WO2008101938A1

WO2008101938A1 - Glucopyranosyl-substituted benzyl-benzonitrile derivatives, medicaments containing such compounds, their use and process for their manufacture

Info

Publication number: WO2008101938A1
Application number: PCT/EP2008/052030
Authority: WO
Inventors: Frank Himmelsbach; Matthias Eckhardt; Peter Eickelmann; Leo Thomas
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2007-02-21
Filing date: 2008-02-20
Publication date: 2008-08-28

Abstract

Glucopyranosyl-substituted benzyl-benzonitrilederivatives as defined according to claim 1, including the tautomers, the stereoisomers thereof, the mixtures thereof and the salts thereof. The compounds according to the invention are suitable for the treatment of metabolic disorders.

Description

Glucopyranosyl-substituted benzyl-benzonitrile derivatives, medicaments containing such compounds, their use and process for their manufacture

The present invention relates to glucopyranosyl-substituted benzyl-benzonitrile derivatives as defined hereinafter, including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof. The invention further relates to pharmaceutical compositions containing a compound according to the invention as well as the use of a compound according to the invention for preparing a pharmaceutical composition for the treatment of metabolic disorders.

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

Glucopyranosyloxy- and glucopyranosyl-substituted aromatic groups and the preparation thereof and their possible activity as SGLT2 inhibitors are known from published International applications WO 98/31697, WO 01/27128, WO 02/083066, WO 03/099836, WO 2004/063209, WO 2004/080990, WO 2004/013118, WO 2004/052902, WO 2004/052903, WO 2005/092877, WO 2006/010557, WO 2006/018150, WO 2006/037537, WO 2006/089872, WO 2006/064033, WO 2007/014894, WO 2007/025943,

WO 2007/031548, WO 2007/093610, WO 2007/128749 and US application US 2003/0114390.

Aim of the invention The aim of the present invention is to find new pyranosyl-substituted benzonitrile derivatives, particularly those which are active with regard to the sodium-dependent glucose cotransporter SGLT, particularly SGLT2. A further aim of the present invention is to discover pyranosyl-substituted benzene derivatives which have a good to very good inhibitory effect on the sodium-dependent glucose cotransporter SGLT2 in vitro and/or in vivo and/or have good to very good pharmacological and/or pharmacokinetic and/or physicochemical properties.

A further aim of the present invention is to provide new pharmaceutical compositions which are suitable for the prevention and/or treatment of metabolic disorders, particularly diabetes.

The invention also sets out to provide processes and intermediates useful for preparing the compounds according to the invention. Other aims of the present invention will become apparent to the skilled man directly from the foregoing and following remarks.

Object of the invention

In a first aspect the present invention relates to a glucopyranosyl-substituted benzyl- benzonitrile derivative selected from the group consisting of:

(1 ) 5-Ethoxy-2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-benzonitrile,

(2) 2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-(isopropyloxy)-benzonitrile,

(3) 5-Cyclobutyloxy-2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,

(4) 2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-((S)-tetrahydrofuran-3-yloxy)- benzonitrile,

(5) 2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-((R)-tetrahydrofuran-3-yloxy)- benzonitrile,

(6) 2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-methylsulfanyl-benzonitrile,

(7) 2-(4-Cyclopropyl-benzyl)-5-ethoxy-4-(β-D-glucopyranos-1-yl)-benzonitrile,

(8) 2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-(isopropyloxy)-benzonitrile,

(9) 5-Cyclobutyloxy-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,

(10) 2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-5-((S)-tetrahydrofuran-3- yloxy)-benzonitrile,

(1 1 ) 2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-5-((R)-tetrahydrofuran-3- yloxy)-benzonitrile,

(12) 2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-5-methylsulfanyl-benzonitrile,

(13) 6-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-2-methylsulfanyl-benzonitrile,

(14) 6-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-2-methylsulfanyl-benzonitrile,

(15) 2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-5-hydroxy-benzonitrile, (16) 2-(4-Cyclopropyl-benzyl)-4-( β-D-glucopyranos-1 -yl)-5-hydroxy-benzonitrile,

or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (Ci.i₈-alkyl)carbonyl, (Ci.i₈-alkyl)oxycarbonyl, phenylcarbonyl, phenyl-(Ci_-3-alkyl)-carbonyl, or a pharmaceutically acceptable salt thereof;

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

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

The compounds according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibitory effect on the sodium- dependent glucose cotransporter SGLT, particularly SGLT2. Moreover compounds according to the invention may have an inhibitory effect on the sodium-dependent glucose cotransporter SGLT1. Compared with a possible inhibitory effect on SGLT1 the compounds according to the invention preferably inhibit SGLT2 selectively.

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

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

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

This invention also relates to the use of at least one compound according to the invention or one of the physiologically acceptable salts thereof for preparing a pharmaceutical composition which is suitable for the treatment of metabolic disorders. In a further aspect the present invention relates to the use of at least one compound according to the invention or one of the physiologically acceptable salts thereof for preparing a pharmaceutical composition for preventing the degeneration of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells.

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

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

The intermediate products described in the following, in particular in the experimental section, are also a subject of this invention.

Detailed Description of the invention

In the compounds according to the present invention one or more hydroxyl groups of the β- D-glucopyranosyl group may be acylated with groups selected from (Ci-i₈-alkyl)carbonyl, (Ci- i₈-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(Ci_-3-alkyl)-carbonyl, preferably selected from (Ci_-8-alkyl)oxycarbonyl, Ci_-8-alkylcarbonyl or benzoyl, particularly preferably selected from methylcarbonyl, methoxycarbonyl and ethoxycarbonyl.

According to one embodiment of the present invention the hydrogen atom of the hydroxyl group in 6-position of the β-D-glucopyranosyl-group is replaced by a group selected from among (Ci_-6-alkyl)carbonyl, (Ci_-6-alkyl)oxycarbonyl. Preferably the hydrogen atoms of the remaining hydroxyl groups of the β-D-glucopyranosyl-group are not replaced.

According to another and preferred embodiment of the present invention the hydrogen atoms of the hydroxyl groups of the β-D-glucopyranosyl-group are not replaced by another group.

According to yet another embodiment of the present invention all hydrogen atoms of the hydroxyl groups of the β-D-glucopyranosyl-group are replaced individually from each other by a group as described hereinbefore, preferably by a group selected from among (Ci_-6- alkyl)carbonyl, (Ci_-6-alkyl)oxycarbonyl.

The compounds according to the invention wherein one or more hydrogen atoms of the hydroxyl groups of the β-D-glucopyranosyl-group are replaced are preferably suitable as intermediate products for the synthesis of compound according to the present invention.

Some terms used above and hereinafter to describe the compounds according to the invention will now be defined more closely.

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

The term Ci_-n-alkyl, wherein n may have a value of 2 to 18, denotes a saturated, branched or unbranched hydrocarbon group with 1 to n C atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.

The term Ci_-n-alkoxy denotes a Ci_-n-alkyl-0 group, wherein Ci_-n-alkyl is as hereinbefore defined. Examples of such groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert- pentoxy, n-hexoxy, iso-hexoxy etc.

The term Ci_-n-alkylcarbonyl denotes a Ci_-n-alkyl-C(=O) group, wherein Ci_-n-alkyl is as hereinbefore defined. Examples of such groups include methylcarbonyl, ethylcarbonyl, n- propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert- pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl, etc.

The compounds according to the invention may be obtained using methods of synthesis known in principle. Preferably the compounds are also obtainable using the methods described in the examples that follow, which may also be combined for this purpose with methods known to the skilled man from the literature, for example the methods described in WO 98/31697, WO 01/27128, WO 02/083066, WO 03/099836, WO 2004/063209, WO 2004/080990, WO 2004/0131 18, WO 2004/052902, WO 2004/052903, WO 2005/092877, WO 06/010557, WO 06/018150, WO 06/037537, WO 06/089872, WO 2006/064033, WO 2006/120208, WO 2007/093610 and US application US 2003/01 14390. The compounds according to the invention obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and ENeI E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 ) into their optical antipodes and compounds with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.

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

Furthermore, the compounds according to the invention may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Moreover, the compounds obtained may be converted into mixtures, for example 1 :1 or 1 :2 mixtures with amino acids, particularly with alpha-amino acids such as proline or phenylalanine, which may have particularly favourable properties such as a high crystallinity. As already mentioned, the compounds according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibitory effect on the sodium-dependent glucose cotransporter SGLT, preferably SGLT2.

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

The ability of the substances to inhibit the SGLT-2 activity may be demonstrated in a test setup in which a CHO-K1 cell line (ATCC No. CCL 61 ) or alternatively an HEK293 cell line (ATCC No. CRL-1573), which is stably transfected with an expression vector pZeoSV (Invitrogen, EMBL accession number L36849), which contains the cDNA for the coding sequence of the human sodium glucose cotransporter 2 (Genbank Ace. No.NM_003041 ) (CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport ¹⁴C-labelled alpha-methyl- glucopyranoside (¹⁴C-AMG, Amersham) into the interior of the cell in sodium-dependent manner.

