DE10359960A1 - 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 02/053573, 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.

Of the The present invention is based on the object, new Glucopyranosyloxypyrazol derivatives 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-pyrazole derivatives, which in in vitro and / or in vivo compared with known, structurally similar Glucopyranosyloxy-pyrazoles an increased inhibitory effect on sodium-dependent glucose cotransporters SGLT2 possess and / or improved pharmacological properties exhibit.

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_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 mit einer 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 sein kann, 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 Arylsulfonylbedeutet, oder
eine Bedeutung ausgewählt aus der Gruppe A 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, R^7a, R^7b, R^7c unabhängig voneinander eine Bedeutung ausgwählt aus der Gruppe Wasserstoff, (C_1–18-Alkyl)carbonyl, (C_1–18-Alkyl)oxycarbonyl, Arylcarbonyl und Aryl-(C_1–3-alkyl)-carbonyl besitzen,
A ausgewählt aus der Gruppe 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, sowie
Pyrrolidin-3-yloxy-, Piperidin-3-yloxy- und Piperidin-4-yloxy-, wobei in den drei zuletzt genannten Gruppen das Stickstoffatom mit 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)-oxycarbonylsubstituiert sein kann,
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, tetrahydrofuranylC _1-3 alkyl, tetrahydropyranylC _1-3 alkyl, pyrrolidine-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, the nitrogen atom having a C _1-4 alkyl, formyl, C _1-4 Alkylcarbonyl, C _1-4 alkylsulphonyl, 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 at the same time R ^{4 is} fluorine, chlorine, bromine, C _1-3 -alkyl, C _1-3 -alkoxy or one by 1 to 3 Fluorine atom substituted methyl or methoxy group means

then R ^{1 is} also hydrogen, C _1-6 alkyl, a C _1-4 alkyl group substituted by from 1 to 3 fluorine atoms, a C _2-4 alkyl group substituted by a hydroxy or C _1-3 alkoxy group C _3-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, aryl or arylC _1-3 alkyl, and
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, C _2-6 -alkynyl, 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, arylC _1-3 -alkyl, heteroaryl, heteroarylC _1-3 -alkyl, aryloxy , ArylC _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 cyano group by a substituted C _1-4 alkyl group, a substituted by a hydroxy or C _1-3 alkyloxy substituted C _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, piperazine 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) c arbonylamino, 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 means, or
has a meaning selected from the group A, and
R ⁴ and R ⁵ , which may be identical or different, denote hydrogen, fluorine, chlorine, bromine, C _1-3 -alkyl, C _1-3 -alkoxy, a methyl or methoxy group which is substituted by 1 to 3 fluorine atoms, 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 , R ^7a , R ^7b , R ^7c 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,
A selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropurran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 -alkoxy, tetrahydropyranyl-C _1-3 -alkoxy, pyrrolidine 3-yloxy, piperidin-3-yloxy, piperidin-4-yloxy group, as well as
Pyrrolidin-3-yloxy, piperidin-3-yloxy and piperidin-4-yloxy, wherein in the last three groups, the nitrogen atom with 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) can beoxycarbonylsubstituiert,
where the aryl groups mentioned in the definition of the abovementioned radicals are phenyl or naphthyl groups which are 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.

• a) zur Herstellung von Verbindungen der allgemeinen Formel I, in der R¹ wie zuvor definiert ist, jedoch nicht Wasserstoff bedeutet, eine Verbindung der allgemeinen Formel
  
  in der R² bis R⁶ sowie R^7a, R^7b, R^7c 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 oder
• b) zur Herstellung von Verbindungen der allgemeinen Formel I, in der R³ gegebenenfalls substituiertes C_1–6-Alkoxy, C_3–6-Cycloalkyl-oxy, C_1–5-Cycloalkyl-C_1–3-alkoxy oder eine Bedeutung ausgewählt aus der Gruppe A, die wie vorstehend erwähnt definiert ist, darstellt, eine Verbindung der allgemeinen Formel
  
