DE10339549A1 - New glucopyranosyloxy-pyrazole derivatives are sodium dependent glucose cotransporter inhibitors used for treating and preventing metabolic disorders, particularly diabetes - Google Patents

Abstract

Glucopyranosyloxy-pyrazole derivatives (I), are new. Glucopyranosyloxy-pyrazole derivatives of formula (I), their tautomers, stereoisomers, mixtures and salts are new. [Image] R 1>pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl (all optionally N-substituted by 1-4C alkyl, formyl, 1-4C alkylcarbonyl, 1-4C alkylsulfonyl, cyano, aminocarbonyl 1-4C alkylaminocarbonyl, di(1-4C alkyl)aminocarbonyl or 1-4C alkyloxycarbonyl), 3-6C alkynyl, tetrahydrofuran-3-yl, tetrahydropyran-3- or 4-yl, tetrahydrofuranyl(1-3C)alkyl or tetrahydropyranyl(1-3C)alkyl, or H, 1-6C alkyl, 1-4C alkyl substituted by 1-3 F, 2-4C alkyl substituted by one hydroxy or 1-3C alkoxy, or 3-6C alkenyl, 3-6C cycloalkyl, 3-6C cycloalkyl(1-3C)alkyl, aryl or aryl(1-3C)alkyl (when R 3> is R 3a>); R 2>1-4C alkyl (optionally substituted by 1-3 F) or 3-6C cycloalkyl; R 3>H, F, Cl, Br, I, 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, 3-6C cycloalkyl, 3-6C cycloalkylidenemethyl, 1-6C alkoxy, 3-6C cycloalkoxy, 3-6C cycloalkyl(1-3C)alkyl, aryl, heteroaryl, aryl(1-3C)alkyl, heteroaryl(1-3C)alkyl, aryloxy, aryl(1-3C)alkoxy, methyl or methoxy (both substituted by 1-3 F), 2-4C alkyl or 2-4C alkoxy (both substituted by 1-5 F), 1-4C alkyl (substituted by CN, hydroxy or 1-3C alkoxy), CN, carboxy, 1-3C alkoxycarbonyl, aminocarbonyl (optionally substituted by 1 or 2 1-3C alkyl), pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(1-3C alkyl)-piperazin-1-ylcarbonyl, nitro, amino (optionally substituted by 1 or 2 1-3C alkyl), 1-4C alkylcarbonylamino, 1-4C alkylsulfonylamino, arylsulfonylamino, aryl(1-3C)alkylsulfonylamino, 1-4C alkylthio, 1-4C alkylsulfinyl, 1-4C alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl or A; A : pyrrolidin-3-yloxy, piperidin-3-yloxy or piperidin-4-yloxy (all optionally N susbtituted by 1-4C alkyl, formyl, 1-4C alkylcarbonyl, 1-4C alkylsulfonyl, CN, aminocarbonyl (optionally substituted by 1 or 2 1-4C alkyl) or 1-4C alkoxycarbonyl), tetrahydrofuran-3-yloxy, tetrahydropyran-3-yl, tetrahydropyran-4-yloxy, tetrahydrofuranyl(1-3C)alkoxy or tetrahydropyranyl(1-3C)alkoxy; R 4>, R 5>H, F, Cl, Br, 1-3C alkyl, 1-3C alkoxy or methyl or methoxy (both substituted by 1-3 F), or adjacent CR 3> + CR 5>3-5C alkylene, methylenedioxy or difluoromethylenedioxy; R 3a>A, or R 3a> + R 4>difluoromethylenedioxy, 3-6C cycloalkoxy or 3-6C cycloalkylidene-methyl, where R 4> is not H; R 6>, R 7a>, R 7b>, R 7c>H, 1-18C alkylcarbonyl, 1-18C alkyloxycarbonyl, arylcarbonyl or aryl(1-3C alkyl)carbonyl; aryl : phenyl or naphthyl (both optionally substituted by 1 or 2 R h); R hF, Cl, Br, I, 1-3C alkyl, di- or tri-fluoromethyl, 1-3C alkoxy, di- or tri-fluoromethoxy or CN; heteroaryl : pyrrolyl, furanyl, thienyl or pyridyl (all with 1 or 2 methine optionally replaced by N), or indolyl, benzofuranyl, benzothienyl, quinolyl or isoquinolyl (all with 1-3 methine optionally replaced by N) (all optionally substituted by 1 or 2 R h). An independent claim is also included for the preparation of (I). ACTIVITY : Antidiabetic; Antiarteriosclerotic; Anorectic; Hypotensive; Cardiant; Antilipemic. Tests are described, but no results are given. MECHANISM OF ACTION : Sodium dependent glucose cotransporter (SGLT) inhibitor; SGLT2 inhibitor.

Description

wobei die Reste R¹ bis R⁶ 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-pyrazoles of the general formula I.

wherein the radicals R ¹ to R ⁶ 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 02/36602, WO 02/088157, WO 01/16147, WO 02/05373, WO 02/068439, WO 02/068440 and WO 02/098893 are glucopyranosyloxy-pyrazole derivatives and their preparation and their possible activity known as SGLT2 inhibitors.

The object of the present invention is to identify novel glucopyranosyloxypyrazole derivatives, in particular those which have an activity with respect to the sodium-dependent glucose cotransporter SGLT2. Another object of the present invention is to provide glucopyranosyloxy-pyrazole derivatives which have an increased inhibitory activity on SGLT2 in vitro and / or in vivo compared to known structurally similar glucopyranosyloxy-pyrazoles and / or
Furthermore, it is an object of the present invention to provide novel medicaments which are suitable for the prophylaxis and / or treatment of metabolic diseases, in particular of diabetes.