The SGLT-2 assay is carried out as follows:

CHO-hSGLT2 cells are cultivated in Ham^'s F12 Medium (BioWhittaker) with 10% foetal calf serum and 250 μg/mL zeocin (Invitrogen), and HEK293-hSGLT2 cells are cultivated in DMEM medium with 10% foetal calf serum and 250 μg/ml zeocin (Invitrogen). The cells are detached from the culture flasks by washing twice with PBS and subsequently treating with trypsin/EDTA. After the addition of cell culture medium the cells are centrifuged, resuspended in culture medium and counted in a Casy cell counter. Then 40,000 cells per well are seeded into a white, 96-well plate coated with poly-D-lysine and incubated overnight at 37 ⁰C, 5% CO₂. The cells are washed twice with 250 μL of assay buffer (Hanks Balanced Salt Solution, 137 mM NaCI, 5.4 mM KCI, 2.8 mM CaCI₂, 1.2 mM MgSO₄ and 10 mM HEPES (pH7.4), 50 μg/mL of gentamycin). 250 μL of assay buffer and 5 μL of test compound are then added to each well and the plate is incubated for a further 15 minutes in the incubator. 5 μL of 10% DMSO are used as the negative control. The reaction is started by adding 5 μL of ¹⁴C-AMG (0.05 μCi) to each well. After 2 hours' incubation at 37 ⁰C, 5% CO₂, the cells are washed again with 250 μL of PBS (20 ⁰C) and then lysed by the addition of 25 μL of 0.1 N NaOH (5 min. at 37 ⁰C). 200 μL of MicroScint20 (Packard) are added to each well and incubation is continued for a further 20 min at 37 ⁰C. After this incubation the radioactivity of the ¹⁴C-AMG absorbed is measured in a Topcount (Packard) using a ¹⁴C scintillation program. To determine the selectivity with respect to human SGLT1 an analogous test is set up in which the cDNA for hSGLTI (Genbank Ace. No. NM000343) instead of hSGLT2 cDNA is expressed in CHO-K1 or HEK293 cells. Data are transferred to the software program GraphPadPrism 4.01 and IC₅o-values are calculated from the CPM (counts per minute) data using the default equation for sigmoidal dose-response (hill slope = 1 ).

The compounds according to the invention listed in the group above predominantly may have IC50 values below 200 nM, preferably below 50 nM.

In view of their ability to inhibit the SGLT activity, the compounds according to the invention and the corresponding pharmaceutically acceptable salts thereof are suitable for the treatment and/or preventative treatment of all those conditions or diseases which may be affected by the inhibition of the SGLT activity, particularly the SGLT-2 activity. Therefore, compounds according to the invention are particularly suitable for the prevention or treatment of diseases, particularly metabolic disorders, or conditions such as type 1 and type 2 diabetes mellitus, complications of diabetes (such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies), metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, edema and hyperuricaemia. These substances are also suitable for preventing beta-cell degeneration such as e.g. apoptosis or necrosis of pancreatic beta cells. The substances are also suitable for improving or restoring the functionality of pancreatic cells, and also of increasing the number and size of pancreatic beta cells. The compounds according to the invention may also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure.

By the administration of a compound according to the invention an abnormal accumulation of fat in the liver may be reduced or inhibited. Therefore according to another aspect of the present invention there is provided a method for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat in a patient in need thereof characterized in that a compound or a pharmaceutical composition according to the present invention is administered. Diseases or conditions which are attributed to an abnormal accumulation of liver fat are particularly selected from the group consisting of general fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), hyperalimentation-induced fatty liver, diabetic fatty liver, alcoholic-induced fatty liver or toxic fatty liver. In particular, the compounds according to the invention, including the physiologically acceptable salts thereof, are suitable for the prevention or treatment of diabetes, particularly type 1 and type 2 diabetes mellitus, and/or diabetic complications.

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

The dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound which is to be administered, the patient, the nature and gravity of the illness or condition and the method and frequency of administration and is for the patient's doctor to decide. Expediently, the dosage may be from 1 to 100 mg, preferably 1 to 30 mg, by intravenous route, and 1 to 1000 mg, preferably 1 to 100 mg, by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds according to 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, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

The compounds according to the invention may also be used in conjunction with other active substances, particularly for the treatment and/or prevention of the diseases and conditions mentioned above. Other active substances which are suitable for such combinations include for example those which potentiate the therapeutic effect of an SGLT antagonist according to the invention with respect to one of the indications mentioned and/or which allow the dosage of an SGLT antagonist according to the invention to be reduced. Therapeutic agents which are suitable for such a combination include, for example, antidiabetic agents such as metformin, sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g. Gl 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha- glucosidase inhibitors (e.g. acarbose, voglibose), DPP-4 inhibitors (e.g. Vildagliptin, Sitagliptin, Saxagliptin, Alogliptin, BI 1356), alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin. The list also includes inhibitors of protein tyrosinephosphatase 1 , substances that affect deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or fructose-1 ,6- bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents such as for example HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and the derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterol absorption inhibitors such as, for example, ezetimibe, bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as CETP inhibitors or ABC1 regulators or active substances for treating obesity, such as sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the cannabinoidi receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or β3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor.

Moreover, combinations with drugs for influencing high blood pressure, chronic heart failure or atherosclerosis such as e.g. A-Il antagonists or ACE inhibitors, ECE inhibitors, diuretics, β- blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2- adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable. Examples of angiotensin Il receptor antagonists are candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671 , GA-0113, RU-64276, EMD-90423, BR-9701 , etc. Angiotensin Il receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.

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

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

The dosage for the combination partners mentioned above is usefully 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose. Therefore, in another aspect, this invention relates to the use of a compound according to the invention or a physiologically acceptable salt of such a compound combined with at least one of the active substances described above as a combination partner, for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be affected by inhibiting the sodium-dependent glucose cotransporter SGLT. These are preferably metabolic diseases, particularly one of the diseases or conditions listed above, most particularly diabetes or diabetic complications.

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

Consequently, in another aspect, this invention relates to a pharmaceutical composition which comprises a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.

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

The compound according to the invention, or a physiologically acceptable salt thereof, and the additional active substance to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so-called kit-of-parts.

In the foregoing and following text, H atoms of hydroxyl groups are not explicitly shown in every case in structural formulae. The Examples that follow are intended to illustrate the present invention without restricting it. The terms "room temperature" and "ambient temperature" are used interchangeably and denote temperatures of about 20 ⁰C. The following abbreviations are used: ffiu ferf.butyl dba dibenzylidenaceton DMF dimethylformamide DMSO dimethyl sulfoxide NMP Λ/-methyl-2-pyrrolidone THF tetrahydrofuran

Preparation of the starting compounds:

Example I

(2-Bromo-4-fluoro-phenyl)-(4-ethyl-phenyl)-methanone

(COCI)₂ (17 ml.) is added to a suspension of 2-bromo-4-fluoro-benzoic acid (30 g) in dichloromethane (1 10 ml_). A few drops of DMF are added and the mixture is stirred at room temperature overnight. Then, the reaction solution is concentrate d under reduced pressure and the residue is taken up in dichloromethane (100 ml.) and ethylbenzene (25 ml_). The resulting solution is cooled in an ice bath and aluminum trichloride (27 g) is added in portions. Then, the cooling bath is removed and the reaction mixture is stirred at room temperature overnight. The reaction mixture is poured onto crushed ice and the organic phase is separated. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed in succession with 1 M hydrochloric acid, aqueous NaHCOs solution and brine. The organic phase is dried (sodium sulfate), the solvent is removed and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:1->8:1 ). Yield: 46 g (79% of theory) Mass spectrum (ESI⁺): m/z = 307/309 (Br) [M+H]⁺

Example Il

(2-Bromo-4-methoxy-phenyl)-(4-ethyl-phenyl)-methanone Sodium methoxide (10.5 g) is added portionwise to (2-bromo-4-fluoro-phenyl)-(4-ethyl- phenyl)-methanone (43.0 g) dissolved in DMF (200 ml_). The solution is stirred overnight, before another portion of sodium methoxide (5.5 g) is added. After another 3 h of stirring, water is added and the resulting mixture is extracted with ethyl acetate. The organic phase is dried (sodium sulfate), the solvent is removed and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 20:1->9:1 ). Yield: 33.7 g (75% of theory) Mass spectrum (ESI⁺): m/z = 319/321 (Br) [M+H]⁺

The following compounds may be obtained analogously to Example II:

The alcoholates needed for the following compounds are either commercially available or may be generated form the respective alcohols by treatment with sodium hydride or sodium tert-butoxide.

