DE10361133A1 - Glucopyranosyloxy-substituted aromatics, medicaments containing these compounds, their use and processes for their preparation - Google Patents

Abstract

in der
R¹ bis R⁶ sowie R^7a, R^7b, R^7c im Anspruch 1 definiert sind, deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren, welche wertvolle pharmakologische Eigenschaften aufweisen, insbesondere eine Hemmwirkung auf den natriumabhängigen Glucose-Cotransporter SGLT2, deren Verwendung zur Behandlung von Krankheiten, insbesondere von Stoffwechselerkrankungen wie Diabetes, und deren Herstellung.The present invention relates to glucopyranosyloxy-substituted aromatics of the general formula

in the
R ¹ to R ⁶ and R ^7a , R ^7b , R ^7c are defined in claim 1, their tautomers, their stereoisomers, mixtures thereof and their salts, in particular their physiologically acceptable salts with inorganic or organic acids, which have valuable pharmacological properties, in particular an inhibitory effect on the sodium-dependent glucose cotransporter SGLT2, its use for the treatment of diseases, in particular of metabolic diseases such as diabetes, and their production.

Description

wobei die Reste R¹ bis R⁶ und R^7a, R^7b und R^7c nachfolgend definiert sind, einschließlich deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze. Ein weiterer Gegenstand dieser Erfindung betrifft Arzneimittel enthaltend eine erfindungsgemäße Verbindung der Formel I sowie die Verwendung einer erfindungsgemäßen Verbindung zur Herstellung eines Arzneimittels zur Behandlung von Stoffwechselerkrankungen. Darüber hinaus sind Verfahren zur Herstellung eines Arzneimittels sowie einer erfindungsgemäßen Verbindung Gegenstand dieser Erfindung.The present invention relates to glucopyranosyloxy-substituted aromatics of the general formula I.

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. A further subject of this invention relates to medicaments containing a compound of the formula I according to the invention and to the use of a compound according to the invention for the preparation of a medicament for the treatment of metabolic diseases. In addition, processes for the preparation of a medicament and of a compound according to the invention are the subject of this invention.

In In the literature, compounds which have an inhibitory effect on the sodium-dependent Glucose cotransporters SGLT2 have, for the treatment of diseases, especially suggested by diabetes.

Out International Publication WO 01/68660, WO 01/74834, WO 02/28872, WO 02/44192, WO 02/64606, WO 03/11880 and WO 03/80635 are glucopyranosyloxy-substituted aromatics and their preparation and their possible activity known as SGLT2 inhibitors.

Object of the invention

Of the The present invention is based on the object, new glucopyranosyloxy-substituted aromatics show, in particular, those who have an activity related to the sodium-dependent Possess glucose cotransporters SGLT2. Another task of present invention is to show glucopyranosyloxy-substituted aromatics, the in vitro and / or in vivo compared with known, structurally similar compounds an increased Inhibitory effect with respect sodium-dependent Possess glucose-cotransporters SGLT2 and / or improved pharmacological or pharmacokinetic properties.

Further It is an object of the present invention to provide new medicines to provide, which for the prophylaxis and / or treatment of Metabolic disorders, especially of diabetes are suitable.

Also An object of this invention is to provide a method of preparation the compounds of the invention to provide.

Further Objects of the present invention will be apparent to those skilled in the art directly from the preceding and following remarks.

