DE102004061145A1 - New glucopyranosyl-substituted benzene derivatives are sodium-dependent glucose cotransporter inhibitors, useful for treating e.g. metabolic disorders (type 1 and type 2 diabetes mellitus or metabolic acidosis) - Google Patents

Abstract

Glucopyranosyl-substituted benzene derivatives (I) and their tautomers, sterioisomers andsalts are new. Glucopyranosyl-substituted benzene derivatives of formula (I) and their tautomers, stereoisomers and salts are new. R 1> : definitions of the group A; R 2> : H, F, Cl, Br, OH, 1-4C alkyl, 1-4C alkoxy, CN or NO 2 (while the alkyl or alkoxy group mono- or polysubstituted by F); R 3> : definitions of the group B 1>; R 4>, R 5> : H, F, Cl, Br, I, CN, NO 2, 1-3C alkyl, 1-3C alkoxy, methyl or methoxy (substituted by 1-3 F atoms); A : e.g. 2-6C alkyn-1-yl, 2-6C alken-1-yl or 3-7C cycloalkyl; B 1> : e.g. tri-(1-4C alkyl)silyl-1-6C alkyl, 2-6C alkyn-1-yl or 2-6C alken-1-yl; R-N : H, 1-4C alkyl, 1-4C alkylcarbonyl or 1-4C alkylsulfonyl; L1 : OH, CN, NO 2, 3-7C cycloalkyl, (hetero)aryl, 1-4C alkylcarbonyl, (hetero)arylcarbonyl, aminocarbonyl, 1-4C alkylaminocarbonyl, di-(1-3C alkyl)-aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, (hetero)arylaminocarbonyl, 1-4C alkoxycarbonyl, (hetero)aryl-1-3C alkoxycarbonyl, 1-4C alkyloxy, (hetero)aryloxy, 1-4C alkylsulfanyl, (hetero)arylsulfanyl, 1-4C alkylsulfinyl, (hetero)arylsulfinyl, 1-4C alkylsulfonyl or (hetero)arylsulfonyl; L2 : F, Cl, Br, I, 1-3C alkyl, difluoromethyl, trifluoromethyl, 1-3C alkoxy, difluoromethoxy, OCF 3 or CN; and R 6>, R-7a, R-7b, R-7c : H, (1-18C alkyl)carbonyl, (1-18C alkyl)oxycarbonyl, arylcarbonyl or aryl-(1-3C alkyl)-carbonyl (while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups which mono- or disubstituted of one another by identical or different groups L2 and by the heteroaryl groups mentioned in the definition of the above groups are meant a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl or tetrazolyl group or is meant a pyrrolyl, furanyl, thienyl or pyridyl group where 1-2 methyne groups are replaced by nitrogen atoms or meant an indolyl, benzofuranyl, benzothiophenyl or (iso)quinolinyl group, where 1-3 methyne groups are replaced by nitrogen atoms, while the above-mentioned heteroaryl groups of one another may be mono- or disubstituted by identical or different groups L2. Provisos are given. Full definitions are given in the "Definitions" section. Independent claims are also included for: (1) physiologically acceptable salts of (I) with inorganic or organic acids; (2) a glucopyranosyl-substituted benzene derivatives of formula (II); (3) composition containing (I) or a physiologically acceptable salt optionally together with one or more inert carriers and/or diluents; (4) process for preparing a composition comprising the step of incorporating one or more inert carriers and/or diluents into the composition by a non-chemical method. (5) a benzene derivatives of formula (IV); (6) the preparation of (I); (7) the preparation of (II) comprises an organometallic compound (V) which may be obtained by halogen-metal exchange or by the insertion of a metal in the carbon-halogen bond of (IV) and optionally subsequent transmetallation, is added to a gluconolactone of formula (VI) then reacting the adduct obtained with water or an alcohol of formula (R-a-OH), in the presence of an acid and optionally the product obtained in the reaction with water is converted in a subsequent reaction with an acylating agent to give (II); and (8) a pharmaceutical composition for use as a diuretic or hypertensive, the composition comprising (I). R-s : H, 1-4C alkyl, (1-8Calkyl)carbonyl, (1-18C-alkyl)oxycarbonyl, arylcarbonyl or aryl-(C1 3-alkyl)-carbonyl (where the alkyl or aryl groups may be mono- or polysubstituted by halo); either R-8a-R-8d : R 6>, R-7a-R-7c or denote a benzyl group or a R-aR-bR-cSi group or a ketal or acetal group; or R-8a-R-8d : may form a cyclic ketal or acetal group or a 1,2-di(1-3C-alkoxy)-1,2-di(13C-alkyl)-ethylene bridge, (while the above-mentioned ethylene bridge forms, together with two oxygen atoms and the two associated carbon atoms of the pyranose ring, a substituted dioxane ring and alkyl, aryl and/or benzyl groups may be mono- or polysubstituted by halogen or 13C-alkoxy and benzyl groups may also be substituted by a di-(1-3C-alkyl)amino group); R-a, R-b, R-c : 1-4C alkyl, aryl or aryl-1-3C-alkyl; and aryl : phenyl (preferred) or naphthyl groups. [Image] [Image] ACTIVITY : Antidiabetic; Vasotropic; Analgesic; Antianginal; Antilipemic; Antiarteriosclerotic; Anorectic; Cardiant; Antiinflammatory. MECHANISM OF ACTION : Sodium-dependent glucose cotransporter inhibitor. The ability of (I) to inhibit sodium-dependent glucose cotransporter was tested in biological assays. The results showed that (I) exhibits a median effective concentration value of less than 50 nM.

Description

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

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

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

Out International Publication WO 98/31697, WO 01/27128, WO 02/083066, WO 03/099836, WO 2004/063209, WO 2004/080990, WO 2004/013118, WO 2004/052902, WO 2004/052903 and US application US 2003/0114390 are glucopyranosyl-substituted aromatics and their preparation and their possible activity known as SGLT2 inhibitors.

Object of the invention

Of the present invention is based on the object, new pyranosyl-substituted To show benzene derivatives in particular, those having an activity with respect to the sodium-dependent glucose cotransporter SGLT, in particular SGLT2 own. Another task of the present Invention is to show pyranosyl-substituted benzene derivatives which in vitro and / or in vivo compared with known, structurally similar Compounds an increased Inhibitory effect with respect of the sodium dependent Possess glucose-cotransporters SGLT2 and / or improved pharmacological or pharmacokinetic properties.

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

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

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

Subject of the invention

in der
R¹ ausgewählt ist aus den Bedeutungen der Gruppe A und
falls R³ ausgewählt ist aus den Bedeutungen der Gruppe B, kann R¹ zusätzlich auch ausgewählt sein aus den Bedeutungen Wasserstoff, Fluor, Chlor, Brom, Iod, C_1-4- Alkyl, C_2-4-Alkenyl-C_1-4-alkyl, C_2-4-Alkinyl-C_1-4-alkyl, C_2-4-Alkenyl-C_1-4-alkoxy, C_2-4-Alkinyl-C_1-4-alkoxy, C_3-7-Cycloalkyl-C_1-4-alkyl, C_5-7-Cycloalkenyl-C_1-4-alkyl, eine durch 1 bis 3 Fluoratome substituierte Methylgruppe, eine durch 1 bis 5 Fluoratome substituierte Ethylgruppe, C_1-4-Alkoxy, eine durch 1 bis 3 Fluoratome substituierte Methoxygruppe, eine durch 1 bis 5 Fluoratome substituierte Ethoxygruppe, eine durch eine Hydroxy- oder C_1-3-Alkoxygruppe substituierte C_1-4-Alkylgruppe, eine durch eine Hydroxy- oder C_1-3-Alkoxygruppe substituierte C_2-4-Alkoxygruppe, C_3-6-Cycloalkyl-C_1-3-alkoxy oder Hydroxy,
wobei in den vorstehend genannten Cycloalkyl- und Cycloalkenyl-Ringen ein oder zwei Methylengruppen unabhängig voneinander durch O oder CO substituiert sein können, und
R² Wasserstoff, Fluor, Chlor, Brom, Hydroxy, C_1-4-Alkyl, C_1-4-Alkoxy, Cyan oder Nitro, wobei die Alkyl- oder Alkoxygruppe ein oder mehrfach mit Fluor substituiert sein kann, und
R³ ausgewählt ist aus den Bedeutungen der Gruppe B und
falls R¹ ausgewählt ist aus den Bedeutungen der Gruppe A, kann R³ zusätzlich auch ausgewählt sein aus den Bedeutungen Wasserstoff, Fluor, Chlor, Brom, Iod, C_1-6-Alkyl, C_2-4-Alkenyl-C_1-4-alkyl, C_2-4-Alkinyl-C_1-4-alkyl, C_2-4-Alkenyl-C_1-4-alkoxy, C_2-4-Alkinyl-C_1-4-alkoxy, C_3-7-Cycloalkyl, C_5-7-Cycloalkenyl, C_3-7-Cycloalkyl-C_1-4-alkyl, C_5-7-Cycloalkenyl-C_1-7-alkyl, C_3-6-Cycloalkylidenmethyl, Hydroxy, C_1-6-Alkoxy, C_3-6-Cycloalkyl-C_1-3-alkoxy, Aryl, Aryl-C_1-3-alkyl, Heteroaryl, Heteroaryl-C_1-3-alkyl, Aryloxy, Aryl-C_1-3-alkyl-oxy, eine durch 1 bis 3 Fluoratome substituierte Methyl- oder Methoxygruppe, eine durch 1 bis 5 Fluoratome substituierte C_2-4-Alkyl- oder C_2-4-Alkoxygruppe, eine durch eine Cyangruppe substituierte C_1-4-Alkylgruppe, eine durch eine Hydroxy- oder C_1-3-Alkyloxygruppe substituierte C_1-4-Alkylgruppe, 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, (C_1-4-Alkyl)carbonylamino-, C_1-4-Alkylsulfonylamino, C_1-4-Alkylsulfanyl-, C_1-4-Alkylsulfinyl-, C_1-4-Alkylsulfonyl-, Arylsulfonylamino, Aryl-C_1-3-alkylsulfonylamino oder Arylsulfonyl,
R⁴, R⁵ unabhängig voneinander Wasserstoff, Fluor, Chlor, Brom, Iod, Cyan, Nitro, C_1-3-Alkyl, C_1-3-Alkoxy, durch 1 bis 3 Fluoratome substituiertes Methyl- oder Methoxy,
A C_2-6-Alkin-1-yl, C_2-6-Alken-1-yl, C_3-7-Cycloalkyl, C_5-7-Cycloalkenyl, Aryl, Heteroaryl, C_1-4-Alkylcarbonyl, Arylcarbonyl, Heteroarylcarbonyl, Aminocarbonyl, C_1-4-Alkylaminocarbonyl, Di-(C_1-3-Alkyl)aminocarbonyl, Pyrrolidin-1-ylcarbonyl, Pipeadin-1-ylcarbonyl, Morpholin-4-ylcarbonyl, Piperazin-1-ylcarbonyl, 4-(C_1-4-Alkyl)piperazin-1-ylcarbonyl, Arylaminocarbonyl, Heteroarylaminocarbonyl, C_1-4-Alkoxycarbonyl, Aryl-C_1-3-alkoxycarbonyl, Heteroaryl-C_1-3-alkoxycarbonyl, Amino, C_1-4-Alkylamino, Di-(C_1-3-alkyl)amino, Pyrrolidin-1-yl, Pyrrolidin-2-on-1-yl, Piperidin-1-yl, Piperidin-2-on-1-yl, Morpholin-4-yl, Morpholin-3-on-4-yl, Piperazin-1-yl, 4-(C_1-3-Alkyl)piperazin-1-yl, C_1-4-Alkylcarbonylamino, Arylcarbonylamino, Heteroarylcarbonylamino, C_3-7-Cycloalkyloxy, C_5-7-Cycloalkenyloxy, Aryloxy, Heteroaryloxy, C_1-4-Alkylsulfinyl, C_1-4-Alkylsulfonyl, C_3-7-Cycloalkylsulfanyl, C_3-7-Cycloalkylsulfinyl, C_3-7-Cycloalkylsulfonyl, C_5-7-Cycloalkenylsulfanyl, C_5-7-Cycloalkenylsulfinyl, C_5-7-Cycloalkenylsulfonyl, Arylsulfanyl, Arylsulfinyl, Arylsulfonyl, Heteroarylsulfanyl, Heteroarylsulfinyl, Heteroarylsulfonyl, Cyan oder Nitro bedeutet,
wobei die vorstehend genannten Alkinyl- und Alkenylgruppen ein- oder mehrfach mit Fluor oder Chlor substituiert sein können, und
wobei die vorstehend genannten Alkinyl- und Alkenylgruppen ein- oder zweifach mit gleichen oder verschiedenen Resten L1 substituiert sein können, und
wobei die vorstehend genannten Cycloalkyl- und Cycloalkenyl-Ringe unabhängig voneinander ein- oder zweifach mit Substituenten ausgewählt aus Fluor und C_1-3-Alkyl substituiert sein können, und
wobei in den vorstehend genannten Cycloalkyl- und Cycloalkenyl-Ringen ein oder zwei Methylengruppen unabhängig voneinander durch O, S, CO, SO, SO₂ oder NR^N substituiert sein können,
B Tri-(C_1-4-alkyl)silyl-C_1-6-alkyl, C_2-6-Alkin-1-yl, C_2-6-Alken-1-yl, Amino, C_1-3-Alkylamino, Di-(C_1-3-alkyl)amino, Pyrrolidin-1-yl, Pyrrolidin-2-on-1-yl, Piperidin-1-yl, Piperidin-2-on-1-yl, Morpholin-4-yl, Morpholin-3-on-4-yl, Piperazin-1-yl, 4-(C_1-3-Alkyl)piperazin-1-yl, Arylcarbonylamino, Heteroarylcarbonylamino, Nitro, C_3-10-Cycloalkyloxy, C_5-10-Cycloalkenyloxy, C_3-10-Cycloalkylsulfanyl, C_3-10-Cycloalkylsulfinyl, C_3-10-Cycloalkylsulfonyl, C_5-10-Cycloalkenylsulfanyl, C_5-10-Cycloalkenylsulfinyl, C_5-10-Cycloalkenylsulfonyl, Arylsulfanyl, Arylsulfinyl, Heteroarylsulfanyl oder Heteroarylsulfinyl,
wobei die vorstehend genannten Alkinyl- und Alkenylgruppen ein- oder mehrfach mit Fluor oder Chlor substituiert sein können, und
wobei die vorstehend genannten Alkinyl- und Alkenylgruppen ein- oder zweifach mit gleichen oder verschiedenen Resten L1 substituiert sein können;
wobei die vorstehend genannten Cycloalkyl- und Cycloalkenyl-Ringe unabhängig voneinander ein- oder zweifach mit Substituenten ausgewählt aus Fluor und C_1-3-Alkyl substituiert sein können, und
wobei in den vorstehend genannten Cycloalkyl- und Cycloalkenyl-Ringen ein oder zwei Methylengruppen unabhängig voneinander durch O, S, CO, SO, SO₂ oder NR^N substituiert sein können,
R^N H, C_1-4-Alkyl, C_1-4-Alkylcarbonyl oder C_1-4-Alkylsulfonyl,
L1 unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Hydroxy, Cyan-, Nitro-, C_3-7-Cycloalkyl, Aryl-, Heteroaryl-, C_1-4-Alkylcarbonyl-, Arylcarbonyl-, Heteroarylcarbonyl-, Aminocarbonyl-, C_1-4-Alkylaminocarbonyl-, Di-(C_1-3-alkyl)aminocarbonyl-, Pyrrolidin-1-ylcarbonyl-, Piperidin-1-ylcarbonyl-, Morpholin-4-ylcarbonyl, Arylaminocarbonyl-, Heteroarylaminocarbonyl-, C_1-4-Alkoxycarbonyl-, Aryl-C_1-3-alkoxycarbonyl-, Heteroaryl-C_1-3-alkoxycarbonyl-, C_1-4-Alkyloxy-, Aryloxy-, Heteroaryloxy-, C_1-4-Alkylsulfanyl-, Arylsulfanyl-, Heteroarylsulfanyl-, C_1-4-Alkylsulfinyl-, Arylsulfinyl-, Heteroarylsulfinyl-, C_1-4-Alkylsulfonyl-, Arylsulfonyl- und Heteroarylsulfonyl-; und
L2 unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Fluor, Chlor, Brom, Iod, C_1-3-Alkyl, Difluormethyl, Trifluormethyl, C_1-3-Alkoxy, Difluormethoxy, Trifluormethoxy und Cyan; und
R⁶, R^7a, R^7b, R^7c unabhängig voneinander eine Bedeutung ausgewählt aus der Gruppe Wasserstoff, (C_1-8-Alkyl)carbonyl, (C_1-8-Alkyl)oxycarbonyl, Arylcarbonyl und Aryl-(C_1-3-alkyl)carbonyl besitzen,
wobei unter den bei der Definition der vorstehend genannten Reste erwähnten Arylgruppen Phenyl- oder Naphthylgruppen zu verstehen sind, welche unabhängig voneinander ein- oder zweifach mit gleichen oder verschiedenen Resten L2 substituiert sein können; und
unter den bei der Definition der vorstehend erwähnten Reste erwähnten Heteroarylgruppen eine Pyrrolyl-, Furanyl-, Thienyl-, Pyridyl-, Indolyl-, Benzofuranyl-, Benzothiophenyl-, Chinolinyl-, Isochinolinyl- oder Tetrazolylgruppe 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 unabhängig voneinander ein- oder zweifach mit gleichen oder verschiedenen Resten L2 substituiert sein können;
wobei, soweit nichts anderes erwähnt wurde, die vorstehend erwähnten Alkylgruppen geradkettig oder verzweigt sein können,
deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.A first subject of the present invention are glucopyranosyl-substituted benzene derivatives of general formula I.

in the
R ^{1 is} selected from the meanings of group A and
In addition, if R ^{3 is} selected from the meanings of group B, R ^{1 may} additionally be selected from the meanings hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 -alkyl, C _2-4 -alkenyl-C _1-4 -alkyl, C _2-4 -alkynyl-C _1-4 -alkyl, C _2-4 -alkenyl-C _1-4 -alkoxy, C _2-4 -alkynyl-C _1-4 -alkoxy, C _3-7 - Cycloalkyl-C _1-4 -alkyl, C _5-7 -cycloalkenyl-C _1-4 -alkyl, a methyl group substituted by 1 to 3 fluorine atoms, an ethyl group substituted by 1 to 5 fluorine atoms, C _1-4 alkoxy, a through 1 to 3 fluorine atom-substituted methoxy group, an ethoxy group substituted by 1 to 5 fluorine atoms, a C _1-4 alkyl group substituted by a hydroxy or C _1-3 alkoxy group, a C substituted by a hydroxy or C _1-3 alkoxy group _2-4 -alkoxy group, C _3-6 -cycloalkyl-C _1-3 -alkoxy or hydroxy,
wherein in the aforementioned cycloalkyl and cycloalkenyl rings one or two methylene groups may be independently substituted by O or CO, and
R ^{2 is} hydrogen, fluorine, chlorine, bromine, hydroxy, C _1-4 -alkyl, C _1-4 -alkoxy, cyano or nitro, where the alkyl or alkoxy group may be mono- or polysubstituted by fluorine, and
R ^{3 is} selected from the meanings of group B and
In addition, if R ^{1 is} selected from the meanings of group A, R ^{3 may} additionally be selected from the meanings hydrogen, fluorine, chlorine, bromine, iodine, C _1-6 -alkyl, C _2-4 -alkenyl-C _1-4 -alkyl, C _2-4 -alkynyl-C _1-4 -alkyl, C _2-4 -alkenyl-C _1-4 -alkoxy, C _2-4 -alkynyl-C _1-4 -alkoxy, C _3-7 - Cycloalkyl, C _5-7 cycloalkenyl, C _3-7 cycloalkylC _1-4 alkyl, C _5-7 cycloalkenylC _1-7 alkyl, C _3-6 cycloalkylidenemethyl, hydroxy, C _1-6 Alkoxy, 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-substituted C _1-4 alkyl group, a through a hydroxy or C _1-3 alkyloxy group substituted C _1-4 alkyl group, cyano, carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, (C _1-3 alkylamino) carbonyl, di (C _1-3 alkyl ) aminocarbonyl, pyrr olidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C _1-3 alkyl) piperazin-1-ylcarbonyl, (C _1-4 alkyl ) carbonylamino, C _1-4 -alkylsulfonylamino, C _1-4 -alkylsulfanyl, C _1-4 -alkylsulfinyl, C _1-4 -alkylsulfonyl, arylsulfonylamino, arylC _1-3 -alkylsulfonylamino or arylsulfonyl,
R ⁴ , R ⁵ independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C _1-3 -alkyl, C _1-3 -alkoxy, methyl or methoxy substituted by 1 to 3 fluorine atoms,
A is C _2-6 alkyn-1-yl, C _2-6 alken-1-yl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, aryl, heteroaryl, C _1-4 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl , Aminocarbonyl, C _1-4 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, pipeadin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C _1-4 -alkyl) piperazin-1-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, C _1-4 -alkoxycarbonyl, arylC _1-3 -alkoxycarbonyl, heteroarylC _1-3 -alkoxycarbonyl, amino, C _1-4 -alkylamino, Di (C _1-3 alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, Morpholin-3-on-4-yl, piperazin-1-yl, 4- (C _1-3 alkyl) piperazin-1-yl, C _1-4 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C _3-7 cycloalkyloxy, C _5-7 cycloalkenyloxy, aryloxy, heteroaryloxy, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, C _3-7 cycloalkylsulfanyl, C _3-7 cycloalkylsulfinyl, C _3-7 cycloalkylsulfonyl, C _5-7 -Cycloalkenylsulfanyl, C _5-7 -cycloalkenylsulfinyl, C _5-7 -cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroarylsulfanyl, heteroarylsulfinyl, heteroarylsulfonyl, cyano or nitro,
wherein the abovementioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, and
wherein the abovementioned alkynyl and alkenyl groups may be mono- or disubstituted by identical or different radicals L1, and
wherein the above-mentioned cycloalkyl and cycloalkenyl rings independently of one another may be mono- or disubstituted by substituents selected from fluorine and C _1-3 -alkyl, and
where in the abovementioned cycloalkyl and cycloalkenyl rings one or two methylene groups can be substituted independently of one another by O, S, CO, SO, SO ₂ or NR ^N ,
B is tri- (C _1-4 alkyl) silylC _1-6 alkyl, C _2-6 alkyn-1-yl, C _2-6 alken-1-yl, amino, C _1-3 alkylamino , Di (C _1-3 alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-1-yl, piperidin-2-one-1-yl, morpholin-4-yl , Morpholin-3-one-4-yl, piper azin-1-yl, 4- (C _1-3 alkyl) piperazin-1-yl, arylcarbonylamino, heteroarylcarbonylamino, nitro, C _3-10 cycloalkyloxy, C _5-10 cycloalkenyloxy, C _3-10 cycloalkylsulfanyl, C _3-10 -cycloalkylsulfinyl, C _3-10 -cycloalkylsulfonyl, C _5-10 -cycloalkenylsulfanyl, C _5-10 -cycloalkenylsulfinyl, C _5-10 -cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, heteroarylsulfanyl or heteroarylsulfinyl,
wherein the abovementioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, and
wherein the aforementioned alkynyl and alkenyl groups may be monosubstituted or disubstituted by identical or different L1 groups;
wherein the above-mentioned cycloalkyl and cycloalkenyl rings independently of one another may be mono- or disubstituted by substituents selected from fluorine and C _1-3 -alkyl, and
where in the abovementioned cycloalkyl and cycloalkenyl rings one or two methylene groups can be substituted independently of one another by O, S, CO, SO, SO ₂ or NR ^N ,
R ^{N is} H, C _1-4 -alkyl, C _1-4 -alkylcarbonyl or C _1-4 -alkylsulfonyl,
L1 independently selected from the group consisting of hydroxy, cyano, nitro, C _3-7 cycloalkyl, aryl, heteroaryl, C _1-4 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, C _{1 4-} alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, C _1-4 alkoxycarbonyl -, arylC _1-3 alkoxycarbonyl, heteroarylC _1-3 alkoxycarbonyl, C _1-4 alkyloxy, aryloxy, heteroaryloxy, C _1-4 alkylsulfanyl, arylsulfanyl, heteroarylsulfanyl, C _1-4 alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, C _1-4 alkylsulfonyl, arylsulfonyl and heteroarylsulfonyl; and
L2 independently of one another are selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-3 -alkyl, difluoromethyl, trifluoromethyl, C _1-3 -alkoxy, difluoromethoxy, trifluoromethoxy and cyano; and
R ⁶ , R ^7a , R ^7b , R ^7c independently of one another are selected from the group consisting of hydrogen, (C _1-8 -alkyl) carbonyl, (C _1-8 -alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _1-3 alkyl) carbonyl,
wherein the aryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning phenyl or naphthyl groups which may be independently of one another monosubstituted or disubstituted by identical or different radicals L 2; and
the heteroaryl groups mentioned in the definition of the abovementioned radicals mean a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl or tetrazolyl group,
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 independently of one another may be monosubstituted or disubstituted by identical or different L2 radicals;
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 SGLT, especially SGLT2. Furthermore, erfindunsgemäße compounds an inhibitory effect on the sodium-dependent glucose cotransporter SGLT1 have. Compared with a possible inhibitory effect on SGLT1 inhibit the compounds of the invention preferably selective 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.

