z = 410/412 (Cl) [M+NH₄]⁺

Example XVIII

Cl

1-chloro-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyll-4-(2₁3₁4₁6-tetra-0-acetyl-8-D-qlucopyranos-1-yl)-benzene

To a solution of 2.02 g of 1 -chloro-4-(3-D-glucopyranos-1 -yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)benzylj-benzene in 20 mL of dichloromethane are added in succession 2.5 mL of pyridine, 2.8 mL of acetic anhydride and 50 mg of 4-dimethylaminopyridine. The reaction solution is stirred at room temperature for 4 h. The solution is diluted with 50 mL of dichloromethane, washed twice with 50 mL of 1 M hydrochloric acid and once with sodium bicarbonate solution. After drying over sodium sulfate, the solvent is evaporated to provide the product.

Yield: 2.53 g (91% of theory) Mass Spectrum (ESI⁺): m/z = 642/644 (Cl) [M+Na]⁺

The following compounds can be obtained analogously to Example XVIII:

(1) 1 -chloro-2-[4-ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-pD-glucopyranos-l -yl)-benzene

EITHER

<img file="ECSP088774A_D0062.tif" />

(2) 2-(4-acetoxy-benzyl)-1 -chloro-4-(2,3,4,6-tetra-0-acetyl-BD-glucopyranos-1 -yl)-benzene

<img file="ECSP088774A_D0063.tif" />

Mass spectrum (EST): m/z = 608/610 (Cl) [M+NH₄]⁺ (3) 1 -cyano-2-(4-methoxy-benzyl)-4-(2,3,4,6-tetra-0-acetyl-8-D-glucopyranos-1 -yl)-benzene

<img file="ECSP088774A_D0064.tif" />

Example XIX

<img file="ECSP088774A_D0065.tif" />

1-chloro-2-(4-methyl-benzyl)-4-(2,3.4,6-tetra-0-acet¡lBD-glucop¡ranos-1-¡l)-benzene

Diisobutylaluminum hydride (54 μ!_, 1 mol/L in toluene) is added to a mixture of 1,1'bis(diphenylphosphino)ferrocene-dichloropalladium(ll) (22 mg) in THF (3 mL) under an atmosphere of Ar and rapidly cooled in an ice bath. The mixture is stirred in the ice bath for 0.5 h, then 1-chloro-4-(2,3,4,6-tetra-O-acetyl-8-D-glucoparanos- 1-yl)-2-[4-(trifluoromethylIsuIfonyloxy)-benziI]benzene (0.60 g) and Me₂Zn (0.88 mL, 1 mol/L in toluene). The ice bath is removed and the mixture is refluxed for 2.5 h. After cooling to room temperature, 1M hydrochloric acid is added and the resulting mixture is extracted with ethyl acetate. The collected extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:0->2:1).

Yield: 0.25 g (52% of theory)

Example XX

<img file="ECSP088774A_D0066.tif" />

1-chloro-2-(4-cyano-benz¡l)-4-(2.3,4,6-tetra-0-acet¡l-8-D-qlucoD¡ranos-1-¡l)-benzene

Tetrakis(triphenylphosphine)palladio(0) (0.13 g) is added to a flask filled with 1-chloro-4-(2,3,4,6-tetra-0-acetyl-3-D-glucopyrans-1- yl)-2-[4-(trifluoromethylsulfonyloxy)-benzyl]-benzene (0.80 g) and zinc cyanide (0.14 g) under Ar. The mixture is stirred at 100⁹C for 3h. After cooling to room temperature, ethyl acetate is added and the resulting mixture is filtered, washed with aqueous NaHCO solution.₃, dried (sodium sulfate) and the solvent removed. The residue is recrystallized from ethanol.