Subject of the invention

in denen
R¹ C_2-6-Alkinyl, Tetrahydrofuran-3-yloxy, Tetrahydropyran-3-yloxy, Tetrahydropyran-4-yloxy, Tetrahydrofuranyl-C_1-3-alkyloxy oder Tetrahydropyranyl-C_1-3-alkyloxy bedeutet, oder,
falls R³
ausgewählt ist aus der Gruppe bestehend aus C_2-6-Alkinyl, Tetrahydrofuran-3-yloxy, Tetrahydropyran-3-yloxy, Tetrahydropyran-4-yloxy, Tetrahydrofuranyl-C_1-3-alkyloxy und Tetrahydropyranyl-C_1-3-alkyloxy,
dann kann R¹ zusätzlich auch Wasserstoff, Fluor, Chlor, Brom, Iod, C_1-4-Alkyl, eine durch 1 bis 3 Fluoratome substituierte Methylgruppe, eine durch 1 bis 5 Fluoratome substituierte Ethylgruppe, eine durch 1 bis 3 Fluoratome substituierte Methoxygruppe, eine durch 1 bis 5 Fluoratome substituierte Ethoxygruppe, eine durch eine Hydroxy- oder C_1-3-Alkoxygruppe substituierte C_1-4-Alkylgruppe, eine durch eine Hydroxy- oder C_1-3-Alkoxygruppe substituierte C_2-4-Alkoxygruppe, C_2-6-Alkenyl, C_3-6-Cycloalkyl, C_3-6-Cycloalkyl-C_1-3-alkyl, C_3-6-Cycloalkoxy, C_3-6-Cycloalkyl-C_1-3-alkoxy, Hydroxy, Amino oder Cyano bedeuten, und
R² Wasserstoff, Fluor, Chlor, Methyl oder durch 1 bis 3 Fluoratome substituiertes Methyl bedeutet, und
R³ C_2-6-Alkinyl, Tetrahydrofuran-3-yloxy, Tetrahydropyran-3-yloxy, Tetrahydropyran-4-yloxy, Tetrahydrofuranyl-C_1-3-alkyloxy oder Tetrahydropyranyl-C_1-3-alkyloxy, oder,
falls R¹ ausgewählt ist aus der Gruppe bestehend aus C_2-6-Alkinyl, Tetrahydrofuran-3-yloxy, Tetrahydropyran-3-yloxy, Tetrahydropyran-4-yloxy, Tetrahydrofuranyl-C_1-3-alkyloxy und Tetrahydropyranyl-C_1-3-alkyloxy,
dann kann R³ zusätzlich auch Wasserstoff, Fluor, Chlor, Brom, Iod, C_1-6-Alkyl, C_2-6-Alkenyl, C_3-6-Cycloalkyl, C_3-6-Cycloalkylidenmethyl, C_1-6-Alkoxy, C_3-6-Cycloalkyl-oxy, C_3-6-Cycloalkyl-C_1-3-alkoxy, Aryl, Aryl-C_1-3-alkyl, Heteroaryl, Heteroaryl-C_1-3-alkyl, Aryloxy, Aryl-C_1-3-alkyl-oxy, eine durch 1 bis 3 Fluoratome substituierte Methyl- oder Methoxygruppe, eine durch 1 bis 5 Fluoratome substituierte C_2-4-Alkyl- oder C_2-4-Alkoxygruppe, eine durch eine Cyangruppe substituierte C_1-4-Alkylgruppe, eine durch eine Hydroxy- oder C_1-3-Alkyloxygruppe substituiertes C_1-4-Alkylgruppe, Cyano-, Carboxy-, C_1-3-Alkoxycarbonyl-, Aminocarbonyl-, (C_1-3-Alkylamino)carbonyl-, Di-(C_1-3-alkyl)aminocarbonyl-, Pyrrolidin-1-ylcarbonyl-, Piperidin-1-ylcarbonyl-, Morpholin-4-ylcarbonyl-, Piperazin-1-yl-carbonyl-, 4-(C_1-3-Alkyl)-piperazin-1-ylcarbonyl-, Nitro-, Amino-, C_1-3-Alkylamino- oder Di-(C_1-3-alkyl)amino-, (C_1-4-Alkyl)carbonylamino-, C_1-4-Alkylsulfonylamino, Arylsulfonylamino, Aryl-C_1-3-alkylsulfonylamino, C_1-4-Alkylsulfanyl-, C_1-4-Alkylsulfinyl-, C_1-4-Alkylsulfonyl, Arylsulfenyl-, Arylsulfinyl-oder Arylsulfonyl- bedeuten,
R⁴ und R⁵, die gleich oder verschieden sein können, Wasserstoff, Fluor, Chlor, Brom, C_1-3-Alkyl, C_1-3-Alkoxy, durch 1 bis 3 Fluoratome substituiertes Methyl- oder Methoxy bedeuten, und
R⁶, R^7a, R^7b, R^7c unabhängig voneinander eine Bedeutung ausgewählt aus der Gruppe Wasserstoff, (C_1-18-Alkyl)carbonyl, (C_1-18-Alkyl)oxycarbonyl, Arylcarbonyl und Aryl-(C_1-3-alkyl)-carbonyl besitzen,
wobei unter den bei der Definition der vorstehend genannten Reste erwähnten Arylgruppen Phenyl- oder Naphthylgruppen zu verstehen sind, welche unabhängig voneinander durch R_h mono- oder disubstituiert sein können, wobei die Substituenten gleich oder verschieden sein können und R_h ein Fluor, Chlor, Brom, Iod, C_1-3-Alkyl, Difluormethyl, Trifluormethyl, C_1-3-Alkoxy, Difluormethoxy, Trifluormethoxy oder Cyan bedeutet,
unter den bei der Definition der vorstehend erwähnten Reste erwähnten Heteroarylgruppen eine Pyrrolyl-, Furanyl-, Thienyl-, Pyridyl-, Indolyl-, Benzofuranyl-, Benzothiophenyl-, Chinolinyl- oder Isochinolinylgruppe zu verstehen ist,
oder eine Pyrrolyl-, Furanyl-, Thienyl- oder Pyridylgruppe zu verstehen ist, in der eine oder zwei Methingruppen durch Stickstoffatome ersetzt sind,
oder eine Indolyl-, Benzofuranyl-, Benzothiophenyl-, Chinolinyl- oder Isochinolinylgruppe zu verstehen ist, in der eine bis drei Methingruppen durch Stickstoffatome ersetzt sind,
wobei die vorstehend erwähnten Heteroarylgruppen durch R_h mono- oder disubstituiert sein können, wobei die Substituenten gleich oder verschieden sein können und R_h wie vorstehend definiert ist,
wobei, soweit nichts anderes erwähnt wurde, die vorstehend erwähnten Alkylgruppen geradkettig oder verzweigt sein können,
deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.A first subject 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-C _1-3 -alkyloxy or tetrahydropyranyl-C _1-3 -alkyloxy, or
if R ³
is selected from the group consisting of C _2-6 -alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 -alkyloxy and tetrahydropyranyl-C _1-3 -alkyloxy,
then R ^{1 may} additionally also be hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 -alkyl, a methyl group substituted by 1 to 3 fluorine atoms, an ethyl group substituted by 1 to 5 fluorine atoms, a methoxy group substituted by 1 to 3 fluorine atoms, an ethoxy group substituted by 1 to 5 fluorine atoms, a C _1-4 alkyl group substituted by a hydroxy or C _1-3 alkoxy group, a C _2-4 alkoxy group substituted by a hydroxy or C _1-3 alkoxy group, C _2-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 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 or substituted by 1 to 3 fluorine atoms methyl, and
R ^{3 is} C _2-6 -alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 -alkyloxy or tetrahydropyranyl-C _1-3 -alkyloxy, or
when R ^{1 is} selected from the group consisting of C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl C _1-3 alkyloxy and tetrahydropyranyl C _1-3 alkyloxy,
then R ^{3 may} additionally also be hydrogen, fluorine, chlorine, bromine, iodine, C _1-6 -alkyl, C _2-6 -alkenyl, C _3-6 -cycloalkyl, C _3-6 -cycloalkylidenemethyl, C _1-6 -alkoxy , C _3-6 -cycloalkyl-oxy, C _3-6 -cycloalkyl-C _1-3 -alkoxy, aryl, aryl-C _1-3 -alkyl, heteroaryl, heteroaryl-C _1-3 -alkyl, aryloxy, aryl- C _1-3 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 ₁ substituted by a cyano group _-4 alkyl group, a substituted by a hydroxy or C _1-3 alkyloxy C _1-4 alkyl, cyano, carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, (C _1-3 alkylamino) carbonyl, di (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-yl-carbonyl, 4- (C _1-3 alkyl) -piperazin-1-ylcarbonyl, nitro, amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino, (C _1-4 alkyl) carbonylamino -, C _1-4 alkylsulfonylamine o, arylsulfonylamino, arylC _1-3 alkylsulfonylamino, C _1-4 alkylsulfanyl, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, arylsulfenyl, arylsulfinyl or arylsulfonyl,
R ⁴ and R ⁵ , which may be identical or different, denote hydrogen, fluorine, chlorine, bromine, C _1-3 -alkyl, C _1-3 -alkoxy, methyl or methoxy substituted by 1 to 3 fluorine atoms, and
R ⁶ , R ^7a , R ^7b , R ^7c independently of one another are selected from the group consisting of hydrogen, (C _1-18 -alkyl) carbonyl, (C _1-18 -alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _1-3 alkyl) carbonyl,
wherein the aryl groups mentioned in the definition of the abovementioned radicals are 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, chlorine, bromine , Iodo, C _1-3 -alkyl, difluoromethyl, trifluoromethyl, C _1-3 -alkoxy, difluoromethoxy, trifluoromethoxy or cyano,
among the heteroaryl groups mentioned in the definition of the abovementioned radicals, a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group is to be understood,
or a pyrrolyl, furanyl, thienyl 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,
wherein the above-mentioned heteroaryl groups may be mono- or disubstituted by R _h , where the substituents may be the same or different and R _{h is} as defined above,
Unless otherwise stated, the abovementioned alkyl groups may be straight-chain or branched,
their tautomers, their stereoisomers, their mixtures and their salts.

