WO2008034859A1

WO2008034859A1 - Glucopyranosyl-substituted difluorobenzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture

Info

Publication number: WO2008034859A1
Application number: PCT/EP2007/059926
Authority: WO
Inventors: Matthias Eckhardt; Frank Himmelsbach; Peter Eickelmann; Leo Thomas
Original assignee: Boehringer Ingelheim International Gmbh; Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority date: 2006-09-21
Filing date: 2007-09-20
Publication date: 2008-03-27
Also published as: JP5372759B2; JP2010504300A; US7858587B2; WO2008034859A8; EP2074130A1; US20090318547A1; CA2664095A1

Abstract

Glucopyranosyl-substituted difluorobenzyl-benzene derivatives of general formula (I) 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

2

Aim of the invention

The aim of the present invention is to find new pyranosyl-substituted benzene 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 a process 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 glucopyranosyl-substituted difluorobenzyl- benzene derivatives of general formula I

wherein

R¹ denotes hydrogen, fluorine, chlorine, bromine, iodine, Ci_-6-alkyl, C_2-6-alkenyl, C_2-6- alkynyl, C_3-7-cycloalkyl, Cs-z-cycloalkyl-Ci-s-alkyl, hydroxy, Ci_-4-alkoxy, C3-7- cycloalkyloxy, Cs-r-cycloalkenyloxy, Ci_-4-alkylsulfanyl, amino, nitro or cyano,

while the above-mentioned alkyl-, alkenyl-, alkynyl-, cycloalkyl- und cycloalkenyl- residues may be mono- or polysubstituted by fluorine and/or mono- or disubstituted by identical or different substituents L2, and while in the above-mentioned C_5-6-cycloalkyl and C_5-6-cycloalkenyl rings one or two methylene groups may be replaced independently of one another by O, S, CO, SO Or SO₂, and

R² denotes hydrogen, fluorine, chlorine, bromine, hydroxy, Ci_-4-alkyl, Ci_-4-alkoxy, C_3-6- cycloalkyl, C3_6-cycloalkyloxy or cyano, while the alkyl or alkoxy group may be mono- or polysubstituted by fluorine, and

R³ hydrogen, fluorine, chlorine, bromine, iodine, Ci_-6-alkyl, C_2-6-alkynyl, C_2-6-alkenyl,

C_3-7-cycloalkyl, Cs-z-cycloalkyl-Ci-s-alkyl, C₅-₇-cycloalkenyl, C_5-7-cycloalkenyl- d-₃-alkyl, aryl, heteroaryl, Ci_-4-alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, Ci_-4-alkylaminocarbonyl, di-(Ci_₃-alkyl)aminocarbonyl, pyrrolidin-1- ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-

(Ci_-4-alkyl)piperazin-1-ylcarbonyl, hydroxycarbonyl, Ci_-4-alkoxycarbonyl, Ci_-4- alkylamino, di-(Ci_-3-alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1 -yl, 4-(Ci_-4-alkyl)piperazin-1 -yl, Ci_-4-alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, Ci_-4-alkylsulfonylamino, arylsulfonylamino, Ci_-6-alkoxy, C_3-7-cycloalkyloxy, Cs-z-cycloalkenyloxy, aryloxy, heteroaryloxy, Ci_-4-alkylsulfanyl, Ci_-4-alkylsulfinyl, Ci_-4-alkylsulfonyl, Cs-_T-cycloalkylsulfanyl, Cs-r-cycloalkylsulfinyl, Cs-r-cycloalkylsulfonyl, Cs-_T-cycloalkenylsulfanyl, Cs-z-cycloalkenylsulfinyl, Cs-z-cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroarylsulfanyl, heteroarylsulfinyl, heteroarylsulfonyl, amino, hydroxy, cyano and nitro,

while the above-mentioned alkyl-, alkenyl-, alkynyl-, cycloalkyl- und cycloalkenyl- residues may be mono- or polysubstituted by fluorine and/or mono- or disubstituted by identical or different substituents L2, and

while in the above-mentioned C_5-6-cycloalkyl and C_5-6-cycloalkenyl rings one or two methylene groups may be replaced independently of one another by O, S, CO, SO Or SO₂, and

while in the above-mentioned N-heterocycloalkyl rings one methylene group may be replaced by CO or SO₂, and 4

L1 independently of one another are selected from among fluorine, chlorine, bromine, iodine, hydroxy, cyano, Ci_-3-alkyl, difluoromethyl, trifluoromethyl, Ci_-3-alkoxy, difluoromethoxy, trifluoromethoxy, amino, d-3-alkyl-amino and di(Ci_3-alkyl)-amino; and

L2 independently of one another are selected from among fluorine, chlorine, hydroxy, hydroxyl-d-₄-alkyl, Ci_-4-alkoxy, trifluoromethoxy, Ci_-4-alkoxy-Ci.₄-alkyl, cyano, hydroxycarbonyl, (Ci_-4-alkyl)oxycarbonyl, aminocarbonyl, Ci_-4-alkyl, trifluoromethyl, amino, Ci_-4-alkyl-carbonylamino, Ci_-3-alkyl-amino and di(Ci_-3-alkyl)-amino; and

R⁶ , R^7a,

R^7b, R^7c independently of one another have a meaning selected from among hydrogen, (Ci-i₈-alkyl)carbonyl, (Ci-i₈-alkyl)oxycarbonyl, arylcarbonyl and aryl-(Ci_-3-alkyl)- carbonyl, while the aryl-groups may be mono- or disubstituted independently of one another by identical or different groups L1 ;

while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups which may be substituted as defined; and

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

the tautomers, the stereoisomers thereof, the mixtures thereof and the salts thereof.

The compounds of general formula I 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 invention further relates to a process for preparing a pharmaceutical composition according to the invention, characterised in that a compound according to the invention or one of the physiologically acceptable salts thereof is incorporated in one or more inert carriers and/or diluents by a non-chemical method.

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

a) in order to prepare compounds of general formula I which are defined as hereinbefore and hereinafter, a compound of general formula Il

wherein

R' denotes H, Ci_-4-alkyl, (Ci.i₈-alkyl)carbonyl, (Ci.i₈-alkyl)oxycarbonyl, arylcarbonyl and aryl-(Ci_-3-alkyl)-carbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted by halogen;

R^bc, R ,¹8d independently of one another have one of the meanings given hereinbefore and hereinafter for the groups R⁶, R^7a, R^7b, R^7c, or denote a benzyl or allyl group or a R^aR^bR^cSi group or a ketal or acetal group, particularly an alkylidene or arylalkylidene ketal or acetal group, while in each case two adjacent groups R^8a, R^8b, R^8c, R^8d may form a cyclic silyl ketal, ketal or acetal group or a 1 ,2-di(d_-3- alkoxy)-1 ,2-di(Ci_-3-alkyl)-ethylene bridge, while the above-mentioned ethylene bridge forms, together with two oxygen atoms and the two associated carbon atoms of the pyranose ring, a substituted dioxane ring, particularly a 2,3-dimethyl- 2,3-di(Ci_-3-alkoxy)-1 ,4-dioxane ring, and while alkyl, aryl and/or benzyl groups may be mono- or polysubstituted by halogen or Ci_-3-alkoxy, and while benzyl groups may also be substituted by a di-(Ci_-3-alkyl)amino group; and

R^a, R , R^c independently of one another denote C-^-alkyl, aryl or aryl-Ci-₃-alkyl, wherein the aryl or alkyl groups may be mono- or polysubstituted by halogen;

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

and wherein the groups R¹ to R³ and R⁶, R^7a, R^7b, R^7c are defined as hereinbefore and hereinafter; is reacted with a reducing agent in the presence of a Lewis or Brønsted acid, while any protective groups present are cleaved simultaneously or subsequently; or

b) in order to prepare compounds of general formula I wherein R⁶, R^7a, R^7b and R^7c denote hydrogen,

a compound of general formula III

wherein R^8a, R^8b, R^8c, R^8d and R¹ to R³ are defined as hereinbefore and hereinafter, but at least one of the groups R^8a, R^8b, R^8c, R^8d does not denote hydrogen, is hydrolysed, and

if desired a compound of general formula I thus obtained wherein R⁶ denotes a hydrogen atom, is converted by acylation into a corresponding acyl compound of general formula I, and/or

if necessary any protective group used in the reactions described above is cleaved and/or

if desired a compound of general formula I thus obtained is resolved into its stereoisomers and/or

if desired a compound of general formula I thus obtained is converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof.