Also An object of this invention is to provide a method of preparation the alkyne 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_3-6-Alkinyl, Tetrahydrofuran-3-yl, Tetrahydropyran-3-yl, Tetrahydropyran-4-yl, Tetrahydrofuranyl-C_{1 - 3}-alkyl-, Tetrahydropyranyl-C_{1- 3}-alkyl-, Pyrrolidin-3-yl-, Piperidin-3-yl-, Piperidin-4-yl-, oder
eine Pyrrolidin-3-yl-, Piperidin-3-yl- oder Piperidin-4-yl-Gruppe bedeutet, wobei in den drei zuletzt genannten Gruppen das Stickstoffatom durch eine C_{1 -4}-Alkyl-Formyl-, C_{1 -4}-Alkyl-carbonyl-, C_{1 -4}-Alkylsulfonyl-, Cyan-, Aminocarbonyl-, (C_{1 -4}-Alkyl)-aminocarbonyl-, Di-(C_{1 -4}-alkyl)-aminocarbonyl- oder (C_{1 -4}-Alkyl)-oxycarbonyl-Gruppe substituiert ist, oder
falls R³

• (a) ausgewählt ist aus einer der Bedeutungen der Gruppe A, oder
• (b) zusammen mit R⁴ Difluormethylendioxy bedeutet, oder,
• (c) C_{3 -6}-Cycloalkyl-oxy oder C_{3 -6}-Cycloalkyliden-methyl bedeutet und

gleichzeitig R⁴ Fluor, Chlor, Brom, C_{1 - 3}-Alkyl, C_{1 - 3}-Alkoxy oder eine durch 1 bis 3 Fluoratome substituierte Methyl- oder Methoxy-Gruppe bedeutet,
dann R¹ auch Wasserstoff, C_{1 -6}-Alkyl, eine durch 1 bis 3 Fluoratome substituierte C_{1 -4}-Alkyl-Gruppe, eine durch eine Hydroxy- oder C_1-3-Alkoxygruppe substituierte C_{2 -4}-Alkyl-Gruppe, C_{3 -6}-Alkenyl, C_{3 -6}-Cycloalkyl, C_{3 -6}-Cycloalkyl-C_{1 - 3}-alkyl, Aryl oder Aryl-C_{1 - 3}-alkyl bedeuten kann, und
R² C_{1 -4}-Alkyl, eine durch 1 bis 3 Fluoratome substituierte C_{1 -4}-Alkyl-Gruppe, oder C_{3 -6}-Cycloalkyl bedeutet, und
R³ Wasserstoff, Fluor, Chlor, Brom, Iod, C_1-6-Alkyl, C_{2 -6}-Alkenyl, C_{2 -6}-Alkinyl, 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 Methoxy-Gruppe, eine durch 1 bis 5 Fluoratome substituierte C_{2 -4}-Alkyl- oder C_{2 -4}-Alkoxy-Gruppe, eine durch eine Cyangruppe substituierte C_{1 -4}-Alkyl-Gruppe, eine durch eine Hydroxy- oder C_{1 - 3}-Alkyloxygruppe substituierte C_{1 -4}-Alkyl-Gruppe, Cyan-, 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- bedeutet, oder
eine Bedeutung ausgewählt aus der Gruppe A bestehend aus Tetrahydrofuran-3-yloxy-, Tetrahydropyran-3-yloxy-, Tetrahydropyran-4-yloxy-, Tetrahydrofuranyl-C_{1 - 3}-alkoxy-, Tetrahydropyranyl-C_{1 - 3}-alkoxy-, Pyrrolidin-3-yloxy-, Piperidin-3-yloxy-, Piperidin-4-yloxy-Gruppe, und
Pyrrolidin-3-yloxy-, Piperidin-3-yloxy- und Piperidin-4-yloxy-, wobei in den drei zuletzt genannten Gruppen das Stickstoffatom durch C_{1 -4}-Alkyl-, Formyl-, C_{1 -4}-Alkyl-carbonyl-, C_1-4-Alkylsulfonyl-, Cyan-, Aminocarbonyl-, (C_{1 -4}-Alkyl)-aminocarbonyl-, Di-(C_{1 -4}-alkyl)-aminocarbonyl- oder (C_{1 -4}-Alkyl)-oxycarbonyl- substituiert ist, besitzt, und
R⁴ und R⁵, die gleich oder verschieden sein können, Wasserstoff, Fluor, Chlor, Brom, C_{1 - 3}-Alkyl, C_{1 - 3}-Alkoxy, eine durch 1 bis 3 Fluoratome substituierte Methyl- oder Methoxy-Gruppe bedeuten, oder
R³ zusammen mit R⁴, sofern diese an benachbarte Kohlenstoffatome gebunden sind, auch eine geradkettige C_{3 - 5}-Alkylengruppe, eine Methylendioxygruppe oder Difluormethylendioxy bedeutet, und
R⁶ Wasserstoff, (C_{1 - 18}-Alkyl)carbonyl, (C_{1 - 18}-Alkyl)oxycarbonyl, Arylcarbonyl oder Aryl-(C_{1- 3}-alkyl)-carbonyl bedeutet,
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 object of the present invention are glucopyranosyloxy-pyrazoles of the general formula I.