(1 ) (2-Bromo-4-ethoxy-phenyl)-(4-ethyl-phenyl)-methanone

(2) (2-Bromo-4-cyclobutoxy-phenyl)-(4-ethyl-phenyl)-methanone

(3) [2-Bromo-4-((S)-tetrahydrofuran-3-yloxy)-phenyl]-(4-ethyl-phenyl)-methanone

(4) [2-Bromo-4-((/?)-tetrahydrofuran-3-yloxy)-phenyl]-(4-ethyl-phenyl)-methanone

(5) (2-Bromo-4-isopropoxy-phenyl)-(4-ethyl-phenyl)-methanone

(6) (2-Bromo-4-methylsulfanyl-phenyl)-(4-ethyl-phenyl)-methanone

NaSMe is used as the nucleophile.

Example

(2-Bromo-5-iodo-4-methoxy-phenyl)-(4-ethyl-phenyl)-methanone

N-lodosuccinimide (5.8 g) is added in portions to an ice-cold solution of (2-bromo-4-methoxy- phenyl)-(4-ethyl-phenyl)-methanone (6.75 g) in sulfuric acid (47 ml_). The mixture is stirred at 5-10 ⁰C for 3 h before warming to room temperature overnight. Then, the mixture is poured on crushed ice and the resultant solution is extracted with ethyl acetate. The combined extracts are washed in succession with aqueous 10% Na₂S₂θ3 solution (2x), water (3x), and brine (1x). After drying (MgSO₄) the organic layer, the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/dichloromethane 9:1->1 :1 ) to give the product as a solid. Yield: 5.1 g (54% of theory) Mass spectrum (ESI^"): m/z = 445/447 (Br) [M+H]⁺

The following compounds may be obtained analogously to Example III: (1 ) (2-Bromo-4-ethoxy-5-iodo-phenyl)-(4-ethyl-phenyl)-methanone

(2) (2-Bromo-4-cyclobutoxy-5-iodo-phenyl)-(4-ethyl-phenyl)-methanone

(3) [2-Bromo-5-iodo-4-((S)-tetrahydrofuran-3-yloxy)-phenyl]-(4-ethyl-phenyl)-methanone

(4) [2-Bromo-5-iodo-4-((/?)-tetrahydrofuran-3-yloxy)-phenyl]-(4-ethyl-phenyl)-methanone

(5) (2-Bromo-5-iodo-4-isopropoxy-phenyl)-(4-ethyl-phenyl)-methanone

(6) (2-Bromo-5-iodo-4-methylsulfanyl-phenyl)-(4-ethyl-phenyl)-methanone

Example IV

N-(4-Bromo-3-methoxy-phenyl)-acetamide

Acetic anhydride (13 mL) is added to an ice-cold solution of 4-bromo-3-methoxy- phenylamine (25.0 g) in acetic acid (100 mL). The mixture is stirred for 1 h and then diluted with ice-cold water (500 mL). The precipitate is separated by filtration, washed with water and dried at 60 ⁰C to give the product.

Yield: 30.0 g (99% of theory)

Mass spectrum (ESI⁺): m/z = 244/246 (Br) [M+H]⁺

The following compounds may be obtained analogously to Example IV:

The anilines needed as starting materials for the following compounds may be prepared from the corresponding phenols or thiophenols via nucleophilic substitution reactions with the respective alkyl halides, e.g. iodide or bromide, or alkyl sulfonates, e.g. trifluoromethylsulfonate, tosylate, or mesylate and a base, e.g. CS₂CO3 or NaOH, in e.g. DMF or ethanol.

(1 ) N-(4-Bromo-3-ethoxy-phenyl)-acetamide

(2) N-(4-Bromo-3-cyclobutoxy-phenyl)-acetamide

(3) N-[4-Bromo-3-((S)-tetrahydrofuran-3-yloxy)-phenyl]-acetamide

(4) N-[4-Bromo-3-((R)-tetrahydrofuran-3-yloxy)-phenyl]-acetamide

(5) N-(4-Bromo-3-isopropoxy-phenyl)-acetamide

(6) N-(4-Bromo-3-methylsulfanyl-phenyl)-acetamide

Alternatively, the residue on the oxygen or sulphur of the compounds above may be introduced after this reaction by a nucleophilic substitution of a halide atom, such as iodide or bromide, or a sulfonyloxy group, such as trifluoromethylsulfonyloxy, tosyloxy or mesyloxy, of the alkyl residue with the respective phenol or thiophenol.

Example V

N-[4-Bromo-2-(4-ethyl-benzoyl)-5-methoxy-phenyl1-acetamide

Phosphorus oxychloride (17 ml.) and tin(IV) chloride (5 ml.) are successively added to a suspension of N-(4-bromo-3-methoxy-phenyl)-acetamide (5.0 g) and 4-ethylbenzoic acid (4.4 g) in 1 ,2-dichloroethane at such a rate that the temperature maintains below 35 ⁰C. The resulting mixture is heated at reflux temperature overnight. Then, the mixture is diluted with dichloromethane and poured onto crushed ice. After stirring the aqueous mixture for 30 min, the organic phase is separated and washed with 10% NaOH in water and water. The organic phase is dried (sodium sulfate), the solvent is removed and the residue is triturated with methanol to give the product. Yield: 5.8 g (75% of theory) Mass spectrum (ESI^"): m/z = 374/376 (Br) [M-H]^"

The following compounds may be obtained analogously to Example V:

(1 ) N-[4-Bromo-5-ethoxy-2-(4-ethyl-benzoyl)-phenyl]-acetamide

(2) N-[4-Bromo-5-cyclobutoxy-2-(4-ethyl-benzoyl)-phenyl]-acetamide

(3) N-[4-Bromo-2-(4-ethyl-benzoyl)-5-((S)-tetrahydrofuran-3-yloxy)-phenyl]-acetamide

(4) N-[4-Bromo-2-(4-ethyl-benzoyl)-5-((R)-tetrahydrofuran-3-yloxy)-phenyl]-acetamide

(5) N-[4-Bromo-2-(4-ethyl-benzoyl)-5-isopropoxy-phenyl]-acetamide

(6) N-[4-Bromo-2-(4-ethyl-benzoyl)-5-methylsulfanyl-phenyl]-acetamide

(7) N-[4-Bromo-5-methoxy-2-(4-methoxy-benzoyl)-phenyl]-acetamide

(8) N-[4-Bromo-5-ethoxy-2-(4-methoxy-benzoyl)-phenyl]-acetamide

(9) N-[4-Bromo-5-cyclobutoxy-2-(4-methoxy-benzoyl)-phenyl]-acetamide

(10) N-[4-Bromo-2-(4-methoxy-benzoyl)-5-((S)-tetrahydrofuran-3-yloxy)-phenyl]-acetamide

(1 1 ) N-[4-Bromo-2-(4-methoxy-benzoyl)-3-((R)-tetrahydrofuran-3-yloxy)-phenyl]-acetamide

(12) N-[4-Bromo-2-(4-methoxy-benzoyl)-5-isopropoxy-phenyl]-acetamide

(13) N-[4-Bromo-2-(4-methoxy-benzoyl)-5-methylsulfanyl-phenyl]-acetamide

Example Vl

4-Bromo-5-(4-ethyl-benzyl)-1-iodo-2-methoxy-benzene

A solution of (2-bromo-5-iodo-4-methoxy-phenyl)-(4-ethyl-phenyl)-methanone (5.1 g) and triethylsilane (5.5 ml.) in dichloromethane (13 ml.) and acetonitrile (38 ml.) is cooled in an ice bath. Then, boron trifluoride diethyletherate (1.8 mL) is added dropwise over 3 min. The resulting solution is stirred for 14 h at ambient temperature, before an aqueous 25% solution of KOH and diisopropylether are added. The organic phase is separated and the aqueous phase is extracted three times with diisopropylether. The combined organic phases are washed with 2 M potassium hydroxide solution and brine and then dried (sodium sulfate). After the solvent is evaporated, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1 :0->19:1 ). Yield: 4.5 g (91 % of theory) Mass spectrum (ESI⁺): m/z = 448/450 (Br) [M+NH₄]⁺

The following compounds may be obtained analogously to Example Vl:

(1 ) 4-Bromo-2-ethoxy-5-(4-ethyl-benzyl)-1-iodo-benzene

(2) 4-Bromo-2-cyclobutoxy-5-(4-ethyl-benzyl)-1 -iodo-benzene

(3) 4-Bromo-5-(4-ethyl-benzyl)-1-iodo-2-((S)-tetrahydrofuran-3-yloxy)-benzene

(4) 4-Bromo-5-(4-ethyl-benzyl)-1-iodo-2-((/?)-tetrahydrofuran-3-yloxy)-benzene

(5) 4-Bromo-5-(4-ethyl-benzyl)-1 -iodo-2-isopropoxy-benzene

(6) 4-Bromo-5-(4-ethyl-benzyl)-1 -iodo-2-methylsulfanyl-benzene

Example VII

N-[4-Bromo-2-(4-ethyl-benzyl)-5-methoxy-phenyl1-acetamide

Sodium borohydride (0.17 g) is added portionwise to an ice-cold suspension of N-[4-bromo- 2-(4-ethyl-benzoyl)-5-methoxy-phenyl]-acetamide (3.25 g) in ethanol (50 ml_). The cooling bath is removed and the solution is stirred at ambient temperature for 2 h. Then, 1 M aqueous NaOH solution (8.5 ml.) is added and the resulting solution is concentrated under reduced pressure. Water is added to the residue and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na₂SC>₄) and concentrated. The residue is taken up in trifluoroacetic acid (20 ml.) and triethylsilane (4.3 ml.) is added. The solution is stirred at ambient temperature overnight and then poured on crushed ice. The resultant mixture is extracted twice with ethyl acetate. The combined extracts are washed with brine, dried (sodium sulphate) and concentrated under reduced pressure. The residue is treated with methanol and the precipitate formed is separated. The precipitate is then washed with diisopropylether and dried to give the desired product. Yield: 2.8 g (89% of theory) Mass spectrum (ESI⁺): m/z = 362/364 (Br) [M+H]⁺

