HK1167409A - Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture - Google Patents

Description

Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing said compounds, their use and process for their preparation

The application is a divisional application of an invention patent application with the application date of 2007, 5 and 2, and the application number of 200780015928.5 (international application number of PCT/EP2007/054248), the invention name of the invention is 'glucopyranosyl-substituted benzonitrile derivative, a pharmaceutical composition containing the compound, the use thereof and a preparation method thereof'.

The invention relates to a glucopyranosyl-substituted benzonitrile derivative of the general formula I:

wherein the radical R³The definitions are given below, including tautomers, stereoisomers, mixtures and salts thereof. The invention also relates to pharmaceutical compositions containing the compounds of formula I according to the invention and to the use of the compounds according to the invention for the preparation of pharmaceutical compositions for the treatment of metabolic disorders. Furthermore, the present invention relates to processes for preparing the pharmaceutical compositions and compounds of the invention.

In the literature, compounds having an inhibitory effect on the sodium-dependent glucose cotransporter SGLT2 are proposed for the treatment of diseases, especially diabetes.

Aromatic groups substituted by glucopyranosyl groups and their preparation and their possible activity as SGLT2 inhibitors are known from international application WO2005/092877 and the publications cited therein.

Object of the Invention

The object of the present invention was to find novel glucopyranosyl-substituted benzonitrile derivatives, especially those active on the sodium-dependent glucose cotransporter SGLT, especially SGLT 2. It is another object of the present invention to find pyranoid glucosyl-substituted benzene derivatives with enhanced inhibitory effect on the sodium-dependent glucose cotransporter SGLT2 in vitro and/or in vivo and/or with better pharmacological or pharmacokinetic properties than known structurally similar compounds.

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

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

Object of the Invention

In a first aspect, the present invention relates to glucopyranosyl-substituted benzonitrile derivative of formula I, including tautomers, stereoisomers or mixtures thereof; and physiologically acceptable salts thereof

Wherein

R³Represents hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-but-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-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, methyl, ethyl, isopropyl, isobutyl, tert-butyl, 3-methyl-but-1-yl, 2-hydroxy-1-ethyl, 2-hydroxy-2-methyl-1-propyl, 2-hydroxy-2-methyl-prop-1-yl, 1, 2, 2, 2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl and cyano,

or a derivative thereof: wherein one or more hydroxyl groups of the beta-D-glucopyranosyl group are selected from (C)_1-18Alkyl) carbonyl (C)_1-18Alkyl) oxycarbonyl, phenylcarbonyl and phenyl- (C)_1-3Of alkyl) -carbonyl groupsThe group is acylated.

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

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

The 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.

The invention also relates to the use of at least one compound of the invention or a physiologically acceptable salt thereof for the preparation of a pharmaceutical composition suitable for the treatment or prevention of a disease or condition which can be influenced by the inhibition of the sodium-dependent glucose cotransporter SGLT, in particular SGLT 2.

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

In another aspect, the present invention relates to the use of at least one compound of the invention or one of its physiologically acceptable salts for the preparation of a pharmaceutical composition for preventing degeneration of pancreatic β -cells and/or for improving and/or restoring pancreatic β -cell function.

In another aspect, the present invention relates to the use of at least one compound of the invention or one of its physiologically acceptable salts for the preparation of a pharmaceutical composition for the prevention, alleviation, delay or treatment of a disease or condition resulting from abnormal accumulation of liver fat in a patient in need thereof.

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

The invention also relates to a process for the preparation of the pharmaceutical compositions according to the invention, characterized in that a compound according to the invention or one of its physiologically acceptable salts is brought into association by non-chemical means with one or more inert carriers and/or diluents.

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

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

in Lewis acids or Bronsted acidsReacting the compound of formula II with a reducing agent in the presence of a reducing agent, while simultaneously or sequentially cleaving any protecting groups present;

wherein

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

R^8a、R^8b、R^8c、R^8dindependently of one another, hydrogen or allyl, benzyl, (C)_1-4Alkyl) carbonyl (C)_1-4Alkyl) oxycarbonyl, arylcarbonyl, aryl- (C)_1-3Alkyl) -carbonyl and aryl- (C)_1-3Alkyl) -oxycarbonyl or R^aR^bR^cSi radical or ketal or acetal radical, especially alkylene or arylalkylene ketal or ketalAn aldehyde group, with in each case two adjacent radicals R^8a、R^8b、R^8c、R^8dCan form a cyclic ketal or acetal group or a 1, 2-di (C)_1-3Alkoxy) -1, 2-bis (C)_1-3Alkyl) -ethylene bridges, the above-mentioned ethylene bridges forming, with two oxygen atoms and two associated carbon atoms of the pyranose ring, a substituted di-radicalAlkyl rings, especially 2, 3-dimethyl-2, 3-di (C)_1-3Alkoxy) -1, 4-bisAlkyl rings, and at the same time the alkyl, allyl, aryl and/or benzyl groups may be substituted by halogen or C_1-3Alkoxy radicals being mono-or polysubstituted and the benzyl radical also being di- (C)_1-3Alkyl) amino substitution; and is

R^a、R^b、R^cIndependently of one another represent C_1-4Alkyl, aryl or aryl-C_1-3Alkyl, wherein aryl or alkyl may be mono-or polysubstituted with halogen;

whilst aryl in the above definition of groups refers to phenyl or naphthyl, preferably phenyl;

and wherein R³The radicals are as defined above and below; or

b) For the preparation of the compounds of the general formula I,

a compound of the general formula III

Wherein R is^8a、R^8b、R^8c、R^8dAnd R³As defined above and below, with the proviso that at least one is selected from R^8a、R^8b、R^8c、R^8dThe substituents of (a) are other than hydrogen;

a protecting group R which is not hydrogen^8a、R^8b、R^8c、R^8dCracking; and is

If desired, converting the compound of the formula I thus obtained into the corresponding acyl compound of the formula I by acylation, and/or

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

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

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

Other aspects of the invention relate to novel intermediates as described in the reaction schemes and experimental section below.

Detailed Description

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

In the following alternative preferred embodiments of the invention:

according to a first embodiment of the invention, R³Represents hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, 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-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-Ethyl, hydroxy, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl or cyano.

According to a second embodiment of the invention, R³Represents hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl or cyano.

According to a third embodiment of the invention, R³Represents methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-butan-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-trifluoromethyl-ethyl, 2-methoxy-ethyl or 2-ethoxy-ethyl.

According to a fourth embodiment of the invention, R³Represents methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-butan-1-yl, difluoromethyl, trifluoromethyl or pentafluoroethyl.

According to a fifth embodiment of the invention, R³Represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

According to a sixth embodiment of the invention, R³Represents 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl or 1-hydroxy-cyclohexyl.

According to a seventh embodiment of the invention, R³Represents 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-propan-1-yl, 3-hydroxy-3-methyl-butan-1-yl, 1-hydroxy-1-methyl-ethyl, 2, 2, 2-trifluoro-1-hydroxy-ethyl1-trifluoromethyl-ethyl, 2-methoxy-ethyl or 2-ethoxy-ethyl.

According to an eighth embodiment of the invention, R³Represents 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl or 1-hydroxy-1-methyl-ethyl.

According to a ninth embodiment of the invention, R³Represents hydroxy, difluoromethoxy, trifluoromethoxy or cyano.

According to a tenth embodiment of the invention, R³Represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group or a pentafluoroethyl group.

Preferably, all hydroxyl groups of the beta-D-glucopyranosyl group as defined are unsubstituted or only the hydroxyl group O-6 of the beta-D-glucopyranosyl group is substituted. Preferred substituents are selected from (C)_1-8Alkyl) carbonyl (C)_1-8Alkyl) oxycarbonyl and phenylcarbonyl. More preferably the substituents are selected from acetyl, methoxycarbonyl and ethoxycarbonyl, especially acetyl and ethoxycarbonyl.

Unless otherwise indicated, in the nomenclature of the formulae used above and below, the bond of a substituent as a cyclic group (e.g. a phenyl ring) is shown towards the centre of the cyclic group meaning that this substituent can be bonded to any free position of the cyclic group having an H atom.

The compounds of the invention can be obtained using synthetic methods known in principle. These compounds are preferably obtained by the process of the invention described below in more detail.