in which
R ¹ is C _3-6 alkynyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-C _1-3 alkyl, tetrahydropyranyl-C _{1- 3} alkyl, pyrrolidin-3 -yl, piperidin-3-yl, piperidin-4-yl, or
a pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl group, where in the last three groups the nitrogen atom is replaced by a C _{1 -4} -alkyl-formyl-, C _{1 -4} - Alkyl carbonyl, C _{1 -4} alkylsulfonyl, cyano, aminocarbonyl, (C _{1 -4} alkyl) aminocarbonyl, di (C _{1 -4} alkyl) aminocarbonyl or (C _{1 -4} Alkyl) -oxycarbonyl group, or
if R ³

• (a) is selected from one of the meanings of group A, or
• (b) together with R ⁴ denotes difluoromethylenedioxy, or
• (c) C _{3 -6} -cycloalkyl-oxy or C _{3 -6} -cycloalkylidene-methyl and

R ^{4 is} simultaneously fluorine, chlorine, bromine, C _{1 - 3} -alkyl, C _{1 - 3} -alkoxy or a methyl or methoxy group substituted by 1 to 3 fluorine atoms,
then R ^{1 is} also hydrogen, C _{1 -6} -alkyl, a C _{1 -4} -alkyl group substituted by 1 to 3 fluorine atoms, a C _{2 -4} -alkyl group substituted by a hydroxy or C _1-3 -alkoxy group , C, C, C _{3 -6} cycloalkyl-C _{1 3 -6} -alkenyl _{3 -6} cycloalkyl _{- 3} may denote alkyl, and _{- 3} alkyl, aryl or aryl-C ₁
R ^{2 is} C _{1 -4} -alkyl, a C _{1 -4} -alkyl group substituted by 1 to 3 fluorine atoms, or C _{3 -6} -cycloalkyl, and
R ³ is hydrogen, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _{2 -6} alkenyl, _{C2 -6} alkynyl, _{C3 -6} cycloalkyl, _{C3 -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, 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-substituted by a cyano group _{1 -4} alkyl group, by a hydroxy or C _{1 -} C ₃ alkyloxy group substituted _{1 -4} alkyl group, 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, aryl-C _1-3 alkylsulfonylamino, C _{1 -4} alkylsulphanyl, C _{1 -4} alkylsulfinyl, C _{1 -4} alkylsulphonyl, Arylsulfenyl-, arylsulfinyl or arylsulfonyl, or
a meaning selected from the group A consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _{1 - 3} alkoxy, tetrahydropyranyl-C _{1 - 3} alkoxy, Pyrrolidin-3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy, and
Pyrrolidin-3-yloxy, piperidin-3-yloxy and piperidin-4-yloxy, wherein in the last three groups, the nitrogen atom by C _{1 -4} alkyl, formyl, C _{1 -4} alkyl carbonyl -, C _1-4 alkylsulfonyl, cyano, aminocarbonyl, (C _{1 -4} alkyl) aminocarbonyl, di- (C _{1 -4} alkyl) aminocarbonyl or (C _{1 -4} alkyl) -oxycarbonyl- substituted, and
R ⁴ and R ^5, which may be the same or different, are hydrogen, fluorine, chlorine, bromine, C _{1 - 3} alkoxy, substituted by 1 to 3 fluorine atoms, methyl or methoxy group, _{- 3} alkyl, C ₁ or
R ³ together with R ⁴ , if they are bonded to adjacent carbon atoms, also denotes a straight-chain C _{3 - 5} -alkylene group, a methylenedioxy group or difluoromethylenedioxy, and
R ⁶ is hydrogen, (C _1-18 -alkyl) carbonyl, (C _1-18 -alkyl) oxycarbonyl, arylcarbonyl or 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 , Iodine, 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 physiological according to the invention compatible Salt next to optionally one or more inert carriers and / or diluents.

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

in der
R² bis R⁶ wie zuvor definiert sind, mit einer Verbindung der allgemeinen Formel Z¹ – R^1' (III), in der
R^1' die eingangs für R¹ erwähnten Bedeutungen besitzt, jedoch kein Wasserstoffatom darstellt, und Z¹ eine Austrittsgruppe darstellt, umgesetzt wird und
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 general formula I in which R ^{1 is} as defined above but not hydrogen,
a compound of the general formula

in the
R ² to R ^{6 are} as defined above, with a compound of the general formula Z ¹ -R ^{1 '} (III), in the
R ^{1 'has} the meanings mentioned above for R ¹ , but does not represent a hydrogen atom, and Z ^{1 represents} a leaving group, is reacted and
if desired, a compound of the general formula I in which R ^{6 is} a hydrogen atom is converted into a corresponding acyl compound of the general formula I by acylation, and / or
if necessary, a protective moiety used in the reactions described above is split off again and / or
if desired, a compound of general formula I thus obtained is separated into its stereoisomers and / or
a compound of the general formula I thus obtained is converted into its salts, in particular for the pharmaceutical application into its physiologically tolerated salts.

Detailed description the invention

Unless stated otherwise, the groups, radicals and substituents, in particular R ¹ to R ⁶ , 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 _{3 - 6} alkynyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-C _1-3 alkyl, tetrahydropyranyl-C _1-3 alkyl-, pyrrolidin-3 -yl, piperidin-3-yl, piperidin-4-yl, or
a pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl group, where in the last three groups the nitrogen atom is replaced by a C _{1 -4} -alkyl-formyl-, C _{1 -4} - Alkyl carbonyl, C _{1 -4} alkylsulfonyl, cyano, aminocarbonyl, (C _{1 -4} alkyl) aminocarbonyl, di (C _{1 -4} alkyl) aminocarbonyl or (C _1-4 -Alkyl) -oxycarbonyl group, and
the remaining radicals R ² to R ^{6 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 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl and tetrahydropyranylmethyl. Very particularly preferred meanings here are 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl and tetrahydrofuran-2-ylmethyl.