Yield: 0.45 g (69% of theory)

mass spectrum (ESI⁺): m/z = 580/582 (Cl) [M+Na]

Example XXI

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2.M 4-Cyclopropyl-phenylboronic acid n-butyllithium in hexane (14.5 mL) is added dropwise to 1-bromo-4-cyclopropyl-benzene (5.92 g) in THF (14 mL) and toluene (50 mL) quenched to -70 °C. The resulting solution is stirred at 70 °C for 30 min before adding triisopropyl borate (8.5 mL). The solution is warmed to -20 °C and then treated with 4 M aqueous hydrochloric acid (15.5 mL). The reaction mixture is further warmed to room temperature and then the aqueous phase is separated. The aqueous phase is extracted three times with ethyl acetate and the combined organic phases are dried (sodium sulfate). The solvent is evaporated and the residue is washed with a mixture of ether and cyclohexane to give the product as a solid. colorless.

Yield: 2.92 g (60% of theory) Mass Spectrum (ESI): m/z = 207 (Cl) [M+HCOO]'

The following compounds are obtained analogously to Example XXI:

(1) 4-difluoromethoxy-phenylboronic acid

<img file="ECSP088774A_D0067.tif" />

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Mass spectrum (ESI ): m/z = 233 (Cl) [M+HCOO]'

Departing from the process described above, the compound is prepared from 4-difluoromethoxy-1-iodobenzene using ¡PrMgCl to generate the arylmetal compound and scavenging this intermediate with trimethyl borate.

(2) 4-diffluoromethyl-phenylboronic acid

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mass spectrum (ESI⁺): m/z = 172 (Cl) [M+H]⁺

Departing from the process described above, the compound is prepared from 4-difluoromethyl-1-iodobenzene (prepared from 4-iodobenzaldehyde using diethylaminosulfur trifluoride (DAST) in dichloromethane) using ¡PrMgCI to generate the aryl metal compound and trapping this intermediate compound with trimethyl borate.

Example XXII

CN

br

1-bromo-4-cyano-3-(4-methoxy¡-benz¡l)-benzene

A mixture of 25 g of ethyl (4-methoxy-phenyl)-acetate, 27.4 g of 1-bromo-4-cyano-3-fluorobenzene, and 20 mL of N-methyl-pyrrolidin-2-one is added slowly. to 31.4 g of potassium ter.-butoxide in 130 mL of N-methyl-pyrrolidin-2-one, keeping the temperature below 10°C. After stirring for 1 hour at room temperature, 100 mL of methanol and 137 mL of 1M aqueous sodium hydroxide are added, and the mixture is stirred overnight at room temperature. The methanol fraction is evaporated, the residue is basified with 1M aqueous sodium hydroxide and extracted with tert-butyl-methyl-ether. The aqueous phase is acidified with 4M hydrochloric acid and extracted several times with ethyl acetate. The combined ethyl acetate extracts are evaporated and the residue is heated, together with 120 mL of N,N-dimethyl-formamide and 24.9 g of potassium carbonate at 100°C for 1 hour. The reaction mixture is diluted with aqueous sodium bicarbonate and extracted several times with ethyl acetate. The combined extracts are evaporated and the residue crystallizes from methanol.

Yield: 13 g (33% of theory) Mass Spectrum (ESI⁺): m/z = 319/321 (Br) [M+NH₄]⁺

The following compound is obtained analogously to Example XXII:

(1) 1-bromo-4-cyano-3-(4-cycloprop¡l-benz¡l)-benzene

CN

br

Mass Spectrum (ESI): m/z = 329/331 (Br) [M+NH₄] ⁺

The phenylacetic acid derivative necessary for the preparation of this compound is synthesized according to the subsequent procedure of Example XXIII.

Example XXIII

<img file="ECSP088774A_D0068.tif" />

Ethyl 4-cyclopropyl-phenylacetate

Prepared from ethyl 4-bromo-phenylacetate by transition metal catalyzed coupling with cyclopropylboronic acid using tricyclohexylphosphonium tetrafluoroborate, palladium acetate, potassium phosphate in toluene and water according to Tetrahedron Lett. 2002, 43, 6987-6990 Mass spectrum (ESl·): m/z = 205 [M+H]⁺