  in der R¹, R² und R⁴ bis R⁶ sowie R^7a, R^7b, R^7c wie eingangs erwähnt definiert sind, mit einer Verbindung der allgemeinen Formel Z² – R^3' (V),in der R^3' gegebenenfalls substituiertes C_1–6-Alkoxy, C_3–6-Cycloalkyl-oxy, C_3–5-Cycloalkyl-C_1–3-alkoxy oder eine Bedeutung ausgewählt aus der Gruppe A, die wie vorstehend erwähnt definiert ist, darstellt, und Z² eine Austrittsgruppe wie ein Halogenatom, z.B. ein Chlor- oder Bromatom, eine Sulfonyloxygruppe, wie eine Methansulfonyloxy- oder p-Toluolsulfonyloxygruppe oder eine Hydroxygruppe darstellt, umgesetzt wird und nach Durchführung des Schrittes a) oder 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 general formula I in which R ^{1 is} as defined above but not hydrogen, a compound of the general formula
  
  in which R ² to R ⁶ and R ^7a , R ^7b , R ^{7c are} as defined above, 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 or
• b) for the preparation of compounds of general formula I in which R ^{3 is} optionally substituted C _1-6 alkoxy, C _3-6 cycloalkyl-oxy, C _1-5 cycloalkyl C _1-3 alkoxy or a meaning selected from the group pe A, which is defined as mentioned above, represents a compound of the general formula
  
  in which R ¹ , R ² and R ⁴ to R ⁶ and R ^7a , R ^7b , R ^7c are defined as mentioned above, with a compound of the general formula Z ² - R ^{3 '} (V), in the R ^{3 '} optionally substituted C _1-6 alkoxy, C _3-6 cycloalkyl-oxy, C _3-5 cycloalkyl C _1-3 alkoxy or a meaning selected from the group A, which defines as mentioned above is, and Z ^{2 represents} a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulfonyloxy group, such as a methanesulfonyloxy or p-toluenesulfonyloxy group or a hydroxy group is reacted and after carrying out step a) or b), if desired thus obtained compound of the general formula I, in which R ^{6 represents} a hydrogen atom, is converted by acylation into a corresponding acyl compound of the general formula I, and / or, if necessary, a protecting residue used in the reactions described above is cleaved off again and / or, if desired, such obtained compound of general formula I is separated into its stereoisomers and / or a compound of general F thus obtained ormel I in their 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 _3-6 alkynyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuranylC _1-3 alkyl, tetrahydropyranylC _1-3 alkyl, pyrrolidine-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, the nitrogen atom having a C _1-4 alkyl, formyl, C _1-4 Alkylcarbonyl, C _1-4 alkylsulphonyl, 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 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 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, tetrahydrofuran-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 _3-6 -alkyl,
C _1-4 alkyl substituted by 1 to 3 fluorine atoms,
C _2-4 -alkyl substituted by a hydroxy or C _1-3 -alkoxy group,
C _3-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, aryl or arylC _1-3 alkyl, and
R ^{3 is} selected from 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
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 C _1-6 -alkyl, a C _1-4 -alkyl group substituted by 1 to 3 fluorine atoms, 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, more preferably methyl, ethyl, propyl or butyl, most 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.

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

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,
C _2-4 -alkyl substituted by a hydroxy or C _1-3 -alkoxy group,
C _3-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, aryl or arylC _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 ^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 C _1-6 -alkyl, a C _1-4 -alkyl group substituted by 1 to 3 fluorine atoms, 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, more preferably methyl, ethyl, propyl or butyl, most preferably isopropyl.

Compounds of the invention according to a fourth embodiment of this invention may be be written by the general formula I, in the
R ^{1 is} hydrogen, C _1-6 -alkyl,
C _1-4 alkyl substituted by 1 to 3 fluorine atoms,
C _2-4 alkyl, C _3-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, aryl or aryl substituted by hydroxy or C _1-3 alkoxy C _1-3 alkyl, and
R ^{3 is} C _3-6 -cycloalkyl-oxy, and
R ^{4 is} fluorine, chlorine, bromine, C _1-3 -alkyl, C _1-3 -alkoxy or a methyl or methoxy group substituted by 1 to 3 fluorine atoms, and
the remaining radicals, in particular R ² , R ⁵ and 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 C _1-6 -alkyl, a C _1-4 -alkyl group substituted by 1 to 3 fluorine atoms, 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, more preferably methyl, ethyl, propyl or butyl, most 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,
C _2-4 -alkyl substituted by a hydroxy or C _1-3 -alkoxy group,
C _3-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, aryl or arylC _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 a methyl or methoxy group substituted by 1 to 3 fluorine atoms, and
the remaining radicals, in particular R ² , R ⁵ and R ^6, and R ^7a , R ^7b , R ^{7c have} the meanings given above,
including their tautomers, their stereoisomers, their mixtures and their salts.