This invention further relates to a process for preparing compounds of general formula Il 8

wherein

R' denotes H, Ci_-4-alkyl, (Ci.i₈-alkyl)carbonyl, (Ci.i₈-alkyl)oxycarbonyl, arylcarbonyl and aryl-(Ci_₃-alkyl)-carbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted by halogen;

R ,8^bc^c, _D R8¹ d independently of one another has one of the meanings given for the groups R⁶ , R^7a, R^7b, R^7c, or denote a benzyl or allyl group or a R^aR^bR^cSi group or a ketal or acetal group, while in each case two adjacent groups R^8a, R^8b, R^8c, R^8d may form a cyclic silyl ketal, ketal or acetal group or may form, with two oxygen atoms of the pyranose ring, a substituted 2,3-oxydioxane ring, particularly a 2,3-dimethyl- 2,3-di(Ci_-3-alkoxy)-1 ,4-dioxane ring, and while alkyl, aryl and/or benzyl groups may be mono- or polysubstituted by halogen or Ci_-3-alkoxy, and while benzyl groups may also be substituted by a di-(Ci_-3-alkyl)amino group; and

R^a, R , R^c independently of one another denote C-^-alkyl, aryl or aryl-Ci-₃-alkyl, while the alkyl or aryl groups may be mono- or polysubstituted by halogen;

and R¹ to R³, R⁶, R^7a, R^7b, R^7c are defined as hereinbefore and hereinafter,

wherein an organometallic compound (V) which may be obtained by halogen-metal exchange or by inserting a metal in the carbon-halogen bond of a halogen-benzylbenzene compound of general formula IV

wherein Hal denotes Cl, Br and I and R¹ to R³ are defined as hereinbefore and hereinafter, and optionally subsequent transmetallation, is added to a gluconolactone of general formula Vl

wherein R^8a, R^8b, R^8c, R^8d are defined as hereinbefore and hereinafter, and

then the resulting adduct is reacted with water or an alcohol R'-OH, while R' denotes optionally substituted C-^-alkyl, in the presence of an acid, such as for example methanesulfonic acid, sulfuric acid, hydrochloric acid, acetic acid or ammonium chloride, and optionally the product obtained in the reaction with water wherein R' denotes H is converted, in a subsequent reaction, with an alcohol in the presence of an acid to yield the alkoxy derivative or with an acylating agent, such as for example the corresponding acid chloride or anhydride, into the product of formula Il wherein R' denotes (Ci-i₈-alkyl)carbonyl, (Ci--_I8- alkyl)oxycarbonyl, arylcarbonyl or aryl-(Ci_-3-alkyl)-carbonyl, which may be substituted as specified.

The intermediate products listed, particularly those of formula IV, formula Il and formula III, are also a subject of this invention.

Detailed Description of the invention

Unless otherwise stated, the groups, residues and substituents, particularly R¹ to R³, L1 , L2, R⁶, R^7a, R^7b, R^7c, R^8a, R^8b, R^8c, R^8d, are defined as above and hereinafter. 10

If residues, substituents or groups occur several times in a compound, as for example L1 and L2, they may have the same or different meanings.

Some preferred meanings of individual groups and substituents of the compounds according to the invention will be given hereinafter.

Preferred compounds according to the present invention can be described by the formulae 1.1 to l.4:

The two fluorine atoms at the benzyl group which also bears the substituent R³ are preferably located at C-2 and C-6 or C-2 and C-3 relative to the -CH₂-bridge. Therefore compounds according to the formulae 1.1 and 1.2 are particularly preferred. 1 1

The group R¹ preferably denotes fluorine, chlorine, bromine, cyano, Ci_-4-alkyl, Ci_-4-alkyloxy, C_3-7-cycloalkyl or C_3-7-cycloalkyloxy, while in a C_5-6-cycloalkyl ring a methylene group may be replaced by O, and wherein any alkyl group or cycloalkyl ring may be mono- or poly- fluorinated and/or mono- or disubstituted with identical or different substituents L2.

Particularly preferred meanings of R¹ are chlorine, bromine, methyl, ethyl, cyano, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl; particularly methyl, cyano and chlorine.

Preferred meanings of the group R² are hydrogen, fluorine, chlorine, methyl, methoxy, ethoxy and methyl substituted by 1 to 3 fluorine atoms.

Particularly preferred meanings of the group R² are hydrogen, fluorine, methoxy, ethoxy and methyl, particularly hydrogen.

Preferred meanings of the group R³ are chlorine, bromine, iodine, Ci_-4-alkyl, C3_-7-cycloalkyl, hydroxyl, Ci_-4-alkyloxy, C_3-7-cycloalkyloxy, Ci_-4-alkylsulfanyl, Cs-r-cycloalkylsulfanyl, while in a C_5-6-cycloalkyl ring a methylene group may be replaced by O, and wherein any alkyl group and cycloalkyl ring may be mono- or polyfluorinated and/or mono- or disubstituted with identical or different substituents L2. In particular chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, difluoromethyl, trifluoromethyl, 2- hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3- methyl-but-1-yl, 1-hydroxy-1 -methyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, (S)-tetrahydrofuran-3-yloxy, (R)-tetrahydrofuran-3-yloxy, tetrahydropyran-4- yloxy, methylsulfanyl and ethylsulfanyl; more particularly methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methylsulfanyl and ethylsulfanyl.

Preferred meanings of the group L1 independently of one another are selected from among fluorine, chlorine, bromine, cyano, hydroxy, Ci_-3-alkyl, difluoromethyl, trifluoromethyl, Ci_-3- alkoxy, difluoromethoxy, trifluoromethoxy and di(Ci_-3-alkyl)-amino.

Particularly preferred meanings of the group L1 are selected from fluorine, chlorine, hydroxy, trifluoromethyl, ethyl, methoxy, ethoxy and dimethylamino, particularly methyl, ethyl, methoxy, ethoxy and dimethylamino. 12

Preferred meanings of the group L2 independently of one another are selected from among fluorine, hydroxy, hydroxy-Ci_-4-alkyl, Ci_-4-alkoxy, Ci_-4-alkoxy-Ci_-4-alkyl, Ci_-4-alkyl, trifluoromethyl, Ci_-4-alkyl-carbonylamino, hydroxycarbonyl and Ci_-4-alkoxycarbonyl.

Particularly preferred meanings of the group L2 are selected from fluorine, hydroxy, hydroxy- Ci_-4-alkyl, Ci_-4-alkoxy, Ci_-4-alkoxy-Ci_-4-alkyl, Ci_-4-alkyl, hydroxycarbonyl and Ci_-4-alkoxy- carbonyl; particularly hydroxy, hydroxymethyl, methoxymethyl, methoxy, methyl, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl.

The group R⁶ preferably denotes according to the invention hydrogen, (Ci_8-alkyl)oxy- carbonyl, Ci_-8-alkylcarbonyl or benzoyl, particularly hydrogen or (Ci_-6-alkyl)oxycarbonyl or C-ι-₆-alkylcarbonyl, particularly preferably hydrogen, methylcarbonyl, methoxycarbonyl or ethoxycarbonyl, most particularly preferably hydrogen.

The substituents R^7a, R^7b, R^7c preferably represent independently of one another hydrogen, (Ci_-8-alkyl)oxycarbonyl, (Ci-i₈-alkyl)carbonyl or benzoyl, particularly hydrogen, (Ci_-6-alkyl)oxy- carbonyl or (Ci_-8-alkyl)carbonyl, particularly preferably hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl. Most particularly preferably R^7a, R^7b and R^7c represent hydrogen.

The compounds of formula I wherein R⁶, R^7a, R^7b and R^7c according to the invention have a meaning other than hydrogen, for example Ci_-8-alkylcarbonyl, are preferably suitable as intermediate products for the synthesis of compounds of formula I wherein R⁶, R^7a, R^7b and R^7c denote hydrogen.