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

Scheme 1: addition of organometallic compounds to gluconolactones

The reaction of scheme 1 is preferably carried out starting from a halogenated benzyl benzene compound of formula IV, wherein Hal represents chlorine, bromine or iodine. R in scheme 1¹Represents cyano or a group which can subsequently be converted into cyano, such as chlorine, bromine, carboxyl, carboxylic ester, carboxamide or a derivative thereof, boron or silyl, a protected or masked aldehyde function, such as acetal or thiazole, or a protected or masked amino function, such as nitro. The Grignard (Grignard) or lithium (V) reagents for the preparation of benzylbenzenes from the corresponding chlorinated, brominated or iodinated benzylbenzenes IV can be prepared by the so-called halogen-metal exchange reaction or by insertion of a metal into a carbon-halogen bond. The halogen-metal exchange can be carried out, for example, with organolithium compounds such as n-, sec-or tert-butyllithium to synthesize the corresponding lithium compound V. Analogous magnesium compounds can also be produced by halogen-metal exchange with suitable Grignard reagents such as isopropylmagnesium bromide or sec-butylmagnesium bromide or chloride or diisopropylmagnesium or di-sec-butylmagnesium, in the absence or presence of other salts such as lithium chloride which accelerate the metalation process; specific transmetallized organomagnesium compounds can also be generated in situ from suitable precursors (see, e.g., Angew. chem.2004, 116, 3396-169 and Angew. chem.2006, 118, 165-169 and the references cited therein). Furthermore, salt complexes of organomagnesium compounds resulting from mixing, for example, butylmagnesium chloride or bromide or isopropylmagnesium chloride or bromide with butyllithium may also be employed (see, for example, Angew. chem.2000, 112, 2594-. The halogen-metal exchange reaction is preferably carried out at a temperature of between 40 ℃ and-100 ℃, particularly preferably between 10 ℃ and-80 ℃, in an inert solvent or a mixture thereof (e.g. diethyl ether, diAlkane, tetrahydrofuran, toluene, hexane, dimethylsulfoxide, dichloromethane, or a mixture thereof). Optionally with a metal salt of, for example, cerium trichloride, zinc chloride or zinc bromide, indium chloride or indium bromideTo form other organometallic compounds (V) suitable for addition. Alternatively, the organometallic compound V may also be prepared by inserting a metal into the carbon-halogen bond of the halogenated aromatic compound IV. Lithium or magnesium are elemental metals suitable for this conversion. The insertion may be carried out at a temperature in the range of-80 to 100 ℃, preferably-70 to 40 ℃ in e.g. diethyl ether, diAlkane, tetrahydrofuran, toluene, hexane, dimethylsulfoxide, and mixtures thereof. In the absence of spontaneous reaction, metal pre-activation may be required, for example with 1, 2-dibromoethane, iodine, trimethylsilyl chloride, acetic acid, hydrochloric acid and/or sonication. The addition reaction of the organometallic compound V to gluconolactone or its derivative (VI) is preferably carried out at a temperature of between 40 ℃ and-100 ℃, particularly preferably at 0 to-80 ℃ in an inert solvent or a mixture thereof, to obtain the compound of formula II. Although all of the above reactions are preferably carried out in an inert atmosphere such as argon and nitrogen, they may also be carried out in air. The metallization and/or coupling reactions can also be carried out in microreactors and/or micromixers which can be carried out at high exchange rates; for example similar to the method described in WO 2004/076470. Suitable solvents for the addition of the metallated phenyl group V to the suitably protected gluconolactone VI are, for example, diethyl ether, dimethoxyethane, benzene, toluene, dichloromethane, hexane, tetrahydrofuran, dioxaneAlkanes, N-methylpyrrolidone, and mixtures thereof. The addition reaction can be carried out without any further adjuvants or, for example, with BF₃*OEt₂Or Me₃In the presence of a coupling partner which reacts slowly in the presence of an accelerator for SiCl (see M.Schlosser, Organometallics in Synthesis, John Wiley&Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1994). Substituent R in scheme 1⁸Preferably defined as benzyl, substituted benzyl, allyl, trialkylsilyl, particularly preferably trimethylSilyls, triisopropylsilyls, allyls, 4-methoxybenzyls and benzyls. If two adjacent substituents R⁸Taken together, the two substituents are preferably part of benzylidene acetal, 4-methoxybenzylidene acetal, isopropyl ketal or di-construction with 2, 3-dimethoxy-butylidene attached to the adjacent oxygen atom of the pyranose via the 2 and 3 positions of butaneAn alkane. The radical R' preferably represents hydrogen, C_1-4Alkyl radical, C_1-4Alkylcarbonyl or C_1-4Alkyloxycarbonyl, particularly preferably hydrogen, methyl or ethyl. The R' group is introduced after addition of the organometallic compound V or a derivative thereof to the gluconolactone VI. If R' is equal to hydrogen or C_1-4Alkyl, the reaction solution is treated with an alcohol such as methanol or ethanol or water in the presence of an acid such as acetic acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, trifluoroacetic acid or hydrochloric acid. R' may also be attached after preparation of the hydrogen compound II by reacting the anomeric (anomeric) hydroxyl group with a suitable electrophile such as methyl iodide, dimethyl sulfate, ethyl iodide, diethyl sulfate, acetyl chloride or acetic anhydride in the presence of a base such as triethylamine, ethyldiisopropylamine, sodium or potassium carbonate or cesium carbonate, sodium or potassium hydroxide or cesium hydroxide. The hydroxyl group can also be deprotonated with, for example, sodium hydride prior to the addition of the electrophile. If during the attachment of R', a protecting group R is present⁸In the case of the compounds employed which produce the corresponding protonation (i.e. R)⁸A compound II) equal to H, unstable under the reaction conditions, then R⁸Can be cleaved.

The synthesis of halogenated aromatic compounds of formula IV can be carried out using standard transformations in organic chemistry or at least methods known from the specialist literature in organic synthesis (see J. March, Advanced organic Reactions, Mechanisms, and Structure, 4 th edition, John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1992 and the literature cited therein, etc.). More particularly, the use of Transition metals and organometallic compounds for the Synthesis of aromatic compounds is described in various monographs (see, for example, L.Brandsma, S.F.Vasilevsky, H.D.Verkruijsse, application of Transmission Metal Catalysts in Organic Synthesis, Springer-Verlag, Berlin/Heidelberg, 1998; M.Schloser, Organometallics in Synthesis, John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1994, P.J.Stang, F.Diederieri, Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1997 and the references cited therein). The synthetic schemes described below provide proof by way of example. Alternatively, the aglycone moiety can be bound to the pyranose moiety already present using the same synthetic method.

And (2) a flow scheme: synthesis of diaryl ketone fragments

Scheme 2 shows the preparation of precursor compounds useful in the synthesis of halogenated aromatic compounds of formula IV starting from benzoyl chloride and a second aromatic group using Friedel-Crafts acylation conditions or variants thereof. R in scheme 2¹Represents cyano or a group which can subsequently be converted into cyano, such as chlorine, bromine, carboxyl, carboxylic ester, carboxamide or a derivative thereof, a protected or masked aldehyde function, such as thioacetal or thiazole, or a protected or masked amino function, such as nitro. This classical reaction has a wide substrate range and is usually used in catalytic or stoichiometric amounts, for example, of AlCl₃、FeCl₃Iodine, iron, ZnCl₂Sulfuric acid or trifluoromethanesulfonic acid in the presence of a catalyst. Instead of benzoyl chloride, the corresponding carboxylic acid, anhydride, ester or benzonitrile can also be used. The reaction is preferably carried out at a temperature of from-30 to 120 c, preferably from 30 to 100 c, in chlorinated hydrocarbons such as dichloromethane and 1, 2-dichloroethane. However, it is also possible to carry out the reaction without solvent or in a microwave oven.

And (3) a flow path: reduction of diaryl ketones and diaryl carbinols to diaryl methanes

In scheme 3 the substituent R represents C_1-3Alkyl or aryl, and R¹Represents cyano or a group which can subsequently be converted into cyano, such as chlorine, bromine, carboxyl, carboxylic ester, carboxamide or a derivative thereof, boron or silyl, a protected or masked aldehyde function, such as acetal or thiazole, or a protected or masked amino function, such as nitro. Diarylmethanes can be obtained in one or two reaction steps starting from diarylketones or diarylmethanols. Diaryl ketones can be reduced in two steps to diarylmethanes via the corresponding diphenylcarbinols or in one step. In a two-step variant, with, for example, a metal hydride (e.g., NaBH)₄、LiAlH₄Or iBu₂AlH) reducing the ketone to form an alcohol. In, for example, BF₃*OEt₂、InCl₃Or AlCl₃In the presence of Lewis acids or Bronsted acids such as hydrochloric acid, sulfuric acid, trifluoroacetic acid or acetic acid, for example in Et₃SiH、NaBH₄Or Ph₂The reducing agent of SiClH converts the resulting alcohol to the desired diphenylmethane. Can be, for example, expressed in Et₃Monosilanes of SiH, e.g. NaBH₄Of boron hydrides or of LiAlH, for example₄In aluminium hydrides, e.g. BF₃*OEt₂Tris (pentafluorophenyl) borane, trifluoroacetic acid, hydrochloric acid, aluminum chloride or InCl₃The one-step process for obtaining diphenylmethane starting from a ketone is carried out in the presence of a Lewis acid or Bronsted acid. The reaction is preferably carried out at a temperature of-30 to 150 ℃, preferably 20 to 100 ℃, in a solvent such as a halogenated hydrocarbon (e.g., dichloromethane, toluene, acetonitrile or mixtures thereof). Reduction of hydrogen in the presence of a transition metal catalyst such as Pd/C is another possible synthesis method. It may also be a reduction reaction according to Wolff-Kishner or a variant thereof. The ketone is first converted to a hydrazone with hydrazine or its derivatives such as 1, 2-bis (tert-butyldimethylsilyl) hydrazine, which decomposes under strong basic reaction conditions and with heat to form diphenylmethane and nitrogen.The reaction may be carried out in one reaction step or after isolation of the hydrazone or its derivative in two separate reaction steps. Suitable bases include, for example, KOH, NaOH, or KOtBu in a solvent such as ethylene glycol, toluene, DMSO, 2- (2-butoxyethoxy) ethanol, or t-butanol; solvent-free reactions are also possible. The reaction may be carried out at a temperature of between 20 and 250 ℃, preferably between 80 and 200 ℃. An alternative to the basic conditions of the woff-chikuno reduction is the clenmensen (Clemmensen) reduction, which occurs under acidic conditions, which may also be used herein. The alcohol function in the diarylcarbinols can also be first converted to a better leaving group, such as a chloride, bromide, iodide, acetate, carbonate, phosphate, or sulfate group; the subsequent reduction step to form diarylmethanes is widely described in the organic chemistry literature.

And (4) a flow chart: synthesis of diarylmethane units and possible precursor compounds thereof

R in scheme 4¹Represents cyano or a group which can subsequently be converted into cyano, such as chlorine, bromine, carboxyl, carboxylic ester, carboxamide or a derivative thereof, boron or silyl, a protected or masked aldehyde function, such as acetal or thiazole, or a protected or masked amino function, such as nitro. The term "Alk" denotes C_1-4Alkyl and each substituent R is independently selected from H, C_1-3Alkyl and C_1-3An alkoxy group. Scheme 4 describes the synthesis of diarylmethanes and their possible precursor compounds starting from metallized phenyl groups. Lithium or magnesium substituted aromatic compounds can be synthesized from chlorinated, brominated or iodinated aromatic compounds by halogen-metal exchange reactions with, for example, butyllithium, isopropylmagnesium halide or diisopropylmagnesium, or by insertion of elemental metal into a halogen-carbon bond. The corresponding boron-substituted compounds, such as boronic acids, boronic esters or dialkylarylboranes, can be obtained from these metallized phenyl groups by reaction with a boron electrophile, such as a boronic ester or derivative thereof. In addition, can also be selected fromBoronated (borylated) aromatic compounds are prepared by the reaction of a halogenated or pseudohalogenated precursor and a diboron or borane compound catalyzed by a transition metal such as palladium (see, for example, tetrahedron lett.2003, pages 4895-4898 and references cited therein). A lithium or magnesium substituted phenyl compound is added to benzaldehyde (step 3) and benzoic acid or a derivative thereof (step 4), for example a benzoate ester, for example a benzamide, benzonitrile or benzoyl chloride of the Weinreb type. These reactions can in principle be carried out without further transition metal catalysts or without conversion to another metal, for example cerium, indium or zinc; it is sometimes advantageous to use one of the alternative methods described later. Arylboronic acids can be added to benzaldehyde over a rhodium catalyst to provide the respective diarylcarbinols (see, e.g., adv. synth. catal.2001, p. 343-350 and references cited therein). In addition, arylboronic acids, esters thereof, dialkylarylboranes or aryltrifluoroborates can be coupled with benzoyl chloride to yield diaryl ketones mediated by a transition metal such as palladium, a complex or a salt thereof. The metallated phenyl group may be reacted with a benzyl electrophile, such as benzyl chloride, benzyl bromide, or benzyl iodide, to give the diarylmethane. The lithium-or magnesium-derived phenyl compounds are advantageously, but not always necessarily, reacted in the presence of transition metals such as copper, iron or palladium (see for example org. Lett.2001, 3, 2871-2874 and the references cited therein). Transmetallation from lithium or magnesium to, for example, boron, tin, silicon or zinc, respectively, provides, for example, the corresponding aromatic boronic acid, stannane, silane or zinc compound, which can undergo a coupling reaction with, for example, a benzyl halide, benzyl carbonate, benzyl phosphate, benzyl sulfonate or a benzyl electrophile of benzyl carboxylate. The reaction is carried out in the presence of a transition metal such as palladium, nickel, rhodium, copper or iron (see for example Tetrahedron lett.2004, pages 8225-8228 and org.lett.2005, pages 4875-4878 and the references cited therein).

