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

[0001] The invention relates to benzonitrile derivatives substituted with glucopyranosyl, of general formula I

<img file="PL2024352T3_D0001.tif" />

in which the R group³ is defined below, including their tautomers, stereoisomers, mixtures and salts thereof. The invention further relates to pharmaceutical compositions comprising a compound of formula I according to the invention and the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment of metabolic disorders. In addition, the invention relates to methods of preparing a pharmaceutical composition as well as a compound of the invention.

[0002] It has been proposed in the literature that compounds showing inhibitory activity against sodium-dependent glucose co-transporters SGLT2 are used to treat diseases, especially diabetes.

[0003] Aromatic groups substituted by glucopyranosyl and their production, as well as their potential activity as SGLT2 inhibitors, are known from international application WO 2005/092877 and the publications cited therein.

Object of the invention [0004] The purpose of the present invention is to find new glucopyranosyl substituted benzonitrile derivatives, especially those that are active against the sodium-dependent glucose co-transporter SGLT, especially SGLT2. Another object of the present invention is to discover benzene derivatives substituted with glucopyranosyl which have a stronger inhibitory effect on the sodium glucose co-transporter SGLT2 in vitro and / or in vivo compared to known structurally similar compounds and / or have better pharmacological or pharmacokinetic properties.

[0005] A further object of the present invention is to provide new pharmaceutical compositions that are suitable for the prevention and / or treatment of metabolic disorders, especially diabetes.

[0006] Other objects of the present invention will become apparent to those skilled in the art directly from the previous and following comments.

Object of the invention [0007] A first aspect of the present invention relates to glucopyranosyl substituted benzonitrile derivatives of general formula I

<img file="PL2024352T3_D0002.tif" />

wherein

R³ cyclopropyl, cyclobutyl, or derivatives thereof, in which one or more hydroxyl groups of the βD-glucopyranosyl group is acetylated with groups selected from (C_1-18alkyl) carbonyl, (C 1-18 -alkyl) oxycarbonyl, phenylcarbonyl and phenyl- (C 1-3 -alkyl) carbonyl, including their tautomers, stereoisomers or mixtures thereof; and their physiologically acceptable salts.

[0008] The compounds of the invention and their physiologically acceptable salts have valuable pharmacological properties, in particular the inhibitory effect on the sodium-dependent glucose co-transporter SGLT, especially SGLT2. In addition, the compounds of the invention show an inhibitory effect on the sodium-dependent glucose co-transporter SGLT1. Compounds of the invention preferably selectively inhibit SGLT2 compared to the potential SGLT1 inhibitory effect.

[0009] The present invention also relates to physiologically acceptable salts of the compounds of the invention with inorganic or organic acids.

[0010] The present invention also relates to pharmaceutical compositions comprising at least one compound of the invention or a physiologically acceptable salt according to the invention, optionally together with one or more inert carriers and / or diluents.

[0011] The present invention also relates to the use of at least one compound of the invention or a physiologically acceptable salt thereof for the manufacture of a pharmaceutical composition which is suitable for treating or preventing diseases or conditions which are affected by inhibition of the sodium-dependent glucose co-transporter SGLT, especially SGLT2.

[0012] The present 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 which is suitable for the treatment of one or more metabolic disorders.

[0013] A further aspect of the present invention relates to the use of at least one compound of the invention or a physiologically acceptable salt thereof in the manufacture of a pharmaceutical composition for preventing degeneration of pancreatic beta cells and / or improving and / or restoring the functionality of pancreatic beta cells.

[0014] Another aspect of the present invention relates to the use of at least one compound of the invention or a physiologically acceptable salt thereof in the manufacture of a pharmaceutical composition for preventing, slowing down, delaying or treating diseases or conditions attributed to abnormal hepatic fat accumulation in patients in need thereof.

[0015] The present invention also relates to the use of at least one compound of the invention or a physiologically acceptable salt thereof in the preparation of a pharmaceutical composition for inhibiting the sodium-dependent glucose co-transporter SGLT, in particular SGLT2.

[0016] The present invention also relates to a process for preparing a pharmaceutical composition according to the invention, characterized in that at least one compound according to the invention or a physiologically acceptable salt thereof is introduced in one or more inert carriers and / or diluents by a non-chemical method.

[0017] The present invention also relates to a process for the preparation of compounds of general formula I according to the invention, characterized in that

a) to obtain compounds of general formula I which are defined as above and below, a compound of formula II

<img file="PL2024352T3_D0003.tif" />

wherein

R 'is H, C₁_₄-alkyl, (C₁_₁₈-alkyl) carbonyl, (C₁_₁₈-alkyl) oxycarbonyl, arylcarbonyl and aryl- (C₁_₃-alkyl) -carbonyl, where the alkyl or aryl groups may be mono- or polysubstituted by halogen;

8a 8b 8c 8d

R, R, R, R are each independently a hydrogen atom or an allyl group, a benzyl group, (C 1-4 alkyl) carbonyl, (C 1-4 alkyl) oxycarbonyl, arylcarbonyl, aryl- (C 1-3 alkyl) carbonyl and aryl- (C 1-3 -alkyl) oxycarbonyl or an R group^andR^bR^cSi or a ketal or acetal group, especially an alkylidene ketal or acetal group

8a 8b 8c arylalkylidene, while in each case two adjacent groups R, R, R, R^8d can form a cyclic ketal or acetal group or a 1,2-di (C1-3alkoxy) -1,2-di (C1-3-alkyl) -ethylene bridge, where the above-mentioned ethylene bridge together with two oxygen atoms and two bonded carbon atoms the pyranose ring forms a substituted dioxane ring, in particular the 2,3-dimethyl-2,3-di (C1-3-alkoxy) -1,4-dioxane ring, and where the alkyl, allyl, aryl and / or benzyl may be mono- or polysubstituted by halogen or C1-3alkoxy and wherein benzyl groups may also be substituted by di- (C1-3alkyl) amino; and

R^and, R^b, R^c are each independently C1-4alkyl, aryl or aryl C1-3alkyl, where aryl or alkyl groups may be mono- or polysubstituted by halogen;

wherein the aryl groups mentioned in the definition of the above groups are phenyl or naphthyl groups, preferably a phenyl group; and where group R³ is defined as above and below;

is reacted with a reducing agent in the presence of Lewis or Bronsted acid, while any protecting groups present are removed simultaneously or sequentially; or

b) to obtain compounds of general formula I, compound of formula III

<img file="PL2024352T3_D0004.tif" />

8a 8b 8c 8d 3 in which R, R, R, R and R are defined as above and below, assuming that

8a 8b 8c 8d at least one substituent selected from R, R, R, R is not a hydrogen atom;

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

[0018] A further aspect of the present invention relates to new intermediates described in the reaction schemes and in the following experimental section.

Detailed description of the invention [0019] Aspects of the present invention, in particular compounds, pharmaceutical compositions and their uses, refer to glucopyranosyl substituted benzonitrile derivatives of general formula I defined above and below, or derivatives thereof, including tautomers, stereoisomers or mixtures thereof, and their physiological acceptable salts.

[0020] The following alternative preferred embodiments of the present invention are described:

[0021] According to the present invention, R³ means cyclopropyl, cyclobutyl.

[0022] Preferably, all hydroxyl groups belonging to the β-Dglucopyranosyl group are unsubstituted or only the O-6 group of the β-Dglucopyranosyl group is substituted as defined. Preferred substituents are selected from (C1-8-alkyl) carbonyl, (C1-8-alkyl) oxycarbonyl and phenylcarbonyl. Even more preferably, the substituents are selected from acetyl, methoxycarbonyl and ethoxycarbonyl, especially acetyl and ethoxycarbonyl.

[0023] The nomenclature in the structural formulas used above and below, in which the bonding of a substituent of a cyclic group, such as a phenyl group, is shown towards the center of the cyclic group, unless otherwise indicated, that the substituent may be bonded in any free position cyclic group having the H atom

[0024] The compounds of the invention can be obtained using essentially known synthetic methods. Preferably, the compounds of the invention are obtained by the following methods of the invention, which are described in more detail below.

[0025] The glucose derivatives of formula II according to the invention can be synthesized from Dgluconolactone or a derivative thereof by the addition reaction of the desired benzylbenzene compound in the form of an organometallic derivative (Scheme 1).

Scheme 1: Addition of an organometallic compound to gluconolactone

<img file="PL2024352T3_D0005.tif" />

[0026] The reaction of Scheme 1 is preferably carried out starting from a halogenated benzylbenzene of general formula IV, where Hal is chlorine, bromine or iodine. R¹ in Scheme 1 is a cyano group or a group that can then be converted to a cyano group such as chlorine, bromine, carboxyl, carboxylic ester, carboxamide or derivative thereof, borane or silyl group, protected or masked aldehyde functional group such as acetal or thiazole , or a protected or masked amino function, e.g. nitro. The Grignard or lithium reagent from benzylbenzene V can be prepared from the corresponding chloro-, bromo- or iodo-benzylbenzene IV in the so-called halogen-metal exchange reaction or by the insertion of a metal into a carbon-halogen bond. The halogen-metal exchange for the synthesis of the corresponding lithium compound V can be carried out, for example, with an organolithium compound, such as, for example, n-, sec- or tert-butyl lithium. An analogous magnesium compound can also be generated by a halogen metal exchange reaction using a suitable Grignard reagent such as, e.g., isopropyl or sec-butyl magnesium bromide or chloride or diisopropyl or disec-butyl magnesium, without or in the presence of an additional salt such as e.g. lithium chloride, which can accelerate the metallization process; a specific organomagnesium compound for transmetallation can also be generated in situ from suitable precursors (see, e.g., Angew. Chem. 2004, 116, 3396-3399 and Angew. Chem. 2006, 118, 165-169 and references cited therein). In addition, consumed complexes of organometallic compounds obtained by combining e.g. butylmagnesium chloride or bromide or isopropylmagnesium chloride or bromide with butyllithium may also be used (see e.g. Angew. Chem. 2000, 112, 2594-2596 and Tetrahedron Lett. 2001, 42, 4841-4844 and references cited therein). The halogen-metal exchange reactions are preferably carried out at a temperature of from 40 to -100 ° C, particularly preferably from 10 to -80 ° C, in an inert solvent or mixtures thereof, such as, for example, diethyl ether, dioxane, tetrahydrofuran, toluene, hexane, dimethyl sulfoxide, dichloromethane or mixtures thereof. The magnesium or lithium derivatives thus obtained may optionally be transmetallized with metal salts, such as e.g. cerium trichloride, zinc chloride or bromide, indium chloride or bromide to form alternative organometallic compounds V suitable for addition. Alternatively, the organometallic compound V can also be prepared by inserting a metal into a carbon-halogen bond of a halogenoaromatic compound IV. Lithium and magnesium are suitable elemental metals for this transformation. Insertion can be made in solvents such as, for example, diethyl ether, dioxane, tetrahydrofuran, toluene, hexane, dimethyl sulfoxide and mixtures thereof, at a temperature in the range from -80 to 100 ° C, preferably from -70 to 40 ° C.