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, cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyl-oxy, etrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy, tetrahydropyranylmethyloxy, methylsulfanyl , 2-methyl-1-propen-1-yl, cyclopropylidenemethyl, ethynyl, phenyl, fluorophenyl, pyridyl and methylthiazolyl. Very particularly preferred meanings here are fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, in particular ethyl.

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, C _1-6 alkyl,
C _{1 - 4} -alkyl substituted by 1 to 3 fluorine atoms,
by a hydroxy or C _1-3 alkoxy substituted C _2-4 alkyl,
C _{3 - 6} alkenyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl-C _{1- 3} alkyl, aryl or aryl-C _1-3 -alkyl, and
R ³ is selected from the group A of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 alkoxy, tetrahydropyranyl-C _{1- 3} alkoxy Pyrrolidin-3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy, and
Pyrrolidin-3-yloxy, piperidin-3-yloxy and piperidin-4-yloxy, wherein in the latter three groups the nitrogen atom by C _1-4 alkyl, formyl, C _1-4 alkyl-carbonyl -, C _1-4 alkylsulfonyl, cyano, aminocarbonyl, (C _1-4 alkyl) aminocarbonyl, di- (C _{1 - 4} alkyl) aminocarbonyl or (C _{1 - 4} alkyl) -oxycarbonyl- substituted, and
the remaining radicals, in particular R ² and R ⁴ to R ^{6 have} the meanings given above,
including their tautomers, their stereoisomers, their mixtures and their salts.

According to this embodiment preferred meanings of the group R ¹ are C _{1 -6} alkyl, substituted by 1 to 3 fluorine atoms, C _1-4 alkyl group, C _{3 -6} cycloalkyl, and C _{3 -6} cycloalkyl-C _{1- 3-} alkyl, in particular C _{1 - 4} -alkyl, which may be substituted by 1 to 3 fluorine atoms, particularly preferably isopropyl.

Preferred meanings of the radical R ³ according to this embodiment are tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy and tetrahydropyranylmethyloxy.

Compounds of the invention according to a third embodiment of this invention can be described by the general formula I in which
R ¹ is hydrogen, C _{1 -6} alkyl,
C _{1 - 4} -alkyl substituted by 1 to 3 fluorine atoms,
by a hydroxy or C _1-3 alkoxy substituted C _2-4 alkyl,
_{C3 -6} alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _{1- 3} alkyl, aryl or aryl-C _1-3 -alkyl, and
R ³ together with R ⁴ attached to adjacent carbon atoms denotes difluoromethylenedioxy, and
the remaining radicals, in particular R ² , R ⁵ and R ^{5 have} the meanings given above,
including their tautomers, their stereoisomers, their mixtures and their salts.

According to this embodiment preferred meanings of the group R ¹ are C _1-6 alkyl, substituted by 1 to 3 fluorine atoms, C _{1 - 4} alkyl group, C _3-6 cycloalkyl, and C _{3 -6} - cycloalkyl-C _{1- 3} alkyl, in particular C _{1- 4} alkyl which may be substituted with 1 to 3 fluorine atoms, most preferably isopropyl.

Compounds of the invention according to a fourth embodiment of this invention can be described by the general formula I in which
R ¹ is hydrogen, C _1-6 alkyl,
C _{1 - 4} -alkyl substituted by 1 to 3 fluorine atoms,
by a hydroxy or C _1-3 alkoxy substituted C _2-4 alkyl,
C _{3 - 6} alkenyl, C _{3 - 6} cycloalkyl, C _{1- 3} alkyl, aryl or aryl-C _{1-C 3- 6} cycloalkyl _{- 3} alkyl group, and
R ^{3 is} C _{3 - 6} -cycloalkyl-oxy, and
R ^{4 is} fluorine, chlorine, bromine, C _{1 - 3} alkyl, C _{1 - 3} alkoxy means or substituted by 1 to 3 fluorine atoms, methyl or methoxy group, and
the remaining radicals, in particular R ² , R ⁵ and R ^{6 have} the meanings given above,
including their tautomers, their stereoisomers, their mixtures and their salts.

According to this embodiment preferred meanings of the group R ¹ are C _1-6 alkyl, substituted by 1 to 3 fluorine atoms, C _1-4 alkyl group, C _{3 - 6} cycloalkyl, and C _3-6 cycloalkyl-C _{1- 3-} alkyl, in particular C _{1 -4} -alkyl, which may be substituted by 1 to 3 fluorine atoms, particularly preferably isopropyl.

According to this embodiment, preferred meanings of the radical R ³ are cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.

According to this embodiment, preferred meanings of the radical R ⁴ are fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy and trifluoromethoxy, in particular fluorine.

Compounds of the invention according to a fifth embodiment of this invention can be described by the general formula I in which
R ¹ is hydrogen, C _1-6 alkyl,
C _{1 - 4} -alkyl substituted by 1 to 3 fluorine atoms,
by a hydroxy or C _1-3 alkoxy substituted C _2-4 alkyl,
C _{3 - 6} alkenyl, C _{3 - 6} cycloalkyl, C _{3 - 6} cycloalkyl-C _{1- 3} alkyl, aryl or aryl-C _1-3 -alkyl, and
R ^{3 is} C _{3 - 6} cycloalkylidene-methyl, and
R ^{4 is} fluorine, chlorine, bromine, C _{1 - 3} alkyl, C _1-3 alkoxy or substituted by 1 to 3 fluorine atoms, methyl or methoxy group, and
the remaining radicals, in particular R ² , R ⁵ and R ^{6 have} the meanings given above,
including their tautomers, their stereoisomers, their mixtures and their salts.