Particularly preferred compounds of general formula I are selected from among formulae 1.2a to I.2L, particularly 1.2b, l.2e, l.2h and 1.2k; even more preferably l.2b and l.2e:

13

14

15

while the groups R¹ to R³ and R⁶ and R^7a, R^7b, R^7c have one of the meanings given previously, particularly have one of the given meanings specified as being preferred; and particularly

R¹ denotes fluorine, chlorine, bromine, cyano, Ci_-4-alkyl, Ci_-4-alkyloxy, C_3-7-cycloalkyl or

C_3-7-cycloalkyloxy, while in a C_5-6-cycloalkyl ring a methylene group may be replaced by O, and wherein any alkyl group and cycloalkyl ring may be mono- or poly- fluorinated and/or mono- or disubstituted with identical or different substituents L2; even more preferably R¹ denotes chlorine, bromine, methyl, ethyl, cyano, methoxy, ethoxy, cyclopropyl, cyclobutyl; and

R² denotes hydrogen, fluorine, methoxy, ethoxy or methyl, particularly hydrogen; and

R³ denotes chlorine, bromine, iodine, Ci_-4-alkyl, C_3-7-cycloalkyl, hydroxyl, Ci_-4-alkyloxy, C_3-7-cycloalkyloxy, Ci_-4-alkylsulfanyl, Cs-r-cycloalkylsulfanyl, while in a C_5-6-cycloalkyl ring a methylene group may be replaced by O; and wherein any alkyl group and cycloalkyl ring may be mono- or polyfluorinated and/or mono- or disubstituted with identical or different substituents L2; even more preferably R³ denotes chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec-butyl, iso-butyl, tert- butyl, difluoromethyl, trifluoromethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy- propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1- methyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, (S)-tetrahydrofuran-3-yloxy, (R)-tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, methylsulfanyl and ethylsulfanyl;

L2 independently of one another are selected from among fluorine, hydroxy, hydroxy-

Ci_-4-alkyl, Ci_-4-alkoxy, Ci_-4-alkoxy-Ci_-4-alkyl, Ci_-4-alkyl, trifluoromethyl, Ci_-4-alkyl- carbonylamino, hydroxycarbonyl and Ci_-4-alkyloxycarbonyl; particularly hydroxy, 16

hydroxymethyl, methoxymethyl, methoxy, methyl, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl; and

R⁶ denotes hydrogen, (Ci_-6-alkyl)oxycarbonyl, (Ci_-6-alkyl)carbonyl or benzoyl, particularly hydrogen, methylcarbonyl, methoxycarbonyl or ethoxycarbonyl, most particularly preferably hydrogen; and

R^7a, R^7b, R^7c independently of one another represent hydrogen, (Ci_-6-alkyl)oxycarbonyl, (Ci_-8- alkyl)carbonyl or benzoyl, particularly hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl, particularly preferably hydrogen;

including the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.

The compounds of general formula I specified in the experimental section that follows, and the derivatives thereof, wherein R⁶ has a meaning according to the invention other than hydrogen, particularly wherein R⁶ denotes acetyl, ethoxycarbonyl or methoxycarbonyl, including the tautomers, the stereoisomers thereof and the mixtures thereof, are preferred according to another variant of this invention.

In the processes according to the invention the groups R¹, R², and R³ preferably have the meanings specified hereinbefore as being preferred. Moreover R' preferably denotes H, Ci_-3- alkyl or benzyl, particularly H, ethyl or methyl. The groups R^8a, R^8b, R^8c and R^8d independently of one another preferably denote H, d-₄-alkylcarbonyl or benzyl, particularly H, methylcarbonyl, ethylcarbonyl or benzyl.

The invention also relates to compounds of general formula IV

wherein Hal denotes chlorine, bromine or iodine and the groups R¹, R² and R³ are as hereinbefore defined, as intermediate products or starting materials in the synthesis of the compounds according to the invention. Particularly preferably, the groups R¹, R² and R³ have the meanings given following formulae 1.2a to l.2f.

The invention also relates to compounds of general formula Il 17

wherein R', R^8a, R^8b, R^8c, R^8d, R¹, R² and R³ are defined as hereinbefore and hereinafter; particularly wherein R' denotes H, d-₃-alkyl or benzyl, particularly H, ethyl or methyl; and the groups R^8a, R^8b, R^8c and R^8d independently of one another represent H, Ci_-4-alkylcarbonyl, allyl or benzyl, particularly H, methylcarbonyl, ethylcarbonyl or benzyl and the groups R¹, R² and R³ are as hereinbefore defined. These compounds may serve as intermediate products or starting materials in the synthesis of the compounds according to the invention. Particularly preferably the groups R¹, R² and R³ have the meanings given following formulae l.2a to l.2L

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, particularly F, Cl and Br.

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 C_2-n-alkynyl, wherein n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C≡C triple bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl etc. Unless otherwise stated alkynyl groups are connected to the remainder of the molecule via the C atom in position 1. Therefore terms such as 1-propynyl, 2-propynyl, 1-butynyl, etc. are equivalent to the terms 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, etc.. This also applies analogously to C₂-_n-alkenyl groups. 18

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 term C₃-_n-cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, decalinyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc. Preferably the term C_3-n- cycloalkyl denotes saturated monocyclic groups.

The term C₅-_n-cycloalkenyl denotes a C₅-_n-cycloalkyl group which is as hereinbefore defined and additionally has at least one unsaturated C=C double bond.

The term Cs-_n-cycloalkylcarbonyl denotes a C_3-n-cycloalkyl-C(=O) group wherein C_3-n-cycloalkyl is as hereinbefore defined.

The term tri-(Ci_-4-alkyl)silyl comprises silyl groups which have identical or two or three different alkyl groups.

The term di-(Ci_3-alkyl)amino comprises amino groups which have identical or two different d-₃-alkyl groups.

The term aryl preferably denotes naphthyl or phenyl, more preferably phenyl.

The term heteroaryl denotes a 5- or 6-membered monocyclic aromatic ring possessing one to four identical or different heteroatoms selected from the group comprising N, O and S. Heteroaryl denotes preferably a pyrrolyl, furanyl, thienyl, pyridyl or tetrazolyl group, or 19

a pyrrolyl, furanyl, thienyl or pyridyl group wherein one or two methine groups are replaced in each case by a nitrogen atom.

The nomenclature in structural formulas used above and hereinafter, in which a bond of a substituent of a cyclic group, as e.g. a phenyl ring, is shown towards the centre of the cyclic group, denotes, unless otherwise stated, that this substituent may be bound to any free position of the cyclic group bearing an H atom.

The compounds according to the invention may be obtained using methods of synthesis known in principle. Preferably the compounds are obtained by the following methods according to the invention which are described in more detail hereinafter.

The glucose derivatives of formula Il according to the invention may be synthesised from D- gluconolactone or a derivative thereof by adding the desired benzylbenzene compound in the form of an organometallic compound (Scheme 1 ).

Scheme 1 : Addition of an Organometal Compound to a Gluconolactone

Vl

The reaction according to Scheme 1 is preferably carried out starting from a halogenated benzylbenzene compound of general formula IV, wherein Hal denotes chlorine, bromine, or iodine. The Grignard or lithium reagent of benzylbenzene (V) may be prepared from the corresponding chlorinated, brominated or iodinated benzylbenzene IV either via a so-called halogen-metal exchange reaction or by inserting the metal into the carbon-halogen bond. The halogen-metal exchange to synthesize the corresponding lithium compound V may be carried out for example with an organolithium compound such as e.g. n-, sec- or tert- butyllithium. The analogous magnesium compound may also be generated by a halogen- 20