In cases where the reaction does not occur spontaneously, prior activation of the metal may be required, e.g. treatment with 1,2-dibromomethane, 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 in the range from 40 to 100 ° C, particularly preferably from 0 to -80 ° C, in an inert solvent or mixtures thereof, to obtain a compound of formula II. All of the above reactions can be carried out in air, although it is preferable to perform under an inert gas such as argon and nitrogen. The metalation and / or coupling reaction can also be carried out in microreactors and / or micromixers enabling high exchange rates, for example in analogy to the processes described in WO 2004/076470. Suitable solvents for the addition reaction of the metalized phenyl (V) group to the appropriately protected gluconolactone (VI) are e.g. diethyl ether, dimethoxyethane, benzene, toluene, methylene chloride, hexane, tetrahydrofuran, dioxane, N-methylpyrrolidone and mixtures thereof. The addition reactions can be carried out without any further auxiliaries or, in the case of slow reacting coupling partners, in the presence of a promoter such as e.g. BF3.OEt2 or Me3SiCl (see M. Schlosser. Organometallics in Synthesis. John Wiley &amp; Sons. Chichester / New York / Brisbane / Toronto / Singapore, 1994). Preferred terms for the R substituents⁸ in Scheme 1 are benzyl, substituted benzyl, allyl, trialkylsilyl, particularly preferably trimethylsilyl, triisopropylsilyl, allyl, 4-methoxybenzyl and benzyl. If two adjacent R substituents⁸ are bound together, these two substituents are preferably part of benzylidene acetal, 4-methoxybenzylidene acetal, isopropyl ketal or are dioxane with 2,3-dimethoxybutylene, which is bonded via 2 and 3 positions of butane to neighboring oxygen pyranose atoms. The group R 'is preferably hydrogen, C 1-4 -alkyl, C 1-4 -alkylcarbonyl or C 1-4 -alkyloxycarbonyl, particularly preferably hydrogen, methyl or ethyl. The R 'group is introduced after the addition of the organometallic compound V or its derivative to gluconolactone (VI). If R 'equals hydrogen or C 1-4 -alkyl, the reaction solution is treated with an alcohol such as e.g. methanol or ethanol or water in the presence of an acid such as e.g. acetic acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, trifluoroacetic acid or hydrochloric acid. R 'can also be attached after the compound with hydrogen (II) is formed by reacting the anomeric hydroxyl group with a suitable electrophilic compound such as methyl iodide, dimethyl sulfate, ethyl iodide, diethyl sulfate, acetyl chloride or acetic anhydride in the presence of a base such as. e.g. triethylamine, ethyl diisopropylamine, sodium or potassium or cesium carbonate, sodium or potassium or cesium hydroxide. The hydroxyl group may also be deprotonated prior to the addition of an electrophilic compound, e.g. sodium hydride. When installing R ', security groups R⁸ may cleave if they are unstable under the reaction conditions used, giving the corresponding protonated compound, i.e. compound II, in which R⁸ equals H.

[0027] The synthesis of the halogen-aromatic compound of formula IV can be carried out using standard transformations known in organic chemistry or at least methods known from the literature specializing in organic chemistry (see, among others, J. March, Advanced Organic Reactions, Reactions, Mechanisms, and Structure, 4th edition, John Wiley and Sons, Chichester / New York / Brisbane / Toronto / Singapore, 1992 and literature cited therein). More specifically, the use of transition metals and organometallic compounds for the synthesis of aromatic compounds have been described in detail in various monographs (see e.g. L. Brandsma, SF Vasilevsky, HD Verkruijsse, Application of Transition Metal Catalysts in Organic Synthesis, SpringerVerlag, Berlin / Heidelberg, 1998; M Schlosser, Organometallics in Synthesis, John Wiley and Sons, Chichester / New York / Brisbane / Toronto / Singapore, 1994; PJ Stang, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1997 and references cited therein). The synthesis strategies described below show how it works based on examples. In addition, the aglycon portion can also be combined with an existing pyranose residue using the same synthetic approaches.

Scheme 2: Synthesis of diaryl ketone fragment

<img file="PL2024352T3_D0006.tif" />

[0028] Scheme 2 shows the preparation of a precursor compound that can be used to synthesize a halogen-aromatic compound of formula IV, starting from benzoyl chloride and a second aromatic derivative under Friedl-Crafts acylation reaction conditions or modifications thereof. R¹ in Scheme 2 is a cyano group or a group that can then be converted into a cyano group such as chlorine, bromine, carboxyl, carboxyl ester, carboxamide or derivative thereof, protected or masked aldehyde function such as thioacetal or thiazole, or protected or masked amino function such as nitro. This classic reaction involves a wide range of substrates and is usually carried out in the presence of a catalyst that is used in catalytic or stoichiometric amounts such as AlCl3, FeCl3, iodine, iron, ZnCl2, sulfuric acid or trifluoromethanesulfonic acid. Instead of benzoyl chloride, the corresponding carboxylic acid, anhydride, ester or benzonitrile may also be used. The reactions are preferably carried out in halogenated hydrocarbons such as e.g. dichloromethane and 1,2-dichloroethane at a temperature of 30 to 120 ° C, preferably at 30 to 100 ° C. However, solvent-free reactions or microwave reactions are possible.

Scheme 3: Reduction of diaryl ketones and diarylmethanols to diarylmethanes

<img file="PL2024352T3_D0007.tif" />

[0029] In Scheme 3, R is C1-3-alkyl or aryl, and R is¹ a cyano group or a group which can then be converted to a cyano group such as chlorine, bromine, carboxyl, carboxyl ester, carboxamide or derivative thereof, borate or silyl group, protected or masked aldehyde function such as thioacetal or thiazole, or protected or masked amino function such as nitro. Starting with diaryl ketone or diarylmethanol, diarylmethane is available in one or two stages. In the two-step variant, the ketone is reduced with a reducing agent such as, for example, a metal hydride such as NaBH4, LiAlH4 or iBu2AlH to form an alcohol. The alcohol obtained can be converted in the presence of Lewis acid_* like BF for example₃ OEt₂, InCl₃ or ALC1₃ or Bronsted acid such as, for example, hydrochloric acid, hydrochloric acid, trifluoroacetic acid or acetic acid, with a reducing agent such as EtSiH, NaBH4 or Ph2SiClH, in the desired diphenylmethane.

The one-step process starting from the ketone to obtain diphenylmethane can be carried out e.g. using a silane such as Et3SiH or a borohydride such as BH4 or aluminum hydride such as LiAlH4 in the presence of Lewis acid such as _*

BF3 OEt2, tris (pentafluorophenyl) borate, trifluoroacetic acid, hydrochloric acid, aluminum chloride or InCl3. The reactions are preferably carried out in solvents such as e.g. halogenated hydrocarbons such as dichloromethane, toluene, acetonitrile or mixtures thereof at a temperature from -30 to 150 ° C, preferably from 20 to 100 ° C. Hydrogen reduction reactions in the presence of a transition metal catalyst such as Pd on carbon and other possible methods of synthesis are another possible method of synthesis. Reduction reactions according to Wolff-Kiżner or their variants are also possible. The ketone is first converted with hydrazine or a derivative thereof, such as 1,210 bis (tert-butyldimethylsilyl) hydrazine, into a hydrazone which decomposes under strongly basic reaction conditions and when heated, forming diphenylmethane and nitrogen. The reactions can be carried out in one reaction step, or after isolation of the hydrazone or its derivative in two separate steps. Suitable rules include e.g. KOH, NaOH or KOt-Bu, in solvents such as e.g. ethylene glycol, toluene, DMSO, 2- (2-butoxyethoxy) ethanol or tert-butanol; solvent-free reactions are also possible. The reactions can be carried out at a temperature of 20 to 250 ° C, preferably 80 to 200 ° C. An alternative to the basic conditions of the Wolff-Kiżner reduction is the Clemmensen reduction under acidic conditions, which can also be used here. The alcohol function in diarylmethanol can also first be converted into a better leaving group such as chlorine, bromine, iodine, acetate, carbonate, phosphate or sulfate; the next stage of reduction to form diarylmethane is widely described in the chemical literature.

Scheme 4: Synthesis of diarylmethane and potential precursors

OR

Y = Ci, Br, L OSOjCFj, OSO₂f> This! or OR

OR

OR .χΧσ '

Hal = Cl, Br, «, OSOjCFj, OSO_?p-Tol

T = COOH, COOAlk, CONR_S,

CN, GOCI addition to a metal, e.g. carboxylic acid or

Li. MgHal, its derivative stage 4 addition to aldehyde stage 2 stage 3

U = CI, Br, I, OOCAlk,

Sp IZ φ 11 cl 1116

OOCOAlk. OPOfOAJkk catalyzed by transition metal step 1 halogen-metal exchange [0030] In Scheme 4, R¹ means a cyano group or a group which can then be converted into a cyano group such as chlorine, bromine, carboxy, carboxyl ester, carboxamide or derivative thereof, borate or silyl group, protected or masked aldehyde function such as e.g. thioacetal or thiazole, or protected or masked amine function such as nitro. The term "Alk" means C_1-3-alkyl and each R is independently of the other selected from the group consisting of H, C_1-3-alkyl and C._1-3-alkoxy. Scheme 4 shows the synthesis of diarylmethanes and their potential precursors starting from a metal-substituted phenyl group. Lithium or magnesium substituted aromatic compounds can be synthesized from chloro-, bromo- or iodo-derived aromatic compounds in a halogen-metal exchange reaction, e.g. with butyllithium, isopropylmagnesium or diisopropylmagnesium halide or by the insertion of an elemental metal into a halogen-carbon bond. A suitable boron-substituted compound, such as boronic acid, boronic acid ester or dialkylaryl borate can be obtained from these metal substituted phenyl groups by reaction with an electrophilic boron compound, such as, for example, a boronic acid ester or derivative thereof. In addition, the boron-substituted aromatic compound can also be produced from the appropriate halogen or pseudohalogen precursor and the diborane or borate compound in a transition metal catalyzed reaction, e.g. palladium (see, e.g., Tetrahedron Lett. 2003, pp. 4895-4898 and references cited therein). Lithium or magnesium substituted phenyl compounds attach to benzaldehydes (step 3) and benzoic acids or their derivatives (step 4), such as benzoic acid esters, benzamides such as, for example, Weinreb-type amide, benzonitriles or benzoyl chlorides. These reactions can generally be carried out without additional transition metal catalyst or transmetallation to another metal such as e.g. cerium, indium or zinc; sometimes it is preferable to use one of the latter alternatives. Aryl boronic acids can be attached to benzaldehydes using a rhodium catalyst to give the corresponding diarylmethanol (see, e.g., Adv. Synth. Catal. 2001, pp. 343-350 and references cited therein). In addition, arylboronic acids, their esters, dialkylarylborates or aryltrifluoroborates can be coupled to benzoyl chlorides through transition metals such as e.g. palladium, its complexes or salts to give diaryl ketones. Metal-substituted phenyl groups can be reacted with electrophilic benzyl compounds such as benzyl chlorides, bromides or iodides to give diarylmethanes. Lithium or magnesium derivatives of phenyl compounds are preferably but not always necessarily reacted in the presence of a transition metal such as e.g. copper, iron or palladium (see e.g. Org. Lett. 2001, 3, 2871-2874 and references cited therein). Transmetallization from lithium or magnesium, e.g. to boron, tin, silicon or zinc, leads e.g. to the corresponding aromatic borate acids, stannates, silanes or zinc compounds, respectively, which can be coupled with electrophilic benzyl compounds, e.g. halides, carbonates, phosphates , benzyl sulfonates or carboxylic esters. The reaction is carried out in the presence of a transition metal, e.g. palladium, nickel, rhodium, copper or iron (see, e.g., Tetrahedron Lett. 2004, p. 8225-8228 and Org. Lett. 2005, p. 48754878 and references cited therein).

<img file="PL2024352T3_D0008.tif" />

[0031] Scheme 5 shows the potential routes for attachment of a cyano residue to a central phenyl group at various stages of the synthesis of the target molecule. The cyano group can be introduced in a transition metal mediated coupling reaction from a suitable source of cyano groups, e.g. sodium, potassium, zinc or copper cyanide, with a phenyl group halide or pseudohalide. Suitable catalysts can be derived from transition metals such as e.g. palladium, rhodium, nickel, iron or copper, which can be used in elemental form, e.g. palladium or carbon, as salts such as palladium chloride, bromide or acetate, or complexes, e.g. with phosphines, e.g. triphenylphosphine, tri- tert-butylphosphine or dppf, or alkenes such as, for example, dibenzylideneacetone. Active catalyst can be generated in situ or before addition to the reaction mixture. Additives such as elemental or salt zinc may be preferred (see, e.g., Tetrahedron Lett. 2005, 46, 1849-1853 and Tetrahedron Lett. 2005, 46, 1815-1818 and references cited therein). Reaction with an appropriate compound of zinc, magnesium or lithium, available from the chloro, bromo or iodo derivative of the compound in a halogen-metal exchange reaction or by the insertion of a suitable metal for a carbon-halogen bond; with electrophilic cyanide, such as e.g. p-tolylsulfonyl cyanide, cyanogen bromide or 2-pyridyl cyanate, is another feasible approach to introduce cyano function (see e.g. Synth. Commun. 1996, 3709-3714 and references cited therein).