Example XXIV

<img file="ECSP088774A_D0069.tif" />

-cyano-4-(BD-qlucopyranos-1 -yl)-2-(4-methoxynecyl)-benzene

A flask loaded with a stir bar and 1-bromo-4-cyano-3-(4-methoxy-benzyl)-benzene (9.90 g), dissolved in dry THF (120 mL) and kept under one atmosphere. of argon, cools down to -87⁵C. A solution of tert-butyllithium in pentane (1.7 M, 39 mL), pre-chilled (approx. -70-C) is slowly added to this solution, and the resulting solution is stirred for 30 min. to -87^SC. A solution of 2,3,4,6-tetrakis-0-(trimethylsil¡l)-D-glucopyranone (16.5 g), dissolved in THF (80 mL) is then added and the combined solution is stirred at -75⁹C for 1h. The reaction is quenched with aqueous NH soln.₄CI, and the resulting mixture is extracted with ethyl acetate. After drying (Na₂SW₄) the organic extracts and removing the solvent, the residue is dissolved in methanol (150 mL) and methanesulfonic acid (5 mL) is added. The resulting solution is stirred at 55^QC for 8 h to provide the desired anomeric configuration. After cooling to room temperature, the solution is neutralized with solid sodium bicarbonate and the methanol is evaporated under reduced pressure. Brine is added to the remainder and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (sodium sulfate) and the solvent is evaporated. The residue is dissolved in acetonitrile (50 mL) and dichloromethane (50 mL) to reduce the anomeric carbon center. After cooling this solution to -20^yesC and adding triethylsilane (16 mL), boron trifluoride diethyl etherate (9.2 mL) is added dropwise. The reaction solution is slowly heated in the cooling bath to 0⁹C and the reaction is then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried (sodium sulfate), the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0 -> 9:1).

Yield: 5.2 g (41% of theory) Mass Spectrum (ESI⁺): m/z = 403 [M+NH₄F

The following compound is obtained analogously to Example XXIV:

(1) 1-cyano-2-(4-c¡cloproD¡l-benc¡l)-4-(BD-alucop¡ranos-1-¡l)-benzene

EITHER

<img file="ECSP088774A_D0070.tif" />

EITHER

Mass spectrum (ESI ): m/z = 413 [M+H]⁺

Advantageously, the reduction of the anomeric carbon center of the appropriate intermediate obtained during the synthesis of this compound is carried out with the oxygen functionalities on the protected pyranose ring. Preferred protecting groups are benzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, ter.-butyldimethylsilyl, triisopropisilyl and allyl.

Example XXV

EITHER

EITHER

<img file="ECSP088774A_D0071.tif" />

1-cyano-2-(4-cycloprop¡l-benc¡l)-4-(tetra-0-acet¡lBD-alucop¡ranos-1-¡l)-benzene

To a charged flask with a stir bar, 4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(4t/fluoromethylsulfonyloxy-benzylj-benzonitrile (4.4 g) , degassed toluene (12 mL) and degassed water (8 mL) and kept under an argon atmosphere is added cyclopropylcarbonic acid (0.20 g), potassium phosphate (5.0 g), t-cyclohexylphosphine (0.19 g) and finally palladium(II) acetate (76mg) The mixture is stirred at 110⁹C for 6 h and meanwhile cyclopropylbonic acid is added every hour (5 times 0.20 g). After cooling to room temperature, the mixture is diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts are dried (sodium sulfate) and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 20:1 —> 1:1) Yield: 3.2 g (87% of theory)

mass spectrum (ESI⁺): m/z = 581 [M+NH₄F

Example XXVI

<img file="ECSP088774A_D0072.tif" />

4-(1-H¡drox¡-C¡clopropyl)-fen¡lbóñco acid

A 3.0 M solution of ethylmagnesium bromide in diethylether (7.6 mL) is added to a stirred solution of titanium(IV) isopropoxide (2.2 mL) in diethylether (70 mL) rapidly cooled to -78⁹C. The resulting solution is stirred at -78⁹C for 1.5 h before adding 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.0 g). The reaction mixture is warmed to room temperature and stirred for a further 12 h. 1M aqueous hydrochloric acid is then added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulfate) and the solvent is evaporated. The residue is dissolved in acetone (60 mL) and aqueous NH solution is added.₄0.1 M OAc (50 mL), followed by NalO₄ (2.3g). The resulting reaction mixture is stirred at room temperature for 18h. After removing the acetone, the residue is extracted with ethyl acetate. The combined extracts are dried (sodium sulfate) and the solvent is evaporated. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate).