The Compounds of the invention the general formula I and their physiologically acceptable salts have valuable pharmacological properties, in particular an inhibitory effect on the sodium-dependent glucose cotransporter SGLT2.

object The present invention also includes the physiologically acceptable Salts of the compounds of the invention with inorganic or organic acids.

One Another object of this invention are medicaments containing at least one compound of the invention or a physiologically acceptable according to the invention Salt next to optionally one or more inert carriers and / or diluents.

One Another object of this invention is the use of at least a compound of the invention for the manufacture of a medicament for the treatment of metabolic diseases suitable is

Further is a process for the preparation of a medicament according to the invention Subject of this invention, characterized in that on non-chemical Ways a compound of the invention in one or more inert carriers and / or diluents is incorporated.

• a) zur Herstellung von Verbindungen der allgemeinen Formel I, in der R⁶, R^7a, R^7a und R^7c wie zuvor definiert ist, jedoch nicht Wasserstoff bedeuten, eine Verbindung der allgemeinen Formel
  
  in der R⁶ sowie R^7a, R^7b, R^7c wie zuvor definiert sind, jedoch nicht Wasserstoff bedeuten, und Z¹ eine Austrittsgruppe darstellt, mit einer Verbindung der allgemeinen Formel
  
  in der R¹ bis R⁵ die eingangs erwähnten Bedeutungen besitzen, umgesetzt wird oder
• b) zur Herstellung von Verbindungen der allgemeinen Formel I, in der R⁶, R^7a, R^7b und R^7c Wasserstoff bedeuten, eine Verbindung der allgemeinen Formel I, in der R⁶ sowie R^7a, R^7b, R^7c wie zuvor definiert sind, jedoch nicht Wasserstoff bedeuten, hydrolysiert wird, und nach Durchführung des Schrittes b) gewünschtenfalls eine so erhaltene Verbindung der allgemeinen Formel I, in der R⁶ ein Wasserstoffatom darstellt, mittels Acylierung in eine entsprechende Acylverbindung der allgemeinen Formel I übergeführt wird, und/oder erforderlichenfalls ein bei den vorstehend beschriebenen Umsetzungen verwendeter Schutzrest wieder abgespalten wird und/oder gewünschtenfalls eine so erhaltene Verbindung der allgemeinen Formel I in ihre Stereoisomere aufgetrennt wird und/oder eine so erhaltene Verbindung der allgemeinen Formel I in ihre Salze, insbesondere für die pharmazeutische Anwendung in ihre physiologisch verträglichen Salze, überführt wird.

The present invention also provides a process for the preparation of the compounds of 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 ^7a and R ^{7c is} as defined ^above but does not denote hydrogen, a compound of the general formula
  
  ^wherein R ⁶ and R ^7a , R ^7b , R ^{7c are} as defined above, but are not hydrogen, and Z ^{1 represents} a leaving group, with a compound of the general formula
  
  in which R ¹ to R ^{5 have} the meanings mentioned above, is reacted or
• b) for the preparation of compounds of general formula I in which R ⁶ , R ^7a , R ^7b and R ^{7c are} hydrogen, a compound of general formula I in which R ⁶ and R ^7a , R ^7b , R ^7c as defined above are, but do not denote hydrogen, is hydrolyzed, and after carrying out step b), if desired, a compound of general formula I in which R ^{6 represents} a hydrogen atom is converted by acylation into a corresponding acyl compound of general formula I, and / or, if necessary, a protecting residue used in the reactions described above is cleaved off again and / or, if desired, a compound of general formula I thus obtained is resolved into its stereoisomers and / or a compound of general formula I thus obtained in its salts, in particular for the pharmaceutical Application in their physiologically acceptable salts, is transferred.

Detailed description the invention

Unless stated otherwise, 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.