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

<img file="PL2024352T3_D0009.tif" />

[0032] Alternative introduction of a cyano group allows synthesis starting from an aldehyde or carboxamide (Scheme 6). The aldehyde function can be introduced as such, protected or masked. Acetals are popular protecting groups for the aldehyde function, but other protecting groups may also be used (see TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, John Wiley &amp; Sons, Inc. New York, 1999). Suitable masking groups for aldehyde function are e.g. olefins and thiazoles. Aldehyde can be converted to cyano function using e.g. hydroxylamine in combination with e.g. formic acid, concentrated hydrochloric acid, polyphosphoric acid or pyridine-toluene. Intermediate oxime formed under these conditions can be secreted before dehydration leading to the final product. Similarly, alternative hydroxylamine reagents such as e.g. bistrifluoroacetylhydroxylamine and NH2OSO3, providing nitrile without additional reagents. Further useful reagents are e.g. NH4PO4H2 and nitropropane in acetic acid, trimethylsilyl azide or S, S-dimethylsulfodiimide. [0033] Carboxamides may also be useful nitrile precursors. Conversion can be carried out with the help of drainage agents, such as trifluoroacetic acid anhydride, phosphorus pentoxide, POCl3, CCl4-phosphine combination, Cl3COCl-amine combination, Burgess reagent, Vilsmeyer reagent, SOCl2 or cyanuric chloride. Starting from the corresponding monosubstituted alkyl carboxamide, carboxylic acid, ester or carboxylic chloride derivative, it is also possible to form nitrile in one reaction vessel without isolating any intermediates.

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

<img file="PL2024352T3_D0010.tif" />

[0034] A well established approach to the introduction of the nitrile function is the so-called Sandmeyer reaction with copper cyanide and the corresponding diazonium salt obtained by diazotization of the corresponding aniline derivative. The synthesis of diazonium compounds and their subsequent cyano-de-diazonization have been well documented in the organic chemistry literature.

Scheme 8: Alternative synthesis of diaryl methane

<img file="PL2024352T3_D0011.tif" />

shown in Scheme 8. It uses benzonitrile substituted with fluorine in the ortho position, which is commercially available or can be obtained by the methods mentioned above. An ortho-substituted benzonitrile is reacted with an R-substituted alkyl phenylacetate³ under basic conditions (see J. Org. Chem. 55, 1990, 4817-4821; J. Heterocycl. Chem. 32, 1995, 1461-1466), followed by ester cleavage and decarboxylation (see J. Hetrocycl. Chem. 32, 14611466; Org. Prep. Procedure Int. 37, 2005, 550-555) or direct dealkoxycarbonylation (see e.g. J. Med. Chem. 46, 2003, 5249-5257; Angew. Chem. Int. Ed. 47, 2004 , 6493-6496).

[0036] In order to obtain compounds of general formula I, in method a) according to the invention, a compound of general formula II

<img file="PL2024352T3_D0012.tif" />

in which R 'and R³ are as defined above and

8a 8b 8c 8d

R, R, R, R are as defined above and independently of each other are, for example, acetyl, pivaloyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, allyl, trialkylsilyl, benzyl or substituted benzyl or whenever two adjacent groups

8a 8b 8c 8d

R, R, R, R form benzylidene acetal or isopropylidene ketal or a 2,3-dimethoxybutylene group which is bonded via the 2 or 3 position of the butylene group to the nitrogen atoms of the pyranose ring and forms with them substituted dioxane, which can be obtained as described above, subjected to reaction with a reducing agent in the presence of Lewis or Bronsted acid. [0037] Suitable reducing agents include, for example, silanes such as triethyl-, tripropyl-, triisopropyl- or diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borates, lithium aluminum hydride, diisobutylaluminum hydride or samarium iodide. The reduction reactions are carried out without or in the presence of the corresponding Bronsted acid, such as e.g. hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid or acetic acid, or Lewis acid, e.g. boron trifluoride complex - ethyl ether, trimethylsilyl trifluoromethanesulfonate, titanium tetrachloride, tin tetrachloride, scandium trifluoromethanesulfonate or zinc iodide. Depending on the reducing agent and acid, the reaction can be carried out in a solvent such as, for example, methylene chloride, chloroform, acetonitrile, toluene, hexane, diethyl ether, tetrahydrofuran, dioxane, ethanol, water or mixtures thereof at a temperature from -60 ° C to 120 ° C. A particularly suitable combination of reagents consists, for example, of triethylsilane and boron trifluoride etherate, which is conveniently used in acetonitrile or dichloromethane at a temperature from -60 to 60 ° C. In addition, hydrogen in the presence of a transition metal catalyst, such as e.g. palladium on carbon or Raney nickel, in solvents such as tetrahydrofuran, ethyl acetate, methanol, ethanol, water or acetic acid may be used for the transformation described.

[0038] Alternatively, to obtain compounds of general formula I according to method b) according to the invention, in a compound of formula III

<img file="PL2024352T3_D0013.tif" />

in which R¹ is as described above and

R^8a to R.^8d are one of the protecting groups described above, such as e.g. acyl, arylmethyl, allyl, acetal, ketal or silyl, and which can be obtained e.g. by reduction from a compound of formula II as described above, the protecting groups are removed.

[0039] It is understood that one or more R groups^8a to R.^8d may be replaced during the abovementioned chemical processes.

[0040] Any acyl protecting group is removed, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at a temperature from 0 to 120 ° C, preferably at a temperature from 10 to 100 ° C. The trifluoroacetyl group is preferably removed under the action of an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at a temperature of 50 to 120 ° C or by heating with a sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran or methanol at a temperature of 0 to 50 ° C.

[0041] Any acetal or ketal protecting group used is removed, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric or sulfuric acid or in the presence of a basic alkali metal such as lithium hydroxide, sodium hydroxide or potassium hydroxide or nonprotoxically, e.g. in the presence of iodotrimethylsilane, at a temperature from 0 to 120 ° C, preferably at a temperature from 10 to 100 ° C.

[0042] The trimethylsilyl group is removed, for example, in water, an aqueous solvent mixture or a lower alcohol such as methanol or ethanol in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methoxide.

[0043] In aqueous or alcoholic solvents, acids such as, for example, hydrochloric acid, trifluoroacetic acid or acetic acid are also useful. For removal in organic solvents such as, for example, diethyl ether, tetrahydrofuran or dichloromethane, it is also preferable to use fluoride reagents such as, for example, tetrabutylammonium fluoride.

[0044] The benzyl, methoxybenzyl or benzyloxycarbonyl group is preferably removed hydrolytically, e.g. by hydrogen in the presence of a catalyst such as palladium / carbon, in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of such acid as hydrochloric acid at a temperature between 0 and 100 ° C, but preferably at ambient temperature between 20 and 60 ° C and hydrogen pressure between 1 and 7 bar, but preferably between 3 and 5 bar. However, the 2,4-dimethoxybenzyl group is preferably removed in trifluoroacetic acid in the presence of anisole.

[0045] The tert-butyl, tert-butyloxycarbonyl group is preferably removed by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

[0046] In the reactions described above, any reactive groups present such as ethynyl, amino, alkylamino or imino may be protected during the reaction with traditional protecting groups which are removed again after the reaction. [0047] For example, the protecting group for an ethynyl group may be a trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.

[0048] The protecting groups for hydroxyl groups are trimethylsilyl, acetyl, trityl, benzyl or tetrahydrophenyl.

[0049] Protecting groups for amino, alkylamino or imino groups may be, for example, formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl.

[0050] In addition, the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers as mentioned above. Thus, for example, cis / trans mixtures can be separated into cis and trans isomers, and compounds with at least one optically active carbon atom can be separated into enantiomers.

[0051] Thus, for example, cis / trans mixtures can be separated chromatographically into cis and trans isomers, the resulting compounds of general formula I which occur as racemates can be separated by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971) into their optical antipodes, and compounds of general formula I with at least 2 asymmetric carbon atoms can be separated into diastereomers on the basis of their physicochemical differences using methods known per se, e.g. by chromatography or fractional crystallization, and if these compounds are obtained in racemic form, they can then be separated into enantiomers as mentioned above.

[0052] Enantiomers are preferably separated by column separation in chiral phases or by recrystallization in an optically active solvent or by reaction with an optically active substance that forms salts or derivatives such as, for example, esters or amides with racemic compounds, especially acids and their activated derivatives or alcohols, and separating the diastereomeric mixtures or salts or derivatives thus obtained, e.g. based on differences in their solubility, while e.g. free antipodes can be released from pure diastereomeric salts or derivatives by appropriate agents. Optically active acids in common use are e.g. D and L forms of tartaric acid or dibenzyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartame acid or quinic acid. The optically active alcohol may be, for example (+) or (-) menthol, and the optically active acyl group in amides, for example, may be (+) or (-) - menthyloxycarbonyl.

[0053] In addition, the compounds of formula I can be converted into their salts, especially for pharmaceutical applications, in physiologically acceptable salts with inorganic or organic acids. Acids that can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

[0054] In addition, the compounds obtained can be converted into mixtures, for example 1: 1 or 1: 2 mixtures with amino acids, especially with alpha-amino acids such as proline or phenylalanine, which may have particularly advantageous properties such as high crystallinity.

[0055] The compounds of the invention are preferably obtainable using the methods disclosed in the following examples, which can be combined for this purpose with methods known to those skilled in the literature, for example the methods described in WO 98/31697, WO 01/27128, WO 02 / 083066, WO 03/099836, WO 2004/063209,

WO 2005/09287 and WO 2006/120208.

[0056] The present invention also relates to new intermediates as described in the reaction schemes above and as described in the experimental section below.

[0057] In particular, an additional aspect of the present invention is the following

<img file="PL2024352T3_D0014.tif" />

<img file="PL2024352T3_D0015.tif" />

<img file="PL2024352T3_D0016.tif" />

in which

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

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

Alk is C1-4alkyl, preferably methyl or ethyl;

R¹ is defined above and is preferably Br or CN, most preferably CN;

R³ is defined above, e.g. cyclopropyl or cyclobutyl, and is preferably selected from the group consisting of chlorine, bromine, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxyl, cyano;

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

U is Cl. Br, I, -O-CO-Ci_-4-alkyl, -OC (= O) -OC_1-4-alkyl or -OPO (OC_1-4alkyl)₂, preferably Br.

[0058] As already mentioned, the compounds of general formula I according to the invention and their pharmaceutically acceptable salts have valuable pharmacological properties, in particular the inhibitory effect of the sodium-dependent glucose co-transporter SGLT, in particular

SGLT2.

[0059] The biological properties of the new compounds can be tested as follows:

[0060] The ability of the substance to inhibit SGLT-2 activity can be demonstrated in a test system in which the CHO-Ki cell line (ATCC No. CCL-6i) or alternatively the HEK293 cell line (ATCC No. CRL-i573) that is stably transfected pZeoSV expression vector (Invitrogen, EMBL, accession no. L36849), which contains cDNA for the coding sequence coding for the sodium dependent human glucose co-transporter 2 (Genbank Acc. No. NM_00304i) (CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport labeledⁱ⁴C alpha-methylglucopyranoside (ⁱ⁴C-AMG, Amersham) into the cell in a sodium-dependent manner.