Yield: 0.45 g (33% of theory)

Mass spectrum (ESI ): m/z = 223 [M+HCOO]'

Preparation of the final compounds:

Reference Example

<img file="ECSP088774A_D0073.tif" />

4-(BD-qlucopyranos-1-yl)-2-[4-((S)-tetrahydrofuranyl-3-ox¡)-benzyl-1-benzonitr¡le

A 1.00 g mixture of 1-chloro-2-[4-((S)-tetrahydrofuranyl-3-oxy)-benzyl]-4-(2,3,4,6-tetra-0-acetyl-pD -glucopyrans-1 -yl)-benzene, 0.16 g sodium cyanide, and 0.35 g nickel bromide in 2.5 mL Nmethyl-2-pyrrolidinone is heated in a microwave oven at 220 Ό for 15 min. . After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate.

After drying over sodium sulfate and evaporation of the solvent, the residue is dissolved in 5 mL of methanol. 4 mL of 4 M aqueous potassium hydroxide are added and the reaction solution is stirred at room temperature for 3 h. The solution is neutralized with 1 M hydrochloric acid and the methanol is evaporated. The residue is extracted with ethyl acetate, the combined extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (dichloromethane/methanol 4:1).

Yield: 0.35 g (49% of theory)

mass spectrum (ESI⁺): m/z = 442 [M+H]⁺

The compounds of examples 1,2, 3 and 4 are obtained analogously to Reference Example 1:

Example 1: 2-(4-ethyl-benzyl)-4-(3-D-glucopyrans-1 -iI)-benzonitrile

<img file="ECSP088774A_D0074.tif" />

Yield: 65% of theoretical value

mass spectrum (ESI⁺): m/z = 401 [M+NH₄]⁺

This compound can also be prepared analogously to Example 6, using 4-ethylphenylboronic acid as coupling partner.

Example 2: 4-(|3-D-glucoparanos-1 -yl)-2-(4-hydroxy-benzyl)-benzonitrile

The compound is prepared from 2-(4-acetoxy-benzyl)-1-chloro-4-(2,3,4,6-tetra-O-acetyl-p-D-glucopyranos-1-yl)-benzene according to with the process described above

<img file="ECSP088774A_D0075.tif" />

either

Yield: 30% of theoretical value

mass spectrum (ESI⁺): m/z = 389 [M+NH₄]⁺

The compound is also obtained by peracetylation of 2-(4-methoxy-benzyl)-4-D-glucopyranos-1-yl)-benzonitrile, followed by boron tribromide ether cleavage and deacetylation.

Example 3: 4-(β-D-gl ucopiran os-1 -yl)-2-(4-methyl-benzyl)-benzonitrile

<img file="ECSP088774A_D0076.tif" />

Yield: 59% of theoretical value

mass spectrum (ESI⁺): m/z = 387 [M+NH₄] ⁺

This compound can also be prepared analogously to Example 6, using 4-methylphenylboronic acid as coupling partner.

Example 4:2-(4-cyano-benzyl)-4-^-D-glucopyrans-1-¡I)-benzonitrile

<img file="ECSP088774A_D0077.tif" />

Yield: 58% of theoretical value

mass spectrum (ESI⁺): m/z = 398 [M+NH₄]

Example 5

<img file="ECSP088774A_D0078.tif" />

2-Bromoethyl-methyl-ether (85 μΙ) is added to a mixture of 4-(3-D-glucopyranos-1 -yl)-2-(4-hydroxybenzyl)-benzonitrile (0.30 g) and cesium carbonate (0.39 g) in 3 mL of dimethylformamide. The mixture is stirred at 80 °C for 16 h, before adding water and brine. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->5:1).