Also An object of this invention is the use of at least one compound of the invention or a physiologically acceptable one Salt of such a compound for the manufacture of a medicament, which is suitable for the treatment or prophylaxis of diseases or conditions by inhibition of the sodium-dependent glucose cotransporter SGLT, in particular SGLT2 can be influenced.

Another object of this invention is the use of at least one inventive A compound or one of its physiologically acceptable salts for the manufacture of a medicament suitable for the treatment of metabolic diseases

One Another object of this invention is the use of at least a compound of the invention or one of its physiologically acceptable salts for the production a drug for inhibiting the sodium-dependent glucose cotransporter SGLT, especially SGLT2.

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 or one of its physiologically compatible Salts in one or more inert carriers and / or diluents is incorporated.

• a) zur Herstellung von Verbindungen der allgemeinen Formel I, die wie vor- und nachstehend definiert ist, eine Verbindung der allgemeinen Formel II
  
  in der R' H, C_1-4-Alkyl, (C_1-18-Alkyl)carbonyl, (C_1-18-Alkyl)oxycarbonyl, Arylcarbonyl und Aryl-(C_1-3-alkyl)-carbonyl bedeutet, worin die Alkyl- oder Arylgruppen ein- oder mehrfach mit Halogen substituiert sein können; R^8a, R^8b R^8c, R^8d unabhängig voneinander eine zuvor und nachstehend für die Reste R⁶, R^7a, R^7b, R^7c angegebenen Bedeutungen aufweisen, eine Benzyl-Gruppe oder eine R^aR^bR^cSi-Gruppe oder eine Ketal- oder Acetalgruppe, insbesondere eine Alkyliden- oder Arylalkyliden- Ketal- oder Acetalgruppe bedeuten, wobei jeweils zwei benachbarte Reste R^8a, R^8b, R^8c, R^8d eine cyclische Ketal- oder Acetalgruppe oder eine 1,2-Di(C_1-3-alkoxy)-1,2-di(C_1-3-alkyl)-ethylen-Brücke bilden können, wobei die genannte Ethylen-Brücke zusammen mit zwei Sauerstoffatomen und den zugehörigen beiden Kohlenstoffatomen des Pyranose-Rings einen substituierten Dioxan-Ring, insbesondere einen 2,3-Dimethyl-2,3-di(C_1-3-alkoxy)-1,4-dioxan-Ring, bildet, und wobei Alkyl-, Aryl- und/oder Benzylgruppen ein- oder mehrfach mit Halogen oder C_1-3-Alkoxy substituiert sein können und Benzyl-Gruppen auch mit einer Di-(C_1-3-alkyl)amino-Gruppe substituiert sein können; und R^a, R^b, R^c unabhängig voneinander C_1-4-Alkyl, Aryl oder Aryl-C_1-3-alkyl, worin die Aryl- oder Alkylgruppen ein- oder mehrfach mit Halogen substituiert sein können; wobei unter den bei der Definition der vorstehend genannten Reste erwähnten Arylgruppen Phenyl- oder Naphthylgruppen, vorzugsweise Phenylgruppen zu verstehen sind; und in der die Reste R¹ bis R⁵ und R⁶, R^7a, R^7b, R^7c wie vor- und nachstehend definiert sind; mit einem Reduktionsmittel in Gegenwart einer Lewis- oder Br⌀nsted-Säure umgesetzt wird, wobei die eventuell vorhandenen Schutzgruppen gleichzeitig oder nachträglich abgespalten werden; oder
• b) zur Herstellung von Verbindungen der allgemeinen Formel I, in der R⁶, R^7a, R^7b und R^7c Wasserstoff bedeuten, eine Verbindung der allgemeinen Formel III
  
  in der R^8a, R^8b, R^Bc, R^8d sowie R¹ bis R⁵ wie zuvor und nachstehend definiert sind, jedoch mindestens einer der Reste R^8a, R^8b, R^8c, R^8d nicht Wasserstoff bedeutet, hydrolysiert 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 gewünschtenfalls 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, which is as defined above and below, a compound of general formula II
  
  wherein R 'is H, C _1-4 alkyl, (C _1-18 alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _1-3 alkyl) carbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted by halogen; R ^8a , R ^8b R ^8c , R ^8d independently of one another have the meanings given above and below for the radicals R ⁶ , R ^7a , R ^7b , R ^7c , a benzyl group or an R ^a R ^b R ^c Si group or a ketal or acetal group, in particular an alkylidene or arylalkylidene ketal or acetal group, where in each case two adjacent radicals R ^8a , R ^8b , R ^8c , R ^{8d is} a cyclic ketal or acetal group or a 1,2-di (C _1-3 -alkoxy) -1,2-di (C _1-3 -alkyl) -ethylene-bridge, said ethylene-bridge together with two oxygen atoms and the associated two carbon atoms of the pyranose ring having a substituted dioxane Ring, in particular a 2,3-dimethyl-2,3-di (C _1-3 alkoxy) -1,4-dioxane ring forms, and wherein alkyl, aryl and / or benzyl groups one or more times with Halogen or C _1-3 alkoxy may be substituted and benzyl groups may also be substituted by a di (C _1-3 alkyl) amino group; and R ^a , R ^b , R ^{c are} independently C _1-4 alkyl, aryl or arylC _1-3 alkyl, wherein the aryl or alkyl groups may be mono- or polysubstituted by halogen; wherein the aryl groups mentioned in the definition of the abovementioned radicals are phenyl or naphthyl groups, preferably phenyl groups; and wherein R ¹ to R ⁵ and R ⁶ , R ^7a , R ^7b , R ^{7c are} as defined above and below; is reacted with a reducing agent in the presence of a Lewis or Br⌀nsted acid, wherein the protective groups are optionally cleaved simultaneously or subsequently; or
• b) for the preparation of compounds of general formula I in which R ⁶ , R ^7a , R ^7b and R ^{7c are} hydrogen, a compound of general formula III
  
  ^wherein R ^8a , R ^8b , R ^Bc , R ^8d and R ¹ to R ^{5 are} as defined above and below, but at least one of R ^8a , R ^8b , R ^8c , R ^{8d is} not hydrogen, is hydrolyzed, and if desired, a 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 a compound of the general formula I thus obtained is separated into its stereoisomers and / or, if desired, 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.

in der
R¹ H, C_1-4-Alkyl, (C_1-18-Alkyl)carbonyl, (C_1-18-Alkyl)oxycarbonyl, Arylcarbonyl und Aryl-(C_1-3-alkyl)-carbonyl bedeutet, worin die Alkyl- oder Arylgruppen ein- oder mehrfach mit Halogen substituiert sein können;
R^8a, R^8b R^8c, R^8d unabhängig voneinander eine für die Reste R⁶, R^7a, R^7b, R^7c angegebenen Bedeutungen besitzt, eine Benzyl-Gruppe oder eine R^aR^bR^cSi-Gruppe oder eine Ketal- oder Acetalgruppe bedeutet, wobei jeweils zwei benachbarte Reste R^8a, R^8b, R^8c, R^8d eine cyclische Ketal- oder Acetalgruppe oder mit zwei Sauerstoffatomen des Pyranose-Rings einen substituierten 2,3-Oxydioxan-Ring, insbesondere einen 2,3-Dimethyl-2,3-di(C_1-3-alkoxy)-1,4-dioxan-Ring, bilden können, und wobei Alkyl-, Aryl- und/oder Benzylgruppen ein- oder mehrfach mit Halogen oder C_1-3-Alkoxy substituiert sein können und Benzyl-Gruppen auch mit einer Di-(C_1-3-alkyl)amino-Gruppe substituiert sein können; und
R^a, R^b, R^c unabhängig voneinander C_1-4-Alkyl, Aryl oder Aryl-C_1-3-alkyl bedeuten, wobei die Alkyl- oder Arylgruppen ein- oder mehrfach mit Halogen substituiert sein können;
wobei unter den bei der Definition der vorstehend genannten Reste erwähnten Arylgruppen Phenyl- oder Naphthylgruppen, vorzugsweise Phenylgruppen zu verstehen sind;
und R¹ bis R⁵, R⁶, R^7a, R^7b, R^7c die zuvor und nachstehend angegebenen Bedeutungen besitzen,
bei dem eine Organometall-Verbindung (V), die durch Halogen-Metall-Austausch oder durch Insertion eines Metalls in die Kohlenstoff-Halogen-Bindung einer Halogen-Benzylbenzol-Verbindung der allgemeinen Formel IV

in der Hal Cl, Br und I bedeuten und R¹ bis R⁵ wie zuvor und nachstehend definiert sind, und gegebenenfalls anschließender Ummetallierung erhältlich ist, an ein Gluconolacton der allgemeinen Formel VI

in der R^8a, R^8b, R^8c, R^8d wie zuvor und nachstehend definiert sind, addiert wird, und
anschließend das erhaltene Addukt, vorzugsweise in situ, mit Wasser oder einem Alkohol R'-OH, wobei R' gegebenenfalls substituiertes C_1-4-Alkyl bedeutet, in Gegenwart einer Säure, wie beispielsweise Methansulfonsäure, Schwefelsäure, Salzsäure, Essigsäure oder Ammoniumchlorid, umgesetzt wird und optional das in der Umsetzung mit Wasser erhaltene Produkt, in dem R' H bedeutet, in einer nachfolgenden Reaktion mit einem Acylierungsmittel, wie beispielsweise des entsprechenden Säurechlorids oder -anhydrids, in das Produkt der Formel II überführt wird, worin R' (C_1-18-Alkyl)carbonyl, (C_1-18-Alkyl)oxycarbonyl, Arylcarbonyl oder Aryl-(C_1-3-alkyl)-carbonyl, das wie angegeben substituiert sein kann, bedeutet.Another object of this invention is a process for the preparation of compounds of general formula II

in the
R ^{1 is} H, C _1-4 alkyl, (C _1-18 alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _1-3 alkyl) carbonyl, wherein the alkyl - or aryl groups may be monosubstituted or polysubstituted by halogen;
R ^8a , R ^8b, R ^8c , R ^8d, independently of one another, have the meanings given for the radicals R ⁶ , R ^7a , R ^7b , R ^7c , a benzyl group or an R ^a R ^b R ^c Si group or a ketal or acetal group, where in each case two adjacent radicals R ^8a , R ^8b , R ^8c , R ^{8d is} a cyclic ketal or acetal group or with two oxygen atoms of the pyranose ring a substituted 2,3-oxydioxane ring, in particular a 2,3- Dimethyl-2,3-di (C _1-3 alkoxy) -1,4-dioxane ring, and wherein alkyl, aryl and / or benzyl groups are mono- or polysubstituted by halogen or C _1-3 Alkoxy can be substituted and benzyl groups can also be substituted with a di (C _1-3 alkyl) amino group; and
R ^a , R ^b , R ^c independently of one another are C _1-4 -alkyl, aryl or aryl-C _1-3 -alkyl, where the alkyl or aryl groups may be mono- or polysubstituted by halogen;
wherein the aryl groups mentioned in the definition of the abovementioned radicals are phenyl or naphthyl groups, preferably phenyl groups;
and R ¹ to R ⁵ , R ⁶ , R ^7a , R ^7b , R ^{7c have} the meanings given above and below,
in which an organometallic compound (V) obtained by halogen-metal exchange or by insertion of a metal into the carbon-halogen bond of a halogen-benzylbenzene compound of general formula IV

in which Hal is Cl, Br and I and R ¹ to R ^{5 are} as defined above and below, and optionally subsequent transmetallation is obtainable, to a gluconolactone of the general formula VI

in which R ^8a , R ^8b , R ^8c , R ^8d are added as before and below, and
then the resulting adduct, preferably in situ, with water or an alcohol R'-OH, wherein R 'is optionally substituted C _1-4 alkyl, in the presence of an acid such as methanesulfonic acid, sulfuric acid, hydrochloric acid, acetic acid or ammonium chloride reacted and optionally converting the product obtained in the reaction with water in which R 'is H in a subsequent reaction with an acylating agent such as the corresponding acid chloride or anhydride into the product of formula II wherein R' (C _1-18 alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl or aryl- (C _1-3 alkyl) carbonyl, which may be substituted as indicated.

The indicated intermediates, in particular of formula IV, the formula II as well as the formula III, likewise constitute objects of this Invention.

Detailed description the invention

Unless otherwise stated, the groups, radicals and substituents, in particular R ¹ to R ⁵ , A, B, L1, L2, R, ^N , R ⁶ , R ^7a , R ^7b , R ^7c , R ^8a , R ^8b , R ^8c , R ^8d are as defined above and below.

Come Residues, substituents or groups in a compound several times, so can these have the same or different meanings.

in der
R¹ ausgewählt ist aus den Bedeutungen der Gruppe A und
falls R³ ausgewählt ist aus den Bedeutungen der Gruppe B, kann R¹ zusätzlich auch ausgewählt sein aus den Bedeutungen Wasserstoff, Fluor, Chlor, Brom, Iod, C_1-4-Alkyl, C_2-4-Alkenyl-C_1-4-alkyl, C_2-4-Alkinyl-C_1-4-alkyl, C_3-7-Cycloalkyl-C_1-4-alkyl, C_5-7-Cycloalkenyl-C_1-4-alkyl, eine durch 1 bis 3 Fluoratome substituierte Methylgruppe, eine durch 1 bis 5 Fluoratome substituierte Ethylgruppe, C_1-4-Alkoxy, eine durch 1 bis 3 Fluoratome substituierte Methoxygruppe, eine durch 1 bis 5 Fluoratome substituierte Ethoxygruppe, eine durch eine Hydroxy- oder C_1-3-Alkoxygruppe substituierte C_1-4-Alkylgruppe, eine durch eine Hydroxy- oder C_1-3-Alkoxygruppe substituierte C_2-4-Alkoxygruppe, C_{3-6 6}-Cycloalkyl-C_1-3-alkoxy oder Hydroxy,
wobei in den vorstehend genannten Cycloalkyl- und Cycloalkenyl-Ringen ein oder zwei Methylengruppen unabhängig voneinander durch O oder CO substituiert sein können, und
R² Wasserstoff, Fluor, Chlor, Brom, Hydroxy, C_1-4-Alkyl, C_1-4-Alkoxy, Cyan oder Nitro, wobei die Alkyl- oder Alkoxygruppe ein oder mehrfach mit Fluor substituiert sein kann, und
R³ ausgewählt ist aus den Bedeutungen der Gruppe B und
falls R¹ ausgewählt ist aus den Bedeutungen der Gruppe A, kann R³ zusätzlich auch ausgewählt sein aus den Bedeutungen Wasserstoff, Fluor, Chlor, Brom, Iod, C_1-6-Alkyl, C_2-4-Alkenyl-C_1-4-alkyl, C_2-4-Alkinyl-C_1-4-alkyl, C_3-7-Cycloalkyl, C_5-7-Cycloalkenyl, C_3-7-Cycloalkyl-C_1-4-alkyl, C_5-7-Cycloalkenyl-C_1-4-alkyl, C_3-6-Cycloalkylidenmethyl, Hydroxy, C_1-6-Alkoxy, C_3-6-Cycloalkyl-C_1-3-alkoxy, Aryl, Aryl-C_1-3-alkyl, Heteroaryl, Heteroaryl-C_1-3-alkyl, Aryloxy, Aryl-C_1-3-alkyl-oxy, eine durch 1 bis 3 Fluoratome substituierte Methyl- oder Methoxygruppe, eine durch 1 bis 5 Fluoratome substituierte C_2-4-Alkyl- oder C_2-4-Alkoxygruppe, eine durch eine Cyangruppe substituierte C_1-4-Alkylgruppe, eine durch eine Hydroxy- oder C_1-3-Alkyloxygruppe substituierte C_1-4-Alkylgruppe, 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, (C_1-4-Alkyl)carbonylamino-, C_1-4-Alkylsulfonylamino, C_1-4-Alkylsulfanyl-, C_1-4-Alkylsulfinyl-, C_1-4-Alkylsulfonyl-, Arylsulfonylamino, Aryl-C_1-3-alkylsulfonylamino oder Arylsulfonyl,
R⁴, R⁵ unabhängig voneinander Wasserstoff, Fluor, Chlor, Brom, Iod, Cyan, Nitro, C_1-3-Alkyl, C_1-3-Alkoxy, durch 1 bis 3 Fluoratome substituiertes Methyl- oder Methoxy,
A C_2-6-Alkin-1-yl, C_2-6-Alken-1-yl, C_3-7-Cycloalkyl, C_5-7-Cycloalkenyl, Aryl, Heteroaryl, C_1-4-Alkylcarbonyl, Arylcarbonyl, Heteroarylcarbonyl, Aminocarbonyl, C_1-4-Alkylaminocarbonyl, Di-(C_1-3-Alkyl)aminocarbonyl, Pyrrolidin-1-ylcarbonyl, Piperidin-1-ylcarbonyl, Morpholin-4-ylcarbonyl, Piperazin-1-ylcarbonyl, 4-(C_1-4-Alkyl)piperazin-1-ylcarbonyl, Arylaminocarbonyl, Heteroarylaminocarbonyl, C_1-4-Alkoxycarbonyl, Aryl-C_1-3-alkoxycarbonyl, Heteroaryl-C_1-3-alkoxycarbonyl, Amino, C_1-4-Alkylamino, Di(C_1-3-alkyl)amino, Pyrrolidin-1-yl, Pyrrolidin-2-on-1-yl, Piperidin-1-yl, Piperidin-2-on-1-yl, Morpholin-4-yl, Morpholin-3-on-4-yl, Piperazin-1-yl, 4-(C_1-3-Alkyl)piperazin-1-yl, C_1-4-Alkylcarbonylamino, Arylcarbonylamino, Heteroarylcarbonylamino, C_3-7-Cycloalkyloxy, C_5-7-Cycloalkenyloxy, Aryloxy, Heteroaryloxy, C_1-4-Alkylsulfinyl, C_1-4-Alkylsulfonyl, C_3-7-Cycloalkylsulfanyl, C_3-7-Cycloalkylsulfinyl, C_3-7-Cycloalkylsulfonyl, C_5-7-Cycloalkenylsulfanyl, C_5-7-Cycloalkenylsulfinyl, C_5-7-Cycloalkenylsulfonyl, Arylsulfanyl, Arylsulfinyl, Arylsulfonyl, Heteroarylsulfanyl, Heteroarylsulfinyl, Heteroarylsulfonyl, Cyan oder Nitro bedeutet,
wobei die vorstehend genannten Alkinyl- und Alkenylgruppen ein- oder mehrfach mit Fluor oder Chlor substituiert sein können, und
wobei die vorstehend genannten Alkinyl- und Alkenylgruppen ein- oder zweifach mit gleichen oder verschiedenen Resten L1 substituiert sein können, und
wobei die vorstehend genannten Cycloalkyl- und Cycloalkenyl-Ringe unabhängig voneinander ein- oder zweifach mit Substituenten ausgewählt aus Fluor und C_1-3-Alkyl substituiert sein können, und
wobei in den vorstehend genannten Cycloalkyl- und Cycloalkenyl-Ringen ein oder zwei Methylengruppen unabhängig voneinander durch O, S, CO, SO, SO₂ oder NR^N substituiert sein können,
B Tri-(C_1-4-alkyl)silyl-C_1-6-alkyl, C_2-6-Alkin-1-yl, C_2-6-Alken-1-yl, Amino, C_1-3-Alkylamino, Di-(C_1-3-alkyl)amino, Pyrrolidin-1-yl, Pyrrolidin-2-on-1-yl, Piperidin-1-yl, Piperidin-2-on-1-yl, Morpholin-4-yl, Morpholin-3-on-4-yl, Piperazin-1-yl, 4-(C_1-3-Alkyl)piperazin-1-yl, Arylcarbonylamino, Heteroarylcarbonylamino, Nitro, C_3-7-Cycloalkyloxy, C_5-7-Cycloalkenyloxy, C_3-7-Cycloalkylsulfanyl, C_3-7-Cycloalkylsulfinyl, C_3-7-Cycloalkylsulfonyl, C_5-7-Cycloalkenylsulfanyl, C_5-7-Cycloalkenylsulfinyl, C_5-7-Cycloalkenylsulfonyl, Arylsulfanyl, Arylsulfinyl, Heteroarylsulfanyl oder Heteroarylsulfinyl,
wobei die vorstehend genannten Alkinyl- und Alkenylgruppen ein- oder mehrfach mit Fluor oder Chlor substituiert sein können, und
wobei die vorstehend genannten Alkinyl- und Alkenylgruppen ein- oder zweifach mit gleichen oder verschiedenen Resten L1 substituiert sein können;
wobei die vorstehend genannten Cycloalkyl- und Cycloalkenyl-Ringe unabhängig voneinander ein- oder zweifach mit Substituenten ausgewählt aus Fluor und C_1-3-Alkyl substituiert sein können, und
wobei in den vorstehend genannten Cycloalkyl- und Cycloalkenyl-Ringen ein oder zwei Methylengruppen unabhängig voneinander durch O, S, CO, SO, SO₂ oder NR^N substituiert sein können,
R^N H oder C_1-4-Alkyl,
L1 unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Cyan-, Nitro-, Aryl-, Heteroaryl-, C_1-4-Alkylcarbonyl-, Arylcarbonyl-, Heteroarylcarbonyl-, Aminocarbonyl-, C_1-4-Alkylaminocarbonyl-, Di-(C_1-3-alkyl)aminocarbonyl-, Pyrrolidin-1-ylcarbonyl-, Piperidin-1-ylcarbonyl-, Morpholin-4-ylcarbonyl, Arylaminocarbonyl-, Heteroarylaminocarbonyl-, C_1-4-Alkoxycarbonyl-, Aryl-C_1-3-alkoxycarbonyl-, Heteroaryl-C_1-3-alkoxycarbonyl-, C_1-4-Alkyloxy-, Aryloxy-, Heteroaryloxy-, C_1-4-Alkylsulfanyl-, Arylsulfanyl-, Heteroarylsulfanyl-, C_1-4-Alkylsulfinyl-, Arylsulfinyl-, Heteroarylsulfinyl-, C_1-4-Alkylsulfonyl-, Arylsulfonyl- und Heteroarylsulfonyl-; und
L2 unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Fluor, Chlor, Brom, Iod, C_1-3-Alkyl, Difluormethyl, Trifluormethyl, C_1-3-Alkoxy, Difluormethoxy, Trifluormethoxy und Cyan; und
R⁶, R^7a R^7b, R^7c unabhängig voneinander eine Bedeutung ausgewählt aus der Gruppe Wasserstoff, (C_1-18-Alkyl)carbonyl, (C_1-18-Alkyl)oxycarbonyl, Arylcarbonyl und Aryl-(C_1-3-alkyl)carbonyl besitzen,
wobei unter den bei der Definition der vorstehend genannten Reste erwähnten Arylgruppen Phenyl- oder Naphthylgruppen zu verstehen sind, welche unabhängig voneinander ein- oder zweifach mit gleichen oder verschiedenen Resten L2 substituiert sein können; und
unter den bei der Definition der vorstehend erwähnten Reste erwähnten Heteroarylgruppen eine Pyrrolyl-, Furanyl-, Thienyl-, Pyridyl-, Indolyl-, Benzofuranyl-, Benzothiophenyl-, Chinolinyl-, 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 unabhängig voneinander ein- oder zweifach mit gleichen oder verschiedenen Resten L2 substituiert sein können;
wobei, soweit nichts anderes erwähnt wurde, die vorstehend erwähnten Alkylgruppen geradkettig oder verzweigt sein können,
deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.According to the invention, glucopyranosyl-substituted benzene derivatives of the general formula I are preferred