And (5) a flow chart: introduction of cyano moieties

Scheme 5 shows possible routes for attaching cyano residues to the central phenyl group at different stages of synthesis of the target molecule. The cyano group may be introduced by a transition metal mediated coupling reaction of a suitable cyano source such as sodium cyanide, potassium chloride, zinc cyanide, or copper cyanide with a halogenated or pseudohalogenated phenyl group. Suitable catalysts can be derived from transition metals such as palladium, rhodium, nickel, iron or copper, which can be used, for example, in the basic form of palladium on carbon, in the form of salts such as palladium chloride, palladium bromide or palladium acetate or complexes with phosphines such as triphenylphosphine, tri-tert-butylphosphine or 1, 1' -bis (diphenylphosphino) ferrocene (dpPf) or alkenes such as dibenzylideneacetone. The active catalyst may be generated in situ or prior to addition to the reaction mixture. Additives such as zinc, either elemental or as a salt, may be advantageous (see Tetrahedron lett.2005, 46, 1849-. Reacting the corresponding zinc, magnesium or lithium compounds obtainable from chlorinated, brominated or iodinated compounds by halogen metal exchange reactions or by insertion of the respective metal into a halogen bond with cyano electrophiles such as p-tolylsulfonyl cyanide, cyanogen bromide or 2-pyridine cyanate is another possible method for adding cyano functionality (see e.g. synth. commun.1996, 3709-.

And (6) a flow path: introducing cyano residues from aldehyde or carboxylic acid derivatives

The introduction of another cyano group is a synthesis starting from an aldehyde or a carboxamide (scheme 6). The aldehyde functionality may itself be introduced, protected or masked. Common protecting Groups for aldehyde functions are acetals, but other protecting Groups can also be used (see T.W Greene, P.G.M.Wuts, Protective Groups in organic Synthesis, John Wiley&Sons, inc., New York, 1999). Suitable masking agents for aldehyde functional groups are, for example, olefins and thiazoles. Can be used with, for example, nailAcid, concentrated hydrochloric acid, polyphosphoric acid, or pyridine-toluene mixed (for example) hydroxylamine converts aldehydes to cyano functionality. The intermediate oximes formed under these reaction conditions can be isolated and then dehydrated to yield the final product. It is also possible to use, for example, bistrifluoroacetylhydroxylamine and NH₂OSO₃And in the absence of other reagents to give the nitrile. Other useful reagents are, for example, NH in acetic acid₄PO₄H₂And nitropropane, trimethylsilyl azide or S, S-dimethylthiodiimide.

Carboxamides may also be suitable nitrile precursors. For example, trifluoroacetic anhydride, phosphorus pentoxide, POCl₃、CCl₄-phosphine combination, Cl₃COCl-amine combinations, Burgess (Burgess) reagent, Vismeier (Vilsmeyer) reagent, SOCl₂Or cyanuric chloride dehydrating agent. It is also possible to start from the corresponding monoalkylated carboxamide, carboxylic acid, ester or carboxylic acid chloride and to form the nitrile in one pot without isolation of any intermediate.

Scheme 7: introduction of cyano residues from aniline precursors

An established method for introducing nitrile functions is the so-called Sandmeyer reaction with copper cyanide and the corresponding diazo compounds obtainable by diazotization of the respective aniline derivatives. The synthesis of diazo compounds and their subsequent cyano-diazotization has been widely documented in the organic chemistry literature.

And (3) a process 8: alternative synthesis of diarylmethane units

Another method for constructing a diarylmethane unit is shown in scheme 8.

The o-fluoro substituted benzonitrile which is commercially available or obtainable by the above-described process is used. Reacting o-fluoro substituted benzonitrile with R under basic conditions³Substituted alkyl phenylacetates (see, e.g., J.org.chem.55, 1990, 4817-.

To prepare the compounds of the formula I, in the process a) according to the invention, the compounds of the formula II are reacted with a reducing agent in the presence of a Lewis acid or a Bronsted acid,

wherein R' and R³As defined above and

R^8a、R^8b、R^8c、R^8das defined above and independently of one another, for example acetyl, pivaloyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, allyl, trialkylsilyl, benzyl or substituted benzyl or in each case two adjacent radicals R^8a、R^8b、R^8c、R^8dForming benzylidene acetals or isopropylidene ketals or 2, 3-dimethoxy-butylidene linked to the oxygen atom of the pyranose ring via the 2 and 3 positions of butylidene and forming substituted di-radicals with the above-mentioned groupsAn alkane, which is a mixture of at least one of,

which can be obtained as described above.

Suitable reducing agents for the reaction include, for example, triethylsilane, tripropylsilane, trisSilyl of isopropylsilane or diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride or samarium iodide. The reduction is carried out in the absence or presence of a suitable Bronsted acid such as hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid or acetic acid or a Lewis acid such as boron trifluoride etherate, trimethylsilyl trifluoromethanesulfonate, titanium tetrachloride, tin tetrachloride, scandium trifluoromethanesulfonate or zinc iodide. Depending on the reducing agent and the acid, the reaction can be carried out at a temperature of from-60 ℃ to 120 ℃ in, for example, dichloromethane, chloroform, acetonitrile, toluene, hexane, diethyl ether, tetrahydrofuran, dioxaneAlkane, ethanol, water or a mixture thereof. A particularly suitable mixture of reagents consists, for example, of triethylsilane and boron trifluoride etherate, the two compounds being conveniently used at temperatures of-60 ℃ and 60 ℃ in acetonitrile or dichloromethane. Furthermore, hydrogen can be used for the conversion in the presence of transition metal catalysts, such as Pd/C or Raney (Raney) nickel, in solvents such as tetrahydrofuran, ethyl acetate, methanol, ethanol, water or acetic acid.

Alternatively, for the preparation of the compounds of the formula I according to process b) according to the invention, in the compounds of the formula III, the protecting groups are cleaved,

wherein R is³As defined above and

R^8ato R^8dRepresents one of the above defined protecting groups, such as acyl, arylmethyl, allyl, acetal, ketal or silyl, and which may be obtained, for example, by reduction of a compound of formula II as described above.

It will be appreciated that the group R may be varied during the synthetic procedures described above^8aTo R^8dOne or several groups of (a).

Any acyl protecting group used is, for example, in an aqueous solvent (e.g., in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or a di-alcohol)Alkane/water) in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or, for example, in the presence of trimethylsilyl iodide, at a temperature between 0 and 120 ℃, preferably at a temperature between 10 and 100 ℃. The 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 a temperature between 50 and 120 ℃, or by treatment with a sodium hydroxide solution, optionally in the presence of a solvent, such as tetrahydrofuran or methanol, at a temperature between 0 and 50 ℃.

Any acetal or ketal protecting group used is, for example, in an aqueous solvent (e.g., in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water, or a di-alcohol)Alkane/water) in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or, for example, in the presence of trimethylsilyl iodide, at a temperature between 0 and 120 c, preferably between 10 and 100 c.

Trimethylsilyl groups are cleaved, for example, in water, aqueous solvent mixtures or lower alcohols such as methanol or ethanol in the presence of bases such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methoxide.

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

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

Preferably by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by optionally using, for example, dichloromethane, bisA solvent of an alkane, methanol or ether is treated with iodotrimethylsilane to cleave the tert-butyl or tert-butoxycarbonyl group.

In the above reaction, any reactive group such as ethynyl, hydroxyl, amino, alkylamino or imino present during the reaction may be protected by a conventional protecting group which is cleaved again after the reaction.

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

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

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

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

Thus, for example, cis/trans mixtures can be resolved into their cis and trans isomers by chromatography, the compounds of the general formula I obtained as racemates can be separated into their optical enantiomers by methods known per se (compare Allinger n.l. and Eliel e.l. "Topics in stereoschemistry", vol 6, Wiley Interscience, 1971) and the compounds of the general formula I having at least 2 asymmetric carbon atoms can be resolved into their diastereomers on the basis of their physico-chemical differences using methods known per se, for example by chromatography and/or fractional crystallization, and if these compounds are obtained in racemic form, they can subsequently be resolved into the enantiomers as described above.

The enantiomers are preferably separated by column separation on a chiral phase or by recrystallization from optically active solvents or by reaction with optically active substances which can form salts or derivatives, for example esters or amides, in particular acids and active derivatives or alcohols thereof, with racemic compounds, and separation of the diastereomeric mixtures of the salts or derivatives thus obtained, for example on the basis of their solubility differences, while the free enantiomers can be liberated from the pure diastereomeric salts or derivatives by the action of suitable reagents. Commonly used optically active acids are, for example, D-and L-tartaric acids or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. The optically active alcohol can be, for example, (+) -or (-) -menthol and, for example, the optically active acyl group in the amide can be (+) -or (-) -menthyloxycarbonyl.

Furthermore, the compounds of formula I can be converted into their salts, in particular into physiologically acceptable salts for pharmaceutical use with inorganic or organic acids. Acids which may 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 compounds obtained 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 can have particularly advantageous properties, for example a high degree of crystallinity.

The compounds according to the invention can also be advantageously obtained using the methods described in the examples below, which can also be combined for this purpose with methods known to the person skilled in the art from the literature (for example the methods described in WO 98/31697, WO 01/27128, WO 02/083066, WO 03/099836, WO 2004/063209, WO2005/092877 and WO 2006/120208).

The present invention also relates to novel intermediate compounds as described in the reaction schemes above and as described in the experimental section below.