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 C _1-3 alkyloxy or tetrahydropyranyl C _1-3 alkyloxy and
the remaining radicals R ² to R ⁶ and R ^7a , R ^7b , R ^{7c are} as defined above,
including their tautomers, their stereoisomers, their mixtures and their salts.

Preferred meanings of the radical R ¹ according to this embodiment are ethynyl, 2-propyn-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.

Preferred meanings of the radical R ³ according to this embodiment 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, oxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl. Particularly preferred meanings here are ethynyl, tetrahydrofuran-3-yloxy, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, 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 of 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, C _1-4 alkyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms , by a hydroxy or C _1-3 alkoxy substituted C _1-4 alkyl, substituted by a hydroxy or C _1-3 alkoxy C _2-4 alkoxy, C _2-6 alkenyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, C _3-6 cycloalkoxy, C _3-6 cycloalkyl C _1-3 alkoxy, hydroxy, amino or cyano, and also C _{2 -6-} alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 -alkyloxy or tetrahydropyranyl-C _1-3 -alkyloxy, and
R ^{3 is} selected from a group consisting of C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl C _1-3 alkyloxy and tetrahydropyranyl C _1-3 alkyloxy, and
the remaining radicals, especially 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.

subsequent versions refer to the compounds of formula I, in particular the previously mentioned first and second embodiment.

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

According to a variant of the abovementioned embodiments, those compounds are also preferred in which the phenyl group which bears 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 which have a substituent R ⁴ meaning fluorine are particularly preferred.

The phenyl radical bearing 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 in} accordance with the invention preferably denotes hydrogen, (C _1-8 -alkyl) oxycarbonyl or C _1-8 -alkylcarbonyl, in particular hydrogen or (C _1-6 -alkyl) oxycarbonyl, more preferably hydrogen, methoxycarbonyl or ethoxycarbonyl, completely particularly preferably hydrogen or methoxycarbonyl.

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

The compounds of the formula I in which R ⁶ , R ^7a , R ^7b and R ^{7c have} a meaning other than hydrogen according to the invention, for example C _1-8 -alkylcarbonyl, are preferably suitable as intermediates in the synthesis of compounds of the formula I in R ^7a , R ^7b and R ^{7c are} hydrogen.

• (a) 1-(β-D-Glucopyranosyloxy)-2-[4-((R)-tetrahydrofuran-3-yloxy)benzyl]-benzol,
• (b) 1-(β-D-Glucopyranosyloxy)-2-(4-ethinylbenzyl)-benzol,

sowie deren Derivate, in denen R⁶ eine erfindungsgemäße, von Wasserstoff verschiedene Bedeutung aufweist, insbesondere R⁶ Ethoxycarbonyl oder Methoxycarbonyl bedeutet,
einschließlich deren Stereoisomere und deren Gemische.Particularly preferred compounds of general formula I are selected from the group

• (a) 1- (β-D-glucopyranosyloxy) -2- [4 - ((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 according to the invention, in particular R ^{6 is} ethoxycarbonyl or methoxycarbonyl,
including their stereoisomers and their mixtures.

in the Following are terms used previously and below for description the compounds of the invention be used, closer Are defined.

The Designation Halogen denotes an atom selected from the group consisting from F, Cl, Br and I, especially F, Cl and Br.

The term C _1-n- alkyl, where n can have a value of 1 to 18, denotes a saturated, branched or unbranched hydrocarbon group having 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 having 2 to n C atoms and a C≡C double bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, isopropynyl, 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 C _1-n -alkoxy refers to a C _1-n -alkyl-O-group in which C _1-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 refers to a C _1-n -alkyl-C (= O) group, wherein 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 having 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1.] Octyl, spiro [4.5] decyl, norpinyl, norbornyl, norcaryl, adamantyl, etc. Preferably, the term includes C _3-7 cycloalkyl saturated monocyclic groups.

The term C _3-n -cycloalkylcarbonyl refers to a C _3-n -cycloalkyl-C (= O) group, wherein C _3-n -cycloalkyl is as defined above.

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

• a) Zur Herstellung von Verbindungen der allgemeinen Formel I, in der R⁶, R^7a, R^7b, R^7c wie eingangs erwähnt definiert sind, jedoch kein Wasserstoffatom darstellen: Umsetzung einer Verbindung der allgemeinen Formel
  
  in der R⁶ sowie R^7a, R^7b, R^7c wie eingangs erwähnt definiert sind, jedoch nicht Wasserstoff bedeuten, und Z¹ eine Austrittsgruppe wie beispielsweise ein Halogenatom, z.B. ein Fluor-, Chlor- oder Bromatom, oder eine Acyloxygruppe, z.B. eine Acetyloxy- oder Trichloracetimidoyloxy-Gruppe darstellt, mit einer Verbindung der allgemeinen Formel
  
  in der R¹ bis R⁵ erwähnten Bedeutungen besitzen.

The compounds according to the invention can be obtained using synthesis methods known in principle. The compounds are preferably obtained according to the preparation process according to the invention 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} as defined above, but do not represent a hydrogen atom: Reaction of a compound of the general formula
  
  in which R ⁶ and R ^7a , R ^7b , R ^{7c are} as defined above, but not 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 a Acetyloxy or trichloroacetimidoyloxy group, with a compound of general formula
  
  in which R ¹ to R ⁵ have meanings mentioned.

• b) Zur Herstellung von Verbindungen der allgemeinen Formel I, in der R⁶, R^7a, R^7b und R^7c Wasserstoff darstellen: Umsetzung einer Verbindung der allgemeinen Formel I, in der R⁶, R^7a, R^7b und R^7c wie eingangs erwähnt definiert sind, jedoch nicht Wasserstoff bedeuten, mit Wasser oder einem niederen Alkohol wie Methanol oder Ethanol.