in the
R ^{1 is} selected from the meanings of group A and
In addition, if R ^{3 is} selected from the meanings of group B, R ^{1 may} additionally be selected from the meanings hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 -alkyl, C _2-4 -alkenyl-C _1-4 alkyl, C _2-4 alkynylC _1-4 alkyl, C _3-7 cycloalkylC _1-4 alkyl, C _5-7 cycloalkenylC _1-4 alkyl, one through 1 to 3 Fluorine atom-substituted methyl group, ethyl group substituted by 1 to 5 fluorine atoms, C _1-4 alkoxy, methoxy group substituted by 1 to 3 fluorine atoms, ethoxy group substituted by 1 to 5 fluorine atoms, one by hydroxy or C _1-3 alkoxy group substituted C _1-4 -alkyl group, a C _2-4 -alkoxy group substituted by a hydroxy or C _1-3 -alkoxy group, C _{3-6 6} -cycloalkyl-C _1-3 -alkoxy or hydroxy,
wherein in the aforementioned cycloalkyl and cycloalkenyl rings one or two methylene groups may be independently substituted by O or CO, and
R ^{2 is} hydrogen, fluorine, chlorine, bromine, hydroxy, C _1-4 -alkyl, C _1-4 -alkoxy, cyano or nitro, where the alkyl or alkoxy group may be mono- or polysubstituted by fluorine, and
R ^{3 is} selected from the meanings of group B and
In addition, if R ^{1 is} selected from the meanings of group A, R ^{3 may} additionally be selected from the meanings hydrogen, fluorine, chlorine, bromine, iodine, C _1-6 -alkyl, C _2-4 -alkenyl-C _1-4 -alkyl, C _2-4 -alkynyl-C _1-4 -alkyl, C _3-7 -cycloalkyl, C _5-7 -cycloalkenyl, C _3-7 -cycloalkyl-C _1-4 -alkyl, C _5-7 - CycloalkenylC _1-4 alkyl, C _3-6 cycloalkylidenemethyl, hydroxy, C _1-6 alkoxy, 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 radical substituted by 1 to 5 fluorine atoms or C _2-4 alkoxy group, a cyano group by a substituted C _1-4 alkyl group, by a hydroxy or C _1-3 alkyloxy substituted C _1-4 alkyl, cyano, carboxy, C _1-3 -alkoxycarbonyl , Aminocarbonyl, (C _1-3 alkylamino) carbonyl, di (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylc arbonyl, piperazin-1-ylcarbonyl, 4- (C _1-3 alkyl) piperazin-1-ylcarbonyl, (C _1-4 alkyl) carbonylamino, C _1-4 alkylsulfonylamino, C _1-4 Alkylsulfanyl, C _1-4 -alkylsulfinyl, C _1-4 -alkylsulfonyl, arylsulfonylamino, arylC _1-3 -alkylsulfonylamino or arylsulfonyl,
R ⁴ , R ⁵ independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C _1-3 -alkyl, C _1-3 -alkoxy, methyl or methoxy substituted by 1 to 3 fluorine atoms,
A is C _2-6 alkyn-1-yl, C _2-6 alken-1-yl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, aryl, heteroaryl, C _1-4 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl , Aminocarbonyl, C _1-4 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C _1-4 -alkyl) piperazin-1-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, C _1-4 -alkoxycarbonyl, arylC _1-3 -alkoxycarbonyl, heteroarylC _1-3 -alkoxycarbonyl, amino, C _1-4 -alkylamino, Di (C _1-3 alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholine 3-on-4-yl, piperazin-1-yl, 4- (C _1-3 alkyl) piperazin-1-yl, C _1-4 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C _3-7 cycloalkyloxy, C _5-7 -cycloalkenyloxy, aryloxy, heteroaryloxy, C _1-4 -alkylsulfinyl, C _1-4 -alkylsulfonyl, C _3-7 -cycloalkylsulfanyl, C _3-7 -cycloalkylsulfinyl, C _3-7 -cycloalkylsulfonyl, C _5-7 - Cycloalkenylsulfanyl, C _5-7 -cycloalkenylsulfinyl, C _5-7 -cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroarylsulfanyl, heteroarylsulfinyl, heteroarylsulfonyl, cyano or nitro,
wherein the abovementioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, and
wherein the abovementioned alkynyl and alkenyl groups may be mono- or disubstituted by identical or different radicals L1, and
wherein the above-mentioned cycloalkyl and cycloalkenyl rings independently of one another may be mono- or disubstituted by substituents selected from fluorine and C _1-3 -alkyl, and
where in the abovementioned cycloalkyl and cycloalkenyl rings one or two methylene groups can be substituted independently of one another by O, S, CO, SO, SO ₂ or NR ^N ,
B is tri- (C _1-4 alkyl) silylC _1-6 alkyl, C _2-6 alkyn-1-yl, C _2-6 alken-1-yl, amino, C _1-3 alkylamino , Di (C _1-3 alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-1-yl, piperidin-2-one-1-yl, morpholin-4-yl , Morpholin-3-on-4-yl, piperazin-1-yl, 4- (C _1-3 alkyl) piperazin-1-yl, arylcarbonylamino, heteroarylcarbonylamino, nitro, C _3-7 cycloalkyloxy, C _5-7 Cycloalkenyloxy, C _3-7 cycloalkylsulfanyl, C _3-7 cycloalkylsulfinyl, C _3-7 cycloalkylsulfonyl, C _5-7 cycloalkenylsulfanyl, C _5-7 cycloalkenylsulfinyl, C _5-7 cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, heteroarylsulfanyl or heteroarylsulfinyl,
wherein the abovementioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, and
wherein the aforementioned alkynyl and alkenyl groups may be monosubstituted or disubstituted by identical or different L1 groups;
wherein the above-mentioned cycloalkyl and cycloalkenyl rings independently of one another may be mono- or disubstituted by substituents selected from fluorine and C _1-3 -alkyl, and
where in the abovementioned cycloalkyl and cycloalkenyl rings one or two methylene groups can be substituted independently of one another by O, S, CO, SO, SO ₂ or NR ^N ,
R ^{N is} H or C _1-4 alkyl,
L1 independently selected from the group consisting of cyano, nitro, aryl, heteroaryl, C _1-4 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, C _1-4 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, C _1-4 alkoxycarbonyl, arylC _1-3 alkoxycarbonyl, heteroarylC _1-3 alkoxycarbonyl, C _1-4 alkyloxy, aryloxy, heteroaryloxy, C _1-4 alkylsulfanyl, arylsulfanyl, heteroarylsulfanyl, C _1-4 alkylsulfinyl, arylsulfinyl -, heteroarylsulfinyl, C _1-4 alkylsulfonyl, arylsulfonyl and heteroarylsulfonyl; and
L2 independently of one another are selected from the group consisting of fluorine, chlorine, bromine, iodine, C _1-3 -alkyl, difluoromethyl, trifluoromethyl, C _1-3 -alkoxy, difluoromethoxy, trifluoromethoxy and cyano; and
R ⁶ , R ^7a, R ^7b , R ^7c independently of one another are selected from the group consisting of hydrogen, (C _1-18 -alkyl) carbonyl, (C _1-18 -alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _1-3 alkyl) carbonyl,
wherein the aryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning phenyl or naphthyl groups which may be independently of one another monosubstituted or disubstituted by identical or different radicals L 2; and
among the heteroaryl groups mentioned in the definition of the abovementioned radicals, a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, 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 independently of one another may be monosubstituted or disubstituted by identical or different L2 radicals;
Unless otherwise stated, the abovementioned alkyl groups may be straight-chain or branched,
their tautomers, their stereoisomers, their mixtures and their salts.

following are preferred meanings of individual groups and substituents the compounds of the invention specified.

The radical R ³ is preferably in the meta or para position to the -CH ₂ -bridge, so that compounds according to the following formulas I.1 and I.2, in particular of the formula I.2, are preferred:

The term aryl occurring in the groups L1, R ¹ , R ³ , A and B is preferably phenyl.

The term heteroaryl occurring in the groups L1, R ¹ , R ³ , A and B preferably denotes pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl.

The group A is preferably C _2-6 -alkine-1-yl, C _2-6 -alken-1-yl, C _3-7 -cycloalkyl, C _5-7 -cycloalkenyl, C _1-4 -alkylcarbonyl, aminocarbonyl, C _1-4 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C _1-4 Alkyl) piperazin-1-ylcarbonyl, C _1-4 alkoxycarbonyl, amino, C _1-4 alkylamino, di (C _1-3 alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1 -yl, piperidin-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-3-one-4-yl, piperazin-1-yl, 4- (C _1-3 alkyl ) piperazin-1-yl, C _1-4 -alkylcarbonylamino, C _3-7 -cycloalkyloxy, C _5-7 -cycloalkenyloxy, C _1-4 -alkylsulfinyl, C _1-4 -alkylsulfonyl, C _3-7 -cycloalkylsulfanyl, C _3-7 -cycloalkylsulfinyl, C _3-7 -cycloalkylsulfonyl, C _5-7 -cycloalkenylsulfanyl, C _5-7 -cycloalkenylsulfinyl, C _5-7 -cycloalkenylsulfonyl, cyano and nitro
wherein the abovementioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, preferably fluorine, and
wherein the abovementioned alkynyl and alkenyl groups may be mono- or disubstituted by identical or different radicals L1, and
wherein the above-mentioned cycloalkyl and cycloalkenyl rings independently of one another may be mono- or disubstituted by substituents selected from fluorine and C _1-3 -alkyl, and
wherein in the aforementioned cycloalkyl and cycloalkenyl rings one or two methylene groups independently of one another by O, S, CO, SO, SO ₂ or NR ^N , preferably O or CO, most preferably by O, may be substituted.

Most preferably, the group is AC _2-6 -alkine-1-yl, C _2-6 -alken-1-yl, C _3-7 -cycloalkyl, C _5-7 -cycloalkenyl, C _3-7 -cycloalkyloxy, C _{5 -7-} cycloalkenyloxy, C _1-4 -alkylsulfinyl, C _1-4 -alkylsulfonyl, C _3-7 -cycloalkylsulfanyl, C _3-7 -cycloalkylsulfinyl, C _3-7 -cycloalkylsulfonyl, C _5-7 -cycloalkenylsulfanyl, C _{5- 7-} cycloalkenylsulfinyl, C _5-7 -cycloalkenylsulfonyl, cyano and nitro,
wherein the abovementioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, preferably fluorine, and
wherein the abovementioned alkynyl and alkenyl groups may be mono- or disubstituted by identical or different radicals L1, and
wherein the above-mentioned cycloalkyl and cycloalkenyl rings independently of one another may be mono- or disubstituted by substituents selected from fluorine and C _1-3 -alkyl, and
wherein in the aforementioned C _5-6 cycloalkyl rings a methylene group may be replaced by O.

Most preferably, the group is AC _2-6 -alken-1-yl, C _2-6 -alken-1-yl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyloxy, cyano, wherein in C _5-6 -Cycloalkyl groups a methylene unit may be replaced by O.

Examples the most preferred meanings of group A are ethynyl, Prop-1-yn-1-yl, but-1-yn-1-yl, Cyano, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

The group B is preferably tri (C _1-4 alkyl) silyl C _1-6 alkyl, C _2-6 alkyn-1-yl, C _2-6 alken-1-yl, amino, C _{1 3-} alkylamino, di (C _1-4 alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-1-yl, piperidin-2-one-1-yl, morpholine 4-yl, morpholin-3-on-4-yl, piperazin-1-yl, 4- (C _1-3 alkyl) piperazin-1-yl, nitro, C _3-7 cycloalkyloxy, C _5-7 Cycloalkenyloxy, C _3-7 -cycloalkylsulfanyl, C _3-7 -cycloalkylsulfinyl, C _3-7 -cycloalkylsulfonyl, C _5-7 -cycloalkenylsulfanyl, C _5-7 -cycloalkenylsulfinyl, C _5-7 -cycloalkenylsulfonyl,
wherein the abovementioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, preferably fluorine, and
wherein the aforementioned alkynyl and alkenyl groups may be monosubstituted or disubstituted by identical or different L1 groups;
wherein the above-mentioned cycloalkyl and cycloalkenyl rings independently of one another may be mono- or disubstituted by substituents selected from fluorine and C _1-3 -alkyl, and
wherein in the aforementioned cycloalkyl and cycloalkenyl rings one or two methylene groups independently of one another by O, S, CO, SO, SO ₂ or NR ^N , preferably O, CO, S, SO ₂ or NR ^N , most preferably by O or CO may be substituted.

Most preferably, the group B is tri- (C _1-4 alkyl) silylC _1-6 alkyl, C _2-6 alkyn-1-yl, C _2-6 alken-1-yl, nitro, C _3-7 cycloalkyloxy, C _5-7 cycloalkenyloxy, C _3-7 cycloalkylsulfanyl, C _3-7 cycloalkylsulfinyl, C _3-7 cycloalkylsulfonyl, C _5-7 cycloalkenylsulfanyl, C _5-7 cycloalkenylsulfinyl, C _{5 -7-} cycloalkenylsulfonyl,
wherein the abovementioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, preferably fluorine, and
wherein the aforementioned alkynyl and alkenyl groups may be monosubstituted or disubstituted by identical or different L1 groups;
wherein the above-mentioned cycloalkyl and cycloalkenyl rings independently of one another may be mono- or disubstituted by substituents selected from fluorine and C _1-3 -alkyl, and
wherein in the aforementioned cycloalkyl and cycloalkenyl rings one or two methylene groups independently of one another by O, S, CO, SO, SO ₂ or NR ^N , preferably O, CO, S, SO ₂ or NR ^N , most preferably by O or CO, may be substituted.

Most preferably, the group B is tri- (C _1-4 alkyl) silyl-C _2-6 alkyl, C _2-6 alkyn-1-yl, C _2-6 alken-1-yl, C _{3 -7-} Cycloalkyloxy, C _5-7 -cycloalkenyloxy, C _3-7 -cycloalkylsulfanyl, C _5-7 -cycloalkenylsulfanyl, where the abovementioned alkynyl and alkenyl groups are monosubstituted or polysubstituted by fluorine or simply by chlorine or the radical L1 can, and wherein in the cycloalkyl and cycloalkenyl one or two methylene groups independently of one another by O, CO, S, SO ₂ or NR ^N , in particular O or CO, may be replaced.

Examples of very particularly preferred meanings of group B are trimethylsilylethyl, ethynyl, 1-propyn-1-yl, 1-butyn-1-yl, tert-butylethynyl, 2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl, 3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, ethenyl, 1-propenyl, 1-butenyl, tert-butylethenyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuranyloxy, tetrahydrothiophenyloxy , 1,1-dioxotetrahydrothiophenyloxy, tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1-dioxotetrahydrothiopyranyloxy, tetrahydrofuranonyloxy, piperidinyloxy, piperidinonyloxy, pyrrolidin-3-yloxy, pyrrolidinone-3-yloxy, tetrahydrofuranyl-sulfanyl, cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl and cyclohexylsulfanyl, where the NH group in a piperidinyl, piperidinonyl, pyrrolidinyl or pyrrolidinonyl ring with R ^N , in particular C _1-3 alkyl or acetyl, may be substituted.

Very particularly preferred meanings here are trimethylsilylethyl, ethynyl, 2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl, 3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy and N-acetylpiperidin-4-yloxy. Particularly noteworthy examples are ethynyl, trimethylsilylethyl, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and tetrahydrofu ran-3-yloxy.

Are present in the radicals or groups A, B, R ¹ or R ³ cycloalkyl or cycloalkenyl rings in which two methylene groups are replaced by O, S or NR ^N or replaced by S, NR, ^N , CO, SO or SO ₂ are, then these methylene groups are preferably not directly connected. However two methylene groups are replaced by O and CO or replaced by NR ^N and CO, these may be connected directly to one another, so that a -O-CO- or -NR ^-CO-N group is formed.

Preferred meanings of the group L1 are selected from the group consisting of hydroxy, cyano, C _3-6 cycloalkyl, C _1-4 -alkylcarbonyl, aminocarbonyl, C _1-4 -alkylaminocarbonyl-, di- (C _{1- 3-} alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, C _1-4 alkoxycarbonyl, C _1-4 alkyloxy, C _1-4 alkylsulfanyl , C _1-4 alkylsulfinyl, and C _1-4 alkylsulfonyl.

Particularly preferred meanings of the radical L1 are selected from the group consisting of hydroxy, C _1-4 -alkyloxy and C _1-4 -alkylsulfanyl-.

means L1 hydroxy, so the hydroxy group is not directly to a C atom a double or triple bond.

Compounds of the invention according to a first embodiment of this invention can be described by the general formula I, in particular the formulas I.1 and I.2, particularly preferably the formula I.2, in which
R ^{3 is} selected from one of the aforementioned meanings of group B and
the remaining radicals and substituents are as defined above and below,
including their tautomers, their stereoisomers, their mixtures and their salts.

Preferred meanings of the radical R ¹ according to this embodiment are hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 -alkyl, C _2-6 -alkynyl, C _1-4 -alkoxy, C _2-4 -alkenyl-C _{1 -4} -alkoxy, C _2-4 alkynyl-C _1-4 alkoxy, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms , by a hydroxy or C _1-3 alkoxy substituted C _1-4 alkyl, substituted by a hydroxy or C _1-3 alkoxy C _2-4 alkoxy, C _2-6 alkenyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, C _3-7 cycloalkyloxy, C _3-6 cycloalkyl C _1-3 alkoxy, C _5-7 cycloalkenyloxy, hydroxy, amino, nitro or cyano, wherein in the C _5-6 cycloalkyl groups, a methylene group may be substituted by O.

Especially preferred meanings here are hydrogen, fluorine, chlorine, bromine, Cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, ethynyl, Prop-1-yn-1-yl, but-1-yn-1-yl, hydroxy, methoxy, ethoxy, difluoromethoxy, Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, in particular Methyl and chlorine.

Compounds of the invention according to a second embodiment of this invention can be described by the general formula I, in particular the formulas I.1 and I.2, particularly preferably the formula I.2, in which
R ^{1 is} selected from the previously mentioned meanings of the group A and
the remaining radicals and substituents are as defined above and below,
including their tautomers, their stereoisomers, their mixtures and their salts.

According to this second embodiment, preferred meanings of the radical R ³ are hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, C _1-6 -alkyl, trimethylsilylethyl, C _2-6 -alkenyl, C _2-6 -alkynyl, difluoromethyl, trifluoromethyl, C _3-7 -cycloalkyl, C _5-7 -cycloalkenyl, C _1-6 -alkyloxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, C _3-7 -cycloalkyloxy, tetrahydrofuranyloxy, tetrahydrofuranonyloxy, C _1-6 -alkylsulfanyl, cyclopropylidenemethyl, aryl or heteroaryl.