[0061] The SGLT-2 test is carried out as follows:

[0062] CHO-hSGLT2 cells are cultured in Ham F12 medium (BioWhittaker) with 10% fetal calf serum and 25% μg / ml Zeocin (Invitrogen), and HEK-hSGLT2 cells are cultured in DMEM medium with 10% fetal calf serum and 25% μg / ml Zeocin (Invitrogen). Cells were secreted from culture-containing flasks by washing twice in PBS followed by treatment with trypsin / EDTA. After adding the cell culture with the medium, the cells are centrifuged, resuspended in the culture medium and counted in a Casy cell counter. 40,000 cells per well are plated on a white 96-well plate coated with poly-D-lysine and incubated overnight at 37 ° C, 5% CO2. Cells are washed twice with 250 μl assay buffer (Hanks Balanced Salt Solution, 137 mM NaCl,

5.4 mM KCl, 2.8 mM CaCl₂, 1.2 mM MgSO₄ and 10 mM HEPES (pH 7.4), 50 pg / ml Gentamycin). 250 µl assay buffer and 5 µl of test compound are added to each well and the plate incubated for a further 15 minutes in an incubator. As a negative control 5 pl of 10% DMSO is used. The reaction starts by adding 5 pl¹⁴C-AMG (0.05 pCi) in each well. After 2 hours incubation at 37 ° C, 5% CO₂, cells are washed again with 250 µl PBS (20 ° C) and then lysed by adding 25 µl 0.1 N NaOH (5 min at 37 ° C). 200 pl MicroScint20 (Packard) is added to each well and incubation continues for another 20 min. at 37 ° C. After this incubation, the absorbed radioactivity is determined in Topcount (Packard)¹⁴C-AMG, using a scintillation program ¹⁴C.

[0063] To determine selectivity for human SGLT1, an analogous assay is performed in which, instead of hSGLT2 cDNA, hSGLT1 cDNA (GenBank Acc. No. NM_000343) is expressed in CHO-K1 or HEK293 cells.

[0064] The compounds of the invention may have, for example, EC50 values ​​below 1000 nM, especially below 200 nM, most preferably below 50 nM.

[0065] In view of their ability to inhibit SGLT activity, the compounds of the invention and their corresponding pharmaceutically acceptable salts are suitable for the treatment and / or prevention of all those conditions or diseases which may be affected by inhibition of SGLT activity, especially SGLT-2 activity. In this connection, the compounds of the invention are particularly useful in the prevention or treatment of diseases, especially metabolic disorders, or conditions such as type 1 or type 2 diabetes, complications of diabetes (such as e.g. retinopathy, nephropathy or neuropathy, diabetic foot, ulceration, macroangiopathy), metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorders, insulin resistance, metabolic syndrome, dyslipidemia of various origins, atherosclerosis and related diseases, obesity, high blood pressure chronic heart failure, edema and hyperuricemia. These substances are also useful in preventing beta cell degeneration, e.g. apoptosis or necrosis of pancreatic beta cells. These substances are also useful for improving or restoring the functioning of pancreatic cells, as well as for increasing the number and size of pancreatic beta cells. The compounds of the invention may also be used as diuretics or antihypertensive agents and are useful for the prevention and treatment of acute renal failure.

[0066] Abnormal liver fat accumulation can be reduced or inhibited by administration of a compound of the invention. Thus, in accordance with a further aspect, the present invention provides a method for preventing, releasing, delaying or treating diseases or conditions attributable to abnormal liver fat accumulation in a patient in need thereof, characterized in that the compound or pharmaceutical composition of the present invention is administered. Diseases or conditions attributable to abnormal fat accumulation in the liver are in particular selected from the group consisting of general fatty liver disease, nonalcoholic fatty liver disease (NAFL), nonalcoholic fatty liver disease (NASH), fatty liver disease caused by excessive consumption, diabetic fatty liver disease. fatty alcohol-induced fatty liver or fatty liver.

[0067] In particular, the compounds of the invention, including their physiologically acceptable salts, are useful for preventing or treating diabetes, especially type I or type II diabetes, and / or diabetic complications.

[0068] In addition, the compounds of the invention are particularly useful for preventing or treating overweight, obesity (including class I, class II and / or class III obesity), visceral and / or abdominal obesity.

[0069] The dose required to obtain appropriate activity for treatment or prevention usually depends on the compound to be administered, the patient, the type and severity of the disease or condition, and the method and frequency of administration, and is at the discretion of the physician in charge of the patient. Dosages from 1 to 100 mg, preferably 1 to 30 mg, for intravenous administration, and 1 to 1000 mg, preferably 1 to 100 mg, for oral administration are indicated, in each case administered 1 to 4 times daily. To this end, the compounds of the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and / or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, ethyl glycol, propylene glycol, cetyl alcohol or fatty substances such as solid fats or mixtures thereof to give traditional galenical preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

[0070] The compounds of the invention may also be used in combination with other active substances, especially for the treatment and / or prevention of the diseases and conditions mentioned above. Other active substances that are suitable for such combinations include, for example, those that enhance the therapeutic effect of an SGLT antagonist according to the invention with respect to one of the aforementioned indications and / or which allow a dose reduction of the SGLT antagonist according to the invention. Therapeutic agents that are suitable for such combinations include, for example, anti-diabetic agents such as metformin, sulfonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), agonists and antagonists (PPAR-gam e.g. GI 262570), PPAR-gamma / alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPPIV inhibitors (e.g. LAF237, MK-431) alpha2 antagonists, insulin and insulin analogues, GLP-1 and GLP-2 analogues (e.g. exendin-4) or amylin. The list also includes inhibitors of protein tyrosinophosphatase 1, substances that affect the deregulation of glucose production in the liver, e.g. inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxyquinases, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents such as, for example, H-G-reductase inhibitors. , atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimib) or cholesterol absorption inhibitors such as ezetimibe, bile acid binders such as cholestyramine, bile acid transport inhibitors, HDL-raising compounds like CETP inhibitors or ABC1 regulators, or active substances for the treatment of obesity such as sibutramine or tetrahydrolipostat dexfenfluramine, axokin, cannabinoid 1 receptor antagonists, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or β3 agonists such as SB-418790 or AD-9677 and 5HT2c receptor agonists.

[0071] In addition, combinations with drugs that affect high blood pressure, chronic heart failure or atherosclerosis, such as, for example, A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, β-blockers, calcium antagonists, antihypertensive drugs, are useful. centrally, alpha-2 adrenoreceptor antagonists, neutral endopeptidase inhibitors, thrombocyte aggregation inhibitors and other or combinations thereof. Examples of angiotensin II receptor antagonists are candesartan cilexetil, losartan potassium, eprosartan methanesulfonate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan medoxomil, tazosartan, KT-0113, GA 64276, EMD-90423, BR9701, etc. Angiotensin II receptor antagonists are preferably used to treat or prevent high blood pressure and diabetes complications, often in combination with diuretics such as hydrochlorothiazide.

[0072] Combination with uric acid synthesis inhibitors or diuretics are suitable for the treatment or prevention of gout. [0073] The combination of GABA receptor antagonists, Na channel blockers, topiramate, protein kinase C inhibitors, advanced glycation end products inhibitors and aldose reductase inhibitors can be used to treat or prevent diabetic complications.

[0074] The dose for the combination of partners mentioned above is preferably 1/5 of the lowest usually recommended dose to 1/1 of the usually recommended dose.

[0075] Accordingly, in another aspect, the invention relates to the use of a compound of the invention or a physiologically acceptable salt of such a compound in combination with at least one of the active substances described above as a combination partner, for the manufacture of a pharmaceutical composition that is useful for the treatment of and / or preventing diseases and conditions that can be affected by inhibition of SGLT activity. They are preferably metabolic diseases, in particular one of the diseases or conditions mentioned above, more particularly diabetes or diabetes complications.

[0076] The use of a compound of the invention or a physiologically acceptable salt thereof, in combination with another active substance, can occur simultaneously or overlap, but especially in a short period of time. If they are administered simultaneously, the two active substances are administered to the patient together, while when they are applied in an overlapping time, the two substances are administered to the patient at an interval of less than or equal to 12 hours, but especially less than or equal to 6 hours.

[0077] Consequently, in another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention or a physiologically acceptable salt thereof, and at least one of the active substances described above as combination partners, optionally in combination with one or more inert carriers and / or diluents.

[0078] Thus, for example, the pharmaceutical composition of the invention comprises a combination of a compound of the invention or a physiologically acceptable salt thereof and at least one angiotensin II receptor antagonist, optionally in combination with one or more inert carriers and / or diluents.

[0079] The compound of the invention, or a physiologically acceptable salt thereof, and an additional active substance to be associated with it may be present together in one preparation, for example a tablet or capsule, or separately in two identical or different preparations, for example in so-called ingredient set. [0080] In the above and the following description, the H atoms of hydroxyl groups are not explicitly shown in each case in the structural formula. The following examples are intended to illustrate the present invention without limiting it.

The terms "room temperature" and "ambient temperature" are used interchangeably and mean a temperature of about 20 ° C. The following abbreviations are used:

DMF dimethylformamide

NMP N-methyl-2-pyrrolidone

THF tetrahydrofuran [0081] With the exception of final compounds wherein R³ means cyclopropyl and / or cyclobutyl (and their synthetic precursors), the following examples are for illustrative purposes.

Preparation of starting compounds:

Example I [0082]

<img file="PL2024352T3_D0017.tif" />

4-Bromo-3-hydroxymethyl-1-iodobenzene [0083] To an ice-cooled solution of 2-bromo-5-iodobenzoic acid in CH2Cl2 (200 mL) is added oxalyl chloride (13.0 mL). DMF (0.2 ml) is added and the solution is stirred at room temperature for 6 h. The solution is then concentrated under reduced pressure and the residue dissolved in THF (100 ml). The resulting solution is cooled in an ice-water bath and LiBH4 (3.4 g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1 M hydrochloric acid. The organic layer is then separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2SO4) and the solvent evaporated under reduced pressure to give the crude product.

Yield: 47.0 g (99% of theory)

Example II [0084]

<img file="PL2024352T3_D0018.tif" />

4-Bromo-3-chloromethyl-i-iodobenzene [0085] To a suspension of 4-bromo-3-hydroxymethyl-i-iodobenzene (47.0 g) in dichloromethane (i00 ml) containing DMF (0 and ml) is added chloride thionyl (13 ml). The mixture is stirred at room temperature for 3 h. Then the solvent and excess reagent are removed under reduced pressure. The residue is triturated with methanol and dried. Yield 4i, 0 g (82% of theory)

Example III [0086] i0

<img file="PL2024352T3_D0019.tif" />

i5

4-Bromo-i-iodo-3-phenoxymethylbenzene [0087] Phenol (i3 g) dissolved in a 4 M KOH solution (60 ml) is added to 4-bromo3-chloromethyl-i-iodobenzene (4i, 0 g) dissolved in acetone (50 ml). NaI (0.5 g) is added and the resulting mixture is stirred overnight at 50 ° C. Water is then added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried and the solvent is evaporated off under reduced pressure. The residue is purified by silica gel chromatography (cyclohexane / ethyl acetate i9: i).

Yield: 38.0 g (79% of theory)

Example IV [0088]

<img file="PL2024352T3_D0020.tif" />

(5-Bromo-2-chlorophenyl) - (4-methoxyphenyl) methanone [0089] To a mixture of 100 g of 5-bromo-2-chlorobenzoic acid in 500 ml of dichloromethane is added 38.3 ml of oxalyl chloride and 0.8 ml of dimethylformamide .