The reaction is conveniently carried out in a solvent such as methylene chloride, chloroform, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, optionally in the presence of a base such as potassium carbonate, cesium carbonate, sodium hydride or potassium tert-butoxide , or a silver compound such as silver (I) oxide, silver (I) carbonate or silver (I) 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 / benzyltriethylammonium bromide, it being possible to cleave off other protective groups, such as the trimethylsilyl group on an ethynyl group.

• b) For the preparation of compounds of the general formula I in which R ⁶ , R ^7a , R ^7b and R ^{7c represent} hydrogen: Reaction of a compound of the general formula I in which R ⁶ , R ^7a , R ^7b and R ^7c, as in the beginning are defined but are not hydrogen, with water or a lower alcohol such as methanol or ethanol.

The Implementation takes place expediently in water, a lower alcohol such as methanol or ethanol or a watery one Solvent mixture such as methanol / tetrahydrofuran, in the presence of a base such as Lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methylate at temperatures between -20 ° C and 60 ° C. At this Implementation can other protecting groups, such as the trimethylsilyl group on an ethynyl group, be split off with.

If, in accordance with the invention, a compound of the general formula I in which R ^{6 represents} a hydrogen atom 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 US Pat R ^{6 represents} (C _1-18 alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl or aryl (C _1-3 alkyl) carbonyl. Suitable acylating agents are, in particular, the corresponding activated acyl derivatives, such as acid chlorides or anhydrides.

at The reactions described above may optionally be present reactive groups such as ethynyl, hydroxy, amino, alkylamino or Imino groups during the implementation by conventional protecting groups protected will be split off after the implementation.

For example come as a protective rest for an ethynyl group is the trimethylsilyl group.

For example come as a protective rest for a hydroxy group the trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.

When Protection residues for an amino, alkylamino or imino group, for example the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, Benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group into consideration.

The optionally subsequent Cleavage of a protective moiety used is carried out, 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 aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

The Cleavage of a Trimethylsilylrestes takes place for example in Water a watery Solvent mixture or a lower alcohol such as methanol or ethanol in the presence a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methylate.

The Cleavage of a benzyl, methoxybenzyl or Benzyloxycarbonylrestes however, it is advantageously 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. The cleavage of a 2,4-dimethoxybenzyl radical however, it is preferably carried out in trifluoroacetic acid in the presence of anisole.

The Cleavage of a tert-butyl or tert-Butyloxycarbonylrestes is preferably carried out by treatment with an acid such as trifluoroacetic or hydrochloric acid or optionally by treatment with iodotrimethylsilane Use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

The Cleavage of a Trifluoracetylrestes is preferably carried out by Treatment with an acid like hydrochloric acid optionally in the presence of a solvent such as acetic acid Temperatures between 50 and 120 ° C or by treatment with caustic soda optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C.

Further can the obtained compounds of general formula I, as already was mentioned in the beginning, be separated into their enantiomers and / or diastereomers. So can for example cis / trans mixtures into their cis and trans isomers, and compounds having at least one optically active carbon atom be separated into their enantiomers.

So For example, the resulting cis / trans mixtures can be allowed to pass through Chromatography into their cis and trans isomers, the obtained Compounds of general formula I, which occur in racemates after methods known per se (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and compounds of the general Formula I with at least 2 asymmetric carbon atoms due their physicochemical Differences according to methods known per se, e.g. by chromatography and / or fractional crystallization, break into their diastereomers, which, if they occur in racemic form, then like mentioned above can be separated into the enantiomers.

The Enantiomer separation is preferably carried out by column separation on chiral phases or by recrystallization from an optical active solvents or by reacting with one, with the racemic compound salts or derivatives such as e.g. Ester or amide-forming optically active Substance, especially acids and their activated derivatives or alcohols, and separating the this diastereomeric salt mixture or derivative obtained, e.g. due to different solubilities, where from the pure diastereomeric salts or derivatives of the free antipodes can be released by the action of appropriate means. Especially common, optically active acids are e.g. the D and L forms of tartaric or dibenzoyltartaric, di-O-toluenoic, malic, mandelic, camphorsulfonic, glutamic, aspartic or China acid. As an optically active alcohol, for example, (+) - or (-) - menthol and as an optically active acyl radical in amides, for example (+) - or (-) - menthyloxycarbonyl into consideration.

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

Farther can the compounds obtained in mixtures, for example in 1: 1 or 1: 2 mixtures with amino acids, especially with alpha-amino acids like proline or phenylalanine, the most favorable Properties such as high crystallinity may have.

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

The Compounds of the invention are also advantageous according to those described in the following examples Method accessible, this also with the expert, for example, from the literature known methods, 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 described methods can be combined.

As already mentioned at the beginning, have the compounds of the invention the general formula I and their physiologically acceptable Salts have valuable pharmacological properties, in particular an inhibitory effect on the sodium-dependent glucose cotransporter SGLT2.

The biological properties of the new compounds are tested as follows:
The ability of the substances to inhibit SGLT-2 activity can be demonstrated in an experimental setup in which a CHO-K1 cell line (ATCC No. CCL 61) stably transfected with an expression vector containing the cDNA for the coding sequence of the human sodium glucose cotransporter 2 (Genbank Acc No.NM_003041) contains (CHO-hSGLT2). This cell line transports 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 cultured in Ham's F12 medium (BioWhittaker) with 10% fetal calf serum and 250 μg / ml Zeocin (Invitrogen) and passaged twice weekly. To measure SGLT activity 50,000 cells are seeded in white 48-well plates and incubated overnight in the incubator at 37 ° C and 5% CO ₂ . The cells are then washed twice with 500 μl assay buffer (Hanks Balanced Salt Solution, 137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl ₂ , 1.2 mM MgSO ₄ and 10 mM HEPES (pH 7.4), 50 μg / ml gentamycin) and then filled with 250 μl assay buffer. Subsequently, 10 .mu.l of test substance in 10% aqueous DMSO solution is added and incubated at 37.degree. C. for 15 min. Subsequently, 50 μl of assay buffer are pipetted with 1.2 μCi / ml [ ¹⁴ C] -AMG and incubated for one hour at 37 ° C and 5% CO2. The cells are then washed twice with 0.5 ml assay buffer and then lysed in 500 μl 0.5 M NaOH and incubated for 30 min at room temperature. Thereafter, 45 μl of the lysate are transferred to a scintillation vial and, after adding 4 ml of UltimaGold (Packard), are measured in the scintillation counter (Packard TriCarb2300TR). As a negative control serve cells that were treated with only 10 ul 10% aqueous DMSO solution.