According to this embodiment preferred meanings of the group R ¹ are C _1-6 alkyl, substituted by 1 to 3 fluorine atoms, C _1-4 alkyl, C _{3- 6} cycloalkyl and C _{3 - 6} cycloalkyl C _1-3 alkyl , in particular C _{1 - 4} -alkyl, which may be substituted by 1 to 3 fluorine atoms, particularly preferably isopropyl.

A preferred meaning of the radical R ³ according to this embodiment is cyclopropylidenemethyl.

According to this embodiment, preferred meanings of the radical R ⁴ are fluorine, chlorine, bromine, Me thyl, trifluoromethyl, methoxy and trifluoromethoxy, in particular fluorine.

Preferred meanings of the radical R ² according to the invention are methyl and trifluoromethyl, in particular methyl.

The radical R ⁶ according to the invention is preferably hydrogen atom, (C _1-8 alkyl) oxycarbonyl or C _1-8 -alkylcarbonyl, in particular H or methoxycarbonyl.

• (a) 1-(2-Propin-1-yl)-3-(β-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazol
• (b) 1-(2-Propin-1-yl)-3-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazol
• (c) 1-((S)-Tetrahydrofuran-3-yl)-3-(β-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazol
• (d) 1-(Tetrahydropyran-4-yl)-3-(β-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazol,

einschließlich deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.Particularly preferred compounds of general formula 1 are selected from the group:

• (a) 1- (2-Propyn-1-yl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole
• (b) 1- (2-Propyn-1-yl) -3- (6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole
• (c) 1 - ((S) -tetrahydrofuran-3-yl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole
• (d) 1- (tetrahydropyran-4-yl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole,

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

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, wherein n has a value of 3 to 8, means a saturated, branched or unbranched hydrocarbon group having 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 _{1 -n} -alkylene, where n can have a value of 1 to 8, means a saturated, branched or unbranched hydrocarbon bridge having 1 to n C atoms. Examples of such groups include methylene (-CH ₂ -), ethylene (-CH ₂ -CH ₂ -), 1-methyl-ethylene (-CH (CH ₃ ) -CH ₂ -), 1,1-dimethyl-ethylene (- C (CH ₃ ) ₂ -CH ₂ -), n -prop-1,3-ylene (-CH ₂ -CH ₂ -CH ₂ -), 1-methylprop-1,3-ylene (-CH (CH ₃ ) -CH ₂ -CH ₂ -), 2-methylprop-1,3-ylene (-CH ₂ -CH (CH ₃ ) -CH ₂ -), etc., as well as the corresponding mirror-image forms.

The term C _{2 -n} alkenyl, 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 vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 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} denotes saturated monocyclic groups.

The term C _{5 -n-} cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic group having 5 to n C atoms. Examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.

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 Compounds of the invention are obtainable using in principle known synthesis methods. Preferably, the compounds are explained in more detail below inventive production process receive.

in der
R² bis R⁶ wie eingangs erwähnt definiert sind, mit einer Verbindung der allgemeinen Formel Z¹ – R^1' (III),in der
R^1' die eingangs für R¹ erwähnten Bedeutungen besitzt, jedoch kein Wasserstoffatom darstellt, und Z¹ eine Austrittsgruppe wie ein Halogenatom, z.B. ein Chlor- oder Bromatom, eine Sulfonyloxygruppe, wie eine Methansulfonyloxy- oder p-Toluolsulfonyloxygruppe oder eine Hydroxygruppe, darstellt.a) For the preparation of compounds of the general formula I in which R ¹ is defined as mentioned above but is not a hydrogen atom: reaction of a compound of the general formula

in the
R ² to R ⁶ are defined as mentioned above, with a compound of the general formula Z ¹ -R ^{1 '} (III), in the
R ^{1 'has} the meanings mentioned above for R ¹ but does not represent a hydrogen atom, and Z ^{1 represents} a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulphonyloxy group, such as a methanesulphonyloxy or p-toluenesulphonyloxy group or a hydroxy group.

The Implementation takes place expediently in a solvent, such as acetonitrile, toluene, tetrahydrofuran, dioxane, Dimethylformamide, dimethylsulfoxide or N-methylpyrrolidinone, if appropriate in the presence of a base such as potassium carbonate, cesium carbonate, Sodium hydride or potassium tert-butoxide, at temperatures between 20 ° C and 160 ° C.

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 is a (C _1-18 alkyl) carbonyl group, a (C _1-18 alkyl) oxycarbonyl group, an arylcarbonyl group or an aryl (C _1-3 alkyl) carbonyl group represents. 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 hydroxy, amino, alkylamino or imino groups while the implementation by usual Protected by protective groups will be split off after the implementation.

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 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 known Methods, e.g. by chromatography and / or fractional crystallisation, into their diastereomers, which, if they are in racemic Form incurred, then as 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 can the compounds of the formula I obtained in their salts, in particular for the pharmaceutical Use in their physiologically acceptable salts with inorganic or organic acids. As acids come for this for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic into consideration.

