WO2005063785A2

WO2005063785A2 - Glucopyranosyloxy-substituted aromates, medicaments containing said compounds, the use thereof, and methods for producing the same

Info

Publication number: WO2005063785A2
Application number: PCT/EP2004/014319
Authority: WO
Inventors: Frank Himmelsbach; Peter Eickelmann; Edward Leon Barsoumian
Original assignee: Boehringer Ingelheim International Gmbh; Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority date: 2003-12-22
Filing date: 2004-12-16
Publication date: 2005-07-14
Also published as: JP2007515441A; CA2548353A1; DE10361133A1; EP1699807A2; WO2005063785A3

Abstract

The invention relates to glucopyranosyloxy-substituted aromates of general formula (I), wherein R1 to R6 and R7a, R7b, R7c are defined according to patent claim 1. The invention also relates to the tautomers, stereoisomers, mixtures and salts of said aromates, especially the physiologically compatible salts comprising inorganic or organic acids and having valuable pharmacological properties, especially an inhibiting effect on the sodium-dependent glucose cotransporter SGLT2. The invention further relates to the treatment of diseases, especially metabolic diseases such as diabetes, and to the production of said compounds.

Description

Aromatic compounds containing glucopyranosyloxy, medicaments containing these compounds, their use and process for their preparation

The present invention relates to aromatics of the general formula I substituted with glucopyranosyloxy

wherein the radicals R ¹ to R ⁶ and R ^7a , R ^7b and R ^7c are defined below, including their tautomers, their stereoisomers, their mixtures and their salts. Another object of this invention relates to medicaments containing a compound of formula I according to the invention and the use of a compound according to the invention for the manufacture of a medicament for the treatment of metabolic diseases. In addition, methods for producing a medicament and a compound according to the invention are the subject of this invention.

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

International publications WO 01/68660, WO 01/74834, WO 02/28872, WO 02/44192, WO 02/64606, WO 03/11880 and WO 03/80635 disclose aromatics substituted by glucopyranosyloxy and their preparation and their possible activity known as SGLT2 inhibitors. Object of the invention

The present invention is based on the object of demonstrating new glucopyranosyloxy-substituted aromatics, in particular those which have an activity with respect to the sodium-dependent glucose cotransporter SGLT, in particular SGLT2. A further object of the present invention is to demonstrate glucopyranosyloxy-substituted aromatics which have an increased inhibitory effect on sodium-dependent glucose cotransporters SGLT2 in vitro and / or in vivo compared to known, structurally similar compounds and / or have improved pharmacological or pharmacokinetic properties.

Furthermore, it is an object of the present invention to provide new medicaments which are suitable for the prophylaxis and / or treatment of metabolic diseases, in particular diabetes.

Another object of this invention is to provide a process for the preparation of the compounds according to the invention.

For the person skilled in the art, further objects of the present invention result directly from the preceding and following explanations.

Object of the invention

A first object of the present invention are glucopyranosyloxy-substituted aromatics of the general formula I.

in which

R ^{1 is} C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-Cι- ₃ -alkyloxy or tetrahydropyranyl-Cι- ₃ -alkyloxy, or if R ^{3 is} selected is from the group consisting of C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl -CC. ₃ -alkyloxy and tetrahydropyranyl-Cι- ₃ -alkyloxy, then R ¹ can also hydrogen, fluorine, chlorine, bromine, iodine, C-ι- ₄ alkyl, a methyl group substituted by 1 to 3 fluorine atoms, one by 1 to 5 Fluorine atoms substituted ethyl group, Cι- alkoxy, a methoxy group substituted by 1 to 3 fluorine atoms, an ethoxy group substituted by 1 to 5 fluorine atoms, a C ι _-4 alkyl group substituted by a hydroxy or Cι- ₃ alkoxy group, one by one hydroxy or C ₁ -3 alkoxy substituted C ₂ alkoxy, C ₂ - ₆ alkenyl, C. ₃ ₆ -cycloalkyl, C _3-6 -cycloalkyl-Cι. ₃ alkyl, C3 ₆ cycloalkoxy, C _3- 6 cycloalkyl-C-ι _-3 alkoxy, hydroxy, amino or cyano, and

R ^{2 is} hydrogen, fluorine, chlorine, methyl, methyl or methoxy substituted by 1 to 3 fluorine atoms, and

R ³ C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-Cι- ₃ -alkyloxy or tetrahydropyranyl-Cι_ ₃ -alkyloxy, or if R ^{1 is} selected from the group consisting of C ₂ . _6- alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-Cι _-3 -alkyloxy and tetrahydropyranyl-Cι-3-alkyloxy, then R ³ may additionally be hydrogen, fluorine, chlorine, bromine, iodine, Cι _-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, C. ₃ _6- Cycloalkylidenmethyl, Cι. ₆ -alkoxy, C _3-6 -cycloalkyloxy, Cs-e-cycloalkyl-cisalkoxy, aryl, aryl-Cι-3-alkyl, heteroaryl, heteroaryl-C _1-3 -alkyl, aryloxy, aryl-Cι. _3- alkyl-oxy, a methyl or methoxy group substituted by 1 to 3 fluorine atoms, a C _2-4 -alkyl or C _2-4 -alkoxy group substituted by 1 to 5 fluorine atoms, a C- -alkyl group substituted by a cyano group, a substituted by a hydroxy or Cι_ ₃ alkyloxy group Cι- ₄ alkyl group, cyano, carboxy, C ₁ -3- alkoxycarbonyl, aminocarbonyl, (Cι. ₃ alkylamino) carbonyI, di- (Cι _-3 - alkyl) aminocarbonyl-, pyrrolidin-1 -ylcarbonyl-, piperidin-1 -ylcarbonyl-, morpholin-4-ylcarbonyl-, piperazin-1 -yl-carbonyl-, 4- (C-ι. _3- alkyl) -piperazin- 1 - ylcarbonyl-, nitro-, amino-, -Cι _-3 -alkylamino-, di- (Cι- ₃ -alkyl) amino-, (Cι _-4 - alkyl) carbonylamino-, -Cι- alkylsulfonylamino, arylsulfonylamino, A1 IC _1st , ₃ - alkylsulfonylamino, C- -Alkylsulfanyl-, Cι _-4 -Alkylsulfinyl-, Cι _-4 -AlkyIsulfonyl, arylsulfenyl-, arylsulfinyl- or arylsulfonyl-,

R ⁴ and R ⁵ , which may be the same or different, are hydrogen, fluorine, chlorine, bromine, C _{3 to 3} alkyl, C _{3 to 3} alkoxy, methyl or methoxy substituted by 1 to 3 fluorine atoms, and