In particular, the following intermediate compounds are further aspects of the invention:

wherein

R^8aTo R^8dAs defined above and preferably represents H or acetyl;

r' is as defined above and preferably represents H, methyl or ethyl;

alk represents C_1-4Alkyl, preferably representing methyl or ethyl;

R¹as defined above and preferably represents Br or CN, most preferably CN;

R³as defined above, such as cyclopropyl or cyclobutyl, and is preferably selected from the group consisting of: chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxyl, cyano;

LG represents a leaving group, e.g. Br, I, -O- (SO)₂)-CF₃preferably-O- (SO)₂)-CF₃；

U represents Cl, Br, I, -O-CO-C_1-4Alkyl, -O-C (═ O) -O-C_1-4Alkyl or-OPO (O-C)_1-4Alkyl radical)₂(ii) a Preferably Br.

As already mentioned, the compounds of 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 SGLT 2.

The biological properties of the novel compounds can be studied as follows:

the ability of these substances to inhibit SGLT-2 activity can be demonstrated in a test apparatus having a CHO-K1 cell line (ATCC number CCL-61) or HEK293 cell line (ATCC number CRL-1573) stably transfected with the expression vector pZeoSV (Invitrogen, EMBL accession number L36849) containing a cDNA encoding the sequence of human sodium glucose cotransporter 2(Genbank accession number NM-003041) (CHO-hSGLT2 or HEK-hSGLT 2). These cell lines will be in a sodium dependent manner¹⁴C-labelled alpha-methyl-glucopyranosides (¹⁴C-AMG, Amersham) to the interior of the cell.

The SGLT-2 experiment was performed as follows:

CHO-hSGLT2 cells were cultured in Ham's F12 medium (BioWhittaker) containing 10% fetal bovine serum and 250. mu.g/mL Zeocin (Invitrogen), and HEK293-hSGLT2 cells were cultured in DMEM medium containing 10% fetal bovine serum and 250. mu.g/mL Zeocin (Invitrogen). Cells were detached from culture flasks by washing 2 times with PBS and subsequent treatment with trypsin/EDTA. After addition of cell culture medium, cells were centrifuged, resuspended in culture medium and counted in a Casy cell counter. 40,000 cells per well were seeded in poly-D-lysine coated white 96-well plates at 37 ℃ with 5% CO₂Incubate overnight. Cells were plated out in 250. mu.l of assay buffer (Hanks, et al)Balanced Salt Solution (Hanks Balanced Salt Solution), 137mM NaCl, 5.4mM KCl, 2.8mM CaCl₂1.2mM MgSO₄And 10mM HEPES (pH 7.4), 50. mu.g/mL gentamicin (Gentamicin)) for 2 washes. Then 250 μ l of assay buffer and 5 μ l of test compound were added to each well and the plates were incubated in the incubator for a further 15 minutes. As a negative control, 5. mu.l of 10% DMSO was used. By mixing 5. mu.l¹⁴C-AMG (0.05. mu. Ci) was added to each well to start the reaction. At 37 deg.C, 5% CO₂After 2 hours of incubation, the cells were washed again with 250. mu.l PBS (20 ℃) and then lysed by adding 25. mu.l of 0.1N NaOH (5 minutes at 37 ℃). 200 μ l of MicroScint20(Packard) were added to each well and incubation continued for another 20 min at 37 ℃. After this incubation, the DNA was used in Topcount (packard)¹⁴C scintillation program measures the absorption¹⁴Emission intensity of C-AMG.

To determine selectivity for human SGLTl, a similar assay was established in which the hSGLTl cDNA (Genbank Acc. No. NM-000343) was expressed in CHO-K1 or HEK293 cells in place of the hSGLT2 cDNA.

EC of the Compounds of the invention₅₀Values below 1000nM, especially below 200nM, most preferably below 50 nM.

In view of their ability to inhibit SGLT activity, the compounds of the present invention and their corresponding pharmaceutically acceptable salts are suitable for the therapeutic and/or prophylactic treatment of all conditions or diseases which can be influenced by the inhibition of SGLT activity, in particular SGLT-2 activity. Accordingly, the compounds of the invention are particularly suitable for the prevention or treatment of diseases, especially metabolic disorders or conditions, such as type 1 and type 2 diabetes, diabetic complications (e.g. retinopathy, nephropathy or neuropathy, diabetic foot, ulcers, macroangiopathy), metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia (hyperinsulinaemia), glucose metabolism disorders, insulin resistance, metabolic syndrome, dyslipidemia of different origin, atherosclerosis and related diseases, obesity, hypertension, chronic heart failure, edema and hyperuricemia. These substances are also suitable for preventing beta-cell degeneration, such as apoptosis or necrosis of pancreatic beta cells. These 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 of the invention are also useful as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure.

By administering the compounds of the present invention, abnormal accumulation of fat in the liver can be reduced or inhibited. Thus, according to another aspect of the present invention, there is provided a method for preventing, slowing, delaying or treating a disease or condition resulting from abnormal accumulation of liver fat in a patient in need thereof, which method is characterized by administering a compound or pharmaceutical composition of the present invention. The disease or condition due to abnormal accumulation of liver fat is selected from among fatty liver in general, non-alcoholic fatty liver disease (NAFL), non-alcoholic steatohepatitis (NASH), fatty liver induced by overnutrition, diabetic fatty liver, fatty liver induced by alcohol, or toxic fatty liver.

In particular, the compounds of the invention, including their physiologically acceptable salts, are suitable for the prevention or treatment of diabetes, especially type 1 and type 2 diabetes and/or diabetic complications.

Furthermore, the compounds of 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 a therapeutic or prophylactic response will generally depend on the compound administered, the patient, the nature and severity of the disease or disorder, and the method and frequency of administration, and is determined by the patient's physician. Advantageously, the dose may be from 1 to 100mg, preferably from 1 to 30mg, by the intravenous route and from 1 to 1000mg, preferably from 1 to 100mg, by the oral route, in each case administered from 1 to 4 times daily. For this purpose, the compounds of the invention may be formulated, optionally with other active substances, with one or more inert conventional carriers and/or diluents, for example with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetearyl alcohol, carboxymethylcellulose or fatty substances such as stearic acid or suitable mixtures thereof, to give conventional galenic formulations, for example plain or coated tablets, capsules, powders, suspensions or suppositories.

The compounds of the invention can also be used in combination with other active substances, in particular for the treatment and/or prophylaxis of the abovementioned diseases or disorders. Other active substances suitable for these combinations include, for example, those which potentiate the therapeutic effect of the SGLT antagonists of the invention for one of the indications already mentioned and/or which allow the dose of the SGLT antagonists of the invention to be reduced. Therapeutic agents suitable for such a combination include, for example, antidiabetic agents such as metformin, sulfonylureas (e.g., glyburide, tolbutamide, glimepiride), nateglinide (nateglinide), repaglinide (repaglinide), thiazolidinediones (e.g., rosiglitazone, pioglitazone), PPAR- γ -agonists (e.g., GI 262570) and antagonists, PPAR- γ/α modulators (e.g., KRP 297), α -glucosidase inhibitors (e.g., acarbose, voglibose), DPPIV inhibitors (e.g., LAF237, MK-431), α 2-insulin antagonists, insulin and insulin analogs, GLP-1 and GLP-1 analogs (e.g., exendin-4) or dextrins (amylin). The list also includes protein tyrosine phosphatase 1 inhibitors, which are substances that influence the deregulation (deregulated) of glucose production in the liver, such as glucose-6-phosphatase or fructose-1, 6-bisphosphatase, phosphate glucosyltransferase inhibitors; glucagon (glucagon) receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase; lipid lowering agents, such as HMG-CoA reductase inhibitors (e.g. simvastatin (simvastatin), atorvastatin (atorvastatin)); fibrates (fibrates) (e.g., bezafibrate, fenofibrate); nicotinic acid and its derivatives; PPAR-alpha agonists; PPAR-delta agonists; ACAT inhibitors (e.g., avasimibe (avasimibe)) or cholesterol absorption inhibitors such as ezetimibe (ezetimibe); bile acid binding substances such as cholestyramine (cholestyramine); ileal bile acid transport inhibitors; HDL-raising compounds, such as CETP inhibitors or ABCl modulators; or an obesity treating active substance such as sibutramine (sibutramine) or tetrahydrolipstatin (tetrahydrolipostatin), dexfenfluramine (dexfenfluramine), axolone (axokine); a cannabinoid 1 receptor antagonist; an MCH-1 receptor antagonist; MC4 receptor agonists; NPY5 or NPY2 antagonists; or beta 3-agonists, such as SB-418790 or AD-9677 and 5HT2c receptor agonists.

Furthermore, combinations with drugs for affecting hypertension, chronic heart failure or atherosclerosis (e.g. a-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, Ca-antagonists, centrally acting antihypertensive agents, alpha-2-adrenoceptor antagonists, neutral endopeptidase inhibitors, platelet aggregation inhibitors and other drugs or combinations thereof) are also suitable. Examples of angiotensin II receptor antagonists are candesartan cilexetil, losartan potassium (potassium losartan), eprosartan mesylate (eprosartan mesylate), valsartan (valsartan), telmisartan (telmisartan), irbesartan (irbesartan), EXP-3174, L-158809, EXP-3312, olmesartan medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, and the like. Angiotensin II receptor antagonists are preferably used for the treatment or prevention of hypertension and diabetic complications, usually in combination with diuretics such as hydrochlorothiazide (hydrochlorothiazide).

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

In combination with GABA-receptor antagonists, Na-channel blockers, topiramate (topiramat), protein kinase C inhibitors, inhibitors of advanced glycation end products or aldose reductase inhibitors, are useful for treating or preventing diabetic complications.

Useful dosages of the above combination partners range from the generally recommended lowest dosage of 1/5 up to the generally recommended dosage of 1/1.

Thus, in a further aspect, the present invention relates to the use of a compound according to the invention or a physiologically acceptable salt of such a compound in combination with at least one of the above-mentioned active substances as a combination partner for the preparation of a pharmaceutical composition suitable for the treatment or prevention of a disease or condition which can be influenced by the inhibition of the sodium-dependent glucose cotransporter SGLT. These diseases are preferably metabolic diseases, in particular one of the diseases or disorders listed above, more in particular diabetes or diabetic complications.

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

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

Thus, for example, the pharmaceutical compositions of the invention comprise a compound of the invention or a physiologically acceptable salt of such a compound and at least one angiotensin II receptor antagonist, optionally in admixture with one or more inert carriers and/or diluents.