metal exchange with a suitable Grignard reagent such as e.g. isopropyl- or sec- butylmagnesium bromide or chloride or diisopropyl- or di-sec-butylmagnesium without or in the presence of an additional salt such as e.g. lithium chloride that may accelerate the metalation process; the specific transmetalating organomagnesium compound may 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 quoted therein). In addition, ate complexes of organomagnesium compounds resulting from combining e.g. butylmagnesium chloride or bromide or isopropylmagnesium chloride or bromide and butyllithium, may be employed as well (see e.g. Angew. Chem. 2000, 112, 2594-2596 and Tetrahedron Lett. 2001 , 42, 4841-4844 and references quoted therein). The halogen-metal exchange reactions are preferably carried out between 40 ⁰C and -100 ⁰C, particularly preferably between 10 ⁰C and -80 ⁰C, in an inert solvent or mixtures thereof, such as for example diethylether, dioxane, 1 ,2-dimethoxyethane, tetrahydrofuran, toluene, hexane, dimethylsulfoxide, dichloromethane or mixtures thereof. The magnesium or lithium derivatized compounds thus obtained may optionally be transmetalated with metal salts such as e.g. cerium trichloride, zinc chloride or bromide, indium chloride or bromide, to form alternative organometal compounds (V) suitable for addition. Alternatively, the organometal compound V may also be prepared by inserting a metal into the carbon-halogen bond of the haloaromatic compound IV. Lithium or magnesium are suitable elemental metals for this transformation. The insertion can be achieved in solvents such as e.g. diethylether, dioxane, 1 ,2-dimethoxyethane, tetrahydrofuran, toluene, hexane, dimethylsulfoxide and mixtures thereof at temperatures ranging from -80 to 100 ⁰C, preferably at -70 to 40 ⁰C. In cases in which no spontaneous reaction takes place prior activation of the metal might be necessary such as e.g. treatment with 1 ,2-dibromoethane, iodine, trimethylsilylchloride, acetic acid, hydrochloric acid and/or sonication. The addition of the organometal compound V to gluconolactone or derivatives thereof (Vl) is preferably carried out at temperatures between 40 ⁰C and -100 ⁰C, particularly preferably at 0 to -80 ⁰C, in an inert solvent or mixtures thereof, to obtain the compound of formula II. All foregoing reactions may be performed in air though execution under inert gas atmosphere such as argon and nitrogen is preferred. The metalation and/or coupling reaction may also be carried out in microreactors and/or micromixers which enable high exchange rates; for example analogously to the processes described in WO 2004/076470. Suitable solvents for the addition of the metalated phenyl group V to the appropriately protected gluconolactone Vl are e.g. diethylether, dimethoxyethane, benzene, toluene, methylene chloride, hexane, tetrahydrofuran, dioxane, Λ/-methylpyrrolidone and mixtures thereof. The addition reactions may be carried out without any further adjuvants or in the case of sluggishly reacting coupling partners in the presence of a promoter such as e.g. BF₃OEt₂ or Me₃SiCI (see M. Schlosser, Organometallics in Synthesis, John Wiley & Sons, Chichester/New 21

York/Brisbane/Toronto/Singapore, 1994). Preferred definitions of the substituents R⁸ in Scheme 1 are benzyl, substituted benzyl, allyl, trialkylsilyl, particularly preferably trimethylsilyl, triisopropylsilyl, allyl, 4-methoxybenzyl and benzyl. If two adjacent substituents R⁸ are linked together, these two substituents are preferably part of a benzylideneacetal, 4- methoxybenzylideneacetal, isopropylketal or constitute a dioxane with 2,3-dimethoxy- butylene which is linked via the 2 and 3 positions of the butane with the adjacent oxygen atoms of the pyranose. The group R' preferably denotes hydrogen, Ci_-4-alkyl, Ci_-4- alkylcarbonyl or d-₄-alkyloxycarbonyl, particularly preferably hydrogen, methyl or ethyl. The group R' is introduced after the addition of the organometallic compound V or a derivative thereof to the gluconolactone Vl. If R' equals hydrogen or d-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' may also be attached after preparation of the hydrogen compound II. During installing R' the protective groups R⁸ may be cleaved if labile under the reaction conditions employed resulting in the corresponding protonated compound, i.e. compound Il in which R⁸ equals H.

The synthesis of haloaromatic compound of formula IV may be carried out using standard transformations in organic chemistry or at least methods known from the specialist literature in organic synthesis (see inter alia J. March, Advanced Organic Reactions, Reactions, Mechanisms, and Structure, 4th Edition, John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1992 and literature cited therein). More specifically, the use of transition metals and organo metal compounds for the synthesis of aromatic compounds has been detailed in different monographs (see e.g. L. Brandsma, S. F. Vasilevsky, H. D. Verkruijsse, Application of Transition Metal Catalysts in Organic Synthesis, Springer-Verlag, Berlin/Heidelberg, 1998; M. Schlosser, Organometallics in Synthesis, John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1994; P.J. Stang, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1997 and references quoted therein). The synthesis strategies described in the following provide a demonstration of this, by way of example. In addition, the aglycon part may also be assembled with the pyranose moiety already present using the same synthetic approaches. 22

Scheme 2: Synthesis of the Diarylketone Fragment

Scheme 2 shows the preparation of a precursor compound that may serve for the synthesis of the haloaromatic compound of formula IV starting from a benzoylchloride and a second aromatic group applying Friedel-Crafts acylation conditions or variations thereof. This classic reaction has a wide substrate scope and is commonly carried out in the presence of a catalyst which is used in catalytic or stoichiometric amounts, such as e.g. AICI3, FeCl3, iodine, iron, ZnCI₂, sulphuric acid, or trifluoromethanesulphonic acid. Instead of the benzoyl chloride the corresponding carboxylic acid, anhydride, ester or benzonitrile may be used as well. The reactions are preferentially carried out in chlorinated hydrocarbons such as e.g. dichloromethane and 1 ,2-dichloroethane at temperatures from -30 to 120⁰C, preferably at 30 to 100⁰C. However, solvent-free reactions or reactions in a microwave oven are also possible.

23

Scheme 3: Reduction of Diarylketones and Diarylmethanols to Diarylmethanes

reduction

conversion to leaving group reduction

reduction

X = leaving group e g IV

Cl, Br, I, OSO₂R, OOCR, OOCOR

In Scheme 3 the substituent R denotes Ci_-3-alkyl or aryl. Starting from the diarylketone or diarylmethanol the diarylmethane is accessible in one or two reaction steps. The diarylketone may be reduced to the diarylmethane in two steps via the corresponding diphenylmethanol or in one step. In the two-step variant the ketone is reduced with a reducing agent such as for example a metal hydride such as e.g. NaBH₄, LiAIH₄ or iBu₂AIH to form the alcohol. The resulting alcohol can be converted in the presence of a Lewis acid such as for example BF₃OEt₂, InCI₃ or AICI₃ or Brønsted acid such as for example hydrochloric acid, sulfuric acid, trifluoroacetic acid, or acetic acid with a reducing agent such as e.g. Et₃SiH, NaBH₄, or Ph₂SiCIH to the desired diphenylmethane. The one-step process starting from the ketone to obtain the diphenylmethane may be carried out e.g. with a silane such as e.g. Et₃SiH, a borohydride such as e.g. NaBH₄ or an aluminum hydride such as LiAIH₄ in the presence of a Lewis or Brønsted acid such as for example BF₃OEt₂, tris(pentafluorophenyl)borane, trifluoroacetic acid, hydrochloric acid, aluminum chloride or InCI₃. The reactions are preferably carried out in solvents such as e.g. halogenated hydrocarbons such as dichloro- methane, toluene, acetonitrile, or mixtures thereof at temperatures of -30 to 150⁰C, preferably at 20 to 100⁰C. Reductions with hydrogen in the presence of a transition metal catalyst such as e.g. Pd on charcoal are another possible method of synthesis. Reductions 24

according to Wolff-Kishner or variants thereof are also possible. The ketone is firstly converted with hydrazine or a derivative thereof, such as e.g. 1 ,2-bis(tert-butyldimethyl- silyl)hydrazine, into the hydrazone which breaks down under strongly basic reaction conditions and heating to form the diphenylmethane and nitrogen. The reaction may be carried out in one reaction step or after isolation of the hydrazone or a derivative thereof in two separate reaction steps. Suitable bases include e.g. KOH, NaOH or KOtBu in solvents such as e.g. ethyleneglycol, toluene, DMSO, 2-(2-butoxyethoxy)ethanol or tert-butanol; solvent-free reactions are also possible. The reactions may be carried out at temperatures between 20 to 250⁰C, preferably between 80 to 200⁰C. An alternative to the basic conditions of the Wolff-Kishner reduction is the Clemmensen reduction which takes place under acidic conditions, which may also be used here. The alcohol function in diarylmethanol may also first be transformed into a better leaving group such as e.g. chloride, bromide, iodide, acetate, carbonate, phosphate, or sulfate; the subsequent reduction step to form the diarylmethane is widely described in the organic chemistry literature.