R ⁶ , R ^7a ,

R ^7b , R ⁷ ° independently of one another have a meaning selected from the group consisting of hydrogen, (-CC ₈ -alkyl) carbonyl, (-CC ₈ -alkyl) oxycarbonyl, arylcarbonyl and aryl- (Cι. ₃ -alkyl) -carbonyl,

where the aryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning phenyl or naphthyl groups which can be mono- or disubstituted independently of one another by R _h , where the substituents can be identical or different and R _{h is} a fluorine or chlorine , Bromine, iodine, C 1 -C 3 -alkyl, difluoromethyl, trifluoromethyl, C 1 -C 3 alkoxy, difluoromethoxy, trifluoromethoxy or cyan, among the heteroaryl groups mentioned in the definition of the abovementioned radicals is a pyrrolyl, furanyl, thienyl, imidazolyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group, or a pyrrolyl, Furanyl, thienyl, imidazolyl or pyridyl group in which one or two methine groups are replaced by nitrogen atoms, or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group in which one to three methine groups are to be understood are replaced by nitrogen atoms, where the heteroaryl groups mentioned above can be mono- or disubstituted by R _h , where the substituents can be the same or different and R _{h is} as defined above,

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

their tautomers, their stereoisomers, their mixtures and their salts.

The compounds of general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory action on the sodium-dependent glucose cotransporter SGLT, in particular SGLT2. Furthermore, compounds according to the invention can have an inhibitory effect on the sodium-dependent glucose cotransporter SGLT1. Compared to a possible inhibitory effect on SGLT1, the compounds according to the invention preferably selectively inhibit SGLT2.

The present invention also relates to the physiologically tolerable salts of the compounds according to the invention with inorganic or organic acids. Therefore, the use of the compounds according to the invention, including the physiologically tolerable salts as medicaments, is also an object of this invention.

Another object of this invention are medicaments containing at least one compound according to the invention or a physiologically compatible salt according to the invention in addition to optionally one or more inert carriers and / or diluents.

The present invention also relates to the use of at least one compound according to the invention or a physiologically tolerable salt of such a compound for the production of a medicament which is suitable for the treatment or prophylaxis of diseases or conditions which can be influenced by inhibition of the sodium-dependent glucose cotransporter SGLT, in particular SGLT2 are.

Another object of this invention is the use of at least one compound according to the invention or one of its physiologically tolerable salts for the production of a medicament which is suitable for the treatment of metabolic diseases.

Another object of this invention is the use of at least one compound according to the invention or one of its physiologically tolerable salts for the production of a medicament for inhibiting the sodium-dependent glucose cotransporter SGLT, in particular SGLT2.

Furthermore, a method for producing a medicament according to the invention is the subject of this invention, characterized in that a compound according to the invention is incorporated into one or more inert carriers and / or diluents in a non-chemical way. The present invention also relates to a process for the preparation of the compounds of the general formula I according to the invention, characterized in that a) for the preparation of compounds of the general formula I in which R ⁶ , R ^7a , R ^7b and R ^{7c are} as previously defined , but not hydrogen, a compound of the general formula

in the

R ⁶ and R ^7a , R ^7b , R ^{7c are} as previously defined, but do not mean hydrogen, and Z ^{1 represents} a leaving group, with a compound of the general formula

in the

R ¹ to R ^{5 have} the meanings mentioned above, is implemented or

b) for the preparation of compounds of the general formula I in which R ⁶ , R ^7a , R ^7b and R ^{7c are} hydrogen,

a compound of the general formula I in which R ⁶ and R ^7a , R ^7b , R ^{7c are} as previously defined, but are not hydrogen, is hydrolyzed, and after carrying out step b) if desired, a compound of the general formula I thus obtained in which R ^{6 represents} a hydrogen atom is converted into a corresponding acyl compound of the general formula I by acylation, and / or

if necessary, a protective residue used in the reactions described above is split off again and / or

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

a compound of the general formula I obtained in this way is converted into its salts, in particular for its pharmaceutical use into its physiologically tolerable salts.

Detailed description of the invention

Unless otherwise stated, the groups, radicals and substituents, in particular R ¹ to R ⁶ and R ^7a , R ^7b , R ^7c , have the meanings given above and below.

If residues, substituents or groups occur more than once in a compound, they can have the same or different meanings.

The term aryl used above and below, for example in the groups R ³ , R ⁶ , R ^7a , R ^7b , R ^7c and R ^7d , preferably denotes phenyl. According to the general definition and unless otherwise stated, the aryl group, in particular the phenyl group, can be substituted once or twice with identical or different R radicals.

The term heteroaryl used above and below, for example in the group R ³ , preferably denotes pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, Oxadiazolyl, thiazolyl or thiadiazolyl. According to the general definition and unless stated otherwise, the heteroaryl group can be substituted once or twice with identical or different radicals Rh.

Compounds of the invention according to a first embodiment of this invention can be described by the general formula I in which R ¹ is C ₂ - ₆ alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-Cι. ₃ -alkyloxy or tetrahydropyranyl-Cι_ ₃ -alkyloxy means and

the remaining radicals R ² to R ⁶ and R ^7a , R ^7b , R ^{7c are} as previously defined,

including their tautomers, their stereoisomers, their mixtures and their salts.

According to this embodiment preferred meanings of the radical R ¹ are ethynyl, 2-propin-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy and

Tetrahydropyranylmethyloxy. Very particularly preferred meanings here are ethynyl, tetrahydrofuran-3-yloxy and tetrahydropyran-4-yloxy, in particular ethynyl.

According to this embodiment, preferred meanings of the radical R ³ are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, 2-cyano-2-propyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy , Difluoromethoxy, trifluoromethoxy, 1, 1,2,2-tetrafluoroethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, methylsulfanyl, 2-methyl-1-propen-1-yl, cyclopropylidenemethyl, ethynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3 yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy, tetrahydropyranylmethyloxy, phenyl-, fluorophenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolylyliaziazylyliaziazyl Particularly preferred meanings here are ethynyl, tetrahydrofuran-3-yloxy, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, in particular ethynyl, tetrahydrofuran-3-yloxy and methoxy. According to this first embodiment, preferred meanings of the radical R ⁴ are hydrogen and fluorine, in particular hydrogen.