Preferred meanings of the radical R ¹ according to this embodiment are C _1-6 -alkyl, C _1-4 -alkyl substituted by 1 to 3 fluorine atoms, 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, more preferably methyl, ethyl, propyl or butyl, most 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, methyl, trifluoromethyl, methoxy and trifluoromethoxy, in particular fluorine.

subsequent versions refer to the compounds of formula I, in particular the previously mentioned first, second, third, fourth and fifth embodiments.

If the group R ^{1 has} the meaning pyrrolidin-3-yl, piperidin-3-yl or piperidin-4-yl, the nitrogen atom is preferably substituted as indicated.

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 methyl and trifluoromethyl, in particular 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 H or (C _1-6 -alkyl) oxycarbonyl, more preferably H, methoxycarbonyl or ethoxycarbonyl, completely particularly preferably H or methoxycarbonyl.

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

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

• (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,
• (e) 1-Isopropyl-3-(β-D-glucopyranosyloxy)-4-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]-5-methyl-1H-pyrazol,
• (f) 1-Isopropyl-3-(β-D-glucopyranosyloxy)-4-[4-((R)-tetrahydrofuran-3-yloxy)benzyl]-5-methyl-1H-pyrazol,

sowie deren Derivate, in denen R⁶ eine erfindungsgemäße, von Wasserstoff verschiedene Bedeutung aufweist, insbesondere R⁶ Ethoxycarbonyl oder Methoxycarbonyl bedeutet,
einschließlich deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.Particularly preferred compounds of general formula I 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,
• (e) 1-isopropyl-3- (β-D-glucopyranosyloxy) -4- [4 - ((S) -tetrahydrofuran-3-yloxy) benzyl] -5-methyl-1H-pyrazole,
• (f) 1-isopropyl-3- (β-D-glucopyranosyloxy) -4- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] -5-methyl-1H-pyrazole,

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 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, where n can have a value of 1 to 8, 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 _1-n -alkylene, where n can have a value of 1 to 8, denotes 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, isopropoxy, 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 _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.

• a) Zur Herstellung von Verbindungen der allgemeinen Formel I, in der R¹ wie eingangs erwähnt definiert ist, jedoch kein Wasserstoffatom darstellt: Umsetzung einer Verbindung der allgemeinen Formel
  
  in der R² bis R⁶ wie eingangs erwähnt definiert sind, mit einer Verbindung der allgemeinen Formel Z1 – R1 ' (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. Die Umsetzung erfolgt zweckmäßigerweise in einem Lösungsmittel, wie beispielsweise Acetonitril, Toluol, Tetrahydrofuran, Dioxan, Dimethylformamid, Dimethylsulfoxid oder N-Methylpyrrolidinon, gegebenfalls in Gegenwart einer Base, wie beispielsweise Kaliumcarbonat, Cesiumcarbonat, Natriumhydrid oder Kalium-tert.-butylat, bei Temperaturen zwischen 20°C und 160°C.
• b) Zur Herstellung von Verbindungen der allgemeinen Formel I, in der R³ gegebenenfalls substituiertes C_1–6-Alkoxy, C_3–6-Cycloalkyl-oxy, C_3–5-Cycloalkyl-C_1–3-alkoxy oder eine Bedeutung ausgewählt aus der Gruppe A, die wie vorstehend erwähnt definiert ist, darstellt: Umsetzung einer Verbindung der allgemeinen Formel
  
  in der R¹, R² und R⁴ bis R⁶ wie eingangs erwähnt definiert sind, mit einer Verbindung der allgemeinen Formel Z² – R^3' (V),in der R^3' gegebenenfalls substituiertes C_1–6-Alkoxy, C_3–6-Cycloalkyl-oxy, C_3–5-Cycloalkyl-C_1–3-alkoxy oder eine Bedeutung ausgewählt aus der Gruppe A, die wie vorstehend erwähnt definiert ist, darstellt, und Z² eine Austrittsgruppe wie ein Halogenatom, z.B. ein Chlor- oder Bromatom, eine Sulfonyloxygruppe, wie eine Methansulfonyloxy- oder p-Toluolsulfonyloxygruppe oder eine Hydroxygruppe, darstellt.