25

Scheme 4: Synthesis of Diarylmethane Unit and Possible Precursor Compounds thereof

Hal = Cl, Br, I, OSO₂CF₃, OSO₂p-Tol or H

halogen-metal or hydrogen-metal step 1 exchange

M

U = Cl, Br, I, OOCAIk, OOCOAIk, OPO(OAIk)₂

IV

Y = Cl, Br, I, OSO₂CF₃, OSO₂p-Tol or

In Scheme 4 the term "AIk" denotes Ci_-3-alkyl and each substituent R is independently selected from each other from the group consisting of H, d-3-alkyl and Ci_3-alkoxy. Scheme 4 delineates the synthesis of diarylmethanes and possible precursor compounds thereof starting from a metalated phenyl group. Lithium or magnesium substituted aromatic 26

compounds may be synthesized from chlorinated, brominated, or iodinated aromatics by a halogen-metal exchange reaction with an organolithium compound such as e.g. n-, sec- or tert-butyllithium or a suitable Grignard reagent such as e.g. isopropyl- or sec- butylmagnesium bromide or chloride or diisopropyl- or di-sec-butylmagnesium without or in the presence of an additional salt such as e.g. lithium chloride that may accelerate the metalation process; the specific transmetalating organomagnesium compound may also be generated in situ from suitable precursors. In addition, ate complexes of organomagnesium compounds resulting from combining e.g. butylmagnesium chloride or bromide or isopropylmagnesium chloride or bromide and butyllithium, may be employed as well. Insertion of the elemental metal into the halogen-carbon bond might be also applicable. The corresponding boron substituted compound such as e.g. boronic acid, boronic acid ester, or dialkylarylborane, is accessible from these metalated phenyl groups by reaction with a boron electrophile such as e.g. boronic acid ester or a derivative thereof. In addition, the borylated aromatic compound may also be prepared from the corresponding halogenated or pseudohalogenated precursor and a diboron or borane compound through a transition metal, e.g. palladium, catalyzed reaction (see e.g. Tetrahedron Lett. 2003, p. 4895-4898 and references quoted therein). Alternatively, the lithium or magenesium derivatized phenylmetal compounds may be accessed by replacement of a hydrogen atom using a lithium or magnesium base. Employable bases may be e.g. n-, sec- or tert-butyllithium, butyl or i- propylmagnesium halide, 2,2,6,6-tetramethylpiperidino lithium or magnesiumhalide, lithium or magnesium diisopropylamide that may be used in combination with additional salts such as e.g. lithium chloride or bases such as e.g. potassium t-butoxide (see e.g. Angew. Chem. 2006, 118, 3024-3027 and Tetrahedron Lett. 2004, 45, 6697-6701 and references cited therein). The lithium or magnesium substituted phenyl compounds add to benzaldehydes (step 3) and benzoic acids or derivatives thereof (step 4) such as benzoic acid esters, benzamides such as e.g. of the Weinreb type, benzonitriles, or benzoyl chlorides. These reactions may principally be conducted without an additional transition metal catalyst or transmetalation to another metal such as e.g. cerium, indium or zinc; sometimes the use of one of the latter alternatives is advantageous. Aryl boronic acids can be added to benzaldehydes by means of a rhodium catalyst furnishing the respective diarylmethanol (see e.g. Adv. Synth. Catal. 2001 , p. 343-350 and references quoted therein). Moreover, arylboronic acids, esters thereof, dialkylarylboranes, or aryltrifluoroborates may be coupled with benzoyl chlorides mediated by a transition metal such as e.g. palladium, a complex or a salt thereof delivering diarylketones. Metalated phenyl groups can be reacted with benzyl electrophiles such as benzyl chlorides, bromides, or iodides affording diarylmethanes.

Lithium or magnesium derivatized phenyl compounds are reacted favorably but not always necessarily in the presence of a transition metal such as e.g. copper, iron, or palladium (see 27

e.g. Org. Lett. 2001 , 3, 2871-2874 and references quoted therein). Transmetallation from lithium or magnesium to e.g. boron, tin, silicon, or zinc furnishes e.g. the corresponding aromatic boronic acids, stannanes, silanes or zinc compounds, respectively, that may undergo coupling with benzyl electrophiles, e.g. benzyl halogenides, carbonates, phosphates, sulfonates, or carboxylic esters. The reaction is conducted 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. 4875-4878 and references cited therein).

In order to prepare compounds of general formula I, in process a) according to the invention, a compound of general formula Il

wherein R', R¹ to R³ are as hereinbefore defined and

R^8a, R^8b, R^8c, R^8d are as hereinbefore defined and independently of one another represent for example acetyl, pivaloyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, trialkylsilyl, allyl, benzyl or substituted benzyl or in each case two adjacent groups R^8a, R^8b, R^8c, R^8d are combined a benzylideneacetal, diisopropylsilylideneketal or isopropylideneketal or a 2,3- dimethoxy-butylene group which is linked via position 2 and 3 of the butylene group to the oxygen atoms of the pyranose ring and forms with them a substituted dioxane,

which may be obtained as hereinbefore described, is reacted with a reducing agent in the presence of a Lewis or Brønsted acid.

Suitable reducing agents for the reaction include for example silanes, such as triethyl-, tripropyl-, triisopropyl- or diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, boranes, lithium aluminium hydride, diisobutylaluminium hydride or samarium iodide. The reductions are carried out without or in the presence of a suitable Brønsted acid, such as e.g. hydrochloric acid, toluenesulphonic acid, trifluoroacetic acid or acetic acid, or Lewis acid, such as e.g. boron trifluoride etherate, trimethylsilyltriflate, titanium tetrachloride, 28

tin tetrachloride, scandium triflate or zinc iodide. Depending on the reducing agent and the acid used the reaction may 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 temperatures between -60⁰C and 120⁰C. One particularly suitable combination of reagents consists for example of triethylsilane and boron trifluoride etherate, which is conveniently used in acetonitrile or dichloromethane at temperatures of -60°C and 60⁰C. Moreover, hydrogen may be used in the presence of a transition metal catalyst, such as e.g. palladium on charcoal or Raney nickel, in solvents such as tetrahydrofuran, ethyl acetate, methanol, ethanol, water or acetic acid, for the transformation described.

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

wherein R¹ to R³ are as hereinbefore defined and

R^8a to R^8d denote one of the protective groups defined hereinbefore, such as e.g. an acyl, allyl, arylmethyl, acetal, ketal or silyl group, and which may be obtained for example by reduction from the compound of formula Il as hereinbefore described, the protective groups are cleaved.

Any acyl protecting group used is cleaved 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 base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120°C, preferably at temperatures between 10 and 100°C. A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120⁰C or by 29

treating with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50⁰C.

Any acetal or ketal protecting group used is cleaved 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 aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120⁰C, preferably at temperatures between 10 and 100⁰C.

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

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

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

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

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

For example, a protecting group for an ethynyl group may be trialkylsilyl such as e.g. trimethylsilyl and triisopropylsilyl or dialkyl-hydroxymethyl such as e.g. 2-hydroxyisoprop-2-yl. 30

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

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

Moreover, the compounds of general formula I 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 of general formula I obtained 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 of general formula I 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 a (+)-or (-)-menthyloxycarbonyl.

Furthermore, the compounds of formula I 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, 31

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.

The compounds according to the invention are advantageously 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 2004/013118, WO 2004/052902, WO 2004/052903, WO 2005/092877, WO 06/010557, WO 06/018150, WO 06/037537, WO 06/089872, WO 2006/064033 and US application US 2003/0114390.

As already mentioned, the compounds of general formula I 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, 32

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°C, 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°C, 5% CO₂, the cells are washed again with 250 μl of PBS (20⁰C) and then lysed by the addition of 25 μl of 0.1 N NaOH (5 min. at 37°C). 200 μl of MicroScint20 (Packard) are added to each well and incubation is continued for a further 20 min at 37°C. 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.

The compounds of general formula I according to the invention may for example have EC50 values below 1000 nM, particularly below 200 nM, most 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 33

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. 34

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), DPPIV inhibitors (e.g. LAF237, MK-431 ), 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 35

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 of formula I 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. 36

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 term "ambient temperature" means temperatures in the range from 20 to 25°C. The Examples that follow are intended to illustrate the present invention without restricting it:

Preparation of the starting compounds:

Example I

4-Bromo-2-bromomethyl-1-chloro-benzene

N-bromosuccinimide (4.0 g) is slowly added to a solution of 4-bromo-1-chloro-2- hydroxymethyl-benzene (5.0 g) and triphenylphosphine (5.9 g) in tetrahydrofuran (50 ml.) chilled to 5 ⁰C. After 1 h stirring at ambient temperature the precipitate is filtered off, and the solvent is removed in vacuo. The residue is purified by chromatography on silica gel

(cyclohexane/ethyl acetate 50:1 ).