The compounds of the invention or their physiologically acceptable salts and the other active substances to be combined therewith can be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as so-called kit-of-parts (kits of parts).

In the above and in the following, the H atom of the hydroxyl group is not explicitly indicated in the structural formulae in each case. The following examples are intended to illustrate the invention without limiting it. The terms "room temperature" and "ambient temperature" are used interchangeably and refer to a temperature of about 20 ℃.

The following abbreviations are used:

DMF dimethyl formamide

NMP N-methyl-2-pyrrolidone

THF tetrahydrofuran

Preparation of the starting compound:

example I

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

Oxalyl chloride (13.0mL) was added to 2-bromo-5-iodo-benzoic acid in CH₂Cl₂(200mL) in an ice-cold solution. DMF (0.2mL) was added, and the solution was stirred at room temperature for 6 hours. It was then concentrated under reduced pressure and the residue was dissolved in THF (100 mL). The resulting solution was cooled in an ice bath and LiBH was added portionwise₄(3.4 g). The cooling bath was removed and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with THF and treated with 0.1M hydrochloric acid. The organic layer was then separated and the aqueous layer was extracted with ethyl acetate. Drying (Na)₂SO₄) The combined organic layers and the solvent was evaporated under reduced pressure to yield the crude product.

Yield: 47.0g (99% of theory)

Example II

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

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

Yield: 41.0g (82% of theory)

Example III

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

Phenol (13g) dissolved in 4M KOH solution (60mL) was added to 4-bromo-3-chloromethyl-1-iodo-benzene (41.0g) dissolved in acetone (50 mL). NaI (0.5g) was added and the resulting mixture was stirred at 50 ℃ overnight. Water was then added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate 19: 1).

Yield: 38.0g (79% of theory)

Example IV

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

38.3mL of oxalyl chloride and 0.8mL of dimethylformamide are added to a mixture of 100g of 5-bromo-2-chloro-benzoic acid in 500mL of dichloromethane. The reaction mixture was stirred for 14 hours, then filtered and separated from all volatile constituents in a rotary evaporator. The residue was dissolved in 150mL of dichloromethane, the resulting solution was cooled to-5 ℃ and 46.5g of anisole was added. 51.5g of aluminum trichloride are then added in portions so that the temperature does not exceed 5 ℃. The solution was stirred at 1 to 5 ℃ for 1 hour and then poured onto crushed ice. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with 1M hydrochloric acid, 1M sodium hydroxide solution (2 times) and brine. The organic phase is then dried over sodium sulfate, the solvent is removed and the residue is recrystallized from ethanol.

Yield: 86.3g (64% of theory)

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

Example V

1-bromo-4-chloro-3- (4-methoxy-benzyl) -benzene

A solution of 86.2g (5-bromo-2-chloro-phenyl) - (4-methoxy-phenyl) -methanone and 101.5mL triethylsilane in 75mL dichloromethane and 150mL acetonitrile was cooled to 10 ℃. Then, with stirring, 50.8mL of boron trifluoride etherate was added so that the temperature did not exceed 20 ℃. The solution was stirred at ambient temperature for 14 hours, followed by the addition of 9mL triethylsilane and 4.4mL boron trifluoride etherate. The solution was stirred at 45-50 ℃ for an additional 3 hour period and then cooled to ambient temperature. A solution of 28g of potassium hydroxide in 70mL of water was added and the resulting mixture was stirred for 2 hours. The organic phase was separated and the aqueous phase was extracted 3 more times with diisopropyl ether. The combined organic phases were washed twice with 2M potassium hydroxide solution and once with brine and then dried over sodium sulfate. After evaporation of the solvent, the residue was washed with ethanol and dried at 60 ℃.

Yield: 50.0g (61% of theory)

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

Example VI

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

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

Yield: 13.9g (98% of theory)

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

Example VII

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

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

Yield: 16.8g (87% of theory)

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

Example VIII

1-bromo-4- (1-methoxy-D-glucopyranos-1-yl) -2- (phenoxymethyl) -benzene

A2M solution of iPrMgCl in THF (11mL) was added to anhydrous LiCl (0.47g) suspended in THF (11 mL). The mixture was stirred at room temperature until all the LiCl had dissolved. This solution was added dropwise to a solution of 4-bromo-1-iodo-3-phenoxymethyl-benzene (8.0g) in tetrahydrofuran (40mL) cooled to-60 ℃ under an argon atmosphere. The solution was warmed to-40 ℃ and then 2, 3, 4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone (10.7g, 90% pure) in tetrahydrofuran (5mL) was added. The resulting solution was warmed to-5 ℃ in a cooling bath and stirred at this temperature for a further 30 minutes. Addition of NH₄Aqueous Cl and the resulting mixture extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in methanol (80mL) and treated with methanesulfonic acid (0.6 mL). After stirring the reaction solution at 35-40 ℃ overnight, it was washed with solid NaHCO₃The solution was neutralized and methanol was removed under reduced pressure. With NaHCO₃The residue was diluted with an aqueous solution and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporatedSolvent to yield a crude product which is reduced without further purification.

Yield: 7.8g (93% of theory)

Example IX

1-bromo-4- (2, 3, 4, 6-tetra-O-acetyl-D-glucopyranos-1-yl) -2- (phenoxymethyl) -benzene

Boron trifluoride etherate (4.9mL) was added to a cooled-to-20 ℃ solution of 1-bromo-4- (1-methoxy-D-glucopyranos-1-yl) -2- (phenoxymethyl) -benzene (8.7g) and triethylsilane (9.1mL) in dichloromethane (35mL) and acetonitrile (50mL) at a rate that the temperature was maintained below-10 ℃. The resulting solution was warmed to 0 ℃ over a period of 1.5h and then treated with aqueous sodium bicarbonate. The resulting mixture was stirred for 0.5 hour, the organic solvent was removed and the residue was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and the solvent was removed. The residue was dissolved in dichloromethane (50mL), and acetic anhydride (9.3mL), 4-dimethylaminopyridine (0.5g) and pyridine (9.4mL) were added to the solution. The solution was stirred at ambient temperature for 1.5 hours and then diluted with dichloromethane. The solution was washed 2 times with 1M hydrochloric acid and dried over sodium sulfate. After removal of the solvent, the residue was recrystallized from ethanol to yield the product as a colorless solid.

Yield: 6.78g (60% of theory)

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

Example X

2- (phenoxymethyl) -4- (2, 3, 4, 6-tetra-O-acetyl-D-glucopyranos-1-yl) -benzonitrile

The vessel was flushed with argon containing zinc cyanide (1.0g), zinc (30mg), Pd₂(dibenzylidene acetone)₃*CHCl₃(141mg) and tri-tert-butyl tetrafluoroborate(111mg) flask. A solution of 1-bromo-4- (2, 3, 4, 6-tetra-O-acetyl-D-glucopyranos-1-yl) -2- (phenoxymethyl) -benzene (5.4g) in degassed NMP (12mL) was then added and the resulting mixture stirred at room temperature for 18 hours. After dilution with ethyl acetate, the mixture was filtered and the filtrate was washed with aqueous sodium bicarbonate. The organic phase was dried (sodium sulfate) and the solvent was removed. The residue was recrystallized from ethanol.

Yield: 4.10g (84% of theory)

Mass spectrometry (ESI)⁺)：m/z＝557[M+NH₄]⁺

The above compound was also obtained according to the following procedure:

a flask equipped with a stir bar, 1-bromo-4- (2, 3, 4, 6-tetra-O-acetyl-D-glucopyranos-1-yl) -2- (phenoxymethyl) -benzene (14.7g), copper cyanide (4.1g), and NMP (100mL) was heated at reflux temperature for 8 hours. After dilution with water (600mL), the precipitate was isolated, washed several times with water and then dissolved in ethyl acetate (200 mL). The resulting solution was filtered through a plug of silica gel using ethyl acetate (300mL) as eluent. The filtrate was concentrated under reduced pressure and the residue was dissolved in dichloromethane (100mL) to re-acetylate the oxo groups deprotected during cyanation. Accordingly, pyridine (4mL), 4-dimethylaminopyridine (0.3g) and acetic anhydride (4.4mL) were added in this order. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was then diluted with dichloromethane (50mL) and washed 3 times with 1M aqueous hydrochloric acid, 1 time with aqueous sodium bicarbonate and 1 time with water. The organic phase was dried (sodium sulfate) and the solvent was removed. The residue was recrystallized from ethanol.

Yield: 10.0g (75% of theory)

Example XI

2-bromomethyl-4- (2, 3, 4, 6-tetra-O-acetyl-D-glucopyranos-1-yl) -benzonitrile

A33% solution of hydrobromic acid in acetic acid (15mL) was added to a solution of 2-phenoxymethyl-4- (2, 3, 4, 6-tetra-O-acetyl-D-glucopyranos-1-yl) -benzonitrile (0.71g) and acetic anhydride (0.12mL) in acetic acid (10 mL). The resulting solution was stirred at 55 ℃ for 6 hours and then cooled in an ice bath. The reaction mixture was neutralized with cooled aqueous potassium carbonate solution, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate/cyclohexane (1: 5) and the precipitate was isolated by filtration and dried at 50 ℃ to yield the pure product.

Yield: 0.52g (75% of theory)

Mass spectrometry (ESI)⁺)：m/z＝543/545(Br)[M+NH₄]⁺

Example XII

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

A solution of 4.0g of [4- (5-bromo-2-chloro-benzyl) -phenoxy ] -tert-butyl-dimethyl-silane in 42mL of dry diethyl ether was cooled to-80 ℃ under argon. 11.6mL of a 1.7M ice-cold (ca. -50 ℃) solution of tert-butyllithium in pentane was slowly added to the cooled solution and the solution was then stirred at-80 ℃ for 30 minutes. This solution was then added dropwise via a dry ice-cooled transfer pin to a solution of 4.78g of 2, 3, 4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone in 38mL of diethyl ether cooled to-80 ℃. The resulting solution was stirred at-78 ℃ for 3 hours. A solution of 1.1mL of methanesulfonic acid in 35mL of methanol was then added and the resulting reaction solution was stirred at ambient temperature for an additional 16 hours. The solution was then neutralized with solid sodium bicarbonate, ethyl acetate was added and the resulting solution was concentrated under reduced pressure. Aqueous sodium bicarbonate was added to the remaining solution extracted 4 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was evaporated. The residue was dissolved in 30mL acetonitrile and 30mL dichloromethane and the resulting solution was cooled to-10 ℃. After the addition of 4.4mL of triethylsilane, 2.6mL of boron trifluoride etherate was added dropwise so that the temperature did not exceed-5 ℃. After the addition was complete, the reaction solution was stirred at-5 to-10 ℃ for a further 5 hours and then quenched by the addition of aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted 4 times with ethyl acetate. The combined organic phases were dried over sodium sulfate, the solvent was removed and the residue was purified by silica gel chromatography (dichloromethane/methanol). The product obtained is then an isomeric mixture which can be isolated by peracetylating the hydroxyl groups with acetic anhydride, pyridine and 4-dimethylaminopyridine in dichloromethane and recrystallising the acetylated product obtained from ethanol. The pure acetylated β -product thus obtained (from precipitation from ethanol solution) was converted into the title product by removal of the acetyl groups in methanol with 4M potassium hydroxide solution.