Yield: 0.19 g (49% of theory) Mass Spectrum (ESI⁺): m/z = 430 [M+H]⁺

EXAMPLE 6

EITHER

<img file="ECSP088774A_D0079.tif" />

EITHER

F

4-(BD-alucoDiranos-1-yl)-2-(4-tr¡fluoromethox¡-benz¡l)-benzonitño

A flask filled with Ar is charged with 2-bromomethyl-4-(2,3,4,6-tetra-0-acetyl-D-glucopyranos-1-yl)benzonitrile (0.25 g), acid 4-trifluoromethoxy-phenylboronic acid (0.20 g), potassium carbonate (0.26 g), and a 3:1 mixture of degassed acetone and water (4 mL). The mixture is stirred at room temperature for 5 min before being cooled in an ice bath. Palladium dichloride (5mg) is then added and the reaction mixture is stirred for 16h at room temperature. The mixture is then diluted with brine and extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is dissolved in methanol (9 mL) and treated with 4 M aqueous potassium hydroxide solution (1 mL). The resulting solution is stirred at room temperature for 1h, then neutralized with 1M hydrochloric acid. The methanol is evaporated and the residue is diluted with brine and extracted with ethyl acetate. The collected organic extracts are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->8:1). Yield: 0.145 g (69% of theory)

mass spectrum (ESI⁺): m/z = 457 [M+NH₄]⁺

In some cases the performance is improved by using 1.5 to 2.0 equivalents of boric acid along with the proportional increase in base.

The following compounds can be obtained analogously to Example 6:

Example 7: 4-(|3-D-glucop¡ranos-1 -yl)-2-(4-trifluoromethyl-benz¡l)-benzon¡trile

Yield: 47% of theoretical value

mass spectrum (ESI⁺): m/z = 441 [M+NH₄]

<img file="ECSP088774A_D0080.tif" />

Example 8: 4-(|3-D-glucoparanos-1 -yl)-2-(4-isopropyl-benzyl)-benzonitrile

<img file="ECSP088774A_D0081.tif" />

Yield: 87% of theoretical value

mass spectrum (ESI⁺): m/z = 415 [M+NH₄]

Example 9:4-(pD-glucopyranos-1 -yl)-2-(4-tert.-butyl-benzyl)-benzonitrile

<img file="ECSP088774A_D0082.tif" />

Yield: 66% of theoretical value

mass spectrum (ESI⁺); m/z = 429 [M+NH₄]⁺

Example 10: 4-(3-D-glucopyranos-1 -yl)-2-(4-trimethylsilyl-benzyl)-benzonitrile

<img file="ECSP088774A_D0083.tif" />

Yield: 70% of theoretical value

mass spectrum (ESI⁺): m/z = 445 [M+NH₄] ⁺

Example 11: 4-(|3-D-glucopyranos-1 -yl)-2-(4-methylsulfanyl-benzyl)-benzonitrile

Yield: 47% of theoretical value

mass spectrum (ESI⁺): m/z = 419 [M+NH₄]⁺

<img file="ECSP088774A_D0084.tif" />

Example 12: 4-( β-D-glucopyran os-1 -yl)-2-[4-(3-methyl-but-1 -yl)benzyl]-benzon itrilo

<img file="ECSP088774A_D0085.tif" />

Yield: 69% of theoretical value

mass spectrum (ESI⁺): m/z = 443 [M+NH₄] ⁺

Example 13: 2-(4-fluoro-benzyl)-4-(pD-glucopyranos-1 -yl)-benzonitrile

<img file="ECSP088774A_D0086.tif" />

Yield: 34% of theoretical value

mass spectrum (ESI⁺): m/z = 391 [M+NH₄] ⁺

Example 14: 2-(4-chloro-benzyl)-4-(3-D-glucopyranos-1-1)-benzonitrile

<td colspan="2" rowspan="2"></td><td colspan="2"></td><td rowspan="2">Cl</td>

<td>SAW</td><td>í VI</td>

<td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td>'either</td><td></td><td></td>