The reaction mixture is stirred for 14 h, then filtered and separated from all volatiles on a rotary evaporator. The residue is dissolved in 150 ml of dichloromethane, the resulting solution is cooled to -5 ° C and 46.5 g of anisole are added. Then 51.5 g of aluminum trichloride are added in portions so that the temperature does not exceed 5 ° C. The solution is stirred for 1 h at 1-5 ° C and then poured onto crushed ice. The organic phase is separated off and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with 1 M hydrochloric acid, twice with 1 M sodium hydroxide solution and brine. The organic phases are dried over sodium sulfate, the solvent is removed and the residue is recrystallized from ethanol. Yield: 66.3 g (ESI⁺): m / z = 325/327/329 (Br⁺Cl) [M + H]⁺

Example V [0090]

<img file="PL2024352T3_D0021.tif" />

1-Bromo-4-chloro-3- (4-methoxybenzyl) benzene A solution of 86.2 g (5-bromo-2-chlorophenyl) - (4-methoxyphenyl) methanone and 101.5 ml of triethylamine in 75 ml of dichloromethane and 150 ml of acetonitrile are cooled to

10 ° C. Then 50.8 ml of boron trifluoride etherate are added portionwise with stirring so that the temperature does not exceed 20 ° C. The solution is stirred for 14 h at ambient temperature, then another 9 ml of triethylsilane and 4.4 ml of boron trifluoride-ethyl ether complex are added. The solution is stirred for a further 3 h at 45-50 ° C and then cooled to ambient temperature. A solution of 28 g potassium hydroxide in 70 ml water is added and the resulting mixture is stirred for 2 h. The organic phase is separated and the aqueous phase is extracted three times with diisopropyl ether successively. The combined organic phases are washed twice with 2 M potassium hydroxide solution and once with brine, then dried over sodium sulfate. After evaporation of the solvent, the residue is washed with ethanol and dried at 60 ° C.

Yield: 50.0 g (61% of theory)

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

Example VI [0092]

<img file="PL2024352T3_D0022.tif" />

4- (5-Bromo-2-chlorobenzyl) -phenol [0093] A solution of 14.8 g of 1-bromo-4-chloro-3- (4-methoxybenzyl) -benzene in a 150 ml dichloromethane is cooled in an ice bath. 50 ml of a 1 M solution of boron tribromide in dichloromethane are added and the resulting solution is stirred for 2 h at ambient temperature. The solution is then cooled again in an ice bath and a saturated aqueous solution of potassium carbonate is slowly added dropwise. At ambient temperature, the mixture is neutralized with an aqueous 1 M hydrochloric acid solution to pH 1, the organic phase is separated off and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed to dryness.

Yield: 13.9 g (98% of theory)

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

Example VII [0094]

<img file="PL2024352T3_D0023.tif" />

[4- (5-Bromo-2-chlorobenzyl) phenoxy) -tert-butyldimethylsilane [0095] A solution of 13.9 g of 4- (5-bromo-2-chlorobenzyl) -phenol in 140 ml of dichloromethane is cooled in an ice bath. 7.54 g of tert-butyldimethylsilyl chloride in 2 ml of dichloromethane are added, followed by 9.8 ml of triethylamine and 0.9 g of 4-dimethylaminopyridine. The organic phase is washed twice with an aqueous 1 M hydrochloric acid solution and once with an 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: 16.8 g (87% of theory)

Mass Spectrum: (ESI⁺): m / z = 410/412/414 (Br + Cl) [M + H]⁺

Example VIII [0096]

<img file="PL2024352T3_D0024.tif" />

1-Bromo-4- (1-methoxy-D-glucopyranose-1-yl) -2- (phenoxymethyl) benzene A 2 M solution of iPrMgCl in THF (11 ml) is added to dry LiCl (0.47 g ) suspended in THF (11 ml). The mixture is stirred at room temperature until LiCl is dissolved. This solution is added dropwise to a solution of 4-bromo-1-iodo-3-phenoxymethylbenzene (8.0 g) in tetrahydrofuran (40 ml) cooled to 60 ° C under argon. The solution is heated to -40 ° C and 2,3,4,6-tetrakis-O- (trimethylsilyl) -D-glucopyranone (10.7 g, 90% pure) in tetrahydrofuran (5 mL) is added. The resulting solution is heated to -5 ° C on a cooling bath and stirred for another 30 min. at the same temperature. Aqueous NH4Cl solution is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the solvent removed under reduced pressure. The residue is dissolved in methanol (80 ml) and treated with methanesulfonic acid (0.6 ml). After stirring the reaction solution overnight at 35-40 ° C, the solution is neutralized with solid NaHCO3 and the methanol removed under reduced pressure. The residue is diluted with aqueous NaHCO3 solution and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and the solvent is evaporated to give a crude product which is reduced without further purification. Yield: 7.8 g (93% of theory)

<img file="PL2024352T3_D0025.tif" />

1-Bromo-4- (2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl) -2- (phenoxymethyl) benzene For 1-bromo-4- (1 solution) -methoxy-D-glucopyranose-1-yl) -2- (phenoxymethyl) benzene (8.7 g) and triethylsilane (9.1 ml) in dichloromethane (35 ml) and acetonitrile (50 ml) boron trifluoride complex is added - ethyl ether (4.9 ml), cooled to 20 ° C at such a rate that the temperature remains below -10 ° C. The resulting solution is heated to 0 ° C for 1.5 h and then treated with aqueous sodium bicarbonate solution. The resulting mixture is stirred for 0.5 h, the organic solvent is removed and the residue is extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate and the solvent removed. The residue is taken up in dichloromethane (50 ml) and then pyridine (9.4 ml), acetic anhydride (9.3 ml) and 4-dimethylaminopyridine (0.5 g) are added to the solution. The solution is stirred for 1.5 h at ambient temperature and then diluted with dichloromethane. This solution is washed twice with 1 M hydrochloric acid and dried over sodium sulfate. After removal of the solvent, the residue is recrystallized from ethanol to give the product as a colorless solid.

Yield: 6.78 g (60% of theory)

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

Example X [0100]

<img file="PL2024352T3_D0026.tif" />

2- (Phenoxymethyl) -4- (2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl) benzonitrile [0101] A flask containing zinc cyanide (1.0 g), zinc (30 mg)

Pd2 (dibenzylideneacetone) 3^.CHCl3 (141 mg) and tri-tert-butyl phosphonium tetrafluoroborate (11 g) are flushed with nitrogen. A solution of 1-bromo-4- (2,3,4,6-tetra-Oacetyl-D-glucopyranose-1-yl) -2- (phenoxymethyl) benzene (5.4 g) in degassed NMP (12) is then added. ml) and the resulting mixture is stirred at room temperature for 18 h. After dilution with ethyl acetate, the mixture is filtered and the filtrate washed with aqueous sodium bicarbonate solution. The organic phase is dried (sodium sulfate) and the solvent removed. The residue is recrystallized from ethanol.

Yield: 4.10 g (84% of theory)

Mass Spectrum: (ESI⁺): m / z = 557 [M + NH4]⁺ [0102] The compound described above is also obtained according to the following procedure: [0103] Magnetic stirring flask containing 1-bromo-4- (2,3,4,6-tetra-Oacetyl-D-glucopyranose-1-yl) - 2- (phenoxymethyl) -benzene (14.7 g), zinc cyanide (4.1 g) and NMP (100 ml) are heated to reflux for 8 h. After dilution with water (500 ml) the precipitate is separated , washed several times with water and then dissolved in ethyl acetate (200 ml). The resulting solution is filtered through a silica gel plug using ethyl acetate (300 mL) as the eluent. The filtrate is concentrated under reduced pressure and the residue is dissolved in dichloromethane (100 mL) to re-acetylate the oxygen groups deprotected during cyanation. Pyridine (4 mL), 4-dimethylaminopyridine (0.3 g) and acetic anhydride (4.4 mL) are respectively added sequentially. The resulting solution is stirred at room temperature for 1 h. The reaction mixture is then diluted with dichloromethane (50 ml) and washed three times with 1 M aqueous hydrochloric acid, once with aqueous sodium bicarbonate and once with water. The organic phase is dried (sodium sulfate) and the solvent removed. The residue is recrystallized from ethanol.

Yield: 10.0 g (75% of theory)

Example XI [0104]

<img file="PL2024352T3_D0027.tif" />

2-Bromomethyl-4- (2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl) benzonitrile [0105] For 2- (phenyloxymethyl) -4- (2,3,4) solution , 6-tetra-O-acetyl-D-glucopyranose-1-yl) -benzonitrile (0.71 g) and acetic anhydride (0.12 ml) in acetic acid (10 ml) are added 33% hydrobromic acid in acid solution acetic (15 ml). The resulting solution is stirred at 55 ° C for 6 h and then cooled in an ice bath. The reaction mixture is neutralized with a cooled aqueous potassium carbonate solution, and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the solvent removed under reduced pressure. The residue is taken up in an ethyl acetate / cyclohexane mixture (1: 5) and the precipitate is separated by filtration and dried at 50 ° C until a pure product is obtained. Yield: 0.52 g (75% of theory)

Mass Spectrum: (ESI⁺): m / z = 543/545 (Br) [M + NH4]⁺Example XII [0i06]

<img file="PL2024352T3_D0028.tif" />

1-Chloro-4- (eD-glucopyranose-1-yl) -2- (4-hydroxybenzyl) benzene. Solution of 4.0 g [4-bromo-2-chlorobenzyl) phenoxy] -tert-butyldimethylsilane in 42 ml dry diethyl ether is cooled to -80 ° C under argon. To the cooled solution is slowly added ii, 6 ml of cooled (approx. -50 ° C) and, 7 M solution of tert-butyllithium in pentane, then the solution is stirred for 30 min. at -80 ° C. This solution is then added dropwise through a through needle, which is cooled with dry ice, into a solution of 4.78 g 2,3,4,6-tetrakis-O (trimethylsilyl) -D-glucopyranone in 30 ml of diethyl ether cooled to 80 ° C. The resulting solution is stirred for 3 h at -78 ° C. A solution of i, and ml of methanesulfonic acid in 35 ml of methanol is then added and the resulting solution is stirred for another 6 h at ambient temperature. The solution is neutralized with solid sodium bicarbonate, ethyl acetate is added and the resulting solution is concentrated under reduced pressure. Aqueous sodium bicarbonate solution is added to the remaining solution, extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is evaporated. The residue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane and the resulting solution is cooled to -0 ° C. After adding 4.4 ml of triethylsilane, 2.6 ml of boron trifluoride-ethyl ether are added dropwise so that the temperature does not exceed -5 ° C. After the addition, the reaction solution is stirred for another 5 h at -5 to -0 ° C, after which the reaction is quenched by the addition of aqueous sodium bicarbonate solution. The organic phase is separated off and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed and the residue is purified by silica gel chromatography (dichloromethane / methanol). The product thus obtained is a mixture of isomers that can be separated by exhaustive acetylation of hydroxyl groups using acetic anhydride, pyridine and 4-dimethylaminopyridine in dichloromethane and recrystallization of the resulting acetylated product from ethanol. The pure acetylated product β thus obtained (precipitates from the ethanol solution) is transformed into the title compound by removing acetyl groups in methanol with a 4 M potassium hydroxide solution.

Yield 1.6 g (46% of theory)

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

Example XIII [0108]

<img file="PL2024352T3_D0029.tif" />

1-Chloro-2- (4-cyclopentyloxybenzyl) -4- (eD-glucopyranose-1-yl) -benzene [0109] To a mixture of 0.25 g of 1-chloro-4- (eD-glucopyranose-1-yl) - 2- (4-hydroxybenzyl) -benzene and 0.4 g cesium carbonate in 2.5 ml dimethylformamide are added 0.16 ml iodocyclopentane. The mixture is stirred for 4 h at 45 ° C, then further 0.1 g cesium carbonate and 0.05 ml iodocyclopentane are added. After another 14 hours of mixing at 45 ° C aqueous sodium chloride solution is added and the resulting mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is removed under reduced pressure and then purified using silica gel (dichloromethane / methanol 1: 0> 5: 1).

Yield: 0.23 g (78% of theory)

Mass Spectrum: (ESI⁺): m / z = 466/468 (Cl) [M + NH4]⁺ [0110] In analogy to Example 13, the following compound was prepared.