Compounds according to the invention according to a second embodiment of this invention can be described by the general formula I, in which

R ^{1 is} hydrogen, fluorine, chlorine, bromine, iodine, Cι. _4- alkyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, CM alkoxy, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms, by a hydroxy or C ₁ - ₃ - Alkoxy group substituted -CC 4 alkyl, by a hydroxy or C ₁ . ₃ - alkoxy group substituted C ₂ -4-alkoxy, C ₂ -6-alkenyl, C3-6-cycloalkyl, C _3-6 - cycloalkyl-Cι- ₃ alkyl, C ₃ - ₆ cycloalkoxy, C _3- 6 cycloalkyl C _1-3 alkoxy, hydroxy, amino or cyano means, and also also C ₂ - ₆ alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl -CC. ₃ -alkyloxy or tetrahydropyranyl-Cι- ₃ -Alkyloxy can mean, and

R ^{3 is} selected from a group consisting of C ₂ -6-alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-Cι-3-alkyloxy and tetrahydropyranyl-Cι _-3 -alkyloxy, and

the other radicals, in particular R ² and R ⁴ to R ⁶ and R ^7a , R ^7b , R ^{7c, have} the meanings given above,

including their tautomers, their stereoisomers, their mixtures and their salts.

According to this embodiment, preferred meanings of the radical R ¹ are hydrogen, fluorine, chlorine, methyl, difluoromethyl, trifluoromethyl, methoxy, Difluoromethoxy, trifluoromethoxy or cyano, particularly preferably hydrogen, fluorine, methyl or cyano, very particularly preferably hydrogen.

According to this embodiment, preferred meanings of the radical R ³ are ethynyl and tetrahydrofuran-3-yloxy.

According to this second embodiment, preferred meanings of the radical R ⁴ are hydrogen and fluorine, in particular hydrogen.

The following statements relate to the compounds of the formula I, in particular to the first and second embodiments mentioned above.

Preferred compounds according to the present invention, in particular according to the first and second embodiment, can be described by the following formulas (la), (Ib), (Ic) and (Id), in particular (la), (Ib) and (Ic) :

According to a variant of the above-mentioned embodiments, those compounds are also preferred in which the phenyl group which carries the substituent R ^{3 has} at least one further substituent R ⁴ and / or R ^{5 which is} different from hydrogen. According to these variants, those compounds are particularly preferred which have a substituent R ⁴ meaning fluorine.

The phenyl radical which carries the substituent R ³ is preferably fluorinated at most once.

Preferred meanings of the radical R ⁵ are hydrogen and fluorine, in particular hydrogen.

Preferred meanings of the radical R ² according to the invention are hydrogen, fluorine and methyl, in particular hydrogen and methyl. The radical R ⁶ according to the invention is preferably hydrogen, (C _1-8 -alkyl) oxycarbonyl- or -C _-8- alkylcarbonyl-, in particular hydrogen or (d. ₆ -alkyl) oxycarbonyl, particularly preferably hydrogen, methoxycarbonyl or ethoxycarbonyl, very particularly preferably Hydrogen or methoxycarbonyl.

The substituents R ^7a , R ^7b , R ^7c independently of one another are preferably hydrogen, (C _1-8 -alkyl) oxycarbonyl-, (C _1-18 -alkyl) carbonyl, benzoyl, in particular hydrogen or (C _1-6 -alkyl) oxycarbonyl-, (-C _-8- alkyl) carbonyl, particularly preferably hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl. R ^7a , R ^7b and R ^{7c are} very particularly preferably hydrogen.

The compounds of formula I in which R ⁶ , R ^7a , R ⁷ and R ^{7c have} a meaning according to the invention other than hydrogen, for example C ₈ alkylcarbonyl, are preferably suitable as intermediates in the synthesis of compounds of formula I in which R ^7a , R ^7b and R ^{7c are} hydrogen. ,

Particularly preferred compounds of the general formula I are selected from the group:

(a) 1- (β-D-glucopyranosyloxy) -2-t4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] benzene,

(b) 1- (β-D-glucopyranosyloxy) -2- (4-ethynylbenzyl) benzene,

and their derivatives in which R ^{6 has} a meaning other than hydrogen, in particular R ^{6 is} ethoxycarbonyl or methoxycarbonyl,

including their stereoisomers and their mixtures.

Terms that are used above and below to describe the compounds according to the invention are defined in more detail below. The term halogen denotes an atom selected from the group consisting of F, Cl, Br and I, in particular F, Cl and Br.

The designation Cι. _n -Alkyl, where n can have a value from 1 to 18, means a saturated, branched or unbranched hydrocarbon group with 1 to n carbon 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, where n has a value from 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C≡C double bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, iso-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5 hexynyl etc.!

The term Cι. _n -AIkoxy denotes a Cι. _n -Alkyl-O group, wherein -CC _n -alkyl is as defined above. 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 C 1 _-n ~ alkylcarbonyl denotes a C 1 _-n- alkyl-C (= 0) group, in which C 1 _-n - alkyl is as defined above. 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 C ₃ -n-cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1.] Octyl, spiro [4.5] decyl, norpinyl, norbonyl, Norcaryl, Adamantyl, etc. Preferably, the term includes C ₃ . _7- Cycloalkyl saturated monocyclic groups.

The term C ₃ -n-cycloalkylcarbonyl denotes a C ₃ . _n- Cycloalkyl-C (= O) group, in which C _3-n -cycloalkyl is as defined above.

The notation used above and below, in which a bond of a substituent to the center of the phenyl ring is shown in a phenyl group, means, unless stated otherwise, that this substituent is attached to any free one. H atom-bearing position of the phenyl ring can be bound.

The compounds according to the invention can be obtained using synthesis processes which are known in principle. The compounds are preferably obtained by the production processes according to the invention which are explained in more detail below.

a) For the preparation of compounds of the general formula I in which R ⁶ , R ^7a , R ^7b , R ^7c are defined as mentioned at the outset, but do not represent a hydrogen atom:

Implementation of a compound of the general formula

in the

R ⁶ and R ^7a , R ^7b , R ^7c are defined as mentioned at the outset, but do not mean hydrogen, and Z ^{1 is} a leaving group such as a halogen atom, for example a fluorine, chlorine or bromine atom, or an acyloxy group, for example an acetyloxy group or trichloroacetimidoyloxy group, with a compound of the general formula

in the

R ¹ to R ⁵ have the meanings mentioned.

The reaction is advantageously carried out in a solvent such as, for example, methylene chloride, chloroform, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, if appropriate in the presence of a base, such as, for example, potassium carbonate, cesium carbonate, sodium hydride or potassium tert-butoxide , or a silver compound such as silver (l) oxide, silver (l) carbonate or silver (l) trifluoroacetate or a catalyst such as boron trifluoride etherate at temperatures between -60 ° C and 120 ° C. The reaction can also be carried out, for example, in a phase transfer system such as sodium hydroxide solution / methylene chloride / benzyl-triethylammonium bromide, it being possible for other protective groups, such as the trimethylsilyl group on an ethynyl group, to be eliminated.

b) For the preparation of compounds of the general formula I in which R ⁶ , R ^7a , R ^7b and R ⁷ ° represent hydrogen:

Implementation of a compound of general formula I in which

R ⁶ , R ^7a , R ^7b and R ^7c are defined as mentioned at the outset, but do not mean hydrogen, with water or a lower alcohol such as methanol or ethanol.