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 and III are partly known from the literature or can after per se literature methods (see Example I), optionally under 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 02/36602, WO 02/088157, WO 01/16147, WO 02/05373, WO 02/068439, WO 02/068440 and WO 02/098893 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. No. 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 assay buffer with 1.2 μCi / ml [ ¹⁴ C] -AMG are added by pipette 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 mol / l NaOH and incubated for 30 min at room temperature. Thereafter, 45 μl of the lysate are transferred to a scintillation vial and measured after addition of 4 ml UltimaGold (Packard) in the scintillation counter (Packard TriCarb2300TR). As a negative control serve cells that were treated with 10μl 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 the Regard to the ability the SGLT-2 activity to inhibit, the compounds of the invention are the general Formula I and its corresponding pharmaceutically acceptable salts suitable, all those states or affect diseases caused by inhibition of SGLT-2 activity can be influenced. Therefore, compounds of the invention especially for prevention or treatment of 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, dyslipidemias of various kinds Genesis, atherosclerosis and related diseases, obesity, suitable. Furthermore If these substances are suitable, the beta cell degeneration such as e.g. To prevent apoptosis or necrosis of pancreatic beta cells. The substances are further suited to the functionality of pancreatic Cells to improve or restore, next to the number and size of pancreatic increase beta cells. The compounds of the invention are also useful as diuretics or antihypertensives and for prevention and treatment of acute renal failure.

The compounds according to the invention can also be used in combination with other active substances. Therapeutics suitable for such a combination include, for example, antidiabetic agents such as metformin, sulfonylureas (eg, glibenclamide, tolbutamide, glimepiride), nateglinides, repaglinide, thiazolidinediones (eg, rosiglitazone, pioglitazone), PPAR-gamma agonists (eg, GI 262570), and Antagonis PPAR-gamma / alpha modulators (eg KRP 297), alpha-glucosidase inhibitors (eg acarbose, voglibose), DPPIV inhibitors, alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (eg exendin-4) or amylin. In addition, inhibitors of protein tyrosine phosphatase 1, substances that affect a deregulated glucose production in the liver, such as inhibitors of glucose-6-phosphatase, or the fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents such as HMG-CoA reductase inhibitors (eg simvastatin, atorvastatin), fibrates (eg bezafibrate, fenofibrate), nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR delta agonists, ACAT inhibitors (eg Avasimibe) or cholesterol resorption inhibitors such as ezetimibe, bile acid sequestrants such as colestyramine, ileal bile acid transport inhibitors, 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, antag onists of the cannabinoid 1 receptor, MCH-1 receptor antagonists, 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, carboxymethyl cellulose 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.

The The following examples are intended to explain the present invention without reference to restrict these:

Preparation of the starting compounds:

Example I

1-(2-Propin-1-yl)-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazol

1- (2-propyn-1-yl) -3- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H- pyrazole

600 mg of 3- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole (see WO 01/16147, WO 02/53573, WO 02/68439), 390 mg of cesium carbonate and 0.091 ml of propargyl bromide are stirred in 5 ml of dimethylformamide for 16 hours. 195 mg of cesium carbonate and 0.046 ml of propargyl bromide are again added and the mixture is stirred at room temperature for a further 3 hours. The reaction mixture is between 25 ml of water and 30 ml of ethyl acetate. The organic phase is separated, dried and concentrated. The residue is purified by chromatography on a silica gel column with a methylene chloride / methanol gradient (99: 1 to 95: 5).
Yield: 234 mg (36% of theory)
Rf value: 0.65 (silica gel, methylene chloride / methanol = 15: 1)
Mass spectrum (ESI ⁺ ): m / z = 585 [M + H] ⁺

R_f-Wert: 0.58 (Kieselgel, Methylenchlorid/Methanol/Cyclohexan = 20:1:2)
Massenspektrum (ESI⁺): m/z = 599 [M + H]⁺ The following compound is obtained analogously to Example I: (1) 1- (2-butyn-1-yl) -3- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -4- ( 4-ethylbenzyl) -5-methyl-1H-pyrazol

R _f value: 0.58 (silica gel, methylene chloride / methanol / cyclohexane = 20: 1: 2)
Mass spectrum (ESI ⁺ ): m / z = 599 [M + H] ⁺

Preparation of the end compounds:

example 1

1-(2-Propin-1-yl)-3-(β-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazol

1- (2-propyn-1-yl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazol

A solution of 250 mg of 1- (2-propyn-1-yl) -3- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5 -methyl-1H-pyrazole in a mixture of 1 ml of methanol and 2 ml of tetrahydrofuran is cooled in an ice bath and treated with 1.81 ml of a 1 M aqueous lithium hydroxide solution and stirred for 2 hours. The reaction mixture is mixed with 5 ml of water and 5 ml of saturated sodium chloride solution and extracted with ethyl acetate. The organic phase is separated, washed with saturated brine, dried and concentrated.
Yield: 167 mg (93% of theory)
Rf value: 0.17 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ⁺ ): m / z = 417 [M + H] ⁺

R_f-Wert: 0.40 (Kieselgel, Methylenchlorid/Methanol = 9:1)
Massenspektrum (ESI⁺): m/z = 431 [M + H]⁺ Analogously to Example 1, the following compound is obtained: (1) 1- (2-Butyn-1-yl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole

R _f value: 0.40 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ⁺ ): m / z = 431 [M + H] ⁺

Example 2

1-(2-Propin-1-yl)-3-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazol

1- (2-propyn-1-yl) -3- (6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazol

100 mg of 1- (2-propyn-1-yl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole in 0.5 ml of 2,4,6-collidine in an ice bath with 0.023 ml of methyl chloroformate and stirred for 6 hours. 3.5 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 taken up in 20 ml of ethyl acetate, washed again with 5 ml of 0.1 N hydrochloric acid and saturated brine, dried and concentrated.
Yield: 85 mg (75% of theory)
R _f value: 0.30 (silica gel, methylene chloride / methanol = 9: 1)
Mass Spectrum (ESI ⁺ ): m / z = 475 [M + H] ⁺