The Compounds of the invention of general formula I can for example, EC50 values below 1000 nM, in particular also below 50 nM.

In view of the ability to inhibit SGLT-2 activity, the compounds of general formula I according to the invention and their corresponding pharmaceutically acceptable salts are in principle suitable for influencing all those conditions or diseases which are influenced by an inhibition of SGLT-2 activity can. Therefore, compounds of the invention are particularly for the prevention or treatment of diseases, especially metabolic diseases, or conditions such as diabetes mellitus type 1 and type 2, diabetic complications (such as retinopathy, nephropathy or neuropathy, diabetic foot), metabolic acidosis or ketosis, reactive hypoglycemia, insulin resistance , Metabolic syndrome, dyslipidaemias of various genesis, atherosclerosis and related diseases, obesity. In addition, these substances are suitable for preventing beta cell degeneration such as apoptosis or necrosis of pancreatic beta cells. The substances are further suited to improve or restore the functionality of pancreatic cells, in addition to increase the number and size of pancreatic beta cells. The compounds of the invention are also useful as diuretics or antihypertensives and ge for the prevention and treatment of acute renal failure suitable.

The Compounds of the invention can also be used in combination with other active ingredients. To the therapeutics suitable for such combination include e.g. Antidiabetics, such as metformin, sulfonylureas (e.g., glibenclamide, Tolbutamide, glimepiride), nateglinides, repaglinide, thiazolidinediones (e.g., rosiglitazone, pioglitazone), PPAR gamma agonists (e.g., GI 262570) and - antagonists, PPAR-gamma / alpha modulators (e.g., KRP 297), alpha-glucosidase inhibitors (e.g., acarbose, voglibose), DPPIV inhibitors, alpha2 antagonists, Insulin and insulin analogs, GLP-1 and GLP-1 analogs (e.g., exendin-4) or amylin. In addition, inhibitors of protein tyrosine phosphatase 1, Substances that cause deregulated glucose production in the liver affect, such as Inhibitors of glucose-6-phosphatase, or fructose 1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor Antagonists and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agent, such as HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin), Fibrates (e.g., bezafibrate, fenofibrate), nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g., Avasimibe) or cholesterol absorption inhibitors such as ezetimibe, bile acid-binding Substances such as colestyramine, inhibitors of the ileal Bile acid transport, HDL enhancing compounds such as inhibitors of CETP or regulators of ABC1 or agents for the treatment of obesity, such as sibutramine or tetrahydrolipstatin, dexfenfluramine, axokines, antagonists of the cannabinoid 1 receptor, MCH-1 receptor antagonist, MC4 receptor Agonists, NPY5 or NPY2 antagonists or β3 agonists such as SB-418790 or AD-9677 as well as agonists of the 5HT2c receptor.

Besides is a combination with drugs to influence high blood pressure such as. A-II antagonists or ACE inhibitors, diuretics, β-blockers, Ca antagonists and others or combinations thereof.

The To achieve a corresponding effect required dosage is expediently at intravenous Administration 1 to 100 mg, preferably 1 to 30 mg, and when given orally 1 to 1000 mg, preferably 1 to 100 mg, 1 to 4 times daily. For this can be prepared according to the invention Compounds of formula I, optionally in combination with others Active substances, together with one or more inert usual excipients and / or diluents, e.g. with cornstarch, 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, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures, in usual galenic preparations such as tablets, dragees, capsules, powders, Suspensions or suppositories incorporated.

above and subsequently, in structural formulas, H atoms of hydroxyl groups not explicitly shown in each case. The following examples are intended to illustrate the present invention without limiting it:

Preparation of the starting compounds:

4-((R)-Tetrahydrofuran-3-yloxy)-brombenzol Example I

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

prepared by stirring 10 g of 4-bromophenol for 32 hours with 21 g of p-Toloulsulfonsäure - ((S) -tetrahydrofuran-3-yl) ester in the presence of 11.98 g of potassium carbonate in 100 ml of dimethylformamide at 60 ° C and subsequent purification by chromatographic Cleaning.
Yield: 13.7 g (97% of theory)
Rf value: 0.80 (alumina, cyclohexane / ethyl acetate = 2: 1)

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

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

To a solution of 2.0 g of 4 - ((R) -tetrahydrofuran-3-yloxy) bromobenzene in 10 ml of tetrahydrofuran are added dropwise at -78 ° C 5.17 ml of a 1.6 M butyllithium solution in hexane and one hour at -78 ° C stirred. Subsequently, 1.75 g of 2-benzyloxy-benzaldehyde, dissolved in 5 ml of tetrahydrofuran are added dropwise and stirred at -78 ° C for 2 hours. After warming to room temperature, it 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 with 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)

2-[4-((R)-Tetrahydrofuran-3-yloxy)benzyl]-phenol Example III

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) at room temperature.
R _f value: 0.52 (silica gel, cyclohexane / ethyl acetate = 2: 1)
Mass spectrum (ESI ^-): m / z = 269 [M - H] ^-

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-2-[4-((R)-tetrahydrofuran-3-yloxy)benzyl]-benzol Example IV