The following compounds may be obtained analogously to Example VII:

(1 ) N-[4-Bromo-5-ethoxy-2-(4-ethyl-benzyl)-phenyl]-acetamide

(2) N-[4-Bromo-5-cyclobutoxy-2-(4-ethyl-benzyl)-phenyl]-acetamide

(3) N-[4-Bromo-2-(4-ethyl-benzyl)-5-((S)-tetrahydrofuran-3-yloxy)-phenyl]-acetamide

(4) N-[4-Bromo-2-(4-ethyl-benzyl)-5-((R)-tetrahydrofuran-3-yloxy)-phenyl]-acetamide

(5) N-[4-Bromo-2-(4-ethyl-benzyl)-5-isopropoxy-phenyl]-acetamide

(6) N-[4-Bromo-2-(4-ethyl-benzyl)-5-methylsulfanyl-phenyl]-acetamide

(7) N-[4-Bromo-5-methoxy-2-(4-methoxy-benzyl)-phenyl]-acetamide

(8) N-[4-Bromo-5-ethoxy-2-(4-methoxy-benzyl)-phenyl]-acetamide

(9) N-[4-Bromo-5-cyclobutoxy-2-(4-methoxy-benzyl)-phenyl]-acetamide

(10) N-[4-Bromo-2-(4-methoxy-benzyl)-5-((S)-tetrahydrofuran-3-yloxy)-phenyl]-acetamide

(1 1 ) N-[4-Bromo-2-(4-methoxy-benzyl)-5-((R)-tetrahydrofuran-3-yloxy)-phenyl]-acetamide

(12) N-[4-Bromo-2-(4-methoxy-benzyl)-5-isopropoxy-phenyl]-acetamide

(13) N-[4-Bromo-2-(4-methoxy-benzyl)-5-methylsulfanyl-phenyl]-acetamide

Example VIII

4-Bromo-2-(4-ethyl-benzyl)-5-methoxy-phenylamine

Half-concentrated hydrochloric acid (5 mL) is added to a solution of N-[4-bromo-2-(4-ethyl- benzyl)-5-methoxy-phenyl]-acetamide (2.8 g) in isopropanol (20 mL). The solution is heated at reflux temperature for 8 h and then concentrated under reduced pressure to remove most of the alcohol. Aqueous NaHCC>3 solution is added to the rest and the resulting mixture is extracted twice with ethyl acetate. The combined organic extracts are washed with brine, dried (Na₂SC>₄) and concentrated to give the title compound.

Yield: 2.5 g (quantitative) Mass spectrum (ESI⁺): m/z = 320/322 (Br) [M+H]⁺

The following compounds may be obtained analogously to Example VIII:

(1 ) 4-Bromo-2-(4-ethyl-benzyl)-5-ethoxy-phenylamine

(2) 4-Bromo-5-cyclobutoxy-2-(4-ethyl-benzyl)-phenylamine

(3) 4-Bromo-2-(4-ethyl-benzyl)-5-((S)-tetrahydrofuran-3-yloxy)-phenylamine

(4) 4-Bromo-2-(4-ethyl-benzyl)-5-((R)-tetrahydrofuran-3-yloxy)-phenylamine

(5) 4-Bromo-2-(4-ethyl-benzyl)-5-isopropoxy-phenylamine

(6) 4-Bromo-2-(4-ethyl-benzyl)-5-methylsulfanyl-phenylamine

(7) 4-Bromo-5-methoxy-2-(4-methoxy-benzyl)-phenylamine

(8) 4-Bromo-5-ethoxy-2-(4-methoxy-benzyl)-phenylamine

(9) 4-Bromo-5-cyclobutoxy-2-(4-methoxy-benzyl)-phenylamine

(10) 4-Bromo-2-(4-methoxy-benzyl)-5-((S)-tetrahydrofuran-3-yloxy)-phenylamine

(1 1 ) 4-Bromo-2-(4-methoxy-benzyl)-5-((R)-tetrahydrofuran-3-yloxy)-phenylamine

(12) 4-Bromo-5-isopropoxy-2-(4-methoxy-benzyl)-phenylamine

(13) 4-Bromo-2-(4-methoxy-benzyl)-5-methylsulfanyl-phenylamine

Example IX

4-Bromo-2-(4-ethyl-benzyl)-5-methoxy-benzonitrile

Te/f-butyl nitrite (1.1 ml.) is added to a 60 °C-warm solution of CuCN (0.36 g) in DMSO (3 ml_). Then, a solution of 4-bromo-2-(4-ethyl-benzyl)-5-methoxy-phenylamine (1.0 g) in DMSO is added dropwise and the resulting solution is stirred for 1 h at 60 ⁰C. After cooling to room temperature, the solution is acidified by the addition of 5 N aqueous hydrochloric acid. The resulting mixture is extracted with ethyl acetate and the combined extracts are dried

(Na₂SO₄). After removal of the solvent, the residue is purified by chromatography on silica gel

(cyclohexane/dichloromethane 3:1->1 :3) to give the title compound.

Yield: 0.3 g (29% of theory)

Mass spectrum (ESI⁺): m/z = 347/349 (Br) [M+NH₄]⁺

The following compounds may be obtained analogously to Example IX:

(1 ) 4-Bromo-5-ethoxy-2-(4-ethyl-benzyl)-benzonitrile

(2) 4-Bromo-5-cyclobutoxy-2-(4-ethyl-benzyl)-benzonitrile

(3) 4-Bromo-2-(4-ethyl-benzyl)-5-((S)-tetrahydrofuran-3-yloxy)-benzonitrile

(4) 4-Bromo-2-(4-ethyl-benzyl)-5-((R)-tetrahydrofuran-3-yloxy)-benzonitrile

(5) 4-Bromo-2-(4-ethyl-benzyl)-5-isopropoxy-benzonitrile

(6) 4-Bromo-2-(4-ethyl-benzyl)-5-methylsulfanyl-benzonitrile

(7) 4-Bromo-5-methoxy-2-(4-methoxy-benzyl)-benzonitrile

(8) 4-Bromo-5-ethoxy-2-(4-methoxy-benzyl)-benzonitrile

(9) 4-Bromo-5-cyclobutoxy-2-(4-methoxy-benzyl)-benzonitrile

(10) 4-Bromo-2-(4-methoxy-benzyl)-5-((S)-tetrahydrofuran-3-yloxy)-benzonitrile

(1 1 ) 4-Bromo-2-(4-methoxy-benzyl)-5-((R)-tetrahydrofuran-3-yloxy)-benzonitrile

(12) 4-Bromo-5-isopropoxy-2-(4-methoxy-benzyl)-benzonitrile

(13) 4-Bromo-2-(4-methoxy-benzyl)-5-methylsulfanyl-benzonitrile

Example X

1-Bromo-4-cvano-3-fluoro-5-(4-ethyl-benzyl)-benzene

KOfBu (6.7 g) is added to a flask charged with a stir bar and dry NMP (30 ml.) and chilled to - 10 ⁰C under argon atmosphere. A solution of ethyl (4-ethyl-phenyl)-acetate (5.6 g) and 1- bromo-4-cyano-3,5-difluoro-benzene (6.4 g) in NMP (20 ml.) is added at such a rate that the solution temperature maintains below 10 ⁰C. After stirring for 1 hour at 10 ⁰C, the solution is neutralized with 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts are dried (Na₂SO₄) and the solvent is evaporated. The residue is dissolved in THF (20 ml.) and treated with 1 M aqueous NaOH solution (80 ml_). After stirring overnight at room temperature, the solution is acidified with 4 M HCI solution and extracted with ethyl acetate. The organic extracts are combined and dried (Na₂SO₄) and the solvent is evaporated. The residue is dissolved in DMF (25 ml.) and K₂COs (5.5 g) is added. The resulting mixture is stirred at 100 ⁰C for 1 h. After cooling to room temperature, the mixture is neutralized with 1 M aqueous hydrochloric acid and the resultant mixture is extracted with ethyl acetate. The combined organic extracts are dried (MgSO₄) and the solvent is evaporated. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1 :0->1 :1 ).