Yield: 4.9 g (76% of theory)

Mass spectrum (El): m/z = 282/284/286/288 (2Br+CI) [M]⁺

Example Il

4-Bromo-2-chloromethyl-1-chloro-benzene 37

A solution of 4-bromo-1-chloro-2-hydroxymethyl-benzene (40.0 g) and thionyl chloride (60 mL) in dichloromethane (150 mL) is stirred at 45-50 ⁰C for 5 h. Then the solvent and the excess reagent is removed in vacuo.

Yield: 43.2 g (100% of theory)

Mass spectrum (El): m/z = 238/240/242/244 (Br+2CI) [M]⁺

Example

4-Bromo-1-chloro-2-phenoxymethyl-benzene To a mixture of phenol (7.1 g) and potassium carbonate (11.1 g) in ethanol (100 mL) is added 4-bromo-2-bromomethyl-1-chloro-benzene (19.5 g). The mixture is stirred at ambient temperature over night. The ethanol is evaporated, and water is added to the residue. The resulting mixture is extracted with ethyl acetate, the combined extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 70:30). Yield: 16.8 g (82% of theory) Mass spectrum (ESI⁺): m/z = 296/298/300 (Br+CI) [M]⁺

Example IV

1 -Chloro-4-(1 -methoxy-D-glucopyranos-1 -yl)-2-(phenoxymethyl)-benzene A solution of 4-bromo-1-chloro-2-phenoxymethyl-benzene (14.40 g) in dry tetrahydrofuran (120 mL) is cooled to -78 ⁰C under argon. n-Butyl lithium (33.5 mL of a 1.7 M solution in hexane) is slowly added to the cooled solution. The resulting solution is stirred for 45 min at -78 ⁰C and then a -78 °C-cold solution of 2,3,4, 6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (25.10 g, ca. 90% pure) in tetrahydrofuran (80 mL) is added through a transfer needle. The resulting solution is stirred for 1 h at -78 ⁰C, and then aqueous acetic acid (150 mL of a 1% solution in water) is added. After warming to room temperature, the resultant reaction mixture 38

is extracted with ethyl acetate, the combined organic extracts are washed with brine and dried over sodium sulfate. After removal of the solvent the residue is dissolved in methanol (90 ml.) and treated with methanesulfonic acid (1 ml_). The solution is stirred at room temperature over night and then neutralized with triethylamine. The solvent is removed under reduced pressure and the residue is dissolved in 250 ml. ethyl acetate. The organic solution is washed with water and brine and dried over sodium sulfate. After removal of the solvent, the crude product is submitted to reduction without further purification. Yield: 17.20 g (crude product) Mass spectrum (ESI⁺): m/z = 433/435 (Cl) [M+Na]⁺

Example V

1-Chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene A solution of 1-chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene (17.20 g) and triethylsilane (13.6 ml.) in dichloromethane (120 ml.) and acetonitrile (360 ml.) is cooled to -10 ⁰C. Then boron trifluoride etherate (8.4 ml.) is added dropwise so that the solution temperature maintained below 0 ⁰C. The resultant solution is stirred for 0.5 h in an ice bath and then warmed to room temperature. Aqueous sodium hydrogen carbonate solution is added, and the resulting mixture is stirred 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 over sodium sulfate. The solvent is removed, and the residue is taken up in dichloromethane (200 ml_). The solution is cooled in an ice-bath and pyridine (36 ml_), acetic anhydride (40 ml.) and 4-dimethylaminopyridine (0.5 g) are added. The resultant solution is stirred for 1 h at ambient temperature and then diluted with dichloromethane (100 ml_). The organic solution is washed twice with hydrochloric acid (1 mol/l in water) and dried over sodium sulfate. Yield: 7.3O g (32% of theory) Mass spectrum (ESI⁺): m/z = 566/568 (Cl) [M+NH₄]⁺ 39

Example Vl

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

To a solution of 1-chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-phenyloxymethyl-benzene

(6.04 g) in acetic acid (200 ml.) is added hydrobromic acid (200 ml_, 33% in acetic acid). The solution is stirred for 2 h at ambient temperature and then cooled in an ice-bath. The reaction mixture is neutralized with chilled aqueous saturated potassium carbonate solution, and the resultant mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate, and the solvent is removed in vacuo. The residue is taken up in ethyl aceate/cyclohexane (1 :3), and the precipitate is separated by filtration and dried at 50 ⁰C to give the pure product.

Yield: 4.50 g (76% of theory)

Mass spectrum (ESI⁺): m/z = 552/554/556 (Br+CI) [M+NH₄]⁺

Example VII

2-Chloro-5-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzaldehvde

To a solution of 1-chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-bromomethyl- benzene (2.0 g) in acetonitrile (20 ml.) is added N-methylmorpholine-N-oxide (0,47 g). The resulting solution is stirred at ambient temperature for 2 h before more N-methylmorpholine- N-oxide (0,20 g) is added. After stirring at ambient temperature overnight, the solvent is removed under reduced pressure and the residue is filtered over silica gel eluting with dichloromethane. Yield: 1.21 g (69% of theory) Mass spectrum (ESI⁺): m/z = 488/490 (Cl) [M+NH₄]⁺ 40

Example VIII

2,6-Difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)anisol

To a solution of 4-bromo-2,6-difluoro-anisol (3.0 g) in dry dioxane (50 mL) and under argon atmosphere is added bis(pinacolato)diboron (5.13 g), potassium acetate (3.94 g), 1 ,1 '- bis(diphenylphosphino)-ferrocene (0.55 g) and 1 ,1'-bis(diphenylphosphino)- ferrocenedichloropalladium (II) (0.82 g). The flask is tightly sealed and heated to 80 ⁰C for 16 h. Then the reaction mixture is concentrated under reduced pressure and the residue is taken up in ethyl acetate. The resulting mixture is washed with water, dried (sodium sulphate) and the solvent is evaporated. The remainder is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1 :0->2:1 ).

Yield: 0.88 g (24% of theory)

Mass spectrum (ESI⁺): m/z = 271 [M+H]⁺

Example IX

2,6-Difluoro-4-methoxy-phenyl-boronic acid

To a solution of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)anisol (0,88 g) in acetone (15 mL) is added aqueous ammonium acetate solution (18 mL, 1 mol/L in water) and sodium metaiodate (2.6 g). Then the solution is stirred at ambient temperature overnight. Then the mixture is concentrate, diluted with water and extracted with ethyl acetate. The combined extracts are dried (sodium sulfate) and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1 :0->1 :1 ).

Yield: 0.27 g (44% of theory) 41

Example X

1-Chloro-2-r2,3-difluoro-4-methyl-phenyl)methyll-4-(2,3,4,6-tetra-O-acetyl-D-qlucopyranos-1- vD-benzene

Pyridine (0.1 1 g), acetic anhydride (0.14 g) and 4-dimethylaminopyridine (0.10 g) are added to a solution of 1-chloro-2-[2,3-difluoro-4-methyl-phenyl)methyl]-4-(D-glucopyranos-1-yl)- benzene (0.1 1 g) in dichloromethane (3 ml_). The resultant solution is stirred for 3 h at ambient temperature and then diluted with dichloromethane. The organic solution is washed twice with hydrochloric acid (1 mol/l in water), dried (sodium sulphate) and concentrated under reduced pressure to give the product. Yield: 0.15 g (97% of theory)

Preparation of the end compounds:

Example 1

1-Chloro-2-[2,3-difluoro-4-methyl-phenyl)methyl1-4-(D-glucopyranos-1-yl)-benzene A solution of 2,3-difluoro-toluene (0,82 g) in dry tetrahydrofuran (13 ml.) is cooled to -80 ⁰C under argon. sec-Butyl lithium (4.55 ml. of a 1.4 M solution in cyclohexane) is slowly added to the cooled solution and the resulting solution is stirred for 2 h at -80 ⁰C. Then a solution of 2-chloro-5-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzaldehyde (0.30 g) in tetrahydrofuran (3 ml.) is added and the resulting solution is stirred for another 0.5 h at -80 ⁰C. The reaction is quenched by the addition of aqueous ammonium chloride solution and warmed to room temperature. The resultant mixture is extracted with ethyl acetate, the combined organic extracts are washed with brine and dried over sodium sulfate. After removal of the solvent, the residue is taken up in dichloromethane (6 ml.) and the resulting solution is cooled in an ice-bath. Triethylsilane (0.7 ml.) followed by boron trifluoride etherate 42

(0.38 ml.) is added and the reaction solution is stirred at ambient temperature for 3 h. Aqueous sodium bicarbonate solution is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (sodium sulfate) and the solvent is removed under reduced pressure. The residue is dissolved in methanol (10 ml.) and treated with aqueous potassium hydroxide solution (1 ml_, 4 mol/L). The solution is stirred at room temperature for 30 min and neutralized with hydrochloric acid (1 mol/L). After removal of the methanol, the residue is diluted with aqueous sodium bicarbonate solution and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The remainder is purified by chromatography on silica gel (dichloromethane/methanol 1 :0->9:1 ). Yield: 0.16 g (57% of theory) Mass spectrum (ESI⁺): m/z = 432/434 (Cl) [M+NH₄]⁺

The following compound may be obtained analogously to Example 1 :

(2) 1 -Chloro-2-[(4-2,3-difluoro-ethyl-phenyl)-methyl1- 4-(β-D-glucopyranos-1 -vD-benzene

Mass spectrum (ESI⁺): m/z = 446/448 (Cl) [M+NH₄]⁺

The compound is prepared starting with 3-ethyl-1 ,2-difluoro-benzene which is synthesized from 2,3-difluoro-acetophenone by hydrogenation with 10% palladium on carbon in the presence of concentrated hydrochloric acid in ethanol.

(3) 1 -Chloro-2-[(2,6-difluoro-4-methoxy-phenyl)-methyl1- 4-(β-D-glucopyranos-1 -yl)-benzene

Mass spectrum (ESI): m/z = 496/498 (Cl) [M]⁺ 43

The compound is prepared using 4-bromo-3,5-difluoro-anisol and n-butyl lithium to generate the intermediate 2,6-difluoro-4-methoxy-phenyl lithium via halogen-metal exchange. All subsequent steps are carried out as described above.

(4) 1 -Chloro-2-[(2,5-difluoro-4-methoxy-phenyl)-methyl1- 4-(β-D-glucopyranos-1 -vD-benzene

The compound is prepared using 4-bromo-2,5-difluoro-anisol and n-butyl lithium to generate the intermediate 2,5-difluoro-4-methoxy-phenyl lithium via halogen-metal exchange. All subsequent steps are carried out as described above.

Example 5

1 -Chloro-2-[(3,5-difluoro-4-methoxy-phenyl)-methyl1- 4-(β-D-glucopyranos-1 -yl)-benzene

A stirred mixture of 1-chloro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-bromomethyl- benzene (0.30 g), 3,5-difluoro-4-methoxy-phenylboronic acid (0,21 g) and potassium carbonate (0.31 g) in acetone (3 ml.) and water (1 ml.) under argon is cooled in an ice-bath. Then palladium dichloride (5 mg) is added and the cooling bath is removed. The reaction mixture is stirred at ambient temperature overnight. Then brine is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried over sodium sulfate, and the solvent is removed in vacuo. The residue is taken up in methanol (5 ml.) aqueous potassium hydroxide solution (1 ml_, 4 mol/L) is added. The solution is stirred at ambient temperature for 0.5 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 organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1 :0 ->9:1 ). 44

Yield: 0.06 g (25% of theory )

Mass spectrum (ESI⁺): m/z = 448/450 (Cl) [M+NH₄]⁺

Example 6

3-[2,3-difluoro-4-methyl-phenyl)methyl1-1-(D-glucopyranos-1-yl)-4-methyl-benzene Toluene (3 ml.) is added to a flask charged with 1-chloro-2-[2,3-difluoro-4-methyl- phenyl)methyl]-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzene (0.15 g), methylboronic acid (35 mg), K₃P(VH₂O (0.16 g), 2-dicyclohexylphospino-2',6'- dimethoxybiphenyl (8 mg) and palladium(ll)-acetate (2.2 mg) under argon atmosphere. The mixture is stirred at 1 15 ⁰C overnight before another portion of methylboronic acid (35 mg), K₃P(VI-I₂O (0.16 g), 2-dicyclohexylphospino-2',6'-dimethoxybiphenyl (8 mg) and palladium(ll)-acetate (2.2 mg) is added. The mixture is stirred at 1 15 ⁰C for another 16 h and then cooled to room temperature. Water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (sodium sulfate) and the solvent is removed under reduced pressure. The residue is dissolved in methanol (4 ml.) and treated with aqueous potassium hydroxide solution (2 ml_, 4 mol/L). The solution is stirred at room temperature for 30 min and then neutralized with hydrochloric acid (1 mol/L). After removal of the methanol, the residue is diluted with aqueous sodium bicarbonate solution and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The remainder is purified by HPLC on reversed phase (YMC C18, acetonitrile/water) to give the pure product. Yield: 60 mg (59% of theory) Mass spectrum (ESI⁺): m/z = 412 [M+NH₄]⁺ 45

The following compounds are also prepared analogously to the above-mentioned Examples and other methods known from the literature:

46

47

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. 48

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. 49

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:

4 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

50Claims

1. Glucopyranosyl-substituted difluorobenzyl-benzene derivatives of general formula I

wherein

R³ hydrogen, fluorine, chlorine, bromine, iodine, Ci_-6-alkyl, C_2-6-alkynyl, C_2-6-alkenyl, C_3-7-cycloalkyl, Cs-z-cycloalkyl-Ci-s-alkyl, C₅-₇-cycloalkenyl, C_5-7-cycloalkenyl- d-₃-alkyl, aryl, heteroaryl, Ci_-4-alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, Ci_-4-alkylaminocarbonyl, di-(Ci_-3-alkyl)aminocarbonyl, pyrrolidin-1- ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (Ci_-4-alkyl)piperazin-1-ylcarbonyl, hydroxycarbonyl, Ci_-4-alkoxycarbonyl, Ci_-4- alkylamino, di-(Ci_₃-alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, 4-(Ci_-4-alkyl)piperazin-1-yl, Ci_-4-alkylcarbonylamino, arylcarbonyl- 51

amino, heteroarylcarbonylamino, Ci_-4-alkylsulfonylamino, arylsulfonylamino, d-6- alkoxy, Cs-7-cycloalkyloxy, Cs-r-cycloalkenyloxy, aryloxy, heteroaryloxy, Ci_-4- alkylsulfanyl, Ci_-4-alkylsulfinyl, Ci_-4-alkylsulfonyl, Cs-z-cycloalkylsulfanyl, Cs-_T-cycloalkylsulfinyl, Cs-z-cycloalkylsulfonyl, Cs-z-cycloalkenylsulfanyl, Cs-_T-cycloalkenylsulfinyl, Cs-r-cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroarylsulfanyl, heteroarylsulfinyl, heteroarylsulfonyl, amino, hydroxy, cyano and nitro,

while in the above-mentioned N-heterocycloalkyl rings one methylene group may be replaced by CO or SO₂, and

L1 independently of one another are selected from among fluorine, chlorine, bromine, iodine, hydroxy, cyano, Ci_-3-alkyl, difluoromethyl, trifluoromethyl, Ci_-3-alkoxy, difluoromethoxy, trifluoromethoxy, amino, Ci_-3-alkyl-amino and di(Ci_-3-alkyl)-amino; and

L2 independently of one another are selected from among fluorine, chlorine, hydroxy, hydroxyl-Ci_-4-alkyl, Ci_-4-alkoxy, trifluoromethoxy, Ci_-4-alkoxy-Ci_-4-alkyl, cyano, hydroxycarbonyl, (Ci_-4-alkyl)oxycarbonyl, aminocarbonyl, Ci_-4-alkyl, trifluoromethyl, amino, Ci_-4-alkyl-carbonylamino, Ci_-3-alkyl-amino and di(Ci_-3-alkyl)-amino; and

R⁶ , R^7a,

while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups which may be substituted as defined; and 52

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

2. Glucopyranosyl-substituted difluorobenzyl-benzene derivatives according to claim 1 characterized in that R¹ denotes fluorine, chlorine, bromine, cyano, Ci_-4-alkyl, Ci_-4- alkyloxy, C_3-7-cycloalkyl or C_3-7-cycloalkyloxy, while in a C_5-6-cycloalkyl ring a methylene group may be replaced by O, and wherein any alkyl group or cycloalkyl ring may be mono- or poly-fluorinated and/or mono- or disubstituted with identical or different substituents L2, wherein L2 is defined as in claim 1.