Yield: 1.6g (46% of theory)

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

Example XIII

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

0.16mL of iodocyclopentane was added to a mixture of 0.25g of 1-chloro-4- (. beta. -D-glucopyranos-1-yl) -2- (4-hydroxybenzyl) -benzene and 0.4g of cesium carbonate in 2.5mL of dimethylformamide. The mixture was stirred at 45 ℃ for 4 hours, followed by the addition of 0.1g cesium carbonate and 0.05ml cyclopentane iodide. After stirring at 45 ℃ for a further 14 hours, aqueous sodium chloride solution was added and the resulting mixture was 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: 0.23g (78% of theory)

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

The following compounds were obtained analogously to example XIII:

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

(S) -toluene-4-sulfonic acid tetrahydrofuran-3-yl ester is used as a coupling partner for reaction.

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

Example XIV

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

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

Yield: 0.33g (64% of theory)

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

The following compounds were obtained analogously to example XIV:

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

Mass spectrometry (ESI)⁺)：m/z＝504[M+H]⁺

Example XV

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

To a solution of 5.6g of 1-chloro-4- (. beta. -D-glucopyranos-1-yl) -2- [4- (trifluoromethylsulfonyloxy) -benzyl) -benzene in 75mL of dichloromethane were added 7mL of pyridine, 7.8mL of acetic anhydride and 0.12g of 4-dimethylaminopyridine in that order. The solution was stirred at ambient temperature for 1 hour. After addition of 50mL of water, the resulting mixture was stirred for a further 5 minutes. The organic phase was separated and washed with 1M aqueous hydrochloric acid and aqueous sodium bicarbonate. After drying over magnesium sulfate and evaporation of the organic solvent, the product was generated as a white solid.

Yield: 7.0g (94% of theory)

Mass spectrometry (ESI)⁺)：m/z＝698/700(Cl)[M+NH₄]⁺

In analogy to example XV, the following compounds were obtained:

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

Mass spectrometry (ESI)⁺)：m/z＝689[M+NH₄]⁺

Example XVI

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

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

Yield: 0.095g (40% of theory)

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

Example XVII

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

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

Yield: 1.0g (34% of theory)

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

Example XVIII

1-chloro-2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -4- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranos-1-yl) benzene

To a solution of 2.02g of 1-chloro-4- (. beta. -D-glucopyranos-1-yl) -2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene in 20mL of dichloromethane were added 2.5mL of pyridine, 2.8mL of acetic anhydride and 50mg of 4-dimethylaminopyridine in that order. The reaction solution was stirred at ambient temperature for 4 hours. The solution was diluted with 50mL of dichloromethane, washed 2 times with 50mL of 1M hydrochloric acid and 1 time with sodium bicarbonate solution. After drying over sodium sulfate, the solvent was evaporated to yield the product.

Yield: 2.53g (91% of theory)

Mass spectrometry (ESI)⁺)：m/z＝642/644(Cl)[M+Na]⁺

The following compounds were obtained in analogy to example XVIII:

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

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

Mass spectrometry (ESI)⁺)：m/z＝608/610(Cl)[M+NH₄]⁺

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

Mass spectrometry (ESI)⁺)：m/z＝567[M+Na]⁺

Example XIX

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

Diisobutylaluminum hydride (54 μ L, 1mol/L in toluene) was added under an Ar atmosphere to a mixture of 1, 1' -bis (diphenylphosphino) ferrocene-dichloropalladium (II) (22mg) in THF (3mL) and cooled in an ice bath. The mixture was stirred in an ice bath for 0.5 h and then 1-chloro-4- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranos-1-yl) -2- [4- (trifluoromethylsulfonyloxy) -benzyl ] -4-methyl-amide was added in sequence]Benzene (0.60g) and Me₂Zn (0.88mL, 1mol/L in toluene). The ice bath was removed and the mixture was heated at reflux for 2.5 hours. After cooling to room temperature, 1M hydrochloric acid was added and the resulting mixture was extracted with ethyl acetate. Warp beamThe collected extracts were dried over sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography (dichloromethane/methanol 1: 0- > 2: 1).

Yield: 0.25g (52% of theory)

Example XX

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

Tetrakis (triphenylphosphine) palladium (0) (0.13g) was added under an argon atmosphere to a solution containing 1-chloro-4- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranos-1-yl) -2- [4- (trifluoromethylsulfonyloxy) -benzyl]Benzene (0.80g) and zinc cyanide (0.14 g). The mixture was stirred at 100 ℃ for 3 hours. After cooling to room temperature, ethyl acetate was added and the resulting mixture was filtered, with NaHCO₃The aqueous solution was washed, dried (sodium sulfate), and the solvent was removed. The residue was recrystallized from ethanol.

Yield: 0.45g (69% of theory)

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

Example XXI

4-cyclopropyl-phenylboronic acid

2.5M n-butyllithium in hexane (14.5mL) was added dropwise to 1-bromo-4-cyclopropyl-benzene (5.92g) in THF (14mL) and toluene (50mL) cooled to-70 ℃. The resulting solution was stirred at-70 ℃ for 30 minutes, followed by the addition of triisopropyl borate (8.5 mL). The solution was warmed to-20 ℃ and then treated with 4M aqueous hydrochloric acid (15.5 mL). The reaction mixture was further warmed to room temperature and the organic phase was then separated. The organic phases were extracted with ethyl acetate and dried (sodium sulfate). The solvent was evaporated and the residue was washed with a mixture of diethyl ether and cyclohexane to yield the product as a colorless solid.

Yield: 2.92g (60% of theory)

Mass spectrometry (ESI)^-)：m/z＝207(Cl)[M+HCOO]^-

The following compounds are obtained analogously to example XXI:

(1) 4-difluoromethoxy-phenylboronic acid

Mass spectrometry (ESI)^-)：m/z＝233(Cl)[M+HCOO]^-

Unlike the above procedure, this compound was prepared using iPrMgCl to generate the aryl metal compound from 4-difluoromethoxy-1-iodo-benzene and capture this intermediate with trimethyl borate.

(2) 4-difluoromethoxy-phenylboronic acid

Mass spectrometry (ESI)⁺)：m/z＝172(Cl)[M+H]⁺

Unlike the above procedure, this compound was prepared using iPrMgCl from 4-difluoromethyl-1-iodo-benzene (prepared from 4-iodobenzaldehyde using diethylaminosulfur trifluoride (DAST) in dichloromethane) to generate the aryl metal compound and capturing this intermediate with trimethyl borate.

Example XXII

1-bromo-4-cyano-3- (4-methoxy-benzyl) -benzene

A mixture of 25g of (4-methoxy-phenyl) -acetic acid ethyl ester, 27.4g of 1-bromo-4-cyano-3-fluoro-benzene and 20mL of N-methyl-pyrrolidin-2-one was slowly added to 31.4g of potassium tert-butoxide in 130mL of N-methyl-pyrrolidin-2-one, maintaining the temperature below 10 ℃. After stirring at room temperature for 1h, 100mL methanol and 137mL 1M aqueous sodium hydroxide solution were added and the mixture was stirred at room temperature overnight. The methanol fraction was evaporated, the residue was basified with 1M aqueous sodium hydroxide solution and extracted with tert-butyl-methyl ether. The aqueous phase was acidified with 4M hydrochloric acid and extracted several times with ethyl acetate. The combined ethyl acetate extracts were evaporated and the residue was heated together with 120mL of N, N-dimethylformamide and 24.9g of potassium carbonate at 100 ℃ for 1 hour. The reaction mixture was diluted with aqueous sodium bicarbonate and extracted several times with ethyl acetate. The combined extracts were evaporated and the residue was crystallized from methanol.

Yield: 13g (33% of theory)

Mass spectrometry (ESI)⁺)：m/z＝319/321(Br)[M+NH₄]⁺

The following compounds are obtained analogously to example XXII:

(1) 1-bromo-4-cyano-3- (4-cyclopropyl-benzyl) -benzene

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

The phenylacetic acid derivative required for the preparation of this compound was synthesized according to the subsequent procedure example XXIII.

Example XXIII

4-cyclopropyl-benzeneacetic acid ethyl ester

According to Tetrahedron Lett.2002, 43, 6987-6990, tricyclohexyl tetrafluoroborate is used in toluene and waterPalladium acetate, potassium phosphate was prepared from ethyl 4-bromo-phenylacetate by transition metal catalyzed coupling with cyclopropylboronic acid.

Mass spectrometry (ESI)⁺)：m/z＝205[M+H]⁺

Example XXIV

1-cyano-4- (. beta. -D-glucopyranos-1-yl) -2- (4-methoxybenzyl) -benzene

The flask, equipped with a stir bar and 1-bromo-4-cyano-3- (4-methoxy-benzyl) -benzene (9.90g) dissolved in anhydrous THF (120mL) and kept under argon, was cooled to-87 ℃. A pre-cooled (about-70 ℃) solution of tert-butyllithium in pentane (1.7M, 39mL) was slowly added to this solution and the resulting solution was stirred at-87 ℃ for 30 minutes. Followed by the addition of 2 of the first,a solution of 3, 4, 6-tetra-O- (trimethylsilyl) -D-glucopyranosone (16.5g) in THF (80mL) was dissolved and the combined solutions were stirred at-75 deg.C for 1 hour. By NH₄The reaction was quenched with aqueous Cl and the resulting mixture was extracted with ethyl acetate. In the presence of dry (Na)₂SO₄) After organic extraction and removal of solvent, the residue was dissolved in methanol (150mL) and methanesulfonic acid (5mL) was added. The resulting solution was stirred at 55 ℃ for 8 hours to yield the desired anomeric (anomeric) configuration. After cooling to the cycle temperature, the solution was neutralized with solid sodium bicarbonate and methanol was evaporated under reduced pressure. Brine was added to the residue and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried (sodium sulfate) and the solvent was evaporated. The residue was dissolved in acetonitrile (50mL) and dichloromethane (50mL) to reduce the anomeric carbon center. After cooling the solution to-20 ℃ and adding triethylsilane (16mL), boron trifluoride etherate (9.2mL) was added dropwise. The reaction solution was slowly warmed to 0 ℃ in a cooling bath and then quenched by the addition of aqueous sodium bicarbonate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (sodium sulfate), the solvent was removed and the residue was purified by silica gel chromatography (dichloromethane/methanol 1: 0- > 9: 1).