Example 3

1-((S)-Tetrahydrofuran-2-ylmethyl)-3-(β-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazol

1 - ((S) -tetrahydrofuran-2-ylmethyl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazol

300 mg of 3- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole (see WO 01/16147, WO 02/53573, WO 02/68439), 1808 mg of cesium carbonate and 666 mg of (S) -p-toluenesulfonic acid (tetrahydrofuran-2-ylmethyl) ester are stirred in 5 ml of dimethylformamide at 100 ° C for 5 hours. The reaction mixture is concentrated, and the residue is added with cooling in an ice bath with 0.9 ml of methanol, 1.8 ml of tetrahydrofuran and 1.5 ml of 1 N aqueous lithium hydroxide solution. After stirring for 2 hours, the reaction mixture is partitioned between 20 ml of water and 30 ml of ethyl acetate. The organic phase is washed with saturated brine, dried and concentrated. The residue is purified by chromatography on a silica gel column with methylene chloride / methanol (9: 1).
Yield: 128 mg (50% of theory)
Rf value: 0.40 (silica gel, methylene chloride / methanol = 7: 1)
Mass spectrum (ESI ⁺ ): m / z = 463 [M + H] ⁺

Analogous Example 3 the following compounds are obtained:

(1) 1 - ((S) -tetrahydrofuran-3-yl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole

Use of (R) -p-toluenesulfonic acid (tetrahydrofuran-3-yl) ester as alkylating agent
R _f value: 0.40 (silica gel, methylene chloride / methanol = 7: 1)
Mass spectrum (ESI ⁺ ): m / z = 449 [M + H] ⁺

(2) 1- (Tetrahydropyran-4-yl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole

Use of p-toluenesulfonic acid (tetrahydropyran-4-yl) ester as alkylating agent
R _f value: 0.40 (silica gel, methylene chloride / methanol = 7: 1)
Mass spectrum (ESI ⁺ ): m / z = 463 [M + H] ⁺

Beispiel 4 Tabletten mit 100 mg Wirksubstanz Zusammensetzung: 1 Tablette enthält: Wirksubstanz 100.0 mg Milchzucker 80.0 mg Maisstärke 34.0 mg Polyvinylpyrrolidon 4.0 mg Magnesiumstearat 2.0 mg 220.0 mg Analogously to the abovementioned examples and other processes known from the literature, the following compounds are also prepared:

Example 4 Tablets with 100 mg of active substance Composition: 1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg

Production process:

Beispiel 5 Tabletten mit 150 mg Wirksubstanz Zusammensetzung: 1 Tablette enthält: Wirksubstanz 150.0 mg Milchzucker pulv. 89.0 mg Maisstärke 40.0 mg Kolloide Kieselgelsäure 10.0 mg Polyvinylpyrrolidon 10.0 mg Magnesiumstearat 1.0 mg 300.0 mg Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a tray drying oven at 50 ° C is again sieved (1.5 mm mesh) and the lubricant mixed. The ready-to-use mixture is processed into tablets.

Example 5 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 silicic acid 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 6 Hard Gelatin Capsules with 150 mg Active Ingredient 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 7 Suppositories with 150 mg 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:

After the suppository mass has melted, the active ingredient is distributed homogeneously therein and the melt is poured into pre-cooled molds. Example 8 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 ingredient is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 2 ml ampoules. Example 9 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-pyrazoles of the general formula