3. Glucopyranosyl-substituted difluorobenzyl-benzene derivatives according to claim 1 or 2 characterized in that R² denotes hydrogen, fluorine, chlorine, methyl, methoxy, ethoxy and methyl substituted by 1 to 3 fluorine atoms.

4. Glucopyranosyl-substituted difluorobenzyl-benzene derivatives according to one or more of the claims 1 to 3 characterized in that R³ denotes chlorine, bromine, iodine, Ci_₄-alkyl, C_3-7-cycloalkyl, hydroxyl, Ci_-4-alkyloxy, C_3-7-cycloalkyloxy, Ci_-4-alkylsulfanyl, C_3-7-cyclo- alkylsulfanyl, while in a C_5-6-cycloalkyl ring a methylene group may be replaced by O, and wherein any alkyl group and cycloalkyl ring may be mono- or polyfluorinated and/or mono- or disubstituted with identical or different substituents L2, wherein L2 is defined as in claim 1.

5. Glucopyranosyl-substituted difluorobenzyl-benzene derivatives according to one or more of the claims 1 to 4 characterized in that R⁶ denotes hydrogen, (Ci_-8-alkyl)oxycarbonyl, Ci_₈-alkylcarbonyl or benzoyl and R^7a, R^7b, R^7c represent independently of one another hydrogen, (Ci_-8-alkyl)oxycarbonyl, (Ci_-8-alkyl)carbonyl or benzoyl. 53

6. Glucopyranosyl-substituted difluorobenzyl-benzene derivatives according to one or more of the claims 1 to 4 characterized in that R⁶, R^7a, R^7b, R^7c represent hydrogen.

7. Physiologically acceptable salts of the compounds according to one or more of the claims 1 to 6 with inorganic or organic acids.

8. Pharmaceutical composition, comprising a compound according to one or more of the claims 1 to 6 or a physiologically acceptable salt according to claim 7, optionally together with one or more inert carriers and/or diluents.

9. Use of at least one compound according to one or more of the claims 1 to 6 or a physiologically acceptable salt according to claim 7 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.

10. Use of at least one compound according to one or more of the claims 1 to 6 or a physiologically acceptable salt according to claim 7 for preparing a pharmaceutical composition which is suitable for the treatment or prevention of one or more metabolic disorders.

1 1. Use according to claim 10, 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.

12. Use of at least one compound according to one or more of the claims 1 to 6 or a physiologically acceptable salt according to claim 7 for preparing a pharmaceutical composition for inhibiting the sodium-dependent glucose cotransporter SGLT2.

13. Use of at least one compound according to one or more of the claims 1 to 6 or a physiologically acceptable salt according to claim 7 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. 54

14. Use of at least one compound according to one or more of the claims 1 to 6 or a physiologically acceptable salt according to claim 7 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.

15. Use of at least one compound according to one or more of the claims 1 to 6 or a physiologically acceptable salt according to claim 7 for preparing a diuretic and/or antihypertensive.

16. Process for preparing a compound according to one or more of the claims 1 to 6, characterised in that

a) a compound of general formula Il

wherein

R' denotes H, Ci_-4-alkyl, (Ci-i₈-alkyl)carbonyl, (Ci-i₈-alkyl)oxycarbonyl, arylcarbonyl and aryl-(Ci-₃-alkyl)-carbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted by halogen;

FT, R 8b R^8c, R^8d independently of one another have one of the meanings given hereinbefore and hereinafter for the groups R⁶, R^7a, R^7b, R^7c, or denote a benzyl or allyl group or a R^aR^bR^cSi group or a ketal or acetal group, particularly an alkylidene or arylalkylidene ketal or acetal group, while in each case two adjacent groups R^8a, R^8b, R^8c, R^8d may form a cyclic silyl ketal, ketal or acetal group or a 1 ,2-di(d_-3- alkoxy)-1 ,2-di(Ci_-3-alkyl)-ethylene bridge, while the above-mentioned ethylene bridge forms, together with two oxygen atoms and the two associated carbon atoms of the pyranose ring, a substituted dioxane ring, particularly a 2,3-dimethyl- 55

2,3-di(Ci_-3-alkoxy)-1 ,4-dioxane ring, and while alkyl, aryl and/or benzyl groups may be mono- or polysubstituted by halogen or Ci_-3-alkoxy, and while benzyl groups may also be substituted by a di-(Ci_-3-alkyl)amino group; and

R^a, R^b, R^c independently of one another denote Ci_-4-alkyl, aryl or aryl-Ci_-3-alkyl, wherein the aryl or alkyl groups may be mono- or polysubstituted by halogen;

and wherein the groups R¹ to R³ and R⁶, R^7a, R^7b, R^7c are defined as in claim 1 ;

is reacted with a reducing agent in the presence of a Lewis or Brønsted acid, while any protective groups present are cleaved simultaneously or subsequently; or

b) a compound of general formula III

wherein R^8a, R^8b, R^8c, R^8d and R¹ to R³ are defined as hereinbefore and hereinafter, but at least one of the groups R^8a, R^8b, R^8c, R^8d does not denote hydrogen, is hydrolysed to yield a compound of the formula I defined as in claim 1 wherein R⁶, R^7a, R^7b and R^7c denote hydrogen, and

if desired a compound of formula I thus obtained wherein R⁶ denotes a hydrogen atom, is converted by acylation into a corresponding acyl compound of general formula I, and/or

if desired a compound of formula I thus obtained is resolved into its stereoisomers and/or 56

if desired a compound of formula I thus obtained is converted into the salts thereof.

16. Process for preparing compounds of general formula Il

wherein

R^8a, R^8b, R^8c, R^8d independently of one another has one of the meanings given for the groups R⁶ , R^7a, R^7b, R^7c, or denote a benzyl or allyl group or a R^aR^bR^cSi group or a ketal or acetal group, while in each case two adjacent groups R^8a, R^8b, R^8c, R^8d may form a cyclic silyl ketal, ketal or acetal group or may form, with two oxygen atoms of the pyranose ring, a substituted 2,3-oxydioxane ring, particularly a 2,3-dimethyl- 2,3-di(Ci_-3-alkoxy)-1 ,4-dioxane ring, and while alkyl, aryl and/or benzyl groups may be mono- or polysubstituted by halogen or d-₃-alkoxy, and while benzyl groups may also be substituted by a di-(Ci_-3-alkyl)amino group; and

R^a, R^b, R^c independently of one another denote Ci_-4-alkyl, aryl or aryl-Ci_-3-alkyl, while the alkyl or aryl groups may be mono- or polysubstituted by halogen;

and R¹ to R³, R⁶, R^7a, R^7b, R^7c are defined as in claim 1 ,

wherein an organometallic compound (V) which may be obtained by halogen-metal 57

exchange or by inserting a metal in the carbon-halogen bond of a halogen-benzylbenzene compound of general formula IV

wherein Hal denotes Cl, Br and I and R¹ to R³ are defined as in claim 1 , and optionally subsequent transmetallation, is added to a gluconolactone of general formula Vl

wherein R^8a, R^8b, R^8c, R^8d are defined as in claim 1 , and

then the resulting adduct is reacted with water or an alcohol R'-OH, while R' denotes optionally substituted C-^-alkyl, in the presence of an acid and optionally the product obtained in the reaction with water wherein R' denotes H is converted, in a subsequent reaction, with an acylating agent into the product of formula Il wherein R' denotes (Ci--_I8- alkyl)carbonyl, (Ci-i₈-alkyl)oxycarbonyl, arylcarbonyl or aryl-(Ci_-3-alkyl)-carbonyl, which may be substituted as specified.