Yield: 5.2g (41% of theory)

Mass spectrometry (ESI)⁺)：m/z＝403[M+NH₄]⁺

The following compounds are obtained analogously to example XXIV:

(1) 1-cyano-2- (4-cyclopropyl-benzyl) -4- (. beta. -D-glucopyranos-1-yl) -benzene

Mass spectrometry (ESI)^-)：m/z＝413[M+H]⁺

Advantageously, the anomeric carbon center of a suitable intermediate obtained during the synthesis of this compound is reduced with an oxygen functional group on the protected pyranose ring. Preferred protecting groups are benzyl, p-methoxybenzyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl and allyl.

Example XXV

1-cyano-2- (4-cyclopropyl-benzyl) -4- (tetra-O-acetyl-beta-D-glucopyranos-1-yl) -benzene

To a flask equipped with a stir bar, 4- (2, 3, 4, 6-tetra-O-acetyl-D-glucopyranos-1-yl) -2- (4-trifluoromethylsulfonyloxy-benzyl) -benzonitrile (4.4g), degassed toluene (12mL) and degassed water (8mL) and kept under an argon atmosphere, was added cyclopropylboronic acid (0.20g), potassium phosphate (5.0g), tricyclohexylphosphine (0.19g) and palladium (II) acetate (76 mg). The mixture was stirred at 110 ℃ for 6 hours while cyclopropylboronic acid (5X0.20g) was added after every 1 hour. After cooling to room temperature, the mixture was diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried (sodium sulfate) and the solvent was removed under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 20: 1- > 1: 1).

Yield: 3.2g (87% of theory)

Mass spectrometry (ESI)⁺)：m/z＝581[M+NH₄]⁺

Example XXVI

4- (1-hydroxy-cyclopropyl) -phenylboronic acid

A3.0M solution of ethylmagnesium bromide in diethyl ether (7.6mL) was added to a stirred solution of titanium (IV) isopropoxide (2.2mL) in diethyl ether (70mL) cooled to-78 ℃. The resulting solution was stirred at-78 ℃ for 1.5 hours, followed by the addition of 4- (4, 4, 5, 5- [1, 3, 2)]Dioxaborolan-2-yl) -benzoic acid methyl ester (2.0 g). The reaction mixture was warmed to ambient temperature and stirred for an additional 12 hours. Then 1M aqueous hydrochloric acid was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and the solvent was evaporated. The residue was dissolved in acetone (60mL) and 0.1M NH was added₄Aqueous OAc solution (50mL), followed by addition of NaIO₄(2.3 g). The resulting reaction mixture was stirred at room temperature for 18 hours. After removal of the acetone, the residue was extracted with ethyl acetate. The combined extracts were dried (sodium sulfate) and the solvent was evaporated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate).

Yield: 0.45g (33% of theory)

Mass spectrometry (ESI)^-)：m/z＝223[M+HCOO]^-

Preparation of the final compound:

reference example 1

4- (beta-D-glucopyranos-1-yl) -2- [4- ((S) -tetrahydrofuryl-3-oxy) -benzyl ] -benzonitrile

A mixture of 1.00g of 1-chloro-2- [4- ((S) -tetrahydrofuryl-3-oxy) -benzyl ] -4- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranos-1-yl) -benzene, 0.16g of sodium cyanide and 0.35g of nickel bromide in 2.5mL of N-methyl-2-pyrrolidone was heated in a microwave oven at 220 ℃ for 15 minutes. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate. After drying over sodium sulfate and evaporation of the solvent, the residue was dissolved in 5mL of methanol. 4mL of 4M aqueous potassium hydroxide solution was added and the reaction solution was stirred at ambient temperature for 3 hours. The solution was neutralized with 1M hydrochloric acid and methanol was evaporated. The residue was extracted with ethyl acetate, the combined extracts were dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol 4: 1).

Yield: 0.35g (49% of theory)

Mass spectrometry (ESI)⁺)：m/z＝442[M+H]⁺

The compounds of examples 1, 2, 3 and 4 were obtained analogously to reference example 1:

example 1: 2- (4-ethyl-benzyl) -4- (beta-D-glucopyranos-1-yl) -benzonitrile

Yield: 65% of theory

Mass spectrometry (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- (beta-D-glucopyranos-1-yl) -2- (4-hydroxy-benzyl) -benzonitrile

This compound was prepared from 2- (4-acetoxy-benzyl) -1-chloro-4- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranos-1-yl) -benzene according to the procedure described above.

Yield: 30% of theory

Mass spectrometry (ESI)⁺)：m/z＝389[M+NH₄]⁺

This compound is also obtained by peracetylating 2- (4-methoxy-benzyl) -4- (β -D-glucopyranos-1-yl) -benzonitrile, followed by cleavage of the ether with boron tribromide and deacetylation.

Example 3: 4- (beta-D-glucopyranos-1-yl) -2- (4-methyl-benzyl) -benzonitrile

Yield: 59% of theory

Mass spectrometry (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- (beta-D-glucopyranos-1-yl) -benzonitrile

Yield: 58% of theory

Mass spectrometry (ESI)⁺)：m/z＝398[M+NH₄]⁺

Example 5

4- (beta-D-glucopyranos-1-yl) -2- (4-methoxyethoxy-benzyl) -benzonitrile

2-Bromoethylmethyl ether (85. mu.l) was added to a mixture of 4- (. beta. -D-glucopyranos-1-yl) -2- (4-hydroxybenzyl) -benzonitrile (0.30g) and cesium carbonate (0.39g) in 3mL of dimethylformamide. The mixture was stirred at 80 ℃ for 16 hours, followed by addition of water and brine. The resulting mixture was extracted with ethyl acetate, the combined extracts were dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol 1: 0- > 5: 1).

Yield: 0.19g (49% of theory)

Mass spectrometry (ESI)⁺)：m/z＝430[M+H]⁺

Example 6

4- (beta-D-glucopyranos-1-yl) -2- (4-trifluoromethoxy-benzyl) -benzonitrile

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

Yield: 0.145g (69% of theory)

Mass spectrometry (ESI)⁺)：m/z＝457[M+NH₄]⁺

In some cases, yield is increased by using 1.5 to 2.0 equivalents of boric acid with a proportionately increased amount of base.

The following compounds were obtained analogously to example 6:

example 7: 4- (beta-D-glucopyranos-1-yl) -2- (4-trifluoromethyl-benzyl) -benzonitrile

Yield: 47% of theory

Mass spectrometry (ESI)⁺)：m/z＝441[M+NH₄]⁺

Example 8: 4- (beta-D-glucopyranos-1-yl) -2- (4-isopropyl-benzyl) -benzonitrile

Yield: 87% of theory

Mass spectrometry (ESI)⁺)：m/z＝415[M+NH₄]⁺

Example 9: 4- (beta-D-glucopyranos-1-yl) -2- (4-tert-butyl-benzyl) -benzonitrile

Yield: 66% of theory

Mass spectrometry (ESI)⁺)：m/z＝429[M+NH₄]⁺

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

Yield: 70% of theory

Mass spectrometry (ESI)⁺)：m/z＝445[M+NH₄]⁺

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

Yield: 47% of theory

Mass spectrometry (ESI)⁺)：m/z＝419[M+NH₄]⁺

Example 12: 4- (beta-D-glucopyranos-1-yl) -2- [4- (3-methyl-but-1-yl) -benzyl ] -benzonitrile

Yield: 69% of theory

Mass spectrometry (ESI)⁺)：m/z＝443[M+NH₄]⁺

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

Yield: 34% of theory

Mass spectrometry (ESI)⁺)：m/z＝391[M+NH₄]⁺

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

Yield: 32% of theory

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

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

Yield: 32% of theory

Mass spectrometry (ESI)⁺)：m/z＝439[M+NH₄]⁺

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

Yield: 65% of theory

Mass spectrometry (ESI)⁺)：m/z＝423[M+NH₄]⁺

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

Mass spectrometry (ESI)⁺)：m/z＝413[M+NH₄]⁺

This compound was obtained according to example 6 using 4-cyclopropyl-phenylboronic acid as coupling partner.

Yield: 83% of theory

Alternatively, this compound was obtained as described in example XXIV (1).

The compound of example 17 was also obtained by using the following procedure:

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

Yield: 0.54g (96% of theory)

Example 18: 2- (4-cyclobutyl-benzyl) -4- (beta-D-glucopyranos-1-yl) -benzonitrile

This compound was obtained according to example 6 using 4-cyclobutyl boronic acid (obtainable analogously to example XXI) as coupling partner.

Yield: 51% of theory

Mass spectrometry (ESI)^-)：m/z＝427[M+NH₄]⁺

Example 19: 4- (beta-D-glucopyranos-1-yl) -2- (4-propan-1-yl-benzyl) -benzonitrile

Yield: 64% of theory

Mass spectrometry (ESI)⁺)：m/z＝415[M+NH₄]⁺

Example 20: 4- (beta-D-glucopyranos-1-yl) -2- [4- (1-hydroxy-cyclopropyl) -benzyl) -benzonitrile

This compound was obtained according to example 6 using 4- (1-hydroxy-cyclopropyl) -phenylboronic acid as coupling partner.

Example 21

4- (beta-D-glucopyranos-1-yl) -2- (4-iodo-benzyl) -benzonitrile

A1M solution of iodine monochloride in dichloromethane (0.9mL) was added to 4- (. beta. -D-glucopyranos-1-yl) -2- (4-trimethylsilyl-benzyl) -benzonitrile (0.26g) dissolved in dichloromethane (5 mL). The solution was stirred at room temperature for 1h and then by addition of Na₂S₂O₃Aqueous solution and NaHCO₃The aqueous solution is stopped. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed. The residue is chromatographed over silica gel (dichloromethane/methanol 1: 0- > 8: 1).