Yield: 4.8 g (51 % of theory)

Mass spectrum (ESI⁺): m/z = 317/319 (Br) [M] ⁺

The following compounds may be obtained analogously to Example X:

(1 ) 1-Bromo-4-cyano-5-(4-cyclopropyl-benzyl)-3-fluoro-benzene

The compound is prepared from 4-bromo-2,6-difluoro-benzonitrile and ethyl (4-cyclopropyl- phenyl)-acetate that in turn may be prepared from ethyl (4-bromo-phenyl)-acetate and cyclopropylboronic acid according to Tetrahedron Lett. 2002, 43, 6987-6990.

(2) 1-Bromo-4-cyano-3-(4-methoxy-benzyl)- benzene

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

The compound is prepared from 4-bromo-2-fluoro-benzonitrile and ethyl 4-methoxy-phenyl acetate.

Example Xl

1-Bromo-4-cvano-5-(4-ethyl-benzyl)-3-methylsulfanyl-benzene A solution of 1-bromo-4-cyano-3-fluoro-5-(4-ethyl-phenyl)-benzene (1.20 g) and MeSNa

(0.27 g) in dimethylformamide (5 ml.) is stirred at 100 ⁰C for 4 h. Then, 1 M NaOH solution is added and the resulting mixture is extracted with ethyl acetate. The combined organic phases are washed with 1 M hydrochloric acid and dried (sodium sulfate). The solvent is removed to give the title compound.

Yield: 1.3 g (100% of theory)

Mass spectrum (ESI⁺): m/z = 346/348 (Br) [M+H]⁺

The following compound may be obtained analogously to Example Xl:

(1 ) 1 -Bromo-4-cyano-5-(4-cyclopropyl-benzyl)-3-methylsulfanyl-benzene

Example XII

1 -Bromo-2-(4-ethylbenzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-5-methoxy-benzene A solution of iPrMgCI^*LiCI in THF (1 mol/L, 5.6 ml.) is added dropwise to a -78 °C-cold solution of 4-bromo-5-(4-ethyl-benzyl)-1-iodo-2-methoxy-benzene (2.0 g) in THF (20 ml_). The solution is stirred at -60 ⁰C for 1 h before a solution of 2,3,4, 6-tetrakis-O-(trimethylsilyl)- D-glucopyranone (3.6 g) in tetrahydrofuran (10 ml.) is added. The resulting solution is stirred at -60 ⁰C for 10 min and then warmed to -10 ⁰C. After stirring at -10 ⁰C for 4 h, the reaction is quenched by the addition of a solution of methanesulfonic acid (0.3 ml.) in methanol (40 ml_). The resulting mixture is diluted with aqueous NH₄CI solution and extracted with ethyl acetate. The combined organic extracts are washed with brine and dried (sodium sulfate). After removal of the solvent, the residue is dissolved in methanol (30 ml.) and treated with methanesulfonic acid (0.3 ml_). The solution is stirred at 40 ⁰C for 2 h and at room temperature overnight. Then, the solution is neutralized by the addition of solid NaHCC>3 and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate. The organic solution is washed with water and brine and dried (sodium sulfate). After removal of the solvent, the crude product is submitted to reduction without further purification. Yield: 2.1 g (crude product)

The following compounds may be obtained analogously to Example XII:

(1 ) 2-(4-Ethylbenzyl)-5-methoxy-4-(1 -methoxy-D-glucopyranos-1 -yl)-benzonitrile

4-Bromo-2-(4-ethyl-benzyl)-5-methoxy-benzonitrile is used as the starting material.

(2) 5-Ethoxy-2-(4-ethylbenzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-benzonitrile

4-Bromo-5-ethoxy-2-(4-ethyl-benzyl)-benzonitrile is used as the starting material.

(3) 2-(4-Ethylbenzyl)-5-isopropoxy-4-(1 -methoxy-D-glucopyranos-1 -yl)-benzonitrile

4-Bromo-2-(4-ethyl-benzyl)-5-isopropoxy-benzonitrile is used as the starting material.

(4) 5-Cyclobutoxy-2-(4-ethylbenzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-benzonitrile

4-Bromo-5-cyclobutoxy-2-(4-ethyl-benzyl)-benzonitrile is used as the starting material.

(5) 2-(4-Ethylbenzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-5-((S)-tetrahydrofuran-3-yloxy)- benzonitrile

4-Bromo-2-(4-ethyl-benzyl)-5-((S)-tetrahydrofuran-3-yloxy)-benzonitrile is used as the starting material.

(6) 2-(4-Ethylbenzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-5-((R)-tetrahydrofuran-3-yloxy)- benzonitrile

4-Bromo-2-(4-ethyl-benzyl)-5-((R)-tetrahydrofuran-3-yloxy)-benzonitrile is used as the starting material.

(7) 1 -Bromo-5-ethoxy-2-(4-ethyl-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-benzene

4-Bromo-2-ethoxy-5-(4-ethyl-benzyl)-1-iodo-benzene is used as the starting material.

(8) 1 -Bromo-2-(4-ethyl-benzyl)-5-isopropoxy-4-(1 -methoxy-D-glucopyranos-1 -yl)-benzene

4-Bromo-5-(4-ethyl-benzyl)-1-iodo-2-isopropoxy-benzene is used as the starting material.

(9) 1 -Bromo-5-cyclobutoxy-2-(4-ethyl-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-benzene

4-Bromo-2-cyclobutoxy-5-(4-ethyl-benzyl)-1-iodo-benzene is used as the starting material.

(10) 1 -Bromo-2-(4-ethylbenzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-5-((S)-tetrahydrofuran-3- yloxy)-benzene

4-Bromo-5-(4-ethyl-benzyl)-1-iodo-2-((S)-tetrahydrofuran-3-yloxy)-benzene is used as the starting material

(1 1 ) 1-Bromo-2-(4-ethylbenzyl)-4-(1-methoxy-D-glucopyranos-1-yl)-5-((R)-tetrahydrofuran-3- yloxy)-benzene

4-Bromo-5-(4-ethyl-benzyl)-1-iodo-2-((/?)-tetrahydrofuran-3-yloxy)-benzene is used as the starting material

(12) 1 -Bromo-2-(4-ethyl-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-5-methylsulfanyl- benzene

4-Bromo-5-(4-ethyl-benzyl)-1-iodo-2-methylsulfanyl-benzene is used as the starting material

(13) 2-(4-Ethyl-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-5-methylsulfanyl-benzonitrile

4-Bromo-2-(4-ethyl-benzyl)-5-methylsulfanyl-benzonitrile is used as the starting material

(14) 5-Methoxy-2-(4-methoxy-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-benzonitrile

4-Bromo-5-methoxy-2-(4-methoxy-benzyl)-benzonitrile is used as the starting material.

(15) 5-Ethoxy-2-(4-methoxy-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-benzonitrile

4-Bromo-5-ethoxy-2-(4-methoxy-benzyl)-benzonitrile is used as the starting material.

(16) 5-lsopropoxy-2-(4-methoxy-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-benzonitrile

4-Bromo-5-isopropoxy-2-(4-methoxy-benzyl)-benzonitrile is used as the starting material. (17) 5-Cyclobutoxy-2-(4-methoxy-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-benzonitrile

4-Bromo-5-cyclobutoxy-2-(4-methoxy-benzyl)-benzonitrile is used as the starting material.

(18) 2-(4-Methoxy-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-5-((S)-tetrahydrofuran-3- yloxy)-benzonitrile

4-Bromo-2-(4-methoxy-benzyl)-5-((S)-tetrahydrofuran-3-yloxy)-benzonitrile is used as the starting material.

(19) 2-(4-Methoxy-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-5-((R)-tetrahydrofuran-3- yloxy)-benzonitrile

4-Bromo-2-(4-methoxy-benzyl)-5-((R)-tetrahydrofuran-3-yloxy)-benzonitrile is used as the starting material.