(1) 1-Chloro-4- (eD-glucopyranose-1-yl) -2- [4 - ((S) -tetrahydrofuran-3-yloxy) -benzyl] benzene [0111] The reaction is used as a reaction partner coupling of (R) -toluene-4-sulfonate tetrahydrofuran-3-yl

<img file="PL2024352T3_D0030.tif" />

Mass Spectrum: (ESI⁺): m / z = 451/453 (Cl) [M + H]⁺Example XIV [0112]

<img file="PL2024352T3_D0031.tif" />

1-Chloro-4- (eD-glucopyranose-1-yl) -2- [4- (trifluoromethylsulfonyloxy) -benzyl] benzene To a solution of 0.38 g 1-chloro-4- (eD-glucopyranose-1- yl) -2- (4- (hydroxybenzyl) benzene, 0.21 ml triethylamine and 0.39 g N, N-bis- (trifluoromethanesulfonyl) -aniline in 10 ml of dried dichloromethane, 10 mg of 4-dimethylaminopyridine are added. for 4 h at ambient temperature and then combined with brine. The resulting mixture is extracted with ethyl acetate, the organic extracts are dried over sodium sulfate and the solvent is removed. The residue is purified by silica gel chromatography (dichloromethane / methanol 1: 0> 4: 1). Yield: 0.33 g (64% of theory)

Mass Spectrum: (ESI⁺): m / z = 530/532 (Cl) [M + NH4]⁺ [0114] In analogy to Example XIV, the following compound is prepared:

(1) 1-Cyano-4- (eD-glucopyranose-1-yl) -2- [4- (trifluoromethylsulfonyloxy) benzyl] benzene [0115]

<img file="PL2024352T3_D0032.tif" />

Mass Spectrum: (ESI⁺): m / z = 504 [M + H]⁺Example XV

<img file="PL2024352T3_D0033.tif" />

(trifluoromethylsulfonyloxy) -benzyl] -benzene [0117] To a solution of 5.6 g of 1-chloro-4- (eD-glucopyranose-1-yl) -2- (4- (hydroxybenzyl) benzene in 75 ml of dichloromethane is successively added 7 ml of pyridine, 7.8 ml of acetic anhydride and 0.12 mg of 4-dimethylaminopyridine The solution is stirred for 1 h at ambient temperature After adding 50 ml of water the resulting mixture is stirred for another 5 min. The organic phase is separated and washed with aqueous solution 1 M hydrochloric acid and aqueous sodium bicarbonate solution. After drying over sodium sulfate and evaporation of the organic solvent, the product is obtained in the form of a white solid.

Yield: 7.0 g (94% of theory)

Mass Spectrum: (ESI⁺): m / z = 698/701 (Cl) [M + NH4]⁺ [0118] In analogy to Example XV, the following compound is prepared: (1) 1-Cyano-4- (2,3,4,6-tetra-O-acetyl-eD-glucopyranose-1-yl) -2- [4 (trifluoromethylsulfonyloxy) -benzyl] -benzene

<img file="PL2024352T3_D0034.tif" />

Example XVI [0120]

<img file="PL2024352T3_D0035.tif" />

1-Chloro-2- (4-ethynylbenzyl) -4- (eD-glucopyranose-1-yl) benzene To a solution of 0.32 g 1-chloro-4-eD-glucopyranose-1-yl) -2 - [4 (Trifluoromethylsulfonyloxy) -benzyl] -benzene in 3 ml of dimethylformamide under argon are added 25 mg copper iodide, 44 mg bis- (triphenylphosphine) palladium dichloride, 0.30 ml triethylamine and finally 0.14 ml trimethylsilylacetylene. The flask is sealed thoroughly and the mixture is stirred for 8 h at 90 ° C. Then 25 mg bis- (triphenylphosphine) palladium dichloride and 0.1 ml trimethylsilylacetylene are added and the solution is stirred for another 10 h at 90 ° C. Aqueous sodium bicarbonate solution is added, the resulting mixture is extracted three times with ethyl acetate and the combined organic phases are dried over sodium sulfate. After evaporation of the solvent, the residue is dissolved in 5 ml of methanol and combined with 0.12 g of potassium carbonate. The mixture is stirred for 1 h at ambient temperature and then neutralized with 1 M hydrochloric acid. The methanol is then evaporated, the residue combined with brine and extracted with ethyl acetate. The collected organic extracts are dried over sodium sulfate and the solvent is removed. The residue is purified by silica gel chromatography (dichloromethane / methanol 1: 0> 5: 1).

Yield: 0.095 g (40% of theory)

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

Example XVII [0122]

<img file="PL2024352T3_D0036.tif" />

1-Chloro-2- (4-ethylbenzyl) -4- (eD-glucopyranose-1-yl) benzene 2.87 g of 1-chloro-2- (4-ethynylbenzyl) -4- (eD-glucopyranose -1-yl) -benzene is dissolved in 10 ml ethyl acetate and 5 ml ethanol. 0.3 g 10% palladium on carbon is added and the resulting mixture is stirred under an atmosphere of hydrogen (1 atm) overnight.

The reaction mixture is filtered through Celite and the filtrate is concentrated. The residue is purified by silica gel chromatography (dichloromethane / methanol 1: 0> 5: 1). Yield: 1.0 g (34% of theory)

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

Example XVIII

<img file="PL2024352T3_D0037.tif" />

glucopyranose-1-yl) -benzene [0125] To a solution of 2.02 g 1-chloro-4- (eD-glucopyranose-1-yl) -2- [4- (S) tetrahydrofuran-3-yloxy) -benzyl] benzene in 20 ml dichloromethane are successively added 2.5 ml pyridine, 2.8 ml acetic anhydride and 50 ml 4-dimethylaminopyridine. The reaction solution is stirred at ambient temperature for

4 h. The solution is diluted with 50 ml of dichloromethane, washed twice with 50 ml of 1 M hydrochloric acid and once with sodium bicarbonate solution. After drying over sodium sulfate, the solvent is evaporated to yield a product.

Yield: 2.53 g (91% of theory)

Mass Spectrum: (ESI⁺): m / z = 642/644 (Cl) [M + Na]⁺ [0126] In analogy to Example 18, the following compounds are prepared:

(1) 1-Chloro-2-4- (ethylbenzyl) -4- (2,3,4,6-tetra-O-acetyl-eD-glucopyranose-1-yl) benzene

<img file="PL2024352T3_D0038.tif" />

(2) 2- (4-Acetoxybenzyl) -1-chloro-4- (2,3,4,6-tetra-O-acetyl-eD-glucopyranose-1-yl) -

<img file="PL2024352T3_D0039.tif" />

Mass Spectrum: (ESI⁺): m / z = 608/610 (Cl) [M + NH4]⁺ (3) 1-Cyano-2- (4-methoxybenzyl) -4- (2,3,4,6-tetra-O-acetyl-eD-glucopyranose-1-yl) -

<img file="PL2024352T3_D0040.tif" />

Mass Spectrum: (ESI⁺): m / z = 576 [M + Na]⁺Example XIX [0127]

<img file="PL2024352T3_D0041.tif" />

1-Chloro-2- (4-methylbenzyl) -4- (2,3,4,6-tetra-O-acetyl-eD-glucopyranose-1-yl) benzene [0128] Diisobutylaluminum hydride (54 µl, 1 mol / l in toluene) is added under argon to the 1,1'-bis (diphenylphosphino) ferrocene-dichloropalladium (II) mixture (22 mg) in

THF (3 ml) and cooled in a water bath. The mixture is stirred in an ice bath for 0.5 h, then 1-chloro-4- (2,3,4,6-tetra-O-acetyl-eD-glucopyranos-1-yl) -2- [4 is added sequentially - (trifluoromethylsulfonyloxy) -benzyl] -benzene (0.60 g) and Me2Zn (0.88 ml, 1 mol / L in toluene). The ice bath is removed and the mixture is heated to reflux for 2.5 h. After cooling to room temperature, 1 M hydrochloric acid solution is added and the resulting mixture is extracted with ethyl acetate. The collected extracts are dried over sodium sulfate and the solvent is removed. The residue is purified by silica gel chromatography (cyclohexane / ethyl acetate 1: 0> 2: 1).

Yield: 0.25 g (52% of theory)

Example XX [0129]

1-Chloro-2- (4-cyanobenzyl) -4- (2,3,4,6-tetra-O-acetyl-eD-glucopyranos-1-yl) -

<img file="PL2024352T3_D0042.tif" />

[0130] Into a flask containing 1-chloro-4- (2,3,4,6-tetra-O-acetyl-eD-glucopyranos-1-yl) -2- [4- (trifluoromethylsulfonyloxy) -benzyl] -benzene (0, 80 g) and zinc cyanide (0.14 g) under argon, tetrakis (triphenylphosphine) palladium (0) (0.13 g) is added. The mixture is stirred at 100 ° C for 3 h. After cooling to room temperature, ethyl acetate is added and the resulting mixture is filtered, washed with aqueous NaHCO 3 solution, dried (sodium sulfate) and the solvent removed. The residue is recrystallized from ethanol.

Yield: 0.45 g (69% of theory)

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

Example XXI [0131]

OH

4-cyclopropylphenylboronic acid [0132] To 1-bromo-4-cyclopropylbenzene (5.92 g) in THF (14 ml) and toluene (50 ml), 2.5 M n-butyllithium in hexane (14.5 ml) is added dropwise. cooled to -70 ° C. The resulting solution is stirred at -70 ° C for 30 min, after which triisopropyl borate (8.5 ml) is added. The solution is warmed to -20 ° C and then treated with 4 M aqueous hydrochloric acid (15.5 ml). The reaction mixture is further warmed to room temperature and the organic phases are separated. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried (sodium sulfate). The solvent was evaporated and the residue washed with a mixture of ether and cyclohexane to give the product as a colorless solid.

Yield: 2.92 g (60% of theory)

Mass Spectrum: (ESI⁺): m / z = 207 (Cl) [M + HCOO]^- [0133] The following compounds are prepared analogously to Example XXI:

(1) 4-Difluoromethoxyphenylboronic acid [0134]

HO

Β

AND

OH

Mass Spectrum: (ESI⁺): m / z = 233 (Cl) [M + HCOO]^- Departing from the procedure described above, the 4-difluoromethoxy-i-iodobenzene compound is obtained by using iPrMgCl to generate a metalaryl compound and capturing this intermediate with trimethyl borate.

(2) 4-Difluoromethylphenylboronic acid [0i36]

<img file="PL2024352T3_D0043.tif" />

i0

Mass Spectrum: (ESI⁺): m / z = i72 [M + H]⁺ Departing from the procedure described above, a compound is obtained from 4-difluoromethoxy-i-iodobenzene (obtained from 4-iodobenzoaldehyde using diethylaminosulfuryl trifluoride (DAST) in dichloromethane), using iPrMgCl to generate the metalaryl compound and catching this intermediate with trimethylborane.

Example XXII [038] i5

<img file="PL2024352T3_D0044.tif" />

i-Bromo-4-cyano-3- (4-methoxybenzyl) -benzene To 3, 4 g of potassium tert-butoxide in i30 ml of N-methylpyrrolidin-2-one, a mixture of 25 g (4-methoxyphenyl) is slowly added. ethyl acetate, 27.4 g i-bromo-4-cyano-3-fluorobenzene and 20 ml N-methylpyrrolidin-2-one, keeping the temperature below 10 ° C. After stirring for 1 hour at room temperature, i00 ml methanol and i37 ml and M aqueous sodium hydroxide solution are added and the mixture is stirred overnight at room temperature. The methanol fraction is evaporated and the residue basified with i M aqueous sodium hydroxide solution and extracted with tert-butyl methyl ether. The aqueous phase is acidified with 4 M hydrochloric acid and extracted several times with ethyl acetate. The combined ethyl acetate extracts are evaporated and the residue together with 120 ml N, N-dimethylformamide and 24.9 g potassium carbonate is heated at 100 ° C for 1h. The reaction mixture is diluted with aqueous sodium bicarbonate solution and extracted several times with ethyl acetate. The combined extracts are evaporated and the residue crystallized from methanol.