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 ¹ is defined as mentioned above but is not a hydrogen atom: reaction of a compound of the general formula
  
  in which R ² to R ⁶ are defined as mentioned above, 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 denotes} 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, represents. The reaction is conveniently carried out in a solvent such as 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, at temperatures between 20 ° C and 160 ° C.
• b) For the preparation of compounds of the general formula I in which R ^{3 is} optionally substituted C _1-6 alkoxy, C _3-6 cycloalkyl-oxy, C _3-5 cycloalkyl C _1-3 alkoxy or a meaning selected from the group A, which is defined as mentioned above, represents: reaction of a compound of the general formula
  
  in which R ¹ , R ² and R ⁴ to R ⁶ are defined as mentioned above, with a compound of the general formula Z ² - R ^{3 '} (V), in the R ^{3 '} optionally substituted C _1-6 alkoxy, C _3-6 cycloalkyl-oxy, C _3-5 cycloalkyl C _1-3 alkoxy or a meaning selected from the group A, which defines as mentioned above and Z ^{2 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 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 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.

However, the cleavage of a benzyl, methoxybenzyl or Benzyloxycarbonylrestes is advantageously carried out hydrogenolytically, for example 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 temperature temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, cleavage of a 2,4-dimethoxybenzyl radical 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 chromato graphy and / or fractional crystallization, 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 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 02/36602, WO 02/088157, WO 01/16147, WO 02/053573, 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.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 of [ ¹⁴ C] -AMG and incubated for one hour at 37 ° C. and 5% CO ₂ . 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 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 in principle suitable for influencing all those states or diseases which can be influenced by an inhibition of SGLT-2 activity. Therefore are 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 more suitable for the functionality of pancreatic cells To improve or restore, in addition, the number and size of pancreatic increase beta cells. The compounds of the invention are also useful as diuretics or antihypertensives and to prevention and treatment of acute renal failure.

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 gammal 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 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.

The nachf olgenden examples are intended to illustrate the present invention without to restrict these:

1-(2-Propin-1-yl)-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazol Preparation of the starting compounds: Example I

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 partitioned 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]⁺ (2) 1-Isopropyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-(4-benzyloxybenzyl)-5-methyl-1H-pyrazol

hergestellt aus der Verbindung des Beispiels IV durch Umsetzung mit Isopropyliodid
R_f-Wert: 0.72 (Kieselgel, Cyclohexan/Essigester = 1 : 1)
Massenspektrum (ESI⁺): m/z = 667 [M+H]⁺ Analogously to Example I, the following compounds are obtained: (1) 1- (2-Butyn-1-yl) -3- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl -1H-pyrazole

R _f value: 0.58 (silica gel, methylene chloride / methanol / cyclohexane = 20: 1: 2)
Mass Spectrum (ESI ⁺ ): m / z = 599 [M + H] ⁺ (2) 1-Isopropyl-3- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -4- (4-benzyloxybenzyl) -5-methyl-1H-pyrazol

prepared from the compound of Example IV by reaction with isopropyl iodide
R _f value: 0.72 (silica gel, cyclohexane / ethyl acetate = 1: 1)
Mass spectrum (ESI ⁺ ): m / z = 667 [M + H] ⁺

2-(4-Benzyloxybenzyl)-acetessigsäure-ethylester hergestellt durch Behandlung von Acetessigsäureethylester mit Natriumhydrid und anschließender Umsetzung mit 4-Benzyloxybenzylbromid. Die Reaktion wird in Tetrahydrofuran durchgeführt.
R_f-Wert: 0.48 (Kieselgel, Cyclohexan/Essigester = 4 : 1)
Massenspektrum (ESI⁺): m/z = 599 [M+H]⁺ Beispiel III

1,2-Dihydro-4-(4-benzyloxybenzyl)-5-methyl-pyrazol-3-on hergestellt aus der Verbindung des Beispiels II durch Umsetzung mit Hydrazin-hydrat in Ethanol
R_f-Wert: 0.35 (Kieselgel, Methylenchlorid/Methanol = 9 : 1)
Massenspektrum (ESI^–): m/z = 293 [M-H]^– Beispiel IV

3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-(4-benzyloxybenzyl)-5-methyl-1H-pyrazol In addition, partially deacetylated derivatives of the title compound are isolated from the reaction mixture with R _f values of 0.48, 0.33 and 0.22 (silica gel, cyclohexane / ethyl acetate = 1: 1). Example II