Particularly preferred meanings of the radical R ³ according to this second embodiment are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, ethynyl, 1-propynyl, trimethylsilylethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy , Isopropoxy, cyclopentyloxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-on-3-yloxy, methylsulfanyl, ethylsulfanyl, isopropylsulfanyl, cyclopropylidenemethyl, phenyl, fluorophenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl , Pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl.

Very particularly preferred meanings of the radical R ³ according to this second embodiment are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, ethynyl, 1-propynyl, trimethylsilylethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, Ethoxy, isopropoxy, cyclopentyloxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-on-3-yloxy, methylsulfanyl, ethylsulfanyl, isopropylsulfanyl, cyclopropylidenemethyl. Examples of such particularly preferred meanings here are methyl, ethyl, methoxy, ethoxy, trimethylsilylethyl, ethynyl, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-on-3-yloxy, in particular trimethylsilylethyl, ethoxy, cyclopentyloxy and tetrahydrofuran-3-yloxy.

The following are meanings of further radicals and substituents which are to be regarded as preferred according to the general formula I, the formulas I.1 and I.2 as well as according to the embodiments described above:
Preferred meanings of the radical R ² are hydrogen, fluorine, chlorine, bromine, methyl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, cyano, nitro and methyl substituted by 1 to 3 fluorine atoms.

Particularly preferred meanings of the radical R ² are hydrogen, fluorine, hydroxyl, methoxy, ethoxy and methyl, in particular hydrogen and methyl.

Preferred meanings of the radical R ⁴ are hydrogen and fluorine, in particular hydrogen.

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

The radical R ^N is preferably H, methyl, ethyl or acetyl.

The radical R ⁶ according to the invention preferably denotes hydrogen, (C _1-8 -alkyl) oxycarbonyl, C _1-8 -alkylcarbonyl or benzoyl, in particular hydrogen or (C _1-6 -alkyl) oxycarbonyl, C _1-6 -alkylcarbonyl, particularly preferably hydrogen, methylcarbonyl, methoxycarbonyl or ethoxycarbonyl, very particularly preferably hydrogen or methoxycarbonyl.

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

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

wobei die Reste R¹ bis R⁶ und R^7a, R^7b, R^7c eine der zuvor angegebenen, insbesondere eine der als bevorzugt angegebenen Bedeutungen aufweisen; insbesondere wobei
R¹ Wasserstoff, Fluor, Chlor, Brom, Iod, C_1-4-Alkyl, C_2-6-Alkinyl, C_1-4-Alkoxy, C_2-4-Alkenyl-C_1-4-alkoxy, C_2-4-Alkinyl-C_1-4-alkoxy, durch 1 bis 3 Fluoratome substituiertes Methyl, durch 1 bis 5 Fluoratome substituiertes Ethyl, durch 1 bis 3 Fluoratome substituiertes Methoxy, durch 1 bis 5 Fluoratome substituiertes Ethoxy, durch eine Hydroxy- oder C_1-3-Alkoxygruppe substituiertes C_1-4-Alkyl, durch eine Hydroxy- oder C_1-3-Alkoxygruppe substituiertes C_2-4-Alkoxy, C_2-6-Alkenyl, C_3-6-Cycloalkyl, C_3-6-Cycloalkyl-C_1-3-alkyl, C_3-7-Cycloalkyloxy, C_3-6-Cycloalkyl-C_1-3-alkoxy, C_5-7-Cycloalkenyloxy, Hydroxy, Amino, Nitro oder Cyan bedeutet, wobei in den C_5-6-Cycloalkylgruppen eine Methylengruppe durch O substituiert sein kann; besonders bevorzugt Wasserstoff, Fluor, Chlor, Brom, Cyan, Methyl, Ethyl, Isopropyl, Difluormethyl, Trifluormethyl, Ethinyl, Prop-1-in-1-yl, But-1-in-1-yl, Hydroxy, Methoxy, Ethoxy, Difluormethoxy, Cyclopropyloxy, Cyclobutyloxy, Cyclopentyloxy oder Cyclohexyloxy bedeutet; und
R² Wasserstoff, Fluor, Hydroxy, Methoxy, Ethoxy oder Methyl, insbesondere Wasserstoff oder Methyl bedeutet; und
R³ ausgewählt ist aus der Gruppe B bestehend aus Trimethylsilylethyl, Ethinyl, 1-Propin-1-yl, 1-Butin-1-yl, tert.-Butylethinyl, 2-Hydroxyprop-2-ylethinyl, 2-Methoxyprop-2-ylethinyl, 3-Hydroxy-1-propin-1-yl, 3-Methoxy-1-propin-1-yl, Ethenyl, 1-Propenyl, 1-Butenyl, tert.-Butylethenyl, Cyclopropyloxy, Cyclobutyloxy, Cyclopentyloxy, Cyclohexyloxy, Tetrahydrofuranyloxy, Tetrahydrothiophenyloxy, 1,1-Dioxotetrahydrothiophenyloxy, Tetrahydropyranyloxy, Tetrahydrothiopyranyloxy, 1,1-Dioxotetrahydrothiopyranyloxy, Tetrahydrofuranonyloxy, Piperidinyloxy, Piperidinonyloxy, Pyrrolidin-3-yloxy, Pyrrolidinon-3-yloxy, Tetrahydrofuranyl-sulfanyl, Cyclopropylsulfanyl, Cyclobutylsulfanyl, Cyclopentylsulfanyl und Cyclohexylsulfanyl, wobei die -NH-Gruppe in einem Piperidinyl-, Piperidinonyl-, Pyrrolidinyl- oder Pyrrolidinonyl-Ring mit R^N, insbesondere C_1-3-Alkyl oder Acetyl, substituiert sein kann; besonders bevorzugt ausgewählt aus Trimethylsilylethyl, Ethinyl, 2-Hydroxyprop-2-ylethinyl, 2-Methoxyprop-2-ylethinyl, 3-Hydroxy-1-propin-1-yl, 3-Methoxy-1-propin-1-yl, Cyclopropyloxy, Cyclobutyloxy, Cyclopentyloxy, Cyclohexyloxy, Tetrahydrofuran-3-yloxy, Tetrahydropyran-4-yloxy, Piperidin-4-yloxy, N-Methylpiperidin-4-yloxy und N-Acetylpiperidin-4-yloxy; und
R⁴ Wasserstoff oder Fluor, insbesondere Wasserstoff bedeutet; und
R⁵ Wasserstoff oder Fluor, insbesondere Wasserstoff bedeutet; und
R⁶ Wasserstoff, (C_1-6-Alkyl)oxycarbonyl, (C_1-4-Alkyl)carbonyl oder Benzoyl, insbesondere Wasserstoff, Methylcarbonyl, Methoxycarbonyl oder Ethoxycarbonyl, ganz besonders bevorzugt Wasserstoff bedeutet; und
R^7a, R^7b, R^7c unabhängig voneinander Wasserstoff, (C_1-6-Alkyl)oxycarbonyl-, (C_1-8-Alkyl)carbonyl oder Benzoyl, insbesondere Wasserstoff, Methoxycarbonyl, Ethoxycarbonyl, Methylcarbonyl oder Ethylcarbonyl, besonders bevorzugt Wasserstoff bedeuten;
einschließlich deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze.Particularly preferred compounds of general formula I are selected from the group of formulas I.2a to I.2d, in particular I.2c:

where the radicals R ¹ to R ⁶ and R ^7a , R ^7b , R ^{7c have} one of the abovementioned meanings, in particular one of the meanings given as being preferred; in particular
R ^{1 is} hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 -alkyl, C _2-6 -alkynyl, C _1-4 -alkoxy, C _2-4 -alkenyl-C _1-4 -alkoxy, C _{2- 4} alkynyl-C _1-4 alkoxy, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, methoxy substituted by 1 to 3 fluorine atoms, ethoxy substituted by 1 to 5 fluorine atoms, by a hydroxy or C _{1 3-} alkoxy group substituted C _1-4 -alkyl, C _2-4 -alkoxy, C _2-6 -alkenyl, C _3-6 -cycloalkyl, C _3-6 -substituted by a hydroxy or C _1-3 -alkoxy group CycloalkylC _1-3 alkyl, C _3-7 cycloalkyloxy, C _3-6 cycloalkylC _1-3 alkoxy, C _5-7 cycloalkenyloxy, hydroxy, amino, nitro or cyano, where in the C _5-6 -cycloalkyl groups a methylene group may be substituted by O; particularly preferably hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, hydroxy, methoxy, ethoxy, Difluoromethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy; and
R ^{2 is} hydrogen, fluorine, hydroxy, methoxy, ethoxy or methyl, in particular hydrogen or methyl; and
R ^{3 is} selected from group B consisting of trimethylsilylethyl, ethynyl, 1-propyn-1-yl, 1-butyn-1-yl, tert-butylethynyl, 2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl , 3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, ethenyl, 1-propenyl, 1-butenyl, tert -butylethenyl, cyclopropyloxy, cyclobutyloxy, cyclopentene tyloxy, cyclohexyloxy, tetrahydrofuranyloxy, tetrahydrothiophenyloxy, 1,1-dioxotetrahydrothiophenyloxy, tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1-dioxotetrahydrothiopyranyloxy, tetrahydrofuranonyloxy, piperidinyloxy, piperidinonyloxy, pyrrolidin-3-yloxy, pyrrolidinone-3-yloxy, tetrahydrofuranyl-sulfanyl, cyclopropylsulfanyl, cyclobutylsulfanyl, Cyclopentylsulfanyl and cyclohexylsulfanyl, wherein the -NH group in a piperidinyl, piperidinonyl, pyrrolidinyl or pyrrolidinonyl ring may be substituted with R ^N , in particular C _1-3 -alkyl or acetyl; particularly preferably selected from trimethylsilylethyl, ethynyl, 2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl, 3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, cyclopropyloxy, Cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy and N-acetylpiperidin-4-yloxy; and
R ^{4 is} hydrogen or fluorine, in particular hydrogen; and
R ^{5 is} hydrogen or fluorine, in particular hydrogen; and
R ^{6 is} hydrogen, (C _1-6 alkyl) oxycarbonyl, (C _1-4 alkyl) carbonyl or benzoyl, in particular hydrogen, methylcarbonyl, methoxycarbonyl or ethoxycarbonyl, very particularly preferably hydrogen; and
R ^7a , R ^7b , R ^7c independently of one another are hydrogen, (C _1-6 alkyl) oxycarbonyl, (C _1-8 alkyl) carbonyl or benzoyl, in particular hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl, particularly preferably hydrogen ;
including their tautomers, their stereoisomers, their mixtures and their salts.

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 this variant, 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.

The compounds of the general formula I given below in the experimental section and their derivatives in which R ^{6 has} a meaning different from hydrogen according to the invention, in particular R ^{6 is} ethoxycarbonyl or methoxycarbonyl, including their tautomers, their stereoisomers and mixtures thereof, are preferred according to the invention ,

• (1) 1-Chlor-2-(4-cyclopentyloxybenzyl)-4-(β-D-glucopyranos-1-yl)-benzol
• (2) 1-Chlor-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzol
• (3) 1-Chlor-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzol
• (4) 1-Chlor-4-(β-D-glucopyranos-1-yl)-2-[4-(tetrahydrofuran-2-on-3-yloxy)-benzyl]-benzol
• (5) 1-Chlor-4-(β-D-glucopyranos-1-yl)-2-(4-cyclobutyloxy-benzyl)-benzol
• (6) 1-Chlor-4-(β-D-glucopyranos-1-yl)-2-(4-cyclohexyloxy-benzyl)-benzol
• (7) 1-Chlor-4-(β-D-glucopyranos-1-yl)-2-[4-(tetrahydropyran-4-yloxy)-benzyl]-benzol
• (8) 1-Chlor-4-(β-D-glucopyranos-1-yl)-2-[4-(1-acetyl-piperidin-4-yloxy)-benzyl]-benzol
• (10) 1-(β-D-Glucopyranos-1-yl)-4-methyl-3-[4-(tetrahydrofuran-3-yloxy)-benzyl]-benzol
• (11) 1-(β-D-Glucopyranos-1-yl)-4-methyl-3-[4-(2-trimethylsilyl-ethyl)-benzyl]-benzol
• (12) 1-Chlor-4-(β-D-glucopyranos-1-yl)-2-(4-ethinyl-benzyl)-benzol
• (13) 1-Chlor-4-(β-D-glucopyranos-1-yl)-2-[4-(piperdin-4-yloxy)-benzyl]-benzol
• (14) 1-Fluor-4-(β-D-glucopyranos-1-yl)-2-(4-ethinyl-benzyl)-benzol
• (15) 1-(β-D-Glucopyranos-1-yl)-3-(4-ethinyl-benzyl)-benzol
• (16) 1-Ethinyl-4-(β-D-glucopyranos-1-yl)-2-(4-ethoxy-benzyl)-benzol
• (17) 1-Methoxy-4-(β-D-glucopyranos-1-yl)-2-(4-ethinyl-benzyl)-benzol

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

• (1) 1-Chloro-2- (4-cyclopentyloxybenzyl) -4- (β-D-glucopyranos-1-yl) -benzene
• (2) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4 - ((R) -tetrahydrofuran-3-yloxy) -benzyl] -benzene
• (3) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4 - ((S) -tetrahydrofuran-3-yloxy) -benzyl] -benzene
• (4) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (tetrahydrofuran-2-on-3-yloxy) benzyl] benzene
• (5) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- (4-cyclobutyloxybenzyl) benzene
• (6) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- (4-cyclohexyloxybenzyl) benzene
• (7) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (tetrahydropyran-4-yloxy) benzyl] benzene
• (8) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (1-acetyl-piperidin-4-yloxy) -benzyl] -benzene
• (10) 1- (β-D-Glucopyranos-1-yl) -4-methyl-3- [4- (tetrahydrofuran-3-yloxy) benzyl] benzene
• (11) 1- (β-D-Glucopyranos-1-yl) -4-methyl-3- [4- (2-trimethylsilylethyl) benzyl] benzene
• (12) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- (4-ethynylbenzyl) benzene
• (13) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (piperdin-4-yloxy) benzyl] benzene
• (14) 1-Fluoro-4- (β-D-glucopyranos-1-yl) -2- (4-ethynylbenzyl) benzene
• (15) 1- (β-D-Glucopyranos-1-yl) -3- (4-ethynylbenzyl) benzene
• (16) 1-Ethynyl-4- (β-D-glucopyranos-1-yl) -2- (4-ethoxybenzyl) benzene
• (17) 1-Methoxy-4- (β-D-glucopyranos-1-yl) -2- (4-ethynylbenzyl) benzene

and their derivatives in which R ^{6 has} a meaning other than hydrogen according to the invention, in particular R ^{6 is} ethoxycarbonyl or methoxycarbonyl,
including their tautomers, their stereoisomers and mixtures thereof.

In the processes according to the invention, the radicals R ¹ , R ² , R ³ , R ⁴ and R ⁵ preferably have the definitions given above as being preferred. Furthermore, R ^{1 here} preferably denotes H, C _1-3 -alkyl or benzyl, in particular H, ethyl or methyl. The radicals R ^8a , R ^8b , R ^8c and R ^{8d are} preferably, independently of one another, H, C _1-4 -alkylcarbonyl or benzyl, in particular H, methylcarbonyl, ethylcarbonyl or benzyl.

in der Hal Chlor, Brom oder Iod bedeutet und die Reste R¹, R², R⁴ und R⁵ wie zuvor definiert sind und der Rest R³ aus der Gruppe B ausgewählt ist, Gegenstand dieser Erfindung. Besonders bevorzugt weisen hierbei die Reste R¹, R², R³, R⁴ und R⁵ die im Anschluss an die Formeln I.2a bis I.2d angegebenen Definitionen auf. Ganz besonders bevorzugt sind Verbindungen der allgemeinen Formel IV', in der Hal Chlor, Brom oder Iod bedeutet und die Reste R¹, R², R⁴ und R⁵ die im Anschluss an die Formeln I.2a bis I.2d angegebenen Definitionen aufweisen und der Rest R³ Ethinyl oder C_3-6-1-Alkin-1-yl bedeutet, wobei die Ethinyl-Gruppe mit dem Rest -SiR₃ substituiert sein kann, wobei die Reste R unabhängig voneinander C_1-4-Alkyl, C_1-4-Alkoxy oder Aryl bedeuten, und wobei die C_3-6-1-Alkin-1-yl-Gruppe mit Hydroxy oder C_1-3-Alkoxy, insbesondere Hydroxy oder Methoxy, substituiert sein kann.As intermediates or starting materials in the synthesis of the compounds of the invention are also compounds of the general formula IV, in particular the general formula IV '

where Hal is chlorine, bromine or iodine and the radicals R ^1, R ^2, R ⁴ and R ⁵ are as defined above and the radical R is selected from the group B ^3, subject of this invention. In this case, the radicals R ¹ , R ² , R ³ , R ⁴ and R ⁵ particularly preferably have the definitions given in the formulas I.2a to I.2d. Very particular preference is given to compounds of the general formula IV 'in which Hal is chlorine, bromine or iodine and the radicals R ¹ , R ² , R ⁴ and R ^{5 have} the definitions given in the formulas I.2a to I.2d and the radical R ^{3 is} ethynyl or C _3-6 -1-alkyn-1-yl, where the ethynyl group may be substituted by the radical -SiR ₃ , where the radicals R independently of one another are C _1-4 -alkyl, C _1-4 alkoxy or aryl, and wherein the C _3-6 -1-alkyn-1-yl group with hydroxy or C _1-3 alkoxy, in particular hydroxy or methoxy, may be substituted.

in der R', R^8a, R^8b, R^8c, R^8d, R¹, R², R³, R⁴ und R⁵ wie zuvor und nachstehend definiert sind; insbesondere in der R' H, C_1-3-Alkyl oder Benzyl, insbesondere H, Ethyl oder Methyl bedeutet; und die Reste R^8a, R^8b, R^8c und R^8d unabhängig voneinander H, C_1-4-Alkylcarbonyl oder Benzyl, insbesondere H, Methylcarbonyl, Ethylcarbonyl oder Benzyl bedeuten und die Reste R¹, R², R⁴ und R⁵ wie zuvor definiert sind und der Rest R³ aus der Gruppe B ausgewählt ist, Gegenstand dieser Erfindung. Besonders bevorzugt weisen hierbei die Reste R¹, R², R³, R⁴ und R⁵ die im Anschluss an die Formeln I.2a bis I.2d angegebenen Definitionen auf.As intermediates or starting materials in the synthesis of the compounds according to the invention are also compounds of the general formula II, in particular the general formula II '

in which R ', R ^8a , R ^8b , R ^8c , R ^8d , R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined previously and below; in particular in which R 'is H, C _1-3 -alkyl or benzyl, in particular H, ethyl or methyl; and the radicals R ^8a , R ^8b , R ^8c and R ^8d independently of one another are H, C _1-4 -alkylcarbonyl or benzyl, in particular H, methylcarbonyl, ethylcarbonyl or benzyl and the radicals R ¹ , R ² , R ⁴ and R ⁵ are as previously defined and the radical R ^{3 is selected} from the group B, the subject of this invention. In this case, the radicals R ¹ , R ² , R ³ , R ⁴ and R ⁵ particularly preferably have the definitions given in the formulas I.2a to I.2d.

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

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

The term C _1-n- alkyl, where n can have a value of 1 to 18, denotes a saturated, branched or unbranched hydrocarbon group having 1 to n C atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.

The term C _2-n alkynyl, wherein n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group having 2 to n C atoms and a C≡C triple bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc. Unless otherwise indicated, alkynyl groups are attached to the remainder of the molecule via the C atom in position 1. Therefore, terms such as 1-propynyl, 2-propynyl, 1-butynyl, etc. are synonymous with the names 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, etc. in an anologic application also applies to C _2-n -alkenyl groups.

The term C _1-n -alkoxy or C _1-n -alkyloxy refers to a C _1-n -alkyl-O-group wherein 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, cyclodecyl, 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 C _5-n -cycloalkyl group which is as defined above and additionally has at least one unsaturated C =C double bond.

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 term tri (C _1-4 alkyl) silyl includes silyl groups having the same or two or three different alkyl groups.

The term di (C _1-3 alkyl) amino includes amino groups having the same or different alkyl groups.

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

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.

The Glucose derivatives according to the invention of the formula II from D-gluconolactone or a derivative thereof by addition of desired Benzylbenzene compound in the form of an organometallic compound (Scheme 1) are constructed.

Scheme 1: Addition of an organometallic compound to a gluconolactone

The reaction according to Scheme 1 is preferably carried out starting from a halogeno-benzylbenzene compound of the general formula IV in which Hal is chlorine, bromine or iodine. Starting from the haloaromatic IV, the corresponding organometallic compound (V) can be prepared either via a so-called halogen-metal exchange or via an insertion of the metal into the carbon-halogen bond. The halogen-metal exchange with bromine- or iodine-substituted aromatics can, for example, with ei ner organolithium compound such as n-, sec- or tert-butyllithium are carried out while supplying the corresponding litiierten aromatics. The analogous magnesium compound can also be generated via a halogen-metal exchange with a suitable Grignard compound such as isopropylmagnesium bromide or diisopropylmagnesium. The reactions are preferably carried out between 0 and -100 ° C, more preferably between -10 and -80 ° C, in an inert solvent or mixtures thereof, such as diethyl ether, tetrahydrofuran, toluene, hexane or methylene chloride. The magnesium or lithium compounds thus obtained may optionally be metalated with metal salts, such as cerium trichloride, to form further organometallic compounds (V) suitable for addition. Alternatively, the organometallic compound (V) can also be prepared by insertion of a metal into the carbon-halogen bond of the haloaromatic IV. For this purpose, metals such as lithium or magnesium are suitable. The addition of the organometallic compound V to the gluconolactone or derivatives thereof of formula VI is preferably carried out at temperatures between 0 and -100 ° C, more preferably at -30 to -80 ° C, in an inert solvent or mixtures thereof to obtain the compound of Formula II. The lithiation and / or coupling reaction can also be carried out in microreactors and / or micromixers to avoid low temperatures; for example, analogously to the method described in WO 2004/076470.