Yield: 13 g (33% of theory)

Mass Spectrum: (ESI⁺): m / z = 319/321 (Br) [M + NH4]⁺ [0140] The following compounds are prepared analogously to Example XXII:

(1) 1-Bromo-4-cyano-3- (4-cyclopropylbenzyl) benzene [0141]

<img file="PL2024352T3_D0045.tif" />

Mass Spectrum: (ESI⁺): m / z = 329/331 (Br) [M + NH4]^- [0142] The phenylacetic acid derivative required to obtain this compound is synthesized according to the procedure described in the next Example XXIII.

Example XXIII [0143]

<img file="PL2024352T3_D0046.tif" />

Ethyl 4-cyclopropylphenylacetate [0144] Prepared from ethyl 4-bromophenylacetate by transition metal catalyzed coupling with cyclopropylboronic acid, using tricyclohexylphosphonium tetrafluoroborate, palladium acetate, potassium phosphate in toluene and water, according to Tetrahedron 6, 2002, 6 Tetrahedron -6990.

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

Example XXIV [0145]

<img file="PL2024352T3_D0047.tif" />

1-Cyano-4- (eD-glucopyranose-1-yl) -2- (4-methoxybenzyl) benzene [0146] Magnetic stirrer flask containing 1-bromo-4-cyano-3- (4-methoxybenzyl) -benzene (9 , 90 g) dissolved in dried THF (120 ml), maintained under argon, cooled to -97 ° C. To this solution, a pre-cooled (approx. -70 ° C) solution of tert-butyllithium in pentane (1.7 M, 39 ml) is slowly added and the resulting solution is stirred for 30 min. at -87 ° C. Then a solution of 2,3,4,6-tetrakis-O- (trimethylsilyl) -D-glucopyranone (16.5 g) dissolved in THF (80 ml) is added and the combined solutions are stirred at -75 ° C for 1

h. The reaction is quenched with aqueous NH4Cl solution and the resulting mixture is extracted with ethyl acetate. After drying (Na2SO4) organic extracts and removal of the solvent, the residue is dissolved in methanol (150 ml) and methanesulfonic acid (5 ml) is added. The resulting solution is stirred at 55 ° C for 8 h to obtain the desired anomeric configuration. After cooling to ambient temperature, the solution is neutralized with solid sodium bicarbonate and the methanol is evaporated under reduced pressure. Brine is added to the residue and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (sodium sulfate) and the solvent is evaporated. The residue is dissolved in acetonitrile (50 ml) and dichloromethane (50 ml) to reduce the anomeric center on carbon. After cooling this solution to -20 ° C and adding triethylsilane (16 ml), boron trifluoride-diethyl ether complex (9.2 ml) is slowly added dropwise. The reaction solution is slowly heated in a cooling bath to 0 ° C., after which the reaction is quenched by the addition of aqueous sodium bicarbonate solution. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried (sodium sulfate), the solvent is removed and the residue is purified by silica gel chromatography (dichloromethane / methanol 1: 0> 9: 1).

Yield: 5.2 g (41% of theory)

Mass Spectrum: (ESI⁺): m / z = 403 [M + NH4]⁺ [0147] In analogy to Example XXIV, the following compounds are prepared:

(1) 1-Cyano-2- (4-cyclopropylbenzyl) -4- (eD-glucopyranose-1-yl) benzene [0148]

<img file="PL2024352T3_D0048.tif" />

Mass Spectrum: (ESI⁺): m / z = 413 [M + H]⁺ [0149] Preferably, the reduction of the anomeric center on the carbon atom of the corresponding intermediate obtained during the synthesis of this compound is carried out on oxygen functions on the protected pyranose ring. Preferred protecting groups are p-methoxybenzyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl and allyl.

Example XXV [0150]

<img file="PL2024352T3_D0049.tif" />

1-Cyano-2- (4-cyclopropylbenzyl) -4- (2,3,4,6-tetra-O-acetyl-eD-glucopyranose-1-yl) -benzene [0151] To a magnetic stirring flask containing 4- (2 , 3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl) -2- (4-trifluoromethylsulfonyloxybenzyl) benzonitrile (4.4 g), degassed toluene (12 ml) and degassed water (8 ml ) and maintained under argon, cyclopropylboronic acid (0.20 g), potassium phosphate (5.0 g), tricyclohexylphosphine (0.19 g) and finally palladium (II) acetate (76 g) are added. The mixture is stirred at 110 ° C for 6 h, meanwhile cyclopropylboronic acid (5 x 0.20 g) is added every hour. After cooling to room temperature, the mixture is diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts are dried (sodium sulfate) and the solvent removed under reduced pressure. The residue is chromatographed on silica gel (cyclohexane / ethyl acetate 20: 1> 1: 1).

Yield: 3.23 g (87% of theory)

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

Example XXVI [0152]

<img file="PL2024352T3_D0050.tif" />

4- (1-hydroxycyclopropyl) -phenylboronic acid [0153] To a mixed solution of titanium (IV) isopropoxide (2.3 ml) in diethyl ether (70 ml), cooled to -78 ° C, 3.0 M is added solution of ethyl magnesium bromide in diethyl ether (7.6 mL). The resulting solution is stirred at -78 ° C for 1.5 h, then 4- (4,4,5,5-tetramethyl- [1.3.2] dioxaborolan-2-yl) -benzoic acid methyl ester (2) is added. , 0 g). The mixture is warmed to ambient temperature and stirred for an additional 12 hours. Then 1 M aqueous hydrochloric acid solution is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulfate) and the solvent is evaporated. The residue is dissolved in acetone (60 ml) and a 0.1 M aqueous solution is added

NH4OAc (50 mL) followed by NaIO4 (2.3 g). The resulting reaction mixture is stirred at room temperature for 18 h. After removing the acetone, the residue is extracted with ethyl acetate. The combined extracts are dried (sodium sulfate) and the solvent is evaporated. The residue is purified by silica gel chromatography (cyclohexane / ethyl acetate).

Yield: 0.45 g (33% of theory)

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

Preparation of final compounds

Reference example 1 [0154]

<img file="PL2024352T3_D0051.tif" />

4- (eD-glucopyranose-1-yl) -2- [4- (S) -tetrahydrofuranyl-3-oxy) -benzyl] -benzonitrile [0155] A mixture of 1.00 g 1-chloro-2- [4- ( S) -tetrahydrofuranyl-3-oxy) -benzyl] -4 (2,3,4,6-tetra-O-acetyl-eD-glucopyranose-1-yl) -benzene, 0.16 g of sodium cyanide and 0.35 g of nickel bromide in 2.5 ml of N-methyl-2-pyrrolidone is heated in a microwave at 220 ° C for 15 min. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. After drying over sodium sulfate and evaporation of the solvent, the residue is dissolved in 5 ml of methanol. 4 ml of 4 M aqueous potassium hydroxide solution are added and the reaction solution is stirred at ambient temperature for 3 h. The solution is neutralized with 1 M hydrochloric acid and the methanol is evaporated off. The residue is extracted with ethyl acetate, the combined extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography (dichloromethane / methanol 4: 1).

Yield: 0.35 g (49% of theory)

Mass Spectrum: (ESI⁺): m / z = 442 [M + H]⁺ [0158] In an analogous manner to Reference Example 1, the compounds of Examples 1, 2, 3 and 4 are obtained.

Example 1: 2- (4-Ethylbenzyl) -4- (eD-glucopyranose-1-yl) benzonitrile [0157]

<img file="PL2024352T3_D0052.tif" />

Yield: 65% of theory.

Mass Spectrum: (ESI⁺): m / z = 401 [M + NH4]⁺ [0158] This compound can also be obtained in an analogous manner to Example 6, using 4-ethylphenylboronic acid as the coupling partner.

Example 2: 4- (eD-glucopyranose-1-yl) -2- (4-hydroxybenzyl) benzonitrile [0159] The compound is prepared from 2- (4-acetoxybenzyl) -1-chloro-4- (2,3, 4,6-tetra-Oacetyl-eD-glucopyranose-1-yl) -benzene according to the procedure described above.

<img file="PL2024352T3_D0053.tif" />

Yield: 30% of theory.

Mass Spectrum: (ESI⁺): m / z = 389 [M + NH4]⁺ [0160] This compound is also obtained by exhaustive acetylation of 2- (4-methoxybenzyl) -4- (eD-glucopyranose-1-yl) -benzonitrile followed by ether cleavage with boron tribromide and deacetylation.

Example 3: 4- (eD-glucopyranose-1-yl) -2- (4-methylbenzyl) benzonitrile [0161]

<img file="PL2024352T3_D0054.tif" />

Yield: 59% of theory.

Mass Spectrum: (ESI⁺): m / z = 387 [M + NH4]⁺ [0162] This compound can also be obtained analogously to Example 6, using 4-methylphenylboronic acid as the coupling partner.

Example 4: 2- (4-Cyanobenzyl) -4- (eD-glucopyranose-1-yl) benzonitrile [0163]

<img file="PL2024352T3_D0055.tif" />

Yield: 58% of theory.

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

Example 5: 4- (BD-glucopyranose-1-yl) -2- (4-methoxyethoxybenzyl) benzonitrile [0164]

<img file="PL2024352T3_D0056.tif" />

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

Yield: 0.18 g (49% of theory)

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

Example 6: 4- (BD-glucopyranose-1-yl) -2- (4-trifluoromethoxybenzyl) benzonitrile [0166]

<img file="PL2024352T3_D0057.tif" />

[0167] 2-Bromomethyl-4- (2,3,4,6-tetra-O-acetyl) -glucopyranose-1-yl) -benzonitrile (0.25 g), 4-trifluoromethoxyphenylboronic acid (0) is placed in the flask. , 20 g), potassium carbonate (0.26 g) and a 3: 1 mixture of degassed acetone and water (4 ml). The mixture is stirred at room temperature for 5 min, then cooled in an ice bath. Palladium dichloride (5 mg) is added and the reaction mixture is stirred for 16 h at ambient temperature. The mixture is diluted with brine and extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and the solvent removed under reduced pressure. The residue is dissolved in methanol (9 ml) and treated with a 4 M aqueous potassium hydroxide solution (1 ml). The resulting solution is stirred at ambient temperature for 1 h and then neutralized with 1 M hydrochloric acid. The methanol is evaporated and the residue is diluted with brine and extracted with ethyl acetate. The collected organic extracts are dried over sodium sulfate and the solvent removed. The residue is chromatographed on silica gel (dichloromethane / methanol 1: 0> 8: 1).

Yield: 0.145 g (69% of theory)

Mass Spectrum: (ESI⁺): m / z = 457 [M + NH4]⁺ [0168] In some cases, the yield is increased by using 1.5 to 2.0 equivalents of boronic acid and proportionally increasing the amount of base.

[0169] In analogy to Example 6, the following compounds are prepared:

Example 7: 4- (eD-glucopyranose-1-yl) -2- (4-trifluoromethylbenzyl) benzonitrile [070]

<img file="PL2024352T3_D0058.tif" />

Yield: 47% of theory.

Mass Spectrum: (ESI⁺): m / z = 44i [M + NH4]⁺

Example 8: 4- (eD-glucopyranose-1-yl) -2- (4-isopropylbenzyl) benzonitrile [0i7i]

<img file="PL2024352T3_D0059.tif" />

Yield: 87% of theory.

Mass Spectrum: (ESI⁺): m / z = 4i5 [M + NH4]⁺

Example 9: 4- (eD-glucopyranose-1-yl) -2- (4-tert-butylbenzyl) benzonitrile [072]

<img file="PL2024352T3_D0060.tif" />

Yield: 66% of theory.

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

Example 10: 4- (eD-glucopyranose-1-yl) -2- (4-trimethylsilylbenzyl) benzonitrile [073]

<img file="PL2024352T3_D0061.tif" />

Yield: 70% of theory.

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

Example 11: 4- (eD-glucopyranose-1-yl) -2- (4-methylsulfanylbenzyl) benzonitrile [0174]

<img file="PL2024352T3_D0062.tif" />

Yield: 47% of theory.