Yield: 0.15g (88% of theory)

Mass spectrometry (ESI)⁺)：m/z＝499[M+NH₄]⁺

The following compounds are obtained analogously to example 20:

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

Yield: 79% of theory

Mass spectrometry (ESI)⁺)：m/z＝451/453[M+NH₄]⁺

This compound was obtained according to the procedure of example 20, using bromine instead of ICl in dichloromethane.

Example 23

4- (beta-D-glucopyranos-1-yl) -2- (4-pentafluoroethyl-benzyl) -benzonitrile

A flask charged with 4- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranos-1-yl) -2- (4-iodo-benzyl) -benzonitrile (0.16g), pentafluoroethyltrimethylsilane (0.14g), KF (43mg), CuI (0.16g), DMF (2mL) and an Ar atmosphere was heated at 60 ℃ for 24 hours. Followed by addition of NaHCO₃Aqueous solution and the resulting mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed. The residue was dissolved in methanol (8mL) and treated with 4M KOH solution (0.8 mL). The solution was stirred at room temperature for 1h and then with NaHCO₃And (5) diluting the aqueous solution. After removal of methanol under reduced pressure, the residue was extracted with ethyl acetate, the combined organic extracts were dried and the solvent was removed. The residue is chromatographed over silica gel (dichloromethane/methanol 1: 0- > 8: 1).

Yield: 0.08g (69% of theory)

Mass spectrometry (ESI)⁺)：m/z＝491[M+NH₄]⁺

Example 24

4- (beta-D-glucopyranos-1-yl) -2- (4-methylsulfinyl-benzyl) -benzonitrile

A 35% aqueous solution of hydrogen peroxide (48 μ L) was added to 4- (. beta. -D-glucopyranos-1-yl) -2- (4-methylsulfanyl-benzyl) -benzonitrile (83mg) in 1, 1, 1, 3, 3, 3-hexafluoroisopropanol (2 mL). The resulting solution was stirred at ambient temperature for 1h and then by addition of Na₂S₂O₃Aqueous solution and NaHCO₃The aqueous solution is stopped. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed. The residue is chromatographed over silica gel (dichloromethane/methanol 1: 0- > 5: 1).

Yield: 24mg (28% of theory)

Mass spectrometry (ESI)⁺)：m/z＝418[M+H]⁺

Example 25

4- (beta-D-glucopyranos-1-yl) -2- (4-methylsulfonyl-benzyl) -benzonitrile

3-Chloroperoxybenzoic acid (70%, 0.14g) was added to 4- (. beta. -D-glucopyranose in dichloromethane (2mL) cooled in an ice bathGlucon-1-yl) -2- (4-methylsulfanyl-benzyl) -benzonitrile (100 mg). The cooling bath was removed and the resulting solution was stirred at ambient temperature for 1 hour. Adding Na₂S₂O₃Aqueous solution and NaHCO₃After the aqueous solution, the organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed. The residue is chromatographed over silica gel (dichloromethane/methanol 1: 0- > 8: 1).

Yield: 68mg (63% of theory)

Mass spectrometry (ESI)⁺)：m/z＝451[M+NH₄]⁺

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

some formulation examples will now be described, wherein the term "active agent" denotes one or more compounds of the present invention, including prodrugs or salts thereof. In the case of a combination with one other active substance as described above, the term "active substance" also includes other active substances.

Example A

Tablet containing 100mg of active substance

Consists of the following components:

1A tablet contains:

the preparation method comprises the following steps:

the active substance, lactose and starch were mixed together and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After the wet mixture was sieved (2.0mm mesh size) and dried in a rack-type dryer at 50 ℃, it was sieved again (1.5mm mesh size) and the lubricant was added. The final mixture was compressed to form tablets.

Tablet weight: 220mg of

Diameter: 10mm, double-sided, delineated on both sides and scored on one side.

Example B

Tablet containing 150mg of active substance

Consists of the following components:

1A tablet contains:

preparation:

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

Tablet weight: 300mg

Diameter: 10mm, flat

Example C

Hard capsules containing 150mg of active substance

Consists of the following components:

1 the capsule contains:

preparation:

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

Filling capsules: about 320mg

Capsule shell: hard capsules of size 1.

Example D

Suppository containing 150mg of active substance

Consists of the following components:

1 suppository contains:

preparation:

after melting the suppository mass, the active substance is homogeneously distributed therein and the melt is poured into a cooled mold.

Example E

Ampoules containing 10mg of active substance

Consists of the following components:

active substance 10.0mg

Proper amount of 0.01N hydrochloric acid

Adding double distilled water to 2.0ml

Preparation:

the active substance was dissolved in the necessary amount of 0.01N HCl, isotonic with common salt, sterile filtered and transferred to a 2ml ampoule.

Example F

Ampoules containing 50mg of active substance

Consists of the following components:

active substance 50.0mg

Proper amount of 0.01N hydrochloric acid

Adding double distilled water to 10.0ml

Preparation:

the active substance was dissolved in the necessary amount of 0.01N HCl, isotonic with common salt, sterile filtered and transferred to 10ml ampoules.

Claims (12)

1. A glucopyranosyl-substituted benzonitrile derivative of formula I; including tautomers, stereoisomers, or mixtures thereof; and physiologically acceptable salts thereof:

wherein

R³Represents hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butylA radical, sec-butyl, isobutyl, tert-butyl, 3-methyl-but-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-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, difluoromethoxy, trifluoromethoxy, 2-methoxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl and cyano,

or a derivative thereof: wherein one or more hydroxyl groups of the beta-D-glucopyranosyl group are selected from (C)_1-18Alkyl) carbonyl (C)_1-18Alkyl) oxycarbonyl, phenylcarbonyl and phenyl- (C)_1-3Acylation of alkyl) -carbonyl groups.

2. The glucopyranosyl-substituted benzonitrile derivative or physiologically acceptable salt thereof as claimed in claim 1, wherein the hydrogen atom of the hydroxyl group O-6 of the β -D-glucopyranosyl group is via a group selected from (C)_1-8Alkyl) carbonyl (C)_1-8Alkyl) oxycarbonyl and phenylcarbonyl.

3. A physiologically acceptable salt of a compound according to claim 1 or 2 with an inorganic or organic acid.

4. A pharmaceutical composition comprising a compound according to claim 1 or 2 or a physiologically acceptable salt according to claim 3, and optionally one or more inert carriers and/or diluents.

5. Use of at least one compound according to claim 1 or 2 or a physiologically acceptable salt according to claim 3 for the preparation of a pharmaceutical composition suitable for the treatment or prevention of a disease or condition which can be influenced by the inhibition of the sodium-dependent glucose cotransporter SGLT.

6. Use of at least one compound according to claim 1 or 2 or a physiologically acceptable salt according to claim 3 for the preparation of a pharmaceutical composition suitable for the treatment or prevention of one or more metabolic disorders.

7. The use of claim 6, wherein the metabolic disorder is selected from the group consisting of type 1 and type 2 diabetes, diabetic complications, metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorders, insulin resistance, metabolic syndrome, dyslipidemia of various origins, atherosclerosis and related diseases, obesity, hypertension, chronic heart failure, edema and hyperuricemia.

8. Use of at least one compound according to claim 1 or 2 or a physiologically acceptable salt according to claim 3 for the preparation of a pharmaceutical composition for inhibiting the sodium-dependent glucose cotransporter SGLT 2.

9. Use of at least one compound according to claim 1 or 2 or a physiologically acceptable salt according to claim 3 for the preparation of a pharmaceutical composition for preventing degeneration of pancreatic β -cells and/or for improving and/or restoring pancreatic β -cell function.

10. Use of at least one compound according to claim 1 or 2 or a physiologically acceptable salt according to claim 3 for the preparation of a pharmaceutical composition for the prevention, alleviation, delay or treatment of a disease or condition resulting from abnormal accumulation of liver fat in a patient in need thereof.

11. Use of at least one compound according to claim 1 or 2 or a physiologically acceptable salt according to claim 3 for the preparation of a diuretic and/or antihypertensive agent.

12. Glucopyranosyl-substituted benzonitrile derivative of formula II, formula III, formula i.1, formula i.2, formula i.3, formula i.4, formula i.5 or formula i.6, including tautomers, stereoisomers or mixtures thereof; and physiologically acceptable salts thereof:

wherein

R³As defined in claim 1, and

r' represents H, C_1-4Alkyl, (C)_1-18Alkyl) carbonyl (C)_1-18Alkyl) oxycarbonyl, arylcarbonyl or aryl- (C)_1-3Alkyl) -carbonyl, wherein these alkyl or aryl groups may be mono-or polysubstituted with halogens;

R^8a、R^8b、R^8c、R^8dindependently of one another, hydrogen or allyl, benzyl, (C)_1-4Alkyl) carbonyl (C)_1-4Alkyl) oxycarbonyl, arylcarbonyl, aryl- (C)_1-3Alkyl) -carbonyl and aryl- (C)_1-3Alkyl) -oxycarbonyl or R^aR^bR^cSi groups or ketal or acetal groups, especially alkylene or arylalkylene ketal or acetal groups, with in each case two adjacent radicals R^8a、R^8b、R^8c、R^8dCan form a cyclic ketal or acetal group or a 1, 2-di (C)_1-3Alkoxy) -1, 2-bis (C)_1-3Alkyl) -ethylene bridges which, together with the two oxygen atoms and the two carbon atoms to which they are attached of the pyranose ring, form substituted di-sAlkyl rings, especially 2, 3-dimethyl-2, 3-di (C)_1-3Alkoxy) -1, 4-bisAlkyl rings, and the alkyl, allyl, aryl and/or benzyl groups may be substituted by halogen or C_1-3Alkoxy being mono-or polysubstituted, and benzyl being optionally di- (C)_1-3Alkyl) amino substitution; and is

R^a、R^b、R^cIndependently of one another represent C_1-4Alkyl, aryl or aryl-C_1-3Alkyl, wherein the aryl or alkyl may be mono-or polysubstituted with halogen;

whilst the aryl groups mentioned in the definitions of these above groups refer to phenyl or naphthyl, preferably phenyl; and is

Alk represents C_1-4An alkyl group; and is

R¹Represents chlorine, bromine, cyano, carboxyl, carboxylic ester, carboxamide or derivative thereof, boron or silyl, a protected or masked aldehyde group, or a protected or masked amino group, R¹Preferably represents Br or CN; and is

LG represents a leaving group, e.g. Br, I or-O- (SO)₂)-CF₃(ii) a And is

U represents Cl, Br, I, -O-CO-C_1-4Alkyl, -O-C (═ O) -O-C_1-4Alkyl or-OPO (O-C)_1-4Alkyl radical)₂。