<td></td><td> 0</td><td></td><td></td><td></td>

<td>Yield: 32% of theoretical value</td><td></td><td></td><td></td><td></td>

mass spectrum (ESI⁺): m/z = 407/409 (Cl) [M+NH₄] ⁺

Example 15: 2-(4-difluoromethoxy-benzyl)-4-(pD-glucopyranos-1-yl)-benzonitrile

Yield: 32% of theoretical value

mass spectrum (ESI⁺): m/z = 439 [M+NH₄]⁺

<img file="ECSP088774A_D0087.tif" />

(λ X

<img file="ECSP088774A_D0088.tif" />

Example 16: 2-(4-difluoromethyl-benzyl)-4-(|3-D-glucopyranos-1 -yl)-benzonitrile

<img file="ECSP088774A_D0089.tif" />

Yield: 65% of theoretical value

mass spectrum (ESI⁺): m/z = 423 [M+NH₄] ⁺

Example 17: 2-(4-cyclopropyl-benzyl)-4-(3-D-glucopyranos-1-yl)-benzonitrile

<img file="ECSP088774A_D0090.tif" />

mass spectrum (ESI⁺): m/z = 413 [M+NH₄]⁺

The compound is obtained according to example 6, using 4-cyclopropyl-phenylboronic acid as coupling partner.'

Yield: 83% of theoretical value

Alternatively, this compound is obtained as described in Example XXIV(1).

The compound of example 17 is also obtained using the following process:

A solution of 2-(4-cyclopropyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)benzonitrile (0.80 g) in methanol ( 5 mL) and THF (5 mL) is treated with aqueous potassium hydroxide solution (4 mol/L, 5 mL). The reaction solution is stirred at room temperature for 1 h, then neutralized with 1 M hydrochloric acid. The organic solvents are evaporated and the residue is diluted with brine and extracted with ethyl acetate. The organic extracts are dried (sodium sulfate) and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0 9:1).

Yield: 0.54 g (96% of theory)

Example 18: 2-(4-cyclobutyl-benz¡l)-4-(3-D-glucop¡ranos-1 -yl)-benzonitr¡le

<img file="ECSP088774A_D0091.tif" />

The compound is obtained according to Example 6, using 4-cyclobutylboronic acid (obtainable in analogy to Example XXI) as coupling partner.

Yield: 51% of theoretical value

mass spectrum (ESI⁺): m/z = 427 [M+NH₄] ⁺

Example 19: 4-(pDg I ucopyranos-1 -yl)-2-(4-prop-1 -yl-benzi I)-benzo n itrile

<img file="ECSP088774A_D0092.tif" />

Yield: 64% of theoretical value

mass spectrum (ESI⁺): m/z = 415 [M+NH₄] ⁺

Example 20: 4-(|3-Dg I ucopyranos-1 -yl)-2-[4-( 1 -hydroxy-cyclopropyl)-benzyl]-benzon-ytrile

<img file="ECSP088774A_D0093.tif" />

The compound can be obtained according to Example 6, using 4-(1-hydroxycyclopropylj-phenylboric acid as coupling partner.

Example 21 or

<img file="ECSP088774A_D0094.tif" />

ooo

4-(6-D-glucop¡ranos-1-¡l)-2-(4-iodo-benz¡l)-benzon¡tr¡lo

A 1 M solution of iodine monochloride in dichloromethane (0.9 mL) is added to 4-(R-Dglucopyranos-1 -µl)-2-(4-trimethylsilyl-benzyl)-benzonitrile (0.26 g ) dissolved in dichloromethane (5 mL). The solution is stirred at room temperature for 1 h and then quenched by addition of aqueous Na solution.₂S₂EITHER₃ and aqueous NaHCO solution₃. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->8:1). Yield: 0.15 g (88% of theory) Mass Spectrum (ESI⁺): m/z = 499 [M+NH₄]⁺

The following compounds can be obtained analogously to Example 20:

(22) 2-(4-bromo-benzyl)-4-(pD-glucopyranos-1 -yl)-benzonitrile

EITHER

<img file="ECSP088774A_D0095.tif" />

EITHER

Yield: 79% of theoretical value

mass spectrum (ESI⁺): m/z = 451/453 [M+NH₄]⁺

The compound is obtained according to the procedure of Example 20 using bromine instead of ICI in dichloromethane.