The reaction is advantageously carried out in water, a lower alcohol such as methanol or ethanol or an aqueous solvent mixture such as methanol / tetrahydrofuran in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methylate Temperatures between -20 ° C and 60 ° C. In this reaction, other protective groups, such as the trimethylsilyl group on an ethynyl group, can also be removed.

If a compound of the general formula I in which R ^{6 represents} a hydrogen atom is obtained according to the invention, it can be converted into a compound by means of acylation, for example by means of acylation in the presence of a base such as pyridine, collidine, triethylamine or N-ethyldiisopropylamine, in which R ^{6 represents} a (-C ₁₈ alkyl) carbonyl group, a (C ₈ alkyl) oxycarbonyl group, an aryl carbonyl group or an aryl (C ₃ alkyl) carbonyl group. Suitable acylating agents are in particular the corresponding activated acyl derivatives such as acid chlorides or anhydrides.

In the reactions described above, any reactive groups present, such as ethynyl, hydroxyl, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.

For example, the trimethylsilyl group can be used as a protective radical for an ethynyl group.

For example, the trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group can be used as a protective radical for a hydroxyl group.

Protective residues for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.

The subsequent subsequent splitting off of a protective radical used takes place, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or Sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

A trimethylsilyl radical is split off, 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 methylate.

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

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

A trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C. , Furthermore, the compounds of general formula I obtained, as already mentioned at the beginning, can be separated into their enantiomers and / or diastereomers. For example, cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.

For example, the cis / trans mixtures obtained can be chromatographed into their cis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in " Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.

The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative obtained in this way, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-O-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Examples of suitable optically active alcohol are (+) - or (-) - menthol, and optically active acyl radicals in amides are, for example, (+) - or (-) - menthyloxycarbonyl.

Furthermore, the compounds of formula I obtained in their salts, in particular for pharmaceutical use in their physiologically compatible Salts with inorganic or organic acids. Examples of suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Furthermore, the compounds obtained can be converted into mixtures, for example in 1: 1 or 1: 2 mixtures with amino acids, in particular with alpha-amino acids such as proline or phenylalanine, which can have particularly favorable properties such as high crystallinity.

Some of the compounds of the general formulas II to V used as starting materials are known from the literature or can be obtained by processes known per se from the literature (see Examples I to VI), optionally with the additional introduction of protective residues.

The compounds according to the invention can also advantageously be obtained by the processes described in the examples below, these also using the processes known to the person skilled in the art, for example from the literature, in particular those described in WO 01/68660, WO 01/74834, WO 02/28872, WO 02/44192, WO 02/64606, WO 03/11880 and WO 03/80635 can be combined.

As already mentioned at the beginning, the compounds of the general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory action on the sodium-dependent glucose cotransporter SGLT, preferably SGLT2.

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

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

The SGLT-2 assay is performed as follows:

CHO-hSGLT2 cells are cultivated in Ham's F12 medium (BioWhittaker) with 10% fetal calf serum and 250 μg / ml Zeocin (Invitrogen), HEK293-hSGLT2 cells in DMEM medium with 10% fetal calf serum and 250 μg / ml Zeocin (Invitrogen). The cells are detached from the culture bottles by washing twice with PBS and then treating them with trypsin / EDTA. After adding cell culture medium, the cells are centrifuged off, resuspended in culture medium and counted in a casy-cell counter. Then 40,000 cells per hole are sown in a white, poly-D-lysine coated 96-well plate and incubated overnight at 37 ° C., 5% CO ₂ . The cells are washed twice with 250 μl assay buffer (Hanks Balanced Salt Solution, 137 mM NaCl, 5.4 mM KCI, 2.8 mM CaCl ₂ , 1, 2 mM MgSO ₄ and 10 mM HEPES (pH 7.4), 50 μg / ml gentamycin ) washed. 250 μl assay buffer and 5 μl test compound are then added to each well and incubated in the incubator for a further 15 minutes. 5 μl of 10% DMSO are used as a negative control. The reaction is started by adding 5 μl of ⁴ C-AMG (0.05 μCi) to each hole. After a 2-hour incubation at 37 ° C., 5% CO ₂ , the cells are washed again with 250 μl PBS (20 ° C.) and then lysed by adding 25 μl 0.1 N NaOH (5 minutes at 37 ° C.). 200 μl of MicroScint20 (Packard) are added to each hole and incubated at 37 ^C for a further 20 min. After this incubation, the radioactivity of the recorded ⁴ C-AMG is measured in a top count (Packard) using a ¹⁴ C scintillation program.

To determine the selectivity for the human SGLT1, an analog test is set up in which the cDNA for hSGLTI (Genbank Acc. No. NM000343) is expressed in CHO-K1 or HEK293 cells instead of the hSGLT2 cDNA. The compounds of general formula I according to the invention can have, for example, EC50 values below 1000 nM, in particular also below 50 nM.

In view of the ability to inhibit SGLT activity, the compounds of general formula I according to the invention and their corresponding pharmaceutically acceptable salts are in principle suitable for treating and / or preventing all those conditions or diseases which are caused by inhibiting SGLT activity , especially the SGLT-2 activity. Compounds according to the invention are therefore, in particular for the prophylaxis or treatment of diseases, in particular metabolic diseases, or conditions such as type 1 and type 2 diabetes mellitus, diabetic complications (such as, for example, retinopathy, nephropathy or neuropathies, diabetic foot, ulcer, macroangiopathies), metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorder, insulin resistance, metabolic syndrome, dyslipidemia of various origins, atherosclerosis and related diseases, obesity, hypertension, chronic heart failure, edema, hyperuricaemia are suitable. In addition, these substances are suitable for beta-cell degeneration such as To prevent apoptosis or necrosis of pancreatic beta cells. The substances are also suitable for improving or restoring the functionality of pancreatic cells, and also increasing the number and size of pancreatic beta cells. The compounds according to the invention can also be used as diuretics or antihypertensives and are suitable for the prophylaxis and treatment of acute kidney failure.

The compounds according to the invention, including their physiologically tolerable salts, are very particularly suitable for the prophylaxis or treatment of diabetes, in particular type 1 and type 2 diabetes mellitus, and / or diabetic complications.