1- (2,3,4,6-tetra-O-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-alpha-glucopyranosylbromide, 2 ml of 1M sodium hydroxide solution and 5 ml Chloroform are stirred for 16 hours at room temperature. Another 400 mg of 2,3,4,6-tetra-O-acetyl-alpha-glucopyranosylbromid, 1 ml of 1M sodium hydroxide solution and 5 ml of methylene chloride are added and stirred for 2.5 days. The organic phase is separated, washed with water, dried and concentrated. The crude product is purified by chromatography on a silica gel column with 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 ] ⁺

Analogous Example IV the following compound is obtained:

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

Reaction with the compound of Example VI in the presence of benzyltriethylammonium bromide
Rf value: 0.30 (silica gel, cyclohexane / ethyl acetate = 2: 1)
Mass spectrum (ESI ⁺ ): m / z = 556 [M + NH ₄ ] ⁺

2-(4-Brombenzyl)-phenol Example V

2- (4-bromobenzyl) -phenol

prepared by reacting sodium phenolate (from 4.0 g of phenol and 1.7 g of 60% sodium hydride in paraffin oil) with 10.27 g of 4-bromobenzyl chloride in toluene under reflux and purifying 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 [M-H] ^-

2-[4-(2-Trimethylsilyl-ethinyl)-benzyl]-phenol Example VI

2- [4- (2-trimethylsilyl-ethynyl) 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 (II) chloride and 23 mg of copper (I) 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] ⁺

Preparation of the end compounds:

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

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

A solution of 400 mg of 1- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -2- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl) benzene a mixture of 2.5 ml of methanol and 5 ml of tetrahydrofuran is cooled in an ice bath and treated with 3.02 ml of a 1M 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, washed with saturated brine, 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] ⁺

R_f-Wert: 0.55 (Kieselgel, Methylenchlorid/Methanol = 6:1)
Massenspektrum (ESI⁺): m/z = 388 [M + NH₄]Analogously to Example 1, the following compound is obtained: (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 ]

1-(6-O-Methoxycarbonyl-β-D-glucopyranosyloxy)-2-(4-ethinylbenzyl)-benzol Example 2

1- (6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -2- (4-ethinylbenzyl) benzene

100 mg of 1- (β-D-glucopyranosyloxy) -2- (4-ethynylbenzyl) benzene in 0.5 ml of 2,4,6-collidine are mixed in an ice bath with 0.026 ml of methyl chloroformate and then stirred for 16 hours at room temperature. 5 ml of 0.1 N hydrochloric acid are added to the reaction mixture and shaken out with 10 ml of ethyl acetate. The organic phase is separated, washed with saturated brine and concentrated. The residue is stirred with 8 ml of diethyl ether / petroleum ether (1: 1), the solid is filtered off and dried at 40 ° C.
Yield: 73.5 mg (63% of theory)
Mass spectrum (ESI ⁺ ): m / z = 429 [M + H] ⁺
Analogously to the abovementioned examples and other processes known from the literature, the following compounds are also prepared:

Example A Tablets with 100 mg 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

Herstellunaverfahren:

agent Lactose and starch are mixed and treated with an aqueous solution of Evenly moistened polyvinylpyrrolidones. After sieving the wet mass (2.0 mm mesh size) and drying in a cupboard at 50 ° C is re-screened (1.5 mm mesh) and the lubricant admixed. The ready to be pressed Mixture is processed into tablets.

Example B Tablets with 150 mg active substance Composition: 1 tablet contains: active substance 150.0 mg Milk sugar powder. 89.0 mg corn starch 40.0 mg

colloids silica gel column 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg

production:

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

The granules dried at 45 ° C are again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. From the mixture tablets are pressed. Tablet weight: 300 mg Stamp: 10 mm, flat

Example C Hard gelatin capsules with 150 mg active substance Composition: 1 capsule contains: active substance 150.0 mg Corn starch drink. approximately 180.0 mg Milk sugar powder approx. 87.0 mg magnesium stearate 3.0 mg approximately 420.0 mg

production:

Of the Active substance is mixed with the excipients, through a sieve of 0.75 mm mesh size and homogeneous in a suitable device mixed.

The final mixture 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 substance 150.0 mg Polyethylene glycol 1500 550.0 mg Polyethylene glycol 6000 460.0 mg Polyoxyäthylensorbitanmonostearat 840.0 mg 2000.0 mg

production:

To the melting of the suppository mass becomes the active ingredient therein distributed homogeneously and the melt poured into pre-cooled molds.

Example E Ampoules with 10 mg active substance Composition: active substance 10.0 mg 0.01 n hydrochloric acid sq Aqua bidest ad 2.0 ml

production:

The Active substance is dissolved in the required amount of 0.01 N HCl, with Saline is isotonic, sterilized by filtration and in 2 ml ampoules bottled.

Example F Ampoules with 50 mg active substance Composition: active substance 50.0 mg 0.01 n hydrochloric acid sq Aqua bidest ad 10.0 ml

production:

The Active substance is dissolved in the required amount of 0.01 N HCl, with Saline is isotonic, sterile filtered and in 10 ml ampoules bottled.

Claims (9)