(20) 2-(4-Methoxy-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-5-methylsulfanyl-benzonitrile

4-Bromo-2-(4-methoxy-benzyl)-5-methylsulfanyl-benzonitrile is used as the starting material

Example XIII

6-(4-Ethyl-benzyl)-4-(1-methoxy-D-glucopyranos-1-yl)-2-methylsulfanyl-benzonitrile A 1.7 M solution of fBuLi in pentane (3.6 ml.) cooled to -78 ⁰C is added dropwise to a solution of 1-bromo-4-cyano-5-(4-ethyl-benzyl)-3-methylsulfanyl-benzene (1.1 g) in THF (20 ml.) chilled to -87 ⁰C. After complete addition and additional 15 min of stirring, a solution of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (1.5 g) in tetrahydrofuran (5 ml.) cooled to -78 ⁰C is added via a transfer cannula. The resulting solution is stirred at -70 ⁰C for 2 h. Then, the reaction is quenched with aqueous NH₄CI solution and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with brine and dried (sodium sulfate). After removal of the solvent, the residue is dissolved in methanol (100 ml.) and treated with methanesulfonic acid (4 ml.) to produce the desired more stable anomeric linkage. Hence, the solution is stirred at 50 ⁰C for 5 h and then neutralized by the addition of solid NaHCC>3. The solvent is removed under reduced pressure and the residue is taken up in ethyl acetate. The organic solution is washed with water and brine and dried (sodium sulfate). The solvent is evaporated to give the crude product which is submitted to reduction without further purification. Yield: 1.3 g (99% of theory)

The following compounds may be obtained analogously to Example XIII:

(1 ) 6-(4-Cyclopropyl-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)-2-methylsulfanyl- benzonitrile

(2) 2-(4-Methoxy-benzyl)-4-(1 -methoxy-D-glucopyranos-1 -yl)- benzonitrile

Example XIV

2-(4-Ethyl-benzyl)-4-(1-hvdroxy-2,3,4,6-tetra-O-benzyl-D-glucopyranos-1-yl)-5-methoxy- benzonitrile

A 1.7 M solution of fBuLi in pentane (5.6 mL) is added dropwise to a solution of 4-bromo-2- (4-ethyl-benzyl)-5-methoxy-benzonitrile (1.5 g) in diethylether (20 mL) and THF (10 mL) chilled to -78 ⁰C. After stirring the resulting solution at -78 ⁰C for 1 h, a solution of 2,3,4,6- tetrakis-O-benzyl-D-glucopyranone (2.5 g) in tetrahydrofuran (10 mL) chilled to -70 ⁰C is added via a transfer cannula. The resulting solution is stirred at -75 ⁰C for 3 h, before the reaction is quenched by the addition of aqueous NH₄CI solution. The resulting mixture is extracted with ethyl acetate, the combined extracts are washed with brine and dried

(magnesium sulfate). The solvent is removed to give the crude product that is submitted to reduction without further purification.

Yield: 3.6 g (crude product) The following compound may be obtained analogously to Example XIV:

(1 ) 6-(4-Cyclopropyl-benzyl)-4-(1 -hydroxy-2,3,4,6-tetra-O-benzyl-D-glucopyranos-1 -yl)-2- methylsulfanyl-benzonitrile

Example XV

1-Bromo-2-(4-ethyl-benzyl)-5-methoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)- benzene

A solution of 1-bromo-2-(4-ethyl-benzyl)-5-methoxy-4-(1-methoxy-D-glucopyranos-1-yl)- benzene (2.1 g) and triethylsilane (1.7 ml.) in dichloromethane (20 ml.) and acetonitrile (60 ml.) is cooled to -15 ⁰C. Then, boron trifluoride diethyletherate (1.0 ml.) is added dropwise at such a rate that the solution temperature maintains below -5 ⁰C. The resultant solution is stirred in the cooling bath for another 1 h and then the reaction is quenched by the addition of aqueous NaHCO₃ solution. After stirring the resulting mixture at room temperature for 0.5 h, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine and dried (sodium sulfate). The solvent is removed and the residue is taken up in dichloromethane (20 ml_). Then, pyridine (2.0 ml_), acetic anhydride (2.2 ml.) and 4-dimethylaminopyridine (10 mg) are added in succession. The solution is stirred at ambient temperature for 1 h and then diluted with dichloromethane (100 ml_). The organic solution is washed twice with hydrochloric acid (1 mol/l in water) and dried (sodium sulfate). After evaporation of the solvent under reduced pressure, the residue is recrystallized from ethanol. Yield: 0.6 g (22% of theory)

Mass spectrum (ESI⁺): m/z = 652/654 (Br) [M+NH₄]⁺

The following compounds may be obtained analogously to Example XV:

(1 ) 2-(4-Ethyl-benzyl)-5-methoxy-4-(2_!3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)- benzonitrile

(2) 5-Ethoxy-2-(4-ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzonitrile

(3) 2-(4-Ethyl-benzyl)-5-isopropoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1 -yl)- benzonitrile

(4) 5-Cyclobutoxy-2-(4-ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)- benzonitrile

(5) 2-(4-Ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-3-D-glucopyranos-1-yl)-5-((S)- tetrahydrofuran-3-yloxy)-benzonitrile

(6) 2-(4-Ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-3-D-glucopyranos-1-yl)-5-((R)- tetrahydrofuran-3-yloxy)-benzonitrile

(7) 1 -Bromo-5-ethoxy-2-(4-ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1 -yl)- benzene

(8) 1 -Bromo-2-(4-ethyl-benzyl)-5-isopropoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1 ^■ yl)-benzene

(9) 1 -Bromo-5-cyclobutoxy-2-(4-ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1 ^■ yl)-benzene

(10) 1 -Bromo-2-(4-ethyl-benzyl)-4-(2_!3_!4,6-tetra-O-acetyl-β-D-glucopyranos-1 -yl)-5-((S)- tetrahydrofuran-3-yloxy)-benzene

(1 1 ) 1-Bromo-2-(4-ethyl-benzyl)-4-(2_!3_!4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-5-((R)- tetrahydrofuran-3-yloxy)-benzene

(12) 1 -Bromo-2-(4-ethyl-benzyl)-4-(2_!3_!4,6-tetra-O-acetyl-β-D-glucopyranos-1 -yl)-5- methylsulfanyl-benzene

(13) 2-(4-Ethyl-benzyl)-4-(2,3 AΘ-tetra-O-acetyl-β-D-glucopyranos-i -yl)-5-methylsulfanyl- benzonitrile

(14) 5-Methoxy-2-(4-methoxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1 -yl)- benzonitrile

(15) 5-Ethoxy-2-(4-methoxy-benzyl)-4-(2_!3_!4,6-tetra-O-acetyl-β-D-glucopyranos-1 -yl)- benzonitrile

(16) 5-lsopropoxy-2-(4-methoxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1 -yl)- benzonitrile

(17) 5-Cyclobutoxy-2-(4-methoxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1 -yl)- benzonitrile

(18) 2-(4-Methoxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-3-D-glucopyranos-1 -yl)-5-((S)- tetrahydrofuran-3-yloxy)-benzonitrile

(19) 2-(4-Methoxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-3-D-glucopyranos-1-yl)-5-((R)- tetrahydrofuran-3-yloxy)-benzonitrile

(20) 2-(4-Methoxy-benzyl)-5-methylsulfanyl-4-(2_!3_!4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)- benzonitrile

(21 ) 6-(4-Cyclopropyl-benzyl)-2-methylsulfanyl-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos- 1-yl)-benzonitrile

(22) 2-(4-Methoxy-benzyl)-4-(2_!3_!4_!6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzonitrile

Mass spectrum (ESI⁺): m/z = 571 [M+NH₄]⁺

Example XVI

2-(4-Ethyl-benzyl)-5-methoxy-5-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl)-benzonitrile A solution of 2-(4-ethyl-benzyl)-4-(1 -hydroxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1 -yl)- 5-methoxy-benzonitrile (3.6 g) and triethylsilane (3.6 mL) in dichloromethane (50 ml.) is cooled to -40 ⁰C under argon atmosphere. Then, boron trifluoride diethyletherate (1.7 mL) is added dropwise at such a rate that the solution temperature maintains below -30 ⁰C. The resultant solution is stirred at -20 ⁰C for another 2 h and then the reaction is quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The combined organic layers are washed with brine and dried (magnesium sulfate). The solvent is removed and the residue is treated with 50 °C-warm ethanol for 10 min. The insoluble remainder is separated by filtration and washed twice with ethanol. After drying the title compound is yielded. Yield: 0.7 g (20% of theory) Mass spectrum (ESI⁺): m/z = 791 [M+NH₄]⁺

The following compound may be obtained analogously to Example XVI:

(1 ) 6-(4-Cyclopropyl-benzyl)-4-(2,3,4,6-tetra-O-benzyl-D-glucopyranos-1-yl)-2-methylsulfanyl- benzonitrile

Example XVII

2-(4-Ethyl-benzyl)-5-methoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzonitrile A flask charged with a stir bar, 1-bromo-2-(4-ethylbenzyl)-5-methoxy-4-(2,3,4,6-tetra-O- acetyl-β-D-glucopyranos-1-yl)-benzene (1.6 g), copper(l) cyanide (0.56 g) and NMP (10 ml.) is stirred at 215 ⁰C for 3 h. Then, water is added and the precipitate is separated by filtration. The precipitate is dissolved in ethyl acetate (50 ml.) and filtered over Celite. The filtrate is dried (Na₂SC>₄) and concentrated. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 2:1->1 :2). Yield: 1.1 g (75% of theory) Mass spectrum (ESI⁺): m/z = 583 [M+NH₄]⁺

The following compounds may be obtained analogously to Example XVII:

(1 ) 5-Ethoxy-2-(4-ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzonitrile

(2) 2-(4-Ethyl-benzyl)-5-isopropoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)- benzonitrile

(3) 5-Cyclobutoxy-2-(4-ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-3-D-glucopyranos-1-yl)- benzonitrile

(4) 2-(4-Ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-3-D-glucopyranos-1-yl)-5-((S)- tetrahydrofuran-3-yloxy)-benzonitrile

(5) 2-(4-Ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-3-D-glucopyranos-1-yl)-5-((R)- tetrahydrofuran-3-yloxy)-benzonitrile

(6) 2-(4-Ethyl-benzyl)-5-methylsulfanyl-4-(2_!3_!4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)- benzonitrile

Alternatively, the compounds listed above may be obtained in analogy to the following procedures:

• with zinc, zinc cyanide, Pd₂(dba)₃ ^*CHCI₃, tri-terfoutylphosphonium tetrafluoroborate in NMP according to Tetrahedron Lett. 2005, 46, 1815-1818.