The dosage required to achieve a corresponding effect in treatment or prophylaxis usually depends on the compound to be administered, on the patient, on the type and severity of the disease or the condition and the The type and frequency of administration depends on the doctor to be treated. Advantageously, the dosage for intravenous administration can range from 1 to 100 mg, preferably 1 to 30 mg, and for oral administration can range from 1 to 1000 mg, preferably 1 to 100 mg, 1 to 4 times a day. For this purpose, the compounds of the formula I prepared according to the invention, optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, Water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in conventional pharmaceutical preparations such as tablets, dragées, capsules, powders, solutions, suspensions or Work in suppositories.

The compounds according to the invention can also be used in combination with other active substances, in particular for the treatment and / or prophylaxis of the diseases and conditions mentioned above. For such combinations, further active substances are in particular those which, for example, increase the therapeutic effectiveness of an SGLT antagonist according to the invention with regard to one of the indications mentioned and / or allow a reduction in the dosage of an SGLT antagonist according to the invention. Therapeutics suitable for such a combination include, for example, anti-diabetic agents such as metformin, sulfonylureas (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 (eg KRP 297), alpha-glucose inhibitors (eg acarbose, Voglibose), DPPIV inhibitors (eg LAF237, MK-431), alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP -1 analogues (e.g. exendin-4) or amylin. In addition, are more suitable as combination partners inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as ^inhibitors' of the glucose-6-phosphatase, or fructose-1, 6-bisphosphatase, of glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvatcarboxykinase, glycogen synthase kinase or Pyruvatdehydrokinase, lipid lowering agents such as HMG-CoA reductase inhibitors (for example, simvastatin, atorvastatin), fibrates (eg bezafibrate, fenofibrate), nicotinic acid and derivatives thereof, PPAR-alpha agonists , PPAR-delta agonists, ACAT inhibitors (eg Avasimibe) or cholesterol absorption inhibitors such as ezetimibe, bile acid-binding substances such as colestyramine, inhibitors of ileal bile acid transport, HDL-increasing compounds such as inhibitors of CETP or regulators for treating ABC1 or active substances Obesitas such as sibutramine or tetrahydrolipstatin, dexfenfluramine, axokines, antagonists of the cannabinoidl receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or β3 agonists such as SB-418790 or AD-9677H as well as agonists of the SB-4187H.

In addition, a combination with drugs to influence high blood pressure, chronic heart failure or atherosclerosis such as 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, platelet aggregation inhibitors and others or combinations thereof are suitable. Examples of angiotensin II 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 II receptor antagonists are preferably used for the treatment or prophylaxis of hypertension and diabetic complications, often in combination with a diuretic such as hydrochlorothiazide.

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

For the treatment or prophylaxis of diabetic complications, a combination with GABA receptor antagonists, Na channel blockers, topiramate, protein kinase C Inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors.

The dose for the combination partners mentioned above is expediently 1/5 of the usually recommended lowest dose up to 1/1 of the normally recommended dose.

A further subject of this invention therefore relates to the use of a compound according to the invention or a physiologically tolerable salt of such a compound in combination with at least one of the active ingredients described above as a combination partner for the production of a medicament which is suitable for the treatment or prophylaxis of diseases or conditions which are caused by Inhibition of the sodium-dependent glucose cotransporter SGLT can be influenced. This is preferably a metabolic disease, in particular one of the diseases or conditions mentioned above, very particularly diabetes or diabetic complications.

The use of the compound according to the invention, or a physiologically tolerable salt thereof, in combination with a further active ingredient can be carried out at the same time or at different times, but in particular in a timely manner. When used at the same time, both active ingredients are administered to the patient together; in the case of staggered use, the two active substances are administered to the patient in succession in a period of less than or equal to 12, in particular less than or equal to 6 hours.

Accordingly, a further subject of this invention relates to a medicament which has a compound according to the invention or a physiologically tolerable salt of such a compound and at least one of the active ingredients described above as a combination partner in addition to optionally one or more inert carriers and / or diluents. For example, a medicament according to the invention has a combination of a compound according to the invention of the formula I or a physiologically tolerable salt of such a compound and at least one angiotensin II receptor antagonist in addition to, if appropriate, one or more inert carriers and / or diluents.

The compound according to the invention, or a physiologically compatible salt, and the further active ingredient to be combined therewith can be present together in one dosage form, for example a tablet or capsule, or separately in two identical or different dosage forms, for example as a so-called kit-of-parts.

Above and below, H atoms of hydroxyl groups are not always explicitly represented in structural formulas. The following examples are intended to illustrate the present invention without restricting it:

Preparation of the starting compounds:

Example I

4 - ((R) -tetrahydrofuran-3-yloxy) bromobenzene

prepared by stirring 10 g of 4-bromophenol with 21 g of p- for 32 hours

Toloulsulfonic acid - ((S) -tetrahydrofuran-3-yl) ester in the presence of 11.98 g

Potassium carbonate in 100 ml dimethylformamide at 60 ° C and subsequent purification by chromatographic purification.

Yield: 13.7 g (97% of theory)

Rf value: 0.80 (aluminum oxide; cyclohexane / ethyl acetate = 2: 1)

The following connection is produced analogously to Example I: (1) 4 - ((S) -tetrahydrofuran-3-yloxy) bromobenzene mass spectrum: m / z = 242/244 [M ⁺ ]

(2-Benzyloxy-phenyl) - [4 - ((R) -tetrahydrofuran-3-yloxy) phenyl] methanol

5.17 ml of a 1.6 M butyllithium solution in hexane are added dropwise to a solution of 2.0 g of 4 - ((R) -tetrahydrofuran-3-yloxy) bromobenzene in 10 ml of tetrahydrofuran at -78 ° C. and another hour at -78 ° for one hour C stirred. Then 1.75 g of 2-benzyloxybenzaldehyde, dissolved in 5 ml of tetrahydrofuran, are added dropwise and the mixture is stirred at -78 ° C. for 2 hours. After warming to room temperature, the mixture is stirred for 1 hour. After aqueous work-up and extraction with ethyl acetate, the organic phase is dried and concentrated. The residue is purified by chromatography on a silica gel column using cyclohexane / ethyl acetate (8: 2 to 1: 1).