Examples of suitable solvents are diethyl ether, toluene, methylene chloride, hexane, tetrahydrofuran or mixtures thereof. The reactions can be carried out without further aids or in the case of inert coupling partners in the presence of Lewis acids such as BF ₃ .OEt ₂ or Me ₃ SiCl (see M. Schlosser, Organometallics in Synthesis, John Wiley & Sons, Chichester / New York / Brisbane / Toronto / Singapore, 1994). Here, preferred meanings of the groups R ^8a , R ^8b , R ^8c and R ^8d are benzyl, substituted benzyl, trialkylsilyl, particularly preferably trimethylsilyl, triisopropylsilyl, 4-methoxybenzyl and benzyl. When two adjacent radicals of the group consisting of R ^8a , R ^8b , R ^8c and R ^8d are linked together, these two radicals are preferably constituents of a benzylidene acetal, 4-methoxybenzylidene acetal, isopropyl ketal or represent a 2,3-dimethoxy-butylene group linked via the 2 and 3 position of the butane with the adjacent oxygen atoms of the pyranose ring. The radical R 'is preferably hydrogen or C _1-4 -alkyl, more preferably hydrogen, methyl or ethyl. The radical R 'is introduced after the addition of the organometallic compound V or a derivative thereof to the gluconolactone VI. For this purpose, the reaction solution is treated with an alcohol such as methanol or ethanol or water in the presence of an acid such as methanesulfonic acid, toluenesulfonic acid, sulfuric acid or hydrochloric acid.

The Synthesis of haloaromatics of the formula IV can be carried out using of standard transformations in organic chemistry or at least from methods known from the literature in the organic Synthesis performed (see, inter alia, J. March, Advanced Organic Reactions, Reactions, Mechanisms, and Structure, 4th Edition, John Wiley & Sons, Chichester / New York / Brisbane / Toronto / Singapore, 1992 and references cited therein). The synthesis strategies presented below are intended to represent this demonstrate.

Scheme 2: Synthesis strategy 1

Synthesis strategy 1 (Scheme 2) shows the preparation of the haloaromatic of formula II starting from a benzoyl chloride and a second aromatic, which is converted by means of a Friedel-Crafts acylation in the Diphenylketonderivat. This classical reaction has a large substrate width and is carried out in the presence of a catalyst which is used catalytically or stoichiometrically, for example AlCl ₃ , FeCl ₃ , iodine, iron, ZnCl ₂ , sulfuric acid or trifluoromethanesulfonic acid. Instead of the carbonyl chloride, it is also possible to use the carboxylic acid, an anhydride or ester thereof or else the corresponding benzonitrile. The reactions are preferably carried out in chlorinated hydrocarbons such as dichloromethane and 1,2-dichloroethane at temperatures of -30 to 120 ° C, preferably at 30 to 100 ° C. But even solvent-free reactions or reactions in a microwave oven are possible. In a second reaction step, the diphenyl ketone is reduced to diphenylmethane. This reaction can be carried out in two stages via the corresponding diphenylmethanol or in one stage. In the two-stage variant, the ketone is reduced to the alcohol with a reducing agent such as a metal hydride such as NaBH ₄ , LiAlH ₄ or iBu ₂ AlH. The resulting alcohol can be in the presence of a Lewis acid such as BF ₃ · OEt ₂ , trifluoroacetic acid, InCl ₃ or AlCl ₃ with a reducing agent such as Et ₃ SiH, NaBH ₄ , or Ph ₂ SiClH to form the desired diphenylmethane. The one-step process starting from ketone to diphenylmethane is, for example, with a silane such as Et ₃ SiH, a borohydride such as NaBH ₄ or an aluminum hydride such as LiAlH ₄ in the presence of a Lewis acid such as BF ₃ · OEt ₂ , tris (pentafluorophenyl) borane , Trifluoroacetic acid, aluminum chloride or InCl ₃ possible. The reactions are preferably carried out in solvents such as halogenated hydrocarbons such as dichloromethane, toluene or acetonitrile at temperatures of -30 to 150 ° C, preferably at 20 to 100 ° C. Reductions with hydrogen in the presence of a transition-metal catalyst such as Pd on carbon are also a possible synthetic route. Reductions according to Wolff-Kishner or variants thereof are also possible. In this case, the ketone with hydrazine or a derivative thereof, such as 1,2-bis (tert-butyldimethylsilyl) hydrazine, first converted into the hydrazone, which decomposes under strong basic reaction conditions and heating to diphenylmethane and nitrogen. The reaction may be carried out in a reaction step or after isolation of the hydrazone or a derivative thereof in two separate reaction steps. The bases used are, for example, KOH, NaOH or KOtBu in solvents such as, for example, ethylene glycol, toluene, DMSO, 2- (2-butoxyethoxy) ethanol or t-butanol; solvent-free reactions are also possible. The reactions can be carried out at temperatures between 20 to 250 ° C, preferably between 80 to 200 ° C. An alternative to the basic conditions of the Wolff-Kishner reduction is the Clemmensen reduction under acidic conditions, which can also be used here.

Scheme 3: Synthesis strategy 2

The second synthesis strategy (Scheme 3) shows a further possibility for the construction of the halogenated aromatic of the formula II 'using the example of a trimethylsilylacetylene-substituted diphenylmethane. Starting from an aromatic, which carries two radicals from the group iodine, bromine, chlorine or sulfonate such as trifluoromethylsulfonate, is attached via a transition metal-catalyzed monocoupling at the more reactive end of Dihalogenaromaten, the iodine-carbon bond, an alkyne (Step 1 ). As catalysts, for example, elemental palladium or nickel or salts or complexes thereof are used. The reactions can be carried out with the alkyne itself or metal acetylides thereof. When the alkyne itself is used, the coupling can be carried out in the presence of a base such as NEt ₃ and a co-catalyst such as a copper salt such as Cul (Sonogashira coupling). The reactions are not limited to trimethylsilylacetylene, but allow the use of a variety of terminal alkynes. The reaction, in all its variations, is extensively documented in the literature (see PJ Stang, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1997, and Angew Chem Chem, Ed., 2003, 42, 1566 -1568 and literature quoted there). The two further stages for the preparation of the diphenylmethane derivative include the Umfunktionalisierung the alkyne-substituted aromatic to a metalated (Mg, Li) aromatic, which can be represented for example by means of a halogen-metal exchange as described above, (step 2 ). This metalated aromatic, which can be used directly or after further transmetallation, is added to a benzaldehyde derivative. This produces the diphenylmethanol shown in the diagram. Alternatively, a benzoic acid derivative such as a benzoic acid ester, anhydride, chloride or the acid itself or the benzonitrile can be used. Instead of the alcohol, the corresponding ketone is formed, which is also accessible via the Friedel-Crafts acylation already described above. The further reaction of both the alcohol and the ketone to the diphenylmethane derivative has already been described above (step 3). However, the trimethylsilylethinylated haloaromatic compound can also be converted directly into the desired product after transmetalation (step 4). For this purpose, the lithium or magnesium aromatic obtained after a halogen-metal exchange with a benzyl electrophile such as a benzyl bromide or chloride. The reaction can be without or better in the presence of a transition tallkatalysators, such as a copper salt or a palladium complex, are carried out (see, for example, Org. Lett. 2001, 3, 2871-2874 and literature cited therein). However, the lithium or magnesium aromatic can also first be re-metalated, for example, to the corresponding boronic acids, boronic acid esters, stannanes, silanes or zinc compounds. Thereafter, the benzyl radical is then attached by means of a transition metal such as palladium, nickel, rhodium, copper or iron (see L. Brandsma, SF Vasilevsky, HD Verkruijsse, Application of Transition Metal Catalysts in Organic Synthesis, Springer-Verlag, Berlin / Heidelberg, 1998 ). The reactions of the alkyne-substituted aromatic to the intermediate of the formula II 'according to steps 2 and 3 or step 4, which are shown here by way of example for R ³ in the meaning of ethynyl or trimethylsilylethynyl, can also be used in analogous application with other R ³ -substituted Aromatics are carried out.

Scheme 4: Synthesis strategy 3

Synthesis strategy 3 (scheme 4) presents a variant to synthesis strategy 2, which is also illustrated by means of a trimethylsilylethinylaromatics II ', but should not be restricted to these. The synthesis starts with an aromatic, which means both a group Hal, which represents a halogen atom chlorine, bromine or iodine, or a pseudohalogen group, such as trifluoromethanesulfonate, as well as a metallic center M, such as a B (OH) ₂ -, Si (OAlk) ₃ or SnBu ₃ radical. The two so "activated" centers can be exchanged chemoselectively one after the other. Synthesis strategy 3 illustrates this with an example in which first the halogen atom Hal is exchanged for an alkyne substituent in a transition metal-catalyzed reaction, such as the so-called Sonogashira coupling. In the second step, the metallic center M in a further transition metal-catalyzed coupling to a benzyl radical which is activated, for example, as a benzyl halide, the desired product is replaced (see, eg, Tetrahedron Lett. 2003, 44, 9255-9258 and cited there literature). Both steps are practicable using transition metals such as palladium, rhodium, nickel, copper or iron, or complexes thereof. Both types of reactions are described in detail in the literature. The procedure is not limited to what is described here, but can also be carried out by reversing the order of the two reaction steps. After this, the metallic center M is first linked to the benzyl radical and then the halogen or pseudohalogen group Hal is exchanged with the alkyne.

in der R', R¹ bis R⁵ wie zuvor definiert sind und
R^8a, R^8b, R^8c, R^8d wie zuvor definiert sind und beispielsweise unabhängig voneinander Acetyl, Pivaloyl, Benzoyl, tert-Butoxycarbonyl, Benzyloxycarbonyl, Trialkylsilyl, Benzyl oder substituiertes Benzyl bedeuten oder jeweils zwei benachbarte Reste R^8a, R^8b, R^8c, R^8d ein Benzylidenacetal oder Isopropylidenketal bilden oder eine 2,3-Dimethoxy-butylen-Gruppe, die über die Position 2 und 3 der Butylengruppe mit den Sauerstoffatomen des Pyranoserings verknüpft ist und mit diesen ein substituiertes Dioxan bildet,
die wie zuvor beschrieben erhältlich ist, mit einem Reduktionsmittel in Gegenwart einer Lewis- oder Br⌀nsted-Säure umgesetzt.For the preparation of compounds of the general formula I, according to the process a) of the invention, a compound of the general formula II

in which R ', R ¹ to R ^{5 are} as defined above and
R ^8a , R ^8b , R ^8c , R ^{8d are} as defined above and represent, for example, independently of one another acetyl, pivaloyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, trialkylsilyl, benzyl or substituted benzyl or in each case two adjacent radicals R ^8a , R ^8b , R ^8c , R ^{8d form} a benzylidene acetal or isopropylidene ketal or a 2,3-dimethoxy-butylene group which is linked via positions 2 and 3 of the butylene group to the oxygen atoms of the pyranose ring and forms a substituted dioxane therewith,
which is obtainable as described above, reacted with a reducing agent in the presence of a Lewis or Br⌀nsted acid.

For the implementation Suitable reducing agents are, for example, silanes, such as triethyl-, Tripropyl, triisopropyl or diphenylsilane, sodium borohydride, Sodium cyanoborohydride, zinc borohydride, borane, lithium aluminum hydride, Diisobutylaluminum hydride or samarium iodide. Find the reductions without or in the presence of a suitable Brønsted acid, such as. Hydrochloric acid, toluene sulfonic acid, trifluoroacetic or acetic acid, or Lewis acid, such as. Boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, Tin tetrachloride, scandium triflate or zinc iodide. Dependent on of the reducing agent and the acid can the reaction be in a solvent, such as methylene chloride, chloroform, acetonitrile, toluene, Hexane, diethyl ether, tetrahydrofuran, dioxane, ethanol, water or Mixtures thereof are carried out at temperatures between -60 ° C and 120 ° C. A particularly suitable Reagent combination consists for example of triethylsilane and Boron trifluoride etherate, conveniently in acetonitrile or Dichloromethane at temperatures of -60 ° C and 60 ° C is used. Furthermore may be hydrogen in the presence of a transition metal catalyst, such as. Palladium on carbon or Raney nickel, in solvents such as tetrahydrofuran, ethyl acetate, methanol, ethanol, water or Acetic acid, for the represented transformation can be applied.

in der R¹ bis R⁵ wie zuvor definiert sind und
R^8a bis R^8d eine der zuvor definierten Schutzgruppen, wie z.B. eine Acyl-, Arylmethyl-, Acetal-, Ketal- oder Silylgruppe bedeuten, und die beispielsweise aus der Verbindung der Formel II wie zuvor beschrieben durch Reduktion erhältlich ist, die Schutzgruppen abgespalten.Alternatively, for the preparation of compounds of general formula I according to the inventive method b) in a compound of general formula III

in which R ¹ to R ^{5 are} as defined above and
R ^8a to R ^{8d represent} one of the protective groups defined above, such as, for example, an acyl, arylmethyl, acetal, ketal or silyl group, and which is obtainable, for example, from the compound of the formula II as described above by reduction, the protective groups are cleaved off.

The cleavage of an acyl protecting group used is carried out, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C. The cleavage of a Trifluoracetylrestes preferably takes place by treatment with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at Temperatu ren between 50 and 120 ° C or by treatment with sodium hydroxide, optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C.

The Cleavage of a used acetal or ketal protecting group occurs 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, hydrochloric acid or sulfuric acid or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

The Cleavage of a Trimethylsilylrestes takes place for example in Water, an aqueous Solvent mixture or a lower alcohol such as methanol or ethanol in the presence a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methylate. In aqueous or alcoholic solvents are also acids, such as. Hydrochloric acid, trifluoroacetic or acetic acid. For cleavage in organic solvents, such as diethyl ether, tetrahydrofuran or dichloromethane, Also suitable are fluoride reagents, e.g. Tetrabutylammonium fluoride.

The Cleavage of a benzyl, methoxybenzyl or Benzyloxycarbonylrestes advantageously takes place hydrogenolytically, e.g. with hydrogen in the presence 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.

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

For example come as a protective rest for an ethynyl group is the trimethylsilyl or triisopropyl group in Consideration. The 2-hydroxisoprop-2-yl group can also act as a protecting group Find application.

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.

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 optically active solvent or by reacting with one, with the race mix compound salts or derivatives such as esters or amides-forming optically active substance, in particular acids and their activated derivatives or alcohols, and separating the diastereomeric salt mixture or derivative thus obtained, for example due to different solubilities, wherein from the pure diastereomeric salts or Derivatives, the free antipodes can be released by the action of suitable agents. Particularly common, optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyltartaric acid, di-O-toluenoic acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Examples of optically active alcohols are (+) - or (-) - menthol and, for example, (+) - or (-) - menthyloxycarbonyl as the optically active acyl radical in amides.

Of Further 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 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 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 98/31697, WO 01/27128, WO 02/083066, WO 03/099836 and WO 2004/063209, 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 sodium-dependent Glucose cotransporter, preferably SGLT2.

The biological properties of the new compounds can be 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) or alternatively a HEK293 cell line (ATCC No. CRL-1573), stable with an expression vector pZeoSV (Invitrogen, EMBL accession number L36849) which contains the cDNA for the coding sequence of the human sodium glucose cotransporter 2 (Genbank Acc No. NM_003041) (CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport sodium-dependent ¹⁴ C-labeled alpha-methyl-glucopyranoside ( ¹⁴ C-AMG, Amersham) into the cell interior.

The SGLT-2 assay is performed as follows:
CHO-hSGLT2 cells are cultured in Ham's F12 medium (BioWhittaker) with 10% fetal calf serum and 250 μg / ml Zeocin (Invitrogen), HEK293-hSGLT2 cells in DMEM medium with 10% fetal calf serum and 250 μg / ml Zeocin (Invitrogen).

The cells are detached from the culture flasks by washing twice with PBS and subsequent treatment with trypsin / EDTA. After addition of cell culture medium, the cells are centrifuged off, resuspended in culture medium and counted in a Casy cell counter. Subsequently, 40,000 cells per well are seeded in a white, poly-D-lysine coated 96-well plate and incubated overnight at 37 ° C, 5% CO ₂ . The cells are washed twice with 300 μl of 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). 250 μl of assay buffer and 5 μl of test compound are then added to each well and incubated for an additional 15 minutes in the incubator. The negative control used is 5 μl of 10% DMSO. By adding 5 μl of ¹⁴ C-AMG (0.05 μCi) to each well, the reaction is started. After a 2 hour incubation at 37 ° C., 5% CO ₂ , the cells are again washed with 300 μl PBS (20 ° C.) and subsequently lysed by addition of 25 μl 0.1 N NaOH (5 min at 37 ° C.). 200 μl MicroScint20 (Packard) are added per well and incubated for a further 20 min at 37 ° C. After this incubation, the radioactivity of the ingested ¹⁴ C-AMG is measured in a Topcount (Packard) using a ¹⁴ C scintillation program.

to Determination of selectivity across from the human SGLT1 an analogous test is constructed in which the cDNA for hSGLT1 (Genbank Acc No. NM000343) instead of the hSGLT2 cDNA in CHO-K1 or HEK293 cells is expressed.

The Compounds of the invention of general formula I can for example, EC50 values below 1000 nM, in particular below 200 nM, more preferably below 50 nM.

in the Regard to the ability the SGLT activity to inhibit, the compounds of the invention are the general Formula I and its corresponding pharmaceutically acceptable salts in principle suitable to treat all those conditions or diseases and / or preventively treat by inhibiting the SGLT Activity, especially the SGLT-2 activity can be influenced. Therefore, compounds of the invention in particular for the prophylaxis or treatment of diseases, in particular Metabolic diseases, or conditions such as diabetes mellitus Type 1 and Type 2, diabetic complications (such as retinopathy, Nephropathy or neuropathies, diabetic foot, ulcer, macroangiopathies), metabolic Acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorder, insulin resistance, Metabolic syndrome, dyslipidemias different genesis, atherosclerosis and related diseases, Obesity, hypertension, chronic heart failure, edema, hyperuricemia suitable. About that In addition, these substances are suitable, the beta cell degeneration such as. 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 suitable for the prophylaxis and treatment of acute renal failure.

All especially the compounds according to the invention, including their physiologically acceptable Salts, for the prophylaxis or treatment of diabetes, in particular Diabetes mellitus type 1 and type 2, and / or diabetic complications suitable.

The to achieve a corresponding effect in the treatment or Prophylaxis required dosage usually depends on the one to be administered Association, the patient, the nature and severity of the disease or the condition and nature and frequency of administration at the discretion of the doctor to be treated. Zweckmäßigennreise The dosage may be intravenous Administration in the range of 1 to 100 mg, preferably 1 to 30 mg, and when administered orally in the range of 1 to 1000 mg, preferably 1 to 100 mg, 1 to 4 times daily. For this purpose, the compounds according to the invention can be of the formula I, optionally in combination with other active substances, together with one or more inert customary carriers 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, Solutions, Suspensions or suppositories incorporated.

The Compounds of the invention can also in combination with other active substances, in particular for treatment and / or prophylaxis of the aforementioned diseases and conditions. For such Combinations come as further active substances in particular such for example, the therapeutic efficacy of a SGLT inhibitor according to the invention with regard to one of the indications mentioned and / or a reduction in the dosage of a SGLT inhibitor according to the invention allow. To the therapeutics suitable for such a combination belong e.g. Antidiabetic agents such as metformin, sulfonylureas (e.g. Glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, Thiazolidinediones (e.g., rosiglitazone, pioglitazone), PPAR gamma agonists (e.g., GI 262570) and antagonists, PPAR gamma / alpha modulators (e.g., KRP 297), alpha-glucosidase inhibitors (e.g., acarbose, voglibose), DPPIV inhibitors (e.g., LAF237, MK-431), alpha2 antagonists, insulin and insulin analogs, GLP-1 and GLP-1 analogs (e.g., exendin-4) or Amylin. In addition, other suitable as combination partners active ingredients Inhibitors of protein tyrosine phosphatase 1, substances that have a deregulated glucose production in the liver, e.g. Inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, the Glycogen phosphorylase, glucagon receptor antagonists and inhibitors the phosphoenolpyruvate carboxykinase, the glycogen synthase kinase or pyruvate dehydrokinase, lipid lowering agents such as HMG CoA reductase inhibitors (e.g., simvastatin, atorvastatin), fibrates (e.g., bezafibrate, fenofibrate), niacin and their derivatives, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g., Avasimibe) or cholesterol resorption inhibitors such as ezetimibe, bile acid-binding substances such as for example colestyramine, inhibitors of ileal bile acid transport, HDL-raising Compounds such as inhibitors of CETP or regulators of ABC1 or agents for the treatment of obesity, such as sibutramine or tetrahydrolipstatin, dexfenfluramine, axokines, antagonists of the cannabinoid 1 receptor, MCH-1 receptor antagonist, MC4 receptor Agonists, NPY5 or NPY2 antagonists or β3 agonists such as SB-418790 or AD-9677 as well as agonists of the 5HT2c receptor.

Besides is a combination with drugs to influence high blood pressure, chronic heart failure or atherosclerosis, e.g. A-II Antagonists or ACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca antagonists, centrally effective antihypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, Platelet aggregation inhibitors and others or combinations thereof suitable. Examples of angiotensin II receptor antagonists are candesartan Cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, Irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, etc .. Angiotensin II receptor antagonists are preferred to Treatment or prophylaxis of hypertension and diabetic complications often used in combination with a diuretic such as hydrochlorothiazide.

to Treatment or prophylaxis of gout is a combination with uric acid synthesis Inhibitors or uricosurics suitable.

to Treatment or prophylaxis of diabetic complications may be one Combination with GABA receptor antagonists, Na channel blockers, topiramate, Protein kinase C inhibitors, advanced glycation endproduct inhibitors or aldose reductase inhibitors.

The Dose for the previously mentioned Combination partner is here zweckmittendnreise 1/5 of the usual recommended lowest dosage up to 1/1 of the normally recommended Dosage.

Therefore Another object of this invention is the use a compound of the invention or a physiologically acceptable one Salt of such a compound in combination with at least one the active ingredients previously described as combination partners for the production of a medicine used for the treatment or prophylaxis of diseases or states suitable by inhibiting the sodium-dependent glucose cotransporter SGLT can be influenced. These are preferably a metabolic disease, especially one of the previously mentioned diseases or states, all the way especially diabetes or diabetic complications.

The Use of the compound according to the invention, or a physiologically acceptable one Salt thereof, in combination with another active ingredient at the same time or offset in time, but in particular carried out promptly. When used concurrently, both agents are given to the patient administered together; with a staggered use both drugs to the patient in a period of less than or equal 12, in particular less than or equal to 6 hours administered sequentially.

consequently another subject of this invention relates to a pharmaceutical the one compound of the invention or a physiologically acceptable Salt of such a compound and at least one of the previously as Combination partners described active ingredients in addition to, where appropriate one or more inert carriers and / or diluents having.