• nickel(ll) cyanide tetrahydrate in NMP at 200 ⁰C in a microwave oven according to J. Org. Chem. 2003, 68, 9122-9125. Example XVIII

2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile At ambient temperature a 1 M solution of BCI₃ in CH₂CI₂ (7.0 ml.) is added dropwise to a solution of 2-(4-ethyl-benzyl)-5-methoxy-4-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1 -yl)- benzonitrile (0.9 g) and pentamethylbenzene (2.6 g) in CH₂CI₂ (25 ml_). After complete addition, the solution is stirred at ambient temperature for 2 h. Then, methanol (5 ml.) is added and the resulting solution is stirred for another 10 min. The solution is concentrated under reduced pressure and the residue is purified by chromatography on silica gel (dichloromethane/methanol 10:1 ->3:1 ). Yield: 0.39 g (82% of theory) Mass spectrum (ESI⁺): m/z = 431 [M+NH₄]⁺

The following compound may be obtained analogously to Example XVIII:

(1 ) 6-(4-Cyclopropyl-benzyl)-4-(D-glucopyranos-1 -yl)-2-methylsulfanyl-benzonitrile

Example XIX

4-(β-D-Glucopyranos-1-yl)-2-(4-hvdroxy-benzyl)-benzonitrile BBr₃ in CH₂CI₂ (15 ml.) is added to a solution of 2-(4-methoxy-benzyl)-4-(2,3,4,6-tetra-O- benzyl-β-D-glucopyranos-1-yl)-benzonitrile (4.27 g) in CH₂CI₂ (20 ml_). The solution is stirred at ca. 50 ⁰C overnight. Then, the solution is cooled in an ice bath and aqueous K₂Cθ3 solution is carefully added. The pH value is adjusted to pH 1 using 1 M hydrochloric acid and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with aqueous NaHCO₃ solution, dried (Na₂SO₄) and concentrated. The residue is taken up in methanol (20 ml.) and 4 M NaOH solution (20 ml.) and the resulting solution is stirred at ambient temperature for 1 h. Then, the solution is acidified using 4 M hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with aqueous NaHCO₃ solution and dried (Na₂SO₄). The solvent is removed under reduced pressure to give the crude product that is used without further purification. Yield: 2.2O g (77% of theory) Mass spectrum (ESI⁺): m/z = 389 [M+NH₄]⁺

The following compounds may be obtained analogously to Example XIX:

(1 ) 5-Ethoxy-4-(β-D-glucopyranos-1 -yl)-2-(4-hydroxy-benzyl)-benzonitrile

(2) 4-(β-D-Glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-5-isopropoxy-benzontirile

(3) 5-Cyclobutoxy-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzonitrile

(4) 4-(β-D-Glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-5-((S)-tetrahydrofuran-3-yloxy)- benzonitrile

(5) 4-(β-D-Glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-5-((R)-tetrahydrofuran-3-yloxy)- benzonitrile

(6) 4-(β-D-Glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-5-methylsulfanyl-benzonitrile

Example XX

4-(β-D-Glucopyranos-1-yl)-2-(4-trifluoromethylsulfonyloxy-benzyl)-benzonitrile N-Phenylbis(trifluoromethanesulfonimide) (3.7 g) is added to a solution of 4-(β-D- glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-benzonitrile (3.5 g), 4-dimethylaminopyridine (0.1 g) and triethylamine (2 ml.) in CH₂Cb (50 ml_). The solution is stirred at ambient temperature for 3 h. Then, the reaction mixture is concentrated, 1 M hydrochloric acid is added, and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with aqueous NaHCO₃ solution and brine and dried (Na₂SO₄). After evaporating the solvent, the residue is purified by chromatography on silica gel (dichloromethane/methanol 1 :0->9:1 ). Yield: 3.3 g (70% of theory) Mass spectrum (ESI⁺): m/z = 521 [M+NH₄]⁺

The following compounds may be obtained analogously to Example XX:

(1 ) 5-Ethoxy-4-(β-D-glucopyranos-1 -yl)-2-(4-trifluoromethylsulfonyloxy-benzyl)-benzonitrile

(2) 4-(β-D-Glucopyranos-1-yl)-5-isopropoxy-2-(4-trifluoromethylsulfonyloxy-benzyl)- benzonitrile

(3) 5-Cyclobutoxy-4-(β-D-glucopyranos-1-yl)-2-(4-trifluoromethylsulfonyloxy-benzyl)- benzonitrile

(4) 4-(β-D-Glucopyranos-1-yl)-5-((S)-tetrahydrofuran-3-yloxy)-2-(4-trifluoromethylsulfonyloxy- benzyl)-benzonitrile

(5) 4-(β-D-Glucopyranos-1-yl)-5-((R)-tetrahydrofuran-3-yloxy)-2-(4-trifluoromethylsulfonyloxy- benzyl)-benzonitrile

(6) 4-(β-D-Glucopyranos-1-yl)-5-methylsulfanyl-2-(4-trifluoromethylsulfonyloxy-benzyl)- benzonitrile

Example XXI

4-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-trifluoromethylsulfonyloxy-benzyl)- benzonitrile

Acetic anhydride (3.1 mL) is added to a solution of 4-(β-D-glucopyranos-1-yl)-2-(4- trifluoromethylsulfonyloxy-benzyl)-benzonitrile (3.3 g), 4-dimethylaminopyridine (80 mg), and pyridine (2.7 mL) in CH₂Cb (30 mL). The solution is stirred at ambient temperature for 3 h and then concentrated under reduced pressure. The residue is taken up in ethyl acetate and the resulting solution is washed twice with 1 M hydrochloric acid and once with aqueous NaHCO₃ solution and brine. Then, the solvent is removed under reduced pressure to give the title compound.

Yield: 4.4 g (100% of theory)

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

The following compounds may be obtained analogously to Example XXI:

(1 ) 5-Ethoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-trifluoromethylsulfonyloxy- benzyl)-benzonitrile

(2) 5-lsopropoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4- trifluoromethylsulfonyloxy-benzyl)-benzontirile

(3) 5-Cyclobutoxy-4-(2,3_!4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4- trifluoromethylsulfonyloxy-benzyl)-benzonitrile

(4) 4-(2_!3_!4_!6-Tetra-O-acetyl-β-D-glucopyranos-1-yl)-5-((S)-tetrahydrofuran-3-yloxy)-2-(4- trifluoromethylsulfonyloxy-benzyl)-benzonitrile

(5) 4-(2_!3_!4,6-Tetra-O-acetyl-β-D-glucopyranos-1-yl)-5-((R)-tetrahydrofuran-3-yloxy)-2-(4- trifluoromethylsulfonyloxy-benzyl)-benzonitrile

(6) 5-Methylsulfanyl-4-(2,3,4,6-tetra-O-acetyl-3-D-glucopyranos-1-yl)-2-(4- trifluoromethylsulfonyloxy-benzyl)-benzonitrile

Example XXII

2-(4-Cvclopropyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzonitrile A flask charged with a stir bar, 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4- trifluoromethylsulfonyloxy-benzyl)-benzonitrile (4.4 g), cyclopropylboronic acid (0.2 g), K₃PO₄ (5.0 g), tricyclohexylphosphine (0.19 g), toluene (80 mL) and water (8 mL) is flushed with argon for 20 min. Then, palladium(ll)acetate (76 mg) is added and the mixture is heated to 1 10 ⁰C. Four portions of cyclopropylboronic acid (4x 0.2 g) are added over the course of the following 4 h, one portion after each hour. After complete addition and stirring for an additional 1.5 h, the mixture is cooled to room temperature and diluted with aqueous NaHCC>3 solution. The resulting mixture is extracted with ethyl acetate and the combined extracts are dried (Na₂SO₄). After removing the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 20:1 ->1 :1 ). Yield: 3.2 g (87% of theory) Mass spectrum (ESI⁺): m/z = 5831 [M+NH₄]⁺

The following compounds may be obtained analogously to Example XXII:

(1 ) 2-(4-Cyclopropyl-benzyl)-5-ethoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1 -yl)- benzonitrile

(2) 2-(4-Cyclopropyl-benzyl)-5-isopropoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)- benzonitrile

(3) 5-Cyclobutoxy-2-(4-cyclopropyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)- benzonitrile

(4) 2-(4-Cyclopropyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-3-D-glucopyranos-1-yl)-5-((S)- tetrahydrofuran-3-yloxy)-benzonitrile

(5) 2-(4-Cyclopropyl-benzyl)-4-(2_!3_!4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-5-((R)- tetrahydrofuran-3-yloxy)-benzonitrile

(6) 2-(4-Cyclopropyl-benzyl)-5-methylsulfanyl-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1- yl)-benzonitrile

Preparation of the end compounds:

Reference Example 1

2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile

Aqueous NaOH solution (0.5 ml_, 4 mol/L) is added to 2-(4-ethyl-benzyl)-5-methoxy-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzonitrile (0.20 g) dissolved in methanol (3 ml.) and THF (3 ml_). The solution is stirred at room temperature for 1 h and then neutralized with hydrochloric acid (1 mol/L). After removal of the organic solvents under reduced pressure, the residue is diluted with aqueous NaHCO₃ solution and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulfate) and the solvent is evaporated. The remainder is purified by HPLC on reversed phase (YMC C18, acetonitrile/water).