Yield: 2.6 g (84% of theory)

R _f value: 0.25 (silica gel, cyclohexane / ethyl acetate = 3: 1)

The following compounds are prepared analogously to Example II:

(1) (2-Benzyloxy-phenyl) - [4 - ((S) -tetrahydrofuran-3-yloxy) phenyl] -methanol mass spectrum (ESI ⁺ ): m / z = 394 [M + NH] ⁺

(2) (2-Benzyloxy-4-fluorophenyl) - [4 - ((R) -tetrahydrofuran-3-yloxy) phenyl] methanol mass spectrum (ESI ⁺ ): m / z = 417 [M + Na] ⁺ (3) (2-Benzyloxy-6-methoxy-phenyl) - [4 - ((R) -tetrahydrofuran-3-yloxy) phenyl] -methanol mass spectrum (ESI ⁺ ): m / z = 424 [M + NH ₄ ] ⁺

example

2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] phenol

prepared from 1.97 g of the compound of Example II by catalytic hydrogenation in methanol in the presence of 0.4 g of palladium on activated carbon (10% Pd)

Room temperature.

RrValue: 0.52 (silica gel, cyclohexane / ethyl acetate = 2: 1)

Mass spectrum (ESI ^" ): m / z = 269 [MH] ^"

The following compounds are prepared analogously to Example III:

(1) 2- [4 - ((S) -tetrahydrofuran-3-yloxy) benzyl] phenol mass spectrum (ESI ⁺ ): m / z = 271 [M + H] ⁺

(2) 2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] -4-fluorophenol mass spectrum (ESP): m / z = 287 [MH] ^"

(3) 2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] -6-methoxyphenol mass spectrum (ESI ⁺ ): m / z = 301 [M + H] ⁺ Example IV

1- (2,3,4,6-Tetra-0-acetyl-β-D-glucopyranosyloxy) -2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] benzene

500 mg of 2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] phenol, 820 mg of 2,3,4,6-tetra-O-acetyl-aipha-glucopyranosylbromide, 2 ml of 1M sodium hydroxide solution and 5 ml Chloroform are stirred for 16 hours at room temperature. 400 mg of 2,3,4,6-tetra-O-acetyl-alpha-glucopyranosyl bromide, 1 ml of 1M sodium hydroxide solution and 5 ml of methylene chloride are added and the mixture is stirred for 2.5 days. The organic phase is separated off, washed with water, dried and concentrated. The crude product is purified by chromatography on a silica gel column using a cyclohexane / ethyl acetate gradient (7: 3 to 1: 1). Yield: 440 mg (40% of theory) Rf value: 0.10 (silica gel; cyclohexane / ethyl acetate = 2: 1) mass spectrum (ESI ⁺ ): m / z = 618 [M + NH ₄ ] ⁺

The following compounds are obtained analogously to Example IV:

(1) 1 - (2,3,4,6-Tetra-0-acetyl-β-D-glucopyranosyloxy) -2- (4-ethynylbenzyl) benzene

Reaction with the compound of Example VI in the presence of benzyl triethylammonium bromide

Rf value: 0.30 (silica gel; cyclohexane / ethyl acetate = 2: 1)

Mass spectrum (ESI ⁺ ): m / z = 556 [M + NH ₄ ] ⁺

(2) 1- (2,3,4,6-Tetra-0-acetyl-β-D-glucopyranosyloxy) -2- [4 - ((S) -tetrahydrofuran-3-yloxy) benzyl] benzene

Rf value: 0.50 (silica gel; cyclohexane / ethyl acetate = 1: 1) mass spectrum (ESI ⁺ ): m / z = 618 [M + NH ₄ ] ⁺

(3) 1- (2,3,4,6-tetra-0-acetyl-β-D-glucopyranosyloxy) -2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] -4-fluoro- benzene

Mass spectrum (ESI ⁺ ): m / z = 636 [M + NH ₄ ] ⁺

(4) 1- (2,3,4,6-tetra-0-acetyl-β-D-glucopyranosyloxy) -2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] -6-methoxy- benzene

Mass spectrum (ESI ⁺ ): m / z = 648 [M + NH ₄ ] ⁺

Example V

2- (4-bromobenzyl) -phenol prepared by reacting sodium phenolate (from 4.0 g phenol and 1.7 g 60% sodium hydride in paraffin oil) with 10.27 g 4-bromobenzyl chloride in toluene under reflux and purification of the reaction mixture by chromatography on a

Silica gel column with cyclohexane / ethyl acetate (8: 2 to 1: 1).

Yield: 1.8 g (16% of theory)

Rf value: 0.40 (silica gel; cyclohexane / ethyl acetate = 4: 1)

Mass spectrum (ESI ^" ): m / z = 261/263 [MH] ^"

Example VI

2- [4- (2-Trimethylsilylethynyl) benzyl] phenol prepared by reacting 1.6 g of 2- (4-bromobenzyl) phenol with 1.03 ml of trimethylsilyl acetylene in the presence of 86 mg of bis (triphenylphosphine) palladium ( ll) - chloride and 23 mg copper (l) iodide in 5 ml triethylamine at 100 ° C in a microwave oven and purification of the reaction mixture by chromatography on a silica gel column with cyclohexane / ethyl acetate (9: 1 to 7: 3) Rf value: 0.62 (silica gel; cyclohexane / ethyl acetate = 4: 1) mass spectrum (ESI ⁺ ): m / z = 281 [M + H] ⁺

Making the end connections:

example 1

1- (ß-D-glucopyranosyloxy) -2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] -benzene

A solution of 400 mg of 1- (2,3,4,6-tetra-0-acetyl-ß-D-glucopyranosyloxy) -2- [4 - ((R) - tetrahydrofuran-3-yloxy) benzyl] benzene in a mixture of 2.5 ml of methanol and 5 ml of tetrahydrofuran is cooled in an ice bath and mixed with 3.02 ml of a 1 M aqueous lithium hydroxide solution and stirred for 1 hour. The reaction mixture is mixed with 5 ml of water and extracted with ethyl acetate. The organic phase is separated off, washed with saturated sodium chloride solution, dried and concentrated. Yield: 190 mg (65% of theory) Rf value: 0.23 (silica gel; methylene chloride / methanol = 9: 1) mass spectrum (ESI ⁺ ): m / z = 433 [M + H] ⁺

The following compounds are obtained analogously to Example 1:

(1) 1 - (β-D-glucopyranosyloxy) -2- (4-ethynylbenzyl) benzene

R _f value: 0.55 (silica gel, methylene chloride / methanol = 6: 1) mass spectrum (ESI ⁺ ): m / z = 388 [M + NH ₄ ] ⁺

(2) 1- (β-D-glucopyranosyloxy) -2- [4 - ((S) -tetrahydrofuran-3-yloxy) benzyl] benzene

Melting point: 134-135 ° C

(3) 1- (β-D-glucopyranosyloxy) -2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] -4-fluorobenzene

Melting point: 145-147 ° C

(4) 1- (β-D-Glucopyranosyloxy) -2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] -6-methoxybenzene