So For example, a pharmaceutical composition according to the invention has a combination from a compound according to the invention of the formula I or a physiologically acceptable salt of such a Compound and at least one angiotensin II receptor antagonist optionally together with one or more inert carriers and / or diluents on.

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

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

Preparation of the starting compounds:

Example I

(5-Brom-2-chlor-phenyl)-(4-methoxy-phenyl)-methanon

(5-Bromo-2-chloro-phenyl) - (4-methoxy-phenyl) -methanone

To a mixture of 100 g of 5-bromo-2-chloro-benzoic acid in 500 ml of dichloromethane are added 38.3 ml of oxalyl chloride and 0.8 ml of dimethylformamide. The reaction mixture is stirred for 14 h, then filtered and separated from all volatiles in a rotary evaporator. The residue is dissolved in 150 ml of dichloromethane, the solution is cooled to -5 ° C., and 46.5 g of anisole are added. Thereafter, 51.5 g of aluminum trichloride are added in portions so that the temperature does not rise above 5 ° C. The solution is stirred for 1 h at 1-5 ° C and then poured onto ice. The organic phase is separated and the aqueous extracted three more times with dichloromethane. The combined organic phases are washed with aqueous 1 M hydrochloric acid, twice with 1 M sodium hydroxide solution and with saturated sodium chloride solution. Thereafter, the organic phase is dried, the solvent is removed and the residue recrystallized in ethanol.
Yield: 86.3 g (64% of theory)
Mass spectrum (ESI ⁺ ): m / z = 325/327/329 (Br + Cl) [M + H] ⁺

Massenspektrum (ESI⁺): m/z = 431/433 (Br) [M + H]⁺ (2) (5-Brom-2-chlor-phenyl)-(4-iod-phenyl)-methanon

The following compounds are obtained analogously to Example 1: (1) (5-bromo-2-iodo-phenyl) - (4-ethoxy-phenyl) -methanone

Mass spectrum (ESI ⁺ ): m / z = 431/433 (Br) [M + H] ⁺ (2) (5-bromo-2-chloro-phenyl) - (4-iodo-phenyl) -methanone

Example II

4-Brom-1-chlor-2-(4-methoxy-benzyl)-benzol

4-bromo-1-chloro-2- (4-methoxy-benzyl) -benzene

A solution of 86.2 g of (5-bromo-2-chlorophenyl) - (4-methoxyphenyl) -methanone and 101.5 ml of triethylsilane in 75 ml of dichloromethane and 150 ml of acetonitrile is cooled to 10 ° C. Then 50.8 ml of boron trifluoride etherate are added with stirring so that the temperature does not rise above 20 ° C. The solution is stirred at room temperature for 14 h before 9 ml of triethylsilane and 4.4 ml of boron trifluoride etherate are added again. The solution is stirred for a further 3 h at 45-50 ° C and then cooled to room temperature. A solution of 28 g of potassium hydroxide in 70 ml of water is added and stirred for 2 h. Thereafter, the organic phase is separated and the aqueous extracted three more times with diisopropyl ether. The combined organic phases are washed twice with 2 M potassium hydroxide solution and once with aqueous sodium chloride solution and then dried over sodium sulfate. After removal of the solvent, the residue is stirred in ethanol, separated again and dried at 60 ° C.
Yield: 50.0 g (61% of theory)
Mass spectrum (ESI ⁺ ): m / z = 310/312/314 (Br + Cl) [M + H] ⁺

Massenspektrum (ESI⁺): m/z = 434/436 [M + NH₄]⁺ The following compounds are obtained analogously to Example II: (1) 4-bromo-1-iodo-2- (4-ethoxybenzyl) benzene

Mass spectrum (ESI ⁺ ): m / z = 434/436 [M + NH ₄ ] ⁺

(2) 4-Bromo-1-chloro-2- (4-iodobenzyl) benzene

Example III

4-(5-Brom-2-chlor-benzol)-phenol

4- (5-bromo-2-chloro-benzene) -phenol

A solution of 14.8 g of 4-bromo-1-chloro-2- (4-methoxybenzyl) benzene in 150 ml of dichloromethane is cooled in an ice bath. Then 50 ml of a 1 M solution of boron tribromide in dichloromethane are added and the solution is stirred for 2 hours at room temperature. The solution is then cooled again in an ice bath, and it is added dropwise saturated potassium carbonate solution. At room temperature is adjusted to a pH of 1 with aqueous 1 M hydrochloric acid, the organic phase separated and the aqueous extracted three more times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is completely removed.
Yield: 13.9 g (98% of theory)
Mass spectrum (ESI ^- ): m / z = 295/297/299 (Br + Cl) [M - H] ^-

Example IV

[4-(5-Brom-2-chlor-benzol)-phenoxyl-tert-butyl-dimethyl-silan

[4- (5-bromo-2-chloro-benzene) -phenoxy-tert-butyl-dimethyl-silane

A solution of 13.9 g of 4- (5-bromo-2-chloro-benzyl) -phenol in 140 ml of dichloromethane is cooled in an ice bath. Then, 7.54 g of tert-butyldimethylsilyl chloride in 20 ml of dichloromethane followed by 9.8 ml of triethylamine and 0.5 g of dimethylaminopyridine are added. The solution is stirred for 16 h at room temperature and then diluted with 100 ml of dichloromethane. The organic phase is washed twice with 1 M aqueous hydrochloric acid and once with aqueous sodium bicarbonate solution and then dried over sodium sulfate. After removal of the solvent, the residue is filtered through silica gel (cyclohexane / ethyl acetate 100: 1).
Yield: 16.8 g (87% of theory)
Mass spectrum (EI): m / z = 410/412/414 (Br + Cl) [M] ⁺

Example V

1-Brom-4-triisopropylsilylethinyl-benzol

1-bromo-4-triisopropylsilylethynyl-benzene

Under argon, to an oxygen-free solution of 15.0 g of 1-bromo-4-iodobenzene in 150 ml of dry tetrahydrofuran are added 11.6 ml of triisopropylacetylene and 14.4 ml of triethylamine followed by 0.2 g of copper iodide and 0.73 g of bis - (Triphenylphosphine) palladium dichloride given. The solution is stirred for 16 h at room temperature and then filtered through Celite and concentrated. The residue is chromatographed on silica gel (cyclohexane).
Yield: 17.4 g (100% of theory)
Mass Spectrum (ESI ⁺ ): m / z = 336/338 (Br) [M] ⁺

Analogous Example V, the following compounds are obtained:

(1) 4-Bromo-1- (triisopropylsilylethynyl) -2- (4-ethoxybenzyl) benzene

Massenspektrum (ESI⁺): m/z = 471/473 (Br) [M + H]⁺ 4-bromo-1-iodo-2- (4-ethoxybenzyl) benzene is used here as the starting material for the coupling reaction described above.

Mass Spectrum (ESI ⁺ ): m / z = 471/473 (Br) [M + H] ⁺

(2) [4- (5-Bromo-2-chloro-benzyl) -phenylethynyl] -triisopropyl-silane

4-bromo-1-chloro-2- (4-iodo-benzyl) -benzene is used as starting material.

These Connection can also be according to example X will be obtained.

Example VI

(5-Brom-2-fluor-phenyl)-{4-[(triisopropylsilyl)-ethinyl]-phenyl}-methanol

(5-Bromo-2-fluoro-phenyl) - {4 - [(triisopropylsilyl) ethynyl] phenyl} methanol

To a -78 ° C-cold solution of 17.4 g of 1-bromo-4-triisopropylsilylethinyl-benzene in 120 ml of dry tetrahydrofuran are added dropwise under argon 33.8 ml of a 1.6 M solution of n-butyllithium in hexane. The solution was stirred at -70 ° C. for 1 h. Thereafter, 10.8 g of 5-bromo-2-fluoro-benzaldehyde dissolved in 30 ml of tetrahydrofuran are added dropwise over 15 min. The resulting solution is allowed to warm to room temperature overnight in the cooling bath. Thereafter, water is added and extracted with ethyl acetate. The combined organic phase is dried over sodium sulfate and the solvent is removed. The residue is purified over silica gel (cyclohexane / ethyl acetate 4: 1).
Yield: 14.3 g (60% of theory)
Mass spectrum (ESI ⁺ ): m / z = 461/463 (Br) [M + H] ⁺

Massenspektrum (ESI^–): m/z = 487/489 (Br) [M + HCOO]^– (2) (5-Brom-2-methoxy-phenyl)-{4-[(triisopropylsilyl)-ethinyl]-phenyl}-methanol

Massenspektrum (ESI⁺): m/z = 473/475 (Br) [M + H]⁺ The following compounds are obtained analogously to Example VI: (1) (3-Bromo-phenyl) - {4 - [(triisopropylsilyl) -ethynyl] -phenyl} -methanol

Mass spectrum (ESI ^-): m / z = 487/489 (Br) [M + HCOO] ^- (2) (5-bromo-2-methoxy-phenyl) - {4 - [(triisopropylsilyl) ethynyl] phenyl} methanol

Mass Spectrum (ESI ⁺ ): m / z = 473/475 (Br) [M + H] ⁺

Example VII

[4-(5-Brom-2-fluor-benzyl)-phenylethinyl]-triisopropyl-silan

[4- (5-bromo-2-fluoro-benzyl) -phenylethynyl] -triisopropyl-silane

A solution of 5.6 g of (5-bromo-2-fluoro-phenyl) - {4 - [(triisopropylsilyl) -ethynyl] -phenyl} -methanol and 4.1 ml of triethylsilane in 50 ml of dichloromethane is cooled in an ice-bath. Then, 4.7 ml of trifluoroacetic acid are slowly added dropwise, and the solution is stirred for 4 hours at room temperature. The solution is diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. After drying over sodium sulfate, the solvent is removed and the residue is purified on silica gel (cyclohexane).
Yield: 2.6 g (48% of theory)
Mass spectrum (EI): m / z = 445/447 (Br) [M] ⁺

Massenspektrum (ESI⁺): m/z = 427/429 (Br) [M + H]⁺ The following compounds are obtained analogously to Example VII: (1) [4- (3-Bromo-benzyl) -phenylethynyl] -triisopropyl-silane

Mass Spectrum (ESI ⁺ ): m / z = 427/429 (Br) [M + H] ⁺

(2) [4- (5-Bromo-2-methoxybenzyl) phenylethynyl] triisopropylsilane

Massenspektrum (ESI⁺): m/z = 457/459 (Br) [M + H]⁺ Notwithstanding the method described above, the reaction solution is stirred here in an ice bath instead of at room temperature until complete reaction.

Mass Spectrum (ESI ⁺ ): m / z = 457/459 (Br) [M + H] ⁺

Example VIII

4-Brom-2-brommethyl-1-chlor-benzol

4-bromo-2-bromomethyl-1-chloro-benzene

To a 5 ° C cold solution of 5.0 g of 4-bromo-1-chloro-2-hydroxymethylbenzene and 5.9 g of triphenylphosphine in 50 ml of tetrahydrofuran are slowly added 4.0 g of N-bromosuccinimide. After 1 h stirring at room temperature, the precipitate is filtered off and the solvent removed in vacuo. The residue is purified over silica gel (cyclohexane / ethyl acetate 50: 1).
Yield: 4.9 g (76% of theory)
Mass spectrum (EI): m / z = 282/284/286 (Br + Cl) [M] ⁺

Example IX

(4-Iod-phenylethinyl)-triisopropyl-silan

(4-iodo-phenylethynyl) -triisopropyl-silane

18.0 g of sodium iodide (dry), 0.6 g of copper iodide and 0.8 g of N, N'-dimethylcyclohexane are added, under argon, to a solution of 20.0 g (4-bromo-phenylethynyl) -triisopropyl-silane. Given 1,2-diamine. The solution is stirred at reflux for 24 h and then cooled to room temperature. Add 1% ammonia solution (100 ml) and extract with ethyl acetate. After drying over sodium sulfate, the solvent is removed and the residue is purified on silica gel (cyclohexane).
Yield: 21.0 g (92% of theory)
Mass spectrum (EI): m / z = 384 [M] ⁺

Example X

[4-(5-Brom-2-chlor-benzyl)-phenylethinyl]-triisopropyl-silan

[4- (5-bromo-2-chloro-benzyl) -phenylethynyl] -triisopropyl-silane

Under argon, 0.66 ml of a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran are added dropwise to a solution of 0.50 g (4-iodo-phenylethynyl) -triisopropyl-silane in 2.2 ml of dry tetrahydrofuran at -25.degree. The solution is stirred for 30 min at -25 ° C and then treated with 0.26 ml of a 1 M solution of CuCN · 2 LiCl in tetrahydrofuran (prepared by dissolving CuCN and LiCl in the ratio 1: 2). Shortly thereafter, 0.35 g of 4-bromo-2-bromomethyl-1-chlorobenzene are added and the reaction mixture is warmed to -5 ° C in a cooling bath. After 6 h stirring at -5 ° C, the solution is warmed to room temperature and stirred overnight. Thereafter, a mixture of saturated ammonium chloride solution and 25% ammonia solution (9: 1) is added and the resulting mixture is added to water. The organic phase is separated and the aqueous extracted with ethyl acetate, the combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is purified over silica gel (cyclohexane).
Yield: 0.28 g (50% of theory)
Mass spectrum (EI): m / z = 461/463/465 (Br + Cl) [M + H] ⁺

Example XI

2,3,4,6-Tetrakis-O-(trimethylsilyl)-D-glucopyranon

2,3,4,6-tetrakis-O- (trimethylsilyl) -D-glucopyranone

A solution of 20 g of D-glucono-1,5-lactone and 98.5 ml of N-methylmorpholine in 200 ml of tetrahydrofuran is cooled to -5 ° C. Then, 85 ml of trimethylsilyl chloride are added dropwise so that the temperature does not rise above 5 ° C. The solution is then stirred for 1 h at room temperature, 5 h at 35 ° C and another 14 h at room temperature. After adding 300 ml of toluene, the solution is cooled in an ice bath and 500 ml of water are added so that the temperature does not rise above 10 ° C. The organic phase is then separated off and washed once each with aqueous sodium dihydrogenphosphate solution, water and saturated aqueous sodium chloride solution. The solvent is removed, the residue is taken up in 250 ml of toluene and the solvent is completely removed again.
Yield: 52.5 g (about 90% pure)
Mass Spectrum (ESI ⁺ ): m / z = 467 [M + H] ⁺

Example XII

1-Fluor-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-triisopropylsilylethinyl-benzyl)-benzol

1-fluoro-4- (1-methoxy-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethynyl-benzyl) -benzene

A solution of 4.46 g of [4- (5-bromo-2-fluoro-benzyl) -phenylethynyl] -triisopropyl-silane in 30 ml of dry diethyl ether is cooled to -80 ° C under argon. 11.8 ml of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred at -80 ° C. for 45 minutes. To this solution, a -80 ° C-cold solution of 5.19 g of 2,3,4,6-tetrakis-O- (trimethylsilyl) -D-glucopyranone in 50 ml of diethyl ether is then added dropwise via a transfer needle. The resulting solution is stirred for 3 h at -78 ° C. Thereafter, a solution of 1.7 ml of methanesulfonic acid in 50 ml of methanol is added, the cooling bath is removed and the solution is stirred for 16 h at room temperature. The solution is then neutralized with ethyldiisopropylamine and concentrated to dryness. The residue is purified over silica gel (dichloromethane / methanol 50: 1 → 4: 1).
Yield: 2.8 g (50% of theory)
Mass spectrum (ESI +): m / z = 576 [M + NH ₄ ] ⁺

Analogous Example XII the following compounds are obtained:

(1) 1-Methoxy-4- (1-methoxy-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethynylbenzyl) benzene

Massenspektrum (ESI⁺): m/z = 588 [M + NH₄] (2) 1-Chlor-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-triisopropylsilylethinyl-benzyl)-benzol

Massenspektrum (ESI⁺): m/z = 592/594 (Cl) [M + NH₄]⁺ Advantageously, the reaction mixture is admixed only with a slight excess of methanesulfonic acid.

Mass Spectrum (ESI ⁺ ): m / z = 588 [M + NH ₄ ] (2) 1-Chloro-4- (1-methoxy-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethynylbenzyl) - benzene

Mass spectrum (ESI ⁺ ): m / z = 592/594 (Cl) [M + NH ₄ ] ⁺

Example XIII

1-Fluor-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-triisopropylsilylethinyl-benzyl)-benzol

1-fluoro-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethynyl-benzyl) -benzene

A solution of 0.8 g of 1-fluoro-4- (1-methoxy-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethynylbenzyl) benzene and 0.5 ml of triethylsilane in 6 ml of dichloromethane and 10 Acetonitrile is cooled to -10 ° C. To the cooled solution is added dropwise 0.27 ml of boron trifluoride etherate. The solution is then stirred for 3 h in an ice bath. To the solution is added sodium hydrogencarbonate aqueous solution and then extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is removed and the residue taken up in 6 ml of dichloromethane. Then, 1.2 ml of pyridine, 1.3 ml of acetic anhydride and 8 mg of 4-dimethylaminopyridine are added. The solution is stirred for 1 h at room temperature and then treated with water. The mixture is extracted with dichloromethane, the organic phase is washed with 1 M hydrochloric acid and dried over sodium sulfate. After removal of the solvent, the residue is chromatographed on silica gel (cyclohexane / ethyl acetate 4: 1 → 1: 1).
Yield: 0.23 g (23% of theory)
Mass spectrum (ESI ⁺ ): m / z = 714 [M + NH ₄ ] ⁺

Massenspektrum (ESI⁺): m/z = 726 [M + NH₄]⁺ (2) 1-Chlor-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-triisopropylsilylethinyl-benzyl)-benzol

Massenspektrum (ESI⁺): m/z = 730/732 (Cl) [M + NH₄]⁺ The following compounds are obtained analogously to Example XIII: (1) 1-methoxy-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -2- (4-triisopropylsilylethinyl) benzyl) -benzene

Mass Spectrum (ESI ⁺ ): m / z = 726 [M + NH ₄ ] ⁺ (2) 1-Chloro-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1 yl) -2- (4-triisopropylsilylethynyl-benzyl) -benzene

Mass spectrum (ESI ⁺ ): m / z = 730/732 (Cl) [M + NH ₄ ] ⁺

Example XIV

1-(2,3,4,6-Tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl)-3-(4-triisopropylsilylethinyl-benzyl)-benzol

1- (2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl) -3- (4-triisopropylsilylethynyl-benzyl) -benzene

A solution of 2.6 g of [4- (3-bromo-benzyl) -phenylethynyl] -triisopropyl-silane in 20 ml of dry diethyl ether is cooled to -80 ° C. under argon. 7.9 ml of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred at -80 ° C. for 30 minutes. To this solution, a -80 ° C-cold solution of 3.2 g of 2,3,4,6-tetrakis-O- (trimethylsilyl) -D-glucopyranone in 30 ml of diethyl ether is then added dropwise via a transfer needle. The resulting solution is stirred for 2 h at -78 ° C and then again a -80 ° C-cold solution of 1.0 gg 2,3,4,6-tetrakis-O- (trimethylsilyl) -D-glucopyranone in 10 ml of diethyl ether added dropwise. After stirring for a further hour at -78 ° C., a solution of 2 ml of methanesulfonic acid in 20 ml of methanol is added, the cooling bath is removed and the solution is stirred for 16 hours at room temperature. The solution is then neutralized with ethyldiisopropylamine, the solvent is completely removed and the residue taken up in 50 ml of toluene. 8.5 ml of ethyldiisopropylamine are added and the solution is cooled in an ice bath. Thereafter, 4.3 ml of acetic anhydride and 0.15 g of 4-dimethylaminopyridine are added. The solution is stirred for 2 h at room temperature and then treated with aqueous sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phases are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (cyclohexane / ethyl acetate 4: 1 → 1: 3).
Yield: 2.0 g (46% of theory)
Mass spectrum (ESI ⁺ ): m / z = 726 [M + NH ₄ ] ⁺

Massenspektrum (ESI⁺): m/z = 770 [M + NH₄]⁺ The following compound is obtained analogously to Example XIV: (1) 1- (triisopropylsilylethynyl) -4- (2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl) -2- ( 4-ethoxy-benzyl) -benzene

Mass spectrum (ESI ⁺ ): m / z = 770 [M + NH ₄ ] ⁺

Example XV

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranos-1-yl)-3-(4-triisopropylsilylethinyl-benzyl)-benzol

1- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -3- (4-triisopropylsilylethynyl-benzyl) -benzene

To an ice-cooled solution of 1.0 g of 1- (2,3,4,6-tetra-O-acetyl-1-methoxy-D-glucopyranos-1-yl) -3- (4-triisopropylsilylethynylbenzyl) benzene and 25 .mu.l of water in 10 ml of acetonitrile are added dropwise 1.2 ml of triethylsilane and 0.36 ml boron trifluoride etherate. The solution is then stirred for 3 h in an ice bath and for 1 h at room temperature. Thereafter, the solution is again cooled in an ice bath, and there are again added 1.2 ml of triethylsilane and 0.36 ml of boron trifluoride etherate. The solution is stirred for an additional 0.5 h in an ice bath and for 2 h at room temperature. To the solution is then added aqueous sodium bicarbonate solution, and the resulting solution is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent removed.
Yield: 0.78 g (81% of theory)
Mass spectrum (ESI ⁺ ): m / z = 696 [M + NH ₄ ] ⁺

The following compound is obtained analogously to Example XV: (1) 1- (triisopropylsilylethynyl) -4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -2- (4-) ethoxy-benzyl) -benzene