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

Example 12: 4- (eD-glucopyranose-1-yl) -2- [4- (3-methylbut-1-yl) benzyl] benzonitrile [0175]

<img file="PL2024352T3_D0063.tif" />

Yield: 69% of theory.

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

Example 13: 2- (4-Fluoro-benzyl) -4- (eD-glucopyranose-1-yl) -benzonitrile [0176]

<img file="PL2024352T3_D0064.tif" />

Yield: 34% of theory.

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

Example 14: 2- (4-Chlorobenzyl) -4- (eD-glucopyranose-1-yl) benzonitrile [0177]

<img file="PL2024352T3_D0065.tif" />

Yield: 32% of theory.

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

Example 15: 2- (4-Difluoromethoxybenzyl) -4- (eD-glucopyranose-1-yl) benzonitrile [0178]

<img file="PL2024352T3_D0066.tif" />

Yield: 32% of theory.

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

Example 16: 2- (4-Difluoromethylbenzyl) -4- (eD-glucopyranose-1-yl) benzonitrile [0179]

<img file="PL2024352T3_D0067.tif" />

Yield: 65% of theory.

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

Example 17: 2- (4-Cyclopropylbenzyl) -4- (eD-glucopyranose-1-yl) benzonitrile [0180]

<img file="PL2024352T3_D0068.tif" />

Mass Spectrum: (ESI⁺): m / z = 413 [M + NH4]⁺ [0181] The compound is prepared according to the procedure of Example 6, using 4-cyclopropylphenylboronic acid as the coupling partner.

Yield: 83% of theory.

[0182] Alternatively, the compound is prepared as described in Example XXIV (1). [0183] The compound of Example 17 is also obtained using the following procedure: [0184] Solution 2- (4-cyclopropylbenzyl) -4- (2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl) - benzonitrile (0.80 g) in methanol (5 ml) and THF (5 ml) are mixed with an aqueous solution of potassium hydroxide (4 mol / l, 5 ml). The reaction solution is stirred at ambient temperature for 1 h, then neutralized with 1 M hydrochloric acid. The organic solvents are evaporated off and the residue is diluted with brine and extracted with ethyl acetate. The organic extracts are dried (sodium sulfate) and the solvent removed. The residue is chromatographed on silica gel (dichloromethane / methanol 1: 0> 9: 1).

Yield: 0.54 g (96% of theory)

Example 18: 2- (4-Cyclobutylbenzyl) -4- (eD-glucopyranose-1-yl) benzonitrile [0185]

<img file="PL2024352T3_D0069.tif" />

[0186] The compound is obtained according to the procedure of Example 6, using 4-cyclobutylboronic acid (obtained in analogy to Example XXI) as the coupling partner.

Yield: 51% of theory.

Mass Spectrum: (ESI⁺): m / z = 427 [M + NH4]⁺

Example 19: 4- (eD-glucopyranose-1-yl) -2- (4-prop-1-ylbenzyl) benzonitrile [0187]

<img file="PL2024352T3_D0070.tif" />

Yield: 64% of theory.

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

Example 20: 4- (eD-glucopyranose-1-yl) -2- (4- (1-hydroxycyclopropyl) benzyl] benzonitrile [0188]

<img file="PL2024352T3_D0071.tif" />

[0189] The compound can be obtained according to the procedure of Example 6, using 4- (1-hydroxycyclopropyl) -phenylboronic acid as the coupling partner.

Example 21:

[0190]

<img file="PL2024352T3_D0072.tif" />

4- (eD-glucopyranose-1-yl) -2- (4-iodobenzyl] benzonitrile [0191] A 1 M solution of iodine chloride in dichloromethane (0.9 mL) is added to 4- (e-D-glucopyranose-1-yl) ) -2- (4-trimethylsilylbenzyl] benzonitrile (0.26 g) dissolved in dichloromethane (5 mL). The solution is stirred at room temperature for 1 h, after which the reaction is quenched by the addition of aqueous Na2S2O3 solution and aqueous NaHCO3 solution. the organic layer is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane / methanol 1: 0> 8: 1). Yield: 0.15 g (88% of theory)

Mass Spectrum: (ESI⁺): m / z = 499 [M + NH4]⁺ [0192] The following compounds can be obtained in analogy to Example 20:

(22) 2- (4-Bromobenzyl) -4- (eD-glucopyranose-1-yl) benzonitrile [0193]

<img file="PL2024352T3_D0073.tif" />

Yield: 79% of theory.

Mass Spectrum: (ESI⁺): m / z = 451/453 [M + NH4]⁺ [0194] The compound is prepared according to the procedure of Example 20 using bromine instead of ICl in dichloromethane.

Example 23 [0195]

<img file="PL2024352T3_D0074.tif" />

4- (eD-glucopyranose-1-yl) -2- (4-pentafluoroethylbenzyl) benzonitrile [0196] A flask containing 4- (2,3,4,6-tetra-O-acetyl-eD-glucopyranose-1-yl ) -2- (4 -odobenzyl) benzonitrile (0.15 g), pentafluoroethyltrimethylsilane (0.14 g), KF (43 mg),

CuI (0.16 g), DMF (2 ml) under argon is heated at 60 ° C for 24 h. Aqueous NaHCO 3 solution is added and the resulting mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is dissolved in methanol (8 ml) and mixed with a 4 M KOH solution (0.8 ml). The solution is stirred at room temperature for 1 h and then diluted with aqueous NaHCO3 solution. After removing methanol under reduced pressure, the residue is extracted with ethyl acetate, the combined organic extracts are dried and the solvent removed. The residue is chromatographed on silica gel (dichloromethane / methanol 1: 0> 8: 1).

Yield: 0.08 g (69% of theory)

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

Example 24 4- (eD-glucopyranose-1-yl) -2- (4-methylsulfinylbenzyl) benzonitrile

<img file="PL2024352T3_D0075.tif" />

[0198] To 4- (eD-glucopyranose-1-yl) -2- (4-methylsulfamylbenzyl) benzonitrile (83 g) in 1,1,1,3,3,3-hexafluoroisopropanol (2 mL) is added % hydrogen peroxide in water (48 pil). The resulting solution is stirred at ambient temperature for 1 h, after which the reaction is quenched by the addition of an aqueous Na2S2O3 solution and an aqueous NaHCO3 solution.

The organic phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane / methanol 1: 0> 5: 1).

Yield: 24 g (28% of theory)

Mass Spectrum: (ESI⁺): m / z = 418 [M + NH4]⁺

Example 25 [0199]

<img file="PL2024352T3_D0076.tif" />

4- (eD-glucopyranose-1-yl) -2- (4-methylsulfonylbenzyl) benzonitrile To 4- (eD-glucopyranose-1-yl) -2- (4-methylsulfanylbenzyl) benzonitrile (100 mg) in dichloromethane (2 mL) cooled in an ice bath, 3-chloroperoxybenzoic acid (70%, 0.14 g) is added. The cooling bath is removed and the resulting solution is stirred at ambient temperature for 1 h. After adding the aqueous solution

Na2S2O3 and aqueous NaHCO3, the organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane / methanol 1: 0> 8: 1).

Yield: 68 g (63% of theory)

Mass Spectrum: (ESI⁺): m / z = 451 [M + NH4]⁺ [0201] In an analogous manner to the above-mentioned examples or other methods known from the literature, the following compounds can also be obtained:

<img file="PL2024352T3_D0077.tif" />

<img file="PL2024352T3_D0078.tif" />

<img file="PL2024352T3_D0079.tif" />

<img file="PL2024352T3_D0080.tif" />

<img file="PL2024352T3_D0081.tif" />

<img file="PL2024352T3_D0082.tif" />

<img file="PL2024352T3_D0083.tif" />

<img file="PL2024352T3_D0084.tif" />

<img file="PL2024352T3_D0085.tif" />

<img file="PL2024352T3_D0086.tif" />

<img file="PL2024352T3_D0087.tif" />

<img file="PL2024352T3_D0088.tif" />

<img file="PL2024352T3_D0089.tif" />

<img file="PL2024352T3_D0090.tif" />

<img file="PL2024352T3_D0091.tif" />

<img file="PL2024352T3_D0092.tif" />

<img file="PL2024352T3_D0093.tif" />

<img file="PL2024352T3_D0094.tif" />

[0202] Several examples of formulations will now be described in which the term "active substance" means one or more compounds of the invention, including prodrugs or esters thereof. In the case of one of the combinations with one or more additional active substances as previously described, the term "active substance" also includes the additional active substance.

Example A [0203] Tablets containing 100 mg of active substance Composition [0204] 1 tablet contains:

Active substance 100.0 mg

Lactose 80.0 mg

Corn starch 34.0 mg

Polyvinylpyrrolidone 4.0 mg

Magnesium stearate 2.0 mg

220.0 mg

Manufacturing Process:

[0205] The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After wiping the wet composition through a sieve (mesh size 2.0 mm) and drying in a shelf dryer at 50C it is wiped again (mesh size 1.5 mm) and a lubricant is added. The finished mix is ​​compressed to form tablets.

Tablet weight: 220 mg

Diameter: 10 mm, flat on both sides, flat on both sides, with a groove on one side.

Example B [0206] Tablets containing 150 mg of active substance

Composition [0207] 1 tablet contains:

<td>Active substance</td><td>150.0 mg</td>

<td>Powdered lactose</td><td>89.0 mg</td>

<td>Corn starch</td><td>40.0 mg</td>

<td>Colloidal silica</td><td>10.0 mg</td>

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

<td>Magnesium stearate</td><td>1.0 mg</td>

<td>Manufacturing Process:</td><td>300.0 mg</td>

[0208] The active substance with lactose, corn starch and silica is moistened with a 20% aqueous solution of polyvinylpyrrolidone and wiped through a 1.5 mm sieve. The granulate, dried at 45 ° C, is again wiped through a sieve with the same size of holes and mixed with a specified amount of magnesium stearate. Tablets are extruded from the blend.

Tablet weight: 300 mg

Matrix: 10 mm, flat.

Example C [0209] Hard gelatin capsules with an active ingredient content of 150 mg

Composition:

[0210] 1 capsule contains: Active substance Corn starch (dried) Lactose (powdered) Magnesium stearate

150.0 mg approx. 180.0 mg approx. 87.0 mg 3.0 mg approx. 420.0 mg

Manufacturing Process:

[0211] The active substance is mixed with excipients, sieved through a 0.75 mm mesh sieve and mixed until uniform using a suitable device. The finished mixture is filled into size 1 gelatin capsules.

Capsule filling: approx. 320 mg

Capsule shell: gelatin capsule size 1.

Example D [0212] Suppositories containing 150 mg of active substance

Composition:

[0213] 1 suppository contains:

Active substance 150, 0 mg

Polyethylene glycol 1500 550.0 mg

Polyethylene glycol 6000 460.0 mg

Polyoxyethylene sorbitan monostearate 840.0 mg 2000.0 mg

Manufacturing Process:

[0214] After the mass of the ingredients has melted, the suppository distributes the active substance uniformly and melts the cooled molds.

Example E [0215] Ampoules containing 10 mg of active substance

Composition:

[0216]

Active substance 10.0 mg

0.01 N hydrochloric acid qs

Distilled water to 2.0 ml twice

Manufacturing Process:

[0217] The active substance is dissolved in the needed amount of 0.01 N HCl, brought to isotonicity with ordinary salt, sterilized and transferred to 2 ml ampoules.

Example F [0218] Ampoules containing 50 mg of active substance

Composition:

[0219]

Active substance 50, 0 mg

0.01 N hydrochloric acid qs

Double distilled water to 10.0 ml

Manufacturing Process:

[0220] The active substance is dissolved in the necessary amount of 0.01 N HCl, brought to isotonicity with ordinary salt, sterilized and transferred to 10 ml ampoules.

Boehringer Ingelheim InternationalGmbH; Germany Representative:

EP 2 024 352 B1 Z-10523