Mass spectrum (ESI ⁺ ): m / z = 480 [M + NH ₄ ] Example 2

1- (6-O-methoxycarbonyl-.beta.-D-gIucopyranosyloxy) -2- (4-ethinylbenzyl) benzene

100 mg of 1- (ß-D-glucopyranosyloxy) -2- (4-ethynylbenzyl) benzene in 0.5 ml of 2,4,6-collidine are mixed with 0.026 ml of methyl chloroformate in an ice bath and then stirred for 16 hours at room temperature. 5 ml of 0.1 N hydrochloric acid are added to the reaction mixture and extracted with 10 ml of ethyl acetate. The organic phase is separated off, washed with saturated sodium chloride solution and concentrated. The residue is stirred with 8 ml of diethyl ether / petroleum ether (1: 1), the solid is filtered off with suction and dried at 40 ° C. Yield: 73.5 mg (63% of theory) mass spectrum (ESI ⁺ ): m / z = 429 [M + Hf

The following compounds are obtained analogously to Example 2:

(1) 1 - (6-0-Methoxycarbonyl-β-D-glucopyranosyloxy) -2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] benzene

Mass spectrum (ESl ⁺ ): m / z = 508 [M + NH ₄ ] ^' (2) 1- (6-0-methoxycarbonyl-β-D-glucopyranosyloxy) -2- [4 - ((S) -tetrahydrofuran-3-yoxy) benzyl] -benzene

Melting point: 149-150 ° C

The following compounds are also prepared analogously to the examples mentioned above and other processes known from the literature:

Example A

Tablets with 100 mg of active substance

Composition: 1 tablet contains: Active ingredient 100.0 mg milk sugar 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg

Herstellunqverfahren:

Active ingredient, milk sugar and starch are mixed and moistened evenly with an aqueous solution of the polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50 ° C, sieving is again carried out (1.5 mm mesh size) and the lubricant is added. The ready-to-press mixture is processed into tablets.

Tablet weight: 220 mg, diameter: 10 mm, biplane with double-sided facet and one-sided partial notch.

Example B

Tablets with 150 mg of active substance

Composition: 1 tablet contains: active substance 150.0 mg milk sugar powder. 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

Production: The active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a 1.5 mm mesh size.

The granules dried at 45 ° C are rubbed through the same sieve again and mixed with the specified amount of magnesium stearate. The mixture becomes

Tablets pressed.

Tablet weight: 300 mg stamp: 10 mm, flat

Example C

Hard gelatin capsules with 150 mg of active substance

Composition:

1 capsule contains: Active ingredient 150.0 mg corn starch dr. approx. 180.0 mg powdered milk sugar approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg

production:

The active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device. The final mix is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg Capsule shell: hard gelatin capsule size 1.

Example D

Suppositories with 150 mg of active substance

Composition: 1 suppository contains: Active ingredient 150.0 mg polyethylene glycol 1500 550.0 mg polyethylene glycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2000.0 mg

production:

After the suppository mass has melted, the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds.

Example E

Ampoules with 10 mg of active substance

Composition: active ingredient 10.0 mg 0.01 n hydrochloric acid s.q. Aqua bidest to 2.0 ml

production:

The active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules. Example F

Ampoules with 50 mg of active substance

Composition: active ingredient 50.0 mg 0.01 n hydrochloric acid s.q. Aqua bidest to 10.0 ml

production:

The active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.

Claims

claims

1. Glucopyranosyloxy-substituted aromatics of the general formula

in which

R ^{1 is} C ₂ - ₆ alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-Cι- ₃ alkyloxy or tetrahydropyranyl-Cι- ₃ -alkyloxy, or if R ^{3 is} selected is from the group consisting of C ₂ . ₆ -alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl -Cι _-3 alkyloxy and tetrahydropyranyl -Cι- ₃ alkyloxy, then R ¹ can also be hydrogen, fluorine, chlorine, Bromine, iodine, Cι_ _4- alkyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, Cι _-4 -alkoxy, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms, by a hydroxy - or -C ₃ alkoxy group substituted C _-4 alkyl, C _2-4 alkoxy substituted by a hydroxy or C ₃ alkoxy group, C ₂ . ₆ alkenyl, _C3-6 cycloalkyl, C ₃ - ₆ - cycloalkyl-Cι-3-alkyl, C _3-6 cycloalkoxy, C. ₃ _6- Cycloalkyl-C _1-3 alkoxy, hydroxy, amino or cyano mean, and R ^{2 is} hydrogen, fluorine, chlorine, methyl, methyl or methoxy substituted by 1 to 3 fluorine atoms, and

R ³ C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-Cι- ₃ -alkyloxy or tetrahydropyranyl-Cι_ ₃ -alkyloxy, or if R ^{1 is} selected from the group consisting of C ₂ . ₆ -alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl -CC. ₃ -alkyloxy and tetrahydropyranyl-Cι_ ₃ -alkyloxy, then R ³ can also be hydrogen, fluorine, chlorine, bromine, iodine, C-ι_ ₆ alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, C _{3 -6-} Cycloalkylidenmethyl, Cι- ₆ alkoxy, C _3-6 - Cycloalkyl-oxy, C ₃ . ₆ -cycloalkyl-Cι _-3 -alkoxy, aryl, aryl-Cι. ₃ -alkyl, heteroaryl, heteroaryl -CC ₃ alkyl, aryloxy, aryl -CC. _3- alkyl-oxy, methyl or methoxy substituted by 1 to 3 fluorine atoms, C _2-4 -alkyl or C _2-4 -alkoxy substituted by 1 to 5 fluorine atoms, C-ι- ₄ -alkyl substituted by a cyano group, by a Hydroxy- or Cι _-3 alkyloxy group substituted C ^ alkyl, cyano, carboxy, Cι- ₃ alkoxycarbonyl, aminocarbonyl, (Cι _-3 - alkylamino) carbonyl, di (Cι. ₃ alkyl) aminocarbonyl -, Pyrrolidin-1 -ylcarbonyl-, piperidin-1 -ylcarbonyl-, morpholin-4-ylcarbonyl-, piperazin-1-yl-carbonyl-, 4- (Cι- ₃ -alkyl) -piperazin-1 -ylcarbonyl-, nitro -, Amino-, Cι- _3- alkylamino- or di- (Cι. ₃ -alkyl) amino-, (Cι-4-alkyl) carbonylamino-, C- _M -alkylsulfonylamino, arylsulfonylamino, aryl-Cι _-3 -alkylsulfonylamino, Cι_ ₄ alkylsulfanyl, Cι _-4 - alkylsulfinyl, Cu alkylsulfonyl, arylsulfonyl, arylsulfinyl or arylsulfonyl mean,