Example XVI

1-Chlor-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzol

1-chloro-4- (β-D-glucopyranos-1-yl) -2- (4-hydroxybenzyl) benzene

A solution of 4.0 g of [4- (5-bromo-2-chloro-benzyl) -phenoxy] -tert-butyl-dimethyl-silane in 42 ml of dry diethyl ether is cooled to -80 ° C under argon. 11.6 ml of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and the solution is then stirred at -80 ° C. for 30 minutes. This solution is then transferred via a crimp needle, which is cooled with dry ice, to a -80 ° C cold solution of 4.78 g of 2,3,4,6-tetrakis-O- (trimethylsilyl) -D-glucopyranone in 38 ml Diethyl ether added dropwise. The resulting solution is stirred for 3 h at -78 ° C. Thereafter, a solution of 1.1 ml of methanesulfonic acid in 35 ml of methanol is added and the solution is stirred for 16 h at room temperature. The solution is then neutralized with solid sodium bicarbonate, ethyl acetate is added and the methanol is removed along with the ether. To the remaining solution, aqueous sodium bicarbonate solution is added and extracted four times with ethyl acetate. The organic phases are dried over sodium sulfate and concentrated. The residue is dissolved in 30 ml of acetonitrile and 30 ml of dichloromethane and the solution is cooled to -10.degree. After addition of 4.4 ml of triethylsilane 2.6 ml of boron trifluoride etherate are added dropwise so that the temperature does not rise above -5 ° C. After complete addition, the solution is stirred for a further 5 h at -5 to -10 ° C and then quenched by the addition of aqueous sodium bicarbonate solution. The organic phase is separated and the aqueous extracted four times with ethyl acetate. The combined organic phase are dried over sodium sulfate, the solvent is removed and the residue is purified on silica gel. The resulting product is an approximately 6: 1 β / a mixture which can be converted to the pure β-anomer by complete acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallization of the product in ethanol. The product thus obtained is converted by reaction in methanol with 4 M potassium hydroxide in the title compound.
Yield: 1.6 g (46% of theory)
Mass spectrum (ESI ⁺ ): m / z = 398/400 (Cl) [M + H] ⁺

Example XVII

1-Chlor-4-(β-D-glucopyranos-1-yl)-2-[4-(trifluormethylsulfonyloxy)-benzyl]-benzol

1-chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (trifluoromethylsulfonyloxy) -benzyl] -benzene

To a solution of 0.38 g of 1-chloro-4- (β-D-glucopyranos-1-yl) -2- (4-hydroxybenzyl) benzene, 0.21 ml of triethylamine and 0.39 g of N, N- Bis (trifluoromethanesulfonyl) aniline in 10 ml of dry dichloromethane is added 10 mg of 4-dimethylaminopyridine. The solution is stirred for 4 h at room temperature and then treated with aqueous sodium chloride solution. It is extracted with ethyl acetate, the organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane / methanol 1: 0 → 4: 1).
Yield: 0.33 g (64% of theory)
Mass spectrum (ESI ⁺ ): m / z = 530/532 (Cl) [M + NH ₄ ] ⁺

Example XVIII

2,3,4,6-Tetra-O-benzyl-D-glucopyranon

2,3,4,6-Tetra-O-benzyl-D-glucopyranone

To a solution of 10.0 g of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranose in 140 ml of dichloromethane is added 4 g of freshly activated molecular sieve 4Å and 3.3 g of N-methylmorpholine N-oxide given. The solution is stirred for 20 minutes at room temperature before adding 0.3 g of tetrapropylammonium barrier hutenate. After 2 h stirring at room temperature, the solution is diluted with dichloromethane and filtered through Celite. The filtrate is washed with aqueous sodium thiosulfate solution and water and then dried over sodium sulfate. After removal of the solvent, the residue is chromatographed on silica gel (cyclohexane / ethyl acetate 4: 1).
Yield: 8.2 g (82% of theory)
Mass spectrum (ESI ⁺ ): m / z = 539 [M + H] ⁺

Example XIX

1-(2,3,4,6-Tetra-O-benzyl-1-hydroxy-D-glucopyranos-1-yl)-3-[4-(tert-butyl-dimethyl-silyloxy)-benzyl]-4-methyl-benzol

1- (2,3,4,6-tetra-O-benzyl-1-hydroxy-D-glucopyranos-1-yl) -3- [4- (tert-butyl-dimethyl-silyloxy) benzyl] -4- methylbenzene

A solution of 0.34 g of [4- (5-bromo-2-methyl-benzyl) -phenoxy] -tert-butyl-dimethyl-silane in 3 ml of dry tetrahydrofuran is cooled to -80 ° C under argon. To the cooled solution is added dropwise 0.54 ml of a 1.6 M solution of n-butyllithium in hexane and the solution is stirred for 1.5 h at -78 ° C. To this solution, a -80 ° C-cold solution of 0.43 g of 2,3,4,6-tetra-O-benzyl-D-glucopyranone in 2.5 ml of tetrahydrofuran is added dropwise by means of a transfer needle. The resulting solution is stirred for 5 h at -78 ° C. The reaction is quenched with a solution of 0.1 ml of acetic acid in 1 ml of tetrahydrofuran and warmed to room temperature. Now, aqueous sodium bicarbonate solution is added and extracted four times with ethyl acetate. The organic phases are dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (cyclohexane / ethyl acetate 15: 1 → 4: 1).
Yield: 0.48 g (about 88% pure)
Mass spectrum (ESI ⁺ ): m / z = 868 [M + H] ⁺

Example XX

1-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-(4-hydroxy-benzyl)-4-methyl-benzol

1- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl) -3- (4-hydroxy-benzyl) -4-methyl-benzene

A solution of 0.48 g (about 88% pure) of 1- (2,3,4,6-tetra-O-benzyl-1-hydroxy-D-glucopyranosyl) -3- [4- (tert-butyl) Dimethyl-silyloxy) benzyl] -4-methyl-benzene in 3.5 ml of dry acetonitrile is cooled to -40 ° C under argon. 0.13 ml of triisopropylsilane and 0.08 ml of boron trifluoride etherate are added dropwise to the cooled solution. The solution is stirred at -35 ° C. for 3 h, before a further 0.02 ml of triisopropylsilane and 0.01 ml of boron trifluoride etherate are added. After a further 2 h at -40 ° C., aqueous potassium carbonate is added and the solution is stirred for 1 h at room temperature. It is then diluted with water and extracted four times with ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and chromatographed on silica gel (cyclohexane / ethyl acetate 10: 1 → 4: 1).
Yield: 0.24 g (68% of theory). Mass spectrum (ESI ⁺ ): m / z = 738 [M + NH ₄ ] ⁺

Example XXI

1-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-T4-(tetrahydrofuran-3-yloxy)-benzyl]-4-methyl-benzol

1- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl) -3-T4 (tetrahydrofuran-3-yloxy) -benzyl] -4-methyl-benzene

To a mixture of 0.24 g of 1- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl) -3- (4-hydroxybenzyl) -4-methyl- benzene and 0.13 g of cesium carbonate in 2.5 ml of dimethylformamide are added 0.10 g of toluene-4-sulfonic acid tetrahydrofuran-3-ylester. The mixture is stirred for 4 h at 65 ° C before adding water. It is extracted three times with ethyl acetate, the organic phase dried over sodium sulfate and the solvent removed. The residue is purified over silica gel (cyclohexane / ethyl acetate 10: 1 → 4: 1).
Yield: 0.23 g (78% of theory). Mass spectrum (ESI ⁺ ): m / z = 808 [M + H] ⁺

Example XXII

1-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-[4-(trifluormethylsulfonyloxy)-benzyl]-4-methyl-benzol

1- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl) -3- [4- (trifluoromethylsulfonyloxy) -benzyl] -4-methyl-benzene

A solution of 0.62 g of 1- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl) -3- (4-hydroxybenzyl) -4-methyl-benzene in 4.5 ml of dry dichloromethane is cooled to -10 ° C under argon. 0.14 ml of pyridine and a solution of 0.3 g of trifluoromethanesulfonic anhydride in 0.5 ml of dichloromethane are added to the cooled solution. The solution is stirred for 0.5 h at -5 to -10 ° C before aqueous sodium bicarbonate solution is added. It is extracted three times with dichloromethane, the collected organic phases are washed with aqueous 1 M hydrochloric acid and dried over sodium sulfate. After removal of the solvent, the residue is chromatographed on silica gel (cyclohexane / ethyl acetate 15: 1 → 7: 1).
Yield: 0.62 g (84% of theory)
Mass spectrum (ESI ⁺ ): m / z = 853 [M + H] ⁺

Example XXIII

1-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-[4-(trimethylsilylethinyl)-benzyl]-4-methyl-benzol

1- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl) -3- [4- (trimethylsilylethynyl) benzyl] -4-methyl-benzene

Under argon, to a solution of 0.60 g of 1- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl) -3- [4- (trifluoromethylsulfonyloxy) benzyl] -4-methyl-benzene in 3 ml of dimethylformamide 27 mg of copper iodide, 49 mg of bis (triphenylphosphine) palladium dichloride, 0.30 ml of triethylamine and finally 0.14 ml of trimethylsilylacetylene. The flask is sealed and stirred at 90 ° C for 4 h. Thereafter, another 20 mg of bis (triphenylphosphine) palladium dichloride and 0.6 ml of trimethylsilylacetylene are added, and the solution is stirred for a further 4 h at 90 ° C. Then, aqueous sodium bicarbonate solution is added, extracted three times with ethyl acetate, and the collected organic phases are dried over sodium sulfate. After removal of the solvent, the residue is chromatographed on silica gel (cyclohexane / ethyl acetate 40: 1 → 10: 1).
Yield: 0.45 g (80% of theory)
Mass spectrum (ESI ⁺ ): m / z = 818 [M + H ₄ ] ⁺

Preparation of the end compounds:

example 1

1-Chlor-2-(4-cyclopentyloxybenzyl)-4-(β-D-glucopyranos-1-yl)-benzol

1-chloro-2- (4-cyclopentyloxybenzyl) -4- (β-D-glucopyranos-1-yl) benzene

To a mixture of 0.25 g of 1-chloro-4- (β-D-glucopyranos-1-yl) -2- (4-hydroxybenzyl) benzene and 0.4 g of cesium carbonate in 2.5 ml of dimethylformamide are added 0, Added 16 ml of iodocyclopentane. The mixture is stirred for 4 h at 45 ° C before adding again 0.1 g of cesium carbonate and 0.05 ml of iodocyclopentane. After a further 14 h stirring at 45 ° C, aqueous sodium chloride solution is added and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is removed and the residue is purified on silica gel (dichloromethane / methanol 1: 0 → 5: 1).
Yield: 0.23 g (78% of theory)
Mass spectrum (ESI ⁺ ): m / z = 466/468 (Cl) [M + NH ₄ ] ⁺

Analogous Example 1 the following compounds are obtained:

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

Massenspektrum (ESI⁺): m/z = 451/453 (Cl) [M + H]⁺ The reaction is carried out with (S) -toluene-4-sulfonic acid-tetrahydrofuran-3-yl ester as a coupling partner.

Mass spectrum (ESI ⁺ ): m / z = 451/453 (Cl) [M + H] ⁺

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

Massenspektrum (ESI⁺): m/z = 451/453 (Cl) (M + H]⁺ The reaction is carried out with (R) -toluene-4-sulfonic acid-tetrahydrofuran-3-yl ester as a coupling partner.

Mass spectrum (ESI ⁺ ): m / z = 451/453 (Cl) (M + H) ⁺

(4) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (tetrahydrofuran-2-on-3-yloxy) benzyl] benzene

Massenspektrum (ESI⁺): m/z = 465/467 (Cl) (M + H]⁺ (5) 1-Chlor-4-(β-D-glucopyranos-1-yl)-2-(4-cyclobutyloxy-benzyl)-benzol

Massenspektrum (ESI⁺): m/z = 452/454 (Cl) [M + NH₄]⁺ (6) 1-Chlor-4-(β-D-glucopyranos-1-yl)-2-(4-cyclohexyloxy-benzyl)-benzol

Massenspektrum (ESI⁺): m/z = 480/482 (Cl) [M + NH₄]⁺ (7) 1-Chlor-4-(β-D-glucopyranos-1-yl)-2-[4-(tetrahydropyran-4-yloxy)-benzyl]-benzol

Massenspektrum (ESI⁺): m/z = 487/489 (Cl) [M + Na]⁺ The reaction is carried out with 3-bromobutyrolactone as coupling partner.

Mass spectrum (ESI ⁺ ): m / z = 465/467 (Cl) (M + H) ⁺ (5) 1-chloro-4- (β-D-glucopyranos-1-yl) -2- (4-cyclobutyloxy-) benzyl) -benzene

Mass Spectrum (ESI ⁺ ): m / z = 452/454 (Cl) [M + NH ₄ ] ⁺ (6) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- (4-cyclohexyloxy benzyl) -benzene

Mass spectrum (ESI ⁺ ): m / z = 480/482 (Cl) [M + NH ₄ ] ⁺ (7) 1-chloro-4- (β-D-glucopyranos-1-yl) -2- [4- ( tetrahydropyran-4-yloxy) -benzyl] -benzene

Mass spectrum (ESI ⁺ ): m / z = 487/489 (Cl) [M + Na] ⁺

(8) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (1-acetyl-piperidin-4-yloxy) -benzyl] -benzene

Massenspektrum (ESI⁺): m/z = 506/508 (Cl) [M + H]⁺ The reaction is carried out with 1-acetyl-4-methylsulfonyloxy-piperidine as electrophile.

Mass spectrum (ESI ⁺ ): m / z = 506/508 (Cl) [M + H] ⁺

(9) 1-Chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (1-tert-butyloxycarbonyl-piperidin-4-yloxy) -benzyl] -benzene

Massenspektrum (ESI⁺): m/z = 586/588 (Cl) [M + Na]⁺ The reaction is carried out with 1-tert-butyloxycarbonyl-4-methylsulfonyloxy-piperidine as electrophile.

Mass spectrum (ESI ⁺ ): m / z = 586/588 (Cl) [M + Na] ⁺

Example 10

1-(β-D-Glucopyranos-1-yl)-4-methyl-3-[4-(tetrahydrofuran-3-yloxy)-benzyl]-benzol

1- (β-D-Glucopyranos-1-yl) -4-methyl-3- [4- (tetrahydrofuran-3-yloxy) -benzyl] -benzene

A mixture of 0.21 g of 1- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl) -3- [4- (tetrahydrofuran-3-yloxy) benzyl] 4-methyl-benzene and 0.1 g of 10% palladium hydroxide on carbon in 3 ml of ethyl acetate is shaken for 24 hours under a hydrogen pressure of 1 atm at room temperature. Thereafter, the same amount of catalyst is added again and shaken for a further 24 h under a hydrogen atmosphere. Then the catalyst is filtered off, the filtrate was concentrated and the residue chromatographed on silica gel (dichloromethane / methanol 1: 0 -> 5: 1).
Yield: 0.06 g (49% of theory)
Mass spectrum (ESI ⁺ ): m / z = 448 [M + NH ₄ ] ⁺

Example 11

1-(β-D-Guucopyranos-1-yl)-4-methyl-3-[4-(2-trimethylsilyl-ethyl)-benzyl]-benzol

1- (β-D-Guucopyranos-1-yl) -4-methyl-3- [4- (2-trimethylsilyl-ethyl) -benzyl] -benzene

A mixture of 0.29 g of 1- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl) -4-methyl-3- [4- (trimethylsilylethynyl) benzyl] -benzene and 0.25 g of 10% palladium hydroxide on carbon in 3 ml of ethyl acetate is shaken for 24 h under a hydrogen pressure of 1 atm at room temperature. Thereafter, 0.2 g of catalyst are added again, and the solution is shaken for another 20 h under a hydrogen atmosphere. Then the catalyst is filtered off, the filtrate was concentrated and the residue chromatographed on silica gel (dichloromethane / methanol 1: 0 -> 5: 1).
Yield: 0.08 g (51% of theory)
Mass spectrum (ESI ⁺ ): m / z = 462 [M + NH ₄ ] ⁺

Example 12

1-Chlor-4-(β-D-glucopyranos-1-yl)-2-(4-ethinyl-benzol)-benzol

1-chloro-4- (β-D-glucopyranos-1-yl) -2- (4-ethynyl-benzene) benzene

Under argon, 25 mg of copper iodide are added to a solution of 0.32 g of 1-chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (trifluoromethylsulfonyloxy) benzyl] benzene in 3 ml of dimethylformamide. 44 mg of bis (triphenylphosphine) palladium dichloride, 0.30 ml of triethylamine and finally 0.14 ml of trimethylsilylacetylene. The flask is sealed and stirred at 90 ° C for 8 h. Thereafter, another 25 mg of bis (triphenylphosphine) palladium dichloride and 0.1 ml of trimethylsilylacetylene are added, and the solution is stirred at 90 ° C for a further 10 h. Then, aqueous sodium bicarbonate solution is added, extracted three times with ethyl acetate, and the collected organic phases are dried over sodium sulfate. After removal of the solvent, the residue is dissolved in 5 ml of methanol and treated with 0.12 g of potassium carbonate. The mixture is stirred for 1 h at room temperature and then neutralized with 1 M hydrochloric acid. Thereafter, the methanol is evaporated off, the residue is treated with aqueous sodium chloride solution and extracted with ethyl acetate. The collected organic extracts are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane / methanol 1: 0 -> 5: 1).
Yield: 0.095 g (40% of theory)
Mass spectrum (ESI ⁺ ): m / z = 406/408 (Cl) [M + NH ₄ ] ⁺

These Connection can also be according to example 14 are obtained.

Example 13

1-Chlor-4-(β-D-glucopyranos-1-yl)-2-[4-(piperdin-4-yloxy)-benzyl]-benzol

1-chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (piperdine-4-yloxy) -benzyl] -benzene

To a solution of 0.19 g of 1-chloro-4- (β-D-glucopyranos-1-yl) -2- [4- (1-tert-butyloxycarbonylpiperidin-4-yloxy) benzyl] benzene in 4 ml Dichloromethane is added 2 ml of trifluoroacetic acid. The solution is stirred for 1.5 h at room temperature and then diluted with ethyl acetate and basified with aqueous potassium carbonate solution. The organic phase is separated and the aqueous extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is completely removed.
Yield: 0.060 g (38% of theory)
Mass spectrum (ESI ⁺ ): m / z = 464/466 (Cl) [M + H] ⁺

Example 14

1-Fluor-4-(β-D-glucopyranos-1-yl)-2-(4-ethinyl-benzyl)-benzol

1-fluoro-4- (β-D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) -benzene

To a solution of 0.23 g of 1-fluoro-4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl) -2- (triisopropylsilylethynylbenzyl) benzene in 1.5 ml of tetrahydrofuran are added 0.33 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. The solution is stirred for 1 h at room temperature. Then 1 ml of methanol and 1.5 ml of 4 M potassium hydroxide solution are added and the solution is stirred for a further hour at room temperature. The solution is neutralized with 1 M hydrochloric acid and then the methanol evaporated. The residue is treated with aqueous sodium chloride solution and extracted with ethyl acetate. The collected organic extracts are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane / methanol 19: 1 → 2: 1).
Yield: 0.060 g (49% of theory)
Mass spectrum (ESI ⁺ ): m / z = 390 [M + NH ₄ ] ⁺

Massenspektrum (ESI⁺): m/z = 372 [M + NH₄]⁺ (16) 1-Ethinyl-4-(β-D-glucopyranos-1-yl)-2-(4-ethoxy-benzyl)-benzol

Massenspektrum (ESI⁺): m/z = 416 [M + NH₄]⁺ (17) 1-Methoxy-4-(β-D-glucopyranos-1-yl)-2-(4-ethinyl-benzyl)-benzol

Massenspektrum (ESI⁺): m/z = 402 [M + NH₄]⁺ The following compounds are obtained analogously to Example 14: (15) 1- (β-D-Glucopyranos-1-yl) -3- (4-ethynylbenzyl) benzene

Mass Spectrum (ESI ⁺ ): m / z = 372 [M + NH ₄ ] ⁺ (16) 1-Ethynyl-4- (β-D-glucopyranos-1-yl) -2- (4-ethoxybenzyl) benzene

Mass Spectrum (ESI ⁺ ): m / z = 416 [M + NH ₄ ] ⁺ (17) 1-Methoxy-4- (β-D-glucopyranos-1-yl) -2- (4-ethynylbenzyl) benzene

Mass spectrum (ESI ⁺ ): m / z = 402 [M + NH ₄ ] ⁺

Massenspektrum (ESI⁺): m/z = 406/408 (Cl) [M + NH₄]⁺ The compound according to Example (12) (1-chloro-4- (β-D-glucopyranos-1-yl) -2- (4-ethynylbenzyl) benzene) can also be synthesized analogously to Example 14. Optionally, in this case, the intermediate, 1-chloro-4- (2,3,4,6-tetra-O-acteyl-β-D-glucopyranos-1-yl) -2- (4-ethynyl-benzyl) benzene, which is obtained after desilylation with tetrabutylammonium fluoride, are purified by recrystallization in ethanol.