Yield: 0.1 O g (70% of theory)

Mass spectrum (ESI⁺): m/z = 431 [M+NH₄]⁺

The following compounds may be obtained analogously to Reference Example 1 :

(1 ) 5-Ethoxy-2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-benzonitrile

(2) 2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-isopropoxy-benzonitrile

(3) 5-Cyclobutoxy-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

(4) 2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-((S)-tetrahydrofuran-3-yloxy)-benzonitrile

(5) 2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-((R)-tetrahydrofuran-3-yloxy)-benzonitrile

(6) 2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-methylsulfanyl-benzonitrile

(7) 2-(4-Cyclopropyl-benzyl)-5-ethoxy-4-(β-D-glucopyranos-1-yl)-benzonitrile

(8) 2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-isopropoxy-benzonitrile

(9) 5-Cyclobutoxy-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile

(10) 2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-5-((S)-tetrahydrofuran-3-yloxy)- benzonitrile

(1 1 ) 2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-((R)-tetrahydrofuran-3-yloxy)- benzonitrile

(12) 2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-methylsulfanyl-benzonitrile

Example 13

6-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-2-methylsulfanyl-benzonitrile

Boron trifluoride diethyletherate (0.7 mL) is added dropwise to a solution of 6-(4-ethyl- benzyl)-4-(1-methoxy-D-glucopyranos-1-yl)-2-methylsulfanyl-benzonitrile (1.3 g, crude product from Example XIII) and triethylsilane (1.20 mL) in dichloromethane (10 ml_) and acetonitrile (40 mL) cooled to -20 ⁰C. The resultant solution is warmed to 5 ⁰C over a period of 2 h and then the reaction is quenched by the addition of aqueous NaHCO₃ solution. The organic solvent is removed under reduced pressure and the residue is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulfate) and the solvent is removed. The residue is purified by HPLC on reversed phase (YMC C18, acetonitrile/water) to give the pure product. Yield: 0.14 g (12% of theory); Mass spectrum (ESI⁺): m/z = 447 [M+NH₄]⁺ In the above described SGLT-2 assay an IC50 = 1.5 nM is determined.

The following compound may be obtained analogously to Example 13:

(14) 6-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-2-methylsulfanyl-benzonitrile

Example 15

2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile

A mixture of 2-(4-ethyl-benzyl)-5-methoxy-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)- benzonitrile (0.80 g) and pyridinium hydrochloride (9.0 g) is stirred at 215 ⁰C for 1 h. After cooling to ambient temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na₂SC>₄) and concentrated. The residue is dissolved in methanol (10 ml.) and treated with 4 M aqueous NaOH solution (2.5 ml_). The solution is stirred at room temperature for 1 h and then acidified using hydrochloric acid (4 mol/L). After removal of the organic solvents, the residue is extracted with ethyl acetate, the combined organic extracts are dried (Na₂SO₄) and the solvent is evaporated. The remainder is purified by HPLC on reversed phase (YMC C18, acetonitrile/water). Yield: 0.25 g (46% of theory); Mass spectrum (ESI⁺): m/z = 417 [M+NH₄]⁺ In the above described SGLT-2 assay an IC50 = 0.3 nM is determined.

The following compound may be obtained analogously to Example 15:

(16) 2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-5-hydroxy-benzonitrile

Some examples of formulations will now be described in which the term "active substance" denotes one or more compounds according to the invention, including the salts thereof. In the case of one of the combinations with one or additional active substances as described previously, the term "active substance" also includes the additional active substances.

Example A

Tablets containing 100 mg of active substance

Composition:

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

Method of Preparation:

The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50⁰C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets. Weight of tablet: 220 mg

Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.

Example B

Tablets containing 150 mg of active substance Composition: 1 tablet contains: active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg

300.0 mg Preparation:

The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45°C, are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture. Weight of tablet: 300 mg die: 10 mm, flat

Example C Hard gelatine capsules containing 150 mg of active substance

Composition:

1 capsule contains: active substance 150.0 mg corn starch (dried) approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420 .O mg

Preparation: The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules. Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule.

Example D

Suppositories containing 150 mg of active substance Composition: 1 suppository contains: active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg

2,000.0 mg Preparation:

After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds. Example E

Ampoules containing 10 mg active substance Composition: active substance 10.0 mg

0.01 N hydrochloric acid q.s. double-distilled water ad 2.0 ml

Preparation: The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.

Example F

Ampoules containing 50 mg of active substance Composition: active substance 50.0 mg

0.01 N hydrochloric acid q.s. double-distilled water ad 10.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCI, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.

Claims

1. A glucopyranosyl-substituted benzyl-benzonitrile derivative selected from the group consisting of:

(1 ) 5-Ethoxy-2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-benzonitrile,

(3) 5-Cyclobutyloxy-2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,

(7) 2-(4-Cyclopropyl-benzyl)-5-ethoxy-4-(β-D-glucopyranos-1-yl)-benzonitrile,

(15) 2-(4-Ethyl-benzyl)-4-(β-D-glucopyranos-1 -yl)-5-hydroxy-benzonitrile,

(16) 2-(4-Cyclopropyl-benzyl)-4-( β-D-glucopyranos-1 -yl)-5-hydroxy-benzonitrile, or a derivative thereof wherein one or more hydroxyl groups of the β-D- glucopyranosyl group are acylated with groups selected from (Ci.i₈-alkyl)carbonyl, (Ci-i₈-alkyl)oxycarbonyl, phenylcarbonyl, phenyl-(Ci_-3-alkyl)-carbonyl, or a pharmaceutically acceptable salt thereof;

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

2. A glucopyranosyl-substituted benzyl-benzonitrile derivative according to claim 1 wherein the hydrogen atom of the hydroxyl group in 6-position of the β-D- glucopyranosyl-group is replaced by a group selected from among (Ci_-6- alkyl)carbonyl, (Ci_-6-alkyl)oxycarbonyl or a pharmaceutically acceptable salt thereof.

3. A glucopyranosyl-substituted benzyl-benzonitrile derivative according to claim 1 wherein the hydrogen atoms of the hydroxyl groups of the β-D-glucopyranosyl-group are not replaced by another group.

4. A glucopyranosyl-substituted benzyl-benzonitrile derivative according to claim 1 wherein the hydrogen atoms of the hydroxyl groups of the β-D-glucopyranosyl-group are replaced by a group selected from among (Ci_-6-alkyl)carbonyl, (Ci_-6- alkyl)oxycarbonyl or a pharmaceutically acceptable salt thereof.

5. Physiologically acceptable salts of the compounds according to one or more of the claims 1 to 4 with inorganic or organic acids.

6. Pharmaceutical composition, comprising a compound according to one or more of the claims 1 to 4 or a physiologically acceptable salt according to claim 5, optionally together with one or more inert carriers and/or diluents.

7. Use of at least one compound according to one or more of the claims 1 to 4 or a physiologically acceptable salt according to claim 5 for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be influenced by inhibiting the sodium-dependent glucose cotransporter SGLT.

8. Use of at least one compound according to one or more of the claims 1 to 4 or a physiologically acceptable salt according to claim 5 for preparing a pharmaceutical composition which is suitable for the treatment or prevention of one or more metabolic disorders.

9. Use according to claim 8, characterised in that the metabolic disorder is selected from the group consisting of type 1 and type 2 diabetes mellitus, complications of diabetes, metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, oedema and hyperuricaemia.

10. Use of at least one compound according to one or more of the claims 1 to 4 or a physiologically acceptable salt according to claim 5 for preparing a pharmaceutical composition for inhibiting the sodium-dependent glucose cotransporter SGLT2.

1 1. Use of at least one compound according to one or more of the claims 1 to 4 or a physiologically acceptable salt according to claim 5 for preparing a pharmaceutical composition for preventing the degeneration of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells.

12. Use of at least one compound according to one or more of the claims 1 to 4 or a physiologically acceptable salt according to claim 5 for preparing a pharmaceutical composition for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat in a patient in need thereof.

13. Use of at least one compound according to one or more of the claims 1 to 4 or a physiologically acceptable salt according to claim 5 for preparing a diuretic and/or antihypertensive.