R ⁴ and R ⁵ , which may be the same or different, are hydrogen, fluorine, chlorine, bromine, C ₃ -C ₃ alkyl, C ₃ -C ₃ alkoxy, methyl or methoxy substituted by 1 to 3 fluorine atoms, and

R ⁶ , R ^7a , R ^7b , R ^7c independently of one another have a meaning selected from the group consisting of hydrogen, (-CC ₈ -alkyl) carbonyl, (-CC ₈ -alkyl) oxycarbonyl, arylcarbonyl and aryl- (Cι _-3 -alkyl) -carbonyl,

where the aryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning phenyl or naphthyl groups which can be mono- or disubstituted independently of one another by R _h , where the substituents can be identical or different and R _{h is} a fluorine or chlorine , Bromine, iodine, C ₃ alkyl, difluoromethyl, trifluoromethyl, C 3 alkoxy, difluoromethoxy, trifluoromethoxy or cyan means

the heteroaryl groups mentioned in the definition of the radicals mentioned above mean a pyrrolyl, furanyl, thienyl, imidazolyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group,

or a pyrrolyl, furanyl, thienyl, imidazolyl or pyridyl group in which one or two methine groups are replaced by nitrogen atoms,

or an indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group in which one to three methine groups are replaced by nitrogen atoms, it being possible for the heteroaryl groups mentioned above to be mono- or disubstituted by R _h , where the substituents are identical or can be different and R _{h is} as defined above,

their tautomers, their stereoisomers, their mixtures and their salts.

2. Glucopyranosyloxy-substituted aromatics of the general formula I according to claim 1, in which

R ^{1 is} ethynyl, or, if R ^{3 is} selected from the group consisting of ethynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy and tetrahydropyranylmethyloxy, then R ¹ can also be hydrogen, fluorine , Chlorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or cyano mean, and

R ^{2 represents} hydrogen, fluorine or methyl,

R ^{3 is} ethynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy or tetrahydropyranylmethyloxy, or, if R ^{1 is} ethynyl, R ³ can also be hydrogen, fluorine, chlorine, methyl, ethyl, Isopropyl, tert-butyl, 2-cyano-2-propyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, 1, 1,2,2-tetrafluoroethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy , Methylsulfanyl, 2-methyl-1-propen-1-yl, cyclopropylidenemethyl-, phenyl-, fluorophenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl or thiazolyl or thiadolyl or thiadolyl or thiadolyl or thiadolyl or thiadolyl or thiadolyl or

R ^{4 is} hydrogen, fluorine or methyl, R ^{5 is} hydrogen,

R ⁶ , R ^7a ,

R ^7b , R ^7c, independently of one another, have a meaning selected from the group consisting of hydrogen, (-CC ₈ -alkyl) carbonyl, (-CC ₈ -alkyl) oxycarbonyl, arylcarbonyl and aryl- (-C _-3 -alkyl) -carbonyl,

their tautomers, their stereoisomers, their mixtures and their salts.

3. glucopyranosyloxy-substituted aromatics of the general formula I according to claim 1, in which

R ^{1 is} ethynyl or, if R ^{3 is} selected from the group consisting of ethynyl and tetrahydrofuran-3-yloxy, then R ¹ can also mean hydrogen, fluorine, methyl, methoxy or cyano,

R ^{2 is} hydrogen or methyl,

R ^{3 is} ethynyl or tetrahydrofuran-3-yloxy or, if R ^{1 is} ethynyl, R ^{3 can} additionally also be methyl, ethyl, methoxy, difluoromethoxy or trifluoromethoxy, R ^{4 is} hydrogen or fluorine,

R ^{5 is} hydrogen,

R ⁶ , R ^7a , R ^7b , R ^7c independently of one another are selected from the group consisting of hydrogen, (Cι.ι ₈ -alkyl) carbonyl, (C-Ms-alkyl) oxycarbonyl, arylcarbonyl and aryl- (Cι. ₃ -alkyl) ) have carbonyl,

their stereoisomers and their mixtures.

4. Compounds of general formula I according to claim 1 selected from the group consisting of

(a) 1- (β-D-glucopyranosyloxy) -2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] benzene,

(b) 1 - (β-D-glucopyranosyloxy) -2- (4-ethynylbenzyl) benzene,

including their tautomers, their stereoisomers and their mixtures.

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

6. Medicament containing a compound according to at least one of claims 1 to 4 or a physiologically acceptable salt according to claim 5 in addition optionally one or more inert carriers and / or diluents.

7. Use of at least one compound according to one or more of claims 1 to 4 or a physiologically tolerable salt according to claim 5 for the manufacture of a medicament which is suitable for the treatment or prophylaxis of diseases or conditions which can be influenced by inhibition of the sodium-dependent glucose cotransporter SGLT are.

8. Use of at least one compound according to at least one of claims 1 to 4 or a physiologically acceptable salt according to claim 5 for the manufacture of a medicament which is suitable for the treatment or prophylaxis of metabolic diseases.

9. Use according to claim 8, characterized in that the metabolic disease is selected from the group consisting of type 1 and type 2 diabetes mellitus, diabetic complications, metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorder, insulin resistance, metabolic syndrome, dyslipidemias in a wide variety of ways Genesis, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, edema, hyperuricaemia.

10. Use of at least one compound according to at least one of claims 1 to 4 or a physiologically tolerable salt according to claim 5 for the manufacture of a medicament for inhibiting the sodium-dependent glucose cotransporter SGLT.

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

12. Use of at least one compound according to at least one of claims 1 to 4 or a physiologically tolerable salt according to claim 5 for the preparation of diuretics and / or antihypertensives.

13. A method for producing a medicament according to claim 6, characterized in that a compound according to at least one of claims 1 to 4 or a physiologically tolerable salt according to claim 5 is incorporated into one or more inert carriers and / or diluents in a non-chemical way ,

14. A process for the preparation of the compounds of general formula I according to claims 1 to 4, characterized in that

a) for the preparation of compounds of the general formula I in which R ⁶ , R ^7a , R ^7b and R ^{7c are} as defined in claim 1 but are not hydrogen,

a compound of the general formula

in the

in the

R ¹ to R ^{5 are} as defined in claim 1, is reacted or b) to prepare compounds of the general formula I in which R ⁶ , R ^7a , R ^7b and R ^{7c are} hydrogen,

a compound of the general formula I in which R ⁶ and R ^7a , R ^7b , R ^{7c are} as previously defined, but are not hydrogen, is hydrolyzed, upd

if desired, a compound of the general formula I thus obtained, in which R ^{6 represents} a hydrogen atom, is converted into a corresponding acyl compound of the general formula I by acylation, and / or