2- (4-Benzyloxybenzyl) acetoacetic acid ethyl ester prepared by treatment of ethyl acetoacetate with sodium hydride and subsequent reaction with 4-benzyloxybenzyl bromide. The reaction is carried out in tetrahydrofuran.
R _f value: 0.48 (silica gel, cyclohexane / ethyl acetate = 4: 1)
Mass Spectrum (ESI ⁺ ): m / z = 599 [M + H] ⁺ Example III

1,2-dihydro-4- (4-benzyloxybenzyl) -5-methyl-pyrazol-3-one prepared from the compound of Example II by reaction with hydrazine hydrate in ethanol
R _f value: 0.35 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ^-): m / z = 293 [MH] ^- Example IV

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

1-Isopropyl-3-(β-D-glucopyranosyloxy)-4-(4-benzyloxybenzyl)-5-methyl-1H-pyrazol hergestellt aus den teilweise deacetylierten Derivaten der Verbindung des Beispiels I(2) durch Behandlung mit Lithiumhydroxid in Tetrahydrofuran/Methanol
Rf-Wert: 0.10 (Kieselgel; Methylenchlorid/Methanol = 9 : 1)
Massenspektrum (ESI⁺): m/z = 499 [M+H]⁺ Beispiel VI

1-Isopropyl-3-(β-D-glucopyranosyloxy)-4-(4-hydroxybenzyl)-5-methyl-1H-pyrazol hergestellt durch katalytische Hydrierung von 1-Isopropyl-3-(β-D-glucopyranosyloxy)-4-(4-benzyloxybenzyl)-5-methyl-1H-pyrazol in Methanol in Gegenwart von Palladium auf Aktivkohle (10% Pd) bei Raumtemperatur
Rf-Wert: 0.36 (Kieselgel; Methylenchlorid/Methanol = 6 : 1)
Massenspektrum (ESI⁺): m/z = 409 [M+H]⁺ 5.1 g of 1,2-dihydro-4- (4-benzyloxybenzyl) -5-methyl-pyrazol-3-one, 7.13 g of 2,3,4,6-tetra-O-acetyl-alpha-glucopyranosylbromide and 4.78 g of silver carbonate Stirred for 3 days at 65 ° C with exclusion of light. The reaction mixture is filtered through a suction filter, the solid residue washed with methylene chloride and the filtrate was concentrated. The crude product is purified by chromatography on a silica gel column with an ethyl acetate / cyclohexane gradient (1: 1 to 3: 1).
Yield: 4.7 g (43% of theory)
Rf value: 0.45 (silica gel, ethyl acetate / cyclohexane = 3: 1)
Mass spectrum (ESI ⁺ ): m / z = 625 [M + H] ⁺ Example V

1-Isopropyl-3- (β-D-glucopyranosyloxy) -4- (4-benzyloxybenzyl) -5-methyl-1H-pyrazole prepared from the partially deacetylated derivatives of the compound of Example I (2) by treatment with lithium hydroxide in tetrahydrofuran / methanol
Rf value: 0.10 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ⁺ ): m / z = 499 [M + H] ⁺ Example VI

1-Isopropyl-3- (β-D-glucopyranosyloxy) -4- (4-hydroxybenzyl) -5-methyl-1H-pyrazole prepared by catalytic hydrogenation of 1-isopropyl-3- (β-D-glucopyranosyloxy) -4- (4-benzyloxybenzyl) -5-methyl-1H-pyrazole in methanol in the presence of palladium on charcoal (10% Pd) at room temperature
Rf value: 0.36 (silica gel, methylene chloride / methanol = 6: 1)
Mass spectrum (ESI ⁺ ): m / z = 409 [M + H] ⁺

Rf-Wert: 0.30 (Kieselgel; Methylenchlorid/Methanol = 9 : 1)The following compound is obtained analogously to Example VI: (1) 1-isopropyl-3- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) -4- (4-hydroxybenzyl) -5-methyl -1H-pyrazole

Rf value: 0.30 (silica gel, methylene chloride / methanol = 9: 1)

1-(2-Propin-1-yl)-3-(β-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazol Preparation of the end compounds: Example 1

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 1M 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]⁺ Beispiel 2

1-(2-Propin-1-yl)-3-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-4-(4-ethylbenzyl)-5-methyl-1H-pyrazol The following compound is obtained analogously to Example 1: (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-propyn-1-yl) -3- (6-O-methoxycarbonyl-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 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)
Rf 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