in which R ^{1 is} C _{3 6} alkynyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranyl-C _{1 - 3} alkyl, tetrahydropyranyl-C _{1 - 3} alkyl, pyrrolidin 3-yl, piperidin-3-yl, piperidin-4-yl, or a pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl group, wherein in the last three groups referred to the nitrogen atom by a C _1-4 alkyl, formyl, C _1-4 alkyl-carbonyl, C _1-4 alkylsulfonyl, cyano, aminocarbonyl, (C _1-4 alkyl) aminocarbonyl -, di (C _{1 - 4} alkyl) aminocarbonyl or (C _{1 - 4} alkyl) oxycarbonyl group is substituted, or when R ³ (a) is selected from one of the definitions of the group a, or ( b) together with R ⁴ difluoromethylenedioxy, or, (c) C _{3 - 6} -cycloalkyl-oxy or C _{3 - 6} -cycloalkyliden-methyl and simultaneously R ^{4 is} fluorine, chlorine, bromine, C _{1 - 3} alkyl, C _1-3 -alkoxy or substituted by 1 to 3 fluorine atoms, methyl or methoxy, then R ¹ is also hydrogen, C _{1 -6} alkyl, d urch 1 to 3 fluorine atoms-substituted C _1-4 alkyl, by a hydroxyl or C _1-3 alkoxy substituted C _2-4 alkyl, C _3-6 alkenyl, C _{3 -6} cycloalkyl, C _3-6 cycloalkyl-C _{1- 3} alkyl, aryl or aryl-C _{1 - 3} may denote alkyl, and R ^{2 is} C _{1 - 4} alkyl, by 1 to 3 fluorine atoms substituted C _{1 - 4} alkyl, or C _{3 - 6} -cycloalkyl, and R ^{3 is} hydrogen, fluorine, chlorine, bromine, iodine, C _{1 -6} -alkyl, C _{2 -6-} alkenyl, C _{2 -6} -alkynyl, 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, substituted by 1 to 3 fluorine atoms methyl or methoxy, substituted by 1 to 5 fluorine atoms C _{2 - 4} alkyl or C _2-4 alkoxy, by a cyano group-substituted C _{1- 4} alkyl, by a hydroxyl or C _{1 - 3} alkyloxy substituted C _{1 - 4 -} alkyl, cyano, carboxy, C _{1- 3} alkoxycarbonyl, aminocarb onyl-, (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, aryl-C _1-3 alkylsulfonylamino, C _1-4 alkylsulphanyl, C _1-4 alkylsulphinyl, C _{1 - 4-} alkylsulfonyl, arylsulfenyl, arylsulfinyl or arylsulfonyl-, or a meaning selected from the group A consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _{1 - 3} alkoxy, tetrahydropyranyl-C _1-3 -alkoxy, pyrrolidin-3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy group, and pyrrolidin-3-yloxy, piperidin-3-yloxy - and piperidin-4-yloxy, wherein in the latter three groups the nitrogen atom by C _{1 - 4} alkyl, formyl, C _{1 -4} alkyl-carbonyl , C _{1 - 4} alkylsulfonyl, cyano, aminocarbonyl, (C _{1 - 4} alkyl) aminocarbonyl, di- (C _{1- 4} alkyl) aminocarbonyl or (C _{1 - 4} alkyl) - is substituted oxycarbonyl, possesses, and R ⁴ and R ^5, which may be the same or different, are hydrogen, fluorine, chlorine, bromine, C _1-3 alkyl, C _1-3 alkoxy, substituted by 1 to 3 fluorine atoms, methyl mean or methoxy, or R ³ together with R ^4, if they are bound to adjacent carbon atoms, a straight-chain C _{3 -} - ₅ alkylene group, a methylenedioxy group or difluoromethylenedioxy, and R ⁶ is hydrogen, (C _{1 - 18} alkyl) carbonyl, (C _1-18 -alkyl) oxycarbonyl, arylcarbonyl or aryl- (C _1-3 alkyl) -carbonyl, while by the mentioned in the definition of the above groups aryl groups are phenyl or naphthyl groups which independently may be mono- or disubstituted by R _h , where the substituents may be the same or different and R _h Fluorine, chlorine, bromine, iodine, C _{1 - 3} alkyl, difluoromethyl, trifluoromethyl, C _{1 - 3} is alkoxy, difluoromethoxy, trifluoromethoxy or cyano, under the conditions mentioned in the definition of heteroaryl above-mentioned groups a pyrrolyl, furanyl , Thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group or is understood to mean 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 the one to three methine groups are replaced by nitrogen atoms, wherein the above-mentioned heteroaryl groups may be mono- or disubstituted by R _h , wherein the substituents may be the same or different and R _{h is} as defined above, wherein, unless otherwise stated, the The above-mentioned alkyl groups may be straight-chain or branched, their tautomers, their stereoisomers, their mixtures and their salts. Glucopyranosyloxy-pyrazoles of general formula I according to claim 1, in which R ^{1 is} 2-propyn-1-yl or 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylmethyl or tetrahydropyranylmethyl or, if R ³ (a) is selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy and tetrahydropyranylmethyloxy, or (b) together with R ⁴ Is difluoromethylenedioxy, or (c) is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclopropylidenemethyl and R ^{4 is} simultaneously fluorine, then R ^{1 may} also be isopropyl, and R ^{2 is} methyl or trifluoromethyl, R ^{3 is} 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, cyclopropyl-oxy , Cyclobutyl-oxy, Cyc lopentyl-oxy, etrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy, tetrahydropyranylmethyloxy, methylsulfanyl, 2-methyl-1-propen-1-yl, cyclopropylidenemethyl, ethynyl, phenyl, fluorophenyl, Pyridyl or methylthiazolyl, and R ^{4 is} hydrogen or fluorine, or, R ³ together with R ⁴ , if they are bonded to adjacent carbon atoms, also 1,3-propylene, methylenedioxy or Difluormethylendioxy-, and R ^{5 is} hydrogen and R ⁶ is hydrogen, _{(C1 -8} alkyl) oxycarbonyl or C _{1 - 8} alkylcarbonyl means, the tautomers, the stereoisomers, the mixtures and salts thereof. Glucopyranosyloxy-pyrazoles of the general formula I according to claim 1, in which R ^{1 is} 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl or tetrahydrofuran-2 -ylmethyl-, R ² is methyl, R ³ is ethyl, R ⁴ and R ⁵ are hydrogen and R ⁶ is hydrogen or methoxycarbonyl, the tautomers, the stereoisomers, the mixtures and salts thereof. Compounds of the general formula I according to claim 1 selected consisting of the group (a) 1- (2-Propyn-1-yl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole (B) 1- (2-propyn-1-yl) -3- (6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazol (C) 1 - ((S) -tetrahydrofuran-3-yl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole and (D) 1- (tetrahydropyran-4-yl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazol, including theirs Tautomers, their stereoisomers, their mixtures and their salts. 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. 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 general formula I in which R ^{1 is} one of the groups mentioned in claims 1 to 4, but no hydrogen atom , a compound of the general formula

in which R ² to R ^{6 are defined} as mentioned in claims 1 to 4, with a compound of the general formula Z ¹ -R ^{1 '} (III), in which R ^{1 'has} the meanings mentioned above for R ¹ , but does not represent a hydrogen atom, and Z ^{1 represents} a leaving group is reacted and, if desired, a compound of general formula I in which R ^{6 represents} a hydrogen atom, by acylation in a corresponding acyl compound of the general formula I is converted, and / or, if necessary, a protective radical used in the reactions described above is cleaved again and / or if desired, a compound of general formula I thus obtained is separated into its stereoisomers and / or a compound thus obtained general formula I in their salts, in particular for the pharmaceutical application in their physiologically acceptable salts, converted.