Mass spectrum (ESI ⁺ ): m / z = 406/408 (Cl) [M + NH ₄ ] ⁺

Analogously to the abovementioned examples and other processes known from the literature, the following compounds are also prepared:

The following describes examples of administration forms in which the term "active ingredient" denotes one or more compounds according to the invention, including their salts. In the case of one of the combinations described with one or more further active substances, the term "active ingredient" also includes the other active substances. Example A Tablets with 100 mg active substance Composition: 1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg

Production process:

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. Tablet weight: 220 mg Diameter: 10 mm, biplane with facet on both sides and one-sided part notch. Example B Tablets with 150 mg of active substance Composition: 1 tablet contains: active substance 150.0 mg Milk sugar powder. 89.0 mg corn starch 40.0 mg Colloidal 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 C 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 D 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 E Ampoules with 10 mg active substance Composition: active substance 10.0 mg 0.01 n hydrochloric acid sq Aqua bidest ad 2.0 ml

production:

The active ingredient is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 2 ml ampoules. Example F Ampoules with 50 mg active substance Composition: active substance 50.0 mg 0.01 n hydrochloric acid sq Aqua bidest ad 10.0 ml

production:

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

Claims (30)

Glucopyranosyl-substituted benzene derivatives of the general formula I.

in which R ^{1 is} selected from the meanings of group A and if R ^{3 is} selected from the meanings of group B, R ^{1 may} additionally be selected from the meanings hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 Alkyl, C _2-4 alkenylC _1-4 alkyl, C _2-4 alkynylC _1-4 alkyl, C _2-4 alkenylC _1-4 alkoxy, C _2-4 alkynyl C _1-4 alkoxy, C _3-7 cycloalkylC _1-4 alkyl, C _5-7 cycloalkenylC _1-4 alkyl, a methyl group substituted by 1 to 3 fluorine atoms, one by 1 to 5 Fluorine atoms, substituted ethyl group, C _1-4 alkoxy, a methoxy group substituted by 1 to 3 fluorine atoms, an ethoxy group substituted by 1 to 5 fluorine atoms, a C _1-4 alkyl group substituted by a hydroxy or C _1-3 alkoxy group, a C _2-4 alkoxy group substituted by a hydroxy or C _1-3 alkoxy group, C _3-6 cycloalkyl-C _1-3 alkoxy or hydroxy, where in the abovementioned cycloalkyl and cycloalkenyl rings one or two methylene groups independent of each other can be substituted by O or CO, and R ^{2 is} hydrogen, fluorine, chlorine, bromine, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, cyano or nitro, wherein the alkyl or alkoxy group one or more times with Fluorine may be substituted, and R ^{3 is} selected from the meanings of group B and if R ^{1 is} selected from the meanings of group A, R ^{3 may} additionally be selected from the meanings hydrogen, fluorine, chlorine, bromine, iodine, C C _1-6 alkyl, C _2-4 alkenylC _1-4 alkyl, C _2-4 alkynylC _1-4 alkyl, C _2-4 alkenylC _1-4 alkoxy, C _{2 -4-} alkynyl-C _1-4 -alkoxy, C _3-7 -cycloalkyl, C _5-7 -cycloalkenyl, C _3-7 -cycloalkyl-C _1-4 -alkyl, C _5-7 -cycloalkenyl-C _{1- 4} -alkyl, C _3-6 -cycloalkylidenemethyl, hydroxy, C _1-6 -alkoxy, C _3-6 -cycloalkyl-C _1-3 -alkoxy, aryl, arylC _1-3 -alkyl, heteroaryl, heteroaryl-C _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 substituted by 1 to 5 fluorine atoms alkyl- or C _2-4 alkoxy group, a cyano group by a substituted C _1-4 alkyl group, by a hydroxy or C _1-3 alkyloxy substituted C _1-4 alkyl, cyano, carboxy, C _1-3 Alkoxycarbonyl, aminocarbonyl, (C _1-3 alkylamino) carbonyl, di (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-yl carbonyl, 4- (C _1-3 alkyl) piperazin-1-ylcarbonyl, (C _1-4 alkyl) carbonylamino, C _1-4 alkylsulfonylamino, C _1-4 alkylsulfanyl, C _1-4 Alkylsulfinyl, C _1-4 alkylsulfonyl, arylsulfonylamino, arylC _1-3 alkylsulfonylamino or arylsulfonyl, R ⁴ , R ^{5 are} independently hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, C _1-3 Alkyl, C _1-3 -alkoxy, methyl or methoxy substituted by 1 to 3 fluorine atoms, A C _2-6 -alkyn-1-yl, C _2-6 -alken-1-yl, C _3-7 -cycloalkyl, C _5-7 cycloalkenyl, aryl, heteroaryl, C _1-4 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, C _1-4 alkylaminocarbonyl, di - (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C _1-4 alkyl) piperazin-1-ylcarbonyl , Arylaminocarbonyl, heteroarylaminocarbonyl, C _1-4 alkoxycarbonyl, arylC _1-3 alkoxycarbonyl, heteroarylC _1-3 alkoxycarbonyl, amino, C _1-4 alkylamino, di (C _1-3 alkyl) amino , Pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-3-on-4-yl, piperazine 1-yl, 4- (C _1-3 alkyl) piperazin-1-yl, C _1-4 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C _3-7 cycloalkyloxy, C _5-7 cycloalkenyloxy, aryloxy, heteroaryloxy, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, C _3-7 cycloalkylsulfanyl, C _3-7 cycloalkylsulfinyl, C _3-7 cycloalkylsulfonyl, C _5-7 cycloalkenylsulfanyl, C _5-7 cycloalkenylsulfinyl, C _5-7 cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroarylsulfanyl, heteroarylsulfinyl, heteroarylsulfonyl, cyano or nitro, where the v above mentioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, and wherein the abovementioned alkynyl and alkenyl groups may be mono- or disubstituted by identical or different radicals L1, and wherein the abovementioned cycloalkyl- and cycloalkenyl Rings independently of one another may be monosubstituted or disubstituted with substituents selected from fluorine and C _1-3 -alkyl, and wherein in the abovementioned cycloalkyl and cycloalkenyl rings one or two methylene groups are independently of one another by O, S, CO, SO , SO ₂ or NR ^N , B tri (C _1-4 alkyl) silylC _1-6 alkyl, C _2-6 alkyn-1-yl, C _2-6 alkene-1 yl, amino, C _1-3 alkylamino, di- (C _1-3 alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-one-1-yl, piperidin-1-yl, piperidin-2-one -1-yl, morpholin-4-yl, morpholin-3-on-4-yl, piper azin-1-yl, 4- (C _1-3 alkyl) piperazin-1-yl, arylcarbonylamino, heteroarylcarbonylamino, nitro, C _3-10 cycloalkyloxy, C _5-10 cycloalkenyloxy, C _3-10 cycloalkylsulfanyl, C _3-10 cycloalkylsulfinyl, C _3-10 -cycloalkylsulfonyl, C _5-10 -cycloalkenylsulfanyl, C _5-10 -cycloalkenylsulfinyl, C _5-10 -cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, heteroarylsulfanyl or heteroarylsulfinyl, wherein the aforementioned alkynyl and alkenyl groups include - or may be substituted several times with fluorine or chlorine, and wherein the abovementioned alkynyl and alkenyl groups may be mono- or disubstituted by identical or different radicals L1; wherein the abovementioned cycloalkyl and cycloalkenyl rings independently of one another may be monosubstituted or disubstituted by substituents selected from fluorine and C _1-3 -alkyl, and in which one or two methylene groups in the abovementioned cycloalkyl and cycloalkenyl rings independently of one another may be substituted by O, S, CO, SO, SO ₂ or NR ^N , R ^{N is} H, C _1-4 alkyl, C _1-4 alkylcarbonyl or C _1-4 alkylsulfonyl, L 1 independently selected from the group consisting of hydroxy-cyano, nitro, C _3-7 -cycloalkyl, aryl, heteroaryl, C _1-4 -alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, C _1-4 -alkylaminocarbonyl, di- (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, C _1-4 -alkoxycarbonyl, aryl-C _{1 3} -alkoxycarbonyl, heteroarylC _1-3 alkoxycarbonyl, C _1-4 alkyloxy, aryloxy, heteroaryloxy, C _1-4 alkylsulfanyl, arylsu lfanyl, heteroarylsulfanyl, C _1-4 alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, C _1-4 alkylsulfonyl, arylsulfonyl and heteroarylsulfonyl; and L2 independently selected from the group consisting of fluoro, chloro, bromo, iodo, C _1-3 alkyl, difluoromethyl, trifluoromethyl, C _1-3 alkoxy, difluoromethoxy, trifluoromethoxy and cyano; and R ^6, R ^7a, R ^7b, R ^7c independently of one another have a meaning selected from the group hydrogen, (C _1-18 alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _{1- 3-} alkyl) carbonyl, wherein among the aryl groups mentioned in the definition of the abovementioned radicals are phenyl or naphthyl groups which may be mono- or disubstituted independently of one another by identical or different radicals L2; and the heteroaryl groups mentioned in the definition of the abovementioned radicals mean a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl or tetrazolyl group, 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 Isochinolinylgruppe is to be understood in which one to three methine groups replaced by nitrogen atoms wherein the above-mentioned heteroaryl groups may be independently of one another mono- or disubstituted by identical or different radicals L2; Unless otherwise stated, the abovementioned alkyl groups may be straight-chain or branched, their tautomers, their stereoisomers, their mixtures and their salts. Glucopyranosyl-substituted benzene derivatives of the general formula I.2

wherein the radicals R ¹ to R ⁶ and R ^7a , R ^7b and R ^{7c are} as defined in claim 1. Glucopyranosyl-substituted benzene derivatives according to claim 1 or 2, characterized in that the group AC _1-6 -alkine-1-yl, C _2-6 -alken-1-yl, C _3-7 cycloalkyl, C _5-7 Cycloalkenyl, C _1-4 alkylcarbonyl, aminocarbonyl, C _1-4 alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazine 1-ylcarbonyl, 4- (C _1-4 alkyl) piperazin-1-ylcarbonyl, C _1-4 alkoxycarbonyl, amino, C _1-4 alkylamino, di (C _1-3 alkyl) amino, pyrrolidine -1-yl, pyrrolidin-2-one-1-yl, piperidin-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-3-one-4-yl, piperazine-1 -yl, 4- (C _1-3 alkyl) piperazin-1-yl, C _1-4 alkylcarbonylamino, C _3-7 cycloalkyloxy, C _5-7 cycloalkenyloxy, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, C _3-7 cycloalkylsulfanyl, C _3-7 cycloalkylsulfinyl, C _3-7 cycloalkylsulfonyl, C _{5 -7-} cycloalkenylsulfanyl, C _5-7 -cycloalkenylsulfinyl, C _5-7 -cycloalkenylsulfonyl, cyano or nitro, where the abovementioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, and wherein the abovementioned alkynyl and alkenyl groups may be monosubstituted or disubstituted by identical or different radicals L1, and in which the abovementioned cycloalkyl and cycloalkenyl rings may be substituted, independently of one another, once or twice by substituents selected from fluorine and C _1-3 -alkyl, and wherein in the aforementioned cycloalkyl and cycloalkenyl rings one or two methylene groups may independently be substituted by O, S, CO, SO, SO ₂ or NR ^N and L1 and R ^{N are} as defined in claim 1. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 3, characterized in that the group B tri (C _1-4 alkyl) silyl-C _1-6 alkyl, C _2-6 alkyn-1 -yl, C _2-6 -alken-1-yl, amino, C _1-3 -alkylamino, di- (C _1-3 -alkyl) -amino, pyrrolidin-1-yl, pyrrolidin-2-one-1 yl, piperidin-1-yl, piperidin-2-one-1-yl, morpholin-4-yl, morpholin-3-on-4-yl, piperazin-1-yl, 4- (C _1-3 -alkyl) piperazin-1-yl, nitro, C _3-7 -cycloalkyloxy, C _5-7 -cycloalkenyloxy, C _3-7 -cycloalkylsulfanyl, C _3-7 -cycloalkylsulfinyl, C _3-7 -cycloalkylsulfonyl, C _5-7 -cycloalkenylsulfanyl, C _5-7 -cycloalkenylsulfinyl or C _5-7 -cycloalkenylsulfonyl, where the abovementioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, and wherein the abovementioned alkynyl and alkenyl groups are identical to one or two times or different radicals L1 may be substituted; wherein the abovementioned cycloalkyl and cycloalkenyl rings independently of one another may be monosubstituted or disubstituted by substituents selected from fluorine and C _1-3 -alkyl, and in which one or two methylene groups in the abovementioned cycloalkyl and cycloalkenyl rings independently of one another may be substituted by O, S, CO, SO, SO ₂ or NR ^N , and L 1 and R ^{N are} as defined in claim 1. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 4, characterized in that the radical R ^{3 is} selected from the meanings of the group B according to claim 1 or 4. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 5, characterized in that the radical R ^{1 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 alkyl, C _{2 -6-} alkynyl, C _1-4 -alkoxy, C _2-4 -alkenyl-C _1-4 -alkoxy, C _2-4 -alkynyl-C _1-4 -alkoxy, methyl substituted by from 1 to 3 fluorine atoms, by 1 to 5 fluorine atoms substituted ethyl, substituted by 1 to 3 fluorine atoms methoxy, substituted by 1 to 5 fluorine atoms ethoxy, by a hydroxy or C _1-3 alkoxy substituted C _1-4 alkyl, by a hydroxy or C _1-3 Alkoxy group substituted C _2-4 alkoxy, C _2-4 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl C _1-3 alkyl, C _3-7 cycloalkyloxy, C _3-6 Cycloalkyl-C _1-3 alkoxy, C _5-7 cycloalkenyloxy, hydroxy, amino, nitro or cyano, wherein in the C _5-6 cycloalkyl groups, a methylene group may be substituted by O. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 5, characterized in that the radical R ^{1 is} selected from the meanings of the group A according to claim 1 or 3. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 4 and 7, characterized in that the radical R ^{3 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, C _1-6 - Alkyl, trimethylsilylethyl, C _2-6 alkenyl, C _2-6 alkynyl, difluoromethyl, trifluoromethyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, C _1-6 alkyloxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, C _3-7- Cycloalkyloxy, tetrahydrofuranyloxy, tetrahydrofuranonyloxy, C _1-6 -alkylsulfanyl, cyclopropylidenemethyl, aryl and heteroaryl. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 8, characterized in that the radical R ^{2 is} hydrogen, fluorine, chlorine, bromine, methyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, cyano, nitro or by 1 to 3 Fluorine atoms substituted methyl means. Glucopyranosyl-substituted benzene derivatives according to one or more of Claims 1 to 9, characterized in that the radicals R ⁴ and / or R ⁵ independently of one another denote hydrogen or fluorine th. Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 10, characterized in that the radical R ^{6 is} hydrogen, (C _1-8 alkyl) oxycarbonyl, C _1-8 alkylcarbonyl or benzoyl, preferably hydrogen , Glucopyranosyl-substituted benzene derivatives according to one or more of claims 1 to 11, characterized in that the radicals R ^7a , R ^7b , R ^{7c are} hydrogen. Physiologically acceptable salts of the compounds according to at least one of the claims 1 to 12 with inorganic or organic acids. Medicament containing a compound after at least one of the claims 1 to 12 or a physiologically acceptable salt according to claim 13 next to optionally one or more inert carriers and / or diluents. Use at least one compound after one or more of the claims 1 to 12 or a physiologically acceptable salt according to claim 13 for the manufacture of a medicament for the treatment or Prophylaxis of diseases or conditions suitable by Inhibition of the sodium-dependent Glucose cotransporters SGLT can be influenced. Use of at least one compound after at least one of the claims 1 to 12 or a physiologically acceptable salt according to claim 13 for the manufacture of a medicament for the treatment or Prevention of metabolic diseases is suitable. Use according to claim 16, characterized that the metabolic disease is selected from the group consisting diabetes mellitus type 1 and type 2, diabetic complications, metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorder, insulin resistance, Metabolic syndrome, dyslipidemias different genesis, atherosclerosis and related diseases, Obesity, hypertension, chronic heart failure, edema, hyperuricemia. Use of at least one compound after at least one of the claims 1 to 12 or a physiologically acceptable salt according to claim 13 for the manufacture of a medicament for inhibiting the sodium-dependent glucose cotransporter SGLT2. Use of at least one compound after at least one of the claims 1 to 12 or a physiologically acceptable salt according to claim 13 for the preparation of a medicament for preventing degeneration pancreatic beta cells and / or for improving and / or Restore the functionality of pancreatic beta cells. Use of at least one compound after at least one of the claims 1 to 12 or a physiologically acceptable salt according to claim 13 for the preparation of diuretics and / or antihypertensives. Process for the preparation of a medicament according to claim 14, characterized in that non-chemical way a A compound according to any one of claims 1 to 12 or a physiological compatible Salt according to claim 13 in one or more inert carriers and / or diluents is incorporated. Process for the preparation of the compounds of general formula I according to claims 1 to 12, characterized in that a compound of general formula II

wherein R 'is H, C _1-4 alkyl, (C _1-18 alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _1-3 alkyl) carbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted by halogen; R ^8a , R ^8b, R ^8c , R ^8d, independently of one another, have the meanings given for the radicals R ⁶ , R ^7a , R ^7b , R ^7c , a benzyl group or an R ^a R ^b R ^c Si group or a ketal or acetal group, it being possible in each case two adjacent groups R ^8a, R ^8b, R ^8c, R ^8d, a cyclic ketal or acetal group or a 1,2-di (C, _ ₃ alkoxy) -1,2-di (C _{1 3-} alkyl) -ethylene bridge, said ethylene bridge forming together with two oxygen atoms and the associated two carbon atoms of the pyranose ring a substituted dioxane ring, and wherein alkyl, aryl and / or benzyl groups - or may be repeatedly substituted with halogen or C _1-3 alkoxy and benzyl groups may also be substituted by a di- (C _1-3 alkyl) amino group; and R ^a , R ^b , R ^c independently of one another are C _1-4 -alkyl, aryl or arylC _1-3 -alkyl, where the alkyl or aryl groups may be mono- or polysubstituted by halogen; wherein the aryl groups mentioned in the definition of the abovementioned radicals are phenyl or naphthyl groups, preferably phenyl groups; and R ¹ to R ⁵ , R ⁶ , R ^7a , R ^7b , R ^{7c have} the meanings given in claims 1 to 12, is reacted with a reducing agent in the presence of a Lewis or Br⌀nsted acid, wherein the possibly present Protecting groups are split off simultaneously or subsequently; if desired, a 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 a compound of the general formula I thus obtained is separated into its stereoisomers and / or, if desired, a compound of the general formula I thus obtained is converted into its physiologically tolerated salts. Method according to claim 22, characterized in that the compound of the general Formula II according to the in Claim 24 or 25 described method is obtained. Process for the preparation of compounds of general formula II

wherein R 'is H, C _1-4 alkyl, (C _1-18 alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _1-3 alkyl) carbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted by halogen; R ^8a , R ^8b, R ^8c , R ^8d, independently of one another, have the meanings given for the radicals R ⁶ , R ^7a , R ^7b , R ^7c , a benzyl group or an R ^a R ^b R ^c Si group or a ketal or acetal group, it being possible in each case two adjacent groups R ^8a, R ^8b, R ^8c, R ^8d, a cyclic ketal or acetal group or a 1,2-di (C _1-3 -alkoxy) -1,2-di (C _{1 3-} alkyl) ethylene bridge, said ethylene bridge being taken together forms a substituted dioxane ring with two oxygen atoms and the associated two carbon atoms of the pyranose ring, and where alkyl, aryl and / or benzyl groups may be mono- or polysubstituted by halogen or C _1-3 -alkoxy and benzyl Groups may also be substituted by a di (C _1-3 alkyl) amino group; and R ^a , R ^b , R ^c independently of one another are C _1-4 -alkyl, aryl or arylC _1-3 -alkyl, where the alkyl or aryl groups may be mono- or polysubstituted by halogen; wherein the aryl groups mentioned in the definition of the abovementioned radicals are phenyl or naphthyl groups, preferably phenyl groups; and R ¹ to R ⁵ , R ⁶ , R ^7a , R ^7b , R ^{7c have} the meanings given in claims 1 to 12, wherein an organometallic compound (V), by halogen-metal exchange or by insertion of a Metal in the carbon-halogen bond of a halogen-benzyl benzene compound of general formula IV

in which Hal is Cl, Br and I and R ¹ to R ^{5 are} as defined above, and optionally subsequent transmetallation is obtainable, to a gluconolactone of the general formula VI

in which R ^8a , R ^8b , R ^8c , R ^{8d are} as previously defined, and then adding the resulting adduct with water or an alcohol R'-OH, wherein R 'is optionally substituted C _1-4 alkyl, in Reacting an acid present and optionally converting the product obtained in the reaction with water in which R 'is H into the product of the formula II in a subsequent reaction with an acylating agent, in which R' is (C _1-18 -alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl or aryl- (C _1-3 alkyl) carbonyl, which may be substituted as indicated. Method according to claim 24, characterized in that the organometallic compound (V) is a lithium or magnesium compound. A process for the preparation of the compounds of general formula I according to claims 1 to 12, in which R ⁶ , R ^7a , R ^7b and R ^{7c are} hydrogen, characterized in that a compound of general formula III

in the R ^8a , R ^8b , R ^8a , R ^8d independently of one another for the radicals R ⁶ , R ^7a , R ^7b , R ^7c meanings, but at least one of the radicals R ^8a , R ^8b , R ^8c , R ^8d not Is hydrogen, has a benzyl group or an R ^a R ^b R ^c Si group or a ketal or acetal group, wherein each two adjacent radicals R ^8a , R ^8b , R ^8c , R ^{8d is} a cyclic ketal or acetal group or a 1,2-di (C _1-3 alkoxy) -1,2-di (C _1-3 alkyl) -ethylene bridge, wherein said ethylene bridge together with two oxygen atoms and the forms a substituted dioxane ring, and wherein alkyl, aryl and / or benzyl groups may be monosubstituted or polysubstituted by halogen or C _1-3 alkoxy and benzyl groups may also be substituted by a di-ring. (C _1-3 alkyl) amino group may be substituted; and R ^a , R ^b , R ^c independently of one another are C _1-4 -alkyl, aryl or arylC _1-3 -alkyl, where the alkyl or aryl groups may be mono- or polysubstituted by halogen; wherein the aryl groups mentioned in the definition of the abovementioned radicals are phenyl or naphthyl groups, preferably phenyl groups; and R ¹ to R ⁵ , R ⁶ , R ^7a , R ^7b , R ^{7c have} the meanings given in claims 1 to 12, and, if desired, a 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 protective moiety 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 thus obtained compound of the general formula I is converted into its salts, in particular for the pharmaceutical application into their physiologically acceptable salts. Method according to claim 26, characterized in that the compound of formula III by means of a Process according to claim 22 or 23 is obtained. Compound of the general formula IV

in which Hal is chlorine, bromine or iodine and the radicals R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined in one or more of claims 1 and 3 to 10. A compound of formula IV according to claim 28 characterized by the formula

in which Hal is chlorine, bromine or iodine and the radicals R ¹ , R ² , R ⁴ and R ^{5 are} as defined in one or more of claims 1, 3, 6, 7, 9, 10 and the radical R ^{3 is} from the Group B according to claim 1 or 4 is selected. Compound of the general formula II

wherein R 'is H, C _1-4 alkyl, (C _1-18 alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _1-3 alkyl) carbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted by halogen; R ^8a , R ^8b R ^8c , R ^8d independently of one another for the radicals R ⁶ , R ^7a , R ^7b , R ^7c meanings be is sitting, a benzyl group or a R ^a R ^b R ^c Si group or a ketal or acetal group, wherein each two adjacent radicals R ^8a , R ^8b , R ^8c , R ^{8d is} a cyclic ketal or acetal group or a 1 , 2-di (C _1-3 alkoxy) -1,2-di (C _1-3 alkyl) ethylene bridge, wherein said ethylene bridge together with two oxygen atoms and the associated two carbon atoms of the pyranose Rings forms a substituted dioxane ring, and wherein alkyl, aryl and / or benzyl groups may be monosubstituted or polysubstituted by halogen or C _1-3 alkoxy and benzyl groups also with a di- (C _1-3 alkyl) amino group may be substituted; and R ^a , R ^b , R ^c independently of one another are C _1-4 -alkyl, aryl or arylC _1-3 -alkyl, where the alkyl or aryl groups may be mono- or polysubstituted by halogen; wherein the aryl groups mentioned in the definition of the abovementioned radicals are phenyl or naphthyl groups, preferably phenyl groups; and R ¹ to R ^{5 are} as defined in one or more of claims 1 and 3 to 10.