Example 23

F

EITHER

<img file="ECSP088774A_D0096.tif" />

FF

EITHER

4-(6-D-qlucopyranos-1-¡l)-2-(4-pentafluoroethyl-benz¡l)-benzon¡tr¡lo

One flask charged with 4-(2,3,4,6-tetra-0-acetyl-BD-glucopyranos-1 -yl)-2-(4-iodo-benzyl)benzonitrile (0.16 g), pentafluoroethyltrimethylsilane (0 0.14 g), KF (43 mg), Cul (0.16 g), DMF (2 mL) and Ar atmosphere is heated to 60 °C for 24 h. Aqueous NaHCO solution is then added.₃ and the resulting mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is dissolved in methanol (8 mL) and treated with 4M KOH solution (0.8 mL). The solution is stirred for 1 h at room temperature and then diluted with aqueous NaHCO solution.₃. After removal of the methanol under reduced pressure, the residue is extracted with ethyl acetate, the combined organic extracts are dried and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->8:1).

Yield: 0.08 g (69% of theory) Mass Spectrum (ESI⁺): m/z = 491 [M+NH₄]⁺

Example 24

<img file="ECSP088774A_D0097.tif" />

4-(8-D-allucop¡ranos-1-¡l)-2-(4-methylsulfinyl-benzyl)-benzonitr¡le

35% hydrogen peroxide in water (48 μί) is added to 4-(BD-glucopyranos-1-yl)-2-(4-methylsulfanyl-benzylj-benzonitrile (83 mg) in 1,1,1,3,3, 3-hexafluoroisopropanol (2 mL) The resulting solution is stirred at room temperature for 1 h, then quenched by addition of aqueous Na soln.₂S₂EITHER₃ and aqueous NaHCO solution₃. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->5:1). Yield: 24 mg (28% of theory).

mass spectrum (ESI⁺): m/z = 418 [M+H]⁺

Example 25

<img file="ECSP088774A_D0098.tif" />

4-(BD-qlucopyranos-1-¡l)-2-(4-methylsulfonyl-benzyl)-benzonitr¡le

3-Chloroperoxybenzoic acid (70%, 0.14 g) is added to 4-(8-D-glucopyranos-1 -yl)-2-(4-methylsulfanyl-benzyl)-benzonitrile (100 mg) in dichloromethane (2 mL) quenched in an ice bath. The cooling bath is removed and the resulting solution is stirred at room temperature for 1 h. After the addition of aqueous Na solution₂S₂EITHER₃ and aqueous NaHCO solution₃, the organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->8:1).

Yield: 68 mg (63% of theory).

mass spectrum (ESI⁺): m/z = 451 [M+NH₄F

The following compounds can also be prepared analogously to the above-mentioned examples or other methods known from the literature:

<td>eg</td><td colspan="5">Structure</td>

<td></td><td></td><td></td><td> 9«</td><td></td><td></td>

<td> 26</td><td></td><td>_xeither</td><td> /9/</td><td></td><td></td>

<td></td><td>either'''</td><td> 0</td><td>either</td><td></td><td></td>

<td></td><td></td><td></td><td>zkx</td><td>I rif</td><td></td>

<td> 28</td><td></td><td></td><td>X//</td><td>\zk/</td><td></td>

<td></td><td>either'</td><td> 0</td><td>either</td><td></td><td></td>

<td></td><td></td><td></td><td>TO</td><td>Yo</td><td></td>

<td> 30</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 0'</td><td> 0</td><td>'Ό</td><td></td><td></td>

<td></td><td></td><td></td><td>[TO</td><td>Yo</td><td></td>

<td> 32</td><td></td><td></td><td>ZV</td><td></td><td></td>

<td></td><td> 0'''</td><td> 0</td><td>'Ό</td><td></td><td></td>

<td>eg</td><td colspan="5">Structure</td>

<td></td><td></td><td></td><td>¿&lt;x</td><td>xxx Γ Vll</td><td></td>

<td> 27</td><td> 0^</td><td>z-°X</td><td>afe</td><td>X/X/</td><td></td>

<td></td><td>either'¹'</td><td> 0</td><td>either</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>X/X</td><td></td>