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] ⁺

Analogously to 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-pyrazol

1-Isopropyl-3-(β-D-glucopyranosyloxy)-4-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]-5-methyl-1H-pyrazol 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] ⁺ Example 4

1-isopropyl-3- (β-D-glucopyranosyloxy) -4- [4 - ((S) -tetrahydrofuran-3-yloxy) benzyl] -5-methyl-1H-pyrazol

50mg of 1-isopropyl-3- (β-D-glucopyranosyloxy) -4- (4-hydroxybenzyl) -5-methyl-1H-pyrazole, 33.92mg (R) -p-Toluolsulfonsäure- (tetrahydrofuran-3-yl) ester and 45.61 mg of cesium carbonate are stirred in 0.5 ml of dimethylformamide at 50 ° C for 16 hours. The reaction mixture is concentrated and the residue is purified by chromatography on a silica gel column.
Yield: 35 mg (60% of theory)
Rf value: 0.55 (silica gel, methylene chloride / methanol = 6: 1)
Mass spectrum (ESI ⁺ ): m / z = 479 [M + H] ⁺

Rf-Wert: 0.55 (Kieselgel, Methylenchlorid/Methanol = 6 : 1)
Massenspektrum (ESI⁺): m/z = 493 [M+H]⁺ (2) 1-Isopropyl-3-(β-D-glucopyranosyloxy)-4-[4-(tetrahydropyran-4-yloxy)benzyl]-5-methyl-1H-pyrazol

Rf-Wert: 0.54 (Kieselgel, Methylenchlorid/Methanol = 6 : 1)
Massenspektrum (ESI⁺): m/z = 493 [M+H]⁺ (3) 1-Isopropyl-3-(β-D-glucopyranosyloxy)-4-[4-((R)-tetrahydrofuran-3-yloxy)benzyl]-5-methyl-1H-pyrazol

hergestellt durch Alkylierung der Verbindung des Beispiels VI(1) und anschließender Hydrolyse der Acetylgruppen analog Beispiel V
Massenspektrum (ESI⁺): m/z = 479 [M+H]⁺ The following compounds are obtained analogously to Example 4: (1) 1-isopropyl-3- (β-D-glucopyranosyloxy) -4- [4 - ((S) -tetrahydrofuran-2-ylmethyloxy) benzyl] -5-methyl- 1H-pyrazole

Rf value: 0.55 (silica gel, methylene chloride / methanol = 6: 1)
Mass Spectrum (ESI ⁺ ): m / z = 493 [M + H] ⁺ (2) 1-Isopropyl-3- (β-D-glucopyranosyloxy) -4- [4- (tetrahydropyran-4-yloxy) benzyl] -5 methyl-1H-pyrazol

Rf value: 0.54 (silica gel, methylene chloride / methanol = 6: 1)
Mass spectrum (ESI ⁺ ): m / z = 493 [M + H] ⁺ (3) 1-Isopropyl-3- (β-D-glucopyranosyloxy) -4- [4 - ((R) -tetrahydrofuran-3-yloxy) benzyl] -5-methyl-1H-pyrazole

prepared by alkylation of the compound of Example VI (1) and subsequent hydrolysis of the acetyl groups analogously to Example V.
Mass spectrum (ESI ⁺ ): m / z = 479 [M + H] ⁺

Beispiel 5 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 5 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

Production process:

Beispiel 6 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 1.0mg 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 6 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 1.0mg 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 7 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: about 320 mg Capsule shell: Hard gelatin capsule size 1. Example 8 Suppositories with 150 mg Active Ingredient 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 9 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 10 ampoules with 50 mg active substance Composition: active substance 50.0 mg 0.01 n hydrochloric acid sq Aqua bidest 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, pyrrolidine 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 the nitrogen atom with 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 difluoromethylenedioxy, or, (c) C _3-6 -cycloalkyl-oxy or C _3-6 -cycloalkylidene-methyl and at the same time R ^{4 is} 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 ff, 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 _{3 6} -alkenyl, C _3-6 -cycloalkyl, C _3-6 -cycloalkyl-C _1-3 -alkyl, aryl or aryl-C _1-3 -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 -cycloalkylidenemethyl, C _1-6 -alkoxy, C _3-6 -cycloalkyl-oxy, C _3-6 -cycloalkyl-C _1-3 -alkoxy, aryl, ArylC _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 substituted by 1 to 5 fluorine atoms _2-4 alkyl or C _3-4 alkoxy, by a cyano-substituted C _1-4 alkyl, 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 alkylsulfonylamino, arylsulfonylamino, arylC _1-3 alkylsulfonylamino, C _1-4 alkylsulfanyl, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, arylsulfenyl, arylsulfinyl or arylsulfonyl, or has a meaning selected from the group A, 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, methyl or methoxy substituted by 1 to 3 fluorine atoms, or R ³ together with R ⁴ , if these are bound to adjacent carbon atoms, also a straight-chain C _3-5 alkylene group, a methyls ndioxygruppe or Difluormethylendioxy, and R ⁶ , R ^7a , R ^7b , R ^7c 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, A is selected from the group 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 piperidine 4-yloxy, where in the last three groups the nitrogen atom is substituted by C _1-4 -alkyl, formyl, C _1-4 -alkylcarbonyl, C _1-4 -alkylsulphonyl, cyano, aminocarbonyl, (C _1-4 alkyl) aminocarbonyl, di (C _1-4 alkyl) aminocarbonyl or (C _1-4 alkyl) oxycarbonyl may be substituted, wherein among those mentioned in the definition of the aforementioned radicals Aryl groups phenyl or naphtha hylgruppen which can be independently mono- or disubstituted by R _h , where the substituents may be identical or different and R _{h is} a fluorine, chlorine, bromine, iodine, C _1-3 alkyl, difluoromethyl, trifluoromethyl, C _1-3 denotes 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 to 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, tetrahydrofuran-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, (C _1-8 -alkyl) oxycarbonyl or C _1-8 -alkylcarbonyl-, their tautomers, their stereoisomers, mixtures thereof and their salts. 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 or, if R ^{3 is} selected from the group consisting of tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy and tetrahydrofuranylmethyloxy then R ^{1 can} also be isopropyl, R ^{2 is} methyl, R ^{3 is} ethyl, tetrahydrofuran-3-yloxy, Tetrahydropyran-4-yloxy or Tetrahydrofuranylmethyloxy R ⁴ and R ^{5 is} hydrogen and R ^{6 is} hydrogen or methoxycarbonyl, their tautomers, their stereoisomers, their mixtures and their salts. Compounds of the general formula I according to Claim 1 selected from the group consisting of (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 and (d) 1- (tetrahydropyran 4-yl) -3- (β-D-glucopyranosyloxy) -4- (4-ethylbenzyl) -5-methyl-1H-pyrazole, (e) 1-isopropyl-3- (β-D-glucopyranosyloxy) -4 - [4 - ((S) -tetrahydrofuran-3-yloxy) benzyl] -5-methyl-1H-pyrazole, (f) 1-isopropyl-3- (β-D-glucopyranosyloxy) -4- [4 - (( R) -tetrahydrofuran-3-yloxy) benzyl] -5-methyl-1H-pyrazole, 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, their mixtures and their salts. Physiologically acceptable salts of the compounds according to at least one of 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 and R ^7a , R ^7b , R ^{7c 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, or b) for the preparation of compounds of general formula I, in which R ³ optionally substituted C _{1- 6} -alkoxy, C _3-6 -cycloalkyl-oxy, C _3-5 -cycloalkyl-C _1-3 -alkoxy or a meaning selected from the group A, which is defined according to claim 1, represents a compound of the general formula

in which R ¹ , R ² and R ⁴ to R ⁶ and R ^7a , R ^7b , R ^{7c are} as defined in claim 1, with a compound of the general formula Z ² - R ^{3 '} (V), in the R ^{3 '} optionally substituted C _1-6 alkoxy, C _3-6 cycloalkyl-oxy, C _3-5 cycloalkyl C _1-3 alkoxy or a meaning selected from the group A, which defines as mentioned above and Z ^{2 is} a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulfonyloxy group, such as a methanesulfonyloxy or p-toluenesulfonyloxy or a hydroxy group is reacted and, if desired, a compound of the general formula I, in R ^{6 represents} a hydrogen atom is converted by acylation into a corresponding acyl compound of the general formula I, and / or if necessary, a protecting residue used in the reactions described above is cleaved again and / or, if desired, a compound of general formula I thus obtained in their stereoisomers is separated and / or a compound of general formula I thus obtained in its salts, in particular for the pharmaceutical application into their physiologically acceptable salts, is converted.