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-C _1-3 -alkyloxy or tetrahydropyranyl-C _1-3 -alkyloxy, or when R ^{3 is} selected from the group consisting of C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl C _1-3 alkyloxy and tetrahydropyranyl C _1-3 In addition, R ^{1 may} additionally be hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 -alkyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, methoxy substituted by 1 to 3 fluorine atoms, substituted by 1 to 5 fluorine atoms substituted ethoxy, by a hydroxy or C _1-3 alkoxy C _1-4 alkyl, substituted by a hydroxy or C _1-3 alkoxy C _2-4 alkoxy, C _2-6 Alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, C _3-6 cycloalkoxy, C _3-6 cycloalkyl C _1-3 alkoxy, hydroxy, amino or cyano mean, and R ² R ^{3 represents} C _2-6 -alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1, hydrogen, fluorine, chlorine, methyl or methyl substituted by 1 to 3 fluorine atoms; ₃ -alkyloxy or tetrahydropyranylC _1-3 -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, In addition, R ³ can also be hydrogen, fluorine, chlorine, bromine, iodine, C _1-6 -alkyl, C _2-6 -alkenyl, C _3, tetrahydrofuranyl-C _1-3 -alkyloxy and tetrahydropyranyl-C _1-3 -alkyloxy _-6- cycloalkyl, C _3-6 -cycloalkylidenemethyl, C _1-6 -alkoxy, C _3-6 -cycloalkyl-oxy, C _3-6 -cycloalkyl-C _1-3 -alkoxy, aryl, aryl-C _1-3 alkyl, heteroaryl, heteroarylC _1-3 -alkyl, aryloxy, arylC _1-3 -alkyl-oxy, methyl or methoxy substituted by 1 to 3 fluorine atoms, C _2-4 -alkyl substituted by 1 to 5 fluorine atoms, or C _2-4 alkoxy, C _1-4 alkyl substituted with a cyano group e is hydroxy or C _1-3 alkyloxy group substituted C _1-4 alkyl, cyano, carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, (C _1-3 alkylamino) carbonyl, di (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-yl-carbonyl, 4- (C _1-3 alkyl) - piperazin-1-ylcarbonyl, nitro, amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino, (C _1-4 alkyl) carbonylamino, C _1-4 Alkylsulfonylamino, arylsulfonylamino, arylC _1-3 alkylsulfonylamino, C _1-4 alkylsulfanyl, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, arylsulfenyl, arylsulfinyl or arylsulfonyl, R ⁴ and R ⁵ , which may be identical or different, denote hydrogen, fluorine, chlorine, bromine, C _1-3 -alkyl, C _1-3 -alkoxy, methyl or methoxy substituted by 1 to 3 fluorine atoms, and R ⁶ , R ^7a , R ^7b , R ^7c independently of one another are selected from the group consisting of hydrogen, (C _1-18 -alkyl) carbonyl, (C _1-18 -alkyl) oxycarbonyl, arylcarbonyl and aryl L- (C _1-3 alkyl) carbonyl, wherein the aryl groups mentioned in the definition of the abovementioned radicals are phenyl or naphthyl groups which may be mono- or disubstituted independently of one another by R _h , where the substituents may be the same or different and R _{h is} fluoro, chloro, bromo, iodo, C _1-3 alkyl, difluoromethyl, trifluoromethyl, C _1-3 alkoxy, difluoromethoxy, trifluoromethoxy or cyano, among those in the definition of those mentioned above Heteroaryl groups mentioned radicals a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or Isochinolinylgruppe to understand, or a pyrrolyl, furanyl, thienyl or pyridyl is to be understood, in the 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 represented by Stic are substituted, wherein the above-mentioned heteroaryl groups by R _{h may be} mono- or disubstituted, wherein the substituents may be the same or different and R _{h is} as defined above, wherein, unless otherwise mentioned, the above-mentioned alkyl groups straight-chain or branched could be, their tautomers, their stereoisomers, their mixtures and their salts. 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 In addition, R ^{1 may} additionally be hydrogen, fluorine, chlorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or cyano, and R ^{2 is} 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, then R ^{3 may} additionally 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, Cyc lobutyloxy, cyclopentyloxy, methylsulfanyl, 2-methyl-1-propen-1-yl, cyclopropylidenemethyl, phenyl, fluorophenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl and R ^{4 is} hydrogen, fluorine or methyl, R ^{5 is} hydrogen, R ⁶ , R ^7a , R ^7b , R ^{7c are} independently of one another selected from the group consisting of hydrogen, (C _1-18 -alkyl) carbonyl, (C _1-18 -Alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _1-3 alkyl) -carbonyl, their tautomers, their stereoisomers, their mixtures and their salts. 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 may} additionally also be hydrogen, fluorine, methyl or cyano R ^{2 is} hydrogen or methyl, R ^{3 is} ethynyl or tetrahydrofuran-3-yloxy or, if R ^{1 is} ethynyl, then R ^{3 may} additionally also be methyl, ethyl, methoxy or difluoromethoxy, 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, (C _1-18 -alkyl) carbonyl, (C _1-18 -alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _1-3 -alkyl) -carbonyl, their stereoisomers and mixtures thereof. Compounds of the 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, and derivatives thereof in which R ^{6 has} a meaning other than hydrogen according to the invention, in particular R ^{6 is} ethoxycarbonyl or methoxycarbonyl, including their tautomers, their stereoisomers and mixtures thereof. Physiologically acceptable salts of the compounds according to at least one of the claims 1 to 4 with inorganic or organic acids. Medicament containing a compound after at least one of the claims 1 to 4 or a physiologically acceptable salt according to claim 5 next to optionally one or more inert carriers and / or diluents. Use of at least one compound after at least one of the claims 1 to 5 for the manufacture of a medicament for the treatment of metabolic diseases is suitable. Process for the preparation of a medicament according to claim 6, characterized in that non-chemical way a compound according to at least one of the claims 1 to 5 in one or more inert carriers and / or diluents is incorporated. 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 do not denote hydrogen, a compound of the general formula

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

in which R ¹ to R ^{5 are} as defined in claim 1, or b) for the preparation of compounds of general formula I, in which R ⁶ , R ^7a , R ^7b and R ^{7c are} hydrogen, a compound of general formula I. in which R ⁶ and R ^7a , R ^7b , R ^{7c are} as previously defined but are not hydrogen, hydrolyzed, and, if desired, a compound of general formula I in which R ^{6 represents} a hydrogen atom, by acylation into one corresponding acyl compound of the general formula I is converted, and / or if necessary, a protecting residue used in the reactions described above is cleaved 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 thus obtained Formula I is converted into their salts, in particular for the pharmaceutical application in their physiologically acceptable salts ,