<td> 29</td><td> 0^</td><td></td><td>afe</td><td>xkxz</td><td></td>

<td></td><td>either'</td><td> 0</td><td>either</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>X/X 1 IXL</td><td></td>

<td> 31</td><td> 0^</td><td></td><td>Αχζ</td><td>XXX/</td><td></td>

<td></td><td> 0'</td><td> 0</td><td>'Ό</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>x/x Γril</td><td></td>

<td> 33</td><td> 0^</td><td> ^0.</td><td>TO//</td><td>A_fexA</td><td> 0 1</td>

<td></td><td> 0’</td><td> 0</td><td>either</td><td></td><td></td>

<img file="ECSP088774A_D0099.tif" />

<img file="ECSP088774A_D0100.tif" />

Some examples of formulations are described below in which the expression active substance indicates one or more compounds according to the invention, including their prodrugs or salts. In the case of one of the combinations with one or more active substances as previously described, the term active substance also includes the other active substances.

Example A

Tablets containing 100 mg of active substance

Composition:

One tablet contains:

active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg

220.0mg

Preparation method:

The active substance, lactose and starch are mixed together and evenly moistened with an aqueous solution of polyvinylpyrrolidone. After the wet composition has been sieved (2.0 mm mesh size) and dried in a rack-type drier at 50°C, it is sieved again (1.5 mm mesh size) and the lubricant is added. The finished blend is compressed to form tablets.

Tablet weight: 220 mg

Diameter: 10mm, biplane, faceted on both sides and notched on one side.

Example B

Tablets containing 150 mg of active substance

Composition:

One tablet contains:

<td>active substance</td><td>150.0mg</td>

<td>lactose powder</td><td>89.0mg</td>

<td>cornstarch</td><td>40.0mg</td>

<td>colloidal silica</td><td>10.0mg</td>

<td>polyvinylpyrrolidone</td><td>10.0mg</td>

<td>magnesium stearate</td><td>1.0mg 300.0mg</td>

Preparation:

The active substance mixed with the lactose, corn starch and silica is moistened with a 20% polyvinylpyrrolidone aqueous solution and passed through a sieve with a mesh size of 1.5 mm. The granules, dried at 45°C, are passed through the same sieve again and mixed with the specified amount of magnesium stearate. Tablets are compressed from the mixture.

Tablet weight: 300 mg punch: 10 mm, flat

Example C

Hard gelatin capsules containing 150 mg of active substance

Composition:

capsule contains:

active substance 150.0 mg corn starch (dried) approx. 180.0 mg lactose (powder) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0mg

Preparation:

The active substance is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously using a suitable apparatus. The finished mixture is filled into size 1 hard gelatin capsules.

Capsule filling: approx. 320mg

Capsule valves: size 1 hard gelatin capsule.

Example D

Suppositories containing 150 mg of active substance

Composition:

suppository contains:

active substance 150.0 mg polyethylene glycol 1500 550.0 mg polyethylene glycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg

2,000.0mg

Preparation:

After the suppository mass has melted, the active substance is distributed homogeneously in it and the melt is poured into cooled moulds.

Example E

Ampoules containing 10 mg of active substance

Composition:

active substance 10.0 mg hydrochloric acid 0.01 N qs

double distilled water to 2.0 ml

Preparation:

The active substance is dissolved in the required amount of 0.01 N HCl, made isotonic with common salt, sterilized by filtration, and transferred to 2-ml ampoules.

Example F

Ampoules containing 50 mg of active substance

Composition:

active substance 50.0 mg hydrochloric acid 0.01 N qs

double distilled water to 10.0 ml

Preparation:

The active substance is dissolved in the required amount of 0.01 N HCl, made isotonic with common salt, filter-sterilized and transferred to 10-ml ampoules.